TW420659B - Substituted benzoylguanidines, process for their preparation, their use as a pharmaceutical, as inhibitors of the cellular Na+/H+ exchange or as a diagnostic, and pharmaceutical containing them - Google Patents

Substituted benzoylguanidines, process for their preparation, their use as a pharmaceutical, as inhibitors of the cellular Na+/H+ exchange or as a diagnostic, and pharmaceutical containing them Download PDF

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TW420659B
TW420659B TW083102858A TW83102858A TW420659B TW 420659 B TW420659 B TW 420659B TW 083102858 A TW083102858 A TW 083102858A TW 83102858 A TW83102858 A TW 83102858A TW 420659 B TW420659 B TW 420659B
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guanidine
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benzamidine
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Hans-Jochin Lang
Andreas Weichert
Heinz-Werner Kleemann
Robert-R Schmidt
Wolfgang Scholz
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Hoechst Ag
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Claims (1)

  1. 經濟部中央樣隼局員工消費合作社印製 六、申請專利範園420659 專利申請案第83102858號 ROC Patent Appln. No.83102858 修正之申請專利範圍中文本一附件一 Amended Claims in Chinese 一 Enel. I (民國86年2月3日送呈) (Submitted on February 3 , 1997) J.式（I )苯甲醢基胍
    其中： R(l)、R⑵及R⑶之一是N3、OH或（G -Cw)-烷氧基，而 其餘的取代基R(l)，R⑵或R(3)中至少一個是具有3 至12個碳原子之烷基， 或者取代基R(l)，R⑵或R⑶之一是 R(4)-CnH2n-〇m，其中 m是0或1 » η 是0，1，2或3， R(4)是 CpF2p+1 其中當η是0或1時，p是1，2或3， 或 -37 - 本紙張尺度逋用中國國家標準（CNS ) Α4規格（210X297公釐） (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 Αδ BS C8 D8六、申請專利範圍 R⑷是（C3 -Go)-環垸基或選擇地經F或Cl取代之苯基， 或者取代基R(l)，R⑵或R(3)之一是-C=CR⑸， R⑸是苯基， 其餘的取代基R(1)、R(2)、R(3)分别獨立地爲氫、F 、（:卜 Br、I或(G -C12)-烷基； 及其禁學上可接受之鹽類，但下列化合物例外： 苯甲醢基胍，4-氣代苯甲酿基胍，3,4-二氣代苯甲醢 基胍，及3-或4-甲基苯甲醯基胍。 2.如申請專利範圍第1項之式（I )苯甲醢基胍，其中： R⑴，R⑵或R⑶之一爲OH或(G -Cs)-烷氧基，而其餘 取代基R(l)，R(2)或R(3)之中至少一個是具3至6個 碳原子之烷基，或者 取代基R(l)，R⑵或R⑶之一爲 R(4)-CnH2n-Om，其中 m是0或1， η 是0，1，2 或 3， R ⑷是 CpF2p+i 其中，當η是0或1時，p是1，或 R(4)是(CS-C7)_環烷基或任經F或CI取代之苯基， 或者，取代基R(l)，R⑵或R(3)之一是-C=CR(5)， R⑸是苯基， -38 - 420659 -11 ^^^1 m HI 1 n^i —^ϋ n ^^^1 1^1 (請先聞讀背面之注意事項再填寫本頁)
