CN108473518B - 双膦酸化合物 - Google Patents
双膦酸化合物 Download PDFInfo
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- CN108473518B CN108473518B CN201780006981.2A CN201780006981A CN108473518B CN 108473518 B CN108473518 B CN 108473518B CN 201780006981 A CN201780006981 A CN 201780006981A CN 108473518 B CN108473518 B CN 108473518B
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Classifications
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- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/3843—Polyphosphonic acids containing no further substituents than -PO3H2 groups
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/3856—Polyphosphonic acids containing halogen or nitro(so) substituents
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/3839—Polyphosphonic acids
- C07F9/3865—Polyphosphonic acids containing sulfur substituents
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- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
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Abstract
Description
技术领域
本发明涉及针对异位性钙化具有显著抑制作用的新双膦酸化合物或其盐、以及含有它们的药物组合物。
背景技术
对于慢性肾脏病(chronic kidney disease:CKD)发展、经过慢性肾衰竭而变成末期肾衰竭的患者,进行人工透析。CKD中,造成骨·矿物质代谢异常,心血管病的发病频率高,该心血管病成为CKD患者的最高死亡原因。CKD患者中高频率地观察到骨量减少、包括血管的异位性钙化。异位性钙化是通过发展与抑制两者来控制的过程。作为主要的异位性钙化的机制,认为是钙化抑制过程减弱、诱导骨软骨形成、细胞死亡、钙以及磷的恒定性异常、磷酸钙存在、底物分解等(非专利文献1)。
异位性钙化之中,将在动脉血管内等不溶性的磷酸钙等沉积的现象称为血管钙化,分为在高龄者、糖尿病患者、CKD患者中观察到的被称为 Moenckeberg型的中膜钙化、和内膜的粥样动脉硬化斑块的动脉硬化性钙化 (粉瘤型内膜钙化)(非专利文献2)。前者可以举出特别是在长期的人工透析患者中显著观察到的异位性钙化障害(包括由活性型维生素D制剂导致的诱发)。另一方面,作为后者的进展过程,像以往动脉硬化的机制那样,认为与过剩的类脂质与巨噬细胞侵入到脉硬化斑块中有关(非专利文献3)。
推测是在Moenckeberg型中膜钙化的形成过程中,血管平滑肌细胞分化成成骨细胞的机制。作为血管钙化的危险因素,包含年龄、透析期间、糖尿病、高血压、血中磷浓度、钙磷沉积、含钙的磷吸附药(在CKD中以治疗继发性甲状旁腺功能亢进症的目的使用)的服用(非专利文献4)。
暗示了在CKD中作为并发症的血管钙化使心血管疾病的发病率以及死亡率的风险增大(非专利文献5)、为了使CKD患者的死亡减少,特别必不可少的是治疗血管钙化。
但是,关于针对异位性钙化疾病以及血管钙化障碍有效果的治疗法,现状是尚未完全确立。例如尝试了将磷吸附剂(含钙的磷吸附药、高分子磷吸附药、碳酸镧等)、钙模拟化合物给药,但难以说是表现了足够的药效。随着CKD患者、伴有动脉硬化的疾病患者增加,有效地阻碍以及预防血管钙化的方法的必要性增高,希望开发出显示有效性的新药物。
作为双膦酸盐化合物之一的依替膦酸具有作为通过骨吸收抑制作用来促进骨量增加的骨质疏松症治疗剂的作用,另一方面,与表现骨吸收抑制作用相比,以高用量显示抑制骨形成(骨的钙化)的作用,从而作为异位性钙化骨化治疗剂使用。有报告在以透析患者为对象的试验中依替膦酸有意义地抑制大动脉钙化(非专利文献6)。进一步有报告依替膦酸有意义地使2型糖尿病患者的颈动脉内膜中膜厚减少(非专利文献7)。
关于除依替膦酸以外的双膦酸盐化合物,除了有报告含氮的双膦酸盐系药剂在人中显示出钙化抑制作用以外(非专利文献8、9),还有报告将双膦酸盐系药剂以改善高钙血症等为目的对人给药(专利文献1)。另外,作为研究双膦酸盐化合物在动物中的作用的例子,有报告大鼠钙化模型(专利文献2)、粉瘤性动脉硬化模型(专利文献3)、大鼠高钙血症模型(专利文献4)。有一些这样的报告,但以异位性钙化特殊化的双膦酸盐化合物的见解极其少。
现有技术文献
专利文献
专利文献1:日本特表平07-507315
专利文献2:日本特表2003-519183
专利文献3:日本特表2006-504749
专利文献4:日本特开昭62-114994
非专利文献
非专利文献1:Lu KC,et al.Vascular calcification and renal bonedisorders. Scientific World Journal.2014;2014:Article ID 637065.
非专利文献2:Karwowski W,et al.The mechanism of vascularcalcification-a systematic review.Med Sci Monit.2012;18(1):RA1-11.
非专利文献3:Rocha-Singh KJ,et al.Peripheral arterial calcification:prevalence,mechanism,detection,and clinical implications.Catheter CardiovascInterv.2014;83(6):E212-20.
非专利文献4:Guerin AP,et al.Arterial stiffening and vascularcalcifications in end-stage renal disease.Nephrol Dial Transplant.2000;15(7):1014-21.
非专利文献5:Giachelli CM.Vascular calcification mechanisms.J Am SocNephrol.2004;15(12):2959-64.
非专利文献6:Nitta K,et al.Effects of cyclic intermittent etidronatetherapy on coronary artery calcification in patients receiving long-termhemodialysis.Am J Kidney Dis.2004;44(4):680-8.
非专利文献7:Koshiyama H,et al.Decrease in carotid intima-mediathickness after 1-year therapy with etidronate for osteopenia associated withtype 2diabetes.J Clin Endocrinol Metab.2000;85(8):2793-6.
非专利文献8:Toussaint ND,et al.Effect of alendronate on vascularcalcification in CKD stages 3and 4:a pilot randomized controlled trial.Am JKidney Dis.2010;56(1):57-68.
非专利文献9:Tanko LB,et al.Effective doses of ibandronate do notinfluence the 3-year progression of aortic calcification in elderlyosteoporotic women.Osteoporos Int.2005;16(2):184-90。
发明内容
钙化抑制作用、骨吸收抑制作用对骨带来影响。由于前者的表现,因此具有骨、软骨的钙化被抑制而引起骨密度降低的骨软化症、血中无极磷升高的倾向,另一方面,骨吸收抑制作用强的双膦酸盐系药剂具有颌骨坏死的副作用。由于这些,当以抑制异位性钙化为目的治疗时,确保强钙化抑制作用,并且回避基于骨吸收抑制作用的副作用,因此希望相同作用不过强、即对骨的作用不偏颇、安全性高的双膦酸盐系药剂。
本发明的课题在于,提供具有显著的异位性钙化抑制作用的新双膦酸化合物或其盐、以及含有它们的药物组合物。
本发明者们为了解决上述课题而进行了深入研究,其结果发现了新双膦酸化合物在大鼠钙化模型中通过口服给药具有显著的异位性钙化抑制作用,至此完成本发明。
即,本发明提供下面的〔1〕~〔6〕。
