CN106536505A - Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof - Google Patents

Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof Download PDF

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CN106536505A
CN106536505A CN201580036778.0A CN201580036778A CN106536505A CN 106536505 A CN106536505 A CN 106536505A CN 201580036778 A CN201580036778 A CN 201580036778A CN 106536505 A CN106536505 A CN 106536505A
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methyl
amino
compound
alkyl
pharmaceutically acceptable
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魏用刚
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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A dabigatran carboalkoxy derivative as indicated in formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a use thereof in preparing medications for preventing and treating thromboembolic diseases, all substituents being defined as in the description.

Description

A kind of dabigatran alkyl ester derivative and preparation method thereof and purposes pharmaceutically Technical field
The present invention relates to a kind of dabigatran alkyl ester derivative and its stereoisomer and 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 dabigatran alkyl ester derivative and its stereoisomer and 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：
X1And X2It is independently selected from O or S；
R1Selected from-(CR1aR1bO)n-(CR1aR1bCR1cR1dO)mR1e；
R2Selected from C1-10Alkyl or-(CR2aR2bCR2cR2dO)mR2e, the alkyl is optionally further by 0 to 12 selected from H, F, Cl, Br, I, C1-4Alkyl or C1-4The substituent of alkoxy is replaced；
R1a、R1b、R1c、R1d、R2a、R2b、R2cAnd R2dIt is independently selected from H, F, Cl, Br, I, C1-4Alkyl or C1-4Alkoxy；
R1eAnd R2eIt is independently selected from H, C1-4Alkyl ,-C (=O) C1-4Alkyl ,-C (=O) C1-4Alkoxy or
R1fIt is independently selected from amino acid side groups；
R1gAnd R1hIt is independently selected from H or amino protecting group；
N is selected from 0 or 1；
M is selected from 1,2,3,4,5 or 6.
Preferred scheme of the present invention, compound and its stereoisomer shown in a kind of logical formula (I) and pharmaceutically acceptable salt, wherein：
R1fIt is independently selected from amino acid side groups；
The amino acid be selected from glycine, alanine, leucine, isoleucine, knot propylhomoserin, proline, phenylalanine, Methionine, tryptophan, serine, glutamine, threonine, cysteine, histidine, asparagine, TYR, aspartic acid, glutamic acid, naphthylamines acid or arginine；
R1gAnd R1hIt is independently selected from H or amino protecting group；
The amino protecting group is selected from benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxycarbonyl group or carbethoxyl group.
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-(CR1aR1bO)n-(CR1aR1bCR1cR1dO)mR1e；
R2Selected from C1-8Alkyl or-(CR2aR2bCR2cR2dO)mR2e, the alkyl is optional further to be replaced by 0 to 12 substituent selected from H, F, Cl or Br；
R1a、R1b、R1c、R1d、R2a、R2b、R2cAnd R2dIt is independently selected from H, F, Cl, Br, I, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or isopropoxy；
R1eAnd R2eIt is independently selected from H, methyl, ethyl ,-C (=O) OCH (CH3)2Or
R1fAmino acid side groups are independently selected from, the amino acid is selected from glycine, alanine, leucine, phenylalanine or knot propylhomoserin；
R1gAnd R1hH or amino protecting group are independently selected from, the amino protecting group is selected from benzyloxycarbonyl group or tertbutyloxycarbonyl；
N is selected from 0 or 1；
M is selected from 1,2 or 3.
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 and 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 and 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.
Amino acid is selected from natural or pharmaceutically acceptable amino acid, it is preferred that glycine, alanine, leucine, isoleucine, knot propylhomoserin, proline, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, histidine, asparagine, TYR, aspartic acid, glutamic acid, naphthylamines acid or arginine, further preferred glycine, alanine, leucine, phenylalanine, asparagine or arginine, more preferably glycine, alanine or phenylalanine.
Amino protecting group mainly includes alkyl oxycarbonyl base class, acyl group class, alkyls.Alkyl oxycarbonyl base class includes but is not limited to benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl or methoxycarbonyl group or carbethoxyl group；Acyl group class includes but is not limited to phthalyl, p-toluenesulfonyl, trifluoroacetyl group, ortho-nitrophenyl sulfonyl, p-nitrophenyl sulfonyl, pivaloyl group or benzoyl；Alkyls includes but is not limited to trityl group, 2,4- dimethoxy-benzyls, to methoxy-benzyl or benzyl.
