WO2016019847A1 - 一种氟代达比加群酯衍生物及其制备方法和在药学上的用途 - Google Patents

一种氟代达比加群酯衍生物及其制备方法和在药学上的用途 Download PDF

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WO2016019847A1
WO2016019847A1 PCT/CN2015/086020 CN2015086020W WO2016019847A1 WO 2016019847 A1 WO2016019847 A1 WO 2016019847A1 CN 2015086020 W CN2015086020 W CN 2015086020W WO 2016019847 A1 WO2016019847 A1 WO 2016019847A1
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methyl
group
pharmaceutically acceptable
stereoisomer
alkyl
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French (fr)
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魏用刚
李瑶
余彦
邱关鹏
雷柏林
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四川海思科制药有限公司
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Priority to CN201580036777.6A priority Critical patent/CN106536504A/zh
Publication of WO2016019847A1 publication Critical patent/WO2016019847A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • the present invention relates to a fluorodabigabate derivative represented by the formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof, and in the preparation of a medicament for preventing and treating a thromboembolic disease the use of.
  • cardiovascular disease is one of the main causes of death in humans.
  • One of its main aspects is thrombosis, which is caused by a series of complex reactions.
  • Blood coagulation is a protective mechanism of the organism whereby the defect of the vessel wall can be "sealed” quickly and reliably, thus avoiding blood loss or minimizing it. Maintaining normal hemostasis, ie hemorrhage and clotting balance, is regulated by a complex mechanism. Unregulated activation of the coagulation system or lack of inhibition of the activation process can lead to a variety of diseases and complications, such as venous thrombosis, deep vein thrombosis, pulmonary embolism, atherosclerosis, acute coronary syndrome, cerebrovascular disease and the like.
  • Oral anti-hemagglutination drugs that have been marketed mainly include direct thrombin inhibitors, factor Xa inhibitors, factor IX inhibitors, tissue factor inhibitors, and novel vitamin K antagonists.
  • dabigatran etexilate is an oral, selective and highly potent thrombin inhibitor. It has been clinically proven to replace warfarin to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation and to replace enoxaparin sodium. The first choice for the prevention of venous thromboembolic events in patients undergoing major plastic surgery.
  • Dabigatran etexilate was marketed in 2008 and is used to prevent stroke or systemic embolism, deep vein thrombosis (DVT) or pulmonary vascular occlusion and its recurrence in patients with non-valvular atrial fibrillation. It is a double prodrug obtained by esterification of the free carboxyl group and the thiol group in the dabigatran group, which solves the problem that the insoluble thiol group can not be taken orally, and improves the oral bioavailability. . After oral administration of dabigatran etexilate, it is absorbed from the gastrointestinal tract and then rapidly converted into dabigatran in the body to exert an anticoagulant effect. However, the oral bioavailability of dabigatran diester is low, only 3 to 7%, so the higher dosage is medicinal and the side effects are increased.
  • dabigatran and its analogs as well as prodrugs thereof such as alkyl carboxylates, sulfonyl substituted carboxylic acid esters or sulfonylamino groups
  • CN102875533 and CN102838588 patents report Dabiga Group of ferulic acid or sulphate prodrugs, and has a certain anti-coagulant effect
  • CN200910211164, CN200910211165 and CN201210158600 disclose dabigatran carbonate, carboxylic acid ester and other prodrugs.
  • the object of the present invention is to solve the problem that dabigatran cannot be taken orally because of its strong alkalinity, and provide a novel and effective problem.
  • Oral dabigatran prodrugs with good stability, solubility, bioavailability, and low dose, low toxic side effects or long-acting effects.
  • the present invention relates to a fluorodabigabate derivative and a stereoisomer or pharmaceutically acceptable salt thereof, and to the use of a medicament for the prevention and treatment of a thromboembolic disease.
  • the present invention provides a compound represented by the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from C 1-10 alkyl, and the alkyl group is optionally further substituted with from 1 to 12 R 1a ;
  • R 2 is selected from C 1-10 alkyl, and the alkyl group is optionally further substituted with from 1 to 12 R 2a ;
  • R 1a and R 2a are each independently selected from the group consisting of H, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy or C 6-10 carbocycle;
  • R 1 or R 2 has a substituent, and at least one R 1a or R 2a is F.
  • a preferred embodiment of the invention a compound of the formula (I), and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from C 1-6 alkyl, and the alkyl group is optionally further substituted with from 1 to 12 R 1a ;
  • R 2 is selected from C 1-8 alkyl groups, which are optionally further substituted with from 1 to 12 R 2a .
  • a preferred embodiment of the invention a compound of the formula (I), and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from C 1-6 alkyl, and the alkyl group is optionally further substituted with from 1 to 12 R 1a ;
  • R 2 is selected from C 1-8 alkyl, and the alkyl group is optionally further substituted with from 1 to 12 R 2a ;
  • R 1a and R 2a are each independently selected from H, F, Cl, Br, methyl, methoxy or cyclopropyl.
