CN102264752A - 苯烷基-咪唑-二膦酸化合物 - Google Patents
苯烷基-咪唑-二膦酸化合物 Download PDFInfo
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- CN102264752A CN102264752A CN2009801522256A CN200980152225A CN102264752A CN 102264752 A CN102264752 A CN 102264752A CN 2009801522256 A CN2009801522256 A CN 2009801522256A CN 200980152225 A CN200980152225 A CN 200980152225A CN 102264752 A CN102264752 A CN 102264752A
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- Prior art keywords
- phenyl
- compound
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- alkyl
- salt
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- 229940122361 Bisphosphonate Drugs 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 150000003839 salts Chemical class 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 40
- 150000002148 esters Chemical class 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 208000006386 Bone Resorption Diseases 0.000 claims abstract description 8
- 230000024279 bone resorption Effects 0.000 claims abstract description 8
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- -1 phenyl-sec.-propyl Chemical group 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 9
- 125000004344 phenylpropyl group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000032683 aging Effects 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 5
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 5
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
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- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 6
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- DRADWUUFBCYMDM-UHFFFAOYSA-L [hydroxy(oxido)phosphinothioyl] 3,7,11-trimethyldodeca-2,6,10-trienyl phosphate Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCOP([O-])(=O)OP(O)([O-])=S DRADWUUFBCYMDM-UHFFFAOYSA-L 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 108010010803 Gelatin Proteins 0.000 description 4
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
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- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 3
- GVVPGTZRZFNKDS-YFHOEESVSA-N Geranyl diphosphate Natural products CC(C)=CCC\C(C)=C/COP(O)(=O)OP(O)(O)=O GVVPGTZRZFNKDS-YFHOEESVSA-N 0.000 description 3
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Landscapes
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Abstract
本发明公开(未取代或取代的苯基)-烷基-取代的[(咪唑-1-基)-1-羟基-1-膦酰基-乙基]-膦酸和它们的制备方法或过程、它们在制备药用制剂中的用途、它们在治疗疾病中的用途、用它们治疗疾病的方法、含它们的药用制剂和/或所述化合物在治疗疾病中的用途。所述化合物可抑制过度或不适当骨吸收。所述化合物具有式(I)，在式(I)中，R1和R2中的一个定义同本说明书，所述化合物可为游离形式、酯和/或盐形式。
Description
本发明涉及新的(未取代或取代的苯基)-烷基-取代的[(咪唑-1-基)-1-羟基-1-膦酰基-乙基]-膦酸和它们的制备方法或过程；它们在制备药用制剂中的用途；它们在治疗疾病中的用途；用它们治疗疾病的方法；含它们的药用制剂和/或所述化合物在治疗疾病中的用途，其中所述疾病尤其为下述疾病。所述化合物可抑制过度或不适当骨吸收。
