[go: up one dir, main page]

WO2016019844A1 - 一种达比加群环基酯衍生物及其制备方法和在药学上的用途 - Google Patents

一种达比加群环基酯衍生物及其制备方法和在药学上的用途 Download PDF

Info

Publication number
WO2016019844A1
WO2016019844A1 PCT/CN2015/086016 CN2015086016W WO2016019844A1 WO 2016019844 A1 WO2016019844 A1 WO 2016019844A1 CN 2015086016 W CN2015086016 W CN 2015086016W WO 2016019844 A1 WO2016019844 A1 WO 2016019844A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
amino
carbonyl
pyridyl
benzimidazole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/086016
Other languages
English (en)
French (fr)
Inventor
魏用刚
邱关鹏
雷柏林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Haisco Pharmaceutical Co Ltd
Original Assignee
Sichuan Haisco Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Haisco Pharmaceutical Co Ltd filed Critical Sichuan Haisco Pharmaceutical Co Ltd
Priority to CN201580036812.4A priority Critical patent/CN106660995A/zh
Publication of WO2016019844A1 publication Critical patent/WO2016019844A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the present invention relates to a dabigatran group-containing cyclic ester derivative, and a stereoisomer or pharmaceutically acceptable salt thereof, and use thereof in the preparation of a medicament for preventing and treating a thromboembolic disease.
  • 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 dabigatran group-based cyclic ester derivative, and stereoisomers thereof and a pharmaceutically acceptable salt thereof, and to use in the preparation of a medicament for preventing and treating a thromboembolic disease.
  • the present invention provides a compound of the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:
  • X 1 and X 2 are each independently selected from O or S;
  • R 1 is selected from a C 6-10 carbocyclic ring, and the carbocyclic ring is optionally further substituted with 0 to 4 R 1a ;
  • R 1a is independently selected from H, F, Cl, Br, I, CN, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl or -(CH 2 ) n COO C 1-4 alkyl, said alkyl or alkoxy optionally further from 0 to 4 selected from H, F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy Substituted by a substituent;
  • R 2 is selected from C 1-10 alkyl, and the alkyl group is optionally further substituted with from 0 to 12 R 2a ;
  • R 2a is independently selected from H, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 carbocyclic, said alkyl, alkoxy or carbon
  • the ring is optionally further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy;
  • n is selected from 0, 1, or 2.
  • 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 substituted or unsubstituted phenyl, benzocyclopentyl or naphthyl, and when substituted, is optionally further substituted with from 0 to 4 R 1a ;
  • R 2 is selected from C 1-8 alkyl groups, and the alkyl group is optionally further substituted with from 0 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 a C 6-10 carbocyclic ring, preferably a substituted or unsubstituted phenyl group, a benzocyclopentyl group or a naphthyl group, and the carbocyclic, phenyl, benzocyclopentyl or naphthyl group is optionally further 0 to 4 R 1a substituted;
  • R 1a is independently selected from the group consisting of H, F, Cl, Br, CN, CF 3 , -CHF 2 , -SCH 3 , -OCF 3 , -OCHF 2 , methyl, ethyl, isopropyl, methoxy, Ethoxy, isopropoxy, -COOCH 2 CH 3 or -CH 2 COOCH 3 ;
  • R 2 is selected from C 1-10 alkyl, preferably C 1-8 alkyl, and the alkyl group is optionally further substituted with from 0 to 12 R 2a ;
  • R 2a is independently selected from H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl.
  • 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 the stereoisomers and pharmaceutically acceptable salts thereof, wherein the salt is selected from the group consisting of hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, 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 hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, Acetate, maleate, succinate, mandelate, fumarate, malonate
  • 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 of any of the foregoing, and a stereoisomer thereof, and a 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.
  • X 2 is O; R 2 is n-hexyl;
  • R 1 and X 1 are identical to the definitions of the above formula (I).
  • X 1 and X 2 are each independently selected from O or S;
  • R 1 is selected from a C 6-10 carbocyclic ring, and the carbocyclic ring is optionally further substituted with 0 to 4 R 1a ;
  • R 1a is independently selected from H, F, Cl, Br, I, CN, C 1-4 alkyl, C 1-4 alkoxy, -SC 1-4 alkyl or -(CH 2 ) n COO C 1-4 alkyl, said alkyl or alkoxy optionally further from 0 to 4 selected from H, F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy Substituted by a substituent;
  • R 2 is selected from C 1-10 alkyl, and the alkyl group is optionally further substituted with from 0 to 12 R 2a ;
  • R 2a is independently selected from H, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy or C 3-6 carbocyclic, said alkyl, alkoxy or carbon
  • the ring is optionally further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy;
  • n is selected from 0, 1, or 2.
  • 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).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), The internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18100 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.
  • Ethyl propionate (1a) (63 g, 100 mmol) was added to a mixed solvent of ethanol (600 mL) and water (300 mL), and sodium hydroxide (8 g, 200 mmol) was added thereto, and the mixture was stirred at room temperature for half an hour until the reaction liquid was clarified.
  • the starting material is 3-(2-(((4-(N'-((hexyloxy))carbonyl)) phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl) -1H-benzo[d]imidazol-5-carboxamido)propanoic acid 2-methoxyphenyl ester (Compound 1) (0.3 g, 0.42 mmol) was dissolved in acetone (10 mL). A solution of mg (0.42 mmol) in acetone (1 mL) was stirred at room temperature for 1 hour. The solid was filtered to give Compound 1 methanesulfonate as a pale yellow solid (250 mg, yield 74.18%).
  • the starting material is 3-(2-(((4-(N'-((hexyloxy))carbonyl)) phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl) -1H-benzo[d]imidazol-5-carboxamido)propanoic acid 2-methoxyphenyl ester (Compound 1) (0.3 g, 0.42 mmol) was dissolved in acetone (15 mL) and concentrated sulfuric acid (42.2 mg) A solution of 0.42 mmol) in acetone (1 mL) was stirred at room temperature for 1 hour. The solid was filtered to give the compound 1 sulfonate as a white solid (50 mg, yield 14.79%).
  • N,N'-carbonyldiimidazole (0.63 g, 3.87 mmol) was added to 10 mL of tetrahydrofuran of n-heptanol (0.415 g, 3.58 mmol) at room temperature, and the mixture was stirred at room temperature for 30 min.
  • the third step 3-[[2-[[4-[N'-heptyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2- Pyridyl)amino]propionic acid 5-fluoro-2-methoxy-phenyl ester (Compound 11)
  • N,N'-carbonyldiimidazole (0.94 g, 5.81 mmol) was added to n-propanol (0.32 g, 5.36 mmol) in tetrahydrofuran (10 mL) at room temperature, and stirred at room temperature for 30 min. 1.
  • Second step 3-(1-methyl-2-((4-(N'-((4-methylpentyl)oxy)carbonyl)methyl) phenyl)amino)methyl)- N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-formylamino)propionic acid (38C)
  • the third step 2-methoxyphenyl 3-(1-methyl-2-((4-(N'-(((4-(methyl)))carbonyl))) Amino)methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionate (Compound 38)
  • Second step 3-[[2-[[4-[N ⁇ -(2-ethylbutoxycarbonyl)methylindolyl]anilino]methyl]-1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl)amino]propionic acid (39C)
  • the third step 3-[[2-[[4-[N ⁇ -(2-ethylbutoxycarbonyl)methylindolyl]anilino]methyl]-1-methyl-benzimidazole-5- 2-methoxyphenyl carbonyl]-(2-pyridyl)amino]propanoate (compound 39)
  • Second step 3-(2-((4-cyclopropylbutoxy)carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N -(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid (47C)
  • 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.
  • Rat plasma was taken at 30 uL at each time point, 200 uL of internal standard solution (7.5 ng/mL verapamil) was added, vortex mixed for 1 min, centrifuged at 13000 rpm for 10 min at 4 ° C, and supernatant 190 uL was taken 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 present invention have good pharmacokinetic characteristics, especially compounds 1, 2, and 3 are significantly superior to dabigatran etexilate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种通式(I)所示的达比加群环基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，结构如式（I）所示，X1、X2、R1、R2的定义与说明书一致。

