CN107027308A - A kind of dabigatran thioes derivatives and preparation method thereof and purposes pharmaceutically - Google Patents

A kind of dabigatran thioes derivatives and preparation method thereof and purposes pharmaceutically Download PDF

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CN107027308A
CN107027308A CN201580036779.5A CN201580036779A CN107027308A CN 107027308 A CN107027308 A CN 107027308A CN 201580036779 A CN201580036779 A CN 201580036779A CN 107027308 A CN107027308 A CN 107027308A
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alkyl
pharmaceutically acceptable
compound
salt
methyl
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魏用刚
邱关鹏
雷柏林
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

One kind such as the dabigatran thioes derivatives and its stereoisomer and pharmaceutically acceptable salt of formula (I), and preparing the purposes in being used to prevent and treat the medicine of thromboembolic disorders, wherein X1、X2、R1And R2It is defined as in the description.

Description

A kind of dabigatran thioes derivatives and preparation method thereof and purposes pharmaceutically Technical field
The present invention relates to a kind of dabigatran thioes derivatives and its stereoisomers and pharmaceutically acceptable salt, and are preparing the purposes in the drug for preventing and treating thromboembolic disorders.
Background technique
Currently, cardiovascular disease is one of the main reason for leading to human death, its main aspect is thrombosis, and thrombosis is to be caused blood coagulation by a series of complex reaction and caused.Blood clotting is a kind of protection mechanism of organism, " can seal " defect of vascular wall quickly and reliably whereby, therefore to avoid blood loss or can be preferably minimized limit.Maintain normal haemostasis effect, i.e. bleeding and coagulation homeostasis, by the regulation of a complex mechanism.The inhibiting effect of not modulated coagulation system activation or shortage activation process all may cause a variety of diseases and complication, such as phlebothrombosis, deep vein thrombosis, pulmonary embolism, atherosclerosis, acute coronary syndrome, cranial vascular disease etc..
The oral anticoagulant drug listed mainly has direct thrombin inhibitor, Xa factor inhibitor, IX factor inhibitors, tissue factor inhibitor and novel vitamin K antagon etc..Wherein dabigatran etcxilate is a kind of oral, selective high performance thrombin inhibitor, and clinic is proved that warfarin can be substituted as the non-valvular atrial fibrillation patient apoplexy of prevention and systemic embolism and substitution Enoxaparin Sodium as the preferred medication for preventing main shaping postoperative patient venous thromboembolic event.
Dabigatran etcxilate was listed in 2008, be used to prevent stroke or systemic embolism, deep vein thrombosis (DVT) or Pulmonary Vascular obstruction and its recurrence of non-valvular heart disease patient.It is free carboxy in dabigatran molecule and amidino groups respectively at the bi precursor drug obtained after ester, solve the problems, such as because dabigatran strong basicity amidino groups there are due to cannot take orally, improve oral administration biaavailability.After dabigatran etcxilate is oral, is absorbed from gastrointestinal tract, then quickly dabigatran is converted into vivo, to play blood coagulation resisting function.But the oral administration biaavailability of dabigatran dibasic acid esters is lower, and only 3~7%, so pharmaceutical dosage is higher, increase gastrointestinal side effect.
Has the pro-drug of many document reports dabigatran at present.Such as pro-drugs such as WO09837075 and WO2004014894 patent discloses dabigatran and the like and its alkyl carboxylic acid ester, is replaced by sulfonyl carboxylate or sulfuryl aminos；Bend piperazine pro-drug for the ferulic acid of CN102875533 and CN102838588 patent report dabigatran or river, and has certain blood coagulation resisting function；Before the patents such as CN200910211164, CN200910211165 and CN201210158600 disclose the carbonic ester of dabigatran, carboxylate etc. Body drug.
It is an object of the invention to solve the problems, such as that dabigatran cannot take orally because of its strong basicity, it is a kind of novel effectively with good stability, solubility, bioavilability and low dosage, less toxic side effect or long-acting orally available dabigatran prodrug to provide.
Summary of the invention
The present invention relates to a kind of dabigatran thioes derivatives and its stereoisomers or pharmaceutically acceptable salt, and are preparing the purposes in the drug for preventing and treating thromboembolic disorders.
