TWI344956B - Caspase inhibitors and uses thereof - Google Patents
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- TWI344956B TWI344956B TW093115134A TW93115134A TWI344956B TW I344956 B TWI344956 B TW I344956B TW 093115134 A TW093115134 A TW 093115134A TW 93115134 A TW93115134 A TW 93115134A TW I344956 B TWI344956 B TW I344956B
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Classifications
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Description
1344956 九、發明說明: 【發明所屬之技術領域】 本發明係在醫藥化學之領域中,且係關於抑制會媒介細胞 调零與發炎之卡司沛酶之化合物及其醫藥組合物。本發明 亦關於製備此等化合物之方法。本發明進一步關於使用本 發明化合物與醫藥組合物以治療其中牽涉卡司沛酶活性之 疾病之方法。 【先前技術】 細胞凋零或程式化之細胞死亡係為生物體藉以脫除不想要 細胞之主要機制。細胞凋零之失調,無論是過度細胞凋零 或未能進行之,係牽連多種疾病,譬如癌症、急性炎性與 自身免疫病症、絕血性疾病及某些神經變性病症(一般性地 參閱 ⑼叱 1998, 281,1283-1312 ; Ellis 等人 μ助·及抑· Ce// 及.〇/,1991, 7,663)。 卡司沛酶係為半胱胺酸蛋白酶之族群,其係為細胞凋零與 細胞分解之發出訊息途徑上之關鍵介體(Th〇mberry,所〇/, 1998, 5, R97-R103)。此等發出訊息途徑係依細胞類型與刺激而 改變,但所有細胞祠零途徑似乎會收斂在一個共同效應子 途徑上’導致關鍵蛋白質之蛋白水解。卡司沛酶係涉及發 出訊息途徑之效應期,及進一步在其引發之上游兩者。涉 及引發事件之上游卡司沛酶係變成經活化,且依次活化涉 及細胞凋零稍後期之其他卡司沛酶。 卡司沛酶-1,第一種經確認之卡司沛酶,亦被稱為間白血 球活素轉化酶或"ICE”。卡司沛酶]係藉由Asp-n6與編17間 93320 1344956 《PIL-W之專一分裂,使先質間白血球活素。轉 化成預發炎活性形式。除了卡司沛酶」之外,亦有十一種其 他已知人類卡司沛酶,其全部均會專一性地在天門冬胺醯 基殘基處分裂。亦發現其對於在分裂位置之Ν·末端側上之 至V四胺基酸殘基’具有嚴厲要求條件。 卡司沛酶已被分類成三個組群,依係為較佳或主要經辨識 之胺基酸順序而^。卡司沛酶之組群,其包括卡司沛酶i、 4、5及13,已被証實較喜歡分裂位置之沁末端側上之位置斗 處之疏水性芳族胺基酸類。另—個包括卡司沛酶2、3及7之 組群,會辨識分裂位置之N_末端側上之丨與4兩位置處之天 門;胺Si基殘基,且較佳為ASp_Qu_x_ASp之順序。包括卡司 沛酶6、8、9及1〇之第三組群,容許多種胺基酸在主要辨識. 順序中’但似乎較喜歡具有分枝狀脂族側鏈之殘基,譬如· 纈' 胺酸與白胺酸在位置4。 卡司沛酶亦已根據其所察覺之功能被分類。第一種亞族群 I括卡司沛酶-1 (ICE)、4、5及13。此等卡司沛酶已被註實 係涉及預發炎細胞活素處理,因此在發炎中扮演一項重要 角色。卡司沛酶-1,此種類之最受研究酵素,其係藉蛋白分 解之分裂作用,使IL_i沒先質活化。因此,此酵素在炎性回 應中係扮演一項重要角色。卡司沛酶-1亦涉及處理干擾素_τ 誘發因子(IGIF,亦稱為IL-18),其會刺激干擾素了之產生’ 〃、為種會凋制抗原呈現、T-細胞活化及細胞黏連之關鍵免 疫調節劑。 其餘卡司·布酶係構成第二個與第三個亞族群。此等酵素在 93320 1344956 導致細胞凋零之胞内發出.訊息途徑中,係具有中樞重要性 。一個亞族群包括在細胞凋零途徑中涉及引發事件之酵素 ,該事件包括來自漿膜之訊息轉導。此亞族群之成員包括 卡司沛酶-2、8、9及10。另一個亞族群包括效應子卡司沛 蛋白酶3、6及7,其係涉及最後下游分裂事件,其會造成細 胞藉由細胞凋零之系統崩解與死亡。涉及上游訊息轉導之 卡司沛酶,會使下游卡司沛酶活化,其接著會使DNA修補 機制無法使用,使DNA破碎,拆除細胞骨架及最後使細胞 破碎。 主要被卡司沛酶辨識之四胺基酸順序之知識,已被用以設 計卡司沛酶抑制劑。可逆四肽抑制劑已被製成具有結構 CH3C0-[P4]-[P3]-[P2]-CH(R)CH2C02H,其中 P2 至 P4 表示最適宜 胺基酸辨識順序,且R為能夠結合至卡司沛酶半胱胺酸氫硫 基之酸、月耷或酮。Rano 與 Thomberry,CAew.所<?/. 4, 149-155 (1997); Mjalli 等人,CAem. /«姐 3, 2689-2692 (1993) ; Nicholson 等 人,Mziwre 376, 37-43 (1995)。以類似四肽辨識順序為基礎之不可 逆抑制劑已被製成,其中R為醯氧基曱基酮-COCH2〇COR’》R' 之實例為視情況經取代之苯基,譬如2,6-二氯苯甲醯氧基, 且其中R為COCH2 X ’其中X為脫離基,譬如F或C1。Thomberry 等人,33, 3934 (1994); Dolle 等人,/攸么 c/iem. 37, 563-564 (1994)。 卡司沛酶抑制劑治療多種與增加細胞凋零有關聯之哺乳動 物疾病狀態之利用性,已使用肽性卡司沛酶抑制劑紐實。 例如,在齧齒動物模式中,卡司沛酶抑制劑已被註實會降 93320 1344956 低梗塞大小’且抑制心肌梗塞後之心肌細胞凋零,降低由 於中風所造成之損害體積與神經不足,降低外傷性腦部傷 害中之外傷後細胞凋零與神經不足,有效治療暴發性肝臟 破壞’及内毒素休克後之經改善存活。Yaoita等人,C/rcw/α如97, 276(1998) ; Endres 等人,18,238, (1998) ; Cheng 等人,/ C/zVz. /nv如.,101, 1992 (1998) ; Yakovlev 等人, 17, 7415 (1997) ; Rodriquez 等人,184, 2067 (1996) ; Grobmyer 等人,Mo/. MM.,5, 585 (1999)。 一般而言,上述肽性抑制劑係極有效抵抗一些卡司沛酶酵 素。但是,此功效並非總是反映在細胞凋零之細胞模式中 。此外,肽抑制劑典型上之特徵為不期望之藥理學性質, 譬如不良口腔吸收性、不良安定性及快速新陳代謝作用。 Plattner與Norbeck,在藥物發現技術中,Clark與Moos編著 (Ellis Horwood, Chichester, England, 1990) 0 在察覺必須改良肽性卡司沛酶抑制劑之藥理學性質後,擬 肽抑制劑已被報告。其中特別是,其中P3胺基酸已被3-胺基 吡啶-2-酮與5-胺基嘧啶-4-酮之衍生物取代之抑制劑已被報告 (美國專利 5,756,466 (Bemis 等人);PCT 公報案號 W0 95/35308 (Bemis 等人);Dolle 等人·/. MWAem. 39, 2438,(1996) ; Golec 等人 Bioorg. Med. Chem. Leii. 7, 2\SU ('997) .,Semipie 等人,Bioorg. Med. Chem. Z故.7, 1337,(1997))。 由於肽性抑制劑之固有問題,故仍需要小分子非肽卡司沛 酶抑制劑,其係有效、安定,且會穿透細胞膜,以提供有 效活體内細胞凋零之抑制。此種化合物係極端地可用於治 93320 療前文所提及之其中卡司沛酶酵素扮演一項角色之疾病。 【發明内容】 本發明係提供式I化合物:
1344956 其中:R1、R2、R3、R4及R5均如本文定義。 本發明亦提供包含式I化合物之醫藥組合物,及使用此種 化合物與組合物以治療卡司沛酶所媒介疾病之方法。本發 明亦提供製備式I化合物之方法。 發明詳沭 本發明係提供式I化合物: R2
其中: R1 為 R6C(0)-、HC(O)-、R6S02-、r6〇c(〇)- ' (R6)2NC(0)-、 (R6)(H)NC(0)-、R6C(0)C(0)-、R6-、(R6)2NC(0)C(0)·、(R6)(H)· NC(0)C(0)-或 R60C(0)C(0)-; R2 為氫、-CF3、函基、-OR7、-N02、-〇CF3 ' -CN 或 R8 ; R3為氮或(Ci -C4 )-脂族-, R4 為-COOH 或-COOR8 ; 93320 1344956 R5 為-CH2 F 或-CH2 0-2,3,5,6-四氟苯基; R6 為(C1-C12)-脂族-(C3-C10)-環脂族-、(C6-C10)-芳基 _、(c3_ci〇)_ 雜環基-' (C5-C10)-雜芳基-、(C3-C10)-環脂族_(C1_C12)_脂族. 、(C6-C10)-芳基-(C1-C12)-脂族-、(C3-C10)-雜環基 _(ci_ci2m 族-、(C5-C10)-雜务基(C1-C12)-脂族-,或兩個結合至相同原 子之R6基團與該原子一起形成3-至10-員芳族或非芳族環 ’其中該壤係視情況調合至(C6-C10)芳基' (C5-C10)雜芳基 、(C3-C10)環烷基或(C3-C10)雜環基;其中至高3個脂族碳 原子可被選自0、N、N(R)、S、SO及S02之基團置換;( 且其中R6係被至高6個獨立選自R之取代基取代; R 為齒素、-OR7、-0C(0)N(R7)2、-N02、-CN、_CF3、-0CT3 、-R7、酮基、硫酮基、=NR7、=N(OR7)、1,2-亞甲二氧基、i,2-. 次乙二氧基、-N(R7)2、-SR7、-SOR7、-S02R7、-S02N(R7)2、-S03R7 . 、-C(0)R7、_C(0)C(0)R7 ' -C(0)C(0)0R7、-C(0)C(0)N(R7)2、 -C(0)CH2 C(0)R7、-C(S)R7、-C(S)OR7、-C(0)0R7、-0C(0)R7、-C(C)N(R7 )2 、-0C(0)N(R7 )2、-C(S)N(R7 )2、-(CH2 )〇. 2 NHC(0)R7、-N(R7 )N(R7 )COR7 { 、-N(R7)N(R7)C(0)0R7、-N(R7)N(R7)CON(R7)2、-N(R7)S02R7、 -N(R7)S02N(R7)2、-N(R7)C(0)OR7、-N(R7)C(0)R7、-N(R7)C(S)R7、 -n(r7)c(o)n(r7)2 ' -N(R7)C(S)N(R7)2、-N(COR7)COR7、-n(or7)r7 、-c(=nh)n(r7)2、-c(o)n(or7)r7、-c(=nor7)r7、-op(o)(or7)2、 -p(o)(r7)2、-p(o)(or7)24-p(o)(h)(or7); 兩個R7基團和彼等所結合之原子一起形成3-至10-員芳 族或非芳族環,具有至高3個獨立選自N、N(R)、0、S、SO 或S02之雜原子,其中該環係視情況稠合至(C6-C10)芳基、 93320 •12- 1344956 (C5-C10)雜芳基、(C3-C10)環烷基或(C3-C10)雜環基,且其中任 何環具有至高3個獨立選自j2之取代基;或 各R7係獨立選自: 氫-, (CU-C12)-月旨族-, (C3-C10)-環脂族-, (C3-C10)-環脂族-(C1-C12)-脂族-, (C6-C10)-芳基-, (C6-C10)-芳基-(C1-C12)脂族-, (C3-C10)-雜環基-, (C6-C10)-雜環基-(C1-C12)脂族-, (C5-C10)-雜芳基-,或 (C5-C10)-雜芳基-(C1-C12)-脂族-; 其中R7具有至高3個獨立選自J2之取代基;且 J2 為自素、-OR7、-0C(0)N(R7)2、-N02、-CN、_CF3、-OCF3、-R7 、酮基、硫酮基、=NR7 ' =NOR7、1,2-亞甲二氧基、1,2-次 乙二氧基、-N(R7)2、-SR7、-SOR7、-S02R7、-S02N(R7)2、-S03R7 、-C(0)R7、-C(0)C(0)R7、-C(0)C(0)0R7、-C(0)C(0)N(R7)2、 -C(0)CH2C(0)R7、-C(S)R7、-C(S)OR7 ' -C(0)0R7、-0C(0)R7、 -c(o)n(r7)2、-oc(o)n(r7)2、-c(s)n(r7)2、-(CH2)0.2NHC(O)R7 、-n(r7)n(r7)cor7、-n(r7)n(r7)c(o)or7、-n(r7)n(r7)con(r7)2 、-n(r7)so2r7、-n(r7)so2n(r7)2、-n(r7)c(o)or7、-n(r7)c(o)r7 、-n(r7)c(s)r7、-n(r7)c(o)n(r7)2、-N(R7)C(S)N(R7)2、 -N(COR7)COR7、-N(OR7)R7、-CN、-c(=nh)n(r7)2、-c(o)n(or7)r7 93320 •13- 1344956 、-C(=NOR7)R7、-op(o)(or7)2、-p(o)(r7)2、-p(o)(or7)2 或 -P(0)(H)(0R7);及 R8 為(C1-C12)-脂族-(C3-C10)-環脂族-、(C6-C10)-芳基-、(C3-C10)-雜環基-、(C5-C10)-雜芳基-、(C3-C10)-環脂族-(C1-C12)-脂族-、(C6-C10)-芳基-(C1-C12)-脂族-、(C3-C10)-雜環基-(C1-C12)-脂 族-、或(C5-C10)-雜芳基(C1-C12)-脂族-,其中至高3個脂族 碳原子可被選自0、N、N(R)、S、SO及S02之基團置換; 且其中R8係視情況被至高6個獨立選自R之取代基取代。 本發明亦提供式I化合物:
