TW202225160A - 一種新型吡嗪結構fxr促效劑、製備方法及應用 - Google Patents
一種新型吡嗪結構fxr促效劑、製備方法及應用 Download PDFInfo
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- TW202225160A TW202225160A TW110148017A TW110148017A TW202225160A TW 202225160 A TW202225160 A TW 202225160A TW 110148017 A TW110148017 A TW 110148017A TW 110148017 A TW110148017 A TW 110148017A TW 202225160 A TW202225160 A TW 202225160A
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Classifications
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
本發明涉及一種新型吡嗪結構FXR促效劑、製備方法及應用,具體來說,涉及一種如以下通式的化合物,其水合物、溶劑合物、藥學上可接受的鹽或其拆分的單一異構物,其具有治療非酒精性脂肪肝的作用。
Description
本發明涉及一種藥物化合物的製備方法,特別涉及一種新型吡嗪結構FXR促效劑、製備方法及應用。
自1999年發現膽汁酸能啟動FXR (Farnesoid X Receptor) 產生多種生理功能以來,具有選擇性和高活性的FXR促效劑 (agonist) 相繼被發現,這些FXR促效劑按結構可分為甾體類 (steroid) 和非甾體類 (non-steroidal)。甾體類主要為鵝去氧膽酸(chenodeoxycholic acid,CDCA,膽汁酸其中一種)及其衍生物和Merck公司開發的FXR促效劑MFA-1;非甾體類包括異噁唑類 (isoxazoles) 化合物GW4064及其類似物,Fexaramine類化合物,氮雜吲哚類 (azaindole) 化合物XL335及其衍生物,苯咪唑基 (benzimidazole) 醯胺類化合物,吡唑啶 (pyrazolidine) 二酮類化合物等。
非酒精性脂肪性肝病 (non-alcoholic fatty liver disease,NAFLD) 是一組無過量飲酒史,肝組織學改變與酒精性肝病相類似,以肝實質細胞脂肪變性和脂肪貯積為特徵的臨床病理綜合症狀,包括單純性脂肪肝以及由其演變的脂肪性肝炎和肝硬化。現今NAFLD已成為僅次於B型肝炎的影響人類健康的第二類慢性肝臟疾病。NASH (nonalcoholic steatohepatitis) 是一種肝內脂肪積聚而導致的慢性進展性肝病,可導致肝硬化、肝衰竭及肝細胞癌,確切的說,NASH只是非酒精性脂肪性肝病(NAFLD)病程發展的一個階段。
臨床在研藥物中,奧貝膽酸 (obeticholic acid,OCA,6-ECDCA) 是一種FXR促效劑。在2016年5月被FDA批准,用於治療原發性膽汁酸肝硬化 (PBC),也是第一個進入III期臨床的NASH藥物。奧貝膽酸針對伴有2~3級肝纖維化的NASH患者的關鍵III期REGENERATE研究的期中分析取得積極結果。
其他的FXR促效劑如PX-104已經進入Ⅱ期臨床,主要適應症也是非酒精性脂肪肝病 (NAFLD)。
2000年Maloney等報導了第一個具有高活性和高選擇性的異噁唑類FXR促效劑GW4064,其胞外活性為EC
50= 15 nmol·L
-1,在細胞水準的EC
50值為90 nmol·L
-1,可以完全活化FXR靶點蛋白;但在藥代動力學方面,在t1/2 = 3.5小時的口服利用度只有10%,不具備成藥的條件,所以作為研究FXR功能和相關疾病的工具化合物。隨後GSK、Novartis、Roche、Lilly、Phenex等公司分別對GW4064的結構進行了改造,以求得到活性更高,口服利用度更好,更具成藥性質的新化合物。到目前為止,數目眾多的異噁唑類化合物被成功合成,但在活性、水溶性及口服生物利用度等成藥性方面均有不足,
中國專利CN103702719A公開了新型FXR (NR1H4) 結合及活性調節化合物,其中具體公開了如下化合物:
以及這些化合物在治療非酒精性脂肪肝病 (NAFLD) 或非酒精性脂肪性肝炎 (NASH) 等疾病中的應用。這些化合物是在WO2011/020615公開的化合物的基礎上進行的改進,通過替換1,2-環亞丙基的1,3-環亞丁基或1,3-亞氮雜環丁烷基上引入極性羥基實現的。結果表明,所得化合物保持了在FXR受體上的活性,而且顯現出改進的物化性能,例如較高的水溶性和/或膜滲透性。而更好的水溶性和膜滲透性導致更高的口服生物利用度。但是,上述化合物在法尼醇核受體FXR靶點的啟動活性相對較低。
為了解決上述技術問題,本發明提供一種具有式(I)結構的化合物,或其藥學上可接受的鹽,水合物 (hydrate)、溶劑化物 (solvate)、藥學上可接受的鹽或其拆分的單一異構物:
式(I)
其中,R
1選自:鹵素、-COOH、
、
;
R
2選自:C
1-C
6的烴基、環烴基、芳香基、取代烴基或取代芳香基;
R
3選自:-H或C
1~C
3的烴基、環烴基、取代烴基;
X為C或N。
優選的,其中,
R
1選自-Br;
R
2選自C
1-C
3的烴基、環烴基;
R
3選自-CH
3;
X為C或N。
最優選的選自以下化合物為:
TM-1 | 化學式: C 28H 23Cl 2N 3O 5質量: 551.10 分子量: 552.41 | |
TM-2 | 化學式: C 27H 22Cl 2N 4O 5質量: 552.10 分子量: 553.39 | |
TM-3 | 化學式: C 27H 22BrCl 2N 3O 3質量: 585.02 分子量: 587.29 | |
TM-4 | 化學式: C 28H 25Cl 2N 3O 5S 質量: 585.1 分子量: 586.49 | |
TM-5 | 化學式: C 33H 27Cl 2N 3O 3S 質量: 615.12 分子量: 616.56 | |
TM-6 | 化學式: C 28H 25Cl 2N 3O 5質量: 553.12 分子量: 554.42 | |
TM-7 | 化學式: C 31H 23Cl 2N 3O 5質量: 587.10 分子量: 588.44 | |
TM-8 | 化學式: C 29H 25Cl 2N 3O 5質量: 565.12 分子量: 566.44 | |
TM-9 | 化學式: C 29H 27Cl 2N 3O 5質量: 567.13 分子量: 568.45 | |
TM-10 | 。 | 化學式: C 32H 25Cl 2N 3O 5質量: 601.12 分子量: 602.47 |
本發明進一步提供以所述的化合物作為活性成分的藥物組合物。
所述的藥物組合物,根據需要,還可含有藥學上可接受的載體。
本發明所述的化合物在製備治療非酒精性脂肪肝的藥物中的用途。
其中所述非酒精性脂肪肝,為非酒精性脂肪肝炎。
本發明所述藥物組合物在製備治療非酒精性脂肪肝的藥物中的用途,優選非酒精性脂肪肝炎。
本發明所述化合物包括其所有異構物形式和異構物混合物的形式。也可以以溶劑合物的形式存在。
本發明的藥物組合物,優選的是單位劑量的藥物製劑形式,在製成藥物製劑時可以製成任何可藥用的劑型,這些劑型選自:片劑、糖衣片劑、薄膜衣片劑、腸溶衣片劑、膠囊劑、硬膠囊劑、軟膠囊劑、口服液、口含劑、顆粒劑、混懸劑、溶液劑、注射劑、栓劑、軟膏劑、硬膏劑、霜劑、噴霧劑、貼劑。優選的是口服製劑形式,最佳優選的是片劑,膠囊劑。
可以採用製劑學常規技術製備該藥物製劑,所述藥學上可接受的載體包括但不限於:甘露醇、山梨醇、山梨酸或鉀鹽、焦亞硫酸鈉、亞硫酸氫鈉、硫代硫酸鈉、半胱胺酸鹽酸鹽、巰基乙酸、蛋氨酸、維生素A、維生素C、維生素E、維生素D、氮酮、EDTA二鈉、EDTA鈣鈉,一價鹼金屬的碳酸鹽、醋酸鹽、磷酸鹽或其水溶液、鹽酸、醋酸、硫酸、磷酸、氨基酸、富馬酸、氯化鈉、氯化鉀、乳酸鈉、木糖醇、麥芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、澱粉、蔗糖、乳糖、矽衍生物、纖維素及其衍生物、藻酸鹽、明膠、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、吐溫60-80、司盤-80、蜂蠟、羊毛脂、液體石蠟、十六醇、沒食子酸酯類、瓊脂、三乙醇胺、鹼性氨基酸、尿素、尿囊素、碳酸鈣、碳酸氫鈣、聚乙二醇、環糊精 (如β-環糊精)、磷脂類材料、高嶺土、滑石粉、硬脂酸鈣、硬脂酸鎂等。
本發明的藥物組合物,在製成藥劑時,單位劑量的藥劑可含有本發明的藥物活性物質0.1-1000 mg,其餘為藥學上可接受的載體。藥學上可接受的載體以重量計可以是製劑總重量的0.1-99.9%。
本發明的藥物組合物在使用時根據病人的情況確定用法用量。
本發明優選的製備方法包括以下步驟:
(1) 異噁唑中間體合成方法為,苯甲醛1a與鹽酸羥胺在鹼性條件下縮合得到苯甲醛肟1b,肟1b在NCS/DMF條件下生成氯代苯甲醛肟1c;接著與酮酸酯通過1,3-偶極環加成反應得到三取代異噁唑環1d-1f;氮氣保護下加入DIBAL-H,還原酯鍵為羥基,得到中間體1-a-1-c;
(2) 異噁唑中間體與二溴吡嗪在鹼性條件下發生親核取代反應,得到吡嗪中間體2-a-2-c;控制溫度保持在零下78℃,用正丁基鋰進行鋰溴交換與四元環2a-d進行碳-碳鍵的連接,生成末端酯基產物3-a-3-g,最後鹼性條件下發生酯水解反應得到目標化合物TM。
本發明的有益效果:本發明的化合物尤其是TM-01和TM-09對肝臟甘油三酯和膽固醇水準有明顯的降低作用,提高了小鼠肝重和肝臟體重比,降低了病理評分和肝臟中的膠原沉積,對非酒精性脂肪肝有改善效果。
本發明的化合物對法尼醇核受體FXR靶點的具有較強激動活性,並表現出了在細胞膜間的高通透性,且在高脂飼餵小鼠模型中,對脂肪富集的肝臟重量呈現劑量依賴影響,預測在肥胖、糖尿病和非酒精性脂肪肝 (NASH) 等代謝類疾病的治療中表現出較好的用途,以下通過實驗資料說明本發明的有益效果。
