WO2016019848A1

WO2016019848A1 - Dabigatran thioester derivative, preparation method therefor, and pharmaceutical use thereof

Info

Publication number: WO2016019848A1
Application number: PCT/CN2015/086021
Authority: WO
Inventors: 魏用刚; 邱关鹏; 雷柏林
Original assignee: 四川海思科制药有限公司
Priority date: 2014-08-06
Filing date: 2015-08-04
Publication date: 2016-02-11
Also published as: CN107027308A

Abstract

A dabigatran thioester derivative as indicated in formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a use thereof in preparing medications for preventing and treating thromboembolic diseases, X₁, X₂, R¹, and R² being defined as in the description.

Description

Dabigatran thioester derivative, preparation method thereof and pharmacy use thereof

Technical field

The present invention relates to a dabigatran thioester derivative, and stereoisomers thereof and pharmaceutically acceptable salts thereof, and to the use of a medicament for the prevention and treatment of a thromboembolic disease.

Background technique

At present, 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. Among them, 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.

There are many reports on the prodrugs of dabigatran. As disclosed in WO09837075 and WO2004014894, 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 a group of ferulic acid or sulphate prodrugs, and has a certain anticoagulant effect; CN200910211164, CN200910211165 and CN201210158600 and other patents disclose dabigatran group of carbonates, carboxylates, etc. Body medicine.

The object of the present invention is to solve the problem that dabigatran can not be taken orally because of its strong alkalinity, and provide a novel and effective oral administration with good stability, solubility, bioavailability and low dose, low toxic side effect or long-acting effect. Dabigatran group of prodrugs.

Summary of the invention

The present invention relates to a dabigatran thioester derivative and a stereoisomer or 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:

R ¹ and R ² are each independently selected from a C _1-10 alkyl group or a C _6-10 carbocyclic ring, and the alkyl group or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I. Substituted by a substituent of CN, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _6-10 carbocycle; X ₁ and X ₂ are each independently selected from O or S, provided that X ₁ and at least one of X ₂ is S.

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 and R ² are each independently selected from C _1-10 alkyl, The alkyl group is optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, CN, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or C _3-6 carbocyclic Substituted by a substituent, X ₁ and X ₂ are each independently selected from O or S, provided that at least one of X ₁ and X ₂ is S.

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 and R ² are each independently selected from C _1-10 alkyl, preferably C _1-8 alkyl, the alkyl optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, CN, NH ₂ , methyl, ethyl, methoxy, ethoxy, Substituted by a substituent of a cyclopropyl or cyclopentyl group, X ₁ and X ₂ are each independently selected from O or S, provided that at least one of X ₁ and X ₂ is S.

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:

Preferred according to the invention, 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 invention further provides 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.

In a preferred embodiment of the invention, the thrombin-related disease is selected from a thromboembolic disorder.

In a preferred embodiment of the invention, 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.

Terms used in the specification and claims have the following meanings unless stated to the contrary.

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 ), 氚 (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-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-Dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethylpentyl , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2 ,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Hexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl and n-decyl; alkyl may be substituted or unsubstituted, when substituted, the substituent may be Any substituent which may be used is substituted, and the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, Mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl = O, carbonyl, aldehyde, carboxylic acid, carboxylate An arylthio group, a thiocarbonyl group, a silyl group or the like.

"Alkoxy" means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, untertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy , haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl , =0, a carbonyl group, an aldehyde, a carboxylic acid, a carboxylate arylthio group, a thiocarbonyl group or a silyl group.

"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 may but not necessarily Substitution by F illustrates 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. Where 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, Substituted by a 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 , -OCH ₂ CH ₂ NH ₂ , -OCH ₂ CH ₂ SH, -OCH ₂ CH ₂ OH, 1-hydroxycyclopropyl, 2-hydroxycyclopropyl, 2-aminocyclopropyl, 4-methyl Furanyl, 2-hydroxyphenyl, 4-aminophenyl, phenyl.

"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. Other metal salts such as iron salts, copper salts, cobalt salts; organic alkali salts such as ammonium salts, triethylamine salts, pyridinium salts, methylpyridine salts, 2,6-dimethylpyridine salts, ethanolamine salts, two Ethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, sulfonium salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, two Methylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, phenicillin salt, glucosamine salt, N-methylglucamine salt, theobromine salt, Tromethamine salt, sulfonium salt, piperazine salt, morpholine salt, piperidine salt, N-ethyl piperidine salt, tetramethylamine , dibenzylamine salt and phenylglycine alkyl ester salt; hydrohalide salt, such as hydrofluoric acid salt, hydrochloride salt, hydroiodide salt, hydrobromide salt; inorganic acid salt, such as nitrate, sulfate Perchlorate, phosphate; lower alkane sulfonate, such as methanesulfonate, triflate, ethanesulfonate; aryl sulfonate, such as besylate, p-toluenesulfonate Organic acid salts such as formic acid salts, fumarates, formates, trifluoroacetates, citrates, gluconates, glutamates, glycolates, isethionates, lactic acid Salt, maleate, malate, mandelate, mucate, pamoate, pantothenate, stearate, succinate, sulfamate, tartrate, malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, glycolate, glucuronide, galacturonic acid Salt, citrate, lysine, arginine, aspartate, cinnamate.

