CN1040110C - 新的含无环脒基团的二膦酸衍生物及基制备方法以及含该物的药用组合物 - Google Patents
新的含无环脒基团的二膦酸衍生物及基制备方法以及含该物的药用组合物 Download PDFInfo
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- CN1040110C CN1040110C CN93108873A CN93108873A CN1040110C CN 1040110 C CN1040110 C CN 1040110C CN 93108873 A CN93108873 A CN 93108873A CN 93108873 A CN93108873 A CN 93108873A CN 1040110 C CN1040110 C CN 1040110C
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Classifications
-
- 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
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Abstract
本发明提供新的通式(Ⅰ)化合物及其药学上可接受的盐，也提供这些化合物的制备方法以及用于治疗钙代谢紊乱的含它们的药用组合物。通式(Ⅰ)化合物的结构如下：
Description
本发明涉及新的含脒基团的二膦酸衍生物、其制备方法以及含这些化合物的药用组合物。
DE1813659中描述了二膦酸衍生物中的1-羟基乙烷-1，1-二膦酸可用作治疗佩吉特氏病(Paget′s disease)的重要药剂。
EP-A-0282320描述了具抗高血钙和抗关节炎作用的取代的3-异噁唑基-氨基亚甲基二膦酸及其酯。
EP-A-0282309中描述了作为高血钙的抑制剂的“噁唑”(“azol”)-氨基亚甲基二膦酸。
此外，从JP-A-63/150290中了解到作为钙代谢调节剂的氨基亚甲基二膦酸以及从EP-A-0274158中得知用以治疗钙和磷酸盐代谢异常的四氢嘧啶基-氨基亚甲基二膦酸和四氢吡啶基-氨基亚甲基二膦酸。
含环脒基团的偕二膦酸由DE-A-3208600、Liebigs Ann.Chem.1982，275页和DE-A-3930130.3得知。
现在我们发现这些化合物的无环衍生物是极好的钙配位形成物，此外也表现出对钙代谢的极佳的作用，因此适宜于广泛治疗钙代谢紊乱。具体来讲，它们具体适用在骨形成和骨断裂的时候，即它们适于治疗骨胳系统的疾病例如骨质疏松症、佩吉特氏病、别赫捷列夫氏病(Bechterew′s disease)等。
然而基于这些性质，也发现它们可用于治疗骨变形、尿石病以及预防异位骨化。它们对钙代谢的影响也是它们用于治疗类风湿性关节炎、骨关节炎和变性的关节病的基础。
因此，本发明提供通式(I)二膦酸酯及其药学上可接受的盐；通式(I)二膦酸酯结构如下：
式中R1是氢原子，具不超过9个碳原子的直链、支链、饱和或不饱和且可被苯基取代的烷基基团，或者是可被C1-C3烷基、C1-C3烷氧基或卤素取代的苯基基团；R2是氢原子或C1-C3烷基基团，其中这两个R2基团可以是相同的或不同的；R是氢原子或者是具不超过4个碳原子的直链或支链烷基基团；X是具不超过6个碳原子的亚烷基链，该亚烷基链可被C1-C3烷基基团取代一次或一次以上并且可被氧所中断，利用该亚烷基链的1个或2个碳原子可以形成环戊基或环己基环的一部分以及Y是氢原子，羟基基团或者是可被具不超过6个碳原子的烷基基团取代的氨基基团。
优选的Y代表氢原子，羟基基团或者可被甲基、乙基或异丙基取代的氨基基团。
优选的基团X是1，2-亚乙基，1，2-亚丙基，亚丁基，1-甲基1，2-亚丙基，2-甲基1，2-亚丙基，1-甲基亚丁基或2-甲基亚丁基基团。此外，优选的X是通过亚甲基、1，2-亚乙基或1，2-亚丙基基团与二膦酸部分相连的1，1-或1，2-取代的环己基环或环戊基环。
优选的R是氢原子或者甲基、乙基或异丁基基团。
特别优选的化合物是R和R2为氢原子、Y是氢原子或羟基基团以及R1是氢原子或烷基基团的通式(I)化合物。
特别优选的X是亚甲基、1，2-亚乙基、1，2-亚丙基或亚丁基基团。
本发明化合物可以立体异构的混合物或者纯的顺式或反式异构体形式存在。
不对称碳原子可具R-或S-构型而且该化合物可以旋光体或外消旋物的形式存在。
通式(I)化合物可按公知的方法制备并且最好是通过下述方法制得：将通式(II)羧酸与亚磷酸或磷酸和卤化磷或磷酰卤的混合物反应或者也可以在水存在下只与卤化磷反应且随后水解成游离的二膦酸，或者必要时将独立的通式(I)化合物转化成酯或其药学上可接受的盐；所述通式(II)羧酸的结构如下：式中R2、R2和X的定义同上。
