TW513431B - 2-phenyl-substituted imidazotriazinones - Google Patents
2-phenyl-substituted imidazotriazinones Download PDFInfo
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- TW513431B TW513431B TW087118724A TW87118724A TW513431B TW 513431 B TW513431 B TW 513431B TW 087118724 A TW087118724 A TW 087118724A TW 87118724 A TW87118724 A TW 87118724A TW 513431 B TW513431 B TW 513431B
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- -1 2-phenyl-substituted imidazotriazinones Chemical class 0.000 title abstract description 20
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Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- C—CHEMISTRY; METALLURGY
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- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
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513431 A7 B7 五、發明說明(1 10 15 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 20 本發明係關於2-經苯基取代之咪唑並三畊酮類,關於 "製法及關於其作為藥品的用途,特別是作為代謝 性麟酸二脂酶之抑制劑。 a開w兒明書DE-28 11 780中記述咪嗤並三σ井類作為具 有解痙活性及對可促使腺菩單磷酸鹽循環代謝(cAMP_ PDEs,根據Beavo命名:pDE_ni及pde-w)的磷酸二脂 酶具抑制活性的支氣管擴張劑。但並未記述對於可促使鳥 糞核糖苷單磷酸鹽循環代謝(cGMP-PDEs,根據Beav〇及 Reifsnyder命名(藥理科學趨勢11,150-155,199〇)的碟 酸二脂酶具抑制活性。在芳基之2_位置上具有一胺磺醯基 的化合物並未被主張。再者,;PR 22 13 058,C:H 59 46 71,DE 22 55 172,DE 23 64 076 及 EP 〇〇〇 9384 中記述在 2-位置上不具有經取代之芳基的咪唑並三畊酮類化合物且 亦被涊定為具有cAMP-PDE抑制作用的支氣管擴張劑。 WO 94/28902中記述適用來治療陽萎的吡唑並嘧啶_ 類。 根據本發明之化合物對於促使鳥糞核糖苷3,,5f-單碟 酸鹽循環產生代謝變化之任一種磷酸二脂酶為有效的抑制 劑。根據Bearo及Reifsnyder命名法(藥理科學趨勢,u 150-155,1990),這些為鱗酸二脂酶異酶PDE-I,pDLjj 及 PDE-V)。 cGMP濃度的提昇可導致有利的抗凝聚,抗血栓塞, -------------------^--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 513431 A7 _____ B7 五、發明說明(2) 抗增生,抗血管痙攣,血管擴張的,利鈉尿的及利尿的效 果。它可影響灰管及心臟收縮,脈博及心臟傳導上短期或 長期的調郎(J.C. Stoclet,T. Keravis,N· Komas 及。· Kugnier,Exp· 〇pin· invest· Drugs (1995),4(11),1081-5 1100)。 因此,本發明係關於表A中所列之化合物
表A
4- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 513431 A7 B7 五、發明說明( ο 11
5 1A 經濟部智慧財產局員工消費合作社印製 20
------------•裝--------訂---------SI. (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431 A7 B7 五、發明說明(
ο IX
5 1X 經濟部智慧財產局員工消費合作社印製 20
6 (請先閱讀背面之注咅?事項再填寫本頁) · 11-----訂---- SI, 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(
