WO2015137680A1 - Pharmaceutical composition for treating or preventing stroke and systemic embolism - Google Patents

Abstract

The present invention relates to a prodrug useful for treating or preventing a stroke and systemic embolism and suitable for being effectively used in the oral delivery of dabigatran, and relates to a compound represented by chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. The compound represented by chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof is useful for treating or preventing a stroke and systemic embolism, and is suitable for being effectively used in oral delivery since the absorption rate, that is, bioavailability of dabigatran is improved.

Description

Pharmaceutical compositions for treating or preventing stroke and systemic embolism

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 (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.

<Formula A>

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.

<Formula B>

In addition, 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 05/028468 describes the physicochemical properties, in particular the stability and hygroscopicity of dabigatran etexilate methanesulfonate. Melting point Tm.p. = 180 ± 3 ° C (form I), Tm.p. = 190 ± 3 ° C (form II) or Tm.p. = 120 ± 5 ° C (hemihydrate) for high stability and low hygroscopicity A crystalline form (measured with a differential scanning calorimeter; measured with a maximum peak; heating rate: 10 ° C./min) and a method for producing the same are disclosed. In the same vein, WO 06/131491 discloses Tm.p. = 135 ± 3 ° C. (anhydrous form I), Tm.p. = 150 ± 3 ° C. (anhydrous form II) or Tmp. = 90 ± 5 Disclosed is the crystalline form of dabigatran etexilate, characterized by a melting point of ° C (tetrahydrate) (crystal by DSC; evaluation by peak maximum value; heating rate: 10 ° C / min). WO 08/059029 discloses anhydrous crystalline III (Tmp = 128 ± 5 ° C.), IV (Tmp = 133 ± 5 ° C.), monohydrate form I (Tmp = 128 ± 5 ° C.) of dabigatran etexilate. ), II (Tmp = 128 ± 5 ° C.) and solvate I (Tmp = 123 ± 5 ° C.). 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.

International Publication No. WO 08/043759 also discloses novel salts of dabigatran etexilate, namely, gentisate (crystalline form II), besylate (crystalline forms I, II, III), hydrochloride (crystalline forms II, V, VI). 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 discloses a novel salt of dabigatran etexilate, namely , Phosphate (crystalline form III), fumarate (crystalline form V), sulfate (crystalline form I), maleate (crystalline form II), oxalate (crystalline form VI), hydrochloride (crystalline form VII, VIII, IX, X), p-toluenesulfonic acid New crystalline forms of salts (forms VIII, IX) and mesylates (form IV) are disclosed.

However, the bioavailability of methanesulfonate and novel salts of dabigatran etexilate having such crystallinity is also very low, about 3-7%, and the situation is required to improve the bioavailability of dabigatran.

The present invention provides a novel prodrug of dabigatran.

And the present invention is to provide a pharmaceutical composition for treating or preventing stroke and systemic embolism comprising the novel prodrug.

In order to achieve the above object, 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.

<Formula 1>

In Chemical Formula 1,

B is ethyl,

,

,

or

Is,

When B is ethyl; A is

,

,

or

ego,

B is

,

,

or

when; A is n-hexyl,

Wherein 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,

Z is

or

ego,

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. However, 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.

Examples of such elements include, but are not limited to, stability of starting material action in different ambient environments, stability in the manufacture of pharmaceutical formulations, and stability in final compositions of pharmaceutical formulations. Thus, 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. Moreover, when the pharmaceutical ingredient is subsequently exposed to an environment that is not protected from moisture, moisture absorption during manufacture may reduce the pharmaceutically active ingredient content. Therefore, preferably, the pharmaceutically active ingredient should be very hygroscopic.

Since 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.

In the present invention, when B in the formula (1) is ethyl,

Ethyl 3- (1-methyl-2-(((4- (N-(((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) carbamimido Yl) phenyl) amino) methyl) -N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (dabigatran medoxomil)

Ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-(((4- (N-((((2E, 6E) -3,7,11-trimethyldodeca-2,6) , 10-trien-1-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (Davi Gatran Panesil)

Ethyl 3- (1-methyl-2-(((4- (N-((2-morpholinoethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -N- (pyridine-2 -Yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (dabigatran mofetil)

2-(((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] imidazole-2 -Yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) acetic acid; (dabigatran acetamecin)

Ethyl 3- (2-(((4- (N-((2- (dimethylamino) ethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridine- 2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (dabigatran ciprodinate)

Ethyl 3- (2-(((4- (N-((3- (dimethylamino) propoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridine- 2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (dabigatran clofibride)

2-(((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] imidazole-2 -Yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) ethyl nicotinate; (dabigatran etofibrate)

3-((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] imidazole-2 -Yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) propyl nicotinate; (dabigatran ronifibrate)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (dabigatran carindacillin)

(E) -1-(((amino (4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d Imidazol-2-yl) methyl) amino) phenyl) methylene) carbamoyl) oxy) ethyl isobutyrate; (dabigatran ennacabil)

((((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) methyl pivalate; (dabigatran coating)

Ethyl 3- (2-(((4- (N-((1-acetoxyethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridine-2- Yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (davigatran acetyl)

Ethyl 3- (1-methyl-2-(((4- (N-((2-methyl-1- (propionyloxy) propoxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (dabigatran posinopril)

In the present invention, when A in Formula 1 is n-hexyl

(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carba) Mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (dabigatran e) Texylate medoxyl wheat)

(2E, 6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl 3- (2-(((4-((Z) -N '-((hexyljade) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propano Eight; (Davigatran etexilate farnesyl)

2-morpholinoethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl- N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (dabigatran etexilate mofetil)

(Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) acetic acid; (dabigatran etexilate acemethacin)

2- (dimethylamino) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl -N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (dabigatran etexilate ciprodinate)

1-((isopropoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) Methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (dabigatran etexilate clofibride)

(Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoyl) oxy) ethyl nicotinate; (dabigatran etexilate etofibrate)

(Z) -3-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) propyl nicotinate; (dabigatran etexilate ronifibrate)

2,3-dihydro-1H-inden-5-yl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino ) Methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (davigatran etexilate carindacillin)

(Z) -1-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) ethyl isobutyrate; (dabigatran etexilate ennacarbyl)

((t-butoxycarbonyl) oxy) methyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl ) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate; (dabigatran etexilate covering room)

1-acetoxyethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N -(Pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (dabigatran etexilate axetyl)

(Z) -1-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) -2-methylpropyl isobutyrate; (dabigatran etexilate albacrofen flakabil )

2-methyl-1- (propionyloxy) propyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl ) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (dabigatran etexilate posinopril)

((Isopropoxycarbonyl) oxy) methyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (dabigatran etexilate isopropyl)

1-(((cyclohexyloxy) carbonyl) 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; (dabigatran etexilate cilexetil)

1-((ethoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl ) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (dabigatran etexilate bacampicillin)

1-((isopropoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) Methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate; (davigatran etexilate proxetyl) Preferred compounds, which may be mesylate salts.

In addition, 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. When the compounds of the present invention are relatively basic, 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.

Pharmaceutically acceptable salts of formula (1) 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.

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate (+)-(1S) -campo-10-sulfonate; (Davi Gatran Carindacillin (+)-(1S) -campo-10-sulfonate)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate citrate; (dabigatran carindacillin citrate)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate fumarate; (dabigatran carindacillin fumarate)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (-)-L-maleate; (dabigatran carindacillin ( -)-L-maleate)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate malonate; (dabigatran carindacillin malonate)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate 2-naphthalenesulfonate; (dabigatran carindacillin 2-naphthalenesulfonic acid salt)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate nicotinate; (dabigatran carindacillin nicotinate)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate ororate; (dabigatran carindacillin ororate)

Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (+)-L-tartarate; (dabigatran carindacillin ( +)-L-tartarate)

1-(((cyclohexyloxy) carbonyl) 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 (+)-(1S) -campo-10 Sulfonates; (dabigatran etexilate cilexetil (+)-(1S) -campo-10-sulfonates)

1-(((cyclohexyloxy) carbonyl) 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 citrate; (dabigatran etexilate cilec) Cetyl citrate)

1-(((cyclohexyloxy) carbonyl) 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 fumarate; (dabigatran etexilate silec) Cetyl fumarate)

1-(((cyclohexyloxy) carbonyl) 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 (-)-L-maleate; (Davi Gatran etexilate cilexetil (-)-L-maleate)

1-(((cyclohexyloxy) carbonyl) 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 malonate; (dabigatran etexilate cilec) Cetyl malonate)

1-(((cyclohexyloxy) carbonyl) 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 ororate; (dabigatran etexilate Silecetyl Orotate

1-(((cyclohexyloxy) carbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamimidoyl) phenyl ) Amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate salicylate; (dabigatran etexilate silec) Cetyl salicylate)

1-(((cyclohexyloxy) carbonyl) 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 (+)-L-tartarate; (Davi Gatran etexilate cilexetil (+)-L-tartarate)

Ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-(((4- (N-((((2E, 6E) -3,7,11-trimethyldodeca-2,6) , 10-trien-1-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) propanoate citrate; (Davigatran Panesyl Citrate)

Ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-(((4- (N-((((2E, 6E) -3,7,11-trimethyldodeca-2,6) , 10-trien-1-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (+) -L-tartarate; (dabigatran panesyl (+)-L-tartarate)

((((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) methyl pivalate (+)-(1S) -campo-10-sulfonate; (dabigatran coating chamber (+)-(1S)- Campo-10-sulfonate)

((((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) methyl pivalate citrate; (dabigatran coated citrate)

((((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) methyl pivalate (-)-L-maleate; (dabigatran coating chamber (-)-L-maleate)

((((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) methyl pivalate 2-naphthalenesulfonate; (dabigatran coating chamber 2-naphthalenesulfonate)

((((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) methyl pivalate ororate; a compound that is (dabigatran coating room ororate).

 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.

Indeed, it has surprisingly been found in the present invention that crystal modifications of the salts of interest can be prepared selectively and uniformly, respectively, by the process described in Example 72 below. For the use of pharmaceutical compositions, the active ingredient contained therein must be a uniform crystal modification to ensure reliable bioavailability. The crystalline form of the salts according to the invention was investigated in more detail with a differential scanning calorimeter. The obtained graph is shown in Figs.

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.

References 1 to 8 below list the data obtained by this assay.

In References 1 to 8, the value "2 [theta] [°]" represents the diffraction angle in degrees and the value "d Value [k]" represents the specific distance between grating planes in k. Within the scope of the present invention the X-ray powder graph used Bruker D8.

Stability tests of dabigatran etexilate mesylate salts and dabigatran pivalate salts prepared in Examples 18, 72, 73, 75, and 76 were performed. As a result, it was found that the compound of Example 72 was more stable than dabigatran etexilate mesylate when the temperature was 40 ° C. and the humidity was 75%.

Solubility tests of dabigatran etexilate mesylate salts and dabigatran pivalate salts prepared in Examples 18, 72, 73, 75, 76 were performed. As a result, DBPM, DBP40 and DBP45 in 20wt% solutol solution showed the same solubility as the control drug (DBEtM). Also, in pH 2.0 buffer solution, DBP16 showed the same solubility as the control drug, and DBPM and DBP11 showed better solubility than the control drug.

In addition, 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.

Oral bioavailability in rats of the compounds according to the invention showed that dabigatran propanoate mesylate salt showed a Cmax similar to that of the reference drug, and dabigatran coated silicyl mesylate salt showed a Cmax equal to or greater than the control drug. The bioavailability (BA) was 63 ~ 84% compared to Pradaxa, but the bioavailability of Pradaxa is very low, so it is hard to see the relative comparison of the values.

Oral bioavailability in the mouse of the compound according to the present invention, Cmax was 63 ~ 85% compared to the control drug (Pradaxa), especially dabigatran propanoate mesylate and dabigatran pivalate mesylate Cmax Both 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. For this purpose, the compounds of the formulas prepared according to the invention, together with other active substances, 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).

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.

1 shows differential scanning calorimetry (DSC) curves of crystalline dabigatran coating chamber (+)-(1S) -campo-10-sulfonate prepared according to Example 72. FIG.

2 shows the DSC curve of the crystalline dabigatran coated chamber citrate prepared according to Example 73. FIG.

3 shows the DSC curve of the crystalline dabigatran coating chamber 2-naphthalenesulfonate prepared according to Example 75.

FIG. 4 shows the DSC curves of the crystalline dabigatran coated chamber ororate prepared according to Example 76.

5 shows the DSC curve of the crystalline dabigatran carindacillin fumarate prepared according to Example 79.

6 shows the DSC curve of the crystalline dabigatran carindacillin malonate prepared according to Example 81.

FIG. 7 shows the DSC curve of the crystalline dabigatran carindacillin nicotinate prepared according to Example 83.

8 shows the DSC curve of the crystalline dabigatran carindacillin ororate prepared according to Example 84.

9 shows the X-ray diffraction (XRD) pattern of the crystalline dabigatran coating chamber (+)-(1S) -campo-10-sulfonic acid salt prepared according to Example 72.

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.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples. However, the following Examples and Experimental Examples are only for illustrating the present invention, and the scope of the present invention is not limited by the Examples and Experimental Examples.

Example 1 (E) -1-(((amino (4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl- Preparation of 1H-benzo [d] imidazol-2-yl) methyl) amino) phenyl) methylene) carbamoyl) oxy) ethyl isobutyrate (Dabigatran Ennacabil)

Step 1: Preparation of 1-chloroethyl-4-nitrophenyl-carbonate

First, 10 g of 4-nitrophenol is added to a 250 ml flask and dissolved with 100 ml of methylene chloride. Cool the reaction to 0-4 ° C. and slowly add 5.92 ml of pyridine. After stirring for 10 minutes, 8.81 ml of 1-chloroethyl chloroformate was slowly added thereto. After stirring for 30 minutes, the temperature was raised to room temperature and stirred overnight. After distillation under reduced pressure, the residue was dissolved in diethyl ether and washed with water, 10 wt% aqueous citric acid solution and water. After drying over anhydrous sodium sulfate, distillation under reduced pressure 1.67 g of 1-chloroethyl-4-nitrophenyl-carbonate were obtained.

¹ H NMR (CDCl ₃ , 400 MHz) 8.30 (dd, 2H), 7.42 (dd, 2H), 6.50 (q, 1H), 1.93 (d, 3H)

Step 2: Preparation of 1-((4-nitrophenoxy) carbonyloxy) ethyl isobutyrate

16.02 ml of isobutyric acid and 0.8 g of 1-chloroethyl-4-nitrophenyl-carbonate (1-1) prepared in Step 1 were added to a 100 ml flask and stirred. 0.8 g of zinc oxide and 0.49 g of sodium iodide are added to the solution, and the mixture is heated to 60 to 70 ° C. Stir for 24 hours. The reaction was cooled to room temperature, distilled under reduced pressure, and the residue was dissolved in ethyl acetate. Wash with saturated sodium bicarbonate and saturated sodium chloride. The organic layer is separated, dried over anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was purified by column chromatography to give 40 mg of 1-((4-nitrophenoxy) carbonyloxy) ethyl isobutyrate.