  • a preferred embodiment of the invention a compound of the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:
  • the compound according to the invention and a stereoisomer or pharmaceutically acceptable salt thereof wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, Acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylic acid Salt, glucuronide, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonic acid Salt, mesylate, ethanesulfonate, triflate, ferulic acid or a combination thereof.
  • the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, Acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the invention further provides the use of a compound according to any of the foregoing, and a stereoisomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with a thrombin inhibitor.
  • the present invention also provides the use of a pharmaceutical composition as described above for the preparation of a medicament for treating a disease associated with thrombin inhibitors.
  • the thrombin-related disease is selected from a thromboembolic disorder.
  • the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolization.
  • the present invention further provides a method of treating a disease associated with a thrombin inhibitor, wherein the method comprises administering a compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, or the present invention Compositions.
  • the thrombin-related disease is selected from a thromboembolic disorder.
  • the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolization.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • the nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably a linear and branched group of 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, most preferably 1 to 2 carbon atoms;
  • examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl -2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl Benzyl
  • a side chain group of an amino acid refers to a general term for a class of organic compounds containing an amino group and a carboxyl group, and has a general structure of
  • the "side chain group of an amino acid” refers to the L group herein, and the non-limiting examples include, but are not limited to, the side chain group of glycine is H, the side chain group of alanine is methyl, benzene The side chain group of alanine is a benzyl group, and a side chain group of valine is an isopropyl group or the like.
  • Optional or “optionally” means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur, such as: "Alkyl optionally substituted by F" "Alkyl can be, but is not necessarily, substituted by F, and is meant to include the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • substitution refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom.
  • the group is substituted, for example, amino, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic, 3 to 6 membered heterocyclic ring, optionally further from 0 to 4 selected from H
  • substituent of F, Cl, Br, I, hydroxy, cyano, amino, C 1-4 alkyl or C 1-4 alkoxy the groups formed include, but are not limited to, methyl, chloromethyl, Trichloromethyl, hydroxymethyl, -CH 2 OCH 3 , -CH 2 SH, -CH 2 CH 2 CN, -CH 2 NH 2 , -NHOH, -NHCH 3 , -OCH 2 Cl, -OCH 2 OCH 2 CH 3 , -
  • Substituted or unsubstituted refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.
  • “As a choice” means that the scheme after “as a choice” is a side-by-side relationship with the scheme before “as a choice” rather than a further selection in the previous scheme.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or the free acid obtained by reacting with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc.
  • metal salts such as iron salts, copper salts, cobalt salts; organic alkali salts such as ammonium salts, triethylamine salts, pyridinium salts, methylpyridine salts, 2,6-dimethylpyridine salts, ethanolamine salts, two Ethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, sulfonium salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, two Methylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, phenicillin salt, glucosamine salt, N-methylglucamine salt, theobromine salt, Tromethamine salt, sulfonium salt, piperazine salt, morpholine salt, piperidine salt, N-ethyl piperidine salt, tetra
  • R 2 is n-hexyl
  • R 1 is consistent with the definitions of the above formula (I).
  • R 1 is selected from C 1-10 alkyl, and the alkyl group is optionally further substituted with from 1 to 12 R 1a ;
  • R 2 is selected from C 1-10 alkyl, and the alkyl group is optionally further substituted with from 1 to 12 R 2a ;
  • R 1a and R 2a are each independently selected from the group consisting of H, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy or C 6-10 carbocycle;
  • R 1 or R 2 has a substituent, and at least one R 1a or R 2a is F.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD).
  • DMSO-d6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • reaction solution Concentrate the reaction solution, steam off most of the ethanol, add water (200 mL), adjust the pH to 4-5 with 10% aqueous citric acid solution, precipitate a large amount of viscous solids, filter, transfer the solid into the reaction flask, add methanol (300 mL), heating until the solids are dissolved, stirring is continued until the solid is in the form of granules, and the mixture is cooled to zero.
  • Step 5 3-(2-(((6)-difluorohexyl)oxy)carbonyl)methyl)phenyl)amino)methyl)-1-methyl Ethyl-N-(pyridin-2-yl)--1H-benzo[d]imidazol-5-formylamino)propanoate (Compound 9)
  • Second step 3-(2-((4-(N'-((ethoxy)carbonyl))methyl)phenyl)amino)methyl)-1-methyl-N-(pyridine-2 -yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid 2,2,3,3,4,4,5,5,6,6,6-undefluorohexyl ester (compound) 11)
  • the suspension of the group prototype drug was collected from the eyelids, anticoagulated by heparin, and centrifuged at 3000 ° C for 10 min at 4 ° C for 5 min before administration (0 h) and 5 min, 15 min, 30 min, 1.0, 2.0, 4.0, 8.0, 24.0 h after administration.
  • the plasma was separated and stored at -80 ° C for testing. Take 30ul of rat plasma at each time point, add 200ul of internal standard solution (7.5ng/ml verapamil), vortex for 1min, centrifuge at 13000rpm for 10min at 4°C, and take 190ul of supernatant for LC-MS/MS (Shimadzu Company lc-20A Technology Co., Ltd., API4000+) analysis.
