CN106470987A - A kind of dabigatran ester derivant and preparation method thereof and purposes pharmaceutically - Google Patents

A kind of dabigatran ester derivant and preparation method thereof and purposes pharmaceutically Download PDF

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CN106470987A
CN106470987A CN201580036785.0A CN201580036785A CN106470987A CN 106470987 A CN106470987 A CN 106470987A CN 201580036785 A CN201580036785 A CN 201580036785A CN 106470987 A CN106470987 A CN 106470987A
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methyl
amino
compound
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魏用刚
邱关鹏
雷柏林
李瑶
张晨
郑苏欣
杨家亮
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Sichuan Haisco Pharmaceutical Co Ltd
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

The present invention relates to a kind of dabigatran ester derivant and its stereoisomer or pharmaceutically acceptable salt, and it is used for the purposes in the medicine preventing and treating thromboembolic disorders in preparation.

Description

A kind of dabigatran ester derivant and preparation method thereof and purposes pharmaceutically Technical field
The present invention relates to a kind of dabigatran ester derivant and its stereoisomer and pharmaceutically acceptable salt, and preparing the purposes in being used to prevent and treat the medicine of thromboembolic disorders.
Background technology
At present, angiocardiopathy is to cause the one of the main reasons of human death, and its main aspect is thrombosis, and thrombosis is to be caused blood coagulation by a series of complex reaction and caused.Blood clotting is a kind of protection mechanism of organism, " can quickly and reliably seal " defect of vascular wall whereby, therefore can avoid losing blood or being preferably minimized limit.Normal haemostasis effect is maintained, i.e. bleeding and coagulation homeostasis is regulated and controled by a complex mechanism.Not modulated coagulation system activation or the inhibitory action of shortage activation process may all cause a variety of diseases and complication, such as phlebothrombosis, DVT, pulmonary embolism, atherosclerosis, acute coronary syndrome, cranial vascular disease.
The oral anticoagulant drug listed mainly has direct thrombin inhibitor, Xa factor inhibitor, IX factor inhibitors, tissue factor inhibitor and new vitamin K antagon etc..Wherein dabigatran etcxilate is a kind of oral, selective high performance thrombin inhibitor, and clinic is proved that warfarin can be substituted as the non-valvular atrial fibrillation patient apoplexy of prevention and systemic embolism and substitutes Enoxaparin Sodium as the preferred medication for preventing main shaping postoperative patient venous thromboembolic event.
Dabigatran etcxilate was listed in 2008, is used to prevent the palsy or systemic embolism of non-valvular heart disease patient, dvt (DVT) or Pulmonary Vascular obstruction and its is recurred.It is free carboxy and amidino groups in dabigatran molecule respectively into the bi precursor medicine obtained after ester, solve because dabigatran strong basicity amidino groups exists can not be orally the problem of, improve oral administration biaavailability.After dabigatran etcxilate is oral, is absorbed from intestines and stomach, then quickly dabigatran is converted into vivo, so as to play blood coagulation resisting function.But the oral administration biaavailability of dabigatran dibasic acid esters is relatively low, only 3~7%, so pharmaceutical dosage is higher, add gastrointestinal side effect.
Many document reports pro-drug of dabigatran is had at present.As WO09837075 and WO2004014894 patents disclose dabigatran and the like, and the pro-drug such as its alkyl carboxylic acid ester, the carboxylate or sulfuryl amino that are replaced by sulfonyl；The forulic acid of CN102875533 and CN102838588 patent reports dabigatran or river bow piperazine pro-drug, and with certain blood coagulation resisting function；The patents such as CN200910211164, CN200910211165 and CN201210158600 disclose the pro-drugs such as the carbonic ester of dabigatran, carboxylate.
It is an object of the invention to solve dabigatran the problem of its strong basicity can not be orally there is provided it is a kind of novel effectively There is good stability, solubility, bioavilability and low dosage, low toxicity side effect or long-acting orally available dabigatran prodrug.
The content of the invention
The present invention relates to a kind of dabigatran ester derivant and its stereoisomer and pharmaceutically acceptable salt, and preparing the purposes in being used to prevent and treat the medicine of thromboembolic disorders.
The present invention relates to a kind of compound and its stereoisomer, and pharmaceutically acceptable salt, the wherein compound is selected from one of following structure：
Preferred scheme of the present invention, according to compound of the present invention and its stereoisomer and pharmaceutically acceptable salt, wherein described salt is selected from hydrochloride, hydrobromate, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalates, oxyacetate, salicylate, glucuronate salt, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate, ferulate or combinations thereof.
The present invention further provides a kind of pharmaceutical composition, described pharmaceutical composition contains the compounds of this invention or its stereoisomer or pharmaceutically acceptable salt for the treatment of effective dose, and pharmaceutically acceptable carrier or excipient.
The present invention further provides a kind of above any described compound and its stereoisomer and pharmaceutically acceptable salt, treatment and the purposes in thrombin inhibitor relevant disease medicine are being prepared.
The present invention also provides a kind of foregoing pharmaceutical composition and is preparing treatment and the purposes in thrombin inhibitor relevant disease medicine.
Preferred scheme of the present invention, wherein described be selected from thromboembolic disorders with thrombin inhibitor relevant disease.
Preferred scheme of the present invention, wherein described thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
The present invention further provides a kind of method treated with thrombin inhibitor relevant disease, wherein methods described includes compound of the present invention or its stereoisomer or pharmaceutically acceptable salt, or composition of the present invention is administered.
Preferred scheme of the present invention, wherein described be selected from thromboembolic disorders with thrombin inhibitor relevant disease.
Preferred scheme of the present invention, wherein described thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
Embodiment
Technical scheme is described in detail below in conjunction with drawings and Examples, but protection scope of the present invention is included still Not limited to this.
The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10-6(ppm) unit is provided.NMR measure is to use (Bruker Avance III 400 and Bruker Avance300) nuclear magnetic resonance spectrometer, and measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
MS measure uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC measure uses Agilent 1260DAD high pressure liquid chromatographs (100 × 4.6mm of Zorbax SB-C18).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used is 0.15mm~0.20mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.
Oneself initiation material known of the present invention can be used or synthesized according to methods known in the art, or be can purchase in the smooth science and technology of Thailand, pacified the companies such as silent resistance to Jilin Chemical, Shanghai moral, the imperial chemical industry of Chengdu section, splendid remote chemistry science and technology, lark prestige science and technology.
Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
The optimum reaction temperature of room temperature, is 20 DEG C~30 DEG C.
