TW530048B - New hydroxyindoles, their use as inhibitors of phosphodiesterase 4 and processes for their preparation - Google Patents
New hydroxyindoles, their use as inhibitors of phosphodiesterase 4 and processes for their preparation Download PDFInfo
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- TW530048B TW530048B TW088106886A TW88106886A TW530048B TW 530048 B TW530048 B TW 530048B TW 088106886 A TW088106886 A TW 088106886A TW 88106886 A TW88106886 A TW 88106886A TW 530048 B TW530048 B TW 530048B
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- hydroxyindole
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Description
530048 A7 B7 五、發明説明(彳) 技術領域 本發明係關於通式1所示之經取代的經基问丨D朵類
經濟部智慧財產局員工消費合作社印製 彼之製備方法、含有彼等化合物之藥學組成物以及彼 等化合物(彼等爲磷酸二酯酶4之抑制劑)作爲用於治療 病症之活性化合物的用途,該病症係會被本發明之化合物 在免疫適格細胞(例如,巨噬細胞及淋巴細胞)內之抑制 磷酸二酯酶活性的作用所影響的病症。 先前技藝 傳送者對於細胞膜受體的活化作用導致所謂「第二信 使」系統的活化。腺嘌呤核苷酸環化酶自A Μ P及G Μ P 合成得活性環A Μ Ρ ( c A Μ Ρ )或環G μ Ρ ( c G Μ Ρ )。這會導致,例如,平滑肌細胞的鬆弛或是抑制炎性細 胞內介體的釋出或合成。該「第二信使」c AMP及 c G Μ P的破壞係由磷酸二酯酶(p d E )來進行的。到 目前爲止,已知有七群PDE酶(pDEi 一了),彼等 之不同處在於受質的特異性(c AMP、c GMP或二者 皆是:)以及彼等對於其他受質(例如,攜釣素)的依存關 係。此等同功酶在身體內各有不同的功能且在各別的細胞 (請先閱讀背面之注意事項再填頁) li- 、π 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) -4- 530048 Α7 Β7 經濟部智慧財產局員工消費合作社印製 五、發明説明(2 ) 種類內各有其不同的顯著程度(Beave JA,Conti M and Heaslip RJ, Multiple cyclic nucleotide phosphodiesterases, Mol. Pharmacol. 1 994,46: 399-405 ;Hall IP,Isoenzyme selective phosphodiesterase inhibitors; potential clinical use,Br· J· clin. Pharmacol. 1 993,35: 1-7 )。將各種不同 種類之P D E同功酶加以抑制,結果會在細胞內累積 c A Μ P或c G Μ P,因而在治療上有利用性(Torphy TJ, Livi GP, Christensen SB, Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6: 203-214 ) o 在對於過敏性炎症很重要的細胞(淋巴細胞、肥大細 胞、嗜伊紅性粒性細胞、巨噬細胞)中,佔優勢的P D E 同功酶爲類型 4 者(Torphy,JT. And Undem,B.J., Phosphodiesterase inhibitors: new opportunities for the treatment of asthma,Thorax 1991, 46: 512-523 )。因此, 藉由適當之抑制劑來抑制P D E 4被認爲是許多由過敏所 引發之病症治療的起點(Schudt Ch,Dent G,Rabe K, Phosphodiesterase Inhibitors, Academic Press London 1996 )° 磷酸二酯酶4抑制劑的重要性質之一係在於抑制腫瘤 壞死因子a ( T N F α )自炎性細胞釋出。T N F α爲一 重要的前炎性(pro-inflammatory )細胞激素(cytokine ) ,其會對於很多的生理過程造成影響。T N F α係由,例 如,經活化的巨噬細胞、經活化的Τ淋巴細胞、肥大細胞 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐)
-5- 530048 A7 B7 五、發明説明(3 ) 、嗜鹼細胞、纖維母細胞、內皮細胞及腦內的星形細胞釋 出。其對於嗜中性白血球、嗜伊紅細胞、纖維母細胞及內 皮細胞具有自體活化的作用,結果會導致各種破壞組織的 介體釋出。在單核白血球、巨噬細胞及T淋巴細胞中, T N F α會使得其他則炎性細胞激素(cytokine ),諸如 G Μ - C S F (粒性細胞一巨噬細胞菌落刺激因子)或間 白素- 8之製造增加。基於TN F α之促進炎症及分解代 謝的作用,其在很多病症中,諸如,氣道的炎症、關節的 炎症、內毒素休克、組織排斥、A I D S及其他許多免疫 病症,皆扮演主要的角色。因此,磷酸二酯酶4之抑制劑 亦適於治療此類與T N F α有關的病症。 慢性阻塞性肺病(C〇P D )在人口中流傳廣泛且在 經濟上亦極具重要性。因此,在已開發國家中,C〇P D 病症的花費佔所有疾病之費用的1 〇 — 1 5%,而且在美 國,在所有死亡原因中,有約2 5%係C0PD所造成的 (Norman P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 1 1 (7), 43 1 -437, 1 998 ) ,然而,病人在死亡時皆已超過5 5歲(Nolte D.: Chronische Bronchitis - eine Volkskrankheit multifaktorieller Genenese. Atemw. -Lungenkrkh. [Chronic bronchitis - a widespread disease of multifactorial origin] ,20(5),260-267,1 994 )。世界衛生組織(W H〇)預估 在未來的2 0年內,C〇PD將成爲第三大的死亡原因。 慢性阻塞性肺病(C 0 P D )綜合了慢性支氣管炎的 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) (請先閲讀背面之注意事項再填頁) 填 訂 經濟部智慧財產局員工消費合作社印製 -6 - 530048 A7 _B7___ 五、發明説明(4 ) 各種症狀,以及咳嗽與咳痰及肺功能之進行性且不可逆的 損害(呼氣特別會受到影響)等症狀.。該疾病的病程係偶 發的且常倂發細菌性感染(Rennard S.I.: COPD: Overview of definitions, Epidemiology,and factors influencing its development. Chest, 113(4) Supp·,235S-241S, 1 998 )。在 該疾病的病程中,肺功能會持續降低、肺氣腫漸增且病人 呼吸困難的現象明顯。此一疾病明顯地對於病人之生活品 質有負面的影響(呼吸困難,運動耐受力低)且會大大縮 短病人的平均壽命。除了環境因素之外,主要的危險因素 爲吸煙(Kummer F.: Asthma und COPD. Atemw. -Lungenkrkh. 20(5), 299-302, 1 994;Rennard S.I.: COPD: Overview of definitions, Epidemiology,and factors influencing its development. Chest, 113(4) Suppl.,235S-24 1S,1 99 8 ),因此,男人顯然較女人較常受到影響。然 而,由於生活習慣的改變以及吸煙人口的增加,在未來, 此一景象將會改變。 目前的治療僅針對於減輕症狀,並未針對原因地介入 該疾病的進展。使用長效性的A 2作用劑(例如,薩梅特 若〔salmeterol,4 —經基—α -(((6 — (4 —苯丁氧 基)己基)胺基)甲基)一 1,3 —苯并二甲醇〕)及可能 倂用之蠅蕈鹼功能拮抗物(例如,依普拉特羅平〔 ipratropium〕)可藉由擴大枝氣管而改善肺功能且正被固 定使用中(Norman P.: C〇PD: New developments and therapeutic opportunities, Drugs News Perspect. 