WO2015137680A1 - Composition pharmaceutique de traitement ou de prévention d'un accident vasculaire cérébral et de l'embolie systémique - Google Patents

Composition pharmaceutique de traitement ou de prévention d'un accident vasculaire cérébral et de l'embolie systémique Download PDF

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WO2015137680A1
WO2015137680A1 PCT/KR2015/002268 KR2015002268W WO2015137680A1 WO 2015137680 A1 WO2015137680 A1 WO 2015137680A1 KR 2015002268 W KR2015002268 W KR 2015002268W WO 2015137680 A1 WO2015137680 A1 WO 2015137680A1
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methyl
phenyl
amino
benzo
pyridin
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PCT/KR2015/002268
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Korean (ko)
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곽우영
최준호
임홍규
차대원
이지혜
이대영
류채림
손병화
김현정
임중인
심현주
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동아에스티 주식회사
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Priority claimed from KR1020150032656A external-priority patent/KR20150106357A/ko
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Publication of WO2015137680A1 publication Critical patent/WO2015137680A1/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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • 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

Definitions

  • the present invention relates to prodrugs suitable for effective use in oral delivery of dabigatran useful for the treatment or prevention of stroke and systemic embolism.
  • Dabigatran is a compound having the structure of formula (A), exhibits thrombin inhibitory activity and thrombin time-extending activity, the compound can be used for postoperative deep vein thrombosis prevention, stroke prevention, in particular with atrial fibrillation It is a potent thrombin inhibitor that can be used to prevent stroke in patients.
  • WO 98/37075 discloses dabigatran prodrugs that degrade into dabigatran, which shows efficacy in vivo. Of about 21 prodrugs, the following Formula B compounds are disclosed: Dabigatran etexilate. Also disclosed is a test for prolonging the thrombin time of dabigatran.
  • WO 03/074056 discloses an improved formulation for oral use of dabigatran-ethexylate and as a preferred salt of the active substance methanesulfonic acid addition salts of dabigatran-ethexylate, That is, dabigatran etexilate methanesulfonate is disclosed.
  • WO 12/027543 discloses new crystalline forms of dabigatran etexilate methanesulfonate (Form A, B, C, D, G, H and III) and new crystalline forms of dabigatran etexilate (Form E, F, J, K and L) are disclosed.
  • Cyclamic acid salts (form I, II), ethane disulfonates (forms I, II, III, IV), 2-naphthalene sulfonates (forms I, II, V), phosphates (forms I, II), saccharin ( Forms I, II, III, IV, V), Salicylates (Forms II, III), Succinates (Forms I, III), D-tartarates (Forms I, II, V), Tosylates (Forms I, V , VI, VII), Fumarate (crystalline Form III, IV), D-glucuronate (crystalline Form I, II, III), Icetaionic acid salt (crystalline Form III), L-maleate (crystalline Form I), D-maleate (Crystalline Form I), mandelate (crystalline Form I), 1,5-naphthalenesulfonate (crystalline Form I), oxalate (crystalline Forms I, II, V), propionate (crystalline Forms I, II) Publication WO 11/110876
  • the present invention provides a novel prodrug of dabigatran.
  • the present invention is to provide a pharmaceutical composition for treating or preventing stroke and systemic embolism comprising the novel prodrug.
  • the present invention provides a novel compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as a prodrug of dabigatran, which is useful for treating or preventing stroke and systemic embolism. to provide.
  • B is ethyl, , , or Is
  • B is , , or when; A is n-hexyl,
  • R 1 is hydrogen, C 1 -C 5 lower alkyl, optionally substituted with C 1 -C 5 lower alkyl at one or more positions, C 3 -C 7 cycloalkyl,
  • R 2 is , , , or ego
  • Y is C 1 -C 5 lower alkyl which is unsubstituted or substituted with C 1 -C 5 lower alkyl at one or more positions,
  • R 3 is hydrogen, cycloalkyl of one or more positions that in the unsubstituted or substituted with lower alkyl, oxo, halogen or phenyl of C 1 ⁇ C 5 C 1 ⁇ C 5 lower alkyl, C 3 ⁇ C 7 of,
  • X is O, S, NH.