Intermediate 1
3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1)
3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carb onyl]-(2-pyridyl)amino]propanoic acid
The first step：3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1)
3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carb onyl]-(2-pyridyl)amino]propanoic acid
By 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] ethyl propionate (1a) (63g, 100mmol) it is added to the in the mixed solvent of ethanol (600mL) and water (300mL), add sodium hydroxide (8g, 200mmol), half an hour is stirred at room temperature, to reaction solution clarification.Concentration of reaction solution, rotate most of ethanol, add water (200mL), pH to 4~5 is adjusted with 10% aqueous citric acid solution, a large amount of thick solids are separated out, filtering, solid is transferred in reaction bulb, add methanol (300mL), it is heated to solid dissolving, continue to stir to solid and be in granular form, it is cooled to 0 DEG C, more products are separated out, filter and dry, obtain title compound 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (50g of white solid, yield 83%).
LCMS m/z=600.2 [M+1].
1H NMR(400MHz,DMSO-d6)：δ8.38(d,1H),7.79(d,2H),7.56(m,1H),7.48(s,1H),7.39(d,1H),7.14(m,2H),6.95(d,2H),6.77(d,2H),4.60(d,2H),4.18(t,2H),3.99(t,2H),3.77(s,3H),2.68-2.58(m,2H),1.58(dd,2H),1.29(d,6H),0.87(t,3H).
Embodiment 1
(R) 3- [[2- [[4- [N`-3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (tetrahydrofuran -3- bases) esters (compound 1)
(R)-tetrahydrofuran-3-yl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
By 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (3g, 5mmol) it is dissolved in anhydrous N, in dinethylformamide (50mL), sequentially add (R)-(-) -3- hydroxyl tetrahydrofurans (1A) (0.98g, 7.5mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.2g, 6.5mmol) with DMAP (0.37g, 3mmol), reaction is stayed overnight at room temperature, stop reaction, it is concentrated under reduced pressure, residue is with silica gel column chromatography separating-purifying (ethanol/methylene (v/v)=0/1~5/95), it is then dissolved in dichloromethane (50mL), washed with 10% sodium dihydrogen phosphate (100mL), with anhydrous sodium sulfate drying, concentration, mixed solvent (dichloromethane/methyl tertiary butyl ether(MTBE) (v/v)=1/2) recrystallization of residue dichloromethane and methyl tertiary butyl ether(MTBE), filter and dry, obtain title compound (R) 3- [[2- [[4- [N`-3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (tetrahydrofuran -3- bases) ester (compound 1) (500mg of pale yellow solid, yield 15%).
LCMS m/z=670.2 [M+1].
1H NMR(400MHz,CDCl3)：δ8.47-8.39(m,1H),7.76(d,2H),7.71(s,1H),7.37-7.28(m,2H),7.12(d,1H),6.99(dd,1H),6.74-6.65(m,3H),5.40-5.20(m,2H),4.50(d,2H),4.43(t,2H),4.14(t,2H),3.95-3.75(m,4H),3.72(s,3H),2.81(t,2H),2.13(dt,1H),2.06-1.94(m,1H),1.79-1.67(m,2H),1.40(dd,2H),1.31(dd,4H),0.89(t,3H).
Embodiment 2
Cvclopropvlmethvl 3- [[2- [[4- [the own oxygen carbonyl carbonamidine bases of N`-] phenylamino] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 2)
cyclopropylmethyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-meth yl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=654.33 [M+1].
1H NMR(400MHz,CDCl3)δ8.41(d,1H),7.78-7.65(m,3H),7.37-7.27(m,2H),7.10(d,1H),6.98(dd,1H),6.71(d,1H),6.66(t,2H),5.38(s,1H),4.44(dd,4H),4.14(t,2H),3.85(d,2H),3.71(d,3H),2.83(t,2H),1.82-1.59(m,2H),1.50-1.36(m,2H),1.36-1.26(m,4H),1.07(m,1H),0.89(t,3H),0.54(m,2H),0.25(t,2H)。
Embodiment 3
Tetrahydropyran -3-base methyl 3- [[2- [[4- [the own oxygen carbonyl carbonamidine bases of N'-] phenylamino] methyl] -1- tolimidazole -5- carbonyls]-(2- pyridine radicals) amino] ethyl propionate (compound 3)
tetrahydropyran-3-ylmethyl 3-[[2-[[4-[N'-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.69(s,1H),8.39(dd,1H),7.79(d,2H),7.54(m,1H),7.47(d,1H),7.40(d,1H),7.19-7.08(m,2H),6.93(t,1H),6.89(d,1H),6.76(d,2H),4.59(d,2H),4.22(t,2H),3.98(t,2H),3.90-3.79(m,2H),3.79-3.75(m,3H),3.70(m,2H),3.26(d,1H),3.12(dd,1H),2.70(t,2H),1.83-1.66(m,2H),1.63-1.51(m,3H),1.48-1.39(m,1H),1.37-1.22(m,8H),0.87(t,3H)。
LCMS m/z=698.2 [M+1].
Embodiment 4
(5- methyl-2- oxo-1,3- Dioxol-4 -yls) methyl 3- (2- (((4- (N "-((hexyloxy) carbonyl)) carbonamidine base) phenyl) amino) methyl)-1- methyl-N- (pyridine-2- bases)-1H- benzos [d] imidazoles-5- formamidos) ethyl propionate (compound 4)
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimido  yl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)pr opanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,CDCl3)δ8.42(dd,1H),7.75(d,2H),7.70(d,1H),7.35-7.23(m,3H),7.12(d,1H),6.98(dd,1H),6.72-6.62(m,3H),5.36(s,1H),4.80(s,2H),4.49(d,2H),4.43(t,2H),4.14(t,2H),3.72(s,3H),2.86(t,2H),2.12(s,3H),1.77-1.66(m,2H),1.47-1.36(m,2H),1.31(dd,4H),0.89(t,3H)。
MS m/z (ESI)=712.2 [M+1].
Embodiment 5
(2- anisyls) methyl 3- [[2- [[4- [the own oxygen carbonyl first of N`- narrows base] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 5)
(2-methoxyphenyl)methyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimiazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=720.34.30 [M+1].