  • the main pharmacokinetic parameters were analyzed by WinNonlin 6.3 software non-compartmental model. The results are shown in Table 1.
  • the compounds of the invention have good pharmacokinetic characteristics.
  • the compounds 5 and 12 have significantly better indices than dabigatran etexilate.

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Abstract

一种如通式(I)所示的氟代达比加群酯衍生物及其立体异构体或药学上可接受的盐，以及在制备用于预防和治疗血栓栓塞疾病的药物中的用途，其中R 1和R 2分别是任选被1~12个R 1a、R 2a取代的C 1-10烷基，且至少有一个R 1a或R 2a是含F的取代基。

Description

一种氟代达比加群酯衍生物及其制备方法和在药学上的用途 技术领域
本发明涉及一种通式(I)所示的氟代达比加群酯衍生物及其立体异构体或药学上可接受的盐，以及在制备用于预防和治疗血栓栓塞疾病的药物中的用途。
背景技术
目前，心血管疾病是导致人类死亡的主要原因之一，它的一个主要方面是血栓形成，血栓形成是由一系列复杂反应引起凝血而致。血液凝固是生物体的一种保护机制，借此可很快并且可靠地“密封”血管壁的缺损，因此可以避免失血或将其降到最低限度。维持正常止血作用，即出血和凝血平衡，受一个复杂机制的调控。不受调控的活化凝血系统或缺乏活化过程的抑制作用都可能导致多种疾病和并发症，例如静脉血栓、深静脉血栓、肺栓塞、动脉粥样硬化、急性冠状综合征、脑血管疾病等。
现已上市的口服抗血凝药物主要有直接凝血酶抑制剂、Xa因子抑制剂、IX因子抑制剂、组织因子抑制剂和新型维生素K拮抗剂等。其中达比加群酯是一种口服的、选择性的高效凝血酶抑制剂，临床已证明能够替代华法林成为预防非瓣膜性心房纤维性颤动患者中风和全身栓塞及替代依诺肝素钠成为预防主要整形术后患者静脉血栓栓塞事件的首选用药。
达比加群酯于2008年上市，被用于预防非瓣膜病性房颤患者的卒中或全身性栓塞、深部静脉血栓(DVT)或肺血管阻塞及其复发。它是达比加群分子中的游离羧基和脒基分别成酯后得到的双前体药物，解决了因达比加群强碱性脒基存在而不能口服的问题，提高了口服生物利用度。达比加群酯口服后，从胃肠道吸收，然后快速在体内转化为达比加群，从而发挥抗凝血作用。但是达比加群双酯的口服生物利用度较低，仅有3～7％，所以药用剂量较高，增加了胃肠道副作用。
目前已有不少文献报道了达比加群的前体药物。如WO09837075和WO2004014894专利公开了达比加群及其类似物，以及其烷基羧酸酯、被磺酰基取代的羧酸酯或磺酰基氨基等前体药物；CN102875533和CN102838588专利报道了达比加群的阿魏酸或川弓嗪前体药物，并具有一定的抗凝血作用；CN200910211164、CN200910211165和CN201210158600等专利公开了达比加群的碳酸酯、羧酸酯等前体药物。
本发明的目的在于解决达比加群因其强碱性而不能口服的问题，提供一种新颖有效 的具有良好稳定性、溶解度、生物利用度以及低剂量、低毒副作用或长效的可口服的达比加群前药。
发明内容
本发明涉及一种氟代达比加群酯衍生物及其立体异构体或药学上可接受的盐，以及在制备用于预防和治疗血栓栓塞疾病的药物中的用途。
本发明提供一种通式(I)所示的化合物及其立体异构体和药学上可以接受的盐，其中：
Figure PCTCN2015086020-appb-000001
R1选自C1-10烷基，所述烷基任选进一步被1至12个R1a取代；
R2选自C1-10烷基，所述烷基任选进一步被1至12个R2a取代；
R1a和R2a各自独立的选自H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基或C6-10碳环；
条件是，R1或R2中至少一个有取代基，且至少有一个R1a或R2a为F。
本发明优选方案，一种通式(I)所示的化合物及其立体异构体和药学上可以接受的盐，其中：
R1选自C1-6烷基，所述烷基任选进一步被1至12个R1a取代；
R2选自C1-8烷基，所述烷基任选进一步被1至12个R2a取代。
本发明优选方案，一种通式(I)所示的化合物及其立体异构体和药学上可以接受的盐，其中：
R1选自C1-6烷基，所述烷基任选进一步被1至12个R1a取代；
R2选自C1-8烷基，所述烷基任选进一步被1至12个R2a取代；
R1a和R2a各自独立的选自H、F、Cl、Br、甲基、甲氧基或环丙基。
本发明优选方案，一种通式(I)所示的化合物及其立体异构体和药学上可以接受的盐，其中该化合物选自如下结构之一：
Figure PCTCN2015086020-appb-000002
Figure PCTCN2015086020-appb-000003
本发明优选方案，根据本发明所述化合物及其立体异构体或药学上可接受的盐，其中所述的盐选自盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐、阿魏酸盐或它们的组合。
本发明进一步提供一种药物组合物，所述药物组合物含有治疗有效剂量的本发明化合物或其立体异构体或药学上可接受的盐，以及药学上可接受的载体或者赋形剂。
本发明进一步提供一种前面任意所述的化合物及其立体异构体或药学上可接受的盐，在制备治疗与凝血酶抑制剂相关疾病药物中的用途。
本发明还提供一种前面所述的药物组合物在制备治疗与凝血酶抑制剂相关疾病药物中的用途。
本发明优选方案，其中所述的与凝血酶抑制剂相关疾病选自血栓栓塞疾病。
本发明优选方案，其中所述的血栓栓塞疾病选自静脉血栓和动脉栓塞。
本发明进一步提供一种治疗与凝血酶抑制剂相关疾病的方法，其中所述方法包括给药本发明所述的化合物或其立体异构体、或药学上可接受的盐，或本发明所述的组合物。
本发明优选方案，其中所述的与凝血酶抑制剂相关疾病选自血栓栓塞疾病。
本发明优选方案，其中所述的血栓栓塞疾病选自静脉血栓和动脉栓塞。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位 素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“烷基”是指直链和支链的饱和脂肪族烃基团，主链包括1至20个碳原子，优选为1至12个碳原子，进一步优选为1至8个碳原子，更优选为1至6个碳原子，再进一步优选1至4个碳原子的直链与支链基团，最优选1至2个碳原子；烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基；烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基＝O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“烷氧基”是指-O-烷基，其中烷基如本文上述定义。烷氧基可以是取代的或未取代的，烷氧基实施例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基和正己氧基；当被取代时，取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或硅烷基等。
