TW449597B - Pharmaceutical compositions with anticholinergic activity - Google Patents
Pharmaceutical compositions with anticholinergic activity Download PDFInfo
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- TW449597B TW449597B TW085108367A TW85108367A TW449597B TW 449597 B TW449597 B TW 449597B TW 085108367 A TW085108367 A TW 085108367A TW 85108367 A TW85108367 A TW 85108367A TW 449597 B TW449597 B TW 449597B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pulmonology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Description
A7 B7 4在9 #87i〇8367號專利申請案 中文說明書修正頁(90年4月） 五、發明説明（1) 本發明係關於（内’順）-(-)-3-(3 -海基-1-氧基_2·苯丙氧 基）-8 -甲基-8-(甲基乙基）·8-氮钂二環[3,2，1]辛燒鹽類。 這些化合物可用來做為有效而且效果特別長之支氣管解瘦 劑。本發明也係關於該鹽類在製造製備供吸入以治療氣^黑 上的用途，和需要以此種療法治療病人之方法。 上述化合物之消旋物（以溴的型態）係以Ipratr〇pium br〇mide 之名做為抗膽素性（anticholinergic)藥之活性物質販售。 目前已發現並且令人驚詩的是，該消旋物、左旋和右旋 對映體的活性情況明顯不同，並且在實質上具有許多與基 準相異之特性。正對映禮（eutomer)(即具有預期或想找尋活 性之對映體）為L-(-)-對映體。CHO-HM受體上的受體結合 研究已顯示L-(-)-對映體的親和力大約為消旋物的2倍。此 比率在觀察比較對映體與消旋物的效果時時常得到映證。 然而，我們意外地發現在本例中使狗（已麻醉）以吸入方 式攝入重量比為1 : 2的正對映體和消旋物後做比較，正對 映體不僅具有較高效力，而且其活性期也相當地長。 因此，一方面我們提供對映純度為90至100%的（内，順）-(-)-3-(3-羥基-1-氧基-2-苯丙氧基）-8 -甲基-8-(甲基乙 基）-8-氮鐳二環[3J，1]辛烷鹽類。 圖1之圖形顯示抑制支氣管痙攣百分比與時間之函數圖。 虛線（曲線B)代表（内，順）-(-)-3-(3-羥基-1-氧基-2-苯丙 氧基）-8 -甲基-8-(甲基乙基）-8 -氮鏆二環[3,2，1]辛烷的圖 形，而實線（曲線A )則是使用之相對應溴化氫消旋物的圖 形。由於施予5//g純L-(-)-對映體，因此消旋物施予量為10哗 -4 - 本紙張尺度適用中國國家標準（CNS > A4規格（210X297公釐) ' *" (請先閲讀背面之注意事項再填寫本頁) 訂 气___ 經濟部中央標準局貝工消费合作社印装 44959 7 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（2 ) 該實驗係對五隻試驗動物施予純L _ (_) _對映體（BIIH 15〇 BR)，而消旋物則施予七隻試驗動物。 圖1顯示對狗施用Ipratr〇pium bromide煙霧劑抑制乙醯膽 素所诱發之支氣管痙攣（曲線A)，在約〗〇分鐘後達到約 55%的尖峰量，而在6〇分鐘後會回復至其最初量。相同量 之正對映體’如消旋物所包含般，（曲線B )在約〖〇分鐘後 達到60%的抑制作用，而在丨8〇分鐘後並不會回復至其起 始量。 測量半衰期顯示該正對映體ΒΠΗ 150 BR之活性期間约爲 4倍之久。 消旋物經由結合應用高壓液體層析法和再結晶作用後， 所獲得之正對映體其實質上的純度很高。使用於本發明目 的之「正對映體」一詞也包括L_(_)_對映體之高度濃縮產 物（約9 0 %以上），含有約9 5 %以上較佳，而9 7 %以上特佳 。陰離子與起始化合物使用者相同。若有需要，二者可以 互換。 以下實例係欲説明L -(-)-和D - (+)-對映體之製備： 利用高壓液體層析法，在Chiralcel OD管柱（250 X 20 mm) 上’以由600己烷、250甲醇、150乙醇和1飽和NaBr醇溶 液（V :V:V:V，通流速率6毫升/分鐘，波長254nm;敏 感度 0.5 A.U.F.S·，包含 1 克 Ipratropium bromide/5 毫升乙醇 + 5毫升流動相+ 2.5毫升濃醋酸）組成的流動相，將18克 Ipratropium bromide分離出來。 藉由乙醇利用重覆層析法和再結晶作用，獲得熔點爲 -5- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 灯 449597 A7 _____ B7 五、發明説明（3 ) 239-40°C (decomp.)，特異旋轉度[α£°=-24_06。（c=l_014 ; H2〇)，對映純度97.4% (HPLC)之白色L-(-)·對映體結晶， 以及熔點爲238-39°C(decomp.)