CN103420980A - Dabigatran derivatives - Google Patents

Dabigatran derivatives Download PDF

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CN103420980A
CN103420980A CN2012101586001A CN201210158600A CN103420980A CN 103420980 A CN103420980 A CN 103420980A CN 2012101586001 A CN2012101586001 A CN 2012101586001A CN 201210158600 A CN201210158600 A CN 201210158600A CN 103420980 A CN103420980 A CN 103420980A
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dabigatran
methyl
carbonyl
amino
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王建明
杨振华
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BEIJING MEIBEITA PHARMACEUTICAL RESEARCH Co Ltd
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BEIJING MEIBEITA PHARMACEUTICAL RESEARCH Co Ltd
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Abstract

The invention aims to provide dabigatran derivatives, which are presented by the formula I with anticoagulant activity, optical isomers, and medicinal salts thereof. R1 represents H or alkyl group with a carbon number between 1 and 3, R2 represents R3 or -OR3, and R3 represents an alkyl group with a carbon number between 1 and 8 or a naphthenic group with a carbon number between 3 and 8.

Description

The dabigatran derivative
Technical field
The present invention relates to derivative and the non-toxicity pharmacy acceptable salt thereof of new dabigatran, and contain the pharmaceutical composition of these compounds as activeconstituents, and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Background technology
Dabigatran (Dabigatran) is a kind of optionally high performance thrombin inhibitor.But due to the existence of strong basicity amidino groups, oral can not the absorption.For improving its bioavailability, respectively the free carboxy in the dabigatran molecule is become to ethyl ester, amidino groups becomes amino hexyl formate, obtains its bi precursor medicine dabigatran dibasic acid esters (Dabigatran Etexilate).After the dabigatran dibasic acid esters is oral, from gastrointestinal absorption, then be converted in vivo the dabigatran of activity form, the performance blood coagulation resisting function.The dabigatran dibasic acid esters, in listing in 2008, becomes first oral thrombin inhibitors, for deep vein thrombosis after preventing artificial joint replacement, forms and pulmonary embolism.But the oral administration biaavailability of dabigatran dibasic acid esters (6.5%) still remains further to be improved.
Summary of the invention
The present invention relates to ester derivative and non-toxicity pharmacy acceptable salt thereof by the dabigatran shown in structural formula I, and contain the pharmaceutical composition of these compounds as activeconstituents, and described compound and pharmaceutical composition are as the purposes of anaesthetic.
First aspect of the present invention provides dabigatran derivative and optical isomer and the pharmacologically acceptable salt thereof of formula I representative:
Figure BSA00000720241200021
Wherein, R 1Represent H, or C 1-C 3Alkyl; R 2Represent R 3Or-OR 3R 3Represent C 1-C 8Alkyl or C 3-C 8Cycloalkyl.