The present invention provides a kind of logical formula (I) compound represented and its stereoisomer and pharmaceutically acceptable salt, in which:
R1And R2It is independently selected from C1-10Alkyl or C6-10Carbocyclic ring, the alkyl or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, CN, NH by 0 to 42、C1-4Alkyl, C1-4Alkoxy or C6-10Replaced the substituent group of carbocyclic ring；X1And X2It is independently selected from O or S, condition is X1、X2In at least one be S.
The preferred solution of the invention, a kind of logical formula (I) compound represented and its stereoisomer and pharmaceutically acceptable salt, in which: R1And R2It is independently selected from C1-10Alkyl, the alkyl are optionally further selected from H, F, Cl, Br, I, CN, NH by 0 to 42、C1-4Alkyl, C1-4Alkoxy or C3-6Replaced the substituent group of carbocyclic ring, X1And X2It is independently selected from O or S, condition is X1、X2In at least one be S.
The preferred solution of the invention, a kind of logical formula (I) compound represented and its stereoisomer and pharmaceutically acceptable salt, in which: R1And R2It is independently selected from C1-10Alkyl, preferably C1-8Alkyl, the alkyl are optionally further selected from H, F, Cl, Br, I, CN, NH by 0 to 42, methyl, ethyl, methoxyl group, ethyoxyl, cyclopropyl or cyclopenta substituent group replaced, X1And X2It is independently selected from O or S, condition is X1、X2In at least one be S.
The preferred solution of the invention, a kind of logical formula (I) compound represented and its stereoisomer and pharmaceutically acceptable salt, wherein the compound is selected from such as one of flowering structure:
The preferred solution of the invention, the compound and its stereoisomer and pharmaceutically acceptable salt according to the present invention, wherein the salt is selected from hydrochloride, hydrobromate, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalates, oxyacetate, salicylate, glucuronate salt, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate, ferulate or their combination.
The present invention further provides a kind of pharmaceutical composition, described pharmaceutical composition contains the compounds of this invention or its stereoisomer or pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient for the treatment of effective dose.
The present invention further provides a kind of front any compounds and its stereoisomer and pharmaceutically acceptable salt, in preparation treatment and the purposes in thrombin inhibitor related disease drug.
The present invention also provides a kind of mentioned-above pharmaceutical compositions in preparation treatment and the purposes in thrombin inhibitor related disease drug.
The preferred solution of the invention, wherein described is selected from thromboembolic disorders with thrombin inhibitor related disease.
The preferred solution of the invention, wherein the thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
The present invention further provides the methods of a kind for the treatment of and thrombin inhibitor related disease, wherein the method includes compound of the present invention or its stereoisomer or pharmaceutically acceptable salt or composition of the present invention is administered.
The preferred solution of the invention, wherein described is selected from thromboembolic disorders with thrombin inhibitor related disease.
The preferred solution of the invention, wherein the thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
Unless there are opposite statement, the term used in the specification and in the claims has following meanings.
Carbon, hydrogen, oxygen, sulphur, nitrogen or halogen involved in group and compound of the present invention include the same of them Optionally further by one or more, their corresponding isotopes substitute carbon, hydrogen, oxygen, sulphur, nitrogen or halogen involved in position element and group of the present invention and compound, and wherein the isotope of carbon includes12C、13C and14C, the isotope of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), and the isotope of oxygen includes16O、17O and18The isotope of O, sulphur includes32S、33S、34S and36The isotope of S, nitrogen includes14N and15N, the isotope of fluorine19The isotope of F, chlorine includes35Cl and37The isotope of Cl, bromine includes79Br and81Br。
" alkyl " refers to the saturated aliphatic hydrocarbons group of straight chain and branch, main chain includes 1 to 20 carbon atom, preferably 1 to 12 carbon atom, further preferably 1 to 8 carbon atom, more preferably 1 to 6 carbon atom, the straight chain and branched group of still further preferably 1 to 4 carbon atom, most preferably 1 to 2 carbon atom；The example of alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, 2- amyl, 3- amyl, 2- methyl -2- butyl, 3- methyl -2- butyl, 3- methyl-1-butyl, 2-methyl-1-butene base, n-hexyl, 2- hexyl, 3- hexyl, 2- methyl -2- amyl, 3- methyl -2- amyl, 4- methyl -2- amyl, 3- methyl -3- amyl, 2- methyl -3- amyl, 2, 3- dimethyl -2- butyl, 3, 3- dimethyl -2- butyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2, 2- dimethyl amyl group, 2, 3- dimethyl amyl group, 2, 4- dimethyl amyl group, 3, 3- dimethyl amyl group , 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,2- dimethylhexanyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl and positive decyl；Alkyl can be substituted or unsubstituted, when substituted, substituent group can be substituted on any workable tie point, and substituent group is preferably 1 to 5 selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, heterocycle, bridged ring base, loop coil base and ring group, hydroxy alkyl=O, carbonyl, aldehyde, carboxylic acid, carboxylate artyl sulfo, thiocarbonyl or silylation etc..
