LT4704B - Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, acitivity - Google Patents
Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, acitivity Download PDFInfo
- Publication number
- LT4704B LT4704B LT99-131A LT99131A LT4704B LT 4704 B LT4704 B LT 4704B LT 99131 A LT99131 A LT 99131A LT 4704 B LT4704 B LT 4704B
- Authority
- LT
- Lithuania
- Prior art keywords
- benzoimidazol
- alkyl
- ethyl
- methyl
- compound
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 366
- 239000000203 mixture Substances 0.000 title claims abstract description 137
- 108060005989 Tryptase Proteins 0.000 title abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 24
- 102000001400 Tryptase Human genes 0.000 title description 22
- 201000010099 disease Diseases 0.000 title description 22
- 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 116
- 239000001257 hydrogen Substances 0.000 claims abstract description 68
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 68
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 52
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 45
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 41
- 125000001424 substituent group Chemical group 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 33
- 238000011282 treatment Methods 0.000 claims abstract description 31
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 15
- 125000003943 azolyl group Chemical group 0.000 claims abstract description 13
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 12
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 10
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 230000000699 topical effect Effects 0.000 claims abstract description 5
- 206010010741 Conjunctivitis Diseases 0.000 claims abstract description 4
- 210000002345 respiratory system Anatomy 0.000 claims abstract description 4
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 4
- -1 amino, carboxy, carbamoyl Chemical group 0.000 claims description 465
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 143
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 86
- 125000005842 heteroatom Chemical group 0.000 claims description 72
- 125000003118 aryl group Chemical group 0.000 claims description 62
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 35
- 125000002947 alkylene group Chemical group 0.000 claims description 33
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 32
- 239000005711 Benzoic acid Substances 0.000 claims description 28
- 239000000651 prodrug Substances 0.000 claims description 27
- 229940002612 prodrug Drugs 0.000 claims description 27
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 26
- 235000010233 benzoic acid Nutrition 0.000 claims description 26
- 125000006413 ring segment Chemical group 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 22
- 125000001931 aliphatic group Chemical group 0.000 claims description 20
- 125000003282 alkyl amino group Chemical group 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 19
- 125000002723 alicyclic group Chemical group 0.000 claims description 17
- 150000001204 N-oxides Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 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
- 125000004423 acyloxy group Chemical group 0.000 claims description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 239000000443 aerosol Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical class N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 9
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 8
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 7
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 7
- FEPAORUNILXIKL-UHFFFAOYSA-N C(CC)C=1NC2=C(N1)C=CC(=C2)C(=O)NCCC2=CC=CC1=CC=CC=C21 Chemical compound C(CC)C=1NC2=C(N1)C=CC(=C2)C(=O)NCCC2=CC=CC1=CC=CC=C21 FEPAORUNILXIKL-UHFFFAOYSA-N 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- 208000036142 Viral infection Diseases 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 230000009385 viral infection Effects 0.000 claims description 6
- 125000001118 alkylidene group Chemical group 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 5
- XSIFPSYPOVKYCO-UHFFFAOYSA-N butyl benzoate Chemical compound CCCCOC(=O)C1=CC=CC=C1 XSIFPSYPOVKYCO-UHFFFAOYSA-N 0.000 claims description 5
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- HWIDVPQENAYPBK-UHFFFAOYSA-N 4-chloro-2-[2-[[2-[1-[6-(diaminomethylideneamino)-1h-benzimidazol-2-yl]ethyl]-3-methylbenzimidazole-5-carbonyl]amino]ethoxy]benzoic acid Chemical compound N=1C2=CC(NC(N)=N)=CC=C2NC=1C(C)C(N(C1=C2)C)=NC1=CC=C2C(=O)NCCOC1=CC(Cl)=CC=C1C(O)=O HWIDVPQENAYPBK-UHFFFAOYSA-N 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- KYZHGEFMXZOSJN-UHFFFAOYSA-N benzoic acid isobutyl ester Natural products CC(C)COC(=O)C1=CC=CC=C1 KYZHGEFMXZOSJN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 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
- 125000003367 polycyclic group Chemical group 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000004924 2-naphthylethyl group Chemical group C1=C(C=CC2=CC=CC=C12)CC* 0.000 claims description 3
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 3
- 239000000808 adrenergic beta-agonist Substances 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 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
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000815 N-oxide group Chemical group 0.000 claims description 2
- 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 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 229960001022 fenoterol Drugs 0.000 claims description 2
- LSLYOANBFKQKPT-UHFFFAOYSA-N fenoterol Chemical compound C=1C(O)=CC(O)=CC=1C(O)CNC(C)CC1=CC=C(O)C=C1 LSLYOANBFKQKPT-UHFFFAOYSA-N 0.000 claims description 2
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- 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 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229960002052 salbutamol Drugs 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004523 tetrazol-1-yl group Chemical class N1(N=NN=C1)* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 4
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 2
- QLSPZJGUNBXVHU-UHFFFAOYSA-N 2-[2-[[2-[1-(5,6-difluoro-1h-benzimidazol-2-yl)ethyl]-3-methylbenzimidazole-5-carbonyl]amino]ethoxy]benzoic acid Chemical compound N=1C2=CC(F)=C(F)C=C2NC=1C(C)C(N(C1=C2)C)=NC1=CC=C2C(=O)NCCOC1=CC=CC=C1C(O)=O QLSPZJGUNBXVHU-UHFFFAOYSA-N 0.000 claims 1
- SYWNNHDBRIRLIJ-UHFFFAOYSA-N 2-[2-[[2-[1-(5-ethanimidoyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)ethyl]-3-methylbenzimidazole-5-carbonyl]amino]ethoxy]benzoic acid Chemical compound N=1C=2CN(C(C)=N)CCC=2NC=1C(C)C(N(C1=C2)C)=NC1=CC=C2C(=O)NCCOC1=CC=CC=C1C(O)=O SYWNNHDBRIRLIJ-UHFFFAOYSA-N 0.000 claims 1
- MTWFINXLTMNGCU-UHFFFAOYSA-N 2-[2-[[3-methyl-2-[1-(4,6,7-trifluoro-1h-benzimidazol-2-yl)ethyl]benzimidazole-5-carbonyl]amino]ethoxy]benzoic acid Chemical compound N=1C2=C(F)C=C(F)C(F)=C2NC=1C(C)C(N(C1=C2)C)=NC1=CC=C2C(=O)NCCOC1=CC=CC=C1C(O)=O MTWFINXLTMNGCU-UHFFFAOYSA-N 0.000 claims 1
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
- 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 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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Abstract
Description
Išradimo sritis:Field of the invention:
Šis išradimas susietas su junginiais ir kompozicijomis, skirtais gydyti ligas, susijusias su serino proteazės, konkrečiai triptazės, aktyvumu.The present invention relates to compounds and compositions for treating diseases associated with the activity of a serine protease, in particular tryptase.
Žinomas technikos lygis:Known state of the art:
Manoma, kad triptazė, kaip vyraujanti proteazė, išskirta iš žmogaus kamieninių ląstelių dalyvauja neuropeptidų virsmuose ir audinių uždegiminiuose procesuose. Triptazės koncentracijos kraujotakoje yra padidintos keletui valandų po anafilaksijos (Schwartz et ai. (1987). N. Engi. J. Med.. 316:1622-1626), po specifinio antigeno poveikio atopiniams subjektams yra padidėjęs nosyje ir plaučiuose lavažinis skystis (Castells et ai. (1988), J. Allerg. Clin. Immunol., 141:563-568) ir po endobronchialinio alerginio poveikio atopiniams astmatikams yra padidėjęs plaučiuose lavažinis skystis. Rūkoriai bronchoalveoliniame lavažiniame skystyje dažnai turi įspūdingą triptazės lygio padidėjimą, ko suradimas sutvirtina hipotezę, kad proteinazės atpalaidavimas iš aktyvuotų kamieninių ląstelių galėtų suteikti kažkiek pagalbos rūkorių emfizemos sukeltai plaučių destrukcijai (Celenteron et ai. (1988), Chest., 94:119-123). Priedo parodyta, kad triptazė yra potencialus mitogenas fibroplastams, siūlant, kad ji yra plaučių fibrozės ir intersticinės plaučių ligos priežastimi (Ross ef ai. (1991), J. Clin. Invest., 88:493-499).As the predominant protease isolated from human stem cells, tryptase is thought to be involved in neuropeptide conversion and tissue inflammatory processes. Circulating levels of tryptase are elevated several hours after anaphylaxis (Schwartz et al. (1987). N. Engi. J. Med .. 316: 1622-1626), followed by increased nasal and pulmonary lavage fluid following specific antigen exposure to atopic subjects (Castells et al. et al., (1988), J. Allerg. Clin. Immunol., 141: 563-568) and there is increased lava lavage fluid after endobronchial allergic action in atopic asthmatics. Smokers in bronchoalveolar lavage fluid often have an impressive increase in tryptase levels, and the finding supports the hypothesis that release of proteinase from activated stem cells could provide some relief for smoker's emphysema-induced pulmonary destruction (Celenteron et al. (1988), Chest. 94: 119-123). . The appendix shows that tryptase is a potential mitogen for fibroplasts, suggesting that it is a cause of pulmonary fibrosis and interstitial lung disease (Ross et al. (1991), J. Clin. Invest. 88: 493-499).
Astma yra pripažįstama kaip uždegiminis sutrikimas (Hood et ai. (1984), Benjamin-Cummings, ed. Immunology, 2nd ed.) ir dažniausiai charakterizuojamas progresuojančiu trachėjos ir bronchų padidinto reaktyvumo vystymusi dėl abiejų tiek imunospecifinių alergenų, tiek ir dėl bendrų cheminių bei fizikinių dirgiklių poveikio. Ligą sukelia daugybė biocheminių mediatorių tiek ūmioje, tiek ir lėtinėje stadijoje. Tikėtina, kad astminių bronchiolių audinių padidintas reaktyvumas yra lėtinio uždegimo reakcijų rezultatas, kuris erzina ir pažeidžia kvėpavimo takų sienelių epitelio išklostymą ir skatina patologinį apatinių audinių sukietėjimą. Pacientų tik su švelnia astma bronchų biopsijos turi kvėpavimo takų sienelių uždegimo požymių.Asthma is recognized as an inflammatory disorder (Hood et al. (1984), Benjamin-Cummings, ed. Immunology, 2nd ed.) And is usually characterized by the progressive development of tracheal and bronchial hyperresponsiveness due to both immunospecific allergens and common chemical and physical properties. exposure to stimuli. The disease is caused by many biochemical mediators, both in the acute and chronic stages. It is likely that the increased reactivity of asthmatic bronchiolar tissues is the result of chronic inflammatory reactions that irritate and damage the airway wall epithelial lining and promote pathologic lower tissue hardening. Bronchial biopsies in patients with mild asthma only show signs of airway inflammation.
Alerginiai atsakai į įkvėptus alergenus gali inicijuoti uždegimų seką. Pavyzdžiui, alergenai gali aktyvuoti kamienines ląsteles ir bazofilinius leukocitus, kurie yra epitelyje ir apatinėse lygiųjų audinių ląstelėse, surišdami IgE, esančius ant ląstelės paviršiaus. Aktyvuotos kamienines ląstelės atpalaiduoja eilę uždegiminio atsako iš anksto suformuotų arba pirminių cheminių mediatorių (pvz., histaminą) ir generuoja eilę kitų antrinio uždegimo mediatorių (pvz., superoksidą, baltymų darinių mediatorius ir kt.) in situ. Priedo, eilė didelių molekulių (pvz., proteoglikanai, triptazė, chimazė ir kt.) yra atpalaiduojamos kamieninių ląstelių degranuliacijos metu.Allergic responses to inhaled allergens can initiate an inflammatory sequence. For example, allergens can activate stem cells and basophilic leukocytes, which are located in the epithelium and lower smooth tissue cells, by binding to IgEs on the cell surface. Activated stem cells release a number of pre-formed or primary chemical mediators of the inflammatory response (e.g., histamine) and generate a number of other secondary inflammatory mediators (e.g., superoxide, protein derivative mediators, etc.) in situ. In addition, a number of large molecules (eg, proteoglycans, tryptase, chymase, etc.) are released during stem cell degranulation.
Šių iš anksto sudarytų mediatorių atpalaidavimas iš kamieninių ląstelių yra priežastimi išankstinio bronchiolių susitraukimo dėl astminės reakcijos j ore esančius alergenus. Astminės reakcijos anstyvosios fazės pikas yra apie penkiolika minučių po alergeno atsiradimo ir yra iš esmės atstatoma po vienos arba dviejų valandų. Nuo dvidešimt penkių iki trisdešimt procentų pacientų patiria tolesnj respiratorinės funkcijos blogėjimą, kuri yra maksimali nuo šešių iki dvilikos valandų po atsiradimo. Šią vėlyvąją reakcijos fazę lydi žymus skaičius uždegiminių ląstelių (pvz.. eozinofilų, neutrofilų, limfocitų ir kt.), infiltruojančių bronchinį audinį. Infiltruojamos ląstelės yra pritvirtintos prie vietų, atpalaiduojant kamieninę ląstelę, gaminančią chemotaktinius agentus ir po to aktyvuojamą vėlyvosios reakcijos fazės metu. Tikėtina, kad vėlyvasis astminis atsakas yra antrinė uždegiminė reakcija, dalinai medijuota išskiriamų granulocitų aktyvumo.The release of these preformed mediators from the stem cells is the cause of the early allergic reaction of airborne allergens to the bronchioles. The peak phase of the asthmatic reaction is about fifteen minutes after allergen onset and is substantially reversible after one to two hours. Twenty-five to thirty percent of patients experience further deterioration of respiratory function, which is maximal between six and twelve hours after onset. This late phase of the reaction is accompanied by a significant number of inflammatory cells (eg eosinophils, neutrophils, lymphocytes, etc.) infiltrating bronchial tissue. Infiltrated cells are attached to sites by releasing the stem cell, which produces chemotactic agents and is then activated during the late reaction phase. The late asthmatic response is likely to be a secondary inflammatory reaction, partially mediated by the activity of secreted granulocytes.
Triptazė yra įtraukta į kraujagysles plečiančių ir bronchus atpalaiduojančių neuropeptidų degradaciją (Caughey et ai. (1988). J. Pharmacol. Exp. Ther., 244:133-137; Franconi et. ai. (1988). J. Pharmacol. Exp. Ther., 248:947-951; ir Tam et ai. (1990), Am. J. Respir. Cell Mol. Biol., 3.27-32) ir bronchų jautrumo histaminui moduliaciją (Sekizavva et ai. (1989). J. Clin. Invest., 83:175-179). Šie atradimai parodo, kad triptazė gali padidinti bronchų susitraukimą sergant astma, suardydama bronchus plečiančius peptidus. Triptazė skaldo fibrinogeno ugrandines ir didelės molekulinės masės kininogeną, kas parodo, kad triptazė su heparinu vaidina tą patį vaidmenį kaip vietiniai antikoaguliantai. Triptazė per MMP3 aktyvuoja prostromeliziną (pro-MMP-3) ir prokolagenazę, kas parodo, kad triptazė dalyvauja audinių uždegime ir permodeliuoja ir sujungia destrukciją reumatiniame artrite. Toliau, triptazės inhibitoriaus įvedimas apsaugo alergenu paveiktą avį nuo vėlyvosios ir kvėpavimo takų padidinto reaktyvumo fazės išsivystymo (Clark et ai. (1995), Am. J. Respir. Crit. Care Med., 152:2076-2083) ir slopina alerginei aviai tiesioginį odos atsaką į intrakutaninę alergeno injekciją (Molinari et ai. (1995), Amer. Physiol. Soc., 79(6):1966-1970). Abu aukščiau aprašyti atradimai aiškiai nurodo, kad triptazės inhibitorių panaudojimas kaip terapinių agentų astmos ir kitų sutrikimų gydyme, surištų su kvėpavimo takų uždegimu.Tryptase is involved in the degradation of vasodilating and bronchodilating neuropeptides (Caughey et al. (1988). J. Pharmacol. Exp. Ther., 244: 133-137; Franconi et al. (1988). J. Pharmacol. Exp. Ther., 248: 947-951; and Tam et al. (1990), Am. J. Respir. Cell Mol. Biol. 3.27-32) and modulation of bronchial susceptibility to histamine (Sekizavva et al. (1989) J. Clin. Invest., 83: 175-179). These findings suggest that tryptase can increase bronchoconstriction in asthma by disrupting bronchodilating peptides. Tryptase cleaves fibrinogen fibrinogens and high molecular weight quininogen, indicating that heparin tryptase plays the same role as topical anticoagulants. Tryptase through MMP3 activates prostromelysin (pro-MMP-3) and prococolagenase, indicating that tryptase is involved in tissue inflammation and remodeling and combining destruction in rheumatoid arthritis. Further, administration of a tryptase inhibitor prevents allergen-exposed sheep from developing late and airway hyperreactivity (Clark et al. (1995), Am. J. Respir. Crit. Care Med. 152: 2076-2083) and inhibits direct allergic sheep. skin response to intracutaneous injection of allergen (Molinari et al. (1995), Amer. Physiol. Soc. 79 (6): 1966-1970). Both of the above findings clearly indicate the use of tryptase inhibitors as therapeutic agents in the treatment of asthma and other disorders associated with airway inflammation.
Šio ir kitų dokumentų atskleidimas, apimant patentus ir patentų paraiškas, nurodytus per šią paraišką, čia įtraukti per nuorodas.Disclosures of this and other documents, including patents and patent applications cited in this application, are incorporated herein by reference.
IŠRADIMO ESMĖTHE SUBSTANCE OF THE INVENTION
Šis išradimas apima I formulės junginius:The present invention includes compounds of formula I:
(O, n1 yra 0 arba 1; n2 yraO, 1,2, 3 arba 4; n3 yra 0, 1,2, 3 arba 4;(O, n1 is 0 or 1; n2 is O, 1,2, 3 or 4; n3 is 0, 1,2, 3 or 4;
A drauge su B sudaro kondensuotą heterobiciklinį radikalą, turinti nuo 8 iki 12 žiedinių atomų, kuriame kiekvienas žiedas turi nuo 5 iki 7 žiedinių narių, o kiekvienas žiedinis atomas pasirinktinai yra heteroatomas, X1 ir X2 aromatinio žiedo gretutiniai žiediniai nariai ir X1 yra heteroatomo liekana, parinkta iš -N=, NR5-, -O- ir -S-, kurioje R5 yra vandenilis, (C4.6)alkilas arba hetero(C2.6)alkilas;A together with B forms a fused heterobicyclic radical containing from 8 to 12 ring atoms, each ring having from 5 to 7 ring members and each ring atom being optionally a heteroatom, X 1 and X 2 being adjacent ring members and X 1 being a heteroatom moiety selected from -N =, NR 5 -, -O- and -S- wherein R 5 is hydrogen, (C 4th 6) alkyl or hetero (C 2nd 6) alkyl;
C sudaro kondensuotą heteropoliciklinį radikalą, turintį nuo 8 iki 18 žiedinių narių, kuriame kiekvienas žiedas turi nuo 5 iki 7 žiedinių narių, o kiekvienas atomas pasirinktinai yra heteroatomas, X4 ir X5 yra aromatinio žiedo gretutiniai nariai, X5 yra heteroatomo liekana, parinkta iš -N=, -NR6-, -O- ir -S-, kurioje R6 yra vandenilis, grupė, parinkta iš (Ci.8)alkilo arba hetero(C2.12)alkilo, kai grupė yra pasirinktinai pakeista vienu arba dviem pakaitais, nepriklausomai parinktais iš (Ci-e)alkanoiloksi, (Ci-6)alkilamino, di(Ci-6)alkilamino, tri(Ci.6)alkilamonio, (Ci.6)alkilkarbamoilo, di(Ci.6)alkilkarbamoilo, (Ci.6)alkiloksi, (Ci.6)alkiloksikarbonilo, (Ci.6)alkiloksisulfonilo, amino, karboksilo, karbamoilo, (C6. i4)arilo, halogeno, hetero(C5-i4)arilo, hidroksilo ir sulfo-grupių, kaip nurodyta žemiau; ir bet kokiu jų karbociklinio ketono, tioketono ir iminoketono dariniu;C forms a fused heteropolycyclic radical having from 8 to 18 ring members, each ring having from 5 to 7 ring members, each atom being optionally a heteroatom, X 4 and X 5 being adjacent members of the aromatic ring, X 5 being a heteroatom residue selected of -N =, -NR 6 -, -O-, and -S-, wherein R 6 is hydrogen, a group selected from (Ci. 8) alkyl or hetero (C 2nd 12) alkyl, are optionally substituted with one or two substituents independently selected from (Ci-e) alkanoyloxy, (Cl-6) alkylamino, di (Ci-6) alkylamino, tri (Ci. 6) alkylammonium (Ci. 6) alkylcarbamoyl, di (Ci. 6) alkylcarbamoyl (Ci. 6) alkyloxy, (Ci. 6) alkyloxycarbonyl, (Ci. 6) alkiloksisulfonilo, amino, carboxy, carbamoyl, (C 6. i 4) aryl, halogen, hetero (C5-i 4), aryl, hydroxy and sulfo groups as below; and any derivative thereof of carbocyclic ketone, thioketone and iminoketone;
X3 yra -0-, -S-, -S(O)-, -S(O)2-, -C(O)-, -NR7- arba -CR7R8-, kuriuose R7 yra vandenilis, (Ci-6)alkilas, hetero(C2-i2)alkilas arba drauge su R6 sudaro (C2.4)alkileną arba hetero(C2.4)alkileną ir R8 yra vandenilis, (Ci-6)alkilas arba hidroksilas arba drauge su R7 sudaro (C2-e)aIkileną arba (Ci-6)alkilideną, kuriuose bet kuri alifatinė arba aliciklinė liekana, turinti R7 ir/arba R8 pasirinktinai yra pakeista nuo vieno iki trijų pakaitų, parinktų iš (Ci.6)alkilamino, d^Cvejalkilamino, tritCveJalkilamonio, (Ci.6)aikiloksi, (Ci.6)a!kiloksikarbonilo, (C^)alkanoiloksi, amino, karboksilo, karbamoilo, (Ci-6)alkilkarbamoilo, di(Ci-6)alkilkarbamoilo, halogeno ir hidroksilo grupių;X 3 is -O-, -S-, -S (O) -, -S (O) 2 -, -C (O) -, -NR 7 - or -CR 7 R 8 - wherein R 7 is hydrogen (Ci-6) alkyl, hetero (C 2 s 2) alkyl, or together with R 6 form a (C2.4) alkylene or hetero (C2.4) alkylene and R 8 is hydrogen, (Cl-6) alkyl, or hydroxyl or together with R 7 forms a (C 2 -C 6) alkylene or (C 1 -C 6) alkylidene wherein any aliphatic or alicyclic residue containing R 7 and / or R 8 is optionally substituted with one to three substituents selected from (C .6) alkylamino, d ^ Cvejalkilamino, tritCveJalkilamonio (Ci. 6) aikiloksi (Ci. 6) a! kiloksikarbonilo (C₄) alkanoyloxy, amino, carboxy, carbamoyl, (Cl-6) alkylcarbamoyl, di (Ci- 6) alkylcarbamoyl, halogen and hydroxyl groups;
R1 yra amino(Ni.4)azoh'dinilas, amino(Ni.4)azolilas, (Ni.4)azo(idinilas, (Ni_4)azolilas, karbamoilas, ciano-grupė, -(CH2)XNHC(NR9)R9, (CH2)xNHC(NH)NR9R9, -C(NR9)R9, -C(NH)NHR10, -C(NH)NR10R10 arba (CR11R11)yNH2 ir surištas su bet kuriuo žiediniu atomu su laisvu valentingumu, apimančiu B, kuriame x yra 0 arba 1, y yra 0, 1, 2 arba 3, o kiekvienas R9 nepriklausomai yra vandenilis arba (C4 -6) alkilas, kiekvienas R10 yra nepriklausomai (Ci.6)alkilas ir kiekvienas R nepriklausomai yra vandenilis, (Ci-3)alkilas arba drauge su kitu R11 ir anglies atomu, prie kurio jie abu yra prijungti, sudaro ciklopropilą, kuriuose bet kuri alifatinė arba aliciklinė liekana, turinti R1 , yra pakeista nuo vieno iki dviejų pakaitų, nepriklausomai parinktų iš (Ci-6)alkiloksikarbonilo, (Ci-6)alkanoiloksi, karboksilo, karbamoilo, (Ci.6)alkilkarbamoilo, di(Ci-6)alkilkarbamoilo, (Ci.6)alkilsulfonilo ir hidroksilo grupių;R 1 is amino (Ni 4) azohinyl, amino (Ni 4) azolyl, (Ni 4) azo (idinyl, (Ni 4) azolyl, carbamoyl, cyano, - (CH 2) x NHC (NR 9 )). R 9, (CH 2) x 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 and bonded to any ring atoms with free valence comprising B wherein x is 0 or 1, y is 0, 1, 2 or 3 and each R 9 is independently hydrogen or (C 4-6 ) alkyl, each R 10 is are independently (Ci. 6) alkyl, and each R is independently hydrogen, (Ci- 3) alkyl, or together with another R11 and a carbon atom to which they are both attached form a cyclopropyl which any aliphatic or alicyclic moiety comprising R 1 has been substituted with one to two substituents independently selected from (Ci-6) alkyloxycarbonyl, (Ci-C 6) alkanoyloxy, carboxy, carbamoyl, (Ci. 6) alkylcarbamoyl, di (Ci-6) alkylcarbamoyl, (Ci. 6 ) alkylsulfonyl and hydroxyl groups;
kiekvienas R2 nepriklausomai yra (Ci.6)alkilas, (Ci.6)alkiloksikarbonilas, (Ci-6)alkanoiloksi, (Ct.6)alkiloksi, karboksilas, karbamoilas, (Ci.6)alkilkarbamoilas, di(C,.6)alkilkarbamoilas, (Cvejalkilsulfinilas, (Ci.6)alkilsulfonilas, (Ci-6)alkiltio, halogenas arba hidroksilas ir surištas su bet kuriuo žiediniu atomu su laisvu valentingumu, apimančiu B, kuriuose bet kuri alifatinė liekana, turinti R2, pasirinktinai yra pakeista nuo vieno iki dviejų pakaitų, nepriklausomai parinktų iš (Ci-6)alkiloksikarbonilo, (Ci.6)alkanoiloksi, karboksilo, karbamoilo, (Ci-6)alkilkarbamoilo, di(Ci-6)alkilkarbamoilo, (CveJalkilsulfonilo ir hidroksilo grupių;each R 2 is independently a (Ci.6) alkyl, (Ci. 6) alkyloxycarbonyl, (Ci-C 6) alkanoyloxy (C t. 6) alkyloxy, carboxy, carbamoyl, (Ci. 6) alkylcarbamoyl, di (C ,. 6 ) alkylcarbamoyl, (C 1-6 alkylsulphinyl, (C 1-6 ) alkylsulphonyl, (C 1-6 ) alkylthio, halogen or hydroxyl and bonded to any free ring valence comprising B, wherein any aliphatic residue containing R 2 is optionally substituted with one to two substituents independently selected from (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxyl, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6 alkylsulfonyl) and hydroxyl groups;
kiekvienas R3 nepriklausomai yra (Ci-6)alkilas, (C^alkiloksi, (Ci^alkiltio, ciano-grupė, halogenas, perhalogen(Ci-e)alkilas arba hidroksilas ir surištas su bet kuriuo žiediniu atomu su laisvu valentingumu, apimančiu C; ireach R 3 is independently (C 1-6) alkyl, (C 1-6 alkyloxy, (C 1-6 alkylthio) cyano, halogen, perhalogen (C 1-6) alkyl or hydroxyl and bonded to any ring atoms with free valence comprising C ; and
R4 yra -R12, -OR12, -N(R13)R12, -SR12, -S(O)R12, -S(O)2 R12, -S(O)2O R12, S(O)2N(R13)R12, -N(R13)S(O)2R12, -C(O)R12, -C(O)OR12, -C(O)N(R13)R12, N(R13)C(O)R12, -OC(O)N(R13)R12, -N(R13)C(O)OR12, -(CH2)zN(R13)C(O)N(R13)R12, OP(O)(OR13)O r12 arba -C(O)N(R14)CH(COOH)R12 ir surištas su bet kuriuo žiediniu atomu su laisvu valentingumu, apimančiu C, kuriame:R 4 is -R 12 , -OR 12 , -N (R 13 ) R 12 , -SR 12 , -S (O) R 12 , -S (O) 2 R 12 , -S (O) 2 O R 12 , S (O) 2 N (R 13 ) R 12 , -N (R 13 ) S (O) 2 R 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) z N ( R 13 ) C (O) N (R 13 ) R 12 , OP (O) (OR 13 ) O r 12 or -C (O) N (R 14 ) CH (COOH) R 12 and bonded to any ring atom with free valence comprising C in which:
z yra 0,1 arba 2,z is 0,1 or 2,
R12 yra -R15 arba -X6-(R15)ni5, kuriame n15 yra 1 or 2, X6 yra (CMo)alkilenas, ciklo(C3.i0)alkilenas, hetero(C2.i0)alkilenas arba heterociklo(C3.io)alkilenas ir kiekvienasR15 nepriklausomai yra vandenilis, (C6-i4)arilas, ciklo(C3-14)alkilas, policiklo(C6-i4)arilas, heteropoliciklo(C6-i4)arilas, heterociklo(C3-i4)alkilas, hetero(C5.i4)arilas arba kaip nurodyta žemiau,R 12 is -R 15 or -X 6 - (R 15 ) n 15 , wherein n 15 is 1 or 2, X 6 is (C 1 -C 10) alkylene, cyclo (C 3 -C 10 ) alkylene, hetero (C 2 -C 10) 0 ) alkylene or heterocyclo (C 3 .io) alkylene and kiekvienasR 15 independently are hydrogen, (C6-i4) aryl, cyclo (C 3-14) alkyl, polycycloalkanes (C6-i4) aryl, heteropolycycle (C 6 -i4) aryl , heterocyclo (C 3 -C 14 ) alkyl, hetero (C 5 -C 14 ) aryl, or as defined below,
R13 yra vandenilis, (CveJalkilas arba hetero(C2-6)alkilas;R 13 is hydrogen, (CveJalkilas or hetero (C 2 -6) alkyl;
R14 yra vandenilis, (Ci-e)alkilas arba drauge su X6 ir R15 sudaro (C3.4)alkileną;R 14 is hydrogen, (C 1 -C 6 ) alkyl, or together with X 6 and R 15 form (C 3 -C 4 ) alkylene;
bet kuri alifatinė arba aliciklinė liekana, turinti R4 pasirinktinai yra pakeista nuo vieno iki penkių pakaitų, nepriklausomai parinktų iš (Ci.6)alkilo, (Ci-6)alkilamino, di(Ci-6)alkilamino, (Ci.6)alkilkarbamoilo, di(Ci.6)alkilkarbamoilo, (Ci.6)alkiloksi, (Ci.6)alkiloksikarbonilo, (C^eJalkilsulfinilo, (CveJalkilsulfonilo, (Ci.6)alkiltio, amino, (C6-io)arilsulfonilo, karbamoilo, karboksilo, ciano-grupės, guanidino, halogeno, hidroksilo, merkapto ir ureido grupių; ir bet kuri aromatinė liekana, turinti R15 pasirinktinai yra pakeista nuo vieno iki trijų pakaitų, nepriklausomai parinktų iš ciano-grupės, guanidino, halogeno, halogenu-pakeisto (Ci.8)alkilo, -R16, -OR16, -SR16, -S(O)R16, S(O)2R16, -S(O)2N(R13)R16-, -C(O)R16, -C(O)OR16 ir -C(O)N(R13)R16, kuriuose R13 yra toks, kaip nurodytas aukščiau ir R16 yra vandenilis, pasirinktinai pakeistas mono-pakeistu(Ci.8)alkilu (kuriame pasirinkti pakaitai yra (Ci.6)alkilaminas, di(Ci.6)alkilaminas, tri(Ci.6)alkilamonis, (C,. 6)alkilkarbamoilas, di(Ci-6)alkilkarbamoilas, (Ci.6)alkiloksikarbonilas, (Cvejalkiloksisulfonilas, amino-grupė, karboksilas, karbamoilas, hidroksilas arba sulfo-grupė), ciklo(C3-6)alkilu, hetero(Ci.8)alkilu, hetero(C5-6)arilu, heterociklo(C3.6)alkilu arba fenilu;any aliphatic or alicyclic moiety comprising R4 optionally is substituted by one to five substituents independently selected from (Ci. 6) alkyl, (Ci- 6) alkylamino, di (Ci-6) alkylamino (Ci. 6) alkylcarbamoyl di (Ci. 6) alkylcarbamoyl, (Ci. 6) alkyloxy, (Ci. 6) alkyloxycarbonyl, (C? eJalkilsulfinilo (CveJalkilsulfonilo (Ci. 6) alkylthio, amino, (C 6 -io) arylsulfonyl, carbamoyl, carboxyl, cyano, guanidine, halogen, hydroxyl, mercapto and ureido groups; and any aromatic residue containing R 15 is optionally substituted with one to three substituents independently selected from cyano, guanidine, halogen, halogen-substituted ( C 1-8 alkyl, -R 16 , -OR 16 , -SR 16 , -S (O) R 16 , S (O) 2 R 16 , -S (O) 2 N (R 13 ) R 16 -, -C ( O) R 16 , -C (O) OR 16, and -C (O) N (R 13 ) R 16 wherein R 13 is as defined above and R 16 is hydrogen optionally substituted with mono-substituted (C 1-8) ) alkyl (wherein the optional substituents is (Ci.6) alkylamino, di (Ci. 6) alki lamin, tri {Ci. 6) alkylammonium (C ,. 6) alkylcarbamoyl, di (Ci-6) alkylcarbamoyl, (Ci. 6) alkyloxycarbonyl, (Cvejalkiloksisulfonilas, amino, carboxy, carbamoyl, hydroxy or sulfo-group), cyclo (C 3 - 6) alkyl, hetero (Ci. 8) alkyl, hetero (C 5 -6) aryl, heterocyclo (C 3 .6) alkyl or phenyl;
su sąlyga, kad n1 nėra 0, kai n2 yra 0 arba R2 yra (Ci-6)alkilas arba (Cvejalkiloksi, n3 yra 0 arba R3 yra (Ci-6)alkilas arba (Ci-6)alkiloksi ir R4 yra vandenilis, (Cb io)alkilas arba (C1.10)alkiloksi; ir /V-oksido dariniai, provaistų dariniai, blokuoti dariniai, individualieji izomerai, izomerų mišiniai ir jų farmaciškai priimtinos druskos.with the proviso that n1 is not 0, when n2 is 0 or R 2 is (Ci-6) alkyl or (Cvejalkiloksi, n3 is 0 or R 3 is (Ci-6) alkyl or (Ci-6) alkyloxy and R 4 is hydrogen, (C b io) alkyl or (C1. 10) alkyloxy, and / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
Šis išradimas taip pat pateikia farmacines kompozicijas, turinčias šio išradimo junginių. Farmacinės kompozicijos gali būti įvairių formų, apimant peroralines dozuotas formas, inhaliuojamas formas, o taip pat injekcinius ir infuzinius tirpalus. Kai naudojamos inhaliacinės arba aerozolinės vaisto formos, tai šio išradimo junginiai yra vartojami derinyje su farmaciškai priimtinu nešiklio tirpalu arba sausais milteliais, kurie gali būti paversti į aerozolio formą. Dažniausiai, kai taikoma peroraliniam vartojimui, tai šio išradimo junginiai yra naudojami derinyje su farmaciškai tinkamu nešikliu, tinkamu tokiam peroraliniam vartojimui. Kai naudojama gydyti imunomedijuojamas odos uždegimines būsenas, tai šio išradimo junginiai yra naudojami derinyje su netoksiškais, farmaciškai tinkamais topiniais nešikliais. Šio išradimo junginiai gali būti naudojami derinyje su priešuždegiminiais ir kitais astmą gydančiais vaistais, tokiais kaip β-adrenerginiais agonistais, priešuždegiminiais kortikosteroidais, anticholinerginiais vaistais, bronchus plečiančiais vaistais, tokiais kaip metilksantenai ir panašūs.The present invention also provides pharmaceutical compositions containing the compounds of the present invention. The pharmaceutical compositions may take a variety of forms, including oral dosage forms, inhalation forms, and solutions for injection and infusion. When used in inhalation or aerosol dosage forms, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier solution or dry powder that can be converted into an aerosol formulation. In general, when used for oral administration, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier suitable for such oral administration. When used to treat immune-mediated inflammatory conditions of the skin, the compounds of the present invention are used in combination with non-toxic, pharmaceutically acceptable topical carriers. The compounds of the present invention may be used in combination with anti-inflammatory and other asthma medications such as β-adrenergic agonists, anti-inflammatory corticosteroids, anticholinergics, bronchodilators such as methylxanthenes and the like.
Čia aprašyti junginiai yra tinkami apsaugoti ir gydyti imunomedijuojamus uždegiminius sutrikimus, ir ypatingai tuos, kurie susieti su kvėpavimo takais, apimant ir astmą, ir konkrečiai padidinto reaktyvumo fazėje, esant chroniškai astmai ir alerginiam rinitui. Šis išradimas taip pat pateikia šio išradimo junginių panaudojimą gamyboje vaistų, skirtų gydyti imunomedijuojamus uždegiminius sutrikimus ir sincitines virusines infekcijas.The compounds described herein are suitable for the protection and treatment of immune-mediated inflammatory disorders, and in particular those associated with the respiratory tract, including both asthma and specifically in the reactive phase of chronic asthma and allergic rhinitis. The present invention also provides the use of the compounds of the present invention in the manufacture of a medicament for the treatment of immune-mediated inflammatory disorders and syncytial viral infections.
TRUMPAS FIGŪRŲ APRAŠYMASBRIEF DESCRIPTION OF THE FIGURES
1 figūroje palygintas specifinis plaučių atsparumas (balti kvadratai) tarp kontrolės ir 2-(5-aminometil-1A/-benzoimidazol-2-ilmetil)-/V-(3-fenilpropil)-1Hbenzoimidazol-5-karboksamido (4 junginys; juodi kvadratai) per laiko tarpą, išmatuotą valandomis.Figure 1 compares specific lung resistance (white squares) between control and 2- (5-aminomethyl-1A / benzoimidazol-2-ylmethyl) - N - (3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 4; black squares). ) over a time period measured in hours.
figūroje yra diagrama, vaizduojanti kvėpavimo takų padidintą reaktyvumą (išmatuotą kaip PC400) antigenu paveiktos avies, gydytos 4 junginio aerozoliu, įvedant tris dozes po 1 mg, palyginus su kontrole gydyta avimi.Figure 3 is a graph depicting airway elevated reactivity (measured as PC400) in antigen-exposed sheep treated with compound 4 aerosol at three doses of 1 mg compared to control treated sheep.
DETALUS IŠRADIMO APRAŠYMASDETAILED DESCRIPTION OF THE INVENTION
Terminologija:Terminology:
Jeigu kitaip nenurodyta, tai šiame išradime ir apibrėžtyje naudojami terminai turi žemiau nurodytas reikšmes:Unless otherwise stated, the terms used in the present invention and the definition have the following meanings:
“Alkanoilas reiškia -C(O)R radikalą, kuriame R yra alkilas, kaip nurodyta žemiau, turintis bendrą nurodytų anglies atomų skaičių (pvz., >(Ci-6)alkanoilas apima formilo, acetilo, propionilo, butirilo, izobutirilo, krotonoilo, izokrotonoilo ir kt. radikalus)."Alkanoyl means a radical of -C (O) R wherein R is alkyl as defined below having the total number of carbon atoms indicated (e.g., (C 1-6) alkanoyl includes formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonoyl etc. radical).
“Aliciklinė liekana” reiškia bet kurią sočiąją arba nesočiąją, monociklinę arba policiklinę angliavandenilio radikalo dalį. Pavyzdžiui, aliciklinė liekana nurodo j cikloalkilą, kaip čia nurodyta, o taip pat ir į aliciklinę dalį, apimant cikloalkilalkilą, cikloalkiloksi, cikloalkilkarbonilą, cikloalkilalkanoilą, cikloalkilkarbamoilą ir panašius."Alicyclic residue" means any saturated or unsaturated, monocyclic or polycyclic moiety of a hydrocarbon radical. For example, an alicyclic moiety refers to cycloalkyl as defined herein, as well as to an alicyclic moiety including cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylcarbamoyl and the like.
“Alifatinė liekana” reiškia linijinę arba šakotą, sočiąją arba nesočiąją angliavandenilio radikalo dalį. Pavyzdžiui, alifatinė liekana nurodo į alkilą arba heteroalkilą, kaip čia nurodyta, o taip pat ir į alifatinę dalį, apimančią alkiloksi, arilalkilą, heteroarilalkilą, alkilkarbamoilą, alkanoilą, arilalkanoilą, heteroarilalkanoilą ir panašius."Aliphatic residue" means a linear or branched, saturated or unsaturated moiety of a hydrocarbon radical. For example, an aliphatic residue refers to alkyl or heteroalkyl as herein defined and also to an aliphatic moiety comprising alkyloxy, arylalkyl, heteroarylalkyl, alkylcarbamoyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl and the like.
“Alkilas”, pagal šios paraiškos tikslus, reiškia linijinį arba šakotą, sotųjį arba neprisotintą alifatinio angliavandenilio radikalą, turintį nurodytą anglies atomų skaičių, ir bet kurį jo ketoną, tioketoną arba iminoketoną (pvz., (Cv8)alkilas apima metilą, etilą, propilą, izopropilą, butilą, antr-butilą, izobutilą, fref-butilą, vinilą, alilą, 1-propenilą, izopropenilą, 1-butenilą, 2-butenilą, 3-butenilą, 2-metilalilą, etinilą, 1propinilą, 2-propinilą, 3-oksopentilą, 3-tiooksopentilą, 3-iminopentilą ir kt.)."Alkyl" as used herein, means a linear or branched, saturated or unsaturated aliphatic hydrocarbon radical having the specified number of carbon atoms and any of its ketones, thioketones or iminoketones (e.g., (Cv 8 ) alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1propynyl, 2-propynyl, 3-oxopentyl, 3-thiooxopentyl, 3-iminopentyl, etc.).
“Alkilenas reiškia sotųjį arba neprisotintą dvivalentį angliavandenilio radikalą, turintį nurodytą anglies atomų skaičių ir bet kurį ketoną, tioketoną, iminoketoną ir jo pakeistą darinį (pvz., (CMo)alkilenas apima metileną (-CH2-), etileną (-CH2-CH2-), metiletileną, vinileną, etinileną, trimetileną (-CH2-CH2-CH2-), 2oksotrimetileną (-CH2-C(O)CH2-), 2-tiatrimetileną (-CH2-S(O)CH2-), 2iminotrimetileną (-CH2-C(NH)CH2-), propenileną (-CH2-CH=CH- arba *CH=CHCH2-), propanililideną (=CHCH2CH2-), propendiileną (=CHCH=CH-), 1aminotetrametileną, pentametileną ir kt.)."Alkylene means a saturated or unsaturated divalent hydrocarbon radical having the specified number of carbon atoms and any ketone, thioketone, iminoketone or substituted derivative thereof (e.g., (CMo) alkylene includes methylene (-CH 2 -), ethylene (-CH 2 -) CH 2 -), methylethylene, vinylene, ethynylene, trimethylene (-CH 2 -CH 2 -CH 2 -), 2 -oxotrimethylene (-CH 2 -C (O) CH 2 -), 2-thiatromethylene (-CH 2 -S ( O) CH 2 -), 2iminotrimethylene (-CH 2 -C (NH) CH 2 -), propenylene (-CH 2 -CH = CH- or * CH = CHCH 2 -), propanylidene (= CHCH 2 CH 2 -). , propendylene (= CHCH = CH-, 1-aminotetramethylene, pentamethylene, etc.).
“Alkilidenas“ reiškia =CRR radikalą, kuriame kiekvienas R nepriklausomai yra vandenilis arba alkilas, kaip nurodyta aukščiau, turintis nurodytą anglies atomų skaičių (pvz.. (Ci-6)alkilidenas apima metilideną, etilideną, propilideną, izopropilideną ir kt.)."Alkylidene" refers to a = CRR radical wherein each R is independently hydrogen or alkyl as above having the specified number of carbon atoms (e.g., (C 1-6) alkylidene includes methylidene, ethylidene, propylidene, isopropylidene, etc.).
“Alkiloksi” reiškia -OR radikalą» kuriame R yra alkilas, kaip nurodyta aukščiau, turintis nurodytą anglies atomų skaičių (pvz.. (Ci.6)alkiloksi-radikalas apima metoksi, etoksi, propoksi, izopropoksi, butoksi, antr-butoksi, izobutoksi, fref-butoksi, viniloksi, aliloksi, 1-propeniloksi, izopropeniloksi, 1 -buteniloksi, 2buteniloksi, 3-buteniloksi, 2-metilaliloksi, etiniloksi, 1 -propiniloksi, 2-propiniloksi ir kt. radikalus)."Alkyloxy" means a radical -OR "wherein R is alkyl as defined above having the indicated number of carbon atoms (eg .. (Ci. 6) alkyloxycarbonyl radical include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy , tert -butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, etc.).
“Alkilsulfinilas”, “alkilsulfonilas ir “alkiltio” reiškia -SOR, -S(O)2R ir -SR radikalus, atitinkamai, kuriuose R yra aukščiau nurodytas alkilas, turintis nurodytą anglies atomų skaičių (pvz.. (Cvejalkilsulfonilas apima metilsulfonilą, etilsulfonilą, propilsulfonilą, izopropilsulfonilą, butilsulfonilą, antr-butilsulfonilą, izobutilsulfonilą, fref-butilsulfonilą, vinilsulfonilą, alilsulfonilą, 1-propensulfonilą, izopropensulfonilą, 1 -butenilsulfonilą, 2-butenilsulfonilą, 3-butenilsulfonilą, 2-metilalilsulfonilą, etinilsulfonilą, 1 -propinilsulfonilą, 2- propinilsulfonilą ir kt.)."Alkylsulfinyl", "alkylsulfonyl and" alkylthio "denote the radicals -SOR, -S (O) 2 R and -SR, respectively, wherein R is the above alkyl having the specified number of carbon atoms (e.g. (C 2 -alkylsulfonyl includes methylsulfonyl, ethylsulfonyl) , for example, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, anth-butylsulfonyl, isobutylsulfonyl, vinylsulfonyl, allylsulfonyl, 1-propensulfonyl, 2-butenylsulfonyl, 2-butenylsulfonyl, 2-butenylsulfonyl, - propynylsulfonyl, etc.).
“Amonio” reiškia -NH3 +radikalą."Ammonium" means the radical -NH 3 + .
“Amidino reiškia -C(NH)NH2 radikalą.“Amidino means a radical of -C (NH) NH 2 .
“Amino” reiškia -NH2 radikalą."Amino" refers to the radical -NH 2 .
“Gyvūnas” apima žmones, ne žmogaus žinduolius (pvz., šunis, kates, triušius, stambiuosius galvijus, arklius, avis, ožkas, kiaules, elnius ir kt.) ir nežinduolius (pvz., paukščius ir kt.)."Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits, large cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (e.g., birds, etc.).
“Arilas” reiškia aromatinį arba kondensuotą policiklinį angliavandenilio radikalą, turintį nurodytą anglies atomų skaičių, kuriame kiekvienas žiedas, esantis čia yra sudarytas iš 6 žiedinių narių (pvz., (Ce-i4)arilas apima fenilą, naftilą, antracenilą, fenantrenilą ir kt.)."Aryl" refers to an aromatic or fused polycyclic hydrocarbon radical having the specified number of carbon atoms, wherein each ring herein is composed of 6 ring members (e.g., (C 6 -C 14) aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like). ).
“Arilsulfonilas” reiškia -S(O)2R radikalą, kuriame R yra arilas, kaip nurodyta aukščiau, turintį nurodytą anglies atomų skaičių (pvz., (Ce-io)anlsulfonilas apima fenilsulfonilą, naft-1 -ilsulfonilą ir kt)."Arylsulfonyl" means a radical of -S (O) 2 R wherein R is aryl as defined above having the specified number of carbon atoms (e.g. (C 6 -C 10) anlsulfonyl includes phenylsulfonyl, naphth-1-ylsulfonyl, etc.).
“Aromatinė liekana reiškia bet kurią aromatino radikalo dalį. Pavyzdžiui, aromatinė liekana nurodo j arilą arba heteroarilą, kaip čia nurodyta, o taip pat aromatinę dalį, apimant arilalkilą, heteroarilalkilą, policikloarilą, heteropolicikloarilą ir panašius.“Aromatic residue refers to any part of an aromatic radical. For example, the aromatic moiety refers to aryl or heteroaryl as defined herein, as well as an aromatic moiety including arylalkyl, heteroarylalkyl, polycycloaryl, heteropolycycloaryl and the like.
“Azolidinilas reiškia sotųjį arba nesotųjį 5-narį monociklinį radikalą, turintį nurodytą azoto atomų skaičių. Pavyzdžiui, (Nv^azolidinilas apima pirazolidinilą, pirolidinilą, imidazolidinilą, trizolidinilą, tetrazolidinilą, dihidropirolilą, dihidroimidazolilą, dihidropirazolilą ir dihidrotriazolilą."Azolidinyl" means a saturated or unsaturated 5-membered monocyclic radical having the specified number of nitrogen atoms. For example, N, N-azolidinyl includes pyrazolidinyl, pyrrolidinyl, imidazolidinyl, trizolidinyl, tetrazolidinyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl and dihydrotriazolyl.
“Azolilas” reiškia aromatinį 5-narį monociklinį radikalą, turintį nurodytą azoto atomų skaičių. Pavyzdžiui, (Ni-4)azolilas apima pirolilą, imidazolilą, pirazolilą, tiazolilą ir tetrazolilą."Azolyl" means an aromatic 5-membered monocyclic radical having the specified number of nitrogen atoms. For example, (Ni 4) azolyl include pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, and tetrazolyl.
“Karbamoilas” reiškia -C(O)NH2 radikalą."Carbamoyl" refers to the radical -C (O) NH 2 .
“Karboksilas” reiškia -C(O)OH radikalą."Carboxyl" refers to the radical -C (O) OH.
“Ciano” reiškia -CN radikalą."Ciano" means a -CN radical.
“Cikloalkilas” reiškia sotųjį arba nesotųjį monociklinį arba kondensuotą policiklinį angliavandenilio radikalą, turintį nurodytą anglies atomų skaičių, kuriuose kiekvienas žiedas, esantis ten sudarytas iš 3-8 žiedinių narių, ir bet koks karbociklinio ketono, jo tioketono arba aminoketono darinys (pvz., (C3. i4)cikloalkilas apima ciklopropilą, ciklobutilą, ciklopentilą, cikloheksilą, cikloheksenilą, 2,5-cikloheksadienilą, biciklo[2.2.2]oktilą, oksocikloheksilą, dioksocikloheksilą, tiocikloheksilą ir kt.)."Cycloalkyl" means a saturated or unsaturated monocyclic or fused polycyclic hydrocarbon radical having the specified number of carbon atoms, each ring containing from 3 to 8 ring members and any carbocyclic ketone, its thioketone or aminoketone derivative (e.g. C 3 - ( 4 ) cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo [2.2.2] octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.).
“Cikloalkilenas reiškia sotųjį arba nesotųjį, monociklinį arba kondensuotą policiklinį dvivaletį angliavandenilio radikalą, turintį nurodytą anglies atomų skaičių, kuriame kiekvienas žiedas, esantis ten yra sudarytas iš 3-8 žiedinių narių, ir bet koks karbociklinio ketono, jo tioketono arba iminoketono darinys (pvz., (C3. io)cikloalkilenas apima 1,2-ciklopropileną, 1,2-ciklobutileną, 1,3-ciklobutileną, 1,2ciklopentileną, 1,3-ciklopentileną, 1,4-ciklopentileną, 1,4-cikloheksileną, cikloheksen-1,2-ileną, 2,5-cikloheksadien-1,4-ileną, 1,4-biciklo[2.2.2]oktileną, 5okso-1,3-cikloheksileną, 2,5-diokso-1,4-cikloheksileną, 5-tiookso-1,4cikloheksileną ir kt.)."Cycloalkylene" means a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon radical having the specified number of carbon atoms, each ring containing from 3 to 8 ring members and any derivative of the carbocyclic ketone, its thioketone or the iminoketone (e.g. (C 3rd io) cycloalkylene includes 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2ciklopentileną, 1,3-cyclopentylene, 1,4-cyclopentylene, 1,4-cyclohexylene, cyclohexene -1,2-ylene, 2,5-cyclohexadien-1,4-ylene, 1,4-bicyclo [2.2.2] octylene, 5-oxo-1,3-cyclohexylene, 2,5-dioxo-1,4-cyclohexylene , 5-thiooxy-1,4-cyclohexylene, etc.).
“Deblokavimas reiškia bet kokios esančios blokuojančiosios grupės pašalinimą, įvykdžius atrankinę reakciją.“Unblocking means removing any existing blocking group by a selective reaction.
“Liga” specifiškai apima bet kokią gyvūno arba jo dalies nesveiką būseną ir apima nesveiką būseną, kurią gali sukelti taikymas tokio· medicininio arba veterinarinio gydymo šiems gyvūnams, t. y., šios terapijos “pašalinis efektas”.“Disease” specifically includes any unhealthy condition of an animal or part thereof and includes any unhealthy condition that may result from application of such medical or veterinary treatment to these animals, i. that is, the “side effect” of this therapy.
“Kondensuotas heteropoliciklinis radikalas” apima “kondensuotą heterobiciklinį radikalą” ir reiškia heterociklinį radikalą, turintį du arba tris kondensuotus žiedus, turinčius nurodytą skaičių žiedinių narių, kuriuose bent jau du vieno žiedo žiediniai nariai yra bendri su antru žiedu (pvz., heteropoliciklinis radikalas, turintis nuo 8 iki 18 žiedinių atomų ir karbociklinis ketonas ir jo tioketono darinys apima 17/-benzimidazol-2-ilą, 1A/-nafto[2,3-d]imidazol-2-ilą, 1Himidazo[4,5-f/chinolin-2-ilą, 1H-imidazo[4,5-b]piridin-2-ilą, 1 H-fenantro [9,1 θά] imidazol-2-ilą, 1H-imidazo[4,5-g]chinoksalin-2-ilą, 2,6-diokso-2,3,6,7-tetrahidro1H-purin-8-ilą, 2,6-ditiookso-2,3,6,7-tetrahidro-1H-purin-8-ilą, 7A7-purin-8-ilą, 1,6dihidrociklopentaimidazol-2-ilą, 4-chinolin-2-ilą ir kt.)."Fused heteropolicyclic radical" includes a "fused heterobicyclic radical" and means a heterocyclic radical having two or three fused rings having a specified number of ring members in which at least two ring members of one ring share a second ring (e.g. 8 to 18 ring atoms and the carbocyclic ketone and its thioketone derivative include 17-benzimidazol-2-yl, 1 N -naphtho [2,3-d] imidazol-2-yl, 1H-imidazo [4,5-f] quinolin- 2-yl, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-phenanthro [9,1 θά] imidazol-2-yl, 1H-imidazo [4,5-g] quinoxaline-2- 2,6-Dioxo-2,3,6,7-tetrahydro-1 H -purin-8-yl, 2,6-Dithiooxy-2,3,6,7-tetrahydro-1 H -purin-8-yl, 7A7- purin-8-yl, 1,6-dihydro-cyclopentoimidazol-2-yl, 4-quinolin-2-yl, etc.).
“Guanidino” reiškia-NHC(NH)NH2 radikalą."Guanidino" refers to the radical-NHC (NH) NH 2 .
“Halogenas” reiškia fluorą, chlorą, bromą arba jodą."Halogen" means fluorine, chlorine, bromine or iodine.
“Heteroatomo liekana”, nebent apskritai imant, reiškia liekaną, parinktą iš N=, -NR17-, -0-, -S-, -S(O)-, -S(O)2-, -P(O)(OR17)-, kur R17 yra vandenilis arba (Ci6)alkilas."Heteroatom residue", unless taken generally, refers to a residue selected from N =, -NR 17 -, -O-, -S-, -S (O) -, -S (O) 2 -, -P (O). (OR 17 ) -, wherein R 17 is hydrogen or (C 1-6) alkyl.
“Heteroalkilas” reiškia alkilą, kaip nurodyta aukščiau, išskyrus vieną arba daugiau nurodytų anglies atomų, yra pakeisti heteroatomo liekana, kaip nurodyta “detaliame išradimo aprašyme” ir bet kurį ketoną, jo tioketono arba iminoketono darinį (pvz., hetero(C2.i2)alkilas apima metoksi, etoksi, etiltio, 2-(2metoksietoksi)etoksi, 3-metoksimetoksikarbonilmetoksi, 2-(A/-etil-A/metilamino)etilą, 2-etiliminoetilą, etoksimetoksifosforiloksi ir kt.)."Heteroalkyl" means an alkyl as defined above, except one or more of the carbon atoms is replaced by a heteroatom moiety as defined in the detailed description of the invention and any ketone, its tioketono or iminoketone derivative thereof (eg., Hetero (C 2 .i 2 ) alkyl includes methoxy, ethoxy, ethylthio, 2- (2-methoxyethoxy) ethoxy, 3-methoxymethoxycarbonylmethoxy, 2- (N-ethyl-N / methylamino) ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.).
“Heteroalkilenas” reiškia alkileną, kaip nurodyta aukščiau, kuriame išskyrus vieną arba daugiau nurodytų anglies atomų, yra pakeisti heteroatomo liekana, kaip nurodyta “detaliame išradimo aprašyme”, arba bet kuris tinkamas jų derinys (pvz., -OS(O)2-, -S(O)2O-, -N(R)S(O)2-, -S(O)2NR17-, -OP(O)(OR17)O- ir panašūs, kai R17 yra vandenilis arba (Ci-e)alkilas, ir bet kuris ketonas, jo tioketono arba iminoketono darinys (pvz., hetero(C2.io)alkilenas apima azaetileną (-CH2NH-), 2azapropileną (-CH2N=CH2-), 1-oksatrimetileną (-CH2CH2O-), 2-okso-3azapentametileną, 3-aza-2-tiopentametileną, 2-oksa-3-oksopentametileną, 3-aza2-iminopentametileną (-CH2CH2NHC(NH)CH2-), 2,4-aza-2-metil-3,3-diokso-3tiopentametileną (-CH2NHS(O)2N(CH3)CH2-), 3-hidroksi-2,4-oksa-3-okso-3fosfapentametileną (-CH2OP(O)(OH)OCH2-). 3-aza-2-okso-4karboksiheksametileną, 4-aza-1 -oksa-3-oksoheksametileną, 1 -tia-3-okso-4azaheksametileną, 1-tia-1,1,3-triokso-4-azaheksametileną (CH2CH2NHC(O)CH2S(O)2-), 3-aza-4-oksoheptametileną, 1,4,7trioksaoktametileną, 6-aza-1-oksa-2,5-dioksooktametileną (CH2CH2NHC(O)CH2CH2C(O)O-), 3-aza-4-oksodekametileną ir kt)."Heteroalkylene" means alkylene as defined above wherein, except for one or more of the indicated carbon atoms, it is substituted with a heteroatom residue as indicated in the "Detailed Description of the Invention" or any suitable combination thereof (e.g., -OS (O) 2 -, -S (O) 2 O-, -N (R) S (O) 2 -, -S (O) 2 NR 17 -, -OP (O) (OR 17 ) O- and the like, when R 17 is hydrogen or (C 1 -C 6) alkyl, and any ketone, its thioketone or iminoketone derivative (e.g., hetero (C 2 -C 10) alkylene includes azaethylene (-CH 2 NH-), 2- azapropylene (-CH 2 N = CH 2 -). ), 1-oksatrimetileną (-CH 2 CH 2 O-), 2-oxo-3azapentametileną, 3-aza2-tiopentametileną, 2-oxa-3-oksopentametileną, 3-aza2-iminopentametileną (-CH 2 CH 2 NHC ( NH) CH 2 -), 2,4-aza-2-methyl-3,3-dioxo-3-thiopentamethylene (-CH 2 NHS (O) 2 N (CH 3 ) CH 2 -), 3-hydroxy-2,4 -oxa-3-oxo-3-phosphapentamethylene (-CH 2 OP (O) (OH) OCH 2 -). 3-aza-2-oxo-4-carboxyhexamethylene, 4-aza-1-oxa-3-oxohexamethylene, 1-thia- 3-oxo-4-azahexamethylene, 1-thia-1,1,3-trioxy o-4-azahexamethylene (CH 2 CH 2 NHC (O) CH 2 S (O) 2 -), 3-aza-4-oxoheptamethylene, 1,4,7-trioxaoctamethylene, 6-aza-1-oxa-2,5- dioxooctamethylene (CH 2 CH 2 NHC (O) CH 2 CH 2 C (O) O-), 3-aza-4-oxodecamethylene, etc.).