Description

一种达比加群环基酯衍生物及其制备方法和在药学上的用途 技术领域
本发明涉及一种达比加群环基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
本发明涉及一种达比加群环基酯衍生物及其立体异构体和药学上可接受的盐，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。
本发明提供了一种通式(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 PCTCN2015086016-appb-000001
X1和X2各自独立的选自O或S；
R1选自C6-10碳环，所述的碳环任选进一步被0至4个R1a所取代；
R1a各自独立的选自H、F、Cl、Br、I、CN、C1-4烷基、C1-4烷氧基、-S-C1-4烷基或-(CH2)nCOO C1-4烷基，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代；
R2选自C1-10烷基，所述的烷基任选进一步被0至12个R2a所取代；
R2a各自独立的选自H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基或C3-6碳环，所述的烷基、烷氧基或碳环任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代；
n选自0、1或2。
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选自取代或未取代的苯基、苯并环戊基或萘基，当被取代时，任选进一步被0至4个R1a所取代；
R2选自C1-8烷基，所述的烷基任选进一步被0至12个R2a所取代。
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C6-10碳环，优选取代或未取代的苯基、苯并环戊基或萘基，所述的碳环、苯基、苯并环戊基或萘基任选进一步被0至4个R1a所取代；
R1a各自独立的选自H、F、Cl、Br、CN、CF3、-CHF2、-SCH3、-OCF3、-OCHF2、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、-COOCH2CH3或-CH2COOCH3；
R2选自C1-10烷基，优选C1-8烷基，所述的烷基任选进一步被0至12个R2a所取代；
R2a各自独立的选自H、F、Cl、Br、甲基、乙基、环丙基、环丁基或环戊基。
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 PCTCN2015086016-appb-000002
Figure PCTCN2015086016-appb-000003
Figure PCTCN2015086016-appb-000004
本发明优选方案，根据本发明所述化合物及其立体异构体和药学上可接受的盐，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和药学上可接受的盐，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。
本发明具体合成方法
方法一：
Figure PCTCN2015086016-appb-000005
X2为O；R2为正己基；
R1、X1与前面通式(I)所述定义一致。
方法二：
Figure PCTCN2015086016-appb-000006
其中，X1和X2各自独立的选自O或S；
R1选自C6-10碳环，所述的碳环任选进一步被0至4个R1a所取代；
R1a各自独立的选自H、F、Cl、Br、I、CN、C1-4烷基、C1-4烷氧基、-S-C1-4烷基或-(CH2)nCOO C1-4烷基，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代；
R2选自C1-10烷基，所述的烷基任选进一步被0至12个R2a所取代；
R2a各自独立的选自H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基或C3-6碳环，所述的烷基、烷氧基或碳环任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代；
n选自0、1或2。
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 Avance300)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-C18100×4.6mm)。
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-[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-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
Figure PCTCN2015086016-appb-000007
Figure PCTCN2015086016-appb-000008
第一步：3-[[2-[[4-[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-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
Figure PCTCN2015086016-appb-000009
将3-[[2-[[4-[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0℃，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-[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)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-甲氧基苯酯(化合物1)
2-methoxyphenyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000010
将3-[[2-[[4-[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)(3g，5mmol)溶于无水N,N－二甲基甲酰胺(50mL)中，加入2-甲氧基苯酚(1A)(0.93g，7.5mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.2g，6.5mmol)、4-二甲氨基吡啶(0.37g，3mmol)，室温下反应过夜。直接用油泵浓缩，残留物用硅胶柱色谱分离提纯(乙酸乙酯:二氯甲烷(v/v)＝1:1～2:1)，然后溶于二氯甲烷(50mL)中，用10％的磷酸二氢钠溶液(100mL)洗涤，用无水硫酸钠干燥，浓缩，然后加入6倍体积的二氯甲烷和12倍体积的甲基叔丁基醚重结晶，过滤，得到标题化合物3-(2-(((4-(N’-((己氧基)羰基)甲脒)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-甲氧基苯酯(化合物1)，白色固体(2.0g，产率57％)。
LCMS m/z＝706.3[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.73(dd,3H),7.37–7.29(m,2H),7.20–7.14(m,1H),7.09(d,1H),7.04–6.96(m,2H),6.96–6.89(m,2H),6.77(d,1H),6.66(d,2H),5.33(t,1H),4.55(t,2H),4.46(d,2H),4.14(t,2H),3.80(s,3H),3.68(s,3H),3.11(t,2H),1.78–1.66(m,2H),1.46–1.35(m,2H),1.35–1.23(m,4H),0.89(t,3H)。
化合物1甲磺酸盐的制备：
将原料3-(2-(((4-(N’-((己氧基)羰基)甲脒)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-甲氧基苯酯(化合物1)(0.3g，0.42mmol)溶于丙酮(10mL)中，加入甲磺酸(40.8mg，0.42mmol)的丙酮(1mL)溶液，室温搅拌1小时。过滤固体，得到化合物1甲磺酸盐，淡黄色固体(250mg，产率74.18％)。
LCMS m/z＝706.3[M+1]。
1H NMR(400MHz,DMSO)δ11.86(s,1H),10.62(s,1H),10.01(s,1H),8.43(dd,1H),7.66(d,2H),7.59(ddd,2H),7.51(d,1H),7.44(d,1H),7.27–7.18(m,2H),7.18–7.09(m,2H),7.06(dd,1H),7.01–6.92(m,2H),6.88(d,2H),4.70(d,2H),4.34(t,2H),4.26(t,2H), 3.79(s,3H),3.75(s,3H),2.98(t,2H),2.30(s,3H),1.67(dd,2H),1.38(dd,2H),1.35–1.21(m,4H),0.89(t,3H)。
化合物1磺酸盐的制备：
将原料3-(2-(((4-(N’-((己氧基)羰基)甲脒)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-甲氧基苯酯(化合物1)(0.3g，0.42mmol)溶于丙酮(15mL)中，加入浓硫酸(42.2mg，0.42mmol)的丙酮(1mL)溶液，室温搅拌1小时。过滤固体，得到化合物1磺酸盐，类白色固体(50mg，产率14.79％)。
LCMS m/z＝706.3[M+1]。
1H NMR(400MHz,DMSO)δ11.86(s,1H),10.61(s,1H),10.00(s,1H),8.43(dd,1H),7.66(d,2H),7.64–7.54(m,2H),7.52(d,1H),7.44(d,1H),7.27–7.18(m,2H),7.14(ddd,2H),7.06(dd,1H),7.01–6.91(m,2H),6.89(s,2H),4.71(s,2H),4.34(t,2H),4.26(t,2H),3.79(s,3H),3.75(s,3H),2.98(t,2H),2.09(s,1H),1.75–1.61(m,2H),1.47–1.34(m,2H),1.30(dd,4H),0.89(t,3H)。
化合物1盐酸盐的制备：
将3-(2-(((4-(N’-((己氧基)羰基)甲脒)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-甲氧基苯酯(化合物1)(0.3g,1.4mmol)溶于丙酮(30mL)中，0℃通入过量的盐酸气体，室温反应2小时。反应结束后减压浓缩得到产品(60mg，产率20％)。
LCMS m/z＝706.3[M+1]。
1H NMR(400MHz,DMSO)δ11.99(s,1H),11.11(s,1H),10.10(s,1H),8.41(dd,1H),7.83(d,1H),7.76(s,1H),7.73(d,2H),7.67(td,1H),7.41(dd,1H),7.26–7.08(m,4H),7.05(dd,1H),6.99(d,2H),6.94(td,1H),5.04(s,2H),4.33(t,2H),4.27(t,2H),4.00(s,3H),3.74(s,3H),3.00(t,2H),2.09(d,2H),1.74–1.60(m,2H),1.37(dd,2H),1.30(dd,4H),0.88(t,3H)。
实施例2
(5-氟-2-甲氧基苯基)3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物2)
(5-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000011
制备方法参见实施例1。
LCMS m/z＝724.32[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.76(s,1H),7.74(d,2H),7.33(ddd,2H),7.11(d,1H),7.03–6.96(m,1H),6.90–6.85(m,2H),6.82(dd,1H),6.75(d,1H),6.68(d,2H),5.34(s,1H),4.55(t,2H),4.49(d,2H),4.14(t,2H),3.78(s,3H),3.71(s,3H),3.10(t,2H),1.76–1.66(m,2H),1.40(dd,2H),1.35–1.27(m,4H),0.89(dd,3H)。
实施例3
(2-甲氧基苯基)3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物3)
(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000012
第一步：3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(3B)
ethyl 3-[[2-[[4-[N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimida zole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000013
室温下在正庚醇(0.415g，3.58mmol)的10mL四氢呋喃中加入N,N'-羰基二咪唑(0.63g，3.87mmol)，室温搅拌30分钟,减压除去溶剂，制备成反应液1。在乙基3-[[2-[(4-甲眯苯胺)甲基]-1甲基-苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸酯对甲基苯磺酸盐(3A)(2g，2.98mmol)中加入丙酮(60mL)、水(30mL)、碳酸钾(1.23g，8.94mmol)，搅拌均匀后加入反应液1，加完后室温反应5小时。之后加入水(100mL)，并用(150mL×2)乙酸乙酯萃取，合并有机层，有机层用(100mL×2)的水洗，之后有机层无水硫酸钠干燥，浓缩除去溶剂得标题化合物3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(3B)，白色固体(1.3g，产率56.76％)。
LCMS m/z＝642.33[M+1]。
第二步：3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(3C)
3-[[2-[[4-[N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
Figure PCTCN2015086016-appb-000014
室温下在3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(3B)(1.3,2.03mmol)的乙醇(15mL)溶液中加入氢氧化钠(162mg,4.06mmol)的水(7.5mL)溶液,加完后室温反应1小时。之后减压出去乙醇，并用柠檬酸的水溶液调节反应溶液至pH为4至5，析出大量固体，将固体过滤，固体加入乙腈(20mL)并搅拌10分钟，再次过滤固体，减压出去残留溶剂，即得产品白色固体3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(3C)(1.0g，产率80.64％)。
LCMS m/z＝614.32[M+1]。
第三步：(2-甲氧基苯基)3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物3)
(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000015
室温下在3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(3C)(1.0g，1.63mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入愈创木酚(0.3g，2.4mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(0.4g，2.08mmol)和4-二甲氨基吡啶(122mg，1mmol)，室温反应15小时。向反应液中加入水(30mL)，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用水溶液洗涤(30mL×2)，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)＝50:1～30:1)得到白色固体，即标题化合物(2-甲氧基苯基)3-[[2-[[4-[N`-庚氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物3)(0.41g，产率35.04％)。
