CN102633780B - Nitric oxide donor with thrombin inhibition effect, as well as preparation method and medical application thereof - Google Patents

Nitric oxide donor with thrombin inhibition effect, as well as preparation method and medical application thereof Download PDF

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CN102633780B
CN102633780B CN201210152246.1A CN201210152246A CN102633780B CN 102633780 B CN102633780 B CN 102633780B CN 201210152246 A CN201210152246 A CN 201210152246A CN 102633780 B CN102633780 B CN 102633780B
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徐云根
庄毅超
龚国清
李天路
王欣慧
刁小娟
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China Pharmaceutical University
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Abstract

The invention relates to the medicinal chemistry field, and discloses a nitric oxide donor with a thrombin inhibition effect, as well as a preparation method and medical application thereof, and particularly relates to a kind of pseudo-peptide antithrombase inhibitor (I), as well as a preparation method and an inhibition effect and an antithrombotic effect thereof on thrombin. Pharmacological experiment proves that the compound can be used for treating and preventing various diseases related to thrombosis, and the diseases comprise arterial thromboembolic diseases, venous thromboembolic diseases and other thrombotic cardiovascular diseases.

Description

One class has the inhibiting nitric oxide donors of zymoplasm, its method for making and medicinal use
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to the non-peptide class of a class antithrombin inhibitor, they preparation method and to the restraining effect of zymoplasm and anti thrombotic action.
Technical background
Now, thrombotic cardiovascular and cerebrovascular diseases has become the formidable enemy who threatens human health, and arterial thromboembolism disease and venous thromboembolism disease are frequently-occurring diseases clinically.Since 1914 find heparin, anticoagulation medicine is being obtained considerable progress aspect prevention and treatment thrombus disease.Along with increasing and cardiovascular disorder multiple of world's elderly population, anticoagulation medicine will have vast potential for future development.
Dabigatran etcxilate (Dabigatran Etexilate) is developed by German Boehringer Ingelheim company, in April, 2008, in Germany and Britain, takes the lead in going on the market, and this is the first new classification oral anticoagulant thing going on the market over 50 years after warfarin.The listing of this product, is a major progress in anticoagulation therapy field and potential lethality thrombus prevention field, has milestone significance.Dabigatran etcxilate is a kind of novel, non-peptide class, competitiveness, reversible thrombin inhibitors, it is the prodrug of dabigatran (Dabigatran), orally after stomach and intestine absorb, be converted in vivo active part dabigatran, produce zymoplasm restraining effect.Dabigatran is incorporated into the scleroproein specific combination site of zymoplasm, stops Fibrinogen to be cracked into scleroproein, thereby has blocked final step and the thrombosis of blood coagulation waterfall network.Dabigatran can dissociate from scleroproein-zymoplasm combination, brings into play reversible anticoagulation.
Figure BSA00000717047900011
Dabigatran: R 1=R 2=H
Dabigatran etcxilate: R 1=-CH 2cH 3,
Figure BSA00000717047900012
Nitrogen protoxide (NO) is as bioinformation mediator in a class body, participates in the adjusting of different physiological roles in organism, in cardiovascular, immunity and the system such as neural, plays a very important role.NO has vasodilator unstriated muscle, suppresses the vasodilator activities such as myocardial contraction, simultaneously can also anticoagulant, resisting vascular smooth muscle cell proliferation etc.These effects of NO are significant for formation and the alleviation ischemic cardiovascular of atherosclerosis.
Furazan oxynitride is as one type of NO donor, due to its comparatively significant biological activity, is widely used in step-down, the field of medicaments such as antitumor.
5-ISMN is from 1981 after Germany goes on the market, and successively, in the listing of a plurality of countries such as the U.S., France, Italy, this drug absorption distributes fast, and without liver first-pass effect, bioavailability is high, becomes dominating in antianginal drug.
The present invention carries out amalgamation by ester bond by dabigatran etcxilate and NO donor, to obtaining active better compound.
Figure BSA00000717047900021
Furazan oxynitride 5-ISMN
Summary of the invention
The invention discloses the compound of a class general formula I, through pharmacological evaluation, show, compound of the present invention has stronger restraining effect to zymoplasm.Therefore, formula I compound of the present invention, can be used for treatment and prevents the various diseases relevant to thrombosis, and these diseases comprise arterial thromboembolism disease, venous thromboembolism disease, and other thrombotic cardiovascular and cerebrovascular diseases.
Figure BSA00000717047900022
R 1representative: C 1～C 8alkyl, benzyl or phenyl; R 2representative: 2-N-oxo-4-aryl-1,2,5-oxadiazole-3-methylene radical or 6-nitre oxygen base-hexahydro furyl be [3,2-b] also) furans-3-carbon-oxygen carbonyl, wherein aryl is: phenyl or benzenesulfonyl.