Each substituting group of objectives compound is defined as follows respectively:
I 1: R 1For H, R 2For-CH 3
I 2: R 1For H, R 2For-CH 2CH 3
I 3: R 1For H, R 2For-CH 2CH 2CH 3
I 4: R 1For H, R 2For-CH (CH 3) 2
I 5: R 1For H, R 2For-C (CH 3) 3
I 6: R 1For H, R 2For-CH (CH 3) CH 2CH 3
I 7: R 1For H, R 2For-CH 2CH (CH 3) CH 3
I 8: R 1For H, R 2For-CH 2CH 2CH 2CH 3
I 9: R 1For H, R 2For
I 10: R 1For H, R 2For
Figure BSA00000720241200031
I 11: R 1For H, R 2For
Figure BSA00000720241200032
I 12: R 1For H, R 2For
Figure BSA00000720241200033
I 13: R 1For CH 3, R 2For-CH 3
I 14: R 1For CH 3, R 2For-CH 2CH 3
I 15: R 1For CH 3, R 2For-CH 2CH 2CH 3
I 16: R 1For CH 3, R 2For-CH (CH 3) 2
I 17: R 1For CH 3, R 2For-C (CH 3) 3
I 18: R 1For CH 3, R 2For-CH (CH 3) CH 2CH 3
I 19: R 1For CH 3, R 2For-CH 2CH (CH 3) CH 3
I 20: R 1For CH 3, R 2For-CH 2CH 2CH 2CH 3
I 21: R 1For CH 3, R 2For
Figure BSA00000720241200034
I 22: R 1For CH 3, R 2For
Figure BSA00000720241200035
I 23: R 1For CH 3, R 2For
I 24: R 1For CH 3, R 2For
I 25: R 1For H, R 2For-OCH 3
I 26: R 1For H, R 2For-OCH 2CH 3
I 27: R 1For H, R 2For-OCH 2CH 2CH 3
I 28: R 1For H, R 2For-OCH (CH 3) 2
I 29: R 1For H, R 2For-OC (CH 3) 3
I 30: R 1For H, R 2For-OCH (CH 3) CH 2CH 3
I 31: R 1For H, R 2For-OCH 2CH (CH 3) CH 3
I 32: R 1For H, R 2For-OCH 2CH 2CH 2CH 3
I 33: R 1For H, R 2For
Figure BSA00000720241200041
I 34: R 1For H, R 2For
I 35: R 1For H, R 2For
Figure BSA00000720241200043
I 36: R 1For H, R 2For
I 37: R 1For CH 3, R 2For-OCH 3
I 38: R 1For CH 3, R 2For-OCH 2CH 3
I 39: R 1For CH 3, R 2For-OCH 2CH 2CH 3
I 40: R 1For CH 3, R 2For-OCH (CH 3) 2
I 41: R 1For CH 3, R 2For-OC (CH 3) 3
I 42: R 1For CH 3, R 2For-OCH (CH 3) CH 2CH 3
I 43: R 1For CH 3, R 2For-OCH 2CH (CH 3) CH 3
I 44: R 1For CH 3, R 2For-OCH 2CH 2CH 2CH 3
I 45: R 1For CH 3, R 2For
Figure BSA00000720241200045
I 46: R 1For CH 3, R 2For
I 47: R 1For CH 3, R 2For
Figure BSA00000720241200047
I 48: R 1For CH 3, R 2For
Figure BSA00000720241200048
Second aspect of the present invention relates to pharmaceutical composition, and it comprises derivative and pharmacologically acceptable salt and one or more pharmaceutically acceptable carrier or the vehicle of the dabigatran of at least one formula I representative.
The 3rd aspect of the present invention relates to derivative and the non-toxicity pharmacy acceptable salt thereof of the dabigatran shown in formula I, and the derivative that comprises the dabigatran shown in formula I and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents the purposes as anticoagulation.
The compound of formula I representative can form pharmaceutical salts with mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can form pharmaceutical salts with organic acid, such as acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc.Selecting and preparing suitable salt is technology as well known to those skilled in the art.
The compounds of this invention or its pharmacologically acceptable salt can form solvate, such as hydrate, alcohol adduct etc.; Selecting and preparing suitable solvate is technology as well known to those skilled in the art.
The compounds of this invention or its pharmacologically acceptable salt can be separately or with the form administration of pharmaceutical composition.
Pharmaceutical composition of the present invention can be made into various suitable formulations according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they are conducive to active compound is processed into to the preparation that can pharmaceutically use.Suitable dosage form depends on selected route of administration, can be manufactured according to general knowledge well known in the art.
Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Can comprise capsule and tablet etc. by oral pharmaceutical preparation.Patient swallows while having any problem, and also can adopt Sublingual tablet or other non-mode administrations of swallowing.The compounds of this invention also can be prepared for administered parenterally or transdermal administration or mucosal.Perhaps adopt the mode administration of suppository or implants.It will be understood by those skilled in the art that the compounds of this invention can adopt suitable drug delivery system (MS) to obtain more favourable effect.