其中〃 R1 為 R6C(0)-、R6S02- ' R60C(0)- ' (R6)2NC(0)-、R6C(0)C(0)-、 R6-、(r6)2nc(o)c(o)-或 r6oc(o)c(o)-; R2 為氫、-CF3、li 基、-OR7、-N02、-OCF3、-CN 或 R8 ; R3為氫或(C1-C4)-脂族-; R4 為-COOH 或-COOR8 ; 尺5為-(:112?或-〇120-2,3,5,6-四氟苯基; R6 為(C1-C12)-脂族-(C3-C10)-環脂族-、(C6-C10)-芳基-' (C3-C10)-雜環基-、(C5-C10)-雜芳基-、(C3-C10)-環脂族-(C1-C12)-脂族-·、(C6-C10)-芳基-(C1-C12)-脂族-、(C3-C10)-雜環基-(C1-C12)-脂 族-、(C5-C10)-雜芳基(C1-C12)-脂族-,或兩個結合至相同原 93320 •14- 1344956 子之R6基團與該原子一起形成3-至10-員芳族或非芳族環 ;其中該環係視情況稠合至(C6-C10)芳基、(C5-C10)雜芳基 、(C3-C10)環烷基或(C3-C10)雜環基;其中至高3個脂族碳 原子可被選自Ο、N(H)、N〇R)、S、SO及S02之基團置換 ;且其中R6係被至高6個獨立選自R之取代基取代; R 為鹵素、-OR7、-0C(0)N(R7)2、-N02、-CN ' -CF3、-0CF3 、-R7、酮基、硫酮基、1,2-亞甲二氧基、1,2-次乙二氧基、 -N(R7)2、-SR7、-S0R7、-S02R7、-S02N(R7)2、-S03R7、-C(0)R7 、-C(0)C(0)R7 ' -C(0)CH2C(0)R7、-C(S)R7、-C(0)0R7、-0C(0)R7 、-c(o)n(r7)2、-oc(o)n(r7)2、-c(s)n(r7)2、-(CH2)0.2NHC(O)R7 、-n(r7)n(r7)cor7、-n(r7)n(r7)c(o)or7、_N(R7)N(R7)CON(R7)2 、-n(r7)so2r7、-n(r7)so2n(r7)2、-N(R7)C(0)0R7、-n(r7)c(o)r7 、-N(R7 )C(S)R7、-N(R7 )C(0)N(R7 )2、-N(R7 )C(S)N(R7 )2、-N(COR7 )C0R7 、-n(or7)r7、-c(=nh)n(r7)2、-c(o)n(or7)r7、-c(=nor7)r7、 -0P(0)(0R7)2、-P(〇)(R7)2、-P(〇)(〇R7)2 或-P(〇)(H)(OR7); 兩個R7基團和彼等所結合之原子一起形成3-至10-員芳 族或非芳族環,具有至高3個獨立選自N(H)、N(R)、Ο、s、 SO或S02之雜原子,其中該環係視情況稠合至(C6-C10)芳基、 (C5-C10)雜芳基' (C3-C10)環烷基或(C3-C10)雜環基,且其中任 何環具有至高3個獨立選自J2之取代基;或 各R7係獨立選自: 氫-, (。1-。12)-月旨族_, (C3-C10)-環脂族-, 93320 -15- 1344956 (C3-C10)-環脂族-(C1-C12)-脂族-, (C6-C10)-芳基-, (C6-C10)-芳基-(C1-C12)脂族-, (C3-C10)-雜環基-, (C6-C10)-雜環基-(C1-C12)脂族-, (C5-C10)-雜芳基-,或 (C5-C10)-雜芳基-(C1_C12)-脂族-; 其中R7具有至高3個獨立選自J2之取代基;及 了2為 _ 素、-OR7、-0C(0)N(R7)2、-N02、-CN、-CF3 ' -OCF3、-R7 、酮基、硫酮基、1,2-亞甲二氧基、1,2-次乙二氧基、-N(R7)2 、-SR7、-SOR7、-S02R7、-S02N(R7)2 ' -S03R7、-C(0)R7、 -C(0)C(0)R7、-C(0)CH2C(0)R7、-C(S)R7、-C(0)OR7、-0C(0)R7 、-c(o)n(r7)2、-oc(o)n(r7)2、-c(s)n(r7)2、-(ch2)〇.2nhc(o)r7 、-n(r7)n(r7)cor7、-n(r7)n(r7)c(o)or7、-N(R7)N(R7)CON(R7)2 、-n(r7)so2r7、-n(r7)so2n(r7)2、-N(R7)C(0)0R7、-n(r7)c(o)r7 、-N(R7)C(S)R7、-N(R7)C(0)N(R7)2、-N(R7)C(S)N(R7)2、 -N(COR7)COR7、-N(OR7)R7、-CN、-c(=nh)n(r7)2、-c(o)n(or7)r7 、-c(=nor7)r7、_op(o)(or7)2、-p(o)(r7)2、-p(o)(or7)2 或 -P(0)(H)(〇R7);且 R8 為(C1-C12)-脂族-(C3-C10)·環脂族-、(C6-C10)-芳基-、(C3-C10)-雜環基-、(C5-C10)-雜芳基-、(C3-C10)-環脂族-(C1-C12)-脂族-、(C6-C10)-芳基-(C1-C12)-脂族-、(C3-C10)-雜環基-(C1-C12)-脂 族-或(C5-C10)-雜芳基(C1-C12)-脂族-,其中至高3個脂族碳 原子可被選自0 ' N(H)、N(R)、S、SO及S02之基團置換。 93320 -16- 1344956 本發明之另一項具體實施例係提供一種化合物,其中R1為 R6C(0)-、R6S(V或R6-。於一項較佳具體實施例中,R1為 R6C(0)-。在另一項較佳具體實施例中,Ri為R6s〇2-。於又另 一項較佳具體實施例中,Rl為R6_。 本發明之另一項具體實施例係提供—種化合物,其中R1為 (R6)2NC(0)-或(R0)0C(0)-。於一項較佳具體實施例中,Ri為 (R6)2NC(0)-。在另一項較佳具體實施例中,Ri為(R6)(H)NC⑼_ 。於又另一項較佳具體實施例中,R1為(R6 )〇C(〇)_。 在本發明之一項具體實施例中,各R6係獨立為((^七分脂族- 、(C3-C10)-環脂族、(C3-C10)-雜環基、(C5-C10)-雜芳基、(C6-C10)-芳基-或(C6-C10)-芳基-(C1-C12)-(應明瞭的是,視情況至高3個 脂族碳原子可被選自◦、N、N(R)、S、SO及S02之基團置換 ;且其中R6係視情況被至高6個獨立選自r之取代基取代, 或R6係如在本文任何具體實施例中所揭示經取代)。 於另一項具體實施例中’各R6係獨立為Η、(C1-C4)-脂族-或(C6-C10)-芳基-,或各R6與Ν_原子一起為(C3_C7)_環脂族。於 另一項具體實施例中,各R6係獨立為(C1_C4)_脂族_、(C5_C10)_ 雜芳基-或(C6-C10)-芳基·,其中雜芳基或芳基係視情況經取 代,或其中各R6與N-原子一起為(C3-C7)-環脂族。 於另一項具體實施例中,各R6係獨立為(C1_C4)_脂族_或(C6_ CIO)-芳基_,其中芳基係視情況經取代,或其中各R6與N_原 子一起為(C3-C7)-環脂族。 於又另一項具體實施例中,各r6係獨立為(C1_C4)_脂族_、 (C3-C7)-環脂族' (C6-C10)-芳基-、(C5-C10)-雜芳基,其中雜芳 93320 -17- 1344956 基與芳基係獨立且視情況經取代,或各R6與N_原子一起為 (C3_C7)-環脂族。 根據本發明之較佳具體實施例,R2為氫,Cl-、C2- ' C3- 或 C4_燒基-,_CF3、'Cl、-OR7、-N02、-〇CF3 或-CN。R2 更佳 為氫、Cl-烷基_、C2-燒基-或CF3。R2更佳為氫或CF3。 根據另一項較佳具體實施例,R3為乙基。 根據另一項較佳具體實施例,以為_Ch2〇_2,3,5,6_四氟苯基。 根據另一項較佳具體實施例,R5為_CH2F。 根據另一項較佳具體實施例,R8為(C1_C12)_烷基。R8更佳 為(C1-C4)-燒基β 根據較佳具體實施例,各R與j2係獨立為鹵素、_〇R7、 -oc(o)n(r7)2、_n〇2、_CN、_Cf3、_οα?3、_r7、酮基、12 亞 f 二氧基、1,2-次乙二氧基、_N(R7)2、_c(〇)r7、_c(〇)c(〇)r7、 -C(0)0R7、-〇c(〇)R7、_c⑼戰7)2或_〇哪離、。 於本文中使用之碳原子指定,可具有所指示之整數,及任 何介於其間之整數。例如,在(C1_C4)_烷基中之碳原子數為1 、2、3或4。應明瞭的是,此等指定係指原子在適當基團中 之總數。例如,在(C3-Cl〇>雜環基中,碳原子與雜原子之總 數為3(譬如在氮丙矣中)、4、5 ' 6(譬如在嗎福琳中卜7、 8、9或 10。 於本文中使用之脂族基團’包括具有所指定原子數之直鏈 狀與分枝狀基團。若原子數為未財,則脂族基團具们至 個碳原子。正如所明瞭的’缔基及/或块基脂族基圏且 有最少2個碳原子。較佳脂族基團為垸基(較佳係具有… 93320 1344956 個原子)。 ,::有:非另有指明,否則本發明之較佳脂族基團為燒基 且具有 1、2、3、4、< + ^ 5或6個碳原子。烷基更佳係且有上 、2、3或4個碳原子。本發明之烯基與块基較㈣且有2 ' 3、…或6個碳原子,且更佳為2、3或4個碳原子。 ^垸基與環埽基具有⑻。個間之礙原子,且為單環狀或 雙環狀,包括線性稠合、^^接或 — 橋接或螺J哀狀。j衣脂族基團較佳 為環烷基或環烯基。更佳環脂族基團為3_、4_、&、“戈 員環’其更佳為環烷基環。 於本文中使用之,,芳族基團"或"芳基"係指含有至少一個 芳族環之㈣.員環系統。芳族環之實例包括苯基與茶基。 於本文中使用之”雜芳基"係指環系統,具有5_1〇個成員與 1、2或3個獨立選自N、N(R)、〇 ' s、沁及3〇2之雜原子, 其中至少一個壤為雜芳族(例如吡啶基、嘍吩或噻唑)。較 佳雜芳基為具有!或2個雜原子之5_或6_員環。在本發明之 某些具體實施例中,更佳雜芳基為含有"=N"基團者。 雜方基環之貫例包括2-呋喃基、3_呋喃基、N_咪唑基、2_ 咪唑基、4-咪唑基、5-咪唑基、苯并咪唑基、3_異哼唑基' 4-異嘮唑基、5-異哼唑基、2-呤唑基、4-崎唑基、5-嘮唑基 、N-吡咯基、2-吡咯基、3-吡咯基、2_吡啶基、3_吡啶基' 4_ 吡啶基、2-嘧啶基、4-嘧啶基、5_嘧啶基、嗒畊基(例如3_ 嗒畊基)、2-噻唑基、4-噹唑基、5_嘍唑基 '四唑基(例如5_ 四吐基)、三唑基(例如2-三唑基與5-三唑基)、2-嘧吩基、3-塞吩基、苯并呋喃基、苯并硫苯基、吲哚基(例如2_吲哚基) 93320 -19- 1344956 、巧I:。坐基(例如2-吡唑基)、異噻唑基、哼二唑基、ι,2,5-°亏二也基、丨,2,4·"号二唑基、1,2,3-三唑基、1,2,3-嘧二唑基、1,3,4-塞二吨基、1,2,5-噻二唑基、嘌呤基、吡畊基、1,3,5_三畊基 、p奎淋基(例如2-喳啉基、3-喳啉基、4-喹啉基)及異喹啉基 (例如I-異p奎'·林基、3-異峻淋基或4-異p奎淋基)。 於本文中使用之"雜環"係指環系統,具有3_1〇個成員與1 、2或3個獨立選自n、N(R)、〇、S、SO及S02之雜原子, 其中供環為芳族(例如六氫吡啶與嗎福啉)。較佳雜環基為 具有1或2個雜原子之5_或6_員環。 雜%之實例包括3-1H-苯并咪唑_2_酮、3-(1-烷基)-苯并咪唑-2-酮2_四氫呋喃基、3-四氫吱喃基、2-四氫硫苯基、3-四氫 硫本基、2-嗎福啉基、3_嗎福啉基、4_嗎福啉基、孓硫代嗎 福啉基、3-硫代嗎福啉基、孓硫代嗎福啉基、丨_四氫吡咯基 、2·四氫吡咯基、3_四氫吡咯基、卜四氫化六氫吡畊基、厶 四氫化六氫吡畊基、3_四氫化六氫吡啡基、[六氫吡啶基、 2-六氫吡啶基、3_六氫吡啶基、丨_二氫吡唑基、弘二氫吡唑 基、4- 一氫吡唑基、5_二氫吡唑基、卜六氫吡啶基、六氫 吡啶基、3-六氫吡啶基、4_六氩吡啶嘧唑啶基、3”塞 嗅咬基4-嗟嗅$基、μ四氫咪4基、2_四氫咪嗅基、四 f咪峻基、5_四氫咪峻基、二氫叫丨哚基 '四氳喳啉基、四氫 并口奎啉基、苯并硫伍圜、苯并二硫陸園及口.二氣_味d 任何此等%脂族、雜環基及雜芳基係視情況與&或卜員芳 基或雜芳基環稠合。再者,各任何脂族、芳基、環脂族、 雜芳基及雜環基可含有獨立選自例如窥基似之適當取代基 93320 -20- 1344956 (較佳為至高5個’更佳為至高3個,且又更佳為0或1個)。 較佳取代基(包括R與J2)為鹵素、-OR7、-Ν02、-CF3、-〇CF3 、-R7、酮基、-OR7、-〇-苄基、〇苯基、1,2-亞甲二氧基、1,2-次乙二氧基、-N(R7)2、-C(0)R7、-COOR7 或-CON(R7)2,其中 R7 係定義於本文中(且較佳為Η、(C1-C6)-烷基或(C2-C6)-烯基與 块基’其中以(Cl -C6)-娱•基為最佳)。應明瞭的是,此定義係 包括全氟化烷基。 在本發明之具體實施例中,其中R為在氮原子上之取代基 ,較佳 R 基團係選自包括-R7、-SOR7、-S02 R7、-S02 N(R7 )2、-S03 R7 、-C(0)R7、-C(0)C(0)R7、-C(0)C(0)0R7、-C(0)C(0)N(R7)2、 -C(0)CH2C(0)R7、-C(S)R7、-C(S)OR7、-C(0)0R7、-C(0)N(R7)2、 -C(S)N(R7)2、-(CH2)0.2NHC(O)R7、-N(R7)N(R7)COR7、-N(R7)N(R7)- c(o)or7、-n(r7)n(r7)con(r7)2、-n(r7)so2r7、-N(R7)S02N(R7)2 、-n(r7)c(o)〇r7 ' _n(r7)c(o)r7、-N(R7)C(S)R7、-N(R7)C(0)N(R7)2 ' -n(r7)c(s)n(r7)2、-n(cor7)cor7、-n(or7)r7、-c(=nh)n(r7)2 、-c(o)n(or7)r7、-c(=nor7)r7、-op(o)(or7)2、-p(o)(r7)2、 -P(0)(0R7 )2及-P(0)(H)(0R7),其中R7係定義於本文中(且較佳 為Η、(q,C6)_烷基或(C2-C6)-烯基與晞基,其中以(Ci -C6)-烷基 為最佳)。此種R基團更佳係選自包括-R7與-C(0)R7。 於本發明之較佳化合物中,立體化學係如下文所描繪: R2
於本文中所揭示之任何具體實施例可合併,以提供本發明 93320 •21 · 1344956 之替代具體實施例。本發明之特定具體實施例’可選自表i 化合物中所描繪之取代基。 本發明化合物為寬廣卡司沛酶抑制劑,且具有經改良之能 力’勝過已報告之化合物,以抑制細胞凋零(參閱實例42與43)。 根據較佳具體實施例,本發明係提供式Ia或Ib化合物 R1、 N Η
R2
F
/、中R、R、r3及R4均如本文任何具體實施例中之定義。 根據更佳具體實施例,本發明之式[化合物係提供選自下 表1之式Π化合物:
發明化合物 ------~1 Γ* —- 1------ -Χίΐι R1 R2 R3 R5 —ί ^ Me(C=OV H Et CH20-2,3,5,6-四氟苯基 — Et(C=〇V H ----I Ht CH2 0-2,3,5,6-四氟苯基 . n-Pr(C=0)- H Et CH20-2,3,5,6-四氟苯基 广4 . c-Pr(C=0)- H Et CH20-2,3,5,6-四氟苯基 5 ---- i-Pr(C=OV H Et CH20-2,3,5,6-四氟苯基 6 ^—-— MeOCH〗 (C=0)- H Et. CH2〇-2,3,5,6-四氟苯基 2-咬喃基(C=0)- H Et CH2〇-2,3,5,6-四氟苯基 3-吱喃基(C=0)- _JEt CH20_2,3,5,6-四氟苯基 3-吡咬基(〇0)- H Et CH20-2,3,5,6-四氟苯基 3-異 4 唑(C=0:h H — 〜 一 _ Et 「CH20-2,3,5,6-四氟苯基 93320
-22- 1344956 .實例 R1 R2 R3 R5 11 Ph(C=0)- Η Et CH20-2,3,5,6-四氟苯基 12 Bn(OO)- Η Et CH20-2,3,5,6-四氟苯基 13 Me(C=0)- cf3 Et CH20-2,3,5,6-四氟苯基 14 EtNH(C=0)- Η Et CH2〇-2,3,5,6-四氟苯基 15 (Et)2N(C=0)- Η Et CH20-2,3,5,6-四氟苯基 16 四氫吡咯基(c=o)- Η Et CH20-2,3,5,6-四氟苯基 17 MeO(OO)- Η Et CH20-2,3,5,6-四氟苯基 18 Et(S02)- Η Et CH20-2,3,5,6-四氟苯基 19 n-Pr(S02)- Η Et CH20_2,3,5,6-四氟苯基 20 i-Pr(S02)- Η Et CH20-2,3,5,6-四氟苯基 21 Ph(S02)- Η Et CH2 0-2,3,5,6-四氟苯基 22 Et(S02)- cf3 Et CH20-2,3,5,6-四氟苯基 23 Bn(OO) Η i-Pr CH2〇-2,3,5,6-四氟苯基 24 Et(S02) Η i-Pr Οί2〇-2,3,5,6-四氟苯基 25 Et(OO) Η Me ch2f 26 Ph(C=0) Η Me ch2f 27 2,6-DiClPh(C=0) Η Me ch2f 28 Bn(C=0) Η Me ch2f 29 Et(C=0) Η Et ch2f 30 Ph(C=0) Η Et ch2f 31 2,6-二 ClPh(C=0) Η Et ch2f 32 2-吡啶基(C=0) Η Et ch2f 33 Bn(C=0) Η Et ch2f 34 3-MeBn(C=0) Η Et ch2f 35 Et(C=0) Η N-Pr ch2f 36 Et(C=0) Η I-Bu ch2f 37 Bn(OO) Me Et ch2f 38 p塞峻-2-基 Η Et CH2 0-2,3,5,6-四氟苯基 39 正-丙基 Η Et CH20-2,3,5,6-四氟苯基 93320 -23 - 本發明係提供一種醫藥組合物