" alkoxy " refers to-O- alkyl, wherein for example hereinbefore definition of alkyl.Alkoxy can be substituted or unsubstituted, and alkoxy embodiment includes but is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy and positive hexyloxy；When substituted, substituent group is preferably 1 to 5 selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, heterocycle, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate artyl sulfo, thiocarbonyl or silylation etc..
" optional " or " optionally " refer to event or environment described later can with but necessarily occur, which includes the occasion that the event or environment occur or do not occur, such as: " alkyl optionally replaced by F " refer to alkyl can with but necessarily Replaced by F, illustrates to include situation that alkyl is not replaced by the F situation replaced and alkyl by F.
" substitution " refers to the situation that one or more hydrogen atoms are replaced by other groups in group, if the group is replaced by hydrogen atom, the group of formation is identical as the group replaced by hydrogen atom.The substituted situation of group, such as amino, C1-4Alkyl, C1-4Alkoxy, C3-6Carbocyclic ring, 3 to 6 circle heterocyclic rings are optionally further selected from H, F, Cl, Br, I, hydroxyl, cyano, amino, C by 0 to 41-4Alkyl or C1-4Replaced the substituent group of alkoxy, the group of formation includes but is not limited to methyl, chloromethyl, trichloromethyl, hydroxymethyl ,-CH2OCH3、-CH2SH、-CH2CH2CN、-CH2NH2、-NHOH、-NHCH3、-OCH2Cl、-OCH2OCH2CH3、-OCH2CH2NH2、-OCH2CH2SH、-OCH2CH2OH, 1- hydroxycyclopropyl, 2- hydroxycyclopropyl, 2- amino cyclopropyl, 4- methylfuran base, 2- hydroxy phenyl, 4- aminophenyl, phenyl.
" substituted or unsubstituted " refers to the situation that group can be substituted or unsubstituted, if not pointing out in the present invention, group can be substituted, then it represents that the group is unsubstituted situation.
" alternatively " scheme before scheme and " alternatively " after referring to " alternatively " is coordination, rather than the further selection situation in the case of front.
" pharmaceutically acceptable salt " or " its pharmaceutically acceptable salt " refers to keeping the biological effectiveness and characteristic of free acid or free alkali, and the free acid by with nontoxic inorganic base or organic base, the free acid by with nontoxic inorganic acid or organic acid reaction acquisition those of salt, including alkali metal salt, such as sodium salt, sylvite, lithium salts；Alkali salt, such as calcium salt, magnesium salts；Other metal salts, such as molysite, mantoquita, cobalt salt；Organic alkali salt, such as ammonium salt, triethylamine salt, pyridiniujm, picoline salt, 2, 6- lutidines salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, guanidine salt, isopropyl amine salt, trismethylamine salt, tripropyl amine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, dimethyl ethanol amine salt, dicyclohexyl amine salt, coffee alkali salt, procaine salt, choline salt, beet alkali salt, Benethamine Penicillin salt, glucose amine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, cocoa alkali salt, amino butanetriol salt, purine salt, piperazine salt, alkylbenzyldimethylasaltsum saltsum, piperidinium salt, N-ethylpiperidine salt, tetramethyl amine salt, dibenzyl amine salt and phenylglycine alkyl ester salt；Halogen acid salt, such as hydrofluoride, hydrochloride, hydriodate, hydrobromate；Inorganic acid salt, such as nitrate, sulfate, perchlorate, phosphate；Rudimentary alkyl sulfonate, such as mesylate, fluoroform sulphonate, esilate；Arylsulphonate, such as benzene sulfonate, tosilate；Acylate, such as formate, fumarate, formates, trifluoroacetate, furoate, gluconate, glutamate, glycollate, isethionate, lactate, maleate, malate, mandelate, mucus hydrochlorate, embonate, pantothenate, stearate, succinate, sulfanilate, tartrate, malonate, 2 hydroxy propanoic acid salt, citrate, salicylate, oxalates, oxyacetate, glucuronate salt, galacturonic acid Salt, citrate, lysine salt, arginine salt, aspartate, cinnamate.