，特異旋轉度[〇 + 24 06。 (c=l.〇18 : H20)，對映純度98.9% (HPLC)之白色 D-(十）-對 映體結晶。元素分析和光譜顯示這些化合物是存在的。 各種鹽類型態的L-(-) -對映體中，以溴、氣或醋酸鹽最 佳’因爲可以抗副交感神經，因此適於以吸入方式治療慢 性阻塞性支氣管炎和氣喘，而且另一方面絕無副作用。 因此根據本發明另一方面’我們提供適於以吸入型態， 包含本發明化合物，可任意與醫藥上可接受之賦形劑和/或 載劑和/或其它活性物質一起製備之方法。 關於用途方面，該活性物質可以以已知的賦形劑和/或載 劑處理形成傳統草藥式療法之製備，例如作爲吸入之溶液 ’液化推進器氣體中的懸浮液，包含脂質體或原脂質體之 製備，和供傳統吸入器使用而可以被吸入之粉末（任意於膠 囊中）。 處方實例（使用的量以重量百分比計算）： 1 ·計量煙霧劑 ^n' Hu I ..... 1 I i in HI l Jn (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 根據本發明之活性物質 0.005 山梨聚糖三油酸鹽 0.1 一氟三氣甲烷和 二氟二氣甲烷2 : 3 加至1 00 將該懸浮液改置於有計量活門之一般煙霧劑容器内0例 如，每次傳動時釋入50W懸浮液。若有需要，該活性物質 -6 - l適用中國國&標準T^T^iFTJTox297公釐) ------ 44959 7 A7 __________B7 五、發明説明（4 ) 也可以以較鬲劑量存在（例如〇 〇2重量百分比）。 除了氣化推進器氣體外，也可使用其它的推進器氣體， 像是TG 134a(l，l，l，2-四-氣乙烷）和/或7(3 227^^2,3,3,3-五-氣丙燒）。 2.供吸入之粉末 將微粒化之活性物質粉末（顆粒大小爲〇5至7jum)與微粒 化的乳糖混合，並隨意與其它添加物一起裝入硬凝膠膠囊 内。例如，每一膠曩内裝入〇〇1毫克活性物質和5毫克乳糖 。使用一般吸入器，例如DE-A 3345772即可吸入該粉末。 3 ·供吸入之溶液 也可以使用該活性物質之水溶液，以例如根據W0 9 1/14468之裝置製造煙霧劑。又舉例來説，每次活性物質 施用之嘴霧劑量爲0.005毫克。 根據本發明之活性物質與其它活性物質一起使用時，對 於呼吸道之治療也有效。需要特別注意々2 ·擬似物：單獨 使用時，這些擬似物係與50-100%的劑量化合。 下列物質也必須加以注意： 巴布德醇（Bambuterol) 經濟部中央樣準局員工消費合作社印製 -m ^^^^1 ^ni ^^^^1 ^ k 、va (請先閲讀背面之注意事項再填寫本頁) 比悦德醇（Bitolterol) 卡布德醇（Carbuterol) 克藍布德醇（Clenbuterol) 非諾德醇（Fenoterol) 弗莫德醇·（Formoteroi) 己普耐林（Hexoprenaline) 本紙張尺度適用中國國家標準（CNS ) Λ4规格（210X297公釐） 49 53 7 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（5 ) 依布德醇（Ibuterol) 波布德醇（Pirbuterol) 普若卡德醇（Procater〇1) 瑞普德醇（Reproterol) 撤布達醇（Salbutamol) 撒来德醇（Salmeterol) 蘇孚德醇（Sulfonterol) 得布塔林（Terbutaline) 審洛布德醇（Tulobuterol) 1-(2 -氟- 4- ¾苯基）-2-[4-(l -苯并味吐基）-2 -甲基-2-丁胺 基] 乙醇赤蘚-51-羥基羥基-2-異丙胺基丁基）-2H-l，4-苯并噁嗪基-3-(4H)-酮 1-(4-胺基-3-氣-5-三氟甲基苯基）_2 -第三-丁胺基）-乙醇 1-(4 -乙氧藏胺基-3-氣基-5-氣苯基）-2-(第三-丁胺基）-乙 醇 可吸入的類固醇，例如布德松奈（Budesonide)，貝可米松 (Beclomethasone)(或 17,2 Ι-dipropionate)，地塞米松-2 1 -異 於酸鹽（dexamethasone-21-isonicotinate)，弗尼索菜 (Flunisolide)和抗過敏藥劑，像是色甘胺酸二鈉鹽（disodium cromoglycate)，尼德克米（Nedocromil)，依匹那斯 J丁 (Epinastine)也可以是化合時的成份。這些化合成份可以與 單獨使用時相同或較小的劑量施藥。 -8 - 本紙張尺度適用中國國家標準（CNS M4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂_
Claims (1)
- A8 B8 C8 D8 449597 第85108367號專利申請案 申請專利範圍修正本(90年4月） 六、申請專利範圍 1. 一種具抗膽素性活性之醫藥組合物，其具延長活性且於 適合吸入形式’其係含對映體純度為90至100%之（内， 順）-(-)-3-(3 -輕基-1-氧基-2-苯丙氧基）_8_甲基_8_(ι_ 甲基乙基）-8 -氮鑌二環[3，2,1]辛燒之鹽類，且視需要同 時併含醫藥可接受之賦形劑及/或載體及/或其他活性物 質。 2. 根據申請專利範圍第1項之醫藥組合物，其特徵在於該 對映體之純度為9 5至1 〇〇%。 3. 根據申請專利範圍第1或2項之醫藥組合物，其包含Br 0，C10或CH3CO20做為該鹽類之陰離子。 {請先；g讀背面之注意事項再填寫本頁) I訂 經濟部中央橾牟局負工消費合作社印装 本紙張尺度逋用中國國家揉準（CNS > A4At格（210X297公釐）