通式(II)羧酸是新的，可按下述方法之一制备：a)将丙烯酸酯或取代的丙烯酸酯与通式(III)脒反应，并将该酯水解成相应的游离羧酸；通式(III)脒的结构如下：
式中R1和R2的定义同上；b)用碱金属或碱土金属氢氧化物打开通式(IV)嘧啶酮的环并转化成游离酸，通式(IV)嘧啶酮的结构如下：式中R1的定义同上；(c)通式(V)腈与胺反应并将该酯基团RE皂化，所述通式(V)腈的结构如下：
N≡C-X-COORE (V)式中RE是酯基团；或者(d)将活化的通式(VI)化合物与通式(III)脒反应并水解该酯得游离酸，通式(VI)化合物结构如下：
Z-X-COORE (VI)
式中RE是酯基团以及Z例如是囱原子。
用在该制备方法中的通式(II)羧酸与1-5mol且最好是2-3mol亚磷酸或磷酸和1-5mol且最好是2-3mol磷酰囱、三卤化磷或五卤化磷混合并于80-130℃且最好于100℃反应。磷和磷酰的卤化物最好是氯化物或溴化物。该反应也可以在稀释剂如卤代烃类且最好是氯苯或四氯乙烷存在下进行，也可以在二噁烷存在下进行，可以加水。随后的水解通过用水加热来完成，但最好是用半浓的(semi-concentrated)盐酸或氢溴酸。
通式(I)的游离的二膦酸用原甲酸烷基酯加热可以被转化成相应的四烷基酯并且可被皂化得双酯或再皂化得游离的四酸。一般来讲，皂化成双酯通过用碱金属卤化物、最好用碘化钠在适当的溶剂如丙酮中于室温处理四烷基酯来完成，结果得对称的双酯/二钠盐，必要时可用酸性离子交换剂将其转化成相应的双酯/二酸。
酯皂化成游离的二膦酸通常通过用盐酸或氢溴酸沸腾来完成。但也可以用三甲基甲硅烷基卤化物最好是溴化物或碘化物进行裂解。
作为药学上可接受的盐，最好使用-碱金属盐或二碱金属盐或者铵盐。这些盐按通常的方法例如通过用无机碱或有机碱滴定该化合物来制备，所述有机碱或无机碱为例如碳酸氢钠或碳酸氢钾、氢氧化钠水溶液、氢氧化钾水溶液、氨水或胺如三甲胺、三乙胺或环己胺。此外，钙盐、锌盐和镁盐尤其重要。这些盐通常通过从水/甲醇或水/丙酮中再沉淀来纯化。
本发明通式(I)的新化合物及其盐可以液体或固体的形式经肠道内或肠道外给药，因此可以采用所有的常规给药方式，例如片剂、胶囊、糖衣丸、糖浆、溶液、悬浮液等。作为注射剂溶媒，优先选用水；至于注射剂溶液，水中含通常的添加剂如稳定剂、增溶剂和缓冲剂。
这样的添加剂包括例如洒石酸盐和柠檬酸盐缓冲剂、乙醇、配位形成物(如乙二胺四乙酸及其无毒盐)、用于调节粘度的高分子量聚合物(如液体的聚环氧乙烷)。用于注射剂溶液中的液体的载体物质必须是灭菌的并且最好是被灌装在安瓿中。固体的载体物质包括例如淀粉、乳糖、甘露糖醇、甲基纤维素、滑石粉、高度分散的硅酸、高分子量的脂肪酸(例如硬脂酸)、明胶、琼脂、磷酸钙、硬脂酸镁、动物脂肪和植物脂肪、固体高分子量的聚合物(例如聚乙二醇)。适于口服给药的组合物如果需要可以含矫味剂和甜味剂。
剂量取决于多种因素例如给药方式、人种、年令和/或个体的健康状况。所用的日剂量约为1-1000mg/人且最好为10-200mg/人，而且可以一次全部服用或分成几次给药。
除在实施例中提到的化合物以及由在权利要求中所述的所有取代基所能衍生的化合物外，本发明优选的还有以下二膦酸以及其钠盐和甲酯和乙酯：优选的化合物：1. 1-羟基-2-(1-亚氨基乙基)-氨基乙烷-1，1-二膦酸，2. 1-羟基-4-(1-亚氨基乙基)-氨基丁烷-1，1-二膦酸，3. 1-羟基-5-(1-亚氨基乙基)-氨基戊烷-1，1-二膦酸，4. 1-羟基-3-(1-亚氨基丙基)-氨基丙烷-1，1-二膦酸，5. 1-羟基-4-(1-亚氨基丁基)-氨基丁烷-1，1-二膦酸，6. 1-羟基-6-(1-亚氨基乙基)-氨基己烷-1，1-二膦酸，7. 1-羟基-3-(1-亚氨基乙基)-氨基丁烷-1，1-二膦酸，8. 1-羟基-4-(1-亚氨基乙基)-氨基戊烷-1，1-二膦酸，9. 1-羟基-5-(1-氨基乙基)-氨基己烷-1，1-二膦酸，10. 1-羟基-3-(1-氨基丙基)-氨基丁烷-1，1-二膦酸，11. 1-羟基-4-(1-亚氨基乙基)-氨基-3-甲基丁烷-1，1-二膦酸12. 1-羟基-3-(1-亚氨基丁基)-氨基丙烷-1，1-二膦酸，13. 1-羟基-3-[1-(甲基亚氨基)-乙基]-氨基丙烷-1，1-二膦酸，14. 1-羟基-3-[2-(1-亚氨基乙基)-氨基环己基]-丙烷-1，1-二膦酸，15. 1-羟基-3-[2-(1-亚氨基乙基)-氨基环戊基]-丙烷-1，1-二膦酸，16. 1-羟基-3-[1-(1-亚氨基乙基)-氨基环己基]-丙烷-1，1-二膦酸，17. 1-羟基-2-[2-(1-亚氨基丙基)-氨基环己基]-乙烷-1，1-二膦酸，18. 1-羟基-2-(亚氨基甲基)-氨基乙烷-1，1-二膦酸，19. 3-(亚氨基乙基)-氨基乙烷-1，1-二膦酸，20. 2-(1-亚氨基乙基)-氨基乙烷-1，1-二膦酸，21. 1-羟基-3-(亚氨基甲基)-氨基丙烷-1，1-二膦酸，22. 3-(1-氨基乙基)-氨基丙烷-1，1-二膦酸，23. 3-[2-(1-亚氨基乙基)-氨基环己基]-丙烷-1，1-二膦酸，24. 1-羟基-3-[2-(亚氨基甲基)-氨基环己基]-丙烷-1，1-二膦酸。