LCMS m/z＝720.34[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.78–7.67(m,3H),7.37–7.27(m,2H),7.21–7.13(m,1H),7.08(d,1H),7.04–6.97(m,2H),6.97–6.88(m,2H),6.77(d,1H),6.66(d,2H),5.34(s,1H),4.55(t,2H),4.46(d,2H),4.13(t,2H),3.79(s,3H),3.68(s,3H),3.10(t,2H),1.71(dd,2H),1.39(dd,2H),1.35–1.24(m,6H),0.88(t,3H)。
实施例4
(2-甲氧基苯基)3-[[2-[[4-[N`-(环戊基甲氧羰基)甲脒基]苯氨基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物4)
(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-(cyclopentylmethoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000016
制备方法参见实施例3。
LCMS m/z＝704.31[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(d,1H),7.76–7.65(m,3H),7.37–7.27(m,2H),7.17(t,1H),7.07(d,1H),7.04–6.96(m,2H),6.92(dd,2H),6.76(d,1H),6.64(d,2H),5.42(s,1H),4.54(t,2H),4.45(d,2H),4.03(d,2H),3.79(s,3H),3.68(s,3H),3.10(t,2H),2.35–2.25(m,1H),1.80(d,2H),1.58(ddd,4H),1.35–1.19(m,2H)。
实施例5
(2-甲氧-4-甲基-苯基)3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物5)
(2-methoxy-4-methyl-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000017
制备方法参见实施例1。
LCMS m/z＝720.34[M+1]。
1H NMR(400MHz,CDCl3)δ8.45–8.39(m,1H),7.72(dd,3H),7.36–7.31(m,1H),7.29(dd,1H),7.07(d,1H),6.99(ddd,1H),6.88(d,1H),6.79–6.68(m,3H),6.65(d,2H),5.34(d,1H),4.53(t,2H),4.44(d,2H),4.13(t,2H),3.77(s,3H),3.67(s,3H),3.08(t,2H),2.32(s,3H),1.71(dd,2H),1.46–1.36(m,2H),1.34–1.28(m,4H),0.89(dd,3H)。
实施例6
邻甲苯基3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物6)
o-tolyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000018
制备方法参见实施例1。
LCMS m/z＝690.33[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.74(s,1H),7.71(d,2H),7.33(td,1H),7.29(dd,1H),7.18(dd,2H),7.12(dd,1H),7.08(dd,1H),6.99(dd,2H),6.74(d,1H),6.64(d,2H),5.35(s,1H),4.56(t,2H),4.44(d,2H),4.13(t,2H),3.67(s,3H),3.10(t,2H),2.16(s,3H),1.79–1.65(m,2H),1.51–1.34(m,2H),1.33–1.18(m,4H),0.88(t,3H)。
实施例7
[2-(三氟甲基)苯基]3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物7)
[2-(trifluoromethyl)phenyl]3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000019
制备方法参见实施例1。
LCMS m/z＝744.30[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.72(d,3H),7.64(d,1H),7.56(t,1H),7.32(m,3H),7.25(d,1H),7.05(d,1H),7.02–6.96(m,1H),6.72(d,1H),6.63(d,2H),5.35(d,1H),4.56(t,2H),4.43(d,2H),4.19–4.05(m,2H),3.66(s,3H),3.08(t,2H),1.76–1.64(m,2H),1.39(dd,2H),1.35–1.26(m,4H),0.88(dd,3H)。
实施例8
(2-甲氧基苯基)3-[[1-甲基-2-[[4-[N`-辛氧羰基甲眯]苯氨基]甲基]苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物8)
(2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-octoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000020
制备方法参见实施例3。
LCMS m/z＝734.36[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.74(dd,3H),7.33(m,2H),7.20–7.14(m,1H),7.09(d,1H),7.04–6.96(m,2H),6.96–6.89(m,2H),6.77(d,1H),6.67(d,2H),5.33(s,1H),4.55(t,2H),4.47(d,2H),4.13(t,2H),3.80(s,3H),3.69(s,3H),3.10(t,2H),1.71(dd,2H),1.46–1.35(m,2H),1.35–1.23(m,8H),0.87(t,3H)。
实施例9
(2-甲氧基-6-甲基-苯基)3-[[2-[[4-[N`-己氧羰基甲脒基]苯氨基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物9)
(2-methoxy-6-methyl-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000021
制备方法参见实施例1。
LCMS m/z＝720.34[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.73(dd,3H),7.35(td,1H),7.31(dd,1H),7.13–7.03(m,2H),7.00(dd,1H),6.78(dd,3H),6.67(d,2H),5.33(t,1H),4.61–4.50(m,2H),4.47(d,2H),4.13(t,2H),3.77(s,3H),3.69(s,3H),3.16(t,2H),2.15(s,3H),1.71(dd,2H),1.40(dd,2H),1.36–1.26(m,4H),0.89(t,3H)。
实施例10
(2-氟-6-甲氧基-苯基)3-[[2-[[4-[(E)-N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物10)
(2-fluoro-6-methoxy-phenyl)3-[[2-[[4-[(E)-N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000022
制备方法参见实施例1。
LCMS m/z＝724.32[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.76(s,1H),7.73(d,2H),7.35(td,1H),7.31(d,1H),7.11(ddd,2H),6.99(dd,1H),6.81–6.73(m,2H),6.73–6.64(m,3H),5.35(s,1H),4.54(t,2H),4.48(d,2H),4.14(t,2H),3.81(s,3H),3.70(s,3H),3.18(t,2H),1.77–1.68(m,2H),1.40(dd,2H),1.34–1.28(m,4H),0.89(t,3H)。
实施例11
3-[[2-[[4-[N'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸5-氟-2-甲氧基-苯酯(化合物11)
(5-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N'-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000023
第一步：3-[[2-[[4-[N'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(11B)
Ethyl 3-[[2-[[4-[N'-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000024
室温下在1-庚醇(1.400g，12.05mmol)的四氢呋喃(10mL)中加入碳酰二咪唑(1.95g，12.0mmol)，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)丙酸乙酯的对甲基苯磺酸盐(11A)(6.77g，10.0mmol)中加入丙酮(100mL)、水(50mL)、碳酸钾(2.77g，20.0mmol)，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100mL二氯甲烷溶解、无水硫酸钠干燥，浓缩除去溶剂得标题化合物3-[[2-[[4-[N'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(11B)，白色固体(6.00g，产率93.2％)。
1H NMR(400MHz,DMSO)δ8.43–8.34(m,1H),7.80(d,2H),7.54(td,1H),7.48(s,1H),7.40(d,1H),7.14(m,2H),7.01(s,1H),6.89(d,1H),6.78(d,2H),4.60(s,2H),4.23(t,2H),3.98(dt,4H),3.78(d,3H),2.69(t,2H),2.01–1.79(m,1H),1.77–1.63(m,1H),1.64–1.54(m,2H),1.28(d,8H),1.12(t,3H),0.86(t,3H)。
第二步：3-[[2-[[4-[N'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(11C)
3-[[2-[[4-[N'-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
Figure PCTCN2015086016-appb-000025
室温下在3-[[2-[[4-[N'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(11B)(3.0g，4.7mmol)的乙醇(50mL)溶液中加入氢氧化钠(390mg，9.75mmol)的水溶液5mL,加完后室温反应3小时。用柠檬酸饱和水溶液调pH到3，过滤析出的固体，二氯甲烷溶解，无水硫酸钠干燥、浓缩除去溶剂得标题化合物3-[[2-[[4-[N'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(11C)，白色固体(1.3g，产率45.0％)。
1H NMR(400MHz,DMSO)δ11.90(s,1H),10.99(s,1H),10.03(s,1H),8.37(d,1H),7.96(s,2H),7.72(d,2H),7.58(dt,3H),7.24(d,1H),7.14(dd,1H),7.02(d,1H),6.93(d,2H),4.82(s,2H),4.26(t,2H),4.18(t,2H),3.87(s,3H),2.79–2.69(m,3H),2.63(m,3H),1.68(m,2H),1.38–1.24(m,10H),0.87(t,3H)。
第三步：3-[[2-[[4-[N'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2- 吡啶基)氨基]丙酸5-氟-2-甲氧基-苯酯(化合物11)
(5-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N'-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000026
室温下在3-[[2-[[4-[N'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(11C)(1.40g，2.28mmol)的二甲基甲酰胺(15mL)溶液中加入5-氟2-甲氧基苯酚(450mg，3.17mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(0.900g，5.07mmol)和4-二甲氨基吡啶(170mg，1.39mmol)，室温反应15小时。向反应液中加入水(30mL)，用二氯甲烷(50mL×3)萃取，合并有机相，有机相用饱和磷酸二氢钾溶液(30mL×2)洗涤，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'-庚氧基羰基甲脒基]苯氨基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸5-氟-2-甲氧基-苯酯(化合物11)，棕色固体(0.20g，产率12.0％)。
LCMS m/z＝738.4[M+1]
1H NMR(400MHz,DMSO)δ9.01(s,1H),8.64(s,1H),8.42(dd,1H),7.80(d,2H),7.56(td,1H),7.50(d,1H),7.41(d,1H),7.20(dd,1H),7.18-7.08(m,3H),7.05(dd,1H),6.94(dd,2H),6.77(d,2H),4.60(d,2H),4.33(t,2H),3.98(t,2H),3.77(s,3H),3.73(s,3H),2.98(t,2H),1.65–1.50(m,2H),1.35–1.21(m,8H),0.86(t,3H)。
实施例12
(2-甲氧基苯基)3-[[2-[[4-[(E)-N`-(2-甲氧基乙氧羰基)甲脒基]苯氨基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物12)
(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-(2-methoxyethoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000027
制备方法参见实施例3。
LCMS m/z＝680.28[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.73(dd,3H),7.38–7.28(m,2H),7.21–7.14(m,1H),7.09(d,1H),7.04–6.97(m,2H),6.96–6.88(m,2H),6.77(d,1H),6.66(d,2H),5.34(s,1H),4.55(t,2H),4.47(d,2H),4.35–4.24(m,2H),3.80(s,3H),3.73–3.65(m,5H),3.40(d,3H),3.10(t,2H)。
实施例13
(2,3-二氟-6-甲氧基-苯基)3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物13)
(2,3-difluoro-6-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000028
制备方法参见实施例1。