在第一方面，本发明尤其涉及式(I)化合物、其酯和/或盐，
其中R1和R2中的一个为氢，另一个为未取代或取代的苯基-烷基。
在本文中使用的通用表述优选具有以下含义，其中各个较广泛的表述彼此独立，可独立被其它表述独立代替，或两种或更多种或尤其是所有表述可被更具体的定义所代替，从而定义得到本发明更优选的实施方案：
低级烷基为例如C1-C5烷基，例如甲基、乙基、丙基或丁基；以及异丁基、仲丁基或叔丁基，或戊基，例如正戊基、异戊基、新戊基、仲戊基或叔戊基。
取代的或未取代的苯基-烷基优选为苯基-C1-C10-烷基，更优选苯基-低级烷基，还更优选苯基-C2-C6-烷基，其中所述烷基为支链或直链，苯基未被取代或被一个或多个例如多达5个，更优选多达3个取代基取代，所述取代基优选独立选自C1-C7-烷基、羟基、C1-C7-烷氧基、C1-C7-烷氧基-C1-C7-烷氧基、卤素、氨基、N-一-或N，N-二-(C1-C7-烷基、苯基-C1-C7-烷基、C1-C7-烷酰基、C1-C7-烷氧基-羰基和/或C1-C7烷基磺酰基)-氨基、羧基、C1-C7-烷氧基羰基、氨基甲酰基、N-一-或N，N-二-(C1-C7-烷基和/或苯基-C1-C7-烷基)-氨基甲酰基、氨磺酰基、N-一-或N，N-二-(C1-C7-烷基和/或苯基-C1-C7-烷基)-氨磺酰基和氰基。
苯基-低级烷基为例如苯基-C1-C7-烷基(例如苄基)，或在式(I)中的R1和R2情况下，优选为苯基-乙基、苯丙基、苯丁基或苯戊基，其中丙基、丁基或戊基可为支链或直链，或在式(III)中的R情况下，优选为苄基。
卤代或(卤素)(又为卤化物)优选为氟、氯、溴或碘。
“约”优选表示给定数值的偏离值与该给定数值间的偏差可高达±20，更优选高达±10％，最优选±5。
式(I)化合物的盐尤其为其与药学上可接受的碱形成的盐(药学上可接受的盐)，例如由Ia、Ib、IIa和IIb族金属衍生的无毒金属盐，例如碱金属盐，优选锂或更优选钠或钾盐；碱土金属盐，优选钙或镁盐；铜、铝或锌盐；以及由氨或有机胺或季铵碱形成的盐，例如与游离或C-羟基化脂族胺，优选一-、二-或三-低级烷基胺，例如甲胺、乙胺、二甲胺或二乙胺；一-、二-或三(羟基-低级烷基)胺，例如乙醇胺、二乙醇胺或三乙醇胺、三(羟-甲基)氨基甲烷或2-羟基-叔丁胺，或N-(羟基-低级烷基)-N，N-二-低级烷基胺或N-(聚羟基-低级烷基)-N-低级烷基胺，例如与2-(二甲基氨基)乙醇或D-葡糖胺形成铵盐，或与脂族季铵氢氧化物，例如氢氧化四丁铵形成盐。
式(I)化合物及其盐具有有价值的药理性质。尤其是，它们在细胞中抑制甲羟戊酸通路，因而对温血动物的钙代谢具有显著的调节作用。
更尤其是，它们在雌激素缺乏(estrogen-deficient)的大鼠中显著抑制骨吸收，对此，可按Hornby等在Calcified Tiss Int 2003；72：519-527和Gasser等在J Bone Miner Res 2008；23：544-551中所述实验方法，通过静脉内或皮下给予切除卵巢的大鼠约1-500μg/kg中的剂量后得到证实。用Peyruchaud等在J Bone Miner Res 2001；16：2027-2034中所述方法，静脉内或皮下给予约1-500μg/kg中的剂量，肿瘤相关性(Tumor-associated)骨质溶解同样受到抑制。另外，当按类似于Newbould在Brit.J.Pharmacology 21，127(1963)和Rordorf等在Int J Tissue React.1987；9(4)：341-7中所述实验方法给药，式(I)化合物及其盐与辅药一起分别显著抑制啮齿类动物中关节炎性病症和胶原关节炎恶化。
新的二膦酸酯类化合物尤其可作为人用和兽用药物用于治疗一种或多种疾病(该术语包括病症或障碍)，尤其可抑制尤其与骨和关节疾病有关的过度或不适当骨吸收，例如
-良性病症，例如骨质疏松症、骨质稀少、骨髓炎、骨关节炎、类风湿性关节炎、骨髓水肿(bone marrow edema)、骨痛、反射交感神经性营养不良(reflex sympathetic dystrophy)、强直性脊柱炎(别赫捷列夫关节炎)、骨佩吉特病或牙周病，
-恶性病症，例如恶性高钙血症、与实体瘤有关的骨转移和血癌，
-矫形病症，例如假体松弛、假体移动、移植物固结、移植物包被、骨折愈合、骨折分离骨生成(distraction osteogenesis)、脊柱融合术、无血管骨坏死、骨移植、骨代用品，
或此类病症的两种或更多种的组合。
用于治疗需要二膦酸酯进入非内吞细胞的疾病的二膦酸酯的效能受到此类细胞对普通二膦酸酯极低摄取的严重限制。这是由于它们的高亲水性所致，高亲水性可通过它们的低辛醇/水分配系数(clogP)，例如伊班膦酸盐的理论低辛醇/水分配系数为-3.3和唑来膦酸的理论低辛醇/水分配系数为-3.0证明。相反，本文中所述的苯烷基-咪唑二膦酸酯化合物的clogP值接近或大于0。这表明亲水性减少而亲油性增加，该性质对于在非内吞细胞中摄取非常有益。增加的细胞通透性可促进其中需要在不为破骨细胞、巨噬细胞或其它内吞细胞的细胞中完全或部分抑制甲羟戊酸通路的疾病治疗。胞吞为细胞通过将外部的细胞和由它们的细胞膜形成的小泡一起吞没而吸收物质的过程。
二膦酸酯(唑来膦酸)与抑制素(普伐他汀)的联合物在细胞实验和人过早衰老例如Hutchinson-Gilford早衰综合征的小鼠模型中显示有益作用(Nature Medicine(2008)14，767-772)。本发明化合物在这些模型中似乎可能增强效力或效率，因为它们的亲油性增加并且与骨结合减少导致它们可更容易透过细胞膜。预期甚至在不存在抑制素的情况下，更强的本发明化合物在这些模型中也有活性。
一般而言，由于它们的亲油性增加，因此预计本发明化合物可更有力或有效地治疗其中在不为破骨细胞、巨噬细胞或其它内吞细胞的细胞中甲羟戊酸通路被抑制的疾病。该治疗包括但不限于
-已在绝经前期乳腺癌中使用唑来膦酸的内分泌疗法中证实的二膦酸酯直接抗癌治疗(Gnant等(2009)NEngl J Med 360，679-91)。
-用本发明化合物作为降胆固醇药，因为FPPS和HMG CoA还原酶均为甲羟戊酸通路的酶。事实上，据报道，在用唑来膦酸治疗的骨髓瘤患者的血清中胆固醇水平较低(Gozzetti，A.等(2008)Calcif Tissue Int 82，258-62)，但由于本发明二膦酸的细胞渗透增加，所以它们的作用更显著。