resolve resolution

method one:

X ₂ is O; R ² is n-hexyl;

R ¹ and X _{1 are} identical to the definitions of the above formula (I).

Method Two:

The definitions of R ¹ , R ² , X ₁ and X ₂ are identical to those defined in the above formula (I).

detailed description

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument 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 measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18100 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.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

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.

Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

Intermediate 1

3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl)amino]propyl Acid (intermediate 1)

3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid

First step: 3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl Amino]propionic acid (intermediate 1)

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] 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. 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 solid is dissolved, stirring is continued until the solid is in the form of a granule, which is cooled to 0 ° C, and more product is precipitated, filtered and dried to give the title compound 3-[[2-[[4-[N] `-Hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid (Intermediate 1) (50 g, yield 83 %).

LCMS m/z = 600.2 [M + 1].

^{1 H NMR (400MHz, DMSO)} : δ8.38 (d, 1H), 7.79 (d, 2H), 7.56 (m 1H), 7.48 (s, 1H), 7.39 (d, 1H), 7.14 (m2H), 6.95(d,2H), 6.77(d,2H), 4.60(d,2H), 4.18(t,2H),3.99(t,2H),3.77(s,3H),2.68-2.58(m,3H) , 1.58 (dd, 2H), 1.29 (d, 6H), 0.87 (t, 3H).

Example 1

3-[[1-Methyl-2-[[4-[N`-pentylthiocarbonylcarbamoyl]anilinyl]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino] Ethyl propionate (Compound 1)

Ethyl 3-[[1-methyl-2-[[4-[N`-pentylsulfanylcarbonylcarbamimidoyl]anilino]methyl]b Enzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

N,N'-carbonyldiimidazole (0.628 g, 3.87 mmol) was added to n-pentyl mercaptan (0.371 g, 3.57 mmol) in tetrahydrofuran (10 mL) at room temperature, stirred at room temperature for 30 min. Liquid 1. Ethyl 3-[[2-[(4-carboxanilide)methyl]-1 methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionate p-toluenesulfonic acid To the salt (1A) (2 g, 2.98 mmol), acetone (80 mL), water (40 mL), and potassium carbonate (1.23 g, 8.93 mmol) were added, and the mixture was stirred and then added to the reaction mixture 1 and allowed to react at room temperature for 5 hours. After that, water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL), and the organic layer was combined. The organic layer was washed with water (150 mL × 2). [[1-methyl-2-[[4-[N`-pentylthiocarbonylmethylindenyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionic acid Ethyl ester (Compound 1), white solid (0.3 g, yield 16%).

LCMS m/z = 630.28 [M + 1].

^{1 H NMR ((400MHz, CDCl} 3) δ8.41 (d, 1H), 7.72 (d, 2H), 7.66 (s, 1H), 7.33 (m, 1H), 7.27 (d, 1H), 7.08 (d , 1H), 6.98 (dd, 1H), 6.71 (d, 1H), 6.63 (d, 2H), 5.53 (s, 1H), 4.43 (dd, 4H), 4.14 - 4.01 (m, 2H), 3.71 ( s, 3H), 2.86 (t, 2H), 2.80 (t, 2H), 1.66 (m, 2H), 1.47 - 1.30 (m, 4H), 1.21 (t, 3H), 0.90 (t, 3H).

Example 2

tert-Butylthio 3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl Amino]propionate (Compound 2)

S-tert-butyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) at room temperature To a solution of amino]propionic acid (Intermediate 1) (1.00 g, 1.67 mmol) in dimethylformamide (15 mL), tert-butyl mercaptan (2A) (0.225 g, 2.505 mmol), 1-ethyl- ( 3-Dimethylaminopropyl)carbodiimide hydrochloride (0.832 g, 4.34 mmol) and 4-dimethylaminopyridine (122 mg, 1.00 mmol) were reacted for 15 hours at room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was combined with ethyl acetate (50 mL × 3), and the organic phase was combined, and the organic phase was washed with water (30 mL × 2), dried over anhydrous sodium sulfate Chromatographic separation and purification ((dichloromethane:methanol (v/v) = 50:1 to 30:1) to give the title compound tert-butylthio 3-[[2-[[[[[[[[[[[[[[[[[ Benzyl]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate (Compound 2), white solid (0.61 g, yield 54.46%)

LCMS m/z =672.33.[M+1].