LCMS m/z＝742.31.[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.74(s,1H),7.71(s,2H),7.34(td,1H),7.28(d,1H),7.07(d,1H),7.02–6.91(m,2H),6.75(d,1H),6.69–6.53(m,3H),5.38(s,1H),4.53(t,2H),4.45(d,2H),4.21–4.04(m,2H),3.78(s,3H),3.68(s,3H),3.19(t,,2H),1.78–1.61(m,2H),1.47–1.35(m,2H),1.35–1.25(m,4H),0.88(t,3H)。
实施例14
(3-氟-2-甲氧基-苯基)3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物14)
(3-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000029
制备方法参见实施例1。
LCMS m/z＝724.32[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(d,1H),7.73(s,1H),7.71(s,2H),7.33(td,1H),7.28(d,1H),7.07(d,1H),6.98(ddd,3H),6.87–6.81(m,1H),6.74(d,1H),6.64(d,,2H),5.36(s,1H),4.55(t,2H),4.45(s,2H),4.13(t,2H),3.89(d,3H),3.68(s,3H),3.11(t,2H),1.77–1.63(m,2H),1.39(dd,2H),1.30(dd,4H),0.88(t,3H)。
实施例15
(2-甲氧基苯基)3-[[1-甲基-2-[[4-[(E)-N`-(2-甲戊氧羰基)甲眯]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物15)
(2-methoxyphenyl)3-[[1-methyl-2-[[4-[(E)-N`-(2-methylpentoxycarbonyl)carbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000030
制备方法参见实施例3。
LCMS m/z＝706.33[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.73(d,3H),7.37–7.28(m,2H),7.21–7.13(m,1H),7.09(d,1H),7.05–6.97(m,2H),6.96–6.88(m,2H),6.77(d,1H),6.66(d,2H),5.36(s,1H),4.55(t,2H),4.47(d,2H),3.97(ddd,2H),3.81(d,3H),3.69(s,3H),3.10(t,2H),1.91(dd,1H),1.52–1.35(m,2H),1.30(ddd,2H),0.97(d,3H),0.90(t,3H)。
实施例16
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)丙酰基)氧基)苯甲酸乙酯(化合物16)
ethyl 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)benzoate
Figure PCTCN2015086016-appb-000031
Figure PCTCN2015086016-appb-000032
0℃下三口瓶中依次加入3-[[2-[[4-[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),水杨酸乙酯(16A)(0.42g，2.5mol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.42g，2.17mmol),4-二甲氨基吡啶(0.122g，1mmol),然后加入N,N-二甲基甲酰胺(16mL)保温搅拌0.5小时，升至室温反应5。停止反应向反应液中加入乙酸乙酯(100mL)，有机相用水(60mL×5)洗涤，在用饱和食盐水(60mL×1)洗涤，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)丙酰基)氧基)苯甲酸乙酯(化合物16)(0.1g,产率8％)。
1H NMR(400MHz,CDCl3):δ8.42(d,1H),8.01-7.99(m,1H),7.78-7.74(m,3H),7.58-7.51(m,1H),7.36-7.30(m,3H),7.14-7.11(m,2H),7.01-6.98(m,1H),6.78-6.76(d,1H),6.71-6.69(m,2H),5.30(s,1H),4.59-4.56(t,2H),4.51-4.50(d,2H),4.34-4.29(m,2H),4.16-4.12(t,2H),3.72(s,3H),3.17-3.13(t,2H),1.76-1.69(m,2H),1.45-1.41(m,2H),1.39-1.29(m,7H),0.91-0.87(t,3H)。
实施例17
(5-溴-2-甲氧基苯基)3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物17)
(5-bromo-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000033
制备方法参见实施例1。
LCMS m/z＝784.24.[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,3H),8.44(dd,3H),7.71(dd,9H),7.38–7.23(m,12H),7.14(d,3H),7.09–6.96(m,6H),6.76(dd,6H),6.63(d,6H),5.35(t,3H),4.53(t,6H),4.43(d,,6H),4.17–4.07(m,6H),3.77(s,8H),3.66(s,8H),3.09(t,6H),2.03(s,1H),1.71(dd,6H),1.60–1.21(m,20H),0.89(dd,9H),-0.01(s,4H)。
实施例18
2-甲氧苯基3-[[1-甲基-2-[[4-[N`-pentoxycarbonylcarbamimidoyl]苯氨基]甲基]苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(化合物18)
2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-pentoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoat
Figure PCTCN2015086016-appb-000034
制备方法参见实施例11。
LCMS m/z＝692.3[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.75-7.71(m,3H),7.38–7.27(m,2H),7.21–7.13(m,1H),7.07(d,1H),7.03-6.98(m,2H),6.95-6.89(m,2H),6.76(d,1H),6.65(d,2H),5.36(t,1H),4.55(t,2H),4.44(d,2H),4.13(t,2H),3.79(s,3H),3.67(s,3H),3.10(t,2H),1.75-1.69(m,2H),1.41–1.33(m,4H),0.91(t,3H)。
实施例19
[2-(二氟甲氧基)苯基]3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物19)
[2-(difluoromethoxy)phenyl]3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000035
制备方法参见实施例1
1H NMR(400MHz,CDCl3)δ8.42(dd,1H),7.69(d,3H),7.32(td,1H),7.23(s,1H),7.21(d,3H),7.17(dt,1H),7.07–6.94(m,2H),6.72(d,1H),6.60(d,2H),5.41(s,1H),4.54(t,,2H),4.40(d,2H),4.12(t,2H),3.64(s,3H),3.10(t,2H),1.70(dd,2H),1.39(dt,2H),1.34–1.27(m,4H),0.88(dd,3H)。
实施例20
(4-氟-2-甲氧基苯基)3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物20)
(4-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000036
制备方法参见实施例1。
LCMS m/z＝724.32[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.73(s,1H),7.72–7.66(m,2H),7.32(dd,1H),7.28(dd,1H),7.06(d,1H),7.03–6.93(m,2H),6.74(d,1H),6.69–6.56(m,4H),5.36(s,1H),4.53(t,2H),4.44(d,2H),4.13(t,2H),3.77(s,3H),3.67(s,3H),3.08(t,2H),1.80–1.62(m,2H),1.47–1.34(m,2H),1.30(dd,4H),0.88(dd,3H)。
实施例21
1-萘基3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物21)
1-naphthyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000037
制备方法参见实施例1。
LCMS m/z＝726.33[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.87(dd,1H),7.84–7.78(m,1H),7.73–7.64(m,4H),7.50–7.45(m,2H),7.45–7.38(m,1H),7.35–7.29(m,1H),7.29–7.26(m,1H),7.25(d,1H),6.99(ddd,2H),6.74(d,1H),6.59(d,2H),5.35(t,1H),4.64(t,2H),4.37(d,2H),4.13(t,2H),3.58(s,3H),3.26(t,2H),1.80–1.63(m,2H),1.45–1.35(m,2H),1.35–1.23(m,4H),0.88(dd,3H)。
实施例22
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-异丙基苯酯(化合物22)
2-isopropylphenyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000038
制备方法参见实施例1。
LCMS m/z＝718.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.59–8.35(m,1H),8.02–7.51(m,3H),7.43–7.23(m,3H),7.23–7.09(m,2H),7.09–6.94(m,3H),6.74(d,1H),6.61(d,2H),5.41(t,1H),4.75–4.46(m,2H),4.39(t,2H),4.28–3.99(m,2H),3.73(d,3H),3.20–2.86(m,3H),1.84–1.66(m,2H),1.50–1.26(m,6H),1.21(t,6H),1.01–0.75(m,3H)。
实施例23
(2-甲氧苯基)3-[[1-甲基-2-[[4-[N`-丙氧羰基甲眯]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物23)
(2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-propoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000039
Figure PCTCN2015086016-appb-000040
第一步：3-[[1-甲基-2-[[4-[N`-丙氧羰基甲脒]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸乙酯(23B)
ethyl 3-[[1-methyl-2-[[4-[N`-propoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000041
室温下在正丙醇(0.32g，5.36mmol)的四氢呋喃(10mL)中加入N,N'-羰基二咪唑(0.94g，5.81mmol)，室温搅拌30分钟,减压除去溶剂，制备成反应液1。在乙基3-[[2-[(4-甲眯苯胺)甲基]-1甲基-苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸酯对甲基苯磺酸盐(11A)(3g，4.47mmol)中加入丙酮(80mL)、水(40mL)、碳酸钾(1.85g，13.41mmol)，搅拌均匀后加入反应液1，加完后室温反应5小时。之后加入水(100mL)，并用(150mL×2)乙酸乙酯萃取二次，合并有机层，有机层用(150mL×2)的水洗2次，之后有机层无水硫酸钠干燥，浓缩除去溶剂得标题化合物3-[[1-甲基-2-[[4-[N`-丙氧羰基甲脒]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸乙酯(23B)，白色固体(1.8g，产率69.2％)。
LCMS m/z＝586.27[M+1]。
第二步：3-[[1-甲基-2-[[4-[N`-丙氧羰基甲脒]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸(23C)
3-[[1-methyl-2-[[4-[N`-propoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid
Figure PCTCN2015086016-appb-000042
室温下在3-[[1-甲基-2-[[4-[N`-丙氧羰基甲脒]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸酯(23B)(1.8g，3.07mmol)的15mL乙醇溶液中加入氢氧化钠(245mg，6.14mmol)的水溶液7.5mL,加完后室温反应1小时。之后减压出去乙醇，并用柠檬酸的水溶液调节反应溶液至pH为4至5,析出大量固体，将固体过滤，固体加入20mL乙腈并搅拌10分钟，再次过滤固体，减压出去残留溶剂，即得产品白色固体3-[[1-甲基-2-[[4-[N`-丙氧羰基甲脒]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸(23C)(1.30g，产率76.47％)。
LCMS m/z＝558.24[M+1]。
第三步：(2-甲氧苯基)3-[[1-甲基-2-[[4-[N`-丙氧羰基甲眯]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物23)
(2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-propoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000043
室温下在3-[[1-甲基-2-[[4-[N`-丙氧羰基甲脒]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶)氨基]丙酸(23C)(1.30g，2.33mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入愈创木酚(0.433g，3.5mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(0.58g，3.03mmol)和4-二甲氨基吡啶(171mg，1.40mmol)，室温反应15小时。向反应液中加入水(30mL)，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用水溶液洗涤(30mL×2)，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)＝50:1～30:1)得到白色固体，即标题化合物(2-甲氧苯基)3-[[1-甲基-2-[[4-[N`-丙氧羰基甲眯]苯胺]甲基]苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物23)(0.45g，产率30.0％)。