¹ H NMR (CDCl ₃ , 400 MHz) 8.28 (dd, 2H), 7.38 (dd, 2H), 6.83 (q, 1H), 2.60 (m, 1H), 1.61 (d, 3H), 1.22 (d, 6H)

Step 3: Preparation of Davigatran Ennacaville

Into a 50 ml flask, 0.168 g of 1-((4-nitrophenoxy) carbonyloxy) ethyl isobutyrate prepared in Step 2 and 15 ml of tetrahydrofuran were added and dissolved. 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl 0.3 g of) -amide-hydrochloride and 0.235 ml of triethylamine were added thereto, and the mixture was stirred at room temperature for 2 days. The reaction is terminated with water and extracted with methylene chloride. It is dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was purified by column chromatography to give 0.15 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.40 (s, 1H), 7.72 (d, 2H), 7.66 (s, 1H), 7.34 (m, 1H), 7.25 (d, 1H), 7.10 (d, 1H) , 6.98 (m, 2H), 6.70 (d, 1H), 6.63 (m, 2H), 4.50 (s, 2H), 4.42 (t, 2H), 4.07 (q, 2H), 3.74 (s, 3H), 2.80 (t, 2H), 2.54 (m, 1H), 1.56 (d, 3H), 1.30 (t, 3H), 1.15 (d, 6H)

Example 2 (E) -1-(((amino (4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl- Preparation of 1H-Benzo [d] imidazol-2-yl) methyl) amino) phenyl) methylene) carbamoyl) oxy) ethyl isobutyrate hydrochloride (Dabigatran Ennacaville Hydrochloride)

100 mg of dabigatran ennacabil prepared in Example 1 was dissolved in methylene chloride. 0.076 ml of a 2 molar hydrochloric acid solution dissolved in diethyl ether was added at room temperature and stirred for 1 day. The reaction was distilled under reduced pressure and solidified with diethyl ether to give 95 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.32 (m, 1H), 7.52 ~ 6.53 (br, 11H), 4.43 (m, 4H), 4.01 (m, 4H), 3.83 (m, 1H), 2.71 (m, 2H), 2.59 (m, 2H), 1.61 (m, 3H), 1.17-1.25 (m, 12H), 0.85 (m, 3H)

Example 3 2-((((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) acetic acid (dabigatran acetamecin)

2.15 g of glycolic acid and 9.17 g of 1,1-carbonyldiimidazole were added to a 250 ml flask and dissolved in 150 ml of N, N-dimethylformamide. Stirred at room temperature for 3 hours 30 minutes. 7.84 ml of triethylamine and 1-methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2 10 g of ethoxycarbonylethyl) -amide-hydrochloride was added and stirred at 70 ° C for 3 days. After cooling to room temperature, the reaction was terminated with water and extracted with methylene chloride. After drying over anhydrous sodium sulfate, the mixture was distilled under reduced pressure. The residue was purified by column chromatography to give 830 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.40 (m, 1H), 7.95 (d, 1H), 7.67 (s, 1H), 7.32 (m, 1H), 7.21 (m, 1H), 7.03 (d, 1H) , 6.97 (m, 1H), 6.71 (d, 1H), 6.67 (m, 2H), 6.19 (m, 1H), 4.61 (s, 2H), 4.52 (m, 2H), 4.39 (t, 2H), 4.05 (q, 2H), 3.68 (s, 3H), 2.77 (t, 2H), 1.19 (t, 3H)

Example 4 2-((((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) acetic acid mesylate (Davigatran acetamecin mesylate)

0.15 g of dabigatran acemethacin prepared in Example 3 was dissolved in ethanol. 0.016 ml of methanesulfonic acid was added at room temperature and stirred for 1 hour. The resulting solid was filtered off. The filtrate was dried under reduced pressure at room temperature for 1 hour to give 134 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.35 (m, 1H), 7.90 (d, 2H), 7.73 (d, 1H), 7.60 (m, 1H), 7.55 (s, 1H), 7.36 (d, 1H), 7.14 (m, 1H), 7.03 (d, 1H), 6.90 (d, 2H), 4.93 (s, 2H), 4.83 (s, 2H), 4.20 (t, 2H), 3.95 (q, 2H ), 3.90 (s, 3H), 2.68 (t, 2H), 2.31 (s, 3H), 1.10 (t, 3H)

Example 5 2-((((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) acetic acid hydrochloride (dabigatran acetamecin hydrochloride)

0.15 g of dabigatran acemethacin prepared in Example 3 was dissolved in ethanol. 0.12 ml of a 2 molar hydrochloric acid solution dissolved in diethyl ether was added at room temperature and stirred for 1 hour. The resulting solid was filtered off. The filtrate was dried under reduced pressure at room temperature for 1 hour to give 95 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.35 (m, 1H), 7.90 (d, 2H), 7.73 (d, 1H), 7.60 (m, 1H), 7.55 (s, 1H), 7.36 (d, 1H), 7.14 (m, 1H), 7.03 (d, 1H), 6.90 (d, 2H), 4.93 (s, 2H), 4.83 (s, 2H), 4.20 (t, 2H), 3.95 (q, 2H ), 3.90 (s, 3H), 2.68 (t, 2H), 1.10 (t, 3H)

Example 6 Ethyl 3- (2-(((4- (N-((1-acetoxyethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- Preparation of (Pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (Dabigatran Axetyl)

Step 1: Preparation of 1-((nitrophenoxy) carbonyloxy) ethyl acetate

30 ml of acetic acid and 2 g of the compound synthesized in Step 1 of Example 1 were added to a 100 ml flask and stirred. 5.67 g of Mercury Acetate was added to the solution, followed by stirring at room temperature for 2 days. The reaction is distilled off under reduced pressure and the residue is dissolved in methylene chloride. Wash with saturated sodium bicarbonate and saturated sodium chloride. The organic layer is separated, dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was purified by column chromatography to give 1.87 g of 1-((nitrophenoxy) carbonyloxy) ethyl acetate.

¹ H NMR (CDCl ₃ , 400 MHz) 8.28 (m, 2H), 7.27 (m, 2H), 6.84 (m, 1H), 1.60 (m, 3H), 1.47 (m, 3H)

Step 2: Preparation of Dabigatran Axetyl

Into a 100 ml flask, 1.85 g of 1-((nitrophenoxy) carbonyloxy) ethyl acetate prepared in Step 1 and 40 ml of N, N-dimethylformamide were added and dissolved. 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl 3.7 g of) -amide-hydrochloride and 1.28 g of diisopropylethylamine are added thereto, and the mixture is stirred at room temperature for 1 day. Terminate the reaction with water and extract with ethyl acetate. It is dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was purified by column chromatography to give 3.5 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.40 (s, 1H), 7.72 (d, 2H), 7.66 (s, 1H), 7.34 (m, 1H), 7.25 (d, 1H), 7.05 (d, 1H) , 6.98 (m, 2H), 6.68 (d, 1H), 6.62 (m, 2H), 5.33 (m, 1H), 4.48 (s, 2H), 4.42 (t, 2H), 4.07 (q, 2H), 3.67 (s, 3H), 2.79 (t, 2H), 2.05 (s, 3H), 1.53 (d, 3H), 1.19 (t, 3H)

Example 7 Ethyl 3- (2-(((4- (N-((1-acetoxyethoxy) carbonyl) carbamidoyl) phenyl) amino) methyl) -1-methyl-N- Preparation of (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate mesylate (dabigatran acetyl mesylate)

0.20 g of dabigatran axetyl prepared in Example 6 was dissolved in ethanol. 0.021 ml of methanesulfonic acid was added at room temperature and stirred for 27 hours. 12 ml of diethyl ether was further added at room temperature and stirred for 16 hours. The reaction was distilled under reduced pressure at an external temperature of 40 ℃ and the residue was dried under reduced pressure to give 217 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.37 (m, 1H), 7.67 (d, 2H), 7.54 (m, 1H), 7.46 (s, 1H), 7.42 (d, 1H), 7.17 (d, 1H), 7.11 (m, 1H), 6.89 (d, 1H), 6.83 (m, 3H), 4.69 (s, 2H), 4.21 (t, 2H), 3.95 (q, 2H), 3.77 (s, 3H ), 2.66 (t, 2H), 2.28 (s, 3H), 2.07 (s, 3H), 1.51 (d, 3H), 1.11 (t, 3H)

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

20 g of dabigatran etexilate was dissolved in 200 ml of ethanol. 35.1 ml of 1N NaOH was added thereto, and the mixture was stirred at room temperature and stirred for 16 hours. The reaction was concentrated under reduced pressure to give 20.7 g of dabigatran etexilate sodium salt.

¹ H NMR (400 MHz, CDOD) δ 8.33 (1H, dd), 7.69 (d, 2H), 7.57 (s, 1H), 7.53 (td, 1H), 7.30 (qd, 2H), 7.11 (dd, 1H ), 7.01 (d, 1H), 6.74 (d, 2H), 4.68 (s, 2H), 4.31 (t, 2H), 4.08 (t, 2H), 3.79 (s, 3H), 2.59 (t, 2H) , 1.68-1.63 (m, 2H), 1.43-1.31 (m, 6H), 0.90 (t, 3H)

Step 2: Preparation of dabigatran etexilate medoxomill

2 g of dabigatran etexilate sodium salt prepared in step 1, 460.4 mg of 4- (hydroxymethyl) -5-methyl-1,3-dioxol-2-one, N- (3-dimethylaminopropyl)- 740.2 mg of N-ethylcarbodiimide hydrochloride, 521.7 mg of 1-hydroxybenzotriazole hydrate, and 1.4 ml of N, N-diisopropyl epitamine were dissolved in 20 ml of N, N-dimethylformamide and 16 hours at 60 ° C. Stirred. After the reaction was completed, the 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.

¹ H NMR (400 MHz, CDCl ₃ ) 9.43 (br, 1H), 8.38 (dd, 1H), 7.67 (d, 2H), 7.62 (s, 1H), 7.31 ~ 7.26 (m, 1H), 7.16 (dd , 1H), 7.00-6.14 (m, 2H), 6.61 (d, 1H), 6.55 (d, 2H), 5.43 (t, 1H), 4.77 (s, 2H), 4.41-4.11 (m, 4H), 4.09 (t, 2H), 3.60 (s, 2H), 2.81 (t, 2H), 2.10 (s, 3H), 1.72-1.64 (m, 2H), 1.41-1.32 (m, 2H), 1.28-1.18 ( m, 4H), 0.85 (t, 3H)

Example 9 ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamididoyl) phenyl) Preparation of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (dabigatran carindacillin)

Step 1: Preparation of 4-nitrophenyl 5-indanyl carbonate

1 g of 4-nitrophenyl chloroformate was added thereto, dissolved in 10 ml of dichloromethane, cooled to 0 ° C., and stirred. 700 mg of 5-indanol and 0.46 ml of pyridine were added to the reaction solution, which was stirred for 16 hours at room temperature. After the reaction was completed, the reaction product was extracted by adding 10 wt% aqueous citric acid solution and dichloromethane. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.23 g of 4-nitrophenyl 5-indanyl carbonate.

¹ H NMR (CDCl ₃ , 400 MHz) 8.32 (dd, 2H), 7.49 (dd, 2H), 7.25 (d, 1H), 7.06 (d, 1H), 7.00 (dd, 1H), 2.96-2.87 (m, 4H), 2.18-2.11 (m, 2H)

Step 2: Preparation of Dabigatran Carindacillin

1.2 g of 4-nitrophenyl 5-indanyl carbonate obtained in Step 1 was dissolved in 43 ml of tetrahydrofuran and stirred at room temperature. 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxy 2.15 g of carbonylethyl) -amide-hydrochloride and 1.7 ml of triethylamine were added thereto, followed by stirring at room temperature for two days. After the reaction was completed, the reaction was extracted by adding water and dichloromethane. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was solidified with ethyl acetate to give 1.7 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 9.59 (br, 1H), 8.42 (d, 1H), 7.82 (d, 2H), 7.70 (s, 1H), 7.33 (td, 1H, 7.30 (dd, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 7.04 (s, 1H), 6.99 (dd, 1H), 6.94 (d, 1H), 6.70 (dd, 4H), 5.37 (s, 1H), 4.49 (d, 2H), 4.43 (t, 2H), 4.05 (q, 2H), 3.72 (s, 3H), 2.93-2.86 (m, 4H), 2.81 (t, 2H), 2.10-2.04 (m, 2H ), 1.26 (t, 3H)

Example 10 2-((((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) ethyl nicotinate (dabigatran etofibrate)

Step 1: Preparation of 2-(((4-nitrophenoxy) carbonyl) oxy) ethyl nicotinate

The reaction was carried out in the same manner as in Step 1 of Example 9, using 1 g of 2-hydroxyethyl nicotinic acid hydrochloride to obtain 1.49 g of 2-(((4-nitrophenoxy) carbonyl) oxy) ethyl nicotinate.

