CN103420985B - As the dabigatran ester derivative and its production and use of prodrug - Google Patents
As the dabigatran ester derivative and its production and use of prodrug Download PDFInfo
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- CN103420985B CN103420985B CN201210164723.6A CN201210164723A CN103420985B CN 103420985 B CN103420985 B CN 103420985B CN 201210164723 A CN201210164723 A CN 201210164723A CN 103420985 B CN103420985 B CN 103420985B
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Abstract
The present invention relates to the preparation method of benzimidizole derivatives formula I, wherein X, R, and R
1, R
2and R
3there is implication respectively that limit in the description.The present invention relates to ester derivative and the non-toxic pharmacy acceptable salt thereof of the dabigatran shown in formula I, and containing these compounds as the pharmaceutical composition of activeconstituents, and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, ester derivative being specifically related to dabigatran and preparation method thereof, the pharmaceutical composition containing these derivatives and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Background technology
Dabigatran etcxilate (Dabigatran) is the novel anticoagulation medicine with various features of German Boehringer Ingelheim company exploitation.In April, 2008, first in Germany and Britain's listing, commodity are called Pradaxa, for preventing and treating Acute Venous thrombus (VTE).This is the oral new drug of anticoagulation of first listing over 50 years after warfarin, is another milestone in anticoagulation therapy field and potential lethality thrombus prevention field.U.S. food and Drug Administration's approval Pradaxa capsule on October 19th, 2010 (dabigatran etcxilate) are for there to be preventing apoplectic and blood coagulation in rhythm abnormality (atrial fibrillation) patient.
Zymoplasm is extracellular Insulin-Like serine protease, in coagulation process, have vital role, and on the one hand, it can make Fibrinogen cracking become scleroproein, and the latter participates in forming hard clot suppository matrix; On the other hand, it can activate and assemble by induced platelet, and then causes the reaction of series of secondary coagulation cascade.Dabigatran etcxilate is prodrug, is converted into activated dabigatran in vivo, and dabigatran plays anticoagulation effect by direct Trombin inhibiting.Dabigatran etcxilate is a kind of direct thrombin inhibitor of novel synthesis, is for oral prodrug, belongs to the thrombin inhibitors of non-peptide class.Oral after gastrointestinal absorption, be converted into the dabigatran with direct anticoagulant active in vivo.Medicine is incorporated into the scleroproein specific binding site of zymoplasm, stops Fibrinogen to be cracked into scleroproein, thus has blocked final step and the thrombosis of blood coagulation waterfall network.
But the oral administration biaavailability of dabigatran etcxilate lower (<6.5%), therefore needs to be improved further.
Summary of the invention
The present invention relates to by the ester derivative of the dabigatran shown in structural formula I and non-toxic pharmacy acceptable salt thereof, and containing these compounds as the pharmaceutical composition of activeconstituents, and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Therefore first aspect of the present invention provides ester derivative and the pharmacologically acceptable salt thereof of the dabigatran representated by formula I:
Wherein,
X represents O, N or S; R represents monosubstituted or disubstituted CH
3or halogen; R
1represent H or C
1-C
5alkyl or the alkyl of replacement; R
2represent H or C
1-C
3alkyl or the alkyl of replacement; R
3represent C
1-C
6alkyl or the alkyl of replacement.
Preferably, the invention provides ester derivative or its pharmacologically acceptable salt of the dabigatran representated by formula I, wherein X represents O, N, and R represents monosubstituted or disubstituted CH
3with F, Cl or Br, R
1represent H, methyl or ethyl, R
2represent H, CH
3or sec.-propyl, R
3represent methyl, ethyl, propyl group, butyl, amyl group or n-hexyl.