-用本发明化合物作为抗寄生虫药物，二膦酸酯显示可有效抗导致利什曼病、疟疾、隐孢子虫病和恰加斯病的寄生原生动物(在Docampo，R.&Moreno，S.N.(2001)Current Drug Targets：Infectious Disorders(当前药物靶标：传染性疾病)1，51-61中的综述)，但由于本发明化合物的亲油性增加，所以它们可能更合适。
在以下刊物(其中各刊物引入本文作为参考，尤其是有关下文中所述测定或方法的描述)中描述了各种测定和方法，可用它们验证式(I)化合物的有利生物学特性：
可按Calcif.Tissue Int.(2003)72，519-527中所述，证明单次i.v.给药对作为绝经后骨质疏松症模型成熟的切除卵巢的(OVX)大鼠的作用，以阐明(1)在骨转换的生化标记和股骨矿物质密度(BMD)中的短暂改变，(2)测量静态和动态组织形态测定的参数(histomorphometric parameter)、骨微结构(micro-architecture)和机械力，和(3)评价用式(I)化合物长期治疗对这些参数的阻抑作用。发现本发明的化合物具有高活性。
如ARTHRITIS&RHEUMATISM(关节炎和风湿病)(2004)，50(7)，2338-2346中所示，可证明式(I)化合物在胶原诱发的关节炎(CIA)的效应期期间的大鼠中对滑液炎症、结构性关节损伤(structural joint damage)和骨代谢的作用。
可按J.Bone Joint Surg.(2005)，87-B，416-420中所述，在其中多孔钽移植物双侧置于狗的尺腕骨内的动物模型中检验式(I)化合物对骨向内生长的作用。
可按J.Natl.Cancer.Inst.(2007)，99，322-30中所述方法，证明在小鼠模型中抑制骨瘤生长。
在Nat.Medicine(2008)，14，767-772中所述细胞实验和Hutchinson-Gilford早衰综合征的小鼠模型中，唑来膦酸和普伐他汀的联合物显示有益作用。本发明化合物具有提高的效率，因为它们可更容易透过细胞膜。
可通过Chem.Med.Chem.(2006)，1，267-273中所述方法或类似方法，当与法尼焦磷酸合成酶结合时，得到式(I)化合物的X射线结构。人FPPS为41-kDa亚基同株异核生殖酶，该酶催化由C5异戊二烯类二甲基烯丙基焦磷酸(DMAPP)和异戊烯焦磷酸两步合成C15代谢物法尼焦磷酸(FPP)。必需GTP酶信号蛋白例如Ras和Rho的翻译后异戊二烯化需要FPP，FPP也是胆固醇、多萜醇和泛醌合成的前体。
例如，在不含细胞的体外测定中，可证实式(I)化合物优于已知化合物的优越性。简而言之，在酶和式(I)的抑制剂的存在下，反应继续进行，反应产物(法尼焦磷酸)通过LC/MS/MS定量。
详细地讲，在加入底物前，将抑制剂和酶一起预温育。
测定为基于LC/MS/MS的法尼焦磷酸合成酶(FPPS)的非标记测定(label-free assay)。该方法用于定量体外未标记法尼焦磷酸(FPP)，且为适合寻找FPPS抑制剂的高通量筛选(HTS)和测定候选化合物的IC50值。分析时间为2.0分钟，总循环时间(cycle time)为2.5分钟。可将该分析格式化为384孔板模式，从而每板分析时间为16小时。
试剂：
戊醇、甲醇和异丙醇为HPLC级，得自Fisher Scientific。DMIPA得自Sigma-Aldrich。水源自内部Milli-Q系统。通过稀释得自Sigma-Aldrich的1mM储备液制备测定缓冲液(20mM HEPES，5mM MgCl2和1mMCaCl2)。狵牛儿焦磷酸(GPP)、异戊烯焦磷酸(FPP)和法尼S-巯基焦磷酸(thiolopyrophosphate)(FSPP)的标准品源自Echelon Biosciences(SaltLake City，UT)。按Rondeau等(ChemMedChem 2006，1，267-273所述制备人法尼焦磷酸合成酶(FPPS，Swissprot ID：P14324)(13.8mg/mL)。
测定：
在具有Agilent 1100二元LC泵Agilent Technologies，Inc.，Santa Clara，CA，USA)界面的Micromass Quattro Micro串联四级质量分析仪(WatersCorp.，Milford，MA，USA)上进行LC/MS/MS分析。用使用2.5μL体积的注射环的CTC Analytics自动进样器(Leap Technologies Inc.，Carrboro，NC，USA)进样。在其中具有带预柱(guard column)架(P/N 186000262)的C18 5μm预柱(P/N186000652)(Waters Corp.，Milford，MA，USA)的Waters 2.1×20mm Xterra MS上进行色谱分离，用0.1％DMIPA/甲醇作为A溶剂，0.1％DMIPA/水作为B溶剂(DMIPA为二甲基异丙胺)。梯度为0.00-0.30min为5％A，0.31min为50％A，1.00min为80％A，1.01-2.00min为5％A。流速为0.3mL/min，在0.00-0.50min期间，将液流引入废液瓶，在1.20-2.00min期间，将液流再次引入废液瓶。
在Ar碰撞能22eV和碰撞单元压力(collision cell pressure)2.1×10-3毫巴下，对于FPP，监测的Multiple Reaction Monitoring(MRM)转变为381-＞79-；对于FSPP，该转变为397-＞159-。每转变的采集时间为400毫秒，时距0.4Da。通道间延迟(interchannel delay)和扫描间延迟(interscandelay)均为0.02秒。其它质量光谱测定操作参数为：毛细管，2.0kV；锥电压(cone)，35V；提取器电压(extractor)，2.0V，离子源温度，100℃；去溶剂化气体温度250℃；去溶剂化气体流速650L/h；锥气体流速25L/h；倍增器电压650V。
每个样品的总循环时间(total cycle time)为2.5分钟。因为分析格式化为384孔板模式，所以用16小时分析板。用Quanlynx软件处理色谱图，该软件将各FPP峰面积除以FSPP峰面积(内标)。按相应样品孔的相对反应报道得到的值。
