SI20115A - Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity - Google Patents
Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity Download PDFInfo
- Publication number
- SI20115A SI20115A SI9720094A SI9720094A SI20115A SI 20115 A SI20115 A SI 20115A SI 9720094 A SI9720094 A SI 9720094A SI 9720094 A SI9720094 A SI 9720094A SI 20115 A SI20115 A SI 20115A
- Authority
- SI
- Slovenia
- Prior art keywords
- benzoimidazol
- ethyl
- compound
- alkyl
- methyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 374
- 239000000203 mixture Substances 0.000 title claims abstract description 151
- 108060005989 Tryptase Proteins 0.000 title abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 28
- 201000010099 disease Diseases 0.000 title description 26
- 102000001400 Tryptase Human genes 0.000 title description 23
- 230000000694 effects Effects 0.000 title description 8
- 102000012479 Serine Proteases Human genes 0.000 title description 3
- 108010022999 Serine Proteases Proteins 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 17
- 230000001404 mediated effect Effects 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 210000002345 respiratory system Anatomy 0.000 claims abstract description 5
- 230000000699 topical effect Effects 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 4
- 206010010741 Conjunctivitis Diseases 0.000 claims abstract description 3
- -1 amino, carboxy, carbamoyl Chemical group 0.000 claims description 338
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 192
- 125000000217 alkyl group Chemical group 0.000 claims description 102
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 88
- 125000005842 heteroatom Chemical group 0.000 claims description 73
- 239000001257 hydrogen Substances 0.000 claims description 66
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- 125000003118 aryl group Chemical group 0.000 claims description 58
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000005843 halogen group Chemical group 0.000 claims description 32
- 125000006413 ring segment Chemical group 0.000 claims description 32
- 239000005711 Benzoic acid Substances 0.000 claims description 31
- 235000010233 benzoic acid Nutrition 0.000 claims description 31
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 30
- 239000000651 prodrug Substances 0.000 claims description 27
- 229940002612 prodrug Drugs 0.000 claims description 27
- 125000002947 alkylene group Chemical group 0.000 claims description 25
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 22
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000001931 aliphatic 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 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000002723 alicyclic group Chemical group 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 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 14
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 13
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 13
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical class N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000003943 azolyl group Chemical group 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 11
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 10
- 239000000443 aerosol Substances 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 7
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 7
- FNLQDVXHDNFXIY-UHFFFAOYSA-N 3h-benzimidazole-5-carboxamide Chemical compound NC(=O)C1=CC=C2NC=NC2=C1 FNLQDVXHDNFXIY-UHFFFAOYSA-N 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 230000009385 viral infection Effects 0.000 claims description 6
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000001118 alkylidene group Chemical group 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 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 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 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
- 239000000843 powder Substances 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- FTNBVAOKBGAXCR-UHFFFAOYSA-N 2-[2-[[2-[1-(5-ethanimidoyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)ethyl]-3-(2-methoxyethyl)benzimidazole-5-carbonyl]amino]ethoxy]benzoic acid Chemical compound C1=C2N(CCOC)C(C(C)C=3NC=4CCN(CC=4N=3)C(C)=N)=NC2=CC=C1C(=O)NCCOC1=CC=CC=C1C(O)=O FTNBVAOKBGAXCR-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- PCCUPAKWDDHPKB-UHFFFAOYSA-N 5-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=C(Cl)C=C1C(O)=O PCCUPAKWDDHPKB-UHFFFAOYSA-N 0.000 claims description 3
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- 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
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- 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
- GIHLYBBKNGKPHR-UHFFFAOYSA-N 2-[(5-ethanimidoyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)methyl]-n-(2-hydroxy-2-naphthalen-1-ylethyl)-3-methylbenzimidazole-5-carboxamide Chemical compound C1=CC=C2C(C(O)CNC(=O)C3=CC=C4N=C(N(C4=C3)C)CC=3NC=4CCN(CC=4N=3)C(=N)C)=CC=CC2=C1 GIHLYBBKNGKPHR-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
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Classifications
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- 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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- 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
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- 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
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Abstract
Description
SPOJINE IN SESTAVKI ZA ZDRAVLJENJE BOLEZNI, POVEZANIH Z AKTIVNOSTJO SERINSKIH PROTEAZ, ZLASTI TRIPTAZECOMPOUNDS AND COMPOSITIONS FOR TREATMENT OF DISEASES RELATED TO THE ACTIVITY OF SERINE PROSTHESAS, IN PARTICULAR TRIPTASE
Področje izuma:FIELD OF THE INVENTION
Ta prijava je deloma nadaljevanje prijave s serijsko št. 08/833,674, vložene 7. aprila 1997, ki je deloma nadaljevanje prijave s serijsko št. 08/357,491, vložene 14. decembra 1994, ki sta tu vključeni z referenco, in se nanaša na spojine in sestavke za zdravljenje bolezni, povezanih z aktivnostjo serinskih proteaz, zlasti triptaze.This application is in part a continuation of the application with serial no. No. 08 / 833,674, filed April 7, 1997, which is, in part, a continuation of application no. No. 08 / 357,491, filed December 14, 1994, incorporated herein by reference, and relates to compounds and compositions for treating diseases related to the activity of serine proteases, in particular tryptase.
Opis področja:Area description:
Za triptazo, prevladujočo proteazo, ki se izloča iz humanih mastocitov, predvidevajo, da je vpletena v procesiranje nevropeptidov in vnetje tkiv. Koncentracije triptaze so v krvnem obtoku zvišane več ur po anafilaksi (Schwartz s sod. (1987) Λ/. Eng. J. Med. 316:16221626), so povišane v nazalni in pljučni lavažni tekočini (izpirku) atopičnih pacientov po specifičnem antigenskem izzivu (Castells s sod. (1988) J. Allerg. Ciin. Immunol. 141:563568) in so zvišane v pljučnem izpirku atopičnih astmatikov po endobronhialnem alergenskem izzivu. Kadilci imajo pogosto presenetljive višine nivojev triptaze v bronhoalveolarnem izpirku, to je ugotovitev, ki zagotavlja podporo hipotezi, da sprostitev proteinaz iz aktiviranih mastocitov lahko prispeva k propadu pljuč pri kadilcih, ki imajo pljučni emfizem. (Celenteron s sod. (1988) Chest 94:119-123). Poleg tega so za triptazo pokazali, da je močan mitogen za fibroblaste, kar daje slutiti, da je triptaza vpletena v pljučno fibrozo in intersticijsko pljučno bolezen (Ross s sod. (1991) J. Ciin. Invest. 88:493499).Tryptase, the predominant protease that is secreted by human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream several hours after anaphylaxis (Schwartz et al. (1987) Eng /. Eng. J. Med. 316: 16221626), are increased in nasal and pulmonary lavage fluid (lavage) of atopic patients after a specific antigen challenge. (Castells et al. (1988) J. Allerg. Ciin. Immunol. 141: 563568) and are elevated in the pulmonary lavage of atopic asthmatics following an endobronchial allergen challenge. Smokers often have surprising levels of tryptase levels in the bronchoalveolar lavage, a finding that supports the hypothesis that the release of proteinases from activated mast cells may contribute to lung failure in smokers with pulmonary emphysema. (Celenteron et al. (1988) Chest 94: 119-123). In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting that tryptase is involved in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991) J. Ciin. Invest. 88: 493499).
Astma je prepoznana kot vnetna motnja (Hood s sod. (1984) V: Benjamin-Cummings, ed. Immunology 2nd ed.) in je pogosto označena s progresivnim razvojem hiperodzivnosti sapnika in bronhijev tako na imunospecifične alergene kakor na kemijske ali fizikalne stimuluse. Bolezen tako v svojem akutnem kakor tudi kroničnem stanju vključuje multiple biokemijske mediatorje. Hiperodzivnost astmatičnega bronhiolarnega tkiva je verjetno rezultat kroničnih vnetnih reakcij, ki dražijo in poškodujejo epitelij, ki obdaja steno zračnihAsthma is recognized as an inflammatory disorder (Hood et al. (1984) In: Benjamin-Cummings, ed. Immunology 2nd ed.) And is often characterized by the progressive development of hypersensitivity of the trachea and bronchi to both immunospecific allergens and chemical or physical stimuli. The disease involves multiple biochemical mediators in both its acute and chronic conditions. The hyperresponsiveness of asthmatic bronchiolar tissue is probably the result of chronic inflammatory reactions that irritate and damage the epithelium surrounding the air wall
-2poti in pospešujejo patološko otekanje spodaj ležečega tkiva. Bronhialne biopsije pri pacientih s samo blago astmo kažejo značilnosti vnetja v steni zračnih poti.-2 Pathways and accelerate pathological swelling of underlying tissue. Bronchial biopsies in patients with mild asthma only show features of inflammation in the airway wall.
Alergijski odzivi na vdihnjene alergene lahko sprožijo vnetno sekvenco. Na primer, alergeni lahko aktivirajo mastocite in bazofilce, ki so prisotni v epiteliju in spodaj ležečem gladkomišičnem tkivu, z vezavo IgE, ki se nahaja na površini celic. Aktivirani mastociti sprostijo številne že pripravljene ali primarne kemijske mediatorje (npr. histamin) vnetnega odziva in proizvajajo številne druge sekundarne mediatorje vnetja (npr. superoksid, iz lipidov dobljene mediatorje, itd.) in situ. Poleg tega se z degranulacijo mastocitov sprosti več velikih molekul (npr. proteoglikani, triptaza, himaza, itd.).Allergic responses to inhaled allergens can trigger an inflammatory sequence. For example, allergens can activate mast cells and basophils present in epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells release many ready-made or primary chemical mediators (eg, histamine) of the inflammatory response and produce many other secondary inflammatory mediators (eg, superoxide, lipid-derived mediators, etc.) in situ. In addition, several large molecules (eg proteoglycans, tryptase, chymase, etc.) are released by mast cell degranulation.
Sprostitev teh, že pripravljenih mediatorjev iz mastocitev, verjetno šteje za zgodnjo bronhiolamo konstrikcijo pri astmatični reakciji na alergene, ki se prenašajo po zraku. Zgodnja faza astmatične reakcije je maksimalna približno petnajst minut po izpostavitvi na alergen in ji običajno sledi izboljšanje tekom naslednje ene do dveh ur. Petindvajset do petintrideset procentov populacije pacientov doživlja nadaljnje upadanje respiratorne funkcije, ki je maksimalno šest do dvanajst ur po izpostavitvi. To pozno fazo astmatične reakcije spremlja izrazito povečanje števila vnetnih celic (npr. eozinofilcev, nevtrofilcev, limfocitov, itd.), ki infiltrirajo bronhiolamo tkivo. Infiltrirane celice so na ta kraj privabljene s sprostitvijo iz mastocitov dobljenih kemotaktičnih sredstev in se potem aktivirajo med pozno reakcijsko fazo. Pozen astmatičen odziv je verjetno sekundarna vnetna reakcija, deloma posredovana s sekretomo aktivnostjo granulocitov.The release of these already prepared mediators from mast cells is probably considered an early bronchiolectric constriction in the asthmatic reaction to airborne allergens. The early phase of the asthmatic reaction is maximal about fifteen minutes after exposure to the allergen and is usually followed by improvement over the next one to two hours. Twenty-five to thirty-five percent of the patient population experiences a further decline in respiratory function, which is a maximum of six to twelve hours after exposure. This late phase of the asthmatic reaction is accompanied by a marked increase in the number of inflammatory cells (eg eosinophils, neutrophils, lymphocytes, etc.) infiltrating bronchiol tissue. The infiltrated cells are attracted to this site by the release of the chemotactic agents obtained from mast cells and then activated during the late reaction phase. A late asthmatic response is probably a secondary inflammatory reaction, mediated in part by the secretory activity of granulocytes.
Triptaza je vpletena v degradacijo vazodilatacijskih in bronhorelaksacijskih nevropeptidov (Caughey s sod. (1988) J. Pharmacol. Exp. Ther. 244:133.137; Franconi s sod. (1988) J. Pharmacol. Exp. Ther. 248:947-951; in Tam s sod. (1990) Am. J. Respir. Celi Mol. Biol. 3:27-32) in modulacijo bronhialne odzivnosti na histamin (Sekizawa s sod. (1989) J. Ciin. Invest. 83:175-179). Te ugotovitve kažejo, da triptaza lahko pri astmi poveča bronhokonstrikcijo z uničenjem bronhodilatacijskih peptidov. Triptaza cepi a-verige fibrinogena in kininogen z visoko molekulsko maso, kar kaže, da triptaza pri heparinu igra vlogo lokalnega antikoagulanta. Triptaza aktivira prostromelizin (pro-MMP-3) in prokolagenazo (pro-MMP-1) preko MMP-3, kar kaže, da je triptaza vpletena v vnetje tkivTryptase has been implicated in the degradation of vasodilatory and bronchorelaxant 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. Whole Mol. Biol. 3: 27-32) and modulation of bronchial histamine responsiveness (Sekizawa et al. (1989) J. Ciin. Invest. 83: 175-179 ). These findings suggest that tryptase can increase bronchoconstriction in asthma by destroying bronchodilator peptides. Tryptase cleaves the fibrinogen α-chain and high molecular weight kininogen, suggesting that tryptase in heparin plays the role of a topical anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, indicating that tryptase is involved in tissue inflammation
-3ir» preoblikovanje in propad sklepov. Nadalje, dajanje triptaznega inhibitorja ščiti pred razvojem pozne faze in hiperodzivnostne faze zračnih poti pri z alergenom izzvanih ovcah (Clark s sod. (1995) Am. J. Respir. Crit. Čare Med. 152:2076-2083) in inhibira takojšen odziv kože na intradermalno injekcijo alergena pri alergičnih ovcah (Molinari s sod. (1995) Amer. Physiol. Soc. 79(6):1966-1970). Vse zgoraj opisane ugotovitve jasno kažejo uporabnost triptaznih inhibitorjev kot terapevtskih sredstev pri zdravljenju astme in drugih bolezni, povezanih z vnetjem respiratornega trakta.-3ir »transformation and collapse of joints. Furthermore, administration of a tryptase inhibitor protects against the development of late-phase and hyper-responsive airway phases in allergen-induced sheep (Clark et al. (1995) Am. J. Respir. Crit. Charms Med. 152: 2076-2083) and inhibits the immediate skin response on intradermal allergen injection in allergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 79 (6): 1966-1970). All of the findings described above clearly demonstrate the utility of tryptase inhibitors as therapeutic agents in the treatment of asthma and other respiratory tract-related diseases.
Razkritja teh in drugih dokumentov, tudi patentov in patentnih prijav, omenjenih skozi vso to prijavo, so v prijavi vključena z referenco.Disclosures of these and other documents, including patents and patent applications mentioned throughout this application, are hereby incorporated by reference.
POVZETEK IZUMASUMMARY OF THE INVENTION
Ta prijava se nanaša na spojino s Formulo I:This application relates to a compound of Formula I:
I v kateri:I in which:
n1 je 0 ali 1;n1 is 0 or 1;
n2 je 0, 1,2, 3 ali 4;n2 is 0, 1,2, 3 or 4;
n3 je 0,1,2, 3 ali 4;n3 is 0,1,2, 3 or 4;
A skupaj z B obsega kondenziran heterobiciklični radikal, ki vsebuje 8 do 12 obročnih atomov, pri čemer vsak obroč vsebuje 5 do 7 obročnih členov, vsak obročni atom jeA together with B comprises a fused heterobicyclic radical containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom being
1 opcijsko heteroatom, X in X sta sosednja obročna člena aromatskega obroča in X je1 optionally heteroatom, X and X are adjacent ring members of the aromatic ring and X is
-45 5 heteroatomski del, izbran izmed -N=, -NR -, -O- in -S-, pri čemer je R vodik, (C-f _g)afkil ali hetero(C2-6)alkil;-45 5 heteroatom moiety selected from -N =, -NR -, -O- and -S-, wherein R is hydrogen, (C 1-10) afkyl or hetero (C 2-6) alkyl;
C obsega kondenziran heteropoliciklični radikal, ki vsebuje 8 do 18 obročnih atomov, pri čemer vsak obroč vsebuje 5 do 7 obročnih členov, vsak obročni atom je opcijsko heteroatom, X4 in X5 sta sosednja obročna člena aromatskega obroča, X5 je 6 6 heteroatomski del, izbran izmed -N=, -NR -, -O- in -S-, pri čemer je R vodik, skupina izbrana izmed (Ci_3)alkila ali hetero(C2--|2)a*Rha, ta skupina je opcijsko substituirana z enim do dvema substituentoma, neodvisno izbranima izmed (C-j.g)alkanoiloksi, (Ci-6)alkilamino, di(C-|_6)a!kilamino, tri(C-| .g)alkilamonio, (Ci-g)alkilkarbamoila, di(C-|.6)alkilkarbamoila, (C-j_g)alkiloksi, (Cv6)a,ki|oksikarbonila, (Ci_6)alkiloksisulfonila, amino, karboksi, karbamoila, (C6_i4)arila, halo, hetero(C5_iparila, hidroksi in suito, ali kot je definirano spodaj; in katerikoli njegov karbociklični ketonski, tioketonski in iminoketonski derivat;C comprises a fused heteropolycyclic radical containing 8 to 18 ring atoms, each ring containing 5 to 7 ring members, each ring atom being optionally heteroatom, X 4 and X 5 being adjacent ring members of the aromatic ring, X 5 being 6 6 heteroatom a moiety selected from -N =, -NR-, -O- and -S-, wherein R is hydrogen, a group selected from (C 1-3) alkyl or hetero (C 2 - | 2) a * Rha, this group being optionally substituted with one to two substituents independently selected from (C1-8) alkanoyloxy, (C1-6) alkylamino, di (C1-6) alkylamino, three (C1-6) alkylammonio, (C1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) alkyloxy, (C1-6) a, which | oxycarbonyl, (C 1-6) alkyloxysulfonyl, amino, carboxy, carbamoyl, (C 6-14) aryl, halo, hetero (C 5 -aryl, hydroxy and sulphide, or as defined below; and any carbocyclic ketone, thioketone and iminoketone derivative thereof;
X3 je -0-, -S-, -S(0)-, -S(0)2-, -C(0)-, -NR7- ali -CR7R8-, pri čemer je R7 vodik, (Ci_X 3 is -O-, -S-, -S (O) -, -S (O) 2 -, -C (O) -, -NR 7 - or -CR 7 R 8 -, wherein R 7 hydrogen, (Ci_
88
g)alkil, hetero(C2-i2)alkil ali skupaj z R tvori (C2-4)alkilen ali hetero(C2-4)alkilen in R je vodik, (C-i-g)alkil ali hidroksi ali skupaj z R7 tvori (C2-6)alkilen ali (C-j _5)alkiliden, pri čemer 7 8 je katerikoli alifatski ali aliciklični del obsegajoč R in/ali R opcijsko substituiran z enim do tremi substituenti, izbranimi izmed (C-|-6)alkilamino, di(C-|.g)alkilamino, tri(C-|_6)alkilamonio, (C-|_6)alkiloksi, (C-j .g)alkiloksikarbonila, (C-i-e)alkanoiloksi, amino, karboksi, karbamoila, (C-j-gjalkilkarbamoila, di(Cj.g)alkilkarbamoila, halo in hidroksi;g) alkyl, hetero (C2-i2) a lkil or together with R form a (C2-4) alkylene or hetero (C2-4) alkylene and R is hydrogen, (Cig) alkyl or hydroxy or together with R 7 form a (C2 -6) alkylene or (C 1-5) alkylidene, wherein 7 8 is any aliphatic or alicyclic moiety comprising R and / or R optionally substituted by one to three substituents selected from (C 1-6) alkylamino, di (C- (g) alkylamino, tri (C 1-6) alkylammonio, (C 1-6) alkyloxy, (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, amino, carboxy, carbamoyl, (C 1-6 alkylcarbamoyl, di (C 1-6). g) alkylcarbamoyl, halo and hydroxy;
R1 je amino(N-|_4)azolidinil, amino(Ni_4)azolil, (N-j_4)azolidinil, (Nf.4)azolil, karbamoil,R 1 is amino (N- 4) azolidinyl, amino (Ni 4) azolyl, (N-4) azolidinyl, (Nf 4) azolyl, carbamoyl,
G G Q Q Q O -ff) ciano, -(CH2)XNHC(NR )R , -(CH2)XNHC(NH)NR R , -C(NR )R , -C(NH)NHR ,GGQQQO -ff) cyano, - (CH 2 ) X NHC (NR) R, - (CH 2 ) X NHC (NH) NR R, -C (NR) R, -C (NH) NHR,
-C(NH)NR10R10 ali -(CR11R11)yNH2 in vezan na katerikoli obročni atom z razpoložljivo 9 valenco, ki ga obsega B, pri čemer x je O ali 1, y je O, 1, 2 ali 3, vsak R je neodvisno vodik ali (C-).g)alkil, vsak R10 je neodvisno (C-).g)alkil in vsak R11 je neodvisno vodik, (Ci-3)alkil ali skupaj z drugim R11 in ogljikovim atomom na katerega sta oba vezana tvori ciklopropil, pri čemer je katerikoli alifatski ali aliciklični del obsegajoč R1 opcijsko substituiran z enim do dvema substituentoma, neodvisno izbranima izmed-C (NH) NR 10 R 10 or - (CR 11 R 11 ) yNH 2 and bonded to any ring atom with an available 9 valence encompassed by B, wherein x is O or 1, y is O, 1, 2 or 3, each R is independently hydrogen or (C-) g) alkyl, each R 10 is independently (C -) g) alkyl and each R 11 is independently hydrogen, (C 1-3) alkyl or together with another R 11 and the carbon atom to which they are both attached forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R 1 is optionally substituted by one to two substituents independently selected from
-5(Ci.gjalkiloksikarbonila, (Ci_6)alkanoiioksi, karboksi, karbamoila, (C-|.6)alkilkarbamoila, di(C-|.e)a!kilkarbamoila, (C-| _6)alkilsulfonila in hidroksi;-5 (C 1-6 alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy;
vsak R je neodvisno (Ci_g)alkil, (Cj.gjalkiloksikarbonil, (C-i-g)alkanoiloksi, (C-l_6)aIkiloksi, karboksi, karbamoil, (Ci-e)alkilkarbamoil, di(C-|-6)alkilkarbamoil, (C-|.g)alkilsulfinil, (C-j _g)alkilsulfonil, (C-|_g)alkiltio, halo ali hidroksi in vezan na katerikoli obročni atom z razpoložljivo valenco, ki ga obsega B, pri čemer je katerikoli alifatski del 2 obsegajoč R opcijsko substituiran z enim do dvema substituentoma, neodvisno izbranima izmed (C-|_6)alkiloksikarbonila, (C-j_6)alkanoiloksi, karboksi, karbamoila, (Cj.g)alkilkarbamoila, di(C-|.g)alkilkarbamoila, (C-|_6)alkilsulfonila in hidroksi;each R is independently (C1-6) alkyl, (C1-6alkyloxycarbonyl, (C1-6) alkanoyloxy, (C1-6) alkyloxy, carboxy, carbamoyl, (C1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) | .g) alkylsulfinyl, (C 1-10) alkylsulfonyl, (C 1-10) alkylthio, halo or hydroxy, and bonded to any ring atom with an available valence of B, wherein any aliphatic moiety 2 comprising R is optionally substituted by one to two substituents independently selected from (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxy, carbamoyl, (C 1-8) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy;
vsak R je neodvisno (Ci-g)alkil, (Ci_6)alkiloksi, (C-j_g)alkiltio, ciano, halo, perhalo(C-|.each R is independently (C 1-6) alkyl, (C 1-6) alkyloxy, (C 1-6) alkylthio, cyano, halo, perhalo (C 1-6).
g)alkil ali hidroksi in vezan na katerikoli obročni atom z razpoložljivo valenco, ki ga obsega C; ing) alkyl or hydroxy and bonded to any ring atom with an available valence of C; and
19 19 19 19 19 19 19 1919 19 19 19 19 19 19 19
R je -R , -OR , -N(R )R , -SR , -S(O)R , -S(O)2R , -S(O)2OR , -S(O)2N(R13)R12, -N(R13)S(O)2R12, -C(O)R12, -C(O)OR12, -C(O)N(R13)R12,R is -R, -OR, -N (R) R, -SR, -S (O) R, -S (O) 2 R, -S (O) 2 OR, -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(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)OR12 ali -C(O)N(R14)CH(COOH)R12 in vezan na katerikoli obročni ogljikov atom z razpoložljivo valenco, ki ga obsega C, pri čemer:-N (R 13 ) C (O) R 12 , -OC (O) N (R 13 ) R 12 , -N (R 13 ) C (O) OR 12 , - (CH 2 ) with 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 and bonded to any ring carbon atom with available valence, covered by C, wherein:
z je 0,1 ali 2,z is 0.1 or 2,
15 θ 15 615 θ 15 6
R je -R ali -X -(R )n15> Pri čemer n15 je 1 ali 2, X je (Ci_io)a,kilen· ciklo(C3.io)alkilen, hetero(C2.-|o)a,kilen ali heterociklo(C3_io)alkilen in vsak R je neodvisno vodik, (Cg_i4)aril, ciklo(C3_i4)alkil, policiklo(Cg_i4)aril, heteropoliciklo(Cg-i4)aril, heterociklo(C3_-j4)alkil, hetero(C5--|4)aril ali kot je definirano spodaj,R is -R or -X - (R) N15> P ri where n15 is 1 or 2, X is a (Ci_io) alkyl, alkylene · cyclo (C3.io) alkyl, hetero (C 2 .- | o) a kylene or heterocyclo (C3-10) alkylene and each R is independently hydrogen, (Cg_4) aryl, cyclo (C3-14) alkyl, polycyclo (Cg_4) aryl, heteropoxycyclo (C3-4) aryl, heterocyclo (C3-14) alkyl, hetero (C5 - | 4) aryl or as defined below,
R13 je vodik, (Cj _g)alkil ali hetero(C2.g)alkil;R 13 is hydrogen, (Cj _g) alkyl or hetero (C 2 .G) alkyl;
6 156 15
R je vodik, (Ci_g)alkil ali skupaj z X in R tvori (C3_4)alkilen;R is hydrogen, (C 1-8) alkyl or together with X and R forms (C 3-4) alkylene;
katerikoli alifatski in aliciklični del obsegajoč R je opcijsko substituiran z enim do petimi substituenti, neodvisno izbranimi izmed (C-i_g)alkila, (Ci.g)alkilamino, di(C-|_6)alkilamino, (Ci-g)alkilkarbamoila, di(C-|.g)alkilkarbamoila, (C-|_e)alkiloksi, (C-i-e)alkiloksikarbonila, (C-j_6)alkilsulfinila, (C-j _6)alkilsulfonila, (C-| _g)alkiltio, amino, (Cg.^ o)arilsulfonila, karbamoila, karboksi, ciano, gvanidino, halo, hidroksi, merkapto in uriedo; in katerikoli aromatski del obsegajoč R je opcijsko substituiran z enim do tremi substituenti, neodvisno izbranimi izmed ciano, gvanidino, halo, halosubstituiranega (C-i_8)alkila, -R16, -OR16, -SR16, -S(O)R16, -S(O)2R16,any aliphatic and alicyclic moiety comprising R is optionally substituted with one to five substituents independently selected from (C 1-6) alkyl, (C 1-8) alkylamino, di (C 1-6) alkylamino, (C 1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) alkyloxy, (C1-6) alkyloxycarbonyl, (C1-6) alkylsulfinyl, (C1-6) alkylsulfonyl, (C1-6) alkylthio, amino, (C1-6) ) arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and uriedo; and any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from cyano, guanidino, halo, halosubstituted (C 1-8 ) alkyl, -R 16 , -OR 16 , -SR 16 , -S (O) R 16 , -S (O) 2 R 16 ,
-S(O)2N(R13)R16-, -C(O)R16 -C(O)OR16 in -C(O)N(R13)R16 pri čemer je R13 16 kot je definiran zgoraj in R je vodik, opcijsko mono-substituiran (C-(.g)alkil (pri čemer je opcijski substituent (C-|_6)alkilamino, di(C-|_g)alkilamino, tri(C-j_ g)alkilamonio, (Ci_6)alkilkarbamoil, di(C-j_g)alkilkarbamoil, (C-|.g)alkiloksikarbonil, (C-) _g)alkiloksisulfonil, amino, karboksi, karbamoil, hidroksi ali sulfo), ciklo(C3.g)alkil, hetero(C-|_8)alkil, hetero(C5.g)aril, heterociklo(C3.g)alkil ali fenil;-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 16 as defined above and R is hydrogen, optionally mono-substituted (C1-6) alkyl (wherein the optional substituent is (C1-6) alkylamino, di (C1-6) alkylamino, tri (C1-6) alkylammonio , (C1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) alkyloxycarbonyl, (C1-6) alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C3-8) alkyl, hetero (C 1-8) alkyl, hetero (C 5-8) aryl, heterocyclo (C 3-8) alkyl or phenyl;
3 s pogojem, da n1 ni 0, kadar n2 je 0 ali R je (C-|-6)alkil ali (C-j _g)alkiloksi, n3 je 0 ali R je (C-|_g)alkil ali (C-j.g)alkiloksi in R je vodik, (C-|.-|o)alkil ali (O-| _-|o)aIkiloksi; in njene Noksidne derivate, derivate predzdravil, zaščitene derivate, posamezne izomere, zmesi izomerov in farmacevtsko sprejemljive soli.3 with the proviso that n1 is not 0 when n2 is 0 or R is (C1-6) alkyl or (C1-6) alkyloxy, n3 is 0 or R is (C1-6) alkyl or (C1-8) alkyloxy, and R is hydrogen, (C- | .- | o) a lkil or (O- | _- | o) a Ikiloksi; and its Noxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.
Pričujoči izum tudi zagotavlja farmacevtske sestavke spojin izuma. Ti farmacevtski sestavki so lahko v različnih oblikah, tudi oralnih odmerjenih oblikah, inhalacijskih oblikah, kakor tudi injekcijskih in infuzijskih raztopinah. Kadar jih uporabljamo v inhalacijski ali aerosolni obliki, spojine pričujočega izuma uporabimo v kombinaciji s farmacevtsko sprejemljivo nosilno raztopino ali suhim praškom, ki ga lahko pretvorimo v aerosolno obliko. Podobno, kadar jih uporabljamo pri oralnem dajanju, jih uporabimo v kombinaciji s farmacevtsko sprejemljivim nosilcem, primernim za tako oralno dajanje. Kadar jih uporabljamo za zdravljenje imunsko posredovanih vnetnih stanj kože, spojine pričujočega izuma uporabimo v kombinaciji z netoksičnim, farmacevtsko sprejemljivim topičnimThe present invention also provides pharmaceutical compositions of the compounds of the invention. These pharmaceutical compositions may take various forms, including oral dosage forms, inhalation forms, as well as injectable and infusion solutions. When used in inhalation or aerosol form, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier solution or a dry powder that can be converted to an aerosol form. Similarly, when used in oral administration, they are used in combination with a pharmaceutically acceptable carrier suitable for such oral administration. When used to treat immune-mediated skin inflammatory conditions, the compounds of the present invention are used in combination with a non-toxic, pharmaceutically acceptable topical
-7nosilcem. Spojine pričujočega izuma lahko uporabljamo v kombinaciji z protivnetnimi ali drugimi terapijami proti astmi, kot β-adrenergičnimi agonisti, protivnetnimi kortikosteroldi, antiholinergiki, bronhodilatatorji, kot metil ksanteni in podobno.- 7 carriers. The compounds of the present invention may be used in combination with anti-inflammatory or other asthma therapies, such as β-adrenergic agonists, anti-inflammatory corticosteroids, anticholinergics, bronchodilators, such as methyl xanten and the like.
Spojine, ki so tu opisane, so uporabne za preprečitev in zdravljenje imunsko posredovanih vnetnih motenj, in posebno tistih, povezanih z respiratornim traktom, vključno z astmo, in zlasti hiperodzivnostno fazo, povezano s kronično astmo in alergijskim rinitisom. Tako pričujoči izum tudi zagotavlja metodo za zdravljenje imunsko posredovanih vnetnih motenj, pri čemer pacientu, ki ima imunsko posredovano vnetno motnjo damo terapevtsko učinkovito dozo (odmerek) ali količino spojine pričujočega izuma. Nadalje so tu notri opisane spojine uporabne za zdravljenje sincicialnih virusnih infekcij.The compounds described herein are useful for the prevention and treatment of immune-mediated inflammatory disorders, and in particular those associated with the respiratory tract, including asthma, and in particular the hyperresponsive phase associated with chronic asthma and allergic rhinitis. Thus, the present invention also provides a method for treating immune-mediated inflammatory disorders, wherein a patient having an immune-mediated inflammatory disorder is administered a therapeutically effective dose (dose) or amount of a compound of the present invention. Further, the compounds described herein are useful for the treatment of syncytial viral infections.
KRATEK OPIS RISBBRIEF DESCRIPTION OF THE DRAWINGS
Slika 1 primerja specifično pljučno rezistenco kontrole (odprti kvadrati) proti 2-(5aminometil-1/-/-benzoimidazol-2-ilmetil)-/V-(3-fenilpropil)-1 /-Abenzoimidazol-5karboksamidu (Spojina 4; zaprti kvadrati) tekom časa, ki smo ga merili v urah.Figure 1 compares the specific lung resistance of the control (open squares) against 2- (5 aminomethyl-1 H -benzoimidazol-2-ylmethyl) - N - (3-phenylpropyl) -1 H -Abenzoimidazole-5carboxamide (Compound 4; closed squares ) over the time we measured in hours.
Slika 2 je stolpični diagram, ki prikazuje hiperodzivnost zračnih poti (merjeno kot PC400) z antigenom izzvanih ovc, zdravljenih s Spojino 13, z dajanjem aerosola v treh 1 mg odmerkih proti ovcam, zdravljenim s kontrolo.Figure 2 is a bar chart showing the airway hypersensitivity (measured as PC400) of antigen-elicited sheep treated with Compound 13 by administering an aerosol at three 1 mg doses to the control treated sheep.
PODROBEN OPIS IZUMADETAILED DESCRIPTION OF THE INVENTION
Definicije:Definitions:
Razen, če ni drugače navedeno, so sledeči izrazi, ki smo jih uporabili v opisu patenta in zahtevkih, definirani za namene te prijave in imajo spodaj navedene pomene:Unless otherwise stated, the following terms used in the patent description and claims are defined for the purposes of this application and have the meanings given below:
Alkanoil pomeni radikal -C(O)R, pri čemer je R alkil, kot je definiran spodaj, ki ima pokazano celotno število ogljikovih atomov (npr:, (Ci-6)alkanoil vključuje radikale formil, acetil, propionil, butiril, izobutiril, krotonoil, izokrotonoil, itd.).Alkanoyl means the radical -C (O) R, wherein R is alkyl, as defined below, having the total number of carbon atoms shown (e.g.: (C 1 -C 6) alkanoyl includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonoyl, etc.).
-8Aliciklični del pomeni katerikoli nasičen ali nenasičen, monociklični ali policiklični ogljikovodikov del radikala. Na primer, aliciklični del se nanaša na cikloalkil, kot je tu definiran, kakor tudi na aliciklične dele obsegajoče cikloalkilalkil, cikloalkiloksi, cikloalkilkarbonil, cikloalkilalkanoil, cikloalkilkarbamoil in podobno.-8Aliccyclic moiety means any saturated or unsaturated, monocyclic or polycyclic hydrocarbon moiety of a radical. For example, the alicyclic moiety refers to cycloalkyl as defined herein, as well as to the alicyclic moieties comprising cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylcarbamoyl and the like.
Alifatski del pomeni katerikoli raven ali razvejan, nasičen ali nenasičen ogljikovodikov del radikala. Na primer, alifatski del se nanaša na alkil ali heteroalkil, kot sta tu definirana, kakor tudi na alifatske dele obsegajoče alkiloksi, arilalkil, heteroarilalkil, alkilkarbamoil, alkanoil, arilalkanoil, heteroarilalkanoil in podobno.Aliphatic moiety means any straight or branched, saturated or unsaturated hydrocarbon moiety of a radical. For example, the aliphatic moiety refers to alkyl or heteroalkyl as defined herein, as well as to aliphatic moieties comprising alkyloxy, arylalkyl, heteroarylalkyl, alkylcarbamoyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl and the like.
Alkil za namene te prijave pomeni raven ali razvejan, nasičen ali nenasičen alifatski ogljikovodikov radikal, ki ima pokazano število ogljikovih atomov, in katerikoli njegov keton, tioketon ali iminoketon (npr., (C-j_3)alkil vključuje metil, etil, propil, izopropil, butil, sek-butil, izobutil, terc-butil, vinil, alil, 1 -propenil, izopropenil, 1 -butenil, 2-butenil, 3-butenil, 2-metilalil, etinil, 1-propinil, 2-propinil, 3-oksopentil, 3-tioksopentil, 3-iminopentil, itd.)Alkyl for the purposes of this application means a straight or branched, saturated or unsaturated aliphatic hydrocarbon radical having a specified number of carbon atoms, and any ketone, thioketone or iminoketone thereof (e.g., (C 1-3) 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, 1-propynyl, 2-propynyl, 3 -oxopentyl, 3-thioxopentyl, 3-iminopentyl, etc.)
Alkilenpomeni nasičen ali nenasičen ogljikovodikov divalentni radikal, ki ima pokazano število ogljikovih atomov in katerikoli njegov ketonski, tioketonski, iminoketonski in substituiran derivat (npr., (Ci_-|o)a,,<i,en vključuje metilen (-CH2-), etilen (-CH2CH2-), metiletilen, vinilen, etinilen, trimetilen (-CH2CH2CH2-), 2-oksotrimetilen (-CH2C(O)CH2-), 2-tiatrimetilen (-CH2C(S)CH2-), 2-iminotrimetilen (-CH2C(NH)CH2-), propenilen (-CH2CH=CH- ali -CH=CHCH2-), propanililiden (=CHCH2CH2-), propendiilen (=CHCH=CH-), 1-aminotetrametilen, pentametilen, itd.).Alkylene refers to a saturated or unsaturated hydrocarbon divalent radical having the indicated number of carbon atoms and any of its ketone, thioketone, iminoketone and substituted derivatives (e.g., (C1_- | o) a ,, <i, one includes methylene (-CH2-), ethylene (-CH2CH2-), methylethylene, vinylene, ethinylene, trimethylene (-CH2CH2CH2-), 2-oxotrimethylene (-CH2C (O) CH2-), 2-thiatrimethylene (-CH2C (S) CH2-), 2-iminotrimethylene ( -CH2C (NH) CH2-), propylene ((CH2CH = CH- or -CH = CHCH2-), propanylylidene (= CHCH2CH2-), propenedylene (= CHCH = CH-), 1-aminotetramethylene, pentamethylene, etc.).
Alkiliden pomeni radikal =CRR, pri čemer je vsak R neodvisno vodik ali alkil, kot je definiran zgoraj, ki ima pokazano celotno število ogljikovih atomov (npr., (C-j_g)atkiliden vključuje metiliden, etiliden, propiliden, izopropiliden, itd.).Alkylidene means radical = CRR, wherein each R is independently hydrogen or alkyl, as defined above, having the total number of carbon atoms shown (e.g., (C 1-10) alkylidene includes methylidene, ethylidene, propylidene, isopropylidene, etc.) .
Alkiloksi pomeni radikal -OR, pri čemer je R alkil, kot je definiran zgoraj, ki ima pokazano število ogljikovih atomov (npr., (C-j_e)alkitoksi vključuje radikale metoksi, etoksi, propoksi, izopropoksi, butoksi, sek-butoksi, izobutoksi, ferc-butoksi, viniloksi, aliloksi, 1-9propeniloksi, izopropeniloksi, 1 -buteniloksi, 2-buteniloksi, 3-buteniloksi, 2-metilaliloksi, etiniloksi, 1 -propiniloksi, 2-propiniloksi, itd.).Alkyloxy means the radical -OR, wherein R is alkyl, as defined above, having the indicated number of carbon atoms (e.g., (C 1-10) alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy , tert-butoxy, vinyloxy, allyloxy, 1-9 propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethinyloxy, 1-propynyloxy, 2-propynyloxy, etc.).
Alkilsulfinil, alkilsulfonii in alkiltio pomenijo radikale -SOR, -S(O)2R oziroma -SR, pri čemer je R alkil, kot je definiran zgoraj, ki ima pokazano število ogljikovih atomov (npr., (C-i .gjalkilsulfonil vključuje metilsulfonil, etilsulfonil, propilsulfonil, izopropilsulfonil, butilsulfonil, se/r-butilsulfonil, izobutilsulfonil, terc-butilsulfonil, vinilsulfonil, alilsulfonil, 1propenilsulfonil, izopropenilsulfonil, 1-butenilsulfonil, 2-butenilsulfonil, 3-butenilsulfonil, 2metilalilsulfonil, etinilsulfonil, 1-propinilsulfonil, 2-propinilsulfonil, itd.).Alkylsulfinyl, alkylsulfonyl and alkylthio mean radicals -SOR, -S (O) 2R and -SR, respectively, wherein R is alkyl as defined above having the number of carbon atoms shown (e.g., (C1-6alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylphenyl, propylphenyl, butylsulfonyl, phenylphenyl, propylsulfonyl, tert-butylphenyl, vinylphenyl, 1propylphenyl, phenylphenylphenylphenyl, propylphenyl, propylphenyl, butyl etc.).
Amonio pomeni radikal -ΝΗθ1-.Ammonio means the radical -ΝΗθ 1- .
Amidino pomeni radikal -C(NH)NH2Amino pomeni radikal -NH2.Amidino means radical -C (NH) NH2Amino means radical -NH2.
Žival vključuje ljudi, nehumane sesalce (npr., pse, mačke, kunce, živino, konje, ovce, koze, svinje, jelenjad, itd.) in nesesalce (npr., ptice, itd.).The animal includes humans, non-human mammals (eg, dogs, cats, rabbits, livestock, horses, sheep, goats, pigs, deer, etc.) and non-mammals (eg, birds, etc.).
Aril pomeni aromatski monociklični ali kondenziran policiklični ogljikovodikov radikal, ki vsebuje pokazano število ogljikovih atomov, pri čemer je vsak obroč sestavljen iz 6 obročnih členov (npr., (C5-14)aril vključuje fenil, naftil, antracenil, fenantrenil, itd.).Aryl means an aromatic monocyclic or fused polycyclic hydrocarbon radical containing a specified number of carbon atoms, each ring consisting of 6 ring members (e.g., (C5-14) aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.).
Arilsulfonil pomeni radikale -S(O)2R, pri čemer je R aril, kot je definiran zgoraj, ki ima pokazano število ogljikovih atomov (npr., (C6~io)arilsulfonil vključuje fenilsulfonil, naft-1 ilsulfonil, itd.).Arylsulfonyl means the radicals -S (O) 2R, wherein R is aryl as defined above having the indicated number of carbon atoms (e.g., (C 6-10) arylsulfonyl includes phenylsulfonyl, naphth-1 ylsulfonyl, etc.).
Aromatski del pomeni katerikoli aromatski del radikala. Na primer, aromatski del se nanaša na aril in heteroaril, kot sta tu definirana, kakor tudi na aromatske dele obsegajoče arilalkil, heteroarilalkil, policikloaril, heteropolicikloaril in podobno.Aromatic moiety means any aromatic moiety of a radical. For example, the aromatic moiety refers to aryl and heteroaryl as defined herein, as well as to aromatic moieties comprising arylalkyl, heteroarylalkyl, polycycloaryl, heteropoxycyloaryl and the like.
-10Azolidinil pomeni nasičen ali nenasičen 5-členski monociklični radikal, ki vsebuje pokazano število dušikovih atomov. Na primer, (Nj.4)azolidinil vključuje pirazolidinil, pirolidinil, imidazolidinil, trizolidinil, tetrazolidinil, dihidropirolil, dihidroimidazolil, dihidropirazolil in dihidrotriazolil.-10Asolidinyl means a saturated or unsaturated 5-membered monocyclic radical containing the indicated number of nitrogen atoms. For example, (Nj.4) azolidinyl includes pyrazolidinyl, pyrrolidinyl, imidazolidinyl, trizolidinyl, tetrazolidinyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl and dihydrotriazolyl.
Azolil pomeni aromatski 5-členski monociklični radikal, ki vsebuje pokazano število dušikovih atomov. Na primer, (N-|_4)azolil vključuje pirolil, imidazolil, pirazolil, triazolil in tetrazolil.Azolyl means an aromatic 5 membered monocyclic radical containing the indicated number of nitrogen atoms. For example, (N- | -4) azolyl includes pyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl.
Karbamoil pomeni radikal -C(O)NH2Karboksi pomeni radikal -C(O)OH.Carbamoyl means radical -C (O) NH2Carboxy means radical -C (O) OH.
Ciano pomeni radikal -CN.Cyano means the radical -CN.
Cikloalkil pomeni nasičen ali nenasičen, monociklični ali kondenziran policiklični ogljikovodikov radikal, ki vsebuje pokazano število ogljikovih atomov, pri čemer vsak njegov obroč obsega od 3 do 8 obročnih členov, in katerikoli njegov karbociklični ketonski, tioketonski in iminoketonski derivat (npr., (C3_i4)cikloalkil vključuje ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheksenil, 2,5-cikloheksadienil, biciklo[2.2.2]oktil, oksocikioheksil, dioksocikloheksil, tiocikloheksil, itd.).Cycloalkyl means a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon radical containing a specified number of carbon atoms, each ring having from 3 to 8 ring members, and any of its carbocyclic ketone, thioketone and iminoketone derivatives (e.g., 4) (e.g., 4) cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo [2.2.2] octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.).
Cikloalkilen pomeni nasičen ali nenasičen, monociklični ali kondenziran policiklični ogljikovodikov divalentni radikal, ki vsebuje pokazano število ogljikovih atomov, pri čemer vsak njegov obroč obsega od 3 do 8 obročnih členov, in katerikoli njegov karbociklični ketonski, tioketonski ali iminoketonski derivat (npr., (C3_io)cikloalkilen vključuje 1,2ciklopropilen, 1,2-ciklobutilen, 1,3-ciklobutilen, 1,2-ciklopentilen, 1,3-ciklopentilen, 1,4ciklopentilen, 1,4-cikloheksilen, 3-cikloheksen-1,2-ilen, 2,5-cikloheksadien-1,4-ilen, 1,4biciklo[2.2.2]oktilen, 5-okso-1,3-cikloheksilen, 2,5-diokso-1,4-cikloheksilen, 5-tiokso-1,4cikloheksilen, itd.).Cycloalkylene means a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon divalent radical containing a specified number of carbon atoms, each ring having from 3 to 8 ring members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. ) cycloalkylene includes 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,4-cyclopentylene, 1,4-cyclohexylene, 3-cyclohexene-1,2-ylene , 2,5-cyclohexadien-1,4-ylene, 1,4bicyclo [2.2.2] octylene, 5-oxo-1,3-cyclohexylene, 2,5-dioxo-1,4-cyclohexylene, 5-thioxo-1 , 4cyclohexylene, etc.).
-11Odstranjevanje zaščite se nanaša na odstranjevanje katerihkoli zaščitnih skupin, prisotnih potem, ko je bila izvedena selektivna reakcija.-11Removal protection refers to the removal of any protecting groups present after a selective reaction has taken place.
Bolezen specifično vključuje katerokoli nezdravo stanje živali ali njenega dela in vključuje bolezensko stanje, ki je lahko povzročeno z, ali ki se dogaja pri zdravniški ali veterinarski terapiji, ko je ta dana taki živali, npr. stranski učinki take terapije.The disease specifically includes any unhealthy condition of the animal or part thereof and includes a disease condition that may be caused by, or that occurs in, medical or veterinary therapy when given to such animals, e.g. side effects of such therapy.
Kondenziran heteropoliciklični radikal vključuje kondenziran heterobiciklični radikal in pomeni heterociklični radikal, ki vsebuje dva do tri kondenzirane (združene) obroče, ki imajo pokazano število obročnih členov, pri čemer sta vsaj dva obročna člena enega obroča skupna z drugim obročem (npr., heteropoliciklični radikal, ki vsebuje od 8 do 18 obročnih atomov in njegovi karbociklični ketonski in tioketonski derivati vključujejo 1Hbenzimidazol-2-il, 1 H-nafto[2,3-c(|imidazol-2-il, 1 H-imidazo[4,5-flkinorm-2-il, 1Himidazo[4,5-b]piridin-2-il, 1 /-/-fenantro[9,10-cQimidazol-2-il, 1 H-imidazo[4,5-g]kinoksalin-2il, 2,6-diokso-2,3,6,7-tetrahidro-1 H-purin-8-il, 2,6-ditiokso-2,3,6,9-tetrahidro-1 H-purin-8-il, 7/7-purin-8-il, 1,6-dihidrociklopentaimidazol-2-il, 4-kinolin-2-il, itd.).Condensed heterocyclic radical includes a fused heterobicyclic radical and means a heterocyclic radical containing two to three fused (united) rings having a shown number of ring members, with at least two ring members of one ring in common with the other ring (e.g., heterocyclic radical, containing from 8 to 18 ring atoms and its carbocyclic ketone and thioketone derivatives include 1 H -benzimidazol-2-yl, 1 H-naphtho [2,3-c (| imidazol-2-yl, 1 H-imidazo [4,5-flkinorm] -2-yl, 1Himidazo [4,5-b] pyridin-2-yl, 1 H -phenantro [9,10-c] imidazol-2-yl, 1 H-imidazo [4,5-g] quinoxalin-2yl , 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl, 2,6-dithioxo-2,3,6,9-tetrahydro-1H-purin-8-yl , 7/7-purin-8-yl, 1,6-dihydrocyclopentaimidazol-2-yl, 4-quinolin-2-yl, etc.).