  • the present invention is based on the surprising finding that the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof has a bioabsorption rate equal to or higher than that of dabigatran etexilate.
  • the compound of formula 1 according to the present invention is converted into the compound of formula A which is actually effective in the body.
  • the pharmacologically advantageous properties of the compounds of formula (1) according to the invention are the main prerequisites for the effective use of the compounds as pharmaceutical compositions.
  • the active ingredient must also meet other requirements for use in pharmaceutical compositions. Most of these factors are related to the physicochemical properties of the active ingredient.
  • the pharmaceutically active ingredient used to prepare the pharmaceutical composition should have high stability and be able to ensure high stability even under different environmental conditions. This is absolutely necessary to prevent the use of pharmaceutical compositions comprising the active ingredient itself, for example its degradation products. In such cases, the amount of active ingredient found in pharmaceutical formulations may be less than a certain amount.
  • Water absorption reduces the content of pharmaceutically active ingredients by increasing weight due to water absorption.
  • Pharmaceutical compositions that tend to absorb moisture should be protected from moisture during storage, and this protection can be achieved, for example, by the addition of a suitable drying agent or by storing the drug in an environment protected from moisture.
  • moisture absorption during manufacture may reduce the pharmaceutically active ingredient content. Therefore, preferably, the pharmaceutically active ingredient should be very hygroscopic.
  • crystal modification of the active ingredient is important for the reproducible active ingredient content of the formulation, it is necessary to identify as many of the present polymorphs of the active ingredient present in the crystalline form as possible. If different polymorphic modifications of the active ingredient are present, care must be taken to ensure that the crystal modification of the ingredient does not change in the pharmaceutical formulations prepared therefrom. Otherwise, this may have a detrimental effect on the reproducibility of the drug. On the basis of this background, active ingredients having characteristics which are only slightly polymorphic are preferred.
  • Another criterion that may be of exceptional importance under certain circumstances depends on the choice of formulation or the choice of manufacturing process is the solubility of the active ingredient. For example, if a pharmaceutical solution is prepared (eg for infusion), it is essential that the active ingredient be sufficiently dissolved in a physiologically acceptable solvent. In addition, it is very important for drugs for oral administration that the active ingredient must be sufficiently soluble.
  • the compounds of the present invention provide pharmaceutically active ingredients that meet the above physicochemical requirements as well as high pharmacological potency, and are capable of industrially synthesizing crystalline dabigatran precursors that are easy to handle and stable. have.
  • the pharmaceutically acceptable salts of the compounds represented by the formula (1) in the present invention refers to salts which are prepared with less toxic or less acid or base.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid and a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include propionic acid, isobutyl acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic, fumaric acid, manderic acid, phthalic acid, benzenesulfonic acid, p-torylsul Phonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, bromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide, phosphorous acid Salts formed of, and the like, but are not limited thereto. It also includes, but is not limited to, salts of amino acids such as arginate and analogs of organic acids such as glucuronic or galactunoric acids.
  • compositions prepared by the present invention are preferably (+)-(1S) -campo-10-sulfonic acid, cinnamic acid, citric acid, fumaric acid, lactic acid, L-malic acid, malonic acid, 2 -Naphthalenesulfonic acid, nicotinic acid, orotic acid, salicylic acid, succinic acid and L (+)-tartaric acid addition salts are as follows.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrate forms.
  • the compounds of the present invention may exist in crystalline or amorphous form, and all such physical forms are included within the scope of the present invention.
  • the invention also relates to a process for the selective production of polymorphic forms as well as variants obtainable by the process.
  • the crystalline form of the salts according to the invention was investigated in more detail by X-ray powder diffraction. The obtained graphs are shown in FIGS. 9-16.
  • the present invention provides a pharmaceutical composition for treating or preventing stroke and systemic embolism comprising a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof and a pharmaceutically acceptable excipient or additive to provide.
  • Cmax was 63 ⁇ 85% compared to the control drug (Pradaxa), especially dabigatran propanoate mesylate and dabigatran pivalate mesylate Cmax
  • AUCall and AUCall showed about 80% of the values compared to the reference drug and showed similar levels.
