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WO2016019849A1 - Dérivé de carboalcoxy de dabigatran, son procédé de préparation, et son utilisation pharmaceutique - Google Patents

Dérivé de carboalcoxy de dabigatran, son procédé de préparation, et son utilisation pharmaceutique Download PDF

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Publication number
WO2016019849A1
WO2016019849A1 PCT/CN2015/086022 CN2015086022W WO2016019849A1 WO 2016019849 A1 WO2016019849 A1 WO 2016019849A1 CN 2015086022 W CN2015086022 W CN 2015086022W WO 2016019849 A1 WO2016019849 A1 WO 2016019849A1
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WO
WIPO (PCT)
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group
methyl
amino
pharmaceutically acceptable
stereoisomer
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PCT/CN2015/086022
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English (en)
Chinese (zh)
Inventor
魏用刚
余彦
邱关鹏
雷柏林
Original Assignee
四川海思科制药有限公司
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Publication date
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Priority to CN201580036778.0A priority Critical patent/CN106536505A/zh
Publication of WO2016019849A1 publication Critical patent/WO2016019849A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a dabigatrandinol derivative and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, and to the use of a medicament for the prevention and treatment of a thromboembolic disease.
  • cardiovascular disease is one of the main causes of death in humans.
  • One of its main aspects is thrombosis, which is caused by a series of complex reactions.
  • Blood coagulation is a protective mechanism of the organism whereby the defect of the vessel wall can be "sealed” quickly and reliably, thus avoiding blood loss or minimizing it. Maintaining normal hemostasis, ie hemorrhage and clotting balance, is regulated by a complex mechanism. Unregulated activation of the coagulation system or lack of inhibition of the activation process can lead to a variety of diseases and complications, such as venous thrombosis, deep vein thrombosis, pulmonary embolism, atherosclerosis, acute coronary syndrome, cerebrovascular disease and the like.
  • Oral anti-hemagglutination drugs that have been marketed mainly include direct thrombin inhibitors, factor Xa inhibitors, factor IX inhibitors, tissue factor inhibitors, and novel vitamin K antagonists.
  • dabigatran etexilate is an oral, selective and highly potent thrombin inhibitor. It has been clinically proven to replace warfarin to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation and to replace enoxaparin sodium. The first choice for the prevention of venous thromboembolic events in patients undergoing major plastic surgery.
  • Dabigatran etexilate was marketed in 2008 and is used to prevent stroke or systemic embolism, deep vein thrombosis (DVT) or pulmonary vascular occlusion and its recurrence in patients with non-valvular atrial fibrillation. It is a double prodrug obtained by esterification of the free carboxyl group and the thiol group in the dabigatran group, which solves the problem that the insoluble thiol group can not be taken orally, and improves the oral bioavailability. . After oral administration of dabigatran etexilate, it is absorbed from the gastrointestinal tract and then rapidly converted into dabigatran in the body to exert an anticoagulant effect. However, the oral bioavailability of dabigatran diester is low, only 3 to 7%, so the higher dosage is medicinal and the side effects are increased.
  • dabigatran and its analogs as well as prodrugs thereof such as alkyl carboxylates, sulfonyl substituted carboxylic acid esters or sulfonylamino groups
  • CN102875533 and CN102838588 patents report Dabiga Group of ferulic acid or sulphate prodrugs, and has a certain anti-coagulant effect
  • CN200910211164, CN200910211165 and CN201210158600 disclose dabigatran carbonate, carboxylic acid ester and other prodrugs.
  • the object of the present invention is to solve the problem that dabigatran cannot be taken orally because of its strong alkalinity, and provide a novel and effective problem.
  • Oral dabigatran prodrugs with good stability, solubility, bioavailability, and low dose, low toxic side effects or long-acting effects.
  • the present invention relates to a dabigatrandinol derivative and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, and to the use of a medicament for the prevention and treatment of a thromboembolic disease.
  • the present invention provides a compound represented by the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:
  • X 1 and X 2 are each independently selected from O or S;
  • R 1 is selected from -(CR 1a R 1b O) n -(CR 1a R 1b CR 1c R 1d O) m R 1e ;
  • R 2 is selected from C 1-10 alkyl or -(CR 2a R 2b CR 2c R 2d O) m R 2e , and the alkyl group is optionally further selected from 0 to 12 selected from H, F, Cl, Br, I Substituted with a substituent of a C 1-4 alkyl group or a C 1-4 alkoxy group;
  • R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are each independently selected from H, F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkane.
  • R 1f is each independently selected from an amino acid side chain group
  • R 1g and R 1h are each independently selected from H or an amino protecting group
  • n is selected from 0 or 1;
  • n is selected from 1, 2, 3, 4, 5 or 6.
  • a preferred embodiment of the invention a compound of the formula (I), and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein:
  • R 1f is each independently selected from an amino acid side chain group
  • the amino acid is selected from the group consisting of glycine, alanine, leucine, isoleucine, tyrosine, valine, phenylalanine, Methionine, tryptophan, serine, glutamine, threonine, cysteine, histidine, asparagine, tyrosine, aspartic acid, glutamic acid, naphthyl acid or fine Amino acid
  • R 1g and R 1h are each independently selected from H or an amino protecting group
  • the amino protecting group is selected from the group consisting of benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl or ethoxycarbonyl.
  • a preferred embodiment of the invention a compound of the formula (I), and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from -(CR 1a R 1b O) n -(CR 1a R 1b CR 1c R 1d O) m R 1e ;
  • R 2 is selected from C 1-8 alkyl or -(CR 2a R 2b CR 2c R 2d O) m R 2e , which is optionally further substituted by 0 to 12 substituents selected from H, F, Cl or Br Substituted by
  • R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are each independently selected from the group consisting of H, F, Cl, Br, I, methyl, ethyl, isopropyl, methoxy. Base, ethoxy or isopropoxy group;
  • R 1f is independently selected from the group consisting of amino acid side chain groups selected from glycine, alanine, leucine, phenylalanine or determinine;
  • R 1g and R 1h are each independently selected from H or an amino protecting group selected from benzyloxycarbonyl or tert-butoxycarbonyl;
  • n is selected from 0 or 1;
  • n is selected from 1, 2 or 3.
  • a preferred embodiment of the invention a compound of the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:
  • the compound according to the invention and the stereoisomers and pharmaceutically acceptable salts thereof, wherein the salt is selected from the group consisting of hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, Acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylic acid Salt, glucuronide, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonic acid Salt, mesylate, ethanesulfonate, triflate, ferulic acid or a combination thereof.
