TW200521108A - Compounds having lysophosphatidic acid receptor(LPA)-antagonizing effect and their use - Google Patents
Compounds having lysophosphatidic acid receptor(LPA)-antagonizing effect and their use Download PDFInfo
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- TW200521108A TW200521108A TW093139286A TW93139286A TW200521108A TW 200521108 A TW200521108 A TW 200521108A TW 093139286 A TW093139286 A TW 093139286A TW 93139286 A TW93139286 A TW 93139286A TW 200521108 A TW200521108 A TW 200521108A
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- fluorenyl
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Description
200521108 九、發明說明: 【發明所屬之技術領域】 本發明為關於一種可你在銥σ 裡」忭马酉条之具溶血磷脂酸受體 (特1是EDG-2)括抗作用之化合物,其之製造方法及用途。 【先前技術】 一般已知藉由來自細胞膜之磷脂酶之作用,可產生 十石厌化合物(Eicosanoid)、血小板活化因子(piatelet activating factor,PAF)等各種脂質類媒介物 (Mediator) 〇 如式(A)所表示之溶血磷脂酸(以下簡稱為LpA)係由 存在於細胞膜或血中之鱗脂所合成之可傳導細胞内各種訊 息而做為傳信物質之脂質。#中天然存在之Lp“ “ 一LPA 〇
(A)
OH
HOj/O
II ο [式中之RA表示醯基、烯基或炔基]。 由於最近已知LPA受體有3種亞型存在,漸可註明其 為經LPA受體達成其生理作用。該3種LpA受體分別稱為 EDG(Endothelial differentiation gene,内皮分化基 因)-2、4、7,與屬於神經鞘胺醇(叩]1丨11§03丨116)〜1〜碌酸受 體之EDG-;l、3、5、6、8同為EDG受體族群之一部份。edg — 2 亦被稱為 LPA1、VZG(Ventricularzone gene,室區基因)
-1(Mol· Pharmacol., 2000, Dec· , 58(6) : 1188-96) 。 LPA 316588 6 200521108 月且了,、LPA結合,經亦與該受 内 又私結合之G蛋白傳導細胞 内之汛息。可與LPA受體結 等,此等受體參與細梦殖二卜白所知有Gs、Gl、Gq 你田斤 Iθ殖几進作用、或相反之增殖抑制 t寺之回應。且G蛋白之下游又與懸p激酶系連動,由 此可知LPA受體可以傳導多種訊息。 LPA受體亞型廣泛地存在於體内,依亞型類型其存在 之局部形態不同,因此可推想各受體之角色依其所在組織 而異。 LPA引电之樂理作用’所知者有引發大鼠血壓上升、 大鼠結腸及天竺鼠迴腸之收縮等現象(j pharm
Pharmacol., 1 991, 43, 774; J. Pharm> PharmacoL , ! 982> M’ 514)。另外所知’LPA經由EDG—2亦參與尿道之收縮(參 考W092/62389號公報)、LPA ,亦可抑制胰臟之分泌(參考 W003/07991 5虎公報)、且LPA亦與-些慢性病(參考w〇〇4/ 02530號公報)有關。 此外,LPA與癌之關聯方面,亦已知lPA會造成來自 前列腺之上皮癌細胞之增殖(J· CeUular physi(K)1., 1 998,174,261)、卵巢癌細胞之增殖亢進(j· Ur〇i.,2〇〇〇, 163, 1027)。 ’ 除癌細胞以外,LPA亦已知與呼吸道平滑肌細胞(Am. j. Physiol. Lung Cell Mol. Physiol., 2002, 282( 1 ) : L91)、 纖維母細胞(Mol· Ce 11 Biol·,1 998,述(12) : 711 9)、腎 間質細胞(Clin· Science,1 999,並,431)、肝細胞、肝 星狀細胞(Biochem· Biophys· Res· Commun·,1 998,248, 7 316588 200521108 436)、血管平滑肌細胞(Am. J. Physiol.,1 994, 267,(Cell Physiol.,36) · C204)、血管内皮細胞(Am. J. Physiol. Cell Physiol·,2000, U1(3):C612)、神經膠質細胞(proc Natl· Acad· Sci· USA,1 999,並,5233)、脂肪細胞(J. Clin· Invest·,1998,1〇丄,1431)等各種細胞之增殖有 關。特別是與多形性膠質母細胞瘤之相關更為一般所知, 因此推想EDG-2拮抗樂劑可作為預防及/或治療多形性膠 質母細胞瘤相關疾病(例如腦瘤等)之藥劑。其他,在細胞 增殖以外,LPA亦已知與自癌細胞至炎症細胞之細胞游走 有關(Biochem· Biophys· Res· Commun·, 1 993,15: 93(2) 497)。其他所知如LPA與免疫細胞增殖·組織介素釋出作 用(J. I_Un〇l.,1 999, M,2049)、血小板凝集作用 (Biochem. Biophys. Res. Commun.,1981,迎,391)之相 關。此外’由LPA受體之一之EDG_2之基因剔除^n〇ck_〇ut) 小鼠解析亦得知,EDG-2亦與腦之功能及痛覺有關(pr〇c. Natl. Acad. Sci. USA, 2000, 97, 13384;Nat. Med., 2004,
Jul,21(7) : 712)。 ’ 因此可知,LPA受體拮抗藥劑可用以預防及/或治療各 ^疾病,例如泌尿系疾病、癌症相關疾病、增殖性疾病、 ^症•免m疾病、分泌失調導致之疾病、腦關聯疾病 及/或慢性疾病等。 ::糸疾病之例可舉如前列腺肥大或神經性膀物 門隨之症狀如排尿困難(排尿開始之延遲、排尿日: 長、尿、線細小、斷續性排尿、排尿分段等)、頻尿、名 316588 8 200521108 間=、排尿痛等。同樣之其他泌尿系器官之症狀有因腦 血管損傷、帕金森氏症、腦瘤、多發性硬化症、㈣一㈣叶 氏症、脊髓瘤、腰椎間盤突出、脊柱狹窄、糖尿病等疾病 所引起之症狀(排尿困難(排尿開始之延遲、排尿時間延 長、展線細小、斷續性排尿、排尿分段等)、頻尿、夜間頻 水排尿痛等)。此外,此等疾病以外之泌尿系器官疾病, y例舉如下尿道疾病(例如下尿道梗塞之疾病等)、下尿道 =性疾病(如感染等)、間質性膀胱炎、頻尿等,此等疾病 被5忍為可由該LPA受體拮抗劑加以抑制。 〜癌症相關疾病可例舉如固形腫瘤、固形腫瘤轉移、血 以維瘤、骨髓瘤、多發性骨髓瘤、卡波特肉瘤、白血病 :吉=腫瘤之例可舉如乳癌、肺癌、胃癌、食道癌、結 2直知癌、大腸癌、肝癌1巢癌、㈣膜細胞瘤、印巢 =瘤典子宮頸癌、子宮内膜癌、前列腺癌、腎臟癌、皮 =、二、肉瘤、胰臟癌、尿道癌、甲狀腺癌、腦瘤等。其 %。之珍潤轉移亦被認為可受該LPA受體拮抗劑抑制。 u =性疾病可例舉如血管新生異常所伴隨之疾病(例 =再狹乍、糖尿病性眼網膜炎、血管新生性綠内障、曰# =.組織增生、甲狀腺宄進(含巴塞多氏病(突眼性甲二 肺纖維變性等。 一症)、動脈梗塞、 等)、炎性疾病可例舉如乾癖、腎病(例如腎病 等。 x症·免疫異常所導致之腎臟炎、肝炎、肺炎 316588 9 200521108 」泌失調可例舉如因自主神經系統異常所導致之分泌 失。周等,口自主神經乐統異常所導致之分泌失調可例舉如 斯耶格侖氏(Sjdgren)症候群等。 、、腦•神經關聯疾病可例舉如腦血管梗塞、腦溢血、腦 或神、工末梢失5周等。疼痛相關之神經性疾病可例舉如癌症 疼痛、慢性骨盤痛徵候群、痛覺過敏、碰觸痛(ai i〇de 等。 —慢性疾病可例舉如慢性氣喘、腎絲球體腎炎、肥胖、 前列腺肥大、慢性前列腺炎、因動脈硬化之發展產生之疾 病、風濕性關節炎及異位性皮膚炎、肝硬化、脂肪肝、慢 性下痢、慢性便秘等。 具有LPA受體括抗作用之化合物,已知者有如式⑻ 所不之化合物或其鹽(w〇〇1/6〇819號公報):
R
(B) [式中之R1B表示可有取代基之烧基、芳基、雜環基、烧 基、芳氧基、烷硫基、芳硫基、或鹵素 取代基之烧基、芳基、雜環基、嶋原子芳氧= 原子,R3B表示氫原子、低級烧基、或⑽基;r4B表 (a)可有取代基之苯基、芳基、或雜環基,⑻取代或益 代之燒基,及⑷取代或無取狀縣所成轉中之基、. 表示氧原子或硫原子;R4B亦可各與其鍵結之碳^ 316588 】0 200521108 共同形成5至10員環之構造;再者,在R3B為氮原子之場 合’ R4B為甲基以外之基]。 具有血管收縮素II(angiotensin)拮抗作用之化合 物,已知者有如式(c)所示之化合物或其鹽(參照日本專利 特開平4-235149號公報):
[式中,R表不無取代或可由鹵素或羥基取代之脂族炉 (C) 基表/ C〇、s〇2或-〇-_)-,其中絲之碳原Γ與式 、之氮原子鍵結;X2C表示無取代或可由經基、叛基、 私基、胍基、脂環式基或芳基取代之二價脂族煙基,或表 ::½月曰%烴基,且脂族烴基之碳原子亦可再與二價脂族 、生土交聯;R2G為可依期望®旨化或賴化之羧基、可取代或 無取代之胺基,可依期望_化之mum某、 ㈣基’可依期望鱗化之經基、s(0)mc_RC(其中之虬為;、 1或2’以氫或脂族烴基)、㈣基、無取代或N-取代之 基广2(其中之η。為2或3。),^表示二價脂 基胺石黃醒基且^及::坐基/編’一㈣ 衣A及Bc互為獨立,可取代或無取代]。 此外,已知如式(D)所示之化合物或其鹽: 316588 11 200521108 rd-gd^
V / tD (〇)
i式Λ’ΑΚβ表示可取代之脂族煙基或可有取代基之環基;G 合鍵或主鏈原子數為個之間隔分子;r表示 乂H2-或主鏈原子數為1 y(m ^ -Γ ^ 之門p八i τβ 可有取代基且含氳鍵接受基 曰 1刀子,j表不氮原子或碳原子; 族烴基或可有取代基之環美.KD * _ η又丁 Ρ 之月曰 nDT» # 衣I,K表不(1)結合鍵或(2)可盥
R %基之取代基、環DD或盥 D τ 次D之取代基共同形成環之主 :::數為1至8個之間隔分子;Q。表示⑴結合鍵或⑵ 可與:RD環基、1^環之取代其式门 為i至8個之間隔分子.二1^形成環之主鍵原子數 為έ士人絲十+ ,衣D為可再含取代基之環基;ld 再::二鏈原子數為1至8個之間隔分子;環^為可 之A p八:之^基,MD為結合鍵或主鍵原子數為1至8個 刀子;Z為酸性基;t。表示。或丨]對 抗活性(麥照W004/31 1 18.號公報)。 【發明内容】 目以PA受體(特別是狐_2受體)拮抗劑方面,迫切 々要開發的是口服吸收性優良 或治療泌尿系界官疾病;:二且可作為預防及/ 症· 疾病、癌症㈣疾病、增殖性疾病、炎 ’正•免疫糸疾病、分泌奂坰遑夕广+ ^ 以失5周¥致之疾病、腦關聯疾病及/ 4 k性疾病等之醫藥品。 316588 12 200521108 1本發明人等發現對LPA受體(特別是肋 杬作用之化合物,加以刻意研究之結果 ^具拮 所示之化合物可達成此目的,而完成本發;式⑴ 亦即本發明提供-種新賴化 有拮抗作用,因此可以作為夂種广广不對LPA受體具 ⑴所示之本發明化合物可作;:^之治療藥。例如如式 系器官疾病等之預防及/或=劑種對血壓無影響之泌尿 化合1 式本之 =^ :糊如高能力 即本發明為關於 或彼等之式x(i)所不之化合物、其之鹽、彼等之溶劑合物、 次彼寻之藥物前體··
OH
M-Z τ A及環β各自獨立,表示可有取代基之環基·,K Q及Μ各自獨办,生一 5 ^ 表不結合鍵或主鏈為原子數1至8之間 (I) 土-衣D及知"Ε各自獨立,表示可有取代基之環基;L· 合鍵或主鏈為原子數1至3個之間隔基;2表酸性基 七表整數〇或11。 13 316588 200521108 [2 ]如前項[1 ]之化合物,其中,式(I)所示之化合物為具光 學活性之如式(Ι-A)所示之化合物者;
[式中,/為/5 -配位,其他之記號表示與前項[1]中所記 載者相同之意義。] [3] 如前項[1]之化合物,其中,環a為可有取代基之苯環鲁 者; [4] 如前項[1]之化合物,其中,κ為可經取代之C1-4烯基 者; [5]如前項[1]之化合物,其中,環β為可有取代基之茚滿 環者; [6 ]如月ίι項[1 ]之化合物,其中,q為可經取代之伸甲基或 可經取代之伸乙基者;
(R1基表示可經取代之脂 唑基者; ,其中 ’ Ζ 為-C00H、-C0NHS02R1 基 族煙基或可有取代基之環基)或四 [9]如前項[1]之化合物,其中, t Μ—為可經 316588 14 200521108 取代之伸曱基、可經取代之伸乙基、可經取代之伸丙基或 可經取代之伸乙烯基者; [10 ]如前項[1 ]之化合物,其中,環A為可有取代基之笨 環;環B為可有取代基之茚滿環;環D為可有取代基之 苯環、可有取代基之吡唑環或可有取代基之吡咯環;
為可經取代之伸曱基、可經取代之伸乙 基、可經取代之伸丙基或可經取代之伸乙烯基,Z為 - C00H、-CONHSOzR1基(R1基表示與前項[8]中所記載者相同 之意義)或四唑基者; [11]如前項[1]之化合物,為選自(1){卜[(23,33)-2-(2,3- 二氫-1Η-茚-2-基甲基)一3 — (3, 5一二曱氧基一4—曱基苯基) -3-羥基丙基]-1Η-吼咯-3-基}乙酸、(2)(1 - {(2S)-2 -[(S)-(3, 5-二曱氧基一4-曱基苯基)(羥基)曱基]一5一噻吩 - 3-基戊基}-111 - 吼咯-3-基)乙酸、(3){1-[(2S,3S) - 2-(1,3-苯并二氧雜環戊烯—2一基甲基)一3一(3, 5-二曱氧基一 4-曱基笨基)-3-髮基丙基]一 iH-吼口各-3-基}乙酸、(4){1 一 [(2S,3S)-2-(2, 3-二氫-1H-萌-2-基曱基)-3- 經基一3- (3,4, 5-三曱氧基苯基)丙基]—1H一吼咯-3一基}乙酸、(5){卜 [(2S,3S)-3-(4-乙醯基-3, 5-二甲氧基苯基)一2一(2, 3-二氫 -1H-茚-2-基曱基)—3 —羥基丙基]一1H—吡咯一 3 一基丨乙酸、
基-3, 5-二甲氧基苯基)一3一羥基丙基]―丨η一吡咯一3一基}乙 316588 15 200521108 酸、(7)3- {1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基)-3- (3, 5-二甲氧基-4-曱基苯基)—3一羥基丙基]—1H一吼咯一3一基} 丙酸、(8)3-{1-[(2S,3S)-2-(2,3-二氫-111-茚-2-基曱基) - 3-羥基-3-(3, 4, 5-三曱氧基笨基)丙基;U H一吼咯一 3 —基} 丙酸、(9)3-{1 -[(2S,3S)-3-(4-乙醯基-3,5-二甲氧基苯 基)-2-(2, 3-二氫-1H-茚-2-基曱基)一3-羥基丙基]— 1H—(]比 咯-3-基}丙酸、(i〇)3 —U —[(2S,3s)-2 —(2,3 —二氫-1H 一茚 -2-基甲基)-3-(4-乙基-3, 5-二曱氧基笨基)一3-羥基丙基] - 1H-毗咯-3-基}丙酸、一(2,3 一二氫 -1H-印-2-基曱基)一3-(3, 5-二甲氧基—4-甲基苯基)一3一羥 基丙基]-1H-吼咯-3-基卜N-(甲基磺醯基)乙醯胺、〇2)[卜 [(2S,3S) - 2-(2, 3-二氫-1Η-茚-2-基曱基)—3-(3, 5 -二甲氧 基-4-甲基苯基)-3-羥基丙基]-4一(甲氧基羰基)— 1Η一吡咯 -3-基]乙酸、(13)Ν-(3-{1 -[(2S,3S)-2-(2,3-二氫-1Η-茚 -2-基甲基)-3-(3, 5-二甲氧基-4-甲基苯基)一3一羥基丙基] - 1H-吡咯-3-基}丙醯基)-2-曱基笨磺醯胺、(14)(2E) 一3一 {1-[(23,33)-2-(2,3-二氫-111-節-2-基甲基)一3-(3 5--甲氧基-4-甲基苯基)-3-羥基丙基]-1H—吡咯一3一基丨丙烯 酸、(15)2-{1 - [(2S,3S)-2 -(2,3-二氫一 1H 一茚一 基甲基) -3-(3, 5-二甲氧基-4-甲基苯基)-3-羥基丙基]—1H一吡咯 -3-基}-2-甲基丙酸、及(l6)(2E)-3-{1-[(2S,3S)〜2 -(2 3 - 二氫-1H-茚-2-基曱基)-3-(3, 5-二甲氧基一4—甲基笨基) -3-羥基丙基]-1H-吡咯-3-基卜2-甲基丙烯酸所成群中者; [12] —種醫藥組成物,係包含前項[丨]之如式(1)所表示之 316588 16 200521108 其中,LPA受體為edg-2 係泌尿系器官疾病、癌症 免疫系統疾病、分泌失調 化合物、其鹽、彼等之溶劑合物及彼等之藥物前體者; [13]如前項[12]之醫藥組成物,係LPA受體拮抗^者; [14 ]如前項[1 3 ]之醫藥組成物 者; [15]如前項[12]之醫藥組成物 相關疾病、增殖性疾病、炎症 =之疾病、腦Μ疾病及慢性疾病之肋及/或治療劑 ^ , Π6]-種預防及/或治療哺乳動物之由哪 =其特徵為將有效量之前述⑴中所表示之::: 物f等之溶劑合物或彼等之藥物前體投與至哺乳鸯 項⑴之如式⑴所表示之化合 專之 >谷劑合物或彼等之藥 胤戈彼 哪-2媒介之疾病之預^;;:^用迷,係用於製造由 ⑽-種醫藥,係由前St輸 其之鹽或彼等之溶劑合物π)所表不之化合物、 自⑽受體拮抗劑、αΐ封皮:之樂物前體與1種以上選 抑制劑及抗雄性激素劑 j、抗膽驗劑、5«~還原酶 式(I)中Λ 市劑所組合而成者。 中之核Λ及環β所 及環D及環Ε所表示之「广之彳有取代基之環基」 基」可舉如碳環或雜環。,玄石山,取代基之環基」中之「環 多環式碳環、螺鍵結严::之例子如⑶巧之單環或 C3-15之單環或多 二碳環或交聯多環式碳環等。 衣式石錢包含C3_15之單環或多環式碳 316588 】7 200521108 環,其之部份或全部飽和之碳 丁烷、環戊烷、環己烷、严 ^ 具之例子如環丙烷、環 烧、環十一碳燒、環十、環壬烧、環癸 環十五碳烷、環戊烯、環 \ —杈烷、裱十四碳烷、 稀、環己二稀、環庚二歸、=環庚稀:環辛稀、環戊二 戊搭烯、奠、全气芎、^ 衣二烯、苯、戊搭烯、全氫 四氫萘、全氫萘乙搭稀'、二氯萌滿、萘、二氫萘、 二萌、s-苯并H烯聯二苯、as-苯并 壬院、螺[“]癸统、螺[5.5]十二vM、螺[4.4] 二環[2. 2. 1]庚-2-烯 反、兀—糸[2· 2· 1]庚烷、 一環“r辛; 或夕裱方私碳環,例如菜、—— 早衣 其雜環之例子如含!至“六、印、奈、菲、蒽環等較佳。 中之雜原子之3至15員,自氧原子、氮原子及硫原子 環雜環或交聯之多式料、含螺鍵結之多 氮原子另^ °含1至5個選自氧原子、 亦勺、人』瓜、子中之雜原子之3至15員單環或多環式雜巧 3 °亥含至5個選自氧原子、氮原子及硫原子中之右隹 原子之3至丨q g留@上 τ 丁 f之# 和之雜严i 環式雜環、及其之全部或部份飽 〜ί、、例子如咄咯、咪唑、三唑、四唑、咄唑、 "啡、嘧啶、嗒啡、吖庚因、二吖庚因、呋1 !二因、噻吩、硫代吼喃、曝庚因、嗓唾、異噪唾、咦唾 :自心—唑、噁畊、噁二啡、噁吖庚因、噁」 大、Π巻—唑、噻啡、噻二啡、噻吖庚因、噻二吖庚因 316588 18 200521108 吲哚、異吲哚、吲哚哄、苯并呋喃、異苯并呋喃、苯并噻 吩、異苯并噻吩、二硫雜萘、D引嗤、喹啉、異嗤啉、喹哄、 σ票吟、S太哄、嗓咬、瞭°定(haphthyr idine)、喹喔啉、喹唾 啉、噌啉、苯并噁唑、苯并噻唑、苯并咪唑、色烯、苯并 噁庚因、苯并噁庚因、苯并噁吖庚因、苯并噁二吖庚因、 苯并噻庚因、苯并噻吖庚因、苯并噻二吖庚因、苯并吖庚 因、苯并二吖庚因、苯并咲咱、苯并噻二唑、苯并三唑、 昨σ坐、/5 -昨啉、卩丫唆、啡哄(phenazine)、二苯并咲喃、 咕噸、二苯并噻吩、啡噻畊、啡噁畊、啡噁噻 (phenoxathine)、噻蒽、啡咬、啡啉、口巨^(perimidine)、 口丫丙咬、口丫 丁 σ定、吼口各啉、D比口各咬、口米σ坐琳、味°坐σ定、三 口坐啉、三口坐口定、四口坐啉、四口坐口定、D比口坐啉、二氫D比口定、四 氫吡啶、哌啶、二氫吡畊、四氫吡畊、哌畊、二氫嘧啶、 四氫嘧啶、全氫嘧啶、二氫嗒畊、四氫嗒畊、全氫嗒畊、 二氫吖庚因、四氫吖庚因、全氫吖庚因、二氫二吖庚因、 四氫二吖庚因、全氫二吖庚因、環氧乙烷(氧雜環丙烷)、 氧雜環丁烧、二氫咲喃、四氫咲鳴、二氫吼喃、四氮吼喃、 二氫噁庚因、四氫噁庚因、全氫噁庚因、環硫乙烷(硫雜環 丙烷)、硫雜環丁烷、二氫噻吩、四氫噻吩、二氫硫代吡喃、 四氫硫代吡喃、二氫噻庚因、四氫噻庚因、全氫噻庚因、 二氫噁唑、四氫噁唑(噁唑啶)、二氫異噁唑、四氫異噁唑(異 噁唑啶)、二氫噻唑、四氫噻唑(噻唑咬)、二氫咲咱、四氫 咲咱、二氫噁二唑、四氫噁二唑(噁二唑啶)、二氫噁畊、 四氫噁哄、二氫噁二畊、四氫噁二哄、二氫噁吖庚因、四 19 316588 200521108 氫噁吖庚因、全氫噁吖庚因、二氫噁二吖庚因、四氫噁二 D丫庚因、全氫噁二D丫庚因、二氫噻二唾、四氫噻二嗤(噻二 唑啶)、二氫噻哄、四氫噻哄、二氫噻二啡、四氫噻二啡、 二氫噻吖庚因、四氫噻吖庚因、全氫噻吖庚因、二氫噻二 吖庚因、四氫噻二吖庚因、全氫噻二吖庚因、嗎啉、硫代 嗎啉、氧雜硫代D比喃(oxathiane)、D引D朵啉、異D引D朵啉、二 氫苯并D夫喃、全氫苯并咲喃、二氫異苯并D夫喃、全氫異苯 并呋喃、二氫苯并噻吩、全氫苯并噻吩、二氫異苯并噻吩、 全氫異苯并噻吩、二氫吲唑、全氫吲唑、二氫喹啉、四氫 喹啉、全氫喹琳、二氫異喹啉、四氫異喹啉、全氫異喹啉、 二氫酞哄、四氫酞哄、全氫酞哄、二氫嘹啶、四氫嘹啶、 全氫嘹啶、二氫喹喔啉、四氫喹喔啉、全氫喹喔啉、二氫 喹ϋ坐啉、四氫喹哇啉、全氫嘆哇啉、二氫σ曾啉、四氫σ曾啉、 全氫噌啉、苯并氧雜吡喃、二氫苯并噁哄、二氫苯并噻畊、 吡畊并嗎啉、二氫苯并噁唑、全氫苯并噁唑、二氫苯并噻 唑、全氫苯并噻唑、二氫苯并咪唑、全氫苯并咪唑、二氫 本弁庚因、四風苯弁庚因、二氮苯弁二庚因、四氮 苯并二吖庚因、苯并二噁庚因、二氫苯并噁吖庚因、四氫 苯并°惡D丫庚因、二氫β卡哇、四氫昨°坐、全氫昨嗤、二氫D丫 啶、四氫吖啶、全氫吖啶、二氫二苯并D夫喃、二氫二苯并 噻吩、四氫二苯并呋喃、四氫二苯并噻吩、全氫二苯并呋 喃、全氫二苯并噻吩、二氧雜環戊烷(di0X0lane)、二噁烧 (二氧雜環己烧,d i oxane)、二硫雜環戊炫、二噻烧(二硫 雜環己烷,dithiane)、二噁茚滿、苯并二噁烷、色滿、苯 20 316588 200521108 并二硫雜環戊烷、苯 王坚m版 嗤乂兀衣寻。含螺鍵έ士之容严斗 衣可例舉如氮雜螺[44]壬烷、氮雜 、口夕衣式雜 [5.5]十一碳烧淨笼^ · 5 ]癸垸、氮雜釋
[2 2 η床父聯之多環式雜環可例舉如氮雜。 I2.2.1]庚燒、氮雜二錄1.軸、氮雜-每 辛炫、氮雜二環f2.22]辛貌環等。其中 =3.2.1J ,子、氮原子及硫原子中之雜原子之3至二:氧 式芳族雜環可例舉如㈣、味唾、 、早衣或夕環 啶、Off D#、忒A —丄四唾、吡唑、咄 疋比哄、口治口疋、口荅哄、咲鳴、_吩、 比 唑、異噻唑、呋咱…亞二 心 兴噁唑、噻 -" 羞—唑、吲哚、異吲晬、芏< 开咲喃、異苯并呋喃、贫丑金 W木本 S妝社 开土 %、異苯并噻吩、吲唑、眩 啉、異喹啉、噪呤、耿啡 - 過·、贫说6 , 嗤喔啉、喹。坐啉、 曰啉、本开噁唑、苯并噻唑、苯 仰 噻二唑、策# - λ1λ此 本开陕咱、苯并 : 开二唑、咔唑、万-咔啉、吖啶、啡啡、二笼其 呋喃、二苯并噻吩、啡啶、啡啉、呕啶環等 所表示之「可有取抑其々卢苴^ 衣Α及% Β 有取代基之%基」及環D及環E所表示之 ^有取代基之環基」中之「取代基」可舉如(a)可取代之烷 基、⑻可取代之烯基、(c)可取代之炔基、⑷可有取代基 之碳環基、(e)可有取代基之雜環基、⑴可經取代之經基、 (g)可經取代之巯基、(h)可經取代之胺基、(丨)可經取代之 胺基曱醯基、⑴可經取代之胺石黃酿基、⑴緩基、⑴烧氧 基羰基(例如甲氧基羰基、乙氧基羰基、第三—丁氧基羰基 等C卜6烧氧基幾基等)、(m)石黃酸基—⑻士)亞石备酸基 (sulfmo)、(0)膦酸基、(p)确基、(q)_基、(〇硫酮基、 (S)氰基、(t)脒基、(1〇亞胺基、(v)二羥哪基卜b(〇h)2)、 316588 21 200521108 (w)齒素原子(氟、氯、溴、碘)、(X)烷基亞磺醯基(例如甲 基亞%酿基、乙基亞磺醯基等C1-6烷基亞磺醯基等)、(y) 芳基亞續酿基(例如苯基亞磺醯基等C6-10芳基亞磺醯基 等)(z):^基磺醯基(例如甲基磺醯基、乙基磺醯基等 烷基磺醯基等)、(aa)芳基磺醯基(例如苯基磺醯基等 C6 1 0芳基石只基等)、(bb)醯基(例如甲醯基、乙醯基、 丙醯基、三甲基乙醯基等cl-6烷醯基,或例如苯甲醯基等 C6 10芳基%基等)等。此等取代基之任一者可在可取代之 位置上取代1至5個。取代基之「可取代之烷基」中之「烷 基」可例舉如甲基、乙基、丙基、異丙基、丁基、異丁基、 第一丁基、第二-丁基、戊基、異戊基、新戊基、己基、 庚基、辛基、壬基、癸基等直鏈或分支鏈C6 —1〇烷基等。 其中烷基之取代基之例可舉如羥基、胺基、羧基、硝基、 皁或二C6-10烷基胺基(例如甲基胺基、乙基胺基、丙基胺 基、二甲基胺基、二乙基胺基等)、cl—6烷氧基(例如甲氧 基、乙氧基、丙氧基、己氧基等)、cl — 6烷基羰基氧基(例 如乙醯氧基、乙基羰基氧基等)、碳環(與前述「可有取代 基之環基」中之「環基」表示之碳環相同之意義)、雜環(鱼 前述「可有取代基之環基」中之「環基」中表示之雜環相 同之意義)、自素原子(氟、氯、溴、碘)等。此等可在任咅 1至4個可取代取代基之位置上取代。取代基中之「可^ 代之稀基」中之「稀基」之例可舉如乙稀基、丙稀基、丁 烯基、丁二烯基、戊烯基、戊二烯基、己烯基、己二烯基、 庚稀基ϋ基、辛烯基、辛二烯基、壬缚基、壬^ 316588 200521108 基、癸烯基、癸二烯基等直鏈或分支鏈C2 — 10烯基等。其 中烯基之取代基與前述「可取代之烷基」中之取代基表示 相同之意義。取代基之「可取代之炔基」中之r炔基」可 例舉如乙快基、丙块基、丁快基、丁二快基、戊炔基、戊 二炔基、己炔基、己二炔基、庚炔基、庚二炔基、辛炔基、 辛二炔基、壬炔基、壬二炔基、癸炔基、癸二炔基等直鏈 或分支鏈C2-10炔基等。其中炔基之取代基與前述「可取 代之烧基」中之取代基表示相同之意義。取代基之「可有 取代基之碳環基」中之碳環與前述「可有取代基之環基」 中「環基」中之石厌環表示相同之意義。其中碳環之取代基 可例舉如直鏈或分支鏈C1-10烷基(與前述「可取代之烧 基」中之烷基表示相同之意義)、直鏈或分支鏈C2 —10烯基 (與前述「可取代之烯基」中之烯基表示相同之意義)、直 鏈或分支鏈C2-10炔基(與前述「可取代之炔基」中之炔基 表示相同之意義)、羥基、C1-6烷氧基(例如曱氧基、乙氧 基、丙氧基、異丙氧基、丁氧基、異丁氧基、第三—丁氧基、 戊氧基、己氧基等)、巯基、C1 — 6烷硫基(例如曱硫基、乙 硫基、丙硫基、異丙硫基、丁硫基、異丁硫氧基、第三一 丁硫基、戊硫基、己硫基等)、胺基、單或雙π — 6烷基胺 基(例如曱基胺基、乙基胺基、丙基胺基、異丙基胺基、丁 基胺基、異丁基胺基、第三—丁基胺基、戊基胺基、己基胺 基、二甲基胺基、二乙基胺基、二丙基胺基、N一甲基一N一 乙基胺基等)、鹵素原子(表示與前述相同之意義)、氰基、 頌基、三氟甲基、三氟曱氧基等,此等任意之取代基可在 316588 23 200521108 1至5個可取代位置上取代。取代基之「可有取代基之雜 環基」中之雜環與前述「可有取代基之環基」中「環基」 中之雜環表示相同之意義。其中雜環之取代基與前述「可 有取代基之碳環基」中之取代基表示相同之意義。取代基 之「可取代之羥基」、「可取代之巯基」及「可取代之胺基」 中之「取代基」可例舉如(〇可取代之烷基(表示與前述相 同之意義)、(ii)可取代之烯基(表示與前述相同之意義)、 (iii)可取代之炔基(表示與前述相同之意義)、(iv)可有取 代基之碳環基(表示與前述相同之意義)、(v)可有取代基之 雜環基(表示與前述相同之意義)、(vi)醯基(例如曱醯基、 乙醯基、丙醯基、三曱基乙醯基、丁醯基、戊醯基、己醯 土專C1 6烧g迪基或其異構物基,例如苯甲酿基等c 6 一 1 〇 方族碳環羰基等)、(vi i)可取代之胺基曱醯基(表示與後述 者相同之思義)、(v i i丨)烧基石黃醯基(例如甲基石黃驢基、乙 基石^ 基寺C1—6烷基磺醯基等)、(ix)芳基磺醯基(例如苯 基磺醯基等C6 — 1〇芳基磺醯基等)等。取代基之「可取代之 ,基甲fc基」可例舉如無取代之胺基甲醯基、N—單一^ 一 6 k基胺基曱酸基(例如^基胺基甲醯基、N—乙基胺美曱 月女基甲fc基、異丁基胺基甲舻美 萨A、m * 妝&甲1基N-U二—丁基)胺基f I基、N-戊基胺基甲醯基 脸其田# 土1N 妝基甲騃基等)、N-苯基 月女基甲fe基等N一單一C6 —1〇 Λ ^ m iU方基月女基甲fe基、N,N-二C1-6
烷基基甲醯基(例如N 基胺基甲醒基、NN—兩其::甲/月女基甲酿基、N,N-二乙 ,—丙基版基f醯基、N,N-二丁基胺基 316588 24 200521108 曱醯基、N,N-二戊基胺基曱醯基、n,N-二己基胺基甲醯基、 N-甲基-N-乙基胺基甲醯基等)、N,N-二苯基胺基甲醯基等 N-二-C6-10芳基胺基甲醯基、n-C6-10芳基N-C1-6烷基胺 基甲酿基(例如N-苯基-N-甲基胺基甲醯基、N-苯基-N-乙 基胺基甲醯基、N-苯基-N-丙基胺基甲醯基、N-苯基-N-丁 基胺基甲醯基、N-苯基-N-戊基胺基甲醯基、N-苯基-N-己 基胺基甲醯基等)等。取代基之「可取代之胺磺醯基」可例 舉如無取代之胺磺醯基、N—單—cl — 6烷基胺磺醯基(例如N— 甲基胺磺醯基、N-乙基胺磺醯基、N-丙基胺磺醯基、N一異 丙基胺磺醯基、N-丁基胺磺醯基、N_異丁基胺磺醯基、N— (第二-丁基)胺磺醯基、N—戊基胺磺醯基、N—己基胺磺醯基 等)、I苯基胺磺醯基等N—單—⑶―1〇芳基胺磺醯基、N,^ —Cl-6烷基胺磺醯基(例如N,N—二甲基胺磺醯基、n,n一二 乙基胺磺醯基、N,N—二丙基胺磺醯基、N,N-二丁基胺磺^ 基、n,n-二戊基胺·磺醯基、N,N—二己基胺磺醯基、n—曱美 i-乙基胺磺醯基等)、N,N—二苯基胺磺醯基等n—二—⑶一^ 芳基胺賴基、N-C6_1G芳基_Ν_Π_6@基胺伽基(例如 ^苯基I甲基胺雜基、NnN_乙基胺包基、N—苯 基-N-丙基胺磺醯基、.笨基—Ν_τ基胺磺醯基、n—苯基一n— 戊基胺磺醯基、Ν-苯基_Ν_己基胺磺醯基等)等。土 K、Q及Μ所表示之「主鏈為κ+赵] 意指i至8個原子連結而成m。其+ 原子最少之數。「主鏈為原子數1至 ^基」可例舉如可有取代基之C1_8伸烧基(例 316588 25 200521108 伸乙基、三伸T基、四伸甲基、五伸、六伸甲基、七 伸甲基、八伸甲基等)、可有取代基之伸C2_8婦基(例如伸 乙烯基、伸丙稀基、伸丁稀基、伸丁二稀基、伸戍稀基、 伸戊二烯基、伸己烯基、伸己二稀基、伸庚烯基、伸庚二 烯基、伸辛烯基、伸辛二烯基等)、可有取代基之伸 炔基(例如伸乙炔基、伸丙炔基、伸丁炔基、伸丁二炔基、 伸戊诀基、伸戊二快基、伸己快基、伸己二块基、伸庚土块 基、伸庚二炔基、伸辛炔基、伸辛二炔基等)等。其中m 伸烷基、伸C2-8烯基及伸C2_8炔基之碳原子亦可由氧原 子、可氧化之硫原子(S、so、s〇2)或可取代之氮原子[其中 之取代基可舉如(1)可取代之烷基(表示與前述者相同之意 我)、(11)可取代之碳環基(表示與前述者相同之意義)、 (111)可取代之雜環基(表示與前述者相同之意義)、(iv) 醯基(表示與前述者相同之意義)等。]取代。其中之「可有 取代基之Π-8伸烧基」、「可有取代基之C2_^婦基」及 「可有取代基之C2-8伸块基」中之「取代基」可舉如可經 -取代之烷基(表示與前述者相同之意義)、鹵素原子(氟、 氯、溴、碘)、可經取代之羥基(表示與前述者相同之意義)、 可經取代之胺基(表示與前述者相同之意義)、酮基、可經 取代之亞胺基(例如C1-6烷基亞胺基、羥基亞胺基、ci_6 烷氧基亞胺基、C1-6氰基亞胺基等)等,此等取代基之任 —者可在可取代之位置上取代1至3個。 L所表示之「主鏈為原子數^之間隔基」意指i至3 個原子連結而成之間隔基。其中之「主鏈之原子數」指主 316588 26 200521108 (CH2)3-等)、_〇_、_s_、_s〇_、_s〇2_、_Nr2 鍵上原子最少之數。L所表示之「主鏈為原子數丄至3之 間隔基」可例舉如可有取代基之C卜3伸烧基(例如_CH卜 -CONR4- > -NR2C〇- > -S〇2NR2 •mr2s〇2-、-mr2conr3-[基中 之R及R各為獨立之氫原子、可經取代之脂族烴基或可有 取代基之環基(表示與前述者相同之意義)。其中之「可經 取代之脂族烴基」中之「脂族烴基」可例舉如「直鏈或: 刀支月日知經基」,「直鍵或分支脂族煙基」可例舉如「直 或分支烧基、烯基或块基」。「直鍵或分支烧基」之例如甲 基、乙基、丙基、異丙基、丁基、異丁基、第二—丁基、第 一-丁基、戊基、異戊基、新戊基、己基、庚基、辛美、 ί例:f寻直鏈或分支CH°烷基等。「直鏈或分支烯基」 子如乙《、丙烯基、丁烯基、丁二烯基、戊稀基、 ί — ^基::己稀基、己二烯基、庚稀基、庚二稀基、辛稀 土、辛一烯基、壬烯基、壬二烯基、癸烯基、癸二烯基 f鏈或分支C2-1。烯基等。「直鏈或分支炔基」之例如:炔 基、丙块基、丁块基、丁二块基、戊块基、戍二块基、己 块基、己二缺基、庚絲、庚二块基、辛块基、辛二块美、 壬炔基、壬二炔基、癸炔基、癸二炔基等直鏈或分支二 =基等。「可經取代之脂族烴基」尹之「取代基」表示盘前 =可有取代基之環基」令之「取代基」相同之等。 其令之㈣傾基之取代基之例如μ原子(m 扑經基、胺基、《等,此等取代基之任—者可在取 代之位置上取代1至3個。 3Ί6588 27 200521108 z所表不之「可受保護之酸性基」可例舉如含-c〇〇RT、 -S〇2〇R、—S〇2RT、—NRTSC^OR1、-P〇(〇H)2、一PCKOR^OR1)、 -CONR R、-CONRTsOzOR1、-CONRTSOzR1、-CONRTS〇2NR4R5、 -C0NRT0R1、-CONNRTR4、—CONRTS〇2Rl、—conrts〇2NR4R5(基中 之RT表示氫原子、可經取代之脂族烴基或可有取代基之環 基(表不與丽述者相同之意義);R1表示可經取代之脂族烴 基或可有取代基之環基;R4與R5各為獨立,表示氫原子、 可經取代之脂族烴基或可有取代基之環基(表示與前述者 相同之意義))、-C0NR"CR12R13C00R1T(基中-NRnCR12R13C0-表 不胺基酸殘基,例如甘胺酸、丙胺酸、纈草胺酸、白胺酸、 異白胺酸、麩胺酸、麩醯胺、天冬胺酸、天冬醯胺、離胺 酸、精胺酸、組胺酸、路胺酸、絲胺酸、曱硫胺酸、半胱 月女酸、脯胺酸、蘇胺酸、色胺酸、苯丙胺酸)、可有取代基 之盼(-C6H4〇H)或可有取代基且含有可脫質子化氫原子之 έ氣環以基專各種布朗斯台德酸(Bronzed acid)等。 Z所表示之「可受保護之酸性基」中之「酸性基」可 例舉如含-C00H、-S〇2〇H、-S〇2H、-NHS020R1、-Ρ0(0Η)2、 -Ρ0(0Η)(0Ι〇、-CONHR4、-CONHSO2OR1、-CONHSO2R1、 -CONHS〇2NR4R5、-C0NH0R1、-CONNHR4、-C0NHS02R1、 -CONHS〇2NR4R5 (基中之各記號表示與前述者相同之意義)、 可有取代基之酚(-C6H4〇H)或含可脫質子化氫原子之含氮 環殘基等各種布朗斯台德酸等。 「布朗斯台德酸」表示可給予其他物質氫離子之物 質。「含可脫質子化氩原子之含氮環殘基」可舉如 28 316588 200521108
r美2中Γ非特別指明’均包含此等之異構物。例」 燒氧基、烧硫基,基、伸締基 伸诀基寻亦包括直鏈者或分支鏈者。同時,雙鍵、产 合環中之異構物(Ε、Ζ、順、反显槿 "1 原早笙而本a田 反兴構物)、因存在不對稱石」 :子寺而產生之兴構物(R、S異構物、α —、“己位、對 映異構物、㈣映異懸)、具有旋紐之光學活性體(d 、d、:1異構物)、藉由層析分離之極性異構物(高極性里 構物、低極性異構物)、平衡化合物、旋轉異構物、及此^ 之任意比例之混合物、消旋混合物均包含於本發明中。 本發明中除非特別指明,如一 I業者所知^記號/、名 不鍵結於紙面對側(即配置),/表示鍵結於紙面側(印 万-配置),/表示α-配置與石-配置之任意比例之混合 物0 之 式(I)所表示化合物之鹽包括全部其藥理上容許 316588 29 200521108 鹽。其藥理上容許之鹽以毒性低、水溶性優良者為佳。其 適宜之鹽可舉如驗金屬(斜、納、鐘等)之鹽、驗土金屬(妈、 鎂等)之鹽、銨鹽(四曱基銨鹽、四丁基銨鹽等)、有機胺鹽 (三乙基胺、甲基胺、二曱基胺、環戍基胺、苯曱基胺、苯 乙基胺、哌啶、單乙醇胺、二乙醇胺、參(羥基曱基)曱基 胺、離胺酸、精胺酸、N-曱基-D-葡糖胺等)之鹽、酸加成 物鹽[無機酸鹽(鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、 磷酸鹽、硝酸鹽等)、有機酸鹽(乙酸鹽、三氟乙酸鹽、乳 酸鹽、酒石酸鹽、草酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、 苯曱酸鹽、檸檬酸鹽、曱磺酸鹽、乙.續酸鹽、苯磺酸鹽、 曱苯磺酸鹽、羥乙磺酸鹽、葡糖醛酸鹽、葡糖酸鹽等)等]。 本發明化合物之鹽亦包括溶劑合物、或上述本發明化合物 之驗(土)金屬鹽、敍鹽、有機胺鹽、酸加成物鹽之溶劑合 物。溶劑合物以無毒性且水溶性者為佳。適當之溶劑合物 可舉如水、醇類溶劑(乙醇等)等之溶劑合物。本發明之化 合物可再以一般所知之方法轉換為其藥理上容許之鹽。 鹽又包括四級銨鹽。四級銨鹽表示式(I)所表示之化合 物之氮原子經R°基四級化之物。 表示由C1-8烷基、苯基取代之C1-8烷基。 本發明之化合物可以以任意之方法製成其N-氧化 物。N-氧化物表示式(I)所表示之化合物之氮原子經氧化之 物。 式(I)之藥物前體指在體内可由酵素或胃酸等反應轉 換為式(I)之化合物。式(I)之藥物前體在式(I)中含胺基之 30 316588 200521108 場合,例如其胺基被醒基[烧基化、碌酸化之化合物(例 如式⑴之胺基被二十碳㈣化、α_胺基㈣基化、庚基 胺基獄基化、("基_2,基二氧雜環戊稀+基) 甲氧基幾基化、四氫咲喃基化、批嘻唆基甲基化、三甲基 乙:f基氧基甲基化、乙醯氧基甲基化、第三丁基化之化: 物寻),式⑴中含經基之場合,例如經基被酿基化、烧基 :匕、她、職匕之化合物(例如式⑴之經基被乙酿基 =十六碳㈣基化、丙縣化、三甲基乙醒基化、㈣ =、反丁烯二醯基化、丙胺醯基化、二甲基胺基甲基 叛土化之化合物等);式⑴中含絲之場合,例如 =化、酿胺化之化合物(例如式⑴之絲被 甲广化、乙氧基幾氧基乙醋化、駄醋化、(5—甲 ==氧雜環戊稀+基)㈣化、環己氧縣乙酉旨化、甲 二〜化合物寻)等。此等化合物可以以其本 二二製成:式⑴之藥物前體亦可為任意水合物或::: 戚 W樂物前體亦可以如廣川書们990年發行之「二 市之開發」第7卷分子設計中第163 西 ,件下轉換為式⑴。式⑴所表示之^ 同位蝴如^、、,謂加以標識:物亦可以 環式2)、中可可含取代基之C3~15單環或多 及硫原子中之_子之 自^原子、i原子 是例如可含取代基之1 κ。。 或夕環式雜環,更好 土 ^3-15早裱或多環式芳族碳環、可含 316588 31 200521108 含1至5個選自氧原子、氮原子及硫原子中之雜 原子之3至1 5員單環哎多^ 之不隹 讦人百飞夕衣式方族雜環等,特別好是例如 可έ取代基之C5-6單環芳祐石山芦 ^ f方知蛱裱、可含取代基且含1至5 個廷自氧原子、氮原子及硫原子至5 芳族雜環等,最好是例 '、 貝早裱 之叫可含取代基之基:,、可含取代基 例如可經取代之坑基、可含二;取,好為 之雜環基、可含取代基之録==可含取代基 之胺基、可經取代之坡心基、可經取代 烷基磺醯基、醯基等,更好π 土 β素原子、 甘也#〜 更好疋例如可經取代之烷基、可含 :之經基、齒素原子、醯基等’最好是例 ;、=、氯原子、甲氧基、乙氧基、二氟甲氧基、; ,三氣甲氧基、甲基續酿基、乙酿基胺基、甲 基、1:,"基乙基、卜丙烯基、氰基等甲 ::之#纟可在可取代之位置上取代1至5個, 以媒取代或由1至3個取代為較佳。 取代itfr如主鏈為原子數1至8之間隔基(例如可有 =之CH伸焼基或可有取代基之㈣伸嫦基等 有:::結二鍵、主鏈為原子數1至4個之間隔基(例如可 a 土之C1_4伸统基、可有取代基之C2-4伸稀基等) 寻=別好是例如伸甲基、伸乙基、伸丙基、伸丁基、伸 乙~基、伸㈣基等’其中之碳原子亦可由氧原子 化之硫原子(SH)或可經取代之氮原子取代,較= 之例是氧原子、可氧化之硫原子(s、s〇、s〇2)等,更好之 316588 32 200521108 3氧::或硫原子。"之取代基較好為例如可取代之 二土:”原子、可取代之羥基、,基等,更好是例如甲 =既原子、絲、酮基。此等取代基之任-者可在可取 奸^上取代1至3個,以無取代或由1至2個取代為 二土寸別好是例如無取代之伸甲基、伸乙基、伸丙基、 伸丁基、—(CH2)2〜〇-基等。 % B較好為例如可有取代基且可部份飽和之㈡ ΓΛ環式芳族碳環、可有取代基且含…個選自氧原 及硫原子中之雜原子之3至15員可部份飽和之 ^或A式雜料,例如可有取代基之苯環、可有取代 :之喻吩環、可有取代基之萌滿環、可有取代基之U—苯 乳雜%戍烯環、可有取代基之苯并D夫喃環、可有取代 ^壞錢環、可有取代基之環己妓、可有取代基之環 庚,環、可有取代基之雙環[4. 3]環壬燒環、可有取代基之 -虱_環等。環B之取代基較好為可經取代之烧基、可 =代之碳環基、可經取代之㈣、硝基、㈣原子、嗣 土寻,更好是例如可取代之烧基、函素原子等,最好是甲 基:乙基、丙基、氟原子、氯原子、甲氧基、乙氧基等。 此寺取代基之任-個可在可取代之位置上取代^至5個, 以無取代或由1至2個取代為較佳。 Q較好為主鏈為原子數!至δ之間隔基(例如可有取代 基之C1-8伸烷基或可有取代基之〇_8伸烯基等),更好是 例如主鏈為原子數1至4個之間隔基(例如可有取代基之 C1-4伸烧基、可有取代基之以―4伸稀基等)等,特別好是 316588 33 200521108 例如主鏈為原子數1至2個之間隔基(例如可有取代基之 C1 2伸1基等)。纟具體例可舉如可經取代之伸甲基、可 經取代之伸乙基等,其中之碳原子亦可由氧原子、可氧化 之石爪原子(S、so、S0O或可經取代之氮原子取代。Q㈣ 如伸甲基、伸乙基、-〇 —基、—CH2-〇—等為較佳。 m環D較好為例如可有取代基之C3-15單環或多環式碳 %可有取代基且含!至5個選自氧原子、氮原子及硫原 子中之雜原子之3至1 5員單環或多環式雜環等,更好是例 如可有取代基之C3-15之單環或多環式芳族碳環、可有取 代基之含1至5個選自氧原子、氮原子及硫原子中之雜原 子之3至1 5員單環或多環式芳族雜環等,特別好是例如可 有取代基之苯、可有取代基之吡咯、可有取代基之咪唑、 可有取代基之吡唑、可有取代基之噁唑、可有取代基之嚷 生可有取代基之D泰吩、可有取代基之d引D朵、可有取代基 之二唑、可有取代基之四唑、可有取代基之哌啶、可有取 代基之吼略啶環等。最好是可有取代基之苯、吡咯或吡唑 環專。環D之取代基較好為例如可取代之烧基、可取代之 赵基、緩基、烧氧基幾基、齒素原子、酮基、胺基幾基、 N,N-一烧基胺基裁基、n —烧基胺基幾基、酿基等,更好是 例如可經取代之烷基、函素原子等,最好是曱基、氟原子、 氣原子、曱氧基数基、乙氧基叛基、胺基I炭基、N一曱基胺 基羰基、N,N-二曱基胺基羰基、乙醯基等。此等取代基之 任一者可在可取代之位置上取代1至5個,以無取代或由 1個取代為較佳。 34 316588 200521108 L較好為例如結合鍵、秦、_〇_、_s_、s 或-NH-等,更好是例如結合鍵、_〇_、—s_。 S〇2— 環E較好為例如可有取代基之⑶i5之單環 石反環、可有取代基且含丨至5 / 衣式 或硫原子令之㈣子之3至二平飞原子、氮原子及/ 虹” 至15貝單環或多環式雜環等,更 二:例如可有取代基之㈣之單環或多環式芳族碳環更 二:::基…至5個選自氧原子、氮原子及 =原:之3至丨5員單環或多環式芳族雜環等 Γ::!Γ基之C5—6單環芳族碳環、可有取代基且二 一 自乳原子、氮原子及硫原子中之雜原子之5至6 貝早環芳㈣料’最好是例如可有取代基之苯環等。環 ^取代基較好為例如可取代之烧基、可經 / =Γ此更,是例如甲基、氯原子、氟原子、甲: 乙乳基寻。此寻取代基之任一者可在可取代之位置上取代 5個,以無取代或由1個取代為較佳。 t以0或1為較佳。 =好為例如結合鍵、可含取代基之㈣伸烧基或可 基之伸縣等,更好是例如結合鍵、主鍵為原 至4個之間隔基(例如可有取代基之CH伸垸基、 2取代基之G2-4伸縣等),特別好是例如結合鍵、伸 土申乙基伸丙基、伸乙稀基等,Μ中之取代基較好 ’、’、歹’口可經取代之炫基,更好是例如甲基。此等取代基之 可在可取代之位置上取代1至3個,以無取代或由 個取代為較佳。Μ特別好是例如結合鍵、伸甲基、伸 316588 35 200521108 乙基、伸乙細基或二曱基伸甲基等
