TWI615390B - ５－氯－噻吩－２－羧酸［（ｓ）－２－［甲基－３－（２－側氧基－吡咯啶－１－基）－苯磺醯基胺基］－３－（４－甲基－哌嗪－１－基）－３－側氧基－丙基］－醯胺之酒石酸鹽 - Google Patents
５－氯－噻吩－２－羧酸［（ｓ）－２－［甲基－３－（２－側氧基－吡咯啶－１－基）－苯磺醯基胺基］－３－（４－甲基－哌嗪－１－基）－３－側氧基－丙基］－醯胺之酒石酸鹽 Download PDFInfo
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- TWI615390B TWI615390B TW103115126A TW103115126A TWI615390B TW I615390 B TWI615390 B TW I615390B TW 103115126 A TW103115126 A TW 103115126A TW 103115126 A TW103115126 A TW 103115126A TW I615390 B TWI615390 B TW I615390B
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- methyl
- oxo
- chloro
- thiophene
- carboxylic acid
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- 150000003892 tartrate salts Chemical class 0.000 title description 5
- 150000001408 amides Chemical class 0.000 title 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 18
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- -1 phosphonium amine Chemical class 0.000 claims description 13
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- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
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Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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Abstract
本發明係關於5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之酒石酸鹽、其結晶型、其製備及其治療用途。
Description
本發明係關於5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之新穎鹽、其結晶型、其製備及其治療用途。
5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺對應於下式(I)之化合物：
呈鹽酸鹽形式之式(I)化合物及其製備製程闡述於文件WO 2009/103440中。
在其他氯噻吩-醯胺中，尤其闡述此化合物作為凝血因子Xa及凝血酶之抑制劑。
然而，式(I)化合物之游離鹼以及其如根據WO 2009/103440獲得
之鹽酸鹽皆為非晶形且因此幾乎不可進行工業處理。
因此，業內需要凝血因子Xa及凝血酶之可易於處理之抑制劑。
現已發現該化合物之L-2,3-二羥基丁二酸(亦稱為L-酒石酸)之鹽展現有利性質，此使得其尤其適於在醫藥中用作活性成份。
因此，本發明之標的物係5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸之鹽(或L-酒石酸鹽)、其製備及其治療應用。
本發明之另一標的物係5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽之結晶型，下文闡述其物理化學特徵。
自式(I)化合物之L-酒石酸鹽之粉末試樣開始記錄粉末X射線繞射圖。
該分析係在配備有Anton-Paar TKK溫度室且展現擁有Bragg-Brentano型聚焦幾何形狀(θ-θ)之反射設置之D8 Advance繞射儀(Bruker-Siemens)上實施。