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19528145A DE19528145A1 (de) | 1995-08-01 | 1995-08-01 | Neue Arzneimittel und ihre Verwendung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW449597B true TW449597B (en) | 2001-08-11 |
Family
ID=7768353
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW085108367A TW449597B (en) | 1995-08-01 | 1996-07-10 | Pharmaceutical compositions with anticholinergic activity |
Country Status (37)
| Country | Link |
|---|---|
| US (1) | US6299861B1 (zh) |
| EP (1) | EP0843676B1 (zh) |
| JP (1) | JPH11510150A (zh) |
| KR (1) | KR100445016B1 (zh) |
| CN (1) | CN1120841C (zh) |
| AR (1) | AR004179A1 (zh) |
| AT (1) | ATE208390T1 (zh) |
| AU (1) | AU6739796A (zh) |
| BG (1) | BG63780B1 (zh) |
| BR (1) | BR9609951A (zh) |
| CA (1) | CA2226934C (zh) |
| CO (1) | CO4750836A1 (zh) |
| CZ (1) | CZ291998B6 (zh) |
| DE (2) | DE19528145A1 (zh) |
| DK (1) | DK0843676T3 (zh) |
| EE (1) | EE04614B1 (zh) |
| ES (1) | ES2167592T3 (zh) |
| HK (2) | HK1013597A1 (zh) |
| HR (1) | HRP960365B1 (zh) |
| HU (1) | HU228056B1 (zh) |
| IL (1) | IL118986A (zh) |
| MX (1) | MX9800864A (zh) |
| MY (1) | MY115201A (zh) |
| NO (1) | NO317561B1 (zh) |
| NZ (1) | NZ315645A (zh) |
| PL (1) | PL183789B1 (zh) |
| PT (1) | PT843676E (zh) |
| RO (1) | RO120260B1 (zh) |
| RU (1) | RU2171258C2 (zh) |
| SI (1) | SI0843676T1 (zh) |
| SK (1) | SK283260B6 (zh) |
| TR (1) | TR199800121T1 (zh) |
| TW (1) | TW449597B (zh) |
| UA (1) | UA55391C2 (zh) |
| WO (1) | WO1997005136A1 (zh) |
| YU (1) | YU49479B (zh) |
| ZA (1) | ZA966494B (zh) |
Families Citing this family (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19921693A1 (de) * | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Neuartige Arzneimittelkompositionen auf der Basis von anticholinergisch wirksamen Verbindungen und ß-Mimetika |
| US20100197719A1 (en) * | 1999-05-12 | 2010-08-05 | Boehringer Ingelheim Pharma Kg | Medicament compositions containing anticholinergically-effective compounds and betamimetics |
| ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
| US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
| US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