  • the dosage required to achieve this effect is suitably from 0.1 to 30 mg / kg, preferably from 0.3 to 10 mg / kg by intravenous route, from 0.1 to 50 mg / kg, preferably from 0.3 to 30 mg by oral route. / kg, in each case 1 to 4 doses per day.
  • the compounds of the formulas prepared according to the invention optionally comprise one or more conventional inert carriers and / or diluents, for example corn starch, lactose, glucose, microcrystalline Cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances (for example, hard fats) or suitable mixtures thereof can be formulated to prepare conventional herbal preparations (eg, skinless or dermal tablets, capsules, powders, suspensions or suppositories).
  • conventional inert carriers and / or diluents for example corn starch, lactose, glucose, microcrystalline Cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water
  • the present invention is useful for the treatment or prevention of stroke and systemic embolism, the compound represented by the formula (1), pharmaceutically acceptable salts thereof, suitable for effective use in oral delivery with improved absorption of dabigatran, ie bioavailability It provides a hydrate or a solvate thereof and a pharmaceutical composition for treating or preventing stroke and systemic embolism comprising the same.
  • FIG. 1 shows differential scanning calorimetry (DSC) curves of crystalline dabigatran coating chamber (+)-(1S) -campo-10-sulfonate prepared according to Example 72.
  • DSC differential scanning calorimetry
  • FIG. 2 shows the DSC curve of the crystalline dabigatran coated chamber citrate prepared according to Example 73.
  • FIG. 4 shows the DSC curves of the crystalline dabigatran coated chamber ororate prepared according to Example 76.
  • FIG. 7 shows the DSC curve of the crystalline dabigatran carindacillin nicotinate prepared according to Example 83.
  • Example 8 shows the DSC curve of the crystalline dabigatran carindacillin ororate prepared according to Example 84.
  • FIG. 10 shows an XRD pattern of crystalline dabigatran coated chamber citrate prepared according to Example 73.
  • FIG. 11 shows an XRD pattern of crystalline dabigatran coated chamber 2-naphthalenesulfonate prepared according to Example 75.
  • FIG. 12 shows an XRD pattern of crystalline dabigatran coated chamber ororate prepared according to Example 76.
  • FIG. 13 shows an XRD pattern of crystalline dabigatran carindacillin fumarate prepared according to Example 79.
  • FIG. 14 shows an XRD pattern of crystalline dabigatran carindacillin malonate prepared according to Example 81.
  • FIG. 15 shows an XRD pattern of crystalline dabigatran carindacillin nicotinate prepared according to Example 83.
  • FIG. 16 shows an XRD pattern of crystalline dabigatran carindacillin ororate prepared according to Example 84.
  • FIG. 17 shows dabigatran posinopril mesylate, dabigatran cladding mesylate, dabigatran etexilate ennacabil mesylate prepared according to Examples 16, 18, 36, 40, 38, 39, 49; , Control in dabigatran etexilate panesyl mesylate, dabigatran etexilate cilexetyl mesylate, dabigatran etexilate clad mesylate, dabigatran etexilate proxetyl mesylate The relative bioavailability versus drug is shown graphically.
  • Step 2 Preparation of 1-((4-nitrophenoxy) carbonyloxy) ethyl isobutyrate
  • Step 1 Preparation of 1-((nitrophenoxy) carbonyloxy) ethyl acetate
  • Example 8 (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl (Z) -3- (2-(((4- (N '-((hexyloxy)) Carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate Manufacture (Dabigatran etexilate medoxomil)
  • Step 1 Preparation of dabigatran etexilate sodium salt
  • Step 2 Preparation of dabigatran etexilate medoxomill
  • reaction mixture was cooled to room temperature, and 100 ml of ethyl acetate and 100 ml of supersaturated ammonium chloride aqueous solution were added to extract the reaction. 100 ml of water was added twice to the extracted ethyl acetate, washed, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give 650 mg of the title compound.