“氨基酸的侧链基团”，氨基酸是指含有氨基和羧基的一类有机化合物的通称，其通式结构为
Figure PCTCN2015086020-appb-000004
所述的“氨基酸的侧链基团”是指此处的L基团，非限定实施例包括但不限于甘氨酸的侧链基团为H、丙氨酸的侧链基团为甲基、苯丙氨酸的侧链基团为苄基、缬氨酸的侧链基团为异丙基等。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合，如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。
“取代”是指基团中一个或多个氢原子被其它基团取代的情形，如果所述的基团被氢原子取代，形成的基团与被氢原子取代的基团相同。基团被取代的情形，例如氨基、C1-4烷基、C1-4烷氧基、C3-6碳环、3至6元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、氰基、氨基、C1-4烷基或C1-4烷氧基的取代基所取代，形成的基团包括但不限于甲基、氯甲基、三氯甲基、羟基甲基、-CH2OCH3、-CH2SH、-CH2CH2CN、-CH2NH2、-NHOH、-NHCH3、-OCH2Cl、-OCH2OCH2CH3、-OCH2CH2NH2、-OCH2CH2SH、-OCH2CH2OH、1-羟基环丙基、2-羟基环丙基、2-氨基环丙基、4-甲基呋喃基、2-羟基苯基、4-氨基苯基、苯基。
“取代或未取代的”是指基团可以被取代或不被取代的情形，若在本发明中没有指出基团可以被取代，则表示该基团为未取代的情形。
“作为选择”是指“作为选择”之后的方案与“作为选择”之前的方案为并列关系，而不是在前方案中的进一步选择情形。
“药学上可接受的盐”或“其药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或有机碱，或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐，包括碱金属盐，如钠盐、钾盐、锂盐等；碱土金属盐，如钙盐、镁盐等；其他金属盐，如铁盐、铜盐、钴盐；有机碱盐，如铵盐、三乙胺盐、吡啶盐、甲基吡啶盐、2,6-二甲基吡啶盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、环己胺盐、乙二胺盐、胍盐、异丙基胺盐、三甲基胺盐、三丙基胺盐、三乙醇胺盐、二乙醇胺盐、乙醇胺盐、二甲基乙醇胺盐、二环己基胺盐、咖啡碱盐、普鲁卡因盐、胆碱盐、甜菜碱盐、苯明青霉素盐、葡萄糖胺盐、N-甲基葡糖胺盐、可可碱盐、氨丁三醇盐、嘌呤盐、哌嗪盐、吗啉盐、哌啶盐、N-乙基哌啶盐、四甲基胺盐、二苄基胺盐和苯基甘氨酸烷基酯盐；氢卤酸盐，如氢氟酸盐、盐酸盐、氢碘酸盐、氢溴酸盐；无机酸盐，如硝酸盐、硫酸盐、高氯酸盐、磷酸盐；低级烷磺酸盐，如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐；芳基磺酸盐，如苯磺酸盐、对甲苯磺酸盐；有机酸盐，如蚁酸盐、富马酸盐、甲酸盐、三氟乙酸盐、糠酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酸盐、羟乙磺酸盐、乳酸盐、马来酸盐、苹果酸盐、扁桃酸盐、粘液酸盐、双羟萘酸盐、泛酸盐、硬脂酸盐、琥珀酸盐、磺胺酸盐、酒石酸盐、丙二酸盐、2-羟基丙酸盐、柠檬酸盐、水杨酸盐、草酸 盐、羟乙酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、赖氨酸盐、精氨酸盐、门冬氨酸盐、肉桂酸盐。
合成方法
方法一：
Figure PCTCN2015086020-appb-000005
R2为正己基；
R1的定义与前面通式(I)所述定义一致。
方法二：
Figure PCTCN2015086020-appb-000006
R1选自C1-10烷基，所述烷基任选进一步被1至12个R1a取代；
R2选自C1-10烷基，所述烷基任选进一步被1至12个R2a取代；
R1a和R2a各自独立的选自H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基或C6-10碳环；
条件是，R1或R2中至少一个有取代基，且至少有一个R1a或R2a为F。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance  300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中无特殊说明，反应在氮气氛下进行。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温。
室温为最适宜的反应温度，为20℃～30℃。
中间体1
3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)
3-[[2-[[4-[(Z)-N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
Figure PCTCN2015086020-appb-000007
Figure PCTCN2015086020-appb-000008
第一步：3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)
3-[[2-[[4-[(Z)-N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
Figure PCTCN2015086020-appb-000009
将3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(1a)(63g,100mmol)加入到乙醇(600mL)和水(300mL)的混合溶剂中，加入氢氧化钠(8g,200mmol)，室温下搅拌半个小时，至反应液澄清。浓缩反应液，旋蒸掉大部分乙醇，加入水(200mL)，用10％的柠檬酸水溶液调节pH至4～5，大量粘稠状固体析出，过滤，将固体转移入反应瓶中，加入甲醇(300mL)，加热至固体溶解，继续搅拌至固体呈颗粒状，冷却至零度，更多产品析出，过滤并干燥，得到白色固体状的标题化合物3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)(50g，产率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)。