1H NMR(400MHz,CDCl3)δ8.39(dd,1H),7.75(d,2H),7.70(d,1H),7.34-7.26(m,4H),7.08(d,1H),7.00-6.89(m,2H),6.87(d,1H),6.68(t,3H),5.33(s,1H),5.13(s,2H),4.46(dd,4H),4.14(t,2H),3.82(s,3H),3.70(s,3H),2.88(t,2H),1.71(dd,2H),1.40(dd,2H),1.35-1.27(m,4H),0.89(t,3H)。
Embodiment 6
3- (2- (((4- (N'- ((4- cyclopropyl butoxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- Base) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate (compound 6)
ethyl 3-(2-(((4-(N'-((4-cyclopropylbutoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
4- cyclopropyl butyl -1- alcohol (1g, 8.76mmol) and tetrahydrofuran (12mL) are added in reaction bulb, N is then added, N'- carbonyl dimidazoles (1.54g, 9.49mmol) are stirred at room temperature 1 hour, and be concentrated under reduced pressure to obtain grease.It is another to take reaction bulb to add 3- (2- (((4- carbamimido-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate tosilate (6A) (4.9g, 7.3mmol), and grease, acetone (120mL), water (60mL).It is stirred at room temperature 5 hours, evaporated under reduced pressure acetone, water (60mL) is added in residue, ethyl acetate extracts (100mL × 3), merge organic phase, saturated common salt water washing (90mL), anhydrous sodium sulfate drying, contracting, residue uses column chromatography purification (dichloromethane：Methanol (v/v)=30:1-10:1) white solid 3- (2- (((4- (N'- ((4- cyclopropyl butoxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate (compound 6) (2.5g, 53.5%) is obtained.
1H NMR(400MHz,CDCl3):δ8.42-8.41(d,1H),7.78-7.76(m,2H),7.71-7.69(m,1H),7.32-7.30(m,2H),7.14-7.11(d,1H),7.00-6.97(m,1H),6.73-6.69(m,3H),5.30(s,1H),4.51-4.50(d,2H),4.45-4.41(m,2H),4.17-4.13(t,3H),4.11-4.05(m,2H),3.73(s,3H),2.83-2.79(t,2H),1.78-1.73(m,2H),1.56-1.48(m,2H),1.27-1.20(m,5H),0.68-0.63(m,1H),0.40-0.37(m,2H),0.09-0.02(m,2H)。
Embodiment 7
Tetrahydrochysene -2H- pyrans -4- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 7)
tetrahydro-2H-pyran-4-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,CDCl3)δ8.41(d,1H),7.73(d,2H),7.69(s,1H),7.33(m,1H),7.31-7.27(m,1H),7.09(d,1H),6.99(dd,1H),6.71(d,1H),6.66(d,2H),5.41(s,1H),4.97-4.86(m,1H),4.48(d,2H),4.43(t,2H),4.14(t,2H),3.94-3.82(m,2H),3.71(s,3H),2.82(t,2H),1.92-1.82(m,2H),1.71(dd,2H),1.64(m,2H),1.41(m,2H),1.31(m,4H),0.89(t,3H)。
LCMS m/z=684.3 [M+1].
Embodiment 8
4- [[amino-[4- [[5- [(3- ethyoxyl -3- oxo-propylls)-(2- pyridine radicals) carbamoyl] -1- methyl-benzoimidazole -2- bases] methylamino] phenyl] methylene] amino] -4- oxobutyrates (compound 8)
methyl 4-[[amino-[4-[[5-[(3-ethoxy-3-oxo-propyl)-(2-pyridyl)carbamoyl]-1-methyl-benzimidazol-2-yl]methylamino]phenyl]methylene]amino]-4-oxo-butanoate
At room temperature, by 3- (2- (((4- carbamimido-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate tosilate (6A) (5.0g, 7.45mmol) it is dissolved in N, in dinethylformamide (30mL), sequentially add 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (3.12g, 8.20mmol), N, N- dimethylethyl amines (12.9g, 74.5mmol) with monomethyl succinate (994mg, 7.53mmol), room temperature reaction 17 hours is stirred at room temperature.Concentration, residue silica gel 100g, methylene chloride/methanol (15:1) elute; obtain white powdery solids 4- [[amino-[4- [[5- [(3- ethyoxyl -3- oxo-propylls)-(2- pyridine radicals) carbamoyl] -1- methyl-benzoimidazole -2- bases] methylamino] phenyl] methylene] amino] -4- oxobutyrates (compound 8) (730mg, 16%).
1H NMR(400MHz,CDCl3)δ8.42(m,1H),7.77(m,2H),7.69(s,1H),7.39-7.27(m, 2H),7.12(d,1H),6.98(m,1H),6.70(m,3H),4.51(d,2H),4.43(t,2H),4.08(q,2H),3.78-3.66(m,7H),2.91(t,2H),2.81(t,2H),2.70(t,2H),1.23(m,4H)。
Embodiment 9
[(3S)-tetrahydrofuran -3- bases] -3- [[2- [[4- [N`-3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 9)
[(3S)-tetrahydrofuran-3-yl]3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,CDCl3)δ8.42(d,1H),7.80-7.65(m,3H),7.37-7.30(m,1H),7.27(d,1H),7.08(d,1H),6.99(dd,1H),6.67(dd,3H),5.40(s,1H),5.25(dd,1H),4.51-4.37(m,4H),4.14(t,2H),3.94-3.74(m,4H),3.70(s,3H),2.81(t,2H),2.13(dt,1H),2.05-1.94(m,1H),1.78-1.66(m,2H),1.48-1.36(m,2H),1.30(dd,4H),0.89(t,3H)。
LCMS m/z=670.3 [M+1].
Embodiment 10
((3- (2- (((4- (N '-((hexyloxy) carbonyl) carbonamidine) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propiono) epoxide) methyl succinate (compound 10)
((3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoyl)oxy)methyl methyl succinate
By 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) ammonia Base] propionic acid (intermediate 1) (3.0g, 5mmol) is dissolved in anhydrous DMF (40mL), adds cesium carbonate (3.3g, 10.0mmol), react at room temperature 10 minutes.Chloromethyl dimethyl succinic acid (10A) (1.35g, 7.5mmol) is added, sodium iodide (0.75g, 5.0mmol) is reacted at room temperature 18 hours.Directly concentrated with oil pump, residue silica gel column chromatography separating-purifying (ethyl acetate：Dichloromethane (v/v)=1:1~2:1); then the dichloromethane of 6 times of volumes of addition and the methyl tertiary butyl ether(MTBE) of 12 times of volumes are recrystallized; filtering; obtain title compound ((3- (2- (((4- (N '-((hexyloxy) carbonyl) carbonamidine) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propiono) epoxide) methyl succinate (compound 10); white solid (2.0g, yield 57%).
1H NMR(400MHz,CDCl3)δ8.44-8.39(m,1H),7.75(d,2H),7.69(s,1H),7.32(ddd,2H),7.11(d,1H),6.98(dd,1H),6.69(dd,3H),5.73(s,2H),5.35(s,1H),4.49(d,2H),4.43(t,2H),4.14(t,2H),3.72(s,3H),3.68(s,3H),2.88(t,2H),2.71-2.61(m,4H),1.76-1.65(m,2H),1.40(dd,2H),1.31(m,4H),0.89(t,3H)。
LCMS m/z=744.2 [M+H].