15 及其鹽。於本發明說明書中,生理上可接受之鹽類較 佳。 生理上可接受之鹽類可為根據本發明之化合物與無機 或有機酸之鹽類。宜為與無機酸之鹽類,例如氫氯酸,氫 20 溴酸,磷酸或硫酸,或為與有機羧酸或磺酸之鹽類,例如 醋酸,順式丁烯二酸,反式丁烯二酸,蘋果酸,檸檬酸, 酒石酸,乳酸,苯甲酸,或甲烷磺酸,乙烷磺酸,苯基磺 酸,甲苯續酸或萘二績酸。 生理上可接受之鹽類亦可為根據本發明之化合物之金 -7- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ------------4P 裝—-----訂---------^一^"· ' rr-/ (請先閱讀背面之注音?事項再填寫本頁) 513431 經濟部智慧財產局員工消費合作社印制衣 A7 B7 五、發明說明(6 ) 屬鹽或銨鹽。特佳者為例如納,鉀,鎮或斜鹽,以及由氨 或有機胺,例如,乙胺,二或三乙胺,二或三乙醇胺,二 環己基胺,二甲基胺基乙醇,精胺酸,離胺酸,伸乙基二 胺或2_苯基乙基胺衍生出之銨鹽。 5 根據本發明之化合物,特別是鹽類,亦可以水合物形 式存在。於本發明說明書中,水合物係指在結晶中含有水 分的化合物。此等化合物可含有一或多,典型地,含1至 5倍當量之水。水合物可藉著例如由水中或由一含水之溶 劑中將所提及之化合物結晶出來而製得。 10 根據本發明之鹽類或水合物為例如下述化合物:
表B
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -----------#裝.:-------訂---------^·— (請先閱讀背面之注意事項再填寫本頁) 川431
、發明說明( 5
ο IX
5 1X
-------------4P 裝--------訂--------- (請先閱讀背面之注咅?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 20 一像及鏡像(鏡像異構物^或其非像7物形式存在,其達 物)。本發明係關於鏡像異構物,像(非鏡像異桶 於彼等之各別混合物。消旋型式可如構物,亦剌 知方法分為立體異構上岣一之組成份。、兄像異構物,以£ 本發明亦提供-種製備 ς 其特徵在於 Θ之化口物的方法, 呈 本紙張尺度賴+關家標準(CNS)A4規格(210 X 297^7 513431 A7 B7 五、發明說明(8 ) 首先將式(II)化合物 10 15 Λγ〇^
(ID 其中 R1代表曱基或乙基及R2代表丙基, 且 L 代表至多具4個碳原子之直鏈或分支烷基 與式(m)化合物 νη2 R5 ΝΗ
ΝΗ xHCI (III) (請先閱讀背面之注音?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 20 25 其中 R5代表乙氧基, 於一兩步驟反應中,在系統乙醇及三氯氧化磷/二氯 乙烷中轉化為式(IV)化合物 其中 R5
Ο R1
(IV) -10· 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431 A7 B7 五、發明說明( R1,R2及R5定義如前, 將此等化合物於下個步驟中與氣磺酸進行反應,可得 到式(V)化合物
(V) 10 其中 R1,R2及R5定義如前, 隶後將此等化合物與對應胺於惰性溶劑中進行反應 根據本發明之製法可用下列製程為例而闡明:
Η Ο I C2H5、〇
NH
NH
HCI 1. ethanol 2. phosphorus oxytrichloride / dichloroethane ------------裝--------訂---------^91 (請先閱讀背面之注咅?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 25
-11- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 經濟部智慧財產局員工消費合作社印製 513431 A7 B7 五、發明說明(10 )
適用於各個步驟中之溶劑為在反應條件下不會改變的 習用有機溶劑。較佳者包括醚類,例如二乙醚、二噚烷、 15 四氫呋喃、乙二醇二曱醚,或烴類,例如苯、甲苯、二甲 苯、己烷、環己烷或礦物油餾份,或鹵化烴類,例如二氯 甲烷,三氣甲烷,四氯化碳,二氯乙烷,三氯乙烯或氣 苯,或醋酸乙酯,二甲基甲醯胺、六次甲基磷酸三醯胺、 乙腈、丙酮、二曱基乙烷或吡啶。亦可使用上述溶濟之混 20 合物。最好在第一步驟中使用乙醇且在第二步驟中使用二 氯乙烧。 反應溫度通常在一相當大的範圍間變化。通常,反應 係在-20°C至200°C範圍間進行,宜在〇°C至70°C範圍間進 行。 -12- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 513431 A7 B7 五、發明說明(〇 經濟部.智慧財產局員工消費合作社印製 根據本發明之製法步驟通常在大氣壓力下進行。然 而,其亦可在超計大氣壓力下或在減壓下進行(例如在0.5 至5巴範圍間)。 製得(V)式化合物的反應係在〇它至室溫之溫度時且在 5 大氣壓下進行。 與對應胺類的反應係在上述任一種_化烴類,例如二 氣甲烷中進行。 反應溫度通常在一相當大的範圍間變化。通常,反應 係在-2(TC至2〇〇°C範圍間進行,宜在(TC至室溫範圍間^ 10 行。 反應通常在大氣壓力下進行。然而,其亦可在赶古十大 氣壓力下或在減壓下進行(例如在0.5至5巴範圍間)。 一些式(II)化合物為已知,或為新穎,且其可藉著將 式(VII)化合物 9 15 R2-CO-T 其中 R2定義如前, 且 τ 代表鹵素,宜為氯, 20 首先與式(VIII)化合物 (VII) ------------------ —訂------ (請先閱讀背面之注意事項再填寫本頁) 义
HOX NH (VIII) 其中 -13- 513431 Α7 Β7 五、發明說明(
Ri定義如前, 在惰性溶劑中進行反應,如果適當,可在一驗及三甲基甲 石夕烧基氣化物存在之下進行反應,轉化為式(IX)化合物
X R2- CO.NH C〇2H (IX) 其中 R1及R2各自定義如前 且最後與式(X)化合物 10