試驗例一、本發明化合物對
FXR
受體的激動活性研究
實驗步驟:FXR (是GST標記的重組人FXR蛋白,廠商:Invitroren,貨號:PV4835) 和SRC-1 (類固醇受體共啟動因數-1) 在冰上進行融化,用緩衝液配製ABC 三種溶液,A液,0.4 n M FXR和 30 nM SRC-1;B 液,10 ug/ml Acceptor Beads(受體微珠);C液,10 ug/ml Donor Beads(供體微珠)。將A液加入到培養盤中,每孔15 μL。室溫培養1小時。將B液加入到板中,每孔7.5 μL。室溫培養1小時。將C液加入板中,每孔7.5 μL。室溫培養1小時。酶標儀Envision讀數。資料用Prism 5.0進行曲線擬合,計算出EC
50。結果見表1。
表1
No. | 樣品編號 | 結構式 | EC 50(μM) |
1 | TNT-747 | 1.06 | |
2 | GW4064 | 0.23 | |
3 | M2 | 1.80 | |
4 | M3 | 1.09 | |
5 | TM-01 | 0.54 | |
6 | TM-02 | 2.32 | |
7 | TM-03 | 0.24 | |
8 | TM-04 | 1.35 | |
9 | TM-05 | 5.01 | |
10 | TM-06 | 2.41 | |
11 | TM-07 | 4.21 | |
12 | TM-08 | 0.24 | |
13 | TM-09 | 0.48 | |
14 | TM-10 | 5.66 |
根據表1中的樣品活性結果,去除活性較差的TM-05、TM-07、TM-10,選擇其餘7個樣品進行了細胞內FXR-TR-FRET實驗。
試驗例二、細胞內
FXR-TR-FRET
實驗
1、細胞培養:
a、用適當的密度在10 mL完整的胰蛋白酶中胰蛋白酶培養盤和種子細胞中在37°C。
b、5%的CO
2和潮濕條件下培養細胞24 小時。
2、細胞接種和轉染:FuGENE HD轉染試劑用作轉染試劑。
a、根據以下流程準備轉染混合物:
融合表達載體(pBIND-FXR) | 25 ng/孔 |
哺乳細胞雙雜交系統載體(pG5Luc) | 25 ng/孔 |
轉染試劑(FuGENE HD) | 0.15 μL/孔 |
非胎牛血清介質(No FBS media) | 1.85 μL/孔 |
總混合(Total mix) | 2.5 μL/孔 |
b、用力敲打試管以混合內容物。將混合物在室溫下培養15分鐘。
c、用胰蛋白酶培養皿並確定細胞密度。
d、將細胞漿以500,000個細胞/ ml的密度稀釋至所需的體積(對於96孔板,為100 μL /孔)。
e、將所需體積的先前製備的轉染混合物添加到兩個細胞漿液中,然後將100 μL /孔的細胞漿液分配到測定板上。
f、在加濕條件下於37°C,5% CO
2下將測定板培養24小時。
3、化合物配製:
a、準備FXR工作濃度為10 mM的化合物庫存,然後在100% DMSO中稀釋3倍。
b、將10 μL化合物添加到90 μL完全培養基中。
c、向每個孔中加入5 μL化合物溶液。
d、將板在37°C,5% CO
2和濕潤條件下培養18小時。
4、雙重螢光素酶測定:螢火蟲和海腎螢光素酶信號通過Promega的Dual Luciferase Reporter Assay System進行分析。Envision用作光度計。
5、結果計算:通過將螢火蟲信號除以海腎信號來歸一化資料值。 「F / R」 表示 「螢火蟲/ Renilla」。 這種標準化消除了每個孔中不同細胞數量和轉染效率的差異。計算% Activation (活性)值。通過以下公式計算% Activation值。
X是每個濃度點的 F / R值。最小值是無化合物對照的平均 F / R值。最大值是參考化合物對照的平均值 F / R值。
6、活性結果見表2,
表2:活性結果
樣品編號 | EC 50(μM) |
TM-01 | 1.28 |
TM-02 | 3.14 |
TM-03 | >5000 |
TM-04 | >5000 |
TM-06 | 1.79 |
TM-08 | 1.51 |
TM-09 | 0.26 |
GW4064 | 0.30 |
M3 | 1.49 |
對受試化合物對於FXR-TR-FRET的活性進行了研究,此類含吡嗪結構的化合物,相比對照品GW4064和M3,多數表現出了細胞水準上較好的激動活性。
根據FXR-TR-FRET實驗結果,去除TM-03和TM-04,對剩餘部分化合物進行Caco-2 單層細胞膜轉運實驗。
試驗例三、
Caco-2
單層細胞膜轉運實驗
利用人源性結腸腺癌細胞系Caco-2單層細胞模型研究目標化合物由絨毛面側 (apical, AP) 到基底面側 (basolateral, BL) 以及從BL側到AP 側的雙向轉運情況,應用高效液相色譜法定量分析,計算轉運參數和表觀滲透係數 (apparent permeabilitycoefficient,Papp)以及外排率 (efflux ratio),以M3為陽性對照,以P-gp的作用受質地高辛為參照物,選取這5個細胞內活性較高的樣品進行試驗,來預測這類吡嗪結構異噁唑類衍生物的體內口服生物利用度以及與P-gp的親和作用情況。
結果見表3、4、5。
表3:在Caco-2細胞模型中的A-to-B 的表觀滲透係數
化合物 | Papp (10-6 cm/s) | ||||
樣品-01 | 樣品-02 | 平均值 | 相對標準差(%) | ||
納多洛兒 | A-B | 0.07 | 0.06 | 0.07 | 10.20 |
B-A | / | / | / | / | |
美托洛爾 | A-B | 19.46 | 16.75 | 18.10 | 10.59 |
B-A | / | / | / | / | |
地高辛 | A-B | <0.05 | <0.04 | <0.04 | NA |
B-A | 11.74 | 11.52 | 11.63 | 1.37 | |
M3 | A-B | <0.16 | <0.14 | <0.15 | NA |
B-A | 13.31 | 9.96 | 11.63 | 20.38 | |
TM-01 | A-B | 6.42 | 9.91 | 8.17 | 0.30 |
TM-02 | A-B | 8.57 | 9.47 | 9.02 | 0.07 |
TM-06 | A-B | 7.86 | 6.48 | 7.17 | 0.13 |
TM-08 | A-B | 1.01 | 0.94 | 0.97 | 0.07 |
TM-09 | A-B | 8.46 | 9.05 | 8.75 | 0.05 |
表4:在Caco-2細胞模型中的透膜質量收率
化合物 | 收率% | ||||
樣品-01 | 樣品-02 | 平均值 | 相對標準差(%) | ||
Nadolol | A-B | 91.54 | 87.96 | 89.75 | 2.82 |
B-A | / | / | / | / | |
Metoprolol | A-B | 93.18 | 94.33 | 93.76 | 0.86 |
B-A | / | / | / | / | |
Digoxin | A-B | <85.23 | <88.72 | <86.97 | NA |
B-A | 93.73 | 95.44 | 94.59 | 1.28 | |
M3 | A-B | <27.17 | <16.42 | <21.80 | NA |
B-A | 36.33 | 35.57 | 35.95 | 1.50 | |
TM-01 | A-B | 63.92 | 78.51 | 71.21 | 0.14 |
TM-02 | A-B | 64.86 | 76.84 | 70.85 | 0.12 |
TM-06 | A-B | 81.02 | 67.31 | 74.17 | 0.13 |
TM-08 | A-B | 99.57 | 98.50 | 99.04 | 0.01 |
TM-09 | A-B | 80.89 | 81.99 | 81.44 | 0.01 |
表5:在Caco-2 细胞模型中的外排率
註:a 外排率=Papp B-A/Papp A-B
化合物 | Caco-2細胞株(21天) | ||||
Papp (10-6 cm/s) | Papp (10-6 cm/s) | 外排率a | |||
A-B | 相對標準差(%) | B-A | 相對標準差(%) | ||
納多洛爾 | 0.07 | 10.20 | / | / | / |
美托洛爾 | 18.10 | 10.59 | / | / | / |
地高辛 | <0.04 | NA | 11.63 | 1.4 | >262.93 |
M3 | <0.15 | NA | 11.63 | 20.4 | >76.78 |
TM-01 | 8.25 | 0.14 | 32.58 | 0.06 | 3.95 |
TM-02 | 8.87 | 0.06 | 33.26 | 0.12 | 3.75 |
TM-06 | 7.54 | 0.08 | 38.57 | 0.32 | 5.12 |
TM-08 | 0.58 | 0.08 | 9.89 | 0.04 | 16.92 |
TM-09 | 6.91 | 0.02 | 29.18 | 0.08 | 4.22 |
實驗結果如表3所示,本發明的這一系列吡嗪結構異噁唑類化合物A-to-B 的Papp值都高於P-gp的受質地高辛(Papp A-to-B<0.04),優於M3(Papp A-to-B<0.15),特別是TM-01、TM-02,TM-06和TM-09這四個化合物的Papp,A-to-B 值>2.5×10-6cm/s,屬於高通透性受質。這些資料表明這類吡嗪結構異噁唑類化合物具有良好的通膜能力,預測在體內的吸收優於M3。
表4中顯示的是這些含吡嗪結構化合物的透膜後的收率情況。對這5個化合物對其雙向轉運情況進行評價,結果如表5所示,從外排率上可以看到相對於M3來說,這類衍生物都很大程度上減弱了外排情況,其外排率均遠遠小於對照品地高辛 (外排率>262.93),預測在體內的口服吸收也會相應得到提高。