  • Step 1 Preparation of 2-(((4-nitrophenoxy) carbonyl) oxy) ethyl nicotinate
  • Example 12 Ethyl 3- (1-methyl-2-(((4- (N-((2-methyl-1- (propionyloxy) propoxy) carbonyl) carbamimidoyl) phenyl) Preparation of amino) methyl) -N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (dabigatran posinopril)
  • Step 1 Preparation of 2-methyl-1-(((4-nitrophenoxy) carbonyl) oxy) propyl propionate
  • Example 14 Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) Preparation of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate mesylate (dabigatran carindacillin mesyl) Acid salts)
  • Example 16 Ethyl 3- (1-methyl-2-(((4- (N-((2-methyl-1- (propionyloxy) propoxy) carbonyl) carbamididoyl) phenyl) Preparation of amino) methyl) -N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate mesylic acid salt (davigatran fosinopril mesylate)
  • Example 17 ((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] Preparation of dazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) methyl pivalate (dabigatran coating chamber)
  • Step 4 preparation of dabigatran cladding chamber
  • reaction product was extracted by adding dichloromethane and supersaturated ammonium chloride aqueous solution. Water was added twice to the extracted dichloromethane, washed, dried over anhydrous sodium sulfate and concentrated. The residue was washed with ethyl acetate and filtered to give 2.38 g of the title compound.
  • Example 18 ((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] Preparation of Dazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) methyl pivalate mesylic acid salt (dabigatran clad mesylate)
  • Step 2 Preparation of dabigatran etexilate ennacaville
  • Example 20 1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbona) Preparation of mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (dabigatran Etexilate cilexetil)
  • Example 22 ((Isopropoxycarbonyl) oxy) methyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl Preparation of (amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (dabigatran etexilate isoprox) room)
  • Step 1 2- (benzyloxy) -2-oxoethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) Preparation of Methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate
  • Step 2 Preparation of dabigatran etexilate acetamecin
  • Step 1 2-hydroxyethyl nicotinic acid hydrochloride
  • Step 2 Preparation of dabigatran etexilate etofibrate
  • Example 29 1-((ethoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamimidoyl) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (Davigatran etexilate bar Campicillin)
  • Example 30 1-acetoxyethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- Preparation of 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate (Dabigatran etexilate axetyl)
  • Step 2 Preparation of dabigatran etexilate albacrofen placaville
  • step 1 5 g of dabigatran etexilate sodium salt and 1.72 g of 1-chloro-2-methylpropylisobutyrate obtained in step 1 were used to react in the same manner as in step 2 of Example 19, to obtain 330 mg of the title compound.
  • Example 32 1-((isopropoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbonamimidyl) Preparation of (phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (dabigatran etexilate Clofibride)
  • Example 33 1-((isopropoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbonamimidyl) Preparation of (phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (dabigatran etexilate Proxetyl)
  • Step 2 Preparation of dabigatran etexilate lonifibrate
  • Example 36 (Z) -1-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1
  • Example 38 1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbona) Preparation of mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate mesylate (Davi Gatran etexilate cilexetyl mesylate)
  • Example 20 196 mg of dabigatran etexilate cilexetil prepared in Example 20 was reacted in the same manner as in Example 36 to obtain 140 mg of the title compound.
  • Example 24 250 mg of the dabigatran etexilate mofetil obtained in Example 24 was reacted in the same manner as in Example 36 to obtain 212 mg of the title compound.
  • Example 25 In the same manner as in Example 36, using 200 mg of dabigatran etexilate ciprodinate obtained in Example 25, 170 mg of the title compound was obtained.
  • Example 26 250 mg of the title compound was obtained in the same manner as in Example 36, using 250 mg of dabigatran etexilate carindacillin obtained in Example 26.
  • Example 27 In the same manner as in Example 36, using 250 mg of dabigatran etexilate acemethacin obtained in Example 27, 227 mg of the title compound was obtained.
  • Example 45 (Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1
  • Example 28 In the same manner as in Example 36, using 500 mg of dabigatran etexilate etofibrate obtained in Example 28 was obtained 450 mg of the title compound.
  • Example 46 1-((ethoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamimidoyl) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate mesylate (Davigatran Etexyl Late bacampicillin mesylate)
  • Example 29 300 mg of the title compound was obtained in the same manner as in Example 36, using 300 mg of dabigatran etexilate bacampicillin obtained in Example 29.
  • Example 47 1-acetoxyethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- Preparation of 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate mesylate (Dabigatran etexilate axetyl mesylate)
  • Example 30 In the same manner as in Example 36, using 1 g of dabigatran etexilate axetyl obtained in Example 30 was obtained 950 mg of the title compound.