LCMS m/z＝664.28[M+1]。
1H NMR(400MHz,MeOD)δ8.31(dd,1H),7.64–7.54(m,2H),7.50(d,1H),7.42(td, 1H),7.27(d,1H),7.21(dd,1H),7.14–7.06(m,1H),7.04(ddd,1H),6.95(dd,1H),6.92–6.85(m,2H),6.85–6.77(m,1H),6.72–6.58(m,2H),4.55(s,1H),4.36(t,2H),3.98(dd,2H),3.72(s,3H),3.68(s,3H),2.94(t,2H),1.61(dd,2H),1.19(s,2H),0.89(t,3H)。
实施例24
(2-甲氧-5-甲基-苯基)3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物24)
(2-methoxy-5-methyl-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000044
制备方法参见实施例1。
LCMS m/z＝720.34[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(d,1H),7.79(d,2H),7.75(s,1H),7.34(dd,2H),7.15(d,1H),7.03–6.91(m,2H),6.81(dd,3H),6.72(d,2H),5.27(s,1H),4.54(dd,4H),4.14(t,2H),3.77(s,3H),3.74(s,3H),3.10(t,2H),2.25(d,3H),1.80–1.69(m,2H),1.46–1.37(m,2H),1.31(dd,4H),0.89(dd,3H)。
实施例25
2-氯苯基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-甲酰氨基)丙酸乙酯(化合物25)
2-chlorophenyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000045
Figure PCTCN2015086016-appb-000046
室温下在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-甲酰氨基)丙酸(中间体1)(1.40g，2.3mmol)的二甲基甲酰胺(15mL)溶液中加入2-氯苯酚(25A)(0.450mg，3.50mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(0.900g，5.07mmol)和4-二甲氨基吡啶(170mg，1.39mmol)，室温反应15小时。向反应液中加入水(30mL)，用二氯甲烷(50mL×3)萃取，合并有机相，有机相用饱和磷酸二氢钾溶液(30mL×2)洗涤，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2-氯苯基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-甲酰氨基)丙酸乙酯(化合物25)，棕色固体(0.65g，产率39.0％)。
LCMS m/z＝710.2[M+1]。
1H NMR(400MHz,DMSO)δ9.01(s,1H),8.65(s,1H),8.48–8.37(m,1H),7.80(d,2H),7.56(m,2H),7.51(d,1H),7.42–7.38(m,2H),7.33–7.28(m,2H),7.19(dd,1H),7.14(m,1H),7.00–6.89(m,2H),6.77(d,2H),4.60(d,2H),4.38(t,2H),4.03–3.93(m,2H),3.77(s,3H),3.06(t,2H),1.67–1.58(m,2H),1.36–1.28(m,6H),0.87(t,3H)。
实施例26
(2-甲氧苯基)3-[[2-[[4-[N`-乙氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物26)
(2-methoxyphenyl)3-[[2-[[4-[N`-ethoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000047
制备方法参见实施例11。
LCMS m/z＝650.26[M+1]。
1H NMR(400MHz,CDCl3)δ8.45(d,1H),7.79(d,2H),7.75(s,1H),7.39–7.30(m, 2H),7.17(dd,2H),7.01(dd,2H),6.97–6.89(m,2H),6.78(d,1H),6.72(d,2H),5.29(s,1H),4.59–4.47(m,4H),4.21(q,2H),3.80(s,3H),3.74(s,3H),3.11(t,2H),1.35(t,3H)。
实施例27
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2,3,-二氢-1H-4-茚酯(化合物27)
2,3-dihydro-1H-inden-4-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000048
0℃下三口瓶中依次加入3-[[2-[[4-[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)，4-茚醇(27A)(0.2g，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2,3,-二氢-1H-4-茚酯(化合物27)(0.08g,产率6％)。
1H NMR(400MHz,CDCl3):δ8.42(d,1H),7.76-7.73(m,3H),7.36-7.30(m,2H),7.12-7.07(m,3H),7.00-6.98(m,1H),6.84-6.82(d,1H),6.76-6.74(d,1H),6.69-6.67(d,2H),5.33(s,1H),4.57-4.53(t,2H),4.49-4.48(d,2H),4.16-4.12(t,2H),3.71(s,3H),3.10-3.06(t,2H),2.95-2.91(t,2H),2.79-2.75(t,2H),2.09-2.02(m,2H),1.76-1.69(m,2H),1.42-1.38(m,2H),1.33-1.29(m,4H),0.91-0.87(t,3H)。
实施例28
(2,6-二甲氧基苯基)3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物28)
(2,6-dimethoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000049
制备方法参见实施例1。
LCMS m/z＝736.34[M+1]。
1H NMR(400MHz,CDCl3)δ8.40(dd,1H),7.69(dd,3H),7.35(td,1H),7.29–7.19(m,1H),7.08(t,1H),7.04–6.92(m,2H),6.80(d,1H),6.57(dd,4H),5.44(t,1H),4.60–4.44(m,2H),4.37(d,2H),4.12(t,2H),3.76(s,6H),3.59(s,3H),3.25–3.03(m,2H),1.83–1.59(m,2H),1.51–1.35(m,2H),1.31(dd,4H),0.88(t,3H)。
实施例29
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-氟苯酯(化合物29)
3-fluorophenyl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000050
制备方法参见实施例1。
LCMS m/z＝694.1[M+1]。
1H NMR(400MHz,CDCl3)δ8.45(dd,1H),7.74(dd,3H),7.36–7.27(m,3H),7.11(d,1H),7.05–6.97(m,1H),6.97–6.83(m,3H),6.70(dd,3H),5.32(s,1H),4.56(t,2H),4.48(d,2H),4.14(t,2H),3.71(s,3H),3.05(t,2H),1.81–1.67(m,2H),1.46–1.28(m,6H),0.89(dd,3H)。
实施例30
2,3-二氢-1H-茚-5-基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-甲酰氨基)丙酸乙酯(化合物30)
2,3-dihydro-1H-inden-5-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000051
制备方法参见实施例1。
LCMS m/z＝716.3[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.79–7.68(m,3H),7.37–7.27(m,2H),7.16(d,1H),7.08(d,1H),6.99(ddd,1H),6.90(s,1H),6.80(dd,1H),6.74(d,1H),6.65(d,2H),5.34(s,1H),4.55(t,2H),4.45(d,2H),4.14(t,2H),3.68(s,3H),3.04(t,2H),2.87(dd,4H),2.15–2.00(m,2H),1.78–1.66(m,2H),1.48–1.35(m,2H),1.37–1.27(m,4H),0.89(dd,3H)。
实施例31
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-甲氧基-2-乙氧基)苯酯(化合物31)
2-(2-methoxy-2-oxoethyl)phenyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000052
0℃下三口瓶中依次加入3-[[2-[[4-[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-羟基苯乙酸甲酯(31A)(0.25g，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N,N-二甲基甲酰胺(20mL)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-甲氧基-2-乙氧基)苯酯(0.1g,产率13.4％)。
1H NMR(400MHz,CDCl3):δ8.45(d,1H),7.76-7.65(m,3H),7.36-7.27(m,3H),7.21-7.17(t,1H),7.13-7.11(d,2H),7.02-6.99(m,2H),6.76-6.69(m,3H),5.37(s,1H),4.57-4.50(m,4H),4.16-4.11(m,2H),3.72(s,3H),3.66(s,3H),3.58(s,2H),3.10-3.07(t,2H),1.74-1.70(m,2H),1.43-1.37(m,2H),1.33-1.31(m,4H),0.89-0.86(t,3H)。
实施例32
(2-甲氧苯基)3-[[2-[[4-[N`甲氧羰基甲眯]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物32)
(2-methoxyphenyl)3-[[2-[[4-[N`-methoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000053
制备方法参见实施例11。
LCMS m/z＝636.25[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(d,1H),7.81–7.66(m,3H),7.34(d,2H),7.15(dd,2H),7.01(t,2H),6.93(dd,2H),6.78(d,1H),6.72(d,2H),5.31(s,1H),4.55(t,2H),4.51(d,2H),3.80(s,3H),3.78(s,3H),3.73(s,3H),3.11(t,2H)。
实施例33
3-氯苯基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-甲酰氨基)丙酸酯(化合物33)
3-chlorophenyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000054
制备方法参见实施例1。
LCMS m/z＝710.0[M+1]。
1H NMR(400MHz,CDCl3)δ8.45(m,1H),7.74(m,3H),7.36–7.27(m,3H),7.23–7.16(m,1H),7.14–7.08(m,2H),7.05–6.96(m,2H),6.69(m,3H),5.31(d,1H),4.56(t,2H),4.48(d,2H),4.14(t,2H),3.70(s,3H),3.05(t,2H),1.77–1.68(m,2H),1.46–1.36(m,2H),1.36–1.27(m,4H),0.89(t,3H)。
实施例34
2,3-二甲氧苯基3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(化合物34)
2,3-dimethoxyphenyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000055
制备方法参见实施例1。
LCMS m/z＝736.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.42(dd,1H),7.71–7.68(m,3H),7.33(m,1H),7.23(d,1H),7.03–6.95(m,3H),6.76(t,2H),6.66(dd,1H),6.58(d,2H),5.43(t,1H),4.54(t,2H),4.37(d,2H),4.12(t,2H),3.80(d,6H),3.59(s,3H),3.11(t,2H),1.77–1.60(m,2H),1.47–1.35(m,2H),1.32-1.28(m,4H),0.90-0.87(m,3H)。
实施例35
(2-甲氧苯基)3-[[2-[[4-[N`-丁氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(化合物35)
2-methoxyphenyl 3-[[2-[[4-[N`-butoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000056
制备方法参见实施例11。
LCMS m/z＝678.2[M+1]。
1H NMR(400MHz,DMSO)δ8.48–8.39(m,1H),7.81(d,2H),7.57(td,1H),7.52(d,1H),7.42(d,1H),7.29–7.17(m,2H),7.18–7.09(m,2H),7.06(dd,1H),7.01–6.90(m,3H),6.78(d,2H),4.61(d,2H),4.35(t,2H),4.00(t,2H),3.76(d,6H),2.99(t,2H),1.71–1.47(m,2H),1.37-1.33(m,2H),0.91(t,3H)。
实施例36
(4-甲氧苯基)3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物36)
(4-methoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000057
制备方法参见实施例1。
LCMS m/z＝706.33[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.73(s,1H),7.72–7.67(m,2H),7.35–7.29(m,1H),7.28(dd,1H),7.07(d,1H),7.02–6.94(m,3H),6.89–6.82(m,2H),6.72(d,1H),6.64(d,2H),5.36(s,1H),4.55(t,2H),4.45(d,2H),4.13(td,2H),3.78(s,3H),3.67(s,3H),3.02(t,2H),1.71(dd,2H),1.44–1.34(m,2H),1.34–1.27(m,4H),0.89(dd,3H)。
实施例37
(3-甲氧苯基)3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物37)