It may be noted that in addition, the compounds of this invention using dosage and using method depend on factors, comprise patient's age, body weight, sex, natural health situation, nutritional status, activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of compound.
Embodiment
The following examples can conduct further description the present invention, yet these embodiment should be as the restriction to scope of the present invention.
At first, reference literature (Hauel NH, Nar H, Priepke H, et al.Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors.J.Med.Chem.2002; 45:1757-1766) the synthetic dabigatran dibasic acid esters (Dabigatran Etexilate) of method:
Figure BSA00000720241200071
The 3-nitro-4-methyl amino-phenylformic acid of take is starting raw material, with sulfur oxychloride, reacts, and becomes acyl chlorides (intermediate 2); Intermediate 2 reacts with N-(pyridine-2-yl)-Beta-alanine ethyl ester, obtains intermediate 4; By the nitro of intermediate 4, under palladium-charcoal effect, catalytic hydrogenation obtains intermediate 5; (4-cyano group-phenyl amino) acetic acid first reacts with carbonyl dimidazoles, then reacts with intermediate 5, obtains intermediate 7; By intermediate 7 and hcl reaction, then, with the volatile salt alkalization, the ethyl ester derivative 8,8 that obtains dabigatran reacts with the own ester of chloroformic acid, obtains dabigatran dibasic acid esters (Dabigatran Etexilate).
The dabigatran dibasic acid esters is hydrolyzed with LiOH, obtains carboxylic acid derivative 9,9 and react with chloro thing 10, obtain target compound:
Figure BSA00000720241200072
Wherein, R 1Represent H, or C 1-C 3Alkyl; R 2Represent R 3Or-OR 3R 3Represent C 1-C 8Alkyl or C 3-C 8Cycloalkyl.
Reference example 1N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-preparation of N-(pyridine-2-yl)-Beta-alanine ethyl ester (dabigatran dibasic acid esters)
40 grams (0.2mol) 3-nitro-4-methyl amino-phenylformic acid is added in the 400mL sulfur oxychloride, add the 0.2mL dimethyl formamide, back flow reaction 0.5h, vacuum concentration, obtain 3-nitro-4-methyl amino-Benzoyl chloride (intermediate 2), be dissolved in the 300mL tetrahydrofuran (THF).
37 grams (0.2mol) N-(pyridine-2-yl)-Beta-alanine ethyl ester and 60mL triethylamine are dissolved in the 500mL tetrahydrofuran (THF), at room temperature drip the tetrahydrofuran solution of intermediate 2.After adding, room temperature reaction spends the night, vacuum concentration.Residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of ethanol (99: 1) obtains 41 gram intermediates 4.
33.4 grams (89.4mmol) intermediate 4 is dissolved in to 400mL ethanol, adds palladium-charcoal 1 gram of 10%, room temperature hydrogenation, remove by filter palladium-charcoal, by the filtrate vacuum concentration.Residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (30: 1) obtains 21 gram intermediates 5.
12.8g (73mmol) (4-cyano group-phenyl amino) acetic acid and 11.8 grams (73mmol) carbonyl dimidazoles are added in the 300mL tetrahydrofuran (THF) to 50 ℃ of stirring reaction 30min.Then, add 21 gram intermediates 5, back flow reaction 24h in this solution.Vacuum concentration, be dissolved in residue in the 150mL glacial acetic acid, and reflux 1h, by 500mL water dilution for this solution, neutralizes with strong aqua.By ethyl acetate, extract, by the extracting solution vacuum concentration.Residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (40: 1) obtains 18 gram N-{[2-(((4-cyano group-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (intermediate 7).