¹ H NMR (CDCl ₃ , 400 MHz) 9.27 (s, 1H), 8.82 (d, 1H), 8.36 (dd, 1H), 8.29 (dd, 2H), 7.51-7.40 (m, 1H), 7.38 (dd, 2H), 4.69 (dd, 2H), 4.64 (dd, 2H)

Step 2: Preparation of Dabigatran Etopibrate

Using 1.49 g of 2-(((4-nitrophenoxy) carbonyl) oxy) ethyl nicotinate obtained in step 1, the reaction was carried out in the same manner as in Step 2 of Example 9, to obtain 970 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 9.55 (br, 1H), 9.24 (d, 1H), 8.75 (dd, 1H), 8.42 (dd, 1H), 8.32 (dt, 1H), 7.74 (d, 2H) , 7.68 (dd, 1H), 7.37 (dd, 1H), 7.32 (td, 1H), 7.29 (dd, 1H), 7.08 (d, 1H), 6.98 (dd, 1H), 6.69 (d, 1H), 6.65 (d, 2H), 5.36 (t, 1H), 4.63 (dd, 2H), 4.51 (dd, 2), 4.45 (dd, 2H), 4.42 (t, 2H), 4.07 (q, 2H), 3.70 (s, 3H), 2.80 (t, 2H), 1.21 (t, 3H)

Example 11 ethyl 3- (1-methyl-2-(((4- (N-((2-morpholinoethoxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -N Preparation of-(pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate (dabigatran mofetil)

Step 1: Preparation of 2-morpholinoethyl (4-nitrophenyl) carbonate

1 g of 4-nitrophenyl chloroformate was added, dissolved in 20 ml of diethyl ether, cooled to 0 ° C., and stirred. A solution in which 0.572 ml of 4- (2-hydroxyethyl) morpholine was dissolved in 17 ml of diethyl ether was slowly added to the reaction solution at 0 ° C. for 1 hour. The temperature of the reaction solution was slowly raised to room temperature and stirred for 13 hours. The resulting solid was filtered to yield 1.35 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.30 (d, 2H), 7.45 (d, 1H), 4.91 (s, 2H), 4.34 (t, 2H), 4.02 (m, 2H), 4.02 (m, 2H) , 3.61 (d, 2H), 3.41 (s, 1H), 3.00 (m, 2H)

Step 2: Preparation of dabigatran mofetil

310 mg of 2-morpholinoethyl (4-nitrophenyl) carbonate obtained in step 1 was dissolved in 11 mL of N, N-dimethylformamide and stirred. 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxy 2.44 g of carbonylethyl) -amide-hydrochloride and 1.9 ml of triethylamine were added thereto, followed by stirring at room temperature for 16 hours. After the reaction was completed, the reaction was extracted by adding water and dichloromethane. The dichloromethane solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 790 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.41 (dd, 1H), 7.71 (d, 2H), 7.66 (d, 1H), 7.32 (td, 1H), 7.24 (dd, 1H), 7.03 (d, 1H) , 6.97 (dd, 1H), 6.68 (d, 1H), 6.61 (d, 2H), 5.35 (t, 1H), 4.43-4.39 (m, 4H), 4.27 (t, 2H), 4.04 (q, 2H ), 3.71-3.69 (m, 4H), 3.67 (s, 3H), 2.78 (t, 2H), 2.70 (t, 2H), 2.54-2,50 (m, 5H), 1.20 (t, 3H)

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

500 mg of 1-chloro-2-methylpropyl (4-nitrophenyl) carbonate was dissolved in 5 ml of propionic acid and stirred. 470 mg of silver oxide was added to the reaction solution and refluxed at 95 ° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, the solid was filtered, and the filtrate was extracted with methyl t-butyl ether and aqueous supersaturated sodium hydrogen carbonate solution. The methyl t-butyl ether solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 296 mg of 2-methyl-1-(((4-nitrophenoxy) carbonyl) oxy) propyl propionate.

¹ H NMR (CDCl ₃ , 400 MHz) 8.21 (dd, 2H), 7.37 (dd, 2H), 6.55 (d, 1H), 2.38 (q, 2H), 2.14-2.06 (m, 1H), 1.12 (t, 3H), 0.99 (d, 6H)

Step 2: Preparation of Dabigatran Posinopril

296 mg of 2-methyl-1-(((4-nitrophenoxy) carbonyl) oxy) propyl propionate obtained in step 1 was dissolved in 5 ml of acetonitrile and 5 ml of dichloromethane and stirred. 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxy 510 mg of carbonylethyl) -amide-hydrochloride and 0.4 ml of triethylamine were added thereto, followed by stirring at room temperature for 16 hours. After the reaction was completed, the reaction was extracted by adding water and dichloromethane. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 384 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 9.61 (br, 1H), 8.43 (dd, 1H), 7.79 (d, 2H), 7.71 (d, 1H), 7.35-7.72 (m, 2H), 7.13 (d, 1H), 6.98 (dd, 1H), 6.76 (d, 1H), 6.71 (d, 3H), 5.26 (t, 1H), 4.50 (d, 2H), 4.43 (t, 2H), 4.08 (q, 2H ), 3.73 (s, 3H), 2.81 (t, 2H), 2.36 (q, 2H), 2.17-2.08 (m, 1H), 1.22 (t, 2H), 1.14 (t, 3H), 1.03 (dd, 6H)

Example 13 (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 mesyl Preparation of Acids (Davigatran Etexylate Medoxomil Mesylate)

200 mg of dabigatran etexilate medoxomil prepared in Example 8 was dissolved in 2 ml of ethanol and stirred. 18 methanesulfonic acid was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and 5 ml of diisopropyl ether was added to the residue, followed by stirring. The resulting solid was filtered under nitrogen and washed with 10 ml diisopropyl ether. The filtrate was dried in vacuo at room temperature to give 140 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.87 (s, 1H), 10.65 (s, 1H), 10.31 (s, 1H), 8.37 (d, 1H), 7.64 (d, 3H), 7.52 (td, 1H), 7.46 (s, 1H), 7.41 (d, 1H), 7.14 (d, 1H), 7.11 (dd, 1H), 6.88 ~ 6.84 (m, 3H), 4.87 (s, 2H), 4.69 (s , 2H), 4.26-4.20 (m, 4H), 3.77 (s, 3H), 2.73 (t, 2H), 2.28 (s, 3H), 2.09 (s, 3H), 1.68-1.63 (m, 2H), 1.38-1.22 (m, 6H), 0.87 (t, 3H)

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)

300 mg of the title compound was obtained in the same manner as in Example 13, using 300 mg of dabigatran carindacillin prepared in Example 9 and dichloromethane.

¹ H NMR (DMSO-d ₆ , 400 MHz) 10.02 (s, 1H), 8.37 (d, 1H), 7.72 (d, 2H), 7.55 (td, 1H), 7.48 (s, 2H), 7.29 (d, 1H), 7.18 (d, 1H), 7.16 (s, 1H), 7.12 (dd, 1H), 7.04 (d, 1H), 6.93-6.84 (m, 3H), 4.74 (s, 2H), 4.21 (t , 2H), 3.95 (q, 2H), 2.88 (q, eH), 2.68 (t, 2H), 2.29 (s, 3H), 2.09-2.01 (m, 1H), 1.11 (t, 3H)

Example 15 2-((((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) ethyl nicotinate mesylate (Davigatran etofibrate mesylate)

300 mg of dabigatran etofibrate prepared in Example 10 was dissolved in 9 ml of acetone and stirred. 28.2ul of mesylic acid was added to the reaction solution and stirred at room temperature for 16 hours. The resulting solid was filtered and dried to give 270 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.01 (br, 1H), 10.70 (br, 1H), 10.05 (br, 1H), 9.12 (d, 1H), 8.83 (dd, 1H), 9.37 (dd, 1H), 8.30 (dt, 1H), 7.64-7.52 (m, 5H), 7.46 (s, 1H), 7.45 (d, 1H), 7.17 (d, 1H), 7.11 (dd, 1H), 6.90 (d , 1H), 6.84 (d, 2H), 4.71 (s, 2H), 4.62 (s, 4H), 4.20 (t, 2H), 3.95 (q, 2H), 3.77 (t, 3H), 2.67 (t, 2H), 2.28 (s, 3H), 1.10 (t, 3H)

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)

Using 300 mg of dabigatran posinopril and dichloromethane prepared in Example 12 in the same manner as in Example 13 to obtain 328 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.36 (d, 1H), 7.75 (d, 2H), 7.55 (td, 1H), 7.45 (d, 1H), 7.18 (d, 1H), 7.11 (td, 1H), 6.91 (d, 1H), 6.85 (d, 2H), 6.61 (d, 1H), 4.71 (br, 2H), 4.21 (t, 2H), 3.94 (q, 2H), 3.78 (s, 3H ), 2.67 (t, 2H), 2.45 ~ 2.33 (m, 2H), 2.10 ~ 2.05 (m, 1H), 1.13 (t, 3H), 1.03 (td, 3H), 0.97 (dd, 6H)

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 1: Preparation of Chloromethyl (4-Nitrophenyl) Carbonate

18 g of 4-nitrophenol were dissolved in 900 ml of dichloromethane and cooled to 0 ° C. 11.6 ml of pyridine and 12.66 ml of chloromethyl chloroform acid salt were added to the reaction solution, and the mixture was stirred at 0 ° C. for 30 minutes. Then stirred at room temperature for 16 hours. After completion of the reaction, the pesticide was depressurized and the reaction was extracted with dichloromethane and water. The extracted dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated. The residue was dispersed in a solution of diisopropyl ether: hexane = 1: 10 and the solid was filtered to give 23.1 g of chloromethyl (4-nitrophenyl) carbonate.

¹ H NMR (400 MHz, CDCl ₃ ) 8.31 (d, 2H), 7.43 (d, 2H), 5.85 (s, 2H)

Step 2: Preparation of Iodomethyl (4-nitrophenyl) Carbonate

23.1 g of chloromethyl (4-nitrophenyl) carbonate obtained in step 1 was dissolved in 690 ml of acetone, and 16.5 g of sodium iodide was added thereto and stirred. The reaction solution was stirred at 40 ° C. for 16 hours, further added 16.5 g of sodium iodide, and stirred for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. It was dissolved in diethyl ether, washed with 10% titanium thiosulfate pentahydrate, separated layers, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 22.34 g of iodomethyl (4-nitrophenyl) carbonate.

¹ H NMR (400 MHz, CDCl ₃ ) 8.30 (dd, 2H), 7.42 (dd, 2H), 6.07 (s, 2H)

Step 3: Preparation of (((4-nitrophenoxy) carbonyl) oxy) methyl pivalate

22.34 g of iodomethyl (4-nitrophenyl) carbonate obtained in step 2 was dissolved in 670 ml of toluene and stirred at room temperature. 7.06 g of pivalic acid and 11.44 g of silver carbonate were added to the reaction solution, and the mixture was stirred at 80 ° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, the solid was filtered through celite, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain 11.84 g of (((4-nitrophenoxy) carbonyl) oxy) methyl pivalate.

¹ H NMR (400 MHz, CDCl ₃ ) 8.29 (d, 2H), 7.40 (d, 2H), 5.89 (s, 2H), 1.26 (s, 9H)

Step 4: preparation of dabigatran cladding chamber

1.64 g of (((4-nitrophenoxy) carbonyl) oxy) methyl pivalate obtained in step 3 was dissolved in 33 ml of N, N-dimethylformamide and stirred at room temperature. 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxy 2.96 g of carbonylethyl) -amide-hydrochloride and 1.93 ml of N, N-diisopropyl epitamine were added and stirred for 16 hours. After completion of the reaction, the 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.

¹ H NMR (400 MHz, CDCl ₃ ) 8.42 (dd, 1H), 7.79 (d, 2H), 7.70 (s, 1H), 7.35 ~ 7.30 (m, 2H), 7.12 (d, 1H), 6.98 (dd , 1H), 6.72-6.68 (m, 3H), 5.86 (s, 2H), 5.33 (t, 1H), 4.49 (d, 2H), 4.43 (t, 2H), 4.07 (q, 2H), 3.72 ( s, 3H), 2.81 (t, 2H), 1.22 (t, 12H)

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)

300 mg of the dabigatran coating chamber prepared in Example 17 was dissolved in 3 ml of ethanol and stirred at room temperature. 29.6ul of mesylic acid was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The concentrate was dispersed in diisopropyl ether and filtered after 1 hour to give 298 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 600 MHz) 8.37 (dd, 1H), 7.66 (d, 2H), 7.54 (td, 1H), 7.46 (s, 2H), 7.17 (d, 1H), 7.11 (dd, 1H), 6.90 (d, 1H). 6.84 (d, 2H), 5.86 (s, 2H), 4.71 (s, 2H), 4.20 (t, 2H), 3.95 (q, 2H (, 3.78 (s, 3H), 2.67 (t, 2H), 2.28 (s, 3H), 1.16 (s, 9H), 1.10 (t, 3H)

Example 19 (Z) -1-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) ethyl isobutyrate (Davigatran etexilate ennacabil )

Step 1: N, N-dimethylformamide was prepared

136 mg of zinc chloride was added to a solution of 10.6 ml of isobutyryl chloride and 6.2 ml of paraaldehyde, followed by stirring at 80 ° C. for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, 150 ml of diethyl ether was added, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated to give 10.6 g of N, N-dimethylformamide.

¹ H NMR (CDCl ₃ , 400 MHz) 6.53 (q, 1H), 2.55 (m, 1H), 1.79 (d, 3H), 1.25 ~ 1.15 (m, 6H)

Step 2: Preparation of dabigatran etexilate ennacaville

3 g of dabigatran etexilate sodium salt and 30 ml of N, N-dimethylformamide prepared in step 1 were added and stirred. 1.33 g of potassium carbonate was added to the reaction solution, and 1.45 g of 1-chloroethyl isobutyrate was added thereto, followed by stirring at room temperature for 16 hours. After completion of the reaction, 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 solidified using a mixture of 40 ml of diethyl ether and 4 ml of ethyl acetate and filtered to obtain 860 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.42 (dd, 1H), 7.77 (d, 2H), 7.70 (s, 1H), 7.35 ~ 7.29 (m, 2H), 7.18 (d, 1H), 6.99 (q, 1H), 6.82 (q, 1H), 6.70 (d, 3H), 5.26 (t, 1H), 4.49 (d, 2H), 4.45-4.39 (m, 2H), 3.72 (s, 3H), 2.85 (t , 2H), 2.56-2.49 (m, 1H), 1.76-1.64 (m, 2H), 1.45-1.25 (m, 9H), 1.15 (d, 6H), 0.89 (t, 3H)

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)

5 g of dabigatran etexilate sodium salt and 1.66 g of 1-chloroethyl cyclohexyl carbonate were reacted in the same manner as in Step 2 of Example 19, to obtain 760 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.42 (dd, 1H), 7.78 (d, 2H), 7.72 (s, 1H), 7.36 ~ 7.31 (m, 2H), 7.15 (d, 1H), 6.99 (dd, 1H), 6.76 ~ 6.70 (m, 4H), 5.27 (br, 1H), 4.65 ~ 4.60 (m, 1H), 4.52 (d, 2H), 4.42 (t, 2H), 4.15 ~ 4.11 (m, 3H) , 3.75 (s, 3H), 2.87 (t, 2H), 1.98-1.87 (m, 2H), 1.76-1.24 (m, 27H), 0.89 (t, 3H)

Example 21 ((t-butoxycarbonyl) oxy) 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 (Davigatran etexilate coating room)

545 g of dabigatran etexilate sodium salt and 1.34 g of t-butyl (chloromethyl) carbonate were reacted in the same manner as in Step 2 of Example 19, to obtain 4.45 g of the title compound.