Embodiment 11
(1,3- dioxolanes -4- bases) methyl 3- (2- (((4- (N '-((hexyloxy) carbonyl) carbonamidine) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 11)
(1,3-dioxolan-4-yl)methyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,CDCl3)δ8.42(d,1H),7.75(d,2H),7.70(s,1H),7.36-7.27(m,2H),7.11(d,1H),6.99(dd,1H),6.69(t,3H),5.36(s,1H),5.02(s,1H),4.89(s,1H),4.49(d,2H),4.44(t,2H),4.30-4.22(m,1H),4.13(dd,4H),3.97(dd,1H),3.75-3.65(m,4H),2.85(t,2H),1.77-1.65(m,2H),1.46-1.35(m,2H),1.35-1.28(m,4H),0.89(t,3H)。
LCMS m/z=343.7 [[M+2]/2].
Embodiment 12
1,3- dioxane -5- bases 3- (2- (((4- (N '-((hexyloxy) carbonyl) carbonamidine) phenyl) amino) methyl) -1- methyl - N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 12)
1,3-dioxan-5-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,CDCl3)δ8.43(d,1H),7.79(d,2H),7.73(s,1H),7.35-7.29(m,2H),7.14(d,1H),6.99(dd,1H),6.72(dd,3H),5.25(s,1H),4.91(d,1H),4.80(d,1H),4.76-4.68(m,1H),4.52(d,2H),4.47(t,2H),4.14(t,2H),3.99(dd,2H),3.91(dd,2H),3.74(s,3H),2.87(t,2H),1.72(dd,2H),1.46-1.36(m,2H),1.31(m,4H),0.89(t,3H)。
LCMS m/z=686.3 [M+H].
Embodiment 13
(1R, 2S, 5R) -2- isopropyl -5- methyl cyclohexylamines 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 13)
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,CDCl3)δ8.54-8.32(m,1H),7.75(d,2H),7.71(s,1H),7.38-7.27(m,2H),7.11(d,1H),6.99(dd,1H),6.71(dd,3H),5.36(s,1H),4.65(m,1H),4.48(t,2H),4.45-4.32(m,2H),4.14(t,2H),3.72(s,3H),2.90-2.70(m,2H),1.97-1.79(m,3H),1.78-1.56(m,5H),1.51-1.18(m,9H),1.12-0.77(m,13H),0.74(d,3H)。
LCMS m/z=738.3 [M+1].
Embodiment 14
3- [[2- [[4- [N`- (2- ethyoxyl -2- oxo-ethoxvs) carbonyl carbonamidine base] anilino-] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridines) amino] propionic acid second fat (compound 14)
ethyl 3-[[2-[[4-[N`-(2-ethoxy-2-oxo-ethoxy)carbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
The first step：2- ethyoxyl -2- oxoethyl 1H- imidazoles -1- formic acid esters (14B)
2-ethoxy-2-oxoethyl 1H-imidazole-1-carboxylate
Carbonyl dimidazoles (3.56g, 22mmol) are dissolved in tetrahydrofuran (20mL), 50 DEG C are warming up to, 2- hydroxyl ethyl acetates (20A) (2.08g, 20mmol) are then added dropwise, are reacted 30 minutes.After reaction terminates, room temperature is cooled to, next step is directly used in, the tetrahydrofuran solution (1.92g, yield 100%) of 2- ethyoxyl -2- oxoethyl 1H- imidazoles -1- formic acid esters (14B) is obtained.
Second step：3- [[2- [[4- [N`- (2- ethyoxyl -2- oxo-ethoxvs) carbonyl carbonamidine base] anilino-] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridines) amino] propionic acid second fat (compound 14)
ethyl 3-[[2-[[4-[N`-(2-ethoxy-2-oxo-ethoxy)carbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
By 3- (2- (((4- carbamimido-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) Ethyl propionate tosilate (6A) (6.7g, 5mmol) it is added to the in the mixed solvent of acetone (70mL) and water (30mL), sodium carbonate (5.53g, 40mmol) is added, half an hour is stirred at room temperature.The tetrahydrofuran solution of 2- ethyoxyl -2- oxoethyl 1H- imidazoles -1- formic acid esters (14B) (1.92g, 10mmol) is added dropwise again, is stirred at room temperature 3 hours.Dichloromethane (100mL) is added, filtering, filtrate washed once (50mL) with saturated aqueous common salt, and anhydrous sodium sulfate drying is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (methanol：Dichloromethane (v/v)=0:1~5:95), obtain title compound 3- [[2- [[4- [N`- (2- ethyoxyl -2- oxo-ethoxvs) carbonyl carbonamidine base] anilino-] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridines) amino] propionic acid second fat (compound 14), white solid (1.5g, yield 23.8%).
1H NMR(400MHz,CDCl3)δ8.42(dd,1H),7.77(d,2H),7.70(d,1H),7.32(m,2H),7.12(d,1H),6.98(dd,1H),6.70(dd,3H),5.38(s,1H),4.66(s,2H),4.50(d,2H),4.43(t,2H),4.25(q,2H),4.08(q,2H),3.73(s,3H),2.81(t,2H),1.28(m,3H),1.22(t,3H)。
LCMS m/z=630.2 [M+1].
Embodiment 15
3- [[1- methyl-2- [[4- [N`- [(5- methyl-2- oxo-1,3- Dioxol-4 -yls) methoxycarbonyl group] carbonamidine base] aniline] methyl] benzimidazole-5- carbonyls]-(2- pyridine radicals) amino] propionic acid second fat (compound 15)
ethyl 3-[[1-methyl-2-[[4-[N`-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl]carbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
The first step：(5- methyl-2- oxo-1,3- Dioxol-4 -yls) methyl chloroformate (15B)
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl carbonochloridate
4- methylol -5- methyl -2- oxos -1,3- dioxole (15A) (1.30g, 10mmol) is dissolved in tetrahydrochysene furan Mutter in (10mL), add triphosgene (1.48g, 5mmol), triethylamine (1.01g, 10mmol) is warming up to 70 DEG C and reacted 1 hour.After reaction terminates, room temperature is cooled to, the tetrahydrofuran solution (1.92g, yield 100%) of (5- methyl-2- oxos-1,3- Dioxol-4 -yl) methyl chloroformate (15B) is obtained.It is directly used in next step.