| US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
| US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
| US20020151541A1 (en) * | 2000-10-31 | 2002-10-17 | Michel Pairet | Pharmaceutical compositions containing tiotropium salts and antihistamines and their use |
| US7776315B2 (en) * | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
| US20100310477A1 (en) * | 2000-11-28 | 2010-12-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg. | Pharmaceutical compositions based on anticholingerics and additional active ingredients |
| UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
| US6455028B1 (en) * | 2001-04-23 | 2002-09-24 | Pharmascience | Ipratropium formulation for pulmonary inhalation |
| AU2002303425A1 (en) * | 2001-04-24 | 2002-11-05 | Epigenesis Pharmaceuticals, Inc. | Composition, formulations and kit for treatment of respiratory and lung disease with non-glucocorticoid steroids and/or ubiquinone and a bronchodilating agent |
| US20030018019A1 (en) * | 2001-06-23 | 2003-01-23 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics |
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| WO2006114379A1 (de) * | 2005-04-23 | 2006-11-02 | Boehringer Ingelheim International Gmbh | Arzneimittelkombination für die inhalation enthaltend neben einem anticholinergikum ein betamimetikum und ein steroid |
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| TW201311649A (zh) * | 2011-09-05 | 2013-03-16 | Everlight Chem Ind Corp | 用於太陽能電池電解液之化合物及其製法、含有該化合物之電解液及太陽能電池 |
| CN111751454B (zh) * | 2019-03-29 | 2023-12-08 | 天津药业研究院股份有限公司 | 一种异丙托溴铵中间体i的含量和有关物质的检测方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3505337A (en) * | 1967-12-22 | 1970-04-07 | Boehringer Sohn Ingelheim | N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof |
| DE2903957A1 (de) * | 1979-02-02 | 1980-08-07 | Boehringer Sohn Ingelheim | Mittel zur behandlung der nasalen hypersekretion |
| US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
| DE4140861C2 (de) * | 1991-12-11 | 2003-12-11 | Boehringer Ingelheim Kg | Verfahren zur Gewinnung von quartären Tropasäurealkaloiden |
| AU6048694A (en) * | 1992-12-09 | 1994-07-04 | Paul D. Jager | Stabilized medicinal aerosol solution formulations |
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1995
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