TWI828155B - 吡咯并嘧啶類化合物的用途 - Google Patents
吡咯并嘧啶類化合物的用途 Download PDFInfo
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- TWI828155B TWI828155B TW111119062A TW111119062A TWI828155B TW I828155 B TWI828155 B TW I828155B TW 111119062 A TW111119062 A TW 111119062A TW 111119062 A TW111119062 A TW 111119062A TW I828155 B TWI828155 B TW I828155B
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- inflammatory bowel
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Abstract
本發明揭示了吡咯并嘧啶類化合物的用途。所述的吡咯并嘧啶類化合物的結構如式I所示,其可用於製備治療和/或預防發炎性腸病藥物;
Description
本申請主張申請日為2021/5/31的中國專利申請2021106018102和申請日為2022/2/28的中國專利申請2022102181538的優先權。本申請引用上述中國專利申請的全文。
本發明涉及一種吡咯并嘧啶類化合物的用途。
發炎性腸病(Inflammatory Bowel Disease,IBD)是一種慢性腸道發炎性疾病,IBD患者腸道菌群的組成與結構發生明顯變化即腸道菌群失調。腸道屏障功能對維持人體腸道功能穩定狀態發揮著重要調節作用。研究表明,在IBD中存在腸道屏障功能受損,腸道通透性增加。腸道菌群失調導致腸道屏障功能受損,從而破壞人體正常的腸道穩定狀態功能,加重IBD的進展。
發炎性腸病主要包括潰瘍性結腸炎(Ulcerative Colitis,UC)和克隆氏病(Crohn Disease,CD),該病與自身免疫功能紊亂密切相關,該病在西方國家很常見,近年我國IBD病例數激增,現已成為消化系統常見病及慢性腹瀉的主要病因。臨床上,發炎性腸病患者表現為反復的腹痛、腹瀉、粘液血便,甚至出現各種全身併發症如視力模糊、關節疼痛、皮疹等。本病經治療可好轉,也可自行緩解。但多數患者反復發作,遷延不癒,其中相當部分患者因出現併發症而需要手術治療。到目前為止,其病因及具體的發病機理仍不清楚,臨床上缺少對該病的根本性治療方案。世界衛生組織把該病列為現代難治病之一。
托法替尼於2012年11月被美國藥品食品監督管理局(FDA)批准用於自身免疫性疾病風濕性關節炎的治療,並於2018年5月被美國FDA批准用於治療中度至重度治療潰瘍性結腸炎,其高劑量(10mg/kg)臨床緩解率約為40%。但因其作用於訊息上游標的,可引起多種非特異反應,包括高血脂、嚴重感染、惡性腫瘤及肺栓塞等毒副反應,其中部分可危及生命,且其毒性與劑量成正比。鑒於此,歐洲藥品管理局安全委員會於2019開始對托法替尼進行綜合評估,同時美國FDA也發佈托法替尼引起凝血及死亡風險的黑框警示(一種罕見的安全警告),同時慎重使用或停用10mg/kg這一臨床劑量,而妥協使用5mg/kg這一臨床劑量。
鑒於最新藥物托法替尼較低的臨床緩解率和較嚴重的不良反應。因此,研究開發能夠安全、有效的預防和治療發炎性腸病的藥物,對於臨床治療發炎性腸病具有重要指導意義。
本發明所要解決的技術問題是提供對發炎性腸病具有良好的預防和/或治療作用的化合物,為此,本發明提供了一種吡咯并嘧啶類化合物的用途。
本發明提供了一種如式Ⅰ所示化合物或其藥學上可接受的鹽在製備治療和/或預防發炎性腸病的藥物中的用途;
。
在一些實施方案中,所述的發炎性腸病為潰瘍性結腸炎。
在一些實施方案中,所述的發炎性腸病為克隆氏病。
在一些實施方案中,所述的發炎性腸病具有便血和/或腹瀉症狀。