〔1〕下述通式(1):
表示的双膦氧化合物或其药学上可接受的盐
(式中,部分表示单键或双键,A表示C3-8的饱和环状烃、或者含有硫原子或氧原子的C3-8的饱和杂环(该饱和环状烃或饱和杂环任选地被 1~6个选自C1-6烷基、C2-6链烯基、C2-6炔基、C1-6烷氧基、C6-10芳基氧基、 C1-6卤代烷氧基、C1-6卤代烷基以及卤素原子中的基团取代);R1及R2分别独立地表示C1-6烷基、C2-6链烯基、C2-6炔基、C1-6烷氧基、C6-10芳基氧基、 C1-6卤代烷氧基、C1-6卤代烷基、卤素原子、或氢原子,但是,部分为双键的情况下R2不存在)。
〔2〕一种药物组合物,含有〔1〕所述的化合物或其盐。
〔3〕一种伴有异位性钙化的疾病的预防治疗药,以〔1〕所述的化合物或其盐为有效成分。
〔4〕〔1〕所述的化合物或其盐在制造伴有异位性钙化的疾病的预防治疗药中的应用。
〔5〕根据〔1〕所述的化合物或其盐,其用于预防治疗伴有异位性钙化的疾病。
〔6〕一种伴有异位性钙化的疾病的预防或治疗方法,其特征在于,施用有效量的〔1〕所述的化合物或其盐。
【发明的效果】
本发明的新双膦酸化合物或其盐安全性高,具有优秀的异位性钙化抑制作用,对于伴有异位性钙化的疾病的预防及治疗是有用的。
具体实施方式
下面,对本发明具体进行说明。
在本说明书中,所谓“饱和环状烃”,可以是单环式、多环式中的任一种,作为C3-C8的环状烃,例如可以举出环丙烷环、环丁烷环、环戊烷环、环己烷环、环庚烷环、环辛烷环、降冰片烷环等。
在本说明书中,所谓“饱和杂环”,可以是单环式、多环式中的任一种,作为含有硫原子或氧原子的C3-C8的饱和杂环,例如可以举出三亚甲基氧化物环、三亚甲基硫化物环、四氢呋喃环、四氢噻吩环、四氢吡喃环、四氢噻喃环等。
在本说明书中,所谓“烷基”,意思是可以为直链状、支链状、环状、或它们的组合中的任一种的饱和烃链。作为C1-6的烷基,例如可以举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、环丙基、环丁基、环己基等。
在本说明书中所谓“链烯基”,意思是可以为直链状、支链状、环状、或它们的组合中的任一种、具有双键的不饱和烃链。作为C2-6链烯基,例如可以举出乙烯基、丙烯基、丁烯基等。
在本说明书中,所谓“炔基”,意思是可以为直链状、支链状、或它们的组合中的任一种、具有三键的不饱和烃链。作为C2-6炔基,例如可以举出乙炔基、丙炔基等。
在本说明书中,作为“C1-6烷氧基”,例如可以举出甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基、苯氧基等。作为“C6-10芳基氧基”,例如可以举出苯氧基、萘基氧基。
在本说明书中,作为“C1-6卤代烷氧基”,例如可以举出三氟甲氧基、三氟乙氧基等。
在本说明书中,作为“C1-6卤代烷基”,例如可以举出三氟甲基、三氟乙基等。
在本说明书中,作为“卤素原子”,可以举出氟、氯、溴、碘。
作为A表示的C3-8的饱和环状烃,优选环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷或降冰片烷。作为具有硫原子或氧元素的C3-8的饱和杂环,优选三亚甲基氧化物、三亚甲基硫化物、四氢呋喃、四氢噻吩、四氢吡喃或四氢噻喃,更优选四氢呋喃、四氢噻吩、四氢吡喃或四氢噻喃。
可以在饱和环状烃或饱和杂环上取代的基团是选自C1-6烷基、C2-6链烯基、C2-6炔基、C1-6烷氧基、C6-10芳基氧基、C1-6卤代烷氧基、C1-6卤代烷基以及卤素原子中的1~6个,这些之中,优选选自C1-6烷基、C1-6烷氧基、 C6-10芳基氧基以及卤素原子中的1~4个,进一步优选选自C1-6烷基、C6-10芳基氧基以及卤素原子中的1~2个。此外,这些取代基取代的位置可以是饱和环状烃或饱和杂环与单键或双键的键合位置。
作为R1及R2,分别表示C1-6烷基、C2-6链烯基、C2-6炔基、C1-6烷氧基、 C6-10芳基氧基、C1-6卤代烷氧基、C1-6卤代烷基、卤素原子或氢原子,这些之中,更优选C1-6烷基、卤素原子或氢原子,进一步优选C1-3烷基、卤素原子或氢原子。
作为通式(1)的更优选状态,是如下的双膦氧化合物、或其药学上可接受的盐:式中,部分表示单键,A表示C3-8的饱和环状烃、或者含有硫原子或氧原子的C3-8的饱和杂环(该饱和环状烃、或饱和杂环任选地被选自C1-6烷基、C1-6烷氧基、C6-10芳基氧基以及卤素原子中的1~4个基团取代);R1及R2分别独立地表示C1-6烷基、卤素原子或氢原子。
作为进一步优选的状态,是如下的双膦氧化合物、或其药学上可接受的盐:式中,部分表示单键,A表示C3-8的环状烃、或者含有硫原子或氧原子的C3-8的饱和杂环(该饱和环状烃或者饱和杂环任选地被选自C1-6烷基、C6-10芳基氧基以及卤素原子中的1~2个基团取代):R1及R2分别独立地表示C1-3烷基、卤素原子或氢原子。另外,进一步优选后述实施例中记载的化合物、或其药学上可接受的盐。
所谓本发明的新双膦酸化合物的盐,是通式(1)的化合物药学上可接受的盐,可以通过使通式(1)的化合物在溶剂中、与所希望的碱进行处理来制造。作为这样的盐的形式,可以举出锂盐、钾盐、钠盐等,优选是钠盐。另外,本发明的化合物也包含用各种放射性或非放射性同位素标签化的化合物。
通式(1)表示的本发明的化合物有时以异构体形式存在,例如有时存在几何异构体、光学异构体或对映异构体。在本发明中,这些异构体分离而得的物质、任意混合物、消旋体等全部包含。
对于通式(1)表示的本发明的化合物、或其药学上可接受的盐,作为其等效化合物的前药也包含在本发明的权利要求范围中。所谓“前药”,是指根据生物体内的代谢机制转换成通式(1)的化合物的化合物、即在生物体内酶方式地通过氧化、还原、水解、或胃酸等引起水解等、变成通式(1) 的化合物的物质。作为通式(1)的化合物的前药,可以举出磷酸基、羟基修饰成酰基、烷基等的化合物,例如乙酰化、新戊酰化、新戊酰氧基甲基化了的化合物等。这些化合物可以通过公知的方法由通式(1)的化合物合成。另外,这些前药例如可以在如“The Organic chemistry of drug design and drug action(second edition)”chapter 8p497-557中记载那样的条件下变成通式(1)的化合物。
本发明化合物的制造方法没有特别限定,例如可以根据下述的工序来制造。另外,对于本发明中包含的各种用放射性或非放射性同位素标签化而得的化合物,也能够通过同位素取代原料与下述制造方法同样地制造。
下面,对于本发明的双膦氧化合物的代表性制造方法进行说明。
(式中,R1、R2、A与前述相同)
第一工序:可以通过有机溶剂中使亚硫酰氯、五氯化磷、三氯化磷、磷酰氯、草酰氯等与作为原料的羧酸中间体(2)进行反应,从而制造酰基氯(3)。
第二工序:可以通过有机溶剂中使三(三甲基甲硅烷基)亚磷酸酯等与酰基氯(3)进行反应,从而制造双膦氧化合物(1)。或者可以通过有机溶剂中使三氯化磷、膦酸与酰基氯(3)进行反应,从而制造双膦氧化合物 (1)。
第一工序中使用的羧酸中间体(2)可以通过以下的反应制造。
(式中,R表示酯残基,R3表示A环上的取代基,A与前述相同)
(A的1位取代的羧酸衍生物(6)的制造法)
例如用烷基、链烯基、炔基取代的羧酸衍生物(6)可以通过将2-亚环烷基丙二酸酯(4)分别烷基化、链烯基化、或炔基化制成丙二酸酯衍生物 (5),水解后通过脱羧反应来制造。作为烷基化、链烯基化、炔基化的条件,例如可以通过Shirley,D.A.Org.React.,1954,8,28.记载的格氏反应来制造。作为脱羧的条件,例如可以通过无溶剂或有机溶剂中根据所希望地添加适量酸、加热来制造。
(式中,R表示烷基,A与前述相同)
(被甲基取代的羧酸衍生物(11)的合成法)
可以将化合物(7)甲苯磺酰化后(8),通过磺酰基甲基化制成(9),接着通过还原的脱磺酰基化(10)、脱保护、氧化制造羧酸衍生物(11)。作为甲苯磺酰化的条件,例如可以举出有机溶剂中添加三甲基胺盐酸盐、N- 甲基咪唑等催化剂,三乙基胺、二异丙基乙基胺、吡啶等碱存在下利用甲苯磺酰氯、甲苯磺酰酸酐等甲苯磺酰化剂的反应。作为磺酰基甲基化的条件,例如可以举出四氢呋喃(以下为THF)、二乙基醚等有机溶剂中,正丁基锂、仲丁基锂、叔丁基锂等碱存在下,与苯基甲基砜等具有磺酰基甲基的砜衍生物的反应。作为还原条件,例如可以举出甲醇、乙醇等醇溶剂中使用镁等金属还原剂。使用由甲硅烷基而得的保护基的情况下,可以使用氟化氢吡啶络合物、四丁基氟化铵等脱保护剂。作为氧化反应的条件,例如可以举出在由Dess-Martin氧化、Swern氧化、PCC氧化、PDC氧化、TEMPO 氧化等获得醛后通过Pinnick氧化制成羧酸的方法;或者添加有柠檬酸、酒石酸等弱酸的有机溶剂、水或它们的混合溶剂中,使亚氯酸钠等氧化剂与催化剂量的AZADO进行反应制成羧酸的方法等。
(式中,R表示烷基,A与前述相同)
(在邻接的碳上具有取代基的羧酸衍生物(18)的合成)
例如将6-氧杂双环[3.1.0]己烷-3-羧酸甲酯(12)甲基化(13)后,进行还原,保护伯羟基获得(14)。可以使其与化学式4同样地进行制造(15)。接着可以通过脱保护、甲苯磺酰化制成(16),通过氰基化(17)、水解制造化合物(18)。作为甲基化的条件,例如可以举出路易斯酸存在下添加催化剂、利用甲基锂、甲基溴化镁等甲基化剂的反应。作为还原的条件,例如可以举出THF、二乙基醚等有机溶剂中通过氢化铝锂、氢化硼锂等氢化物还原剂进行还原的条件。作为氰基化,例如可以举出有机溶剂中、水中或与有机溶剂的混合溶剂中利用氰化钠、氰化钾等氰化剂的反应。
