CN1251579A - Compound and compositions for treating diseases associated with serine protease, particularly tryptase, activity - Google Patents
Compound and compositions for treating diseases associated with serine protease, particularly tryptase, activity Download PDFInfo
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- CN1251579A CN1251579A CN97182098A CN97182098A CN1251579A CN 1251579 A CN1251579 A CN 1251579A CN 97182098 A CN97182098 A CN 97182098A CN 97182098 A CN97182098 A CN 97182098A CN 1251579 A CN1251579 A CN 1251579A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 369
- 239000000203 mixture Substances 0.000 title claims abstract description 144
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 41
- 201000010099 disease Diseases 0.000 title description 26
- 102000001400 Tryptase Human genes 0.000 title description 23
- 108060005989 Tryptase Proteins 0.000 title description 23
- 230000000694 effects Effects 0.000 title description 13
- 102000012479 Serine Proteases Human genes 0.000 title description 3
- 108010022999 Serine Proteases Proteins 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 111
- 239000001257 hydrogen Substances 0.000 claims abstract description 69
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 69
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 56
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 52
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 30
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- 230000001404 mediated effect Effects 0.000 claims abstract description 13
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 11
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims abstract description 11
- -1 amino, carboxyl Chemical group 0.000 claims description 181
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 155
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 135
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 117
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 92
- 125000003118 aryl group Chemical group 0.000 claims description 59
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 43
- 125000001118 alkylidene group Chemical group 0.000 claims description 39
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 39
- 125000006413 ring segment Chemical group 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 35
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 30
- 206010061218 Inflammation Diseases 0.000 claims description 28
- 230000004054 inflammatory process Effects 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 239000000651 prodrug Substances 0.000 claims description 24
- 229940002612 prodrug Drugs 0.000 claims description 24
- 241001597008 Nomeidae Species 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 125000001931 aliphatic group Chemical group 0.000 claims description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- 125000002723 alicyclic group Chemical group 0.000 claims description 17
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 17
- 150000001204 N-oxides Chemical class 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 150000002576 ketones Chemical class 0.000 claims description 14
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 13
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 13
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 13
- 208000035475 disorder Diseases 0.000 claims description 13
- POPRCUFMXZJTQI-UHFFFAOYSA-N oxomethanedisulfonic acid Chemical compound OS(=O)(=O)C(=O)S(O)(=O)=O POPRCUFMXZJTQI-UHFFFAOYSA-N 0.000 claims description 13
- 239000000443 aerosol Substances 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 10
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 10
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 9
- XSIFPSYPOVKYCO-UHFFFAOYSA-N butyl benzoate Chemical compound CCCCOC(=O)C1=CC=CC=C1 XSIFPSYPOVKYCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 7
- 241000700605 Viruses Species 0.000 claims description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 3
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 claims description 3
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- UDEWPOVQBGFNGE-UHFFFAOYSA-N benzoic acid n-propyl ester Natural products CCCOC(=O)C1=CC=CC=C1 UDEWPOVQBGFNGE-UHFFFAOYSA-N 0.000 claims description 3
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims description 3
- 229960001022 fenoterol Drugs 0.000 claims description 3
- 229960002848 formoterol Drugs 0.000 claims description 3
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 210000002345 respiratory system Anatomy 0.000 claims description 3
- 229960002052 salbutamol Drugs 0.000 claims description 3
- DUAYDERMVQWIJD-UHFFFAOYSA-N 2-n,2-n,6-trimethyl-1,3,5-triazine-2,4-diamine Chemical compound CN(C)C1=NC(C)=NC(N)=N1 DUAYDERMVQWIJD-UHFFFAOYSA-N 0.000 claims description 2
- 206010010741 Conjunctivitis Diseases 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- KYZHGEFMXZOSJN-UHFFFAOYSA-N benzoic acid isobutyl ester Natural products CC(C)COC(=O)C1=CC=CC=C1 KYZHGEFMXZOSJN-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 4
- 239000000808 adrenergic beta-agonist Substances 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 2
- 125000000815 N-oxide group Chemical group 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- 210000003630 histaminocyte Anatomy 0.000 abstract description 12
- 125000003943 azolyl group Chemical group 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 208000027866 inflammatory disease Diseases 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 2
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 239000002585 base Substances 0.000 description 280
- 238000005160 1H NMR spectroscopy Methods 0.000 description 106
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 86
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- 239000000243 solution Substances 0.000 description 72
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- 239000007787 solid Substances 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 238000005406 washing Methods 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 29
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- 239000000427 antigen Substances 0.000 description 8
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
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- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
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- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
Novel compounds, compositions and methods effective for the prevention and treatment of mast-cell mediated inflammatory disorders are described. A preferred aspect of the invention are compounds of Formula (II) in which: the dashed lines independently represent optional bonds; each R<2> independently is (C1-6)alkyl, (C1-6)alkyloxy, halo or hydroxy; each R<3> independently is (C1-6)alkyl, (C1-6)alkyloxy, halo or hydroxy; X<3> is -C(O)- or -CR<7>R<8>-, X<8> is -CH(R<1>)n1- or -C(R<1>)n1=, wherein R<1> is amino(N1-4)azolidinyl, amino(N1-4)azolyl, (N1-4)azolidinyl, (N1-4)azolyl, -NHC(NH)NR<9>R<9>, -C(NR<9>)R<9>, -C(NH)NHR<10>, -C(NH)NR<10>R<10> or -(CR<11>R<11>)yNH2, or X<8> is -N= or -NH(R<1>)n1-, wherein R<1> is -C(NR<9>)R<9>, -C(NH)NHR<10> or -C(NH)NR<10>R<10>, wherein each R<9> independently is hydrogen or (C1-6)alkyl and each R<10> independently is (C1-6)alkyl; and X<9> is -CH(R<4>)- or -C(R<4>)=, wherein R<4> is -R<12>, -OR<12>, -N(R<13>)R<12>, -SR<12>, -S(O)R<12>, -S(O)2R<12>, -S(O)2OR<12>, -S(O)2N(R<13>)R<12>, -N(R<13>)S(O)2R<12>, -C(O)R<12>, -C(O)OR<12>, -C(O)N(R<13>)R<12>, -N(R<13>)C(O)R<12>, -OC(O)N(R<13>)R<12>, -N(R<13>)C(O)OR<12>, -(CH2)n4N(R<13>)C(O)N(R<13>)R<12>, -OP(O)(OR<13>)OR<12> or -C(O)N(R<14>)CH(COOH)R<12>, or X<9> is -N= or -N(R<4>)-, wherein R<4> is -C(O)R<12>, -C(O)OR<12>, -C(O)N(R<13>)R<12>, -OC(O)N(R<13>)R<12> or -C(O)N(R<14>)CH(COOH)R<12>, wherein R<12>, R<13> and R<14> are as defined in the Summary of the Invention; R<5> is hydrogen or (C1-4)alkyl, R<6> is hydrogen or (C1-4) alkyl, which alkyl optionally is substituted with one to two substituents independently selected from (C1-4)alkyloxy, hydroxy and sulfo, R<7> is hydrogen or methyl and R<8> is hydrogen, methyl or hydroxy.
Description
Invention field:
The application is the patent application NO.08/833 that submits on April 7th, 97,674 part continuation application, and the latter is the patent application NO.08/357 that submits on December 14th, 94, and 491 part continuation application is incorporated herein them at this and does reference.The application relates to and being used for the treatment of and serine protease, particularly the compound and the composition of the active diseases associated of tryptase.
This area is described:
Tryptase as from the oozy important proteolytic enzyme of people's mastocyte, is considered to relate in neuropeptide processing and tissue inflammation.Tryptase concentration increases (Schwartz et al. (1987) in blood at several hrs after the allergy, N.Eng.J.Med.316:1622-1626), increase (Castells etal. (1988) J.Allerg.Clin.Immunol.141:563-568) in the nasal cavity after specific antigen is invaded and the atopy material elutriant of lung, increase in the lung elutriant of the atopic asthma disease after invading by the entobronchus anaphylactogen.The normally wonderful height of tryptase level in smoker's the bronchovesicular elutriant.This is found to be following hypothesis provides some to support that promptly the proteolytic enzyme that discharges may cause the emophysematous injury of lung of smoker (Celenteron et al. (1988) Chest 94:119-123) from the activated mastocyte.And tryptase also shows as a fibroblastic effective mitogen, points out it to relate to a pulmonary fibrosis and a matter tuberculosis (Ross et al. (1991) J.Clin.Invest.88:493-499).
Asthma is considered to inflammatory disorder (Hood et al. (1984) In:Benjamin-Cummings, ed.Immunology 2nd ed.), and usually the hyperergy to immunologic opsonin anaphylactogen and general chemistry or physical stimulation thing with tracheae and the progressive generation of segmental bronchus is a feature.This disease all relates to multiple biochemical intermediate in its acute and chronic phase.The hyperergy of asthma patient bronchiole tissue is considered to the result of chronic inflammatory reaction, and these response stimulus connect with the epithelium that has damaged tracheal wall, and promotes the pathologic of substrate tissue to thicken.Mild asthma patient's bronchiole biopsy is presented at inflammation feature on its tracheal wall.
Anaphylaxis to the anaphylactogen that sucks can cause the inflammation result.For example, irritated proper energy is by activating mastocyte and the basophilic cell that is positioned at epithelium and substrate smooth muscle tissue in conjunction with the IgE that is arranged in cell surface.The activated mastocyte discharges the preformed or initial chemical intermediate (as histamine) of many inflammatory reactions, produces a large amount of other secondary intermediates of inflammation (as super-oxide, the lipoid intermediate etc. of deriving) in position.In addition, several macromole (as protein-polysaccharide, tryptase, chymase etc.) are discharged by the degranulationization of mastocyte.
From mastocyte, discharge these preformed intermediates, the early stage bronchiole contraction to the asthma reaction of aeroallergen may be described.Early stage asthma reaction reached the peak in 15 minutes greatly after touching anaphylactogen, and general recovery from illness in thereafter 1 to 2 hour.The further reduction that 25 to 30 percent Five Classics of patient population is gone through respiratory function, it reaches maximum in contact allergy after former 6 to 12 hours.This late phase response stage is accompanied by the remarkable increase of inflammatory cell (for example eosinophil, neutrophil leucocyte, the lymphocyte etc.) number that infiltrates the bronchiole tissue.Infiltrate cell and attracted to this place by discharging mastocyte deutero-chemotaxis material, and step of reaction activation late.This in late period asthma reaction to be considered to part be secondary inflammatory reaction by granulocytic secretion activity mediation.
Tryptase participates in degraded (Caughey etal. (1998) J.Pharmacol.Exp.Ther.244:133-137 of vasodilation and the lax neuropeptide of segmental bronchus; Franconi etc. (1988) J.Pharmacol.Exp.Ther.248:947-951; With Tam et al. (1990) Am.J.Respir.CellMol.Biol.3:27-32) and bronchiole to the adjusting (Sekizawa etal. (1989) J.Clin.Invest.83:175-179) of histamine response.These find that the prompting tryptase may be by destroying the tracheae contraction that the tracheaectasy peptide improves asthma.α-the chain and the high molecular weight kininogen of tryptase cutting fibre proteinogen, it is solid that this prompting tryptase and heparin play a part partially anti-freezing function together.Tryptase activates prostromelysin (pro-MMP-3) and precollagen enzyme (procollagenase) (pro-MMP-1) by MMP3, the tissue inflammation that this prompting tryptase participates in rheumatoid arthritis with reinvent and the destruction of joint process.Further; use the late period of the sheep that tryptase inhibitors invades anaphylactogen and the development in hyperergy stage and produce protection (Clark et al. (1995) Am.J.Respir.Cirt.CareMed.152:2076-2083), and be suppressed at intradermal injection skin immediate reaction (Molinari et al. (1995) Amer.Physiol.Soc.79 (6): 1966-1970) that anaphylactogen caused of irritated sheep.All above-mentioned discoveries all clearly illustrate that the using property of tryptase inhibitors as the treatment factor of treatment asthma and other disorder relevant with respiratory inflammation.
The announcement of these and other files comprises the patent and the patent application of quoting in this application, all quotes as reference at this.
The present invention's general introduction
Wherein n1 is 0 or 1;
N2 is 0,1,2,3 or 4;
N3 is 0,1,2,3 or 4;
A comprises with B and contains the assorted bicyclic radicals of condensing of 8-12 ring atom, and wherein each ring contains 5-7 ring and goes up the member, is heteroatoms each ring atom arbitrariness, X
1And X
2Be member and X on the adjacent ring of aromatic ring
1Be be selected from-N=,-NR
5-,-O-and-the heteroatoms structure division of S-, wherein R
5Be hydrogen, (C
1-C
6) alkyl or assorted (C
2-C
6) alkyl;
C comprises the many cyclic groups of mixing that condense that contain 8-18 ring atom, and wherein each ring contains upward member of 5-7 ring, is heteroatoms each ring atom arbitrariness, X
4And X
5Be member on the adjacent ring of aromatic ring, X
5Be be selected from-N=,-NR
5-,-O-and-the heteroatoms structure division of S-, wherein R
6Be hydrogen, be selected from (C
1-C
8) alkyl or assorted (C
2-C
12) group of alkyl, this group arbitrariness ground is independently selected from (C by one or two
1-C
6) alkanoyloxy, (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, three (C
1-C
6) alkylamino, (C
1-C
6) alkyl-carbamoyl, two (C
1-C
6) alkyl-carbamoyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxy carbonyl, (C
1-C
6) alkoxyl group alkylsulfonyl, amino, carboxyl, formamyl, (C
6-C
14) aryl, halogen, assorted (C
5-C
14) substituting group of aryl, hydroxyl and sulfo group replaces, or as following definition; With its any carbocyclic ring ketone, sulfo-ketone and imino-ketone deriveding group;
X
3Be-O-,-S-,-S (O)-,-S (O)
2-,-C (O)-,-NR
7-or-CR
7R
8-, R wherein
7Be hydrogen, (C
1-C
6) alkyl, assorted (C
2-C
12) alkyl or and R
6Form (C together
2-C
4) alkylidene group or assorted (C
2-C
4) alkylidene group and R
8Be hydrogen, (C
1-C
6) alkyl or hydroxyl or and R
7Form (C together
2-C
6) alkylidene group or (C
1-C
6) alkylidene; Comprising R
7And/or R
8Any aliphatic series or alicyclic structure part arbitrariness ground be selected from (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, three (C
1-C
6) alkylamino, (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxy carbonyl, (C
1-C
6) alkanoyloxy, amino, carboxyl, formamyl, (C
1-C
6) alkyl-carbamoyl, two (C
1-C
6) 1 to 3 substituting group of alkyl-carbamoyl, halogen and hydroxyl replaces;
R
1Be amino (N
1-4) pyrrolidyl, amino (N
1-4) pyrryl, (N
1-4) pyrrolidyl, (N
1-4) pyrryl, formamyl, cyano group ,-(CH
2)
xNHC (NR
9) R
9,-(CH
2)
xNHC (NH) NR
9R
9,-C (NR
9) R
9-,-C (NH) NHR
10-,-C (NH) NR
10R
10Or-(CR
11R
11) yNH
2And be bonded in any ring atom that belongs to B with effective valence state, and wherein x is 0 or 1, y is 0,1,2 or 3, each R
9Be hydrogen or (C independently
1-6) alkyl, each R
10Be (C independently
1-6) alkyl and each R
11Be hydrogen, (C independently
1-3) alkyl or with another R
11Form cyclopropyl with carbon atom (both links to each other with this carbon atom), wherein belong to R
1Any aliphatic series or alicyclic structure part arbitrariness ground be independently selected from (C by one or two
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) substituting group of alkyl sulphonyl and hydroxyl replaces;
Each R
2Be (C independently
1-6) alkyl, (C
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, (C
1-6) alkoxyl group, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) alkyl sulphinyl, (C
1-6) alkyl sulphonyl, (C
1-6) alkylthio, halogen or hydroxyl and be bonded in any ring atom with effective valence state that belongs to B, wherein belong to R
2Any aliphatic structure part arbitrariness ground be independently selected from (C by one or two
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) substituting group of alkyl sulphonyl and hydroxyl replaces;
Each R
3Be (C independently
1-6) alkyl, (C
1-6) alkoxyl group, (C
1-6) alkylthio, cyano group, halogen, perhalogeno (C
1-6) alkyl or hydroxyl and be bonded in any ring atom with effective valence state that belongs to C; With
R
4Be-R
12-,-OR
12,-N (R
13) R
12,-SR
12,-S (O) R
12,-S (O)
2R
12,-S (O)
2OR
12,-S (O)
2N (R
13) R
12,-N (R
13) S (O)
2R
12,-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12,-N (R
13) C (O) R
12,-OC (O) N (R
13) R
12,-N (R
13) C (O) OR
12,-(CH
2)
2N (R
13) C (O) N (R
13) R
12,-OP (O) (OR
13) OR
12Or-C (O) N (R
14) CH (COOH) R
12And be bonded in any ring atom that belongs to C with effective valence state, wherein
Z is 0,1 or 2,
R
12Be-R
15Or-X
6-(R
15)
N15, wherein n15 is 1 or 2, X
6Be (C
1-10) alkylidene group, ring (C
3-6) alkylidene group, assorted (C
2-10) alkylidene group or heterocycle (C
3-10) alkylidene group and each R
15Be hydrogen, (C independently
6-14) aryl, ring (C
3-14) alkyl, many ring (C
6-14) aryl, much more assorted ring (C
6-14) aryl, heterocycle (C
3-14) alkyl, assorted (C
5-14) aryl or as following definition;
R
13Be hydrogen, (C
1-6) alkyl or assorted (C
2-6) alkyl;
R
14Be hydrogen, (C
1-6) alkyl or and X
6And R
15Form (C together
3-4) alkylidene group;
Belong to R
4Any aliphatic series or alicyclic structure part arbitrariness ground be independently selected from (C by 1-5
1-6) alkyl, (C
1-6) alkylamino, two (C
1-6) alkylamino, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) alkoxyl group, (C
1-6) alkoxy carbonyl, (C
1-6) alkyl sulphinyl, (C
1-6) alkyl sulphonyl, (C
1-6) alkylthio, amino, (C
6-10) substituting group of aryl sulfonyl, formamyl, carboxyl, cyano group, guanidine radicals, halogen, hydroxyl, sulfydryl and urea groups replaces; With
Belong to R
15Any aromatic structure part arbitrariness ground be independently selected from the (C that cyano group, guanidine radicals, halogen, halogen replace by 1-3
1-8) alkyl ,-R
16,-OR
16,-SR
16,-S (O) R
16,-S (O)
2R
16,-S (O)
2N (R
13) R
16,-C (O) R
16,-C (O) OR
16With-C (O) N (R
13) (R
16) substituting group replace R wherein
13As defined above and R
16Be hydrogen, optional mono-substituted (C
1-8) (wherein optional substituting group is (C to alkyl
1-6) alkylamino, two (C
1-6) alkylamino, three (C
1-6) alkylamino, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) alkoxy amino formyl radical, (C
1-6) alkoxyl group alkylsulfonyl, amino, carboxyl, formamyl, hydroxyl or sulfo group), ring (C
3-6) alkyl, assorted (C
1-8) alkyl, assorted (C
5-6) aryl, heterocycle (C
3-6) alkyl or phenyl;
Precondition is when n2 is 0 or R
2Be (C
1-6) alkyl or (C
1-6) alkoxyl group, n3 is 0 or R
3Be (C
1-6) alkyl or (C
1-6) alkoxyl group and R
4Be hydrogen, (C
1-10) alkyl or (C
1-6) n1 is not 0 during alkoxyl group; And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt.
The present invention also provides the medicinal compositions of being made up of compound of the present invention.These medicinal compositionss can adopt several forms, comprise oral, suction, injection and primer solution.When adopting inhalation or aerosol form, the dry powder that the solution of compound of the present invention and pharmaceutically acceptable carrier maybe can be converted into aerosol share.Similarly, when medicine for oral use, compound of the present invention be suitable for so oral pharmaceutically acceptable carrier and share.When being used for the treatment of immune-mediated skin inflammation, compound of the present invention and a kind of nontoxic pharmaceutically useful external application carrier share.Compound of the present invention can share with anti-inflammatory medicaments or other asthma medicine, as beta-adrenaline stimulant (adrenergic agonist), anti-inflammatory reflunomide, anticholinergic drug, tracheae relaxant such as methyl xanthene and resemblance.
Compound described here is useful for stoping and treating immune-mediated inflammation disorder, and particularly those diseases that are associated with respiratory tract comprise asthma, the super-reaction stage that particularly is associated with chronic asthma, and allergic rhinitis.Thereby the present invention also provides a kind of method by the immune-mediated inflammation disorder of the compounds for treating of the present invention of using effective therapeutic dose or consumption to patient.Further, compound described here can be used to treat the syncytial virus infection.
Illustrated concise description
Fig. 1 has compared the special lung resistibility of control group (blank square), with 2-(5-aminomethyl-1H-benzimidazolyl-2 radicals-methyl)-N-(3-hydrocinnamyl)-1H-benzoglyoxaline-5-carbonylation acid amides (compound 4; The black square) contrast, the time in hour.
Fig. 2 is a histogram, the hyperergy of expression airway (with the PC400 metering): the sheep that antigen is invaded, handle with compound 4, and aerosol drug delivery, 3 1mg dosage contrast with control group.Of the present invention being described in detail
Definition:
Except as otherwise noted, in this specification and claim, use below term be that purpose for the application defines and has the meaning given below:
" alkanoyl " refers to group-C (O) R, and wherein R is following defined alkyl, has specified whole carbon atom numbers (for example, (C1-6) alkanoyl comprises formoxyl, acetyl Base, propiono, bytyry, isobutyryl, crotonyl, different crotonyl etc.).
" alicyclic structure part " refers to any saturated or undersaturated, the monocycle or many of group The hydrocarbon part of ring. For example, alicyclic structure partly refers to defined cycloalkyl here, and refers to Comprise cycloalkyl-alkyl, cycloalkyl oxy, naphthene base carbonyl, cycloalkyl alkanoyl, cycloalkanes The alicyclic part of base carbamoyl etc.
" aliphatic structure part " refer to group any straight or branched, saturated or unsaturated The hydrocarbon part. For example aliphatic structure partly refers to here defined alkyl or assorted alkyl, and Comprise alkoxyl, aryl alkyl, heteroaryl alkyl, alkyl-carbamoyl, alkanoyl, The aliphatic part of Arylalkanoyl, heteroaryl alkanoyl etc.
" alkyl " for the application's purpose, refers to have straight or branched, the saturated or undersaturated aliphatic hydrocarbyl of specified number carbon atom, and any ketone, sulfo-ketone or imino group ketone ((C for example1-C
8) alkyl comprise methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl, Isobutyl group, the tert-butyl group, vinyl, pi-allyl, 1-acrylic, isopropenyl, 1-cyclobutenyl, 2-cyclobutenyl, 3-cyclobutenyl, 2-methacrylic, acetenyl, 1-propinyl, 2-propynyl, 3-oxo amyl group, 3-sulfo-amyl group, 3-imino group amyl group etc.).
" alkylidene " refers to have the saturated of specified number carbon atom or unsaturated hydrocarbons divalent group and any ketone, sulfo-ketone, imino group ketone and is substituted derivative ((C for example1-C
10) alkylidene comprises methylene (CH2)-, ethylidene (CH2CH
2-), methyl ethylidene, ethenylidene, ethynylene, trimethylene (CH2CH
2CH
2-), 2-oxo trimethylene (CH2C(O)CH
2-), 2-sulfo-trimethylene (CH2C(S)CH
2-), 2-imino group trimethylene (CH2C(NH)CH
2-), allylidene (CH2CH=CH-or-CH=CHCH2-), propyl group fork base (=CHCH2CH
2-), third Thiazolinyl fork base (=CHCH=CH-), 1-imino group tetramethylene, pentamethylene etc.).
" alkylidene radical " refers to group=CRR, and wherein each R is hydrogen or alkyl independently, as defined above, has carbon atom (for example, (C of specified number1-6) alkylidene radical comprise the methene base, Ethidine, propylidene base, isopropylidene etc.).
" alkoxyl " refers to group-OR, and wherein R is the alkyl ((C for example of the carbon atom with specified number as defined above1-6) alkoxyl comprises group methoxyl group, ethyoxyl, third oxygen Base, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyl oxygen Base, pi-allyl oxygen base, 1-acrylic oxygen base, isopropenyl oxygen base, 1-cyclobutenyl oxygen base, 2-Cyclobutenyl oxygen base, 3-cyclobutenyl oxygen base, 2-methacrylic oxygen base, acetenyl oxygen base, 1-propine Base oxygen base, 2-propynyl oxygen base etc.).
" alkyl sulphinyl ", " alkyl sulphonyl " and " alkylthio group " refer to respectively group-SOR ,-S (O)2R and-SR, wherein R is the alkyl ((C for example of the carbon atom with specified number as defined above1-6) alkyl sulphonyl comprises methyl sulphonyl, ethylsulfonyl, sulfonyl propyl Base, isopropyl sulfonyl, butyl sulfonyl, sec-butyl sulfonyl, isobutyl group sulfonyl, uncle Butyl sulfonyl, vinylsulfonyl, pi-allyl sulfonyl, 1-acrylic sulfonyl, isopropyl Thiazolinyl sulfonyl, 1-cyclobutenyl sulfonyl, 2-cyclobutenyl sulfonyl, 3-cyclobutenyl sulfonyl, 2-Methacrylic sulfonyl, acetenyl sulfonyl, 1-propinyl sulfonyl, 2-propynyl sulfonyl Etc.).
" ammonium " refers to group-NH3 +。
" amidino groups " refers to group-C (NH) NH2。
" amino " refers to-NH2。
" animal " comprise people and the mammal except the people (for example dog, cat, rabbit, ox, Horse, sheep, goat, pig, deer etc.) and nonmammalian (such as birds etc.).
" aryl " refers to contain aromatic monocyclic or the fused polycycle alkyl of specified number carbon atom, and the ring that wherein comprises forms ((C for example by 6 ring atoms6-14) aryl comprise phenyl, naphthyl, Anthryl, phenanthryl etc.).
" aryl sulfonyl " refers to group-S (O)2R, wherein R is the ((C for example of the aryl with specified number carbon atom as defined above6-14) aryl sulfonyl comprises phenyl sulfonyl, naphthalene-1-Base sulfonyl etc.).
" aromatic structure part " refers to any aromatics part of this group. For example, aromatic structure section Divide to refer to here defined aryl and heteroaryl, and comprise aryl alkyl, heteroaryl alkyl, The aromatics part of polyaromatic, assorted polyaromatic etc.
" pyrrolidinyl (azolidinyl) " refers to contain nitrogen-atoms saturated of specified number or not Saturated 5-person's monocyclic groups. For example, (N1-4) pyrrolidinyl comprise pyrazolidinyl, pyrrolidinyl, Imidazolidinyl, triazolidinyl, tetrazolium alkyl, pyrrolin base, glyoxalidine base, dihydro pyrrole Azoles base and dihydro triazolyl.
" pyrrole radicals (azolyl) " refers to contain the aromatics 5-person monocycle base of the nitrogen-atoms of specified number Group. For example, (N1-4) pyrrole radicals (azolyl) comprises pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl And tetrazole radical.
" carbamoyl " refers to group-C (O) NH2。
" carboxyl " refers to group-C (O) OH.
" cyano group " refers to group-CN.
" cycloalkyl " refers to contain the saturated or undersaturated monocycle or the fused polycycle alkyl of the carbon atom of specified number, and each ring that is wherein contained is by member composition and its any carbocyclic ring ketone, sulfo-ketone and imino-ketone derivatives (for example, (C on 3-8 the ring
3-14) cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, dicyclo [2.2.2] octyl group, oxo cyclohexyl, dioxo cyclohexyl, sulfo-cyclohexyl or the like).
" cycloalkylidene " refers to contain the saturated or unsaturated monocycle or the fused polycycle bivalent hydrocarbon radical of the carbon atom of specified number, and each ring that is wherein contained is by member composition and its any ketone carbocyclic ring ketone on 3-8 the ring, sulfo-ketone and imino-ketone derivatives (for example, (C
3-10) cycloalkylidene comprises 1,2-cyclopropylidene, 1, the inferior cyclobutyl, 1 of 2-, the inferior cyclobutyl, 1 of 3-, 2-cyclopentylidene, 1,3-cyclopentylidene, 1,4-cyclopentylidene, 1,4-cyclohexylidene, 3-tetrahydrobenzene-1,2-subunit, 2,5-cyclohexadiene-1,4-subunit, 1, inferior dicyclo [2.2.2] octyl group of 4-, 5-oxo-1,3-cyclohexylidene, 2,5-dioxo-1,4-cyclohexylidene, 5-sulfo--1,4-cyclohexylidene etc.
" go protection " and refer to remove existing any blocking group after selective reaction is carried out.
" disease " specifically comprise any unhealthy situation of animal or its part and comprise by medical treatment that this animal is carried out or veterinary treatment causes or incidental unhealthy situation, " side effect " that promptly should treatment.
" condensed mix many cyclic groups " comprise " condensed mix bicyclic radicals " and refer to have specified number carbon atom contain two heterocyclic groups to three fused rings, the member (for example is connected in second ring at least two rings of one of them ring, contain assorted many cyclic groups of 8-18 ring atom and carbocyclic ring ketone thereof and sulfo-ketone derivatives and comprise 1H-benzimidazolyl-2 radicals-Ji, 1H-naphtho-[2,3-d] imidazoles-2-base, 1H-imidazo [4,5-f] quinoline-2-base, 1H-imidazo [4,5-b] pyridine-2-base, 1H-phenanthro-[9,10-d] imidazoles-2-base, 1H-imidazo [4,5-g] quinoxaline-2-base, 2,6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-8-base, 2,6-dithio-2,3,6,9-tetrahydrochysene-1H-purine-8-base, 7H-purine-8-base, 1,6-dihydro pentamethylene imidazoles-2-base, 4-quinoline-2-base etc.).
" guanidine radicals " refers to-NHC (NH) NH
2
" halogen " refers to fluorine, chlorine, bromine or iodine.
" heteroatoms " refers to be selected from the atom of N, O, S and P.
" heteroatoms structure division ", except as otherwise noted, refer to be selected from-N=,-NR
17-,-O-,-S-,-S (O)-,-S (O)
2-,-P (O) (OR
17)-structure division, R wherein
17Be hydrogen or (C
1-6) alkyl.
" assorted alkyl " refers to alkyl as defined above, be one or morely in the specified carbon atom to be replaced by the heteroatoms structure division, such as in of the present invention being described in detail definition, and any carbocyclic ring ketone, sulfo-ketone and imino-ketone derivatives (for example assorted (C
2-12) alkyl comprises methoxyl group, oxyethyl group, ethylmercapto group, 2-(2-methoxyl group-oxyethyl group) oxyethyl group, 3-methoxymethoxy carbonyl methoxyl group, 2-(N-ethyl-N-methylamino) ethyl, 2-ethyl imino-ethyl, oxyethyl group methoxy base phosphorus acyloxy etc.).