“Heteroarilas” reiškia aromatinį monociklinį arba kondensuotą policiklinį dvivalentį radikalą, turintį nurodytą žiedinių atomų skaičių, kuriame kiekvienas čia esantis žiedas susideda iš 5-6 žiedinių narių ir vienas arba daugiau žiedinių atomų yra heteroatomo liekana, parinkta iš -N=, -NR17-, -O- arba -S-, kurioje R17 yra vandenilis arba (Ci-e)alkilas, o kiekvienas čia esantis žiedas yra sudarytas iš 5-6 žiedinių narių (pvz., hetero(C5-i4)arilas apima tienilą, furilą, pirolilą, pirimidinilą, izoksazolilą, oksaksolilą, indolilą, benzo[b]tienilą, izobenzofuranilą, purinilą, izochinolilą, pteridinilą, perimidinilą, imidazolilą, piridilą, pirazolilą, pirazinilą, chinolilą ir kt.)."Heteroaryl" means an aromatic monocyclic or fused polycyclic divalent radical having the specified number of ring atoms, wherein each ring herein consists of 5-6 ring members and one or more of the ring atoms is a heteroatom residue selected from -N =, -NR 17 - , -O- or -S-, wherein R 17 is hydrogen or (C 1 -C 6) alkyl and each ring herein is composed of 5-6 ring members (e.g., hetero (C 5 -C 4 ) aryl includes thienyl , furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo [b] thienyl, isobenzofuranyl, purinyl, isoquinolyl, pteridinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl), pyrazolyl, pyrazolyl.
“Heterocikloalkilas” reiškia cikloalkilą, kaip nurodyta aukščiau, išskyrus tai, kad vienas arba daugiau nurodytų žiedinių anglies atomų yra pakeisti heteroatomo liekana, kaip nurodyta “detaliame išradimo aprašyme” ir bet kokiu karbocikliniu ketonu arba jo tipketono arba iminoketono dariniu (pvz., terminas heterociklo(C5-i4)alkilas apima piperidilą, pirolidinilą, pirolinilą, imidazolidinilą, chinuklidinilą, morfolinilą ir kt.)."Heterocycloalkyl" means cycloalkyl as defined above, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom residue as defined in the "Detailed Description of the Invention" and any carbocyclic ketone or its tipketone or iminoketone derivative (e.g. (C 5 -C 14) alkyl includes piperidyl, pyrrolidinyl, pyrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).
“Heterocikloalkilenas” reiškia cikloalkileną, kaip nurodyta aukščiau, išskyrus tai, kad vienas arba daugiau nurodytų žiedinių anglies atomų yra pakeisti heteroatomo liekana, kaip nurodyta “detaliame išradimo aprašyme” ir bet kokiu karbocikliniu ketonu arba jo tioketono arba iminoketono dariniu (pvz., terminas heterociklo(C3.i4)alkilenas apima piperidileną, pirolidinileną, pirolinileną, imidazolidinileną, chinuklidinileną, morfolinileną ir kt.)."Heterocycloalkylene" means cycloalkylene as defined above, except that one or more of the indicated ring carbon atoms is substituted with a heteroatom residue as defined in the "Detailed Description of the Invention" and any carbocyclic ketone or thioketone or iminoketone derivative thereof (e.g. (C 3. 14) alkylene includes piperidylene, pyrrolidinylene, pyrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, etc.).
“Heteropolicikloarilas” reiškia policikloarilą, kaip nurodyta aukščiau, išskyrus, kad vienas arba daugiau nurodytų žiedinių anglies .atomų yra pakeisti heteroatomo liekana, kaip nurodyta “detaliame išradimo aprašyme” ir bet kokiu karbociklinių ketonu arba jo tioketono arba iminoketono dariniu (pvz., terminas heteropoliciklo(C8-io)alkilas apima 3,4-dihidro-2/7-chinolinilą, 5,6,7,8tetrahidrochinolinilą, 3,4-dihidro-2H-[1,8]-naftiridinilą, 2,4-diokso-3,4-dihidro-2Hchinazolinilą, 3-okso-2,3-dihidrobenzo[1,4]oksazinilą ir kt.)."Heteropolycycloaryl" means polycycloaryl as defined above, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom residue as defined in the "Detailed Description of the Invention" and any carbocyclic ketone or thioketone or iminoketone derivative thereof (e.g. (C 8 -C10) alkyl includes 3,4-dihydro-2/7-quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H- [1,8] -naphthyridinyl, 2,4-dioxo- 3,4-dihydro-2H-quinazolinyl, 3-oxo-2,3-dihydrobenzo [1,4] oxazinyl, etc.).
“Hidroksilas” reiškia -OH radikalą."Hydroxyl" refers to the -OH radical.
“Imunomedijuotas uždegiminis sutrikimas” reiškia tokias ligas, kurios susietos su kamieninių ląstelių mediatorių atpalaidavimu ir pasiduodančias gydymui triptazės inhibitoriumi (pvz., tiesioginis tipas padidinto jautrumo susirgimų, tokių kaip astma, alerginis rinitas, urtikarija (dilgėlinė) ir angioedema, egzeminė anafilaksija, dermatitai, tokie kaip atopinis dermatitas, padidinto išvešėjimo odos susirgimas, skrandžio opa, uždegiminis žarnų susirgimas, akies ir pavasarinis konjunktivitas, reumatinis artritas uždegiminė odos būsena ir panašūs susirgimai)."Immune-mediated inflammatory disorder" refers to diseases that are associated with the release of stem cell mediators and are susceptible to treatment with a tryptase inhibitor (e.g., a direct type of hypersensitivity disorders such as asthma, allergic rhinitis, urticaria and urticaria, eczema anaphylaxis, dermatitis, such as atopic dermatitis, dermatitis, gastric ulcer, inflammatory bowel disease, ocular and spring conjunctivitis, inflammatory skin condition of rheumatoid arthritis and the like).
“Padidintas reaktyvumas” reiškia bronchų stenozės ir kvėpavimo takų padidinto aktyvumo, surišto su chronine astma, vėlyvąją fazę. Tikėtina, kad astmatinių bronchiolių audinių padidintas reaktyvumas atsiranda dėl lėtinės uždegiminės reakcijos, kuri erzina ir pažeidžia kvėpavimo takų užtvaros epitelio sieneles ir skatina pagrindinių audinių plonėjimą."Increased reactivity" refers to the late phase of bronchial stenosis and airway hyperactivity associated with chronic asthma. It is likely that the increased reactivity of asthmatic bronchiolar tissues results from a chronic inflammatory reaction that annoys and damages the airway barrier epithelial walls and promotes thinning of underlying tissues.
“Sincitinė virusinė infekcija” reiškia užkratą virusu, tokiu kaip respiratorinis sinicitinis virusas, sukeliantis ląstelinės protoplazminės masės susidarymą, t. y., sincitijus, per infekciją."Syncytial viral infection" means infection by a virus, such as respiratory cytosolic virus, which causes the formation of a cellular protoplasmic mass, i. i.e., syncytia, through infection.
“Imino” reiškia =NH radikalą."Imino" means = NH radical.
“Izomeras” reiškia I formulės junginius, turinčius tą pačią molekulės formulę, bet skirtigą struktūrą arba jų atomų ryšių seką, arba skirtingą jų atomų išsidėstymą erdvėje. Izomerai, kurie skiriasi savo atomų išsidėstymu erdvėje, vadinami “stereoizomerais. Stereoizomerai, kurie nėra vienas kito veidrodinis atspidys, vadinami “diastereomerais ir stereoizomerai, kurie yra vienas kito veidrodinis atspindys, vadinami “enantiomerais” arba kartais “optiniais izomerais”. Anglies atomas, surištas su keturiais skirtingais pakaitais, vadinamas “chiraliniu centru”. Junginys su vienu chiraliniu centru ir turintis dvi priešingo chirališkumo enantiomerines formas, vadinamas “raceminiu mišiniu”. Junginys, kuris turi daugiau negu vieną tokį centrą, turi 2n'1 enantiomerinių porų, kai n yra chiraliniu centrų skaičius. Junginai su daugiau negu vienu chirliniu centru gali egzistuoti tiek kaip individualus diastereomeras, tiek ir kaip diastereomerų mišinys, vadinamas “diastereomeriniu mišiniu”. Kai vienas chiralinis centras atstovauja stereoizomerą, tai jis gali būti charakterizuojamas šio chiralinio centro absoliučia konfigūracija. Absoliuti konfigūracija nurodo j pakaitų, prisijungusių prie chiralinio centro išsidėstymą erdvėje. Pakaitai, prisijungę prie chiralinio centro pagal svarbumą yra išrikiuojami pagal Cahn’o, Ingold’o ir Prelog'o Pakaitų vyresniškumo taisyklę, o absoliutūs deskriptoriai P ir S yra cituojami įterpinyje, einančiame po brūkšnelio ir po to eina cheminio junginio pavadinimas. I formulės junginiai, kurie turi chiralinį centrą, gali egzistuoti kaip individualūs stereoizomerai arba jų mišinys. Pagal šios paraiškos tikslus, kai nurodoma j I formulės junginio pavadinimą arba formulę, o konfigūracija yra nenurodoma, tai turi būti suprantama, kad nuoroda yra į visas galimas junginio konfigūracijas."Isomer" means compounds of formula I having the same molecular formula but different structure, or atomic bond sequence, or different arrangement of their atoms in space. Isomers which differ in the arrangement of their atoms in space are called 'stereoisomers. Stereoisomers which are not mirror reflections of one another are called "diastereomers" and stereoisomers which are mirror reflections of one another are called "enantiomers" or sometimes "optical isomers". A carbon atom bound to four different substituents is called a "chiral center". A compound having one chiral center and having two enantiomeric forms of opposite chirality is called a "racemic mixture". A compound having more than one such center has 2 n ' 1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center can exist both as an individual diastereomer and as a mixture of diastereomers called a "diastereomeric mixture". When a single chiral center represents a stereoisomer, it may be characterized by the absolute configuration of that chiral center. The absolute configuration specifies the distribution of the substituents attached to the chiral center in space. Substituents joined to the chiral center are ranked according to Cahn, Ingold, and Prelog's Substitute Superiority Rule, and absolute descriptors P and S are quoted in the parenthesis followed by the chemical name. Compounds of formula I which have a chiral center may exist as individual stereoisomers or as a mixture thereof. For purposes of this application, when a compound name or formula of formula I is given and no configuration is specified, it is to be understood that reference is made to all possible configurations of the compound.
“Parinkta(as)” arba “pasirinktinai” reiškia, kad vėliau aprašytas įvykis arba sąlygos gali arba negali įvykti, ir kad aprašymas apima atvejus, kai įvykis arba sąlygos įvyksta, ir atvejus kai jis neįvyksta. Pavyzdžiui, frazė “pasirinktinai pakeista(as) nuo vieno iki trijų radikalų” reiškia, kad nurodyta grupė gali arba negali būti pakeista dėl tvarkos, kuri susidaro išradimo apimtyje."Optional" or "optional" means that the event or conditions described below may or may not occur, and that the description includes instances where the event or conditions occur and events that do not occur. For example, the phrase "optionally substituted with one to three radicals" means that the specified group may or may not be substituted due to the order which forms within the scope of the invention.
“A/-oksido darinys” reiškia I formulės junginio darinius, kuriuose azotas yra oksiduotoje būsenoje (pvz., O <- N), ir kuri turi norimą farmakologinį aktyvumą. I formulės junginių N-oksidai gali būti gaunami būdais, kuriuos žino toje srityje patyrę specialistai."N -oxide derivative" means derivatives of a compound of formula I wherein the nitrogen is in the oxidized state (e.g., O <- N) and has the desired pharmacological activity. The N-oxides of the compounds of formula I may be prepared by methods known to those skilled in the art.
Ligos “patologija” reiškia esminę savybę, atsiradusią ir besivystančią tiek dėl ligos, tiek ir dėl struktūrinių ir funkcinių pakitimų, atsiradusių ligos eigoje."Pathology" of a disease refers to an intrinsic property that arises and develops both as a result of the disease and as a result of structural and functional changes that occur in the course of the disease.
“Farmaciškai priimtinas reiškia tą, kuris yra naudingas farmacinių kompozicijų gamyboje, kad jis yra iš esmės saugus, netoksiškas, nei biologiškai nei kitaip nėra nepageidautinas ir gali būti vartojamas tiek veterinarinėms, tiek ir žmonių reikmėms."Pharmaceutically acceptable" means one which is useful in the manufacture of pharmaceutical compositions, is intrinsically safe, non-toxic, is not biologically or otherwise undesirable and may be used for both veterinary and human purposes.
“Farmaciškai priimtinos druskos reiškia I formulės junginių druskas, kurios yra farmaciškai priimtinos, kaip apibrėžta aukščiau, ir kurios turi norimas farmakologines savybes. Tokios druskos apima rūgščių prijungimo druskas, susidarančias su nerganinėmis rūgštimis, tokiomis kaip vandenilio chloridas, vandenilio bromidas, sieros rūgštis, azoto rūgštis, fosforo rūgštis, ir panašiomis; arba su organinėmis rūgštimis, tokiomis kaip acto rūgštis, propiono rūgštis, heksano rūgštis, heptano rūgštis, ciklopentanpropiono rūgštis, glikolio rūgštis, piruvo rūgštis, pieno rūgštis, malono rūgštis, gintaro rūgštis, obuolių rūgštis, maleino rūgštis, fumaro rūgštis, vyno rūgštis, citrinų rūgštis, benzenkarboksirūgštis, o-(4-hidroksibenzoil)benzenkarboksirūgštis, cinamono rūgštis, migdolų rūgštis, metansulfonrūgštis, etansulfonrūgštis, 1,2etandisulfonrūgštis, 2-hidroksietansulfonrūgštis, benzensulfonrūgštis, pchlorbenzensulfonrūgštis, 2-naftalensulfonrūgštis, p-toluensulfonrūgštis, kamforosulfonrūgštis, 4-metilbiciklo[2.2.2]okt-2-en-1-karboksirūgštis, gliukoheptono rūgštis, 4,4’-metilenbis-(3-hidroksi-2-en-1-karboksirūgštis), 3fenilpropiono rūgštis, trimetilacto rūgštis, ketvirtinė butilacto rūgštis, laurilsulforūgštis, gliukono rūgštis, glutamo rūgštis, hidroksinaftoinė rūgštis, salicilo rūgštis, stearino rūgštis, mukono rūgštis ir panašiomis."Pharmaceutically acceptable salts" means salts of the compounds of the formula I which are pharmaceutically acceptable as defined above and which possess the desired pharmacological properties. Such salts include acid addition salts formed with non-acidic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2etandisulfonrūgštis, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, pchlorbenzensulfonrūgštis, 2-naphthalenesulfonic acid, p-toluenesulfonic kamforosulfonrūgštis, 4-methylbicyclo [2.2 .2] oct-2-en-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, butyl acetic acid, lauryl sulfonic acid, gluconic acid acid, glutamic acid, hydroxynaphthoic acid, salicylic acid s, stearic acid, muconic acid and the like.
Farmaciškai priimtinos druskos taip pat apima ir bazių prijungimo druskas, kurios gali būti sudarytos, kai duotos rūgšties protonas gali reaguoti su neorganine arba organine baze. Priimtinos neorganinės bazės apima natrio hidroksidą, natrio karbonatą, kalio hidroksidą, kalio hidroksidą, aliuminio hidroksidą ir kalcio hidroksidą. Priimtinos organinės bazės apima etanolaminą, dietanolaminą, trietanolaminą, trometaminą, /V-metilgliukaminą ir panašias.Pharmaceutically acceptable salts also include base addition salts which may be formed when a given acid proton can react with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
“Policikloarilas” reiškia kondensuotą policiklinį radikalą, turintį nurodytą anglies atomų skaičių, kuriame iš kondensuotų žiedų bent jau vienas, bet ne visi, turi aromatinį radikalą, o kiekvienas čia esantis žiedas yra sudarytas iš 5-6 žiedinių narių, ir bet kokio karbociklinio ketono ir jo tioketono darinio (pvz., policiklo(Cg."Polycycloaryl" means a fused polycyclic radical having the specified number of carbon atoms, wherein at least one, but not all, of the condensed rings contains an aromatic radical and each ring herein is composed of 5-6 ring members and any carbocyclic ketone and of its thioketone derivative (e.g.
10)arilas apima indanilą, indenilą, 1,2,3,4-tetrahidronaftilą, 1,2-dihidronaftilą, 2,4diokso-1,2,3,4-tetrahidronaftilą ir kt.). 10 ) aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, etc.).
“Provaisto dariniai” reiškia I formulės junginių darinius, kurie in vivo paverčiami į I formulės junginių atitinkamas nederivatizuotas formas. Tinkami provaistų dariniai apima tokius I formulės junginius, kuriuose vienas arba daugiau azoto ir/arba deguonies atomų su galimai laisvais valentingumais yra pakeisti grupe, kuri lengvai skyla in vivo procesuose. Pavyzdžiui, I formulės junginių provaistų dariniai gali turėti vieną arba daugiau /V-pakeistų aminogrupių (pvz., NH2(R18)), /V-pakeistus azoto atomus, {jungtus į alifatinę, aliciklinę arba aromatinę struktūrą (pvz., -N(R18)-), /V-pakeistą imino- arba amidino-grupėmis(pvz., C(NR18)H, -C(NR18)NH2 arba -C(NH)NHR18), /V-pakeistą guanidino grupėmis (pvz., -NHC(NR18)NHR18 , -NHC(NH)NHR18 arba -NHC(NR18)NH2)NH2) ir panašius, kuriuose R18 yra (i) -C(O)R19 arba -CH(R20)OC(O)R19 , kuriuose R19 yra (CMojalkilas, (Cb 10)alkoksi, karbamoilas, (Ci-io)alkilkarbamoilas, di(Ci-io)alkilkarbamoilas, c/s-2-(Ci10)alkanoilfenilvinilas, 3-(Ci-io)alkanoiloksibutirilas, (C3.io)cikloalkilas, hetero(C310)cikloalkilas, (C6-io)arilas arba hetero(C5-io)arilas ir R20 yra vandenilis arba (Cų io)alkilas; (ii) -X7-R21, kuriame X7 yra (Cnojalkilenas ir R21 yra karboksilas; arba (iii) -C(O)OCH(R22)OC(O)R23, kuriame R22 yra vandenilis, (Ci_10)alkilas arba (C3. io)cikloalkilas ir R23 yra (CMo)alkilas arba (C3-10)cikloalkilas. Priedo, I formulės junginių provaistų dariniai gali turėti vieną arba daugiau /V-hidroksilintų imino- arba amidino-grupių (pvz., -C(NOR24)H, -C(NOR24)NH2 arba -C(NH)NHOR24) arba Nhidroksilintas guanidino grupes (pvz., -NHC(NOR24)NH2., -NHC(NH)NHOR24), kuriuose R24 yra vandenilis, metilas, -C(O)R25 arba -CH(R26)OC(O)R25, kuriuose R25 yra (Ci.10)alkilas arba (C3.10)cikloalkilas ir R26 yra vandenilis arba (Cnojalkilas; /V-pakeistą hidroksilo grupėmis (pvz. -OR27), kuriame R27 yra -C(O)R19 arba CH(R20)OC(O)R19, kuriuose R19 ir R20 yra nurodyti aukščiau; ir/arba karboksirūgščių esterių darinių (pvz.. -C(O)OR28, kuriame R28 yra (Ci-io)alkilas arba (C3.i0)cikloalkilas."Prodrug derivatives" means derivatives of the compounds of the formula I which are converted in vivo to the corresponding non-derivatized forms of the compounds of the formula I. Suitable prodrug derivatives include those compounds of Formula I wherein one or more nitrogen and / or oxygen atoms with a possible free valence are replaced by a group that is readily degradable in vivo. For example, prodrug derivatives of compounds of formula I may have one or more N-substituted amino groups (e.g. NH 2 (R 18 )), N-substituted nitrogen atoms {attached to an aliphatic, alicyclic, or aromatic structure (e.g., - N (R 18 ) -), N-substituted with imino or amidino groups (e.g. C (NR 18 ) H, -C (NR 18 ) NH 2 or -C (NH) NHR 18 ), N-substituted guanidine groups (e.g., -NHC (NR 18 ) NHR 18 , -NHC (NH) NHR 18 or -NHC (NR 18 ) NH 2) NH 2 ) and the like, wherein R 18 is (i) -C (O) R 19 or -CH (R 20 ) OC (O) R 19 wherein R 19 is (C 1-4 alkyl, (C b 10) alkoxy, carbamoyl, (C 1-10) alkylcarbamoyl, di (C 1-10) alkylcarbamoyl, cis-2). - (C 1-10) alkanoylphenyl vinyl, 3- (C 1-10) alkanoyloxybutyryl, (C 3-10) cycloalkyl, hetero (C 3-10) cycloalkyl, (C 6-10) aryl or hetero (C 5-10) aryl and R 20 is hydrogen or (C 20 ) io) alkyl; (ii) -X 7 -R 21 wherein X 7 is (C 1 -C 4 alkylene and R 21 is carboxyl) or (iii) -C (O) OCH (R 22 ) OC (O) R 23 wherein R 22 is hydrogen, (Ci_10) alkyl or (C 3rd io ) cycloalkyl and R 23 is (C 1-10) alkyl or (C 3-10) cycloalkyl. In the appendix, the prodrug derivatives of the compounds of formula I may have one or more N-hydroxylated imino or amidino groups (e.g., -C (NOR 24 ) H, -C (NOR 24 ) NH 2 or -C (NH) NHOR 24 ). or N-hydroxylated guanidine groups (e.g., -NHC (NOR 24 ) NH 2., -NHC (NH) NHOR 24 ) wherein R 24 is hydrogen, methyl, -C (O) R 25 or -CH (R 26 ) OC ( O) R 25 wherein R 25 is (Ci.10) alkyl or (C3. 10) cycloalkyl and R 26 is hydrogen or (Cnojalkilas; / V-substituted hydroxy groups (eg. 27 -OR) wherein R 27 is -C (O) R 19 or CH (R 20 ) OC (O) R 19 wherein R 19 and R 20 are as defined above and / or derivatives of carboxylic acid esters (e.g. -C (O) OR 28 where R 28 is (Ci-io) alkyl or (C 3 .i 0) cycloalkyl.
“Blokuojanti grupė” turi reikšmę, įprastai surištą su sintetine organine chemija, t.y., grupė, kuri pasirinktinai blokuoja daugiafunkciniame junginyje vieną reaktyviąją vietą tam, kad galėtų įvykti pasirinkta cheminė reakcija neblokuotoje reaktyviojoje vietoje, ir kuri gali būti lengvai nuimta, kai bus įvykdyta atrankinė reakcija."Blocking group" has the meaning usually associated with synthetic organic chemistry, that is, a group that optionally blocks a single reactive site in a multifunctional compound to undergo a selected chemical reaction at an unblocked reactive site and which can be readily removed by a selective reaction. .
“Užblokuoti dariniai” reiškia I formulės junginių darinius, kuriuose reakyvioji vieta arba vietos yra užblokuotos blokuojančiomis grupėmis. I formulės junginių užblokuoti dariniai yra naudingi I formulės junginių sintezėje. Tinkamos reaktyviajam azoto atomui blokuojančiosios grupės apima fref-butoksikarbonilą, benziloksikarbonilą ir bet kurias kitas tinkamas aminogrupę blokuojančias grupes (pvz., žiūr. T. W. Greene, Protective groups in Organic Syntesis, John Wiley & Sons, Ine. 1981). Konkrečiai, tinkamų užblokuotų I formulės darinių pavyzdžiu yra 2-(5-(1,3-diokso-1,3-dihidroizoindol-2-ilmetil)-1 H-benzoimidazol-2-ilmetil]-4,5,6,7tetrahidro-1H-benzoimidazol-5-karboksirūgštis."Blocked derivatives" means derivatives of compounds of formula I wherein the reactive site or sites are blocked by protecting groups. Blocked derivatives of compounds of formula I are useful in the synthesis of compounds of formula I. Suitable protecting groups for the reactive nitrogen atom include tert-butoxycarbonyl, benzyloxycarbonyl, and any other suitable amino protecting group (e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Ine. 1981). Specifically, examples of suitable blocked derivatives of Formula I include 2- (5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -4,5,6,7-tetrahydro-. 1H-benzoimidazole-5-carboxylic acid.
“Terapiškai efektyvus kiekis” reiškia tą kiekį, kuris skiriamas gyvūnui ir yra efektyvus gydyti ligas."Therapeutically effective amount" means an amount administered to an animal that is effective in treating a disease.
“Gydymas” arba “gydyti” nurodo į bet kurio šio išradimo junginio skyrimą ir apima:"Treatment" or "treat" refers to the administration of any compound of the present invention and includes:
(1) gyvūno apsaugą nuo susirgimo, kuris turi polinkį į susirgimą, bet dar neturi tos ligos patirties arba ligos patologijos ar simptomų požymių, (2) ligos slopinimą, t, y., jos patologijos ir/arba simtomų vystymosi sustabdymą, arba (3) ligos pagerėjimą, t. y., jos patologijos ir/arba simptomų sugrąžinimą į buvusią padėtį.(1) protection of an animal from a disease which is predisposed to the disease but not yet experienced or showing signs or symptoms of the disease, (2) suppressing the disease, i.e., arresting its pathology and / or symptoms, or (3) ) improvement in disease, i.e. that is, a return to its pathology and / or symptoms.
“Sulfo” reiškia -S(O)OH radikalą."Sulfo" means a radical of -S (O) OH.
“Ureido” reiškia -NHC(O)NH2 radikalą."Ureido" refers to the radical -NHC (O) NH 2 .
I formulės junginiai, tarpiniai junginiai ir pradinės medžiagos, naudojamos jų sintezėje yra vadinami pagal IUPAC nomenklatūros taisykles. Pavyzdžiui, I formulės junginiuose, kuriuose:The compounds of formula I, intermediates and starting materials used in their synthesis are referred to as IUPAC nomenclature rules. For example, compounds of formula I wherein:
A drauge su B sudaro 5-guanidino-1A/-benzoimidazol-2-ilą, C apima 5-(2naft-1-iletilkarbamoil)-1/7-benzoimidazol-2-ilą ir X3 yra -CH2- yra vadinamas 2-(518 guanidino-1 H-benzoimidazol-2-ilmetil)-N-(2-naft-1 -ii et i I) -1 H-benzoimidazol-5karboksamidu;A together with B forms 5-guanidino-1A / benzoimidazol-2-yl, C includes 5- (2-naphth-1-yl-ethylcarbamoyl) -1,7-benzoimidazol-2-yl and X 3 is -CH 2 - is referred to as 2 - (518 guanidino-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-yl-ethyl) -1H-benzoimidazole-5-carboxamide;
A drauge su B sudaro 5-guanidino-1H-benzoimidazol-2-ilą, C apima 6-(2naft-1-iletilkarbamoil)-1-metil-1/7-benzoimidazol-2-ilą ir X3 yra -CH2-yra vadinamas 2-(5-guanidino-1H-benzoimidazol-2-ilmetil)-3-metil-/V-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamidu;A together with B forms 5-guanidino-1H-benzoimidazol-2-yl, C includes 6- (2-naphth-1-yl-ethylcarbamoyl) -1-methyl-1/7-benzoimidazol-2-yl, and X 3 is -CH 2 -. is called 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;
A drauge su B sudaro 5-guanidino-1/7-benzoimidazol-2-ilą, C apima 6-[2(2-karboksifenil)etilkarbamoil]-1-(3-sulfopropil-1/7-benzoimidazol-2-ilą ir X3 yra CH2- yra vadinamas 2-{2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-(3sulfopropil)-3H-benzoimidazol-5-ilkarbonilamino]etil}benzkarboksirūgštimi; irA together with B forms 5-guanidino-1/7-benzoimidazol-2-yl, C includes 6- [2- (2-carboxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl-1/7-benzoimidazol-2-yl) and X 3 is CH 2 - is called 2- {2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino] ethyl} benzoic acid;
A drauge su B sudaro 5-guanidino-1H-benzoimidazol-2-ilą, C apima 6-[2(2-metoksifenil)etilkarbamoil]-1-(3-sulfopropil-1/7-benzoimidazol-2-ilą ir X3 yra CH2- yra vadinamas 3-{2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-6-[2-(2metoksifenil)etilkarbamoil]benzoimidazol-1-il}propan-1-sulfonrūgštimi.A together with B forms 5-guanidino-1H-benzoimidazol-2-yl, C includes 6- [2- (2-methoxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl-1/7-benzoimidazol-2-yl) and X 3 is CH 2 - is called 3- {2- (5-guanidino-1/7-benzoimidazol-2-ylmethyl) -6- [2- (2-methoxyphenyl) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid.
Tam tikri I formulės junginiai egzistuoja tautomerinėje pusiausvyroje. Pavyzdžiui, I formulės junginys, kuriame C yra 4,5,6,7-tetrahidro-3H-imidazo[4,5c]piridin-2-ilas egzistuoja pusiausvyroje tarp sekančių formulių tautomerų:Certain compounds of formula I exist in tautomeric equilibrium. For example, a compound of formula I wherein C is 4,5,6,7-tetrahydro-3H-imidazo [4,5c] pyridin-2-yl exists in equilibrium between the tautomers of the following formulas:
ir, vadinasi, nors šio išradimo junginiai gali būti pavadinti, pailiustruoti ir aprašyti šioje paraiškoje kaip vienas iš galimų tautomerų, turi būti suprantama, kad visi galimi tautomerai turi būti vadinami tais pačiais pavadinimais, iliustracijomis ir aprašymais. Taip, pavadinimas 2-(4-{2-[1-(5-guanidino-1H19 benzoimidazoi-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-il}-4oksobutil)etilo benzoatas reiškia, kad apima jo tautomerus 2-(4-{2-[1-(5guanidino-3H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-il}4-oksobutil)etilo benzoatą, 2-(4-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]3,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-il}-4-oksobutil)etilo benzoatą ir 2-(4-{2-[1 (5-guanidino-3H-benzoimidazol-2-il)etil]-3,4,6,7-tetrahidroimidazo[4,5-c]piridin-5il}-4-oksobutil)etilo benzoatą.and thus, although the compounds of the present invention may be named, illustrated and described as one of the possible tautomers herein, it is to be understood that all the possible tautomers are to be referred to by the same names, illustrations and descriptions. Yes, the name 2- (4- {2- [1- (5-guanidino-1H19 benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl } -4-oxobutyl) ethyl benzoate means that its tautomers include 2- (4- {2- [1- (5-guanidino-3H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5] -c] pyridin-5-yl} 4-oxobutyl) ethyl benzoate, 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 3,4,6,7- tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) ethyl benzoate and 2- (4- {2- [1- (5-guanidino-3 H -benzoimidazol-2-yl) ethyl] -3, 4,6,7-Tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) ethyl benzoate.
Šiuo metu pageidautini įgyvendinimai:Currently preferred implementations are:
Nors šio išradimo plačiausias apibrėžimas yra pateiktas skyriuje “Išradimo esmė”, visgi tam tikriems išradimo aspektams yra teikiama pirmenybė. Pageidautinu šio išradimo aspektu yra I formulės junginys, kuriame A drauge su B sudaro kondensuotą heterobiciklinį radikalą, kuriame A turi 5 žiedinius narius ir X4 ir X5 yra oksazol-2-ilo, 1/7-imidazol-2-ilo arba tiazol-2-ilo žiedo gretutiniai nariai.Although the broadest definition of the present invention is set forth in the "Gist of the Invention", certain aspects of the invention are preferred. In a preferred aspect of the present invention there is provided a compound of formula I wherein A together with B forms a fused heterobicyclic radical wherein A has 5 ring members and X 4 and X 5 are oxazol-2-yl, 1/7-imidazol-2-yl or thiazol-2-yl. Related members of 2nd ring.
Pageidautinu išradimo aspektu yra junginiai, turintys Ii formulę:In a preferred aspect of the invention are compounds having the formula IIi:
kurioje:where:
brūkšniuotos linijos nepriklausomai reiškia pasirinktas jungtis; kiekvienas R2 nepriklausomai yra (Ci.6)alki!as, (Ch^alkiloksi, halogenas arba hidroksilas;dashed lines independently represent the selected connections; each R 2 is independently (Ci. 6) alki I (Ch ^ alkyloxy, halo or hydroxy;
kiekvienas R3 neprikiausoami yra (Ci-6)alkilas, (Ci.6)alkiloksi, halogenas arba hidroksilas;each R 3 is unsubstituted is (C 1-6) alkyl, (C 1-6) alkyloxy, halo or hydroxyl;
X3 yra -C(O)- arba -CR7R8-;X 3 is -C (O) - or -CR 7 R 8 -;
X8 yra -CH(R1)ni- arba -C(R1)ni=, kuriuose R1 yra amino(NM)azolidinilas, amino(Ni-4)azolilas, (Ni.4)azolidinilas, (Ni.4)azolilas, -NHC(NH)NR9R9, -C(NR9)R9 , -C(NH)NHR10. -C(NH)NR10R10 arba -CR11(R11)yNH2. arba X8 yra -N= arba NH(R1)ni-, kuriame R1 yra -C(NR9)R9, -C(NH)NHR10 arba -C(NH)NR10R10, kuriuose kiekvienas R9 nepriklausomai yra vandenilis arba (Ci.6)alkilas ir kiekvienas R10 nepriklausomai yra (Ci-6)alkilas; irX 8 is -CH (R 1 ) ni - or -C (R 1 ) ni = wherein R 1 is amino (NM) azolidinyl, amino (Ni-4) azolyl, (Ni 4) azolidinyl, (Ni 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 ) y NH 2 . or X 8 is -N = or NH (R 1 ) n i -, wherein R 1 is -C (NR 9 ) R 9 , -C (NH) NHR 10, or -C (NH) NR 10 R 10 , wherein each R 9 is independently hydrogen or (C 1-6 ) alkyl and each R 10 is independently (C 1-6 ) alkyl; and
X9 yra -CH(R4)- arba -C(R4)=, kuriuose R4 yra -R12, -OR12, -N(R13)R12, -SR12, S(O)R12, -S(O)2R12, -S(O)2OR12, -S(O)2N(R13)R12, -N(R13)S(O)2R12, -C(O)R12, C(O)OR12, -C(O)N(R13)R12, -N(R13)C(O)R12, -OC(O)N(R13)R12, -N(R13)C(O)OR12, (CH2)n4N(R13)C(O)N(R13)R12, -OP(O)(OR13)OR12 arba -C(O)N(R14)CH(COOH)R12, arba X9 yra -N= arba -N(R4)-, kuriuose R4 yra -C(O)R12, -C(O)OR12, -C(O)N(R13)R12, -OC(O)N(R13)R12 arba -C(O)N(R14)CH(COOH)R12, kuriuose R12, R13 ir R14 yra tokie, kaip nurodyti skyriuje “Išradimo esmė”.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) 2 R 12 , -S (O) 2 OR 12 , -S (O) 2 N (R 13 ) R 12 , -N (R 13 ) S (O) 2 R 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 ) n 4 N (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 such as those set forth in the section of the Invention.
Pageidautinu išradimo aspektu yra junginiai, turintys I formulę, kurioje:In a preferred aspect of the invention are compounds of formula I wherein:
R5 yra vandenilis arba (Ci.4)alkilas, R6 yra vandenilis arba (Ci-4)alkilas, kuriuose alkilas yra pasirinktinai pakeistas nuo vieno iki dviejų pakaitų, nepriklausomai parinktų iš (Ci.4)alkiloksi, hidroksilo ir sulfo-grupės, R7 yra vandenilis arba metilas ir R8 yra vandenilis, metilas arba hidroksilas;R 5 is hydrogen or (C 1-4) alkyl, R 6 is hydrogen or (C 1-4) alkyl wherein alkyl is optionally substituted with one to two substituents independently selected from (C 1-4 ) alkyloxy, hydroxy and sulfo. , R 7 is hydrogen or methyl and R 8 is hydrogen, methyl or hydroxyl;
R8 yra -CH(R4)- arba -C(R1)ni=, kuriuose R1 yra aminometilas, 1aminociklopropilas, 2-aminoimidazol-1-ilas, 2-amino-1,1-dimetiletilas, imidazolilas, tetrazolilas, -(CH2)NHC(NR9)R9, -(CH2)xNHC(NH)NR9R9 ir -C(NR9)R9, kuriuose kiekvienas R9 nepriklausomai yra vandenilis arba metilas, arba X8 yra -N(R1)ni-, kuriame R1 yra -C(NR9)R9, -C(NH)NHR10 arba -C(NH)NR10R10, kuriuose kiekvienas R9 nepriklausomai yra vandenilis arba metilas ir kiekvienas R10 yra metilas, kuriuose bet kuri alifatinė arba aliciklinė liekana, turinti R1 pasirinktinai yra pakeista vienu arba dviem pakaitais, nepriklausomai parinktais iš metilsulfonilo ir karboksilo;R 8 is -CH (R 4 ) - or -C (R 1 ) ni = wherein R 1 is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2-amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, - (CH 2) NHC (NR 9 ) R 9 , - (CH 2) x NHCH (NH) NR 9 R 9 and -C (NR 9 ) R 9 wherein each R 9 is independently hydrogen or methyl, or X 8 is -N (R 1 ) ni - wherein R 1 is -C (NR 9 ) R 9 , -C (NH) NHR 10 or -C (NH) NR 10 R 10 wherein each R 9 is independently hydrogen or methyl and each R 10 is methyl, wherein any aliphatic or alicyclic residue containing R 1 is optionally substituted with one or two substituents independently selected from methylsulfonyl and carboxyl;
X9 yra -CH(R4)=, kuriame R4 yra -R12, -OR12, -C(O)R12, -C(O)OR12, C(O)N(R13)R12, arba -C(O)N(R14)CH(COOH)R12, kuriuose R13 ir R14, nepriklausomai vienas nuo kito, yra vandenilis arba (Cvejalkilas; R12 yra -R15 arba X6-(R15)ni5, kai X6 yra (Ci.10)alkilenas arba hetero(C2.i0)alkilenas, o kiekvienas R15 nepriklausomai yra vandenilis, (C6-i4)arilas, ciklo(C3.i4)alkilas, policiklo(C6-i4)arilas, heteropoliciklo(C6.14)arilas, heterociklo(C3-14)alkilas arba hetero(C5.i4)arilas;X 9 is -CH (R 4 ) = wherein R 4 is -R 12 , -OR 12 , -C (O) R 12 , -C (O) OR 12 , C (O) N (R 13 ) R 12. , or -C (O) N (R 14 ) CH (COOH) R 12 wherein R 13 and R 14 are each independently hydrogen or (C 2 -alkyl); R 12 is -R 15 or X 6 - (R 15). ) ni 5 when X 6 is (C 1-10) alkylene or hetero (C 2-10) alkylene and each R 15 is independently hydrogen, (C 6 -C 14) aryl, cyclo (C 3 -C 14 ) alkyl, polycyclic (C 6 s 4) aryl, heteropolycycle (C sixth 14) aryl, heterocyclo (C 3-14) alkyl or hetero (C 5 .i 4) aryl;
bet kuri alifatinė arba aliciklinė liekana, turinti R4, pasirinktinai pakeista nuo vieno iki penkių pakaitų, nepriklausomai parinktų iš (Ci_4)alkiloksi, (Cb 4)alkiloksikarbonilo, amino, karbamoilo, karboksilo ir hidroksilo; ir bet kuri aromatinė liekana, turinti R15, pasirinktinai pakeista nuo nuo vieno iki trijų pakaitų, nepriklausomai parinktų iš (Cb4)alkilo, (Cb4)alkiloksi, (Cb 4)alkiloksikarbonilo, karbamoilo, karboksilo, ciano, ciklo(C3.6)alkiloksi, halogeno, hetero(Cb8)alkilo, hetero(Cb8)alkilkarbonilo, hetero(C5-6)arilo, ir trifluormetilo; ir jų A/-oksidų dariniai, provaistų dariniai, blokuoti dariniai, individualūs izomerai, izomerų mišiniai ir jų farmaciškai priimtinos druskos.any aliphatic or alicyclic moiety comprising R4 optionally substituted by one to five substituents independently selected from (Ci_ 4) alkyloxy, (C b 4) alkyloxycarbonyl, amino, carbamoyl, carboxyl, and hydroxyl; and any aromatic moiety comprising R15 optionally substituted with one to three substituents independently selected from (C b4) alkyl, (C b4) alkyloxy, (C b 4) alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo (C 3rd 6) alkyloxy, halo, hetero (C b 8) alkyl, hetero (C b 8) alkylcarbonyl, hetero (C5-6) aryl and trifluoromethyl; and their N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
Pageidautinu išradimo aspektu yra I formulės junginiai, kurioje:In a preferred aspect of the invention are compounds of formula I wherein:
A drauge su B sudaro 4,5,6,7-tetrahidro-1F/-imidazo[4,5-c]piridin-2-ilą, kuriame n2 yra 0 ir R1 yra-C(NR9)R9, arba A drauge su B sudaro 1/7benzoimidazol-2-ilą arba 4,5,6,7-tetrahidro-1/7-benzoimidazol-2-ilą, kurioje R1 yra aminometilas arba guanidinas, o kiekvienas R2 nepriklausomai yra halogenas arba hidroksilas;A together with B forms 4,5,6,7-tetrahydro-1 H, -imidazo [4,5-c] pyridin-2-yl wherein n 2 is 0 and R 1 is -C (NR 9 ) R 9 , or A together with B forms 1/7-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1/7-benzoimidazol-2-yl wherein R 1 is aminomethyl or guanidine and each R 2 is independently halo or hydroxyl ;
C apima 4,5,6,7-tetrahidro-1F/-imidazo[4,5-c]piridin-2-ilą arba 1Hbenzoimidazol-2-ilą, kuriuose R4 yra -C(O)X6-R15, -C(O)OX6-R15 arba -C(O)NHX6R15, kuriuose X6 yra (Ci.4)alkilenas arba hetero(C2^»)alkilenas ir R15 yra (C6-io)arilas, (C6-io)ariloksi, policiklo(C6-io)arilas, (C6-io)ariloksi, policiklo(C5-10)arilas, hetero(C5. io)arilas, hetero(C5-io)ariloksi arba heteropoliciklo(C6-i4)arilas; ir bet kuri aromatinė liekana, turinti R15, pasirinktinai pakeista nuo nuo vieno iki trijų pakaitų, nepriklausomai parinktų iš (Ci_4)alkilo, (Ci_4)alkiloksi, (Cb 4)alkiloksikarbonilo, karboksilo, karbamoilo, halogeno, hidroksilo, ir tetrazol-1 -ilo; ir jų /V-oksidų dariniai, provaistų dariniai, blokuoti dariniai, individualūs izomerai, izomerų mišiniai ir jų farmaciškai priimtinos druskos.C includes 4,5,6,7-tetrahydro-1 H, -imidazo [4,5-c] pyridin-2-yl or 1H-benzoimidazol-2-yl, wherein R 4 is -C (O) X 6 -R 15 , -C (O) OX 6 -R 15 or -C (O) NHX 6 R 15 where X 6 is (C 1-4) alkylene or hetero (C 2-4 alkyl) and R 15 is (C 6-10) aryl, (C6-io) aryloxy, polycycloalkanes (C 6 -io) aryl, (C 6 -io) aryloxy, polycycloalkanes (C5 10) aryl, hetero (C 5. io) aryl, hetero (C5-io) aryloxy or heteropolycycle (C 6 s 4) aryl; and any aromatic residue containing R 15 optionally substituted with one to three substituents independently selected from (C 1-4 ) alkyl, (C 1-4 ) alkyloxy, (C 1-4 ) alkyloxycarbonyl, carboxyl, carbamoyl, halo, hydroxyl, and tetrazol-1-yl; and their N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
Pageidautinu išradimo aspektu yra junginiai, turintys I formulę, kurioje n1 yra 0, o kiekvienas R2 nepriklausomai yra halogenas arba hidroksilas, konkrečiai:In a preferred aspect of the invention are compounds of formula I wherein n 1 is 0 and each R 2 is independently halogen or hydroxyl, in particular:
2-(2-{2-[1-(4,6,7-trifluor-1/7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis;2- (2- {2- [1- (4,6,7-trifluoro-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid;
2-(2-{2-[1-(5,6-difluor-1/7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol5-ilkarbonilamino}etoksi)benzenkarboksirūgštis;2- (2- {2- [1- (5,6-Difluoro-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid;
2-(2-{2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol5-ilkarbonilamino}etoksi)butilo benzoatas;2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) butyl benzoate;
2-(2-{2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol5-ilkarbonilamino}etoksi)propilo benzoatas; ir2- (2- {2- [1- (5-Hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) propyl benzoate; and
2-(2-{2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol5-ilkarbonilamino}etoksi)izobutilo benzoatas.2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) isobutyl benzoate.
Pageidautinu išradimo aspektu yra junginiai, turintys I formulę, kurioje R1 yra aminometilo guanidinas, konkrečiai:In a preferred aspect of the invention are compounds of formula I wherein R 1 is aminomethyl guanidine, in particular:
2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-metil-/V-(2-naft-1-iletil)-3/7benzoimidazol-5-karboksamidas;2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3,7-benzoimidazole-5-carboxamide;
2-(4-{2-[1 -(5-guanidino-1 A/-benzoimidazol-2-il)etil)-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-il}-4-oksobutil)etilo benzoatas;2- (4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} - 4-oxobutyl) ethyl benzoate;
2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-/V-(2naft-1-iletil)-3H-benzoimidazol-5-karboksamidas;2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;
2-(5-guanidino-1W-benzoimidazol-2-ilkarbonil)-3-(2,3-dihidroksi)propil-/V-(2naft-1-iletil)-3H-benzoimidazol-5-karboksamidas;2- (5-guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide;
2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-(3-hidroksi)propil-/V-(2-naft-1iletil)-3W-benzoimidazol-5-karboksamidas;2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl- N - (2-naphthylethyl) -3W-benzoimidazole-5-carboxamide;
2-(5-guanidino-1H-benzoimidazol-2-ilmetil)-3-(2-hidroksi)propil-/V-(2-naft-1iletil)-3A/-benzoimidazol-5-karboksamidas;2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3- (2-hydroxy) propyl- N - (2-naphthylethyl) -3 N -benzoimidazole-5-carboxamide;
2-[1-(5-guanidino-1/-/-benzoimidazol-2-il)etil)-N-[2-(2-karbamoilfenoksi)etil]3-metil-3H-benzoimidazol-5-karboksamidas;2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] 3-methyl-3 H -benzoimidazole-5-carboxamide;
2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil)-A/-[2-(2-karbamoil-4chlorfenoksi)etil]-3-metil-3A/-benzoimidazol-5-karboksamidas;2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3 N-benzoimidazole-5-carboxamide;
4- chlor-2-[2-({2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonil}amino)etoksi]benzenkarboksirūgštis;4-chloro-2- [2 - ({2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid;
5- chlor-2-[2-({2-[1-(5-guanidino-1H-benzoimidazo!-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonil}amino)etoksi]benzenkarboksirūgŠtis;5-Chloro-2- [2 - ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid ;
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-3-rnetil-/V-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamidas; ir2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide; and
2-(5-aminometil-4,5,6,7-tetrahidro-1/7-benzoimidazol-2-ilmetil)-3-metil-/V-(2naft-1-iletil)-3/7-benzoimidazol-5-karboksamidas.2- (5-Aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-yl-ethyl) -3,7-benzoimidazol-5 -carboxamide.
Pageidautinu išradimo aspektu yra junginiai, turintys I formulę, kurioje C turi 4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilą ir R1 yra -C(NH)R9, konkrečiai:In a preferred aspect of the invention are compounds of formula I wherein C has 4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl and R 1 is -C (NH) R 9 , specifically:
2-(2-(2-(1-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2il]etil}-3-metil-3/7-benzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis;2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl) ethyl) -3 -methyl-3,7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid;
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1/-/-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-(2-naft-1-iletil)-3/7-benzoimidazol-5-karboksamidas;2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphthyl) -1-ylethyl) -3,7-benzoimidazole-5-carboxamide;
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilkarbonil]-3metil-/V-(2-naft-1-iletil)-3/-/-benzoimidazol-5-karboksamidas;2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl-N- (2-naphth-1-yl) ethyl (ethyl) -3H-benzoimidazole-5-carboxamide;
2-(5-iminometil)-4,5,6,7-tetrahidro-1H-imida2o[4,5-c]piridin-2-ilmetil)-3metil-/V~(2-naft-1 -iletil)-3/7-benzoimidazol-5-karboksamidas;2- (5-Iminomethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-1-ethyl) - 3,7-benzoimidazole-5-carboxamide;
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1/-/-imidazo[4,5-c]piridin-2-ilmetil]-3metil-A/-(2-hidroksi-2-naft-1-iletil)-3H-benzoimidazol-5-karboksamidas;2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-hydroxy) -2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;
2-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-ilmetil]-3metil-A/-[2-(2-hidroksinaft-1-il)etil]-3/7-benzoimidazol-5-karboksamidas;2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (2 -hydroxynaphth-1-yl) ethyl] -3,7-benzoimidazole-5-carboxamide;
2-[5-(1-irriinoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-N-[2-(4-hidroksinaft-1-il)etil]-3/-/-benzoimidazol-5-karboksamidas;2- [5- (1-Irriinoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (4-hydroxynaphthyl) 1-yl) ethyl] -3 H -benzoimidazole-5-carboxamide;
2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1A/-imidazo[4,5-c]piridin-2-il]etil]-3metil-A/-(2-naft-1-iletil)-3/7-benzoimidazol-5-karboksamidas;2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 N -imidazo [4,5-c] pyridin-2-yl] ethyl] -3-methyl-N - ( 2-naphth-1-ylethyl) -3,7-benzoimidazole-5-carboxamide;
2-[2-(2-{1-[5-(1-iminoetil)-4,5,6,7-tėtrahidro-1/-/-imidazo[4,5-c]piridin-2il]etil}-3-metil-3H-benzoimidazol-5-ilkarbonilamino)etoksi]etilo benzoatas;2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] ethyl benzoate;
2-[2-(2-{1-[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2il]etil}-3-(2-metoksietil)-3W-bęnzoimidazol-5-ilkarbonilamino)etoksijbenzenkarboksirūgštis;2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3- (2-methoxyethyl) -3W-benzoimidazol-5-ylcarbonylamino) ethoxybenzoic acid;
2-[2-(2-{1-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2il]etil}-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-ilkarbonilamino)etoksi]etilo benzoatas; ir2- [2- (2- {1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -1) , 4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] ethyl benzoate, and
2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil]-3metil-/V-[2-(2-tetrazolilfenoksi)etil]-3/-/-benzoimidazol-5-karboksamidas.2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl] -3-methyl-N- [2 - (2-Tetrazolylphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide.
Farmakologija ir pritaikymas:Pharmacology and application:
Šio išradimo junginiai yra serino proteazės inhibitoriais ir, kaip tokie, yra naudingi gydyti ligas, susijusias su padidintu serino proteazės aktyvumu.The compounds of the present invention are serine protease inhibitors and, as such, are useful in the treatment of diseases associated with increased serine protease activity.
Konkrečiai, šio išradimo junginiai yra triptazės inhibitoriai ir yra naudingi gydyti ligas, susijusias su padidintu triptazės aktyvumu. In vitro protokolai apie potencialių inhibitorių atranką, kaip ir jų gebėjimą inhibuoti triptazę jau yra žinomi. Žiūr., pvz., Sturzebecher et ai. (1992), Biol. Chem. Hoppe-Seyler, 373:1025-1030. Paprastai šiose analizėse išmatuojama chromogeninių medžiagų peptidų pagrindu fermentų indukuota hidrolizė. Pavyzdinio būdo detalės, kaip išmatuoti triptazės inhibavimo aktyvumą, yra aprašytos žemiau.In particular, the compounds of the present invention are tryptase inhibitors and are useful in the treatment of diseases associated with increased tryptase activity. In vitro protocols for the selection of potential inhibitors as well as their ability to inhibit tryptase are already known. See, e.g., Sturzebecher et al. (1992) Biol. Chem. Hoppe-Seyler, 373: 1025-1030. Typically, these assays measure peptide-based enzyme-induced hydrolysis of chromogenic substances. Exemplary methods of measuring tryptase inhibition activity are described below.
Priedo, šio išradimo junginių aktyvumas gali būti įvertintas vienu iš eilinių gyvulių astmos modeliu in vivo. Žiūr., Larson, “Eksperimentai Models ot Reversible Airvvay Obstruction” (“Grįžtamosios kvėpavimo takų obstrukcijos eksperimentiniai modeliai”), in THE LUNG: SCIENTIFIC FOUNDATIONS, Crystal, West et ai., eds., Raven Press, New York, 1991; VVarner et ai. (1990), Am. Rev. Respir. Dis., 141:253-257. Idealus gyvulių modelis turi atkartoti pagrindinius klinikinius ir fiziologinius žmogaus astmos požymius, apimant: kvėpavimo takų padidintą reaktuvumą cheminiams mediatoriams ir fizikiniams stimuliatoriams;In addition, the activity of the compounds of the present invention can be assessed by one of the in vivo animal models of asthma. See Larson, "Experimental Models of Reversible Airway Obstruction", in THE LUNG: SCIENTIFIC FOUNDATIONS, Crystal, West et al., Eds., Raven Press, New York, 1991; Varner et al. (1990) Am. Rev. Respir. Dis., 141: 253-257. The ideal animal model should replicate the basic clinical and physiological signs of human asthma, including: increased respiratory responsiveness to chemical mediators and physical stimuli;
grįžtamąją kvėpavimo takų obstrukciją vaistais, naudojamais žmogaus astmai gydyti (β-adrenoblokatoriai, metilksantinai, kortikosteroidai ir panašūs); kvėpavimo takų uždegimą su aktyvuotų leukocitų uždegimu; ir chroniškus uždegiminius išsigimimo pakitimus, tokius kaip pagrindinės membranos sukietėjimas, lygiųjų raumenų hipertrofija ir epitelio pažeidimas. Gyvulių rūšys, kaip gyvūnų modeliai, yra pelės, žiurkės, jūros kiaulytės, triušiai, šunys ir avys. Visi turi tam tikrų apribojimų, todėl tinkamas gyvūno modelio pasirinkimas priklauso nuo to, koks klausimas turi būti išspręstas.reversible airway obstruction with drugs used to treat asthma in humans (β-blockers, methylxanthines, corticosteroids and the like); respiratory tract inflammation with activated leukocyte inflammation; and chronic inflammatory lesions such as hardening of the basement membrane, hypertrophy of smooth muscle, and epithelial damage. Animal species as animal models include mice, rats, guinea pigs, rabbits, dogs and sheep. Everyone has some limitations, so choosing the right animal model depends on what issue needs to be addressed.
Pirminė astmatinė reakcija gali būti įvertinta su jūros kiaulytėmis, šunimis ir ypatingai su baseto-kurto hibridu, kuris išvysto nespecifinį kvėpavimo takų padidintą reaktyvumą j eilę nealerginančių medžiagų, tokių kaip metacholinas ir citrinų rūgštis. Kai kurios atrinktos avys rodo dvigubą reakciją paveikus antigenu su Ascaris baltymais. Dvigubai reaguojantiems gyvūnams po 6-8 valandų poveikio pirminę astmatinę reakciją lydi (IAR) vėlyvoji astmatinė reakcija (LAR). Hiperjautrumas į cholinerginj agonistą karbacholj padidėja po 24 valandų po povekio antigenu tiems gyvūnams, kurie rodo LAR.The primary asthmatic reaction can be assessed with guinea pigs, dogs, and especially with the basset-greyhound hybrid, which develops nonspecific respiratory reactivity to a series of non-allergenic substances such as methacholine and citric acid. Some selected sheep show a double reaction when exposed to antigen with Ascaris proteins. In double-reactive animals, the primary asthmatic reaction is accompanied by a (IAR) late asthmatic reaction (LAR) after 6-8 hours of exposure. Hypersensitivity to the cholinergic agonist carbachol increases 24 hours after subcutaneous antigen in animals showing LAR.
Buvo panaudotas alerginės avies modelis (žiūr. žemiau), kad būtų galima įvertinti šio išradimo junginių potencialų antiastmatinį efektą. Kompozicijų, turinčių šio išradimo junginių skyrimas alerginėms avims tiek per burną, tiek ir inhaliacijų arba aerozolių pavidalu, prieš arba specifinių alergenų poveikio metu parodo, kad tokios kompozicijos iš esmės sumažina arba panaikina vėlyvąją astmatinę reakciją ir atitinkamą padidintą reaktyvumą.An allergic sheep model (see below) was used to evaluate the potential antistatic effect of the compounds of the present invention. Administration of compositions containing the compounds of the present invention to oral allergic sheep, as well as inhalation or aerosol administration, prior to or during exposure to specific allergens, demonstrates that such compositions substantially reduce or eliminate late asthmatic response and consequent increased reactivity.
Šio išradimo junginiai yra naudingi gydyti kitus imunomedijuotus uždegiminius sutrikimus, kuriems triptazės aktyvumas sukelia patologinę būseną. Tokios ligos apima uždegimines ligas, susijusias su kamieninėmis ląstelėmis, tokiomis kaip reumatinis artritas, konjunktivitas, reumatinė spondiliozė, osteoartritas, podagrinis artritas ir kitos artritų būsenos, uždegiminis žarnų susirgimas, skrandžio opa ir įvairios odos būklės. Toliau, šio išradimo junginiai gali būti naudojami gydyti sincitines virusines infekcijas.The compounds of the present invention are useful in the treatment of other immunomediated inflammatory disorders in which tryptase activity causes a pathological condition. Such diseases include inflammatory diseases involving stem cells such as rheumatoid arthritis, conjunctivitis, rheumatic spondylosis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease, gastric ulcer and various skin conditions. Further, the compounds of the present invention can be used to treat syncytial viral infections.
Šio išradimo junginių efektyvumas gydyti daugybę imunomedijuotų uždegiminių sutrikimų gali būti įvertintas tiek in vitro, tiek ir in vivo metodais. Taip, šio išradimo junginių priešuždegiminis efektyvumas gali būti pademonstruotas gerai žinomais bandymais, pavyzdžiui, grįžtamojo pasyvaus sąnario reakcijos (RPAR)-PAVV technika (žiūr., pvz., Gangly et ai. (1992), US Patentas Nr. 5126352). Bandymai nustatyti junginių terapinę vertę gydant įvairias odos būkles, tokias kaip labai išvešėjusias odos ligas, yra gerai žinomi, payzdžiui, arachidono rūgšties pelės ausiai testas (ld). Šio išrdimo junginiai gali būti įvertinti pagal jų antiopinj aktyvumą pagal būdus, apršytus Chiu et ai. (1984), Archives Internationales de Pharmacodynamie et de Therapie, 270:128-140.The efficacy of the compounds of the present invention in the treatment of a variety of immune-mediated inflammatory disorders can be evaluated by both in vitro and in vivo methods. Yes, the anti-inflammatory efficacy of the compounds of the present invention can be demonstrated by well known tests, such as the Reverse Passive Joint Reaction (RPAR) -PAVV technique (see, e.g., Gangly et al. (1992), U.S. Patent No. 5,126,352). Attempts to determine the therapeutic value of compounds in the treatment of various skin conditions, such as highly advanced skin conditions, are well known in the art, the test for arachidonic acid in the mouse ear (ld). The compounds of this invention may be evaluated for their anti-opine activity according to the methods described by Chiu et al. (1984), Archives Internationales de Pharmacodynamie et de Therapie, 270: 128-140.