实施例1
3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸3,3,3,-三氟丙酯(化合物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
Figure PCTCN2015086020-appb-000010
0℃下三口瓶中依次加入3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)(0.6g，0.001mol),3,3,3-三氟丙-1-醇(1A)(0.17g，0.0015mol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.25g，0.0013mol),4-二甲氨基吡啶(0.073g，0.0006mol),然后加入的N,N-二甲基甲酰胺(10mL)保温搅拌0.5小时，升至室温反应5小时。停止反应向反应液中加入乙酸乙酯(60mL)，有机相用水洗涤(40mL×5)，在用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，浓缩，残留物用柱层析分离提纯(二氯甲烷：甲醇(v/v)＝100:1-20:1)得到白色固体3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸3,3,3,-三氟丙酯(化合物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)。
实施例2
3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,4,4,4-七氟丁酯(化合物2)
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
Figure PCTCN2015086020-appb-000011
Figure PCTCN2015086020-appb-000012
0℃下三口瓶中依次加入3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)(0.6g，0.001mol),七氟丁醇(2A)(0.3g，0.0015mol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.25g，0.0013mol),4-二甲氨基吡啶(0.073g，0.0006mol),然后加入的N,N-二甲基甲酰胺(10mL)保温搅拌0.5小时，升至室温反应5小时。停止反应向反应液中加入乙酸乙酯(60mL)，有机相用水洗涤(40mL×5)，在用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，浓缩，残留物用柱层析分离提纯(二氯甲烷：甲醇(v/v)＝100:1-20:1)得到白色固体3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,4,4,4-七氟丁酯(化合物2)(0.113g,14.5％)。
1H NMR(400MHz,CDCl3):δ8.42(d,1H),7.75-7.70(m,3H),7.34-7.29(m,2H),7.12-7.10(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)。
实施例3
3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,4,4,5,5,6,6,6-十一氟己酯(化合物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
Figure PCTCN2015086020-appb-000013
0℃下三口瓶中依次加入3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)(0.6g，0.001mol),十一氟正己烷-1-醇(3A)(0.45g，0.0015mol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.25g，0.0013mol),4-二甲氨基吡啶(0.073g，0.0006mol),然后加入的N,N-二甲基甲酰胺(10mL)保温搅拌0.5小时，升至室温反应5小时。停止反应向反应液中加入乙酸乙酯(60mL)，有机相用水洗涤(40mL×5)，在用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，浓缩，残留物用柱层析分离提纯(二氯甲烷：甲醇(v/v)＝100:1-20:1)得到白色固体3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,4,4,5,5,6,6,6-十一氟己酯(化合物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)。
实施例4
3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸三氟乙酯(化合物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
Figure PCTCN2015086020-appb-000014
将3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)(0.85g，1.4mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.43g，2.24mmol),4-二甲氨基吡啶(0.1g，0.84mmol),加入到的N,N-二甲基甲酰胺(5mL)中室温搅拌1小时然后加入三氟乙醇(4A)(0.14g，1.4mmol)，室温反应16小时，再向反应液中加入水(100mL)，水相用乙酸乙酯萃取(50mL×2)，合并有机相，有机相 用饱和食盐水洗涤(100mL×1)，无水硫酸钠干燥，浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷：甲醇(v/v)＝100:1～20:1)得到标题化合物：3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸三氟乙酯(化合物4)，白色固体(100mg，产率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)。
实施例5
3-(1-甲基-N-(吡啶-2-基)-2-(((4-(N'-((3,3,3-三氟丙氧基)羰基)甲脒基)苯基)氨基)甲基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(化合物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