較好為可經取代之伸甲基、可經取 代之伸乙基、可經取代之伸丙基或可經取代之伸乙烯基。 Z車乂好是例如—C00H、-CONHSOzR1、四唑基等。-CONHS〇2R】 二:所3之R較好是例如可經取代之Cl -8烷基、可含取 代基之碳環基、可含取代基之雜環基等。 (I-A) 以具光學活性之式 [式中 或式(I〜B) 化孥式(I)所表示之化合物中,
Μ—Z ,口。己唬表不與前述者相同之意義] (I-A)
〇H
3*6588 36 200521108 更佳。 本發明中具光學活性之式(I—A)所表示之化合物,不只 可為純粹100%者,亦包含式(I—A)所表示之化合物超過50〇/〇 者。具光學活性之式(I-B)所表示之化合物,亦不只可為純 10(U者,亦包含式(I—β)所表示之化合物超過者。 化學式(I)所表示之化合物中,較佳之化合物可舉如 (Ι-Α-1)所表示之化合物: 工 ΟΗ
COOH [式中之各記號表示與前述者相同之意義] 或如式(Ι-Α-2)所表示之化合物: (Ι-Α-1) ΟΗ
[式中之各記號表示與前述者相音 或如式(Η,所表示之化合物,我] 3】6588 37 200521108
OH
(Ι-Α-3)
[式中之各記號表示與前述者相同之意義], 或如式(I-A-4)所表示之化合物:
[式中之各記號表示與前述者相同之意義], 或如式(I-A-5)所表示之化合物:
[式中之各記號表示與前述者相同之意義], 或如式(I-A-6)所表不之化合物: 38 316588 200521108
OH
(I-A-6)
[式中之各記號表示與前述者相同之意義] 或如式(I-A-7)所表不之化合物: OH
(I-A-7)
[式中之各記號表示與前述者相同之意義] 或如式(I-A-8)所表不之化合物·· OH
(I-A-8)
[式中之各記號表示與前述者相同之意義] 或如式(I_ A - 9)所表不之化合物· OH
(I-A-9) [式中之各記號表示與前述者相同之意義] 或如式(I-A-10)所表示之化合物: 39 316588 200521108
〇H
(Ι-Α-10) [式中之各記號表示與前述者相同之意義], 或如式(I-A-10-1)所表示之化合物:
、 ϋ…i双不興前迷者相同之: 或如式(Ι-Α-10-2)所表示之化合物: ΟΗ
[式 ’、ch2C00H 或 、α圯號表示與前述者相同之意義], 一 式(I〜Α-Π-1)所表示之化合物: 316588 40 200521108
OH
[式中之各記號表示與前述者相同之意義], 或如式(I-A-1卜2)所表示之化合物:
OH
[式中之各記號表示與前述者相同之意義], 或如式(I-A-12)所表示之化合物:
OH
[气中之各記號表示與前述者相同之意義] 或如式(I-A-13-1)所表示之化合物:
COOH 0-A-12) [式中夕 . ^ Q記號表示與前述者相同之意義], 乂如式(I-A-13 - 2)所表示之化合物: 41 200521108
[式中之各記號表示與前述者相同之意義], 或如式(I-A-13-3)所表不之化合物:
[式中之各記號表示與前述者相同之意義], 或如式(I-A-13-4)所表不之化合物·
OH
=/ (I-A-13-4)
COOH
[式中之各記號表示與前述者相同之意義], 或如式(I-A-13-5)所表示之化合物: 42 316588 200521108
[式t之各記號表示與前述者相同之意義], 上述化合物之鹽,或者上述化合物或其鹽之溶 物戒藥 物前體。 物可表示之化合物之其他樣態中,較佳之化合 了牛如式(I-A-14-1)所表示之化合物:
OH
(I-A-14-1) (R2), 1至3之整數, ::R表示環基之取代基,Z表示〇或 ^也。記號表示與前述者相同之意義], 或如式(1 + 14-2)所表示之化合物: 316588 43 200521108
OH
(Ι-Α-14-2) (RZ)z [式中之各記號表示與前述者相同之意義], 或如式(I~~A-14-3)所表示之化合物·
OH
〇 [式中之Rw表示可經取代之烷基,其他各記號表示與前述 者相同之意義], 或如式(I-A-14-4)所表示之化合物:
OH
(I-A-14-4) 44 316588 200521108 [式中之各記號表示與前述者相同之意義], 或如式(I-A-14-5)所表示之化合物:
[式中之環G表示雜環,其他各記號表示與前述者相同之意 義], 或如式(I-A-14-6)所表不之化合物··
[式中之各記號表示與前述者相同之意義], 或如式(I-A-a)所表示之化合物:
45 316588 200521108 [式中之Rp、Rq&RrS表示獨立之取代基,p、q及r各為 獨立,表示0或1至3之整數,μ1表示可取代之伸甲基、 可取代之伸乙基、可取代之伸丙基或可取代之伸乙烯基、 Z1表示-C00H、-CONHSCbR1基(基中之Ri表示與前述者相同 之意義)或四唑基。且複數之rp、Μ及rr亦各獨立,互為 相同或不同],或如式(I-A-b)所表示之化合物:
[式中之各記號表示與前述者相同之意義] 或如式(I-A-c)所表示之化合物:
OH
[式中之各記號表示與前述者相同之意義], 上述化合物之鹽、上述化合物或其鹽之溶劑合物、 减 物前體。 $ 式(I)所表示之化合物中,除在實施例中所記載之化/ 物外,又以以下化合物(1)至(32)、其鹽或其溶劑合物、 其藥物前體為較佳。 σ · 316588 46 200521108 (1) {4-[(21〇-2-[(3)-(3,5-二甲氧基-4-甲基苯基)(經基) 曱基]-4-(3-氟化苯氧基)丁基]苯基}乙酸、 (2) (4-{(2R)-4-(3-氣苯氧基)—2—[(S) — (3, 5一二甲氧基—4一 曱基苯基)(羥基)曱基]-丁基}苯基)乙酸、 (3) 4-(1-{(23)-2-[(3)-(3,5-二甲氧基-4—甲基苯基)(羥 基)甲基]-5-本基戊基} 一;[Η-D比嗤-4-基)丁酸、 (4) (4-{(2S)-2-[(S)-(4-乙醯基-3,5-二甲氧基苯基)(羥 基)曱基]-5 -苯基戊基丨苯基)乙酸、 (5) (3-{(2S)-2-[(S)-(3, 5-二曱氧基-4-甲基苯基)(羥基) 曱基]-5-苯基戊基}異噁唑-5-基)乙酸、 (6) 3-{卜[(28)-2-[(3)-(3,5-二曱氧基-4-曱基苯基)(羥 基)曱基]-5-(3-氟笨基)戊基]η一吼咯一3一基丨丙酸、 (7) {4-[(2S)-2-[(S)-(3, 5-二曱氧基-4-甲基苯基)(羥基) 曱基]-5-(3-氟苯基)戊基]苯基}乙酸、 (8) {1-[(23)-2-[(3)-(3,5-二甲氧基-4-甲基苯基)(羥基) 曱基]-5-(3-氟苯基)戊基]— 1H-□比咯—3-基}乙酸、 (9) (1-{(2S)-5-(3-氣苯基)-2-[(S)-(3, 5-二曱氧基一4一曱 基本基)(沒基)曱基]戊基}-1Η - 口比略-3-基)乙酸、 (10) (4-{(2S)-5-(3-氯苯基)-2-[(S)-(3, 5-二甲氧基—4一 曱基苯基)(羥基)曱基]戊基}苯基)乙酸、 (11) 4-(4-{(28)-2-[(3)-羥基(3,4,5-三甲氧基苯基)曱基] -5 -苯基戊基}苯基)丁酸、 (12) (1- {(2S)-2-[(S)-羥基(3, 4, 5-三曱氧基苯基)曱基] 一5-本基戍基}_1H -口比口各-3-基)乙酸、 316588 47 200521108 (13) 3-(1-{(2S)-2 - [(S)-(3, 5-二曱氧基-4-曱基苯基)(羥 基)曱基]-5-噻吩-3-基戊基}一1[1-吼咯—3-基)丙酸、 (14) (1-{(28)-2-[(8)-羥基(3,4,5-三曱氧基苯基)曱基] -5-噻吩-3-基戊基}-1H-d比略-3-基)乙酸、 (15) (4-{(23)-2-[(3)-羥基(3,4,5-三曱氧基苯基)曱基] -5 -嚷吩-3 -基戊基}苯基)乙酸、 (16) 3-(1-{(23)-2-[(3)-羥基(3,4,5-三甲氧基苯基)曱基] - 5-苯基戊基}-1^1-口比口各—3-基)丙酸、 (17) 3-( 1 - {(2S)-2-[(S)-羥基(3, 4, 5-三曱氧基苯基)曱基] - 5-噻吩-3-基戊基}-111-口比咯-3-基)丙酸、 (18) (4-{(23)-2-[(8)-(4-溴-3,5-二曱氧基苯基)(羥基) 曱基]-5-苯基戊基}苯基)乙酸、 (19) (1-{(2S)-2-[(S)-(4-溴-3, 5-二曱氧基苯基)(羥基) 曱基]-5-苯基戊基丨-iH-吡咯一3-基)乙酸、 (20) {1-[(2S)-2-[(S)-(4-氣-3, 5-二曱氧基苯基)(羥基) 曱基]-5-(3-氟苯基)戊基]—1H一吼咯—3 —基丨乙酸、 (2.1)(1_{(23)-2-[(8)-(4-氣-3,5-二甲氧基苯基)(羥基) 曱基]-5-苯基戊基}-1 η-吼咯一3-基)乙酸、 (22) (1-丨(23)-2-[(3)-(4-氣-3,5-二甲氧基苯基)(羥基) 曱基]-5-_吩-3-基戊基} — 1Η -口比口各-3 -基)乙酸、 (23) 4-(1-{(2S)-2-[(S)-(二甲氧基一4-甲基苯基)(羥基) 曱基]一5一苯基戊基卜1Η-吼咯-3-基)-4-酮基丁酸、 (24) (1S,2S)-1-(3, 5-二曱氧基一4-甲基苯基)-5-苯基-2- {[3-(1H-四唑-5-基甲基)—1H—吡咯—卜基]甲基丨戊—i—醇、 48 316588 200521108 (25) 2-(1-{(23)-2-[(3)-(3,5-二甲氧基-4-曱基苯基)(經 基)曱基]-5-苯基戊基}-1 Η-吡唑-4-基)苯甲酸、 (26) (1S,2S)-1-(4-氣-3, 5-二甲氧基苯基)-2-{[3-(1Η-四 唑-5-基曱基)- 1H-口比咯—卜基]曱基}一5-噻吩-3-基戊-1一 醇、 (27) (1S,2S)-1-(4-氣-3, 5-二甲氧基苯基)-5-(3-氟苯基) -2-{[3-(1Η-四唑-5-基甲基)-1Η-吼咯-1-基]曱基丨戊一卜 醇、 (28) (1-{(23)-2-[(3)-(4-乙醯基-3,5-二甲氧基苯基)(經 基)曱基]-5-苯基戊基}-lH-口比口各-3-基)乙酸、 (29) [4-((2S)-2-{(S)-羥基[4-(羥基甲基)—3, 5-二甲氧基 苯基]曱基}-5 -苯基戊基)苯基]乙酸、 (30) 3-(1-( (2S)-2-[(S)-(3, 5-二曱氧基一4-曱基苯基)(羥 基)甲基]-5-_吩-2-基戊基} — ih-d比口各一 3-基)丙酸、 (31) (1-K2S)-2-[(S)-(3, 5-二曱氧基一4一甲基苯基)(羥基) 曱基]-5-噻吩-2-基戊基卜1 η-口比咯一3-基)乙酸、及 U2S)-2-[(SM3, 5-二曱氧基一4—曱基笨基)(羥 基)曱基]-噻吩-3-基戊基卜1{1—吡咯—3_基)—4 —酮基丁 實施例中所表示之化合物中特別以以下之化合物(33) 至(84)、其鹽、或者彼此等之溶劑合物、或彼等之藥物前 體為更佳。 (33){H(2S,3S)-2 — (2H〜1h,—2 — *t&) — 3 — (3, 5-二曱氧基-4-曱基苯基)—3 —羥基丙基]—1H —吼唑一4―基 316588 49 200521108 乙酸、 (34) 3-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚一2-基甲基)一3 — (3, 5-二曱氧基-4-曱基苯基)一3 —羥基丙基]—1H一吡唑一4一基} 丙酸' 土 (35) {1-[(2S,3S)-2-(2, 3-二氫-1H-茚一2-基曱基)一3一 (3, 5-一曱氧基-4-甲基苯基)一3-羥基丙基]qH—吡咯一3一芙 乙酸、 土 (36) (1-{(2S)-2-[(S)-以^-二曱氧基一斗一曱基苯基^羥基) 曱基]-5-噻吩-3-基戊基卜1 η-吼咯一3一基)乙酸、 (37) {1-[(2S,3S)-2-(1,3-苯并二氧雜環戊烯一 2一基甲基) -3-(3, 5-二甲氧基-4-甲基苯基)一3一羥基丙基]一1{1—吡咯 -3-基}乙酸、 (38) {1-[(2S,3S)-2-(2, 3-二氫-1H-節-2-基甲基)-3-羥基 3 (3, 4,5 一甲氧基本基)丙基]- 1H-D比嘻-3-基}乙酸、 (39) {1-[(2S,3S)-3-(4-乙驢基-3, 5-二甲氧基苯基)一 2- (2, 3-二氫-1H-茚-2-基曱基)一3一羥基丙基]-1H一吡咯—3一基} 乙酸、 (40) {1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基)-3-(4- 乙基-3, 5-二曱氧基苯基)一3 —羥基丙基]-1H—吡咯-3 —基}乙 酸、 (41) 3-{1 -[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基)-3- (3, 5-二甲氧基-4-曱基苯基)一3一羥基丙基]―丨η-吡咯一3 —基} 丙酸、 (42) 3-{1-[(23,33)-2-(2,3-二氫-1{1-茚-2-基曱基)-3-羥 316588 50 200521108 基-3-(3, 4, 5-三甲氧基苯基)丙基]„1H—吡咯—3 一基丨丙酸、 (43){1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基)-3- (3,5-二甲氧基苯基)一3-羥基丙基]- 1H-吼咯-3-基}乙酸、 (44M-K2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基)-3-羥基 -3-[4-(l-羥基-1-甲基乙基)—3, 5_二曱氧基苯基]丙基} -111-1]比17各-3-基}乙酸、 (45) 3-{1-[(2S,3S)-3-(4-乙醯基-3, 5-二甲氧基苯基)一2-(2, 3-二氫-1H-茚-2-基曱基)-3-羥基丙基]-1H-吼咯-3-基} 丙酸、 (46) (2E)-3-{1 -[(2S,3S)-2-(2,3-二氫-1H-節-2-基甲基) -3-(4-乙基-3, 5-二曱氧基苯基)一3一羥基丙基]jη一吼咯 - 3 -基}丙稀酸、 (47) 3-{1-[(23,33)-2-(2,3-二氫-111-茚-2-基曱基)一3- (4-乙基-3, 5-二曱氧基苯基)一3-羥基丙基]一1Η一吼咯-3一基} 丙酸、 (48) 2-{1-[(28,33)-2-(2,3-二氫-111-茚-2-基曱基)—3一 (3, 5-二曱氧基-4-曱基苯基)一3-羥基丙基]—1 η一吼口各―3一基) -Ν-(曱基石黃醯基)乙醯胺、 (49) [1-[(2S,3S)-2-(2, 3-二氫-1Η-茚-2-基甲基)一3- (3, 5-二曱氧基一4-曱基苯基)一3-羥基丙基]一4-(甲氧基羰 基)-1Η - D比略-3-基]乙酸、 (50) N-(3-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱 基)-3-(3, 5-二曱氧基一4-曱基苯基)一3-羥基丙基]〜1H一吼 咯-3-基}丙醯基)曱磺醯胺、 316588 51 200521108 (51) N (3 {l〜[(2s,3S)-2-(2,3-二氫-H2-基甲基) -3-(3, 5-二甲氧基+甲基苯基)—3_經基丙基]—n各 - 3-基丨丙醯基)苯磺醯胺、 σ (52) Ν—({1 —[(2S,3S) —2 —(2, 3 —二氫—1Η—茚—2一基甲基)j (3, 5-一甲氧基一4一甲基苯基)-3 —羥基丙基]—吡咯一3一基) 乙醯基)-1,1,丨―三氟甲磺醯胺、 土 ' (53) N-(3-U — [(2S,3S) —2 —(2,3 —二氫—1H,—2 —基甲基) -3-(3, 5-二甲氧基—4—曱基苯基)—3 —羥基丙基]-ih—吡咯 - 3-基丨丙醯基氟苯磺醯胺、 (54) 3 {1 [(2S,3S)-2-(2,3-二氫-1H-萌-2-基甲基)一3- (,5甲氧基-4-曱基苯基)一3-羥基丙基]一吡咯一3 一基} - 2 -甲基丙酸、 (55) N (3-{1-[(2S,3S)-2-(2, 3-二氫—1H-萌-2-基曱基) - 3-(3, 5-二甲氧基一4 一甲基苯基)—%羥基丙基]-ih-吡咯 - 3-基}丙醯基)〜2—曱基苯磺醯胺、 (56X2E) —3—{1 —[(2S,3S) —2 —(2,3〜二氫—1H—茚—2 —基曱基) 3 (3,5 一甲氧基—4 一甲基苯基)一3…羥基丙基卜-吡咯 - 3 -基}丙稀酸、 (57) N —(2—U —[(2S,3S)-2-(2,3-二氫鲁節_2_基曱基) 3 (4乙基-3,5-二曱氧基苯基)_3〜羥基丙基]_1H-吡咯 -3-基}乙醯基)曱磺醯胺、 (58) N (2—“ — [(2S,3S) —2 —(2, 3 —二氫]H—茚—2 —基曱基) 3 (4乙基-3,5-二曱氧基苯基)一3、羥基丙基]_1H—吡咯 -3-基}乙醯基)苯磺醯胺、
31658S 52 200521108 (59) 2-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基)—3- (3, 5-二曱氧基一4-甲基苯基)一3 —羥基丙基]—jH一吼咯一3 —基} -2 -甲基丙酸、 (60) 2-{[(3-{1 -[(2S,3S)-2-(2, 3-二氫-1Η-茚-2-基曱基) -3-(3, 5-二甲氧基—4-甲基苯基)—3一羥基丙基]—1Η一吼咯 3基}丙基)胺基]石黃醒基丨苯甲酸甲醋、 (61) N-(3-{l-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基) -3-(3, 5-二甲氧基一4-曱基苯基)一3 —羥基丙基]—1H—吼咯 - 3-基}丙醯基)—2-噻吩磺醯胺、 (62川-(2-{1-[(23,3幻—2一(2,3 —二氫一1}1一茚—2一基曱基) 3-(3, 5-二曱氧基一4-甲基苯基)一3 —羥基丙基]y H一吼咯 -3-基}-2-曱基丙醯基)曱磺醯胺、 (63) N-({1 -[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基)-3- (3, 5-二甲氧基一4一甲基苯基)_3一羥基丙基]—iH一吡咯_3一基} 乙酿基)-4-氟苯石黃酸胺、 (64) N -(3-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基) -3-U,5-二甲氧基一4-甲基苯基)—3一羥基丙基]H一吡咯 -3-基丨丙醯基)—n,n-二甲基磺醯胺、 (65) N-({1一[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基)-3- (3, 5一一曱氧基-4-曱基苯基)一3 —羥基丙基]—1H 一吡咯—3一基} 乙醯基)-2-甲基苯磺醯胺、 (66) 1({1-[(23,33)-2-(2,3-二氫-111-茚-2-基曱基)-3-(3,5-二甲氧基一4—甲基苯基)一3一羥基丙基]_ih —吡咯—3 —基} 乙醯基)-2-(三氟甲基)笨磺醯胺、 53 316588 200521108 (67) N—({1 —[(2、3S)〜2 —(2, 3 —二氫—1H-茚—2 —基 T 基)-3 — (3,5-二曱氧基—4—甲基苯基)—3 —經基丙基]—n各_3 —基} 乙醯基)-2-氟笨磺醯胺、 (68) 2-氣-Ν-⑴-[(2S,3S)_2_(2, 3_:氫鲁節令基甲基) 3 (3,5 一甲氧基一 4-甲基苯基)-3-羥基丙基]-1H-吡咯 - 3-基}乙醯基)苯磺醯胺、 (69) N-({1-"[(2S,3s)_2_(2,3_二氫_1H—萌_2_基曱基)_3_ (3’ 5 一甲氧基—4—甲基苯基)-3 —羥基丙基]-1H-吡咯-3-基} 乙醯基)-2, 6-二氟笨磺醯胺、 (70) N-({1-[(2S,3S)-2-(2, 3-二氫-1HI2-基 f 基)-3- (3, 5 一甲氧基一4—甲基苯基)-3-羥基丙基]-1Η-吼咯-3-基} 乙醯基)-3-氟苯磺醯胺、 (71) 3_氯一N—({1-[(2S,3S)-2-(2, 3-二氳-1Η-茚-2-基甲基) 3 (3,5 一甲氧基_4-甲基苯基)_3_羥基丙基]-1Η_吡咯 3 -基丨乙酿基)苯石黃酿胺、 (72川-(2-{1-[(23,33)-2-(2,3-二氫—1[1-茚-2-基曱基) - 3-(3, 5-二甲氧基一4一曱基苯基)一3一羥基丙基]—1Η—吡咯 —3-基丨乙醯基2 —噻吩磺醯胺、 (73) 2-氯-Ν-(3-{1-[(2S,3S)-2-(2, 3-二氫-1Η-茚-2-基甲 基)-3-(3, 5-二甲氧基一4一甲基苯基)一3 一羥基丙基]_1H一吼 咯-基}丙醯基)—6 一甲基苯磺醯胺、 (74) 付-(3-{1-[(23,33)-2-(2,3-二氫—1[1-茚-2-基甲基) -3-(3, 5-二甲氧基—4-甲基苯基)一3一羥基丙基]qη—吡咯 —3-基丨丙醯基)一2_f氧基—4一甲基苯磺醯胺、 。 316588 54 200521108 (75) N-(3-{1 -[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基) -3-(3, 5-二甲氧基一4—甲基苯基)一%羥基丙基]_1H一批咯 - 3-基}丙醯基)—4-氟-2-甲基苯磺醯胺、 (76) N-(3-{1 -[(2S,3S)-2-(2, 3-二氳一 1H-茚-2-基甲基) -3-(3, 5-二甲氧基—4—甲基苯基)一3一羥基丙基]jH一批咯 -3-基}丙醯基)一 5一甲基一 2一呋喃磺醯胺、 (Π)Ν-({1-[(23,33)-2-(2,3-二氫-111-茚-2-基甲基)-3- (3, 5一二甲氧基―4—甲基苯基)-3-羥基丙基]一1Η-口比咯-3-基} 乙驢基)- 4-(三氟甲基)苯磺醯胺、 (78).({1-[(23,33)-2-(2,3-二氳-111-茚-2-基甲基)-3- (3, 5一二甲氧基—4—甲基苯基)-3-羥基丙基]一1Η-吼咯-3-基} 乙醯基)-4-甲氧基苯磺醯胺、 (79)Ν (3-{1-[(2S,3S)-2-(2, 3-二氫— 1Η-茚-2-基曱基) 3 (3, 5 —一甲氧基一4—甲基苯基)-3-羥基丙基]-1Η-吡咯 3-基}丙酿基)—4-嗎啉石黃酿胺、 (〇0)1^-(2-{1-[(23,38)-2-(2,3-二氫-;^-茚-2-基甲基) 〇 (3, 5-一甲氧基—4—曱基笨基)一3 —羥基丙基]—iη一吡咯 - 3-基}乙醯基嗎啉石黃酿胺、 (81) Ν-(3-{1-[(2S,3S)-2-(2, 3-二氫-1Η-茚—2-基曱基) 3 (3,5 一甲氧基-4-曱基苯基)一3-經基丙基]一1 η-口比咯 一3-基}丙醯基)一4 一甲基—L3一噻唑—2—磺醯胺、 (82) 2{1-[(23,33)-2-(2,3-二氫-1}1-_-2-基甲基)-3-(4乙基-3,5-二曱氧基苯基)一3-羥基丙基]一口比洛一3 — 基}-2-曱基丙酸、 316588 55 200521108 (83川-((2£)-3-{1-[(23,33)-2-(2,3-二氫-111-茚-2-基甲 基)-3-(3, 5-二甲氧基-4-甲基苯基)一3-羥基丙基]—ιη一批 咯-3-基}-2-丙烯醯基)甲績醯胺、及 (84)(2Ε)-3-{1-[(2S,3S)-2-(2, 3-二氫-1Η-茚-2-基甲基) 3(3,5 一甲氧基4甲基本基)一3-餐基丙基]—- D比咯 -3-基}-2-甲基丙烯酸。 本發明中以含上述中列舉之較佳基、較佳環組合之式 (I)化合物為佳。 [本發明化合物之製造方法] 如式(I )表示之本發明化合物,可以以例如以下所表示 之方法或在實施例中所表示之方法或依據此等之方法,或 公知之方法(例如「comprehensive 0rganic
Transformation: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley&SonsInc·,1 999)」中所載之方法適當改良製造。 以下之各製造方法中,其原料化合物亦可使用其鹽。此等 鹽亦可使用前述做為式(〗)之鹽者。 式(I)所表示之化合物可由式(2)所表示之化合物: 〇
316588 56 200521108 經羰基之還原反應而製成。 羰基之逛原反應為一般所知之反應,例如在有機溶劑 (甲醇四氫咲喃、或此等之混合溶劑等)中,以還原劑(氫 硼化鈉、二乙醯氧基氫硼化鈉、氰基氫硼化鈉、氫硼化四 丁基銨等)在0至loot:之溫度進行反應。 式(I)中之至少1基表示含羧基、羥基、胺基或巯基之 基之化合物,可由各基以保護基保護之化合物經脫保護反 應而製成。 羧基之保護基可例舉如甲基、乙基、烯丙基、第三丁 基、二氯乙基、苯甲基(Bn基)、苯甲醯甲基(phenacyl)等。 羥基之保護基可例舉如甲基、三苯甲基、甲氧基曱基 (MOM)、1-乙氧基乙基(EE)、甲氧基乙氧基甲基(mem)、2一 四虱吡喃基(THP)、三甲基矽烷基(TMS)、三乙基矽烷基 (TES)、第三丁基二甲基矽烷基(T]BDMS)、第三丁基二苯基 矽:kS(TBDPS)、乙醯基(ac)、三甲基乙醯基、苯曱醯基、 本甲基(Bn)、p-甲氧基苯曱基、烯丙基氧基羰基(AU〇c)、 2,2,2 —三氯乙氧基羰基(Troc)等。 ^胺基之保護基可例舉如苯曱基氧基羰基、第三丁氧基 羰基、烯丙基氧基羰基(AU〇c)、卜曱基—^(4 —聯苯基)乙 氧基羰,基(BP0C)、三氟乙醯基、9—苟基曱氧基羰基、苯曱 基(Bn)、對-曱氧基苯甲基、苯甲基氧基曱基⑶⑽卜2一(三 曱基矽烷基)乙氧基甲基(SEM)等。 巯基之保護基可例舉如苯曱基、甲氧基苯曱基、甲氧 基曱基(Μ0Μ)、2-四氫哦喃基(THP)、二苯基曱基、乙酿基 316588 57 200521108 (Ac)。 羧基、羥基、胺基或巯基之保護基,除上述外只要為 可容易地選擇性脫離之基即可,並無特別之限定。可使用 例如 Protective Groups in Organic Synthesis(T· w· Greene,J〇hn Wiley & Sons Inc.,1 999)中所載者。 鲮基、羥基、胺基或巯基之保護基之脫保護反應為一 般所熟知,例如(1)經鹼水解之脫保護反應、(2)經酸性條 件下之脫保護反應、(3)經水解之脫保護反應、(4)矽烷基 之脫保護反應、(5)使用金屬之脫保護反應、(6)使用有機 金屬之脫保護反應等。 此等方法可再具體地加以說明。 (1) 經鹼水解之脫保護反應之例,如在有機溶劑(曱 -享四氫咲喃、1,4-一噁烧等單獨,或以此等之複數種之 溶劑以任意之比例之混合溶劑)中,經鹼金屬之氫氧化物 (風氧化鈉、氫氧化鋰、氫氧化鉀等)、鹼土金屬之氫氧化 =(氫氧化鋇、氫氧化鈣等)或其碳酸鹽(碳酸鈉、碳酸鉀 等)、或其水溶液及此等之混合物,在〇至4(rc溫度下進 行反應。 (2) 在酸性條件下之脫保護反應之例,如在有機溶劑 (氯甲火元氣仿、1,4 - — °惡烧、乙酸乙酯、苯甲_等單獨, 或乂此荨之複數種之浴剩以任意之比例之混合溶劑)中,以 有枝酉文(乙g文、二氟乙酸、對—甲苯石黃酸、甲苯石黃酸等)、或 無機酸(鹽酸、硫酸等)、或此等之混合物(溴化氫/乙酸 等),在〇至100t之溫度進行反應。 3165S8 58 200521108 (3)經由水解之脫保護反應 呋喃、1,4-二噍产、_田,貧例如在浴制(醚類(四氫 醇、乙醇等)、笨::⑤土乙烷、二乙趟等)、醇類(甲 子寺)本類(本、甲苯等)、酮類(丙綱、甲紅其 嗣等)、腈類(乙腈等)姻類⑽-:曱基μ胺&水基 乙酸乙醋、乙酸或以此等2種以上之 聊巴-碳,黑、氣氧化妃、氧化翻、拉尼錄;在在下催 =或加壓线下、或甲酸銨存在下,在q至 進行反應。 度 ⑷石夕炫基之脫保護反應之例如在可與水混合之有機 洛劑(四氫呋喃、乙腈等單獨或以此等複數種之溶劑以任咅、 之比例之混合溶劑)中,經氟化四丁基銨,在0至4(rc “ 溫度進行反應。 (5) 使用金屬之脫保護反應之例,如在酸性溶劑(乙 酸、pH 4. 2至7· 2之緩衝溶液或此等溶液與四氫呋喃等有 機溶劑之混合液)中,在鋅粉存在下,利用超音波或不利用 超音波,在0至40°C之溫度進行反應。 (6) 使用有枝金屬之脫保護反應之例,如在有機溶劑 (一氯甲烷、N,N-二曱基曱醯胺、四氫呋喃、乙酸乙酯、乙 腈、1,4-二噁烷、乙醇等)、水或此等之混合溶劑中,在捕 獲劑(氫化三丁基錫、三乙基矽烷、雙甲酮、嗎啉、二乙基 胺、毗啶等)、有機酸(乙酸、甲酸、2—乙基己酸等)及/或 有機酸鹽(2-乙基己酸鈉、2-乙基己酸鉀等)存在下,在膦 類5式樂(二本基膦等)存在下或不存在下,經金屬錯合物(肆 三苯基膦化鈀(〇)、二氣化雙(三苯基膦)化鈀(11)、乙酸鈀 316588 59 200521108 (π)、氯化蒼(三苯基膦)铑⑴等),在〇至1〇吖之溫度 進行反應。 除上述反應以外,亦可以例如在Pm tec tlve Groups 1Π 〇rganiC (T· Greene, John WUey & Sons
InC.,1 999)中所載之方法進行脫保護反應。 本技術領域人士當易理解,藉由制此等脫保護反 應’即可容易地製造為目的之本發明化合物。 必要k,此等反應之後,亦可再經由公知之方法,將 其轉換為目的之藥理上容許之鹽。 式(1)所表示之化合物中,Q為-0-或-CH2-〇-(但在各 基右側鍵結有環D)之化合物,即式(1-1)所表示之化合物:
OH
[式中,Q1為-〇-或—CH2—◦一(但各基在右侧鍵結有環D),其 他各5己#b表示與前述者相同之意義] 係式(3)所表示之化合物··
[式中’ Y為羥基之保護基(例如三曱矽烷基、第三丁基二 316588 60 200521108
曱基矽烷基、曱氧基曱基、^ 0 . nfL 丄乙乳基乙基、2 -四虱fl比喃基 等)’其他各記號表示與前述者相同之意義] 與式(4)所表示之化合物:
HO
(4) [式中之各記號表示與前述者相同之意義] 經喊化反應,再㈣基上保護基之脫保護反應,於必要時 可再經保護基之脫保護反應而製成。 該_化反應為-般所知之反應,可例如在有機溶劑(二 鼠甲烧、二乙_、四氫咲。南、乙腈、苯、甲苯等)中,在偶 氮化合物(偶氮二缓酸二乙醋(DEAD)、偶氮二幾酸二昱 酯、M,-(偶氮二羰基)二哌σ定、丨 ,、 瓜疋丄,i -偶虱雙(Ν,二 甲酿胺)等〉及膦化合物(三苯基麟、三丁基麟、 土 :聚合物支撐之三苯基膦等)存在下與適 :、 〇至6(TC下進行反應。 5物在 羥基之保護基之脫保護反應或保護基 以依與前述相同之方法操作。 ’、5蔓反應可 式(I)所表示之化合物中,Q表示C1_8 伸烯基或C2-8伸炔基,環D為芳族碳環 70基、C2-8 物,即式(1-2)所表示之化合物: —方麵雜環之化合 316588 61 200521108
[式中,Q為C1-8伸烷基、 環D2為芳族碳環或芳族雜環,其他=二C2_-8伸」夬基, 同之意義]· 。°己5虎表示與前述者相 係式(5)所表示之化合物:
(5) 其他各記號表示與前述者相同之意 [式中’Y為鹵素原子 義] 與式(6)所表示之化合物··
^弋中之X為鹵素原子或三氟曱磺醯氧基,其他各記號表 示與珂述者相同之意義] 、、二偶〇反應,再經羥基上保護基之脫保護反應,於必要時 可再經保護基之脫保護反應而製成。 。亥偶合反應為一般所知之反應,例如可經由將 62 316588 200521108
Ei-ichi Negishi, J.Org, Chem., 4^(1977)1821; Shouquan Ho. 5 Organic Letters, 5(2003)423 ; Paul Knochel, Tetrahedron, 54(1998)8275, Paul Knochel, Chem.Rev., 93(1 993)21 17等中所載之方法再經適當改良後進行。例如 式(5)所表示之化合物在有機溶劑(二曱基曱醯胺、二曱基 乙醯胺、四氫呋喃、二乙醚、乙腈、苯或甲苯或此等之混 合物等)中,在金屬(例如辞或鎂等)存在下、金屬活化劑(例 如氣化三曱基矽烷或1,2-二溴乙烷等)存在下或不存在 下,在-20 C至80 C下反應,之後再經催化劑[例如參(二 亞苯曱基丙酮)二鈀(0)-氣仿錯合物、參(二亞苯曱基丙酮) 二鈀錯合物、乙酸鈀、二氯雙(乙腈)鈀、二氣雙(苯曱腈) 鈀、二氣[1,Γ-雙(二苯基膦基)二茂鐵]化鎳或肆(三苯基 膦基)鈀等]及有機磷化合物[例如三苯基膦、表(2—曱芙苯 基)膦、參(第三丁基)膦、u,_雙(二苯基膦基)二茂ς或 二-2-咲喃基膦等]存在下,與式所表示之化 至150°c下反應而製成。 # 羥基之保護基之脫保護及庙★ π + 干X反應或保濩基之脫保護反應可 以依刖述相同之方法操作。
式(I)所表示之化合物中,Q
y表不C1-8伸烷基、環D 表不經由氮原子與Q鍵結之雜 示之化合物: A之化合物,即式0-3)所表 316588 63 200521108
號表示與前述者相同之意義] 係式(7)所表示之化合物:
(1-3) 之雜環,其他各記 ⑺ ^卜X7為㈣基(脫離基指ώ素原子、甲雜氧基(〇Ms 二、對-甲苯石黃驢氧基㈣基)、三氟甲磧醒氧基(〇Tf幻 '' 其他各§己號表示與前述者相同之意義] 與式(8)所表示之化合物:
[式中各記號表示與前述者相同之意義] 經N-烷基化反應,再經羥基上保護基之脫保護反應,於必 要時可再經保護基之脫保護反應而製成。 ^该N—烷基化反應為一般所知之反應,可例如在有機溶 j (四氫呋喃、二乙醚、N,N—二甲基曱醯胺等單獨,或以此 等之複數種之溶劑以任意之比例之混合溶劑)中,在鹼(二 316588 64 200521108 異丙基胺化鋰(必要時在胺基(IV,N,N,,IT,N"-五甲基二伸 乙基二胺、Ν,Ν,Ν’,Ν’ -四甲基伸乙二胺等)存在下進行。)、 氫化鈉、碳酸鉀、碳酸鉋等)存在下,在—78至4(rc下進行 反應。 羥基之保護基之脫保護反應或保護基之脫保護反應可 以依前述相同之方法操作。 、式(I)所表示之化合物中,z表示為四唑基之化合物, 即式(1-4)所表示之化合物:
(1-4) U中之各記號表示與前述者相@之意義 係式(9 )所表示之化合物:
[式中之各記號表示 與疊氮化合物反應, 而製成。 與前述者相同之意義] 於必要時可再經保護基之脫保 護反應 可例如在水或有機溶劑 該反應為-般所知之反應, 316588 65 200521108 (本曱* 一甲本、N,N_二甲基甲酸胺、四氯咲喃、1 * 二喔烷、異丙醇等)單獨,或以此等之複數種之溶劑以任立 之比例之混合溶财,在添加偷彳如漠化鋅、氯化鐘^ 貺乙馱—乙基胺、吡啶等)存在下或不存 在下’與疊氮化合物(例如疊氮化納、疊氮化鐘、疊氮三甲 基石夕烧、疊氮化三〒基錫、疊氮化三丁基錫等)在2〇至15〇 C下進行反應。 式(I)所表示之化合物中,ζ表示為⑶匪s〇2Rl之化合 物’即式(1-5)所表示之化合物:
[式中之各記號表示與前述者相同之意義] 士式(1 0 )所表示之化合物: '
气中之各記號表示與前述者相同之音義 與式(Π)所表 示之化合物: I 316588 66 200521108 〇2 H、rs、RiA (11)
I
H
[式中,R1A為與R1表不相同之意義,在需要保護之場合 被保護之基] σ 經酿胺化反應,再經羥基之保護基之脫保護反應,於必要 時可再經保護基之脫保護反應而製成。 酿胺化反應為一般所知之反應,可例舉如 (1) 使用酸鹵化物之方法、 (2) 使用混合酸酐之方法、 (3) 使用縮合劑之方法等。 此等方法再更具體說明。 (1) 使用酸鹵化物之方法,例如羧酸在有機溶劑(氯 仿、一氯曱烧、二乙輕、四氫咲喃等)中或在無溶劑下,與 酸鹵化劑(氯化噁唑、亞硫醯氯)一起在-20°c —回流溫度下 反應,該製成之酸鹵化物再於鹼(吼啶、三乙胺、二曱基笨 月女、一曱基胺基吼咬、二異丙基乙基胺等)存在下,與胺在 非活性有機溶劑(氯仿、二氯曱烷、二乙醚、四氫咲喃等) 中,在0至4 0 C溫度下進行反應。亦可在機溶劑(二嚼烧、 四氫咲喃等)中,以鹼水溶液(碳酸氫鈉或氫氧化納溶液 等),與酸鹵化物在〇至40。(:下進行反應。 (2) 使用混合酸酐之方法,例如將魏酸在有機溶劑(氣 仿一氣曱丈元、—乙謎、四氫咲σ南等)中或在無溶劑下,在 鹼(吼啶、三乙胺、二曱基苯胺、二曱基胺基吡啶、二異丙 316588 67 200521108 基乙基胺等)存在下,與酸鹵化物(三曱基乙醯氣、曱苯碏 醯氣、曱磺醯氯等)、或酸衍生物(氣曱酸乙酯:氣曱酸: 丁酷等)在4(rc下進行反應’然後將製成之混合酸酐 再於有機溶劑(氣仿、二氣曱烷、二乙醚、四氫呋喃等)中, 在0至40°c與胺反應而進行。 (3^使用縮合劑之方法,例如羧酸與胺在有機溶劑(氯 氯甲丈兀一甲基曱^胺、一乙峻、四氫□夫喃等)中或 在無溶劑下,在鹼(吡啶、三乙胺、二甲基笨胺、二曱基胺 基吡啶、1,8-二氮雜雙環[5· 4· 〇]十一碳—7 —烯等)存在^或 不存在下使用縮合劑(1,3-二環己基碳化二亞胺(dcc)、 1乙基3 [3-(_甲基胺基)丙基]碳化二亞胺(ed〇、1 1, 羰基一咪唑(CDI)、碘化(2-氣-1—曱基吡啶銹)、丨―丙基膦 酸環狀酐(PPA)等),在使用或不使用卜羥基苯并三唑 (HOBt)下,於〇至4〇r進行反應。 此反應(1)、(2)及(3)最好在惰性氣體(氬氣、氮氣等) 下、無水條件下進行為佳。 作為起始原料或試藥使用之式(”至^丨)中所示之化 合物本身為一般所知或可以一般所知之方法,例如如 「C〇mprehensive Organic Transformations : A Guide t0
Functional Group Preparations, 2nd Edition (Richard C. Larock,John Wiley & Sons Inc·,1 999)」中所載之 方法或貫施例中所示之方法,即可容易地製成。 本明細書中之各反應中經加熱之反應,可由業者所知 之水浴、油浴、砂浴或微波操作。 316588 68 200521108 本明細書中之各反應中,亦可適當地使用高分子聚合 :(例如聚笨乙烯、聚丙烯醯胺、聚丙烯、聚乙二醇等)固 疋之載體固定試藥。 、本明細書中之各反應中,反應生成物可以一般之精製 、、去、如¥壓下或減壓下蒸餾、使用矽膠或矽酸鎂之高速 :夜相層析、薄層層析、離子交換樹脂、異構物消除樹脂或 官柱層析及洗淨、再結晶等方法精製。精製可於每一反應 進行,或在數反應終了後再進行。 本說明書中使用聚苯乙烯樹脂之反應中,其反庫生成 ::以一般之精製方法,如溶劑(U-二甲基 製Γ、甲®[四峨、甲苯、乙酸/甲苯等)多次洗淨精 [毒性] 式(1)所示之本發明化合物之毒性低,已碹# γ ^ ^ 作為醫藥品使用。 w生低已確疋可安全地 [醫藥品之適用性] 弋(I )所示之本發明化合物因對 跳具拮抗作用,應該可用以預別疋 媒介之咗了貝I万及/或治療由;EDG-2 之疾病(例如泌尿系統疾病、癌相网 病、發炎性•备、內 < 从— 祁⑸疾病、增殖性疾 關疾病、慢性疾病等)等。 (之疾病、腦相 ’必尿系統疾病可例舉如前列腺一 :延:其伴隨之症狀如排尿困難(排尿開二::膀= 間延長、尿線細小、斷續性排尿、排尿分 316588 69 200521108 間頻尿、排尿痛等。同樣之其他泌尿系器官之症狀有因腦 血官損傷、帕金森氏症、腦瘤、多發性硬化症、Shy_Drager 氏症、脊髓瘤、腰椎間盤突出、脊柱狹窄、糖尿病等疾病 所引起之症狀(排尿困難(排尿開始之延遲、排尿時間延 長、尿線細小、斷續性排尿、排尿分段等)、頻尿、夜間頻 尿、排尿痛等)。此外,此等疾病以外之泌尿系器官疾病, I例舉如下尿道疾病(例如下尿道梗塞之疾病等)、下尿道 火性疾病(如感染等)、間質性膀胱炎、頻尿等,此等疾病 被認為可由該LPA受體拮抗劑加以治療。 、 癌相關疾病可例舉如固形腫瘤、固形腫瘤轉移、血管 纖維瘤、骨髓瘤、多發性骨髓瘤、卡波特肉瘤、白血病等。 ,形腫瘤之例可舉如乳癌、肺癌、胃^、食道癌、結腸直 知癌、大腸癌、肝癌、卵巢癌、卵囊膜細胞瘤、卵巢男胚 瘤、子宮頸癌、子宮内膜癌、前列腺癌、腎臟癌、皮膚癌、 骨肉瘤、胰臟癌、尿道癌、甲狀腺癌、多形性膠質母細山胞 瘤、神經母細胞瘤等腦痧笙· ^ ΰ足寻。其他癌之滲潤轉移亦被認為 可受该LPΑ受體拮抗劑抑制。 =性疾病可例舉如血管新生異常所伴隨之疾病(例 如再狹乍、糖尿病性視網膜炎、血管新生性綠内障、曰卿 後纖維組織增生、甲狀腺充進(含巴塞多氏病)、肺炎曰、曰二 病症候群、及骨質疏鬆症)、動脈梗塞、肺纖維變性等。 發炎性•免疫系統疾Γ办丨I i & 腎病等)、因其他炎症免二 肺炎等。 免疫異常料紅”炎、肝炎 316588 70 200521108 之分之舉如因自主神經系統異常所導致 ,斯耶格彻心導致之分泌失調可 細神纟里關聯疾病可你|與a . 或神經末梢失調尊。、广=例舉如月句血管梗塞、腦溢企、腦 疼痛、_ Μ相關之神經性疾病可例舉如癌症 疼痛^骨盤痛徵候群、痛覺過敏、碰觸痛等。 前二炎'肥胖、 瘤、慢性便秘等。皮“、肝硬化、脂肪肝、慢性下 如式(I)所示之本發明化人 物Μ π h h 月化D物、其之鹽及彼等之溶劑合 防及二二::具有υ可補充及/或增強化合物之預 寧量及= 善化合物之動態.吸收、減少投 組合為併用藥劑投藥。…乍用’因此可與其他藥劑 i制二)所示本發明化合物與其他藥劑之併用劑,可以以 :毕ΖΓ二成份之配合劑之形態投藥、亦可以嗔 ==:段時晴。相隔—段時間差投藥二门 Z 所7^之本發明化合物’之後再投與其他藥劑, 2可先投,其他藥劑’之後再投與式⑴所示之本發明化合 物’各投藥方法可相同亦可不同。 ^述之制劑不限於可發揮其預防及/或治療疾病之 效果者’亦可.為能補充及/或增強式⑴所示本發明化合物 316588 71 200521108 之預防及/或治療疾病之效果者。 例如補充及/或增強式(1)所示本發明化合物對泌尿系 疾病之預防及/或治療效果之其他藥劑,可以列舉其他之泌 尿系疾病之治療藥劑,例如其他之LPA受體拮抗劑、〇 1 =阻劑、抗膽鹼劑、5α -還原酶抑制劑及/或抗雄性激素劑 等。但抗膽鹼劑只可用在未伴隨前列腺肥大之場合。主要 用於治療未伴隨前列腺肥大之場合的頻尿、尿失禁。 例如補充及/或增強式(1)所示本發明化合物對癌症相 關疾病方面之預防及/或治療效果之其他藥劑,可列舉其他 癌症治療劑等。 山例如補充及/或增強式(I )所示本發明化合物對慢性氣 喘之預防及/或治療效果之其他藥劑,可列舉如類固醇劑、 促腎上腺素受體藥、白三稀素受體抬抗劑、血检凝素 。成酶抑制劑、血栓素(thrQmbQXane)A2受體拮抗劑、媒介 物(mediator)游離抑制劑、抗組織胺劑、黃嘌呤衍生物、 抗膽知劑(antich〇linergie drugs)、細胞激素(⑺也此) 抑制劑、前列腺素類、鱗膽鹼(ph〇sch〇i丄此)製劑、磷酸雔 _抑制劑、彈性蛋白酶抑制劑、金屬蛋白酶抑 : 痰藥、抗生物質等。 例如補充及/或增強式⑴所示本發明化合物對前列腺 肥,之預防及/或治療效果之其他藥劑,可列舉如抗雄性激 素劑、α 1受體封阻劑、5α-還原酶抑制劑等。 /