在一些實施方案中,所述的治療和/或預防發炎性腸病的藥物包含藥用佐劑。
在一些實施方案中,所述的如式Ⅰ所示化合物或其藥學上可接受的鹽為所述藥物的有效成分之一或者唯一有效成分。
在一些實施方案中,向有需要的受試者可施用治療有效量的所述如式Ⅰ所示化合物或其藥學上可接受的鹽。所述施用的方式可為任何合適的方式,例如口服。
所述施用治療有效量可為4~100 mg/kg/d,優選為6~60 mg/kg/d,例如為6mg/kg/d、20mg/kg/d或60mg/kg/d。
所述施用頻率可為1-3次/日,例如為1-2次/日。
本發明中,如式I所示化合物或其藥學上可接受的鹽可以任何合適的途徑給予受試者,例如口服。
本發明還提供了一種用於治療和/或預防受試者發炎性腸病的藥物組合物,其包括:如式I所示化合物或其藥學上可接受的鹽,以及藥用佐劑。
在一些實施方案中,所述的發炎性腸病為潰瘍性結腸炎或克隆氏病。
本發明還提供了一種治療和/或預防受試者發炎性腸病的方法,其包括:給予所述受試者治療或預防有效量的如式I所示化合物或其藥學上可接受的鹽。
在一些實施方案中,所述的發炎性腸病為潰瘍性結腸炎或克隆氏病。
定義和說明
除非另有說明,本文所用的下列術語和短語旨在具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的,而應該按照普通的含義去理解。當本文中出現商品名時,意在指代其對應的商品或其活性成分。
本發明中,術語“藥學上可接受的”是指針對那些化合物、材料、組合物和/或劑型而言,它們在可靠的醫學判斷的範圍之內,適用於與人類和動物的組織接觸使用,而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症,與合理的利益/風險比相稱。
本發明中,術語“藥學上可接受的鹽”可為本發明化合物與相對無毒的、藥學上可接受的酸或鹼製備得到的鹽。當本發明的化合物中含有相對酸性的官能基時,可以通過在純的溶液或合適的惰性溶劑中用足夠量的鹼與該化合物接觸獲得鹼加成鹽。藥學上可接受的鹼加成鹽可包括但不限於:鋰鹽、鈉鹽、鉀鹽、鈣鹽、鋁鹽、鎂鹽、鋅鹽、鉍鹽、銨鹽、二乙醇胺鹽等。當本發明的化合物中含有相對鹼性的官能基時,可以通過在純的溶液或合適的惰性溶劑中用足夠量的酸與該化合物接觸獲得酸加成鹽。所述的藥學上可接受的酸可包括無機酸,所述無機酸可包括但不限於:鹽酸、氫溴酸、氫碘酸、硝酸、碳酸、磷酸、亞磷酸、硫酸等。所述的藥學上可接受的酸可包括有機酸,所述有機酸可包括但不限於:乙酸、丙酸、草酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、水楊酸、酒石酸、甲磺酸、異煙酸、酸式檸檬酸、油酸、單寧酸、泛酸、酒石酸氫、抗壞血酸、龍膽酸、丁烯二酸、葡糖酸、糖酸、甲酸、乙磺酸、雙羥萘酸(即4, 4’-亞甲基-雙(3-羥基-2-萘甲酸))、胺基酸(例如麩胺酸、精胺酸)等。當本發明的化合物中含有相對酸性和相對鹼性的官能基時,可以被轉換成鹼加成鹽或酸加成鹽。具體可參見Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66: 1-19 (1977)、或、Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002)。
本發明中,所述的治療和/或預防發炎性腸病的藥物可為本領域中常規劑型,例如片劑、膠囊劑、靜脈注射劑、腹腔注射劑、吸入劑、霧化劑、凍乾劑、貼劑、凝膠劑、噴霧劑或栓劑等。
術語“藥用佐劑”是指生產藥品和調配處方時使用的賦形劑和附加劑,可以是除活性成分以外,包含在藥物製劑中的所有物質。可參見中華人民共和國藥典(2020年版)四部、或Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)。
術語“治療”指治療性療法。涉及具體病症時,治療指:(1)緩解疾病或者病症的一種或多種生物學表現,(2)干擾(a)導致或引起病症的生物級聯中的一個或多個點或(b)病症的一種或多種生物學表現,(3)改善與病症相關的一種或多種症狀、影響或副作用,或者與病症或其治療相關的一種或多種症狀、影響或副作用,或(4)減緩病症或者病症的一種或多種生物學表現發展。