根據試驗例三結果,去除效果較差的TM-08,保留其他化合物進行動物實驗,關於對照組:M3因為透膜效果較差而被排除。GW4064因為報導成藥性較差,生物口服利用度較低,目前作為前期研究的一個工具分子而被排除。M2也是作為前期一個對照化合物,在首次蛋白水準的篩選中活性低於本專利中化合物而被排除。奧貝膽酸是目前非酒精性脂肪領域處在臨床研究的藥物,接近獲批,選取作為動物試驗的對照品。
試驗例四:高脂飼料飼餵
(MCD)
模擬非酒精性脂肪肝的藥效試驗
奧貝膽酸是目前非酒精性脂肪領域處在臨床研究的藥物,接近獲批,選取作為動物試驗的對照品。
1
、實驗動物
動物品系:C57/BL6,動物等級:SPF級,性別:雄性 ,動物年齡:8周齡,動物接受日期:2018年09月28日,動物來源:上海靈暢生物科技有限公司,動物合格證號:SCXK(滬)2013-0018 2013001836799,小鼠飼養環境:溫度 20-26 ℃,濕度 40-70 %,12小時晝夜循環。
2
、試驗設計與方法
2.1 藥物配置
2.1.1 溶劑配製:
5% Solutol HS15/生理鹽水:Solutol HS15 (聚乙二醇15羥硬脂酸酯增溶劑)在37℃水浴鍋中溶化後,取5 mL溶於100 mL生理鹽水中,充分攪拌後備用。
2.1.2 給藥溶液配製:
奧貝膽酸/5% Solutol HS15/生理鹽水:精確稱取12 mg奧貝膽酸,加入0.15 ml Solutol HS15使之充分溶解,加入2.85 ml生理鹽水,劇烈渦旋,超聲助溶使其充分溶解。
TM-01組/5% Solutol HS15/生理鹽水:取2.5 mL 6 mg/ml的TM-01懸浮液,加入2.5 mL 5% Solutol HS15/生理鹽水,充分混勻。
TM-02組/5% Solutol HS15/生理鹽水:取2.5 mL 6 mg/mL的TM-02懸浮液,加入2.5 mL 5% Solutol HS15/生理鹽水,充分混勻。
TM-06組/5% Solutol HS15/生理鹽水:取2.5 mL 6 mg/mL的TM-06懸浮液,加入2.5 mL 5% Solutol HS15/生理鹽水,充分混勻。
TM-09組/5% Solutol HS15/生理鹽水:取2.5 mL 6 mg/mL的TM-09懸浮液,加入2.5 mL 5% Solutol HS15/生理鹽水,充分混勻。
所有藥物給藥前新鮮配製。
2.2
給藥途徑及給藥容積
溶劑與測試物灌胃給藥,給藥體積為10 mL/kg;
2.3
實驗過程、分組和具體給藥方式
70隻8周齡的C57/BL6小鼠到達動物房後,進行適應餵養,待平均體重到達23 g後,根據體重將小鼠隨機分成7組,並更換成模型飼料。第一組給予對照飼料MCS,其餘組給予MCD糧食,同時各組小鼠按以下方式接受化合物處理:
組1 對照組:MCS,溶劑,每天一次灌胃給藥;
組2 對照組:MCD,溶劑,每天一次灌胃給藥;
組3 奧貝膽酸組:MCD,40 mpk 奧貝膽酸,每天一次灌胃給藥;
組4. TM-01組:MCD,30mpk TM-01,每天一次灌胃給藥;
組5. TM-02組:MCD,30 mpk TM-02,每天一次灌胃給藥;
組6. TM-06組:MCD,30 mpk TM-06,每天一次灌胃給藥;
組7. TM-09組:MCD,30 mpk TM-09,每天一次灌胃給藥;
2.4
實驗方法
在實驗過程中,每週測定體重和攝食量。給藥21天后,用微量毛細管進行尾尖取血進行AST,ALT測定。給藥28天后,犧牲小鼠,心臟取血,收集肝組織,稱重,一部分用液氮速凍用於後續分析,另一部分固定進行病理學分析。
2.4.1血液指標測定
小鼠血液在5000 rpm離心10分鐘,收集上清,用於TG (甘油三酯),TC (總膽固醇),HDL (高密度脂蛋白),LDL (低密度脂蛋白),AST (穀草轉氨酶)和ALT (穀丙轉氨酶)的測定。
給藥三周和四周後的AST和ALT按試劑盒說明書進行測定;給藥4周後的血液脂質指標送艾迪康醫學檢驗所有限公司檢測。
2.4.2血液細胞因數的測定
小鼠血液在5000 rpm離心10分鐘,收集上清,用於細胞因數(mKC和MCP1)的檢測。檢測前血清儲存於- 80℃。
mKC和MCP1的測定按試劑盒說明書進行。
2.4.3肝臟TC和TG的測定
肝臟從-80℃取出後,PBS (磷酸鹽緩衝生理鹽水)中勻漿,氯仿甲醇有機相抽提後,用試劑盒進行TC和TG的測定,用蛋白量進行歸一化。
2.4.4組織收集
給藥4周後,麻醉小鼠,心臟取血後,分離肝臟稱重,取右側葉用液氮速凍,保存於- 80℃用於肝臟脂質分析。分離左側葉,於10%福馬林中固定,用於後續的HE和Sirius Red染色。
2.5
結果處理和資料分析
試驗結果以均數±標準誤 (Mean±SEM) 表示,用T-Test進行顯著性分析。與對照組比較,*表示p<0.05為有顯著性差異,**表示p<0.01為有強顯著性差異,***p<0.001為有極顯著性差異。
3
試驗結果
3.1 化合物對小鼠體重和攝食量的影響
小鼠經MCD餵養後,體重即如預期顯著性下降。並且隨著時間的延長,體重持續下降。經化合物處理的各實驗組較對照組體重也略有下降(表6)。
表6:化合物對小鼠體重的影響
組別 | 體重 (g) | ||||
0 week | 1 week | 2 week | 3 week | 4 week | |
組1-control | 23.75±0.30 | 23.64±0.26 | 23.62±0.30 | 25.13±0.34 | 25.73±0.33 |
組2-model+vehicle | 23.59±0.27 | 21.27±0.24 | 19.09±0.28 | 18.21±0.21 | 16.97±0.27 |
組3-obeticholic acid | 23.72±0.46 | 21.28±0.42 | 18.97±0.41 | 17.60±0.35 | 15.72±0.35 |
組4-TM-01: 30mpk | 23.78±0.47 | 21.24±0.42 | 18.49±0.41 | 16.97±0.38 | 14.70±0.20 |
組5-TM-02: 30mpk | 23.71±0.35 | 21.52±0.42 | 18.81±0.49 | 16.69±0.34 | 15.48±0.35 |
組6-TM-06: 30mpk | 23.75±0.27 | 21.36±0.27 | 18.29±0.28 | 16.41±0.25 | 15.70±0.22 |
組7-TM-09: 30mpk | 23.60±0.29 | 21.26±0.34 | 19.29±0.39 | 17.18±0.31 | 15.90±0.31 |
表7:化合物對小鼠攝食量的影響
組別 | 攝食量 (g) | |||
1 week | 2 week | 3 week | 4 week | |
組1-control | 2.472±0.018 | 2.429±0.139 | 2.940±0.014 | 2.316±0.458 |
組2-model+vehicle | 2.378±0.116 | 2.572±0.188 | 1.934±0.150 | 1.881±0.347 |
組3-obeticholic acid | 2.992±0.396 | 2.945±0.315 | 2.092±0.320 | 2.073±0.031 |
組4-TM-01: 30mpk | 3.011±0.555 | 2.746±0.466 | 1.909±0.215 | 1.697±0.027 |
組5-TM-02: 30mpk | 2.190±0.504 | 2.400±0.288 | 1.688±0.266 | 1.518±0.376 |
組6-TM-06: 30mpk | 2.356±0.213 | 2.664±0.194 | 2.093±0.250 | 1.932±0.137 |
組7-TM-09: 30mpk | 2.364±0.186 | 2.707±0.187 | 2.284±0.342 | 2.109±0.661 |
3.2 化合物對血液指標的影響
MCD和化合物處理3周後,取尾尖血進行AST和ALT測定。結果表明,對照組的ALT較對照組升高了約3倍,AST升高了2倍以上,奧貝膽酸組導致了比對照組更高的AST和ALT水準。TM-01組、TM-06組和TM-09組的ALT和AST較對照組有顯著下降,TM-02組與奧貝膽酸組表現一致(表8)。
MCD和化合物處理4周後,對照組中動物血脂水準略高於對照組。奧貝膽酸處理降低了血液中的膽固醇含量。TM-01組、TM-02組、TM-06組和TM-09組對血脂有不同的降低作用 (表9)。
表8:化合物處理3周和4周後AST和ALT變化
組別 | ALT (U/L) | AST (U/L) | ||
3 week | 4 week | 3 week | 4 week | |
組1-control | 5.64±0.29** | 10.24±2.27** | 25.54±1.14*** | 36.24±2.27** |
組2-model+vehicle | 60.80±9.73 | 18.66±1.30 | 74.04±10.45 | 67.27±10.16 |
組3-obeticholic acid | 323.00±37.79*** | 93.37±10.36*** | 197.24±21.54*** | 126.59±20.25*** |
組4-TM-01: 30mpk | 41.58±10.32 | 14.28±13.21** | 53.50±19.62 | 40.36±26.31* |
組5-TM-02: 30mpk | 183.36±29.85*** | 90.68±42.13*** | 113.46±13.79** | 83.24±12.08 |
組6-TM-06: 30mpk | 48.97±26.07 | 49.13±33.04 | 52.14±18.73 | 45.23±13.21* |
組7-TM-09: 30mpk | 40.27±21.48* | 14.30±4.19* | 45.04±12.08* | 38.40±4.19* |
表9:化合物處理4周後血脂水準變化
組別 | TG(mmol/L) | TC(mmol/L) | LDL(mmol/L) | HDL(mmol/L) |