α 人 C02L (X) 經濟部,智慧財產局員工消費合作社印製 其中’ L定義如前, 在惰性溶劑中進行反應,如果適當,可在一驗存在之下進 15 行反應而製得。 各個反應步驟中適宜的溶劑為在反應條件下不會改變 的習用有機溶劑。較佳者包括醚類,例如二乙醚、二σ号 烧、四氫呋喃、乙二醇二曱醚,或烴類,例如,苯、曱 苯、二甲苯、己烷、環己烷或礦物油餾份,或鹵化烴類, 2〇 例如二氣甲烷、三氣曱烷、四氯化碳、二氯乙烯、三氣乙 烯或氣笨,或酯酸乙酯、二甲基甲醯胺、六次甲基鱗酸三 醯胺、乙腈、丙酮、二甲氧基乙炫或吡淀。亦可使用上述 溶劑之混合物。最好在第一步驟中使用二氣甲烷且在第二 步驟中使用四氫呋喃及吡啶之混合物。 -14- -------------------訂--------- (請先閱讀背面之注咅?事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431 A7 B7 經濟部.智慧財產局員工消費合作社印製 五、發明說明( k宜的鹼通常為鹼金屬氫化物或鹼金屬醇鹽類,例 如’氫化納或第三丁醇鉀,或環胺類,例如六氣咐啶、吼 啶、二甲基胺基吼唆,或Cl_c4_燒基胺類,例如三乙胺。 宜為二乙胺、吡啶及/或二甲基胺基吡啶。 5 通常驗的使用量為於每—情形中每莫耳式(X)化合 物使用1莫耳至4莫耳,宜為丨.2莫耳至3莫耳。 口 反應溫度通常在-相當大的範圍間變化。通常,反應 係在-20°C至20(TC範圍間進行,宜在吖至1〇吖範圍^ 進行。 0 式(VII),(VIII),(IX)及(X)化合物本身為已知,或它們可 藉習用方法製得。 式(m)化合物可藉著將式(XI)化合物
(XI) 其中 R5定義如前, 與氯化銨在甲苯中且於三甲基銨存在之下時在己烷中,於 -20C至室溫的温度範圍間,較好於〇。0及大氣壓力下進行 20反應,且將製得之脎,如果適當於原處,與水合肼進行反 應而製得。 式(XI)化合物本身為已知,或它們可藉習用方法製 得。 一些式(IV)化合物為已知,或為新穎,此時其可藉著 -15- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 513431 經濟部智慧財產局員工消費合作社印製 A7 ____B7_^__ 五、發明說明(14 ) 已知方法製得[參考David R. Morshall,化學與工業,1983 年 5 月 2 日,331-335]。 式(V)化合物本身為已知,然而,它們可根據文獻 Orgonikum,VEB Deutscher Verlag der Wissenschaften, 5 Berlin 1974,第 338-339 頁而製得。 根據本發明之式(I)化合物具有一不可預期得知之有效 的藥理活性範圍。 它們可抑制一或多種cGMP-代謝性峨酸二脂酶(pde I,PDE II及PDE V)。如此造成cGMP之增加。該填酸二 10 脂酶於不同細胞,組織及器官之差別性表現,和這些酵素 的差別性細胞下定位,以及根據本發明之選擇性抑制劑, 使得可以選擇地注意各種cGMP-調節過程。 再者,根據本發明之化合物可強化一些物質,例如, EDRF (内皮導引鬆弛因子),ANP (前房促進鈉尿胜 15 肽),硝基血管擴張劑及所有以不同於麟酸二脂酶抑制劑 之方式增加cGMP濃度之所有物質的活性。 因此,它們可以應用在醫藥上以治療心血管疾病,例 如,用來治療高血壓、神經性血壓過高、穩定性及不穩定 性心絞痛、周邊及心臟血管疾病、心律不整,用來治療血 20 栓性栓塞疾病及局部缺血,例如心肌梗塞、中風、一過性 血管缺血發作、心絞痛、周邊循環障礙、預防血栓溶解治 療,經由表皮穿過空腔之血管形成術(PTA),經由表皮 穿過空腔之冠狀動脈形成術(PTCA)及繞道術後之再狹 窄。再者,它們於腦血管疾病上亦功能顯著。由於其對於 -16- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注音?事項再填寫本頁) II---------si. A7
513431 五、發明說明(15) 平滑肌之鬆弛作用,它們可用來治療泌尿生殖系統的疾 病,例如,前列腺肥大,失禁且特別可用來治療勃起功能 不良及女性之性功能障礙。 磷酸二脂酶(PDEs)之活性 5 cGMP·刺激性PDE Π,cGMP-抑制性pDE瓜及 cGMP-特定PDE IV可由豬或牛的心肌中分離出來。Ca2+_ 鈣調節素-刺激性PDE I係由豬主動脈,豬腦或較好由牛 主動脈中分離出來。cGMP-特定PDE V可由猪小腸,豬主 動脈,人類血小板,且宜由豬主動脈中得到。純化係藉降 10 離子交換色層分離法於Mono Q® Pharmacia上進行,主要 是依循M. Hoey及Miles D. Housley,生化藥理學,第4〇 冊,193-202(1990)及C· Lugman等,生化藥理學,第35 冊,1743-1751(1986)中之方法進行。 酵素活性係用100毫升的測試混合物檢測,其中 15 20mM 三/HC1-緩衝液 ρΗ=7·5 含有 5mM MgCl2,〇·ι 毫克 /毫升牛血清蛋白及800Bq[3H]cAMP或[3H]cGMP。議題 中核苷酸的最終濃度為1〇_6莫耳/升。該反應係藉添加酵 素而起動且該酵素的添加量係使得於3 0分鐘培育期間有 大約50%的物質被轉化。為了測試cGMP-刺激性pDE 20 Π,[3H]cAMP係用作為作用物質且將10_6莫耳/升未標 記cGMP加到混合物中。為了測試Ca2+-鈣調節素-依賴性 PDE I,將1 mM CaCl]及〇· 1 mM約調節素添加到反應混合 物中。將反應混合物藉添加100毫升含ImM cAMP及 -17- -------------------丨訂--------- (請先閱讀背面之注咅?