WO2014012236A1

WO2014012236A1 - Dabigatran etexilate derivative and preparation method and application thereof

Info

Publication number: WO2014012236A1
Application number: PCT/CN2012/078897
Authority: WO
Inventors: 王志岩
Original assignee: 北京普禄德医药科技有限公司
Priority date: 2012-07-19
Filing date: 2012-07-19
Publication date: 2014-01-23

Abstract

The present invention provides a dabigatran etexilate derivative shown as a formula (I), or pharmaceutically acceptable salt, a solvate, a polymorph, an antipode, or a racemic mixture thereof. In the formula (I), R₁ is hydrogen or C₁ to C₅ alkyl, R₂ is a formula (II), R₃ and R₄ are independently hydrogen or C₁ to C₅ alkyl, n is 0 or 1, and R₅ is C₁ to C₈ alkyl or optionally substituted C₁ to C₈ alkyl. The compound has the activity of a thrombin inhibitor. The present invention also provides a preparation method for the compound, a compound-containing medical composition, and application of the compound and the medicinal composition to preparation of thrombin inhibitor medicines and treatment of related diseases.

Description

Ester derivative of dabigatran group, preparation method and use thereof

The present invention relates to the field of medicine, and in particular, the present invention relates to an ester derivative of dabigatran having thrombin inhibitor activity, a process for preparing the derivative, a pharmaceutical composition comprising the derivative, and the Use of derivatives and pharmaceutical compositions in the preparation of thrombin inhibitors and treatment related diseases. Scenery technology

Dabigatran (see formula 1⁄2) is a selective high-efficiency thrombin inhibitor, but due to its strong alkaline sulfhydryl group, it is not absorbed orally:

In order to improve the bioavailability of dabigatran, the free carboxyl groups in the dabigatran group have been converted to ethyl esters, and the thiol groups have been converted to hexyl aminodecanoate to obtain the diester prodrug dabigatran etexilate. ( Dabigatran Etexilat

Dabigatran etexilate (hereinafter referred to as "the compound of the formula 15") is orally absorbed from the gastrointestinal tract and then converted into an active form of dabigatran (formula 1⁄2) in vivo to exert an anticoagulant effect. After its market launch in 2008, it was called the first oral thrombin inhibitor to prevent deep vein thrombosis and pulmonary embolism after artificial joint replacement. However, studies have shown that the oral bioavailability of dabigatran etexilate is still relatively low. Therefore, there remains a need in the art to develop ester derivatives of novel dabigatran, which are safe, have high oral bioavailability, and have significant anticoagulant effects. Summary of the invention

In view of the above technical problems, it is an object of the present invention to provide an ester derivative of dabigatran having a thrombin inhibitor activity, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or external thereof. Racemic mixture to meet current demand for antithrombin inhibitor drugs.

Another object of the present invention is to provide a process for the preparation of the above-mentioned ester derivative of dabigatran or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof.

Still another object of the present invention is to provide a pharmaceutical composition comprising the ester derivative of dabigatran or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof as an active ingredient .

A further object of the present invention is to provide an pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture or pharmaceutical composition of the dabigatran group ester derivative or pharmaceutically acceptable use.

It is still another object of the present invention to provide an ester derivative of the dabigatran or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof or to employ the pharmaceutical composition A method for treating a related disease.

In order to achieve the above object, the technical solution adopted by the present invention is as follows:

In one aspect, the present invention provides a derivative of dabigatran etexilate of formula I or a pharmaceutically acceptable salt thereof, dissolved

among them

Ri is hydrogen or (^-( ₅ alkyl); I II

- C-(0) -C - R ₅

R ₂ is ^R 3 , wherein R ₃ and R _{4 are} independently hydrogen or dC ₅ alkyl, n is

0 or 1, R ₅ is Ci-C ₈ alkyl or an optionally substituted C _r C ₈ alkyl.

According to some embodiments of the present invention, the present invention provides a derivative of dabigatran etexilate or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein is dC ₅ alkyl;

Preferably, R ₃ and R _{4 are} independently hydrogen or an alkyl group of dC ₃ ;

Preferably, n is 1;

Preferably, it is (^-(3 ₆ alkyl or optionally substituted dC ₆ alkyl).

According to some embodiments of the present invention, the present invention provides a derivative of dabigatran etexilate or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein (^- ( ₃ alkyl group, preferably -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , further preferably -CH ₂ CH ₃ ;

Preferably, and independently is hydrogen.