組1-control | 0.52±0.10* | 0.77±0.09*** | 2.05±0.06*** | 0.34±0.03** |
組2-model+vehicle | 0.60±0.03 | 1.12±0.08 | 2.90±0.04 | 0.60±0.01 |
組3-obeticholic acid | 0.56±0.02 | 0.86±0.04** | 2.80±0.03 | 0.55±0.01** |
組4-TM-01:30mpk | 0.53±0.10 | 0.95±0.44* | 2.61±0.26* | 0.59±0.11 |
組5-TM-02: 30mpk | 0.57±0.06 | 1.25±0.14 | 2.93±0.12 | 0.61±0.02* |
組6-TM-06: 30mpk | 0.59±0.02 | 0.97±0.16 | 3.01±0.09* | 0.42±0.06*** |
組7-TM-09: 30mpk | 0.54±0.04* | 0.86±0.09* | 2.52±0.07** | 0.56±0.02* |
3.3 化合物對肝脂含量的影響
MCD和化合物處理4周後,收集肝臟測定脂質,肝脂含量用蛋白進行均一化。在對照組中,肝臟甘油三酯和膽固醇顯著高於對照組。奧貝膽酸處理後,這兩個指標均略有所下降。TM-01組、TM-02組、TM-06組和TM-09組對肝臟甘油三酯 (liver TC) 和總膽固醇的含量 (liver TG) 有不同的降低效果,其中TM-01組和TM-09組表現出顯著降低水準 (表10)。
表10:化合物處理後肝臟脂含量變化
組別 | liver TG (mol/g protein) | liver TC (mol/g protein) |
組1-control | 112.55±8.59*** | 21.47±1.29*** |
組2-model+vehicle | 339.42±40.24 | 44.94±5.50 |
組3-obeticholic acid | 298.46±36.25 | 35.7±3.38 |
組4-TM-01:30mpk | 246.69±54.09* | 34.85±8.20 |
組5-TM-02: 30mpk | 307.38±26.30 | 41.67±5.73 |
組6-TM-06: 30mpk | 303.5±46.52 | 38.23±5.04 |
組7-TM-09: 30mpk | 231.73±18.4* | 37.67±3.65* |
3.4 化合物對小鼠肝重的影響
MCD和化合物處理4周後,收集肝臟,稱重。對照組小鼠的肝重和肝臟體重比均顯著低於對照組。分析結果時意外的發現此類化合物對肝重有明顯的影響,其中TM-01組、TM-02組、TM-06組和TM-09組均顯著提高了小鼠肝重 (liver weight) 和肝臟體重比 (即liver/body weight) (表11)。
表11:化合物處理對肝重的影響
組別 | 化合物處理對肝重的影響 | |
liver weight (g) | liver/body weight (%) | |
組1-control | 0.98±0.02** | 3.79±0.05* |
組2-model+vehicle | 0.51±0.01 | 3.02±0.05 |
組3-obeticholic acid | 0.90±0.03*** | 5.76±0.26*** |
組4-TM-01: 30mpk | 0.89±0.05*** | 6.32±0.26*** |
組5-TM-02: 30mpk | 0.85±0.05*** | 5.48±0.28*** |
組6-TM-06: 30mpk | 0.67±0.03*** | 4.23±0.13*** |
組7-TM-09: 30mpk | 0.74±0.04*** | 4.98±0.25*** |
3.5 化合物肝臟病理的影響
小鼠肝臟固定後,進行HE和Sirius Red染色。染色結束後,全片掃描。隨機選取6個20x視野。HE染色的6個20x視野綜合進行病理評分(即HE score)。病理評分標準如表12。Sirius Red染色的6個20x視野圖像用Image J計算Sirius Red的陽性染色面積與總面積比(即Sirius red staining area)。
表12:病理評分標準
病理表現 | 標準 | 評分 |
肝細胞氣球樣變性 | 無 | 0 |
少量細胞 | 1 | |
許多細胞 | 2 | |
肝小葉發炎 | 無炎性灶點 | 0 |
每200x視野中小於2個炎性灶 | 1 | |
每200x視野中2-4個炎性灶 | 2 | |
每200x視野中大於4個炎性灶 | 3 | |
脂肪變性 | 小於5% | 0 |
5%-33% | 1 | |
大於33%至66% | 2 | |
大於66% | 3 |
經MCD餵養4周後,對照組肝臟中有脂肪細胞堆積,間或可見炎性細胞浸潤。奧貝膽酸處理後,脂肪細胞堆積和炎性細胞浸潤更為顯著。病理評分顯示,MCD餵養後,對照組病理評分在2左右,奧貝膽酸處理後評分有所升高,而化合物處理後,病理狀況有一定的減輕 (表13)。
表13:病理評分結果
組別 | 化合物處理後的肝臟病理變化影響 | |
HE score | Sirius red staining area (%) | |
組1-control | 0 | 0.232±0.023*** |
組2-model+vehicle | 2 | 0.559±0.051 |
組3-obeticholic acid | 2.6 | 0.344±0.057 |
組4-TM-01: 30mpk | 1 | 0.365±0.069** |
組5-TM-02: 30mpk | 1.4 | 0.398±0.030 |
組6-TM-06: 30mpk | 1.6 | 0.421±0.081 |
組7-TM-09: 30mpk | 1.1 | 0.392±0.057** |
3.4 結論:MCD餵養小鼠4周後,誘導了血液中AST,ALT和脂質的上升,促使脂肪在肝臟中的堆積和炎性灶的生成,建模具有非酒精性脂肪肝的各項指標特徵。
本發明提供的化合物尤其是TM-01和TM-09對肝臟甘油三酯和膽固醇水準有明顯的降低作用,提高了小鼠肝重和肝臟體重比,並在一定程度上降低了病理評分和肝臟中的膠原沉積,初步判定在動物體內對非酒精性脂肪肝有改善效果。
以下結合具體實施例詳細地解釋本發明,使得本領域技術人員更全面地理解本專利。具體實施例僅用於說明本發明的技術方案,並不以任何方式限定本發明。
合成方法如下:
將鹽酸羥胺 (11 g, 1 eq) 和氫氧化鈉 (6.3 g, 1.2 eq) 溶於水中,室溫下加入2,6-二氯苯甲醛 (25 g, 0.14 mmol, 1.2 eq) 的乙醇 (200 mL) 溶液,90°C下攪拌1小時,冷卻至室溫後減壓蒸餾除去乙醇,抽濾,水洗滌濾餅 (2×100 mL),乾燥後得白色固體 (2,6-二氯苯甲醛肟) 9.46 g,收率84%。
於40℃下,將N-氯代丁二醯亞胺 (16.08g, 0.12mol, 1eq) 的DMF (90mL) 溶液緩慢滴加到2,6-二氯苯甲醛肟 (22.8g, 0.12mol, 1eq) 的DMF (90mL) 溶液中,攪拌,TLC監測,反應完全後冷卻到室溫,將溶液倒入冰水 (200mL) 中,甲基叔丁基醚萃取3次 (3×100mL),合併有機相後用水 (3×100mL)、飽和食鹽水 (100mL) 洗滌。無水硫酸鈉乾燥酯層後抽濾,減壓蒸餾除去有機溶劑得黃色油狀粗品,矽膠柱層析法梯度洗脫分離純化 (PE:EA= 5: 1, v/v) 得白色固體 (2,6-二氯-N-羥基-氯代苯甲醛肟) 26 g,收率97%。
將3-環丙基-3-氧代丙酸甲酯 (637.7mg, 4.49mmol, 1eq) 加入到100 mL反應瓶,膠塞密閉,用針管把三乙胺 (907.9 mg, 8.97 mmol, 2 eq) 加入到反應瓶內,室溫下劇烈攪拌30min,反應液冰浴冷卻低於10℃,攪拌下緩慢滴加2,6-二氯-N-羥基-氯代苯甲醛肟 (1.0 g, 4.49 mmol, 1eq) 的乙醇溶液 (監測內溫<24℃),緩慢升至室溫,劇烈攪拌過夜,減壓蒸餾除去乙醇,加入乙酸乙酯萃取3次 (3×100 mL),有機層用水 (3×100 mL)、飽和食鹽水 (100mL) 洗滌,無水硫酸鈉乾燥除去溶劑得油狀粗品。矽膠柱層析法梯度洗脫分離純化 (PE:EA=40: 1, v/v) 得白色固體 (3-(2,6-二氯苯基)-5-環丙基異噁唑-4-甲酸甲酯) 0.89 g,收率55%。
氮氣保護和冰浴條件下將二異丁基氫化鋁的甲苯溶液 (4.0 mL, 6.0 mmol, 2.1 eq, 1.5 M的甲苯溶液)緩慢滴加至3-(2,6-二氯苯基)-5-環丙基異噁唑- 4-甲酸甲酯 (0.89 g, 2.8 mmol, 1 eq) 的無水THF中,升至室溫劇烈攪拌過夜。重新將反應液冷卻至0℃,緩慢滴加甲醇 (2 mL) 攪拌10 min,反應液倒入50 mL冰水混合物中,生成凝膠狀懸浮物。矽藻土過濾,用乙酸乙酯 (3×100 mL) 萃取三次,合併酯層,用水 (3×100 mL) 和飽和食鹽水 (100 mL) 洗滌,無水硫酸鈉乾燥,過濾除去溶劑得白色固體。矽膠柱層析法梯度洗脫分離純化(PE:EA=20: 1, v/v)得到白色固體 (3-(2,6-二氯苯基)-4-羥甲基-5-環丙基異噁唑) 0.45 g,收率56% 。
2 3-(2,6-
二氯苯基
)-4-
羥甲基
-5-
異丙基異噁唑的合成
將異丁醯乙酸甲酯 (16.6 mL, 0.12 mol, 1 eq) 加入到100 mL反應瓶,膠塞密閉,用針管把三乙胺 (33.25 mL, 0.24 mol, 2 eq) 加入到反應瓶內,室溫下劇烈攪拌30min,反應液冰浴冷卻低於10℃,攪拌下緩慢滴加2,6-二氯-N-羥基-氯代苯甲醛肟 (26.6 g, 0.12 mol, 1 eq) 的乙醇溶液 (監測內溫<24℃),緩慢升至室溫,劇烈攪拌過夜,減壓蒸餾除去乙醇,加入乙酸乙酯萃取3次 (3×100mL),有機層用水 (3×100mL)、飽和食鹽水 (100mL) 洗滌,無水硫酸鈉乾燥除去溶劑得油狀粗品。矽膠柱層析法梯度洗脫分離純化(PE:EA=40: 1, v/v)得白色固體 (3-(2,6-二氯苯基)-5-異丙基異噁唑-4-甲酸甲酯) 21 g,收率56%。