Gvanidino pomeni radikal -NHC(NH)NH2·Guanidino means radical -NHC (NH) NH2 ·
Halo pomeni fluoro, kloro, bromo ali jodo.Halo means fluoro, chloro, bromo or iodo.
Heteroatom pomeni atom, izbran izmed N, O, S in P.Heteroatom means an atom selected from N, O, S and P.
Heteroatomski del, razen, če je drugače pokazano, pomeni del, izbran izmed -N=, -NR17-, -0-, -S-, -S(0)-, -S(0)2-, -P(O)(OR17)-, pri čemer je R17 vodik ali (Ci_e)alkil.Heteroatomic moiety, unless otherwise indicated, means a moiety selected from -N =, -NR 17 -, -0-, -S-, -S (O) -, -S (O) 2-, -P ( O) (OR 17 ) -, wherein R 17 is hydrogen or (C 1-6) alkyl.
Heteroalkil pomeni alkil, kot je definiran zgoraj, razen, da je eden ali več pokazanih ogljikovih atomov nadomeščenih s heteroatomskim delom, kot je definiran v Podrobnem opisu izuma, in katerikoli njegov ketonski, tioketonski ali iminoketonski derivat (npr., hetero(C2--|2)a,kil vključuje metoksi, etoksi, etiltio, 2-(2-metoksietoksi)etoksi, 3metoksimetoksikarbonilmetoksi, 2-(/V-etil-/V-metilamino)etil, 2-etiliminoetil, etoksimetoksifosforiloksi, itd.).Heteroalkyl means alkyl as defined above, except that one or more of the indicated carbon atoms is replaced by a heteroatom moiety as defined in the Detailed Description of the Invention and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero (C 2 - 2) a, kil includes methoxy, ethoxy, ethylthio, 2- (2-methoxyethoxy) ethoxy, 3methoxymethoxycarbonylmethoxy, 2- (N-ethyl- / N-methylamino) ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.).
-12Heteroalkilen pomeni alkilen, kot je definiran zgoraj, razen, da je eden ali več ogljikovih atomov nadomeščenih s heteroatomskim delom, kot je definiran v Podrobnem opisu izuma, ali katerokoli njegovo ustrezno kombinacijo (npr., -OS(O)2-, -S(O)2O-, -N(R)S(O)2, -S(O)2NR17-, -OP(O)(OR17)O- in podobno, pri čemer je R17 vodik ali (C-,_e)alkil), in katerikoli njegov ketonski, tioketonski ali iminoketonski derivat (npr., hetero(C2-io)alkilen vključuje azaetilen (-CH2NH-), 2-azapropenilen (-CH2N=CH2-), 1-oksatrimetilen (-CH2CH2O-), 2-okso-3-azapentametilen, 3-aza-2-tiopentametilen, 2-oksa-3oksopentametilen, 3-aza-2-iminopentametilen (-CH2CH2NHC(NH)CH2-), 2,4-aza-2-metil3,3-diokso-3-tiapentametilen (-CH2NHS(O)2N(CH3)CH2-), 3-hidroksi-2,4-oksa-3-okso-3fosfapentametilen (-CH2OP(O)(OH)OCH2-), 3-aza-2-okso-4-karboksiheksametilen, 4-aza1 -oksa-3-oksoheksametilen, 1 -tia-3-okso-4-azaheksametilen, 1 -tia-1,1,3-triokso-4azaheksametilen (-CH2CH2NHC(O)CH2S(O)2-), 3-aza-4-oksoheptametilen, 1,4,7trioksaoktametilen, 6-aza-1 -oksa-2,5-dioksooktametilen (-CH2CH2NHC(O)CH2CH2C(O)O-), 3-aza-4-oksodekametilen, itd.).-12Heteroalkylene means alkylene as defined above, except that one or more carbon atoms is replaced by a heteroatom moiety as defined in the Detailed Description of the Invention, or any suitable combination thereof (e.g., -OS (O) 2-, - S (O) 2O-, -N (R) S (O) 2, -S (O) 2NR 17 -, -OP (O) (OR 17 ) O- and the like, wherein R 17 is hydrogen or (C (, (e) alkyl), and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero (C2-10) a l kylene includes azaethylene (-CH2NH-), 2-azapropenylene (-CH2N = CH2-), 1- oxatrimethylene (-CH2CH2O-), 2-oxo-3-azapentamethylene, 3-aza-2-thiopentamethylene, 2-oxa-3oxopentamethylene, 3-aza-2-iminopentamethylene (-CH2CH2NHC (NH) CH2-), 2,4- aza-2-methyl3,3-dioxo-3-thiapentamethylene (-CH2NHS (O) 2N (CH3) CH2-), 3-hydroxy-2,4-oxa-3-oxo-3phosphapentamethylene (-CH2OP (O) (OH OCH2-), 3-aza-2-oxo-4-carboxyhexamethylene, 4-aza1-oxa-3-oxohexamethylene, 1-thia-3-oxo-4-azahexamethylene, 1-thia-1,1,3-trioxo -4azahexamethylene (-CH2CH2NHC (O) CH2S (O) 2-), 3-aza-4-oxoheptamethylene, 1,4,7 trioxaoctamethylene, 6-aza-1-oxa-2,5-dioxooctamethylene (-CH2CH2NHC (O) CH2CH2C (O) O-), 3-aza-4-oxodecamethylene, etc.).
Heteroaril pomeni aromatski monociklični ali kondenziran policiklični divalentni radikal, ki ima pokazano število obročnih atomov, pri čemer vsak obroč radikala obsega od 5 do 6 obročnih členov in je eden ali več obročnih atomov heteroatomski del, izbran izmed -N=, -NR17-, -O- ali -S-, pri čemer je R17 vodik ali (C-j_g)alkil, in vsak v njem vsebovan obroč obsega 5 do 6 obročnih členov (npr., hetero(C5.-|4)aril vključuje tienil, furil, pirolil, pirimidinil, izoksazolil, oksaksolil, indolil, benzo[b]tienil, izobenzofuranil, purinil, izokinolil, pterdinil, perimidinil, imidazolil, piridil, pirazolil, pirazinil, kinolil, itd.).Heteroaryl means an aromatic monocyclic or fused polycyclic divalent radical having the indicated number of ring atoms, each ring of the radical having from 5 to 6 ring members and one or more ring atoms being a heteroatom moiety selected from -N =, -NR 17 -, -O- or -S-, wherein R 17 is hydrogen or (C 1-10) alkyl, and each ring contained therein comprises 5 to 6 ring members (e.g., hetero (C 5 - 4) aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo [b] thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, etc.).
Heterocikloalkil pomeni cikloalkil, kot je definiran zgoraj, razen, da je eden ali več pokazanih obročnih ogljikovih atomov nadomeščenih s heteroatomskim delom, kot je definiran v Podrobnem opisu izuma, in katerikoli njegov karbociklični ketonski, tioketonski ali iminoketonski derivat (npr., izraz heterociklo(C5_i4)alkil vključuje piperidil, pirolidinil, pirolinil, imidazolidinil, kinuklidinil, morfolinil, itd.).Heterocycloalkyl means cycloalkyl as defined above, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom moiety as defined in the Detailed Description of the Invention and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., heterocyclo term (e.g., the term heterocyclo) C 1-4 alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).
Heterocikloalkilen pomeni cikloalkilen, kot je definiran zgoraj, razen, da je eden ali več pokazanih obročnih ogljikovih atomov nadomeščenih s heteroatomskim delom, kot jeHeterocycloalkylene means cycloalkylene as defined above, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom moiety such as
-13definiran v Podrobnem opisu izuma, in katerikoli njegov karbociklični ketonski, tioketonski ali iminoketonski derivat (npr., izraz heterociklo(C3_i4)alkilen vključuje piperidilen, pirolidinilen, pirolinilen, imidazolidinilen, kinuklidinilen, morfolinilen, itd.).-13defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo (C3-14) alkylene includes piperidylene, pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, etc. morpholin, etc. morpholin.
Heteropolicikloaril pomeni policikloaril, kot je definiran spodaj, razen, da je eden ali več pokazanih obročnih ogljikovih atomov nadomeščenih s heteroatomskim delom, kot je definiran v Podrobnem opisu izuma, in katerikoli njegov karbociklični ketonski, tioketonski ali iminoketonski derivat (npr., heteropoliciklo(C8-io)alkil vključuje 3,4-dihidro-2H-kinolinil, 5,6,7,8-tetrah idrokinolinil, 3,4-dihidro-2H-[1,8]naftiridinil, 2,4-diokso-3,4-dihidro-2Hkinazolinil, 3-okso-2,3-dihidrobenzo[1,4]oksazinil, itd.).Heteropolycycloaryl means polycycloaryl as defined below, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom moiety as defined in the Detailed Description of the Invention and any of its carbocyclic ketone, thioketone or iminoketone derivative (e.g. -io) alkyl includes 3,4-dihydro-2H-quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H- [1,8] naphthyridinyl, 2,4-dioxo-3,4 -dihydro-2Hquinazolinyl, 3-oxo-2,3-dihydrobenzo [1,4] oxazinyl, etc.).
Hidroksi pomeni radikal -OH.Hydroxy means the radical -OH.
Imunsko posredovana vnetna motnja pomeni tiste bolezni, ki so povezane s sproščanjem mastocitnih mediatorjev, in ki se dajo zdraviti s triptaznim inhibitorjem (npr., bolezni tipa takojšnje preobčutljivosti, kot so astma, alergijski rinitis, urtikarija in angioedem, ekcematozna anafilaksa, dermatitis, kot atopični dermatitis, hiperproliferativna kožna bolezen, peptični ulkusi, vnetna motnja črevesja, okulami in vernalni konjunktivitis, revmatoidni artritis, vnetna stanja kože in podobno).Immune-mediated inflammatory disorder means those diseases that are associated with the release of mast cell mediators and that can be treated with a tryptase inhibitor (e.g., immediate-type sensitization diseases such as asthma, allergic rhinitis, urticaria and angioedema, eczema anaphylaxis, dermatitis, as atopic dermatitis, hyperproliferative skin disease, peptic ulcers, inflammatory bowel disorder, ocular and vernal conjunctivitis, rheumatoid arthritis, inflammatory skin conditions, and the like).
Hiperodzivnost pomeni pozno fazo bronhokonstrikcije in hiperreaktivnosti zračnih poti, ki sta povezani s kronično astmo. Hiperodzivnost astmatičnega bronhiolarnega tkiva verjetno izhaja iz kroničnih vnetnih reakcij, ki iritirajo in poškodujejo epitelij, ki oblaga steno zračnih poti in pospešujejo patološko otekanje spodaj ležečega tkiva.Hyperresponsiveness means a late phase of bronchoconstriction and hyperreactivity of the airways that are associated with chronic asthma. The hyperresponsiveness of asthmatic bronchiolar tissue probably results from chronic inflammatory reactions that irritate and damage the epithelium lining the airway wall and accelerate pathological swelling of underlying tissue.
Sincicialna virusna infekcija pomeni infekcijo z virusom, kot je respiratorni sincicijski virus, ki povzroča tvorbo celulame protoplazmatske mase, to je sincicija, preko infekcije.A syncytial viral infection means an infection with a virus, such as a respiratory syncytial virus, that causes the formation of a cellulame protoplasmic mass, that is, syncytia, through infection.
Imino pomeni radikal =NH.Imino means radical = NH.
Izomeri pomenijo spojine s Formulo I, ki imajo identične molekulske formule, toda razlikujejo se v naravi ali zaporedju vezanja njihovih atomov ali v razporeditvi njihovihIsomers mean compounds of Formula I that have identical molecular formulas but differ in the nature or sequence of bonding of their atoms or in the arrangement of their
-14atomov v prostoru. Izomeri, ki se razlikujejo v razporeditvi njihovih atomov v prostoru se imenujejo stereoizomeri. Stereoizomeri, ki niso zrcalne slike drug drugega se imenujejo diastereomeri in stereoizomeri, ki niso superimpozicijske zrcalne slike se imenujejo enantiomeri ali včasih optični izomeri. Ogljikov atom, vezan na štiri neidentične substituente, se imenuje kiralni center. Spojina z enim kiralnim centrom ima dve enantiomemi obliki z nasprotno kiralnostjo in se imenuje racemna zmes. Spojina, ki ima fi več kot en kiralni center ima 2 enantiomernih parov, kjer je n število kiralnih centrov. Spojine z več kot enim kiralnim centrom lahko obstajajo bodisi kot posamezen diastereomer ali zmes diastereomerov, imenovana diastereomerna zmes. Kadar je prisoten en kiralni center, stereoizomer lahko označimo po absolutni konfiguraciji tega kiralnega centra. Absolutna konfiguracija se nanaša na prostorsko razporeditev substituentov, vezanih na kiralni center. Substituente, vezane na kiralni center, ki ga proučujemo, razvrstimo v skladu s Sequence Rule Cahna, Ingolda in Preloga in absolutni opisovalec R ali S je naveden v oklepaju, ki mu sledi vezaj in kemijsko ime spojine. Spojine s Formulo I, ki vsebujejo kiralni center lahko obstajajo kot posamezni stereoizomeri ali zmesi stereoizomerov. Za namene pričujoče prijave, kadar se nanaša na spojino s Formulo I z imenom ali formulo in konfiguracija ni navedena, je potrebno razumeti, da referenca velja za vse možne konfiguracije spojine.-14 atoms in space. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of each other are called diastereomers and stereoisomers that are not superimposition mirror images are called enantiomers or sometimes optical isomers. The carbon atom bonded to four non-identical substituents is called a chiral center. A compound with a single chiral center has two enantiome forms with opposite chirality and is called a racemic mixture. A compound having more than one chiral center has 2 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either a single diastereomer or a mixture of diastereomers, called a diastereomeric mixture. When one chiral center is present, the stereoisomer can be characterized by the absolute configuration of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under study are classified according to the Sequence Rule of Cahn, Ingold, and Prelog, and the absolute descriptor of R or S is indicated in parentheses, followed by the hyphen and the chemical name of the compound. Compounds of Formula I containing a chiral center may exist as single stereoisomers or mixtures of stereoisomers. For the purposes of this application, when referring to a compound of Formula I by name or formula and configuration not indicated, it should be understood that the reference applies to all possible configurations of the compound.
Opcijski ali opcijsko pomeni, da se kasneje opisan dogodek ali okoliščina lahko ali pa se lahko ne zgodi, in da opis vključuje primere, kjer se dogodek ali okoliščina zgodi in primere pri katerih se ne zgodi. Na primer, izraz je opcijsko substituiran z enim do tremi radikali pomeni, da je omenjena skupina lahko ali pa tudi ni substituirana, zato da spada v obseg izuma.Optional or optional means that the event or circumstance described later may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, the term optionally substituted with one to three radicals means that said group may or may not be substituted to fall within the scope of the invention.
/V-oksidni derivati pomeni derivate spojine s Formulo I pri katerih so dušiki v oksidiranem stanju (npr., O-N), in ki imajo želeno farmakološko aktivnost. /V-oksidne derivate spojin s Formulo I lahko pripravimo po metodah, ki so poznane povprečnim strokovnjakom na tem področju.N-oxide derivatives means derivatives of a compound of Formula I wherein the nitrogen is in an oxidized state (e.g., O-N) and which has the desired pharmacological activity. The / V-oxide derivatives of compounds of Formula I can be prepared by methods known to one of ordinary skill in the art.
Patologija bolezni pomeni izvorno naravo, vzroke in razvoj bolezni, kot tudi strukturalne in funkcionalne spremembe, ki izvirajo iz bolezenskih procesov.Disease pathology means the original nature, causes and development of the disease, as well as the structural and functional changes that result from the disease processes.
-15Farmacevtsko sprejemljiv pomeni, da je to, kar je koristno pri pripravi farmacevtskega sestavka, splošno varno, netoksično in niti biološko niti drugače neželjeno in vključuje, da je to, kar je sprejemljivo za veterinarsko uporabo, sprejemljivo tudi za humano farmacevtsko uporabo.Pharmaceutically acceptable means that what is useful in the preparation of the pharmaceutical composition is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes that what is acceptable for veterinary use is also acceptable for human pharmaceutical use.
Farmacevtsko sprejemljive soli pomeni soli spojin s Formulo I, ki so farmacevtsko sprejemljive, kot je definirano zgoraj, in ki imajo želeno farmakološko aktivnost. Take soli vključujejo soli, dobljene z dodatkom kislin, ki jih tvorimo z anorganskimi kislinami, kot klorovodikovo kislino, bromovodikovo kislino, žvepleno kislino, dušikovo kislino, fosforno kislino in podobnimi; ali z organskimi kislinami, kot ocetno kislino, propionsko kislino, heksanojsko kislino, heptanojsko kislino, ciklopentanpropionsko kislino, glikolno kislino, piruvično kislino, mlečno kislino, malonsko kislino, jantarno kislino, jabolčno kislino, maleinsko kislino, fumamo kislino, vinsko kislino, citronsko kislino, benzojsko kislino, o-(4hidroksibenzoil)benzojsko kislino, cimetno kislino, mandelno kislino, metansulfonsko kislino, etansulfonsko kislino, 1,2-etandisulfonsko kislino, 2-hidroksietansulfonsko kislino, benzensulfonsko kislino, p-klorobenzensulfonsko kislino, 2-naftalensulfonsko kislino, ptoluensulfonsko kislino, kafrasulfonsko kislino, 4-metilbiciklo[2.2.2]okt-2-en-1 -karboksilno kislino, glukoheptonsko kislino, 4,4'-metilenbis(3-hidroksi-2-en-1 -karboksilno kislino), 3fenilpropionsko kislino, trimetilocetno kislino, terciarno butilocetno kislino, lavril žvepleno kislino, glukonsko kislino, glutaminsko kislino, hidroksinaftojsko kislino, salicilno kislino, stearinsko kislino, mukonsko kislino in podobnimi.Pharmaceutically acceptable salts means salts of compounds of Formula I that are pharmaceutically acceptable as defined above and which have the desired pharmacological activity. Such salts include salts obtained by the addition of acids formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid 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, maleic acid, maleic acid, citric acid , benzoic acid, o- (4hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-sulfonobenzenesulfonate, sulfonic acid acid, camphrasulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3phenylpropionic acid , trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid saliva, muconic acid and the like.
Farmacevtsko sprejemljive soli tudi vključujejo soli, dobljene z dodatkom baz, ki jih lahko tvorimo, kadar so prisotni kislinski protoni zmožni reagirati z anorganskimi ali organskimi bazami. Sprejemljive anorganske baze vključujejo natrijev hidroksid, natrijev karbonat, kalijev hidroksid, aluminijev hidroksid in kalcijev hidroksid. Sprejemljive organske baze vključujejo etanolamin, dietanolamin, trietanolamin, trometamin, /V-metilglukamin in podobne.Pharmaceutically acceptable salts also include salts obtained by the addition of bases which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
Policikloaril pomeni kondenziran policiklični radikal, ki vsebuje navedeno število ogljikovih atomov, pri čemer je vsaj eden, toda ne vsi, izmed kondenziranih obročev, kiPolycycloaryl means a fused polycyclic radical containing a specified number of carbon atoms, with at least one, but not all, of the fused rings being
-16obsegajo radikal aromatski, in vsak v njem vsebovan obroč obsega pet do šest obročnih členov, in katerikoli njegov karbociklični ketonski in tioketonski derivat (npr., policiklo(C9_ 10)aril vključuje indanil, indenil, 1,2,3,4-tetrahidronaftil, 1,2-dihidronaftil, 2,4-diokso1,2,3,4-tetrahidronaftil, itd.).-16 comprise a radical aromatic, and each ring contained therein comprises five to six ring members, and any of its carbocyclic ketone and thioketone derivatives (e.g., polycyclo (C9_10) aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl , 1,2-dihydronaphthyl, 2,4-dioxo1,2,3,4-tetrahydronaphthyl, etc.).
Derivati predzdravil pomeni derivate spojin s Formulo I, ki se in vivo pretvorijo v odgovarjajočo nederivatizirano obliko spojine s Formulo I. Ustrezni derivati predzdravil vključujejo tiste spojine s Formulo I, pri katerih je eden ali več dušikovih in/ali kisikovih atomov z razpoložljivo prosto valenco, substituiranih s skupino, ki se zlahka cepi pri in vivo procesih. Na primer, derivati predzdravil spojin s Formulo I lahko vsebujejo eno ali 18 več /V-substituiranih amino skupin (npr., -NH2(R )), /V-substituirane dušikove atome, 18 inkorporirane v alifatsko, aliciklično ali aromatsko strukturo (npr., -N(R )-), N18 18 substituirane imino ali amidino skupine (npr., -C(NR )H, -C(NR )NH2 aliProdrug derivatives means derivatives of compounds of Formula I that are converted in vivo to the corresponding non-derivatized form of a compound of Formula I. Suitable prodrug derivatives include those compounds of Formula I in which one or more nitrogen and / or oxygen atoms are available with free valence, substituted by an easily cleavable group in in vivo processes. For example, derivatives of prodrugs of compounds of Formula I may contain one or 18 more N-substituted amino groups (e.g., -NH 2 (R)), N-substituted nitrogen atoms, 18 incorporated into an aliphatic, alicyclic or aromatic structure (e.g. ., -N (R) -), N18 18 substituted imino or amidino groups (e.g., -C (NR) H, -C (NR) NH2 or
1818 -C(NH)NHR ), /V-substituirane gvanidino skupine (npr., -NHC(NR )NHR ,1818 -C (NH) NHR), / V-substituted guanidino groups (e.g., -NHC (NR) NHR,
18 18 1Q18 18 1Q
-NHC(NH)NHR ali -NHC(NR )NH2) in podobno, v katerih je R (i) -C(O)R ali-NHC (NH) NHR or -NHC (NR) NH 2 ) and the like in which R (i) is -C (O) R or
1Q -tq1Q -tq
-CH(R )OC(O)R , pri čemer R je (C-j_io)alkil, (Ci_io)a*kiloksi, karbamoil, (C-|.io)alkilkarbamoil, di(C-|_io)aIkilkarbamoil, c/s-2-(Ci_io)alkanoiloksifenilvinil, 3(C-i-io)alkanoiloksibutiril, (C3_-io)cikloalkil, hetero(C3.io)cikloalkil, (Ce-io)aril ali-CH (R) OC (O) R, wherein R is (C 1-10) alkyl, (C 1-10) * xyloxy, carbamoyl, (C 1-10) alkylcarbamoyl, di (C 1-10) alkylcarbamoyl, c (s-2- (C 1-10) alkanoyloxyphenylvinyl, 3 (C 1-10) alkanoyloxybutyryl, (C 3-10) cycloalkyl, hetero (C 3-10) cycloalkyl, (C 1-10) aryl, or
7 21 7 hetero(C5_io)aril in R je vodik ali (Ci-io)alkil; (ϋ) -X -R , pri čemer X je7 21 7 hetero (C 5-10) aryl and R is hydrogen or (C 1-10) alkyl; (ϋ) -X -R, where X is
22 22 (C-i.io)alkilen in R je karboksi; ali (iii) -C(O)OCH(R )OC(O)R , pri čemer R je vodik, (C-j.-io)alkil ali (C3_-jo)cikloalkil in R je (C-j.-io)alkil ali (C3_io)c»kloalkil. Poleg tega, derivati predzdravil spojin s Formulo I lahko vsebujejo eno ali več /V-hidroksiliranih imino ali amidino skupin (npr., -C(NOR24)H, -C(NOR24)NH2 ali -C(NH)NHOR24) ali N24 24 hidroksilirane gvanidino skupine (npr., -NHC(NOR )NH2, -NHC(NH)NHOR ), v katerih22 is (C 1-10) alkylene and R is carboxy; or (iii) -C (O) OCH (R) OC (O) R, wherein R is hydrogen, (C 1-10) alkyl or (C 3-10) cycloalkyl and R is (C 1-10) alkyl or (C3_10) c »chloalkyl. In addition, prodrugs of the compounds of Formula I may contain one or more / V-hydroxylated imino or amidino groups (e.g., -C (NOR 24 ) H, -C (NOR 24 ) NH 2 or -C (NH) NHOR 24 ) or N24 24 hydroxylated guanidino groups (e.g., -NHC (NOR) NH2, -NHC (NH) NHOR) in which
25 26 25 2525 26 25 25
R je vodik, metil, -C(O)R ali -CH(R )OC(O)R , pri čemer R je (CMojalkil ali (C3_io)cikloalkil in R je vodik ali (C-i-io)alkil; /V-substituirane hidroksi skupine (npr.,R is hydrogen, methyl, -C (O) R or -CH (R) OC (O) R, wherein R is (C 1-10 alkyl or (C 3-10) cycloalkyl and R is hydrogen or (C 1-10) alkyl; substituted hydroxy groups (e.g.,
27 1Q 20 1Q 1Q 2027 1Q 20 1Q 1Q 20
-OR ), pri čemer R je -C(O)R ali -CH(R )0C(0)R , pri čemer R in R sta kot je definirano zgoraj: in/ali esterske derivate karboksilnih kislin (npr., -C(O)OR ), pri 28 čemer R je (Cj _i o)a,kil ali (C3-1 o)c>k,oalkil·-OR), wherein R is -C (O) R or -CH (R) 0C (O) R, wherein R and R are as defined above: and / or carboxylic acid ester derivatives (e.g., -C (O) OR), at 28 where R is (C 1-10) a, kil or (C 3-1 o) c > k, alkyl ·
Zaščitna skupina ima pomen, ki je običajno povezan z njo v sintezni arganski kemiji, npr., skupina, ki selektivno blokira eno reaktivno mesto v multifunkcionalni spojini tako, daA protecting group has the meaning usually associated with it in synthetic argan chemistry, e.g., a group that selectively blocks one reactive site in a multifunctional compound such that
-17kemijsko reakcijo lahko izvedemo selektivno na drugem nezaščitenem reaktivnem mestu, in ki jo lahko zlahka odstranimo, ko je selektivna reakcija končana.The -17chemical reaction can be carried out selectively at another unprotected reactive site, and can be easily removed when the selective reaction is complete.
Zaščiteni derivati pomeni derivate spojin s Formulo I v katerih je reaktivno mesto ali so reaktivna mesta blokirana z zaščitnimi skupinami. Zaščiteni derivati spojin s Formulo I so uporabni pri pripravi spojin s Formulo I. Primerne zaščitne skupine za reaktivne dušikove atome vključujejo terc-butoksikarbonil, benziloksikarbonil in katerekoli druge primerne amino zaščitne skupine (npr., glej T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981). Posebno primerno zaščiten derivat s Formulo I je ponazorjen s spojino 2-[5-(1,3-diokso-1,3-dihidroizoindol-2-ilmetil)-1W-benzoimidazol-2ilmetil]-4,5,6,7-tetrahidro-1H-benzoimidazol-5-karboksilno kislino.Protected derivatives means derivatives of compounds of Formula I in which the reactive site or reactive sites are blocked by protecting groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I. Suitable protecting groups for reactive nitrogen atoms include tert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protecting groups (e.g., see TW Greene, Protective Groups and Organic Synthesis, John Wiley & Sons, Inc. 1981). A particularly suitably protected derivative of Formula I is exemplified by compound 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1W-benzoimidazol-2ylmethyl] -4,5,6,7-tetrahydro -1H-benzoimidazole-5-carboxylic acid.
Terapevtsko učinkovita količina pomeni količino, ki je, ko je dana živali, učinkovita za zdravljenje bolezni.Therapeutically effective amount means an amount that, when given to an animal, is effective in treating the disease.
Zdravljenje se nanaša na vsako dajanje spojine pričujočega izuma in vključuje:Treatment refers to any administration of a compound of the present invention and includes:
(1) preprečevanje pojava bolezni pri živali, ki je lahko predispozirana za bolezen ampak še ni izkusila ali pokazala patologije oz. simptomov bolezni, (2) inhibiranje bolezni, to je zaviranje razvoja njene patologije in/ali simptomov, ali (3) izboljšanje bolezni, to je ukinitev njene patologije in/ali simptomov.(1) prevention of disease occurrence in an animal that may be predisposed to the disease but has not yet experienced or demonstrated pathology or disease. symptoms of the disease, (2) inhibiting the disease, that is, inhibiting the development of its pathology and / or symptoms, or (3) improving the disease, that is, eliminating its pathology and / or symptoms.
Suito pomeni radikal -S(O)OH.Suite means the radical -S (O) OH.
Uriedo pomeni radikal -NHC(O)NH2Spojine s Formulo I in intermediati in izhodni materiali, ki smo jih uporabili pri njihovi pripravi so poimenovani v skladu z IUPAC pravili nomenklature. Na primer, spojina s Formulo I v kateri:Uriedo means the radical -NHC (O) NH 2 Compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with the IUPAC nomenclature rules. For example, a compound of Formula I in which:
-18A skupaj z B obsega 5-gvanidino-1H-benzoimidazol-2-il, C obsega 5-(2-naft-13 iletilkarbamoil)-1H-benzoimidazol-2-il in X je -CH2- se imenuje 2-(5-gvanidino-1 Hbenzoimidazol-2-ilmetil)-/V-(2-naft-1-iletil)-1H-benzoimidazol-5-karboksamid;-18A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl, C comprises 5- (2-naphth-13 ylethylcarbamoyl) -1H-benzoimidazol-2-yl and X is -CH2- called 2- (5 -guanidino-1H-benzoimidazol-2-ylmethyl) - N - (2-naphth-1-ylethyl) -1H-benzoimidazole-5-carboxamide;
A skupaj z B obsega 5-gvanidino-1H-benzoimidazol-2-il, C obsega 6-(2-naft-13 iletilkarbamoil)-1-metil-1 H-benzoimidazol-2-il in X je -CH2- se imenuje 2-(5-gvanidino1H-benzoimidazol-2-ilmetil)-3-metil-/V-(2-naft-1-iletil)-3H-benzoimidazol-5-karboksamid;A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl, C comprises 6- (2-naphth-13 ylethylcarbamoyl) -1-methyl-1H-benzoimidazol-2-yl and X is -CH 2 - called 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;
A skupaj z B obsega 5-gvanidino-1H-benzoimidazol-2-il, C obsega 6-[2-(23 karboksifenil)etilkarbamoil]-1-(3-sulfopropil)-1H-benzoimidazol-2-il in X je -CH2- se imenuje 2-{2-[2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-(3-sulfopropil)-3/-/benzoimidazol-5-ilkarbonilamino]etil}benzojska kislina; inA together with B comprises 5-guanidino-1H-benzoimidazol-2-yl, C comprises 6- [2- (23 carboxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl) -1H-benzoimidazol-2-yl and X is - CH2- is called 2- {2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino] ethyl} benzoic acid; and
A skupaj z B obsega 5-gvanidino-1 H-benzoimidazol-2-il, C obsega 6-(2-(23 metoksifenil)etilkarbamoil]-1-(3-sulfopropil)-1H-benzoimidazol-2-il in X je -CH2- se imenuje 3-{2-(5-gvanidino-1 H-benzoimidazol-2-ilmetil)-6-[2-(2metoksifenil)etilkarbamoil]benzoimidazol-1 -il}propan-1 -sulfonska kislina.A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl, C comprises 6- (2- (23 methoxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl) -1H-benzoimidazol-2-yl and X is -CH2- is called 3- {2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -6- [2- (2methoxyphenyl) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid.
Določene spojine s Formulo I obstajajo v tavtomernem ravnotežju. Na primer, spojine s Formulo I, v kateri C obsega 4,5,6,7-tetrahidro-3H-imidazo[4,5-c]piridin-2-il obstajajo v ravnotežju med tavtomeroma s sledečima formulama:Certain compounds of Formula I exist in tautomeric equilibrium. For example, compounds of Formula I in which C comprises 4,5,6,7-tetrahydro-3H-imidase [4,5-c] pyridin-2-yl exist in equilibrium between tautomers of the following formulas:
-19in zato, medtem ko so spojine tega izuma v tej prijavi lahko imenovane, ponazorjene ali sicer opisane kot en možen tavtomer, je potrebno razumeti, da to pomeni, da so s takimi imeni, ponazoritvami in opisi zaobseženi vsi možni tavtomeri. Tako je mišljeno, da ime etil 2-(4-{2-[1 -(5-gvanidino-1H-benzoimidazol-2-il)etil]-1 A^J-tetrahidro-imidazo^.S-cjpiridin5-il}-4-oksobutil)benzoat vključuje njegove tavtomere etil 2-(4-{2-[1-(5-gvanidino-3Hbenzoimidazol-2-il)etil]-1,4,6,7-tetrahidro-imidazo[4,5-c]piridin-5-il}-4-oksobutil)benzoat, etil 2-(4-{2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-3,4,6,7-tetrahidroimidazo[4,5c]piridin-5-il}-4-oksobutil)benzoat in etil 2-(4-{2-[1-(5-gvanidino-3H-benzoimidazol-2il)etil]-3,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-il}-4-oksobutil)benzoat.-19and therefore, while the compounds of the present invention may be named, illustrated or otherwise described as one possible tautomer in this application, it should be understood that this means that all possible tautomers are covered by such names, illustrations and descriptions. Thus, it is thought that the name ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1 N-tetrahydro-imidazo. S-cypyridin5-yl} -4-Oxobutyl) benzoate includes its tautomers ethyl 2- (4- {2- [1- (5-guanidino-3H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydro-imidase [4,5 -c] pyridin-5-yl} -4-oxobutyl) benzoate, ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3,4,6 , 7-tetrahydroimidazo [4,5c] pyridin-5-yl} -4-oxobutyl) benzoate and ethyl 2- (4- {2- [1- (5-guanidino-3H-benzoimidazol-2yl) ethyl] -3, 4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) benzoate.
Prednostne izvedbe:Preferred designs:
Medtem ko je najširša definicija tega izuma pojasnjena v Povzetku izuma, so določeni vidiki izuma prednostni. Prednostni vidik izuma je spojina s Formulo I, v kateri A skupaj z B obsega kondenziran heterobiciklični radikal, pri čemer A vsebuje 5 obročnih členov in B vsebuje 6 obročnih členov in X4 in X5 sta sosednja člena oksazol-2-il, 1 H-imidazol-2-il ali tiazol-2-il obroča.While the broadest definition of this invention is explained in the Summary of the Invention, certain aspects of the invention are preferred. A preferred aspect of the invention is a compound of Formula I, wherein A together with B comprises a fused heterobicyclic radical, wherein A contains 5 ring members and B contains 6 ring members and X 4 and X 5 are adjacent oxazol-2-yl, 1 H -imidazol-2-yl or thiazol-2-yl ring.
Prednosten vidik izuma so spojine s Formulo II:A preferred aspect of the invention are compounds of Formula II:
v kateri:in which:
črtkaste črte neodvisno predstavljajo opcijske vezi;the dashed lines independently represent optional bonds;
-202 vsak R je neodvisno (C-j .gjalkil, (C-j_6)alkiloksi, halo ali hidroksi;-202 each R is independently (C 1-6 alkyl, (C 1-6) alkyloxy, halo or hydroxy;
vsak R je neodvisno (C-j _e)alkil, (Ci .gjalkiloksi, halo ali hidroksi;each R is independently (C 1-10) alkyl, (C 1-3 alkyloxy, halo or hydroxy;
X3je -C(O)- ali -CR7R8-;X 3 is -C (O) - or -CR 7 R 8 -;
11 1 X je -CH(R )n-|- ali -C(R )ni=, pri čemer je R amino(N-|-4)azolidinil, amino(Ni_4)azolil, (N-|_4)a20lidinil, (N^jazolil, -NHC(NH)NR9R9, -C(NR9)R9, -C(NH)NHR1° -C(NH)NR10R10 ali -(CR11R11)yNH2, ali X8 je -N= ali -NH(R1)n-|-, pri čemer R1 je -C(NR9)R9, -C(NH)NHR10 ali -C(NH)NR10R10, pri čemer je vsak R9 neodvisno vodik ali (C-i-β)alkil in vsak R10 je neodvisno (C-| .g) alkil; in11 1 X is -CH (R) n - | - or -C (R) n i =, wherein R is amino (N- | -4) azolidinyl, amino (Ni_4) azolyl, (N- | _ 4 ) a20lidinyl, (N ^ jazolyl, -NHC (NH) NR 9 R 9 , -C (NR 9 ) R 9 , -C (NH) NHR 1 ° -C (NH) NR 10 R 10 or - (CR 11 R 11 ) yNH2, or X 8 is -N = or -NH (R 1 ) n- | -, 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 -C 5) alkyl and each R 10 is independently (C 1-10) alkyl; and
X9 je -CH(R4)- ali -C(R4)=, pri čemer R4 je -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,X 9 is -CH (R 4 ) - or -C (R 4 ) =, wherein R 4 is -R 12 , -OR 12 , -N (R 13 ) R 12 , -SR 12 , -S (O) R 12 , -S (O) 2R 12 , -S (O) 2OR 12 , -S (O) 2N (R 13 ) R 12 -N (R 13 ) S (O) 2R 12 , -C (O) R 12 , -C (O) OR 12 , -C (O) N (R 13 ) R 12 , -N (R 13 ) C (O) R 12 , -OC (O) N (R 13 ) R 12 , - N (R 13 ) C (O) OR 12 ,
-(CH2)n4N(R13)C(O)N(R13)R12, -OP(O)(OR13)OR12 ali -C(O)N(R14)CH(COOH)R12, ali X9 je -N= ali -N(R4)-, pri čemer R4 je -C(O)R12, -C(O)OR12, -C(O)N(R13)R12, -OC(O)N(R13)R12 ali -C(O)N(R14)CH(COOH)R12, pri čemer so R12, R13 in R14 kot je definirano v Povzetku izuma.- (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 as defined in the Summary of the Invention.
Prednosten vidik izuma so spojine s Formulo I, v kateri:A preferred aspect of the invention are compounds of Formula I in which:
66
R je vodik ali (Ci-4)alkil, R je vodik ali (C-|_4)alkil, kjer je alkil opcijsko substituiran z enim do dvema substituentoma, neodvisno izbranima izmed (Cj-4)alkiloksi, hidroksi in 7 8 sulfo, R je vodik ali metil in R je vodik, metil ali hidroksi;R is hydrogen or (C 1-4) alkyl, R is hydrogen or (C 1-4) alkyl, wherein the alkyl is optionally substituted with one to two substituents independently selected from (C 1-4) alkyloxy, hydroxy and 7 8 sulfo, R is hydrogen or methyl and R is hydrogen, methyl or hydroxy;
X8 je -CH(R4)- ali -C(R1)ni=, pri čemer je R1 aminometil, 1 -aminociklopropil, 29 9 aminoimidazol-1-il, 2-amino-1,1 -dimetiletil, imidazolil, tetrazolil, -(CH2)XNHC(NR )R ,X 8 is -CH (R 4 ) - or -C (R 1 ) n i =, wherein R 1 is aminomethyl, 1-aminocyclopropyl, 29 9 aminoimidazol-1-yl, 2-amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, - (CH 2 ) X NHC (NR) R,
-(CH2)XNHC(NH)NR9R9 in -C(NR9)R9, pri čemer je vsak R9 neodvisno vodik ali metil, ali- (CH 2 ) X NHC (NH) NR 9 R 9 and -C (NR 9 ) R 9 , wherein each R 9 is independently hydrogen or methyl, or
X8 je -N(R1)nr, pri čemer R1 je -C(NR9)R9, -C(NH)NHR1° ali -C(NH)NR1°R10, pri 9 10 čemer je vsak R neodvisno vodik ali metil in vsak R je metil, pri čemer je katerikoliX 8 is -N (R 1 ) nr , where R 1 is -C (NR 9 ) R 9 , -C (NH) NHR 1 ° or -C (NH) NR 1 ° R 10 , at 9 10 which is each R is independently hydrogen or methyl and each R is methyl, whichever is the one
-21alifatski ali aliciklični del obsegajoč R1 opcijsko substituiran z enim do dvema substituentoma, neodvisno izbranima izmed metilsulfonila in karboksi;-21aliphatic or alicyclic moiety comprising R 1 optionally substituted with one to two substituents independently selected from methylsulfonyl and carboxy;
X9 je -C(R4)=, pri čemer R4 je -R12, -OR12, -C(O)R12, -C(O)OR12, -C(O)N(R13)R12 aliX 9 is -C (R 4 ) =, where 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(R14)CH(COOH)R12, pri čemer sta R13 in R14 neodvisno vodik ali (C-|-6)alkil; R12 15 6 15 6 je -R ali -X -(R )n15> Pri čemer X je (C-f.·) o)alkilen ali hetero(C2-io)a'k'len *n vsak 15-C (O) N (R 14 ) CH (COOH) R 12 , wherein R 13 and R 14 are independently hydrogen or (C 1-6) alkyl; R 12 15 6 15 6 is -R or -X - (R) N15> P R wherein X is (Cf. ·)) alkyl or hetero (C2-io), a 'to' len * n each 15
R je neodvisno vodik, (Ce_i4)aril, ciklo(C3_i4)alkil, policiklo(Ce_i4)ariU heteropoliciklo(Ce_-|4)aril, heterociklo(C3--|4)alkil ali hetero(C5.i4)aril;R is independently hydrogen, (C 1-4) aryl, cyclo (C 3-4) alkyl, polycyclo (C 1-4) aryU heteropoxycyclo (C 1-4) aryl, heterocyclo (C 3-4) alkyl or hetero (C 5-4) aryl;
katerikoli alifatski in aliciklični del obsegajoč R4 je opcijsko substituiran z enim do petimi substituenti, neodvisno izbranimi izmed (C-|_4)alkiloksi, (Ci _4)alkiloksikarbonila, amino, karbamoila, karboksi in hidroksi; in katerikoli aromatski del obsegajoč R je opcijsko substituiran z enim do tremi substituenti, neodvisno izbranimi izmed (Ci_4)alkila, (C-| _4)alkiloksi, (C-). 4)alkiloksikarbonila, karbamoila, karboksi, ciano, ciklo(C3_e)alkiloksi, halo, hetero(C-). 8)alkila, hetero(C-|_8)alkilkarbonila, hetero(C5.6)arila in trifluorometila; in njihovi /V-oksidni derivati, derivati predzdravil, zaščiteni derivati, posamezni izomeri, zmesi izomerov in farmacevtsko sprejemljive soli.any aliphatic and alicyclic moiety comprising R 4 is optionally substituted with one to five substituents independently selected from (C 1-4) alkyloxy, (C 1-4) alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy; and any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from (C 1-4) alkyl, (C 1-4) alkyloxy, (C-). 4) alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo (C3-8) alkyloxy, halo, hetero (C-). 8) alkyl, hetero (C- | _8) al kilkarbonila, hetero (C5-6) aryl and trifluoromethyl; and their / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.
Prednosten vidik izuma so spojine s Formulo I, v kateri:A preferred aspect of the invention are compounds of Formula I in which:
A skupaj z B obsega 4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il, pri čemer n2 je 0 in 1 9 9A together with B comprises 4,5,6,7-tetrahydro-1 H-imidase [4,5-c] pyridin-2-yl, wherein n 2 is 0 and 1 9 9
R je -C(NR )R , ali A skupaj z B obsega 1 B-benzoimidazol-2-il ali 4,5,6,7-tetrahidro-1 H1 2 benzoimidazol-2-il, pri čemer je R aminometil ali gvanidino in vsak R je neodvisno halo ali hidroksi;R is -C (NR) R, or A together with B comprises 1 B-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1 H 1 2 benzoimidazol-2-yl, wherein R is aminomethyl or guanidino and each R is independently halo or hydroxy;
C obsega 4,5,6,7-tetrahidro-1/-/-imidazo[4,5-c]piridin-2-il ali 1 H-benzoimidazol-2-il, pri čemer R4 je -C(O)X6-R15, -C(O)OX6-R15 ali -C(O)NHX6-R15, pri čemer X6 je (C·,. 15C comprises 4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl or 1 H-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 , wherein X 6 is (C ·,. 15
4)alkilen ali hetero(C2-4)alkilen in R je (C6.io)ari1· (Ce„-io)aril°ksi, policiklo(Cg_io)aril· hetero(C5.io)ar>l, hetero(C5.-|o)ar>'oks· a'> heteropoliciklo(C6-i4)aril; in4) alkylene or hetero (C2-4) alkylene and R is (C6-10) aryl · (C 1 -io) arylOxy, polycyclo (C 8-10) aryl · hetero (C 5-10) ar > 1, hetero (C 5) .- | o) ar >' ox · a '> heteropolicyclo (C6-i4) aryl; and
-2215 katerikoli aromatski del obsegajoč R je opcijsko substituiran z enim do tremi substituenti, neodvisno izbranimi izmed (C-|.4)alkila, (C-|_4)alkiloksi, (Ci_ 4)alkiloksikarbonila, karboksi, karbamoila, halo, hidroksi in tetrazol-1-ila; in njihovi Noksidni derivati, derivati predzdravil, zaščiteni derivati, posamezni izomeri, zmesi izomerov in farmacevtsko sprejemljive soli.-2215 any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from (C 1-4) alkyl, (C 1-4) alkyloxy, (C 1-4) alkyloxycarbonyl, carboxy, carbamoyl, halo, hydroxy and tetrazol-1-yl; and their Noxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.
Prednosten vidik izuma so spojine s Formulo I, v kateri n1 je 0 in vsak R je neodvisno halo ali hidroksi, zlasti:A preferred aspect of the invention are compounds of Formula I in which n1 is 0 and each R is independently halo or hydroxy, in particular:
2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojska kislina;2- (2- {2- [1- (4,6,7-Trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid;
2-(2-{2-[1 -(5,6-difluoro-1A7-benzoimidazol-2-il)etil]-3-metil-3/-/-benzoimidazol-5ilkarbonilamino}etoksi)benzojska kislina;2- (2- {2- [1- (5,6-Difluoro-1A7-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid;
butil 2-(2-{2-[1 -(5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat;butyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate;
propil 2-(2-{2-[1 -(5-h id roksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat; in izobutil 2-(2-{2-[1 -(5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino}etoksi]benzoat.propyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate; and isobutyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3-7-benzoimidazol-5ylcarbonylamino} ethoxy] benzoate.
Prednosten vidik izuma so spojine s Formulo I, v kateri je R1 gvanidino ali aminometil, zlasti:A preferred aspect of the invention are compounds of Formula I in which R 1 is guanidino or aminomethyl, in particular:
2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-metil-N-(2-naft-1 -iletil)-3H-benzoimidazol-5karboksamid;2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5carboxamide;
etil 2-(4-{2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5c]piridin-5-il}-4-oksobutil)benzoat;ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5c] pyridin-5-yl} - 4-Oxobutyl) benzoate;
-232-(5-gvanidino-1 W-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-/V-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamid;-232- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;
2-(5-gvanidino-1H-benzoimidazol-2-ilkarbonil)-3-(2,3-dihidroksi)propil-/V-(2-naft-1-iletil)3W-benzoimidazol-5-karboksamid;2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) 3W-benzoimidazole-5-carboxamide;
2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-(3-hidroksi)propil-A/-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamid;2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;
2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-(2-hidroksi)etil-/V-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamid;2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;
2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-/\/-[2-(2’karbamoilfenoksi)etil]-3-metil-3Wbenzoimidazol-5-karboksamid;2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2'carbamoylphenoxy) ethyl] -3-methyl-3Wbenzoimidazole-5-carboxamide;
2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-/V-[2-(2-karbamoil-4-klorofenoksi)etil]-3-metil2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl
3H-benzoimidazol-5-karboksamid;3H-benzoimidazole-5-carboxamide;
4- kloro-2-[2-({2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonil}amino)etoksi]benzojska kislina;4-chloro-2- [2 - ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonyl} amino) ethoxy] benzoic acid;
5- kloro-2-[2-({2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonil}amino)etoksi]benzojska kislina;5-Chloro-2- [2 - ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonyl} amino) ethoxy] benzoic acid;
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-3-metil-A/-(2-naft-1-iletil)-3/-/-benzoimidazol-5 karboksamid; in2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3 H -benzoimidazole-5 carboxamide; and
2-(5-aminometil-4,5,6,7-tetrahidro-1H-benzoimidazol-2-ilmetil)-3-metil-/\/-(2-naft-1 -iletil)3H-benzoimidazol-5-karboksamid.2- (5-Aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) 3H-benzoimidazole-5-carboxamide .