事項再填寫本頁) 經濟部智慧財產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(210 X 297公釐) 513431 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(Μ) hnM AMP之乙腈而驟冷。將⑽毫升反應混合物藉 HPLC分離,且將解離之產物於線上用連續閃爍記數器予 以定量測定。該測定之物質濃度係為反應迷率降低5〇%之 濃度。此外’ Amersham Life Sci⑽中之“磷酸二脂酶 5細cAMP_SPA酵素分析’,* “魏二月旨酶細GMp_ SPA酵素分析”係用來作檢測。該檢__製造者的摘 要記錄進行m収PDE π之活性,係制細cAMp SPA刀析’且係將1〇-6M之eGMp加到反應混合物中以活 化酵素。為了測量PDE I,係將10_7]y[鈣調節素及ImM 10之CaCl2加到反應混合物中。PDE V係用[3h]cGMP SPA 分析來測量。 磷酸二脂酶於體外之抑制性 表1 --------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 實例編號 PDEI ^5〇[ηΜ] *--- PDEII IC5〇[nM] PDE V 1 300 >1000 2 2 200 >1000 2 3 100 —-—--- >1000 1 4 200 >1000 3 5 100 >1000 4 -18- 本紙張尺度適用中國標準(CNS)A4 ϋ x 297公爱) 513431 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(17) 6 800 >1000 4 8 300 >1000 10 9 50 >1000 3 掌備實例 原則上,此類型之一或多種碟酸二脂酶的抑制性會造 成cGMP濃度的增加。因此,在所有因為cGMP濃度增加 5 被認為有利之治療中,該化合物倍受注意。 心血管效應係用SH-鼠及狗進行研究。該物質係經靜 脈或口服給藥。 勃起刺激作用係用 >月醒的兔子進行研究〔Naganuma H,Egashira T,Fuji J·臨床及實驗之藥理學及生理學20, 10 177-183(1"3)〕。該物質係經靜脈,口服或神經腸胃給 藥。 該新穎活性化合物及其生理上可接受之鹽類(例如, 氫氯化物,順式丁浠二酸鹽或反式丁稀二酸鹽)可藉已知 方式用惰性無毒性之製藥上適宜的賦形劑或溶劑而轉化成 15習用配方形式,例如,錠劑,包膜錠劑,丸劑,粒劑,氣 溶膠’糖m,乳驗,懸雜及麵。於此情況,該治療 上具活性之化合物的濃度於任何情況下雜近G.5至9〇% 全部混合物之重量含量使得足以達到所指明之劑量範圍。 -19- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐 ----------1 --------^--------- (請先閱讀背面之注意事項再填寫本頁) 513431 經濟部智慧財產局員工消費合作社印制衣 A7 五、發明說明(18) 該配方形式之配製係藉著例如用溶劑及/或賦形劑, 如果適當,可用乳化劑及/或分散劑來延展活性化合物, 如果所用的稀釋劑為水,可選擇地使用’例如有機溶劑作 為輔助溶劑。 5 、給藥係依習用方式進行,宜為口服,經皮膚或非經腸 月,例如經舌吸收,經口頰,經靜脈,經鼻,經直腸或吸 入給藥。 使用於人類時,如為口服給藥,由〇 〇〇1至5〇毫克/ 公斤之給藥劑量為好的應用例,宜為〇〇1毫克/公斤_2〇毫 10克/公斤。如為非經腸胃給藥,例如,經由鼻部分泌黏液 的薄膜,給口頰或經由吸入給藥,0.001毫克/公斤_〇·5毫 克/公斤的使用劑量為好的應用例。 毛 儘管如此,如果適當,也許需要放棄所提之劑量,亦 即需根據體重或給藥路徑之形式,根據對於藥劑的各別回 15應,根據其配方方式及給藥發生的時間及間隔。因此,於 某些情況下,亦適合採用較上述最小劑量為小之量,而於 其他情況下,亦可超過上述最大劑量。當給予相對較大之 劑量時,將之分成數個各別劑量於一天的過程給藥亦屬適 當。 20 根據本發明之化合物亦適用作為獸醫用藥。當作為獸 醫用藥時該化合物或其無毒性鹽類可根據一般獸醫慣例以 一適合配方給藥。依據所治療動物之種類,獸醫師 使用性質及劑量。 /、疋 -20- ϋ氏張尺度適用家標準(CNS)A4規格(21Q χ 297公羞)' ------— ---------------------訂--------- (請先閱讀背面之注咅?事項再填寫本頁) 513431 Α7 Β7 經濟部智慧財產局員工消費合作社印製
五、發明說明(V 起始物質
實例1 A 2-丁醯胺基丙酸
將22·27克(250毫莫耳沿丄-丙氨酸及55·66克(55〇毫 10莫耳)二乙胺溶解於25〇毫升二氯甲烧中,並將溶液冷却 到〇°C。將说75克(55〇毫莫耳)三甲基甲石夕絲氯逐滴加 入,並將溶液於室溫攪拌丨小時且於4〇t攪拌丨小時。冷 却到-l〇°C後逐滴加入26.64克(25〇毫莫耳)丁酿氯,並將 產生的混合物於-1(TC攪拌2小時且於室溫攪拌丨小時。 15 財冷㈣,们25毫升水逐滴加人並將反應混合物 於至/皿攪拌I5分鐘。將水相蒸發至乾,將殘質用丙嗣滴 定並將母液用空吸法過渡。將溶劑移除並將殘質予以色層 刀離將產生的產物洛解於3N氫氧化納水溶液中並將產 生之溶液蒸發至乾。將殘質置於濃鹽酸巾並再次蒸發至 20乾。將殘質與丙酮一起櫈拌,用空吸法將沈殿固體過滤出 來並將溶劑於減壓下移除得到28·2克(71%)枯稠油,一些 時間後會呈結晶。 -21- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -----------------—^---------^__w— (請先閱讀背面之注意事項再填寫本頁) 50431 A7 B7 五、發明說明()〇
