CN106536504A - Fluorine substituted dabigatran ester derivative, preparation method therefor, and pharmaceutical use thereof - Google Patents

Fluorine substituted dabigatran ester derivative, preparation method therefor, and pharmaceutical use thereof Download PDF

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Publication number
CN106536504A
CN106536504A CN201580036777.6A CN201580036777A CN106536504A CN 106536504 A CN106536504 A CN 106536504A CN 201580036777 A CN201580036777 A CN 201580036777A CN 106536504 A CN106536504 A CN 106536504A
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methyl
alkyl
pharmaceutically acceptable
salt
compound
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魏用刚
李瑶
余彦
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

Abstract

The present invention relates to a fluorine substituted dabigatran ester derivative as indicated in formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a use thereof in preparing medications for preventing and treating thromboembolic diseases. The structure is as indicated below, wherein R1 and R2 are optional C1-C10 alkyl groups replaced by 1-12 R1a and R2a and at least one R1a or R2a is a substituent group containing F.

Description

A kind of fluoro dabigatran ester derivant and preparation method thereof and purposes pharmaceutically Technical field
The present invention relates to the fluoro dabigatran ester derivant shown in a kind of logical formula (I) and its stereoisomer or pharmaceutically acceptable salt, and preparing the purposes in being used to prevent and treat the medicine of thromboembolic disorders.
Background technology
At present, angiocardiopathy is to cause the one of the main reasons of human death, and 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 quickly and reliably seal " defect of vascular wall whereby, therefore can avoid losing blood or being preferably minimized limit.Normal haemostasis effect is maintained, i.e. bleeding and coagulation homeostasis is regulated and controled by a complex mechanism.Not modulated coagulation system activation or the inhibitory action of shortage activation process may all cause a variety of diseases and complication, such as phlebothrombosis, DVT, pulmonary embolism, atherosclerosis, acute coronary syndrome, cranial vascular disease.
The oral anticoagulant drug listed mainly has direct thrombin inhibitor, Xa factor inhibitor, IX factor inhibitors, tissue factor inhibitor and new 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 substitutes Enoxaparin Sodium as the preferred medication for preventing main shaping postoperative patient venous thromboembolic event.
Dabigatran etcxilate was listed in 2008, is used to prevent the palsy or systemic embolism of non-valvular heart disease patient, dvt (DVT) or Pulmonary Vascular obstruction and its is recurred.It is free carboxy and amidino groups in dabigatran molecule respectively into the bi precursor medicine obtained after ester, solve because dabigatran strong basicity amidino groups exists can not be orally the problem of, improve oral administration biaavailability.After dabigatran etcxilate is oral, is absorbed from intestines and stomach, then quickly dabigatran is converted into vivo, so as to play blood coagulation resisting function.But the oral administration biaavailability of dabigatran dibasic acid esters is relatively low, only 3~7%, so pharmaceutical dosage is higher, add gastrointestinal side effect.
Many document reports pro-drug of dabigatran is had at present.As WO09837075 and WO2004014894 patents disclose dabigatran and the like, and the pro-drug such as its alkyl carboxylic acid ester, the carboxylate or sulfuryl amino that are replaced by sulfonyl；The forulic acid of CN102875533 and CN102838588 patent reports dabigatran or river bow piperazine pro-drug, and with certain blood coagulation resisting function；The patents such as CN200910211164, CN200910211165 and CN201210158600 disclose the pro-drugs such as the carbonic ester of dabigatran, carboxylate.
It is an object of the invention to solve dabigatran the problem of its strong basicity can not be orally there is provided it is a kind of novel effectively There is good stability, solubility, bioavilability and low dosage, low toxicity side effect or long-acting orally available dabigatran prodrug.
The content of the invention
The present invention relates to a kind of fluoro dabigatran ester derivant and its stereoisomer or pharmaceutically acceptable salt, and preparing the purposes in being used to prevent and treat the medicine of thromboembolic disorders.
The compound and its stereoisomer of the invention provided shown in a kind of logical formula (I) and pharmaceutically acceptable salt, wherein：
R1Selected from C1-10Alkyl, the alkyl is optionally further by 1 to 12 R1aSubstitution；
R2Selected from C1-10Alkyl, the alkyl is optionally further by 1 to 12 R2aSubstitution；
R1aAnd R2aIt is independently selected from H, F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxy or C6-10Carbocyclic ring；
Condition is, R1Or R2In at least one substituted base, and at least one R1aOr R2aFor F.
Preferred scheme of the present invention, compound and its stereoisomer shown in a kind of logical formula (I) and pharmaceutically acceptable salt, wherein：
R1Selected from C1-6Alkyl, the alkyl is optionally further by 1 to 12 R1aSubstitution；
R2Selected from C1-8Alkyl, the alkyl is optionally further by 1 to 12 R2aSubstitution.