Second step：3- [[1- methyl-2- [[4- [N`- [(5- methyl-2- oxo-1,3- Dioxol-4 -yls) methoxycarbonyl group] carbonamidine base] aniline] methyl] benzimidazole-5- carbonyls]-(2- pyridine radicals) amino] propionic acid second fat (compound 15)
ethyl 3-[[1-methyl-2-[[4-[N`-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl]carbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
By 3- (2- (((4- carbamimido-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate tosilate (6A) (3.36g, 5mmol) it is added to the in the mixed solvent of acetone (35mL) and water (15mL), add sodium carbonate (2.76g, 20mmol), half an hour is stirred at room temperature.It is added dropwise that (tetrahydrofuran solution of (5- methyl-2- oxos-1,3- Dioxol-4 -yl) methyl chloroformate (15B) (1.92g, 10mmol), is stirred at room temperature 3 hours again.Dichloromethane (50mL) is added, filtering, filtrate washed once (50mL) with saturated aqueous common salt, and anhydrous sodium sulfate drying is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (methanol：Dichloromethane (v/v)=0:1~5:95), obtain title compound 3- [[1- methyl-2- [[4- [N`- [(5- methyl-2- oxos-1,3- Dioxol-4 -yls) methoxycarbonyl group] carbonamidine base] aniline] methyl] benzimidazole-5- carbonyls]-(2- pyridine radicals) amino] propionic acid second fat (compound 15), white solid (0.7g, yield 21.3%).
1H NMR(400MHz,CDCl3)δ8.42(dd,1H),7.75(d,2H),7.69(s,1H),7.32(ddd,2H),7.08(d,1H),6.99(m,1H),6.71(d,1H),6.65(d,2H),5.40(s,1H),4.91(s,2H),4.50-4.38(m,4H),4.08(q,2H),3.71(d,3H),2.81(t,2H),2.19(s,3H),1.22(t,3H)。
LCMS m/z=656.2 [M+1].
Embodiment 16
(pyridin-3-yl) methyl 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases base) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 16)
(pyridin-3-yl)methyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method reference implementation example 1.
1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.53(dd,1H),8.41-8.33(m,1H),7.84-7.72(m,3H),7.51(m,1H),7.46(d,1H),7.42-7.33(m,2H),7.12(m,2H),6.93(t,1H),6.86(d,1H),6.77(d,2H),5.07(s,2H),4.59(d,2H),4.25(t,2H),3.98(t,2H),3.76(s,3H),3.31(s,2H),2.77(t,2H),1.64-1.52(m,2H),1.30(m,6H),0.87(t,3H)。
LCMS m/z=691.3 [M+1].
Embodiment 17
3- [[2- [[4- [N`- (2- dimethylaminos carbethoxyl group) carbonamidine base] anilino-] methyl] -1 tolimidazole -5- carbonyls]-(2- pyridine radicals) amino] ethyl propionate (compound 17)
ethyl 3-[[2-[[4-[N`-(2-dimethylaminoethyloxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method reference implementation example 8.
1H NMR(400MHz,CDCl3)δ8.42(d,1H),7.78-7.71(m,3H),7.33-7.30(m,2H),7.11(d,1H),6.99-6.98(m,1H),6.72-6.67(m,3H),5.30(s,1H),4.49(s,2H),4.43(t,2H),4.27(t,2H),4.08(q,2H),3.72(s,3H),2.81(t,2H),2.73(t,2H),2.36(s,6H),1.22(t,3H)。
LCMS m/z=615.3 [M+1].
Embodiment 18
3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid Coronex (compound 18)
(3R,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method reference implementation example 1.
1H NMR(400MHz,CDCl3)δ8.41(ddd 1H),7.84-7.61(m,3H),7.37-7.27(m,2H),7.08(dd,1H),7.02-6.94(m,1H),6.77(d,1H),6.72-6.57(m,2H),5.51(s,1H),5.13(m,1H),4.79(t,1H),4.56-4.34(m,5H),4.30(t,1H),4.13(t,2H),3.86(m,2H),3.69(d,3H),2.86(m,2H),1.78-1.63(m,2H),1.48-1.22(m,6H),0.89(t,3H)。
LCMS m/z=728.2 [M+1].
Embodiment 19
2- diethyllaminoethyls 3- [[2- [[4- [the own oxygen carbonyl carbonamidine bases of N`-] phenylamino] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 19)
2-diethylaminoethyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,MeOD)δ8.42-8.37(m,1H),7.74-7.67(m,2H),7.65(d,1H),7.58(m,2H),7.42(dd,1H),7.18(m,1H),7.03(d,1H),6.97-6.88(m,2H),4.93(s,1H),4.48-4.30(m,6H),3.95(s,3H),3.60-3.47(m,2H),3.33(m,6H),2.85(t,2H),1.84-1.72(m,2H),1.50-1.42(m,2H),1.41-1.32(m,10H),0.95(m,3H)。
Embodiment 20
1- methyl-pi -4- bases 3- (2- ((4- (N'- (hexyloxy carbonyl) carbonamidines base) phenyl amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 20)
1-methylpiperidin-4-yl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method reference implementation example 1.
1H NMR(400MHz,CDCl3)δ8.41(s,1H),7.83(d,2H),7.63(s,1H),7.35(d,2H),7.20(d,1H),7.07-6.91(m,1H),6.74(d,3H),5.08(s,1H),4.56(d,2H),4.44(t,2H),4.15(t,2H),3.78(s,3H),3.12(m,4H),2.83(t,2H),2.64(s,3H),2.45(s,2H),2.05(s,2H),1.76-1.18(m,14H),0.89(s,3H)。
LCMS m/z=697.2 [M+1].
Embodiment 21
(1- methyl-pi -4- bases) methyl 3- (2- ((4- (N'- (hexyloxy carbonyl) carbonamidines base) phenyl amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 21)
(1-methylpiperidin-4-yl)methyl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.39(dd,1H),7.66(d,2H),7.58-7.51(m,1H),7.44(dd,2H),7.14(m,2H),6.88(dd,3H),4.69(s,2H),4.24(q,4H),3.86(d,2H),3.77(s,4H),3.42(d,2H),2.90(s,2H),2.74(s,3H),2.71(d,2H),1.83(d,3H),1.73-1.62(m,1H),1.38(m,4H),1.29(m,4H),0.88(t,3H)。
Embodiment 22
2- dimethylaminoethyls 3- [[2- [[4- [the own oxygen carbonyl carbonamidine bases of N`-] phenylamino] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 22)
2-dimethylaminoethyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=671.36 [M+1].