氮氣保護和冰浴條件下將二異丁基氫化鋁的甲苯溶液(92 mL, 0.1 4mol, 2.1 eq, 1.5 Μ的甲苯溶液)緩慢滴加至3-(2,6-二氯苯基)-5-異丙基異噁唑- 4-甲酸甲酯 (20 g, 0.06 mol, 1 eq) 的無水THF中,升至室溫劇烈攪拌過夜。重新將反應液冷卻至0℃,緩慢滴加甲醇 (20 mL) 攪拌10 min,反應液倒入200 mL冰水混合物中,生成凝膠狀懸浮物。矽藻土過濾,用乙酸乙酯 (3×100 mL) 萃取三次,合併酯層,用水 (3×100 mL) 和飽和食鹽水 (100 mL) 洗滌,無水硫酸鈉乾燥,過濾除去溶劑得白色固體。矽膠柱層析法梯度洗脫分離純化 (PE:EA=40: 1, v/v) 得到白色固體 (3-(2,6-二氯苯基)-4-羥甲基-5-異丙基異噁唑) 18 g,收率94%。
3 3-(2,6-
二氯苯基
)-4-
羥甲基
-5-
苯基異噁唑的合成
將苯甲醯乙酸乙酯 (5.7 mL,50 mmol, 1 eq) 加入到100 mL反應瓶,膠塞密閉,用針管把三乙胺 (13.86 mL, 100 mmol, 2 eq) 加入到反應瓶內,室溫下劇烈攪拌30 min,反應液冰浴冷卻低於10℃,攪拌下緩慢滴加2,6-二氯-N-羥基-氯代苯甲醛肟 (10 g, 50 mmol, 1 eq) 的乙醇溶液 (監測內溫<24℃),緩慢升至室溫,劇烈攪拌過夜,減壓蒸餾除去乙醇,加入乙酸乙酯萃取3次 (3×100 mL),有機層用水 (3×100 mL)、飽和食鹽水 (100 mL) 洗滌,無水硫酸鈉乾燥除去溶劑得油狀粗品。矽膠柱層析法梯度洗脫分離純化 (PE:EA=40: 1, v/v) 得白色固體 (3-(2,6-二氯苯基)-5-苯基異噁唑-4-甲酸甲酯) 11.7g,收率65%。
氮氣保護和冰浴條件下將二異丁基氫化鋁的甲苯溶液 (18 mL, 27 mmol, 2.1eq, 1. 5 M的甲苯溶液) 緩慢滴加至3-(2,6-二氯苯基)-5-苯基異噁唑- 4-甲酸甲酯(4.72 g, 13 mmol, 1 eq) 的無水THF中,升至室溫劇烈攪拌過夜。重新將反應液冷卻至0℃,緩慢滴加甲醇 (20 mL) 攪拌10 min,反應液倒入200 mL冰水混合物中,生成凝膠狀懸浮物。矽藻土過濾,用乙酸乙酯 (3×100 mL) 萃取三次,合併酯層,用水 (3×100 mL) 和飽和食鹽水 (100 mL) 洗滌,無水硫酸鈉乾燥,過濾除去溶劑得白色固體。矽膠柱層析法梯度洗脫分離純化 (PE:EA=20: 1, v/v) 得到白色固體(3-(2,6-二氯苯基)-4-羥甲基-5-苯基異噁唑) 9.1 g,收率70%。
試驗步驟:
在-15℃條件下,向N,N-二甲基甲醯胺 (2.1 g, 24.6 mmol) 的1,2-二氯乙烷 (40 mL),溶液中,緩慢滴加三氟甲磺酸酐 (11.6 g, 41.0 mmol),在-15℃攪拌30分鐘。然後加入3-溴苯乙烯 (3.0 g, 16.4 mmol) 和2,4,6-三甲基吡啶 (2.9 g, 24.6 mmol),室溫攪拌過夜。加水猝滅反應,室溫攪拌過夜,加入二氯甲烷稀釋分離有機相,分別用水和飽和食鹽水 (200ml) 洗滌有機相,無水硫酸鎂乾燥,抽濾,減壓濃縮,矽膠柱層析法梯度洗脫分離純化 (PE:EA=15:1, v/v) 得到黃色固體3-(3-溴苯基)環丁酮1.3 g,產率35%。
在室溫,一氧化碳氣球環境中,將三乙胺 (2.2 g, 21.3 mmol) 加入3-(3-氧代環丁基)苯甲酸甲酯 (1.6 g, 7.1 mmol) 和 (1,1'-雙(二苯基膦基)二茂鐵)二氯化鈀 (520 mg, 0.7 mmol) 在甲醇 (20 mL) 和N,N-二甲基甲醯胺 (10 mL) 的混合溶劑中,加熱到55℃反應18小時,減壓蒸餾除去溶劑並溶於乙酸乙酯中,用水洗滌,有機層用無水硫酸鎂乾燥,抽濾,減壓濃縮,矽膠柱層析法梯度洗脫分離純化 (PE:EA=3:1, v/v) 得到黃色油狀固體3-(3-氧代環丁基)苯甲酸甲酯1.1 g, 產率75%。
在100 mL的圓底燒瓶中,放入氫化鈉 (4.9 g, 121.6 mmol),加入少量石油醚,洗滌氫化鈉表面的煤油層,洗滌兩次。加入四氫呋喃 (30 mL),反應瓶置於0℃冰浴下冷卻,將2,5-二溴吡嗪(13.1 g, 55.3 mmol) 溶於四氫呋喃 (10 mL),攪拌下滴加到圓底燒瓶中。反應20 min後,將1(5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲醇(15.7 g, 55.3 mmol)溶於四氫呋喃 (10 mL) 中,針管緩慢滴加到反應瓶中,升至室溫反應12 h。反應完畢,將反應液倒入100 mL冰水混合物中,然後用乙酸乙酯 (3×100 mL) 萃取,合併有機相後用水、飽和食鹽水洗滌。無水MgSO
4進行乾燥。矽膠柱層析法梯度洗脫分離純化 (PE:EA=10:1, v/v) 得到白色固體6(4-(5-溴吡嗪-2-亞甲氧基)-5-環丙基-3-(2,6-二氯苯基)異噁唑) 20.2 g,產率為83%。
100 mL三頸燒瓶氮氣保護,將6 (20.2 g, 45.8 mmol)溶於四氫呋喃 (80 mL)加入反應瓶,然後將溫度降到-78℃,緩慢滴加正丁基鋰(1.6 M 己烷, 30.0 mL, 48.0 mmol),攪拌10 min後,緩慢滴加溶於四氫呋喃 (20 mL) 中的3-(3-氧代環丁基)苯甲酸甲酯2(9.0 g, 43.6 mmol) 溶液,-78℃反應2 h後升至室溫反應過夜。反應完畢後,用飽和氯化銨猝滅反應,用乙酸乙酯萃取,飽和食鹽水 (200 mL) 洗滌有機相,無水硫酸鎂乾燥,抽濾,減壓蒸餾除去有機溶劑,矽膠柱層析法梯度洗脫分離純化 (PE:EA=15:1, v/v) 得到黃色固體3-(3-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)苯甲酸甲酯5.6g,產率為19%。
將3-(3-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)苯甲酸甲酯(5.6 g, 10.1 mmol)溶解於THF(10 mL)和甲醇(10 mL)混合溶劑中,35℃下加入LiOH·H
2O(1.8 g, 42.6 mmol)的水(5 mL)溶液,攪拌過夜。減壓蒸餾除去有機溶劑,用1 N鹽酸調節pH至5,加入乙酸乙酯萃取三次,用無水硫酸鎂乾燥,減壓蒸餾除去溶劑,經高壓製備液相色譜儀分離純化 (乙腈:水=3:4, v/v) 得白色固體TM-1 3-(3-(5-(5-環丙基-3-(2,6-二氯苯基)異噁唑-4-亞甲氧基)-2-吡嗪)-1-羥基環丁烷)苯甲酸3.28 g,收率57%。
圖1所示、
1H-NMR (400 MHz, DMSO-D6): δ12.95 (s,1H), 8.22-8.21 (m, 1H), 8.12-8.11 (m, 1H), 7.95-7.94 (m, 1H), 7.72 (d,
J=2Hz, 1H), 7.66-7.49 (m, 4H), 7.48-7.37 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H), 3.57-3.37 (m, 1H), 2.94-2.89 (m, 2H), 2.55-2.42 (m, 3H), 1.21 (d,
J=24Hz, 2H), 1.15 (d,
J=16Hz, 2H)。
圖2所示,SI-MS: m/z[M+H]+: Calcd.for C
28H
23Cl
2N
3O
5: 551.1, Found: 552.2。
合成步驟:
向3-碘苯甲酸甲酯3a (5.0 g, 19.1 mmol) 在DMSO-D
6(70 mL) 的溶液中加入3-氮雜環環丁烷-3-醇鹽酸鹽 (2.5 g, 22.9 mmol)、Cs
2CO
3(15.5 g, 47.7 mmol)、CuI (726 mg, 3.8 mmol) 和L-脯氨酸 (878 mg, 7.6 mmol),然後將該混合物在氬氣氣氛下在90℃加熱18小時。溶液用乙酸乙酯和水稀釋,然後將有機層用鹽水洗滌三次,減壓濃縮,用矽膠柱層析色譜分離純化(DCM/MeOH=10/1, v/v),得到白色固體產物3b (2.7 g, 68%)。
將二甲亞碸 (1.6 g, 20.3 mmol) 溶於二氯甲烷 (30 mL) 中,在-78℃下,加入草醯氯 (1.3 g, 10.1 mmol),並在-78℃攪拌30分鐘,然後加入3-(3-羥基氮雜環丁烷-1-基)苯甲酸甲酯 (1.4 g, 6.8 mmol) 溶於二氯甲烷,在-78℃下緩慢滴加到反應液中,並控制時間在30分鐘,然後在-78℃攪拌30分鐘,隨後加入三乙胺 (4.1 g, 40.5 mmol),在-78℃反應1小時,升至室溫並在室溫下反應2小時。反應液用水稀釋,並用乙酸乙酯萃取,有機相用飽和食鹽水洗滌,無水硫酸鈉乾燥,抽濾濃縮,用矽膠柱層析色譜分離純化 (PE/EA=2/1) 得到白色固體產物3 (0.9g, 65%)。
100 mL三頸燒瓶氮氣保護,將6 (1.9 g, 4.4 mmol) 溶於四氫呋喃 (25ml) 加入反應瓶,然後將溫度降到-78℃,緩慢滴加正丁基鋰(2.5M in hexane,2.6 mL, 6.6 mmol),攪拌10 min後,緩慢滴加溶於四氫呋喃 (5 mL) 中的3-(3-氧代氮雜環丁烷-1-基)苯甲酸甲酯3 (0.9 g, 4.4 mmol) 溶液,-78℃反應2h後升至室溫反應過夜。反應完畢後,用飽和氯化銨猝滅反應,用乙酸乙酯萃取,飽和食鹽水 (200 mL) 洗滌有機相,無水硫酸鎂乾燥,抽濾,減壓蒸餾除去有機溶劑,矽膠柱層析法梯度洗脫分離純化 (PE:EA=15:1, v/v) 得到黃色固體7 3-(3-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)苯甲酸甲酯560 mg,產率為22%。