18 gram intermediates 7 are dissolved in 800mL ethanol, are cooled to 0 ℃, logical anhydrous hydrogen chloride gas 2h, then stirring at room 5h.By the solvent evaporated in vacuo, then residue is dissolved in to 600mL ethanol, add 40 gram volatile salts, stirred overnight at room temperature.By the reaction solution vacuum concentration, residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (5: 1) obtains 13 gram N-{[2-(((4-amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (intermediate 8). 1H?NMR?δ(ppm，DMSO-d 6)：1.14(t，3H)，2.69(t，2H)，3.78(s，3H)，3.99(q，2H)，4.24(t，2H)，4.68(d，2H)，6.90(d，1H)，6.99(t，1H)，7.15(m，2H)，7.42(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.42(m，1H)，8.55-9.28(bs，3H)。
12.0g (22.3mmol) intermediate 8 is dissolved in the solvent mixture of 500mL tetrahydrofuran (THF) and 100mL water, adds 10g salt of wormwood (72mmol), stirring at room 20min.Add the n-hexyl chloride manthanoate of 3.72g (22.3mmol), continue to stir 2h.Vacuum is steamed and is desolventized, and adds the 500ml saturated brine, uses dichloromethane extraction 3 times, 180ml/ time; United extraction liquid, use anhydrous sodium sulfate drying; Vacuum is steamed and is desolventized, and residue is separated with silica gel column chromatography, and use methylene dichloride: ethanol (95: 5) wash-out obtains target compound 9.1g, mp 128-130 ℃. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.16(t，3H)，1.31(m，6H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(m，4H)，4.25(t，2H)，4.62(d，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 1N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-preparation of N-(pyridine-2-yl)-Beta-alanine (9)
By 9g dabigatran etcxilate 250ml dissolve with methanol, stirring at room, add 80ml to contain the aqueous solution of 3.6g LiOH, stirs 60 minutes.Add 150ml water, the dilute hydrochloric acid neutralization with 1N, have solid to separate out.Filter, by solid drying, obtain target compound 97.4g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.31(m，6H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)，12.15(s，1H)。
Embodiment 2N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine acetyl-o-methyl ester (I 1) preparation
Figure BSA00000720241200101
0.4g intermediate 9 use 8ml DMF are dissolved, logical drying nitrogen, stirring at room, add the 0.3ml triethylamine.Stir the lower 0.1ml of dropping chloromethyl acetate, gradually be warming up to 50 ℃ after adding, stirring reaction 5 hours.Remove solvent under reduced pressure, by residue 50ml acetic acid ethyl dissolution, washing; Organic layer is spent the night with anhydrous sodium sulfate drying.Filter, remove organic solvent under reduced pressure, residue is separated with silica gel column chromatography, with methylene dichloride: methyl alcohol (30: 1) mixed solvent wash-out, collect required component, evaporated under reduced pressure, obtain target compound I 10.25g. 1HNMRδ(ppm，DMSO-d 6)：0.89(t，3H)，1.31(m，6H)，1.60(m，2H)，2.23(s，3H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 3N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isobutyl acyl-oxygen methyl ester (I 4) preparation
Figure BSA00000720241200102
With reference to the method for embodiment 2,0.4g intermediate 9 is reacted with the isopropylformic acid chloromethyl ester, with silica gel column chromatography, separate, obtain target compound I 40.28g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.14(d，6H)，1.31(m，6H)，1.60(m，2H)，2.53(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 4N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine pivaloyl oxygen methyl ester (I 5) preparation
Figure BSA00000720241200111
With reference to the method for embodiment 2, intermediate 9 is reacted with chloromethyl pivalate, with silica gel column chromatography, separate, obtain target compound I 50.22g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.23(s，9H)，1.31(m，6H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 5N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isoamyl acyl-oxygen methyl ester (I 6) preparation
Figure BSA00000720241200112
With reference to the method for embodiment 2, intermediate 9 is reacted with the isovaleric acid chloromethyl ester, with silica gel column chromatography, separate, obtain target compound I 60.21g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.02(t，3H)，1.21(d，3H)，1.25(m，2H)，1.31(m，6H)，1.60(m，2H)，2.59(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 6N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine cyclohexanecarbonyl oxygen methyl ester (I 12) preparation
Figure BSA00000720241200121
With reference to the method for embodiment 2, intermediate 9 is reacted with the heptanaphthenic acid chloromethyl ester, with silica gel column chromatography, separate, obtain target compound I 120.20g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.31(m，6H)，1.32-1.41(m，6H)，1.60(m，2H)，1.66(m，2H)，1.91(m，2H)，2.25(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 7N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isobutyl acyl-oxygen ethyl ester (I 16) preparation