11(7),431 本紙張尺度適用中國國家標準(cns ) A4規格(2iox297公釐) 一 (請先閱讀背面之注意事項再填頁) 訂 經濟部智慧財產局員工消費合作社印製 530048 經濟部智慧財產局員工消費合作社印製 A7 B7五、發明説明(5 ) -437,1 9998 )。在C〇P D此一事件中,細菌感染佔了大 部分,而該細菌感染須以抗生素來治療(Wilson R.: The role of infection in COPD, Chest, 113(4) Suppl., 242S-248S, 1 998; Brossman R.F.: The value of antibiotics and the outcomes of antibiotic therapy in exacerbations of C〇PD,Chest, 113(4) Suppl., 249S-25 5 S, 1 998 )。然而, 該疾病的治療係不能令人滿意的,尤其在肺功能持續降低 方面。能夠影響炎性介體、蛋白酶或黏連分子的新治療方 向係非常具有潛力的(Barnes P.J.: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415-423, 1998 )。 獨立在該疾病所倂發之細胞感染之外,在枝氣管中還 發現到由嗜中性粒性細胞所支配的慢性炎症。由嗜中性粒 性細胞所釋出之介體及酶尤其已被認爲是造成氣道中所發 現之結構變化(氣腫)的原因。因此,對嗜中性粒性細胞 活性進行抑制乃預防或減緩C Ο P D之進展(肺功能參數 的損傷)的合理處理方式。該粒性細胞之活性化的一重要. 刺激爲前炎性細胞激素(cytokine ) T N F α (腫瘤壞死 因子)。因此,T N F α藉由嗜中性粒性細胞來刺激氧游 離基形成(Jersmann,Η.Ρ.Α.; Rathjen,D.A. and Ferrante A.: Enhancement of LPS-induced neutrophil oxygen radical production by TNF a , Infection and Immunity, 4,1744-1 7 47,1 99 8 ) 。P D E 4能夠非常有效地抑制T N F α自 很多的細胞釋出,因而可制止嗜中性粒性細胞的活性。非 本紙張尺度適用中國國家標準(CNS )八4規格(210X297公釐) (請先閱讀背面之注意事項再填頁) 裝- 訂 -線」 -8- 530048 A7 B7 五、發明説明( 6 經濟部智慧財產局員工消費合作社印製 特異的P D E抑制劑,已酮可可豆鹼,能夠同時抑制氧游 離基的形成及嗜中性粒性細胞的呑噬細胞能力( Weni sch, C.; Zedtwitz-Liebenstein, K.; Parschalk, B. and Graningeer W.: Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability assessed by flow cytometry, clin. Drug. Invest., 1 3 (2): 99- 104, 1 997 )。 有多種的P D E 4已爲人知。根據先後順序.,已知者 有黃嘌呤素衍生物、羅利普蘭姆(rolipram ,4 一〔 3 -(環戊氧基)一 4 一甲氧基苯基〕—2 -吡咯啶酮)類似 物及奈措擴總(nitraquazone )衍生物(有關槪況性的槪觀 可見於:Karlsson J-A,Aldos D, Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1 997,7: 989- 1 003 )。直到目前爲止,還不可能將 任何前述化合物用於臨床上。此等已知的P D E已確定亦 具有各種副作用,諸如Η惡心及D區吐,而此等副作用到目前 爲止都還未能壓制。因此,具有較佳治療應用範圍之新穎. P D Ε 4抑制劑的發現係需要的。 雖然多年來,吲哚類在各種適效之新穎活性化合物的 發展上扮演重要的部分,然而直至目前,完全不知羥基吲 哚可作爲P D Ε 4的抑制劑。 發明之詳細說明 本發明係關於通式1所示之經取代的羥基吲哚類 請 先 閱%, 背 之 注 意 事 項 再 頁 訂 線 本紙張尺度適用中國國家標準(CNS ) Α4規格(210x297公釐) -9 530048 Α7 Β7 五、發明説明(
其中 R 1 R 5爲 C i i 2烷基,直鏈或支鏈者, 其可任意經下列基團單-或多取代:- ◦ Η 經濟部智慧財產局員工消費合作社印製 — S Η 、 - Ν Η 2、一 Ν H C 1 - 6 烷基、 — Ν ( C 1 — 6 烷基)2、 -Ν H C 6-14; 芳基 、 — Ν ( C 6 — -1 4芳基)2 、一 Ν ( C 1 — 6 院 基 ) ( C 6 — -1 4方基/ )、-Ν Η COR4 、-N 〇2 Λ — C Ν 、 一 F —— Cl 、一 B r 、-I 、 — 〇 — C 1 — -6 烷基 -0 - C 6 -i 4芳基 、一〇 ( c 〇 ) R 6 —S - — C i — 6烷基 、一 s - -C 6 - 1 4 芳 基 Λ — S 〇 R 6 -S 0 3 Η 、一 s〇 2 R 6、 — 〇 S 〇2 C 1 - 6院基、 一〇S〇2 C 6 -1 4 芳 基 、 — ( C S ) R 6、一 C 〇〇H 、 -(CO ) R 6 Λ 具 有 3 - 1 4個環成員之單一 、 — 或 二 1¾ 飽 和 的 或 是單 — 或多不飽和的碳環 、具有 5 — 1 5 個 rm. 成 員及 1 一 6個雜原子(以 N 、〇 及 S 較 佳 )之單-、二一或三環飽和的或是單一或多不飽 和的雜環,其中該C 6 - 1 4芳基及彼等所包含之碳
本紙張尺度適用中國國家標準(CNS ) Α4規格(210X 297公釐) -10- ^0048 A7 B7 五、發明説明(8 ) ' — 環或雜環取代基可任意經R 4單一或多取代, — C2_12烯基,經單或多取代者,直鏈或支鏈者, 其可任思經下列基團卓一或多取代:一〇Η、 —SH、— ΝΗ2、— NHc:1 — 6 烷基、 —N(Cl — 6 烷基)2、— NHC6 — 14 芳基、 —N(C6 — 14 芳基)2、— N(Ci — 6 烷基)( c6-l4 芳基)、一NHCOR4、— n〇2、 - CN、-f—— Cl、〜— Cl-6 烷基、一 0—C6 — 14 芳基、—〇(c〇) R6、—S — Cl — 6 烷基、—s — c6 — 14 芳基、 一 SOR6、一 s〇3H、一 s〇2r6、 —〇SQ2Ci-6烷基、一〇s〇2c6- 14芳基 、—(CS) R6、一 C〇〇H、一 (c〇)R6 、具有3 - 1 4個環成員之單一、二一或三環飽 和的或是單一或多不飽和的碳環、具有5 一 1 5 個環成員及1一6個雜原子(以N、〇及S較佳 )之單一、二一或三環飽和的或是單一或多不飽 和的雜環,其中該C 6 - i 4芳基及彼等所包含之碳 環或雜環取代基可任意經R 4單-或多取代, 一 具有3 — 14個環成員之單一、二一或三環之飽和 的或是單-或多不飽和的碳環, 其可任意經下列基團單-或多取代:一 〇 Η、 —SH、— ΝΗ2、— NHCi- 6 院基、 —N (Cl-6 院基)2、— NHC6- 14 方基、 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頁) 、言
T 經濟部智慧財產局員工消費合作社印製 -11 - 530048 A7 B7 五、發明説明(9 ) — Ν ( C 6 -1 4芳基)2、 -N ( C 1 - 6院基 )( C 6 - -1 4芳基) 、一Ν H C 〇 R 4、- -Ν 〇 2、 — C Ν 、 — F 、一 C 1 、- -B r 、 —I 、一 〇一 C 1 - -6 院 基 > —〇一C 6 - 1 4芳基、 一〇(C 0 ) R 6 、 — S -( ::1 - 6烷基、 -S - C 6 - 1 4 芳 基、 — S 〇 R 6 -S 〇 3 Η、- -S 〇 2 R 6 λ — 〇 S 〇 2 C ] L - 6垸基、— 〇S〇2 C 6 - 1 4 芳基 Λ — ( C S ) R 6、- C 〇 〇Η、一 (CO) R 6 、 具 有 3 — 1 4個環成員之單一、: 二-或三 環飽 (請先閲讀背面之注意事項再填頁) 和的或是單一或多不飽和的碳環、具有5 - 1 5 個環成員及1 一 6個雜原子(以N、0及S較佳 )之單-、二-或三環飽和的或是單-或多不飽 和的雜環,其中該C 6 - i 4芳基及彼等所包含之碳 環或雜環取代基可任意經R 4單-或多取代, 具有5 -1 5個環成員及1 一 6個雜原子(以N、 〇及N較佳)之單一、二一或三環飽和的或是單一 或多不飽和的雜環, 其可任意經下列基團單一或多取代:一 Ο Η、 —SH、— ΝΗ2、— NHCi — 6 烷基、 —N (Cl- 6 院基)2、一 NHC6- 14 方基、 —N (C6-14 芳基)2、 N (Cl — 6 院基)( C6- η 芳基)、一NHCOR4、一 N〇2、 一 CN、一 F 一 C 1 、一 B r 、一 I 、一 〇一