(式中,R表示酯残基,R'表示烷基或芳基,A与前述相同)
(被氟原子、烷氧基取代的羧酸衍生物的制造法)
例如可以将化合物(19)氟化(20),接着通过水解获得化合物(21)。作为氟化的条件,例如可以举出有机溶剂中使用DAST、Deoxo-fluorTM等脱氧的氟化剂的反应。另外,可以将化合物(19)通过光延反应制成化合物(22),通过水解获得化合物(23)。作为光延反应的条件,例如可以举出Hughes,D.L.Org.React.,1992,42,335.中记载的方法。
(式中,R表示烷基,A与前述相同)
(以环状酮为原料时的制造法)
可以将环状酮(24)通过Wittig反应、Horner-Wadsworth-Emmons反应制成化合物(25),接着酯还原后,对羟基进行保护(26),接着通过接触还原(27)、脱保护、氧化,从而获得化合物(28)。作为Wittig反应的条件,例如可以举出Maercker,A.Org.React.,1965,14,270.中记载的条件。作为Horner-Wadsworth-Emmons反应的条件,例如可以举出Wadsworth,W.S., Jr.Org.React.,1977,25,73.中记载的条件。
本发明化合物的制造方法在原料或中间体阶段具有官能团的情况下,也能够通过脱除适当的保护基来制造。作为这样的官能团,可以举出氨基、羟基、羧基等,作为保护基的种类、脱除方法,例如可以举出“Protective Groups in Organic Synthesis(FourthEdition)”(Greene,Wuts著)中记载的方法等。
在本发明化合物的制造方法中,需要水解反应的情况下,可以通过将对象化合物在适当的有机溶剂、水、或它们的混合溶剂中,在反应对应量的酸或碱存在下,室温以及加热回流下进行反应来制造。作为酸可以举出盐酸、硫酸等,作为碱,可以举出氢氧化钠、氢氧化锂等。
按上述方式合成的通式(1)的化合物可以直接游离、或以其盐的形式通过属于通常的化学操作的萃取、浓缩、蒸馏、结晶化、过滤、再结晶、各种色谱法等进行分离、精制。或者含有光学异构体、立体异构体、位置异构体的情况下,可以分别通过再结晶法、手性柱法、非对映体法等分离各自。
本发明的化合物或其盐如后述实施例所示显示优秀的异位性钙化抑制作用。该异位性钙化抑制作用比作为异位性钙化骨化治疗剂使用的依替膦酸更强力。另外,由于本发明化合物的异位性钙化抑制作用比骨吸收抑制作用更强力,因此,本发明化合物作为异位性钙化抑制剂优秀,作为伴有异位性钙化的疾病的预防治疗药特别有用。
作为伴有异位性钙化的疾病,例如可以举出以下疾病。即可以举出透析以及非透析患者中的血管钙化、钙过敏形成、糖尿病性血管病、软组织钙化、异位性钙化骨化(包含股关节形成术后、脊椎损伤后、头部外伤后等)、风湿病、变形性关节病、进行性骨化性纤维增殖症、癌、癌转移、高钙血症、硬皮病、皮肌炎、钙沉积性腱炎、钙沉积性滑膜囊炎、局灶性钙沉积症、全身性钙沉积症、颈椎后纵韧带骨化症、脊椎韧带骨化症、甲状旁腺功能亢进症、维生素D代谢异常、维生素D中毒、动脉硬化、粉瘤性硬化症、小动脉硬化症、高血压性小动脉硬化症、动脉硬化症、心脏瓣膜狭窄、血块形成、尿毒症、糖尿病、高血压、沃纳综合症、弹性纤维性假黄瘤、心绞痛、心肌梗塞、心肌损伤、心力衰竭、心脏传导阻滞、脑梗塞、转移性钙化、牙石形成、牙周病、骨·关节痛、骨变形、骨折、肌肉痛、创伤、炎症、皮肤缺血性溃疡、尿路结石、肾结石、肾衰竭、慢性肾衰竭等。本发明化合物对透析以及非透析患者中的血管钙化、钙过敏形成、动脉硬化、粉瘤性硬化症、门克伯格动脉硬化症等特别有效。
在本说明书中,所谓“血管钙化”,意思是细胞外基体羟基磷灰石(磷酸钙)在血管中结晶沉积的生成、生长或沉积。血管钙化包括大动脉、冠动脉、心脏瓣膜、以及其它血管的钙化。另外,该钙化包括中膜的钙化(门克伯格型)以及内膜的粥样动脉硬化斑块的钙化(粉瘤型)。
通式(1)表示的化合物或其药学上可接受的盐可以直接使用,也可以以含有药学上可接受的载体、例如一种或两种以上制剂用添加物的药物组合物的形式使用。该药物组合物可以以任何一种剂型使用,可以以片剂、丸剂、胶囊剂、散剂、微粒剂、颗粒剂、液剂、悬浮剂、糖浆剂、注射剂、外用剂、栓剂等形式应用。
含有通式(1)表示的化合物或其药学上可接受的盐作为有效成分而形成的药物组合物中使用的制剂用添加物的种类没有特别限定,例如可以单独或适当组合使用药品添加物辞典(2007药事日报社)记载的主剂、赋形剂、润滑剂、包衣剂、糖衣剂、润湿剂、粘合剂、崩解剂、溶剂、可溶化剂、溶解剂、助溶剂、悬浮化剂、分散剂、乳化剂、表面活性剂、等渗化剂、缓冲剂、pH调节剂、舒缓剂、防腐剂、保险剂、稳定化剂、抗氧化剂、着色剂、甜味剂等。
本发明的化合物可以与认为本发明化合物显示有效性的疾病的其它治疗剂或预防剂并用。该并用意思是同时给药、或者个别地连续或按所希望的时间间隔给药。同时给药制剂可以是复合剂、试剂盒制剂。
通常口服给药的情况,本发明化合物或其盐的1次给药量相对于体重为约0.01~100mg/kg左右,将其以1天1次或每周1以及3次给药。静脉内给药的情况,1次的给药量相对于体重为约0.0001~1mg/kg是适当的,1 天1次或每月1次~数次给药。给药量考虑症状、年龄、性别等根据各个情况适当决定。
实施例
下面,举出实施例对本发明具体地进行说明,但本发明不限定于下述实施例。
实施例中简写符号的意思是如下。
1H-NMR:质子核磁共振光谱,31P-NMR:磷核磁共振光谱,CDCl3:氘代氯仿,DMSO-d6:氘代二甲基亚砜,D2O:重水,Hz:赫兹,J:偶合常数、m:多重,sept:七重,quint:五重,q:四重,dt:双三重、dd:双二重、ddd:双双二重,t:三重,d:二重,s:单,br:宽,M:摩尔浓度, N:规定。此外,MS表示质谱分析,使用离子化法为ESI(电喷雾离子化法)的机器,将实施例化合物溶解在0.1%甲酸-乙腈中,以Dowex 50×8(H-Form)自由化进行测定。
实施例1:(2-环丙基-1-羟基丙烷-1,1-二基)双膦酸二钠
将2-环丙基丙酸(0.43g)溶解在二氯乙烷(4.0mL)中,加入亚硫酰氯 (0.35mL),在60℃下搅拌3小时,对反应液减压浓缩。在冰冷却下向残渣中加入三(三甲基甲硅烷基)亚磷酸酯(3.1mL),室温下搅拌48小时。在反应液中加入甲醇(5.0mL),室温下搅拌1小时后,对溶剂减压蒸馏。将得到的残渣在甲醇(4.0mL)中溶解,室温下加入5M甲醇钠甲醇溶液(1.5mL)搅拌2小时后,过滤反应液,获得标题化合物(1.10g)为无色固体。
实施例2:(2-环丁基-1-羟基乙烷-1,1-二基)双膦酸二钠
由环丁基乙酸(0.34g)与实施例1同样地合成,获得标题化合物(0.70g) 为无色固体。
实施例3:(2-环丁基-1-羟基丙烷-1,1-二基)双膦酸二钠
由2-环丁基丙酸(0.45g)与实施例1同样地合成,获得标题化合物 (0.75g)为无色固体。
实施例4:[1-羟基-2-(1-甲基环丁基)乙烷-1,1-二基]双膦酸二钠
由(1-甲基环丁基)乙酸(0.60g)与实施例1同样地合成,获得标题化合物(0.65g)为无色固体。
实施例5:(2-亚环丁基-1-羟基丙烷-1,1-二基)双膦酸二钠
由2-亚环丁基丙酸(0.50g)与实施例1同样地合成,获得标题化合物 (0.92g)为无色固体得。
实施例6:(2-环戊基-1-羟基乙烷-1,1-二基)双膦酸二钠
由环戊基乙酸(0.31g)与实施例1同样地合成,获得标题化合物(0.74g) 为无色固体。
实施例7:(2-亚环戊基-1-羟基乙烷-1,1-二基)双膦酸二钠
由亚环戊基乙酸(0.59g)与实施例1同样地合成,获得标题化合物 (0.65g)为无色固体。
实施例8:(2-环戊基-1-羟基丙烷-1,1-二基)双膦酸二钠
由2-环戊基丙酸(1.07g)与实施例1同样地合成,获得标题化合物 (1.46g)为淡褐色固体。
实施例9:[1-羟基-2-(3-甲基环戊基)丙烷-1,1-二基]双膦酸二钠
由2-(3-甲基环戊基)丙酸(0.47g)与实施例1同样地合成,获得标题化合物(0.50g)为无色固体。
实施例10:(2-亚环戊基-1-羟基丙烷-1,1-二基)双膦酸二钠
由2-亚环戊基丙酸(0.23g)与实施例1同样地合成,获得标题化合物 (0.51g)为无色固体。
实施例11:[1-羟基-2-(1-甲基环戊基)乙烷-1,1-二基]双膦酸二钠
由(1-甲基环戊基)乙酸(1.85g)与实施例1同样地合成,获得标题化合物(3.20g)为无色固体。
实施例12:[2-(1-乙基环戊基)-1-羟基乙烷-1,1-二基]双膦酸二钠
由(1-乙基环戊基)乙酸(0.31g)与实施例1同样地合成,获得标题化合物(0.43g)为无色固体。
制造例1:(a)2-(1-丙基环戊基)丙二酸二甲酯
在二乙基醚(8.5mL)中0℃下加入氯化铜(17mg)、1M溴化正丙基镁 THF溶液(15mL),在室温下搅拌1小时后,0℃下滴加(2-亚环戊基)丙二酸二甲酯(0.99g)的二乙基醚溶液(10mL),在室温下进一步搅拌2小时。加入1M盐酸(10mL)停止反应,用饱和食盐水洗涤、用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.42g)。
1H-NMR(CDCl3,270MHz)δ:0.88(3H,t,J=7.2Hz),1.11-1.36(2H,m),1.40-1.5 1(1H,m),1.59-1.73(7H,m),1.75-1.97(2H,m),3.57(1H,s),3.71(3H,s), 3.74(3H,s).
