CN1027167C - 杂环双膦酸衍生物的制备方法 - Google Patents
杂环双膦酸衍生物的制备方法 Download PDFInfo
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Classifications
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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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Adhesives Or Adhesive Processes (AREA)
- Detergent Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
制备通式(I)所示新的杂环双膦酸衍生物或其药用盐的方法。式中各符号的含义见说明书。式(I)化合物具有骨吸收抑制作用。
Description
本发明涉及新的杂环双膦酸衍生物或其药用盐以及以该化合物为有效成分的骨吸收抑制剂。
人们已知并合成出多种双膦酸类衍生物,但具有本发明所述杂环的这类化合物是新化合物。
发明人发现,通式(Ⅰ)所示化合物及其药用盐是新化合物,并且根据动物试验,它们不但有骨吸收抑制作用,而且还具有抑制由骨吸收所引起的血钙过多的作用,发明人进而完成了本发明。
本发明提供了以下通式(Ⅰ)所示的杂环双膦酸类衍生物或其药用盐,以及以此化合物为有效成分的骨吸收抑制剂:
式中
(A)中的虚线表示两个相邻原子以单键或双键相连,
(B)中R6和R7可以相同或不同,各代表氢原子、低级烷基、卤原子或羟基,
R1代表氢原子或羟基,
R2、R3、R4、R5可以相同或不同,各代表氢原子或低级烷基,
“n”为0或1,
在通式(Ⅰ)基团的定义中,所谓“低级”在未另外说明的情况下是指含1-5个碳原子的直链或带支链的碳链。因此“低级烷基”可以是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等。
式(A)所示“杂环基”:
式(B)所示“杂环基”:
本发明的化合物(Ⅰ)包括R2-R5是低级烷基的四酯或R2-R5中的1至3个为低级烷基的单酯、双酯和三酯。
当本发明化合物为游离的膦酸时,它们可以形成盐。所以本发明的化合物包括化合物(Ⅰ)的药用盐。优选的盐可以举出与无机碱形成的盐,例如与碱金属形成的盐,如钠盐、钾盐,以及与碱土金属形成的盐,例如钙盐或镁盐;与有机碱形成的盐,例如铵盐、甲胺盐、乙胺盐、二甲胺盐、二乙胺盐、三甲胺盐、三乙胺盐、环己胺盐、乙醇胺盐或二乙醇胺盐;与碱性氨基酸形成的盐,例如赖氨酸盐或鸟氨酸盐等。
本发明化合物可按以下反应式所表示的方法之一进行制备。
方法1
通式(Ⅰa)所代表的化合物可以这样制得:使通式(Ⅱ)所示化合物与通式(Ⅲ)所示的亚乙烯基双膦酸衍生物反应,反应式如下:
化合物(Ⅱ)与(Ⅲ)的反应在对反应呈惰性的溶剂如四氢呋喃、苯、甲苯、二甲苯等中进行。二者之间的用量比是,对于化合物(Ⅱ),化合物(Ⅲ)的量等于或超过反应式中所示的量。该反应也可以在无溶剂条件下进行。
反应温度可以是室温或回流温度。反应最好在加热或回流下进行。
所得双膦酸酯可任选将其通过水解转变为相应的双膦酸。通常是在回流下于浓盐酸中加热双膦酸酯来进行水解。另一水解法是在
无水溶剂中用强酸或三甲基甲硅烷基卤处理双膦酸酯。此法通常在市售的直接溶解在乙酸中的无水氢溴酸或其适当稀释的溶液中进行,或在三甲基甲硅烷基碘溶于四氯化碳、二甲基甲酰胺、氯仿、甲苯等溶剂的溶液内进行。水解可在冷却或加热下进行。例如,当在-10℃或更低温度下以三甲基甲硅烷基卤进行酯水解时,可以得到部分水解产物。