Cl- 6院基、一〇一C6-14方基、一〇(C〇) 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)
、1T 經濟部智慧財產局員工消費合作社印製 -12- 530048 A7 B7 五、發明説明(彳0 ) R6、— S — Cl-6 院基 一 S〇R6、一 S〇3H、 —〇S〇2Cl- 6院基、 —S — C6 — 14 芳基、 S 〇 2 R 6、 〇S〇2 C 6 - i 4芳基 、一(CS) R6、 一 C〇〇H、一 (C〇)R6 、具有3 - 1 4個環成員之單一、二一或三環飽 和的或是單-或多不飽和的碳環、具有5 - 1 5 個環成員及1 一 6個雜原子(以N、〇及S較佳 )之單一、二一或三環飽和的或是單一或多不飽 和的雜環,其中該C 6 - i 4芳基及彼等所包含之碳 環或雜環取代基可任意經R 4單-或多取代, 具有3 - 1 0個環成員之碳環或雜環飽和的或是單 -或多不飽和的螺環,其中該雜環系統含有1 - 6 個雜原子(以N、◦及S較佳), 其可任意經下列基團單一或多取代:一 Ο Η、 請 先 閱 讀 背 fir 之 注
I
訂 經濟部智慧財產局員工消費合作社印製 — S Η 、 — N H 2 、-Ν Η C 1 — 6 烷基 > — Ν ( C 1 -6 烷 基 )2、 — Ν Η C 6 一 1 4芳基 、 — Ν ( C 6 -1 4 芳 基)2 、 -Ν ( C 1 - 6院基 )( C 6 - -1 4芳基: ) > -Ν Η C 〇R 4 、一 N 〇 2、 — C Ν Ν - F Λ - -C 1 Λ - -Β r 、 - I 、一 〇- C 1 - -6 烷基 Λ — 〇 -C 6 - 1 4芳基 Λ - 〇(c 〇) R 6 Λ —s — c 1 - -6烷基 Λ -s - -C 6 - 1 4芳 基、 — S 〇 R 6 — s 0 3 Η 、 - -so 2 R 6 Λ — 〇 s 0 2 c 1 - - 6 烷基、 — 0 S 0 2 c 6-14 芳基 一 ( C S ) R 6 、一 C 〇 〇H 、 -( c〇) R 6 Μ 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) -13-
R 530048 A7 B7_ 五 '發明説明(彳彳) 、具有3 - 1 4個環成員之單一、二一或三環飽 和的或是單一或多不飽和的碳環、具有5 — 1 5 個環成員及1 一 6個雜原子(以N、0及s較佳 )之單一、二-或三環飽和的或是單一或多不飽 和的雜環,其中該C 6 - i 4芳基及彼等所包含之碳 環或雜環取代基可任意經R 4單-或多取代, 其中R1及R5可相同或互異; R 3可爲氫或一〇Η,此二取代基中至少有一者必須 爲一〇Η ; R 4爲 (請先閱讀背面之注意事項再填頁) 叫 一 Η 、一〇 Η S Η
Ν Η 2 、一 N H C 烷基
C 1 一 6 烷基)
Ν Η C 6 — 14 方基 Ν
C 1 4 芳基)
烷基)(C 6 - 1 經濟部智慧財產局員工消費合作社印製 芳基)、一NHCOR6、一 N〇2、一 CN、 —C〇〇H、一 (C〇) R6、一 (CS) R6、一 F 、一Cl 、一 Br 、一 I 、一〇一Ci-6 烷基、一〇 —C6 — 14 芳基、—〇(c〇)R6、一 S — C!-6 烷 基、一S — C6-14 芳基、一S〇R6、一 S〇2R6, R 6可爲
H
Ν H
-Ν H C 1 - 6 院基 基)2、— NHC6 — 芳基、一 N (C6-14 芳基)2 、一 NCCbe 烷基)(C6- 14 芳基)、一〇一 基、—〇—C6- 14方基、一 S — Cl- 6火兀基 S — C6- 14芳基、一 Cl — 12院基(直鍵或支鍵本紙張尺^ -線. -14- 530048 A7 B7 五、發明説明(12 ) 者)、一 C 2 - 1 2烯基(單一或多不飽和、直鏈或支鏈 者)、 一具有3 - 1 4個環成員之單一、二或三環飽和的或 是單-或多不飽和碳環、 一具有5 - 1 5個環成員及1 一 6個雜原子(以N、 ◦及S較佳)之單-、二-或三環飽和的或是單-或 多不飽和的雜環; A爲一*鍵或是 -(CH2)m-> - (CH2)m - (CH-CH) η 一 (CH2) Ρ—、 一 (CH〇Z)m — 、 一 (C = 〇 )-、-(C = s) -、- (C = N - Z) -、-0 一、一 S —、一 NZ —, 其中,m、p=〇 — 3且η=〇 一 2’以及 Ζ爲 一 Η,或是 — Ci — 12烷基,直鏈或支鏈者, 一 C2 — 12烯基,單一或多不飽和、直鏈或支鏈者’ 一具有3 - 1 4個環成員之單一、二或三環飽和的或 是單-或多不飽和碳環、 ,一具有5 - 1 5個環成員及1 一 6個雜原子(以N、 〇及S較佳)之單一、二-或三環飽和的或是單一或 多不飽和的雜環; B可爲碳或硫,或是爲一(S = 〇)一; D可爲氧、硫、CH2或N—Z ; 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頁) 訂 -線. 經濟部智慧財產局員工消費合作社印製 -15- 530048 at B7 五、發明説明(13) 當B爲碳時,D只能爲S或C Η 2 ; Ε可爲一1鍵或是 —(CH2)m S —、—(Ν— Ζ) - ,其中m及Z如前文所定義。 本發明還關於式1所示化合物之生理上可耐受的鹽類 〇 經濟部智慧財產局員工消費合作社印製 生理上可耐受的鹽類係依慣用的方式,藉用無機或有 機酸類來中和鹼類或是用無機或有機鹼類來中和酸類而製 得。可用之無機酸類爲,例如,氫氯酸、硫酸、磷酸或氫 溴酸;有機酸類則有,例如,羧酸類或磺酸類,諸如,乙 酸、酒石酸、乳酸、丙酸、乙醇酸、丙二酸、馬來酸、富 馬酸、丹寧酸、琥珀酸、藻酸、苯甲酸、2 —苯甲氧基苯 甲酸、2 —乙醯氧基苯甲酸、肉桂酸、苯乙醇酸、檸檬酸 、蘋果酸、水楊酸、3 -胺基水楊酸、抗壞血酸、雙羥萘 酸、菸酸、異菸酸、草酸、胺基酸、甲烷磺酸、乙烷磺酸 、2 -羥基乙烷磺酸、乙烷一 1,2 -二磺酸、苯磺酸、4 -甲基苯磺酸或2 -萘磺酸。可用之無機鹼類爲,例如, 氫氧化鈉溶液、氫氧化鉀溶液或氨;而可用之有機鹼類爲 胺類,但以三級胺類較佳,諸如,三甲胺、三乙胺、吡啶 、N , N —二甲基苯胺、喹啉、異喹啉、α —皮考啉、石一 皮考啉、Τ 一皮考啉、喹哪啶或嘧啶。 此外,式1化合物之生理上可耐受的鹽類可藉由使用 成四級鹼劑,依已知的方式,將具有三級胺基的衍生物轉 化爲對應的四級銨鹽類,而製得。可用的成四級劑爲,例 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 530048 Α7 Β7 五、發明説明(14) 如,烷基鹵化物,如甲基碘、乙基溴及正丙基氯;但亦可 爲方基院基鹵化物’如玉基氯或2 -苯基乙基漠。 本發明之式1化合物含有不對稱碳原子,有關該化合 物的發明係關於其D形式、L形式以及D,L混合物以及非 對映立體異構物(當不對稱碳原子有多個時)。彼等含有 不對稱碳原子且通常係以消旋物形式獲得之式1化合物可 依已知的方式(例如,使用具旋光活性的酸),分離成具 旋光活性的異構物。然而,亦可能自一開始就採用具旋光 活性的起始物,然後就可得到對應之具旋光活性或非對映 立體異構的化合物爲最終產物。 本發明之化合物被發現具有藥理上的重要性質,而可 利用在治療上。 本發明之化合物爲抑制T N F α釋出的抑制劑。 因此,本發明的標的係式1化合物以及彼等之鹽類, 且含有此等化合物或彼等之鹽類的藥學組成物可用於治療 可因TNF α之抑制而受益的病症。 經濟部智慧財產局員工消費合作社印製 此等病症包括有,例如,關節炎疹(包括關節炎及風 濕性關節炎)以及其他關節炎病症,諸如,風濕性脊椎炎 及骨關節炎。其他可能的應用在於患有下列病症之患者的 治療:敗血症、敗血性中風、革蘭陰性敗血病、中毒性休 克徵候簇、呼吸困難徵候簇、氣喘或其他慢性肺病、骨耗 損病症或移植排斥反應或是其他自動免疫病症(諸如,紅 斑性狼瘡)、多發性硬化、絲球體性腎炎及葡萄膜炎、胰 島素依存性糖尿病及慢性髓鞘脫失。 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) -17- 530048 Α7 Β7 五、發明説明(15) 此外,本發明之化合物亦可用於治療諸如病毒感染及 寄生蟲感染之感染症,例如,可用於治療瘧疾、與感染有 關的發熱、與感染有關之肌痛、A I D S及惡病質。 本發明之化合物爲磷酸二酯酶4之抑制劑。 因此,本發明的主題之一在於式1化合物及彼等之鹽 類以及含有此等化合物或彼等之鹽類之藥學組成物可用於 治療因磷酸二酯酶4之抑制而受益的病症。 本發明之化合物因此可用作爲枝氣管擴大劑.,且可用 於預防氣喘。