根據另 TZJ 象另—项具體實施例 其包含: 或其藥學上可接受之鹽; :)如本文中定義之式1化合物 Μ藥學上可接受之載劑、佐劑或媒劑。 形】:此藝者將明瞭的是,某些本發明化合物可以互變異構 之範式存在’化合物之所有此種形式係在本發明 意 。除非另有述及,否則本文中所描緣之結構,亦 -G括此結構之所有立體化學形式;意即各不對稱中心 (與S組態。因此,本發明化合物之單一立體化學異構物 以及對掌異構物與非對映異構物混合物,均在本發明之 =圍内。除非另有述及’否則本文中所描緣之結構亦意欲 -括僅於-或多個同位素上富含之原子存在下有差異之化 合物。例如’具有本發明結冑,惟—個氫被U氣置換或 一個碳被13c-或14c-富含之碳置換之化合物,係在本發明之 範圍内。 本發明化合物可一般性地藉熟諳此藝者已知關於類似化合 物之方法及藉&了文製備實例製成。料說明纟目的,故 提供下文關於合成本發明化合物之圖式WII。應明瞭的是, 於圖式中Μ之任何保護基,可料與其他取代基之相容 性,按適當方式改變。 不同保護基可使用於本發明方法中(參閱,例如TWG痕& P.G.M. Wutz,”有機合成上之保護基",第3版,J〇hn斯㈣& s〇ns公 司(1999) ’及此書之較早期版本)。必'須被保護之典型官能基 93320 '24- 1344956 為胺類。任何胺類及其他官能基可根據此項技藝中已知之 方法被保護。化合物,包括胺類,可自反應混合物單離或 未單離下使用。
圖式I
圖式 I ω EDC/DMAP/HOBt/THF ; (b) Dess-Martin 過碘烷;(c) TFA/DCM 於上文圖式I中,係使用下列縮寫:EDC為1-(3-二甲胺基丙 基)-3-乙基碳化二亞胺;HOBt為卜羥基苯并三唑;THF為四氫 呋喃;TFA為三氟醋酸;DCM為二氯甲烷;DMAP為4-二甲 胺基吡啶β使酸1偶合至胺基醇2。此處偶合係使用EDC/DMAP/ HOBt/THF描述,但是,亦可使用其他適當條件。依R4與R5之 性質而定,可使用胺基酮,取代胺基醇,因此避免隨後之 氧化步驟。在氟基曱基酮類其中R5為CH2F之情況中,胺基 醇 2 可根據 Revesz 等人,Zeii. 1994, 35, 9693 之方法獲得 。在四氟基苯氧基酮類其中反5為-(:1120-2,3,5,6-四氟苯基之情 況中,胺基醇2可藉由類似Semple等人,所沉以c aW施办:/⑽/ 1997, 7, 1337 之方法獲得(圖式 Π)。 93320 •25- 最後使化σ物3中之起基氧化(例如使$ ^ _ 幻,並將所形成之化合物根據尺4之性質以適當方式處理: 例如,在產物I中,若R4為羧酸,則在3中之Μ較佳為酯, 其係在此圖式之最後步驟中水解。若該§旨為第三_丁§旨(意 即若R4為CC^tBu),則以三氟醋酸之處理將獲得該酸。當1中 又其他取代基可與酸性條件相容時,該酯較佳為第三-丁酯。 右產物I中l R4為酯,則所要之酯可經由使其相應之酸酯 化,或經由具有已存在於化合物2中之所要酯基而製成。
iiJL(a) KF/DMF/ArOH ; (b)NaBH4/THF ; (c) H2/Pd/C/MeOH 在上文圖式II中’係使用下列縮寫:KF為氟化鉀;DMF為 N,N-二甲基甲醯胺;ArOH為2,3,5,6-四氟基酚;THF為四氫吱 喃;MeOH為甲醇。使市購可得之溴基酮4 (R4=C02tBu)與2,3,5,6-四氟基酴及氟化钾反應’而得苯氧基酮5。然後,使此酮以 例如硼氫化鈉還原,而得醇6,利用例如纪/後作為觸媒, 使其氫化,而得胺基醇2 (R4 =C02 tBu, R5 =CH2 0-2,3,5,6-四氟苯基)。 93320 -26· 1344956
圖式III
.圖式 ln(a) H2 Pd/c MeOH ; (b) PhCH2 0(C0)C1/Na2 C03 /H2 O/THF ; (c) DMAP/DCM ; (f) TFA/DCM 在圖式III中,係使用下列縮寫:z為芊氧羰基保護基;Ne〇H 為甲醇;DCM為二氯曱烷;TFA為三氟醋酸;DMAP為4-二 甲胺基p比咬·’ THF為四氫吱喃。峨咬酮衍生物I可使用圖式in 中所示之合成順序,以對掌性形式製備。起始(2_酮基_丨,二 氫-说哫-3-基)-胺甲基酸苄酯(r2=h)係使用類似Warner等人, / C/zem. 1994, 37 (19),3090-3099所述之程序製備。將市講可 得之(R)-2-經基丁酸第三-丁酯(R3 =乙基)以三氟甲烷磺酸酐及 2,6-二甲基吡啶’在DCM中處理,而得其相應之三氟f烷磺 酸酯。三氟甲燒續酸酯與(2-酮基-1,2-二氫p比咬-3-基)-胺甲基 酸宇醋之陰離子(經由以氫化鈉在THF中之去質子化作用而 製成)之反應’獲得N-坑基化p比症S同。使用氫與把/碳,移 除+氧羰基保護基,獲得胺。然後’使其與適當親電子劑 、三乙胺及DMAP在DCM中反應。例如,若需要Ri為rc=0 (醯胺)’則可使用經適當取代之氣化醯。若需要Ri為RS(=〇)2 93320 -27- 1344956 (績si胺)’則可使用經適當取代之氯化磺醯。若RlgR〇(c=〇) (胺基甲酸酯),則可使用經適當取代之氯曱酸酯。若Rl為 RN(O0)(脲),則可使用經適當取代之氣化胺甲酿或異氛酸 酯。可據此製備其他Ri基團。然後,利用例如三氟醋酸, 使忒酯去除保έ蔓’製成故1。接著,使此酸偶合至胺基醇2 (圖式1)。 因此’本發明之另一項具體實施例係提供一種製備式I化 合物之方法: R2
其中R1、R2、R3 ' R4及R5均如本文任何具體實施例中之定義 ’其包括: ⑷使式(III)化合物: R2 R9
0 0
ΌΗ (III> 其中: R9 為-N02、-C(0)OR10、R6C(0)N(H)-、R6S〇2N(H)-、R60C(0)N(H)-、(R6)2NC(0)N(H)-、R6C(0)C(0)N(H)-、r6N(H)-、(r6)2nc(o)- C(0)N(H)-或 R60C(0)C(0)N(H)-; R10 係獨立為氫 ' (C1-C12)-脂族-(C3-C10)-環脂族-' (C6-C10)-芳 93320 -28 · 1344956 基-、(C3-C10)-雜環基-、(C5-C10)-雜芳基-、(C3-C10)-環脂族-(C1-C12)-脂族-、(C6-C10)-芳基-(C1-C12)-脂族-、(C3-C10)-雜環 基-(C1-C12)-脂族-、(C5-C10)-雜芳基(C1-C12)-脂族-,其中至 高3個脂族碳原子可被選自0、N(H)、N(R)、S、SO及S02 之基團置換;且其中R1 G係視情況被至高6個獨立選自R 之取代基取代;及 R、R2、R3及R6均如本文任何式(I)具體實施例中之定義; 與式(IV)化合物: R4 h2n
(IV) R5 其中Y為無論是羰基或OH基;且R4與R5均如本文任何式(I) 具體實施例中之定義; 於肽偶合條件與溶劑存在下反應; 其條件是若Y為0H基,則此方法進一步包括⑻使0H基氧化 ,以提供式(I)化合物;且 其條件是若R9為-N02、-CCCOOR1 〇或-CN ’則此方法包括使-N02 、-C(0)OR10 或-CN 轉化成 R6C(0)N(H)- 、R6S02N(H)-、 R60C(0)N(H)-、(R6)2NC(0)N(H)-、R6C(0)C(0)N(H)-、R6N(H)- ' (R6)2NC(0)C(0)N(H)-或 R60C(0)C(0)N(H)-之另一步驟。 偶合條件可為熟練執行者關於形成肽基鍵之任何已知者。 較佳偶合條件為EDC/DMAP/HOBt。於上文具體實施例中,較 佳溶劑為THF。 93320 -29- 於—項較佳具體實施例中 式(HI)化合物: R9
VI V X J. X ; 其中R2、R3W均如本文定義; 係藉由以下方法製成,其包括: (c)使式(V)化合物: R9
(V) ,、中R、R2、R3及妒均如本文定義; 在溶劑中,於去除保護條件存在下反應。
=保護條件係依特定保護基(意即r1。)而定。例如,若 TFA /基’則較佳去除保護條件包括酸水解。較佳® 。若R ^與水解條件包㈣八與!: 為甲基或乙基1㈣去除
臓水溶液)。若R1G為爷基,料/為驗性W 於—項較佳^風解作用移作 佳具租實她例中,式(V)化合物: 93320 R9
(V) -30- 1344956 其中R2、R3、R9及R10均如本文定義; 係藉由以下方法製成,其包括: (d)使式(VI)化合物: R2
0H (VI) 其中R2與R9均如本文定義; 與式(VII)化合物:
X
(VII) 其中X為適當脫離基;且 R3與R10均如本文定義; 於溶劑與鹼存在下反應。
X較佳為-I、-Br、-Cl、-0H、烷基磺酸酯或芳基磺酸酯。 當X為-0Η時,適當脫離基可當場產生(例如,當在Mitsun〇bu 反應中時)。較佳磺酸酯包括三氟甲烷磺酸酯、_〇_〒烷磺 酸酉0 苯♦酸酯、對-甲苯績酸酯、間-硝基苯續酸酯 及-〇-對-靖基苯磺酸酯。可用於本發明方法中之適當脫離基, 係為此項技藝中所習知。參閱,例如"March氏高等有機化學", 第 5 版.Smith Μ·Β.與 March,J.,John Wi】ey & Sons, New York (2001)。 可使用任何可與陰離子之產生相容之溶劑。較佳溶劑包括 DMF、曱苯及丁hf。 93320 31 1344956 適當鹼包括任何可自(v)中< 括 BuLi ' LDA、LHMDS 及 NaH。 羥基移除質子 較佳鹼為NaH。 者。此種鹼包 本發明之另 物之方法: 項具體實施例係提供-種製備式(vm)化合 R2
其中: R2 為-CF3、-Cl、-OR7、·ν〇2、-〇CF3、-CN 或 R8 ;且 R3、R8、R9及R1G均如本文定義; 其包括⑷使式(IX)化合物: R2
0H (IX)
其中R_2與R9均如本文定義; 與式(VII)化合物: 0
Xs^〇R1。 (vii> 其中R3與Ri 〇均如本文定義;且 X為適當脫離基; 於浴劑與鹼存在下反應之步驟。 93320 -32- 1344956 Μ X 為 q ' _Br、_α ' _〇H、燒基績酸* ^ χ % nu —日或方基績酸酯。 田X為-cm時,適當脫離基可當場產生 P- ,* , Α * 如’當在 Mitsunobu /…寺卜較佳績酸醋包括_〇·三氟甲⑼酸酿、·〇_甲院續 ㈣、◦如酸目旨' ·〇·對·甲苯魏§旨、_◦,·硝基苯績酸酿 及-0-對-硝基笨磺酸酯。 可使用任何可與陰離子之產生相容之溶劑。此種溶劑包括 DMF、甲苯及THF。較佳溶劑 適當鹼包括任何可自(V)中之羥基移除質子者。此種鹼包 括 BuLi ' LDA、LHMDS 及 NaH。較佳鹼為 NaH。 本發明之另一項具體實施例係提供一種製備式(1)化合物之 方法:
⑴ 其中R1、R2、R3、R4及R5均如本文任何具體實施例中之定義 ,其包括: ⑷使式(VI或以)化合物: R2
0H / (VI 或 IX) 其中: R9 為-N〇2、-QC^OR10、-CN ' R6 c(〇)n(H)-、R6 S〇2 N(H)-、 93320 •33· 1344956 R60C(0)N(H)- ' (R6)2NC(0)N(H)- ' R6C(0)C(0)N(H)- ' R6N(H)- 、(r6)2nc(o)c(o)n(h)-或 r6oc(o)c(o)n(h)-;且 R2、R3及R6均如本文定義; 與式(X)化合物:
(X) 其中γ為無論是羰基或OH基;且 R4與R5均如本文定義; 於本文中定義之任何偶合條件與溶劑存在下反應; 其條件是,若Y為OH基,則此方法進一步包括(b)使OH基 氧化,以提供式(I)化合物;及 其條件是,若R9為-N〇2、-C(0)0R1G或-CN,則此方法包括 使-N〇2、-C(0)OR10 或-CN 轉化成 R6C(0)N(H)-、R6S02N(H)-、 R60C(0)N(H)-、(R6)2NC(0)N(H)-、R6C(0)C(0)N(H)-、R6N(H)-、 (R6)2NC(0)C(0)N(H)-或 R6〇C(0)C(0)N(H)-之另一步驟。 可檢測本發明化合物直接抑制IL-1 /5釋出、卡司沛酶活性 或細胞凋零之能力。對於各活性之檢測,係為此項技藝中 已知。經選擇之檢測係描述於下文。 若本發明化合物之藥學上可接受鹽類被利用於此等組合物 中,則此等鹽較佳係衍生自無機或有機酸與鹼。被包含在 此種酸鹽中者係為下列:醋酸鹽、己二酸鹽、海藻酸鹽、 天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、酸性硫酸鹽、丁酸鹽 、檸檬酸鹽 '樟腦酸鹽、樟腦磺酸鹽、環戊烷丙酸鹽、二 93320 -34· 1344956 葡萄糖酸鹽、十二基硫酸鹽、乙烷磺酸鹽、反丁烯二酸鹽 、葡萄糖庚酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸 鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2_羥基乙烷磺酸鹽、乳 酸鹽、順丁烯二酸鹽、子烷磺酸鹽、2_莕磺酸鹽、菸鹼酸鹽 '草酸鹽、雙羥莕酸鹽、果膠酯酸鹽、過硫酸鹽、3_苯基· 丙酸鹽、苦味酸鹽、三曱基醋酸鹽、丙酸鹽、琥珀酸鹽、 酒石酸鹽、硯氰酸鹽、甲苯績酸鹽及_|--燒酸鹽。鹼鹽包 括銨鹽,鹼金屬鹽,譬如鈉與鉀鹽,鹼土金屬鹽,譬如鈣 與鎂鹽,與有機鹼之鹽,譬如二環己基胺鹽、N_曱基七-葡 萄糖胺鹽,及與胺基酸譬如精胺酸、離胺酸之鹽,等等。 驗性含氮基團亦可以作用劑四級化,譬如低碳燒基由化物 譬如甲基、乙基、丙基及丁基之氯化物、溴化物及碘化 物;二烷基硫酸酯,譬如二甲基、二乙基、二丁基及二戊 Μ㈣’長鏈自化物’譬如癸基、月㈣、肉豆莲基及 硬脂基氯化物、溴化物及碘化物,芳編化物,譬如宇 基與苯乙基溴化物’及其他。於是獲得水或油可溶性或可 分散性產物。 被利用於本發明組合物斑古 、 ,汰二 奶,、万法中爻化合物,亦可藉由附加 =^能基而被改質,以加強選擇性生物學性質。此種改 為此項技藝中已知,且包括會增加生物穿透至特定生 物系統(例如血液、就p g 履淋巴系統'中枢神經系統)中,增加口 服可利用性,增加溶解度以 — 允4精由注射投樂,改變新陳 代身作用,及改變排泄速率者。 可用於此等组合物中之藥學… 于工j接文 < 載劑’包括但不限 93320 •35· 1344956 於離子交換劑、氧化銘、硬脂酸銘、㈣脂,血清蛋白質 ’譬如亡類血清白蛋白,緩衝物質,譬如磷酸鹽,甘胺酸 、花楸酸、花楸酸卸、飽和植物脂肪酸類之部份甘油酉旨混 合物、水’鹽或電解質’譬如魚精蛋白硫酸鹽、磷酸氫二 钟、磷酸氫卸' 氯化鈉、辞鹽 '膠態二氧切、三石夕酸鎂 、聚乙烯基四氫吡咯酮、纖維素系物質、聚乙二醇、羧甲 基纖維素鈉,聚丙晞酸醋 '樣類、聚 , 永g埽-聚虱化丙晞_嵌段 聚合體、聚乙二醇及羊毛脂。 根據較佳具體實施例,本發明組合物係經調配,以供醫藥 投予哺乳動物’較佳為人類。 本發明之此種醫藥組合物可以服 服非經妨 '藉由吸入噴 務、局部、直腸、鼻、面麵 '降增十r丄仏 — 頌陰道或經由植入儲器方式投 藥。於本文中使用之"非經腸"一詞 〗包括皮下、靜脈内、 肌内、關節内、滑膜内、胸骨内、 、 稍円肝内、病灶内及 顱内注射或灌注技術。此等組人犏& /t ~ 令、、且0物較佳係以口服方式或靜 脈内方式投藥。 本發明組合物之無菌可注射形式 '了為水性或油性懸浮液。 此等懸浮液可根據此項技藝中已知 十又技術,使用適當分散 或潤濕劑及懸浮劑調配而成。矣菌死 <"、囷可·王射製劑亦可為無菌 可注射溶液或懸浮液’在無毒性非 母f玍非經%上可接受之稀釋劑 或溶劑中’例如在1,3- 丁二醇中作忐a、, 甲作成落夜。其中可採用之可 接受媒劑與溶劑,係為水、林格氏 合履及♦滲氯化鈉溶液 。此外,習用上係採用無菌不揎麻1 揮發油作為溶劑或懸浮媒質 。對此項目的而言’任何溫和夕丁杜六 不揮發油均可採用,包括 93320 -36 - 1344956 合成單·或二-甘油酯。脂肪酸類,譬如油酸及其甘油酯衍 生物,可用於製備可注射劑,其係為天然藥學上可接受之 油類二譬如橄欖油或萬麻油’尤其是呈其聚氧乙基化變型 此等'm懸浮液亦可含有長鏈酵稀釋劑或分散劑, 譬如竣甲基纖維素,或常用於調配藥學上可接受劑型包括 乳化液與懸浮液之類似分散劑β其他常用界面活性劑,譬 如Tween、Spans,及其他常用於製造藥學上可接受之固體、 液體或其他劑型之乳化劑或生物利用率增強劑,亦可用於 調配目的。 ,本發明之醫藥組合物可以任何卩服上可接受之劑型經口投 ^括i_不限於膠囊 '片劑、含水懸浮液或溶液。在供 口、服使用之片劑情況中’常用之載劑係包括乳糖與玉米殿 ’八上亦叫、加潤滑劑,譬如硬脂酸鎂。對於以膠囊形 ::'、去:投藥’可使用之稀釋劑包括乳糖與乾燥之玉米澱 :田南要含水懸浮液以供口服使用日寺,係將活性成份與 =及懸浮劑合併。若需要亦可添加某些增甜、矯味或著 藥或::本發明疋醫藥組合物可以供直腸投藥之拴劑形式 ,賦:::由將樂劑與適當無刺激性賦形劑混合而製成 4峡形劑在倉 ^ m,但在直腸溫度下為液體,因 蜂蠟及聚乙::。’以釋出藥物。此種物質包括可可豆脂 各地藉由局部塗敷接近之區域或器官時, 93320 括眼晴、皮膚或下方腸道之疾病。適當局部配方係容易地 針對各此等區域或器官製成。 供下方腸道用之局部塗敷可以直腸栓劑配方(參閱上文)或 以適當灌腸劑配方達成。局部經皮貼藥亦可使用。 對局部應用而言,可將醫藥組合物調配在適當軟膏中,含 有被懸浮或溶解於一或多種載劑中之活性成份。供本發曰^ 化合物局部投藥用之載劑,包括但不限於礦油、液體石蠟 油、白色石蠟油、丙二醇、聚氧化乙烯、聚氧化丙晞化合 ‘、乳化用蠟及水。或者,可將醫藥組合物調配在適當洗 =或乳β中,含有被懸浮或溶於—或多種藥學上可接受載 财,活性成份。冑當載劑包括但不限於礦油、單硬脂酸 花楸聚糖s旨、聚花楸酸g|6G、_基§旨堪、料硬脂基醇 、2、辛基十二醇、苄醇及水。