¹ H NMR (CDCl ₃ , 600 MHz) 9.57 (br, 1H), 8.42 (dd, 1H), 7.75 (d, 2H), 7.68 (s, 1H), 7.32 (td, 1H), 7.27 (dd, 1H) , 7.08 (d, 1H), 7.98 (dd, 1H), 6.70-6.66 (m, 3H), 5.71 (s, 2H), 5.29 (t, 1H), 1.39-1.27 (m, 4H), 1.20 (s , 9H), 0.88 (t, 3H)

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)

Reaction was carried out in the same manner as in Step 2 of Example 19, using 3 g of dabigatran etexilate sodium salt and 491 mg of chloromethyl isopropyl carbonate to obtain 1.27 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.43 (dd, 1H), 7.81 (d, 2H), 7.73 (s, 1H), 7.35-7.31 (m, 2H), 7.17 (d, 1H), 6.99 (q, 1H), 6.74 (d, 2H), 6.69 (d, 1H), 5.72 (s, 2H), 5.22 (t, 1H), 4.93-4.90 (m, 1H), 4.53 (d, 2H), 4.44 (t , 2H), 4.14 (t, 2H), 3.75 (s, 3H), 2.91 (t, 2H), 1.75-1.69 (m, 1H), 1.41-1.31 (m, 12H), 0.89 (t, 3H)

Example 23 (2E, 6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl 3- (2-(((4-((Z) -N ' -((Hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carbox Amido) Preparation of propanoate (Dabigatran etexilate farnesyl)

5 g of dabigatran etexilate sodium salt, 2.22 ml of farnesol, 740.2 mg of N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride, 521.7 mg of 1-hydroxybenzotriazole hydrate, N, N- 1.4 ml of diisopropyl epitamine was dissolved in 50 ml of N, N-dimethylformamide and stirred at 60 ° C. for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and 200 ml of ethyl acetate and 200 ml of supersaturated ammonium chloride aqueous solution were added to extract the reaction. 200 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 940 mg of the title compound.

¹ H NMR (CD ₃ OD, 400 MHz) 8.38 (dd, 1H), 7.63 (d, 2H), 7.56 (s, 1H), 7.50 (td, 1H), 7.37 (d, 1H), 7.28 (dd, 1H) ), 7.12 (q, 1H), 6.93-6.67 (m, 3H), 5.28 (t, 1H), 5.08 (t, 2H), 4.72 (s, 2H), 4.53 (d, 2H), 4.34 (q, 4H), 3.82 (s, 3H), 2.91-2.73 (m, 2H), 2.11-1.95 (m, 8H), 1.77-1.57 (m, 14H), 1.45-1.32 (m, 6H), 0.92 (t, 3H)

Example 24 2-morpholinoethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) Preparation of -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate (dabigatran etexilate mofetil)

Reaction was carried out in the same manner as in Example 23 using 2 g of dabigatran etexilate sodium salt and 429 l of 2-morpholinoethan-1-ol to obtain 410 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.39 (dd, 1H), 7.69 (d, 2H), 7.63 (d, 1H), 7.31 (td, 1H), 7.20 (dd, 1H), 7.01-6.95 (m, 2H), 6.68 (d, 1H), 6.57 (d, 2H), 5.39 (t, 1H), 4.41-4.37 (m, 4H), 4.16-4.08 (m, 6H), 3.70-3.59 (m, 7H) , 2.80 (t, 2H), 2.58-2.45 (m, 6H), 1.72-1.65 (m, 2H), 1.39-1.26 (m, 6H), 0.86 (t, 3H)

Example 25 2- (dimethylamino) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl ) -1-Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (Davigatran etexilate ciprodinate)

Using 3 g of dabigatran etexilate sodium salt and 535 l of 2-dimethylaminoethanol, the reaction was carried out in the same manner as in Example 23 to obtain 1.27 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.42 (dd, 1H), 7.79 (d, 2H), 7.71 (s, 1H), 7.35 ~ 7.31 (m, 2H), 7.14 (d, 1H), 6.99 (q, 1H), 6.71 (m, 3H), 5.24 (t, 1H), 4.51 (d, 2H), 4.31 (t, 2H), 4.15 ~ 4.11 (m, 4H), 3.73 (s, 3H), 2.84 (t , 2H), 2.54 (t, 2H), 2.26 (s, 6H), 1.76 ~ 1.69 (m, 2H), 1.42 ~ 1.24 (m, 6H), 0.89 (t, 3H)

Example 26 2,3-dihydro-1H-inden-5-yl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbonamido) I) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate preparation (dabigatran etecil Late carindacillin)

3 g of dabigatran etexilate sodium salt and 475 mg of 5-indanol were reacted in the same manner as in Example 23 to obtain 810 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.45 (dd, 1H), 7.79 (d, 2H), 7.74 (s, 1H), 7.36-7.31 (m, 2H), 7.16 (t, 2H), 7.00 (q, 1H), 6.90 (d, 1H), 6.80 (dd, 1H), 6.73 (t, 3H), 5.23 (t, 1H), 4.56 (t, 3H), 4.51 (d, 2H), 4.14 (t, 2H ), 3.74 (s, 3H), 3.05 (t, 2H), 2.88 (q, 4H), 2.08 (m, 2H), 1.73 (m, 2H), 1.43-1.25 (m, 6H), 0.89 (t, 3H)

Example 27 (Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) acetic acid (Dabigatran etexilate acetamecin)

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

Reaction was carried out in the same manner as in Example 23 using 2 g of dabigatran etexilate sodium salt and 502 l of benzyl glycolate, to thereby obtain 2- (benzyloxy) -2-oxoethyl (Z) -3- (2-(((4 -(N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5 -Carboxamido) 1.18 g of propanoate was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) 8.42 (dd, 1H), 7.79 (d, 2H), 7.71 (s, 1H), 7.36 ~ 7.30 (m, 7H), 7.14 (d, 2H), 6.98 (q, 1H), 6.71 (d, 3H), 5.24 (t, 1H), 5.18 (s, 2H), 4.62 (s, 2H), 4.51 (d, 2H), 4.46 (t, 2H), 4.13 (t, 2H) ), 3.73 (s, 3H), 2.94 (t, 2H), 1.73 (m, 2H), 1.43-1.29 (m, 6H), 0.89 (t, 3H)

Step 2: Preparation of dabigatran etexilate acetamecin

2- (benzyloxy) -2-oxoethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) obtained in step 1 above) 1.18 g of amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate was dissolved in 15 ml of methanol. 240 mg of palladium carbon was added to the reaction solution, and hydrogen gas was flowed until the reaction was completed. After the reaction was completed, the reaction solution was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain 600 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.39 (dd, 1H), 7.79 (d, 2H), 7.53 (td, 1H), 7.47 (s, 1H), 7.39 (d, 1H), 7.16-7.10 ( m, 2H), 6.96 (t, 1H), 6.91 (d, 1H), 6.75 (d, 2H), 4.58 (d, 2H), 4.47 (s, 2H), 4.22 (t, 2H), 3.96 (t , 2H), 3.75 (s, 3H), 2.76 (t, 2H), 1.57 (m, 2H), 1.30 ~ 1.28 (m, 6H), 0.86 (t, 3H)

Example 28 (Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) ethyl nicotinate (Davigatran Etexylate Etopy Brate)

Step 1: 2-hydroxyethyl nicotinic acid hydrochloride

128 ml of ethylene glycol were cooled to -10 ° C. 16 ml of thionyl chloride was added dropwise to the reaction mixture. 24.6 g of niacin was added to the reaction mixture in eight portions, followed by stirring at 60 ° C. for 16 hours. After the completion of the reaction was added 1.7L hot tetrahydrofuran and cooled to room temperature and stirred. The resulting solid was filtered off and washed with diethyl ether. The filtrate was dried in vacuo at room temperature to obtain 20 g of 2-hydroxyethyl nicotinic acid hydrochloride.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.21 (d, 1H), 8.91 (dd, 1H), 8.54 (dd, 1H), 7.77 (q, 1H), 4.32 (t, 2H), 3.71 (t , 2H)

Step 2: Preparation of dabigatran etexilate etofibrate

920 mg of the title compound was obtained in the same manner as in Example 23, using 2 g of dabigatran etexilate sodium salt and 1.08 g of 2-hydroxyethyl nicotinic acid hydrochloride obtained in Step 1.

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.20 (d, 1H), 8.76 (dd, 1H), 8.41 (dd, 1H), 7.28 (dt, 1H), 7.78 (d, 2H), 7.70 (s, 1H ), 7.38 (dd, 1H), 7.33-7.29 (m, 2H), 7.11 (d, 1H), 6.98 (dd, 1H), 6,70 (t, 3H), 5.28 (t, 1H), 4.54- 4.39 (m, 8H), 4.13 (t, 2H), 3.72 (s, 3H), 2.88 (t, 2H), 1.72 (m, 2H), 1.42-1.29 (m, 6H), 0.88 (t, 3H)

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)

3 g of dabigatran etexilate sodium salt and 433 l of 1-chloroethyl ethyl carbonate were reacted in the same manner as in Step 2 of Example 19, to obtain 580 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.42 (dd, 1H), 7.79 (d, 2H), 7.71 (s, 1H), 7.35 ~ 7.30 (m, 2H), 7.14 (d, 1H), 6.99 (dd , 1H), 6,77-6.69 (m, 4H), 5.24 (t, 1H), 4.51 (d, 2H), 4.24 (t, 2H), 4.21 (q, 2H), 4.13 (t, 2H), 3.73 (s, 3H), 2.87 (t, 2H), 1.72 (m, 2H), 1.49 (d, 3H), 1.43 ~ 1.29 (m, 9H), 0.89 (t, 3H)

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)

Using 3 g of dabigatran etexilate sodium salt and 806 mg of 1-bromoethyl acetate, the reaction was carried out in the same manner as in Step 2 of Example 19, to obtain 1.27 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.43 (dd, 1H), 7.77 (d, 2H), 7.70 (s, 1H), 7.35-7.29 (m, 2H), 7.12 (d, 1H), 6.99 (q , 1H), 6.83 (q, 1H), 6.70 (d, 3H), 5.26 (t, 2H), 4.49 (d, 2H), 4.19 (t, 2H), 4.13 (t, 2H), 3.72 (s, 3H), 2.85 (t, 2H), 2.06 (s, 3H), 1.44 (d, 3H), 1.41-1.29 (m, 6H), 0.87 (t, 3H)

Example 31 (Z) -1-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) -2-methylpropyl isobutyrate (Dabigatran Etexyl Late Albacrofen Placaville)

Step 1: Preparation of 1-chloro-2-methylpropylisobutyrate

10 ml of isobutyryl chloride was cooled to −20 ° C. and 25 mg of zinc chloride was added thereto. 10.4 ml of isobutyralaldehyde was added to the reaction solution, followed by stirring at 0 ° C for 1 hour. After stirring for 2 hours at room temperature, the reaction solution was filtered using silica gel. The filtrate was evaporated under reduced pressure to give 11.3 g of 1-chloro-2-methylpropylisobutyrate.

¹ H NMR (CDCl ₃ , 400 MHz) δ 6.29 (d, 2H), 2.62 to 2.58 (m, 1H), 2.18 to 2.14 (m, 1H), 1.20 (d, 6H), 1.07 to 1.04 (m, 6H)

Step 2: Preparation of dabigatran etexilate albacrofen placaville

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.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.42 (dd, 1H), 7.80 (d, 2H), 7.72 (s, 1H), 7.37 ~ 7.31 (m, 2H), 7.15 (d, 1H), 7.00 (q , 1H), 6.74 to 6.72 (m, 3H), 6.63 (d, 1H), 5.23 (t, 1H), 4.53 (d, 2H), 4.41 (t, 2H), 4.14 (t, 2H), 3.75 ( s, 3H), 2.88 (t, 2H), 2.58-2.54 (m, 1H), 2.03-1.99 (m, 1H), 1.76-1.69 (m, 2H), 1.41-1.29 (m, 6H), 1.17 ( t, 6H), 0.96-0.87 (m, 9H)

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)

Using 3 g of dabigatran etexilate sodium salt and 627 l of 3-dimethylamino-1-propanol, the reaction was carried out in the same manner as in Example 23 to obtain 2.21 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.42 (dd, 1H), 7.79 (d, 2H), 7.71 (s, 1H), 7.35 ~ 7.32 (m, 2H), 7.14 (d, 1H), 6.99 (q , 1H), 6.71 (m, 3H), 5.22 (t, 1H), 4.51 (d, 2H), 4.26 (t, 2H), 4.13 (t, 2H), 4.07 (t, 2H), 3.74 (s, 3H), 2.83 (t, 2H), 2.32 (t, 2H), 2.21 (s, 6H), 1.80-1.69 (m, 4H), 1.42-1.29 (m, 6H), 0.89 (t, 3H)

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)

3 g of dabigatran etexilate sodium salt and 804 mg of 1-chloroethyl isopropyl carbonate were reacted in the same manner as in Step 2 of Example 19, to obtain 1.9 g of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.42 (dd, 1H), 7.77 (d, 2H), 7.70 (d, 1H), 7.35 ~ 7.29 (m, 2H), 7.12 (d, 1H), 6.99 (q , 1H), 6.76 to 6.07 (m, 4H), 5.28 (t, 2H), 4.88 (m, 1H), 4.50 (d, 2H), 4.42 (t, 2H), 4.13 (t, 2H), 3.72 ( s, 3H), 2.86 (t, 2H), 1.72 (m, 2H), 1.48 (d, 3H), 1.42-1.34 (m, 2H), 1.32-1.29 (m, 10H), 0.89 (t, 3H)

Example 34 2-Methyl-1- (propionyloxy) propyl (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 posi Nopril)

3 g of dabigatran etexilate sodium salt and 796 l of 1-chloro-2-methylpropyl propionate were reacted in the same manner as in Step 2 of Example 19 to obtain 290 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.39 (dd, 1H), 7.70 (d, 2H), 7.65 (d, 1H), 7.2 (td, 1H), 7.21 (dd, 1H), 7.02 to 6.95 (m , 2H), 6.69 (1H), 6.64 ~ 6.58 (m, 3H), 5.41 (t, 2H), 4.41 ~ 4.37 (m, 4H), 4.11 (t, 2H), 3.64 (s, 3H), 2.85 ( t, 2H), 2.33 (q, 2H), 2.01-1.96 (m, 1H), 1.72-1.66 (m, 2H), 1.42-1.29 (m, 6H), 1.12 (t, 3H), 0.94-0.85 ( m, 9H)

Example 35 (Z) -3-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) propyl nicotinate (Davigatran etexilate ronipi Brate)

Step 1: Preparation of 3-hydroxypropyl Nicotinate

Reaction was carried out in the same manner as in Step 1 of Example 28 using 27 ml of 1,3-propanediol to give 5 g of 3-hydroxypropyl nicotinate.

Step 2: Preparation of dabigatran etexilate lonifibrate

Using 3 g of dabigatran etexilate sodium salt and 1.75 g of 3-hydroxypropyl nicotinate prepared in Step 1, 340 mg of the title compound was obtained in the same manner as in Example 23.