FPPS测定方法
将溶于20％DMSO/水的5μL化合物加入384孔板的各孔中。将10μLFPPS(用测定缓冲液将1体积稀释至80000体积)加入各孔，与化合物一起预温育5分钟。此时，加入25μL GPP/IPP(溶于测定缓冲液后各自为5μM)，启动反应。30分钟后，通过加入10μL 2μM FSPP的2％DMIPA/IPA溶液终止反应。然后用旋转方式混合，用50μL正戊醇萃取反应混合物。相分离后，将25μL上层(正戊醇)转移至新的384孔板中，用真空离心机将戊醇蒸发。将干燥残渣再溶于50μL 0.1％DMIPA/水，用于LC/MS/MS法分析。
用FSPP作为质谱的内标。磷酸盐部分产生的(M-H)-离子作为光谱中的基峰。
在该试验系统中，优选本发明化合物的IC50范围为0.8-10nM，优选IC50为1.2-3.6nM。具体而言，它们可显示优于现有技术化合物例如[2-(5-苯基-丙基-咪唑-1-基)-1-羟基-1-膦酰基-乙基]-膦酸的预料之外的优越性。按它们的辛醇/水分配系数(clogP)评判，这些化合物的亲水性减少，这些化合物的优越性甚至更在预料之外。
用已知FPPS的二膦酸酯抑制剂唑来膦酸验证IC50测定方法的实用性。
本发明尤其涉及式(I)化合物或其酯，和/或其(尤其是药学上可接受的)盐，其中R1为未取代或取代的苯基-C2-C7-烷基，尤其是苯基-乙基、苯基-丙基或苯基-异丙基，还包括苯基-正丁基、苯基-仲丁基、苯基-叔丁基或苯基-异丁基，其中取代的苯基优选定义同上，尤其为甲苯基(＝甲基苯基)，例如对-甲苯基，R2为氢。
或者，本发明尤其涉及式(I)化合物或其酯，和/或其(尤其是药学上可接受的)盐，其中R1为氢，R2为未取代或取代的苯基-C2-C7-烷基，尤其是苯基-乙基、苯基-丙基、苯基-异丙基或甲苯基丙基，尤其是对-甲苯基丙基，还包括苯基-正丁基、苯基-仲丁基、苯基-叔丁基或苯基-异丁基。
优选式(I)化合物或其酯，和/或其(尤其是药学上可接受的)盐，其中R1为氢，R2为未取代或取代的苯基-丙基，尤其是未取代或取代的3-苯基-丙基，其中取代的苯基优选定义同上。
更优选式(I)化合物或其酯，和/或其(尤其是药学上可接受的)盐，其中R1为未取代或取代的苯基-丙基，尤其是为未取代或取代的3-苯基-丙基，其中取代的苯基优选定义同上，R2为氢。
最优选式(I)化合物或其酯，和/或其(尤其是药学上可接受的)盐，其中R1为苯基-丙基，尤其是3-苯基-丙基。
可按用于本领域中已知的不同化合物的方法制备本发明化合物。例如，至少根据得到的新产物和/或使用的新离析物，优选新方法，该方法包括使式(II)羧酸化合物，
其中R1和R2定义同式(I)化合物，与磷酰卤化物反应，得到式(I)化合物或其盐，
并且，当需要时，将可得到的游离式(I)化合物转化为盐、将可得到的式(I)化合物的盐转化为游离式(I)化合物和/或将可得到的式(I)化合物的盐转化为其不同的盐。
尤其优选磷酰氯(POCl3)作为磷酰卤化物。优选在升高的温度下，例如在50℃-反应混合物的回流温度下，例如(约)80-(约)120℃下，在H3PO3的存在下，优选在常规溶剂或溶剂混合物例如在芳烃例如甲苯中进行反应。
可通过用所述碱之一将式(I)化合物部分或完全中和，使游离式(I)化合物转化为碱式盐。
可按已知方式例如通过用酸试剂例如无机酸处理，将盐转化为游离化合物。
也可得到水合物形式的化合物，这种形式的化合物包括它们的盐，或在它们的结晶结构中可含有用于结晶的溶剂。
因为游离形式与盐形式的新化合物之间存在密切关系，所以，在本说明书中当述及游离化合物和它们的盐时也适用于相应的盐和游离化合物。
本发明还涉及所述方法的这样一些实施方案，其中在方法的任何阶段可得到的作为中间体的化合物可用作原料，将它们用于其余步骤，或使用盐形式作为原料，或优选在反应环境下形成原料。
例如，可优选通过将式(III)化合物皂化得到原料，
其中R1和R2定义同式(I)化合物，R为未取代或取代的烷基，尤其是低级烷基或苯基-低级烷基，在适当的酸(例如氢卤酸，例如盐酸)的存在下，优选在水性溶剂(例如水)的存在下，优选在升高的温度下(例如在(约)50-(约)100℃，例如80-100℃下)，得到式(II)化合物或其盐。
例如，可优选通过以下反应得到式(III)化合物：优选在强碱例如碱金属醇化物，尤其是叔丁醇钾(KOtBu)的存在下，在适当的溶剂或溶剂混合物(例如环醚，例如四氢呋喃)中，优选在(约)-10至(约)80℃，例如20-30℃温度下，使式(IV)咪唑化合物
其中R1和R2定义同式(I)化合物，与式(V)酯反应，
其中R定义同式III化合物，X为卤素，尤其是氟、氯、碘，或尤其是溴、低级烷基磺酰氧基或甲苯磺酰氧基。如果需要，可通过色谱方法、分级结晶等将得到的式III化合物的混合物(其中在一个化合物中，R1为未取代或取代的苯基-烷基，R2为氢，在另一个化合物中，R2为未取代或取代的苯基-烷基，R1为氢)分离。
可通过本领域中已知方法或类似方法制备式(IV)和(V)原料和使用目前尚未描述的其它原料，这些原料或者是市售的和/或以类似于本文中所述，尤其是实施例中所述方法制备得到。
本发明还涉及任何新的方法步骤或方法步骤的组合，涉及任何新的原料或中间体，或(a)其盐。
例如，可按类似于现有技术中所述用于相似化合物的方法制备式(I)化合物的酯。
含式(I)化合物或其药学上可接受的无毒的盐的药用组合物为肠道(例如口服或直肠)和肠胃外给予温血动物的那些组合物，药理活性成分可单独或与药学上合适的载体一起给予。
新的药用组合物含例如约0.0001-80％，优选约0.001-10％的活性成分。用于肠道或肠胃外给药的药用组合物为例如剂量单位形式的那些组合物，例如糖锭剂、片剂、凝胶剂或栓剂；以及安瓿、小瓶、预灌装注射器。按已知方式，例如通过常规混合、制粒、调制、溶解或冻干方法制备这些药用组合物。例如，可通过将活性成分与固体载体结合，任选将得到的混合物制粒，酌情加入合适的赋性剂后，将混合物或颗粒处理加工为片剂或糖锭剂芯，得到用于口服给药的药用组合物。