(b)(1-丙基环戊基)乙酸
在0℃下向2-(1-丙基环戊基)丙二酸二甲酯(0.42g)的甲醇/THF(= 1∶1)(4.0mL)溶液中加入8M氢氧化钠水溶液(2.0mL),室温下整夜搅拌。0℃下加入6M盐酸(4.0mL)停止反应,用乙酸乙酯萃取。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣在180℃下加热2小时。在残渣中加入乙酸乙酯,用水、饱和食盐水洗涤。用无水硫酸钠干燥,将溶剂减压蒸馏,获得褐色油状物(0.21g)。
1H-NMR(CDCl3,270MHz)δ:0.90(3H,t,J=6.9Hz),1.18-1.72(12H,m),2.33(2H ,s).
实施例13:[1-羟基-2-(1-丙基环戊基)乙烷-1,1-二基]双膦酸二钠
由通过制造例1(b)得到的(1-丙基环戊基)乙酸(0.21g)与实施例 1同样地合成,获得标题化合物(0.36g)为无色固体。
实施例14:[1-羟基-2-(2-甲基环戊基)乙烷-1,1-二基]双膦酸二钠
由(2-甲基环戊基)乙酸(0.43g)与实施例1同样地合成,获得标题化合物(0.64g)为无色固体。
实施例15:[1-羟基-2-(3-甲基环戊基)乙烷-1,1-二基]双膦酸二钠
由(3-甲基环戊基)乙酸(5.00g)与实施例1同样地合成,获得标题化合物(4.10g)为无色固体。
制造例2:(a)乙酸(1R*,3S*)-3-(2-叔丁基二甲基甲硅烷基氧基乙基) 环戊基
在1R*,3R*)-3-(2-叔丁基二甲基甲硅烷基氧基乙基)环戊烷-1-醇(2.33g) 的THF(25mL)溶液中加入三苯基膦(7.48g)、乙酸(1.64mL)、偶氮二羧酸二异丙酯(5.6mL),在室温下搅拌1小时。将溶剂减压蒸馏,加入乙酸乙酯(10mL)、己烷(50mL),除去不溶物,将溶剂减压蒸馏,得到的残渣用于合成(b)。
(b)(1R*,3S*)-3-(2-叔丁基二甲基甲硅烷基氧基乙基)环戊烷-1-醇
在乙酸(1R*,3S*)-3-(2-叔丁基二甲基甲硅烷基氧基乙基)环戊基的甲醇(10mL)溶液中加入5M甲醇钠甲醇溶液(2.5mL),室温下搅拌2小时。将溶剂减压蒸馏,加入水,用乙酸乙酯萃取。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(2.05g)。
1H-NMR(CDCl3,270MHz)δ:0.05(6H,s),0.89(9H,s),1.09-1.42(3H,m),1.47 -1.61(3H,m),1.74-1.84(1H,m),1.88-2.05(2H,m),2.12-2.27(1H,m),3 .62(2H,t,J=6.9Hz),4.35(1H,br).
(c)(1R*,3S*)-3-(2-叔丁基二甲基甲硅烷基氧基乙基)环戊基4-甲基苯磺酸酯
在(1R*,3S*)-3-(2-叔丁基二甲基甲硅烷基氧基乙基)环戊烷-1-醇 (2.05g)的THF(40mL)溶液中加入吡啶(1.0mL)、N-甲基咪唑(1.0mL)、甲苯磺酰氯(3.19g),室温下搅拌24小时。加入水室温下搅拌2小时后将溶剂减压蒸馏,加入1M盐酸用乙酸乙酯萃取。将有机层用1M氢氧化钠、饱和食盐水洗涤、用无水硫酸钠干燥。将溶剂减压蒸馏,得到的残渣用于合成(d)。
(d)叔丁基二甲基{2-[(1R*,3S*)-3-(苯基磺酰基甲基)环戊基]乙氧基}硅烷
在甲基苯基砜(3.03g)的THF(45mL)溶液中0℃下滴加2.65M正丁基锂正己烷溶液(7.2mL),同温下搅拌5分钟。滴加(1R*,3S*)-3-(2-叔丁基二甲基甲硅烷基氧基乙基)环戊基4-甲基苯磺酸酯的THF(15mL)溶液,55℃下搅拌3小时。用饱和氯化铵水溶液停止反应,将溶剂减压蒸馏。将得到的残渣用乙酸乙酯稀释、用水、饱和食盐水洗涤、用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(1.86g)。
1H-NMR(CDCl3,270MHz)δ:0.03(6H,s),0.88(9H,s),1.15-1.39(2H,m),1.46 -1.60(3H,m),1.68-1.98(3H,m),2.03-2.14(1H,m),2.23-2.37(1H,m),3 .14(2H,d,J=6.8Hz),3.57(2H,t,J=6.8Hz),7.53-7.69(3H,m),7.89-7.95( 2H,m).
(e)叔丁基二甲基{2-[(1R*,3S*)-3-甲基环戊基]乙氧基}硅烷
在镁(1.77g)中加入THF(5.0mL)、0.98M溴化甲基镁THF溶液(5 滴),室温下搅拌35分钟。加入叔丁基二甲基{2-[(1R*,3S*)-3-(苯基磺酰基甲基)环戊基]乙氧基}硅烷(1.86g)的甲醇(40mL)溶液,50℃下搅拌3小时。用1M盐酸-乙酸乙酯(1∶1)溶液停止反应,用乙酸乙酯萃取水层。将有机层用1M盐酸、饱和食盐水洗涤、用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物 (0.75g)。
1H-NMR(CDCl3,270MHz)δ:0.05(6H,s),0.62-0.72(1H,m),0.96(9H,s),0.97 (3H,d,J=6.5Hz),1.09-1.30(2H,m),1.49-1.60(2H,m),1.67-1.78(2H,m), 1.83-1.97(3H,m),3.60(2H,t,J=6.5Hz).
(f)2-[(1R*,3S*)-3-甲基环戊基]乙醇
在叔丁基二甲基{2-[(1R*,3S*)-3-甲基环戊基]乙氧基}硅烷(0.64g) 的THF(6mL)溶液中加入1M四丁基氟化铵·THF溶液(4.0mL),在室温下搅拌1小时。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.21g)。
1H-NMR(CDCl3,270MHz)δ:0.61-0.77(1H,m),0.98(3H,d,J=6.2Hz),1.08-1. 34(3H,m),1.52-1.64(1H,m),1.67-1.81(2H,m),1.83-1.99(3H,m),3.65 (2H,t,J=6.8Hz).