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.20 (d, 1H), 8.77 (dd, 1H), 8.42 (dd, 1H), 8.28 (dt, 1H), 7.80 (d, 2H), 7.72 (s, 1H ), 7.39 (m, 1H), 7.34-7.31 (m, 2H), 7.16 (d, 1H), 6.98 (dd, 1H), 6.75-6.69 (m, 3H), 5.25 (t, 1H), 4.53 ( d, 2H), 4.46-4.41 (m, 4H), 4.21 (t, 2H), 4.14 (t, 2H), 3.75 (s, 3H), 2.84 (t, 2H), 2.10 (m, 2H), 1.73 (m, 2H), 1.43-1.31 (m, 6H), 0.89 (t, 3H)

Example 36 (Z) -1-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) ethyl isobutyrate mesylate (dabigatran etexilate en Nacaville mesylate)

270 mg of dabigatran etexilate ennacarbyl obtained in Example 19 was dissolved in 3 ml of ethanol and stirred. 24.5 l of methanesulfonic acid was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and 5 ml of diisopropyl ether was added to the concentrate, followed by stirring. The resulting solid was filtered under nitrogen and washed with 10 ml diisopropyl ether. The filtrate was dried in vacuo at room temperature to give 250 mg of the title compound.

NMR (DMSO-d ₆ , 400 MHz) δ 11.88 (s, 1H), 10.68 (br, 1H), 10.04 (s, 1H), 8.38 (dd, 1H), 7.63 (d, 3H), 7.55 (m, 1H ), 7.45 (d, 2H), 7.18-7.10 (m, 2H), 6.90 (d, 1H), 6.85 (d, 2H), 6.67 (q, 1H), 4.71 (s, 2H), 4.26-4.19 ( m, 4H), 3.78 (s, 3H), 2.72 (t, 2H), 2.28 (s, 3H), 1.66 (m, 2H), 1.36-1,28 (m, 9H), 1.04 (m, 6H) , 0.87 (t, 3H)

Example 37 ((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 mesylate (dabigatran etexilate Isoproxyl mesylate)

Reaction was carried out in the same manner as in Example 36, using 500 mg of dabigatran etexilate isoproxyl obtained in Example 22 to obtain 460 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.86 (s, 1H), 10.62 (br, 1H), 10.03 (s, 1H), 8.38 (dd, 1H), 7.63 (d, 3H), 7.53 (td , 1H), 7.46 (s, 1H), 7.41 (d, 1H), 7.16 ~ 7.10 (m, 2H), 6.90 ~ 6.84 (m, 3H), 5.62 (s, 2H), 4.79 (m, 1H), 4.68 (br, 2H), 4.26-4.19 (m, 4H), 3.76 (s, 3H), 2.77 (t, 2H), 2.28 (s, 3H), 1.66 (m, 2H), 1.38-1.28 (m, 6H), 1.22 (d, 6H), 0.87 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.90 (s, 1H), 10.71 (s, 1H), 10.07 (s, 1H), 8.37 (dd, 1H), 7.64 (d, 2H), 7.57 ~ 7.49 (m, 3H), 7.21 (d, 1H), 7.13 (q, 1H), 6.93 (d, 1H), 6.86 (d, 2H), 6.57 (q, 1H), 4.76 (s, 2H), 4.3 ( m, 1H), 4.25 (t, 2H), 4.20 (t, 2H), 3.81 (s, 3H), 3.59 (m, 1H), 2.73 (t, 2H), 2.29 (s, 3H), 1.79 (br) , 2H), 1.67 (m, 4H), 1.46-1.18 (m, 16H), 1.02 (d, 3H), 0.87 (t, 3H)

Example 39 ((t-butoxycarbonyl) oxy) 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 mesylate (Davigatran Etexyl Cladding mesylate)

Reaction was carried out in the same manner as in Example 36, using 1 g of the dabigatran etexilate coating chamber prepared in Example 21, to obtain 890 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.86 (s, 1H), 10.61 (s, 1H), 10.01 (s, 1H), 8.38 (dd, 1H), 7.63 (d, 2H), 7.54 (td , 1H), 7.46 (s, 1H), 7.41 (d, 1H), 7.16 ~ 7.10 (m, 2H), 6.89 (d, 1H), 6.85 (d, 2H), 5.64 (s, 2H), 4.68 ( d, 2H), 4.25-4.18 (m, 4H), 3,76 (s, 3H), 2.75 (t, 2H), 2.28 (s, 3H), 1.66 (m, 2H), 1.38-1.26 (m, 6H), 1.12 (s, 9H), 0.87 (t, 3H)

Example 40 (2E, 6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl 3- (2-(((4-((Z) -N ' -((Hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carbox Amido) Preparation of Propanoate Mesylate (Dabigatran Etexylate Panesyl Mesylate)

Reaction with the same method as in Example 36 using 300 mg of dabigatran etexilate farnesyl obtained in Example 23 to obtain 460 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.91 (s, 1H), 10.78 (s, 1H), 10.08 (s, 1H), 8.35 (dd, 1H), 7.67 ~ 7.53 (m, 5H), 7.27 (br, 1H), 7.13 (t, 1H), 6.98 (br, 1H), 6.88 (d, 2H), 5.22 (t, 1H), 5.04 (t, 2H), 4.84 (s, 2H), 4.45 ( d, 2H), 4.25 (t, 2H), 4.19 (t, 2H), 3,85 (s, 3H), 2.67 (d, 2H), 2.30 (s, 3H), 2.03-1.89 (m, 8H) , 1.70 to 1.53 (m, 14H), 1.38 to 1.24 (m, 6H), 0.87 (t, 3H)

Example 41 2-morpholinoethyl (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 mofetyl mesylate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.39 (d, 1H), 7.69 (d, 2H), 7.56 ~ 7.52 (m, 1H), 7.46 (s, 1H), 7.40 (d, 1H), 7.35 ( br, 1H), 7.15-7.10 (m, 2H), 6.90 (d, 1H), 6.80 (d, 2H), 4.64 (d, 2H), 4.22 (t, 2H), 4.16-4.4.11 (m, 4H), 3.75 (s, 3H), 3.65 (br, 4H), 2.94-2.66 (br, 6H), 2.29 (s, 3H), 1.62 (m, 2H), 1.36-1.27 (m, 6H), 0.86 (t, 3H)

Example 42 2- (dimethylamino) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl Preparation of 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate mesylate (dabigatran etexilate ciprodinate mesyl) Acid salts)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.39 (dd, 1H), 7.75 (d, 2H), 7.54 (td, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 7.14 to 7.11 ( m, 2H), 7.05 (br, 1H), 6.89 (d, 1H), 6.75 (d, 2H), 4.59 (d, 2H), 4.25 (m, 4H), 3.99 (t, 2H), 3.75 (s , 3H), 2.76 (m, 8H), 2.29 (s, 3H), 1.58 (m, 2H), 1.31 (m, 6H), 0.85 (t, 3H)

Example 43 2,3-dihydro-1H-inden-5-yl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbonamido) I) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate mesylate (Davigatran Etexilate carindacillin mesylate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.88 (s, 1H), 10.68 (s, 1H), 10.05 (s, 1H), 8.41 (dd, 1H), 7.63 (d, 3H), 7.58 ~ 7.54 ( m, 2H), 7.48 (br, 2H), 7.20 (m, 2H), 7.14 (dd, 1H), 6.94 (d, 1H), 6.87 (m, 3H), 6.79 (dd, 1H), 4.72 (s , 2H), 4.34 (t, 2H), 4.25 (t, 2H), 3.78 (s, 3H), 2.93 (t, 2H), 2.82 (q, 4H), 2.28 (s, 3H), 2.00 (m, 2H), 1.66 (m, 2H), 1.38-1.28 (m, 6H), 0.87 (t, 3H)

Example 44 (Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) acetic acid mesylate (Dabigatran etexilate acemethacin Mesylate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.88 (s, 1H), 10.68 (s, 1H), 10.04 (s, 1H), 8.39 (dd, 1H), 7.63 (d, 3H), 7.57 ~ 7.53 ( m, 2H), 7.48 (br, 2H), 7.27 (d, 1H), 7.12 (dd, 1H), 6.94 (d, 1H), 6.86 (m, 2H), 4.71 (s, 2H), 4.50 (s , 2H), 4.23 (m, 4H), 3.78 (s, 3H), 2.77 (t, 2H), 2.28 (s, 3H), 1.66 (m, 2H), 1.38-1.28 (m, 6H), 0.87 ( t, 3H)

Example 45 (Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) ethyl nicotinate mesylate (dabigatran etexilate Etofibrate mesylate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.87 (br, 1H), 10.66 (s, 1H), 10.03 (s, 1H), 9.06 (d, 1H), 8.80 (dd, 1H), 8.35 (dd , 1H), 8.25 (dt, 1H), 7.63 (d, 3H), 7.55-7.48 (m, 2H), 7.45 (s, 1H), 7.39 (d, 1H), 7.15-7.08 (m, 2H), 6.86 (t, 3H), 4.69 (br, 2H), 4.47 (m, 2H), 4.32 (m, 2H), 4.26-4.19 (m, 4H), 3.76 (s, 3H), 2.71 (t, 2H) , 2.28 (s, 3H), 1.66 (m, 2H), 1.38 ~ 1.28 (m, 6H), 1.02 (d, 1H), 0.86 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.87 (s, 1H), 10.67 (s, 1H), 10.04 (s, 1H), 8.38 (dd, 1H), 7.63 (d, 3H), 7.54 (td , 1H), 7.44 (m, 2H), 7.177.10 (m, 2H), 6.91-6.84 (m, 3H), 6.57 (q, 1H), 4.70 (s, 2H), 4.26-4.19 (m, 4H ), 4.13 (q, 2H), 3.77 (s, 3H), 2.73 (t, 3H), 2.28 (s, 3H), 1.67 (m, 2H), 1.39-1.28 (m, 9H), 1.19 (t, 3H), 0.87 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.87 (s, 1H), 10.64 (s, 1H), 10.02 (s, 1H), 8.38 (dd, 1H), 7.63 (d, 3H), 7.54 (td , 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.16-7.10 (m, 2H), 6.89 (d, 1H), 6.85 (d, 2H), 6.67 (q, 1H), 4.69 ( br, 2H), 4.36-4.18 (m, 4H), 3.76 (s, 2H), 2.71 (t, 2H), 2.28 (s, 3H), 2.00 (s, 3H), 1.66 (m, 2H), 1.38 ~ 1.28 (m, 9H), 0.87 (t, 3H)

Example 48 3- (dimethylamino) propyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl Preparation of 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate mesylate (dabigatran etexilate clopibride mesyl) Acid salts)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.38 (dd, 1H), 7.76 (d, 2H), 7.54 (td, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 7.14-7.10 ( m, 2H), 7.03 (br, 1H), 6.88 (d, 1H), 6.75 (d, 2H), 4.59 (d, 2H), 4.22 (t, 2H), 4.02-3.97 (m, 4H), 3.75 (s, 3H), 3.07 (t, 2H), 2.74 (s, 6H), 2.70 (t, 2H), 2.30 (s, 3H), 1.89 (m, 2H), 1.57 (m, 2H), 1.27 ( m, 6H), 0.85 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.86 (s, 1H), 10.65 (s, 1H), 10.02 (s, 1H), 8.38 (dd, 1H), 7.63 (d, 3H), 7.54 (td , 1H), 7.46 (s, 1H), 7.42 (d, 1H), 7.16 ~ 7.10 (m, 2H), 6.90 ~ 6.84 (m, 3H), 6.57 (q, 1H), 4.76 (m, 1H), 4.69 (br, 2H), 4.26-4.18 (m, 4H), 3.77 (s, 3H), 2.73 (t, 2H), 2.28 (s, 3H), 1.66 (m, 2H), 1.38-1.26 (m, 9H), 1.20 (dd, 6H), 0.87 (t, 3H)

Example 50 2-Methyl-1- (propionyloxy) propyl (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 posinopril mesylate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.86 (s, 1H), 10.67 (s, 1H), 10.04 (s, 1H), 8.37 (dd, 1H), 7.63 (d, 2H), 7.55 (td , 1H), 7.47-7.43 (m, 1H), 7.16 (d, 1H), 7.12 (dd, 1H), 6.92 (d, 1H), 6.86 (d, 2H), 6.51 (d, 1H), 4.71 ( s, 2H), 4.25 (t, 2H), 4.20 (t, 2H), 3.78 (s, 3H), 2.74 (t, 2H), 2.36-2.28 (m, 5H), 1.95-1.90 (m, 1H) , 1.70-1.63 (m, 2H), 1.38-1.28 (m, 6H), 1.00 (t, 3H), 0.88-0.86 (m, 6 H)

Example 51 (Z) -3-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1 Preparation of -methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) propyl nicotinate mesylate (dabigatran etexilate Ronifibrate mesylate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.87 (s, 1H), 10.67 (s, 1H), 10.04 (s, 1H), 9.07 (d, 1H), 8.80 (dd, 1H), 8.36 (d, 1H), 8.28 (m, 1H), 7.62 (d, 2H), 7.57 to 7.50 (m, 2H), 7.45 (s, 1H), 7.41 (d, 1H), 7.14 (d, 1H), 7.08 (q , 1H), 6.86 (m, 3H), 4.69 (s, 2H), 4.34 (t, 2H), 4.26-4.18 (m, 4H), 4.10 (t, 2H), 3.76 (s, 3H), 2.67 ( t, 2H), 2.28 (s, 3H), 1.99 (m, 2H), 1.66 (m, 2H), 1.36-1.28 (m, 6H), 0.86 (t, 3H)

Example 52 Ethyl 3- (1-methyl-2-(((4- (N-(((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl ) Carbamididoyl) phenyl) amino) methyl) -N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate Preparation (Davigatran Medoc Roughness)

Step 1: Preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (4-nitrophenyl) carbonate

10 g of 4-nitrophenyl chloroformate was added thereto, dissolved in 10 ml of dichloromethane, and cooled to 0 ° C. and stirred. 500 mg of 4- (hydroxymethyl) -5-methyl-1,3-dioxol-2-one and 223 l of pyridine were added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction product was extracted by adding 10 wt% aqueous citric acid solution and dichloromethane. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 320 mg of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (4-nitrophenyl) carbonate.