More preferably, the invention provides the ester derivative of the dabigatran representated by formula I or its pharmacologically acceptable salt and be selected from compound representated by following structural formula:
Each substituting group of objectives compound is defined as follows respectively:
I
1: X is O, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
2: X is O, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
3: X is O, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
4: X is O, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for n-hexyl;
I
5: X is O, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
6: X is O, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
7: X is O, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
8: X is O, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for n-hexyl;
I
9: X is O, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
10: X is O, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
11: X is O, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
12: X is O, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-n-hexyl;
I
13: X is O, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
14: X is O, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
15: X is O, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
16: X is O, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-CH
3, R
3for n-hexyl;
I
17: X is N, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
18: X is N, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
19: X is N, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
20: X is N, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for n-hexyl;
I
21: X is N, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
22: X is N, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
23: X is N, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-CH(CH
3)
2, R
3for-CH
3;
I
24: X is N, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-CH(CH
3)
2, R
3for n-hexyl;
I
25: X is N, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
26: X is N, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
27: X is N, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
28: X is N, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for n-hexyl;
I
29: X is N, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
30: X is N, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
31: X is N, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
32: X is N, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-CH
3, R
3for n-hexyl;
Second aspect of the present invention relates to pharmaceutical composition, and it comprises ester derivative or its pharmacologically acceptable salt of the dabigatran representated by least one formula I, and one or more pharmaceutically acceptable carrier or vehicle.
Second aspect of the present invention relates to ester derivative and the non-toxic pharmacy acceptable salt thereof of the dabigatran shown in formula I, and the ester derivative of the dabigatran shown in contained I and non-toxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents as anticoagulant purposes.
Compound representated by formula I can form pharmaceutical salts with mineral acid, such as vitriol, phosphoric acid salt, hydrochloride, hydrobromate; Also pharmaceutical salts can be formed with organic acid, such as acetate, oxalate, Citrate trianion, succinate, gluconate, tartrate, tosilate, benzene sulfonate, 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 separately or with the form administrations of pharmaceutical composition.Pharmaceutical composition of the present invention can be made into various suitable dosage forms according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they are conducive to active compound being processed into the preparation that can pharmaceutically use.Suitable dosage form depends on selected route of administration, can be prepared according to general knowledge well known in the art.
Route of administration can be oral, non-bowel or topical, preferred oral and injection form administration.Capsule and tablet etc. can be comprised by oral pharmaceutical preparation.The compounds of this invention also can be prepared for administered parenterally or transdermal administration or mucosal, or adopts 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 (DDS) to obtain more favourable effect.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
First reference (Hauel NH, Nar H, Priepke H, et al.Structure-Based Design of Novel Potent NopePtide Thrombin Inhibitors. J.Med. Chem.2002; 45:1757-1766) the ester derivative of method synthesis dabigatran etcxilate and the dabigatran shown in formula I:
X represents O, N, and R represents monosubstituted or disubstituted CH
3with F or Cl, R
1represent methyl, R
2represent H, methyl and sec.-propyl, R
3represent methyl, n-hexyl.
With compound 1 for starting raw material, obtain intermediate 2 through amidation, condensation; Intermediate 2 and sodium hydroxide are reacted and be obtained by reacting intermediate 3 with chloroparaffin again, intermediate 3 is obtained by reacting intermediate 4 with acidic alcohol and ammonia ethanolic soln, and intermediate 4 and the Acibenzolar of different replacement are obtained by reacting the ester derivative (I of dabigatran
1-32)
Embodiment 1 (instead) 3-(2-((the fluoro-4-of 3-(N'-((hexyloxy) carbonyl) amidino) benzene oxygen) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I
2) preparation
1) synthesis of 3-(2-((4-cyano group-3-fluorobenzene oxygen) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) ethyl propionate (2A)
2-(4-cyano group-3-fluorobenzene oxygen) acetic acid (1.94g, 0.0lmo1), EDC1 (1.9g, 0.01mo1), I-hydroxybenzotriazole (1.35g, 0.01mo1) is dissolved in THF (35mL) and DMF (5mL) mixed solution.Stir 35min in ice-water bath, rise to room temperature, slowly drip THF (15mL) solution of 1 (3.1g, 0.009mo1).Finish and stir 6h.Boil off solvent, add methylene dichloride (30mL), wash with saturated brine (5mL x 3), filter after anhydrous sodium sulfate drying, filtrate is concentrated into dry, ice acetic acid (45mL) in residuum, reflux 2h, is evaporated to dry, strong aqua (15mL) is added in residuum, stirring at room temperature 30min boils off solvent, adds methylene dichloride (25mL) in residuum, washs through saturated brine (5mL x 3), filter after anhydrous sodium sulfate drying, filtrate is concentrated into dry, and residuum, through purification by column chromatography, obtains amorphous yellow solid 3.1 g.