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 isotope in group of the present invention and compound, and involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen is optionally further substituted by their one or more corresponding isotopes in group of the present invention and compound, 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, simultaneously 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 or 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, three Ethylamine 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, oxalates, oxyacetate, glucuronate salt, galacturonic hydrochlorate, citrate, lysine salt, arginine salt, aspartate or cinnamate.
Synthetic method
Method one：
X2For O；R2For n-hexyl；
R1、X1It is consistent with above leading to definition described in formula (I)；
Method two：
R1、R2、X1、X2It is consistent with above leading to definition described in formula (I).
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 Avance300) nuclear magnetic resonance spectrometer, and 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- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1)
3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
The first step：3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) 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 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- [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(m,2H),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,2H),1.58(dd,2H),1.29(d,6H),0.87(t,3H).
Embodiment 1
(2R) -2- methoxy-propyls 3- [[2- [[4- [the own oxygen carbonyl first of N`- is narrowed] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 1)
(2R)-2-methoxypropyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
At room temperature in 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (1.00g, (R) -2- methoxy-1-propanols (1A) (0.226mg is added in dimethylformamide (15mL) solution 1.67mmol), 2.505mmol), 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (0.832g, 4.34mmol) with DMAP (122mg, 1.00mmol), room temperature reaction 15 hours.Water (30mL) is added into reaction solution, is extracted with ethyl acetate (50mL × 3), merges organic phase, organic phase is washed (30mL × 2) with the aqueous solution, and anhydrous sodium sulfate drying is used, concentrate, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=50:1~30:1) title compound (2R) -2- methoxy-propyls 3- [[2- [[4- [the own oxygen carbonyl first of N`- is narrowed] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 1) is obtained, white solid, (0.5g, yield 44.64%).
LCMS m/z=672.34 [M+1].
1H NMR(400MHz,CDCl3)δ8.41(d,1H),7.76(d,2H),7.71(s,1H),7.32(dd,2H),7.12(d,1H),6.98(dd,1H),6.75–6.62(m,3H),5.34(s,1H),4.50(s,2H),4.43(t,2H),4.14(t,2H),4.02(dd,2H),3.72(d,3H),3.57–3.49(m,1H),3.36(s,2H),2.85(dd,2H),1.72(m,2H),1.40(dd,2H),1.31(dd,2H),1.25(s,3H),1.15(d,3H),0.89(dd,3H)。
Embodiment 2
[(1R) -2- methoxy -1- methyl-ethyls] 3- [[2- [[4- [the own oxygen carbonyl first of N`- narrows base] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 2)
[(1R)-2-methoxy-1-methyl-ethyl]3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=672.34. [M+1].
1H NMR(400MHz,CDCl3)δ8.41(dd,1H),7.73(d,2H),7.68(s,1H),7.32(m,1H),7.28(d,1H),7.25(s,1H),7.07–6.98(m,1H),6.71(d,1H),6.65(d,2H),5.37(s,1H),5.04(m,1H),4.55–4.33(m,4H),4.13(dd,2H),3.69(s,3H),3.44–3.36(m,2H),3.34(s,3H),2.81(t,2H),1.71(dd,2H),1.39(dd,2H),1.31(dd,4H),1.20(d,3H),0.88(t,3H)。
Embodiment 3
2- (2- methoxy ethoxies) ethyl 3- [[2- [[4- [(Z)-N`-3- [[2- [[4- [(Z)-N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 3)
2-(2-methoxyethoxy)ethyl 3-[[2-[[4-[(Z)-N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=702.3 [M+1].
1H NMR(400MHz,CDCl3)δ8.44–8.38(m,1H),7.77(d,2H),7.71(s,1H),7.36–7.29(m,2H),7.13(d,1H),6.98(dd,1H),6.71(t,3H),5.31(d,1H),4.50(d,2H),4.43(t,2H),4.17(m,4H),3.73(s,3H),3.71–3.66(m,2H),3.63(dd,2H),3.54(dd,2H),3.37(s,3H),2.85(t,2H),1.77–1.67(m,2H),1.40(dd,2H),1.31(dd,4H),0.89(t,3H)。
Embodiment 4
2- [3- [[2- [[4- [N'- hexyloxy carbonyl carbonamidines base] phenylamino] methyl] -1- methyl-benzo [d] imidazoles -5- carbonyls]-(2- pyrroles Piperidinyl) amino) propionyloxy) ethyl (2S) -2- amino -3 Methylbutanoic acid ester (compound 4)
2-[3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoyloxy]ethyl(2S)-2-amino-3-methyl-butanoate
Preparation method is referring to embodiment 1.