" inferior assorted alkyl " refers to alkylidene group as defined above, is that one or more in the specified carbon atom are replaced by heteroatoms structural portion branch, as defining in of the present invention being described in detail, or its any suitable binding substances (for example ,-OS (O)
2-,-S (O)
2O-,-N (R) S (O)
2-,-S (O)
2NR
17-,-OP (O) (OR
17) O-and similar group, wherein R
17Be hydrogen or (C
1-6) alkyl) and any ketone, sulfo-ketone and imino-ketone derivatives (for example, assorted (C
2-10) alkylidene group comprises azepine ethylidene (CH
2NH-), 2-azepine propenylidene (CH
2N=CH
2-), 1-oxa-trimethylene (CH
2CH
2O-), 2-oxo-3-azepine pentamethylene, 3-azepine-2-sulfo-pentamethylene, 2-oxa--3-oxo pentamethylene, 3-aza-2-imino pentamethylene (CH
2CH
2NHC (NH) CH
2-), 2,4-azepine-2-methyl-3,3-dioxo-3-thia pentamethylene (CH
2NHS (O)
2N (CH
3) CH
2-), 3-hydroxyl-2,4-oxa--3-oxo-3-phospha pentamethylene (CH
2OP (O) is OCH (OH)
2-), 3-azepine-2-oxo-4-carboxyl hexa-methylene, 4-azepine-1-oxa--3-oxo hexa-methylene, 1-thia-3-oxo-4-azepine hexa-methylene, 1-thia-1,1,3-trioxy--4-azepine hexa-methylene (CH
2CH
2NHC (O) CH
2S (O)
2-), 3-azepine-4-oxo heptamethylene, 1,4,7-trioxa eight methylene radical, 6-azepine-1-oxa--2,5-dioxo eight methylene radical (CH
2CH
2NHC (O) CH
2CH
2C (O) O-), 3-azepine-4-oxo decamethylene or the like).
" heteroaryl " refers to have the aromatic monocyclic or the fused polycycle divalent group of the ring atom of specified number, each ring that is wherein contained by one or more in member composition and these ring atoms on 5-6 the ring be selected from-N=,-NR
17-,-O-or-structure division of S-, (R wherein
17Be hydrogen or (C
1-6) alkyl) and each ring that is wherein comprised be to go up member composition (for example, (C that mixes by 5-6 ring
5-14) aryl comprises thienyl, furyl, pyrryl, pyrimidyl, isoxazolyl, oxazolyl, indyl, benzo [b] thienyl, isobenzofuran-base, purine radicals, isoquinolyl, pteridyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl or the like).
" Heterocyclylalkyl " refers to cycloalkyl defined above, just one or more in these ring atoms are replaced by heteroatoms structural portion branch, such as in of the present invention being described in detail definition, and any carbocyclic ring ketone, sulfo-ketone and imino-ketone derivatives (for example, term heterocycle (C
5-14) alkyl comprises piperidyl, pyrrolidyl, pyrrolinyl, tetrahydroglyoxaline alkyl, quinuclidinyl, morpholinyl or the like).
" inferior Heterocyclylalkyl " refers to cycloalkylidene defined above, be one or morely in the middle of the carbon atom on the specified ring to be replaced by heteroatoms structural portion branch, such as of the present invention in being described in detail definition, and any carbocyclic ring ketone, sulfo-ketone and imino-ketone derivatives (for example, term heterocycle (C
3-14) alkylidene group comprises piperidylidene, pyrrolidinylidene, inferior pyrrolinyl, inferior imidazolidyl, inferior quinuclidinyl, inferior morpholinyl or the like.
" assorted polyaromatic " refers to as following defined polyaromatic, just ring is gone up one or more in the middle of the carbon atom and is replaced by heteroatoms structural portion branch, be described in detail middle the definition as of the present invention, and any carbocyclic ring ketone, sulfo-ketone and imino-ketone derivatives (for example assorted many ring (C
8-10) alkyl comprises 3,4-dihydro-2H-quinolyl, 5,6,7,8-tetrahydric quinoline group, 3,4-dihydro-2H-[1,8] naphthyridinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolyl, 3-oxo-2, the 3-dihydrobenzo [1,4] oxazinyl or the like).
" hydroxyl " refers to group-OH.
" immune-mediated inflammation disorder " is meant with mastocyte vehicle and discharges the disease (for example: direct (immediated) type hypersensitization disease such as asthma, allergic rhinitis, rubella and vasodilation, eczema allergy, dermatitis such as atopic dermatitis, super hyperplasia dermatosis, stomach ulcer, inflammatory bowel disorder, vision and vernal conjunctivitis, rheumatoid arthritis, inflammation tetter and analogue) that is associated and tryptase inhibitors is treated sensitivity.
" hyperergy " is meant that the tracheae in late period that is associated with chronic asthma shrinks and the hyperergy of airway.The hyperergy of the bronchiole tissue of asthma is considered to by due to the chronic inflammatory reaction, and these reactions evoke and destroy epithelium connection tracheal wall and promote the pathologic of substrate tissue to thicken.
" syncytial virus inflammation " is meant the inflammation by a kind of virus, and as a kind of respiratory syncytial virus, it can bring the cellular plasm material by infection is plasmodial formation.
" imino-" is meant group=NH.
" isomer " be meant that the compound with formula I has identical molecular formula but its by nature or on its atom binding sequence or its atom different on spatial is arranged.Its atom is called " steric isomer " at the different isomer of spatial disposition.The steric isomer that is not mirror image each other is called as " diastereomer ", and mirror image can not be called as " enantiotropy " or be called as " optical isomer " sometimes by the eclipsed steric isomer.The substituting group bonded carbon atoms different with four are called as " chiral centre ".Have the compound of a chiral centre to have two enantiotropies that chirality is opposite, it is called as " raceme ".There is the compound of an above chiral centre to have 2
N-1Individual enantiotropy is right, is the chiral centre number at this n.Have an above chiral centre compound or with one independently the form of diastereomer exist, perhaps the form of mixtures with diastereomer exists, and is called as " non-enantiomer mixture ".When having a chiral centre, a steric isomer may be by the absolute configuration of that chiral centre institute mark.Absolute configuration is meant that substituting group and chiral centre arrange at spatial.At this, arrange according to Cahn, Ingold and Prelog " sequence rules " with the substituting group that chiral centre connects, in the bracket critical descriptor R or S, then be a hyphen, be thereafter the chemical name of compound.Compound with formula I comprises a chiral centre, and the form of the steric isomer that it can be independent exists, and form of mixtures that also can steric isomer exists.In the present patent application, when not indicating its configuration, be construed as all configurations that it is meant this compound when indicating compound with formula I with name and formula.
" selection " or " selectively " is meant that described incident or environment may take place or may not take place, and this description includes incident or environment takes place and situation about not taking place.For example, " selectively by one to three group replacement " to be meant the group possibility quilt of indication or may not to be substituted, so to be to fall within the scope of the present invention in order making it.
" N-oxidized derivatives " is meant a derivative of the compound with formula I, and its N atom is in oxidized state (being O-N), and this derivative has the pharmaceutical activity of expectation.Derivative with compound of formula I can be prepared by the method known to the people who knows ordinary skill.
A kind of " pathology " of disease be meant characteristic, reason and the development of necessity of this disease and thus the 26S Proteasome Structure and Function that brings of lysis change.
" pharmaceutically useful " be meant when preparation a kind of safe, nontoxic, both be useful during the also non-thereby unavailable medicinal compound of inanimate, and comprise that it can be used for veterinary drug and people's medicine.
" pharmacologically acceptable salt " is meant the salt of the compound with formula I, has the pharmaceutical activity of pharmaceutically acceptable as defined above property and expectation.These salt comprise the acid salt that is formed by mineral acid or organic acid, mineral acid example hydrochloric acid wherein, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid and analogue, organic acid such as acetate, propionic acid, caproic acid, enanthic acid, the pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, hydroxy-butanedioic acid, maleic acid, fumaric acid, tartrate, citric acid, phenylformic acid, adjacent (4-oxybenzene formyl) phenylformic acid, cinnamic acid, madelic acid, methylsulphonic acid, ethylsulfonic acid, 1, the 2-ethionic acid, 2-hydroxyl ethane sulfonic acid, Phenylsulfonic acid, p-chlorobenzenesulfonic acid, the 2-naphthene sulfonic acid, tosic acid, camphorsulfonic acid, 4-methyl bicyclic [2,2,2] eight-2-alkene-1-carboxylic acid, glucoheptonic acid, 4,4 '-positive methyl two (3-hydroxyl-2-alkene-1-carboxylic acid), the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, lauryl sulfonic acid, glyconic acid, L-glutamic acid, the hydroxyl naphthoic acid, Whitfield's ointment, stearic acid, muconic acid and analogue.
Pharmacologically acceptable salt also comprises base addition salt, and this can and obtain by sour proton and the reaction of inorganic or organic bases.The available mineral alkali comprises sodium hydroxide, yellow soda ash, potassium hydroxide, aluminium hydroxide and calcium hydroxide.The available organic bases comprises thanomin, diethanolamine, trolamine, Tutofusin tris, N-methylglucosamine and analogue.
" polyaromatic " is meant the many cyclic groups of condensed, it includes the carbon atom of stating number, have one at least--but be not all-fused rings is fragrant, and each ring comprises that all 5 to 6 ring memberses and any carbocyclic ring ketone that obtains therefrom and 40 thione derivatives are (as many ring (C
9-10) aryl comprises 2,3-dihydro indenyl, indenyl, 1,2,3,4-tetralyl, 1,2-dihydro naphthyl, 2,4-dioxo-1,2,3,4-naphthane etc.).
" preceding medicaments derivative " is meant the derivative of the compound with formula I, and they are converted into the corresponding non-derivative form of the compound with formula I in vivo.The preceding medicaments derivative that is fit to comprises that those have the compound of formula I, they are one or more have the nitrogen-atoms of available free key and/or Sauerstoffatom be easy to react in vivo in the cracked group replace.For example, the prodrug derivant of the compound of formula I can contain the amino that one or more N-replace (for example ,-NH
2(R
18)), be introduced in N-substituted nitrogen atom in aliphatic series, the alicyclic or aromatic structure (for example-N (R
18)-), and imines that N-replaces or amidino groups (for example-C (NR
18) H ,-C (NR
18) NH
2Or-C (NH) NHR
18), the guanidine radicals that N-replaces (for example-NHC (NR
18) NHR
18,-NHC (NH) NHR
18Or-NHC (NR
18) NH
2), and analogue, wherein R
18Be (i)-C (O) R
19Or-CH (R
20) OC (O) R
19, R wherein
19Be (C
1-10) alkyl, (C
1-10) alkoxyl group, formamyl, (C
1-10) alkyl-carbamoyl, two (C
1-10) alkyl-carbamoyl, suitable-2-(C
1-10) the alkanoyloxy phenyl vinyl, 3-(C
1-10) the alkanoyloxy butyryl radicals, (C
3-10) cycloalkyl, assorted (C
3-10) cycloalkyl, (C
6-10) aryl or assorted (C
5-10) aryl and R
20Be hydrogen or (C
1-10) alkyl; (ii)-X
7-R
21, X wherein
7Be (C
1-10) alkylidene group and R
21It is carboxyl; Or (iii)-C (O) OCH (R
22) OC (O) R
23, R wherein
22Be hydrogen, (C
1-10) alkyl or (C
3-10) cycloalkyl and R
23Be (C
1-10) alkyl or (C
3-10) cycloalkyl.Also have, the prodrug derivant of the compound of formula I contain one or more N-hydroxylation imino-s or amidino groups (for example ,-C (NOR
24) H ,-C (NOR
24) NH
2Or-C (NH) NHOR
24) or N-hydroxylation guanidine radicals (for example ,-NHC (NOR
24) NH
2,-NHC (NH) NHOR
24), R wherein
24Be hydrogen, methyl ,-C (O) R
25Or-CH (R
26) OC (O) R
25, R wherein
25Be (C
1-10) alkyl or (C
3-10) cycloalkyl and R
26Be hydrogen or (C
1-10) alkyl; The hydroxyl that N-replaces (for example-OR
27), R wherein
27Be-C (O) R
19Or-CH (R
20) OC (O) R
19, R wherein
19And R
20As defined above; And/or the ester derivative of carboxylic acid (for example-C (O) OR
28), R wherein
28Be (C
1-10) alkyl or (C
3-10) cycloalkyl.
" blocking group " has general meaning in the synthetic organic chemistry field; promptly a kind of like this group, it optionally protects in the multiple functionalized compound reaction active site so that optionally carry out chemical reaction and can easily remove in another not protective reaction active sites after finishing selective reaction.
" protected derivative " refers to the derivative of the compound of formula I, and the protected group of wherein one or more reaction active sites is protected.The protected derivative of the compound of formula I can be used for the compound of preparation formula I.The suitable blocking group of reactive behavior nitrogen-atoms comprises tert-butoxycarbonyl, and benzyloxycarbonyl and any other suitable amido protecting group (for example, referring to T.W.Greene, the blocking group in the organic synthesis, John Wiley; Sons, Inc., 1981).Especially, the suitable protected derivative of formula I for example has compound 2-[5-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-4,5,6,7-tetrahydrochysene-1H-benzoglyoxaline-5-carboxylic acid.
" treatment significant quantity " is meant that be effective dosage when giving an animal administering therapeutic disease.
" treatment " is meant any a kind of compound of the present invention of using, and comprising:
(1) prevention animal morbidity, this animal may this diseases of easy infection but experience or show the pathology or the symptom of this disease not,
(2) suppress this disease, promptly stop the development of its pathology and/or symptom, perhaps
(3) alleviate this disease, even its pathology and/or symptom revolution.
" sulfo group " refers to group-S (O) OH.
" urea groups " refers to group-NHC (O) NH
2
Intermediate and starting raw material that the compound of formula I and being used to prepares them are to name according to the naming rule of IUPAC.The compound of formula I for example, wherein:
A comprises 5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji with B, and C comprises 5-(2-naphthalene-1-base ethylamino formyl radical)-1H-benzimidazolyl-2 radicals-Ji and X
3Be-CH2-to be named as 2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-1-base ethyl-1H-benzoglyoxaline-5-carboxylic acid amides;
A comprises 5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji with B, and C comprises 6-(2-naphthalene-1-base ethylamino formyl radical)-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji and X
3Be-CH2-to be named as 2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl-3H-benzoglyoxaline-5-carboxylic acid amides;
A comprises 5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji with B, and C comprises 6-[2-(2-carboxyl phenyl) ethylamino formyl radical]-1-(3-sulfo group propyl group-1H-benzimidazolyl-2 radicals-Ji and X
3Be-CH2-to be named as 2-{2-[2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(3-sulfo group propyl group)-3H-benzoglyoxaline-5-base carbonylamino] ethyl } phenylformic acid; With
A comprises 5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji with B, and C comprises 6-[2-(2-p-methoxy-phenyl) ethylamino formyl radical]-1-(3-sulfo group propyl group-1H-benzimidazolyl-2 radicals-Ji and X
3Be-CH2-to be named as 3-{2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-6-[2-(2-p-methoxy-phenyl) ethylamino formyl radical] benzoglyoxaline-1-yl } propane-1-sulfonic acid.
There is tautomeric equilibrium in some compound of formula I.For example, wherein C comprises 4,5,6, and there is balance below in the compound of the formula I of 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-2-base between the tautomer of structural formula:
Therefore, although compound of the present invention has carried out name, explanation or description in this manual as a kind of tautomer, it should be understood that all possible tautomer is understood that to be covered by these names, explanation and description.Therefore, title 2-(4-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6,7-tetrahydrochysene-imidazo [4,5-c] pyridine-5-yl-4-oxo butyl) ethyl benzoate be understood to include it tautomer 2-(4-{2-[1-(and the ethyl of 5-guanidine radicals-3H-benzimidazolyl-2 radicals-yl)]-1,4,6,7-tetrahydrochysene-imidazo [4,5-c] pyridine-5-yl }-4-oxo butyl) ethyl benzoate, 2-(4-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3,4,6,7-tetrahydrochysene-imidazo [4,5-c] pyridine-5-yl }-4-oxo butyl) ethyl benzoate, and 2-(4-{2-[1-(ethyl of 5-guanidine radicals-3H-benzimidazolyl-2 radicals-yl)]-3,4,6,7-tetrahydrochysene-imidazo [4,5-c] pyridine-5-yl }-4-oxo butyl) ethyl benzoate.
Present embodiment preferred:
Although the wideest definition of the present invention has been listed in the general introduction of the present invention, some aspect of the present invention is preferred.Preferred aspect of the present invention is that wherein A comprises the compound of the formula I that condenses assorted bicyclic group with B, and wherein A contains on 5 rings member and B and contains member and X on 6 rings
4And X
5Shi oxazole-2-base, the adjacent member of 1H-imidazoles-2-base or thiazol-2-yl ring.
Preferred aspect of the present invention is the compound of formula II:
Wherein
Dotted line is represented the dispensable key of selectivity independently;
Each R
2Be (C independently
1-6) alkyl, (C
1-6) alkoxyl group, halogen or hydroxyl;
Each R
3Be (C independently
1-6) alkyl, (C
1-6) alkoxyl group, halogen or hydroxyl;
X
3Be-C (O)-or-CR
7R
8-,
X
8Be-CH (R
1) n1-or-C (R
1) n1=, wherein R
1Be amino (N
1-4) pyrrolidyl, amino (N
1-4) pyrryl, (N
1-4) pyrrolidyl, (N
1-4) pyrryl ,-NHC (NH) NR
9R
9,-C (NR
9) R
9,-C (NH) NHR
10,-C (NH) NR
10R
10Or-(CR
11R
11) yNH
2, or X
8Be-N=or-NH (R
1)
N1-, R wherein
1Be-C (NR
9) R
9,-C (NH) NHR
10Or-C (NH) NR
10R
10, each R wherein
9Be hydrogen or (C independently
1-6) alkyl and each R
10Be (C independently
1-6) alkyl; With
X
9Be-CH (R
4)-or-C (R
4)=, be R wherein
4Be-R
12,-OR
12,-N (R
13) R
12,-SR
12,-S (O) R
12,-S (O)
2R
12, S (O)
2OR
12,-S (O)
2N (R
13) R
12,-N (R
13) S (O)
2R
12,-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12,-N (R
13) C (O) R
12,-OC (O) N (R
13) R
12,-N (R
13) C (O) OR
12,-(CH
2)
N4N (R
13) C (O) N (R
13) R
12,-OP (O) (OR
13) OR
12Or-C (O) N (R
14) CH (COOH) R
12, or X
9Be-N=or-N (R
4)-, be R wherein
4Be-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12,-OC (O) N (R
13) R
12Or-C (O) N (R
14) CH (COOH) R
12, R wherein
12, R
13And R
14Identical with the definition in the general introduction of the present invention.
A compound that preferred aspect is formula I of the present invention, wherein:
R
5Be hydrogen or (C
1-4) alkyl, R
6Be hydrogen or (C
1-4) alkyl, this alkyl arbitrariness ground is independently selected from (C by one or two
1-4) alkoxyl group, the substituting group of hydroxyl and sulfo group replaces, R
7Be hydrogen or methyl and R
8Be hydrogen, methyl or hydroxyl;
X
8Be-CH (R
4)-or-C (R
1)
N1=, R wherein
1Be amino methyl, the amino cyclopropyl of 1-, 2-aminooimidazole-1-base, 2-amino-1,1-dimethyl ethyl, imidazolyl, tetrazyl ,-(CH
2)
xNHC (NR
9) R
9,-(CH
2)
xNHC (NH) NR
9R
9With-C (NR
9) R
9, each R wherein
9Be hydrogen or methyl independently, or X
8Be-N (R
1)
N1-, R wherein
1Be-C (NR
9) R
9,-C (NH) NHR
10Or-C (NH) NR
10R
10, each R wherein
9Be hydrogen or methyl and each R independently
10Be methyl, wherein belong to R
1Any aliphatic series or alicyclic structure part arbitrariness ground replaced by 1-2 substituting group that is independently selected from methyl sulphonyl and carboxyl;
X
9Be-C (R
4)=, be R wherein
4Be-R
12,-OR
12,-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12Or-C (O) N (R
14) CH (COOH) R
12, R wherein
13And R
14Be hydrogen or (C independently
1-6) alkyl; R
12Be-R
15Or-X
6-(R
15)
N15, X wherein
6Be (C
1-10) alkylidene group or assorted (C
2-10) alkylidene group and each R
15Be hydrogen independently, (C
6-14) aryl, ring (C
3-14) alkyl, many ring (C
6-14) aryl, assorted many ring (C
6-14) aryl, heterocycle (C
3-14) alkyl or assorted (C
5-14) aryl;
Belong to R
4Any aliphatic series and alicyclic structure part arbitrariness ground be independently selected from (C by 1-5
1-4) alkoxyl group, (C
1-4) alkoxy carbonyl, amino, formamyl, the substituting group of carboxyl and hydroxyl replaces; With
Belong to R
15Any aromatic structure part arbitrariness ground be independently selected from (C by 1 to 3
1-4) alkyl, (C
1-4) alkoxyl group, (C
1-4) alkoxy carbonyl, formamyl, carboxyl, cyano group, ring (C
3-6) alkoxyl group, halogen, assorted (C
1-8) alkyl, assorted (C
1-8) alkyl-carbonyl, assorted (C
5-6) substituting group of aryl and trifluoromethyl replaces; And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt.
Preferred aspect of the present invention is the compound of formula I, wherein:
A comprises 4,5,6 with B, 7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base, and wherein n2 is 0 and R
1Be-C (NR
9) R
9, or A comprises 1H-benzimidazolyl-2 radicals-Ji or 4,5,6 with B, 7-tetrahydrochysene-1H-benzimidazolyl-2 radicals-Ji, wherein R
1Be amino methyl or guanidine radicals and each R
2Be halogen or hydroxyl independently.
C comprises 4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base or 1H-benzimidazolyl-2 radicals-Ji, wherein R
4Be-C (O) X
6-R
15,-C (O) OX
6-R
15Or-C (O) NHX
6-R
15, X wherein
6Be (C
1-4) alkylidene group or assorted (C
2-4) alkylidene group and R
15Be (C
6-10) aryl, (C
6-10) aryloxy, many ring (C
6-10) aryl, assorted (C
5-10) aryl, assorted (C
5-10) aryloxy or assorted many ring (C
6-14) aryl; With
Any aromatic structure part that belongs to R15 is independently selected from (C by 1-3
1-4) alkyl, (C
1-4) alkoxyl group, (C
1-4) alkoxy carbonyl, carboxyl, formamyl, halogen, the substituting group of hydroxyl and tetrazolium-1-base replaces; And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt.
Preferred aspect of the present invention is the compound of formula I, and wherein n1 is 0 and each R
2Be halogen or hydroxyl independently, especially:
2-(2-{2-[1-(4,6, the ethyl of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid;
2-(2-{2-[1-(5, the ethyl of 6-two fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid;
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) butyl benzoate;
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) propyl benzoate; With
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) isobutyl benzoate.
Preferred aspect of the present invention is the compound of formula I, wherein R
1Be guanidine radicals or amino methyl, especially:
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(4-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-yl also }-4-oxo butyl) ethyl benzoate;
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(2, the 3-dihydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-(2, the 3-dihydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(3-hydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(2-hydroxyl) ethyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-carbamyl phenoxyl) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-formamyl-4-chlorophenoxy) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides;
4-chloro-2-[2-(2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonyl } amino) oxyethyl group] phenylformic acid;
5-chloro-2-[2-(2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonyl } amino) oxyethyl group] phenylformic acid;
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides; With
2-(5-amino methyl-4,5,6,7-tetrahydrochysene-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides.
Preferred aspect of the present invention is the compound of formula I, and wherein C comprises 4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base and R
1Be-C (NH) R
9, especially:
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base carbonyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(5-iminomethyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-hydroxyl-2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(2 hydroxy naphthalene-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(4-hydroxyl naphthalene-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides;
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] ethyl benzoate;
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-(2-methoxy ethyl)-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid;
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base carbonylamino also) oxyethyl group] ethyl benzoate; With
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-[2-(2-tetrazyl phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides.Pharmacology and application:
Compound of the present invention is a serpin, thereby is useful for the disease that is associated of serine protease of treatment and increase.Especially, compound of the present invention is a tryptase inhibitors, is useful for treatment with the disease that the tryptase activity that increases is associated.For this area, all know external and how suppress the method that the ability of tryptase is screened possible inhibitor according to their.See, as (1992) Biol.Chem.Hoppe-Seyler 373:1025-1030 such as Sturzebecher.Typically, these methods are measured the hydrolysis reaction of peptide-Ji product color substance of enzyme induction.The mensuration tryptase suppresses an active routine preface and will be described below.
And compound activity of the present invention can obtain measuring in the body of many animal models of asthma.See Larson, " can reply the experimental model that airway stops up ", in " lung: the discovery of science ", volumes such as Crystal, West, Raven Press, New York, 1991; Warner etc. (1990) Am.Rev.Respir.Dis.141:253-257.An ideal animal model can repeat the main clinical and physilogical characteristics of people's asthma, comprising: airway is to the hyperergy of chemical vector and physical stimulation thing; Make the reversibility of airway obstruction with the medicine useful (beta-adrenaline, methyl xanthine, reflunomide and analogue) to people's asthma; The airway inflammation that has the activated white corpuscle to infiltrate; The degenerative of chronic inflammatory diseases changes, as basilar membrane thickening, unstriated muscle hypertrophy and epithelial damage.The kind that is used for doing animal model comprises mouse, rat, cavy, rabbit, dog and sheep.All animals all have some limitations, select appropriate animal model according to the problem that will solve.
Initial asthma reaction can be estimated in cavy and dog, especially, uses a basenji-greyhound hybridization strain, and it can cause multiple nonallergic material such as methacholine and all responsive nonspecific airway hyperergy of citric acid.The sheep of some selections shows double stress reaction after being subjected to invading as antigen with roundworm protein.In the animal of double stress reaction, an asthma reaction in late period (LAR) is arranged behind initial asthma reaction (IAR), it approximately occurs in antigen and invaded the back 6-8 hour.In those animals of performance LAR, the hyperergy of choline agonist stimulant carbachol is invaded increase in back 24 hours at antigen.
Irritated sheep model (as follows) is used to estimate the sick effect of the possible anti-asthma of compound of the present invention.Before or after being exposed to special anaphylactogen, mode by oral cavity and suction or aerosol is administered to the composition of being made up of compound of the present invention in the irritated sheep and goes, and shows these compositions and can greatly reduce or eliminate asthma reaction and hyperergy thereafter in late period.
Compound of the present invention also is useful for other immune-mediated inflammation disorders for the treatment of the pathological condition that is caused by the tryptase activity.These diseases comprise the inflammation disorder that is associated with mastocyte, as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic symptoms, inflammation intestinal disease, stomach ulcer and different skin symptoms.Further, compound of the present invention can be used for treating the syncytial virus inflammation.
The effect of a large amount of immune-mediated inflammation disorders of compounds for treating of the present invention can by in the body or vitro procedure estimate.Thereby, the anti-inflammatory effect of compound of the present invention can be showed by the measuring method of this area notice, for example, reverse passive anaphylactic hypersensitivity (Reversed PassiveArthus Reaction, RPAR)-and the PAW technology (see, for example, Ganley etc. (1992) U.S. patent No. No.5,126,352).Measure compound of the present invention to the method for different skin symptoms, in this area, be widely known by the people, as arachidonic acid mouse ear check (the same) as the therapeutic value of super hyperplasia dermatosis.The program that available Chiu etc. describe in Archives Internationales dePharmacodynamie et de Therapie 270:128-140 is measured the antiulcer activity of compound of the present invention.
Compound of the present invention stops the effect of the cytogamy of being brought by the syncytial virus inflammation can use the method that is generally provided in J.Med.Chem.26:294-298 (1983) by Tidwell etc. to measure.Composition and administration:
According to the present invention, effective treatment of compound of the present invention or pharmaceutical dosage are used to suffer from the patient of immune-mediated inflammation disorder.According to an embodiment, composition of the present invention is effective for stoping or alleviating asthma.When using composition of the present invention and treat asthma, compound defense sector in advance uses before former or other precipitation factors in contact allergy, or in use thereafter.In the tissue injury in late period of compound of the present invention in the sacroiliitis that alleviates seasonal or long-term property is effective especially.Another aspect of the present invention is to point to other immune-mediated inflammation disorders that prevention and treatment are associated with mastocyte, as rubella, vasodilation, eczematoid dermatitis (atopic dermatitis), anaphylaxis, super proliferative skin disorders, stomach ulcer and similar disease.In another embodiment, compound of the present invention is used for treating syncytial virus and infects, particularly respiratory syncytial virus infection.
Contain this compound compositions and can be used as treating and/or preventing property treatment usefulness.In curative application, as mentioned above, composition is used to patient's administration of suffering from a kind of disease, and its consumption can enough be used for curing or partly stoping this disease at least.The dosage that is enough to finish this task is defined as " effectively therapeutic dose or dosage ".The effective dose of this application will depend on severity of disease and process, former treatment, patient's healthy state, to the reaction of medicine and doctor judgement to the state of an illness.
In preventative application, contain compound compositions of the present invention and be used to, otherwise patient just there is the danger of suffering from this kind disease to patient's medication of easily suffering from certain disease, dosage is enough to stop or the beginning of mitigation symptoms.These dosage are defined as " effectively preventive dose ".Medicine can be used to oral or suck.In this used, accurate drug dose depended on patient's healthy state, body weight and similar situation again.
In case patient's situation takes a turn for the better to some extent, if desired, a dosage of keeping just is applied.Then, dosage or medicine frequency or the two as the function of symptom, just can be eased down to the level of the circumstances of keeping improvement together.When sx to the expectation level the time, treatment can stop.Yet patient can require treatment intermittently because of any recurrence of disease symptoms.
Usually, suitable effective dose of compound of the present invention is that each patient every day is between 0.05-1000 milligram (mg), preferably between every day 0.1-100mg.The dosage of expectation be preferably split into 1,2,3,4 or more sub-doses give patient's dispenser with appropriate gap at one day.These sub-doses can be made into the form of unitary dose, and for example per unit dosage contains 0.01-1000mg, preferably the 0.01-100mg activeconstituents.
Composition in these treatments can be in different ways.These comprise, for example solid, semisolid and liquid dosages mode are as tablet, enteric coated tablets, pill, pulvis, liquor or suspension liquid, liposome, injectable and pourable solution.In preparation that can suck such as aerosol are also included within.Preferred dosage form for can be suitable in oral cavity, the nose, epidermis and parenteral application, but its optimal way should be selected according to treatment problem especially at hand.Particularly preferred dosage form is oral or aerosol.The method of preparation preparation and the therapeutic composition be made up of compound of the present invention is widely known by the people in this area, for example at " Remington ' sPharmaceutical Science and the Merck Index " 11 editions (MERCK ﹠amp; Description is just arranged Co.1989).
Although can use active ingredient of the present invention individually, more preferably be its component as medicinal preparations.Preparation of the present invention comprises at least a treatment effective dose and a kind of pharmaceutically acceptable carrier described here.Medicinal compositions thereby the compound of the present invention that contains enough concentration are can obtain proper dosage.For example, when proper dosage is every day during 0.05mg, the concentration of compound of the present invention in medicinal compositions will be every dosage 0.05mg, and usage quantity is for once a day.For inhalation or aerosol, the concentration of compound of the present invention in medicinal compositions will usually rely on the size of dosage.The typical concentration of compound of the present invention is to about 30mg/ml from about 0.01 in inhalation or aerosol.But preparation may comprise the compound of other clinical applications, as the beta-adrenergic medicine (for example: salbutamol (albuterol), Arubendol (terbutaline), formoterol (formoterol), fenoterol (fenoterol), (prenaline) and reflunomide (for example: beclometasone (beclomethasome), fluorine hydroxyl Ultracortene-H (triamcinolone), flunisolide (flunisolide) and dexamethasone (dexamethasone)).Chemistry:
In general, compound of the present invention is that skilled person's reagent known and that use synthesizes in standard technique and the prior art by using.Should be noted that the keyed jointing group (linkage) between each functional group generally comprises the nitrogen with acid amides or carbamate, the carbon of the carbon phase keyed jointing of the oxygen of carbamate or carbonyl.Those of ordinary skill will recognize that in the art, and the method and the reagent that form these keys are well-known and are to realize easily and acquisition.Referring to, for example, March, modern organic chemistry, the 4th edition (Wiley 1992), Larock, Comprehensive Organic Transformations (VCH 1989); With people such as Furniss, Vogel ' s Textbook of Practical Organic Chemical, the 5th edition (Longman1989), it is for reference all to be introduced into this paper.