Šio išradimo junginių efektyvumas blokuojant ląstelių susiliejimą, kylantį dėl sincitines virusinės infekcijos gali būti įvertintas metodais, pagrindinai pateiktais Tidwell etai., J. Med. Chem., 26:294-298 (1983).The efficacy of the compounds of the present invention in blocking cell fusion due to syncytial viral infection can be assessed by the methods essentially provided by Tidwell et al., J. Med. Chem., 26: 294-298 (1983).
Kompozicijos ir skyrimas:Compositions and assignments:
Pagal šį išradimą pacientams, kenčiantiems nuo imunomedijuojamų uždegiminių sutrikimų, yra skiriamas terapiškai arba farmaciškai efektyvus šio išradimo junginių kiekis. Pagal vieną iš išradimo įgyvendinimų, šio išradimo kompozicijos yra naudingos apsaugoti arba palengvinti astmą. Panaudojant šio išradimo kompozicijas astmos gydyme, junginiai gali būti skiriami profilaktiškai prieš paveikiant alergenu arba kitu pagreitinančiu faktoriumi, arba jau po tokio poveikio. Šio išradimo junginiai yra ypatingai veiksmingi pagerinant audinių destrukcijos vėlyvąją fazę, stebimą tiek sezoninio, tiek ir nuolatinio rinito atvejais. Kitas šio išradimo aspektas yra nukreiptas į kitų imunomedijuojamų uždegiminių sutrikimų, susijusių su kamieninėmis ląstelėmis, tokių kaip urtikarija (dilgėlinė) ir angioedema, ir egzeminis dermatitas (atopinis dermatitas) ir anafilaksija, o taip pat labai išvešėjusi odos liga, skrandžio opa ir panašios, profilaktiką ir gydymą. Dar kitame įgyvendinime šio išradimo junginiai yra naudojami gydyti sincitines virusines infekcijas, ypatingai kvėpavimo sincitinių virusų infekcijas.According to the present invention, a therapeutically or pharmaceutically effective amount of the compounds of the present invention is administered to patients suffering from immune-mediated inflammatory disorders. In one embodiment of the invention, the compositions of the present invention are useful for the protection or alleviation of asthma. When used in the treatment of asthma, the compounds of the present invention may be administered prophylactically before or after exposure to an allergen or other accelerating factor. The compounds of the present invention are particularly effective in improving the late phase of tissue destruction observed in both seasonal and persistent rhinitis. Another aspect of the present invention is directed to the prophylaxis of other immune-mediated inflammatory disorders associated with stem cells such as urticaria (urticaria) and angioedema, and eczema dermatitis (atopic dermatitis) and anaphylaxis, as well as highly advanced skin disease, gastric ulcer and the like. and treatment. In yet another embodiment, the compounds of the present invention are used to treat syncytial viral infections, in particular respiratory syncytial viral infections.
Kompozicijos, turinčios šių junginių, gali būti skiriamos terapiniam ir/arba profilaktiniam gydymui. Terapiniame panaudojime kompozicijos skiriamos nuo ligos jau kenčiantiems pacientams, kaip aprašyta aukščiau tokiais kiekiais, kurie gali išgydyti arba bent jau dalinai pagerinti ligos simptomus arba jos komplikacijas. Tam atitinkantis kiekis yra nurodytas kaip “terapiškai efektyvus kiekis arba dozė”. Kiekiai, efektyvūs tokiam panaudojimui priklausys nuo ligos sunkumo ir jos eigos, ankstesnio gydymo, paciento sveikatos būsenos ir reakcijos j vaistus, bei gydančio gydytojo kompetencijos.Compositions containing these compounds may be administered for therapeutic and / or prophylactic treatment. In therapeutic use, the compositions are administered to patients already suffering from the disease, as described above, in amounts that can cure or at least partially ameliorate the symptoms or complications of the disease. The corresponding amount is referred to as a "therapeutically effective amount or dose." The amounts effective for such use will depend upon the severity and course of the disease, the prior treatment, the patient's state of health and response to the medications, and the competence of the attending physician.
Profilaktiniame pritaikyme kompozicijos, turinčios šio išradimo junginių, yra skiriamos pacientui, pasiduodančiam arba, apskritai imant, konkrečios ligos rizikos kiekiu, galinčiu apsaugoti arba pagerinti simptomų pasireiškimą. Toks nurodytas kiekis turi būti “profilaktiškai efektyvus kiekis arba dozė”. Jis gali būti skiriamas per bumą arba inhaliacijos būdu. Tokiame panaudojime tikslus kiekis vėl gi priklauso nuo ligonio sveikatos būklės, kūno masės ir panašiai.In prophylactic applications, the compositions comprising the compounds of the invention are administered to a patient who is susceptible or, more generally, to an amount of a particular disease risk that may protect or ameliorate the onset of symptoms. Such stated amount should be the "prophylactically effective amount or dose". It can be administered by boom or by inhalation. Again, in such applications, the exact amount again depends on the patient's state of health, body weight, and the like.
Jeigu kartą pavyko pagerinti paciento būseną, tai, jeigu reikia, gali būti skiriama tik palaikomoji dozė. Atitinkamai, dozė arba skyrimo dažnis, arba abu, kaip simptomų funkcija gali būti sumažinti iki tokio lygio, prie kurio palaikoma pagerėjusi būsena. Kai simptomai pasiekia norimą lygį, tai gydymas gali būti » nutrauktas. Tačiau, per ilgą laiko tarpą pacientas protarpiais gali reikalauti gydymo, nes ligos simptomai gali recidyvuoti.Once the patient's condition has been corrected, only a maintenance dose can be administered if necessary. Accordingly, the dose or frequency of administration, or both, as a function of symptoms, may be reduced to a level at which improvement is maintained. When symptoms reach the desired level, treatment may be »interrupted. However, over a long period of time, the patient may require intermittent treatment because the symptoms of the disease may recur.
Bendrai paėmus, šio išradimo junginių tinkama efektyvi dozė recipientui yra nuo 0,05 iki 1000 miligramų (mg) per dieną ribose, geriau, kai nuo 0,1 iki 100 mg per dieną.·Geriau, kai norima dozė skiriama atitinkamais intervalais per vieną, du, tris, keturis arba daugiau kartų (subdozių) per dieną. Subdozės gali būti skiriamos kaip dozuotos vaisto formos vienetas, pavyzdžiui, turinčios nuo 0,01 iki 1000 mg, dar geriau, kai nuo 0,01 iki 100 mg aktyvaus ingrediento dozuotos vaisto formos vienete.Generally, a suitable effective dosage for the recipient of the present invention is in the range of 0.05 to 1000 milligrams (mg) per day, preferably 0.1 to 100 mg per day. two, three, four or more times (sub-dose) per day. Subdoses may be administered as a unit dosage form, for example, 0.01 to 1000 mg, more preferably 0.01 to 100 mg of active ingredient per unit dosage form.
Kompozicijos, naudojamos gydymui gali būti jvairių vaisto formų. Jos apima, pavyzdžiui, kietas, pusiau kietas ir skystas dozuotas vaisto formas, tokias kaip tabletės, padengtas enterotirpia danga tabletes, piliules, miltelius, skystus tirpalus arba suspensijas, liposomas, tirpalus, skirtus injekcijoms arba infuzijoms. Inhaliuojami preparatai, tokie kaip aerozoliai, yra taip pat vartojami. Pageidautinos vaistų formos yra tokios, kurios tinka vartoti per burną, per nosį, vietiškai arba parenteraliai, bet būtų pageidautina, kad pirmenybė būtų teikiama tokiai vaisto formai, kuri turėtų patogų terapinį panaudojimą. Ypatingai pageidautinos vaisto formos būtų tokios, kurios tiktų vartoti per nosį arba aerozolis. Būdai pagaminti vaisto formą ir farmacines kompozicijas, turinčias šio išrdimo junginių yra gerai žinomi ir aprašyti, pavyzdžiui, REMINGTON’S PHARMACEUTICAL SCIENCES ir THE MERCK INDEX, 11-tas leidimas, (Merck & Co. 1989).The compositions used for treatment may take various forms. These include, for example, solid, semi-solid and liquid dosage forms such as enteric-coated tablets, pills, powders, liquid solutions or suspensions, liposomes, solutions for injection or infusion. Inhaled preparations such as aerosols are also used. Preferred dosage forms are those suitable for oral, nasal, topical or parenteral administration, but it is desirable to have a dosage form which has a convenient therapeutic use. Particularly desirable formulations would be those suitable for nasal or aerosol administration. Methods for preparing the dosage form and pharmaceutical compositions containing the compounds of this invention are well known and described, for example, by REMINGTON'S PHARMACEUTICAL SCIENCES and THE MERCK INDEX, 11th Edition (Merck & Co. 1989).
Kadangi šio išradimo aktyvųjį ingredientą galima skirti vieną, tai pageidautina, kad jis būtų pateiktas kaip vaisto formos dalis. Šio išradimo vaisto formos sudarytos bent jau iš vieno čia aprašyto junginio, kurio paimama terapiškai arba farmaciškai efektyvi dozė, kartu su farmakologiškai priimtinu nešikliu. Farmacinės kompozicijos taip pat turės šio išradimo junginių tokiomis koncentracijomis, kurios iš esmės atitiktų atitinkamą dozę. Pavyzdžiui, jeigu atitinkama dozė sudaro 0,05 mg/dienai, tai išradimo junginio farmacinėje kompozicijoje sudarytų 0,05 mg/dozei, kai per dieną suvartojama viena dozė. Inhaliacijoms arba aerozoliams skirtose kompozicijose šio išradimo junginių koncentracijos iš esmės priklausys nuo dozės kiekio. Šio išradimo junginių inhaliacijoms arba aerozoliams skirtų kompozicijų įprastos koncentracijos būtų nuo maždaug 0,01 iki maždaug 30 mg/ml. Vaisto formos gali turėti kitų kliniškai naudingų junginių, tokių kaip β-adrenoblokatorių (pvz., albuterolio, terbutalino, formoterolio, fenoterolio ir prenalino) ir kortikosteroidų (pvz., beklometazomo, triamsinolono, flunizolido ir deksametazono).Since the active ingredient of the present invention can be administered alone, it is desirable that it be presented as part of a dosage form. The dosage forms of the present invention comprise at least one compound described herein in a therapeutically or pharmaceutically effective dosage form, together with a pharmacologically acceptable carrier. The pharmaceutical compositions will also contain compounds of the present invention at concentrations substantially equivalent to the appropriate dosage. For example, if the corresponding dose is 0.05 mg / day, the pharmaceutical composition of the invention would be 0.05 mg / dose when taken at a single daily dose. In formulations for inhalation or aerosol formulation, the concentrations of the compounds of this invention will be substantially dose dependent. Typical concentrations of the compounds of the present invention for inhalation or aerosol formulation will range from about 0.01 to about 30 mg / ml. The formulations may contain other clinically useful compounds such as β-adrenergic blocking agents (e.g., albuterol, terbutaline, formoterol, phenoterol and prenaline) and corticosteroids (e.g., beclomethasome, triamcinolone, flunisolide and dexamethasone).
Chemija:Chemistry:
Bendrai, šio išradimo junginiai yra susintetinti naudojant standartines metodikas ir reagentus, žinomus tiems, kurie yra patyrę šioje srityje. Pažymima, kad jungtys tarp įvairių funkcinių grupių dažniausiai apima anglies jungtį į amido arba karbamido grupių azotą, karbamato grupės deguonį arba karbonilo grupės anglies atomą. Tie, kurie patyrę šioje srityje atpažins, kad būdai ir reagentai sudaryti šias jungtis yra gerai žinomi ir legvai prieinami. Žiūr., pvz.. March, ADVANCED ORGANIC CHEMISTRY, 4-tas leid., (Wiley. 1992), Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH 1989); ir Furniss etai., VOGEL’S ΤΕΧΤΒΟΟΚ OF PRACTICAL ORGANIC CHEMISTRY, 5-tas leid., (Longman 1989), iš kurių kiekvienas čia Įtrauktas į nuorodas.In general, the compounds of the present invention are synthesized using standard techniques and reagents known to those skilled in the art. It is noted that the bonds between the various functional groups usually include a carbon bond to the nitrogen of the amide or urea groups, the oxygen of the carbamate group or the carbon atom of the carbonyl group. Those skilled in the art will recognize that the methods and reagents for making these linkages are well known and readily available. See, e.g., March, ADVANCED ORGANIC CHEMISTRY, 4th ed. (Wiley. 1992), Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH 1989); and Furniss et al., VOGEL'S OF PRACTICAL ORGANIC CHEMISTRY, 5th Edition (Longman 1989), each of which is incorporated herein by reference.
I formulės junginiai, kurioje X4 ir X5 yra oksazol-2-ilo, 1/7-imidazol-2-ilo arba tiazol-2-ilo gretutiniai nariai, gali būti susintetinti pagal būdą, pateiktą šioje reakcijos schemoje:Compounds of formula I wherein X 4 and X 5 are adjacent members of oxazol-2-yl, 1/7-imidazol-2-yl or thiazol-2-yl may be synthesized according to the following reaction scheme:
schemascheme
kurioje L yra pasišalinanti grupė, D kartu su vinileno liekana, su kuria ji yra kondensuota, apima monociklinį arba kondensuotą biciklinį dvivalentį radikalą, turintį nuo 5 iki 15 žiedinių atomų, kai kiekvienas žiedas turi nuo 5 iki 7 žiedinių atomų, o kiekvienas žiedinis atomas pasirinktinai yra heteroatomas, R29 yra -OH, NHR6, arba -SH, X8 yra -0-, -NR6- arba -S- ir n2, n3, n4, A, B, X1, X2, X3, X5, R1, R2, R3, R4 ir R5 yra tokie, kaip nurodyti skyriuje Išradimo esmė”.wherein L is a leaving group, D together with the vinylene residue to which it is fused include a monocyclic or fused bicyclic divalent radical having from 5 to 15 ring atoms, each ring having from 5 to 7 ring atoms and each ring atom being optionally is a heteroatom, R 29 is -OH, NHR 6 , or -SH, X 8 is -O-, -NR 6 - or -S-, and n 2, n 3, n 4, A, B, X 1 , X 2 , X 3 , X 5 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the Summary of the Invention.
I formulės junginiai, kurioje X4 ir X5 yra oksazol-2-ilo, 1W-imidazol-2-ilo arba tiazol-2-ilo gretutiniai nariai (l(a) formulė), gali būti susintetinti reaguojant I formulės junginiui arba jo blokuotam dariniui su 2 formulės junginiu arba jo blokuotu dariniu ir po to, jeigu reikia, deblokuojama. Reakcija tarp I ir ll formulių junginių gali vykti lengvai, tačiau geriau vyksta dalyvaujant 1,3-dimetil-3,4,5tetrahidro-2(1W)-pirimidinonui (DMPU) arba polifosforo rūgščiai 160-200 °C, dar geriau 180-190 °C temperatūroje, ir reikia nuo 1 iki 5 valandų, kad reakcija pasibaigtų (pvz., žiūr. žemiau 4(d), 6(h), 8(k), 9(d) ir 10 (d) pavyzdžius). Deblokavimas gali būti vykdomas bet kuriomis priemonėmis kurios nuima blokuojančią grupę ir su priimtina išeiga duoda norimą produktą (pvz., žiūr. žemiau 2(g) pavyzdį).Compounds of formula I wherein X 4 and X 5 are adjacent members of oxazol-2-yl, 1 W -imidazol-2-yl or thiazol-2-yl (Formula I (a)) may be synthesized by reacting a compound of formula I or a block thereof. with a compound of formula 2 or a blocked derivative thereof followed by deprotection if necessary. The reaction between the compounds of formulas I and II can be carried out readily, but is preferably carried out in the presence of 1,3-dimethyl-3,4,5-tetrahydro-2 (1W) -pyrimidinone (DMPU) or polyphosphoric acid, 160-200 ° C, more preferably 180-190 ° C. ° C, and it takes 1 to 5 hours for the reaction to complete (e.g., see Examples 4 (d), 6 (h), 8 (k), 9 (d) and 10 (d) below). The deprotection may be accomplished by any means which removes the protecting group and yields the desired product with acceptable yield (e.g., see Example 2 (g) below).
Panašiu būdu junginiai, turintys I formulę, kurioje X1 ir X2 yra oksazol-2-ilo,Similarly, compounds of formula I wherein X 1 and X 2 are oxazol-2-yl,
1H-imidazol-2-ilo arba tiazol-2-ilo gretutiniai nariai, gali būti susintetinti pagal būdą, pateiktą šioje reakcijos schemoje:The 1H-imidazol-2-yl or thiazol-2-yl contiguous members may be synthesized according to the procedure outlined in the following reaction scheme:
schemascheme
I(b) kurioje L yra pasišalinanti grupė, R30 yra -OH, -NHR5 arba -SH, XS8 yra -0-, -NR6- arba -S- ir n2, n3, n4, B, C, X1, X3, X5, R1, R2, R3, R4 ir R6 yra tokie, kaip nurodyti skyriuje Išradimo esmė” (pvz., žiūr. žemiau 2(e) ir 7(h) pavyzdžius).I (b) wherein L is a leaving group, R 30 is -OH, -NHR 5 or -SH, XS 8 is -O-, -NR 6 - or -S- and n 2, n 3, n 4, B, C, X 1 , X 3 , X 5 , R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the Summary of the Invention (e.g., see Examples 2 (e) and 7 (h) below).
Čia aprašytų junginių ir tarpinių junginių išskyrimas ir gryninimas gali būti įgyvendintas, jeigu pageidaujama, bet kuriuo iš tinkančių atskyrimo arba gryninimo būdų, tokių kaip, pavyzdžiui, filtavimas, ekstrahavimas, kristalizavimas, kolonėlių chromatografija, plonasluoksnė chromatografija, storasluoksnė chromatografija, didelio slėgio skysčių chromatografija (HPLC) arba derinant minėtus būdus. Tinkamų atskyrimo ir išskyrimo būdų specialia iliustracija gali būti nuorodos j čia žemiau pateiktus pavyzdžius. Tačiau, žinoma, gali būti naudojami ir kiti atitinkami atskyrimo ir išskyrimo būdai. Branduolių magnetinio rezonanso (BMR) spektrai buvo užrašyti General Electric “QE Plūs spektrometru (300 MHz).Isolation and purification of the compounds and intermediates described herein can be carried out, if desired, by any suitable separation or purification techniques such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography ( HPLC) or a combination of the two. Specific illustrations of suitable separation and isolation techniques may be provided by reference to the examples below. However, other appropriate methods of separation and isolation may of course be used. Nuclear Magnetic Resonance (NMR) spectra were recorded on a General Electric QE Plus spectrometer (300 MHz).
Infraraudonieji (IR) spektrai buvo užrašyti Perkin-Elmer 1600 Fourier Transform IR (FTIR) spektrometru. Analitinė HPLC buvo atliekama ultragreituoju baltymų mikroanalizatoriumi, Michrom BioResources, Ine. su įrengta PLRP kolonėle, 1 mm χ 15 mm. Preparatyvinė HPLC buvo atliekama Gilson LC, naudojant VYDAC 1 χ 25 cm C™ atvirkštinės fazės (RP) kolonėlę arba VVaters Prep LC2000 sistemą, naudojant VYDAC 5 χ 25 cm C^ RP kolonėlę. Masių spektrai (MS) buvo gauti Finnigan SSQ 710, turinčiu ESI šaltinį tiesiogine infuzija arba HPLC MS (ultragreitasis baltymų mikroanalizatorius, Cie 2 mmx 150 mm kolonėlė). Jeigu kitaip nenurodyta, tai visi reagentai ir įranga buvo pagaminti arba pagal publikuotas metodikas, arba įsigyjami prekyboje iš tokių firmų kaip Aldrich Chemical Co. (Milvvaukee, Wl), Sigma Chemical Co. (St. Louis MO) ir INC Chemical Co. (Irvine, CA). Metodikos, naudojamos įvykdyti sintezes, aprašytos žemiau, bus pripažintos patyrusių šioje srityje specialistų kaip įprastinės (žiūr., pvz., aukščiau nurodytus March, Larock arba Furniss).Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 Fourier Transform IR (FTIR) spectrometer. Analytical HPLC was performed on an ultrafast protein microanalyzer, Michrom BioResources, Ine. with PLRP column fitted, 1 mm χ 15 mm. Preparative HPLC was performed on a Gilson LC using a VYDAC 1 χ 25 cm C ™ Reverse Phase (RP) column or a Vaters Prep LC2000 system using a VYDAC 5 χ 25 cm C ^ RP column. Mass spectra (MS) were obtained on a Finnigan SSQ 710 equipped with an ESI source by direct infusion or by HPLC MS (Ultra-High Speed Microanalyzer, Cie 2mm x 150mm column). Unless otherwise stated, all reagents and equipment were either manufactured according to published procedures or commercially available from Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (St. Louis MO) and INC Chemical Co. (Irvine, CA). Methods used to carry out the syntheses described below will be recognized by those of ordinary skill in the art (see, for example, March, Larock, or Furniss, supra).
I formulės jungių papildomi gavimo būdai:Additional methods for preparing the compounds of formula I:
I formulės junginiai gali būti gauti kaip farmaciškai priimtinos rūgščių prijungimo druskos, reaguojant I formulės junginiui laisvos bazės formoje su farmaciškai priimtina nerganine arba organine rūgštimi. Atitinkamai, farmaciškai priimtinos I formulės junginių bazių prijungimo druskos gali būti gaunamos reaguojant I formulės junginiams su farmaciškai priimtinomis nerganinėmis arba organinėmis bazėmis. Neorganinės ir organinės rūgštys bei bazės, tinkančios gauti I formulės junginių farmaciškai priimtinas druskas yra pateiktos paraiškos nuorodų dalyje. Atitinkamai, I formulės junginių druskų formos gali būti gautos naudojant pradinių medžiagų arba tarpinių junginių druskas.Compounds of formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting a compound of formula I in free base form with a pharmaceutically acceptable inorganic or organic acid. Accordingly, the pharmaceutically acceptable addition salts of the bases of the compounds of the formula I can be obtained by reacting the compounds of the formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compounds of formula I are provided in the references section of the application. Accordingly, the salt forms of the compounds of formula I may be prepared using the salts of the starting materials or intermediates.
I formulės junginių laisvos rūgštys arba laisvos bazės gali būti gautos iš atitinkamų bazių prijungimo druskų arba rūgščių druskų prijungimo formų. Pavyzdžiui, I formulės junginiai rūgščių prijungimo formoje gali būti paversti į atitinkamas laisvas bazes paveikiant atitinkama baze (pvz., amonio hidroksido tirpalu, natrio hidroksidu ir kt.). I formulės junginiai bazių prijungimo formoje gali būti paversti į atitinkamas laisvas rūgštis paveikiant atitinkama rūgštimi (pvz., vandenilio choridu ir kt.).The free acids or free bases of the compounds of the formula I may be obtained from the corresponding base addition salts or acid addition salts thereof. For example, the compounds of formula I in the acid addition form may be converted into the corresponding free bases by treatment with an appropriate base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The compounds of formula I in the form of the base addition may be converted to the corresponding free acids by treatment with the appropriate acid (e.g., hydrogen chloride, etc.).
I formulės junginių /V-oksidai gali būti gauti metodais, kurie žinomi tiems, kurie turi patirties šioje srityje. Pavyzdžiui, /V-oksidai gali būti gauti paveikiant I formulės junginio neoksiduotą formą oksiduojančiu agentu (pvz., trifluorperoksiacto rūgštimi, peroksipieno rūgštimi, benzenperoksikarboksirūgštimi, peroksiacto rūgštimi, metachlorperoksibenzenkarboksirūgštimi ir kt.) tinkamame inertiniame organiniame tirpiklyje (pvz., halogeniniame angliavandenilyje, tokiame kaip metileno chloridas) apie 0 °C temperatūroje. Taip pat I formulės junginių /V-oksidai gali būti gauti iš atitinkamų pradinių medžiagų /V-oksidų.The A / V-oxides of the compounds of the formula I may be obtained by methods known to those skilled in the art. For example, N-oxides can be obtained by treating the unoxidized form of a compound of formula I with an oxidizing agent (e.g., trifluoro-peroxyacetic acid, peroxy-lactic acid, benzenperoxycarboxylic acid, peroxyacetic acid, methachlorperoxybenzoic acid, etc.) in a suitable inert organic solvent such as methylene chloride) at about 0 ° C. Also, the V-oxides of the compounds of formula I may be obtained from the corresponding starting materials / V-oxides.
I formulės junginiai neoksiduotoje formoje gali būti gauti iš I formulės junginių /V-oksidų paveikiant redukuojančiu agentu (pvz.. siera, sieros dioksidu, trifenilfosfinu, ličio borhidridu, natrio borhidridu, fosforo trichloridu, tribromidu ir kt.) tinkamame inertiniame organiniame tirpiklyje (pvz., acetonitrile, etanolyje, vandeniniame dioksane ir kt.) nuo 0 iki 80 °C temperatūroje.The compounds of formula I in unoxidized form may be prepared from the compounds of formula I / V-oxides by treatment with a reducing agent (e.g. sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in a suitable inert organic solvent (e.g. ., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 ° C.
I formulės junginių provaistų dariniai gali būti gaunami būdais, kuriuos žino eiliniai šios srities specialistai (pvz., žiūr. žemiau 12 pavyzdį). Detaliau apie provaistus ir jų gavimą žiūr. Saulnier et ai. (1994), Bioorganic and Medicinai Chemistry Letters, 4:1985).Prodrug derivatives of the compounds of the formula I may be prepared by methods known to one of ordinary skill in the art (e.g., see Example 12 below). For more details on prodrugs and how to obtain them, see: Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, 4: 1985).
I formulės junginių blokuotieji dariniai gali būti pagaminti būdais, kuriuos žino eiliniai šios srities specialistai. Detalus metodikų, tinkančių blokavimo grupių sukūrimui ir jų deblokavimui aprašymas gali būti rastas T, W. Greene, Protective Groups in Organic Syntesis, John Wiley & Sons, Ine. 1981.Blocked derivatives of the compounds of Formula I may be prepared by methods known to one of ordinary skill in the art. A detailed description of procedures for the creation and deprotection of blocking groups can be found in T, W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Ine. 1981.
I formulės junginiai gali būti susintetinti kaip jų individualūs stereoizomerai reaguojant junginio raceminiam mišiniui su optiškai aktyviu skaidančiu agentu, kad sudarytų diastereomerinių junginių porą, diastereomerus atskiriant ir išgaunant optiškai gryną enantiomerą. Kadangi enantiomerų atskyrimas gali būti įvykdytas naudojant I formulės junginių kovalentinius diastereomerinius darinius, tai pirmenybė teikiama disociuojantiems kompeksams (pvz., kristalinėms diastereoizomerinėms druskoms). Diastereomerai turi skirtingas fizikines savybes (pvz., lydymosi temperatūras, virimo temperatūras, tirpumus, reaktyvumus ir kt.) ir dėl tokių skirtumų gali būti lengvai atskiriami. Diastereomerai gali būti atskirti chromatografiškai, arba dar geriau, atskyrimo/perskyrimo technika, paremta tirpumo skirtumais. Optiškai grynas enantiomeras yra išgaunarnas per skaidantį agentą bet kuriomis praktinėmis priemonėmis, kurios nesukeltų racemizacijos. Detaliau metodikų, aprašančių ir tinkančių atskirti junginių stereoizomerus nuo raceminių mišinių, gali būti randama knygoje Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Ine. (1981).Compounds of formula I may be synthesized as individual stereoisomers thereof by reacting a racemic mixture of the compound with an optically active cleavage agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. Since the separation of enantiomers can be accomplished using covalent diastereomeric derivatives of the compounds of formula I, preference is given to dissociating complexes (e.g., crystalline diastereoisomeric salts). Diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated due to such differences. The diastereomers may be separated by chromatography or, better still, by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is recovered via the cleavage agent by any practical means that does not result in racemization. Further methods for describing and suitable stereoisomers of compounds from racemic mixtures can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Ine. (1981).
Apibendrinant, šio išradimo aspektu yra I formulės junginių gavimo būdas, kuris apima:In a general aspect, the present invention provides a process for the preparation of compounds of formula I which comprises:
(a) 1 formulės junginio arba jo blokuoto darinio(a) a compound of formula 1 or a blocked derivative thereof
reagavimą su 2 formulės junginiu arba jo blokuotu dariniu:with a compound of formula 2 or a blocked derivative thereof:
kurioje L yra pasišalinanti grupė, D kartu su vinileno liekana, prie kurios ji yra kondensuota, apima monociklinius arba kondensuotus biciklinius dvivalenčius radikalus, turinčius nuo 5 iki 15 žiedinių atomų, kuriuose kiekvienas žiedas turi nuo 5 iki 7 žiedinių atomų, o kiekvienas žiedinis atomas pasirinktinai yra heteroatomas, R29 yra -OH, -NHR6. arba -SH ir n1, n2, n3, A, B, X1, X2, X3, R1, R2, R3, R4 ir R6 yra tokie, kaip nurodyti skyriuje Išradimo esmė” ir po to, jeigu reikia, deblokavimą, gaunant I formulės junginj, kurioje X4 ir X5 yra yra oksazol-2-ilo, 1/7imidazol-2-ilo arba tiazol-2-ilo žiedų gretutiniai nariai; arba (b) 3 formulės junginio arba jo blokuoto darinio:wherein L is a leaving group, D together with the vinylene residue to which it is condensed include monocyclic or fused bicyclic divalent radicals having from 5 to 15 ring atoms, each ring having from 5 to 7 ring atoms and each ring atom being optionally is a heteroatom, R 29 is -OH, -NHR 6 . or -SH and n 1, n 2, n 3, A, B, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the Summary of the Invention, and thereafter, if necessary, deprotection to provide a compound of formula I wherein X 4 and X 5 are adjacent rings of oxazol-2-yl, 1/7-imidazol-2-yl or thiazol-2-yl; or (b) a compound of formula 3 or a blocked derivative thereof:
reagavimą su 4 formulės junginiu arba jo blokuotu dariniu:with a compound of formula 4 or a blocked derivative thereof:
kurioje L yra pasišalinanti grupė, R30 yra -OH, -NHR5 arba -SH, ir n1, n2, n3, B, C, X3, X4, X5, R1, R2, R3, R4 ir R5 yra tokie, kaip nurodyti skyriuje Išradimo esmė” ir po to, jeigu reikia, deblokavimą, gaunant I formulės junginį, kurioje X1 ir X2 yra yra oksazol-2-ilo, 1 H-imidazol-2-ilo arba tiazol-2-ilo žiedų gretutiniai nariai;wherein L is a leaving group, R 30 is -OH, -NHR 5 or -SH, and n 1, n 2, n 3, B, C, X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the 'Substance of the Invention' section followed by deprotection if necessary to give a compound of Formula I wherein X 1 and X 2 are oxazol-2-yl, 1H-imidazol-2-yl or thiazole. Related members of the -2-yl rings;
(c) pasirinktinai tolimesnį I formulės junginio pavertimą į farmaciškai priimtiną druską;(c) optionally further converting a compound of Formula I into a pharmaceutically acceptable salt;
(d) pasirinktinai tolimesnį I formulės junginio druskos formos pavertimą į nedruskos formą;(d) optionally further converting the salt form of the compound of formula I into a non-salt form;
(e) pasirinktinai tolimesnį I formulės junginio neoksiduotos formos pavertimą į farmaciškai priimtiną /V-oksidą;(e) optionally further converting the non-oxidized form of the compound of formula I into a pharmaceutically acceptable N-oxide;
(f) pasirinktinai tolimesnį I formulės junginio N-oksido formos pavertimą į neoksiduotą formą;(f) optionally further converting the N-oxide form of the compound of Formula I into an unoxidized form;
(g) pasirinktinai tolimesnį I formulės junginio nederivatizuotos formos pavertimą j farmacinį provaisto darinį; ir (h) pasirinktinai tolimesnį I formulės junginio provaisto darinio pavertimą į jo nederivatizuotą formą.(g) optionally further converting the non-derivatized form of the compound of formula I into a pharmaceutical prodrug derivative; and (h) optionally further converting the prodrug derivative of the compound of formula I to its non-derivatized form.
Pavyzdžiai:Examples:
Sekantys pavyzdžiai yra pteikiami daugiau iliustraciniais tikslais ir jokiu būdu nėra sudaryti kaip limituojantys išradimo apimtį. Tie, kurie patyrę šioje srityje supras, kad kai kurios variacijos ir modifikacijos gali būti atliktos šio išradimo apimtyje.The following examples are provided for purposes of illustration only and are in no way intended to limit the scope of the invention. Those skilled in the art will appreciate that some variations and modifications may be made within the scope of the present invention.
PAVYZDYS 2-Naft-2-iletilaminasEXAMPLE 2-Naft-2-ylethylamine
Tirpalas, kurį sudaro 2-naft-2-iletanolis (0,5 g, 2,9 mmol) sausame DMF-de (5 ml) azoto atmosferoje sujungtas su difenilfosforilazidu (0,74 ml, 3,42 mmol) ir 1,8-diazabiciklo[5.4.0]undec-7-enu (0,47 ml, 3,14 mmol). Mišinys šildytas 65 °C temperatūroje 3 valandas ir po to padalintas tarp vandens ir dietileterio. Vandeninis sluoksnis atskirtas ir išekstrahuotas dietileteriu. Sujungti organiniai sluoksniai perplauti 3 N vandenilio chloridu, po to sočiu natrio bikarbonatu, džiovinti (MgSO4), perfiltruoti ir sukoncentruoti rotoriniu garintuvu. Nuosėdos ištirpintos THF-ne (5 ml), o gautas tirpalas sujungtas su trifenilfosfinu (1 g, 3,81 mmol), maišomas 2 valandas kambario temperatūroje, praskiestas vandeniu (100 ml), maišytas 3 valandas, praskiestas koncentruotu vandenilio chloridu (0,33 ml), duoda nuosėdas, kurios, apdorotos etanoliu (5 ml), ištirpina nuosėdas, po to lėtai pridėta dietileterio, gaunant baltas nuosėdas. Šios baltos nuosėdos nulitruotos, perplautos dietileteriu ir išdžiovintos vakuume, duoda 2-naft-2-iletilamino hidrochloridą (0,447 g, 75 % išeiga);A solution of 2-naphth-2-ylethanol (0.5 g, 2.9 mmol) in dry DMF (5 mL) under nitrogen was combined with diphenylphosphoryl azide (0.74 mL, 3.42 mmol) and 1.8 mL. -Diazabicyclo [5.4.0] undec-7-enu (0.47 mL, 3.14 mmol). The mixture was heated at 65 ° C for 3 hours and then partitioned between water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were washed with 3N hydrochloric acid, then saturated sodium bicarbonate, dried (MgSO 4 ), filtered and concentrated by rotary evaporation. The precipitate was dissolved in THF (5 mL) and the resulting solution was combined with triphenylphosphine (1 g, 3.81 mmol), stirred at room temperature for 2 hours, diluted with water (100 mL), stirred for 3 hours, diluted with concentrated hydrochloric acid (0 33 ml) gives a precipitate which, after treatment with ethanol (5 ml), dissolves the precipitate, followed by slow addition of diethyl ether to give a white precipitate. This white precipitate was titrated, washed with diethyl ether and dried in vacuo to give 2-naphth-2-ylethylamine hydrochloride (0.447 g, 75% yield);
1H-BMR (300 MHz, DMSO-ds): 8,18 (pi. s, 3H), 7,82-7,88 (m, 3H), 7,74 (s, 1H), 7,38-7,48 (m, 3H), 3,07 (m, 4H). 1 H-NMR (300 MHz, DMSO-d 6): 8.18 (bs, 3H), 7.82-7.88 (m, 3H), 7.74 (s, 1H), 7.38-. 7.48 (m, 3H), 3.07 (m, 4H).
Sintetinant pagal 1 pavyzdžio metodiką, gauti tokie tarpiniai aminai:The following intermediate amines were synthesized according to the procedure of Example 1:
2- naft-1-iletilaminas, išeiga=56 %; ’H-BMR (300 MHz, DMSO-d6): 8,26 (pi. s, 3H), 8,16 (d, 1H, J= 8,1 Hz), 7,92 (dd, 1H, J=1,5, 7,8 Hz), 7,81 (dd, 1H, J=1,2, 7,5 Hz), 7,40-7,56 (m, 4H), 3,37 (m, 2H), 3,05 (t, 2H, 3=7,4 Hz);2-naphth-1-ylethylamine, yield = 56%; 1 H-NMR (300 MHz, DMSO-d 6 ): 8.26 (ppm s, 3H), 8.16 (d, 1H, J = 8.1 Hz), 7.92 (dd, 1H, J = 1.5, 7.8 Hz), 7.81 (dd, 1H, J = 1.2, 7.5 Hz), 7.40-7.56 (m, 4H), 3.37 (m, 2H), 3.05 (t, 2H, 3 = 7.4 Hz);
3- cikloheksilpropilaminas, išeiga=40 %; 1H-BMR (300 MHz, CDCb): 2,68 (t, 2H, J=7,2 Hz), 2,17 (pi, s, 2H), 1,64-1,71 (m, 5H), 1,46 (m, 2H), 1,18 (m, 6H) 0,87 (m, 2H);3-cyclohexylpropylamine, yield = 40%; 1 H-NMR (300 MHz, CDCl 3): 2.68 (t, 2H, J = 7.2 Hz), 2.17 (pi, s, 2H), 1.64-1.71 (m, 5H). , 1.46 (m, 2H), 1.18 (m, 6H), 0.87 (m, 2H);
3-fenil-2-propenilaminas, išeiga=53 %; 1H-BMR (300 MHz, DMSO-d6): 8,39 (pi. s, 3H), 7,26-7,41 (m, 5H), 6,72 (d, 1H, J = 16,2 Hz), 6,29 (dt, 1H, J = 16,2, 6,6 Hz), 3,56 (d, 2H, J=6,6Hz);3-phenyl-2-propenylamine, yield = 53%; 1 H-NMR (300 MHz, DMSO-d 6 ): 8.39 (bs, 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-fenil-2-propinilaminas, išeiga=62 %; ’H-BMR (300 MHz, DMSO-d6): 8,67 (pi. s, 2H), 7,38-7,42 (m, 5H), 3,91 (m, 2H); ir3-phenyl-2-propynylamine, yield = 62%; 1 H-NMR (300 MHz, DMSO-d 6 ): 8.67 (bs, 2H), 7.38-7.42 (m, 5H), 3.91 (m, 2H); and
3,3-difenilpropilaminas, išeiga=50 %; 1H-BMR (300 MHz, DMSO-de): 8,10 (pi. s, 3H), 7,30 (m, 8H), 7,19 (m, 2H), 4,11 (t, 1H, J=7,9 Hz), 2,62 (m, 2H) 2,33 (m, 2H).3,3-diphenylpropylamine, yield = 50%; 1 H-NMR (300 MHz, DMSO-d 6): 8.10 (bs, 3H), 7.30 (m, 8H), 7.19 (m, 2H), 4.11 (t, 1H, J = 7.9 Hz), 2.62 (m, 2H), 2.33 (m, 2H).
PAVYZDYSEXAMPLE
2-(5-Aminometil-1/7-benzoimidazol-2-ilmetil)-/V-4-fenilbutil)-1/7benzoimidazol-5-karboksamido trifluoracetatas (1 junginys) (a) Etilo cianoacetatas (8 ml, 75 mmol) bevandeniame benzene (100 ml) sujungtas azoto atmosferoje su bevandeniu etanoliu (6 ml, 105 mmol). Mišinys atšaldytas iki 10 °C temperatūros (ledas/acetonas) ir į jį 20 minučių barbatuotos sauso vandenilio chlorido dujos. Mišinys lėtai sušildytas iki kambario temperatūros, hermetizuotas ir maišytas apie 18 valandų. Mišinys praskiestas dietileteriu (400 ml) ir paliktas stovėti kambario temperatūroje 5 valandas, duoda kristalines nuosėdas. Nuosėdos nufiltruotos, praplautos keletą kartų bevandeniu dietileteriu ir išdžiovintos, duoda 3-etoksi-3-iminoetilpropionatą (13,2 g, 90 % išeiga) kaip kietą bespalvę kristalinę medžiagą; 1H-BMR (300 MHz, CDCI3): 7,84 (d, 1H, J=10,0 Hz), 7,19-7,36 (m, 5H), 7,00-7,06 (m, 2H), 4,10 (t, 2H, J=5,7 Hz), 2,73 (t, 2H, J=6,5 Hz), 1,89 (m, 4H).2- (5-Aminomethyl-1,7-benzoimidazol-2-ylmethyl) -N-4-phenylbutyl) -1,7-benzoimidazole-5-carboxamide trifluoroacetate (Compound 1) (a) Ethyl cyanoacetate (8 mL, 75 mmol) anhydrous benzene (100 mL) was combined with anhydrous ethanol (6 mL, 105 mmol) under nitrogen. The mixture was cooled to 10 ° C (ice / acetone) and bubbled with dry hydrogen chloride gas for 20 minutes. The mixture was slowly warmed to room temperature, sealed and stirred for about 18 hours. The mixture was diluted with diethyl ether (400 mL) and left to stand at room temperature for 5 hours to give a crystalline precipitate. The precipitate was filtered off, washed several times with anhydrous diethyl ether and dried to give 3-ethoxy-3-iminoethylpropionate (13.2 g, 90% yield) as a solid colorless crystalline solid; 1 H-NMR (300 MHz, CDCl 3 ): 7.84 (d, 1H, J = 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m , 2H), 4.10 (t, 2H, J = 5.7 Hz), 2.73 (t, 2H, J = 6.5 Hz), 1.89 (m, 4H).
(b) Mišinys, sudarytas iš 3.4-diaminobenzenkarboksirūgšties (9,4 g, 62 mmol), 3-etoksi-3-iminoetilpropionato ir ledinės acto rūgšties (15 ml) maišytas azoto atmosferoje 30 minučių 110 °C temperatūroje. Mišinys išpiltas ant susmulkinto ledo (50 ml) ir maišytas dar 30 minučių, duoda tamsiai geltonos spalvos alyvą. Mišinys maišytas, kol pridedama dietileterio (25 ml), gaunant pilkas nuosėdas. Nuosėdos nufiltruotos, keletą kartų perplautos dietileteriu ir išdžiovintos vakuume, duoda 2-etoksikarbonilmetil-1/7-benzoimidazol-5karboksirūgštį (12,6 g, 83 % išeiga); 1H-BMR (300 MHz, DMSO-d6): 12,77 (pi. s, 1H), 8,10 (s, 1H), 7,79 (d, 1H, J=8,4 Hz), 7,57 (d, 1H, J=8,4 Hz), 4,11 (kv., 2H, J=7,1 Hz), 4,02 (s, 2H), 1,17 (t, 3H, J=7,1 Hz).(b) A mixture of 3,4-diaminobenzoic acid (9.4 g, 62 mmol), 3-ethoxy-3-iminoethylpropionate and glacial acetic acid (15 mL) was stirred under nitrogen at 110 ° C for 30 min. The mixture was poured onto crushed ice (50 mL) and stirred for another 30 minutes to give a dark yellow oil. The mixture was stirred until diethyl ether (25 mL) was added to give a gray precipitate. The precipitate was filtered off, washed several times with diethyl ether and dried in vacuo to give 2-ethoxycarbonylmethyl-1/7-benzoimidazole-5-carboxylic acid (12.6 g, 83% yield); 1 H-NMR (300 MHz, DMSO-d 6 ): 12.77 (pi s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J = 8.4 Hz), 7.57 (d, 1H, J = 8.4 Hz), 4.11 (quart, 2H, J = 7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J = 7.1 Hz).
(c) Mišinys, sudarytas iš dinitrofenilmetanolio (22 g, 111 mmol), trifenilfosfino (34,5 g, 131 mmol) ir ftalimido (17,6 g, 119 mmol) THF-ne (450 ml), maišytas azoto atmosferoje -10 °C temperatūroje (ledas/acetonas), kol sulašintas azodikarboksilatas (20,7 ml, 131 mmol). Mišinys maišytas 2 valandas -10 °C temperatūroje, o po to praskiestas dietileteriu (900 ml) ir laikytas -20 °C temperatūroje apie 18 valandų, duoda kristalinę kietą medžiagą. Medžiaga nufiltruota ir perplauta, gaunant 2-(3,4-dinitrobenzil)-izoindol-1,3-dioną (24,6 g, 67 % išeiga) kaip balkšvą kristalinę medžiagą; 1H-BMR (300 MHz, DMSO-d6): 7,877,94 (m, 5H), 7,74-7,82 (m, 2H), 4,96 (s, 2H).(c) A mixture of dinitrophenylmethanol (22 g, 111 mmol), triphenylphosphine (34.5 g, 131 mmol) and phthalimide (17.6 g, 119 mmol) in THF (450 mL) stirred under a nitrogen atmosphere of -10 ° C (ice / acetone) until azodicarboxylate (20.7 mL, 131 mmol) was added dropwise. The mixture was stirred for 2 hours at -10 ° C and then diluted with diethyl ether (900 mL) and kept at -20 ° C for about 18 hours to give a crystalline solid. The material was filtered off and washed to give 2- (3,4-dinitrobenzyl) -isoindole-1,3-dione (24.6 g, 67% yield) as an off-white crystalline solid; 1 H-NMR (300 MHz, DMSO-d 6 ): 7.877.94 (m, 5H), 7.74-7.82 (m, 2H), 4.96 (s, 2H).
(d) 2-(3.4-dinitrobenzil)izoindol-1,3-diono (8 g, 24,4 mmol), gauto kaip 1 pavyzdyje ir 10 % paladžio ant anglies (300 mg) pastovioje azoto srovėje sujungta su bevandeniu etanoliu (200 ml), bevandeniu THF-nu (100 ml) ir ledine acto rūgštimi (30 ml). Po to mišinys, leidžiant vandenilį, smarkiai maišytas 15 valandų kambario temperatūroje, nufiltruotas ir sukoncentruotas rotoriniu garintuvu iki maždaug 30 ml tūrio. Mišinys praskiestas vandeniu (100 ml) ir pridėjus amonio hidroksido, gaunamos oranžinės spalvos nuosėdos. Nuosėdos nufiltruotos ir kelis kartus perplautos vandeniu yra 2-(3,4-diaminobenzil)izoindol-1,3-dionas (6 g, 91 % išeiga); 1H-BMR (300 MHz, DMSO-d6); 7,76-7,85 (m, 4H), 6,31-6,43 (m, 3H), 4,51 (pi. s, 4H), 4,47 (s, 2H).(d) 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (8 g, 24.4 mmol) obtained in Example 1 and 10% palladium on carbon (300 mg) was combined with anhydrous ethanol (200 g) ml), anhydrous THF-nu (100 ml) and glacial acetic acid (30 ml). The mixture was then stirred vigorously for 15 hours at room temperature under a hydrogen atmosphere, filtered and concentrated on a rotary evaporator to a volume of about 30 ml. The mixture was diluted with water (100 mL) and the addition of ammonium hydroxide gave an orange precipitate. The precipitate was filtered off and washed several times with water containing 2- (3,4-diaminobenzyl) isoindole-1,3-dione (6 g, 91% yield); 1 H-NMR (300 MHz, DMSO-d 6 ); 7.76-7.85 (m, 4H), 6.31-6.43 (m, 3H), 4.51 (pi, 4H), 4.47 (s, 2H).
(e) Smulkiai susmulkintas 2-(3,4-diaminobenzil)izoindol-1,3-diono (2,0 g, 7,5 mmol) ir 2-etoksikarbonilmetil-1Z7-benzimidazol-5-karboksirūgšties (0,93 g,(e) Fine trituration of 2- (3,4-diaminobenzyl) isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1Z7-benzimidazole-5-carboxylic acid (0.93 g,
3,75 mmol) mišinys azoto atmosferoje šildytas 1 valandą 185 °C temperatūroje. Mišinys suspenduotas j metileno chlorido/etanolio (200 ml) mišinį, santykiu 1:1 ir po to smarkiai maišytas 1 valandą. Susidariusi kieta medžiaga nufiltruota, perplauta metileno chlorido/etanolio mišinu, santykiu 1:1 (3 χ 20 ml) ir išdžiovinta, yra 2-(5-(1,3-diokso-1,3-dihidroizoindol-2-ilmetil)-1 H-benzoimidazol-2-ilmetil]-1 Hbenzoimidazol-5-karboksirūgštis (0,98 g, 29 % išeiga); 1H-BMR (300 MHz, DMSOd6): 12,45 (pi. s, 1H), 8,07 (s, 1H), 7,80-7,83 (m, 6H), 7,51 (d, 1H, J=7,5 Hz), 7,43 (s, 1 H), 7,11 (d, 1H, J=7,2 Hz), 4,82 (s, 2H), 4,48 (s, 2H).The mixture (3.75 mmol) was heated at 185 ° C for 1 h under nitrogen. The mixture was suspended in a 1: 1 mixture of methylene chloride / ethanol (200 mL) and stirred vigorously for 1 hour. The resulting solid was filtered, washed with methylene chloride / ethanol 1: 1 (3 x 20 mL) and dried to give 2- (5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H-benzoimidazol-2-ylmethyl] -1H-benzoimidazole-5-carboxylic acid (0.98 g, 29% yield); 1 H-NMR (300 MHz, DMSOd 6 ): 12.45 (pi s, 1H), δ , 07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J = 7.5 Hz), 7.43 (s, 1H), 7.11 (d, 1H, J = 7.2 Hz), 4.82 (s, 2H), 4.48 (s, 2H).
(f) 2-(5-(1,3-Diokso-1,3-dihidroizoindol-2-ilmetil)-1 /7-benzoimidazol-2ilmetil]-1/7-benzoimidazol-5-karboksirūgštis (0,05 g, 0,111 mmol) ištirpinta bevandeniame dimetilformamide (0,5 ml) ir tirpalas sujungtas sauso azoto atmosferoje kambario temperatūroje su 1-hidroksibenzotriazolo hidratu (0,017 g, 0,126 mmol), benzotriazol-1-iloksitrispirolidinofosfonio heksafluorfosfatu (0,063 g, 0,121 mmol) ir N-metilmorfolinu (0,013 ml, 0,118 mmol). Po 2 minučių pridedama(f) 2- (5- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1,7-benzoimidazol-2-ylmethyl] -1,7-benzoimidazole-5-carboxylic acid (0.05 g, 0.111 mmol) was dissolved in anhydrous dimethylformamide (0.5 mL) and the solution was combined under dry nitrogen at room temperature with 1-hydroxybenzotriazole hydrate (0.017 g, 0.126 mmol), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (0.063 g, 0.121 mmol) (0.013 mL, 0.118 mmol) After 2 min add
4-fenilbutilamino (0,02 ml, 0,127 mmol) ir mišinys maišytas kambario temperatūroje 2 valandas. Mišinys perkeltas j dalomąjį piltuvą, turintį 20 % etanolio/etilo acetato tirpalo (7 ml). 0,2 N HCI (3,5 ml) ir sotaus vandeninio NaCI (3,5 ml). Vandeninė fazė 1 kartą išekstrahuota 20 % etanolio/etilo acetato tirpalu (7 ml), o sujungti organiniai sluoksniai perplauti tirpalu, turinčiu 0,2 N HCI (3,5 ml) sočiame vandeniniame NaCI (3,5 ml) tirpale, o po to galiausiai perplauta sočiu vandeniniu bikarbonato tirpalu (7 ml). Organinė fazė išdžiovinta bevandeniu natrio sulfatu, perfiltruota ir sukoncentruota iki sausumo rotoriniu garintuvu, duoda 2-[5(1,3-diokso-1,3-d ihi d roizoi ndol-2-i I m eti I) -1 H-benzoimidazol-2-ilmetil]-/V-(3fenilpropil)-1/7-benzoimidazol-5-karboksamidą kaip nevalytą medžiagą (0,14 g).Of 4-phenylbutylamine (0.02 mL, 0.127 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a separatory funnel containing 20% ethanol / ethyl acetate solution (7 mL). 0.2 N HCl (3.5 mL) and saturated aqueous NaCl (3.5 mL). The aqueous phase was extracted once with 20% ethanol / ethyl acetate solution (7 mL), and the combined organic layers were washed with 0.2 N HCl (3.5 mL) in saturated aqueous NaCl (3.5 mL), followed by finally washed with saturated aqueous bicarbonate solution (7 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in a rotary evaporator to give 2- [5 (1,3-dioxo-1,3-dihydro-doloizol-2-ylmethyl) -1H-benzoimidazole. -2-ylmethyl] - N - (3-phenylpropyl) -1,7-benzoimidazole-5-carboxamide as a crude material (0.14 g).
(g) 2-(5-(1,3-Diokso-1,3-d ihidroizoindol-2-i I meti I) -1 /7-benzoimidazol-2ilmetil]-/V-(3-fenilpropil)-1/7-benzoimidazol-5-karboksamidas (0,14 g, nevalyta medžiaga) ištirpintas bevandeniame etanolyje (0,5 ml) ir gautas tirpalas sujungtas su bevandeniu hidrazinu (0,15 ml, 0,48 mmol). Mišinys virintas su grįžtamuoju šaldytuvu azoto atmosferoje 1 valandą, o po to sukoncentruotas rotoriniame garintuve. Liekana patalpinama į vakuumą (0,2 bar) 2 valandoms, kad pasišalintų hidrazinas. Liekana praskiesta 3 M HCI (0,5 ml) ir mišinys šildytas 50 °C temperatūroje 20 minučių. Reakcijos mišinys atšaldytas iki kambario temperatūros ir maišytas dar 20 minučių, duoda kietas nuosėdas. Nuosėdos nufiltruotos ir perplautos vandeniu (4 χ 1,5 ml). Filtratai sujungti ir perplauti 20 % etanolio/etilo acetato tirpalu (2x7 ml). Sujungtos vandeninės fazės liofilizuotos, duoda nevalytą produktą kaip hidrochlorido druską. Nevalytas produktas išgrynintas preparatyvine atvirkštinių fazių HPLC duoda 2-[5-(1,3-diokso-1,3dihidroizoindol-2-ilmetil)-1H-benzoimidazol-2-ilmetilj-A/-(3-fenilpropil)-1/7benzoimidazol-5-karboksamidą (0,04 g, 0,07 mmol) kaip baltą kietą medžiagą: 1H-BMR (300 MHz, CD3OD): 8.14 (s, 1H), 7,84-7,89 (m, 2H), 7,77 (d, 1H, J=8,1 Hz), 7,71 (d, 1H, J=8,1 Hz), 7,56 (d, 1H, J=8,1 Hz), 7,12-7,27 (m, 5H), 4,29 (s, 2H), 3,43 (t, 2H, J=7,2 Hz), 2,66 (t, 2H, J=7,2 Hz), 1,69 (m, 4H).(g) 2- (5- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1,7-benzoimidazol-2-ylmethyl] -N- (3-phenylpropyl) -1- 7-Benzoimidazole-5-carboxamide (0.14 g, crude) was dissolved in anhydrous ethanol (0.5 mL) and the resulting solution was combined with anhydrous hydrazine (0.15 mL, 0.48 mmol). The reaction mixture was concentrated in a vacuum (0.2 bar) for 2 hours to remove hydrazine, diluted with 3 M HCl (0.5 mL) and heated at 50 ° C for 20 minutes. The mixture was cooled to room temperature and stirred for a further 20 minutes to give a solid precipitate. The precipitate was filtered off and washed with water (4 χ 1.5 ml). The filtrates were combined and washed with 20% ethanol / ethyl acetate solution (2x7 ml). yields the crude product as the hydrochloride salt. The crude product is purified by preparative reverse phase HPLC gives 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -N- (3-phenylpropyl) -1,7-benzoimidazole-5-carboxamide (O). , 04 g, 0.07 mmol) as a white solid: 1 H-NMR (300 MHz, CD 3 OD): 8.14 (s, 1H), 7.84 to 7.89 (m, 2H), 7.77 (d, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 8.1 Hz), 7.56 (d, 1H, J = 8.1 Hz), 7.12-7 , 27 (m, 5H), 4.29 (s, 2H), 3.43 (t, 2H, J = 7.2 Hz), 2.66 (t, 2H, J = 7.2 Hz), 1 69 (m, 4H).