1H NMR(400MHz,CDCl3)δ8.41(dd,1H),7.74(d,2H),7.70(s,1H),7.37–7.27(m,2H),7.12(d,1H),6.99(m,1H),6.70(t,3H),5.47(s,1H),4.50(d,2H),4.42(t,2H),4.31(dd,2H),4.26(dd,2H),4.14(t,2H),3.71(s,3H),3.48(s,2H),3.32(d,1H),2.83(t,2H),2.08–1.98(m,1H),1.76–1.66(m,2H),1.45–1.36(m,2H),1.35–1.28(m,2H),0.96(d,3H),0.91–0.86(m,6H)。
Embodiment 5
2- (2- hydroxyl-oxethyls) ethyl 3- [[2- [[4- [(Z)-N` hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 5)
2-(2-hydroxyethoxy)ethyl 3-[[2-[[4-[(Z)-N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=688.3 [M+1].
1H NMR(400MHz,CDCl3)δ8.40(dd,1H),7.77–7.68(m,3H),7.37–7.29(m,2H),7.11(d,1H),7.01–6.94(m,1H),6.73(d,1H),6.66(d,2H),5.43(s,1H),4.51–4.37(m,4H),4.27–4.19(m,2H),4.19–4.10(m,2H),3.78–3.64(m,7H),3.62–3.57(m,2H),2.83(t,2H),1.76–1.68(m,2H),1.40(dd,2H),1.36–1.28(m,4H),0.89(dd,3H)。
Embodiment 6
(S) -1- methoxy propyls -2- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propionic ester (compound 6)
(S)-1-methoxypropan-2-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
At room temperature in 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (1.50g, S-1- methoxy-2-propanols (0.450mg is added in dimethylformamide (15mL) solution 2.50mmol), 4.99mmol), 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (0.90g, 5.1mmol) with DMAP (185mg, 1.51mmol), react at room temperature 15 hours.Water (30mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed (30mL × 2) with saturation potassium dihydrogen phosphate, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=100:1~30:1) title compound (S) -1- methoxy propyl -2- bases 3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propionic ester (compound 6) is obtained, Orange red solid (0.400g, yield 23.8%).
LCMS m/z=672.3 [M+1].
1H NMR(400MHz,DMSO)δ9.01(s,1H),8.67(s,1H),8.39(dd,1H),7.80(d,2H),7.54(m,1H),7.47(d,1H),7.39(d,1H),7.16(dd,1H),7.12(dd,1H),6.98–6.86(m,2H),6.76(d,2H),4.90(m,1H),4.59(d,2H),4.22(t,2H),3.98(t,2H),3.76(s,3H),3.38–3.27(m,4H),3.31(s,2H),3.23(s,3H),2.68(t,2H),1.58(m,2H),1.39–1.22(m,6H),1.07(d,3H),0.87(t,3H)。
Embodiment 7
[(2S) -2- methoxy-propyls] 3- [[2- [[4- [the own oxygen carbonyl carbonamidine bases of N`-] phenylamino] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 7)
[(2S)-2-methoxypropyl]3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1- methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=672.34 [M+1].
1H NMR(400MHz,CDCl3)δ8.38(d,1H),7.67(d,3H),7.32(m,1H),7.23(dd,1H),7.04(d,1H),6.99–6.92(m,1H),6.70(d,1H),6.58(d,2H),5.61(s,1H),4.42(dd,4H),4.13(t,2H),4.01(m,2H),3.64(d,3H),3.56–3.45(m,1H),3.35(s,3H),2.84(t,2H),1.78–1.55(m,2H),1.46–1.34(m,2H),1.34–1.21(m,4H),1.14(d,3H),0.88(t,3H)。
Embodiment 8
2- methoxy (ethoxy) methyl 3- [[2- [[4- [the own oxygen carbonyl carbonamidine bases of N`-] phenylamino] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 8)
2-methoxyethoxymethyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=688.34 [M+1].