200 MHz iH-NMR (DMS0-d6): 0.84, t,3H; 1.22, d,3H; 1.50, hex,2H; 2.07, t,2H; 4.20, quin·,1H; 8.09, d,1R (請先閱讀背面之注意事項再填寫本頁)
實例2A 2-乙氧基苯曱腈
10 將25克(210毫莫耳)2-羥基苯甲腈與87克碳酸鉀及 34.3克(314.8毫莫耳)乙基溴於500毫升丙酮中迴流過夜。 將固體過濾出來,將溶劑於減壓下移除並將殘質於減壓下 蒸餾。得到30.0克(97%)無色液體。
200 MHz iH-NMR (DMSO-d6): 1.48, t,3H; 4.15, quart.,2H; 15 6.99, dt,2H; 7.51,dt,2R
實例3A 2·乙氧基苯甲脎氫氣化物 經濟部智慧財產局員工消費合作社印製 20
-22- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 5i13431 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(2)1 將21.4克(400毫莫耳)氯化銨懸浮於375毫升甲苯 中,並將懸浮液冷卻至0°C。將200毫升含於己烷之2M 三甲基銨溶液逐滴加入,並將混合物於室溫攪拌直到氣體 停止放出。添加29.44克(200毫莫耳)2-乙氧基苯甲腈後, 5 將反應混合物於80°C(浴)攪拌過夜。 用冰冷卻時,將冷卻的反應混合物加至一含1〇〇克石夕 膠及950毫升氣仿之懸浮液中,並將混合物於室溫授拌3〇 分鐘。將混合物用空吸法過濾出來,並將過濾殘質用等量 之曱醇清洗。將母液濃縮,將產生的殘質與含二氯甲烷及 10甲醇(9:1)之混合物一起攪拌,將固體用於空吸法過濾出來 並將母液濃縮。得到30.4克(76%)無色固體。 200 MHz h-NMR (DMSO-d6): 1.36, t,3H; 4.12, quart·,2H; 7.10, t,1H; 7.21,d,1H; 7.52, m,2H; 9.30, s,broad, 4H_
實例4A 15 2-(2-乙氧基-苯基)_5-曱基_7-丙基-3H-咪唑並[5,l-f][l,2,4] 三畊-4-酮
將7.16克(45毫莫耳)2-丁醯胺基-丙酸及10.67克比啶 -23- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -----------•裝--------訂.-------- (請先閱讀背面之注咅?事項再填寫本頁) 513431 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(22) 溶解於45毫升THF中且加入一刮勺尖DMAP,加熱至迴 流。將12.29克(90毫莫耳)乙基乙二醯氯逐滴緩緩加入, 並將反應混合物迴流3小時。將混合物倒入冰水中並用醋 酸乙酯萃取三次且將有機相於硫酸納上乾燥並用一旋轉蒸 5發器濃縮。將殘質置於15毫升乙醇中並與2.15克碳酸氫 鈉一起迴流2·5小時。將冷卻的溶液過濾。 用冰冷卻時,將2.25克(45毫莫耳)水合肼逐滴加到一 含有9.03克(45毫莫耳)2-乙氧基苄脒氫氯化物於45毫升 乙醇之溶液中,並將產生的懸浮液於室溫再攪拌1〇分 10 鐘。將上述乙醇溶液加到這個反應混合物中,並將混合物 於70 C浴溫中擾拌4小時。過渡後,將混合物濃縮,將殘 質在二氯甲烷及水間分佈,將有機相於硫酸鈉上乾燥並將 溶劑於減壓下移除。 將此殘質溶解於60毫升1,2-二氯乙烷中並加入7.5毫 15升鱗醯氯後,迴流2小時。將混合物用二氯甲烧稀釋並藉 加入碳酸氫鈉溶液及固態碳酸氫鈉而中和。將有機相乾 燥,並將溶劑於減壓下移除。用醋酸乙酯進行色層分離並 結晶化,得到4.00克(28〇/0)無色固體,Rf=〇 42 (二氯曱烷 / 甲醇 95:5)。 20 200 MHz k-NMR (CDC13): 1.02, t,3H; 1.56, t,3H; 1.89, hex,2H; 2·67, s,3H; 3.00, t,2H; 4.26, quart” 2H; 7.05, m, 2H; 7.50, dt,1H; 8.17, dd,1H; 10.00, s,1H.
實例5A -24- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -----------4|^農--------訂---------^9— (請先閱讀背面之注音?事項再填寫本頁) A7 A7 10 五、發明說明(>3 4-乙氧基-3-(5甲基_4_酮基_7_丙基-3,4-二氫_咪唑並[5,l f][l,2,4]三畊-2-基)苯磺醯氣 ’
於〇°C時,將2.00克(6·4毫莫耳)2_(2-乙氧基_苯基)j 甲基-7-丙基_3H-咪唑並[5,1 -f] [ 1,2,4]三畊-4-酮緩鍰加入到 3.83毫升氣磺酸中。於室溫時,將反應混合物攪拌過夜, 且然後倒至冰水中並用二氣曱烷萃取。得到2·40克(91%) 無色泡珠。 200 MHz h-NMR (CDC13): 1.03, t,3Η; 1.61,t,2Η; 1.92, hex,2H; 2.67, s,3H; 3.10, t,2H; 4.42, quart·,2H; 7.27, t,1H; 15 8.20, dd,1H; 8.67, d,1H; 10.18, s,1H.