Figure BSA00000720241200131
With reference to the method for embodiment 2,0.4g intermediate 9 is reacted with isopropylformic acid chloroethene ester, with silica gel column chromatography, separate, obtain target compound I 160.19g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.16(t，3H)，1.31(m，6H)，1.33(d，2H)，1.60(m，2H)，2.53(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.65(m，1H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 8N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine pivaloyl oxygen ethyl ester (I 17) preparation
Figure BSA00000720241200132
With reference to the method for embodiment 2,0.4g intermediate 9 is reacted with trimethylacetic acid chloroethene ester, with silica gel column chromatography, separate, obtain target compound I 170.17g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.23(s，9H)，1.31(m，6H)，1.33(d，2H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.66(m，1H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 9N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isopropyl oxygen ketonic oxygen methyl ester (I 28) preparation
Figure BSA00000720241200141
0.4g intermediate 9 use 8ml DMF are dissolved, logical drying nitrogen, stirring at room, add the 0.3ml triethylamine.Stir the lower 0.13ml of dropping chloromethyl sec.-propyl carbonic ether, gradually be warming up to 60 ℃ after adding, stirring reaction 5 hours.Remove solvent under reduced pressure, by residue 50ml acetic acid ethyl dissolution, washing; Organic layer is spent the night with anhydrous sodium sulfate drying.Filter, remove organic solvent under reduced pressure, residue is separated with silica gel column chromatography, with methylene dichloride: methyl alcohol (30: 1) mixed solvent wash-out, collect required component, evaporated under reduced pressure, obtain target compound I 280.29g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.19(d，6H)，1.31(m，6H)，1.60(m，2H)，2.23(s，3H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，4.79(m，1H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 10N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine hexamethylene oxygen ketonic oxygen methyl ester (I 36) preparation
Figure BSA00000720241200142
With reference to the method for embodiment 9, by 0.4g intermediate 9 and chloromethyl cyclohexyl carbonate reaction, with silica gel column chromatography, separate, obtain target compound I 360.18g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.31(m，6H)，1.32-1.41(m，6H)，1.60(m，2H)，1.66(m，2H)，1.91(m，2H)，4.35(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 11N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isopropyl oxygen ketonic oxygen ethyl ester (I 40) preparation
Figure BSA00000720241200151
With reference to the method for embodiment 9, by 0.4g intermediate 9 and chloroethyl sec.-propyl carbonate reaction, with silica gel column chromatography, separate, obtain target compound I 400.20g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.19(d，6H)，1.31(m，6H)，1.33(d，2H)，1.60(m，2H)，2.23(s，3H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，4.79(m，1H)，5.66(m，1H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 12N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine hexamethylene oxygen ketonic oxygen ethyl ester (I 48) preparation
Figure BSA00000720241200161
With reference to the method for embodiment 9, by 0.4g intermediate 9 and chloroethyl cyclohexyl carbonate reaction, with silica gel column chromatography, separate, obtain target compound I 480.13g. 1H?NMR?δ(ppm，DMSO-d 6)：0.89(t，3H)，1.31(m，6H)，1.32-1.41(m，9H)，1.60(m，2H)，1.66(m，2H)，1.91(m，2H)，4.35(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.65(m，1H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
The evaluation of embodiment 13 anticoagulating actives
27.1 the mensuration of activated partial thromboplastin time (aPTT)
By the kunming mice of quality 18-20g, random packet, 10 every group, overnight fasting.Dabigatran etcxilate (Dabigatran Etexilate) and target compound to be measured are suspended or be dissolved in the aqueous solution of 1% Xylo-Mucine, be made into the concentration of 1mg/ml, dosage (amounting to into dabigatran calculates) gastric infusion by 5mg/kg, pass through heart puncturing extracting blood after half an hour, add 4% liquor sodii citratis to 0.4% final concentration anti-freezing, centrifugal 5 minutes of 12000r/min, get blood plasma 0.1ml, add aPTT reagent (Shanghai medical electric company limited product) 0.1ml, 37 ℃ of pre-temperature are after 3 minutes, the calcium chloride solution 0.1mL that adds 37 ℃ of pre-temperature, measure setting time with platelet aggregation thrombin analyser (Puli gives birth to the PLSC2000-4 type), be the aPTT value.The results are shown in Table 1.