Sintetinant pagal 2 pavyzdžio metodiką, gauti tokie junginiai:Synthesis according to the procedure of Example 2 gave the following compounds:
2-(5-aminometil-1 H-benzoimidazol-2-ilmetil)-N-naft-1 -ilmetil-1 Hbenzoimidazol-5-karboksamidas (2 junginys): 1H-BMR (300 MHz, CD3OD): 8,13 (m, 2H), 7,88 (m, 2H), 7,80 (m, 2H), 7,73 (d, 1H, J=7,9 Hz), 7,67 (d, 1H, J=7,9 Hz), 7,38-7,54 (m, 5H), 5,01 (s, 2H), 4,26 (s, 2H);2- (5-aminomethyl-1 Hbenzoimidazol-2-ylmethyl) -N-naphth-1-ylmethyl-1 Hbenzoimidazol-5-carboxamide (Compound 2): 1 H-NMR (300 MHz, CD 3 OD): 8 , 13 (m, 2H), 7.88 (m, 2H), 7.80 (m, 2H), 7.73 (d, 1H, J = 7.9 Hz), 7.67 (d, 1H, J = 7.9 Hz), 7.38-7.54 (m, 5H), 5.01 (s, 2H), 4.26 (s, 2H);
2-(5-aminometil-1/7-benzoimidazol-2-ilmetil)-N-benzil-1/7-benzoimidazol5-karboksamidas (3 junginys); 1H-BMR (300 MHz, CD3OD): 8,18 (s, 1H), 7,91 (d, 1H, J=7,9 Hz), 7,82 (s, 1H), 7,76 (d, 1H, J=7,9), 7,72 (d, 1H, J=7,9 Hz), 7,54 (d, 1H, J=7,9 Hz), 7,23-7,38 (m, 5H), 4,60 (s, 2H), 4,28 (s, 2H);2- (5-Aminomethyl-1/7-benzoimidazol-2-ylmethyl) -N-benzyl-1/7-benzoimidazole-5-carboxamide (Compound 3); 1 H-NMR (300 MHz, CD 3 OD): 8.18 (s, 1H), 7.91 (d, 1H, J = 7.9 Hz), 7.82 (s, 1H), 7.76 (d, 1H, J = 7.9), 7.72 (d, 1H, J = 7.9 Hz), 7.54 (d, 1H, J = 7.9 Hz), 7.23-7, 38 (m, 5H), 4.60 (s, 2H), 4.28 (s, 2H);
2-(5-arninometil-1/-/-benzoimidazol-2-ilmetil)-/\/-(3-fenilpropil)1/7-benzoimidazol-5-karboksamidas (4 junginys): 1H-BMR (300 MHz, CD3OD): 8,14 (s, 1H), 7,87 (d, 1H, J=8,6 Hz), 7,8 (s, 1H), 7,76 (d, 1H, J=8,6 Hz), 7,71 (d, 1H, J=8,6 Hz), 7,54 (d, 1H, J=8,6 Hz), 7,24 (m, 4H), 7,16 (m, 1H), 4,28 (s, 2H), 3,46 (t, 2H, J=7,9 Hz), 2,95 (t, 2H, J=7,9 Hz), 1,62 (kvintetas, 2H, 7,9 Hz);2- (5-aminomethyl-1 H -benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1,7-benzoimidazole-5-carboxamide (Compound 4): 1 H-NMR (300 MHz, CD 3 OD): 8.14 (s, 1H), 7.87 (d, 1H, J = 8.6 Hz), 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 = 7.9 Hz), 2.95 (t, 2H, J = 7.9 Hz), 1.62 ( quintet, 2H, 7.9 Hz);
2-(5-aminometil-1/7-benzoimidazol-2-ilmetil)-N-(2-feniletil)-1Hbenzoimidazol-5-karboksamidas (5 junginys); 1H-BMR (300 MHz, DMSO-ds): 8,12 (s, 1H), 7,83 (m, 2H), 7,78 (d, 1H, J=9,3 Hz), 7,71 (d, 1H, J=9,3 Hz), 7,55 (d, 1H, J=9,3 Hz), 7,29 (m, 4H), 7,22 (m, 1H), 4,29 (s, 2H), 3,65 (t, 2H, J=7,9 Hz), 2,95 (t, 2H, J=7,9 Hz);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-phenylethyl) -1H-benzoimidazole-5-carboxamide (Compound 5); 1 H-NMR (300 MHz, DMSO-d s): 8.12 (s, 1H), 7.83 (m, 2H), 7.78 (d, 1H, J = 9.3 Hz), 7, 71 (d, 1H, J = 9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz), 7.29 (m, 4H), 7.22 (m, 1H), 4, 29 (s, 2H), 3.65 (t, 2H, J = 7.9 Hz), 2.95 (t, 2H, J = 7.9 Hz);
2-(5-aminometil-1/7-benzoimidazol-2-ilmetil)-A/-(3-aminometil)benzil1W-benzoimidazol-5-karboksamidas (6 junginys); 1H-BMR (300 MHz, DMSO-d6): 9,31 (t, 1 H, J=5,7 Hz), 8,58 (pi, s, 3H), 8,41 (pi, s, 3H), 8,28 (s, 1H), 7,97 (m, 2H), 7,79 (d, 1H, J=9,3 Hz), 7,75 (d, 1H, J=9,3 Hz), 7,59 (d, 1H, J=9,3 Hz), 7,43 (s,2- (5-aminomethyl-1/7-benzoimidazol-2-ylmethyl) -N- (3-aminomethyl) benzyl-1 H -benzoimidazole-5-carboxamide (Compound 6); 1 H-NMR (300 MHz, DMSO-d 6): 9.31 (t, 1H, J = 5.7 Hz), 8.58 (pi, s, 3H), 8.41 (pi, s, 3H) ), 8.28 (s, 1H), 7.97 (m, 2H), 7.79 (d, 1H, J = 9.3 Hz), 7.75 (d, 1H, J = 9.3 Hz) ), 7.59 (d, 1H, J = 9.3 Hz), 7.43 (s,
1H), 7,35 (s, 3H), 5,07 (s, 2H), 4,50 (m, 2H), 4,18 (m, 2H), 3,97 (m, 2H);1H), 7.35 (s, 3H), 5.07 (s, 2H), 4.50 (m, 2H), 4.18 (m, 2H), 3.97 (m, 2H);
2-(5-aminometil-1A/-benzoimidazol-2-ilmetil)-/V-(2-aminoetil)-1-metil1A/-benzoimidazol-5-karboksamidas (7 junginys); 1H-BMR (300 MHz, DMSO-d6): 8,86 (pl.s, 1H), 8,50 (pi. s, 3H), 8,24 (s, 1H), 8,08 (pi, s, 3H), 7,93 (m, 2H), 7,77 (d, 1H, J=8,7 Hz), 7,55 (d, 1H, J=9,2 Hz), 5,02 (pi. s, 2H), 4,16 (m, 2H), 3,94 (s, 2H),2- (5-aminomethyl-1 N-benzoimidazol-2-ylmethyl) -N- (2-aminoethyl) -1-methyl-1 N-benzoimidazole-5-carboxamide (Compound 7); 1 H-NMR (300 MHz, DMSO-d 6 ): 8.86 (m.s, 1H), 8.50 (ppm s, 3H), 8.24 (s, 1H), 8.08 (ppm) , s, 3H), 7.93 (m, 2H), 7.77 (d, 1H, J = 8.7 Hz), 7.55 (d, 1H, J = 9.2 Hz), 5.02 (pi s, 2H), 4.16 (m, 2H), 3.94 (s, 2H),
3,50 (m, 2H), 2,96 (m, 2H);3.50 (m, 2H), 2.96 (m, 2H);
2-(5-aminometil-1/7-benzoimidazoI-2-ilmetil)-A/-(2-aminoetil)1H-benzoimidazol-5-karboksamidas (8 junginys); 1H-BMR (300 MHz, DMSO-ds): 8,97 (t, 1H, J=4,3 Hz), 8,58 (pi. s, 3H), 8,31 (s, 1H), 8,16 (pi. s, 3H), 7,97 (m, 2H), 7,79 (d, 1H, J=10 Hz), 7,73 (d, 1H, J=10 Hz), 7,59 (d, 1H, J=10 Hz), 5,09 (s, 1H),2- (5-aminomethyl-1/7-benzoimidazol-2-ylmethyl) -N- (2-aminoethyl) -1 H -benzoimidazole-5-carboxamide (Compound 8); 1 H-NMR (300 MHz, DMSO-d 6): 8.97 (t, 1H, J = 4.3 Hz), 8.58 (pi s, 3H), 8.31 (s, 1H), δ , 16 (pi s, 3H), 7.97 (m, 2H), 7.79 (d, 1H, J = 10 Hz), 7.73 (d, 1H, J = 10 Hz), 7.59 (d, 1H, J = 10Hz), 5.09 (s, 1H),
4,19 (m, 2H), 3,54 (m, 2H), 2,99 (m, 2H);4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m, 2H);
2-(5-aminometil-1H-benzoimidazoI-2-ilmetil)-N-(4-aminobutil)1/7-benzoimidazol-5-karboksamidas (9 junginys); 1H-BMR (300 MHz, DMSO-d6): 8,77 (t, 1H, J=5,7 Hz), 8,61 (pi. s, 3H), 8,24 (s, 1H), 7,90-8,02 (m, 5H), 7,78 (d, 1 H, J=9,3 Hz), 7,74 (d, 1H, J=9,3 Hz), 7,60 (d, 1H, J=9,3 Hz), 5,09 (s, 1H), 4,18, (m,2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (4-aminobutyl) -1,7-benzoimidazole-5-carboxamide (Compound 9); 1 H-NMR (300 MHz, DMSO-d 6 ): 8.77 (t, 1H, J = 5.7 Hz), 8.61 (ppm s, 3H), 8.24 (s, 1H), 7.90-8.02 (m, 5H), 7.78 (d, 1H, J = 9.3 Hz), 7.74 (d, 1H, J = 9.3 Hz), 7.60 ( d, 1H, J = 9.3 Hz), 5.09 (s, 1H), 4.18, (m,
2H), 3,28 (m, 2H), 2,78 (m, 2H), 1,12 (m, 4H);2H), 3.28 (m, 2H), 2.78 (m, 2H), 1.12 (m, 4H);
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-/V-(3-aminopropil)1/7-benzoimidazol-5-karboksamidas (10 junginys); 1H-BMR (300 MHz, DMSO-d6):2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1,7-benzoimidazole-5-carboxamide (Compound 10); 1 H-NMR (300 MHz, DMSO-d 6 ):
8,9 (t, 1H, J=5,0 Hz), 8,53 (pi. s, 3H), 8,23 (s, 1H), 7,97 (pi. s, 3H), 7,94 (s, 1H), 7,89 (d, 1H, J=8,6 Hz), 7,78 (d, 1H, J=8,6 Hz), 7,71 (d, 1H, J=8,6), 7,57 (d, 1H,8.9 (t, 1H, J = 5.0 Hz), 8.53 (pi, 3H), 8.23 (s, 1H), 7.97 (pi, 3H), 7.94 (s, 1H), 7.89 (d, 1H, J = 8.6 Hz), 7.78 (d, 1H, J = 8.6 Hz), 7.71 (d, 1H, J = 8, 6), 7.57 (d, 1H,
J=8,6 Hz), 5,03 (s, 2H(, 4,40 (m, 2H), 3,34 (m, 2H), 2,81 (m, 2H), 1,81 (m, 2H); irJ = 8.6 Hz, 5.03 (s, 2H (, 4.40 (m, 2H), 3.34 (m, 2H), 2.81 (m, 2H), 1.81 (m, 2H) and
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-/V-cikloheksilmetil1H-benzimidazol-5-karboksarnidas (11 junginys); 1H-BMR (300 MHz, CD3OD): 8,15 (s, 1H), 7,88 (d, 1H, J=7,6 Hz), 7,84 (s, 1H), 7,76 (d, 1 H, J=7,6 Hz), 7,72 (d, 1H, J=7,6 Hz), 7,54 (d, 1H, J=7,6 Hz), 4,29 (s, 2H), 3,26 (d, 2H, J=7,2 Hz), 1,6430 1,86 (m,2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-cyclohexylmethyl-1H-benzimidazole-5-carboxamide (Compound 11); 1 H-NMR (300 MHz, CD 3 OD): 8.15 (s, 1H), 7.88 (d, 1H, J = 7.6 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J = 7.6 Hz), 7.72 (d, 1H, J = 7.6 Hz), 7.54 (d, 1H, J = 7.6 Hz), 4.29 ( s, 2H), 3.26 (d, 2H, J = 7.2 Hz), 1.6430 1.86 (m,
PAVYZDYSEXAMPLE
2-(5-Aminometil-1 /7-benzoimidazol-2-ilmetil)-/V-(3-aminopropil)-1 -metil1H-benzoimidazol-5-karboksamidas (12 junginys) (a) Mišinys, susidedantis iš 3-nitro-4-chlorbenzenkarboksirūgšties (1,3 g, 6,45 mmol), 10 % metilamino ir vandens (10 ml) užlydytame mėgintuvėlyje šildytas 100 °C temperatūroje 11 valandų, sukoncentruotas iki 1 ml ir po to praskiestas koncentruotu vandenilio chloridu, duoda geltonas nuosėdas. Nuosėdos atskirtos filtruojant, perplautos vandeniu, po to dietileteriu ir išdžiovintos, duoda 3-nitro-4-metilaminobenzenkarboksirūgštį (2,1 g, 86 % išeiga); 1H-BMR (300 MHz, CDCI3): 8,56 (d, 1H, J= 2,1 Hz), 8,52 (kvartetas, 1H, J=8,6 Hz), 7,94 (dd, 1H, 9,3, 2,1 Hz), 7,00 (d, 1H, J=9,3 Hz), 2,97 (d, 3H, J=8,6 Hz).2- (5-Aminomethyl-1,7-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1-methyl-1H-benzoimidazole-5-carboxamide (Compound 12) (a) Mixture of 3-nitro -4-Chlorobenzoic acid (1.3 g, 6.45 mmol), 10% methylamine and water (10 mL) in a sealed tube was heated at 100 ° C for 11 h, concentrated to 1 mL and then diluted with concentrated hydrochloric acid to give a yellow precipitate. . The precipitate was separated by filtration, washed with water, then with diethyl ether and dried to give 3-nitro-4-methylaminobenzoic acid (2.1 g, 86% yield); 1 H-NMR (300 MHz, CDCl 3 ): 8.56 (d, 1H, J = 2.1 Hz), 8.52 (quartet, 1H, J = 8.6 Hz), 7.94 (dd, 1H, 9.3, 2.1 Hz), 7.00 (d, 1H, J = 9.3 Hz), 2.97 (d, 3H, J = 8.6 Hz).
(b) Etilo alkoholis (100 ml) pastovioje azoto srovėje supiltas į kolbą, turinčią 3-nitro-4-metilaminobenzenkarboksirūgšties (2,09 g, 10,7 mmol) ir 10 % Pd/C (30 mg). Mišinys maišytas vandenilio atmosferoje 16 valandų, nufiltruotas per 0,22 pm GV tipo miliporų filtrą ir sukoncentruotas rotoriniu garintuvu. Liekana, išdžiovinta vakuume, duoda 3-amino-metilaminobenzenkarboksirūgštj (1,1 g, 61 % išeiga).(b) Ethyl alcohol (100 mL) was added under a stream of nitrogen to a flask containing 3-nitro-4-methylaminobenzoic acid (2.09 g, 10.7 mmol) and 10% Pd / C (30 mg). The mixture was stirred under a hydrogen atmosphere for 16 hours, filtered through a 0.22 µm GV millipore filter and concentrated on a rotary evaporator. The residue, dried in vacuo, gave 3-amino-methylaminobenzoic acid (1.1 g, 61% yield).
(c) 3-Etoksi-3-iminoetilpropionatas, gautas kaip 2(a) pavyzdyje, pagal artimas 2(b) pavyzdžio sąlygas, reaguoja su 3-aminometilaminobenzenkarboksirūgštimi, duodamas 2-etoksikarbonilmetil-1-metil-1/-/benzoimidazol-5-karboksirūgštį (71 % išeiga); 1H-BMR (300 MHz, DMSO-d6): 7,18 (dd, 1H, J=8,1 Hz), 7,11 (d, 1H, J = 1,2 Hz), 6,33 (d, 1H, J=8,1 Hz), 5,28 (pi. s, 1H), 4,67 (pi. s, 1H), 3,34 (pi. s, 2H), 2,72 (s, 3H).(c) 3-Ethoxy-3-iminoethylpropionate, obtained as in Example 2 (a), under close conditions to Example 2 (b), reacts with 3-aminomethylaminobenzoic acid to give 2-ethoxycarbonylmethyl-1-methyl-1 H / benzoimidazole-5 -carboxylic acid (71% yield); 1 H-NMR (300 MHz, DMSO-d 6 ): 7.18 (dd, 1H, J = 8.1 Hz), 7.11 (d, 1H, J = 1.2 Hz), 6.33 ( d, 1H, J = 8.1 Hz), 5.28 (pi, 1H), 4.67 (pi, 1H), 3.34 (pi, 2H), 2.72 (s) , 3H).
(d) 2-(3,4-Diaminobenzil)izoindol-1,3-dionas, gautas kaip 2(d) pavyzdyje, pagal artimas 2(e) pavyzdžio sąlygas, reaguoja su 2-etoksikarbonilmetil-1-metil1/7-benzoimidazol-5-karboksirūgštimi, duodamas 2-(5-(1,3-diokso-1,3dihidroizoindol-2-ilmetil)-1 H-benzoimidazol-2-ilmetil]-1 -metil-1 H-benzoimidazol-5karboksirūgštj (48 % išeiga); ’H-BMR (300 MHz, DMSO-de): 8,10 (s, 1H), 7,80-7,84 (m, 5H), 7,58 (d, 1H, J=10,0 Hz), 7,40 (pi. s, 2H), 7,10 (pi. s, 1H), 4,80 (s, 2H), 4,56 (s, 2H), 3,79 (s, 3H).(d) 2- (3,4-Diaminobenzyl) isoindole-1,3-dione, obtained as in Example 2 (d), under conditions close to Example 2 (e), reacts with 2-ethoxycarbonylmethyl-1-methyl-1, 7-benzoimidazole. -5-carboxylic acid to give 2- (5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl-1H-benzoimidazole-5-carboxylic acid (48% 1 H-NMR (300 MHz, DMSO-d 6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.58 (d, 1H, J = 10, 0 Hz), 7.40 (s, 2H), 7.10 (s, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 3.79 (s, 3H).
(e) 2-[5-(1,3-diokso-1,3-dihidroizoindol-2-ilmetil)-1/7-benzoimidazol-2ilmetil]-1-metil-1/7-benzoimidazol-5-karboksirūgštis (0,05 g, 0,108 mmol), 1hidroksibenzotriazolas (0,016 g, 0,118 mmol), 1-(3-dimetilaminopropil)-3etilkarbodiimido hidrochloridas (0,023 g, 0,12 mmol) ir mono-BOC blokuotas 1,3diaminopropano darinys 0 °C temperatūroje ištirpinti metileno chloride (1 ml) ir DMF-de (minimaliame kiekyje, duodančiame tirpumo efektą). Tirpalas supusiausvirintas A/-metilmorfolinu iki pH apie 8, ir mišinys paliktas lėtai sušilti iki kambario temperatūros, o po to maišytas 20 valandų. Mišinys perkeltas į dalomąjį piltuvą, praskiestas metileno chloridu, perplautas 0,1 N HCI tirpalu, po to NaHCO3 tirpalu, išdžiovintas natrio sulfatu, nufiltruotas ir sukoncentruotas. Liekana išgryninta preparatyvine plonasluoksne chromatografija (TLC) (10 % metanolis/etilo acetatas), duoda 2-[6-(1,3-diokso-1,3-dihidroizoindol-2-ilmetii)-1Hbenzoimidazol-2-ilmetil]-1-metil-N-(3-aminopropil)-1H-benzoimidazol-5karboksamidą (0,02 g, 28 % išeiga): ’H-BMR (300 MHz, CDCI3): 7,75-7,81 (m, 4H), 7,61-7,68 (m, 3H), 7,33 (pi. s, 1H), 7,27 (d, 1H, J=8,6 Hz), 7,15 (d, 1H, J=9,3 Hz),(e) 2- [5- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1,7-benzoimidazol-2-ylmethyl] -1-methyl-1/7-benzoimidazole-5-carboxylic acid (O) , 05 g, 0.108 mmol), 1-hydroxybenzotriazole (0.016 g, 0.118 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.023 g, 0.12 mmol) and mono-BOC-blocked 1,3-diaminopropane were dissolved at 0 ° C. methylene chloride (1 ml) and DMF-de (in a minimal amount giving a solubility effect). The solution was boiled with N-methylmorpholine to pH about 8, and the mixture was allowed to warm slowly to room temperature and then stirred for 20 hours. The mixture was transferred to a separatory funnel, diluted with methylene chloride, washed with 0.1 N HCl solution, followed by NaHCO 3 solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography (TLC) (10% methanol / ethyl acetate) to give 2- [6- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-. methyl N- (3-aminopropyl) -1H-benzoimidazole-5-carboxamide (0.02 g, 28% yield): 1 H-NMR (300 MHz, CDCl 3 ): 7.75-7.81 (m, 4H) , 7.61-7.68 (m, 3H), 7.33 (s, 1H), 7.27 (d, 1H, J = 8.6 Hz), 7.15 (d, 1H, J) = 9.3 Hz),
5,10 (pi. t, 1H), 4,90 (pi. s, 2H), 4,57 (s, 2H), 3,71 (s, 3H), 3,49 (kvartetas, 2H, J=7,2 Hz), 3,24 (kvartetas, 2H, J=7,2 Hz), 1,72 (m, 2H), 1,41 (s, 9H).5.10 (pi, t, 1H), 4.90 (pi, s, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (quartet, 2H, J = 7.2 Hz), 3.24 (quartet, 2H, J = 7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H).
(f) 2- [6- (1,3-diokso-1,3-dih id roizoi ndol-2-i l metil)-1 H-benzoimidazol-2ilmetil]-1 -meti!-N-(3-aminopropil)-1 H-benzoimidazol-5-karboksamidas deblokuotas panašiomis sąlygomis kaip 2(g) pavyzdyje, duoda 2-(5-aminometil1/7-benzoimidazol-2-ilmetil)-/V-(3-aminopropi1)-1-metil-1H-benzoimidazol-5karboksamidą (20 % išeiga); 1H-BMR (300 MHz, DMSO-de): 8,85 (t, 1H, J=5,7 Hz), 8,55 (pi. s, 3H), 8,20 (s, 1H), 8,01 (pi. s, 3H), 7,74 (m, 2H), 7,80 (d, 1H, J=6,6 Hz), 5,07 (s, 2H), 4,16 (m, 2H), 3,96 (s, 3H), 3,32 (m, 2H), 2,79 (m, 2H), 1,80 (m, 2H).(f) 2- [6- (1,3-Dioxo-1,3-dihydroisolindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl-N- (3-aminopropyl) The 1H-benzoimidazole-5-carboxamide is deprotected under similar conditions as in Example 2 (g) to give 2- (5-aminomethyl-1, 7-benzoimidazol-2-ylmethyl) - N - (3-aminopropyl) -1-methyl-1H benzoimidazole-5-carboxamide (20% yield); 1 H-NMR (300 MHz, DMSO-d 6): 8.85 (t, 1H, J = 5.7 Hz), 8.55 (ppm, 3H), 8.20 (s, 1H), δ , 01 (pi s, 3H), 7.74 (m, 2H), 7.80 (d, 1H, J = 6.6 Hz), 5.07 (s, 2H), 4.16 (m, 2H), 3.96 (s, 3H), 3.32 (m, 2H), 2.79 (m, 2H), 1.80 (m, 2H).
Sintetinant kaip 3 pavyzdyje, gauti sekantys šio išradimo junginiai: 3-[2-(5-aminometil-1/7-benzoimidazol-2-iimetil)-/\/-(2-naft-1-iletil)1/7-benzoimidazol-5-karboksamidas (13 junginys): 1H-BMR (300 MHz, CD3OD): 8,25 (d, 1H, J= 8,1 Hz), 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=7,4 Hz), 3,41 (t, 2H, J=7,4 Hz);Synthesized as in Example 3, the following compounds of the present invention were obtained: 3- [2- (5-Aminomethyl-1/7-benzoimidazol-2-ylmethyl) - N - (2-naphth-1-ylethyl) -1,7-benzoimidazole -5-carboxamide (compound 13) 1 H-NMR (300 MHz, CD 3 OD): 8.25 (d, 1H, J = 8.1 Hz), 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 = 7.4 Hz), 3, 41 (t, 2H, J = 7.4 Hz);
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-/\/-(3,3-difenilpropil)1A/-benzoimidazol-5-karboksamidas (14 junginys); 1H-BMR (300 MHz, CD3OD):2- (5-aminomethyl-1 H -benzoimidazol-2-ylmethyl) - N - (3,3-diphenylpropyl) -1 N -benzoimidazole-5-carboxamide (Compound 14); 1 H-NMR (300 MHz, CD3OD)
8,11 (s, 1H), 7,77-7,86 (m, 3H), 7,70 (d, 1H, J=9,3), 7,56 (d, 1H, J=9,3 Hz), 7,237,39 (m, 8H), 7,13-7,19 (m, 2H), 4,30 (s, 2H), 4,07 (t, 1H, J=7,2 Hz), 3,40 (t, 2H,8.11 (s, 1H), 7.77-7.86 (m, 3H), 7.70 (d, 1H, J = 9.3), 7.56 (d, 1H, J = 9.3). Hz), 7.237.39 (m, 8H), 7.13-7.19 (m, 2H), 4.30 (s, 2H), 4.07 (t, 1H, J = 7.2 Hz), 3.40 (t, 2H,
J=7,2 Hz), 2,44 (kvartetas, 2H, J=7,2 Hz);J = 7.2 Hz), 2.44 (quartet, 2H, J = 7.2 Hz);
2-(5-aminometil-1/7-benzoimidazol-2-ilmetil)-A/-(2-naft-2-iletil)-1/7benzoimidazol-5-karboksamidas (15 junginys); 1H-BMR (300 MHz, CD3OD): 8,10 (s, 1H), 7,67-7,86 (m, 8H), 7,55 (d, 1H, J=10,0 Hz), 7,38-7,44 (m, 3H), 4,28 (s, 2H), 3,72 (t, 2H, J=7,2 Hz), 3,10 (t, 2H, J=7,2 Hz);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-2-ylethyl) -1,7-benzoimidazole-5-carboxamide (Compound 15); 1 H-NMR (300 MHz, CD 3 OD): 8.10 (s, 1H), 7.67-7.86 (m, 8H), 7.55 (d, 1H, J = 10.0 Hz). , 7.38-7.44 (m, 3H), 4.28 (s, 2H), 3.72 (t, 2H, J = 7.2 Hz), 3.10 (t, 2H, J = 7 , 2 Hz);
2-(1H-benzoimidazoI-2-ilmetil)-A/-[2-(1/7-indol-3-il)etil]-1H-benzoimidazol5-karboksamidas (16 junginys); 1H-BMR (300 MHz, CD3OD): 8,09 (s, 1H), 7,817,84 (m, 2H), 7,74 (d, 1H, J=8,6 Hz), 7,67 (d, 1H, J=8,6 Hz), 7,52-7,58 (m, 2H), 7,30 (d, 1H, J=7,9), 7,01-7,08 (m, 2H), 6,94 (t, 1H, J=7,9 Hz), 4,26 (s, 2H), 3,68 (t, 2H, J=6,8 Hz), 3,06 (t, 2H, J=6,8 Hz);2- (1H-benzoimidazol-2-ylmethyl) -N- [2- (1H-indol-3-yl) ethyl] -1H-benzoimidazole-5-carboxamide (Compound 16); 1 H-NMR (300 MHz, CD 3 OD): 8.09 (s, 1H), 7.817.84 (m, 2H), 7.74 (d, 1H, J = 8.6 Hz), 7.67 (d, 1H, J = 8.6 Hz), 7.52-7.58 (m, 2H), 7.30 (d, 1H, J = 7.9), 7.01-7.08 (m , 2H), 6.94 (t, 1H, J = 7.9 Hz), 4.26 (s, 2H), 3.68 (t, 2H, J = 6.8 Hz), 3.06 (t , 2H, J = 6.8 Hz);
2-(5-aminometil-1 /7-benzoimidazol-2-ilmetil)-A/-[2-(5-metoksi)indol-3-il]-1 Hbenzoimidazol-5-karboksamidas (17 junginys); ^-BMR (300 MHz, CD3OD): 8,10 (s, 1H), 7,81-7,85 (m, 2H), 7,76 (d, 1H, J=8,2 Hz), 7,69 (d, 1H, J=8,2 Hz), 7,54 (d, 1H, J=8,2 Hz), 7,20 (d, 1H, J=8,2 Hz), 7,07 (m, 2H), 6,70 (dd, 1H, J=10,0, 2,2 Hz), 4,27 (s, 2H), 3,65-3,71 (m, 5H), 3,04 (t, 2H, J=7,2 Hz);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- [2- (5-methoxy) indol-3-yl] -1H-benzoimidazole-5-carboxamide (Compound 17); 1 H-NMR (300 MHz, CD 3 OD): 8.10 (s, 1H), 7.81-7.85 (m, 2H), 7.76 (d, 1H, J = 8.2 Hz), 7.69 (d, 1H, J = 8.2 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.20 (d, 1H, J = 8.2 Hz), 7, 07 (m, 2H), 6.70 (dd, 1H, J = 10.0, 2.2 Hz), 4.27 (s, 2H), 3.65-3.71 (m, 5H), 3 , 04 (t, 2H, J = 7.2 Hz);
2-(5-aminometil-1 H-benzoimidazol-2-ilmetil)-/\/-(2,3,4,5,6pentahidroksiheksil)-1H-benzoimidazol-5-karboksamidas (18 junginys); 1H-BMR (300 MHz, CD3OD/D2O (1/1)): 8,15 (s, 1H), 7,86-7,90 (m, 2H), 7,83 (d, 1H, J=9,6 Hz), 7,77 (d, 1H, J=9,6 Hz), 7,61 (d, 1H, J=9,6 Hz), 4,32 (s, 2H), 4,01 (m, 1H), 3,62-3,86 (m, 6H), 3,47-3,55 (m, 1H);2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - N - (2,3,4,5,6-pentahydroxyhexyl) -1H-benzoimidazole-5-carboxamide (Compound 18); 1 H-NMR (300 MHz, CD 3 OD / D 2 O (1/1)): 8.15 (s, 1H), 7.86-7.90 (m, 2H), 7.83 (d, 1H, J = 9.6 Hz), 7.77 (d, 1H, J = 9.6 Hz), 7.61 (d, 1H, J = 9.6 Hz), 4.32 (s, 2H) , 4.01 (m, 1H), 3.62-3.86 (m, 6H), 3.47-3.55 (m, 1H);
• 25 2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-A/-(2-fenoksietil)-1Hbenzoimidazol-5-karboksamidas (19 junginys); 1H-BMR (300 MHz, CD3OD): 8,16 (s, 1H), 7,88 (d, 1H, J=9,3 Hz), 7,84 (s, 1H), 7,76 (d, 1 H, J=9,3 Hz), 7,71 (d, 1H, J=9,3 Hz), 7,55 (d, 1H, J=9,3 Hz), 7,23 (2H, J=7,9 Hz), 6,85-6,96 (m, 3H), 4,27 (s, 2H), 4,16 (t, 2H, J=6,1 Hz), 3,78 (t, 2H, J=6,1 Hz);• 2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-phenoxyethyl) -1H-benzoimidazole-5-carboxamide (Compound 19); 1 H-NMR (300 MHz, CD 3 OD): 8.16 (s, 1H), 7.88 (d, 1H, J = 9.3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J = 9.3 Hz), 7.71 (d, 1H, J = 9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz), 7.23 ( 2H, J = 7.9 Hz), 6.85-6.96 (m, 3H), 4.27 (s, 2H), 4.16 (t, 2H, J = 6.1 Hz), 3, 78 (t, 2H, J = 6.1 Hz);
2-(5-aminometil-1 H-benzoimidazol-2-ilmetil)-W-(3-fenilprop-2-inil)-1 Hbenzoimidazol-5-karboksamidas (20 junginys); 1H-BMR (300 MHz, CD3OD): 8,18 (s, 1H), 7,91 (d, 1H, J=9,3 Hz), 7,84 (s, 1H), 7,76 (d, 1H, J=9,3), 7,71 (d, 1H,2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-phenylprop-2-ynyl) -1H-benzoimidazole-5-carboxamide (Compound 20); 1 H-NMR (300 MHz, CD 3 OD): 8.18 (s, 1H), 7.91 (d, 1H, J = 9.3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J = 9.3), 7.71 (d, 1H,
J=9,3 Hz), 7,55 (d, 1H, J=9,3 Hz), 7,38-7,43 (m, 2H), 7,28-7,32 (m, 3H), 4,40 (s,J = 9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz), 7.38-7.43 (m, 2H), 7.28-7.32 (m, 3H), 4.40 (s,
2H), 4,27 (s, 2H);2H), 4.27 (s, 2H);
2-(5-aminometil-1A/-benzimidazol-2-ilmetil)-/V-(E-3-fenilalil)-1Wbenzimidazol-5-karboksamidas (21 junginys); 1H-BMR (300 MHz, CD3OD): 8,19 (s, 1H), 7,92 (d, 1H, J=9,3 Hz), 7,86 (s, 1H), 7,76 (d, 1H, J=9,3 Hz), 7,71 (d, 1H, J=9,3 Hz), 7,55 (d, 1H, J=9,3 Hz), 7,33-7,39 (m, 2H), 7,18-7,30 (m, 3H), 6,60 (d, 1H, J = 15,8 Hz), 6,34 (dt, 1H, J = 15,8, 6,1 Hz), 4,27 (s, 2H), 4,17 (d, 2H, J=6,1 Hz);2- (5-Aminomethyl-1 H -benzimidazol-2-ylmethyl) -N- (E-3-phenylallyl) -1 H -benzimidazole-5-carboxamide (Compound 21); 1 H-NMR (300 MHz, CD 3 OD): 8.19 (s, 1H), 7.92 (d, 1H, J = 9.3 Hz), 7.86 (s, 1H), 7.76 (d, 1H, J = 9.3 Hz), 7.71 (d, 1H, J = 9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz), 7.33-7 , 39 (m, 2H), 7.18-7.30 (m, 3H), 6.60 (d, 1H, J = 15.8 Hz), 6.34 (dt, 1H, J = 15.8 , 6.1 Hz), 4.27 (s, 2H), 4.17 (d, 2H, J = 6.1 Hz);
2- (5-aminometil-1H-benzoimidazol-2-ilmetil)-A/-(3-cikloheksilpropil)-1Wbenzoimidazol-5-karboksamidas (22 junginys); 1H-BMR (300 MHz, CD3OD): 8,13 (s, 1H), 7,86 (d, 1H, J=9,3 Hz), 7,81 (s, 1H), 7,74 (d, 1H, J=9,3 Hz), 7,69 (d, 1H, J=9,3 Hz), 7,53 (d, 1H, J=9,3 Hz), 4,27 (s, 2H), 3,36 (t, 2H, J=7,2 Hz), 1,61-1,78 (m, 7H), 1,19-1,32 (m, 6H), 0,90 (m, 2H);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-cyclohexylpropyl) -1 H -benzoimidazole-5-carboxamide (Compound 22); 1 H-NMR (300 MHz, CD 3 OD): 8.13 (s, 1H), 7.86 (d, 1H, J = 9.3 Hz), 7.81 (s, 1H), 7.74 (d, 1H, J = 9.3 Hz), 7.69 (d, 1H, J = 9.3 Hz), 7.53 (d, 1H, J = 9.3 Hz), 4.27 (s , 2H), 3.36 (t, 2H, J = 7.2 Hz), 1.61-1.78 (m, 7H), 1.19-1.32 (m, 6H), 0.90 ( m, 2H);
3- [2-(5-aminometil-1A/-benzoimidazol-2-ilmetil)-A/-okt-1-il-1A/-benzimidazol5-karboksamidas (23 junginys); 1H-BMR (300 MHz, CD3OD): 8,13 (s, 1H), 7,86 (d, 1H, J=9,7 Hz), 7,82 (s, 1H), 7,74 (d, 1H, J=9,7 Hz), 7,69 (d, 1H, J=9,7), 7,49 (d, 1H, J=9,7 Hz), 4,27 (s, 2H), 3,39 (t, 2H, J=7,2 Hz), 1,64 (m, 2H), 1,26-1,43 (m, 11 H), 0,88 (m, 2H);3- [2- (5-Aminomethyl-1A / benzoimidazol-2-ylmethyl) -N-oct-1-yl-1A-benzoimidazole-5-carboxamide (Compound 23); 1 H-NMR (300 MHz, CD 3 OD): 8.13 (s, 1H), 7.86 (d, 1H, J = 9.7 Hz), 7.82 (s, 1H), 7.74 (d, 1H, J = 9.7 Hz), 7.69 (d, 1H, J = 9.7 Hz), 7.49 (d, 1H, J = 9.7 Hz), 4.27 (s, 2H), 3.39 (t, 2H, J = 7.2 Hz), 1.64 (m, 2H), 1.26-1.43 (m, 11H), 0.88 (m, 2H) ;
2-(5-aminometil-1H-benzoirnidazol-2-ilmetil)-/V-metil-/V-(2-feniletil)-1Hbenzimidazol-5-karboksamidas (24 junginys); 1H-BMR (300 MHz, CD3OD): 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 (pi. s), 4,19 (s), 3,72 (t), 3,47 (t), 3,22 (s), 3,08 (s), 2,87 (t), 2,76 (t); ir2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-methyl- N - (2-phenylethyl) -1H-benzimidazole-5-carboxamide (Compound 24); 1 H-NMR (300 MHz, CD 3 OD): 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 (pi), 4.19 (s), 3.72 (t), 3.47 (t), 3.22 (s), 3.08 (s), 2.87 (t), 2.76 (t); and
2-(5-aminometil-1 /7-benzoimidazol-2-ilmetil)-A/-(1 - meti l-3-f en ii propi I)-1Hbenzoimidazol-5-karboksamidas (25 junginys); 1H-BMR (300 MHz, CD3OD): 8,05 (s, 1H), 7,79 (d, 1H, J=9,3 Hz), 7,75 (s, 1H), 7,68 (d, 1H, J=9,3 Hz), 7,63 (d, 1H, J=9,3 Hz), 7,46 (d, 1H, J=9,3 Hz), 7,09-7,17 (m, 4H), 7,03 (m, 1H), 4,43 (s, 2H), 4,08 (m, 1H), 2,61 (t, 2H, J=7,9 Hz), 1,17-1,93 (m, 2H), 1,18 (d, 3H, J=7,2 Hz).2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (1-methyl-3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 25); 1 H-NMR (300 MHz, CD 3 OD): 8.05 (s, 1H), 7.79 (d, 1H, J = 9.3 Hz), 7.75 (s, 1H), 7.68 (d, 1H, J = 9.3 Hz), 7.63 (d, 1H, J = 9.3 Hz), 7.46 (d, 1H, J = 9.3 Hz), 7.09-7 , 17 (m, 4H), 7.03 (m, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 2.61 (t, 2H, J = 7.9 Hz) , 1.17-1.93 (m, 2H), 1.18 (d, 3H, J = 7.2 Hz).
PAVYZDYSEXAMPLE
C-{2-[5-(4-fenilbutoksi)-1H-benzoimidazol-2-ilmetil]-1H-benzoimidazol-5il}metilaminas (26 junginys) (a) 4-Fenil-1-butanolis (1 ml, 6,49 mmol) THF-ne sujungtas sauso azoto atmosferoje su natrio hidridu (0,26 g, 6,5 mmol) 60 % mineralinės alyvos dispersijoje. Mišinys stipriai maišytas 5 minutes, sujungtas su 3,4dinitrochlorbenzenu (1,3 g, 6,42 mmol), o po to maišyta 10 valandų kambario temperatūroje. Mišinys padalintas tarp dietileterio ir 3 N vandenilio chlorido. Vandeninis sluoksnis atskirtas ir keletą kartų ekstrahuotas dietileteriu. Sujungti organiniai sluoksniai išdžiovinti (MgSO4), perfiltruoti ir sukoncentruoti rotoriniu garintuvu. Liekana, išgryninta staigiąja chromatografija (9:1 heksanas/dietileteris), duoda 4-(4-fenilbutoksi)-1,2-dinitrobenzeną (1,16 g, 72% išeiga): 1H-BMR (300 MHz, CDCI3): 7,84 (d, 1H, J=10,0 Hz), 7,19-7,36 (m, 5H), 7,00-7,06 (m, 2H), 4,10 (t, 2H, J=5,7 Hz), 2,73 (t, 2H, J=6,5 Hz), 1,89 (m, 4H).C- {2- [5- (4-Phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazol-5-yl} methylamine (Compound 26) (a) 4-Phenyl-1-butanol (1 mL, 6, 49 mmol) THF-not combined under dry nitrogen atmosphere with sodium hydride (0.26 g, 6.5 mmol) in a 60% mineral oil dispersion. The mixture was stirred vigorously for 5 minutes, combined with 3,4-dinitrochlorobenzene (1.3 g, 6.42 mmol) and then stirred at room temperature for 10 hours. The mixture was partitioned between diethyl ether and 3N hydrogen chloride. The aqueous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgSO 4 ), filtered and concentrated on a rotary evaporator. The residue was purified by flash chromatography (9: 1 hexane / diethyl ether) to give 4- (4-phenylbutoxy) -1,2-dinitrobenzene (1.16 g, 72% yield): 1 H-NMR (300 MHz, CDCl 3 ). 7.84 (d, 1H, J = 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H) , J = 5.7 Hz), 2.73 (t, 2H, J = 6.5 Hz), 1.89 (m, 4H).
(b) 3-Etoksi-3-iminoetilo propionatas, gautas kaip 2(a) pavyzdyje, reaguoja su 2-(3,4-diaminobenzil)izoindol-1,3-dionu sąlygomis, panašiomis kaip 2(b) pavyzdyje, duodamas 5-(1,3-diokso-1,3-dihidroizoindol-2-ilmetil)-1Hbenzoimidazol-2-iletilo acetatą (71% išeiga): 1H-BMR (300 MHz, DMSO-d6): 7,787,9 (m, 4H), 7,43-7,47 (m, 2H), 7,12 (d, 1H, J=9,43 Hz), 4,82 (s, 2H), 4,07 (kvartetas, 2H, J=7,2 Hz), 3,44 (s, 2H), 1,38 (t, 3H, J=7,2 Hz).(b) 3-Ethoxy-3-iminoethyl propionate obtained as in Example 2 (a) is reacted with 2- (3,4-diaminobenzyl) isoindole-1,3-dione under conditions similar to Example 2 (b) to give 5 - (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1H-benzoimidazol-2-yl-ethyl acetate (71% yield): 1 H-NMR (300 MHz, DMSO-d 6 ): 7.787.9 (m , 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J = 9.43 Hz), 4.82 (s, 2H), 4.07 (quartet, 2H, J = 7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J = 7.2 Hz).
(c) 4-(4-Fenilbutoksi)-1,2-dinitrobenzenas suredukuotas sąlygomis, panašiomis kaip 3(b) pavyzdyje, duoda 4-(4-fenilbutoksi)benzen-1,2-diaminą (86% nevalyto produkto).(c) 4- (4-Phenylbutoxy) -1,2-dinitrobenzene is reduced under reduced conditions similar to Example 3 (b) to give 4- (4-phenylbutoxy) benzene-1,2-diamine (86% of crude product).
(d) Mišinys, sudarytas iš 5-(4-fenilbutoksi)benzen-1,2-diamino (0,06 g, 0,234 mmol) ir 5-(1,3-diokso-1,3-dihidroizoindol-2-ilmetil)-1H-benzoimidazol-2iletilo acetato (0,1 g, 0,234 mmol) šildytas 1 valandą 185 °C temperatūroje azoto atmosferoje. Mišinys suspenduotas į dietileterį ir smarkiai maišytas 1 valandą. Kieta dalis nufiltruota, perplautą dietileteriu ir išdžiovinta, duoda 2-{2-[5-(446 fenilbutoksi)-1H-benzoimidazol-2-ilmetil]-3/7-benzoimidazol-5-ilmetil}izoindol-1,3dioną (0,1 g, 0,18 mmol).(d) A mixture of 5- (4-phenylbutoxy) benzene-1,2-diamine (0.06 g, 0.234 mmol) and 5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-Benzoimidazole-2-ethyl acetate (0.1 g, 0.234 mmol) was heated at 185 ° C for 1 h under a nitrogen atmosphere. The mixture was suspended in diethyl ether and stirred vigorously for 1 hour. The solid was filtered, washed with diethyl ether and dried to give 2- {2- [5- (446 phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -3,7-benzoimidazol-5-ylmethyl} isoindole-1,3-dione (0, 1 g, 0.18 mmol).
(e) 2-{2-[5-(4-Fenilbutoksi)-1/7-benzoimidazol-2-ilmetilj-3F/-benzoimidazol5-ilmetil}izoindol-1,3-dionas, deblokuotas pagal sąlygas, panašias kaip 2(g) pavyzdyje, duoda C- {2- [5-(4-fen i I butoksi)-1 W-benzoimidazol-2-ilmetil]-1 Hbenzoimidazol-5-i!}metilaminą (0,05 g, 55% išeiga); 1H-BMR (300 MHz, CD3OD): 7,83 (d, 1H, J=8,6 Hz), 7,76 (s, 1H), 7,69 (d, 1H, J=10,0 Hz), 7,48 (d, 1H, J=8,6 Hz), 6,99-7,16 (m, 5H), 6,92 (d, 1H, J = 10,0 Hz), 6,80 (t, 1H, J=7,2 Hz), 4,44 (s, 2H), 3,93 (t, 2H, J=6,5 Hz), 2,56 (t, 2H, J=7,2 Hz), 1,72 (m, 2H).(e) 2- {2- [5- (4-Phenylbutoxy) -1,7-benzoimidazol-2-ylmethyl] -3F-benzoimidazol-5-ylmethyl} isoindole-1,3-dione deprotected under conditions similar to 2 ( g) in the example gives C- {2- [5- (4-phenylbutoxy) -1 H -benzoimidazol-2-ylmethyl] -1 H -benzoimidazol-5-yl} methylamine (0.05 g, 55% yield) ); 1 H-NMR (300 MHz, CD 3 OD): 7.83 (d, 1H, J = 8.6 Hz), 7.76 (s, 1H), 7.69 (d, 1H, J = 10.0 Hz) ), 7.48 (d, 1H, J = 8.6 Hz), 6.99-7.16 (m, 5H), 6.92 (d, 1H, J = 10.0 Hz), 6.80 (t, 1H, J = 7.2 Hz), 4.44 (s, 2H), 3.93 (t, 2H, J = 6.5 Hz), 2.56 (t, 2H, J = 7, 2 Hz), 1.72 (m, 2H).
PAVYZDYSEXAMPLE
2-(5-Aminometil-1H-benzoimidazol-2-ilmetil)-1H-benzoimidazol-5karbamato 2-feniletilo trifluoracetatas (27 junginys)2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazole-5-carbamate 2-phenylethyl trifluoroacetate (Compound 27)
2-[5-(1,3-Diokso-1,3-dihidroizoindol-2-ilmetil)-1F/-benzoimidazol-2-ilmetilj1/7-benzoimidazol-5-karboksirūgštis (0,060 g, 0,133 mmol) fenetanolyje (0,160 ml, 1,34 mmol) sujungtas azoto atmosferoje kambario temperatūroje su difenilfosforilo azidu (0,034 ml, 0,158 mmol) ir trietilaminu (0,22 ml, 0,158 mmol). Mišinys maišytas 1 valandą 120 °C temperatūroje, atšaldytas iki kambario temperatūros ir sujungtas su etanoliu (0,5 ml) ir hidrazinu (0,020 ml, 0,637 mmol). Mišinys maišytas 45 minutes 95 °C temperatūroje, atšaldytas iki kambario temperatūros ir praskiestas 3 N vandenilio chloridu (0,5 ml). Mišinys maišytas 20 minučių 55 °C temperatūroje, o po to nufiltruotas. Nufiltruotos kietos dalys perplautos 3 N vandenilio chloridu ir sujungtos su filtratu, perplautos etilo acetatu (15 ml) ir liofilizuotos. Liekana, išgryninta prepartayvine atvirkščių fazių HPLC, yra norimas produktas (0,008 g, 11 % išeiga); ’H-BMR (300 MHz, CD3OD): 8,10 (s, 1H), 7,75 (s, 1H), 7,68 (d, 1H, J=9,3 Hz), 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=6,8 Hz), 4,23 (s, 2H), 1,98 (t, 2H, J=6,8 Hz).2- [5- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1F-benzoimidazol-2-ylmethyl] -7-benzoimidazole-5-carboxylic acid (0.060 g, 0.133 mmol) in phenethanol (0.160 mL) , 1.34 mmol) was combined with diphenylphosphoryl azide (0.034 mL, 0.158 mmol) and triethylamine (0.22 mL, 0.158 mmol) under nitrogen at room temperature. The mixture was stirred for 1 hour at 120 ° C, cooled to room temperature, and combined with ethanol (0.5 mL) and hydrazine (0.020 mL, 0.637 mmol). The mixture was stirred for 45 minutes at 95 ° C, cooled to room temperature and diluted with 3N hydrochloric acid (0.5 mL). The mixture was stirred at 55 ° C for 20 minutes and then filtered. The filtered solids were washed with 3N hydrochloric acid and combined with the filtrate, washed with ethyl acetate (15 mL) and lyophilized. The residue, purified by preparative reverse phase HPLC, was the desired product (0.008 g, 11% yield); 1 H-NMR (300 MHz, CD 3 OD): 8.10 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H, J = 9.3 Hz), 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 , 8 Hz), 4.23 (s, 2H), 1.98 (t, 2H, J = 6.8 Hz).
PAVYZDYSEXAMPLE
2-(5-Guanidino-1 /7-benzoimidazol-2-ilmetil)-/V-(2-naftalen-1 -i letil)-3-m eti Ι-3Λ7benzoimidazol-5-karboksamidas (28 junginys) (a) Mišinys, sudarytas iš 2-nitro-1,4-fenilendiamino (21,0 g, 137 mmol) etanolyje (350 ml) ir 4,0 M vandenilio chlorido dioksane (30,8 ml, 123 mmol) maišyti kambario temperatūroje 15 minučių, po to įpilta dietileterio (1 I) ir gautos nuosėdos. Nuosėdos nufiltruotos, perplautos papildomu kiekiu eterio ir išdžiovintos vakuume, duoda 2-nitro-1,4-fenilendiamino hidrochloridą (23,3 g, 100 % išeiga).2- (5-Guanidino-1/7-benzoimidazol-2-ylmethyl) -N- (2-naphthalen-1-yl-ethyl) -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 28) (a) A mixture of 2-nitro-1,4-phenylenediamine (21.0 g, 137 mmol) in ethanol (350 mL) and 4.0 M hydrogen chloride in dioxane (30.8 mL, 123 mmol) was stirred at room temperature for 15 minutes, followed by the addition of diethyl ether (1 L) and the resulting precipitate. The precipitate was filtered off, washed with additional ether and dried in vacuo to give 2-nitro-1,4-phenylenediamine hydrochloride (23.3 g, 100% yield).
(b) Mišinys, sudarytas iš 2-nitro-1,4-fenilendiamino hidrochlorido (15,0 g, 79,1 mmol), cianamido (25,0 g, 595 mmol) ir vandens (5 ml), šildytas 60 °C temperatūroje ir maišytas 1,5 valandos, paliktas atšalti iki kambario temperatūros, o po to pripiltas perteklius dietileterio, kad iškristų nuosėdos. Nuosėdos nufiltruotos, perplautos papildomu kiekiu eterio ir išdžiovintos vakuume, duoda N(4-amino-3-nitrofenil)guanidino hidrochloridą (18,0 g, 98 % išeiga); 1H-BMR (300 MHz, DMSO-d6): 9,7 (s), 7,8 (s), 7,6 (s), 7,5 (s), 7,3 (d), 7,1 (d).(b) A mixture of 2-nitro-1,4-phenylenediamine hydrochloride (15.0 g, 79.1 mmol), cyanamide (25.0 g, 595 mmol) and water (5 mL) heated at 60 ° C. and stirred for 1.5 hours, allowed to cool to room temperature, and then added with excess diethyl ether to precipitate a precipitate. The precipitate was filtered off, washed with additional ether and dried in vacuo to give N (4-amino-3-nitrophenyl) guanidine hydrochloride (18.0 g, 98% yield); 1 H-NMR (300 MHz, DMSO-d 6 ): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d), 7 , 1 (d).
(c) Mišinys, sudarytas iš N-(4-amino-3-nitrofenil)guanidino hidrochlorido (12,0 g, 51,8 mmol), 10 % paladžio ant anglies (1,0 g), tetrahidrofurano (100 ml) ir metanolio (100 ml) hidrintas vienos atmosferos slėgyje, perfiltruotas ir sukoncentruotas vakuume, duoda A/-(3,4-diaminofenil)guanidino hidrochloridą (10,3 g, 98 % išeiga) kaip tamsią kietą medžiagą; 'H-BMR (300 MHz, DMSO-de):(c) A mixture of N- (4-amino-3-nitrophenyl) guanidine hydrochloride (12.0 g, 51.8 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 mL), and methanol (100 mL) hydrogenated at atmospheric pressure, filtered, and concentrated in vacuo to give N - (3,4-diaminophenyl) guanidine hydrochloride (10.3 g, 98% yield) as a dark solid; 1 H-NMR (300 MHz, DMSO):
9,4 (s), 7,2 (s), 6,5 (d), 6,3 (s),, 6,2 (d), 4,7 (s).9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).
(d) Mišinys, sudarytas iš N-(3,4-diaminofenil)guanidino hidrochlorido (9,9 g, 49 mmol), etoksikarbonimidoilacto rūgšties etilo esterio hidrochlorido (12,4 g, 59 mmol) ir acto rūgšties (20 ml), šildytas alyvos vonioje 110 °C temperatūroje 1,5 valandos, po to atšaldytas iki kambario temperatūros ir sukoncentruotas vakuume. Liekana ištirpinta etanolyje (15 ml), o po to į tirpalą pripilta etilo acetato (10 ml), gaunant nuosėdas suspensijoje. Suspensija nufiltruota ir į suspensiją pripiltas papildomas kiekis etileterio, duoda antras nuosėdas. Nuosėdos nufiltruotos, perplautos papildomu kiekiu etileterio ir išdžiovintos vakuume, duoda(d) A mixture of N- (3,4-diaminophenyl) guanidine hydrochloride (9.9 g, 49 mmol), ethoxycarbonimidoyl acetic acid ethyl ester hydrochloride (12.4 g, 59 mmol) and acetic acid (20 mL), heated in an oil bath at 110 ° C for 1.5 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethanol (15 mL), and then ethyl acetate (10 mL) was added to the solution to give a precipitate in suspension. The suspension was filtered and additional ethyl ether was added to the suspension to give a second precipitate. The precipitate was filtered off, washed with additional ethyl ether and dried in vacuo to give
5-guanidino-1H-benzoimidazol-2-ilacetato hidrochloridą (14,1 g, 94 % išeiga) kaip balkšvą kietą medžiagą; ’H-BMR (300 MHz, DMSO-d6): 10,2 (s), 7,8 (d), 7,7 (m),5-guanidino-1H-benzoimidazol-2-yl acetate hydrochloride (14.1 g, 94% yield) as an off-white solid; 1 H-NMR (300 MHz, DMSO-d 6 ): 10.2 (s), 7.8 (d), 7.7 (m),
7.3 (d), 4,5 (s), 4,2 (kvartetas), 1,2 (t).7.3 (d), 4.5 (s), 4.2 (quartet), 1.2 (t).
(e) Mišinys, sudarytas iš 4-nitro-3-metoksibenzenkarboksirūgšties (5,0 g,(e) A mixture of 4-nitro-3-methoxybenzoic acid (5.0 g,
25,4 mmol) ir vandeninio metilamino (40 %, 15 ml) užlydytame mėgintuvėlyje šildytas alyvos vonioje 100 °C temperatūroje 12 valandų, paliktas atšalti iki kambario temperatūros, o po to išpiltas į maišomą mišinį, sudarytą iš 1 M vandeninio vandenilio chlorido ir vandens, duoda oranžinės spalvos nuosėdas. Nuosėdos nufiltruotos, perplautos vandeniu ir perkristalintos iš karšto etanolio, duoda 3-metilamino-4-nitrobenzenkarboksirūgštį kaip ryškiai raudonos spalvos kristalinę medžiagą (3,6 g, 73 % išeiga); 1H-BMR (300 MHz, DMSO-d6): 13,5 (s),25.4 mmol) and aqueous methylamine (40%, 15 mL) in a sealed tube was heated in an oil bath at 100 ° C for 12 hours, allowed to cool to room temperature and then poured into a stirred mixture of 1 M aqueous hydrochloric acid and water. , yields an orange precipitate. The precipitate was filtered off, washed with water and recrystallized from hot ethanol to give 3-methylamino-4-nitrobenzoic acid as a bright red crystalline solid (3.6 g, 73% yield); 1 H-NMR (300 MHz, DMSO-d 6 ): 13.5 (s),
8.3 (kvartetas), 8,2 (d), 7,4 (s), 7,1 (d), 3,0 (d).8.3 (quartet), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d).
(f) Mišinys, sudarytas iš 3-metilamino-4-nitrobenzenkarboksirūgšties (13,0 g, 66,3 mmol), PyBOP (38,0 g, 73,0 mmol), hidroksibenzentriazolo hidrato (9,9 g, 73, 0 mmol), dimetilformamido (100 ml) ir N-metilmorfolino (18,3 ml), maišytas kambario temperatūroje 15 minučių, o po to pridėta 2-naftilen-1 -iletilamino (13,8 g,(f) A mixture of 3-methylamino-4-nitrobenzoic acid (13.0 g, 66.3 mmol), PyBOP (38.0 g, 73.0 mmol), hydroxybenzenetriazole hydrate (9.9 g, 73.0) mmol), dimethylformamide (100 mL) and N-methylmorpholine (18.3 mL) were stirred at room temperature for 15 minutes, and then 2-naphthylene-1-ethyl ethylamine (13.8 g,
66.3 mmol). Mišinys maišytas dar 30 minučių ir sukoncentruotas vakuume. Liekana padalinta tarp vandens ir etilo acetato, o organinis sluoksnis perplautas vandeniu, 0,1 M vandeniniu vandenilio chloridu, prisotintu vandeniniu natrio hidrokarbonatu ir sočiu vandeniniu natrio chloridu, išdžiovintas (magnio sulfatu), nufiltruotas ir sukoncentruotas vakuume. Liekana išgryninta perkristalinant iš karšto etanolio, duoda 3-metilamino-N-(2-naftalen-1-iletil)-4-nitrobenzamidą kaip ryškiai raudonos spalvos kristalinę medžiagą (21,3 g, 92 % išeiga); 1H-BMR (300 MHz, DMSO-de): 8,8 (t), 8,3 (d), 8,2 (kvartetas), 8,1 (d), 7,9 (d), 7,8 (d), 7,6-7,3 (m), 7,2 (s), 7,0 (d), 3,6 (kvartetas), 3,3 (t), 3,0 (d).66.3 mmol). The mixture was stirred for another 30 minutes and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, and the organic layer was washed with water, 0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by recrystallization from hot ethanol to give 3-methylamino-N- (2-naphthalen-1-ylethyl) -4-nitrobenzamide as a bright red crystalline solid (21.3 g, 92% yield); 1 H-NMR (300 MHz, DMSO-d 6): 8.8 (t), 8.3 (d), 8.2 (quartet), 8.1 (d), 7.9 (d), 7 8 (d), 7.6-7.3 (m), 7.2 (s), 7.0 (d), 3.6 (quartet), 3.3 (t), 3.0 (d) .
(g) Mišinys, sudarytas iš 3-metilamino-/V-(2-naft-1-iletil)-4-nitrobenzamido (21,3 g, 61 mmol), 10 % paladžio ant anglies (1,0 g), tetrahidrofurano (100 ml) ir metanolio (100 ml), hidrintas vienos atmosferos slėgyje, perfiltruotas ir sukoncentruotas vakuume, duoda 4-amino-3-metiiamino-A/-(2-naft-1-iletii)-4benzamidą (18,4 g, 95 % išeiga) kaip bespalvę amorfinę medžiagą; 1H-BMR (300(g) A mixture of 3-methylamino- N - (2-naphth-1-ylethyl) -4-nitrobenzamide (21.3 g, 61 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 mL) and methanol (100 mL), hydrogenated under one atmosphere, filtered and concentrated in vacuo to give 4-amino-3-methylamino-N - (2-naphth-1-ylethyl) -4-benzamide (18.4 g, 95% yield) as a colorless amorphous substance; 1 H-NMR (300
MHz, DMSO-d6): 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 (kvartetas), 3,2 (t), 2,7 (s).MHz, 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 (quartet), 3.2 (t), 2.7 (s).
(h) Mišinys, sudarytas iš 5-guanidino-1H-benzoimidazol-2-iletilo acetato hidrochlorido (0,5 g, 1,7 mmol), 4-amino-3-metilamino-N-(2-naft-1-iletil)-4benzamido (0,5 g, 1,7 mmol) ir dimetilformamido (2 ml), šildytas alyvos vonioje 185 °C temperatūroje ir maišytas azoto atmosferoje 3,5 valandos, atšaldytas iki kambario temperatūros ir išpiltas j maišomą acetonitrilą (150 ml), duoda nuosėdas. Nuosėdos, perplautos papildomu kiekiu acetonitrilo ir dietileterio (150 ml), nufiltruotos ir išdžovintos vakuume, duoda balkšvą medžiagą. Medžiaga, gryninta preparatyvine atvirkščių fazių HPLC, yra 2-(5-guanidino-1/7benzoimidazol-2-ilmetil)-N-(2-naftalen-1-iletil)-3-metil-3H-benzoimidazol-5karboksamidas kaip balta kieta medžiaga (0,5 g, 57 % išeiga); LRMS(ESI): C30H28N8O. Išskaičiuota: 516,6; Rasta (MH+): 517,2.(h) A mixture of 5-guanidino-1H-benzoimidazol-2-yl-ethyl acetate hydrochloride (0.5 g, 1.7 mmol), 4-amino-3-methylamino-N- (2-naphth-1-yl-ethyl) ) -4-benzamide (0.5 g, 1.7 mmol) and dimethylformamide (2 mL), heated in an oil bath at 185 ° C and stirred under nitrogen for 3.5 hours, cooled to room temperature and poured into stirred acetonitrile (150 mL) , yields a precipitate. The precipitate, washed with additional acetonitrile and diethyl ether (150 mL), filtered and dried in vacuo, gave an off-white solid. The material purified by reverse phase preparative HPLC is 2- (5-guanidino-1/7-benzoimidazol-2-ylmethyl) -N- (2-naphthalen-1-ylethyl) -3-methyl-3H-benzoimidazole-5-carboxamide as a white solid. (0.5 g, 57% yield); LRMS (ESI): C 30 H 28 N 8 O. Calculated: 516.6; Found (MH + ): 517.2.
PAVYZDYSEXAMPLE
2-(4-{2-[1-(5-Guanidino-1H-benzoimidazol-2-il)etil]-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-il}-4-oksobutil)etilo benzoatas (29 junginys) (a) Tirpalas, turintis 2-cianetilo propionato (100 g, 0,29 mol) etanolyje (65 ml), atšaldytas iki 0 °C temperatūros, o po to prisotintas vandenilio chlorido garais. Mišinys paliktas sušilti iki kambario temperatūros, maišytas 24 valandas, vėl atšaldytas iki 0 °C, ir vėl prisotintas vandenilio chlorido garais. Mišinys paliktas sušilti iki kambario temperatūros ir maišytas dar 24 valandas. Į mišinį pridėjus etileterio:heksano (1:1), gaunamos nuosėdos. Nuosėdos, nufiltruotos ir išdžiovintos vakuume, yra 2-(A/-etoksiamidino)etilo propionato hidrochloridas (119,6 g, 73 % išeiga) kaip balta kieta medžiaga; 1H-BMR (300 MHz, DMSO-de):2- (4- {2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4- oxobutyl) ethyl benzoate (Compound 29) (a) A solution of 2-cyanoethyl propionate (100 g, 0.29 mol) in ethanol (65 mL) was cooled to 0 ° C and then saturated with hydrogen chloride vapor. The mixture was allowed to warm to room temperature, stirred for 24 hours, cooled to 0 ° C again, and saturated with hydrogen chloride vapor. The mixture was allowed to warm to room temperature and stirred for another 24 hours. Addition of ethyl ether: hexane (1: 1) to the mixture gives a precipitate. The precipitate, filtered off and dried in vacuo, is 2- (N -ethoxyamidine) ethyl propionate hydrochloride (119.6 g, 73% yield) as a white solid; 1 H-NMR (300 MHz, DMSO):
12,5 (pi. s, 2H), 4,50 (kvartetas, 2H), 4,15 (m, 3H), 1,30 (m, 6H), 1,20 (tr, 3H).12.5 (pi. S, 2H), 4.50 (quartet, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1.20 (tr, 3H).