要把双膦酸转变成其盐时,可用碱例如氢氧化钠、氢氧化钾、氨、有机胺等按常用方法处理该酸。
方法2
R1是羟基的式(Ⅰ)化合物:化合物(Ⅰb)
其中
环,R2、R3、R4和R5以及“n”的定义同前述,R8代表氢原子或低级烷基,“X”代表卤原子。
可以按以上反应式制得在亚乙基链上有羟基的化合物(Ⅰb)。
在此反应中,使式(Ⅳ)所示的羧酸衍生物与三卤化磷(Ⅴ)和亚磷酸或其低级烷基酯(Ⅵ)反应。卤原子可以是氯、溴、碘原子等。
首先在60-120℃,最好是80-110℃将羧酸衍生物(Ⅳ)与亚磷酸或其酯(Ⅵ)的混合液加热几分钟至几小时。然后向反应液中加入三卤化磷(Ⅴ),再于60-120℃,最好是80-110℃加热反应液几小时。反应进程用薄层层析法(展开***为氯仿-甲醇)易于监控。
如果需要,可将所得双膦酸酯按以上所述的方法转变为其盐。
目的产物(Ⅰ)的分离、纯化可按常用化学处理法(如提取、结晶、多种层析法等)进行。
抑制血钙过多的效果
本发明提供的化合物(Ⅰ)及其盐具有骨吸收抑制作用,还有抑制由骨吸收所致血钙过多的作用。此外,还发现这些化合物具有优良的抗炎作用和止痛作用。
以下叙述试验方法及结果,以证实本发明化合物和对照化合物(C1)和(C2)对血钙过多的抑制作用。
试验动物采用因给予甲状旁腺激素导致血钙过多的大鼠,并测
定给予上述化合物后血钙量下降的情况。
试验方法
将人1-34甲状旁腺激素(PTH,由Peptide Laboratory制备)溶解在含有0.1%BSA(牛血清蛋白)的生理盐水中,按30μg/kg(即5ml溶液/kg)的用量经静脉注入已禁食20小时的5周龄雄性Wistar大鼠内。对正常的对照组则仅静注含0.1%BSA的生理盐水。注射PTH后45分钟,将大鼠用醚麻醉,并剖腹,用真空集血管从腹腔中收集血液。立即于40℃在3000rpm转速下对收集到的血液进行离心以分离出血清。再立刻用Ca++计(Sera 250,Horiba制造公司制造)测量血清中离子化钙(Ca++)的浓度。
本发明化合物经皮下给药时,将其溶于生理盐水中并用氢氧化钠和盐酸调pH值至7.4。经口服给药时,则制成pH7.4的5ml/kg生理盐水溶液。在注射PTH前72小时给予上述溶液。按同样方法,正常对照组和对照组只给予生理盐水。
各组所得结果以平均值+S.E(标准误)表示,用一元方差分析检验各组间的差异。显著性水平为5%。
结果
皮下给药和口服给药所得的结果列于表1。
表1
剂量 给药方法 N 血清Ca++
(mg/kg) (mmol/L)
正常对照组 - 皮下给药 5 1.26±0.04**
对照组 - 皮下给药 5 1.38±0.02
实例化合物3 0.03 皮下给药 5 1.37±0.02
0.1 皮下给药 5 1.35±0.02
0.3 皮下给药 5 1.30±0.01*
正常对照组 - 口服 5 1.37±0.02
对照组 - 口服 4 1.41±0.02
实例化合物3 100 口服 5 1.37±0.02
300 口服 5 1.32±0.01*
表1(续)
剂量 给药方法 N 血清Ca++
(mg/kg) (mmol/L)
正常对照组 - 口服 5 1.35±0.01
对照组 - 口服 5 1.43±0.01
实例化合物5 0.001 皮下给药 5 1.38±0.02
0.003 皮下给药 5 1.26±0.02**
0.01 皮下给药 5 1.08±0.02**
3 口服 5 1.35±0.01
10 口服 5 1.26±0.03**
平均值:±S.E.