  • the salt is selected from the group consisting of hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, Acetate, maleate, succinate, mandelate, fumarate, malonate
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the invention further provides the use of a compound of any of the foregoing, and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with a thrombin inhibitor.
  • the present invention also provides the use of a pharmaceutical composition as described above for the preparation of a medicament for treating a disease associated with thrombin inhibitors.
  • the thrombin-related disease is selected from a thromboembolic disorder.
  • the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolization.
  • the present invention further provides a method of treating a disease associated with a thrombin inhibitor, wherein the method comprises administering a compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, or the present invention Compositions.
  • the thrombin-related disease is selected from a thromboembolic disorder.
  • the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolization.
  • the amino acid is selected from natural or pharmaceutically acceptable amino acids, preferably glycine, alanine, leucine, isoleucine, tyrosine, valine, phenylalanine, methionine, tryptophan, serine, Glutamine, threonine, cysteine, histidine, asparagine, tyrosine, aspartic acid, glutamic acid, naphthyl acid or arginine, further preferably glycine, alanine, Leucine, phenylalanine, asparagine or arginine, more preferably glycine, alanine or phenylalanine.
  • natural or pharmaceutically acceptable amino acids preferably glycine, alanine, leucine, isoleucine, tyrosine, valine, phenylalanine, methionine, tryptophan, serine, Glutamine, threonine, cysteine, histidine, asparagine
  • the amino protecting group mainly includes an alkylcarbonyl group, an acyl group, and an alkyl group.
  • Alkylcarbonyls include, but are not limited to, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl or methoxycarbonyl or ethoxycarbonyl;
  • acyl groups include, but are not limited to, adjacent a phthaloyl, p-toluenesulfonyl, trifluoroacetyl, o-nitrobenzenesulfonyl, p-nitrophenylsulfonyl, pivaloyl or benzoyl; alkyls including, but not limited to, triphenylmethyl, 2,4-Dimethoxybenzyl, p-methoxybenzyl or benzyl.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • the nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably a linear and branched group of 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, most preferably 1 to 2 carbon atoms;
  • examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl -2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl Benzyl
  • a side chain group of an amino acid refers to a general term for a class of organic compounds containing an amino group and a carboxyl group, and has a general structure of
  • the "side chain group of an amino acid” refers to the L group herein, and the non-limiting examples include, but are not limited to, the side chain group of glycine is H, the side chain group of alanine is methyl, benzene The side chain group of alanine is a benzyl group, and a side chain group of valine is an isopropyl group or the like.
  • Optional or “optionally” means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur, such as: "Alkyl optionally substituted by F" "Alkyl can be, but is not necessarily, substituted by F, and is meant to include the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • substitution refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom.
  • the group is substituted, for example, amino, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic, 3 to 6 membered heterocyclic ring, optionally further from 0 to 4 selected from H
  • substituent of F, Cl, Br, I, hydroxy, cyano, amino, C 1-4 alkyl or C 1-4 alkoxy the groups formed include, but are not limited to, methyl, chloromethyl, Trichloromethyl, hydroxymethyl, -CH 2 OCH 3 , -CH 2 SH, -CH 2 CH 2 CN, -CH 2 NH 2 , -NHOH, -NHCH 3 , -OCH 2 Cl, -OCH 2 OCH 2 CH 3 , -
  • Substituted or unsubstituted refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.
  • “As a choice” means that the scheme after “as a choice” is a side-by-side relationship with the scheme before “as a choice” rather than a further selection in the previous scheme.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or the free acid obtained by reacting with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc.
  • metal salts such as iron salts, copper salts, cobalt salts; organic alkali salts such as ammonium salts, three Ethylamine salt, pyridinium salt, methylpyridine salt, 2,6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, phosphonium salt, isopropylamine Salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, dimethylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, Betaine salt, phenamine penicillin salt, glucosamine salt, N-methylglucamine salt, theobromine salt, tromethamine salt, sulfonium salt, piperazine salt, morpholine salt, piperidine salt, N-B a piperidinium salt, a tetramethylamine salt, a dibenzyl
  • X 2 is O; R 2 is n-hexyl;
  • R 1 and X 1 are identical to the definitions of the above formula (I);
  • R 1 , R 2 , X 1 and X 2 are identical to the definitions of the above formula (I).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), The internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • Ethyl propionate (1a) (63 g, 100 mmol) was added to a mixed solvent of ethanol (600 mL) and water (300 mL), and sodium hydroxide (8 g, 200 mmol) was added thereto, and the mixture was stirred at room temperature for half an hour until the reaction liquid was clarified.
  • reaction solution Concentrate the reaction solution, steam off most of the ethanol, add water (200 mL), adjust the pH to 4-5 with 10% aqueous citric acid solution, precipitate a large amount of viscous solids, filter, transfer the solid into the reaction flask, add methanol (300 mL), heating until the solids are dissolved, stirring is continued until the solids are in the form of granules, and the mixture is cooled to zero.
  • the suspension of the group prototype drug was collected from the eyelids, anticoagulated by heparin, and centrifuged at 3000 ° C for 10 min at 4 ° C for 5 min before administration (0 h) and 5 min, 15 min, 30 min, 1.0, 2.0, 4.0, 8.0, 24.0 h after administration.
  • the plasma was separated and stored at -80 ° C for testing. Take 30ul of rat plasma at each time point, add 200ul of internal standard solution (7.5ng/mL verapamil), vortex for 1min, centrifuge at 13000rpm for 10min at 4°C, and take 190ul of supernatant for LC-MS/MS (Shimadzu Company lc-20A Technology Co., Ltd., API4000+) analysis.
  • the main pharmacokinetic parameters were analyzed by WinNonlin 6.3 software non-compartmental model. The results are shown in Table 1.
  • the compound of the present invention has good pharmacokinetic characteristics, especially the compounds 6, 12, 14, 15 have significantly better indexes than dabigatran etexilate.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un dérivé de carboalcoxy de dabigatran comme indiqué dans la formule (I), un stéréoisomère de celui-ci, un sel pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci dans la préparation de médicaments pour la prévention et le traitement de maladies thromboemboliques, tous les substituants étant tels que définis dans la description.
PCT/CN2015/086022 2014-08-06 2015-08-04 Dérivé de carboalcoxy de dabigatran, son procédé de préparation, et son utilisation pharmaceutique WO2016019849A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201580036778.0A CN106536505A (zh) 2014-08-06 2015-08-04 一种达比加群烷酯衍生物及其制备方法和在药学上的用途