:=充及/或增強式⑴所示本發明化合物對動脈硬 、 或冶療效果之其他藥劑,可例舉如Hmg_CqA 316588 72 200521108 逖原酶抑制劑、貝特(fibrate)系製劑、丙丁酚(pr〇buc〇i) 製劑、陰離子交換樹脂、EPA(二十碳五烯酸)製劑、菸鹼酸 製劑、MTP(微粒體三酸甘油脂轉移蛋白質,micr〇s_al triglyCeride transfer pr〇tein)抑制劑、ppAR(過氧化物 酶體-增殖因子活化受體,per〇xis⑽e pr〇liferat〇卜 activated receptir)催動製劑、其他之抗高膽固醇藥。 例如補充及/或增強式(I)所示本發明化合物對風濕性 關即炎之預防及/或治療效果之其他藥劑,可列舉如非類固 醇系抗發炎劑、疾病修飾性抗風濕性關節炎劑(緩效型抗風 濕性關節炎劑)、類固醇劑、免疫抑制劑、消炎酵素劑、軟 骨保護劑、τ細胞抑制劑、TNF α抑制劑(含抗TNF α 蛋白質製劑)、前列腺素合成酵素抑制劑、丨L _ β抑制劑S(含 抗IL-6受體抗體等蛋白質製劑)、干擾素^作用藥、丨乙一丄 抑制劑、前列腺素類、磷酸雙酯酶抑制劑、金屬蛋白酶等。 例如補充及/或增強式(丨)所示本發明化合物對異位性 皮膚炎之預防及/或治療效果之其他藥劑,可列舉如類固醇 劑、非類固醇糸抗發炎劑、免疫抑制劑、前列腺素類、抗 過敏劑、媒介物游離抑制劑、抗組織胺劑、磷膽鹼、 (Phoscholm)製劑、磷酸雙酯酶抑制劑、^之誘引 制(decoy)製劑、促大麻驗—2受體劑等。 、 其他之LPA受體拮抗劑,可列舉如3 —(丨4—丨[卜。一 氯苯基)乙氧基]隸}胺基)_3_f基_5_異。惡 硫基)丙酸甲酯等。 」尽丫丞} αΐ封阻劑,可列舉如鹽酸帖拉若欣(ter♦⑷、鹽 316588 200521108 酸布那嗤哄(bunazosin)、烏拉地爾(urapidi 1)、鹽酸 (tamuslosiη)、曱石黃酸多沙。坐(doxazosin)、鹽酸帕若欣 (prazosin)、吲哚拉敏(ind〇lamine)、萘哌地爾 (仙€1:(^1心1)、鹽酸阿呋唑啡(以1112〇3]^)、塞羅多辛 (selodosin) 、 AIO-8507L 等。 抗膽鹼劑(antichol inergic drugs)之例可舉如鹽酸 羥丁寧(oxybutynin)、氣化倍舒可(bethanechol)、鹽酸丙 哌維林(propiverine)、溴化丙胺太林(propantheline bromide)、溴曱貝那替秦、溴化丁基莨菪鹼(sc〇p〇丨amine bromide)、酒石酸托特羅定(t〇iterodine tartrate)、氯 化曲司氯敍(trospium chloride)、Z-338、UK-112166 - 04、 KRP-197(ONO-8025)、達非那新(darifenacin)、YM-905 (soli fenacin succinate)等 〇 5 α -還原酶抑制劑之例可舉如非那雄安 (finasteride) 、 GI-998745 等。 抗雄性激素㈣之例可舉如普樂舒定(〇xend〇i〇ne)、乙 酸奥沙特隆(osaterone acetate)、白卡羅他邁 (bicalutamide)等。 其他之癌症治療劑之例可舉如烷基化劑(鹽酸癌得平 (nitrogen-mustard-N-oxide)、環鱗醯胺 (cyclophosphamide)、異環磷醯胺(ifosfamide)、左旋溶 肉瘤素(melphalan)、塞替派(thiotepa)、卡波酉昆 (carboquone)、白消安(busulfan)等)、硝基脲衍生物(鹽 酸尼莫司汀(1^1111131^116)、雷莫司汀(1^11][1111131;]^6)等)、代 316588 74 200521108 謝拮抗劑(滅癌靈(methotrexate)、氫硫基嘌呤、6-氫硫基 嘌吟核糖苷(6-mercaptopurine r iboside)、氟尿。密咬、替 加氟(tegafur)、UFT、卡莫氟(carmofur)、去氧氟尿:g: (doxyfluridine)、阿糖胸苔(cytarabine)、依諾他濱 (enocitabine)等)、抗癌抗生物質(放線菌素d、絲裂黴素 C(Mitomycin C)、鹽酸柔紅黴素(daunorubicin HC1)、鹽 酸14-經基柔紅黴素(doxorubicin HC1 )、鹽酸阿柔比辛 (aclarubicin HC1、新制癌素(neocarzinostatin)、D比口南 阿极素(0丨^]:1113丨(:111)、艾皮如比辛(€0丨1'11]3丨(3丨11)、鹽酸去 曱氧柔紅黴素(idarubicin)、色黴素A3(chr〇momycin A3)、博萊黴素(ble⑽ycin)、硫酸海普洛黴素等)、植物性 生物鹼(硫酸紡錘絲毒、硫酸長春新鹼、硫酸長春地辛 (Vindesine)等)、賀爾蒙劑(雌二醇胺芥(es1:ramus1:ine) 石粦酸納、美雄烧(mepitiostane)、環硫雄醇 (epitiostanol)、檸檬酸他莫昔芬(tamoxifen)、礙酸乙稀 雌驗(diethylstilbestrol)、乙酸每保隆 (medroxyprogesterone aecetate)等)、免疫增強劑(麻兹 多糖(lentinan)、溶血鏈球菌(Picibanii)、雲芝多酿 (krestin)、裂褶菌多醣(schizophyl lan)、烏班美司 (ubenimex)、干擾素等)、及其他(L-天冬醯胺酶、鹽酸丙 卡巴肼(procarbazine)、鹽酸米托蒽醌(mit〇xantr〇ne)、 順氯胺鉑(cisplatin)、卡鉑(carb〇piatin)等)。 類固醇劑之例可舉如外用藥之丙酸氣倍他索 (clobetasol propionate)、二乙酸二氟拉松(dif 1〇ras〇ne 316588 75 200521108 diacetate)、氣輕松乙 S曼 ^ (f luocinonide acetate)、莫 米松糠酸g旨(monometasone furoate)、二丙酸倍他米松 (betamethasone dipropionate)、正丁酸丙酸倍他米松 (betamethasone butyrate propionate)、戍酸倍他米松 (betamethasone valerate)、雙氟潑尼酯 (di f luprednate)、布地奈德(budesonide)、戊酸雙氟可龍 (diflucortolone)、安西奈德(amcinonide)、哈西奈德 (halcinonide)、地塞米松(dexamethasone)、丙酸地塞米 松(dexamethasone propionate)、戊酸地塞米松 (dexamethasone valerate)、乙酸地塞米松 (dexamethasone acetate)、乙酸氫化可的松 (hydrocortisone acetate)、正丁酸氫可的松、正丁酸丙 酸氫化可的松、丙酸21-去經強的松龍(deprodone propionate)、戊酸乙酸氫化可的松、乙酿胺氟輕松 (fluocinolene)、丙酸倍氯米松(beclomethasone propionate)、乙臨胺曲安西、龍縮酮(triamcinolone)、特 戊酸敦美他松(f lumethasorie pivalate)、丙酸阿氣米松 (alclometasone propionate) Λ 丁酸氣倍他松 (clobetasone butyrate)、氫化強的松、丙酸倍氣米松 (beclomethason propionate) N II 氮、缩松 (fludroxycortide)等。 内服藥、注射劑之例可舉如乙酸可的松、氫化可的松、 石粦酸氫化可的松納、破珀酸氫化可的松納、乙酸氤氫可的 松、氫化強的松、乙酸氫化強的松、琥珀酸氫化強的松納、 76 316588 200521108 丁基乙酸氫化強的松、磷酸氫化強的松鈉、乙酸鹵潑尼松 (halopredone)、甲基潑尼松(methylprednis〇1〇ne)、乙酸 曱基潑尼松、玻珀酸曱基潑尼松納、去炎松 (tnamcmolone)、乙酸去炎松、丙炎松(triamcin〇1〇ne acetonide)、地基米松(dexame1:hasone)、乙酸地塞米松、 磷酸地塞米松鈉、棕櫚酸地塞米松、乙酸對氟米松 (par am ethasone acetate)、倍他米松(betamethasone)等。 吸入劑之例可舉如丙酸倍氣米松(l)ec 1⑽ethas〇ne propionate)、丙酸氟替卡松(fiuticasoneprophnate)、 布地奈德(budesonide)、氣尼縮松(fiunis〇iide)、去炎 松、ST-126P、希克里奈德(cycies〇nide)、棕櫚酸地塞米 松、莫米松呋喃甲酸酯(mometasone fuorate)、普拉睪酮 (pr aster one sulfonate)、地夫可特(deflazacort)、石黃庚 酸甲基潑尼松(methylprednisolone suleptanate)、破 ί白 酸甲基潑尼松鈉。 促/3 2-腎上腺素受體藥之例可舉如氫溴酸酚丙喘寧 (phenoterol HBr)、硫酸舒喘靈(salbutamol sulfate)、 硫酸叔丁喘寧(terbutal ine sul fate)、反丁烯二酸福莫特 羅(formoterol fumarate)、沙美特羅羥萘曱酸鹽 (salmeterol xinafoate)、異丙基腎上腺素 (isoproterenol sul fate)、硫酸間羥異丙腎上腺素 (orciprenaline sulfate)、硫酸氣喘通(chlorprenaline sulfate)、腎上腺素(epinephrine)、鹽酸喘速寧 (trimethoquinol HC1)、硫酸六曱雙喘定(hexoprenal ine 77 316588 200521108 sulfate)、鹽酸丙卡特羅(procater〇i HCl)、鹽酸妥洛特 羅(tulobuterol HC1)、妥洛特羅、鹽酸吡丁醇 (pirbuterol)、鹽酸氨雙氣喘通(cienbuterol HC1)、鹽酸 馬布特羅(mabuterol)、鹽酸利托君(ritodrine HC1)、幫 備(bambuterol)、鹽酸多培沙明(d〇pexamine HC1)、酒石 酸-美拉林(meradrin- tartrate)、AR-C68397、左旋沙布 它莫(levosalbutamol)、R,R-福莫特羅 (R,R-formeterol)、膽-1246、KUL-7211、AR-C89855、 S-1319 等。 白二稀素受體拮抗劑之例可舉如普蘭魯卡 (pranlukast)水合物、蒙特硫卡酸(m〇nte][ukast)、扎非留 卡(zafirlukast)、舍曲達斯(serat;r〇das1:)、mcc—847、 KCA-757、CS-615、YM-158、L-740515、CP-1 95494、LM-1484、 RS-635 、 A-93178 、 S-36496 、 BIIL-284 、 0N0-4057 等。 血栓素合成酶抑制劑之例可舉如鹽酸奥扎格雷 (ozagrel HC1)、伊米達斯鈉(lmitr〇dast Na)等。 血权素A2文體拮抗劑之例可舉如舍曲達斯 (seratrodast)、雷馬曲班(ramatr〇ban)、多米特羅班鈣 (domitroban Ca)水合物、κτ —2 —962 等。 媒介物遊游離抑制劑之例可舉如曲尼司特 (tranilaSt)、色甘酸納(sodium cr⑽oglicate)、安來喏 克司(amleXan〇X)、瑞吡司特(rePirinast)、異丁斯特° (ibudilast)他礼司特、吼。密司特—鉀 (pemilolast-K)等 。 316588 78 200521108 抗組織胺劑之例可舉如反丁烯二酸酮替芬 (ketotifen)、美喹他畊(mequitazine)、鹽酸氮箪斯汀 (azelastine)、奥沙米特(oxat〇mide)、特非那定 (terfenadine)、反丁烯二酸依美斯、;丁(emedastine fumarate)、鹽酸依匹斯丁(epinastine HC1)、阿斯咪唾 (astemizole)、依巴斯汀(ebastine)、鹽酸西替利D井 (cetirizine)、白泊塔斯、;丁(bepotastine)、緩基特非那定 (fexofenadine)、氣雷他定(loratadine)、脫叛氣雷他定 (desloratadine)、鹽酸奥洛他定(〇i〇patadine)、 TAK-427、ZCR-2060、NIP-530、莫米松咲喃曱酸酯 (mometasone furoate)、味唾斯、汀(miz〇iastine)、 BP-294、安付留(ando 1 ast)、金諾芬(auranof iη)、阿伐斯 丁(acrivastin)等。 黃嘌呤衍生物之例可舉如胺基非林 (aminophylline)、茶(葉)鹼、多克索非林 ((1〇乂〇^117111116)、西帕非林(以阳111以111116)、二羥丙茶鹼 (diprophy11ine)等。 抗膽驗劑之例可舉如漠化異丙托胺(i pratr〇p i um br⑽ide)、溴化氧托胺(oxitropium bromide)、溴化氟托 敍(flutropium bromide)、漠化西托胺(cimetropium bromide)、替米維林(temiverine)、溴化噻托品 (tiotropium bromide)、瑞伐托 g旨(revatropate, UK-112166)等。 細胞素抑制劑之例可舉如曱磺斯特(sup 1 atast 79 316588 200521108 tosy late)(商品名 IPD)等。 前列腺素類(以下簡稱為PG)之例可舉如PG受體催動 劑、PG受體拮抗劑等。 PG受體之例可舉如PGE受體(EP1、EP2、EP3、EP4)、 PGD 受體(DP、CRTH2)、PGF 受體(FP)、PGI 受體(Ιρ)、τχ 受體(TP)等。 磷酸雙酯酶抑制劑之例可舉如PDE4抑制劑之羅利普 蘭(rolipram)、cilomi last (商品名亞力扶羅)、Bayl9 — 8004、NIK-616、roflumilast(BY-217)、西帕非林 (Cipamfylline)(BRL-61 063)、阿提唑蘭(atiz〇lam) (CP-80633)、SCH-351 59bYM-976、V-1 1294A、PD-1 68787、 D-4396 、 IC-485 等。 彈性蛋白酶抑制劑之例可舉如ΟΝΟ—5046、ΟΝΟ-6818、 MR-889、PBI-l 1 01、ΕΡΙ-ΗΝΕ-4、R-665、ZD-0892、ZD-8321、 GW-311616 、 AE-3763 等。 止痰藥之例可舉如茴香油銨、碳酸氫鈉、鹽酸溴己胺 (bromh ex ine HC1)、魏曱基半脱胺酸(carbo cysteine)、鹽 酸氨溴索(ambroxol HC1)、鹽酸氨溴索緩釋劑、甲基半胱 胺酸鹽酸鹽(methylcysteine HC1)、乙醯半胱胺酸 (acetylcysteine)、鹽酸L-乙基半胱胺酸、四丁酚醛等。 HMG-CoA還原酶抑制劑之例可舉如辛發他汀 (simvastatin)、洛發他汀(lovastatin)、普巴他汀 (pravastatin)、氟發他汀(fluvast at in)、阿托發司他汀 (atorvastin)、匹發他汀(pitavastatin)、阿托發司他汀 80 316588 200521108 (lovastatiη)等。 貝特(fibrate)系製劑之例可舉如非諾貝特 (fenofibrate)、克利貝特鹽(ciinofibrate)、氯貝特 (clofibrate)、氯貝特銘(aluminum clofibrate)、雙貝特 (simfibrate)、苯紮貝特(bezafibrate)等。 丙丁酚(probucol)製劑之例可舉如丙丁盼等。 菸驗酸製劑之例可舉如菸驗酸生育酚酯、菸驗酸環已 醇醋、於驗酸戊四醇S旨(1)丨〇61*]11::1:〇1)等。 其他之抗高膽固醇藥之例可舉如消膽胺 (cholestyramine)、大豆固醇(soyster〇i)、 等。 非類固醇系抗發炎劑之例可舉如水揚酿水楊酸 (Sasapyrine)、水楊酸鈉、阿司匹靈、阿司匹靈二紹酸鹽 配合劑、雙氟尼酸((1丨丨11111丨331)、[1引[1朵美辛 (indomethacine)、名于 各芬(suprof en)、優芬男p 美特 (ufenamate)、二曱基異丙奠、丁苯羥酸(bufexamac)、聯 苯乙酸(felbinac)、雙氯芬酸(diclofenac)、痛滅定鈉 (tolmet in-Na)、舒林酸(cl inor i 1)、芬布芬(f enbuf en)、 萘丁美酮(nabumetone)、丙榖美辛(proglumetacin)、吲哚 美辛金合歡S旨(indomethacine farnesyl) 、 P可西美辛 (acemetacin)、順丁稀二酸丙穀美辛、胺芬酸納 (amf enac)、莫本唑酸(mof ezolac)、依托度酸(etodolac)、 布洛芬(ibuprof en)、吼σ定曱基-酸布洛芬(ibuprof en pi conol)、萘普生(naproxen)、氟比洛芬(flurbiprofen)、 81 316588 200521108 氟比洛芬乙醯乙酯(f lurbiprof en axety 1)、酮洛芬 (ketoprofen)、本氧基虱化阿托酸化詞(fen〇pr〇fen —ca)、 []卷洛芬(1:1&0]:〇(611)、嗓丙[1井(〇又叩]:〇21]1)、普拉洛芬 、pranoprofen)、氣索洛芬鈉(i0X0pr0fen_Na)、阿明洛芬 (alminoprofen)、扎托洛芬(sait〇pr〇fen)、曱滅酸 (mefenamic acid)、曱滅酸鋁、托芬那酸(t〇ifenamic acid)、夫洛非寧(fl〇c ta fen in)、豈几布宗 (ketophenylbutazone)、羥布宗(oxyphenbutazone)、吡羅 昔康(piroxicam)、替諾昔康(tenoxicam)、安D比昔康 (ampiroxicam)、聯苯乙酸(napagel)軟膏、依匹唾 (epirizole)、鹽酸噻拉米特(tiaramide HC1)、鹽酸替諾 利定(t inor idine HC1)、依莫法宗(emorf azone)、蘇爾匹 林(sulpyrin)、米格來寧(migrenin)、散利痛(sar id〇n)、 胺基比林(Sedes G)、胺丙吡酮(Amipylo-N)、舒邦 (sor bon)、比林系感冒藥、乙醯胺基盼(acetamin〇phen)、 非那西汀(phenacetin)、二曱替D井曱石黃酸鹽 (dimethothiazine mesylate)、西美催德(Simetrid)配合 劑、非比林糸感冒藥等。 疾病修飾性抗風濕性關節炎劑(緩效型抗風濕性關節 炎劑)之例可舉如硫代葡萄糖金(aurothioglucose)、硫代 蘋果酸金(aurothioma 1 ate)納、金諾芬(auranof iη)、阿特 力(actar i t)、D-青黴胺(penici 1 lamine)製劑、氣苯扎利 二鈉(lobenzarit)、布西拉明(bucillamine)、伯勞奎寧 (hydroxychloroquine)、柳氮磺胺吡啶 82 316588 200521108 (salazosulfapyridin)等 ° 軟骨保護劑之例可舉如玻糖醛酸鈉、葡萄糖胺 (glucosamine)、硫酸軟骨素(ch〇ndr〇itin sulfate)、多 硫酸糖酿胺聚糖(Glycosaminoglycan)等。 前列腺素合成酵素抑制劑之例可舉如柳氮磺胺吡啶、 胺基水楊酚(mesalazine)、奥沙拉秦(〇isaiazine)、4-胺 基水楊酸、JTE-522、金諾芬、卡洛芬(carpr〇fen)、聯苯 肶胺(diphenpyramide)、弗諾噁洛芬(flun〇xapr〇fen)、氟 比洛芬(flurbiprofen)、吲哚美辛(ind⑽ethacine)、酮洛 芬(ketoprofen)、氯諾昔康(1〇]^〇}(;[(:_)、氯索洛芬 (loxoprofen)、美洛昔康(meloxicam)、噁丙哄 (oxaprozin)、帕沙米得(parsaimide)、吡普森 (piproxen)、吡羅昔康(pir〇xicam)、吡羅昔康万—環糊精 Cpiroxicam betadex)吡羅昔康桂皮酸酯、托品吲哚美辛 P n indometacinate)、扎托洛芬(zait〇profen)、普 拉洛芬(pranoprofen)等。 式(I)所示之本發明化合物與其他藥劑之重量比並無 特別之限定。 ” 其他藥劑亦可以任意2種以上組合投藥。 仏補充及/或增強式(1)所示本發明化合物之預防及/或 /σ療效果之其他藥劑’包含目前已發現,以及今後所發現 具有上述機制者。 物ί(Ι)所示之本發明化合物或式(I)所示之本發明化名 H他藥劑之併用劑係使用於上述目的中,—般可以乂 316588 83 200521108 全身或局部、口服或非口服之形式投藥。 投藥量可依據其年齡、體重、症狀、治療效果、投藥 方法處理日守間專而異,但一般而言,經口投藥時,成人 每人、每次〇. 01邶至10〇〇mg,以〇. lmg至500mg為較佳, 或、〇 · 1 mg至3 0 0mg為更佳,1日投與1次至數次;非口 服投藥時,成人每人、每次O.Olmg至500mg,以〇. lmg至 l〇〇mg為較佳,以〇. lmg至5〇呢為更佳,^日投藥1次至 數次;亦可每日持續投與靜脈,歷時丨小時至24小時。 田然,如丽所述其投藥量可依照種種條件變動,因此 /、 上述技^畺少亦充份之場合,及投藥必須超過該範 圍之場合。 摩 ,()所示之本餐明化合物或式(I)所示之本發明化合 物與其他藥劑之制劑在投藥時,口服投藥可以使用内服 用固形劑、内服用液劑,非口服投藥可以使用注射劑、外 用劑、栓劑、點眼劑、吸入劑等。 志^服投藥使用之内服用固形劑包含錠劑、丸劑、膠囊 政片]顆粒劑等。膠囊劑包含硬勝囊劑及軟膠囊劑。 所此種内服用固形劑中可以單包含工種或以上之活性物 二亦T再:昆合賦形劑(乳糖、甘露糖醇、葡萄糖、微晶纖 甲其、?分等)、結合劑(羥丙基纖維素、聚乙烯吡咯烷酮、 (::夕f、鋁酸鎂等)、崩解劑(纖維素乙醇酸鈣等)、滑潤劑 Μ曰㈣等)、安定劑、助溶劑(麩胺酸、天門冬胺酸等) 寺’再依一般配方製劑。. 糖、明嘐、經丙Α纖唯广 以再包覆糖衣劑(白 基,.·減維素、羥丙基甲基纖維素酞酸酯等), 316588 84 200521108 亦可以以2層以上包覆0 士认 此外亦包含可吸收物質製成之膠 囊。 ^ 内服用液劑包含藥劑上交 上谷許之水劑、懸浮劑、乳劑、 糖漿劑、酏劑等。此種液劑中 從4中可以包含1種或以上之活性 物質,再以-般使用之稀釋劑(精製水、乙醇或其混合 等)溶解、懸浮或乳化。此 ^ ^ 此檀液劑中亦可以再包含濕潤劑、 懸浮化劑、乳化劑、甜口夬添1 …J、風味劑、芳香劑、保存劑、 緩衝劑等。 非經口服投與之外用劑之劑形包含例如軟膏劑、膠 劑、乳膠劑、濕貼劑、貼劑、擦劑、喷霧劑、吸入劑、嘖 劑、氣化喷霧劑、點眼劑及點鼻劑等。Λ等可以包含4 或以上,活性物質’再以一般所知或通常使用之配方製造。 軟嘗劑可以以一般所知或通常使用之配方製造。例如 將上種或以上之活性物質與基劑混合研磨、或炫融製造。 軟膏基劑可選擇-般所知或通常使用之物質。可列舉如高 級脂肪酸或高級脂肪酸酷(己二酸、肉豆㈣、掠搁酸、二 脂酸、油酸、己二酸酯、肉立謹酸酯、棕櫊酸醋、硬脂酸 酯、油y酸醋等)、蠟類(蜜蠟、鯨蠟、純地蠟等)、界面活性 劑(聚氧伸乙基烷基醚磷酸酯等)、高級醇(鯨蠟醇、硬脂 醇、十八醇十六醇混合物等)、矽油(二甲基聚矽氧烷等)、 煙類(親水性凡士林、白凡士林、精製綿羊油、液體石虫鼠 等)、二醇類(乙二醇、二乙二醇、丙二醇、聚乙二醇、1 乙二醇(Macrogoi)等)、植物油(蓖麻油、撖欖油、麻油、 萜烯油等)、動物油(貂油、印黃油、三十碳烷、角紧烯等)、 316588 85 200521108 =物吸防斑.劍中選擇之單獨或2種以上之混 合物。亦可以再含保濕劑、 芳香劑等。 Μ子劑、安定劑、抗氧化劑、 凝膠劑可以以一妒於 將1種或以上之活性:質=通:使用之配方製造。例如 擇-般所知或通常使用者凝膠基劑可選 等)、凝谬化劑⑽基纖 二二:::(乙醇、異丙醇 維素、乙基纖維素等)、中=:2,維素、經丙基纖 界面活性劑(單硬脂酸聚二-異丙㈣專)、
促進劑、防斑療劑中選擇之單獨或2種以上之、、θ入物1 可以再含保存劑、抗氧化劑、增香劑等。,亦 乳膠劑可以以一 'S 將!種或以上之活二=:使用之配方製造。例如 乳隸,可、1 / ㈣卿制中調製。 ,基片丨了进擇一般所知或通常使用者。可 如古 肪酸醋、低級醇、烴類、多元醇(丙二醇、丁二:等曰 南級醇(2-十六垸醇、㈣醇等)、乳子、 基_、脂肪酸醋類等)、水、吸 ^來乳伸乙基•烷ί 擇之單獨或2種以上之混合 化劑、芳香劑等。 了乂再含保存劑、抗氧 =劑可以以—般所知或通常使用之配方製造。例如 屏、=之活性物質溶於賦形劑中’再將其混拌物延 於支持物上製成。濕布劑賦形劑可選擇一般所知或 、吊使用者。可列舉如增黏劑(聚丙稀酸、聚乙稀卩比嘻烧 s问、阿拉伯膠、澱粉、明膠、甲基纖維素等)、濕麵尿 316588 86 200521108 素、甘油/两二醇等)、填充劑(高嶺土、氧化辞、滑石粉、 鈣、鎮等)、水、助溶劑'黏著劑、防斑疹劑中選擇之單獨 或2種以上之混合物。亦可以再含保存劑 香劑等。 平 …方 1猶Γ劑可以以—般所知或通常使用之配方製造。例如將 札二以上之活性物質溶於賦形劑中,再延展塗布於支持 列舉…二 了廷擇一般所知或通常使用者。可 二基劑、油脂、高級脂肪酸、黏著劑、防斑产 :中選擇之單獨或2種以上之混合物。亦可以再含保:療 剎、彳几氧化劑、芳香劑等。 ’、 :: 可以以一般所知或通常使用之配方製造。例如將 .一;t之活,物質溶解、懸浮或乳化於水、醇(乙醇、 小—醇等)、高級脂肪酸、甘、、由、白相 " 劑中選擇之單獨或2種以上之中制^ 化劑、懸浮化 劑、抗氧化劑、芳香劑等。之中衣成。亦可以再含保存 噴霧劑、吸入劑、喷劑, 亦可再含亞硫酸氯納等安定劑及賦稀釋劑以外, 如氣化納、檸檬酸.㈣於讲及城予寻張性之緩衝劑,例 在美國專利第2 86δ 6丁 :酸等等張劑。噴劑之製造方法 有詳細之=,69丨就及美國專利第⑽5,咖號令 非經口投與之注射劑包々 使用時於溶劑中加以溶解…:液:懸浮液、乳化液及在 注射劑可以將!種或以上之之固形注射劑。 溶劑中使用。溶劑可使用之例可懸浮或乳化於 Τ舉如〉主射用蒸餾水、生理 3Ϊ6588 87 200521108 良鹽水、植物油、而一幢、取一 一-子+乙一釦、乙醇等醇類等及彼 Λ ,,且σ。该〉主射劑中亦可以再含安定劑、助溶劑(麩胺 丄 、、胺S文承山梨糖醇酯8 0 (登錄商標)等)、懸浮化 劑、乳化劑、消痛劑、緩衝劑、保存劑等。此等再^最後 二驟中滅菌或以無菌操作法製造。無菌之固形劑可以例 冷編品,使用前再以經無菌化或無菌之注射用 和衣水、或其他溶劑溶解後使用。 月“又*之點眼劑包含點眼液、懸浮型點眼液、乳 化尘點眼液、使用時溶解型點眼液及眼軟膏等。 此等點眼劑可以依一般所知之方法製:。例如们種 :之活性物質溶解、懸浮或乳化於溶劑中使用。眼劑 款洛制可使用之例可舉如減菌精製水、生理食鹽水、其 =水性溶劑或注射用非水性溶劑(例如植物油等)等及其 、、且a。點眼制中依其必要亦者 、 化納、濃甘油等)含有寺張劑(氯 )、友衝月丨(&酉夂鈉、乙酸鈉等)、界面活性 片J (♦山梨糖醇酯8 〇 (两σ么、 w商㈤名)、聚核氧乙烷聚硬脂酸酯 4U、聚核氧乙烷硬化芎府、、占堃、^ ^ 心… 昆麻,由寺)、文定劑(檸檬酸鈉、依地 酉文鈉寻)、防腐劑(烷基二 土卞基叙虱化物、對羥苯甲酸 > _^年此'再於取後之步驟中滅菌或以無g操作法製造。 熙囷之固形劑可以例如製成 菌化或無菌之注㈣精μ tr 知衣水或其他溶劑溶解後使用。 二口服投藥之吸入劑包含噴氣劑、吸入用粉劑或吸入 m用液劑亦可為使料財或其他適當之溶 劑溶解或懸浮之形態使用。 316588 88 200521108 此等吸入劑可以依照一般所知之方法製造。 例如在製造吸入用液劑之場合,可以依照須要適當地 選擇防腐劑(烷基二曱基苄基銨氣化物、對羥笨曱酸等)、 著色劑、緩衝化劑(磷酸鈉、乙酸鈉等)、等張化劑(氯化納、 濃甘油等)、增黏劑(羧乙烯聚合物等)、吸收促進劑等調製。 在製造吸入用粉劑之場合,可以依照須要適當地選擇 滑潤劑(硬脂酸及其鹽等)、結合劑(澱粉、環狀糊精等)、 賦形劑(乳糖、纖維素等)、著色劑、防腐劑(烷基二曱基苄 基銨氯化物、對羥苯曱酸等)、吸收促進劑等調製。 ^吸入用液劑在投藥時一般可使用喷霧器(霧化器、喷霧 (nebul izer)),吸入用粉劑在投藥時一般可使益 劑用吸入投藥器。 木市 非口服投藥之其他組成物,可以包含丨種或以上之 貝、包括依照一般方法處方之舌下投藥用之舌下劑 腸内投樂用之拴劑及膣内投藥用之子宮劑等。 f (1)所不之本發明化合物之局部投藥,只要可以 在心部部位上供給藥劑者 。 可列舉如肌肉内、皮下、哭:丄方法亚無限定 入荜穿為j、 口口 S、關即部位等之注射劑、〗 二):散劑等固形製劑、軟膏劑等。 續性在患邛邻:之广發明化合物之持續性製劑,只要可以. 舉如緩釋性:射:給樂劑者即可,製劑並無限定。可〗 劑等)、吸如微❹ 、入樂製劑(例如膜製劑等)等。 上述微囊製劑、矜 ㈣叔製劑、奈米粒製劑為含活性i 316588 89 200521108 份式(I)所示本發明化合物或式(i)所示本發明化合物與其 他藥劑之併用劑之體内分解性聚合物之微粒狀醫藥組成 物。 本發明之體内分解性聚合物可列舉如脂肪酸酯聚合物 或其共聚物、聚丙烯酸酯類、聚羥基丁酸類、聚伸烷基草 酸酯類、聚正烷酯、聚碳酸酯及聚胺基酸類,可以其1種 或其以上混合使用。脂肪酸酯聚合物或其共聚物可例舉如 聚乳酸、聚乙醇酸、聚檸檬酸、聚蘋果酸及乳酸-乙醇酸共 聚物,可以其1種或其以上混合使用。亦可使用其他之聚-α -氰基丙婦酸酯、聚-/3 -經基丁酸、聚氧雜環丁烧、聚原 酸酯、聚原碳酸酯、聚碳酸伸乙酯、聚-Τ-苯曱基-L-麩胺 酸及聚-L-丙胺酸之1種或其以上之混合物。其中以聚乳 酸、聚乙醇酸或乳酸-乙醇酸共聚物為佳,以乳酸-乙醇酸 共聚物更佳。 本發明中所使用之此等體内分解性高分子聚合物,平 均分子量以約2, 000至約800, 000者為佳,以約5, 000至 約20 0, 000者為更佳。例如聚乳酸以平均分子量約5, 000 至約1 00, 0 00者為佳。平均分子量約6, 000至約50, 000 者為更佳。聚乳酸可以以其本身一般所知之製造方法合 成。乳酸-乙醇酸共聚物乳酸與乙醇酸組成之比例以約 100/0至約50/50(W/W)者為佳,特別是約90/10至約 50/50 (W/W)者更佳。乳酸-醇酸共聚物之重量平均分子量以 約5, 000至約1 00, 000者為佳。約1 0, 000至80, 000者更 佳。乳酸-乙醇酸共聚物可以以其本身一般所知之製造方法 90 316588 200521108 合成。 本。兒明書中之重置平均分子量指以膠體層析(Gpc)測 定後換算為聚苯乙稀之分子量。 前述之體内分解性高分子聚合物,只要可達成本發明 之目的亦可以改、交式⑴所不本發明化合物藥理活性之強 度、及目的樂物之釋出’例如可使用對該生理活性物質約 〇· 2至10, 〇〇〇倍(重量比)之量,或約i至i,刪倍(重量 比)之量更佳,約1至100倍(重量比)之量又更佳。 本發明化合物之命名如下所示。 參 本口兒明書中所使用之命名法為佑、照J UPAC規則之方 法’或依照IUPAC通俗命名規則電腦化之系统acd/n_ 或 ACD/Name Batch 版(登錄商標,均為 Advanced chemi Development Inc.公司製)之方法。例如
所表示之化合物命名為4_K2S)_2_[(SM3,5_二甲氧基 -4-曱基苯基)(經基)甲基]_5 —苯基戊基}苯基)乙酸。土 [發明之效果] 本發明式⑴表示之本發明化合物、其鹽、或其溶劑人 物、或其藥物前體對LPA受體(特別是EDG_2)具拮抗作用, 因此可用以預防及/或治療泌尿系統疾病、癌相關疾病、增 316588 91 200521108 殖丨生疾病叙义性·免疫系統疾病、分泌障礙引起之 腦相關疾病、慢性疾病等。 ;、病、 【實施方式】 以下即以參考例及實施例詳細說明本發明,但 並不受此限定。 ★明 藉由層析分離時,於TLC處所示之括號内之溶巧 示所使用溶出之溶劑或展開溶劑,其中之比例表示體/ 比。在NMR測定中所使用之溶劑,在未特別註明時^ 用重氣仿(CDC13)。 錢 無定形物經偏光顯微鏡確定。
實施例苯基_2_(3,4,5_三?氧基苯甲酿 基]苯氧基}苯甲酸 A 將3’4, 5-三甲氧基苯甲酸與乙二酸氯反應所製成之 酸氯化物,再經與N,〇一二f基經胺·鹽酸鹽反應,可製成 3’4’5-四甲氧基甲基苯甲軸。再將該製成之化合物 與4-苯基丁基鎮氣化物反應,可製成5-苯基-丨―(3,4 5_ 三甲氧基苯基)戊+酮。該製成之化合物再於n,n,n,, 五甲基二伸乙基三胺存在下與二異丙基胺化鐘及 2-[4-(溴T基)苯氧基]苯甲酸鍾反應,即可製成2_{4_[5_ 苯基-2-(3, 4, 5-三甲氧基苯子酿基)戊基]苯氧基}苯甲酸 甲酯。該製成之化合物再經氫氧化納水解,即可製成具有 以下物性值之標題化合物。 TLC : Rf 〇· 43 (二氣甲烷··甲醇=9 : ^ · 316588 92 200521108 ^NMR : 5 8.19 (dd, 1H), 7.45 (m, 1H), 7.30-7.08 (m n , u> 7.04 (s> 2H) 6.95 (d, 2H), 6.63 (d, 1H), 3.90 (s, 3H), 3.85 (s, 6H), 3 65 (m ’ • 出),3.07 (dd 1H),2.83 (dd, 1H),2.60 (t,2H), 1·98·1·45 (m, 4H)。 , 實施例2: 2-(4-{2-[羥基(3,4,5-三曱氧基笨基)曱基]_5_ 苯基戊基}苯氧基)苯甲酸
OH
在貝施例1中製成之化合物(l〇〇mg)之四氫D夫喃(化1) 與曱醇(4ml)之混合溶液中,加入氫硼化鈉(1〇〇mg)。將該 反應混合物再於室溫下攪拌1小時。反應混合物中再加入 飽和氯化銨水溶液,並經乙酸曱酯萃取。該萃取物再經飽 和食鹽水洗淨、無水硫酸鈉乾燥後濃縮。其殘留物再經石夕 膠管柱層析(二氣曱烷:曱醇=30: 1— 20: 1 )精製,即可製 成具有以下物性之標題化合物(34mg)。 TLC.Rf 0.46 (二氣曱烧:曱醇;1); lENMR : 6 8.23 (dd, 1H), 7.46 (ddd, 1H), 7.30-6.98 (m, l〇H), 6.79 (d, 1H), 6.56-6.48 (m, 2H), 4.58 (m, 1H), 3.88-3.80 (m, 9H), 2.92*2.45 (m, 4H), 2.02 (m, 1H), 1.82-1.30 (m, 4H)。 實施例2 (1)至實施例2 ( 7) 由3, 4, 5-三曱氧基笨曱酸或其相當之羧酸衍生物、4一 93 316588 200521108 笨基丁基鎂氯化物或其相當之格利雅試藥及2_[4—(溴甲 基)苯氧基]苯甲酸曱酯或其相當之苯曱基溴衍生物,進行 與實施例1—實施例2相同之操作,即可製成以下之本發 明化合物。 & 貫施例2(1):2-(4-{2-[(3,5-二甲氧基-4-甲基笨基)(羥 基)甲基]-5-苯基戊基}苯氧基)苯曱酸 TLC : Rf 0· 48 (二氯甲烷:甲醇=9 : 1); HNMR : δ 8.23 (dd, 1H), 7.45 (dd, 1H), 7.30-7.04 (m, 8H), 7.00 (d, 2H) 6.77 (m, 1H), 6.52-6.44 (m, 2H), 4.60 (m, 1H), 3.82-3.78 (m, 6H), 2.95-2.45 (m, 4H), 2.10-1.98 (m, 4H), 1·80·1·30 (m,4H)。 實施例2(2) : 3-{2-[羥基(3, 4, 5-三甲氧基苯基)甲基卜5〜 苯基戊基}苯曱酸 TLC ·· Rf 0· 28 (二氣曱烷:曱醇=9 : 1); 'HNMR : (5 7.98-7.88 (m, 2H), 7.40*7.02 (m, 7H), 6.58-6.46 (m, 2H), 4.62-4.54 (m, 1H), 3.88-3.78 (m, 9H),2·95·2·44 (m,4H), 2.05 (m, 1H), 1.80Ί.15 (m, 4H)〇 實施例2(3) : 2-(4-{2-[( 3, 5-二曱氧基-4—曱基苯基)(經 基)曱基]-5-苯基戊基}苯氧基)-4-曱基苯曱酸 TLC ·· Rf 0· 55 (二氣甲烷:曱醇=9 : 1); 1 HNMR : <5 8.11 (d,1H),7.28-6.96 (m,10H), 6.58 (s,1H), 6.52-6.45 (m, 2H), 4.60 (m, 1H), 3.83-3.78 (m, 6H), 2.92-2.45 (m, 4H), 2.28 (s, 3H), 2.12-2.06 (m, 3H),2.04 (m, 1H), 1·82· 1·42 (m, 4H)。 實施例2(4) : (4-{2 - [(3, 5-二甲氧基-4 -曱基苯基)(羥基) 曱基]-4-苯基丁基}苯基)乙酸 316588 94 200521108 TLC : Rf 0· 32 (二氣曱烷:甲醇二9 : 1); 1 HNMR : d 7.35-6.92 (m, 9H), 6.50-6.42 (m, 2H), 4.64 (m, 1H), 3.81*3.75 (m, 6H), 3.63 (s, 2H), 2.92-2.44 (m, 4H), 2.08-2.04 (m, 3H), 2.03-1.35 (m, 3H)〇 實施例2(5) : (4-{2-[(3, 5-二甲氧基-4-曱基苯基)(羥基) 甲基]- 6-苯基己基}苯基)乙酸 TLC ·· Rf 0· 31 (二氯甲烷:甲醇=9 ·· 1); 1 HNMR : d 7.32-7.05 (m, 9H), 6.52-6.42 (m, 2H), 4.60 (m, 1H), 3.82-3.78 (m, 6H), 3.62 (s, 2H), 2.82*2.42 (m, 4H), 2.10-2.02 (m, 3H), 2.02-1.20 (m, _ 7H)〇 實施例2(6) ·· (4-{2-[(3, 5-二曱氧基-4-曱基苯基)(羥基) 曱基]-5-四氫-2H-D比喃-4-基戊基}苯基)乙酸 TLC : Rf 0· 67 (乙酸乙酯:甲醇=9 : 1); ^NMR . δ 7.19 (d, 2H), 7.11 (d, 2H), 6.51-6.45 (m,2H), 4.60 (m, 2H), 4.00-3.50 (m, 10H), 3.40-3.20 (m, 2H), 2.90-2.40 (m, 2H), 2.20-1.90 (m, 4H), 1·50·1·00 (m, 11H)。 貫施例2(7) · {4-[2-苯曱基-3-(3,5-二曱氧基-4—曱基苯 基)-3-羥基丙基]苯基}乙酸 TLC ·· Rf 0· 46 (氣仿:甲醇: 1); 1 H NMR : ί 2.06 (s, 3H), 2.44 (m, 2H), 2.69 (m, 3H), 3.58 (m, 2H), 3.72 (s, 1H),3·79 (s, 6H), 4·61 (d, 1H), 6.45 (s, 2H), 7·15 (m, 9 H)。 只施例3 · (4 - {2-[(3,5-二曱氧基-4-甲基苯基)(經基)曱 基]- 5-本基戊基}苯基)乙酸甲|旨 將3, 5-二甲氧基-4-甲基苯甲酸與乙二醯氯化物反 316588 95 200521108 應,製成酸氣化物,將其再與N,0-二曱基羥胺·鹽酸鹽反 應,可製成Ν,3, 5-三甲氧基-Ν,4-二曱基苯曱醯胺。再將 該製成之化合物與4-苯基丁基鎂氯化物反應,可製成工一 (3, 5-二甲氧基-4-甲基苯基)-5-苯基戊—卜酮。該製成之化 合物再於Ν,Ν,Ν’,N",IT-五曱基二伸乙基三胺存在下與二 異丙基胺化鐘及[4-(溴曱基)苯基]乙酸曱酯反應,即可製 成{4-[ 2-(3, 5-二曱氧基-4-曱基苯曱醯基)一5一苯基戊基] 苯基}乙酸曱酯。該製成之化合物再經與實施例2相同之操 作,即可製成具有以下物性之標題化合物。 TLC : Rf 〇· 40 (己烷··乙酸乙酯=1:1); 1H NMR : d 7.32-7.02 (m, 9H), 6.50 (s, 1/2H), 6.44 (s, 3/2H), 4.60 (m, 1H), 3.81 (s, 3/2H), 3.78 (s, 9/2H), 3.69 (s, 3H), 3.60 (s, 2H), 2.90-2.42 (m, 4H), 2.07 (s, 3H), 2.02 (m,1H), 1·75-1·〇5 (m, 4H)。 實施例4(1)至實施例4(4) 將實施例3中製成之化合物在下述HPLC條件下精製, 以使順~非對映異構物(實施例4(1)與實施例4(2)之混合 物)與反-非對映異構物(實施例4(3)與實施例4(4)之混合 物)分離。 HPLC分離條件 管柱:順相系矽膠管柱YMC-Pack SIL(250x 30mm); 溶出溶劑:己烷:四氫呋喃=85 : 15 ; 流速· 2 5 m 1 / m i η ; 滯留時間:37.03111]^(順-非對映異構物)、39.56111]^(反-非對映異構物); 96 316588 200521108 將依上述方法製成之順-非對映異構物及反—非對映豈 構物,在下述HPLC條件下精製,即可各分離出以下所示之 化合物。 HPLC分離條件 管柱:順相系 CHIRALCEL 0J-H(2cm0 X 25cm); 溶出溶劑:曱醇; 流速:9. 5 in 1 / m i η ; 滞留時間:2 7 · 5 0 m i η [實施例4 (1) ]、2 4,7 3 m i η [實施例4 (2)]、40.56min[實施例 4(3)]、48.83min[實施例 4(4)] 實施例4(1):(4-{2-(23)-2-[(3)-(3,5-二曱氧基-4-曱基 苯基)(羥基)曱基]-5-苯基戊基}苯基)乙酸曱酯
TLC : Rf 0· 40 (己烷··乙酸乙酯=1 : 1); ^NMR : δ 7.27-7.02 (m, 9H), 6.50 (s, 2H), 4.59 (m, 1H), 3.81 (s, 6H), 3.70 (s, 3H), 3.60 (s, 2H), 2.82 (dd, 1H), 2.61 (dd, 1H), 2.45 (t, 2H), 2.09 (s, 3H), 2.02 (m, 1H), 1.68-1.10 (m,4H)。 實施例 4(2) : (4-{(2R)_2-[(R)-(3, 5-二曱氧基-4-甲基苯 基)(羥基)曱基]-5-苯基戊基}苯基)乙酸曱酯 97 316588 200521108