According to some embodiments of the present invention, the present invention provides a derivative of dabigatran etexilate or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein R ₅ is ( ^-( ₆ alkyl, preferably -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ ,

-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , further preferably -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , more preferably -CH(CH ₃ ) ₂ .

According to a particular embodiment of the invention, the invention provides a derivative of dabigatran etexilate or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, said dabigatran The ester derivative is shown in the following formula 12:

12.

In another aspect, the present invention provides a process for the preparation of the above derivative of dabigatran etexilate or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, the preparation method

La X

Among them, 1 ₆ is? , Cl, Br or I, R ₃ to R ₅ and n are as defined above in the specification. According to a particular embodiment of the invention, the invention provides a process for the preparation of a derivative of dabigatran etexilate or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, said preparation The method includes the following steps:

Object:

III IVII

(2 M 吏 Compound of formula IV is reacted with (HCHO)n in the presence of ZnCl ₂ to form a 4t compound of formula V:

IV V

(3) reacting a compound of formula V with a compound of formula Nal to form a compound of formula VI:

V VI as well as

( 4 M 吏 Formula IVII is reacted with a compound of formula VI to form a compound of formula 12

12.

In a further aspect, the present invention provides a pharmaceutical composition comprising a derivative of dabigatran etexilate according to the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer thereof or A racemic mixture, and a pharmaceutically acceptable excipient.

The pharmaceutically acceptable salt means that the compound of the present invention can form a pharmaceutically acceptable salt with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; The organic acid is, for example, sulfonic acid, trifluorosulfonium sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid.

The solvate is, for example, a hydrate, an alcoholate or the like.

The selection and preparation of pharmaceutically acceptable salts and solvates and the like are well known in the art.

The pharmaceutically acceptable excipients in the pharmaceutical composition may include one or more of the following depending on the particular dosage form and mode of administration: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders , fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, encapsulants, and pigments.

The pharmaceutical composition may be in any dosage form for clinical administration, such as tablets, suppositories, dispersible tablets, enteric coated tablets, chewable tablets, orally disintegrating tablets, capsules, dragees, granules, dry powders, oral solutions, injections. Use a small needle, a lyophilized powder for injection or a large infusion, preferably an oral dosage form or an injection Type.

In still another aspect, the present invention provides the above-described derivative of dabigatran etexilate or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof or the above pharmaceutical composition for preparing thrombin inhibition Use in the class of drugs.

In still another aspect, the present invention provides a method for treating, preventing or delaying the following diseases: venous thrombosis (including deep vein thrombosis and pulmonary embolism), stroke in patients with atrial fibrillation (AF), and acute coronary syndrome (ACS) a heart attack of a patient, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a derivative of dabigatran etexilate according to the invention or a pharmaceutically acceptable salt, solvate, polymorph thereof, enantiomer thereof A body or racemic mixture or a pharmaceutical composition according to the invention. Furthermore, the derivative of dabigatran etexilate provided by the present invention or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof or the pharmaceutical composition provided by the present invention may be combined with other therapies Or the therapeutic agents are co-administered. The mode of administration can be simultaneous, sequential or at certain time intervals.

The dose of the compound or pharmaceutical composition required to effect a therapeutic, prophylactic or prolonged action will generally depend on the particular compound being administered, the patient, the particular disease or condition and its severity, the route of administration and frequency, and the like, and The specific situation is judged. For example, when the compound or pharmaceutical composition provided by the present invention is administered by an oral route, the dose may be from 1 to 100 mg/day, preferably from 100 to 300 mg/day, further preferably from 300 mg/day; the dose may be divided into from 1 to 1 Two doses are administered, preferably two times.

In summary, the present invention provides a novel compound having thrombin inhibitor activity. Experiments have shown that the novel dabigatran etexilate derivatives of the present invention have higher oral bioavailability and stronger anticoagulant inhibition than the existing dabigatran etexilate (Formula 15), and thus are more suitable for preparation. A variety of dosage forms of drugs for the treatment of related diseases. DRAWINGS

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings:

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows the results of pharmacokinetic experiments of the compounds of II, 12, 15 and 1⁄2 in Example 4; Fig. 2 shows the results of aPTT experiments of the compounds of II, 12 and 15 in Example 5. The best way to implement the invention

The present invention is further described in detail with reference to the preferred embodiments of the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagent materials and the like used in the following examples can be purchased from a conventional biochemical reagent store or a pharmaceutical business enterprise unless otherwise specified.