(3-methoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000058
制备方法参见实施例1。
LCMS m/z＝706.33[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.73(dd,3H),7.36–7.27(m,2H),7.23(d,1H),7.08(d,1H),6.99(dd,1H),6.80–6.69(m,2H),6.69–6.60(m,4H),5.33(s,1H),4.55(t,2H),4.46(d,2H),4.13(td,2H),3.77(s,3H),3.69(s,3H),3.05(t,2H),1.71(dd,2H),1.40(dd,2H),1.31(dd,4H),0.89(t,3H)。
实施例38
2-甲氧基苯基3-(1-甲基-2-(((4-(N'-(((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸酯(化合物38)
2-methoxyphenyl 3-(1-methyl-2-(((4-(N'-(((4-methylpentyl)oxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000059
第一步：3-(1-甲基-2-(((4-(N'-(((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡 啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(38B)
ethyl 3-(1-methyl-2-(((4-(N'-(((4-methylpentyl)oxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000060
室温下在4-甲基戊醇(1.50g，14.7mmol)的四氢呋喃(10mL)中加入碳酰二咪唑(2.40g，1.48mmol)，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)丙酸乙酯的对甲基苯磺酸盐(11A)(6.71g，10.0mmol)中加入丙酮(160mL)、水(80mL)、碳酸钾(4.20g，30.4mmol)，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/水混合溶剂(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，浓缩除去溶剂得标题化合物3-(1-甲基-2-(((4-(N'-(((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(38B)，白色固体(6.00g，产率95.5％)。
LCMS m/z＝628.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.42(d,1H),7.78(d,2H),7.70(s,1H),7.37–7.28(m,2H),7.11(d,1H),7.04–6.94(m,1H),6.70(t,3H),5.25(s,1H),4.48(d,2H),4.43(t,2H),4.10(dt,4H),3.71(s,3H),2.81(t,2H),1.72(dd,3H),1.66–1.53(m,2H),1.29(dd,2H),1.22(t,3H),0.90(d,6H)。
第二步：3-(1-甲基-2-(((4-(N'-((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡啶-2-基基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸(38C)
3-(1-methyl-2-(((4-(N'-(((4-methylpentyl)oxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoic acid
Figure PCTCN2015086016-appb-000061
室温下在3-(1-甲基-2-(((4-(N'-(((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸乙酯(38B)(2.00g，3.19mmol)的乙醇 (50mL)溶液中加入氢氧化钠(320mg，8.00mmol)的水(5mL)溶液,加完后室温反应2小时。用稀盐酸(2mol/L)调pH到4，过滤析出的固体，二氯甲烷溶解，无水硫酸钠干燥、浓缩除去溶剂得标题化合物3-(1-甲基-2-(((4-(N'-((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡啶-2-基基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸(38C)，白色固体(1.50g，产率79.0％)。
LCMS m/z＝600.2[M+1]。
第三步：2-甲氧基苯基3-(1-甲基-2-(((4-(N'-(((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸酯(化合物38)
2-methoxyphenyl 3-(1-methyl-2-(((4-(N'-(((4-methylpentyl)oxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000062
室温下在3-(1-甲基-2-(((4-(N'-((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡啶-2-基基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸(38C)(2.00g，3.30mmol)的二甲基甲酰胺(15mL)溶液中加入愈创木酚(0.790mg，6.36mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(1.80g，10.1mmol)和4-二甲氨基吡啶(244mg，2.00mmol)，室温反应15小时。向反应液中加入水(30mL)，用二氯甲烷萃取(50mL×3)，合并有机相，有机相用饱和磷酸二氢钾溶液洗涤(30mL×2)，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2-甲氧基苯基3-(1-甲基-2-(((4-(N'-(((4-甲基戊基)氧基)羰基)甲脒基)苯基)氨基)甲基)-N-(吡啶-2-基)-1H-苯并[d]咪唑-5-甲酰氨基)丙酸酯(化合物38)，棕色固体(0.80g，产率30.0％)。
LCMS m/z＝706.2[M+1]。
1H NMR(400MHz,DMSO)δ9.08(s,1H),8.59(d,1H),8.42(dd,1H),7.80(d,2H),7.57(td,1H),7.51(d,1H),7.41(d,1H),7.26–7.17(m,2H),7.12(ddd,2H),7.05(dd,1H),7.00–6.89(m,3H),6.77(d,2H),4.60(d,2H),4.34(t,2H),3.97(t,2H),3.77(s,3H),3.74(s,3H),2.98(t,2H),1.57(m,3H),1.21(dt,2H),0.87(d,6H)。
实施例39
3-[[2-[[4-[N`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸2-甲氧基苯酯(化合物39)
(2-methoxyphenyl)3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000063
第一步：3-[[2-[[4-[N`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(39B)
Ethyl 3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000064
室温下在2-乙基-1-丁醇(1.00g，9.79mmol)的四氢呋喃(10mL)溶液中加入碳酰二咪唑(1.08g，10.4mmol)，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)丙酸乙酯的对甲基苯磺酸盐(11A)(3.35g，5.00mmol)中加入丙酮(100mL)、水(50mL)、碳酸钾(2.16g，15.6mmol)，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100mL二氯甲烷溶解、无水硫酸钠干燥，浓缩除去溶剂得标题化合物3-[[2-[[4-[N`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(39B)，白色固体(3.00g，产率96.0％)。
LCMS m/z＝628.2[M+1]。
1H NMR(400MHz,DMSO)δ8.39(s,1H),7.79(d,2H),7.53(d,1H),7.50(d,1H),7.40(d,1H),7.26–7.02(m,2H),7.03–6.83(m,2H),6.77(d,2H),4.59(d,2H),4.22(s,2H),4.04–3.94(m,2H),3.92(d,2H),3.76(s,3H),2.68(s,2H),1.49(d,1H),1.33(s,4H),1.12(t,3H),0.87(t,6H)。
第二步：3-[[2-[[4-[N`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(39C)
3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanic acid
Figure PCTCN2015086016-appb-000065
室温下在3-[[2-[[4-[N`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(39B)(3.00g，4.80mmol)的乙醇(50mL)溶液中加入氢氧化钠(390mg，9.75mmol)的水(5mL)溶液，加完后室温反应2小时。用稀盐酸(2mol/L)调pH到4，过滤析出的固体，二氯甲烷溶解，无水硫酸钠干燥、浓缩除去溶剂得标题化合物3-[[2-[[4-[N`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(39C)，白色固体(1.50g，产率52.0％)。
1H NMR(400MHz,DMSO)δ12.03(m,2H),9.25(s,1H),8.37(s,1H),7.77(s,2H),7.476(t,3H),7.12(s,2H),6.99(d,2H),6.79(s,2H),4.61(s,2H),4.18(s,2H),3.96(s,2H),3.77(s,3H),2.67(d,2H),1.51(s,1H),1.34(s,4H),0.87(s,6H)。
第三步：3-[[2-[[4-[N`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸2-甲氧基苯酯(化合物39)
(2-methoxyphenyl)3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000066
室温下在3-[[2-[[4-[N`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(39C)(2.00g，3.30mmol)的二甲基甲酰胺(15mL)溶液 中加入愈创木酚(0.790mg，6.36mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(1.80g，10.1mmol)和4-二甲氨基吡啶(244mg，2.00mmol)，室温反应15小时。向反应液中加入水(30mL)，用二氯甲烷萃取(50mL×3)，合并有机相，有机相用饱和磷酸二氢钾溶液洗涤(30mL×2)，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`-(2-乙基丁氧基羰基)甲脒基]苯胺基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸2-甲氧基苯酯(化合物39)，棕色固体(0.250g，产率11.0％)。
LCMS m/z＝706.2[M+1]。
1H NMR(400MHz,DMSO)δ9.08(s,1H),8.84(s,1H),8.42(dd,1H),7.80(d,2H),7.57(td,1H),7.51(d,1H),7.41(d,1H),7.21(m,2H),7.12(m,2H),7.05(dd,1H),6.94(dt,3H),6.77(d,2H),4.60(d,2H),4.34(t,2H),3.77(s,3H),3.74(d,3H),2.98(t,2H),1.50(dd,1H),1.32(m,4H),0.87(t,6H)。
实施例40
3-[[2-[[4-[N`-己氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸2,4-二甲氧苯酯(化合物40)
(2,4-dimethoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000067
将3-[[2-[[4-[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)(2g，3.3mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.82g，4.3mmol),4-二甲氨基吡啶(0.24g，2mmol),2,4-二甲氧基苯酚(40A)(0.72g，5.0mmol)，加入到的N,N-二甲基甲酰胺(5mL)中，室温反应6小时，再向反应液中加入水(50mL)，水相用乙酸乙酯(50mL×3)萃取，合并有机相，有机相用水(50mL×2)洗涤，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]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸2,4-二甲氧苯酯(化合物40)，白色固体(0.70g，产率29.1％)。
LCMS m/z＝736.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.80–7.68(m,3H),7.40–7.29(m,2H),7.11(d,1H),6.99(dd,1H),6.93(d,1H),6.77(d,1H),6.68(d,2H),6.51(d,1H),6.42(dd,1H),5.33(s,1H),4.54(t,2H),4.48(d,2H),4.14(t,2H),3.76(d,6H),3.69(d,3H),3.08(t,2H),1.71(dd,2H),1.47–1.37(m,2H),1.31(dd,4H),0.89(t,3H)。
实施例41
3-[[2-[[4-[N`-己氧基羰基甲脒基]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸2,5-二甲氧苯酯(化合物41)
(2,5-dimethoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000068
将3-[[2-[[4-[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(0.41g，2.17mmol),4-二甲氨基吡啶(0.12g，1mmol),2,5-二甲氧基苯酚(41A)(0.38g，2.5mmol),加入到N,N-二甲基甲酰胺(5mL)中，室温反应6小时，再向反应液中加入水(50mL)，水相用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用水洗涤(50mL×2)，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]苯氨基]甲基]-1-甲基苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸2,5-二甲氧苯酯(化合物41)，白色固体(1.0g，产率83.3％)。
LCMS m/z＝736.2[M+1]。
1H NMR(400MHz,CDCl3)δ8.44(dd,1H),7.85–7.66(m,3H),7.40–7.31(m,2H),7.13(d,1H),7.00(dd,1H),6.87(d,1H),6.78(d,1H),6.75–6.68(m,3H),6.65(d,1H),5.30(s,1H),4.58–4.49(m,4H),4.14(t,2H),3.76-3.71(m,9H),3.11(t,2H),1.76-1.69(m,2H),1.43-1.38(m,2H),1.33-1.29(m,4H),0.89(t,3H)。