Preferred scheme of the present invention, compound and its stereoisomer shown in a kind of logical formula (I) and pharmaceutically acceptable salt, wherein：
R1Selected from C1-6Alkyl, the alkyl is optionally further by 1 to 12 R1aSubstitution；
R2Selected from C1-8Alkyl, the alkyl is optionally further by 1 to 12 R2aSubstitution；
R1aAnd R2aIt is independently selected from H, F, Cl, Br, methyl, methoxyl group or cyclopropyl.
Preferred scheme of the present invention, wherein compound and its stereoisomer shown in a kind of logical formula (I) and pharmaceutically acceptable salt, the compound are selected from one of following structure：
Preferred scheme of the present invention, according to compound of the present invention and its stereoisomer or pharmaceutically acceptable salt, wherein described 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 combinations thereof.
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 for the treatment of effective dose, and pharmaceutically acceptable carrier or excipient.
The present invention further provides a kind of above any described compound and its stereoisomer or pharmaceutically acceptable salt, treatment and the purposes in thrombin inhibitor relevant disease medicine are being prepared.
The present invention also provides a kind of foregoing pharmaceutical composition and is preparing treatment and the purposes in thrombin inhibitor relevant disease medicine.
Preferred scheme of the present invention, wherein described be selected from thromboembolic disorders with thrombin inhibitor relevant disease.
Preferred scheme of the present invention, wherein described thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
The present invention further provides a kind of method treated with thrombin inhibitor relevant disease, wherein methods described includes compound of the present invention or its stereoisomer or pharmaceutically acceptable salt, or composition of the present invention is administered.
Preferred scheme of the present invention, wherein described be selected from thromboembolic disorders with thrombin inhibitor relevant disease.
Preferred scheme of the present invention, wherein described 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 implications.
Involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen include their same position in group of the present invention and compound Involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen are optionally further substituted by their one or more corresponding isotopes in element, and group of the present invention and compound, and the isotope of wherein carbon includes12C、13C and14C, the isotope of hydrogen includes protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), and the isotope of oxygen includes16O、17O and18O, the isotope of sulphur includes32S、33S、34S and36S, the isotope of nitrogen includes14N and15N, the isotope of fluorine19F, the isotope of chlorine includes35Cl and37Cl, the isotope of bromine includes79Br and81Br。
" alkyl " refers to the saturated aliphatic hydrocarbons group of straight chain and side chain, main chain includes 1 to 20 carbon atom, preferably 1 to 12 carbon atom, more 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, the tert-butyl group, n-pentyl, 2- amyl groups, 3- amyl groups, 2- methyl -2- butyl, 3- methyl -2- butyl, 3- methyl isophthalic acids-butyl, 2-methyl-1-butene base, n-hexyl, 2- hexyls, 3- hexyls, 2- methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- methyl -2- amyl groups, 3- methyl -3- amyl groups, 2- methyl -3- amyl groups, 2,3- dimethyl -2- butyl, 3,3- dimethyl -2- butyl, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,2- dimethyl amyl groups, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2,2- dimethylhexanyls, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- ethylhexyls, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethylhexyls and positive decyl；Alkyl can be substituted or unsubstituted, when substituted, substituent can be substituted on any workable tie point, and substituent is preferably 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, 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, the 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 is preferably 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate artyl sulfo, thiocarbonyl or silylation etc..
" side-chain radical of amino acid ", amino acid refers to the common name of the class organic compound containing amino and carboxyl, and its formula isDescribed " side-chain radical of amino acid " refers to L groups herein, and the side-chain radical that non-limiting examples include but is not limited to glycine is that H, the side-chain radical of alanine are that methyl, the side-chain radical of phenylalanine are that benzyl, the side-chain radical of valine are isopropyl etc..
" optional " or " optionally " refer to event described later or environment can with but necessarily occur, the explanation includes the occasion that the event or environment occur or do not occurred, such as：" alkyl optionally replaced by F " refer to alkyl can with but necessarily replaced by F, illustrate to include the situation that alkyl is not replaced by the F situations replaced and alkyl by F.
" substitution " refers to that one or more hydrogen atoms are by the situation of other substituent groups in group, if described group is replaced by hydrogen atom, the group of formation is identical with 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 heterocycles are optionally further selected from H, F, Cl, Br, I, hydroxyl, cyano group, amino, C by 0 to 41-4Alkyl or C1-4The substituent of alkoxy is replaced, and 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- hydroxycyclopropyls, 2- amino cyclopropyl, 4- methylfurans base, 2- hydroxy phenyls, 4- aminophenyls, 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 after " alternatively " and the scheme before " alternatively " are referred to for 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 described free acid by with nontoxic inorganic base or organic base, or described free acid passes through those salt with nontoxic inorganic acid or organic acid reaction acquisition, 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, guanidinesalt, 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, oxalic acid Salt, oxyacetate, glucuronate salt, galacturonic hydrochlorate, citrate, lysine salt, arginine salt, aspartate, cinnamate.
Synthetic method
Method one：
R2For n-hexyl；
R1Definition it is consistent with above leading to definition described in formula (I).