將3-(3-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)苯甲酸甲酯 (270 mg, 0.5 mmol) 溶解於THF (3 mL) 和甲醇 (3 mL) 混合溶劑中,35℃下加入LiOH·H
2O (60 mg, 1.5 mmol) 的水 (3 ml) 溶液,攪拌過夜。減壓蒸餾除去有機溶劑,用1N鹽酸調節pH至5,加入乙酸乙酯萃取三次,用無水硫酸鎂乾燥,減壓蒸餾除去溶劑,經高壓製備液相色譜儀分離純化 (乙腈:水=3:4,v/v) 得白色固體3-(3-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基苯甲酸) 40 mg,收率15%。
圖3所示、
1H-NMR (400MHz, DMSO-D6): δ8.22-8.21 (m, 1H), 8.08-8.08 (m,1H), 7.59-7.51 (m, 4H), 7.27-7.25 (m, 2H),7.00 (s, 1H), 6.67 (s, 1H), 5.24 (s, 2H), 4.21 (d, J=16 Hz, 2H), 3.98 (d, J=16 Hz, 2H), 2.51-2.50 (m, 1H), 1.22-1.18 (m, 2H), 1.15-1.12 (m, 2H)。
圖4所示、ESI-MS: m/z[M+H]
+: Calcd.for C
27H
22Cl
2N
4O
5: 552.1, Found: 553.1 (註:數值在圖的右側)。
實施例
3
:化合物
TM-3
合成路線
100 mL三頸燒瓶氮氣保護,將4-(5-溴吡嗪-2-亞甲氧基)-5-環丙基-3-(2,6-二氯苯基)異噁唑(1.14 g,2.3 mmol)溶於無水四氫呋喃 (5 mL) 打入反應瓶,然後將乙醇與液氮加入500 mL低溫杜瓦瓶使溫度降到-78℃,緩慢滴加正丁基鋰 (1.7 mL, 2.7 mmol),攪拌10 min後,緩慢滴加溶於四氫呋喃 (10 mL) 中的3-(3-氧代環丁酮)苯甲酸甲酯(0.56 g, 2.5 mmol) 溶液,-78℃反應2h後升至室溫反應過夜。反應完畢將反應液緩慢倒入冰水混合物中,用乙酸乙酯萃取,水 (100 mL) 洗滌酯層,無水硫酸鎂乾燥,抽濾,減壓蒸餾除去有機溶劑,矽膠柱層析法梯度洗脫分離純化 (PE:EA = 10:1,v/v) 得到白色固體3-(3-溴苯基)-(5-(5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)環丁烷-1-醇,567 mg,產率為42%。
圖5所示、
1H-NMR (400 MHz, CDCl
3): δ8.30 (1H, s), 8.06 (1H, d,J=4Hz), 7.45 (1H, s), 7.42 (1H, d, J=1.6Hz), 7.40 (1H, s), 7.36-7.32 (2H, m, J=16Hz), 7.22-7.18 (2H, m, J=16Hz), 5.23 (2H, s), 3.35-3.26 (1H, m), 2.99-2.93 (2H, m), 2.63-2.57 (2H, m), 2.36-2.29 (1H, m), 1.33-1.29 (2H, d, J=24Hz), 1.21-1.16 (2H, d,J=16Hz);
圖6所示、
13C-NMR (100 MHz, DMSO-D6): 173.0, 159.6, 158.4, 150.9, 147.1, 130.0, 129.8, 129.3, 128.0, 127.9, 125.3, 122.6, 110.3, 71.0, 56.8, 44.5, 29.8, 8.5,7.8。
圖7所示、ESI-MS: m/z[M+2+H]
+: Calcd.for C
27H
22BrCl
2N
3O
3: 585.0222, Found:588.0300。
實施例
4
:化合物
TM-4
合成路線
向3-(3-溴苯基)-1-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)環丁醇 (500 mg, 0.85 mmol) 在DMSO-D6中的溶液中,加入甲烷亞磺酸鈉 (130 mg, 1.28 mmol)、CuI (50.2 mg, 0.26 mmol)、L-脯氨酸 (97.9 mg, 0.85 mmol) 和二異丙基乙胺 (DIEA) (109.9 mg, 0.85 mmol)。將該混合物在95℃攪拌過夜,然後用水稀釋並用EA萃取。有機相合併,用水洗滌並用Na
2SO
4乾燥。減壓濃縮至幹經高壓製備液相色譜儀分離純化 (乙腈:水=3:4, v/v) 得白色固體1-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-(3-(甲基磺醯基)苯基)環丁醇324 mg,收率65%。
圖8所示、
1H-NMR (400MHz, CDCl3): δ8.15 (s, 1H), 7.92 (s,1H),7.72-7.65 (m, 2H), 7.42-7.40 (m, 2H), 7.28-7.12 (m, 2H), 5.08 (s, 2H), 3.33-3.29 (m, 1H),2.93-2.85(m, 5H), 2.51-2.46 (m,2H), 2.21-2.18 (m, 1H), 1.15 (d, J=16Hz, 2H), 1.05 (d, J=16Hz, 2H)。
圖9所示、ESI-MS: m/z[M+H]+: Calcd.for C
28H
25Cl
2N
3O
5S: 585.1, Found: 586.3。
實施例
5
:化合物
TM-5
合成路線
在氬氣保護下,向3-(3-溴苯基)-1-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)環丁醇 (1.0 g, 1.7 mmol) 在甲苯中的溶液中加入DIEA (0.44 g, 3.41 mmol)、苯甲硫醇 (0.21 g, 1.7 mmol)、Pd
2(dba)
3(0.34 g, 0.37 mmol) 和4,5-雙二苯基膦-9,9-二甲基氧雜蒽 (0.16 g, 0.27 mmol)。然後將混合物在115℃攪拌4小時。冷卻至室溫,用水稀釋並用EA萃取。有機相合併,用水洗滌並用Na
2SO
4乾燥。減壓濃縮至幹經高壓製備液相色譜儀分離純化 (乙腈:水=3:4, v/v) 得白色固體1-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-(3-(苯硫基)苯基)環丁醇367 mg, 收率35%。
圖10所示、
1H-NMR(400 MHz, CDCl
3): δ8.23 (s, 1H), 8.01 (s, 1H), 7.46 - 7.54 (m, 3H), 7.23 - 7.33 (m, 8H), 7.14 (br d, J = 7.6 Hz, 1H), 5.28 (s, 2H), 3.31-3.34 (m, 1H), 4.85(H
2O), 4.58 (HDO), 3.30 (CD
3OD), 2.92 - 3.02 (m, 2H), 2.41 - 2.50 (m, 2H), 1.23 (s, 1H), 1.21 (br d, J = 2.0 Hz, 2H), 1.19 (br d, J = 2.0 Hz, 2H)。
圖11所示、ESI-MS: m/z[M+H]
+: Calcd.for C
33H
27Cl
2N
3O
3S: 615.1150, Found: 616.1421。
實施例
6
:化合物
TM-6
的合成
在100 mL的圓底燒瓶中,放入氫化鈉 (60%, 0.83 g, 21 mmol),加入少量石油醚,洗滌NaH表面的煤油層,洗滌兩次。加入30 mL四氫呋喃,反應瓶置於0 ℃冰浴下冷卻。將2,5-二溴吡嗪 (833 mg, 3.5 mmol) 溶於10 mL四氫呋喃,攪拌下滴加到圓底燒瓶中。反應20 min後,將3-(2,6-二氯苯基)-4-羥甲基-5-異丙基異噁唑 (1 g, 3.5 mmol) 溶於10 mL四氫呋喃中,針管緩慢滴加到反應瓶中。升至室溫反應12 h。反應完畢,將反應液倒入100 mL冰水混合物中,然後用乙酸乙酯 (3×100 mL) 萃取,合併有機相後用水、飽和食鹽水洗滌。無水MgSO
4進行乾燥。矽膠柱層析法梯度洗脫分離純化 (PE:EA=10:1, v/v) 得到白色固體4-(5-溴吡嗪-2-亞甲氧基)-5-異丙基-3-(2,6-二氯苯基)異噁唑0.7 g,產率為53%。
100 mL三頸燒瓶氮氣保護,將4-(5-溴吡嗪-2-亞甲氧基)-5-異丙基-3-(2,6-二氯苯基)異噁唑(1 g, 2.3 mmol)溶於無水四氫呋喃 (20 mL) 打入反應瓶,然後將乙醇與液氮加入500 mL低溫杜瓦瓶使溫度降到-78℃,緩慢滴加正丁基鋰 (1.7 ml, 2.7 mmol),攪拌10 min後,緩慢滴加溶於四氫呋喃 (10 mL) 中的3-(3-氧代環丁酮)苯甲酸甲酯 (0.51 g, 2.5 mmol) 溶液,-78℃反應2h後升至室溫反應過夜。反應完畢將反應液緩慢倒入冰水混合物中,用乙酸乙酯萃取,水 (100 mL) 洗滌酯層,無水硫酸鎂乾燥,抽濾,減壓蒸餾除去有機溶劑,矽膠柱層析法梯度洗脫分離純化(PE:EA=10:1, v/v)得到白色固體3-(3-(5-((3-(2,6-二氯苯基)-5-異丙基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)苯甲酸甲酯549 mg, 產率為42%。
將3-(3-(5-((3-(2,6-二氯苯基)-5-異丙基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)苯甲酸甲酯 (319 mg, 0.6 mmol, 1eq)溶 解於20 mL THF中,35°C下LiOH·H
2O (99 mg, 2.4 mmol, 4.2 eq) 的水 (5 mL) 溶液,攪拌過夜。減壓蒸餾除去有機溶劑,用1 N鹽酸調節pH至5,加入乙酸乙酯萃取三次,用無水硫酸鎂乾燥,減壓蒸餾除去溶劑,使用高壓製備液相色譜儀分離純化,採用Waters XBridge C18柱 (150 mm*4.6 mm*3.5 μm),流動相為乙腈和水,流速18 mL/min,收集梯度為45%-75%的餾分,濃縮除掉大部分乙腈,用凍乾機凍乾得白色粉末狀固體(3-(3-(5-(5-異丙基-3-(2,6-二氯苯基)異噁唑-4-亞甲氧基)-2-吡嗪)-1-羥基環丁烷)苯甲酸) 126 mg, 收率38%。