  • Example 32 In the same manner as in Example 36, using 200 mg of dabigatran etexilate clofibride obtained in Example 32, 175 mg of the title compound was obtained.
  • Example 49 1-((isopropoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbonamidoyl) ) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate mesylate (Davigatran et al. Texylate proxetyl mesylate)
  • Example 33 920 mg of the title compound was obtained in the same manner as in Example 36, using 1 g of dabigatran etexilate proxetyl obtained in Example 33.
  • Example 34 160 mg of the title compound was obtained in the same manner as in Example 36, using 160 mg of dabigatran etexilate posinopril obtained in Example 34.
  • Example 51 (Z) -3-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1
  • Example 35 250 mg of the title compound was obtained in the same manner as in Example 36, using 250 mg of dabigatran etexilate ronifibrate obtained in Example 35.
  • Step 1 Preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (4-nitrophenyl) carbonate
  • Step 1 Preparation of 4-nitrophenyl ((2E, 6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl) carbonate
  • Example 52 The step of Example 52, using 17.68 g of 4-nitrophenyl ((2E, 6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl) carbonate obtained in step 1 above. Reaction was carried out in the same manner as 2 to obtain 19.21 g of the title compound.
  • Step 1 Preparation of 2- (dimethylamino) ethyl (4-nitrophenyl) carbonate hydrochloride
  • Step 1 3-(((4-nitrophenoxy) carbonyl) oxy) propyl nicotinate
  • Step 2 Preparation of dabigatran lonifibrate
  • Example 58 Ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-(((4- (N-((((2E, 6E) -3,7,11-trimethyl) Deca-2,6,10-trien-1-yl) oxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) pro Preparation of Panoate Mesylate (Dabigatran Panesyl Mesylate)
  • Example 54 Using 164 mg of dabigatran cyprodinate obtained in Example 54, the reaction was carried out in the same manner as in Example 57, to obtain 146 mg of the title compound.
  • Example 60 Ethyl 3- (2-(((4- (N-((3- (dimethylamino) propoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl- Preparation of N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate mesylate (dabigatran clopibride mesylate)
  • Example 55 Using 250 mg of dabigatran ciprodinate obtained in Example 55, the reaction was carried out in the same manner as in Example 57, to obtain 228 mg of the title compound.
  • Example 61 3-((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d ] Imidazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) propyl nicotinate mesylate (Davigatran Ronifibrate Mesylate)
  • Example 56 127 mg of dabigatran ronifibrate obtained in Example 56 was used to obtain 100 mg of the title compound.
  • Example 62 1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbona) Mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (+)-(1S Preparation of) -campo-10-sulfonate (dabigatran etexilate cilexetil (+)-(1S) -campo-10-sulfonate)
  • Example 63 1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbona) Preparation of mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate citrate (Daviga Tran etexilate cilexetil citrate)
  • Example 20 250 mg of dabigatran etexilate cilexetil obtained in Example 20 was added to a 25 mL flask, dissolved in 2.5 ml of chloroform, and stirred. 68.3 mg of citric acid monohydrate was added to the reaction solution, followed by stirring at room temperature for 16 hours. The resulting solid was filtered to give 305 mg of the title compound.
  • Example 64 1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbona) Preparation of mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate fumarate Tran etexilate cilexetil fumarate)
  • Example 20 300 mg of dabigatran etexilate cilexetil obtained in Example 20 was added to a 25 mL flask, dissolved in 3 mL of acetone, and stirred. 45.2 mg of fumaric acid was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. No solid was formed so 2 ml of isopropyl ether was added. After stirring for 2 hours at room temperature, the resulting solid was filtered to give 231 mg of the title compound.
  • Example 65 1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbona) Mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (-)-L- Preparation of Maleate (Davigatran Etexylate Silectyl (-)-L-Malate)
  • Example 20 250 mg of dabigatran etexilate cilexetil obtained in Example 20 was added to a 25 mL flask, dissolved in 2.5 mL of ethanol, and stirred. 43.6 mg of (-)-L-malic acid was added to the reaction solution, followed by stirring at room temperature for 16 hours. The resulting solid was filtered to give 226 mg of the title compound.
