CN102633780A - 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 PDFInfo
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- 0 CC(c1ccc2[n](C)c(CNc(cc3)ccc3C(N)=NC(O*)=O)nc2c1)=O Chemical compound CC(c1ccc2[n](C)c(CNc(cc3)ccc3C(N)=NC(O*)=O)nc2c1)=O 0.000 description 2
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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
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to one type of non-peptide class the antithrombin suppressor factor, they the preparation method and to the restraining effect and the anti thrombotic action of zymoplasm.
Technical background
Now, thrombus property cardiovascular and cerebrovascular diseases has become the formidable enemy who threatens human health, and arterial thromboembolism property disease and VTE property disease are frequently-occurring diseases clinically.Since 1914 found heparin, anticoagulation medicine was being obtained considerable progress aspect prevention and the treatment thrombus disease.Along with increasing and the pilosity of cardiovascular disorder of world's elderly population, anticoagulation medicine will have vast potential for future development.
Dabigatran ester (Dabigatran Etexilate) is taken the lead in going on the market in Germany and Britain in April, 2008 by the exploitation of German Boehringer Ingelheim company, and this is the first new classification OA thing that after warfarin, goes on the market over 50 years.The listing of these article is major progresses in ACT field and potential lethality thrombus prevention field, has milestone significance.The dabigatran ester is a kind of novel, non-peptide class, competitiveness, reversible thrombin inhibitors, is the prodrug of dabigatran (Dabigatran), orally after stomach and intestine absorb, is converted into the active part dabigatran in vivo, produces the zymoplasm restraining effect.Dabigatran is incorporated into the scleroproein specific combination site of zymoplasm, stops Fibrinogen to be cracked into scleroproein, thereby has blocked the final step and the thrombosis of blood coagulation waterfall network.Dabigatran can dissociate from scleroproein-zymoplasm combination, performance reversible anticoagulation.
Dabigatran: R
1=R
2=H
Dabigatran ester: R
1=-CH
2CH
3,
Nitrogen protoxide (NO) is as bioinformation mediator in one type of body, participates in the adjusting of different physiological roles in the organism, in systems such as cardiovascular, immunity and nerve, plays crucial effect.NO has the vasodilator unstriated muscle, suppress vasodilator activity such as myocardial contraction, simultaneously can also anticoagulant, resisting vascular smooth muscle cell proliferation etc.These effects of NO are significant for preventing atherosclerotic formation and alleviating ischemic cardiovascular.
The furazan oxynitride is as one type of the NO donor, because its comparatively significant biological activity, is widely used in step-down, the field of medicaments such as antitumor.
The 5-Ismo 20 from 1981 after Germany listing, successively in the listing of a plurality of countries such as the U.S., France, Italy, this drug absorption distributes fast, no liver first-pass effect, bioavailability is high, becomes dominating in the antianginal drug.
The present invention carries out amalgamation through ester bond with dabigatran ester and NO donor, in the hope of obtaining active better compound.
Furazan oxynitride 5-Ismo 20
Summary of the invention
The invention discloses the compound of one type of general formula I, show that through pharmacological evaluation compound of the present invention has stronger restraining effect to zymoplasm.Therefore, formula I compound of the present invention can be used for treating and prevents the various diseases relevant with thrombosis, and these diseases comprise arterial thromboembolism property disease, VTE property disease, and other thrombus property cardiovascular and cerebrovascular diseases.
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):
Reactant A does
R wherein
1Be C
1～C
8Straight or branched alkane, C
5～C
7Naphthenic hydrocarbon or replace naphthenic hydrocarbon, benzyl or substituted benzyl, phenyl or substituted-phenyl; Work as R
1During for the tertiary butyl, reactant A is a tert-Butyl dicarbonate.Solvent orange 2 A is the mixed solvent of THF, acetone, methylene dichloride, acetonitrile, THF and water or the mixed solvent of acetone and water; The mixed solvent of preferred THF and water.
Reactant B is sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, yellow soda ash or salt of wormwood; Preferred sodium hydroxide.Solvent B is water, aqueous alcohol, aqueous acetone; Preferred aqueous ethanol.
Reactant C is nitric oxide donors such as furazan oxynitride and 5-Ismo 20.