Part of compounds of the present invention is:
3-[2-((4-(N '-(own oxygen carbonyl) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid-2-oxide compound-4-phenyl-1,2,5-oxadiazole-3-methyl ester (I-1)
(6-nitre oxygen base-hexahydro furyl is [3,2-b] also) furans-3-carbon-oxygen carbonyl 3-[2-((4-(N '-(own oxygen carbonyl) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid (I-2)
3-[2-((4-(N '-(carbobenzoxy-(Cbz)) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid-2-oxide compound-4-phenyl-1,2,5-oxadiazole-3-methyl ester (I-3)
(6-nitre oxygen base-hexahydro furyl is [3,2-b] also) furans-3-carbon-oxygen carbonyl 3-[2-((4-(N '-(carbobenzoxy-(Cbz)) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid (I-4)
3-[2-((4-(N '-(isobutyl boc) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid-2-oxide compound-4-phenyl-1,2,5-oxadiazole-3-methyl ester (I-5)
(6-nitre oxygen base-hexahydro furyl is [3,2-b] also) furans-3-carbon-oxygen carbonyl 3-[2-((4-(N '-(isobutyl boc) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid (I-6)
The available following method preparation of general formula compound of the present invention (I):
Figure BSA00000717047900031
Reactant A is
Figure BSA00000717047900032
r wherein 1for C 1～C 8straight or branched alkane, C 5～C 7naphthenic hydrocarbon or substituted ring alkane, benzyl or substituted benzyl, phenyl or substituted-phenyl; Work as R 1during for the tertiary butyl, reactant A is tert-Butyl dicarbonate.Solvent orange 2 A is the mixed solvent of tetrahydrofuran (THF), acetone, methylene dichloride, acetonitrile, tetrahydrofuran (THF) and water or the mixed solvent of acetone and water; The mixed solvent of preferred tetrahydrofuran (THF) and water.
Reactant B is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or salt of wormwood; Preferred sodium hydroxide.Solvent B is water, aqueous alcohol, aqueous acetone; Preferred aqueous ethanol.
Reactant C is the nitric oxide donors such as furazan oxynitride and 5-ISMN.
Condensing agent D is dicyclohexylcarbodiimide (DCC), N, N '-carbonyl dimidazoles (CDI), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and DMAP (DMAP); Preferred 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and DMAP (DMAP).Solvent E is DMF, acetonitrile, methylene dichloride or both mixed solvents arbitrarily; Preferred DMF.
Wherein the preparation of Compound I I can reference literature (J Med Chem.2002,45:1757-1766; Chinese Journal of Pharmaceuticals .2010,41 (5): 321-325.), 3-nitro-4-chloro-benzoic acid of take is raw material, and synthetic method is as follows:
Figure BSA00000717047900041
Wherein a～f is reaction conditions: a:25%-30% aqueous methylamine solution; B: thionyl chloride; C: triethylamine, methylene dichloride; D: Sodium Hydrosulphite, 50% ethanol; E: carbonyl dimidazoles, anhydrous tetrahydro furan; F: 1. hydrogenchloride, dehydrated alcohol; 2. volatile salt, dehydrated alcohol.
Below pharmacological testing and the result of part of compounds of the present invention.
The inhibiting testing method of the platelet aggregation of part of compounds thrombin induction of the present invention is as follows:
Experiment material and instrument:
Material: new zealand rabbit (China Medicine University's Experimental Animal Center, body weight 2.2-2.3kg)
Reagent: (1) zymoplasm: Yige Pharmaceutical Co., Ltd., Hunan Prov.;
(2) sodium chloride injection: Anhui Double-Crane Pharmaceutical Co., Ltd;
(3) methyl-sulphoxide: traditional Chinese medicines group chemical reagent company limited produces.
Instrument: (1) SC-2000 platelet aggregation tester: Saikexide Science & Technology Development Co., Ltd., Beijing;
(2) TG1650-WS table model high speed centrifuge: Shanghai Lu Xiang whizzer company limited;
(3) HH-4 thermostat water bath: Guo Hua instrument company;
(4) the adjustable supercentrifuge of FSH-2A: great Sheng laboratory apparatus company limited;
(5) analytical balance: Shanghai Min Qiao precision instrument company.
Medicine activation and solution preparation:
(1) preparation of hepatomicrosome: the hepatic tissue of getting rabbit is cut into fragment, with containing KCl (0.15molL -1) phosphoric acid buffer (0.1molL -1, pH 7.4) repeatedly rinse and remove the blood component in tissue, finally by 1: 4 (W/V), add above-mentioned KCl phosphate buffer solution, liver homogenate is made by Yong Nei cut tissue refiner.By the liver homogenate preparing centrifugal (9000rmin on ultracentrifuge -1) 15min, get supernatant liquor centrifugal (16000rmin again -1) 60min, get pink supernatant liquor, i.e. hepatomicrosome solution.