QH CH, CH30
COOCH3 TLC、沱匪R數據與實施例4(1)相同。 實施例 4(3) ·· (4-{(2R) —2-[(S)-(3, 5-二曱氧基-4-曱基苯 基)(羥基)曱基]-5-苯基戊基}苯基)乙酸曱酯
TLC · Rf 0.40 (己烧·乙酸乙 S旨=1 · 1),
2HNMR : δ 7.25-7.04 (m, 9H), 6.44 (s, 2H), 4.59 (m, 1H), 3.78 (s, 6H), 3.69 (s, 3H), 3.60 (s, 2H), 2.66 (dd, 1H), 2.55-2.45 (m, 3H), 2.07 (s, 3H), 2.03 (m, 1H), 1.78-1.38 (m, 4H)〇 實施例 4(4) : (4-{ (2S)-2-[(R)-(3, 5-二曱氧基-4-曱基苯 基)(羥基)曱基]-5-苯基戊基}苯基)乙酸曱酯
QH
98 316588 200521108 TLC、1關MR數據與實施例4(3)相同。 實施例 5(1) : (4-{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱基苯 基)(羥基)曱基]-5-苯基戊基}苯基)乙酸 在實施例4( 1)中精製之化合物(1 〇〇mg)之曱醇(3mi) 溶液中加入IN氫氧化鈉(3ml ),再於室溫下攪拌30分鐘。 在該反應混合物中再加入1N鹽酸並加以濃縮。其殘留物中 再加入水,並經乙酸曱酯萃取。該萃取物再經飽和食鹽洗 淨、無水硫酸鈉乾燥後濃縮,即可製成具有以下物性值之 標題化合物(85mg)。 TLC : Rf 〇· 39 (二氯曱烷··曱醇=9 : 1); HNMR : δ 7.24-7.03 (m, 9H), 6.50 (s, 2H), 4.59 (d, 1H), 3.81 (s, 6H), 3.63 (s, 2H), 2.82 (dd, 1H), 2.61 (dd, 1H), 2.45 (t, 2H), 2.09 (s, 3H), 2.04 (m, 1H), 1.75.1.10 (m, 4H)。 實施例5(2)至實施例5(4) 使用實施例4(2)至4(4)中精製之化合物取代實施例 4(1)中精製之化合物,再如實施例5(1)同樣操作,即可製 成以下之本發明化合物。 實施例 5(2) : (4 - {(2R)-2-[(R) -(3, 5-二甲氧基一 4-甲基苯 基)(羥基)甲基]-5-苯基戊基}苯基)乙酸 TLC、WNMR數據與實施例5(1)相同。 實施例 5(3) : (4-{(2R) - 2-[(S) -(3, 5-二甲氧基一 4-甲基苯 基)(輕基)甲基]-5-苯基戊基}苯基)乙酸 TLC ·· Rf 〇· 40 (二氯甲烷:甲醇=9 ·· 1); 316588 99 200521108 'HNMR : δ 7.30-7.05 (m, 9H), 6.43 (s, 2H), 4.59 (d, 1H), 3.78 (s, 6H), 3.63 (s, 2H), 2.66 (dd, 1H), 2.55-2.45 (m, 3H), 2.07 (s, 3H), 2.03 (m, 1H), 1.78.1.58 (m, 4H)〇 實施例 5(4) : (4-{(2S)-2-[(R)-(3, 5-二曱氧基-4-曱基苯 基)(羥基)甲基]-5-苯基戊基}苯基)乙酸 TLC、WNMR數據與實施例5(3)相同。 實施例 6: (± )-2-[4-({(1S*)-卜[(R*M3,5-二曱氡基—4一 曱基苯基)(曱氧基曱氧基)甲基]-4-苯基丁基}氧基)苯氧 基]-4-甲基苯曱酸(± )甲酯 鲁 在(± )-(lR*,2R*)-1 -(3, 5-二曱氧基-4-曱基笨基)一;[一 (甲氧基曱氧基)-5 -苯基戊-2-醇(142 mg)與2-(4-經基苯 氧基)-4-曱基苯曱酸曱酯(249mg)之四氫呋喃(4ml)溶液中 加入三苯基膦(262mg)及偶氮二羧酸二乙酯(〇· 47ml),再於 室溫下攪拌一晚。反應混合物經濃縮後,其殘留物再經石夕 膠管柱層析(己烷:乙酸乙酯=9 : 1)精製,即可製成具有以 下物性之標題化合物(丨28mg)。 __ p _ TLC · Rf 〇· 62 (己烷:乙酸乙酯=2 : 1); HNMR ·· $ 丄66 (m,1H),1.85 (m,3H),2·06 (s,3H),2.30 (s,3H),2·59 (m, 2Η), 3.37 (s, 3H), 3.77 (s, 6H), 3.81 (s, 3H), 4.33 (m, 1H), 4.59 (s, 2H), 4*76 (d, 1H), 6.50 (s, 2H), 6.68 (s, 1H), 6.85 (m, 5H), 7.15 (m, 5H) 7 79 (d lH)〇 , ’ 實施例 7 : (± 5_二曱氧基_4_ 甲基笨基)(羥基)曱基]—4_笨基丁基丨氧基)苯氧基]_4一曱 基苯甲酸甲酯 316588 100 200521108 在實施例β中製成之化合物(128mg)之四氫□夫喃(4mi) 溶液中加入5 N鹽酸(1 m 1) ’該反應混合物再於5 〇 下授拌 20小時。反應混合物經乙酸乙酯稀釋、再依序經水及飽和 食鹽水洗淨、無水硫酸鎂乾燥後濃縮。其殘留物再經;g夕膠 管柱層析(己烧:乙酸乙酯=4 : 1)精製,即可製成具有以下 物性值之標題化合物(113mg)。 TLC : Rf 0·40 (己烷:乙酸乙酯=2 : 1); 1 H NMR : d 1.78 (m, 4H), 2.08 (s, 3H), 2.31 (s, 3H), 2.56 (t, 2H), 3.70 (m, 1H), 3.81 (m, 9H), 4.34 (m, 1H), 4.95 (t, 1H), 6.55 (s, 2H), 6.71 (br. s., 1H), 6.89 (m, 4H), 6.95 (m, 1H),7.13 (m, 5H), 7·80 (d, 1H)。 實施例 8 : (± )-2-[4-({(IS*)-卜[(R*)-(3, 5-二甲氧基-4-甲基苯基)(羥基)曱基]-4-苯基丁基}氧基)苯氧基]一4-曱 基苯甲酸 使用實施例7中精製之化合物取代實施例4( 1)中精製 之化合物,再如實施例5 (1)同樣操作,即可製成具有以下 物性值之標題化合物。 TLC : Rf 〇· 59 (己烷:乙酸乙韻=1 : 4); 'HNMR : 1.50-1.90 (m, 4H), 2.08 (sy 3H), 2.31 (s, 3H), 2.58 (t, 2H), 3.81 (s, 6H), 4.42 (m, 1H), 4.93 (d, 1H), 6.56 (s, 3H), 6.92-7.28 (m, 10 H), 8.10 (d, 1H)。 實施例 9 : (± )-2-[4-({(lS*)-l-[(S*)-(苯甲醯基氧基) (3, 5-二曱氧基一 4-曱基苯基)曱基]-4-苯基丁基}氧基)苯 氧基]-4-曱基苯曱酸曱酯 使用實施例7中製成之化合物取代(± )- 101 316588 200521108 (3,5-—曱氧基-4 -甲基苯基)-1 -(甲氧基曱氧基)一5一苯芙 戊-2-醇,再以苯曱酸取代2-(4-羥基笨氧基)—4一曱基苯甲 酸曱酯,再如實施例6同樣操作,即可製成具有以下物性 值之標題化合物。 實施例10:(±)-2-[4-({(13*)-1-[(3*)-(3,5-二甲氧基 -4-甲基苯基)(羥基)曱基]-4-苯基丁基}氧基)笨氧基卜4一 曱基苯曱酸甲酯 在實施例9中製成之化合物(43mg)之甲醇(2mi)溶液 中加入碳酸鉀(20mg),該反應混合物再於室溫下授掉5小 時。反應混合物中再加入水,並以乙酸乙酯萃取。該萃取 物經飽和食鹽水洗淨、無水硫酸鎂乾燥後濃縮。其殘留物 再經石夕膠管柱層析(己烧:乙酸乙酯=4 : 1)精製,即可製成 具有以下物性之標題化合物(29mg)。 TLC : Rf 0· 32 (己烧:乙酸乙酯=2 : 1); 1 H NMR : d 1.76 (m, 4H), 2.08 (s, 3H), 2.30 (s, 3H), 2.52 (m, 2H), 2.71 (d, 1H), 3.81 (m, 9H), 4.32 (m, 1H), 4.73 (dd, 1H), 6.55 (s, 2H), 6.71 (s, 1H), 6.89 (s, 4H), 6.95 (m, 1H), 7.05 (m, 2H), 7.17 (m, 3H), 7.80 (d,1H)。 貫施例11-(±)-2-[4-({(18*)-1-[(3*)-(3,5-二曱氧基 - 4-甲基苯基)(羥基)甲基]-4-苯基丁基}氧基)苯氧基]一4一 曱基苯曱酸 使用實施例1 0中製成之化合物取代實施例4 ( 1)中製 成之化合物,再如實施例5 (1)同樣操作,即可製成具有以 下物性值之標題化合物。 TLC :R;f 0.56 (己烧:乙酸乙酯二1:4); 316588 102 200521108 1 HNMR : δ 1.50-2.00 (m, 4H), 2.06-2.11 (m, 3H), 2.30 (s, 3H), 2.48*2.63 (m, 2H), 3.81 (s, 6H), 4.35-4.45 (m, 1H), 4.73-4.95 (m, lH), 6.54*6.59 (m, 3H), 6.92-7.28 (m, 10H), 8.10 (d, 1H)。 實施例12 : (4S)-4-苯曱基-3-(5-苯基戊醯基)-1,3-噁唑 σ定- 2 -酉同 於氬氣、-78°C下在(4S) - 4-苯曱基-1,3-噁唑啶-2-酮 (26· 58g)之四氫呋喃(3〇〇ml)溶液中加入1. 58M之正丁基 鐘(四氫呋喃溶液,l〇〇ml),該混合物再於同溫度下攪拌40 分知。在該混合物中,再加入5-苯基戍蕴氣(32. 4g)之四 氫咲喃(100ml )溶液,再於-78°C下攪拌5分鐘。該反應混 合物中再加入氯化銨水溶液,並經乙酸乙酯萃取。該萃取 物再依序經飽和碳酸氫納水溶液及飽和食鹽水洗淨、以無 水硫酸鈉乾燥後濃縮,即可製成具有以下物性值之標題化 合物(55. 29g)。 丁LC ·· Rf 〇· 43 (己烷··乙酸乙酯=4 : 1); HNMR : 6 4H), 2.72 (m,3H), 2.94 (m,2H), 3.29 (dd, 1H), 4.16 (m,2H), 4.66 (m, 1H), 7·26 (m, 10H)。 實施例 13 : (4S)-4-苯甲基-3-{(2R)-2-[(S)-(3, 5-二甲氧 基4曱基笨基)(經基)曱基]一5 一苯基戊酿基卜— 坐咬 -2-酮 在實施例12中製成之化合物(6.13g)與3,5_二曱氧基 一4_甲基苯甲醛(3. 60g)之乙酸乙酯(18ml)溶液中加入三乙 基胺(5.071111)、氯化三曱基矽烷(3 471111)及氣化鎂 (347mg) ’將該混合物再於室溫下攪拌一晚。於反應混合物 316588 103 200521108 中再加入水,並以乙酸乙g旨萃取。該萃取物經飽和食鹽水 洗淨、無水硫酸鈉乾燥後濃縮。將殘留物再溶於曱醇(1 ^) 中,再加入IN鹽酸(1· 8ml)。該反應混合物再於室溫下攪 拌5分鐘’並加以濃縮。其殘留物再經石夕膠管柱層析(己 烧·乙酸乙酯=49: 1—19: 1—9: 1—>4: 1)精製,即可製 成具有以下物性之標題化合物(8. 24g)。 TLC -Rf 0.61 (己烧··乙酸乙醋= 2:1); 1 HNMR : d 1.58 (m,2H),1.86 (m,1H), 2.08 (s, 3H), 2.49 (dd,1H),2‘57 (t, 2H), 3.09 (dd, 1H), 3.20 (d, 1H), 3.82 (s, 6H), 4.10 (m, 2H), 4.62 (m, 2H), 4.80 (m, 1H), 6.63 (s, 2H), 7.19 (m, 10H)。 實施例 14 : (4S)-4-苯曱基-3-{(2R)-2-[(S)-{[第三 丁基 (二甲基)石夕烧基]氧基}(3, 5-二曱氧基-4-曱基苯基)曱基] -5-苯基戊酸基}-1,3-σ惡唾咬-2-酮 於0°C下在實施例13中製成之化合物(28· 2g)之二氯 甲烧(109πι4 )溶液中加入2,6-二曱基吼咬(7ml )與三氟甲 磺酸[第三丁基二曱基矽烷基]酯(13· 7ml),混合物再於室 溫下攪拌30分鐘。反應混合物經濃縮後,其殘留物再經石夕 膠管柱層析(己烷:乙酸乙酯=49 : 1— 19 9 : 1)精製, 即可製成具有以下物性值之標題化合物(32. 5g)。 TLC : Rf 〇· 64 (己烷:乙酸乙酯=4 : 1); 1 HNMR : ^ -0.27 (s, 3H), -0.03 (s, 3H), 0.83 (s, 9H), 1.43 (m, 4H), 2.10 (s, 3H), 2.41 (m, 2H), 2.58 (dd, 1H), 3.54 (dd, lH), 3.82 (s, 6H), 4.10 (m, 2H), 4.44 (m, 1H), 4·64 (m, 1H), 4.80 (d, 1H),6.59 (s,2H), 7.19 (m, 10H)。 貫施例15: (2S)-2-[(S)-{[第三丁基(二曱基)石夕:):完基]氧 104 316588 200521108 基丨(3, 5-二甲氧基_4_甲基苯基)甲基]_5_苯基戊η—醇 在實施例14 t製成之化合物(31.59g)之四氫呋喃 (500ml)溶液中加人氫缝鐘(1Q 9g),將該反應混合物再 於室溫下擾拌4小時。於fC下再於該反應混合物中加入 鹽酸’並經經乙酸乙sl萃取。該萃取物再經飽和碳酸氮 納水溶液及飽和食鹽水洗淨、以無水硫酸納乾燥後濃縮。 其殘留物再經矽膠管柱層析(己烷:乙酸乙酯=50:丨―20: 1—9: 1)精製’即可製成具有以下物性值之標題化合物 (6·52g)。 TLC ·· Rf 〇· 47 (己烷··乙酸乙酯=4 : j); HNMR . ^ 0.17 (s, 3H), 0.05 (s, 3H), 0.92 (s, 9H), 1.59 (m, 4H), 2.07 (s 3H), 2,9 (t, 2H), 3.01 (dd, 1H), 3.55 (m, 1H), 3.77 (m, 1H), 3.8〇 (s> 6R); 4.70 (d, 1H), 6·46 (s, 2H), 7.21 (m, 5H)。 實施例16 :甲石黃酸[(2S)-2~[⑻第三丁基(二甲基w 烷基]氧基}(3, 5-二甲氧基-4-曱基苯基)甲基]_5_苯基戊] 於下在實施例15中製成之化合物(200mg)之四氫 呋喃(44ml)溶液中加入三乙基胺(218从〇及曱磺醯氯(1〇2 M),混合物再於室溫下攪拌2小時。在反應混合物中再 加入水,並經乙酸乙酯卒取。該萃取物再經飽和食鹽水洗 平、無水硫酸鈉乾燥後濃縮,即可製成具有以下物性值之 標題化合物(253mg)。 TLC .Rf 0.76 (曱苯:乙酸乙酯二❾:1); 316588 105 200521108 1 H NMR : (5 -0.21 (s, 3H), 0.03 (s, 3H), 0.89 (s, 9H), 1.51 (m, 4H), 1.92 (m, 1H), 2.08 (s, 3H), 2.55 (m, 2H), 2.89 (s, 3H), 3.80 (s, 6H), 4.29 (dd, 1H), 4.36 (m, 1H), 4.58 (d, 1H), 6·43 (s, 2H), 7.19 (m,5H)。 實施例17:第三丁基{[(IS,2R) -1 -(3,5 -二曱氧基-4 -曱基 苯基)-2-(碘甲基)-5-苯基戊基]氧基}二甲基矽烷 在實施例16中製成之化合物(253mg)之丙酮(4.4ml) 溶液中加入蛾化納(6 5 4mg),混合物再於9 0 下擾拌3小 時。反應混合物中再加入水,並經乙酸乙酯萃取。該萃取 物再經飽和食鹽水洗淨、無水硫酸鈉乾燥後濃縮,即可製 成具有以下物性值之標題化合物(263mg)。 TLC .Rf 0.71 (己烧:乙酸乙酯=19:1); 1 H NMR : d -0.24 (s, 3H), 0.08 (s, 3H), 0.87 (m, 9H), 1.25 (m, 4H), 1.58 (m, 1H), 2.08 (s, 3H), 2.49 (m, 2H), 3.32 (dd, 1H), 3.65 (dd, 1H), 3.80 (s, 6H),4.34 (d,1H),6·44 (s, 2H), 7.19 (m, 5H)。 貫施例18 : 3-(3-{(2S)-2-[ (S)-{[第三丁基(二曱基)矽烷 基]氧基}(3, 5-二曱氧基-4-曱基苯基)曱基]一5一苯基戊基} 苯基)丙酸曱g旨 於氬氣下,在鋅(276mg)與N,N-二甲基曱醯胺(〇· 8ml) 之混合物中加入:l,2 —二溴乙烷(18//υ,將該混合物再於 6〇 C下攪拌30分鐘。於該混合物中再加入氯化三曱基矽烷 (50//1)並於至溫下攪拌30分鐘。之後再於下在該 混合物中加入實施例17中製成之化合物(4〇〇mg)之n,n一二 曱基曱月女(〇 · 1)溶液,該混合物再於〇下擾拌1小 時。再於該混合物中加入參(二亞苯曱基丙酮)二鈀(〇)一氯 316588 106 200521108 仿錯合物(73mg)、參(2-甲基苯基)膦(171mg)及3 —(3 —碘苯 基)丙酸曱酯(408mg)之N,N-二甲基曱醯胺(0.8ml)溶液、,· 该混合物再於40°C下攪拌2小時。該反應混合物經乙酸乙 酯稀釋,再經矽藻土(商品名)過濾於其濾液中再加入 〇·〇1Ν鹽酸,並經乙酸乙酯萃取。該萃取物再經飽和食鹽 火洗淨、热水硫酸納乾燥後濃縮。其殘留物再經石夕膠管柱 層析(己烧:乙酸乙酯=50 : 1— 20 : 1— 1 2 : 1 )精製,即可 製成具有以下物性值之標題化合物(l86mg)。 TLC : Rf 〇· 51 (己烷:乙酸乙酯=9 : 1); ^NMR : ^ -0.17 (s, 3H), 0.03 (s, 3H), 0.94 (m, 9H), 1.19 (m, 1H), 1.55 (m, 2H), 1.85 (m, 1H), 2.08 (s, 3H), 2.67 (m, 9H), 3.67 (m, 3H), 3.81 (m, 6H), 4·68 (d, 1H),6.48 (s, 2H), 7.19 (m, 9H)。 貫施例 19:3 -(3-{(2S)-2 - [(S)-(3,5-二曱氧基-甲基苯 基)(輕基)曱基]-5-苯基戊基}苯基)丙酸曱酯 於0C下在貫施例18中製成之化合物(186 mg)之四氫 1:1夫喃(lml)溶液中,加1. 0M氟化四丁基銨之四氫呋喃溶液 (2. 66ml),並將該混合物於室溫下攪拌2小時。再於反應 混合物中加入飽和氯化鈹水溶液,並經乙酸乙g旨萃取。該 卒取物再依序經0 · 01N鹽酸、水及飽和食鹽水洗淨、無水 硫酸鈉乾燥後濃縮。其殘留物再經矽膠管柱層析(己烧:乙 酸乙酯=19 : 1—9 : 1—6 : 1)精製’即可製成具有以下物性 值之標題化合物(129mg)。 TLC : Rf 〇· 25 (己烷··乙酸乙酯=4 : 1); 316588 107 200521108 1 HNMR : ί 1.52 (m, 5H), 2.09 (s, 3H), 2.45 (t, 2H), 2.63 (m, 3H), 2.82 (dd, 1H), 2.91 (t, 2H), 3.66 (s, 3H), 3.82 (s, 6H), 4.59 (d, 1H), 6.51 (s, 2H), 7.15 (m, 9H)〇 實施例 20 : 3 -(3-{(2 S) - 2 - [(S) -(3,5- 二曱氧基 -4 -曱基苯 基)(經基)曱基]-5 -苯基戊基}苯基)丙酸
使用實施例19中精製之化合物取代實施例4( 1)中製 成之化合物,再進行與實施例5 (1)同樣之操作,即可製成 以下之本發明化合物。 TLC : Rf 〇· 13 (己烷:乙酸乙酯=2 ·· 1); 'HNMR : (5 1.26 (m, 2H), 1.58 (m, 2H), 2.04 (m, 4H), 2.45 (t, 2H), 2.61 (m, 3H), 2.79 (dd, 1H), 2.90 (t, 2H), 3.80 (s, 6H), 4.56 (d, 1H), 6.50 (s, 2H), 7.11 (m,9H)〇 ’ ’ 實施例20(1)至實施例20(26) 由5-苯基戊醯氣或其相當之酸氣化物衍生物、3,5一二 曱氧基4曱基苯曱醛或其相當之醛衍生物、3一( 3一块苯基) 丙酉文曱酯或其相當之芳基鹵化物衍生物,進行與實施例12 戶、施例13— A轭例14—實施例15—實施例1實施例 貫施例18—實施例19—實施例2G相同之操作,即可 製成以下之本發明化合物。 316588 108 200521108 貧施例 20(1) : (4-{(2S)-2-[(S)-(3,5 -二曱氧基一 4 -曱基 笨基)(經基)曱基]-5 -苯基戊基}苯基)乙酸 TLC : Rf 0· 45 (己烷:乙酸乙酯=1 : 2); iHNMR : 6 7.24-7.03 (m,9H),6·50 (s,2H), 4.59 (d,1H),3.81 (s,6H), 3.63 (s, 2H), 2.82 (dd, 1H), 2.61 (dd, 1H), 2.45 (t, 2H), 2.09 (s, 3H), 2.04 (m, 1H),1.75-1.10 (m,4H)〇 實施例20(2):(4-{(28)-2-[(8)-經基(3,4,5一三曱氧基苯 基)曱基]-5 -苯基戊基}苯基)乙酸 TLC : Rf 0· 38 (二氣曱烷:曱醇=9 ·· 1) ; · 1 HNMR : d 7.26-7.02 (m,9H),6.53 (s, 2H), 4.57 (d,1H),3.84 (s, 3H) 3.84 (s, 6H), 3.62 (s, 2H), 2.80 (dd, 1H), 2.59 (dd, 1H), 2.46 (t 2H) 2.05*1.96 (m, 1H), 1.67-1.14(m, 4H)〇 實施例 20(3) ·· (3-{(2S)-2-[(S)-(3,5-二曱氧基-4_ 甲基 苯基)(經基)曱基]-5 -苯基戊基}苯基)乙酸 TLC : Rf 0· 44 (二氯甲烷:曱醇=9 : 1); 'HNMR : d 7.30-7.00 (m, 9H), 6.50 (s, 2H), 4.59 (d, 1H), 3.81 (s, 6H), _ 3.60 (s, 2H), 2.83 (dd, 1H), 2.60 (dd, 1H), 2.45 (t, 2H), 2.09 (s 3H) 2 1 0·2·00 (m, 1H), 1.65·1·20 (m, 4H)。 貫施例 20(4) ·· 3-(4-{(2S)-2-[(S)-(3, 5-二曱氧基一4一甲 基苯基)(羥基)曱基]-5-苯基戊基}苯基)丙酸 TLC : Rf 〇· 15 (己烷:乙酸乙酯二2 : 1); 1 H NMR : 1.28 (m, 2H), 1.58 (m, 2H), 2.02 (m, ιΗ), 2.09 (s, 3H), 2.45 (t, 2H), 2.62 (m, 3H), 2.80 (dd, 1H), 2.93 (t, 2H), 3.81 (s, 6H), 4.56 (d, 1H), 6.50 (s, 2H), 7.14 (m, 9H)〇 316588 109 200521108 實施例 20(5) : {4-[(2S)-2-[(S)-(3, 5-二曱氧基-4-甲基 苯基)(羥基)曱基]-5-(2-噻吩基)戊基]苯基}乙酸 TLC : Rf 0.45 (己烷:乙酸乙酯=1 : 2); 1 H NMR : 5 7.18 (d, 2H), 7.11-7.06 (m, 3H), 6.86 (dd, 1H), 6.64 (dd, 1H), 6.50 (s, 2H), 4.61 (d, 1H), 3.81-3.75 (m, 6H), 3.62 (s, 2H ), 2.83 (dd, 1H), 2.69-2.57 (m, 3H), 2·10-1·98 (m, 4H), 1.72-1.57 (m, 2H), 1.44-1.15 (m, 2H)〇 實施例 20(6) : (4-{(2S)-2-[(S)-(3, 5-二曱氧基苯基)(經 基)甲基]-5-苯基戊基}苯基)乙酸 TLC : Rf 0· 42 (二氯甲烷:曱醇=9 : 1); 'HNMR : (5 7.26-7.03 (m, 9H), 6.49 (d, 2H), 6.37 (t, 1H), 4.62 (d, 1H), 3.79 (s, 6H), 3.62 (s, 2H), 2.79 (dd, 1H), 2.55 (dd, 1H), 2.46 (t, 2H), 2.08Ί.96 (m, 1H), 1.69Ί.16 (m, 4H)〇 實施例 20(7) · (3-{(2S)-2 -[(S)-(3,5- 二曱氧基-4 -曱基 苯基)(羥基)曱基]-5-苯基戊基}苯氧基)乙酸 TLC : Rf 0· 22 (二氣曱烷··曱醇=9 ·· 1); 1 HNMR : ^ 1.27 (m, 2H), 1.58 (m, 2H), 2.04 (m, 4H), 2.46 (t, 2H), 2.60 (m, 1H), 2.81 (m, 1H), 3.81 (s, 6H), 4.59 (m, 3H), 6.49 (s, 2H), 6.74 (m, 3H), 7.16 (m, 6H)〇 實施例 20(8) ·· (4-{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱基 苯基)(羥基)曱基]-5-苯基戊基}苯氧基)乙酸 TLC : Rf 0· 17 (二氯甲烷:曱醇=9 : 1); 1 H NMR : ί 1.25 (m, 2H), L57 (m, 2H), 1.98 (m, 1H), 2.08 (s, 3H), 2.44 (t, 2H), 2.59 (m, 1H), 2.77 (m, 1H), 3.80 (s, 6H), 4.56 (d, 1H), 4.65 (s, 2H), 6.49 (s,2H), 6.81 (m, 2H),7.05 (m, 4H ),7.20 (m, 3H)。 110 316588 200521108 實施例 20(9) ·· 4-{(2S)-2-[(S)-(3, 5-二甲氧基-4-曱基苯 基)(經基)曱基]-5-苯基戊基}苯曱酸 TLC : Rf 0· 42 (二氯曱烷:曱醇=9 : 1); lHNMR:(5 8.01-7.95 (m, 2H), 7.25-7.10 (m, 5H), 7.06*7.00 (m, 2H), 6.50 (s, 2H), 4.59 (d, 1H), 3.81 (s, 6H), 2.92 (dd, 1H), 2.69 (dd, 1H), 2.45 (t, 2H), 2.09 (s, 3H), 2.11-2.01 (m, 1H), 1.70-L09 (m,4H)。 實施例 20(10) : {4-[(2S)-2-[(S)-(3, 5-二甲氧基-4—曱基 苯基)(羥基)甲基]-5-(3-噻吩基)戊基]苯基}乙酸 TLC· Rf 0.31 (己烧·乙酸乙醋··乙酸=2 : 1 : 〇 1); 1 Η N MR : ί 1.29 (m, 2H), 1.56 (m, 2H), 2.04 (m, IH), 2.08 (s, 3H), 2.46 (t, 2H), 2.58 (m, 1H), 2.82 (dd, 1H), 3.60 (s, 2H), 3.80 (s, 6H), 4.59 (d, 1H) 6·49 (s, 2 H), 6.78 (m, 2H), 7.08 (d, 2H), 7.17 (m, 3H)。 實施例 20(11) : 3-{(2S)-2-[(S)-(3, 5-二曱氧基一4 -曱基 苯基)(羥基)曱基]-5-苯基戊基}苯曱酸 TLC ·· Rf 0· 52 (二氯曱烷:曱醇=9 : 1); 'HNMR : (5 7.97-7.91 (m, 2H), 7.37*7.01 (m, 7H), 6.50 (s, 2H), 4.60 (d, 1H), 3.81 (s, 6H), 2.91 (dd, 1H), 2.69 (dd, 1H), 2.45 (t, 2H), 2.08 (s, 3H), 2.12-2.03 (m, 1H), 1.70-1.13 (m, 4H)〇 實施例 20(12) : 2-(4-{(2S)-2-[(S)-(3, 5-二曱氧基一4一甲 基苯基)(羥基)曱基]-5-苯基戊基}苯氧基)—2-甲基丙酸 TLC : Rf 0· 60 (二氯曱烷:曱醇=9 : 1); 'HNMR : 7.25-7.15 (m, 3H), 7.10*7.00 (m, 4H), 6.83 (d, 2H), 6.49 (s, 2H), 4.58 (d, 1H), 3.81 (s, 6H), 2.80 (dd, 1H), 2.56 (dd, 1H), 2.45 (t, 2H), 2.08 (s, 3H), 2.05-1.90 (m, 1H), 1.56 (s, 6H), 1.60*1.10 (m, 4H)〇 200521108 實施例 20(13) : 2-(4-{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱 基苯基)(經基)甲基]-5-苯基戊基}苯氧基)苯曱酸 TLC : Rf 0· 20 (己烷:乙酸乙酯=2 : 1); lHNUR : δ 8.22 (dd, 1H), 7.48-7.42 (m, 1H), 7.26*7.13 (m, 6H), 7.08-7.04 (m, 2H), 7.00-6.96 (m, 2H), 6.79 (dd, 1H), 6.50 (s, 2H), 4.61 (d, 1H), 3.82 (s, 6H), 2.88 (dd, 1H), 2.64 (dd, 1H), 2.48 (t, 2H), 2.10-1.98 (m, 4H), 1.66-1.54 (m, 2H), 1.44-1.15 (m, 2H)。 實施例20(14):2-(4-{(23)-2-[(3)-(3,5-二曱氧基-4-甲 基苯基)(羥基)曱基]-5-苯基戊基}苯基)-2-曱基丙酸 TLC : Rf 0· 25 (己烷:乙酸乙酯=2 : 1); 'HNMR : d 7.30-7.03 (m, 9H), 6.50 (s, 2H), 4.60 (d, 1H), 3.81 (s, 6H), 2.82 (dd, 1H), 2.58 (dd, 1H), 2.45 (t, 2H), 2.08 (s, 3H), 2.10*2.00 (m, 1 H), 1.70-1.20 (m, 4H), 1.59 (s, 6H)〇 實施例 20(15) : (4-{(2S)-2-[(S)-(2-氣-4, 5-二曱氧基苯 基)(經基)曱基]_5-笨基戊基}苯基)乙酸 TLC :Rf 0.24 (己烧:乙酸乙西旨二1:4); ^NMR : δ 7.26-6.94 (m, 10H), 6.81 (s, 1H), 5.13 (d, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.58 (s,2H), 2.81 (dd,1H), 2·56·2·36 (m,3H), 2.19-2.05 (m, 1H), 1.77-1.24 (m, 4H)〇 實施例 20(16) : (4-{(2S)-2-[(S)-(3, 4-二曱氧基苯基) (經基)曱基]-5 -苯基戊基}苯基)乙酸 TLC :Rf 0.50 (二氣曱烷:曱醇= 9:1); 112 316588 200521108 lHNMR : 1.24 (m, 2H), 1.57 (m, 2H), 2.02 (m, 1H), 2.43 (t, 2H), 2.59 (dd, 1H), 2.81 (m, 1H), 3.62 (s, 2H), 3.87 (s, 3H), 3.89(s, 3H), 4.58 (d, 1H), 6.84 (m, 3H), 7.15 (m, 9H)。 實施例 20(17) : (4-{(2R)-2-[(S)-(3, 5_二甲氧基-4-曱基 苯基)(羥基)甲基]-4-苯氧基丁基}苯基)乙酸 TLC : Rf 0· 17 (己烷··乙酸乙酯=1 : 1); lHNMR : δ 1.79 (m, 2H), 2.08 (s, 3H), 2.30 (d, 1H), 2.61 (m, 1H), 2.85 (dd, 1H), 3.60 (m, 2H), 3.87 (m, 8H), 4.78 (d3 1H), 6.55 (s , 2H), 6:78 (dd, 2H), 6.92 (m, 1H),7.19 (m, 6H)。 _ 實施例 20(18): (4-{(2S)-2-[(S)-(3-氯-2-噻吩基)(經基) 曱基]-5-苯基戊基}苯基)乙酸 TLC : Rf 0· 32 (己烷:乙酸乙酯=1 : 1); 'HNMR : d 7.26-7.00 (m, 10H), 6.90-6.86 (m, 1H), 5.09 (d, 1H), 3.60 (s, 2H), 2.95 (dd, 1H), 2.60-2.37 (m, 3H), 2.25*2.11 (m, 1H), 1.71-1:20 (m, 4H)〇 實施例 20(19) : (4-{(2S)-2-[(S)-(2, 6 -二甲氧基 -3-吼咬 基)(羥基)曱基]-5-苯基戊基}苯基)乙酸 0 TLC : Ri 〇· 34 (己烷:乙酸乙酯=1 : 1); 1HNMR : 7.48 (d, 1H), 7.24-7.00 (m, 9H), 6.27 (d,1H),4.76 (d,1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.58 (s, 2H), 2.84 (dd, 1H), 2.55-2.34 (m, 3H), 2·18·2·09 (m, 1H), 1·66·1·12 (m, 4H)。 實施例 20(20) : 4-(4-{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱 基苯基)(羥基)曱基]-5-苯基戊基}苯基)丁酸 TLC : Rf 〇· 26 (己烷:乙酸乙酯=2 : 1); 113 316588 200521108 !HNMR : δ 7.20-7.00 (m, 9H), 6.50 (s, 2H), 4.60 (d, 1H), 3.81 (s, 6H), 2.80 (dd, 1H), 2.64 (t, 2H), 2.58 (dd, 1H), 2.45 (t, 2H), 2.37 (t, 2H), 2.09 (s, 3H),2.05-1.90 (m, 3H), 1.70· 1.10 (m, 4H)。 實施例 20(21) : (4-{(2S)-2-[(S)-(2, 3-二氫-1,4-苯并二 氧雜環己稀-6 -基)(經基)甲基]-5 -苯基戊基}苯基)乙酸 TLC : Rf 0. 48 (二氯曱烷:甲醇=9 : 1); 1 HNMR : 6 1.25 (m, 2H), 1.57 (m, 2H),1.99 (m, 1H),2.44 (t,2H),2.55 (dd, 1H), 2.79 (dd, 1H), 3.60 (s, 2H), 4.25 (s, 4H), 4.55 (d, 1H), 6.77 (dd, 1H), 6·82 (m, 1H),6.86 (d, 1H),7.15 (m, 9H)。 實施例 20(22) ·· (4-{(2S)-2-[(S)-[4-(二氟曱氧基)苯基] (羥基)曱基]-5-苯基戊基}苯基)乙酸 TLC : Rf 0· 26 (己烷:乙酸乙酯=1 : 1); ^NMR : d 7.34-7.02 (m, 13H), 6.50 (t, 1H), 4.67 (d, 1H), 3.61 (s, 2H), 2.74 (dd, 1H), 2.56 (dd, 1H), 2.45 (t, 2H), 2.07-1.95 (m, 1H), 1.66-1.11 (m, 4H)〇 實施例 20(23) : (4-{(2S)-2-[(S)-羥基(4-曱氧基-3, 5-二 曱基苯基)曱基]-5-苯基戊基}苯基)乙酸 TLC : Rf 0· 43 (己烷:乙酸乙酯=1 : 1); 1 H NMR : d 7.25-7.01 (m, 9H), 6.94 (s, 2H),4.54 (d, 1H), 3.71 (s, 3H),3.60 (s, 2H),2.82 (dd, 1H),2.55 (dd, 1H),2.43 (t, 2H), 2.67 (s, 6H),2.06*1.95 (m, 1H), 1·66·1.1〇(ιη, 4H)。 實施例 20(24): (4-{(2S)-2-[(S)-[3-(環戊基氧基)-4-曱 氧基苯基](經基)曱基]-5 -苯基戊基}苯基)乙酸 TLC : Rf 〇· 30 (己烷:乙酸乙酯=1 ·· 1); 114 316588 200521108 1 Η N M R : (5 7.25-7.00 (m, 9H), 6.87-6.80 (m, 3H), 4.80-4.73 (m, 1H), 4.56 (d, 1H), 3.84 (s, 3H), 3.61 (s, 2H), 2.81 (dd, 1H), 2.57 (dd, 1H), 2.43 (t, 2H), 2.04-L75 (m, 7H), L65-1.49 (m, 4H), 1.40Ί.10 (m, 2H)〇 實施例 20(25) : (4-{(2S)-2-[(S)-(3, 5-二甲氧基-4-曱基 笨基)(羥基)曱基]-4-苯基丁基}苯基)乙酸 TLC : Rf 0.45 (己烷··乙酸乙酯=1 : 2); 1 H NMR : d 7.22-7.09 (m, 7H), 6.99*6.95 (m, 2H), 6.47 (s, 2H), 4.64 (d, 1H), 3.79 (s, 6H), 3.63 (s, 2H), 2.87 (dd, 1H), 2.67 (dd, 1H), 2.55 (t, 2H), 2·10·1·99 (m, 4H), 1.69-1.43 (m, 2H)〇 實施例 20(26): {4-[(2S,3S)-2-[2,3-二氫-111-茚-2-基曱 基]-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基]苯基}乙 酸 TLC : Rf 0· 40 (二氯曱烷:曱醇=9 : 1); 1 Η NMR : 6 7.22-7.04 (m, 8H), 6·53 (s, 2H),4.64 (d, 1H), 3.82 (s, 6H), 3.62 (s, 2H), 3.00-2.90 (m, 2H), 2.82 (dd 1H), 2.70 (dd, 1H), 2.62-2.28 (m, 3H), 2.18 (m, 1H), 2.07 (s, 3H), 1.70-1.30 (m, 2H)〇 實施例21:(4-{(21〇-2-[(1〇-(3,5-二曱氧基-4_甲基苯基) (經基)曱基]-4-苯基丁基}苯基)乙酸 使用(4R)-4-苯甲基-1,3-噁哇唆-2-酮取代(4S)-4-苯 曱基-1,3 - °惡°坐咬-2 -酮’用4 -苯基丁酿氯取代5 -苯基戊臨 氣及用(4-碘苯基)乙酸曱酯取代3-(3-碘苯基)丙酸曱 酯,進行與實施例12—實施例13—實施例14—實施例15 —實施例16—實施例17->實施例實施例19—實施例 20相同之操作,即可製成具有以下物性值之標題化合物。 115 316588 200521108 TLC : Rf 〇· 41 (己烷:乙酸乙酯: 2); 1 H NMR ·· d 7.22-7.09 (m,7H),7.00-6.95 (m, 2H>, 6.47 (s,2H),4·64 (d, 1H), 3.79 (s, 6H), 3.62 (s, 2H), 2.87 (dd, 1H), 2.67 (dd, 1H), 2.54 (t, 2H), 2·10·1·98 (m, 4H), 1.69-1·42 (m, 2H)〇 實施例22: 2-({(2S)-2-[(S)-{[第三丁基(二曱基)矽烷基] 氧基}(3, 5-二曱氧基-4 -曱基苯基)曱基]-5-苯基戊基}氧 基)苯曱酸曱酯 以實施例15中製成之化合物取代(± )一 (3, 5-二曱氧基-4-f基苯基)-1-(曱氧基曱氧基)-5 一苯基 戊-2-醇,及以2-羥基笨曱酸曱酯取代2-(4-羥基笨氧基) -4-曱基苯曱酸曱酯,進行與實施例6相同之操作,即可製 成具有以下物性值之標題化合物。 TTLC· Rf 〇·73 (己烧:乙趟=4 : 1); 貫施例 23· 2 -({(2S)-2-[(S)-(3,5 -二曱氧基一4 -曱基苯 基)(經基)甲基]-5-苯基戊基}氧基)苯曱酸 以實施例22中製成之化合物取代實施例18中製成之 化合物’進行與實施例19—實施例20相同之操作,即可 製成具有以下物性值之標題化合物。 TLC : Rf 0· 64 (己烷:乙酸乙酯二1 : 2); 1 HNMR : 6 1.73 (m, 4H),2.04 (s,3H),2.10 (m,1H),2.62 (m,2H),3.66 (s, 6H), 4.12 (m, 2H), 4.87 (d, 1H), 6.46 (s, 2H), 6.89 (d, 1H), 7.17 (m, 6H) 7.48 (m, 1H), 8.13 (d, 1H)。 實施例23(1)至實施例23(4) 2-經基苯曱酸甲酯以相當之酚衍生物取代,進行與實 316588 116 200521108 施例22—實施例23相同之操作,即可製成以下之本發明 化合物。 實施例 23(1) · 3-({(2S)-2-[(S)-(3,5-二曱氧基-4 -曱基 苯基)(經基)曱基]-5-笨基戊基}氧基)苯曱酸 TLC : Rf 0· 098 (二氯曱烷:曱醇=9 : 1); ^NMR : d 7.70 (d, 1H), 7.61 (m, 1H), 7.42-7.06 (m, 7H), 6.49 (s, 2H), 4.83 (d, 1H), 4.20 (dd, 1H), 4.03 (dd, 1H), 3.74 (s, 6H), 2.58 (m 2H) 2 15 (m, 1H),2.07 (s, 3H), 1.95-1.20 (m, 4H)。 實施例 23(2) : 4-( {(2S)-2-[(S)-( 3, 5-二曱氧基-4-甲基籲 苯基)(經基)曱基]-5-苯基戊基}氧基)苯曱酸 TLC : Rf 0· 64 (己烧:乙酸乙酯=1 : 2); 1 HNMR : (5 1.59 (m,4H), 2.08 (s,3H), 2.14 (m, 1H), 2.60 (m, 2H), 3.75 (s, 6H), 4.05 (dd, 1H), 4.22 (dd, 1H), 4.81 (d, 1H), 6.48 (s, 2H), 6.93 (d, 2H), 7.18 (m, 5H), 8.04 (d, 2H)。 實施例 23(3) : [3-({(2S)-2 - [(S) -(3,5-二曱氧基 -4 -曱基 苯基)(羥基)曱基]-5-苯基戊基}氧基)苯基]乙酸 _ TLC : R:f 0· 31 (二氯曱烷:曱醇=9 : 1); 'HNMR : d 7.32-7.08 (m, 6H), 6.92-6.78 (m, 3H), 6.47 (s, 2H), 4.82 (d, 1H), 4.12 (dd, 1H), 3.95 (dd, 1H), 3.72 (s, 6H), 3.61 (s, 2H), 2.62-2.50 (m, 2H), 2.08-1.20 (m, 5H), 2.07 (s, 3H)。 