TW473389B - New pharmacological use of AII-receptor antagonists - Google Patents

New pharmacological use of AII-receptor antagonists Download PDF

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TW473389B
TW473389B TW085106910A TW85106910A TW473389B TW 473389 B TW473389 B TW 473389B TW 085106910 A TW085106910 A TW 085106910A TW 85106910 A TW85106910 A TW 85106910A TW 473389 B TW473389 B TW 473389B
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Lars Faendriks
Anders Pettersson
Anders Aaneman
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Astrazeneca Ab
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Description

五、發明説明（1 ) 發明領域 本發明係有關使用血管收縮素〖丨之第1型受體拮抗劑，預防 及/或治療多重系統器官衰竭（M〇F)及係有關製造對]^〇{7 有效的藥物製劑。 發明背景 —本發明所發現具有藥理學上新類用途的血管收縮 梵體拮抗劑，是在本技藝中爲人所知的。然而， 、二土 化合物對MOF之效用的藥理學及/或治療特性，關绝些 記載或尚爲未知。 則尚未有 採用舆本發明有關的通式ί血管收縮素第】型 又如推挽齊!）· (請先閱讀背面之注意事項再填寫本頁」
其中A爲 經濟部中央標準局員工消費合作社印製
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V A7 B7 五、發明説明
CI
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L5 經濟部中央標準局員工消費合作杜印製 Μ
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L7 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） > V五、發明説明（3)
A7 B7 1:8 L9 L10 L11 (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
L12 L13 -6 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） B7 經濟部中央標準局員工消費合作社印製
^ P >? V A7 五、發明説明（4 上列化合物，可以其濟游 ^ ± 肖旋形式或以大體上純爲鏡像異構 ^的形式使用；其可以巾_式或 ::學上可接受的鹽，像是納十銨、罐。：:; 用化合物中’可以其可水解自旨的形式使用。 當式！化合物中A爲1:1部份時，通稱爲&她n，可自歐洲 專利η 〇 · 2 5 3 3 1 0中得知。 當式1化合物中Α爲1: 5部份時，通稱爲candesamn cilexetil ，暗碼n〇. TCV-116 ’可自歐洲專利n〇 459 136中得知。 當式I化合物中A爲1:9部份時，通稱爲的⑽論。 當式1化合物中A爲1:13部份時，通稱爲candesartan，可自 歐洲專利no_ 459 136中得知。 出血及/或創傷引起血管收縮反應，其特別會減少血流 至腸繫膜的器官。嚴重時，出血可波及循環休克，此情況 係因氧氣輸送變得不足以保持組織完整及其功能。於腸繫 膜器官之循環休克的表徵包括：腸道通透性障壁萎陷，使 腸道病原越過腸黏膜終致藉淋巴及血管散佈至各系統區間 。此種障壁的官能障碍使微生物移位，加上最初受損的系 統循環，導致各種器官系統（如，腎、心臟、肺、止血）之功 能衰竭。如此毀壞趨式之順序發展，定義爲多重系統器官 衰竭（MOF)。 治療MOF非常花錢，且導致長期在加護病房（丨以⑶“… care unit)治療。現今治療M0F在治療學上努力的目標爲 支撑生命療法，像是抗生素，血容積擴張，及呼吸輔助。 然而，現今尚典可用以保持腸繫膜血流及氧氣輸送之治療 7 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） —— — ——— II #! . - (請先閱讀背面之注意事項再填寫本頁) -訂 五、發明説明（ A7 B7 門徑。 