-24Prednosten vidik tega izuma so spojine s Formulo I, v kateri C obsega 4,5,6,7-tetrahidro1 H-imidazo[4,5-c]piridin-2-il in R1 je -C(NH)R9, zlasti:-24 A preferred aspect of the present invention are compounds of Formula I in which C comprises 4,5,6,7-tetrahydro 1 H-imidase [4,5-c] pyridin-2-yl and R 1 is -C (NH) R 9 , especially:
2-[2-(2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}-3-metil-3Hbenzoimidazol-5-ilkarbonilamino)etoksi]benzojska kislina;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] benzoic acid;
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-A/-(2-naft-1iletil)-3W-benzoimidazol-5-karboksamid;2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-napht- 1ylethyl) -3W-benzoimidazole-5-carboxamide;
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-ilkarbonil]-3-metil-A/-(2-naft1- iletil)-3H-benzoimidazol-5-karboksamid;2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl-N- (2- naphthyl-ylethyl) -3H-benzoimidazole-5-carboxamide;
2- (5-iminometil-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil)-3-meti!-/V-(2-naft-1iletil)-3H-benzoimidazol-5-karboksamid;2- (5-iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl- N - (2-naphthylethyl) - 3H-benzoimidazole-5-carboxamide;
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-A/-(2hidroksi-2-naft-1-iletil)-3H-benzoimidazol-5-karboksamid;2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2hydroxy-2 -naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;
2-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-A/-[2-(2hidroksinaft-1-il)etil]-3H-benzoimidazol-5-karboksamid;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] -3H-benzoimidazole-5-carboxamide;
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-A/-[2-(4hidroksinaftal-1-il)etil]-3H-benzoimidazol-5-karboksamid;2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (4-hydroxynaphthalene) -1-yl) ethyl] -3H-benzoimidazole-5-carboxamide;
2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}-3-metil-/V-(2-naft1- iletil)-3H-benzoimidazol-5-karboksamid;2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- N- (2-naphthyl-ylethyl) -3H-benzoimidazole-5-carboxamide;
etil 2-(2-(2-(1 -[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil }-3-metil3H-benzoimidazol-5-ilkarbonilamino)etoksi]benzoat;ethyl 2- (2- (2- (1- (5- [1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate;
2- (2-(2-(1 -(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil} -3-(2metoksietil)-3H-benzoimidazol-5-ilkarbonilamino)etoksi]benzojska kislina;2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 3- (2methoxyethyl) -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid;
-25etil 2-[2-(2-{1 -[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil}-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-ilkarbonilamino)etoksi]benzoat; in-25ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl } -1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate; and
2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1f7-imidazo[4,5-c]piridin-2-il]etil}-3-metil-A/-[2-(2tetrazolilfenoksi)etil]-3H-benzoimidazol-5-karboksamid.2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- [2- (2tetrazolylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide.
Farmakologija in koristnost:Pharmacology and utility:
Spojine tega izuma so inhibitorji serinskih proteaz, in kot take, so koristne pri zdravljenju bolezni, povezanih s povečano aktivnostjo serinskih proteaz. Zlasti so spojine tega izuma inhibitorji triptaze in so koristne pri zdravljenju bolezni, povezanih s povečano aktivnostjo triptaze. In vivo protokoli za pregledovanje potencialnih inhibitorjev glede na njihovo zmožnost, da inhibirajo triptazo, so v stroki poznani. Glej, npr., Sturzebecher s sod. (1992) Biol. Chem. Hoppe-Sey/er 373:1025-1030. Tipično ti testi merijo z encimom povzročeno hidrolizo na peptidu osnovanih kromogenih substanc. Podrobnosti ponazorilnega postopka za merjenje inhibitome aktivnosti za triptazo so opisani spodaj.The compounds of this invention are serine protease inhibitors, and as such, are useful in the treatment of diseases associated with increased activity of serine proteases. In particular, the compounds of this invention are tryptase inhibitors and are useful in treating diseases associated with increased tryptase activity. In vivo protocols for screening potential inhibitors for their ability to inhibit tryptase are known in the art. See, e.g., Sturzebecher et al. (1992) Biol. Chem. Hoppe-Sey / er 373: 1025-1030. Typically, these assays measure enzyme-induced hydrolysis of peptide-based chromogenic substances. Details of the illustrative method for measuring the inhibitory activity of tryptase are described below.
Poleg tega aktivnost spojin pričujočega izuma lahko ovrednotimo in vivo na enem od številnih živalskih modelov astme. Glej, Larson, Experimental Models of Reversible Airway Obstruction, v THE LUNG: SCIENTIFIC FOUNDATIONS, Crystal, West s sod., eds., Raven Press, New York, 1991; Wamer s sod. (1990) Am. Rev. Respir. Dis. 141:253-257. Idealen živalski model bi ponovil glavne klinične in fiziološke značilnosti humane astme, ki vključujejo: hiperodzivnost zračnih poti na kemijske mediatorje in fizikalne stimuluse; prebrat v obstrukciji zračnih poti z zdravili, ki so koristna pri humani astmi (β-adrenergiki, metilksantini, kortikosteroidi in podobno); vnetje zračnih poti z infiltracijo aktiviranih levkocitov; in kronične vnetne degenerativne spremembe, kot otekanje bazalne membrane, hipertrofija gladkih mišic in poškodba epitelija. Vrste živali, ki jih uporabljamo kot živalske modele vključujejo miši, podgane, morske prašičke, kunce, pse in ovce. Vse živali imajo nekaj omejitev in prava izbira živalskega modela je odvisna od vprašanja, na katerega je potrbno poiskati odgovor.In addition, the activity of the compounds of the present invention can be evaluated in vivo in one of many 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; Wamer et al. (1990) Am. Rev. Respir. Dis. 141: 253-257. An ideal animal model would replicate the main clinical and physiological characteristics of human asthma, which include: airway hyperresponsiveness to chemical mediators and physical stimuli; read in airway obstruction with medicines useful in human asthma (β-adrenergics, methylxanthines, corticosteroids and the like); airway inflammation by infiltration of activated leukocytes; and chronic inflammatory degenerative changes such as swelling of the basement membrane, smooth muscle hypertrophy, and epithelial damage. The species of animals used as animal models include mice, rats, guinea pigs, rabbits, dogs and sheep. All animals have some limitations and the right choice of animal model depends on the question that needs to be answered.
-26Začetni astmatični odziv lahko ovrednotimo na morskih prašičkih in psih, in zlasti s križanci med vrstama basenji in veliki angleški hrt (greyhound), ki razvijejo nespecifično hiperodzivnost zračnih poti na številne nealergene substance, kot sta metaholin in citronska kislina. Določene izbrane ovce kažejo dvojen odziv po antigenskem izzivu z Ascaris proteini. Pri živalih, ki se dvakrat odzovejo začetnemu astmatičnemu odzivu (IAR) sledi pozen astmatičen odziv (LAR) pri 6-8 urah po izpostavitvi. Preobčutljivost na holinergičen agonist karbahol se poveča pri 24 urah po antigenskem izzivu pri tistih živalih, ki kažejo LAR.-26The initial asthmatic response can be evaluated in guinea pigs and dogs, and in particular with crossbreeds between species of fables and Greyhound, which develop non-specific airway hypersensitivity to many non-allergenic substances, such as methacholine and citric acid. Certain selected sheep show a dual response after an antigen challenge with Ascaris proteins. In animals that respond twice to an initial asthmatic response (IAR), a late asthmatic response (LAR) is followed at 6-8 hours after exposure. Hypersensitivity to the cholinergic agonist carbachol is increased at 24 hours after the antigen challenge in those animals showing LAR.
Model alergičnih ovc (glej spodaj) smo uporabili, da smo ovrednotili potencialne antiastmatične učinke spojin pričujočega izuma. Dajanje sestavkov, ki so obsegali spojine pričujočega izuma alergičnim ovcam, tako v oralnih kakor v inhalacijskih ali aerosolnih formulacijah pred ali po izpostavitvi na specifične alergene, nazorno kaže, da taki sestavki znatno zmanjšajo ali odpravijo pozen astmatičen odziv in posledično hiperodzivnost.The allergic sheep model (see below) was used to evaluate the potential anti-asthmatic effects of the compounds of the present invention. Administration of compositions comprising the compounds of the present invention to allergic sheep, both in oral or inhalation or aerosol formulations, before or after exposure to specific allergens, demonstrates that such compositions significantly reduce or eliminate the late asthmatic response and, consequently, hyperresponsiveness.
Spojine tega izuma so tudi koristne za zdravljenje drugih imunsko posredovanih vnetnih motenj pri katerih aktivnost triptaze prispeva k patološkemu stanju. Take bolezni vključujejo vnetne bolezni, povezane z mastociti, kot revmatoidni artritis, konjunktivitis, revmatoidni spondilitis, osteoartritis, protinski artritis in druga artritična stanja, vnetno bolezen črevesja, peptične ulkuse in različna stanja kože. Nadalje spojine pričujočega izuma lahko uporabljamo, da zdravimo infekcije s sincicijskim virusom.The compounds of the present invention are also useful for the treatment of other immune-mediated inflammatory disorders in which tryptase activity contributes to a pathological condition. Such diseases include mast cell-related inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease, peptic ulcers and various skin conditions. Further, the compounds of the present invention can be used to treat syncytial virus infections.
Učinkovitost spojin pričujočega izuma za zdravljenje velike večine imunsko posredovanih vnetnih bolezni lahko ovrednotimo z bodisi in vitro ali in vivo postopki. Tako protivnetno učinkovitost spojin pričujočega izuma lahko nazorno prikažemo s testi, ki so v stroki dobro poznani, na primer, s PAW-tehniko reverzne pasivne Arthusove reakcije (RPAR) (glej, npr., Gangly s sod. (1992) U.S. patent št. 5,126,352). Testi za določitev terapevtske vrednosti spojin pri zdravljenju različnih stanj kože, kot je hiperproliferativna kožna bolezen, so v stroki dobro poznani, na primer, test z arahidonsko kislino na ušesu miši (angl. Arachidonic Acid Mouse Ear Test) (glej isti patent). Spojine pričujočega izuma lahko ovrednotimo glede na njihovo protiulkusno aktivnost po postopkih, ki jih je opisal Chiu s sod. (1984) v Archives Intemationales de Pharmacodynamie etde Therapie 270:128-140.The efficacy of the compounds of the present invention for the treatment of the vast majority of immune-mediated inflammatory diseases can be evaluated by either in vitro or in vivo methods. Such anti-inflammatory efficacy of the compounds of the present invention can be clearly demonstrated by tests well known in the art, for example, the PAW technique of reverse passive Arthus reaction (RPAR) (see, e.g., Gangly et al. (1992) U.S. Pat. No. 5,126,352). Tests for determining the therapeutic value of compounds in the treatment of various skin conditions, such as hyperproliferative skin disease, are well known in the art, for example, the arachidonic Acid Mouse Ear Test (see same patent). The compounds of the present invention can be evaluated for their antitumor activity according to the methods described by Chiu et al. (1984) in Archives Intemationales de Pharmacodynamie etde Therapie 270: 128-140.
-27Učinkovitost spojin pričujočega izuma pri blokiranju zlitja celic, povzročenega z infekcijo s sincicijskim virusom lahko ovrednotimo po metodah, ki so na splošno pojasnjene v Tidwell, s sod., J. Med. Chem. 26:294-298 (1983).-27The efficacy of the compounds of the present invention in blocking cell fusion caused by syncytial virus infection can be evaluated by methods generally explained in Tidwell et al., J. Med. Chem. 26: 294-298 (1983).
Sestavki in dajanje:Ingredients and administration:
Po tem izumu terapevtsko učinkovito količino spojine izuma damo pacientu, ki trpi zaradi imunsko posredovane vnetne motnje. Po eni izvedbi so sestavki tega izuma koristni za preprečevanje ali izboljšanje astme. Ob uporabi sestavkov pričujočega izuma pri zdravljenju astme, sestavke lahko damo profilaktično pred izpostavitvijo na alergen ali drug precipitani faktor ali po taki izpostavitvi. Spojine pričujočega izuma so zlasti koristne pri izboljšanju pozne faze destrukcije tkiva, ki jo lahko opazimo tako pri sezonskem, kakor celo leto trajajočem rinitisu. Drug vidik pričujočega izuma je usmerjen k preprečitvi in zdravljenju imunsko posredovanih vnetnih motenj, povezanih z mastociti, kot so urtikarija in angioedem, ekcematozni dermatitis (atopični dermatitis) in anafilaksa, kot tudi hiperproliferativna bolezen kože, peptični ulkusi in podobno. V še nadaljnji izvedbi se spojine pričujočega izuma uporabljajo za zdravljenje infekcij s sincicijskim virusom, zlasti infekcij z respiratornim sincicijskim virusom.According to the present invention, a therapeutically effective amount of a compound of the invention is administered to a patient suffering from an immune-mediated inflammatory disorder. In one embodiment, the compositions of the present invention are useful for preventing or ameliorating asthma. When using the compositions of the present invention for the treatment of asthma, the compositions can be administered prophylactically before or after exposure to an allergen or other precipitating factor. The compounds of the present invention are particularly useful in improving the late phase of tissue destruction that can be observed in both seasonal and year-round rhinitis. Another aspect of the present invention is directed to the prevention and treatment of immune-mediated inflammatory disorders associated with mast cells, such as urticaria and angioedema, eczema dermatitis (atopic dermatitis) and anaphylaxis, as well as hyperproliferative skin disease, peptic ulcers and the like. In a further embodiment, the compounds of the present invention are used to treat syncytial virus infections, in particular respiratory syncytial virus infections.
Sestavke, ki vsebujejo spojine lahko damo za terapevtska in/ali profilaktična zdravljenja. Pri terapevtskih aplikacijah sestavke damo pacientu, ki že trpi zaradi bolezni, kot je opisana zgoraj, v količini, ki je zadostna, da zdravi ali vsaj deloma zadrži simptome bolezni in njihove komplikacije. Količina, ki je zadostna, da to dosežemo, je definirana kot terapevtsko učinkovita količina ali doza. Količine, ki bodo učinkovite za to uporabo, bodo odvisne od resnosti in poteka bolezni, prejšnje terapije, pacientovega zdravstvenega stanja in odziva na zdravila in presoje lečečega zdravnika.Compounds containing the compounds may be administered for therapeutic and / or prophylactic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from the disease as described above in an amount sufficient to cure or at least partially contain the disease symptoms and their complications. An amount sufficient to achieve this is defined as a therapeutically effective amount or dose. The amounts effective for this use will depend on the severity and course of the disease, previous therapy, the patient's medical condition, and response to medication and judgment of the treating physician.
Pri profilaktičnih aplikacijah sestavke, ki vsebujejo spojine izuma damo pacientu, ki je nagnjen k določeni bolezni ali drugače v nevarnosti pred določeno boleznijo, v količini, ki je zadostna, da prepreči ali izboljša nastop simptomov. Taka količina je definirana, da je profilaktično učinkovita količina ali doza. Te spojine lahko damo oralno ali z inhalacijo.In prophylactic applications, compositions containing the compounds of the invention are administered to a patient prone to a particular disease or otherwise at risk of a particular disease, in an amount sufficient to prevent or improve the onset of symptoms. Such an amount is defined to be a prophylactically effective amount or dose. These compounds may be administered orally or by inhalation.
-28Pri tej uporabi so natančne količine zopet odvisne od pacientovega zdravstvenega stanja, teže in podobno.-28With this use, the exact amounts again depend on the patient's medical condition, weight and the like.
Ko se pacientovo stanje enkrat izboljša, če je potrebno, dajemo vzdrževalno dozo. Pozneje doziranje (odmerjanje) ali pogostost dajanja ali oboje lahko zmanjšamo kot funkcijo simptomov na nivo, na katerem vzdržujemo izboljšano stanje. Kadar simptome zmanjšamo na želen nivo se zdravljenje lahko neha. Vendar pacienti lahko zahtevajo zdravljenje v presledkih na dolgoročni osnovi, po vsakem ponovnem nastopu bolezenskih simptomov.Once the patient's condition has improved once, if necessary, a maintenance dose is given. Subsequent dosing (dosing) or frequency of administration, or both, can be reduced as a function of symptoms to the level at which we maintain an improved state. Treatment can be stopped when symptoms are reduced to the desired level. However, patients may require intermittent treatment on a long-term basis, after any recurrence of disease symptoms.
Na splošno bo primerna učinkovita doza (odmerek) spojin pričujočega izuma v območju od 0.05 do 1000 miligramov (mg) na prejemnika na dan, prednostno v območju od 0.1 do 100 mg na dan. Želeno odmerjanje prednostno dajemo v eni, dveh, treh štirih ali več poddozah, danih v določenih intervalih preko dneva. Te poddoze lahko dajemo kot enotne dozirane oblike, na primer, vsebujoče 0.01 do 1000 mg, prednostno 0.01 do 100 mg aktivne sestavine na enotno dozirano obliko.In general, an effective dose (dose) of the compounds of the present invention will be in the range of 0.05 to 1000 milligrams (mg) per recipient per day, preferably in the range of 0.1 to 100 mg per day. The desired dosage is preferably administered at one, two, three four or more sub-doses given at specified intervals throughout the day. These sub-doses can be administered as unit dosage forms, for example, containing 0.01 to 1000 mg, preferably 0.01 to 100 mg of active ingredient per unit dosage form.
Sestavek, ki ga uporabimo pri teh terapijah je lahko v raznolikih oblikah. Te vključujejo, na primer, trdne, poltrdne in tekoče odmerjene oblike, kot tablete, enterično obložene tablete, pilule, praške, tekoče raztopine ali suspenzije, liposome, injekcijske in infuzijske raztopine. Inhalacijski pripravki, kot aerosoli, so tudi vključeni. Prednostne formulacije so tiste, usmerjene k oralnim, intranazalnim, topičnim in parenteralnim aplikacijam, toda upoštevali bomo, da bo prednostna oblika odvisna od določene terapevtske aplikacije, ki bo na voljo. Posebno prednostni aplikaciji sta oralna in aerosolna. Metode za formuliranje in pripravo terapevtskih sestavkov, ki obsegajo spojine izuma so v stroki poznane in so opisane v, na |L primer, REMINGTON'S PHARMACEUTICAL SCIENCES and THE MERCK INDEX 11 Ed., (Merck &Co. 1989).The composition to be used in these therapies can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, enteric coated tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusion solutions. Inhalation preparations, such as aerosols, are also included. Preferred formulations are those directed to oral, intranasal, topical and parenteral applications, but it will be appreciated that the preferred formulation will depend on the particular therapeutic application that is available. Oral and aerosol applications are particularly preferred. Methods for formulating and preparing therapeutic compositions comprising the compounds of the invention are known in the art and are described in, for example, the REMINGTON'S PHARMACEUTICAL SCIENCES and THE MERCK INDEX 11 Ed., (Merck & Co. 1989).
Medtem ko je možno, da damo aktivno sestavino tega izuma samo, je prednostno, da jo damo kot del farmacevtske formulacije. Formulacije pričujočega izuma obsegajo vsaj eno spojino, ki je tu opisana, v terapevtsko ali farmacevtsko učinkoviti dozi, skupaj s farmakološko sprejemljivim nosilcem. Farmacevtski sestavki bodo tako vsebovali spojineWhile it is possible to administer the active ingredient of the present invention only, it is preferable to administer it as part of a pharmaceutical formulation. The formulations of the present invention comprise at least one compound described herein in a therapeutically or pharmaceutically effective dose, together with a pharmacologically acceptable carrier. The pharmaceutical compositions will thus contain the compounds
-29pričujočega izuma v koncentracijah, ki bodo zadostovale za dajanje primerne doze. Na primer, kjer je primerna doza 0.05 mg na dan in kjer uporabimo eno dozo na dan, bi bile koncentracije spojine izuma v farmacevtskem sestavku 0.05 mg na dozo. Za inhalacijske ali aerosolne sestavke bo koncentracija spojin pričujočega izuma v sestavku na splošno odvisna od količine doze. Tipične koncentracije spojin pričujočega izuma v inhalacijskih ali aerosolnih sestavkih bi bile od okoli 0.01 do okoli 30 mg/ml. Formulacija lahko vključuje druge klinično koristne spojine, kot β-adrenergike (npr., albuterol, terbutalin, formoterol, fenoterol in prenalin) in kortikosteroide (npr., beklometasom, triamcinolon, flunisolid in deksametason).-29 of the present invention in concentrations sufficient to give a suitable dose. For example, where the appropriate dose is 0.05 mg per day and where one dose per day is used, the concentrations of the compound of the invention in the pharmaceutical composition would be 0.05 mg per dose. For inhalable or aerosol compositions, the concentration of the compounds of the present invention in the composition will generally depend on the amount of dose. Typical concentrations of the compounds of the present invention in inhalable or aerosol compositions would be from about 0.01 to about 30 mg / ml. The formulation may include other clinically useful compounds, such as β-adrenergics (e.g., albuterol, terbutaline, formoterol, phenoterol and prenalin) and corticosteroids (e.g., beclometasoma, triamcinolone, flunisolid and dexamethasone).
Kemija:Chemistry:
Na splošno spojine pričujočega izuma sintetiziramo ob uporabi standardnih tehnik in reagentov, ki so strokovnjakom na tem področju poznani in jih tudi uporabljajo. Upoštevali bomo, da vezi med različnimi funkcionalnimi skupinami na splošno obsegajo ogljik, vezan na dušik amida ali karbamata, kisik karbamata ali ogljik karbonila. Strokovnjaki na tem področju bodo spoznali, da so metode in reagenti za tvorbo teh vezi dobro poznani inIn general, the compounds of the present invention are synthesized using standard techniques and reagents that are known to and practiced by those skilled in the art. It will be appreciated that the bonds between the various functional groups generally comprise carbon bound to amide or carbamate nitrogen, carbamate oxygen or carbonyl carbon. Those skilled in the art will recognize that the methods and reagents for forming these bonds are well known and known
1U zlahka dostopni. Glej, npr., March, ADVANCED ORGANIC CHEMISTRY, 4 Ed. (Wiley1U easily accessible. See, e.g., March, ADVANCED ORGANIC CHEMISTRY, 4 Ed. (Wiley
1992), Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH 1989); in Furniss, th s sod., VOGEUS ΤΕΧΤΒΟΟΚ OF PRACTICAL ORGANIC CHEMISTRY 5 ed. (Longman 1989), od katerih je vsak tu vključen z referenco.1992), Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH 1989); in Furniss, th et al., VOGEUS ΤΕΧΤΒΟΟΚ OF PRACTICAL ORGANIC CHEMISTRY 5 ed. (Longman 1989), each of which is incorporated herein by reference.
55
Spojine s Formulo I, v kateri sta X in X sosednja člena oksazol-2-il, 1 H-imidazol-2-il ali tiazol-2-il obroča, lahko pripravimo po metodah, opisanih v sledeči reakcijski shemi:Compounds of Formula I in which X and X are adjacent members of oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring can be prepared by the methods described in the following reaction scheme:
-30Shema 1-30 Scheme 1
v kateri je L izstopajoča skupina, D skupaj z vinilenskim delom na katerega je kondenziran obsega monociklični ali kondenziran biciklični divalentni radikal, ki vsebuje od 5 do 15 obročnih atomov, pri čemer vsak obroč vsebuje 5 do 7 obročnih atomov in vsak obročni po 6 fi fi atom je opcijsko heteroatom, R je -OH, -NHR ali -SH, X je -0-, -NR - ali -S- in n2, n3, 12351234 6 n4, A, B, X , X , X , X , R , R , R , R in R so kot je definirano v Povzetku izuma.in which L is a prominent group, D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring having 6 f the atom is optionally a heteroatom, R is -OH, -NHR or -SH, X is -O-, -NR - or -S-, and n2, n3, 12351234 6 n4, A, B, X, X, X, X, R, R, R, R and R are as defined in the Summary of the Invention.
55
Spojine s Formulo I, v kateri sta X in X sosednja člena oksazol-2-il, 1 H-imidazol-2-ii ali tiazol-2-il obroča (Formula l(a)), lahko pripravimo z reagiranjem spojine s Formulo I, ali njenega zaščitenega derivata, s spojino s Formulo 2, ali njenim zaščitenim derivatom, in potem, če je potrebno odstranimo zaščito. Reakcijo med spojinami s Formulama 1 in 2 lahko izvedemo brez razredčenja reaktantov, toda prednostno jo izvedemo v prisotnosti 1,3-dimetil-3,4,5,6-tetrahidro-2(1/-/)-pirimidinona (DMPU) ali polifosforne kisline pri 160 do 200°C, prednostno 180-190°C, in potrebuje 1 do 5 ur, da je končana (npr., glej Primere 4(d), 6(h), 8(k), 9(d) in 10(d), spodaj). Odstranitev zaščite lahko izvedemo na katerikoliCompounds of Formula I in which X and X are adjacent members of oxazol-2-yl, 1H-imidazol-2-ii or thiazol-2-yl ring (Formula l (a)) can be prepared by reacting a compound of Formula I , or a protected derivative thereof, with a compound of Formula 2, or a protected derivative thereof, and then, if necessary, deprotected. The reaction between the compounds of Formulas 1 and 2 can be carried out without diluting the reactants, but is preferably carried out in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H -pyrimidinone (DMPU) or polyphosphorus acid at 160 to 200 ° C, preferably 180-190 ° C, and takes 1 to 5 hours to complete (e.g., see Examples 4 (d), 6 (h), 8 (k), 9 (d) and 10 (d), below). Removal of protection can be performed on any
-31način, ki odstrani zaščitno skupino in daje želen produkt v razumnem dobitku (npr., glej Primer 2(g), spodaj).-31 A method that removes the protecting group and gives the desired product in reasonable yield (e.g., see Example 2 (g), below).
22
Na podoben način lahko pripravimo spojine s Formulo I, v kateri sta X in X sosednja člena oksazol-2-il, 1 H-imidazol-2-il ali tiazol-2-il obroča po metodah, opisanih v sledeči reakcijski shemi:In a similar manner, compounds of Formula I can be prepared in which X and X are adjacent members of oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring according to the methods described in the following reaction scheme:
Shema 2Scheme 2
l(b)l (b)
ΟΛ R fi fi v kateri je L izstopajoča skupina, R je -OH, -NHR ali -SH, X je -0-, -NR - ali -S- in n2, n3, n4, B, C, X1, X3, X4, X5, R1, R2, R3, R4 in R6 so kot je definirano v Povzetku izuma (npr., glej Primere 2(e) in 7(h), spodaj).ΟΛ R fi fi in which L is a prominent group, R is -OH, -NHR or -SH, X is -0-, -NR - or -S- and n2, n3, n4, B, C, X 1 , X 3 , X 4 , 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).
Izolacijo in čiščenje tu opisanih spojin in derivatov lahko izvedemo, če je zaželeno, po kateremkoli primernem separacijskem postopku ali postopku čiščenja, kot so, na primer, filtracija, ekstrakcija, kristalizacija, kolonska kromatografija, tankoplastna kromatografija aliThe isolation and purification of the compounds and derivatives described herein may be carried out, if desired, by any suitable separation or purification process, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography or
-32debeloplastna kromatografija, visokotlačna tekočinska kromatografija (HPLC), ali kombinacijo teh postopkov. Specifične pojasnitve primernih separacijskih in izolacijskih postopkov so lahko navedene z referenco k spodnjim primerom. Vendar se seveda lahko uporablja tudi druge primerne separacijske ali izolacijske procedure. Nuklearne magnetno resonančne (NMR) spektre smo posneli na spektrometru General Electric QE Plus (300 MHz). Infrardeče spektre smo posneli na Perkin-Elmerjevem 1600 Fourier Transform IR (FTIR) spektrofotometru. Analitsko HPLC smo izvedli na ultrahitrem mikroproteinskem analizatorju, Michrom BioResources, Inc., opremljenem s PLRP kolono, 1 mm x 150 mm. Preparativno HPLC smo izvedli na Gilsonovem LC (tekočinskem kromatografu) ob uporabi VYDAC 1x25 cm C-|g kolone z reverzno fazo (RP) ali VVatersovega Prep LC2000 sistema ob uporabi Vydac 5x25 cm C-ig RP kolone. Masne spektre (MS) smo dobili na aparatu Finnigan SSQ 710 z ESI izvorom, z direktnim injiciranjem ali s HPLC MS (ultrahitri mikroproteinski analizator, Cig kolona, 2 mm X 150 mm). Razen, če ni drugače zabeleženo smo vse reagente in opremo bodisi pripravili po objavljenih postopkih ali pa smo jih kupili pri komercialnih virih, kot so Aldrich Chemical Co. (Milwaukee, Wl), Sigma Chemical Co. (St. Louis, MO) in ICN Chemical Co. (Irvine, CA). Uporabljene tehnike za izvedbo spodaj opisanih sintez, bodo strokovnjaki na tem področju prepoznali kot rutinske (glej, npr., March, Larock ali Furniss, zgoraj).-32-thick chromatography, high-pressure liquid chromatography (HPLC), or a combination of these methods. Specific explanations of suitable separation and isolation procedures can be given by reference to the examples below. However, other appropriate separation or isolation procedures may of course be used. Nuclear magnetic resonance (NMR) spectra were recorded on a General Electric QE Plus (300 MHz) spectrometer. Infrared spectra were recorded on a Perkin-Elmer 1600 Fourier Transform IR (FTIR) spectrophotometer. Analytical HPLC was performed on an ultrafast microprotein analyzer, Michrom BioResources, Inc. equipped with a PLRP column, 1 mm x 150 mm. Preparative HPLC was performed on a Gilson LC (liquid chromatograph) using a VYDAC 1x25 cm C-g reverse phase (RP) column or Vaters Prep LC2000 system using a Vydac 5x25 cm C-ig RP column. Mass spectra (MS) were obtained on a Finnigan SSQ 710 apparatus with ESI source, direct injection or HPLC MS (ultrafast microprotein analyzer, Cig column, 2 mm X 150 mm). Unless otherwise noted, all reagents and equipment were either prepared according to published procedures or purchased from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wl), Sigma Chemical Co. (St. Louis, MO) and ICN Chemical Co. (Irvine, CA). The techniques used to perform the syntheses described below will be recognized by those skilled in the art as routine (see, e.g., March, Larock or Furniss, supra).
Dodatni postopki za pripravo spojin s Formulo I:Additional procedures for the preparation of compounds of Formula I:
Spojine s Formulo I lahko pripravimo kot farmacevtsko sprejemljive soli, dobljene ob dodatku kislin, z reagiranjem oblik proste baze spojine s Formulo l s farmacevtsko sprejemljivo anorgansko ali organsko kislino. Alternativno farmacevtsko sprejemljive soli spojin s Formulo I, dobljene ob dodatku baz, lahko pripravimo z reagiranjem oblik prostih kislin spojin s Formulo I, s farmacevtsko sprejemljivimi anorganskimi ali organskimi bazami. Anorganske in organske kisline in baze, ki so primerne za pripravo farmacevtsko sprejemljivih soli spojin s Formulo I, so navedene v sekciji z definicijami te objave. Alternativno oblike soli spojin s Formulo I lahko pripravimo ob uporabi soli izhodnih materialov ali intermediatov.The compounds of Formula I can be prepared as pharmaceutically acceptable salts obtained by the addition of acids by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively the pharmaceutically acceptable salts of the compounds of Formula I obtained by the addition of bases can be prepared by reacting the free acid forms of the compounds of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of compounds of Formula I are listed in the definition section of this publication. Alternatively, salt forms of compounds of Formula I may be prepared using salts of starting materials or intermediates.
-33Oblike prostih kislin ali prostih baz spojin s Formulo I lahko pripravimo iz odgovarjajoče oblike soli, dobljene z dodatkom baze ali soli, dobljene z dodatkom kisline. Na primer, spojine s Formulo I v obliki soli, dobljene z dodatkom kisline, lahko pretvorimo v odgovarjajočo prosto bazo z obdelavo s primemo bazo (npr., raztopino amonijevega hidroksida, natrijevim hidroksidom, itd.). Spojine s Formulo I v obliki soli, dobljene z dodatkom baze, lahko pretvorimo v odgovarjajočo prosto kislino z obdelavo s primerno kislino (npr., klorovodikovo kislino, itd.).-33 Forms of free acids or free bases of compounds of Formula I can be prepared from the corresponding salt form obtained by the addition of a base or a salt obtained by the addition of acid. For example, compounds of Formula I in the form of a salt obtained by the addition of acid can be converted to a corresponding free base by treatment with a primed base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). Compounds of Formula I in the form of salts obtained by the addition of a base can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.).
/V-okside spojin s Formulo I lahko pripravimo po metodah, ki so običajnim strokovnjakom na tem področju poznane. Na primer, /V-okside lahko pripravimo z obdelavo neoksidirane oblike spojine s Formulo I z oksidantom (npr., trifluoroperocetno kislino, permaleinsko kislino, perbenzojsko kislino, perocetno kislino, mefa-kloroperoksibenzojsko kislino, itd.) v primernem inertnem organskem topilu (npr., halogeniranem ogljikovodiku, kot je metilen klorid) pri približno 0°C. Alternativno /V-okside spojin s Formulo I lahko pripravimo iz Noksida primernega izhodnega materiala.The V-oxides of the compounds of Formula I can be prepared by methods known to one of ordinary skill in the art. For example, / V-oxides can be prepared by treating the non-oxidized form of a compound of Formula I with an oxidant (e.g., trifluoroperoxyacetic acid, permaleic acid, perbenzoic acid, peracetic acid, mefa-chloroperoxybenzoic acid, etc.) in a suitable inert organ (e.g. ., a halogenated hydrocarbon such as methylene chloride) at about 0 ° C. Alternatively, the V-oxides of the compounds of Formula I can be prepared from the Noxide of a suitable starting material.
Spojine s Formulo I v neoksidirani obliki lahko pripravimo iz /V-oksidov spojin s Formulo I z obdelavo z reducentom (npr. žveplom, žveplovim dioksidom, trifenil fosfinom, litijevim borohidridom, natrijevim borohidridom, fosforjevim trikloridom, tribromidom, itd.) v primernem inertnem organskem topilu (npr., acetonitrilu, etanolu, vodnemu dioksanu, itd.) pri 0 do 80°C.Compounds of Formula I in non-oxidized form can be prepared from the V-oxides of compounds of Formula I by treatment with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, etc. tribromide). an organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 ° C.
Derivate predzdravil spojin s Formulo I lahko pripravimo po metodah, ki so običajnim strokovnjakom na tem področju poznane (npr., glej Primer 12, spodaj). Za nadaljnje podrobnosti o predzdravilih in njihovi pripravi glej Saulnier s sod., (1994), Bioorganic and Medicina! Chemistry Letters. 4:1985).The prodrug derivatives of the compounds of Formula I may be prepared by methods known to one of ordinary skill in the art (e.g., see Example 12, below). For further details on prodrugs and their preparation, see Saulnier et al., (1994), Bioorganic and Medicine! Chemistry Letters. 4: 1985).
Zaščitene derivate spojin s Formulo I lahko izdelamo po metodah, ki so običajnim strokovnjakom na tem področju poznane. Podroben opis primernih tehnik za tvorbo zaščitnih skupin in njihovo odstranitev lahko najdemo v T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.Protected derivatives of compounds of Formula I can be made by methods known to one of ordinary skill in the art. A detailed description of suitable techniques for forming protecting groups and removing them can be found in T.W. Greene, Protective Groups in Organic Synthesis by John Wiley & Sons, Inc. 1981.
-34Spojine s Formulo I lahko pripravimo kot njihove posamezne stereoizomere z reagiranjem racemne zmesi spojine z optično aktivnim resolventom, da se tvori par diastereoizomemih spojin, ločevanjem diastereomerov in pridobivanjem optično čistega enantiomera. Medtem ko resolucijo enantiomerov lahko izvedemo ob uporabi kovalentnih diastereomernih derivatov spojin s Formulo I, so prednostni disociabilni kompleksi (npr., kristalinične diastereoizomerne soli). Diastereomeri imajo značilne fizikalne lastnosti (npr., tališča, vrelišča, topnosti, reaktivnost, itd.) in jih lahko zlahka ločimo z izkoriščanjem teh različnosti. Diastereomere lahko ločimo s kromatografijo ali, prednostno, s tehnikami separacije oz. resolucije, osnovanimi na razlikah v topnosti. Optično čist enantiomer potem zopet dobimo skupaj z resolventom, na katerikoli praktičen način, ki ne rezultira v racemizaciji. Bolj podroben opis primernih tehnik za resolucijo stereoizomer spojin iz njihove racemne zmesi lahko najdemo v Jean Jacques Andre Collet, Samuel H. VVilen, Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).-34 Compounds of Formula I can be prepared as their individual stereoisomers by reacting the racemic mixture of the compound with an optically active resolvent to form a pair of diastereoisomeric compounds, separating the diastereomers and obtaining the optically pure enantiomer. While resolution of enantiomers can be performed using covalent diastereomeric derivatives of compounds of Formula I, dissociable complexes (e.g., crystalline diastereoisomeric salts) are preferred. Diastereomers have characteristic physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated by exploiting these differences. The diastereomers can be separated by chromatography or, preferably, by separation or separation techniques. resolutions based on differences in solubility. The optically pure enantiomer is then again obtained together with the resolvent in any practical manner that does not result in racemization. A more detailed description of suitable techniques for resolving stereoisomeric compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Vilen, Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).
V povzetku je en vidik tega izuma postopek za pripravo spojine s Formulo I, ta postopek obsega:In summary, one aspect of the present invention is a process for the preparation of a compound of Formula I, this process comprising:
(a) reagiranje spojine s Formulo 1:(a) reacting a compound of Formula 1:
ali njenega zaščitenega derivata, s spojino s Formulo 2:or a protected derivative thereof, with a compound of Formula 2:
K)n3K) n3
-35ali njenim zaščitenim derivatom, pri čemer je L izstopajoča skupina, D skupaj z vinilenskim delom, na katerega je kondenziran obsega monociklični ali kondenziran biciklični divalentni radikal, ki vsebuje od 5 do 15 obročnih atomov, pri čemer vsak obroč vsebuje 5 29 6 do 7 obročnih atomov in vsak obročni atom je opcijsko heteroatom, R je -OH, -NHR ali 12 3 1 2 3 4 β-35 or a protected derivative thereof, wherein L is a protuberant group, D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 ring atoms, each ring containing from 5 29 6 to 7 ring atoms and each ring atom is optionally heteroatom, R is -OH, -NHR or 12 3 1 2 3 4 β
-SH in n1, n2, n3, A, B, X , λ , X , R , R , R , R in R so kot je definirano v Povzetku izuma, in potem, Če je potrebno odstranjevanje zaščite, da dobimo spojino s Formulo I v 4 5 kateri sta X in X sosednja člena oksazol-2-il, 1 H-imidazol-2-il ali tiazol-2-il obroča; ali (b) reagiranje spojine s Formulo 3;-SH and n1, n2, n3, A, B, X, λ, X, R, R, R, R and R are as defined in the Summary of the Invention, and then, If protection is required to obtain a compound of Formula I in 4 5 wherein X and X are adjacent members of oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl rings; or (b) reacting a compound of Formula 3;
ali njenega zaščitenega derivata, s spojino s formulo 4:or a protected derivative thereof, with a compound of formula 4:
5 ali njenim zaščitenim derivatom, pri čemer je L izstopajoča skupina, R je -OH, -NHR ali5 or a protected derivative thereof, wherein L is a leaving group, R is -OH, -NHR or
-SH in n1, n2, n3, B, C, X3, X4, X5, R1, R2, R3, R4 in R5 so kot je definirano v Povzetku izuma in potem, če je potrebno odstranjevanje zaščite, da dobimo spojino s Formulo I v 1 2 kateri sta X in X sosednja člena oksazol-2-il, 1 H-imidazol-2-il ali tiazol-2-il obroča;-SH and n1, n2, n3, B, C, X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the Summary of the Invention and then if removal is required protection to give a compound of Formula I in 1 2 wherein X and X are adjacent members of oxazol-2-yl, 1 H-imidazol-2-yl or thiazol-2-yl of the ring;
(c) opcijsko nadaljnje pretvarjanje spojine s Formulo I v farmacevtsko sprejemljivo sol;(c) optionally further converting the compound of Formula I into a pharmaceutically acceptable salt;
(d) opcijsko nadaljnje pretvarjanje oblike soli spojine s Formulo I v obliko, ki ni sol;(d) optionally further converting a salt form of a compound of Formula I into a form other than a salt;
-36(e) opcijsko nadaljnje pretvarjanje neoksidirane oblike spojine s Formulo I v farmacevtsko sprejemljiv /V-oksid;-36 (e) optionally further converting a non-oxidized form of a compound of Formula I into a pharmaceutically acceptable / V-oxide;
(f) opcijsko nadaljnje pretvarjanje /V-oksidne oblike spojine s Formulo I v njeno neoksidirano obliko;(f) optionally further converting the / V-oxide form of the compound of Formula I into its non-oxidized form;
(g) opcijsko nadaljnje pretvarjanje nederivatizirane spojine s Formulo I v farmacevtsko sprejemljiv derivat predzdravila; in (h) opcijsko nadaljnje pretvarjanje derivata predzdravila spojine s Formulo I v njegovo nederivatizirano obliko.(g) optionally further converting a non-derivatized compound of Formula I into a pharmaceutically acceptable prodrug derivative; and (h) optionally further converting the prodrug derivative of the compound of Formula I into its non-derivatized form.
Primeri:Examples:
Sledeči primeri so dani samo za namene pojasnitve in se jih v nobenem primeru ne sme razlagali kot omejevanje obsega pričujočega izuma. Strokovnjakom na tem področju bo razvidno, da se v obsegu izuma lahko izvaja določene variacije in modifikacije.The following examples are given for purposes of explanation only and should in no case be construed as limiting the scope of the present invention. It will be apparent to those skilled in the art that certain variations and modifications may be made within the scope of the invention.
PRIMER 1 2-Naft-2-iletilaminEXAMPLE 1 2-Naphth-2-ylethylamine
Raztopino, obsegajočo 2-naft-2-iletanol (0.5 g, 2.9 mmol) v suhem DMF (5 ml) smo v atmosferi dušika združili z difenifosforil azidom (0.74 ml, 3.42 mmol) in 1,8diazabiciklo[5.4.0]undek-7-enom (0.47 ml, 3.14 mmol). Zmes smo segrevali pri 65°C 3 ure in potem porazdelili med vodo in dietil eter. Vodno plast smo ločili in ekstrahirali z dietil etrom. Združene organske plasti smo sprali s 3 N klorovodikovo kislino in potem nasičenim natrijevim bikarbonatom, posušili (MgSO4), filtrirali in koncentrirali z rotacijsko evaporacijo. Ostanek smo raztopili v THF (5 ml) in raztopino smo združili s trifenilfosfinom (1 g, 3.81 mmol), mešali 2 uri pri sobni temperaturi, razredčili z vodo (0.100 ml), mešali 3 ure, razredčili s koncentrirano klorovodikovo kislino (0.33 ml), da smo dobili oborino, obdelali z etanolom (5 ml), da smo raztopili oborino in obdelali z dietil etrom, dodanim počasi, da smo dobili belo oborino. Belo oborino smo izolirali s filtracijo, sprali z dietilA solution comprising 2-naphth-2-ylethanol (0.5 g, 2.9 mmol) in dry DMF (5 ml) was combined with dipheniphosphoryl azide (0.74 ml, 3.42 mmol) and 1,8diazabicyclo [5.4.0] undec- in a nitrogen atmosphere. 7-ene (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 3 N hydrochloric acid and then saturated sodium bicarbonate, dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was dissolved in THF (5 ml) and the solution was combined with triphenylphosphine (1 g, 3.81 mmol), stirred for 2 hours at room temperature, diluted with water (0.100 ml), stirred for 3 hours, diluted with concentrated hydrochloric acid (0.33 ml ) to give a precipitate, treated with ethanol (5 ml) to dissolve the precipitate and treated with diethyl ether added slowly to give a white precipitate. The white precipitate was isolated by filtration, washed with diethyl
-37etrom in posušili v vakuumu, da smo dobili hidroklorid 2-naft-2-iletilamina (0.447 g, 75% dobitek);-37 ether and dried in vacuo to give 2-naphth-2-ylethylamine hydrochloride (0.447 g, 75% yield);
1H-NMR (300MHz, DMSO-d6): 8.18 (brs, 3H), 7.82-7.88 (m, 3H), 7.74 (s, 1H), 7.38-7.48 (m, 3H), 3.07 (m, 4H). 1 H-NMR (300MHz, DMSO-d 6 ): 8.18 (brs, 3H), 7.82-7.88 (m, 3H), 7.74 (s, 1H), 7.38-7.48 (m, 3H), 3.07 (m, 4H) ).
Po postopku kot v Primeru 1 smo pripravili sledeče intermediame amine:Following the procedure as in Example 1, the following amine intermediates were prepared:
2- naft-1-iletilamin, dobitek=56%, 1H-NMR (300MHz, DMSO-d6): 8.26 (brs, 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, J = 7.4 Hz);2-naphth-1-ylethylamine, yield = 56%, 1 H-NMR (300MHz, DMSO-d 6 ): 8.26 (brs, 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, J = 7.4 Hz) ;
3- cikloheksilpropilamin, dobitek=40%, 1H-NMR (300MHz, CDCI3): 2.68 (t, 2H, J = 7.2 Hz), 2.17 (br 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 (300MHz, CDCl 3): 2.68 (t, 2H, J = 7.2 Hz), 2.17 (br s, 2H), 1.64-1.71 (m, 5H), 1.46 ( m, 2H), 1.18 (m, 6H), 0.87 (m, 2H);
3-fenil-2-propenilamin, dobitek=53%, 1H-NMR (300MHz, DMSO-dg): 8.39 (brs, 3H), 7.267.41 (m, 5H), 6.72 (d, 1 H, J = 16.2 Hz), 6.29 (dt, 1H, J = 16.2, 6.6 Hz), 3.56 (d, 2H, J = 6.6 Hz);3-phenyl-2-propenilamin, yield = 53% 1 H-NMR (300MHz, DMSO-dg): 8.39 (br s, 3H), 7.267.41 (m, 5H), 6.72 (d, 1 H, J = 16.2 Hz), 6.29 (dt, 1H, J = 16.2, 6.6 Hz), 3.56 (d, 2H, J = 6.6 Hz);
3-fenil-2-propinilamin, dobitek=62%, 1H-NMR (300MHz, DMSO-dg): 8.67 (br s, 2H), 7.387.42 (m, 5H), 3.91 (m, 2H); in3-phenyl-2-propinilamin, yield = 62% 1 H-NMR (300MHz, DMSO-dg): 8.67 (br s, 2H), 7.387.42 (m, 5H), 3.91 (m, 2H); and
3,3-difenilpropilamin, dobitek=50%, 1H-NMR (300MHz, DMSO-dg): 8.10 (br s, 3H), 7.30 (m, 8H), 7.19 (m, 2H), 4.11 (t, 1 H, J = 7.9 Hz), 2.62 (m, 2H), 2.33 (m, 2H).3,3-difenilpropilamin, yield = 50% 1 H-NMR (300MHz, DMSO-dg) 8.10 (br s, 3H), 7.30 (m, 8H), 7.19 (m, 2H), 4.11 (t, 1 H, J = 7.9 Hz), 2.62 (m, 2H), 2.33 (m, 2H).
PRIMER 2EXAMPLE 2
2-(5-Aminometil-1H-benzoimidazol-2-ilmetil)-A/-(4-fenilbutil)-1H-benzoimidazol-5karboksamida trifluoroacetat (Spojina 1) (a) Etil cianoacetat (8 ml, 75 mmol) v brezvodnem benzenu (100 ml) smo v atmosferi dušika združili z brezvodnim etanolom (6 ml, 105 mmol). Zmes smo ohladili na 10°C (led/aceton) in jo prepihovali 20 minut s suhim plinom vodikovim kloridom. Zmes smo2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (4-phenylbutyl) -1H-benzoimidazole-5carboxamide trifluoroacetate (Compound 1) (a) Ethyl cyanoacetate (8 ml, 75 mmol) in anhydrous benzene (100 ml) was combined with anhydrous ethanol (6 ml, 105 mmol) under nitrogen atmosphere. The mixture was cooled to 10 [deg.] C. (ice / acetone) and dried over 20 minutes with dry gas hydrogen chloride. We're a mixture
-38počasi segreli na sobno temperaturo, zamašili in mešali približno 18 ur. Zmes smo razredčili z dietil etrom (400 ml) in jo pustili stati 5 ur pri sobni temperaturi, da smo dobili kristalinično trdno snov. Trdno snov smo izolirali s filtracijo, večkrat sprali z brezvodnim dietil etrom in posušili, da smo dobili etil 3-etoksi-3-iminopropionat (13.2 g, 90% dobitek) kot brezbarvno, kristalinično trdno snov; 1H-NMR (300MHz, CDCI3): 7.84 (d, 1 H, 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).-38 Slowly warm to room temperature, stopper and stir for about 18 hours. The mixture was diluted with diethyl ether (400 ml) and allowed to stand for 5 hours at room temperature to give a crystalline solid. The solid was isolated by filtration, washed several times with anhydrous diethyl ether and dried to give ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as a colorless, crystalline solid; 1 H-NMR (300MHz, CDCl 3): 7.84 (d, 1 H, 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) Zmes 3,4-diaminobenzojske kisline (9.4 g, 62 mmol), etil 3-etoksi-3-iminopropionata in ledocta (15 ml) smo mešali 30 minut pri 110°C v atmosferi dušika. Zmes smo zlili preko zdrobljenega ledu (50 ml) in mešali 30 minut, da smo dobili temno rumeno olje. Zmes smo mešali, medtem ko smo dodajali dietil eter (25 ml), da smo dobili sivo oborino. Oborino smo izolirali s filtracijo, jo večkrat sprali z dietil etrom in posušili v vakuumu, da smo dobili 2-etoksikarbonilmetil-1/7-benzoimidazol-5-karboksilno kislino (12.6 g, 83% dobitek); 1HNMR (300MHz, DMSO-d6): 12.77 (širok s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 7.57 (d, 1 H, J = 8.4 Hz), 4.11 (q, 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), ethyl 3-ethoxy-3-iminopropionate and glacial (15 ml) was stirred for 30 minutes at 110 ° C under a nitrogen atmosphere. The mixture was poured over crushed ice (50 ml) and stirred for 30 minutes to give a dark yellow oil. The mixture was stirred while diethyl ether (25 ml) was added to give a gray precipitate. The precipitate was isolated by filtration, 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 HNMR (300MHz, DMSO-d 6 ): 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J = 8.4 Hz), 7.57 (d, 1 H, J = 8.4 Hz) , 4.11 (q, 2H, J = 7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J = 7.1 Hz).