實施例 23(4) : [4-({(2S)-2-[(S)-(3, 5- 二曱氧基 -4 -曱基 苯基)(羥基)曱基]-5-苯基戊基}氧基)苯基]乙酸 TLC : Rf 0· 33 (二氣曱烷:曱醇二9 : 1); 117 316588 200521108 !HNMR : d 7.30-7.08 (m, 7H), 6.86 (d, 2H), 6.47 (s, 2H), 4.81 (d, 1H), 4.10 (dd, 1H), 3.94 (dd, 1H), 3.72 (s, 6H), 3.59 (s, 2H), 2.62-2.50 (m, 2H), 2.08 (m, 1H), 2.07 (s, 3H),1.80-1.20 (m, 4H)。 實施例24: l-({(2S)-2-[(S)-{[第三丁基(二甲基)矽烷基] 氧基} (3, 5-二曱氧基-4-曱基苯基)曱基]-5-苯基戊基} -1Η-吼洛-2-叛酸乙酷 於氬氣下在60%氫化鈉(24mg)之二曱基曱酸胺(2mi) 溶液中加入1H-吼σ各-2-叛酸乙g旨(78mg)之N, N-二曱基曱 醯胺(2ml)溶液。將該混合物再於50°C下攪拌30分鐘。再 於室溫下,在該混合物中加入實施例16中製成之化合物 (20 0mg)。將該反應混合物於50°C下攪拌15小時。再於室 溫下’在該反應混合物中加入1N鹽酸,並經乙酸乙g旨萃 取。卒取物再依序經水及飽和食鹽水洗淨、無水硫酸鈉乾 燥後濃縮。其殘留物再經矽膠管柱層析(己烷:乙酸乙酉旨 =10 : 1)精製,即可製成具有以下物性值之標題化合物 (166mg)。 TLC : Rf 〇· 58 (己烷:乙酸乙酯=4 : 1); 1HNMR : d 7.26-7.02 (m, 5H), 6.91 (dd, 1H), 6.66 (dd, 1H), 6.46 (s, 2H), 6.06 (dd, 1H), 4.71 (d, 1H), 4.37 (dd, 1H), 4.27 (dd, 1H), 4.17 (q, 2H), 3.79 (s, 6H), 2.42 (m, 2H), 2.07 (s, 3H), 1.60*1.00 (m, 4H), 1.27 (t, 3H), 0.95 (s, 9H), 0.05 (s,3H), -0.15 (s, 3H)〇 貫施例25:1-({(28)-2-[(8)-(3,5-二曱氧基-4-曱基苯基) (¾基)甲基]-5_苯基戊基}-1}1 -D比口各-2-魏酸 使用實施例24中製成之化合物取代實施例18中製成 316588 118 200521108 之化合物,進行與實施例19—實施例2〇相同之操作,即 可製成具有以下物性值之標題化合物。 TLC ·· Rf 0· 49 (二氣甲烷:甲醇=9 : 1); ^HNMR : d 7.26-7.00 (m,6H), 6.79 (dd, 1H), 6.47 (s, 2H), 6.11 (dd, 1H), 4.65-4.55 (m, 2H), 4.26 (dd, 1H), 3.80 (s, 6H), 2.42 (m, 2H), 2.30 (m, 1H), 2.08 (s, 3H), 1.58-1.08 (m, 4H)。 實施例25(1)至實施例25(4) .1H-吼略-2-羧酸乙酯以相當之雜環衍生物取代,進行 與貫施例24—貫施例2 5相同之操作,即可製成以下之本 發明化合物。 實施例25(1):卜{(2S)-2-[(S)-(3, 5-二曱氧基一4-曱基笨 基)(經基)曱基]-5-苯基戊基}-ih-d比口坐一 4 一叛酸 TLC : Rf 0· 19 (二氯甲烷:甲醇=9 : 1); ^NMR : ^ 7.97 (s, 1H), 7.84 (s, 1H), 7.30-7.04 (m, 5H), 6.50 (s, 2H), 4.48-4.38 (m, 2H), 4.22 (dd, 1H), 3.81 (s, 6H), 2.60-2.40 (m, 2H) 2 22 (m 1H), 2.08 (s, 3H), 1.80-1.10 (m, 4H)〇 實施例 25(2): 1-{(2S)-2-[(S)-(3,5-二甲氧基一4-曱基苯 基)(經基)甲基]-5-苯基戊基吼σ各~3-幾_酸 TLC : Rf 0· 66 (己烷:乙酸乙酯=1 : 3); iHNMR : (5 1.25 (m,2H),1.58 (m,2H),1·99 (m, 1H), 2.09 (s, 3H),2.47 (m, 2H), 3.81 (s, 6H), 4.03 (dd, 1H), 4.14 (m, 1H), 4.40 (d, 1H), 6.45 (s, 2H), 6.53 (m, 1H), 6.59 (m, 1H), 7.05 (m,2H), 7.21 (m, 3H), 7.36 (t, 1H)。 實施例 25(3) : (1 -{(2S)-2-[(S)-(3, 5-二曱氧基一4一曱基 苯基)(羥基)曱基]-5-苯基戊基}-lΗ-咪唑-4-基)乙酸 316588 119 200521108 TLC : Rf 0· 16 (二氯甲烷:曱醇=9 : 1); 1 HNMR : 6 8·00 (brs, 1Η),7·28·7· 10 (m,3H),7.03-6.97 (m,2H),6.68 (brs, 1H), 6.45 (s, 2H), 4.30 (m, 1H), 4.20-3.95 (m, 2H), 3.75 (s, 6H), 3.74-3.50 (m, 2H), 2.60-2.20 (m, 3H), 2·05 (s, 3H), 1.80-1.20 (m, 4H)。 實施例 25(4) · (1-{(2S)-2-[(S)-(3,5-二曱氧基-4-甲基 本基)(輕基)曱基]-5-苯基戍基}-3,5-二曱基-1H- D比σ坐-4-基)乙酸 TLC : Rf 0· 38 (二氯甲烷:甲醇=4 : 1); 1 HNMR : d 7.28-7.12 (m, 3H), 7.08-7.02 (m, 2Η), 6·56 (s,2H), 4.55 (d, 1Η), 4.07 (dd, 1H), 3.94 (dd, 1H), 3.80 (s, 6H), 3.34 (s, 2H), 2.62-2.40 (m, 2H), 2.19 (s, 3H), 2.15 (m, 1H), 2.07 (s, 6H), 1.70*1.55 (m, 2H), 1.45-1.10 (m, 2H)〇 實施例26 : (1-{(2S)-2-[(S)-{[第三丁基(二曱基)石夕烷基] 氧基}(3, 5-二甲氧基-4-曱基苯基)甲基]一5-苯基戊基} -3 -基)乙膳 以1H-D比洛-3-基乙腈取代1H-D比洛-2-叛酸乙酯,進行 與實施例24相同之操作,即可製成具有以下物性值之標題 化合物。 TLC ·· Rf 0· 39 (己烷:乙酸乙酯=4 : 1); 1HNMR : 5 -0.19 (s, 3H), 0.04 (s, 3H), 0.94 (s, 9H), 1.13 (m, 1H), 1.42 (m, 2H), 1.64 (m, 1H), 1.92 (m, 1H), 2.08 (s, 3H), 2.46 (m, 2H), 3.52 (s, 2H) 3.65 (dd, 1H), 3.80 (s, 6H), 3.97 (dd, 1H), 4.65 (d, 1H), 6.00 (m, 1H), 6 44 (m,4H), 7.07 (m, 2H), 7.22 (m, 3H)。 實施例27: (1-{(2S)-2 -[(S)-(3, 5-二曱氧基一4 —甲基苯美) 316588 120 200521108 (輕基)甲基]- 5 -苯基戊基丨-lH -吼α各-3-基)乙酸 在貫施例26中製成之化合物(95mg)之乙醇(2ml)溶液 中加入5N氫氧化鈉水溶液(lml),該混合物再於微波爐中 以80W、150 C、15bar下反應45分鐘。於其反應混合物中 再加入1N鹽酸,並以乙酸乙酯萃取。該萃取物經飽和食鹽 水洗淨、無水硫酸鎂乾燥後濃縮。其殘留物再經矽膠管柱 層析(己烧:乙:酸乙酯=2 : 1)精製,即可製成具有以下物性 值之標題化合物(75mg)。 TLC ·· Rf 0·46 (己烷··乙酸乙酯=1 : 2); !HNMR : δ 1.18 (m,2H), 1.54 (in, 2H), 1.98 (m, 1H), 2.08 (s, 3H), 2.47 (m, 2H), 3.50 (s, 2H), 3.80 (s, 6H), 3.96 (dd, 1H), 4.05 (dd, 1H); 4.41 (d, 1H),6.06 (m,1H), 6·46 (s,2H), 6.55 (m, 2H), 7.05 (m, 2H), 7·21 (m, 3H)。 實施例28·•(卜{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱基苯基) (赵基)甲基]-5-苯基戊基}-1H-d弓丨D朵-3-基)乙酸 使用1H-D弓丨晚-3-基-乙酸取代1H-D比洛-2-緩酸乙g旨, 進行與實施例24—實施例19相同之操作,即可製成具有 以下物性值之標題化合物。 TLC ·· Rf 0· 1 6 (己烷:乙酸乙酯=1 : 1); 1H NMR : ί 1.47 (m, 4H), 2.09 (s, 3H), 2.22 (m, 1H), 2.42 (t, 2H), 3.76 (s, 2H), 3.78 (s, 6H), 4.12 (dd, 1H), 4.28 (dd, 1H), 4.65 (d, 1H), 6.48 (s, 2H), 6.99 (m, 3H),7.15 (m, 6H), 7.57 (d,1H)。 實施例29 : (1-{(2S)-2 - [(S)-{[第三丁基(二曱基)矽烷基] 氧基}(3,5-二曱氧基-4 -曱基苯基)曱基]-5 -苯基戊基} - 1H-吡唑-4-基)曱醇 121 316588 200521108 在氫化鋰鋁(15mg)之四氫呋喃(lml)溶液中加入卜 {(2S)-2-[(S)-{[第三丁基(二甲基)矽烷基]氧基Kg,5一二 曱氧基-4-曱基苯基)曱基]一5一苯基戊基}一1}1一吡唑—4一羧酸 乙酯(以實施例16中製成之化合物與1H—吡唑—羧酸乙酯 依與實施例24相同之方法製成)(4〇mg)之四氫呋喃(lml) 溶液,混合物並於室溫下攪拌15分鐘。反應混合物中再依 序加入飽和硫酸鈉水溶液、無水硫酸鎂及乙酸乙酯,混合 物並於室溫下攪拌20分鐘。過濾混合物並濃縮濾液,即可 製成具有以下物性值之標題化合物(35mg)。 TLC : Rf 0· 23 (己烧:乙酸乙酯=2 : 1); ^NMR : δ 7.42 (s, 1H), 7.30-7.05 (m, 6H), 6.45 (s, 2H), 4.72 (d, 1H), 4.50 (d, 2H), 4.21 (dd, 1H), 3.94 (dd, 1H), 3.79 (s, 6H), 2.50 (m, 2H), 2.20 (m., 1H), 2.06 (s, 3H), 1.78-1.12 (m, 4H), 0.94 (s, 9H), 0.04 (s, 3H), -0.16 (s, 3H)〇 實施例30: 1-{(2S)-2-[(S)-{[第三丁基(二甲基)矽烷基] 氧基}-(3, 5-二甲氧基一4-曱基苯基)甲基]一5一苯基戊基} -4 -(氣甲基)-1H-口比。坐 於0 C下在實施例2 9中製成之化合物(10 0 mg )之四氫 呋喃(2ml)溶液中加入三乙基胺(52// u、氣化鋰(15.8mg) 及曱續酿氯(22 // 1 ),將該反應混合物於〇°c下攪拌2小 時、於室溫下攪拌1小時。反應混合物再經乙酸乙酯稀釋、 過濾、。濃縮該濾液後,即可製成具有以下物性值之標題化 合物。 TLC ·· Rf 〇· 70 (己烷:乙酸乙酯=2 : 1); 122 316588 200521108 1 HNMR : d 7·44 (s, 1H),7.28-7.04 (m, 6H),6.45 (s,2H),4.69 (m, 1H), 4.49 (s, 2H), 4.21 (dd, 1H), 3.95 (dd, 1H), 3.79 (s, 6H), 2.50 (m, 2H), 2.18 (m, 1H), 2.06 (s, 3H), 1.70Ί.08 (m, 4H), 0.94 (s, 9H), 0.03 (s, 3H), *0.171 (s> 3H)。 實施例31:(1-{(2S)-2-[(S)-{[第三丁基(二甲基)石夕烧基] 氧基}-(3, 5-二甲氧基-4-甲基苯基)曱基]-5-苯基戊基} - 1H-吼嗤-4-基)乙猜 在實施例30中製成之化合物之二甲基亞楓(2ml)溶液 中加入氰化鈉(46mg),將該反應混合物於室溫下攪拌2〇 分鐘。於反應混合物中再加入水,並經乙酸乙酯萃取。萃 取液再依序經水及飽和食鹽水洗淨、無水硫酸納乾燥後濃 縮,即可製成具有以下物性值之標題化合物(88mg)。 TLC : Rf 0· 49 (己烷:乙酸乙酯=2 : 1); 1 HNMR : 7.37 (s,1H), 7.30-7.05 (m,6H), 6.45 (s,2H), 4.72· (d, 1H), 4.21 (dd, 1H), 3.9 6 (dd, 1H), 3.80 (s, 6H), 3.52 (s, 2H), 2.50 (m, 2H), 2.07 (s, 3H), 1.75-1.02 (m, 4H), 0.94 (s, 9H)? 0.04 (s, 3H), *0.17 (s, 3H)〇 實施例32:(卜{(23)-2-[(3)-(3,5-二曱氧基-4-曱基苯基) (經基)甲基]-5-笨基戊基}-ih-d比。坐-4-基)乙酸 在實施例31中製成之化合物之乙醇溶液中加入5N氫 氧化納水 >谷液’該反應混合物再於8 q 下攪拌2小時。於 反應混合物中再加入1N鹽酸,並經乙酸乙酯萃取。萃取液 再經飽和食鹽水洗淨、無水硫酸鎂乾燥後濃縮。其殘留物 再經石夕膠管柱層析精製,即可製成具有以下物性值之標題 化合物。 123 316588 200521108 TLC ·· Rf 0· 45 (氣仿··曱醇二9 ·· 1); 1 HNMR : d 7·46 (s,1H), 7·28·7·05 (m, 6H),6.52 (s, 2H),4.42-4.35 (m, 2H), 4.06 (dd, 1H), 3.80 (s, 6H), 3.52 (s, 2H), 2.62-2.38 (m, 2H), 2.15 (m, 1H), 2.07 (s, 3H), 1.85· 1.02 (m, 4H)。 , 實施例33 ·· 1-{(2S)-2-[ (S)-{[第三丁基(二甲基)矽烷基] 氧基} (3, 5-二甲氧基-4-甲基苯基)甲基]-5 —苯基戊基} -1Η -口比唾- 4 -甲酉筌 在實施例29中製成之化合物(i6〇mg)之乙酸乙酯(iml) 一曱基亞楓谷液中加入三乙基胺(248// 1)及三氧化 硫-D比咬錯合物(142mg),該混合物再於室溫下授拌1小 時。反應混合物再經乙酸乙酯稀釋。萃取液再依序經水及 飽和食鹽水洗淨、以無水硫酸鈉乾燥後濃縮,即可製成具 有以下物性值之標題化合物。其殘留物再經矽膠管柱層析 精製過濾。濃縮該濾液後,即可製成具有以下物性值之標 題化合物(274mg)。 TLC· Rf 0.50 (己烧:乙鱗=4 : 1); ^NMR : δ 9.78 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.28-7.03 (m, 5H), 6.44 (s, 2H), 4.74 (d, 1H), 4.26 (dd, 1H), 4.〇2 (dd, 1H), 3.79 (s, 6H) 2.54-2.44 (m, 2H), 2.19 (m, 1H), 2.06 (s, 3H), 1.76-1.39 (m, 3H), 1.12 (m, 1H),0.95 (s,9H), 0.04 (s, 3H),-0.16 (s, 3H)。 實施例 34: (2E)-3-(;l-{(2S)-2-[(s)-{[第三 丁基(二曱基) 矽烷基]氧基} (3, 5-二曱氧基-4-曱基苯基)曱基]一5〜苯基 戊基} -1Η-吼°坐-4-基)丙稀酸乙|旨 於氬氣、0°C下在2-(乙氧基磷醯基)乙酸乙酯(1〇〇mg) 316588 124 200521108 之四氫咲喃(0. 5ml)溶液中加入氫化鈉(1〇. 7mg)。將該混合 物再攪拌10分鐘,並加入在實施例33中製成之化合物 (274mg)之四氫呋喃(丨· 5mi)溶液,該反應混合物再於室溫 下擾拌30分鐘。於反應混合物中再加入水,並經乙酸乙酯 萃取。該萃取物再依序經水及飽和食鹽水洗淨,以無水硫 酸納乾紐後濃縮。其殘留物再經矽膠管柱層析(己烷:乙酸 乙酉曰—9 · 1 — 4 : 1)精製,即可製成具有以下物性值之標題 化合物(11 2mg)。 TLC : Rf 〇· 56 (己烷:乙醚=4 : 1); ^NMR : d 7.63 (s, 1H), 7.49 (d, 1H), 7.30 (s, 1H), 7.27-7.12 (m, 3H), 7.10-7.03 (m, 2H), 6.45 (s, 2H), 6.12 (d, 1H), 4.71 (d, 1H), 4.28*4.17 (m, 3H), 3.97 (dd, 1H), 3.79 (s, 6H), 2.52-2.42 (m, 2H), 2.17 (m, 1H), 2.06 (s, 3H), 1.7M.37 (m, 3H), 1.32 (t, 3H), 1.12 (m, 1H), 0.94 (s, 9H), 〇.〇3 (s, 3H), •0.17 (s, 3H)〇 ’ κ 把例 35 · (2E)-3-(1-{(2S)-2-[ (S)-(3, 5-二曱氧基一4 — 甲基苯基)(羥基)曱基]-5-苯基戊基卜1H-CI比唑一4一基)丙烤 酸 使用實施例34中製成之化合物取代實施例18中y成 之化合物,進行與實施例19—實施例20相同之操作,即 可製成具有以下物性值之標題化合物。 TLC .Rf 0.35 (己烧:乙酸乙 S旨=1:3); 316588 125 200521108 1 HNMR : 1.20 (m, 2H), 1.65 (m, 2H), 2.08 (s, 3H), 2.16 (m, 1H), 2.45 (m, 1H), 2.58 (m, 1H), 3.81 (s, 6H), 4.15 (dd, lH), 4.35 (d, 1H), 4.41 (dd, 1H), 6.15 (d, 1H), 6.50 (s, 2H), 7.08 (m, 2H), 7.24 (m, 4H), 7.60 (d, 1H), 7.73 (s, lH)〇 實施例 36 : 3-(1-{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱基苯 基)(經基)曱基]-5-苯基戊基}-4 -基)丙酸乙g旨 使用實施例34中製成之化合物取代實施例18中製成 之化合物,進行與實施例19相同之操作,再於製成之(2E) -3-(卜{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱基苯基)(羥基)· 曱基]-5 -苯基戊基}-1}]-口比°坐-4-基)丙稀酸乙酯(38mg)之 曱醇(5ml)溶液中加入10%鈀-碳(8mg)。將該混合物再於氫 氣、室溫下攪拌8小時。過濾該反應混合物並濃縮濾液, 即可製成具有以下物性值之標題化合物(39mg)。 TLC .Rf 0·50 (己烧:乙酸乙酯=1:1); 'HNMR : d 7.35 (s, 1H), 7.29-7.12 (m, 3H), 7.10-7.04 (m, 2H), 7.00 (s, 1H), 6.53 (s, 2H), 4.77 (d, 1H), 4.40-4.29 (m, 2H), 4.14 (t, 2H), 4.02 (dd, _ 1H), 3.81 (s, 6H), 2.77 (t, 2H), 2.64-2.38 (m, 4H), 2.10 (m, 1H), 2.07 (s, 3H), 1.72· 1.57 (m, 3H),1_25 (t, 3H), 1.12 (m, 1H)。 實施例 37 : 3-(1 -{(2S)-2-[(S)-(3, 5-二曱氧基一4-曱基苯 基)(經基)甲基]-5-苯基戊基}-1Η-口比。坐-4-基)丙酸 使用實施例36中製成之化合物取代實施例4(1)中製 成之化合物,依實施例5(1)相同之操作,即可製成具有以 下物性值之標題化合物。 TLC ·· Rf 〇· 35 (己烷:乙酸乙酯=1 : 3); 126 316588 200521108 1 HNMR : 6 1.23 (m, 2H),1.62 (m, 2H),2.07 (s,3H),2·17 (m,1Η), 2·55 (m, 4H), 2.75 (t, 2H), 3.79 (s, 6H), 4.03 (dd, 1H), 4.34 (m, 2H), 6.51 (s, 2H), 7.00 (s,1H),7.08 (m, 2H),7.23 (m, 3H), 7.35 (s, 1H)。 實施例38: 1-{(2S)-2-[(S)-{[第三丁基(二甲基)石夕烧基] 氧基} (3, 5-二甲氧基-4-甲基苯基)甲基]-5-苯基戊基} —1Η - 口比口坐一 3 -甲醒1 使用1H-D比唾-3-曱搭取代1Η-D比略-2-羰酸乙酯,進行 與實施例24相同之操作,即可製成具有以下物性值之標題 化合物。 HPTLC · Rf 0· 22 (己烧:乙酸乙 g旨:=9 : 1); 1 HNMR : d 9.92 (s, 1H),7.30-7.05 (m, 6H),6.73 (d,1H), 6.46 (s,2H), 4.72 (d, 1H), 4.30 (dd, 1H), 4.11 (dd, 1H), 3.80 (s, 6H), 2.49 (m, 2H), 2.22 (m, 1H), 2.07 (s, 3H), 1.75*1.10 (m, 4H), 0.94 (s, 9H), 0.04 (s, 3H), *0.16 (s, 實施例 39: 3-(1 -{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱基笨 基)(羥基)曱基]-5-苯基戊基卜ΙΗ-Dtt唑-3-基)丙酸 使用實施例38中製成之化合物取代實施例33中製成 之化合物,進行與實施例34—實施例36—實施例37相同 之操作’即可製成具有以下物性值之標題化合物。 TLC : Rf 0· 32 (二氣甲烷:曱醇=9 :; !HNMR : 6 7.32-7.05 (m, 6H), 6.53 (s, 2H), 6.01 (d, 1H), 4.39 (d, 1H), 4.32 (dd, 1H), 4.03 (dd, 1H), 3.81 (s, 6H), 2.97 (t, 2H), 2.72* (t, 2H), 2.62-2.38 (m, 2H), 2.10 (m, m), 2.07 (s, 3H), 1.70-1.55 (m, 2H), 1.40-1.05 (m, 2H)〇 127 316588 200521108 實施例40 : U-{(2S)-2-[(S)-(3, 5-二甲氧基-4-甲基苯 基)(經基)甲基]-5-苯基戊基卜1 η-吼唑—3-基)乙酸 使用實施例38中製成之化合物取代1一{(2s) — 2 一 [(s) -{[第三丁基(二曱基)矽烷基]氧基} (3, 5 一二曱氧基—4―曱基 苯基)曱基]-5-苯基戊基}-1Η-吡唑-4-羧酸乙酯,進行與實 施例29-^貫施例3 0實施例31 —實施例32相同之操作, 即可製成具有以下物性值之標題化合物。 TLC : Rf 0· 50 (氯仿:曱醇=9 : 1); 1 HNMR : 1.23 (m, 2H), 1.64 (m, 2H), 2.07 (s, 3H), 2.15 (m, 1H), 2.50 (m, 2H), 3.72 (s, 2H), 3.79 (s, 6H), 4.09 (dd, 1H), 4.31 (dd, 1H), 4.43 (d, 1H), 6·13 (d, 1H), 6.51 (s, 2H),7·08 (m, 2H), 7.20 (m, 4H)。 實施例41(1)至實施例41(2) 使用3-甲基-1H-D比唾-5-緩酸乙酯取代1H-吼略-2-缓 酸乙酯,依與實施例24相同之操作,即可製成具有以下物 性值之標題化合物。 實施例41 (1 ) : ;l-{(2S)-2-[ (S)-{[第三丁基(二曱基)矽烷 基]氧基}(3,5 -一曱氧基-4 -曱基苯基)曱基]一5 -苯基戊基} - 3-曱基-1H - 〇比σ坐-5-叛酸乙酉旨 TLC : Rf 0· 63 (己烷:乙酸乙酯=2 : 1); 'HNMR : d 7.28-7.04 (m, 6H), 6.55 (s, 2H), 4.67 (d, 1H), 4.59 (dd, 1H), 4.41 (dd, 1H), 4.25 (q, 2H), 3.80 (s, 6H), 2.42 (m, 2H), 2.40 (m, 1H), 2.23 (s, 3H), 2.06 (s, 3H), 1.60Ί.20 (m, 4H), 1.32 (t, 3H), 0.91 (s, 9H), 0.00 (s, 3H), -0.18 (s, 3H)〇 實施例41(2): 1-{(2S)-2 - [(S) - {[第三丁基(二曱基)石夕烧 128 316588 200521108 基]氧基} (3, 5-二曱氧基-4-甲基苯基)甲基]-5-苯基戊基} - 5-甲基-1Η-吡唑-3-羧酸乙酯 TLC : Rf 0· 52 (己烷:乙酸乙酯=2 : 1); 'HNMR : d 7.30-7.06 (m, 6H), 6.47 (s, 2H), 4.78 (d, 1H), 4.37 (q, 1H),4.14 (m, 1H), 4.03 (dd, 1H), 3.80 (s, 6H), 2.48 (m, 2H), 2.08 (m, 1H), 2.06 (s, 3H), 2.02 (s, 3H), 1.72-1.20 (m, 4H), 1.37 (t, 3H), 0.95 (s, 9H), 0.04 (s, 3H),-0.15 (s, 3H)〇 實施例42(1)至實施例42(2) 使用實施例41(1)中製成之化合物或實施例41(2)中 _ 製成之化合物取代1-K2S)-2-[(S)-{[第三丁基(二曱基) 矽烷基]氧基} (3, 5-二曱氧基-4-曱基苯基)曱基]-5-苯基 戊基} -1 H-吼。坐-4-叛酸乙S旨,進行與實施例29—實施例30 —實施例31—實施例32相同之操作,即可製成具有以下 物性值之標題化合物。 實施例 42(1) ·· 1-{(2S)-2-[(S)-(3, 5-二曱氧基-4-甲基苯 基)(經基)曱基]-5 -苯基戊基}-3-曱基-1H-Q比唾-5-基)乙 φ 酸 TLC : Rf 0· i9 (二氣曱烷:曱醇=9 : 1); ^NMR : 5 7.32-7.04 (m, 5H), 6.54 (s, 2H), 5.96 (s, 1H), 4.58 (d, 1H), 4.15*3.90 (m, 2H), 3.79 (s, 6H), 3.51 (d, 2H), 2.65-2.38 (m, 2H), 2.23 (s, 3H) 2·20 (m, 1H), 2.07 (s, 3H), 1.75-1.10 (m, 4H)。 實施例42(2):(1-{(23)-2-[(3)-(3,5-二曱氧基-4-甲基 苯基)(羥基)甲基]-5-苯基戊基}一5 一曱基一;[h -□比唾-3一基) 乙酸 TLC : Ri 0.37 (二氣曱烷:曱醇=9 : d ; 316588 129 200521108 'HNMR : (5 7.32-7.04 (m, 5H), 6.52 (s, 2H), 5.90 (s, lH), 4.64 (d, 1H), 4.03 (m, 2H), 3.80 (s, 6H), 3.67 (s, 2H), 2.62-2.40 (m, 2H), 2.20 (m, 1H), 2· 15 (s, 3H), 2.07 (s, 3H), 1.72-1.16 (m, 4H)。 實施例43(1)至實施例43(2) 使用3-曱基-1H-吡唑-4-羧酸乙酯取代1H-吡π各—2 一竣 酸乙酯,進行與實施例24—實施例29相同之操作,即可 製成具有以下物性值之標題化合物。 實施例43(1) : (1-{(2S) - 2-[(S)-{[第三丁基(二甲基)石夕 烷基]氧基} (3, 5-二曱氧基-4-甲基苯基)甲基]-5-笨基戊魯 基}-3-甲基-1Η-吡唑-4-基)曱醇 HPTLC· Rf 0.41 (己烧:乙酸乙醋=1 ·· 1); 'HNMR : ί 7.30-7.02 (m, 6H), 6.44 (s, 2H), 4.71 (d, 1H), 4.44 (d, 2H), 4.15 (m, 1H), 3.86 (dd, 1H), 3.79 (s, 6H), 2.52 (m, 2H), 2.21 (s, 3H), 2.20 (m,1H), 2.05 (s, 3H), 1.80-1.10 (m, 4H), 0.94 (s, 9H), 0.04 (s, 3H), -0.16 (s, 3H)〇 實施例43(2) : (l-{(2S)-2-[(S) - {[第三丁基(二曱基)石夕 烧基]氧基}(3, 5-二曱氧基-4-曱基苯基)曱基]一5-笨基戊 基}-5 -曱基-1Η-〇ϋ^-4-基)曱醇 HPTLC : Rf 0· 34 (己烷:乙酸乙酯=1 : 1); !HNMR : d 7.36 (s, 1H), 7.28*7.04 (m, 5H), 6.48 (s, 2H), 4.80 (d, 1H), 4.44 (s, 2H), 4.07 (m, 1H), 3.91 (dd, 1H), 3.79 (s, 6H), 2.52 (m, 2H), 2.18 (m, 1H), 2.06 (s, 3H), 2.01 (s, 3H), 1.78*1.10 (m, 4H), 0.97 (s, 9H), 0.05 (s, 3H), _0.14(s, 3H)〇 實施例44(1)至實施例44(2) 316588 130 200521108 使用貫施例4 3 (1)中製成之化合物或實施例4 3 (2)中 製成之化合物取代1-K2S) - 2-[(s)-{[第三丁基(二曱基) 矽烷基]氧基} (3, 5-二曱氧基-4-曱基苯基)曱基]一5一苯基 戊基卜1HH4-叛酸乙酯,進行與實施例29—實施例3〇 —實施例31 —實施例3 2相同之操作,即可製成以下之化 合物。 貫施例44(1).(1-{(28)-2-[(8)-(3,5-二曱氧基-4-甲基 苯基)(經基)曱基]_5 -苯基戊基}一3-曱基-1H-D比π坐一4一基) 乙酸 籲 TLC : Rf 0· 44 (二氣曱烷:曱醇二9 : 1); 1 HNMR : 6 7.29-7.05 (m,6H),6.54 (s, 2H), 4.39 (d, 1H),4.27 (dd, 1H), 3.97 (dd, lH), 3.81 (s, 6H), 3.43 (s, 2H), 2.62"2.38 (m, 2H), 2 21 (s 3H) 2·10 (m, 1H), 2.07 (s, 3H),1.70-1.52 (m, 2H), 1.38-1.05 (m, 2H)。 實施例 44(2) : U-{(2S)-2-[(S)-(3,5-二曱氧基-4-曱基 苯基)(羥基)曱基]-5-苯基戊基}-5-甲基-1H-吡唑-4-基) 乙酸 _ TLC :Rf 0·44 (二氣曱烷:曱醇=9: 1); iHNMR : d 7.43 (s,1Η),7.29-7.04 (m,5Η), 6.55 (s, 2Η),457 (d, 1Η), 4.14 (dd, 1H), 4.02 (dd, 1H), 3.80 (s, 6H), 3.43 (s, 2H), 2.62*2.38 (m, 2H), 2.18 (m, 1H), 2.10 (s, 3H), 2.07 (s, 3H), 1.80*1.10 (m, 4H)〇 實施例45 : 3-(卜{(2S)-2-[(S)-(3, 5-二曱氧基-4-曱基笨 基)(經基)曱基]-5 -本基戍基}-1[1_〇比洛-3_基)丙酸 使用卜{(2S)-2-[(S)-{[第三丁基(二曱基)矽烷基] 氧}(3, 5-二曱氧基-4-曱基苯基)甲基]-5-苯基戊基}-1H- 131 316588 200521108 吼咯-3-羧酸乙酯(即實施例16中製成之化合物與iH-吡咯 -3-緩酸乙酯進行與實施例24相同之操作所製成者)取代 1-{(23)-2-[(8)-{[第三丁基(二曱基)矽烷基]氧基丨(3,5一 二曱氧基-4-甲基苯基)曱基]-5-苯基戊基卜1 η-吼唑-4-羧 酉文乙酯’進行與實施例29—實施例33—實施例34—實施 例36—實施例37相同之操作,即可製成具有以下物性值 之標題化合物。 TLC : Rf 〇· 21 (己烷:乙酸乙酯=1 : 1); ^NMR : d 1.19 (m, 2H), 1.53 (m, 2H), 1.98 (m, 1H), 2.08 (s, 3H), 2.43 (m, 2H), 2.56 (t, 2H), 2.76 (t, 2H), 3.80 (s, 6H), 3.94 (dd, 1H), 4.02 (dd, 1H), 4.40 (d, 1H), 5.95 (m, 1H), 6.40 (m, 1H), 6.46 (s, 2H), 6.51 (t, 1H), 7.14 (m, 5H)〇 貫施例46 : (3S)-3-[(S)-{[第三丁基(二曱基)矽烷基]氧 基} (3, 5-二曱氧基-4-甲基苯基)曱基]一6—苯基己腈 使用實施例17中製成之化合物取代實施例3〇中製成 之化合物,再如實施例31同樣操作,即可製成具有以下物 性之標題化合物。 TLC :Rf 0.50 (己烧:乙酸乙酯=8:1); HNMR : δ 7.30-7.09 (m, 5H), 6.41 (s, 2H), 4.55 (d, 1H), 3.80 (s, 6H), 2.63-2.52 (m, 3H), 2.37 (dd, 1H), 2.08 (s, 3H), 1.94-1.84 (m, 1H), 1.75-1.39 (m, 4H), 0.92 (s, 9H〉,0·06 (s, 3H), ·0·20 (s, 3H)。 實施例47 : (3S)-3-[(S)-{[第三丁基(二曱基)矽烷基]氧 基} (3, 5-二曱氧基-4-曱基苯基)曱基]一6一苯基己醛 於氬氣、-78C下,在實施例46中製成之化合物(357mg) 316588 132 200521108 之曱苯(7ml)溶液中,加入L 01M之氫化二異丁基鋁曱苯溶 液(1· 5ml)。將該混合物於-78°C下攪拌10分鐘、再於0°C 下攪拌50分鐘。然後於冰冷卻下加入1 n鹽酸攪拌。於該 反應混合物中加入乙酸乙酯,再依序經水及飽和食鹽水洗 淨、以無水硫酸鎂乾燥後濃縮,即可製成具有以下物性值 之標題化合物(370mg)。 TLC : Rf 0· 49 (己烷:乙酸乙酯=8 : 1); 實施例48 : (3S)-3-[(S)-{[第三丁基(二甲基)矽烷基]氧 基}(3, 5-二曱氧基一 4 -甲基苯基)曱基]一6一苯基己酸 在貫施例47中製成之化合物(370mg)之第三丁醇(8mi) 與水(2ml)之混合溶液中,加入2 —曱基—2-丁烯(〇·3 7ml)、 磷酸二氫鈉(138mg)與亞氯酸鈉(260mg),將該混合物再於 室溫下攪拌70分鐘。然後於該反應混合物中加入1N鹽酸, 並以乙酸乙酯稀釋。其有機層再依序經水及飽和食鹽水洗 、淨,以無水硫酸鎂乾燥後濃縮,即可製成具有以下物性值 之標題化合物(320mg)。 TLC : Ri 〇· 13 (己烧:乙酸乙酯: 1); 實施例49:4-({(3S)-3-[⑻_{[第三丁基(二曱基)石夕烧基] 乳基}(3,5-二甲氧基+甲基苯基)曱基]_6_苯基己酸基} 胺基)-3-羥基丁酸甲酯 在實施例48中製成之化合物(32〇mg)之二氣曱烷 (l〇ml)溶液中’加人4_胺基_3_經基了酸甲g旨鹽酸^ (218mg)、三乙基⑽.基苯并三唾⑽⑷、 卜乙基-3-[3 —(二甲基胺基)丙基]碳化二亞胺鹽酸鹽 316588 133 200521108 (2 4 7 m g)。將該混合物再於室溫下㈣—晚。該反應混合物 再經二氯甲烷稀釋,並依序經飽和碳酸氫鈉水溶液、Μ鹽 酸、水及飽和食鹽水洗淨,以無水硫酸鎂乾燥後濃縮,其 殘留物再經矽膠管柱層析(己烷:乙酸乙酯=2:丨)精製’即 可製成具有以下物性值之標題化合物(33〇mg)。 TLC ·· Rf 〇· 36 (己烧··乙酸乙酯: 1); ^NMR : d 7.31^7.12 (m, 5H), 6.43 (s, 2H), 5.86-5.77 (m, 1H), 4.70 (d, 1H), 4.07-3.96 (m, 1H), 3.79 (s, 6H), 3.70 (s, 3H), 3.63 (t, 1H), 3.47-3.35 (m, 1H), 3.17-3.04 (m, 1H), 2.62-2.53 (in, 2H), 2.47-2.41 (m, 2H), 2.35 (d, 1H), 2.11-2.02 (m, 4H), 1.75-1.22 (m, 4H), 0.92 (s, 9H), 0.02 (s, 3H), -0.16 (s, 3H)〇 ’ 貫施例50 : 4-({(3S)-3-[(S)-{[第三丁基(二曱基)矽烷基] 氧基}(3, 5-二曱氧基-4-甲基苯基)甲基]—6-笨基己醯基} 胺基)-3-酮基丁酸曱酯 在實施例49中製成之化合物(99mg)之二氯曱烧(5ml) 溶液中加入1,1,卜參(乙醯氧基)—1,卜二氫2一苯并碘 雜氧雜環戊稀-3- (1Η)-酮(戴斯-馬丁試藥,1 〇 5mg),該混 合物再於室溫下攪拌1 5小時。該反應混合物再經二氯曱烷 稀釋,並依序經飽和碳酸氫鈉水溶液、水及飽和食鹽水洗 淨’以無水硫酸鎮乾燥後濃縮。其殘留物再經石夕膠管柱層 析(己烷:乙酸乙酯=2 : 1)精製,即可製成具有以下物性值 之標題化合物(61mg)。 TLC : Rf 〇· 54 (己烷··乙酸乙酯二1 : 1); 134 316588 200521108 1 H NMR : d 7.29-7.12 (m,5H),6.44 (s,2H),6.08 (t, 1Η),4·68 (d, 1H), 4.17-4.12 (m, 2H), 3.79 (s, 6H), 3.74 (s, 3H), 3.47 (s, 2H), 2.60*2.53 (m, 2H), 2.43-2.34 (m, 1H), 2.15*2.03 (m, 5H), L74-1.22 (m, 4H), 0.92 (s, 9H), 0.02 (s, 3H), -0.17 (s, 3H)〇 實施例51 ·· (2 - {(2S)-2-[(S)-{[第三丁基(二曱基)矽烷基] 氧基}(3, 5-二曱氧基-4 -曱基苯基)曱基]-5-苯基戊基}-1,3-噻唑-5-基)乙酸曱酯 在實施例50中製成之化合物(30mg)之曱苯(3ml)溶液 中加入2, 4-雙(4-甲氧基苯基)-1,3-二硫雜-2, 4-二鱗雜 環丁烧-2, 4-二硫化物(羅森試藥,23mg)。該混合物再經回 流3 0分鐘,並濃縮其反應混合物。其殘留物再經石夕膠管柱 層析(己烷:乙酸乙酯=8 ·· 1)精製,即可製成具有以下物性 值之標題化合物(28mg)。 TLC.Rf 0.28 (己烧·乙酸乙醋=4: 1); ^NMR : d 7.40 (t, 1H), 7.28-7.08 (m, 5H), 6.48 (s, 2H), 4.71 (d lH) 3.80 (s, 6H), 3.78 (d, 2H), 3.73 (s, 3H), 3.09 (dd, 1H), 2.88 (dd 1H) 2.54 2.46 (m, 2H), 2.16-2.03 (m, 4H), 1.7M.23 (m, 4H), 0.92 (s, 9H), 0.02 (s, 3H),-0.18(s, 3H)〇 ' 實施例 52 : (2-({(2S)-2-[(S)-(3, 5-二曱氧基一4—曱基苯 基)(羥基)曱基]-5-苯基戊基}一1,3 —噻唑〜5—基)乙酸 使用實施例51中製成之化合物,進行與實施例2〇一 #施例19相同之操作’即可製成具有以下物性值之標題化 合物。 TLC : Rf 0· 33 (二氯曱烷:曱醇: d ; 316588 135 200521108 1 H NMR(CDaOD): d 7.42 (s, lH), 7.19*6.99 (m, 5H), 6.58 (s, 2H), 4.59 (d, 1H), 3.81 (s, 2H), 3.79 (s, 6H), 3.14 (dd, 1H), 2.94 (dd, 1H), 2.44 (t, 2H), 2.26-2.13 (m, 1H), 2.01 (s, 3H), 1.6M.15 (m, 4H)〇 實施例53 : (2-{(2S)-2-[(S)-{[第三丁基(二曱基)矽烷基] 氧基} (3, 5-二甲氧基-4-曱基苯基)曱基]-5-苯基戊基}一 1,3-噁唑-5-基)乙酸曱酯 在三苯基膦(137mg)與蛾(132mg)之二氣乙烧(5mi)溶 液中,加入實施例50製成之化合物(l〇4mg)與三乙基胺 (0. 15ml)之二氯曱烷(5ml)溶液,該混合物再於35cc下擾 拌3 · 5小時。再濃縮反應混合物。其殘留物再經石夕膠管柱 層析(己烷:乙酸乙酯=6 : 1)精製,即可製成具有以下物性 值之標題化合物(29mg)。 TLC· Rf 〇·25 (己烧:乙酸乙 g旨=4: 1); JHNMR : (5 7.28-7.09 (m, 5H), 6.80 (s, 1H), 6.46 (s, 2H), 4.68 (d, 1H) 3.79 (s, 6H), 3.71 (s, 3H), 3.62 (s, 2H), 2.86 (dd, 1H), 2.72 (dd, 1H) 2.56-2.47 (m, 2H), 2.20-2.10 (m,1H), 2.05 (s, 3H), 1.71.1.19 (m, 4H), 〇 91 ’ (s, 9H), O.Oi (s,3H),-019 (s, 3H)。 實施例54 : (2-{(2S)-2-[(S)-(3, 5-二曱氧基一4〜曱基苯基) (每基)甲基]-5-苯基戊基}-1,3-噁唑-5-基)乙酸 使用貫施例5 3中製成之化合物取代實施例19中制成 之化合物,進行與實施例20—實施例19相同之操作,即 可‘成具有以下物性值之標題化合物。 TLC : Rf 0· 32 (二氯曱烷:曱醇=9 : 1); 316588 136 200521108 1 H NMR(CD3OD): ί 7.21-7.01 (m, 5Η), 6.82 (s, 1H), 6.55 (s, 2H), 4.57 (d, 1H), 3.78 (s, 6H), 3.67 (s, 2H), 2.92 (dd, 1H), 2.74 (dd, 1H), 2.47 (t, 2H), 2.30-2.16 (m, 1H), 2.00 (s, 3H), 1.59-1.12 (m, 4H)〇 實施例55 : (2R)-2-[(S)-{[第三丁基(二曱基)矽烷基]氧 基} (3, 5-二曱氧基-4-甲基苯基)曱基]一5-苯基戊酸 於0°C下,在實施例13中製成之化合物(4· 97g)之四 氫咲皆(7 5ml)與水(25ml)之混合溶液中,加入氫氧化鐘 (2· 43g)之30%過氧化氫(1 〇ml )懸浮液,該混合物再於〇。〇 下授拌3小時。於反應混合物中再加入亞硫酸鈉(14. 5g) 之水(1 QOml)溶液、5N鹽酸(14ml)。濃縮該反應混合物, 並經乙酸乙酯萃取。該萃取物再依序經水及飽和食鹽水洗 淨’以無水硫酸鎮乾燥後濃縮。其殘留物再經石夕膠管柱層 析(己烧:乙酸乙酯二1: 1)精製,即可製成化合物(2.〇5g)。 以该製成之化合物取代實施例1 3中製成之化合物,再如實 施例14同樣彳呆作’並經1N鹽酸水解,即可製成且有以下 物性值之標題化合物。 TLC.Rf 0·26 (己烧·乙酸乙 g旨=4: 1); 1 HNMR : d -0.21 (s, 3H), 0.01 (s, 3H), 0.83 (s, 9H), 1.21 (m, 1H), 1.59 (m, 3H), 2.08 (s, 3H), 2.50 (m, 2H), 2.71 (m, 1H), 3.80 (s, 6H), 4.65 (d, 1H), 6·46 (s, 2H), 7.04 (m, 2H), 7.17 (m, 3H)。 實施例56 : 4-({(2R)-2-[ (S)-{[第三丁基(二甲基)矽烷基] 氧基}(3, 5-二曱氧基-4-曱基苯基)甲基]—5-苯基戊醯基} 胺基)苯曱酸甲酯 於0°C下,在實施例55製成之化合物(i〇0mg)之二氯 137 316588 200521108 曱烷(1πΐ1)溶液中加入乙二醯氯(37// 1)及催化劑量之二曱 基甲醯胺,並於室溫下攪拌30分鐘。再濃縮該反應混合 物,即製成酸氣化物。於〇。〇下在4一胺基苯曱酸曱酯(384mg) 之二氣曱烷(lull)溶液中,加入三乙基胺(44//1)與該製成 之酸氯化物(l〇〇mg)之二氣曱烷(lml)溶液。將該反應混合 物於室溫下攪拌20分鐘。於反應混合物中再加入水並經乙 酸乙酯萃取。該萃取物再經1N鹽酸、飽和食鹽水洗淨,以 無水硫酸鈉乾燥後濃縮。其殘留物再經矽膠管柱層析(己 烷:乙酸乙酯=8 : 1—4 : 1)精製,即可製成具有以下物性 值之標題化合物(42mg)。 TLC : Rf 〇· 54 (己烷:乙酸乙酯=2 : 1); 'HNMR : d 8.20 (s, 1H), 8.00 (d, 2H), 7.60 (d, 2H), 7.28-7.08 (m, 5H), 6.42 (s, 2H), 4.73 (d, 1H), 3.90 (s, 3H), 3.69 (s, 6H), 2.58 (t, 2H), 2.49 (in, 1H), 2.04 (s, 3H), 1.90-1.30 (m, 4H), 0.86 (s, 9H), -0.01 (s, 3H), -0.15 (Sj 3H)〇 ’ , 實施例57: 4-({(2R)-2-[(S)-(3, 5-二曱氧基一4—甲基苯基) (羥基)曱基]-5-苯基戊醯基}胺基)苯曱酸 使用實施例56中製成之化合物取代實施例19中製成 之化合物,進行與實施例20—實施例19相同之操作,即 可製成具有以下物性值之標題化合物。 TLC ·· Rf 〇· 30 (二氯曱烷··曱醇=9 : 1); lHNMR : d 8.04 (d, 2H), 7.67 (s, 1H), 7.58 (d, 2H), 7.30-7.08 (m, 5H), 6.49 (s, 2H), 4.83 (d, 1H), 3.75 (s, 6H), 2.65*2.50 (m, 3H), 2.06 (s, 3H) 2.02*1.20 (m,4H)〇 316588 138 200521108 實施例57(1)至實施例57(3) 4-胺基苯曱酸曱酯以相當之笨胺衍生物取代,依實施 例56—實施例57相同之彳呆作,即可製成以下之本發明化 合物。 實施例 57(1) : 3-({(2R)-2-[(S)-(3, 5-二甲氧基一4-甲基 苯基)(羥基)甲基]-5-苯基戊醯基}胺基)苯曱酸 TLC : Rf 0· 17 (二氯甲烷:曱醇=9 : 1); 1 HNMR : ci 7.98 (m,1Η),7·92 (d,1H),7.81 (d,1H), 7.70 (s, 1H) 7 40 (dd, 1H), 7.29-7.09 (m, 5H), 6.50 (s, 2H), 4.83 (d, 1H), 3.75 (s, 6H), 2.65-2.52 (m, 3H), 2.06 (s, 3H), 2.05-1.40 (m,4H)。 實施例 57(2) : [4-( {(2R)-2-[(S)-(3, 5-二曱氧基一4—曱基 苯基)(羥基)曱基]-5-苯基戊醯基}胺基)苯基]乙酸 TLC : Rf 0· 10 (二氯曱烷:曱醇=9 : 1); 'HNMR : d 7.43-7.36 (m, 2H), 7.30-7.10 (m, 8H), 6.49 (s, 2H), 4.80 (d, 1H), 3.75 (s, 6H), 3.62 (s, 2H), 2.65-2.42 (m, 3H), 2.06 (s, 3H), 2.00-1.30 (m, 4H)〇 實施例 57(3) : [3-({(2R)-2-[(S)-(3, 5-二曱氧基-4-曱基 苯基)(羥基)曱基]-5 -苯基戊醯基}胺基)苯基]乙酸 TLC : Rf 0· 14 (二氣曱烷:甲醇=9 : 1); !HNMR : δ 7.47 (s, 1H), 7.40*7.35 (m, 2H), 7.29-7.08 (m, 6H), 7.02 (d, 1H), 6.47 (s, 2H), 4.79 (d, 1H), 3.74 (s, 6H), 3.61 (s, 2H), 2.58 (m, 2H), 2.50 (m,1H), 2.06 (s, 3H), 2.00-1.42 (m, 4H)。 實施例58 :甲石黃酸[(2S,3S)-3-{[第三丁基(二曱基)石夕烧 基]氧基卜2-(2, 3-二氫-1H-茚-2-基甲基)-3-(3, 5-二曱氧 139 316588 200521108 基-4-曱基苯基)丙]酉旨 使用3 -(2,3-二氫-ΙΗ-節-2-基)丙醯氯取代5-苯基戊 龜氯,進行與實施例12—實施例13—實施例丨4—實施例 15—實施例16相同之操作,即可製成具有以下物性值之標 題化合物。 TLC : Rf 〇· 86 (曱苯··乙酸乙酯=4 ·· 1); 'HNMR : d 7.18-7.02 (m, 4H), 6.46 (s, 2H), 4.65 (d, 1H), 4.41 (dd, 1H), 4.31 (dd, 1H), 3.80 (s, 6H), 3.10-2.92 (m, 2H), 2.95 (s, 3H), 2.60-2.38 (m, 4H),2.06 (S, 3H),[58122 (m, 2H〉,〇 9〇 (s,9H), 〇 〇6 & 3H) -〇 i9 (s,鄉 實施例 59 : {1-[(2S,3S)-2-(2,3-二氫-111-茚-2-基曱基) -3-(3, 5-二曱氧基一4—曱基苯基)一3一羥基丙基]一1{1—吼咯 - 3 -基}乙酸