病危病人腸繫膜血流減少主要是經腎激素_血管收縮素系 統使血清血管收縮素II(AII)量上升所調控。投予可阻斷 All形成的化合物（ie血管收縮素轉換酶抑制物，ACE-抑 制物）顯示在嚴重休克期間可促進腸繫膜的和氧作用 (oxygenation)。 然而’使用A C E抑制物治療嚴重休克是有礙的，因其作 用是非專一性酶抑制物並會導致數個血管活性肽之堆積， 例如舒緩激肽（類似鴉片物的bradykinin)，p物質θα" 内生性。P〇ids。結果可導致血壓調節不穩粒增加過 敏性表徵與上呼吸道刺激的危險。 對另外經改善的預防及/或治療多重玄y 、A / 系统器官衰竭方 法之需求，將會被認同。 發明揭示 本發明非預期地發現：已知通式化合物 ———————#τι . - (請先閲讀背面之注意事項再填寫本頁)
1T 經濟部中央標隼局員工消費合作杜印製
N= N
其中A爲 -8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 42^7 >? ^f A7 B7 五、發明説明（6 )
本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閱讀背面之注意事項再填寫本頁) cf A7 B7 五、發明説明（ r
N Ν'
vCOOH 1:6 ,Ν Ν
,Ν L7 (請先閲讀背面之注意事項再填寫本頁)
L8
9 L·
VI 經濟部中央標準局員工消費合作社印製
ο. 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） A7 B7 五 、發明説明
趣濟部中央檩準局員工消費合作、社印製 或此處（所示化合物）生理學上可接受的鹽及/或立體化學 異構物可有效預防及/或治療多重系统器官衰竭（M〇F)。 已發現帶有根據化學式I化合物之All第1型受體藥理學專 —性阻斷劑，在相當的病危病人情況的狀況中，對胃腸組 織和氧作用具有意外良好的效果。此外，在有血清AII濃度 上升的情況下，此一 All第1型受體專一性阻斷劑顯示可增 -11 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（9 ) 強上胃腸道之黏膜障壁功能。 本發明係以我們的意外發現爲基礎：投予對保持氧氣輸 送及對胃腸黏膜障壁有正面刺激效力之專一性AII第1型受 體拮抗劑，對於多重系統器官衰竭之預防及/或治療有用。 該化學式I化合物可以其中性的形式或鹽的式、經口、由 直腸（rectally)或非腸道（途徑）投予。而其對内臟氧和作用 及障壁功能的效力已經由靜脈途經以動物（模型）建立，相信 該效力爲一種系統性的效力而非取決於所使用的投藥形式 ，因此該效力亦將在以其它途徑投藥時，像是直腸或口服 投藥時看到。 用以預防及/或治療多重系統器官衰竭之化學式I化合物 劑量，取決於一些因素，像是疾病的嚴重性及病人的狀況 。經口、直腸及靜脈投藥的劑量範圍是每天自1至5〇〇 mg 〇 本發明最好的形式是使用化學式I化合物中，A爲1:1 (Losartan)或1:5(1'(：¥-116)者〇 科學試驗 動物實驗是在相當於病危病人的情況之狀況中進行，如 在 Aneman et al 1995 ; Anesth. Analg. No 80, p 135-142 中所述 。胃腸的和氧作用是以經麻醉的豬，在其急性出血期間進 行研究（出血量爲經估計血容積之4 〇%)。在未經治療组的動 物（n = 6)，觀察到在40%出血後其腸繫膜和氧化作用嚴重降 低。在經losartan治療之動物（n = 5),在4〇%出血後，其腸繫 膜的氧氣輸送未有減少。 __- 12 - 本紙張尺度適用中國國^^率（CNS ) M規格（加“7公羞- --- -------；—衣— (請先閱讀背面之注意事項再填寫本頁) 訂 A7 B7 五 '發明説明（ 中和fc性的能力是構成胃腸黏膜障壁功能的要素，特別 是於上腸道但亦於較下方的部分，以下實驗是以經麻醉大 白鼠的十二指腸進行。由靜脈投與AII其後在未經治療的動 物（n = 6)會降低其中和腸腔中酸性的能力。在以ΑΠ_受器阻 斷劑losartan預處理之後，在對同樣劑量αΠ的反應中，該抑 制作用，意外地被逆轉爲經促進的中和酸性能力（η = 6)。 藥物製劑 可使用傳統的藥物製劑。該藥物製劑最好以注射溶液劑 的形式，但也可使用其它種類製劑，像是口服溶液劑或懸 液劑，錠劑或膠囊劑。另外，投藥途徑爲舌下錠劑或溶液 劑及直腸溶液劑，懸液劑或r e c t i ο 1 s。 藥物製劑含有1 mg至5 0〇 mg活性物質，較宜爲1 〇至2 5 0 mg 0 (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 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）

Claims (1)