2) synthesis of 3-(2-((4-cyano group-3-fluorobenzene oxygen) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) methyl propionate (3A)
Be dissolved in 200mL ethanol by 5.0 g intermediate 2A, add the sodium hydroxide solution 10mL of 1N, stirred at ambient temperature reaction is complete to hydrolysis, evaporate to dryness, dissolves with 20mL DMF, adds 1.86 g methyl iodide, stirring at room temperature 24 hours, concentrated, post is separated and obtains 4.0 g title intermediate.
3) synthesis of 3-(2-((4-amidino-3-fluorobenzene oxygen) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) methyl propionate (4 A)
4.0g intermediate 3A is dissolved in 80mL DMF, gets salt of wormwood (4.8g, 0.036 mol) and be dissolved in 24 mL water and add in above-mentioned solution, stir under normal temperature.Taking N-acetylhydroxylamine (1.632g, 0.024mol) adds in above-mentioned reaction solution, room temperature reaction 3 days, leaches solvent evaporated after solid, crosses post and obtains sterling 2.5 g.
4) (instead) 3-(2-((the fluoro-4-of 3-(N'-((hexyloxy) carbonyl) amidino) benzene oxygen) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzoglyoxaline-5-formamido-) methyl propionate (I
2) synthesis
Be dissolved in tetrahydrofuran (THF) (50 mL) by upper step product (4 A), (0.620 g) and DIEA (3 mL), stirred overnight at room temperature, evaporate to dryness, and column chromatography purification obtains target product 1.8 g of white to add the just own ester of chloroformic acid.
1H NMR(DMSO-d
6,400 MHz)δ: 1.05(t,J=7.0, 3H, CH3), 1.259(m, 6H, CH2), 1.55(t,J=6.8, 2H, CH2), 2.68(t, J=7.2, 2H, CH2), 3.72(s, 3H, CH
3), 3.80(s, 3H, CH3), 3.98(m, 2H, CH2), 4.23(t,J=7.2, 2H, CH2), 5.52(s, 2H, CH
2), 6.89(d, J=8, 1H,ArH), 7.00(d, J=8.8, 1H, ArH), 7.11(m, 2H, ArH), 7.22(d, J=8.4, 1H, ArH), 7.45~7.56(m, 3H, ArH), 7.65(t,J=8.8, 1H, ArH), 8.38(d, J=3.6, 1H, ArH), 8.4~9.2(br,2H, NH2), ESI-MS: m/z 633 [M+H]
+。
Embodiment 2-32
With reference to the operation of embodiment 1, difference is to select different phenoxy acetic acids, and different carboxylicesterss reacts from different Acibenzolar side chains, obtains the compound of following formula I.
The mensuration of embodiment 33 anticoagulating active evaluation-activated partial thromboplastin time (aPPT)
By the kunming mice of quality 18-20g, random packet, often organizes 10, overnight fasting.Dabigatran etcxilate and target compound to be measured are suspended or be dissolved in the aqueous solution of Xylo-Mucine of 1%, be made into the concentration of 1mg/mL, by dosage (amounting to into the dabigatran to calculate) gastric infusion of 10mg/Kg, heart puncturing extracting blood is passed through after half an hour, add 4% matrimony vine acid sodium solution to 0.4% final concentration anti-freezing, centrifugal 5 minutes of 12000r/min, get blood plasma 0.1mL, add aPPT reagent 0.1mL, 37 DEG C of pre-temperature are after 3 minutes, add the calcium chloride solution 0.1mL of 37 DEG C of pre-temperature, by platelet aggregation thrombin analysis-e/or determining setting time, be aPPT value.The results are shown in Table 1.