¹ H NMR (CDCl ₃ , 400 MHz) 8.31 (dd, 2H), 7.41 (dd, 1H), 5.04 (s, 2H), 2.22 (s, 3H)

Step 2: Preparation of dabigatran medoxomill

320 mg of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (4-nitrophenyl) carbonate obtained in step 1 was dissolved in 10 ml of tetrahydrofuran and stirred at room temperature. 1-Methyl-2- [N- (4-amidinophenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxy 582 mg of carbonylethyl) -amide-hydrochloride and 453 l of triethylamine were added thereto, followed by stirring at room temperature for two days. After the reaction was completed, the reaction was extracted by adding water and dichloromethane. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was solidified with methyl t-butyl ether to give 530 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.43 (dd, 1H), 7.77 (d, 2H), 7.70 (s, 1H), 7.35-7.30 (m, 2H), 7.11 (d, 1H), 6.99 (q, 1H), 6.70 (m, 3H), 5.34 (t, 1H), 4.91 (s, 2H), 4.90 (d, 2H), 4.07 (q, 2H), 3.72 (s, 3H), 2.82 (t, 2H ), 2.19 (s, 3H), 1.22 (t, 3H)

Example 53 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 (Dabigatran Panesil)

Step 1: Preparation of 4-nitrophenyl ((2E, 6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl) carbonate

Reaction was carried out in the same manner as in Step 1 of Example 52, using 12.4 ml of farnesol, to obtain 4-nitrophenyl ((2E, 6E) -3,7,11-trimethyldodeca-2,6,10-triene-1 17.68 g of carbonate were obtained.

¹ H NMR (CDCl ₃ , 400 MHz) 8.27 (d, 2H), 7.38 (d, 2H), 5.45 (t, 1H), 5.11-5.07 (m, 2H), 4.81-4.76 (m, 2H), 2.18- 1.96 (m, 8H), 1.81-1.60 (m, 12H)

Step 2: Preparation of Dabigatran Panesil

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.

¹ H NMR (CDCl ₃ , 600 MHz) 8.41 (dd, 1H), 7.75 (d, 2H), 7.69 (s, 1H), 7.33 (td, 1H), 7.28 (d, 1H), 7.09 (d, 1H) , 6.98 (q, 1H), 6.70 (d, 1H), 6.66 (d, 2H), 5.47 (br, 1H), 5.33 (s, 1H), 5.12-5.08 (m, 2H), 4.69-4.65 (m , 2H), 4.46 (d, 2H), 4.42 (t, 2H), 4.07 (q, 2H), 3.70 (s, 3H), 2.80 (t, 2H), 2.14 ~ 1.95 (m, 8H), 1.76 ~ 1.59 (m, 12H), 1.21 (t, 3H)

Example 54 Ethyl 3- (2-(((4- (N-((2- (dimethylamino) ethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl- Preparation of N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (dabigatran cyprodinate)

Step 1: Preparation of 2- (dimethylamino) ethyl (4-nitrophenyl) carbonate hydrochloride

500 l of 2-dimethylaminoethanol was dissolved in 10 ml of diethyl ether. 1 g of 4-nitrophenyl chloroformate was dissolved in 10 ml of diethyl ether and added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 3 hours, and the resulting solid was filtered and washed with 10 ml of diethyl ether. 1.1 g of 2- (dimethylamino) ethyl (4-nitrophenyl) carbonate was obtained after vacuum drying at room temperature.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.11 (d, 2H), 6.93 (d, 2H), 3.69 (br, 2h), 3.10 (t, 2H), 2.74 (s, 6H)

Step 2: Preparation of Dabigatran Cyprodinate

500 mg of 2- (dimethylamino) ethyl (4-nitrophenyl) carbonate hydrochloride obtained in step 1 was reacted in the same manner as in Step 2 of Example 52, to obtain 270 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.38 (dd, 1H), 7.65 (d, 2H), 7.61 (d, 1H), 7.32 ~ 7.28 (m, 1H), 7.17 (dd, 1H), 6.97 ~ 6.94 ( m, 2H), 6.61 (d, 1H), 6.51 (d, 2H), 5.50 (br, 1H), 4.39 (t, 2H), 4.33 (s, 2H), 4.21 (t, 2H), 4.04 (q , 2H), 3.59 (s, 3H), 2.76 (t, 2H), 2.63 (t, 2H), 2.27 (s, 6H), 1.1 (t, 3H)

Example 55 Ethyl 3- (2-(((4- (N-((3- (dimethylamino) propoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl- Preparation of N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (dabigatran clopibride)

Step 1: Preparation of 3- (dimethylamino) propyl (4-nitrophenyl) carbonate hydrochloride

Reaction was carried out in the same manner as in Step 1 of Example 52, using 1.17 ml of 3-dimethylamino-1-propanol to give 2 g of 3- (dimethylamino) propyl (4-nitrophenyl) carbonate hydrochloride.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.11 (d, 2H), 6.93 (d, 2H), 3.47 (m, 2h), 3.06 (t, 2H), 2.07 (s, 6H), 1.78 (br, 2H)

Step 2: Preparation of Dabigatran Clofibride

Using 1 g of 3- (dimethylamino) propyl (4-nitrophenyl) carbonate hydrochloride obtained in step 1, the reaction was carried out in the same manner as in Step 2 of Example 52, to obtain 840 mg of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) 8.43 (dd, 1H), 8.31 (dt, 1H), 7.77 (d, 2H), 7.71 (d, 1H), 7.35-7.30 (m, 3H), 7.12 (d, 1H), 6.98 (q, 1H), 6.71 (d, 3H), 5.25 (t, 1H), 4.49 (d, 4H), 4.43 (t, 2H), 4.19 (m, 2H), 4.07 (q, 2H) ), 3.72 (s, 3H), 2.81 (t, 2H), 2.41 (t, 2H), 2.24 (s, 6H), 1.91 (m, 2H), 1.21 (t, 3H)

Example 56 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 (dabigatran ronifibrate)

Step 1: 3-(((4-nitrophenoxy) carbonyl) oxy) propyl nicotinate

159 mg of 3-(((4-nitrophenoxy) carbonyl) oxy) propyl nicotinate was obtained by reaction in the same manner as in Step 1 of Example 52, using 1.17 ml of 3-hydroxypropyl nicotinic acid.

¹ H NMR (CDCl ₃ , 400 MHz) 9.19 (s, 1H), 8.75 (s, 1H), 8.27-8.19 (m, 3H), 7.40-7.31 (m, 3H), 4.51-4.20 (m, 4H), 2.47-2.21 (m, 2H)

Step 2: Preparation of dabigatran lonifibrate

159 mg of the title compound was obtained in the same manner as in Step 1 of 52, using 159 mg of 3-(((4-nitrophenoxy) carbonyl) oxy) propyl nicotinate obtained in Step 1 above.

¹ H NMR (CDCl ₃ , 400 MHz) 9.23 (d, 1H), 8.75 (dd, 1H), 8.42 (dd, 1H), 8.31 (dt, 1H), 7.77 (d, 2H), 7.72 (s, 1H) , 7.37 ~ 7.32 (m, 3H), 7.14 (d, 1H), 6.99 (q, 1H), 6.72 (m, 3H), 5.28 (t, 1H), 4.52 (m, 4H), 4.43 (t, 2H ), 4.34 (t, 2H), 4.07 (q, 2H), 3.74 (s, 3H), 2.81 (t, 2H), 2.23 (m, 2H), 2.19 (s, 3H), 1.21 (t, 3H)

Example 57 Ethyl 3- (1-methyl-2-(((4- (N-(((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl ) Carbamimidoyl) phenyl) amino) methyl) -N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate mesylate Tran Medoxomil Mesylate)

200 mg of dabigatran medoxomil obtained in Example 52 was dissolved in 2 ml of dichloromethane and stirred. 10 l of methanesulfonic acid was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and 5 ml of diisopropyl ether was added to the concentrate, followed by stirring. The resulting solid was filtered under nitrogen and washed with 10 ml diisopropyl ether. The filtrate was dried in vacuo at room temperature to give 232 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 10.85 (br, 1H), 10.01 (br, 1H), 8.37 (dd, 1H), 7.64 (d, 2H), 7.55 (td, 1H), 7.46 (m, 2H), 7.18 (d, 1H), 7.11 (dd, 1H), 6.90 (d, 1H), 6.85 (d, 2H), 5.20 (s, 2H), 4.71 (s, 2H), 4.20 (t, 2H) ), 3.95 (q, 2H), 3.78 (s, 3H), 2.67 (t, 2H), 2.28 (s, 3H), 2.21 (s, 3H), 1.10 (t, 3H)

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)

Reaction was carried out in the same manner as in Example 57, using 500 mg of dabigatran farnesyl obtained in Example 53 to obtain 460 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 600 MHz) 11.89 (s, 1H), 10.68 (br, 1H), 10.05 (s, 1H), 8.37 (dd, 1H), 7.62 (d, 2H), 7.54 (td, 1H), 7.46-7.43 (m, 2H), 7.16 (d, 1H), 7.10 (dd, 1H), 6.89 (d, 1H), 6.85 (d, 2H), 5.39 (t, 1H), 5.08-5.02 (m, 2H), 4.79 (d, 2H), 4.70 (s, 2H), 4.21 (t, 2H), 3.96 (q, 2H), 3.77 (s, 3H), 2.67 (t, 2H), 2.28 ( s, 3H), 2.14-1.90 (m, 8H), 1.76-1.53 (m, 12H), 1.11 (t, 3H)

Example 59 Ethyl 3- (2-(((4- (N-((2- (dimethylamino) ethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl- Preparation of N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate mesylate (dabigatran cyprodinate mesylate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.38 (dd, 1H), 7.80 (d, 2H), 7.52 (td, 1H), 7.46 (s, 2H), 7.39 (d, 1H), 7.15-7.09 ( m, 3H), 6.88 (d, 1H), 6.77 (d, 2H), 4.59 (d, 2H), 4.32 (br, 2H) 4.21 (t, 2H), 3.95 (q, 2H), 3.75 (s, 3H), 2.81 (m, 8H), 2.67 (t, 2H), 2.29 (s, 3H), 1.11 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.37 (dd, 1H), 7.79 (d, 2H), 7.54 (td, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 7.15-7.09 ( m, 2H), 7.00 (br, 1H), 6.87 (d, 1H), 6.75 (d, 2H), 4.58 (d, 2H), 4.21 (t, 2H) 4.04 (t, 2H), 3.95 (q, 2H), 3.75 (s, 3H), 3.05 (br, 2H), 2.72 (s, 6H), 2.67 (t, 2H), 2.28 (s, 3H), 1.93 (m, 2H), 1.11 (t, 3H )

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)

127 mg of dabigatran ronifibrate obtained in Example 56 was used to obtain 100 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.88 (s, 1H), 10.66 (s, 1H), 10.02 (s, 1H), 9.11 (d, 1H), 8.80 (dd, 1H), 8.30 (dt, 1H), 7.64 to 7.52 (m, 5H), 7.45 (m, 2H), 7.16 (d, 1H), 7.11 (dd, 1H), 6.90 (d, 1H), 6.85 (d, 2H), 4.70 (s , 2H), 4.44 (t, 4H) 4.20 (t, 2H), 3.95 (q, 2H), 3.77 (s, 3H), 2.67 (t, 2H), 2.28 (s, 3H), 2.17 (m, 2H ), 1.10 (t, 3H)

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)

250 mg of dabigatran etexilate cilexetil obtained in Example 20 was added to a 25 mL flask, followed by stirring with diethyl ether. 75.5 mg of (+)-(1S) -campo-10-sulfonic acid was added to the reaction solution, followed by stirring at room temperature for 3 hours. No solid was produced so isopropyl ether was added. After filtration of the resulting solid to give 310mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.87 (br, 1H), 10.60 (br, 1H), 9.99 (s, 1H), 8.38 (dd, 1H), 7.64 to 7.59 (m, 3H), 7.54 ( td, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.15-7.10 (m, 2H), 6.90-6.84 (m, 3H), 6.57 (q, 1H), 4.67 (d, 2H) , 4.53 (m, 1H), 4.24-4.18 (m, 4H), 3.76 (s, 3H), 2.84 (d, 1H), 2.74-2.66 (m, 3H), 2.34 (d, 1H), 2.23 (de , 1H), 1.91 (t, 1H), 1.83-1.75 (m, 4H), 1.69-1.62 (m, 4H), 1.43-1.19 (m, 18H), 1.03 (d, 3H), 0.86 (t, 3H ), 0.72 (s, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 600 MHz) 8.38 (dd, 1H), 7.76 (d, 2H), 7.53 (td, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.15-7.10 ( m, 2H), 6.87 (d, 1H), 6.76 (d, 2H), 6.57 (q, 1H), 4.59 (d, 2H), 4.53 (m, 1H), 4.20 (t, 3H), 3.99 (br) , 2H), 3.75 (s, 3H), 2.75 ~ 2.72 (m, 6H), 1.80 (br, 2H), 1.59 ~ 1.53 (m, 4H), 1.47 ~ 1.19 (m, 14H), 0.86 (t, 3H )

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.38 (dd, 1H), 7.78 (d, 2H), 7.53 (td, 1H), 7.46 (d, 1H), 7.38 (d, 1H), 7.14 (dd, 1H), 7.13-7.10 (m, 1H), 6.94 (t, 1H), 6.88 (d, 1H), 6.75 (d, 2H), 6.61 (s, 2H), 6.57 (q, 1H), 4.58 (d , 2H), 4.53 (m, 1H), 4.20 (t, 3H), 3.96 (t, 2H), 3.75 (s, 3H), 2.73 (t, 2H), 1.80 (br, 2H), 1.60-1.53 ( m, 4H), 1.47-1.21 (m, 14H), 0.86 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.38 (dd, 1H), 7.77 (d, 2H), 7.53 (td, 1H), 7.45 (s, 1H), 7.39 (d, 1H), 7.15-7.10 ( m, 2H), 7.00 (br, 1H), 6.87 (d, 1H), 6.75 (d, 2H), 6.57 (q, 1H), 4.59 (d, 2H), 4.53 (m, 1H), 4.19 (br) , 3H), 3.97 (t, 2H), 3.75 (s, 3H), 2.73 (t, 2H), 1.80 (br, 2H), 1.59 ~ 1.54 (m, 4H), 1.42 ~ 1.21 (m, 14H), 0.86 (t, 3 H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.38 (dd, 1H), 7.75 (d, 2H), 7.53 (td, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.15-7.06 ( m, 4H), 6.88 (d, 1H), 6.77 (d, 2H), 6.57 (q, 1H), 4.59 (d, 2H), 4.53 (m, 1H), 4.20 (t, 3H), 4.02 (t , 2H), 3.75 (s, 3H), 3.13 (s, 2H), 2.73 (t, 2H), 1.80 (br, 2H), 1.59 ~ 1.53 (m, 4H), 1.47 ~ 1.19 (m, 14H), 0.86 (t, 3 H)

Example 67 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 ororate Dabigatran etexilate cilexetil ororate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.14 (s, 1H), 10.33 (s, 1H), 9.48 (br, 1H), 8.38 (dd, 1H), 7.73 (d, 2H), 7.53 (td, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 7.18-7.10 (m, 3H), 6.88 (d, 1H), 6.79 (d, 2H), 6.57 (q, 1H), 5.87 (s , 1H), 4.62 (d, 2H), 4.54 (m, 1H), 4.20 (t, 3H), 4.07 (t, 2H), 3.76 (s, 3H), 2.73 (t, 2H), 1.81 (br, 2H), 1.62-1.57 (m, 4H), 1.43-1.18 (m, 14H), 0.86 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.38 (dd, 1H), 7.75-7.73 (m, 3H), 7.53 (td, 1H), 7.46 (d, 1H), 7.39 (m, 2H), 7.15- 7.10 (m, 3H), 6.89 ~ 6.76 (m, 4H), 6.57 (q, 1H), 4.60 (d, 2H), 4.53 (m, 1H), 4.20 (t, 3H), 4.03 (t, 2H) , 3.75 (s, 3H), 2.73 (t, 2H), 1.80 (br, 2H), 1.61 ~ 1.55 (m, 4H), 1.43 ~ 1.21 (m, 14H), 0.86 (t, 3H)

Example 69 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 Tartarate (Dabigatran Etexylate Silecetyl (+)-L-Tartrate)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.39 (dd, 1H), 7.77 (d, 2H), 7.53 (td, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 7.15-7.10 ( m, 2H), 6.99 (br, 1H), 6.87 (d, 1H), 6.75 (d, 2H), 6.57 (q, 1H), 4.59 (d, 2H), 4.53 (m, 1H), 4.27 (s , 2H), 4.20 (t, 3H), 3.97 (t, 2H), 3.75 (s, 3H), 2.73 (t, 2H), 1.80 (br, 2H), 1.59-1.53 (m, 4H), 1.42- 1.18 (m, 14H), 0.86 (t, 3H)

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.