    本紙張尺度適用中國國家橾準（CNS > A4規格（210X297公釐） 4 20659 A8 B8 C8 D8 々、申請專利範圍 其餘的取代基R(l)、R(2)、R⑶分别獨立地爲氫、p C卜Br或（G-C*)-烷基； ' 及其藥學上可接受之厘類’但下列化合物例 外：苯甲醯基胍’ 4_氯代苯甲醯基胍，3,4_二 基脈·，及3-或4·-甲基苯甲磁基狐。 ^表甲随 3.如申請專利範圍第1項之式（Ϊ)苯甲醯基胍，其係選自 列包括： 下 3_三氟甲基苯甲醯基胍鹽酸鹽’ 3,5-雙三氟甲基苯甲酿 * 基胍鹽酸鹽，％甲基三氟曱基苯甲醯基孤鹽酸鹽4_ ♦ 氟-3-三氟曱基苯甲醯基胍鹽酸鹽，4_(4_氟代苯氧基)一3_ 裝------,訂 f請先閱續背面之注##.項再填寫本頁)
    三氟甲基苯曱醯基胍鹽酸鹽，5_氟-3-三氟甲甲醯基 經濟部中央標準局員工消費合作社印裝 胍鹽酸鹽，3-氣*-4-異丙基苯曱醯基胍鹽酸鹽％-第三 丁基~3-甲氧基苯曱醯基胍鹽酸鹽，3-第三丁基-4-羥基 苯曱醯基胍鹽酸鹽，3-第三丁基斗·異丙基苯甲醯基狐鹽 酸鹽》 -39 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） A8 八： B8 … C8 D8 六、申請專利範圍 4· 一種製備如申.請專利範圍第1項之式（I)化合物的方 法，包括於惰性有機溶劑中及於20¾至溶劑滩點的 溫度下，倘適當，於酸清除劑的存在下，令式（π) 化合物與脈反應 • ·* R(l)
    其中R(l)至R(3)界定如上且L爲離去基，其可輕易 被親核性基團取代。 5. 如申請專利範圍第1項之式（丨）苯甲醯基胍，其係用 於製備治療心節律不整之蔡物。 6. 如申請專利範圍第1項之式（I)苯甲醢基胍，其係用 於治療或預防心梗塞。 7. 如申請專利範圍第i項之式苯甲璉基胍，其係用 於治療或預防心绞痛。 經濟部中央標準局負工消費合作社印製 -----1---策—---—――訂 (請先聞讀背面之注意^項再填寫本萸) 8. 如申請專利範圍第1項之式〇-)^甲璉基胍，其係用 於治療或預防絶血性心病症。 9. 如申請專利範園第1項之式（I)苯曱釀基胍，其係用 於製備一種蔡物，該蔡物係用於治療其係急性或慢 •性之絶金謗生塑傷害或疾病，由絶血初次或二次誘 發〇 -40 ™ 本紙張尺度適用中國國家標準（CNS ) A#規格（2ΐ〇χ297公嫠） 經濟部中央標率局負工消費合作社印製 420659 锰 C8 D8六、申請專利範園 m如申請專科範圍第1項之式（I)苯甲醯基胍，其係用 於製備一種蔡物，此禁物係用於治療器官移植後病 症，及保護器官切除前及切除過程中，以及轉移至 接受者時，贈與者輿接受者之器官。 让如申請專利範圍第1項之·式（I)苯曱醯基胍，其係用 於製備保護離開活體之器官之藥物。 i2如申請專利範圍第1項之式（I)苯曱醯基胍，其係用 於製備進行侵略性血管移植治療上之蔡物。 货如申請專利範圍第1項之式（I)苯曱醯基胍，其係用 於製備治療中風及腦水腫之蔡物。 i 兒如申請專利範圍第1項之式（I)苯甲醢基胍，其係用 於製備治療休克病症之藥物。 瓜如申請專利範園第1項之式（I)苯甲醯基胍，4係用 於製備治療致粥瘤症及動脈硬化之蔡物。 瓜如申請專利碎圍第1項之式（I)苯甲醯基胍，用 於製備治療糖尿病之末期併發症的蔡物。 仪如申請專利範圍第1項之式（Ϊ)苯甲醯基胍，其係用 於製備治療癌症之蔡物。 m如申請專利範圍第1項之式（I)苯甲醢基胍，其係用 於製備治療纖維性病變之藥物。 m如申請專利範圍第1項之式（I)苯甲醯基胍，其係， 於製備治療器官肥大及增生之禁物。 (請先間讀背面之注意事項再填寫本頁) 41 - 本紙張尺度適用中國國家標準（CNS ) A4現格（210X297公釐） 420659Γ、申請專利範圍 Α8 Β8 L8 D8 2α如申請專利範圍第1項之式（I)苯甲璉基胍，其係用 於製備預防高血壓形成之辏物。 21.如申請專利範圍第1項之式U)苯甲醯基胍，其係用 於製備治療由增生性過程所導致的失調症之蔡物。 • ·* 21如申請專利範圍第1項之式U)苯甲醢基胍，其係用 於製備治療胃腸道失調及由胃酸過度分泌所致之食 道失調症的蔡物。 2a—種用於治療或預防心節律不整、心梗塞、心絞痛 、絶血性心病症、心臟移植後的病症、中風、腦水 腫、休克病症、致粥瘤症、動脈硬化、搪尿病末期 併發症、癌症、纖維性病變、器官肥大及增生.、高 血壓、由增生性過程所導致的失調症、及由胃酸分 泌過度所產生的疾病的華學組合物，其係包括有效 量之如申請專利範園第1項的化合物（1)。 I —^1 I— IK - I I - I In 1 - t i- HI - — (請先聞讀背面之注$項再填寫本頁) 經濟部中央標準局員工消費合作社印裝