Condensing agent D is NSC 57182 (DCC), N, N '-carbonyl dimidazoles (CDI), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and 4-Dimethylamino pyridine (DMAP); Preferred 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and 4-Dimethylamino pyridine (DMAP).Solvent E is N, dinethylformamide, acetonitrile, methylene dichloride or both mixed solvents arbitrarily; Preferred N, dinethylformamide.
But the preparation reference literature of compound I I (J Med Chem.2002,45:1757-1766 wherein; Chinese Journal of Pharmaceuticals .2010,41 (5): 321-325.), be raw material with 3-nitro-4-chloro-benzoic acid, compound method is following:
Wherein a～f is a reaction conditions: the 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, absolute ethyl alcohol; 2. volatile salt, absolute ethyl alcohol.
Below be the 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 following:
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 ltd 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 ltd;
(3) HH-4 thermostat water bath: state China instrument company;
(4) the adjustable supercentrifuge of FSH-2A: contain laboratory apparatus ltd greatly;
(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 flushing remove the blood component in the tissue, add above-mentioned KCl phosphate buffer solution by 1: 4 (W/V) at last, process LH with interior cut tissue refiner.With the LH for preparing centrifugal (9000rmin on ultracentrifuge
-1) 15min, get the centrifugal again (16000rmin of supernatant
-1) 60min, get pink supernatant, i.e. hepatomicrosome solution.
(2) medicine activation and solution preparation: take by weighing I series and respectively receive reagent and dabigatran ester 2mg, add methyl-sulphoxide 40 μ L dissolving, add above-mentioned LH 1mL, mixing places 37 ℃ of water-bath incubation 4h, is diluted to 10 with saline water then
-5, 10
-6, 10
-7, 10
-8MolL
-1Isoconcentration.
Operating process:
Get one of new zealand rabbit, the right carotid intubate is got blood after the PROCAINE HCL, PHARMA GRADE local anaesthesia.Whole blood with the centrifugal 5min of rotating speed 1000r/min, is got supernatant according to volume ratio 9: 1 and 3.8% Sodium Citrate mixing, is platelet rich plasma (PRP); Residue blood gets platelet poor plasma (PPP) with the centrifugal 10min of rotating speed 3000r/min.With the PPP zeroing, be the thrombocyte donor with PRP, get 200 μ L PRP respectively; With solvent control group, each concentration positive controls and mixed by the reagent group; Behind 37 ℃ of incubation 1min, add the Thr 20 μ L of 15U/mL respectively, utilize the SC-2000 platelet aggregation instrument to trace curve of platelet aggregation; Observe thrombocyte MA (MAR) in the 10min, press instrument specification sheets time-and-motion study platelet aggregation rate.
The screening active ingredients result:
With the positive contrast of dabigatran ester, The compounds of this invention is carried out the active screening of inhibition of external platelet aggregation to thrombin induction, the result sees table 1.
Table 1: the IC of dabigatran ester and The compounds of this invention Trombin inhibiting inductive platelet aggregation
50Value
Visible by table 1, The compounds of this invention I-2 is active suitable with positive drug dabigatran ester.
It is following that the external NO of part of compounds of the present invention discharges the Research of measuring method:
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 by weighing exsiccant Sodium Nitrite 0.15g and places the 100ml volumetric flask, with dissolved in distilled water and be diluted to scale.Precision is measured in 0.1ml to the 100ml volumetric flask, is diluted with water to scale, promptly gets 1.5mg/L Sodium Nitrite standard inventory solution.
The preparation of standard operation solution: precision is measured standard reserving solution, and being mixed with concentration is the Sodium Nitrite series standard working fluid of 0.21-1.5mg/L.
Measure working solution 2ml respectively, with the abundant mixing of Griess reagent 0.5ml, room temperature is placed 10min, measures its optical density at the 540nm place.According to gained data drawing standard curve, Sodium Nitrite concentration of standard solution C is carried out regression Calculation with optical density value A.
The mensuration of nitrogen protoxide extracorporeal releasing quantity: contain the preparation of the phosphate buffer soln (pH7.4) of excessive L-halfcystine (5mmol): precision takes by weighing potassium primary phosphate 6.8g; Add 0.1mol/L sodium hydroxide solution 395mL and L-halfcystine 0.6g, with water dissolution and be diluted to 1000mL.Promptly get the pH7.4 phosphate buffer soln that contains excessive L-halfcystine (5mmol).