(b) Mišinys, sudarytas iš 3,4-diaminopiridino (51,7 g, 0,46 mol), 2-(Netoksiamidino)etilo propionato hidrochlorido (125 g, 0,69 mol) ir ledinės acto rūgšties (200 ml), šildytas 85 °C temperatūroje ir maišytas 18 valandų, o po to šildytas 120 °C temperatūroje ir maišytas papildomą valandą. Mišinys paliktas atšalti iki kambario temperatūros ir sukoncentruotas vakuume. Liekana neutralizuota pertekliumi 5 M vandeninio amonio hidroksido, o mišinys išekstrahuotas etilo acetatu. Organinis sluoksnis perplautas sočiu vandeniniu natrio hidrokarbonatu, o po to sočiu vandeniniu natrio chloridu, išdžiovintas (MgSO4), nufiltruotas ir sukoncentruotas vakuume, duoda 1H-imidazo[4,5c]piridin-2-etilo karboksilatą (60,4 g, 58 % išeiga); 1H-BMR (300 Mhz, CDCb): 9,00 (s,1H), 8,45 (d, 1H), 7,50 (d, 1 H), 4,25 (kvartetas, 2H), 3,90 (kvartetas, 1H), 1,75 (d, 3H), 1,25 (tr, 3H).(b) A mixture of 3,4-diaminopyridine (51.7 g, 0.46 mol), 2- (Netroxyamidine) ethyl propionate hydrochloride (125 g, 0.69 mol) and glacial acetic acid (200 ml), heated at 85 ° C and stirred for 18 hours and then heated at 120 ° C and stirred for an additional hour. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was neutralized with an excess of 5 M aqueous ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, dried (MgSO 4 ), filtered and concentrated in vacuo to give 1H-imidazo [4,5c] pyridine-2-ethyl carboxylate (60.4 g, 58%). yield); 1 H-NMR (300 MHz, CDCl 3): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (quartet, 2H), 3, 90 (quartet, 1H), 1.75 (d, 3H), 1.25 (tr, 3H).
(c) Mišinys, sudarytas iš 1/7-imidazo[4,5-c]piridin-2-etilo karboksilato (34,7 g, 158 mmol), trifluoracto rūgšties (50 ml) ir platinos oksido (2,5 g) Parr’o aparate hidrintas 344,7 kPa slėgyje 24 valandas, nufiltruotas ir sukoncentruotas vakuume. Alyvinga liekana ištirpinta minimaliame etanolio kiekyje ir į gautą tirpalą įpilta sauso vandenilio chlorido dioksane tirpalo (4 M, 120 ml, 475 mmol). į šj tirpalą įpiltas perteklius etileterio, gaunant nuosėdas. Nuosėdos nufiltruotos, išdžiovintos vakuume, duoda 1,4,6,7-tetrahidro-1W-imidazo[4,5-c]piridin-2-etilo karboksilato dihidrochloridą (30,7 g, 66 % išeiga); 1H-BMR (300 MHz, DMSO-de): 10,00 (pi. s, 2H), 4,35 (kvartetas, 1 H), 4,20 (pi. s, 2H), 4,10 (m, 2H), 3,35 (m, 2H), 2,90 (pi. s, 2H), 1,55 (d, 3H), 1,15 (tr, 3H).(c) A mixture of 1/7-imidazo [4,5-c] pyridine-2-ethyl carboxylate (34.7 g, 158 mmol), trifluoroacetic acid (50 mL) and platinum oxide (2.5 g) Hydrogenated in a Parr apparatus at 344.7 kPa for 24 hours, filtered and concentrated in vacuo. The oily residue was dissolved in a minimum amount of ethanol and treated with dry hydrogen chloride in dioxane solution (4 M, 120 mL, 475 mmol). excess ethyl ether was added to this solution to give a precipitate. The precipitate was filtered off, dried in vacuo to give 1,4,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridine-2-ethyl carboxylate dihydrochloride (30.7 g, 66% yield); 1 H-NMR (300 MHz, DMSO-d 6): 10.00 (pi, 2H), 4.35 (quartet, 1H), 4.20 (pi, 2H), 4.10 (m , 2H), 3.35 (m, 2H), 2.90 (pi, 2H), 1.55 (d, 3H), 1.15 (tr, 3H).
(d) Mišinys, sudarytas iš 1,4,6,7-tetrahidro-1 /7-imidazo[4,5-c]piridin-2-etilo karboksilato dihidrochlorido (60,2 g, 0,20 mol), acetonitrilo (500 ml) ir diizopropiletilamino (100 ml, 0,60mol), atšaldytas iki 0 °C temperatūros ir maišytas, kol lėtai supilamas benzilchlorformiatas (58 ml, 0,40 mol). Mišinys paliktas lėtai atšilti iki kambario temperatūros, maišomas paildomas 16 valandų ir sukoncentruotas vakuume. Liekana ištirpinta etileteryje (500 ml) ir tirpalas perplautas 0,1 M vandeniniu vandenilio chloridu, sočiu natrio hidrokarbonatu ir sočiu natrio chloridu, išdžiovinta bevandeniu natrio sulfatu, nufiltruota ir sukoncentruota vakuume, duoda bespalvę alyvą. Liekana ištirpinta etanolyje (320 ml), gautas tirpalas atšaldytas iki 0 °C temperatūros, o po to lėtai pridedama natrio etoksido tirpalo etanolyje (2,6 M, 85 ml, 0,22 mol). Mišinys maišytas vieną valandą 0 °C temperatūroje ir po to pridedama vandenilio chlorido tirpalo dioksane (4 M, ml). Mišinys sukoncentruotas vakuume ir liekana ištirpinta etilo acetate (250 ml) ir sočiame vandeniniame natrio hidrokarbonate. Organinis sluoksnis atskirtas ir perplautas sočiu vandeniniu natrio chloridu, išdžiovintas bevandeniu natrio sulfatu, nufiltruotas ir sukoncentruota vakuume, duoda 5-benzil-2-etil-1,4,6,7tetrahidroimidazo[4,5-c]piridin-2,5-dikarboksilatą kaip geltoną amorfinę medžiagą (52 g, 72 % išeiga): 1H-BMR (300 MHz, DMSO-d6): 11,75 (pi. s, 1 H), 7,30 (s, 5H), 5,10 (s, 2H), 4,40 (pi. s, 2H), 4,05 (m, 2H), 3,75 (kvartetas, 1 H), 3,65 (pi. s, 2H), 1,40 (d, 3Η), 1,15 (tr, 3H).(d) A mixture of 1,4,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridine-2-ethyl carboxylate dihydrochloride (60.2 g, 0.20 mol), acetonitrile ( 500 mL) and diisopropylethylamine (100 mL, 0.60 mol) cooled to 0 ° C and stirred until benzyl chloroformate (58 mL, 0.40 mol) was added slowly. The mixture was allowed to warm slowly to room temperature, stirred for 16 hours, and concentrated in vacuo. The residue was dissolved in ethyl ether (500 mL) and the solution was washed with 0.1 M aqueous hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a colorless oil. The residue was dissolved in ethanol (320 mL), the resulting solution was cooled to 0 ° C, and then a solution of sodium ethoxide in ethanol (2.6 M, 85 mL, 0.22 mol) was added slowly. The mixture was stirred for one hour at 0 ° C and then a solution of hydrogen chloride in dioxane (4 M, ml) was added. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (250 mL) and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-benzyl-2-ethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-2,5-dicarboxylate. as a yellow amorphous material (52 g, 72% yield): 1 H-NMR (300 MHz, DMSO-d 6 ): 11.75 (ppm, 1H), 7.30 (s, 5H), δ 10 (s, 2H), 4.40 (pi, 2H), 4.05 (m, 2H), 3.75 (quartet, 1H), 3.65 (pi, 2H), 1, 40 (d, 3Η), 1.15 (tr, 3H).
(e) Mišinys, sudarytas iš 4-chlorbutirilchlorido (12,6 g, 89,2 mmol), tretbutanolio (25 ml), piridino (6,9 g, 86,5 mmol) ir 4-dimetilaminopiridino (1,0 g, 8,2 mmol), šildytas 50 °C temperatūroje sauso azoto atmosferoje 12 valandų, duodamas baltą suspensiją. Ši suspensija padalinta tarp etileterio (250 ml) ir vandens, organinis sluoksnis atskirtas ir paeiliui perplautas vandeniu, po to 0,1 M vandeniniu vandenilio chloridu, sočiu vandeniniu natrio karbonatu ir sočiu vandeniniu natrio chloridu, išdžiovinta bevandeniu magnio sulfatu, nufiltruota ir sukoncentruota vakuume iki bespalvės alyvos. Alyva, perdistiliuota prie 0,5 mm Hg stulpelio (51 °C), yra fref-butil-4-chlorbutiratas kaip bespalvis skystis (11,27 g, 73 % išeiga); 1H-BMR (300 MHz, CDCb): 3,60 (tr, 2H), 2,40 (tr, 2H), 2,10 (m, 2H), 1,45 (s, 9H).(e) A mixture of 4-chlorobutyryl chloride (12.6 g, 89.2 mmol), tert-butanol (25 mL), pyridine (6.9 g, 86.5 mmol) and 4-dimethylaminopyridine (1.0 g, 8.2 mmol), heated at 50 ° C under a dry nitrogen atmosphere for 12 hours, yielding a white suspension. The suspension was partitioned between ethyl ether (250 mL) and water, the organic layer was separated and washed successively with water, followed by 0.1 M aqueous hydrochloric acid, saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to colorless oils. The oil redistilled at a column of 0.5 mm Hg (51 ° C) is tert-butyl 4-chlorobutyrate as a colorless liquid (11.27 g, 73% yield); 1 H-NMR (300 MHz, CDCl 3): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H).
(f) Mišinys, sudarytas iš etilo salicilato (3,14 g, 18,9 mmol) ir cezio karbonato (6,2 g, 18,9 mmol), dimetilformamido (25 ml) ir 4-chlor-/ref-butilo butirato (4,08 g, 22,8 mmol), šildytas 70 °C temperatūroje ir maišytas 12 valandų. Mišinys padalintas tarp etileterio (100 ml) ir vandens, organinis sluoksnis atskirtas ir perplautas vandeniu (3 kartus), po to sočiu vandeniniu natrio chloridu, išdžiovinta bevandeniu magnio sukfatu, nufiltruotas ir sukoncentruotas vakuume iki bespalvės alyvos. Liekana gryninta silikagelio staigiąja chromatografija, naudojant gryną heksaną su (10:1) heksanu:etilo acetatu, gaunant 2-(3-irefbutoksikarbonilpropoksi)etilo benzoatą (3,6 g, 62 % išeiga); 1H-BMR (300 MHz, CDCb): 7,80 (d, 1H), 7,49 (tr, 1H), 7,00 (m, 2H), 4,40 (kvartetas, 2H), 4,10 (tr, 2H), 2,50 (tr, 2H), 2,10 (m, 2H), 1,45 (s, 9H), 1,40 (tr, 3H).(f) A mixture of ethyl salicylate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g, 18.9 mmol), dimethylformamide (25 mL) and 4-chloro-tert-butyl butyrate (4.08 g, 22.8 mmol), heated at 70 ° C and stirred for 12 h. The mixture was partitioned between ethyl ether (100 mL) and water, the organic layer was separated and washed with water (3 times), then with saturated aqueous sodium chloride, dried over anhydrous magnesium succinate, filtered and concentrated in vacuo to a colorless oil. The residue was purified by silica gel flash chromatography using pure hexane with (10: 1) hexane: ethyl acetate to give 2- (3-irefbutoxycarbonylpropoxy) ethyl benzoate (3.6 g, 62% yield); 1 H-NMR (300 MHz, CDCl 3): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (quartet, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).
(g) 2-(3-fref-Butoksikarbonilpropoksi)etilo benzoatas (3,60 g, 11,7 mmol) ilgiau nei valandą paveiktas kambario temperatūroje pertekliumi trifluoracto rūgšties. Tirpalas sukoncentruotas vakuume, o aliejinga liekana gryninta silikagelio staigiąja chromatografija, naudojant (10:1) heksaną:etilo acetatą su grynu etileteriu, gaunant 4-(2-etoksikarbonilfenoksi)butano rūgštį kaip bespalvę kristalinę kietą medžiagą (2,81 g, 95 % išeiga); 1H-BMR (300 MHz, CDCI3): 7,80 (d, 1H), 7,50 (tr, 1H), 7,00 (m, 2H), 4,40 (kvartetas, 2H), 4,15 (tr, 2H), 2,65 (tr, 2H), 2,20 (m, 2H), 1,40 (tr, 3H).(g) 2- (3-tert-Butoxycarbonylpropoxy) ethyl benzoate (3.60 g, 11.7 mmol) was treated with excess trifluoroacetic acid at room temperature for more than one hour. The solution was concentrated in vacuo and the oily residue was purified by silica gel flash chromatography using (10: 1) hexane: ethyl acetate with pure ethyl ether to give 4- (2-ethoxycarbonylphenoxy) butanoic acid as a colorless crystalline solid (2.81 g, 95% yield). ); 1 H-NMR (300 MHz, CDCl 3 ): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (quartet, 2H), 4, 15 (tr, 2H), 2.65 (tr, 2H), 2.20 (m, 2H), 1.40 (tr, 3H).
(h) Mišinys, sudarytas iš 2-etoksikarbonilmetil-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-etilo karboksilato (1,7 g, 4,8 mmol), N-(3,4diaminofenil)guanidino hidrochlorido (0,8 g, 4,0 mmol) ir dimetilformamido (2 ml), šildytas alyvos vonioje 185 °C temperatūroje ir maišytas azoto atmosferoje 2,5 valandos. Mišinys, atšaldytas iki kambario temperatūros ir išpiltas j maišomą acetonitrilą (150 ml), duoda nuosėdas. Nuosėdos, perplautos papildomu kiekiu acetonitrilo ir dietileterio (150 ml), nufiltruotos ir išdžovintos vakuume, duoda balkšvą medžiagą. Medžiaga, gryninta preparatyvine atvirkščių fazių HPLC, yra 2[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin5-benzilo karboksilatas kaip balta kieta medžiaga (1,0 g, 55 % išeiga); LRMS (ESI): C24H26N8O2. Išskaičiuota: 458,5; Rasta (MH+): 459,2.(h) A mixture of 2-ethoxycarbonylmethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-ethylcarboxylate (1.7 g, 4.8 mmol), N- (3,4-diaminophenyl) guanidine hydrochloride (0.8 g, 4.0 mmol) and dimethylformamide (2 mL) heated in an oil bath at 185 ° C and stirred under a nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature and poured into stirring acetonitrile (150 mL) to give a precipitate. The precipitate, washed with additional acetonitrile and diethyl ether (150 mL), filtered and dried in vacuo, gave an off-white solid. The material purified by reverse phase preparative HPLC is 2 [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-benzyl carboxylate white solid (1.0 g, 55% yield); LRMS (ESI): C 24 H 26 N 8 O 2 . Calculated: 458.5; Found (MH + ): 459.2.
(i) Mišinys, sudarytas iš 2-[1-(5-guanidino-1H-benzoimidazol-2-il)etilj1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-benzilo karboksilato (1,0 g, 2,2 mmol), 10 % paladžio ant anglies (0,5 g), tetrahidrofurano (50 ml) ir metanolio (50 ml), hidrintas vienos atmosferos slėgyje, perfiltruotas ir sukoncentruotas vakuume, duoda N- {2- [ 1,4,6,7-tetrah i d roimidazo [4,5-c] pi rid ίη-2-il) etil] -1 ft-benzoimidazol-5il}-guanidiną (0,69 g, 97 % išeiga); LRMS (ESI): Ci6H20N8. Išskaičiuota: 324,4; Rasta (MH+): 325,2.(i) A mixture of 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) -ethyl] -1,4,6,7-tetrahydro-imidazo [4,5-c] pyridine-5-benzylcarboxylate (1, 0 g, 2.2 mmol), 10% palladium on carbon (0.5 g), tetrahydrofuran (50 mL) and methanol (50 mL), hydrogenated at atmospheric pressure, filtered and concentrated in vacuo to give N- {2- [ 1,4,6,7-Tetrahydroimidazo [4,5-c] pyridyl-2-yl) ethyl] -1-benzoimidazol-5-yl} guanidine (0.69 g, 97% yield); LRMS (ESI): C 16 H 20 N 8 . Calculated: 324.4; Found (MH + ): 325.2.
(j) Mišinys, sudarytas iš 4-(2-etoksikarbonilfenoksi)butano rūgšties (155 mg, 0,61 mmol), PyBOP (360 mg, 0,69 mmol), hidroksibenzotriazolo hidrato (87 mg, 0,64 mmol), N-metilmorfolino (0,16 ml, 0,92 mmol) ir dimetilformamido (2,5 ml), maišytas kambario temperatūroje 10 minučių, o po to pridėta /7-(2-(1,4,6,7tetrahidroimidazo[4,5-c]piridin-2-il)etil]-lA7-benzoimidazol-5-il}-guanidino (203 mg,(j) A mixture of 4- (2-ethoxycarbonylphenoxy) butanoic acid (155 mg, 0.61 mmol), PyBOP (360 mg, 0.69 mmol), hydroxybenzotriazole hydrate (87 mg, 0.64 mmol), N -methylmorphorpholine (0.16 mL, 0.92 mmol) and dimethylformamide (2.5 mL) were stirred at room temperature for 10 minutes, and then 7- [2- (1,4,6,7-tetrahydroimidazo [4.5]) was added. -c] pyridin-2-yl) ethyl] -1,7-benzoimidazol-5-yl} guanidine (203 mg,
0,63 mmol). Mišinys maišytas kambario temperatūroje 3 valandas ir sukoncentruotas vakuume. Liekana ištirpinta 5 % vandeniniame acetonitrile, o produktas išgrynintas atvirkščių fazių HPLC. Grynos frakcijos sujungtos ir Ii of i lizuotos, yra 2-(4-{2-[1 -(5-guanidino-1 /7-benzoimidazol-2-il) eti l]-1,4,6,75 tetrahidroimidazo[4,5-c]piridin-5-il}-4-oksobutil)etilo benzoatas; LRMS (Biolon): C29H34N8O4. Išskaičiuota: 558,6; Rasta (MH+): 559,3.0.63 mmol). The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was dissolved in 5% aqueous acetonitrile and the product was purified by reverse phase HPLC. The pure fractions pooled and lysed are 2- (4- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -1,4,6,75 tetrahydroimidazo [4 , 5-c] pyridin-5-yl} -4-oxobutyl) ethyl benzoate; LRMS (Biolon): C 29 H 34 N 8 O 4. Calculated: 558.6; Found (MH + ): 559.3.
PAVYZDYSEXAMPLE
2-[1-(5-Hidroksi-1H-benzoimidazol-2-il)etil]-A/-[2-(2-metoksifenoksi)etil]-31 o metil-3H-benzoimidazol-5-karboksamidas (30 junginys) (a) fref-Butilo 2-hidroksietilkarbamato (25 ml, 161,6 mmol) tirpalas dichlormetane (60 ml) atšaldytas iki 0 °C temperatūros ir maišytas, kol pirma pridedamas diizopropiletilaminas (33,8 ml, 193,9 mmol), o po to sulašinamas mezilchloridas (13,7 ml, 177,8 mmol). Mišinys paliktas sušilti iki 23 °C temperatūros, maišytas 18 valandų, išpiltas j dichlormetaną (200 ml) ir perplautas vandeniniu vandenilio chloridu (3 M, 3 χ 25 ml) ir sočiu vandeniniu natrio hidrokarbonatu (2 χ 25 ml). Organinis sluoksnis atskirtas, išdžiovintas (MgSO4) ir sukoncentruotas vakuume, duoda fref-butilo 2-metilsulfoniloksietilkarbamatą (37,39 g, 97 % išeiga); MS (PB-PCI): C8H,7NO4S, m/e. Išskaičiuota: 239,08; Rasta (MH+): 240.2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -31 ° methyl-3 H -benzoimidazole-5-carboxamide (Compound 30) (a) A solution of tert -butyl 2-hydroxyethylcarbamate (25 mL, 161.6 mmol) in dichloromethane (60 mL) was cooled to 0 ° C and stirred until diisopropylethylamine (33.8 mL, 193.9 mmol) was first added and followed by the dropwise addition of mesyl chloride (13.7 mL, 177.8 mmol). The mixture was allowed to warm to 23 ° C, stirred for 18 hours, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3 M, 3 χ 25 mL) and saturated aqueous sodium bicarbonate (2 χ 25 mL). The organic layer was separated, dried (MgSO 4 ) and concentrated in vacuo to give tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield); MS (PB-PCI): C 8 H 7 NO 4 S, m / e. Calculated: 239.08; Found (MH + ): 240.
(b) Ličio bromidas (136 g, 1,56 mol) ištirintas tetrahidrofurane (600 ml) 0 °C temperatūroje. Mišinys paliktas sušilti iki 23 °C 18 valandų ir po to sukoncentruotas vakuume. Liekana ištirpinta heksane, o organinis sluoksnis plautas vandeniu ir sūrymu, išdžiovintas (Na2SO4) ir sukoncentruotas vakuume, duoda fref-butilo 2-brometilkarbamatą (33,48 g, 96 % išeiga) rudos alyvos pavidalu; MS (PB-PCI): C7H14BrNO2, m/e. Išskaičiuota: 224,10; Rasta (MH+): 225.(b) Lithium bromide (136 g, 1.56 mol) was dissolved in tetrahydrofuran (600 mL) at 0 ° C. The mixture was allowed to warm to 23 ° C for 18 hours and then concentrated in vacuo. The residue was dissolved in hexane and the organic layer was washed with water and brine, dried (Na 2 SO 4 ) and concentrated in vacuo to afford fref-butyl 2-bromoethylcarbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI): C 7 H 14 BrNO 2 , m / e. Calculated: 224.10; Found (MH + ): 225.
(c) Mišinys, sudarytas iš 2-metoksifenolio (9,8 ml, 89,3 mmol), dimetilformamido (100 ml) ir kalio karbonato (61,5 g, 445 mmol), maišytas 23 °C temperatūroje, kol sudedamas fref-butilo 2-brometilkarbamatas (20 g, 89,3 mmol).(c) A mixture of 2-methoxyphenol (9.8 mL, 89.3 mmol), dimethylformamide (100 mL) and potassium carbonate (61.5 g, 445 mmol) was stirred at 23 ° C until fref. butyl 2-bromoethylcarbamate (20 g, 89.3 mmol).
Mišinys maišytas 24 valandas, o po to išpiltas į etileterio.’heksano (1:1, 400 ml) mišinj ir plautas vandeniu (5 χ 50 ml). Vandeninis sluoksnis išekstrahuotas etileterio:heksano (1:1, 3 χ 40 ml) mišiniu, o sujungti organiniai sluoksniai išdžiovinti (Na2SO4) ir sukoncentruoti vakuume, duoda fref-butilo 2-(2metoksifenoksi)etilkarbamatą (23,22 g, 97 % išeiga) geltonos alyvos pavidalu; MS (PB-PCI): C14H21NO4, m/e. Išskaičiuota: 267,32; Rasta (MH+): 268.The mixture was stirred for 24 h and then poured into ethyl ether: hexane (1: 1, 400 mL) and washed with water (5 x 50 mL). The aqueous layer was extracted with ethyl ether: hexane (1: 1, 3 x 40 mL) and the combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo to give tert-butyl 2- (2-methoxyphenoxy) ethylcarbamate (23.22 g, 97%). % yield) as a yellow oil; MS (PB-PCI): C 14 H 21 NO 4 , m / e. Calculated: 267.32; Found (MH + ): 268.
(d) fref-Butilo 2-(2-metoksifenoksi)etilkarbamatas (23,8 g, 89 mmol) atšaldytas iki 0 °C temperatūros ir maišytas, kol sulašintas trifluoracto rūgšties: dichlormetano (1:1, 40 ml) mišinys. Mišinys paliktas sušilti iki 23 °C, maišytas 2 valandas ir sukoncentruotas vakuume. Liekana sugrąžinta j dichlormetaną (100 ml), o tirpalas plautas sočiu natrio hidrokarbonatu (3 χ 20 ml) ir vandeniniu natrio hidroksidu (10 %, 3 χ 20 ml), išdžiovintas (Na2SO4), nufiltruotas ir sukoncentruotias vakuume, duoda 2-(2-metoksifenoksi)etilaminą (13 g, 88 % išeiga) kaip šviesiai geltonos spalvos kietą medžiagą; MS (PB-PCI): C9Hi3NO2, m/e. Išskaičiuota: 167,21; Rasta (MH+): 168.(d) tert-Butyl 2- (2-methoxyphenoxy) ethylcarbamate (23.8 g, 89 mmol) was cooled to 0 ° C and stirred until a mixture of trifluoroacetic acid: dichloromethane (1: 1, 40 mL) was added. The mixture was allowed to warm to 23 ° C, stirred for 2 hours and concentrated in vacuo. The residue was returned to dichloromethane (100 mL) and the solution was washed with saturated sodium bicarbonate (3 x 20 mL) and aqueous sodium hydroxide (10%, 3 x 20 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give 2 - (2-methoxyphenoxy) ethylamine (13 g, 88% yield) as a light yellow solid; MS (PB-PCI): C 9 H 31 NO 2 , m / e. Calculated: 167.21; Found (MH + ): 168.
(e) Heterogeninis mišinys, sudarytas iš 3-metoksi-4nitrobenzenkaroksirūgšties (15,42 g, 78,2 mmol) ir tionilo chlorido (70 ml, 391 mmol), virintas su grįžtamuoju šaldytuvu vieną valandą. Tionilo chlorido perteklius nudistiliuotas, o liekana, sukoncentruota vakuume, duoda 3-metoksi-4nitrobenzoilo chloridą (16,8 g, 99 % išeiga) kaip šviesiai geltonos spalvos kietą medžiagą: MS (PB-PCI): C8H6CINO4, m/e. Išskaičiuota: 215,59; Rasta (MH+): 216.(e) A heterogeneous mixture of 3-methoxy-4-nitrobenzoic acid (15.42 g, 78.2 mmol) and thionyl chloride (70 mL, 391 mmol) was refluxed for one hour. The excess thionyl chloride was distilled off and the residue concentrated in vacuo to give 3-methoxy-4-nitrobenzoyl chloride (16.8 g, 99% yield) as a light yellow solid: MS (PB-PCI): C 8 H 6 CINO 4 , m / e. Calculated: 215.59; Found (MH + ): 216.
(f) Mišinys, sudarytas iš 2-(2-metoksifenoksi)etilamino (10g, 59,9 mmol), diizopropiletilamino (13,9 ml, 81,6 mmol) ir dichlormetano (80 ml), atšaldytas iki 0 °C temperatūros, o po to sulašintas 3-metoksi-4-nitrobenzoilo chlorido (11,76 g, 54,4 mmol) tirpalas dichlormetane (50 ml). Mišinys paliktas dvi valandas sušilti iki 23 °C temperatūros, užgęsintas vandeniniu vandenilio chloridu (3 M, 20 ml), plautas vandeniu (3 χ 20 ml), išdžiovintas (Na2SO4) ir sukoncentruotas vakuume, duoda /V-[2-(2-metoksifenoksi)etil]-3-metoksi-4-nitrobenzamidą (14 g, 74 % išeiga) kaip balkšvą kietą medžiagą; MS (PB-PCI): ϋΐ7Ηι8Ν2Ο6, m/e. Išskaičiuota: 346,34; Rasta (MH+): 347.(f) A mixture of 2- (2-methoxyphenoxy) ethylamine (10g, 59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) cooled to 0 ° C, followed by a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g, 54.4 mmol) in dichloromethane (50 mL). The mixture was allowed to warm to 23 ° C for two hours, quenched with aqueous hydrochloric acid (3 M, 20 mL), washed with water (3 x 20 mL), dried (Na 2 SO 4 ) and concentrated in vacuo to give / V- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (14 g, 74% yield) as an off-white solid; MS (PB-PCI):? 7? 2? 6 , m / e. Calculated: 346.34; Found (MH + ): 347.
(g) Mišinys, sudarytas iš /V-[2-(2-metoksifenoksi)etil]-3-metoksi-4nitrobenzamido (4,0 g, 11,6 mmol), vandeninio metilamino (40 % , 10 ml), užlydytame mėgintuvėlyje šildytas 4 valandas 11 °C temperatūroje, po to atšaldytas ir išpiltas į vandenį (25 ml). Praskiestas tirpalas paveiktas 3 M vandeniniu vandenilio chloridu duoda oranžinės spalvos kietą medžiagą. Ši kieta medžiaga nufiltruota, yra /V-[2-(2-metoksifenoksi)etil]-3-metilamino-4nitrobenzamidas (3,56 g, 89 % išeiga); MS (PB-PCI): C17H19N3O5, m/e. Išskaičiuota: 345,35; Rasta (MH+): 346.(g) A mixture of N- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol) in aqueous methylamine (40%, 10 mL) in a sealed tube. heated at 11 ° C for 4 h, then cooled and poured into water (25 mL). The diluted solution was treated with 3 M aqueous hydrochloric acid to give an orange solid. This solid was filtered off, and was N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI): C 17 H 19 N 3 O 5, m / e. Calculated: 345.35; Found (MH + ): 346.
(h) Mišinys, sudarytas iš /V-[2-(2-metoksifenoksi)etil]-3-metilamino-4nitrobenzamido (3,56 g, 10,3 mmol), suspenduoto paladžio ant anglies (10 %, 0,5 g) metanolyje (100 ml) ir tetrahidrofurano (50 ml), maišytas azoto atmosferoje įprastame slėgyje 2,5 valandos. Mišinys perfiltruotas, o tirpalas sukoncentruotas vakuume, duoda 4-amino-A/-[2-(2-metoksifenoksi)etil]-3-metilaminobenzamidą (3,37 g, 100 % išeiga); MS (PB-PCI): Ci7H2iN3O3, m/e. Išskaičiuota: 315,37; Rasta (MH+): 316.(h) Mixture of N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol) suspended in palladium on carbon (10%, 0.5 g) ) in methanol (100 mL) and tetrahydrofuran (50 mL), stirred under nitrogen at normal pressure for 2.5 hours. The mixture was filtered and the solution concentrated in vacuo to give 4-amino-N- [2- (2-methoxyphenoxy) ethyl] -3-methylaminobenzamide (3.37 g, 100% yield); MS (PB-PCI) H 7 Cl 2 IN 3 O 3 m / e. Calculated: 315.37; Found (MH + ): 316.
(i) Mišinys, turintis 4-amino-3-nitrofenolio (5,0 g, 32,4 mmol), paladžio ant anglies (10 %, 1,0 g) ir metanolio (50 ml), Parr’o aparate hidrintas 344,7 kPa slėgyje 3 valandas, perfiltruotas per celitą ir sukoncentruotas vakuume, duoda 3,4-diaminofenolj (4,02 g, 91 % išeiga) kaip tamsios spalvos kietą medžiagą; MS (PB-PCI): C6H8N2O, m/e. Išskaičiuota: 124,16; Rasta (MH+); 125.(i) A mixture of 4-amino-3-nitrophenol (5.0 g, 32.4 mmol), palladium on carbon (10%, 1.0 g) and methanol (50 mL) hydrogenated in a Parr apparatus 344 , At 7 kPa for 3 hours, filtered through celite and concentrated in vacuo to give 3,4-diaminophenol (4.02 g, 91% yield) as a dark colored solid; MS (PB-PCI): C 6 H 8 N 2 O, m / e. Calculated: 124.16; Rasta (MH + ); 125.
G) Mišinys, turintis 3,4-diaminofenolio (3,661 g, 29,5 mmol), 2-(/Vetoksiamidino)etilo propionato (7,423 g, 38,4 mmol) ir etanolio (30 ml), virintas su grįžtamuoju šaldytuvu 6 valandas ir sukoncentruotas vakuume. Liekana, ištirpinta etilo acetate (200 ml) ir tirpalas plautas sočiu vandeniniu natrio hidrokarbonatu (3 χ 20 ml) ir sūrymu (1 χ 20 ml), išdžiovintas (MgSO4) ir sukoncentruotas vakuume, duoda 2-(5-hidroksi-1H-benzoimidazol-2-il)etilo propionatą (6,3 g, 91 % išeiga) kaip tamsios spalvos kietą medžiagą. Ši medžiaga gryninta silikagelio staigiąja chromatografija (100 % etilo acetatas); MS (PB-PCI): Ci2H)4N2O3, m/e. Išskaičiuota: 234,28; Rasta (MH+): 235.G) A mixture of 3,4-diaminophenol (3.661 g, 29.5 mmol), 2 - (/ vethoxamidine) ethyl propionate (7.423 g, 38.4 mmol) and ethanol (30 mL) was refluxed for 6 hours. and concentrated in vacuo. The residue, dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (3 x 20 mL) and brine (1 x 20 mL), dried (MgSO 4 ) and concentrated in vacuo, gave 2- (5-hydroxy-1H benzoimidazol-2-yl) ethyl propionate (6.3 g, 91% yield) as a dark colored solid. This material was purified by silica gel flash chromatography (100% ethyl acetate); MS (PB-PCI): C 12 H 14 N 2 O 3 , m / e. Calculated: 234.28; Found (MH + ): 235.
(k) Mišinys, turintis 2-(5-hidroksi-1A7-benzoimidazol-2-il)etilo propionato (148 mg, 0,63 mmol), 4-amino-A/-[2-(2-metoksifenoksi)etil]-356 metilaminobenzamido (200 mg, 0,63 mmol) ir 1,3-dimetil-3,4,5,6-tetrahidro-2(1H)pirimidono (0,5 ml), maišytas kambario temperatūroje iki taps homogenišku, azoto atmosferoje vakuume degazuotas ir sukoncentruotas šildant 170 °C temperatūroje 2 valandas. Liekana atšaldyta iki kambario temperatūros ir perplauta etileterio pertekliumi. Susidariusi amorfinė medžiaga patalpinta į 50 % vandeninį acetonitrilą ir išgryninta preparatyvine atvirkščių fazių HPLC (2-50 % CH3CN/H2O), duoda 2- [ 1 - (5-hid roksi-1 W-benzoimidazol-2-il) etil]-N- [2-(2metoksifenoksi)etilj-3-metil-3/7-benzoimidazol-5-karboksamidą (40 mg, 13 % išeiga) kaip šviesiai rožinę kietą medžiagą; MS (Biolon): C27H27N5O4, m/e. Išskaičiuota: 485,59; Rasta (MH+): 486.(k) Mixture containing 2- (5-hydroxy-1β-benzoimidazol-2-yl) ethyl propionate (148 mg, 0.63 mmol), 4-amino-N- [2- (2-methoxyphenoxy) ethyl] -356 methylaminobenzamide (200 mg, 0.63 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidone (0.5 mL), stirred at room temperature until homogeneous under nitrogen vacuum degassed and concentrated by heating at 170 ° C for 2 hours. The residue was cooled to room temperature and washed with excess ethyl ether. The resulting amorphous material was taken up in 50% aqueous acetonitrile and purified by reverse phase preparative HPLC (2-50% CH 3 CN / H 2 O) to give 2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl). ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (40 mg, 13% yield) as a light pink solid; MS (Biolon): C 27 H 27 N 5 O 4, m / e. Calculated: 485.59; Found (MH + ): 486.
Sintetinant kaip 8 pavyzdyje, gauti tokie išradimo junginiai:Synthesized as in Example 8, the following compounds of the invention were obtained:
2-(2-{2-[1-(5-fluor-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)metilo benzoatas (31 junginys); MS (Biolon): C28H26N5O4F, m/e. Išskaičiuota: 515,54; Rasta: 516 (MH+);2- (2- {2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) methyl benzoate (Compound 31); MS (Biolon): C 28 H 26 N 5 O 4 F, m / e. Calculated: 515.54; Found: 516 (MH + );
2-(2-{2-[1-(5-fluor-1/7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino}etoksi)benzenkarboksirūgštis (32 junginys); MS (Biolon): C27H24N5O4F, m/e. Išskaičiuota: 501,52; Rasta: 502,1 (MH+);2- (2- {2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 32); MS (Biolon): C 27 H 24 N 5 O 4 F, m / e. Calculated: 501.52; Found: 502.1 (MH + );
2-(2-{2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimazol-5ilkarbonilamino}etoksi)etilo benzoatas (33 junginys); MS (Biolon): C29H29N5O5, m/e. Išskaičiuta: 527,58; Rasta: 528,1 (MH+);2- (2- {2- [1- (5-Hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 33); MS (Biolon): C 29 H 29 N 5 O 5, m / e. Calculated: 527.58; Found: 528.1 (MH + );
2-(2-{2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3W-benzoimazol-5ilkarbonilamino}etoksi)benzenkarboksirūgštis (34 junginys); MS (Biolon): C27H25N5O5, m/e. Išskaičiuota: 499,53; Rasta: 500,1 (MH+);2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 34); MS (Biolon): C 27 H 25 N 5 O 5, m / e. Calculated: 499.53; Found: 500.1 (MH + );
/V-etil-2-[1-(5-hidroksi-1F/-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol5-karboksamidas (35 junginys); MS (Biolon): C2OH21N5O2, m/e. Išskaičiuota: 363,42; Rasta: 364,1 (MH+);N-ethyl-2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 35); MS (Biolon): C 2 OH 21 N 5 O 2, m / e. Calculated: 363.42; Found: 364.1 (MH + );
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-N-(2-metoksietil)-3-metil-3Hbenzoimidazol-5-karboksamidas (36 junginys); MS (Biolon) C21H23N5O3, m/e. 393,45; Rasta: 394,1 (MH+);2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- (2-methoxyethyl) -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 36); MS (Biolon) C 21 H 23 N 5 O 3, m / e. 393.45; Found: 394.1 (MH + );
2- (2-{2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol5-ilkarbonilamino}etoksi)butilo benzoatas (37 junginys); MS (Biolon): Ο3ιΗ33Ν5Ο5, m/e. Išskaičiuota: 555,64; Rasta: 555,7 (MH+);2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) butyl benzoate (Compound 37); MS (Biol) 3 ιΗ33Ν Ο 5 Ο 5, m / e. Calculated: 555.64; Found: 555.7 (MH + );
3- {2-[1-(5-guanidino-1W-benzoimidazol-2-il)etil]-6-[2-(2metoksifenoksi)etilkarbamoil]benzimidazol-1 -ii} propan-1 -sulfonrūgštis (38 junginys); MS (LGMS): C30H35N3O6S, m/e. Išskaičiuota: 635,72; Rasta: 635,4 (MH+);3- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzimidazol-1-yl} propane-1-sulfonic acid (Compound 38); MS (LGMS): C 30 H 35 N 3 O 6 S, m / e. Calculated: 635.72; Found: 635.4 (MH + );
A/-[2-(2-etoksifenoksi)etil]-2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3metil-3/-/-benzoimidazol-5-karboksamidas (39 junginys); MS (Biolon): C28H29N5O4, m/e. Išskaičiuota: 499,58; Rasta: 500,4 (MH+);N- [2- (2-Ethoxyphenoxy) ethyl] -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 39) ); MS (Biolon): C 28 H 29 N 5 O 4, m / e. Calculated: 499.58; Found: 500.4 (MH + );
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-A/-[2-(2-izopropoksifenoksi)etil]3-metil-3ft-benzoimidazol-5-karboksamidas (40 junginys); MS (Biolon): C29H31N5O4, m/e. Išskaičiuota: 513,61; Rasta: 514,5 (MH+);2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxyphenoxy) ethyl] 3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 40); MS (Biolon): C 29 H 31 N 5 O 4, m / e. Calculated: 513.61; Found: 514.5 (MH + );
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-propoksifenoksi)etil]-3H-benzoimidazol-5-karboksamidas (41 junginys); MS (Biolon): C29H3iN5O4l m/e. Išskaičiuota: 513,61; Rasta: 514,2 (MH+);2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-propoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 41) ; MS (Biol) C29H3iN 4l 5 O m / e. Calculated: 513.61; Found: 514.2 (MH + );
2-(2-{2-[1-(5-hidroksi-1W-benzoimidazol-2-il)etil]-3-metil-3A/-benzoimidazol5-ilkarbonilamino}etoksi)propilo benzoatas (42 junginys): MS (ESI): C3oH31N505, m/e. Išskaičiuota: 541,61; Rasta: 542,2 (MH+);2- (2- {2- [1- (5-Hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 N-benzoimidazol-5-ylcarbonylamino} ethoxy) propyl benzoate (Compound 42): MS (ESI) ): C 3 H 31 N 5 0 5 , m / e. Calculated: 541.61; Found: 542.2 (MH + );
2-(2-(2- [1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/-/-benzoimidazol5-ilkarbonilamino}etoksi)izobutilo benzoatas (43 junginys); MS (Biolon): θ3ΐΗ33Ν5θ5, m/e. Išskaičiuota: 555,64; Rasta: 556,3 (MH+);2- (2- (2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) isobutyl benzoate (Compound 43); MS (Biol) θ3ΐΗ 3Ν5θ5 3, m / e. Calculated: 555.64; found: 556.3 (MH +);
4- {2-[1-(5-hidroksi-1A/-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilaminoetilo butiratas (44 junginys): MS (Biolon): C24H27N5O4, m/e. Išskaičiuota: 449,51; Rasta: 449,9 (MH+);4- {2- [1- (5-Hydroxy-1 N-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylaminoethyl butyrate (Compound 44): MS (Biolon): C24H27N5O4, m. / e. Calculated: 449.51; Found: 449.9 (MH + );
4-{2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3W-benzoimidazol-5ilkarbonilaminojbutano rūgštis (45 junginys); MS (Biolon): C22H23N5O4, m/e. Išskaičiuota: 421,46; Rasta: 422,1 (MH+);4- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino] butanoic acid (Compound 45); MS (Biolon): C 22 H 23 N 5 O 4, m / e. Calculated: 421.46; Found: 422.1 (MH + );
2-(2-{2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol5-ilkarbonilamino}etoksi)izopropilo benzoatas (46 junginys); MS (ESI): C30H31N5O5, m/e. Išskaičiuota: 541,61; Rasta: 542,2 (MH+);2- (2- {2- [1- (5-Hydroxy-1,7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) isopropyl benzoate (Compound 46); MS (ESI): C 30 H 31 N 5 O 5, m / e. Calculated: 541.61; Found: 542.2 (MH + );
A/-{2-[2-(1-etilpropoksi)fenoksi]etil}-2-[1-(5-hidroksi-1H-benzoimidazol-2il)etil]-3-metil-3H-benzoimidazol-5-karboksamidas (47 junginys); MS (Biolon):N- {2- [2- (1-ethylpropoxy) phenoxy] ethyl} -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide ( Compound 47); MS (Biolon):
C3iH3sN5O4> m/e. Išskaičiuota: 541,65; Rasta: 542,5 (MH+);C 31 H 35 N 5 O 4> m / e. Calculated: 541.65; Found: 542.5 (MH + );
2-(2-{2-[1-(5-fluor-1W-benzoimidazol-2-il)etil]-3-metil-3A7-benzoimidazol-5ilkarbonilamino}etoksi)etilo benzoatas (48 junginys); MS (Biolon): C29H28N5O4F, m/e. Išskaičiuota: 529,57; Rasta: 529,5 (MH+);2- (2- {2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3β-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 48); MS (Biolon): C 29 H 28 N 5 O 4 F, m / e. Calculated: 529.57; Found: 529.5 (MH + );
2-(2-{2-[1'(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol5-ilkarbonilamino}etoksi)-2-metoksietilo benzoatas (49 junginys); MS (Biolon): C30H31N5O6, m/e. Išskaičiuota: Išskaičiuota: 557,61; Rasta: 558,2 (MH+);2- (2- {2- [1 '(5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) -2-methoxyethyl benzoate (Compound 49) ; MS (Biolon): C 30 H 31 N 5 O 6, m / e. Withheld: Withheld: 557.61; Found: 558.2 (MH + );
/V-(3-metoksipropil)-2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-karboksamidas (50 junginys); MS (Biolon): C22H25N5O3, m/e. Išskaičiuota: 407,47; Rasta: 408,0 (MH+);N - (3-methoxypropyl) -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 50); MS (Biolon): C 22 H 25 N 5 O 3, m / e. Calculated: 407.47; Found: 408.0 (MH + );
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-A/-[2-(2-metoksimetilfenoksi)etil]3-metil-3/7-benzoimidazol-5-karboksamidas (51 junginys); MS (Biolon): C2eH29N5O4, m/e. Išskaičiuota: 499,57; Rasta: 499,8 (MH+);2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxymethylphenoxy) ethyl] 3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 51) ); MS (Biolon): C 29 H 29 N 5 O 4 , m / e. Calculated: 499.57; Found: 499.8 (MH + );
/V-[2-(2-etoksimetilfenoksi)etil]-2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]3-metil-3/7-benzoimidazol-5-karboksamidas (52 junginys); MS (Biolon): C29H31N5O4, m/e. Išskaičiuota: 513,60; Rasta: 514,1 (MH+);N - [2- (2-Ethoxymethylphenoxy) ethyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 52) ); MS (Biolon): C 29 H 31 N 5 O 4, m / e. Calculated: 513.60; Found: 514.1 (MH + );
2-(2-{2-[1-(6-fluor-5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (53 junginys); MS (ESI): C^FfeaNsOsF, m/e. Išskaičiuota: 545,57; Rasta: 546,3 (MH+);2- (2- {2- [1- (6-Fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 53) ); MS (ESI): mass calcd. Calculated: 545.57; Found: 546.3 (MH + );
2-(2-{2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol5-ilkarbonilamino}etoksi)cikloheksanetilo karboksilatas (54 junginys); MS (Biolon): C29H35N5O5, m/e. Išskaičiuota: 533,63; Rasta: 534 (MH+);2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) cyclohexanethyl carboxylate (Compound 54); MS (Biolon): C 29 H 35 N 5 O 5, m / e. Calculated: 533.63; Found: 534 (MH + );
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2propoksimetilfenoksi)etil]-3/7-benzoimidazol-5-karboksamidas (55 junginys); MS (Biolon): C30H33N5O4, m/e. Išskaičiuota: 527,62; Rasta: 527,6 (MH+);2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-propoxymethylphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 55) ; MS (Biolon): C 30 H 33 N 5 O 4 , m / e. Calculated: 527.62; Found: 527.6 (MH + );
2-[1-(5-hidroksi-1H-benzoirnidazol-2-il)etil]-N-[2-(2izopropoksimetilfenoksi)etil]-3-metil-3/7'benzoimidazoI-5-karboksamidas (56 junginys); MS (Biolon): C30H33N5O4, m/e. Išskaičiuota: 527,62; Rasta: 527,9 (MH+);2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3,7'-benzoimidazole-5-carboxamide (Compound 56); MS (Biolon): C 30 H 33 N 5 O 4, m / e. Calculated: 527.62; Found: 527.9 (MH + );
2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-A/-{2-[2-(2metoksietoksimetil)fenoksi]etil}-3-metil-3/-/-benzoimidazol-5-karboksamidas, (57 junginys); MS (Biolon): C3oH33N505l m/e. Išskaičiuota: 543,62; Rasta: 543,4 (MH+);2- [1- (5-Hydroxy-1,7-benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3-methyl-3 H -benzoimidazole -5-carboxamide, (compound 57); MS (Biolon): C 30 H 33 N 5 O 5 m / e. Calculated: 543.62; Found: 543.4 (MH + );
2-(1-(1 W-benzoimidazol-2-il)etil]-/V-[2-(2-metoksimetilfenoksi)etil]-3-metil3/7-benzoimidazol-5-karboksamidas (58 junginys); MS (Biolon): C28H29N5O3l m/e. Išskaičiuota: 483,57; Rasta: 484 (MH+);2- (1- (1H-Benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 58); MS ( Biol): C 28 H 29 N 5 O 3l m / e Calcd: 483.57 Found: 484 (MH + );
A/-[2-(2-etoksimetilfenoksi)etil]-2-[1-(1/7-benzoimidazol-2-il)etil]-3-metil3H-benzoimidazol-5-karboksamidas (59 junginys); MS (Biolon): C29H3iN5O3, m/e. Išskaičiuota: 497,6; Rasta: 498,3 (MH+);N- [2- (2-Ethoxymethyl-phenoxy) -ethyl] -2- [1- (1H-benzoimidazol-2-yl) -ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 59); MS (Biolon): C 29 H 31 N 5 O 3 , m / e. Calculated: 497.6; Found: 498.3 (MH + );
2-(1-(1H-benzoimidazol-2-il)etil]-3-metil-A/-(2-(2-propoksimetilfenoksi)etil]3W-benzoimidazol-5-karboksamidas (60 junginys): MS (Biolon): C3oH33N503) m/e. Išskaičiuota: 511,62; Rasta: 511,5 (MH+);2- (1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-N- (2- (2-propoxymethylphenoxy) ethyl] 3 H -benzoimidazole-5-carboxamide (Compound 60): MS (Biolon) : C 30 H 33 N 5 O 3) m / e calcd: 511.62; Found: 511.5 (MH + );
2-[1-(1H-benzoimidazol-2-il)etil]-/V-[2-(2-izopropoksimetilfenoksi)etil]-3metil-3H-benzoimidazol-5-karboksamidas (61 junginys): MS (Biolon): C3oH33N503, m/e. Išskaičiuota: 511,62; Rasta: 511,6 (MH+);2- [1- (1H-Benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 61): MS (Biolon): C 3 H 33 N 50 3 , m / e. Calculated: 511.62; Found: 511.6 (MH + );
2-[1-(1H-benzoimidazol-2-il)etil]-/V-{2-[2-(2-metoksietoksimetil)fenoksi]etil}3-metil-3H-benzoimidazol-5-karboksamidas (62 junginys); MS (Biolon): C3oH33N504, m/e. Išskaičiuota: 527,62; Rasta: 5277 (MH+);2- [1- (1H-Benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} 3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 62) ; MS (Biol) C 3 oH 33 N 5 0 4, m / e. Calculated: 527.62; Found: 5277 (MH + );
2-(1-(5-hidroksi-1W-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-morfolin-4ilfenoksi)etil]-3A/-benzoimidazol-5-karboks.amidas (63 junginys); MS (Biolon): C3oH32N604l m/e. Išskaičiuota: 540,73; Rasta: 541,8 (MH+);2- (1- (5-Hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-morpholin-4-ylphenoxy) ethyl] -3 N -benzoimidazole-5-carboxyl. amide (Compound 63) MS (Biolon): C 30 H 32 N 6 O 4l m / e Calcd: 540.73; Found: 541.8 (MH + );
/V-(2-fenilsulfoniletil)-2-[1 -(5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-karboksamidas (64 junginys); MS (Biolon): C26H25N5O4S, m/e. Išskaičiuota: 503,59; Rasta: 504,2 (MH+);N - (2-Phenylsulfonylethyl) -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 64); MS (Biolon): C 26 H 25 N 5 O 4 S, m / e. Calculated: 503.59; Found: 504.2 (MH + );
2-(2-{2-[1-(6-fluor-5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi]benzkarboksirūgštis (65 junginys); MS (ESI): C27H24N5O5F, m/e. Išskaičiuota: 517,52; Rasta: 518,2 (MH+);2- (2- {2- [1- (6-Fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy] benzoic acid (Compound 65) MS (ESI): C 27 H 24 N 5 O 5 F, m / e Calcd: 517.52 Found: 518.2 (MH + );
2-hidroksi-5-{2-[1 -(5-htdroksi-1 /7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etilo benzoatas (66 junginys); MS (Biolon): C27H25N5O5, m/e. Išskaičiuota: 499,52; Rasta: 500,2 (MH+);2-Hydroxy-5- {2- [1- (5-hydroxy-1,7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethyl benzoate (Compound 66); MS (Biolon): C 27 H 25 N 5 O 5 , m / e. Calculated: 499.52; Found: 500.2 (MH + );
2-[1-(5-fluor-1H-benzoimidazol-2-il)etilj-3-metil-/V-[2-(2-morfolin-4ilfenoksi)etil]-3/7-benzoimidazol-5-karboksamidas (67 junginys); MS (Biolon):2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-morpholin-4-ylphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide ( Compound 67); MS (Biolon):
CaoHaiNsOaF, m/e. Išskaičiuota: 542,62; Rasta: 543,4 (MH+);CaoHaiNsOaF, m / e. Calculated: 542.62; Found: 543.4 (MH + );
A/-(2-fenilsulfoniletil)-2-[1-(5-fluor-1F/-benzoimidazol-2-il)etiij-3-metil3W-benzoimidazol-5-karboksamidas (68 junginys); MS (Biolon): C26H24N5O3FS, m/e. Išskaičiuota: 505,58; Rasta: 506,5 (MH+);N - (2-Phenylsulfonylethyl) -2- [1- (5-fluoro-1 H -benzoimidazol-2-yl) ethyl] 3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 68); MS (Biolon): C 26 H 24 N 5 O 3 FS, m / e. Calculated: 505.58; Found: 506.5 (MH + );
2-(-2-(2-(1-(4,6-difluor-5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimida2ol-5-ilkarbonilamino}etoksi)etilo benzoatas (69 junginys); MS (Biolon): C29H27N5O5F2, m/e. Išskaičiuota: 563,52; Rasta: 563,4 (MH+);2 - (- 2- (2- (1- (4,6-Difluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (69 MS (Biolon): C 29 H 27 N 5 O 5 F 2, m / e Calcd: 563.52; Found: 563.4 (MH + );
2-(2-{2-[1-(4,6-difluor-5-hidroksi-1/-/-benzoimidazol-2-iI)etilj-3-metil-3/9benzoimidazol-5-ilkarbonilamino)etoksi)benzkarboksirūgštis (70 junginys); MS (Biolon): C27H23N5O5F2, m/e. Išskaičiuota: 536,51; Rasta: 563 (MH+);2- (2- {2- [1- (4,6-Difluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3/9-benzoimidazol-5-ylcarbonylamino) ethoxy) benzoic acid (Compound 70); MS (Biolon): C 27 H 23 N 5 O 5 F 2, m / e. Calculated: 536.51; Found: 563 (MH + );
2-(-2-(2-(1-(4,6-difIuor-5-imidazol-1-iI-1Ay-benzoimidazol-2-il)etilj-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (71 junginys); MS (Biolon): C32H29N7O4F2, m/e. Išskaičiuota: 613,62; Rasta: 614,3 (MH+);2 - (- 2- (2- (1- (4,6-Difluoro-5-imidazol-1-yl-1A) -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 71) MS (Biolon): C 32 H 29 N 7 O 4 F 2, m / e Calcd: 613.62; Found: 614.3 (MH + );
2-[1-(5-guanidino-1A7-benzoimidazol-2-il)etil]-3-metil-/V-(2-[2-(3-metil[1,2,4]oksadiazol-5-il)fenoksi]etil}-3A/-benzoimidazol-5-karboksamidas (72 junginys); MS (Biolon): C30H30N10O3, m/e. Išskaičiuota: 578,63; Rasta: 579,4 (MH+); ir2- [1- (5-guanidino-1β, 7-benzoimidazol-2-yl) ethyl] -3-methyl- N - (2- [2- (3-methyl [1,2,4] oxadiazol-5-yl) ) phenoxy] ethyl} -3 N-benzoimidazole-5-carboxamide (Compound 72) MS (Biolon): C 30 H 30 N 10 O 3, m / e calcd: 578.63, Found: 579.4 (MH + ), and
2-[1 -(5-imidazol-1 -i 1-1 H-benzoimidazol-2-il)etil]-3-metil-A/-{2-[2-(3metil(1,2,4]oksadiazol-5-il)fenoksi]etil}-3H-benzoimidazol-5-karboksamidas (73 junginys); MS (Biolon): C32H29N9O3, m/e. Išskaičiuota: 587,64; Rasta: 588,2 (MH+).2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- {2- [2- (3-methyl (1,2,4] oxadiazole) -5-yl) phenoxy] ethyl} -3 H -benzoimidazole-5-carboxamide (Compound 73) MS (Biolon): C 32 H 29 N 9 O 3, m / e calcd: 587.64; Found: 588.2 (MH + ).
PAVYZDYSEXAMPLE
2-(2-(2-(1 -(5-(1 -lminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c] piridin-2il]etil}-3-metil-3H-benzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis (74 junginys) (a) 3,4-Diaminopiridino (51,7 g, 0,46 mol) tirpalas acto rūgštyje (400 ml) šildytas 85 °C temperatūroje, o po to sudedamas metil-1 -iminodietilo malonatas (125 g, 0,60 mol) per tris lygias porcijas 6-ių valandų laikotarpyje. Mišinys šildytas 85 °C temperatūroje 12 valandų ir 120 °C temperatūroje dar 1 valandą, atšaldytas ir sukoncentruotas sumažintame slėgyje. Liekana atšaldyta iki 0 °C ir neutralizuota 5 N amonio hidroksidu. Vandeninis sluoksnis išekstrahuotas,keletą kartų etilo acetatu, o sujungti ekstraktai plauti paeiliui natrio bikarbonatu ir natrio chloridu, išdžiovinti (NažSCU), nufiltruoti ir sukoncentruoti sumažintame slėgyje, duoda 2(1/7-imidazo[4,5-c]piridin-2-il)etilo propionatą (60,4 g, 58 % išeiga) į gintarą panašią kietą medžiagą. ’H-BMR (300 MHz, CDCI3), δ, m. d. : 9, 00 (s, 1H), 8,35 (d, 1H, J=9,4 Hz), 7,50 (d, 1H, J=9,4 Hz), 4,25 (m, 3H), 1,78 (d, 3H, J-7,8 Hz), 1,30 (t, 3H, J=4,7 Hz).2- (2- (2- (1- (5- (1-mininoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl) ethyl) -3 -methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 74) (a) A solution of 3,4-diaminopyridine (51.7 g, 0.46 mol) in acetic acid (400 mL) was heated to 85 ° C, followed by addition of methyl 1-iminodiethyl malonate (125 g, 0.60 mol) in three equal portions over a period of 6 hours, heated at 85 ° C for 12 hours and at 120 ° C for 1 hour, cooled and concentrated under reduced pressure. The residue was cooled to 0 ° C and neutralized with 5N ammonium hydroxide The aqueous layer was extracted several times with ethyl acetate and the combined extracts were washed successively with sodium bicarbonate and sodium chloride, dried (Na 2 SO 4), filtered and concentrated under reduced pressure (2). / 7-Imidazo [4,5-c] pyridin-2-yl) ethyl propionate (60.4 g, 58% yield) as an amber-like solid. 1 H-NMR (300 MHz, CDCl 3 ), δ, md : 9.00 (s, 1H), 8.35 (d, 1H, J = 9.4 Hz), 7.50 (d, 1H, J = 9.4 Hz), 4.25 (m, 3H) , 1.78 (d, 3H, J = 7.8 Hz), 1.30 (t, 3H, J = 4.7 Hz).