Method two：
R1Selected from C1-10Alkyl, the alkyl is optionally further by 1 to 12 R1aSubstitution；
R2Selected from C1-10Alkyl, the alkyl is optionally further by 1 to 12 R2aSubstitution；
R1aAnd R2aIt is independently selected from H, F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxy or C6-10Carbocyclic ring；
Condition is, R1Or R2In at least one substituted base, and at least one R1aOr R2aFor F.
Embodiment
Technical scheme is described in detail below in conjunction with drawings and Examples, but protection scope of the present invention includes but is not limited to this.
The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10-6(ppm) unit is provided.NMR measure is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
MS measure uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC measure uses Agilent 1260DAD high pressure liquid chromatographs (100 × 4.6mm of Zorbax SB-C18).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used 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 carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.
Oneself initiation material known of the present invention can be used or synthesized according to methods known in the art, or be can purchase in the smooth science and technology of Thailand, pacified the companies such as silent resistance to Jilin Chemical, Shanghai moral, the imperial chemical industry of Chengdu section, splendid remote chemistry science and technology, lark prestige science and technology.
Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to the 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- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1)
3-[[2-[[4-[(Z)-N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
The first step：3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1)
3-[[2-[[4-[(Z)-N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
By 3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] ethyl propionate (1a) (63g, 100mmol) it is added to the in the mixed solvent of ethanol (600mL) and water (300mL), add sodium hydroxide (8g, 200mmol), half an hour is stirred at room temperature, to reaction solution clarification.Concentration of reaction solution, rotate most of ethanol, add water (200mL), pH to 4~5 is adjusted with 10% aqueous citric acid solution, a large amount of thick solids are separated out, filtering, solid is transferred in reaction bulb, add methanol (300mL), it is heated to solid dissolving, continue to stir to solid and be in granular form, it is cooled to zero degree, more products are separated out, filter and dry, obtain title compound 3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (50g of white solid, yield 83%).
LCMS m/z=600.2 [M+1].
1H NMR(400MHz,DMSO)：δ8.38(d,1H),7.79(d,2H),7.56(m 1H),7.48(s,1H),7.39(d,1H),7.14(m2H),6.95(d,2H),6.77(d,2H),4.60(d,2H),4.18(t,2H),3.99(t,2H),3.77(s,3H),2.68-2.58(m,3H),1.58(dd,2H),1.29(d,6H),0.87(t,3H).
Embodiment 1
3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 3,3,3,-trifluoro propyl ester (compound 1)
3,3,3-trifluoropropyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (0.6g is sequentially added at 0 DEG C in there-necked flask, 0.001mol), 3, 3, 3- trifluoros propyl- 1- alcohol (1A) (0.17g, 0.0015mol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.25g, 0.0013mol), DMAP (0.073g, 0.0006mol), then the N added, dinethylformamide (10mL) insulated and stirred 0.5 hour, it is warmed to room temperature reaction 5 hours.Stop reaction and ethyl acetate (60mL) is added into reaction solution, (40mL × 5) are washed with water in organic phase, with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, residue uses column chromatography purification (dichloromethane：Methanol (v/v)=100:1-20:1) white solid 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 3 is obtained, 3,3,-trifluoro propyl ester (compound 1) (0.05g, 7.32%).
1H NMR(400MHz,CDCl3):δ8.42(d,1H),7.73-7.63(m,3H),7.35-7.30(m,1H),7.25-7.17(m,1H),7.10-7.07(m,1H),7.00-6.97(m,1H),6.71-6.64(m,3H),5.37(s,1H),4.47-4.41(m,4H),4.27-4.24(t,2H),4.15-4.11(m,2H),3.70(s,3H),2.85-2.81(t,3H),2.46-2.39(m,2H),1.74-1.70(m,2H),1.43-1.40(m,2H),1.32-1.27(m,4H),0.89-0.87(t,3H)。
Embodiment 2
3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2,2,3,3,4, the fluorine butyl esters (compound 2) of 4,4- seven
2,2,3,3,4,4,4-heptafluorobutyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (0.6g is sequentially added at 0 DEG C in there-necked flask, 0.001mol), seven fluoro butanols (2A) (0.3g, 0.0015mol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.25g, 0.0013mol), DMAP (0.073g, 0.0006mol), then the N added, dinethylformamide (10mL) insulated and stirred 0.5 hour, it is warmed to room temperature reaction 5 hours.Stop reaction and ethyl acetate (60mL) is added into reaction solution, (40mL × 5) are washed with water in organic phase, with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, residue uses column chromatography purification (dichloromethane：Methanol (v/v)=100:1-20:1) white solid 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2 is obtained, 2,3,3,4, the fluorine butyl esters (compound 2) (0.113g, 14.5%) of 4,4- seven.