  • Example 66 1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbona) Preparation of mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate malonate (Davi Gatran etexilate cilexetyl malonate)
  • Example 20 250 mg of dabigatran etexilate cilexetil obtained in Example 20 was added to a 25 mL flask, followed by stirring with chloroform. 33.8 mg of malonic acid was added to the reaction solution and stirred at room temperature for 7 hours. No solid was produced so isopropyl ether was added. The resulting solid was filtered to give 240 mg of the title compound.
  • Example 20 300 mg of dabigatran etexilate cilexetil obtained in Example 20 was added to a 25 mL flask, followed by stirring with ethanol. 68 mg of orotic acid was added to the reaction solution and stirred at room temperature for 3 hours. The resulting solid was filtered to give 280 mg of the title compound.
  • Example 68 1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbona) Preparation of mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate salicylate (Daviga Tran etexilate cilexetyl salicylate)
  • Example 20 250 mg of dabigatran etexilate cilexetil obtained in Example 20 was added to a 25 mL flask, dissolved in 2.5 ml of chloroform, and stirred. 68.3 mg of salicylic acid was added to the reaction solution and stirred at room temperature for 1 hour. No solid was formed, so 13 ml of isopropyl ether was added. After stirring for 16 hours, the resulting solid was filtered to give 215 mg of the title compound.
  • Example 20 250 mg of dabigatran etexilate cilexetil obtained in Example 20 was added to a 25 mL flask, dissolved in 2.5 mL of ethanol, and stirred. 48.8 mg of (+)-L-tartaric acid was added to the reaction solution, followed by stirring at room temperature for 16 hours. The resulting solid was filtered to give 278 mg of the title compound.
  • Example 70 Ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-(((4- (N-((((2E, 6E) -3,7,11-trimethyl) Deca-2,6,10-trien-1-yl) oxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) pro Preparation of Panoate Citrate (Davigatran Panesyl Citrate)
  • 500 mg of the title compound was obtained by the same method as Example 63, using 500 mg of dabigatran farnesyl obtained in Example 53.
  • Example 72 ((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] Preparation of Dazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) methyl pivalate (+)-(1S) -campo-10-sulfonate (dabigatran coating chamber (+) -(1S) -campo-10-sulfonate)
  • Example 17 100 mg of the dabigatran coating chamber obtained in Example 17 was added to a 25 ml flask, dissolved in 2.5 mL of ethanol, and stirred. 35.3 mg of (+)-(1S) -campo-10-sulfonic acid was added to the reaction solution, followed by stirring at room temperature for 3 hours. The resulting solid was filtered to give 128 mg of the title compound.
  • Example 73 ((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] Preparation of dazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) methyl pivalate citrate (dabigatran coated citrate)
  • Example 17 1.5 g of the dabigatran coating chamber obtained in Example 17 was added to a 25 mL flask, dissolved in 15 ml of chloroform, and stirred. 480 mg of citric acid monohydrate was added to the reaction solution, and the resultant was stirred at room temperature for 5 hours. The resulting solid was filtered to give 1.3 g of the title compound.
  • Example 74 ((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] Preparation of Dazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) methyl pivalate (-)-L-maleate (dabigatran coating chamber (-)-L-maleate )
  • Example 17 100 mg of the dabigatran coating chamber obtained in Example 17 was placed in a 25 mL flask, dissolved in a mixed solution of 2.5 ml of chloroform and 0.3 ml of methanol, and stirred. 68.3 mg of (-)-L-malic acid was added to the reaction solution and stirred at room temperature for 1 hour. No solid was produced, so 3 ml of isopropyl ether was added. After stirring for 16 hours, the resulting solid was filtered to obtain 90 mg of the title compound.
  • Example 75 ((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] Preparation of Dazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) methyl pivalate 2-naphthalenesulfonate (dabigatran coating chamber 2-naphthalenesulfonate)
  • Example 17 100 mg of the dabigatran coating chamber obtained in Example 17 was added to a 25 ml flask, dissolved in 2.5 mL of ethanol, and stirred. 31.6 mg of 2-naphthalenesulfonic acid was added to the reaction solution and stirred at room temperature for 3 hours. No solid was produced, so 6 ml of isopropyl ether was added. After stirring for 16 hours, the resulting solid was filtered to give 106 mg of the title compound.