Synthetic method
Method one:
X2For O；R2For n-hexyl；
R1、X1It is consistent to lead to definition described in formula (I) with front.
Method two:
R1、R2、X1、X2Definition leads to definition described in formula (I) unanimously with front.
Specific embodiment
The technical solution that the present invention will be described in detail with reference to the accompanying drawings and embodiments, but protection scope of the present invention includes but is not limited to this.
The structure of compound be by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) is come what is determined.NMR is displaced (δ) with 10-6(ppm) unit provides.The measurement of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
(Agilent 6120B (ESI) and Agilent 6120B (APCI)) is used in the measurement of MS.
The measurement of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100 × 4.6mm).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that the silica gel plate that thin-layered chromatography (TLC) uses uses is 0.15mm~0.20mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.
Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
Known starting material of the invention can be used or be synthesized according to methods known in the art, or be can purchase in safe smooth science and technology, pacified the companies such as silent resistance to Jilin Chemical, Shanghai moral, Chengdu section Long Huagong, splendid remote chemical science and technology, lark prestige science and technology.
Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Without specified otherwise in embodiment, reaction carries out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.
Intermediate 1
3- [[2- [[4- [N`- hexyloxy carbonyl carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic acid (intermediate 1)
3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
Step 1: 3- [[2- [[4- [N`- hexyloxy carbonyl carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic acid (intermediate 1)
3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
By 3- [[2- [[4- [N`- hexyloxy carbonyl carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] ethyl propionate (1a) (63g, 100mmol) it is added to the in the mixed solvent of ethyl alcohol (600mL) and water (300mL), sodium hydroxide (8g is added, 200mmol), half an hour is stirred at room temperature, until reaction solution is clarified.Concentration of reaction solution, rotate most of ethyl alcohol, it is added water (200mL), pH to 4~5 is adjusted with 10% aqueous citric acid solution, a large amount of thick solids are precipitated, filtering, solid is transferred in reaction flask, it is added methanol (300mL), it is heated to solid dissolution, continue stirring to solid to be in granular form, it is cooled to 0 DEG C, more products are precipitated, it filters and dries, obtain title compound 3- [[2- [[4- [N`- hexyloxy carbonyl carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic acid (intermediate 1) (50g of white solid, yield 83%).
LCMS m/z=600.2 [M+1].
1H NMR (400MHz, DMSO): δ 8.38 (d, 1H), 7.79 (d, 2H), 7.56 (m 1H), 7.48 (s, 1H), 7.39 (d, 1H), 7.14 (m2H), 6.95 (d, 2H), 6.77 (d, 2H), 4.60 (d, 2H), 4.18 (t, 2H), 3.99 (t, 2H), 3.77 (s, 3H), 2.68-2.58 (m, 3H), 1.58 (dd, 2H), 1.29 (d, 6H), 0.87 (t, 3H).
Embodiment 1
3- [[1- methyl -2- [[4- [N`- pentylthio carbonyl first narrows base] anilino-] methyl] benzimidazole -5- carbonyl]-(2- pyridine) amino] ethyl propionate (compound 1)
Ethyl 3-[[1-methyl-2-[[4-[N`-pentylsulfanylcarbonylcarbamimidoyl]anilino]methyl]b enzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
N is added in the tetrahydrofuran (10mL) of n-amyl mercaptan (0.371g, 3.57mmol) at room temperature, N'- carbonyl dimidazoles (0.628g, 3.87mmol) are stirred at room temperature 30 minutes, solvent is removed under reduced pressure, are prepared into reaction solution 1.In ethyl 3- [[2- [(4- first narrows aniline) methyl] -1 methyl-benzoimidazole -5- carbonyl]-(2- pyridine) amino] propionic ester toluenesulfonate (1A) (2g, acetone (80mL), water (40mL), potassium carbonate (1.23g are added in 2.98mmol), 8.93mmol), it is stirring evenly and then adding into reaction solution 1, is reacted at room temperature 5 hours after adding.Water (100mL) is added later, and it is extracted with (150mL × 2) ethyl acetate, merge organic layer, the organic layer washing of (150mL × 2), organic layer anhydrous sodium sulfate is dry later, concentration removes solvent and obtains title compound 3- [[1- methyl -2- [[4- [N`- pentylthio carbonyl first narrows base] anilino-] methyl] benzimidazole -5- carbonyl]-(2- pyridine) amino] ethyl propionate (compound 1), white solid (0.3g, yield 16%).