式1化合物更是嗜伊紅細胞之累積及活性的 抑制劑。因此,本發明之化合物亦可用於與嗜伊紅細胞有 關的病症。此等病症包括有,例如,炎性氣道病症(諸如 ,枝氣管氣喘)、變應性鼻炎、過敏性結合膜炎、異位性 皮膚炎、濕疹、變應性血管炎、由嗜伊紅細胞所調介的炎 症(諸如,嗜伊紅細胞肌膜炎、嗜伊紅細胞肺炎以及 P I E徵候簇〔帶有嗜紅細胞過多的肺浸潤〕)、蓴麻疹 、潰瘍性結腸炎、克隆氏病及增殖性皮膚病(諸如,牛皮 癬或角化病)。 本發明的主題之一在於式1化合物及彼等之鹽類可在 體外抑制人類血液中因脂多糖(L P S )所誘發之 丁 N F α的釋出,還可在活體中抑制白鼬及牷養豬體內由 L P S所誘發之肺嗜中性白血球浸潤。所有發現到之藥理 上重要的性質證明式1化合物及彼等之鹽類連同含有此等 化合物或彼等之鹽類的藥學組成物可用於治療慢性阻塞性 肺病0 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) 請 先 閱 讀 背 之 注 意 事 項 再 寫 本 頁 經濟部智慧財產局員工消費合作社印製 330048 A7 _ B7 五、發明説明(16 ) 請 先 閱 讀 背 面 之 注 意 事 項 再 填 寫 本 頁 此外,本發明之化合物還具有神經保護性質且可用於 治療因神經保護而受益的病症。如是之病症爲,例如,老 年癡呆(阿耳滋海默氏症)、記憶喪失、巴金生氏症、抑 鬱症、中風及間歇跛。 本發明化合物之其他可能的應用爲預防及治療前列腺 病症(諸如,良性前列腺增殖、頻尿、夜搜症),以及治 療膀胱無力及因腎結石所引起的腹痛。 最後,本發明之化合物還可用於抑制因再三使用止痛 劑(諸如,嗎啡)所造成之藥物依賴性的發生,以及用於 降低因再三使用此等止痛劑所造成之耐藥性的發生。 關於藥物之製造,除了有效劑量之本發明化合物或彼 等之鹽類外,還使用慣用的輔劑、載體及添加劑。 活性化合物的劑量係取決於投藥的途徑、病患的年齡 及體重、所治療之病症的性質及嚴重性及類似因素。 每曰劑量可以各別的劑量形式一次投用或分成2或多 次在一天內投用,且一般而言,該每日劑量爲0 · 0 0 1 至 1 0 0 m g。 經濟部智慧財產局員工消費合作社印製 可用的投藥形式爲口服、非經腸、經靜脈、經皮、局 部、吸入及經鼻製劑。 就口服而言,可用的習用藥學製劑形式爲,諸如,錠 劑、糖衣錠劑、囊劑、分散粉劑、粒劑、水溶液、水性或 油性懸浮液、糖漿劑、液劑或滴劑。 固體藥劑形式可含有惰性成份及載體,諸如,碳酸鈣 、磷酸鈣、磷酸鈉、乳糖、澱粉、甘露糖醇、藻酸鹽、明 ‘紙張尺度適用中國國家標準(CNS ) A4規格(2丨〇'〆297公釐) -19- 530048 A7 B7 五、發明説明(17 ) 請 先 閱 讀 背 面 之 注 意 事 項 再 膠、巴西樹膠、硬脂酸鎂或鋁、甲基纖維素、滑石、高度 分散的水楊酸類、矽酮油、局分子量脂肪酸類(諸如,硬 脂酸)、明膠、瓊脂或是植物或動物性脂或油類、固體高 分子量聚合物(諸如,聚乙二醇);適用於口服的製劑, 視需要,可含有額外的調味劑及/或增甜劑。 液體的藥劑形式可爲經過滅菌及/或任意含有輔劑, 諸如,防腐劑、安定劑、濡濕劑、浸透劑、乳化劑、分散 劑、增溶劑、鹽類、供調節滲透壓或供緩衝的糖類或糖醇 類、及/或黏度調節劑。 經濟部智慧財產局員工消費合作社印製 此類的添加劑爲,例如,酒石酸鹽及檸檬酸鹽緩衝劑 、乙醇、錯合劑(諸如,乙二胺四乙酸及其無毒性的鹽類 )。就黏度的調節而言,可用之高分子量聚合物爲,諸如 ,液體聚環氧乙烷、微晶形纖維素、羧甲基纖維素、聚乙 烯基吡咯酮、葡聚糖或明膠。固體載體爲,例如,澱粉、 乳糖、甘露糖醇、甲基纖維素、滑石、高分散性水楊酸類 、高分子量脂肪組織類(諸如,硬脂酸)、明膠、瓊脂、 磷酸鈣、硬脂酸鎂、動物及植物油脂、固態高分子量聚合 物(諸如,聚乙二醇)。供非經腸或局部投藥所用的油性 懸浮液可爲植物性之合成或半合成油類,諸如,在脂肪酸 鏈部分各含有8至2 2個碳原子的液體脂肪酸酯類,例如
經一元至三元之C C 6醇類(例如,甲醇、乙醇、丙 醇、丁醇、戊醇彼等之異構物、乙二醇或甘油)所酯化之 棕櫚酸、月桂酸、十三烷酸、十七酸、硬脂酸、花生油酸 、肉豆蔻酸、廿二烷酸、十五烷酸、亞油酸、反油酸、巴 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇χ297公釐) -20- 530048 A7 B7 五、發明説明(18 ) 西烯酸、芥酸或油酸。此類脂肪酸酯類有,例如,市面上 可購得之M i g 1 y 〇 1 s 、肉豆蔻酸異丙酯、棕櫚酸異丙酯、硬 脂酸異丙酯、P E G 6 -癸酸、飽和脂肪酸之辛酸酯/ 癸酸酯、聚氧乙烯三油酸甘油酯、油酸乙酯、含蠘脂肪酸 酯(諸如,人工的潤羽脂腺脂)、椰子酸異丙酯( isopropyl cocoate )、油酸油酯、油酸癸酯、乳酸乙酯、駄 酸二丁酯、己二酸二異丙酯、多元醇脂肪酸酯等等。亦可 適用者爲不同黏度的矽酮油類或脂肪醇類(諸如.,異三癸 基醇、2 -辛基十二烷醇、十六烷基硬脂醇或油醇),脂 肪酸類爲,例如,油酸。此外,還可使用植物油類,諸如 ,箆麻油、杏仁油、橄欖油、芝麻油、棉籽油、花生油或 大豆油。 經濟部智慧財產局員工消費合作社印製 可用之溶劑、成膠劑及增溶劑爲水或水可混溶的溶劑 。適合者爲,例如,醇類(諸如,乙醇或異丙醇、苄醇、 2 —辛基十二烷醇、聚乙二醇、酞酸酯、己二酸酯、丙二 醇、甘油、二一或三丙二醇)、鱲類、甲基溶纖劑、溶纖 劑、酯類、嗎福啉、二噚烷、二甲亞硕、二甲基甲醯胺、 .四氫呋喃、環己酮等等。 可用之成膜劑爲可同時溶於或溶脹於水及有機溶劑中 的纖維素酯類,例如,羥丙基纖維素、甲基纖維素、乙基 纖維素或可溶性澱粉。 成膠及成膜劑的混合形式亦可完全可用。在此所用者 尤其係指離子性大分子,例如,羧甲基纖維素鈉、聚丙烯 酸、聚甲基丙烯酸及其鹽類、支鏈澱粉半乙醇酸鈉、藻酸 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -21 - 530048 A7 B7 五、發明説明(19 ) 或丙二醇藻酸鈉、阿拉伯膠、黃耆膠、巴西膠或角叉菜膠 其他可用的調劑用輔劑爲:甘油、不同黏度的石鱲、 三乙醇胺、骨膠原、尿囊素、諾凡提索利酸(novantlsollc acid )。 在調劑上,亦可能使用到界面活性劑、乳化劑或濡濕 劑,諸如,月桂基硫酸鈉、脂肪醇醚硫酸酯、N -月桂基 -/5 -亞胺基二丙酸二鈉、聚乙氧基化箆麻油或單油酸山 梨聚糖酯、單硬脂酸山梨聚糖酯、聚山梨酸(例如,Tween )、十六烷醇、暖卵磷脂、單硬脂酸甘油酯、聚氧乙烯硬 脂酸酯、烷基苯基聚乙二醇醚類、氯化十六烷基三甲基銨 或單-/二烷基聚乙二醇醚正磷酸單乙醇胺鹽類。 同樣地,在製備所要的製劑時,可視需要採用安定劑 (諸如,蒙脫石或膠態水楊酸)以供乳液的安定或供預防 活性物質的分解,如是之安定劑有,諸如,抗氧化劑(例 如,生育酚或丁基羥基茴香醚)或防腐劑(例如,對羥基 苯甲酸酯類)。 用於非經腸投藥的製劑可呈各別的劑量形式,諸如, 安瓿劑或管瓶劑。宜使用活性化合物的溶液,較佳的是水 溶液,尤指等滲溶液,但亦可爲懸浮液。此等注射用形式 可製成隨時可用之最終製劑或是在投藥前才藉由將活性化 合物(例如,冷凍乾燥物)與非必要之其他固體載體以及 所要的溶劑或懸浮劑混合,直接予以製備。 經鼻製劑可呈水性或油性溶液或是呈水性或油性懸浮 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 請 閲 讀 背 面 之 注 意 事 項 再 填 馬 頁 經濟部智慧財產局員工消費合作社印製 -22- 530048 A7 B7 五、發明説明(20 ) 液的形式。彼等亦可呈冷凍乾燥物的形式,在投藥前才藉 由使用適當的溶劑或懸浮劑予以製備。 製劑的製造、調劑及密封皆係於習用的抗菌及無菌條 件下進行。 本發明還關於本發明化合物的製法。 依本發明,式1化合物 E - R5 /
(其中 R1、R2、R3、R4、R5、A、B、D 及 E 係如前所定義) 係藉其中之R2或R3或R2及R3二一〇一R7的式1 化合物將其R 7移除而轉化爲本發明之化合物,而製得的。 經濟部智慧財產局員工消費合作社印製 在此,R 7係示適作爲離去基之取代基(諸如,烷基、 環烷基、芳烷基、芳基、雜芳基、醯基、烷氧羰基、芳氧 羰基、胺羰基、N -經取代的胺羰基、甲矽烷基或磺醯基 ),以及錯合劑〔諸如,硼酸、磷酸及共價或配位鍵結金 屬(例如,鋅、鋁或銅)的化合物〕。 在本發明之製法的定義範圍內,供去除R 7之特別較佳 的反應係以適當鹼類(諸如,氫氧化鈉溶液、氫氧化鉀溶 液或是碳酸鈉或碳酸鉀)來進行的水解反應。 此等水解反應適用於R7 =醯基、烷氧羰基、芳氧羰基 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) " -23- 530048 A7 ______B7__ 五、發明説明(21 ) 、胺羰基、N -經取代的胺羰基、甲矽烷基或磺醯基以及 錯合劑〔諸如,硼酸、磷酸及共價或配位鍵結金屬(例如 ’鋅、鋁或銅)的化合物〕。 在本發明之製法的定義範圍內,由R 7爲烷基、環烷基 、芳烷基、芳基或雜芳基之化合物去除R 7的特別較佳反應 爲醚裂解,例如,藉用氫溴酸、氫氯酸、氫碘酸且使用活 化的路易士酸類(例如,A 1 C 1 3、B F 3、B B r 3或 L i C 1 ),在有或無額外的活化劑(例如,乙烷-1 , 2 -二硫醇或苄基硫醇)存在下所進行的醚裂解,以及藉 用氫在升壓或常壓下、適當觸媒(例如,鈀或銥觸媒)存 在下所進行的醚裂解。 依本發明,其 D及E如前所定義之式1化合物亦可藉由將本發明之式1 化合物轉化爲另一本發明的式1化合物而製得,該轉化反 應係指藉由已知的反應進行下列結構的轉化 請 先 閱 讀 背 面 之 注 意 項 再 頁 訂 E-