對眼科用途而^'’可將醫藥組合物調配成在等渗、經pH
調整之無菌M水中之微純懸浮液,或較佳為在等滲、經pH 周:疋播菌鹽水中之溶液,無論使用或未使用防腐劑,譬 如乳化下燒氧按。或者,對眼科用途而言,可將醫藥組合 物調配在軟膏譬如石蠟油中。 本發月〈醫藥組合物亦可藉由鼻氣溶膠或吸入投藥。此種 二口物係根據醫藥調配技藝中所習知之技術製成,且可被 ^成在现水中〇客液’ @用字醇或其他適當防腐劑 '為加 強生物利用率之吸收促進劑、氟碳類及/或其他習用促溶 或分散劑。 上述組合物係絲丨 ''待別了用於治療應用,關於IL-1所媒介之疾 93320 -38- 丄344956 病細胞凋零所媒介之疾病、炎性疾病、自身免疫性疾病 、破壞性骨質病症、增生病症、傳染病、變性疾病、與細 胞死ΤΓ有關聯之疾病或各種形式之肝病。此種疾病包括與 下述有關聯者,風濕病學與自身免疫性,譬如風濕性關節 泛、骨關節炎、骨質疏鬆症、系統紅斑狼瘡、硬皮病、慢 欧甲狀腺炎、格雷武司氏疾病、重症肌無力、自身免疫唁 中性白血球減少症、自身免疫溶血性貧血、血小板減少症 幼年風濕性關節炎' 痛風、Behcet氏徵候簇、Still氏徵候 蔟、巨噬細胞活化作用徵候簇及肉狀瘤病;自身炎性徵候 誤’譬如與冷熱有關聯之週期性徵候簇(包括Muckle-Wells徵 候簇 '豕族性冷蓴麻療、慢性幼兒神經性皮膚與關節徵候 簇(a.k_a.新生兒展開多系統炎性疾病)),家族性地中海熱 '與 TNFR1有關聯之週期性徵候蔟(TRAps)、高_IgD週期性熱徵候 簇(HIDS)及Blau氏徵候簇;皮膚病學,譬如牛皮癬、異位性 皮炎、傷疤、禿髮 '尋常痤瘡及天疱瘡;呼吸道,譬如氣 喘 '成人呼吸困難徵候簇、膽囊纖維變性、氣腫、慢性枝 氣管炎、慢性阻塞肺病及自發性肺纖維變性;内科,譬如 炎性腹膜炎 '炎性腸疾病、克隆氏病、潰瘍性結腸炎、自 身免疫胃A、與幽門螺旋桿菌有關聯之胃與十二指腸潰瘍 疾病、糖尿病、姨腺炎、絲球體性腎炎、慢性活性肝炎、 過量食用酒精攝取疾病、螫症、夕杳& 、 腎病、多囊腎臟病、灼傷、燒傷 後器官細胞凋零、屮士 M斗* _ . ^ ^ 休克、益· g哀竭(例如肝衰竭 '急 f生腎衰竭及急性呼吸道衰竭)及子宮内膜組織異位形成;移 植物’譬如移植物抗宿主疾病(gvhd)與器官移植排斥;腫 93320 •39· 1344956 瘤學’譬如白血病及相關病症' 脊髓發育不良徵候簇、多 發性骨髓瘤相關之骨質病症、急性骨髓性白血病、慢性骨 髓性白血病、轉移性黑色素瘤、卡波西氏肉瘤及多發性骨 髓瘤;心血管,譬如慢性心臟疾病 '急性心臟疾病 '心肌 梗塞、心肌絕血、鬱血性心衰竭、動脈粥瘤硬化、冠狀動 脈分流移植(CABG)及急性冠狀徵候誤;中樞與末梢 統’譬如阿耳滋海默氏疾病、巴金生氏病、亨丁頓氏疾病 、Kennedy氏疾病、朊病毒疾病、大腦絕血 '癲癇、脊柱肌 肉萎縮、肌萎縮性側索硬化.、多發性硬化、HIV相關之腦炎 、外傷性腦部傷害、脊髓損傷、由於中風所致之神經病傷 害、糖尿病患者之神經病及急性與慢性疼痛;眼科學,譬 如葡萄膜火、視網膜病症、糖尿病患者之視網膜病 '青光 眼及角膜炎;#染性疾病,譬如病毒所媒介疾病、敗血病 次血性休克、志賀桿菌病、肝炎-Β、肝炎-C、肝炎_G、 黃,病' 登革熱、日本腦炎、勝感染、結核病、腦膜炎、 假單胞:滴屬感染及不動桿菌屬感》;及其他疾病,譬如老 化°此寺化合物與組合物亦可用於治療與冠狀動脈 ㈣有關聯之併發症。化合物存在於上述組合物中之量移 田藉由此料藝中已知之任何檢測度量時,應足以 又嚴重性上或在卡司 庆媽 得之降低。 m性及/或細胞料上造成可測 步包含另 ,譬如組 二種藥劑 根據另一項具體實施例’本發明之組合物可; η血::刈。此種藥劑包括但不限於溶解血, 、“纖維蛋白溶酶原活化劑與鏈激酶。當使, 93320 1344956 時,第二種藥劑可無論是作為個別劑&,或作為具有本發 明化合物或組合物之單一劑型之_部份投藥。因此,供同 時、個別或相繼使用之合併製劑,係由本發明提供。 在每天約0.01與約100毫克/公斤髎舌弓, θ 吓版重間(劑量程度,較佳 係在每天約0.5與約75毫克/公斤體f門士女、山 w瓶里間 < 本又中所述蛋白 酶抑制劑化合物,可使用於單—療法中 馆:古〒,以預防與治療涉 及卡司沛酶活性及/或細胞凋零之疾病。 典型上,本發明之醫藥組合物係每天投藥約丨至約5次, 或者’以連㈣注。此缝藥可作輕性或,練療法使用 。可與載劑物質合併以產生單—劑型之活性成份量,係依 待治療之宿主及特定投藥模式而改變。典型製劑係含有… %至約95%活性化合物(w/w)。此種製劑較佳係含有約_至 約80%活性化合物。 當本發明組合物包含幻化合物與—或多種其他治療或預 防劑之組合時,該化合物與該其他藥劑兩者應於約1〇至1〇〇 :間之劑量程度下存在’且更佳係在單一治療服用法中正 常投予劑量之約10至80%之間。 耶應明瞭的是,對於任何特定病患之特定劑量與;台療服用 法,係依多種因素而定,包括所採用特定化合物之活性、 年齡、體重、-般健康狀態、性別、膳食、投藥時間、排 ’世速率、藥物組合及治療醫師之判斷以及被治療特定疾病 之嚴重性。活性成份之量亦依特定化合物及若存在於組合 物中之其他治療劑而定。 " 於一項較佳具體實施例中 本發明係提供一種治療具有前 93320 1344956 文所提及疾病之一之哺乳動物之方法,其包括對令 物投予上述藥學上可接受組合物之步驟。在此具體實施例 中’若病患亦被投予另一種治療劑或卡司沛酶抑制劑,則 其可伴隨著本發明化合物在單一劑型中,或作為個別劑型 傳輸。當以個別劑型投藥時,該另一種卡司沛酶抑制 藥劑可在投予包含本發明化合物之藥學上可接受組合物之 前、同時或之後投藥。 【實施方式】 為使本發明更充分被瞭解’故提出下述製備與測試實例。 此等實例僅為說明目的,而非欲被解釋為以任何方式限制 本發明之範圍。 實例1 (S,S)-3-[2-(3-乙醯胺基-2-酮基-2H-p比症-1-基)-丁縫基胺基]_4·|同基 5-(2,3,5,6-四氟-苯氧基)戊酸
方法A : (S)-2-(3-宇氧羰基胺基_2_酮基-2H-吡啶-1-基)-丁酸第三-丁酯
於(R)-經基丁酸第三-丁酯(1.03克,6.43毫莫耳)在二氣甲烷 (25毫升)中之經冷卻)溶液内,慢慢添加2,6-二甲基吡啶 (1.38克,12.9毫莫耳),然後是三氟甲烷磺酸酐(3_45克,12.2 93320 -42- 1344956 愛莫耳)。將所形成之混合物在〇°C下攪拌1小時,然後於第 三-丁基甲基醚(150毫升)與1M HC1水溶液(30毫升)之間作分 液處理。將有機層以鹽水(3〇毫升)洗滌,脫水乾燥(硫酸鈉) ’過遽及濃縮’而得三氟甲燒績酸鹽,為淡褐色油。 於(2-酮基-l,2-二氫-P比啶-3-基)-胺曱基酸芊酯(p. Warner等人, / Med C/zem·,37, 19, 1994, 3090-3099) (1·73 克,7.07 毫莫耳)在無水 THF (60毫升)中之溶液内,添加氫化鈉(6〇%分散液,257毫克 ’ 6·43毫莫耳)’並將此溶液於室溫下攪拌45分鐘。然後, 將反應混合物以套管慢慢地轉移至上文製成之三氟甲烷磺 酸鹽在THF中之溶液(3毫升)内。將反應混合物在室溫下攪 拌90分鐘’並以氯化銨水溶液(10毫升)使反應淬滅。蒸發大 部份溶劑’並使殘留物於EtOAc與飽和NH4C1水溶液之間作 分液處理。將有機層以鹽水(30毫升)洗滌,脫水乾燥(MgS04) ’過濾並蒸發。使殘留物藉急驟式層析純化(10%醋酸乙酯 /己烷)而得標題化合物,為無色油(2.48克,100% ) : 1H NMR (400 MHz, CDC13) <5 0.92 (3H, t), 1.45 (9H, s), 1.94 (1H, m), 2.25 (1H} m), 5.23 (2H, s), 5.47 (1H, dd), 6.32 (1H, t), 7.01 (1H, d), 7.32- 7.43 (5H, m), 7.92 (lH,s),8.06(lH,brd). 方法B : ⑸-2-(3-胺基-2-酮基-2H-p比淀-1-基)-丁酸第三-丁酉旨 〇 \ 於⑶-2-(3-芊氧談基胺基-2-酮基-2H-p比咬-1-基)-丁酸第三-丁酯 (2.48克,6.43毫莫耳)在MeOH (15毫升)與EtOAc (15毫升)混合 93320 -43· 1344956 物中之溶液内,添加10% Pd/C (250毫克)。使混合物脫氣,並 於氫大氣(氣瓶壓力)下,在室溫下攪拌90分鐘。使反應混 合物經過短矽膠墊片過濾,然後將其以MeOH溢流。使合併 之遽液在減壓下蒸發’而得標題化合物,為白色固體(1.62克 -100% ); 1H NMR (400 MHz, CDC13) ^ 0.91 (3H, t), 1.44 (9H, s), 1.91 (1H, m), 2.21 (1H, m), 4.24 (2H, br s), 5.50 (1H, dd), 6.11 (1H, t), 6.53 (1H, d), 6.77 (1H, d). 方法C : (S)-2-(3-乙醯胺基-2-酮基-2H-吡啶小基)-丁酸第三-丁酯
於(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸第三-丁酯(5〇〇毫克 ,1.98毫莫耳)在二氯甲烷(5毫升)中之經冷卻(〇。〇)溶液内, 添加三乙胺(220毫克’ 2.18毫莫耳)’接著是醋酸肝(2〇2毫克 ’ 1.98毫莫耳)。將反應混合物在室溫下攪拌12小時,然後 於EtOAc與1MHC1水溶液之間作分液處理。將有機層以飽和 NaHC〇3水溶液、鹽水(3〇毫升)洗滌,脫水乾燥(MgS〇4),過 滤並蒸發。使殘留物藉急驟式層析純化(4〇%醋酸乙醋/己 燒)’而得標題化合物’為無色油(569毫克,97% ) : 1H NMR (400 MHz, CDC13) (5 0.87 (3H, t), 1.40 (9H, s), 1.91 (1H, m), 2.13 (3H, s), 2.19 (1H, m), 5.38 (1H, dd), 6.26 (1H, t), 6.99 (1H, d), 8.33 (1H, d), 8.43 (lH,br s). 方法D : (S)-2-(3-乙醯胺基-2-@同基-2H-p比淀-1-基)-丁酸 93320
1344956 使(S)-2-(3-乙醯胺基-2-酮基-2H-p比啶-1-基)·丁酸第三-丁酯(569 毫克,1.93毫莫耳)在二氯曱烷(5毫升)中之溶液冷卻至〇。〇。 添加三氟醋酸(5毫升),並使所形成之混合物溫熱至室溫, 且攪拌2小時。然後,使混合物於減壓下濃縮,並使殘留物 再溶解於二氣甲烷中。將此程序重複數次,以移除過量三 氟醋酸。將所形成之固體在乙酸中配成漿液,過濾,及以 更多乙醚洗滌。然後,使固體在真空下乾燥至恒重。這獲 得標題產物,為白色固體(327毫克,71%) ; ^NMR(400MHz, d6-DMSO) (5 0.78 (3H, t), 2.02-2.17 (5H, m), 4.98 (1H, dd), 6.29 (1H, t), 7.35 (1H, d), 8.21 (1H, d), 9.30 (1H, s), 13.07 (1H, vbr s). 方法E : (S,S)-3-[2-(3-乙醯胺基-2-酮基-2H-吡啶-1-基)-丁醯基胺基]-4-羥基-5-(2,3,5,6-四氟-苯氧基)-戊酸第三-丁酯
使(S)-2-(3-乙醯胺基-2-_基·2Η-ρ比咱:小基)-丁酸(1〇〇毫克,0.42 毫莫耳)、3-胺基-5-(2,3,5,6-四氟基苯氧基)-4-¾基-戊酸第三-丁 酯(163毫克,0.462毫莫耳)、HOBt (62毫克,0.462毫莫耳)、DMAP (56毫克,0.462毫莫耳)及THF (5毫升)之經攪拌混合物冷卻至 〇°C ’然後添加EDC (89毫克,0.462毫莫耳卜使混合物在16 小時期間溫熱至室溫,然後於減壓下濃縮。使殘留物藉急 93320 •45- 1344956 驟式層析純化(50-50%醋酸乙酯/己院)而得標題化合物,為 白色泡沫物(221 毫克 ’ 92% ); 1 H NMR (400 MHz, CDC13) (5 0.88-0.93 (3H, m), 1.37-1.38 (9H, 2s), 1.86-1.96 (1H, m), 2.15-2.25 (4H, m), 2.55-2.71 (2H, m), 3.70-4.64 (5H, m), 5.30-5.39 (1H, m), 6.30-6.35 (1H, m), 6.75-6.86 (1H, m), 7.17-7.31 (2H, m), 8.31-8.47 (2H, m). 方法F : (S,S)-3-[2-(3-乙趨胺基-2-酮基-2H-p比淀-1-基)-丁酿基胺基]_4_酮基· 5-(2,3,5,6-四氟-苯氧基)-戊酸第三-丁酯
將(S,S)-3-[2-(3-乙醯胺基-2-酮基-2H-峨啶-1-基)-丁醯基胺基]-4-羥基-5-(2,3,5,6-四氟-苯氧基)-戊酸第三-丁酯(221毫克,0.385毫 莫耳)在無水DCM (10毫升)中之經攪拌溶液,以,卜三乙醯 氧基-U-二氫-1,2-苯并碘氧伍園-3(1H)-酮(212毫克,0.5毫莫耳) 在〇°C下處理。將所形成之混合物在〇它下保持2小時,以醋 酸乙S旨稀釋’然後倒入飽和碳酸氫鈉水溶液與飽和硫代硫 酸鈉水溶液之1 : 1混合物中。移除有機層,並將水層以醋 酸乙酯再萃取。使合併之有機萃液脫水乾燥(硫酸鎂)及濃 縮。使殘留物藉急驟式層析純化(50-50%醋酸乙酯/己烷)而 得標題化合物’為白色固體(187毫克,85%); iHNMR(4〇〇MHz, CDC13) (5 0.93 (3H, t), 1.36 (3H, s), 1.95 (1H, m), 2.21 (3H, s), 2.25 (1H, m), 2.73 (2H, dd), 2.89 (1H, dd), 4.91 (1H, m), 5.04-5.17 (2H, m), 5.47 (1H, m), 6.34 (1H, t), 6.80 (1H, m), 7.19 (1H, m), 7.68 (1H, d), 8.36-8.41 (2H, m). 93320 -46- 1344956 方法G : (S,S)-3-[2-(3-乙醯胺基-2-酮基-2H-吡啶-1-基)-丁醯基胺基]-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