III IVII

To a stirred solution of the formula III (2.0 g, 4.15 mmol) in EtOAc (50 mL), EtOAc (1. At 90. The mixture was stirred at C for 16 hours. The solution was cooled to room temperature and then the solvent was removed under reduced pressure. The residue was partitioned between EA (50 mL) and water (20 mL). The aqueous phase was further extracted with EA (2 x 30 mL) and the organic extracts were combined. Dry over NaS04, filter and concentrate. Purification of crude product on silica gel column MW1207

1H NMR (DMSO-d6, 400 MHz) δ 9.24 (s, 1H), 8.38-8.39 (m, 1H), 7.37-7.56 (m, 5H), 7.09-7.15 (m, 2H), 6.88 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.8 Hz, 2H), 6.44 (t, J = 5.2 Hz, 1H), 5.56 (br s, 2H), 4.51 (d, J = 5.6 Hz, 2H) , 4.22 (t, J = 7.2 Hz, 2H), 3.97 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 2.66-2.69 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). ESI-LCMS: m/z 516 [M + H] +.

Step (2):

〇〇

(HCHO)n ZnCl ₂

CI CI 〇

IV V

A mixture of the compound (212 _§ , 2.011101), polyfurfural (60.1 g, 2 mol) and ZnCl ₂ (0.5 g, cat.) was stirred at room temperature under nitrogen for 40 minutes and then stirred at 50-60 °C. 24 hours. Fractional distillation gave the pure compound of formula V as a colourless oil (215, 77.9%).

Step (3):

〇〇

Nal

C1 〇〇

V VI A mixture of the compound of the formula V (14.0 g, 0.103 mol) and sodium iodide (27.75 g, 0.185 mol) in MeCN (50 mL) was stirred at 30 °C for 5 hours. The solution was then diluted with dichloromethane (100 mL) and water (100 mL) and the organic layer was washed with 2% Na ₂ S ₂ ₃ aqueous. Concentrate under vacuum

Compound VI, a yellow oil (19.6 g, 77%).

IVII

12 IVn compound of formula (550 mg, 0.95 mmol) and _{_{Cs 2 C0 3 (919 mg,}} 2.82 mmol) was added the compound of formula VI (429 mg, 1.88 mmol) in DMF (20 mL) stirred solution. The mixture was stirred at room temperature for 22 hours and then diluted with water (50 mL) and CHCI ( ₃ mL). The organic layer was further washed with water (3x100 mL), the organic layer was then dried over Na ₂ S0 ₄ dried and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc)

^: H NMR (DMSO-d6, 400 MHz) δ 8.38 (br s, 1H), 7.37-7.56 (m, 5H), 7.10-7.16 (m, 2H), 6.88 (d, J = 8.0 Hz, 1H), 6.71 (d, J= 8.8 Hz, 2H), 6.57 (br s, 1H), 5.58 (br s, 2H), 4.52 (br s, 2H), 4.22 (t, J = 6.8 Hz, 2H), 3.95- 4.00 (m, 2H), 3.76 (s, 3H), 2.68-2.70 (m, 2H), 2.49 (s, 1H), 1.06-1.14 (m, 9H).

ESI-LCMS: m/z 616 [M + H] ⁺ .

II

A compound of the formula IVII was prepared in the same manner as in Example 1, followed by a stirred solution of the compound of the formula ινπ (420 mg, 3.11 mmol), DMAP (20 mg) and TEA (0.45 mL) in THF (30 mL). Two drops of the compound of formula IV were added. The mixture was stirred at 0 °C for 10 minutes and then quenched with MeOH. The solvent was removed and the crude was purified by EtOAc EtOAc (EtOAc)

^: H NMR (DMSO-d6,400 MHz) ί58.38 (d, J= 3.6 Hz, 1H), 7.38-7.56 (m, 5H), 7.12-7.16 (m, 2H), 6.88 (d, J= 8.0 Hz, 1H), 6.74 (d, J= 8.4 Hz, 2H), 6.66 (br s, 1H), 6.42 (br s, 2H ), 4.55 (d, J= 4.0 Hz, 2H), 4.21 (t, J= 7.6 Hz, 2H), 3.97 (q, J= 7.2 Hz, 2H), 3.75 (s, 3H), 2.66-2.75 (m , 3H), 1.21 (t, J= 7.2 Hz, 3H).