Applications Claiming Priority (4)

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CN201410383909 2014-08-06
CN201410383909.X 2014-08-06
CN201510201569 2015-04-27
CN201510201569.9 2015-04-27

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* Cited by examiner, † Cited by third party
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CN110343089A (zh) * 2018-04-02 2019-10-18 上海美悦生物科技发展有限公司 苯并咪唑类衍生物及其药学用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1248251A (zh) * 1997-02-18 2000-03-22 贝林格尔英格海姆法玛公司 二取代双环杂环,其制备法及作为药物的用途
CN102766134A (zh) * 2012-07-19 2012-11-07 北京普禄德医药科技有限公司 达比加群的酯衍生物及其制备方法和用途
CN102875529A (zh) * 2011-07-15 2013-01-16 天津药物研究院 达比加群的酯衍生物及其制备方法
CN103420980A (zh) * 2012-05-22 2013-12-04 北京美倍他药物研究有限公司 达比加群衍生物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1248251A (zh) * 1997-02-18 2000-03-22 贝林格尔英格海姆法玛公司 二取代双环杂环,其制备法及作为药物的用途
CN102875529A (zh) * 2011-07-15 2013-01-16 天津药物研究院 达比加群的酯衍生物及其制备方法
CN103420980A (zh) * 2012-05-22 2013-12-04 北京美倍他药物研究有限公司 达比加群衍生物
CN102766134A (zh) * 2012-07-19 2012-11-07 北京普禄德医药科技有限公司 达比加群的酯衍生物及其制备方法和用途

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