以下实施例用以举例说明本发明。
实施例1
2-甲基-5，6-二氢-1H-嘧啶-4-酮
将14g盐酸乙脒加到3.4g钠的无水乙醇(118ml)溶液中并于室温搅拌30分钟，然后在30分钟时间内向其中滴加15.4ml丙烯酸甲酯并将该反应混合物于室温再搅拌5小时。加入100ml丙酮后，吸滤出得到的沉淀，将滤液真空蒸发，残留物用乙醇重结晶，得13.5g(收率为56％)；m.p.127-131℃(据在二甲亚砜中的NMR，判断它为烯醇式)。
3-(1-亚氨基乙基)-氨基丙酸
将4g 2-甲基-5，6-二氢-1H-嘧啶-4-酮于50℃在350ml水中与20g八水氢氧化钡一起加热5小时。将反应混合物冷至室温，滤出白色沉淀并将滤液用2N硫酸酸化。在冰箱中静置20小时后，吸滤出硫酸钡沉淀，将滤液置旋转蒸发器中蒸发并用乙醚将残留物从乙醇中沉淀析出。不经进一步纯化，将该干燥的沉淀用于磷酸化。
1-羟基-3-[1-亚氨基乙基)-氨基丙烷-1，1-二膦酸
将5g 3-(1-亚氨基乙基)-氨基丙酸于80℃与6.7g亚磷酸熔融，将它在缓慢搅拌下与7.5ml三氯氧化磷混合并于80℃放置24小时。然后真空去除过量的三氯氧化磷，将残留物与80ml水混合并将该澄清液加热至100℃ 1小时。冷却后，置旋转蒸发器中蒸发并用离子交换色谱法纯化：离子交换剂为Amberlite IR 120(H+型)，水作洗脱剂。将经TLC检查为单一物质的流份合并，蒸发并用水/丙酮结晶，得5.2g(相对于所用的2-甲基-5，6-二氢-1H-嘧啶-4-酮，收率为53％)；m.p.＞106℃(分解)；Rf＝0.36(乙醇/水/乙酸9∶1∶1体积/体积/体积)。
类视色素(Retinoid)试验
本试验参考Trechsel，Stutzer和Fleisch的方法(J.Clin.Invest.，80，1679-1686页/1987)在甲状腺-甲状旁腺切除的大鼠(TPTX)身上进行。为了与文献和以前获得的客观数据有可比性，将二膦酸酯(bisphosphonate)的剂量用mg P/Kg来表示(1mg P/Kg相当于16.13μmol/kg)。所给的剂量均为日剂量。
就测定而言，将类视色素诱导的钙水平增加(3天与0天的差别)定为100％。通过将该二膦酸酯与类视色素的作用相比较，二膦酸酯的作用(相对抑制百分数)被定义为对类视色素诱导的钙增加的抑制作用。若经二膦酸酯给药后所增加的钙水平与仅给类视色素所增加的钙水平的数值相同，则该二膦酸酯的作用为0％；若使钙水平不增加，则该作用为100％；若使钙水平降至初始值之下，则该作用大于100％。
对在该测定中产生的作用(相对抑制百分数)的计算按照以下公式：
ΔCaR：给类视色素后(连续给药的第3天)产生的血清钙血症(serium calcaemia)与基值之差。ΔCaBP：给类视色素后(连续给药的第3天)给相应的二膦酸酯产生的血清钙血症与基值之差。
表
| 化合物 | 剂量mgP/kg | 给药 | 相对抑制百分数 | n |
| 实施例1 | 0.0100.030 | S.C.S.C. | 57.07103.92 | 55 |
| pamidronate | 0.0100.030 | S.C.S.C. | 29.1237.52 | 55 |
pamidronate＝1-羟基-3-氨基丙基-1，1-二膦酸。
Claims (6)
1.通式(I)化合物及其药学上可接受的盐，所述通式(I)化合物的结构如下：式中R1是氢原子，具不超过9个碳原子的直链或支链、饱和或不饱和且可被苯基取代的烷基基团，或者是可被C1-C3烷基、C1-C3烷氧基或囱素取代的苯基基团；R2是氢原子或C1-C3烷基基团，其中这两个R2基团可以是相同的或不同的；R是氢原子或者是具不超过4个碳原子的直链或支链烷基基团；X是具不超过6个碳原子的亚烷基链，该亚烷基链可被C1-C3烷基基团取代一次或一次以上并且可被氧所中断，利用该亚烷基链的1个或2个碳原子可以形成环戊基或环己基环的一部分以及Y是氢原子，羟基基团或者是可被具不超过6个碳原子的烷基基团取代的氨基基团。
2.根据权利要求1的化合物，它是1-羟基-3-(1-亚氨基乙基)-氨基丙烷-1，1-二膦酸。
3.制备权利要求1的通式(I)化合物及其药学上可接受的盐的方法，其特征在于：将通式(II)羧酸与亚磷酸或磷酸和卤化磷或磷酰卤的混合物反应或者也可以在水存在下只与卤化磷反应且随后将其水解成游离的二膦酸；或者必要时将独立的通式(I)化合物转化成酯或其药学上可接受的盐；所述通式(I)化合物的结构如下：