X wherein
4And X
5Shi oxazole-2-base, the compound of the adjacent member's of 1H-imidazoles-2-base or thiazol-2-yl ring formula I can be prepared by the method that following reaction mechanism is described:
Wherein L is a leavings group, and D comprises monocycle or the condensed-bicyclic divalent group that contains 5-15 ring atom with the vinylidene part that condenses up, and wherein each ring is a heteroatoms with containing 5-7 ring atom and each ring atom arbitrariness, R
29Be-OH-NHR
6Or-SH, X
8Be-O--NR
6-or-S-and n2, n3, n4, A, B, X
1, X
2, X
3, X
5, R
1, R
2, R
3, R
4And R
6Identical with the definition in the general introduction of the present invention.
X wherein
4And X
5Shi oxazole-2-base; the compound of the adjacent member's of 1H-imidazoles-2-base or thiazol-2-yl ring formula I (structural formula I (a)) can be by allowing the compound of formula 1 or compound or its protected derivative of its protected derivative and formula 2 react; if the words that need are gone protection, prepare then.Reaction between the compound of formula 1 and 2 can be carried out in pure mode, but preferably 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (DMPU) or polyphosphoric acid exist down, at 160-200 ℃, carry out under the temperature between preferred 180-190 ℃, and needed finish in 1-5 hour (for example, referring to embodiment 4 (d), 6 (h), 8 (k), 9 (d) and 10 (d), infra.).Going to protect can be by removing blocking group and carrying out (for example, referring to embodiment 2 (g), infra.) with any way that reasonable productive rate obtains required product.
In a comparable manner, X wherein
1And X
2Shi oxazole-2-base, the adjacent member's of 1H-imidazoles-2-base or thiazol-2-yl ring formula I compound can be prepared by the described method of following reaction mechanism:
Wherein L is a leavings group, R
30Be-OH-NHR
5Or-SH, X
8Be-O--NR
6-or-S-and n2, n3, n4, B, C, X
1, X
3, X
4, X
5, R
1, R
2, R
3, R
4And R
6Identical with the definition in the general introduction of the present invention (for example, referring to embodiment 2 (e) and 7 (h), infra.).
Compound described here and intermediate separate and purification (if desired) can be undertaken by any suitable segregation or method of purification, for example, filter, extraction, crystallization, column chromatography, thin-film chromatography or thin-layer chromatography, the combination of high pressure liquid chromatography (HPLC) or these methods.The suitable separation and the certain illustrated of isolation process can be with reference to the following examples.Yet separation that other is equal to or segregation program can be used certainly.Go up record nuclear magnetic resonance spectrum (NMR) at General Electirc " QE Plus " spectrometer (300MHz).Already change IR (FTIR) at Perkin-Elmer 1600 Fouriers and go up record IR spectrum.(the last HPLC of Inc. analyzes and carries out for the UltrafastMicroProtein Analyzer of 1mm * 150mm), Michrom BioResources in that the PLRP post is housed.By using VYDAC 1 * 25cm C
18Anti-phase (RP) post is on Gilson LC or by using Vydac 5 * 25cm C
18The RP post is being prepared property HPLC in Waters Prep LC2000 system.Mass spectrum (MS) is to be equipped with on the Finnigan SSQ 710 in ESI source by direct perfusion (infusion) or by HPLC MS (Ultrafast Microprotein Analyzer, C
18Post 2mm * 150mm) obtain.Except as otherwise noted, all reagent and device are to make or buy from supplier there according to disclosed schedule of operation, as Aldrich ChemicalCo. (Milwaukee, WI), Sigma Chemical Co. (St.Louis, MO) and ICNChemical Co. (Irvine, CA).Be used to carry out synthetic technology described below generally can be known by those of ordinary skill in the art (referring to, for example, March, Larock, or Furniss, Supra).
The addition method of the compound of preparation formula I:
The compound of formula I can be by free alkali form formula I compound and pharmaceutically acceptable inorganic or organic acid reaction prepare as pharmaceutically acceptable acid additive salt form.In addition, formula I compound that the pharmaceutically acceptable base addition salt of formula I compound can be by free acid form and pharmaceutically acceptable inorganic or organic bases react and prepare.Inorganic and the organic bronsted lowry acids and bases bronsted lowry that is suitable for the pharmacologically acceptable salt of preparation I compound is listed in the application's the definitional part.In addition, the salt form of formula I compound can prepare by salt or the intermediate that uses initial substance.
The formula I compound of free acid or free alkali form can be from corresponding base addition salt or acid salt preparation.For example, the formula I compound of acid salt form can be by being converted to corresponding free alkali with suitable alkali (for example solution of ammonium hydroxide, sodium hydroxide etc.) reaction.The formula I compound of base addition salt form can be by being converted to corresponding free acid with suitable acid (for example hydrochloric acid etc.) reaction.
The N-oxide compound of formula I compound can be prepared by the known method of those of ordinary skill in the art.For example, the N-oxide compound can be by using oxygenant (for example, trifluoroperacetic acid, cross toxilic acid, peroxybenzoic acid, peracetic acid ,-chlorine peroxybenzoic acid etc.) handle under about 0 ℃ in suitable inert organic solvents (halogenated hydrocarbon such as methylene dichloride) not that the formula I compound of oxidised form prepares.In addition, the N-oxide compound of formula I compound can be from the N-oxide compound preparation of suitable starting raw material.
The formula I compound of oxidised form can be by at suitable inert organic solvents (acetonitrile for example, ethanol, aqueous diox, etc.) at 0-80 ℃ down (for example with reductive agent, sulphur, sulfurous gas, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide etc.) handle, from the N-oxide compound preparation of formula I compound.
The prodrug derivant of formula I compound can be by the known method preparation of those of ordinary skill in the art (for example, referring to embodiment 12, infra.).About the details of prodrug and its preparation method sees also people such as Saulnier (1994), Bioorganic and Medical ChemistryLetters, 4:1985).
The protected derivative of formula I compound can be by the known method preparation of those of ordinary skill in the art.Being described in detail of relevant technologies that can be used for producing blocking group and removing blocking group can see T.W.Greene, Protective Groups in Organic Synthesis (protecting group in the organic synthesis), John Wiley ﹠amp; Sons, Inc.1981.
Formula I compound can form a pair of diastereomeric compound by the racemic mixture of this compound and the reagent react of optically active, diastereomer is disassembled and reclaimed the pure enantiomer of opticity, make as their stereoisomer forms separately.The covalent linkage diastereomer derivative that can use formula I compound of disassembling of enantiomer carries out, and separable mixture is preferred (for example crystalline diastereomeric salt).Each diastereomer has the physicals (for example fusing point, boiling point, solubleness, reactive behavior etc.) of obvious boundary and can utilize these non-similarities easily to separate.Diastereomer can be by chromatography or is preferably separated by the separation/disassembling technology based on dissolubility difference.The enantiomer of this optical purity is reclaimed by any practicable mode of racemization that do not cause together with disassembling agent.More being described in detail of technology that is used for disassembling out from racemic mixture the steric isomer compound can see Jean Jacques Andre Collet, Samuel H.Wilen, enantiomer, raceme and disassemble Honh, Wiley ﹠amp; Sons, Inc. (1981).
Generally speaking, one aspect of the invention is the method for preparation I compound, and this method comprises: (a) allow the compound of formula 1
Or its protected derivative, with the compound of formula 2
Or its protected derivative reacts; wherein L is a leavings group; D comprises monocycle or the condensed-bicyclic divalent group that contains 5-15 ring atom with the vinylidene part that condenses up, and wherein each ring is a heteroatoms with containing 5-7 ring atom and each ring atom arbitrariness, R
29Be-OH-NHR
6Or-SH, and n1, n2, n3, A, B, X
1, X
2, X
3, R
1, R
2, R
3, R
4And R
6Identical with the definition in the general introduction of the present invention, then, if necessary, go protection and obtain wherein X
4And X
5Shi oxazole-2-base, the adjacent member's of 1H-imidazoles-2-base or thiazol-2-yl ring formula I compound; Or
(b) allow the compound of formula 3
Or its protected derivative, with the compound of formula 4
Or its protected biology that spreads out reacts, and wherein L is a leavings group, R
30Be-OH-NHR
5Or-SH, and n1, n2, n3, B, C, X
3, X
4, X
5, R
1, R
2, R
3, R
4And R
5Identical with the definition in the general introduction of the present invention, then, if necessary, go protection and obtain wherein X
1And X
2Shi oxazole-2-base, the adjacent member's of 1H-imidazoles-2-base or thiazol-2-yl ring formula I compound;
(c) optionally formula I compound is changed into pharmacologically acceptable salt;
(d) optionally the formula I compound of salt form is changed into salt-independent shape;
(e) optionally the formula I compound of non-oxidised form is changed into pharmaceutically useful N-oxide compound;
(f) optionally the N-oxygenate conversion of formula I compound is become its non-oxidised form;
(g) optionally will be not deutero-formula I compound change into its pharmaceutically acceptable prodrug derivant; With
(h) optionally the prodrug derivant of formula I compound is changed into its not derivative form.
Embodiment
The following examples only are provided for illustrative purposes and never think the scope of the present invention that limits.The skilled person will recognize that in the scope of the invention and in fact can do some changes and improvements in the art.
Embodiment 1
2-naphthalene-2-base ethylamine
2-naphthalene-2-base ethanol (0.5g; 2.9mmol) solution in dry DMF (5ml) under nitrogen atmosphere with diphenyl phosphoryl azide (0.74ml; 3.42mmol) and 1, (0.47ml 3.14mmol) mixes 8-diazabicyclo [5.4.0] 11 carbon-7-alkene.Mixture heated 3 hours down at 65 ℃ then, distributed between water and ether then.Isolate water layer and use extracted with diethyl ether.The organic phase that merges is with 3N salt acid elution and wash dry (MgSO then with saturated sodium bicarbonate solution
4), filter and concentrated by rotary evaporation.Resistates is dissolved among the THF (5ml), then, resulting solution and triphenylphosphine (1g, 3.81mmol) mix, at room temperature stirred 2 hours, dilute with water (0.100ml) stirred 3 hours, obtain throw out with concentrated hydrochloric acid (0.33ml) dilution, with ethanol (5ml) handle and dissolving wherein throw out and handle (interpolation lentamente) with ether and obtain white depositions.White depositions emanates out by filtration, with ether washing and under vacuum drying obtain 2-naphthalene-2-base ethylamine hydrochloride (0.447g, 75% productive rate);
1H-NMR(300Mhz,DMSO-d
6):8.18(brs,3H),7.82-7.88(m,3H),7.74(s,1H),7.38-7.48(m,3H),3.07(m,4H)
With carry out equally among the embodiment 1, the preparation below the intermediate amine:
2-naphthalene-1-base ethylamine, productive rate=56%,
1H-NMR (300Mhz, DMSO-d
6): 8.26 (brs, 3H), 8.16 (d, 1H, J=8.1Hz), 7.92 (dd, 1H, J=1.5,7.8Hz), 7.81 (dd, 1H, J=1.2,7.5Hz), 7.40-7.56 (m, 4H), 3.37 (m, 2H), 3.05 (t, 2H, J=7.4Hz)
3-cyclohexyl propyl group amine, productive rate=40%,
1H-NMR (300Mhz, CDCL
3): 2.68 (t, 2H, J=7.2Hz), 2.17 (brs, 2H), 1.64-1.71 (m, 5H), 1.46 (m, 2H), 1.18 (m, and 6H) 0.87 (m, 2H);
3-phenyl-2-propenyl amine, productive rate=53%,
1H-NMR (300Mhz, DMSO-d
6): 8.39 (brs, 3H), 7.26-7.41 (m, 5H), 6.72 (d, 1H, J=16.2Hz), 6.29 (dt, 1H, J=16.2,6.6Hz), 3.56 (d, 2H, J=6.6Hz);
3-phenyl-2-propynyl amine, productive rate=62%,
1H-NMR (300Mhz, DMSO-d
6): 8.67 (brs, 2H), 7.38-7.42 (m, 5H), 3.91 (m, 2H); And
3,3-diphenyl propyl amine, productive rate=50%,
1H-NMR (300Mhz, DMSO-d
6): 8.10 (brs, 3H), 7.30 (m, 8H), 7.19 (m, 2H), 4.11 (t, 1H, J=7.9Hz), 2.62 (m, 2H) 2.33 (m, 2H).
Embodiment 2
2-(5-amino methyl)-1H-benzimidazolyl-2 radicals-ylmethyl)-N-(4-phenyl butyl)-1H-benzoglyoxaline-5-carboxylic acid amides trifluoroacetate
(compound 1)
(a) (8ml, 75mmol) (6ml 105mmol) mixes under nitrogen atmosphere for solution in dry-out benzene (100ml) and dehydrated alcohol with ethyl cyanacetate.Mixture is cooled to 10 ℃ (ice/acetone) and with dry hydrogen chloride gas air blowing bubbling 20 minutes.Mixture rises to room temperature lentamente, seals and stirs about 18 hours.Mixture dilutes (400ml) and at room temperature leaves standstill with ether and obtained crystalline solid in 5 hours.By filtering to isolate solid, with the anhydrous diethyl ether washing several times and in addition dry, obtain 3-oxyethyl group-3-imino-ethyl propionate (13.2g, 90% productive rate), be the colourless crystallization solid;
1H-NMR (300Mhz, CDCL
3): 7.84 (d, 1H, J=10.0Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J=5.7Hz), 2.73 (t, 2H, J=6.5Hz), 1.89 (m, 4H).
(b) 3, (9.4g, 62mmol), the mixture of 3-oxyethyl group-3-imino-ethyl propionate and glacial acetic acid (15ml) was stirring 30 minutes under nitrogen atmosphere under 110 ℃ the 4-diaminobenzoic acid.Mixture is poured onto on the trash ice (50ml) and stirs and obtained deep yellow oil in 30 minutes.Mixture adds ether (25ml) when being stirred, and obtains the gray precipitate thing.Throw out comes out by filtering separation, with ether washing several times and dry under vacuum, obtains 2-ethoxy carbonyl methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid (12.6g, 83% productive rate);
1H-NMR (300Mhz, DMSO-d
6): 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J=8.4Hz), 7.57 (d, 1H, J=8.4Hz), 4.11 (q, 2H, J=7.1Hz), 4.02 (s, 2H), 1.17 (t, 3H, J=7.1Hz).
(c) dinitrophenyl methyl alcohol (22g, 111mmol), triphenylphosphine (34.5g, 131mmol) and phthalic imidine (17.6g, 119mmol) mixture in THF (450ml) stirs under nitrogen atmosphere under-10 ℃ (ice/acetone), and drip simultaneously the diethylazodicarboxylate (20.7ml, 131mmol).Mixture stirred 2 hours down at-10 ℃, then with ether dilution (900ml) with left standstill under-20 ℃ about 18 hours, obtained crystalline solid.Solid by filtration is separated and is washed, and obtains 2-(3,4-dinitrobenzene benzyl) isoindole-1, and 3-diketone (24.6g, 67% productive rate) is the colourless crystallization solid;
1H-NMR (300Mhz, DMSO-d
6): 7.87-7.94 (m, 5H), 7.74-7.82 (m, 2H), 4.96 (s, 2H).
(d) 2-(3,4-dinitrobenzene benzyl) isoindole-1,3-diketone (8g, 24.4mmol), in embodiment 1, make, with the mixture of 10% palladium/carbon (300mg) again with dehydrated alcohol (200ml), anhydrous THF (100ml) and glacial acetic acid (30ml) are mixing under the nitrogen gas stream continuously.Mixture is vigorous stirring 15 hours under hydrogen atmosphere at room temperature then, filters and is concentrated into about 30ml volume by the rotary evaporation method.Mixture is dilute with water (100ml) then, adds ammonium hydroxide, obtains the orange throw out.By filtering to isolate throw out and washing with water several times, obtain 2-(3,4-diamino benzyl) isoindole-1,3-diketone (6g, 91%);
1H-NMR (300Mhz, DMSO-d
6): 7.76-7.85 (m, 4H), 6.31-6.43 (m, 3H), 4.51 (broad s, 4H) .4.47 (s, 2H)
(e) 2-(3,4-diamino benzyl) isoindole-1, and the 3-diketone (2.0g, 7.5mmol) and (0.93g, the mixture that fine grinding 3.75mmol) the is crossed heating 1 hour under 185 ℃ and nitrogen atmosphere of 2-ethoxy carbonyl methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid.Mixture is suspended in 1: 1 methylene dichloride/ethanol (20ml) and vigorous stirring 1 hour then.Solid by filtration is collected, (3 * 20ml) washings and drying obtained 2-[5-(1 with 1: 1 methylene dichloride/ethanol, 3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-1H-benzoglyoxaline-5-carboxylic acid (0.98g, 29% productive rate);
1H-NMR (300Mhz, DMSO-d
6): 12.45 (broad s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J=7.5Hz) .7.43 (s, 1H), 7.11 (d, 1H, J=7.2Hz), 4.82 (s, 2H), 4.48 (s, 2H).
(f) 2-[5-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-1H-benzoglyoxaline-5-carboxylic acid (0.05g, 0.111mmol) be dissolved in the anhydrous dimethyl formamide (0.5ml), the solution of gained and I-hydroxybenzotriazole hydrate (0.017g, 0.126mmol), benzotriazole-1-base oxygen base tripyrrole alkyl phosphorus hexafluorophosphate (0.063g, 0.121mmol) and N-methylmorpholine (0.013ml 0.118mmol) mixes under room temperature and dry nitrogen atmosphere.After 2 minutes, (0.02ml, 0.127mmol), mixture at room temperature stirred 2 hours to add 4-phenyl butyl amine.Mixture is transferred to and contains 20% ethanol/ethyl acetate solution (7ml), in the aqueous solution separating funnel of 0.2N HCl (3.5ml) and saturated NaCl (3.5ml).Water extracts once with 20% ethanol/ethyl acetate solution (7ml), and the organic phase of merging is used in the solution washing that contains 0.2N HCl (3.5ml) in the saturated sodium-chloride water solution (3.5ml), uses saturated sodium bicarbonate aqueous solution (7ml) washing at last.Organic phase is used anhydrous sodium sulfate drying then, filter and on rotatory evaporator, concentrate, obtain 2-[5-(1,3-dioxo-1,3-xylylenimine-2-the ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl of thick material form]-N-(3-phenyl propyl)-1H-benzoglyoxaline-5-carboxylic acid amides (0.14g).
(g) with 2-[5-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-N-(3-phenyl propyl)-1H-benzoglyoxaline-5-carboxylic acid amides (0.14g coarse raw materials) is dissolved in the dehydrated alcohol (0.5ml), (0.15ml 0.48mmol) mixes for resulting solution and anhydrous hydrazine.Mixture under refluxad heated under N2 1 hour, concentrated on rotatory evaporator then.Resistates (0.15 torr) under vacuum leaves standstill 2 hours to remove excessive hydrazine.Resistates dilutes with 3MHCl (0.5ml), and mixture heated 20 minutes down at 50 ℃.Reaction mixture is cooled to room temperature and stirred other 20 minutes, obtains solid sediment.Throw out comes out by filtering separation and washes (4 * 1.5ml) with water.Filtrate is merged, and uses (2 * 7ml) washings of 20% ethanol/ethyl acetate solution then.The water that merges is obtained the crude product of hydrochloride form by freeze-drying.Thick material is purified by preparation property reversed-phase HPLC and is obtained 2-[5-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-(0.04g 0.07mmol), is white solid to N-(3-phenyl propyl)-1H-benzoglyoxaline-5-carboxylic acid amides;
1H-NMR (300Mhz, CD
3OD): 8.14 (s, 1H), 7.84-7.89 (m, 2H), 7.77 (d, 1H, J=8.1Hz), 7.71 (d, 1H, J=8.1Hz), 7.56 (d, 1H, J=8.1Hz), 7.12-7.27 (m, 5H), 4.29 (s, 2H), 3.43 (t, 2H, J=7.2Hz), 2,66 (t, 2H, J=7.2Hz), 1.69 (m, 4H).
With the same carrying out among the embodiment 2, prepare following compound of the present invention:
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-naphthalene-1-ylmethyl-1H-benzoglyoxaline-5-carboxylic acid amides (compound 2),
1H-NMR (300Mhz, CD
3OD): 8.13 (m, 2H), 7.88 (m, 2H), 7.80 (m, 2H), 7.73 (d, 1H, J=7.9Hz), 7.67 (d, 1H, J=7.9Hz), 7.38-7.54 (m, 5H), 5.01 (s, 2H), 4.26 (s, 2H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-benzyl-1H-benzoglyoxaline-5-carboxylic acid amides (compound 3),
1H-NMR (300Mhz, CD
3OD): 8.18 (s, 1h), 7.91 (d, 1H, J=7.9Hz), 7.82 (s, 1H), 7.76 (d, 1H, J=7.9), 7.72 (d, 1H, J=7.9Hz), 7.54 (d, 1H, J=7.9Hz), 7.23-7.38 (m, 5H), 4.60 (s, 2H), 4.28 (s, 2H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-phenyl propyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 4),
1H-NMR (300Mhz, CD
3OD): 8.14 (s, 1H), 7.87 (d, 1H, J=8.6Hz), 7.8 (s, 1H), 7.76 (d, 1H, J=8.6Hz), 7.71 (d, 1H, J=8.6Hz), 7.54 (d, 1H, J=8.6Hz), 7.24 (m, 4H), 7.16 (m, 1H), 4.28 (s, 2H), 3.46 (t, 2H, J=7.9Hz), 2.95 (t, 2H, J=7.9Hz), 1.62 (quintet, 2H, 7.9Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-phenylethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 5),
1H-NMR (300Mhz, DMSO-d
6): 8.12 (s, 1H), 7.83 (m, 2H), 7.78 (d, 1H, J=9.3Hz), 7.71 (d, 1H, J=9.3Hz), 7.55 (d, 1H, J=9.3Hz), 7.29 (m, 4H), 7.22 (m, 1H), 4.29 (s, 2H), 3.65 (t, 2H, J=7.9Hz), 2.95 (t, 2H, J=7.9Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-amino methyl) benzyl-1H-benzoglyoxaline-5-carboxylic acid amides (compound 6),
1H-NMR (300Mhz, DMSO-d
6): 9.31 (t, 1H, J=5.7Hz), 8.58 (brs, 3H), 8.41 (brs, 3H), 8.28 (s, 1H), 7.97 (m, 2H), 7.79 (d, 1H, J=9.3Hz), 7.75 (d, 1H, J=9.3Hz), 7.59 (d, 1H, J=9.3Hz), 7.43 (s, 1H), 7.35 (s, 3H), 5.07 (s, 2H), 4.50 (m, 2H), 4.18 (m, 2H), 3.97 (m, 2H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-amino-ethyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid amides (compound 7),
1H-NMR (300Mhz, DMSO-d
6): 8.86 (br, 1H), 8.50 (brs, 3H), 8.24 (s, 1H), 8.08 (brs, 3H), 7.93 (m, 2H), 7.77 (d, 1H, J=8.7Hz), 7.55 (d, 1H, J=9.2Hz), 5.02 (br, s, 2H), 4.16 (m, 2H), 3.94 (s, 2H), 3.50 (m, 2H), 2.96 (m, 2H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-amino-ethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 8),
1H-NMR (300Mhz, DMSO-d
6): 8.97 (t, 1H, J=4.3Hz), 8.58 (brs, 3H), 8.31 (s, 1H), 8.16 (brs, 3H), 7.97 (m, 2H), 7.79 (d, 1H, J=10Hz), 7.73 (d, 1H, J=10Hz), 7.59 (d, 1H, J=10Hz), 5.09 (s, 1H), 4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m, 2H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(the amino butyl of 4-)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 9),
1H-NMR (300Mhz, DMSO-d
6): 8.77 (t, 1H, J=5.7Hz), 8.61 (brs, 3H), 8.24 (s, 1H), 7.90-8.02 (m, 5H), 7.78 (d, 1H, J=9.3Hz), 7.74 (d, 1H, J=9.3Hz), 7.60 (d, 1H, J=9.3Hz), 5.09 (s, 1H), 4.18, (m, 2H), 3.28 (m, 2H), 2.78 (m, 2H), 1.12 (m, 4H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-aminopropyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 10),
1H-NMR (300Mhz, DMSO-d
6): 8.9 (t, 1H, J=5.0Hz), 8.53 (brs, 3H), 8.23 (s, 1H), 7.97 (brs, 3H), 7.94 (s, 1H), 7.89 (d, 1H, J=8.6Hz), 7.78 (d, 1H, J=8.6Hz), 7.71 (d, 1H, J=8.6), 7.57 (d, 1H, J=8.6Hz), 5.03 (s, 2H (, 4,40 (m, 2H), 3,34 (m, 2H), 2.81 (m, 2H), 1.81 (m, 2H); With
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-cyclohexyl methyl-1H-benzoglyoxaline-5-carboxylic acid amides (compound 11),
1H-NMR (300Mhz, CD
3OD): 8.15 (s, 1H), 7.88 (d, 1H, J=7.6Hz), 7.84 (s, 1H), 7.76 (d, 1H, J=7.6hz), 7.72 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 4.29 (s, 2H), 3.26 (d, 2H, J=7.2Hz), 1.64-1.86 (m, 6H), 1.20-1.37 (m, 3H), 0.95-1.09 (m, 2H).
Embodiment 3
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-aminopropyl)-1-methyl-
1H-benzoglyoxaline-5-carboxylic acid amides
(compound 12)
(a) comprise that in sealed tube (1.3g, 6.45mmol), the mixture of 10% methylamine and water (10ml) heated 11 hours down at 100 ℃ 3-nitro-4-chloro-benzoic acid, was concentrated into 1ml and then with the concentrated hydrochloric acid dilution, obtained yellow mercury oxide.Throw out separates by filtration, washes with water and washs with ether then, obtains 3-nitro-4-methyl benzaminic acid (2.1g, 86% productive rate) after the drying;
1H-NMR (300Mhz, CDCL
3): 8.56 (d, 1H, J=2.1Hz), 8.52 (q, 1H, J=8.6Hz), 7.94 (dd, 1H, 9.3,2.1Hz), 7.00 (d, 1H, J=9.3Hz), 2.97 (d, 3H, J=8.6Hz).
(b) ethanol (100ml) is joined contain 3-nitro-4-methyl benzaminic acid (2.09g, 10.7mmol) and 10%Pd/C (30mg), be connected with in the flask of stablizing nitrogen gas stream.Mixture is stirred 16 hours under hydrogen atmosphere, filter by micropore 0.22um type GV filter, concentrates on rotatory evaporator then.Resistates is dry under vacuum, obtains 3-amino-4-methylamino phenylformic acid (1.1g, 61% productive rate).
(c) allow 3-oxyethyl group-3-imino-ethyl propionate of making among the embodiment 2 (a) and 3-amino-4-methylamino phenylformic acid with embodiment 2 (b) in similarly react under the condition, obtain 2-ethoxy carbonyl methyl isophthalic acid-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid (71% productive rate);
1H-NMR (300Mhz, DMSO-d
6): 7.18 (dd, 1H, J=8.1Hz), 7.11 (d, 1H, J=1.2Hz), 6.33 (d, 1H, J=8.1Hz), 5.28 (brs, 1H), 4.67 (brs, 1H), 3.34 (brs, 2H), 2.72 (s, 3H).
(d) 2-(3,4-diamino benzyl) isoindole-1, the 3-diketone, in embodiment 2 (d), make, with 2-ethoxy carbonyl methyl isophthalic acid-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid with embodiment 2 (e) in similarly react under the condition, obtain 2-[5-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid (48% productive rate);
1H-NMR (300Mhz, DMSO-d
6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H, J=10.0Hz), 7.40 (brs, 2H), 7.10 (brs, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 3.79 (s, 3H).
(e) with 2-[5-(1; 3-dioxo-1; 3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid (0.05g; 0.108mmol); I-hydroxybenzotriazole (0.016g, 0.118mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.023g; 0.12mmol) and 1, the derivative of the list of 3-diaminopropanes-BOC protection is dissolved under 0 ℃ among methylene dichloride (1ml) and the DMF (being enough to the dissolved minimum quantity).Solution is adjusted to PH~8 with N-methylmorpholine, and mixture slowly is warming up to room temperature, stirs then 20 hours.Mixture is transferred in the separating funnel, with the methylene dichloride dilution, with the washing of 0.1N hydrochloric acid soln with then with the saturated sodium bicarbonate solution washing, uses dried over sodium sulfate, filters and concentrates.Resistates is purified by preparation property TCL (10% methanol/ethyl acetate), obtain 2-[6-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-1-methyl-N-(3-aminopropyl)-1H-benzoglyoxaline-5-carboxylic acid amides (0.02g, 28% productive rate);
1H-NMR (300Mhz, CDCL
3): 7.75-7.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (brs, 1H), 7.27 (d, 1H, J=8.6Hz), 7.15 (d, 1H, J=9.3Hz), 5.10 (br, 1H), 4.90 (brs, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (q, 2H, J=7.2Hz), 3.24 (q, 2H, J=7.2Hz), 1.72 (m, 2H), 1.41 (s, 9H);
(F) 2-[6-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-1-methyl-N-(3-aminopropyl)-1H-benzoglyoxaline-5-carboxylic acid amides with embodiment 2 (g) in similarly gone protection under the condition, obtain 2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-aminopropyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid amides (20% productive rate);
1H-NMR (300Mhz, DMSO-d
6): 8.85 (t, 1H, J=5.7Hz), 8.55 (brs, 3H), 8.20 (s, 1H), 8.01 (brs, 3H), 7.74 (m, 2H), 7.80 (d, 1H, J=6.6Hz), 5.07 (s, 2H), 4.16 (m, 2H), 3.96 (s, 3H), 3.32 (m, 2H), 2.79 (m, 2H), 1.80 (m, 2H).