(c) Zmes dinitrofenilmetanola (22 g, 111 mmol), trifenilfosfina (34.5 g, 131 mmol) in ftalimida (17.6 g, 119 mmol) v THF (450 ml) smo mešali pri -10°C (zmes ledu in acetona) v atmosferi dušika, medtem ko smo po kapljicah dodajali dietil azodikarboksilat (20.7 ml, 131 mmol). Zmes smo mešali 2 uri pri -10°C in potem razredčili z dietil etrom (900 ml) in shranili pri -20°C za približno 18 ur, da smo dobili kristalinično trdno snov. Trdno snov smo izolirali s filtracijo in sprali, da smo dobili 2-(3,4-dinitrobenzil)izoindol-1,3-dion (24.6 g, 67% dobitek) kot sivo belo kristalinično trdno snov; 1H-NMR (300MHz, DMSO-dg): 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) was stirred at -10 ° C (ice-acetone mixture) in nitrogen atmosphere, while diethyl 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 stored at -20 ° C for about 18 hours to give a crystalline solid. The solid was isolated by filtration and washed to give 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (24.6 g, 67% yield) as a gray-white crystalline solid; 1 H-NMR (300MHz, DMSO-d 6): 7.877.94 (m, 5H), 7.74-7.82 (m, 2H), 4.96 (s, 2H).
(d) Zmes 2-(3,4-dinitrobenzil)izoindol-1,3-diona (8 g, 24.4 mmol), pripravljenega kot v Primeru 1, in 10% paladija na ogljiku (300 mg) smo združili z brezvodnim etanolom (200 ml), brezvodnim THF (100 ml) in ledoctom (30 ml) pod kontinuimim tokom dušika. Zmes smo potem močno mešali 15 ur pri sobni temperaturi v atmosferi vodika, filtrirali in koncentrirali na volumen približno 30 ml z rotacijsko evaporacijo. Zmes smo razredčili z vodo (100 ml) in dodali amonijev hidroksid, da smo dobili oranžno oborino. Oborino smo(d) A mixture of 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (8 g, 24.4 mmol) prepared as in Example 1 and 10% palladium on carbon (300 mg) was combined with anhydrous ethanol ( 200 ml), anhydrous THF (100 ml) and ice (30 ml) under a continuous stream of nitrogen. The mixture was then stirred vigorously for 15 hours at room temperature under a hydrogen atmosphere, filtered and concentrated to a volume of about 30 ml by rotary evaporation. The mixture was diluted with water (100 ml) and ammonium hydroxide was added to give an orange precipitate. We're precipitation
-39izotirali s filtracijo in jo večkrat sprali z vodo, da smo dobili 2-(3,4-diaminobenzil)izoindol1,3-dion (6 g, 91% dobitek); 1H-NMR (300MHz, DMSO-d6): 7.76-7.85 (m, 4H), 6.31-6.43 (m, 3H), 4.51 (širok s, 4H), 4.47 (s, 2H).-39 was filtered and washed several times with water to give 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 (broad s, 4H), 4.47 (s, 2H).
(e) Fino zdrobljeno zmes 2-(3,4-diaminobenzil)izoindol-1,3-diona (2.0 g, 7.5 mmol) in 2-etoksikarbonilmetil-1 H-benzimidazol-5-karboksilne kisline (0.93 g, 3.75 mmol) smo segrevali 1 uro pri 185°C v atmosferi dušika. Zmes smo suspendirali v 1:1 zmesi metilen klorida in etanola (20 ml) in močno mešali 1 uro. Trdne snovi smo zbrali s filtracijo, sprali z 1:1 zmesjo metilen klorid/etanol (3 x 20 ml) in posušili, da smo dobili 2-[5-(1,3-diokso-1,3dihidroizoindol-2-ilmetil)-1/7-benzoimidazol-2-ilmetil]-1 /-/-benzoimidazol-5-karboksilno kislino (0.98 g, 29% dobitek); 1H-NMR (300MHz, DMSO-d6): 12.45 (širok s, 1H), 8.07 (s, 1 H), 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).(e) Finely ground mixture of 2- (3,4-diaminobenzyl) isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1H-benzimidazole-5-carboxylic acid (0.93 g, 3.75 mmol) was heated for 1 hour at 185 ° C under a nitrogen atmosphere. The mixture was suspended in a 1: 1 mixture of methylene chloride and ethanol (20 ml) and stirred vigorously for 1 hour. The solids were collected by filtration, washed with a 1: 1 methylene chloride / ethanol mixture (3 x 20 mL) and dried to give 2- [5- (1,3-dioxo-1,3 dihydroisoindol-2-ylmethyl) - 1 H -benzoimidazol-2-ylmethyl] -1 H -benzoimidazole-5-carboxylic acid (0.98 g, 29% yield); 1 H-NMR (300MHz, DMSO-d 6 ): 12.45 (broad s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J = 7.5 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 H-benzoimidazol-2-ilmetil]-1 Hbenzoimidazol-5-karboksilno kislino (0.05 g, 0.111 mmol) smo raztopili v brezvodnem dimetilformamidu (0.5 ml) in raztopino združili z 1-hidroksibenzotriazol hidratom (0.017 g, 0.126 mmol), benzotriazol-1-iloksitrispirolidinofosfonijevimheksafluoro-fosfatom (0.063 g, 0.121 mmol) in /V-metilmorfolinom (0.013 ml, 0.118 mmol) pri sobni temperaturi v atmosferi suhega N2. Po 2 minutah smo dodali 4-fenilbutilamin (0.02 ml, 0.127 mmol) in zmes mešali pri sobni temperaturi 2 uri. Zmes smo prenesli v lij ločnik, ki je vseboval 20% raztopino etanola v etil acetatu (7 ml), 0.2 N HCI (3.5 ml) in nasičeni vodni NaCI (3.5 ml). Vodno fazo smo enkrat ekstrahirali z 20% raztopino etanola v etil acetatu (7 ml) in združene organske faze sprali z raztopino, ki je vsebovala 0.2 N HCI (3.5 ml) v nasičenem vodnem NaCI (3.5 ml), čemur je sledilo končno spiranje z nasičeno vodno raztopino natrijevega bikarbonata (7 ml). Organsko fazo smo potem posušili preko brezvodnega natrijevega sulfata, filtrirali in koncentrirali do suhega na rotavaporju, da smo dobili 2-[5(1,3-diokso-1,3-dihidroizoindol-2-ilmetil)-1 /-/-benzoimidazol-2-ilmetil]-/V-(3-fenilpropil)-1 Hbenzoimidazol-5-karboksamid kot surovi material (0.14 g).(f) 2- [5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazole-5-carboxylic acid (0.05 g, 0.111 mmol) was dissolved in anhydrous dimethylformamide (0.5 ml) and the solution was combined with 1-hydroxybenzotriazole hydrate (0.017 g, 0.126 mmol), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (0.063 g, 0.121 mmol) and N-0.01 mmol (0.13 mmol), N-8 mmol ) at room temperature in an atmosphere of dry N2. After 2 minutes, 4-phenylbutylamine (0.02 ml, 0.127 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a separatory funnel containing 20% ethanol solution in ethyl acetate (7 ml), 0.2 N HCl (3.5 ml) and saturated aqueous NaCl (3.5 ml). The aqueous phase was extracted once with a 20% solution of ethanol in ethyl acetate (7 ml) and the combined organic phases were washed with a solution containing 0.2 N HCl (3.5 ml) in saturated aqueous NaCl (3.5 ml), followed by final washing with saturated aqueous sodium bicarbonate solution (7 ml). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to dryness on a rotavapor to give 2- [5 (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazole- 2-ylmethyl] - N - (3-phenylpropyl) -1 Hbenzoimidazole-5-carboxamide as a crude material (0.14 g).
(g) 2-(5-(1,3-Diokso-1,3-dihidroizoindol-2-ilmetil)-1 H-benzoimidazol-2-ilmetil]-/V-(3fenilpropil)-1/-/-benzoimidazol-5-karboksamid (0.14 g, surovi material) smo raztopili v(g) 2- (5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] - N - (3-phenylpropyl) -1 H -benzoimidazole- 5-carboxamide (0.14 g, crude material) was dissolved in
-40brezvodnem etanolu (0.5 ml) in raztopino združili z brezvodnim hidrazinom (0.15 ml, 0.48 mmol). Zmes smo segrevali ob refluksu v atmosferi N2 1 uro in potem koncentrirali na -4 rotavaporju. Preostanek smo postavili v vakuum (2x10 bar) za 2 uri, da smo odstranili prebitni hidrazin. Preostanek smo razredčili s 3 M HCI (0.5 ml) in zmes segrevali pri 50°C 20 minut. Reakcijsko zmes smo ohladili na sobno temperaturo in mešali dodatnih 20 minut, da smo dobili trdno oborino. Oborino smo izolirali s filtracijo in sprali z vodo (4 x 1.5 ml). Filtrate smo združili in sprali z 20% raztopino etanola v etil acetatu (2x7 ml). Združene vodne faze smo liofiiizirali, da smo dobili surovi produkt kot hidrokloridno sol. Surovi material smo očistili s preparativno HPLC na reverzni fazi, da smo dobili 2-(5-(1,3diokso-1,3-dihidroizoindol-2-ilmetil)-1 H-benzoimidazol-2-ilmetil]-N-(3-fenilpropil)-1 Hbenzoimidazol-5-karboksamid (0.04 g, 0.07 mmol) kot belo trdno snov; 1H-NMR (300MHz, 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).-40hydrous ethanol (0.5 ml) and the solution combined with anhydrous hydrazine (0.15 ml, 0.48 mmol). The mixture was heated at reflux in an N 2 atmosphere for 1 hour and then concentrated on a -4 rotavapor. The residue was placed in a vacuum (2x10 bar) for 2 hours to remove excess hydrazine. The residue was diluted with 3 M HCl (0.5 ml) and the mixture was heated at 50 ° C for 20 minutes. The reaction mixture was cooled to room temperature and stirred for an additional 20 minutes to give a solid precipitate. The precipitate was isolated by filtration and washed with water (4 x 1.5 ml). The filtrates were combined and washed with a 20% solution of ethanol in ethyl acetate (2x7 ml). The combined aqueous phases were lyophilized to give the crude product as the hydrochloride salt. The crude material was purified by preparative reverse phase HPLC to give 2- (5- (1,3 dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -N- (3- Phenylpropyl) -1H-benzoimidazole-5-carboxamide (0.04 g, 0.07 mmol) as a white solid; 1 H-NMR (300 MHz, CD 3 OD): 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).
Po postopku kot v Primeru 2 smo pripravili sledeče spojine izuma:Following the procedure as in Example 2, the following compounds of the invention were prepared:
2-(5-aminometil-1 /-/-benzoimidazol-2-ilmetil)-/V-naft-1 -ilmetil-1 H-benzoimtdazol-5karboksamid (Spojina 2), 1H-NMR (300MHz, 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 H -benzoimidazol-2-ylmethyl) - N-naphth-1-ylmethyl-1 H -benzoimidazole-5carboxamide (Compound 2), 1 H-NMR (300MHz, 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)-/\/-benzil-1/7-benzoimidazol-5-karboksamid (Spojina 3), 1H-NMR (300MHz, CD3OD): 8.18 (s, 1H), 7.91 (d, 1H, J=7.9 Hz), 7.82 (S, 1H), 7.76 (d, 1H, J=7.9 Hz), 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) - / \ / - benzyl-1/7-benzoimidazole-5-carboxamide (Compound 3) 1 H-NMR (300MHz, CD3OD) 8.18 ( s, 1H), 7.91 (d, 1H, J = 7.9 Hz), 7.82 (S, 1H), 7.76 (d, 1H, J = 7.9 Hz), 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-aminometil-1H-benzoimidazol-2-ilmetil)-/V-(3-fenilpropil)-1 H-benzoimidazol-5karboksamid (Spojina 4), 1H-NMR (300MHz, 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 (kvintet, 2H, 7.9 Hz);2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (3-phenylpropyl) -1 H-benzoimidazol-5karboksamid (Compound 4) 1 H-NMR (300MHz, 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 (quintet, 2H, 7.9 Hz);
-412-(5-aminometil-1H-benzoimidazol-2-ilmetil)-/V-(2-feniletil)-1H-benzoimidazol-5karboksamid (Spojina 5), 1H-NMR (300MHz, DMSO-d6): 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, 1 H), 4.29 (s, 2H), 3.65 (t, 2H, J=7.9 Hz), 2.95 (t, 2H, J=7.9 Hz);-412- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (2-phenylethyl) -1H-benzoimidazol-5karboksamid (Compound 5) 1 H-NMR (300MHz, DMSO-d6): 12.8 ( 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-1H-benzoimidazol-2-ilmetil)-/V-(3-aminometil)benzil-1H-benzoimidazol-5karboksamid (Spojina 6), 1H-NMR (300MHz, DMSO-dg): 9.31 (t, 1H, J=5.7 Hz), 8.58 (br s, 3H), 8.41 (br 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);2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (3-aminomethyl) benzyl-1H-benzoimidazol-5karboksamid (Compound 6) 1 H-NMR (300MHz, DMSO-dg): 9.31 ( t, 1H, J = 5.7 Hz), 8.58 (br s, 3H), 8.41 (br 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);
2-(5-aminometil-1 H-benzoimidazol-2-ilmetil)-/V-(2-aminoetil)-1 -metil-1 H-benzoimidazol-5karboksamid (Spojina 7), 1H-NMR (300MHz, DMSO-d6): 8.86 (br, 1H), 8.50 (br s, 3H), 8.24 (s, 1 H), 8.08 (br s, 3H), 7.93 (m, 2H), 7.77 (d, 1 H, J = 8.7 Hz), 7.55 (d, 1 H, J=9.2 Hz), 5.02 (brs, 2H), 4.16 (m, 2H), 3.94 (s, 2H), 3.50 (m, 2H), 2.96 (m, 2H);2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (2-aminoethyl) -1-methyl-1H-benzoimidazol-5karboksamid (Compound 7) 1 H-NMR (300MHz, DMSO- d6): 8.86 (br, 1H), 8.50 (br s, 3H), 8.24 (s, 1H), 8.08 (br s, 3H), 7.93 (m, 2H), 7.77 (d, 1H, J = 8.7 Hz), 7.55 (d, 1 H, J = 9.2 Hz), 5.02 (brs, 2H), 4.16 (m, 2H), 3.94 (s, 2H), 3.50 (m, 2H), 2.96 (m, 2H) );
2-(5-aminometil-1 W-benzoimidazol-2-ilmetil)-/V-(2-aminoetil)-1H-benzoimidazol-5karboksamid (Spojina 8), 1H-NMR (300MHz, DMSO-dg): 8.97 (t, 1H, J=4.3 Hz), 8.58 (br s, 3H), 8.31 (s, 1H), 8.16 (brs, 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), 4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m, 2H);2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (2-aminoethyl) -1H-benzoimidazol-5karboksamid (Compound 8) 1 H-NMR (300MHz, DMSO-dg): 8.97 ( t, 1H, J = 4.3 Hz), 8.58 (br s, 3H), 8.31 (s, 1H), 8.16 (brs, 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), 4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m. 2H);
2-(5-aminomefil-1H-benzoimidazol-2-ilmetil)-/V-(4-aminobutil)-1/7-benzoimidazol-5karboksamid (Spojina 9), 1H-NMR (300MHz, DMSO-d6): 8.77 (t, 1H, J=5.7 Hz), 8.61 (br 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);2- (5-Aminomephyl-1H-benzoimidazol-2-ylmethyl) - N - (4-aminobutyl) -1H-benzoimidazole-5carboxamide (Compound 9), 1 H-NMR (300MHz, DMSO-d 6 ): 8.77 (t, 1H, J = 5.7 Hz), 8.61 (br 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);
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-/V-(3-aminopropil)-1H-benzoimidazol-5karboksamid (Spojina 10), 1H-NMR (300MHz, DMSO-de): 8.9 (t, 1H, J=5.0 Hz), 8.53 (br s, 3H), 8.23 (s, 1H), 7.97 (br s, 3H), 7.94 (s, 1H), 7.89 (d, 1H, J=8.6 Hz), 7.78 (d, 1H,2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (3-aminopropyl) -1H-benzoimidazol-5karboksamid (Compound 10) 1 H-NMR (300MHz, DMSO-de): 8.9 (t , 1H, J = 5.0 Hz), 8.53 (br s, 3H), 8.23 (s, 1H), 7.97 (br s, 3H), 7.94 (s, 1H), 7.89 (d, 1H, J = 8.6 Hz). , 7.78 (d, 1H,
-42J=8.6 Hz), 7.71 (d, 1H, J=8.6 Hz), 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); in-42J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz), 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); and
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-/\/-cikloheksilmetil-1H-benzoimidazol-5karboksamid (Spojina 11), 1H-NMR (300MHz, CD3OD): 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), 1.64-1.86 (m, 6H), 1.20-1.37 (m, 3H), 0.95-1.09 (m, 2H).2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / \ / - cyclohexylmethyl-1H-benzoimidazol-5karboksamid (Compound 11) 1 H-NMR (300MHz, CD3OD)?: 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), 1.64-1.86 (m, 6H), 1.20-1.37 (m, 3H), 0.95-1.09 (m, 2H).
PRIMER 3EXAMPLE 3
2-(5-Aminometil-1 /7-benzoimidazol-2-ilmetil)-N-(3-aminopropil)-1 -metil-1 H-benzoimidazol5-karboksamid (Spojina 12) (a) Zmes, ki je obsegala 3-nitro-4-klorobenzojsko kislino (1.3 g, 6.45 mmol), 10% metilamin in vodo (10 ml) smo v zaprti epruveti segrevali pri 100°C 11 ur, koncentrirali na 1 ml in potem razredčili s koncentrirano klorovodikovo kislino, da smo dobili rumeno oborino. Oborino smo izolirali s filtracijo, sprali z vodo in potem dietil etrom in posušili, da smo dobili 3-nitro-4-metilaminobenzojsko kislino (2.1 g, 86% dobitek);2- (5-Aminomethyl-1/7-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1-methyl-1H-benzoimidazole5-carboxamide (Compound 12) (a) A mixture comprising 3- nitro-4-chlorobenzoic acid (1.3 g, 6.45 mmol), 10% methylamine and water (10 ml) were heated in a sealed tube at 100 ° C for 11 hours, concentrated to 1 ml and then diluted with concentrated hydrochloric acid to give yellow precipitate. The precipitate was isolated by filtration, washed with water and then diethyl ether and dried to give 3-nitro-4-methylaminobenzoic acid (2.1 g, 86% yield);
1H-NMR (300MHz, CDCI3): 8.56 (d, 1 H, J = 2.1 Hz), 8.52 (q,1 H, J = 8.6 Hz), 7.94 (dd, 1 H, 9.3, 2.1 Hz), 7.00 (d, 1 H, J = 9.3 Hz), 2.97 (d, 3H, J = 8.6 Hz). 1 H-NMR (300 MHz, CDCl 3): 8.56 (d, 1 H, J = 2.1 Hz), 8.52 (q, 1 H, J = 8.6 Hz), 7.94 (dd, 1 H, 9.3, 2.1 Hz), 7.00 (d, 1H, J = 9.3 Hz), 2.97 (d, 3H, J = 8.6 Hz).
(b) Etilni alkohol (100 mi) smo dodali v bučko, vsebujočo 3-nitro-4-metilaminobenzojsko kislino (2.09 g, 10.7 mmol) in 10% Pd/C (30 mg) pod stalnim tokom N2. Zmes smo mešali v atmosferi vodika 16 ur, filtrirali skozi miliporni 0.22 pm filtrni disk, tip GV in koncentrirali na rotavaporju. Ostanek smo posušili v vakuumu, da smo dobili 3-amino-4metilaminobenzojsko kislino (1.1 g, 61% dobitek).(b) Ethyl alcohol (100 mi) was added to a flask containing 3-nitro-4-methylaminobenzoic acid (2.09 g, 10.7 mmol) and 10% Pd / C (30 mg) under a constant stream of N 2 . The mixture was stirred under a hydrogen atmosphere for 16 hours, filtered through a 0.22 [mu] m filter disk, type GV, and concentrated on a rotary evaporator. The residue was dried in vacuo to give 3-amino-4methylaminobenzoic acid (1.1 g, 61% yield).
(c) Etil 3-etoksi-3-iminopropionat, pripravljen kot v Primeru 2(a), smo pustili, da je reagiral s 3-amino-4-metilaminobenzojsko kislino pod pogoji, podobnimi tistim, ki smo jih opisali v Primeru 2(b), da smo dobili 2-etoksikarbonilmetil-1 -metil-1 H-benzoimidazol-5karboksilno kislino (71% dobitek);1 H-NMR (300MHz, DMSO-dg); 7.18 (dd, 1H, J=8.1 Hz),(c) Ethyl 3-ethoxy-3-iminopropionate prepared as in Example 2 (a) was allowed to react with 3-amino-4-methylaminobenzoic acid under conditions similar to those described in Example 2 ( b) to give 2-ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5carboxylic acid (71% yield); 1 H-NMR (300MHz, DMSO-dg); 7.18 (dd, 1H, J = 8.1 Hz),
-437.11 (d, 1H, J=1.2 Hz), 6.33 (d, 1H, J=8.1 Hz), 5.28 (br s, 1H), 4.67 (br s, 1H), 3.34 (br s, 2H), 2.72 (s, 3H).-437.11 (d, 1H, J = 1.2 Hz), 6.33 (d, 1H, J = 8.1 Hz), 5.28 (br s, 1H), 4.67 (br s, 1H), 3.34 (br s, 2H), 2.72 (s, 3H).
(d) 2-(3,4-Diaminobenzil)izoindol-1,3-dion, pripravljen kot v Primeru 2(d), smo pustili reagirati z 2-etoksikarbonilmetil-1 -metil-1 H-benzoimidazol-5-karboksiino kislino pod pogoji, podobnimi tistim, opisanim v Primeru 2(e), da smo dobili 2-(5-(1,3-diokso-1,3dihidroiziondol-2-ilmetil)-1 /-/-benzoimidazol-2-ilmetil]-1 -metil-1 H-benzoimidazol-5karboksilno kislino (48% dobitek); 1H-NMR (300MHz, DMSO-d6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H, J=10.0 Hz), 7.40 (br s, 2H), 7.10 (br s, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 3.79 (S, 3H).(d) 2- (3,4-Diaminobenzyl) isoindole-1,3-dione prepared as in Example 2 (d) was allowed to react with 2-ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5-carboxylic acid under conditions similar to those described in Example 2 (e) to give 2- (5- (1,3-dioxo-1,3 dihydroisiondol-2-ylmethyl) -1 H -benzoimidazol-2-ylmethyl] - 1-methyl-1H-benzoimidazol-5karboksilno acid (48% yield); 1 H-NMR (300MHz, DMSO-d6) 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H , J = 10.0 Hz), 7.40 (br s, 2H), 7.10 (br 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 H-benzoimidazol-2-ilmetil]-1 -metil1 H-benzoimidazol-5-karboksilno kislino (0.05 g, 0.108 mmol), 1-hidroksibenzotriazol (0.016 g, 0.118 mmol), hidroklorid 1-(3-dimetilaminopropil)-3-etilkarbodiimida (0.023 g, 0.12mmol) in mono-BOC zaščiten derivat 1,3-diaminopropana smo raztopili pri 0°C v metilen kloridu (1 ml) in DMF (minimalna količina je zadostovala, da je nastala raztopina). Raztopino smo naravnali na pH~8 z /V-metilmorfolinom in zmes pustili počasi segreti na sobno temperaturo in potem mešali 20 ur. Zmes smo prenesli v lij ločnik, razredčili z metilen kloridom, sprali z 0.1 N raztopino HCI in potem nasičeno raztopino NaHCC>3, posušili preko natrijevega sulfata, filtrirali in koncentrirali. Preostanek smo očistili s preparativno TLC (10% metanol/etil acetat), da smo dobili 2-[6-(1,3-diokso-1,3dih idroizoi ndol-2-ilmetil )-1 H-benzoimidazol-2-ilmetil]-1 -metil-/V-(3-aminopropil)-1 Hbenzoimidazol-5-karboksamid (0.02 g, 28% dobitek); 1H-NMR (300MHz, CDCI3): 7.757.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (brs, 1H), 7.27 (d, 1H, J=8.6 Hz), 7.15 (d, 1H, J=9.3 Hz), 5.10 (brt, 1H), 4.90 (brs, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (q, 2H, J=7.2 Hz), 3.24 (q, 2H, J=7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H).(e) 2- (5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methylH-benzoimidazole-5-carboxylic acid (0.05 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 the mono-BOC protected derivative of 1,3-diaminopropane were dissolved at 0 ° C in methylene chloride (1 ml) and DMF (the minimum amount was sufficient to form a solution) The solution was adjusted to pH ~ 8 with N-methylmorpholine and the mixture was allowed to warm slowly to room temperature and then stirred for 20 hours. was transferred to a funnel separator, diluted with methylene chloride, washed with 0.1 N HCl solution and then saturated NaHCC solution> 3, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (10% methanol / ethyl acetate) to give 2- [6- (1,3-dioxo-1,3 dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl- N - (3-aminopropyl) -1H-benzoimidazole was obtained -5-carboxamide (0.02 g, 28% profit); 1 H-NMR (300MHz, CDCl 3): 7.757.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (brs, 1H), 7.27 (d, 1H, J = 8.6 Hz), 7.15 (d , 1H, J = 9.3 Hz), 5.10 (brt, 1H), 4.90 (brs, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (q, 2H, J = 7.2 Hz), 3.24 (q, 2H, J = 7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H).
(f) 2-(6-(1,3-Diokso-1,3-dih idroizoin dol-2-ilmetil)-1 /7-benzoimidazol-2-ilmetil]-1 -metil-A/(3-aminopropil)-1H-benzoimidazol-5-karboksamidu smo odstranili zaščito pod pogoji, podomnimi tistim, opisanim v Primeru 2(g), da smo dobili 2-(5-aminometil-1 Hbenzoimidazol-2-iimetil)-/V-(3-aminopropil)-1 -metil-1 H-benzoimidazol-5-karboksamid (20% dobitek); 1H-NMR (300MHz, DMSO-d6): 8.85 (t, 1H, J=5.7 Hz), 8.55 (br s, 3H), 8.20 (s,(f) 2- (6- (1,3-Dioxo-1,3-dihydroisoin dol-2-ylmethyl) -1,7-benzoimidazol-2-ylmethyl] -1-methyl-N / (3-aminopropyl) -1H-benzoimidazole-5-carboxamide was deprotected under conditions similar to those described in Example 2 (g) to give 2- (5-aminomethyl-1 Hbenzoimidazol-2-ylmethyl) - N - (3-aminopropyl) ) -1-methyl-1H-benzoimidazole-5-carboxamide (20% yield); 1 H-NMR (300MHz, DMSO-d 6): 8.85 (t, 1H, J = 5.7 Hz), 8:55 (br s, 3H), 8.20 (s,
-441Η), 8.01 (brs, 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).-441Η), 8.01 (brs, 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).
Po postopku kot v Primeru 3 smo pripravili sledeče spojine izuma:Following the procedure as in Example 3, the following compounds of the invention were prepared:
3-[2-(5-aminometil-1 H-benzoimidazol-2-ilmetil)-A/-(2-naft-1 -ileti l)-1 /7-benzoimidazol-5karboksamid (Spojina 13), 1H-NMR (300MHz, 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);3- [2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N / - (2-naphth-1-ylethyl l) -1 / 7-benzoimidazol-5karboksamid (Compound 13) 1 H-NMR (300MHz, 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-1/-/-benzoimidazol-2-ilmetil)-A/-(3,3-difenilpropil)-1H-benzoimidazol-5karboksamid (Spojina 14), 1H-NMR (300MHz, CD3OD): 8.11 (s, 1H), 7.77-7.86 (m, 3H), 7.70 (d, 1H, J=9.3 Hz), 7.56 (d, 1H, J=9.3 Hz), 7.23-7.39 (m, 8H), 7.13-7.19 (m, 2H), 4.30 (S, 2H), 4.07 (t, 1 H, J=7.2 Hz), 3.40 (t, 2H, J=7.2 Hz), 2.44 (q, 2H, J=7.2 Hz);2- (5-Aminomethyl-1 H -benzoimidazol-2-ylmethyl) -N- (3,3-diphenylpropyl) -1H-benzoimidazole-5carboxamide (Compound 14), 1 H-NMR (300MHz, CD 3 OD): 8.11 (s, 1H), 7.77-7.86 (m, 3H), 7.70 (d, 1H, J = 9.3 Hz), 7.56 (d, 1H, J = 9.3 Hz), 7.23-7.39 (m, 8H), 7.13 -7.19 (m, 2H), 4.30 (S, 2H), 4.07 (t, 1 H, J = 7.2 Hz), 3.40 (t, 2H, J = 7.2 Hz), 2.44 (q, 2H, J = 7.2 Hz) );
2-(5-aminometil-1/7-benzoimidazol-2-ilmetil)-/\/-(2-naft-2-iletil)-1H-benzoimidazol-5karboksamid (Spojina 15), 1H-NMR (300MHz, CD3OD): 8.10 (s, 1H), 7.67-7.86 (m, 8H),2- (5-aminomethyl-1/7-benzoimidazol-2-ylmethyl) - / \ / - (2-naphth-2-yl-ethyl) -1H-benzoimidazol-5karboksamid (Compound 15) 1 H-NMR (300MHz, 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);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-(1 H-benzoimidazol-2-ilmetil)-N-[2-(1 H-indol-3-il)etil]-1 H-benzoimidazol-5-karboksamid (Spojina 16), 1H-NMR (300MHz, CD3OD): 8.09 (s, 1H), 7.81-7.84 (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- (1 H-benzoimidazol-2-ylmethyl) -N- [2- (1H-indol-3-yl) ethyl] -1 H-benzoimidazole-5-carboxamide (Compound 16) 1 H-NMR (300MHz , CD3OD): 8.09 (s, 1H), 7.81-7.84 (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-1H-benzoimidazol-2-ilmetil)-N-[2-(5-metoksi)indol-3-il]-1H-benzoimidazol5-karboksamid (Spojina 17), 1H-NMR (300MHz, CD3OD): 8.10 (s, 1H), 7.81-7.85 (m, 2H),2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- [2- (5-methoxy) indol-3-yl] -1H-benzoimidazol5-carboxamide (Compound 17) 1 H-NMR (300MHz, 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);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);
-452-(5-aminometil-1H-benzoimidazol-2-ilmetil)-/V-(2,3,4,5,6-pentahidroksiheksil)-1Hbenzoimidazol-5-karboksamid (Spojina 18), 1H-NMR (300MHz, 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);-452- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (2,3,4,5,6-pentahydroxyhexyl) -1Hbenzoimidazol-5-carboxamide (Compound 18) 1 H-NMR (300MHz , 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-aminometil-1H-benzoimidazol-2-ilmetil)-/\/-(2-fenoksietil)-1/7-benzoimidazol-5karboksamid (Spojina 19), 1H-NMR (300MHz, CD3OD): 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-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / \ / - (2-phenoxyethyl) -1 / 7-benzoimidazol-5karboksamid (Compound 19) 1 H-NMR (300MHz, CD3OD) 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)-/V-(3-fenilprop-2-inil)-1 W-benzoimidazol-5karboksamid (Spojina 20), 1H-NMR (300MHz, CD3OD): 8.18 (s, 1H), 7.91 (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), 7.38-7.43 (m, 2H), 7.28-7.32 (m, 3H), 4.40 (s, 2H), 4.27 (s, 2H);2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (3-phenylprop-2-ynyl) -1-benzoimidazol-5karboksamid (Compound 20) 1 H-NMR (300MHz, 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 Hz), 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, 2H), 4.27 (s, 2H);
2-(5-aminometil-1H-benzoimidazol-2-iimetil)-/V-(E-3-fenilalil)-1H-benzoimidazol-5karboksamid (Spojina 21), 1H-NMR (300MHz, 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-1H-benzoimidazol-2-ylmethyl) - / V- (E-3-phenylallyl) -1 H-benzoimidazol-5karboksamid (Compound 21) 1 H-NMR (300MHz, 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-aminometil-1H-benzoimidazol-2-ilmetil)-/V-(3-cikloheksilpropil)-1H-benzoimidazol-5karboksamid (Spojina 22), 1H-NMR (300MHz, 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) - / V- (3-cyclohexylpropyl) -1H-benzoimidazol-5karboksamid (Compound 22) 1 H-NMR (300MHz, 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) ;
3- [2-(5-aminometil-1 H-benzoimidazol-2-ilmetil)-/V-okt-1 -il-1 H-benzoimidazol-5karboksamid (Spojina 23), 1H-NMR (300MHz, 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 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, 11 H), 0.88 (m, 2H);3- [2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V-oct-1-yl-1 H-benzoimidazol-5karboksamid (Compound 23) 1 H-NMR (300MHz, 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 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, 11 H), 0.88 ( m, 2H);
-462-(5-aminometil-1 H-benzoimidazol-2-ilmetil)-N-metil-N-(2-feniletil)-1 H-benzoimidazol-5karboksamid (Spojina 24), 1H-NMR (300MHz, CD3OD); 7.76 (s), 7.69 (d), 7.63 (d), 7.447.55 (m), 7.20-7.28 (m), 7.09-7.14 (m), 6.97 (d), 6.85 (brs), 4.19 (s), 3.72 (t), 3.47 (t), 3.22 (s), 3.08 (s), 2.87 (t), 2.76 (t); in-462- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-methyl-N- (2-phenylethyl) -1H-benzoimidazole-5carboxamide (Compound 24), 1 H-NMR (300MHz, CD 3 OD); 7.76 (s), 7.69 (d), 7.63 (d), 7.447.55 (m), 7.20-7.28 (m), 7.09-7.14 (m), 6.97 (d), 6.85 (brs), 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 H-benzoimidazol-2-ilmetil)-/V-(1 -metil-3-fenilpropil)-1 H-benzoimidazol-5karboksamid (Spojina 25), 1H-NMR (300MHz, 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), 1.171.93 (m, 2H), 1.18 (d, 3H, J=7.2 Hz).2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (1-methyl-3-phenylpropyl) -1 H-benzoimidazol-5karboksamid (Compound 25) 1 H-NMR (300MHz, 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), 1.171.93 (m, 2H), 1.18 (d, 3H, J = 7.2 Hz).
PEIMER4PEIMER4
C-{2-[5-(4-Fenilbutoksi)-1H-benzoimidazol-2-ilmetil]-1 H-benzoimidazol-5-il}metilamin (Spojina 26) (a) 4-Fenil-1-butanol (1 ml, 6.49 mmol) v THF (3 ml) smo v atmosferi suhega dušika združili z natrijevim hidridom (0.26 g, 6.5 mmol) v 60% disperziji mineralnega olja. Zmes smo močno mešali 5 minut, združili s 3,4-dinitroklorobenzenom (1.3 g, 6.42 mmol) in potem mešali 10 ur pri sobni temperaturi. Zmes smo porazdelili med dietil eter in 3 N klorovodikovo kislino. Vodno plast smo ločili in večkrat ekstrahirali z dietil etrom. Združene organske plasti smo posušili (MgSO4), filtrirali in koncentrirali z rotacijsko evaporacijo. Preostanek smo očistili s flash kromatografijo (zmes heksana in dietil etra, 9:1), da smo dobili 4-(4-fenilbutoksi)-1,2-dinitrobenzen (1.16 g, 72% dobitek); 1H-NMR (300MHz, CDCI3): 7.84 (d, 1 H, 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) in THF (3 ml) was combined under dry nitrogen atmosphere with sodium hydride (0.26 g, 6.5 mmol) in 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 for 10 hours at room temperature. The mixture was partitioned between diethyl ether and 3 N hydrochloric acid. The aqueous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography (mixture of hexane and diethyl ether, 9: 1) to give 4- (4-phenylbutoxy) -1,2-dinitrobenzene (1.16 g, 72% yield); 1 H-NMR (300MHz, CDCl 3): 7.84 (d, 1 H, 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) Etil 3-etoksi-3-iminopropionat, pripravljen kot v Primeru 2(a), smo pustili reagirati z 2-(3,4-diaminobenzil)izoindol-1,3-dionom pod pogoji, podobnimi tistim, opisanim v Primeru 2(b), da smo dobili etil 5-(1,3-diokso-1,3-dihidroizoindol-2-ilmetil)-1 H-benzoimidazol-2ilacetat (71% dobitek); 1H-NMR (300MHz, DMSO-d6): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J=9.43 Hz), 4.82 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J=7.2 Hz).(b) Ethyl 3-ethoxy-3-iminopropionate prepared as in Example 2 (a) was allowed to react with 2- (3,4-diaminobenzyl) isoindole-1,3-dione under conditions similar to those described in Example 2 (b) to give ethyl 5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazole-2yl acetate (71% yield); 1 H-NMR (300 MHz, DMSO-d 6 ): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J = 9.43 Hz), 4.82 (s, 2H). 4.07 (q, 2H, J = 7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J = 7.2 Hz).
-47(c) 4-(4-Fenilbutoksi)-1,2-dinitrobenzen smo reducirali pod pogoji, podobnimi tistim, opisanim v Primeru 3(b), da smo dobili 4-(4-fenilbutoksi)benzen-1,2-diamin (86% surovi dobitek).-47 (c) 4- (4-Phenylbutoxy) -1,2-dinitrobenzene was reduced under conditions similar to those described in Example 3 (b) to give 4- (4-phenylbutoxy) benzene-1,2- diamine (86% crude yield).
(d) Zmes 5-(4-fenilbutoksi)benzen-1,2-diamina (0.06 g, 0.234 mmol) in etil 5-(1,3diokso-1,3-dihidroizoindol-2-ilmetil)-1H-benzoimidazol-2-ilacetata (0.1 g, 0.234 mmol) smo segrevali 1 uro pri 185°C v atmosferi dušika. Zmes smo suspendirali v dietil etru in močno mešali 1 uro. Trdne snovi smo zbrali s filtracijo, sprali z dietil etrom in posušili, da smo dobili 2-{2-[5-(4-fenilbutoksi)-1H-benzoimidazol-2-ilmetil]-3/-/-benzoimidazol-5ilmetil}izoindol-1,3-dion (0.1 g, 0.18 mmol).(d) A mixture of 5- (4-phenylbutoxy) benzene-1,2-diamine (0.06 g, 0.234 mmol) and ethyl 5- (1,3 dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2 -yl acetate (0.1 g, 0.234 mmol) was heated for 1 hour at 185 ° C under a nitrogen atmosphere. The mixture was suspended in diethyl ether and stirred vigorously for 1 hour. The solids were collected by filtration, washed with diethyl ether and dried to give 2- {2- [5- (4-phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -3 H -benzoimidazol-5ylmethyl} isoindole -1,3-dione (0.1 g, 0.18 mmol).
(e) 2-{2-[5-(4-Fenilbutoksi)-1H-benzoimidazol-2-ilmetil]-3/7-benzoimidazol-5ilmetil}izoindol-1,3-dionu smo zaščito odstranili pod pogoji, podobnimi tistim, opisanim v Primeru 2(g), da smo dobili C-{2-[5-(4-fenilbutoksi)-1 H-benzoimidazol-2-ilmetil]-1 Hbenzoimidazol-5-il}metilamin (0.05 g, 55% dobitek); 1H-NMR (300MHz, CD3OD): 7.83 (d, 1 H, 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, 1 H, J=7.2 Hz), 4.44 (s, 2H), 3.93 (t, 2H, J=6.5 Hz),(e) 2- {2- [5- (4-Phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -3 / 7-benzoimidazol-5ylmethyl} isoindole-1,3-dione was deprotected under conditions similar to those observed; described in Example 2 (g) to give C- {2- [5- (4-Phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -1Hbenzoimidazol-5-yl} methylamine (0.05 g, 55% yield ); 1 H-NMR (300MHz, CD 3 OD): 7.83 (d, 1 H, 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, 1 H, 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).2.56 (t, 2H, J = 7.2 Hz), 1.72 (m, 2H).
PRIMER 5EXAMPLE 5
2-Feniletil 2-(5-aminometil-1 W-benzoimidazol-2-ilmetil)-1 H-benzoimidazol-5-karbamata trifluoroacetat (Spojina 27)2-Phenylethyl 2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazole-5-carbamate trifluoroacetate (Compound 27)
2-(5-(1,3-Diokso-1,3-dihidroizoindol-2-ilmetil)-1 H-benzoimidazol-2-ilmetil]-1 Hbenzoimidazol-5-karboksilno kislino (0.060 g, 0.133 mmol) v fenetanolu (0.160 ml, 1.34 mmol) smo združili z difenilfosforil azidom (0.034 ml, 0.158 mmol) in trietilaminom (0.022 ml, 0.158 mmol) pri sobni temperaturi v atmosferi dušika. Zmes smo mešali 1 uro pri 120°C, ohladili na sobno temperaturo in združili z etanolom (0.5 ml) in hidrazinom (0.020 ml, 0.637 mmol). Zmes smo mešali 45 minut pri 95°C, ohladili na sobno temperaturo in razredčili s 3 N klorovodikovo kislino (0.5 ml). Zmes smo mešali 20 minut pri 55°C in jo2- (5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1H-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 (0.022 ml, 0.158 mmol) at room temperature under a nitrogen atmosphere. 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 3 N hydrochloric acid (0.5 ml), and the mixture was stirred for 20 minutes at 55 ° C. C and jo
-48potem filtrirali. Filtrirane trdne snovi smo sprali s 3 N klorovodikovo kislino in združene filtrate sprali z etil acetatom (15 ml) in liofilizirali. Ostanek smo očistili s preparativno HPLC na reverzni fazi, da smo dobili želen produkt (0.008 g, 11% dobitek); 1 H-NMR (300MHz, CD3OD): 8.10 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1 H, J=9.3 Hz), 7.63 (d, 1H, J=9.3 Hz), 7.387.44 (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).-48 then filtered. The filtered solids were washed with 3 N hydrochloric acid and the combined filtrates were washed with ethyl acetate (15 ml) and lyophilized. The residue was purified by preparative reverse phase HPLC to give the desired product (0.008 g, 11% yield); 1 H-NMR (300MHz, 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) , 7.387.44 (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).
PRIMER 6EXAMPLE 6
2-(5-Gvanidino-1/-/-benzoimidazol-2-ilmetil)-/V-(2-naftalen-1-iletil)-3-metil-3Hbenzoimidazol-5-karboksiamid (Spojina 28) (a) Raztopino, obsegajočo 2-nitro-1,4-fenilendiamin (21.0 g, 137 mmol) v etanolu (350 ml) in 4.0 M vodikov klorid v dioksanu (30.8 ml, 123 mmol) smo mešali pri sobni temperaturi 15 minut in potem dodali dietil eter (1 I), da smo dobili oborino. Oborino smo zbrali s filtracijo, sprali z dodatnim dietil etrom in posušili v vakuumu, da smo dobili hidroklorid 2-nitro-1,4-fenilendiamina (23.3 g, 100% dobitek).2- (5-Guanidino-1 H -benzoimidazol-2-ylmethyl) - N - (2-naphthalen-1-ylethyl) -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 28) (a) Solution. comprising 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) were stirred at room temperature for 15 minutes and then diethyl ether ( 1 I) that we were given a precipitate. The precipitate was collected by filtration, washed with additional diethyl ether and dried in vacuo to give 2-nitro-1,4-phenylenediamine hydrochloride (23.3 g, 100% yield).
(b) Zmes, obsegajočo hidroklorid 2-nitro-1,4-fenilendiamina (15.0 g, 79.1 mmol), cianamid (25.0 g, 595 mmol) in vodo (5 ml) smo segrevali pri 60°C in mešali 1.5 ure, jo pustili ohladiti na sobno temperaturo in potem počasi dodali prebitni dietil eter, da smo dobili oborino. Oborino smo zbrali s filtracijo, sprali z dodatnim dietil etrom in posušili v vakuumu, da smo dobili hidroklorid /V-(4-amino-3-nitrofenil)gvanidina (18.0 g, 98% dobitek);1 H-NMR (300MHz, DMSO-d6): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d), 7.1 (d).(b) A mixture comprising 2-nitro-1,4-phenylenediamine hydrochloride (15.0 g, 79.1 mmol), cyanamide (25.0 g, 595 mmol) and water (5 ml) was heated at 60 ° C and stirred for 1.5 hours, allowed to cool to room temperature and then slowly added excess diethyl ether to obtain a precipitate. The precipitate was collected by filtration, washed with additional diethyl ether and dried in vacuo to give the hydrochloride of N- (4-amino-3-nitrophenyl) guanidine (18.0 g, 98% yield); 1 H-NMR (300MHz, DMSO-d 6 ): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d), 7.1 (d).
(c) Zmes, obsegajočo hidroklorid /V-(4-amino-3-nitrofenil)gvanidina (12.0 g, 51.8 mmol), 10% paladij na ogljiku (1.0 g), tetrahidrofuran (100 ml) in metanol (100 ml) smo hidrogenirali pri 1.013 bar, filtrirali in koncentrirali v vakuumu, da smo dobili hidroklorid N(3,4-diaminofenil)gvanidina (10.3 g, 98% dobitek) kot temno trdno snov; 1 H-NMR (300MHz, DMSO-d6): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).(c) A mixture comprising hydrochloride / N- (4-amino-3-nitrophenyl) guanidine (12.0 g, 51.8 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 ml) and methanol (100 ml) hydrogenated at 1.013 bar, filtered and concentrated in vacuo to give the hydrochloride N (3,4-diaminophenyl) guanidine (10.3 g, 98% yield) as a dark solid; 1 H-NMR (300MHz, DMSO-d6): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).
-49(d) Zmes, obsegajočo hidroklorid /V-(3,4-diaminofenil)gvanidina (9.9 g, 49 mmol), hidroklorid etil estra etoksikarbonimidoilocetne kisline (12.4 g, 59 mmol) in ocetno kislino (20 ml) smo segrevali v oljni kopeli pri 110°C in mešali 1.5 ur, ohladili na sobno temperaturo in koncentrirali v vakuumu. Preostanek smo raztopili v etanolu (15 ml) in potem k raztopini dodali etil acetat (10 ml), da smo dobili oborino v suspenziji. Suspenzijo smo filtrirali in prebitek etil etra dodali k filtratu, da smo dobili drugo oborino. Oborino smo zbrali s filtracijo, sprali z dodatnim etil etrom in posušili v vakuumu, da smo dobili hidroklorid etil 5-gvanidino-1H-benzoimidazol-2-ilacetata (14.1 g, 94% dobitek) kot sivo belo trdno snov; 1H-NMR (300MHz, DMSO-d6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s),-49 (d) A mixture comprising hydrochloride / N- (3,4-diaminophenyl) guanidine (9.9 g, 49 mmol), ethoxycarbonimidoylacetic acid ethyl ester hydrochloride (12.4 g, 59 mmol) and acetic acid (20 ml) was heated to oil bath at 110 ° C and stirred for 1.5 hours, 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 excess ethyl ether was added to the filtrate to give a second precipitate. The precipitate was collected by filtration, washed with additional ethyl ether and dried in vacuo to give the hydrochloride of ethyl 5-guanidino-1H-benzoimidazol-2-ylacetate (14.1 g, 94% yield) as a gray-white solid; 1 H-NMR (300MHz, DMSO-d6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s),
4.2 (q), 1.2 (t).4.2 (q), 1.2 (t).
