CN103420983B - Dabigatran derivative, and preparation method and application thereof - Google Patents

Dabigatran derivative, and preparation method and application thereof Download PDF

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CN103420983B
CN103420983B CN201210164265.6A CN201210164265A CN103420983B CN 103420983 B CN103420983 B CN 103420983B CN 201210164265 A CN201210164265 A CN 201210164265A CN 103420983 B CN103420983 B CN 103420983B
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pharmaceutically acceptable
derivative
dabigatran etexilate
acceptable salt
dabigatran
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CN103420983A (en
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孔维苓
蔡志强
龚珉
黄长江
徐为人
汤立达
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

The invention relates to a preparation method of a benzimidazole derivative shown as a general formula I, wherein R1, R2 and R3 are defined as in the specification. The invention relates to a Dabigatran derivative shown as the general formula I and non-toxic pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing these compounds as active components, and application of the compounds and the pharmaceutical composition as thrombin inhibitors.

Description

Dabigatran etexilate derivative and preparation method and application thereof
Technical Field
The invention relates to the field of drug synthesis, in particular to dabigatran etexilate derivatives and a preparation method thereof, a pharmaceutical composition containing the derivatives and application of the compound and the pharmaceutical composition as thrombin inhibitors.
Background
Dabigatran (Dabigatran) is a novel anticoagulant with multiple characteristics developed by the company buerger invager, germany. In 4 months 2008, first marketed in germany and uk under the trade name Pradaxa, for the prevention and treatment of acute Venous Thrombosis (VTE). The oral anticoagulant new drug is first marketed 50 years after warfarin and is a further milestone in the field of anticoagulant treatment and the field of potential lethal thrombus prevention. Pradaxa capsules (dabigatran etexilate) were approved by the U.S. food and drug administration at 10/19/2010 for the prevention of stroke and clotting in patients with cardiac arrhythmias (atrial fibrillation).
Thrombin is an extracellular insulin-like serine protease which plays an important role in the coagulation process, on the one hand, it is capable of cleaving fibrinogen into fibrin, which participates in the formation of an insoluble thrombotic matrix; on the other hand, it can induce platelet activation and aggregation, which in turn triggers a series of secondary coagulation cascades. Dabigatran is a prodrug, which is converted into active dabigatran in vivo, and dabigatran exerts an anticoagulant effect by directly inhibiting thrombin. Dabigatran etexilate is a novel synthetic direct thrombin inhibitor, is a prodrug for oral administration, and belongs to a non-peptide thrombin inhibitor. After oral gastrointestinal absorption, the dabigatran etexilate is converted into dabigatran with direct anticoagulant activity in vivo. The drug binds to the fibrin specific binding site of thrombin, preventing the cleavage of fibrinogen into fibrin, thereby blocking the final step of coagulation cascade network and thrombus formation.
However, oral bioavailability of dabigatran etexilate is low (< 6.5%), and thus further improvements are desired.
Disclosure of Invention
The invention relates to dabigatran etexilate derivatives shown in a structural formula I, non-toxic pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compounds as active ingredients, and application of the compounds and the pharmaceutical composition as thrombin inhibitors.
Accordingly, in a first aspect, the present invention provides an ester derivative of dabigatran represented by formula i:
wherein,
R1represents H or C1-C5Alkyl groups of (a); r2Represents H or C1-C3Alkyl groups of (a); r3Represents C1-C6Alkyl or substituted alkyl of (a).
Preferably, the present invention provides an ester derivative of dabigatran represented by formula I or a pharmaceutically acceptable salt thereof, wherein R is1Represents H or C1-C2Alkyl of R2Represents H or CH3，R3Represents C1-C6Alkyl group of (1).
More preferably, the present invention provides an ester derivative of dabigatran represented by formula i or a pharmaceutically acceptable salt thereof selected from the group consisting of compounds represented by the following structural formulae:
the substituents of a particular target compound are each defined as follows:
I1：R1is-CH3，R2is-H, R3is-CH3；
I2：R1is-CH3，R2is-H, R3is-CH2CH3；
I3：R1is-CH3，R2is-H, R3is-CH2CH2CH3；
I4：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH3；
I5：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH2CH3；
I6：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH2CH2CH3；
I7：R1is-CH2CH3，R2is-H, R3Is R3-CH3；
I8：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH3；
I9：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH3；
I10：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH3；
I11：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH2CH3；
I12：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH2CH2CH3；
I13：R1is-CH3，R2is-CH3，R3is-CH3；
I14：R1is-CH3，R2is-CH3， R3is-CH2CH3；
I15：R1is-CH3，R2is-CH3， R3is-CH2CH2CH3；
I16：R1is-CH3，R2is-CH3， R3is-CH2CH2CH2CH3；
I17：R1is-CH3，R2is-CH3， R3is-CH2CH2CH2CH2CH3；
I18：R1is-CH3，R2is-CH3， R3is-CH2CH2CH2CH2CH2CH3；
I19：R1is-CH2CH3，R2is-CH3，R3Is R3-CH3；
I20：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH3；
I21：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH3；
I22：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH3；
I23：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH2CH3；
I24：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH2CH2CH3；
A second aspect of the invention relates to a pharmaceutical composition, which comprises at least one ester derivative of dabigatran represented by formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
The second aspect of the invention relates to an ester derivative of dabigatran shown as a formula I and non-toxic pharmaceutically acceptable salts thereof, and application of a pharmaceutical composition containing the ester derivative of dabigatran shown as the formula I and the non-toxic pharmaceutically acceptable salts thereof as active ingredients as anticoagulation.
The compounds represented by formula i can form pharmaceutically acceptable salts with inorganic acids, such as sulfates, phosphates, hydrochlorides, hydrobromides; pharmaceutically acceptable salts can also be formed with organic acids such as acetates, oxalates, citrates, succinates, gluconates, tartrates, p-toluenesulfonates, benzenesulfonates, methanesulfonates, benzoates, lactates, maleates, and the like. The selection and preparation of suitable salts is well known to those skilled in the art.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered alone or in the form of pharmaceutical compositions. The pharmaceutical composition of the present invention can be formulated into various suitable dosage forms according to the administration route. The use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration chosen and may be prepared in accordance with common general knowledge in the art.
The administration route can be oral, parenteral or topical, preferably oral and injectable. The oral pharmaceutical preparation comprises capsules, tablets and the like. The compounds of the invention may also be formulated for parenteral or transdermal or transmucosal administration, or by means of suppositories or implants. It will be appreciated by those skilled in the art that the compounds of the present invention may employ a suitable Drug Delivery System (DDS) to achieve a more beneficial effect.
Detailed Description
The following examples are presented to enable those skilled in the art to more fully understand the present invention and are not intended to limit the invention in any way.
Dabigatran etexilate and ester derivatives of dabigatran shown in formula I are synthesized by the methods of references (Hauel NH, Nar H, Prepke H, et al.Structure-Based Design of Novel patent polypeptide Thrombin inhibitors. J.Med.Chem.2002; 45: 1757-:
R1 = H， -CH3， -CH2CH3； R2=H，CH3，R3 = C1-C6alkyl or substituted alkyl of (a).
Taking a compound 1 as a starting material, and carrying out amidation and condensation to obtain an intermediate 2; reacting the intermediate 2 with sodium hydroxide and then with chloralkane to obtain an intermediate 3, reacting the intermediate 3 with acetohydroxamic acid to obtain an intermediate 4, reacting the intermediate 4 with different substituted activated esters to obtain the dabigatran ester derivative (I)1-32）
EXAMPLE 13 methyl (I) 2- (((3- ((methoxycarbonyl) amino) benzisoxazol-6-yl) oxy) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamide) propanoate1) Preparation of
1) Synthesis of ethyl 3- (2- ((4-cyano-3-fluorophenoxy) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate (2A)