With carry out equally among the embodiment 3, prepare of the present invention below compound:
3-[2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-1-base ethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 13);
1H-NMR (300Mhz, CD
3OD): 8.25 (d, 1H, J=8.1Hz), 8.09 (s, 1H), 7.67-7.86 (m, 6H), 7.37-7.54 (m, 5H), 4.27 (s, 2H), 3.73 (t, 2H, J=7.4Hz), 3.41 (t, 2H, J=7.4Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3, the 3-diphenyl propyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 14);
1H-NMR (300Mhz, CD
3OD): 8.11 (s, 1H), 7.77-7.86 (m, 3H), 7.70 (d, 1H, J=9.3), 7.56 (d, 1H, J=9.3Hz), 7.23-7.39 (m, 8H), 7.13-7.19 (m, 2H), 4.30 (s, 2H), 4.07 (t, 1H, J=7.2Hz), 3.40 (t, 2H, J=7.2 Hz), 2,44 (q, 2H, J=7.2Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-2-base ethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 15);
1H-NMR (300Mhz, CD
3OD): 8.10 (s, 1H), 7.67-7.86 (m, 8H), 7.55 (d, 1H, J=10.0Hz), 7.38-7.44 (m, 3H), 4.28 (s, 2H), 3.72 (t, 2H, J=7.2Hz), 3.10 (t, 2H, J=7.2Hz);
2-(1H-benzimidazolyl-2 radicals-ylmethyl)-N-[2-(1H-indol-3-yl) ethyl]-1H-benzoglyoxaline-5-carboxylic acid amides (compound 16);
1H-NMR (300Mhz, CD
3OD): 8.09 (s, 1H), 7.81-7.84 (m, 2H), 7.74 (d, 1H, J=8.6Hz), 7.67 (d, 1H, J=8.6Hz), 7.52-7.58 (m, 2H), 7.30 (d, 1H, J=7.9), 7.01-7.08 (m, 2H), 6.94 (t, 1H, J=7.9Hz), 4.26 (s, 2H), 3.68 (t, 2H, J=6.8Hz), 3.06 (t, 2H, J=6.8Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-[2-(5-methoxyl group) indol-3-yl]-1H-benzoglyoxaline-5-carboxylic acid amides (compound 17);
1H-NMR (300Mhz, CD
3OD): 8.10 (s, 1H), 7.81-7.85 (m, 2H), 7.76 (d, 1H, J=8.2Hz), 7.69 (d, 1H, J=8.2Hz), 7.54 (d, 1H, J=8.2Hz), 7.20 (d, 1H, J=8.2Hz), 7.07 (m, 2H), 6.70 (dd, 1H, J=10.0,2.2Hz), 4.27 (s, 2H), 3.65-3.71 (m, 5H), 3.04 (t, 2H, J=7.2Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(2,3,4,5,6-penta hydroxy group hexyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 18);
1H-NMR (300Mhz, CD
3OD/D
2O (1/1)): 8.15 (s, 1H), 7.86-7.90 (m, 2H), 7.83 (d, 1H, J=9.6Hz), 7.77 (d, 1H, J=9.6Hz), 7.61 (d, 1H, J=9.6Hz), 4.32 (s, 2H), 4.01 (m, 1H), 3.62-3.86 (m, 6H), 3.47-3.55 (m, 1H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-phenoxy group ethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 19);
1H-NMR (300Mhz, CD
3OD): 8.16 (s, 1H), 7.88 (d, 1H, J=9.3Hz), 7.84 (s, 1H), 7.76 (d, 1H, J=9.3Hz), 7.71 (d, 1H, J=9.3Hz), 7.55 (d, 1H, J=9.3Hz), 7.23 (2H, J=7.9Hz), 6.85-6.96 (m, 3H), 4.27 (s, 2H), 4.16 (t, 2H, J=6.1Hz), 3.78 (t, 2H, J=6.1Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-phenyl Propargyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 20);
1H-NMR (300Mhz, CD
3OD): 8.18 (s, 1H), 7.91 (d, 1H, J=9.3Hz), 7.84 (s, 1H), 7.76 (d, 1H, J=9.3), 7.71 (d, 1H, J=9.3Hz), 7.55 (d, 1H, J=9.3Hz), 7.38-7.43 (m, 2H), 7.28-7.32 (m, 3H), 4.40 (s, 2H), 4.27 (s, 2H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(E-3-phenyl allyl group)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 21);
1H-NMR (300Mhz, CD
3OD): 8.19 (s, 1H), 7.92 (d, 1H, J=9.3Hz), 7.86 (s, 1H), 7.76 (d, 1H, J=9.3Hz), 7.71 (d, 1H, J=9.3Hz), 7.55 (d, 1H, J=9.3Hz), 7.33-7.39 (m, 2H), and 7.18-7.30 (m, 3H), 6.60 (d, 1H, J=15.8Hz), 6.34 (dt, 1H, J=15.8,6.1Hz), 4.27 (s, 2H), 4.17 (d, 2H, J=6.1Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-cyclohexyl propyl group)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 22);
1H-NMR (300Mhz, CD
3OD): 8.13 (s, 1H), 7.86 (d, 1H, J=9.3Hz), 7.81 (s, 1H), 7.74 (d, 1H, J=9.3Hz), 7.69 (d, 1H, J=9.3Hz), 7.53 (d, 1H, J=9.3Hz), 4.27 (s, 2H), 3.36 (t, 2H, J=7.2Hz), 1.61-1.78 (m, 7H), 1.19-1.32 (m, 6H) .0.90 (m, 2H);
3-[2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-suffering-1-base-1H-benzoglyoxaline-5-carboxylic acid amides (compound 23);
1H-NMR (300Mhz, CD
3OD): 8.13 (s, 1H), 7.86 (d, 1H, J=9.7Hz), 7.82 (s, 1H), 7.74 (d, 1H, J=9.7Hz), 7.69 (d, 1H, J=9.7), 7.49 (d, 1H, J=9.7Hz), 4.27 (s, 2H), 3.39 (t, 2H, J=7.2Hz), 1.64 (m, 2H), 1.26-1.43 (m, 11H), 0.88 (m, 2H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-methyl-N-(2-phenylethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 24);
1H-NMR (300Mhz, CD
3OD): 7.76 (s), 7.69 (d), 7.63 (d), 7.44-7.55 (m), 7.20-7.28 (m), 7.09-7.14 (m), 6.97 (d), 6.85 (br s), 4.19 (s), 3.72 (t), 3.47 (t), 3.22 (s), 3.08 (s), 2.87 (t), 2.76 (t); With
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(1-methyl-3-phenyl propyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 25);
1H-NMR (300Mhz, CD
3OD): 8.05 (s, 1H), 7.79 (d, 1H, J=9.3Hz), 7.75 (s, 1H), 7.68 (d, 1H, J=9.3Hz), 7.63 (d, 1H, J=9.3Hz), 7.46 (d, 1H, J=9.3Hz), 7.09-7.17 (m, 4H), 7.03 (m, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 2.61 (t, 2H, J=7.9Hz), 1.17-1.93 (m, 2H), 1.18 (d, 3H, J=7.2Hz).
Embodiment 4
C-{2-[5-(4-phenyl butoxy)-1H-benzimidazolyl-2 radicals-ylmethyl]
-1H-benzoglyoxaline-5-yl } methylamine
(compound 26)
(a) (1ml, 6.49mmol) (0.26g 6.5mmol) mixes the solution in THF (3ml) 4-phenyl-1-butanols with the sodium hydride of 60% mineral oil dispersion form under drying nitrogen.Mixture vigorous stirring 5 minutes, with 3, (1.3g 6.42mmol) mixes the 4-dinitrochlorobenzene, at room temperature stirs then 10 hours.Mixture is dispensed between ether and the 3N hydrochloric acid.Water layer is separated and with extracted with diethyl ether several times.The organic phase drying (sal epsom) that merges is filtered and is concentrated by rotatory evaporator.Resistates is purified by flash chromatography (9: 1 hexane/ether), obtains 4-(4-phenyl butoxy)-1,2-dinitrobenzene (1.16g, 72% productive rate);
1H-NMR (300Mhz, CDCL
3): 7.84 (d, 1H, J=10.0Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J=5.7Hz), 2.73 (t, 2H, J=6.5Hz), 1.89 (m, 4H).
(b) the 3-oxyethyl group-3-imino-ethyl propionate and the 2-(3 of preparation in embodiment 2 (a), 4-diamino benzyl) isoindole-1, the 3-diketone with embodiment 2 (b) in similarly react under the condition, obtain 5-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-guanidine-acetic acid ethyl ester (71% productive rate);
1H-NMR (300Mhz, DMSO-d
6): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J=9.43Hz), 4.82 (s, 2H), 4.07 (q, 2H, J=7.2Hz), 3.44 (s, 2H), 1.38 (t, 3H, J=7.2Hz).
(c) with embodiment 3 (b) in similarly under the condition with 4-(4-phenyl butoxy)-1, the reduction of 2-dinitrobenzene obtains 4-(4-phenyl butoxy) benzene-1,2-diamines (86% thick productive rate).
(d) 5-(4-phenyl butoxy) benzene-1, the 2-diamines (0.06g, 0.234mmol) and 5-(1,3-dioxo-1,3-xylylenimine-2-ylmethyl)-(0.1g, mixture 0.234mmol) heated 1 hour down at 185 ℃ under nitrogen atmosphere 1H-benzimidazolyl-2 radicals-guanidine-acetic acid ethyl ester.Mixture is suspended in the ether, vigorous stirring 1 hour.Solid by filtration is collected, with the ether washing, and dry, obtain 2-{2-[5-(4-phenyl butoxy)-1H-benzimidazolyl-2 radicals-ylmethyl]-3H-benzoglyoxaline-5-ylmethyl } isoindole-1, the 3-diketone (0.1g, 0.18mmol).
(e) with embodiment 2 (g) similarly under the condition with 2-{2-[5-(4-phenyl butoxy)-1H-benzimidazolyl-2 radicals-ylmethyl]-3H-benzoglyoxaline-5-ylmethyl isoindole-1, the 3-diketone goes protection, obtain C-{2-[5-(4-phenyl butoxy)-1H-benzimidazolyl-2 radicals-ylmethyl]-1H-benzoglyoxaline-5-yl } methylamine (0.05g, 55% productive rate);
1H-NMR (300Mhz, CD
3OD): 7.83 (d, 1H, J=8.6Hz), 7.76 (s, 1H), 7.69 (d, 1H, J=10.0Hz), 7.48 (d, 1H, J=8.6Hz), and 6.99-7.16 (m, 5H), 6.92 (d, 1H, J=10.0Hz), 6.80 (t, 1H, J=7.2Hz), 4,44 (s, 2H), 3.93 (t, 2H, J=6.5Hz), 2.56 (t, 2H, J=7.2Hz), 1.72 (m, 2H).
Embodiment 5
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-1H-benzoglyoxaline
-5-carboxylamine-2-phenylethylester trifluoroacetate
(compound 27)
2-[5-(1; 3-dioxo-1; 3-xylylenimine-2-ylmethyl)-1H-benzimidazolyl-2 radicals-ylmethyl]-1H-benzoglyoxaline-5-carboxylic acid (0.060g; 0.133mmol) at phenylethyl alcohol (0.160ml; 1.34mmol) in solution and diphenyl phosphoryl azide (0.034ml; 0.158mmol) and triethylamine (0.022ml, 0.158mmol) mixing at room temperature under nitrogen atmosphere.Mixture stirred 1 hour down at 120 ℃, be cooled to room temperature and then with ethanol (0.5ml) and hydrazine (0.020ml, 0.637mmol) mixing.Mixture is stirred 45 minutes under 95 ℃, be cooled to room temperature, with 3N hydrochloric acid (0.5ml) dilution.Mixture stirred 20 minutes down at 55 ℃, filtered then.The solid that filters out is used ethyl acetate (15ml) washing with 3N salt acid elution, the filtrate of merging, and freeze-drying.Resistates is purified by preparation property reversed-phase HPLC, obtains required product (0.008g, 11% productive rate);
1H-NMR (300Mhz, CD
3OD): 8.10 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H, J=9.3Hz), 7.63 (d, 1H, J=9.3.Hz), 7.38-7.44 (m, 2H), 7.19-7.32 (m, 5H), 4.36 (t, 2H, J=6.8Hz), 4.23 (s, 2H), 1.98 (t, 2H, J=6.8Hz).
Embodiment 6
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-1-base ethyl)-3-methyl-3H-
Benzoglyoxaline-5-carboxylic acid amides
(compound 28)
(a) comprise 2-nitro-1, the 4-phenylenediamine (21.0g, 137mmol) solution in ethanol (350ml) and 4.0M hydrogenchloride dioxane solution (30.8ml, 123mmol) both solution at room temperature stirred 15 minutes, add ether (1L) then, obtain throw out.Throw out is collected by filtering, and with additional ether washing and vacuum-drying, obtains 2-nitro-1,4-phenylenediamine hydrochloride (23.3g, 100% productive rate).
(b) comprise 2-nitro-1, and 4-phenylenediamine hydrochloride (15.0g, 79.1mmol), cyanamide (25.0g, 595mmol) and the mixture of water (5ml) under 60 ℃, heat and stirred 1.5 hours, be cooled to room temperature and excessive ether added lentamente, obtain throw out.Throw out is collected by filtering, and with additional ether washing and vacuum-drying, obtains N-(4-amino-3-nitrophenyl) guanidinesalt hydrochlorate (18.0g, 98% productive rate);
1H-NMR (300MHz, DMSO-d
6): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d), 7.1 (d).
(c) comprise N-(4-amino-3-nitrophenyl) guanidinesalt hydrochlorate (12.0g, 51.8mmol), 10% palladium/carbon (1.0g), the mixture of tetrahydrofuran (THF) (100ml) and methyl alcohol (100ml) carries out hydrogenation under a normal atmosphere, concentrate under filtration and the vacuum, obtain N-(3, the 4-diamino-phenyl) guanidinesalt hydrochlorate (10.3g, 98% productive rate), be black solid;
1H-NMR (300MHz, DMSO-d
6): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).
(d) comprise N-(3; the 4-diamino-phenyl) the guanidinesalt hydrochlorate (9.9g, 49mmol), the oxyethyl group imido is for formyl radical ethyl acetate hydrochloride (12.4g; 59mmol) and the mixture of acetate (20ml) in 110 ℃ oil bath, heat and stirred 1.5 hours, be cooled to room temperature and vacuum concentration.Resistates is dissolved in the ethanol (15ml), adds ethyl acetate (10ml) then in solution, obtains being in the throw out in the suspension.Suspension filters, and adds filtering ether and obtain second batch of throw out in filtrate.Throw out is collected by filtering, and with additional ether washing and vacuum-drying, obtains 5-guanidine radicals-1H-benzimidazolyl-2 radicals-guanidine-acetic acid carbethoxy hydrochloride (14.1g, 94% productive rate), is the pure white solid;
1H-NMR (300MHz, DMSO-d
6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s), 4.2 (q), 1.2 (t).
(e) in sealed tube, comprise 4-nitro-3-methoxybenzoic acid (5.0g, 25.4mmol) and the methylamine aqueous solution (40%, mixture 15ml) heated 12 hours in 100 ℃ of oil baths, was cooled to room temperature, be poured over then in the stirring what slurry of 1M hydrochloric acid soln and ice, obtain the orange throw out.Throw out is collected by filtering, and with water rinse with from the hot ethanol recrystallization, obtains 3-methylamino-4-nitrobenzoic acid, is light red crystalline solid (3.6g, 73% productive rate);
1H-NMR (300MHz, DMSO-d
6): 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d).
(f) comprise 3-methylamino-4-nitrobenzoic acid (13.0g, 66.3mmol), PyBOP (38.0g, 73.0mmol), hydroxy benzotriazole hydrate (9.9g, 73.0mmol), the mixture of dimethyl formamide (100ml) and N-methylmorpholine (18.3ml) at room temperature stirred 15 minutes, add then 2-naphthalene-1-base ethylamine (13.8g, 66.3mmol).Mixture is stirred other 30 minutes and vacuum concentration.Resistates is dispensed between water and the ethyl acetate, and organic phase water, 0.1M aqueous hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution wash successively, carries out drying (using sal epsom), filters and vacuum concentration.Resistates obtains 3-methylamino-N-(2-naphthalene-1-base ethyl)-4-nitrobenzamide by recrystallization from hot ethanol, is light red crystalline solid (21.3g, 92% productive rate);
1H-NMR (300MHz, DMSO-d
6): 8.8 (t), 8.3 (d), 8.2 (q), 8.1 (d), 7.9 (d), 7.8 (d), 7.6-7.3 (m), 7.2 (s), 7.0 (d), 3.6 (q), 3.3 (t), 3.0 (d).
(g) comprise 3-methylamino-N-(2-naphthalene-1-base ethyl)-4-nitrobenzamide (21.3g, 61mmol), 10% palladium/carbon (1.0g), the mixture of tetrahydrofuran (THF) (100ml) and methyl alcohol (100ml) is hydrogenated under a normal atmosphere, filter and vacuum concentration, obtain 4-amino-3-methylamino-N-(2-naphthalene-1-base ethyl)-4-benzamide (18.4g, 95% productive rate), be the amorphous solid of band look;
1H-NMR (300MHz, DMSO-d
6): 8.3 (d), 8.2 (t), 7.9 (d), 7.8 (d), 7.6-7.4 (m), 7.1 (d), 6.9 (s), 6.5 (d), 5.0 (s), 3.5 (q), 3.2 (t), 2.7 (s).
(h) comprise 5-guanidine radicals-1H-benzimidazolyl-2 radicals-guanidine-acetic acid carbethoxy hydrochloride (0.5g, 1.7mmol), 4-amino-3-methylamino-N-(2-naphthalene-1-base ethyl)-4-benzamide (0.5g, 1.7mmol) and the mixture of dimethyl formamide (2ml) heats in 185 ℃ oil bath and stirred 3.5 hours in nitrogen atmosphere, be cooled to room temperature and be poured over to stir in the acetonitrile (150ml) and obtain throw out.Throw out is collected and vacuum-drying by filtering with additional acetonitrile and ether (150ml) washing, obtains the pure white solid.Solid is purified by preparation property reversed-phase HPLC, obtains 2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-1-base ethyl)-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides, is white solid (0.5g, 57%); LRMS (ESI): for C
30H
28N
8The calculated value of O: 516.6; Measured value (MH
+): 517.2.
Embodiment 7
2-(4-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is also
[4,5-c] pyridine-5-yl }-4-oxo butyl) ethyl benzoate
(compound 29)
(a) (100g, solution 0.29mmol) are cooled to 0 ℃, use dry hydrogen chloride gas saturated then will to comprise the 2-cyanopropionate in ethanol (65ml).Mixture is warming up to room temperature, stirs 24 hours, is cooled to 0 ℃ and saturated with hydrogen chloride gas.Mixture is risen to room temperature and was stirred other 24 hours.With ether: hexane (1: 1) joins and obtains throw out in the mixture.Throw out is separated and vacuum-drying after filtration, obtains 2-(N-oxyethyl group amidino groups) ethyl propionate hydrochloride (119.6g, 73% productive rate), is white solid;
1H-NMR (300MHz, DMSO-d
6): 12.05 (brs, 2H), 4.50 (q, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1.20 (tr, 3H).
(b) will comprise 3, the 4-diamino-pyridine (51.7g, 0.46mmol), 2-(N-oxyethyl group amidino groups) ethyl propionate hydrochloride (125g, 0.69mmol) and the mixture of glacial acetic acid (200ml) under 85 ℃, heat and stirred 18 hours, under 120 ℃, heat then and stirred other 1 hour.Mixture is cooled to room temperature and vacuum concentration.Resistates neutralizes the mixture ethyl acetate extraction by adding excessive 5M ammonium hydroxide aqueous solution.Organic phase is carried out drying (using sal epsom) with the saturated sodium bicarbonate aqueous solution washing with then with the saturated sodium-chloride water solution washing, filters and vacuum concentration, obtains 1H-imidazo [4,5-c] pyridine-2-carboxylic acids ethyl ester (60.4g, 58% productive rate);
1HNMR (300MHz, CDCl
3): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 3.90 (q, 1H), 1.75 (d, 3H), 1.25 (tr, 3H).
(c) (34.7g, 158mmol), the mixture of trifluoroacetic acid (50ml) and platinum oxide (2.5g) is hydrogenation 24 hours under 50psi in the Parr hydrogenation apparatus, filters and vacuum concentration will to comprise 1H-imidazo [4,5-c] pyridine-2-carboxylic acids ethyl ester.The oily resistates is dissolved in the ethanol of minimum quantity, (4M, 120ml 475mmol) join in the solution with the solution in the dry hydrogen chloride Zai diox.Excessive ether joined obtain throw out in the solution.Throw out is collected by filtering, and vacuum-drying obtains 1,4,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-carboxylic acids carbethoxy hydrochloride (30.7g, 66% productive rate);
1H NMR (300MHz, DMSO-d
6): 10.00 (brs, 2H), 4.35 (q, 1H), 4.20 (brs, 2H), 4.10 (m, 2H), 3.35 (m, 2H), 2.90 (brs, 2H), 1.55 (d, 3H), 1.15 (tr, 3H).
(d) will comprise 1,4,6,7-tetrahydrochysene-1H-imidazo [4,5-c] and pyridine-2-carboxylic acids ethyl ester dihydrochloride (60.2g, 0.20mmol), acetonitrile (500ml) and diisopropyl ethyl amine (100ml, 0.60mmol) mixture be cooled to 0 ℃ and slowly adding benzyl chloroformate (58ml stirs in the time of 0.40mol).Mixture is warming up to room temperature lentamente, stirs other 16 hours and vacuum concentration.Resistates is dissolved in the ether (500ml), solution 0.1M aqueous hydrochloric acid, and saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution wash successively, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtain water white oil.Resistates is dissolved in the ethanol (320ml), solution be cooled to 0 ℃ and add lentamente then the solution of Sodium Ethoxide in ethanol (2.6M, 85ml, 0.22mmol).Mixture is stirred 1 hour under 0 ℃, add then solution in the hydrogenchloride Zai diox (4M, 50ml).Mixture is dissolved in ethyl acetate (250ml) and the saturated sodium bicarbonate aqueous solution by vacuum concentration and resistates.Isolate organic phase and, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtain 1 with the saturated sodium-chloride water solution washing, 4,6, the 7-imidazolidine is [4,5-c] pyridine-2 also, 5-dicarboxylic acid 5-benzyl 2-ethyl diester is yellow amorphous substance (52g, 72% productive rate);
1HNMR (300MHz, DMSO-d
6): 11.75 (brs, 1H), 7.30 (s, 5H), 5.10 (s, 2H), 4.40 (brs, 2H), 4.05 (m, 2H), 3.75 (q, 1H), 3.65 (brs, 2H), 1.40 (d, 3H), 1.15 (tr, 3H).
(e) will comprise the 4-chlorobutanoylchloride (12.6g, 89.2mmol), the trimethyl carbinol (25ml), pyridine (6.9g, 86.5mmol) and 4-dimethylaminopyridine (1.0g, mixture 8.2mmol) heated 12 hours down and under the dry nitrogen atmosphere at 50 ℃, obtained white suspension.Suspension is dispensed between ether (250ml) and the water, isolate organic phase and water and use the 0.1M aqueous hydrochloric acid then, saturated aqueous sodium carbonate and saturated sodium-chloride water solution repetitive scrubbing are used anhydrous magnesium sulfate drying, filter and vacuum concentration, obtain water white oil.This oil distills the 4-chloro-butyric acid tert-butyl ester (11.27g, 73% productive rate) that obtains the colourless liquid shape down at 0.5mmHg (51 ℃);
1HNMR (300MHz, CDCl
3): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H).
(f) will comprise salicylic ether (3.14g, 18.9mmol) and cesium carbonate (6.2g, 18.9mmol), (4.08g, mixture 22.8mmol) heat under 70 ℃ and stirred 12 hours for the dimethyl formamide (25ml) and the 4-chloro-butyric acid tert-butyl ester.Mixture is dispensed between ether (100ml) and the water, and organic phase is separated and with additional water (3x) and saturated sodium-chloride water solution washing, uses anhydrous magnesium sulfate drying, filters and vacuum concentration acquisition water white oil.Resistates is by using pure hexane to hexane: ethyl acetate (10: 1) is purified by the silicagel column flash chromatography, obtains 2-(3-tert-butoxycarbonyl propoxy-) ethyl benzoate (3.6g, 62% productive rate), is water white oil;
1HNMR (300MHz, CDCl
3): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).
(g) (3.60g 11.7mmol) at room temperature handles more than 1 hour with excessive trifluoroacetic acid 2-(3-tert-butoxycarbonyl propoxy-) ethyl benzoate.Solution is by vacuum concentration, and the oily resistates is by using (10: 1) hexane: ethyl acetate to absolute ether is purified by the silicagel column flash chromatography, obtains 4-(2-ethoxy carbonyl phenoxy group) butyric acid, colourless crystallization solid (2.81g, 95% productive rate);
1HNMR (300MHz, CDCl
3): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.15 (tr, 2H), 2.65 (tr, 2H), 2.20 (m, 2H), 1.40 (tr, 3H).
(h) will comprise 2-ethoxy carbonyl methyl isophthalic acid, 4,6,7-imidazolidine also [4,5-c] and pyridine-5-carboxylic acid benzyl ester (1.7g, 4.8mmol), N-(3, the 4-diamino-phenyl) the guanidinesalt hydrochlorate (0.8g, 4.0mmol) and the mixture of dimethyl formamide (2ml) heats in 185 ℃ oil bath and stirred in nitrogen atmosphere 2.5 hours.Mixture is cooled to room temperature and is poured over and stirs in the acetonitrile (150ml), obtains throw out.Throw out is with the washing of additional acetonitrile and ether (150ml), by filtering the collecting precipitation thing, and vacuum-drying and obtain the pure white solid.Solid is purified by preparation property reversed-phase HPLC, obtain 2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-carboxylic acid benzyl ester also, is white solid (1.0g, 55% productive rate); LRMS (ESI): for C
24H
26N
8O
2Calculated value: 458.5; Measured value (MH
+): 459.2.
(i) will comprise 2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine also [4,5-c] pyridine-5-carboxylic acid benzyl ester (1.0g, 2.2mmol), 10% palladium/carbon (0.5g), mixture hydrogenation under a normal atmosphere of tetrahydrofuran (THF) (50ml) and methyl alcohol (50ml) is filtered and vacuum concentration, obtain N-{2-[1-(4,5,6,7-imidazolidine also [4,5-c] pyridine-2-yl) ethyl]-1H-benzoglyoxaline-5-yl }-guanidine (0.69g, 97% productive rate); LRMS (ESI): for C
16H
20N
8Calculated value: 324.4; Measured value (MH
+): 325.2.
(j) will comprise 4-(2-ethoxy carbonyl phenoxy group) butyric acid (155mg, 0.61mmol), PyBOP (360mg, 0.69mmol), hydroxy benzotriazole hydrate (87mg, 0.64mmol), N-methylmorpholine (0.16ml, 0.92mmol) and the mixture of dimethyl formamide (2.5ml) at room temperature stirred 10 minutes and add N-{2-[1-(4,5 then, 6, the 7-imidazolidine is [4,5-c] pyridine-2-yl also) ethyl]-3H-benzoglyoxaline-5-yl }-guanidine (203mg, 0.63mmol).Mixture at room temperature stirred 3 hours, vacuum concentration.Resistates is dissolved in 5% acetonitrile solution, and product is purified by preparation property reversed-phase HPLC.The pure fraction that merges is then by freeze-drying, obtain 2-(4-{2-[1-(and the ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-yl also }-4-oxo butyl) ethyl benzoate, LRMS (Bioion): for C
29H
34N
8O
4Calculated value: 558.6; Measured value: 559.3.
Embodiment 8
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-methoxyl group phenoxy group) second
Base]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides
(compound 30)
(a) 2-hydroxyethyl t-butyl carbamate (25ml, 161.6mmol) solution in methylene dichloride (60ml) is cooled to 0 ℃ and at first adding diisopropyl ethyl amine (33.8ml, 193.9mmol) and (13.7ml stirs in the time of 177.8mmol) to drip methylsulfonyl chloride then.Mixture rises to 23 ℃, stirs 18 hours, be poured in the methylene dichloride (200ml) and with aqueous hydrochloric acid (3M, 3 * 25ml) and saturated sodium bicarbonate aqueous solution (2 * 25ml) wash.Isolate organic phase, carry out drying (using sal epsom) and vacuum concentration, obtain the 2-methyl sulphonyl oxygen base ethyl carbamic acid tert-butyl ester (37.39g, 97% productive rate), be brown oil; MS (PB-PCI) C
8H
17NO
5S m/e calculated value 239.08; Measured value 240 (MH
+).
(b) (136g 1.56mmol) is dissolved in 0 ℃ the tetrahydrofuran (THF) with lithiumbromide.Mixture rises to 23 ℃, drip then the 2-methyl sulphonyl oxygen base ethyl carbamic acid tert-butyl ester (37.39g, 156mmol).Mixture is stirred 18 hours and vacuum concentration under 23 ℃.Resistates is dissolved in the hexane, and drying (using sodium sulfate) and vacuum concentration are carried out in organic phase water and salt water washing, and obtaining 2-bromotrifluoromethane t-butyl carbamate (33.48g, 96% productive rate) is brown oil; MS (PB-PCI) C
7H
14BrNO
2M/e calculated value 224.10; Measured value 225 (MH
+).
(c) the 2-methoxyphenol (9.8ml, 89.3mmol), dimethyl formamide (100ml) and salt of wormwood (when 61.5g, mixture 445mmol) stir under 23 ℃, add 2-bromotrifluoromethane t-butyl carbamate (20g, 89.3mmol).Mixture is stirred 24 hours and is poured over ether then: hexane (1: 1,400ml) in, and water (5 * 50ml) washing.The water layer ether: hexane (1: 1,3 * 40ml) extractions, the organic phase of merging be dried (sodium sulfate) and vacuum concentration obtain 2-(2-methoxyl group phenoxy group) the ethyl carbamic acid tert-butyl ester (23.22g, 97% productive rate), yellow oil; MS (PB-PCI) C
14H
21NO
4M/e calculated value 267.32; Measured value 268 (MH
+).
(d) with 2-(2-methoxyl group phenoxy group) the ethyl carbamic acid tert-butyl ester (23.8g 89mmol) is cooled to 0 ℃ and dripping trifluoroacetic acid: methylene dichloride (1: 1, stir in the time of 40ml) mixture.Mixture is warming up to 23 ℃, stirs 2 hours and vacuum concentration.Resistates is dissolved in the methylene dichloride (100ml) again, solution is with saturated sodium bicarbonate aqueous solution (3 * 20ml) and aqueous sodium hydroxide solution (10%, 3 * 20ml) washings, carry out drying (using sodium sulfate), filter and vacuum concentration, obtain 2-(the 2-methoxyl group phenoxy group) ethylamine (13g, 88% productive rate) of light yellow solid form; MS (PB-PCI) C
9H
13NO
2M/e calculated value 167.21; Measured value 168 (MH+).
(e) comprise 3-methoxyl group-4-nitrobenzoic acid (15.42g, 78.2mmol) and thionyl chloride (70ml, non-homogeneous mixture 391mmol) heating 1 hour under refluxing.Remove excessive thionyl chloride by distillation, resistates is carried out vacuum concentration and obtains 3-methoxyl group-4-nitrobenzoyl chloride (16.8g, 99% productive rate), be light yellow solid; MS (PB-PCI) C
8H
6ClNO
4M/e calculated value 215.59; Measured value 216 (MH
+).
(f) will comprise 2-(2-methoxyl group phenoxy group) ethylamine (10g, 59.9mmol), diisopropyl ethyl amine (13.9ml, 81.6mmol) and the mixture of methylene dichloride (80ml) be cooled to 0 ℃, drip 3-methoxyl group-4-nitrobenzoyl chloride (11.76g, 54.4mmol) solution in methylene dichloride then.Make mixture be warming up to 23 ℃ through 2 hours, with aqueous hydrochloric acid (3M, 20ml) quenching, water (3 * 20L) washings, carry out drying (using sodium sulfate) and vacuum concentration, obtain N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methoxyl group-4-nitrobenzamide (14g, 74% productive rate), be the pure white solid; MS (PB-PCI) C
17H
18N
2O
6M/e calculated value 346.34; Measured value 347 (MH
+).
(g) will be encapsulated in comprise N-[2-(2-methoxyl group phenoxy group) ethyl in the sealed tube]-3-methoxyl group-4-nitrobenzamide (4.0g, 11.6mmol), the methylamine aqueous solution (40%, 10ml) and the mixture of DMSO (2ml) 110 ℃ of down heating 4 hours, cooling also is poured in the water (25ml) then.Diluent is handled with the 3M aqueous hydrochloric acid and is obtained the orange solid.Solid by filtration is separated, and obtains N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methylamino-4-nitrobenzamide (3.56g, 89% productive rate); MS (PB-PCI) C
17H
19N
3O
5M/e calculated value 345.35; Measured value 346 (MH
+).