式中R1是氢原子，具不超过9个碳原子的直链或支链、饱和或不饱和且可被苯基取代的烷基基团，或者是可被C1-C3烷基、C1-C3烷氧基或卤素取代的苯基基团；R2是氢原子或C1-C3烷基基团，其中这两个R2基团可以是相同的或不同的；R是氢原子或者是具不超过4个碳原子的直链或支链烷基基团；X是具不超过6个碳原子的亚烷基链，该亚烷基链可被C1-C3烷基基团取代一次或一次以上并且可被氧所中断，利用该亚烷基链的1个或2个碳原子可以形成环戊基或环己基环的一部分以及Y是氢原子，羟基基团或者是可被具不超过6个碳原子的烷基基团取代的氨基基团；所述通式(II)羧酸的结构如下：式中R1、R2和X的定义同上。
4.根据权利要求3的方法，其中制备的是1-羟基-3-(1-亚氨基乙基)氨基丙烷-1，1-二膦酸。
5.含有至少一种权利要求1或2的通式(I)化合物以及常规载体和辅助物质的药用组合物。
6.权利要求1或2的化合物在制备用于治疗钙代谢紊乱方面的药物中的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4223940A DE4223940A1 (de) | 1992-07-21 | 1992-07-21 | Neue acyclische Amidingruppen-haltige Diphosphonsäurederivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
| DEP4223940.0 | 1992-07-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1084852A CN1084852A (zh) | 1994-04-06 |
| CN1040110C true CN1040110C (zh) | 1998-10-07 |
Family
ID=6463698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93108873A Expired - Lifetime CN1040110C (zh) | 1992-07-21 | 1993-07-21 | 新的含无环脒基团的二膦酸衍生物及基制备方法以及含该物的药用组合物 |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5543561A (zh) |
| EP (1) | EP0651757B1 (zh) |
| JP (1) | JP3489830B2 (zh) |
| KR (1) | KR100246809B1 (zh) |
| CN (1) | CN1040110C (zh) |
| AT (1) | ATE148467T1 (zh) |
| AU (1) | AU670307B2 (zh) |
| CA (1) | CA2138127C (zh) |
| DE (2) | DE4223940A1 (zh) |
| DK (1) | DK0651757T3 (zh) |
| ES (1) | ES2099960T3 (zh) |
| FI (1) | FI109698B (zh) |
| GR (1) | GR3023109T3 (zh) |
| HU (1) | HU221496B (zh) |
| IL (1) | IL106393A (zh) |
| MX (1) | MX9304313A (zh) |
| NO (1) | NO304792B1 (zh) |
| NZ (1) | NZ254130A (zh) |
| WO (1) | WO1994002492A1 (zh) |
| ZA (1) | ZA935224B (zh) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW258729B (zh) * | 1992-06-22 | 1995-10-01 | Ciba Geigy | |
| US6298081B1 (en) | 1996-05-31 | 2001-10-02 | Telefonaktiebolaget Lm Ericsson (Publ) | Channel hopping in a radio communications system |
| KR100327786B1 (ko) * | 1999-03-25 | 2002-03-14 | 유승필 | 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 또는 이의 염의 제조방법 |
| AU778431B2 (en) * | 2000-05-05 | 2004-12-02 | F. Hoffmann-La Roche Ag | Gel-like pharmaceutical composition for subcutaneous administration comprising bisphosphonic acids or their salts |