(e) Zmes, obsegajočo 4-nitro-3-metoksibenzojsko kislino (5.0 g, 25.4 mmol) in vodni metilamin (40%, 15 ml) v zaprti epruveti smo segrevali v oljni kopeli pri 100°C 12 ur, jo pustili ohladiti na sobno temperaturo in potem zlili v premešavano goščo 1M vodne klorovodikove kisline in ledu, da smo dobili oranžno oborino. Oborino smo zbrali s filtracijo, sprali z vodo in prekristalizirali iz vročega etanola, da smo dobili 3-metilamino-4nitrobenzojsko kislino kot živo rdečo kristalinično trdno snov (3.6 g, 73% dobitek); 1HNMR (300MHz, DMSO-d6); 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d).(e) A mixture comprising 4-nitro-3-methoxybenzoic acid (5.0 g, 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 slurry of 1M aqueous hydrochloric acid and ice to give an orange precipitate. The precipitate was collected by filtration, washed with water and recrystallized from hot ethanol to give 3-methylamino-4-nitrobenzoic acid as a living red crystalline solid (3.6 g, 73% yield); 1 HNMR (300MHz, DMSO-d 6 ); 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d).
(f) Zmes, obsegajočo 3-metilamino-4-nitrobenzojsko kislino (13.0 g, 66.3 mmol), PyBOP (38.0 g, 73.0 mmol), hidroksibenztriazol hidrat (9.9 g, 73.0 mmol), dimetilformamid (100 ml) in N-metilmorfolin (18.3 ml) smo mešali pri sobni temperaturi 15 minut in potem dodali 2-naftilen-1-iletilamin (13.8 g, 66.3 mmol). Zmes smo mešali dodatnih 30 minut in koncentrirali v vakuumu. Preostanek smo porazdelili med vodo in etil acetat in organsko plast sprali z vodo, 0.1 M vodno klorovodikovo kislino, nasičenim vodnim natrijevim hidrogen karbonatom in potem nasičenim vodnim natrijevim kloridom, posušili (magnezijev sulfat), filtrirali in koncentrirali v vakuumu. Ostanek smo očistili s prekristalizacijo iz vročega etanola, da smo dobili 3-metilamin-W-(2-naftalen-1-il-etil)-4nitrobenzamid kot živo rdečo kristalinično trdno snov (21.3 g, 92% dobitek); 1H-NMR (300MHz, DMSO-dg): 8.8 (t), 8.3 (d), 8.2 (q), 8.1 (d), 7.9 (d), 7.8 (d), 7.6-7.3 (m), 7.2 (s), 7.0 (d), 3.6 (q), 3.3 (t), 3.0 (d).(f) Mixture comprising 3-methylamino-4-nitrobenzoic acid (13.0 g, 66.3 mmol), PyBOP (38.0 g, 73.0 mmol), hydroxybenztriazole hydrate (9.9 g, 73.0 mmol), dimethylformamide (100 ml) and N-methylmorpholine (18.3 ml) was stirred at room temperature for 15 minutes and then 2-naphthylene-1-ylethylamine (13.8 g, 66.3 mmol) was added. The mixture was stirred for an additional 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 hydrogen carbonate and then saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by recrystallization from hot ethanol to give 3-methylamine-W- (2-naphthalen-1-yl-ethyl) -4nitrobenzamide as a living red crystalline solid (21.3 g, 92% yield); 1 H-NMR (300MHz, DMSO-dg): 8.8 (t), 8.3 (d), 8.2 (q), 8.1 (d), 7.9 (d), 7.8 (d), 7.6-7.3 (m), 7.2 (s), 7.0 (d), 3.6 (q), 3.3 (t), 3.0 (d).
-50(g) Zmes, obsegajočo 3-metilamino-/V-(2-naft-1-iletil)-4-nitrobenzamid (21.3 g, 61 mmol), 10% paladij na ogljiku (1.0 g), tetrahidrofuran (100 ml) in metanol (100 ml) smo hidrogenirali pri 1.013 bar vodika, filtrirali in koncentrirali v vakuumu, da smo dobili 4amino-3-metilamino-/V-(2-naft-1-iletil)-4-benzamid (18.4 g, 95% dobitek) kot razbarvano amorfno trdno snov; 1H-NMR (300MHz, 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 (q), 3.2 (t), 2.7 (s).-50 (g) Mixture comprising 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) were hydrogenated at 1,013 bar of hydrogen, 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 discolored amorphous solid; 1 H-NMR (300MHz, DMSO-d 6 ); 8.3 (d), 8.2 (t), 7.9 (d), 7.8 (d), 7.6-7.4 (m), 7.1 (d), 6.9 (s), 6.5 (d), 5.0 (s), 3.5 (q ), 3.2 (t), 2.7 (s).
(h) Zmes, obsegajočo hidroklorid etil 5-gvanidino-1 H-benzoimidazol-2-ilacetata (0.5 g, 1.7 mmol), 4-amino-3-metilamino-N-(2-naft-1-iletil)-4-benzamid (0.5 g, 1.7 mmol) in dimetilformamid (2 ml) smo segrevali v oljni kopeli pri 185°C in mešali v atmosferi dušika(h) A mixture comprising the hydrochloride of ethyl 5-guanidino-1H-benzoimidazol-2-ylacetate (0.5 g, 1.7 mmol), 4-amino-3-methylamino-N- (2-naphth-1-ylethyl) -4- benzamide (0.5 g, 1.7 mmol) and dimethylformamide (2 ml) were heated in an oil bath at 185 ° C and stirred under a nitrogen atmosphere
3.5 ur, ohladili na sobno temperaturo in zlili v premešavani acetonitril (150 ml), da smo dobili oborino. Oborino smo sprali z dodatnim acetonitrilom in dietil etrom (150 ml), zbrali s filtracijo in posušili v vakuumu, da smo dobili sivo belo trdno snov. Trdno snov smo očistili s preparativno HPLC na reverzni fazi, da smo dobili 2-(5-gvanidino-1 /-/-benzoimidazol-2ilmetiI)-A/-(2-naft-1 -iletil)-3-metil-3H-benzoimidazol-5-karboksamid kot belo trdno snov (0.5 g, 57%); LRMS(ESI): Izračunano za C30H28N8O: 516.6; Ugotovljeno (MH+): 517.2.3.5 hours, cooled to room temperature and poured into stirred acetonitrile (150 ml) to give a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150 ml), collected by filtration and dried in vacuo to give a gray-white solid. The solid was purified by preparative reverse phase HPLC to give 2- (5-guanidino-1 H -benzoimidazol-2ylmethyl) -N- (2-naphth-1-ylethyl) -3-methyl-3H- benzoimidazole-5-carboxamide as a white solid (0.5 g, 57%); LRMS (ESI): Calculated for C30H28N8O: 516.6; Found (MH + ): 517.2.
PRIMER 7EXAMPLE 7
Etil 2-(4-{2-[ 1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5c]piridin-5-il}-4-oksobutil)benzoat (Spojina 29) (a) Raztopino, obsegajočo etil 2-cianopropionat (100 g, 0.29 mol) v etanolu (65 ml) smo ohladili na 0°C in potem nasitili s suhim plinom vodikovim kloridom. Zmes smo pustili segreti na sobno temperaturo, mešali 24 ur, ohladili na 0°C in nasitili s plinom vodikovim kloridom. Zmes smo pustili segreti na sobno temperaturo in mešali drugih 24 ur. K zmesi smo dodali etil eter:heksan (1:1), da smo dobili oborino. Oborino smo izolirali s filtracijo in jo posušili v vakuumu, da smo dobili hidroklorid etil 2-(/V-etoksiamidino)propionata (119.6 g, 73% dobitek) kot belo trdno snov; 1H NMR (300MHz, DMSO-d6): 12.05 (br s, 2H), 4.50 (q, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1.20 (tr, 3H).Ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5c] pyridin-5-yl} - 4-Oxobutyl) benzoate (Compound 29) (a) A solution comprising ethyl 2-cyanopropionate (100 g, 0.29 mol) in ethanol (65 ml) was cooled to 0 ° C and then saturated with dry gas hydrogen chloride. The mixture was allowed to warm to room temperature, stirred for 24 hours, cooled to 0 ° C and saturated with hydrogen chloride gas. The mixture was allowed to warm to room temperature and stirred for a further 24 hours. Ethyl ether: hexane (1: 1) was added to the mixture to give a precipitate. The precipitate was isolated by filtration and dried in vacuo to give the ethyl hydrochloride ethyl 2- ((V-ethoxyamidino) propionate (119.6 g, 73% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 ): 12.05 (br s, 2H), 4.50 (q, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1.20 (tr, 3H).
-51(b) Zmes, obsegajočo 3,4-diaminopiridin (51.7 g, 0.46 mol), hidroklorid etil 2-(Netoksiamidino)propionata (125 g, 0.69 mol) in ledoct (200 ml) smo segrevali pri 85°C in mešali 18 ur in potem segrevali pri 120°C in mešali dodatno eno uro. Zmes smo ohladili na sobno temperaturo in jo koncentrirali v vakuumu. Preostanek smo nevtralizirali z dodatkom prebitka 5M vodnega amonijevega hidroksida in zmes ekstrahirali z etil acetatom. Organsko plast smo sprali z nasičenim vodnim natrijevim hidrogen karbonatom in potem nasičenim vodnim natrijevim kloridom, posušili (MgSO4), filtrirali in koncentrirali v vakuumu, da smo dobili etil 1H-imidazo[4,5-c]piridin-2-karboksilat (60.4 g, 58% dobitek); 1H NMR (300MHz, CDCI3): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 3.90 (q, 1 H), 1.75 (d, 3H), 1.25 (tr, 3H).-51 (b) A mixture comprising 3,4-diaminopyridine (51.7 g, 0.46 mol), ethyl 2- (Netoxyamidino) propionate hydrochloride (125 g, 0.69 mol) and glacial (200 ml) was heated at 85 ° C and stirred 18 hours and then warmed to 120 ° C and stirred for an additional hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was neutralized by the addition of excess 5M aqueous ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated in vacuo to give ethyl 1H-imidase [4,5-c] pyridine-2-carboxylate (60.4 g , 58% yield); 1 H NMR (300MHz, CDCl 3 ): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 3.90 (q, 1H), 1.75 (d. 3H), 1.25 (tr, 3H).
(c) Zmes, obsegajočo etil 1H-imidazo[4,5-c]piridin-2-karboksilat (34.7 g, 158 mmol), trifluoroocetno kislino (50 ml) in platinov oksid (2.5 g) smo v Parrovem hidrogenirnem aparatu hidrogenirali pri 3.44 bar vodika 24 ur, filtrirali in koncentrirali v vakuumu. Oljnat preostanek smo raztopili v minimalni količini etanola in k raztopini dodali suh vodikov klorid v raztopini dioksana (4 M, 120 ml, 475 mmol). K raztopini smo dodali prebitek etil etra, da smo dobili oborino. Oborino smo zbrali s filtracijo in posušili v vakuumu, da smo dobili dihidroklorid etil 1,4,6,7-tetrahidro-1/4-imidazo-[4,5-c]piridin-2-karboksilata (30.7 g, 66% dobitek); 1H NMR (300MHz, DMSO-d6): 10.00 (br s, 2H), 4.35 (q, 1H), 4.20 (br s, 2H), 4.10 (m, 2H), 3.35 (m, 2H), 2.90 (brs, 2H), 1.55 (d, 3H), 1.15 (tr, 3H).(c) A mixture comprising ethyl 1H-imidase [4,5-c] pyridine-2-carboxylate (34.7 g, 158 mmol), trifluoroacetic acid (50 ml) and platinum oxide (2.5 g) was hydrogenated in a Parr hydrogenation apparatus at 3.44 bar of hydrogen for 24 hours, filtered and concentrated in vacuo. The oily residue was dissolved in a minimal amount of ethanol and dry hydrogen chloride in dioxane solution (4 M, 120 ml, 475 mmol) was added to the solution. An excess of ethyl ether was added to the solution to give a precipitate. The precipitate was collected by filtration and dried in vacuo to give ethyl 1,4,6,7-tetrahydro-1/4-imidazo [4,5-c] pyridine-2-carboxylate dihydrochloride (30.7 g, 66% yield) ); 1 H NMR (300MHz, DMSO-d 6 ): 10.00 (br s, 2H), 4.35 (q, 1H), 4.20 (br s, 2H), 4.10 (m, 2H), 3.35 (m, 2H), 2.90 (brs, 2H), 1.55 (d, 3H), 1.15 (tr, 3H).
(d) Zmes, obsegajočo dihidroklorid etil 1,4,6,7-tetrahidro-1H-imidazo-[4,5-c]piridin-2karboksilata (60.2 g, 0.20 mol), acetonitril (500 ml) in diizopropiletilamin (100 ml, 0.60 mol) smo ohladili na 0°C in mešali, medtem ko smo počasi dodajali benzilkloroformat (58 ml, 0.40 mol). Zmes smo počasi segreli na sobno temperaturo, mešali dodatnih 16 ur in koncentrirali v vakuumu. Preostanek smo raztopili v etil etru (500 ml) in raztopino sprali z 0.1 M vodno klorovodikovo kislino, nasičenim vodnim natrijevim hidrogen karbonatom in nasičenim vodnim natrijevim kloridom, posušili preko brezvodnega natrijevega sulfata, filtrirali in koncentrirali v vakuumu, da smo dobili brezbarvno olje. Ostanek smo raztopili v etanolu (320 ml) in raztopino ohladili na 0°C in potem počasi dodali natrijev etoksid v etanolni raztopini (2.6 M, 85 ml, 0.22 mol). Zmes smo mešali eno uro pri 0°C in potem dodali raztopino vodikovega klorida v dioksanu (4 M, 50 ml). Zmes smo koncentrirali v(d) A mixture comprising the dihydrochloride ethyl 1,4,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-2carboxylate (60.2 g, 0.20 mol), acetonitrile (500 ml) and diisopropylethylamine (100 ml , 0.60 mol) was cooled to 0 ° C and stirred while benzylchloroformate (58 ml, 0.40 mol) was added slowly. The mixture was slowly warmed to room temperature, stirred for an additional 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 aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a colorless solution. The residue was dissolved in ethanol (320 ml) and the solution cooled to 0 ° C, then sodium ethoxide in ethanol solution (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, 50 ml) was added. The mixture was concentrated in
-52vakuumu in ostanek raztopili v etil acetatu (250 ml) in nasičenem vodnem natrijevem hidrogen karbonatu. Organsko plast smo ločili in sprali z nasičenim vodnim natrijevim kloridom, posušili preko brezvodnega natrijevega sulfata, filtrirali in koncentrirali v vakuumu, da smo dobili 5-benzil 2-etil 1,4,6,7-tetrahidroimidazo[4,5-c]piridin-2,5dikarboksilat kot rumen amorfen material (52 g, 72% dobitek); 1H NMR (300MHz, DMSOdg): 11.75 (brs, 1H), 7.30 (s, 5H), 5.10 (s, 2H), 4.40 (brs, 2H), 4.05 (m, 2H), 3.75 (q, 1H),-52 vacuum and the residue was dissolved in ethyl acetate (250 ml) and saturated aqueous sodium hydrogen carbonate. 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-tetrahydroimidase [4,5-c] pyridine -2,5 Dicarboxylate as yellow amorphous material (52 g, 72% yield); 1 H NMR (300MHz, DMSOdg): 11.75 (br s, 1H), 7.30 (s, 5H), 5.10 (s, 2H), 4.40 (br s, 2H), 4:05 (m, 2H), 3.75 (q, 1H) ,
3.65 (br s, 2H), 1.40 (d, 3H), 1.15 (tr, 3H).3.65 (br s, 2H), 1.40 (d, 3H), 1.15 (tr, 3H).
(e) Zmes, obsegajočo 4-klorobutiril klorid (12.6 g, 89.2 mmol), ferc-butanol (25 ml), piridin (6.9 g, 86.5 mmol) in 4-dimetilaminopiridin (1.0 g, 8.2 mmol) smo segrevali pri 50°C v atmosferi suhega dušika 12 ur, da smo dobili belo suspenzijo. Suspenzijo smo porazdelili med etil eter (250 ml) in vodo in organsko plast ločili in zaporedoma sprali z vodo, potem 0.1 M vodno klorovodikovo kislino, nasičenim vodnim natrijevim karbonatom in nasičenim vodnim natrijevim kloridom, posušili preko brezvodnega magnezijevega sulfata, filtrirali in koncentrirali v vakuumu do brezbarvnega olja. Olje smo destilirali pri -4 o(e) A mixture comprising 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) was heated at 50 °. C under a dry nitrogen atmosphere for 12 hours to give a white suspension. The suspension was partitioned between ethyl ether (250 ml) and the water and the organic layer separated and washed successively with water, then 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 a colorless oil. The oil was distilled at -4 o
6.66 x10 bar (51 C), da smo dobili ferobutil 4-klorobutirat kot brezbarvno tekočino (11.27 g, 73% dobitek); 1H NMR (300MHz, CDCI3): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), (f) Zmes, obsegajočo etil salicilat (3.14 g, 18.9 mmol) in cezijev karbonat (6.2 g, 18.9 mmol), dimetilformamid (25 ml) in terc-butii-4-klorobutirat (4.08 g, 22.8 mmol) smo segrevali pri 70°C in mešali 12 ur. Zmes smo porazdelili med etil eter (100 ml) in vodo in organsko plast ločili in sprali z dodatno vodo (3x) in nasičenim vodnim natrijevim kloridom, posušili preko brezvodnega magnezijevega sulfata, filtrirali in koncentrirali v vakuumu, da smo dobili brezbarvno olje. Ostanek smo očistili s silikagelno flash kromatografijo ob uporabi čistega heksana do zmesi heksan:etil acetat (10:1), da smo dobili etil 2-(3-tercbutoksikarbonilpropoksi)benzoat (3.6 g, 62% dobitek) kot brezbarvno olje; 1H NMR (300MHz, CDCI3): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).6.66 x 10 bar (51 C) to give ferrobutyl 4-chlorobutyrate as a colorless liquid (11.27 g, 73% yield); 1 H NMR (300MHz, CDCl 3 ): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), (f) Mixture comprising ethyl salicylate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g, 18.9 mmol), dimethylformamide (25 ml) and tert-butyl 4-chlorobutyrate (4.08 g, 22.8 mmol) were heated at 70 ° C and stirred for 12 hours. The mixture was partitioned between ethyl ether (100 ml) and the water and organic layer separated and washed with additional water (3x) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a colorless oil. The residue was purified by silica gel flash chromatography using pure hexane to a mixture of hexane: ethyl acetate (10: 1) to give ethyl 2- (3-tert-butoxycarbonylpropoxy) benzoate (3.6 g, 62% yield) as a colorless oil; 1 H NMR (300MHz, CDCl 3): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H) , 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).
(g) Etil 2-(3-ferc-butoksikarbonilpropoksi)benzoat (3.60 g, 11.7 mmol) smo obdelali s prebitkom trifluoroocetne kisline pri sobni temperaturi v teku ene ure. Raztopino smo(g) Ethyl 2- (3-tert-butoxycarbonylpropoxy) benzoate (3.60 g, 11.7 mmol) was treated with excess trifluoroacetic acid at room temperature for one hour. We are the solution
-53koncentrirali v vakuumu in oljnat ostanek očistili s silikagelno flash kromatografijo ob uporabi zmesi heksan:etil acetat (10:1) do čistega etil etra, da smo dobili 4-(2etoksikarbonilfenoksi)butirično kislino kot brezbarvno kristalinično trdno snov (2.81 g, 95% dobitek); 1H NMR (300MHz, CDCI3): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.15 (tr, 2H), 2.65 (tr, 2H), 2.20 (m, 2H), 1.40 (tr, 3H).-53 concentrated in vacuo and the oily residue purified by silica gel flash chromatography using a mixture of hexane: ethyl acetate (10: 1) to pure ethyl ether to give 4- (2ethoxycarbonylphenoxy) butyric acid as a colorless crystalline solid (2.81 g, 95%, 2.81 g, 95%) profit); 1 H NMR (300MHz, CDCl 3 ): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.15 (tr, 2H), 2.65 (tr, 2H) ), 2.20 (m, 2H), 1.40 (mp, 3H).
(h) Zmes, obsegajočo benzil 2-etoksikarbonilmetil-1,4,6,7-tetrahidroimidazo[4,5c]piridin-5-karboksilat (1.7 g, 4.8 mmol), hidroklorid /V-(3,4-diaminofenil)gvanidina (0.8 g, 4.0 mmol) in dimetilformamid (2 ml) smo segrevali v oljni kopeli pri 185°C in mešali v atmosferi dušika 2.5 ur. Zmes smo ohladili na sobno temperaturo in jo zlili v premešavan acetonitril (150 ml), da smo dobili oborino. Oborino smo sprali z dodatnim acetonitrilom in dietil etrom (150 ml), zbrali s filtracijo in posušili v vakuumu, da smo dobili sivo belo trdno snov. Trdno snov smo očistili s preparativno HPLC na reverzni fazi, da smo dobili benzil 2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5karboksilat kot belo trdno snov (1.0 g, 55% dobitek); LRMS(ESI); Izračunano za θ24Η26Ν8θ2· 458.5; Ugotovljeno (MH+); 459.2.(h) Mixture comprising benzyl 2-ethoxycarbonylmethyl-1,4,6,7-tetrahydroimidazo [4,5c] pyridine-5-carboxylate (1.7 g, 4.8 mmol), hydrochloride / N- (3,4-diaminophenyl) guanidine (0.8 g, 4.0 mmol) and dimethylformamide (2 ml) were 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 stirred acetonitrile (150 ml) to give a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150 ml), collected by filtration and dried in vacuo to give a gray-white solid. The solid was purified by preparative reverse phase HPLC to give benzyl 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidase [4,5 -c] pyridine-5carboxylate as a white solid (1.0 g, 55% yield); LRMS (ESI); Calculated for θ24 Η 26Ν8θ2 · 458.5; Found (MH + ); 459.2.
(i) Zmes, obsegajočo benzil 2-[1-(5-gvanidino-1W-benzoimidazol-2-il)etil]-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-karboksilat (1.0 g, 2.2 mmol), 10% paladij na ogljiku (0.5 g), tetrahidrofuran (50 ml) in metanol (50 ml) smo hidrogenirali pri 1.013 bar, filtrirali in koncentrirali v vakuumu, da smo dobili Λ/-{2-[1 -(4,5,6,7-tetrahidroimidazo[4,5-c]piridin-2il)etil]-1 H-benzoimidazol-5-il}-gvanidin (0.69 g, 97% dobitek); LRMS(ESI); Izračunano za C-I6H20N8·· 324.4; Ugotovljeno (MH+): 325.2.(i) A mixture comprising benzyl 2- [1- (5-guanidino-1W-benzoimidazol-2-yl) ethyl] -1,4,6,7tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (1.0 g , 2.2 mmol), 10% palladium on carbon (0.5 g), tetrahydrofuran (50 ml) and methanol (50 ml) were hydrogenated at 1,013 bar, filtered and concentrated in vacuo to give Λ / - {2- [1 - (4,5,6,7-tetrahydroimidazo [4,5-c] pyridin-2yl) ethyl] -1H-benzoimidazol-5-yl} -guanidine (0.69 g, 97% yield); LRMS (ESI); Calculated for C-I6H20N8 ·· 324.4; Found (MH + ): 325.2.
(j) Zmes, obsegajočo 4-(2-etoksikarbonilfenoksi)butirično kislino (155 mg, 0.61 mmol), PyBOP (360 mg, 0.69 mmol), hidroksibenztriazol hidrat (87 mg, 0.64 mmol), Nmetilmorfolin (0.16 ml, 0.92 mmol) in dimetilformamid (2.5 ml) smo mešali pri sobni temperaturi 10 minut in potem dodali /V-{2-[1-(4,5,6,7-tetrahidroimidazo[4,5-c]piridin-2il)etii]-3/-/-benzimidazol-5-il}gvanidin (203 mg, 0.63 mmol). Zmes smo mešali 3 ure pri sobni temperaturi in koncentrirali v vakuumu. Ostanek smo raztopili v 5% vodnem acetonitrilu in produkt očistili s preparativno HPLC na reverzni fazi. Združene čiste frakcije smo potem liofilizirali, da smo dobili etil 2-(4-{2-[1-(5-gvanidino-1 H-benzoimidazol-2-54il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-il}-4-oksobutil)benzoat; LRMS (Bioion): Izračunano za 02^34^04:558.6; Ugotovljeno: 559.3.(j) Mixture comprising 4- (2-ethoxycarbonylphenoxy) butyric acid (155 mg, 0.61 mmol), PyBOP (360 mg, 0.69 mmol), hydroxybenztriazole hydrate (87 mg, 0.64 mmol), Nmethylmorpholine (0.16 ml, 0.92 mmol) and dimethylformamide (2.5 ml) was stirred at room temperature for 10 minutes and then N- {2- [1- (4,5,6,7-tetrahydroimidase [4,5-c] pyridin-2yl) ethyl] -3 N - Benzimidazol-5-yl} guanidine (203 mg, 0.63 mmol). The mixture was stirred for 3 hours at room temperature and concentrated in vacuo. The residue was dissolved in 5% aqueous acetonitrile and the product was purified by preparative reverse phase HPLC. The combined pure fractions were then lyophilized to give ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-54yl) ethyl] -1,4,6,7-tetrahydroimidase [4 , 5-c] pyridin-5-yl} -4-oxobutyl) benzoate; LRMS (Bioion): Calculated for 02 ^ 34 ^ 04: 558.6; Found: 559.3.
PRIMER 8EXAMPLE 8
2-[1-(5-Hidroksi-1H-benzoimidazol-2-il)etil]-N-[2-(2-metoksifenoksi)etii]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 30) (a) Raztopino terc-butil 2-hidroksietilkarbamata (25 ml, 161.6 mmol) v diklorometanu (60 ml) smo ohladili na 0°C in mešali, medtem ko smo najprej dodali diizopropiletilamin (33.8 ml, 193.9 mmol) in nato po kapljicah mezil klorid (13.7 ml, 177.8 mmol). Zmes smo pustili, da se je segrela na 23°C, mešali 18 ur, zlili v diklorometan (200 ml) in sprali z vodno klorovodikovo kislino (3M, 3 x 25 ml) in nasičenim vodnim natrijevim hidrogen karbonatom (2 x 25 ml). Organsko plast smo ločili, posušili (MgSO4) in koncentrirali v vakuumu, da smo dobili terc-butil 2-metilsulfoniloksietilkarbamat (37.39 g, 97% dobitek) kot rjavo olje; MS (PB-PCI) C8H17NO5S m/e izrač. 239.08; ugot. 240 (MH+).2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-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, while diisopropylethylamine (33.8 ml, 193.9 mmol) was added first and then mesyl chloride (13.7) was added dropwise. 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 (3M, 3 x 25 ml) and saturated aqueous sodium hydrogen carbonate (2 x 25 ml). . The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI) C8H17NO5S m / e calcd. 239.08; found 240 (MH + ).
(b) Litijev bromid (136 g, 1.56 mol) smo raztopili v tetrahidrofuranu (600 ml) pri 0°C. Zmes smo pustili segreti na 23°C in po kapljicah dodali terc-butil-2metilsulfoniloksietilkarbamat (37.39 g, 156 mmol). Zmes smo mešali pri 23°C 18 ur in jo koncentrirali v vakuumu. Preostanek smo raztopili v heksanu in organsko plast sprali z vodo in slanico, posušili (Na2SO4) in koncentrirali v vakuumu, da smo dobili ferobutil 2bromoetilkarbamat (33.48 g, 96% dobitek) kot rjavo olje; MS (PB-PCI) C7H-|4BrNO2 m/e izrač. 224.10; ugot. 225 (MH+).(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 and tert-butyl-2methylsulfonyloxyethylcarbamate (37.39 g, 156 mmol) was added dropwise. The mixture was stirred at 23 ° C for 18 hours and concentrated in vacuo. The residue was dissolved in hexane and the organic layer was washed with water and brine, dried (Na 2 SO4) and concentrated in vacuo to give ferrobutyl 2bromoethylcarbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI) C7H- | 4BrNO 2 m / e calcd. 224.10; found 225 (MH < + >).
(c) Zmes 2-metoksifenola (9.8 ml, 89.3 mmol), dimetilformamida (100 ml) in kalijevega karbonata (61.5 g, 445 mmol) smo mešali pri 23°C, medtem ko smo dodajali ferc-butil 2bromoetilkarbamat (20 g, 89.3 mmol). Zmes smo mešali 24 ur in jo potem zlili v zmes etil eter:heksan (1:1, 400 ml) in jo sprali z vodo (5 x 50 ml). Vodno plast smo ekstrahirali z zmesjo etil eter.heksan (1:1, 3 x 40 ml) in združene organske plasti posušili (Na2SO4) in koncentrirali v vakuumu, da smo dobili terc-butil 2-(2-metoksifenoksi)etilkarbamat (23.22(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 while tert -butyl 2bromoethylcarbamate (20 g, 89.3) was added. mmol). The mixture was stirred for 24 hours 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 a mixture of ethyl ether.hexane (1: 1, 3 x 40 ml) and the combined organic layers were dried (Na 2 SO4) and concentrated in vacuo to give tert-butyl 2- (2-methoxyphenoxy) ethylcarbamate ( 23.22
-55g, 97% dobitek) kot rumeno olje; MS (PB-PCI) C14H21NO4 m/e izrač. 267.32; ugot. 268 (MH+).-55g, 97% yield) as a yellow oil; MS (PB-PCI) C14H21NO4 m / e calcd. 267.32; found 268 (MH < + >).
(d) terc-Butil 2-(2-metoksifenoksi)etilkarbamat (23.8 g, 89 mmol) smo ohladili na 0°C in mešali, medtem ko smo po kapljicah dodajali zmes trifluoroocetna kislina:diklorometan (1:1, 40 ml). Zmes smo pustili segreti na 23°C, mešali 2 uri in koncentrirali v vakuumu. Preostanek smo raztopili v diklorometanu (100 ml) in raztopino sprali z nasičenim vodnim natrijevim hidrogen karbonatom (3 x 20 ml) in vodnim natrijevim hidroksidom (10%, 3 x 20 ml), posušili (Na2SO4), filtrirali in koncentrirali v vakuumu, da smo dobili 2-(2metoksifenoksi)etilamin (13 g, 88% dobitek), svetlo rumeno trdno snov; MS (PB-PCI) C9H13NO2 m/e izrač. 167.21; ugot.168 (MH+).(d) Tert-Butyl 2- (2-methoxyphenoxy) ethylcarbamate (23.8 g, 89 mmol) was cooled to 0 ° C and stirred while trifluoroacetic acid: dichloromethane (1: 1, 40 ml) was added dropwise. The mixture was allowed to warm to 23 ° C, stirred for 2 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (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- (2methoxyphenoxy) ethylamine (13 g, 88% yield), a pale yellow solid, was obtained; MS (PB-PCI) C9H13NO2 m / e calcd. 167.21; found.168 (MH + ).
(e) Heterogeno zmes, vsebujočo 3-metoksi-4-nitrobenzojsko kislino (15.42 g, 78.2 mmol) in tionil klorid (70 ml, 391 mmol) smo segrevali ob refluksu eno uro. Prebitni tionil klorid smo odstranili z destilacijo in ostanek koncentrirali v vakuumu, da smo dobili 3metoksi-4-nitrobenzoil klorid (16.8 g, 99% dobitek) kot svetlo rumeno trdno snov; MS (PBPCI) C8H6CINO4 m/e izrač. 215.59; ugot. 216 (MH+).(e) A heterogeneous mixture containing 3-methoxy-4-nitrobenzoic acid (15.42 g, 78.2 mmol) and thionyl chloride (70 ml, 391 mmol) was refluxed for one hour. Excess thionyl chloride was removed by distillation and the residue was concentrated in vacuo to give 3methoxy-4-nitrobenzoyl chloride (16.8 g, 99% yield) as a pale yellow solid; MS (PBPCI) C 8 H 6 CINO 4 m / e calc. 215.59; found 216 (MH < + >).
(f) Zmes, obsegajočo 2-(2-metoksifenoksi)etilamin (10 g, 59.9 mmol), diizopropiletilamin (13.9 ml, 81.6 mmol) in diklorometan (80 ml) smo ohladili na 0°C in potem po kapljicah dodali raztopino 3-metoksi-4-nitrobenzoil klorida (11.76 g, 54.4 mmol) v diklorometanu (50 ml). Zmes smo pustili, da se je segrela na 23°C tekom dveh ur, pogasili z vodno klorovodikovo kislino (3 M, 20 ml), sprali z vodo (3 x 20 ml), posušili (Na2SO4) in kocentrirali v vakuumu, da smo dobili A/-[2-(2-metoksifenoksi)etil]-3-metoksi-4nitrobenzamid (14 g, 74% dobitek), neizrazito belo trdno snov; MS (PB-PCI) Cj7H-|qN2O6 m/e izrač. 346.34; ugot. 347 (MH+).(f) A mixture comprising 2- (2-methoxyphenoxy) ethylamine (10 g, 59.9 mmol), diisopropylethylamine (13.9 ml, 81.6 mmol) and dichloromethane (80 ml) was cooled to 0 ° C and a solution of 3- was added dropwise. 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 gave N - [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4nitrobenzamide (14 g, 74% yield), a fuzzy white solid; MS (PB-PCI) C17H- [qN2O6] m / e calcd. 346.34; found 347 (MH < + >).
(g) Zmes, obsegajočo /V-[2-(2-metoksifenoksi)etil]-3-metoksi-4-nitrobenzamid (4.0 g, 11.6 mmol), vodni metilamin (40 %, 10 ml) in DMSO (2 ml) v zaprti epruveti smo segrevali pri 110°C 4 ure, ohladili in potem zlili v vodo (25 ml). Razredčeno zmes smo obdelali s 3 M vodno klorovodikovo kislino, da smo dobili oranžno trdno snov. Trdno snov smo izolirali(g) Mixture comprising N- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol), aqueous methylamine (40%, 10 ml) and DMSO (2 ml) in a sealed tube, it was heated at 110 ° C for 4 hours, cooled and then poured into water (25 ml). The diluted mixture was treated with 3 M aqueous hydrochloric acid to give an orange solid. The solid was isolated
-56s filtracijo, da smo dobili /V-[2-(2-metoksifenoksi)etil]-3-metilamino-4-nitrobenzamid (3.56 g, 89% dobitek); MS (PB-PCI) C17H19N3O5 m/e izrač. 345.35; ugot. 346 (MH+).-56s filtration to give N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI) C17H19N3O5 m / e calcd. 345.35; found 346 (MH < + >).
(h) Zmes, obsegajočo N-[2-(2-metoksifenoksi)etil]-3-metilamino-4-nitrobenzamid (3.56 g, 10.3 mmol), suspendiran paladij na ogljiku (10 %, 0.5 g) v metanolu (100 ml) in tetrahidrofuran (50 ml) smo mešali v atmosferi vodika pri ambientnem tlaku 2.5 ur. Zmes smo filtrirali in raztopino koncentrirali v vakuumu, da smo dobili 4-amino-/V-[2-(2metoksifenoksi)etil]-3-metilaminobenzamid (3.37 g, 100% dobitek) kot zeleno peno; MS (PB-PCI) C-17H21N3O3 m/e izrač. 315.37; ugot. 316 (MH+).(h) Mixture comprising N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol), suspended palladium on carbon (10%, 0.5 g) in methanol (100 ml ) and tetrahydrofuran (50 ml) were stirred under a hydrogen atmosphere at ambient pressure for 2.5 hours. The mixture was filtered and the solution concentrated in vacuo to give 4-amino- N- [2- (2methoxyphenoxy) ethyl] -3-methylaminobenzamide (3.37 g, 100% yield) as a green foam; MS (PB-PCI) C-17H21N3O3 m / e calcd. 315.37; found 316 (MH < + >).
(i) Zmes, obsegajočo 4-amino-3-nitrofenol (5.0 g, 32.4 mmol), paladij na ogljiku (10 %, 1.0 g) in metanol (50 ml) smo v Parrovem aparatu hidrogenirali pri 3.44 bar 3 ure, filtrirali skozi celit in koncentrirali v vakuumu, da smo dobili 3,4-diaminofenol (4.02 g, 91% dobitek) kot temno trdno snov; MS (PB-PCI) C6H8N2O m/e izrač. 124.16; ugot. 125 (MH+).(i) A mixture comprising 4-amino-3-nitrophenol (5.0 g, 32.4 mmol), palladium on carbon (10%, 1.0 g) and methanol (50 ml) was hydrogenated in a Parr apparatus at 3.44 bar for 3 hours, filtered through celite and concentrated in vacuo to give 3,4-diaminophenol (4.02 g, 91% yield) as a dark solid; MS (PB-PCI) C6H8N2O m / e calcd. 124.16; found 125 (MH < + >).
(j) Zmes, obsegajočo 3,4-diaminofenol (3.661 g, 29.5 ml), etil 2-(/Vetoksiamidino)propionat (7.423 g, 38.4 mmol) in etanol (30 ml) smo segrevali ob refluksu 6 ur in koncentrirali v vakuumu. Preostanek smo raztopili v etil acetatu (200 ml) in raztopino sprali z nasičenim vodnim natrijevim hidrogen karbonatom (3 x 20 ml) in slanico (1 x 20 ml), posušili (MgSO4) in koncentrirali v vakuumu, da smo dobili etil 2-(5-hidroksi1 H-benzoimidazol-2-il)propionat (6.3 g, 91% dobitek) kot temno trdno snov. Trdno snov smo nadalje očistili s silikagelno flash kromatografijo (100% etil acetat); MS (PB-PCI) C12H14N2O3 m/e izrač. 234.28; ugot. 235 (MH+).(j) A mixture comprising 3,4-diaminophenol (3.661 g, 29.5 ml), ethyl 2 - (/ Vetoxyamidino) propionate (7.423 g, 38.4 mmol) and ethanol (30 ml) was refluxed for 6 hours and concentrated in vacuo. . The residue was dissolved in ethyl acetate (200 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3 x 20 ml) and brine (1 x 20 ml), dried (MgSO4) and concentrated in vacuo to give ethyl 2- ( 5-hydroxyH-benzoimidazol-2-yl) propionate (6.3 g, 91% yield) as a dark solid. The solid was further purified by silica gel flash chromatography (100% ethyl acetate); MS (PB-PCI) C12H14N2O3 m / e calcd. 234.28; found 235 (MH < + >).
(k) Zmes, obsegajočo etil 2-(5-hidroksi-1 H-benzoimidazol-2-il)propionat (148 mg, 0.63 mmol), 4-amino-/V-[2-(2-metoksifenoksi)etil]-3-metilaminobenzamid (200 mg, 0.63 mmol) in 1,3-dimetil-3,4,5,6-tetrahidro-2(1 H)-pirimidon (0.5 ml) smo mešali pri sobni temperaturi dokler ni bila homogena, degazirali v vakuumu in koncentrirali s segrevanjem pri 170°C 2 uri v toku N2. Ostanek smo ohladili na sobno temperaturo in sprali s prebitkom dietil etra. Nastali amorfni material smo raztopili v 50 % vodnem acetonitrilu in očistili s preparativno HPLC na reverzni fazi (2-50 % CH3CN/H2O), da smo dobili 2-[1 -(5-hidroksi-1 H-57benzoimidazol-2-il)etil]-/V-[2-(2-metoksifenoksi)etil]-3-metil-3H-benzoimidazol-5karboksamid (40 mg, 13% dobitek) kot svetlo rožnato trdno snov; MS (Biolon) C27H27N5O4 m/e izrač. 485.59; ugot. 486.5 (MH+).(k) Mixture comprising ethyl 2- (5-hydroxy-1H-benzoimidazol-2-yl) propionate (148 mg, 0.63 mmol), 4-amino- N - [2- (2-methoxyphenoxy) ethyl] - 3-Methylaminobenzamide (200 mg, 0.63 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (0.5 ml) were stirred at room temperature until homogeneous, degassed in vacuum and concentrated by heating at 170 ° C for 2 hours under N2 flow. The residue was cooled to room temperature and washed with excess diethyl ether. The resulting amorphous material was dissolved in 50% aqueous acetonitrile and purified by preparative reverse phase HPLC (2-50% CH3CN / H2O) to give 2- [1- (5-hydroxy-1H-57benzoimidazol-2-yl) ethyl] - N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5carboxamide (40 mg, 13% yield) as a light pink solid; MS (Biolon) C27H27N5O4 m / e calcd. 485.59; found 486.5 (MH < + >).