1H NMR(400MHz,CDCl3):δ8.42(d,1H),7.75-7.70(m,3H),7.34-7.29(m,2H),7.12-7.10(d,2H),7.01-6.97(m,1H),6.68-6.65(m,3H),5.38(s,1H),4.59-4.52(t,2H),4.49-4.44(m,4H),4.16-4.12(t,2H),3.72(s,3H),2.95-2.91(t,3H),1.76-1.68(m,2H),1.42-1.38(m,2H),1.33-1.29(m,4H),0.90-0.87(t,3H)。
Embodiment 3
3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2,2,3,3,4,4,5,5,6, the own ester of the fluorine of 6,6- 11 (compound 3)
2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (0.6g is sequentially added at 0 DEG C in there-necked flask, 0.001mol), 11 fluorine n-hexane -1- alcohol (3A) (0.45g, 0.0015mol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.25g, 0.0013mol), DMAP (0.073g, 0.0006mol), then the N added, dinethylformamide (10mL) insulated and stirred 0.5 hour, it is warmed to room temperature reaction 5 hours.Stop reaction and ethyl acetate (60mL) is added into reaction solution, (40mL × 5) are washed with water in organic phase, with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, residue uses column chromatography purification (dichloromethane：Methanol (v/v)=100:1-20:1) white solid 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2 is obtained, 2,3,3,4,4,5,5,6, the own ester of the fluorine of 6,6- 11 (compound 3) (0.113g, 14.5%).
1H NMR(400MHz,CDCl3):δ8.42(d,1H),7.75-7.70(m,3H),7.34-7.29(m,2H),7.14-7.12(d,2H),7.01-6.98(m,1H),6.71-6.65(m,3H),5.38(s,1H),4.60-4.44(m,6H),4.16-4.13(t,2H),3.74(s,3H),2.95-2.92(t,2H),1.76-1.69(m,2H),1.42-1.38(m,2H),1.33-1.31(m,4H),0.89-0.87(t,3H)。
Embodiment 4
3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid trifluoro ethyl ester (compound 4)
(Z)-2,2,2-trifluoroethyl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
By 3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (0.85g, 1.4mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.43g, 2.24mmol), DMAP (0.1g, 0.84mmol), the N being added to, trifluoroethanol (4A) (0.14g is stirred at room temperature 1 hour and then added in dinethylformamide (5mL), 1.4mmol), room temperature reaction 16 hours, water (100mL) is added into reaction solution again, aqueous phase is extracted with ethyl acetate (50mL × 2), merge organic phase, organic phase With saturated common salt water washing (100mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=100:1~20:1) title compound is obtained：3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid trifluoro ethyl ester (compound 4), white solid (100mg, yield 10.4%).
LCMS m/z=682.2 [M+1].
1H NMR(400MHz,CDCl3)δ8.43(d,1H),7.81–7.68(m,3H),7.31(d,2H),7.14(d,1H),6.99(dd,1H),6.69(dd,3H),5.33(s,1H),4.69–4.39(m,6H),4.14(dd,2H),3.74(s,3H),2.93(t,2H),1.85–1.62(m,3H),1.44–1.23(m,6H),0.88(d,3H)。
Embodiment 5
3- (1- methyl-N- (pyridine -2- bases) -2- (((4- (N'- ((3,3,3- trifluoros propoxyl group) carbonyl) carbonamidine base) phenyl) amino) methyl) -1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate (compound 5)
ethyl 3-(1-methyl-N-(pyridin-2-yl)-2-(((4-(N'-((3,3,3-trifluoropropoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
At room temperature 3, phosphinylidyne diimidazole (1.00g, 6.17mmol) is added in the tetrahydrofuran (10mL) of 3,3- tri- fluoro- 1- propyl alcohol (0.685g, 6.01mmol), is stirred at room temperature 30 minutes, removal of solvent under reduced pressure is prepared into reaction solution 1.In 3- (2- (((4- carbamimido-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate toluenesulfonate (5A) (2.67g, acetone (100mL), water (50mL), potassium carbonate (1.65g are added in 4.00mmol), 11.9mmol), reaction solution 1 is stirring evenly and then adding into, is reacted at room temperature 5 hours after adding.Filter the white solid separated out, acetone/water (acetone：Water (v/v)=1:2) filter cake, afterwards with dichloromethane (100mL) dissolving, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane are washed：Methanol (v/v)=100:1~30:1) title compound 3- (1- methyl-N- (pyridine -2- bases) -2- (((4- (N'- ((3 are obtained, 3,3- trifluoros propoxyl group) carbonyl) carbonamidine base) phenyl) amino) methyl) -1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate (compound 5), brown solid (0.60g, yield 23.0%).
LCMS m/z=640.3 [M+1].