| KR100327787B1 (ko) * | 2001-02-27 | 2002-03-15 | 유승필 | 4-아미노-1-하이드록시부틸리덴-1,1-비스포스폰산 일나트륨 삼수화물의 제조방법 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2439355A1 (de) * | 1974-08-16 | 1976-02-26 | Benckiser Gmbh Joh A | N-(diphosphonomethyl)-formamidine und verfahren zur herstellung |
| WO1991003481A1 (de) * | 1989-09-09 | 1991-03-21 | Boehringer Mannheim Gmbh | Neue amidingruppen-haltige diphosphonsäurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1196315B (it) * | 1984-10-29 | 1988-11-16 | Gentili Ist Spa | Procedimento per la preparazione di acidi difosfonici |
| DE69216514T2 (de) * | 1991-08-27 | 1997-07-31 | Ciba Geigy Ag | N-Substituierte Aminomethandiphosphonsäuren |
| TW222637B (zh) * | 1991-12-12 | 1994-04-21 | Hoechst Ag | |
| TW258729B (zh) * | 1992-06-22 | 1995-10-01 | Ciba Geigy | |
| DE59309360D1 (de) * | 1992-12-02 | 1999-03-18 | Hoechst Ag | Guanidinalkyl-1, 1-bisphosphonsäurederivate, Verfahren zu ihrer Herstellung und ihre Verwendung |
| US5366965A (en) * | 1993-01-29 | 1994-11-22 | Boehringer Mannheim Gmbh | Regimen for treatment or prophylaxis of osteoporosis |
-
1992
- 1992-07-21 DE DE4223940A patent/DE4223940A1/de not_active Withdrawn
-
1993
- 1993-07-13 HU HU9500180A patent/HU221496B/hu unknown
- 1993-07-13 ES ES93915895T patent/ES2099960T3/es not_active Expired - Lifetime
- 1993-07-13 AT AT93915895T patent/ATE148467T1/de active
- 1993-07-13 DE DE59305351T patent/DE59305351D1/de not_active Expired - Lifetime
- 1993-07-13 KR KR1019950700005A patent/KR100246809B1/ko not_active IP Right Cessation
- 1993-07-13 DK DK93915895.2T patent/DK0651757T3/da active
- 1993-07-13 JP JP50411994A patent/JP3489830B2/ja not_active Expired - Lifetime
- 1993-07-13 WO PCT/EP1993/001833 patent/WO1994002492A1/de active IP Right Grant
- 1993-07-13 CA CA002138127A patent/CA2138127C/en not_active Expired - Lifetime
- 1993-07-13 AU AU45680/93A patent/AU670307B2/en not_active Expired
- 1993-07-13 EP EP93915895A patent/EP0651757B1/de not_active Expired - Lifetime
- 1993-07-13 US US08/367,325 patent/US5543561A/en not_active Expired - Lifetime
- 1993-07-13 NZ NZ254130A patent/NZ254130A/en not_active IP Right Cessation