-R
D 經濟部智慧財產局員工消費合作社印製 對本發明之式1化合物而言較佳的轉化反應爲,例如 ,就A = —( C =〇)一來說,利用已知的還原劑(例如 ,硼氫化鈉)或藉由氫化(其視需要可可以立體選擇性的
方式來進行)而產生A (C Η — 〇 Η ) 或
A C Η 的還原反應 其他較佳的轉化反應爲將其D及Ε爲氧之化合物轉化^ 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) ~~ ---- -24- 530048 A7 B7 五、發明説明( 22 爲其D爲氧而E爲一(N — Z) —(其中Z如前所定義) 之物質的轉化反應。 實施例 下文之本發明化合物的例示製備方法係依已述及種類 的物質爲起始物,其中R 7爲烷基、環烷基、芳烷基、芳基 或雜芳基。 實施例
N (3,5 —二氯吡啶—4 一基)一2 —〔 1 — 4 一 請 先 閱 之 注 意
I 頁 -氧基乙醯胺 氟苄基)一 5 —羥基吲哚一 开寸1 · 4g之]M — (3,5 - —^氯吼D定一 4 —基)— 2 —〔 1 一(4 一氟苄基)—5 —甲氧基吲哚一 3 —基〕 一 2 —氧基乙醯胺溶於1 〇 〇 m 1之二氯甲烷中。將該溶 液加熱至回流並在攪拌的情況下,用在1 5 m 1之二氯甲 院中的1 4 m m ο 1 B B r 3予以處理。將所得之反應混 合物回流3小時。在冷卻後,於2 0 °C下,令該溶液與 2 0 0 m 1之碳酸氫鈉水溶液一同強烈地攪拌3小時。在 此過程中,產物晶體晶析出。將其分離出來、於6 〇 °C下 乾燥並令其自8 0 m 1之乙醇再結晶析出。 產量:1 · lg (理論値之80%) 熔點:2 1 3 — 2 1 4 °C。 實施例2 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 訂 經濟部智慧財產局員工消費合作社印製 -25 530048 A7 B7______ 五、發明説明(23 ) N— (3,5 —二氯吡啶—4 —基)—2 —〔 1— (4 — 氟苯基)—5 —羥基吲哚一 3 —基〕—2 —氧基乙醯胺( 1 ) 將5g (38mmol)之無水氯化鋁導入50ml 之乙烷一 1 ,2 —二硫醇中。於〇。(:下,添加由4 · 7 g 之1^ — (3 ,5 — 二氯吡啶—4 —基)—2 —〔 1— (4 一氟苄基)一 5 —甲氧基吲哚—3 —基〕一 2 —氧基乙醯 胺(1 0 m m ο 1 )於5 0 m 1之二氯甲烷所形成的溶液 。在0 t下,將所得之混合物攪拌4小時。.於0 — 1 0 °C 下’一邊攪拌,一邊逐滴添加5 〇m 1之1 〇%強度的氫 氯酸。分離出晶析出的產物,用水予以淸洗並在2 0 °C下 ’予以乾燥。藉由自乙醇(1 8 0 m 1 )再結晶析出,可 得純的產物。 產率:3 · 1 g (理論値的6 7 % ) 熔點:2 1 2 — 2 1 4 t:。 經濟部智慧財產局員工消費合作社印製 下文之本發明化合物的例示製備方法係依已述及種類 的物質爲起始物,其中R7爲醯基、烷氧羰基、芳氧羰基、 胺羰基、N -經取代的胺羰基、甲矽烷基或磺醯基。 實施例3 N — (3,5 —二氯吡啶—4 —基)一2 —〔1一( 4 一氟苄基)一5 —羥基吲哚一 3 —基〕一 2 —氧基乙醯 胺鈉鹽(2 ) 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -26- 530048 A7 B7 五、發明説明(24 ) 令5g之N — (3,5 —二氯吡啶—4 —基)—2 — 〔5 —乙醯氧基一 1 一( 4 一氟禾基)一 d引ti朵一 3 —基〕 —2 -氧基乙醯胺(1 Ommo 1 )於5 Om 1之稀氫氧 化鈉溶液中,在4 0 - 5 0 °C下攪拌1小時。在用冰進行 冷卻的同時,用氫氯酸(1 0 %強度),將該溶液中和, 並予以濃縮至乾。將所得殘留物溶於8 0 m 1之丙酮中。 去除未溶解的成份。令澄淸的溶液受〇 . 4 g之氫氧化鈉 於3 m 1水中之溶液的處理並於2 0 °C下,予以.攪拌2小 時。分離出結晶析出的產物,用丙酮予以淸洗且於6 0 °C 下予以乾燥。 產量:2 · 4 4 g (理論値的5 1 % ) 熔點:2 6 5 t。 下文所述者係由其他之本發明式1化合物製備本發明 之式1化合物的例示製備方法。 實施例4 經濟部智慧財產局員工消費合作社印製 N -(3,5 - 二氯吼 D定一 4 一基)—2 -〔 1— (4一 氟苄基)一 5 -羥基吲哚一 3 —基〕一 2 —羥基乙醯胺( 3 ) 將lg之N— (3 ’ 5 —二氯吡啶—4 一基)一 2 — 〔1 一(4 一氟苄基)一 5 -羥基吲哚一 3 —基〕一 2 — 氧基乙醯胺(1 ; 2 m m ο 1 )懸浮於7 5 m 1之甲醇中 。在添加0 · 2 g之硼氫化鈉(於3 m 1之稀氫氧化鈉溶 本矣氏張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)" -27 - 530048 A7 B7 五、發明説明(25 ) 液中)後,在2 0 °C下,將所得之反應混合物攪拌6小時 。在蒸餾去除溶劑後,令所得之殘留物自4 0 m 1之乙醇 再結晶析出。 產量:0 · 5 g (理論値的5 0 % ) 熔點:2〇5 — 2〇7 °C 。 使用所述之例示變數,可製得無數的其他式1化合物 ,茲列舉下列化合物爲例: e-R5 /
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(210X 297公釐) -28- 530048 7 Β 經濟部智慧財產局員工消費合作社印製 五、發明説明(26 ) ,~N mt iff ^ r λ un CN 〇\ CN cn oo CNl CN OO CN r- 寸 CNI ΟΟ 寸 CN oo r-H csi r—H CN oo r—H cn H C<l i—H 逡β CN vO CNl VO 〇 CN r- CN cn VO CN oo CO CNl 1 cn CN 0 OO CN 寸 CN VO 寸 CSI \ < C^l a\ a\ i H 卜 f · H CNI 7~i CNl ck cn csi ΓτΊ K έ έ K K ? K ? έ έ K M-i z 1 z 1 z 1 Z I z 1 z 1 Z 1 z 1 z 1 z 1 1 z 1 1 z 1 Q 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 PQ u u u U u u u u U U u U u u < 1 1 〇 〇 u 1 1 1 1 1 1 o 1 1 1 1 1 /^s II II II II II II II II II II II II 1 u 1 u 1 u 1 u 1 u 1 u 1 u 1 u I u 1 u 1 u 1 u 1 稍 稍 稍 稍 稍 擀 祕 ffi- li 11] 鹏 蹏 111 m m 稍 擀 寸 1 寸 1 寸 1 智 f 1 1 寸 i 寸 1 寸 1 寸 1 寸 1 Jj^ 寸 1 寸 1 lj^ .1 \ 1 lj^ ίΐ^ ίΐ^ 感 11 1 1 1 lj^ JJ^ 11 1 wo 11 1 1 1 1 ^Γ) 寸 11 1 wo 1 1 11 1 un 11 1 wn 1 1 1 un oJ 11 J|^ 1 1 1 1 1 wo 1 1 1 ^Γ) cn cn cn cn cn cn m c〇 1 1 1 oi 1 1 瞧 oi c〇 CO K K κ ffi κ K K K κ K K K 〇 1 κ + c^j 〇 I ffi + 〇3 2 〇 1 K κ 〇 1 〇 1 〇 1 〇 1 〇 〇 I 〇 1 〇 1 〇 1 〇 1 〇 1 稍 鹅 cn 稍 稍 屮 稍 Ε TT\! Jii U LLL li 4 li 4 ϋ 4 11 1 CN 11 1 \o oi 瞰 TT\I β U 4 蹏 4 li 4 li 祕 1 寸 H CNl cn 寸 un vo 〇 ΟΟ a\ O 1 < (N1 cn 寸 (請先閲讀背面之注意事項再填寫本頁)