(g)(1R*,3S*)-(3-甲基环戊基)乙酸
在2-[(1R*,3S*)-3-甲基环戊基]乙醇(0.46g)的乙腈(5.0mL)溶液中加入水(5.0mL)、柠檬酸(1.04g)、亚氯酸钠(0.61g)、2-氮杂金刚烷-N- 氧(55mg),在室温下搅拌1小时。用亚硫酸氢钠停止反应,将溶剂减压蒸馏。将得到的残渣溶解在1M氢氧化钠中,用二异丙基醚洗涤,加入4M盐酸用乙酸乙酯萃取。将有机层用饱和食盐水洗涤、用无水硫酸钠干燥,将溶剂减压蒸馏,获得无色油状物(0.32g)。
1H-NMR(CDCl3,270MHz)δ:0.67-0.83(1H,m),0.99(3H,d,J=6.5Hz),1.10-1. 39(2H,m),1.67-2.12(4H,m),2.17-2.41(3H,m).
实施例16:{1-羟基-2-[(1R*,3S*)-3-甲基环戊基]乙烷-1,1-二基}双膦酸二钠
由制造例2(g)得到的(1R*,3S*)-(3-甲基环戊基)乙酸(0.32g)与实施例1同样地合成,获得标题化合物(0.52g)为无色固体。
实施例17:{1-羟基-2-[(1R*,3R*)-3-甲基环戊基]乙烷-1,1-二基}双膦酸二钠
由(1R*,3R*)-(3-甲基环戊基)乙酸(0.46g)与实施例1同样地合成,获得标题化合物(0.98g)为无色固体。
制造例3:(a)(1R*,3S*)-(3-氟环戊基)乙酸甲酯
0℃下在(1R*,3S*)-(3-羟基环戊基)乙酸甲酯(0.59g)的二氯甲烷 (5.0mL)溶液中加入Deoxo-fluorTM(0.81mL),室温下搅拌20小时。加入饱和碳酸氢钠水(5.0mL)停止反应,用饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,将得到的残渣用于合成(b)。
(b)(1R*,3S*)-(3-氟环戊基)乙酸
在(1R*,3S*)-(3-氟环戊基)乙酸甲酯中加入甲醇(7.4mL)、2N氢氧化钠(3.7mL),室温下搅拌5小时。将溶剂减压蒸馏,加入1N盐酸用乙酸乙酯萃取。用无水硫酸钠干燥有机层。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色固体(0.18g)。
1H-NMR(CDCl3,270MHz)δ:1.23-1.50(2H,m),1.60-2.09(4H,m),2.23-2.43 (3H,m),5.02-5.26(1H,m),12.03(1H,br).
实施例18:{2-[(1R*,3R*)-3-氟环戊基]-1-羟基乙烷-1,1-二基}双膦酸二钠
由制造例3(b)得到的(1R*,3S*)-(3-氟环戊基)乙酸(0.18g)与实施例1同样地合成,获得标题化合物(0.24g)为无色固体。
制造例4:与制造例3同样地进行,合成以下化合物
(a)(1R*,3R*)-(3-氟环戊基)乙酸甲酯
1H-NMR(CDCl3,270MHz)δ:1.42-2.46(9H,m),3.67(3H,s),5.00-5.24(1H,m) .
(b)(1R*,3R*)-(3-氟环戊基)乙酸
1H-NMR(CDCl3,270MHz)δ:1.18-2.31(9H,m),4.98-5.26(1H,m).
实施例19:{2-[(1R*,3S*)-3-氟环戊基]-1-羟基乙烷-1,1-二基}双膦酸二钠
由制造例4(b)得到的(1R*,3R*)-(3-氟环戊基)乙酸(0.22g)与实施例1同样地合成,获得标题化合物(0.34g)为无色固体。
制造例5:(a)(1R*,3R*)-(3-苯氧基环戊基)乙酸甲酯
在(1R*,3S*)-(3-羟基环戊基)乙酸甲酯(1.44g)的THF(20mL) 溶液中加入苯酚(1.03g)的THF(10mL)溶液、三苯基膦(3.59g),0℃下滴加偶氮二羧酸二异丙酯(2.7mL),室温下搅拌30分钟。用乙酸乙酯稀释,用饱和碳酸氢钠水、饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.64g)。
1H-NMR(CDCl3,270MHz)δ:1.20-1.35(1H,m),1.47-1.58(1H,m),1.83-1.92 (1H,m),2.00-2.19(3H,m),2.37(2H,d,J=7.3Hz),2.54-2.66(1H,m),3.67( 3H,s),4.76-4.80(1H,m),6.85(2H,d,J=7.6Hz),6.91(1H,t,J=7.3Hz),7.2 6(2H,t,J=8.0Hz).
(b)(1R*,3R*)-(3-苯氧基环戊基)乙酸
在(1R*,3R*)-(3-苯氧基环戊基)乙酸甲酯(0.64g)中加入甲醇(14mL)、 2N氢氧化钠(6.8mL),室温下搅拌18小时。将溶剂减压蒸馏,加入1N盐酸用乙酸乙酯萃取。用无水硫酸钠干燥有机层。将溶剂减压蒸馏,获得无色油状物(0.60g)。
1H-NMR(CDCl3,270MHz)δ:1.13-1.30(1H,m),1.44-1.74(2H,m),1.84-2.46 (6H,m),4.78-4.86(1H,m),6.84-6.93(3H,m),7.26(2H,t,J=8.1Hz),11.99 (1H,br).
实施例20:{1-羟基-2-[(1R*,3R*)-3-苯氧基环戊基]乙烷-1,1-二基} 双膦酸二钠
由制造例5(b)得到的(1R*,3R*)-(3-苯氧基环戊基)乙酸与实施例 1同样地合成,获得标题化合物(0.94g)为无色固体。
实施例21:[2-(3,3-二甲基环戊基)-1-羟基乙烷-1,1-二基]双膦酸二钠
由(3,3-二甲基环戊基)乙酸(0.37g)与实施例1同样地合成,获得标题化合物(0.30g)为无色固体。
实施例22:[2-(3,3-二甲基亚环戊基)-1-羟基乙烷-1,1-二基]双膦酸二钠
由(3,3-二甲基亚环戊基)乙酸(0.47g)与实施例1同样地合成,获得标题化合物(0.48g)为无色固体。
实施例23:[2-(3,3-二氟环戊基)-1-羟基乙烷-1,1-二基]双膦酸二钠
由(3,3-二氟环戊基)乙酸(0.11g)与实施例1同样地合成,获得标题化合物(0.06g)为无色固体。
制造例6:(a)(1R*,3S*,4S*)-3-羟基-4-甲基环戊烷-1-羧酸甲酯
-78℃下在氰化铜(1.82g)的THF(25mL)溶液中滴加3.1M甲基锂二乙氧基甲烷溶液(13mL),同温下搅拌10分钟、0℃下15分钟、-78℃下10 分钟。(1R,3s,5S)-6-氧杂双环[3.1.0]己烷-3-羧酸甲基(1.31g)的THF (15mL)溶液,在-78℃下滴加三氟化硼-二乙基醚络合物(4.6mL),搅拌20 分钟。加入饱和氯化铵水溶液(15mL)停止反应,将不溶物通过硅藻土过滤除去。用乙酸乙酯萃取滤液,用无水硫酸钠干燥有机层。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(1.29g)。
1H-NMR(CDCl3,270MHz)δ:1.05(3H,d,J=7.0Hz),1.37-1.51(1H,m)),1.78-1. 92(2H,m),2.18-2.28(2H,m),3.00(1H,quint,J=8.9Hz),3.68(3H,m),3.81 -3.92(1H,m).
(b)(1R*,2R*,4S*)-4-(羟基甲基)-2-甲基环戊烷-1-醇
0℃下在由制造例6(a)得到的(1R*,3S*,4S*)-3-羟基-4-甲基环戊烷-1- 羧酸甲酯(0.30g)的THF(10mL)溶液中加入氢化铝锂(0.14g),室温下搅拌30分钟。加入10%氢氧化钠停止反应,将不溶物通过硅藻土过滤除去后,用无水硫酸钠干燥有机层。将溶剂减压蒸馏,得到的残渣用于合成(c)。
(c)(1R*,2R*,4S*)-2-甲基-4-(三异丙基甲硅烷基氧基甲基)环戊烷-1- 醇
在由制造例6(b)得到的(1R*,2R*,4S*)-4-(羟基甲基)-2-甲基环戊烷-1-醇的二氯甲烷(8.5mL)溶液中加入咪唑(0.15g),0℃下滴加三异丙基甲硅烷基氯(0.40mL),同温下搅拌5小时。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.37g)。
1H-NMR(CDCl3,270MHz)δ:1.01-1.10(24H,m),1.41-2.05(5H,m),2.26-2.3 4(1H,m),3.56(2H,dd,J=5.9,1.1Hz),3.67-3.79(1H,m).