使(S,S)-3-[2-(3-乙醯胺基-2-酮基-2H-吡啶-1-基)-丁醯基胺基]-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸第三-丁酯(187毫克,0.327毫 莫耳)在二氯甲烷(5毫升)中之溶液冷卻至0°C。添加三氟醋 酸(5毫升),並使所形成之混合物溫熱至室溫,且攪拌2小 時。然後,使混合物於減壓下濃縮,並使殘留物再溶解於 二氯甲烷中。將此程序重複數次,以移除過量三氟醋酸。 將所形成之固體在乙醚中配成漿液,過濾及以更多乙醚洗 滌。然後,使固體在真空下乾燥至恒重。這獲得標題產物 ,為白色固體(138 毫克,82% ) ; iHNMRGOOMHidS-DMSO) δ 0.78 (3H, t), 1.87-2.13 (5H, m), 2.56-2.78 (2H, m), 4.62 (1H, m), 5.18-5.29 (2H, m), 5.40 (1H, m), 6.28 (1H, t), 7.37 (1H, d), 7.53-7.66 (1H, m), 8.17-8.21 (1H, m), 8.92 (1H, d), 9.21 (1H, s), 12.51 (1H, br s) ; 19F NMR (376 MHz, d6-DMSO,質子-去偶合)<5 -156.9,-141.1 ; M+H516.2, M-H514.2. 實例2 (S,S)-4-自同基-3-[2-(2-S同基-3-丙酿基胺基比淀-1-基)-丁酿基胺 基]-5-(2,3,5,6-四氟-苯氧基)_戊酸
F 93320 -47- 1344956
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與丙酐;白色固體;IR (固體)1584, 1642, 1662, 1717, 1749 公分-1 ; 1 H NMR (400 MHz, d6-DMS0) 5 0.78 (3H, t),1.04 (3H, t), 1.88-2.11 (2H, m), 2.43 (2H, q), 2.59 (1H, d), 2.75 (1H, dd), 4.61 (1H, m), 5.18-5.29 (2H, 2dd), 5.40 (1H, m), 6.29 (1H, t), 7.37 (1H, d), 7.58 (1H, m), 8.22 (1H, d), 8.91 (1H, d), 9.08 (1H, s), 12.50 (1H, br s); 19F NMR (376 MHz, d6-DMSO, 質子-去偶合)<5 -140_6, -140.8, -141.1,-156.8, -157.0 ; M+H 530.2, M-H
528.3. 實例3 (S,S)-3-[2-(3-丁醯基胺基-2-酮基-2H-吡啶小基)-丁醯基胺基]-4-酮 基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法C-G,製自⑸-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與氣化丁醯;米黃色固體;IR (固體)1659, 1645, 1509, 1490 公分-1; 1H NMR (400 MHz, d6-DMSO) ά 0.76-0.80 (3H,m),0.88 (3H, t), 1.53-1.58 (2H,m), 1.88-1.93 (1H, m), 2.01-2.09 (1H, m), 2.37-2.41 (2H,m), 2.59 (1H, dd), 2.70-2.81 (1H, m), 4.59-4.63 (1H, m), 5.20-5.25 (2H, m), 5.38-5.50 (1H, 2 x m), 7.36-7.38 (1H, m), 7.55-7.61 (1H, m), 8.21-8.23 (1H, m), 8.61-8.92 (1H, 3 x d), 9.06-9.10 (1H, m), 12.49 (1H, br s); 19F NMR(376 MHz, d6-DMSO,質子-去偶合)5 -140.6,-141.1,-156.9,-157.0 ; M+H 544.3, M-H 542.3. 實例4 93320 •48· 1344956 (S,S)-3-{2-[3-(環丙烷羰基-胺基;)-2-酮基-2H-吡啶-1-基]-丁醯基胺 基}-4-g同基-5-(2,3,5,6-四氟-苯氧基)-戊酸 0
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與環丙烷氣化碳醯;白色固體;1H NMR (400 MHz, d6-DMSO) δ 0.74-0.82 (7Η, m), 1.93 (1Η, m), 2.07 (1H, m), 2.17 (1H, m), 2.59 (1H, d), 2.75 (1H, dd), 4.62 (1H, m), 5.19-5.30 (2H, 2dd), 5.41 (1H, m), 6.27 (1H, t), 7.37 (1H, d), 7.57 (1H, m), 8.17 (1H, d), 8.92 (1H, d), 9.49 (1H, s), 12.51 (lH,brs) ; M+H 542.2, M-H 540.3. 實例5 (S,S)-3-[2-(3-異丁醯基胺基-2-酮基-2H-吡啶-1-基)-丁醯基胺基]-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與氣化異丁醯;白色固體;IR(固體)1664, 1517, 1491 公分·1 ; 1H NMR (400 MHz, d6-DMSO) (5 1.75-1.85 (3H,m),1.05 (6H,d), 1.9-2.1 (2H, m), 2.6-2.9 (3H, m), 4.55-4.62 (1H, m), 5.2-5.35 (2H, m), 5.4-5.43 (1H, m), 6.25 (1H, t), 7.4-7.45 (1H, m), 7.6-7.7 (1H, m), 8.2-8.24 (1H, m), 8.8-9.0 (2H, m) ; M+H 544.3, M-H 542.3. 實例6 93320 -49- 1344956 (33)-3-{2-[3-(2-甲氧基-乙醯胺基)-2-酮基-211-吡啶-1-基]-丁醯基胺 基}-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法C-G,製自(S>2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與氯化曱氧基乙醯;粉紅色固體;lHNMR(400MHz, d6-DMS0) δ 0.75-0.80 (3Η, m), 1.88-1.97 (1H, m), 2.02-2.10 (1H, m), 2.56- 2.63 (1H, m), 2.72-2.79 (1H, m), 3.37-3.40 (3H, m), 4.00-4.03 (2H, m), 4.53- 4.65 (1H, m), 5.13-5.46 (3H, m), 6.32-6.35 (1H, m), 7.39-7.45 (1H, m), 7.51- 7.66 (1H, m), S.21-8.26 (1H, m), 8.92-8.98 (1H, m), 9.12-9.17 (1H, m), 12.51 (1H, br s) ; M+H 546.2, M-H 544.2. 實例7 (S,S)-3-(2-{3-[(呋喃_2-羰基)-胺基]-2-酮基-2H-吡啶_1-基}-丁醯基胺 基)-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法C-G,製自⑶-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與氣化2-呋喃甲醯;白色固體;1 HNMR (400 MHz, d6-DMSO) ^ 0.81 (3H, m), 1.95 (1H, m), 2.09 (1H, m), 2.60 (1H, dd), 2.77 (1H, dd), 4.61 (1H, m), 5.19-5.29 (2H, m), 5.42 (1H, m), 6.39 (1H, t), 6.74 (1H, m), 7.30 (1H, m), 7.46-7.58 (2H, m), 7.95 (1H, m), 8.27 (1H, d), 8.98 (1H, d), 93320 -50· 1344956 9.16 (lH,s), 12.50 (lH,brs) ; M+H 568.3, M-H 566.3. 實例8 (S,S)-3-(2-{3-[(咬喃-3-談基)-胺基]-2-嗣基-2H-17比淀-l-基}-丁酿基胺 基)-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2E-吡啶-1-基)-丁酸 第三-丁酯與氣化3-呋喃曱醯;灰白色固體;IR(固體)1748, 1711, 1663,1640, 1583, 1517,1488 公分.1 ; WNMRGOOMH^c^-DMSO) (5 0.80 (3H, m), 1.90-2.20 (2H, m), 2.60-2.90 (2H, m), 4.65 (1H, m), 5.10-5.60 (3H, m), 6.40 (1H, t), 6.95 (1H, m), 7.40-7.65 (2H, m), 7.85 (1H, s), 8.20 (1H, m),8.50 (1H,m),8.90-9.20 (2H,m) ; 19 F NMR (376 MHz, d6-DMSO,質子-去偶合)5 -141.0,-156.8 ; M+H 568·2,Μ-Η 566.3. 實例9 (S,S)-4-酮基-3-(2-{2-酮基-3-[(吡啶-3-羰基)-胺基]-2H-吡啶·1-基卜丁 醯基胺基)-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法C-G,製自(S)-2-(3-胺基-2-g同基-2H-p比咬-1-基)-丁酸 弟二-丁酿與3- p比咬氣化複酿(以TFA鹽單離);黃色固體;JR 1344956 (固體)1745, 1678, 1650, 1517, 1488 ; βΝΜΚ^ΟΟΜΗζ,οΙό-ΟΜεΟ) <5 0.80 (3Η, m), 1.90-2.30 (2H, m), 2.50-2.90 (2H, m), 4.65 (1H, m), 5.10-5.65 (3H, m), 6.45 (1H, t), 7.40-7.80 (3H, m), 8.10-8.40 (2H, m), 8.85 (1H, s), 8.90-9.20 (2H,m), 9.65 (1H, m) ; 19 F NMR (376 MHz, d6-DMSO,質子-去偶 合)5 -141.0,-156·8 ; M+H579.2,M-H577.3. 實例10 (S,S)-3-(2-{3-[(異嘍唑-3-羰基)-胺基]-2-酮基-2H-吡啶-l-基}-丁醯基 胺基)-4-酮基-5-(2,3,5,6-四氟基苯氧基)-戊酸 〇
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與3-異嘍唑氣化碳醯;粉紅色固體;IR (固體)1678, 1649, 1516, 1493 公分-1 ; MHz, d6-DMSO) 5 0.85 (3H,m), 1.85-2.30 (2H, m), 2.50-2.90 (2H, m), 4.20-4.70 (1H, 2m), 5.10-5.60 (3H, m), 6.45 (1H, t), 7.40-7.70 (2H, m), 7.95 (1H, m), 8.40 (1H, d), 8.95-9.15 (1H, 2m), 9.30 (1H,d),10.00 (1H, 2s) ; 19F NMR (376 MHz,d6-DMSO,質子-去偶 合)(5 -141.0,-156.9 ; M+H 585.1, Μ·Η 583·2· 實例11 (S,S)-3-[2-(3-苯甲醯胺基-2-酮基-2Η-吡啶·1·基)-丁醯基胺基]-4-酮 基-5-(2,3,5,6-四氟-苯氧基)-戊酸
1344956 根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與氣化苯甲醯;粉紅色固體;IR (固體)1645, 1509, 1490 &*-l;1HNMR(400MHz,d6-DMSO)5 0.79-0.85 (3H,m),l_95-1.99 (1H, m), 2.06-2.10 (1H, m), 2.60 (1H, dd), 2.77 (1H, dd), 4.59-4.63 (1H, m), 5.25 (2H, m), 5.42-5.55 (1H, m), 6.38-6.42 (1H, m), 7.51-7.62 (5H, m), 7.89-7.91 (2H, m), 8.27-8.31 (1H, m), 8.69-8.99 (1H, m), 9.28 (1H, m); 19FNMR (376MHz,d6-DMSO,質子·去偶合)5 -140.6,-141.0,-156.9,
-157.0; M+H 578.2, M-H 576.2. 實例12 (S,S)-4-酮基-3-[2-(2-酮基-3-苯乙醯基胺基-2H-吡啶-1-基)-丁醯基 胺基]-5-(2,3,5,6-四氟-苯氧基)-戊酸 〇
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與氣化苯乙醯;粉紅色固體;IR (固體)1659, 1635, 1519 公分-1; iHNMR(400MHz,d6-DMSO) (5 0.77(3H,t),1.85-1.96 (lH, m), 2.03-2.07 (1H, m), 2.59 (1H, dd), 2.71-2.77 (1H, m), 3.79 (2H, s), 4.61-4.66 (1H, m), 5.16-5.29 (2H, m), 5.35-5.44 (1H, m), 6.28 (1H, t), 7.24-7.39 (6H, m), 7.52-7.67 (1H, m), 8.19-8.21 (1H, m), 8.61-8.92 (1H, m), 9.28 (1H, br s); 19FNMR(376 MHz,d6-DMSO,質子-去偶合)5 -140.6,-141.0,-156.90, -157.0; M+H 592.2, M-H 590.2. 實例13 (S,S)-3-[2-(3-乙醯胺基-2-酮基-5-三氟甲基-2H-吡啶-1-基)-丁醯基 93320 -53- 1344956 胺基]-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法A-G,製自(2-酮基-5-三氟甲基-1,2-二氫“比啶-3-基)-胺甲基酸芊酯;白色固體;IR(固體)1659, 1514公分M ; iHNMR (400 MHz, d6-DMSO) δ 0.79 (3Η, t), 2.07-2.33 (5Η, m), 2.59-2.79 (2H, m), 4.59-4.63 (1H, m), 5.18-5.29 (2H, m), 5.41-5.45 (1H, m), 7.55-7.62 (1H, m), 7.89 (1H, s), 8.41-8.43 (1H, m), 9.04 (1H, d), 9.61-9.63 (1H, m) ; 19F NMR (376 MHz, d6-DMSO,質子-去偶合)(5 -61.4,-140.7,-141.1,-156.8-, 156.9-157.02,-157.1 ; M+H 584.2, M-H 582.2. 實例14 (S,S)-3_{2-[3-(3-乙基-脲基)-2-酮基-2H-吡啶-1-基]-丁醯基胺基}-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與異氰酸乙酯;粉紅色固體;IR(固體)1664, 1645, 1550,1493,1208 &*-1;1HNMR(400MHz,d6-DMSO)<5 0.80(3H,t), 1.05 (3H, t), 1.80-2.20 (2H, m), 2.50-2.85 (2H, m), 3.15 (2H, m), 4.65 (1H, m), 5.25 (2H, dd), 5.40 (1H, m), 6.25 (1H, t), 7.15 (1H, s), 7.25 (1H, d), 7.60 (1H, m), 8.05 (1H, m), 8.20 (1H, s), 8.95 (1H, d) ; 1 9 F NMR (376 MHz, d6-DMSO, 93320 -54- 1344956 質子-去偶合)(5 -14U,-156.9 ; Μ+Η 545·2,Μ-Η543·2. 實例15 (S,S)-3-{2-[3-(3,3-二乙基-脲基)_2-酮基-2Η-吡啶-1-基]-丁醯基胺基 }-4-g同基-5-(2,3,5,6-四氟-苯氧基)-戊酸