術語“預防”是指獲得或發生疾病或障礙的風險降低。
術語“治療有效量”是指在給予受試者時足以有效治療本文所述的疾病或病症的化合物的量。“治療有效量”將根據化合物、病症及其嚴重度、以及欲治療患者的年齡而變化,但可由本領域技術人員根據需要進行調整。
術語“預防有效量”是指足以預防疾病或障礙的量,或足以預防與疾病或障礙有關的一或多種症狀的量,或防止疾病或障礙復發的量。
術語“受試者”是指根據本發明的實施例,即將或已經接受了該化合物給藥的任何動物,哺乳動物為優,人類最優。術語“哺乳動物”包括任何哺乳動物。哺乳動物的實例包括但不限於牛、馬、羊、豬、貓、狗、小鼠、大鼠、家兔、豚鼠、猴、人等,以人類為最優。
在不違背本領域常識的基礎上,上述各優選條件,可任意組合,即得本發明各較佳實例。
本發明所用試劑和原料均市售可得。
本發明的積極進步效果在於:化合物I或其藥學上可接受的鹽對發炎性腸病如潰瘍性結腸炎和克隆氏病具有良好的預防或治療作用。
具體實施方式
下面通過實施例的方式進一步說明本發明,但並不因此將本發明限制在所述的實施例範圍之中。下列實施例中未註明具體條件的實驗方法,按照常規方法和條件,或按照商品說明書選擇。本發明所使用的溶劑和對照品均可經市售獲得。
化合物I由廣州嘉越醫藥科技有限公司提供,按照WO2020244614A1中實施例1製備得到;
托法替尼購於上海源葉生物科技有限公司。
環孢素A,商品名山地明,購於NOVARTIS公司。
葡聚糖硫酸鈉鹽(Dextran sulfate sodium , DSS, MW=36,000-50,000):貨號: 160110;
實施例 11. 實驗動物
動物種屬及品系:C57BL/6小鼠;雌性,體重18-22 g左右,6-8周齡;購于北京維通利華試驗動物技術有限公司;
表1 動物分組及給藥方式
a:溶媒為0.5%(w/v) 羥丙甲基纖維素(HPMC E5)、 0.5%(w/v)聚乙烯吡咯烷酮(PVP K30)和0.2%(w/v)十二烷基硫酸鈉(SDS)混合水溶液;
b: 溶媒為生理鹽水。
分組 | 組別名稱 | 動物數 | 化合物 | 給藥方式 | |
給藥途徑 | 給藥頻次 | ||||
G1 | 正常對照組 a | 8 | 溶媒 | 口服 | 每日兩次 |
G2 | 模型對照組 a | 12 | 溶媒 | 口服 | 每日兩次 |
G3 | 化合物Ⅰ組 a | 12 | 化合物Ⅰ | 口服 | 每日兩次 |
G4 | 環孢素A組 b | 12 | 環孢素A | 口服 | 每日一次 |
G5 | 托法替尼組 a | 12 | 托法替尼 | 口服 | 每日兩次 |
G6 | 化合物Ⅰ組 a | 12 | 化合物Ⅰ | 口服 | 每日兩次 |
G7 | 化合物Ⅰ組 a | 12 | 化合物Ⅰ | 口服 | 每日兩次 |
將小鼠隨機分為正常對照組(G1)、模型對照組(G2)、化合物I組(G3)、陽性藥環孢素A組(G4)、托法替尼組(G5)、化合物I組(G6)和化合物I組(G7),動物分組及給藥方式詳見表1。模型對照組(G2)和模型給藥組動物(G3-G7)連續給予含2%DSS(葡聚糖硫酸鈉)的飲用水進行模型建立6天,之後換為正常飲用水,4天後取樣。正常對照組小鼠不進行模型建立,始終飲用正常飲用水。從模型建立當天開始至終點取樣,化合物I組動物(G3)接受化合物I口服給藥(每日兩次, 6mg/kg/d),環孢素A組動物(G4)接受環孢素A口服給藥(每日一次, 25mg/kg/d),托法替尼組動物(G5)接受托法替尼口服給藥(每日兩次, 60mg/kg/d),化合物I組動物(G6)接受化合物I口服給藥(每日兩次, 20mg/kg/d),化合物I組動物(G7)接受化合物I口服給藥(每日兩次, 60mg/kg/d),對照組動物口服給予溶媒(溶媒為0.5%(w/v) 羥丙甲基纖維素(HPMC E5)、0.5%(w/v)聚乙烯吡咯烷酮(PVP K30)和0.2%(w/v)十二烷基硫酸鈉(SDS)混合水溶液)。所有動物給藥體積為10mL/kg。實驗過程中每日記錄動物體重和臨床疾病評分。每天記錄所有組小鼠體重、腹瀉及便血情況。根據以下評分體系來進行每日評分。