(h) comprise N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methylamino-4-nitrobenzamide (3.56g, 10.3mmol), (10%, 0.5g) mixture of suspension in methyl alcohol (100ml) and tetrahydrofuran (THF) (50ml) stirred 2.5 hours in normal pressure and hydrogen atmosphere palladium/carbon.Mixture filters and makes solution carry out vacuum concentration and obtain 4-amino-N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methylamino benzamide (3.37g, 100% productive rate), be green foam; MS (PB-PCI) C
17H
21N
3O
3M/e calculated value 315.37; Measured value 316 (MH
+).
(i) in the Parr device, comprise 4-amino-3-nitro phenol (5.0g, 32.4mmol), palladium/carbon (10%, 1.0g) and the mixture of methyl alcohol (150ml) under 50psi, be hydrogenated 3 hours, filtering also by Celite (diatomite), vacuum concentration obtains 3,4-diaminophenol (4.02g, 91% productive rate) is dark solid; MS (PB-PCI) C
6H
8N
2O m/e calculated value 124.16g; Measured value 125 (MH
+).
(j) will comprise 3, the 4-diaminophenol (3.661g, 29.5mmol), 2-(N-oxyethyl group amidino groups) ethyl propionate (7.423g, 38.4mmol) and the mixture of ethanol (30ml) heating 6 hours and vacuum concentration then under refluxing.Resistates be dissolved in ethyl acetate (200ml) and resulting solution with saturated sodium bicarbonate aqueous solution (3 * 20ml) and salt solution (1 * 20ml) washs, carry out drying (using sal epsom) and vacuum concentration, and obtain the 2-(ethyl propionate (6.3g of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl), 91% productive rate), be dark solid.Solid is further by flash chromatography on silica gel method purification (100% ethyl acetate); MS (PB-PCI) C
12H
14N
2O
3M/e calculated value 234.28; Measured value 235 (MH
+).
(k) comprise the 2-(ethyl propionate (148mg of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl), 0.63mmol), 4-amino-N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methylamino benzamide (200mg, 0.63mmol) and 1,3-dimethyl-3,4,5, till the mixture of 6-tetrahydrochysene-2 (1H)-pyrimidone (0.5ml) at room temperature was stirred to evenly, outgasing under vacuum and heating under 170 ℃ in nitrogen gas stream concentrated in 2 hours.Resistates is cooled to room temperature also with excessive ether rinse.Resulting amorphous substance is dissolved in 50% acetonitrile solution and by the preparation property reversed-phase HPLC (2-50%CH that purifies
3CN/H
2O), obtain 2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (40mg, 13% productive rate), be shallow magenta solid; MS (BioIon) C
27H
27N
5O
4M/e calculated value 485.59; Measured value 486.5 (MH
+).
With carry out equally among the embodiment 8, prepare of the present invention below compound:
2-(2-{2-[1-(ethyl of 5-fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) methyl benzoate (compound 31), MS (BioIon) C
28H
26N
5O
4Fm/e calculated value 515.54; Measured value 516 (MH
+);
2-(2-{2-[1-(ethyl of 5-fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 32), MS (BioIon) C
27H
24N
5O
4F m/e calculated value 501.52; Measured value 502.1 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 33), MS (BioIon) C
29H
29N
5O
5M/e calculated value 527.58; Measured value 528.1 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 34), MS (BioIon) C
27H
25N
5O
5M/e calculated value 499.53; Measured value 500.1 (MH
+);
N-ethyl 2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 35), MS (BioIon) C
20H
21N
5O
2M/e calculated value 363.42; Measured value 364.1 (MH
+);
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-(2-methoxy ethyl)-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 36), MS (BioIon) C
21H
23N
5O
3M/e calculated value 393.45; Measured value 394.1 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) butyl benzoate (compound 37), MS (BioIon) C
31H
33N
5O
5M/e calculated value 555.64; Measured value 555.7 (MH
+);
3-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-6-[2-(2-methoxyl group phenoxy group) ethylamino formyl radical] benzoglyoxaline-1-yl } propane-1-sulfonic acid (compound 38), MS (LCMS) C
30H
35N
8O
6S m/e calculated value 635.72; Measured value 635.4 (MH
+);
N-[2-(2-ethoxy phenoxy) ethyl]-2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 39), MS (BioIon) C
28H
29N
5O
4M/e calculated value 499.58; Measured value 500.4 (MH
+);
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-isopropoxy phenoxy group) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 40), MS (BioIon) C
29H
31N
5O
4M/e calculated value 513.61; Measured value 514.5 (MH
+);
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-propoxy-phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 41), MS (BioIon) C
29H
31N
5O
4M/e calculated value 513.61; Measured value 514.2 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) propyl benzoate (compound 42), MS (ESI) C
30H
31N
5O
5M/e calculated value 541.61; Measured value 542.2 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid isobutyl (compound 43), MS (BioIon) C
31H
33N
5O
5M/e calculated value 555.64; Measured value 556.3 (MH
+);
4-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } ethyl butyrate (compound 44), MS (BioIon) C
24H
27N
5O
4M/e calculated value 449.51; Measured value 449.9 (MH
+);
4-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } butyric acid (compound 45), MS (BioIon) C
22H
23N
5O
4M/e calculated value 421.46; Measured value 422.1 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) isopropyl benzoate (compound 46), MS (ESI) C
30H
31N
5O
5M/e calculated value 541.61; Measured value 542.2 (MH
+);
N-{2-[2-(1-ethyl propoxy-) phenoxy group] ethyl }-2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 47), MS (BioIon) C
31H
35N
5O
4M/e calculated value 541.65; Measured value 542.5 (MH
+);
2-(2-{2-[1-(ethyl of 5-fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 48), MS (BioIon) C
29H
28N
5O
5Fm/e calculated value 29.57; Measured value 29.5 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid 2-methoxyl group ethyl ester (compound 49), MS (BioIon) C
30H
31N
5O
6M/e calculated value 557.61; Measured value 558.2 (MH
+);
N-(3-methoxy-propyl)-2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 50), MS (BioIon) C
22H
25N
5O
3M/e calculated value 407.47; Measured value 408.0 (MH
+);
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-methoxy methyl phenoxyl) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 51), MS (BioIon) C
28H
29N
5O
4M/e calculated value 499.57; Measured value 499.8 (MH
+);
N-[2-(2-(ethoxymethyl) phenoxyl) ethyl]-2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 52), MS (BioIon) C
29H
31N
5O
4M/e calculated value 513.60; Measured value 514.1 (MH
+);
2-(2-{2-[1-(ethyl of 6-fluoro-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 53), MS (ESI) C
29H
28N
5O
5F m/e calculated value 545.57; Measured value 546.3 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) naphthenic acid ethyl ester (compound 54), MS (BioIon) C
29H
35N
5O
5M/e calculated value 533.63; Measured value 534 (MH
+);
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-propoxy-methylphenoxy) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 55), MS (BioIon) C
30H
33N
5O
4M/e calculated value 527.62; Measured value 527.6 (MH
+);
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-isopropoxy methylphenoxy) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 56), MS (BioIon) C
30H
33N
5O
4M/e calculated value 527.62; Measured value 527.9 (MH
+);
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-{2-[2-(2-methoxy ethoxy methyl) phenoxy group] ethyl }-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 57), MS (BioIon) C
30H
33N
5O
5M/e calculated value 543.62; Measured value 543.4 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-methoxy methyl phenoxyl) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 58), MS (BioIon) C
28H
29N
5O
3M/e calculated value 483.57; Measured value 484 (MH
+);
N-[2-(2-(ethoxymethyl) phenoxyl) ethyl]-2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 59), MS (BioIon) C
29H
31N
5O
3M/e calculated value 497.6; Measured value 498.3 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-propoxy-methylphenoxy) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 60), MS (BioIon) C
30H
33N
5O
3M/e calculated value 511.62; Measured value 511.5 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-isopropoxy methylphenoxy) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 61), MS (BioIon) C
30H
33N
5O
3M/e calculated value 511.62; Measured value 511.6 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-N-{2-[2-(2-methoxy ethoxy methyl) phenoxy group] ethyl }-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 62), MS (BioIon) C
30H
33N
5O
4M/e calculated value 527.62; Measured value 527.7 (MH
+);
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-morpholine-4-phenoxyl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 63), MS (BioIon) C
30H
32N
6O
4M/e calculated value 540.73; Measured value 541.8 (MH
+);
N-(2-phenyl sulfonyl ethyl)-2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 64), MS (BioIon) C
26H
25N
5O
4S m/e calculated value 503.5; Measured value 504.2 (MH
+);
2-(2-{2-[1-(ethyl of 6-fluoro-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 65), MS (ESI) C
27H
24N
5O
5Fm/e calculated value 517.52; Measured value 518.2 (MH
+);
2-hydroxyl-5-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } ethyl benzoate (compound 66), MS (BioIon) C
27H
25N
5O
5M/e calculated value 499.52; Measured value 500.2 (MH
+);
2-[1-(ethyl of 5-fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-morpholine-4-phenoxyl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 67), MS (BioIon) C
30H
31N
6O
3F m/e calculated value 542.62; Measured value 543.4 (MH
+);
N-(2-phenyl sulfonyl ethyl)-2-[1-(ethyl of 5-fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 68), MS (BioIon) C
26H
24N
5O
3FS m/e calculated value 505.58; Measured value 506.5 (MH
+);
2-(2-{2-[1-(4, the ethyl of 6-two fluoro-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 69), MS (BioIon) C
29H
27N
5O
5F
2M/e calculated value 563.52; Measured value 563.4 (MH
+);
2-(2-{2-[1-(4, the ethyl of 6-two fluoro-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 70), MS (BioIon) C
27H
23N
5O
5F
2M/e calculated value 536.51; Measured value 563 (MH
+);
2-(2-{2-[1-(4, the ethyl of 6-two fluoro-5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 71), MS (BioIon) C
32H
29N
7O
4F
2M/e calculated value 613.62; Measured value 614.3 (MH
+);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-{2-[2-(3-methyl-[1,2,4]-oxadiazole one 5-yl) phenoxy group] ethyl }-3H-benzoglyoxaline-5-carboxylic acid amides (compound 72), MS (BioIon) C
30H
30N
10O
3M/e calculated value 578.63; Measured value 579.4 (MH
+); With
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-{2-[2-(3-methyl-[1,2,4]-oxadiazole-5-yl) phenoxy group] ethyl }-3H-benzoglyoxaline-5-carboxylic acid amides (compound 73), MS (BioIon) C
32H
29N
9O
3M/e calculated value 587.64; Measured value 588.2 (MH
+);
Embodiment 9
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-
The 2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid
(compound 74)
(a) will comprise 3 at acetate (400ml), the 4-diamino-pyridine ((51.7g, solution 0.46mol) are heated to 85 ℃, then through 6 hours branch 3 equal portions add methyl isophthalic acid-imino-diethyl malonate (125g, 0.60mmol).Mixture heated 12 hours down and heats another hour under 120C at 85 ℃, cooled off then with under reduced pressure concentrated.Resistates is cooled to 0 ℃ also with the neutralization of 5N ammonium hydroxide.Water layer with saturated sodium bicarbonate and sodium chloride solution washing, carries out drying (using sodium sulfate) successively with several parts of ethyl acetate extractions, the extraction liquid of merging, filtration and decompression concentrate down, obtain 2-(1H-imidazo [4,5-c] pyridine-2-yl) ethyl propionate (60.4g, 58%), is amber solid.
1H-NMR(300MHz,CDCl
3)d?ppm:9.00(s,1H),8.35(d,1H,J=9.4Hz),7.50(d,1H,J=9.4Hz),4.25(m,3H),1.78(d,3H,J=7.8Hz),1.30(t,3H,J=4.7Hz).
(b) will in trifluoroacetic acid (100ml), comprise 2-(1H-imidazo [4,5-c] pyridine-2-yl) ethyl propionate (60.4g, solution 0.28mmol) platinum oxide (IV) (5g) in the presence of hydrotreatment 2 days under 50psi.Mixture is filtered and concentrating under reduced pressure.Resistates is cooled to 0 ℃, handles with the 4MHCl/ diox, is suspended in the ether, and is by filtering separation, dry then.The solution that will comprise resistates (every part of 15-20g) at fresh trifluoroacetic acid (every part of 50ml) is hydrotreatment 24 hours under 50psi in the presence of platinum oxide (IV) (every part of 5g).Mixture is filtered and concentrating under reduced pressure.Each resistates carries out azeotropic drying with the mixture of toluene/ethanol (1: 1), carry out azeotropic drying with the 4MHCl/ diox again, be suspended in the ether then, by filtering separation and dry on vacuum pipeline, obtain 2-(4,5,6, the 7-imidazolidine is [4,5-c] pyridine-2-yl also) ethyl propionate dihydrochloride (61.80g, 75% productive rate);
1H-NMR (300MHz, DMSO-d
6) d ppm:10.00 (brs, 2H), 4.35 (q, 1H, J=7.1Hz), 4.25 (brs, 2H), 4.15 (m, 2H), 3.35 (m, 2H), 2.90 (brs, 2H), 1.60 (d, 3H, J=7.1Hz), 1.20 (t, 3H, J=6.9Hz).
(c) in acetonitrile (400ml), comprise 2-(4,5,6, the 7-imidazolidine is [4,5-c] pyridine-2-yl also) (60.2g, solution 0.20mol) are cooled to 0 ℃ to the ethyl propionate dihydrochloride under nitrogen, use N, (35ml 0.20mol) handles the N-diisopropyl ethyl amine, further is cooled to-5 ℃ (ice/acetone), in 30 minutes time, be used alternatingly benzyl chloroformate (58ml then, 0.41mol) and N, (70ml 0.40mol) handles the N-diisopropyl ethyl amine.Mixture cooled off 1 hour under-5 ℃ and is warming up to 20 ℃, after 16 hours, and concentrating under reduced pressure.Resistates is suspended in the ether, and suspension is used saturated sodium bicarbonate, saturated sodium-chloride successively, and drying (using sodium sulfate) is carried out in 0.1M hydrochloric acid and saturated nacl aqueous solution washing, filters and concentrating under reduced pressure.Resistates is dissolved in the ethanol (320ml), and this solution is cooled to-5 ℃ under nitrogen, and (0.22mol), meanwhile temperature of reaction is maintained at below 0 ℃ for 21wt%, 85ml to drip sodium ethylate then in 1 hour time.Mixture cooled off 1 hour down at-5 ℃, was adjusted to neutral PH with 50ml 4M hydrochloric acid, concentrating under reduced pressure.The resistates acetic acid ethyl dissolution, solution carries out drying (using sodium sulfate) with saturated sodium bicarbonate and sodium chloride aqueous solution washing, filters and concentrating under reduced pressure.Resistates is purified by silica gel chromatography (hexane/ethyl acetate), obtains 2-(1-ethoxy carbonyl ethyl)-1,4,6, and the 7-imidazolidine is [4,5-c] pyridine-5-carboxylic acid benzyl ester (52g, 72%) also, is light yellow oil;
1H-NMR (300MHz, DMSO-d
6) d ppm:11.72 (brs, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (brs, 2H), 4.02 (q, 2H, J=9.3Hz), 3.77 (q, 1H, J=8.3Hz), 3.66 (s, 2H), 2.55 (s, 2H), 1.38 (d, 3H, J=8.3Hz), 1.13 (t, 3H, J=9.3Hz).
(d) will comprise 2-(1-ethoxy carbonyl ethyl)-1,4,6,7-imidazolidine also [4,5-c] and pyridine-5-carboxylic acid benzyl ester (6.37g, 0.01 8mol), 4-amino-3-(N-methylamino) phenylformic acid (2.70g, 0.016mol) and the degassing simply on vacuum pipeline of the mixture of DMPU (20ml), in nitrogen atmosphere and 185 ℃ heating 4 hours down, cool off then and merge with isopyknic benzene.In mixture, add ether and obtain throw out.Throw out comes out by filtering separation, and is dry simply on vacuum pipeline, further purifies by recrystallization from hot ethanol/water.Throw out is by filtering Separation and Recovery, and dry and obtain 2-[1-(5-benzyl oxygen base carbonyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid (4.73g, 58%);
1H-NMR (300MHz, DMSO-d
6) d ppm:12.70 (brs, 1H), 11.80 (s, 1H), 8.15 (s, 1H), 7.78 (d, 1H, J=8.3Hz), 7.64 (d, 1H, J=8.3Hz), 7.31 (s, 5H), 5.09 (s, 2H), 4.66 (q, 1H, J=5.2Hz), 4.32 (brs, 2H), 3.78 (s, 3H), 3.65 (brs, 2H), 2.52 (brs, 2H), 1.73 (d, 3H, J=5.2Hz).
(e) comprise 2-[1-(5-benzyl oxygen base carbonyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid (0.75g, 1.6mmol), DMF (6.5ml), 2-(2-amino ethoxy) methyl benzoate (0.38g, 1.6mmol) and HOBT (0.22g, 1.6mmol) mixture under nitrogen atmosphere, be cooled to-40 ℃, with EDC (0.32g, 1.6mmol) and N, N-diisopropyl ethyl amine (0.29ml, 1.6mmol) handle and 15 minutes after, use additional N, N-diisopropyl ethyl amine (0.29ml) is handled, be warming up to 20 ℃ with stirring 16 hours.Then mixture is cooled to-40 ℃, with additional EDC (0.080g) and N, N-diisopropyl ethyl amine (0.050ml) is handled, and stirs 15 minutes down and stirs 2 hours down at 20 ℃ at-40 ℃, concentrates by short path distillation mode.Resistates is dispensed between chloroform and the sodium bicarbonate, and organic phase is carried out drying (using sodium sulfate) with sodium-chlor, 0.5M vitriolate of tartar and sodium-chlor washing, filters and concentrating under reduced pressure.Resistates is by silica gel chromatography (chloroform/methanol/ethanol: 95/5/1) purify, obtain 2-(1-{6-[2-(2-methoxycarbonyl phenoxy group) ethylamino formyl radical]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl ethyl)-1,4,6,7-imidazolidine also [4,5-c] pyridine-5-carboxylic acid benzyl ester (0.69g, 66%), be glassy brown foam;
1H-NMR (300MHz, DMSO-d
6) d ppm:11.92 (s, 1H), 8.49 (t, 1H, J=5.0Hz), 8.02 (s, 1H), 7.69 (d, 1H, J=9.9Hz), 7.60 (m, 2H), 7.50 (t, 1H, J=8.3Hz), 7.30 (m, 5H), 7.19 (d, 1H, J=9.9Hz), 6.99 (t, 1H, J=8.3Hz), 5.04 (s, 2H), 4.61 (q, 1H, J=8.8Hz), 4.30 (brs, 2H), 4.20 (t, 2H, J=5.0Hz), 3.74 (s, 3H), 3.68 (s, 3H), 3.63 (m, 4H), 2.55 (brs, 2H), 1.67 (d, 3H, J=8.8Hz).
(f) in THF (2ml) and water (2ml), comprise 2-(1-{6-[2-(2-methoxycarbonyl phenoxy group) ethylamino formyl radical]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl ethyl)-1; 4; 6; 7-imidazolidine also [4; 5-c] (0.69g, solution 1.1mmol) are cooled to 0 ℃ to pyridine-5-carboxylic acid benzyl ester under nitrogen atmosphere, with 2N lithium hydroxide (1.1ml; 2.2mmol) handle, be warming up to 20 ℃ and stirred 8 hours.Mixture is cooled to 0 ℃ then, handles with additional 2N lithium hydroxide (1.1ml), rises to 20 ℃, stirs 6 hours, is cooled to 0 ℃, is adjusted to PH7 with 1M hydrochloric acid, then concentrating under reduced pressure.Resistates is used cold saturated nacl aqueous solution and water washing carefully, dry on vacuum pipeline then, obtain 5-benzyloxycarbonyl-2-(2-{3-methyl-2-[1-(4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl) ethyl]-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (0.56g, 83%) glassy resistates;
1H-NMR (300MHz, DMSO-d
6) d ppm:11.87 (brs, 1H), 9.74 (s, 1H), 8.45 (s, 1H), 7.84 (d, 1H, J=9.7Hz), 7.56 (d, 1H, J=9.7Hz), 7.42 (d, 1H, J=7.7Hz), 7.32 (s, 5H), 7.23 (t, 1H, J=7.7Hz), 7.06 (d, 1H, J=7.7Hz), 6.90 (t, 1H, J=7.7Hz), 5.08 (s, 2H), 4.63 (q, 1H, J=7.7Hz), 4.32 (s, 2H), 4.19 (m, 2H), 3.84 (s, 3H), 3.64 (m, 4H), 2.55 (s, 2H), 1.71 (d, 3H, J=7.7Hz).
(g) in glacial acetic acid (2ml), comprise 5-benzyloxycarbonyl-2-(2-{3-methyl-2-[1-(4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl) ethyl]-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) (0.561g, solution 0.90mmol) are heated to 10 ℃ to phenylformic acid in water-bath and under nitrogen atmosphere, handle with the solution (2ml 30% solution) of hydrogen bromide in acetate, be warming up to 20 ℃, after 1 hour, concentrate with nitrogen gas stream.Resistates is dissolved in a spot of ethanol, then drips of solution is added to stir in the ether and obtain the taupe brown throw out.Throw out separates and in addition obtains 2-(2-{3-methyl-2-[(4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl) ethyl after the drying by filtering]-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid hydrobromate (0.651g);
1H-NMR (300MHz, DMSO-d
6) d ppm:9.31 (brs, 2H), 8.63 (m, 1H), 8.24 (s, 1H), 7.79 (d, 1H, J=7.9Hz), 7.63 (m, 2H), 7.47 (t, 1H, J=7.9Hz), 7.21 (d, 1H, J=7.9Hz), 7.00 (t, 1H, J=7.9Hz), 5.21 (q, 1H, J=6.3Hz), 4.29 (s, 2H), 4.21 (s, 2H), 3.91 (s, 3H), 3.68 (m, 2H), 3.43 (m.2H), 2.89 (s, 2H), 1.79 (d, 3H, J=6.3Hz).
(h) in DMF (1.5ml), comprise 2-(2-{3-methyl-2-[(4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl) ethyl]-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid hydrobromate (0.30g, 0.46mmol) solution in nitrogen atmosphere, be cooled to 0 ℃, with imido for ethyl acetate (ethyl acetimidate) (0.12g, 0.92mmol) and N, N-diisopropyl ethyl amine (0.25ml, 1.4mmol) handle, 0 ℃ of cooling 30 minutes and rise to 20 ℃ and stirred 20 hours then down.Mixture is cooled to 0 ℃ then, and with additional imido for ethyl acetate (ethylacetimidate) (0.06g) and N, N-diisopropyl ethyl amine (0.16ml) is handled, and is warming up to 20 ℃ and stirred 2 hours.Mixture is cooled to 0 ℃, (0.03g) handles for ethyl acetate (ethylacetimidate) with other imido, is warming up to 20 ℃ and stirred 2 hours.Mixture is added dropwise to then and stirs in the ether to obtain throw out.Throw out is separated by decanting solvent, and dry on vacuum pipeline.Resistates precipitates from ethanol/ether, and purifies by preparation property RP-HPLC: 2 parts, and 50%MeCN/H
2O (20mM HCl) was through 50 minutes.Each fraction by freeze-drying obtain 2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (0.145g, 52%);
1H-NMR (300MHz, DMSO-d
6) d ppm:9.77 (s, 1H), 9.34 (2s, 1H), 8.81 (m, 1H), 8.36 (s, 1H), 7.89 (d, 1H, J=8.6Hz), 7.71 (d, 1H, J=8.6Hz), 7.60 (d, 1H, J=7.7Hz), 7.49 (t, 1H, J=7.7Hz), 7.21 (d, 1H, J=7.7Hz), 6.99 (t, 1H, J=7.7Hz), 5.37 (m, 1H), 4.71 (2s, 2H), 4.23 (s, 2H), 3.97 (s, 3H), 3.82 (s, 1H), 3.66 (m, 2H), 2.83 (m, 2H), 2.49 (s, 1H), 2.40 (d, 3H, J=3.5Hz), 1.85 (d, 3H, J=5.1Hz) .MS (ESI) C
28H
31N
7O
4The m/e calculated value: 529.61, measured value: 530.3 (MH
+).
2-(2-{2-[1-(4,6, the ethyl of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzo
Imidazoles-5-base carbonylamino) oxyethyl group] ethyl benzoate
(compound 75)
(a) with the Zai diox (Aldrich, 0.5M comprise 2,3,4 in 7.5mmol), 6-tetrafluoro oil of mirbane (0.6g, 3.1mmol) and the solution of ammonia at room temperature stir and obtained thin white depositions in 3 hours.Mixture makes the white depositions dissolving and obtains yellow crystals with the water dilution of equal volume.The crystal of being separated is collected and is in addition dry and obtain 2,3, and 5-three fluoro-6-N-methyl-p-nitroanilines (307mg, 51%) are yellow spicule, m.p.66 ℃;
1H-NMR (CDCl
3): δ 6.4 (1H, m), δ 6.0 (2H, s).
(b) 2,3, (300mg 1.56mmol) is hydrogenated a night with the mixture of 10% palladium/carbon in dehydrated alcohol to 5-three fluoro-6-N-methyl-p-nitroanilines under normal pressure, under nitrogen, filter and concentrate, obtain 1,2-diamino-3,4,6-trifluoro-benzene (219mg, 87% productive rate) is the purple crystal solid; MS M
+162.7 ,+41.+82 (+CAN ,+2CAN).(for C
6H
5F
3N
2Calculated value: 162.11).
(c) will comprise 1; 2-diamino-3; 4; 6-trifluoro-benzene (1.92g; 11.8mmol), 2-oxyethyl group imido is for formyl radical ethyl propionate (3.1g; 14.7mmol) and the heating under refluxing of the mixture of dehydrated alcohol (6ml), till the reaction process that is shown by TLC shows that no longer reaction is proceeded, use NH
4Cl filters, and concentrates then.Resistates is purified (hexane: methylene dichloride: ethyl acetate, 5: 5: 1) by the column chromatography on silica gel, and (4,6, the ethyl propionate (1.37g, 42%) of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl) is the tawny crystalline solid to obtain 2-; NMR (CDCI
3): δ 10.35 (s, 1/2H), δ 7.05 (s, 1/2H), 6.7 (m, 1H), δ 4.25 (dd, 2H), δ 4.15 (dd, 1H), δ 1.73 (d, 3H), δ 1.31 (t, 3H); M
+272.9 (C
12H
11F
3N
2O
2Calculated value: 272.23).
(d) with 2-(4; 6; ethyl propionate (the 988mg of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl); 3.63mmol) and 2-[2-(4-amino-3-methylamino benzoyl amino) oxyethyl group] ethyl benzoate (1.3g; 3.63mmol) merge; under vacuum, placed 4 hours, further mix then with DMPU (4ml).Mixture is stirred to into till the solution state, and one night of suction is heated to 195 ℃ and kept 4 hours to remove remaining gas under nitrogen gas stream under condition of high vacuum degree, be cooled to room temperature and be distributed in ethyl acetate and water between.Isolate organic phase and use the salt water washing, with dried over sodium sulfate and concentrated.Resistates is purified by the column chromatography on silica gel (respectively going on foot gradient from 100% hexane to 100% ethyl acetate), further purify by recrystallization from methyl alcohol/THF/ water, (2-{2-[1-(4 to obtain 2-, 6, the ethyl of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] ethyl benzoate (1.0g, 49%), is the white crystalline solid.NMR (CDCl
3): δ 6.84-8.07 (m, 8H), δ 4.93 (dd, 1H), δ 4.34 (dd, 2H), δ 4.27 (m, 2H), δ 3.95 (m, 2H), δ 3.9 (s, 3H), δ 1.93 (d, 3H), δ 1.78 (s, 2H), δ 1.38 (t, 3H); LCMS M
+566.2 BioIon M
+565.7 (C
29H
26F
3N
5O
4Calculated value: 565.55).
With carry out equally among the embodiment 10, prepare of the present invention below compound:
2-(2-{2-[1-(5, the ethyl of 6-two fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] ethyl benzoate (compound 76), MS (BioIon) C
29H
27N
5O
4F
2M/e calculated value 547.56; Measured value 548.1 (MH
+);
2-(2-{2-[1-(4, the ethyl of 6-two fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] ethyl benzoate (compound 77), MS (LCMS) C
29H
27F
2N
5O
4M/e calculated value 547.56; Measured value 548.3 (MH
+);
2-(2-{2-[1-(4,5, the ethyl of 6-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] ethyl benzoate (compound 78), MS (LCMS) C
29H
26F
3N
5O
4M/e calculated value 565.55; Measured value 566.2 (MH
+); With
2-{2-[3-methyl-2-(4,6,7-three fluoro-1H-benzimidazolyl-2 radicals-ylmethyls)-3H-benzoglyoxaline-5-base carbonylamino] oxyethyl group } ethyl benzoate (compound 79), MS (BioIon) C
28H
24F
3N
5O
4M/e calculated value 551.52; Measured value 551.2 (MH
+);
Embodiment 11
2-(2-{2-[1-(4,6, the ethyl of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzo
Imidazoles-5-base carbonylamino } oxyethyl group) phenylformic acid
(compound 80)
(2-{2-[1-(4 to comprise 2-, 6, the ethyl of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (118mg, 0.21mmol), the mixture of methyl alcohol (4ml) and 2N sodium hydroxide (2.1ml) at room temperature stirred 4 hours, neutralize and be distributed between ethyl acetate and the saturated ammonium chloride with 2N hydrochloric acid (2.1ml).Isolate water layer, with ethyl acetate extraction (X3).The organic phase salt water washing that merges is with dried over sodium sulfate and be condensed into white solid.Resistates is dissolved in warm ethanol (10ml) and the 4M hydrochloric acid/dioxane solution.Solution dilutes with ether, obtains throw out.Isolate obtain after throw out and the drying 2-(2-{2-[1-(4,6, the ethyl of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino oxyethyl group) phenylformic acid, be white solid; MS (LCMS) C
27H
22F
3N
5O
4M/e calculated value 537.50; Measured value 538.4 (MH
+).
With carry out equally among the embodiment 11, prepare of the present invention below compound:
2-(2-{2-[1-(5, the ethyl of 6-two fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 81), MS (LCMS) C
27H
23N
5O
4F
2M/e calculated value 519.51; Measured value 520.2 (MH
+);
2-(2-{2-[1-(4, the ethyl of 6-two fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 82), MS (LCMS) C
27H
23F
2N
5O
4M/e calculated value 519.51; Measured value 520.2 (MH
+); With
2-(2-{2-[1-(4,5, the ethyl of 6-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 83), MS (BioIon) C
27H
22F
3N
5O
4M/e calculated value 537.5; Measured value 537.7 (MH
+);
Embodiment 12
2-(2-{2-[1-(the second of 1-isobutyryl-5-methoxycarbonyl Oxy-1 H-benzimidazolyl-2 radicals-yl)
Base]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate
(compound 84)
To comprise 2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino oxyethyl group) ethyl benzoate (0.50g, 0.95mmol), dimethyl formamide (5ml), cesium carbonate (0.93g, 2.85mmol) and isobutyric anhydride (0.17ml, 1.05mmol) mixture stirred 2 hours, use methylene dichloride (50ml) to dilute then and make it Packing seat by Celite (diatomite).Solvent removed in vacuo, resistates are dissolved in the methylene dichloride (5ml).Solution and diisopropyl ethyl amine (0.47ml, 2.7mmol) and methyl-chloroformate (0.1ml 1.3mmol) mixes, and then mixture is stirred 1 hour.Solvent removed in vacuo, resistates is purified by silica gel chromatography as eluent by using ethanol and methylene dichloride, obtain 2-(2-{2-[1-(ethyl of 1-isobutyryl-5-methoxycarbonyl Oxy-1 H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino oxyethyl group) ethyl benzoate (0.20g, 32% productive rate), be colourless amorphous solid; MS (BioIon) C
35H
37N
5O
8M/e calculated value 655.72; Measured value 656.1 (MH
+).