¹ H NMR (DMSO-d ₆ , 600 MHz) 8.38 (dd, 1H), 7.75 (d, 2H), 7.53 (td, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.14 (dd, 1H), 7.10 (dd, 1H), 7.06 (br, 1H), 6.87 (d, 1H), 6.76 (d, 2H), 5.34 (t, 1H), 5.08 (br, 1H), 5.04 (t, 1H ), 4.59 (d, 2H), 4.53 (m, 2H), 4.21 (t, 2H), 3.96 (q, 2H), 3.75 (s, 3H), 2.72-2.60 (m, 6H), 2.09-1.90 ( m, 8H), 1.72-1.53 (m, 12H), 1.11 (t, 3H)

Example 71 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 (+)-L-Tartrate (Dabigatran Panesyl (+)-L-Tartrate)

Using the dabigatran farnesyl 500mg obtained in Example 53 in the same manner as in Example 69 to obtain the title compound 360mg.

¹ H NMR (DMSO-d ₆ , 600 MHz) 8.38 (dd, 1H), 7.77 (d, 2H), 7.53 (td, 1H), 7.45 (s, 1H), 7.39 (d, 1H), 7.14 (dd, 1H), 7.10 (dd, 1H), 6.99 (br, 1H), 6.87 (d, 1H), 6.75 (d, 2H), 5.33 (t, 1H), 5.08 (br, 1H), 5.04 (t, 1H ), 4.58 (d, 2H), 4.51 (m, 2H), 4.27 (s, 2H), 4.21 (t, 2H), 3.95 (q, 2H), 3.75 (s, 3H), 2.67 (t, 2H) , 2.07-1.90 (m, 8H), 1.71-1.53 (m, 12H), 1.11 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.37 (dd, 1H), 7.67 (d, 2H), 7.54 (td, 1H), 7.46 (m, 2H), 7.18 (d, 1H), 7.11 (dd, 1H), 6.91 (d, 1H), 6.84 (d, 2H), 5.86 (s, 2H), 4.70 (s, 2H), 4.21 (t, 2H), 3.96 (q, 2H), 3.78 (s, 3H ), 3.59 (m, 1H), 2.84 (d, 1H), 2.72-2.65 (m, 3H), 2.34 (d, 1H), 2.21 (dt, 1H), 1.92 (t, 1H), 1.84-1.76 ( m, 1H), 1.26 (q, 2H), 1.17 (s, 9H), 1.11 (t, 3H), 1.04 to 1.02 (m, 10H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.37 (dd, 1H), 7.81 (d, 2H), 7.53 (td, 1H), 7.45 (s, 1H), 7.39 (d, 1H), 7.15 (dd, 1H), 7.10 (dd, 1H), 7.04 (br, 1H), 6.87 (d, 1H), 6.76 (d, 2H), 5.71 (s, 2H), 4.60 (d, 2H), 4.21 (t, 2H) ), 3.96 (q, 2H), 3.75 (s, 3H), 2.76-2.62 (m, 6H), 1.13-1.09 (m, 12H)

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 )

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.38 (dd, 1H), 7.83-7.77 (m, 2H), 7.53 (td, 1H), 7.45 (s, 1H), 7.39 (d, 1H), 7.14 ( dd, 1H), 7.11 (dd, 1H), 7.02 (t, 1H), 6.87 (d, 1H), 6.76 (d, 2H), 5.71 (s, 2H), 4.59 (d, 2H), 4.21 (t , 2H), 3.96 (q, 2H), 3.75 (s, 3H), 2.67 (t, 2H), 2.61-2.38 (m, 2H), 1.13-1.09 (m, 12H)

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)

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.

¹ H NMR (DMSO-d ₆ , 600 MHz) 10.06 (br, 1H), 8.37 (d, 1H), 7.95 (m, 1H), 7.89 (m, 1H), 7.84 (d, 1H), 7.70 ~ 7.65 ( m, 4H), 7.56 (td, 1H), 7.51-7.49 (m, 4H), 7.21 (d, 1H), 7.12 (dd, 1H), 6.95 (d, 1H), 6.86 (d, 2H), 4.75 (s, 2H), 4.21 (t, 2H), 3.96 (q, 2H), 3.80 (s, 3H), 2.67 (t, 2H), 1.17 (s, 9H), 1.11 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.26 (s, 1H), 10.71 (s, 1H), 8.37 (dd, 1H), 7.80 (d, 2H), 7.53 (td, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 7.16-7.09 (m, 3H), 6.88 (d, 1H), 6.77 (d, 2H), 5.95 (s, 1H), 5.73 (s, 2H), 4.60 (d , 2H), 4.21 (t, 2H), 3.96 (q, 2H), 3.75 (s, 3H), 2.67 (t, 2H), 1.13 (s, 9H), 1.11 (t, 3H)

Example 77 Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) Amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (+)-(1S) -campo-10- Preparation of Sulfonate (Davigatran Carindacillin (+)-(1S) -Campo-10-Sulfonate)

300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 9 ml of chloroform, and stirred. 106 mg of (+)-(1S) -campo-10-sulfonic acid was added to the reaction solution, followed by stirring at room temperature for 2 hours. 12 ml of diisopropyl ether was added dropwise to the reaction solution, followed by concentration under reduced pressure. The concentrate was dispersed in 9 ml of diisopropyl ether and stirred at room temperature for 1 hour. The resulting solid was washed with diisopropyl ether, filtered and dried to give 398 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.37 (d, 1H), 7.73 (d, 2H), 7.62 ~ 7.52 (m, 2H), 7.47 (s, 1H), 7.43 (d, 1H), 7.18 ~ 7.10 (m, 3H), 7.01 (d, 1H), 6.91 ~ 6.84 (m, 3H), 4.70 (s, 2H), 4.21 (t, 2H), 3.96 (q, 2H), 3.78 (s, 3H) , 2.86 (q, 4H), 2.72-2.65 (m, 3H), 2.34 (d, 1H), 2.22 (dt, 1H), 2.09-2.01 (m, 2H), 1.93-1.90 (m, 1H), 1.87 ~ 1.76 (m, 2H), 1.28-1.21 (m, 2H), 1.11 (t, 3H), 1.03 (t, 3H), 0.73 (s, 3H)

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 )

300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 3 ml of chloroform, and stirred. 96 mg of citric acid was added to the reaction solution and stirred at room temperature. After 1 hour, 6 ml of diisopropyl ether was added to the thickened solution, and the mixture was stirred for 16 hours. The resulting solid was filtered and dried to give 328 mg of the title compound.

¹ H NMR (DMS0-d ₆ , 400 MHz) δ 9.12 (br, 1H), 8.38 (d, 1H), 7.82 (d, 2H), 7.54 (td, 1H), 7.47 (s, 1H), 7.39 (d , 1H), 7.17 (td, 2H), 7.11 (dd, 1H), 7.03 (t, 1H), 6.96 (s, 1H), 6.88 (d, 1H), 6.84 (d, 1H), 6.77 (d, 2H), 4.60 (d, 2H), 4.22 (t, 2H), 3.96 (q, 2H), 3.76 (s, 3H), 2.83 (q, 4H), 2.81-2.61 (m, 6H), 2.06-1.99 (m, 2H), 1.11 (t, 3H)

Example 79 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 fumarate (dabigatran carindacillin fumarate )

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.

¹ H NMR (DMS0-d ₆ , 400 MHz) δ 8.35 (ddd, 1H), 7.79 (d, 2H), 7.52 (td, 1H), 7.46 (d, 1H), 7.37 (d, 1H), 7.18 ~ 7.09 (m, 3H), 6.99 (t, 1H), 6.93 (s, 1H), 6.87 (d, 1H), 6.81 (d, 1H), 6.75 (d, 2H), 6.60 (s, 2H), 4.58 ( d, 2H), 4.18 (t, 2H), 3.91 (q, 2H), 2.81 (q, 4H), 2.64 (t, 2H), 2.04-1.98 (m, 2H), 1.08 (t, 3H)

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)

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.

¹ H NMR (DMS0-d ₆ , 400 MHz) δ 8.38 (d, 1H), 7.82 (d, 2H), 7.53 (td, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 7.19 ~ 7.09 (m, 3H), 7.01 (t, 1H), 6.95 (s, 1H), 6.89-6.83 (m, 2H), 6.77 (d, 2H), 4.60 (d, 2H), 4.23-4.17 (m, 3H) ), 3.96 (q, 2H), 3.76 (s, 3H), 2.83 (q, 4H), 2.67 (t, 2H), 2.58 (dd, 1H), 2.40 (dd, 1H), 2.06-1.99 (m, 2H), 1.11 (t, 3H)

Example 81 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 malonate (dabigatran carindacillin malone) Acid salts)

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.

¹ H NMR (DMS0-d ₆ , 400 MHz) δ 8.38 (d, 1H), 7.82 (d, 2H), 7.53 (td, 1H), 7.46 (s, 1H), 7.39 (d, 1H), 7.19 ~ 7.09 (m, 3H), 7.04 (t, 1H), 6.96 (s, 1H), 6.89-6.83 (m, 2H), 6.77 (d, 2H), 4.60 (d, 2H), 4.21 (t, 2H), 3.94 (q, 2H), 3.76 (s, 3H), 3.16 (s, 2H), 2.83 (q, 4H), 2.67 (t, 2H), 2.06-1.99 (m, 2H), 1.11 (t, 3H)

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)

300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 9 ml of chloroform, and stirred. 135.3 mg of 2-naphthalenesulfonic acid was added to the reaction solution and stirred at room temperature for 1 hour. 7 ml of diisopropyl ether was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour to form a solid, which was concentrated under reduced pressure. The concentrate was dispersed in 6 ml of diisopropyl ether and stirred at room temperature for 1 hour. The resulting solid was washed with diisopropyl ether, filtered and dried to give 347 mg of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) 10.68 (br, 1H), 10.00 (br, 1H), 8.37 (d, 1H), 8.13 (s, 1H), 7.95 (dd, 1H), 7.89 (dd, 1H), 7.86 (d, 1H), 7.74-7.61 (m, 4H), 7.58-7.46 (m, 4H), 7.29 (d, 1H), 7.19 (d, 1H), 7.15 (s, 1H), 7.12 (dt, 1H), 7.03 (d, 1H), 6.30-6.84 (m, 3H), 4.74 (s, 2H), 4.20 (t, 2H), 3.94 (q, 2H), 3.80 (s, 3H), 2.87 (q, 4H), 2.68 (t, 2H), 2.09-2.01 (m, 2H), 1.11 (t, 3H)

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) )

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 9.05 (d, 1H), 8.75 (d, 1H), 8.38 (dd, 1H), 8.24 (dd, 1H), 7.82 (d, 2H), 7.54 (qd, 2H), 7.46 (s, 1H), 7.39 (d, 1H), 7.16 (t, 2H), 7.11 (td, 1H), 7.01 (t, 1H), 6.96 (s, 1H), 6.88 (d, 1H) ), 6.83 (dd, 1H), 6.77 (d, 2H), 4.59 (d, 2H), 4.21 (t, 2H), 3.96 (q, 2H), 3.76 (s, 3H), 2.83 (q, 4H) , 2.67 (t, 2H), 2.06-1.99 (m, 2H), 1.11 (t, 3H)

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)

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.

¹ H NMR (DMSO-d ₆ , 400 MHz) 11.23 (br, 1H), 10.61 (br, 1H), 9.22 (br, 1H), 8.38 (dd, 1H), 7.81 (d, 2H), 7.53 (td, 1H), 7.46 (dd, 1H), 7.40 (d, 1H), 7.20-7.10 (m, 4H), 6.99 (s, 1H), 6.87 (t, 2H), 6.79 (d, 2H), 5.93 (d , 1H), 4.61 (d, 2H), 4.21 (t, 2H), 3.96 (q, 2H), 3.76 (s, 3H), 2.84 (q, 4H), 2.67 (t, 2H), 2.07-1.99 ( m, 2H), 1.11 (t, 3H)

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)

300 mg of dabigatran carindacillin obtained in Example 9 was added to a 25 ml flask, dissolved in 3 ml of chloroform and 0.3 ml of methanol, and stirred. 68.3 mg of (+)-L-tartaric acid was added to the reaction solution and stirred at room temperature. After 1 hour, 30 ml of diisopropyl ether was added to the thickened solution, and the mixture was stirred for 16 hours. The resulting solid was filtered and dried to give 309 mg of the title compound.

¹ H NMR (DMS0-d ₆ , 400 MHz) δ 9.08 (br, 1H), 8.35 (d, 1H), 7.78 (d, 2H), 7.54 (td, 1H), 7.45 (s, 1H), 7.37 (d , 1H), 7.18-7.09 (m, 3H), 7.01 (t, 1H), 7.93 (s, 1H), 6.87 (d, 1H), 6.81 (d, 1H), 6.75 (d, 2H), 4.58 ( d, 2H), 4.23 (s, 2H), 4.19 (t, 2H), 3.92 (q, 2H), 2.82 (q, 4H), 2.64 (t, 2H), 2.04-1.97 (m, 2H), 1.08 (t, 3H)

Experimental Example 1 Stability Test of Dabigatran Coated Salt

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.