體重變化(0,<1%; 1,1-5%; 2,6-10%; 3,11-20%;);
出血評分(0,潛血陰性;1,潛血陽性;2,糞便中肉眼可見微量血;3,明顯直腸出血);
糞便評分(0,正常;1,輕微軟便;2,糞便非常軟,濕;3,水樣腹瀉)
三部分的分數相加得到日常疾病指數值DAI。
2. 組織病理檢測
取樣後,將結腸浸入10% 福馬林液固定。固定好的腸組織用石蠟包埋,切片後用蘇木精和伊紅染色後使用如下的評分標準進行評級。
表2 腸炎組織病理學評分標準
表3 腸炎組織病理學評分標準
3. 試驗結果
A.疾病活動指數(DAI)(表3,圖1)
表3 受試物化合物I連續給藥對小鼠疾病活動指數(DAI)評分的影響
發炎細胞浸潤 | |
0 | 偶然的或沒有浸潤 |
1 | 浸潤到固有層 |
2 | 浸潤到粘膜下層 |
3 | 透壁性浸潤 |
組織損傷 | ||
0 | 沒有粘膜損傷 | |
1 | 局灶性病變 | |
2 | 粘膜侵蝕或潰爛 | |
3 | 廣泛的損傷影響到粘膜下層 |
組別 | DAI總分AUC | 體重變化AUC | 出血AUC | 糞便AUC | |
G1(正常對照) | 平均值(Mean) | 1.63 | 1.63 | 0.00 | 0.00 |
標準誤差(SEM) | 0.80 | 0.80 | 0.00 | 0.00 | |
G2(模型對照) | 平均值(Mean) | 30.67 | 8.17 | 10.21 | 12.29 |
標準誤差(SEM) | 2.47 | 0.87 | 0.88 | 0.92 | |
G3(化合物I) | 平均值(Mean) | 25.67 | 8.67 | 7.42 | 9.58 |
標準誤差(SEM) | 1.26 | 0.75 | 0.48 | 0.62 | |
G4(環孢素A) | 平均值(Mean) | 21.63 | 4.67 | 6.29 | 10.67 |
標準誤差(SEM) | 1.74 | 1.08 | 0.54 | 0.43 | |
G5(托法替尼) | 平均值(Mean) | 29.67 | 9.33 | 9.29 | 11.04 |
標準誤差(SEM) | 2.00 | 1.06 | 0.73 | 0.68 |
DAI總分為便血,腹瀉和體重降低三個參數評分的加和。模型對照組在多數動物出現明顯便血和水樣腹瀉等臨床症狀,表明本試驗腸炎模型模型建立成功。與模型對照組相比,陽性對照環孢素A可明顯改善臨床症狀,疾病活動指數DAI總分曲線下面積(AUC)顯著降低。受試物化合物Ⅰ在6mg/kg/d劑量下能亦顯著降低DAI總分的AUC。陽性對照環孢素A對動物便血症狀有明顯改善,受試物化合物Ⅰ在6mg/kg/d劑量下對便血亦有顯著緩解作用,而參考藥物托法替尼對便血無明顯改善。對DAI糞便評分曲線下面積AUC分析表明,受試物化合物Ⅰ在6mg/kg/d顯著緩解腹瀉症狀,而陽性對照環孢素A和托法替尼對腹瀉症狀均無明顯改善。因此,化合物I對腸炎DAI的改善優於托法替尼。
B.病理評價(表4,表5,圖2)
表4 受試物化合物I連續給藥對小鼠病理評分(發炎)的影響
表5 受試物化合物I連續給藥對小鼠病理評分(損傷)的影響
組別 | 發炎 | |
G1 (正常對照) | 平均值(Mean) | 0.00 |
標準誤差(SEM) | 0.00 | |
G2(模型對照) | 平均值(Mean) | 2.42 |
標準誤差(SEM) | 0.15 | |
G3(化合物I,6mg/kg/d) | 平均值(Mean) | 2.08 |
標準誤差(SEM) | 0.08 | |
G4(環孢素A) | 平均值(Mean) | 2.08 |
標準誤差(SEM) | 0.08 | |
G5(托法替尼) | 平均值(Mean) | 1.92 |
標準誤差(SEM) | 0.15 | |