Figure PCTCN2015086020-appb-000015
室温下在3,3,3-三氟-1-丙醇(0.685g，6.01mmol)的四氢呋喃(10mL)中加入碳酰二咪唑(1.00g，6.17mmol)，室温搅拌30分钟,减压除去溶剂，制备成反应液1。在3-(2-(((4-脒基苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯对甲基苯磺酸盐(5A)(2.67g，4.00mmol)中加入丙酮(100mL)、水(50mL)、碳酸钾(1.65g，11.9mmol)，搅拌均匀后加入反应液1，加完后室温反应5小时。过滤析出的白色固体，丙酮/水(丙酮：水(v/v)＝1:2)洗涤滤饼，之后用二氯甲烷(100mL)溶解、无水硫酸钠干燥、浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷：甲醇(v/v)＝100:1～30:1)得到标题化合物3-(1-甲基-N-(吡啶-2-基)-2-(((4-(N'-((3,3,3-三氟丙氧基)羰基)甲脒基)苯基)氨基)甲基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(化合物5)，棕色固体(0.60g，产率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)。
实施例6
3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2-氟乙酯(化合物6)
2-fluoroethyl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086020-appb-000016
将3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)(1g,1.67mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.96g,5.01mmol),4-二甲氨基吡啶(0.3g,2.5mmol),加入到的N,N-二甲基甲酰胺(5mL)中室温搅拌1小时然后加入氟乙醇(10A)(0.106g,01.67mmol)，室温反应16小时，再向反应液中加入水(100mL)，水相用乙酸乙酯萃取(50ml×2)，合并有机相，有机相用饱和食盐水洗涤(100ml×1)，无水硫酸钠干燥，浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷：甲醇(v/v)＝100:1～20:1)得到标题化合物3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2-氟乙酯(化合物6)，白色固体(300mg，产率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)。
实施例7
3-(-1-甲基-N-(吡啶-2-基)-2(((4-(N'-(((2,2,3,3,4,4,5,5,6,6,6-十一氟)氧基)羰基)甲脒基)苯基)氨基)甲基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸乙酯(化合物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
Figure PCTCN2015086020-appb-000017
反应瓶中加入十一氟正己烷-1-醇(0.58g，1.93mmol)和四氢呋喃(3mL),然后加入N,N'-羰基二咪唑(0.34g，2.08mmol),室温搅拌1小时，减压浓缩得油状物。另取反应瓶加入3-(2-(((4-脒基苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(7A)(1g，1.49mmol),及油状物，丙酮(30mL),水(15mL)。室温搅拌5小时，减压蒸干丙酮，残留物中加入水(60mL)，乙酸乙酯萃取(70mL×3)，合并有机相，饱和食盐水洗涤(90mL)，无水硫酸钠干燥，缩，残留物用柱层析分离提纯(二氯甲烷：甲醇(v/v)＝30:1-10:1)得到白色固体3-(-1-甲基-N-(吡啶-2-基)-2(((4-(N'-(((2,2,3,3,4,4,5,5,6,6,6-十一氟)氧基)羰基)甲脒基)苯基)氨基)甲基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸乙酯(化合物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)。
实施例8
3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,3,-五氟丙酯(化合物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
Figure PCTCN2015086020-appb-000018
0℃下三口瓶中依次加入3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中间体1)(0.6g,0.001mol),2,2,3,3,3,-五氟丙醇(8A)(0.225g,0.0015mol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.25g,0.0013mol),4-二甲氨基吡啶(0.073g,0.0006mol),然后加入的N,N-二甲基甲酰胺(10mL)保温搅拌0.5小时，升至室温反应5小时。停止反应向反应液中加入乙酸乙酯(60mL)，有机相用水洗涤(40mL×5)，在用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，浓缩，残留物用柱层析分离提纯(二氯甲烷：甲醇(v/v)＝100:1-20:1)得到白色固体3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,3,-五氟丙酯(化合物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)。
实施例9
3-(2-(((4-(N'-(((6,6-二氟己基)氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)--1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(化合物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
Figure PCTCN2015086020-appb-000019
Figure PCTCN2015086020-appb-000020
第一步：6-((叔丁基二甲基硅基)氧基)己基-1-醇(9B)