、1T 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) -29- 530048 A7 B7 五、發明説明(27 ) 本發明之化合物乃磷酸二酯酶4及T N F α釋出的強力抑 制劑◦彼等化合物之治療上的效力係於活體內證實,例如 ,藉由在天竺鼠體內對氣喘之晚期反應(嗜伊紅細胞過多 )的抑制作用以及藉由在自動起敏之挪威棕鼠(brown Norways rats )體對於變應原所引起之血管滲透性的改變予 以證實。 對於磷酸二酯酶的抑制作用 經濟部智慧財產局員工消費合作社印製 在人類多核淋巴細胞(Ρ Μ N L s )之酶製劑中測定 P D Ε 4活性,P D Ε 2、3及活性則以得自人類血小板 的P D Ε來測定。用檸檬酸鹽使人血抗凝固。藉由在室溫 下、於7 0 0 X g下離心2 0分鐘,以將紅血球及白 血球與在上淸液中之富含血小板的血漿分離。用超音波對 血小板進行溶胞作用,並將其用於P D E 3及P D E 5的 分析。至於P D E 2活性的測定,則係在利用N a C 1梯 度的之陰離子交換層柱上純化出細胞溶質的血小板部分, 並回收P D E 2頂峰級分以供分析所用。供P D E 4測定 所用之Ρ Μ N L s係藉由接著所進行之聚葡糖沉潑作用及 後續之利用Ficoll-Paque進行的梯度離心作用分離所得。在 第二次淸洗細胞後,藉由添加1 0 m 1之低張緩衝劑( 1 5 5 m Μ Ν Η 4 C 1 ^ 1 0 m Μ NaHC〇3、 O.lmM EDTA,pH 7.4),在 4°C 下、6 分鐘的過程中,將仍然含有之紅血球溶解。再用P B s將 仍然完整的Ρ Μ N L s淸洗二次並利用超音波,對其進行 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -30 - 530048 A7 B7 五、發明説明(28) 溶胞作用。在4 t、4 8,0 0 〇 X g下進行1小時離 心所得之上淸液含有P D E 4之細胞溶質部分,且係用於 P D E 4的測量。 磷酸二酯酶活性之測定係根據T h 〇 m p s ο n e t a 1.所發表 的方法(Thompson, W.J.; Appleman,M.M·,Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme, Adv. Cycl. Nucl. Res. 1 979,10,69-92 ),但稍作修正後來進行的.。 反應混合物含有50mM tris H C 1 (pH 7 · 4 ) 、5 m Μ M g C 1 2、在各種濃度下的抑制劑 經濟部智慧財產局員工消費合作社印製 、對應的酶製劑、還有各個同功酶測定所需的其他成份( 參見下文)。藉由添加受質〇 · 5//M〔3H〕一 cAMP 或〔3H〕— cGMP (每一試驗約 6000 CPM), 來起動反應。反應混合物中的D M S 0濃度爲1 % ( ν / ν )。在該D M S〇濃度下,對於p D Ε活性未有任 何影響。在藉由添加受質而起動反應後,於3 7 °C下,將 試樣培養3 0分鐘。藉由在1 1 〇 °C下將試管加熱2分鐘. ,以終止反應。令該試樣再留在冰中1 〇分鐘。添加3 0 // 1之5 / —核苷酸酶(1 m g / m 1之由響尾蛇所得的 蛇毒液懸浮液),然後,在3 7 °C下,進行培養1 〇分鐘 。令試樣停留在冰上,添加各爲4 0 // 1之Dowex -水— 乙醇(1 + 1 + 1 )混合物,並將試樣充分混合且再次於 冰上培養1 5分鐘。於3 0 0 0 X g下,將反應容器 離心2 0分鐘。將2 0 0 // 1 —整份的上淸液直接移到閃 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) -31 - 530048 A7 B7 __ 五、發明説明(29) 爍容器中。在添加3 m 1之發光物後,於/3計數器中,對 試樣進行測量。 (請先閱讀背面之注意事項再填寫本頁) P D E 4、3及2活性的測量係使用〔3 Η〕一 c A Μ Ρ爲受質,而P D Ε 5活性之測量所用的受質爲〔 3 Η〕一 c G Μ Ρ。在各個情況下,非特異性酶活性的測量 ,就P D Ε 4的情形而言,係於羅利普蘭姆(rolipram ) 存在下進行;而就PDE 3及5而言,則係於1 0 0 //Μ 之I Β Μ X存在下進行測量,且自試驗値扣除該活性値。 P D Ε 3分析之培養批液中含有1 〇 //Μ之羅利普蘭姆( rolipram )以抑制P D Ε 4所可能造成的污染。P D Ε 2係 利用Amersham之S Ρ A分析來進行試驗。該分析係於 PDE2之活化劑(5//M cGMP)存在下進行的。 本發明化合物對於抑制磷酸二酯4之I C 5。値經計算 係在1 0 — 9至1 0 — 5 Μ之間。對於P D E 2、3及5型的 選擇率爲係數100至10,000。 趾制T N F α自鼻息肉細胞釋出的抑制作用 經濟部智慧財產局員工消費合作社印製 本實驗的設計基本上係根據Campbell Α.Μ.及Bousquet J.所發表的方法(Anti-allergic activity of Hi-blockers,
Int. Arch. Allergy Immunol·,1993,101,308-310 )。起始 物係得自經過外科處理之患者所得的鼻息肉(手術物)。 用R Ρ Μ I 1 6 4 0淸洗該組織,然後,利用蛋白 酶(2 · 〇mg/ml)、膠原酶(1 · 5mg/ml) 、玻尿酸酶(〇.75mg/ml)及 DNAase ( 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -32- 530048 A7 _B7_______ 五、發明説明(3〇) (請先閱讀背面之注意事項再填寫本頁) 0 · 5 m g / m 1 ) ( 1 g之組織相對於4 m 1之帶有酶 的R Ρ Μ I 1 6 4 0 ),在3 7 °C下,對其進行分解。 所得之細胞乃爲上皮細胞、單核白血球、巨噬細胞、淋巴 細胞、纖維母細胞及粒性細胞的混合物,對其進行過濾並 藉由在營養液中所進行的重複離心,對其進行淸洗;添加 人類I g E予以被動敏化並將細胞上淸液的濃度調整爲2 百萬個細胞/ m 1 (在R Ρ Μ I 1 6 4 0中)(補充有 抗生素、10%胎牛血淸、2mM穀胺醯胺以及2 5mM H e p e s )。將該懸浮液分置於6 -孔的細胞培養平 皿中(1 m 1 /孔)。用各種不同最終濃度之受試物將彼 等細胞預培養3 0分鐘,然後,藉由添加抗一 I g E ( 經濟部智慧財產局員工消費合作社印製 7 . 2 // g / m 1 ),刺激TNFa的釋出。該釋出至營 養培養基的釋出量在約1 8小時後,會達到最大。在該期 間,細胞係於3 7 °C、5 % C 0 2的條件下培養。利用離 心(5分鐘,4 0 0 0 r p m )來收集該培養基(上淸液 ),並將其儲存於一 7 0 °C下’直到要進行細胞激素( cytokine )的測量爲止。該上淸液中之T N F α的測量係使 用所謂的夾心式E L I S A s (基本物質’ Pharmingen ) 來進行,其中所偵測得之細胞激素(cytokine )的濃度係 於3〇一l〇〇〇Pg/ml範圍內。 未經抗- I g E予以刺激的細胞幾乎不會產生 T N F α,但是,經過刺激的細胞則會分泌出大量的 T N F α,該T N F α可被P D Ε 4抑制劑以依存於劑量 的方式予以降低。由各種濃度之受試物質的抑制百分比( 本紙張尺度適用中國國家標準(CNS ) Α4規格(210x297公釐)~~' ' -33- 530048 A7 _^_B7__ 五、發明説明(31) 經抗一 I g E刺激之細胞的T N F α釋出量=1 0 0 % ) 計算出I C 5。値(抑制率爲5 0 %時的濃度)。 就本發明之化合物而言,測得之I C 5。値係在1 〇 1 至1 0 — 5 Μ範圍內。 在對自動敏化之天竺鼠進行吸入卵淸蛋白激發2 4小時後 晚期嗜伊紅細胞過多的抑制作用 藉由活體內試驗,在對卵淸蛋白(Ο V A >已自動起 敏之Dunkin-Hartley天竺鼠(200 — 250g)體內進行 受試物質對於肺嗜伊紅細胞浸潤之抑制作用的硏究。該起 敏作用係藉由在連續的二天,經腹膜內注射二次由2 0 V g之〇VA連同2 Omg之氫氧化鋁(作爲佐劑)在 0 · 5 m 1之生理食鹽溶液所形成的懸浮液來進行的。在 第二次注射後的第1 4天,用新安替根馬來酸鹽( mepyramine maleate ) ( 1 0 m g / k g,經腹膜內)來保 護動物免於因過敏而死亡。3 0分鐘後,令動物在塑膠盒 內曝露於OVA氣溶膠(〇 · 5g/ml)下30秒,該 氣溶膠係藉由壓縮空氣(1 9 · 6 k P a )所驅動的噴霧 氣產生的(過敏原的激發)。對照組的動物則噴以生理食 鹽溶液。在進行該激發後2 4小時,用劑量過量之氨脲( 1 · 5 g / k g (體重),經腹膜內)將動物麻醉,並使 用2 X 5 m 1之生理食鹽溶液來進行枝氣管與肺胞的 灌洗(BAL)。