方法Η : 於⑶-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸第三-丁酯(400毫克 ’ 1.59毫莫耳)在二氯乙烷(3毫升)中之經冷卻(〇。〇)溶液内, 添加三乙胺(0.254毫升,1.82毫莫耳)。將此溶液逐滴添加至 雙光氣(0.11毫升’ 〇_91毫莫耳)在二氯乙烷(7毫升)中,於〇t 下之溶液内’歷經10分鐘。將反應混合物在室溫下攪拌90 分鐘’然後於EtOAc與1MHC1水溶液之間作分液處理。將有 機層以鹽水洗滌’脫水乾燥(MgS04),過濾並蒸發,而得異 氣酸S旨’為褐色油。 於上文製成之異氰酸酯(244毫克,0.79毫莫耳)在二氯乙烷(4 毫升)中乏經冷卻(〇°C )溶液内,添加三乙胺(0.122毫升,0.87 毫莫耳),接著為二乙胺(0.082毫升,0.79毫莫耳)^將反應混 合物在室溫下攪拌3小時,然後於EtOAc與1M HC1水溶液之間 作分液處理。將有機層以鹽水洗滌,脫水乾燥,過 滤並蒸發而得褐色油狀殘留物’使其藉急驟式管柱層析純 化(50%醋酸乙酯/己烷)而得二乙基脲,為無色油。 93320 -55- 1344956 此中間物係涉及方法D-G中所述之順序,而得標題化合物 ;粉紅色固體;IR(固體)1640,1512, 1213 公分-1 ; iHNMR (400 MHz, d6-DMSO) δ 0.75-0.95 (3Η, m), 1.10-1.40 (6Η, m), 1.90-2.25 (2H, m), 2.60-2.90 (2H, m), 3.30-3.50 (4H, m), 4.75 (1H, m), 5.10-5.60 (3H, m), 6.35 (1H, t), 7.30 (1H, m), 7.75 (1H, m), 7.80 (1H, m), 8.05 (1H, m), 8.95-9.05 (lH,m) ; 19FNMR (376 MHz, d6-DMSO,質子-去偶合)(5 -141.0,-156.9 ;M+H 573.3, M-H 571.2. 實例16 (S,S)-4-酮基-3-(2-{2-酮基-3-[(四氫吡咯-1-羰基)-胺基]-2H-吡啶-1-基}-丁醯基胺基)-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法Η、D-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸第三-丁酯與四氫吡咯;粉紅色固體;IR (固體)1650, 1593, 1512,1489,1208&*-1;1HNMR(400MHz,d6-DMSO)5 0.80(3H,m), 1.80-2.20 (6H, m), 2.60-2.90 (2H, m), 3.30-3.50 (4H, m), 4.60-4.75 (1H, m), 5.10-5.50 (3H, m), 6.30 (1H, t), 7.35 (1H, m), 7.50-7.75 (2H, m), 8.00 (1H, m), 8.85-8.95 (1H,m) ; 19F NMR (376 MHz,d6-DMSO,質子-去偶合)5 -141.1,-156.9 ; M+H 571.3, M-H 569·3. 實例17 (S,S)-3-[2-(3-甲氧1藏基胺基-2-嗣基-2Η-<»比淀-1-基)_丁酿基胺基]-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸 93320 -56- 1344956 Ο
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2Η-吡啶-1-基)-丁酸 第三-丁酯與氣甲酸甲酯;粉紅色固體;IR (固體)1644, 1661, 1709 公分 M 〗H NMR (400 MHz, d6-DMS0) 0.81 (3H, m),1.95 (1H,m), 2.09 (1H, m), 2.50-2.98 (2H, m), 3.70 (3H, s), 4.20-5.50 (4H, m), 6.31 (1H, m), 7.40 (1H, m), 7.59 (1H, m), 7.82 (1H, m), 8.20 (1H, s), 8.55-9.00 (1H, d); 19FNMR(376 MHz,d6-DMSO,質子-去偶合)(5 -140.6,-141.0,-141.1, -156.80,-156.9,-157.0,-157.1 ; M+H 532.3, M-H 530.3. 實例18 (S,S)-3-[2-(3-乙烷磺醯基胺基-2-酮基-2H-吡啶-1-基)-丁醯基胺基]-4-酉同基-5-(2,3,5,6-四鼠-冬氧基)-戍酸
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸 第三-丁酯與氣化乙烷磺醯;粉紅色固體;iHNMRGOOMHz, d6-DMS0) δ 0.74-0.82 (3Η, m), 1.17-1.25 (3H, m), 1.85-2.10 (2H, m)5 2.54-2.79 (2H, m), 3.09-3.15 (2H, m), 4.58-4.68 (1H, m), 5.13-5.38 (2H, m), 6.26-6.31 (1H, m), 7.34-7.38 (1H, m), 7.51-7.73 (2H, m), 8.72-8.76 (1H, m), 8.89-8.97 (1H, m), 12.51 (1H, br s) ; M+H 566.2, M-H 564.2. 實例19 93320 -57- 1344956 (S,S)-4-酮基-3-{2-[2-酮基-3-(丙烷_i-磺醯基胺基)-2H-吡啶-1-基]-丁 醯基胺基}·5-(2,3,5,6-四氟-苯氧基)-戊酸 〇
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2Η-吡啶-1-基)-丁酸 第三-丁酯與氣化丙烷磺醯;粉紅色固體;iHNMRMOOMHz, d6-DMSO) δ 0.74-0.82 (3Η, m), 0.88-0.94 (3H, m), 1.63-1.74 (2H, m), 1.85-2.10 (2H, m), 2.56-2.79 (2H, m), 3.06-3.13 (2H, m), 4.58-4.68 (1H, m), 5.13-5.40 (2H, m), 6.26-6.31 (1H, m), 7.34-7.37 (1H, m), 7.50-7.62 (2H, m), 8.71-8.75 (1H, m), 8.90-8.97 (1H, m), 12.53 (1H, br s) ; M+H 580.3, M-H 578.3. 實例20 (S,S)-4-酉同基-3-{2-(2-酉同基-3-(丙-2-績酸基胺基)-2H-p比淀-1-基]-丁 醯基胺基}-5-(2,3,5,6-四氟-苯氧基)-戊酸
使用類似C-G之方法,製自(S)-2-(3-胺基-2-酮基-2H-吡啶-1-基)-丁酸第三-丁酯與氯化異丙基磺醯;粉紅色固體;IR (固體) 1645, 1518 &*-1;1HNMR(400MHz,d6-DMSO)(5 1.7-1.8(3H,m),U8-1.25 (6H, m), 1.85-2.05 (2H, m), 2.55-2.8 (2H, m), 3.2-3.3 (1H, m), 4.52-4.62 (1H, m), 5.15-5.32 (3H, m), 5.4-5.43 (1H, m), 6.25 (1H, t), 7.3-7.35 (1H, m), 93320 -58- 1344956 7.45-7.6 (2H, m), 8.6-8.7 (1H, m), 8.9-9.0 (1H, m) ; M+H 580.2, M-H 578.2. 實例21 (S,S)-3-[2-(3-苯橫gi胺基-2-酮基-2H-p比咬-1-基)-丁醯基胺基]-4-酮 基-5-(2,3,5,6-四氣-苯氧基)-戊酸
根據方法C-G,製自(S)-2-(3-胺基-2-酮基-2H-吡啶_1·基)-丁酸 第三-丁酯與氣化苯磺醯;粉紅色固體;111]^111(40〇]\^2,(16-DMSO) δ 0.55-0.66 (3Η, m), 1.72-1.84 (1H, m), 1.91-2.01 (1H, m), 2.53-2.61 (1H, m), 2.68-2.76 (1H, m), 4.54-4.63 (1H, m), 5.06-5.32 (2H, m), 6.20-6.25 (1H, m), 6.98-7.86 (9H, m), 8.84-8.90 (1H, m), 9.40-9.45 (1H, m), 12.51 (1H, brs); M+H 614.1, M-H 612.1. 實例22 (S,S)-3-[2-(3-乙:i克續酸基胺基-2-嗣基-5-三氣甲基-214-0比淀-1-基)-丁醯基胺基]-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法A-G,製自(2-酮基-5-三氟甲基-1,2-二氫-咕啶-3-基)-胺甲基酸芊酯:灰白色固體;IR (固體)1664, 1519公分M ; 1HNMR(400MHz,d6-DMSO) δ 0.78-0.87 (3Η, m), 1.18-1.23 (3Η, m), 1.99- 93320 -59- 1344956 2.14 (2H, m), 2.55-2.80 (2H, m), 3.19-3.25 (2H, m), 4.54-4.66 (1H, m), 5.20-5.30 (2H, m), 5.35-5.45 (1H, m), 7.47 (1H, m), 7.55-7.71 (1H, m), 8.01 (1H, s), 9.05 (lH,m), 9.31 (lH,s); 19FNMR (376 MHz, d6-DMSO,質子-去偶合) 5 -63.11,-139.6,-157.1,-157.2 ; M+H 634.1,M-H 632.1. 實例23 (S,S)-3-[3-曱基-2-(2-酬基-3-苯乙酸基胺基-2H-p比淀-1-基)-丁驢基 胺基]-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
根據方法A-G,製自(2-酮基-1,2-二氫-吡啶-3-基)-胺甲基酸苄 酯;粉紅色固體;IR(固體)1644, 1683, 1740, 1791 公分-1 ; iHNMR (400 MHz, d6-DMSO) δ 0.6 (3Η, m), 1.0 (3Η, m), 2.2-2.3 (1H, m), 2.5-3.0 (2H, m), 3.7-3.8 (2H, m), 4.1-5.4 (4H, m), 6.2-6.3 (1H, m), 7.2-7.4 (5H, m), 7.5-7.7 (2H, m), 8.1-8.2 (1H, m), 8.7-9.2 (2H, m); 19F NMR (376 MHz, d6-DMSO, 質子-去偶合)5 -140.6, -141.0, -156.8, -157.0, -157.2 ; M+H 606.3, M-H 604.3. 實例24 (S,S)-3-[2-(3-乙烷磺醯基胺基-2-酮基-2H-吡啶小基)-3-甲基-丁醯 基胺基]-4-酮基-5-(2,3,5,6-四氟-苯氧基)-戊酸
F 93320 •60- 1344956 根據方法A-G,製自(2-酮基-1,2-二氫-吡啶-3-基)-胺甲基酸芊 酯;灰白色固體;IR (固體)1595, 1646, 1682, 1742, 1789 公分—1 ; 1 H NMR (400 MHz, d6-DMSO) δ 0.7 (3Η, m), 0.9-1.0 (3Η, m), 1.2 (3H, m), 2.3 (1H, m), 2.6-3.0 (2H, m), 3.1 (2H, m), 4.1-5.4 (4H, m), 6.3 (1H, m), 7.3 (1H, m),7.5-7.7 (2H,m),8.7-9.2 (2H,m) ; 1 9F NMR (376 MHz,d6-DMSO,質子 -去偶合)5 -140·6,-141.0,-156·7,-157.0,-157·1 ; M+H580.2,M-H 578.3_ 實例25 (S)-5-氣基-4-嗣基-3-[2-(2-嗣基-3-丙酿基胺基-2Η_ρ比咬-1-基)-丙縫 基胺基]-戊酸
根據方法A-G,製自(2-酮基-1,2-二氫-吡啶-3-基)-胺甲基酸芊 酯與3-胺基-5-氟基-4-幾基•戊酸第三-丁酯;粉紅色固體;IR (固體)1643, 1658, 1711,1740 公分—1 ; 1HNMR (400 MHz,d6-DMSO) δ 1.0-1.2 (3H, m), 1.4-1.6 (3H, m), 2.4-3.2 (4H, m), 4.2-4.6 (1.5H, m), 5.0-5.6 (2.5H, m), 6.3 (1H, m), 7.3 (1H, m), 8.2 (1H, m), 8.3-8.8 (1H, m), 9.1 (1H, m); 1 9 F NMR (376 MHz, d6-DMSO,質子-去偶合)5 -226.8, -226.9, -230.6, -231.4,-232.7,-232.8 ; M+H 370.4, M-H 368.3. 實例26 (S)-3-[2-(3-苯曱醯胺基-2-酮基-2H-吡啶-1-基)-丙醯基胺基]-5-氟基 -4-酮基-戊酸 〇
93320 -61 · 1344956 根據方法A-G,製自(2-酮基-1,2-二氫-咕啶-3-基)-胺曱基酸芊 酯與3-胺基-5-氟基-4-羥基-戊酸第三-丁酯;粉紅色固體;ir (固體)1523, 1644 公分 '1 ; 1 H NMR (400 MHz, d6-DMS0) 5 1 _6 (3H,m), 2.5-3.2 (2H, m), 4.2-4.7 (1.5H, m), 5.0-5.6 (2.5H, m), 6.4 (1H, m), 7.4-7.6 (3H, m), 7.9 (2H, m), 8.3 (1H, m), 8.5-8.9 (1H, m), 9.3 (1H, m) ; 19 F NMR (376 MHz, d6-DMSO,質子-去偶合)5 -226.7, -226.8, -230.4, -231.3, -232.8, -232.9; M+H 418.3, M-H 416.3. 實例27 (S)-3-{2-[3-(2,6-二氯-苯曱醯胺基)-2-酮基-2H-吡啶-1-基]-丙醯基胺 基}_5_氟基-4-嗣基-戊酸 0