1H NMR(400MHz,DMSO)δ9.12(s,1H),8.75(s,1H),8.39(dd,1H),7.81(d,2H),7.54(m,1H),7.48(d,1H),7.40(d,1H),7.16(dd,1H),7.14–7.06(m,1H),6.97(t,1H),6.89(d,1H),6.77(d,2H),4.60(d,2H),4.22(m,4H),3.98(q,2H),3.77(s,3H),2.76–2.59(m,4H),1.12(t,3H)。
Embodiment 6
3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2- fluorine ethyl ester (compound 6)
2-fluoroethyl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
By 3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (1g, 1.67mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.96g, 5.01mmol), DMAP (0.3g, 2.5mmol), the N being added to, fluoroethanol (10A) (0.106g is stirred at room temperature 1 hour and then added in dinethylformamide (5mL), 01.67mmol), room temperature reaction 16 hours, water (100mL) is added into reaction solution again, aqueous phase is extracted with ethyl acetate (50ml × 2), merge organic phase, organic phase is with saturated common salt water washing (100ml × 1), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=100:1~20:1) title compound 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2- fluorine ethyl ester (compound 6) is obtained, white solid (300mg, yield 28%).
LCMS m/z=646.4 [M+1].
1H NMR(400MHz,CDCl3)δ8.42(d,1H),7.80–7.64(m,3H),7.31(m,2H),7.11(d,1H),6.98(dd,1H),6.69(t,3H),5.34(s,1H),4.67–4.59(m,1H),4.55–4.39(m,5H),4.36–4.28(m,1H),4.28–4.22(m,1H),4.14(t,2H),3.72(s,3H),2.86(t,2H),1.80–1.62(m,3H),1.46–1.22(m,6H),0.89(t,3H)。
Embodiment 7
3- ((((4- (the N'- (((2 of -1- methyl-N- (pyridine -2- bases) -2,2,3,3,4,4,5,5,6, the fluorine of 6,6- 11) epoxide) carbonyl) carbonamidine base) phenyl) amino) methyl) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate (compound 7)
ethyl 3-(1-methyl-N-(pyridin-2-yl)-2-(((4-(N'-(((2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyl)oxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
11 fluorine n-hexane -1- alcohol (0.58g, 1.93mmol) and tetrahydrofuran (3mL) are added in reaction bulb, N is then added, N'- carbonyl dimidazoles (0.34g, 2.08mmol) are stirred at room temperature 1 hour, and be concentrated under reduced pressure to obtain grease.It is another to take reaction bulb to add 3- (2- (((4- carbamimido-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate (7A) (1g, 1.49mmol), and grease, acetone (30mL), water (15mL).It is stirred at room temperature 5 hours, evaporated under reduced pressure acetone, water (60mL) is added in residue, ethyl acetate extracts (70mL × 3), merge organic phase, saturated common salt water washing (90mL), anhydrous sodium sulfate drying, contracting, residue uses column chromatography purification (dichloromethane：Methanol (v/v)=30:1-10:1) the white solid 3- ((((4- (N'- (((2 of -1- methyl-N- (pyridine -2- bases) -2 are obtained, 2,3,3,4,4,5,5,6,6,6- ten one fluorine) epoxide) carbonyl) carbonamidine base) phenyl) amino) methyl) -1H- benzos [d] imidazoles -5- formamidos) ethyl propionate (compound 7) (0.609g, 49%).
1H NMR(400MHz,CDCl3):δ8.43-8.41(d,1H),7.76-7.75(m,2H),7.69-7.67(m,1H),7.34-7.28(m,2H),7.10-7.08(d,1H),7.00-6.97(m,1H),6.73-6.71(d,1H),6.67-6.64(m,2H),5.38(s,1H),4.73-4.66(t,2H),4.47-4.41(m,4H),4.11-4.05(m,2H),3.70(s,3H),2.83-2.79(t,2H),1.24-1.20(t,3H)。
Embodiment 8
3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2,2,3,3,3,-five fluorine propyl ester (compound 8)
2,2,3,3,3-pentafluoropropyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (0.6g is sequentially added at 0 DEG C in there-necked flask, 0.001mol), 2, 2, 3, 3, 3,-five fluorine propyl alcohol (8A) (0.225g, 0.0015mol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.25g, 0.0013mol), DMAP (0.073g, 0.0006mol), then the N added, dinethylformamide (10mL) insulated and stirred 0.5 hour, it is warmed to room temperature reaction 5 hours.Stop reaction and ethyl acetate (60mL) is added into reaction solution, (40mL × 5) are washed with water in organic phase, with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, residue uses column chromatography purification (dichloromethane：Methanol (v/v)=100:1-20:1) white solid 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2 is obtained, 2,3,3,3,-five fluorine propyl ester (compound 8) (0.11g, 15%).