實例6A (4-六氫吡啶曱基)-膦酸二乙齡 -------------------^---------^9. (請先閱讀背面之注音?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 }〇C2H5 '、oc2h5 20 -25- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431
10 首先將2.u克(528毫莫耳)6〇%強度的氮化納 宅升無水四氫吱喃中’且將15.7克(52 8毫莫耳)甲燒〇 酸二乙醋逐滴加入。將混合物於室溫再授摔3〇分名=,且 然後加入HM克(52·8毫莫耳㈣基冰六氫吼销。將混 合物於室溫授拌i小時且於週流中搜拌!小時,濃縮之, 與水摻和並用二氯曱烧萃取三次,且將有機相於硫酸納上 乾燥並濃縮。於室溫及3巴時,將殘質於5〇毫升乙醇中 在1.7克10%鈀-炭上氫化。將催化劑用空吸法過濾出來旅 將濾出液濃縮。 產量:12.5克(理論值之loo%) 400 MHz,kNMR (CDC13): 1.13, m,2H; h32, t,6H; 169, dd,2H; 1.74-1.95, m,4H; 2.62, dt,2H; 3.05, m,2H; 4.1, ni, 4H. 製備實例 15 實例1 2-[2-乙氧基-5-(4-曱基-六氫吡畊小石黃醯基)苯基]-5-甲基 丙基-3H-咪唑並[5,l_f][l,2,4]三畊-4-酮 -------裝.!丨丨丨訂·丨! -----*^1^· (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 20
本紙張尺度適用中國國家標準(CNS)A4規格(21〇 X 297公爱) ^431 Α7 Β7 10 五、發明說明(类 將1.23克(3宅莫耳)4-乙氧基_3_ (5-甲基-4-酮基-7-丙基-3,4-二氫-咪唑並[5,14[1,2,4]三畊_2-基)_苯磺醯氣溶 解於40耄升二氣曱院中並冷却到〇。〇。加入1到勺尖的 DMAP後,加入0.90克(9·〇〇毫莫耳)N_甲基六氫吡畊,並 將反應混合物於室溫攪拌過夜。將混合物用二氣甲烷稀 釋,將有機相用水清洗兩次並於硫酸鈉上乾燥且將溶劑於 減壓下移除。由乙醚中結晶出來得到1β25 1 (88%) 1色 固體。 200 MHz 1H-NMR (CDC13): 1·〇1,t5 3H; I.59, t? 3H; 1 88 hex5 2H; 2.29? s5 3H; 2.51, m5 4H; 2.63, s5 3H; 3.00, 2H;? 3.08, m,4H; 4.33, quart” 2H; 7.17, d,1H; 7.88, dd,1H; Μ' d,9.75, s· 1H. ’ ’ 實例2 2_[2-乙氧基-5-(4-乙基六氫吡畊-l-磺醯基)笨基]_5_甲基_7· 15 丙基-3Η-咪唑並[5,l-f][l,2,4]三畊_4-酮
-----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 513431 A7 B7 五、發明說明(l\ 將470毫克(ι·14毫莫耳)φ_乙氧基_3_(5_甲基_4_酮基_7_ 丙基_3,4-二氫-味唑並[5,1_!][1,2,4]三畊_2-基)_苯磺醯氯溶 解於20毫升二氯甲烷中並冷却到〇°C。加39〇毫克(3芯 毫莫耳)N_乙基六氫吡啡加入,並將反應混合物於室溫 5拌過夜。將混合物用二氯甲烧稀釋,將有機相用水清=免 次並於硫酸鈉上乾燥,且將溶劑於減壓下移除。由乙鍵Z 結晶得到37〇毫克(66%)無色固體。 ~ ' 400 MHz 1H-NMR (CDCI3): 1.01, t, 3H; 1.59, t, 3H; 1-88 hex,2H; 2.42, quart” 2H; 2.56, m,4H; 2.63, s,3H; 3·〇〇 t’ 10 2H; 3.10, m,4H; 4.33, quart” 2H; 7.17, d,1H; 7.88, dd,1H•’ 8.44, d,1H; 9.75, s,1Η· ’ 實例3 2-[2-乙氧基-5-(4-羥基-六氫吡畊_;μ磺醯基)苯基]_5_曱基心 丙基-3H-咪唑並[5,1_幻[1,2,4]三畊-4_酮 —----------装 -------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 20
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431 A7 B7 五、發明說明(2) 用相同方法,以531毫克(1.29毫莫耳)4-乙氧基-3-(5-甲基-4_酮基-7-丙基-3,4-二氫-咪唑並[5,l-f][l,2,4]三畊-2-基)-苯磺醯氯及393毫克(3.88毫莫耳)4-羥基六氫吡畊開 始,可得到400毫克(64%)2-[2-乙氧基-5-(4-羥基-六氳吡畊 5 -1-磺醯基)-苯基>5-甲基-7-丙基-3H-咪唑並[5,1-幻[1,2,4]三 口井-4-嗣。 200 MHz 1H-NMR (DMSO-d6): 0.941,t,3H; 1.32, t,3H; 1.45, m,2H; 1.71,m,4H; 2.48,s,3H; 2.82, m,4H; 3.11,m, 2H; 3.55, m,1H; 4.20, quart·,2H; 4.72, d,1H,7·39, d,1H; 10 7.87, m,2H; 11.70, s,1H. 實例4 2-{2-乙氧基-5-[4-(2-經基-乙基)-六氮17比17井-1-績酿基]苯基}-5-甲基-7-丙基-3H-咪唑並[5,1-:{][1,2,4]三畊-4-酮 (請先閱讀背面之注音?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製
-29- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431
五、發明說明(J 用相同方法,以川毫克(1亳莫耳)‘乙氧基_3_(5_ 甲基-4-酮基_7_丙基_3,4_二氫-咪唾並[5, j [工,2,4]三啡-2_ 基)·苯俩氯及別毫克(3 $莫耳M名基乙基六氫^井開 始,可得到380毫克(75%)2-{2_乙氧基·5卜(2_經基_乙 5基)-六氫吡畊-1·磺醯基]-苯基}_5_甲基-7-丙基-3Η-咪唑並 [5,1_幻[1,2,4]三畊-4__。