(d)(1R*,2R*,4S*)-2-甲基-4-(三异丙基甲硅烷基氧基甲基)环戊基4- 甲基苯磺酸酯
在由制造例6(c)得到的(1R*,2R*,4S*)-2-甲基-4-(三异丙基甲硅烷基氧基甲基)环戊烷-1-醇(0.37g)的二氯甲烷(5.0mL)溶液中加入N,N- 二甲基-4-氨基吡啶(39mg)、吡啶(0.26mL),0℃下加入对甲苯磺酰氯 (0.36g)。室温下搅拌14小时后,对溶剂减压蒸馏。将得到的残渣用乙酸乙酯稀释,用1M盐酸、水、饱和碳酸氢钠水、水、饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(93mg)。
1H-NMR(CDCl3,270MHz)δ:0.90(3H,d,J=7.0Hz),0.97-1.07(21H,m),1.62-2 .31(6H,m),2.44(3H,s),3.47-3.58(2H,m),4.39(1H,q,J=5.9Hz),7.32(2H ,d,J=8.3Hz),7.79(2H,d,J=8.3Hz).
(e)三异丙基{(1R*,3S*,4R*)-[3-甲基-4-(苯基磺酰基甲基)环戊基] 甲氧基}硅烷
0℃下在甲基苯基砜(0.22g)的THF(4.0mL)溶液中滴加2.6M正丁基锂正己烷溶液(0.52mL),同温下搅拌5分钟。在其中滴加由制造例6(d) 得到的(1R*,2R*,4S*)-2-甲基-4-(三异丙基甲硅烷基氧基甲基)环戊基4- 甲基苯磺酸酯(0.20g)的THF(3.0mL)溶液,55℃下搅拌13小时。用饱和氯化铵水溶液停止反应,对溶剂减压蒸馏。将得到的残渣用乙酸乙酯稀释,用水、饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(64mg)。
1H-NMR(CDCl3,270MHz)δ:0.82(3H,d,J=7.0Hz),0.98-1.30(23H,m),1.85-2 .44(5H,m),3.05(1H,dd,J=14.0,8.4Hz),3.22(1H,dd,J=14.0,5.4Hz),3.57( 2H,d,J=5.9Hz),7.53-7.68(3H,m),7.90-7.94(2H,m).
(f)(1r,3R,4S)-[(3,4-二甲基环戊基)甲氧基]三异丙基硅烷
在镁(0.11g)中加入THF(0.50mL)、2M氯化甲基镁THF(3滴),室温下搅拌15分钟。接着加入由制造例6(e)得到的三异丙基{(1R*,3S*,4R*) -[3-甲基-4-(苯基磺酰基甲基)环戊基]甲氧基}硅烷(0.13g)的甲醇(5.0mL) 溶液,50℃下搅拌17小时。用1M盐酸-乙酸乙酯(1∶1)溶液停止反应,用乙酸乙酯萃取水层。将有机层用1M氢氧化钠水溶液、饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(46mg)。
1H-NMR(CDCl3,270MHz)δ:0.85(6H,d,J=6.5Hz),0.99-1.12(23H,m),1.82-2 .14(5H,m),3.58(2H,d,J=6.5Hz).
(g)(1r,3R,4S)-(3,4-二甲基环戊基)甲醇
0℃下在由制造例6(f)得到的(1r,3R,4S)-[(3,4-二甲基环戊基)甲氧基]三异丙基硅烷(0.42g)的THF(5.0mL)溶液中加入1M四丁基氟化铵THF溶液(1.8mL),室温下搅拌16小时。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.21g)。
1H-NMR(CDCl3,270MHz)δ:0.86(6H,d,J=6.8Hz),0.92-1.05(2H,m),1.27(1H,br),1.85-2.19(5H,m),3.54(2H,d,J=5.4Hz).
(h)(1r,3R,4S)-(3,4-二甲基环戊基)甲基4-甲基苯磺酸酯
在由制造例6(g)得到的(1r,3R,4S)-(3,4-二甲基环戊基)甲醇(0.21g) 的二氯甲烷(5.0mL)溶液中加入三乙基胺(0.41mL)、N-甲基咪唑(0.15mL)、甲苯磺酰氯(0.44g),室温下搅拌7小时。对溶剂减压蒸馏,将得到的残渣用乙酸乙酯稀释,用1M盐酸、水、饱和碳酸氢钠水、水、饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,得到的残渣用于合成(i)。
(i)(1r,3R,4S)-(3,4-二甲基环戊基)乙腈
在由制造例6(h)得到的(1r,3R,4S)-(3,4-二甲基环戊基)甲基4- 甲基苯磺酸酯的N,N-二甲基甲酰胺(7.0mL)溶液中加入氰化钠(0.15g), 75℃下搅拌7小时。将反应液用水稀释,用二乙基醚萃取。将有机层用水、饱和食盐水洗涤,用无水硫酸钠干燥。对溶剂减压蒸馏,得到的残渣用于合成(j)。
(j)(1r,3R,4S)-(3,4-二甲基环戊基)乙酸
在由制造例6(i)得到的(1r,3R,4S)-(3,4-二甲基环戊基)乙腈中加入甲醇(3.7mL)、2N氢氧化钠(7.4mL),100℃下搅拌20小时。将溶剂减压蒸馏,加入1N盐酸用乙酸乙酯萃取。用无水硫酸钠干燥有机层。将溶剂减压蒸馏,获得无色油状物(0.18g)。
1H-NMR(CDCl3,270MHz)δ:0.86(6H,J=6.2Hz),0.91-0.99(2H,m),1.96-2.10 (4H,m),2.15-2.32(1H,m),2.37(2H,d,J=7.0Hz).
实施例24:{2-[(1r,3R,4S)-3,4-二甲基环戊基]-1-羟基乙烷-1,1-二基} 双膦酸二钠
由制造例6(j)得到的(1r,3R,4S)-(3,4-二甲基环戊基)乙酸(0.17g) 与实施例1同样地合成,获得标题化合物(0.30g)为无色固体。
制造例7:与制造例6同样地进行合成以下化合物。
(a)(1R*,3R*,4R*)-3-羟基-4-甲基环戊烷-1-羧酸甲基
1H-NMR(CDCl3,270MHz)δ:0,98(3H,d,J=6.5Hz),1.84-2.29(6H,m),2.84-2. 95(1H,m),3.72(3H,s),3.75-3.83(1H,m).
(b)(1R*,2R*,4R*)-2-甲基-4-(三异丙基甲硅烷基氧基甲基)环戊烷-1-醇
1H-NMR(CDCl3,270MHz)δ:0.91(3H,d,J=7.0Hz),1.03-1.47(23H,m),1.81-1 .97(2H,m),2.10-2.32(2H,m),2.63(1H,d,J=7.6Hz),3.59-3.68(3H,m).
(c)(1R*,2R*,4R*)-2-甲基-4-(三异丙基甲硅烷基氧基甲基)环戊基4- 甲基苯磺酸酯
1H-NMR(CDCl3,270MHz)δ:0.87(3H,d,J=7.0Hz),1.00-1.09(21H,m),1.22-1 .76(3H,m),1.97-2.17(3H,m),2.44(3H,s),3.51-3.57(2H,m),4.37(1H,q,J=6.8Hz),7.32(2H,d,J=8.1Hz),7.79(2H,d,J=8.1Hz).
(d)三异丙基{(1R*,3R*,4S*)-[3-甲基-4-(苯基磺酰基甲基)环戊基] 甲氧基}硅烷
1H-NMR(CDCl3,270MHz)δ:0.80(3H,d,J=7.0Hz),0.98-1.08(21H,m),1.40- 1.66(4H,m),2.19-2.40(3H,m),3.01(1H,dd,J=14.1,7.8Hz),3.19(1H,dd,J= 14.1,5.7Hz),3.51(2H,d,J=7.3Hz),7.53-7.68(3H,m),7.89-7.93(2H,m).
(e)(1s,3R,4S)-[(3,4-二甲基环戊基)甲氧基]三异丙基硅烷
1H-NMR(CDCl3,270MHz)δ:0.83(6H,d,J=6.5Hz),1.00-1.10(21H,m),1.33-1 .51(4H,m),1.91-2.02(2H,m),2.21-2.33(1H,m),3.52(2H,d,J=6.5Hz).
(f)(1s,3R,4S)-(3,4-二甲基环戊基)甲醇
1H-NMR(CDCl3,270MHz)δ:0.85(6H,d,J=6.5Hz),1.41-1.62(4H,m),1.91-2. 07(2H,m),2.29(1H,sept,J=8.1Hz),3.48(2H,d,J=7.3Hz).
(g)(1s,3R,4S)-(3,4-二甲基环戊基)乙酸
1H-NMR(CDCl3,270MHz)δ:0.84(6H,d,J=6.8Hz),1.37-1.47(2H,m),1.58-1. 66(2H,m),1.98-2.10(2H,m),2.34(2H,d,J=7.8Hz),2.42-2.60(1H,m).