圖12所示
1H-NMR (400MHz, DMSO-D
6): δ12.97 (s,1H), 8.20 (d,
J=1.3Hz, 1H), 8.09 (d,
J=1.3Hz, 1H), 7.95 (s, 1H), 7.79-7.77 (d,
J=7.7Hz, 1H), 7.63-7.61 (m, 2H), 7.55-7.53 (m, 2H), 7.44 (t,
J=7.7 Hz, 1H), 6.09 (s, 1H), 5.19 (s, 2H), 3.61-3.54 (m, 1H), 3.42-3.33 (m, 1H), 2.90 (td,
J=8.9, 2.5Hz, 2H), 2.47-2.42 (m, 2H), 1.37 (d,
J=7.0Hz, 6H);
圖13所示、
13C-NMR (100MHz, CDCl3): 176.8, 171.0, 159.3, 158.4, 150.9, 145.2, 131.2, 129.4, 128.7, 128.4, 128.2, 128.1, 128.0, 109.1, 71.1, 56.8, 44.5, 29.9, 27.0, 20.9, 1.0;
圖14所示、ESI-MS: m/z[M+H]+: Calcd.for C
28H
25Cl
2N
3O
5: 553.1171, Found: 554.1211。
實施例
7
:化合物
TM-7
的合成
在100 mL的圓底燒瓶中,放入氫化鈉 (60%, 0.83 g, 21 mmol),加入少量石油醚,洗滌NaH表面的煤油層,洗滌兩次。加入30 mL四氫呋喃,反應瓶置於0 ℃冰浴下冷卻。將2,5-二溴吡嗪 (833 mg, 3.5 mmol)溶於10 mL四氫呋喃,攪拌下滴加到圓底燒瓶中。反應20 min後,將3-(2,6-二氯苯基)-4-羥甲基-5-苯基異噁唑 (1.12 g, 3.5 mmol)溶於10 mL四氫呋喃中,針管緩慢滴加到反應瓶中。升至室溫反應12h。反應完畢,將反應液倒入100 mL冰水混合物中,然後用乙酸乙酯 (3×100 mL) 萃取,合併有機相後用水、飽和食鹽水洗滌。無水MgSO
4進行乾燥。矽膠柱層析法梯度洗脫分離純化 (PE:EA=10:1, v/v) 得到白色固體 (4-(5-溴吡嗪-2-亞甲氧基)-5-苯基-3-(2,6-二氯苯基)異噁唑),752 mg,產率為45%。
100mL三頸燒瓶氮氣保護,將4-(5-溴吡嗪-2-亞甲氧基)-5-苯基-3-(2,6-二氯苯基)異噁唑(1g, 2.1 mmol)溶於無水四氫呋喃(20 mL)打入反應瓶,然後將乙醇與液氮加入500 mL低溫杜瓦瓶使溫度降到-78℃,滴加正丁基鋰溶液 (1.1 N環己烷溶液, 1.75 ml, 2.8 mmol),攪拌10 min後,緩慢滴加溶於四氫呋喃 (10 mL) 中的3-(3-氧代環丁酮)苯甲酸甲酯(0.47 g, 2.3 mmol) 溶液,-78℃反應2 h後升至室溫反應過夜。反應完畢將反應液緩慢倒入冰水混合物中,用乙酸乙酯萃取,水 (100 mL) 洗滌酯層,無水硫酸鎂乾燥,抽濾,減壓蒸餾除去有機溶劑,矽膠柱層析法梯度洗脫分離純化 (PE:EA=10:1, v/v) 得到白色固體3-(3-(5-((3-(2,6-二氯苯基)-5-苯基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基) 苯甲酸甲酯329 mg,產率為26%。
將3-(3-(5-((3-(2,6-二氯苯基)-5-苯基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)苯甲酸甲酯 (118 mg, 0.2 mmol, 1 eq) 溶解於20mL THF中,35°C下LiOH·H
2O (35 mg, 0.8 mmol, 4.2 eq)的水 (5 mL) 溶液,攪拌過夜。減壓蒸餾除去有機溶劑,用1 N鹽酸調節pH至5,加入乙酸乙酯萃取三次,用無水硫酸鎂乾燥,減壓蒸餾除去溶劑,使用高壓製備液相色譜儀分離純化,採用Waters X Bridge C18柱 (150 mm*4.6 mm*3.5 μm),流動相為乙腈和水,流速18 mL/min,收集梯度為45%-75%的餾分,濃縮除掉大部分乙腈,用凍乾機凍乾得白色粉末狀固體(3-(3-(5-(5-苯基-3-(2,6-二氯苯基)異噁唑-4-亞甲氧基)-2-吡嗪)-1-羥基環丁烷)苯甲酸) 39 mg,收率33%。
圖15所示、
1H-NMR (400 MHz, DMSO-D6): δ12.97 (s,1H), 8.15 (d,
J=1.3Hz, 1H), 8.10 (d,
J=1.3Hz, 1H), 7.99-7.95 (m,
J=16Hz, 3H), 7.79-7.78 (d,
J=4Hz, 1H), 7.67-7.65 (m,
J=8Hz, 5H), 7.61-7.55 (m,
J=8Hz, 2H), 7.46-7.42 (m, 1H), 6.08 (s, 1H), 5.38 (s, 2H), 5.39-3.33 (m, 1H), 2.94-2.88 (m, 2H), 2.47-2.42 (m, 2H);
圖16所示,ESI-MS: m/z[M+H]+: Calcd.for C
31H
23Cl
2N
3O
5: 587.1015, Found: 588.1062。
100 mL圓底燒瓶,加入3-溴苯甲酸甲酯 (1.12 g,5 mmol),乙烯三氟硼酸鉀 (820 mg, 6.12 mmol),PdCl2 (17.5 mg, 0.1 mmol),PPh3 (80 mg, 0.3 mmol) 和Cs
2CO
3(5 g, 15 mmol),然後在N
2下加入THF (18 mL)和H
2O (2 mL)。混合物在80℃下攪拌反應22 h,冷卻至室溫後,用水洗滌、無水硫酸鎂乾燥、抽濾。減壓蒸餾,用矽膠柱層析法梯度洗脫分離純化 (PE:EA=60:1, v/v) 得到淺粉色油狀液體 (3-甲基-5-乙烯基苯甲酸甲酯) 164 mg,產率30%。
氮氣保護下,將3-甲基-5-乙烯基苯甲酸甲酯 (5.46g,31 mmol, 1eq) 溶解於乙醚 (150 mL) 中。加入鋅粉 (6 g, 93 mmol, 3 eq),超音波震盪30 min後,滴加一種三氯乙醯氯 (8.7 mL, 77.5 mmol, 2.5 eq) 的Et
2O溶液 (50 mL),繼續超聲30分鐘。混合物加熱到35℃。持續超聲2.5h,反應完成後冷卻至室溫,緩慢滴加水 (50 mL) 淬滅。混合物倒入水中攪拌20 min後,過濾,再用Et
2O漂洗。有機層用水 (250 mL)、飽和碳酸氫鈉 (250 mL) 和飽和氯化鈉 (250 mL) 洗滌,用無水硫酸鎂乾燥,過濾後減壓蒸餾除去溶劑得黃色油狀粗品。矽膠柱層析法梯度洗脫分離純化 (PE:EA=50:1, v/v) 得到黃色油狀液體3-(2,2-二氯-3-氧環丁酮)-5-甲基苯甲酸甲酯3.56g,產率40%。
混合3-(2,2-二氯-3-氧環丁酮)-5-甲基苯甲酸甲酯 (2.79 g, 9.7 mmol,1 eq) 與鋅粉 (2.54 g, 38.8 mmol, 4 eq) 溶於60 mL乙酸中,室溫下攪拌1h。然後在油浴80°C下回流3.5h,反應完畢後冷卻至室溫。用100 mL水稀釋溶劑乙酸,用乙醚 (3×40 mL) 萃取。合併有機相後依次用飽和碳酸鈉溶液 (3×40 mL)、水 (100 mL)、飽和食鹽水 (100 mL) 洗滌。用一定量的無水MgSO
4進行乾燥。矽膠柱層析法梯度洗脫分離純化 (PE:EA=50:1, v/v) 得到化合物 (3-(3-氧代環丁酮)苯甲酸甲酯) 1.38 g,產率65%。
100 mL三頸燒瓶氮氣保護,將4-(5-溴吡嗪-2-亞甲氧基)-5-環丙基-3-(2,6-二氯苯基)異噁唑 (1.02 g, 2.3 mmol) 溶於無水四氫呋喃 (20 mL) 打入反應瓶,然後將乙醇與液氮加入500 mL低溫杜瓦瓶使溫度降到-78℃,緩慢滴加正丁基鋰 (1.7 ml, 2.7 mmol),攪拌10 min後,緩慢滴加溶於四氫呋喃 (10 mL) 中的3-甲基-5-(3-氧環丁基)苯甲酸甲酯 (0.55 g, 2.5 mmol) 溶液,-78℃反應2h後升至室溫反應過夜。反應完畢將反應液緩慢倒入冰水混合物中,用乙酸乙酯萃取,水 (100 mL) 洗滌酯層,無水硫酸鎂乾燥,抽濾,減壓蒸餾除去有機溶劑,矽膠柱層析法梯度洗脫分離純化 (PE:EA=10:1, v/v) 得到白色固體3-(3-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)-5-甲基苯甲酸甲酯,產率為47%。
將3-(3-(5-((3-(2,6-二氯苯基)-5-環丙基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)苯甲酸甲酯 (116 mg, 0.2 mmol, 1 eq)溶解於20 mL THF中,35°C下LiOH·H
2O (35 mg, 0.8 mmol, 4.2 eq) 的水(5 mL) 溶液,攪拌過夜。減壓蒸餾除去有機溶劑,用1N鹽酸調節pH至5,加入乙酸乙酯萃取三次,用無水硫酸鎂乾燥,減壓蒸餾除去溶劑,使用高壓製備液相色譜儀分離純化,採用Waters XBridge C18柱 (150 mm*4.6 mm*3.5 μm),流動相為乙腈和水,流速18 mL/min,收集梯度為45%-75% 的餾分,濃縮除掉大部分乙腈,用凍乾機凍乾得白色粉末狀固體3-(3-(5-((5-環丙基-3-(2,6-二氯苯基)異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)-5-甲基苯甲酸,37 mg,收率33%。
圖17所示、