銅對陰極管提供入射輻射(λKα1=1.5406埃(angström)及1.5444埃)。
在環境溫度下在4度至45度之2θ下記錄圖表。
繞射圖之特徵線係於下表中給出。
式(I)化合物之L-酒石酸鹽之繞射圖示於圖1中。
式(I)化合物之L-酒石酸鹽係結晶固體。繞射圖指標化顯示其為純結晶相(空間群P21；晶胞體積1618Å3)。
在Nexus IRTF分光計上在4000cm-1與400cm-1之間記錄式(I)化合物之L-酒石酸鹽之紅外(IR)光譜，且解析度為4cm-1。
此光譜之特徵在於下表中給出之吸收帶。
對本發明化合物實施之差示熱力學分析在203.9℃下熔化前未展
現任何熱事件。
本發明之另一標的物係製備5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之酒石酸鹽及其結晶型之製程。
根據本發明，可在鹽形成反應中藉由使呈游離形式之式(I)化合物與酒石酸在溶劑中反應來製備本發明之酒石酸鹽。
式(I)化合物可根據以下製程獲得：
另一選擇為，可根據闡述於WO 2009/103440中之一個製程製備式(I)化合物。
下述實例闡述根據上文所闡述之一般方案製備本發明式(I)化合物之酒石酸鹽。
使用以下縮寫及實驗式：
EtOAc 乙酸乙酯
Boc 第三丁氧基羰基
DAP 二胺基庚二酸
T3P 丙基膦酸酐
EtOH 乙醇
DIEA N,N-二異丙基乙胺
HCl 鹽酸
MeTHF 2-甲基四氫呋喃
t-BuOK 第三丁醇鉀
THF 四氫呋喃
iPrOH 異丙醇
℃ 攝氏度
步驟(a)：5-氯-噻吩-2-羰基氯(化合物III)
自100g(1.1當量)式(II)之5-氯-噻吩-2-羧酸，藉由在80℃下在1.4份體積甲苯中與1.5當量亞硫醯氯發生反應獲得式(III)之醯氯。
步驟(b)：2-第三丁氧基羰基胺基-3-[(5-氯-噻吩-2-羰基)-胺基]-丙酸(化合物IV)
使包含於步驟(a)中獲得之醯氯(化合物III)之反應介質在包含1當量Boc-DAP-OH存於3份體積THF及1.2份體積水中之5℃溶液上在3.3當量30% NaOH存在下流動，以便獲得式(IV)化合物，在蒸發後對該式(IV)化合物進行分離。
步驟(c)：[1-{[(5-氯-噻吩-2-羰基)-胺基]-甲基}-2-(4-甲基-哌嗪-1-基)-2-側氧基-乙基]-胺甲酸第三丁基酯(化合物V)
化合物(V)係由3當量步驟(b)所獲得之化合物(IV)與甲基哌嗪，使用1.5當量T3P作為偶合劑，在EtOAc溶液中偶合18小時期間而獲得。
然後，利用EtOAc萃取化合物(V)，然後藉由在1.5份體積至2份體
積EtOAc中結晶進行分離。
步驟(d)：5-氯-噻吩-2-羧酸[2-胺基-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]-醯胺(化合物VI)
化合物(VI)係藉由水解化合物(V)之Boc官能基獲得。在1小時期間使存於6.5份體積EtOH及0.36份體積水中之化合物(V)在3當量已加熱(70℃)之12N HCl水溶液上流動。
步驟(e)：N-(3-溴-2-甲基-苯基)-4-氯-丁醯胺(化合物VIII)
化合物(VIII)係藉由在20℃下在5份體積THF中在1.2當量DIEA存在下利用1當量4-氯丁醯氯醯基化200g 3-溴-甲基苯胺(化合物VII)來製備。
2小時後，使所得混合物在15℃下流至13當量水上，從而使得化合物VIII沈澱。
步驟(f)：1-(3-溴-2-甲基-苯基)-吡咯啶-2-酮(化合物IX)
化合物(IX)係藉由在10℃下在10份體積MeTHF中在1.2當量tBuOK存在下環化290g化合物(VIII)獲得。
步驟(g)：1-(3-苄基硫基-2-甲基-苯基)-吡咯啶-2-酮(化合物X)
化合物(X)係由20g化合物(IX)，在100℃下在8份體積甲苯中在1.2當量苄基硫醇、0.06當量膦、0.03Pd(0)及2當量DIEA存在下保持4小時而獲得。
步驟(h)：2-甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯氯(化合物XI)
化合物(XI)係藉由在5.7當量乙酸及0.3份體積水中在4當量硫醯氯存在下氧化化合物(IX)獲得。
步驟(i)：5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺(式(I)化合物)
式(I)化合物係藉由偶合化合物(VI)及化合物(XI)獲得。
在10℃下在3份體積水及2份體積二氯甲烷中在8當量K2CO3存在下使化合物(XI)之溶液流動至208.85g化合物(VI)上，由此獲得游離形式之式(I)化合物。
所獲得式(I)化合物為非晶形產物。
在獲得游離形式之式(I)化合物後，使其經受結晶反應以便獲得其L-酒石酸鹽。