    -42 本紙桀尺度逋用中國國家樣率（CNS ) A4规格（210X297公釐）
    申請曰期 案 類 號 則 -e4- 420659 (以上各棚由本局填註） (83102858) u專利説’明書 發明 名稱 人 中 文 英文 姓 名 國 籍 住、居所 性名 (名稱） 1^Ι¥Λ$Ι1Μ n £ Substituted benzoylguanidlnes, process for their preparations their use as a pharmaceuticalt as Inhibitors of the cellular Na+/IT^ exchange or as a diagnostic, and phamaceuticai/ CtltilU —-- — — — -—- — - - 1 藍漢奇 （Hans-Jochen Lang) 2 韋安徳 （Andreas Weictiert) 3 由 _ 成 （Heinz-Werner Kleemarm) 4 史羅伯 （Jan-Robert Schwark) 5 史伍福 ^folfgang Scholz) 6 歡伍德 （Udo Albus) 裝 經濟部中央標準局貞工消費合作拉印乾 三、申請人- 國 籍 住、居所 (事務所） 代表人 姓 名 1 一 6皆德画1德画哈福匿康徳街7號 Ruedeshelmer Str, 7, D-65719 Hofheim, Federal Republic of Germany2德圃法蘭克福區處梭路11號 Rauenthaler Weg 11, D-60529 Frankfurt, Federal Republic of Germany3徳國貝哈區赫儉街3號 An der hohlen Eiche 3, D-61350 Bad Homburg, Federal Republic of Germany4德画法蘭克福區羅瑞街63號 Loreleistrasse 63» 0^65929 Frankfurt, Federal Republic of Germany5德國依奇堡思待街30號 Unterortstrasse 30* D-65760 Eschborn, Federal Republic of Germany6德國彿洛區羅馬街9號 Am Roemerkastell 9, D-61197 Florstadt, Federal Republic of Germany 德國法蘭克福城6230號 6230 Frankfurt am Main 80, Federal Republic of Germany 安哈德·亞伯特（A丨brecht Enge丨hardt) 烏 ί(!希·特高（Ulrich Tergau) 本紙張又度適用中國國家棵準（CNS ) A4说格（2〖〇><297公釐) 訂 線 五、發明説明（9-1) 420659 A7 B7 專利申請案第83102858號 ROC Patent Appln· No.83102858 補充之中文説明書第11-1、1卜2、II-3及11-4頁-財件二 Supplemented Pages 11-1, 11-2，11-3 and 11-4 of the Chinese Specification 一 End. B (民國86年2月3日送呈） {Submitted on February 3 » 1997) 經濟部中央標準局員工消費合作社印製 可證明各種疾病與蔡理作用/試驗之間的闞係之文 獻資料如下： 狹心症與節律不整： ， 狭心症之形成乃係由於冠狀動脈之暫時關閉，而使 得血液之供應暫時短缺，此一短暫的時間造成了心律失 常，降低了心臟的效率，進而使心臟受損。上述之情形 可以藉著抑制"antiporter"而減至最小，蓋其可避免細 胞内之鈣堆積。. 當心臟再灌注之血液（區域或整體的）中氧短缺後 ，於再灌注期開始之際，亦即在捕充氧氣時，會發生節 律不整的現象，而NHE-交換抑制劑會減少這些節律不 整的發生次數與持續時間。 11-1 本紙張尺度適用中國國家標隼（CNS ) A4現格（210X297公釐） ------------裝-- (請先閲讀背面之注意事項再填寫本頁) 訂 • H— —^1 |修正 420659 補充 Β7 五、發明説明（11 于们甲铕茶畢肋1似858號 - ^ R£S Patent Appln. No.83102858 ./，正/補充之實例部分中文本一附件1 Amended / Supplemented Example Part in Chinese - FnrI ID ，·(民芦¥^2月3日送呈） -’― (Submitted on February 3 , 1997) 經濟部中央標隼局員工消費合作社印製 浮液或乳劑，該溶劑例如有，特別是已醇或水，或這些溶 劑之混合液。 