收集BAL液,在300 r pm之下予 以離心1 0分鐘,然後,將細胞九粒再懸浮於1 m丨的生 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) 辞· 訂 線ί 經濟部智慧財產局員工消費合作社印製 -34- 530048 A7 B7 五、發明説明(32) (請先閱讀背面之注意事項再填寫本頁) 理食鹽溶液中。使用自動的細胞鑑別裝置(Bayer Diagnostics Technic on HI ),對於B A L中的嗜伊紅細胞 進行計數。每一試驗包括有二組對照組(以生理食鹽溶液 噴霧者及以OVA溶液噴霧者)。 依下面的公式來計算經受試物質處理過之試驗組對於 嗜伊紅細胞的抑制百分比: 抑制 % = 1 〇 〇 — 1 0 0 ^ (^7C) . (A-C) A =經〇 V A激發且有賦形劑之對照組的嗜伊紅細胞 B =經0 V A激發且經受試物質處理之試驗組的嗜伊紅細 胞 C =經強度〇 · 9 %之氯化鈉激發且有賦形劑之對照組的 嗜伊紅細胞 經濟部智慧財產局員工消費合作社印製 彼等受試物質係以在1 0 %之聚乙二醇3 0 0及強度 〇· 5 %之2 -羥乙基纖維素內的懸浮液形式,在過敏原 激發前2小時,經腹膜或經口投服的。對照組則係依照受 試物質的投服方式,來投用賦形劑。 在經腹膜內投用1 0 m g / k g之本發明之化合物後 ,本發明之化合物可抑制3 0 %至8 0 %之晚期嗜伊紅細 胞過多,而在經口投用3 0 m g / k g後,則可抑制4 0 % 至 7 0 %。 因此,本發明之化合物特別適用於製造可供治療與嗜 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)~" -35- 530048 A7 B7 五、發明説明(33) 伊紅細胞有關病症的藥物。 (請先閱讀背面之注意事項再填寫本頁) 在經自動起敏之棕色挪威鼠體內對於過敏原所引起之血管 滲透性的影響
對於重2 8 0 - 3 0 0 g之雄性棕色挪威鼠進行自動 敏化,連續二天,對每一動物,經腹膜內注射由1 m g之 卵淸蛋白連同1 0 Omg之氫氧化鋁於lm 1之生理食鹽 溶液所形成的懸浮液。在起敏化三星期後,用硫代巴比妥 鈉將鼠麻醉並將彼等動物固定於仰臥的姿勢。爲了進行鼻 腔的灌流,茲將聚乙烯導管以向後的方向推進至氣管,盡 可能到達鼻後孔的內孔,以使溶液有可能自鼻腔慢慢地洩 流。將一短的氣管導管以直立的方式接合至氣管,以使動 物能夠呼吸。在進行灌流時,係利用一滾筒式泵,將經磷 酸鹽緩衝之食鹽溶液連續抽送穿過鼻腔(0 · 5 m 1 / m i η ),並用級分收集器來收集。使用依文斯藍(Evans B1 u e )作爲血漿標記物並在頭靜脈的位置,利用一導管, 經靜脈注射至動物體內(每一動物1 m 1 ,各爲在p b S 經濟部智慧財產局員工消費合作社印製 內的1 %強度的溶液)。 受試物質的投服係以局部方式來進行。在該投服過程 中,受試物質係添加至灌流介質(P B S )中。用含有 P D E 4抑制劑的溶液來灌流鼻黏膜3 0分鐘。然後,在 開始用含有卵淸蛋白之溶液進行灌流(激發)之前,立即 注射伊文斯藍。在卵淸蛋白激發(1 0 m g / m 1之溶於 P B S的卵淸蛋白)開始進行了 1 5分鐘後,在6 0分鐘 ^紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 一 -36· 530048 A7 B7 五、發明説明(34) (請先閱讀背面之注意事項再填寫本頁) 期間,於級分收集器中,每1 5分鐘收集一次級分。用 Digiscan光度計,在6 2 0 n m的波長下,測量灌流液中之 伊文斯藍的濃度。在該過程中,空白値自動被扣除。6〇 分鐘期間的作用過程係以A U C程式來計算。製劑組中受 試物質的作用係以相對於賦形劑對照的%計算得的。 就本發明之化合物而言,所測得之I C 5 (3値係在 1 0— 8至1 0— 5M的範圍內。 式1所示之本發明化合物用於治療慢性阻塞性肺病的 實用性係經藉由對於人類血液內由L P S所引發之 T N F α釋出的抑制作用以及藉由對於白鼬及牷養豬體內 由L P S所誘發之肺嗜中性白血球浸潤的抑制作用,予以 證實。 經濟部智慧財產局員工消費合作社印製 單離出之白血球細胞對於細胞激素(cytokine )釋出 的刺激作用可以各種方式發生。脂多糖(L P S )係適用 於T N F α釋出之硏究的刺激。L P S係細菌細胞壁的組 成份且係藉由殺死細菌(抗生素或免疫系統)而被釋出。 L P S特別會刺激會吞噬細胞之白血球(組織巨噬細胞、 粒性細胞、單核白血球細胞)的活性且會造成白血球自血 液浸潤至受感染的組織。對於此等機轉非常重要的細胞激 素(c y t 〇 k i n e )爲T N F α,其會被受感染的細胞(單核 白血球細胞及巨噬細胞爲主要來源)大量分泌出來,並會 靠著其他介體,起始並維持發炎狀態。 經1 : 5稀釋人血中之由LPS所引發的TNFa釋出 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) -37- 530048 A7 B7 五、發明説明(35) (請先閱讀背面之注意事項再填寫本頁) 爲進行對於T N F α釋出之影響的硏究’茲自數個捐 血者取得血液(藉助檸檬鹽來抑制凝固),並用R Ρ Μ I 1 6 4 0細胞培養基,以1 : 5的比例稀釋血液。在 L P S激發之前,將各種濃度的受試化合物添加至血液試 樣中。3 0分鐘後,使用得自馬流產桿菌的脂多糖類( L Ρ S )(最終濃度爲1 0 // g / m 1 )來刺激白血球。 於3 7 °C、5 % C〇2下,於培養器中,將試驗批液培養 2 4小時,然後,將該稀釋的血液離心並用E L I S A來 測量不含細胞之上淸液中的T N F α濃度。 就本發明之化合物而言,所測得之I C 5 (D値係於 1〇—7至1 0 _ 5 Μ的範圍內。例如,實施例1之化合物所 測得的I C 5。値爲〇 · 5 // m ο 1 / 1 。相較之下,參考 標準物S B 2 0 7 4 9 9所測得之I C 5 Q値爲7 · 0 // m ο 1 / 1 。 對於白鼬體內之由脂多糖(L P S )所引起之嗜中性白血 球過多的抑制作用 經濟部智慧財產局員工消費合作社印製 於活體實驗中,在白鼬(0 · 6 — 2 k g )體中進行 受試物質對於肺嗜中性白血球浸潤的抑制作用。用戊基巴 比特魯鈉(4 0 m g / k g (體重),經腹膜內),將試 驗動物麻醉,分別放在容量爲5 <之封閉的噴霧箱中,並 令彼等曝露於〇 · 〇 1 %強度之L P S (脂多糖)溶液( 額外之0 · 1 %之於Ρ B S中的羥基胺)的經超音波霧化 氣溶膠下1 〇分鐘。該氣溶膠係由壓縮空氣(〇 · 2 本紙張尺度適用中國國家標準(CNS )八4規格(210X297公釐) 38- 530048 A7 B7 五、發明説明(36) (請先閱讀背面之注意事項再填寫本頁) M p a )所驅動之噴霧器產生的。對照組的動物係用生理 食鹽溶液之氣溶膠予以處理。在整個過程中對彼等動物進 行觀察並在有新鮮空氣進入後,將動物移出噴霧箱。在被 吸入後,霧化的L P S立即引發氣道炎症,其係以嗜中性 粒性細胞大量浸潤於試驗動物之肺部爲特徵。在L P S曝 露後4至6小時,嗜中性細胞過多的情況達到最大。爲了 能夠測量浸潤嗜中性粒性細胞的數目,在經L P S激發6 小時後,用劑量過量之乙基脲(1 · 5 g / k g (體重) 經濟部智慧財產局員工消費合作社印製 ,經腹膜內),將動物麻醉,並用2 X 1 0 m 1之生 理食鹽溶液來進行枝氣管與肺胞的灌洗(B A L )。用 Technicon H1E 自動細胞計數裝置(Bayer Diagnostic ), 測定混合之B A L原始液(1 〇 〇 // 1 )中的細胞數目, 並對每一 # 1中的不同白血球進行鑑別。在各試驗中,包 括有二組對照組(以生理食鹽溶液噴霧者或以L P S溶液 噴霧者)。具有抗發炎活性的物質,尤其是會影響 T N F α之釋出或是影響嗜中性粒性細胞之功能的物質, 會抑制白血球的浸潤。對於浸潤的抑制作用係藉由與未經 處理之試驗動物(有或無L P S的激發)的浸潤嗜中性白 血球數目進行比較而得者。 就本發明之化合物而言,所得之I D 5。値係在1至 2 0 m g / k g (經腹膜內)的範圍內。例如,在l P S 激發前,分別以1、3及1 0 m g / k g之劑量,經腹膜 內,將實施例1之化合物投予3隻試驗動物(一種劑量投 予一隻動物)。B A L中的嗜中性白血球過多係以取決於 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -39- 530048 A7 B7__ 五、發明説明(37) 劑量的方式被抑制(1 8 %、6 4 %及7 8 % ) 。I D 5 〇 爲2 · 4 m g / k g (經腹膜內)。. (請先閲讀背面之注意事項再填寫本頁) 以1 m g / k g (經腹膜內)之劑量,投用經選擇的 P D E 4抑制劑R P R 一 7 3 4 0 1 (參考物質),可對 於嗜中性白血球過多造成4 9 %之抑制。 