合适的载体尤其为填充剂例如糖，例如乳糖、蔗糖、甘露醇或山梨醇、纤维素制剂和/或磷酸钙，例如磷酸三钙或磷酸二氢钙；粘合剂例如淀粉浆，例如玉米(maize)、玉米、水稻或马铃薯淀粉；明胶、黄芪胶、甲基纤维素和/或聚乙烯吡咯烷酮，和/或酌情加入崩解剂例如上述淀粉；还有羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂、藻酸或其盐，例如藻酸钠。赋性剂尤其为助流剂和润滑剂，例如硅石、滑石粉、硬脂酸或其盐，例如硬脂酸镁或硬脂酸钙，和/或聚乙二醇。为糖锭芯提供阻抗胃液的合适包衣，用其中可含阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛的浓糖溶液；在合适的有机溶剂或溶剂混合物中的虫胶溶液；合适的纤维素制剂例如邻苯二甲酸乙酰纤维素或邻苯二甲酸羟丙基甲基纤维的溶液制备阻抗胃液的包衣。可将染料或色素加入片剂或糖锭剂包衣，例如用于鉴别或标识不同剂量的活性成分。
用于口服给药的其它药用组合物为干法填充的由明胶或羟丙甲纤维素制备的胶囊剂和密封的含明胶和增塑剂例如甘油或山梨醇的软胶囊剂。干法填充的胶囊剂在胶囊中可含与活性成分混合的颗粒形式的例如填充剂例如(乳糖)、粘合剂(例如淀粉)和/或助流剂(例如滑石粉或硬脂酸镁)以及任选的稳定剂。在软胶囊剂中，优选将活性成分溶于或悬浮于合适的液体例如脂肪油、石蜡油或液体聚乙二醇，也可将稳定剂加入所述液体。
用于直肠给药的合适的药用组合物为例如栓剂，栓剂由活性成分和栓剂基质的组合组成。合适的栓剂基质的实例为天然或合成甘油三酯、石蜡烃、聚乙二醇和高级链烷醇。也可使用含活性成分和基质材料的组合的明胶直肠胶囊剂。合适的基质材料为例如液体甘油三酯、聚乙二醇和石蜡烃。
尤其合适的用于肠胃外给药的剂型(尤其优选)为水溶性形式的活性成分，例如水溶性盐的水溶液。可用无机或有机酸或碱将溶液调至生理上可接受的约pH 4-9的pH值，或最优选约5.5-7.5。也可用无机盐如氯化钠或有机化合物如糖、糖醇或氨基酸，最优选用甘露醇或甘油将溶液制成等渗。合适的组合物还可为活性成分的混悬液，例如相应的注射油混悬液，其中使用合适的亲油性溶剂或溶媒例如脂肪油例如芝麻油，或合成脂肪酸酯例如油酸乙酯或甘油三酯，或注射水混悬液，该混悬液含增加粘性的物质，例如羧甲基纤维素钠、山梨醇和/或右旋糖苷，并任选含稳定剂。
本发明还涉及式(I)化合物及其盐优选在治疗炎性病症、主要是与钙代谢损害有关的疾病例如风湿性疾病，尤其是骨质疏松症中的用途。
低于0.1μg/kg体重的肠胃外剂量仅轻微影响硬组织代谢。在高于1000μg/kg体重剂量下，可产生长期毒副作用。可通过口服和皮下、肌内或静脉内，通过等渗或高渗溶液给予式(I)化合物及其盐。优选的口服给药的日剂量为约1-100mg/kg，静脉内、皮下和肌内给药的日剂量为约20-500μg/kg。
但是可根据相应条件例如疾病的性质和严重性、疗程的持续时间和相应化合物，可改变式(I)化合物及其盐的剂量。用于肠胃外例如静脉内给药的剂量单位形式含例如10-300μg/kg体重，优选15-150μg/kg体重；口服剂量单位形式含例如0.1-5mg，优选0.15-3mg/kg体重。优选的口服给药的单次剂量为10-200mg，静脉内给药的单次剂量为1-10mg。由于口服给药吸收有限，所以用于口服给药的剂量必须较高。在长期治疗中，通常，给予初始较高剂量后，可将剂量减至较低水平以维持需要的作用。可按1-52次/年，定期间歇给予肠胃外(例如静脉内或皮下)剂量。可按每日一次、每周一次、每月一次或每季一次给药方案，定期给予口服剂量。
本发明还涉及治疗动物，尤其是人的方法，该方法包括给予有需要的动物，尤其是人足以治疗上述疾病的量的式(I)化合物、其酯和/或药学上可接受的盐。
本发明还涉及药物制剂，尤其是输注或注射液，该制剂含式(I)化合物、其酯和/或盐，以及至少一种药学上可接受的载体材料。
以下非限制性实施例用于说明本发明，但不限制本发明的范围。
如果无另外说明，按摄氏度(℃)给出温度。若未给出温度，则反应或其它方法步骤在室温中进行。
缩写：
| Ac | 乙酰基 |
| aq. | 水溶液 |
| DMSO | 二甲基亚砜 |
| Et | 乙基 |
| h | 小时 |
| HPLC | 高效液相色谱 |
| KOtBu | 叔丁醇钾 |
| Me | 甲基 |
| ml | 毫升 |
| NMR | 核磁共振 |
| rt | 室温 |
| THF | 四氢呋喃 |
按D.Horne等Heterocycles(杂环)，1994，第39卷，第1期，第139-153页中所述制备5-(3-苯基-丙基)-1H-咪唑和除4-苄基咪唑外的所有其它咪唑衍生物。按文献方法(Chadwick等Tetrahedron(四面体)，1986，第42卷，第8期，第2351-2358页)制备4-苄基咪唑。
实施例1：{1-羟基-2-[5-(3-苯基-丙基)-咪唑-1-基]-1-膦酰基-乙基}-膦酸
在室温、氮气下，将1.5g(5.3mmol)[5-(3-苯基-丙基)-咪唑-1-基]-乙酸溶于58ml甲苯。加入1.33g(16.0mmol)H3PO3，将混合物加热至80℃。滴加1.47ml(16.0mmol)POCl3。将得到的混合物加热至120℃，搅拌过夜。将溶剂倾去，加入35ml 6N HCl，将混合物加热回流3小时。将得到的浅黄色溶液真空浓缩。用丙酮(40ml)稀释后，将混合物与丙酮(4×35ml)一起剧烈搅拌至形成灰色固体。将灰色固体在高真空中干燥，在EtOH/水中结晶，得到标题化合物。
HPLC-MS：t＝2.35min，(M-H)-＝389；1H-NMR(D2O/NaOD)：δ＝1.81(m，2H)，2.55-2.66(m，4H)，4.27-4.33(m，2H)，6.64(s，1H)，7.07-7.1(m，1H)，7.15-7.22(m，4H)，7.90(s，1H)
31P-NMR(d6-DMSO)：δ＝16.50ppm.
合成概览：
原料制备如下：
a)[5-(3-苯基-丙基)-咪唑-1-基]-乙酸乙酯和[4-(3-苯基-丙基)-咪唑-1-基]-乙酸乙酯
在室温、氮气下，将20.2g(97mmol)5-(3-苯基-丙基)-1H-咪唑溶于100ml THF。加入11.5g(102mmol)KOtBu，将反应物在室温下搅拌2h。用45分钟，滴加11.9ml(107mmol)溴乙酸乙酯，将得到的混合物在室温下搅拌2.5h。加入85ml H2O和275ml AcOEt，将有机层分离，将水层用250ml AcOEt再洗涤3×。将合并的有机层用盐水洗涤，经MgSO4干燥，真空浓缩。反应物经闪层析(Chiralpak AD 1101，庚烷/异丙醇)纯化，分别得到[5-(3-苯基-丙基)-咪唑-1-基]-乙酸乙酯和[4-(3-苯基-丙基)-咪唑-1-基]-乙酸乙酯。