*:p<0.05
**:p<0.01
从试验结果可见,本发明化合物具有优良的降低血钙的作用。这样就证实了本发明化合物具有骨吸收抑制作用。由过量骨吸收引起的疾病有佩吉特氏病、血钙过多、转移性骨癌和骨质疏松症。从临床观点来看,炎性关节炎(例如类风湿性关节炎)中的骨吸收亢进也是一个严重的问题。本发明所提供的化合物可以用作治疗上述疾病的药物以抑制骨吸收、防止骨量下降或者防止或减少由骨吸收亢进所引起的血钙增高。
本发明化合物及其盐既可以直接使用,也可以与任何药用载体、赋形剂、稀释剂等混合制成药物组合物,如供口服的片剂、胶囊剂、粉剂、粒剂、丸剂等,供非口服给药的注射液、糖浆剂、栓剂、软膏剂等。本发明化合物(Ⅰ)的剂量可以根据给药方式、患者症状等予以调整,但一般未说成人口服时的剂量可为每天每人1mg到1g,成人非口服给药时剂量可为每天每人0.1到10mg。
下面参照实例更详细地介绍本发明。
实例1
将0.6g 5,6-二氢-7H-咪唑并[1,2-a]咪唑和3.0g四异丙基亚乙烯基双(膦酸酯)溶于2ml四氢呋喃中,加热回流6小时。减压浓缩反应液。残余物再用硅胶柱层析法(甲醇/氯仿=1/39)纯化,得2.3g四异丙基-2-(2,3-二氢-1H-咪唑并[1,2-a]咪唑-1-基)乙烷-1,1-双(膦酸酯),为黄色油状物。
此产物的物化性质如下:
(ⅰ)质谱(m/z):快速原子轰击质量466(M++1)
(ⅱ)核磁共振谱(在CDCl3中,四甲基硅烷(TMS)为内标)
δ:2.96(1H,-CH2CH-)
6.53,6.68(2H,芳香族H)
按与实例1同样的方法制得如下化合物:
实例2
四异丙基-2-(咪唑并[1,2-a]咪唑-1-基)乙烷-1,1-双(膦酸酯)。
物化性质:
(ⅰ)质谱(m/z):快速原子轰击质量464(M++1)
(ⅱ)核磁共振谱(在CDCl3中,TMS为内标)
2.58(1H,t,t,J=24Hz,8Hz,
),
3.54(2H,d,t,J=8Hz,16Hz,CH2CH),
4.60~4.90(4H,m,、
),
6.80(1H,s,咪唑-H)
7.0-7.20(3H,咪唑-H)
实例3
将0.9g四异丙基-2-(2,3-二氢-1H-咪唑并[1,2-a]咪唑-1-基)乙烷-1,1-双膦酸酯溶解在15ml浓盐酸中,并加热回流2小时。冷却后,减压浓缩反应液以除去盐酸。再向残余物中加入20ml纯化水,混合物再次减压浓缩。所得黄色固体用水-甲醇重结晶,得0.5g 2-(2,3-二氢-1H-咪唑并[1,2-a]咪唑-1-基)乙烷-1,1-双(膦酸酯),为黄色针状结晶。
此产物的物化性质如下:
(ⅰ)熔点:252-254℃(分解)
(自水-甲醇中重结晶)
(ⅱ)元素分析(按C7H13N3O6P2计)
C(%) H(%) N(%) P(%)
计算值:28.30,4.41,14.14,20.05
实测值:28.10,4.28,14.06,20.81
(ⅲ)质谱(m/z):快速原子轰击质量298(M++1)
按与实例3相同的方法制得如下化合物:
实例4
2-(咪唑并[1,2-a]咪唑-1-基)乙烷-1,1-双(膦酸)物化性质:
(ⅰ)质谱(m/z):快速原子轰击质量296(M++1)
(ⅱ)核磁共振谱(D2O,TMS为内标)
3.14(2H,d,t,J=8Hz,16Hz,CH2CH),
6.90(2H,s,咪唑-H)
7.04(2H,s,咪唑-H)
实例5
将2.4g 2-(咪唑并[1,2-a]吡啶-3-基)乙酸盐酸盐和2.0g亚磷酸溶于25ml氯苯中,并于110℃加热搅拌10分钟。再向混合物中滴加5.1g三氯化磷。进一步加热搅拌混合物8小时,然后倾去氯苯。向残余物中加入45ml 6N盐酸,混合物加热回流4小时。冷却后,混合物用活性炭处理,减压浓缩所得反应液。所得无
色固体用水-甲醇重结晶,得1.3g 1-羟基-2-(咪唑并[1,2-a]吡啶-3-基)乙烷-1,1-双(膦酸),为无色针状晶体。
此产物的物化性质如下:
(ⅰ)熔点:222-224℃(分解)
(自甲醇-水中重结晶)
(ⅱ)元素分析(按C9H12N2O7P2·0.5H2O计)
C(%) H(%) N(%) P(%)
计算值:32.64,3.96,8.46,18.71
实测值:32.45,3.91,8.65,19.05
(ⅲ)质谱(m/z):快速原子轰击质量323(M++1)按与实例5同样的方法制得如下化合物:
实例6
1-羟基-2-(8-羟基-2-甲基咪唑并[1,2-a]吡啶-3-基)乙烷-1,1-双(膦酸)