ESI-LCMS: m/z 608 [M + Na] ⁺ . Example 3: In vitro stability test

This example examined the in vitro liver microsome stability of the compound of formula II of the present invention, a compound of formula 12, which was compared to a known compound of formula 15 by detecting the formation of dabigatran.

Test compound: a compound of formula 11 , a compound of formula 12, and a compound of formula 15;

Control compound: verapamil.

Microsomes: Human liver microsomes and rat liver microsomes were purchased from CellzDirect (Invitrogen); stored at -80 °C prior to use.

Method:

1) A mother liquid was prepared according to Table 1, and then a test compound or a control compound was added so that the final concentration of these compounds in the reaction system was 2 μM. The mixed solution was then preheated at 37 ° C for 2 minutes.

Table 1. Preparation of mother liquor

2) NADPH was added to the mixed solution to a final concentration of 1 mM, and then the reaction system was placed at 37 °C. The same volume of ultrapure water was added to the blank control instead of NADPH.

3) A 50 μ aliquot was taken from the reaction system at 0, 15, 30, 45 and 60 minutes, and the reaction was stopped by adding 3 volumes of cold methanol. The aliquots were centrifuged at 16000 g for 10 minutes to precipitate the protein. The supernatant of 100 L was used for LC/MS/MS analysis to determine the amount of the remaining test compound and control compound. Detection was performed in duplicate.

The instruments and conditions used for LC analysis are:

Shimadzu (Degasser DGU - 20A3, Solvent Delivery Unit LC - 20ADXR,

System Controller CBM - 20A, Column Oven CTO - 1 OAS VP), CTC Analytics HTC PAL - XT System

Column: Phenomenex 5μ C 18(2) (2.0x50mm)

Mobile phase: 0.1% aqueous solution of citric acid (B) and 0.1% citric acid-acetonitrile (A); elution procedure is 0~2min, mobile phase A is 5~100%, mobile phase B is 95%~0%; 2 ~2.2min, mobile phase A is 100%, mobile phase B is 0%; 2.2~2.4min, mobile phase A is 100%~5%, mobile phase B is 0%~95%; 2.4~3min, mobile phase A At 5%, mobile phase B is 95%.

Flow rate: 0.5mL/min;

Column temperature: 25 °C;

Loading volume: ΐθμΐ^

The instruments and conditions used for MS/MS analysis are:

AB API4000 LC/MS/MS instrument

Source: Turbo spray

Ionization mode: ESI

Scan Type: MRM

Collision gas: 6 L/min; Curtain gas: 30 L/min; Atomizing gas: 50 L/min; Auxiliary gas: 50 L/min; Temperature: 500 ° C; Spray voltage: 4500 v.

Test results:

Test compound II, formula in human liver or rat liver microsome system with NADPH

The compound of formula 12 and the compound of formula 15 produced a percentage of dabigatran. The results are shown in Table 2 and Table 3 ₍ (%), day, ,, ,

^^Sample Dabigatran% (100 nm) Dabigatran Group% (1 μΜ) Formula 11 Formula 12 Formula 15 Formula 11 Formula 12 Style 15 Time

Blank 0.0 0.0 0.0 0.0 0.0 0.0

T=60 115.7 100.0 51.1 13.3 11.5 5.9

Τ=45 81.5 74.8 56.2 9.4 8.6 6.4

Τ=30 74.6 71.1 70.6 8.6 8.2 8.1

Τ=15 41.2 42.9 57.1 4.7 4.9 6.6

Τ=5 28.3 41.7 76.5 3.3 4.8 8.8

Τ=0 1.0 1.5 2.1 0.1 0.2 0.2

T=NCF 7.1 32.6 176.0 0.8 3.7 20.2 Table 3. Percentage of dabigatran (%) of compounds produced in rat liver microsomes at different times. Sample dabigatran group (100 nm) dabigatran group % (1 μΜ) formula 11 formula 12 formula 15 11 Equation 12 Equation 15 Time (minutes

Blank 0.0 0.0 0.0 0.0 0.0 0.0

T=60 852.7 636.9 140.9 1 1 1.7 83.4 18.5

Τ=45 866.5 639.8 177.3 1 13.5 83.8 23.2

Τ=30 886.6 654.4 230.3 1 16.2 85.7 30.2

Τ=15 600.8 509.6 219.2 78.7 66.8 28.7

Τ=5 496.7 387.1 278.4 65.1 50.7 36.5

Τ=0 16.6 10.8 7.9 2.2 1.4 1.0

T=NCF 14.7 37.0 347.6 1.9 4.8 45.5 It can be seen from the data of Tables 2 and 3 that the compound of the formula II and the compound of the formula 12 of the present invention are transformed in the human liver microsome and the rat liver microsome system in which NADPH is present. The percentage of dabigatran group produced is much higher than the existing dabigatran group (formula 5). Example 4: In vivo pharmacokinetic test

This example examined the in vivo pharmacokinetics of the 11 compounds, 12 compounds and 16 compounds of the present invention and known dabigatran etexilate (Formula 15).