Receive the preparation of test sample solution:
Precision takes by weighing test-compound, with dmso solution and be diluted to 10mL, shakes up, and makes the solution that concentration is 0.01mol/L.
Precision takes by weighing Ismo 20 19.1mg, with dmso solution and be diluted to 10mL, shakes up, and promptly gets the solution that concentration is 0.01mol/L.
Precision is measured all dimethyl sulphoxide solution that receives test product (0.01mol/L) 1.0mL, is diluted to 100mL with the pH7.4 phosphate buffer soln that contains excessive L-halfcystine (5mmol/L) respectively.Finally, the concentration of need testing solution is 10
-4Mol/L.Place 37 ℃ of environment to hatch solution, get reaction solution 2mL and griess reagent 0.5mL is blended in the triangular flask in different time points, room temperature is placed 10min, surveys optical density in the 540nm wavelength.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 the dative is measured optical density A in the 540nm place, to trial-product concentration C (10
-4Mol/L) carry out linear regression, regression equation is: A=3.1206C+0.0079, r
2=0.9991.
(2) through testing part of compounds NO burst size of the present invention except indivedual time points occur than great fluctuation process, totally show a rising trend in time, positive control drug 5-Ismo 20 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
The present invention also provides the pharmaceutical composition of a kind of prevention and treatment vascular thrombosis embolism class diseases, wherein contains the compound of Formula I and the pharmaceutically acceptable carrier of treating significant quantity.Said pharmaceutical composition can be a 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 was used to treat, the human dosage range was 1mg～5000mg/ days.Also can be according to the difference and the disease severity of formulation, using dosage exceeds this scope.
Embodiment
Embodiment 1
The preparation of 3-[2-((4-(N '-(own oxygen carbonyl) amidino groups) anilino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-carboxamido-group] ethyl propionate (III-1)
Under 0-5 ℃, with II (2g, 0.0037mol) and salt of wormwood (1.55g; 0.0112mol) be dissolved in the mixed solvent of 60mL THF and 12mL water, behind the 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, after continuing to stir 5h, and stopped reaction.Tell the THF layer, anhydrous sodium sulfate drying filters, and revolves to carry out column chromatography after doing, and eluent is a methylene dichloride: methyl alcohol=30: 1, the 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]
+.
The preparation of 3-[2-((4-(N '-(own oxygen carbonyl) amidino groups) anilino) methyl)-1-methyl-N-(2-pyridyl)-1H-benzoglyoxaline-5-formamido-] propionic acid (IV-1)
With III-1 (1.22g, 0.002mol) and sodium hydroxide (0.28g 0.007mol) joins in the mixed solvent of 30mL ethanol and 15mL water, finishes reaction behind the stirring at room 6h; Concentrating under reduced pressure revolves most of ethanol, adds the dilution of 5mL water, under ice bath, transfers pH to 4～5 with 10% Hydrocerol A; Solid is separated out, and places refrigerator overnight, filters, and filter cake is with the filtrating washing; With the small amount of ice water washing, filter again, get the 1.03g white solid, need not purifying and 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) is dissolved among the 20ml DMF; Stir 30min, slowly rise to room temperature, behind the 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, filters, and concentrates; Column chromatography (eluent is a methylene dichloride: methyl alcohol=30: 1), get the 0.43g white solid, productive rate: 55.6%, and 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), the 5-Ismo 20 (0.29g 0.0015mol) is raw material, and class of operation is like the preparation of I-1, the 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，?
4.24(2H，t，J＝7.5Hz，-O
CH 2 CH
2-)，4.40(1H，d，J＝5.0Hz，?
4.60(2H，d，J＝5.0Hz，-
CH 2 NH-)，4.94(1H，t，J＝5Hz，?
5.01(1H，d，J＝5.0Hz，?
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-carboxamido-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) is raw material, and class of operation is like the preparation of III-1, the 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)
With III-2 (1.27g, 0.002mol) and sodium hydroxide (0.28g 0.007mol) is raw material, and class of operation is like the preparation of IV-1, the 1.11g white solid, need not purifying and directly drop 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) with 3-methylol-4-phenyl-1,2,5-oxadiazole-2-oxide compound (0.29g 0.0015mol) be raw material, and class of operation is like the preparation of I-1, must the 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)
With IV-2 (0.60g, 0.001mo1) with the 5-Ismo 20 (0.29g 0.0015mo1) be raw material, and class of operation is like the preparation of I-1, must the 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，?