LCMS m/z=630.28 [M+1].
1H NMR((400MHz,CDCl3) δ 8.41 (d, 1H), 7.72 (d, 2H), 7.66 (s, 1H), 7.33 (m, 1H), 7.27 (d, 1H), 7.08 (d, 1H), 6.98 (dd, 1H), 6.71 (d, 1H), 6.63 (d, 2H), 5.53 (s, 1H), 4.43 (dd, 4H), 4.14-4.01 (m, 2H), 3.71 (s, 3H), 2.86 (t, 2H), 2.80 (t, 2H), 1.66 (m, 2H), 1.47-1.30 (m, 4H), 1.21 (t, 3H), 0.90 (t, 3H).
Embodiment 2
Tertiary butylthio 3- [[2- [[4- [the own oxygen carbonyl first of N`- narrows base] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic ester (compound 2)
S-tert-butyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate
At room temperature in 3- [[2- [[4- [N`- hexyloxy carbonyl carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic acid (intermediate 1) (1.00g, tert-butyl mercaptan (2A) (0.225m g is added in dimethylformamide (15mL) solution 1.67mmol), 2.505mmol), 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (0.832g, 4.34mmol) and 4-dimethylaminopyridine (122mg, 1.00mmol), it reacts at room temperature 15 hours.Water (30mL) is added into reaction solution, (50mL × 3) are extracted with ethyl acetate, merge organic phase, organic phase washs (30mL × 2) with aqueous solution, and it is dry with anhydrous sodium sulfate, concentration, with silica gel column chromatography separating-purifying, ((methylene chloride: methanol (v/v)=50:1~30:1) obtains title compound tertiary butylthio 3- [[2- [[4- [the own oxygen carbonyl first of N`- narrows base] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic ester (compound 2) to residue, white solid (0.61g, yield 54.46%)
LCMS m/z=672.33. [M+1].
1H NMR((400MHz,CDCl3) δ 8.40 (d, 1H), 7.77-7.70 (m, 2H), 7.68 (d, 1H), 7.32 (t, 1H), -7.24 (s, 1H), 7.06 (t, 1H), 7.00-6.91 (m, 1H), 6.71 (d, 1H), 6.64 (t, 2H), 5.33 (s, 1H), 4.50-4.42 (m, 2H), 4.40 (d, 2H), 4.13 (dd, 2H), 3.72-3.63 (s, 3H), 2.95 (t, 2H), 1.71 (dd, 2H), 1.40 (s, 9H), 1.31 (dd, 6H), 0.88 (t, 3H).
Embodiment 3
Positive butylthio 3- [[2- [[4- [the own oxygen carbonyl carbonamidine base of N`-] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic ester (compound 3)
S-butyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate
Preparation method is referring to embodiment 2.
LCMS m/z=672.33. [M+1].
1H NMR((400MHz,CDCl3) 8.40 (dd of δ, 1H), 7.77-7.70 (m, 2H), 7.69 (s, 1H), 7.32 (m, 1H), -7.22 (m, 1H), 7.08 (d, 1H), 6.97 (dd, 1H), 6.71 (d, 1H), 6.65 (d, 2H), 5.37 (s, 1H), 4.54-4.32 (m, 4H), 4.13 (t, 2H), 3.69 (s, 3H), 3.06 (t, 2H), 2.83 (t, 2H), 1.71 (dd, 2H), 1.51 (m, 2H), 1.46-1.35 (m, 2H), 1.30 (m, 6H), 0.95-0.78 (m, 6H).
Embodiment 4
Rosickyite base 3- [[2- [[4- [the own oxygen carbonyl carbonamidine base of N`-] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic ester (compound 4)
S-propyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate
Preparation method is referring to embodiment 2.
LCMS m/z=658.31. [M+1].
1H NMR((400MHz,CDCl3) 8.40 (d of δ, 1H), 7.76-7.62 (m, 3H), 7.33 (t, 1H), 7.18 ((m, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 6.71 (d, 1H), 6.66 (d, 2H), 5.43 (s, 1H), 4.57-4.35 (m, 4H), 4.13 (dd, 2H), 3.70 (s, 3H), 3.06 (t, 2H), 2.81 (t, 2H), 1.71 (dd, 2H), 1.55 (m, 2H), 1.46-1.35 (m, 2H), 1.30 (dd, 4H), 0.94 (t, 3H), 0.88 (t, 3H).