(b) 2-(1H-imidazo[4,5-c]piridin-2-il)etilo propionato (60,4 g, 0,28 mol) tirpalas trifluoracto rūgštyje (100 ml) hidrintas 2 dienas 344,7 kPa slėgyje, esant platinos (IV) oksidui (5 g). Mišinys nufiltruotas ir sukoncentruotas sumažintame slėgyje. Liekana atšaldyta iki 0 °C, paveikta 4 M HCI/dioksanu, suspenduota j eterį, nufiltruota ir išdžiovinta. Tirpalai, turintys nuosėdų (15-20 g kiekvienas) naujoje trifluoracto rūgštyje (50 ml kiekvienas) hidrinti 24 valandas 344,7 kPa slėgyje, esant platinos (IV) oksidui (5 g kiekvienas). Mišiniai nufiltruoti ir sukoncentruoti sumažintame slėgyje. Liekanos azeotropiškai džiovintos tolueno/etanolio mišiniu ~ 1:1, 4 M HCI/dioksanu, suspenduotos į eterį, nufiltruotos ir išdžiovintos vakuume, duoda 2-(4,5,6,7-tetrahidroimidazo[4,5c]piridin-2-il)etilo propionato dihidrochloridą (61,80 g, 75 % išeiga); 1H-BMR (300 MHz, DMSO-d6), δ, m. d.: 10, 00 (pi. s, 2H), 4,35 (kvartetas, 1H, J=7,1 Hz), 4,25 (pi. s, 2H), 4,15 (m, 2H), 3,35 (m, 2H), 2,90 (pi. s, 2H), 1,60 (d, 3H, J=7,1 Hz), 1,20 (t, 3H, J=6,9 Hz).(b) A solution of 2- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl propionate (60.4 g, 0.28 mol) in trifluoroacetic acid (100 mL) was hydrogenated for 2 days at 344.7 kPa. , in the presence of platinum (IV) oxide (5 g). The mixture was filtered and concentrated under reduced pressure. The residue was cooled to 0 ° C, treated with 4 M HCl / dioxane, slurried in ether, filtered and dried. Solutions containing a precipitate (15-20 g each) in hydrogenated trifluoroacetic acid (50 ml each) were pressurized for 24 hours at 344.7 kPa in the presence of platinum (IV) oxide (5 g each). The mixtures were filtered off and concentrated under reduced pressure. The residue was azeotropically dried with toluene / ethanol ~ 1: 1, 4 M HCl / dioxane, slurried in ether, filtered and dried in vacuo to give 2- (4,5,6,7-tetrahydroimidazo [4,5c] pyridin-2-yl). ethyl propionate dihydrochloride (61.80 g, 75% yield); 1 H-NMR (300 MHz, DMSO-d 6 ), δ, md: 10.00 (pi s, 2H), 4.35 (quartet, 1H, J = 7.1 Hz), 4.25 (pi s, 2H), 4.15 (m, 2H), 3.35 (m, 2H), 2.90 (pi, 2H), 1.60 (d, 3H, J = 7.1 Hz). , 1.20 (t, 3H, J = 6.9 Hz).
(c) 2-(4,5,6,7-Tetrahidroimidazo[4,5-c]piridin-2-il)etilo propionato dihidrochlorido (60,2 g, 0,20 mol) tirpalas acetonitrile (400 ml) atšaldytas azoto atmosferoje iki 0 °C, paveiktas A/,N-diizopropiletilaminu (35 ml, 0,20 mol), po to atšaldytas iki ~ 5 0 °C (ledas/acetonas), o po to 30 minučių laikotarpyje besikeičiančiomis dalimis paveiktas benzilo chlorformiatu (58 ml, 0,41 mol) ir N.Ndiizopropiletilaminu (70 ml, 0,40 mol). Mišinys atšaldytas iki ~ 5 0 °C 1 valandai, paliktas sušilti iki 20 °C ir po 16 valandų sukoncentruotas sumažintame slėgyje. Liekana suspenduota j eterį, o suspensija paeiliui plauta natrio bikarbonatu, natrio chloridu, 0,1 M vandenilio chloridu ir natrio chloridu, išdžiovinta (Na2SO4), nufiltruota ir sukoncentruota sumažintame slėgyje. Liekana ištirpinta etanolyje (320 ml) ir tirpalas atšaldytas iki ~ 5 0 °C azoto atmosferoje, o po to per 1 valandą sulašintas natrio etoksidas (21 masės %, 85 ml, 0,22 mol) palaikant reakcijos temperatūrą žemiau 0 °C. Mišinys atšaldytas iki ~ 5 °C 1 valandai, supusiausvirintas iki neutralaus pH, naudojant 50 ml 4 M vandenilio chlorido ir sukoncentruotas sumažintame slėgyje. Liekana ištirpinta etilo acetate ir tirpalas perplautas natrio bikarbonatu ir natrio chloridu, išdžiovinta (Na2SO4), nufiltruota ir sukoncentruota sumažintame slėgyje. Liekana, išgryninta chromatografiškai silikageliu (heksanas/etilo acetatas), duoda 2-(1-etoksikarboniletil)-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-karboksilatą (52 g, 72 % išeiga) šviesiai geltonos alyvos pavidalu; 1H-BMR (300 MHz, DMSO-de), δ, m. d.: 11,72 (pi. s, 1H), 7,32 (s, 5H), 5,07 (s, 2H), 4,32 (pi. s, 2H), 4,02 (kvartetas, 2H, J=9,3 Hz), 3,77 (kvartetas, 1H, J=8,3 Hz), 3,66 (s, 2H), 2,55 (s, 2H), 1,38 (d, 3H, J=8,3 Hz), 1,13 (t, 3H, J=9,3 Hz).(c) 2- (4,5,6,7-Tetrahydroimidazo [4,5-c] pyridin-2-yl) ethyl propionate dihydrochloride (60.2 g, 0.20 mol) in acetonitrile (400 mL) cooled with nitrogen at 0 ° C, treated with N, N-diisopropylethylamine (35 mL, 0.20 mol), then cooled to 550 ° C (ice / acetone) and then treated with benzyl chloroformate in portions for 30 minutes ( 58 mL, 0.41 mol) and N.Ndiisopropylethylamine (70 mL, 0.40 mol). The mixture was cooled to ~ 5 ° C for 1 hour, allowed to warm to 20 ° C, and concentrated under reduced pressure after 16 hours. The residue was suspended in ether and the suspension was washed successively with sodium bicarbonate, sodium chloride, 0.1 M hydrochloric acid and sodium chloride, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (320 mL) and the solution was cooled to 550 ° C under a nitrogen atmosphere, followed by dropwise addition of sodium ethoxide (21 wt%, 85 mL, 0.22 mol) over 1 hour while maintaining the reaction temperature below 0 ° C. The mixture was cooled to 55 ° C for 1 h, boiled to neutral pH with 50 mL of 4 M hydrochloric acid, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate and sodium chloride, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (52 g, 72% yield) as a light yellow solid. in the form of an oil; 1 H-NMR (300 MHz, DMSO-d 6), δ, md: 11.72 (s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 ( pi. s, 2H), 4.02 (quartet, 2H, J = 9.3 Hz), 3.77 (quartet, 1H, J = 8.3 Hz), 3.66 (s, 2H), 2, 55 (s, 2H), 1.38 (d, 3H, J = 8.3 Hz), 1.13 (t, 3H, J = 9.3 Hz).
(d) Mišinys, sudarytas iš 2-(1-etoksikarboniletil)-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-karboksilato (6,37 g, 0,018 mol), 4-amino-3-(/Vmetilamino)benzenkarboksirūgšies (2,70 g, 0,016 mol) ir DMPU (20 ml) trumpai degazuotas vakuume, šildytas 4 valandas 185 °C temperatūroje azoto atmosferoje, atšaldytas ir sujungtas su ekvivalenčių benzeno kiekiu. Į mišinį pripylus eterio, gaunamos nuosėdos. Nuosėdos nufiltruotos, greitai išdžiovintos vakuume, o po to grynintos išsodinant iš karšto etanolio/vandens. Nuosėdos nufiltruotos ir išdžiovintos, gaunant 2-[1-(5-benziloksikarbonil-4,5,6,7-tetrahidro1H-imidazo[4,5-c]piridin-2-il)etil]-3-metil-3W-benzoimidazol-5-karboksirūgštį (4,73 g, 58 % išeiga); ’H-BMR (300 MHz, DMSO-d6), δ, m. d.: 12,70 (pi. s, 1H), 11,8 (s, 1H), 8,15 (s, 1H), 7,78 (d, 1H, J=8,3 Hz), 7,64 (d, 1H, J=8,3 Hz), 7,31 (s, 5H), 5,09 (s, 2H), 4,66 (kvartetas, 1H, J=5,2 Hz), 4,32 (pi. s, 2H), 3,78 (s, 3H), 3,65 (pi. s, 2H), 2,52 (pi. s, 2H), 1,73 (d, 3H, J=5,2 Hz).(d) A mixture of 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (6.37 g, 0.018 mol), 4-amino-3- (N -methylamino) benzoic acid (2.70 g, 0.016 mol) and DMPU (20 mL) were briefly degassed in vacuo, heated at 185 ° C for 4 hours under nitrogen, cooled and combined with equivalent benzene. Addition of ether to the mixture gives a precipitate. The precipitate was filtered off, dried quickly in vacuo and then purified by precipitation from hot ethanol / water. The precipitate was filtered off and dried, yielding 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-3 H -benzoimidazole. -5-carboxylic acid (4.73 g, 58% yield); 1 H-NMR (300 MHz, DMSO-d 6 ), δ, md: 12.70 (s, 1H), 11.8 (s, 1H), 8.15 (s, 1H), 7.78 (d, 1H, J = 8.3 Hz), 7.64 (d, 1H, J = 8.3 Hz), 7.31 (s, 5H), 5.09 (s, 2H), 4.66 (quartet, 1H, J = 5.2 Hz), 4.32 (pi. s, 2H), 3.78 (s, 3H), 3.65 (pi. s, 2H), 2.52 (pi. s, 2H), 1.73 (d, 3H, J = 5.2 Hz).
(e) Mišinys, sudarytas iš 2-[1-(5-benziloksikarbonil-4,5,6,7-tetrahidro-1/-/imidazo[4,5-c]piridin-2-il)etil]-3-metil-3/-/-benzoimidazol-5-karboksirūgšties (0,75 g, 1,6 mmol), DMF-do (6,5 ml), metil-2-(2-aminoetoksi)benzoato (0,38 g, 1,6 mmol) ir HOBT (0,22 g, 1,6 mmol), atšaldytas azoto atmosferoje iki -40 °C temperatūros, paveiktas EDC (0,32 g, 1,6 mmol) ir Λ/,/V-diizopropiletilaminu (0,29 ml, 1,6 mmol), o po 15 minučių papildomu A/,A/-diizopropiletilamino (0,29 ml) kiekiu, paliktas sušilti iki 20 °C temperatūros ir maišytas 16 valandų. Po to mišinys atšaldytas iki 40 °C temperatūros, paveiktas papildomu kiekiu EDC (0,080 g) ir Λ/,/Vdiizopropiletilaminu (0,50 ml), maišytas 15 minučių -40 °C temperatūroje ir 2 valandas 20 °C temperatūroje, nudistiliuotas naudojant trumpą distiliatorių. Liekana padalinta tarp chloroformo ir natrio bikarbonato, o organinis sluoksnis perplautas natrio chloridu, 05 M kalio sulfatu, išdžiovintas (Na2SO4), nufiltruotas ir sukoncentruotas sumažintame slėgyje. Liekana, išgryninta chromatografiškai silikageliu (CHCl3/MeOH/AcOH:95/5/1), yra 2-(1-{6-[2-(2metoksikarbonilfenoksi)etilkarbamoil]-1-metil-1 Z7-benzoimidazol-2-il}etil)-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-benzilo karboksilatas (0,69 g, 66 % išeiga) kaip stiklingos rudos putos; 1H-BMR (300 MHz, DMSO-de), δ, m. d.: 11,92 (s, 1H), 8,49 (t, 1H J=5,0 Hz), 8,02 (s, 1H), 7,69 (d, 1H, J=9,9 Hz), 7,60 (m, 2H), 7,50 (t, 1H, J=8,3 Hz), 7,30 (m, 5H), 7,19 (d, 1H, J=9,9 Hz), 6,99 (t, 1H, J=8,3 Hz), 5,04 (s, 2H), 4,61 (kvartetas, 1H, J=8,8 Hz), 4,30 (pi. s, 2H), 4,20 (t, 1H, J=5,0 Hz), 3,74 (s, 3H), 3,68 (s, 3H), 3,63 (m, 4H), 2,55 (pi. s, 2H), 1,67 (d, 3H, J=8,8 Hz).(e) A mixture of 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3- methyl 3 H - benzoimidazole-5-carboxylic acid (0.75 g, 1.6 mmol), DMF-do (6.5 mL), methyl 2- (2-aminoethoxy) benzoate (0.38 g, 1.6 mmol) and HOBT (0.22 g, 1.6 mmol) cooled in a nitrogen atmosphere to -40 ° C, treated with EDC (0.32 g, 1.6 mmol) and N, N-diisopropylethylamine (0.29 mL, 1.6 mmol) and after 15 minutes with additional N, N-diisopropylethylamine (0.29 mL) was allowed to warm to 20 ° C and stirred for 16 h. The mixture was then cooled to 40 ° C, treated with additional EDC (0.080 g) and N, N-diisopropylethylamine (0.50 ml), stirred for 15 minutes at -40 ° C and 2 hours at 20 ° C, distilled using a brief distillation. The residue was partitioned between chloroform and sodium bicarbonate, and the organic layer was washed with sodium chloride, 05 M potassium sulfate, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue, purified by silica gel chromatography (CHCl3 / MeOH / AcOH: 95/5/1), contains 2- (1- {6- [2- (2-methoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1Z7-benzoimidazol-2-yl} ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-benzyl carboxylate (0.69 g, 66% yield) as a vitreous brown foam; 1 H-NMR (300 MHz, DMSO-d 6), δ, md: 11.92 (s, 1H), 8.49 (t, 1H J = 5.0 Hz), 8.02 (s, 1H), 7.69 (d, 1H, J = 9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1H, J = 8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1H, J = 9.9 Hz), 6.99 (t, 1H, J = 8.3 Hz), 5.04 (s, 2H), 4.61 (quartet, 1H, J) = 8.8 Hz), 4.30 (s, 2H), 4.20 (t, 1H, J = 5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H) ), 3.63 (m, 4H), 2.55 (bs, 2H), 1.67 (d, 3H, J = 8.8 Hz).
(f) 2-(1 -{6-[2-(2-Metoksikarbonilfenoksi)etilkarbamoil]-1 -metil-1 Hbenzoimidazol-2-il}etil)-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-benzilo karboksilato (0,69 g, 1,1 mmol) tirpalas THF-ne (2 ml) ir vandenyje (2 ml) atšaldytas azoto atmosferoje iki 0 °C temperatūros, paveiktas 2 N ličio hidroksidu (1,1 ml, 2,2 mmol), paliktas sušilti iki 20 °C temperatūros ir maišytas 8 valandas. Po to mišinys atšaldytas iki 0 °C temperatūros, paveiktas papildomu kiekiu 2 N ličio hidroksido (1,1 ml), paliktas sušilti iki 20 °C temperatūros, maišytas 6 valandas, atšaldytas iki 0 °C temperatūros, supusiausvirintas 1 M vandenilio chlorido ir sukoncentruotas sumažintame slėgyje. Liekana rūpestingai perplauta šaltu natrio chloridu ir vandeniu, o po to išdžiovinta vakuume, duoda 5όβηζί^3ίΚ3^οηιΊ-2-(2-{3-Γηθ{ίΙ-2-[1-(4,5,6,74θΐΓ3ΐ^Γθ-1/7-ίΓΤ^3ζο[4,5-ο]ρίπΰίη-2il)etil]-3H-benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštį (0,56 g, 83 % išeiga) kaip stiklingas nuosėdas; 1H-BMR (300 MHz, DMSO-de), δ, m. d.: 11,87 (pi. s, 1H), 9,74 (s, 1H), 8,45 (s, 1H), 7,84 (d, 1H, J=9,7 Hz), 7,56 (d, 1H, J=9,7 Hz), 7,42 (d, 1 H. J=7,7 Hz), 7,32 (s, 5H), 7,23 (t, 1 H. J=7,7 Hz), 7,06 (d, 1H, J=7,7 Hz), 6,90 (t, 1H, J=7,7 Hz), 5,08 (s, 2H), 4,63 (kvartetas, 1H, J=7,7 Hz), 4,32 (s, 2H), 4,19 (m, 2H), 2,55 (s, 2H), 1,71 (d, 3H, J=7,7 Hz).(f) 2- (1- {6- [2- (2-Methoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -1,4,6,7-tetrahydroimidazo [4,5- c] A solution of pyridine-5-benzyl carboxylate (0.69 g, 1.1 mmol) in THF (2 mL) and water (2 mL) was cooled to 0 ° C under 2 N lithium hydroxide (1, 1 mL, 2.2 mmol), allowed to warm to 20 ° C and stirred for 8 hours. The mixture was then cooled to 0 ° C, treated with additional 2N lithium hydroxide (1.1 mL), allowed to warm to 20 ° C, stirred for 6 hours, cooled to 0 ° C, boiled in 1M hydrochloric acid and concentrated. under reduced pressure. The residue was carefully washed with cold sodium chloride and water and then dried in vacuo to give 5όβηζί ^ 3ίΚ3 ^ οηιΊ-2- {2- {3-Γηθ {ίΙ-2- [1- (4,5,6,74θΐΓ3ΐ ^ Γθ-). 1/7-benzo [4,5-d] [1,2,4] ethyl] -3H-benzoimidazol-5-ylcarbonylamino} -ethoxy) -benzoic acid (0.56 g, 83% yield) as a vitreous precipitate; 1 H-NMR (300 MHz, DMSO-d 6), δ, md: 11.87 (pi s, 1H), 9.74 (s, 1H), 8.45 (s, 1H), 7.84 ( d, 1H, J = 9.7 Hz), 7.56 (d, 1H, J = 9.7 Hz), 7.42 (d, 1H J = 7.7 Hz), 7.32 (s) , 5H), 7.23 (t, 1H, J = 7.7 Hz), 7.06 (d, 1H, J = 7.7 Hz), 6.90 (t, 1H, J = 7.7 Hz), 5.08 (s, 2H), 4.63 (quartet, 1H, J = 7.7 Hz), 4.32 (s, 2H), 4.19 (m, 2H), 2.55 ( s, 2H), 1.71 (d, 3H, J = 7.7 Hz).
(g) 5-Benziloksikarbonil-2-(2-{3-metil-2-[1 -(4,5,6,7-tetrahidro-1 Himidazo[4,5-c]piridin-2-il)etil]-3W-benzoimidazol-5ilkarbonilamino}etoksi)benzenkarboksirūgštis (0,561 g, 0 90 mmol) tirpalas ledinėje acto rūgštyje (2 ml) šildytas azoto atmosferoje vandens vonioje iki 10 °C temperatūros, po to paveiktas vandenilio bromidu acto rūgštyje (2 ml 30 tirpalo) ir paliktas sušilti iki 20 °C temperatūros vienai valandai, sukoncentruotas azoto srovėje. Liekana ištirpinta mažame etanolio kiekyje, o gautas tirpalas sulašintas j maišomą eterį, gaunant rudos spalvos nuosėdas. Nuosėdos, nufiltruotos ir išdžiovintos, duoda 2-(2-(3metil-2-[(4I5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il)etil]-37/-benzoimidazol-5ilkarbonilamino}etoksi)-benzenkarboksirūgšties hidrobromidą (0,651 g); 1H-BMR (300 MHz, DMSO-d6), δ, m. d.: 9,31 (pi. s, 2H), 8,63 (m, 1 H). 8,24 (s, 1H), 7,79 (d, 1H, J =7,9 Hz), 7,63 (m, 2H), 7,47 (t, 1H, J=7,9 Hz), 7,21 (d, 1H, J=7,9 Hz), 7,00 (t, 1H, J=7,9 Hz), 5,21 (kvartetas, 1H, J=6,3 Hz), 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=6,3 Hz).(g) 5-Benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1 Himidazo [4,5-c] pyridin-2-yl) ethyl] A solution of -3W-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.561 g, 0 90 mmol) in glacial acetic acid (2 mL) was heated under nitrogen in a water bath to 10 ° C then treated with hydrogen bromide in acetic acid (2 mL of 30 mL). and left to warm to 20 ° C for one hour, concentrated in a stream of nitrogen. The residue was dissolved in a small amount of ethanol and the resulting solution was added dropwise to a stirred ether to give a brown precipitate. The precipitate was filtered off and dried to give 2- (2- (3-methyl-2 - [(4 I, 5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -37 / -benzoimidazol-5ilkarbonilamino} -ethoxy) -benzoic acid hydrobromide (0.651 g); 1 H-NMR (300 MHz, DMSO-d 6) δ, ppm: 9.31 (br. s, 2H), 8.63 (m, 1H) 8.24 (s, 1H), 7.79 (d, 1H, J = 7.9 Hz), 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 (quartet, 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 = 6.3 Hz).
(h) 2-(2-{3-Metil-2-[(4,5,6,7-tetrahidro-1H-imidazoi4,5-c]piridin-2-il)etil]-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)-benzenkarboksirūgšties hidrobromido (0,30 g, 0,46 mmol) tirpalas DMF-de (1,5 ml) atšaldytas azotu iki 0 °C temperatūros, paveiktas etilo acetimidatu (0,12 g, 0,92 mmol) ir N,Ndiizoprpiletilaminu (0,25 ml, 1,4 mmol), atšaldytas iki 0 °C 30 minučių, o po to paliktas sušilti iki 20 °C temperatūros, maišytas 20 valandų. Po to mišinys vėl atšaldytas iki 0 °C, paveiktas papildomu kiekiu etilo acetimidato (0,06 g) ir N,Ndiizoprpiletilamino (0,16 ml), paliktas sušilti iki 20 °C temperatūros ir maišytas 2 valandas. Mišinys atšaldytas iki 0 °C, paveiktas papildomu kiekiu etilo acetimidato (0,03 g), paliktas sušilti iki 20 °C temperatūros ir maišytas 2 valandas, gautas mišinys sulašintas į maišomą eteri*, gaunant nuosėdas. Nuosėdos atskirtos dekantuojant nuo tirpiklio ir išdžiovintos vakuume. Liekana išsodinta iš etanolio/eterio ir išgryninta preparatyvine atvirkščių fazių HPLC: 2 50 % MeCN/H2O (20 ml HCI) per 50 minučių. Liofilizuotos frakcijos duoda 2-[2-(2-{1 -[5(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-il)etil]-3A7-benzoimidazoi5-ilkarbonilamino}etoksi)-benzenkarboksirūgštį (0,145 g, 52 % išeiga); 1H-BMR (300 MHz, DMSO-d6), δ, m. d. : 9,77 (s, 2H), 9,34 (2s, 1H), 8,81 (m, 1H), 8,36 (s, 1H), 7,89 (d, 1H, J=8,6 Hz), 7,71 (d, 1H, J=8,6 Hz), 7,71 (d, 1H, J=8,6 Hz), 7,60 (d, 1H, 3=7,7 Hz), 7,49 (t, 1H, J=7,7 Hz), 7,21 (d, 1H, 3=7,7 Hz), 6,99 (t, 1H, J=7,7 Hz), 5,37 (m, 1H), 4,71 (2s, 2H), 4,23 (s, 2H), 3,97 (s, 3H), 3,82 (s, 1 H), 3,66 (m, 2H), 2,83 (m, 2H), 2,49 (s, 1H), 2,40 (d, 3H, J=3,5 Hz) 1,85 (d, 3H, J=5,1 Hz). MS (ESI): C29H31N7O4, m/e. Išskaičiuota: 529,61; Rasta: 530,3 (MH+).(h) 2- (2- {3-Methyl-2 - [(4,5,6,7-tetrahydro-1 H -imidazol-4,5-c] pyridin-2-yl) ethyl] -3 H -benzoimidazol-5-ylcarbonylamino} Ethoxy) benzoic acid hydrobromide (0.30 g, 0.46 mmol) in DMF (1.5 mL) was cooled with nitrogen to 0 ° C, treated with ethyl acetimidate (0.12 g, 0.92 mmol) and N Of Ndiisopropyl-ethylamine (0.25 mL, 1.4 mmol), cooled to 0 ° C for 30 minutes and then allowed to warm to 20 ° C, stirred for 20 hours. The mixture was then cooled again to 0 ° C, treated with additional ethyl acetimidate (0.06 g) and N, N-diisopropyl-ethylamine (0.16 ml), allowed to warm to 20 ° C and stirred for 2 hours. The mixture was cooled to 0 ° C, treated with additional ethyl acetate imidate (0.03 g), allowed to warm to 20 ° C and stirred for 2 hours, and the resulting mixture was added dropwise to the stirred ether * to give a precipitate. The precipitate was separated by solvent decantation and dried in vacuo. The residue was precipitated from ethanol / ether and purified by reverse phase preparative HPLC: 2 50% MeCN / H 2 O (20 mL HCl) over 50 min. The lyophilized fractions give 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl). ethyl] -3α-benzoimidazol-5-ylcarbonylamino} ethoxy) -benzoic acid (0.145 g, 52% yield); 1 H-NMR (300 MHz, DMSO-d 6 ), δ, md: 9.77 (s, 2H), 9.34 (2s, 1H), 8.81 (m, 1H), 8.36 (s) , 1H), 7.89 (d, 1H, J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz) ), 7.60 (d, 1H, 3 = 7.7 Hz), 7.49 (t, 1H, J = 7.7 Hz), 7.21 (d, 1H, 3 = 7.7 Hz), 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) , 5 Hz) 1.85 (d, 3H, J = 5.1 Hz). MS (ESI): C 29 H 31 N 7 O 4, m / e. Calculated: 529.61; Found: 530.3 (MH + ).
PAVYZDYSEXAMPLE
2-(2-{2-[1-(4,6,7-Trifluor-1/7-imidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5karbonilamino]etoksi}etilo benzoatas (75 junginys) (a) 2,3,4,6-Tetrafluornitrobenzeno (0,6 g, 3,1 mmol) tirpalas amoniako/dioksano mišinyje (Aldrich, 0,5 M, 7,5 mmol), maišytas kambario temperatūroje 3 valandas, duoda smulkias baltas nuosėdas. Mišinys praskiedžiamas lygiu tūriu vandens, kad ištirpintų baltas nuosėdas ir duotų geltonus kristalus. Kristalai, atskirti ir išdžiovinti, duoda 2,3,5-trifluor-6-nitroaniliną (307 mg, 51 % išeiga) geltonų adatų pavidalu; lyd. temp. 66 °C; 1H-BMR (CDCI3), δ: 6,4 (m, 1H),6,0 (s, 2H).2- (2- {2- [1- (4,6,7-Trifluoro-1/7-imidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazole-5-carbonylamino] ethoxy} ethyl benzoate ( Compound 75) (a) A solution of 2,3,4,6-tetrafluoronitrobenzene (0.6 g, 3.1 mmol) in ammonia / dioxane (Aldrich, 0.5 M, 7.5 mmol) stirred at room temperature for 3 hours The mixture is diluted with an equal volume of water to dissolve the white precipitate to give yellow crystals The crystals, separated and dried, yield 2,3,5-trifluoro-6-nitroaniline (307 mg, 51% yield) as yellow needles. mp 66 ° C; 1 H-NMR (CDCl 3 ), δ: 6.4 (m, 1H), 6.0 (s, 2H).
(b) Mišinys, sudarytas iš 2,3,5-trifluor-6-nitroanilino (300 mg, 1,56 mmol) ir 10 % paladžio ant anglies absoliučiame etanolyje, hidrintas per naktj atmosferos slėgyje, nufiltruotas azoto atmosferoje, duoda 1,2-diamino-3,4,6-trifluorbenzeną (219 mg, 87 % išeiga) purpurines spalvos kietos medžiagos pavidalu; MS (M+):(b) A mixture of 2,3,5-trifluoro-6-nitroaniline (300 mg, 1.56 mmol) and 10% palladium on carbon in absolute ethanol, hydrogenated overnight at atmospheric pressure, filtered under nitrogen, gives 1.2 -diamino-3,4,6-trifluorobenzene (219 mg, 87% yield) as a purple solid; MS (M + ):
162,7, +41 +82 (+ACN, +2ACN). Išskaičiuta: C6H5F3N2: 162,11.162.7, +41 +82 (+ ACN, + 2ACN). Calculated for C 6 H 5 F 3 N 2: 162.11.
(c) Mišinys, sudarytas iš 1,2-diamino-3,4,6-trifluorbenzeno (1,92 g, 11,8 mmol), 2-etoksikarbonimidoetilo propionato (3,1 g, 14,7 mmol) ir absoliutaus etanolio (6 ml), šildytas su grįžtamuoju šaldytuvu iki kol nebevyksta jokių tolimesnių reakcijos pokyčių pagal plonasluoksnės chromatografijos duomenis, nufiltruotas nuo NH4CI ir sukoncentruotas. Liekana, gryninta chromatografiškai silikageliu (heksanas:metileno chloridas:etilo acetatas, 5:5:1), duoda 2-(4,6,7trifluor-1/-/-benzoimidazol)etilo propionatą (1,37 g, 42 % išeiga) gelsvai rudos kristalinės medžiagos pavidalu; 1H-BMR (CDCI3), δ: 10,35 (s, 1/2H), 7,05 (s, 1/2H), 6,7 (m, 1H), 4,25 (dd, 2H), 4,15 (dd, 1H), 1,73 (d, 3H), 1,31 (t, 3H); M+ : 272,9; Išskaičiuota: C12H11F3N2O2: 272,23.(c) A mixture of 1,2-diamino-3,4,6-trifluorobenzene (1.92 g, 11.8 mmol), 2-ethoxycarbonimidoethyl propionate (3.1 g, 14.7 mmol) and absolute ethanol (6 ml), heated under reflux until no further reaction was observed by thin layer chromatography, filtered from NH 4 Cl and concentrated. The residue was purified by silica gel chromatography (hexane: methylene chloride: ethyl acetate, 5: 5: 1) to give 2- (4,6,7trifluoro-1 H -benzoimidazole) ethyl propionate (1.37 g, 42% yield). in the form of a yellowish-brown crystalline substance; 1 H-NMR (CDCl 3 ), δ: 10.35 (s, 1 / 2H), 7.05 (s, 1 / 2H), 6.7 (m, 1H), 4.25 (dd, 2H) , 4.15 (dd, 1H), 1.73 (d, 3H), 1.31 (t, 3H); M + : 272.9; Calculated for C12H11F3N2O2: 272.23.
(d) 2-(4,6,7-Trifluor-1W-benzoimidazol)etilo propionatas (988 mg, 3,63 mmol) sujungtas su 2-[2-(4-amino-3-metilaminobenzoilamino)etoksi]benzoatu (1,3 g, 3,63 mmol) ir patalpintas į vakuumą 4 valandoms, o po to sujungtas su(d) 2- (4,6,7-Trifluoro-1 H -benzoimidazole) ethyl propionate (988 mg, 3.63 mmol) combined with 2- [2- (4-amino-3-methylaminobenzoylamino) ethoxy] benzoate (1) , 3 g, 3.63 mmol) and placed in vacuo for 4 hours and then combined with
DMPU (4 ml). Mišinys maišytas iki kol pavirsta tirpalu, po to laikytas per naktj giliame vakuume, kad būtų pašalintos liekamosios dujos, po to šildytas 195 °C temperatūroje azoto atmosferoje 4 valandas, atšaldytas iki kambario temperatūros, ir padalintas tarp etilo acetato ir vandens. Organinis sluoksnis atskirtas ir perplautas sūrymu, išdžiovintas natrio sulfatu ir sukoncentruotas. Liekana, gryninta chromatografiškai silikageliu (pakopinis gradientas nuo 100 % heksano iki 100 % etilo acetato) ir po to kristalinta iš MeOH/THF/vandens, duoda 2-(2-{2-([1-(4,6,7-trifluor-1/7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5karbonilamino}etoksi)etilo benzolą (1,0 g, 49 % išeiga) kaip baltą kristalinę kietą medžiagą; ’H-BMR (CDCI3), δ: 6,84-8,07 (m, 8H), 4,93 (dd, 1H), 4,34 (dd, 2H), 4,27 (m, 2H), 3,95 (m, 2H), 3,9 (s, 3H), 1,93 (d, 3H), 1,78 (s, 2H), 1,38 (t, 3H); LCMS M+ : 566,2; Biolon M+ : 565,7. Išskaičiuota: C29H26F3N5O4: 565,55.DMPU (4 mL). The mixture was stirred until it became a solution, then held overnight under a deep vacuum to remove the residual gas, then heated at 195 ° C under nitrogen for 4 hours, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (step gradient 100% hexane to 100% ethyl acetate) and then crystallized from MeOH / THF / water to give 2- (2- {2 - ([1- (4,6,7-trifluoro) -1,7-Benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazole-5-carbonylamino} ethoxy) ethyl benzene (1.0 g, 49% yield) as a white crystalline solid; (CDCl 3 ), δ: 6.84-8.07 (m, 8H), 4.93 (dd, 1H), 4.34 (dd, 2H), 4.27 (m, 2H), 3.95 (m, 2H), 3.9 (s, 3H), 1.93 (d, 3H), 1.78 (s, 2H), 1.38 (t, 3H), LCMS M + : 566.2; Biolon M + : 565.7 Calc'd: C29H26F3N5O4: 565.55.
Sintetinant pagal 10 pavyzdžio metodiką, gauti tokie išradimo junginiai:Synthesized according to the procedure of Example 10, the following compounds of the invention were obtained:
2-(2-(2-((1-(5,6-difluor-1tf-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (76 junginys); MS (Biolon), m/e. C29H27N5O4F2. Išskaičiuota: 547,56; Rasta: 548,1 (MH+);2- (2- (2 - ((1- (5,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 76); MS (Biolon) m / e for C29H27N5O4F2 Calc'd: 547.56 Found: 548.1 (MH + );
2-(2-(2-((1-(4,6-difluor-1/7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (77 junginys); MS (LCMS), m/e. C29H27N5O4F2. Išskaičiuota: 547,56; Rasta: 548,3 (MH+);2- (2- (2 - ((1- (4,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (77 MS (LCMS) m / e calcd for C 29 H 27 N 5 O 4 F 2: 547.56 Found: 548.3 (MH + );
2-(2-(2-((1-(4,5,6-trifluor-1H-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (78 junginys); MS (LCMS), m/ė. C29H26N5O4F3. Išskaičiuota: 565,55; Rasta: 566,2 (MH+);2- (2- (2 - ((1- (4,5,6-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (78 MS (LCMS) m / e calcd for C 29 H 26 N 5 O 4 F 3: 565.55; Found: 566.2 (MH + );
2-(2-{2-([1-(4,6,7-trifluor-1W-benzoimidazol-2-itmetil]-3H-benzoimidazol-5ilkarbonilamino}etoksi)etilo benzoatas (79 junginys); MS (LCMS), m/e. C28H24N5O4F3. Išskaičiuota: 551,52; Rasta: 551,2 (MH+).2- (2- {2 - ([1- (4,6,7-trifluoro-1 H -benzoimidazol-2-ylmethyl] -3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 79); MS (LCMS), m / e calcd for C 28 H 28 N 5 O 4 F 3 : 551.52; Found: 551.2 (MH + ).
PAVYZDYSEXAMPLE
2-(2-{2-([1-(4,6,7-Trifluor-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (80 junginys)2- (2- {2 - ([1- (4,6,7-Trifluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 80)
Mišinys, sudarytas iš 2-(2-(2-((1-(4,6l7-trifluor-1H-benzoimidazol-2-il)etil]-3metil-3H-benzoimidazol-5-karbonilamino}etoksi)etilo benzoato (118 mg, 0,21 mmol), metanolio (4 ml) ir 2 N natrio hidroksido (2,1 ml), maišytas kambario temperatūroje 4 valandas, neutralizuotas 2 N vandenilio chloridu (2,1 ml) ir padalintas tarp etilo acetato ir sotaus amonio chlorido. Vandeninis sluoksnis atskirtas ir išekstrahuotas etilo acetatu (3 kartus). Sujungti organiniai sluoksniai perplauti sūrymu, išdžiovinti natrio sulfatu ir sukoncentruoti iki baltos kietos medžiagos. Liekana ištirpinta šiltame etanolyje (10 ml) ir 4 M vandenilio chlorido/dioksano tirpale. Tirpalas, praskiestas etileteriu, duoda nuosėdas. Nuosėdos, atskirtos ir išdžiovintos, duoda 2-(2-(2-((1-(4,6,7-trifluor-1Hbenzoimidazol-2-il)etil]-3-metil-3/-/-benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštį kaip baltą kietą medžiagą; MS (LCMS), m/e. C27H22N5O4F3. Išskaičiuota: 537,50; Rasta: 538,4 (MH+).Mixture of 2- (2- (2 - ((1- (4.6 L 7-trifluoro-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazole-5-carbonylamino} ethoxy) ethyl benzoate (118 mg, 0.21 mmol), methanol (4 mL) and 2 N sodium hydroxide (2.1 mL), stirred at room temperature for 4 hours, neutralized with 2 N hydrochloric acid (2.1 mL) and partitioned between ethyl acetate and Saturated ammonium chloride The aqueous layer was separated and extracted with ethyl acetate (3 times) The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to a white solid The residue was dissolved in warm ethanol (10 mL) and 4M hydrogen chloride / dioxane solution. diluted with ethyl ether to give a precipitate, which was separated and dried to give 2- (2- (2 - ((1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3 / - / - benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid as a white solid, MS (LCMS) m / e for C 27 H 2 N 5 O 4 F 3 : Calc'd: 537.50; Found: 538.4 (MH + ).
Sintetinant pagal 11 pavyzdžio metodiką, gauti tokie išradimo junginiai:Synthesized according to the procedure of Example 11, the following compounds of the invention were obtained:
2-(2-{2-([ 1 -(5,6-difIuor-1 H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (81 junginys); MS (LCMS), m/e. C^bhNsCUFs. Išskaičiuota: 519,51; Rasta: 520,2 (MFl·);2- (2- {2 - ([1- (5,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 81); MS (LCMS) m / e calcd for C 11 H 11 N 5 ClF 3 O: 519.51; Found: 520.2 (MH +);
2-(2-{2-([1-(4,6-difluor-1/7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (82 junginys); MS (LCMS), m/e: C27H23N5O4F2. Išskaičiuota: 519,51; Rasta: 520,2 (MH+); ir2- (2- {2 - ([1- (4,6-Difluoro-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 82) MS (LCMS) m / e: C 27 H 23 N 5 O 4 F 2 Calc'd: 519.51 Found: 520.2 (MH + ) and
2-(2-{2-([1-(4,6,7-trifluor-1H-benzoimidazol-2-ilmetil]-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzenkarboksirūgštis (83 junginys); MS (Biolon), m/e. C27H22N5O4F3. Išskaičiuota: 537,5; Rasta: 537,7 (MH+).2- (2- {2 - ([1- (4,6,7-trifluoro-1H-benzoimidazol-2-ylmethyl] -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 83); MS (Biolon), m C27H22N5O4F3 Calc'd: 537.5 Found: 537.7 (MH + ).
PAVYZDYSEXAMPLE
2-(2-{2-([1-(1-lzobutiril-5-metoksikarboniloksi-7/-/-benzoimidazol-2-il)etil]-3metil-3/7-benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (84 junginys)2- (2- {2 - ([1- (1-Isobutyryl-5-methoxycarbonyloxy-7 H -benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl Benzoate (Compound 84)
Mišinys, sudarytas iš 2-(2-{2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-3metil-3/7-benzoimidazol-5-karbonilamino}etoksi)etilo benzoato (0,50g, 0,95 mmol), dimetilformamido (5 ml), cezio karbonato (0,93 g, 2,85 mmol) ir izobutano rūgšties anhidrido (0,17 ml, 1,05 mmol), maišytas 2 valandas, po to praskiestas dichlormetanu (50 ml) ir perleistas per celito filtrą. Tirpiklis pašalintas vakuume, o liekana ištirpinta dichlormetane (5. ml). Tirpalas sujungtas su diizopropiletilaminu (0,47 ml, 2,7 mmol) ir metileno chlorformiatu (0,1 ml, 1,3 mmol), gautas mišinys maišytas 1 valandą. Tirpiklis pašalintas vakuume, o liekana išgryninta chromatografiškai silikageliu, eliuentais naudojant etanolį ir dichlormetaną, gaunant 2-(2-{2-([1-(1-izobutiril-5-metoksikarboniloksi-7/-/-benzoimidazol-2-il)etilj3-metil-3/7-benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatą (0,20 g, 32 % išeiga) kaip bespalvę amorfinę medžiagą; MS (Biolon), m/e. C35H37N5O8 : Išskaičiuota: 655,72; Rasta: 656,1 (MH+).Mixture of 2- (2- {2- [1- (5-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazole-5-carbonylamino} ethoxy) ethyl benzoate ( 0.50 g, 0.95 mmol), dimethylformamide (5 mL), cesium carbonate (0.93 g, 2.85 mmol) and isobutanoic anhydride (0.17 mL, 1.05 mmol) were stirred for 2 hours, followed by it was diluted with dichloromethane (50 mL) and passed through a celite filter. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (5. mL). The solution was combined with diisopropylethylamine (0.47 mL, 2.7 mmol) and methylene chloroformate (0.1 mL, 1.3 mmol), and the resulting mixture was stirred for 1 h. The solvent was removed in vacuo and the residue purified by silica gel chromatography eluting with ethanol and dichloromethane to give 2- (2- {2 - ([1- (1-isobutyryl-5-methoxycarbonyloxy-7 H- benzoimidazol-2-yl) ethyl)] -methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (0.20 g, 32% yield) as a colorless amorphous material, MS (Biolon), m / e C35H37N5O8: Calculated: 655.72; Found: : 656.1 (MH + ).
Sintetinant pagal 12 pavyzdžio metodiką, gauti tokie išradimo provaistai:Synthesized according to the procedure of Example 12, the following prodrugs of the invention were obtained:
2-(1-{6-[2-(2-etoksikarbonilfenoksi)etilkarbamoil]-1-metil-1tt-benzoimidazol2-il}etil)-5-hidroksibenzoimidazol-1 -metilo karboksilatas (85 junginys); MS (ESI)2- (1- {6- [2- (2-Ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -5-hydroxybenzoimidazol-1-methyl carboxylate (Compound 85); MS (ESI)
C31H31N5O7, m/e. Išskaičiuota: 585,62; Rasta: 586,2 (MH+);C31H31N5O7, m / e. Calculated: 585.62; Found: 586.2 (MH + );
2-(1 -{6-[2-(2-etoksikarbonilfenoksi)etilkarbamoil]-1 -metil-1 W-benzoimidazol2-il}etil)-5-metoksikarboniloksibenzoimidazol-1 -etilo karboksilatas (86 junginys); MS (ESI): C33H33N5O7, m/e. Išskaičiuota: 643,66; Rasta: 644,2 (MH+);2- (1- {6- [2- (2-Ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1 H -benzoimidazol-2-yl} ethyl) -5-methoxycarbonyloxybenzoimidazol-1-ethyl carboxylate (Compound 86); MS (ESI): C 33 H 33 N 5 O 7, m / e. Calculated: 643.66; Found: 644.2 (MH + );
2-(2-{2-[ 1 - (5-hidroksi-1 -izobutiril-1 H-benzoimidazol-2-il)etil]-3-metil-3/710 benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (87 junginys); MS (ESI):2- (2- {2- [1- (5-Hydroxy-1-isobutyryl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,710-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate ( Compound 87); MS (ESI):
C33H35N5O6, m/e. Išskaičiuota: 597,68; Rasta: 598,2 (MH+);C33H35N5O6, m / e. Calculated: 597.68; Found: 598.2 (MH + );
2-(2-{2- [1 -(1 -benzoil-5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (88 junginys): MS (ESI): C36H33N5O6 , m/e. Išskaičiuota: 631,69; Rasta: 632,3 (MH+);2- (2- {2- [1- (1-Benzoyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (88 Compound): MS (ESI): C 36 H 33 N 5 O 6, m / e. Calculated: 631.69; Found: 632.3 (MH + );
2-(2-{2-[1-(1-dimetilkarbamoil-5-hidroksi-1A7-benzoimidazol-2-il)etil]-3-metil3H-benzoimidazol-5-ilkarbonilamino)etoksi}etilo benzoatas (89 junginys): MS (ESI): C32H34N6O6, m/e. Išskaičiuota: 598,66; Rasta: 599,3 (MH+);2- (2- {2- [1- (1-Dimethylcarbamoyl-5-hydroxy-1?, 7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy} ethyl benzoate (Compound 89): MS (ESI): C 32 H 34 N 6 O 6, m / e. Calculated: 598.66; Found: 599.3 (MH + );
2-(2-{2-[1-(1-acetoksimetil-5-hidroksi-1A7-benzoimidazol-2-il)etil]-3-metil-3/-/benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (90 junginys), MS (Biolon): C32H33N5O7, m/e. Išskaičiuota: 599,65; Rasta: 600,7 (MH+);2- (2- {2- [1- (1-Acetoxymethyl-5-hydroxy-1?, 7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate ( Compound 90), MS (Biolon): C 32 H 33 N 5 O 7, m / e. Calculated: 599.65; Found: 600.7 (MH + );
2-[2-(2-{1-[1-(2,2-dimetilpropioniloksimetil)-5-hidroksi-1H-benzoimidazol-2il]etil}-3-metil-3/7-benzoimidazol-5-ilkarbonilamino)etoksi]-etilo benzoatas (91 junginys); MS (ESI): C35H39N5O7, m/e. Išskaičiuota: 641,74; Rasta: 642,3 (MH+);2- [2- (2- {1- [1- (2,2-Dimethylpropionyloxymethyl) -5-hydroxy-1H-benzoimidazol-2-yl] ethyl} -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino) ethoxy ] -ethyl benzoate (Compound 91); MS (ESI): C 35 H 39 N 5 O 7, m / e. Calculated: 641.74; Found: 642.3 (MH + );
2-(2-{2-[1-(1-izobutirl-5-metoksikarboniloksi-1H-benzoimidazol-2-il)etil]-325 metil-3H-benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (92 junginys); MS (Biolon): C35H37N5O8, m/e. Išskaičiuota: 655,72; Rasta: 656,1 (MH+);2- (2- {2- [1- (1-Isobutyl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -325-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 92) ; MS (Biolon): C 35 H 37 N 5 O 8, m / e. Calculated: 655.72; Found: 656.1 (MH + );
5-etoksikarboniloksi-2-(1-{6-[2-(2-etoksikarbonilfenoksi)etilkarbamoil]-1metil-1/7-benzoimidazol-2-il}etil)benzoimidazol-1-etilo karboksilatas (93 junginys): MS (ESI): C35H37N5O9, m/e. Išskaičiuota: 671,72; Rasta: 672,4 (MH+);5-Ethoxycarbonyloxy-2- (1- {6- [2- (2-ethoxycarbonyl-phenoxy) -ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} -ethyl) -benzoimidazole-1-ethyl-carboxylate (Compound 93): MS ( ESI): C 35 H 37 N 5 O 9, m / e. Calculated: 671.72; Found: 672.4 (MH + );
2-(1-{6-[2-(2-etoksikarbonilfenoksi)etilkarbamoilj-1-metil-1H-benzoimidazol2-il}etil)-5-izopropoksikarboniloksibenzoimidazol-1 -izopropilo karboksilatas (94 junginys); MS (ESI): C37H41N5O9, m/e. Išskaičiuota: 699,79; Rasta: 700,4 (MH+); ir2- (1- {6- [2- (2-Ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -5-isopropoxycarbonyloxybenzoimidazole-1-isopropyl carboxylate (Compound 94); MS (ESI): C 37 H 41 N 5 O 9, m / e. Calculated: 699.79; Found: 700.4 (MH + ); and
2-(2-{2-[1-(1-acetil-5-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3Wbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (95 junginys); MS (ESI): C31H31N5O6, m/e. Išskaičiuota: 569,62; Rasta: 570,1 (MH+).2- (2- {2- [1- (1-Acetyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 95) ); MS (ESI): C 31 H 31 N 5 O 6, m / e. Calculated: 569.62; Found: 570.1 (MH + ).
Sintetinant kaip aprašyta šioje paraiškoje, arba pagal metodus, žinomus patyrusiems šios srities specialistams, gauti tokie papildomi išradimo junginiai:When synthesized as described in this application or by methods known to those skilled in the art, the following additional compounds of the invention were obtained:
C-[2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-3/7-benzoimidazol-5-il]metilaminas (96 junginys);C- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3,7-benzoimidazol-5-yl] methylamine (Compound 96);
C-[2-(1H-nafto[2,3-d]imida2ol-2-ilmetil)-1/7-benzoimidazol-5-il]metilaminas (97 junginys): MS (Biolon): C20H17N5, m/e. Išskaičiuota: 327,4; Rasta: 328,1 (MH+);C- [2- (1H-naphtho [2,3-d] imidazol-2-ylmethyl) -1,7-benzoimidazol-5-yl] methylamine (Compound 97): MS (Biolon): C20H17N5, m / e. Calculated: 327.4; Found: 328.1 (MH + );
C-[2-(5-metil-1A7-benzoimidazol-2-ilmetil)-1/7-benzoimidazol-5-il]metilaminas (98 junginys); MS (Biolon): Ci7H17N5, m/e. Išskaičiuota: 291,4; Rasta:C- [2- (5-Methyl-1β-benzoimidazol-2-ylmethyl) -1,7-benzoimidazol-5-yl] methylamine (Compound 98); MS (Biolon): C 17 H 17 N 5 , m / e. Calculated: 291.4; Found:
292,3 (MH+);292.3 (MH + );
2- (5-aminometil-1H-benzoimidazol-2-ilmetil)-1H-benzoimidazol-5karboksirūgštis (99 junginys);2- (5-Aminomethyl-1 H -benzoimidazol-2-ylmethyl) -1 H -benzoimidazole-5-carboxylic acid (Compound 99);
3- [2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-1H-benzoimidazol-5ilkarbonilaminojpropiono rūgštis (100 junginys); 'H-BMR (300 MHz, CD3OD): 1,92 (m, 2H, J=7,2Hz), 2,38 (t, 2H, J=7,2,Hz), 3,47 (t, 2H, J=7,2 Hz), 4,30 (s, 2H), 7,54 (d, 1H, J = 10,0 Hz), 7,69 (d, 1H, J=8,6 Hz), 7,75 (d, 1H, J = 10,0 Hz), 7,81 (s, 1H), 7,87 (d, 1H, J=8,6 Hz), 8,12 (s, 1H);3- [2- (5-Aminomethyl-1 H -benzoimidazol-2-ylmethyl) -1 H -benzoimidazole-5-ylcarbonylamino] propionic acid (Compound 100); 1 H-NMR (300 MHz, CD 3 OD): 1.92 (m, 2H, J = 7.2Hz), 2.38 (t, 2H, J = 7.2, Hz), 3.47 (t , 2H, J = 7.2 Hz), 4.30 (s, 2H), 7.54 (d, 1H, J = 10.0 Hz), 7.69 (d, 1H, J = 8.6 Hz) ), 7.75 (d, 1H, J = 10.0 Hz), 7.81 (s, 1H), 7.87 (d, 1H, J = 8.6 Hz), 8.12 (s, 1H );
2-(5-aminometil-1/7-benzoimidazol-2-ilmetil)-/V-(2-naft-1-iletil)-1/7benzoimidazol-5-karboksamidas (101 junginys);1 H-BMR (300 MHz, CD3OD): 3,42 (t, 2H, J=7,5 Hz), 3,75 (t, 2H, J=7,5 Hz), 7,39-7,81 (m, 12H), 8,08 (s, 1H), 8,27 (d, 1H, J=10,0 Hz);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -1,7-benzoimidazole-5-carboxamide (Compound 101); 1 H-NMR (300 MHz, CD 3 OD): 3.42 (t, 2H, J = 7.5 Hz), 3.75 (t, 2H, J = 7.5 Hz), 7.39-7 , 81 (m, 12H), 8.08 (s, 1H), 8.27 (d, 1H, J = 10.0 Hz);
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-3-metil-A/-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamidas (102 junginys); 1 H-BMR (300 MHz, CD3OD): 3,41 (t, 2H, J=7,4 Hz), 3,72 (t, 2H, J=7,4 Hz), 3,96 (s, 3H), 4,27 (s, 2H), 7,37-7,54 (m, 5H), 7,67 (d, 1 H, J=8,7 Hz), 7,71-7,77 (m, 2H), 7,80-7,85 (m, 2H), 8,70 (d, 1H,2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 102); 1 H-NMR (300 MHz, CD 3 OD): 3.41 (t, 2H, J = 7.4 Hz), 3.72 (t, 2H, J = 7.4 Hz), 3.96 (s , 3H), 4.27 (s, 2H), 7.37-7.54 (m, 5H), 7.67 (d, 1H, J = 8.7 Hz), 7.71-7.77 (m, 2H), 7.80-7.85 (m, 2H), 8.70 (d, 1H,
J=0,9 Hz), 8,24 (d, 1H, J=8,1 Hz);J = 0.9 Hz), 8.24 (d, 1H, J = 8.1 Hz);
2-(5-aminometil-1/7-benzoimidazol-2-ilmetil)-3-metil-A/-(2-naft-1-iletil)-3/7benzoimidazol-4-karboksamidas (103 junginys); 1H-BMR (300 MHz, CD3OD):2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3,7-benzoimidazole-4-carboxamide (Compound 103); 1 H-NMR (300 MHz, CD 3 OD):
3,45 (t, 2H, J=7,2 Hz), 3,74 (s, 3H), 3,83 (t, 2H, J=7,2 Hz), 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=8,1 Hz);3.45 (t, 2H, J = 7.2 Hz), 3.74 (s, 3H), 3.83 (t, 2H, J = 7.2 Hz), 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 , 1 Hz);
(S)-2-[2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-1/V-benzoimidazol-5ilkarbonilamino]-3-indol-3-ilpropiono rūgštis (104) junginys); 1H-BMR (300 MHz, CD3OD): 3,36 (dd, 1H, J=14,6, 8,1 Hz), 3,53 (dd, 1H, J=14,6, 5,0 Hz), 3,92 (s,(S) -2- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-ylcarbonylamino] -3-indol-3-yl-propionic acid (Compound 104); 1 H-NMR (300 MHz, CD 3 OD): 3.36 (dd, 1H, J = 14.6, 8.1 Hz), 3.53 (dd, 1H, J = 14.6, 5.0 Hz), 3.92 (s,
3H), 4,27 (s, 2H), 6,97 (t, 1H, J=7,4 Hz), 7,07 (t, 1H, J=7,4 Hz), 7,16 (s, 1H), 7,33 (d, 1H J=7,8 Hz), 7,51 (dd, 1H, J=8,4, 1,5 Hz), 7,60-7,66 (m, 2H), 7,73-7,80 (m, 3H), 7,96 (d, 1H, J=0,9 Hz), 8,39 (d, J=7,5 Hz, dalinai pakeistas);3H), 4.27 (s, 2H), 6.97 (t, 1H, J = 7.4 Hz), 7.07 (t, 1H, J = 7.4 Hz), 7.16 (s, 1H), 7.33 (d, 1H J = 7.8 Hz), 7.51 (dd, 1H, J = 8.4, 1.5 Hz), 7.60-7.66 (m, 2H) , 7.73-7.80 (m, 3H), 7.96 (d, 1H, J = 0.9 Hz), 8.39 (d, J = 7.5 Hz, partially substituted);
(R)-2-[2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-1H-benzoimidazol-5ilkarbonilamino]-3-indol-3-ilpropiono rūgštis (105 junginys); 1H-BMR (300MHz,(R) -2- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-ylcarbonylamino] -3-indol-3-yl-propionic acid (Compound 105); 1 H-NMR (300MHz,
CD3OD): 3,35 (dd, 1H, J=14,5, 8,1 Hz), 3,51 (dd, 1H, J=14,4, 4,8 Hz), 3,90 (s, 3H), 4,23 (s, 2H), 6,96 (t, 1H, J=7,4 Hz), 7,06 (t, 1H, J=7,4 Hz), 7,14 (s, 1H), 7,31 (d, 1H, J=7,8 Hz), 7,44 (d, 1H, J=7,8 Hz), 7,58-7,74 (m, 5H), 7,94 (s, 1H), 8,33 (d, J=8,1 Hz, dalinai pakeistas);CD 3 OD): 3.35 (dd, 1H, J = 14.5, 8.1 Hz), 3.51 (dd, 1H, J = 14.4, 4.8 Hz), 3.90 (s , 3H), 4.23 (s, 2H), 6.96 (t, 1H, J = 7.4 Hz), 7.06 (t, 1H, J = 7.4 Hz), 7.14 (s) , 1H), 7.31 (d, 1H, J = 7.8 Hz), 7.44 (d, 1H, J = 7.8 Hz), 7.58-7.74 (m, 5H), 7 , 94 (s, 1H), 8.33 (d, J = 8.1 Hz, partially substituted);
2-(1 H-benzoimidazol-2-ilmetil)-A/-(2-naft-1 -ii eti I) -1 H-benzoimidazol-520 karboksamidas (106 junginys); 1H-BMR (300 MHz, CD3OD): 3,42 (t, 2H, J=7,4 Hz), 3,76 (t, 2H, J=7,4 Hz), 3,97 (s, 3H), 7,38-7,60 (m, 5H), 7,65 (d, 1 H, J=8,7Hz), 7,72-7,79 (m, 4H), 7,85 (dd, 1H, J=8,6, 1,5 Hz), 8,04 (d, 1H, J=1,2 Hz), 8,26 (d, 1H, J=8,4 Hz);2- (1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-yl-ethyl) -1H-benzoimidazole-520-carboxamide (Compound 106); 1 H-NMR (300 MHz, CD 3 OD): 3.42 (t, 2H, J = 7.4 Hz), 3.76 (t, 2H, J = 7.4 Hz), 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, 1.5 Hz), 8.04 (d, 1H, J = 1.2 Hz), 8.26 (d, 1H, J = 8.4 Hz);
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-3-rnetil-/V-(4-aminobutil)-3H• 25 benzoimidazol-4-karboksamidas (107 junginys); MS (Biolon): C22H27N7O1, m/e.2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (4-aminobutyl) -3H-benzoimidazole-4-carboxamide (Compound 107); MS (Biolon): C 22 H 27 N 7 O 1, m / e.
Išskaičiuota: 405,4; Rasta: 406,5 (MH+);Calculated: 405.4; Found: 406.5 (MH + );
2-[1-(5-aminometil-1/7-benzoimidazol-2-il)etil]-3-metil-/V-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamidas (108 junginys); MS (Biolon): C3iH30N6Oi, m/e. Išskaičiuota: 502,6; Rasta: 503,3 (MH+);2- [1- (5-Aminomethyl-1H-benzoimidazol-2-yl) -ethyl] -3-methyl- N - (2-naphth-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 108); MS (Biol) 30 C 3 N 6 iH Oh, m / e. Calculated: 502.6; Found: 503.3 (MH + );
2-(1 H-imidazo[4,5-c]piridin-2-ilmetil)-3-metil-A/-(2-naft-1 -iletiI)-3/7benzoimidazol-5-karboksamidas (109 junginys); MS (Biolon): C^H^NsO,, m/e.2- (1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-1-ethyl-ethyl) -3,7-benzoimidazole-5-carboxamide (Compound 109); MS (Biolon): C 24 H 34 N 5 O 2 m / e.