  • Example 76 ((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] Preparation of Dazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) methyl pivalate ororate (dabigatran coating room ororate)
  • Example 17 100 mg of the dabigatran coating chamber obtained in Example 17 was added to a 25 ml flask, and the mixture was dissolved in 2.5 ml of ethanol and 0.3 ml of dichloromethane and stirred. 26.5 mg of orotic acid was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. No solid was produced, so 2 ml of isopropyl ether was added. After stirring for 16 hours, the resulting solid was filtered to give 95 mg of the title compound.
  • Example 78 Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) Preparation of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate citrate (dabigatran carindacillin citrate )
  • Example 9 300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 9 ml of chloroform, and stirred. 53 mg of fumaric acid was added to the reaction solution and stirred at room temperature for 16 hours. The resulting solid was washed with diisopropyl ether, filtered and dried to give 220 mg of the title compound.
  • Example 80 Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) Preparation of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (-)-L-maleate (Davi Gatran Carindacillin (-)-L-maleate)
  • Example 9 300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 9 ml of chloroform, and stirred. 61 mg of malic acid was added to the reaction solution and stirred at room temperature for 2 hours. 3 ml of diisopropyl ether was added dropwise to the reaction solution and stirred at room temperature for 16 hours. The resulting solid was washed with diisopropyl ether, filtered and dried to give 283 mg of the title compound.
  • Example 9 300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 9 ml of chloroform, and stirred. 47.5 mg of malonic acid was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. 5 ml of diisopropyl ether was added dropwise to the reaction solution to form a solid, which was stirred for 16 hours at room temperature. The resulting solid was washed with diisopropyl ether, filtered and dried to give 197 mg of the title compound.
  • Example 82 Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) Preparation of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate 2-naphthalenesulfonate (dabigatran karinda Silin 2-naphthalenesulfonate)
  • Example 83 Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) Preparation of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate nicotinate (dabigatran carindacillin nicotinate) )
  • Example 9 300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 9 ml of chloroform, and stirred. 57.2 mg of nicotinic acid was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. 7 ml of diisopropyl ether was added dropwise to the reaction solution, followed by stirring at room temperature for 2 hours. The resulting solid was washed with diisopropyl ether, filtered and dried to give 341 mg of the title compound.
  • Example 84 Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) Preparation of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate ororate (dabigatran carindacillin Orotates)
  • Example 9 300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 9 ml of chloroform, and stirred. 82 mg orotic acid was added to the reaction solution and stirred at room temperature for 2 hours. 6 ml of diisopropyl ether was added dropwise to the reaction solution, followed by stirring at room temperature for 2 hours. The resulting solid was washed with diisopropyl ether, filtered and dried to give 369 mg of the title compound.
  • Example 85 Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) Preparation of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (+)-L-tartarate Tran carindacillin (+)-L-tartarate)
  • the stability test of dabigatran etexilate mesylate was performed with dabigatran-coated salts prepared in Examples 18, 72, 73, 75, and 76, the dabigatran prodrug according to the present invention, and a control drug.
  • the test method is as follows.
  • Test subject dabigatran etexilate mesylate (Pradaxa), dabigatran coating chamber (+)-(1S) -campo-10-sulfonate (Example 72), dabigatran coating chamber citrate ( Example 73), dabigatran coating chamber 2-naphthalene sulfonate (Example 75), dabigatran coating chamber orotate (Example 76), dabigatran coating chamber mesylate (Example 18) or more 6 kinds
  • Test conditions The samples were placed in a constant temperature and humidity chamber with an internal temperature of 40 ° C. and a humidity of 75%, and the plugs and the open ones were taken out at intervals of 1, 2, 4, and 7 days for purity analysis by HPLC. .
  • the solubility test of dabigatran etexilate mesylate was performed with dabigatran-coated salts prepared in Examples 18, 72, 73, 75, and 76, the dabigatran prodrug according to the present invention, and a control drug.
  • the test method is as follows.