(2) medicine activation and solution preparation: take I series and be respectively subject to reagent and dabigatran etcxilate 2mg, add methyl-sulphoxide 40 μ L to dissolve, add above-mentioned liver homogenate 1mL, mix, be placed in 37 ℃ of water-bath incubation 4h, then with normal saline dilution, become 10 -5, 10 -6, 10 -7, 10 -8molL -1isoconcentration.
Operating process:
Get one of new zealand rabbit, after PROCAINE HCL, PHARMA GRADE local anaesthesia, right carotid intubate is got blood.Whole blood mixes according to volume ratio 9: 1 and 3.8% Sodium Citrate, with the centrifugal 5min of rotating speed 1000r/min, gets supernatant liquor, is platelet rich plasma (PRP); Residual blood, with the centrifugal 10min of rotating speed 3000r/min, obtains platelet poor plasma (PPP).With PPP, return to zero, take PRP as thrombocyte donor, get respectively 200 μ L PRP, with solvent control group, each concentration positive controls and mixed by reagent group, after 37 ℃ of incubation 1min, add respectively the Thr 20 μ L of 15U/mL, utilize SC-2000 platelet aggregation instrument to trace curve of platelet aggregation, observe thrombocyte MA (MAR) in 10min, by instrument specification sheets time-and-motion study platelet aggregation rate.
Screening active ingredients result:
With the positive contrast of dabigatran etcxilate, the compounds of this invention is carried out to the external screening to the inhibition activity of the platelet aggregation of thrombin induction, the results are shown in Table 1.
Table 1: the IC of the platelet aggregation of dabigatran etcxilate and the enzyme induction of the compounds of this invention anticoagulant 50value
Figure BSA00000717047900051
Figure BSA00000717047900061
From table 1, the compounds of this invention I-2 is active suitable with positive drug dabigatran etcxilate.
The research method that the external NO of part of compounds of the present invention discharges test is as follows:
Experimental technique:
The preparation of Griess reagent:
Sulfanilamide (SN) 4g, N-naphthodiamide hydrochloride 0.2g, 85% phosphatase 11 0ml, with distilled water diluting to 100ml.The drafting of typical curve:
Precision takes dry Sodium Nitrite 0.15g and is placed in 100ml volumetric flask, with distilled water, dissolves and is diluted to scale.Precision measures in 0.1ml to 100ml volumetric flask, is diluted with water to scale, obtains 1.5mg/L Sodium Nitrite standard inventory solution.
The preparation of standard operation solution: precision measures standard reserving solution, being mixed with concentration is the Sodium Nitrite series standard working fluid of 0.21-1.5mg/L.
Measure respectively working solution 2ml, 0.5ml fully mixes with Griess reagent, and room temperature is placed 10min, measures its optical density at 540nm place.According to the data obtained drawing standard curve, with optical density value A, Sodium Nitrite concentration of standard solution C is carried out to regression Calculation.
The mensuration of nitrogen protoxide extracorporeal releasing quantity: the preparation of the phosphate buffer soln that contains excessive Cys (5mmol) (pH7.4): precision takes potassium primary phosphate 6.8g, add 0.1mol/L sodium hydroxide solution 395mL and Cys 0.6g, by water dissolution and be diluted to 1000mL.The pH7.4 phosphate buffer soln that must contain excessive Cys (5mmol).
Be subject to the preparation of test sample solution:
Precision takes test-compound, with dmso solution and be diluted to 10mL, shakes up, and makes the solution that concentration is 0.01mol/L.
Precision takes Ismo 20 19.1mg, with dmso solution and be diluted to 10mL, shakes up, and obtains the solution that concentration is 0.01mol/L.
Precision measures all dimethyl sulphoxide solution (0.01mol/L) 1.0mL that are subject to test product, is diluted to 100mL respectively with the pH7.4 phosphate buffer soln that contains excessive Cys (5mmol/L).Finally, the concentration of need testing solution is 10 -4mol/L.Solution is placed in to 37 ℃ of environment and hatches, in different time points, extract reaction solution 2mL and griess reagent 0.5mL is blended in triangular flask, room temperature is placed 10min, surveys optical density at 540nm wavelength place.Nitric oxide production burst size is with its oxide compound nitrite (NO 2 -) scale show.
Experimental result:
(1) get the sodium nitrite solution of series concentration, this reagent react in dative, measures optical density A, to trial-product concentration C (10 in 540nm place -4mol/L) carry out linear regression, regression equation is: A=3.1206C+0.0079, r 2=0.9991.
(2) part of compounds NO burst size of the present invention is except occurring, larger fluctuation, totally showing a rising trend in time at indivedual time points after tested, and positive control drug 5-ISMN and I-2 general trend are comparatively steady.Specifically as shown in table 2.