1H NMR(400MHz,CDCl3)δ8.40(dd,1H),7.72(d,2H),7.67(d,1H),7.32(m,1H),7.27–7.24(d,1H),7.06(d,1H),7.01–6.93(m,1H),6.70(d,1H),6.63(d,2H),5.39(s,1H),5.28(s,2H),4.43(dd,4H),4.12(t,2H),3.80–3.73(m,2H),3.68(s,3H),3.57–3.48(m,2H),3.36(s,3H),2.85(t,2H),1.70(dd,2H),1.39(dd,2H),1.30(dd,4H),0.88(dd,3H)。
Embodiment 9
(S) -2- ((3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propiono) epoxide) ethyl 2- ((tertbutyloxycarbonyl) amino) -3- phenylpropionic acid esters (compound 9)
(S)-2-((3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoyl)oxy)ethyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate
The first step：(S) -2- hydroxyethyls 2- ((tertbutyloxycarbonyl) amino) -3- Phenpropionates (9B)
(S)-2-hydroxyethyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate
In S-N- tertbutyloxycarbonyl phenylalanines (5.3g under ice bath, ethylene glycol (5.0g is added in dichloromethane (150mL) solution 20mmol), 81mmol), DMAP (0.50g, 4mmol) and N, N '-dicyclohexylcarbodiimide (4.3g, 21mmol), react at room temperature 10 hours.Water (100mL) is added into reaction solution, is extracted with dichloromethane (100mL × 2), merges organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=100:1~30:1) title compound (S) -2- hydroxyethyls 2- ((tertbutyloxycarbonyl) amino) -3- Phenpropionates (9B), colorless oil (5.0g, yield 81.0%) are obtained.
1H NMR(400MHz,CDCl3)δ7.34–7.27(m,2H),7.25(dd,1H),7.19–7.17(m,2H),5.00(s,1H),4.53(d,1H),4.29–4.17(m,2H),3.72(m,2H),3.09(d,2H),1.45–1.37(m,9H)。
Second step：(S) -2- ((3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propiono) epoxide) ethyl 2- ((tertbutyloxycarbonyl) amino) -3- phenylpropionic acids ester (compound 9)
(S)-2-((3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoyl)oxy)ethyl 2-((tert-butoxy  carbonyl)amino)-3-phenylpropanoate
At room temperature in 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (3.0g, (S) -2- hydroxyethyls 2- ((tertbutyloxycarbonyl) amino) -3- Phenpropionates (9B) (2.85g is added in dimethylformamide (15mL) solution 5.0mmol), 9.21mmol), 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (1.80g, 10.1mmol) with DMAP (370mg, 3.03mmol), room temperature reaction 15 hours.Water (30mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed (30mL × 2) with saturation potassium dihydrogen phosphate, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=100:1~30:1) title compound (S) -2- ((3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propiono) epoxide) ethyl 2- ((tertbutyloxycarbonyl) amino) -3- phenylpropionic acids ester (compound 9) is obtained; brown solid (2.00g, yield 45.0%).
LCMS m/z=446.4 [M+2]/2.
1H NMR(400MHz,DMSO)δ9.07(s,1H),8.92–8.50(m,1H),8.38(dd,1H),7.79(d,2H),7.52(m,1H),7.47(d,1H),7.38(d,1H),7.29–7.15(m,7H),7.10(dd,1H),6.92(t,1H),6.88(d,1H),6.76(d,2H),4.59(d,2H),4.19(m,5H),4.13–4.05(m,2H),3.97(t,2H),3.75(s,3H),2.97(dd,1H),2.91–2.81(m,1H),2.71(dd,2H),1.57(dd,2H),1.39–1.20(m,15H),0.87(t,3H)。
Embodiment 10
(S) -2- ((3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propiono) epoxide) ethyl -2- amino -3- phenylpropionic acids esters (compound 10)
(S)-2-((3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoyl)oxy)ethyl-2-amino-3-phenylpropanoate
In (S) -2- ((3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propiono) epoxide) ethyl 2- ((tertbutyloxycarbonyl) amino) -3- phenylpropionic acids ester (compound 9) (700mg under ice bath; trifluoroacetic acid (5.0mL) is added in dichloromethane (10mL) solution 0.786mmol), is reacted at room temperature 1 hour.Removal of solvent under reduced pressure, water (10mL) is added into reaction solution, and pH to 13 is adjusted with saturated sodium bicarbonate aqueous solution, dichloromethane extracts (50mL × 3), merges organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=100:2~30:1) title compound (S) -2- ((3- (2- (((4- (N'- ((hexyloxy) carbonyl) carbonamidine base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propiono) epoxide) ethyl -2- amino -3- phenylpropionic acids esters (compound 10) are obtained; yellow solid (580mg, yield 93.3%).