使於步驟(i)中獲得之式(I)化合物經受結晶反應。
在燒瓶中，加熱於4ml水中之0.5g式(I)化合物，然後加熱0.132g L(+)酒石酸用於總溶液，然後在攪拌下保持24小時。
然後，過濾並乾燥所形成之固體，然後從而獲得本發明化合物之白色粉末。
由此獲得之式(I)化合物之L-酒石酸鹽具有極高純度(98.9%)。
如前文所提及，應注意呈鹽酸鹽形式之式(I)化合物為非晶形且使其結晶之嘗試皆未成功。
出乎意料地，已明確證明式(I)化合物之酒石酸鹽具有純度、穩定性及溶解性之性質，該化合物之L-乳酸鹽及L-鈉形式(皆為結晶鹽)之該等性質有所改良。
呈鈉鹽、L-乳酸鹽及L-酒石酸鹽形式之式(I)化合物之物理性質概述於下表中。
該等結果顯示，L-酒石酸鹽在應力條件下展現之吸濕性、水吸收及穩定性比鈉鹽及L-乳酸鹽更好，此意味著L-酒石酸鹽可易於處置及儲存。
在兩種不同溶劑(非極性溶劑(乙酸乙酯或EtOAc)及極性質子溶劑(異丙醇或iPrOH))中分析呈鈉鹽、L-乳酸鹽及L-酒石酸鹽形式之式(I)化合物之結晶之若干特徵。
結果係於下表中進行闡述。
鑒於上述結果，發現式(I)化合物之L-酒石酸鹽在兩種測試溶劑中之結晶特徵比L-乳酸鹽及鈉鹽更好。
具體而言，L-酒石酸鹽之結晶較快，且產率優良，且所獲得產物易於過濾。
因此，該等結果證明式(I)化合物之L-酒石酸鹽具有優良的結晶可處理性。
在以下條件下儲存一週後分析式(I)化合物之鈉鹽、L-乳酸鹽及L-酒石酸鹽：- 80℃
- 80℃及飽和濕度。
結果係於下表中進行闡述。
鑒於上文所獲得之結果，發現式(I)化合物之鈉鹽及L-乳酸鹽在熱量及濕度之效應下不穩定，因此其必須免受濕度之影響進行儲存。
相比之下，L-酒石酸鹽未改變。因此，該等結果證明式(I)化合物之L-酒石酸鹽在測試條件下之穩定性更大。
在不同緩衝液中分析式(I)化合物之鈉鹽、L-乳酸鹽及L-酒石酸鹽之溶解度。
結果係於下表中進行闡述(所測試化合物之溶解度係以mg/ml表示)。
鑒於上文所獲得之結果，發現所有三種測試鹽皆高度溶於所有研究介質中，且L-酒石酸鹽係其中溶解性最強之鹽。
在強氧化溶液中儲存一週後分析式(I)化合物之鈉鹽、L-乳酸鹽及L-酒石酸鹽：在室溫下在0.3% H2O2溶液中維持三種化合物。
6小時或一週之後，量測式(I)化合物之主要N氧化物雜質之比例
。
結果係於下表中進行闡述。
鑒於上文所獲得之結果，發現L-酒石酸鹽在氧化性溶液中比式(I)化合物之L-乳酸鹽及鈉鹽更穩定。
式(I)化合物之L-酒石酸鹽之物理化學性質容許其在正常條件下進行儲存，而無需過度限制的防範光之存在、溫度及濕度，且因此易
於處理。
5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之酒石酸鹽係凝血因子Xa及凝血酶之抑制劑。
因此，其可用於製備醫藥，具體而言為凝血因子Xa及凝血酶之抑制劑之醫藥。
因此，在本發明之另一態樣中，本發明提供包含5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽之醫藥。
該等醫藥係在治療上使用，其尤其用於治療及預防心血管病症、血栓栓塞性疾病或再狹窄。
該等醫藥亦在治療上用於抑制因子Xa及凝血酶或影響血液凝血或纖維蛋白分解或治療或預防上文或下文所提及之疾病，例如用於治療及預防心血管病症、血栓栓塞性疾病或再狹窄，及針對該等目的治療之方法(包括用於該等治療及預防之方法)。
該等醫藥亦用於治療諸如以下等疾病狀態：異常血栓形成；急性心肌梗塞；不穩定型心絞痛；血栓性栓塞；與血栓溶解療法或經皮腔內冠狀動脈血管成形術(PTCA)相關之急性血管閉塞；短暫性缺血發作；中風；間歇性跛行或冠狀動脈或外周動脈之旁路移植；血管管腔狹窄；冠狀動脈或靜脈血管成形術後再狹窄；長期血液透析患者中血管通路通暢之維持；腹部、膝部或臀部外科手術後在下肢靜脈中發生之病理性血栓形成；腹部、膝部及臀部外科手術後在下肢靜脈中發生之病理性血栓形成；肺血栓性栓塞之風險；或敗血性休克期間在血管系統中發生之播散性系統性血管內凝血症；某些病毒感染或癌症。
本發明化合物亦可用於減少發炎反應。可使用本發明化合物治療或預防之特定病症之實例係冠狀動脈心臟病、心肌梗塞、心絞痛、
血管再狹窄(例如血管成形術(如PTCA)後之再狹窄)、成人呼吸窘迫症候群、多器官衰竭及播散性血管內凝血病症。與外科手術相關之相關併發症之實例係血栓形成(如深靜脈及近端靜脈血栓形成)，其可在外科手術後發生。
根據本發明之另一態樣，本發明係關於醫藥組合物，其包含本發明之5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽作為活性成份。該等醫藥組合物含有有效劑量之本發明化合物及至少一種醫藥上可接受之賦形劑。