根據方法A-G,製自(2-酮基-1,2-二氫-吡啶-3-基)-胺甲基酸芊 酯與3-胺基-5-氟基-4-羥基-戊酸第三-丁酯;粉紅色固體;IR (固體)1521,1646 公分-1 ; iHNMRGOOMH^dS-DMSO) (5 1·5_Ι·6(3Η, m),2.5-3.2(2H,m),4.2-4.7(1.5H,m),5.0-5.5(2.5H,m),6.3-6.4(lH,m),7.4-7.5 (3H, m), 8.3 (1H, m), 8.5-8.9 (1H, m), 10.2 (1H, m) ; 1 9F NMR (376 MHz, d6-DMSO,質子-去偶合)(5 -226.7, -226.8, -230.6, -231·4,-232.8, -232.9 ; M+H 486.3, M-H 484.3. 實例28 (S)'5-氟基-4-酮基-3-[2-(2-酮基-3-苯乙醯基胺基-2H^比啶-1-基)-丙 醯基胺基]-戊酸 1344956
根據方法A-G,製自(2-酮基-1,2-二氫-吡啶-3-基),胺甲基酸苄 酯與3-胺基-5-氟基-4-羥基-戊酸第三-丁酯;粉紅色固體;IR (固體)1524.2, 1652.4 公分·1; 1 HNMR(400 MHz,d6-DMS0) 5 1.5 (3H, m), 2.5-3.2 (2H, m), 3.8 (2H, m), 4.2-4.7 (1.5H, m), 5.0-5.5 (2.5H, m), 6.3 (1H, m), 7.2-7.4 (6H, m), 8.2 (1H, m), 8.4-8.9 (1H, m), 9.3 (1H, m); 1 9F NMR (376 MHz, d6-DMSO,質子-去偶合)5 -226.7, -226.8, -230.6, -231.5, -232_8, -232.9; M+H 432.3, M-H 430.3. 實例29 (S)-5-氟基-4·酮基-3-[2-(2-酮基-3-丙醯基胺基-2H-吡啶-1-基)-丁醯 基胺基]-戊酸
根據方法A-G,製自(2-酮基-12-二氫-u比啶-3-基)-胺甲基酸苄 酯與3-胺基-5-氟基-4·羥基-戊酸第三-丁酯;粉紅色固體;IR (固體)1644, 1585, 1518,1214 公分―1 ; iHNMR^OOMH^dS-DMSO) δ 0.8-0.9 (3H, m), 1.05 (3H, t), 1.9-2.1 (2H, m), 2.4-2.5 (2H, m), 2.6-2.95 (2H, m), 4.2-4.5 (2H, m), 5.1-5.5 (3H, m), 6.3-6.35 (1H, m), 7.4-7.45 (1H, m), 8.2-8.25 (1H, m), 8.8-8.9 (1H, m), 9.1-9.15 (1H, m) ; 19F NMR(376 MHz, d6-DMSO,質子-去偶合)(5 -226.7, -232.6 ; M+H 384.3, M-H 382.3. 實例30 93320 ·63· 1344956 (S)-3-[2-(3-苯甲醯胺基-2-酮基-2H-吡啶-1-基)-丁醯基胺基]-5-氟基 -4-嗣基-戊酸
根據方法A-G,製自(2-酮基-1,2-二氫·吡啶-3-基)·胺甲基酸芊 酯與3-胺基-5-氟基-4-羥基-戊酸第三-丁酯;粉紅色固體;IR (固體)1643, 1522, 1204 &*_1;1HNMR(400MHz,d6-DMSO)50.75-0.85 (3H, m), 1.9-2.2 (2H, m), 2.6-2.9 (2H, m), 4.3-4.7 (2H, m), 5.1-5.6 (2H, m) 6.4-6.5 (1H, m), 7.5-7.85 (4H, m), 7.9-8.0 (1H, m), 8.3-8.4 (1H, m), 8.85-6.95 (1H, m), 9.35 (1H, s) ; M+H 432.3, M-H 430.3. 實例31 (S)-3-{2-[3-(2,6-二氯-苯曱醯胺基)-2-酮基-2H-吡啶-1-基]-丁醯基胺 基}_5_氣基-4-嗣基-戊酸
根據方法A-G,製自(2-酮基-1,2-二氫-说啶-3-基)-胺曱基酸芊 酉旨與3-胺基_5·鼠基-4-喪基-戊酸第二丁 @旨,白色固體,IR (固 體)1682,1645,1580,1516,1216&*-1;1HNMR(400MHz,d6-DMSO) δ 0.8-0.9 (3H, m), 1.9-2.1 (2H, m), 2.6-2.85 (2H, m), 4.4-4.7 (2H, m), 5.1-5.5 (2H, m), 6.4-6.5 (1H, m), 7.5-7.6 (4H, m), 8.33-8.38 (1H, m), 8.85-8.95 (1H, m), 9.15-9.25 (1H, s) ; M+H 500.3, M-H 498.3. 實例32 93320 -64- 1344956 (S)-5-鼠基-4-嗣基-3-(2-(2-嗣基-3-[(u比咬-2-叛基)-胺基]-2H-p比淀-1-基}-丁醯基胺基)-戊酸
根據方法A-G,製自(2-酮基-1,2-二氫-吡啶-3-基)-胺甲基酸芊 酯與3-胺基-5-氟基-4-羥基-戊酸第三··丁酯;乳黃色固體;IR (固體)1685, 1644, 1521 &*-1;1HNMR(400MHz,d6-DMSO)<50.81-0.86 (3H, m), 1.90-2.05 (1H, m), 2.06-2.19 (1H, m), 2.54-2.90 (2H, m), 4.58-4.72 (1H, m), 5.07-5.31 (2H, m), 5.42-5.57 (1H, m), 6.40-6.44 (1H, m), 7.47-7.49 (1H, m), 6.68-7.72 (1H, m), 8.09-8.11 (1H, m), 8.18 (1H, d), 8.45-8.47 (1H, m), 8.73-8.75 (1H, m), 8.87 (1H, dd), 10.74 (1H, s), 12.45 (1H, brd s); 1 9F NMR (376 MHz, d6-DMSO,質子-去偶合)^ -226.8, -230.4, -230.6, -231.0, -232.5, -232.6, -232.8, -232.9 ; M+H 433.4, M-H 431.4. 實例33 (S)-5-氟基-4-酮基-3-[2-(2-酮基-3-苯乙醯基胺基-2H-吡啶-1-基)-丁 籲 酿基胺基]-戊酸
根據方法A-G,製自(2-酮基-i,2-二氫·Ρ比啶-3-基)-胺甲基酸苄 酯與3·胺基-5-氟基-4-經基-戊酸第三_丁酯;粉紅色固體;IR (固體)1644, 1672, 1742, 1785 公分-1 ; iHNMR(400MHz,d6_DMSO) δ 0.7-0.8 (3H, m), 1.8-2.2 (2H, m), 2.5-3.2 (2H, m), 3.8 (2H, s), 4.2-4.7 (2H, 93320 -65 - 1344956 m), 5.1-5.5 (2H, m), 6.3 (1H, m), 7.2-7.4 (6H, m), 8.2 (1H, m), 8.5-9.4 (2H, m); 1 9 F NMR (376 MHz, d6-DMSO,質子-去偶合)占-226.7, -226.7, -230.4, -231.2,-232.6,-232.6 ; M+H 446.3, M-H 444.3. 實例34 ⑸-5-氣基-4-自同基-3-{2-[2-嗣基-3-(2-間-曱苯基-乙酿胺基)-2H-p比 啶-1-基]-丁醯基胺基}-戊酸
根據方法A-G,製自(2-酮基-1,2-二氫-吡啶-3-基)-胺甲基酸苄 酯與3-胺基-5-氟基-4-羥基-戊酸第三-丁酯;土黃色固體;IR (固體)1644, 1678 公分1 ; 1HNMR (400 MHz,d6-DMSO) <5 0.7-0.8 (3H, m), 1.8-2.2 (2H, m), 2.3 (3H, s), 2.5-3.2 (2H, m), 3.7-3.8 (2H, s), 4.2-5.5 (4H, m), 6.3 (1H, m), 7.0-7.3 (4H, m), 7.4 (1H, m), 8.2 (1H, m), 8.5-8.9 (1H, m), 9.2-9.3 (1H,m) ; 19F NMR (376 MHz,d6-DMSO,質子-去偶合)(5 -226.7, -226.7, -230.4, -231.2, -232.6, -232.7 ; M+H 460.3, M-H 459.4. 實例35 (S)-5-氟基_4_酮基-3-[2-(2·酮基-3-丙醯基胺基-2H-吡啶-1-基)-戊醯 基胺基]-戊酸
根據方法A-G,製自(2-酮基-1,2-二氫-p比淀-3-基)-胺甲基酸_ 酯與3-胺基-5-氟基-4-羥基-戊酸第三-丁酯;白色固體;1 HNMR 93320 • 66 - 1344956 (400 MHz, d6-DMSO) δ 0.85-0.95 (3H, m), 1.0-1.1 (3H, m), 1.1-1.17 (2H, m), 1.9-2.0 (2H, m), 2.4-2.5 (2H, m), 2.6-2.90 (2H, m), 4.5-4.65 (1H, m), 5.1-5.5 (3H, m), 6.3-6.35 (1H, m), 7.4-7.43 (1H, m), 8.2-8.23 (1H, m), 8.8-8.9 (1H, m), 9.05-9.1 (1H, m); 1 9F NMR (376 MHz, d6-DMSO,質子-去偶合)(5 -226.7, -232.6 ; M+H 398.4, M-H 396.4. 實例36 (S)-5-氟基-3-[4-f基-2-(2-酮基-3-丙醯基胺基-2H-吡啶-1-基)-戊醯 基胺基]-4-酮基-戊酸
根據方法A-G,製自(2-酮基-1,2-二氫-说啶-3-基)-胺曱基酸苄 酯與3-胺基-5-氟基-4-羥基-戊酸第三-丁酯;粉紅色固體; ^NMRC^OMHz, d6-DMSO) δ 0.85 (6Η, m), 1.05 (3H, t), 1.30 (lH,m), 1.70-2.10 (2H, 2 x m), 2.30-3.00 (4H, m), 4.60-4.80 (1H, m), 5.05-5.40 (2H, m), 5.65 (1H, m), 6.35 (1H, m), 7.45 (1H, m), 8.25 (1H, m), 8.95 (1H, m), 9.15 (1H, m) ; 1 9F NMR (376 MHz, d6-DMSO,質子-去偶合)(5 -226.7, -232.5 ; M+H 412.3. 實例37 (S)-5-氟基-3-[2-(5-曱基-2-酮基-3-苯乙醯基胺基-2H-吡啶-1-基)-丁 醯基胺基]-4-酮基-戊酸
93320 • 67· 1344956 根據方法A-G,製自(5-甲基-2-酮基-1,2-二氫-吨啶-3-基)-胺曱 基酸芊酯與3-胺基-5-氟基-4-羥基-戊酸第三-丁酯;黃色固體 ;IR(固體)1654, 1741,1785 公分 M ; iHNMR (400 MHz,d6-DMS0) (5 0.7-0.8 (3H, m), 1.8-2.2 (5H, m), 2.5-3.2 (2H, m), 3.8 (2H, s), 4.2-5.5 (4H, m), 7.1-7.4 (6H, m), 8.1 (1H, m), 8.4-8.9 (1H, m), 9.2-9.4 (1H, m) ; 19F NMR (376 MHz,d6-DMSO,質子-去偶合)5 -226.7, -226.7, -227.5, -230.5, -231.3,-232.6,-232.6,-233.4 ; M+H 460.4, M-H 458.4. 實例38 (S,S)-4-酮基-3_{2-[2-酮基-3-0塞唑-2-基胺基)-2H-吡啶-1-基]-丁醯基 胺基}-5-(2,3,5,6-四氟-苯氧基)-戊酸 〇
方法I 3-(魂唑-2-基胺基)-1Η-吡啶-2-酮
αΝ Η 於3-胺基-1Η-吡啶-2-酮(2.0克,18.7毫莫耳)在水(2毫升)中之 溶液内,添加15% HC1 (10毫升,18毫莫耳),接著為硫氰酸 銨(1.5克,18毫莫耳),並將混合物加熱至回流,歷經兩小 時。在冷卻時,發現中間物硫脲以紅褐色固體沉澱。過濾 混合物,並將固體以水(5毫升)洗滌。於硫脲(1.3克,77毫 莫耳)在EtOH (20耄升)與水(5毫升)中之溶液内,添加氣乙醛 93320 •68- 1344956 (2.3毫升,16.4毫莫耳)’並將混合物加熱至回流歷經四小 時。於冷卻時,將混合物以EtOAc (30毫升)稀釋,並以1〇% NaHC〇3及鹽水洗滌。將有機相以MgS〇4脫水乾燥,及在真空 中濃縮。將殘留物藉急驟式管柱層析純化(100% Et〇Ac)而得 標題化合物’為淡綠色固體(1.43克,40% ) : 1H NMR (400 MHz, CDC13) (5 1.6 (1H, s), 6.45 (1H, t), 6.75 (1H, s), 7.05-7.10 (lH, m), 7.40-7.42 (1H, m), 8.35-8.5 (2H, m) ; M+H 194.1, M-H 192.1. 此中間物係涉及方法A與B-G中所述之順序,而得實例38 ,為白色固體;IR(固體)1648, 1593, 1517, 1490 公分; iHNMR (400 MHz, d6-DMSO) δ 0.75-0.85 (3Η, t), 1.9-2.2 (2Η, m), 2.6-2.8 (2H, m), 4.6-4.7 (1H, m), 5.2-5.3 (2H, m), 5.35-5.45 (1H, m), 6.3-6.35 (1H, m), 6.96-6.98 (1H, m), 7.2-7.3 (2H, m), 7.5-7.65 (1H, m), 8.4-8.43 (1H, m), 8.8-8.9 (1H, 2 x d),9.9 (1H,br s),12.5 (1H,brd s) ; 1 9 F NMR (376 MHz,d6-DMSO,質 子-去偶合)5 -141.0, -156.9 ; M+H 557.2, M-H 555.2. 實例39 (S,S)-4-酮基-3-[2-(2-酮基-3-丙胺基-2H-吡啶-1-基)-丁醯基胺基]-5-(2,3,5,6-四氟-苯氧基)-戊酸
方法J : (S)-2-[3-(苄氧羰基-丙基-胺基)-2-酮基-2H-吡啶-1-基]-丁酸第三-丁酯 93320 -69-
1344956 於(S) 2 (3苄氧碳基胺基_2_酮基_2Η_υ比咬小基)_丁酸第三_丁酉匕 (100毫克,0.26毫莫耳)在無水DMF(3毫升)中之溶液内添 加麵(60%分散液,1〇毫克,〇26毫莫耳),並將反應物於環 境皿度下攪拌,歷經3〇分鐘。逐滴添加碘丙烷(3〇微升 毫莫耳),並將反應物於環境溫度下攪拌過夜。使混合物在 真空中濃縮成固體,並於EtOAc(10毫升)與水(1〇毫升)之間作 分液處理。分離有機層,以MgS〇4脫水乾燥,及在真空中濃 縮。將殘留物藉急驟式管柱層析純化(30% Et〇Ac/己烷)而得 標題化合物’為淡綠色固體(1.43克,40%” iHNMR(400MHz, CDC13) 5 0.85-0.95 (6H, m), 1.35 (9H, s), 1.55-1.65 (2H, m), 1.85-1.95 (1H, m), 2.20-2.27 (1H, m), 3.6-3.7 (2H, m)} 5.15-5.2 (2H, m), 5.5-5.6 (1H, m), 6.25 (1H, t), 7.25-7.45 (7H, m) ; M+H 429.4.