Rr0·198(二氯甲烷/ 甲醇=95··5) 200 MHz h-NMR (CDC13): 1.02, t,3Η; 1.61,t,3Η; 1.87, hex,3H; 2.60, m,7H; 3.00, t,2H; 3.10, m,4H; 3.60, t,2H; 10 4·36, quart” 2H; 7·18, d,1H,7.89, dd,1H,8.47, d,1H,9.71, s. 1H. 實例5 裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 20
ο 3 N,N-二乙基-4-乙氧基_3-(5-甲基-4-酮基-7-丙基-3,4-二氫-咪 唑並[5,l-f][l,2,4]三畊_2_基)苯磺醯胺
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431 A7 B7 五、發明說明(y 用相同方法,以400毫克(0.97毫莫耳)4-乙氧基-3-(5_甲基-4-酮基-7-丙基-3,4-二氫-口米唑並[5,l-f][i,2,4]三畊-2·基)-苯磺醯氣及210毫克(2.92毫莫耳)二乙胺開始, 可得到398毫克(89%) N,N-二乙基-4_乙氧基-3-(5-甲基-5 4_酮基·7_丙基_3,4_二氫·咪唑並[5,1-£][1,2,4]三畊_2-基)苯磺 醯胺。 R广0.49(二氯甲烷/甲醇=20··1) 200 MHz h-NMR (CDC13): 1.02, t,3Η; 1.20, t,6Η; 1.49, t, 1.61,t,3H; 1.88,sex·,2H; 2.30,s,broad,1H; 2.62,s,3H; 10 2.99, t,2H; 3.32, m,4H; 3.78, t,2H; 3.80, m,2H; 4.37, quart·, 2H; 7.15, d,1H; 7.98, dd,1H; 8.56, d,1H; 9.70, s,1H. 實例6 2-[2-乙氧基-5-(4-甲基六氫吡畊-1-磺醯基)-苯基]-5-乙基-7-丙基-3H_咪唑並[5,1-]〇[1,2,4]三畊-4-酮 (請先閱讀背面之注意事項再填寫本頁) f裝--------訂---- 經濟部智慧財產局員工消費合作社印製 20
ch3 -31- 拳 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 經濟部智慧財產局員工消費合作社印製 513431 A7 B7 五、發明說明(3G) 用相同方法,以640毫克(1_50毫莫耳)4-乙氧基-3-(5-乙基-4-酮基-7-丙基-3,4-二氫-咪唑並[5,1-幻[1,2,4]三畊-2-基)-苯磺醯氯及450毫克(4.5毫莫耳)4-羥基乙基六氫吡畊 開始,可得到495毫克(66%)2-[2-乙氧基-5-(4-甲基六氫吡 5 畊-1-磺醯基)-苯基]-5-乙基-7-丙基-3H-咪唑並[1,2,4] 三口井-4-晒。
Rf-0.30(二氯曱烷 / 甲醇=19: 1) 200 MHz iH-NMR (CDC13): 1.01,t,3H; 1.35, t,3H; 1.61,t, 3H; 1.89, sex·,2H; 2.31,s,3H; 2.53, m,4H; 3.05, m,8H; 10 4.35, quart·,2H; 7.17, d,1H; 7.89, dd,1H; 8.48, d,1H; 9.65, s? 1H. 下述磺醯胺藉由自動化平行合成及使用下述三種標準 程序之一自4-乙乳基-3-(5-甲基-4-嗣基-7 -丙基-3,4-二鼠_ [5,1-幻[1,2,4]三畊-2-基)-苯磺醯氯及適當胺製得。 15 終產物之純度以HPLC測量,及藉由LC-MS描述其特 徵。所要化合物之含量根據HPLC-MS在表内「HPLC」一 欄中以百分比表示。標準程序A使用具有酸性官能性之 胺,標準程序B使用具有中性官能性之胺,標準程序C 使用具有額外之鹼性官能性之胺。 20 下述結構式中,某些情形下並未顯示氫原子。因此具 有自由價之氮原子被理解為-NH-基。 標準程序A:具有酸性官能性之胺的反應 -32- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -----------裝--------訂--------- (請先閱讀背面之注音?事項再填寫本頁) 513431 A7 B7 五、發明說明(31) 先加入0·05毫莫耳之胺,0.042毫莫耳之磺醯氯及〇1〇毫 莫耳Na2C〇3,以手操作吸取加入0.5毫升THF/H20之混 合物。室溫下24小時後,混合物與〇·5毫升之1 μ H2S04 溶液混合並通過二段筒(500毫克溶離劑(上層)及5〇〇毫克 5 Sl〇2,移動相:乙酸乙酯)過濾。真空中濃縮濾液取得產 物。 遂孕程序B:具有中性官能性之胺的反應 先加入0.125毫莫耳之胺,再藉由合成器將〇〇3毫莫耳磺 δ&氣於1,2-一氣乙烧之溶液吸取加入。24小時後,混合物 10與0·5宅升之1 M H2S04溶液混合並通過二段筒(500毫克 洛離劑(上層)及500毫克Si02,移動相:乙酸乙酯)過濾。真 空中》辰縮滤、液取得產物。 具有鹼性官能性之胺的反應 先加入0·05毫莫耳之胺。再藉由合成器將0.038毫莫耳磺 15醯氯於1,2-二氣乙烧之溶液及〇·〇5毫莫耳三乙胺於l,2-二 氣乙烧之溶液吸取加入。24小時後,混合物先與3毫升飽 和之NaHC〇3溶液混合並使反應混合物通過二段筒過濾。 真空中濃縮濾液取得產物。 所有反應藉由薄層色層分析監控。若室溫下24小時後反 20應未完全,則再加熱混合物至60°C 12小時之後終止實 驗。 -33- 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 x 297公釐) (請先閱讀背面之注咅?事項再填寫本頁) _裝--------訂---- 參· 經濟部智慧財產局員工消費合作社印製 513431 A7 __B7 五、發明說明(32 ) 經濟部.智慧財產局員工消費合作社印製
-34- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 五、發明說明(y 10 9
\ /N、 / o=s=:o Η〆 A7 B7
0 N
477.5896 >95 478
、OH 實例10 2-[2-乙氧基-5-(4-乙基-六氫吡畊-磺醯基苯基]_5_甲基-7_丙基-3H-咪唑並[5,1-£][1,2,4]三畊-4-酮二氫氯化物 經濟部智慧財產局員工消費合作社印製 15