若有需要，此製劑亦可备有其它蘖學佐劑，例如界面 活性劑，乳化劑與安定劑，及推造氣體。於這類製劑中之 活性物質濃度通常介於重量百分比0.1至10之間，尤其是約0.3 至3。 式I活性物質之用藥劑量及用藥頻率將由所用化合物 之作用強度及作用期決定；此外亦由欲治療之疾病性質及 嚴重性，欲治療之哺乳動物之性別，年齡及個別特性決定 〇 平均而論，以約75公斤體重之病患而言，式I化合物 之每日劑量為每公斤體重至少0.001毫克/公斤，較好0.01 毫克/公斤，至多不超過10毫克/公斤，較好1毫克/公斤。若 疾病為急性，例如剛發生心梗塞之後，需要更高，特別是 ’更頻繁之劑去，例如每日高達4次單劑量。可能需要高 達2〇〇毫克之日劑量，特別是靜脈内注射時，例如病患遭 逢梗塞或為侵略性病症時。 實例部份 由苯曱酸(II ’ L=OH)製備苯甲醯基胍⑴之一般方法：： 將0.1毫升之式ΪΙ苯甲酸衍生物溶於或懸浮於升之 無水四氫呋喃(THF)，然後添加1.78克（0.011莫耳）之襄醯二 咪唑。反應溶液於室溫攪拌2小時後，加入2.95克(〇,〇5莫耳） 胍。令此混合物攪拌一夜後，減壓下（Rotavapor)將THF蒸餾 13- 本紙張尺錢财關家標準（CNS ) 297公楚_ ) {請先閲讀背面之注意事項再填寫本頁) •丨 '裝- 訂
    經濟部中央樣隼局員工消費合作社印製 六、申請專利範園420659 專利申請案第83102858號 ROC Patent Appln. No.83102858 修正之申請專利範圍中文本一附件一 Amended Claims in Chinese 一 Enel. I (民國86年2月3日送呈) (Submitted on February 3 , 1997) J.式（I )苯甲醢基胍
    其中： R(l)、R⑵及R⑶之一是N3、OH或（G -Cw)-烷氧基，而 其餘的取代基R(l)，R⑵或R(3)中至少一個是具有3 至12個碳原子之烷基， 或者取代基R(l)，R⑵或R⑶之一是 R(4)-CnH2n-〇m，其中 m是0或1 » η 是0，1，2或3， R(4)是 CpF2p+1 其中當η是0或1時，p是1，2或3， 或 -37 - 本紙張尺度逋用中國國家標準（CNS ) Α4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁)
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JP3806431B2 (ja) 2006-08-09
FI940756A (fi) 1994-08-21
EP0612723A1 (de) 1994-08-31
ES2107698T3 (es) 1997-12-01
JP2004189755A (ja) 2004-07-08
AU668265B2 (en) 1996-04-26
ATE157351T1 (de) 1997-09-15
GR3024855T3 (en) 1998-01-30
NO940563D0 (no) 1994-02-18
NZ250919A (en) 1996-01-26
ZA941119B (en) 1994-08-30
US5866610A (en) 1999-02-02
IL108697A0 (en) 1994-05-30
FI940756A0 (fi) 1994-02-17
JPH06256291A (ja) 1994-09-13
NO940563L (zh) 1994-08-22
HU9400466D0 (en) 1994-05-30
HUT70535A (en) 1995-10-30
EP0612723B1 (de) 1997-08-27
DK0612723T3 (da) 1998-03-30
HU218915B (hu) 2000-12-28
JP3554352B2 (ja) 2004-08-18
IL108697A (en) 2000-07-16
AU5522994A (en) 1994-08-25
CA2115967A1 (en) 1994-08-21
DE59403818D1 (de) 1997-10-02
FI114467B (fi) 2004-10-29

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