Po postopku kot v Primeru 8 smo pripravili sledeče spojine izuma:Following the procedure as in Example 8, the following compounds of the invention were prepared:
metil 2-(2-{2-[1 -(5-f I uoro-1 H-benzoimidazol-2-il)etil]-3-metil-3/-/-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 31), MS (Biolon) C28H26N5O4F m/e izrač. 515.54; ugot. 516 (MH+);Methyl 2- (2- {2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoate (Compound 31 ), MS (Biolon) C28H26N5O4F m / e calcd. 515.54; found 516 (MH < + >);
2-(2-{2-[1-(5-fluoro-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 32), MS (Biolon) C27H24N5O4F m/e izrač. 501.52; ugot. 502.1 (MH+);2- (2- {2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoic acid (Compound 32), MS (Biolon) C27H24N5O4F m / e calcd. 501.52; found 502.1 (MH < + >);
etil 2-(2-{2-[1 -(5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3W-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 33), MS (Biolon) C29H29N5O5 m/e izrač. 527.58; ugot 528.1 (MH+);Ethyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 33), MS (Biolon ) C29H29N5O5 m / e calcd. 527.58; found 528.1 (MH + );
2-(2-{2-[1 -(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 34), MS (Biolon) C27H25N5O5 m/e izrač. 499.53; ugot. 500.1 (MH+);2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 34), MS (Biolon) C27H25N5O5 m / e calcd. 499.53; found 500.1 (MH < + >);
A/-etil-2-[1-(5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5karboksamid (Spojina 35), MS (Biolon) C20H21N5O2 m/e izrač. 363.42; ugot. 364.1 (MH+);N-ethyl-2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carboxamide (Compound 35), MS (Biolon) C20H21N5O2 m / e calc. . 363.42; found 364.1 (MH < + >);
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-/V-(2-metoksietil)-3-metil-3A7-benzoimidazol-5karboksamid (Spojina 36), MS (Biolon) C21H23N5O3 m/e izrač. 393.45; ugot. 394.1 (MH+);2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] - N - (2-methoxyethyl) -3-methyl-3A7-benzoimidazole-5carboxamide (Compound 36), MS (Biolon) C21H23N5O3 m / e calc. 393.45; found 394.1 (MH < + >);
-58butil 2-(2-{2-[ 1 -(5-h id roksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 37), MS (Biolon) C31H33N5O5 m/e izrač. 555.64;-58-Butyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoate (Compound 37). MS (Biolon) C31H33N5O5 m / e calcd. 555.64;
ugot. 555.7 (MH+);found 555.7 (MH < + >);
3-{2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-6-[2-(2metoksifenoksi)etilkarbamoil]benzimidazol-1-il}propan-1-sulfonsko kislino (Spojina 38), MS (LCMS) C3oH35N806S m/e izrač. 635.72; ugot. 635.4 (MH+);3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -6- [2- (2methoxyphenoxy) ethylcarbamoyl] benzimidazol-1-yl} propane-1-sulfonic acid (Compound 38 ), MS (LCMS) C 30 H 3 5 N 8 O 6 S m / e calcd. 635.72; found 635.4 (MH < + >);
/V-[2-(2-etoksifenoksi)etil]-2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 39), MS (Biolon) C28H29N5O4 m/e izrač. 499.58; ugot. 500.4 (MH+);N- [2- (2-Ethoxyphenoxy) ethyl] -2- [1- (5-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 39) , MS (Biolon) C28H29N5O4 m / e calcd. 499.58; found 500.4 (MH < + >);
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-/\/-[2-(2-izopropoksifenoksi)etil]-3-rnetil-3Hbenzoimidazol-5-karboksamid (Spojina 40), MS (Biolon) C29H31N5O4 m/e izrač. 513.61; ugot. 514.5 (MH+);2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-isopropoxyphenoxy) ethyl] -3-phenyl-3H-benzoimidazole-5-carboxamide (Compound 40). MS (Biolon) C29H31N5O4 m / e calcd. 513.61; found 514.5 (MH + );
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-/\/-[2-(2-propoksifenoksi)etil]-3Hbenzoimidazol-5-karboksamid (Spojina 41), MS (Biolon) C29H31N5O4 m/e izrač. 513.61; ugot. 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 (Biolon) C29H31N5O4 m / e calcd. 513.61; found 514.2 (MH + );
propil 2-(2-{2-[1 -(5-h idroksi-1 /7-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 42), MS (ESI) C30H31N5O5 m/e izrač. 541.61; ugot. 542.2 (MH+);Propyl 2- (2- {2- [1- (5-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 42), MS (ESI) C30H31N5O5 m / e calcd. 541.61; found 542.2 (MH < + >);
izobutil 2-(2-{2-[1 -(5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3/-/-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 43), MS (Biolon) C31H33N5O5 m/e izrač. 555.64; ugot. 556.3 (MH+);isobutyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 43). MS (Biolon) C31H33N5O5 m / e calcd. 555.64; found 556.3 (MH < + >);
etil 4- {2-[1 -(5-h idroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}butirat (Spojina 44), MS (Biolon) C24H27N5O4 m/e izrač. 449.51; ugot. 449.9 (MH+);ethyl 4- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} butyrate (Compound 44), MS (Biolon) C24H27N5O4 m / is calcd. 449.51; found 449.9 (MH + );
-594- {2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/-/-benzoimidazol-5ilkarbonilamino}butirično kislino (Spojina 45), MS (Biolon) C22H23N5O4 m/e izrač. 421.46; ugot. 422.1 (MH+);-594- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} butyric acid (Compound 45), MS (Biolon) C22H23N5O4 m / e calcd. 421.46; found 422.1 (MH < + >);
izopropil 2-(2-{2-[1 -(5-hidroksi-1 /-/-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 46), MS (ESI) C30H31N5O5 m/e izrač. 541.61; ugot. 542.2 (MH+);isopropyl 2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 46) , MS (ESI) C30H31N5O5 m / e calcd. 541.61; found 542.2 (MH < + >);
/V-{2-[2-(1 -etilpropoksi)fenoksi]etil}-2-[1 -(5-hidroksi-1 /7-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 47), MS (Biolon) C31H35N5O4 m/e izrač. 541.65; ugot. 542.5 (MH+);N- {2- [2- (1-ethylpropoxy) phenoxy] ethyl} -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5- carboxamide (Compound 47), MS (Biolon) C31H35N5O4 m / e calcd. 541.65; found 542.5 (MH < + >);
etil 2-(2-{2-[1 -(5-fluoro-1 H-benzoimidazol-2-il)etil]-3-metil-3/+benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 48), MS (Biolon) C29H28N5O4F m/e izrač. 529.57; ugot. 529.5 (MH+);ethyl 2- (2- {2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H + benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 48), MS ( Biolone) C29H28N5O4F m / e calcd. 529.57; found 529.5 (MH + );
2-metoksietil 2-(2-{2-[1 -(5-hidroksi-1 /-/-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol5- ilkarbonilamino}etoksi)benzoat (Spojina 49), MS (Biolon) C30H31N5O6 m/e izrač. 557.61; ugot. 558.2 (MH+);2-Methoxyethyl 2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoate (Compound 49) , MS (Biolon) C30H31N5O6 m / e calcd. 557.61; found 558.2 (MH < + >);
N-(3-metoksipropil)-2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol5-karboksamid (Spojina 50), MS (Biolon) C22H25N5O3 m/e izrač. 407.47; ugot. 408.0 (MH+);N- (3-methoxypropyl) -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole5-carboxamide (Compound 50), MS (Biolon) C22H25N5O3 m / is calcd. 407.47; found 408.0 (MH < + >);
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-/V-[2-(2-metoksimetilfenoksi)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 51), MS (Biolon) C28H29N5O4 m/e izrač. 499.57; ugot. 499.8 (MH+);2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 51), MS (Biolon) C28H29N5O4 m / e calcd. 499.57; found 499.8 (MH < + >);
/\/-[2-(2-etoksimetilfenoksi)etil]-2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3/-/benzoimidazol-5-karboksamid (Spojina 52), MS (Biolon) C29H31N5O4 m/e izrač. 513.60; ugot. 514.1 (MH+);N - [2- (2-ethoxymethylphenoxy) ethyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide ( Compound 52), MS (Biolon) C29H31N5O4 m / e calcd. 513.60; found 514.1 (MH < + >);
-60etil 2-(2-{2-[1 -(6-fluoro-5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 53), MS (ESI) C29H28N5O5F m/e izrač. 545.57; ugot. 546.3 (MH+);-60ethyl 2- (2- {2- [1- (6-fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 53 ), MS (ESI) C29H28N5O5F m / e calcd. 545.57; found 546.3 (MH < + >);
etil 2-(2-{2-[1 -(5-hidroksi-1 /7-benzoimidazol-2-il)etil]-3-metil-3B-benzoimidazol-5ilkarbonilamino}etoksi)cikloheksankarboksilat (Spojina 54), MS (Biolon) C29H35N5O5 m/e izrač. 533.63; ugot. 534 (MH+);ethyl 2- (2- {2- [1- (5-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3B-benzoimidazole-5ylcarbonylamino} ethoxy) cyclohexanecarboxylate (Compound 54), MS ( Biolone) C29H35N5O5 m / e calcd. 533.63; found 534 (MH < + >);
2-[1 -(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-N-[2-(2-propoksimetilfenoksi)etil]-3Hbenzoimidazol-5-karboksamid (Spojina 55), MS (Biolon) C30H33N5O4 m/e izrač. 527.62; ugot. 527.6 (MH+);2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-propoxymethylphenoxy) ethyl] -3Hbenzoimidazole-5-carboxamide (Compound 55), MS ( Biolone) C30H33N5O4 m / e calcd. 527.62; found 527.6 (MH + );
2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-A/-[2-(2-izopropoksimetilfenoksi)etil]-3-metil3H-benzoimidazol-5-karboksamid (Spojina 56), MS (Biolon) C30H33N5O4 m/e izrač. 527.62; ugot. 527.9 (MH+);2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl3H-benzoimidazole-5-carboxamide (Compound 56) , MS (Biolon) C30H33N5O4 m / e calcd. 527.62; found 527.9 (MH + );
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-/V-{2-[2-(2-metoksietoksimetil)fenoksi]etil}-3metil-3/-/-benzoimidazol-5-karboksamid (Spojina 57), MS (Biolon) C30H33N5O5 m/e izrač. 543.62; ugot. 543.4 (MH+);2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] - N - {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3methyl-3 H -benzoimidazol-5 -carboxamide (Compound 57), MS (Biolon) C30H33N5O5 m / e calcd. 543.62; found 543.4 (MH < + >);
2-(1-(1 B-benzoimidazol-2-il)etil]-/\/-[2-(2-metoksimetilfenoksi)etil]-3-metil-3Bbenzoimidazol-5-karboksamid (Spojina 58), MS (Biolon) 028Η29Ν5θ3 m/θ izrač. 483.57; ugot. 484 (MH+);2- (1- (1B-benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3Bbenzoimidazole-5-carboxamide (Compound 58), MS (Biolon ) 028 Η 29 Ν 5θ3 m / θ calc 483.57; found 484 (MH + );
/V-[2-(2-etoksimetilfenoksi)etil]-2-[1-(1H-benzoimidazol-2-il)etil]-3-metil-3B-benzoimidazol5-karboksamid (Spojina 59), MS (Biolon) C29H31N5O3 m/e izrač. 497.6; ugot. 498.3 (MH+);N- [2- (2-Ethoxymethylphenoxy) ethyl] -2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3B-benzoimidazole5-carboxamide (Compound 59), MS (Biolon) C29H31N5O3 m / e calcd. 497.6; found 498.3 (MH < + >);
2-(1-(1 B-benzoimidazol-2-il)etil]-3-rnetil-A/-[2'(2propoksimetilfenoksi)etil]-3Hbenzoimidazol-5-karboksamid (Spojina 60), MS (Biolon) C30H33N5O3 m/e izrač. 511.62; ugot. 511.5 (MH+);2- (1- (1 B-benzoimidazol-2-yl) ethyl] -3-phenyl-N- [2 '(2-propoxymethylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 60), MS (Biolon) C30H33N5O3 m / e calc 511.62; found 511.5 (MH + );
-612-[1 -(1 H-benzoimidazol-2-il)etil]-/V-[2-(2-izopropoksimetilfenoksi)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 61), MS (Biolon) C30H33N5O3 m/e izrač. 511.62; ugot. 511.6 (MH+);-612- [1- (1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3Hbenzoimidazole-5-carboxamide (Compound 61), MS (Biolon ) C30H33N5O3 m / e calcd. 511.62; found 511.6 (MH + );
2-(1-(1 H-benzoimidazol-2-il)etil]-A/-{2-[2-(2-metoksietoksimetil)fenoksi]etil}-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 62), MS (Biolon) C30H33N5O4 m/e izrač. 527.62; ugot. 527.7 (MH+);2- (1- (1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3-methyl-3Hbenzoimidazole-5-carboxamide (Compound 62) , MS (Biolon) C30H33N5O4 m / e calc 527.62; found 527.7 (MH + );
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-/\/-[2-(2-morfolin-4-ilfenoksi)etil]-3Hbenzoimidazol-5-karboksamid (Spojina 63), MS (Biolon) C30H32N6O4 m/e izrač. 540.73; ugot. 541.8 (MH+);2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-morpholin-4-ylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide ( Compound 63), MS (Biolon) C30H32N6O4 m / e calcd. 540.73; found 541.8 (MH < + >);
/\/-(2-fenilsulfoniletil)-2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol5-karboksamid (Spojina 64), MS (Biolon) C26H25N5O4S m/e izrač. 503.59; ugot. 504.2 (MH+);N- (2-Phenylsulfonylethyl) -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole5-carboxamide (Compound 64), MS (Biolon) C26H25N5O4S m / e calcd. 503.59; found 504.2 (MH < + >);
2-(2-{2-[1 -(6-fluoro-5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3W-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 65), MS (ESI) C27H24N5O5F m/e izrač. 517.52; ugot. 518.2 (MH+);2- (2- {2- [1- (6-Fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 65). MS (ESI) C27H24N5O5F m / e calcd. 517.52; found 518.2 (MH + );
etil 2-hidroksi-5-{2-[1 -(5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}benzoat (Spojina 66), MS (Biolon) C27H25N5O5 izrač. 499.52; ugot.ethyl 2-hydroxy-5- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} benzoate (Compound 66), MS (Biolon) C27H25N5O5 calcd. 499.52; found
500.2 (MH+);500.2 (MH < + >);
2-[1-(5-fluoro-1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-morfolin-4-ilfenoksi)etil]-3Wbenzoimidazol-5-karboksamid (Spojina 67), MS (Biolon) C30H31N6O3F m/e izrač. 542.62; ugot. 543.4 (MH+);2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-morpholin-4-ylphenoxy) ethyl] -3W-benzoimidazole-5-carboxamide (Compound 67), MS (Biolon) C30H31N6O3F m / e calcd. 542.62; found 543.4 (MH < + >);
/\/-(2-fenilsulfoniletil)-2-[1-(5-fluoro-1/7-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5karboksamid (Spojina 68), MS (Biolon) C26H24N5O3FS m/e izrač. 505.58; ugot. 506.5 (MH+);N- (2-Phenylsulfonylethyl) -2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carboxamide (Compound 68), MS (Biolon ) C26H24N5O3FS m / e calcd. 505.58; found 506.5 (MH + );
-62etil 2-(2-{2-[1 -(4,6-difluoro-5-hidroksi-1 /+benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 69), MS (ESI) C29H27N5O5F2 m/e izrač. 563.52; ugot. 563.4 (MH+);-62ethyl 2- (2- {2- [1- (4,6-difluoro-5-hydroxy-1 H + benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate ( Compound 69), MS (ESI) C29H27N5O5F2 m / e calcd. 563.52; found 563.4 (MH < + >);
2-(2-{2-[1-(4,6-difluoro-5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 70), MS (Biolon) C27H23N5O5F2 m/e izrač. 536.51; ugot. 563 (MH+);2- (2- {2- [1- (4,6-Difluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 70 ), MS (Biolon) C27H23N5O5F2 m / e calcd. 536.51; found 563 (MH < + >);
etil 2-(2-{2-[1 -(4,6-difluoro-5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-3/+ benzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 71), MS (Biolon) C32H29N7O4F2 m/e izrač. 613.62; ugot. 614.3 (MH+);ethyl 2- (2- {2- [1- (4,6-difluoro-5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H + benzoimidazol-5- ylcarbonylamino} ethoxy) benzoate (Compound 71), MS (Biolon) C32H29N7O4F2 m / e calcd. 613.62; found 614.3 (MH < + >);
2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-3-metil-/V-{2-[2-(3-metil-[1,2,4]oksadiazol-5il)fenoksi]etil}-3/-/-benzoimidazol-5-karboksamid (Spojina 72), MS (Biolon) C30H30N10O3 m/e izrač. 578.63; ugot. 579.4 (MH+); in2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - {2- [2- (3-methyl- [1,2,4] oxadiazol-5yl) ) phenoxy] ethyl} -3 H -benzoimidazole-5-carboxamide (Compound 72), MS (Biolon) C30H30N10O3 m / e calcd. 578.63; found 579.4 (MH + ); and
2-[l -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-/\/-{2-[2-(3-metil-[1,2,4]oksadiazol5-il)fenoksi]etil}-3H-benzoimidazol-5-karboksamid (Spojina 73), MS (Biolon) C32H29N9O3 m/e izrač. 587.64; ugot. 588.2 (MH+).2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- {2- [2- (3-methyl- [1,2, 4] Oxadiazol5-yl) phenoxy] ethyl} -3H-benzoimidazole-5-carboxamide (Compound 73), MS (Biolon) C32H29N9O3 m / e calc. 587.64; found 588.2 (MH < + >).
PRIMER 9EXAMPLE 9
2-[2-(2-{1-[5-(1-lminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}-3-metil-3/7benzoimidazol-5-ilkarbonilamino)etoksi]benzojska kislina (Spojina 74) (a) Raztopino, obsegajočo 3,4-diaminopiridin (51.7 g, 0.46 mol) v ocetni kislini (400 ml) smo segrevali pri 85°C in potem dodali dietil metil-1-iminomalonat (125 g, 0.60 mol) v 3 ekvivalentnih porcijah tekom 6 ur. Zmes smo segrevali pri 85°C 12 ur in pri 120°C še eno uro, ohladili in koncentrirali pod znižanim tlakom. Ostanek smo ohladili na 0°C in nevtralizirali s 5 N amonijevim hidroksidom. Vodno plast smo ekstrahirali z več porcijami etil acetata in združene ekstrakte zaporedoma sprali z natrijevim bikarbonatom in natrijevim kloridom, posušili (Na2SO4), filtrirali in koncentrirali pod znižanim tlakom, da2- [2- (2- {1- [5- (1-aminoethyl) -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 74) (a) A solution containing 3,4-diaminopyridine (51.7 g, 0.46 mol) in acetic acid (400 ml) was heated at 85 ° C. and then diethyl methyl-1-iminomalonate (125 g, 0.60 mol) was added in 3 equivalent portions over 6 hours. The mixture was heated at 85 ° C for 12 hours and at 120 ° C for another hour, cooled and concentrated under reduced pressure. The residue was cooled to 0 ° C and neutralized with 5 N ammonium hydroxide. The aqueous layer was extracted with several portions of ethyl acetate and the combined extracts were sequentially washed with sodium bicarbonate and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to give
-63smo dobili etil 2-(1H-imidazo[4,5-c]piridin-2-il)propionat (60.4 g, 58 %) kot rumenkasto rjavo trdno snov. 1H-NMR (300 MHz, CDCI3) d ppm: 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).-63 Ethyl 2- (1H-imidazo [4,5-c] pyridin-2-yl) propionate (60.4 g, 58%) was obtained as a tan solid. 1 H-NMR (300 MHz, CDCl 3) δ ppm: 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) Raztopino, obsegajočo etil 2-(1 H-imidazo[4,5-c]piridin-2-il)propionat (60.4 g, 0.28 mol) v trifluoroocetni kislini (100 ml) smo hidrogenirali pri 3.44 bar v prisotnosti platinovega (IV) oksida (5 g) 2 dni. Zmes smo filtrirali in koncentrirali pod znižanim tlakom. Ostanek smo ohladili na 0°C, obdelali s 4 M zmesjo HCI/dioksan, suspendirali v etru, izolirali s filtracijo in posušili. Raztopine, obsegajoče ostanek (vsaka 15-20 g) v sveži trifluoroocetni kislini (vsaka 50 ml) smo hidrogenirali pri 3.44 bar v prisotnosti platinovega (IV) oksida (vsaka 5 g) 24 ur. Zmesi smo filtrirali in koncentrirali pod znižanim tlakom. Preostanke smo azeotropno posušili z zmesjo toluen/etanol ~ 1:1, s 4 M HCI v dioksanu, suspendirali v etru, izolirali s filtracijo in posušili v vakuumu, da smo dobili dihidroklorid etil 2-(4,5,6,7tetrahidroimidazo[4,5-c]piridin-2-il)propionata (61.80 g, 75% dobitek); 1H-NMR (300 MHz, DMSO-de) d ppm: 10.00 (br s, 2H), 4.35 (q, 1 H, J = 7.1 Hz), 4.25 (br s, 2H), 4.15 (m, 2H), 3.35 (m, 2H), 2.90 (br s, 2H), 1.60 (d, 3H, J = 7.1 Hz), 1.20 (t, 3H, J = 6.9 Hz).(b) A solution comprising ethyl 2- (1H-imidase [4,5-c] pyridin-2-yl) propionate (60.4 g, 0.28 mol) in trifluoroacetic acid (100 ml) was hydrogenated at 3.44 bar in the presence of platinum (IV) oxide (5 g) for 2 days. The mixture was filtered and concentrated under reduced pressure. The residue was cooled to 0 ° C, treated with 4 M HCl / dioxane, suspended in ether, isolated by filtration and dried. Solutions containing the residue (15-20 g each) in fresh trifluoroacetic acid (50 ml each) were hydrogenated at 3.44 bar in the presence of platinum (IV) oxide (5 g each) for 24 hours. The mixtures were filtered and concentrated under reduced pressure. The residue was azeotropically dried with toluene / ethanol ~ 1: 1 mixture, with 4 M HCl in dioxane, suspended in ether, isolated by filtration and dried in vacuo to give ethyl 2- (4,5,6,7tetrahydroimidase dihydrochloride [4 , 5-c] pyridin-2-yl) propionate (61.80 g, 75% yield); 1 H-NMR (300 MHz, DMSO-d6) d ppm: 10.00 (br s, 2H), 4.35 (q, 1 H, J = 7.1 Hz), 4.25 (br s, 2H), 4.15 (m, 2H) , 3.35 (m, 2H), 2.90 (br s, 2H), 1.60 (d, 3H, J = 7.1 Hz), 1.20 (t, 3H, J = 6.9 Hz).
(c) Raztopino, obsegajočo dihidroklorid etil 2-(4,5,6,7-tetrahidroimidazo[4,5-c]piridin2-il)propionata (60.2 g, 0.20 mol) v acetonitrilu (400 ml) smo ohladili na 0°C v atmosferi dušika, obdelali z /V,/V-diizopropiletilaminom (35 ml, 0.20 mol), nadalje ohladili na ~ -5°C (zmes led/aceton) in potem obdelali z benzil kloroformatom (58 ml, 0.41 mol) in N,Ndiizopropiletilaminom (70 ml, 0.40 mol) v izmeničnih porcijah tekom 30 minut. Zmes smo hladili na -5°C 1 uro in jo pustili, da se je segrela na 20°C in po 16 urah koncentrirali pod znižanim tlakom. Ostanek smo suspendirali v etru in suspenzijo zaporedoma sprali z natrijevim bikarbonatom, natrijevim kloridom, 0.1 M klorovodikovo kislino in natrijevim kloridom, posušili (Na2SO4), filtrirali in koncentrirali pod znižanim tlakom. Ostanek smo raztopili v etanolu (320 ml) in raztopino ohladili na -5°C v atmosferi dušika in potem dodali natrijev etoksid (21 ut.%, 85 ml, 0.22 mol) po kapljicah tekom 1 ure, medtem ko smo reakcijsko temperaturo ohranjali pod 0°C. Zmes smo hladili pri -5°C 1 uro, jo naravnali na nevtralen pH s 50 ml 4 M klorovodikove kisline in koncentrirali pod znižanim tlakom. Ostanek smo raztopili v etil acetatu in raztopino sprali z natrijevim bikarbonatom in(c) A solution comprising the dihydrochloride of ethyl 2- (4,5,6,7-tetrahydroimidase [4,5-c] pyridin2-yl) propionate (60.2 g, 0.20 mol) in acetonitrile (400 ml) was cooled to 0 ° C under nitrogen atmosphere, treated with N, N-diisopropylethylamine (35 ml, 0.20 mol), further cooled to ~ -5 ° C (ice / acetone mixture) and then treated with benzyl chloroformate (58 ml, 0.41 mol) and N, Ndiisopropylethylamine (70 ml, 0.40 mol) in alternating portions over 30 minutes. The mixture was cooled to -5 ° C for 1 hour and allowed to warm to 20 ° C and concentrated under reduced pressure after 16 hours. The residue was suspended in ether and the suspension was sequentially washed with sodium bicarbonate, sodium chloride, 0.1 M hydrochloric acid and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (320 ml) and the solution was cooled to -5 ° C under a nitrogen atmosphere and then sodium ethoxide (21% by weight, 85 ml, 0.22 mol) was added dropwise over 1 hour while maintaining the reaction temperature below 16 ° C. The mixture was cooled to -5 ° C for 1 hour, adjusted 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
-64natrijevim kloridom, posušili (Na2SO4), filtrirali in koncentrirali pod znižanim tlakom. Preostanek smo očistili s silikagelno kromatografijo (zmes heksan/etil acetat), da smo dobili benzil 2-(1-etoksikarboniletil)-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-karboksilat (52 g, 72 %) kot bledo rumeno olje; 1H-NMR (300 MHz, DMSO-cfe) d ppm: 11.72 (br s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (br s, 2H), 4.02 (q, 2H, J = 9.3 Hz), 3.77 (q, 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).-64Natrium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate mixture) to give benzyl 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidase [4,5-c] pyridine-5-carboxylate (52 g , 72%) as pale yellow oil; 1 H-NMR (300 MHz, DMSO-cfe) d ppm: 11.72 (br s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (br s, 2H), 4.02 (q, 2H) , J = 9.3 Hz), 3.77 (q, 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) Zmes, obsegajočo benzil 2-(1-etoksikarboniletil)-1,4,6,7-tetrahidroimidazo[4,5c]piridin-5-karboksilat (6.37 g, 0.018 mol), 4-amino-3-(/V-metilamino)benzojsko kislino (2.70 g, 0.016 mol) in DMPU (20 ml) smo kratek čas degazirali v vakuumu, segrevali pri 185°C v atmosferi dušika 4 ure, ohladili in združili z ekvivalentnim volumnom benzena. Potem smo k zmesi dodali eter, da smo dobili oborino. Oborino smo izolirali s filtracijo, hitro posušili v vakuumu in nadalje očistili s preobarjanjem iz zmesi vročega etanola in vode. Oborino smo zopet izolirali s filtracijo in posušili, da smo dobili 2-[1-(5benziloksikarbonil-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il)etil]-3-metil-3Hbenzoimidazol-5-karboksilno kislino (4.73 g, 58 %); 1H-NMR (300 MHz, DMSO-cfe) d ppm: 12.70 (brs, 1H), 11.80 (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 (q, 1H, J = 5.2 Hz), 4.32 (br S, 2H), 3.78 (s, 3H), 3.65 (br s, 2H), 2.52 (br s, 2H), 1.73 (d, 3H, J = 5.2 Hz).(d) A mixture comprising benzyl 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidazo [4,5c] pyridine-5-carboxylate (6.37 g, 0.018 mol), 4-amino-3 - (/ V-methylamino) benzoic acid (2.70 g, 0.016 mol) and DMPU (20 ml) were briefly degassed in vacuo, heated at 185 ° C under a nitrogen atmosphere for 4 hours, cooled and combined with an equivalent volume of benzene. Then ether was added to the mixture to give a precipitate. The precipitate was isolated by filtration, dried rapidly in vacuo and further purified by conversion from a mixture of hot ethanol and water. The precipitate was again isolated by filtration and dried to give 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3 -methyl-3H-benzoimidazole-5-carboxylic acid (4.73 g, 58%); 1 H-NMR (300 MHz, DMSO-cfe) d ppm: 12.70 (brs, 1H), 11.80 (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 (q, 1H, J = 5.2 Hz), 4.32 (br S, 2H), 3.78 (s, 3H) , 3.65 (br s, 2H), 2.52 (br s, 2H), 1.73 (d, 3H, J = 5.2 Hz).
(e) Zmes, obsegajočo 2-[1-(5-benziloksikarbonil-4,5,6,7-tetrahidro-1H-imidazo[4,5c]piridin-2-il)etil]-3-metil-3H-benzoimidazol-5-karboksilno kislino (0.75 g, 1.6 mmol), DMF (6.5 ml), metil 2-(2-aminoetoksi)benzoat (0.38 g, 1.6 mmol) in HOBT (0.22 g, 1.6 mmol) smo ohladili v atmosferi dušika na -40°C, obdelali z EDC (0.32 g, 1.6 mmol) in N,Ndiizopropiletilaminom (0.29 ml, 1.6 mmol) in 15 minut kasneje z dodatnim N,Ndiizopropiletilaminom (0.29 ml), pustili segreti na 20°C in mešali 16 ur. Zmes smo potem ohladili na -40°C, obdelali z dodatnim EDC (0.080 g) in /V,/V-diizopropiletilaminom (0.050 ml), mešali 15 minut pri -40°C in 2 uri pri 20°C in koncentrirali z destilacijo ob uporabi kratke kolone. Ostanek smo porazdelili med kloroform in natrijev bikarbonat in organsko plast sprali z natrijevim kloridom, 0.5 M kalijevim sulfatom in natrijevim kloridom, posušili (Na2SO4), filtrirali in koncentrirali pod znižanim tlakom. Preostanek smo očistili s silikagelno kromatografijo (ΟΗΟΙβ/ΜβΟΗ/ΑοΟΗ : 95/5/1), da smo dobili benzil 2-(1-{6-[2-65(2-metoksikarbonilf enoksi)etilkarbamoil]-1 -metil-1 H-benzoimidazoi-2-il}etil)-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-karboksilat (0.69 g, 66 %) kot steklasto rjavo peno; 1HNMR (300 MHz, DMSO-d6) d ppm: 11.92 (s, 1H), 8.49 (t, 1H, J = 5.0 Hz), 8.02 (s, 1H), 7.69 (d, 1 H, J = 9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1 H, J = 8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1 H, J = 9.9 Hz), 6.99 (t, 1H, J = 8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H, J = 8.8 Hz), 4.30 (br s, 2H),(e) A mixture comprising 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl) ethyl] -3-methyl-3H-benzoimidazole -5-carboxylic acid (0.75 g, 1.6 mmol), DMF (6.5 ml), methyl 2- (2-aminoethoxy) benzoate (0.38 g, 1.6 mmol) and HOBT (0.22 g, 1.6 mmol) were cooled under nitrogen to -40 ° C, treated with EDC (0.32 g, 1.6 mmol) and N, Ndiisopropylethylamine (0.29 ml, 1.6 mmol) and 15 minutes later with additional N, Ndiisopropylethylamine (0.29 ml), allowed to warm to 20 ° C and stirred for 16 hours . The mixture was then cooled to -40 ° C, treated with additional EDC (0.080 g) and N, N-diisopropylethylamine (0.050 ml), stirred for 15 minutes at -40 ° C and 2 hours at 20 ° C and concentrated by distillation using a short column. The residue was partitioned between chloroform and sodium bicarbonate, and the organic layer was washed with sodium chloride, 0.5 M potassium sulfate and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ΟΗΟΙβ / ΜβΟΗ / ΑοΟΗ: 95/5/1) to give benzyl 2- (1- {6- [2-65 (2-methoxycarbonyl-enoxy) ethylcarbamoyl] -1-methyl-1 H-benzoimidazoi-2-yl} ethyl) -1,4,6,7tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (0.69 g, 66%) as a glassy brown foam; 1 H NMR (300 MHz, DMSO-d 6 ) d ppm: 11.92 (s, 1H), 8.49 (t, 1H, J = 5.0 Hz), 8.02 (s, 1H), 7.69 (d, 1 H, J = 9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1 H, J = 8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1 H, J = 9.9 Hz), 6.99 (t, 1H, J = 8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H, J = 8.8 Hz), 4.30 (br s, 2H),
4.20 (t, 2H, J = 5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H), 3.63 (m, 4H), 2.55 (br s, 2H), 1.67 (d, 3H, J = 8.8 Hz).4.20 (t, 2H, J = 5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H), 3.63 (m, 4H), 2.55 (br s, 2H), 1.67 (d, 3H, J = 8.8) Hz).
(f) Raztopino, obsegajočo benzil 2-(1-{6-[2-(2-metoksikarbonilfenoksi)etilkarbamoil]1 -metil-1 H-benzoimidazol-2-il}etil)-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-karboksilat (0.69 g, 1.1 mmol) v THF (2 ml) in vodo (2 ml) smo ohladili na 0°C v atmosferi dušika, obdelali z 2 N litijevim hidroksidom (1.1 ml, 2.2 mmol), pustili segreti na 20°C in mešali 8 ur. Zmes smo potem ohladili na 0°C, obdelali z dodatnim 2 N litijevim hidroksidom (1.1 ml), pustili segreti na 20°C, mešali 6 ur, ohladili na 0°C, naravnali na pH 7 z 1 M klorovodikovo kislino in koncentrirali pod znižanim tlakom. Preostanek smo previdno sprali s hladnim natrijevim kloridom in vodo in potem posušili v vakuumu, da smo dobili 5benziloksikarbonil-2-(2-{3-metil-2-[1-(4,5,6,7-tetrahidro-1/-/-imidazo-[4,5-c]piridin-2-il)etil]3H-benzoimidazol-5-ilkarbonilamino}etoksi)benzojsko kislino (0.56 g, 83 %) kot steklast ostanek; 1H-NMR (300 MHz, DMSO-cfe) d ppm; 11.87 (br 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 (q, 1H, J = 7.7 Hz), 4.32 (s, 2H), 4.19 (m, 2H), 3.84 (s, 3H), 3.64 (m, 4H), 2.55 (s, 2H), 1.71 (d, 3H, J = 7.7 Hz).(f) A solution comprising benzyl 2- (1- {6- [2- (2-methoxycarbonylphenoxy) ethylcarbamoyl] 1-methyl-1H-benzoimidazol-2-yl} ethyl) -1,4,6,7-tetrahydroimidase [4,5-c] pyridine-5-carboxylate (0.69 g, 1.1 mmol) in THF (2 ml) and water (2 ml) were cooled to 0 ° C under a nitrogen atmosphere, treated with 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 2 N lithium hydroxide (1.1 ml), allowed to warm to 20 ° C, stirred for 6 hours, cooled to 0 ° C, adjusted to pH 7 with 1 M 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 5-benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1 / - N-imidazo [4,5-c] pyridin-2-yl) ethyl] 3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.56 g, 83%) as a glassy residue; 1 H-NMR (300 MHz, DMSO-d 6) δ ppm; 11.87 (br 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 (q, 1H, J = 7.7 Hz), 4.32 (s, 2H), 4.19 (m, 2H), 3.84 (s, 3H), 3.64 (m, 4H), 2.55 ( s, 2H), 1.71 (d, 3H, J = 7.7 Hz).
(g) Raztopino, obsegajočo 5-benziloksikarbonil-2-(2-{3-metil-2-[1-(4,5,6,7-tetrahidro1H-imidazo-[4,5-c]piridin-2-il)etil]-3H-benzoimidazol-5-ilkarbonilamino}etoksi)benzojsko kislino (0.561 g, 0.90 mmol) v ledoctu (2 ml) smo segreli v atmosferi dušika v vodni kopeli na 10°C, obdelali z vodikovim bromidom v ocetni kislini (2 ml 30 % raztopine) in pustili, da se je segrela na 20°C in jo eno uro kasneje koncentrirali s tokom dušika. Preostanek smo raztopili v majhni količini etanola in raztopino po kapljicah dodali k premešavanemu etru, da smo dobili bledo rjavo oborino. Oborino smo izolirali s filtracijo in posušili, da smo dobili hidrobromid 2-(2-{3-metil-2-[4,5,6,7-tetrahidro-1 H-imidazo-[4,5-c]piridin-2-il)etil]-3H-66benzoimidazol-5-ilkarbonilamino}etoksi)benzojske kisline (0.651 g); 1H-NMR (300 MHz, DMSO-d6) d 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 = 7.9 Hz), 7.21 (d, 1 H, J = 7.9 Hz), 7.00 (t, 1H, J = 7.9 Hz),(g) A solution comprising 5-benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ) ethyl] -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.561 g, 0.90 mmol) in ice (2 ml) was heated under a nitrogen atmosphere in a water bath to 10 ° C, treated with hydrogen bromide in acetic acid ( 2 ml of 30% solution) and allowed to warm to 20 ° C and concentrated one hour later with a stream of nitrogen. The residue was dissolved in a small amount of ethanol and the solution was added dropwise to the stirred ether to give a pale brown precipitate. The precipitate was isolated by filtration and dried to give 2- (2- {3-methyl-2- [4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-2 hydrobromide -yl) ethyl] -3H-66benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.651 g); 1 H-NMR (300 MHz, DMSO-d 6 ) d 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 = 7.9 Hz), 7.21 (d, 1 H, J = 7.9 Hz), 7.00 (t, 1H, J = 7.9 Hz).
5.21 (q, 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).5.21 (q, 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).
(h) Raztopino, obsegajočo hidrobromid 2-(2-{3-metil-2-[4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il)etil]-3H-benzoimidazol-5-ilkarbonilamino}etoksi)benzojske kisline (0.30 g, 0.46 mmol) v DMF (1.5 ml) smo ohladili v atmosferi dušika na 0°C, obdelali z etil acetimidatom (0.12 g, 0.92 mmol) in Λ/,/V-diizopropiletilaminom (0.25 ml, 1.4 mmol), hladili pri 0°C 30 minut in potem pustili segreti na 20°C in mešali 20 ur. Zmes smo potem ohladili na 0°C, obdelali z dodatnim etil acetimidatom (0.06 g) in Λ/,/V-diizopropiletilaminom (0.16 ml), pustili segreti na 20°C in mešali 2 uri. Zmes smo ohladili na 0°C, obdelali z dodatnim etil acetimidatom (0.03 g), pustili segreti na 20°C in mešali 2 uri. Zmes smo potem po kapljicah dodali k premešavanemu etru, da smo dobili oborino. Oborino smo izolirali z oddekantiranjem topila in posušili v vakuumu. Ostanek smo oborili iz zmesi etanol/eter in očistili s preparativno RP-HPCL: 2 50% MeCN/HgO (20 mM HCI) tekom 50 minut. Frakcije smo liofilizirali, da smo dobili 2-(2-(2-( 1-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1/-/imidazo[4,5-c]piridin-2-il]etil}-3-metil-3H-benzoimidazol-5ilkarbonilamino)etoksi]benzojsko kislino (0.145 g, 52 %); 1H-NMR (300 MHz, DMSO-dg) d ppm: 9.77 (s, 1H), 9.34 (2s, 1H), 8.81 (m, 1H), 8.36 (s, 1H), 7.89 (d, 1H, J = 8.6 Hz), 7.71 (d, 1 H, J = 8.6 Hz), 7.60 (d, 1 H, J = 7.7 Hz), 7.49 (t, 1 H, J = 7.7 Hz), 7.21 (d, 1 H, J = 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, 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) C28H31N7O4 m/e izrač. 529.61, ugot. 530.3 (MH+).(h) A solution comprising hydrobromide 2- (2- {3-methyl-2- [4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] - 3H-Benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.30 g, 0.46 mmol) in DMF (1.5 ml) was cooled under nitrogen to 0 ° C, treated with ethyl acetimidate (0.12 g, 0.92 mmol) and Λ /. N-diisopropylethylamine (0.25 ml, 1.4 mmol) was cooled at 0 ° C for 30 minutes and then allowed to warm to 20 ° C and stirred for 20 hours. The mixture was then cooled to 0 ° C, treated with additional ethyl acetimidate (0.06 g) and N, N-diisopropylethylamine (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 acetimidate (0.03 g), allowed to warm to 20 ° C and stirred for 2 hours. The mixture was then added dropwise to the stirred ether to give a precipitate. The precipitate was isolated by decanting the solvent and dried in vacuo. The residue was precipitated from ethanol / ether and purified by preparative RP-HPCL: 2 50% MeCN / HgO (20 mM HCl) for 50 minutes. The fractions were lyophilized to give 2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H- imidazo [4,5-c] pyridine) -2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ilkarbonilamino) ethoxy] benzoic acid (0.145 g, 52%); 1 H-NMR (300 MHz, DMSO-dg) d ppm: 9.77 (s, 1H ), 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), 7.60 ( d, 1 H, J = 7.7 Hz), 7.49 (t, 1 H, J = 7.7 Hz), 7.21 (d, 1 H, J = 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, 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) C28H31N7O4 m / e calc 529.61, found 530.3 (MH + ).
PRIMER 10EXAMPLE 10
Etil 2-(2-{2-[1 -(4,6,7-trifluoro-1 H-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5karbonilamino}etoksi)benzoat (Spojina 75)Ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazole-5carbonylamino} ethoxy) benzoate (Compound 75)
-67(a) Raztopino, obsegajočo 2,3,4,6-tetrafluoronitrobenzen (0.6 g, 3.1 mmol) in amoniak v dioksanu (Aldrich, 0.5 M, 7.5 mmol) smo mešali pri sobni temperaturi 3 ure, da smo dobili fino belo oborino. Zmes smo razredčili z enakim volumnom vode, da smo raztopili belo oborino in dobili rumene kristale. Kristale smo izolirali, zbrali in posušili, da smo dobili 2,3,5-trifluoro-6-nitroanilin (307 mg, 51 %) kot rumene iglice; tališče 66°C; 1H NMR (CDCI3) δ 6.4 (1 H, m), δ 6.0 (2H, s).-67 (a) A solution comprising 2,3,4,6-tetrafluororonitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5 M, 7.5 mmol) was stirred at room temperature for 3 hours to give a fine white precipitation. The mixture was diluted with an equal volume of water to dissolve the white precipitate to give yellow crystals. The crystals were isolated, collected and dried to give 2,3,5-trifluoro-6-nitroaniline (307 mg, 51%) as yellow needles; melting point 66 ° C; 1 H NMR (CDCl 3 ) δ 6.4 (1 H, m), δ 6.0 (2H, s).
(b) Zmes 2,3,5-trifluoro-6-nitroanilina (300 mg, 1.56 mmol) in 10% paladija na ogljiku v absolutnem etanolu smo hidrogenirali preko noči pri pritisku 1.013 bar, filtrirali v atmosferi dušika in koncentrirali, da smo dobili 1,2-diamino-3,4,6-trifluorobenzen (219 mg, 87 % dobitek) kot vijolično kristalinično trdno snov; MS M+ 162.7, +41, +82 (+ ACN, +2ACN). (izrač. za ΟρΠΥβΥ 162.11).(b) A mixture of 2,3,5-trifluoro-6-nitroaniline (300 mg, 1.56 mmol) and 10% palladium on carbon in absolute ethanol was hydrogenated overnight at a pressure of 1,013 bar, filtered under a nitrogen atmosphere and concentrated to give 1,2-diamino-3,4,6-trifluorobenzene (219 mg, 87% yield) as a violet crystalline solid; MS M + 162.7, +41, +82 (+ ACN, + 2ACN). (calculated for ΟρΠΥβΥ 162.11).
(c) Zmes 1,2-diamino-3,4,6-trifluorobenzena (1.92 g, 11.8 mmol), etil 2etoksikarbonimidoilpropionata (3.1 g, 14.7 mmol) in absolutnega etanola (6 ml) smo segrevali pri temperaturi refluksa dokler TLC ni pokazala, da reakcija več ne poteka, filtrirali iz NH4CI in koncentrirali. Preostanek smo očistili s kromatografijo na silikagelu (heksan : metilen klorid : etil acetat, 5:5:1), da smo dobili etil 2-(4,6,7-trifluoro-1 Hbenzoimidazol-2-il)propionat (1.37 g, 42 %) kot rumeno rjavo kristalinično trdno snov; NMR (CDCI3): δ 10.35 (s, 1/2 H), δ 7.05 (s, 1/2 H), 6.7 (m, 1H), δ 4.25 (dd, 2H), δ 4.15 (dd, 1 H), δ 1.73 (d, 3H), δ 1.31 (t, 3H); M+ 272.9 (izrač. za C12Hi 1F3N2O2:272.23).(c) A mixture of 1,2-diamino-3,4,6-trifluorobenzene (1.92 g, 11.8 mmol), ethyl 2ethoxycarbonimidoylpropionate (3.1 g, 14.7 mmol) and absolute ethanol (6 ml) was heated at reflux until TLC showed , to prevent the reaction from proceeding, filtered from NH4Cl and concentrated. The residue was purified by chromatography on silica gel (hexane: methylene chloride: ethyl acetate, 5: 5: 1) to give ethyl 2- (4,6,7-trifluoro-1 Hbenzoimidazol-2-yl) propionate (1.37 g. 42%) as a yellow-brown crystalline solid; NMR (CDCl3): δ 10.35 (s, 1/2 H), δ 7.05 (s, 1/2 H), 6.7 (m, 1H), δ 4.25 (dd, 2H), δ 4.15 (dd, 1 H) , δ 1.73 (d, 3H), δ 1.31 (t, 3H); M + 272.9 (calcd. For C 12 Hi 1F3N2O2: 272.23).
(d) Etil 2-(4,6,7-trifluoro-1H-benzoimidazol-2-il)propionat (988 mg, 3.63 mmol) in etil 2-[2-(4-amino-3-metilaminobenzoilamino)etoksi]benzoat (1.3 g, 3.63 mmol) smo združili in postavili v vakuum za 4 ure in potem nadalje združili z DMPU (4 ml). Zmes smo mešali, da je nastala raztopina, ki smo jo evakuirali preko noči v visokem vakuumu, da smo odstranili preostale pline, segrevali na 195°C v toku dušika 4 ure, ohladili na sobno temperaturo in porazdelili med etil acetat in vodo. Organsko plast smo ločili in sprali s slanico, posušili preko natrijevega sulfata in koncentrirali. Preostanek smo očistili s kromatografijo na silikagelu (stopenjski gradient od100% heksana do 100% etil acetata) in nadalje očistili s kristalizacijo iz zmesi MeOH/THF/voda, da smo dobili etil 2-(2-{2-[1-68(4,6,7-trifluoro-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5karbonilamino}etoksi)benzoat (1.0 g, 49%) kot belo kristalinično trdno snov:(d) Ethyl 2- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) propionate (988 mg, 3.63 mmol) and ethyl 2- [2- (4-amino-3-methylaminobenzoylamino) ethoxy] benzoate (1.3 g, 3.63 mmol) was combined and vacuumed for 4 hours and then further combined with DMPU (4 ml). The mixture was stirred to form a solution which was evacuated overnight in high vacuum to remove residual gases, heated to 195 ° C under a stream of 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 chromatography on silica gel (gradient gradient from 100% hexane to 100% ethyl acetate) and further purified by crystallization from a mixture of MeOH / THF / water to give ethyl 2- (2- {2- [1-68 (4 , 6,7-Trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carbonylamino} ethoxy) benzoate (1.0 g, 49%) as a white crystalline solid:
NMR (CDCI3): δ 6.84-8.07 (m, 8H), δ 4.93 (dd, 1H), δ 4.34 (dd, 2H), δ 4.27 (m, 2H), δ 3.95 (m, 2H), δ 3.9 (s, 3H), δ 1.93 (d, 3H), δ 1.78 (s, 2H), δ 1.38 (t, 3H); LCMS M+ 566.2 Bioion M+ 565.7 (izrač. za C29H26F3N5O4: 565.55).NMR (CDCI 3 ): δ 6.84-8.07 (m, 8H), δ 4.93 (dd, 1H), δ 4.34 (dd, 2H), δ 4.27 (m, 2H), δ 3.95 (m, 2H), δ 3.9 (s, 3H), δ 1.93 (d, 3H), δ 1.78 (s, 2H), δ 1.38 (t, 3H); LCMS M + 566.2 Bioion M + 565.7 (calcd for C29H26F3N5O4: 565.55).
Po postopku kot v Primeru 10 smo pripravili sledeče spojine izuma:Following the procedure of Example 10, the following compounds of the invention were prepared:
etil 2-(2-{2-[1 -(5,6-difluoro-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 76), MS (Bioion) C29H27N5O4F2 m/e izrač. 547.56; ugot. 548.1 (MH+);ethyl 2- (2- {2- [1- (5,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 76), MS (Bioion) C29H27N5O4F2 m / e calcd. 547.56; found 548.1 (MH < + >);
etil 2-(2-{2-[1 -(4,6-difluoro-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 77), MS (LCMS) C29H27F2N5O4 m/e izrač. 547.56; ugot. 548.3 (MH+);ethyl 2- (2- {2- [1- (4,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 77), MS (LCMS) C29H27F2N5O4 m / e calcd. 547.56; found 548.3 (MH < + >);
etil 2-(2-{2-[1 -(4,5,6-trifl uoro-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 78), MS (LCMS) 029Η26ρ3Ν5θ4 m/e izrač. 565.55; ugot. 566.2 (MH+); in etil 2-{2-[3-metil-2-(4,6,7-trifluoro-1H-benzoimidazol-2-ilmetil)-3H-benzoimidazol-5ilkarbonilamino]etoksi}benzoat (Spojina 79), MS (Bioion) C28H24F3N5O4 m/e izrač. 551.52; ugot. 551.52 (MH+).Ethyl 2- (2- {2- [1- (4,5,6-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 78 ), MS (LCMS) 029 Η 26 ρ 3 Ν 5θ4 m / e calc. 565.55; found 566.2 (MH < + >); and ethyl 2- {2- [3-methyl-2- (4,6,7-trifluoro-1H-benzoimidazol-2-ylmethyl) -3H-benzoimidazol-5ylcarbonylamino] ethoxy} benzoate (Compound 79), MS (Bioion) C28H24F3N5O4 m / e calcd. 551.52; found 551.52 (MH < + >).
PRIMERUEXAMPLE
2-(2-{2-[1 -(4,6,7-T rifluoro-1 /7-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojska kislina (Spojina 80)2- (2- {2- [1- (4,6,7-Trifluoro-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 80)
Zmes, obsegajočo etil 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-karbonilamino}etoksi)benzoat (118 mg, 0.21 mmol), metanol (4 ml) in 2 N natrijev hidroksid (2.1 ml) smo mešali pri sobni temperaturi 4 ure, nevtralizirali z 2NMixture comprising ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carbonylamino} ethoxy) benzoate (118 mg, 0.21 mmol), methanol (4 ml) and 2 N sodium hydroxide (2.1 ml) were stirred at room temperature for 4 hours, neutralized with 2N
-69klorovodikovo kislino (2.1 ml) in porazdelili med etil acetat in nasičen amonijev klorid. Vodno plast smo ločili in ekstrahirali z etil acetatom (3 X). Združene organske plasti smo sprali s slanico, posušili preko natrijevega sulfata in koncentrirali do bele trdne snovi. Ostanek smo raztopili v toplem etanolu (10 ml) in 4 M raztopini vodikovega klorida in dioksana. Raztopino smo razredčili z etil etrom, da smo dobili oborino. Oborino smo izolirali in posušili, da smo dobili 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-il)etil]-3metil-3H-benzoimidazol-5-ilkarbonilamino}etoksi)benzojsko kislino kot belo trdno snov; MS (LCMS) C27H22F3N5O4 m/e izrač. 537.50; ugot. 538.4 (MH+).-69 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 X). 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 a 4 M solution of hydrogen chloride and dioxane. The solution was diluted with ethyl ether to give a precipitate. The precipitate was isolated and dried to give 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid as a white solid; MS (LCMS) C27H22F3N5O4 m / e calcd. 537.50; found 538.4 (MH < + >).
Po postopku kot v Primeru 11 smo pripravili sledeče spojine izuma:Following the procedure as in Example 11, the following compounds of the invention were prepared:
2-(2-{2-[1 -(5,6-difluoro-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 81), MS (LCMS) C27H23N5O4F2 m/e izrač. 519.51; ugot. 520.2 (MH+);2- (2- {2- [1- (5,6-Difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 81), MS (LCMS) C27H23N5O4F2 m / e calcd. 519.51; found 520.2 (MH + );
2-(2-{2-[1-(4,6-difluoro-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 82), MS (LCMS) C27H23F2N5O4 m/e izrač. 519.51; ugot. 520.2 (MH+); in2- (2- {2- [1- (4,6-Difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 82), MS ( LCMS) C27H23F2N5O4 m / e calcd. 519.51; found 520.2 (MH + ); and
2-(2-{2-[1-(4,5,6-trifluoro-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5karbonilamino}etoksi)benzojsko kislino (Spojina 83), MS (Biolon) C27H22F3N5O4 m/e izrač. 537.5; ugot. 537.7 (MH+).2- (2- {2- [1- (4,5,6-Trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carbonylamino} ethoxy) benzoic acid (Compound 83). MS (Biolon) C27H22F3N5O4 m / e calcd. 537.5; found 537.7 (MH < + >).
PRIMER 12EXAMPLE 12
Etil 2-(2-{2-[1 -(1 -izobutiril-5-metoksikarboniloksi-1 /7-benzoimidazol-2-il)etil]-3-metil-3/7benzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 84)Ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate ( Compound 84)
Zmes, obsegajočo etil 2-(2-{2-[1-(1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3Wbenzoimidazol-5-karbonilamino}etoksi)benzoat (0.50 g, 0.95 mmol), dimetilformamid (5 ml), cezijev karbonat (0.93 g, 2.85 mmol) in izobutirični anhidrid (0.17 ml, 1.05 mmol) smo mešali 2 uri, potem razredčili z diklorometanom (50 ml) in spustili skozi plast celita. TopilaMixture comprising ethyl 2- (2- {2- [1- (1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3Wbenzoimidazole-5-carbonylamino} ethoxy) benzoate (0.50 g , 0.95 mmol), dimethylformamide (5 ml), cesium carbonate (0.93 g, 2.85 mmol) and isobutyric anhydride (0.17 ml, 1.05 mmol) were stirred for 2 hours, then diluted with dichloromethane (50 ml) and passed through a pad of celite.
-70smo odstranili v vakuumu in preostanek raztopili v diklorometanu (5 ml). Raztopino smo združili z diizopropiletilaminom (0.47 ml, 2.7 mmol) in metil kloroformatom (0.1 ml, 1.3 mmol) in zmes mešali 1 uro. Topila smo odstranili v vakuumu in preostanek očistili s silikagelno kromatografijo ob uporabi etanola in diklorometana kot eluent, da smo dobili etil 2-(2-{2-[1 -(1 -izobutiril-5-metoksikarboniloksi-1 H-benzoimidazol-2-il)etil]-3-metil-3/-/benzoimidazol-5-ilkarbonilamino}etoksi)benzoat (0.20 g, 32 % dobitek) kot brezbarvno amorfno trdno snov; MS (Biolon) 0351437^03 m/e izrač. 655.72; ugot. 656.1 (MH+).-70 was removed in vacuo and the residue dissolved in dichloromethane (5 ml). The solution was combined with diisopropylethylamine (0.47 ml, 2.7 mmol) and methyl chloroformate (0.1 ml, 1.3 mmol) and the mixture stirred for 1 hour. The solvents were removed in vacuo and the residue purified by silica gel chromatography using ethanol and dichloromethane as eluent to give ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazole-2- yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (0.20 g, 32% yield) as a colorless amorphous solid; MS (Biolon) 0351437 ^ 03 m / e calcd. 655.72; found 656.1 (MH < + >).