G6(化合物I,20mg/kg/d) | 平均值(Mean) | 2.00 |
標準誤差(SEM) | 0.00 | |
G7(化合物I,60mg/kg/d) | 平均值(Mean) | 1.83 |
標準誤差(SEM) | 0.11 |
組別 | 損傷 | |
G1(正常對照) | 平均值(Mean) | 0.00 |
標準誤差(SEM) | 0.00 | |
G2(模型對照) | 平均值(Mean) | 2.00 |
標準誤差(SEM) | 0.12 | |
G3(化合物I) | 平均值(Mean) | 1.25 |
標準誤差(SEM) | 0.22 | |
G4(環孢素A) | 平均值(Mean) | 1.33 |
標準誤差(SEM) | 0.31 | |
G5(托法替尼) | 平均值(Mean) | 1.58 |
標準誤差(SEM) | 0.15 |
本試驗在試驗終點取樣,對結腸進行的病理分析,評價發炎細胞浸潤和組織損傷。病理結果顯示,模型對照組動物出現明顯病理改變,發炎細胞浸潤至粘膜下層甚至出現透壁性浸潤,腸粘膜出現侵蝕或潰爛。與模型對照組相比,陽性對照環孢素A顯著改善發炎細胞浸潤和組織損傷。代表性圖片見圖3。受試物化合物Ⅰ連續給藥10天對明顯改善結腸的發炎反應,劑量組6mg/kg/d、20mg/kg/d及60mg/kg/d顯著降低發炎浸潤,劑量組6mg/kg/d對組織損傷亦有顯著改善。托法替尼僅對發炎浸潤有一定療效。因此,受試物化合物I對腸炎組織病理的改善優於托法替尼。
結論,化合物I對小鼠腸炎模型的DAI的疾病活動指數和組織病理均有顯著改善,且優於托法替尼。
圖1為受試物化合物I連續給藥對小鼠疾病活動指數DAI的影響。其中,A為疾病活動指數總分,B為體重變化評分,C為出血評分,D為糞便評分;
圖2 為受試物化合物I連續給藥對小鼠病理評分的影響。其中,A為發炎細胞浸潤,B為組織損傷;
圖3 為受試物化合物I病理代表性圖片。其中,A為G1(正常對照)代表性圖(蘇木精-伊紅染色),發炎:0,偶然的或沒有浸潤;損傷:0,沒有粘膜損傷; B為G2(模型對照)代表性圖(蘇木精-伊紅染色),發炎:3,透壁性浸潤;損傷:2,粘膜侵蝕或潰爛; C為G3(化合物I)代表性圖(蘇木精-伊紅染色),發炎:2,浸潤到粘膜下層;損傷:1,局灶性病變;D為G4(環孢素A)代表性圖(蘇木精-伊紅染色),發炎:2,浸潤到粘膜下層;損傷:1,局灶性病變;E為G5(托法替尼)代表性圖(蘇木精-伊紅染色),發炎:2,浸潤到粘膜下層;損傷:1,局灶性病變;
#,P<0.05;##,P<0.01;###,P<0.001;正常對照組與模型對照組相比;
*,P<0.05;**,P<0.01;***,P<0.001;與模型對照組相比。
Claims (10)
- 如請求項1所述的用途,其特徵在於,所述的發炎性腸病為潰瘍性結腸炎。
- 如請求項1所述的用途,其特徵在於,所述的發炎性腸病為克隆氏病。
- 如請求項1-3中至少一項所述的用途,其特徵在於,所述的發炎性腸病具有便血和/或腹瀉症狀。
- 如請求項1-3中至少一項所述的用途,其特徵在於,所述的治療和/或預防發炎性腸病的藥物包含藥用佐劑。
- 如請求項1-3中至少一項所述的用途,其特徵在於,所述的如式I所示化合物或其藥學上可接受的鹽為所述藥物的有效成分之一或者唯一有效成分。
- 如請求項1-3中至少一項所述的用途,其特徵在於,向有需要的受試者施用治療有效量的所述如式I所示化合物或其藥學上可接受的鹽。
- 如請求項7所述的用途,其特徵在於,所述施用的方式為口服; 和/或,所述施用治療有效量為4~100mg/kg/d;和/或,所述施用頻率為1-3次/日。
- 如請求項8所述的用途,其特徵在於,所述施用治療有效量為6~60mg/kg/d;和/或,所述施用頻率為1-2次/日。
- 如請求項8所述的用途,其特徵在於,所述施用治療有效量為6mg/kg/d、20mg/kg/d或60mg/kg/d。
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