LCMS m/z=791.2 [M+1].
1H NMR(400MHz,DMSO)δ9.09(s,1H),8.67(s,1H),8.38(m,1H),7.80(d,2H),7.53(m,1H),7.48(d,1H),7.39(d,1H),7.22(dd,2H),7.19–7.13(m,4H),7.11(m,1H),6.93(t,1H),6.89(d,1H),6.77(d,2H),4.59(d,2H),4.23(t,2H),4.16(dd,2H),4.14–4.04(m,2H),3.98(t,2H),3.76(s,3H),3.57(t,1H),2.91–2.81(m,1H),2.77(dd,1H),2.71(dd,2H),1.75(s,2H),1.57(dd,2H),1.38–1.25(m,6H),0.87(t,3H)。
Embodiment 11
2- ((isopropyl) epoxide) ethyl 3- (2- (((4- (N'- (butoxy carbonyl) carbonamidines base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -- 1H- benzos [d] imidazoles -5- formamido groups) propionic ester (compound 11)
2-((isopropoxycarbonyl)oxy)ethyl 3-(2-(((4-(N'-(butoxycarbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
The first step：3- ((2- ((4- (N'- di-butoxycarbonyl carbonamidines base) phenylamino) methyl) -1- tolimidazole -5- carbonyls)-(2- pyridine radicals) amino) ethyl propionate (11B)
Ethyl 3-[[2-[[4-[N'-butoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Phosphinylidyne diimidazole (1.50g, 9.25mmol) is added in n-butyl alcohol (0.685g, 9.24mmol) tetrahydrofuran (10mL) at room temperature, 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 (11A) (3.00g, acetone (100mL), water (50mL), potassium carbonate (2.50g are added in 6.00mmol), 18.1mmol), 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 is washed, afterwards with dichloromethane (100mL) dissolving, anhydrous sodium sulfate drying, concentration removes solvent and obtains title compound 3- ((2- ((4- (N'- di-butoxycarbonyl carbonamidines base) phenylamino) methyl) -1- tolimidazole -5- carbonyls)-(2- pyridine radicals) amino) ethyl propionate (11B), white solid (3.00g, yield 83.3%).
Second step：3- [[2- [[4- [N'- oxygen carbonyl carbonamidines base] phenylamino] methyl] -1- tolimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (11C)
3-[[2-[[4-[N'-butoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
At room temperature in 3- ((2- ((4- (N'- di-butoxycarbonyl carbonamidines base) phenylamino) methyl) -1- tolimidazole -5- carbonyls)-(2- pyridine radicals) amino) ethyl propionate (11B) (2.3g, 3.84mmol) ethanol (50mL) solution in add sodium hydroxide (450mg, water (5mL) solution 11.3mmol), is reacted at room temperature 2 hours after adding.PH to 3 is adjusted with citric acid saturated aqueous solution, filter the solid separated out, dichloromethane dissolves, anhydrous sodium sulfate drying, concentration remove solvent and obtain title compound 3- [[2- [[4- [N'- oxygen carbonyl carbonamidines base] phenylamino] methyl] -1- tolimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (11C), white solid (2.00g, yield 91.2%).
3rd step：2- ethoxys butylperoxyisopropyl carbonate (11E)
2-hydroxyethyl isopropyl carbonate
Triethylamine (12.1g, 120mmol) is added under ice bath in dichloromethane (150mL) solution of ethylene glycol (11D) (25.0g, 403mmol).- 50 DEG C are cooled to, isopropyl phosgene (12.26g, 100mmol) is slowly added dropwise, is reacted at room temperature 3 hours after adding.Water (100mL) is added into reaction solution, is extracted with dichloromethane (100mL × 2), merges organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=100:0~30:1) title compound 2- ethoxys butylperoxyisopropyl carbonate (11E), colorless oil (8.0g, yield 54.0%) are obtained.