2- (4-cyano-3-fluorophenoxy) acetic acid (1.77 g, 0.0l mo1), EDC1 (1.9 g, 0.01 mo1), 1-hydroxybenzotriazole (1.35 g, 0.01 mo1) were dissolved in a mixture of THF (35 mL) and DMF (5 mL). The mixture was stirred in an ice-water bath for 35 min, warmed to room temperature, and a solution of 1 (3.1 g, 0.009 mo1) in THF (15 mL) was slowly added dropwise. Stirring for 6 h after the addition. The solvent was evaporated, dichloromethane (30 mL) was added, washing was performed with saturated brine (5 mLx 3), drying was performed with anhydrous sodium sulfate and then filtration, the filtrate was concentrated to dryness, glacial acetic acid (45 mL) was added to the residue, heating was performed under reflux for 2 h, concentration was performed under reduced pressure to dryness, concentrated ammonia water (15 mL) was added to the residue, the solvent was evaporated by stirring at room temperature for 30 min, dichloromethane (25 mL) was added to the residue, washing was performed with saturated brine (5 mL x 3), drying was performed with anhydrous sodium sulfate and then filtration, the filtrate was concentrated to dryness, and the residue was purified by column chromatography to obtain 3.1 g of an amorphous yellow solid.
2) Synthesis of methyl 3- (2- ((4-cyano-3-fluorophenoxy) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate (3 Aa)
Dissolving 5.0 g of intermediate 2A in 200 mL of ethanol, adding 10 mL of 1N sodium hydroxide solution, stirring at room temperature to react until hydrolysis is complete, evaporating to dryness, dissolving with 20 mL of DMF, adding 1.86 g of methyl iodide, stirring at room temperature for 24 hours, concentrating, and performing column separation to obtain 4.0 g of target intermediate.
3) Synthesis of methyl 3- (2- (((3-aminobenzisoxazol-6-yl) oxy) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate (4 Aa)
4.0 g of intermediate 3Aa was dissolved in 80 mL of DMF, and potassium carbonate (4.8 g, 0.036 mol) was dissolved in 24 mL of water and added to the solution, followed by stirring at room temperature. Acetohydroxamic acid (1.632 g, 0.024 mol) was weighed and added to the above reaction solution, reacted at room temperature for 3 days, filtered off the solid and evaporated to dryness, and passed through a column to obtain 2.5 g of pure product.
4) Methyl 3- (2- (((3- ((methoxycarbonyl) amino) benzisoxazol-6-yl) oxy) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamide) propanoate (I1) Synthesis of (2)
The product (4 Aa) obtained in the above step was dissolved in tetrahydrofuran (50 mL), and methyl chloroformate (0.519 g) and DIEA (3 mL) were added thereto, and the mixture was stirred at room temperature overnight, evaporated to dryness, and purified by column chromatography to obtain 1.8 g of a white aimed product.1H NMR(DMAO-d6,400 MHz): 2.68(t, J=7.1Hz, 2H, CH2), 3.68(s, 3H, CH3), 3.72(s, 3H, CH3), 3. 8(s, 3H, CH3), 4.22(t, J=7.1 Hz, 2H, CH2), 5.51(s, 2H, CH2), 6.34(s, 1H, NH), 6.89~6.95(m, 2H, ArH ), 7.09~7.12(m, 1H, ArH), 7.19~7.22(m, 2H, ArH), 7.47(d, J=8.4, 1H, ArH), 7.5~7.56(m, 2H, ArH), 7.67(d,J=8.4, 1H, ArH), 8.37(m, 1H), ESI-MS: m/z 559 [M+H]+。
Examples 2 to 24
Referring to the procedure of example 1, except that different phenoxyacetic acids were selected, different carboxylic acid esters were reacted with different activated ester side chains to give the compounds of formula I below.
Example 25 evaluation of anticoagulant Activity-determination of activated partial Thromboplastin time (aPPT)
Kunming mice, 18-20g in mass, were randomly grouped into groups of 10 mice each, fasted overnight. Suspending or dissolving dabigatran etexilate and a target compound to be detected in 1% sodium carboxymethylcellulose water solution to prepare 1mg/mL concentration, performing intragastric administration according to a dose of 10mg/Kg (calculated by being converted into dabigatran), after half an hour, taking blood through cardiac puncture, adding a 4% sodium lycii solution to a final concentration of 0.4% for anticoagulation, centrifuging for 5 minutes at 12000r/min, taking 0.1mL of plasma, adding 0.1mL of aPPT reagent, pre-heating at 37 ℃ for 3 minutes, adding 0.1mL of calcium chloride solution pre-heated at 37 ℃, and determining the coagulation time by using a platelet aggregation coagulation factor analyzer to obtain the aPPT value. The results are shown in Table 1.
TABLE 1 measurement of activated partial thromboplastin time (aPPT)
Compound (I) aPPT(sec)
Physiological saline 21.4±4.3
Dabigatran etexilate 75.3±2.1
Ⅰ3 77.1±2.8
Ⅰ4 165.1±2.9
Ⅰ5 145.2±4.5
Ⅰ10 147.6±3.6
Ⅰ12 135.9±3.0
Ⅰ13 112.4±3.9
Ⅰ14 80.9±3.6
Ⅰ16 102.4±3.0
Ⅰ17 95.9±3.2
Ⅰ18 165.2±4.7
Ⅰ22 127.6±3.3
Ⅰ23 68.5±3.7
Ⅰ24 105.9±3.1