1H NMR(400MHz,CDCl3):δ8.42(d,1H),7.75-7.70(m,3H),7.34-7.29(m,2H),7.12-7.10(d,2H),7.01-6.98(m,1H),6.69-6.65(m,3H),5.39(s,1H),4.55-4.44(m,6H),4.16-4.12(t,2H),3.72(s,3H),2.94-2.91(t,3H),1.76-1.68(m,2H),1.42-1.38(m,2H),1.33-1.31(m,4H),0.91-0.87(t,3H)。
Embodiment 9
3- (2- (((4- (N'- (((6,6- difluoros hexyl) epoxide) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -- 1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate (compound 9)
ethyl 3-(2-(((4-(N'-(((6,6-difluorohexyl)oxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
The first step：6- ((t-Butyldimethylsilyl) epoxide) hexyl -1- alcohol (9B)
6-((tert-butyldimethylsilyl)oxy)hexan-1-ol
1 under ice bath, 6- hexylene glycols (9A) (10g, imidazoles (8.85g is added in dichloromethane (150mL) 85mmol), 130mmol), tert-butyl chloro-silicane (12.8g is added dropwise after 10 minutes in stirring, dichloromethane (100mL) solution 84.9mmol), is reacted at room temperature 5 hours after adding.Water (200mL) is added into reaction solution, is extracted with dichloromethane (100mL × 3), merges organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=10:1~3:1) title compound 6- ((t-Butyldimethylsilyl) epoxide) hexyl -1- alcohol (9B), colourless liquid (8.0g, yield 41%) are obtained.
1H NMR(400MHz,CDCl3)δ3.62(m,4H),1.55(m,4H),1.40(s,1H),1.40–1.33(m,4H),0.89(s,9H),0.04(s,6H)。
Second step：6- ((t-Butyldimethylsilyl) epoxide) hexanal (9C)
6-((tert-butyldimethylsilyl)oxy)hexanal
At room temperature in 6- ((t-Butyldimethylsilyl) epoxide) hexyl -1- alcohol (9B) (5g, 6g silica gel and pyridinium chloro-chromate (7.0g are added in 150mL dichloromethane 22mmol), 33mmol), reacted at room temperature 3 hours after adding.Concentration, residue silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=100:1~20:1) title compound 6- ((t-Butyldimethylsilyl) epoxide) hexanal (9C), colourless liquid (2.0g, yield 40%) are obtained.
1H NMR(400MHz,CDCl3)δ9.72(t,1H),3.57(dd,2H),2.39(td,2H),1.65–1.57(m,2H),1.52–1.46(m,2H),1.37–1.30(m,2H),0.85(s,9H),-0.00(s,6H)。
3rd step：The tert-butyl group ((6,6- difluoros hexyl) epoxide) dimethylsilane (9D)
tert-butyl((6,6-difluorohexyl)oxy)dimethylsilane
In 6- ((t-Butyldimethylsilyl) epoxide) hexanal (9C) (1.8g under ice bath, diethylin sulfur trifluoride (2.3g is added in toluene (15mL) solution 7.1mmol), 14mmol), reacted at room temperature 2 hours after adding.Into reaction solution Water (20mL) is added, is extracted with dichloromethane (50mL × 2), merges organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=100:0~20:1) the title compound tert-butyl group ((6,6- difluoro hexyl) epoxide) dimethylsilane (9D), colourless liquid (1.4g, yield 78%) is obtained.
1H NMR(400MHz,CDCl3)δ5.79(tt,1H),3.60(td,2H),1.84(m,2H),1.58–1.32(m,6H),0.90(d,9H),0.05(d,6H)。
4th step：6,6- difluoro hexyl -1- alcohol (9E)
6,6-difluorohexan-1-ol
In the tert-butyl group ((6 under ice bath, 6- difluoros hexyl) epoxide) dimethylsilane (9D) (1.4g, tetrabutyl amine fluoride (2.2g, 8.4mmol) is added in 15mL tetrahydrofuran solutions 5.5mmol), is reacted at room temperature 3 hours after adding.Water (20mL) is added into reaction solution, is extracted with dichloromethane (50mL × 2), merges organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=100:0~20:1) title compound 6,6- difluoro hexyl -1- alcohol (9E), colourless liquid (0.45g, yield 59%) are obtained.
1H NMR(400MHz,CDCl3)δ5.80(tt,1H),3.66(t,2H),1.84(m,2H),1.60(m,2H),1.48(m,4H)。
5th step：3- (2- (((4- (N'- (((6,6- difluoros hexyl) epoxide) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -- 1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate (compound 9)
ethyl 3-(2-(((4-(N'-(((6,6-difluorohexyl)oxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Phosphinylidyne diimidazole (0.470g is added in the tetrahydrofuran (10mL) of 6,6- difluoro hexyl -1- alcohol (9E) (0.400g, 2.90mmol) at room temperature, 2.90mmol), it is stirred at room temperature 30 minutes, removal of solvent under reduced pressure is prepared into reaction solution 1.3- (2- (((4- carbamimido-phenyls) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate toluenesulfonate (5A) (2.44g, acetone (100mL), water (50mL), potassium carbonate (1.65g are added in 3.60mmol), 11.9mmol), reaction solution 1 is stirring evenly and then adding into, is reacted at room temperature 5 hours after adding.Filter the white solid separated out, acetone/water (acetone：Water (v/v)=1:2) filter cake, afterwards with dichloromethane (100mL) dissolving, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane are washed：Methanol (v/v)=100:1~30:1) To title compound 3- (2- (((4- (N'- (((6,6- difluoros hexyl) epoxide) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -- 1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate (compound 9), white solid (0.400g, yield 16.7%).
LCMS m/z=664.2 [M+1].