Table 2: the external NO burst size of part of compounds of the present invention
Figure BSA00000717047900071
Figure BSA00000717047900081
The present invention also provides the pharmaceutical composition of a kind of prevention and treatment vascular thrombosis embolism class diseases, wherein contains compound of Formula I and the pharmaceutically acceptable carrier for the treatment of significant quantity.Described pharmaceutical composition can be dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when compound of Formula I of the present invention is used for the treatment of, people is 1mg～5000mg/ days with dosage range.Also can be according to the difference of formulation and disease severity, using dosage exceeds this scope.
Embodiment
Embodiment 1
3-[2-((4-(N '-(own oxygen carbonyl) amidino groups) anilino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-amide group] preparation of ethyl propionate (III-1)
At 0-5 ℃, by II (2g, 0.0037mol) and salt of wormwood (1.55g, 0.0112mol) be dissolved in the mixed solvent of 60mL tetrahydrofuran (THF) and 12mL water, after stirring at room 15min, in above-mentioned solution, add the just own ester (0.74g of chloroformic acid, 0.0045mol), reaction rises to room temperature, continues to stir after 5h stopped reaction.Separate tetrahydrofuran (THF) layer, anhydrous sodium sulfate drying, filters, and carries out column chromatography after being spin-dried for, and eluent is methylene dichloride: methyl alcohol=30: 1, obtain 1.47g white solid, productive rate: 63.3%, m.p.130～132 ℃.
1H-NMR(300MHz?DMSO-d6)δ(ppm)：0.87(3H，t，J＝6.9Hz，-CH 2CH 2 CH 3 )，1.12(3H，t，J＝7.2Hz，-CH 2 CH 3 )，1.27-1.29(6H，m，-CH 2 CH 2 CH 2 CH 2 CH 3)，1.57(2H，q，J＝6.6Hz，-OCH 2 CH 2 CH 2-)，2.68(2H，t，J＝6.9Hz，＞NCH 2 CH 2 -)，3.77(3H，s，＞N CH 3 )，3.94-4.00(4H，m，-O CH 2 CH 3，-O CH 2 CH 2CH 2-)，4.22，(2H，t，J＝6.9Hz，＞N CH 2 CH 2-)，4.59(2H，d，J＝5.4Hz，- CH 2 NH-)，6.76(2H，d，J＝8.7Hz，ArH)，6.88(1H，d，J＝8.1Hz，ArH)，6.98(1H，m，NH)，7.10-7.17(2H，m，ArH)，7.39(1H，d，J＝8.4Hz，ArH)，7.47(1H，s，ArH)，7.54(1H，t，J＝7.7Hz，ArH)，7.79(2H，d，J＝8.7Hz，ArH)，8.39(1H，d，J＝4.8Hz，ArH)，8.60-9.30(2H，brs，-NH 2)；ESI-MS(m/z)：628.4[M+H] +.
3-[2-((4-(N '-(own oxygen carbonyl) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzoglyoxaline-5-formamido-] preparation of propionic acid (IV-1)
III-1 (1.22g, 0.002mol) and sodium hydroxide (0.28g, 0.007mol) are joined in the mixed solvent of 30mL ethanol and 15mL water, after stirring at room 6h, finish reaction, concentrating under reduced pressure revolves most of ethanol, adds the dilution of 5mL water, under ice bath, with 10% citric acid, adjust pH to 4～5, solid is separated out, place refrigerator overnight, filter, filter cake washs with filtrate, again with a small amount of frozen water washing, filter, obtain 1.03g white solid, without purifying, directly drop into next step reaction.Productive rate: 90.1%, m.p.226～228 ℃.
1H-NMR(500MHz?DMSO-d6)δ(ppm)：0.87(3H，t，J＝7.0Hz，-CH 2CH 2 CH 3 )，1.28-1.34(6H，m，-CH 2 CH 2 CH 2 CH 2 CH 3)，1.58(2H，qui，J＝7.6Hz，-OCH 2 CH 2 CH 2-)，2.61(2H，t，J＝7.5Hz，＞NCH 2 CH 2 -)，3.76(3H，s，＞N CH 3 )，3.98(2H，t，J＝6.7Hz，-O CH 2 CH 2CH 2-)，4.18，(2H，t，J＝7.5Hz，＞N CH 2 CH 2-)，4.59(2H，d，J＝4.5Hz，- CH 2 NH-)，6.76(2H，d，J＝8.9Hz，ArH)，6.95(1H，d，J＝8.1Hz，ArH)，7.10-7.13(1H，m，ArH)，7.16(1H，dd，J 1＝8.5Hz，J 2＝1.5Hz，ArH)，7.39(1H，d，J＝8.5Hz，ArH)，7.48(1H，s，ArH)，7.55(1H，td，J 1＝7.8Hz，J 2＝2.0Hz，ArH)，7.79(2H，d，J＝8.9Hz，ArH)，8.38(1H，d，J＝4.8Hz，ArH)，8.50-9.50(2H，brs，-NH 2)，11.30-12.55(1H，brs，-COOH)；
ESI-MS(m/z)：600.3[M+H] +，622.3[M+Na] +.