¹ H NMR ((400MHz, CDCl ₃ ) δ 8.40 (d, 1H), 7.77 - 7.70 (m, 2H), 7.68 (d, 1H), 7.32 (t, 1H), -7.24 (s, 1H), 7.06(t,1H), 7.00–6.91 (m,1H), 6.71(d,1H), 6.64(t,2H),5.33(s,1H),4.50–4.42(m,2H), 4.40(d, 2H), 4.13 (dd, 2H), 3.72 - 3.63 (s, 3H), 2.95 (t, 2H), 1.71 (dd, 2H), 1.40 (s, 9H), 1.31 (dd, 6H), 0.88 (t , 3H).

Example 3

n-Butylthio 3-[[2-[[4-[N`-hexyloxycarbonylmethyl) anilide]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl Amino]propionate (compound 3)

S-butyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate

See Example 2 for the preparation method.

LCMS m/z =672.33.[M+1].

¹ H NMR ((400MHz, CDCl ₃ ) δ 8.40 (dd, 1H), 7.77 - 7.70 (m, 2H), 7.69 (s, 1H), 7.32 (m, 1H), -7.22 (m, 1H), 7.08(d,1H), 6.97(dd,1H),6.71(d,1H),6.65(d,2H),5.37(s,1H),4.54–4.32(m,4H),4.13(t,2H) , 3.69 (s, 3H), 3.06 (t, 2H), 2.83 (t, 2H), 1.71 (dd, 2H), 1.51 (m, 2H), 1.46 - 1.35 (m, 2H), 1.30 (m, 6H) ), 0.95–0.78 (m, 6H).

Example 4

Propylthio 3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) Amino]propionate (Compound 4)

S-propyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate

See Example 2 for the preparation method.

LCMS m/z = 658.31. [M+1].

^{1 H NMR ((400MHz, CDCl} 3) δ8.40 (d, 1H), 7.76-7.62 (m, 3H), 7.33 (t, 1H), 7.18 ((m, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 6.71 (d, 1H), 6.66 (d, 2H), 5.43 (s, 1H), 4.57 - 4.35 (m, 4H), 4.13 (dd, 2H), 3.70 (s, 3H) , 3.06 (t, 2H), 2.81 (t, 2H), 1.71 (dd, 2H), 1.55 (m, 2H), 1.46 - 1.35 (m, 2H), 1.30 (dd, 4H), 0.94 (t, 3H) ), 0.88 (t, 3H).

Example 5

3-[[2-[[4-[N'-hexyloxycarbonylmethyl)phenylamino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Ethyl propionate (compound 5)

Ethyl 3-[[2-[[4-[N`-ethylsulfanylcarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 588.23 [M + 1].

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.41 (dd, 1H), 7.72 (d, 2H), 7.67 (s, 1H), 7.33 (m, 1H), 7.28 (d, 1H), 7.08 (d, 1H), 7.01–6.90 (m, 1H), 6.71 (d, 1H), 6.63 (d, 2H), 5.36 (s, 1H), 4.53–4.31 (m, 4H), 4.07 (q, 2H), 3.70 (s, 3H), 2.92 - 2.72 (m, 4H), 1.32 (t, 3H), 1.21 (t, 3H).

Example 6

3-(2-(((4-(N-((hexylthio)carbonyl)methyl) phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)- 1H-benzo[d]imidazol-5-formylamino)propionic acid ethyl ester (Compound 6)

Ethyl 3-(2-(((4-(N-((hexylthio)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d] Imidazole-5-carboxamido)propanoate

See Method 1 for the preparation method.

LCMS m/z = 644.2 [M + 1].

^{1 H NMR ((400MHz, DMSO} ) δ9.22 (s, 1H), 8.75 (s, 1H), 8.39 (dd, 1H), 7.80 (d, 2H), 7.54 (m, 1H), 7.47 (d, 1H), 7.40 (d, 1H), 7.16 (dd, 1H), 7.11 (m, 1H), 7.02 (t, 1H), 6.89 (d, 1H), 6.77 (d, 2H), 4.60 (d, 2H) ), 4.22 (t, 2H), 3.97 (q, 2H), 3.76 (s, 3H), 2.73 (t, 2H), 2.68 (t, 2H), 1.54 (dd, 2H), 1.34 (dd, 2H) , 1.31 - 1.24 (m, 4H), 1.12 (t, 3H), 0.86 (dd, 3H).