实施例25:{2-[(1s,3R,4S)-3,4-二甲基环戊基]-1-羟基乙烷-1,1-二基} 双膦酸二钠
由(1s,3R,4S)-(3,4-二甲基环戊基)乙酸(0.29g)与实施例1同样地合成,获得标题化合物(0.50g)为无色固体。
制造例8:(a)(3,3,4,4-四甲基亚环戊基)乙酸乙酯
冰冷却下在六甲基二硅氮烷(0.75g)的THF(5.0mL)溶液中加入2.65M 正丁基锂正己烷溶液(1.8mL)、膦酰乙酸三乙酯(0.86mL),搅拌10分钟。冰冷却下加入3,3,4,4-四甲基环戊酮(0.50g)的THF(5.0mL)溶液,室温下搅拌5小时。对溶剂减压蒸馏,将得到的残渣用乙酸乙酯稀释,用水、饱和食盐水洗涤,用无水硫酸钠干燥。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.54g)。
1H-NMR(CDCl3,270MHz)δ:0.90(6H,s),0.92(6H,s),1.27(3H,t,J=7.0Hz), 2.42(2H,s),2.75(2H,s),4.14(2H,q,J=7.0Hz),5.73(1H,quint,J=2.7Hz).
(b)2-(3,3,4,4-四甲基亚环戊基)乙醇
在由制造例8(a)得到的(3,3,4,4-四甲基亚环戊基)乙酸乙酯(0.52g) 的THF(10mL)溶液中加入1.04M二异丁基铝正己烷溶液(6.0mL),室温下搅拌15分钟。加入1M盐酸停止反应,用乙酸乙酯萃取。用饱和食盐水洗涤,用无水硫酸钠干燥,将溶剂减压蒸馏。对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.42g)。
1H-NMR(CDCl3,270MHz)δ:0.87(6H,s),0.90(6H,s),2.23(2H,s),2.26(2H,s ),4.09(2H,br),5.41-5.49(1H,m).
(c)三异丙基[2-(3,3,4,4-四甲基亚环戊基)乙氧基]硅烷
在由制造例8(b)得到的2-(3,3,4,4-四甲基亚环戊基)乙醇(0.25g) 的二氯甲烷(5.0mL)溶液中加入咪唑(0.20g)、三异丙基甲硅烷基氯 (0.38mL),室温下搅拌15分钟。加入1M盐酸停止反应,用乙酸乙酯萃取。用饱和食盐水洗涤,用无水硫酸钠干燥,将溶剂减压蒸馏。对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.54g)。
1H-NMR(CDCl3,270MHz)δ:0.86(6H,s),0.88(6H,s),1.02-1.10(21H,m),2. 14(2H,s),2.25(2H,s),4.15-4.21(2H,m),5.34-5.42(1H,m).
(d)三异丙基[2-(3,3,4,4-四甲基环戊基)乙氧基]硅烷
在由制造例8(c)得到的三异丙基[2-(3,3,4,4-四甲基亚环戊基)乙氧基]硅烷(0.54g)的乙酸乙酯(5.0mL)溶液中加入5%钯活性炭(0.11g),氢气氛下室温下搅拌18小时。用硅藻土过滤除去不溶物,将溶剂减压蒸馏。得到的残渣用于合成(e)。
1H-NMR(CDCl3,270MHz)δ:0.84(6H,s),0.85(6H,s),1.00-1.08(21H,m),1 .28(2H,dd,J=13.0,7.3Hz),1.60(2H,d,J=7.0Hz),1.73(2H,dd,J=13.0,9.7Hz ),1.97-2.14(1H,m),3.63(2H,t,J=7.0Hz).
(e)2-(3,3,4,4-四甲基环戊基)乙醇
在由制造例8(d)得到的三异丙基[2-(3,3,4,4-四甲基环戊基)乙氧基]硅烷的THF(5.0mL)溶液中加入1M四丁基氟化铵THF溶液(2.2mL),在室温下搅拌1小时。将溶剂减压蒸馏,对得到的残渣采用硅胶色层法进行精制,获得无色油状物(0.22g)。
1H-NMR(CDCl3,270MHz)δ:0.85(6H,s),0.86(6H,s),1.29(2H,dd,J=13.0,7.3Hz),1.62(2H,q,J=7.3Hz),1.75(2H,dd,J=13.0,9.5Hz),2.02-2.16(1H,m), 3.62(2H,t,J=6.8Hz).
(f)(3,3,4,4-四甲基环戊基)乙酸
在由制造例8(e)得到的2-(3,3,4,4-四甲基环戊基)乙醇(0.22g)的乙腈(2.0mL)溶液中加入水(2.0mL)、柠檬酸(0.37g)、亚氯酸钠(0.22g)、 2-氮杂金刚烷-N-氧(10mg),在室温下搅拌1小时。用亚硫酸氢钠停止反应,对溶剂减压蒸馏。将得到的残渣溶解在1M氢氧化钠中,用二异丙基醚洗涤,加入4M盐酸用乙酸乙酯萃取。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥,将溶剂减压蒸馏,获得无色油状物(0.22g)。
1H-NMR(CDCl3,270MHz)δ:0.86(6H,s),0.87(6H,s),1.32(2H,dd,J=13.2,7.3Hz),1.84(2H,dd,J=13.2,9.2Hz),2.36-2.52(3H,m).
实施例26:[1-羟基-2-(3,3,4,4-四甲基环戊基)乙烷-1,1-二基]双膦酸二钠
由制造例8(f)得到的(3,3,4,4-四甲基环戊基)乙酸(0.22g)与实施例1同样地合成,获得标题化合物(0.36g)为无色固体。
实施例27:(2-环己基-1-羟基乙烷-1,1-二基)双膦酸二钠
由环己基乙酸(6.0g)与实施例1同样地合成,获得标题化合物(12.7g) 为无色固体。
实施例28:(2-环己基-1-羟基丙烷-1,1-二基)双膦酸二钠
由2-环己基丙酸(0.34g)与实施例1同样地合成,获得标题化合物 (0.13g)为无色固体。
实施例29:[2-(4,4-二甲基环己基)-1-羟基丙烷-1,1-二基]双膦酸二钠
由2-(4,4-二甲基环己基)丙酸(0.80g)与实施例1同样地合成,获得标题化合物(1.15g)为无色固体。
实施例30:[1-羟基-2-(1-甲基环己基)乙烷-1,1-二基]双膦酸二钠
由(1-甲基环己基)乙酸(0.34g)与实施例1同样地合成,获得标题化合物(0.51g)为无色固体。
实施例31:[2-(双环[2.2.1]庚烷-2-基)-1-羟基乙烷-1,1-二基]双膦酸二钠
由(双环[2.2.1]庚烷-2-基)乙酸(0.60g)与实施例1同样地合成,获得标题化合物(1.20g)为无色固体。
实施例32:[2-(双环[2.2.1]庚烷-2-基)-1-羟基丙烷-1,1-二基]双膦酸二钠
由2-(2-双环[2.2.1]庚烷-2-基)丙酸(0.76g)与实施例1同样地合成,获得标题化合物(1.29g)为无色固体。
实施例33:[(1R*,2S*,4S*)-2-(双环[2.2.1]庚烷-2-基)-1-羟基乙烷-1,1-二基]双膦酸二钠
由(1R*,2S*,4S*)-(双环[2.2.1]庚烷-2-基)乙酸(1.12g)与实施例 1同样地合成,获得标题化合物(1.84g)为无色固体。
实施例34:[(1R*,2R*,4S*)-2-(双环[2.2.1]庚烷-2-基)-1-羟基乙烷-1,1-二基]双膦酸二钠
由(1R*,2R*,4S*)-(双环[2.2.1]庚烷-2-基)乙酸(1.00g)与实施例 1同样地合成,获得标题化合物(1.46g)为无色固体。
实施例35:[1-羟基-2-(3,3,5,5-四甲基环己基)乙烷-1,1-二基]双膦酸二钠
由(3,3,5,5-四甲基环己基)乙酸(0.60g)与实施例1同样地合成,获得标题化合物(0.60g)为无色固体。
制造例9:(a)(3,3,5,5-四甲基亚环己基)乙酸乙酯
由3,3,5,5-四甲基环己烷-1-酮.31g)与制造例8(a)同样地合成,获得无色油状物(1.5g)。
1H-NMR(CDCl3,270MHz)δ:0.96(6H,s),0.98(6H,s),1,28(3H,t,J=7.1Hz),1 .33(2H,s),1.96(2H,s),2.62(2H,s),4.15(2H,q,J=7.1Hz),5.69(1H,s).