該等賦形劑係根據醫藥形式及期望投與模式選自熟習此項技術者熟知之常用賦形劑。
圖1係式(I)化合物之L-酒石酸鹽之繞射圖。
Claims (9)
- 一種5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽。
- 如請求項1之5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽，其中其為結晶。
- 如請求項1或2中任一項之5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽，其中其具有根據圖1之X射線繞射圖。
- 一種製備5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽之方法，其特徵在於使5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之游離鹼形式與L-酒石酸在溶劑中反應。
- 如請求項4之方法，其中5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之該游離形式係藉由添加5-氯-噻吩-2-羧酸[2-胺基-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]-醯胺及2-甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯氯獲得。
- 一種醫藥，其特徵在於其包含5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽。
- 一種醫藥組合物，其特徵在於其包含作為活性成份之5-氯-噻吩- 2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽，及至少一種醫藥上可接受之賦形劑。
- 如請求項1至3中任一項之5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽，其用於治療或預防心血管病症。
- 如請求項8之5-氯-噻吩-2-羧酸[(S)-2-[甲基-3-(2-側氧基-吡咯啶-1-基)-苯磺醯基胺基]-3-(4-甲基-哌嗪-1-基)-3-側氧基-丙基]醯胺之L-酒石酸鹽，其用於治療或預防血栓栓塞性疾病或再狹窄。
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| US5952379A (en) * | 1996-05-31 | 1999-09-14 | Sigma-Tau Industrie Farmaceutiche | Stable, non-hygroscopic salts of L(-)carnitine and alkanoyl L(-)carnitines, a process for their preparation and solid, orally administrable compositions containing such salts |
| SE510305C2 (sv) * | 1997-05-30 | 1999-05-10 | Astra Ab | Nytt salt |
| GB0030304D0 (en) * | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
| GB0114005D0 (en) * | 2001-06-08 | 2001-08-01 | Glaxo Group Ltd | Chemical compounds |
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| CA2537170A1 (en) * | 2003-08-28 | 2005-03-10 | Mayne Pharma Pty Ltd | Acid containing oxaliplatin formulations |
| US7371743B2 (en) * | 2004-02-28 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
| KR100953535B1 (ko) | 2008-07-17 | 2010-04-21 | 재단법인 포항산업과학연구원 | 염소계 화합물을 이용한 배가스 내 수은 제거 방법 |
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