Embodiment 5
3- [[2- [[4- [the own oxygen carbonyl carbonamidine base of N`-] phenylamino] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] ethyl propionate (compound 5)
Ethyl 3-[[2-[[4-[N`-ethylsulfanylcarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=588.23 [M+1].
1H NMR(400MHz,CDCl3)δ8.41(dd,1H),7.72(d,2H),7.67(s,1H),7.33(m,1H),7.28(d,1H),7.08(d,1H),7.01–6.90(m,1H),6.71(d,1H),6.63(d,2H),5.36(s,1H),4.53–4.31(m,4H),4.07(q,2H),3.70(s,3H),2.92–2.72(m,4H),1.32(t,3H),1.21(t,3H)。
Embodiment 6
3- (2- (((4- (N'- ((own sulfenyl) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- base) -1H- benzo [d] imidazoles -5- formamido group) ethyl propionate (compound 6)
Ethyl 3-(2-(((4-(N'-((hexylthio)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=644.2 [M+1].
1H NMR ((400MHz, DMSO) 9.22 (s of δ, 1H), 8.75 (s, 1H), 8.39 (dd, 1H), 7.80 (d, 2H), 7.54 (m, 1H), 7.47 (d, 1H), 7.40 (d, 1H), 7.16 (dd, 1H), 7.11 (m, 1H), 7.02 (t, 1H), 6.89 (d, 1H), 6.77 (d, 2H), 4.60 (d, 2H), 4.22 (t, 2H), 3.97 (q, 2H), 3.76 (s, 3H), 2.73 (t, 2H), 2.68 (t, 2H), 1.54 (dd, 2H), 1.34 (dd, 2H), 1.31-1.24 (m, 4H), 1.12 (t, 3H), 0.86 (dd, 3H).
Embodiment 7
Ethylmercapto group 3- [[2- [[4- [the own oxygen carbonyl first of N`- is narrowed] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic ester (compound 7)
S-ethyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate
Preparation method is referring to embodiment 1.
LCMS m/z=644.29 [M+1].
1H NMR(400MHz,CDCl3)δ8.39(dd,1H),7.79–7.56(m,3H),7.32(m,1H),7.23(dd,1H),7.03(d,1H),6.97(dd,1H),6.70(d,1H),6.60(d,2H),5.42(s,1H),4.52–4.36(m,4H),4.12(t,2H),3.65(s,3H),3.04(t,2H),2.82(q,2H),1.81–1.57(m,2H),1.38(dd,2H),1.30(dd,4H),1.20(t,3H),0.88(t,3H)。
Embodiment 8
Isopropyisulfanyl 3- [[2- [[4- [the own oxygen carbonyl carbonamidine base of N`-] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyl]-(2- pyridyl group) amino] propionic ester (compound 8)
S-isopropyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanethioate
Preparation method is referring to embodiment 2.
LCMS m/z=658.31 [M+1].
1H NMR((400MHz,CDCl3) δ 8.41 (d, 1H), 7.76 (d, 2H), (7.71 s, 1H), 7.32 (dd, 2H), (7.12 d, 1H), 6.98 (dd, 1H), (6.71 t, 3H), 5.34 (s, 1H), 4.50 (d, 2H), 4.44 (t, 2H), 4.14 (t, 2H), 3.73 (s, 3H), 3.59 (m, 1H), 3.03 (t, 2H), 1.78-1.68 (m, 2H), 1.40 (dd, 2H), 1.36-1.28 (m, 4H), 1.27 (s, 3H), 1.25 (s, 3H), 0.89 (t, 3H).