1H NMR(400MHz,CDCl3)δ8.42(dd,1H),7.79(s,1H),7.77(s,1H),7.71(s,1H),7.37-7.28(m,2H),7.13(d,1H),6.99(dd,1H),6.71(dd,3H),5.25(t,1H),4.51(d,2H),4.43(t,2H),4.19(t,2H),4.14(t,2H),3.76-3.70(m,3H),2.83(t,2H),2.64(t,2H),2.34(s,6H),1.76-1.66(m,2H),1.42-1.35(m,2H),1.31(m,4H),0.89(t,3H)。
Embodiment 23
2- oxo -1,3- dioxanes -5- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 23)
2-oxo-1,3-dioxan-5-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
The first step：2- phenyl -1,3- dioxanes -5- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) first Base) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (23B)
2-phenyl-1,3-dioxan-5-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
By raw material 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (3g, 5mmol) it is dissolved in N, in dinethylformamide (50mL), add 2- phenyl -1, 3- dioxane -5- alcohol (23A) (1.35g, 7.5mmol), DMAP (0.366g, 3mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.2g, after 6.5mmol) room temperature reaction reactions in 24 hours terminate, add ethyl acetate (100mL), wash (100mL × 2), saturated common salt water washing (100mL), anhydrous sodium sulfate drying, it is concentrated under reduced pressure, column chromatography (methylene chloride/methanol=100/1~100/3) obtains compound as white solid 2- phenyl -1, 3- dioxanes -5- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (23B) (1g, yield 26.31%)
1H NMR(400MHz,CDCl3)δ8.41(dd,1H),7.72(dd,3H),7.46(dd,2H),7.34-7.27(m,3H),7.20(dd,1H),7.03(d,1H),6.99-6.92(m,1H),6.72(d,1H),6.66(d,2H),5.55(s,1H),5.35(s,1H),4.71(s,1H),4.50(t,2H),4.45(d,2H),4.29(d,2H),4.14(dd,4H),3.68(d,3H),2.87(t,2H),1.80-1.66(m,2H),1.41(dd,2H),1.36-1.28(m,4H),0.89(m,3H)。
MS m/z (ESI)=762.3 [M+1].
Second step：1,3- dihydroxy propyl- 2- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1-1H- benzos [d] imidazoles -5- formamidos) propionic ester (23C)
1,3-dihydroxypropan-2-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
By 2- phenyl -1,3- dioxanes -5- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (23B) (0.7g, 0.9mmol) it is dissolved in ethanol (10mL), add palladium charcoal (140mg), hydrochloric acid (0.7mL), hydrogen is passed through, room temperature reaction is stayed overnight.Filter palladium charcoal, pH is adjusted to be 8-9 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (60mL × 2), saturated common salt water washing (60mL), anhydrous sodium sulfate drying, it is concentrated under reduced pressure, column chromatography (methylene chloride/methanol=100/1~100/5) obtains compound as white solid 1, 3- dihydroxy propyl- 2- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1-1H- benzos [d] imidazoles -5- formamidos) propionic ester (23C) (190mg, yield 30.6%)
1H NMR(400MHz,CDCl3)δ8.44-8.35(m,1H),7.73-7.58(m,3H),7.35(dd,1H),7.24(d,1H),7.01(dd,2H),6.75(d,1H),6.60(d,2H),5.49(s,1H),4.43(d,4H),4.22-4.14(m,2H),4.12(d,2H),3.97(d,1H),3.84(d,1H),3.74-3.57(m,5H),2.74(s,2H),1.76-1.66(m,2H),1.45-1.35(m,2H),1.35-1.28(m,4H),1.26(s,1H),0.89(m,3H)。
MS m/z (ESI)=674.2 [M+1].
3rd step：2- oxo -1,3- dioxanes -5- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 23)
2-oxo-1,3-dioxan-5-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
By 1,3- dihydroxy propyl- 2- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1-1H- benzos [d] imidazoles -5- formamidos) propionic ester (23C) (2.2g, 3.2mmol) it is dissolved in dichloromethane (200mL), add triethylamine (0.45mL, 3.2mmol), N, N'- carbonyl dimidazoles (1g, 6.4mmol), 404 reactions are stayed overnight.After reaction terminates, wash (500mL), saturated common salt water washing (200mL), anhydrous sodium sulfate drying is concentrated under reduced pressure, column chromatography (dichloromethane:Methanol (v/v)=100/1~100/3) obtain compound as white solid 2- oxos -1,3- dioxanes -5- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic ester (compound 23) (1.3g, yield 59%).
1H NMR(400MHz,CDCl3)δ8.42(dd,1H),7.74(d,2H),7.68(d,1H),7.36-7.24(m,3H),7.10(d,1H),6.99(m,1H),6.67(t,3H),5.37(s,1H),5.00-4.87(m,1H),4.55(t,1H),4.50-4.44(m,3H),4.44-4.36(m,2H),4.29(m,2H),4.13(t,2H),3.70(s,3H),2.87-2.78(m, 2H),1.71(dd,2H),1.44-1.35(m,2H),1.37-1.22(m,4H),0.89(m,3H)。
MS m/z (ESI)=700.3 [M+1].
Embodiment 24
3- [[1- methyl 2- [[4- [N'- (3- pyrovinic acid bases propoxycarbonyl) carbonamidine base] aniline] methyl] benzimidazole -5- carbonyls]-(2- pyridines) amine] propionic acid second fat (compound 24)
ethyl 3-[[1-methyl-2-[[4-[N'-(3-methylsulfonylpropoxycarbonyl)carbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 14.
1H NMR(400MHz,MeOD)δ8.41(d,1H),7.73(d,2H),7.59(d,1H),7.52(d,1H),7.39(d,1H),7.31(dd,1H),7.15(dd,1H),6.94(d,1H),6.79(d,2H),4.68(s,2H),4.38(t,2H),4.27(t,2H),4.07(q,2H),3.84(s,3H),3.63(q,2H),3.03(dd,1H),2.99-2.86(m,1H),2.77(t,2H),2.68(s,3H),2.28-2.08(m,1H),1.21(m,2H)。
Embodiment 25
3- (1- methyl-N- (pyridine -2- bases) -2- (((4- (N'- ((tetradecyloxyaniline) carbonyl) carbonamidine base) phenyl) amino) methyl) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate (compound 25)
ethyl 3-(1-methyl-N-(pyridin-2-yl)-2-(((4-(N'-((tetradecyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 14.
1H NMR(400MHz,CDCl3)δ8.41(dd,1H),7.72(d,2H),7.67(d,1H),7.33(m,1H),7.27-7.23(m,1H),7.04(d,1H),7.01-6.95(m,1H),6.70(d,1H),6.62(d,2H),5.37(d,1H),4.42(dd,4H),4.13(t,2H),4.07(q,2H),3.68(d,3H),2.80(t,2H),1.77-1.67(m,2H),1.45-1.35(m,2H),1.26(m,20H),1.21(m,4H),0.88(t,3H)。
Embodiment 26
3- (1- methyl-N- (pyridine -2- bases) -2- (((4- (N'- ((hexadecane epoxide) carbonyl) carbonamidine base) phenyl) amino) methyl) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate (compound 26)
ethyl 3-(1-methyl-N-(pyridin-2-yl)-2-(((4-(N'-((Hexadecyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 14.