With the same carrying out among the embodiment 12, prepare following compound of the present invention:
2-(1-{6-[2-(2-ethoxy carbonyl phenoxy group) ethylamino formyl radical]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl } ethyl]-5-hydroxy benzo imidazoles-1-carboxylate methyl ester (compound 85), MS (ESI) C
31H
31N
5O
7M/e calculated value 585.62; Measured value 586.2 (MH
+);
2-(1-{6-[2-(2-ethoxy carbonyl phenoxy group) ethylamino formyl radical]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl } ethyl]-5-methoxycarbonyl oxygen base benzoglyoxaline-1-carboxylic acid, ethyl ester (compound 86), MS (ESI) C
33H
33N
5O
7M/e calculated value 643.66; Measured value 644.2 (MH
+);
2-(2-{2-[1-(ethyl of 5-hydroxyl-1-isobutyryl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 87), MS (ESI) C
33H
35N
5O
6M/e calculated value 597.68; Measured value 598.2 (MH
+);
2-(2-{2-[1-(ethyl of 1-benzoyl-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 88), MS (ESI) C
36H
33N
5O
6M/e calculated value 631.69; Measured value 632.3 (MH
+);
2-(2-{2-[1-(ethyl of 1-formyl-dimethylamino-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 89), MS (ESI) C
32H
34N
6O
6M/e calculated value 598.66; Measured value 599.3 (MH
+);
2-(2-{2-[1-(ethyl of 1-acetoxy-methyl-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 90), MS (BioIon) C
32H
33N
5O
7M/e calculated value 599.65; Measured value 600.7 (MH
+);
2-[2-(2-{1-[1-(2,2-dimethyl propylene acyloxy methyl)-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 91), MS (ESI) C
35H
39N
5O
7M/e calculated value 641.74; Measured value 642.3 (MH
+);
2-(2-{2-[1-(ethyl of 1-isobutyryl-5-methoxycarbonyl Oxy-1 H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 92), MS (BioIon) C
35H
37N
5O
3M/e calculated value 655.72; Measured value 656.1 (MH
+);
5-ethoxy carbonyl oxygen base-2-(1-{6-[2-(2-ethoxy carbonyl phenoxy group) ethylamino formyl radical]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl } ethyl) benzoglyoxaline-1-carboxylic acid, ethyl ester (compound 93), MS (ESI) C
35H
37N
5O
9M/e calculated value 671.72; Measured value 672.4 (MH
+);
2-(1-{6-[2-(2-ethoxy carbonyl phenoxy group) ethylamino formyl radical]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl } ethyl)-5-isopropoxy carbonyl oxygen base-benzoglyoxaline-1-carboxylic acid isopropyl (compound 94), MS (ESI) C
37H
41N
5O
9M/e calculated value 699.79; Measured value 700.4 (MH
+); With
2-(2-{2-[1-(ethyl of 1-ethanoyl-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 95), MS (ESI) C
31H
31N
5O
6M/e calculated value 569.62; Measured value 570.1 (MH
+);
According to the schedule of operation described in the application or by the known method of those of ordinary skill in the art, prepare other compound of the present invention:
C-[2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3H-benzoglyoxaline-5-yl] methylamine (compound 96);
C-[2-(1H-naphtho-[2,3-d] imidazoles-2-ylmethyl)-1H-benzoglyoxaline-5-yl] methylamine (compound 97), MS (BioIon) C
20H
17N
5M/e calculated value 327.4; Measured value 328.1 (MH
+);
C-[2-(5-methyl isophthalic acid H-benzimidazolyl-2 radicals-ylmethyl)-1H-benzoglyoxaline-5-yl] methylamine (compound 98); MS (BioIon) C
17H
17N
5M/e calculated value 291.4; Measured value 292.3 (MH
+);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-1H-benzoglyoxaline-5-carboxylic acid (compound 99);
3-[2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-1H-benzoglyoxaline-5-base carbonylamino] propionic acid (compound 100);
1H-NMR (300Mhz, CD
3OD): 1.92 (m, 2H, J=7.2Hz), 2.38 (t, 2H, J=7.2Hz), 3.47 (t, 2H, J=7.2Hz), 4.30 (s, 2H), 7.54 (d, 1H, J=10.0Hz), 7.69 (d, 1H, J=8.6Hz), 7.75 (d, 1H, J=10.0Hz), 7.81 (s, 1H), 7.87 (d, 1H, J=8.6Hz), 8.12 (s, 1H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-1-base ethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 101),
1H-NMR (300Mhz, CD
3OD): 3.42 (t, 2H, J=7.5Hz), 3.75 (t, 2H, J=7.5Hz), 7.39-7.81 (m, 12H), 8.08 (s, 1H), 8.27 (d, 1H, J=10.0Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 102),
1H-NMR (300Mhz, CD
3OD): 3.41 (t, 2H, J=7.4Hz), 3.72 (t, 2H, J=7.4Hz), 3.96 (s, 3H), 4.27 (s, 2H), and 7.37-7.54 (m, 5H), 7.67 (d, 1H, J=8.7Hz), 7.71-7.77 (m, 2H), 7.80-7.85 (m, 2H), 8.70 (d, 1H, J=0.9Hz), 8.24 (d, 1H, J=8.1Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzimidazole-4-carboxamides (compound 103),
1H-NMR (300Mhz, CD
3OD): 3.45 (t, 2H, J=7.2Hz), 3.74 (s, 3H), 3.83 (t, 2H, J=7.2Hz), 4.27 (s, 2H), 7.36-7.55 (m, 7H), 7.71-7.77 (m, 3H), 7.83-7.86 (m, 2H), 8.24 (d, 1H, J=8.1Hz);
(S)-2-[2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-1H-benzoglyoxaline-5-base carbonylamino]-3-indol-3-yl propionic acid (compound 104),
1H-NMR (300Mhz, CD
3OD): 3.36 (dd, 1H, J=14.6,8.1Hz), 3.53 (dd, 1H, J=14.6,5.0Hz), 3.92 (s, 3H), 4.27 (s, 2H), 6.97 (t, 1H, J=7.4Hz), 7.07 (t, 1H, J=7.4Hz), 7.16 (s, 1H), 7.33 (d, 1H, J=7.8Hz), 7.51 (dd, 1H, J=8.4,1.5Hz), 7.60-7.66 (m, 2H), 7.73-7.80 (m, 3H), 7.96 (d, 1H, J=0.9Hz), 8.39 (d, J=7.5Hz, part exchanges);
(R)-2-[2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-1H-benzoglyoxaline-5-base carbonylamino]-3-indol-3-yl propionic acid (compound 105),
1H-NMR (300Mhz, CD
3OD): 3.35 (dd, 1H, J=14.5,8.1Hz), 3.51 (dd, 1H, J=14.4,4.8Hz), 3.90 (s, 3H), 4.23 (s, 2H), 6.96 (t, 1H, J=7.4Hz), 7.06 (t, 1H, J=7.4Hz), 7.14 (s, 1H), 7.31 (d, 1H, J=7.8Hz), 7.44 (d, 1H, J=7.8Hz), 7.58-7.74 (m, 5H), 7.94 (s, 1H), 8.33 (d, J=8.1Hz, part exchanges);
2-(1H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-1-base ethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 106),
1H-NMR (300Mhz, CD
3OD): 3.42 (t, 2H, J=7.4Hz), 3.76 (t, 2H, J=7.4Hz), 3.97 (s, 3H), 7.38-7.60 (m, 5H), 7.65 (d, 1H, J=8.7Hz), 7.72-7.79 (m, 4H), 7.85 (dd, 1H, J=8.6,1.5Hz), 8.04 (d, 1H, J=1.2Hz), 8.26 (d, 1H, J=8.4Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(the amino butyl of 4-)-3H-benzimidazole-4-carboxamides (compound 107), MS (BioIon) C
22H
27N
7O
1M/e calculated value 405.4; Measured value 406.5 (MH
+);
2-[1-(ethyl of 5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 108), MS (BioIon) C
31H
30N
6O
1M/e calculated value 502.6; Measured value 503.3 (MH
+);
2-(1H-imidazo [4,5-c] pyridine-2-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 109), MS (BioIon) C
28H
24N
6O
1M/e calculated value 460.5; Measured value 461.3 (MH
+);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-Ji carbonyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 110), MS (BioIon) C
30H
26N
6O
2M/e calculated value 502.6; Measured value 503.6 (MH
+);
2-(5-formamyl-1H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-1-base ethyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 111);
2-(5-amino methyl-4,5,6,7-tetrahydrochysene-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 112),
1H-NMR (300Mhz, CD
3OD): 1.67 (m, 1H), 2.14 (m, 1H), 2.24 (m, 1H), 2.47 (dd, 1H, J=15.3,9.3Hz), 2.76 (m, 2H), 2.90 (dd, 1H, J=15.7,7.5Hz), 3.05 (d, 2H, J=6.9Hz), 3.41 (t, 2H, J=7.4Hz), 3.75 (t, 2H, J=7.4Hz), 3.90 (s, 3H), 7.35-7.53 (m, 5H), 7.61 (d, 1H, J=8.4Hz), 7.72-7.75 (m, 2H), 7.85 (dd, 1H, J=8.1,1.2Hz), 7.99 (d, 1H, J=0.9Hz), 8.26 (d, 1H, J=8.4Hz);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(3-phenyl propyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 113),
1H-NMR (300Mhz, CD
3OD): 1.98 (m, 2H), 2.72 (t, 2H, J=7.6Hz), 3.46 (t, 2H, J=7.2Hz), 4.01 (s, 3H), 4.29 (s, 2H), 7.12-7.17 (m, 1H), 7.21-7.28 (m, 4H), 7.56 (d, 1H, J=8.1Hz), 7.70 (d, 1H, J=8.7Hz), 7.77 (d, 1H, J=8.4Hz), 7.85-7.88 (m, 2H), 8.16 (s, 1H, J=1H);
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-phenoxy group ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 114),
1H-NMR (300Mhz, CD
3OD): 3.80 (t, 2H, J=5.0Hz), 3.99 (s, 3H), 4.17 (t, 2H, J=5.0Hz), 4.27 (s, 2H), 6.88 (t, 1H, J=7.5Hz), 6.92 (d, 2H, J=7.5Hz), 7.22 (t, 2H, J=7.5Hz), 7.55 (d, 1H, J=8.7Hz), 7.68 (d, 1H, J=6.6Hz), 7.77 (d, 1H, J=8.4Hz), 7.84 (s, 1H), 7.88 (d, 1H, J=8.7Hz), 8.18 (s, 1H);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 115),
1H-NMR (300Mhz, CD
3OD): 2.45 (2.43, s, 3H), 2.96 (m, 2H), 3.42 (t, 2H, J=7.4Hz), 3.75 (t, 2H, J=7.4Hz), 3.93 (s, 3H), 3.98 (m, 2H), 4.70 (4.80, s, 2H), 7.38-7.53 (m, 4H), 7.63-7.87 (m, 4H), 8.04 (d, J=1.5Hz, 8.08, s, 1H), 8.26 (d, 1H, J=8.0Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base carbonyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 116),
1H-NMR (300Mhz, CD
3OD): 2.45 (2.43, s, 3H), 3.03 (m, 2H), 3.41 (t, 2H, J=7.4Hz), 3.74 (t, 2H, J=7.4Hz), 3.97 (m, 2H), 4.18 (4.18, s, 3H), 4.66 (4.80, s, 2H), 7.38-7.54 (m, 4H), and 7.72-7.92 (m, 4H), 8.04 (s, 1H), 8.26 (d, 1H, J=7.8Hz);
2-(5-imino-ethyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 117),
1H-NMR (300Mhz, CD
3OD): 2.95 (m, 2H), 3.40 (t, 2H, J=7.4Hz), 3.74 (t, 2H, J=7.4Hz), 3.90 (3.89, s, 3H), 3.98 (m, 2H), 4.70 (4.82, s, 2H), and 7.39-7.52 (m, 4H), 7.63-7.84 (m, 4H), 8.03 (s, 1H), 8.16 (8.18, s, 1H), 8.24 (d, 1H, J=8.4Hz);
2-(5-amino-ethyl-4,5,6,7-tetrahydrochysene-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 118),
1H-NMR (300Mhz, CD
3OD): 1.69 (m, 1H), 2.15 (m, 1H), 2.20 (m, 1H), 2.55 (dd, 1H, J=15.0,11.4Hz), 2.81-3.08 (m, 5H), 3.44 (t, 2H, J=7.5Hz), 3.74 (m, 2H), 4.23 (s, 3H), and 7.39-7.52 (m, 4H), 7.75 (dd, 1H, J=6.1,3.2Hz), 7.83-7.88 (m, 2H), 7.97 (d, 1H, J=8.7Hz), 8.10 (s, 1H), 8.27 (d, 1H, J=8.1Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-phenoxy group ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 119),
1H-NMR (300Mhz, CD
3OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.80 (t, 2H, J=5.6Hz), 3.95 (s, 3H), 3.98 (m, 2H), 4.17 (t, 2H, J=5.6Hz), 4.71 (4.81, s, 2H), 6.89 (t, 1H, J=7.3Hz), 6.93 (d, 2H, J=8.6Hz), 7.23 (dd, 2H, J=8.6,7.3Hz), 7.66 (d, 1H, J=7.8Hz), 7.85 (d, 1H, J=7.8Hz), 8.13 (s, 1H);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-benzo [1,3] dioxole-4-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 120),
1H-NMR (300Mhz, CD
3OD): 2.45 (2.43, s, 3H), 2.89-2.97 (m, 4H), 3.65 (t, 2H, J=7.1Hz), 3.94 (s, 3H), 3.98 (m, 2H), 4.71 (4.81, s, 2H), 5.83 (s, 2H), 6.65-6.74 (m, 3H), 7.64 (d, 1H, J=7.8Hz), 7.76-7.79 (m, 1H), 8.06 (m, 1H);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(benzoglyoxaline-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 121),
1H-NMR (300Mhz, CD
3OD): 2.46 (2.44, s, 3H), 2.96 (m, 2H), 3.92 (s, 3H), 3.95-4.01 (m, 4H), 4.73 (4.79, s, 2H), 4.80 (m, 2H), 7.54-7.64 (m, 4H), 7.83 (dd, 1H, J=6.5,2.2Hz), 7.93 (s, 1H), 7.98 (dd, J=6.5,2.1Hz), 9.49 (s, 1H);
N-[2-(5-hydroxyl-1H-indoles-2-yl) ethyl]-2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 122),
1H-NMR (300Mhz, CD
3OD): 2.42 (2.39, s, 3H), 2.90 (m, 2H), 2.99 (t, 2H, J=7.1Hz), 3.67 (t, 2H, J=7.1Hz), 3.75 (s, 3H), 3.93 (m, 2H), 4.66 (4.76, s, 2H), 6.61 (dd, 1H, J=8.5,2.3Hz), 6.94 (d, 1H, J=2.3Hz), 7.06 (s, 1H), 7.12 (d, 1H, J=8.5Hz), 7.59 (d, 1H, J=8.4Hz), 7.76 (dd, 1H, J=8.4,1.2Hz), 7.87 (d, 1H, J=1.2Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(2-chlorophenoxy) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 123), MS (BioIon) C
26H
28N
7O
2Cl m/e calculated value 506.0; Measured value 506.3 (MH
+);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(3-chlorophenoxy) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 124), MS (BioIon) C
26H
28N
7O
2Cl m/e calculated value 506.0; Measured value 506.7 (MH
+);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 125),
1H-NMR (300MHz, CD
3OD): 2.48 (2.46, s, 3H), 3.00 (m, 2H), 3.60 (t, 2H, J=6.6Hz), 3.90-4.05 (m, 7H), 4.76 (4.76, s, 2H), (6.64 6.66, s, part exchange), 7.45-7.95 (m, 9H), 8.02 (m, part exchanges), 8.17 (d, 1H, J=8.1Hz), 8.96 (s, part exchanges);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-hydroxyl-2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 1 26),
1H-NMR (300Mhz, CD
3OD): 2.45 (2.43, s, 3H), 2.94 (m, 2H), 3.55 (dd, 1H, J=13.6,8.3Hz), 3.91-3.99 (m, 6H), 4.70 (4.80, s, 2H), 5.78 (dd, 1H, J=8.3,3.6Hz), 7.44-7.54 (m, 3H), 7.66 (d, 1H, J=8.4Hz), 7.76-7.88 (m, 4H), 8.08 (m, 1H), 8.39 (d, 1H, J=8.4Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(2 hydroxy naphthalene-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 127),
1H-NMR (300Mhz, CD
3OD): 2.43 (2.41, s, 3H), 2.92 (m, 2H), 3.41 (t, 2H, J=7.1Hz), 3.69 (t, 2H, J=7.1Hz), 3.85 (s, 3H), 3.93-3.96 (m, 2H), 4.68 (4.78, s, 2H), 7.11 (d, 1H, J=8.7Hz), 7.21 (t, 1H, J=7.5Hz), 7.38 (dt, 1H, J=1.2,7.6Hz), 7.50-7.61 (m, 2H), 7.69-7.75 (m, 2H), 7.93 (s, 1H), 8.07 (d, 1H, J=8.4Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(4-hydroxyl naphthalene-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 128),
1H-NMR (300Mhz, CD
3OD): 2.42 (2.40, s, 3H), 2.89 (m, 2H), 3.27 (m, 2H), 3.69 (t, 2H, J=7.2Hz), 3.82 (3.83, s, 3H), 3.93 (m, 2H), 4.64 (4.76, s, 2H), 6.72 (d, 1H, J=7.8Hz), 7.17 (d, 1H, J=7.5Hz), 7.37 (t, 1H, J=7.5Hz), 7.46 (dt, 1H, J=0.9,6.9Hz), 7.62 (d, 1H, J=8.5Hz), 7.77 (d, 1H, J=8.5Hz), 7.95 (s, 1H), 8.12 (d, 1H, J=8.4Hz), 8.17 (d, 1H, J=8.4Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(2-methoxyl group phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 129),
1H-NMR (300Mhz, CD
3OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.80 (m, 5H), 3.95 (s, 3H), 3.98 (m, 2H), 4.17 (t, 2H, J=5.4Hz), 4.71 (4.81, s, 2H), 6.85-7.00 (m, 4H), 7.66 (d, 1H, J=8.7Hz), 7.84 (m, 1H), 8.13 (s, 1H);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-naphthalene-2-ylmethyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 130),
1H-NMR (300Mhz, CD
3OD): 2.44 (2.42, s, 3H), 2.92 (m, 2H), 3.91 (s, 3H), 3.95 (m, 2H), 4.68 (4.78, s, 2H), 4.77 (s, 2H), 7.41-7.44 (m, 2H), 7.50 (dd, 1h, J=8.6,1.1Hz), 7.67 (d, 1H, J=8.4Hz), 7.78-7.83 (m, 4H), 7.90 (m, 1H), 8.16 (m, 1H);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(3-pyridin-4-yl propyl group)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 131),
1H-NMR (300Mhz, CD
3OD): 2.11 (m, 2H), 2.46 (2.43, s, 3H), 2.96 (m, 2H), 3.06 (t, 2H, J=7.7Hz), 3.51 (t, 2H, J=6.8Hz), 3.98 (m, 5H), 4.72 (4.82, s, 2H), 7.67 (d, 1H, J=8.5Hz), 7.83 (dd, 1H, J=8.5,1.3Hz), 8.00 (d, 2H, J=6.6Hz), 8.15 (d, 1H, J=1.3Hz), 8.70 (d, 2H, J=6.6Hz);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(2, the 3-dihydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 132), MS (BioIon) C
32H
32N
8O
3M/e calculated value 576.6; Measured value 577.5 (MH
+);
1H-NMR (300Mhz, CD
3OD): 3.41 (t, 2H, J=7.5Hz), 3.58-3.76 (m, 4H), 4.05 (m, 1H), 4.45 (dd, 1H, J=14.9,8.5Hz), 4.61 (dd, 1H, J=14.9,3.2Hz), 7.36-7.52 (m, 4H), 7.66-7.85 (m, 4H), 8.14 (s, 1H), 8.25 (d, 1H, J=7.8Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(4-methoxyl group phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 133),
1H-NMR (300Mhz, CD
3OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.70 (m, 2H), 3.77 (t, 2H, J=5.6Hz), 3.95 (s, 3H), 3.98 (m, 2H), 4.12 (t, 2H, J=5.6Hz), 4.71 (4.81, s, 2H), 6.78-6.89 (m, 4H), 7.66 (d, 1H, J=8.4Hz), 7.84 (m, 1H), 8.13 (d, 1H, J=1.2Hz);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-(2, the 3-dihydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 134), MS (BioIon) C
32H
30N
7O
4M/e calculated value 590.6; Measured value 590.7 (MH
+);
1H-NMR (300Mhz, CD
3OD): 3.42 (t, 2H, J=7.4Hz), 3.74 (t, 2H, J=7.4Hz), 4.00 (d, 2H, J=4.2Hz), 4.38 (t, 1H, J=11.7Hz), 4.56 (dd, 1H, J=12.5,3.5Hz), 7.34-7.51 (m, 5H), 7.61-7.65 (m, 2H), 7.72-7.86 (m, 4H), 8.05 (d, 1H, J=1.2Hz), 8.25 (d, 1H, J=8.1Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(1,2,3,4-naphthane-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 135),
1H-NMR (300Mhz, CD
3OD): 1.69-2.11 (m, 6H), 2.45 (2.43, s, 3H), 2.73 (m, 2H), 2.88 (m, 1H), 2.95 (m 2H), 3.52 (t, 2H, J=7.4Hz), 3.97 (m, 5H), 4.72 (4.81, s, 2H), 6.99-7.06 (m, 3H), 7.15-7.18 (m, 1H), 7.67 (d, 1H, J=8.7Hz), 7.82-7.86 (m, 1H), 8.14 (d, 1H, J=0.9Hz);
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(3-methoxyl group phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 136),
1H-NMR (300Mhz, CD
3OD): 2.45 (2.42, s, 3H), 2.95 (m, 2H), 3.71 (s, 3H), 3.78 (t, 2H, J=5.6Hz), 3.94 (s, 3H), 3.97 (m, 2H), 4.15 (t, 2H, J=5.6Hz), 4.71 (4.80, s, 2H), 6.46-6.54 (m, 3H), 7.12 (t, 1H, J=8.0Hz), 7.66 (d, 1H, J=8.4Hz), 7.83 (m, 1H), 8.12 (m, 1H, J=1.2Hz);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-N-(3-phenyl propyl)-1H-benzoglyoxaline-5-carboxylic acid amides (compound 137),
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(3-hydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 138),
1H-NMR (300Mhz, CD
3OD): 2.09 (m, 2H), 3.44 (t, 2H, J=7.4Hz), 3.58 (t, 2H, J=5.6Hz), 3.77 (t, 2H, J=7.4Hz), 4.55 (t, 2H, J=7.1Hz), 7.32 (dd, 1H, J=8.6,1.9Hz), 7.37-7.55 (m, 4H), 7.61 (d, 1H, J=1.9Hz), 7.69 (d, 1H, J=8.4Hz), 7.73-7.88 (m, 4H), 8.11 (s, 1H), 8.28 (d, 1H, J=8.1Hz);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(2, the 3-dihydroxyl) propyl group-N-[2-(2-methoxyl group) phenoxy group ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 139), MS (BioIon) C
29H
32N
8O
5M/e calculated value 572.62; Measured value 573.3 (MH
+);
1H-NMR (300Mhz, CD
3OD): 3.58-3.69 (m, 2H), 3.80 (m, 5H), 4.07 (m, 1H), 4.17 (t, 2H, J=5.3Hz), 4.47 (dd, 1H, J=15.0,8.4Hz), 4.64dd, 1H, J=15.0,3.0Hz), 6.66-7.00 (m, 4H), 7.38 (dd, 1H, J=8.6,1.7Hz), 7.66 (d, 1H, J=1.7Hz), 7.70 (d, 1H, J=8.6Hz), 7.78 (d, 1H, J=8.6Hz), 7.87 (dd, 1H, J=8.6,1.5Hz), 8.24 (d, 1H, J=1.5Hz);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-(2, the 3-dihydroxypropyl)-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 140), MS (BioIon) C
33H
34N
8O
3M/e calculated value 590.7; Measured value 591.3 (MH
+);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-(2, the 3-dihydroxypropyl)-N-[2-(2-methoxyl group phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 141, MS (BioIon) C
29H
30N
8O
6M/e calculated value 586.6; Measured value 587.5 (MH
+);
1H-NMR (300Mhz, CD
3OD): 3.33 (m, 1H), 3.81 (m, 5H), 3.98 (d, 2H, J=4.5Hz), 4.18 (t, 2H, J=5.4Hz), 4.38 (t, 1H, J=12.0Hz), 4.57 (dd, 1H, J=12.0,3.5Hz), 6.85-7.00 (m, 4H), 7.30 (dd, 1H, J=8.7,2.2Hz), 7.60 (d, 1H, J=2.2Hz), 7.64 (d, 1H, J=8.4Hz), 7.74 (d, 1H, J=8.7Hz), 7.80 (dd, 1H, J=8.4,1.5Hz), 8.14 (d, 1H, J=1.5Hz);
2-[5-(1-imino-ethyl) aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl]-3-(2, the 3-dihydroxyl) propyl group-N-[2-(2-methoxyl group) phenoxy group ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 142),
1H-NMR (300Mhz, CD
3OD): 2.28 (s, 3H), 3.64 (m, 2H), 3.80 (s, 3H), 3.79-3.85 (m, 2H), 4.05 (m, 1H), 4.18 (t, 2H, J=5.4Hz), 4.46 (dd, 1H, J=15.0,8.7Hz), 4.62-4.66 (m, 3H), 6.86-7.00 (m, 4H), 7.53 (dd, 1H, J=8.7,1.2Hz), 7.68 (d, 1H, J=8.4Hz), 7.77-7.80 (m, 2H), 7.84 (dd, 1H, J=8.4,1.4Hz), 8.21 (d, 1H, J=1.4Hz);
2-{2-[2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-3H-benzoglyoxaline-5-base carbonylamino] oxyethyl group } methyl benzoate (compound 143), MS (BioIon) C
28H
28N
8O
4M/e calculated value 540.56; Measured value 541.4 (MH
+);
2-{2-[2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-3H-benzoglyoxaline-5-base carbonylamino] oxyethyl group } phenylformic acid (compound 144);
3-{2-[2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-3H-benzoglyoxaline-5-base carbonylamino] oxyethyl group } methyl benzoate (compound 145), MS (BioIon) C
28H
28N
8O
4M/e calculated value 540.5; Measured value 541.4 (MH
+);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-[2-(2, the 6-dimethoxy) phenoxy group ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 146),
1H-NMR (300Mhz, CD
3OD): 3.71 (t, 2H, J=5.3Hz), 3.73 (s, 6H), 4.01 (s, 3H), 4.13 (t, 2H, J=5.3Hz), 6.63 (d, 2H, J=8.4Hz), 6.99 (t, 1H, J=8.4Hz), 7.33 (dd, 1H, J=8.6,1.9Hz), 7.63 (d, 1H, J=1.9Hz), 7.74 (d, 1H, J=8.7Hz), 7.75 (d, 1H, J=8.6Hz), 7.90 (dd, 1H, J=8.7,1.5Hz), 8.21 (d, 1H, J=1.5Hz);
2-(5-guanidine radicals methyl isophthalic acid H-benzimidazolyl-2 radicals-ylmethyl)-3-(2, the 3-dihydroxyl) propyl group-N-[2-(2-methoxyl group phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 147),
1H-NMR (300Mhz, CD
3OD): 3.57-3.69 (m, 2H), 3.80 (m, 5H), 4.05 (m, 1H), 4.17 (t, 2H, J=5.4Hz), 4.45 (dd, 1H, J=15.0,8.7Hz), 4.58-4.65 (m, 3H), 6.85-7.00 (m, 4H), 7.50 (dd, 1H, J=8.7,1.5Hz), 7.67 (d, 1H, J=8.5Hz), 7.72 (d, 1H, J=1.5Hz), 7.76 (d, 1H, J=8.7Hz), 7.82 (dd, 1H, J=8.5,1.4Hz), 8.19 (d, 1H, J=1.4Hz);
2-(5-iminomethyl aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3-(2, the 3-dihydroxyl) propyl group-N-[2-(2-methoxyl group) phenoxy group ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 148),
1H-NMR (300Mhz, CD
3OD): 3.58-3.70 (m, 2H), 3.81 (m, 5H), 4.06 (m, 1H), 4.19 (t, 2H, J=5.4Hz), 4.46 (dd, 1H, J=15.0,8.7Hz), 4.64 (dd, 1H, J=15.0,3.0Hz), 4.69 (4.73, s, 2H), 6.86-7.01 (m, 4H), 7.51 (dd, 1H, J=8.1,1.5Hz), 7.69 (d, 1H, J=8.6Hz), 7.76-7.79 (m, 2H), 7.84 (dd, 1H, J=8.6,1.3Hz), 7.96 (8.12, s, 1H), 8.21 (d, 1H, J=1.3Hz);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-hydroxyl-2-quinolyl-4 ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 149),
1H-NMR (300Mhz, CD
3OD): 3.60 (dd, 1H, J=13.8,7.5Hz), 3.97-4.06 (m, 4H), 5.99 (dd, 1H, J=7.5,3.6Hz), 7.35 (dd, 1H, J=8.7,2.0Hz), 7.65 (d, 1H, J=2.0Hz), 7.69 (d, 1H, J=8.7Hz), 7.77 (d, 1H, J=8.7Hz), 7.84 (dd, 1H, J=8.7,1.5Hz), 7.99 (m, 1H), 8.11-8.18 (m, 2H), 8.26 (d, 1H, J=8.4Hz), 8.33 (d, 1H, J=5.7Hz), 8.88 (d, 1H, J=8.7Hz), 8.15 (d, 1H, J=5.7Hz);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-[2-(3-methyl-2,4-dioxo quinazoline-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 150), MS (BioIon) C
29H
28N
10O
3M/e calculated value 564.6; Measured value 565.5 (MH
+);
2-{2-[2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-methyl-3H-benzoglyoxaline-5-base carbonylamino] oxyethyl group } methyl benzoate (compound 151), MS (BioIon) C
28H
26N
8O
5M/e calculated value 554.5; Measured value 554.8 (MH
+);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(2-hydroxyl) ethyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 152),
1H-NMR (300Mhz, CD
3OD): 3.44 (t, 2H, J=7.4Hz), 3.77 (t, 2H, J=7.4Hz), 3.95 (t, 2H, J=4.9Hz), 4.56 (t, 2H, J=4.9Hz), 7.32 (dd, 1H, J=8.7,1.8Hz), 7.40-7.54 (m, 4H), 7.61 (d, 1H, J=1.8Hz), and 7.67-7.89 (m, 5H), 8.09 (d, 1H, J=1.2Hz), 8.28 (d, 1H, J=8.1Hz);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-[2-(3-oxo-2, the 3-dihydrobenzo [1,4] oxazine-4-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 153),
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-(2-hydroxyethyl)-N-(2-naphthalene-2-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 154),
1H-NMR (300Mhz, CD
3OD): 3.42 (t, 2H, J=7.3Hz), 3.75 (t, 2H, J=7.3Hz), and 4.48-4.51 (m, 2H), 7.29 (dd, 1H, J=8.6,1.9Hz), 7.38-7.52 (m, 4H), 7.58 (d, 1H, J=1.9Hz), 7.62 (d, 1H, J=8.7Hz), 7.71-7.76 (m, 3H), 7.86 (d, 1H, J=8.6Hz), 8.06 (s, 1H), 8.26 (d, 1H, J=8.1Hz);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 155),
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-(3-hydroxypropyl)-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 156),
2-(5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 157),
2-[1-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl) ethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 158), MS (BioIon) C
31H
30N
8O
1M/e calculated value 530.6; Measured value 531.1 (MH
+);
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 159), MS (BioIon) C
33H
29N
7O
1M/e calculated value 539.6; Measured value 540.1 (MH
+);
2-{1-[5-(2-aminooimidazole-1-yl)-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 160), MS (BioIon) C
33H
30N
8O
1M/e calculated value 554.7; Measured value 555.2 (MH
+);
1-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)-3-hydroxyl-1-methyl-N-(2-naphthalene-1-base ethyl)-3,4-dihydro-1H-2-oxa--4a, 9-diaza fluorenes-6-carboxylic acid amides (compound 161),
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-(4-hydroxybutyl)-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 162), MS (BioIon) C
34H
36N
8O
2M/e calculated value 588.7; Measured value 589.3 (MH
+);
3-[2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-6-(2-naphthalene-1-base ethylamino formyl radical) benzoglyoxaline-1-yl] propane-1-sulfonic acid (compound 163), MS (BioIon) C
33H
34N
8O
4Sm/e calculated value 638.7; Measured value 639.2 (MH
+);
3-[2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-6-(2-naphthalene-1-base ethylamino formyl radical) benzoglyoxaline-1-yl] propane-1-sulfonic acid (compound 164), MS (BioIon) C
35H
33N
7O
4S m/e calculated value 647.8; Measured value 648.2 (MH
+);
2-[1-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)-the 2-methyl-propyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 165), MS (BioIon) C
33H
34N
8O
1M/e calculated value 558.7; Measured value 559.6 (MH
+);
2-[1-(1H-imidazo [4,5-c] pyridine-2-yl) ethyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 166), MS (BioIon) C
29H
26N
6O
1M/e calculated value 474.6. measured value 475.2 (MH
+);
2-{5-[1-(N-methyl-imino) ethyl]-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl }-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 167), MS (BioIon) C
31H
33N
7O m/e calculated value 519.71; Measured value 520.9 (MH
+);
Imino-(2-{1-[1-methyl-6-(2-naphthalene-1-base ethylamino formyl radical)-1H-benzimidazolyl-2 radicals-yl] ethyl }-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-yl also) and acetate (compound 168), MS (BioIon) C
31H
31N
7O
3M/e calculated value 549.6; Measured value 550.2 (MH
+);
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base ethyl }-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 169), MS (BioIon) C
31H
33N
7O
1M/e calculated value 519.6; Measured value 520.3 (MH
+);
2-{1-[5-(N-methyl amidino groups)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 170), MS (BioIon) C
31H
34N
8O
1M/e calculated value 534.7; Measured value 535.1 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group)-5-methoxybenzoic acid (compound 171), MS (BioIon) C
29H
30N
8O
5M/e calculated value 570.6; Measured value 571.2 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) m-phthalic acid (compound 172), MS (BioIon) C
29H
30N
8O
5M/e calculated value 570.6; Measured value 571.3 (MH
+);
2-(2-{2-[1-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)-the 1-hydroxyethyl]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group)-6-methoxybenzoic acid (compound 173), MS (BioIon) C
29H
30N
8O
6M/e calculated value 586.6; Measured value 587.2 (MH
+);
2-[2-(ethyl of 2-{1-[5-(N-ethanoyl guanidine radicals)-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 174), MS (BioIon) C
31H
32N
8O
5M/e calculated value 596.6; Measured value 597.2 (MH
+);
2-{1-[5-(N, N-dimethyl amidino groups)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 175);
2-{1-[5-(2-amino-1,1-dimethyl ethyl)-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 176);
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-N-ethyl-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 177);
2-[2-(2-{1-[5-(N-ethanoyl guanidine radicals)-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 178); MS (BioIon) C
30H
30N
8O
5M/e calculated value 582.6; Measured value 583.3 (MH
+);
2-[2-(2-{1-[5-(the amino cyclopropyl of 1-)-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 179); MS (BioIon) C
30H
30N
6O
4M/e calculated value 538.6; Measured value 539.3 (MH
+);
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-(3-methyl butyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 180); MS (BioIon) C
26H
29N
7O
1M/e calculated value 455.6; Measured value 456.2 (MH
+);
2-(1H-benzimidazolyl-2 radicals-Ji ethyl)-3-methyl-N-(2-phenoxy group ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 181); MS (BioIon) C
26H
25N
5O
2M/e calculated value 439.5; Measured value 440.2 (MH
+);
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] ethyl benzoate (compound 182);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2,4-dioxo-3,4-dihydro-2H-quinazoline-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 183);
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-N-(3-methoxy-propyl)-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 184);