1H NMR(400MHz,CDCl3)δ4.89(dt,1H),4.32–4.17(m,2H),3.91–3.78(m,2H),2.00(s,1H),1.31(d,6H)。
4th step：2- ((isopropyl) epoxide) ethyl 3- (2- (((4- (N'- (butoxy carbonyl) carbonamidines base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propionic ester (compound 11)
2-((isopropoxycarbonyl)oxy)ethyl 3-(2-(((4-(N'-(butoxycarbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
2- ethoxy isopropyls are added in the 15mL dimethyl formamide solutions of 3- [[2- [[4- [N'- oxygen carbonyl carbonamidines base] phenylamino] methyl] -1- tolimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (11C) (1.0g, 1.7mmol) at room temperature Base carbonic ester (11E) (400mg, 2.70mmol), 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (0.620g, 3.49mmol) with DMAP (128mg, 1.05mmol), react at room temperature 15 hours.Water 30mL is added into reaction solution, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed (30mL × 2) with saturation potassium dihydrogen phosphate, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=100:1~30:1) title compound 2- ((isopropyl) epoxide) ethyl 3- (2- (((4- (N'- (butoxy carbonyl) carbonamidines base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -- 1H- benzos [d] imidazoles -5- formamido groups) propionic ester (compound 11) is obtained, brown solid (300mg, yield 24.0%).
LCMS m/z=702.4 [M+1].
1H NMR(400MHz,DMSO)δ9.11(s,1H),8.71(s,1H),8.39(dd,1H),7.79(d,2H),7.53(td,1H),7.48(d,1H),7.39(d,1H),7.15(dd,1H),7.12(dd,1H),6.94(t,1H),6.89(d,1H),6.76(d,2H),4.80–4.69(m,1H),4.59(d,2H),4.22(dd,4H),4.17(dd,2H),3.99(t,2H),3.76(s,3H),2.71(t,2H),1.57(dt,2H),1.42–1.30(m,2H),1.20(d,6H),0.91(dd,3H)。
Embodiment 12
2- methoxy ethyls 3- [[2- [[4- [N`-3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 12)
2-methoxyethyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
By 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (3g, 5mmol) it is dissolved in anhydrous N, in dinethylformamide (10mL), add glycol monoethyl ether (12A) (0.76g, 10mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.92g, 10mmol), DMAP (0.12g, 1mmol), reaction is stayed overnight at room temperature.Add water (30mL), extracted with dichloromethane (30mL × 3), merge organic layer, washed with saturated sodium-chloride (20mL × 2), anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain crude product addition dichloromethane (24mL), and being heated to backflow makes to be completely dissolved, and adds methyl tertiary butyl ether(MTBE) (48 ML), it is stirred at room temperature 30 minutes, filtering, filter cake is washed with dichloromethane/methyl tertiary butyl ether(MTBE) (v/v=1/2) mixed solvent (20mL), collect filter cake, it is dried under reduced pressure, obtain title compound 2- methoxy ethyls 3- [[2- [[4- [N`-3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 12), white solid (1.9g, yield 57.7%).
LCMS m/z=658.4 [M+1].
1H NMR(400MHz,CDCl3)δ8.41(d,1H),7.76(d,2H),7.70(s,1H),7.36–7.28(m,2H),7.11(d,1H),6.98(dd,1H),6.70(dd,3H),5.32(s,1H),4.49(d,2H),4.44(t,2H),4.21–4.17(m,2H),4.14(t,2H),3.72(s,3H),3.60–3.54(m,2H),3.37(s,3H),2.85(t,2H),1.77–1.68(m,2H),1.40(dd,2H),1.31(dd,4H),0.89(t,3H)。
The hydrochloride of compound 12：
By 2- methoxy ethyls 3- [[2- [[4- [N`-3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 12) (0.3g, 0.5mmol) it is dissolved in acetone (10mL), 0 DEG C is passed through excessive HCl gas, reacts at room temperature 2 hours.Reaction terminates to be concentrated under reduced pressure to give the hydrochloride of compound 12, off-white powder (0.15g, yield 50%).