(b)(3,3,5,5-四甲基亚环己基)乙酸
在制造例9(a)得到的(3,3,5,5-四甲基亚环己基)乙酸乙酯中加入甲醇(5.0mL)、THF(5.0mL)、4M氢氧化钠(10mL),室温下搅拌5小时。将溶剂减压蒸馏,加入1M盐酸,用乙酸乙酯萃取。将有机层用无水硫酸钠干燥。对溶剂减压蒸馏,获得无色固体(1.94g)。
1H-NMR(CDCl3,270MHz)δ:0.97(6H,s),0.99(6H,s),1.35(2H,s),1.96(2H,s ),2.63(2H,s),5.73(1H,s).
实施例36:[1-羟基-2-(3,3,5,5-四甲基亚环己基)乙烷-1,1-二基]双膦酸二钠
由制造例9(b)得到的(3,3,5,5-四甲基亚环己基)乙酸(0.59g)与实施例1同样地合成,获得标题化合物(0.74g)为无色固体。
实施例37:{1-羟基-2-[(1r,4r)-4-甲基环己基]乙烷-1,1-二基}双膦酸二钠
由(1r,4r)-(4-甲基环己基)乙酸(1.00g)与实施例1同样地合成,获得标题化合物(1.38g)为无色固体。
实施例38:[2-(4,4-二甲基环己基)-1-羟基乙烷-1,1-二基]双膦酸二钠
由(4,4-二甲基环己基)乙酸(0.39g)与实施例1同样地合成,获得标题化合物(0.61g)为无色固体。
实施例39:[1-羟基-2-(4-丙基环己基)乙烷-1,1-二基]双膦酸二钠
由(4-丙基环己基)乙酸(1.13g)与实施例1同样地合成,获得标题化合物(1.98g)为无色固体。
实施例40:[1-羟基-2-(四氢-2H-噻喃-4-基)乙烷-1,1-二基]双膦酸二钠
由(四氢噻喃-4-基)乙酸(0.19g)与实施例1同样地合成,获得标题化合物(0.35g)为无色固体。
实施例41:[1-羟基-2-(四氢噻吩-3-基)乙烷-1,1-二基]双膦酸二钠
由(四氢噻吩-3-基)乙酸(0.14g)与实施例1同样地合成,获得标题化合物(0.28g)为无色固体。
实施例42:[1-羟基-2-(四氢噻吩-3-基)丙烷-1,1-二基]双膦酸二钠
由2-(四氢噻吩-3-基)丙酸(0.33g)与实施例1同样地合成,获得标题化合物(0.47g)为无色固体。
实施例43:[1-羟基-2-(四氢-2H-吡喃-4-基)乙烷-1,1-二基]双膦酸二钠
由(四氢-2H-吡喃-4-基)乙酸(1.16g)与实施例1同样地合成,获得标题化合物(1.12g)为无色固体。
实施例44:(2-环庚基-1-羟基乙烷-1,1-二基)双膦酸二钠
由环庚基乙酸(0.69g)与实施例1同样地合成,获得标题化合物(1.20g) 为无色固体。
实施例45:(2-环庚基-1-羟基丙烷-1,1-二基)双膦酸二钠
由2-环庚基丙酸(1.00g)与实施例1同样地合成,获得标题化合物 (1.50g)为无色固体。
实施例46:(2-环辛基-1-羟基乙烷-1,1-二基)双膦酸二钠
由环辛基乙酸(0.98g)与实施例1同样地合成,获得标题化合物(1.60g) 为无色固体。
实施例47:(2-环己基-1-羟基乙烷-1,1-二基)双膦酸
在实施例化合物27(20.0g)中加入水(300mL)、Dowex 50×8(H-Form) (159mL),室温下搅拌19小时。过滤反应液后,减压浓缩し,获得标题化合物(17.2g)为无色固体。
实施例48:(2-环己基-1-羟基乙烷-1,1-二基)双膦酸二锂
在实施例化合物47(0.58g)中加入水(9.0mL)、乙醇(9.0mL)、氢氧化锂一水合物(0.17g)搅拌2小时后,过滤反应液,获得标题化合物(0.51g) 为无色固体。
实施例49:(2-环己基-1-羟基乙烷-1,1-二基)双膦酸四钠
在实施例化合物47(0.29g)中加入水(6.0mL)、甲醇(6.0mL)、5M 甲醇钠甲醇溶液(0.80mL)室温下搅拌2小时后,过滤反应液,获得标题化合物(0.37g)为无色固体。
实施例50:(2-环己基-1-羟基乙烷-1,1-二基)双膦酸二钾
在实施例化合物47(0.30g)中加入水(5.0mL)、氢氧化钾(0.14g),室温下搅拌18小时。将反应液减压浓缩,获得标题化合物(0.37g)为无色固体。
[表1]
[表2]
[表3]
[表4]
[表5]
[表6]
试验例:维生素D3诱发大鼠血管钙化模型中的异位性钙化抑制作用对于雄性Wistar/ST大鼠以体重为指标分组(1组6只),将胆钙化醇(和光纯药工业株式会社)125000IU/kg反复3天皮下给药,使血管钙化诱发。被验物质从胆钙化醇的给药日起1天1次反复2周口服给药。此外,从被验物质给药约6小时前到给药约2小时后断食。在最终给药第二天用异氟烷麻醉下从下腔动脉全采血后,摘出从大动脉起始部起到后肢分支部的大动脉。大动脉切细后,加入1N盐酸5mL破碎,在室温下放置1小时后以4℃、 15000rpm离心15分钟,得到的上清为测定试样。使用Phospha C-测试Wako (和光纯药工业株式会社)测定测定试样中的磷量,为钙化的指标。求得各组大动脉磷量的平均值,计算出被验物质相对于对照(介质给药)的、由给药而带来的钙化抑制率(表7)。
[表7]
由被验物质给药带来的异位性钙化的抑制率
制剂例1(片剂):片剂1片中,按实施例1(50mg)、乳糖(73mg)、玉米淀粉(15mg)、交联羧甲基纤维素钠(7.5mg)、羟基丙基纤维素(3mg)、硬脂酸镁(1.5mg)的方式通过流化床制造颗粒,与润滑剂混合后压片。
制剂例2(注射剂):适量加入实施例1(1mg)、D-甘露糖醇(200mg)、 pH调节剂,通过冷冻干燥法制造。
产业上的可利用性
本发明的化合物具有优秀的异位性钙化抑制作用,特别是对于血管钙化相关的疾病的预防和/或治疗是有用的。
Claims (8)
3.根据权利要求1所述的双膦氧化合物或其药学上可接受的盐,其中,该饱和环状烃任选地被选自C1-6烷基、C1-6烷氧基、C6-10芳基氧基、卤素原子中的1~4个基团取代。
4.根据权利要求1所述的双膦氧化合物或其药学上可接受的盐,其中,R1及R2分别独立地是C1-6烷基、卤素原子或氢原子。
5.一种药物组合物,含有权利要求1~4中任一项所述的化合物或其盐。
6.一种预防治疗伴有异位性钙化的疾病的药物组合物,以权利要求1~4中任一项所述的化合物或其盐为有效成分。
7.权利要求1~4中任一项所述的化合物或其盐在制造伴有异位性钙化的疾病的预防治疗药的应用。
8.根据权利要求1~4中任一项所述的化合物或其盐,其用于预防治疗伴有异位性钙化的疾病。
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2017
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- 2017-01-27 CN CN201780006981.2A patent/CN108473518B/zh not_active Expired - Fee Related
- 2017-01-27 JP JP2017538251A patent/JP6259957B2/ja not_active Expired - Fee Related
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Also Published As
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JPWO2017131127A1 (ja) | 2018-02-01 |
MX2018009231A (es) | 2018-11-09 |
KR20180111791A (ko) | 2018-10-11 |
CN108473518A (zh) | 2018-08-31 |
EP3409679A1 (en) | 2018-12-05 |
WO2017131127A1 (ja) | 2017-08-03 |
JP6259957B2 (ja) | 2018-01-10 |
RU2731615C2 (ru) | 2020-09-07 |
CO2018007788A2 (es) | 2018-08-10 |
MY195906A (en) | 2023-02-27 |
AU2017211464A1 (en) | 2018-08-09 |
BR112018015552A2 (pt) | 2018-12-26 |
CA3012957A1 (en) | 2017-08-03 |
PH12018501586A1 (en) | 2019-04-08 |
RU2018130994A (ru) | 2020-03-03 |
AR107472A1 (es) | 2018-05-02 |
US10689408B2 (en) | 2020-06-23 |
TWI730039B (zh) | 2021-06-11 |
ZA201804945B (en) | 2019-09-25 |
SG11201806125UA (en) | 2018-08-30 |
EP3409679A4 (en) | 2019-11-06 |
HK1257616A1 (zh) | 2019-10-25 |
AU2017211464B9 (en) | 2021-07-22 |
AU2017211464B2 (en) | 2021-07-01 |
RU2018130994A3 (zh) | 2020-03-13 |
TW201728332A (zh) | 2017-08-16 |
US20190002482A1 (en) | 2019-01-03 |
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