Po postopku kot v Primeru 12 smo pripravili sledeče derivate predzdravil izuma:Following the procedure as in Example 12, the following derivatives of the prodrugs of the invention were prepared:
metil 2-(1 -{6-[2-(2-etoksikarbonilfenoksi)etilkarbamoil]-1 -metil-1 H-benzoimidazol-2-il}etil)5-hidroksibenzoimidazol-1-karboksilat (Spojina 85), MS (ESI) C31H31N5O7 m/e izrač. 585.62; ugot. 586.2 (MH+);methyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) 5-hydroxybenzoimidazole-1-carboxylate (Compound 85), MS (ESI ) C31H31N5O7 m / e calcd. 585.62; found 586.2 (MH < + >);
etil 2-(1 -{6-[2-(2-etoksikarbonilfenoksi)etilkarbamoil]-1 -metil-1 /4-benzoimidazol-2-il}etil)-5metoksikarboniloksibenzoimidazol-1-karboksilat (Spojina 86), MS (ESI) C33H33N5O7 m/e izrač. 643.66; ugot. 644.2 (MH+);ethyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1/4-benzoimidazol-2-yl} ethyl) -5methoxycarbonyloxybenzoimidazole-1-carboxylate (Compound 86), MS (ESI ) C33H33N5O7 m / e calcd. 643.66; found 644.2 (MH < + >);
etil 2-(2-{2-[1 -(5-hidroksi-1 -izobutiril-1 H-benzoimidazol-2-il)etil]-3-metil-3/4-benzoimidazol5-ilkarbonilamino}etoksi)benzoat (Spojina 87), MS (ESI) C33H35N5O6 m/e izrač. 597.68; ugot. 598.2 (MH+);Ethyl 2- (2- {2- [1- (5-hydroxy-1-isobutyryl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/4-benzoimidazol5-ylcarbonylamino} ethoxy) benzoate (Compound 87), MS (ESI) C33H35N5O6 m / e calcd. 597.68; found 598.2 (MH < + >);
etil 2-(2-{2-[1 -(1 -benzoil-5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol5-ilkarbonilamino}etoksi)benzoat (Spojina 88), MS (ESI) C35H33N5O6 m/e izrač. 631.69; ugot. 632.3 (MH+);Ethyl 2- (2- {2- [1- (1-benzoyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoate (Compound 88) , MS (ESI) C35H33N5O6 m / e calcd. 631.69; found 632.3 (MH < + >);
etil 2-(2-{ 2-[1 -(1 -dimetilkarbamoil-5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 89), MS (ESI) C32H34N5O5 m/e izrač. 598.66; ugot. 599.3 (MH+);Ethyl 2- (2- {2- [1- (1-dimethylcarbamoyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 89) , MS (ESI) C32H34N5O5 m / e calcd. 598.66; found 599.3 (MH < + >);
-71etil 2-(2-{2-[1 -(1 -acetoksimetil-5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 90), MS (Biolon) C32H33N5O7 m/e izrač. 599.65; ugot. 600.7 (MH+);-71ethyl 2- (2- {2- [1- (1-acetoxymethyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 90 ), MS (Biolon) C32H33N5O7 m / e calcd. 599.65; found 600.7 (MH < + >);
etil 2-[2-(2-{ 1 -[1 -(2,2-dimetilpropioniloksimetil)-5-hidroksi-1 H-benzoimidazol-2-il]etil}-3metil-3H-benzoimidazol-5-ilkarbonilamino)etoksi]benzoat (Spojina 91), MS (ESI) C35H39N5°7 m/e izrač. 641.74; ugot. 642.3 (MH+);ethyl 2- [2- (2- {1- [1- (2,2-dimethylpropionyloxymethyl) -5-hydroxy-1H-benzoimidazol-2-yl] ethyl} -3methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy ] benzoate (Compound 91), MS (ESI) C 35 H 39 N 5 ° 7 m / e calc. 641.74; found 642.3 (MH < + >);
etil 2-(2-{2-[1 -(1 -izobutiril-5-metoksikarboniloksi-1 H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 92), MS (Biolon) C35H37N5O8 m/e izrač. 655.72; ugot. 656.1 (MH+);Ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 92) , MS (Biolon) C35H37N5O8 m / e calcd. 655.72; found 656.1 (MH < + >);
etil 5-etoksikarboniloksi-2-(1 -{6-[2-(2-etoksikarbonilfenoksi)etilkarbamoil]-1 -metil-1 Hbenzoimidazol-2-il}etil)benzoimidazol-1 -karboksilat (Spojina 93), MS (ESI) C35H37N5O9 m/e izrač. 671.72; ugot. 672.4 (MH+);ethyl 5-ethoxycarbonyloxy-2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) benzoimidazole-1-carboxylate (Compound 93), MS (ESI ) C35H37N5O9 m / e calcd. 671.72; found 672.4 (MH < + >);
izopropil 2-(1 -{6-[2-(2-etoksikarbonilfenoksi)etilkarbamoil]-1 -metil-1 /-/-benzoimidazol-2il}etil)-5-izopropoksikarboniloksi-benzoimidazol-1-karboksilat (Spojina 94), MS (ESI) C37H41N5O9 m/e izrač. 699.79; ugot. 700.4 (MH+); in etil 2-(2-{2-[1 -(1 -acetil-5-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 95), MS (ESI) C31H31N5O5 m/e izrač. 569.62; ugot. 570.1 (MH+).isopropyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2yl} ethyl) -5-isopropoxycarbonyloxy-benzoimidazole-1-carboxylate (Compound 94). MS (ESI) C37H41N5O9 m / e calcd. 699.79; found 700.4 (MH < + >); and ethyl 2- (2- {2- [1- (1-acetyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 95 ), MS (ESI) C31H31N5O5 m / e calcd. 569.62; found 570.1 (MH < + >).
Po postopku kot je opisan v tej prijavi ali po metodah, ki so običajnim strokovnjakom poznane, smo pripravili sledeče dodatne spojine izuma:The following additional compounds of the invention have been prepared by the method described in this application or by methods known to one of ordinary skill in the art:
C-[2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-3H-benzoimidazol-5-il]metilamin (Spojina 96);C- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3H-benzoimidazol-5-yl] methylamine (Compound 96);
C-[2-(1 B-nafto[2,3-c/|imidazol-2-ilmetil)-1 H-benzoimidazol-5-il]metilamin (Spojina 97), MS (Biolon) C20H17N5 m/e izrač. 327.4; ugot. 328.1 (MH+);C- [2- (1B-naphtho [2,3-c] imidazol-2-ylmethyl) -1H-benzoimidazol-5-yl] methylamine (Compound 97), MS (Biolon) C20H17N5 m / e calc. 327.4; found 328.1 (MH < + >);
-72C-[2-(5-metil-1 H-benzoimidazol-2-ilmetil)-1 H-benzoimidazol-5-il]metilamin (Spojina 98), MS (Biolon) C17H17N5 m/e izrač. 291.4; ugot. 292.3 (MH+);-72C- [2- (5-methyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-yl] methylamine (Compound 98), MS (Biolon) C17H17N5 m / e calc. 291.4; found 292.3 (MH < + >);
2- (5-aminometil-1 H-benzoimidazol-2-ilmetil)-1 H-benzoimidazol-5-karboksilno kislino (Spojina 99),2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazole-5-carboxylic acid (Compound 99),
3- [2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-1H-benzoimidazol-5ilkarbonilaminojpropionsko kislino (Spojina 100),1H-NMR (300 MHz, CD3OD): 1.92 (m, 2H, J = 7.2 Hz), 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, 1 H, J = 10.0 Hz), 7.81 (S, 1H), 7.87 (d, 1H, J = 8.6 Hz), 8.12 (s, 1H);3- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5ylcarbonylamino} propionic acid (Compound 100), 1 H-NMR (300 MHz, CD 3 OD): 1.92 (m, 2H, J = 7.2 Hz), 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, 1 H, J = 10.0 Hz), 7.81 (S, 1H), 7.87 (d, 1H, J = 8.6 Hz), 8.12 (s, 1H);
2-(5-aminometil-1 H-benzoimidazol-2-ilmetil)-/\/-(2-naft-1 -ileti I )-1 H-benzoimidazol-5karboksamid (Spojina 101), 1H-NMR (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, 1 H, J = 10.0 Hz);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) - N - (2-naphth-1-ylethI) -1H-benzoimidazole-5carboxamide (Compound 101), 1 H-NMR (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-aminometil-1H-benzoimidazol-2-ilmetil)-3-metil-N-(2-naft-1 -iletil)-3H-benzoimidazol-5karboksamid (Spojina 102), 1H-NMR (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, 1H, J=8.7 Hz), 7.717.77 (m, 2H), 7.80-7.85 (m, 2H), 8.70 (d, 1H, J=0.9 Hz), 8.24 (d, 1H, J = 8.1 Hz);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5carboxamide (Compound 102), 1 H-NMR (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, 1H, J = 8.7 Hz), 7.717.77 (m, 2H), 7.80-7.85 (m, 2H), 8.70 (d, 1H, J = 0.9 Hz), 8.24 (d, 1H, J = 8.1 Hz);
2- (5-aminometil-1H-benzoimidazol-2-ilmetil)-3-metil-A/-(2-naft-1-iletil)-3/-/-benzoimidazol-4karboksamid (Spojina 103), 1H-NMR (300 MHz, CD3OD): 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, 1 H, J=8.1 Hz);2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-A / - (2-naphth-1-ylethyl) -3 / - / - benzoimidazol-4karboksamid (Compound 103) 1 H-NMR (300 MHz, CD3OD): 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)-1H-benzoimidazol-5-ilkarbonilamino]3- indol-3-ilpropionsko kislino (Spojina 104), 1H-NMR (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, 3H), 4.27 (s, 2H), 6.97 (t, 1H, J =(S) -2- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-ylcarbonylamino] 3-indol-3-ylpropionic acid (Compound 104), 1 H-NMR (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, 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 = 8.4,7.4 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).
-731.5 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, deloma zamenjan);-731.5 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 replaced);
(fl)-2-[2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-1 H-benzoimidazol-5-ilkarbonilamino]3-indol-3-ilpropionsko kislino (Spojina 105), 1H-NMR (300 MHz, 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 =(R) -2- [2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -1 H-benzoimidazol-5-ylcarbonylamino] -3-indol-3-ylpropionic acid (Compound 105) 1 H-NMR ( 300 MHz, 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, deloma zamenjan);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 replaced);
2-(1 H-benzoimidazol-2-ilmetil)-N-(2-naft-1 -iletil)-1 H-benzoimidazol-5-karboksamid (Spojina 106), 1H-NMR (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, 1H, J=8.7 Hz), 7.72-7.79 (m, 4H), 7.85 (dd, 1 H, J=8.6,1.5 Hz), 8.04 (d, 1 H, J = 1.2 Hz), 8.26 (d, 1 H, J=8.4 Hz);2- (1 H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -1H-benzoimidazol-5-carboxamide (Compound 106) 1 H-NMR (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, 1H, J = 8.7 Hz) , 7.72-7.79 (m, 4H), 7.85 (dd, 1 H, J = 8.6,1.5 Hz), 8.04 (d, 1 H, J = 1.2 Hz), 8.26 (d, 1 H, J = 8.4 Hz) ;
2-(5-aminometil-1H-benzoimidazol-2-ilmetil)-3-metil-/\/-(4-aminobutil)-3H-benzoimidazol-4karboksamid (Spojina 107), MS (Biolon) C22H27N7O1 m/e izrač. 405.4; ugot. 406.5 (MH+);2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (4-aminobutyl) -3H-benzoimidazole-4carboxamide (Compound 107), MS (Biolon) C22H27N7O1 m / e calc. 405.4; found 406.5 (MH + );
2-[1 -(5-aminometil-1 H-benzoimidazol-2-il)etil]-3-metil-/V-(2-naft-1 -iletil)-3/7-benzoimidazol5-karboksamid (Spojina 108), MS (Biolon) C31H30N6O1 m/e izrač. 502.6; ugot. 503.3 (MH+);2- [1- (5-Aminomethyl-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - (2-naphth-1-ethyl) -3 / 7-benzoimidazole5-carboxamide (Compound 108) , MS (Biolon) C31H30N6O1 m / e calcd. 502.6; found 503.3 (MH < + >);
2-(1H-imidazo[4,5-c]piridin-2-ilmetil)-3-metil-/V-(2-naft-1-iletil)-3H-benzoimidazol-5karboksamid (Spojina 109), MS (Biolon) C28H24NgO-| m/e izrač. 460.5; ugot. 461.3 (MH+);2- (1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5carboxamide (Compound 109), MS (Biolon ) C28H24NgO- | m / e calcd. 460.5; found 461.3 (MH < + >);
2-(5-aminometil-1H-benzoimidazol-2-ilkarbonil)-3-metil-/V-(2-naft-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 110), MS (Biolon) θ3θΗ26^6θ2 m/e izrač. 502.6; ugot. 503.6 (MH+);2- (5-Aminomethyl-1H-benzoimidazol-2-ylcarbonyl) -3-methyl- N - (2-naphth-1-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 110), MS (Biolon) θ3θΗ26 ^ 6θ2 m / e calcd. 502.6; found 503.6 (MH < + >);
2-(5-karbamoil-1 H-benzoimidazol-2-ilmetil)-/V-(2-naft-1 -i letil)-1 H-benzoimidazol-5karboksamid (Spojina 111);2- (5-Carbamoyl-1H-benzoimidazol-2-ylmethyl) - N - (2-naphth-1-ylethyl) -1H-benzoimidazole-5carboxamide (Compound 111);
-742-(5-aminometil-4,5,6,7-tetrahidro-1 B-benzoimidazol-2-ilmetil)-3-metil-/V-(2-naft-1-iletil)3B-benzoimidazol-5-karboksamid (Spojina 112), 1H-NMR (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);-742- (5-Aminomethyl-4,5,6,7-tetrahydro-1 B-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) 3B-benzoimidazol-5- carboxamide (Compound 112), 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 = 6.9 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-aminometil-1 B-benzoimidazoi-2-ilmetil)-3-metil-N-(3-fenilpropil)-3B-benzoimidazol-5karboksamid (Spojina 113), 1H-NMR (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=1H);2- (5-Aminomethyl-1 B-benzoimidazo-2-ylmethyl) -3-methyl-N- (3-phenylpropyl) -3B-benzoimidazole-5carboxamide (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 = 7.2 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 = 1H);
2-(5-aminometil-1B-benzoimidazol-2-ilmetil)-3-metil-/\/-(2-fenoksietil)-3B-benzoimidazol-5karboksamid (Spojina 114), 1H-NMR (300 MHz, CD3OD): 3.80 (t, 2H, J=5.0 Hz), 3.99 (s, 3H), 4.17 (t, 2H, J=5.0 Hz), 4.27 (s, 2H), 6.88 (t, 1H, J=7.5 Hz), 6.92 (d, 2H, J=7.5 Hz),2- (5-aminomethyl-1B-benzoimidazol-2-ylmethyl) -3-methyl - / \ / - (2-phenoxyethyl) -3B-benzoimidazol-5karboksamid (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 = 5.0 Hz), 4.27 (s, 2H), 6.88 (t, 1H, J = 7.5 Hz) , 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, 1 H);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-1B-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-/V-(2-naft-1iletil)-3B-benzoimidazol-5-karboksamid (Spojina 115), 1H-NMR (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),2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1B-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2-napht- 1iletil) -3B-benzoimidazole-5-carboxamide (compound 115) 1 H-NMR (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);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 B-imidazo[4,5-c]piridin-2-ilkarbonil]-3-metil-/V-(2-naft1-iletil)-3B-benzoimidazol-5-karboksamid (Spojina 116), 1H-NMR (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), 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- (1-iminoethyl) -4,5,6,7-tetrahydro-1 B-imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl- N - (2-naphthyl) -ylethyl) -3B-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);
-752-(5-iminometil-4,5,6,7-tetrahidro-1/-/-imidazo[4,5-c]piridin-2-ilmetil)-3-metil-A/-(2-naft-1iletil)-3H-benzoimidazol-5-karboksamid (Spojina 117), 1 H-NMR (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, 1 H, J=8.4 Hz);-752- (5-iminomethyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-napht- 1iletil) -3H-benzoimidazole-5-carboxamide (compound 117) 1 H-NMR (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-aminometil-4,5,6,7-tetrahidro-1H-benzoimidazol-2-ilkarbonil)-3-metil-/V-(2-naft-1iletil)-3H-benzoimidazol-5-karboksamid (Spojina 118), 1 H-NMR (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),2- (5-Aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylcarbonyl) -3-methyl- N - (2-naphthylethyl) -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=6.1,3.44 (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);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-1 H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-A/-(2fenoksietil)-3/7-benzoimidazol-5-karboksamid (Spojina 119),1 H-NMR (300 MHz, CD3OD):2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-phenoxyethyl) - 3/7-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, 1 H, J=7.8 Hz), 7.85 (d, 1 H, J=7.8 Hz), 8.13 (s, 1 H);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, 1 H, J = 7.8 Hz), 7.85 (d, 1 H, J = 7.8 Hz), 8.13 (s, 1 H);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-N-(2benzo[1,3]dioksol-4-iletil)-3/-/-benzoimidazol-5-karboksamid (Spojina 120), 1 H-NMR (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),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), 6.65-6.74 (m, 3H), 7.64 (d, 1H, J=7.8 Hz), 7.76-7.79 (m, 1H), 8.06 (m, 1 H);3.98 (m, 2H), 4.71 (4.81, s, 2H), 5.83 (s, 2H), 6.65-6.74 (m, 3H), 7.64 (d, 1H, J = 7.8 Hz), 7.76-7.79 (m. 1H), 8.06 (m, 1H);
2-[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 /7-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-/\/-(benzoimidazol-1-iletil)-3H-benzoimidazol-5-karboksamid (Spojina 121), 1 H-NMR (300 MHz, CD3OD): 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),2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (benzoimidazole -1-ylethyl) -3H-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, 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-tetrahidro-1 H-imidazo[4,5c]piridin-2-ilmetil]-3-metil-3H-benzoimidazol-5-karboksamid (Spojina 122), 1 H-NMR (300N- [2- (5-hydroxy-1H-indol-2-yl) ethyl] -2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4 , 5c] Pyridin-2-ylmethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 122), 1 H-NMR (300
-76MHz, 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);-76MHz, 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-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-A/-[2-(2klorofenoksi)etil]-3H-benzoimidazol-5-karboksamid (Spojina 123), MS (Biolon) C26h28N7O2CI m/e izrač. 506.0; ugot. 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] -3H-benzoimidazole-5-carboxamide (Compound 123), MS (Biolon) C26 h 28 N7 O 2 CI m / e calc 506.0; found 506.3 (MH + );
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetii]-3-metil-A/-[2-(3klorofenoksi)etil]-3H-benzoimidazol-5-karboksamid (Spojina 124), MS (Biolon) C26H28N7O2CI m/e izrač. 506.0; ugot. 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] -3H-benzoimidazole-5-carboxamide (Compound 124), MS (Biolon) C26H28N7O2CI m / e calc 506.0; found 506.7 (MH + );
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-/\/-(2-naft-1 iletil)-3H-benzoimidazol-5-karboksamid (Spojina 125), 1H-NMR (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, deloma zamenjan), 7.45-7.95 (m, 9H), 8.02 (m, deloma zamenjan), 8.17 (d, 1H, J=8.1 Hz), 8.96 (s, deloma zamenjan);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2- naphth-1 ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 125), 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 replaced), 7.45-7.95 (m, 9H), 8.02 (m, partially replaced ), 8.17 (d, 1H, J = 8.1 Hz), 8.96 (s, partially replaced);
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-/V-(2hidroksi-2-naft-1-iletil)-3H-benzoimidazol-5-karboksamid (Spojina 126), 1H-NMR (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=8.4 Hz);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2hydroxy-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 = 8.4 Hz);
2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-/V-[2-(2hidroksinaft-1-il)etil]-3H-benzoimidazol-5-karboksamid (Spojina 127),1H-NMR (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, 1 H), 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- (2hydroxynaphthyl) -1-yl) ethyl] -3H-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, 7.6 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);
-ΊΊ2-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 /7-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-/V-(2-(4hidroksinaftal-1-il)etil]-3H-benzoimidazol-5-karboksamid (Spojina 128),1H-NMR (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, 1 H, 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, 1 H, J=8.4 Hz), 8.17 (d, 1H, J = 8.4 Hz);-2- (5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2 - (4hydroxynaphthal-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, 1 H, 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, 1 H, J = 8.4 Hz), 8.17 (d, 1H, J = 8.4). Hz);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-A/-[2-(2metoksifenoksi)etil]-3/7-benzoimidazol-5-karboksamid (Spojina 129)?H-NMR (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-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (2methoxyphenoxy) ethyl] -3-7-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-1/7-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-/\/-naft-2ilmetil-3/7-benzoimidazol-5-karboksamid (Spojina 130)?H-NMR (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, 1 H);2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N-naphthyl- 2ylmethyl-3/7-benzoimidazole-5-carboxamide (Compound 130)? H-NMR (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 -iminoetil)-4,5,6I7-tetrahidro-1/7-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-/V-(3-pirid-4ilpropil)-3/7-benzoimidazol-5-karboksamid (Spojina 131)?H-NMR (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 I 7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (3- Pyrid-4ylpropyl) -3 / 7-benzoimidazole-5-carboxamide (Compound 131)? H-NMR (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-gvanidino-1 /7-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-/V-(2-naft-1 -iletil)- 3/7benzoimidazol-5-karboksamid (Spojina 132), MS (Biolon) ¢32^2^03 m/e izrač. 576.6; ugot. 577.5 (MH+); 1H-NMR (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-1/7-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3-7benzoimidazole-5-carboxamide ( Compound 132), MS (Biolon) ¢ 32 ^ 2 ^ 03 m / e calcd. 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);
-782-(5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metii-A/-[2-(4metoksifenoksi)etil]-3W-benzoimidazol-5-karboksamid (Spojina 133)?H-NMR (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, 1 H, J=8.4 Hz), 7.84 (m, 1 H), 8.13 (d, 1 H, J=1.2 Hz);-782- (5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- ( 4methoxyphenoxy) ethyl] -3W-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, 1 H, J = 8.4 Hz), 7.84 (m, 1 H), 8.13 (d, 1 H, J = 1.2 Hz);
2-(5-gvanidino-1H-benzoimidazol-2-ilkarbonil)-3-(2,3-dihidrok$i)propil-/V-(2-naft-1-iletil)3H-benzoimidazol-5-karboksamid (Spojina 134), MS (Biolon) C32H30N7O4 m/e izrač. 590.6; ugot. 590.7 (MH+); 1H-NMR (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), 7.61-7.65 (m, 2H), 7.72-7.86 (m, 4H), 8.05 (d, 1H, J=1.2 Hz), 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) 3H-benzoimidazole-5-carboxamide (Compound 134), MS (Biolon) C32H30N7O4 m / e calcd. 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), 7.61-7.65 (m, 2H), 7.72-7.86 (m, 4H). 8.05 (d, 1H, J = 1.2 Hz), 8.25 (d, 1H, J = 8.1 Hz);
2-[5-(1-irninoetil)-4,5,6,7-tetrahidro-1/-/-imidazo[4,5-c]piridin-2-ilmetil]-3-metil-A/-[2(1,2,3,4-tetrahidronaft-1 -il)etil]-3H-benzoimidazol-5-karboksamid (Spojina 135)? H-NMR (300 MHz, CD3OD): 1.69-2.11 (m, 6H), 2.45 (2.43, s, 3H), 2.73 (m, 2H), 2.88 (m, 1H),2- [5- (1-yninoethyl) -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] -3H-benzoimidazole-5-carboxamide (Compound 135)? H-NMR (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), 7.82-7.86 (m, 1H), 8.14 (d, 1H, J=0.9 Hz);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), 7.82-7.86 (m, 1H), 8.14 (d, 1H, J = 0.9 Hz);
2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo(4,5-c]piridin-2-iimetil]-3-metil-N-(2-(3metoksifenoksi)etil]-3H-benzoimidazol-5-karboksamid (Spojina 136)?H-NMR (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, 1 H, J=8.0 Hz), 7.66 (d, 1 H, J=8.4 Hz), 7.83 (m, 1 H), 8.12 (m, 1 H, 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- (3methoxyphenoxy) ethyl] -3H-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, 1 H, J = 8.0 Hz), 7.66 (d, 1 H, J = 8.4 Hz), 7.83 (m, 1 H), 8.12 (m, 1 H, J = 1.2 Hz) ;
2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-N-(3-fenilpropil)-1H-benzoimidazol-5karboksamid (Spojina 137);2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1H-benzoimidazole-5carboxamide (Compound 137);
2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-(3-hidroksi)propil-N-(2-naft-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 138), 1H-NMR (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=7.12- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphth-1-ylethyl) -3Hbenzoimidazol-5-carboxamide (Compound 138), 1 H- NMR (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
-79Ηζ), 7.32 (dd, 1Η, 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=8.1 Hz);-79Ηζ), 7.32 (dd, 1Η, 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 = 8.1 Hz);
2-(5-gvanidino-1/7-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-/\/-[2-(2metoksi)fenoksietil]-3H-benzoimidazol-5-karboksamid (Spojina 139), MS (Biolon) C29H32N8O5 m/e izrač. 572.62; ugot. 573.3 (MH+); 1H-NMR (300 MHz, CD3OD): 3.583.69 (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), 8.24 (d, 1H, J=1.5 Hz);2- (5-guanidino-1/7-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - [2- (2methoxy) phenoxyethyl] -3H-benzoimidazole-5-carboxamide ( Compound 139), MS (Biolon) C29H32N8O5 m / e calcd. 572.62; found 573.3 (MH < + >); 1 H-NMR (300 MHz, CD 3 OD): 3.583.69 (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), 8.24 (d , 1H, J = 1.5 Hz);
2-[1 -(5-gvanidino-1 /7-benzoimidazol-2-il)etil]-3-(2,3-dih idroksipropil)-A/-(2-naft-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 140), MS (Biolon) C33H34N8O3 m/e izrač. 590.7; ugot. 591.3(MH+);2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-ethyl) -3H-benzoimidazol-5 -carboxamide (Compound 140), MS (Biolon) C33H34N8O3 m / e calcd. 590.7; found 591.3 (MH < + >);
2-(5-gvanidino-1/-/-benzoimidazol-2-i|karbonil)-3-(2,3-dihidroksipropil)-/\/-[2-(2metoksifenoksi)etil]-3H-benzoimidazol-5-karboksamid (Spojina 141), MS (Biolon) C29H30N8O6 m/e izrač. 586.6; ugot. 587.5 (MH+); 1H-NMR (300 MHz, CD3OD): 3.33 (m, 1H), 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),2- (5-guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxypropyl) - N - [2- (2methoxyphenoxy) ethyl] -3H-benzoimidazole-5- carboxamide (Compound 141), MS (Biolon) C29H30N8O6 m / e calcd. 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 = 5.4 Hz), 4.38 (t, 1H, J = 12.0 Hz),
4.57 (dd, 1H, J=12.0, 3.5 Hz), 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, 1 H, 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);4.57 (dd, 1H, J = 12.0, 3.5 Hz), 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-1H-benzoimidazol-2-ilmetil]-3-(2,3-dihidroksi)propil-/\/-[2-(2metoksi)fenoksietil]-3H-benzoimidazol-5-karboksamid (Spojina 142),1H-NMR (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 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=1.4Hz);2- (5- (1-iminoethyl) aminomethyl-1H-benzoimidazol-2-ylmethyl] -3- (2,3-dihydroxy) propyl- N - [2- (2methoxy) phenoxyethyl] -3H-benzoimidazol-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, 8.7 Hz), 4.62-4.66 (m, 3H), 6.86-7.00 (m, 4H), 7.53 (dd, 1H, J = 8.7,1.2 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);
-80metil 2-{2-[2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-metil-3H-benzoimidazol-5ilkarbonilamino]etoksi}benzoat (Spojina 143), MS (Biolon) 02δΗ28Ν8θ4 m/e izrač. 540.56; ugot. 541.4 (MH+);-80methyl 2- {2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-3H-benzoimidazol-5ylcarbonylamino] ethoxy} benzoate (Compound 143), MS (Biolon) 02δΗ28 Ν 8θ4 m / e calc. 540.56; found 541.4 (MH < + >);
2-{2-[2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-metil-3H-benzoimidazol-5ilkarbonilamino]etoksi}benzojsko kislino (Spojina 144);2- {2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-3H-benzoimidazol-5ylcarbonylamino] ethoxy} benzoic acid (Compound 144);
metil S-^-p-jS-gvanidino-IH-benzoimidazol^-ilmetiO-S-metil-SH-benzoimidazol-Silkarbonilamino]etoksi}benzoat (Spojina 145), MS (Biolon) 02δΗ28Ν8θ4 m/e izrač. 540.5; ugot. 541.4 (MH+);methyl S - N - [beta] -S-guanidino-1H-benzoimidazol-4-ylmethyl-S-methyl-SH-benzoimidazole-Silcarbonylamino] ethoxy} benzoate (Compound 145), MS (Biolon) 02δΝ28 Ν 8θ4 m / e calc. 540.5; found 541.4 (MH < + >);
2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-metil-A/-[2-(2,6-dimetoksi)fenoksietil]-3Hbenzoimidazol-5-karboksamid (Spojina 146), 1H-NMR (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);2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-A / - [2- (2,6-dimethoxy) phenoxyethyl] -3Hbenzoimidazol-5-carboxamide (Compound 146) 1 H-NMR (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);
2-(5-gvanidinometil-1H-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-/\/-[2-(2metoksifenoksi)etil]-3H-benzoimidazol-5-karboksamid (Spojina 147), 1H-NMR (300 MHz, CD3OD): 3.57-3.69 (m, 2H), 3.80 (m, 5H), 4.05 (m, 1H), 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), 7.76 (d, 1H, J=8.7 Hz), 7.82 (dd, 1H, J=8.5,2- (5-guanidinomethyl-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - [2- (2methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 147 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 = 5.4 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), 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);1.4 Hz), 8.19 (d, 1H, J = 1.4 Hz);
2-(5-iminometilaminometil-1H-benzoimidazol-2-ilmetil)-3-(2,3-dihidroksi)propil-A/-[2-(2metoksi)fenoksietil]-3H-benzoimidazol-5-karboksamid (Spojina 148), 1H-NMR (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, 3.0 Hz), 4.69 (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-iminomethylaminomethyl-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2methoxy) phenoxyethyl] -3H-benzoimidazole-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 (4.69 (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);
-812-(5-gvanidino-1W-benzoimidazol-2-ilmetil)-3-metil-/V-(2-hidroksi-2-kinol-4-iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 149), 1H-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, 1 H), 8.11-8.18 (m, 2H), 8.26 (d, 1H, J=8.4 Hz), 8.33 (d, 1H, J=5.7 Hz), 8.88 (d, 1 H, J=8.7 Hz), 8.15 (d, 1H, J=5.7 Hz);-812- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- / V- (2-hydroxy-2-quinol-4-ylethyl) -3Hbenzoimidazol-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 = 5.7 Hz) , 8.88 (d, 1H, J = 8.7 Hz), 8.15 (d, 1H, J = 5.7 Hz);
2-(5-gvanidino-1H-benzoimidazol-2-ilmetil)-3-metil-/\/-[2-(3-metil-2,4-dioksokinazolin-1il)etil]-3/-/-benzoimidazol-5-karboksamid (Spojina 150), MS (Biolon) C29H28N10O3 m/e izrač. 564.6; ugot. 565.5 (MH+);2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2- (3-methyl-2,4-dioxoquinazolin-1yl) ethyl] -3 H -benzoimidazole- 5-carboxamide (Compound 150), MS (Biolon) C29H28N10O3 m / e calcd. 564.6; found 565.5 (MH < + >);
metil 2-{2-[2-(5-gvanidino-1/7-benzoimidazol-2-ilkarbonil)-3-metil-3W-benzoimidazol-5ilkarbonilamino]etoksi}benzoat (Spojina 151), MS (Biolon) C29H26N8O5 m/e izrač. 554.5; ugot. 554.8 (MH+);methyl 2- {2- [2- (5-guanidino-1/7-benzoimidazol-2-ylcarbonyl) -3-methyl-3W-benzoimidazol-5ylcarbonylamino] ethoxy} benzoate (Compound 151), MS (Biolon) C29H26N8O5 m / is calcd. 554.5; found 554.8 (MH < + >);
2-(5-gvanidino-1 H-benzoimidazol-2-ilmetil)-3-(2-hidroksi)etil-A/-(2-naft-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 152), 1H-NMR (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-naphth-1-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 152), 1 H-NMR (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-gvanidino-1H-benzoimidazol-2-ilmetil)-3-metil-N-[2-(3-okso-2,3dihidrobenzo[1,4]oksazin-4-il)etil]-3H-benzoimidazol-5-karboksamid (Spojina 153);2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4-yl) ethyl] -3H-benzoimidazole -5-carboxamide (Compound 153);
2-(5-gvanidino-1H-benzoimidazol-2-ilkarbonil)-3-(2-hidroksietil)-/V-(2-naft-2-iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 154), 1H-NMR (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), 7.387.52 (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) - / V- (2-naphth-2-ylethyl) -3Hbenzoimidazol-5-carboxamide (Compound 154), 1 H- NMR (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), 7.387.52 (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-gvanidino-1H-benzoimidazol-2-ilkarbonil)-3-metil-A/-(2-naft-1 -iletil)-3H-benzoimidazol5-karboksamid (Spojina 155);2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-N- (2-naphth-1-ethyl) -3H-benzoimidazole 5-carboxamide (Compound 155);
-822-(5-gvanidino-1H-benzoimidazol-2-ilkarbonil)-3-(3-hidroksipropil)-/V-(2-naft-1-iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 156);-822- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (3-hydroxypropyl) - N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 156);
2-(5-imidazol-1-il-1H-benzoimidazol-2-ilmetil)-3-metil-/\/-(2-naft-1-iletil)-3H-benzoimidazol5-karboksamid (Spojina 157);2- (5-imidazol-1-yl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole5-carboxamide (Compound 157);
2-[1 -(5-gvanidino-1 /-/-benzoimidazol-2-il)etil] -3-meti l-/\A(2-naft-1 -iletil)-3H-benzoimidazol5-karboksamid (Spojina 158), MS (Biolon) C31H30N8O-1 nri/e izrač. 530.6; ugot. 531.1 (MH+);2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-1 H (2-naphth-1-ethyl) -3H-benzoimidazole 5-carboxamide (Compound 158 ), MS (Biolon) C31H30N8O-1 nri / e calcd. 530.6; found 531.1 (MH < + >);
2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-/\/-(2-naft-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 159), MS (Biolon) C33H29N7O1 m/e izrač. 539.6; ugot. 540.1 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide ( Compound 159), MS (Biolon) C33H29N7O1 m / e calcd. 539.6; found 540.1 (MH < + >);
2-{1 -[5-(2-aminoimidazol-1 -il)-1 H-benzoimidazol-2-il]etil}-3-metil-/V-(2-naft-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 160), MS (Biolon) C33H30N8O1 m/e izrač. 554.7; ugot. 555.2 (MH+);2- {1- [5- (2-aminoimidazol-1-yl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazol-5 -carboxamide (Compound 160), MS (Biolon) C33H30N8O1 m / e calcd. 554.7; found 555.2 (MH < + >);
-(5-gvanidino-1 H-benzoimidazol-2-il)-3-hidroksi-1 -metil-/V-(2-naft-1 -iletil)-3,4-di hid ro-1 H2-oksa-4a,9-diazafluoren-6-karboksamid (Spojina 161);- (5-guanidino-1H-benzoimidazol-2-yl) -3-hydroxy-1-methyl- N - (2-naphth-1-ethyl) -3,4-dihydro-1 H2-oxa- 4a, 9-diazafluoren-6-carboxamide (Compound 161);
2- [1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-3-(4-hidroksibutil)-/V-(2-naft-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 162), MS (Biolon) C34H35N8O2 m/e izrač. 588.7; ugot. 589.3 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (4-hydroxybutyl) - N - (2-naphth-1-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 162), MS (Biolon) C34H35N8O2 m / e calcd. 588.7; found 589.3 (MH < + >);
3- [2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-6-(2-naft-1 -iletilkarbamoil)benzoimidazol1-il]propan-1-sulfonsko kislino (Spojina 163), MS (Biolon) C33H34N8O4S m/e izrač. 638.7; ugot. 639.2 (MH+);3- [2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -6- (2-naphth-1-ylethylcarbamoyl) benzoimidazol-1-yl] propane-1-sulfonic acid (Compound 163) , MS (Biolon) C33H34N8O4S m / e calcd. 638.7; found 639.2 (MH < + >);
-833-(2-(1 -(5-imidazol-1 -il-1 /7-benzoimidazol-2-il)etil]-6-(2-naft-1 iletilkarbamoil)benzoimidazol-1-il]propan-1-sulfonsko kislino (Spojina 164), MS (Bioion) C35H33N7O4S m/e izrač. 647.8; ugot. 648.2 (MH+);-833- (2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -6- (2-naphth-1-ylethylcarbamoyl) benzoimidazol-1-yl] propan-1 -sulfonic acid (Compound 164), MS (Bioion) C35H33N7O4S m / e calc 647.8; found 648.2 (MH + );
2-(1 -(5-gvanidino-1 H-benzoimidazol-2-il)-2-metilpropil]-3-metil-A/-(2-naft-1 -iletil)-3 Hbenzoimidazol-5-karboksamid (Spojina 165), MS (Bioion) C33H34N8O1 m/e izrač. 558.7; ugot. 559.6 (MH+);2- (1- (5-guanidino-1H-benzoimidazol-2-yl) -2-methylpropyl] -3-methyl-N- (2-naphth-1-ethyl) -3 Hbenzoimidazole-5-carboxamide (Compound 165), MS (Bioion) C33H34N8O1 m / e calc 558.7; found 559.6 (MH + );
2-[1 -(1 B-im idazo[4,5-c]pi ridin -2-il)eti l]-3-metil-A/-(2-n aft-1 -iletil)-3H-benzoimidazol-5karboksamid (Spojina 166), MS (Bioion) C29H26N6O1 m/e izrač. 474.6; ugot. 475.2 (MH+);2- [1- (1B-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ethyl) -3H-benzoimidazole -5carboxamide (Compound 166), MS (Bioion) C29H26N6O1 m / e calcd. 474.6; found 475.2 (MH < + >);
2-(5-(1 -(A/-metilimino)etil]-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-ilmetil}-3-metil-/V(2-naft-1-iletil)-3/-/-benzoimidazol-5-karboksamid (Spojina 167), MS (Bioion) C31H33N7O m/e izrač. 519.71; ugot. 520.9 (MH+);2- (5- (1- (N-Methylimino) ethyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl} -3-methyl- / V (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 167), MS (Bioion) C31H33N7O m / e calc 519.71; found 520.9 (MH + );
imino(2-( 1 -(1 -metil-6-(2-naft-1 -iletilkarbamoil)-1 H-benzoimidazol-2-il]etil}-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-il)ocetno kislino (Spojina 168), MS (Bioion) C31H31N7O3 m/e izrač. 549.6; ugot. 550.2 (MH+);imino (2- (1- (1-methyl-6- (2-naphth-1-ylethylcarbamoyl) -1H-benzoimidazol-2-yl] ethyl} -1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-yl) acetic acid (Compound 168), MS (Bioion) C31H31N7O3 m / e calc 549.6; found 550.2 (MH + );
2-(1-(5-(1-iminoetil)-4)5,6,7-tetrahidro-1B-imidazo[4,5-c]piridin-2-il]etil}-3-metil-/\/-(2-naft1- iletil)-3H-benzoimidazol-5-karboksamid (Spojina 169), MS (Bioion) C31H33N7O1 m/e izrač. 519.6; ugot. 520.3 (MH+);2- (1- (5- (1-iminoethyl) -4 ) 5,6,7-tetrahydro-1B-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- - (2-naphthyl-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 169), MS (Bioion) C31H33N7O1 m / e calc 519.6; found 520.3 (MH + );
2- (1-[5-(/V-metilamidino)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}-3-metil-/V-(2naft-1-iletil)-3B-benzoimidazol-5-karboksamid (Spojina 170), MS (Bioion) C31H34N8O1 m/e izrač. 534.7; ugot. 535.1 (MH+);2- (1- [5 - (N-methylamidino) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- / V - (2naphth-1-ylethyl) -3B-benzoimidazole-5-carboxamide (Compound 170), MS (Bioion) C31H34N8O1 m / e calc 534.7; found 535.1 (MH + );
2-(2-(2-(1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)-5-metoksibenzojsko kislino (Spojina 171), MS (Bioion) C29H30N8O5 m/e izrač. 570.6; ugot. 571.2 (MH+);2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) -5-methoxybenzoic acid (Compound 171), MS (Bioion) C29H30N8O5 m / e calc 570.6; found 571.2 (MH + );
-842-(2-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)izoftalno kislino (Spojina 172), MS (Biolon) C29H30N8O5 m/e izrač. 570.6; ugot. 571.3 (MH+);-842- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) isophthalic acid (Compound 172), MS (Biolon ) C29H30N8O5 m / e calcd. 570.6; found 571.3 (MH < + >);
2-(2-{2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)-1 -hidroksietil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)-6-metoksibenzojsko kislino (Spojina 173), MS (Biolon) ^29^30^806 m/e izrač. 586.6; ugot. 587.2 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) -1-hydroxyethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) -6-methoxybenzoic acid (Compound 173), MS (Biolon) ^ 29 ^ 30 ^ 806 m / e calcd. 586.6; found 587.2 (MH < + >);
etil 2-[2-(2-{1 -[5-(/V-acetilgvanidino)-1 H-benzoimidazol-2-il]etil}-3-metil-3/7-benzoimidazol5-ilkarbonilamino)etoksi]benzoat (Spojina 174), MS (Biolon) C31H32N8O5 m/e izrač. 596.6; ugot. 597.2 (MH+);ethyl 2- [2- (2- {1- [5- (N-acetylguanidino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3/7-benzoimidazol5-ylcarbonylamino) ethoxy] benzoate ( Compound 174), MS (Biolon) C31H32N8O5 m / e calcd. 596.6; found 597.2 (MH < + >);
2-{1-[5-(A/,N-dimetilamidino)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}-3-metilA/-(2-naft-1 -iletil)-3H-benzoimidazol-5-karboksamid (Spojina 175);2- {1- [5- (N, N-dimethylamidino) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methylA / - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 175);
2-{1 -[5-(2-amino-1,1 -dimetiletil)-1 H-benzoimidazol-2-il]etil}-3-metil-/V-(2-naft-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 176);2- {1- [5- (2-Amino-1,1-dimethylethyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole -5-carboxamide (Compound 176);
2-{1-[5-(1-iminoetil)-4l5,6,7-tetrahidro-1/-/-imidazo[4,5-c]piridin-2-il]etil}-A/-etil-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 177);2- {1- [5- (1-iminoethyl) -4 l 5,6,7-tetrahydro-1 / - / - imidazo [4,5-c] pyridin-2-yl] ethyl} -N / ethyl -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 177);
2-[2-(2-{1-[5-(/V-acetilgvanidino)-1H-benzoimidazol-2-il]etil}-3-metil-3/7-benzoimidazol-5ilkarbonilamino)etoksi]benzojsko kislino (Spojina 178), MS (Biolon) C30H30N8O5 m/e izrač. 582.6; ugot. 583.3 (MH+);2- [2- (2- {1- [5 - (N-acetylguanidino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3/7-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 178), MS (Biolon) C30H30N8O5 m / e calcd. 582.6; found 583.3 (MH < + >);
2-[2-(2-{ 1 -[5-(1 -aminociklopropil)-1 H-benzoimidazol-2-il]etil}-3-metil-3H-benzoimidazol-5ilkarbonilamino)etoksi]benzojsko kislino (Spojina 179), MS (Biolon) θ3οΗ3οΝθθ4 m/e izrač. 538.6; ugot. 539.3 (MH+);2- [2- (2- {1- [5- (1-Aminocyclopropyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 179) , MS (Biolon) θ3οΗ3οΝθθ4 m / e calcd. 538.6; found 539.3 (MH < + >);
2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-/\/-(3-metilbutil)-3H-benzoimidazol5-karboksamid (Spojina 180), MS (Biolon) C26H29N7O1 m/e izrač. 455.6; ugot. 456.2 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (3-methylbutyl) -3H-benzoimidazole5-carboxamide (Compound 180). MS (Biolon) C26H29N7O1 m / e calcd. 455.6; found 456.2 (MH < + >);
-852-(1/7-benzoimidazol-2-iletil)-3-metil-/\/-(2-fenoksietil)-3/-/-benzoimidazol-5-karboksamid (Spojina 181), MS (Biolon) C26H25N5O2 m/e izrač. 439.5; ugot. 440.2 (MH+);-852- (1/7-Benzoimidazol-2-ylethyl) -3-methyl - N - (2-phenoxyethyl) -3 H - benzoimidazole-5-carboxamide (Compound 181), MS (Biolon) C26H25N5O2 m / e calc. 439.5; found 440.2 (MH < + >);
etil 2-[2-(2-{1 -[5-(1-iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil}-3-metil3H-benzoimidazol-5-ilkarbonilamino)etoksi]benzoat (Spojina 182);ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate (Compound 182);
2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2,4-diokso-3,4-dihidro-2/-/kinazolin-1 -il)etil]-3H-benzoimidazol-5-karboksamid (Spojina 183);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2,4-dioxo-3,4-dihydro-2 H -quinazoline- 1-yl) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 183);
2-{1 -[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 /7-imidazo[4,5-c]piridin-2-il]etil}-Λ/-(3metoksipropil)-3-metil-3H-benzoimidazol-5-karboksamid (Spojina 184);2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl} -1 H- (3methoxypropyl) ) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 184);
/\/-etil-2-[1 -(5-imidazol-1 -il-1 /-/-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5karboksamid (Spojina 185), MS (Biolon) 023Η23Ν7θ1 'zra^· 413.5; ugot. 414.1 (MH+);N-ethyl-2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carboxamide (Compound 185), MS ( Biolon) 023 Η 23 Ν 7θ1 ' zra ^ · 413.5; found 414.1 (MH < + >);
2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-A/-(2-metoksietil)-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 186), MS (Biolon) C24H25N7O2 m/e izrač. 443.5; ugot. 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) C24H25N7O2 m / e calcd. 443.5; found 444.2 (MH < + >);
-(2-[l -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino)-4-metilpentanojsko kislino (Spojina 187), MS (Biolon) C27H29N7O3 m/e izrač. 499.6; ugot. 500.3 (MH+);- (2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino) -4-methylpentanoic acid (Compound 187); MS (Biolon) C27H29N7O3 m / e calcd. 499.6; found 500.3 (MH < + >);
2-(2-{2-[1 -(5-imidazol-1 -il-1 /7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 188), MS (Biolon) C30H27N7O4 m/e izrač. 549.6; ugot. 550.2 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid ( Compound 188), MS (Biolon) C30H27N7O4 m / e calcd. 549.6; found 550.2 (MH < + >);
2-(2-{ 1 -[5-( 1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil} -3-metil-3Hbenzoimidazol-5-ilkarbonilamino)-4-metilpentanojsko kislino (Spojina 189);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) -4-methylpentanoic acid (Compound 189);
-862-{1-[5-(A/,/V-dimetilamidino)-4I5,6l7-tetrahidro-1H-imidazo[4,5-c]piriclin-2-il]etil}-3-metil3H-benzoimidazol-5-ilkarbonilamino)etoksi]benzojsko kislino (Spojina 190), MS (Biolon) C39H34N8O4 m/e izrač. 558.6; ugot. 559.3 (MH+);-862- {1- [5- (A /, / V-dimetilamidino) -4 I 5.6 l of 7-tetrahydro-1H-imidazo [4,5-c] piriclin-2-yl] ethyl} -3- methyl3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 190), MS (Biolon) C39H34N8O4 m / e calcd. 558.6; found 559.3 (MH < + >);
2- [2-(2-{1 -[5-(2-karboksi-1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil}3- metil-3/7-benzoimidazol-5-ilkarbonilamino)etoksi]benzojsko kislino (Spojina 191), MS (Biolon) C29H31 ΝχΟθ m/e izrač. 573.6; ugot. 530.3 (MH+), izguba CO2;2- [2- (2- {1- [5- (2-carboxy-1-iminoethyl) -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 191), MS (Biolon) C29H31 ΝχΟθ m / e calcd. 573.6; found 530.3 (MH + ), loss of CO2;