1H-NMR (400 MHz, DMSO-D6): δ12.90 (1H, s), 8.21 (1H, d, J=1.2Hz), 8.11 (1H, d, J=1.2Hz), 7.74 (1H, s),7.62-7.60 (3H, m), 7.56-7.52 (1H, m), 7.37 (1H, s), 6.06 (1H, s), 5.24 (2H, s), 3.38-3.29 (1H, m), 2.92-2.87 (2H, m), 2.59-2.53 (1H, m), 2.46-2.41 (2H, m), 2.35 (3H, s), 1.24-1.18 (2H, m), 1.16-1.14 (2H, m);
圖18所示、
13C-NMR (400MHz, DMSO-D6): δ176.9, 168.9, 168.0, 159.3, 157.9, 153.5, 146.2, 135.1, 133.4, 133.0, 128.9, 127.6, 125.1, 109.9, 70.9, 56.3, 45.5, 29.8, 26.5, 21.3, 21.1;
圖19所示、ESI-MS: m/z[M+H]
+: Calcd.for C
29H
25Cl
2N
3O
5: 565.1171, Found: 566.1234。
實施例
9
:化合物
TM-9
的合成
100mL三頸燒瓶氮氣保護,將4-(5-溴吡嗪-2-亞甲氧基)-5-異丙基-3-(2,6-二氯苯基)異噁唑 (1.02 g, 2.3 mmol) 溶於無水四氫呋喃 (20 mL) 打入反應瓶,然後將乙醇與液氮加入500 mL低溫杜瓦瓶使溫度降到-78℃,緩慢滴加正丁基鋰 (1.7 ml, 2.7 mmol),攪拌10 min後,緩慢滴加溶於四氫呋喃 (10 mL) 中的3-甲基-5-(3-氧環丁基)苯甲酸甲酯 (0.55 g, 2.5 mmol) 溶液,-78℃反應2h後升至室溫反應過夜。反應完畢將反應液緩慢倒入冰水混合物中,用乙酸乙酯萃取,水 (100 mL) 洗滌酯層,無水硫酸鎂乾燥,抽濾,減壓蒸餾除去有機溶劑,矽膠柱層析法梯度洗脫分離純化 (PE:EA=10:1, v/v,PE是石油醚,EA是乙酸乙酯) 得到白色固體 (3-(3-(5-((3-(2,6-二氯苯基)-5-異丙基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)-5-甲基苯甲酸甲酯) 643 mg,產率為48%。
將3-(3-(5-((3-(2,6-二氯苯基)-5-異丙基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)-5-甲基苯甲酸甲酯 (117 mg, 0.2 mmol, 1 eq) 溶解於20 mL THF中,35°C下LiOH·H
2O (35 mg, 0.8 mmol, 4.2eq) 的水 (5 mL) 溶液,攪拌過夜。減壓蒸餾除去有機溶劑,用1 N鹽酸調節pH至5,加入乙酸乙酯萃取三次,用無水硫酸鎂乾燥,減壓蒸餾除去溶劑,使用高壓製備液相色譜儀分離純化,採用Waters X Bridge C18柱 (150 mm*4.6 mm*3.5 μm),流動相為乙腈和水,流速18mL/min,收集梯度為45%-75%的餾分,濃縮除掉大部分乙腈,用凍乾機凍乾得白色粉末狀固體(3-(3-(5-((3-(2,6-二氯苯基)-5-異丙基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)-5-甲基苯甲酸),46 mg,收率40%。
圖20所示、
1H-NMR (400 MHz, DMSO-D6): δ12.88 (1H, brs), 8.20 (1H, d, J=1.2Hz), 8.08 (1H, d, J=1.2Hz), 7.73 (1H, s), 7.63-7.60 (3H, m), 7.56-7.52 (1H, s), 7.37 (1H, s), 6.06 (1H, brs), 5.19 (2H, s), 3.61-3.54 (1H, m), 2.91-2.85 (2H, m), 2.45-2.40 (2H, m), 2.35 (3H, s), 1.38-1.36 (6H,d, J=8Hz);
圖21所示、
13C-NMR (100 MHz, DMSO-D6): 176.9, 168.0, 159.3, 157.9, 153.5, 146.2, 135.1, 133.4, 133.0, 128.9, 127.6, 125.1, 109.9, 70.9, 56.3, 45.5, 29.8, 26.5, 21.3, 21.1;
圖22所示、ESI-MS: m/z[M+H]+: Calcd.for C
29H
27Cl
2N
3O
5: 567.1328, Found: 568.1412。
實施例
10
:化合物
TM-10
的合成
100 mL三頸燒瓶氮氣保護,將4-(5-溴吡嗪-2-亞甲氧基)-5-苯基-3-(2,6-二氯苯基)異噁唑 (1.03 g, 2.3 mmol) 溶於無水四氫呋喃 (20 mL) 打入反應瓶,然後將乙醇與液氮加入500 mL低溫杜瓦瓶使溫度降到-78℃,緩慢滴加正丁基鋰 (1.7 ml, 2.7 mmol),攪拌10 min後,緩慢滴加溶於四氫呋喃 (10 mL) 中的3-甲基-5-(3-氧環丁基)苯甲酸甲酯 (0.55 g, 2.5 mmol) 溶液,-78℃反應2h後升至室溫反應過夜。反應完畢將反應液緩慢倒入冰水混合物中,用乙酸乙酯萃取,水 (100 mL) 洗滌酯層,無水硫酸鎂乾燥,抽濾,減壓蒸餾除去有機溶劑,矽膠柱層析法梯度洗脫分離純化 (PE:EA=10:1,v/v) 得到白色固體 (3-(3-(5-((3-(2,6-二氯苯基)-5-苯基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)-5-甲基苯甲酸甲酯) 496 mg,產率為35%。
將3-(3-(5-((3-(2,6-二氯苯基)-5-苯基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)-5-甲基苯甲酸甲酯(123 mg, 0.2 mmol, 1 eq)溶解於20mL THF中,35°C下LiOH·H
2O (35 mg, 0.8 mmol, 4.2 eq) 的水 (5 mL) 溶液,攪拌過夜。減壓蒸餾除去有機溶劑,用1 N鹽酸調節pH至5,加入乙酸乙酯萃取三次,用無水硫酸鎂乾燥,減壓蒸餾除去溶劑,使用高壓製備液相色譜儀分離純化,採用Waters XBridge C18柱 (150 mm*4.6 mm*3.5 μm),流動相為乙腈和水,流速18 mL/min,收集梯度為45%-75%的餾分,濃縮除掉大部分乙腈,用凍乾機凍乾得白色粉末狀固體(3-(3-(5-((3-(2,6-二氯苯基)-5-苯基異噁唑-4-基)甲氧基)吡嗪-2-基)-3-羥基環丁基)-5-甲基苯甲酸),37 mg,收率31%。
圖23所示、
1H-NMR (400 MHz, DMSO-D6): δ12.89 (1H, s), 8.14 (1H, d,
J=1.6Hz), 8.09 (1H, d,
J=1.6Hz), 7.99-7.96 (3H, m), 7.73 (1H, s), 7.67-7.65 (5H, m), 7.61-7.57 (2H, m), 7.37 (1H, s), 6.06 (1H, s), 5.38 (2H, s), 3.33-3.28 (1H, m), 2.91-2.86 (2H, m), 2.45-2.40 (2H, m), 2.35 (3H, s);
圖24所示、
13C-NMR (100MHz, DMSO-D6): 168.4, 168.0, 160.4, 157.8, 153.7, 146.2, 135.2, 133.3, 131.6, 130.0, 129.0, 127.7, 127.2, 125.1, 111.5, 70.9, 57.0, 45.5, 29.8, 21.3;
圖25所示、ESI-MS: m/z[M+H]
+: Calcd.for C
32H
25Cl
2N
3O
5: 601.1171, Found: 602.1249。
無
圖1為本發明化合物TM-1的
1H-NMR譜圖;
圖2為本發明化合物TM-1的質譜圖;
圖3為本發明化合物TM-2的
1H-NMR譜圖;
圖4為本發明化合物TM-2的質譜圖;
圖5為本發明化合物TM-3的
1H-NMR譜圖;
圖6為本發明化合物TM-3的
13C-NMR譜圖;
圖7為本發明化合物TM-3的質譜圖;
圖8為本發明化合物TM-4的
1H-NMR譜圖;
圖9為本發明化合物TM-4的質譜圖;
圖10為本發明化合物TM-5的
1H-NMR譜圖;
圖11為本發明化合物TM-5的質譜圖;
圖12為本發明化合物TM-6的
1H-NMR譜圖;
圖13為本發明化合物TM-6的
13C-NMR譜圖;
圖14為本發明化合物TM-6的質譜圖;
圖15為本發明化合物TM-7的
1H-NMR譜圖;
圖16為本發明化合物TM-7的質譜圖;
圖17為本發明化合物TM-8的
1H-NMR譜圖;
圖18為本發明化合物TM-8的
13C-NMR譜圖;
圖19為本發明化合物TM-8的質譜圖;
圖20為本發明化合物TM-9的
1H-NMR譜圖;
圖21為本發明化合物TM-9的
13C-NMR譜圖;
圖22為本發明化合物TM-9的質譜圖;
圖23為本發明化合物TM-10的
1H-NMR譜圖;
圖24為本發明化合物TM-10的
13C-NMR譜圖;
圖25為本發明化合物TM-10的質譜圖。
Claims (10)
- 如請求項1所述之化合物,其中: R 1選自-Br; R 2選自C 1~C 3的烴基、環烴基; R 3選自-CH 3。
- 一種藥物組合物,包括如請求項1-4之中任一項所述的化合物或其藥學上可接受的鹽作為活性成分。
- 如請求項5所述之藥物組合物,該藥物組合物更包括一藥學上可接受的載體。
- 如請求項1-4之中任一項所述之化合物,具有在製備治療一非酒精性脂肪肝的藥物中之用途。
- 如請求項8所述之用途,其中該非酒精性脂肪肝為非酒精性脂肪肝炎。
- 如請求項5所述之藥物組合物在製備治療該非酒精性脂肪肝的藥物中的用途,優選為非酒精性脂肪肝炎。
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