Išskaičiuota: 460,5; Rasta: 461,3 (MH+);Calculated: 460.5; Found: 461.3 (MH + );
2-(5-aminometil-1/7-benzoimidazol-2-ilkarbonil)-3-metil-/V-(2-naft-1-iletil)-3/-/benzoimidazol-5-karboksamidas (110 junginys); MS (Biolon): C3oH26N602, m/e. Išskaičiuota: 502,6; Rasta: 503,6 (MH+);2- (5-Aminomethyl-1H-benzoimidazol-2-ylcarbonyl) -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 110); MS (Biolon): C 30 H 26 N 6 O 2 , m / e. Calculated: 502.6; Found: 503.6 (MH + );
2-(5-karbamoil-1 H-benzoimidazol-2-ilmetil)-/V-(2-naft-1 -i letil)-1Hbenzoimidazol-5-karboksamidas (111 junginys);2- (5-Carbamoyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-yl-ethyl) -1H-benzoimidazole-5-carboxamide (Compound 111);
2-(5-aminometil-4,5,6,7-tetrahidro-1H-benzoimidazol-2-ilmetil)-3-metilA/-(2-naft-1-iletil)-3H-benzoimidazol-5-karboksamidas (112 junginys); 1H-BMR (300 MHz, CD3OD): 1,67 (m, 1H), 2,14 (m, 1H), 2,24 (m, 1H), 2,47 (dd, 1H, J = 15,3, 9,3 Hz), 2,76 (m, 2H), 2,90 (dd, 1H, J = 15,7, 7,5 Hz), 3,05 (d, 2H, J=6,9 Hz), 3,41 (t, 2H, J=7,4 Hz), 3,75 (t, 2H, J=7,4 Hz), 3,90 (s, 3H), 7,35-7,53 (m, 5H), 7,61 (d, 1H, J=8,4 Hz), 7,72-7,75 (m, 2H), 7,85 (dd, 1H, J=8,1, 1,2 Hz), 7,99 (d, 1H, J=0,9 Hz), 8,26 (d, 1H, J=8,4 Hz);2- (5-Aminomethyl-4,5,6,7-tetrahydro-1 H -benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (112 compound); 1 H-NMR (300 MHz, CD 3 OD): 1.67 (m, 1H), 2.14 (m, 1H), 2.24 (m, 1H), 2.47 (dd, 1H, J = 15.3, 9.3 Hz), 2.76 (m, 2H), 2.90 (dd, 1H, J = 15.7, 7.5 Hz), 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 = 8.4 Hz), 7.72-7.75 (m, 2H), 7.85 (dd, 1H, J = 8, 1, 1.2 Hz), 7.99 (d, 1H, J = 0.9 Hz), 8.26 (d, 1H, J = 8.4 Hz);
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-3-metil-/V-(3-fenilpropil)-3Hbenzoimidazol-5-karboksamidas (113 junginys); 1H-BMR (300 MHz, CD3OD): 1,98 (m, 2H), 2,72 (t, 2H, J=7,6 Hz), 3,46 (t, 2H, J=7,2 Hz), 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=8,1 Hz), 7,70 (d, 1H, J=8,7 Hz), 7,77 (d, 1H, J=8,4 Hz), 7,85-7,88 (m, 2H), 8,16 (s, 1H, J = 1 H);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (3-phenylpropyl) -3H-benzoimidazole-5-carboxamide (Compound 113); 1 H-NMR (300 MHz, CD 3 OD): 1.98 (m, 2H), 2.72 (t, 2H, J = 7.6 Hz), 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 = 8.1 Hz), 7.70 (d, 1H, J = 8.7 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.85- 7.88 (m, 2H), 8.16 (s, 1H, J = 1H);
2-(5-aminometil-1/7-benzoimidazol-2-ilmetil)-3-metil-/V-(2-fenoksietil)-3/7benzoimidazol-5-karboksamidas (114 junginys); 1H-BMR (300 MHz, CD3OD): 3,80 (t, 2H, J=5,0 Hz), 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=7,5 Hz), 7,22 (t, 2H, J=7,5 Hz), 7,55 (d, 1H, J=8,7 Hz), 7,68 (d, 1H, J=6,6 Hz), 7,77 (d, 1H, J=8,4 Hz), 7,84 (s, 1H), 7,88 (d, 1H, J=8,7 Hz), 8,18 (s, 1H);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-phenoxyethyl) -3,7-benzoimidazole-5-carboxamide (Compound 114); 1 H-NMR (300 MHz, CD 3 OD): 3.80 (t, 2H, J = 5.0 Hz), 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 = 7.5 Hz), 7.55 (d, 1H, J = 8.7 Hz), 7.68 (d, 1H, J = 6.6 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.84 (s, 1H), 7.88 (d, 1H, J = 8.7 Hz), 8.18 (s, 1H);
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 /7-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-(2-naft-1-ileti!)-3H-benzoimidazol-5-karboksamidas (115 junginys); 1H-BMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,96 (m, 2H), 3,42 (t, 2H, J=7,4 Hz), 3,75 (t, 2H, J=7,4 Hz), 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=1.5 Hz, 8,08, s, 1H), 8,26 (d, 1H, J=8,0 Hz);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphthyl) 1-yl-3H-benzoimidazole-5-carboxamide (Compound 115); 1 H-NMR (300 MHz, CD 3 OD): 2.45 (2.43, s, 3H), 2.96 (m, 2H), 3.42 (t, 2H, J = 7.4 Hz), 3.75 (t, 2H, J = 7.4 Hz), 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 = 1.5 Hz, 8.08, s, 1H), 8.26 (d, 1H, J = 8.0 Hz);
2-[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-ilkarbonil]-3metil-/V-(2-naft-1-iletil)-3H-benzoimidazol-5-karboksamidas (116 junginys); ’H-BMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 3,03 (m, 2H), 3,41 (t, 2H, J=7,4 Hz), 3,74 (t, 2H, J=7,4 Hz), 3,97 (m, 2H), 4,18 (4,18, s, 3H), 4,66 (4,80, s, 2H),2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl-N- (2-naphth-1) -ethyl) -3H-benzoimidazole-5-carboxamide (Compound 116); 1 H-NMR (300 MHz, CD 3 OD): 2.45 (2.43, s, 3H), 3.03 (m, 2H), 3.41 (t, 2H, J = 7.4 Hz). , 3.74 (t, 2H, J = 7.4 Hz), 3.97 (m, 2H), 4.18 (4.18, s, 3H), 4.66 (4.80, s, 2H) ),
7.38- 7,54 (m, 4H), 7,72-7,92 (m, 4H), 8,04 (s, 1H), 8,26 (d, 1H, J=7,8 Hz);7.38- 7.54 (m, 4H), 7.72-7.92 (m, 4H), 8.04 (s, 1H), 8.26 (d, 1H, J = 7.8 Hz);
2-(5-iminometil-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-ilmetil)-3-metilA/-(2-naft-1-iletil)-3Ay-benzoimidazol-5-karboksamidas (117 junginys); 1H-BMR (300 MHz, CD3OD): 2,95 (m, 2H), 3,40 (t, 2H, J=7,4 Hz), 3,74 (t, 2H, J=7,4 Hz), 3,90 (3,89, s, 3H), 3,98 (m, 2H), 4,70 (4,82, s, 2H), 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=8,4 Hz);2- (5-Iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3α-benzoimidazole-5-carboxamide (Compound 117); 1 H-NMR (300 MHz, CD 3 OD): 2.95 (m, 2H), 3.40 (t, 2H, J = 7.4 Hz), 3.74 (t, 2H, J = 7, 4 Hz), 3.90 (3.89, s, 3H), 3.98 (m, 2H), 4.70 (4.82, s, 2H), 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 = 8.4). Hz);
2-(5-aminometil-4,5,6,7-tetrahidro-1/7-benzoimidazol-2-ilkarbonil)-3-metil-A/(2-naft-1-iletil)-3H-benzoimidazol-5-karboksamidas (118 junginys), 1H-BMR (300 MHz, CD3OD): 1,69 (m, 1H), 2,15 (m, 1H), 2,20 (m, 1H), 2,55 (dd, 1H, J=15.0, 11,4 Hz), 2,81-3,08 (m, 5H), 3,44 (t, 2H, J=7,5 Hz), 3,74 (m, 2H), 4,23 (s, 3H),2- (5-Aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5 carboxamide (Compound 118), 1 H-NMR (300 MHz, CD 3 OD): 1.69 (m, 1H), 2.15 (m, 1H), 2.20 (m, 1H), 2.55 ( dd, 1H, J = 15.0, 11.4 Hz), 2.81-3.08 (m, 5H), 3.44 (t, 2H, J = 7.5 Hz), 3.74 (m, 2H) ), 4.23 (s, 3H),
7.39- 7,52 (m, 4H), 7,75 (dd, 1H, J=6,1, 3,2 Hz), 7,83-7,88 (m, 2H), 7,97 (d, 1H, J=8,7 Hz), 8,10 (s, 1H), 8,27 (d, 1H, J=8,1 Hz);7.39- 7.52 (m, 4H), 7.75 (dd, 1H, J = 6.1, 3.2 Hz), 7.83-7.88 (m, 2H), 7.97 (d, 1H, J = 8.7 Hz), 8.10 (s, 1H), 8.27 (d, 1H, J = 8.1 Hz);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-A/-(2-fenoksietil)-3H-benzoimidazol-5-karboksamidas (119 junginys); 1H-BMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,95 (m, 2H), 3,80 (t, 2H, J=5,6 Hz), 3,95 (s, 3H), 3,98 (m, 2H), 4,17 (t, 2H, J=5,6 Hz), 4,71 (4,81, s, 2H), 6,89 (t, 1H, J=7,3 Hz), 6,93 (d, 2H, J=8,6 Hz), 7,23 (dd, 2H, J=8,6, 7,3 Hz), 7,66 (d, 1H, J=7,8 Hz), 7,85 (d, 1H, J=7,8 Hz), 8,13 (s, 1H);2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-phenoxyethyl) -3H Benzoimidazole-5-carboxamide (Compound 119); 1 H-NMR (300 MHz, CD 3 OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.80 (t, 2H, J = 5.6 Hz). , 3.95 (s, 3H), 3.98 (m, 2H), 4.17 (t, 2H, J = 5.6 Hz), 4.71 (4.81, s, 2H), 6, 89 (t, 1H, J = 7.3 Hz), 6.93 (d, 2H, J = 8.6 Hz), 7.23 (dd, 2H, J = 8.6, 7.3 Hz), 7.66 (d, 1H, J = 7.8 Hz), 7.85 (d, 1H, J = 7.8 Hz), 8.13 (s, 1H);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-(2-benzo[1,3]dioksol-4-iletil)-3H-benzoimidazol-5-karboksamidas (120 junginys); 1H-BMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,89-2,97 (m, 4H), 3,65 (t, 2H, J=7,1 Hz), 3,94 (s, 3H), 3,98 (m, 2H), 4,71 (4,81, s, 2H), 5,83 (s, 2H), 6,656,74 (m, 3H), 7,64 (d, 1H, J=7,8 Hz), 7,76-7,79 (m, 1H), 8,06 (m, 1H);2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2-benzo [1, 3] dioxol-4-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 120); 1 H-NMR (300 MHz, CD 3 OD): 2.45 (2.43, s, 3H), 2.89-2.97 (m, 4H), 3.65 (t, 2H, J = 7 , 1 Hz), 3.94 (s, 3H), 3.98 (m, 2H), 4.71 (4.81, s, 2H), 5.83 (s, 2H), 6.656.74 (m , 3H), 7.64 (d, 1H, J = 7.8 Hz), 7.76-7.79 (m, 1H), 8.06 (m, 1H);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-17/-imidazo[4,5-c]piridin-2-ilmetil]-3metil-A/-(benzoimidazol-1-iletil)-3H-benzoimidazol-5-karboksamidas (121 junginys); 1H-BMR (300 MHz, CD3OD): 2,46 (2,44, s, 3H), 2,96 (m, 2H), 3,92 (s,2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-17 H -imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (benzoimidazol-1-yl ethyl) ) -3 H -benzoimidazole-5-carboxamide (Compound 121); 1 H-NMR (300 MHz, CD 3 OD): 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, 2,2 Hz), 7,93 (s, 1H), 7,98 (dd, J=6,5, 2,1 Hz), 9,49 (s, 1 H);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, 2.2 Hz), 7.93 (s, 1H), 7.98 (dd, J = 6.5, 2.1 Hz), 9, 49 (s, 1H);
N-[2-(5-hidroksi-1/7-indol-2-il)etil]-2-[5-(1-iminoetil)-4,5,6,7-tetrahidro1/y-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-3/7-benzoimidazol-5-karboksamidas (122 junginys); 1H-BMR (300 MHz, CD3OD): 2,42 (2,39, s, 3H), 2,90 (m, 2H), 2,99 (t, 2H, J=7,1 Hz), 3,67 (t, 2H, J=7,1 Hz), 3,75 (s, 3H), 3,93 (m, 2H), 4,66 (4,76, s, 2H), 6,61 (dd, 1H, J=8,5, 2,3 Hz), 6,94 (d, 1H, J=2,3 Hz), 7,06 (s, 1H), 7,12 (d, 1H, J=8,5 Hz),· 7,59 (d, 1H, J=8,4 Hz), 7,76 (dd, 1H, J=8,4, 1,2 Hz), 7,87 (d, 1H, J=1,2 Hz);N- [2- (5-Hydroxy-1H-indol-2-yl) ethyl] -2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4, 5-c] pyridin-2-ylmethyl] -3-methyl-3β-benzoimidazole-5-carboxamide (Compound 122); 1 H-NMR (300 MHz, CD 3 OD): 2.42 (2.39, s, 3H), 2.90 (m, 2H), 2.99 (t, 2H, J = 7.1 Hz). , 3.67 (t, 2H, J = 7.1 Hz), 3.75 (s, 3H), 3.93 (m, 2H), 4.66 (4.76, s, 2H), 6, 61 (dd, 1H, J = 8.5, 2.3 Hz), 6.94 (d, 1H, J = 2.3 Hz), 7.06 (s, 1H), 7.12 (d, 1H) , J = 8.5 Hz), 7.59 (d, 1H, J = 8.4 Hz), 7.76 (dd, 1H, J = 8.4, 1.2 Hz), 7.87 ( d, 1H, J = 1.2 Hz);
2-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-[2-(2-chlorfenoksi)etil]-3W-benzoimidazol-5-karboksamidas (123 junginys); MS (Biolon): C26H28N7O2CI, m/e. Išskaičiuota: 506,0; Rasta: 506,3 (MH+);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2 -chlorophenoxy) ethyl] -3W-benzoimidazole-5-carboxamide (Compound 123); MS (Biolon): C 26 H 28 N 7 O 2 Cl, m / e calcd: 506.0; Found: 506.3 (MH + );
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-A/-[2-(3-chlorfenoksi)etil]-3/7-benzoimidazol-5-karboksamidas (124 junginys); MS (Biolon): C26H28N7O2CI, m/e. Išskaičiuota: 506,0; Rasta: 506,7 (MH+);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (3-chlorophenoxy) ) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 124) MS (Biolon): C26H28N7O2Cl, m / e Calcd: 506.0 Found: 506.7 (MH + );
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-(2-naft-1 -iletil)-3/7-benzoimidazol-5-karboksamidas (125 junginys);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphth-1 ethyl) -3,7-benzoimidazole-5-carboxamide (Compound 125);
’H-BMR (300 MHz, CD3OD): 2,48 (2,46, s, 3H), 3,00 (m, 2H), 3,60 (t, 2H, J=6,6 Hz), 3,90-4,05 (m, 7H), 4,76 (4,76, s, 2H), 6,64 (6,66, s, dalinai pakeistas), 7,457,95 (m, 9H), 8,02 (m, dalinai pakeistas), 8,17 (d, 1H, J=8,1 Hz), 8,96 (s, dalinai pakeistas);1 H-NMR (300 MHz, CD 3 OD): 2.48 (2.46, s, 3H), 3.00 (m, 2H), 3.60 (t, 2H, J = 6.6 Hz), 3 , 90-4.05 (m, 7H), 4.76 (4.76, s, 2H), 6.64 (6.66, s, partially substituted), 7.457.95 (m, 9H), 8, 02 (m, partially substituted), 8.17 (d, 1H, J = 8.1 Hz), 8.96 (s, partially substituted);
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-(2-hidroksi-2-naft-1-iletil)-3H-benzoimidazol-5-karboksamidas (126 junginys); ’H-BMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,94 (m, 2H), 3,55 (dd, 1H, J=13,6, 8,3 Hz), 3,91-3,99 (m, 6H), 4,70 (4,80, s, 2H), 5,78 (dd, 1H, J=8,3, 3,6 Hz), 7,44-7,54 (m, 3H), 7,66 (d, 1H, J=8,4 Hz), 7,76-7,88 (m, 4H), 8,08 (m, 1H), 8,39 (d, 1H,J=8,4Hz);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2-hydroxy- 2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 126); 1 H-NMR (300 MHz, CD 3 OD): 2.45 (2.43, s, 3H), 2.94 (m , 2H), 3.55 (dd, 1H, J = 13.6, 8.3 Hz), 3.91-3.99 (m, 6H), 4.70 (4.80, s, 2H), 5.78 (dd, 1H, J = 8.3, 3.6 Hz), 7.44-7.54 (m, 3H), 7.66 (d, 1H, J = 8.4 Hz), 7 , 76-7.88 (m, 4H), 8.08 (m, 1H), 8.39 (d, 1H, J = 8.4Hz);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-[2-(2-hidroksinaft-1 -il)etil]-3/7-benzoimidazol-5-karboksamidas (127 junginys); 1H-BMR (300 MHz, CD3OD): 2,43 (2,41, s, 3H), 2,92 (m, 2H), 3,41 (t, 2H, J=7,1 Hz), 3,69 (t, 2H, J=7,1 Hz), 3,85 (s, 3H), 3,93-3,96 (m, 2H), 4,68 (4,78, s, 2H), 7,11 (d, 1H, J=8,7 Hz), 7,21 (t, 1H, J=7,5 Hz), 7,38 (dt, 1H, J = 1,2, 7,6 Hz), 7,50-7,61 (m, 2H), 7,69-7,75 (m, 2H), 7,93 (s, 1H), 8,07 (d, 1H, J=8,4 Hz);2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2-hydroxynaphthyl) -1-yl) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 127); 1 H-NMR (300 MHz, CD 3 OD): 2.43 (2.41, s, 3H), 2.92 (m, 2H), 3.41 (t, 2H, J = 7.1 Hz). , 3.69 (t, 2H, J = 7.1 Hz), 3.85 (s, 3H), 3.93-3.96 (m, 2H), 4.68 (4.78, s, 2H). ), 7.11 (d, 1H, J = 8.7 Hz), 7.21 (t, 1H, J = 7.5 Hz), 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 , 4 Hz);
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1W-imidazo[4,5-c]piridin-2-ilmetilj-3meti I-/V- [2-(4-hidroksinaftal-1 -il)etil]-3H-benzoimidazol-5-karboksamidas (128 junginys); ’H-BMR (300 MHz, CD3OD): 2,42 (2,40, s, 3H), 2,89 (m, 2H), 3,27 (m, 2H), 3,69 (t, 2H, J=7,2 Hz), 3,82 (3,83, s, 3H), 3,93 (m, 2H), 4,64 (4,76, s, 2H), 6,72 (d, 1H, J=7,8 Hz), 7,17 (d, 1H, J=7,5 Hz), 7,37 (t, 1H, J=7,5 Hz), 7,46 (dt, 1H, J=0,9, 6,9 Hz), 7,62 (d, 1H, J=8,5 Hz), 7,77 (d, 1H, J=8,5 Hz), 7,95 (s, 1 H), 8,12 (d, 1H, J=8,4 Hz), 8,17 (d, 1H, J=8,4 Hz);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (4-hydroxynaphthalene) -1-yl) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 128); 1 H-NMR (300 MHz, CD 3 OD): 2.42 (2.40, s, 3H), 2.89 ( m, 2H), 3.27 (m, 2H), 3.69 (t, 2H, J = 7.2 Hz), 3.82 (3.83, s, 3H), 3.93 (m, 2H) ), 4.64 (4.76, s, 2H), 6.72 (d, 1H, J = 7.8 Hz), 7.17 (d, 1H, J = 7.5 Hz), 7.37 (t, 1H, J = 7.5 Hz), 7.46 (dt, 1H, J = 0.9, 6.9 Hz), 7.62 (d, 1H, J = 8.5 Hz), 7 , 77 (d, 1H, J = 8.5 Hz), 7.95 (s, 1H), 8.12 (d, 1H, J = 8.4 Hz), 8.17 (d, 1H, J) = 8.4 Hz);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-[2-(2-metoksifenoksi)etil]-3A/-benzoimidazol-5-karboksamidas (129 junginys); ’H-BMR (300 MHz, CD3OD): 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=5,4 Hz), 4,71 (4,81, s, 2H), 6,85-7,00 (m, 4H), 7,66 (d, 1H, J=8,7 Hz), 7,84 (m, 1H), 8,13 (s, 1H);2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2-methoxyphenoxy) ) ethyl] -3 N-benzoimidazole-5-carboxamide (Compound 129); 1 H-NMR (300 MHz, CD 3 OD): 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 = 5.4 Hz), 4.71 (4.81, s, 2H), 6.85-7.00 (m , 4H), 7.66 (d, 1H, J = 8.7 Hz), 7.84 (m, 1H), 8.13 (s, 1H);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-naft-2-ilmetil-3H-benzoimidazol-5-karboksamidas (130 junginys); ’H-BMR (300 MHz, CD3OD): 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, 1,1 Hz), 7,67 (d, 1H, J=8,4 Hz), 7,78-7,83 (m, 4H), 7,90 (m, 1H), 8,16 (m, 1H);2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N-naphth-2-ylmethyl-3H Benzoimidazole-5-carboxamide (Compound 130); 1 H-NMR (300 MHz, CD 3 OD): 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, 1.1 Hz), 7.67 (d, 1H, J = 8.4 Hz), 7.78-7.83 (m, 4H), 7.90 (m, 1H), 8.16 ( m, 1H);
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1W-imidazo[4,5-c]piridin-2-ilmetil]-3metil-N-(3-pirid-4-ilpropil)-3/7-benzoimidazol-5-karboksamidas (131 junginys); ’H-BMR (300 MHz, CD3OD): 2,11 (m, 2H), 2,46 (2,43, s, 3H), 2,96 (m, 2H), 3,06 (t, 2H, J=7,7 Hz), 3,51 (t, 2H, J=6,8 Hz), 3,98 (m, 5H), 4,72 (4,82, s, 2H), 7,67 (d, 1H, J=8,5 Hz), 7,83 (dd, 1H, J=8,5, 1,3 Hz), 8,00 (d, 2H, J=6,6 Hz), 8,15 (d, 1H, J=1,3 Hz), 8,70 (d, 2H, J=6,6 Hz);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (3-pyrid-4-ylpropyl) ) -3,7-Benzoimidazole-5-carboxamide (Compound 131); 1 H-NMR (300 MHz, CD 3 OD): 2.11 (m, 2H), 2.46 (2.43, s, 3H). , 2.96 (m, 2H), 3.06 (t, 2H, J = 7.7 Hz), 3.51 (t, 2H, J = 6.8 Hz), 3.98 (m, 5H) , 4.72 (4.82, s, 2H), 7.67 (d, 1H, J = 8.5 Hz), 7.83 (dd, 1H, J = 8.5, 1.3 Hz), 8.00 (d, 2H, J = 6.6 Hz), 8.15 (d, 1H, J = 1.3 Hz), 8.70 (d, 2H, J = 6.6 Hz);
2-(5-guanidino-1H-benzoimidazo!-2-ilmetil)-3-(2,3-dihidroksi)propil-/V(2-naft-1-iletil)-3H-benzoimidazol-5-karboksamidas (132 junginys); MS (Biolon): C32H32N8O3, m/e. Išskaičiuota: 576,6; Rasta: 577,5 (MH+); ’H-BMR (300 MHz, CD3OD): 3,41 (t, 2H, J=7,5 Hz), 3,58-3,76 (m, 4H), 4,05 (m, 1H), 4,45 (dd, 1H, J=14,9, 8,5 Hz), 4,61 (dd, 1H, J = 14,9, 3,2 Hz), 7,36-7,52 (m, 4H), 7,66-7,85 (m, 4H), 8,14 (s, 1H), 8,25 (d, 1H, J=7,8 Hz);2- (5-Guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 132) ); MS (Biolon): C 32 H 32 N 8 O 3 , m / e. Calculated: 576.6; Found: 577.5 (MH + ); 1 H-NMR (300 MHz, CD 3 OD): 3.41 (t, 2H, J = 7.5 Hz), 3.58-3.76 (m, 4H), 4.05 (m, 1H) , 4.45 (dd, 1H, J = 14.9, 8.5 Hz), 4.61 (dd, 1H, J = 14.9, 3.2 Hz), 7.36-7.52 (m , 4H), 7.66-7.85 (m, 4H), 8.14 (s, 1H), 8.25 (d, 1H, J = 7.8 Hz);
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-[2-(4-metoksifenoksi)etil]-3/7-benzoimidazol-5-karboksamidas (133 junginys); 1H-BMR (300 MHz, CD3OD): 2,45 (2,43, s, 3H), 2,95 (m, 2H), 3,70 (m, 2H), 3,77 (t, 2H, J=5,6 Hz), 3,95 (s, 3H), 3,98 (m, 2H), 4,12 (t, 2H, J=5,6 Hz), 4,71 (4,81, s, 2H), 6,78-6,89 (m, 4H), 7,66 (d, 1H, J=8,4 Hz), 7,84 (m, 1H), 8,13 (d, 1H, J=1,2 Hz);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (4-methoxyphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 133); 1 H-NMR (300 MHz, CD 3 OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.70 (m, 2H), 3.77 (t, 2H, J = 5.6 Hz), 3.95 (s, 3H), 3.98 (m, 2H), 4.12 ( t, 2H, J = 5.6 Hz), 4.71 (4.81, s, 2H), 6.78-6.89 (m, 4H), 7.66 (d, 1H, J = 8, 4 Hz), 7.84 (m, 1H), 8.13 (d, 1H, J = 1.2 Hz);
2-(5-guanidino-1H-benzoimidazol-2-ilkarbonil)-3-(2,3-dihidroksi)propil-A/(2-naft-1-iletil)-3/7-benzoimidazole-5-karboksamidas (134 junginys); MS (Biolon): C32H30N7O4, m/e. Išskaičiuota: 590,6; Rasta: 590,7 (MH+); 1H-BMR (300 MHz, CD3OD): 3,42 (t, 2H, J=7,4 Hz), 3,74 (t, 2H, J=7,4 Hz), 4,00 (d, 2H, J=4,2 Hz), 4,38 (t, 1H, J=11,7 Hz), 4,56 (dd, 1H, J = 12,5, 3,5 Hz), 7,34-7,51 (m, 5H), 7,617,65 (m, 2H), 7,72-7,86 (m, 4H), 8,05 (d, 1H, J=1,2Hz), 8,25 (d, 1H, J=8,1 Hz);2- (5-Guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl-N- (2-naphth-1-ylethyl) -3,7-benzoimidazole-5-carboxamide (134 compound); MS (Biolon): C 32 H 30 N 7 O 4, m / e. Calculated: 590.6; Found: 590.7 (MH + ); 1 H-NMR (300 MHz, CD 3 OD): 3.42 (t, 2H, J = 7.4 Hz), 3.74 (t, 2H, J = 7.4 Hz), 4.00 (d, 2H , J = 4.2 Hz), 4.38 (t, 1H, J = 11.7 Hz), 4.56 (dd, 1H, J = 12.5, 3.5 Hz), 7.34-7 , 51 (m, 5H), 7.617.65 (m, 2H), 7.72-7.86 (m, 4H), 8.05 (d, 1H, J = 1.2Hz), 8.25 (d , 1H, J = 8.1 Hz);
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo(4,5-c]piridin-2-ilmetil]-3metil-A/-[2-(1,2,3,4-tetrahidronaft-1 -il)etil]-3H-benzoimidazol-5-karboksamidas (135 junginys), 1H-BMR (300 MHz, CD3OD): 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=7,4 Hz), 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=8,7 Hz), 7,827,86 (m, 1H), 8,14 (d, 1H, J=0,9 Hz);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo (4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (1 , 2,3,4-Tetrahydronaphth-1-yl) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 135), 1 H-NMR (300 MHz, CD 3 OD): 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 = 7.4 Hz), 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 = 8.7 Hz), 7.827.86 (m, 1H), 8.14 (d, 1H, J = 0.9 Hz);
2-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1A7-imidazo[4,5-c]piridin-2-ilmetil]-3metil-/V-(2-(3-metoksifenoksi)etil]-3/7-benzoimidazol-5-karboksamidas (136 junginys); ’H-BMR (300 MHz, CD3OD): 2,45 (2,42, s, 3H), 2,95 (m, 2H), 3,71 (s, 3H), 3,78 (t, 2H, J=5,6 Hz), 3,94 (s, 3H), 3,97 (m, 2H), 4,15 (t, 2H, J=5,6 Hz), 4,71 (4,80, s, 2H), 6,46-6,54 (m, 3H), 7,12 (t, 1H, J=8,0 Hz), 7,66 (d, 1H, J=8,4 Hz), 7,83 (m, 1 H), 8,12 (m, 1H, J=1,2 Hz);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1β-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2- (3-methoxyphenoxy) ) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 136); 1 H-NMR (300 MHz, CD 3 OD): 2.45 (2.42, s, 3H), 2.95 (m, 2H), 3.71 (s, 3H), 3.78 (t, 2H, J = 5.6 Hz), 3.94 (s, 3H), 3.97 (m, 2H), 4.15 ( t, 2H, J = 5.6 Hz), 4.71 (4.80, s, 2H), 6.46-6.54 (m, 3H), 7.12 (t, 1H, J = 8, 0 Hz), 7.66 (d, 1H, J = 8.4 Hz), 7.83 (m, 1H), 8.12 (m, 1H, J = 1.2 Hz);
2-(5-guanidino-1H-benzoimidazol-2-ilmetil)-A/-(3-fenilpropil)-1A/benzoimidazol-5-karboksamidas (137 junginys);2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1 N-benzoimidazole-5-carboxamide (Compound 137);
2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-(3-hidroksi)propil-N-(2-naft-1iletil)-3/7-benzoimidazol-5-karboksamidas (138 junginys); 1H-BMR (300 MHz, CD3OD): 2,09 (m, 2H), 3,44 (t, 2H, J=7,4 Hz), 3,58 (t, 2H, J=5,6 Hz), 3,77 (t, 2H, J=7,4 Hz), 4,55 (t, 2H, J=7,1 Hz), 7,32 (dd, 1H, J=8,6, 1,9 Hz), 7,37-7,55 (m, 4H),2- (5-Guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphthylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 138) ; 1 H-NMR (300 MHz, CD 3 OD): 2.09 (m, 2H), 3.44 (t, 2H, J = 7.4 Hz), 3.58 (t, 2H, J = 5.6 Hz) ), 3.77 (t, 2H, J = 7.4 Hz), 4.55 (t, 2H, J = 7.1 Hz), 7.32 (dd, 1H, J = 8.6, 1, 9 Hz), 7.37-7.55 (m, 4H),
7,61 (d, 1H, J = 1,9 Hz), 7,69 (d, 1H, J=8,4 Hz), 7,73-7,88 (m, 4H), 8,11 (s, 1H), 8,28 (d, 1H, J=8,1Hz);7.61 (d, 1H, J = 1.9 Hz), 7.69 (d, 1H, J = 8.4 Hz), 7.73-7.88 (m, 4H), 8.11 (s , 1H), 8.28 (d, 1H, J = 8.1 Hz);
2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-A/-[2-(2metoksi)fenoksietil]-3/7-benzoimidazole-5-karboksamidas (139' junginys); MS (Biolon): C29H32N8O5, m/e. Išskaičiuota: 572,62; Rasta: 573,3 (MH+); 1H-BMR (300 MHz, CD3OD): 3,58-3,69 (m, 2H), 3,80 (m, 5H), 4,07 (m, 1H), 4,17 (t, 2H, J=5,3 Hz), 4,47 (dd, 1H, J=15,0, 8,4 Hz), 4,64 dd, 1H, J = 15,0, 3,0 Hz), 6,66-7,00 (m, 4H), 7,38 (dd, 1H, J=8,6, 1,7 Hz), 7,66 (d, 1H, J = 1,7Hz), 7,70 (d, 1H, J=8,6 Hz), 7,78 (d, 1H, J=8,6 Hz), 7,87 (dd, 1H, J=8,6, 1,5 Hz), 8,24 (d, 1H, J = 1,5 Hz);2- (5-Guanidino-1/7-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3,7-benzoimidazole-5-carboxamide (Compound 139 '); MS (Biolon): C 29 H 32 N 8 O 5 , m / e. Calculated: 572.62; Found: 573.3 (MH + ); 1 H-NMR (300 MHz, CD 3 OD): 3.58-3.69 (m, 2H), 3.80 (m, 5H), 4.07 (m, 1H), 4.17 (t, 2H, J = 5.3 Hz), 4.47 (dd, 1H, J = 15.0, 8.4 Hz), 4.64 dd, 1H, J = 15.0, 3.0 Hz), 6 , 66-7.00 (m, 4H), 7.38 (dd, 1H, J = 8.6, 1.7 Hz), 7.66 (d, 1H, J = 1.7 Hz), 7.70 (d, 1H, J = 8.6 Hz), 7.78 (d, 1H, J = 8.6 Hz), 7.87 (dd, 1H, J = 8.6, 1.5 Hz), δ , 24 (d, 1H, J = 1.5 Hz);
2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-(2,3-dihidroksipropil)-N(2-naft-1-iletil)-3/7-benzoimidazol-5-karboksamidas (140 junginys); MS (Biolon): C33H34N8O3, m/e. Išskaičiuota: 590,7; Rasta: 591,3 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-ylethyl) -3,7-benzoimidazole- 5-Carboxamide (Compound 140); MS (Biolon): C 33 H 34 N 8 O 3, m / e. Calculated: 590.7; Found: 591.3 (MH + );
2-(5-guanidino-1H-benzoimidazol-2-ilcarbonil)-3-(2,3-dihidroksipropil)-/7[2-(2-metoksifenoksi)etil]-3H-benzoimidazol-5-karboksamidas (141 junginys); MS (Biolon): C29H30N8O6, m/e. Išskaičiuota: 586,6; Rasta: 587,5 (MH+); 1H-BMR (300 MHz, CD3OD): 3,33 (m, 1 H), 3,81 (m, 5H), 3,98 (d, 2H, J=4,5 Hz), 4,18 (t, 2H, J=5,4 Hz), 4,38 (t, 1H, J=12,0 Hz), 4,57 (dd, 1H, J = 12,0, 3,5Hz), 6,85-7,00 (m, 4H), 7,30 (dd, 1H, J=8,7, 2,2 Hz), 7,60 (d, 1H, J=2,2Hz), 7,64 (d, 1H, J=8,4 Hz), 7,74 (d, 1H, J=8,7 Hz), 7,80 (dd, 1H, J=8,4,1,5 Hz), 8,14 (d, 1H, J = 1,5 Hz);2- (5-Guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxypropyl) - [7 - [2- (2-methoxyphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 141) ; MS (Biolon): C 29 H 30 N 8 O 6, m / e. Calculated: 586.6; Found: 587.5 (MH + ); 1 H-NMR (300 MHz, CD 3 OD): 3.33 (m, 1H), 3.81 (m, 5H), 3.98 (d, 2H, J = 4.5 Hz), 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, 2.2 Hz), 7.60 (d, 1H, J = 2.2 Hz), 7.64 (d) , 1H, J = 8.4 Hz), 7.74 (d, 1H, J = 8.7 Hz), 7.80 (dd, 1H, J = 8.4.1.5 Hz), 8.14 (d, 1H, J = 1.5 Hz);
2-(5-(1 -iminoetil)aminometil-1 /7-benzoimidazol-2-ilmetil]-3(2,3-dihidroksi)propil-N-[2-(2-metoksi)fenoksietil]-3H-benzoimidazol-5karboksamidas (142 junginys); 1H-BMR (300 MHz, CD3OD): 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=5,4 Hz), 4,46 (dd, 1H, J=15,0, 8,7 Hz), 4,62-4,66 (m 3H), 6,86-7,00 (m, 4H), 7,53 (dd, 1H, J=8,7, 1,2 • 25 Hz), 7,68 (d, 1H, J=8,4 Hz), 7,77-7,80 (m, 2H), 7,84 (dd, 1H, J=8,4, 1,4 Hz), 8,21 (d, 1H, J=1,4 Hz);2- (5- (1-iminoethyl) aminomethyl-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3H-benzoimidazole- 5-carboxamide (Compound 142); 1 H-NMR (300 MHz, CD 3 OD): 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 = 5.4 Hz), 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, 1.2 x 25Hz) , 7.68 (d, 1H, J = 8.4 Hz), 7.77-7.80 (m, 2H), 7.84 (dd, 1H, J = 8.4, 1.4 Hz), 8.21 (d, 1H, J = 1.4 Hz);
2-{2-[2-(5-guanidino-1H-benzoimidazol-2-ilmetil)-3-metil-3/-/-benzoimidazol5-ilkarbonilamino]etoksi}metilo benzoatas (143 junginys); MS (Biolon): C28H28N8O4, m/e. Išskaičiuota: 54,56; Rasta: 541,4 (MH+);2- {2- [2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino] ethoxy} methyl benzoate (Compound 143); MS (Biolon): C 28 H 28 N 8 O 4 , m / e. Calculated: 54.56; Found: 541.4 (MH + );
2-{-2-[2-(5-guanidino-1/-/-benzoimidazol-2-ilmetil)-3-metil-Ay-benzoimidazol5-ilkarbonilamino]etoksi}benzenkarboksirūgštis (144 junginys);2 - {- 2- [2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3-methyl-Ay-benzoimidazol-5-ylcarbonylamino] ethoxy} benzoic acid (Compound 144);
3-{-2-[2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-metil-3/-/benzoimidazol-5-ilkarbonilamino]etoksi}metilo benzoatas (145 junginys); MS (Biolon): ϋ28Η28Ν3Ο4, m/e. Išskaičiuota: 540,5; Rasta: 541,4 (MH+);3 - {- 2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy} methyl benzoate (Compound 145); MS (Biol) ϋ 8Η 2 28 3 Ν Ο 4, m / e. Calculated: 540.5; Found: 541.4 (MH + );
2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-metil-/V-[2-(2,6-.2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - [2- (2,6-.
dimetoksi)fenoksietil]-3/7-benzoimidazol-5-karboksamidas (146 junginys);1H-BMR (300 MHz, CD3OD): 3,71 (t, 2H, J=5,3 Hz), 3,73 (s, 6H), 4,01 (s, 3H), 4,13 (t, 2H, J=5,3 Hz), 6,63 (d, 2H, J=8,4 Hz), 6,99 (t, 1H, J=8,4 Hz), 7,33 (dd, 1H, J=8,6, 1,9 Hz), 7,63 (d, 1H, J=1,9 Hz), 7,74 (d, 1H, J=8,7 Hz), 7,75 (d, 1H, J=8,6 Hz), 7,90 (dd, 1H, J=8,7, 1,5 Hz), 8,21 (d, 1H, J=1,5 Hz);dimethoxy) phenoxyethyl] -3,7-benzoimidazole-5-carboxamide (Compound 146); 1 H-NMR (300 MHz, CD 3 OD): 3.71 (t, 2H, J = 5.3 Hz), 3.73 (s, 6H), 4.01 (s, 3H), 4.13 (t, 2H, J = 5.3 Hz), 6.63 (d, 2H, J = 8.4 Hz), 6.99 (t, 1H, J = 8.4 Hz), 7.33 (dd) , 1H, J = 8.6, 1.9 Hz), 7.63 (d, 1H, J = 1.9 Hz), 7.74 (d, 1H, J = 8.7 Hz), 7.75 (d, 1H, J = 8.6 Hz), 7.90 (dd, 1H, J = 8.7, 1.5 Hz), 8.21 (d, 1H, J = 1.5 Hz);
2-(5-guanidinometil-1/7-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-W[2-(2-metoksifenoksi)etil]-3H-benzoimidazol-5-karboksamidas (147 junginys); 1H-BMR (300 MHz, CD3OD): 3,57-3,69 (m, 2H), 3,80 (m, 5H), 4,05 (m, 1 H), 4,17 (t, 2H, J=5,4 Hz), 4,45 (dd, 1H, J=15,0, 8,7 Hz), 4,58-4,65 (m, 3H), 6,85-7,00 (m, 4H), 7,50 (dd, 1H, J=8,7, 1,5 Hz), 7,67 (d, 1H, J=8,5 Hz), 7,72 (d, 1H, J=1,5 Hz),2- (5-guanidinomethyl-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (147 compound); 1 H-NMR (300 MHz, CD 3 OD): 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, 1.5 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.72 (d, 1H , J = 1.5 Hz),
7,76 (d, 1H, J=8,7 Hz), 7,82 (dd, 1H, J=8,5, 1,4 Hz), 8,19 (d, 1H, J = 1,4 Hz);7.76 (d, 1H, J = 8.7 Hz), 7.82 (dd, 1H, J = 8.5, 1.4 Hz), 8.19 (d, 1H, J = 1.4 Hz) );
2-(5-iminometilaminometil-1/7-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-/V-[2-(2-metoksi)fenoksietil]-3/7-benzoimidazol-5-karboksamidas (148 junginys), 1H-BMR (300 MHz, CD3OD): 3,58-3,70 (m, 2H), 3,81 (m, 5H), 4,06 (m, 1H), 4,19 (t, 2H, J=5,4 Hz), 4,46 (dd, 1H, J = 15,0, 8,7 Hz), 4,64 (dd, 1H, J = 15,0,2- (5-Iminomethylaminomethyl-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - [2- (2-methoxy) phenoxyethyl] -3,7-benzoimidazol-5 -carboxamide (compound 148), 1 H-NMR (300 MHz, CD 3 OD): 3.58-3.70 (m, 2H), 3.81 (m, 5H), 4.06 (m, 1H) , 4.19 (t, 2H, J = 5.4 Hz), 4.46 (dd, 1H, J = 15.0, 8.7 Hz), 4.64 (dd, 1H, J = 15.0) ,
3,0 Hz), 4,69 (4,73, s, 2H), 6,86-7,01 (m, 4H), 7,51 (dd, 1H, J=8,1, 1,5 Hz), 7,69 (d, 1H, J=8,6 Hz), 7,76-7,79 (m, 2H), 7,84 (dd, 1H, J=8,6, 1,3 Hz), 7,96 (8,12, s, 1H), 8,21 (d, 1H, J=1,3Hz);3.0 Hz), 4.69 (4.73, s, 2H), 6.86-7.01 (m, 4H), 7.51 (dd, 1H, J = 8.1, 1.5 Hz) ), 7.69 (d, 1H, J = 8.6 Hz), 7.76-7.79 (m, 2H), 7.84 (dd, 1H, J = 8.6, 1.3 Hz) , 7.96 (8.12, s, 1H), 8.21 (d, 1H, J = 1.3 Hz);
2-(5-guanidino-1W-benzoimidazol-2-ilmetil)-3-metil-/V-(2-hidroksi-2-chinol-4iletil)-3/7-benzoimidazol-5-karboksamidas (149 junginys); 1 H-BMR (300 MHz,2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3-methyl- N - (2-hydroxy-2-quinol-4-ylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 149); 1 H-NMR (300 MHz,
CD3OD): 3,60 (dd, 1H, J=13,8, 7,5 Hz), 3,97-4,06 (m, 4H), 5,99 (dd, 1H, J=7,5, 3,6 Hz), 7,35 (dd, 1H, J=8,7, 2,0 Hz), 7,65 (d, 1H, J=2,0 Hz), 7,69 (d, 1H, J=8,7 Hz), 7,77 (d, 1H, J=8,7 Hz), 7,84 (dd, 1H, J=8,7, 1,5 Hz), 7,99 (m, 1H), 8,11-8,18 (m, 2H), 8,26 (d, 1H, J=8,4 Hz), 8,33 (d, 1H, J=5,7Hz), 8,88 (d, 1H, J=8,7 Hz), 8,15 (d, 1H, J=5,7 Hz);CD3OD): 3.60 (dd, 1H, J = 13.8, 7.5 Hz), 3.97-4.06 (m, 4H), 5.99 (dd, 1H, J = 7.5, 3.6 Hz), 7.35 (dd, 1H, J = 8.7, 2.0 Hz), 7.65 (d, 1H, J = 2.0 Hz), 7.69 (d, 1H, J = 8.7 Hz), 7.77 (d, 1H, J = 8.7 Hz), 7.84 (dd, 1H, J = 8.7, 1.5 Hz), 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 = 8.7 Hz), 8.15 (d, 1H, J = 5.7 Hz);
2-(5-guanidino-1H-benzoirnidazol-2-ilmetil)-3-metil-A/-[2-(3-metil-2,4dioksochinazolin-1-il)etil]-3/7-benzoimidazol-5-karboksamidas (150 junginys); MS (Biolon): C29H28N10O3, m/e. Išskaičiuota: 564,6; Rasta: 565,5 (MH+);2- (5-Guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2- (3-methyl-2,4-dioxoquinazolin-1-yl) ethyl] -3,7-benzoimidazol-5-one. carboxamide (compound 150); MS (Biolon): C 29 H 28 N 10 O 3 , m / e. Calculated: 564.6; Found: 565.5 (MH + );
2-{2-[2-(5-guanidino-1/7-benzoimidazol-2-ilkarbonil)-3-metil-3Hbenzoimidazol-5-ilkarbonilamino]etoksi}metilo benzoatas (151 junginys); MS (Biolon): Ο28Η26Ν3Ο5, m/e. Išskaičiuota: 554,5; Rasta: 554,8 (MH+);2- {2- [2- (5-Guanidino-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] -ethoxy} methyl-benzoate (Compound 151); MS (Biol) 2 Ο 3 Ο 8Η26Ν 5, m / e. Calculated: 554.5; Found: 554.8 (MH + );
2-(5-guanidino-1/7-benzoimidazol-2-ilmetil)-3-(2-hidroksi)etil-/V-(2-naft-1iletil)-3/7-benzoimidazol-5-karboksamidas (152 junginys); 1H-BMR (300 MHz, CD3OD): 3,44 (t, 2H, J=7,4 Hz), 3,77 (t, 2H, J=7,4 Hz), 3,95 (t, 2H, J=4,9 Hz), 4,56 (t, 2H, J=4,9 Hz), 7,32 (dd, 1H, J=8,7, 1,8 Hz), 7,40-7,54 (m, 4H), 7,61 (d, 1H, J=1,8 Hz), 7,67-7,89 (m, 5H), 8,09 (d, 1H, J = 1,2 Hz), 8,28 (d, 1H, J=8,1 Hz);2- (5-Guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl- N - (2-naphthylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 152) ); 1 H-NMR (300 MHz, CD 3 OD): 3.44 (t, 2H, J = 7.4 Hz), 3.77 (t, 2H, J = 7.4 Hz), 3.95 (t, 2H , J = 4.9 Hz), 4.56 (t, 2H, J = 4.9 Hz), 7.32 (dd, 1H, J = 8.7, 1.8 Hz), 7.40-7 , 54 (m, 4H), 7.61 (d, 1H, J = 1.8 Hz), 7.67-7.89 (m, 5H), 8.09 (d, 1H, J = 1.2) Hz), 8.28 (d, 1H, J = 8.1 Hz);
2-(5-guanidino-1H-benzoimidazol-2-ilmetil)-3-metil-N-[2-(3-okso-2,3dihidrobenzo[1,4]oksazin-4-il)etil]-3/7-benzoimidazol-5-karboksamidas (153 junginys);2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4-yl) ethyl] -3/7 Benzoimidazole-5-carboxamide (Compound 153);
2-(5-guanidino-1H-benzoimidazol-2-ilkarbonil]-3-(2-hidroksietil)-/V-(2-naft-2- / iletil)-3H-benzoimidazol-5-karboksamidas (154 junginys); 1H-BMR (300 MHz,CD3OD): 3,42 (t, 2H, J=7,3 Hz), 3,75 (t, 2H, J=7,3 Hz), 4,48-4,51 (m, 2H), 7,29 (dd, 1H, J=8,6, 1,9 Hz), 7,38-7,52 (m, 4H), 7,58 (d, 1H, J=1,9 Hz), 7,62 (d, 1H, J=8,7 Hz), 7,71-7,76 (m, 3H), 7,86 (d, 1H, J=8,6 Hz), 8,06 (s, 1H), 8,26 (d, 1H, J=8,1 Hz) ;2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2-hydroxyethyl) -N- (2-naphth-2-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 154); 1 H-NMR (300 MHz, CD 3 OD): 3.42 (t, 2H, J = 7.3 Hz), 3.75 (t, 2H, J = 7.3 Hz), 4.48-4 , 51 (m, 2H), 7.29 (dd, 1H, J = 8.6, 1.9 Hz), 7.38-7.52 (m, 4H), 7.58 (d, 1H, J = 1.9 Hz), 7.62 (d, 1H, J = 8.7 Hz), 7.71-7.76 (m, 3H), 7.86 (d, 1H, J = 8.6 Hz) ), 8.06 (s, 1H), 8.26 (d, 1H, J = 8.1 Hz);
2-(5-guanidino-1/y-benzoimidazol-2-ilkarbonil)-3-metil-/V-(2-naft-1-iletil)-3/7benzoimidazol-5-karboksamidas (155 junginys);2- (5-guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3-methyl- N - (2-naphth-1-ylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 155);
2-(5-guanidino-1H-benzoimidazol-2-ilkarbonil)-3-(3-hidroksipropil)-/V-(2naft-l-iletiO-S/y-benzoimidazokS-karboksamidas (156 junginys);2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (3-hydroxypropyl) -N- (2-naphth-1-yl-ethyl) -N-benzoimidazole-5-carboxamide (Compound 156);
2-(5-imidazol-1-il-1H-benzoimidazol-2-ilmetil)-3-metil-A/-(2-naft-1-iIetil)-3Hbenzoimidazol-5-karboksamidas (157 junginys);2- (5-Imidazol-1-yl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 157);
2-[1-(5-guanidino-1//-benzoimidazol-2-il)etil]-3-metil-/V-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamidas (158 junginys); MS (Biolon): C3iH3oNsOi, m/e. Išskaičiuota: 530,6; Rasta: 531,1 (MH+);2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 158); MS (Biol) C 3 3 oN iH s Oh, m / e. Calculated: 530.6; Found: 531.1 (MH + );
2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-A/-(2-naft-1 -i lėti I) -3/7benzoimidazol-5-karboksamidas (159 junginys); MS (Biolon): C33H29N7O1, m/e. Išskaičiuota; 539,6; Rasta: 540,1 (MH+);2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N - (2-naphth-1-yl) -3,7-benzoimidazol-5 -carboxamide (compound 159); MS (Biolon): C 33 H 29 N 7 O 1, m / e. Excluded; 539.6; Found: 540.1 (MH + );
2-{1-[5-(2-aminoimidazol-1-il)-1H-benzoimidazol-2-il]etil}-3-metil-/V-(2-naft5 1-iletil)-3H-benzoimidazol-5-karboksamidas (160 junginys); MS (Biolon):2- {1- [5- (2-Amino-imidazol-1-yl) -1H-benzoimidazol-2-yl] -ethyl} -3-methyl-N- (2-naphth-5-yl-ethyl) -3H-benzoimidazol-5-one. -carboxamide (compound 160); MS (Biolon):
C33H3oNaOi, m/e. Išskaičiuota: 554,7; Rasta: 555,2 (MH+);C33H30NaO1, m / e. Calculated: 554.7; Found: 555.2 (MH + );
1- (5-guanidino-1/7-benzoimidazol-2-il)-3-hidroksi-1-metil-A/-(2-naft-1-iletil)3,4-dihidro-1 /7-2-oksa-4a,9-diazafluoren-6-karboksamidas (161 junginys);1- (5-guanidino-1/7-benzoimidazol-2-yl) -3-hydroxy-1-methyl-N- (2-naphth-1-yl-ethyl) 3,4-dihydro-1 / 7-2- oxa-4a, 9-diazafluorene-6-carboxamide (Compound 161);
2- [1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-(4-hidroksibutil)-N-(2-naft-110 iletil)-3H-benzoimidazol-5-karboksamidas (162 junginys); MS (Biolon):2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (4-hydroxybutyl) -N- (2-naphth-110-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 162) ); MS (Biolon):
C34H36N8O2, m/e. Išskaičiuota: 588,7; Rasta: 589,3 (MH+);C34H36N8O2, m / e. Calculated: 588.7; Found: 589.3 (MH + );
3- [2-[1 -(5-guanidino-1 /7-benzoimidazol-2-il)etil]-6-(2-naft-1 iletilkarbamoil)benzoimidazol-1-il]propan-1-sulfonrūgštis (163 junginys): MS (Biolon): C33H34N8O4S, m/e. Išskaičiuota: 638,7; Rasta: 639,2 (MH+);3- [2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -6- (2-naphth-1-yl-ethylcarbamoyl) -benzoimidazol-1-yl] -propane-1-sulfonic acid (Compound 163) ): MS (Biolon): C 33 H 34 N 8 O 4 S, m / e. Calculated: 638.7; Found: 639.2 (MH + );
3-[2-[1-(5-imidazol-1-il-17/-benzoimidazol-2-il)etil]-6-(2-naft-1iletilkarbamoil)benzoimidazol-1-il]propan-1-sulfonrūgštis (164 junginys): MS (Biolon): C35H33N7O4S, m/e. Išskaičiuota: 647,8; Rasta: 648,2 (MH+);3- [2- [1- (5-Imidazol-1-yl-17H-benzoimidazol-2-yl) -ethyl] -6- (2-naphthylethyl-ethylcarbamoyl) -benzoimidazol-1-yl] -propane-1-sulfonic acid ( Compound 164): MS (Biolon): C 35 H 33 N 7 O 4 S, m / e. Calculated: 647.8; Found: 648.2 (MH + );
2-[ 1 -(5-guanidino-1 /-/-benzoimi dazol-2-il)-2-meti I propi I] -3-m eti l-N- (2-naft-1 iletil)-3/7-benzoimidazol-5-karboksamidas (165 junginys); MS (Biolon):2- [1- (5-guanidino-1H-benzoimidazol-2-yl) -2-methylpropyl] -3-methyl-N- (2-naphth-1-yl-ethyl) -3 / 7- benzoimidazole-5-carboxamide (compound 165); MS (Biolon):
C33H34N8O1, m/e. Išskaičiuota: 558,7; Rasta: 559,6 (MH+);C33H34N8O1, m / e. Calculated: 558.7; Found: 559.6 (MH + );
2- [ 1 -(1 /7-imidazo[4,5-c]piridin-2-il)etil]-3-metil-N-(2-naft-1 -i lėti I)-3/7benzoimidazol-5-karboksamidas (166 junginys); MS (Biolon): C29H26N6O1, m/e. Išskaičiuota: 474,6; Rasta: 475,2 (MH+);2- [1- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-N- (2-naphth-1-yl) -3,7-benzoimidazole-5 -carboxamide (compound 166); MS (Biolon): C 29 H 26 N 6 O 1, m / e. Calculated: 474.6; Found: 475.2 (MH + );
2-{5-[1-(N-metilimino)etil]-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-225 ilmetil}-3-metil-N-(2-naft-1 -iletil)-3/7-benzoimidazol-5-karboksamidas (167 junginys); MS (Biolon) : C31H33N7O, m/e. Išskaičiuota: 519,71; Rasta: 520,9 (MH ), imino(2-{1-[1-metil-6-(2-naft-1-iletilkarbamoil)-1/7-benzoimidazol-2-il]etil}1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-il)acto rūgštis (168 junginys); MS (Biolon): C31H31N7O3, m/e. Išskaičiuota: 549,6; Rasta: 550,2 (MH+);2- {5- [1- (N-Methylimino) ethyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-225-ylmethyl} -3-methyl-N- (2-naphth-1-ethyl) -3,7-benzoimidazole-5-carboxamide (Compound 167); MS (Biolon): C 31 H 33 N 7 O, m / e. Calculated: 519.71; Found: 520.9 (MH), imino (2- {1- [1-methyl-6- (2-naphth-1-yl-ethylcarbamoyl) -1,7-benzoimidazol-2-yl] ethyl} 1,4,6 , 7-tetrahydroimidazo [4,5-c] pyridin-5-yl) acetic acid (Compound 168); MS (Biolon): C 31 H 31 N 7 O 3, m / e. Calculated: 549.6; Found: 550.2 (MH + );
2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-il]etil}3-meti!-N-(2-naft-1-iletil)-3H-benzoimidazol-5-karboksamidas (169 junginys); MS (Biolon); C31H33N7O1, m/e. Išskaičiuota: 519,6; Rasta; 520,3 (MH+);2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl-N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 169); MS (Biolon); C31H33N7O1, m / e. Calculated: 519.6; Found; 520.3 (MH + );
2-{1-[5-(/V-metilamidino)-4,5,6,7-tetrahidro-1W-imidazo[4,5-c]piridin-2il]etil}-3-metil-A/-(2-naft-1-iletil)-3W-benzoimidazol-5-karboksamidas (170 junginys); MS (Biolon); C31H34N8O1, m/e. Išskaičiuota: 534,7; Rasta: 535,1 (MH+);2- {1- [5 - (N-methylamidino) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-N - ( 2-naphth-1-ylethyl) -3W-benzoimidazole-5-carboxamide (Compound 170); MS (Biolon); C31H34N8O1, m / e. Calculated: 534.7; Found: 535.1 (MH + );
2-(2-{2-[1-(5-guanidino-1A7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)-5-metoksibenzenkarboksirūgštis (171 junginys); MS (Biolon): C29H30N8O5, m/e. Išskaičiuota: 570,6; Rasta: 571,2 (MH+);2- (2- {2- [1- (5-guanidino-1β, 7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) -5-methoxybenzoic acid (Compound 171); MS (Biolon): C 29 H 30 N 8 O 5, m / e. Calculated: 570.6; Found: 571.2 (MH + );
2-(2-{2-[1-(5-guanidino-1/-/-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)izoftalio rūgštis (172 junginys); MS (Biolon): C29H30N8O5, m/e. Išskaičiuota: 570,6; Rasta: 571,3 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 172) ; MS (Biolon): C 29 H 30 N 8 O 5, m / e. Calculated: 570.6; Found: 571.3 (MH + );
2-(2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)-1-hidroksietil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)-6-metoksibenzenkarboksirūgštis (173 junginys); MS (Biolon): C29H30N8O6, m/e. Išskaičiuota: 586,6; Rasta: 587,2 (MH+);2- (2- {2- [1- (5-Guanidino-1/7-benzoimidazol-2-yl) -1-hydroxyethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) -6-methoxybenzoic acid (Compound 173); MS (Biolon): C 29 H 30 N 8 O 6, m / e. Calculated: 586.6; Found: 587.2 (MH + );
2-[2-(2-{1-[5-(/V-acetilguanidino)-1/V-benzoimidazol-2-il]etil}-3-metil-3Hbenzoimidazol-5-ilkarbonilamino)etoksi]etilo benzoatas (174 junginys); MS (Biolon); C31H32N8O5, m/e. Išskaičiuota: 596,6; Rasta: 597,2 (MH+);2- [2- (2- {1- [5 - (N-acetylguanidino) -1 N-benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] ethyl benzoate (174 compound); MS (Biolon); C31H32N8O5, m / e. Calculated: 596.6; Found: 597.2 (MH + );
2-{1-[5-(A/,A/-dimetilamidino)-4,5,6,7-tetrahidro-1W-imidazo[4,5-c]piridin-2il]etil}-3-metil-/V-(2-naft-1-iletil)-3/7-benzoimidazol-5-karboksamidas (175 junginys);2- {1- [5- (N, N-Dimethylamidino) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl- N- (2-naphth-1-ylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 175);
2-{1-[5-(2-amino-1,1-dimetiletil)-1A/-benzoimidazol-2-il]etil}-3-metil-A/-(2naft-1-iletil)-3W-benzoimidazol-5-karboksamidas (176 junginys);2- {1- [5- (2-Amino-1,1-dimethylethyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-N- (2-naphth-1-yl-ethyl) -3W-benzoimidazole -5-carboxamide (compound 176);
2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-il]etil}A/-etil-3-metil-3/-/-benzoimidazol-5-karboksamidas (177 junginys);2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -N-ethyl-3 -methyl-3H-benzoimidazole-5-carboxamide (Compound 177);
2-[2-(2-{1-[5-(/V-acetilguanidino)-1/7-benzoimidazol-2-il]etil}-3-metil3H-benzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis (178 junginys); MS (Biolon): C30H30N8O5, m/e. Išskaičiuota: 582,6; Rasta: 583,3 (MH+);2- [2- (2- {1- [5 - (N-acetylguanidino) -1,7-benzoimidazol-2-yl] ethyl} -3-methyl3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 178) ); MS (Biolon): C 30 H 30 N 8 O 5, m / e. Calculated: 582.6; Found: 583.3 (MH + );
2-[2-(2-{ 1 -[5-(1 -aminociklopropil)-1 W-benzoimidazol-2-il]etil}-3-metil3/7-benzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis (179 junginys); MS (Biolon): C30H30N6O4, m/e. Išskaičiuota: 538,6; Rasta: 539,3 (MH+);2- [2- (2- {1- [5- (1-Aminocyclopropyl) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 179) ); MS (Biolon): C 30 H 30 N 6 O 4, m / e. Calculated: 538.6; Found: 539.3 (MH + );
2-(1-(5-imidazol-1-il-1 H-benzoimidazol-2-il)etil]-3-metil-A/-(3-metilbutil)3H-benzoimidazol-5-karboksamidas (180 junginys); MS (Biolon): C26H29N7O1, m/e. Išskaičiuota: 455,6; Rasta: 456,2 (MH+);2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (3-methylbutyl) 3H-benzoimidazole-5-carboxamide (Compound 180); MS (Biolon): C 26 H 29 N 7 O 1, m / e Calcd: 455.6; Found: 456.2 (MH + );
2-(1/7-benzoimidazol-2-iletil)-3-metil-/V-(2-fenoksietil)-3tf-benzoimidazol-5karboksamidas (181 junginys); MS (Biolon): C26H25N5O2, m/e. Išskaičiuota: 439,5; Rasta: 440,2 (MH+);2- (1H-Benzoimidazol-2-ylethyl) -3-methyl- N - (2-phenoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 181); MS (Biolon): C 26 H 25 N 5 O 2, m / e. Calculated: 439.5; Found: 440.2 (MH + );
2-(2-(2-(1-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1W-imidazo[4,5-c]piridin-2il]etil}-3-metil-3/-/-benzoimidazol-5-ilkarbonilamino)etoksi]etilo benzoatas (182 junginys);2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl) -3-methyl) -3 H - benzoimidazol-5-ylcarbonylamino) ethoxy] ethyl benzoate (Compound 182);
2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-N-[2-(2,4-diokso-3,4dihidro-2H-chinazolin-1-il)etil]-3/-/-benzoimidazol-5-karboksamidas (183 junginys);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl) ethyl) -3H-benzoimidazole-5-carboxamide (Compound 183);
2-(1-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}/V-(3-metoksipropil)-3-metil-3W-benzoimidazol-5-karboksamidas (184 junginys);2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -N- (3-methoxypropyl) -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 184);
A/-etil-2-[1-(5-imidazol-1 -il-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-karboksamidas (185 junginys); MS (Biolon): C23H23N7O1, m/e. Išskaičiuota: 413,5; Rasta: 414,1 (MH+);N-ethyl-2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 185); MS (Biolon): C 23 H 23 N 7 O 1, m / e. Calculated: 413.5; Found: 414.1 (MH + );
2-[1-(5-imidazol-1-il-1H-benzoimidazol-2-il)etil]-/V-(2-metoksietil)-3-metil3H-benzoimidazol-5-karboksamidas (186 junginys); MS (Biolon): C24H25N7O2, m/e. Išskaičiuota: 443,5; Rasta: 444,2 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -N- (2-methoxyethyl) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 186); MS (Biolon): C 24 H 25 N 7 O 2, m / e. Calculated: 443.5; Found: 444.2 (MH + );
-(2-(1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il) etil] -3-m etil-3/7benzoimidazol-5-ilkarbonilamino)-4-metilpentano rūgštis (187 junginys); MS (Biolon): C27H29N7O3, m/e. Išskaičiuota: 499,6; Rasta: 500,3 (MH+);- (2- (1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino) -4-methylpentanoic acid (Compound 187) MS (Biolon): C 27 H 29 N 7 O 3, m / e Calcd: 499.6, Found: 500.3 (MH + );
2-(2-(2-(1 -(5-imidazol-1 -il-1 Z7-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (188 junginys); MS (Biolon): C30H27N7O4, m/e. Išskaičiuota: 549,6; Rasta: 550,2 (MH+);2- (2- (2- (1- (5-imidazol-1-yl-1 H, 7-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 188); MS (Biolon): C 30 H 27 N 7 O 4, m / e calcd: 549.6, Found: 550.2 (MH + );
2-(2-(1 -(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1A/-imidazo[4,5-c]piridin-2-il]etil}3-metil-3/-/-benzoimidazol-5-ilkarbonilamino)-4-metilpentano rūgštis (189 junginys);2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 N -imidazo [4,5-c] pyridin-2-yl] ethyl) 3-methyl- 3 - [(benzoimidazol-5-ylcarbonylamino) -4-methylpentanoic acid (Compound 189);
2-{1-[5-(/V,/V-dimetilamidino)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il] etil}-3-metil-3/7-benzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis (190 junginys); MS (Biolon): C39H34N8O4, m/e. Išskaičiuota: 558,6; Rasta: 559,3 (MH+);2- {1- [5 - (N, N-dimethylamidino) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl -3,7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 190); MS (Biolon): C 39 H 34 N 8 O 4, m / e. Calculated: 558.6; Found: 559.3 (MH + );
2-[2-(2-{1-[5-(2-karboksi-1-iminoetil)-4,5,6,7-tetrahidro-1/-/-imidazo[4,5c]piridin-2-il]etil}-3-metil-3/7-benzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis (191 junginys); MS (Biolon): C29H31N7O6, m/e. Išskaičiuota: 573,6; Rasta: 530,3 (MH+), praradus CO2;2- [2- (2- {1- [5- (2-Carboxy-1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl) ] ethyl} -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 191); MS (Biolon): C 29 H 31 N 7 O 6, m / e. Calculated: 573.6; Found: 530.3 (MH + ), with loss of CO 2 ;