N-ethyl-2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 185); MS (BioIon) C
23H
23N
7O
1M/e calculated value 413.5; Measured value 414.1 (MH
+);
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-N-(2-methoxy ethyl)-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 186); MS (BioIon) C
24H
25N
7O
2M/e calculated value 443.5; Measured value 444.2 (MH
+);
1-(2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino)-4-methylvaleric acid (compound 187); MS (BioIon) C
27H
29N
7O
3M/e calculated value 499.6; Measured value 500.3 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 188); MS (BioIon) C
30H
27N
7O
4M/e calculated value 549.6; Measured value 550.2 (MH
+);
2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino)-4-methylvaleric acid (compound 189);
2-{1-[5-(N, N-dimethyl amidino groups)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 190); MS (BioIon) C
39H
34N
8O
4M/e calculated value 558.6; Measured value 559.3 (MH
+);
2-[2-(2-{1-[5-(2-carboxyl-1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 191); MS (BioIon) C
29H
31N
7O
6M/e calculated value 573.6; Measured value 530.3 (MH
+); CO
2Loss;
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-(2-methoxy ethyl)-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 192); MS (BioIon) C
32H
31N
7O
5M/e calculated value 593.6; Measured value 594.2 (MH
+);
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-(2-methoxy ethyl)-N-(2-methoxy ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 193); MS (BioIon) C
26H
29N
7O
3M/e calculated value 487.6; Measured value 488.2 (MH
+);
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-(2-methoxy ethyl)-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 194);
3-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 195); MS (BioIon) C
28H
28N
8O
4M/e calculated value 540.6; Measured value 541.3 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-(2-methoxy ethyl)-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 196); MS (BioIon) C
30H
32N
8O
5M/e calculated value 584.6; Measured value 585.3 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-(3-sulfo group propyl group)-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 197); MS (BioIon) C
30H
32N
8O
7S m/e calculated value 648.7; Measured value 649.6 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-(3-sulfo group propyl group)-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 198); MS (BioIon) C
32H
31N
7O
7S m/e calculated value 657.7; Measured value 658.4 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-3-methyl-3H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 199); MS (BioIon) C
31H
29N
7O
4M/e calculated value 563.6; Measured value 564.2 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-(2-hydroxypropyl)-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 200); MS (BioIon) C
32H
31N
7O
5M/e calculated value 593.6; Measured value 594.3 (MH
+);
2-{2-[2-(1-{5-[1-(N-oxyimino) ethyl]-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl } ethyl)-3-methyl-3H-benzoglyoxaline-5-base carbonylamino] oxyethyl group } phenylformic acid (compound 201);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 202); MS (BioIon) C
30H
32N
8O
4M/e calculated value 568.6; Measured value 569.5 (MH
+);
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base carbonylamino also) oxyethyl group] ethyl benzoate (compound 203); MS (BioIon) C
28H
36N
8O
4M/e calculated value 549.0; Measured value 548.2 (MH
+);
4-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } ethyl butyrate (compound 204); MS (BioIon) C
25H
30N
8O
3M/e calculated value 490.57; Measured value 491.3 (MH
+);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-tetrazolium-1-phenoxyl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 205); MS (BioIon) C
28H
28N
12O
2M/e calculated value 564.56; Measured value 565.3 (MH
+);
2-[2-(2-{1-[5-(1-imino-ethylamino)-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 206); MS (BioIon) C
31H
33N
7O
4M/e calculated value 567.6; Measured value 568.4 (MH
+);
4-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 207); MS (BioIon) C
30H
32N
8O
4M/e calculated value 568.6; Measured value 569.4 (MH
+);
5-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) m-phthalic acid (compound 208); MS (BioIon) C
29H
28N
8O
6M/e calculated value 584.6; Measured value 585.3 (MH
+);
4-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 209); MS (BioIon) C
28H
28N
8O
4M/e calculated value 540.6; Measured value 541.2 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-(2-hydroxypropyl)-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 210); MS (BioIon) C
30H
32N
8O
5M/e calculated value 584.6; Measured value 585.4 (MH
+);
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-methoxyl group phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 211); MS (BioIon) C
30H
29N
7O
2M/e calculated value 535.6; Measured value 536.3 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 212); MS (BioIon) C
27H
26N
8O
4M/e calculated value 526.6; Measured value 527.2 (MH
+);
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-(2-phenoxy group ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 213); MS (BioIon) C
29H
27N
7O
2M/e calculated value 505.6; Measured value 506.2 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-1H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 214); MS (BioIon) C
29H
25N
7O
4M/e calculated value 535.6; Measured value 536.4 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group]-4-tolyl acid ethyl ester (compound 215); MS (BioIon) C
31H
34N
8O
4M/e calculated value 582.7; Measured value 583.5 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-benzoglyoxaline-5-base carbonylamino) oxyethyl group]-4-tolyl acid (compound 216); MS (BioIon) C
29H
30N
8O
4M/e calculated value 554.6; Measured value 555.5 (MH
+);
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base carbonylamino also) oxyethyl group] benzoic ether (compound 217); MS (ESI) C
26H
32N
8O
4M/e calculated value 520.58; Measured value 521.3 (MH
+);
2-(2-{2-[5-(N-methyl amidino groups)-1H-benzimidazolyl-2 radicals-ylmethyl]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 218); MS (BioIon) C
30H
31N
7O
4M/e calculated value 553.6; Measured value 554.3 (MH
+);
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-(3-sulfo group propyl group)-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 219); MS (BioIon) C
30H
35N
7O
7M/e calculated value 637.7; Measured value 638.3 (MH
+);
2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino)-4-methylvaleric acid ethyl ester (compound 220);
2-{2-[2-(1-{5-[1-(N-oxyimino) ethyl]-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group } ethyl benzoate (compound 221);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-methoxyl group phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 222); MS (BioIon) C
27H
27N
5O
3M/e calculated value 469.5; Measured value 469.5 (MH
+);
2-[1-(ethyl of 6-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-carboxylic acid 2-(2-ethoxy carbonyl phenoxy group) ethyl ester (compound 223) also; MS (BioIon) C
28H
32N
8O
5M/e calculated value 560.62; Measured value 561.3 (MH
+);
4-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } butyric acid (compound 224); MS (BioIon) C
23H
26N
8O
3M/e calculated value 462.52; Measured value 462.8 (MH
+);
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-[2-(2-tetrazyl phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 225); MS (ESI) C
28H
31N
11O
2M/e calculated value 553.6; Measured value 553.6 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid isopropyl esters (compound 226); MS (BioIon) C
33H
33N
7O
4M/e calculated value 591.3; Measured value 591.4 (MH
+);
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-[2-(3-tetrazyl phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 227); MS (BioIon) C
28H
31N
11O
2M/e calculated value 553.59; Measured value 553.5 (MH
+);
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-[2-(4-tetrazyl phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 228); MS (ESI) C
28H
31N
11O
2M/e calculated value 553.59; Measured value 553.5 (MH
+);
2-(2-{2-[1-(5-imidazoles-1-yl)-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) ethoxybenzoic acid cyclohexyl ester (compound 229); MS (ESI) C
36H
37N
7O
4M/e calculated value 631.3; Measured value 631.5 (MH
+);
2-[2-(2-{1-[5-(N-methyl amidino groups)-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 230); MS (BioIon) C
28H
27N
7O
4M/e calculated value 525.6; Measured value 525.5 (MH
+);
2-[2-(2-{1-[5-(1-imino-ethylamino)-1H-benzimidazolyl-2 radicals-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid (compound 231); MS (BioIon) C
29H
29N
7O
4M/e calculated value 539.6; Measured value 539.8 (MH
+);
2-(3-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base carbonyl also } propoxy-) phenylformic acid (compound 232); MS (BioIon) C
27H
30N
8O
4M/e calculated value 530.60; Measured value 531.7 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base formyl radical oxygen base also } oxyethyl group) phenylformic acid (compound 233); MS (BioIon) C
26H
28N
8O
5M/e calculated value 532.56; Measured value 533.2 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid 2-methoxy ethyl ester (compound 234); MS (BioIon) C
33H
33N
7O
5M/e calculated value 607.3; Measured value 607.4 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid isobutyl (compound 235); MS (BioIon) C
34H
35N
7O
4M/e calculated value 605.3; Measured value 605.4 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid 2-(2-methoxy ethoxy) ethyl ester (compound 236); MS (BioIon) C
35H
37N
7O
6M/e calculated value 651.3; Measured value 651.3 (MH
+);
2-(2-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid butyl ester (compound 237); MS (BioIon) C
34H
35N
7O
4M/e calculated value 605.3; Measured value 605.4 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(3-oxo-2,3-dihydrobenzo [1,4] oxazine-4-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 238); MS (BioIon) C
28H
26N
6O
3M/e calculated value 494.2; Measured value 494.5 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-fluorophenoxy) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 239);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(3-fluorophenoxy) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 240);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-isopropoxy phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 241); MS (BioIon) C
29H
31N
5O
3M/e calculated value 497.2; Measured value 497.6 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-methylphenoxy) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 242); MS (BioIon) C
27H
27N
5O
2M/e calculated value 453.2; Measured value 453.5 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-ethoxy phenoxy) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 243); MS (BioIon) C
28H
29N
5O
3M/e calculated value 483.2; Measured value 483.5 (MH
+);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[2-(2-methoxyl group phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 244); MS (BioIon) C
28H
30N
8O
3M/e calculated value 526.6; Measured value 526.8 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base carbonylamino also } oxyethyl group) ethyl benzoate (compound 245); MS (BioIon) C
28H
33N
9O
4M/e calculated value 559.6; Measured value 559.6 (MH
+);
2-(2-{2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid 2-methoxy ethyl ester (compound 246); MS (BioIon) C
30H
31N
5O
4M/e calculated value 541.6; Measured value 541.5 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 247); MS (BioIon) C
29H
30N
8O
4M/e calculated value 554.6; Measured value 555.4 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 248); MS (BioIon) C
28H
28N
8O
4M/e calculated value 540.6; Measured value 541.3 (MH
+);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-carbamyl phenoxyl) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 249); MS (BioIon) C
28H
29N
9O
3M/e calculated value 539.6; Measured value 540.5 (MH
+);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-formamyl-4-chlorophenoxy) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 250); MS (BioIon) C
28H
28N
9O
3Cl m/e calculated value 574.0; Measured value 574.2 (MH
+);
4-chloro-2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 251); MS (BioIon) C
28H
27N
8O
4Cl m/e calculated value 575.0; Measured value 575.2 (MH
+);
5-chloro-2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 252); MS (BioIon) C
28H
27N
8O
4Cl m/e calculated value 575.0; Measured value 575.2 (MH
+);
6-chloro-2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 253); MS (BioIon) C
28H
27N
8O
4Cl m/e calculated value 575.0; Measured value 575.2 (MH
+);
4,6-two chloro-2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid (compound 254); MS (BioIon) C
28H
26N
8O
4Cl
2M/e calculated value 609.5; Measured value 609.1 (MH
+);
2-(2-{2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) ethyl benzoate (compound 255); MS (BioIon) C
29H
29N
5O
4M/e calculated value 511.6; Measured value 512.2 (MH
+);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-{2-[2,4-dioxo-3-(2-trimethyl silyl ethyl)-3,4-dihydro-2H-quinazoline-1-yl] ethyl }-3H-benzoglyoxaline-5-carboxylic acid amides (compound 256); MS (BioIon) C
34H
40N
10O
3Si m/e calculated value 664.8; Measured value 665.4 (MH
+);
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-{2-[2,4-dioxo-3,4-dihydro-2H-quinazoline-1-yl] ethyl }-3H-benzoglyoxaline-5-carboxylic acid amides (compound 257); MS (BioIon) C
29H
28N
10O
3M/e calculated value 564.6; Measured value 565.2 (MH
+);
2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-cyano-benzene oxygen) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 258); MS (BioIon) C
27H
24N
6O
2M/e calculated value 454.5; Measured value 465.1 (MH
+);
5-(2-{2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) m-phthalic acid (compound 259); MS (BioIon) C
28H
25N
5O
6M/e calculated value 527.5; Measured value 528.4 (MH
+);
2-(2-{2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid 2-(2-methoxy ethoxy) ethyl ester (compound 260); MS (BioIon) C
32H
35N
5O
6M/e calculated value 585.7; Measured value 585.4 (MH
+);
2-(2-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base carbonylamino also } oxyethyl group) phenylformic acid (compound 261); MS (BioIon) C
29H
29N
9O
4M/e calculated value 531.6; Measured value 531.5 (MH
+);
2-[1-(1H-imidazo [4,5-c] pyridine-2-yl) ethyl]-N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 262); MS (BioIon) C
26H
26N
6O
3M/e calculated value 470.54; Measured value 471.4 (MH
+);
2-[1-(ethyl of 5-fluoro-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 263); MS (BioIon) C
27H
26N
5O
3Fm/e calculated value 487.54; Measured value 488.1 (MH
+);
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-(2-tetrazolium-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides (compound 264); MS (ESI) C
24H
23N
11Om/e calculated value 481.47; Measured value 482.6 (MH
+);
2-[1-(ethyl of 4-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 265); MS (BioIon) C
27H
27N
5O
4M/e calculated value 485.59; Measured value 486.3 (MH
+);
2-[1-(the amino benzoxazole of 4--2-yl) ethyl]-N-[2-(2-methoxyl group phenoxy group) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 266); MS (BioIon) C
27H
27N
5O
4M/e calculated value 485.59; Measured value 486.1 (MH
+);
3-{2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-6-[2-(2-methoxyl group phenoxy group) ethylamino formyl radical] benzoglyoxaline-1-yl } propane-1-sulfonic acid (compound 267), MS (BioIon) C
29H
31N
5O
6S m/e calculated value 577.66; Measured value 577.4 (MH
+);
3-{2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-6-[2-(2-methoxyl group phenoxy group) ethylamino formyl radical] benzoglyoxaline-1-yl } propane-1-sulfonic acid (compound 268), MS (BioIon) C
32H
33N
7O
6S m/e calculated value 643.72; Measured value 644.6 (MH
+);
2-[2-(ethyl of 2-{1-[1-(2-methoxy ethyl)-1H-benzimidazolyl-2 radicals-yl) }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group) ethyl benzoate (compound 269); MS (BioIon) C
32H
35N
5O
5M/e calculated value 569.66; Measured value 570.5 (MH
+);
2-[1-(ethyl of 5-imidazoles-1-base-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-carboxylic acid benzyl ester (compound 270) also; MS (BioIon) C
29H
30N
8O
6M/e calculated value 586.6; Measured value 587.2 (MH
+);
2-(4-{2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-yl also }-4-oxo butoxy) ethyl benzoate (compound 271);
1-{2-[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-yl also }-4-(2-methoxyl group phenoxy group) fourth-1-ketone (compound 272);
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-N-(2-naphthalene-1-base ethyl) imidazo [1,2-a] pyridine-6-carboxylic acid amides (compound 273);
N-[3-(2-ethoxyl phenenyl) propyl group]-2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 274), MS (BioIon) C
29H
31N
5O
3M/e calculated value 497.62; Measured value 497.4;
N-[3-(2-butoxy phenyl) propyl group]-2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 275), MS (BioIon) C
31H
35N
5O
3M/e calculated value 525.65; Measured value 526.3;
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-N-[3-(2-propoxy-phenyl) propyl group]-3H-benzoglyoxaline-5-carboxylic acid amides (compound 276), MS (BioIon) C
30H
33N
5O
3M/e calculated value 511.62; Measured value 512.3;
2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-N-{2-[2-(3-methyl-[1,2,4]-oxadiazole-5-yl) phenoxy group] ethyl }-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides (compound 277), MS (BioIon) C
29H
27N
7O
4M/e calculated value 538.1; Measured value 537.58;
2-(2-{2-[1-(ethyl of 4-fluoro-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group) ethyl benzoate (compound 278); MS (ESI) C
29H
28N
5O
5F m/e calculated value 545.57; Measured value 545.6;
2-(2-{2-[1-(ethyl of 4-fluoro-5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group) phenylformic acid (compound 279); MS (BioIon) C
27H
24N
5O
5F m/e calculated value 517.52; Measured value 517.4;
2-(2-{2-[1-(ethyl of 6-fluoro-4-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group) ethyl benzoate (compound 280); MS (BioIon) C
29H
28N
5O
5F m/e calculated value 545.57; Measured value 545.9;
2-(2-{2-[1-(ethyl of 6-fluoro-4-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group) phenylformic acid (compound 281); MS (BioIon) C
27H
24N
5O
5F m/e calculated value 517.52; Measured value 517.6;
2-(2-{2-[1-(4, the ethyl of 5-two fluoro-7-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group) ethyl benzoate (compound 282); MS (BioIon) C
29H
27N
5O
5F
2M/e calculated value 563.56; Measured value 563.9; With
2-(2-{2-[1-(4, the ethyl of 5-two fluoro-7-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group) phenylformic acid (compound 283); MS (ESI) C
29H
27N
5O
5F
2M/e calculated value 536.1; Measured value 535.51.
Embodiment 13
External tryptase suppresses to measure
The tryptase of purifying is dissolved in preparation tryptase solution (60g/ml) in the solvent mixture.Used tryptase comes from people's lung or skin histology preparation or people's mast cell line (HMC-1) or commercially available, as ICN Biomeidals, and Irvine, California, AthensResearch ﹠amp; Technology, Athens, Georgia etc., described solvent mixture comprises: 10mM 2-N-morpholino ethane sulfonic acid, 2mM CaCl
2, 20% glycerine and 50g/ml heparin.Substrate solution comprises that 2mM derives from the synthetic tripeptides of Sigma company (tosyl group-Gly-Pro-Lys-right-p-nitroanilide).Experimental compound solution is prepared as follows: ten times of stock solutions (the 1mg experimental compound is dissolved in the 200 μ l methyl-sulphoxides (DMSO)) are diluted in the mensuration damping fluid (comprise: Tris-HCl (pH 8.2), 50mM; NaCl, 100mM; The single lauryl (Tween-20 ) of 0.05% polyoxyethylene sorbitol; And zinc chloride, 150 μ M) in, and then in 10%DMSO mensuration damping fluid, do seven three times of extra dilutions.
Take out aliquots containig (50 μ l) in from eight diluents of experimental compound solution each, join in the U-shape titer plate hole separately, 96 hole.(25 μ l) joins in each hole with tryptase solution, at room temperature solution mixed 1 hour.Adding substrate solution (25 μ l) also moves on to titer plate under the UV/MAX KineticMicroplate Reader (Molecular Devices) immediately with initial enzyme reaction.The then hydrolysis 5 minutes of chromatographic determination color-producing bodies under 405 nanometers.With dynamic analysis software (BatchKi; Peter Kuzmic, University of Wisconsin, Madison WI) calculates starting velocity from carrying out curve (progress curve).With the standard mathematical model from enzymolysis march line computation apparent inhibition constant (Ki).
Use the program of the application's description or the method that those skilled in the art knew, the tryptase of having measured following compound of the present invention suppresses active:
Compound 1, K
i=0.09 μ M; Compound 12, K
i=29 μ M; Compound 26, K
i=33 μ M; Compound 27, K
1=0.6 μ M; Compound 28, K
i=0.00007 μ M; Compound 29, K
i=0.0008 μ M; Compound 30, K
i=0.009 μ M; Compound 37, K
i=0.002 μ M; Compound 42, K
i=0.008 μ M; Compound 43, K
i=0.002 μ M; Compound 74, K
i=0.006 μ M; Compound 75, K
i=0.03 μ M; Compound 80, K
i=0.01 μ M; Compound 81, K
i=0.01 μ M; Compound 84, K
i=2.6 μ M; Compound 102, K
i=0.00007 μ M; Compound 112, K
i=0.00005 μ M; Compound 115, K
i=0.003 μ M; Compound 116, K
i=0.006 μ M; Compound 117, K
i=0.008 μ M; Compound 126, K
i=0.008 μ M; Compound 127, K
i=0.006 μ M; Compound 128, K
i=0.002 μ M; Compound 169, K
i=0.001 μ M; Compound 132, K
i=0.00002 μ M; Compound 134, K
i=0.00002 μ M; Compound 138, K
i=0.0002 μ M; Compound 152, K
i=0.0005 μ M; Compound 182, K
i=0.004 μ M; Compound 194, K
i=0.009 μ M; Compound 203, K
i=0.008 μ M; Compound 225, K
i=0.008 μ M; Compound 249, K
i=0.0007 μ M; Compound 250, K
i=0.0004 μ M; Compound 251, K
i=0.0008 μ M; With compound 252, K
i=0.0004 μ M.
Embodiment 14
The sheep model of asthma
The irritated sheep model of asthma is used to estimate the sick effect of anti-asthma of compound of the present invention.These methods before came forth and (saw Abraham et al. (1983) Am.Rev.Respir.Dis.128:839-844; Allegra et al. (1983) J.Appl.Physiol.55:726-730; Russi et al. (1985) J.Appl.Physiol.59:1416-1422; Soler et al. (1989) J.Appl.Physiol.67:406-413).Every sheep is all as oneself contrast.The body weight of these animals is distributed in the 20-50 kilogram scope.
In these researchs, 1mg compound 13 is dissolved in the 3ml distilled water, antigen attack preceding 0.5 hour, attack back 4 hours and 24 hours this solution used (total dose=1mg as aerosol; N=3).Fig. 1 is listed in these result of experiment letters.
In control group and drug study group, to attack back 24 hours at antigen, sheep is developed the hyperergy that airway.Use PC400, the carbachol concentration of promptly bringing SRL400% to increase is represented the hyperergy of airway; Thereby hyperergy is just being represented in the reduction of PC400.Find that compound 13 can stop the beginning of hyperergy.As shown in Figure 2, this compound can maintain PC400 15 breathing units on the baseline substantially.In the animal of blank group, breathe the unit number and reduce to 7.Thereby, will in the sheep of being attacked by antigen, cause the remarkable improvement of airway function with the treatment of compound 13.
Thereby, the invention provides and can stop and treat useful compound and composition, particularly those diseases that are associated with respiratory tract, as asthma and hyperergy stage of being associated with the chronic asthma disease, allergic rhinitis in addition immune-mediated inflammation is disorderly.The method of a kind of treatment to the immune-mediated inflammation disorder of compound sensitivity of the present invention that provide also is provided in the present invention.
The above description that it should be understood that this paper is to be used for explanation rather than to be used to limit of the present invention.Many embodiments are conspicuous for the those of ordinary skill in the art who has read behind the above-mentioned specification sheets.Therefore, scope of the present invention should not determine by consulting above-mentioned specification sheets, and should be determined by appending claims and four corner that these claims covered.
Claims (26)
1. compound in structural formula I and its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt:
Wherein
N1 is 0 or 1;
N2 is 0,1,2,3 or 4;
N3 is 0,1,2,3 or 4;
A comprises with B and contains the assorted bicyclic radicals of condensing of 8-12 ring atom, and wherein each ring contains 5-7 ring and goes up the member, is heteroatoms each ring atom arbitrariness, X
1And X
2Be member on the two adjacent rings of aromatic ring, and X
1Be be selected from-N=,-NR
5-,-O-and-the heteroatoms structure division of S-, wherein R
5Be hydrogen, (C
1-C
6) alkyl or assorted (C
2-C
6) alkyl;
C comprises the many cyclic groups of mixing that condense that contain 8-18 ring atom, and wherein each ring contains upward member of 5-7 ring, is heteroatoms each ring atom arbitrariness, X
4And X
5Be member on two adjacent ring of aromatic ring, X
5Be be selected from-N=,-NR
6-,-O-and-the heteroatoms structure division of S-, wherein R
6Be hydrogen, be selected from (C
1-C
8) alkyl or assorted (C
2-C
12) group of alkyl, this group arbitrariness ground is independently selected from (C by one or two
1-C
6) alkanoyloxy, (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, three (C
1-C
6) alkylamino, (C
1-C
6) alkyl-carbamoyl, two (C
1-C
6) alkyl-carbamoyl, (C
1-C
6) alkyl oxy, C
1-C
6) alkyl oxy carbonyl, (C
1-C
6) alkyl oxy alkylsulfonyl, amino, carboxyl, formamyl, (C
6-C
14) aryl, halogen, assorted (C
5-C
14) substituting group of aryl, hydroxyl and sulfo group replaces; Or such as following definition with and any carbocyclic ring ketone, sulfo-ketone and imino-ketone deriveding group;
X
3Be-O-,-S-,-S (O)-,-S (O)
2-,-C (O)-,-NR
7-or-CR
7R
8-, R wherein
7Be hydrogen, (C
1-C
6) alkyl, assorted (C
2-C
12) alkyl or and R
6Form (C together
2-C
4) alkylidene group or assorted (C
2-C
4) alkylidene group, and R
8Be hydrogen, (C
1-C
6) alkyl or hydroxyl or and R
7Form (C together
2-C
6) alkylidene group or (C
1-C
6) alkylidene, comprising R
7And/or R
8Any aliphatic series or alicyclic structure part arbitrariness ground be selected from (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, three (C
1-C
6) alkylamino, (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxy carbonyl, (C
1-C
6) alkanoyloxy, amino, carboxyl, formamyl, (C
1-C
6) alkyl-carbamoyl, two (C
1-C
6) 1 to 3 substituting group of alkyl-carbamoyl, halogen and hydroxyl replaces;
R
1Be amino (N
1-4) pyrrolidyl, amino (N
1-4) pyrryl, (N
1-4) pyrrolidyl, (N
1-4) pyrryl, formamyl, cyano group ,-(CH
2)
xNHC (NR
9) R
9,-(CH
2)
xNHC (NH) NR
9R
9,-C (NR
9) R
9-,-C (NH) NHR
10-,-C (NH) NR
10R
10Or-(CR
11R
11)
yNH
2And be bonded in any ring atom that belongs to B with effective valence state, and wherein x is 0 or 1, y is 0,1,2 or 3, each R
9Be hydrogen or (C independently
1-6) alkyl, each R
10Be (C independently
1-6) alkyl, and each R
11Be hydrogen, (C independently
1-3) alkyl or with another R
11Form cyclopropyl with carbon atom (both links to each other with this carbon atom), wherein belong to R
1Any aliphatic series or alicyclic structure part arbitrariness ground be independently selected from (C by one or two
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) substituting group of alkyl sulphonyl and hydroxyl replaces.