1H NMR(400MHz,DMSO-d6)δ8.40(dd,1H),7.80(d,2H),7.55(d,1H),7.48(s,1H),7.40(d,1H),7.20-7.10(m,2H),6.94(s,1H),6.89(d,1H),6.77(d,2H),4.60(d,2H),4.23(t,2H),3.98(q,4H),3.77(s,3H),2.69(t,2H),1.57(d,2H),1.24(s,26H),1.13(t,3H),0.85(m,3H)。
Embodiment 27
3- first sulfopropyls 3- [[2- [[4- [the own oxygen carbonyl first of N`- is narrowed] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 27)
3-methylsulfonylpropyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=720.31 [M+1].
1H NMR(400MHz,CDCl3)δ8.41(d,1H),7.82-7.62(m,3H),7.38-7.27(m,2H),7.14(d,1H),6.99(dd,1H),6.72(dd,3H),5.42(s,1H),4.52(d,2H),4.46-4.35(m,2H),4.17(m,4H),3.74(s,3H),2.88-2.66(m,4H),2.53(s,3H),2.15-2.04(m,2H),1.71(dd,2H),1.39(dd,2H),1.31(m,4H),0.89(t,3H)。
Embodiment 28
(S) -2- (((amino (4- (((5- ((3- ethyoxyl -3- oxopropyls) (pyridine -2- bases) carbamoyl)-methyl isophthalic acid H- benzos [d] imidazoles -2- bases) methyl) amino) phenyl) methylene) carbamoyl) epoxide) ethyl 2- amino -3 Methylbutanoic acid ester (compound 28)
(S)-2-(((amino(4-(((5-((3-ethoxy-3-oxopropyl)(pyridin-2-yl)carbamoyl)-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)amino)phenyl)methylene)carbamoyl)oxy)ethyl 2-amino-3-methylbutanoate
The first step：2- Benzyloxyethyls (2S) -2- (tert-butoxycarbonyl) -3 Methylbutanoic acid ester (28B)
2-benzyloxyethyl(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate
By raw material (S) -2- (tert-butoxycarbonyl-amino) -3 Methylbutanoic acid (28A) (6.5g, 0.03mol) it is dissolved in dichloromethane (80mL), 2- BOEs (4.1g is added under ice bath, 0.027mol), dicyclohexylcarbodiimide (7.1g, 0.034mol), DMAP (0.665g, 0.005mol), 0 DEG C is reacted 18 hours.After reaction terminates, add water 300mL, extracted with dichloromethane (200mL × 2), merge organic phase, (0.5mol/L is washed with watery hydrochloric acid, 100mL × 2), saturated common salt water washing (100mL × 2), anhydrous sodium sulfate drying is concentrated under reduced pressure, column chromatography, uses 2% ethanol/methylene.Obtain title compound 2- Benzyloxyethyls (2S) -2- (tert-butoxycarbonyl) -3 Methylbutanoic acid ester (28B), colourless liquid (8g, yield 84.2%).
1H NMR(400MHz,CDCl3)δ7.41-7.23(m,5H),5.03(d,1H),4.56(d,2H),4.35(t,1H), 4.32-4.22(m,2H),3.68(t,2H),2.24-2.07(m,1H),1.48-1.41(m,9H),0.96(d,3H),0.89(d,3H)。
Second step：2- ethoxys (2S) -2- (tert-butoxycarbonyl) -3 Methylbutanoic acid ester (28C)
2-hydroxyethyl(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate
By 2- Benzyloxyethyls (2S) -2- (tert-butoxycarbonyl) -3 Methylbutanoic acid ester (28B) (6.0g, 17.1mmol) it is dissolved in methanol (60mL), palladium carbon (1.2g) is added, hydrogen is passed through, reacted at room temperature 4 hours.After reaction terminates, palladium carbon is filtered, is concentrated under reduced pressure, product is obtained, title compound 2- ethoxys (2S) -2- (tert-butoxycarbonyl) -3 Methylbutanoic acid ester (28C), colorless oil is obtained, (4.0g, yield 89.68%).
3rd step：2- (((amino (4- (((5- ((3- ethyoxyl -3- oxopropyls) (pyridine -2- bases) carbamoyl)-methyl isophthalic acid H- benzos [d] imidazoles -2- bases) methyl) amino) phenyl) methylene) carbamoyl) epoxide) ethyl (S) -2- tertbutyloxycarbonylaminos -3 Methylbutanoic acid ester (28D)
2-[[amino-[4-[[5-[(3-ethoxy-3-oxo-propyl)-(2-pyridyl)carbamoyl]-1-methyl-benzimidazol-2-yl]methylamino]phenyl]methylene]carbamoyl]oxyethyl(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate
By 2- ethoxys (2S) -2- (tert-butoxycarbonyl) -3 Methylbutanoic acid ester (28C) (1.6g, 6.0mmol) it is dissolved in tetrahydrofuran (10mL), add N, N'- carbonyl dimidazoles (1.05g, 6.5mmol), room temperature reaction 1 hour, removal of solvent under reduced pressure is reaction solution 1, standby.By 3- (2- (((4- carbamimido-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate tosilate (6A) (3.35g, 5mmol) it is dissolved in the in the mixed solvent of acetone (80mL) and water (40mL), add potassium carbonate (2.07g, 15mmol), the reaction solution 1 prepared in addition, is reacted at room temperature 5 hours after adding.After reaction terminates, add water (50mL), it is extracted with ethyl acetate (50mL × 2), anhydrous sodium sulfate drying, it is concentrated under reduced pressure, column chromatography (methylene chloride/methanol=100/1~100/3) obtains title compound 2- (((amino (4- (((5- ((3- ethyoxyl -3- oxopropyls) (pyridine -2- bases) carbamoyl)-methyl isophthalic acid H- benzos [d] imidazoles -2- bases) methyl) amino) phenyl) methylene) carbamoyl) epoxide) ethyl (S) -2- tertbutyloxycarbonylaminos -3 Methylbutanoic acid ester (28D), White solid (2.0g, yield 51.28%).