6-((tert-butyldimethylsilyl)oxy)hexan-1-ol
Figure PCTCN2015086020-appb-000021
冰浴下在1,6-己二醇(9A)(10g,85mmol)的二氯甲烷(150mL)中加入咪唑(8.85g,130mmol)，搅拌10分钟后滴加叔丁基二甲基氯硅烷(12.8g,84.9mmol)的二氯甲烷(100mL)溶液，加完后室温反应5小时。向反应液中加入水(200mL)，用二氯甲烷萃取(100mL×3)，合并有机相，无水硫酸钠干燥、浓缩，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝10:1～3:1)得到标题化合物6-((叔丁基二甲基硅基)氧基)己基-1-醇(9B)，无色液体(8.0g，产率41％)。
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)。
第二步：6-((叔丁基二甲基硅基)氧基)己醛(9C)
6-((tert-butyldimethylsilyl)oxy)hexanal
Figure PCTCN2015086020-appb-000022
室温下在6-((叔丁基二甲基硅基)氧基)己基-1-醇(9B)(5g,22mmol)的150mL二氯甲烷中加入6g硅胶和氯铬酸吡啶盐(7.0g,33mmol)，加完后室温反应3小时。浓缩，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝100:1～20:1)得到标题化合物6-((叔丁基二甲基硅基)氧基)己醛(9C)，无色液体(2.0g，产率40％)。
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)。
第三步：叔丁基((6,6-二氟己基)氧基)二甲基硅烷(9D)
tert-butyl((6,6-difluorohexyl)oxy)dimethylsilane
Figure PCTCN2015086020-appb-000023
冰浴下在6-((叔丁基二甲基硅基)氧基)己醛(9C)(1.8g,7.1mmol)的甲苯(15mL)溶液中加入二乙胺基三氟化硫(2.3g,14mmol)，加完后室温反应2小时。向反应液中 加入水(20mL)，用二氯甲烷萃取(50mL×2)，合并有机相，无水硫酸钠干燥、浓缩，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝100:0～20:1)得到标题化合物叔丁基((6,6-二氟己基)氧基)二甲基硅烷(9D)，无色液体(1.4g，产率78％)。
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)。
第四步：6,6-二氟己基-1-醇(9E)
6,6-difluorohexan-1-ol
Figure PCTCN2015086020-appb-000024
冰浴下在叔丁基((6,6-二氟己基)氧基)二甲基硅烷(9D)(1.4g,5.5mmol)的15mL四氢呋喃溶液中加入四丁基氟化胺(2.2g,8.4mmol)，加完后室温反应3小时。向反应液中加入水(20mL)，用二氯甲烷萃取(50mL×2)，合并有机相，无水硫酸钠干燥、浓缩，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(v/v)＝100:0～20:1)得到标题化合物6,6-二氟己基-1-醇(9E)，无色液体(0.45g，产率59％)。
1H NMR(400MHz,CDCl3)δ5.80(tt,1H),3.66(t,2H),1.84(m,2H),1.60(m,2H),1.48(m,4H)。
第五步：3-(2-(((4-(N'-(((6,6-二氟己基)氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)--1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(化合物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
Figure PCTCN2015086020-appb-000025
室温下在6,6-二氟己基-1-醇(9E)(0.400g,2.90mmol)的四氢呋喃(10mL)中加入碳酰二咪唑(0.470g,2.90mmol)，室温搅拌30分钟,减压除去溶剂，制备成反应液1。3-(2-(((4-脒基苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯对甲基苯磺酸盐(5A)(2.44g,3.60mmol)中加入丙酮(100mL)、水(50mL)、碳酸钾(1.65g,11.9mmol)，搅拌均匀后加入反应液1，加完后室温反应5小时。过滤析出的白色固体，丙酮/水(丙酮：水(v/v)＝1:2)洗涤滤饼，之后用二氯甲烷(100mL)溶解、无水硫酸钠干燥、浓缩，残留物用硅胶柱色谱分离提纯(二氯甲烷：甲醇(v/v)＝100:1～30:1)得 到标题化合物3-(2-(((4-(N'-(((6,6-二氟己基)氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)--1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(化合物9)，白色固体(0.400g，产率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)。
实施例10
3-(2-(((4-(N'-(((6,6-二氟戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(化合物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
Figure PCTCN2015086020-appb-000026
制备方法参见实施例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)。
实施例11
3-(2-(((4-(N'-((乙氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,4,4,5,5,6,6,6-十一氟己酯(化合物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
Figure PCTCN2015086020-appb-000027
第一步：3-(2-(((4-(N'-((乙氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸(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
Figure PCTCN2015086020-appb-000028