1) 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

2) Preparation of Samples: Each sample was weighed eight times by 50mg, and each sample was placed in a glass vial, and divided into four open closures and four open ones.

3) 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. .

4) Analysis conditions are as follows.

As a result, in case of dabigatran coating chamber (+)-(1S) -campo-10-sulfonic acid salt (DBP11-14746), which is the compound of Example 72, when the temperature was 40 ° C. and the humidity was 75%, dabigatran E. It was found to be more stable than texylate mesylate. Each result is shown in Table 1.

Table 1

Experimental Example 2 Solubility of Dabigatran Coated Salt

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.

1) 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

2) Preparation of Samples: Each sample was weighed 6 times by 10mg and prepared in glass vials.

3) 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.

As a result of the test, 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. In addition, in the pH 2.0 buffer 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. Each analysis result is shown in Table 2.

TABLE 2

Experimental Example 3 Solubility of Dabigatran Carindacillin Salt

Of dabigatran etexilate mesylate as a control drug with dabigatran carindacillin salts prepared in Examples 14, 78, 79, 80, 81, 83, 84, and 85, which are the dabigatran prodrugs according to the present invention. Solubility test was carried out in the same manner as in Experiment 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

As a result, 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.

TABLE 3

Experimental Example 4 Oral Bioavailability Tests in Rats

Oral in vivo in Rat using dabigatran, dabigatran etexilate mesylate (Pradaxa), dabigatran cladding mesylate (Example 18), dabigatran carindacillin mesylate (Example 14) Utilization was tested. The test method is as follows.

As a result of the test, dabigatran carindacillin mesylate (Example 14) showed a Cmax similar to that of the reference drug, and dabigatran coated silicyl mesylate (Example 18) showed a Cmax equal to or higher than the control drug. The bioavailability (BA) was 63 ~ 84% compared to Pradaxa, but the bioavailability of Pradaxa is very low, so it is hard to see the relative comparison of the values. Each result is shown in Table 4.

Table 4

Experimental Example 5 Oral Bioavailability Tests in Mice

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.

1) Method of pretreatment of analytical sample: 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.

Analytical method: This test was conducted in MRM mode using Triple Quad 5500 mass spectrometer (AB / SCIEX). LC conditions and Mass analysis conditions are shown in the following table.

As a result of the test, 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. Each result is shown in Table 5, and the values compared with the reference drug are shown graphically in FIG.

Table 5

Claims (26)

1. A compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

   <Formula 1>

   

   In Chemical Formula 1,

   A is n-hexyl,

   

   ,

   

   ,

   

   or

   

   Is,

   B is ethyl,

   

   ,

   

   ,

   

   or

   

   ego;

   Where B is ethyl, then A is

   

   ,

   

   ,

   

   or

   

   ego,

   B is

   

   ,

   

   ,

   

   or

   

   when; A is n-hexyl,

   Wherein 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,

   Z is

   

   or

   

   ego,

   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.
2. The compound of claim 1, wherein B is ethyl and A is

   

   ego,

   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,

   Z is

   

   or

   

   Phosphorus compounds, mesylate salts thereof.
3. The compound according to claim 2, or a mesylic acid salt thereof, selected from the following compounds.

   Ethyl 3- (1-methyl-2-(((4- (N-(((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) carbamimido Yl) phenyl) amino) methyl) -N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

   Ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-(((4- (N-((((2E, 6E) -3,7,11-trimethyldodeca-2,6) , 10-trien-1-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

   Ethyl 3- (1-methyl-2-(((4- (N-((2-morpholinoethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -N- (pyridine-2 -Yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

   2-(((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] imidazole-2 -Yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) acetic acid;
4. The compound of claim 2, wherein R ₁ is hydrogen and R ₂ is

   

   Y is C ₁ -C ₅ lower alkyl substituted or unsubstituted with C ₁ -C ₅ lower alkyl at one or more positions, and Z is

   

   or

   

   Phosphorus compounds, mesylate salts thereof.
5. The compound according to claim 4, or a mesylic acid salt thereof, selected from the following compounds.

   Ethyl 3- (2-(((4- (N-((2- (dimethylamino) ethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridine- 2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate;

   Ethyl 3- (2-(((4- (N-((3- (dimethylamino) propoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridine- 2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate;

   2-(((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] imidazole-2 -Yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) ethyl nicotinate;

   3-((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] imidazole-2 -Yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) propyl nicotinate;

   Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;
6. The compound of claim 1, wherein B is ethyl; A is

   

   ego,

   R ₁ is hydrogen, C ₁ -C ₅ lower alkyl, optionally substituted with C ₁ -C ₅ lower alkyl at one or more positions, or C ₃ -C ₇ cycloalkyl,

   R ₃ is hydrogen, cycloalkyl of from one or more positions that are not substituted or substituted with lower alkyl, oxo, halogen or phenyl of _{C 1 ~ C 5 C 1 ~} C 5 lower alkyl or C ₃ ~ C ₇ of,

   X is O, S or NH, a mesylate salt thereof.
7. The compound according to claim 6 or a mesylic acid salt thereof, selected from the following compounds.

   (E) -1-(((amino (4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d ] Imidazol-2-yl) methyl) amino) phenyl) methylene) carbamoyl) oxy) ethyl isobutyrate;

   ((((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) methyl pivalate;

   Ethyl 3- (2-(((4- (N-((1-acetoxyethoxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridine-2- Yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

   Ethyl 3- (1-methyl-2-(((4- (N-((2-methyl-1- (propionyloxy) propoxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;
8. The compound of claim 1, wherein B is ethyl; A is

   

   ego,

   R ₁ is hydrogen, that at least one location in the optionally substituted by lower alkyl of _{C 1 ~ C 5 C 1 ~} C 5 lower alkyl or C ₃ ~ C ₇ cycloalkyl, in the,

   R ₃ is hydrogen, cycloalkyl of from one or more positions that are not substituted or substituted with lower alkyl, oxo, halogen or phenyl of _{C 1 ~ C 5 C 1 ~} C 5 lower alkyl or C ₃ ~ C ₇ of,

   X is O, S or NH, a mesylate salt thereof.
9. The compound of claim 1, wherein A is n-hexyl and B is

   

   ego;

   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,

   Z is

   

   or

   

   Phosphorus compounds, mesylate salts thereof.
10. The compound according to claim 9, or a mesylic acid salt thereof, selected from the following compounds.

    (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carba) Mimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

    (2E, 6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl 3- (2-(((4-((Z) -N '-((hexyljade) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propano Eight;

    2-morpholinoethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl- N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

    (Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoyl) oxy) acetic acid;
11. The compound of claim 9, wherein R ₁ is hydrogen and R ₂ is

    

    Y is C ₁ -C ₅ lower alkyl substituted or unsubstituted with C ₁ -C ₅ lower alkyl at one or more positions, and Z is

    

    or

    

    Phosphorus compounds, mesyl acid salts thereof.
12. The compound according to claim 11 or a mesylic acid salt thereof, selected from the following compounds.

    2- (dimethylamino) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl -N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

    1-((isopropoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) Methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

    (Z) -2-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoyl) oxy) ethyl nicotinate;

    (Z) -3-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoyl) oxy) propyl nicotinate;

    2,3-dihydro-1H-inden-5-yl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino ) Methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;
13. The compound of claim 1, wherein A is n-hexyl, and B is

    

    ego;

    R ₁ is hydrogen, that at least one location in the optionally substituted by lower alkyl of _{C 1 ~ C 5 C 1 ~} C 5 lower alkyl or C ₃ ~ C ₇ cycloalkyl, in the,

    R ₃ is hydrogen, cycloalkyl of from one or more positions that are not substituted or substituted with lower alkyl, oxo, halogen or phenyl of _{C 1 ~ C 5 C 1 ~} C 5 lower alkyl or C ₃ ~ C ₇ of,

    X is O, S or NH, a mesylic acid salt thereof.
14. The compound according to claim 13, or a mesylic acid salt thereof, selected from the following compounds.

    (Z) -1-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) ethyl isobutyrate;

    ((t-butoxycarbonyl) oxy) methyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl ) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;

    1-acetoxyethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N -(Pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate;

    (Z) -1-((3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoyl) oxy) -2-methylpropyl isobutyrate;

    2-methyl-1- (propionyloxy) propyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl ) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;
15. The compound of claim 1, wherein A is n-hexyl, and B is

    

    ego;

    R ₁ is hydrogen, that at least one location in the optionally substituted by lower alkyl of _{C 1 ~ C 5 C 1 ~} C 5 lower alkyl or C ₃ ~ C ₇ cycloalkyl, in the,

    R ₃ is hydrogen, cycloalkyl of from one or more positions that are not substituted or substituted with lower alkyl, oxo, halogen or phenyl of _{C 1 ~ C 5 C 1 ~} C 5 lower alkyl or C ₃ ~ C ₇ of,

    X is O, S or NH, a mesylic acid salt thereof.
16. The compound according to claim 15, or a mesylic acid salt thereof, selected from the following compounds.

    ((Isopropoxycarbonyl) oxy) methyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate;

    1-(((cyclohexyloxy) carbonyl) 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;

    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;

    1-((isopropoxycarbonyl) oxy) ethyl (Z) -3- (2-(((4- (N '-((hexyloxy) carbonyl) carbamididoyl) phenyl) amino) Methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate;
17. The pharmaceutically acceptable salt of the compound represented by the formula (I) according to claim 1, wherein the inorganic or organic acid is hydrochloric acid, (+)-(1S) -campo-10-sulfonic acid, cinnamic acid, citric acid, fumaric acid, lactic acid, L A salt, characterized in that selected from the group consisting of malic acid, malonic acid, 2-naphthalenesulfonic acid, nicotinic acid, orotic acid, salicylic acid, succinic acid, L (+)-tartaric acid.
18. The compound according to claim 17, which is a salt selected from the following compounds.

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (+)-(1S) -campo-10-sulfonate;

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate citrate;

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate fumarate;

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propanoate (-)-L-maleate;

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate malonate;

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate 2-naphthalenesulfonate;

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate nicotinate;

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate ororate;

    Ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)- 1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (+)-L-tartarate;

    1-(((cyclohexyloxy) carbonyl) 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 (+)-(1S) -campo-10 Sulfonates;

    1-(((cyclohexyloxy) carbonyl) 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 citrate;

    1-(((cyclohexyloxy) carbonyl) 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 fumarate;

    1-(((cyclohexyloxy) carbonyl) 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 (-)-L-maleate;

    1-(((cyclohexyloxy) carbonyl) 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 malonate;

    1-(((cyclohexyloxy) carbonyl) 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 ororate;

    1-(((cyclohexyloxy) carbonyl) 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 salicylate;

    1-(((cyclohexyloxy) carbonyl) 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 (+)-L-tartarate;

    Ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-(((4- (N-((((2E, 6E) -3,7,11-trimethyldodeca-2,6) , 10-trien-1-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) propanoate citrate;

    Ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-(((4- (N-((((2E, 6E) -3,7,11-trimethyldodeca-2,6) , 10-trien-1-yl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) propanoate (+) -L-tartarate;

    ((((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) methyl pivalate (+)-(1S) -campo-10-sulfonate;

    ((((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) methyl pivalate citrate;

    ((((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) methyl pivalate (-)-L-maleate;

    ((((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) methyl pivalate 2-naphthalenesulfonate;

    ((((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) methyl pivalate ororate.
19. 19. The compound of claim 18 wherein ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl ) Amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate fumarate is about 14.84, 16.28, 17.22, 18.64 , 19.05, 21.32, 22.50, 23.63, 24.70, 26.48, 28.46, 29.03, and 38.29 ± 0.2 degrees in crystal form having a characteristic X-ray powder diffraction pattern with peaks represented by 2θ Salts.
20. 19. The compound of claim 18 wherein ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl ) Amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate malonate is 15.35, 17.06, 17.71, 20.34, 20.80, 22.24, 22.74, 24.33, 24.94, 25.49, 26.54, 27.91 and 28.16 ± 0.2 degrees is a crystalline salt characterized by having a distinctive X-ray powder diffraction pattern with peaks represented by 2θ compound.
21. 19. The compound of claim 18 wherein ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl ) Amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate nicotinate is 13.72, 15.42, 19.56, 20.74, A compound which is a crystalline salt characterized by having a unique X-ray powder diffraction pattern having a peak represented by 2θ at 23.10, 24.53 and 26.60 ± 0.2 degrees iseta.
22. 19. The compound of claim 18 wherein ethyl 3- (2-(((4- (N-(((2,3-dihydro-1H-inden-5-yl) oxy) carbonyl) carbamimidoyl) phenyl ) Amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate ororate is 4.68, 8.74, 15.14, 19.36 And a salt having a characteristic X-ray powder diffraction pattern having a peak represented by 2θ at 28.70 ± 0.2 degrees iseta.
23. 19. The compound of claim 18, wherein ((((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) methyl pivalate (+)-(1S) -campo-10-sulfonate is 11.74, 14.79, 16.06, 16.61, Crystalline form characterized by having a unique X-ray powder diffraction pattern with peaks represented by 2θ at 17.26, 17.84, 18.91, 19.87, 20.335, 20.85, 21.93, 22.97, 23.92 and 25.02 ± 0.2 degrees iseta Phosphorus salt.
24. 19. The compound of claim 18, wherein ((((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) methyl pivalate citrate is 12.35, 13.27, 14.01, 16.73, 17.16, 18.12, 20.23, 20.41, 23.41, 24.57, A compound which is a crystalline salt characterized by having a unique X-ray powder diffraction pattern having a peak represented by 2θ at 25.88 and 26.80 ± 0.2 degrees iseta.
25. 19.A compound according to claim 18, wherein ((((4-(((5-((3-ethoxy-3-oxopropyl) (pyridin-2-yl) carbamoyl) -1-methyl-1H-benzo [d] Dazol-2-yl) methyl) amino) phenyl) (imino) methyl) carbamoyl) oxy) methyl pivalate 2-naphthalenesulfonate was 5.52, 6.23, 9.76, 13.16, 16.73, 16.89, 17.33, 18.13, 18.90, 20.18, 21.74, and 21.98 ± 0.2 degrees A compound which is a crystalline salt characterized by having a unique X-ray powder diffraction pattern having a peak expressed in 2θ at iseta.
26. 19. The compound of claim 18, wherein ((((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) methyl pivalate orotate is 6.75, 7.96, 13.64, 14.89, 18.59, 20.17, 20.54, 25.18, 26.00, 27.69 And a salt which is a crystalline form characterized by having a unique X-ray powder diffraction pattern having a peak represented by 2θ at 28.51 ± 0.2 degrees iseta.

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