LC-MS 787.3[M+1]。
4th step：(S) -2- (((amino (4- (((5- ((3- ethyoxyl -3- oxopropyls) (pyridine -2- bases) carbamoyl)-methyl isophthalic acid H- benzos [d] imidazoles -2- bases) methyl) amino) phenyl) methylene) carbamoyl) epoxide) ethyl 2- amino -3 Methylbutanoic acid ester (compound 28)
(S)-2-(((amino(4-(((5-((3-ethoxy-3-oxopropyl)(pyridin-2-yl)carbamoyl)-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)amino)phenyl)methylene)carbamoyl)oxy)ethyl 2-amino-3-methylbutanoate
Raw material 2- (((amino (4- (((5- ((3- ethyoxyl -3- oxopropyls) (pyridine -2- bases) carbamoyl)-methyl isophthalic acid H- benzos [d] imidazoles -2- bases) methyl) amino) phenyl) methylene) carbamoyl) epoxide) ethyl (S) -2- tertbutyloxycarbonylaminos -3 Methylbutanoic acid ester (28D) (0.3g; 0.4mmol) it is dissolved in dichloromethane (25mL); trifluoroacetic acid (5mL) is added, is reacted at room temperature 2 hours.Reaction is concentrated under reduced pressure after terminating, pH is adjusted to be 8 or so with saturated sodium bicarbonate, extracted with dichloromethane (30mL × 1), saturated aqueous common salt (30mL salt 1) is washed, anhydrous sodium sulfate drying, it is concentrated under reduced pressure, obtain (S) -2- (((amino (4- (((5- ((3- ethyoxyl -3- oxopropyls) (pyridine -2- bases) carbamoyl)-methyl isophthalic acid H- benzos [d] imidazoles -2- bases) methyl) amino) phenyl) methylene) carbamoyl) epoxide) ethyl 2- amino -3 Methylbutanoic acid ester (compound 28), off-white color (0.2g, yield 80%)
1H NMR(400MHz,CDCl3)δ8.42(dd,1H),7.74(d,2H),7.70(s,1H),7.36-7.27(m,2H),7.08(d,1H),6.98(m,1H),6.71(d,1H),6.66(d,2H),5.39(s,1H),4.51-4.33(m,8H),4.08(q,2H),3.69(s,3H),3.34(d,1H),2.81(t,2H),2.09-2.02(m,1H),1.22(t,3H),0.97(d,3H),0.90(d,3H)。
LC-MS 687.2[M+1]。
Embodiment 29
3- (2- (((4- (N'- ((2- ((isopropoxy carbonyl) epoxide) ethyoxyl) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate (compound 29)
ethyl 3-(2-(((4-(N'-((2-((isopropoxycarbonyl)oxy)ethoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 14.
1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.73(s,1H),8.39(dd,1H),7.82(d,2H),7.54(m,1H),7.48(d,1H),7.40(d,1H),7.16(dd,1H),7.11(dd,1H),6.97(t,1H),6.89(d,1H),6.77(d,2H),4.76(m,1H),4.60(d,2H),4.27(dd,2H),4.25-4.20(m,4H),3.98(q,2H),3.77(s,3H),2.68(t,2H),1.22(d,6H),1.12(t,3H)。
LCMS m/z=674.3 [M+1].
Embodiment 30
3- [[2- [[4- [N`- [2- [2- (2- hydroxyl-oxethyls) ethyoxyl] ethoxy carbonyl] carbonamidine base] phenylamino] methyl] -1- tolimidazole -5- carbonyls]-(2- pyridine radicals) amino] ethyl propionate mesylate (compound 30)
ethyl 3-[[2-[[4-[N`-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxycarbonyl]carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoatemethanesul fonic acid
Preparation method is referring to embodiment 15 and conventional salt production process.
1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),10.76(s,1H),10.07(s,1H),8.38(d,1H),7.68(d,2H),7.57(dd,3H),7.26(d,1H),7.14(dd,1H),6.98(d,1H),6.89(d,2H),4.82(s,2H),4.46-4.36(m,2H),4.23(t,2H),3.98(q,2H),3.85(s,3H),3.74(d,2H),3.62-3.56(m,2H),3.54(dd,2H),3.50(t,2H),3.43(t,2H),2.69(t,2H),2.32(s,3H),1.13(t,3H)。
LCMS m/z=676.2 [M+1].
Test case
1st, Pharmacokinetic Evaluation
Healthy adult SD rat (male and female half and half tie up the magnificent Experimental Animal Center of tonneau, animal productiong licensing SCXK (capital) 2012-0001 purchased from Beijing), administration fasted for one day prior can't help water.6 rat oral gavage administration 5mg/kg (in terms of dabigatran original shape medicine), compound is configured to 0.5mg × mL with 0.5%CMC-Na (containing 1% Tween 80)-1(with dabigatran original shape Medicine meter) suspension, in 5min, 15min, 30min, 1.0 after (0h) before administration and administration, 2.0,4.0,8.0,24.0h are taken a blood sample by eye socket, anticoagulant heparin, separated plasma after 4 DEG C of 3000rpm centrifugation 10min, to be measured in -80 DEG C of preservations.Take each time point rat plasmas of 30ul, inner mark solution (7.5ng/mL Verapamils) 200ul, vortex mixing 1min is added, in 4 DEG C of 13000rpm centrifugations 10min, supernatant 190ul is taken to carry out LC-MS/MS (lc-20A Science and Technology Ltd.s of Shimadzu Corporation, API4000+) analyses.Main pharmacokinetic parameter is analyzed with the non-compartment model of the softwares of WinNonlin 6.3, as a result as shown in table 1.
Table 1：Pharmacokinetic parameter result
Conclusion：The compounds of this invention has good Pharmacokinetic Characteristics, it is oral after, active component is quickly converted into vivo, or so half an hour can reach maximum plasma concentration.

Claims (9)

  1. A kind of compound and its stereoisomer, or pharmaceutically acceptable salt, the wherein compound are selected from one of following structure：
  2. Compound and its stereoisomer according to claim 1, or pharmaceutically acceptable salt, wherein described salt is selected from hydrochloride, hydrobromate, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalates, oxyacetate, salicylate, glucuronate salt, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate, ferulate or combinations thereof.
  3. A kind of pharmaceutical composition, described pharmaceutical composition contains the compound according to any one in claim 1~2 or its stereoisomer or pharmaceutically acceptable salt for the treatment of effective dose, and pharmaceutically acceptable carrier or excipient.
  4. Compound and its stereoisomer or pharmaceutically acceptable salt in claim 1~2 described in any one, and purposes of the composition in treatment and thrombin inhibitor relevant disease medicine is prepared described in claim 3.
  5. Purposes according to claim 4, wherein described be selected from thromboembolic disorders with thrombin inhibitor relevant disease.
  6. Purposes according to claim 5, wherein described thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
  7. A kind of method treated with thrombin inhibitor relevant disease, wherein methods described include the compound or its stereoisomer or pharmaceutically acceptable salt described in administration claim 1 or 2, or the composition described in claim 3.
  8. Method according to claim 7, wherein described be selected from thromboembolic disorders with thrombin inhibitor relevant disease.
  9. Method according to claim 8, wherein described thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
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CN102838588A (en) * 2011-06-24 2012-12-26 中国药科大学 Oral thrombin inhibitors, preparation methods and medical uses thereof
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