1H NMR(400MHz,DMSO)δ9.08(s,1H),8.69(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),7.12(m,1H),6.94(t,1H),6.89(d,1H),6.77(d,2H),6.05(tt,1H),4.59(d,2H),4.23(t,2H),3.98(q,4H),3.76(s,3H),2.68(t,2H),1.85–1.74(m,1H),1.68–1.53(m,2H),1.49–1.30(m,4H),1.12(t,3H)。
Embodiment 10
3- (2- (((4- (N'- (((fluorine amyl groups of 6,6- bis-) epoxide) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate (compound 10)
ethyl 3-(2-(((4-(N'-(((6,6-difluoropentyl)oxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 9.
1H NMR(400MHz,CDCl3)δ8.42(d,1H),7.82–7.67(m,3H),7.32(d,2H),7.13(d,1H),7.02–6.95(m,1H),6.71(d,3H),5.81(dd,1H),5.30(s,1H),4.51(d,2H),4.43(t,2H),4.17(t,2H),4.08(q,2H),3.73(s,3H),2.81(t,2H),1.87(s,2H),1.83–1.74(m,2H),1.61(d,2H),1.22(t,3H)。
Embodiment 11
3- (2- (((4- (N'- ((ethyoxyl) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2,2,3,3,4,4,5,5,6, the own ester of the fluorine of 6,6- 11 (compound 11)
2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyl 3-(2-(((4-(N'-((ethyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
The first step：3- (2- (((4- (N'- ((ethyoxyl) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid (11B)
3-(2-(((4-(N'-((ethyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propionic acid
3- [[2- [[4- [(Z)-N`- carbethoxyl groups amidino groups] anilino-] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridines) amino] propionic acid second fat (11A) (0.80g is added into reaction bulb, 1.40mmol), water (16ml), ethanol (8ml), sodium hydroxide (0.18g, 4.5mmol), react at room temperature 2 hours.Add acetic acid and be adjusted to neutrality, it is filtrated to get white solid 3- (2- (((4- (N'- ((ethyoxyl) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid (11B) (0.38g, yield：50.0%).
LCMS m/z=544.3 [M+1].
1HNMR(400MHz,DMSO)δ8.37(dd,1H),7.80(d,2H),7.56(m,1H),7.48(d,1H),7.39(d,1H),7.28–7.08(m,3H),6.94(dd,2H),6.76(d,2H),4.59(d,2H),4.19–4.10(m,2H),4.03(q,2H),3.76(s,3H),2.59–2.52(m,2H),2.30(s,1H),1.90(s,1H),1.21(m,3H)。
Second step：3- (2- (((4- (N'- ((ethyoxyl) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2,2,3,3,4,4,5,5,6, the own ester of the fluorine of 6,6- 11 (compound 11)
2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyl 3-(2-(((4-(N'-((ethyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
3- (2- (((4- (N'- ((ethyoxyl) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid (11B) (0.38g is added into reaction bulb, 0.70mmol) with 11 fluorine n-hexane -1- alcohol (0.31g, 1.00mmol), N, dinethylformamide (14ml), after stirring, it is cooled to 0 DEG C, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.21g, 1.10mmol) with DMAP (0.05g, 0.42mmol), 0 DEG C is stirred 0.5 hour, it is warmed to room temperature reaction 5 hours.Water (20ml) is added, ethyl acetate (30mL), stirring separates organic layer, (20mL × 2) are separately washed with water, obtain organic layer, dry, filters, concentration.Silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=40:1-30:1) white solid 3- (2- (((4- (N'- ((ethyoxyl) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamidos) propionic acid 2 is obtained, 2,3,3,4,4,5,5,6,6, the 6- ten one own ester of fluorine (compound 11) (0.38g, yield：66.0%).
LCMS m/z=826.0 [M+1].
Embodiment 12
3- (1- methyl-N- (pyridine -2- bases) -2- (((4- (N'- ((3,3,3- trifluoro ethoxies) carbonyl) carbonamidine base) phenyl) amino) methyl) -1H- benzos [d] imidazoles -5- formamido groups) ethyl propionate (compound 12)
ethyl 3-(1-methyl-N-(pyridin-2-yl)-2-(((4-(N'-((3,3,3-trifluoroethoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Preparation method is referring to embodiment 5.
LCMS m/z=626.1 [M+1].