实施例42
(5-氰基-2-甲氧基-苯基)3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物42)
(5-cyano-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000069
制备方法参见实施例1。
LCMS m/z＝731.32.[M+1]。
1H NMR(400MHz,CDCl3)δ8.45(dd,1H),7.73(dd,3H),7.50(dd,1H),7.37–7.27(m,3H),7.10(d,1H),7.01(dd,1H),6.98(d,1H),6.72(d,1H),6.66(d,2H),5.34(s,1H),4.55(t,2H),4.47(d,2H),4.13(t,2H),3.86(s,3H),3.70(s,3H),3.11(t,2H),1.71(dd,2H),1.39(m,2H),1.35–1.28(m,4H),0.89(dd,3H)。
实施例43
(2-异丙氧苯基)3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物43)
(2-isopropoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000070
制备方法参见实施例1。
LCMS m/z＝734.36.[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.75(s,1H),7.73–7.67(m,2H),7.38–7.31(m,1H),7.30(dd,1H),7.16–7.10(m,1H),7.08(d,1H),7.00(m,2H),6.96–6.85(m,2H),6.76(d,1H),6.65(d,2H),5.35(s,1H),4.54(dd,2H),4.51–4.47(m,1H),4.45(d,2H),4.13(t,2H),3.68(s,3H),3.15–3.01(m,2H),1.71(dd,2H),1.46–1.36(m,2H),1.33(t,2H),1.30(s,4H),1.29(s,4H),0.89(dd,3H)。
实施例44
(2-甲硫基苯基)3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物44)
(2-methylsulfanylphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000071
制备方法参见实施例1。
LCMS m/z＝722.30.[M+1]。
1H NMR(400MHz,CDCl3)δ8.43(dd,1H),7.74(s,1H),7.72(d,2H),7.33(td,1H),7.29(d,1H),7.24(d,1H),7.18(m,2H),7.06(dd,2H),6.99(dd,1H),6.76(d,1H),6.64(d,2H),5.33(t,1H),4.57(t,2H),4.43(d,2H),4.13(t,2H),3.66(s,3H),3.13(t,2H),2.39(s,3H),1.71(dd,2H),1.45–1.35(m,2H),1.35–1.27(m,4H),0.88(t,3H)。
实施例45
(2-乙氧苯基)3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物45)
(2-ethoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000072
制备方法参见实施例1。
LCMS m/z＝720.34.[M+1]。
1H NMR(400MHz,CDCl3)δ8.41(dd,1H),7.70(s,1H),7.68(s,2H),7.32(td,1H),7.24(d,1H),7.15–7.09(m,1H),7.02–7.00(m,1H),7.00–6.94(m,2H),6.88(m,2H),6.74(d,1H),6.58(d,2H),5.40(t,1H),4.53(t,2H),4.38(d,2H),4.12(t,2H),4.00(q,2H),3.61(s,3H),3.09(t,2H),1.70(dd,2H),1.39(dd,2H),1.34(t,4H),1.30(dd,4H),0.88(dd,3H)。
实施例46
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-(三氟甲氧基)苯酯(化合物46)
2-(trifluoromethoxy)phenyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000073
0℃下三口瓶中依次加入3-[[2-[[4-[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),2-(三氟甲氧基)苯酚(46A)(0.45g，2.5mol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.42g，2.17mmol)，4-二甲氨基吡啶(0.122g，1mmol),然后加入N,N-二甲基甲酰胺(16mL)保温搅拌0.5小时，升至室温反应5。停止反应向反应液中加入乙酸乙酯(100mL)，有机相用水洗涤(60mL×5)，在用饱和食盐水洗涤(60mL×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-(三氟甲氧基)苯酯(化合物46)(0.136g,产率10.8％)。
1H NMR(400MHz,CDCl3):δ8.46(d,1H),7.80-7.75(m,3H),7.34-7.29(m,5H),7.23-7.21(m,1H),7.17-7.15(m,1H),7.02-6.99(m,1H),6.75-6.72(m,3H),5.25(s,1H),4.59-4.52(m,4H),4.16-4.13(t,2H),3.75(s,3H),3.13-3.10(t,2H),1.75-1.69(m,2H), 1.42-1.38(m,2H),1.33-1.29(m,4H),0.91-0.87(t,3H)。
实施例47
3-(2-(((4-(N'-((4-环丙基丁氧基)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-甲氧基苯酯(化合物47)
2-methoxyphenyl 3-(2-(((4-(N'-((4-cyclopropylbutoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxami do)propanoate
Figure PCTCN2015086016-appb-000074
第一步：3-(2-(((4-(N'-((4-环丙基丁氧基)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)丙酸乙酯(47B)
ethyl 3-(2-(((4-(N'-((4-cyclopropylbutoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate
Figure PCTCN2015086016-appb-000075
反应瓶中加入4-环丙基丁基-1-醇(1g，8.76mmol)和四氢呋喃(12mL)，然后加入N,N'-羰基二咪唑(1.54g，9.49mmol)，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-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)丙酸乙酯(47A)(4.9g，7.3mmol)、上述油状物、丙酮(120mL)和水(60mL)。室温搅拌5小时，减压蒸干丙酮，残留物中加入水(60mL)，用乙酸乙酯(100mL×3)萃取， 合并有机相，饱和食盐水洗涤(90mL)，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)＝30:1-10:1)得到白色固体3-(2-(((4-(N'-((4-环丙基丁氧基)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)丙酸乙酯(47B)(2.5g，产率53.5％)。
1H NMR(400MHz,CDCl3):δ8.42-8.41(d,1H),7.78-7.76(m,2H),7.71-7.69(m,1H),7.32-7.30(m,2H),7.14-7.11(d,1H),7.00-6.97(m,1H),6.73-6.69(m,3H),5.30(s,1H),4.51-4.50(d,2H),4.45-4.41(m,2H),4.17-4.13(t,3H),4.11-4.05(m,2H),3.73(s,3H),2.83-2.79(t,2H),1.78-1.73(m,2H),1.56-1.48(m,2H),1.27-1.20(m,5H),0.68-0.63(m,1H),0.40-0.37(m,2H),0.09-0.02(m,2H)。
第二步：3-(2-(((4-(N'-((4-环丙基丁氧基)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(47C)
3-(2-(((4-(N'-((4-cyclopropylbutoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoic acid
Figure PCTCN2015086016-appb-000076
称取3-(2-(((4-(N'-((4-环丙基丁氧基)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)丙酸乙酯(47B)(0.85g，1.33mmol)和氢氧化钠(0.106g，2.66mmol)至反应瓶中，加入水(5mL)和乙醇(10mL),室温搅拌1小时，减压浓缩干乙醇，水相用10％柠檬酸调节pH至4-5，析出白色固体，过滤真空干燥得白色固体3-(2-(((4-(N'-((4-环丙基丁氧基)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(47C)(0.62g，产率76.5％)。
第三步：3-(2-(((4-(N'-((4-环丙基丁氧基)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-甲氧基苯酯(化合物47)
2-methoxyphenyl 3-(2-(((4-(N'-((4-cyclopropylbutoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxami do)propanoate
Figure PCTCN2015086016-appb-000077
0℃下三口瓶中依次加入3-(2-(((4-(N'-((4-环丙基丁氧基)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(47C)(0.61g，1mmol),2-甲氧基苯酚(0.189g，1.5mol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.25g，1.3mmol),4-二甲氨基吡啶(0.073g，0.6mmol),然后加入N,N-二甲基甲酰胺(10mL)保温搅拌0.5小时，升至室温反应5。停止反应向反应液中加入乙酸乙酯(80mL)，有机相用水(50mL×5)洗涤，在用饱和食盐水(50mL×1)洗涤，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'-((4-环丙基丁氧基)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-甲氧基苯酯(化合物47)(0.43g，产率59％)。
实施例48
3-[[2-[[4-[N'-(3,3,3-三氟丙氧基)羰基甲脒基]苯氨基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸5-氟-2-甲氧基-苯酯(化合物48)
(5-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N'-(3,3,3-trifluoropropoxy)carbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000078
制备方法参见实施例47；
LCMS m/z＝736.2.[M+1]。
实施例49
3-[[2-[[4-[N'-(3,3,3-三氟丙氧基)羰基甲脒基]苯氨基]甲基]-1-甲基-苯并咪唑-5-羰基]-(2-吡啶基)氨基]丙酸2-甲氧基-苯酯(化合物49)
(2-methoxy-phenyl)3-[[2-[[4-[N'-(3,3,3-trifluoropropoxy)carbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate
Figure PCTCN2015086016-appb-000079
制备方法参见实施例47。
LCMS m/z＝718.1.[M+1]。
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 PCTCN2015086016-appb-000080
结论：本发明化合物具有良好的药代动力学特征，特别是化合物1、2、3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 PCTCN2015086016-appb-100001
    X1和X2各自独立的选自O或S；
    R1选自C6-10碳环，所述的碳环任选进一步被0至4个R1a所取代；
    R1a各自独立的选自H、F、Cl、Br、I、CN、C1-4烷基、C1-4烷氧基、-S-C1-4烷基或-(CH2)nCOO C1-4烷基，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代；
    R2选自C1-10烷基，所述的烷基任选进一步被0至12个R2a所取代；
    R2a各自独立的选自H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基或C3-6碳环，所述的烷基、烷氧基或碳环任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代；
    n选自0、1或2。
  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选自取代或未取代的苯基、苯并环戊基或萘基，当被取代时，任选进一步被0至4个R1a所取代；
    R2选自C1-8烷基，所述的烷基任选进一步被0至12个R2a所取代。
  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各自独立的选自H、F、Cl、Br、CN、CF3、-CHF2、-SCH3、-OCF3、-OCHF2、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、-COOCH2CH3或-CH2COOCH3；
    R2a各自独立的选自H、F、Cl、Br、甲基、乙基、环丙基、环丁基或环戊基；
  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 PCTCN2015086016-appb-100002
    Figure PCTCN2015086016-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和药学上可接受的盐，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和药学上可接受的盐，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。
PCT/CN2015/086016 2014-08-06 2015-08-04 一种达比加群环基酯衍生物及其制备方法和在药学上的用途 Ceased WO2016019844A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201580036812.4A CN106660995A (zh) 2014-08-06 2015-08-04 一种达比加群环基酯衍生物及其制备方法和在药学上的用途