3-[2-((4-(N '-(own oxygen carbonyl) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid-2-oxide compound-4-phenyl-1,2,5-oxadiazole-3-methyl ester (I-1)
Under 0～5 ℃ of condition, get IV-1 (0.60g, 0.001mol), 3-methylol-4-phenyl-1, 2, 5-oxadiazole-2-oxide compound (0.29g, 0.0015mol), EDCI (0.25g, 0.0013mol) and DMAP (0.07g, 0.0006mol) be dissolved in 20ml DMF, stir 30min, slowly rise to room temperature, after reaction 24h, add the dilution of 50mL methylene dichloride, 20mL saturated common salt water washing 5 times, organic layer spends the night with anhydrous sodium sulfate drying, filter, concentrated, (eluent is methylene dichloride to column chromatography: methyl alcohol=30: 1), obtain 0.43g white solid, productive rate: 55.6%, m.p.130-132 ℃.
1h-NMR (500MHz d 6-DMSO) δ (ppm): 0.87 (3H, t, J=5.0Hz ,-CH 2 cH 3 ) 1.27-1.36 (6H, m ,-CH 2 cH 2 cH 2 cH 2 cH 3), 1.59 (2H, qui, J=5.0Hz ,-CH 2 cH 2 cH 2-), 2.69 (2H, t, J=7.5Hz, > NCH 2 cH 2 -), 3.77 (3H, s, > N cH 3 ), 3.98 (2H, t, J=7.5Hz ,-O cH 2 cH 2-), 4.17 (2H, t, J=5.0Hz, > N cH 2 cH 2-), 4.60 (2H, d, J=5.0Hz ,- cH 2 nH-), 5.13 (2H, s, furazan-CH 2o-), 6.77 (2H, d, J=10Hz, ArH), 6.81 (1H, d, J=5.0Hz, ArH), 6.93 (1H, t, J=5.0Hz, ArH), 7.08-7.12 (2H, m, ArH), 7.37 (1H, d, J=5.0Hz, ArH), 7.45 (1H, s, ArH), 7.50 (1H, td, J 1=7.5Hz, J 2=5.0Hz, ArH), 7.56-7.63 (3H, m, ArH), 7.77 (1H, d, J=5.0Hz, ArH), 7.78 (2H, s, ArH), 7.81 (1H, s, ArH), 8.32-8.36 (2H, m ,-NH 2);
IR(KBr，cm -1)：526.53，692.65，746.41，767.31，813.62，1013.50，1073.89，1106.33，1143.11，1220.55，1253.60，1326.34，1385.55，1469.42，1608.46，1750.21，2857.14，2928.58，2957.45，3302.04，3397.07；
HRMS(EI+)：m/z?774.3363[M+H] +，[C 41H 44N 9O 7] +calc.for?774.3285，found?774.3363.
Embodiment 2
(6-nitre oxygen base-hexahydro furyl is [3,2-b] also) furans-3-carbon-oxygen carbonyl 3-[2-((4-(N '-(own oxygen carbonyl) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid (I-2)
With IV-1 (0.60g, 0.001mol), 5-ISMN (0.29g, 0.0015mol) is raw material, and class of operation, like the preparation of I-1, obtains 0.35g white solid, productive rate: 45.3%, m.p.134-136 ℃.
1H-NMR?(500MHz?d 6-DMSO)δ(ppm)：0.86(3H，t，J＝5.0Hz，-CH 2 CH 3 )，1.09(2H，t，J＝5.0Hz，- CH 2 CH 3)，1.29-1.34(4H，m，-CH 2 CH 2 CH 2 CH 2CH 3)，1.58(2H，qui，J＝5.0Hz，-CH 2 CH 2 CH 2-)，2.71(2H，t，J＝7.5Hz，＞NCH 2 CH 2 -)，3.38(1H，q，J 1＝7.5Hz，J 2＝5Hz，＞N CH 2CH 2-)，3.77(3H，s，＞N CH 3)，3.90(1H，dd，J 1＝27.5Hz，J 2＝5Hz，＞N CH 2CH 2-)，3.95-3.99(4H，m，?
Figure BSA00000717047900101
4.24(2H，t，J＝7.5Hz，-O CH 2 CH 2-)，4.40(1H，d，J＝5.0Hz，?
Figure BSA00000717047900102
4.60(2H，d，J＝5.0Hz，- CH 2 NH-)，4.94(1H，t，J＝5Hz，?
Figure BSA00000717047900103
5.01(1H，d，J＝5.0Hz，?