[5-(3-苯基-丙基)-咪唑-1-基]-乙酸乙酯：HPLC-MS：t＝1.83min；100％面积，MH+＝273；1H-NMR(d6-DMSO)δ＝1.16(t，3H)，1.76-1.84(m，2H)，2.42(t，2H)，2.60(t，2H)，4.10(q，2H)，4.83(s，2H)，6.66(s，1H)，7.19(m，3H)，7.26(m，2H)，7.50(s，1H)
[4-(3-苯基-丙基)-咪唑-1-基]-乙酸乙酯：HPLC-MS：t＝1.83min，100％面积，MH+＝273；1H-NMR(d6-DMSO)：δ＝1.19(t，3H)，1.82(m，2H)，2.42(t，2H)，2.58(t，2H)，4.13(q，2H)，4.85(s，2H)，6.84(s，1H)，7.14-7.19(m，3H)，7.26(m，2H)，7.46(m，1H)
b)[5-(3-苯基-丙基)-咪唑-1-基]-乙酸
将1.09g(4mmol)[5-(3-苯基-丙基)-咪唑-1-基]-乙酸乙酯溶于15ml(60mmol)4N HCl，将混合物加热至回流。1.5h后，将混合物冷却至室温，将溶剂在真空中除去。将得到的产物与丙酮(15ml)一起搅拌至形成浅褐色固体。将固体滤出，在高真空中干燥，使用时无需进一步纯化。
MS：MH+＝245，1H-NMR(DMSO)：δ＝1.86(m，2H)，2.61(m，4H)，5.10(s，2H)，7.15-7.21(m，3H).7.25-7.29(m，2H)，7.52(s，1H)，9.05(s，1H)
按类似于上述方法制备以下实施例：
实施例2：[2-(4-苄基-咪唑-1-基)-1-羟基-1-膦酰基-乙基]-膦酸
HPLC-MS：t＝1.63min，(M-H+)-333
1H-NMR(NaOD/D2O)：δ＝3.64(s，2H)，4.21(broad t，2H)，6.82(s，1H)，7.01-7.07(m，1H)，7.08-8.17(m，4H)，7.45(s，1H)
31P-NMR(NaOD/D2O)：δ＝16.87ppm
实施例3：[1-羟基-2-(4-苯乙基-咪唑-1-基)-1-膦酰基-乙基]-膦酸
HPLC-MS：t＝1.63min，ES-＝375；
1H-NMR(d6-DMSO)：δ＝2.80(d，2H)，4.49(m，2H)，7.16-7.29(m，5H)，8.83(s，1H)
31P-NMR(d6-DMSO)：δ＝15.58ppm
实施例4：[1-羟基-2-(5-苯乙基-咪唑-1-基)-1-膦酰基-乙基]-膦酸
HPLC-MS：t＝1.47min，ES-＝375；
1H-NMR(d6-DMSO)：δ＝2.88(t，2H)，3.05(t，2H)，4.48(t，2H)，7.11-7.27(m，5H)，8.83(s，1H)
31P-NMR(d6-DMSO)：δ＝15.63ppm
实施例5：{1-羟基-1-膦酰基-2-[5-(3-对-甲苯基-丙基)-咪唑-1-基]-乙基}-膦酸
HPLC-MS：t＝1.25min，ES-＝403.1；
1H-NMR(D2O)：δ＝1.85(q，2H)，2.24(st，3H)，2.62(t，3H)，2.70(t，2H)，4.41(t，2H)，6.62(s，1H)，7.15(m，4H)，7.9(s，1H)
31P-NMR(d6-D2O)：δ＝17.0ppm
实施例6：注射或输注液：
例如可如下制备0.2％注射或输注液：
将活性成分例如实施例1或2化合物或其盐、氢氧化钠、氯化钠和注射用水混合，使总体积达至2500.0ml。
将22.0g氯化钠溶于约2000mL注射用水。加入活性成分，将pH调至例如pH 6.5。加入注射用水至2500ml。通过除菌级滤器(例如用0.2μm孔径)将溶液过滤。为制备单位剂型，将1.0或2.5ml溶液灌入除菌和去热原的玻璃安瓿或小瓶(分别含2.0或5.0mg活性成分)。将小瓶用除菌和去热原的橡胶塞封闭。用铝卷曲盖将橡皮塞固定。
按相似方式，也可制备在实施例3-10中得到的另一种式(I)化合物的溶液，该化合物也可为与碱形成的盐形式，例如钠盐。在后一种情况下，将溶液用酸例如稀盐酸调至需要的pH值。
实施例7：实施例1-5化合物的抑制数据
按上述FPPS测定方法，实施例1-5化合物显示以下IC50值：
| 实施例化合物 | IC50(nM) |
| 1 | 1.9 |
| 2 | 1.4 |
| 3 | 1.9 |
| 4 | 6.7 |
| 5 | 3.5 |
Claims (15)
1.式(I)化合物、其酯和/或盐，
其中R1和R2中的一个为氢，另一个为未取代或取代的苯基-烷基。
2.权利要求1的式(I)化合物、其酯和/或其(尤其是药学上可接受的)盐或其酯，和/或其(尤其是药学上可接受的)盐，
其中
R1为未取代或取代的苯基-C2-C7-烷基，尤其是苯基-乙基、苯基-丙基、苯基-异丙基、苯基-正丁基、苯基-仲丁基、苯基-叔丁基或苯基-异丁基，其中取代的苯基为被一个或多个取代基取代的苯基，所述取代基独立选自C1-C7-烷基、羟基、C1-C7-烷氧基、C1-C7-烷氧基-C1-C7-烷氧基、卤素、氨基、N-一-或N，N-二-(C1-C7-烷基、苯基-C1-C7-烷基、C1-C7-烷酰基、C1-C7-烷氧基-羰基和/或C1-C7烷基磺酰基)-氨基、羧基、C1-C7-烷氧基羰基、氨基甲酰基、N-一-或N，N-二-(C1-C7-烷基和/或苯基-C1-C7-烷基)-氨基甲酰基、氨磺酰基、N-一-或N，N-二-(C1-C7-烷基和/或苯基-C1-C7-烷基)-氨磺酰基和氰基，且
R2为氢。
3.权利要求1的式(I)化合物、其酯和/或其(尤其是药学上可接受的)盐，
其中
R1为氢，且
R2为未取代或取代的苯基-C2-C7-烷基，尤其是苯基-乙基、苯基-丙基、苯基-异丙基、苯基-正丁基、苯基-仲丁基、苯基-叔丁基或苯基-异丁基，其中取代的苯基为被一个或多个取代基取代的苯基，所述取代基独立选自C1-C7-烷基、羟基、C1-C7-烷氧基、C1-C7-烷氧基-C1-C7-烷氧基、卤素、氨基、N-一-或N，N-二-(C1-C7-烷基、苯基-C1-C7-烷基、C1-C7-烷酰基、C1-C7-烷氧基-羰基和/或C1-C7烷基磺酰基)-氨基、羧基、C1-C7-烷氧基羰基、氨基甲酰基、N-一-或N，N-二-(C1-C7-烷基和/或苯基-C1-C7-烷基)-氨基甲酰基、氨磺酰基、N-一-或N，N-二-(C1-C7-烷基和/或苯基-C1-C7-烷基)-氨磺酰基和氰基，尤其为苯基-丙基。