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410383909 2014-08-06
CN201410383909.X 2014-08-06
CN201510201176.8 2015-04-27
CN201510201176 2015-04-27

Publications (1)

Publication Number Publication Date
WO2016019844A1 true WO2016019844A1 (zh) 2016-02-11

Family

ID=55263147

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/086016 Ceased WO2016019844A1 (zh) 2014-08-06 2015-08-04 一种达比加群环基酯衍生物及其制备方法和在药学上的用途

Country Status (2)

Country Link
CN (1) CN106660995A (zh)
WO (1) WO2016019844A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102838588A (zh) * 2011-06-24 2012-12-26 中国药科大学 一类可用于口服的凝血酶抑制剂、其制法以及医药用途
CN102875533A (zh) * 2012-11-06 2013-01-16 中国药科大学 达比加群衍生物、其制法及抗血栓用途
CN103044404A (zh) * 2013-01-14 2013-04-17 中国药科大学 达比加群衍生物、其制法及抗血栓用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102838588A (zh) * 2011-06-24 2012-12-26 中国药科大学 一类可用于口服的凝血酶抑制剂、其制法以及医药用途
CN102875533A (zh) * 2012-11-06 2013-01-16 中国药科大学 达比加群衍生物、其制法及抗血栓用途
CN103044404A (zh) * 2013-01-14 2013-04-17 中国药科大学 达比加群衍生物、其制法及抗血栓用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG, XIAOZHI YANG ET AL.: "Design, Synthesis and Antithrombotic Evaluation of Novel Dabigatran Prodrugs Containing Methyl Ferulatea", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, no. 7, 8 February 2013 (2013-02-08), pages 2091, XP028997370, ISSN: 0960-894X, DOI: doi:10.1016/j.bmcl.2013.01.126 *

Also Published As

Publication number Publication date
CN106660995A (zh) 2017-05-10

Similar Documents

Publication Publication Date Title
JP6134338B2 (ja) Ｂ型肝炎ウイルス共有結合閉環状ｄｎａ形成の阻害剤およびそれらの使用方法
CN100508975C (zh) 吡唑并吡啶化合物的用途
CA2890003A1 (en) Amine derivatives or salt thereof as tnf"alpha"inhibitors
JP2008540597A (ja) 置換されたべンゾ［ｄ］イソオキサゾール−３−イル−アミン−化合物及バニロイド受容体リガンドとしてのその使用
TW200911245A (en) Pyridone derivatives
JP2003520270A (ja) ミクロソームトリグリセリド輸送タンパク質およびアポリポタンパク質分泌の阻害剤として有用なカルボキサミド
JPWO2000015603A1 (ja) ベンゼン誘導体及びその医薬用途
CN111303121A (zh) 含喹喔啉酮的4-苯氧基吡啶类化合物及其应用
CA2838703A1 (en) Indanone derivatives, pharmaceutically acceptable salts or optical isomers thereof, preparation method for same, and pharmaceutical compositions containing same as active ingredient for preventing or treating viral diseases
JP2000063363A (ja) 新規なトリアゾール誘導体
CN116854668A (zh) 酞嗪酮类化合物及其药物组合物和应用
US20050043304A1 (en) Novel amine derivative having human beta-tryptase inhibitory activity and drugs containing the same
KR20220068224A (ko) Perk 억제 화합물
US9550746B2 (en) Benzofuran-2-sulfonamides derivatives as chemokine receptor modulators
JPH07267954A (ja) 新規の３−フェニルスルホニル−３，７−ジアザビシクロ［３，３，１ノナン−化合物、その製法及び抗不整脈剤
WO2016019844A1 (zh) 一种达比加群环基酯衍生物及其制备方法和在药学上的用途
KR20030016267A (ko) 토라세마이드의 신규한 동질다상체 ｖ
CN102250099B (zh) 一类非肽类抗凝血酶抑制剂、其制法以及医药用途
WO2016019846A1 (zh) 一种达比加群酯衍生物及其制备方法和在药学上的用途
WO2016019847A1 (zh) 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
WO2016019849A1 (zh) 一种达比加群烷酯衍生物及其制备方法和在药学上的用途
CN114436945B (zh) 一种苯磺酰胺类化合物、制备方法及应用
TWI682928B (zh) 達比加群烷酯衍生物及其製備方法和在藥學上的用途
TWI678365B (zh) 氟代達比加群酯衍生物及其製備方法和在藥學上的用途
KR101418078B1 (ko) ｍＧｌｕＲ5 길항제로서의 2-(치환된에티닐)퀴놀린 유도체

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15829309

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15829309

Country of ref document: EP

Kind code of ref document: A1