向反应瓶中加入3-[[2-[[4-[(Z)-N`-乙氧羰基脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸乙脂(11A)(0.80g，1.40mmol)，水(16ml)，乙醇(8ml)，氢氧化钠(0.18g，4.5mmol)，室温反应2小时。加入乙酸调至中性，过滤得到白色固体3-(2-(((4-(N'-((乙氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸(11B)(0.38g，收率：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)。
第二步：3-(2-(((4-(N'-((乙氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,4,4,5,5,6,6,6-十一氟己酯(化合物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
Figure PCTCN2015086020-appb-000029
向反应瓶中加入3-(2-(((4-(N'-((乙氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸(11B)(0.38g，0.70mmol)和十一氟正己烷-1-醇(0.31g，1.00mmol)，N,N-二甲基甲酰胺(14ml),搅拌均匀后，冷却至0℃，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.21g，1.10mmol)和4-二甲氨基吡啶(0.05g,0.42mmol)，0℃搅拌0.5小时，升至室温反应5小时。加入水(20ml)，乙酸乙酯(30mL)，搅拌，分出有机层，另用水洗(20mL×2)，得到有机层，干燥，过滤，浓缩。硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝40:1-30:1)得到白色固体3-(2-(((4-(N'-((乙氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰胺基)丙酸2,2,3,3,4,4,5,5,6,6,6-十一氟己酯(化合物11)(0.38g，收率：66.0％)。
LCMS m/z＝826.0[M+1]。
实施例12
3-(1-甲基-N-(吡啶-2-基)-2-(((4-(N'-((3,3,3-三氟乙氧基)羰基)甲脒基)苯基)氨基)甲基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(化合物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
Figure PCTCN2015086020-appb-000030
制备方法参见实施例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)。
测试例
1、药代动力学评价
健康成年SD大鼠(雌雄各半，购自北京维通利华实验动物中心，动物生产许可证号SCXK(京)2012-0001)，给药前一天禁食不禁水。6只大鼠灌胃给药5mg/kg(以达比加群原形药物计)，化合物以0.5％CMC-Na(含1％吐温80)配制成0.5mg×mL-1(以达比加群原形药物计)的混悬液，于给药前(0h)及给药后5min,15min,30min,1.0,2.0,4.0,8.0,24.0h由眼眶采血，肝素抗凝，4℃3000rpm离心10min后分离血浆，于-80℃保存待测。取30ul各时间点大鼠血浆，加入内标溶液(7.5ng/ml维拉帕米)200ul，涡流混合1min，于4℃13000rpm离心10min，取上清液190ul进行LC-MS/MS(岛津公司lc-20A科技有限公司，API4000+)分析。主要药代动力学参数用WinNonlin 6.3软件非房室模型分析，结果如表1所示。
表1：药代动力学参数结果
Figure PCTCN2015086020-appb-000031
结论：本发明化合物具有较好的药代动力学特征。特别是化合物5、12各项指数明显优于达比加群酯。

Claims (12)

  1. 一种通式(I)所示的化合物及其立体异构体和药学上可以接受的盐，其中：
    Figure PCTCN2015086020-appb-100001
    R1选自C1-10烷基，所述烷基任选进一步被1至12个R1a取代；
    R2选自C1-10烷基，所述烷基任选进一步被1至12个R2a取代；
    R1a和R2a各自独立的选自H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基或C6-10碳环；
    条件是，R1或R2中至少一个有取代基，且至少有一个R1a或R2a为F。
  2. 根据权利要求1所述的化合物及其立体异构体和药学上可以接受的盐，其中：
    R1选自C1-6烷基，所述烷基任选进一步被1至12个R1a取代；
    R2选自C1-8烷基，所述烷基任选进一步被1至12个R2a取代。
  3. 根据权利要求2所述的化合物及其立体异构体和药学上可以接受的盐，其中：
    R1a和R2a各自独立的选自H、F、Cl、Br、甲基、甲氧基或环丙基。
  4. 根据权利要求3所述的化合物及其立体异构体和药学上可以接受的盐，其中该化合物选自如下结构之一：
    Figure PCTCN2015086020-appb-100002
    Figure PCTCN2015086020-appb-100003
  5. 根据权利要求1～4中任一项所述的化合物及其立体异构体，或药学上可接受的盐，其中所述的盐选自盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐、阿魏酸盐或它们的组合。
  6. 一种药物组合物，所述药物组合物含有治疗有效剂量的根据权利要求1～5中任意一项所述的化合物或其立体异构体或药学上可接受的盐，以及药学上可接受的载体或者赋形剂。
  7. 权利要求1～5中任意一项所述的化合物及其立体异构体、或药学上可接受的盐，以及权利要求6所述的组合物在制备治疗与凝血酶抑制剂相关疾病药物中的用途。
  8. 根据权利要求7所述的用途，其中所述的与凝血酶抑制剂相关疾病选自血栓栓塞疾病。
  9. 根据权利要求8所述的用途，其中所述的血栓栓塞疾病选自静脉血栓和动脉栓塞。
  10. 一种治疗与凝血酶抑制剂相关疾病的方法，其中所述方法包括给药权利要求1～5中任意一项所述的化合物或其立体异构体、或药学上可接受的盐，或权利要求6所述的组合物。
  11. 根据权利要求10所述的方法，其中所述的与凝血酶抑制剂相关疾病选自血栓栓塞疾病。
  12. 根据权利要求11所述的方法，其中所述的血栓栓塞疾病选自静脉血栓和动脉栓塞。
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