使用實施例58令製成之化合物取代實施例16中製成 之化合物,進行與實施例26—實施例27—實施例19相同 之插作’即可製成具有以下物性值之標題化合物。 TLC · Rf 0· 39 (二氯甲烷:曱醇=9 : 1); 140 316588 200521108 1 H NMR : d 7.15-7.02 (m, 4H), 6.64 (m, 2H), 6.49 (s, 2H), 6.08 (dd, 1H), 4.46 (d, 1H), 4.15 (dd, 1H), 4.01 (dd, 1H), 3.81 (s, 6H), 3.53 (s, 2H), 3.02-2.88 (m, 2H), 2.50*2.28 (m, 3H), 2.15 (m, 1H), 2.06 (s, 3H), 1.42-1.35 (m, 2H)〇 實施例59(1)至實施例59(5) 3-(2, 3-二氫-1H-節-2-基)丙驢氯以相當之酸氯化合 物取代、3, 5-二曱氧基-4-曱基苯曱醛以相當之醛化合物取 代,依與實施例58—實施例59相同之操作,即可製成以 下之化合物。 鲁 實施例 59(1): (1 -{(2S)-2-[(S)-(3,5-二曱氧基-4 -曱基 苯基)(輕基)甲基]-5-噻吩-3-基戊基洛-3-基)乙 酸 性狀:非晶物(無定形物) TLC : Rf 0· 52 (二氯甲烷:曱醇=9 : 1); ^NMR : δ 7.20 (dd, 1H), 6.83-6.77 (m, 2H), 6.58*6.54 (m, 2H), 6.47 (s, 2H), 6.08-6.05 (m, 1H), 4.43 (d, 1H), 4.09-3.93 (m, 2H), 3.81 (s, 6H), 3.52 (s, _ 2H), 2.58-2.40 (m, 2H), 2.08 (s, 3H), 2.08*1.95 (m, 1H), 1.62-1.48 (m, 2H), 響 1.31·1·11 (m,2H)〇 實施例 59(2) : {1-[(23,38)-2-(1,3-苯并二噁唑-2-基曱 基)-3-(3,5-一甲氧基-4-曱基苯基)_3_經基丙基]_1丑_卩比 咯-3-基}乙酸 性狀:非晶物 TLC : Rf 0. 51 (二氯甲烷:曱醇=9 : 1); 316588 141 200521108 !HNMR : δ 1.77-2.00 (m, 2H), 2.06 (s, 3H), 2.42-2.60 (m, 1H), 3.51 (s, 2H), 3.80 (s,6H), 3.98-4.09 (m, 1H), 4.09-4.22 (m,1H), 4.62 (d,1H), 5.81-5.89 (m, 1H), 6.08 (t, 1H), 6.48 (s, 2H), 6.65 (d, 2H), 6.70-6.84 (m, 4H)〇 實施例 59(3) : {1-[(2S,3S)-2-(2,3-二氫-111-茚-2-基曱 基)-3_羥基-3-(3, 4, 5-三甲氧基苯基)丙基]-1H-吡咯-3-基}乙酸 性狀:非晶物 TLC : Rf 0· 17 (己烷:乙酸乙酯=1 : 2); 1HNMR : d 7.20-7.05 (m, 4H),6.65-6.60 (m, 2H),6.52 (s,2H), 6.08 (m, 參 1H), 4.44 (d, 1H), 4.20-3.90 (m, 2H), 3.84 (s, 6H), 3.83 (s, 3H), 3.52 (s, 2H), 3.00·2·90 (m, 2H), 2·50·2·30 (m, 3H), 2.20-2.10 (m, 1H), 1.40-1.30 (m, 2H)。 實施例 59(4) : {1-[(2S,3S)-3-(4-乙醯基-3, 5-二曱氧基 苯基)-2 -(2,3-二氫-1H-節-2_基曱基)- 3-經基丙基] 口比咯-3 -基}乙酸 性狀:非晶物 TLC : Rf 0· 20 (二氣曱烷:曱醇=9 : 1) ; φ 1 HNMR : d 7.20-7.08 (m, 4H), 6.61 (dd, 1H), 6.56 (m, 1H), 6.49 (s, 2H), 6.06 (m, 1H), 4.54 (d, 1H), 4.10 (dd, 1H), 3.97 (dd, 1H), 3.79 (s, 6H), 3.50 (s, 2H), 3.06-2.94 (m, 2H), 2.60*2.38 (m, 3H), 2.46 (s, 3H), 2.18 (m, lH), 1.42 (m,2H)〇 實施例 59(5) : {1-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基曱 基)- 3 -(4 -乙基-3, 5-二曱氧基苯基)-3-經基丙基]-1H-口比 咯-3-基}乙酸 性狀:非晶物 142 316588 200521108 TLC : Rf 0· 56 (己烷:乙酸乙酯=1 : 2); 1 H NMR : 6 7.20-7.05 (m,4H), 6·65·6.60 (m,2H),6.49 (s, 2H),6.08 <t, 1H), 4.46 (d, 1H), 4.20-3.90 (m, 2H), 3.80 (s, 6H), 3.52 (s, 2H), 3.00-2.90 (m 2H), 2.62 (q, 2H), 2.50-2.30 (m, 3H), 2.20-2.10 (m, 1H), 1.40-L30 (m> 2H), 1.05 (t, 3H)〇 實施例60:1 - [(2S,3S)-3 - {[第三丁基(二曱基)石夕烧基]氧 基}-2-(2, 3-二氫 -1H-節-2-基曱基)-3-(3, 5-二曱氧基一4- 曱基苯基)丙基]-1H-D比17各-3-曱酸 使用1Η-吼σ各-3-曱搭取代1 Η-D比略-3-基乙腈並以實 施例58中製成之化合物取代實施例16中製成之化合物, 再如實施例26同樣操作,即可製成具有以下物性值之標題 化合物。 TLC : Rf 0· 53 (己烧:乙酸乙酯=2 : 1); 1 HNMR : δ 9.67 (s, 1H), 7.20-7.05 (m, 5H), 6.55 (m, 1H), 6.51 (m, 1H), 6.46 (s, 2H), 4.76 (d,1H), 4.07 (dd, 1H), 3.82 (s, 6H), 3.76, (m, 1H), 3.02-2.88 (m, 2H), 2.58-2.35 (m, 2H), 2.29 (dd, 1H), 2.08 (s, 3H), 2.04 (m,1H), 1.75 (m, 1H), 1.24 (m, 1H),0.98 (s, 9H), 0.08 (s, 3H), -0·15 (s, 3H)。 實施例 61 : (2E)-3-{1-[(2S,3S)-2-(2,3-二氫-1H-節一2- 基曱基)-3 -(3,5-二曱氧基-4 -曱基苯基)- 3-經基丙基] -1Η - D比σ各—3 —基}丙稀酸 使用實施例60中製成之化合物取代實施例33中製成 之化合物,進行與實施例34—實施例35相同之操作,即 可製成具有以下物性值之標題化合物。 性狀·非晶物 143 316588 200521108 TLC : Rf 0· 42 (二氯曱烷:曱醇=9 : 1); 1 HNMR : (5 7.69 (d, 1H), 7.18*7.08 (m, 4H), 6.96 (m, 1H), 6.69 (dd 1H), 6.49 (s, 2H), 6.40 (m, 1H), 6.07 (d, 1H), 4.43 (d, 1H), 4.23 (dd, 1H), 4.04 (dd, 1H), 3.81 (s, 6H), 3.04-2.90 (m, 2H), 2.55*2.28 (m, 3H), 2 16 (m 1H) 2.06 (s, 3H), 1.37 (m, 2H)〇 實施例 62 : 3-{l-[(2S,3S)-2-(2, 3-二氫—iH-茚-2-基曱基) -3 -(3, 5-二曱氧基-4-甲基苯基)- 3-經基丙基]一1 η—d比洛 -3-基}丙酸 使用貫施例61中製成之化合物取代實施例中製成 之化合物,進行與實施例36相同之操作,即可製成具有以 下物性值之標題化合物。 性狀:非晶物 TLC : Rf 〇· 58 (二氯甲烷:甲醇=9 : j); ^NMR : d 7.18-7.05 (m(4H), 6.58 (dd,lH), 6.51 (m, 1H), 6.49 (s, 2H), 5-97 (dd, 1H), 4.44 (d, 1H), 4.12 (dd, 1H), 3.98 (dd, 1H), 3.81 (s, 6H), 3.01-2.85 (m, 2H), 2.78 (t, 2H), 2.57 (t, 2H), 2.44-2.28 (m> 3H), 2.15 (m, 1H),2.06 (s, 3H), 1·41_ 1.32 (m,2H)。 實施例 62⑴:3-U_[(2S,3S)-2-(2,3_二氩鲁萌一2_基 甲基)-3-經基-(3,4,5_三甲氧基苯基)丙基]_ih—吼洛_3_ 基}丙酸 使用3, 4, 5 —二甲氧基苯甲醛取代3, 5-二甲氧基-4-曱 基苯甲酸’進行與實施例5卜實施例6〇—實施例61—實 施例62相同之操作,即可製成具有以下物性值之標題化合 物0 316588 144 200521108 性狀:非晶物 TLC : Rf 0· 44 (二氯甲烷:曱醇=9 : 1); 'HNMR : δ 7.16-7.08 (m, 4H), 6.59*6.55 (m, 1H), 6.54*6.50 (m, 3H), 5.98*5.95 (m, 1H), 4.40 (d, 1H), 4.17*4.08 (m, 1H), 4.00*3.92 (m, 1H), 3.85 (s, 6H), 3.82 (s, 3H), 3.00-2.89 (m, 2H), 2.81-2.74 (m, 2H), 2.60-2.53 (m, 2H), 2·46·2·30 (m, 3H), 2.12-2.03 (m, 1H),1·40·1.32 (m, 2H)。 實施例63(1)至實施例63(10) 使用(4S)-4 -苯曱基-1,3-嗯°坐咬-2-酮或(4R)-4-苯甲 基-1,3-噁唑啶-2-酮,使用5-苯基戊醯氯或以其相當之酸 氣化合物取代,使用3, 5-二曱氧基-4-曱基苯甲搭或以其 相當之搭化合物取代,使用1 Η-D比洛-3-基乙腈或以其相當 之氰化合物取代,並與實施例12—實施例13—實施例14 —實施例15—實施例16—實施例26—實施例27->實施例 19所示之方法同樣地操作,即可製成以下之標題化合物。 實施例63(1) ·· {1-[(2S,3S)-2-(1-笨并呋喃-2-基曱基) 〜3-(3, 5-二曱氧基-4- f基苯基)~3-經基丙基]- 111-〇比口各 〜3 -基}乙酸
TLC : Rf 0· 25 (己烷:乙酸乙酯: 2); 145 316588 200521108 1HNMR : J 7.50-7.46 (m, 1H),7.43-7.39 (m,1H),7.29-7.15 (m,2H), 6.69-6.66 (m, 2H), 6.52 (s, 2H), 6.38 (s, 1H), 6.10 (t, 1H), 4.54 (d, 1H), 4.18 (dd, 1H), 4.00 (dd, 1H), 3.81 (s, 6H), 3.53 (s, 2H), 2.73-2.50 (m, 3H), 2.06 (s, 3H)〇 實施例 63(2) : {1 -[(2R,3R)-2-(2,3-二氫-111-節-2-基曱 基)- 3 -(3,—曱氧基-4 -曱基苯基)-3-經基丙基]-1H-口比 咯-3-基}乙酸 TLC ·· Rf 0· 44 (二氯曱烷:曱醇=9 : 1); 1 HNMR : 1·37 (t, 2H), 2.06 (s, 3H),2.08-2.20 (m, 1H), 2.28-2.54 (m, 3H), 2.87-3.05 (m, 2H), 3.52 (s, 2H), 3.81 (s, 6H), 4.00 (dd, 1H), 4.15 (dd, 1H), 4.45 (d, 1H), 6.06*6.09 (m, 1H), 6.48 (s, 2H), 6.59-6.68 (m, 2H), 7.00-7.17 (m, 4H)〇 實施例 63(3) : {1-[(2S,3S)-2-(2,3-二氫-111-茚-2-基曱 基)_3-(3, 5-二曱氧基-4-甲基苯基)-3-羥基丙基]-ΙΗ-ti比 唑-4-基}乙酸 TLC : Rf 0· 40 (氣仿:曱醇=9 : 1); 'HNMR : δ 1.3M.57(m,2H), 2.06 (s,3H), 2.16*2.62 (m,4H), 2.85-3.13 (m, 2H), 3.54 (s, 2H), 3.77 (s, 6H), 4.10 (dd, 1H), 4.40 (dd, 1H), 4.49 (d, 1H),6.55 (s, 2H), 7·00·7·19 (m, 4H), 7.37 (s, 1H), 7.48 (s, lH)〇 實施例 63(4) : {1 -[(2S,3S)-2-(2,3-二氫-1H-茚-2-基曱 基)-3-(3, 5-二曱氧基苯基)一3一羥基丙基]-1H-吼咯-3-基} 乙酸 TLC : Rf 0· 23 (己烷:乙酸乙酯: 1); 146 316588 200521108 1 HNMR : 7.20-7.05 (m, 4H), 6·60·6·55 (m,2H), 6·50·6·45 (m, 2H), 6.40-6.35 (m, 1H), 6.05 (m, 1H), 4.50 (d, 1H), 4.10*3.90 (m, 2H), 3.78 (s, 6H), 3.50 (s, 2H), 3.00-2.90 (m, 2H), 2.50*2.30 (m, 3H), 2.20-2.10 (m, 1H), 1.50-1.30 (m,2H)。 實施例 63(5) : {1-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基甲 基)-3-(4-乙氧基-3, 5 -二曱氧基苯基)-3-羥基丙基]一1 η- 口比17各-3 -基}乙酸 TLC ·· Rf 0· 20 (己烷:乙酸乙酯=1 : 2); 1 HNMR : ¢5 7.20-7.05 (m, 4H), 6石5-6.60 (m, 2H), 6·52 (s,2H),6·07 (t, 1H), 4.44 (d, 1H), 4.20-3.90 (m, 2H), 4.02 (q, 2H), 3.83 (s, 6H), 3.52 (s, 2H), 3.00-2.90 (m, 2H), 2.50*2.30 (m, 3H), 2.20-2.10 (m, 1H), 1.40Ί.30 (m, 2H), 1.33 (t, 3H)。 實施例 63(6) : (1-{(2S,3S)-2-(2,3-二氫-111-茚-2-基甲 基)-3-羥基-3-[4-(1-羥基-1-曱基乙基)一3, 5-二甲氧基苯 基]丙基}-1H-吡咯-3-基)乙酸 TLC· Rf 0.37 (二氣曱烧:曱醇=9: 1); 1 HNMR : 5 7.20-7.05 (m, 4H), 6.57 (dd, 1H), 6.54 (s, 2H), 6.37 (m, 1H), 6.02 (dd, 1H), 4.58 (d, 1H), 4.01 (m, 2H), 3.83 (s, 6H), 3.45 (s, 2H), 3.10*2.90 (m, 2H), 2.60-2.35 (m, 3H), 2.15 (m, 1H), 1.65 (s, 3H), 1.63 (s, 3H),1.51 (m, 2H)〇 實施例 63(7): {l-[(2S,3S)-3-(4-氣-3,5-二曱氧基苯基) -2-(2,3-二氫-1H-茚-2-基曱基)_3_羥基丙基]_1}1_吡咯 -3-基}乙酸 TLC :Rf 0·45 (二氣甲燒:甲醇=9:1); 316588 147 200521108 1 Η N M R : d 7.14-7.08 (m, 4H), 6.66-6.59 (m, 2H), 6.52 (s, 2H), 6.09-6.05 (m, 1H), 4.44 (d, 1H), 4.16 (dd, 1H), 3.95 (dd, 1H), 3.88 (s, 6H), 3.53 (s, 2H), 3.01*2.88 (m, 2H), 2.50*2.29 (m, 3H), 2.17-2.08 (m, 1H), 1.4M.33 (m, 2H)〇 實施例 63(8) : (1-{(2S,3S)-3-(3, 5-二曱氧基-4-曱基苯 基)-3-羥基-2-[(2-曱基-2, 3-二氫-1 Η-茚-2-基)曱基]丙 基}-1Η-吼17各-3-基)乙酸 TLC: Rf 0.57 (己烧:乙酸乙酯=1 : 2); 'HNMR : d 7.10-6.95 (m, 4H), 6.55 (m, 2H), 6.40 (s, 2H), 6.05 (t, 1H), 4.49 (d, 1H), 4.13 (dd, 1H), 3.82 (dd, 1H), 3.75 (s, 6H), 3.51 (s, 2H), 2.61 (s, 2H), 2.60-2.40 (m, 2H), 2.15-2.05 (m, 1H), 2.06 (s, 3H), 1.55 (dd, 1H), 1.40 (dd, 1H), 1.03 (s, 3H)。 貫施例 63(9) · (1-{(2S,3S)-3-(3,5- 二曱氧基 -4-曱基苯 基)-3-羥基-2-[(4-曱氧基-2, 3-二氫-1 Η-茚-2-基)曱基] 丙基}-1Η-吼咯-3-基)乙酸 TLC ·· Rf 0· 35 (二氣曱烷:曱醇=9 : 1); lENUR : δ 7.08 (m, 1H), 6.74 (m, 1H), 6.68-6.59 (m, 3H), 6.49 (s, 2H), 6.07 (m, 1H), 4.50-4.40 (m, 1H), 4.17 (m, 1H), 4.00 (m, 1H), 3.81 (s, 6H), 3.80 (s, 3/2H), 3.79 (s, 3/2H), 3.53 (s, 2/2H), 3.52 (s, 2/2H), 3.10-2.90 (m, 2H), 2.55-2.00 (m, 4H), 2.06 (s, 3/2H), 2.05 (s, 3/2H), 1.40 (m, 2H)〇 實施例63(10):4-(羧基曱基)-1-[(23,33)-2-(2,3-二氫 -1H-節-2-基曱基)-3-(3, 5-二甲氧基-4 -曱基苯基)-3-經 基丙基]-1Η-口比17各-3 -叛酸 TLC : Rf 0· 24 (二氣曱烷:曱醇=9 ·· 1); 148 316588 200521108 iHNMlUCDsOD): 6 7.29 (d,1H), 7.08-6.96 (m,4H),6.62 (s,1H),6.57 (s, 2H), 4.46 (d, 1H), 4.11-3.98 (m, 2H), 3.79 (s, 6H), 3.61 (s, 2H), 3.00-2.81 (m, 2H),2.37-2.10 (m, 4H),1.99 (s, 3H), 1.51-1.25 (m, 2H)。 實施例64(1)至實施例64(3) 使用實施例60中製成之化合物或其相當之醛化合物 取代實施例33中製成之化合物,進行與實施例34—實施 例1實施例20相同之操作,即可製成具有以下物性值 之標題化合物。 實施例 64(1) ·· (2E)-3-U-[(2S,3S)-2-(2,3-二氫_1H-茚 _ - 2 -基甲基)-3 -(4-乙基-3,5-二曱氧基苯基)-3 -經基丙基] - 1H -吼洛-3 -基}丙稀酸 TLC : Rf 0· 50 (己烷:乙酸乙酯: 2); 1 HNMR : d 7.69 (d, 1H), 7.15-7.05 (m, 4H), 6.96 (m, 1H), 6.68 (m, 1H), 6.48 (s, 2H), 6.40 (m, 1H), 6.06 (d, 1H), 4.42 (d, 1H), 4.30-4.00 (m, 2H), 3.81 (s, 6H), 3.00-2.90 (m, 2H), 2.62 (q, 2H), 2.50-2.30 (m, 3H), 2.20-2.10 (m, 1H), 1.40-1.30 (m. 2H), 1.05 (t, 3H)〇 實施例 64(2) : (2E)-3-{1 -[(23,38)-2-(2,3-二氫-111-茚 -2-基曱基)-3-羥基-3-(3, 4, 5-三曱氧基苯基)丙基]-lH-吡咯-3-基}丙烯酸 TLC : Rf 0· 47 (二氯甲烷:曱醇=5 : 1); 1 HNMR : d 1.29-1.40 (m,2H),2.06-2.17 (m,1H), 2.31-2.46 (m,3H), 2.90-3.03 (m, 2H), 3.83 (s, 3H), 3.85 (s, 6 H), 4.03 (dd, 1H), 4.15-4.27 (m, 1H), 4.40 (d, 1H), 6.06 (d, 1H), 6.37*6.42 (m, 1H), 6.52 (s, 2H), 6.63-6.69 (m,1H),6.93 · 6.97 (m,1H),7.04-7.15 (m, 4 H), 7.68 (d, 1H)。 149 316588 200521108 實施例 64(3) : (2E)-3-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 -2-基甲基)-3-(3, 5-二甲氧基-4-甲基苯基)-3-羥基丙基] -1H -吼洛-3-基}-2-甲基丙稀酸 性狀·非晶物 TLC ·· Rf 0· 16 (正己烷··乙酸乙酯=1 : 1); 1 HNMR : d 7.71 (s, 1H), 7.10 (m, 4H), 6.99 (s, 1H),6.73 (m, 1Η), 6·49 (s, 2Η), 6.43 (s, 1Η); 4.43 (d, 1Η), 4.25 (dd, 1H), 4.08 (dd, 1H), 3.82 (s, 6H), 3.00-2.90 (m, 2H), 2.60-2.30 (m, 4H), 2.11 (s, 3H), 2.06 (s, 3H), 1.38 (t, 2H)〇 實施例65(1)至實施例65(8) 使用苯基戊醯氣或以其相當之酸氯化物取代,使用 3, 5-二甲氧基-4-甲基苯甲醛或以其相當之醛取代,使用 1H-吡咯-3-曱醛或以其相當之醛化合物取代,並與實施例 12—實施例13—實施例14—實施例15—實施例16—實施 例24—實施例29—實施例33—實施例34—實施例19—實 施例36—實施例20同樣地操作’於必要時可再加上保護 ,之脫保護反應,即可製成具有以下物性值之標題化合物。 貫施例 65(1) : 3-9 〇
Km)—2—(2,3 〜二氫-1H-茚-2-基 甲基)-3-(3,5-二甲氧基—4 —甲美装其、、,一 ‘ 丨 土 土)—3-經基丙基]一1 η- 吼σ坐-4-基丨丙酸 ΟΗ
316588 150 200521108 TLC : Rf 0· 45 (氣仿:曱醇=9 : 1); ^NMR : δ 1.29-1.52 (m, 2H), 2.05 (s, 3H), 2.20-2.51 (m, 4H), 2.58 (t, 2H), 2.78 (t, 2H), 2.88-3.12 (m, 2H), 3.81 (s, 6H), 4.10 (dd, 1H), 4.37 (dd, 1H), 4.46 (d, 1H),6.55 (s, 2H), 7.01-7.18 (m,4H), 7.20 (s, 1H), 7.39 (s, 1H)。 實施例 65(2) ·· 3-U-[(2S,3S)-3-(4-氯-3, 5-二曱氧基苯 基)-2 -(2,3-二氫-1H -印-2-基甲基)-3 -經基丙基]-1H -口比 咯-3 -基}丙酸 TLC : Rf 0· 55 (二氯曱烷:曱醇=9 : 1); ^NMR : δ 7.18-7.08 (m, 4H), 6.60*6.53 (m, 3H), 6.52-6.46 (m, 1H), 5.98-5.96 (m, 1H), 4.45 (d, 1H), 4.12 (dd, 1H), 3.95 (dd? 1H), 3.89 (s, 6H), 3.03-2.89 (m, 2H), 2.81-2.72 (m, 2H), 2.60-2.53 (m, 2H), 2.50-2.28 (m, 3H), 2.13-2.06 (m, 1H), 1.44Ί.30 (m, 2H)〇 實施例 65(3) : 3-{l-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基 曱基)-3 -(4 -乙基-3,5-二甲氧基苯基)- 3-經基丙基]-1H -D比洛-3-基}丙酸 TLC : Rf 0· 52 (己烷:乙酸乙酯=1 : 2); 1 HNMR : (5 7.15-7.05 (m, 4H), 6.58 (m, 1H), 6.51 (m, 1H), 6.49 (s, 2H), 5.97 (d, 1H), 4.43 (d, 1H), 4.20-3.95 (m, 2H), 3.80 (s, 6H), 3.00-2.90 (m, 2H), 2.78 (q, 2H), 2.70-2.50 (m, 4H), 2.50-2.30 (m, 3H), 2.20-2.10 (m, 1H), 1.40-1.30 (m, 2H), 1.05 (t, 3H)。 實施例 65(4) · 3-{1-[(2S,3S)-2-(1,3 -苯并二°惡吨-2- 基 曱基)-3-(3, 5-二曱氧基-4-甲基苯基)-3-羥基丙基]-1 Η-口比略-3-基}丙酸 TLC : Rf 0· 42 (二氣曱烷:曱醇二19 : 1); 151 316588 200521108 1 HNMR : ί 1.76-1.98 (m, 2H), 2.06 (s7 3H), 2.42*2.52 (m, 1H), 2.52*2.59 (m, 2H), 2.76 (t, 2H), 3.80 (s, 6H), 3.97-4.05 (m, 1H), 4.06*4.15 (m, 1H), 4.60 (d, 1H), 5.80 (t, 1H), 5.96-5.99 (m, 1H), 6.48 (s, 2H), 6.51 (t, 1H), 6.60 (t, 1H), 6.71-6.82 (m, 4H)〇 實施例 65(5) : 3-(l-{(2S,3S)-2-(2,3-二氫-1H-茚-2-基 曱基)-3-經基-3 - [4-(1-經基-1-甲基乙基)一3, 5-二曱氧基 苯基]丙基}-lH-D比17各-3-基)丙酸 TLC : Rf 0. 29 (二氯曱烷:曱醇二9 : 1); 1 HNMR : (^ 7.20*7.03 (m, 4H), 6.56 (s, 2H), 6.53 (m, 1H), 6.25 (in, 1H), 5.93 (m, 1H), 4.57 (d, 1H), 3.97 (m, 2H), 3.84 (s, 6H), 3.10-2.90 (m, 2H), 2.75 (m, 2H), 2.62-2.30 (m, 5H), 2.10 (m, 1H), 1.65 (s, 3H), 1.63 (s, 3H), 1.60-1.40 (m, 2H)。 實施例 65(6) : 3-(1-( (2S,3S)-3-(3, 5-二曱氧基-4-甲基 苯基)_2-[(4-氟-2, 3-二氫-1Η-茚-2-基)甲基]-3-羥基丙 基}-111-吼略-3-基)丙酸 TLC : Rf 0· 47 (二氣曱烷:曱醇=9 : 1) ; ^ 1 Η N M R : d 7.05 (m, 1H), 6.88 (m, 1H), 6.77 (m, 1H), 6.58 (dd, 1H), 6.51 (m, 1H), 6.49 (s, 2H), 5.98 (dd, 1H), 4.44 (m, 1H), 4.11 (m, 1H), 4.00 (m, 1H), 3.81 (s, 6H), 3.12-2.90 (m, 2H), 2.78 (t, 2H), 2.57 (t, 2H), 2.50-2.25 (m, 3H), 2.15 (m, 1H), 2.06 (s, 3H), 1·45·1·30 (m,2H)。 實施例 65(7) : 3-(1-{(2S,3S)-3-(3, 5-二甲氧基-4-曱基 本基)2 [(5 -氣-2,3 -二氮-1H -印-2-基)曱基]-3 -經基丙 基}-111-吼咯-3-基)丙酸 TLC : Rf 0· 37 (二氯甲烷··曱醇=9 ·· 1); 152 316588 200521108 1 H NMR : d 7.01 (m, lH), 6.85-6.72 (m, 2H), 6.58 (dd, 1H), 6.50 (m, 1H), 6.48 (s, 2H), 5.98 (m, 1H), 4.43 (d, 1H), 4.11 (m, 1H), 3.99 (dd, 1H), 3.81 (s, 6H), 2.98-2.82 (m, 2H), 2.78 (t, 2H), 2.57 (t, 2H), 2.48-2.20 (m, 3H), 2.10 (m, 1H), 2.06 (s, 3H), 1.40-1.32 (m, 2H)。 實施例 65(8) : 3 -(1 -{(2S)-4-環戊基-2- [(S)-(3,5- 二曱 氧基-4-曱基苯基)(羥基)曱基]丁基}-1Η-吼咯-3-基)丙酸 TLC : Rf 0· 37 (己烷··乙酸乙酯: 1); 1 H NMR : 0.85-1.33 (m, 6H), 1.35-1.75 (m, 7H), 1.90-2.05 (m, 1H), 2.07 (s, 3H), 2.54-2.63 (m, 2H), 2.78 (t, 2H), 3.81 (s, 6H), 3.91-4.00 (m, 1H), 4.01-4.11 (m, 1H), 4.40 (d, 1H), 5.96-6.00 (m, 1H), 6.44-6.53 (m, 3H), 6.57 (t, 1H)。 實施例66(1)至實施例66(2) 以實施例58中製成之化合物取代實施例16中製成之 化合物,並使用曱磺酸[(2S,3S)-3-{[第三丁基(二甲基) 石夕烧基]氧基}-2-(1,3-苯并二。惡嗤-2-基甲基)-3-(4 -乙基 -3,5-二曱氧基笨基)丙]酯,再使用1H-吡咯-3-羧酸曱酯 或4-曱基-1H-n比略-3-敌酸乙酯取代1H-D比洛-2-緩酸乙 酉旨,與實施例24—實施例19->實施例20同樣地操作,gp 可製成以下之標題化合物。 實施例66(1) : 1-[(2S,3S)-2-(1, 3-苯并二噁唑-2-基甲基) -3-(4-乙基-3, 5-二曱氧基苯基)一3-羥基丙基]-1H-吡咯 - 3 -叛酸 TLC : Rf 0· 39 (二氣曱烷:曱醇=9 : 1); 153 316588 200521108 1 HNMR : (5* 7.45 (t, 1H), 6.83-6.73 (m, 4H), 6.70*6.66 (m, 1H), 6.64-6.59 (m, 1H), 6.47 (s, 2H), 5.96 (t, 1H), 4.58 (d, 1H), 4.28 (dd, 1H), 4.12 (dd, 1H), 3.80 (s, 6H), 2.63 (q, 2H), 2.59-2.48 (m, 1H),2.00.1.77 (m,2H), 1.06 (t, 3H)。 實施例 66(2) · 1-[(2S,3S)- 2 -(2,3-二氫-1H- 萌-2- 基曱基) -3-(3,5-二曱氧基-4-曱基苯基)-3 -經基丙基]一4-曱基 - 1H-吡咯-3-羧酸 TLC : Rf 0.37 (己烷:乙酸乙酯=1 : 1); iHNMR : d 7·36 (d,1H),7·20-7·10 (m, 4H),6.49 (s, 2H), 6·43 (s, 1H), 4.45 (s, 1Η), 4.16 (dd, 1H), 3.98 (dd, 1H), 3.82 (s, 6H), 3.10-2.90 (m, 2H), 2.50-2.30 (m, 3H), 2.27 (s, 3H), 2.20-2.10 (m, 1H), 2.07 (s, 3H), 1.45-1.35 (m, 2H)〇 實施例67(1)至實施例67(6) 以實施例58中製成之化合物取代實施例16中製成之 化合物,並使用吼洛-2 -緩酸乙酯或以其相當之化合物取 代,進行與實施例24—實施例19->實施例20相同之操作, 即可製成以下之標題化合物。 實施例 67(1) : 4-{1-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基 曱基)-3-(3, 5-二曱氧基-4-曱基苯基)一3-羥基丙基]-1Η-吡咯-3-基} 丁酸 TLC : Rf 〇β 39 (二氣曱烷:曱醇=9 : 1); 1 H NMR : d 7.18-7.00 (m, 4H), 6.59 (dd, 1H), 6.49 (s, 2H), 6.48 (m, 1H), 5.96 (dd, 1H), 4.11 (m, 1H), 4.46 (d, 1H), 3.98 (dd, 1H), 3.81 (s, 6H), 3.02-2.90 (m, 2H), 2.60-2.35 (m, 3H), 2.51 (t, 2H), 2.36 (t, 2H), 2.15 (m, 1H),2·06 (s,3H),1.95-1.82 (m, 2H), 1.37 (m, 2H)。 154 316588 200521108 實施例 67(2) ·· 3-{1-[(2S,3S)-2_(2,3 -二氫-1H -節-2- 基 甲基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基]-in-吡咯-3-基}-2-曱基丙酸 TLC : Rf 0· 56 (己烷:乙酸乙酯=1 : 1); 1 HNMR : d 7.20-7.05 (m, 4H), 6.60-6.40 (m, 4H), 5.95(m, 1H), 4.45-4.40 (m, 1H), 4.10-3.90 (m, 2H), 3.81 (s, 6H), 3.00-2.10 (m, 9H), 2.06 (s, 3H), 1.40-1.30 (m, 2H), 1,20-1.10 (m, 3H)。 實施例 67(3) : 3-{l-[(2S, 3S)-2-(2, 3 -二氫-1H -萌~2- 基 曱基)-3 -(3,5 -二曱氧基-4 -曱基苯基)-3-經基丙基]一;[H- 鲁 吡咯-3-基卜2-(羥基曱基)丙酸 TLC : Rf 0· 68 (乙酸乙酯) 'HNMRiCDCla+CDaOD) : δ 7.16-7.05 (m, 4H), 6.59-6.54 (m, 2H), 6.51 (s, 2H), 5.98-5.95 (m, 1H), 4.42-4.36 (m, 1H), 4.17-4.07 (m, 1H), 4.00-3.92 (m, 1H), 3.82 (s, 6H), 3.74-3.69 (m, 2H), 3.02-2.65 (m, 5H), 2.48*2.30 (m, 3H), 2.18-2.03 (m, 4H), 1.40-1.31 (m, 2H)〇 實施例 67(4) : 2-{1 - [ (2S,3S)-2-(2,3-二氫-1H-萌-2-基塵 曱基)-3-(3, 5-二曱氧基-4-曱基笨基)-3-經基丙基]一 口比咯- 3 -基} - 2 -曱基丙酸 TLC : Rf 0.41 (己烷:乙酸乙酯=1 : 1); LHNMR : d 7.16-7.06 (m, 4H), 6.64*6.56 (m, 2H), 6.49 (s, 2H), 6.12 (dd, 1H), 4.48 (d, 1H), 4.08*4.02 (m, 2H), 3.81 (s, 6H), 3.02-2.82 (m, 2H), 2.42-2.28 (m, 3H), 2.15 (m, 1H), 2 06 (s, 3H), 1·52 (s, 6H), 1.40 (m, 2H)。 貫施例 67(5) · 3-{1-[(2S,3S)-2-(2,3 -二氮-1H -節 -基 曱基)-3 -(3, 5-二曱氧基-4 -曱基苯基)-3-經基丙基]— 316588 155 200521108 吡咯-3-基}-2,2-二甲基丙酸 TLC : Rf 0· 55 (己烷··乙酸乙酯=1 : 1) ·, 1 HNMR : d 7.20-7.00 (m, 4H), 6.55 (m, 1H), 6.49 (s, 2H), 6.47 (m, 1H), 5.94 (m, 1H), 4.41 (d, 1H), 4.10 (dd, 1H), 3.99 (dd, 1H), 3.81 (s, 6H), 3.00-2.90 (m, 2H), 2.74- 2.60 (m, 2H), 2.40*2.30 (m, 3H), 2.20*2.00 (m, 1H), 2.06 (s, 3H), 1.40· 1.30 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H)。 實施例 67(6) ·· 2-{l-[(2S,3S)-2-(2,3 -二氮_1H -印-2- 基 曱基)-3 -(4 -乙基-3, 5 -二甲氧基苯基)-3 -羥基丙基]- 1H-吡咯-3-基}-2-曱基丙酸 TLC :Rf 0.32 (己烧:乙酸乙酯=1:1); 1 HNMR : 7.16-7.05 (m, 4H), 6.62-6.56 (m, 2H), 6.49 (s, 2H), 6.11 (dd, 1H), 4.47 (d, 1H), 4.08*3.96 (m, 2H), 3.80 (s, 6H), 3.00*2.94 (m, 2H), 2.62 (q, 2H), 2.45-2.30 (m, 3H), 2.15 (m, 1H), 1.51 (s, 6H), 1.38 (m, 2H), 1.05 (t, 3H)〇 實施例 68 ·· 2-{1 -[(2S, 3S)-2-(2, 3-二氫-1H-茚-2-基曱基) -3 (3,5 一曱氧基-4 -曱基苯基)-3-經基丙基]- 1H-口比口各 -3-基(甲基磺醯基)乙醯胺