MS m/z(ESI):658.2[M+1]。
1H NMR(400MHz,DMSO)δ11.99(s,1H),11.11(s,1H),10.10(s,1H),8.38(d,1H),7.82(d,,1H),7.74(d,2H),7.69(s,1H),7.64(t,1H),7.38(d,1H),7.22–7.14(m,1H),7.10(d,1H),6.98(d,2H),5.04(s,2H),4.25(dt,4H),4.13–4.03(m,2H),3.99(s,3H),3.53–3.43(m,2H),3.24(s,3H),2.72(t,2H),2.09(s,1H),1.68(dd,2H),1.38(s,2H),1.34–1.23(m,4H),0.87(d,3H)。
The mesylate of compound 12：
By 2- methoxy ethyls 3- [[2- [[4- [N`-3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 12) (0.33g, 0.44mmol) it is dissolved in acetone (10mL), add methanesulfonic acid (42.3mg, 0.44mmol), react at room temperature 2 hours.After reaction terminates, filter solid is crossed, the mesylate of compound 12, white solid 1 (0.3g, yield 90%) is obtained.
LCMS m/z=658.2 [M+1].
1H NMR(400MHz,DMSO)δ11.87(s,1H),10.69(s,1H),10.04(s,1H),8.39(dd,1H),7.66(d,,3H),7.56(td,1H),7.50(d,1H),7.46(d,1H),7.20(dd,1H),7.16–7.10(m,1H),6.94(d,1H),6.88(d,2H),4.73(s,2H),4.25(dt,4H),4.07(dd,2H),3.80(s,3H),3.48(dd,2H),3.24(s,3H),2.71(t,2H),2.31(s,3H),1.68(dd,2H),1.38(dd,2H),1.35–1.26(m,4H),0.89(t,3H)。
Embodiment 13
2- ((isopropyl) epoxide) ethyl 3- (2- (((4- (N'- (hexyloxy carbonyl) carbonamidines base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propionic ester (compound 13)
2-((isopropoxycarbonyl)oxy)ethyl 3-(2-(((4-(N'-(hexoxycarbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
At room temperature in 3- [[2- [[4- [N`- hexyloxy carbonyls carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid (intermediate 1) (1.5g, 2- ethoxys butylperoxyisopropyl carbonate (11E) (655mg is added in dimethylformamide (15mL) solution 2.50mmol), 4.42mmol), 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (0.900g, 5.07mmol) with DMAP (185mg, 1.51mmol), react at room temperature 15 hours.Water (30mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed (30mL × 2) with saturation potassium dihydrogen phosphate, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=100:1~30:1) title compound 2- ((isopropyl) epoxide) ethyl 3- (2- (((4- (N'- (hexyloxy carbonyl) carbonamidines base) phenyl) amino) methyl) -1- methyl-N- (pyridine -2- bases) -1H- benzos [d] imidazoles -5- formamido groups) propionic ester (compound 13) is obtained, brown solid (550mg, yield 30.0%).
LCMS m/z=730.2 [M+1].
1H NMR(400MHz,CDCl3)δ8.45–8.37(m,1H),7.80–7.63(m,3H),7.33(td,1H),7.29–7.23(m,2H),7.08(d,1H),6.98(dd,1H),6.70(d,1H),6.65(d,2H),5.41(s,1H),4.87(dt,1H),4.49–4.39(m,4H),4.30–4.27(m,2H),4.25(dd,2H),4.14(t,2H),3.69(s,3H),2.85(t,2H),1.71(dd,2H),1.49–1.36(m,2H),1.37–1.23(m,10H),0.89(t,3H)。
Embodiment 14
2- isopropoxyethyls 3- [[2- [[4- [the own oxygen carbonyl first of N`- is narrowed] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 14)
2-isopropoxyethyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 1.
LCMS m/z=686.36 [M+1].
1H NMR(400MHz,CDCl3)δ8.41(dd,1H),7.75(d,2H),7.70(s,1H),7.32(m,2H),7.10(d,1H),6.98(dd,1H),6.72(d,1H),6.68(d,2H),5.36(s,1H),4.48(d,2H),4.43(t,2H),4.14(dd,4H),3.71(s,3H),3.63–3.60(m,1H),3.60–3.55(m,2H),2.84(t,2H),1.77–1.67(m,2H),1.40(dd,2H),1.31(dd,6H),1.15(d,4H),0.89(t,3H)。
Embodiment 15
(1S) -1- methyl -2- methoxy ethyls 3- [[2- [[4- [N`-3- [[2- [[4- [N`- Epoxide carbonyls in heptan carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 15)
(1S)-1-methyl-2-methoxyethyl 3-[[2-[[4-[N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 11.