  • Test subject dabigatran etexilate mesylate (Pradaxa), dabigatran coating chamber (+)-(1S) -campo-10-sulfonate (Example 72), dabigatran coating chamber citrate ( Example 73), dabigatran coating chamber 2-naphthalene sulfonate (Example 75), dabigatran coating chamber orotate (Example 76), dabigatran coating chamber mesylate (Example 18) or more 6 kinds
  • Test condition 20 wt% Solutol solution and 5 kinds of phosphate 50mM buffer solution (made by adjusting pH2.0, pH4.0, pH6.3, pH7.4, pH9.0 using 3N HCl and 10wt% KOH) ) Were tested in a total of six conditions.
  • Examples 18, 75 and 76 according to the present invention showed a solubility equivalent to that of the control drug (DBEtM) in 20 wt% solutol solution.
  • Example 73 according to the present invention showed solubility equivalent to that of the reference drug, and Examples 18 and 72 according to the present invention showed better solubility than the control drug.
  • Table 2 Each analysis result is shown in Table 2.
  • Test subject dabigatran etexilate mesylate (Pradaxa), dabigatran carindacillin mesylate (Example 14), dabigatran carindacillin citrate (Example 78), dabigatran carindacillin Fumarate (Example 79), dabigatran carindacillin (-)-L-maleate (Example 80), dabigatran carindacillin malonate (Example 81), dabigatran carindacillin nicotinate (Example 83), dabigatran carindacillin ororate (Example 84), dabigatran carindacillin (+)-L- tartarate (Example 85) or more than nine
  • Example 14 according to the present invention in 20wt% solutol solution showed the same solubility as the control drug, and all 8 dabigatran carindacillin salts including Example 14 according to the present invention in pH 2.0 buffer solution. Showed solubility equivalent to that of the reference drug. Each result is shown in Table 3.
  • Dabigatran etexilate mesylate (Pradaxa), dabigatran posinopril mesylate (Example 16), dabigatran coated yarn mesylate (Example 18), dabigatran etexilate ennacabil mesyl Acid salt (Example 36), dabigatran etexilate panesyl mesylate (Example 40), dabigatran etexilate cilexetyl mesylate (Example 38), dabigatran etexilate coated thread mesylate ( Example 39) Oral bioavailability in mice was tested using dabigatran etexilate proxetyl mesylate (Example 49). The test method is as follows.
  • the standard solution for calibration curve is made of dabigatran standard (NNM11069) and (NNM11084) compounds at 10, 30, 100, 300, 1000, 3000, 10000, 20000ng / mL concentrations, respectively.
  • Working standard solution and plasma were mixed at 1: 9 (v / v) so that the standard solution concentration was 1, 3, 10, 30, 100, 300, 1000, 2000ng / mL.
  • the standard solution and analytical sample for spiked calibration curve were mixed with 0.01N HCl / 85% ACN containing 1: ng (mL) 5ng / mL at 1:19 (v / v) and vortexed for 5 minutes. 27,000 g) was centrifuged at 4 ° C for 10 minutes. 200l of the supernatant was separated and analyzed by LC / MS / MS MRM mode.
  • the Cmax of the compound according to the present invention was 63-85% compared to the control drug (Pradaxa), and especially dabigatran posinopril mesylate and dabigatran-coated mesylate were both Cmax and AUCall control drugs. Compared with, the value was about 80% and showed similar degree.
  • Table 5 the values compared with the reference drug are shown graphically in FIG.

Abstract

La présente invention concerne un promédicament utile pour le traitement ou la prévention d'un accident vasculaire cérébral et de l'embolie systémique et qui est approprié pour être utilisé efficacement dans l'administration par voie orale de dabigatran, et concerne un composé représenté par la formule chimique 1, un sel de qualité pharmaceutique de celui-ci, un hydrate ou un solvate de celui-ci. Le composé représenté par la formule chimique 1, un sel de qualité pharmaceutique de celui-ci, un hydrate ou un solvate de celui-ci est utile pour le traitement ou la prévention d'un accident vasculaire cérébral et de l'embolie systémique, et est approprié pour être utilisé efficacement dans l'administration par voie orale, étant donné que la vitesse d'absorption, c'est-à-dire la biodisponibilité du dabigatran, est améliorée.
PCT/KR2015/002268 2014-03-10 2015-03-10 Composition pharmaceutique de traitement ou de prévention d'un accident vasculaire cérébral et de l'embolie systémique WO2015137680A1 (fr)

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