於室溫下一面攪拌U-[(2S,3S)-3-{[第三丁基(二曱 316588 156 200521108 基)石夕烧基]氧基}]-2-(2, 3-二氫-1H--基甲基)-3-(3, 5-二曱氧基-4 -甲基苯基)丙基卜1H-D比口各-3-基}乙酸 (以實施例58中製成之化合物取代實施例1 6中製成之化合 物,依實施例26—實施例27相同之操作製成)(3〇5mg)與 曱磺醯胺(76mg)之二氯曱烷(l〇ml)溶液,一面加入i—乙基 -3-(3-二曱基胺基丙基)碳化二亞胺·鹽酸鹽(153mg)與4一 二曱基胺基D比咬(65mg),該混合物再於室溫下攪拌一晚。 於该反應混合物中加入1N鹽酸,並經乙酸乙酯萃取。該有 機層再經飽和食鹽水洗淨、無水硫酸鎂乾燥後濃縮。其殘 留物再經矽膠管柱層析(己烷:乙酸乙酯^^ : 1 — 1 :丨)精 製,即可製成2-{l-[(2S,3S)-3-{[第三丁基(二甲基)矽烷 基]氧基}]-2-(2,3-二氫-111-節-2-基曱基)—3-(3,5-二甲 氧基-4 -曱基苯基)丙基} — ih-d比洛一 3-基}—n-(曱基石黃酿基) 乙醯胺(265mg)。再以本化合物取代實施例18中製成之化 合物,依實施例1 9所示之方法同樣操作,即可製成具有以 下物性值之標題化合物(220mg)。 TLC : Rf 〇· 60 (二氯曱烷:曱醇=9 : 1); ^NMR : d 8.08-8.00 (m, 1H), 7.15-7.08 (m, 4H), 6.73-6.65 (m, 2H), 6.50 (s, 2H), 6.04-5.98 (m, 1H), 4.42 (dd, 1H), 4.21 (dd, 1H), 4.03 (dd, 1H), 3.82 (s, 6H), 3.56 (s, 2H), 3.24 (s, 3H), 3.03-2.90 (m, 2H), 2.51-2.31 (m, 3H) 2.18-2.07 (m,1H),2.06 (s, 3H),1.94 (d, 1H),1·42·1·33 (m, 2H)。 實施例68(1)至實施例68(63) 以{1 -[ (2S,3S)-3-{[第三丁基(二曱基)矽烷基]氧基} -2-(2, 3-二氫-1Η-茚-2-基甲基)-3-(3, 5-二曱氧基一4一 曱 316588 157 200521108 基苯基)丙基]-1H-D比略—3-基}乙酸或其相當之羧酸、以曱 烷磺醯胺或其相當之胺化合物,依實施例68同樣操作,即 可製成以下之標題化合物。 實施例 68(1) : 1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基) -3-(3, 5-二曱氧基-4-曱基苯基)一3-羥基丙基]一4-{2-[(曱 基石黃酿基)胺基]-2- _基乙基} 一 1H-□比略-3-緩酸曱酯 TLC.Rf 0.52 (己烧·乙酸乙g旨:=1:2); ^NMR : δ 10.4 (s, 1H, NH), 7.28 (d, 1H), 7.15-7.08 (m, 4H), 6.68 (d, 1H), 6.48 (s, 2H), 4.42 (d, l), 4.18 (dd, 1H), 4.02 (dd, 1H), 3.85 (s, 3H), 3.82 (s, 6H), 3.65 (s, 2H), 3.17 (s, 3H), 3.05-2.88 (m, 2H), 2.49*2.30 (m, 3H), 2.20-2.08 (m,1H), 2.06 (s, 3H), 2·00·1·98 (m, 1H, OH), 1.48-1.32 (m,2H)。 實施例 68(2) : N-(3-{l-[(2S,3S)-2-(2, 3-二氫-1H-茚-2- 基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基] -1Η-口比咯-3 -基}丙酿基)乙石黃酿胺 TLC : Rf 0· 40 (二氣甲烷:甲醇=9 ·· 1); 'HNMR : δ 7.77-7.71 (m, 1H), 7.15-7.06 (m, 4H), 6.68*6.65 (m, 1H), 6.65-6.53 (m, 1H), 6.52 (s, 2H), 6.02-5.97 (m, 1H), 4.42 (d, 1H), 4.19 (dd, 1H), 3.99 (dd, 1H), 3.81 (s, 6H), 3.38 (q, 2H), 3.02-2.84 (m, 2H), 2.83*2.75 (m, 2H), 2.60-2.52 (m, 2H), 2.47-2.29 (m, 3H), 2.20-2.06 (m, 1H),2.06 (s, 3H), 1·41·1.31 (m, 2H), 1·29 (t, 3H)。 實施例 68(3) : N-(3-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚一2- 基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)- 3-羥基丙基] -1Η -吼17各-3 -基}丙酿基)曱磺酷胺 TLC : Rf 0· 43 (二氣曱烷:曱醇=9 : 1); 316588 158 200521108 1 HNMR : 6 7.88-7.84 (m,IH),7.15-7.06 (m,4H),6.68·6·65 (m, 1H), 6.63-6.53 (m, 1H), 6.52 (s, 2H), 6.01-5.97 (m, 1H), 4.42 (d, 1H), 4.19 (dd, 1H), 3.99 (dd, 1H), 3.82 (s, 6H), 3.20 (s, 3H), 3.00-2.90 (m, 2H), 2.87-2.78 (m, 2H), 2.60-2.52 (m, 2H), 2.47-2.29 (m, 3H), 2.20*2.06 (m, 1H), 2.06 (s, 3H), 1.41-1.33 (m,2H)。 實施例 68(4) : N-(3-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基)-3 -(3, 5-二甲氧基-4-甲基苯基)-3-經基丙基] -1H-吡咯-3-基}丙醯基)-1,1,:1 -三氟甲磺醯胺 TLC :Rf 0.008 (己烧:乙酸乙酯=1:2); 1 H NMR : 6 8.39-8.05 (m, 1H),7.16-7:06 (m,4H),6,71-6·67 (m, 1H), 6.58-6.51 (m, 1H), 6.51 (s, 2H), 6.02-5.97 (m, 1H), 5.60*5.26 (m, 1H), 4.42 (d, 1H), 4.19 (dd, 1H), 4.02 (dd, 1H), 3.81 (s, 6H), 3.02-2.84 (m, 2H), 2.83-2.78 (m, 2H), 2.72-2.65 (m, 2H), 2.47-2.29 (m, 3H), 2.20*2.06 (m, 1H), 2.06 (s, 3H), 1.41-1.31 (m, 2H)。 實施例 68(5) : N-(3-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基)-3-(3,5-二曱氧基-4-曱基苯基)- 3-羥基丙基] -1H-吡咯-3-基}丙醯基)苯磺醯胺 TLC : Rf 0· 50 (二氣曱烷:曱醇二9 : 1); 1HNMR : 6 8.39-8.05 (m, 1H), 8.00.7.94 (m,2H),7.64-7.57 (m,1H), 7.50*7.44 (m, 2H), 7.16*7.06 (m, 4H), 6.63-6.59 (m, 1H), 6.53 (s, 2H), 6.52*6.46 (m, 1H), 5.90*5.86 (m, 1H), 4.43 (d, 1H), 4.18 (dd, 1H), 3.97 (dd, 1H), 3.79 (s, 6H), 3.02-2.89 (m, 2H), 2.75*2.68 (m, 2H), 2.49-2.29 (m, 5H), 2.22-2.06 (m, 1H), 2.06 (s, 3H), 1.41-1.31 (m, 2H)。 實施例 68(6) : N-(2-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2- 159 316588 200521108 基甲基)-3-(3, 5-二甲氧基-4-甲基苯基)-3-羥基丙基] -1Η - D比洛-3 -基}乙酿基)乙石黃酸胺 TLC : Rf 0· 33 (己烷:乙酸乙酯=1 : 1); 'HNMR : (5 L27-1.40(m, 5H), 2.06 (s,3H), 2.09-2.19 (m, 1H), 2.34-2.48 (m, 3H), 2.91-3.03 (m, 2H), 3.42 (q, 2H), 3.55 (s, 2H), 3.82 (s, 6H), 4.03 (dd, 1H), 4.22 (dd, 1H), 4.41 (d, 1H), 5.99-6.05 (m, 1H), 6.50 (s, 2H), 6.64-6.72 (m, 2H),7·06·7·15 (m, 4H), 7.94 (s, 1H)。 貫施例 68(7) · N-({1-[(2S,3S)-2-(2,3_二氮-1H~*印-2- 基 曱基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基]-1H-口比洛-3-基}乙驢基)-1,1,1-三氟曱石黃臨胺 TLC : Rf 0· 05 (己烷:乙酸乙酯=1 : 2); 1 H NMR : δ 1.29-1.40 (m, 2H), 2.06 (s, 3H), 2.09-2.20 (m, 1H), 2.31-2.46 (m, 3H), 2.89-3.03 (m, 2H), 3.64 (s, 2H), 3.81 (s, 6H), 4.04 (dd, 1H), 4.24 (dd, 1H), 4.38 (d, 1H), 6.01-6.06 (m, 1H), 6.48 (s, 2H), 6.66-6.75 (m, 2H), 7.05-7.15 (m, 4H)〇 實施例 68(8) : N-(2-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基)-3-(3, 5-二甲氧基-4-曱基苯基)-3-羥基丙基] -1Η - D比洛-3 -基}乙驢基)笨石黃酿胺 TLC· Rf 0.40 (己烧·乙酸乙 g旨=1 : 1); iHNMR : 6 1.32-1.43 (m,2H),2.07 (s,3H),2.09-2.19 (m,1H),2.32-2.49 (m, 3H), 2.90-3.04 (m, 2H), 3.43 (s, 2H), 3.82 (s, 6H), 4.02 (dd, 1H), 4.22 (dd, 1H), 4.42 (d, 1H), 5.91-5.97 (m, 1H), 6.51 (s, 2H), 6.59-6.64 (m, lH), 6.64-6.71 (m, 1H), 7.05-7.15 (m, 4H), 7.45-7.55 (m, 2H), 7.57-7.65 (m, lH), 7.95-8.02 (m, 2H), 8.23-8.31 (m, lH)〇 實施例 68(9) ·· N-(3-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2- 160 316588 200521108 基曱基)-3-(3, 5-二甲氧基-4-曱基苯基)—3 —羥基丙基] - 1H-吡咯-3-基}丙醯基)-4-氟苯磺醯胺 TLC : Rf 0.47 (己烷:乙酸乙酯: 1); 1 HNMR : d 8.01 (dd, 2H), 7.97 (s, 1H), 7.20-7.06 (m, 6H), 6.63 (m, 1H), 6.54 (s, 2H), 6.51 (m, 1H), 5.89 (m, 1H), 4.45 (d, 1H), 4.18 (dd 1H) 4 00 (dd, 1H), 3-81 (s, 6H), 3·03·2·90 (m,2H),2.74 (t, 2H>, 2·52·2 30 (m 5H) 2.15 (m, 1H), 2.06 (s, 3H), 1.40 (m, 2H)。 實施例 68(10) : 4 -第三丁基 -N-(3-{l-[(2S,3S)-2 -(2,3- 二氫-1H-茚-2-基曱基)-3-(3, 5-二曱氧基一4—曱基苯基) -3-經基丙基]-1Η-吼咯-3 -基}丙酿基)苯石黃驢胺 TLC ·· Rf 0· 55 (己烷:乙酸乙酯=1 : 1); ^NMR : 5 7.96 (s, 1H), 7.90 (d, 2H), 7.50 (d, 2H), 7.18-7.04 (m, 4H), 6.64 (m, 1H), 6.55 (m, 3H), 5.90 (m, 1H), 4.44 (d, 1H), 4.21 (dd, 1H), 4.00 (dd, 1H), 3.80 (s, 6H), 3.02*2.90 (m, 2H), 2.74 (t, 2H), 2.52-2.30 (m, 5H), 2.15 (m, 1H), 2.06 (s, 3H), 1.38 (m,2H), 1·33 (s, 9H)。 實施例 68(11) : N-(3-{1-[(2S,3S)-2-(2,3-二氫-1H-萌 - 2-基曱基)-3 -(3,5-二曱氧基-4-曱基苯基)- 3-經基丙基] -1H-吼17各-3-基}丙醯基)-4 -曱氧基苯石黃酿胺 TLC : Rf 0· 38 (己烷··乙酸乙酯二1 : 1); 1 HNMR : 7·93 (s, 1H), 7.92 (d,2H), 7.19-7.05 (m, 4H), 6.95 (d, 2H), 6.64 (m, 1H), 6.55 (s, 2H),6.53 (m, 1H), 5.91 (m, 1H), 4.44 (d, 1H), 4.20 (dd, 1H), 4.00 (dd, 1H), 3.86 (s, 3H), 3.8l(s, 6H), 3.02-2.90 (m, 2H), 2.73 (t, 2H), 2.52-2.30 (m, 5H), 2.15 (m, 1H), 2.06 (s, 3H), 1.39 (m, 2H)〇 實施例 68(12) ·· N-(3-{l-[(2S,3S)-2-(2,3-二氫-1H-茚 161 316588 200521108 -2-基曱基)-3-(3,5-二曱氧基-4-甲基苯基)-3-羥基丙基] -111-〇比σ各-3-基}丙醋基)- 4 -曱基苯石黃醯胺 TLC : Rf 0· 52 (己烷:乙酸乙酯二1 : 1); 1 HNMR : d 1.3M.45 (m, 2H), 2.06 (s, 3H), 2.08-2.17 (m, 1H), 2.34*2.48 (m, 8H), 2.68-2.77 (ra, 2H), 2.90-3.02 (m, 2H), 3.80 (s, 6H), 3.99 (dd, 1H), 4.20 (dd, 1H), 4.44 (dd, 1H),5.88.5.93 (m, 1H), 6.50-6.58 (m, 3H), 6.61-6.67 (m, 1H), 7.06*7.16 (m, 4H), 7.27-7.33 (m, 2H), 7.83-7.91 (m, 2H), 7.98 (s, lH)〇 實施例 68(13) ·· N-(3-{1-[(2S,3S)-2-(2,3-二氫-1H-節 -2-基曱基)-3-(3, 5-二曱氧基-4 -曱基苯基)-3-經基丙基]Φ -1H-D比17各-3-基}丙酸基)-4-(三氟曱基)苯石黃臨胺 TLC : Rf 0· 43 (己烷:乙酸乙酯: 1); LHNMR : ί 1.33Ί.44 (m,2H), 2.06 (s,3H), 2.08-2.19 (m, 1Η), 2.34-2.50 (m, 5H), 2.69-2.78 (m, 2H), 2.89-3.03 (m, 2H), 3.81 (s, 6H), 4.00 (dd, 1H), 4.18 (dd, 1H), 4.45 (d, 1H), 5.86-5.91 (m, 1H), 6.50-6.57 (m, 3H), 6.61-6.67 (m, 1H),7.07-7.15 (m, 4H), 7.74-7.80 (m, 2H), 8·02·8· 16 (m, 3H)。 實施例 68(14) ·· 4-氣-N-(3-{1-[(2S,3S)-2-(2, 3-二氫 -1H-印-2 -基曱基)-3-(3, 5-二曱氧基-4 -曱基苯基)- 3〜經 基丙基]-1Η -口比洛-3 -基}丙醯基)苯石黃酿胺 TLC : Rf 0· 52 (己烷:乙酸乙酯=1 : 1); 'HNMR : δ 1.30-1.44 (m,2H), 2.06 (s,3H), 2.09-2.18 (m, 1Η), 2.34-2.49 (m, 5H), 2.69-2.78 (m, 2H), 2.90-3.02 (m, 2H), 3.81 (s, 6H), 3.99 (dd, 1H), 4.18 (dd, 1H), 4.44 (d, 1H), 5.87-5.91 (m, 1H), 6.47-6.52 (m, 1H), 6.54 (s, 2H), 6.61-6.67 (m, 1H), 7.07-7.16 (m, 4H), 7.43-7.50 (m, 2H), 7.88:7.95 (m, 2H), 8.05 (s, lH)〇 162 316588 200521108 實施例 68(15) : N-(3-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 - 2-基曱基)-3-( 3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基] -1H-哦17各-3-基} -2-曱基丙臨基)甲石黃醯胺 TLC : Rf 0· 16 (己烷:乙酸乙酯=2 : 1); ^NMR : δ 7.80-7.60 (m, 1H), 7.20*7.05 (m, 4H), 6.70*6.50 (m, 4H), 6.00-5.95 (m, 1H), 4.41 (d, 1H), 4.25-4.15 (m, 1H), 4.00-3.95 (m, 1H), 3.81 (s, 6H), 3.16 (m, 3H), 3.00-2.90 (m, 2H), 2.75-2.65 (m, 2H), 2.60-2.30 (m, 4H), 2.20-2.10 (m, 1H), 2.06 (s, 3H), 1.40-1.20 (m, 5H)。 實施例 68(16) : N-(3-{l-[(2S, 3S)-2-(2, 3-二氫-1H-節· - 2-基甲基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基] -1H-D比咯-3-基} -2-曱基丙驢基)苯石黃酸胺 TLC : Rf 0· 33 (己烷:乙酸乙酯=2 : 1); ^NMR : 6 8.00-7.95 (m, 2H), 7.90-7.75 (m, 1H), 7.60-7.40 (m, 3H), 7.20-7.05 (m, 4H), 6.65 (s, 1H), 6.60-6.40 (m, 3H), 5.86 (s, 1H), 4.50-4.40 (m, 1H), 4.30-3.90 (m, 2H), 3.80 (s, 6H), 3.05*2.90 (m, 2H), 2.70*2.10 (m, 7H), 2.06 (s, 3H),1.40-1.30 (m, 2H), 1.20-1.10 (m, 3H)。 實施例 68(17) ·· N-(3-{l-[(2S,3S)-2-(2, 3-二氫-1H- - 2 -基甲基)_3-(3,5- 一曱乳基-4-曱基苯基3-經基丙基] -1Η - 口比17各-3 -基}丙酸基)-2 -氟苯石黃酿胺 TLC : Rf 0.46 (己烷:乙酸乙酯: 1); 316588 163 200521108 ^NMR : δ 1.31-1.46 (m, 2H), 2.05 (s, 3H), 2.09*2.17 (m, 1H), 2.31*2.46 (m, 3H), 2.46-2.54 (m, 2H), 2.74 (t, 2H), 2.90-3.01 (m, 2H), 3.7ii (s, 6H), 3.96-4.03 (m, 1H), 4.21 (dd, 1H), 4.43 (d, 1H), 5.93-5.96 (m, 1H), 6.52-6.57 (m, 3H), 6.63*6.67 (m, 1H), 7.07-7.19 (m, 5H), 7.25-7.32 (m, 1H), 7.56-7.64 (m, 1H), 8.00-8.06 (m,1H), 8.34 (s,1H)。 實施例 68(18) ·· N-(3-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 -2-基曱基)-3-(3, 5-二曱氧基-4 -曱基苯基)-3-經基丙基] -1H -吼洛-3 -基}丙醯基)-2-(三氟曱基)苯石黃臨胺 TLC : Rf 0· 53 (己烷··乙酸乙酯=1 : 1); 修 'HNMR : (5 1.30-1.45(m, 2H), 2.05 (s,3H), 2.07^2.17 (m, 1H), 2.37-2.52 (m, 5H), 2.69*2.77 (m, 2H), 2.90-3.02 (m, 2H), 3.79 (s, 6H), 3.98 (dd, 1H), 4.22 (dd, 1H), 4.42 (d, 1H), 5.89*5.94 (m, 1H), 6.51-6.58 (m, 3H), 6.61-6.67 (m, 1H), 7.05-7.15 (m, 4H), 7.69-7.77 (m, 2H), 7.80-7.87 (m, 1H), 8.30 (s, 1H), 8·43·8.49 (m, 1H)。 實施例68(19):2,6-二氣州-(3-{1-[(28,33)-2-(2,3-二 氫-1H-節-2-基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)—3 — 經基丙基]-1Η -口比洛-3 -基}丙酿基)苯石黃酿胺 TLC : Rf 0· 39 (己烷:乙酸乙酯=1 : 1); 1 HNMR : 6 1.30-1.45 (m, 2H), 2.04 (s, 3H),2·07·2.17 (m,1H), 2.33-2.46 (m, 3H), 2.53*2.60 (m, 2H), 2.73*2.81 (m, 2H), 2.90-3.02 (m, 2H), 3.79 (s, 6H), 3.99 (dd, 1H), 4.21 (dd, 1H), 4.43 (d, 1H), 5.44 (s, 1H), 5.94-5.98 (m, 1H), 6.53 (s, 2H), 6.55-6.61 (m, 1H), 6.63*6.67 (m, 1H), 7.04-7.14 (m, 4H), 7.31-7.38 (m, 1H), 7·41·7·49 (m, 2H), 8_55 (s, lH)〇 實施例 68(20) ·· N-(3-{1-[(2S,3S)-2-(2,3-二氫-1H-節 316588 164 200521108 - 2-基曱基)-3 -(3, 5-二曱氧基-4-曱基苯基)- 3-羥基丙基] -1H-〇比17各-3-基}丙酿基)-2-甲基苯石黃醯胺 性狀:無定形物 TLC : Rf 0· 68 (己烷:乙酸乙酯: 2); ^NMR : δ 8.14 (s, 1H), 8.10 (dd, 1H), 7.48 (ddd, 1H), 7.34 (dd, 1H), 7.26 (m, 1H), 7.18-7.05 (m, 4H), 6.65 (m, 1H), 6.58-6.52 (m, 3H), 5.93 (dd, 1H), 4.45 (d, 1H), 4.21 (dd, 1H), 3.99 (dd, 1H), 3.80 (s, 6H), 3.04-2.90 (m, 2H), 2.75 (t, 2H), 2.58*2.30 (m, 5H), 2.53 (s, 3H), 2.18 (m, 1H), 2.06 (s, 3H), 1.40 (m,2H)。 實施例 68(21) : N-(3-{l-[(2S,3S)-2-(2,3-二氫-1H-茚 - 2-基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基] -1H -D比嘻-3 -基}丙酸基)- 2,6-二氣苯石黃酿胺 TLC : Rf 0· 58 (己烷:乙酸乙酯=1 : 2); 1 H NMR : δ 8.46 (s, 1H), 7.55 (m, 1H), 7.16-7.06 (m, 4H), 7.01 (dd, 2H), 6.67 (m, 1H), 6.57 (m, 1H), 6.54 (s, 2H), 5.96 (m, 1H), 4.44 (d, 1H), 4.21 (dd, 1H), 4.01 (dd, 1H), 3.81 (s, 6H), 3.04-2.92 (m, 2H), 2.77 (t, 2H), 2.55 (m, 2H), 2·50·2·30 (m, 3H), 2.15 (m, 1H), 2.06 (s, 3H),1.40 (m, 2H)。 實施例 68(22) : 4-氯-N-(3-{l-[(2S,3S)-2-(2,3-二氫 -1H-節-2-基曱基)-3-(3, 5-二曱氧基-4 -申基苯基)-3 一經 基丙基]-1Η -口比17各-3 -基}丙醯基)- 3 - D比σ定石黃醒胺 TLC : Rf 0· 28 (己烷:乙酸乙酯=1 ·· 2); 165 316588 200521108 iHNMR J 9.30 (s,1Η),8.70 (d,1Η),8·48 (s,1Η),7·42 (d,1H), 7.18-7.05 (m, 4H), 6.67 (m, 1H), 6.59 (m, 1H), 6.54 (s, 2H), 5.97 (m, 1H), 4.44 (d, 1H), 4.23 (dd, 1H), 4.02 (dd, 1H), 3.80 (s, 6H), 3.02-2.90* (m, 2H), 2.78 (t, 2H), 2.55 (m, 2H), 2.50-2.30 (m, 3H), 2.14 (m, 1H), 2.06 (s, 3H), 1.40 (m, 2H)。 實施例 68(23) : N-(3-{1-[(2S,3S)-2-(2,3-二氫-1H-節 - 2 -基曱基)-3 -(4-乙基-3, 5-二甲氧基苯基)一3 一羥基丙基] -1Η - 〇比17各-3 -基}丙醯基)曱石黃酿胺 TLC : Rf 0· 28 (己烷:乙酸乙酯=1 : 1); 鲁 1 H NMR : δ 1.05 (t, 3H), 1.33-1.42 (m, 2H), 2.08-2.18 (m, 1H), 2.32-2.47 (m, 3H), 2.53-2.66 (m, 4H), 2.78-2.87 (m, 2H), 2.90^3.02 (m, 2H), 3.20 (s, 3H), 3.81 (s, 6H), 3.96-4.05 (m, 1H), 4.13*4.22 (m, 1H), 4.42 (d, 1H), 5.97-6.01 (m, 1H), 6.52 (s, 2H), 6.55*6.60 (m, 1H), 6.63-6.68 (m, 1H), 7.06-7.15 (m, 4H), 7.84 (s, lH)〇 實施例 68(24) : N-(3-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 -2-基曱基)-3-(4-乙基-3,5-二曱氧基苯基)- 3-經基丙基]鲁 -1Η -口比略-3 -基}丙酿基)苯石黃驢胺 TLC : Rf 0· 49 (己烷:乙酸乙酯=1 : 1); iHNMR : 6 1.05 (t,3H),1.33-1.44 (m,2H), 2.08-2.18 (m,1H), 2.35-2.49 (m, 5H), 2.62 (q, 2H), 2.69-2.77 (m, 2H), 2.89-3.02 (m, 2H), 3.80 (s, 6H), 3.95*4.04 (m, 1H), 4.13*4.22 (m, 1H), 4.45 (d, 1H), 5.86-5.91 (m, 1H), 6.47-6.56 (m, 3H), 6.60-6.66 (m, 1H), 7.06*7.16 (m, 4H), 7.46-7.53 (m, 2H), 7.58-7.64 (m, 1H), 7·94·8·03 (m, 3H)〇 實施例 68(25) : N-(2-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 166 316588 200521108 -2 -基甲基)-3-(4 -乙基-3, 5 -二甲氧基苯基)一 3 -經基丙基] -1Η-吡咯-3-基丨乙醯基)甲磺醯胺 TLC : Rf 0· 24 (己烷:乙酸乙酯=1 : 1); 1 HNMR : δ 1.05 (t, 3Π), 1.32-1.45 (m, 2H), 2.09*2.19 (m, 1H), 2.32-2.48 (m, 3H), 2.62 (q, 2H), 2.91-3.04 (m, 2H), 3.24 (s, 3H), 3.56 (s, 2H), 3.81 (s, 6H), 4.00-4.11 (m, 1H), 4.13*4.25 (m, 1H), 4.43 (d, 1H), 5.99*6.04 (m, 1H), 6.50 (s, 2H), 6.64-6.71 (m,2H), 7.06-7.16 (m, 4H), 8.06 (s, 1H)。 實施例 68(26) : N-(2-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 - 2-基曱基)-3-(4-乙基-3, 5-二曱氧基苯基)一3-經基丙基] -1Η - D比σ各-3 -基}乙酿基)苯石黃酿胺 TLC : Rf 0· 46 (己烷:乙酸乙酯=1 : 1); 1 HNMR : (5* 1.06 (t,3H),1.34-1.45 (m,2H),2· 10·2.18 (m, 1H),2.33-2.49 (m, 3H), 2.63 (q, 2H), 2.91*3.03 (m, 2H), 3.44 (s, 2H), 3.81 (s, 6H), 3.99*4.08 (m, 1H), 4.11-4.25 (m, 1H), 4.43 (d, 1H), 5.93-5.96 (m, 1H), 6.51 (s, 2H), 6.59-6.63 (m, 1H), 6.67-6.70 (m, 1H), 7.07*7.16 (m, 4H), 7.47-7.54 (m, 2H), 7.59-7.66 (m, lH), 7·97·8·02 (m, 2H), 8·21 (s, 1H)。 實施例 68(27) : N-(2-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 -2 -基曱基)-3-(3,o -二曱氧基-4 -曱基苯基3-經基丙基] -1Η - 〇比17各- 3 -基} - 2 -曱基丙酿基)苯石黃醯胺 TLC ·· Rf 0. 58 (己烧··乙酸乙酯=1 : 1); HNMR : 8.14 (s, 1H), 7.94 (d, 2H), 7.60 (m, 1H), 7.49 (m, 2H), 7.18-7.05 (m, 4H), 6.69 (dd, 1H), 6.58 (dd, 1H), 6.53 (s, 2H), 5.94 (dd, 1H), 4.45 (d, 1H), 4.20 (dd, 1H), 4.04 (dd, 1H), 3.83 (s, 6H), 3.04-2.90 (m, 2H), 2.55-2.35 (m, 3H), 2.18 (m, 1H), 2.07 (s, 3H), 1.50-1.38 (m, 2H), 1.4l(s, 3H), 1.40 (s, 3H)。 167 316588 200521108 實施例 68(28):2-氣-1^-(3-{卜[(28,33)-2-(2,3-二氳 -1H-茚-2-基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥 基丙基]-1Η -口比17各-3 -基}丙酸基)苯石黃醯胺 TLC ·· Rf 0_40 (己烷:乙酸乙酯=1 : 1);
1 HNMR : d 1.29-1.50 (m, 2H), 2.05 (s, 3H), 2.08-2.22 (m, 1H), 2.28-2.50 (m, 3H), 2.50*2.60 (m, 2H), 2.77 (t, 2H), 2.90-3.05 (m, 2H), 3.79 (s, 6H), 4.00 (dd, 1H), 4.23 (dd, 1H), 4.43 (dd, 1H), 5.93*6.01 (m, 1H), 6.54 (s, 2H), 6.59 (s, 1H), 6.66 (t, 1H), 7.00-7.20 (m, 4H), 7.38-7.60 (m, 3H), 8.17-8.27 (m, 1H), 8.37 (s, lH)〇 實施例 68(29):2-{[(3-{l-[(2S,3S)-2-(2,3-二氫-1H-§5 -2-基曱基)-3-(3,5-二曱氧基-4 -曱基苯基)-3-經基丙基] -1Η-吡咯-3-基}丙醯基)胺基]磺醯基}苯曱酸甲酯 TLC : Rf 0· 29 (己烷:乙酸乙酯=1 : 1); 1 HNMR : 6 1.29-1.45 (m, 2H), 2.01-2.20 (m, 5H), 2·27-2·50 (m, 3H),
2.51-2.61 (m, 2H), 2.76 (t, 2H), 2.94 (dd, 2H), 3.80 (s, 6H), 3.90*4.00 (m, 4H), 4.12-4.24 (m, 1H), 4.41 (dd, 1H), 5.92 (t, 1H), 6.51 (s, 2H), 6.53 (s, 1H), 6.57 (t, 1H), 7.00-7.19 (m, 4H), 7.58-7.71 (m, 2H), 7.73·7‘82 (m, 1H), 8.21-8.35 (m, 1H), 8.58 (s, lH)〇 實施例 68(30) : 3-氯-N-(3-{l-[(2S,3S)-2-(2,3-二氫 - 1H-節-2-基甲基)-3-(3, 5-二曱氧基-4-曱基苯基3一經 基丙基]-1Η- 口比略-3 -基}丙醯基)苯石黃醯胺 TLC : Rf 0· 34 (己烷··乙酸乙酯: 1); 316588 168 200521108 1 H NMR : d 1.29- 1.49 (m, 2H), 2.02 (d, 1H), 2.06 (s, 3H), 2.08-2.24 (m, 1H), 2.28-2.58 (m, 5H), 2.74 (t, 2H), 2.85*3.08 (m, 2H), 3.80* (s, 6H), 3.94-4.07 (m, 1H), 4.13*4.25 (m, 1H), 4.45 (dd, 1H), 5.84-5.91 (m, 1H), 6.50-6.52 (m, 1H), 6.53 (s, 2H), 6.65 (t, 1H), 6.99-7.19 (m, 4H), 7.43 (t, 1H), 7.51*7.63 (m, 1H), 7.83-8.14 (m, 3H)〇 實施例 68(31) : N-(3-{l-[(2S,3S)-2-(2,3-二氫-1H-茚 -2-基曱基)-3-(3, 5-二曱氧基-4-甲基苯基)-3-經基丙基] -1H-吡咯-3-基}丙醯基)-2-噻吩磺醯胺 TLC : Rf 0· 30 (己烷··乙酸乙酯=1 : 1) ; _ 1HNMR : d 1.29-1.48 (m,2H), 2.02 (d, 1H), 2.06 (s,3H), 2.08-2-21 (m, 1Η), 2.28-2.62 (m, 5H), 2.75 (t, 2H), 2.87*3.05 (in, 2H), 3.81 (s, 6H), 3.98 (dd, 1H), 4.18 (dd, 1H), 4.44 (dd, 1H), 5.79-5.96 (m, 1H), 6.50 (s> 1H), 6.54 (s, 2H), 6.64 (t, 1H), 7.01-7.20 (m, 5H), 7.63 (dd, 1H), 7.82 (dd, 1H), 8.04 (s, lH)〇 實施例 68(32) : N-(2-{l-[(2S,3S)-2-(2, 3-二氫-1H-節 - 2-基甲基)-3-(3, 5-二甲氧基-4-曱基笨基)一3一羥基丙基] -1Η -口比17各- 3 -基} - 2 -曱基丙酸基)曱石黃醮胺 TLC : Rf 0· 34 (己烷:乙酸乙酯=1 : 1); 'HNMR : δ 7.95 (s, 1H), 7.18-7.05 (m, 4H), 6.70 (dd, 1H), 6.63 (dd, 1H), 6.51 (s, 2H), 6.05 (dd, 1H), 4.43 (d, 1H), 4.19 (dd, 1H), 4.04 (dd, 1H), 3.82 (s, 6H), 3.19 (s, 3H), 3.08*2.90 (m, 2H), 2.52-2.28 (m, 3H), 2.14 (m, 1H), 2.06 (s, 3H), 1·53 (s, 6H), 1.40 (m,2H)。 實施例 68(33) · N-({1-[(2S,3S)-2-(2,3-二氫-ih-茚-2- 基曱基)-3-(3, 5-二甲氧基-4-曱基苯基)-3一經基丙基] 316588 169 200521108 -1Η-吡咯-3-基}乙醯基)-4-曱基笨磺醯胺 TLC : Rf 0· 33 (己烧:乙酸乙酯: 1); iHNMR : d 8.2G (s,1H), 7.87 (d,2H),7·29 (d,2H),7·18·7·06 (m,4H), 6.69 (m, 1H), 6.61 (m, 1H), 6.51 (s, 2H), 5.94 (m, 1H), 4.42 (d, 1H), 4.22 (dd, 1H), 4.03 (dd, 1H), 3.82 (s, 6H), 3.43 (s, 2H), 3.04-2.92 (m, 2H), 2.58-2.30 (m, 3H), 2.43 (s, 3H), 2.15 (m, 1H), 2.07 (s, 3H), 1.40 (m, 2H)。 實施例 68(34) : 4-氯-N-({1-[(2S,3S)-2-(2,3-二氫-1H- 茚-2-基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙 基]-1H-口比口各-3-基}乙酿基)苯石黃酿胺 鲁 TLC : Rf 0· 33 (己烷:乙酸乙酯: 1); ^NMR : δ 8.21 (s, 1H), 7.92 (d, 2H), 7.47 (d, 2H), 7.17*7.05 (m, 4H), 6.69 (dd, 1H), 6.61 (m, 1H), 6.51 (s, 2H), 5.94 (dd, 1H), 4.43 (dd, 1H), 4.20 (dd, 1H), 4.03 (dd, 1H), 3.82 (s, 6H), 3.44 (s, 2H), 3.04-2.92 (m, 2H), 2.52-2.30 (m, 3H), 2.15 (m, 1H), 2.07 (s, 3H), 1.39 (m, 2H)〇 實施例 68(35) : N-(U-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基曱基)-3-(3, 5-二曱氧基-4-甲基苯基)-3-羥基丙基] φ -1 Η-D比略-3-基}乙酿基)- 4 -氟笨石黃酿胺 TLC : Rf 0· 32 (己烷:乙酸乙酯二1 : 1); ^NMR : δ 8.21 (s, 1H), 8.01 (dd7 2H), 7.17 (dd, 2H), 7.17-7.06 (m, 4H), 6.69 (dd, 1H), 6.61 (m, 1H), 6.51 (s, 2H), 5.94 (dd, 1H), 4.43 (dd, 1H), 4.20 (dd, 1H), 4.03 (dd, 1H), 3.82 (s, 6H), 3.44 (s, 2H), 3.04-2.90 (m, 2H), 2.55-2.30 (m,3H), 2·15 (m, 1H),2.07 (s,3H), 1_40 (m, 2H)〇 實施例 68(36) : N-(3-{l-[(2S,3S)-2-(2,3-二氫_1H-茚 -2 -基曱基)-3-(3, 5-二曱氧基-4-甲基苯基)- 3-經基丙基] 170 316588 200521108 - 1H - D比17各-3-基}丙酿基)-2-(三氟^甲氧基)本石黃酸胺 TLC· Rf 0.53 (己烧:乙酸乙醋二1 · 1), 1 H NMR : d 1.27-1.48 (m, 2H), 2.01-2.21 (m, 4H), 2.27*2.57 (m, 5H), 2.75 (t, 2H), 2.88-3.06 (m, 2H), 3.80 (s, 6H), 3.99 (dd, lH), 4.21 (dd, 1H), 4.42 (d, 1H), 5.92-5.99 (m, 1H), 6.53 (s, 2H), 6.56 (s, 1H), 6.64 (t, 1H), 7.03-7.19 (m, 4H), 7.34-7.49 (m, 2H),7.61-7.72 (m, 1H),8.17 (dd,1H)。 