物化性质:
(ⅰ)熔点:260-264℃(分解)
(自甲醇-水中重结晶)
(ⅱ)元素分析(按C10H14N2O8P2·1H2O计):
C(%) H(%) N(%) P(%)
计算值:32.45,4.36,7.57,16.73
实测值:32.60,4.11,7.60,16.44
(ⅲ)质谱(m/z):快速原子轰击质量353(M++1)
实例7
将2.4g(咪唑并[1,2-a]吡啶-2-基)碳酸·盐酸盐和2.1g亚磷酸在25ml氯苯中的混合溶液于110℃加热搅拌15分钟,再滴加36ml三氯化磷。继续在110℃加热搅拌混合物9小时,再倾出氯苯相。向残余物中加入30ml 6N盐酸后将混合物加热回流6小时。冷却后,所得反应液用活性炭处理,然后减压浓缩。把残余物溶于纯化水中。溶液pH值用2N NaOH溶液调至pH5。然后加入30ml甲醇。混合物在室温下搅拌过夜,得0.44g 1-羟基-1-
(咪唑并[1,2-a]吡啶-2-基)甲烷-1,1-双膦酸三氢钠。
此产物的物化性质如下:
(ⅰ)熔点:高于270℃(分解)
(自甲醇-水中重结晶)
(ⅱ)元素分析(按C8H9N2O7P2Na计)
C(%) H(%) N(%)
计算值:29.11,2.75,8.49
实测值:29.38,3.06,8.60
(ⅲ)质谱(m/z):快速原子轰击质量331(M++1)
实例8
按与实例5相同的方法,由0.2g 2-(咪唑并[1,2-a]吡啶-2-基)乙酸盐酸盐制得0.2g 1-羟基-2-(咪唑并[1,2-a]吡啶-2-基)乙烷-1,1-双(膦酸)。
物化性质:
(ⅰ)质谱(m/z):快速原子轰击质量323(M++1)
(ⅱ)核磁共振谱(D2O,TMS为内标)
δ:3.40 (2H,t,J=12Hz)
6.94 (1H,t,J=6Hz,吡啶环-H)
7.20-7.60 (2H,吡啶环-H)
7.84 (1H,s,咪唑环-H)
8.10-8.20 (1H,吡啶环-H)
配方实例
下面举出本发明化合物作为药物的配方实例。
(a)片剂:
实例3化合物 5mg
乳糖 119mg
玉米淀粉 67mg
羟丙基纤维素 4mg
羟甲基纤维素钙 4mg
硬脂酸镁 1mg
总计 200mg
将5g实例3化合物、119g乳糖和67g玉米淀粉均匀混合后,加入40ml 10%(重量/重量)的羟丙基纤维素水溶液,并用湿法将所得混合物制粒。所得颗粒与4g羧甲基纤维素钙和1g硬脂酸镁混合,所得混合物制成每片重200mg的片剂。
按上述同样方法制备另一片剂。
实例5化合物 5mg
乳糖 119mg
玉米淀粉 67mg
羟丙基纤维素 4mg
羧甲基纤维素钙 4mg
硬脂酸镁 1mg
总计 200mg
制此片剂时,重复上述操作,只是配方中用5g实例5化合物代替实例3化合物,得到每片重200mg的片剂。
(b)胶囊剂:
实例3化合物 5mg
结晶纤维素 50mg
结晶乳糖 144mg
硬脂酸镁 1mg
总计 200mg
将1000倍于上述量的各个成分相混合,并密封在明胶胶囊内,每粒胶囊含200mg混合物。
按上述同样方法制备另一胶囊剂。
实例5化合物 5mg
结晶纤维素 50mg
结晶乳糖 144mg
硬脂酸镁 1mg
总计 200mg
制作此胶囊剂时,重复上述操作,只是在配方中用5g实例5化合物代替实例3化合物,制得的胶囊剂每粒含200mg混合物。
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-
1989
- 1989-08-07 US US07/390,090 patent/US4990503A/en not_active Expired - Lifetime
- 1989-08-08 AU AU39419/89A patent/AU624405B2/en not_active Ceased
- 1989-08-09 CA CA000607874A patent/CA1332058C/en not_active Expired - Fee Related
- 1989-08-11 HU HU894150A patent/HU205766B/hu unknown
- 1989-08-11 ES ES89308180T patent/ES2082780T3/es not_active Expired - Lifetime
- 1989-08-11 EP EP89308180A patent/EP0354806B1/en not_active Expired - Lifetime