x2 HCI 將0.35克(0.712愛:莫耳)2-[2-乙氧基·5-(4-乙基-六氫吼啡-1-磺醯基)-苯基]-5_甲基-7-丙基-3Η-咪唑並[5,l-f][l,2,4] 三4-4-酮懸浮於8毫升乙醚中並將二氯甲烷加入直到 -35- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公爱) -----------裝--------訂--------- (請先閱讀背面之注音3事項再填寫本頁) 513431 A7 B7 五、發明說明(3) 形成一均勻相。將24毫升於乙醚之1M HC1溶液加入 且將混合物於室溫攪拌20分鐘並用於空吸法過濾出 來。可得到372毫克(99%)2-[2-乙氧基-5-(4-乙基-六氫 吡畊-1-磺醯基)-苯基]-5-甲基_7_丙基-3H-咪唑並[5,1-5 f][l,2,4]三畊-4-酮二氫氣化物。 200 MHz ^-NMR (DMSO-d6):0.96? t5 3H;1.22? t5 3H; 1.36, t,3H; 1.82,sex·,2H; 2.61,s,3H; 2_88, m,2H; 3.08, m,6H; 3.50, m,2H; 3.70, m,2H; 4.25,quart·,2H; 7.48, d, 1H; 7.95, m,2H; 11.42, s,1H; 12.45, s,1H· 10 實例11 2-[2-乙氧基-5-(4-乙基-六氮^比σ井-1 -石黃酿基)-苯基]-5-甲基-7-丙基_3Η-味σ坐並[5,1 -f][ 1,2,4]二。井-4-綱氮氯化物三水合物 15
Ή h3ct (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 20 25 如果來自實例19之自由態驗係由有機溶劑及稀釋含 水氫氣酸之混合物中結晶出來,可得到一氫氯化物三水合 物。 熔點:218°C -36- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 513431 A7 _B7 五、發明說明(35 ) 水含量:9·4%(Κ· Fischer) 氯含量:6.1% (請先閱讀背面之注音?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 3 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)
Claims (1)
- 513431 /:fc, π ,脅補充 ,.一一一一·申請專利範圍 專利申請案第87118724號 ROC Patent Appln. No. 87118724 修正之申請專利範圍中文本-附件(二) Amended Claims in Chinese - Enel. (ID (民國91年5月X7曰送呈) (Submitted on May x?, 2002) 1. 一種選自下表A之化合物: 表A : 經濟部智慧財產局員工消費合作社印製—-------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐)87407b 90. 11. 2,000 513431 A8 B8 C8 D8 六、申請專利範圍(CH2)2-〇H2 so I Μ本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐) 90. 11. 2,000 (請先閱讀背面之注意事項再填寫本頁) 513431 A8 B8 C8 D8 六、申請專利範圍 經濟部智慧財產局員工消費合作社印製—------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 90. 11. 2,000 513431 A8 B8 C8 D8六、申請專利範圍 Π及其生理上可接受之鹽類與水合物。 2·根據申請專利範圍第丨項之化合物,其具有下式 H3C 一^9 HIT^ CH.f〇2 hi CH,N i c2h5 3·根據申請專利範圍第i項之化合物,其具有下式 ----------------------訂---I-----線 C請先閱讀背面之注意事項再填寫本頁} 經濟部智慧財產局員工消費合作社印製-41 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 9〇· 11. 2,0〇〇 A8 B8 C8 D8 六、申請專利範圍 4. 根據申請專利範圍第1項之化合物,其具有下式+ 2x HCI ΜΝ 1 c2h5 5·根據申請專利範圍第1項之化合物,其具有下式--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) -------- 經濟部智慧財產局員工消費合作社印製 6· 一種如申請專利範圍第丨至5項中任一項之化合物, 其用於治療需抑制CGMP代謝性磷酸二酯_之疾病。 種製備如申請專利範圍第1至5項中任一項之化合 物的方法,其特徵在於 首先將式(II)化合物 -42 -(210 X 297 公釐) 90. 11. 2,000 513431 A8 B8 C8 D8R1 Ο V ψ2 R5 ΝΗ•ΝΗ xHCi 六、申請專利範圍 (II) 其中 R1代表曱基或乙基及R2代表丙基, 且 L代表至多具4個碳原子之直鏈或分支烷基 與式(Π)化合物 (ΠΙ) 其中 R5代表乙氧基, 於一兩步驟反應中,在系統乙醇及三氯氧化磷/二氯 乙烷中轉化為式(IV)化合物 ill —--------费.——trl---------線一 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 〇 D1其中 R1,R2及R5定義如前, -43 - sl (IV) 表紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 90. 11. 2,000 513431 A8 B8 C8 D8 D1六、申請專利範圍 將此等化合物於下個步驟中與氯磺酸進行反應,可得 到式(V)化合物 (V) 其中 R1,R2及R5定義如前, 最後將此等化合物與對應胺於惰性溶劑中進行反應。 8· —種用於治療需抑制cGMP代謝性磷酸二酯酶之醫藥 組成物,其含有至少一種如申請專利範圍第1至5項 中任一項之化合物以及藥理上可接受之調配劑。 9·如申請專利範圍第8項之醫藥組成物,其中該疾病為 心血管及腦血管疾病及/或泌尿生瘦道疾病。 10_如申請專利範圍第9項之醫藥組成物,其係用於治療 勃起障礙。 费--------訂---------線· (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -44 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 90. 11. 2,000
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