WO2014012236A1 - Dérivé de dabigatran étexilate et son procédé de préparation et son application - Google Patents

Dérivé de dabigatran étexilate et son procédé de préparation et son application Download PDF

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Publication number
WO2014012236A1
WO2014012236A1 PCT/CN2012/078897 CN2012078897W WO2014012236A1 WO 2014012236 A1 WO2014012236 A1 WO 2014012236A1 CN 2012078897 W CN2012078897 W CN 2012078897W WO 2014012236 A1 WO2014012236 A1 WO 2014012236A1
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WO
WIPO (PCT)
Prior art keywords
formula
derivative
pharmaceutically acceptable
compound
acceptable salt
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PCT/CN2012/078897
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English (en)
Chinese (zh)
Inventor
王志岩
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北京普禄德医药科技有限公司
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Priority to PCT/CN2012/078897 priority Critical patent/WO2014012236A1/fr
Publication of WO2014012236A1 publication Critical patent/WO2014012236A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • 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 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.
  • 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:
  • 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 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.
  • the first oral thrombin inhibitor to prevent deep vein thrombosis and pulmonary embolism after artificial joint replacement.
  • 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
  • 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
  • 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.
  • the present invention provides a derivative of dabigatran etexilate of formula I or a pharmaceutically acceptable salt thereof, dissolved
  • Ri is hydrogen or ( ⁇ -( 5 alkyl); I II
  • R 2 is R 3 , wherein R 3 and R 4 are independently hydrogen or dC 5 alkyl, n is
  • R 5 is Ci-C 8 alkyl or an optionally substituted C r C 8 alkyl.
  • 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;
  • R 3 and R 4 are independently hydrogen or an alkyl group of dC 3 ;
  • n 1;
  • it is ( ⁇ -(3 6 alkyl or optionally substituted dC 6 alkyl).
  • 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 ;
  • 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 .
  • 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:
  • 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
  • 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:
  • the present invention provides a pharmaceutical composition
  • 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 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.
  • a small needle, a lyophilized powder for injection or a large infusion preferably an oral dosage form or an injection Type.
  • 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.
  • 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.
  • venous thrombosis including deep vein thrombosis and pulmonary embolism
  • AF atrial fibrillation
  • ACS acute coronary syndrome
  • 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.
  • 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.
  • the present invention provides a novel compound having thrombin inhibitor activity.
  • 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.
  • 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.
  • 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 ⁇ (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)
  • 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.
  • 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 ⁇ M.
  • the mixed solution was then preheated at 37 ° C for 2 minutes.
  • 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.
  • 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%.
  • 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 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, ,, ,
  • 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.
  • 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.
  • Quantitative method internal standard method
  • 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.
  • 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;
  • 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.
  • the Coagulometer measures aPPT.
  • 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.

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Abstract

La présente invention concerne un dérivé de dabigatran étexilate tel que représenté par la formule (I), ou un sel pharmaceutiquement acceptable, un solvate, un polymorphe, un antipode ou un mélange racémique de celui-ci. Dans la formule (I), R1 représente l'atome d'hydrogène ou un groupe alkyle en C1 à C5, R2 répond à la formule (II), R3 et R4 représentent chacun indépendamment l'atome d'hydrogène ou un groupe alkyle en C1 à C5, n vaut 0 ou 1 et R5 représente un groupe alkyle en C1 à C8 ou un groupe alkyle en C1 à C8 éventuellement substitué. Le composé présente l'activité d'un inhibiteur de la thrombine. La présente invention concerne également un procédé de préparation du composé, une composition médicale contenant le composé et l'application du composé et de la composition médicinale à la préparation de médicaments inhibiteurs de la thrombine et au traitement de maladies s'y rapportant.
PCT/CN2012/078897 2012-07-19 2012-07-19 Dérivé de dabigatran étexilate et son procédé de préparation et son application WO2014012236A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3247332A1 (fr) * 2015-01-20 2017-11-29 Incarda Therapeutics, Inc. Doses aérosols unitaires pour anticoagulation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1675193A (zh) * 2002-08-02 2005-09-28 贝林格尔英格海姆法玛两合公司 1－甲基－2－(4－脒基苯基氨甲基)－苯并咪唑－5－基－羧酸－(n－2－吡啶基－n－2－羟基羰基乙基－酰胺的新颖前药，其制法及其作为药物制剂的用途
WO2006045756A1 (fr) * 2004-10-25 2006-05-04 Boehringer Ingelheim International Gmbh Utilisation de dipyridamole en association avec des antithrombotiques pour traiter et prevenir des maladies thromboemboliques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1675193A (zh) * 2002-08-02 2005-09-28 贝林格尔英格海姆法玛两合公司 1－甲基－2－(4－脒基苯基氨甲基)－苯并咪唑－5－基－羧酸－(n－2－吡啶基－n－2－羟基羰基乙基－酰胺的新颖前药，其制法及其作为药物制剂的用途
WO2006045756A1 (fr) * 2004-10-25 2006-05-04 Boehringer Ingelheim International Gmbh Utilisation de dipyridamole en association avec des antithrombotiques pour traiter et prevenir des maladies thromboemboliques

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3247332A1 (fr) * 2015-01-20 2017-11-29 Incarda Therapeutics, Inc. Doses aérosols unitaires pour anticoagulation
US10668015B2 (en) 2015-01-20 2020-06-02 Incarda Therapeutics, Inc. Unit aerosol doses for anticoagulation
GB2542064B (en) * 2015-01-20 2020-11-18 Univ California Unit aerosol doses for anticoagulation
US11547663B2 (en) 2015-01-20 2023-01-10 Incarda Therapeutics, Inc. Unit aerosol doses for anticoagulation

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