Method:

The II compound, the 12 compound, the 15 compound and the 16 compound were each dissolved in a blank solution (30% PEG-400 and physiological saline) at a concentration of lg/L.

The experimental animals were male SD rats, 6 to 8 weeks old, weighing 190-215 g, purchased from Beijing Weili Tonghua Experimental Animal Technology Co., Ltd. The SD rats were randomly divided into 4 groups, 3 animals in each group. The doses and routes of administration of each group of rats are shown in Table 4.

Table 4. Grouping and administration of pharmacokinetic tests

Group 3 15 Compound 10 Oral 3 Group 4 16 Compound 1 By intravenous 3 SD rats were fasted for 16 hours prior to the pharmacokinetic test. A single dose of the compound or blank solution was then administered intravenously (1 mg/kg) or orally (10 mg/kg) as indicated in Table 4. The jugular vein puncture method was used to collect 200 uL of blood at the time of administration, wherein for the intravenously administered animal group, 0, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 after administration. Blood was collected at an hour; for the group of animals orally administered, blood was collected at 0, 15 minutes, 30 minutes, 45 minutes, 75 minutes, 135 minutes, 4 hours, 8 hours, and 24 hours after administration. Blood samples were collected in a sample tube with EDTA, and the blood samples were immediately centrifuged at 4000 rpm for 5 minutes at 4 ° C, then the plasma was transferred to another sample tube and stored at -20 ° C.

The samples were subjected to pharmacokinetic tests using the following methods and instruments:

HPLC: Shimadzu (DGV-20A3, Serial NO: SSI-3-0536; LC-20AD Serial

NO: L20104551674 USB and L20104551673 USB;), CTC Analytics HTC PAL System (Serial NO: 4353);

MS: AB API4000 Q Trap LC/MS/MS instrument (Serial NO. AR19020706) Column: Phenomenex Luna 5μ C18 (2.0x50 mm)

Mobile phase: 100% acetonitrile ( ² mM ammonium acetate) and 100% water ( ² mM ammonium acetate)

Quantitative method: internal standard method

The pharmacokinetic profiles of the II compound, the 12 compound, the 15 compound, and the 1⁄2 compound are shown in Figure 1, respectively. The comparison results are shown in Table 5.

Table 5. Comparison of pharmacokinetic data of II compounds, 12 compounds, 15 compounds and 1⁄2 compounds

NA: The data is not available.

Comparing the compound of 12 with the known dabigatran etexilate compound 15, the pharmacokinetic data in Table 5 indicates that the 12 compound has a half-life of 1⁄2 in vivo significantly longer than 15 compounds, which is twice as high as 15 compounds; In terms of utilization, 12 compounds achieved 21.3% utilization, which was also superior to 11.2% utilization of 15 compounds.

Comparing the II compound with the 15 compound, the data in Table 5 shows that the pharmacological characteristics of the II compound and the 15 compound are similar in vivo. Example 5: In vivo pharmacodynamic test - aPPT coagulation inhibition experiment

This example examined the in vivo efficacy, i.e., clotting activity, of a compound of formula II, a compound of formula 12, and a known compound of formula 15 of the present invention.

Test compounds and treatment:

Compound of formula II: 16.0 mg of the compound of formula II is dissolved in 8.0 mL of 30% PEG400 solution to a final concentration of 2.0 mg/mL;

Compound of formula 12: 16.2 mg of the compound of formula 12 is dissolved in 8.1 mL of 30% PEG400 solution to a final concentration of 2.0 mg/mL;

Compound of formula 15: 15.8 mg of the compound of formula 15 is dissolved in 7.9 mL of 30% PEG400 solution to a final concentration of 2.0 mg/mL;

Laboratory animals and treatment:

The experimental animals were male SD rats, and the body weights were randomly divided into 4 groups of 5 animals each. Group 1 was a blank control group and 30% PEG400 solution was administered. The doses and routes of administration of each group of rats are shown in Table 6.