4.权利要求1的式(I)化合物、其酯和/或其(尤其是药学上可接受的)盐，
其中
R1为氢，且
R2为3-苯基-丙基。
5.权利要求1的式(I)化合物、其酯和/或其(尤其是药学上可接受的)盐，
其中
R1为3-苯基-丙基，且
R2为氢。
6.用于诊断和/或治疗性治疗动物，尤其人的权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐。
7.用于治疗过度或不适当骨吸收的权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐。
8.药用组合物，所述组合物含权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐和至少一种药学上可接受的载体。
9.治疗动物，尤其是人的方法，所述方法包括给予有需要的动物，尤其人足以治疗过度或不适当骨吸收的量的权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐。
10.治疗动物，尤其是人的方法，所述方法包括给予需要的动物，尤其人足以治疗早衰的量的权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐。
11.权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐在治疗过度或不适当骨吸收中的用途。
12.权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐在治疗早衰中的用途。
13.权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐在治疗过度或不适当骨吸收中的用途。
14.权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐在治疗早衰中的用途。
15.制备权利要求1-5中任一项的式(I)化合物、其酯和/或药学上可接受的盐的过程或方法，所述方法包括
使式(II)羧酸化合物，
其中R1和R2定义同权利要求1-5中任一项的式(I)化合物，与磷酰卤化物反应，得到式(I)化合物或其盐，
并且，当需要时，将可得到的游离式(I)化合物转化为盐，将可得到的式(I)化合物的盐转化为游离式(I)化合物和/或将式(I)化合物的盐转化为其不同的盐。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08172824.8 | 2008-12-23 | ||
| EP08172824 | 2008-12-23 | ||
| US14275509P | 2009-01-06 | 2009-01-06 | |
| US61/142,755 | 2009-01-06 | ||
| PCT/EP2009/067679 WO2010076258A1 (en) | 2008-12-23 | 2009-12-21 | Phenylalkyl-imidazole-bisphosphonate compounds |
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| Publication Number | Publication Date |
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| CN102264752A true CN102264752A (zh) | 2011-11-30 |
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Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20110257131A1 (zh) |
| EP (1) | EP2382223A1 (zh) |
| JP (1) | JP2012513443A (zh) |
| KR (1) | KR20110110219A (zh) |
| CN (1) | CN102264752A (zh) |
| AU (1) | AU2009334889A1 (zh) |
| BR (1) | BRPI0924887A2 (zh) |
| CA (1) | CA2746612A1 (zh) |
| EA (1) | EA201100964A1 (zh) |
| MX (1) | MX2011006605A (zh) |
| WO (1) | WO2010076258A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109608492A (zh) * | 2018-12-19 | 2019-04-12 | 深圳市第二人民医院 | 一种用于骨质疏松的二膦酸化合物及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9273357B2 (en) | 2011-04-04 | 2016-03-01 | The Trustees Of Columbia University In The City Of New York | Pharmacogenetic test anti-resorptive therapy-associated osteonecrosis of the jaw |
| WO2016081281A1 (en) * | 2014-11-17 | 2016-05-26 | Salk Institute For Biological Studies | Lipophilic bisphosphonates and methods of use |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3428524A1 (de) * | 1984-08-02 | 1986-02-13 | Boehringer Mannheim Gmbh, 6800 Mannheim | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