- 1989-08-11 PH PH39086A patent/PH26376A/en unknown
- 1989-08-11 DK DK394789A patent/DK170257B1/da not_active IP Right Cessation
- 1989-08-11 KR KR1019890011432A patent/KR0156239B1/ko not_active IP Right Cessation
- 1989-08-11 AT AT89308180T patent/ATE129714T1/de not_active IP Right Cessation
- 1989-08-11 IE IE260189A patent/IE71185B1/en not_active IP Right Cessation
- 1989-08-11 DE DE68924681T patent/DE68924681T2/de not_active Expired - Fee Related
- 1989-08-12 CN CN89106373A patent/CN1027167C/zh not_active Expired - Fee Related
-
1990
- 1990-08-10 US US07/566,145 patent/US5039669A/en not_active Expired - Fee Related
-
1995
- 1995-06-30 HU HU95P/P00618P patent/HU211949A9/hu unknown
- 1995-11-15 GR GR950403204T patent/GR3018086T3/el unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102153585A (zh) * | 2011-02-24 | 2011-08-17 | 北京欧克兰医药技术开发中心 | 一种米诺膦酸中间体的合成方法及米诺膦酸的合成 |
CN102153585B (zh) * | 2011-02-24 | 2013-04-17 | 北京欧克兰医药技术开发中心 | 一种米诺膦酸中间体的合成方法及米诺膦酸的合成 |
Also Published As
Publication number | Publication date |
---|---|
AU624405B2 (en) | 1992-06-11 |
ATE129714T1 (de) | 1995-11-15 |
KR900003186A (ko) | 1990-03-26 |
DE68924681D1 (de) | 1995-12-07 |
DK170257B1 (da) | 1995-07-17 |
IE892601L (en) | 1990-02-12 |
HU205766B (en) | 1992-06-29 |
AU3941989A (en) | 1990-02-15 |
EP0354806B1 (en) | 1995-11-02 |
PH26376A (en) | 1992-06-01 |
CN1040590A (zh) | 1990-03-21 |
HU211949A9 (en) | 1996-01-29 |
CA1332058C (en) | 1994-09-20 |
US4990503A (en) | 1991-02-05 |
DK394789D0 (da) | 1989-08-11 |
KR0156239B1 (ko) | 1998-12-01 |
HUT51637A (en) | 1990-05-28 |
GR3018086T3 (en) | 1996-02-29 |
IE71185B1 (en) | 1997-01-29 |
EP0354806A3 (en) | 1991-05-02 |
EP0354806A2 (en) | 1990-02-14 |
DK394789A (da) | 1990-02-13 |
ES2082780T3 (es) | 1996-04-01 |
DE68924681T2 (de) | 1996-04-04 |
US5039669A (en) | 1991-08-13 |
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