Figure BSA00000717047900104
5.48-5.51(1H，m，? 6.77(2H，d，J＝10Hz，ArH)，6.88(1H，d，J＝10.0Hz，ArH)，6.92(1H，t，J＝5.0Hz，ArH)，7.12(1H，t，J＝5.0Hz，ArH)，7.16(1H，d，J＝5.0Hz，ArH)，7.39(1H，d，J＝10.0Hz，ArH)，7.47(1H，s，ArH)，7.54(1H，td，J 1＝7.5Hz，J 2＝5.0Hz，ArH)，7.80(2H，d，J＝10.0Hz，ArH)，8.38-8.40(2H，m，-NH 2)；
IR(KBr，cm -1)：744.75，850.83，1007.00，1096.77，1127.74，1145.50，1170.29，1256.56，1280.57，1327.54，1391.46，1469.74，1608.71，1643.65，1739.76，2849.56，2926.47，2961.65，3386.43；
HRMS(EI+)：m/z?773.3255[M+H] +，[C 38H 45N 8O 10] +?calc.for?773.3180，found?773.3255.
Embodiment 3
3-[2-((4-(N '-(carbobenzoxy-(Cbz)) amidino groups) anilino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-amide group] ethyl propionate (III-2)
With II (2g, 0.0037mol), salt of wormwood (1.55g, 0.0112mol) and chloroformic acid benzyl ester (0.76g, 0.0045mol) be raw material, class of operation, like the preparation of III-1, obtains 1.73g white solid, productive rate: 73.8%, mp.165～167 ℃.
1H-NMR(500MHzCDCl 3)δ(ppm)：1.21(3H，t，J＝7.1Hz，-CH 2 CH 3 )，2.80(2H，t，J＝7.2Hz，＞NCH 2 CH 2 -)，3.64(3H，s，＞N CH 3 )，4.07(2H，q，J＝7.1Hz，- CH 2 CH 3)，4.40-4.43(4H，m，＞N CH 2 CH 2-，- CH 2 NH-)，5.19(2H，s，-O CH 2 Ph)5.32(1H，s，- NH-)，6.60(2H，d，J＝8.4Hz，ArH)，6.70(1H，d，J＝8.0Hz，ArH)，6.95-6.98(1H，m，ArH)，7.04(1H，d，J＝8.4Hz)，7.25-7.34(5H，m，ArH)，7.43(2H，d，J＝7.3Hz，ArH)，7.67-7.72(3H，m，ArH)，8.40(1H，d，J＝3.8Hz，ArH)，9.20-9.70(2H，brs，-NH 2)；
ESI-MS(m/z)：634.0[M+H] +，656.0[M+Na] +.
3-[2-((4-(N '-(carbobenzoxy-(Cbz)) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzoglyoxaline-5-formamido-] propionic acid (IV-2)
Take III-2 (1.27g, 0.002mol) and sodium hydroxide (0.28g, 0.007mol) is raw material, and class of operation, like the preparation of IV-1, obtains 1.11g white solid, without purifying, directly drops into next step reaction.Productive rate: 91.6%, m.p.179～181 ℃.
1H-NMR(500MHz?DMSO-d6)δ(ppm)：2.60(2H，t，J＝7.5Hz，＞NCH 2 CH 2 -)，3.76(3H，s，＞N CH 3 )，4.17(2H，t，J＝7.5Hz，＞N CH 2 CH 2 -)，4.59(2H，s，- CH 2 NH-)，5.08(2H，s，-O CH 2 Ph)，6.77(2H，d，J＝8.9Hz，ArH)，6.95(1H，d，J＝8.1Hz，ArH)，7.10-7.12(1H，m，ArH)，7.15-7.17(1H，m，ArH)，7.31-7.40(6H，m，ArH)，7.48(1H，s，ArH)，7.55(1H，td，J 1＝7.8Hz，J 2＝1.8Hz，ArH)，7.81(2H，d，J＝8.8Hz，ArH)，8.37(1H，d，J＝3.6Hz，ArH)，9.00-9.70(2H，brs，-NH 2)，11.70-12.50(1H，brs，-COOH)；
ESI-MS(m/z)：606.0[M+H] +，628.0[M+Na] +.
3-[2-((4-(N '-(carbobenzoxy-(Cbz)) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid-2-oxide compound-4-phenyl-1,2,5-oxadiazole-3-methyl ester (I-3)
With IV-2 (0.60g, 0.001mol) and 3-methylol-4-phenyl-1,2,5-oxadiazole-2-oxide compound (0.29g, 0.0015mol) is raw material, and class of operation, like the preparation of I-1, obtains 0.30g white solid, productive rate: 39.2%, mp.190-192 ℃.