The measurement result of table 1 activated partial thromboplastin time (aPTT)
Figure BSA00000720241200171
27.2 the mensuration in bleeding time
By the kunming mice of quality 18-20g, random packet, 10 every group, overnight fasting.Dabigatran etcxilate (Dabigatran Etexilate) and target compound to be measured are suspended or be dissolved in the aqueous solution of 1% Xylo-Mucine, be made into the concentration of 1mg/ml, by dosage (amounting to into the dabigatran calculates) gastric infusion of 5mg/kg, after half an hour.Animal is fixed, make tail be dipped in 2min in the physiological saline of 37 ℃, then at distance tail end 2mm place, cut off the mouse tail, again immerse immediately in the physiological saline of 37 ℃, take and stop hemorrhagely continuing 30 seconds as the judgement terminal, measure the bleeding time.The results are shown in Table 2.
The measurement result in table 2 bleeding time
Figure BSA00000720241200181

Claims (4)

1. the dabigatran derivative of formula I representative and optical isomer and pharmacologically acceptable salt thereof:
Figure FSA00000720241100011
Wherein, R 1Represent H, or C 1-C 3Alkyl; R 2Represent R 3Or-OR 3R 3Represent C 1-C 8Alkyl or C 3-C 8Cycloalkyl.
2. according to the compound of claim 1, be selected from:
I 1: R 1For H, R 2For-CH 3
I 2: R 1For H, R 2For-CH 2CH 3
I 3: R 1For H, R 2For-CH 2CH 2CH 3
I 4: R 1For H, R 2For-CH (CH 3) 2
I 5: R 1For H, R 2For-C (CH 3) 3
I 6: R 1For H, R 2For-CH (CH 3) CH 2CH 3
I 7: R 1For H, R 2For-CH 2CH (CH 3) CH 3
I 8: R 1For H, R 2For-CH 2CH 2CH 2CH 3
I 9: R 1For H, R 2For
Figure FSA00000720241100012
I 10: R 1For H, R 2For
Figure FSA00000720241100013
I 11: R 1For H, R 2For
Figure FSA00000720241100014
I 12: R 1For H, R 2For
Figure FSA00000720241100021
I 13: R 1For CH 3, R 2For-CH 3
I 14: R 1For CH 3, R 2For-CH 2CH 3
I 15: R 1For CH 3, R 2For-CH 2CH 2CH 3
I 16: R 1For CH 3, R 2For-CH (CH 3) 2
I 17: R 1For CH 3, R 2For-C (CH 3) 3
I 18: R 1For CH 3, R 2For-CH (CH 3) CH 2CH 3
I 19: R 1For CH 3, R 2For-CH 2CH (CH 3) CH 3
I 20: R 1For CH 3, R 2For-CH 2CH 2CH 2CH 3
I 21: R 1For CH 3, R 2For
Figure FSA00000720241100022
I 22: R 1For CH 3, R 2For
Figure FSA00000720241100023
I 23: R 1For CH 3, R 2For
Figure FSA00000720241100024
I 24: R 1For CH 3, R 2For
Figure FSA00000720241100025
I 25: R 1For H, R 2For-OCH 3
I 26: R 1For H, R 2For-OCH 2CH 3
I 27: R 1For H, R 2For-OCH 2CH 2CH 3
I 28: R 1For H, R 2For-OCH (CH 3) 2
I 29: R 1For H, R 2For-OC (CH 3) 3
I 30: R 1For H, R 2For-OCH (CH 3) CH 2CH 3
I 31: R 1For H, R 2For-OCH 2CH (CH 3) CH 3
I 32: R 1For H, R 2For-OCH 2CH 2CH 2CH 3
I 33: R 1For H, R 2For
Figure FSA00000720241100031
I 34: R 1For H, R 2For
Figure FSA00000720241100032
I 35: R 1For H, R 2For
Figure FSA00000720241100033
I 36: R 1For H, R 2For
Figure FSA00000720241100034
I 37: R 1For CH 3, R 2For-OCH 3
I 38: R 1For CH 3, R 2For-OCH 2CH 3
I 39: R 1For CH 3, R 2For-OCH 2CH 2CH 3