Example 7

Ethylthio 3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl)amino Propionate (Compound 7)

S-ethyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate

See Method 1 for the preparation method.

LCMS m/z = 644.29 [M + 1].

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.39 (dd, 1H), 7.79-7.56 (m, 3H), 7.32 (m, 1H), 7.23 (dd, 1H), 7.03 (d, 1H), 6.97 ( Dd,1H), 6.70(d,1H), 6.60(d,2H),5.42(s,1H),4.52–4.36(m,4H), 4.12(t,2H),3.65(s,3H),3.04 (t, 2H), 2.82 (q, 2H), 1.81 - 1.57 (m, 2H), 1.38 (dd, 2H), 1.30 (dd, 4H), 1.20 (t, 3H), 0.88 (t, 3H).

Example 8

Isopropylthio 3-[[2-[[4-[N`-hexyloxycarbonylmethyl) anilide]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl Amino]propionate (compound 8)

S-isopropyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate

See Example 2 for the preparation method.

LCMS m/z = 658.31 [M + 1].

^{1 H NMR ((400MHz, CDCl} 3) δ8.41 (d, 1H), 7.76 (d, 2H), 7.71 (s, 1H), 7.32 (dd, 2H), 7.12 (d, 1H), 6.98 (dd , 1H), 6.71 (t, 3H), 5.34 (s, 1H), 4.50 (d, 2H), 4.44 (t, 2H), 4.14 (t, 2H), 3.73 (s, 3H), 3.59 (m, 1H), 3.03 (t, 2H), 1.78–1.68 (m, 2H), 1.40 (dd, 2H), 1.36–1.28 (m, 4H), 1.27 (s, 3H), 1.25 (s, 3H), 0.89 (t, 3H).

Example 9

3-[[1-Methyl-2-[[4-[N`-heptylthiocarbonylcarbamoyl]anilinyl]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino] Ethyl propionate (compound 9)

Ethyl 3-[[1-methyl-2-[[4-[N`-heptylsulfanylcarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

Test case

1. Pharmacokinetic evaluation

Healthy adult SD rats (both male and female, purchased from Beijing Weitong Lihua Experimental Animal Center, animal production license number SCXK (Beijing) 2012-0001), fasted one day before the administration of water. 6 rats were intragastrically administered with 5 mg/kg (based on dabigatran group), and the compound was formulated into 0.5 mg CmL-Na (containing 1% Tween 80) to make 0.5 mg × mL ^-1 (in Dabiga). The suspension of the group prototype drug was collected from the eyelids, anticoagulated by heparin, and centrifuged at 3000C 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.

Table 1: Results of pharmacokinetic parameters

Conclusion: The compounds of the present invention have good pharmacokinetic characteristics compared with dabigatran etexilate, especially compounds 6 and 8 are superior to dabigatran etexilate.

Claims

A compound of the formula (I): a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are each independently selected from a C 1-10 alkyl group or a C 6-10 carbocyclic ring, and the alkyl group or carbocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I. Substituted with a CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-10 carbocyclic substituent;

X 1 and X 2 are each independently selected from O or S, provided that at least one of X 1 and X 2 is S.
The compound according to claim 1 and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are each independently selected from a C 1-10 alkyl group, and the alkyl group is optionally further further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, CN, NH 2 , C 1-4 Substituted by a substituent of an alkyl group, a C 1-4 alkoxy group or a C 3-6 carbocyclic ring.
The compound according to claim 2, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are each independently selected from a C 1-10 alkyl group, and the alkyl group is optionally further further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, CN, NH 2 , methyl, and B. Substituted by a substituent of a methoxy group, an ethoxy group, a cyclopropyl group or a cyclopentyl group.
The compound according to claim 3, 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 any one of claims 1 to 4, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein the salt is selected from the group consisting of a hydrochloride, a hydrobromide, a sulfate, a nitrate, Phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, Salicylate, glucuronide, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, Benzene sulfonate, methanesulfonate, ethanesulfonate, triflate, ferulic acid or a combination thereof.
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Carrier or excipient.
Use of a compound according to any one of claims 1 to 5, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, and a composition according to claim 6 for the preparation of a medicament for treating a thrombin inhibitor-related disease .
The use according to claim 7, wherein the thrombin inhibitor-related disease is selected from the group consisting of thromboembolic diseases.
The use according to claim 8, wherein said thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolism.
A method of treating a disease associated with a thrombin inhibitor, wherein the method comprises administering a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt, or a right The composition of claim 6.
The method of claim 10 wherein said thrombin inhibitor associated disease is selected from the group consisting of a thromboembolic disorder.
The method of claim 11 wherein said thromboembolic disorder is selected from the group consisting of venous thrombosis and arterial embolism.