| DE3626058A1 (de) * | 1986-08-01 | 1988-02-11 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
| EP0275821B1 (de) * | 1986-11-21 | 1992-02-26 | Ciba-Geigy Ag | Neue substituierte Alkandiphosphonsäuren |
| JPH05148279A (ja) * | 1991-08-01 | 1993-06-15 | Kaken Pharmaceut Co Ltd | ビスホスホン酸誘導体 |
| GB0029111D0 (en) * | 2000-11-29 | 2001-01-10 | Novartis Ag | Organic compounds |
| US8012949B2 (en) * | 2004-10-08 | 2011-09-06 | The Board Of Trustees Of The University Of Illinois | Bisphosphonate compounds and methods with enhanced potency for multiple targets including FPPS, GGPPS, and DPPS |
| US7358361B2 (en) * | 2004-10-08 | 2008-04-15 | The Board Of Trustees Of The University Of Illinois | Biophosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases |
| BRPI0616081A2 (pt) * | 2005-09-12 | 2011-06-07 | Reddy S Lab Inc | triidrato cristalino de ácido zoledrÈnico |
| CA2646334A1 (en) * | 2006-03-17 | 2007-09-27 | The Board Of Trustees Of The University Of Illinois | Bisphosphonate compounds and methods |
| AU2007304205A1 (en) * | 2006-10-05 | 2008-04-10 | Novartis Ag | Pharmaceutical compositions comprising bisphosphonates |
-
2009
- 2009-12-21 MX MX2011006605A patent/MX2011006605A/es not_active Application Discontinuation
- 2009-12-21 CA CA2746612A patent/CA2746612A1/en not_active Abandoned
- 2009-12-21 WO PCT/EP2009/067679 patent/WO2010076258A1/en active Application Filing
- 2009-12-21 EP EP09806020A patent/EP2382223A1/en not_active Withdrawn
- 2009-12-21 EA EA201100964A patent/EA201100964A1/ru unknown
- 2009-12-21 JP JP2011542807A patent/JP2012513443A/ja active Pending
- 2009-12-21 CN CN2009801522256A patent/CN102264752A/zh active Pending
- 2009-12-21 AU AU2009334889A patent/AU2009334889A1/en not_active Abandoned
- 2009-12-21 BR BRPI0924887-0A patent/BRPI0924887A2/pt not_active IP Right Cessation
- 2009-12-21 KR KR1020117017256A patent/KR20110110219A/ko not_active Application Discontinuation
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109608492A (zh) * | 2018-12-19 | 2019-04-12 | 深圳市第二人民医院 | 一种用于骨质疏松的二膦酸化合物及其制备方法 |
| CN109608492B (zh) * | 2018-12-19 | 2021-02-09 | 深圳市第二人民医院 | 一种用于骨质疏松的二膦酸化合物及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2382223A1 (en) | 2011-11-02 |
| AU2009334889A1 (en) | 2011-06-30 |
| JP2012513443A (ja) | 2012-06-14 |
| MX2011006605A (es) | 2011-06-30 |
| KR20110110219A (ko) | 2011-10-06 |
| US20110257131A1 (en) | 2011-10-20 |
| CA2746612A1 (en) | 2010-07-08 |
| EA201100964A1 (ru) | 2012-02-28 |
| WO2010076258A1 (en) | 2010-07-08 |
| BRPI0924887A2 (pt) | 2015-07-07 |
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