I 40: R 1For CH 3, R 2For-OCH (CH 3) 2
I 41: R 1For CH 3, R 2For-OC (CH 3) 3
I 42: R 1For CH 3, R 2For-OCH (CH 3) CH 2CH 3
I 43: R 1For CH 3, R 2For-OCH 2CH (CH 3) CH 3
I 44: R 1For CH 3, R 2For-OCH 2CH 2CH 2CH 3
I 45: R 1For CH 3, R 2For
Figure FSA00000720241100035
I 46: R 1For CH 3, R 2For
Figure FSA00000720241100036
I 47: R 1For CH 3, R 2For
Figure FSA00000720241100037
I 48: R 1For CH 3, R 2For
Figure FSA00000720241100038
3. contain the pharmaceutical composition that the described compound of claim 1～2 and atoxic pharmacy acceptable salt thereof form as activeconstituents and suitable excipient.These pharmaceutical compositions can be solution, tablet, capsule or injection; These pharmaceutical compositions can pass through injection administration or oral administration.
4. the described compound of claim 1～2 and atoxic pharmacy acceptable salt thereof, and contain the described compound of claim 1～6 and atoxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents the purposes as anticoagulation.
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CN104130185A (en) * 2014-07-01 2014-11-05 蚌埠丰原医药科技发展有限公司 Method for preparing pradaxa intermediate
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
CN104892501A (en) * 2015-05-27 2015-09-09 上海应用技术学院 Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate
WO2016019849A1 (en) * 2014-08-06 2016-02-11 四川海思科制药有限公司 Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof
TWI682928B (en) * 2015-04-27 2020-01-21 大陸商四川海思科製藥有限公司 Dabigatran alkyl ester derivative, its preparation method and use in pharmacy
CN111793058A (en) * 2019-04-09 2020-10-20 鲁南制药集团股份有限公司 Improved method for preparing dabigatran etexilate intermediate

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CN102391250A (en) * 2011-08-29 2012-03-28 石药集团欧意药业有限公司 Dabigatran compound and preparation method and medicinal composition thereof

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CN102050815A (en) * 2009-11-06 2011-05-11 北京美倍他药物研究有限公司 Dabigatran ester derivatives as prodrug
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Publication number Priority date Publication date Assignee Title
CN104130185A (en) * 2014-07-01 2014-11-05 蚌埠丰原医药科技发展有限公司 Method for preparing pradaxa intermediate
WO2016019849A1 (en) * 2014-08-06 2016-02-11 四川海思科制药有限公司 Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof
CN106536505A (en) * 2014-08-06 2017-03-22 四川海思科制药有限公司 Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof
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
TWI682928B (en) * 2015-04-27 2020-01-21 大陸商四川海思科製藥有限公司 Dabigatran alkyl ester derivative, its preparation method and use in pharmacy
CN104892501A (en) * 2015-05-27 2015-09-09 上海应用技术学院 Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate
CN111793058A (en) * 2019-04-09 2020-10-20 鲁南制药集团股份有限公司 Improved method for preparing dabigatran etexilate intermediate

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