在經肺內投藥的情況下,係於麻醉的狀態下(4 0 m g / k g (經腹膜內)之戊基巴比特魯鈉,3 %強度, 1 · 3 m 1 / k g ),將動物的氣管打開,然後,接上7 公分之P V C導管並在L P S激發前2小時,利用唧筒式 注射筒,將受試物質以粉末的形式(混合有2 0 m g / k g乳糖),經肺內投予。 1、3及1 0 m g / k g劑量之如實施例1的化合物 係以取決於劑量的方式,抑制由L P S所引起的嗜中性白 血球過多(43%、65%及100%) 。ID5 ◦爲 1 · 65mg/kg (經手掌)。 牷養豬之由L P S所引起的嗜中性白血球過多 經濟部智慧財產局員工消費合作社印製 依對白鼬所進行的方式,可在牷養豬體內引起肺嗜中 性白血球過多。將動物麻醉(戊基巴比特,1 0 m g / k g,經靜脈)並插入喉管。使用枝氣管鏡,進行部分的 枝氣管及肺胞灌洗,以便在生理條件下測定嗜中性粒性細 胞的比例。然後,投用受試物質並令動物透過氣管用管吸 入0 · 0 3 %強度之L P S (脂多糖)溶液(額外含有 0 · 1 %之在P B S中的羥基胺)的超音波霧化氣溶膠, 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) -40 - 530048 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明(38) 歷時2 0分鐘。被吸入的L P S會引起氣道的變應性發炎 以及嗜中性粒性細胞大範圍的浸潤。嗜中性白血球的過多 狀態在曝露於L P S之後的4 一 6小時達到最大。在6小 時後,重覆枝氣管及肺胞灌流,並以算數的方法,測定嗜 中性白血球的數目。 因豬類的動物在解剖學上及生理上與人類有相當大部 分的類似性,所以彼等特別適用於此類硏究。 就本發明之化合物而言,以1 0 m g /動物之劑量經 肺內投用,可測得2 0 %至6 5 %之抑制L p s所引起嗜 中性白血球過多的抑制作用。 以l〇mg/動物(約〇 · 75mg/kg)之劑量 ,經肺內投用實施例1之化合物,可將由L p s所引起的 肺嗜中性白血球過多抑制5 1 %。 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)
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Claims (1)
- 530048 A8 B8 C8 D8 六、申請專利範圍 附件A : 第88106886號專利申請案 一一手女申請專利範圍修正本 v\- 修正 補充 /1.. 民國91年12月17日修正 種如式1所示之羥基吲哚 μR1 R5 (請先閲讀背面之注意事項再填寫本頁) 一裝· 其中 R1爲可任意經苯基或C3- C8環烷基所取代之直鏈 或含支鏈之Ci- C4烷基,或爲吡啶基,其中該 苯基可任意經鹵素、硝基、羥基、C i 一 C 4烷基 、Ci 一 C4烷氧基或一C〇〇H所取代, R2和R3各自獨立地爲氫或一 OH,其中R2和R3至 少其中一個必須爲一 Ο Η, R 5爲苯基或吡啶基,其中該苯基或吡啶基可任意經下 列基團所取代:可任意經鹵化之C i - C 4烷基, 可任意經鹵化之Ci— C4烷氧基,一C〇〇H, 及一 C〇〇(Ci — C4烷基),且該苯基或吡啶 基具有至少一個選自—F、一 C1、— Br與—I 之取代基,以及 _ A爲一鍵,C二〇或CH〇H, 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 訂 1^ 經濟部智慧財產局員工消費合作社印製 530048 A8 B8 C8 D8 ____ 六、申請專利範圍 及其鹽類。 (請先閱讀背面之注意事項再填寫本頁) 2 ·如申請專利範圍第1項之式1所示化合物,其爲 鹽類,且係由無機或有機酸與鹼類的中和作用或是無機或 有機鹼類與酸類的中和作用或是將三級胺類四級化爲四級 銨鹽類的成四級化反應而得。 .3 .如申請專利範圍第1或2項之式1所示的化合物 ,其具有不對稱碳原子而呈D形式、L形式及D,L混合 物形式且在有數個不對稱碳原子的情況,呈非對映立體異 構的形式。 4 ·如申請專利範圍第1項之式1所示化合物,其特 別爲下列化合物之一: N— (3, 5 -二氯吡啶—4 —基)一 2 -〔1—( 4 —氟苄基)一 5 —羥基吲哚一 3 -基〕—2 —氧基乙醯 胺; N— (3,5 — 一氯吼11 定—4 —基)—2 —〔 1—( 4 一氟苄基)一 5 —羥基吲哚一 3 —基〕—2 -氧基乙醯 胺鈉鹽; 經濟部智慧財產局員工消費合作社印製 N -(3, 5 — 一氯 d 比 B定—4 —基)一2_〔 1—( 4 一氟苄基)一 5 -羥基吲哚一 3 -基〕一 2 —羥基乙醯 胺; N — (3, 5 —二氯吡啶一4 —基)一2 — 〔 1—( 2, 6 -二氟苄基)—5 —羥基吲哚—3 -基〕一2 -氧 基乙醯胺; . n—(3, 5 —二氯吡啶一 4 —基)一2 —〔1 一( — 本、”氏張尺度適用中_家標準(cns )八4祕(2似297公釐) -2 - 530048 ABCD 六、申請專利範圍 3 -硝苄基)一 5 -羥基吲哚—3 —基〕—2 —氧基乙醯 胺鈉鹽;· N — (3, 5 —二氯吡啶—4一基)—2—〔1—丙 基一 5 -羥基吲哚—3 —基〕一 2 -氧基乙醯胺; N - (3, 5 —二氯吡啶—4 —基)—2 —〔1—異 丙基一 5 —羥基吲哚一 3 —基.〕一 2 -氧基乙醯胺; N — (3,5 - 一氯吼陡—4 —基)一 2 —〔1—環 戊基甲基—5 —經基11引晚一 3 -基〕一 2 —氧基乙醯胺; N — (2,6 — —^氯苯基)—2 —〔1— (4—赢卡 基)—5 -羥基吲哚一 3 -基〕一 2 —氧基乙醯胺; N — (2, 6 —二氯—4 —三氟甲基苯基)—2 —〔 1— (4 —氟苄基)—5 -羥基吲哚一 3 -基〕—2 —氧 基乙醯胺; N — (2, 6 — 一氯一 4 一二氟甲氧苯基)—2 —〔 1— (4 一氣;基)一 5 —經基D引D朵一 3 -基〕—2 —氧 基乙醯胺; N — (3, 5 — 一氯吼陡—4 —基)一2 — 〔1—.( 4 —氟苄基)一 6 -羥基吲哚一 3 -基〕一 2 —氧基乙醯 胺; N -( 3,5 — 一氯吼 Η定—4 ·—基)一 5,—經基一 1 —(4 一甲氧苄基)吲哚一3 —基〕—2 —甲醯胺。 5 . —種如申請專利範圍第1項之式1化合物的製備 方法,其特徵在於藉由R 7的移除,將其中之R1或R 3或 是R 2及R 3示-〇- R 7的式1化合物轉化爲本發明之化 本紙張尺度適用中國國家標準(CNS ) Α4規格( 210 X 297公釐) : -3- --------0^—— (請先閱讀背面之注意事項再填寫本頁) .1Τ 經濟部智慧財產局員工消費合作社印製 530048 A8 B8 C8 D8 々、申請專利範圍 合物,其中,在此情況下,R 7係示適作爲離去基的取代基 〇 6 .如申請專利範圍第5項之製備方法,其尤其係以 R 7示下列基團的式1化合物爲起始物:烷基、環烷基、芳 烷基、芳基、雜芳基、醯基、烷氧羰基、芳氧羰基、胺羰 基' N -經取代的胺羰基、甲矽烷基或磺醯基,以及錯合 劑,例如,硼酸、磷酸及共價或配位鍵結金屬(諸如,鋅 、鋁或銅)之化合物。 7 · —種如申請專利範圍第1項之式1化合物的製備 方法,其特徵在於通式1所示化合物藉由下式所示次結構 的轉化而轉化爲其他式1化合物: 其中a與R 5如申請專利範圍第1項定義。 8 ·如申請專利範圍第1項之式1所示化合物,其係 用作爲治療上的活性成份,用於製造供治療因T N F α之. 抑制而在治療上受益之病症的藥物。 9 ·如申請專利範圍第1項之式1所示化合物,其係 用作爲治療上的活性成份,用於製造供治療因磷酸二酯酶 4之抑制而在治療上受益之病症的藥物。 1 〇 .如申請專利範圍第1項之式1所示化合物,其 係作爲治療上的活性成份,用於製造供治療與嗜伊紅細胞 有關之病症的藥物。 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) 、1Τ 經濟部智慧財產局員工消費合作社印製 -4 - 530048 A8 B8 C8 D8 六、申請專利範圍 1 1 .如申請專利範圍第1項之式1所示化合物,其 係用作爲治療上的活性成份,用於製造供治療慢性阻塞性 肺病(C〇P D )的藥物。 1 2 . —種具有磷酸二酯酶4抑制劑活性的藥學組成 物,其包含如申請專利範圍第1至4項之一或多個化合物 以及慣用之生理上可耐受的載體及/或稀釋劑或輔劑。 1 3 .如申請專利範圍第4項之式1所示化合物,其 係選自下列群體: N - ( 3 , 5 —二氯吡啶—4 —基)—2 —〔1—( 4 —氟苄基)—5 —羥基吲哚一 3 -基〕一 2 —氧基乙醯 胺;以及 藥學上可接受鹽類。 (請先閱讀背面之注意事項再填寫本頁) 訂 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) -5 -
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