2-(2-{2-[1 -(5-imidazol-1 -il-1 /-/-benzoimidazol-2-il)etil]-3-(2-metoksietil)-3H-benzoimidazol5-ilkarbonilamino}etoksi)benzojsko kislino (Spojina 192), MS (Biolon) C32H31N7O5 m/e izrač. 593.6; ugot. 594.2 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoic acid (Compound 192), MS (Biolon) C32H31N7O5 m / e calcd. 593.6; found 594.2 (MH < + >);
2-[ 1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-(2-metoksietil)-A/-(2-metoksietil)-3Hbenzoimidazol-5-karboksamid (Spojina 193), MS (Biolon) C26H29N7O3 m/e izrač. 487.6; ugot. 488.2 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -N- (2-methoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 193), MS (Biolon) C26H29N7O3 m / e calcd. 487.6; found 488.2 (MH < + >);
2- [2-(2-{1 -[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil }-3-(2metoksietil)-3H-benzoimidazol-5-ilkarbonilamino)etoksi]benzojsko kislino (Spojina 194);2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 3- (2methoxyethyl) -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 194);
3- (2-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 195), MS (Biolon) 028Η28Ν8θ4 m/e izrač. 540.6; ugot. 541.3 (MH+);3- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 195), MS (Biolon) 028Η28 Ν 8θ4 m / e calc. 540.6; found 541.3 (MH < + >);
2-(2-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-(2-metoksietil)-3/-/-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 196), MS (Biolon) C30H32N8O5 m/e izrač. 584.6; ugot. 585.3 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoic acid (Compound 196), MS (Biolon) C30H32N8O5 m / e calcd. 584.6; found 585.3 (MH < + >);
2-(2-{2-[1-(5-gvanidino-1/7-benzoimidazol-2-il)etil]-3-(3-sulfopropil)-3W-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 197), MS (Biolon) C30H32N8O7S m/e izrač. 648.7; ugot. 649.6 (MH+);2- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3W-benzoimidazole-5ylcarbonylamino} ethoxy) benzoic acid (Compound 197 ), MS (Biolon) C30H32N8O7S m / e calcd. 648.7; found 649.6 (MH < + >);
-872-(2-{2-[1 -(5-imidazol-1 -il-1 /7-benzoimidazol-2-il)etil]-3-(3-sulfopropil)-3H-benzoimidazol5-ilkarbonilamino}etoksi)benzojsko kislino (Spojina 198), MS (Biolon) C32H31N7O7S m/e izrač. 657.7; ugot. 658.4 (MH+);-872- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoic acid (Compound 198), MS (Biolon) C32H31N7O7S m / e calcd. 657.7; found 658.4 (MH < + >);
2-(2-{2-[1 -(5-imidazol-1-il-3-metil-3H-benzoimidazol-2-il)etil]-3-metil-3/+benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 199), MS (Biolon) C31H29N7O4 m/e izrač. 563.6; ugot. 564.2 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-3-methyl-3H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H + benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 199), MS (Biolon) C31H29N7O4 m / e calcd. 563.6; found 564.2 (MH < + >);
2-(2-{2-[1 -(5-imidazol-1 -il-3H-benzoimidazol-2-il)etilj-3-(2-hidroksipropil)-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzojsko kislino (Spojina 200), MS (Biolon) C32H31N7O5 m/e izrač. 593.6; ugot. 594.3 (MH+);2- (2- {2- [1- (5-imidazol-1-yl-3H-benzoimidazol-2-yl) ethyl-3- (2-hydroxypropyl) -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 200), MS (Biolon) C32H31N7O5 m / e calcd. 593.6; found 594.3 (MH < + >);
2- {2-[2-(1 -{5-[1-(/V-hidroksiimino)etil]-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il}etil)3- metil-3H-benzoimidazol-5-ilkarbonilamino]etoksi}benzojsko kislino (Spojina 201);2- {2- [2- (1- {5- [1- (N-hydroxyimino) ethyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2 -yl} ethyl) 3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy} benzoic acid (Compound 201);
etil 2-(2-{2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 202), MS (Biolon) θ30Η32Νδθ4 m/e izrač. 568.6; ugot. 569.5 (MH+);Ethyl 2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 202), MS (Biolon ) θ30 Η 32Νδθ4 m / e calc. 568.6; found 569.5 (MH < + >);
etil 2-[2-(2-{1 -[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil} -1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-ilkarbonilamino)etoksi]benzoat (Spojina 203), MS (Biolon) 028^36^804 m/θ izrač. 549.0; ugot. 548.2 (MH+);ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (Compound 203), MS (Biolon) 028? 36? 804 m / θ calc. 549.0; found 548.2 (MH < + >);
etil 4-{2-[1 -(5-gvanidino-1 /-/-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}butirat (Spojina 204), MS (Biolon) C25H30N8O3 m/e izrač. 490.57; ugot. 491.3 (MH+);ethyl 4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} butyrate (Compound 204), MS (Biolon) C25H30N8O3 m / e calc. 490.57; found 491.3 (MH < + >);
2-[ 1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-tetrazol-1 -ilfenoksi)eti l]-3Hbenzoimidazol-5-karboksamid (Spojina 205), MS (Biolon) 02βΗ28Νΐ2θ2 m/θ 'zra^. 564.56; ugot. 565.3 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-tetrazol-1-ylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 205), MS (Biolon) 02βΗ28 Ν ΐ2θ2 m / θ ' zra ^. 564.56; found 565.3 (MH < + >);
-882-[2-(2-{1 -[5-(1 -iminoetilamino)-1 W-benzoimidazol-2-il]etil}-3-metil-3H-benzoimidazol-5ilkarbonilamino)etoksi]benzojsko kislino (Spojina 206), MS (Biolon) C31H33N7O4 m/e izrač. 567.6; ugot. 568.4 (MH+);-882- [2- (2- {1- [5- (1-Iminoethylamino) -1W-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 206 ), MS (Biolon) C31H33N7O4 m / e calcd. 567.6; found 568.4 (MH < + >);
etil 4-(2-{2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 207), MS (Biolon) C30H32N8O4 m/e izrač. 568.6; ugot. 569.4 (MH+);ethyl 4- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 207), MS (Biolon ) C30H32N8O4 m / e calcd. 568.6; found 569.4 (MH < + >);
5-(2-{2-[1-(5-gvanidino-1W-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)izoftalno kislino (Spojina 208), MS (Biolon) C29H28N8O6 m/e izrač. 584.6; ugot. 585.3 (MH+);5- (2- {2- [1- (5-guanidino-1W-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) isophthalic acid (Compound 208), MS (Biolon) C29H28N8O6 m / e calcd. 584.6; found 585.3 (MH < + >);
4- (2-{2-[1 -(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 209), MS (Biolon) 02δΗ28Ν8θ4 m/e izrač. 540.6; ugot. 541.2 (MH+);4- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 209), MS (Biolon) 02δΗ28 Ν 8θ4 m / e calc. 540.6; found 541.2 (MH < + >);
2-(2-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-(2-hidroksipropil)-3H-benzoimidazol5- ilkarbonilamino}etoksi)benzojsko kislino (Spojina 210), MS (Biolon) C30H32N8O5 m/e izrač. 584.6; ugot. 585.4 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2-hydroxypropyl) -3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoic acid (Compound 210). MS (Biolon) C30H32N8O5 m / e calcd. 584.6; found 585.4 (MH < + >);
2-[1-(5-imidazol-1 -il-1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-metoksifenoksi)etil]-3Wbenzoimidazol-5-karboksamid (Spojina 211), MS (Biolon) C30H29N7O2 m/e izrač. 535.6; ugot. 536.3 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-methoxyphenoxy) ethyl] -3Wbenzoimidazole-5-carboxamide (Compound 211), MS (Biolon) C30H29N7O2 m / e calcd. 535.6; found 536.3 (MH < + >);
2-(2-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 212), MS (Biolon) C27H26N8O4 m/e izrač. 526.6; ugot. 527.2 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 212), MS (Biolon) C27H26N8O4 m / e calcd. 526.6; found 527.2 (MH < + >);
2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-/V-(2-fenoksietil)-3Hbenzoimidazol-5-karboksamid (Spojina 213), MS (Biolon) C29H27N7O2 m/e izrač. 505.6; ugot. 506.2 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - (2-phenoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 213), MS (Biolon) C29H27N7O2 m / e calcd. 505.6; found 506.2 (MH < + >);
-892-(2-(2-(1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-1 B-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 214), MS (Biolon) C29H25N7O4 m/e izrač. 535.6; ugot. 536.4 (MH+);-892- (2- (2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1B-benzoimidazole-5ylcarbonylamino} ethoxy) benzoic acid (Compound 214), MS (Biolon) C29H25N7O4 m / e calc 535.6; found 536.4 (MH + );
etil 2-(2-(2-(1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)-4-metilbenzoat (Spojina 215), MS (Biolon) C31H34N8O4 m/e izrač. 582.7; ugot. 583.5 (MH+);ethyl 2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) -4-methylbenzoate (Compound 215). MS (Biolon) C31H34N8O4 m / e calc 582.7; found 583.5 (MH + );
2-(2-(2-(1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-benzoimidazol-5ilkarbonilamino}etoksi)-4-metilbenzojsko kislino (Spojina 216), MS (Biolon) C29H30N8O4 m/e izrač. 554.6; ugot. 555.5 (MH+);2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-benzoimidazole-5ylcarbonylamino} ethoxy) -4-methylbenzoic acid (Compound 216), MS (Biolon ) C29H30N8O4 m / e calc 554.6; found 555.5 (MH + );
2-(2-(2-(1 -[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil}-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-ilkarbonilamino)etoksi]benzoat (Spojina 217), MS (ESI) C26H32N8O4 m/e izrač. 520.58; ugot. 521.3 (MH+);2- (2- (2- (1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (Compound 217), MS (ESI) C26H32N8O4 m / e calc 520.58; found 521.3 (MH + );
etil 2-(2-(2-[5-(/V-metilamidino)-1H-benzoimidazol-2-ilmetil]-3-metil-3/-/-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 218), MS (Biolon) C30H31N7O4 m/e izrač. 553.6; ugot. 554.3 (MH+);Ethyl 2- (2- (2- [5 - (N-methylamidino) -1H-benzoimidazol-2-ylmethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 218), MS (Biolon) C30H31N7O4 m / e calc 553.6; found 554.3 (MH + );
2-(2-(2-(1 -(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil}-3-(3sulfopropii)-3B-benzoimidazol-5-ilkarbonilamino)etoksi]benzojsko kislino (Spojina 219), MS (Biolon) C30H35N7O7 m/e izrač. 637.7; ugot. 638.3 (MH+);2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 3- (3sulfopropyl) -3B-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 219), MS (Biolon) C30H35N7O7 m / e calc 637.7; found 638.3 (MH + );
etil 2-(2-(1-(5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 H-imidazo[4,5-c]piridin-2-il]etil}-3-metil-3Wbenzoimidazol-5-ilkarbonilamino)-4-metilvalerat (Spojina 220);ethyl 2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3- methyl-3Wbenzoimidazol-5-ylcarbonylamino) -4-methylvalerate (Compound 220);
etil 2-(2-(2-(1-(5-(1 -(A/-hidroksiimino)etil]-4,5,6,7-tetrahidro-1 B-imidazo(4,5-c]piridin-2il}etil)-3-metil-3W-benzoimidazol-5-ilkarbonilamino]etoksi}benzoat (Spojina 221);ethyl 2- (2- (2- (1- (5- (1- (N-hydroxyimino) ethyl) -4,5,6,7-tetrahydro-1 B-imidazo (4,5-c] pyridine) 2yl} ethyl) -3-methyl-3W-benzoimidazol-5-ylcarbonylamino] ethoxy} benzoate (Compound 221);
-902-[1 -(1 H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-metoksifenoksi)etil]-3H-benzoimidazol-5karboksamid (Spojina 222), MS (Biolon) C27H27N5O3 m/e izrač. 469.5; ugot. 469.5 (MH+);-902- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5carboxamide (Compound 222), MS (Biolon ) C27H27N5O3 m / e calcd. 469.5; found 469.5 (MH < + >);
2-(2-etoksikarbonilfenoksi)etil 2-[ 1 -(6-gvanidino-1 H-benzoimidazol-2-il)etil]-1,4,6,7tetrahidroimidazo[4,5-c]piridin-5-karboksilat (Spojina 223), MS (Biolon) C2sH32N805 m/e izrač. 560.62; ugot. 561.3 (MH+);2- (2-ethoxycarbonylphenoxy) ethyl 2- [1- (6-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7tetrahydroimidazo [4,5-c] pyridine-5-carboxylate ( Compound 223), MS (Biolon) C 2 H 32 N 8 O 5 m / e calcd. 560.62; found 561.3 (MH < + >);
4- {2-[1 -(5-gvanidino-1/-/-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilaminojbutirično kislino (Spojina 224), MS (Biolon) C23H26N8O3 m/e izrač. 462.52; ugot. 462.8 (MH+);4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylaminobutyric acid (Compound 224), MS (Biolon) C23H26N8O3 m / e calcd. 462.52; found 462.8 (MH < + >);
2-{1 -[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1 /7-imidazo[4,5-c]piridin-2-il]etil }-3-metil-A/-[2-(2tetrazolilfenoksi)etil]-3/-/-benzoimidazol-5-karboksamid (Spojina 225), MS (ESI) ^28^31 N1-(02 m/e izrač. 553.6; ugot. 553.5 (MH+);2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-A N - [2- (2-Tetrazolylphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 225), MS (ESI) N 28 N 31 N 1 - (02 m / e calc. 553.6; found 553.5 (MH + );
izopropil 2-(2-{2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-3W-benzoimidazol5- ilkarbonilamino}etoksi)benzoat (Spojina 226), MS (Biolon) C33H33N7O4 m/e izrač. 591.3; ugot. 591.4 (MH+);Isopropyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol5-ylcarbonylamino} ethoxy) 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-1 H-imidazo[4,5-c]piridin-2-il]etil}-3-metil-/V-[2-(3tetrazolilfenoksi)etil]-3H-benzoimidazol-5-karboksamid (Spojina 227), MS (Biolon) C28H31N -j 1O2 m/e izrač. 553.59; ugot. 553.5 (MH+);2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- / V - [2- (3tetrazolylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 227), MS (Biolon) C28H31N-j 10 O 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-(4tetrazolilfenoksi)etil]-3H-benzoimidazol-5-karboksamid (Spojina 228), MS (ESI) θ28Η31Ν11θ2 m/e izrač. 553.59; ugot. 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- (4tetrazolylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 228), MS (ESI) θ28 Η 31 Ν 11θ2 m / e calc. 553.59; found 553.5 (MH < + >);
cikloheksil 2-(2-{2-[1 -(5-imidazol-1 -il)-1 H-benzoimidazol-2-il]etil}-3-metil-3Hbenzoimidazol-5-ilkarbonilamino)etoksibenzoat (Spojina 229), MS (ESI) C36H37N7O4 m/e izrač. 631.3; ugot. 631.5 (MH+);cyclohexyl 2- (2- {2- [1- (5-imidazol-1-yl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxybenzoate (Compound 229). MS (ESI) C36H37N7O4 m / e calcd. 631.3; found 631.5 (MH < + >);
-912-[2-(2-{1 -[5-(/V-metilamidino)-1 /-/-benzoimidazol-2-il]etil}-3-metil-3H-benzoimidazol-5ilkarbonilamino)etoksi]benzojsko kislino (Spojina 230), MS (Biolon) 028Η27Ν7θ4 m/e izrač. 525.6; ugot. 525.5 (MH+);-912- [2- (2- {1- [5 - ((N-methylamidino) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 230), MS (Biolon) 028 Η 27 Ν 7θ4 m / e calcd. 525.6; found 525.5 (MH + );
2-[2-(2-{1 -[5-(1 -iminoetilamino)-1 H-benzoimidazol-2-il]etil}-3-metil-3H-benzoimidazol-5ilkarbonilamino)etoksi]benzojsko kislino (Spojina 231), MS (Biolon) C29H29N7O4 m/e izrač. 539.6; ugot. 539.8 (MH+);2- [2- (2- {1- [5- (1-Iminoethylamino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 231) , MS (Biolon) C29H29N7O4 m / e calcd. 539.6; found 539.8 (MH < + >);
2-(3-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin5-ilkarbonil}propoksi)benzojsko kislino (Spojina 232), MS (Biolon) C27H3qNqO4 m/e izrač. 530.60; ugot. 531.7 (MH+);2- (3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin5-ylcarbonyl} propoxy) benzoic acid (Compound 232), MS (Biolon) C27H3qNqO4 m / e calcd. 530.60; found 531.7 (MH < + >);
2-(2-{2-[1 -(5-gvanidino-1 A7-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin5-ilformiloksi}etoksi)benzojsko kislino (Spojina 233), MS (Biolon) 02θΗ28Ν8θ5 m/θ izrač. 532.56; ugot. 533.2 (MH+);2- (2- {2- [1- (5-guanidino-1? 7-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin5-ylformyloxy} ethoxy) benzoic acid (Compound 233), MS (Biolon) 02θΗ28 Ν 8θ5 m / θ calc. 532.56; found 533.2 (MH < + >);
2-metoksietil 2-(2-{2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 234), MS (Biolon) C33H33N7O5 m/e izrač. 607.3; ugot. 607.4 (MH+);2-Methoxyethyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 234), MS (Biolon) C33H33N7O5 m / e calcd. 607.3; found 607.4 (MH < + >);
izobutil 2-(2-{2-[1 -(5-imidazol-1 -il-1 /-/-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 235), MS (Biolon) C34H35N7O4 m/e izrač. 605.3; ugot. 605.4 (MH+);Isobutyl 2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 235), MS (Biolon) C34H35N7O4 m / e calcd. 605.3; found 605.4 (MH < + >);
2-(2-metoksietoksi)etil 2-(2-{2-[1 -(5-imidazol-1 -il-1 /-/-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 236), MS (Biolon) C35H37N7O6 m/e izrač. 651.3; ugot. 651.3 (MH+);2- (2-methoxyethoxy) ethyl 2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5- ylcarbonylamino} ethoxy) benzoate (Compound 236), MS (Biolon) C35H37N7O6 m / e calcd. 651.3; found 651.3 (MH < + >);
butil 2-(2-{2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-3/-/-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 237), MS (Biolon) C34H35N7O4 m/e izrač. 605.3; ugot. 605.4 (MH+);butyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate ( Compound 237), MS (Biolon) C34H35N7O4 m / e calcd. 605.3; found 605.4 (MH < + >);
-922-[1 -(1 H-benzoimidazol-2-il)etil]-3-metil-A/-[2-(3-okso-2,3-dihidrobenzo[1,4]oksazin-4il)etil]-3H-benzoimidazol-5-karboksamid (Spojina 238), MS (Biolon) 02δΗ26Ν6θ3 m^e izrač. 494.2; ugot. 494.5 (MH+);-922- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4yl) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 238), MS (Biolon) 02δΗ26 Ν 6θ3 m ^ e calcd. 494.2; found 494.5 (MH < + >);
2-(1-(1 ^7-benzoimidazol-2-il)etil]-3-metil-Λ/-[2-(2-fluorofenoksi)etil]-3H-benzoimidazol·5karboksamid (Spojina 239);2- (1- (1H-7-benzoimidazol-2-yl) ethyl] -3-methyl-N - [2- (2-fluorophenoxy) ethyl] -3H-benzoimidazole · 5carboxamide (Compound 239);
2-(1-(1 H-benzoimidazol-2-il)etil]-3-metil-/\/-[2-(3-fluorofenoksi)etil]-3H-benzoimidazol-5karboksamid (Spojina 240);2- (1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (3-fluorophenoxy) ethyl] -3H-benzoimidazole-5carboxamide (Compound 240);
2-(1-(1 H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-izopropoksifenoksi)etil]-3Hbenzoimidazol-5-karboksamid (Spojina 241), MS (Biolon) C29H31N5O3 m/e izrač. 497.2; ugot. 497.6 (MH+);2- (1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-isopropoxyphenoxy) ethyl] -3Hbenzoimidazole-5-carboxamide (Compound 241), MS (Biolon) C29H31N5O3 m / e calc 497.2; found 497.6 (MH + );
2-(1-(1 H-benzoimidazol-2-il)etil]-3-metil-/V-(2-(2-metilfenoksi)etil]-3H-benzoimidazol-5karboksamid (Spojina 242), MS (Biolon) C27H27N5O2 m/e izrač. 453.2; ugot. 453.5 (MH+);2- (1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - (2- (2-methylphenoxy) ethyl] -3H-benzoimidazole-5carboxamide (Compound 242), MS (Biolon) C27H27N5O2 m / e calc 453.2; found 453.5 (MH + );
2-(1-(1 H-benzoimidazol-2-il)etil]-3-metil-A/-(2-(2-etoksifenoksi)etil]-3H-benzoimidazol-5karboksamid (Spojina 243), MS (Biolon) 028Η29Ν5θ3 m/e izrač- 483.2; ugot. 483.5 (MH+);2- (1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2- (2-ethoxyphenoxy) ethyl] -3H-benzoimidazole-5carboxamide (Compound 243), MS (Biolon) 028Η29 Ν 5θ3 m / e calc 483.2; found 483.5 (MH + );
2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-/V-[2-(2-metoksifenoksi)etil]-3Hbenzoimidazol-5-karboksamid (Spojina 244), MS (Biolon) θ2δΗ30Ν8θ3 m^e izrač- 526.6; ugot 526.8 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 244), MS (Biolon) θ2δΗ30 Ν 8θ3 m ^ e calc- 526.6; found 526.8 (MH + );
etil 2-(2-(2-(1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5c]piridin-5-ilkarbonilamino}etoksi)benzoat (Spojina 245), MS (Biolon) C28H33N9O4 m/e izrač. 559.6; ugot. 559.6 (MH+);ethyl 2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5c] pyridin-5-ylcarbonylamino} ethoxy) ) benzoate (Compound 245), MS (Biolon) C28H33N9O4 m / e calc 559.6; found 559.6 (MH + );
-932-metoksietil 2-(2-{2-[1 -(1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 246), MS (Biolon) C30H31N5O4 m/e izrač. 541.6;-932-Methoxyethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 246), MS (Biolon) C30H31N5O4 m / e calcd. 541.6;
ugot. 541.5 (MH+);found 541.5 (MH < + >);
etil 2-(2-{2-[1 -(5-gvanidino-1 H-benzoimidazol-2-il)etil]-3-metil-3W-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 247), MS (Biolon) C29H30N8O4 m/e izrač. 554.6; ugot. 555.4 (MH+);Ethyl 2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 247), MS (Biolon ) C29H30N8O4 m / e calcd. 554.6; found 555.4 (MH < + >);
2-(2-(2-(1 -(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3/-Fbenzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 248), MS (Biolon) 02βΗ28Ν8θ4 m/θ izrač. 540.6; ugot. 541.3 (MH+);2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 248), MS (Biolon ) 02βΗ28 Ν 8θ4 m / θ calc 540.6; found 541.3 (MH + );
2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-/V-[2-(2-karbamoilfenoksi)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 249), MS (Biolon) 02δΒ29Ν9θ3 m/θ '2ra^· 539.6; ugot. 540.5 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-carbamoylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 249), MS (Biolon) 02δΒ29 Ν 9θ3 m / θ ' 2ra ^ · 539.6; found 540.5 (MH < + >);
2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-/\/-[2-(2-karbamoil-4-klorofenoksi)etil]-3-metil· 3H-benzoimidazol-5-karboksamid (Spojina 250), MS (Biolon) 028Η28Ν9θ3θ' m^e izra^· 574.0; ugot. 574.2 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl · 3H-benzoimidazole-5- carboxamide (Compound 250), MS (Biolon) 028Η28 Ν 9θ3θ ' m ^ e calcd · 574.0; found 574.2 (MH < + >);
4- kloro-2-(2-{2-[1-(5-gvanidino-1/7-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 251), MS (Biolon) C28H27N8O4CI m/e izrač. 575.0; ugot. 575.2 (MH+);4-Chloro-2- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid ( Compound 251), MS (Biolon) C28H27N8O4CI m / e calcd. 575.0; found 575.2 (MH < + >);
5- kloro-2-(2-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 252), MS (Biolon) C28H27N8O4CI m/e izrač. 575.0; ugot. 575.2 (MH+);5-Chloro-2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 252). MS (Biolon) C28H27N8O4CI m / e calcd. 575.0; found 575.2 (MH < + >);
6- kloro-2-(2-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 253), MS (Biolon) C28H27N8O4CI m/e izrač. 575.0; ugot. 575.2 (MH+);6-chloro-2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 253). MS (Biolon) C28H27N8O4CI m / e calcd. 575.0; found 575.2 (MH < + >);
-944,6-dikloro-2-(2-{2-[1 -(5-gvanidino-1 /7-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol5-ilkarbonilamino}etoksi)benzojsko kislino (Spojina 254), MS (Biolon) C2sH26N8O4cl2 m/e izrač. 609.5; ugot. 609.1 (MH+);-944,6-Dichloro-2- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoic acid (compound 254), MS (Biolon) C2sH26 N 8O4 Cl 2 m / e calcd. 609.5; found 609.1 (MH < + >);
etil 2-(2-{2-[1 -(1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5karbonilamino}etoksi)benzojsko kislino (Spojina 255), MS (Biolon) C29H29N5O4 m/e izrač. 511.6; ugot. 512.2 (MH+);Ethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carbonylamino} ethoxy) benzoic acid (Compound 255), MS (Biolon) C29H29N5O4 m / e calc. 511.6; found 512.2 (MH + );
2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-3-metil-/\/-{2-[2,4-diokso-3-(2trimetilsilaniletil)-3,4-dihidro-2W-kinazolin-1-il]etil}-3W-benzoimidazol-5-karboksamid (Spojina 256), MS (Biolon) C34H40N10O3S1 m/e izrač. 664.8; ugot. 665.4 (MH+);2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- {2- [2,4-dioxo-3- (2-trimethylsylanylethyl) -3,4-dihydro -2W-quinazolin-1-yl] ethyl} -3W-benzoimidazole-5-carboxamide (Compound 256), MS (Biolon) C34H40N10O3S1 m / e calcd. 664.8; found 665.4 (MH < + >);
2-[1-(5-gvanidino-1/7-benzoimidazol-2-il)etil]-3-metil-/V-{2-[2,4-diokso-3,4-dihidro-2Hkinazolin-1-il]etil}-3H-benzoimidazol-5-karboksamid (Spojina 257), MS (Biolon) C29H28N10O3 m/e izrač. 564.6; ugot. 565.2 (MH+);2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl- N - {2- [2,4-dioxo-3,4-dihydro-2Hquinazoline-1- yl] ethyl} -3H-benzoimidazole-5-carboxamide (Compound 257), MS (Biolon) C29H28N10O3 m / e calcd. 564.6; found 565.2 (MH < + >);
2-[1-(1H-benzoimidazol-2-il)etil]-/\/-[2-(2-cianofenoksi)etil]-3-metil-3/-/-benzoimidazol-5karboksamid (Spojina 258), MS (Biolon) C27H24N6O2 m/e izrač. 454.5; ugot. 465.1 (MH+);2- [1- (1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-cyanophenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5carboxamide (Compound 258), MS (Biolon) C27H24N6O2 m / e calcd. 454.5; found 465.1 (MH < + >);
5-(2-{2-[1-(1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)izoftalno kislino (Spojina 259), MS (Biolon) C28H25N5O6 m/e izrač. 527.5; ugot. 528.4 (MH+);5- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) isophthalic acid (Compound 259), MS (Biolon) C28H25N5O6 m / e calcd. 527.5; found 528.4 (MH < + >);
2-(2-metoksietoksi)etil 2-(2-{2-[1 -(1 H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 260), MS (Biolon) C32H35NgOg m/e izrač. 585.7; ugot. 585.4 (MH+);2- (2-methoxyethoxy) ethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 260). MS (Biolon) C32H35NgOg m / e calcd. 585.7; found 585.4 (MH < + >);
2-(2-{2-[1-(5-gvanidino-1H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]pirid-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 261), MS (Biolon) C29H29N9O4 m/e izrač. 531.6; ugot. 531.5 (MH+);2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyrid-5ylcarbonylamino} ethoxy) benzoic acid (Compound 261), MS (Biolon) C29H29N9O4 m / e calcd. 531.6; found 531.5 (MH < + >);
-952-[1-(1H-imidazo[4,5-c]piridin-2-il)etil]-A/-[2-(2-metoksifenoksi)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 262), MS (Biolon) C26H26N6°3 m/e izrač. 470.54; ugot. 471.4 (MH+);-952- [1- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide ( Compound 262), MS (Biolon) C 26 H 26 N 6 ° 3 m / e calc. 470.54; found 471.4 (MH < + >);
2-[1-(5-fluoro-1/-/-benzoimidazol-2-il)etil]-/\/-[2-(2-metoksifenoksi)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 263), MS (Biolon) C27H26N5O3F m/e izrač. 487.54; ugot. 488.1 (MH+);2- [1- (5-Fluoro-1 H -benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxyphenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 263), MS (Biolon) C27H26N5O3F m / e calcd. 487.54; found 488.1 (MH < + >);
2-[ 1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-3-metil-A/-(2-tetrazol-1 -iletil)-3Hbenzoimidazol-5-karboksamid (Spojina 264), MS (ESI) C24H23N11O m/e izrač. 481.47; ugot. 482.6 (MH+);2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-tetrazol-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 264), MS (ESI) C24H23N11O m / e calcd. 481.47; found 482.6 (MH < + >);
2-[1-(4-hidroksi-1H-benzoimidazol-2-il)etil]-N-[2-(2-metoksifenoksi)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 265), MS (Biolon) C27H27N5O4 m/e izrač. 485.59; ugot. 486.3 (MH+);2- [1- (4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 265), MS ( Biolone) C27H27N5O4 m / e calcd. 485.59; found 486.3 (MH < + >);
2- [1-(4-aminobenzoksazol-2-il)etil]-/V-[2-(2-metoksifenoksi)etil]-3-metil-3H-benzoimidazol5-karboksamid (Spojina 266), MS (Biolon) C27H27N5O4 m/e izrač. 485.59; ugot. 486.1 (MH+);2- [1- (4-aminobenzoxazol-2-yl) ethyl] - N - [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole5-carboxamide (Compound 266), MS (Biolon) C27H27N5O4 m / e calcd. 485.59; found 486.1 (MH < + >);
3- {2-[1 -(1 /7-benzoimidazol-2-il)etil]-6-[2-(2-metoksifenoksi)etilkarbamoil]benzoimidazol-1 il}propan-1-sulfonsko kislino (Spojina 267), MS (Biolon) C29H31N5O6S m/e izrač. 577.66; ugot. 577.4 (MH+);3- {2- [1- (1-7-benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid (Compound 267). MS (Biolon) C29H31N5O6S m / e calcd. 577.66; found 577.4 (MH + );
3-{2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-6-[2-(2metoksifenoksi)etilkarbamoil]benzoimidazol-1-il}propan-1-sulfonsko kislino (Spojina 268), MS (Biolon) C32H33N7O5S m/e izrač. 643.72; ugot. 644.6 (MH+);3- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -6- [2- (2methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfone acid (Compound 268), MS (Biolon) C32H33N7O5S m / e calcd. 643.72; found 644.6 (MH < + >);
etil 2-[2-(2-{ 1 -[1 -(2-metoksietil)-1 H-benzoimidazol-2-il]etil}-3-metil-3H-benzoimidazol-5karbonilamino)etoksi]benzoat (Spojina 269), MS (Biolon) C32H35N5O5 m/e izrač. 569.66; ugot. 570.5 (MH+);Ethyl 2- [2- (2- {1- [1- (2-methoxyethyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazole-5carbonylamino) ethoxy] benzoate (Compound 269) , MS (Biolon) C32H35N5O5 m / e calcd. 569.66; found 570.5 (MH < + >);
-96benzil 2-[1 -(5-imidazol-1 -il-1 H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5c]piridin-5-karboksilat (Spojina 270), MS (Biolon) C29H30N8O6 m/e izrač. 586.6; ugot.-96benzyl 2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5c] pyridine-5-carboxylate (Compound 270 ), MS (Biolon) C29H30N8O6 m / e calcd. 586.6; found
587.2 (MH+);587.2 (MH < + >);
etil 2-(4-{2-[1 -(1 H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-il}-4oksobutoksi)benzoat (Spojina 271);ethyl 2- (4- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4oxobutoxy) benzoate (Compound 271);
1- {2-[1-(1H-benzoimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo[4,5-c]piridin-5-il}-4-(2metoksifenoksi)butan-1-on (Spojina 272);1- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4- (2methoxyphenoxy) butane- 1-one (Compound 272);
2- (5-gvanidino-1 H-benzoimidazol-2-ilmetil)-/\/-(2-naft-1 -iletil)imidazo[1,2-a]piridin-6karboksamid (Spojina 273);2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) - N - (2-naphth-1-ethyl) imidazo [1,2-a] pyridine-6carboxamide (Compound 273);
A/-[3-(2-etoksifenil)propil]-2-[1-(5-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 274), MS (Biolon) C29H31N5O3 m/e izrač. 497.62; ugot. 497.4;N- [3- (2-Ethoxyphenyl) propyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 274) , MS (Biolon) C29H31N5O3 m / e calcd. 497.62; found 497.4;
A/-[3-(2-butoksifenil)propil]-2-[1 -(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3Hbenzoimidazol-5-karboksamid (Spojina 275), MS (Biolon) C31H35N5O3 m/e izrač. 525.65; ugot. 526.3;N- [3- (2-Butoxyphenyl) propyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3Hbenzoimidazole-5-carboxamide (Compound 275), MS (Biolon) C31H35N5O3 m / e calcd. 525.65; found 526.3;
2-[1-(5-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-A/-[3-(2-propoksifenil)propil]-3Hbenzoimidazol-5-karboksamid (Spojina 276), MS (Biolon) C30H33N5O3 m/e izrač. 511.62; ugot. 512.3;2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [3- (2-propoxyphenyl) propyl] -3H-benzoimidazole-5-carboxamide (Compound 276), MS (Biolon) C30H33N5O3 m / e calcd. 511.62; found 512.3;
2-[1 -(5-hidroksi-1 H-benzoimidazol-2-il)etil]-A/-{2-[2-(3-metil-[1,2,4]oksadiazol-5il)fenoksi]etil}-3-metil-3H-benzoimidazol-5-karboksamid (Spojina 277), MS (Biolon) C29H27N7O4 m/e izrač. 538.1; ugot. 537.58;2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (3-methyl- [1,2,4] oxadiazol-5yl) phenoxy] ethyl } -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 277), MS (Biolon) C29H27N7O4 m / e calcd. 538.1; found 537.58;
etil 2-(2-{2-[1 -(4-fluoro-5-hidroksi-1 /7-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 278), MS (ESI) C29H28N5O5F m/e izrač. 545.57; ugot. 545.6;Ethyl 2- (2- {2- [1- (4-fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 278 ), MS (ESI) C29H28N5O5F m / e calcd. 545.57; found 545.6;
-972-(2-{2-[1-(4-fluoro-5-hidroksi-1 /7-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 279), MS (Biolon) C27H24N5O5F m/e izrač. 517.52; ugot. 517.4;-972- (2- {2- [1- (4-Fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 279), MS (Biolon) C27H24N5O5F m / e calcd. 517.52; found 517.4;
etil 2-(2-{2-[1 -(6-fluoro-4-hidroksi-1 H-benzoimidazol-2-il)etil]-3-metil-3/7-benzoimidazol-5ilkarbonilamino}etoksi)benzoat (Spojina 280), MS (Biolon) C29H28N5O5F m/e izrač. 545.57; ugot. 545.9;Ethyl 2- (2- {2- [1- (6-fluoro-4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 280), MS (Biolon) C29H28N5O5F m / e calcd. 545.57; found 545.9;
2-(2-{2-[1 -(6-fluoro-4-hidroksi-1H-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 280), MS (Biolon) C27H24N5O5F m/e izrač. 517.52; ugot 517.6;2- (2- {2- [1- (6-Fluoro-4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 280). MS (Biolon) C27H24N5O5F m / e calcd. 517.52; Found 517.6;
etil 2-(2-{2-[1 -(4,5-difluoro-7-hid roksi-1 H-benzoimidazol-2-ii)etil]-3-metil-3Hbenzoimidazol-5-ilkarbonilamino}etoksi)benzoat (Spojina 281), MS (Biolon) C29H27N5O5F2 m/e izrač. 563.56; ugot. 563.9; inethyl 2- (2- {2- [1- (4,5-difluoro-7-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate ( Compound 281), MS (Biolon) C29H27N5O5F2 m / e calcd. 563.56; found 563.9; and
2-(2-{2-[1-(4,5-difluoro-7-hidroksi-1/7-benzoimidazol-2-il)etil]-3-metil-3H-benzoimidazol-5ilkarbonilamino}etoksi)benzojsko kislino (Spojina 282), MS (ESI) C29H27N5O5F2 m/e izrač. 536.1; ugot. 535.51.2- (2- {2- [1- (4,5-Difluoro-7-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid ( Compound 282), MS (ESI) C29H27N5O5F2 m / e calcd. 536.1; found 535.51.
-98PRIMER13-98PRIMER13
In vitro test inhibicije triptazeIn vitro tryptase inhibition assay
Raztopino triptaze (60 g/ml) smo pripravili tako, da smo raztopili triptazo, ki smo jo očistili iz preparatov humanega pljučnega ali kožnega tkiva oz. humane vrste mastocitov (HMC1) ali dobili iz komercialnih virov, npr. ICN Biomedicals, Irvine, California, Athens Research & Technology, Athens, Georgia, itd., v zmesi topila, ki je obsegala: 10 mM 2-Nmorfolinoetan sulfonsko kislino, 2 mM CaCIg, 20 % glicerol in 50 g/ml heparina. Raztopino substrata, ki je vsebovala 2 mM sintetičen tripeptid (tozil-Gly-Pro-Lys-/>nitroanilid) smo dobili pri Sigma. Raztopine testnih spojin smo pripravili tako, da smo desetkrat razredčili osnovno raztopino (1 mg testne spojine v 200 μΙ dimetilsulfoksida (DMSO)) v testnem pufru (ki je obsegal: Tris-HCI (pH 8.2), 50 mM; NaCl, 100 mM; 0.05 % polioksietilen sorbitanov monolavrat (Tween-20®); in cinkov klorid, 150 μΜ) in potem pripravili sedem dodatnih trikratnih razredčitev v 10 % DMSO v testnem pufru.Tryptase solution (60 g / ml) was prepared by dissolving tryptase, which was purified from preparations of human lung or skin tissue, respectively. human mast cells (HMC1) or obtained from commercial sources, e.g. ICN Biomedicals, Irvine, California, Athens Research & Technology, Athens, Georgia, etc., in a solvent mixture comprising: 10 mM 2-N-morpholinoethane sulfonic acid, 2 mM CaCIg, 20% glycerol and 50 g / ml heparin. A substrate solution containing 2 mM synthetic tripeptide (tosyl-Gly-Pro-Lys - /> nitroanilide) was obtained from Sigma. Solutions of test compounds were prepared by diluting ten times the stock solution (1 mg of test compound in 200 μ 200 dimethyl sulfoxide (DMSO)) in assay buffer (comprising: Tris-HCl (pH 8.2), 50 mM; NaCl, 100 mM; 0.05% polyoxyethylene sorbitan monolaurate (Tween-20®); and zinc chloride, 150 μΜ) and then prepared seven additional triple dilutions in 10% DMSO in assay buffer.
Alikvote (50 μΙ) iz vsake izmed osmih razredčitev raztopine testne spojine smo nalili v ločene jamice v mikrotitrski plošči z U-dnom in 96-jamicami. Raztopino triptaze (25 μΙ) smo dodali v vsako jamico in raztopine mešali 1 uro pri sobni temperaturi. Dodali smo raztopino substrata (25 μΙ), da smo sprožili encimatsko reakcijo in mikrotitrske plošče takoj prenesli na UV/MAX kinetični čitalnik mikroplošč (Molecular Devices). Hidrolizo kromogenega substrata smo sledili spektrofotometrično pri 405 nanometrih pet minut. Dimenzije začetnih hitrosti smo izračunali iz progresivnih krivulj s kinetičnim analiznim programom (BatchKi; Petr Kuzmič, University ot VVisconsin, Madison, Wl). Dejanske inhibicijske konstante (Kj) smo izračunali iz encimskih progresivnih krivulj ob uporabi standardnih matematičnih modelov.Aliquots (50 μΙ) of each of the eight dilutions of the test compound solution were poured into separate wells in a U-bottom microtiter plate and 96 wells. Tryptase solution (25 μΙ) was added to each well and the solutions were stirred for 1 hour at room temperature. Substrate solution (25 μΙ) was added to initiate the enzymatic reaction and the microtiter plates were immediately transferred to a UV / MAX kinetic microplate reader (Molecular Devices). Hydrolysis of the chromogenic substrate was followed spectrophotometrically at 405 nanometers for five minutes. The initial velocity dimensions were calculated from progressive curves using a kinetic analysis program (BatchKi; Petr Kuzmic, University of Wisconsin, Madison, Wl). Actual inhibition constants (Kj) were calculated from enzyme progressive curves using standard mathematical models.
Po postopku kot je opisan v tej prijavi ali po metodah, ki so običajnim strokovnjakom poznane, smo glede na inhibitorno aktivnost za triptazo testirali sledeče spojine izuma:The following compounds of the invention were tested according to the tryptase inhibitory activity according to the method as described in this application or by methods known to one of ordinary skill in the art:
Spojina 1, Kj=0.09 μΜ; Spojina 12, K,=29 μΜ; Spojina 26, Kj=33 μΜ;Compound 1, Kj = 0.09 μΜ; Compound 12, K, = 29 μΜ; Compound 26, Kj = 33 μΜ;
Spojina 27, Kj=0.6 μΜ; Spojina 28, Kj=0.00007 μΜ; Spojina 29, Kj=0.0008 μΜ;Compound 27, Kj = 0.6 μΜ; Compound 28, Kj = 0.00007 μΜ; Compound 29, Kj = 0.0008 μΜ;
Spojina 30, Kj=0.009 μΜ; Spojina 37, Kj=0.002 μΜ; Spojina 42, Kj=0.008 μΜ;Compound 30, Kj = 0.009 μΜ; Compound 37, Kj = 0.002 μΜ; Compound 42, Kj = 0.008 μΜ;
-99Spojina 43, Kj=0.002 μΜ; Spojina 74, Kj=0.006 μΜ; Spojina 75, K·,=0.03 μΜ;-99 Compound 43, Kj = 0.002 μΜ; Compound 74, Kj = 0.006 μΜ; Compound 75, K ·, = 0.03 μΜ;
Spojina 80, Kj=0.01 μΜ; Spojina 81, Kj=0.01 μΜ; Spojina 84, Kj=2.6 μΜ;Compound 80, Kj = 0.01 μΜ; Compound 81, Kj = 0.01 μΜ; Compound 84, Kj = 2.6 μΜ;
Spojina 102, Kj=0.00007 μΜ; Spojina 112, Kj=0.00005 μΜ; Spojina 115, Kj=0.003 μΜ; Spojina 116, Kj=0.006 μΜ; Spojina 117, Kj=0.008 μΜ; Spojina 126, Kj=0.008 μΜ; Spojina 127, Kj=0.006 μΜ; Spojina 128, K;=0.002 μΜ; Spojina 169, Kj=0.001 μΜ; Spojina 132, Kj=0.00002 μΜ; Spojina 134, Kj=0.00002 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, Kj = 0.008 μΜ; Compound 126, Kj = 0.008 μΜ; Compound 127, Kj = 0.006 μΜ; Compound 128, K; = 0.002 μΜ; Compound 169, Kj = 0.001 μΜ; Compound 132, Kj = 0.00002 μΜ; Compound 134, Kj = 0.00002 μΜ;
Spojina 138, Kj=0.0002 μΜ; Spojina 152, Kj=0.0005 μΜ; Spojina 182, Kj=0.004 μΜ; Spojina 194, Kj=0.009 μΜ; Spojina 203, Kj=0.008 μΜ; Spojina 225, Kj=0.008 μΜ; Spojina 249, Kj=0.0007 μΜ; Spojina 250, Kj=0.0004 μΜ; Spojina 251, Kj=0.0008 μΜ; in Spojina 252, Kj=0.0004 μΜ.Compound 138, Kj = 0.0002 μΜ; Compound 152, Kj = 0.0005 μΜ; Compound 182, Kj = 0.004 μΜ; Compound 194, Kj = 0.009 μΜ; Compound 203, Kj = 0.008 μΜ; Compound 225, Kj = 0.008 μΜ; Compound 249, Kj = 0.0007 μΜ; Compound 250, Kj = 0.0004 μΜ; Compound 251, Kj = 0.0008 μΜ; and Compound 252, Kj = 0.0004 μΜ.
PRIMERU Model astme na ovcahEXAMPLE A model of asthma on sheep
Model astme na alergičnih ovcah smo uporabili za in vivo vrednotenje spojin izuma kot antiastmatikov. Te metode so bile že prej objavljene (glej Abraham s sod. (1983) Am. Rev. Respir. Dis. 128:839-844; Allegra s sod. (1983) J. Appl. Physiol. 55:726-730; Russi s sod. (1985) J. Appl. Physiol. 59:1416-1422; Soler s sod. (1989) J. Appl. Physiol. 67:406413). Vsaka ovca služi kot svoja lastna kontrola. Telesne teže teh živali so bile v območju od 20-50 kilogramov.The allergic sheep model of asthma was used to evaluate in vivo the compounds of the invention as anti-asthmatics. 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 J. Appl. Physiol. 59: 1416-1422; Soler et al. (1989) J. Appl. Physiol. 67: 406413). Each sheep serves as its own control. The body weights of these animals were in the range of 20-50 pounds.
Pri teh študijah smo 1 mg Spojine 4 raztopili v 3 ml destilirane vode in celotno raztopino dali kot aerosol 0.5 ure pred, 4 ure po in 24 ur po antigenskem izzivu (celotna doza = 1 mg; n = 3). Rezultati teh poskusov so povzeti v Sliki 1.In these studies, 1 mg of Compound 4 was dissolved in 3 ml of distilled water and the whole solution was aerosolized 0.5 hours before, 4 hours after, and 24 hours after the antigen challenge (total dose = 1 mg; n = 3). The results of these experiments are summarized in Figure 1.
Štiriindvajset ur po antigenskem izzivu tako pri kontrolnem kot pri poskusu z zdravilom ovce razvijejo hiperodzivnost dihalnih poti. Hiperodzivnost zračnih poti je izražena kot PC400, koncentracija karbahola, ki povzroči 400% povečanje v SRL (specifična rezistenca pljuč); zato zmanjšanje v PC400 kaže hiperodzivnost. Ugotovili smo, da Spojina 13 blokira nastop hiperodzivnosti. Kot je prikazano v Sliki 2, ta spojina ohranja PC400 na vrednosti bazne linije 15 dihalnih enot. Število dihalnih enot je za tiste živali vTwenty-four hours after the antigen challenge, both the control and the sheep experiment developed airway hyperresponsiveness. Airway hyperresponsiveness is expressed as PC400, a carbachol concentration that causes a 400% increase in SRL (specific lung resistance); therefore, the decrease in PC400 indicates hyperresponsiveness. Compound 13 was found to block the onset of hyperresponsiveness. As shown in Figure 2, this compound maintains the PC400 at a baseline value of 15 respiratory units. The number of respiratory units is for those animals in
-100kontrolni skupini padlo na 7. Tako je zdravljenje s Spojino 13 rezultiralo v znatnem izboljšanju v funkciji zračnih poti pri z antigenom izzvanih ovcah.The control group dropped to 7. Thus, treatment with Compound 13 resulted in a significant improvement in airway function in antigen-induced sheep.
Tako pričujoči izum zagotavlja spojine in sestavke, ki so koristni za preprečitev in zdravljenje imunsko posredovanih vnetnih motenj, zlasti tistih, povezanih z respiratornim traktom, vključujoč astmo in hiperodzivnostno fazo, povezano s kronično astmo poleg alergijskega rinitisa. Pričujoči izum je tudi spoznan kot tak, ki zagotavlja metodo za zdravljenje imunsko posredovanih vnetnih motenj, ki so dovzetne za zdravljenje s spojino pričujočega izuma.Thus, the present invention provides compounds and compositions useful for the prevention and treatment of immune-mediated inflammatory disorders, especially those associated with the respiratory tract, including asthma and the hyperresponsive phase associated with chronic asthma in addition to allergic rhinitis. The present invention is also recognized as providing a method for treating immune-mediated inflammatory disorders that are susceptible to treatment with a compound of the present invention.
Potrebno je razumeti, da je zgornji opis predvidoma ilustrativen in ne restriktiven. Mnoge izvedbe bodo strokovnjakom na tem področju razvidne po pregledovanju zgornjega opisa. Obseg izuma bi zato moral biti določen ne z referenco k zgornjemu opisu, ampak bi namesto tega moral biti določen z referenco k priloženim zahtevkom, skupaj s celotnim obsegom ekvivalentov na katere so taki zahtevki naslovljeni.It should be understood that the foregoing description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those skilled in the art after reviewing the description above. The scope of the invention should therefore be determined not by reference to the foregoing description, but should instead be determined by reference to the appended claims, together with the full range of equivalents to which such claims are addressed.
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US6221914B1 (en) | 1997-11-10 | 2001-04-24 | Array Biopharma Inc. | Sulfonamide bridging compounds that inhibit tryptase activity |
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ATE256666T1 (en) * | 1999-06-04 | 2004-01-15 | Elan Pharma Int Ltd | COMPOSITIONS AND METHODS FOR PREVENTING CELL DEATH |
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-
1999
- 1999-10-06 NO NO19994858A patent/NO314183B1/en unknown
- 1999-11-02 LV LVP-99-153A patent/LV12495B/en unknown
- 1999-11-05 LT LT99-131A patent/LT4704B/en not_active IP Right Cessation
Also Published As
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HUP0001522A2 (en) | 2001-05-28 |
SK136799A3 (en) | 2000-07-11 |
EE04055B1 (en) | 2003-06-16 |
EP1019382A1 (en) | 2000-07-19 |
KR20010006119A (en) | 2001-01-26 |
AU5895098A (en) | 1998-10-30 |
CN1251579A (en) | 2000-04-26 |
CA2285454A1 (en) | 1998-10-15 |
NZ500029A (en) | 2001-02-23 |
JP2001519806A (en) | 2001-10-23 |
NO314183B1 (en) | 2003-02-10 |
PL336233A1 (en) | 2000-06-19 |
AU752064B2 (en) | 2002-09-05 |
LV12495B (en) | 2001-01-20 |
LV12495A (en) | 2000-06-20 |
LT4704B (en) | 2000-09-25 |
NO994858D0 (en) | 1999-10-06 |
LT99131A (en) | 2000-04-25 |
HUP0001522A3 (en) | 2001-08-28 |
WO1998045275A1 (en) | 1998-10-15 |
NO994858L (en) | 1999-12-06 |
EE9900477A (en) | 2000-06-15 |
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