Embodiment 9
3- [[1- methyl -2- [[4- [N`- heptyl sulfenyl carbonyl first narrows base] anilino-] methyl] benzimidazole -5- carbonyl]-(2- pyridine) amino] ethyl propionate (compound 9)
Ethyl 3-[[1-methyl-2-[[4-[N`-heptylsulfanylcarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
Test case
1, Pharmacokinetic Evaluation
Healthy adult SD rat (half male and half female ties up tonneau China Experimental Animal Center, animal productiong licensing SCXK (capital) 2012-0001 purchased from Beijing), administration fasted for one day prior can't help water.5mg/kg (in terms of dabigatran original shape drug) is administered in 6 rat oral gavages, and compound is configured to 0.5mg × mL with 0.5%CMC-Na (containing 1% Tween 80)-1The suspension of (in terms of dabigatran original shape drug), before administration (0h) and administration after 5min, 15min, 30min, 1.0,2.0,4.0,8.0,24.0h is taken a blood sample by eye socket, anticoagulant heparin, separated plasma after 4 DEG C of 3000rpm centrifugation 10min, to be measured in -80 DEG C of preservations.Take each time point rat plasma of 30ul, inner mark solution (7.5ng/ml Verapamil) 200ul is added, vortex mixing 1min, 10min is centrifuged in 4 DEG C of 13000rpm, supernatant 190ul is taken to carry out LC-MS/MS (lc-20A Science and Technology Ltd., Shimadzu Corporation, API4000+) analysis.Main pharmacokinetic parameter is analyzed with the non-compartment model of 6.3 software of WinNonlin, and the results are shown in Table 1.
Table 1: pharmacokinetic parameter result
Conclusion: the compounds of this invention compared with dabigatran etcxilate there is good Pharmacokinetic Characteristics, especially compound 6,8 to be substantially better than dabigatran etcxilate.

Claims (12)

  1. A kind of logical formula (I) compound represented and its stereoisomer and pharmaceutically acceptable salt, in which:
    R1And R2It is independently selected from C1-10Alkyl or C6-10Carbocyclic ring, the alkyl or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, CN, NH by 0 to 42、C1-4Alkyl, C1-4Alkoxy or C3-10Replaced the substituent group of carbocyclic ring；
    X1And X2It is independently selected from O or S, condition is X1、X2In at least one be S.
  2. Compound and its stereoisomer according to claim 1 and pharmaceutically acceptable salt, in which:
    R1And R2It is independently selected from C1-10Alkyl, the alkyl are optionally further selected from H, F, Cl, Br, I, CN, NH by 0 to 42、C1-4Alkyl, C1-4Alkoxy or C3-6Replaced the substituent group of carbocyclic ring.
  3. Compound and its stereoisomer according to claim 2 and pharmaceutically acceptable salt, in which:
    R1And R2It is independently selected from C1-10Alkyl, the alkyl are optionally further selected from H, F, Cl, Br, I, CN, NH by 0 to 42, methyl, ethyl, methoxyl group, ethyoxyl, cyclopropyl or cyclopenta substituent group replaced.
  4. Compound and its stereoisomer according to claim 3 and pharmaceutically acceptable salt, wherein the compound is selected from such as one of flowering structure:
  5. Compound and its stereoisomer and pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein the salt is selected from hydrochloride, hydrobromate, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalates, oxyacetate, salicylate, glucuronate salt, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate, ferulate or their combination.
  6. A kind of pharmaceutical composition, described pharmaceutical composition contain treatment effective dose according to claim 1~any one of 5 described in compound or its stereoisomer or pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
  7. Compound described in any one of Claims 1 to 5 and its stereoisomer and pharmaceutically acceptable salt and composition as claimed in claim 6 are in preparation treatment and the purposes in thrombin inhibitor related disease drug.
  8. Purposes according to claim 7, wherein described is selected from thromboembolic disorders with thrombin inhibitor related disease.
  9. Purposes according to claim 8, wherein the thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
  10. A method for the treatment of and thrombin inhibitor related disease, wherein the method includes compounds or its stereoisomer or pharmaceutically acceptable salt or composition as claimed in claim 6 described in any one of administration Claims 1 to 5.
  11. According to the method described in claim 10, being selected from thromboembolic disorders with thrombin inhibitor related disease described in wherein.
  12. According to the method for claim 11, wherein the thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
CN201580036779.5A 2014-08-06 2015-08-04 A kind of dabigatran thioes derivatives and preparation method thereof and purposes pharmaceutically Pending CN107027308A (en)

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CN103554087A (en) * 2013-11-19 2014-02-05 南京工业大学 Dabigatran derivative, preparation method and antithrombotic application thereof
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CN1675193A (en) * 2002-08-02 2005-09-28 贝林格尔英格海姆法玛两合公司 Prodrugs of 1-methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carboxylic acid-(n-2-pyridyl-n-2-hydroxycarbonylethyl)-amide
CN103945845A (en) * 2011-07-25 2014-07-23 第三专利投资有限两合公司 Dabigatran-amidoxime acid esters as prodrugs and use thereof as pharmaceuticals
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