Embodiment 16
2- methoxy ethyls 3- [[2- [[4- [N`-3- [[2- [[4- [N`- Epoxide carbonyls in heptan carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 16)
2-methoxyethyl 3-[[2-[[4-[N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 11.
Embodiment 17
2- methoxy ethyls 3- [[2- [[4- [N`- (3,3,3- trifluoros propoxyl group) carbonyl first narrows] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic ester (compound 17)
2-methoxyethyl 3-[[2-[[4-[N`-(3,3,3-trifluoropropoxy)carbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 11.
Embodiment 18
(1S) -1- methyl -2- methoxy ethyls 3- [[2- [[4- [N`-3- [[2- [[4- [N`- (3,3,3- trifluoros propoxyl group) carbonyl carbonamidine] aniline] methyl] -1- methyl-benzoimidazole -5- carbonyls]-(2- pyridine radicals) amino] propionic acid fat (compound 18)
(1S)-1-methyl-2-methoxyethyl 3-[[2-[[4-[N`-(3,3,3-trifluoropropoxy)carbonylcarbamimi doyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Preparation method is referring to embodiment 11.
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 is substantially better than dabigatran etcxilate compared with dabigatran etcxilate with the every index of good Pharmacokinetic Characteristics, particularly compound 6,12,14,15.

Claims (12)

  1. Compound and its stereoisomer shown in a kind of logical formula (I) and pharmaceutically acceptable salt, wherein：
    X1And X2It is independently selected from O or S；
    R1Selected from-(CR1aR1bO)n-(CR1aR1bCR1cR1dO)mR1e；
    R2Selected from C1-10Alkyl or-(CR2aR2bCR2cR2dO)mR2e, the alkyl is optionally further by 0 to 12 selected from H, F, Cl, Br, I, C1-4Alkyl or C1-4The substituent of alkoxy is replaced；
    R1a、R1b、R1c、R1d、R2a、R2b、R2cAnd R2dIt is independently selected from H, F, Cl, Br, I, C1-4Alkyl or C1-4Alkoxy；
    R1eAnd R2eIt is independently selected from H, C1-4Alkyl ,-C (=O) C1-4Alkyl ,-C (=O) C1-4Alkoxy or
    R1fIt is independently selected from amino acid side groups；
    R1gAnd R1hIt is independently selected from H or amino protecting group；
    N is selected from 0 or 1；
    M is selected from 1,2,3,4,5 or 6.
  2. Compound according to claim 1 and its stereoisomer and pharmaceutically acceptable salt, wherein：
    The amino acid is selected from glycine, alanine, leucine, isoleucine, knot propylhomoserin, proline, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, histidine, asparagine, TYR, aspartic acid, glutamic acid, naphthylamines acid or arginine；
    The amino protecting group is selected from benzyloxycarbonyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxycarbonyl group or carbethoxyl group.
  3. Compound according to claim 2 and its stereoisomer and pharmaceutically acceptable salt, wherein：
    R2Selected from C1-8Alkyl or-(CR2aR2bCR2cR2dO)mR2e, the alkyl optionally further by 0 to 12 selected from H, F, Cl or Br substituent are replaced；
    R1a、R1b、R1c、R1d、R2a、R2b、R2cAnd R2dIt is independently selected from H, F, Cl, Br, I, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or isopropoxy；
    R1eAnd R2eIt is independently selected from H, methyl, ethyl ,-C (=O) OCH (CH3)2Or
    R1fAmino acid side groups are independently selected from, the amino acid is selected from glycine, alanine, leucine, phenylalanine or knot propylhomoserin；
    R1gAnd R1hH or amino protecting group are independently selected from, the amino protecting group is selected from benzyloxycarbonyl group or tertbutyloxycarbonyl；
    N is selected from 0 or 1；
    M is selected from 1,2 or 3.
  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 and 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 and 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.
CN201580036778.0A 2014-08-06 2015-08-04 Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof Pending CN106536505A (en)

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