1h-NMR (500MHz d 6-DMSO) δ (ppm): 2.68 (2H, t, J=7.5Hz, > NCH 2 cH 2 -), 3.76 (3H, s, > N cH 3 ), 4.16 (2H, t, J=5.0Hz, > N cH 2 cH 2-), 4.59 (2H, d, J=5.0Hz ,- cH 2 nH-), 5.08 (2H, s ,-O cH 2 ph), 5.13 (2H, s, furazan-CH 2o-), 6.77 (2H, d, J=10Hz, ArH), 6.81 (1H, d, J=10.0Hz, ArH), 6.94 (1H, t, J=5.0Hz, ArH), 7.07-7.12 (2H, m, ArH), 7.31 (1H, d, J=10.0Hz, ArH), 7.35-7.39 (5H, m, ArH), 7.45 (1H, s, ArH), 7.48 (1H, t, J=5.0Hz, ArH), 7.56-7.61 (3H, m, ArH), 7.77 (2H, d, J=5.0Hz, ArH), 7.81 (2H, d, J=5Hz, ArH), 8.32-8.36 (2H, m ,-NH 2);
IR(KBr，cm -1)：526.53，698.21，767.70，1013.58，1097.74，1141.72，1254.85，1316.08，1381.21，1467.11，1610.08，1746.75，2942.86，3375.69；
HRMS(EI+)：m/z?780.2904[M+H] +，[C 42H 38N 9O 7] +calc.for?780.2816，found?780.2904.
Embodiment 4
(6-nitre oxygen base-hexahydro furyl is [3,2-b] also) furans-3-carbon-oxygen carbonyl 3-[2-((4-(N '-(carbobenzoxy-(Cbz)) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid (I-4)
Take IV-2 (0.60g, 0.001mo1) and 5-ISMN (0.29g, 0.0015mo1) is raw material, and class of operation, like the preparation of I-1, obtains 0.30g white solid, productive rate: 39.2%, mp.186-188 ℃ (charing).，
1H-NMR(500MHz?d 6-DMSO)δ(ppm)：2.71(2H，t，J＝5.0Hz，＞NCH 2 CH 2 -)，3.98(3H，s，＞N CH 3 )，4.00-4.04(4H，m，?
Figure BSA00000717047900121
4.26(2H，t，J＝10.0Hz，＞N CH2CH2-)，4.40(1H，d，J＝5.0Hz，?
Figure BSA00000717047900122
4.60(2H，d，J＝5.0Hz，- CH 2 NH-)，4.89-4.95(1H，m，? 5.02(1H，d，J＝5.0Hz，?
Figure BSA00000717047900124
5.08(2H，s，-O CH 2 Ph)，5.48-5.50(1H，m，?
Figure BSA00000717047900125
6.77(2H，d，J＝10Hz，ArH)，6.88(1H，q，J 1＝15.0Hz，J 2＝5.0Hz，ArH)，6.94(1H，t，J＝5.0Hz，ArH)，7.10-7.12(1H，m，ArH)，7.16(1H，d，J＝5.0Hz，ArH)，7.31(1H，d，J＝5.0Hz，ArH)，7.34(1H，s，-CH 2 NH)，7.36-7.40(5H，m，ArH)，7.48(1H，s，ArH)，7.53(1H，t，J＝7.5Hz，ArH)，7.83(2H，d，J＝7.5Hz，ArH)，8.35-8.45(2H，m，-NH 2)；
IR(KBr，cm -1)：693.88，751.02，857.14，1004.08，1097.87，1128.56，1143.59，1316.98，1397.14，1470.80，1640.26，1738.78，2930.61，3377.66；
HRMS(EI+)：m/z?779.2796[M+H] +，[C 39H 39N 8O 10] +calc.for?779.2711，found?779.2796.
Embodiment 5
3-[2-((4-(N '-(isobutyl carbalkoxy) amidino groups) anilino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-amide group] ethyl propionate (III-3)
With II (2g, 0.0037mol), salt of wormwood (1.55g, 0.0112mol) and chloroformic acid benzyl ester (0.76g, 0.0045mol) are raw material, and class of operation, like the preparation of III-1, obtains crude product 2.5g, without purifying, directly drops into next step reaction.
3-[2-((4-(N '-(isobutyl boc) amidino groups) anilino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-amide group] propionic acid (IV-3)
Take III-3 (1.20g, 0.002mol) and sodium hydroxide (0.28g, 0.007mol) is raw material, and class of operation, like the preparation of IV-3, obtains 0.92g white solid, without purifying, directly drops into next step reaction.Productive rate: 80.7%.
3-[2-((4-(N '-(isobutyl boc) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid-2-oxide compound-4-phenyl-1,2,5-oxadiazole-3-methyl ester (I-5)
With IV-3 (0.57g, 0.001mol) and 3-methylol-4-phenyl-1,2,5-oxadiazole-2-oxide compound (0.29g, 0.0015mol) is raw material, and class of operation, like the preparation of I-1, obtains 0.35g white solid, productive rate 44.5%, mp.170-172 ℃.