2-(2-{2-[1 -(5-imidazol-1 -il-1 A/-benzoimidazol-2-il)etil]-3-(2-metoksietil)3tf-benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (192 junginys); MS (Biolon): C32H31N7O5, m/e. Išskaičiuota: 593,6; Rasta: 594,2 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) 3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (compound 192); MS (Biol) 31 C 2 H 3 N7O5 m / e. Calculated: 593.6; Found: 594.2 (MH + );
2-[1 -(5-imidazol-1 -il-1 W-benzoimidazol-2-il)etil ]-3-(2-metoksieti I) -Λ/(2-metoksietil)-3/7-benzoimidazol-5-karboksamidas (193 junginys); MS (Biolon): C26H29N7O3, m/e. Išskaičiuota: 487,6; Rasta: 488,2 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -N- (2-methoxyethyl) -3,7-benzoimidazol-5 -carboxamide (compound 193); MS (Biolon): C 26 H 29 N 7 O 3, m / e. Calculated: 487.6; Found: 488.2 (MH + );
2- [2-(2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1/-/-imidazo[4,5-c]piridin-2il]etil}-3-(2-metoksietil)-3/7-benzoimidazol-5-ilkarbonilamino)etoksijbenzenkarboksirūgštis (194 junginys);2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 3- (2-methoxyethyl) -3,7-benzoimidazol-5-ylcarbonylamino) ethoxybenzoic acid (Compound 194);
3- (2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (185 junginys); MS (Biolon): C28H28N8O4, m/e. Išskaičiuota: 540,6; Rasta: 541,3 (MH+);3- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 185); MS (Biolon): C 28 H 28 N 8 O 4, m / e. Calculated: 540.6; Found: 541.3 (MH + );
2-(2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-(2-metoksietil)-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (196 junginys); MS (Biolon): C30H32N8O5, m/e. Išskaičiuota: 584,6; Rasta: 585,3 (MH+);2- (2- {2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 196) ; MS (Biolon): C 30 H 32 N 8 O 5, m / e. Calculated: 584.6; Found: 585.3 (MH + );
2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-(3-sulfopropil)-3/7benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (197 junginys); MS (Biolon): C30H32N8O7S, m/e. Išskaičiuota: 648,7; Rasta: 649,6 (MH+);2- (2- {2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 197) ; MS (Biolon): C 30 H 32 N 8 O 7 S, m / e. Calculated: 648.7; Found: 649.6 (MH + );
2-(2-{2-[1 -(5-imidazol-i -il-1 /7-benzoimidazol-2-iI)etil]-3-(3-sulfopropil)-3/7benzoimidazo!-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (198 junginys); MS (Biolon): C32H31N7O7S, m/e. Išskaičiuota: 657,7; Rasta: 658,4 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (compound 198); MS (Biolon): C 32 H 31 N 7 O 7 S, m / e. Calculated: 657.7; Found: 658.4 (MH + );
2-(2-{2-[1-(5-imidazol-1-il-3-metil-3/7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi) benzenkarboksirūgštis (199 junginys); MS (Biolon): C31H29N7O4, m/e. Išskaičiuota: 563,6; Rasta: 564,2 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-3-methyl-3,7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy ) benzoic acid (compound 199); MS (Biolon): C 31 H 29 N 7 O 4, m / e. Calculated: 563.6; Found: 564.2 (MH + );
2-(2-{2-[1-(5-imidazol-1-il-1H-benzoimidazol-2-il)etil]-3-(2-hidroksipropil)3A7-benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (200 junginys);2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3- (2-hydroxypropyl) -3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid ( Compound 200);
MS (Biolon): C32H31N7O5, m/e. Išskaičiuota: 593,6; Rasta: 594,3 (MH+);MS (Biolon): C 32 H 31 N 7 O 5, m / e. Calculated: 593.6; Found: 594.3 (MH + );
2-{2-[2-(1 -{5-[1 - (/V-hidroksii mi no) eti I] -4,5,6,7-tetrahid ro-1 H-imidazo[4,5c]piridin-2-il}etil)-3-metil-3AY-benzoimidazol-5-ilkarbonilamino]etoksi}benzenkarboksirūgštis (201 junginys);2- {2- [2- (1- {5- [1 - (N-Hydroxyamino) ethyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridine -2-yl} ethyl) -3-methyl-3AY-benzoimidazol-5-ylcarbonylamino] ethoxy} benzoic acid (Compound 201);
2-(2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (202 junginys); MS (Biolon): C30H32N8O4, m/e. Išskaičiuota: 568,6; Rasta: 569,5 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 202); MS (Biolon): C 30 H 32 N 8 O 4, m / e. Calculated: 568.6; Found: 569.5 (MH + );
2-[2-(2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2iljetil}-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-ilkarbonilamino)etoksi]etilo benzoatas (203 junginys); MS (Biolon): C28H36N8O4, m/e. Išskaičiuota: 549,0; Rasta: 548,2 (MH+);2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl} ethyl) -1,4,6 7-Tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] ethyl benzoate (Compound 203); MS (Biolon): C 28 H 36 N 8 O 4, m / e. Calculated: 549.0; Found: 548.2 (MH + );
4-{2-[1-(5-guanidino-1W-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol5-ilkarbonilamino}etilo butiratas (204 junginys); MS (Biolon): C25H30N8O3, m/e. Išskaičiuota: 490,57; Rasta: 491,3 (MH+);4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethyl butyrate (Compound 204); MS (Biolon): C 25 H 30 N 8 O 3, m / e. Calculated: 490.57; Found: 491.3 (MH + );
2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-tetrazol-1ilfenoksi)etil)-3/7-benzoimidazol-5-karboksamidas (205 junginys); MS (Biolon): C28H28N12O2, m/e. Išskaičiuota: 564,56; Rasta: 565,3 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-tetrazol-1-ylphenoxy) ethyl] -3,7-benzoimidazol-5 -carboxamide (compound 205); MS (Biolon): C 28 H 28 N 12 O 2, m / e. Calculated: 564.56; Found: 565.3 (MH + );
2-[2-(2-{1-[5-(1-iminoetilamino)-1/7-benzoimidazol-2-il]etil}-3-metil-3Hbenzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis (206 junginys); MS (Biolon): C31H33N7O4, m/e. Išskaičiuota: 567,6; Rasta: 568,4 (MH+);2- [2- (2- {1- [5- (1-iminoethylamino) -1,7-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 206) ; MS (Biolon): C 31 H 33 N 7 O 4 , m / e. Calculated: 567.6; Found: 568.4 (MH + );
4- (2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-3Wbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (207 junginys); MS (Biolon): C30H32N8O4, m/e. Išskaičiuota: 568,6; Rasta: 569,4 (MH+);4- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 207); MS (Biolon): C 30 H 32 N 8 O 4, m / e. Calculated: 568.6; Found: 569.4 (MH + );
5- (2-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)izoftalio rūgštis (208 junginys); MS (Biolon): C29H28N8O6, m/e. Išskaičiuota: 584,6; Rasta: 585,3 (MH+);5- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 208); MS (Biolon): C 29 H 28 N 8 O 6, m / e. Calculated: 584.6; Found: 585.3 (MH + );
4-(2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirugštis (209 junginys); MS (Biolon): C28H28N8O4, m/e. Išskaičiuota: 540,6; Rasta: 541,2 (MH+);4- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 209); MS (Biolon): C 28 H 28 N 8 O 4 , m / e. Calculated: 540.6; Found: 541.2 (MH + );
2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-(2-hidroksipropil)-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (210 junginys);2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3- (2-hydroxypropyl) -3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 210);
MS (Biolon): C30H32N8O5, m/e. Išskaičiuota: 584,6; Rasta: 585,4 (MH+);MS (Biolon): C 30 H 32 N 8 O 5 , m / e. Calculated: 584.6; Found: 585.4 (MH + );
2-[1-(5-imidazol-1-il-1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2metoksifenoksi)etil]-3H-benzoimidazol-5-karboksamidas (211 junginys); MS (Biolon): C3oH29N702, m/e. Išskaičiuota: 535,6; Rasta: 536,3 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (211 compound); MS (Biolon): C 30 H 29 N 7 O 2 , m / e. Calculated: 535.6; Found: 536.3 (MH + );
2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (212 junginys); MS (Biolon): C27H26N8O4, m/e. Išskaičiuota: 526,6; Rasta: 527,2 (MH+);2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 212); MS (Biolon): C 27 H 26 N 8 O 4 , m / e. Calculated: 526.6; Found: 527.2 (MH + );
2-[ 1 -(5-imidazol-1 -ii-1 A/-benzoimidazol-2-il)etil]-3-metil-A/-(2-fenoksietil)-3/7benzoimidazol-5-karboksamidas (213 junginys); MS (Biolon): C29H27N7O2, m/e. Išskaičiuota: 505,6; Rasta: 506,2 (MH+);2- [1- (5-Imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-phenoxyethyl) -3,7-benzoimidazole-5-carboxamide (Compound 213) ); MS (Biolon): C 29 H 27 N 7 O 2 , m / e. Calculated: 505.6; Found: 506.2 (MH + );
2-(2-{2-[1-(5-imidazol-1-il-1H-benzoimidazol-2-il)etil]-1/7-benzoimidazol-5ilkarbonilamino}etoksi)benzenkarboksirūgštis (214 junginys); MS (Biolon): C29H25N7O4, m/e. Išskaičiuota: 535,6; Rasta: 536,4 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 214); MS (Biolon): C 29 H 25 N 7 O 4 , m / e. Calculated: 535.6; Found: 536.4 (MH + );
2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-3/-/benzoimidazol-5-ilkarbonilamino}etoksi)-4-metiletilbenzoatas (215 junginys); MS (Biolon): 03ΐΗ34Ν804, m/e. Išskaičiuota: 582,7; Rasta: 583,5 (MH+);2- (2- {2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H- benzoimidazol-5-ylcarbonylamino} ethoxy) -4-methylethylbenzoate (Compound 215) ); MS (Biol) 34 Ν 03ΐΗ 8 04 m / e. Calculated: 582.7; Found: 583.5 (MH + );
2-(2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-benzoimidazol-5ilkarbonilamino}etoksi)-4-metilbenzenkarboksirūgštis (216 junginys); MS (Biolon): C29H30N8O4, m/e. Išskaičiuota: 554,6; Rasta: 555,5 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-benzoimidazol-5-ylcarbonylamino} -ethoxy) -4-methyl-benzoic acid (Compound 216); MS (Biolon): C 29 H 30 N 8 O 4 , m / e. Calculated: 554.6; Found: 555.5 (MH + );
2-[2-(2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1/-/-imidazo[4,5-c]piridin-2il]etil}-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-ilkarbonilamino)etoksi]benzoatas (217 junginys); MS (ESI): C26H32N8O4, m/e. Išskaičiuota: 520,58; Rasta: 521,3 (MH+);2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 1,4,6,7-Tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (Compound 217); MS (ESI): C 26 H 32 N 8 O 4 , m / e. Calculated: 520.58; Found: 521.3 (MH + );
2-(2-{2-[5-(N-metilamidino)-1/7-benzoimidazol-2-ilmetil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (218 junginys); MS (Biolon): C3oH3iN704, m/e. Išskaičiuota: 553,6; Rasta: 554,3 (MH+);2- (2- {2- [5- (N-Methylamidino) -1,7-benzoimidazol-2-ylmethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 218); MS (Biol) C3oH iN 7 3 0 4, m / e. Calculated: 553.6; Found: 554.3 (MH + );
2-[2-(2-{ 1 - [5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 A7-imidazo[4,5-c]piridin-2il]etil}-3-(3-sulfopropil)-3H-benzoimidazol-5-ilkarbonilamino)etoksi]86 benzenkarboksirūgštis (219 junginys): MS (Biolon): C30H35N7O7, m/e. Išskaičiuota: 637,7; Rasta: 638,3 (MH+);2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl} -3- (3-sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] 86 benzoic acid (Compound 219): MS (Biolon): C30H35N7O7, m / e. Calculated: 637.7; Found: 638.3 (MH + );
2-(2-(1-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-il]etil}3-metil-3H-benzoimidazol-5-ilkarbonilamino)-4-etilmetilo valeratas (220 junginys):2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl) 3-methyl -3 H -benzoimidazol-5-ylcarbonylamino) -4-ethylmethyl valerate (Compound 220):
2-(2-(2-(1-(5-(1-(/V-hidroksiimino)etil]-4,5,6,7-tetrahidro-1H-imidazo[4,5c]piridin-2-il}etil)-3-metil-3/7-benzoimidazol-5-ilkarbonilamino]etoksi}etilo benzoatas (221 junginys):2- (2- (2- (1- (5- (1 - (N-hydroxyimino) ethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl)}) ethyl) -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino] ethoxy} ethyl benzoate (Compound 221):
2-(1-(1 /7-benzoimidazol-2-il)etil]-3-metil-A/-[2-(2-metoksifenoksi)etil]-3Hbenzoimidazol-5-karboksamidas (222 junginys): MS (Biolon): C27H27N5O3, m/e.2- (1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 222): MS (Biolon ): C27H27N5O3, m / e.
Išskaičiuota: 469,5; Rasta: 469,5 (MH+);Calculated: 469.5; Found: 469.5 (MH + );
2-(2-etoksikarbonilfenoksi)etil 2-[1-(6-guanidino-1H-benzoimidazol-2-il)etil]1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-karboksilatas (223 junginys): MS (Biolon): C28H32N8O5l m/e. Išskaičiuota: 560,62; Rasta: 561,3 (MH+);2- (2-Ethoxycarbonylphenoxy) ethyl 2- [1- (6-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate ( Compound 223): MS (Biolon): C 28 H 32 N 8 O 5l m / e. Calculated: 560.62; Found: 561.3 (MH + );
4-(2-(1-(5-guanidino-1A/-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol15 5-ilkarbonilamino}butano rūgštis (224 junginys): MS (Biolon): C23H26N8O3, m/e. Išskaičiuota: 462,52; Rasta: 462,8 (MH+);4- (2- (1- (5-guanidino-1A-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-15-ylcarbonylamino} butanoic acid (Compound 224): MS (Biolon): C23H26N8O3, m / e Calculated: 462.52 Found: 462.8 (MH + );
2-(1 -(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}3-metil-A/-[2-(2-tetrazolilfenoksi)etil]-3/7-benzoimidazol-5-karboksamidas (225 junginys); MS (ESI): C28H31N11O2, m/e. Išskaičiuota: 553,6; Rasta: 553,5 (MH+);2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl-N - [ 2- (2-Tetrazolylphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 225); MS (ESI): C 28 H 31 N 11 O 2, m / e calcd: 553.6; Found: 553.5 (MH + ). ;
2-(2-(2-(1 -(5-imidazol-1 -il-1 /-/-benzoimidazol-2-il) eti I j-3-m eti I-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)izopropilo benzoatas (226 junginys); MS (Biolon): C33H33N7O4, m/e. Išskaičiuota: 591,3; Rasta: 591,4 (MH+);2- (2- (2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) isopropyl benzoate (Compound 226) MS (Biolon): C33H33N7O4, m / e Calcd: 591.3; Found: 591.4 (MH + );
2-(1 -(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}3-metil-A/-[2-(3-tetrazolilfenoksi)etil]-3A/-benzoimidazol-5-karboksamidas (227 junginys): MS (Biolon): C28H31NHO2, m/e. Išskaičiuota: 553,59; Rasta: 553,5 (MH+);2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl-N - [ 2- (3-Tetrazolylphenoxy) ethyl] -3 N-benzoimidazole-5-carboxamide (Compound 227): MS (Biolon): C 28 H 31 NHO 2, m / e calcd: 553.59; Found: 553.5 (MH + );
2-(1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}3-metil-/V-[2-(4-tetrazolilfenoksi)etil]-3H-benzoimidazol-5-karboksamidas (228 junginys); MS (ESI): C28H3iNuO2, m/e. Išskaičiuota: 553,59; Rasta: 553,5 (MH+);2- (1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl-N- [ 2- (4-Tetrazolylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 228); MS (ESI): C 28 H 31 N 6 O 2 , m / e calcd: 553.59; Found: 553.5 (MH +). );
2- (2-{2-[1 -(5-imidazol-1 -ii)-1 W-benzoimidazol-2-il]etil}-3-metil-3Hbenzoimidazol-5-ilkarbonilamino)cikloheksiletoksibenzoatas (229 junginys); MS (ESI): C36H37N7O4, m/e. Išskaičiuota: 631,3; Rasta: 631,5 (MH+);2- (2- {2- [1- (5-imidazol-1-yl) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) cyclohexylethoxybenzoate (Compound 229); MS (ESI): C 36 H 37 N 7 O 4, m / e. Calculated: 631.3; Found: 631.5 (MH + );
2-[2-(2-{1-[5-(/V-metilamidino)-1H-benzoimidazol-2-il]etil}-3-metil-3F/5 benzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis (230 junginys); MS (Biolon): C28H27N7O4, m/e. Išskaičiuota: 525,6; Rasta: 525,5 (MH+);2- [2- (2- {1- [5 - (N-methylamidino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3F / 5 benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (230 compound); MS (Biolon): C 28 H 27 N 7 O 4, m / e. Calculated: 525.6; Found: 525.5 (MH + );
2-[2-(2-{1-[5-(1-iminoetilamino)-1/-/-benzoimidazol-2-il]etil}-3-metil-3Hbenzoimidazol-5-ilkarbonilamino)etoksi]benzenkarboksirūgštis (231 junginys); MS (Biolon): C29H29N7O4, m/e. Išskaičiuota: 539,6; Rasta: 539,8 (MH+);2- [2- (2- {1- [5- (1-iminoethylamino) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 231) ); MS (Biolon): C 29 H 29 N 7 O 4, m / e. Calculated: 539.6; Found: 539.8 (MH + );
2-(3-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-ilkarbonil}propoksi)benzenkarboksirūgštis (232 junginys); MS (Biolon): C27H30N8O4, m/e. Išskaičiuota: 530,60; Rasta: 531,7 (MH+);2- (3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonyl} propoxy ) benzoic acid (compound 232); MS (Biolon): C 27 H 30 N 8 O 4, m / e. Calculated: 530.60; Found: 531.7 (MH + );
2-(2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-1,4,6,715 tetrahidroimidazo[4,5-c]piridin-5-ilformiloksi}etoksi)benzenkarboksirūgštis (233’ junginys); MS (Biolon): C26H28N8O5, m/e. Išskaičiuota: 532,56; Rasta: 533,2 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,715 tetrahydroimidazo [4,5-c] pyridin-5-ylformyloxy} ethoxy) benzoic acid (compound 233 '); MS (Biolon): C 26 H 28 N 8 O 5, m / e. Calculated: 532.56; Found: 533.2 (MH + );
2-(2-{2-[1 -(5-imidazol-1 -ii-1 H-benzoim idazol-2-i I) eti I ]-3-meti I-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)-2-metoksietilo benzoatas (234 junginys);2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) -2 -methoxyethyl benzoate (compound 234);
MS (Biolon): C33H33N7O5, m/e. Išskaičiuota: 607,3; Rasta: 607,4 (MH+);MS (Biolon): C 33 H 33 N 7 O 5, m / e. Calculated: 607.3; Found: 607.4 (MH + );
2-(2- {2- [ 1 -(5-imidazol-1 -ii-1 H-benzoimidazol-2-il)etil]-3-metil-3A/benzoimidazol-5-ilkarbonilamino}etoksi)izobutilo benzoatas (235 junginys); MS (Biolon): C34H35N7O4, m/e. Išskaičiuota: 605,3; Rasta: 605,4 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 N / benzoimidazol-5-ylcarbonylamino} ethoxy) isobutyl benzoate (235 compound); MS (Biolon): C 34 H 35 N 7 O 4, m / e. Calculated: 605.3; Found: 605.4 (MH + );
2-(2-{2-[1-(5-imidazol-1-il-1H-benzoimidazol-2-il)etil]-3-metil-3H25 benzoimidazol-5-ilkarbonilamino}etoksi)-2-(2-metoksietoksi)etilo benzoatas (236 junginys); MS (Biolon): C35H37N7O6, m/e. Išskaičiuota: 651,3; Rasta: 651,3 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H25 benzoimidazol-5-ylcarbonylamino} ethoxy) -2- (2- methoxyethoxy) ethyl benzoate (Compound 236); MS (Biolon): C 35 H 37 N 7 O 6, m / e. Calculated: 651.3; Found: 651.3 (MH + );
2-(2-{2-[1-(5-imidazol-1-il-1/7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)butilo benzoatas (237 junginys); MS (Biolon): C34H35N7O4, m/e. Išskaičiuota: 605,3; Rasta: 605,4 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) butyl benzoate ( Compound 237); MS (Biol) H35N 7 3 4 O 4, m / e. Calculated: 605.3; Found: 605.4 (MH + );
2-[1-(1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(3-okso-2,3dihidrobenzo[1,4]oksazin-4-il)etil]-3H-benzoimidazol-5-karboksamidas (238 junginys); MS (Biolon); C28H26N6O3, m/e. Išskaičiuota: 494,2; Rasta: 494,5 (MH+);2- [1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4-yl) ethyl] -3H Benzoimidazole-5-carboxamide (Compound 238); MS (Biolon); C28H26N6O3, m / e. Calculated: 494.2; Found: 494.5 (MH + );
2-[1-(1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-fluorofenoksi)etil]-3Hbenzoimidazol-5-karboksamidas (239 junginys);2- [1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-fluorophenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 239);
2-(1-(1 H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(3-fluorofenoksi)etil]-3Wbenzoimidazol-5-karboksamidas (240 junginys);2- (1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (3-fluorophenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 240);
2-(1-(1 W-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-izopropoksifenoksi)etil]3/7-benzoimidazol-5-karboksamidas (241 junginys); MS (Biolon): C29H31N5O3, m/e. Išskaičiuota: 497,2; Rasta: 497,6 (MH+);2- (1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-isopropoxyphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 241); MS (Biolon): C29H31N5O3, m / e Calc'd: 497.2 Found: 497.6 (MH + );
2-[1-(1/7-benzoimidazol-2-il)etil]-3-metil-A/-(2-(2-metilfenoksi)etil]-3/7benzoimidazol-5-karboksamidas (242 junginys); MS (Biolon): 027^7^02, m/e. Išskaičiuota: 453,2; Rasta: 453,5 (MH+);2- [1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-N- (2- (2-methylphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 242); MS (Biolon): 027 ^ 7 ^ 02, m / e Calc'd: 453.2 Found: 453.5 (MH + );
2-(1-(1 A/-benzoimidazol-2-il)etil]-3-metil-/\/-[2-(2-etoksifenoksi)etil]-3/7benzoimidazol-5-karboksamidas (243 junginys); MS (Biolon): C28H29N5O3, m/e. Išskaičiuota: 483,2; Rasta: 483,5 (MH+);2- (1- (1 H -benzoimidazol-2-yl) ethyl] -3-methyl-N - [2- (2-ethoxyphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 243); MS (Biolon): C 28 H 29 N 5 O 3, m / e Calcd: 483.2 Found: 483.5 (MH + );
2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-A/-[2-(2metoksifenoksi)etil]-3W-benzoimidazol-5-karboksamidas (244 junginys); MS (Biolon): C28H30N8O3, m/e. Išskaičiuota: 526,6; Rasta: 526,8 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methoxyphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 244); MS (Biolon): C 28 H 30 N 8 O 3, m / e. Calculated: 526.6; Found: 526.8 (MH + );
2- (2-(2- (1 -(5-guanidino-1 H-benzoimidazol-2-il)etil]-1,4,6,7tetrahidroimidazo[4,5-cjpiridin-5-ilkarbonilamino}etoksi)etilo benzoatas (245 junginys); MS (Biolon): C28H33N9O4, m/e. Išskaičiuota: 559,6; Rasta: 559,6 (MH+);2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 245) MS (Biolon): C 28 H 33 N 9 O 4, m / e calcd: 559.6; Found: 559.6 (MH + );
2-(2-(2-(1-(1A/-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino}etoksi)-2-metoksietilo benzoatas (246 junginys); MS (Biolon): C3oH31N504) m/e. Išskaičiuota: 541,6; Rasta: 541,5 (MH+);2- (2- (2- (1- (1A) -benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) -2-methoxyethyl benzoate (Compound 246); Biol): C 30 H 31 N 5 O 4) m / e calcd: 541.6 Found: 541.5 (MH + );
2-(2-(2-(1 -(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (247 junginys); MS (Biolon): C29H3oN804, m/e. Išskaičiuota: 554,6; Rasta: 555,4 (MH+);2- (2- (2- (1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 247); MS (Biolon) : C 29 H 30 N 8 O 4 , m / e calcd: 554.6; Found: 555.4 (MH + );
2-(2-(2-(1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-3Wbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (248 junginys); MS (Biolon): CzsHžsNsCL, m/e. Išskaičiuota: 540,6; Rasta: 541,3 (MH+);2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 248); MS (Biolon ): C 25 H 25 N 2 Cl 2, m / e Calcd: 540.6 Found: 541.3 (MH + );
2-[1-(5-guanidino-1/-/-benzoimidazol-2-il)etil]-/V-[2-(2-karbamoilfenoksi)etiljS-metil-SH-benzoimidazol-S-karboksamidas (249 junginys); MS (Biolon):2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] -S-methyl-5 H -benzoimidazole-5-carboxamide (Compound 249) ; MS (Biolon):
C28H29N9O3, m/e. Išskaičiuota: 539,6; Rasta: 540,5 (MH+);C28H29N9O3, m / e. Calculated: 539.6; Found: 540.5 (MH + );
2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-/V-[2-(2-karbamoil-4chlorofenoksi)etil]-3-metil-3H-benzoimidazol-5-karboksamidas (250 junginys); MS (Biolon): C28H28NgO3CI, m/e. Išskaičiuota: 574,0; Rasta: 574,2 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 250); MS (Biolon): C 28 H 28 N 8 O 3 Cl, m / e. Calculated: 574.0; Found: 574.2 (MH + );
4- chlor-2-(2-{2-[1-(5-guanidino-1/7-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (251 junginys); MS (Biolon): C28H27N8O4CI, m/e. Išskaičiuota: 575,0; Rasta: 575,2 (MH+);4-Chloro-2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 251) ; MS (Biolon): C 28 H 27 N 8 O 4 Cl, m / e. Calculated: 575.0; Found: 575.2 (MH + );
5- chlor-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (252 junginys); MS (Biolon): Ο28Η27Ν8Ο40Ι, m/e. Išskaičiuota: 575,0; Rasta; 575,2 (MH+);5-chloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 252); MS (Biolon): Ο 28 Η 27 Ν 8 Ο 4 0., M / e. Calculated: 575.0; Found; 575.2 (MH + );
6- chlor-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (253 junginys); MS (Biolon): C28H27NaO4CI, m/e. Išskaičiuota: 575,0; Rasta: 575,2 (MH+);6-chloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 253); MS (Biolon): C 28 H 27 NaO 4 Cl, m / e. Calculated: 575.0; Found: 575.2 (MH + );
4,6-dichlor-2-(2-{2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (254 junginys); MS (Biolon): Ο28Η26Ν8Ο4ΟΙ2, m/e. Išskaičiuota: 609,5; Rasta: 609,1 (MH+);4,6-Dichloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 254) ; MS (Biolon): Ο 28 8 Η 2 6Ν 8 Ο 4 ΟΙ 2 , m / e. Calculated: 609.5; Found: 609.1 (MH + );
2-(2-{2-[1-(1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5karbonilamino}etoksi)etilo benzoatas (255 junginys); MS (Biolon): C29H29N5O4, m/e. Išskaičiuota: 511,6; Rasta: 512,2 (MH+);2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carbonylamino} ethoxy) ethyl benzoate (Compound 255); MS (Biol) 2 C 9 H 29 N5O 4, m / e. Calculated: 511.6; Found: 512.2 (MH + );
2-[1-(5-guanidino-1H-benzoimidazol-2-il)etil]-3-metil-/V-{2-[2,4-diokso3-(2-trimetilsilaniletil)-3,4-dihidro-2H-chinazolin-1 -iljetil}-3H-benzoimidazol-5karboksamidas (256 junginys); MS (Biolon): C34H4oNi003Si, m/e. Išskaičiuota: 664,8; Rasta; 665,4 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - {2- [2,4-dioxo-3- (2-trimethylsilanylethyl) -3,4-dihydro- 2H-quinazolin-1-yl-ethyl} -3H-benzoimidazole-5-carboxamide (Compound 256); MS (Biol) 34 C 4 H 3 0 0 ONI Si m / e. Calculated: 664.8; Found; 665.4 (MH + );
2-[1-(5-guanidino-1/-/-benzoimidazol-2-il)etil]-3-metil-/V-{2-[2,4-diokso3,4-dihidro-2H-chinazolin-1-iljetil}-3H-benzoimidazol-5-karboksamidas (257 junginys); MS (Biolon): C29H28Nio03, m/e. Išskaičiuota: 564,6; Rasta: 565,2 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - {2- [2,4-dioxo-3,4-dihydro-2H-quinazoline-1] -yl-ethyl} -3H-benzoimidazole-5-carboxamide (Compound 257); MS (Biolon): C 29 H 28 N 10 O 3 , m / e. Calculated: 564.6; Found: 565.2 (MH + );
2-[1-(1/7-benzoimidazol-2-il)etil]-/V-[2-(2-cianofenoksi)etil]-3-metil3/7-benzoimidazol-5-karboksamidas (258 junginys); MS (Biolon): C27H24N6O2l m/e. Išskaičiuota: 454,5; Rasta: 465,1 (MH+);2- [1- (1H-Benzoimidazol-2-yl) ethyl] -N- [2- (2-cyanophenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 258); MS (Biol) 2 C 6 H 2l 7H24N m / e. Calculated: 454.5; Found: 465.1 (MH + );
5-(2-{2-[1-(1/7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino}etoksi)izoftalio rūgštis (259 junginys); MS (Biolon): C26H25N5O6, m/e. Išskaičiuota: 527,5; Rasta: 528,4 (MH+);5- (2- {2- [1- (1/7-Benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 259); MS (Biolon): C 26 H 25 N 5 O 6, m / e. Calculated: 527.5; Found: 528.4 (MH + );
2-(2-{2-[1-(1/-/-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)-2-(2-metoksietoksi)etilo benzoatas (260 junginys); MS (Biolon): C32H35N5O6, m/e. Išskaičiuota: 585,7; Rasta: 585,4 (MH+);2- (2- {2- [1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) -2- (2-methoxyethoxy) ethyl benzoate (260 compound); MS (Biolon): C 32 H 35 N 5 O 6, m / e. Calculated: 585.7; Found: 585.4 (MH + );
2-(2-{2-[1 -(5-guanidino-1 /7-benzoimidazol-2-il)etil]-1,4,6,7tetrahidroimidazo[4,5-c]pirid-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (261 junginys); MS (Biolon): C29H29N9O4, m/e. Išskaičiuota: 531,6; Rasta: 531,5 (MH+);2- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyrid-5-ylcarbonylamino} ethoxy ) benzoic acid (compound 261); MS (Biolon): C 29 H 29 N 9 O 4, m / e. Calculated: 531.6; Found: 531.5 (MH + );
2-[1-(1/7-imidazo[4l5-c]piridin-2-il)etil]-/V-[2-(2-metoksifenoksi)etil]-3-metil3H-benzoimidazol-5-karboksamidas (262 junginys); MS (Biolon): C26H26N6O3) m/e. Išskaičiuota: 470,54; Rasta: 471,4 (MH+);2- [1- (1/7-imidazo [4, 5-a] pyridin-2-yl) ethyl] - / V- [2- (2-methoxyphenoxy) ethyl] -3-metil3H-benzoimidazol-5-carboxamide (Compound 262); MS (Biolon): C 26 H 26 N 6 O 3) m / e. Calculated: 470.54; Found: 471.4 (MH + );
2-[1-(5-fluor-1/7-benzoimidazol-2-il)etil]-/V-[2-(2-metoksifenoksi)etil]-3-metil3F/-benzoimidazol-5-karboksamidas (263 junginys); MS (Biolon): C27H26N5O3F, m/e. Išskaičiuota: 487,54; Rasta: 488,1 (MH+);2- [1- (5-Fluoro-1/7-benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxyphenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 263) ); MS (Biolon): C 27 H 26 N 5 O 3 F, m / e. Calculated: 487.54; Found: 488.1 (MH + );
2-[1-(5-imidazol-1-il-1H-benzoimidazol-2-il)etil]-3-metil-N-(2-tetrazol-1-iletil)3W-benzoimidazol-5-karboksamidas (264 junginys); MS (ESI): C24H23NHO, m/e. Išskaičiuota: 481,47; Rasta: 482,6 (MH+);2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-tetrazol-1-yl-ethyl) -3W-benzoimidazole-5-carboxamide (Compound 264) ); MS (ESI): C 24 H 23 NHO, m / e. Calculated: 481.47; Found: 482.6 (MH + );
2-[1-(4-hidroksi-1F/-benzoimidazol-2-il)etil]-/V-[2-(2-metoksifenoksi)etil]-3metil-3/7-benzoimidazol-5-karboksamidas (265 junginys); MS (Biolon): C27H27N5O4l m/e. Išskaičiuota: 485,59; Rasta: 486,3 (MH+);2- [1- (4-Hydroxy-1 H -benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 265) ); MS (Biol) C27H27N 4l 5 O m / e. Calculated: 485.59; Found: 486.3 (MH + );
2- [1-(4-aminobenzoksazol-2-il)etil]-A/-[2-(2-metoksifenoksi)etil]-3-metil3/7-benzoimidazol-5-karboksamidas (266 junginys); MS (Biolon): C27H27N5O4, m/e. Išskaičiuota: 485,59; Rasta: 486,1 (MH+);2- [1- (4-Aminobenzoxazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 266); MS (Biol) 2 C 5 H 4 7H27N, m / e. Calculated: 485.59; Found: 486.1 (MH + );
3- {2-[1-(1H-benzoimidazol-2-il)etil]-6-[2-(2-metoksifenoksi)etilkarbamoiljbenzoimidazol-1-il}propan-1-sulfonrūgštis (267 junginys), MS (Biolon): C29H3iN5O6S, m/e. Išskaičiuota: 577,66; Rasta: 577,4 (MH+);3- {2- [1- (1H-Benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] -benzoimidazol-1-yl} -propane-1-sulfonic acid (Compound 267), MS (Biolon) : C 29 H 3 iN 5 O 6 S, m / e. Calculated: 577.66; Found: 577.4 (MH + );
3-{2-[1-(5-imidazol-1-il-1H-benzoimidazol-2-il)etil]-6-[2-(2metoksifenoksi)etilkarbamoil]benzoimidazol-1-il}propan-1-sulfonrūgštis (268 junginys); MS (Biolon): C32H33N7O6S, m/e. Išskaičiuota: 643,72; Rasta: 644,6 (MH+);3- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid ( Compound 268); MS (Biolon): C 32 H 33 N 7 O 6 S, m / e. Calculated: 643.72; Found: 644.6 (MH + );
2-[2-(2-{1 -[1 -(2-metoksietil)-1 H-benzoimidazol-2-il]etil}-3-metil3/7-benzoimidazol-5-karbonilamino)etoksi]etilo benzoatas (269 junginys); MS (Biolon): C32H35N5O5, m/e. Išskaičiuota: 569,66; Rasta: 570,5 (MH+);2- [2- (2- {1- [1- (2-methoxyethyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3,7-benzoimidazole-5-carbonylamino) ethoxy] ethyl benzoate (269 compound); MS (Biolon): C 32 H 35 N 5 O 5, m / e. Calculated: 569.66; Found: 570.5 (MH + );
2-[1 -(5-imidazol-1 -ii-1 H-benzoimidazol-2-il)etil]-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-benzilo karboksilatas (270 junginys); MS (Biolon): C29H30N3O6, m/e. Išskaičiuota: 586,6; Rasta: 587,2 (MH+);2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-benzyl carboxylate (Compound 270) ; MS (Biolon): C 29 H 30 N 3 O 6, m / e. Calculated: 586.6; Found: 587.2 (MH + );
2-(4-{2-[1-(1/7-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5c]piridin-5-il}-4-oksobutoksi)etilo benzoatas (271 junginys);2- (4- {2- [1- (1H-Benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5c] pyridin-5-yl} -4-oxobutoxy) ethyl benzoate (compound 271);
1- {2-[1-(1W-bęnzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin5-il}-4-(2-metoksifenoksi)butan-1-onas (272 junginys);1- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin5-yl} -4- (2-methoxyphenoxy) butane- 1-one (compound 272);
2-(5-guanidino-1 H-benzoimidazol-2-ilmetil)-A/-(2-naft-1 iletil)imidazo[1,2-a]piridin-6-karboksamidas (273 junginys);2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) imidazo [1,2-a] pyridine-6-carboxamide (Compound 273);
/V-[3-(2-etoksifenil)propil]-2-[1-(5-hidroksi-1 W-benzoimidazol-2-il)etil]-3metil-3/7-benzoimidazol-5-karboksamidas (274 junginys); MS (Biolon): C29H31N5O3, m/e. Išskaičiuota: 497,62; Rasta: 497,4 (MH+);N - [3- (2-Ethoxyphenyl) propyl] -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 274). ); MS (Biolon): C 29 H 31 N 5 O 3, m / e. Calculated: 497.62; Found: 497.4 (MH + );
/V-[3-(2-butoksifenil)propil]-2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3metil-3W-benzoimidazol-5-karboksamidas (275 junginys); MS (Biolon): C31H35N5O3, m/e. Išskaičiuota: 525,65; Rasta: 526,3 (MH+);N- [3- (2-Butoxyphenyl) propyl] -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 275); MS (Biolon): C 31 H 35 N 5 O 3, m / e. Calculated: 525.65; Found: 526.3 (MH + );
2- [1-(5-hidroksi-1/-/-benzoimidazol-2-il)etil]-3-metil-A/-[3-(2propoksifenil)propil]-3H-benzpimidazol-5-karboksamidas (276 junginys); MS (Biolon): C3oH33N503l m/e. Išskaičiuota: 511,62; Rasta: 512,3 (MH+);2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [3- (2-propoxyphenyl) propyl] -3 H -benzpimidazole-5-carboxamide (Compound 276) ); MS (Biolon): C 30 H 33 N 5 O 3 / l m / e. Calculated: 511.62; Found: 512.3 (MH + );
2-[1 - (5-hidroksi-1 H-benzoimidazol-2-il)etil]-A/-{2-[2-(3-metil-[1,2,4]oksadiazol-5-il)fenoksi]etil}-3-metil-3A/-benzoimidazol-5-karboksamidas (277 junginys); MS (Biolon): C29H27N7O4, m/e. Išskaičiuota: 538,1; Rasta: 537,58 (MH+);2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (3-methyl- [1,2,4] oxadiazol-5-yl) phenoxy ] ethyl} -3-methyl-3 N-benzoimidazole-5-carboxamide (Compound 277); MS (Biolon): C 29 H 27 N 7 O 4, m / e. Calculated: 538.1; Found: 537.58 (MH + );
2-(2-{2-[1-(4-fluoro-5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (278 junginys); MS (ESI):2- (2- {2- [1- (4-Fluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 278); MS (ESI):
C29H28N5O5, m/e. Išskaičiuota: 545,57; Rasta: 545,6 (MH+);C29H28N5O5, m / e. Calculated: 545.57; Found: 545.6 (MH + );
2-(2-{2-[1-(4-fiuor-5-hidroksi-1F/-benzoimidazol-2-il)etilj-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (279 junginys); MS (Biolon): C27H24N5O5F, m/e. Išskaičiuota: 517,52; Rasta: 517,4 (MH+);2- (2- {2- [1- (4-Fluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 279); MS (Biolon): C 27 H 24 N 5 O 5 F, m / e. Calculated: 517.52; Found: 517.4 (MH + );
2-(2-{2-[1-(6-fluor-4-hidroksi-1/-/-benzoimidazol-2-il)etil]-3-metil-3A7benzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (280 junginys); MS (Biolon): C29H28N5O5F, m/e. Išskaičiuota: 545,57; Rasta: 545,9 (MH+);2- (2- {2- [1- (6-Fluoro-4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (280 compound); MS (Biolon): C 29 H 28 N 5 O 5 F, m / e. Calculated: 545.57; Found: 545.9 (MH + );
2-(2-{2-[1-(6-fluor-4-hidroksi-1F/-benzoimidazol-2-il)etilj-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (280 junginys); MS (Biolon): C27H24N5O5F, m/e. Išskaičiuota: 517,52; Rasta: 517,6 (MH+);2- (2- {2- [1- (6-Fluoro-4-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 280); MS (Biolon): C 27 H 24 N 5 O 5 F, m / e. Calculated: 517.52; Found: 517.6 (MH + );
2-(2-{2-[1-(4,5-difluor-7-hidroksi-1/7-benzoimidazol-2-il)etilj-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)etilo benzoatas (281 junginys); MS (Biolon): C29H27N5O5F2, m/e. Išskaičiuota: 563,56; Rasta: 563,9 (MH+); ir2- (2- {2- [1- (4,5-Difluoro-7-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (281 compound); MS (Biolon): C 29 H 27 N 5 O 5 F 2, m / e. Calculated: 563.56; Found: 563.9 (MH + ); and
2-(2-{2-[1-(4,5-difluor-7-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/-/benzoimidazol-5-ilkarbonilamino}etoksi)benzenkarboksirūgštis (282 junginys); MS (ESI): C29H27N5O5F2, m/e. Išskaičiuota: 536,1; Rasta: 535,51 (MH+).2- (2- {2- [1- (4,5-Difluoro-7-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 282); MS (ESI): C 29 H 27 N 5 O 5 F 2, m / e. Calculated: 536.1; Found: 535.51 (MH + ).
PAVYZDYSEXAMPLE
Triptazės inhibavimo tyrimai in vitroIn vitro studies of tryptase inhibition
Triptazės tirpalas (60 g/ml) paruoštas ištirpinant triptazę, išgrynintą iš žmogaus plaučių arba odos audinio pavyzdžių arba žmogaus kamieninių ląstelių linijos (HMC-1) arba įgyjamą prekyboje, pvz., ICN Biomedicals, Irvine, California; Athens Research & Technology, Athens, Georgia ir kt., tirpiklių mišinyje, sudarytame iš 10 mM 2-A/-morfolinoetansulfonrūgšties, 2 mM CaCI2, 20 % glicerolio ir 50 g/ml heparino. Substrato tirpalas, turintis 2 mM sintetinio tripeptido (tozil-Gly-Pro-Lys-para-nitroanilidas), gautas iš Sigma. Junginių tirpalai buvo ruošiami praskiedžiant dešimt kartų pradinį tirpalą (1 mg tiriamo junginio/200 μΙ dimetilsulfoksido (DMSO)) bandyminiame buferyje (turinčiame: Tris-HCI (pH 8,2), mM; NaCI, 100 mM; 0,05 % polioksietilensorbitano monolauroato (Tween20®); ir cinko chlorido, 150 μΜ) ir po to atliekant septynis papildomus tri-kartinius skiedimus 10 % DMSO bandyminiame buferyje.Tryptase solution (60 g / ml) was prepared by dissolving tryptase purified from human lung or skin tissue samples or human stem cell line (HMC-1) or commercially available, e.g., ICN Biomedicals, Irvine, California; Athens Research & Technology, Athens, Georgia, et al., In a solvent mixture of 10 mM 2-N-morpholinoethanesulfonic acid, 2 mM CaCl 2 , 20% glycerol and 50 g / ml heparin. Substrate solution containing 2 mM synthetic tripeptide (tosyl-Gly-Pro-Lys-para-nitroanilide) obtained from Sigma. Compounds solutions were prepared by diluting ten times the stock solution (1 mg test compound / 200 μils dimethylsulfoxide (DMSO)) in assay buffer (containing: Tris-HCl (pH 8.2), mM; NaCl, 100 mM; 0.05% polyoxyethylene sorbitan monolauroate (Tween20®); and zinc chloride, 150 μΜ) followed by seven additional triplicate dilutions in 10% DMSO assay buffer.
Mėginio dalys (50 μΙ) iš kiekvieno tiriamo junginio aštunto skiedimo tirpalo supiltos j atskirus 96-šulinėlių U-pavidalo dugno mikrotitravimo plokštelės šulinėlius. Į kiekvieną šulinėlį įpiltas triptazės tirpalas (25 μΙ) ir tirpalai maišyti kambario temperatūroje 1 valandą. Pridėtas substrato tirpalas (25 μΙ), kad inicijuotų fermentinę reakciją, o mikrotitravimo plokštelė tuojau pat perkelta j UV/MAX kinetinį mikroplokštelės skaitytuvą (molekulinį prietaisą). Chromogeninio substrato hidrolizė vykdyta spektrofotometriškai prie 405 nanometrų 5 minutes. Pradinio greičio reikšmės buvo išskaičiuotos iš progresyvių kreivių pagal kinetinės analizės programas (BatchKr, Peter Kuzmic, University of VVisconsin, Madison, Wl). Tariamos inhibavimo konstantos (Κ;) buvo išskaičiuotos iš fermentinės reakcijos kreivių, naudojant standartinius matematinius modelius.Portions of the sample (50 μΙ) from the eighth dilution of each test compound were added to separate wells of a 96-well U-bottom microtiter plate. Tryptase solution (25 μΙ) was added to each well and the solutions were stirred at room temperature for 1 hour. A substrate solution (25 μΙ) was added to initiate the enzymatic reaction and the microtiter plate was immediately transferred to a UV / MAX kinetic microplate reader (molecular instrument). The hydrolysis of the chromogenic substrate was performed spectrophotometrically at 405 nanometers for 5 minutes. Initial velocity values were subtracted from progressive curves by kinetic analysis programs (BatchKr, Peter Kuzmic, University of Wisconsin, Madison, Wl). The putative inhibition constants (Κ;) were subtracted from the enzymatic reaction curves using standard mathematical models.
Dirbant kaip aprašyta šioje paraiškoje arba metodais, kuriuos žino patyrę šios srities specialistai, buvo ištirtas tokių išradimo junginių triptazės inhibuojantis aktyvumas:Using the methods described herein or by methods known to those of skill in the art, the following compounds of the invention have been tested for their tryptase inhibitory activity:
junginys, Kj = 0,09 μΜ; 12 junginys, Kj = 29 μΜ; 26 junginys, K, = 33 μΜ; 27 junginys, Kj = 0,6 μΜ; 28 junginys, K, = 0,00007 μΜ; 29 junginys, K = 0,0008 μΜ; 30 junginys, K = 0,009 μΜ; 37 junginys, Kj = 0,002 μΜ; 42 junginys, Kj = 0,008 μΜ; 43 junginys, Kj = 0,002 μΜ; 74 junginys, K = 0,006 μΜ; 75 junginys, K = 0,03 μΜ; 80 junginys, K = 0,01 μΜ; 81 junginys, Kj = 0,01 μΜ; 84 junginys, Kj = 2,6 μΜ; 102 junginys, Kj = 0,00007 μΜ; 112 junginys, Kj = 0,00005 μΜ; 115 junginys, Kj = 0,003 μΜ; 116 junginys, Kj = 0,006 μΜ; 117 junginys, K = 0,008 μΜ; 126 junginys, K, = 0,008 μΜ; 127 junginys, Kj = 0,006 μΜ; 128 junginys, K, = 0,002 μΜ; 169 junginys, K = 0,001 μΜ; 132 junginys, Kj = 0,00002 μΜ; 134 junginys, Kj = 0,00002 μΜ; 138 junginys, K = 0,0002 μΜ; 152 junginys, Kj = 0,0005 μΜ; 182 junginys, K = 0,004 μΜ; 194 junginys, Kj = 0,009 μΜ; 203 junginys, K = 0,008 μΜ; 225 junginys,compound, Kj = 0.09 μΜ; Compound 12, Kj = 29 μΜ; Compound 26, K, = 33 μΜ; Compound 27, Kj = 0.6 μΜ; Compound 28, K, = 0.00007 μΜ; Compound 29, K = 0.0008 μΜ; Compound 30, K = 0.009 μΜ; Compound 37, Kj = 0.002 μΜ; Compound 42, Kj = 0.008 μΜ; Compound 43, Kj = 0.002 μΜ; Compound 74, K = 0.006 μΜ; Compound 75, K = 0.03 μΜ; Compound 80, K = 0.01 μΜ; Compound 81, Kj = 0.01 μΜ; Compound 84, Kj = 2.6 μΜ; Compound 102, Kj = 0.00007 μΜ; Compound 112, Kj = 0.00005 μΜ; Compound 115, Kj = 0.003 μΜ; Compound 116, Kj = 0.006 μΜ; Compound 117, K = 0.008 μΜ; Compound 126, K, = 0.008 μΜ; Compound 127, Kj = 0.006 μΜ; Compound 128, K, = 0.002 μΜ; Compound 169, K = 0.001 μΜ; Compound 132, Kj = 0.00002 μΜ; Compound 134, Kj = 0.00002 μΜ; Compound 138, K = 0.0002 μΜ; Compound 152, Kj = 0.0005 μΜ; Compound 182, K = 0.004 μΜ; Compound 194, Kj = 0.009 μΜ; Compound 203, K = 0.008 μΜ; Compound 225,
Kj - 0,008 μΜ; 249 junginys, K, = 0,0007 μΜ; 250 junginys, K, = 0,0004 μΜ; 251 junginys, K, = 0,0008 μΜ; ir 252 junginys, K = 0,0004 μΜ.Kj - 0.008 μΜ; Compound 249, K, = 0.0007 μΜ; Compound 250, K, = 0.0004 μΜ; Compound 251, K, = 0.0008 μΜ; and compound 252, K = 0.0004 μΜ.
PAVYZDYS Avies astmos modelisEXAMPLE Sheep Asthma Model
Alerginės avies astmos modelis buvo naudotas išradimo junginių kaip antiastmatinių junginių įvertinimui in vivo. Šie metodai buvo publikuoti anksčiau (žiūr., Abraham et ai., (1983), Am. Rev. Respir. Dis., 128:839-844; Allegra et ai., (1983), J. Appl. Physiol., 55:726-730; Russi etai., (1985), J. Appl. Physiol.,59:14161422; Soler et ai., (1989), J. Appl. Physiol., 67:406-413). Kiekviena avis tarnavo tik savo bandymui. Šių gyvulių kūno masė sudarė nuo 20 iki 50 kilogramų.The allergic sheep asthma model was used to evaluate the compounds of the invention as anti-asthmatic compounds in vivo. These methods have been previously published (see, 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: 14161422; Soler et al., (1989), J. Appl. Physiol., 67: 406-413). Each sheep served only its own test. These animals weighed between 20 and 50 kilograms.
Šiuose tyrimuose 1 mg 13 junginio ištirpintas 3 ml distiliuoto vandens, o visas tirpalas pateiktas kaip aerozolis prieš 0,5 valandos, po 4 valandų ir po 24 valandų po poveikio antigenu (visa dozė = 1 mg; n = 3). Šio eksperimento rezultatai susumuoti 1 figūroje.In these studies, 1 mg of Compound 13 was dissolved in 3 ml of distilled water and the whole solution was presented as an aerosol 0.5 hours before, 4 hours and 24 hours after antigen challenge (total dose = 1 mg; n = 3). The results of this experiment are summarized in Figure 1.
Po 24 valandų po poveikio antigenu abiem atvejais tiek kontrolei, tiek ir vaisto bandymui, aviai išsivystė kvėpavimo takų padidintas reaktyvumas. Kvėpavimo takų padidintas reaktyvumas yra išreikštas kaip PC400, t. y., karbacholio koncentracija, kuri iššaukia SRL padidėjimą 400 %; todėl, PC400 sumažėjimas parodo padidintą reaktyvumą. Rasta, kad 13 junginys blokuoja kilusį padidintą reaktyvumą. Kaip parodyta 2 figūroje, šis junginys palaiko PC400 prie pagrindinio bazinio 15 įkvėpimo vienetų reikšmės. Gyvuliams kontrolinėje grupėje įkvėpimo vienetai nukrenta iki 7. Taigi, gydant 13 junginiu atsiranda antigenu paveiktoje avyje žymus kvėpavimo takų funkcijų pagerėjimas.24 hours after antigen challenge in both cases for both control and drug testing, sheep developed increased airway reactivity. The increased airway reactivity is expressed as PC400, i. i.e., the concentration of carbachol which causes a 400% increase in SRL; therefore, a decrease in PC400 indicates increased reactivity. Compound 13 was found to block the resulting increased reactivity. As shown in Figure 2, this compound maintains PC400 at a baseline value of 15 inhalation units. In animals in the control group, the inspiratory units drop to 7. Thus, treatment with compound 13 results in a significant improvement in airway function in the antigen-treated sheep.
Taigi, šis išradimas pateikia junginius ir kompozicijas, kurie yra naudingi apsaugoti arba gydyti imunomedijuotus uždegiminius sutrikimus, o ypatingai tuos, kurie surišti su kvėpavimo traktu, apimant ir astmą, ir padidinto reaktyvumo fazę, surištą su chronine astma, priedo, su alerginiu rinitu. Šis išradimas taip pat pateikia imunomedijuotų uždegiminių sutrikimų gydymą, kurie pasiduoda gydytui šio išradimo junginiais.Thus, the present invention provides compounds and compositions useful for the protection or treatment of immune-mediated inflammatory disorders, and in particular those associated with the respiratory tract, including asthma, and the reactive phase associated with chronic asthma, an additive, and allergic rhinitis. The present invention also provides for the treatment of immuno-mediated inflammatory disorders which are treated with the compounds of the present invention.
Turi būti suprasta, kad aukščiau pateiktas aprašymas yra iliustratyvus ir nėra apribojantis. Daugelis įgyvendinimų tiems, kurie patyrę šioje srityje, gali būti akivaizdūs iš aukščiau pateikto aprašymo. Todėl išradimo apimtis neturi būti nustatyta apimant nuorodas, pateiktas aprašyme, bet turi būti nustayta apibrėžties apimtyje, apimant visus ekvivalentus, pateiktus apibrėžtyje.It should be understood that the above description is illustrative and not limiting. Many embodiments for those skilled in the art may be apparent from the description above. Therefore, the scope of the invention is not to be construed as embracing the references given in the description, but must be defined within the scope of the disclosure, including all equivalents in the specification.
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WO1999026933A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | Substituted amidinoaryl derivatives and their use as anticoagulants |
WO1999026932A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | By amidino group substituted heterocyclic derivatives and their use as anticoagulants |
GT199900167A (en) * | 1998-10-01 | 2001-03-21 | NEW BIS-BENZIMIDAZOLES. | |
WO2000020400A1 (en) * | 1998-10-05 | 2000-04-13 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions for treating hepatitis c infections |
ATE256666T1 (en) * | 1999-06-04 | 2004-01-15 | Elan Pharma Int Ltd | COMPOSITIONS AND METHODS FOR PREVENTING 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 |
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US8759535B2 (en) | 2010-02-18 | 2014-06-24 | High Point Pharmaceuticals, Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
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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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NO314183B1 (en) | 2003-02-10 |
PL336233A1 (en) | 2000-06-19 |
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LV12495B (en) | 2001-01-20 |
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