Table 6. Grouping and administration of aPPT coagulation inhibition experiments

Group 2 Formula 11 Compound 10 Oral 5 Group 3 Formula 12 Compound 10 Oral 5 Group 4 Formula 15 Compound 10 Oral 5 Prior to the test, the rats were fasted for 16 hours and then orally administered with a blank solution or compound. At 30 minutes after administration, blood samples were collected by cardiac puncture into tubes containing anticoagulants. Immediately, centrifugation was performed at 1800 g for 5 minutes at 4 ° C to obtain plasma. By using the Instrumentation Laboratory ACL9000

The Coagulometer measures aPPT.

For statistical analysis, the significance level was set to P < 0.05. Calculate the mean and standard deviation for all measurement parameters of the study design. One-way analysis of variance (ANOVA) was performed with multiple comparisons between groups using the software GraphPad Prism 5.0.

The results are shown in Table 7 and Figure 2.

Table 7· aPPT measurement results ( Mean ± SD )

Note: ** p<0.01 relative to group 1

The data from Table 7 indicates that the aPTT can be prolonged compared to the blank control group, Group 1, the compound of Formula 15 and the compound of Formula 12 of the present invention, and the anti-clotting inhibitory effect of the compound of Formula 12 provided by the present invention is 2 of the compound of Formula 15 Double, the effect is better.

Claims

Rights request

1. A derivative of dabigatran etexilate represented by formula I or its pharmaceutically acceptable salt, solvate, polymorph

It is characterized by,

Ri is hydrogen or (^-( ₅ alkyl;

R _4〇

I II

- C-(0) -C - R

, where R ₃ and R ₄ are independently hydrogen or dC ₅ alkyl, n is 0 or 1, and R ₅ is cc ₈ alkyl or optionally substituted _cc ₈ alkyl.

2. The derivative of dabigatran etexilate or its pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture according to claim 1, characterized in that,! ^is an alkyl group of ^-^;

Preferably, R ₃ and R ₄ are independently hydrogen or dC ₃ alkyl;

Preferably, n is 1;

Preferably, is C-(3 ₆ alkyl or optionally substituted dC ₆ alkyl.

3. The derivative of dabigatran etexilate or its pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture according to claim 1 or 2, characterized in that, is ( The alkyl group of -( ₃ is preferably -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , and further preferably -CH ₂ CH ₃ ;

Preferably, and are independently hydrogen.

4. The derivative of dabigatran etexilate or its pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture according to any one of claims 1 to 3, characterized by exist is an alkyl group of (^-( ₆ , preferably -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CH( CH ₃ )CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ ,

-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , more preferably -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , more preferably -CH(CH ₃ ) ₂ .

5. The derivative of dabigatran etexilate or its pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture according to any one of claims 1 to 4, characterized by That is, the derivative of dabigatran etexilate is shown in the following formula 12:

12.

6. Preparation of a dabigatran etexilate derivative or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof according to any one of claims 1 to 5 method, so:

la

Among them, 1 ₆ are? , Cl, Br or I, R ₃ to R ₅ and n are as defined in any one of claims 1 to 4.

7. A method for preparing the derivative of dabigatran etexilate or its pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture according to claim 5, the preparation method Includes the following steps:

(1) React the compound represented by formula III with NH ₂ OH to generate the compound represented by formula IVII:

III IVII

(2M The compound represented by formula IV reacts with (HCHO)n in the presence of ZnCl ₂ to generate the compound represented by formula V:

〇〇

(HCHO)nZnCl:

CI Cl 〇

IV V

(3) React the compound represented by formula V with formula Nal to generate the compound represented by formula VI:

Cl

as well as

The reaction produces the compound shown in formula 12

12'

8. A pharmaceutical composition comprising the derivative of dabigatran etexilate according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, Enantiomeric or racemic mixtures, and pharmaceutically acceptable excipients.

9. The derivative of dabigatran etexilate or its pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture according to any one of claims 1 to 5 or according to the rights Use of the pharmaceutical composition described in claim 8 in the preparation of thrombin inhibitor drugs.

10. A method for treating, preventing or delaying the following diseases: venous thrombosis (including deep vein thrombosis and pulmonary embolism), stroke and acute coronary syndrome in patients with atrial fibrillation (AF)

(ACS) cardiac disease in a patient, the method includes administering to a patient in need of treatment a therapeutically effective amount of the derivative of dabigatran etexilate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 , solvates, polymorphs, enantiomers or racemic mixtures or a pharmaceutical composition according to claim 9.