1h-NMR (500MHz d 6-DMSO) δ (ppm): 0.90 (3H, s ,- cH 3 ), 0.91 (3H, s ,- cH 3 ), 1.85-1.93 (1H, m,
Figure BSA00000717047900131
), 2.68 (2H, d, J=7.5Hz, > NCH 2 cH 2 -), 3.76 (3H, s, > N cH 3 ), 3.78 (2H, d, J=5.0Hz, > N cH 2 cH 2-), 4.16 (2H, t, J=7.5Hz ,-O cH 2 -), 4.60 (2H, d, J=5.0Hz ,- cH 2 nH-), 5.12 (2H, s,, furazan-CH 2o-), 6.77 (2H, d, J=10.0Hz, ArH), 6.81 (1H, d, J=10.0Hz, ArH), 6.92 (1H, t, J=5.0Hz, ArH), 7.10 (2H, t, J=10.0Hz, ArH), 7.37 (1H, d, J=10.0Hz, ArH), 7.45 (1H, s, ArH), 7.49 (1H, t, J=7.5Hz, ArH), 7.56-7.63 (3H, m, ArH), 7.77-7.81 (4H, m, ArH), 8.30-8.40 (2H, m ,-NH 2);
IR(KBr，cm -1)：767.35，1127.85，1146.09，1256.78，1396.96，1436.18，1469.51，1607.85，1751.02，2963.27，3183.67，3379.59；
HRMS(EI+)：m/z?746.3058[M+H] +，[C 39H 40N 9O 7] +calc.for?746.2972，found?746.3058.
Embodiment 6
(6-nitre oxygen base-hexahydro furyl is [3,2-b] also) furans-3-carbon-oxygen carbonyl 3-[2-((4-(N '-(isobutyl boc) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzo [d] imidazoles-5-formamido-] propionic acid (I-6)
Take IV-3 (0.57g, 0.001mol) and 5-ISMN (0.29g, 0.0015mol) is raw material, and class of operation, like the preparation of ZNO-1-1, obtains 0.25g white solid, productive rate: 33.6%, mp.180-182 ℃.
1H-NMR(500MHz?d 6-DMSO)δ(ppm)：0.89(3H，s，-CH3)，0.92(3H，s，-CH 3)，1.86-1.94(1H，m，?
Figure BSA00000717047900141
2.72(2H，t，J＝7.5Hz，＞NCH 2 CH 2 -)，3.77(3H，s，＞N CH 3 )，3.79-3.88(4H，m，?
Figure BSA00000717047900142
4.26(2H，t，J＝5.0Hz，＞NCH2CH2-)，4.41(1H，J＝5.0Hz，?
Figure BSA00000717047900143
4.60(2H，d，J＝5.0Hz，-CH2NH-)，4.95(1H，t，J＝5.0Hz，?
Figure BSA00000717047900144
5.03(1H，d，J＝5.0Hz，?
Figure BSA00000717047900145
5.50(1H，t，J＝5.0Hz，?
Figure BSA00000717047900146
6.79(2H，d，J＝10Hz，ArH)，6.89(1H，d，J＝10.0Hz，ArH)，6.93(1H，t，J＝5.0Hz，ArH)，7.11-7.14(1H，m，ArH)，7.17-7.19(1H，m，ArH)，7.39(1H，d，J＝10.0Hz，ArH)，7.34(1H，s，-CH 2 NH)，7.50(1H，s，ArH)，7.54(1H，td，J 1＝10.0Hz，J 2＝5Hz，ArH)，7.82(2H，d，J＝10.0Hz，ArH)，8.35-8.45(2H，m，-NH 2)；
IR(KBr，cm -1)：742.86，848.98，1004.08，1097.44，1128.25，1145.45，1170.41，1280.67，1327.86，1377.52，1395.70，1470.66，1591.84，1608.72，1739.58，3387.89；
HRMS(EI+)：m/z?745.2947[M+H] +，[C 36H 41N 98O 10] +calc.for?745.2867，found?745.2947.

Claims (6)

1. the compound of general formula (I) or its pharmacy acceptable salt:
Figure FSB0000115401800000011
R wherein 1representative: C 1～C 8alkyl, benzyl or phenyl; R 2representative: 2-N-oxo-4-aryl-1,2,5-oxadiazole-3-methylene radical or 6-nitre oxygen base-hexahydro furyl be [3,2-b] also) furans-3-base, wherein aryl is: phenyl or benzenesulfonyl.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein R 1represent n-hexyl, benzyl or isobutyl-.
3. the compound of claim 1 or its pharmacy acceptable salt, the acid salt that general formula (I) compound that wherein pharmacy acceptable salt is claim 1 and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, citric acid, succsinic acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or forulic acid.
4. a pharmaceutical composition, wherein contains general formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
5. the compound of claim 1 or its pharmacy acceptable salt purposes in the medicine of preparation prevention or treatment vascular thrombosis embolism class diseases.
6. the purposes of claim 5, wherein vascular thrombosis embolism class diseases is venous thromboembolism disease or arterial thromboembolism disease.
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