4.26(2H，t，J＝10.0Hz，＞N
CH2CH2-)，4.40(1H，d，J＝5.0Hz，?
4.60(2H，d，J＝5.0Hz，-
CH 2 NH-)，4.89-4.95(1H，m，?
5.02(1H，d，J＝5.0Hz，?
5.08(2H，s，-O
CH 2 Ph)，5.48-5.50(1H，m，?
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-carboxamido-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) is raw material, and class of operation is like the preparation of III-1, bullion 2.5g, need not purifying and directly drop into next step reaction.
3-[2-((4-(N '-(isobutyl boc) amidino groups) anilino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-carboxamido-group] propionic acid (IV-3)
With III-3 (1.20g, 0.002mol) and sodium hydroxide (0.28g 0.007mol) is raw material, and class of operation is like the preparation of IV-3, the 0.92g white solid, need not purifying and directly drop 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)
(0.57g, 0.001mol) with 3-methylol-4-phenyl-1,2, (0.29g 0.0015mol) is raw material to 5-oxadiazole-2-oxide compound, and class of operation gets the 0.35g white solid, productive rate 44.5%, mp.170-172 ℃ like the preparation of I-1 with IV-3.
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,
), 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)
With IV-3 (0.57g, 0.001mol) with the 5-Ismo 20 (0.29g 0.0015mol) be raw material, and class of operation is like the preparation of ZNO-1-1, must the 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，?
2.72(2H，t，J＝7.5Hz，＞NCH
2 CH 2 -)，3.77(3H，s，＞N
CH 3 )，3.79-3.88(4H，m，?
4.26(2H，t，J＝5.0Hz，＞NCH2CH2-)，4.41(1H，J＝5.0Hz，?
4.60(2H，d，J＝5.0Hz，-CH2NH-)，4.95(1H，t，J＝5.0Hz，?
5.03(1H，d，J＝5.0Hz，?
5.50(1H，t，J＝5.0Hz，?
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:
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-carbon-oxygen carbonyl, 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, wherein pharmacy acceptable salt is general formula (I) compound of claim 1 and the acid salt that following acid forms: hydrochloric acid, Hydrogen bromide, sulfuric acid, carbonic acid, Hydrocerol A, succsinic acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or FLA.
4. 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 1, wherein the vascular thrombosis embolism class diseases is VTE property disease or arterial thromboembolism property disease.
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Cited By (4)
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| CN102875533A (en) * | 2012-11-06 | 2013-01-16 | 中国药科大学 | Dabigatran derivative, preparation method of dabigatran derivative and anti-thrombus application |
| CN104356111A (en) * | 2014-10-14 | 2015-02-18 | 蚌埠丰原医药科技发展有限公司 | Method for preparing dabigatran etexilate hydrolysis impurities |
| CN104628733A (en) * | 2015-03-02 | 2015-05-20 | 中国药科大学 | Tetrahydrobenzo[4,5] imidazo[1,2-a] pyrazine thrombin inhibitors |
| CN105622576A (en) * | 2014-10-27 | 2016-06-01 | 上海医药工业研究院 | Preparation of benzimidazole methyl ester related substance |
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| CN1861596A (en) * | 2005-12-16 | 2006-11-15 | 复旦大学 | Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind |
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| CN1861596A (en) * | 2005-12-16 | 2006-11-15 | 复旦大学 | Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875533A (en) * | 2012-11-06 | 2013-01-16 | 中国药科大学 | Dabigatran derivative, preparation method of dabigatran derivative and anti-thrombus application |
| CN102875533B (en) * | 2012-11-06 | 2015-06-17 | 中国药科大学 | Dabigatran derivative, preparation method of dabigatran derivative and anti-thrombus application |
| CN104356111A (en) * | 2014-10-14 | 2015-02-18 | 蚌埠丰原医药科技发展有限公司 | Method for preparing dabigatran etexilate hydrolysis impurities |
| CN105622576A (en) * | 2014-10-27 | 2016-06-01 | 上海医药工业研究院 | Preparation of benzimidazole methyl ester related substance |
| CN104628733A (en) * | 2015-03-02 | 2015-05-20 | 中国药科大学 | Tetrahydrobenzo[4,5] imidazo[1,2-a] pyrazine thrombin inhibitors |
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