The measurement result of table 1 activated partial thromboplastin time (aPPT)
| Compound | aPPT(sec) |
| Physiological saline | 21.4±4.3 |
| Dabigatran etcxilate | 75.3±2.1 |
| Ⅰ 3 | 100.9±2.8 |
| Ⅰ 4 | 63.5±3.4 |
| Ⅰ 5 | 122.6±3.0 |
| Ⅰ 10 | 142.6±3.3 |
| Ⅰ 12 | 97.4±2.7 |
| Ⅰ 13 | 90.9±2.9 |
| Ⅰ 14 | 75.9±3.3 |
| Ⅰ 16 | 130.9±2.7 |
| Ⅰ 17 | 117.4±3.6 |
| Ⅰ 18 | 160.2±4.4 |
| Ⅰ 22 | 140.2±4.2 |
| Ⅰ 23 | 160.1±2.6 |
| Ⅰ 24 | 72.1±2.5 |
| Ⅰ 26 | 120.2±4.3 |
| Ⅰ 27 | 140.5±2.5 |
| Ⅰ 29 | 52.2±2.7 |
| Ⅰ 30 | 140.3±2.7 |
| Ⅰ 32 | 52.1±2.4 |
Claims (7)
1. there is ester derivative or its pharmacy acceptable salt of the dabigatran of structure shown in formula I:
Wherein,
X is O, N;
R is monosubstituted or disubstituted CH
3or halogen;
R
1for methyl;
R
2for H or C
1-C
3alkyl;
R
3for C
1-C
6alkyl.
2. derivative or its pharmacy acceptable salt with the ester of the dabigatran of structure shown in formula I according to claim 1:
Wherein,
X is O, N;
R is monosubstituted or disubstituted CH
3, F, Cl;
R
1for methyl;
R
2for H, CH
3;
R
3for methyl, ethyl, propyl group, butyl, amyl group or n-hexyl.
3. ester derivative or its pharmacy acceptable salt with the dabigatran of structure shown in formula I according to claim 2, is selected from the compound representated by following structural formula:
Wherein, X, R, R
1, R
2and R
3be defined as follows respectively:
I
3: X is O, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
5: X is O, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
10: X is O, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
12: X is O, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-n-hexyl;
I
13: X is O, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
16: X is O, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-CH
3, R
3for n-hexyl;
I
17: X is N, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-H, R
3for-CH
3;
I
18: X is N, R is that between X, position F is monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
22: X is N, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
23: X is N, R is that between X, position Cl is monosubstituted, R
1for-CH
3, R
2for-CH (CH
3)
2, R
3for-CH
3;
I
26: X is N, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-H, R
3for n-hexyl;
I
27: X is N, R is position CH between X
3monosubstituted, R
1for-CH
3, R
2for-CH
3, R
3for-CH
3;
I
30: X is N, R is position Cl and CH between X
3two replacement, R
1for-CH
3, R
2for-H, R
3for n-hexyl.
4. the ester derivative with the dabigatran of structure shown in formula I according to any one of claim 1-3 or its pharmacy acceptable salt, salt formed by the ester derivative that described salt is the dabigatran of formula 1 structure and organic acid or mineral acid.
5. ester derivative or its pharmacy acceptable salt with the dabigatran of structure shown in formula I according to claim 4, described salt can be vitriol, phosphoric acid salt, hydrochloride, hydrobromate, acetate, oxalate, Citrate trianion, succinate, gluconate, tartrate, tosilate, benzene sulfonate, mesylate, benzoate, lactic acid salt, maleate.
6. a pharmaceutical composition, is characterized in that, comprises the ester derivative with the dabigatran of structure shown in formula I at least as described in any one of claim 1-3 or its pharmacy acceptable salt, and one or more pharmaceutically acceptable carrier or vehicle.
7. the ester derivative with the dabigatran of structure shown in formula I according to any one of claim 1-3 or its pharmacy acceptable salt are preparing the purposes in thrombin inhibitors.
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| WO2016019847A1 (en) * | 2014-08-06 | 2016-02-11 | 四川海思科制药有限公司 | Fluorine substituted dabigatran ester derivative, preparation method therefor, and pharmaceutical use thereof |
| CN105732491B (en) * | 2016-03-28 | 2018-01-02 | 沈阳工业大学 | Ester derivant of dabigatran and its production and use |
| CN109897028B (en) * | 2017-12-11 | 2021-05-28 | 上海美悦生物科技发展有限公司 | Dabigatran etexilate derivative and pharmaceutical application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101980697A (en) * | 2008-03-28 | 2011-02-23 | 贝林格尔.英格海姆国际有限公司 | Process for preparing orally administered dabigatran formulations |
| CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101980697A (en) * | 2008-03-28 | 2011-02-23 | 贝林格尔.英格海姆国际有限公司 | Process for preparing orally administered dabigatran formulations |
| CN102123707A (en) * | 2008-08-19 | 2011-07-13 | 贝林格尔.英格海姆国际有限公司 | Dabigatran for percutaneous interventional cardiac catheterisation |
| 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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