- 1993-07-16 MX MX9304313A patent/MX9304313A/es unknown
- 1993-07-19 IL IL10639393A patent/IL106393A/en not_active IP Right Cessation
- 1993-07-20 ZA ZA935224A patent/ZA935224B/xx unknown
- 1993-07-21 CN CN93108873A patent/CN1040110C/zh not_active Expired - Lifetime
-
1995
- 1995-01-20 NO NO945015A patent/NO304792B1/no not_active IP Right Cessation
- 1995-01-20 FI FI950259A patent/FI109698B/fi not_active IP Right Cessation
-
1997
- 1997-04-11 GR GR970400771T patent/GR3023109T3/el unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2439355A1 (de) * | 1974-08-16 | 1976-02-26 | Benckiser Gmbh Joh A | N-(diphosphonomethyl)-formamidine und verfahren zur herstellung |
| WO1991003481A1 (de) * | 1989-09-09 | 1991-03-21 | Boehringer Mannheim Gmbh | Neue amidingruppen-haltige diphosphonsäurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
Also Published As
| Publication number | Publication date |
|---|---|
| DE59305351D1 (de) | 1997-03-13 |
| ES2099960T3 (es) | 1997-06-01 |
| NO304792B1 (no) | 1999-02-15 |
| JP3489830B2 (ja) | 2004-01-26 |
| DK0651757T3 (da) | 1997-07-28 |
| NZ254130A (en) | 1996-11-26 |
| EP0651757B1 (de) | 1997-01-29 |
| GR3023109T3 (en) | 1997-07-30 |
| HU221496B (en) | 2002-10-28 |
| ATE148467T1 (de) | 1997-02-15 |
| CA2138127A1 (en) | 1994-02-03 |
| DE4223940A1 (de) | 1994-01-27 |
| JPH09502158A (ja) | 1997-03-04 |
| MX9304313A (es) | 1994-02-28 |
| CA2138127C (en) | 2006-01-24 |
| IL106393A0 (en) | 1993-11-15 |
| CN1084852A (zh) | 1994-04-06 |
| HU9500180D0 (en) | 1995-03-28 |
| IL106393A (en) | 1999-05-09 |
| HUT72603A (en) | 1996-05-28 |
| WO1994002492A1 (de) | 1994-02-03 |
| ZA935224B (en) | 1995-01-20 |
| EP0651757A1 (de) | 1995-05-10 |
| KR100246809B1 (ko) | 2000-04-01 |
| KR950702566A (ko) | 1995-07-29 |
| FI950259A0 (fi) | 1995-01-20 |
| FI109698B (fi) | 2002-09-30 |
| FI950259A (fi) | 1995-01-20 |
| AU4568093A (en) | 1994-02-14 |
| NO950221D0 (no) | 1995-01-20 |
| AU670307B2 (en) | 1996-07-11 |
| US5543561A (en) | 1996-08-06 |
| NO950221L (no) | 1995-01-20 |
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