Claims (10)

1. Dabigatran etexilate derivatives having the structure of formula i or pharmaceutically acceptable salts thereof:
wherein,
R1is H or C1-C5Alkyl groups of (a); r2Is H or C1-C3Alkyl groups of (a); r3Is C1-C6Alkyl group of (1).
2. The dabigatran etexilate derivative having the structure of formula i or a pharmaceutically acceptable salt thereof according to claim 1:
wherein,
R1is H or C1-C2Alkyl of R2Is H or CH3，R3Is C1-C6Alkyl group of (1).
3. The dabigatran etexilate derivative having the structure of formula i or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, selected from the group consisting of compounds represented by the following structural formulae:
wherein R is1、R2And R3Are respectively defined as follows:
I1：R1is-CH3，R2is-H, R3is-CH3；
I2：R1is-CH3，R2is-H, R3is-CH2CH3；
I3：R1is-CH3，R2is-H, R3is-CH2CH2CH3；
I4：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH3；
I5：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH2CH3；
I6：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH2CH2CH3；
I7：R1is-CH2CH3，R2is-H, R3is-CH3；
I8：R1is-CH2CH3，R2is-H, R3is-CH2CH3；
I9：R1is-CH2CH3，R2is-H, R3is-CH2CH2CH3；
I10：R1is-CH2CH3，R2is-H, R3is-CH2CH2CH2CH3；
I11：R1is-CH2CH3，R2is-H, R3is-CH2CH2CH2CH2CH3；
I12：R1is-CH2CH3，R2is-H, R3is-CH2CH2CH2CH2CH2CH3；
I13：R1is-CH3，R2is-CH3，R3is-CH3；
I14：R1is-CH3，R2is-CH3，R3is-CH2CH3；
I15：R1is-CH3，R2is-CH3，R3is-CH2CH2CH3；
I16：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH3；
I17：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH2CH3；
I18：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH2CH2CH3；
I19：R1is-CH2CH3，R2is-CH3，R3is-CH3；
I20：R1is-CH2CH3，R2is-CH3，R3is-CH2CH3；
I21：R1is-CH2CH3，R2is-CH3，R3is-CH2CH2CH3；
I22：R1is-CH2CH3，R2is-CH3，R3is-CH2CH2CH2CH3；
I23：R1is-CH2CH3，R2is-CH3，R3is-CH2CH2CH2CH2CH3；
I24：R1is-CH2CH3，R2is-CH3，R3is-CH2CH2CH2CH2CH2CH3。
4. The dabigatran etexilate derivative with the structure of the general formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein the salt is formed by the dabigatran etexilate derivative with the structure of the general formula I and an organic acid or an inorganic acid.
5. The dabigatran etexilate derivative with the structure of the general formula I or the pharmaceutically acceptable salt thereof according to claim 3, wherein the salt is formed by the dabigatran etexilate derivative with the structure of the general formula I and an organic acid or an inorganic acid.
6. The dabigatran etexilate derivative with the structure of the general formula I or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the salt can be sulfate, phosphate, hydrochloride, hydrobromide, acetate, oxalate, citrate, succinate, gluconate, tartrate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, benzoate, lactate, maleate.
7. A pharmaceutical composition comprising at least one dabigatran etexilate derivative having a structure according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
8. A pharmaceutical composition, comprising at least one dabigatran etexilate derivative having a structure of formula i or a pharmaceutically acceptable salt thereof according to claim 3, and one or more pharmaceutically acceptable carriers or excipients.
9. Use of the dabigatran etexilate derivative with the structure of the general formula i or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 for the preparation of thrombin inhibitors.
10. Use of the dabigatran etexilate derivative with the structure of the general formula i or the pharmaceutically acceptable salt thereof according to claim 3 for preparing thrombin inhibitors.
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CN104628714B (en) * 2015-02-04 2018-02-16 沈阳工业大学 Ester derivant of dabigatran and its production and use
CN106554370A (en) * 2015-09-25 2017-04-05 陕西合成药业股份有限公司 Dabigatran derivant containing phosphate ester and its production and use

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