Each R
2Be (C independently
1-6) alkyl, (C
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, (C
1-6) alkoxyl group, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) alkyl sulphinyl, (C
1-6) alkyl sulphonyl, (C
1-6) alkylthio, halogen or hydroxyl and be bonded in any ring atom with effective valence state that belongs to B, wherein belong to R
2Any aliphatic structure part arbitrariness ground be independently selected from (C by one or two
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) substituting group of alkyl sulphonyl and hydroxyl replaces;
Each R
3Be (C independently
1-6) alkyl, (C
1-6) alkoxyl group, (C
1-6) alkylthio, cyano group, halogen, perhalogeno (C
1-6) alkyl or hydroxyl and be bonded in any ring atom with effective valence state that belongs to C; And
R
4Be-R
12-,-OR
12,-N (R
13) R
12,-SR
12,-S (O) R
12,-S (O)
2R
12,-S (O)
2OR
12,-S (O)
2N (R
13) R
12,-N (R
13) S (O)
2R
12,-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12,-N (R
13) C (O) R
12,-OC (O) N (R
13) R
12,-N (R
13) C (O) OR
12,-(CH
2)
zN (R
13) C (O) N (R
13) R
12,-OP (O) (OR
13) OR
12Or-C (O) N (R
14) CH (COOH) R
12And be bonded in any ring atom that belongs to C with effective valence state, wherein
Z is 0,1 or 2,
R
12Be-R
15Or-X
6-(R
15)
N15, wherein n15 is 1 or 2, X
6Be (C
1-0) alkylene
Base, ring (C
3-6) alkylidene group, assorted (
2-10) alkylidene group or heterocycle (C
3-10) alkylidene group and each
R
15Be hydrogen, (C independently
6-14) aryl, ring (C
3-14) alkyl, many ring (C
6-14) aryl, assorted
Many ring (C
6-14) aryl, heterocycle (C
3-14) alkyl, assorted (C
5-14) aryl or as following definition,
R
13Be hydrogen, (C
1-6) alkyl or assorted (C
2-6) alkyl;
R
14Be hydrogen, (C
1-6) alkyl or and X
6And R
15Form (C together
3-4) alkylidene group;
Belong to R
4Any aliphatic series or alicyclic structure part arbitrariness ground by 1-5 solely
On the spot be selected from (C
1-6) alkyl, (C
1-6) alkylamino, two (C
1-6) alkylamino, (C
1-6) alkane
Base formamyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) alkoxyl group, (C
1-6) alkane
Oxygen base carbonyl, (C
1-6) alkyl sulphinyl, (C
1-6) alkyl sulphonyl, (C
1-6) alkylthio,
Amino, (C
6-10) aryl sulfonyl, formamyl, carboxyl, cyano group, guanidine radicals, halogen,
The substituting group of hydroxyl, sulfydryl and urea groups replaces; With
Belong to R
15Any aromatic structure part arbitrariness ground be independently selected from by 1-3
(the C that cyano group, guanidine radicals, halogen, halogen replace
1-8) alkyl ,-R
16,-OR
16,-SR
16,
-S (O) R
16,-S (O)
2R
16,-S (O)
2N (R
13) R
16,-C (O) R
16,-C (O) OR
16With
-C (O) N (R
13) (R
16) substituting group replace R wherein
13As defined above and R
16
Be hydrogen, optional mono-substituted (C
1-8) (wherein said optional substituting group is (C to alkyl
1-6) alkyl
Amino, two (C
1-6) alkylamino, three (C
1-6) alkylamino, (C
1-6) alkyl carbamoyl
Base, two (C
1-6) alkyl-carbamoyl, (C
1-6) alkoxy carbonyl, (C
1-6) alkoxyl group sulphur
Acyl group, amino, carboxyl, formamyl, hydroxyl or sulfo group), the ring (C
3-6) alkyl, assorted
(C
1-8) alkyl, assorted (C
5-6) aryl, heterocycle (C
3-6) alkyl or phenyl; Precondition be when n2 be 0 or R
2Be (C
1-6) alkyl or (C
1-6) alkoxyl group, n3 is 0 or R
3Be (C
1-6) alkyl or (C
1-6) alkoxyl group and R
4Be hydrogen, (C
1-10) alkyl or (C
1-6) during alkoxyl group, n1 is not 0.
2. the compound of claim 1 and its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt, wherein A contains member on 5 rings, and B contains member on 6 rings, X
1And X
5Adjacent member on Shi oxazole-2-base, 1H-imidazoles-2-base or the thiazol-2-yl ring.
Wherein
Dotted line is represented dispensable key independently;
Each R
2Be (C independently
1-6) alkyl, (C
1-6) alkoxyl group, halogen or hydroxyl;
Each R
3Be (C independently
1-6) alkyl, (C
1-6) alkoxyl group, halogen or hydroxyl;
X
3Be-C (O)-or-CR
7R
8-;
X
8Be-CH (R
1) n
1-or-C (R
1) n
1=, R wherein
1Be amino (N
1-4) pyrrolidyl, amino (N
1-4) pyrryl, (N
1-4) pyrrolidyl, (N
1-4) pyrryl ,-NHC (NH) NR
9R
9,-C (NR
9) R
9,-C (NH) NHR
10,-C (NH) NR
10R
10Or-(CR
11R
11)
yNH
2, or X
8Be-N=or-NH (R
1)
N1-, R wherein
1Be-C (NR
9) R
9,-C (NH) NHR
10Or-C (NH) NR
10R
10, each R wherein
9Be hydrogen or (C independently
1-6) alkyl and each R
10Be (C independently
1-6) alkyl; And
X
9Be-CH (R
4)-or-C (R
4)=, be R wherein
4Be-R
12,-OR
12,-N (R
13) R
12,-SR
12,-S (O) R
12,-S (O)
2R
12, S (O)
2OR
12,-S (O)
2N (R
13) R
12,-N (R
13) S (O)
2R
12,-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12,-N (R
13) C (O) R
12,-OC (O) N (R
13) R
12,-N (R
13) C (O) OR
12,-(CH
2)
N4N (R
13) C (O) N (R
13) R
12,-OP (O) (OR
13) OR
12Or-C (O) N (R
14) CH (COOH) R
12, or X
9Be-N=or-N (R
4)-, be R wherein
4Be-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12,-OC (O) N (R
13) R
12Or-C (O) N (R
14) CH (COOH) R
12
4. the compound of claim 3 and its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt, wherein
R
5Be hydrogen or (C
1-4) alkyl, R
6Be hydrogen or (C
1-4) alkyl, this alkyl arbitrariness ground is independently selected from (C by one or two
1-4) substituting group of alkoxyl group, hydroxyl and sulfo group replaces R
7Be hydrogen or methyl and R
8Be hydrogen, methyl or hydroxyl;
X
8Be-C (R
1)
N1=, R wherein
1Be the amino cyclopropyl of amino methyl, 1-, 2-aminooimidazole-1-base, 2-amino-1,1-dimethyl ethyl, imidazolyl, tetrazyl ,-(CH
2)
xNHC (NR
9) R
9,-(CH
2)
xNHC (NH) NR
9R
9Or-C (NR
9) R
9, each R wherein
9Be hydrogen or methyl independently, or X
8Be-N (R
1)
N1-, R wherein
1Be-C (NR
9) R
9,-C (NH) NHR
10Or-C (NH) NR
10R
10, each R wherein
9Be hydrogen or methyl and each R independently
10Be methyl, wherein belong to R
1Any aliphatic series or alicyclic structure part arbitrariness ground replaced by 1-2 substituting group that is independently selected from methyl sulphonyl and carboxyl;
X
9Be-C (R
4)=, be R wherein
4Be-R
12,-OR
12,-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12Or-C (O) N (R
14) CH (COOH) R
12, R wherein
13And R
14Be hydrogen or (C independently
1-6) alkyl; R
12Be-R
15Or-X
6-(R
15)
N15, X wherein
6Be (C
1-10) alkylidene group or assorted (C
2-10) alkylidene group and each R
15Be hydrogen, (C independently
6-14) aryl, ring (C
3-14) alkyl, many ring (C
6-14) aryl, much more assorted ring (C
6-14) aryl, heterocycle (C
3-14) alkyl or assorted (C
5-14) aryl;
Belong to R
4Any aliphatic series and alicyclic structure part arbitrariness ground be independently selected from (C by 1-5
1-4) alkoxyl group, (C
1-4) substituting group of alkoxy carbonyl, amino, formamyl, carboxyl and hydroxyl replaces; With
Belong to R
15Any aromatic structure part arbitrariness ground be independently selected from (C by 1 to 3
1-4) alkyl, (C
1-4) alkoxyl group, (C
1-4) alkoxy carbonyl, formamyl, carboxyl, cyano group, ring (C
3-6) alkoxyl group, halogen, assorted (C
1-8) alkyl, hydroxyl, assorted (C
1-8) alkyl-carbonyl, assorted (C
5-6) substituting group of aryl and trifluoromethyl replaces.
5. the compound of claim 4; And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt,
Wherein
A comprises 4,5,6 with B, 7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base, and wherein n2 is 0, R
1Be-C (NR
9) R
9And R
5Be hydrogen, or A comprise 1H-benzimidazolyl-2 radicals-Ji or 4,5,6 with B, 7-tetrahydrochysene-1H-benzimidazolyl-2 radicals-Ji, wherein R
1Be amino methyl or guanidine radicals and each R
2Be halogen or hydroxyl independently;
C comprises 4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base or 1H-benzimidazolyl-2 radicals-Ji, wherein R
4Be-C (O) X
6-R
15,-C (O) OX
6-R
15Or-C (O) NHX
6-R
15, X wherein
6Be (C
1-4) alkylidene group or assorted (C
2-4) alkylidene group and R
15Be (C
6-10) aryl, (C
6-10) aryloxy, many ring (C
6-10) aryl, assorted (C
5-10) aryl, assorted (C
5-10) aryloxy or assorted many ring (C
6-14) aryl; With
Any aromatic structure part that belongs to R15 is independently selected from (C by 1-3
1-4) alkyl, (C
1-4) alkoxyl group, (C
1-4) substituting group of alkoxy carbonyl, carboxyl, formamyl, halogen, hydroxyl and tetrazolium-1-base replaces.
6. the compound of claim 5, wherein A comprises 1H-benzimidazolyl-2 radicals-Ji and each R with B
2Be halogen or hydroxyl independently; And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt.
7. the compound of claim 6, wherein n1 is 0; And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt.
8. the compound of claim 7 and its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt, described compound is selected from:
2-(2-{2-[1-(4,6, the ethyl of 7-three fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid;
2-(2-{2-[1-(5, the ethyl of 6-two fluoro-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) phenylformic acid;
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) butyl benzoate;
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) propyl benzoate; With
2-(2-{2-[1-(ethyl of 5-hydroxyl-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonylamino } oxyethyl group) isobutyl benzoate.
9. the compound of claim 5, wherein R
1Be guanidine radicals or amino methyl; And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt.
10. the compound of claim 9 and its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt, described compound is selected from:
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(3-{2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base carbonylamino also } propoxy-) ethyl benzoate;
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(2, the 3-dihydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-Ji carbonyl)-3-(2, the 3-dihydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(3-hydroxyl) propyl group-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(5-guanidine radicals-1H-benzimidazolyl-2 radicals-ylmethyl)-3-(2-hydroxyl) ethyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-carbamyl phenoxyl) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-N-[2-(2-formamyl-4-chlorophenoxy) ethyl]-3-methyl-3H-benzoglyoxaline-5-carboxylic acid amides;
4-chloro-2-[2-(2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonyl } amino) oxyethyl group] phenylformic acid;
5-chloro-2-[2-(2-[1-(ethyl of 5-guanidine radicals-1H-benzimidazolyl-2 radicals-yl)]-3-methyl-3H-benzoglyoxaline-5-base carbonyl } amino) oxyethyl group] phenylformic acid;
2-(5-aminomethyl-1,2 H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides; With
2-(5-amino methyl-4,5,6,7-tetrahydrochysene-1H-benzimidazolyl-2 radicals-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides.
11. the compound of claim 5, wherein A comprises 4,5,6 with B, 7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base and R
1Be-C (NH) R
9And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt.
12. the compound of claim 11 and its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt, described compound is selected from:
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-base carbonyl]-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-(5-iminomethyl-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl)-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-(2-hydroxyl-2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(2 hydroxy naphthalene-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-ylmethyl]-3-methyl-N-[2-(4-hydroxyl naphthalene-1-yl) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides;
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-(2-naphthalene-1-base ethyl)-3H-benzoglyoxaline-5-carboxylic acid amides;
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] ethyl benzoate;
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-(2-methoxy ethyl)-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid;
2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-1,4,6, the 7-imidazolidine is [4,5-c] pyridine-5-base carbonylamino also) oxyethyl group] ethyl benzoate; With
2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-N-[2-(2-tetrazyl phenoxy group) ethyl]-3H-benzoglyoxaline-5-carboxylic acid amides.
13. the compound of claim 12, it be 2-[2-(2-{1-[5-(1-imino-ethyl)-4,5,6,7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-2-yl] ethyl }-3-methyl-3H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] phenylformic acid; And its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt.
14. comprise the compound of claim 1 and the pharmaceutical composition of pharmaceutically useful carrier.
15. the pharmaceutical composition according to claim 14 advances-goes on foot to comprise the beta-Adrenergic agonists compound.
16. according to the pharmaceutical composition of claim 14, wherein said beta-Adrenergic agonists compound is selected from salbutamol, Arubendol, formoterol, fenoterol and prenaline.
17. according to the pharmaceutical composition of claim 14, wherein said composition comprises pharmaceutically useful topical application carrier.
18. according to the pharmaceutical composition of claim 14, wherein said composition comprises pharmaceutically useful oral carrier.
19. according to the pharmaceutical composition of claim 14, wherein said composition comprises pharmaceutically useful aerosol carrier.
20. an aerosol device, it comprises: the compound of the claim 1 in pharmaceutically acceptable carrier solution or dry powder and be used for described solution or dry powder are changed into the device that is fit to the aerosol form that sucks.
21. treat the method for mammiferous immune-mediated inflammation disorder, this method comprises the compound to the claim 1 of described administration treatment significant quantity.
22. treat the method for mammiferous rheumatoid arthritis, this method comprises the compound to the claim 1 of described administration treatment significant quantity.
23. treat the method for mammiferous conjunctivitis, this method comprises the compound to the claim 1 of described administration treatment significant quantity.
24. treat the method that mammiferous syncytial virus infects, this method comprises the compound to the claim 1 of described administration treatment significant quantity.
25. treat the method for the immune-mediated inflammation disorder that mammiferous respiratory tract suffers from, this method comprises the compound to the claim 1 of described administration treatment significant quantity.
26. the method for the compound of preparation formula I and its N-oxide derivative, prodrug derivant, protected derivative, various isomer, mixture of isomers and pharmaceutically useful salt,
Wherein n1 is 0 or 1; N2 is 0,1,2,3 or 4; N3 is 0,1,2,3 or 4;
A comprises with B and contains the assorted bicyclic radicals of condensing of 8-12 ring atom, and wherein each ring contains 5-7 ring and goes up the member, is heteroatoms each ring atom arbitrariness, X
1Be be selected from-N=,-O-and-the heteroatoms structure division of S-, and X
1And X
2Be member on the two adjacent rings on oxazole-2-base, 1H-imidazoles-2-base or the thiazol-2-yl ring, but wherein on the ring of 1H-imidazoles-2-basic ring member's arbitrariness ground be-NR
5-, R wherein
5Be hydrogen, (C
1-C
6) alkyl or assorted (C
2-C
6) alkyl; Or
C comprises the many cyclic groups of mixing that condense that contain 8-18 ring atom, and wherein each ring contains upward member of 5-7 ring, is heteroatoms each ring atom arbitrariness, X
5Be be selected from-N=,-O-and-heteroatoms structure division and the X of S-
4And X
5Be member on two adjacent ring on oxazole-2-base, 1H-imidazoles-2-base or the thiazol-2-yl ring, wherein member's arbitrariness ground is-NR on the ring of 1H-imidazoles-2-basic ring
6-, R wherein
6Be hydrogen, be selected from (C
1-C
8) alkyl or assorted (C
2-C
12) group of alkyl, this group arbitrariness ground is independently selected from (C by one or two
1-C
6) alkanoyloxy, (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, three (C
1-C
6) alkylamino, (C
1-C
6) alkyl-carbamoyl, two (C
1-C
6) alkyl-carbamoyl, (C
1-C
6) alkyl oxy, C
1-C
6) alkyl oxy carbonyl, (C
1-C
6) alkyl oxy alkylsulfonyl, amino, carboxyl, formamyl, (C
6-C
14) aryl, halogen, assorted (C
5-C
14) substituting group of aryl, hydroxyl and sulfo group replaces; Or such as following definition with and any carbocyclic ring ketone, sulfo-ketone and imino-ketone deriveding group;
X
3Be-O-,-S-,-S (O)-,-S (O)
2-,-C (O)-,-NR
7-or-CR
7R
8-, R wherein
7Be hydrogen, (C
1-C
6) alkyl, assorted (C
2-C
12) alkyl or and R
6Form (C together
2-C
4) alkylidene group or assorted (C
2-C
4) alkylidene group and R
8Be hydrogen, (C
1-C
6) alkyl or hydroxyl or and R
7Form (C together
2-C
6) alkylidene group or (C
1-C
6) alkylidene, wherein belong to R
7And/or R
8Any aliphatic series or alicyclic structure part arbitrariness ground be selected from (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, three (C
1-C
6) alkylamino, (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxy carbonyl, (C
1-C
6) alkanoyloxy, amino, carboxyl, formamyl, (C
1-C
6) alkyl-carbamoyl, two (C
1-C
6) 1 to 3 substituting group of alkyl-carbamoyl, halogen and hydroxyl replaces;
R
1Be amino (N
1-4) pyrrolidyl, amino (N
1-4) pyrryl, (N
1-4) pyrrolidyl, (N
1-4) pyrryl, formamyl, cyano group ,-(CH
2)
xNHC (NR
9) R
9,-(CH
2)
xNHC (NH) NR
9R
9,-C (NR
9) R
9-,-C (NH) NHR
10-,-C (NH) NR
10R
10Or-(CR
11R
11)
yNH
2And be bonded in any ring atom that belongs to B with effective valence state, and wherein x is 0 or 1, y is 0,1,2 or 3, each R
9Be hydrogen or (C independently
1-6) alkyl, each R
10Be (C independently
1-6) alkyl and each R
11Be hydrogen, (C independently
1-3) alkyl or with another R
11Form cyclopropyl with carbon atom (both links to each other with this carbon atom), wherein belong to R
1Any aliphatic series or alicyclic structure part arbitrariness ground be independently selected from (C by one or two
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) substituting group of alkyl sulphonyl and hydroxyl replaces.
Each R
2Be (C independently
1-6) alkyl, (C
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, (C
1-6) alkoxyl group, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) alkyl sulphinyl, (C
1-6) alkyl sulphonyl, (C
1-6) alkylthio, halogen or hydroxyl and be bonded in any ring atom with effective valence state that belongs to B, wherein belong to R
2Any aliphatic structure part arbitrariness ground be independently selected from (C by one or two
1-6) alkoxy carbonyl, (C
1-6) alkanoyloxy, carboxyl, formamyl, (C
1-6) alkyl-carbamoyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) substituting group of alkyl sulphonyl and hydroxyl replaces;
Each R
3Be (C independently
1-6) alkyl, (C
1-6) alkoxyl group, (C
1-6) alkylthio, cyano group, halogen, perhalogeno (C
1-6) alkyl or hydroxyl and be bonded in any ring atom with effective valence state that belongs to C; With
R
4Be-R
12-,-OR
12,-N (R
13) R
12,-SR
12,-S (O) R
12,-S (O)
2R
12,-S (O)
2OR
12,-S (O)
2N (R
13) R
12,-N (R
13) S (O)
2R
12,-C (O) R
12,-C (O) OR
12,-C (O) N (R
13) R
12,-N (R
13) C (O) R
12,-OC (O) N (R
13) R
12,-N (R
13) C (O) OR
12,-(CH
2)
zN (R
13) C (O) N (R
13) R
12,-OP (O) (OR
13) OR
12Or-C (O) N (R
14) CH (COOH) R
12And be bonded in any ring atom that belongs to C with effective valence state, wherein
Z is 0,1 or 2,
R
12Be-R
15Or-X
6-(R
15)
N15, wherein n15 is 1 or 2, X
6Be (C
1-10) alkylene
Base, ring (C
3-10) alkylidene group, assorted (C
2-10) alkylidene group or heterocycle (C
3-10) alkylidene group and each R
15
Be hydrogen, (C independently
6-14) aryl, ring (C
3-14) alkyl, many ring (C
6-14) aryl, much more assorted ring
(C
6-14) aryl, heterocycle (C
3-14) alkyl, assorted (C
5-14) aryl or as following definition,
R
13Be hydrogen, (C
1-6) alkyl or assorted (C
2-6) alkyl;
R
14Be hydrogen, (C
1-6) alkyl or and X
6And R
15Form (C together
3-4) alkylidene group;
Belong to R
4Any aliphatic series or alicyclic structure part arbitrariness ground by 1-5 solely
On the spot be selected from (C
1-6) alkyl, (C
1-6) alkylamino, two (C
1-6) alkylamino, (C
1-6) alkane
Base formamyl, two (C
1-6) alkyl-carbamoyl, (C
1-6) alkoxyl group, (C
1-6) alkane
Oxygen base carbonyl, (C
1-6) alkyl sulphinyl, (C
1-6) alkyl sulphonyl, (C
1-6) alkylthio,
Amino, (C
6-10) aryl sulfonyl, formamyl, carboxyl, cyano group, guanidine radicals, halogen,
The substituting group of hydroxyl, sulfydryl and urea groups replaces; And
Belong to R
15Any aromatic structure part arbitrariness ground be independently selected from by 1-3
(the C that cyano group, guanidine radicals, halogen, halogen replace
1-8) alkyl ,-R
16,-OR
16,-SR
16,
-S (O) R
16,-S (O)
2R
16,-S (O)
2N (R
13) R
16,-C (O) R
16,-C (O) OR
16With
-C (O) N (R
13) R
16Substituting group replace R wherein
13As defined above and R
16Be
Hydrogen, optional mono-substituted (C
1-8) (wherein said optional substituting group is (C to alkyl
1-6) alkyl ammonia
Base, two (C
1-6) alkylamino, three (C
1-6) alkylamino, (C
1-6) alkyl-carbamoyl,
Two (C
1-6) alkyl-carbamoyl, (C
1-6) alkoxy carbonyl, (C
1-6) the alkoxyl group alkylsulfonyl,
Amino, carboxyl, formamyl, hydroxyl or sulfo group), the ring (C
3-6) alkyl, assorted (C
1-8)
Alkyl, assorted (C
5-6) aryl, heterocycle (C
3-6) alkyl or phenyl; Precondition be when n2 be 0 or R
2Be (C
1-6) alkyl or (C
1-6) alkoxyl group, n3 is 0 or R
3Be (C
1-6) alkyl or (C
1-6) alkoxyl group and R
4Be hydrogen, (C
1-10) alkyl or (C
1-6) during alkoxyl group, n1 is not 0;
This method comprises:
Or its protected derivative reacts; wherein L is a leavings group; D and with it condensed vinylidene part comprise monocycle or the condensed-bicyclic divalent group that contains 5-15 ring atom together, wherein each ring is a heteroatoms with containing 5-7 ring atom and each ring atom arbitrariness, R
29Be-OH ,-NHR
6Or-SH, wherein R
6Be hydrogen or be selected from (C
1-C
8) alkyl or assorted (C
2-C
12) group of alkyl, this group arbitrariness ground is independently selected from (C by one or two
1-C
6) alkanoyloxy, (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, three (C
1-C
6) alkylamino, (C
1-C
6) alkyl-carbamoyl, two (C
1-C
6) alkyl-carbamoyl, (C
1-C
6) alkyl oxy, C
1-C
6) alkyl oxy carbonyl, (C
1-C
6) alkyl oxy alkylsulfonyl, amino, carboxyl, formamyl, (C
6-C
14) aryl, halogen, assorted (C
5-C
14) substituting group of aryl, hydroxyl and sulfo group replaces n1, n2, n3, A, B, X
1, X
2, X
3, R
1, R
2, R
3, R
4And R
6Definition as above, then, if necessary, go the protection; Or
Or its protected derivative reacts, and wherein L is a leavings group, R
30Be-OH ,-NHR
5Or-SH, and n1, n2, n3, B, C, X
3, X
4, X
5, R
1, R
2, R
3, R
4And R
5Definition as above, then, if necessary, go the protection;
(c) optionally further formula I compound is changed into pharmacologically acceptable salt;
(d) optionally further the formula I compound of salt form is changed into salt-independent shape;
(e) optionally further the formula I compound of non-oxidised form is changed into pharmaceutically useful N-oxide compound;
(f) optionally further the N-oxide form of formula I compound is changed into its non-oxidised form;
(g) optionally further inciting somebody to action not, deutero-formula I compound changes into pharmaceutically useful prodrug derivant; With
(h) optionally the prodrug derivant of formula I compound is changed into its not deutero-form.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US83367497A | 1997-04-07 | 1997-04-07 | |
US08/833,674 | 1997-04-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1251579A true CN1251579A (en) | 2000-04-26 |
Family
ID=25264996
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN97182098A Pending CN1251579A (en) | 1997-04-07 | 1997-12-01 | Compound and compositions for treating diseases associated with serine protease, particularly tryptase, activity |
Country Status (16)
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---|---|
EP (1) | EP1019382A1 (en) |
JP (1) | JP2001519806A (en) |
KR (1) | KR20010006119A (en) |
CN (1) | CN1251579A (en) |
AU (1) | AU752064B2 (en) |
CA (1) | CA2285454A1 (en) |
EE (1) | EE04055B1 (en) |
HU (1) | HUP0001522A3 (en) |
LT (1) | LT4704B (en) |
LV (1) | LV12495B (en) |
NO (1) | NO314183B1 (en) |
NZ (1) | NZ500029A (en) |
PL (1) | PL336233A1 (en) |
SI (1) | SI20115A (en) |
SK (1) | SK136799A3 (en) |
WO (1) | WO1998045275A1 (en) |
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WO2020233645A1 (en) * | 2019-05-21 | 2020-11-26 | 浙江海正药业股份有限公司 | Macrolide derivatives, preparation method and application thereof |
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US6221914B1 (en) | 1997-11-10 | 2001-04-24 | Array Biopharma Inc. | Sulfonamide bridging compounds that inhibit tryptase activity |
WO1999026932A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | By amidino group substituted heterocyclic derivatives and their use as anticoagulants |
WO1999026933A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | Substituted amidinoaryl derivatives and their use as anticoagulants |
GT199900167A (en) * | 1998-10-01 | 2001-03-21 | NEW BIS-BENZIMIDAZOLES. | |
AU1099000A (en) * | 1998-10-05 | 2000-04-26 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions for treating hepatitis c infections |
AU5314900A (en) * | 1999-06-04 | 2000-12-28 | Elan Pharma International Limited | Compositions and methods for inhibiting cell death |
DE19953899A1 (en) * | 1999-11-10 | 2001-05-17 | Boehringer Ingelheim Pharma | Carboxamide-substituted benzimidazole derivatives, process for their preparation and their use as medicaments |
WO2001052883A1 (en) * | 2000-01-20 | 2001-07-26 | Amgen Inc. | Inhibitors of protease-activated receptor-2 (par-2) as novel asthma therapeutics |
US6448281B1 (en) * | 2000-07-06 | 2002-09-10 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
DE10048715A1 (en) * | 2000-09-30 | 2004-05-19 | Grünenthal GmbH | Use of amino acid for the treatment of pain |
WO2002070491A1 (en) * | 2001-03-01 | 2002-09-12 | Shionogi & Co., Ltd. | Nitrogenous heteroaromatic ring derivative having hiv integrase inhibitory activity |
GB0406282D0 (en) * | 2004-03-19 | 2004-04-21 | Arrow Therapeutics Ltd | Therapeutic compounds |
US8759535B2 (en) | 2010-02-18 | 2014-06-24 | High Point Pharmaceuticals, Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
DE102011111991A1 (en) | 2011-08-30 | 2013-02-28 | Lead Discovery Center Gmbh | New cyclosporin derivatives |
AP2014007662A0 (en) * | 2011-11-29 | 2014-05-31 | Perosphere Inc | Anticoagulant reversal agents |
WO2016089648A1 (en) | 2014-12-01 | 2016-06-09 | Vtv Therapeutics Llc | Bach 1 inhibitors in combination with nrf2 activators and pharmaceutical compositions thereof |
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US3105837A (en) * | 1961-10-20 | 1963-10-01 | Upjohn Co | 2, 2'-alkylenebisbenzimidazoles |
US3210370A (en) * | 1964-06-22 | 1965-10-05 | Upjohn Co | Process for preparing 2, 2'-methylene-bisareneimiazoles |
HUT71345A (en) * | 1993-09-22 | 1995-11-28 | Wellcome Found | Bis(amidinobenzimidazolyl)alkanes and pharmaceutical compositions containing them |
US6815461B1 (en) * | 1994-01-20 | 2004-11-09 | The University Of North Carolina At Chapel Hill | Method of inhibiting retroviral integrase |
US5693515A (en) * | 1995-04-28 | 1997-12-02 | Arris Pharmaceutical Corporation | Metal complexed serine protease inhibitors |
-
1997
- 1997-12-01 EE EEP199900477A patent/EE04055B1/en not_active IP Right Cessation
- 1997-12-01 CN CN97182098A patent/CN1251579A/en active Pending
- 1997-12-01 HU HU0001522A patent/HUP0001522A3/en unknown
- 1997-12-01 WO PCT/US1997/021849 patent/WO1998045275A1/en not_active Application Discontinuation
- 1997-12-01 SK SK1367-99A patent/SK136799A3/en unknown
- 1997-12-01 SI SI9720094A patent/SI20115A/en unknown
- 1997-12-01 EP EP97954520A patent/EP1019382A1/en not_active Withdrawn
- 1997-12-01 AU AU58950/98A patent/AU752064B2/en not_active Ceased
- 1997-12-01 JP JP54273998A patent/JP2001519806A/en active Pending
- 1997-12-01 CA CA002285454A patent/CA2285454A1/en not_active Abandoned
- 1997-12-01 PL PL97336233A patent/PL336233A1/en unknown
- 1997-12-01 KR KR1019997009197A patent/KR20010006119A/en not_active Application Discontinuation
- 1997-12-01 NZ NZ500029A patent/NZ500029A/en unknown
-
1999
- 1999-10-06 NO NO19994858A patent/NO314183B1/en unknown
- 1999-11-02 LV LVP-99-153A patent/LV12495B/en unknown
- 1999-11-05 LT LT99-131A patent/LT4704B/en not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020233645A1 (en) * | 2019-05-21 | 2020-11-26 | 浙江海正药业股份有限公司 | Macrolide derivatives, preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CA2285454A1 (en) | 1998-10-15 |
AU5895098A (en) | 1998-10-30 |
AU752064B2 (en) | 2002-09-05 |
KR20010006119A (en) | 2001-01-26 |
HUP0001522A2 (en) | 2001-05-28 |
WO1998045275A1 (en) | 1998-10-15 |
NZ500029A (en) | 2001-02-23 |
PL336233A1 (en) | 2000-06-19 |
EP1019382A1 (en) | 2000-07-19 |
NO994858D0 (en) | 1999-10-06 |
JP2001519806A (en) | 2001-10-23 |
EE04055B1 (en) | 2003-06-16 |
SK136799A3 (en) | 2000-07-11 |
EE9900477A (en) | 2000-06-15 |
NO994858L (en) | 1999-12-06 |
LV12495A (en) | 2000-06-20 |
NO314183B1 (en) | 2003-02-10 |
HUP0001522A3 (en) | 2001-08-28 |
LT99131A (en) | 2000-04-25 |
LT4704B (en) | 2000-09-25 |
LV12495B (en) | 2001-01-20 |
SI20115A (en) | 2000-06-30 |
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