此中間物係涉及方法C-G中所述之順序,且最後如方法B 中所述,接受氫解作用,而得實例39,為灰白色固體;IR (固 體)1581,1517,1489,938 公分-1;1111<[]\111(400]^4112,(16-〇]\/13〇)(5 0.80 (3H, t), 0.9 (3H,t), 1.5-1.6 (2H, m), 1.8-2.05 (2H, m), 2.5-2.7 (2H, m), 2.9-3.0 (2H, m), 4.6-4.7 (1H, m), 5.1-5.4 (3H, m), 6.1-6.2 (2H, m), 6.85-6.9 (1H, m), 7.5-7.65 (1H, m), 8.7-8.90 (1H, 3 x d), 12.5 (1H, brd s) ; M+H 516.2, M-H 514.2. 實例40 酵素檢測 93320 -70- 卡司沛酶抑制之檢測係以螢光原受質被重組純化人類卡司 沛酶-1、-3或-8之分裂為基礎。此等檢測係以基本上如由 Garcia-Calvo 等人 μ 伽/. 273 (1998),326〇8·326ι3)所報告之相 同方式,使用對各酵素專一之受質進行操作。卡司沛酶_丨之 受質為乙醯基-Tyr-Val-Ala-Asp-胺基-4-甲基香豆素。卡司沛酶_3 與-8之丈質為乙醯基_八印_(5丨11_%1_八印_胺基-4,曱基香豆素。兩 種受質均為此項技藝中已知。 於特疋抑制劑濃度下所發現之酵素失活速率、以,係藉由 數據之直接吻合至由 Thomberry 等人(Biochemistry 33 (1994),3943-3939)所導出之方程式’使用非線性最小平方分析電腦程式 (Prism2.0 ; GmphPad軟體)計算而得。為獲得第二級速率常數 kinact ’故將kobs值對其個別抑制劑濃度作圖,且值係接 著藉由電腦化線性回歸計算而得。 經選擇之本發明化合物抑制卡司沛酶_丨、_3及_8活性,係 藉由上述方法測得。化合物1_39抑制卡司沛酶-1,具有 kinact>200,000 (NT 1 s_1),抑制卡司沛酶 _3,具有 kinact>50,000 (M·1 s·1) ’及抑制卡司沛酶-8,具有kinact>50,000 (Μ·1 )。 實例41 抑制IL-1石自全血法今 ά 人類血液係剛從健康供應者取出,且以1 : 2稀釋於PBS中 。於500微升經稀釋血液中’添加rpm][培養基與1〇毫升LPS 中之50毫升經預稀釋待測化合物(5毫微克/毫升最後濃度, 於板上)(LPS ’血清型0Ui : B4, Sigma, L3012)。於刺激18小時 後’收集上層清液,並使用適當ELISA套件(R&D系統)檢測IL-1 93320 • 71 · 1344956 /5含量。 下表2顯示經選擇之本發明化合物抑制_自人類全血液 分泌,其係個別藉由上述方法測定。 表2. IL-1石分泌之抑舍丨 ----------- --化;^編號 ~~~~2 IC,〇(^M) --11, 14,17 & 29 — "" <0.5 _ 4, 6, 8, 9, 12, 13, 15, 16, 18, 19, 20, 21, 22, 0.5-5 --_23> 28., 36, 38 & 39 實例42 太白A皮質神經元之毯一氧所引致之細胞湖觉 皮質神經元係藉由R0gers等人,1997,价細敲公禮,44 : ι3ΐ程 序之修正,自Wistar大白氣胎兒㈣解離。簡言之,大腦皮 質係以無菌方式單離自15_2〇隻Wistar大白鼠胎兒。細胞懸浮 液係經由將大腦皮質切碎,並將其以木瓜蛋白酶煮解而製 成。將細胞以卵類黏蛋白酵素抑制劑及DNaseI洗滌,並覆蓋 於聚D離胺酸塗覆之板上,在含有1〇%熱失活牛胎兒血清、 L-麩醯胺、青黴素及鏈黴素之高葡萄糖〇]^]^中。神經元之 產量為每胎兒10x7,而當藉由錐藍排除評估時,其係為8〇_9〇 %存活。 在缺氧實驗之前,將神經元在完全培養基中,於37力下, 在正常大氣中培養48小時。關於缺氧,係將正常細胞培養 基以氧已耗乏之不含血清培養基置換。將細胞在95% N2/5% C02氧層中培養,歷經不同時間長度。使化合物於丨〇〇 下 4於DMSO中,然後稀釋於培養基中,及添加至培養物中’ 自時間=〇起。細胞凋零之程度係使用細胞死亡偵測ELISA套 93320 •72· 1344956 件⑽㈣度量’其係偵測職碎裂。板係在毫微米下讀 取。對照組包括在需氧條件下,於含血清培養基(+血清)中 培養之細胞,及在需氧條件下,Μ奪血清之培養基(-血清) 中培養之細胞。 表3顯示個別在大白鼠皮質神經元之缺氧所引致細胞调零 中所測試經選擇本發明化合物活性之、纟士果。 表3.在缺氧所引致細胞凋ι烚測中^活性 ---—'~~Μ -下训爪丨下 < 沽性 __化合物編號____ 2, 5, 10, 11, 12, 13, 15, 17, 20, 22. 38 Λ- IC5〇(/M) <1 1,3, 4, 6, 7, 8, 9, 14,16,18,19, 21,24, 29, 30 — 31,34,35,36 & 37 ' 1-10 貫例43 抗-Fas所引致之細胞凋零撿測 細胞调零可經由Fas配位體(FasL)結合至其受體CD95 (Fas)而 引致。CD95為被稱為死亡受體之有關聯受體族群之一,其 可經由卡司布§母階式反應之活化作用,觸發細胞中之細胞 凋零。此過程係經由接合分子FADD/M0RT-1結合至CD-95受體 參 -配位體複合物之細胞質功能部位而被引發。然後,卡司沛 酶-8係结合FADD ’且變成被活化’引發涉及下游卡司沛酶 活化作用及後續細胞凋零之一連串階式事件。細胞凋零 亦可在表現CD95之細胞中引致,例如Jurkai E6.1 T細胞淋巴瘤 · 細胞系,使用抗體,而非FasL,以使細胞表面CD95交聯。抗 -Fas-所引致之細胞凋零,亦經由卡司沛酶_8之活化作用而觸 發。這提供細胞為基礎之檢測篩檢抑制卡司沛酶冬所媒介 細胞凋零途徑之化合物之基礎。 93320 -73· 1344956 實驗程序 將JurkatE6.1細胞在包含RPMI-1640 (Sigma編號)+ 10%牛胎兒 血清(Gibco BRL 編號 10099-141) + 2mM L-越醯胺(Sigma 編號 G-7513) 之完全培養基中培養。細胞係在對數生長期中採集。將100 毫升在5-8xl05個細胞/毫升下之細胞,轉移至無菌50毫升 Falcon離心管,並在室溫下,於100xg下離心5分鐘。移除上 層清液,並使合併之細胞丸粒再懸浮於25毫升完全培養基 中。將細胞計數,並以完全培養基調整密度至2xl06個細胞 0 /毫升。 使待測化合物溶於二甲亞颯(DMSO)(Sigma編號D-2650)中, 而得100mM儲備溶液。將其在完全培養基中稀釋至400 #, w 然後在添加至細胞檢測板之前,於96-井板中連續性地稀釋。 將100微升細胞懸浮液(2xl06個細胞)添加至無菌96-井圓底 ‘ 群集板(Costar編號3790)之各井中。將50微升化合物溶液,在 適當稀釋下,與50微升抗-Fas抗體,無性繁殖系CH-11 (Upstate, 目錄編號1 544 675),在最後濃度為10毫微克/毫升下,添加 籲 至井中。設立對照井,減去抗體及減去化合物,但使用DMSO 之連續稀釋,作為媒劑對照物。將板在37°C下,於5% C02與 95%濕度中,培養16-18小時。 細胞之凋零係藉由DNA碎裂之定量,使用得自Roche診斷 · 學,編號1544 675之π細胞死亡偵測檢測π度量。於培養16-18小 時後,使檢測板在室溫下,於l〇〇xg下離心5分鐘。移除150 微升上層清液,並以150微升新的完全培養基置換。然後採 集細胞,並將檢測套件中所提供之200微升溶胞緩衝劑,添 93320 -74- 1344956 加至各井。將細胞研製,以確保完全溶解,並於4°C下培養30 分鐘。然後’使板在丨9〇〇xg下離心1〇分鐘,並將上層清液以 1 . 20稀釋於所提供之培養緩衝劑中。然後,將100微升此溶 液根據伴隨著套件所提供之製造者說明書進行檢測。〇D4〇5 耄微米係於添加最後受質後,在SpECTRAmax加上板讀取器 (分子裝置公司)中度量20分鐘。將OD405毫微米對化合物濃 度作圖,並使用曲線吻合程式s〇FTmaxPr〇 (分子裝置公司), 利用四參數吻合選擇,計算化合物之IC50值。 經選擇之化合物已在此項檢測中測試,且顯示會抑制此也缸 細胞之Fas所引致之細胞凋零,具有IC5〇值在〇〇〇1 _與〇丨5以 Μ之間。 敢之細胞凋零檢測中乏法敁
化合物編號___ 2, 4, 5, 7,11, 13, 17, 18, 19, 22, 25, 27, 29, 30,31,32.33.34.35. 37 26, 28, 36 0.5-2 雖然吾人已描述本發明之許多具體實施例,但顯而易見的 ^吾人之基本實例可以改變,以提供利用本發明化合物 ’:万去《其他具體實施例。0此,應明瞭的是,本發明、 範圍係欲被隨文所附之申請專利範圍 ^ 丄, 心而非被已拉 由上文實例表示之特殊具體實施例。 曰 93320 •75-
Claims (1)
1344956 '
«修(更)it本 第^[15134號專利申請案 中々^請專利範圍替換本(99年6月) 申請專利範圍 1. 一種式I化合物,
或其藥學上可接受之鹽。 2.根據申請專利範園第!項之化合物,其係表為式广:
3.根射請專利範圍第2項之化合物,其係表為式j
Γ 4. 一種醫樂組合物,其包含: am據中請專利範圍第⑴項中任—項之化合物;與 b)樂:上可接受之载劑、佐劑或媒劑。 種醫藥、’Α σ物’其係在病患中用於治療風濕性關節炎、 骨關節炎、骨質疏鬆症、系統紅斑狼瘡、硬皮病、慢性甲 93320-990604.doc 狀腺炎、格雷武司氏疾病、重症肌無力、自身免疫嗜中性 白血球減少症、自身免疫溶血性貧血、血小板減少症、幼 年風濕性關節炎、痛風、Beheet氏徵候簇、識氏徵候藤、 巨_活化作用徵候鎮 '肉狀瘤病 '一職徵候簽 三家族性冷蓴財、慢性幼兒神經性皮膚與關節徵候娱、 家族f生地中海熱、與咖幻有關聯之週期性徵候鎮 、高-IgD週期性熱徵候鎮_幻、㈣徵㈣、牛皮癬、異 位性皮炎、傷症、充髮、尋常痤瘡、天疮瘡、氣喘 人 呼吸困難徵㈣、膽囊纖維變性、氣腫、慢性枝氣管炎、 慢性阻塞肺病、自發性肺_變性、炎性腹膜炎、炎性腸 疾病、克隆氏病、潰癌性結腸炎、自身免疫胃[與幽門 螺旋桿时關聯之胃與十二指腸潰癌疾病、糖尿病、姨腺 炎、絲球體性腎炎、慢性活性肝炎、過量食用酒精攝取疾 病、腎病、多囊腎臟病、灼傷、燒傷後器官細胞凋零、出 血性休克、器官衰竭、子宮内膜組織異位形成、移植物抗 值主疾病、器官移植排斥、白血病、脊髓發育不良徵候簇 、多發性骨髓瘤相關之骨質病症 '急性骨髓性白血病、慢 性骨髓性白血病、轉移性黑色素瘤、卡波西氏肉瘤、多發 性月知瘤丨又性心臟疾病、急性心臟疾病、心肌梗塞、心 肌絕血、鬱血性心衰竭、動脈粥瘤硬化、冠狀動脈分流移 植(CABG)與冠狀動脈分流移植有關聯之併發症、急性冠 狀徵候簇、阿耳滋海默氏疾病、巴金生氏病、亨丁頓氏疾 病、Kennedy氏疾病、朊病毒疾病、大腦絕血、癲癇、脊柱 肌肉萎縮、肌萎縮性側索硬化、多發性硬化、fflV相關之 93320-990604.doc 腦炎、外傷性腦部傷害、脊趙損傷、由於中風所致之神經 病傷害、糖尿病患者之神經病、急性與慢性疼痛、葡萄膜 炎、視網膜病症、糖尿病患者之視網膜病、青光眼、角膜 火、病毒所媒介疾病、敗血病、敗灰性休克、志贺桿菌病 肝乂 B肝k -C '肝炎-G、黃熱病、登革熱、曰本腦炎 * HIV感染、結核病、腦膜炎、假單胞菌屬感染' 不動桿 菌屬感染或老化,其包含治療上有效量之根據申請專利範 圍第1項之化合物。 根據申叫專利範圍第5項之醫藥組合物,其中疾病為骨關 卽炎、胰腺炎、氣喘、成人呼吸困難徵候簇、絲球體性腎 炎、風濕性關節炎、系統紅斑狼瘡、硬皮病、慢性曱狀腺 炎、格雷武司氏疾病、自身免疫胃炎、騰島素依賴性糖尿 病(第I型)自身免疫溶血性貧血、自身免疫嗜中性白血 球減少症、血小板減少症、慢性活性肝炎、重症肌無力、 炎性腸疾病、克隆氏病、牛皮癖、移植物抗宿主疾病、骨 質疏鬆症、多發性骨髓瘤相關之骨質病症、急性骨髓性白 血病、k性骨髓性白血病、轉移性黑色素瘤、卡波西氏肉 瘤、多發性骨髓瘤、敗血病、敗血性休克、志贺桿菌病、 大腦絕血 '心肌絕企、脊柱肌肉萎縮或由於中風所致之神 經病傷害。 7.根據申請專利範圍第5項之醫藥組合物,其中該疾病為與 冠狀動脈分流移植有關聯之併發症。 8· —種醫藥組合物’其係在病患中抑制卡司沛酶所媒介之功 月b ’其包含治療上有效量之根據申請專利範圍第1項之化 93320-990604.doc 1344956 合物》 種邊藥組合物,其係在病患令降低IG正或正Ν_γ生產,其 匕3藥學上有效量之根據申請專利範圍第丨項之化合物。 !〇·種保存細胞之方法,該方法包括將細胞浸泡在根據申請 專利範圍第1項化合物之溶液中之步驟。 根據中請專利範圍第1G項之方法,其t該細胞係在: a) 欲供移植之器官中;或 b) 血液產物中。
12·-種醫藥組合物,其係使用免疫療法治療癌症, 免 疫療法包含根據申請專利範圍第i項之化合物作為其〆種 級合物 13.根據申請專利範圍第4至9及12項中任一項之醫藥 其包含另一種治療劑。 、 14· 一種製備式(I)化合物之方法,
其包括 (a)使式(III)化合物: 93320-990604.doc 1344956
於偶合條件及溶劑存在下反應。 15.根據申請專利範圍第14項之方法,其中式(III)化合物係具 式(ΠΓ):
(III,) 其係藉由以下方法製備,包括: ⑹使式(V)化合物: 93320-990604.doc 1344956 (V) 在溶劑中,於去除保護條件存在下反應。 16.根據申請專利範圍第15項之方法,其中式(V)化合物 Λ Η
Ο
Ο (V) 係藉由以下方法製備,其包括: ⑷使式(VI)化合物:
與式(VII)化合物:
於溶劑與鹼存在下反應。 17. —種製備式(I)化合物之方法 93320-990604.doc 1344956
(i) 其包括: (a)使式(III)化合物: ο
(III) 與式(X)化合物:
於偶合條件與溶劑存在下反應。 93320-990604.doc
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