  1. > V > V
    第85106910號專利申請案 中文申請專利範圍修正本(90年7月） 六、申請專利範圍 1. 一種用於預防及/或治療多重系統器官衰竭之醫 藥組合物，其包括如下通式化合物或其生理學上可接 受之鹽及/或其立體化學異構物作為活性物質，
    其中A為 (請先閱讀背面之注意事項再填寫本1) Cl N
    N CHsOH L-l Cl N
    L2 N C〇〇H 經濟部中央標隼局員工消費合作社印製
    L3
    L4 本紙張尺度逋用中國國家標準（CNS ) A4说格（2丨OX297公釐） if A8 B8 C8 D8 申請專利範圍 COOCHOCOCH3
    L5 Μ
    C〇〇H L6 (請先閱讀背面之注意事項再填寫本頁)
    L7
    L-8 經濟部中央標準局員工消費合作社印製
    L9 L10 本紙張尺度逋用中國國家揉準（CNS ) A4規格（210X297公釐） V A8 B8 C8 D8 申請專利範圍
    1:11
    1:12 (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 1:13 及醫藥上可接受之載體。 2. 根據申請專利範圍第1項之醫藥組合物，其包括 式I化合物，其中A為1: 1部份。 3. 根據申請專利範圍第1項之醫藥組合物，其包括 式I化合物，其中A為1: 5部份。 4. 根據申請專利範圍第1至3項中任一項之醫藥組 合物，其係經口投遞。 5. 根據申請專利範圍第1至3項中任一項之醫藥組 合物，其係經直腸投遞。 6. 根據申請專利範圍第1至3項中任一項之醫藥組 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 25»7公釐） >> Λ!/. 7
    ABCD 六、申請專利範圍 合物，其係經非腸道投遞。 7. 根據申請專利範圍第1至3項中任一項之醫藥组 合物，其係經靜脈投遞。 8. 根據申請專利範圍第1至3項中任一項之醫藥組 合物，其中該活性物質之投予量係為每日自1至 5 00毫克。 9. 根據申請專利範園第1至3項中任一項之醫藥組 合物，其中該活性物質之投予量係為自1 〇至2 5 0 毫克。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消费合作社印製 本紙張又度逋用中國國家梂準（CNS ) Α4規格（210Χ297公釐）
TW085106910A 1995-05-19 1996-06-08 New pharmacological use of AII-receptor antagonists TW473389B (en)

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SE9800550D0 (sv) * 1998-02-24 1998-02-24 A & Science Invest Ab A pharmaceutical preparation comprising an angiotensin II type 2 receptor agonist, and use thereof
ES2559766T3 (es) * 1998-05-18 2016-02-15 Takeda Pharmaceutical Company Limited Comprimidos disgregables en la boca
ES2237121T3 (es) * 1998-07-28 2005-07-16 Takeda Pharmaceutical Company Limited Preparacion solida disgregable rapidamente.
KR20030016229A (ko) 2000-02-18 2003-02-26 다케다 야쿠힌 고교 가부시키가이샤 ＴＮＦ-α 억제제
AU2005249794A1 (en) 2004-06-04 2005-12-15 Teva Pharmaceutical Industries, Ltd. Pharmaceutical composition containing irbesartan
KR20130074808A (ko) 2011-12-16 2013-07-05 한올바이오파마주식회사 스타틴계 지질저하제에 의한 근육계 부작용의 치료 또는 예방을 위한 로사르탄을 포함하는 약제학적 조성물
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CN104261284A (zh) * 2014-09-18 2015-01-07 中邮建技术有限公司 一种无线基站的天线吊装装置
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CN1093761C (zh) 2002-11-06
MX9708557A (es) 1997-12-31
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HUP9900227A3 (en) 2002-11-28
ZA963569B (en) 1996-11-19
US5900428A (en) 1999-05-04
NO975221D0 (no) 1997-11-13
KR19990014905A (ko) 1999-02-25
EE03666B1 (et) 2002-04-15
WO1996036336A1 (en) 1996-11-21
HUP9900227A2 (hu) 2000-03-28
NO975221L (no) 1997-11-13
EE9700309A (et) 1998-06-15
SE9501881D0 (sv) 1995-05-19
CZ345497A3 (cs) 1998-03-18
EP0830131A1 (en) 1998-03-25
AU706301B2 (en) 1999-06-10
SK151397A3 (en) 1998-08-05
BR9608407A (pt) 1998-12-29
JPH11505243A (ja) 1999-05-18
RU2194505C2 (ru) 2002-12-20
CN1184424A (zh) 1998-06-10
AU5784596A (en) 1996-11-29
IL118299A (en) 2000-07-26
IL118299A0 (en) 1996-09-12
CA2219395A1 (en) 1996-11-21
IS4597A (is) 1997-10-22
NZ308260A (en) 2000-12-22

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