1H NMR(400MHz,CDCl3)δ8.41(dd,1H),7.70(d,2H),7.64(d,1H),7.32(t,1H),7.24(dd,1H),7.01(d,1H),7.00-6.95(m,1H),6.70(s,1H),6.56(d,2H),5.41(s,1H),4.55(q,2H),4.46-4.29(m,4H),4.07(q,2H),3.65(s,3H),2.79(t,3H),1.21(t,3H)。
Test case
1st, Pharmacokinetic Evaluation
Healthy adult SD rat (male and female half and half tie up the magnificent Experimental Animal Center of tonneau, animal productiong licensing SCXK (capital) 2012-0001 purchased from Beijing), administration fasted for one day prior can't help water.6 rat oral gavage administration 5mg/kg (in terms of dabigatran original shape medicine), 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 medicine), in 5min, 15min, 30min after (0h) before administration and administration, 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 centrifugations 10min, to be measured in -80 DEG C of preservations.Take each time point rat plasmas of 30ul, inner mark solution (7.5ng/ml Verapamils) 200ul, vortex mixing 1min is added, in 4 DEG C of 13000rpm centrifugations 10min, supernatant 190ul is taken to carry out LC-MS/MS (lc-20A Science and Technology Ltd.s of Shimadzu Corporation, API4000+) analyses.Main pharmacokinetic parameter is analyzed with the non-compartment model of the softwares of WinNonlin 6.3, as a result as shown in table 1.
Table 1：Pharmacokinetic parameter result
Conclusion：The compounds of this invention has preferable Pharmacokinetic Characteristics.The particularly every index of compound 5,12 is substantially better than dabigatran etcxilate.

Claims (12)

  1. Compound and its stereoisomer shown in a kind of logical formula (I) and pharmaceutically acceptable salt, wherein：
    R1Selected from C1-10Alkyl, the alkyl is optionally further by 1 to 12 R1aSubstitution；
    R2Selected from C1-10Alkyl, the alkyl is optionally further by 1 to 12 R2aSubstitution；
    R1aAnd R2aIt is independently selected from H, F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxy or C6-10Carbocyclic ring；
    Condition is, R1Or R2In at least one substituted base, and at least one R1aOr R2aFor F.
  2. Compound according to claim 1 and its stereoisomer and pharmaceutically acceptable salt, wherein：
    R1Selected from C1-6Alkyl, the alkyl is optionally further by 1 to 12 R1aSubstitution；
    R2Selected from C1-8Alkyl, the alkyl is optionally further by 1 to 12 R2aSubstitution.
  3. Compound according to claim 2 and its stereoisomer and pharmaceutically acceptable salt, wherein：
    R1aAnd R2aIt is independently selected from H, F, Cl, Br, methyl, methoxyl group or cyclopropyl.
  4. Compound according to claim 3 and its stereoisomer and pharmaceutically acceptable salt, the wherein compound are selected from one of following structure：
  5. According to compound according to any one of claims 1 to 4 and its stereoisomer, or pharmaceutically acceptable salt, wherein described 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 combinations thereof.
  6. A kind of pharmaceutical composition, described pharmaceutical composition contains the compound according to any one in Claims 1 to 5 or its stereoisomer or pharmaceutically acceptable salt for the treatment of effective dose, and pharmaceutically acceptable carrier or excipient.
  7. Compound and its stereoisomer or pharmaceutically acceptable salt in Claims 1 to 5 described in any one, and purposes of the composition in treatment and thrombin inhibitor relevant disease medicine is prepared described in claim 6.
  8. Purposes according to claim 7, wherein described be selected from thromboembolic disorders with thrombin inhibitor relevant disease.
  9. Purposes according to claim 8, wherein described thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
  10. A kind of method treated with thrombin inhibitor relevant disease, wherein methods described include the compound or its stereoisomer or pharmaceutically acceptable salt described in any one in administration Claims 1 to 5, or the composition described in claim 6.
  11. Method according to claim 10, wherein described be selected from thromboembolic disorders with thrombin inhibitor relevant disease.
  12. Method according to claim 11, wherein described thromboembolic disorders are selected from phlebothrombosis and arterial embolism.
CN201580036777.6A 2014-08-06 2015-08-04 Fluorine substituted dabigatran ester derivative, preparation method therefor, and pharmaceutical use thereof Pending CN106536504A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110343089A (en) * 2018-04-02 2019-10-18 上海美悦生物科技发展有限公司 Benzimidazole derivative and pharmaceutical use thereof

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CN109897028B (en) * 2017-12-11 2021-05-28 上海美悦生物科技发展有限公司 Dabigatran etexilate derivative and pharmaceutical application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103242296A (en) * 2013-05-16 2013-08-14 上海应用技术学院 Dabigatran etexilate analogue with fluorine-containing group modified pyridine ring as center and synthesis method of analogue
CN103420985A (en) * 2012-05-24 2013-12-04 天津药物研究院 Dabigatran derivative used as prodrug, and preparation method and application thereof

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* Cited by examiner, † Cited by third party
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CN104592204B (en) * 2014-12-26 2017-05-17 华润赛科药业有限责任公司 Dabigatran derivatives as well as preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103420985A (en) * 2012-05-24 2013-12-04 天津药物研究院 Dabigatran derivative used as prodrug, and preparation method and application thereof
CN103242296A (en) * 2013-05-16 2013-08-14 上海应用技术学院 Dabigatran etexilate analogue with fluorine-containing group modified pyridine ring as center and synthesis method of analogue

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110343089A (en) * 2018-04-02 2019-10-18 上海美悦生物科技发展有限公司 Benzimidazole derivative and pharmaceutical use thereof

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