實施例 68(37) : 6-氣-N-(3-U-[(2S,3S)-2-(2,3-二氫 -1H-茚-2-基曱基)-3-(3, 5-二甲氧基-4-甲基苯基)-3-羥 基丙基]- 1H-吼咯-3-基}丙醯基)-3-吡啶磺醯胺 TLC : Rf 0· 17 (己烷:乙酸乙酯=1 : 1); 1HNMR : d 1.38 (t,2H),1·99·2·23 (m, 4H), 2.28-2.56 (m, 5H),2.74 (t, 2H), 2.87*3.04 (m, 2H), 3.81 (s, 6H), 3.94*4.06 (m, 1H), 4.12*4.25 (m, 1H), 4.43 (d, 1H), 5.84-5.90 (m, 1H), 6.48-6.50 (m, 1H), 6.53 (s, 2H), 6.65 (t, 1H), 7.01-7.20 (m, 4H), 7.45 (d, 1H), 8.26 (dd, 1H), 8.85 (dd, lH)〇 實施例 68(38) : Ν’-(3-{l-[(2S,3S)-2-(2,3-二氫-1H-茚 -2 -基甲基)-3 -(3,5 -二曱氧基-4 -曱基苯基)-3 -經基丙基]鲁 -1H-吡咯-3-基}丙醯基)-N,N-二曱基磺醯胺 TLC : Rf 0· 44 (己烷:乙酸乙酯=1 : 1); !HNMR : (5 1.30-1.47 (m, 2H), 2.01-2.20 (m, 4H), 2.27-2.48 (m, 3H), 2.48-2.57 (m, 2H), 2.81 (t, 2H), 2.88 (s, 6H), 2.90-3.04 (m, 2H), 3.81 (s, 6H), 3.93-4.04 (m, 1H), 4.15*4.26 (m, 1H), 4.42 (dd, 1H), δ.96-6.03 (m, 1H), 6.52 (s, 2H), 6.57 (s, 1H), 6.64 (t, 1H), 7.03-7.17 (m, 4H), 7·74 (s, 1H)。 實施例 68(39) : N-(3-{l-[(2S,3S)-2-(2,3-二氫-1H-節 - 2-基甲基)-3 -(3, 5-二曱氧基-4-甲基苯基)-3-羥基丙基] 316588 171 200521108 -1 Η-口比口各-3*~基}丙酿基)-1 -甲基-1Η-口米哇-4-石黃酿胺 TLC : Rf 0· 27 (乙酸乙酯); WNMR: 6 1.23-1.47 (m,2H),2.04(s,3H),2.06-2.21(m,lH),2.26-2.62 (m, 5H), 2.74 (t, 2H), 2.8Φ3.05 (m, 2H), 3.67 (s, 3H), 3.78 (s, 6H), 3.95 (dd, 1H), 4.24 (dd, 1H), 4.38 (d, 1H), 5.91*5.96 (m, 1H), 6.49-6.55 (m, 2H), 6·56·6·65 (m, 2H), 7·03·7·17 (m, 4H), 7.37 (d, 1H), 7.61 (d, 1H)。 實施例 68(40) : N-({1-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基甲基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-經基丙基] -1H- 口比σ各-3-基}乙醒基)-2-曱基苯石黃醒胺 TLC : Rf 0· 39 (己烷:乙酸乙酯=1 : 1); 1 HNMR : d 1.31Ί.42 (m, 2H), 1.92-2.00 (m, 1H), 2.06 (s, 3H), 2.09-2J9 (m, 1H), 2.35-2.50 (m, 6H), 2.90-3.04 (m, 2H), 3.43 (s, 2H), 3.81 (s, 6H), 4.02 (dd, 1H), 4.24 (dd, 1H), 4.42 (d, 1H), 5.93-6.00 (m, 1H), 6.51 (s, 2H), 6.62-6.73 (m, 2H), 7.05-7.15 (m, 4H), 7.22-7.30 (m, 1H), 7.30*7.40 (m, lH), 7.43-7.52 (m, 1H), 8.09-8.17 (m, 1H), 8.29 (s, 1H)。 實施例 68(41) : N-({1-[(2S,3S)-2-(2,3-二氫-1H-茚-2- 基甲基)-3 -(3,5-二甲氧基-4-甲基苯基)-3-經基丙基] - 111-〇比°各-3-基}乙酿基)-2-(三氟曱基)苯石黃酿胺 TLC : Rf 0· 43 (己烷:乙酸乙酯=1 : 1); JHNMR : δ 1.3Μ.41 (m, 2H), 1.85*2.00 (m, 1H), 2.05 (s, 3H), 2.09*2.17 (m, 1H), 2.34-2.49 (m, 3H), 2.90-3.03 (m, 2H), 3.44 (s, 2H), 3.81 (s, 6H), 4.02 (dd, 1H), 4·29 (dd, 1H), 4.38 (d, 1H), 5.93-5.99 (m,1H), 6.51 (s,2H), 6.62-6.67 (m, 1H), 6.68-6.74 (m, 1H), 7.05*7.15 (m, 4H), 7.72-7.86 (m, 3H), 8.38·8·45 (m, 1H),8.48-8.54 (m, 1H)。 實施例 68(42) : N-({1-[(2S,3S)-2-(2,3-二氫-1H-茚-2- 172 316588 200521108 基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基] -1Η -吼σ各- 3 -基}乙醯基)-2 -氟苯石黃酸胺 TLC· Rf 0.35 (己烧·乙酸乙醋=1 : 1); !HNMR : δ 1.32-1.42 (m, 2H), 1.89-2.01 (m, 1H), 2.05 (s, 3H), 2.09-2.18 (m, 1H), 2.35-2.49 (m, 3H), 2.91-3.04 (m, 2H), 3.46 (s, 2H), 3.80 (s, 6H), 4.03 (dd, 1H), 4.27 (dd, 1H), 4.40 (d, 1H), 5.97-6.03 (m, 1H), 6.51 (s, 2H), 6.64-6.74 (m, 2H), 7.05-7.18 (m, 5H), 7.27-7.35 (m, 1H), 7.56-7.66 (m, 1H), 8.03-8.12 (m, 1H), 8.47 (s, lH)〇 實施例 68(43) ·· 2-氯-N-({1-[(2S,3S)-2-(2,3-二氫_1H-節-2-基甲基)-3-(3, 5-二曱氧基-4 -曱基苯基)一 3-經基丙 基]-1Η-口比17各-3 -基}乙酿基)苯石黃酸胺 TLC : Rf 0· 39 (己烷··乙酸乙酯=1 : 1); 1 HNMR : d 1·32·1·42 (m,2H), 1.89-1.99 2.05 (s, 3H),2.09-2.19 (m, 1H), 2.35-2.49 (m, 3H), 2.91-3.04 (m, 2H), 3.46 (s, 2H), 3.81 (s, 6H), 3.99-4.08 (m, 1H), 4.27 (dd, 1H), 4.40 (d, 1H), 6.00-6.05 (m, 1H), *6.51 (s, 2H), 6.65-6.73 (m, 2H), 7.05-7.15 (m, 4H), 7.43-7.57 (m, 3H), 8.23 8.30 (m, 1H), 8.51 (s, lH)〇 實施例 68(44) ·· N-({1-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基甲基)-3-(3,5-二甲氧基-4 -曱基苯基)- 3 -經基丙基] -1H-D比洛-3-基}乙酿基)-2,6-二氟苯石黃酿胺 TLC : Rf 0· 22 (己烷:乙酸乙酯: 1); 173 316588 200521108 ^NMR : δ 1.32-1.41 (m, 2H), 1.90*2.01 (m, 1H), 2.05 (s, 3H), 2.08-2.18 (m, 1H), 2.34*2.48 (m, 3H), 2.90-3.03 (m, 2H), 3.50 (s, 2H), 3.80 (s, 6H), 4.03 (dd, 1H), 4.25 (dd, 1H), 4.40 (d, 1H), 5.97-6.03 (m, 1H), 6.50 (s, 2H), 6·64·6.73 (m, 2H),6·97-7·13 (m, 6H), 7.48-7.60 (m, lH),8.57 (s, lH)〇 實施例 68(45) : 2,6-二氯-N-({卜[(2S,3S)-2-(2,3-二氫 -1H-茚-2-基曱基)-3-(3, 5-二曱氧基-4-甲基苯基)-3-羥 基丙基]-1Η -口比17各-3 -基}乙酸基)苯石黃酿胺 TLC : Rf 0· 35 (己烷:乙酸乙酯二1 : 1); ^NMR : δ 1.32-1.40 (m, 2H), 1.83-2.00 (m, 1H), 2.05 (s, 3H), 2.08*2.18 (m, 1H), 2.34-2.49 (m, 3H), 2.90-3.04 (m, 2H), 3.48 (s, 2H), 3.81 (s, 6H), 4.02 (dd, 1H), 4.25 (dd, 1H), 4.40 (d, 1H), 5.99-6.05 (m, 1H), 6.51 (s, 2H), 6.64-6.72 (m, 2H), 7.05-7.15 (m, 4H), 7.32-7.39 (m, 1H), 7.42-7.49 (m, 2H), 8.64 (s, lH)〇 實施例 68(46) : N-({1-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基曱基)-3-(3,5-二甲氧基-4-曱基苯基)- 3-經基丙基] -1Η - D比咯-3 -基}乙酿基)-3 -氟苯石黃酿胺 0 TLC : Rf 0· 35 (己烷:乙酸乙酯=1 : 1); 'HNMR : δ 1.30-1.42 (m,2HX 2.06 (s,3H), 2.08-2.17 (m, 1Η), 2.34-2.48 (m, 3H), 2.90-3.03 (m, 2H), 3.45 (s, 2H), 3.81 (s, 6H), 3.98*4.07 (m, 1H), 4.17-4.25 (m, 1H), 4.42 (d, 1H), 5.90-5.96 (m, 1H), 6.47-6.52 (m, 2H), 6.59-6.64 (m, 1H), 6.66-6.71 (m, 1H), 7.04*7.15 (m, 4H), 7.27*7.35 (m, 1H), 7·44·7·53 (m, 1H), 7.64-7.72 (m, 1H),7.76-7.81 (m, 1H), 8·24 (s, 1H)。 實施例 68(47) : 3-氣-N-({1-[(2S,3S)-2-(2,3-二氫-1H- 節-2-基曱基)-3-(3, 5-二曱氧基-4 -曱基苯基)一 3_經基丙 316588 174 200521108 基]-1Η -吼洛-3 -基}乙酸基)苯石黃酿胺 TLC : Rf 0.37 (己烷:乙酸乙酯=1 : 1); 1 HNMR : 6 1.3Μ.42 (m, 2H), 2.06 (s, 3H), 2.10-2.18 (m, 1H), 2.34-2.48 (m, 3H), 2.90-3.04 (m, 2H), 3.45 (s, 2H), 3.81 (s, 6H), 3.97-4.07 (m, 1H), 4.21 (dd, 1H), 4.42 (d, 1H), 5.91-5.97 (m, 1H), 6.50 (s, 2H), 6.59*6.64 (m, 1H), 6.66-6.72 (m, 1H), 7.05-7.15 (m, 4H), 7.38-7.50 (m, 1H), 7.54-7.61 (m, 1H),7.86-7.92 (m, 1H),7.93-7.98 (m,1H), 8·24 (s, 1H)。 實施例 68(48) : N-(2-{l-[(2S,3S)-2-(2,3-二氫-1H-· -2-基甲基)-3 -(3,5-二曱氧基-4 -曱基苯基)- 3-經基丙基]鲁 -1Η -吼洛-3 -基}乙酿基)-2 -嚷吩石黃酿胺 TLC :Rf 0.30 (己烧:乙酸乙酯=1: 1); XHNMR : δ 1.30-1.40(m,2H), 1.88-2.00 (ηχ,ΙΗ), 2.05 (s,3H), 2.08-2.17 (m, 1H), 2.31-2.46 (m, 3H), 2.89*3.02 (m, 2H), 3.47 (s, 2H), 3.81 (s, 6H), 3.97-4.06 (m, 1H), 4.15-4.25 (m, 1H), 4.41 (d, 1H), 5.93-5.97 (m, 1H), 6.50 (s, 2H), 6.59*6.63 (m, 1H), 6.65-6.70 (m, 1H), 7.05-7.14 (m, 5H), 7.60-7.66 (m. 1H), 7.81-7.86 (m, 1H), 8.30 (s,1H)。
實施例 68(49) : N-({l-[(2S,3S)-2-(2,3-二氫-1H-節-2- 基曱基)-3-(3,5-二曱氧基-4-甲基苯基)-3-經基丙基] -1Η-口比咯- 3 -基}乙醯基)-3,5 -二曱基- 4 -異°惡唾石黃酿胺 TLC : Rf 0· 37 (己烷:乙酸乙酯=1 : 1); 316588 175 200521108 iHNMR : d 1.30-1.41 (m,2H),1.88-2.00 (m,lH),2.05(s,3HXl〇8-2.19 (m, 1H), 2.28 (s, 3H), 2.31-2.46 (m, 3H), 2.70 (s, 3H), 2.89*3.03 (m, 2H); 3.45 (s, 2H), 3.81 (s, 6H), 3.98*4.07 (m, 1H), 4.17-4.26 (m, 1H), 4.42 (d, 1H), 5.92-5.97 (m, 1H), 6.49 (s, 2H), 6.60-6.65 (m, 1H), 6.67*6.71 (m, 1H), 7.05-7.14 (m, 4H), 8.31 (s, lH)〇 實施例 68(50) : N-(3-{l-[(2S,3S)-2-(2,3-二氫-1H-茚 -2-基甲基)-3 -(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基] -1Η - D比17各-3 -基}丙酿基)-2,4 -二貌苯石黃酿胺 TLC : Rf 0· 52 (己烷:乙酸乙酯=1 : 1); ^NMR : δ 1.29-1.49 (m, 2H), 2.01-2.21 (m, 5H), 2.28-2.56 (m, 5H), 2.75 (t, 2H), 2.87-3.05 (m, 2H), 3.79 (s, 6H), 3.94-4.04 (m, 1H), 4.20 (dd, 1H), 4.43 (d, 1H), 5.91-5.96 (m, 1H), 6.52 (s, 2 H), 6.53-6.57 (m, 1H), 6.65 (t, 1H), 6.84-6.93 (m, 1H), 6.96-7.05 (m, 1H), 7.05-7.15 (m, 4H), 7.98-8.12 (m, 1H)。 實施例68(51):2-氯-1^-(3-{1-[(28,33)-2-(2,3-二氫 -1H-節-2-基曱基)-3 -(3, 5-二曱氧基-4 -甲基苯基)-3 -經 基丙基]-lH-Dit17各-3-基}丙酿基)-6 -曱基苯石黃酿胺 TLC : Rf 0· 62 (己烷:乙酸乙酯=1 : 1); !HNMR : δ 1.28-1.50 (m, 2H), 1.98-2.23 (m, 5H), 2.28*2.49 (m, 3H), 2.49-2.61 (m, 2H), 2.71-2.82 (m, 5H), 2.88^3.08 (m, 2H), 3.79 (s, 6H), 3.99 (dd, 1H), 4.21 (dd, 1H), 4.42 (dd, 1H), 5.92-5.99 (m, 1H), 6.53 (s, 2 H), 6.57 (s, 1H), 6.65 (t, 1H), 7.05-7.15 (m, 4H), 7.18-7.23 (m, 1H), 7.29*7.35 (m, 2H), 8.49 (s, lH)〇 實施例 68(52) : N-(3-U-[(2S,3S)-2-(2,3-二氫-1H-茚 176 316588 200521108 -2-基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-羥基丙基] - 1H-吼洛-3-基}丙醯基)-2 -甲氧基-4 -曱基苯石黃酿胺 TLC : Rf 0· 29 (己烷:乙酸乙酯=1 : 1); !HNMR: δ 1.28-1.47(m,2H),2.05(s,3H), 2.09-2.18 (m,2H), 2.28-2.48 (m, 6H), 2.48*2.57 (m, 2H), 2.72 (t, 2H), 2.86-3.04 (m, 2H), 3.78 (s, 6H), 3.90 (s, 3H), 3.93-4.02 (m, 1H), 4.14-4.24 (m, 1H), 4.40 (dd, 1H), 5.89-5.95 (m, 1H), 6.51 (s, 2H), 6.54 (s, 1H), 6.60 (t, 1H), 6.77 (s, 1H), 6.85 (dd, 1H), 7.02-7.17 (m, 4H), 7.86 (d, 1H), 8.27 (s, lH)〇 實施例 68(53) ·· N-(3-{l-[(2S, 3S)-2-(2, 3-二氫-1H-茚 鲁 -2 -基曱基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-經基丙基] -1H-吡咯-3-基}丙醯基)-4-氟-2-曱基苯磺醯胺 TLC : Rf 0· 51 (己烷:乙酸乙酯: 1); !HNMR : d 1.25-1.48 (m, 2H), 2.01-2.18 (m, 5H), 2.27-2.57 (m, 8H), 2.75 (t, 2H), 2.89-3.05 (m, 2H), 3.80 (s, 6H), 3.99 (dd, 1H), 4.19 (dd, 1H), 4.38-4.49 (m, 1H), 5.88-5.95 (m, 1H), 6.50-6.57 (m, 3H), 6.64 (t, 1H), 6·90-7·05 (m, 2H), 7·06·7·15 (m, 4H), 8.11 (dd, 2H)。 實施例 68(54) : N-(3-U-[(2S, 3S)-2-(2, 3-二氫-1H-茚· -2-基曱基)-3-(3,5 -二曱氧基-4-曱基苯基)-3-經基丙基] -1H-〇比17各-3-基}丙酿基)-5-曱基-2-咲喃石黃醯胺 TLC : Rf 0· 42 (己烷:乙酸乙酯=1 : 1); 177 316588 200521108 1 Η N M R : 5 1.28 - 1.50 (m, 2H), 1.99 - 2.08 (m, 4 H), 2.09-2.22 (m, 1H), 2.28-2.49 (m, 6 H), 2.49-2.65 (m, 2H), 2.77 (t, 2H), 2.86-3.07 (m, 2H), 3.80 (s, 6H), 4.00 (dd, 1H), 4.20 (dd, 1H), 4.44 (d, 1H), 5.93-5.97 (m, 1H), 6.13 (dd, 1H), 6.53 (s, 2 H), 6.56 (t, 1H), 6.64 (t, 1 H), 7.07-7.15 (m, 4 H), 7.18 (d, 1H), 8·00 (s, 1H)。 實施例 68(55) : N-(3-{l-[(2S,3S)-2-(2,3-二氫-1H-節 -2 -基曱基)-3 -(3,5-二曱氧基-4-曱基苯基3-經基丙基] -1H-吡咯-3-基}丙醯基)-1,3-噻唑-2-磺醯胺 TLC : Rf 0· 22 (己烷:乙酸乙酯=1 : 4) ; · ^NMR : δ 1.29*1.50 (m, 2H), 2.05 (s, 3H), 2.08-2.22 (m, 1H), 2.22*2.52 (m, 4H), 2.51-2.61 (m, 2H), 2.72*2.82 (m, 2 H), 2.89-3.06 (m, 2 H), 3.76-3.83 (m, 6H), 3.98 (dd, 1H), 4.20 (dd, 1H), 4.42 (d, 1H), 5.92-5.97 (m, 1H), 6.49-6.53 (m, 2H), 6.56 (s, 1H), 6.63 (t, 1H), 7.02-7.18 (m, 4H), 7.67 (d, 1H), 7.91 (d, 1H)。 實施例 68(56) : N-({1-[(2S, 3S)-2-(2, 3-二氫-1H-茚-2-基曱基)-3-(3,5-二曱氧基-4-曱基苯基)-3-經基丙基] 0 - 1H-D比σ各-3-基}乙驢基)-4-(三氟曱基)苯石黃酿胺 TLC : Rf 0· 27 (己烷:乙酸乙酯=1 : 1); 1 HNMR : 6 8.28 (s, 1H), 8.12 (d,2H), 7.77 (d, 2H),7· 18-7.06 (m,4H), 6.70 (m, 1H), 6.62 (m, 1H), 6.51 (s, 2H), 5.95 (m, 1H), 4.44 (d, 1H), 4.20 (dd, 1H), 4.04 (dd ,1H), 3.82 (s, 6H), 3.45 (s, 2H), 3.08-2.90 (m, 2H), 2·52·2·30 (m, 3H),2.18 (m, 1H), 2.07 (s, 3H), 1.40 (m,2H)。 實施例 68(57) : N-(U-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基)-3-(3, 5-二曱氧基-4 -曱基苯基)-3 一羥基丙基] 178 316588 200521108 -1H-D比17各-3-基}乙醯基)-4-曱氧基苯石黃醯胺 TLC :Rf 0.27 (己烷:乙酸乙酯1); 1 HNMR : d 8.19 (s, 1H), 7.93 (d, 2H), 7.19-7.06 (m, 4H), 6.95 (d, 2H), 6.68 (dd, 1H), 6.61 (m, 1H), 6.51 (s, 2H), 5.94 (dd, 1H), 4.42 (d, 1H), 4.22 (dd, 1H), 4.03 (dd, 1H), 3.86 (s, 3H), 3.82 (s, 6H), 3.43 (s, 2H), 3.05-2.92 (m, 2H), 2.55-2.30 (m, 3H), 2.15 (m, 1H),2.07 (s, 3H), 1.40 (m, 2H)。 實施例 68(58) : N-({l-[(2S,3S)-2-(2,3-二氫-1H-茚-2-基甲基)-3-(3, 5-二曱氧基-4-甲基苯基)-3 —經基丙基] -1H - 口比口各-3-基}乙驢基)-2 -曱基-2-丙石黃酿胺 籲 TLC : Rf 0· 27 (己烷:乙酸乙酯: 1); WNMR : 6 7.66 (s, 1H), 7.18-7.04 (m, 4H),6.73 (m,2H),6.51 (s,2H), 6.03 (dd, 1H), 4.40 (d, 1H), 4.24 (dd, 1H), 4.03 (dd, 1H), 3.82 (s, 6H), 3.56 (s, 2H), 3.04-2.92 (m, 2H), 2.58-2.30 (m, 3H), 2.15 (m, 1H), 2.06 (s, 3H), 1.39 (s,9H), 1.35 (m, 2H)。 實施例 68(59) : N-(3-U-[(2S,3S)-2-(2,3-二氫-1H-茚 -2-基曱基)-3 -(3, 5-二曱氧基-4 -曱基苯基)-3-經基丙基]鲁 -1Η -唯17各-3 -基}丙臨基)-4 -嗎琳續S藍胺 TLC : Rf 0· 30 (己烷:乙酸乙酯=1 : 1); 1 Η N M R : d 7.77 (s, 1H), 7.09 (m, 4H), 6.64 (m, 1H), 6.58 (s, 1H), 6.52 (s, 2H), 5.99 (s, 1H), 4.41 (d, 1H), 4.18 (dd, 1H), 3.98 (dd, 1H), 3.81 (s, 6H), 3.70-3.60 (m, 4H), 3.30*3.20 (m, 4H), 3.00*2.90 (m, 2H), 2.80-2.90 (m, 2H), 2.60-2.30 (m, 5H), 2.20-2.10 (m, 1H), 2.04 (s, 3H), 1.40-1.35 (m, 2H)〇 實施例 68(60 ) : N-(2-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 -2 -基曱基)-3 -(3,5-二曱氧基-4 -曱基苯基)-3 -經基丙基] 179 316588 200521108 -1Η -吼17各-3 -基}乙酸基)-4 -嗎琳石黃臨胺 TLC : Rf 0· 33 (己烷:乙酸乙酯二1 : 1); 1 HNMR : d 7.97 (s, 1H), 7.09 (m, 4H), 6.69 (m, 1H), 6.65 (m, 1H), 6.50 (s, 2H), 6.02 (t, 1H), 4.42 (d, 1H), 4.22*4.00 (m, 2H), 3.82 (s, 6H), 3.71-3.65 (m, 4H), 3.51 (s, 2H), 3.35-3.30 (m, 4H), 3.00*2.90 (m, 2H), 2.50-2.30 (m, 3H), 2.20-1.80 (m,2H), 2.06 (s,3H), 1·40·1·30 (m, 2H)。 貫施例 68(61) · N-(3-{l-[(2S,3S)-2-(2,3 -二氮-1H-印 - 2 -基曱基)-3 -(3,5-二曱氧基-4-甲基苯基)-3 -經基丙基] -1Η-吡咯-3-基}丙醯基)-2-曱基-2-丙磺醯胺 TLC : Rf 0·38 (己烷:乙酸乙酯: 1); 'HNMR : d 1.32-1.45 (m, 11H), 2.06 (s, 4H), 2.08-2.20 (m, 1H), 2.28-2.53 (m, 3H), 2.58 - 2.66 (m, 2 H), 2.83 (t, 2H), 2.89*3.05 (m, 2H), 3.81 (s, 6H), 3.97 (dd, 1H), 4.12 - 4.24 (m, 1H), 4.44 (d, 1H), 5.96*6.03 (m, 1H), 6·52 (s, 2H),6·57 (t, 1H), 6.63 (t, 1H),7.04-7.17 (m, 4H), 7.42 (s, 1H)。 實施例 68(62) ·· N-(3-{1-[(2S,3S)-2-(2,3-二氫-1H-茚 -2 -基曱基)-3 -(3,5 -二曱氧基-4 -曱基苯基)-3-經基丙基] 一 1H-〇比口各一3-基}丙酿基)-4 -曱基一 1,3-噻σ坐一2 —石黃醒胺 TLC :Rf 0.30 (己烧:乙酸乙酯=1:4); ^NMR : δ 1.28-1.47(m,2H), 2.04 (s,3H), 2.07-2.21 (m, 1Η), 2.24-2.52 (m, 7H), 2.51-2.61 (m, 2H), 2.76 (t, 2H), 2.85*3.04 (m, 2H), 3.78 (s, 6H), 3.97 (dd, 1H), 4.21 (dd, 1H), 4.41 (d, 1H), 5.92 - 5.96 (m, 1H), 6.51 (s, 2H), 6.57 (s,1H), 6.62 (t, 1H), 7.06-7.13 (m, 4H), 7.23 (d, 1H)。 實施例 68(63) : N-((2E)-3-{1-[(2S,3S)-2-(2,3-二氫 -1H-印-2-基曱基)-3-(3,5-二曱氧基-4 -甲基苯基)-3-經 180 316588 200521108 基丙基]-1Η-吡咯-3-基}-2-丙醯基)甲磺醯胺 TLC : Rf 0· 20 (己烧:乙酸乙醋=1 : 1); !HNMR : δ 7.77 (s, 1H), 7.71 (d, 1H), 7.15-7.02 (m, 4H), 6.99 (m, 1H), 6.68 (m, 1H), 6.48 (s, 2H), 6.38 (m, 1H), 6.01 (d, 1H), 4.43 (d, 1H), 4.21 (dd, 1H), 4.06 (dd, 1H), 3.81 (s, 6H), 3.36 (s, 1H), 3.04-2.88 (m, 2H), 2.55-2.30 (m, 3H),2·18 (m, 1H), 2.06 (s, 3H), 1·40 (m, 2H)。 實施例 69 : ((E)-2-U-[(2S,3S)-3-{[第三 丁基(二甲基) 石夕烧基]氧基}-2-(2, 3-二氫-1Η-節-2-基甲基)-3-(3, 5-二 曱氧基-4-甲基苯基)丙基]-1Η-吼咯-3-基}乙烯基)石黃酸二 曱醋 於冰浴下,在伸甲基二膦酸四曱酯(262mg)之四氫咲味 (10ml)溶液中加入氫化鈉(60%,45mg),混合物再於同溫度 下攪拌10分鐘。其次,再加入實施例60中製成之化合物 (561mg),並於50C下稅拌一晚。於反應混合物中再加入 1N鹽酸,並經乙酸乙酯萃取。該有機層再依序經水及飽和 食鹽水洗淨、及以無水硫酸鎂乾燥後濃縮。其殘留物再經 矽膠管柱層析(己烷:乙酸乙酯=1 :丨)精製,即可製成具有 以下物性值之標題化合物(46〇nig)。 TLC : Rf 0· 35 (己烧··乙酸乙酯=ι ·· 1)。 實施例 70 : 2-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基甲基 - 3-(3, 5-二曱氧基-4-甲基苯基)—3 一羥基丙基]η η一吼咯 -3 -基}乙基石黃酸二曱酉旨 使用實施例69中製成之化合物取代(2Ε) —3 一 q —{(2幻 -2-[(S)-(3, 5-二曱氧基-4-曱基苯基)(羥基)曱基]—5〜笨 316588 181 200521108 ^戍基} 1H〜吼唾—4 —基)丙烯酸乙酯,進行與實施例训— 貝細例19相同之操作,即可製成具有以下物性值之標題化 合物。 TLC · Rf 0· 33 (乙酸乙酯); 1HNMR : ^ 7·16'7·04 (m' 4Η)^ 6·59 (t, 1HX 6.51-6.48 (m, 3H), 5.97 (t, 1H), 4.46 (dd, 1H), 4.12 (dd, 1H), 3.99 (dd, 1H), 3.81 (s, 6H), 3.73 (d, 3H), 3.72 (d, 3H), 3.03-2.88 (m, 2H), 2.83-2.70 (m> 2H), 2.49-2.30 (m 3H) 2.19-1.95 (m,6H), 1.37 (t,2H)。 ’ , 貝轭例 71 · 2-{卜[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基)· -3-(3, 5-二甲氧基一4-甲基苯基)—3 —羥基丙基]—1H一吡咯 - 3 -基}乙基石黃酸甲g旨 在貫施例70中製成之化合物(4〇111§)之2—戊酮(2ml)溶 液中加入溴化鋰(8mg),混合物再於}Q51下攪拌4小時 半。反應混合物經濃縮後,於其殘留物中再加入丨N鹽酸, 並經乙酸乙酯萃取。該有機層再依序經水及飽和食鹽水洗 淨、無水硫酸鎂乾燥後濃縮。其殘留物再經矽膠管柱層析 (一氯曱烷·曱醇=4 · 1)精製,即可製成具有以下物性值之® 標題化合物(34mg)。 TLC ·· Rf 0·46 (乙酸:曱醇:二氣曱烷二 i : 2〇 ·· 8〇); 1 H NMR(CD3OD) ·· (5 7.06-6.95 (m,4H),6.57 (s,2H),6.53 (t,1H), 6.46*6.43 (m, 1H), 5.88-5.86 (m, 1H), 4.46 (d, 1H), 4.01 (dd, 1H), 3.88 (dd, 1H), 3.79 (s, 6H), 3.53 (d, 3H), 2.94*2.78 (m, 2H), 2.70*2.59 (m, 2H), 2.32-2.05 (m, 4H), 2·00 (s, 3H),1·85·1·71 (m 2H), 1.47-123 (m, 2H)。 貫施例72.4-(2-曱氧基-2-酮基乙基)-1只-〇比洛~3-緩酸甲 316588 182 200521108
於- 7 8 °C下在雙(三曱基石夕烧基)胺化鐘(i μ,四氫咲ϋ南 溶液)(21ml)中滴入ρ-曱苯石黃醯曱基異氰化物(4. 〇4g)之 四氫呋喃(10 Oml)溶液,該混合物再攪拌30分鐘。其次, 再滴入戊稀二酸二曱酯(3· 78g)之四氫d夫喃(2〇mi)溶液,使 其升溫至至溫並稅掉2小時。反應混合物經濃縮後,殘留 物再依序經水及1N鹽酸洗淨、以乙酸乙酯萃取。其有機層 再依序經1N鹽酸、飽和竣酸氫納水溶液、水及飽和食鹽水 洗淨,經無水硫酸鎂乾燥後濃縮。其殘留物再經石夕膠管柱 層析(己力元·乙酸乙醋=3 · 2)精製,即可製成具有以下物性 值之標題化合物(2· 11 g)。 TLC .Rf 〇·49 (己烧:乙酸乙 |旨=1: 1)。 實施例73: 1-[(2S,3S)-3-{[第三丁基(二曱基)矽烷基]氧 基}-2-(2, 3-二氫-1H-茚-2-基甲基)-3-(3, 5-二甲氧基-4- 甲基本基)丙基]-4-(2 -曱氧基-2-酮基乙基)—ι η-吼略一3-羧酸曱酯 在實施例58中製成之化合物(52 3mg)之Ν,Ν-二曱基曱 醯胺(10ml)溶液中加入實施例72中製成之化合物(376mg) 與碳酸铯(933mg),再於12(TC下攪拌1小時。反應混合物 中再加入水稀釋,並經第三丁基曱基醚萃取。該有機層再 依序經水及飽和食鹽水洗淨、經無水硫酸鎂乾燥後濃縮。 -、歹4迢物再經石夕膠管柱層析(己烧:乙酸乙酯=6 ·· 1)精製, 即可製成具有以下物性值之標題化合物(364mg)。 TLC · Rf 〇· 39 (己烷:乙酸乙酯=4 : 1)。 316588 183 200521108 實施例 74 : [1-[(23,33)-2-(2,3-二氫-111-茚-2-基曱基) 3 (3, 5-一曱氧基一 4 -甲基苯基)一3-羥基丙基]—4-(曱氧基 羰基)-1H-吡咯-3-基]乙酸 在’、施例73中製成之化合物(364mg)之甲醇(4ml )-四 氫咲喃(4ml)溶液中加入in氫氧化鈉水溶液(2mi),該混合 物再於35°C下攪拌2· 5小時。反應混合物經濃縮後,殘留 物再經1N鹽酸稀釋,並經乙酸乙酯萃取。其有機層再依序 經1N鹽酸、水及飽和食鹽水洗淨經無水硫酸鎂乾燥後濃 縮。其殘留物再經矽膠管柱層析(己烷··乙酸乙酯=2 ·· !) 精製,即可製成[1 —[(2S,3S)-3-{[第三丁基(二甲基)矽烷 基]氧基} 2-(2,3 -一風-1H-印-2-基甲基)-3-(3,5-二甲氧 基-4-甲基苯基)丙基]一4一(2-甲氧基-2-酮基乙基)-1 Η-吼 17各-3-基]乙酸(328mg)。接著再依實施例19相同之操作, 即可製成具有以下物性值之標題化合物(235mg)。 TLC : Rf 〇· 32 (乙酸乙酯··己烷=2 : 1); 'HNMR : 7.28 (d, 1H), 7.16-7.06 (m, 4H), 6.67 (d, 1H), 6,47 (s, 2H), 4.39 (d, 1H), 4.21 (dd, 1H), 4.01 (dd, 1H), 3.85 (s, 3H), 3.81 (sr 6H), 3.70 (s, 2H), 3.05-2.89 (m, 2H), 2.52-2.28 (m, 3H), 2.19*2.03 (m, 4H), 1.44Ί.28 (m, 2H)〇 實施例 74(1) : [1 -[(2S,3S)-2-(2,3-二氫-1H-茚-2-基曱 基)-3-(3, 5-二曱氧基-4-曱基苯基)-3-經基丙基]- 4-(乙 氧基幾基)-1Η -吼°各~ 3 -基]乙酸 使用4~λ2 -曱氧基-2- _基乙基)- 1Η-吼17各-3-緩酸乙 §曰取代貫施例72中製成之化合物,依實施例73—實施例 184 316588 200521108 7 4所示之方法同樣操作,即可製成具有以下物性值之標題 化合物。 TLC : Rf 0· 59 (二氣曱烷:甲醇二9 : 1); ^NMRteDCla+CDaOD):^ 7.30 (d, 1H), 7.15-7.07 (m, 4H), 6.64 (d, 1H), 6.50 (s, 2H), 4.40 (d, 1H), 4.27 (q, 2H), 4.18 (dd, 1H), 3.99 (dd, 1H), 3.82 (s, 6H), 3.70 (s, 2H), 3.02-2.92 (m, 2H), 2.52-2.32 (m, 3H), 2.19*2.08 (m, 1H), 2.06 (s, 3H), 1.481.29 (m, 5H)。 實施例75:乙酸[(28,33)-3-(4-乙醯基-3,5-二曱氧基苯. 基)-3-{[第三丁基(二曱基)矽烷基]氧基卜2 — (2, 3 一二氫籲 -1Η-節-2-基曱基)丙基]酯 於氬氣下,使(28,38)-3-{[第三丁基(二曱基)矽烧基] 氧基卜2-(2, 3-二氫—1Η-茚-2-基甲基)-3-(3, 5-二曱氧基 _ 苯基)丙醇(使用3-(2,3-二氫-1Η-茚-2-基)丙醯氣取代5— ^ 苯基戊醯氯,並使用3, 5一二曱氧基苯甲醛取代3,5一二曱氧 " 基-4-甲基苯曱醛,依實施例12—實施例13—實施例ι4— 實施例15相同之操作製成)(37〇g)之四氫呋喃(4〇1111)溶 液冷卻至〇°C,並滴八正丁基鋰(1· 58M己烷溶液, 15.4ml),一面使其升溫至室溫一面攪拌丨小時。再冷卻至 o°c後,加入溴化亞銅(2 32g)及乙醯氯(2 31ml),一面使 其升溫至室溫-面撥拌2小時。在該反應混合物中加入飽 和氣化銨水溶液,並經乙酸乙酯萃取。該萃取物再經飽和 食鹽水洗淨、無水硫酸鎂乾燥後濃縮,即可製成具有以下 物性值之標題化合物。 TLC · Rf 0· 55 (n—己;I:完:乙酸乙 g旨: 1); 316588 185 200521108 1 HNMR : 6 7.20-7.05 (m, 4H),6.49 (s, 2H),4·68 (d,1H),4.25:4.08 (m, 2H), 3.79 (s, 6H), 3.12-2.90 (in, 2H), 2.60-2.38 (m, 4H), 2.48 (s, 3H), 2.02 (s, 3H), 1·50 (m, 2H),0.90 (s, 9H), 0·04 (s, 3H), -0.15 (s,3H)。 實施例76 : l-{4-[(lS,2S)-卜{[第三丁基(二曱基)矽烷基] 氧基卜3-(2, 3-二氫-1H-茚-2-基)-2-(羥基曱基)丙基] -2, 6-二曱氧基苯基}乙酮 在實施例75中製成之化合物之曱醇(5Om 1)溶液中加 入碳酸鉀(4· 00g),該混合物再於50°C下攪拌15小時。反 應混合物中再加入水,並經乙酸乙酯萃取。其萃取物再經鲁 飽和食鹽水洗淨、無水硫酸鎂乾燥後濃縮。其殘留物再經 矽膠管柱層析(己烷:乙酸乙酯=6 : 1— 4 ·· 1— 2 : 1)精製, 即可製成具有以下物性值之標題化合物(1. 40g)。 丁LC ·· Rf 〇· 32 (己烧:乙酸乙酯=2 ·· 1); LHNMR : δ 7.20-7.05 (m, 4H), 6.52 (s, 2H), 4.77 (d, 1H), 3.84 (m, 1H), 3.80 (s, 6H), 3.58 (m, 1H3.15-2.95 (m, 2H), 2.83 (m, 1H), 2.68-2.42 (m, 3H), 2.49 (s, 3H),1.78 (m, 2H), 0.94 (s,9H), 0.10 (s,3H) -〇13 (s,3H)〇 實施例77 : 3-{卜[(2S,3S)-3-(4-乙醯基-3, 5-二曱氧基笨_ 基)-2-(2, 3-二氫-1Η-茚基甲基)一3一羥基丙基]一!η一吼 °各-3 -基丨丙酸 使用貫施例76中製成之化合物取代實施例15中製成 之化合物,依實施例16—實施例實施例34—實施例 36—實施例20—實施例19相同之操作,即可製成具有以 下物性值之標題化合物。 TLC: Rf 〇·45 (二氣曱烷:曱醇: η ; 316588 186 200521108 1 H NMR : 5 7.18-7.05 (m, 4H), 6.55 (dd, 1H), 6.50 (s, 2H), 6.47 (brs, 1H), 5.97 (dd, 1H), 4.49 (d, 1H), 4.08 (m, 1H), 3.94 (dd, 1H), 3.79^ (s, 6H), 3.04-2.92 (m, 2H), 2.77 (t, 2H), 2.56 (t, 2H), 2.55-2.35 (m, 3H), 2.46 (s, 3H), 2.12 (m, 1H), 1.40 (m, 2H)。 實施例 78 ·· 3-{1-[(2S,3S)-2-(2, 3-二氫-1H-茚-2-基曱基) - 3-經基-3-(4-異丙烯基—3, 5-二曱氧基苯基)-丙基]-1Η-吡咯~3-基}丙酸 於氬氣下,在實施例77中製成之化合物(350mg)之二 氣曱烷(3ml)溶液中加入溴化鋅(937mg),該混合物再於室 溫下授拌1小時。混合物再冷卻至〇它後加入甲基鋰 一乙醚溶液,1〇· 4ml),一面使其升溫至室溫一面攪拌3小 恰。在该反應混合物中加入2n鹽酸,並經乙酸乙酯萃取。 將该卒取物再經飽和食鹽水洗淨、無水硫酸鎂乾燥後濃 縮。其殘留物再經矽膠管柱層析(己烷:乙酸乙酯=2 :丨―丄: 1)精製,即可製成具有以下物性值之標題化合物(57_)。 TLC : Rf 〇. 42 (二氣曱烷:甲醇=9 : HNMR . ί 7.20-7.03 (m, 4H), 6.59 (m, 1H), 6.53 (s, 2H), 6.52 (m 1H) (m, 1H), 5.32 (brs, 1H), 4.85 (brs, 1H), 4.47 (d, 1H), 4.11 (m, 1H) 3 99 2 50-232(38° (S,6HX 310'2·90 2HX 279 (t> 2HX 258 2H), 2.50 2.32 (m> 3H), 2.18 (m> 1H), 1.99 (s, 3H), 1.42-1.38 (m, 2H)o [生物化學實施例] 可由匕合物對LPA受體(例如edg_2)具拮抗作用 Φ以下所示之實驗等証明。 h之知作,基本上為依據基因工程方法製作基因 316588 187 200521108 表現細胞加以活用之一般方法。如下所述,本發明之測定 方法為評估本發明之化合物,再提高其測定精度及/或改良 其測定靈敏度。以下所示為詳細之實驗方法。 EDG-2拮抗作用係藉由細胞内鈣離子濃度之變化來評 估: 以過剩表現人類EDG-2基因之中國倉鼠卵巢(Chinese
Hamster Ovary, CH0)細胞評估該受體拮抗劑活性。edG-2 表現細胞疋以含1 0%FBS(牛胎兒血清)、青黴素/鏈黴素、 保米黴素(5// g/ml)之Ham’s F12培養基(GIBCO BRL公司 製造,No· 1 1 765-047)培養。同時,為使細胞攝入Fura2 — AM (Dojindo 公司製造,No· 348-05831 ),將細胞在 371:下, 在 5" M Fura2-AM 溶液(含 l〇%FBS、20mM HEPES 緩衝液 (ρΗ7· 4)及 2· 5mM 羧苯磺二丙胺(probenecid,Sigma 公司 製造,No· P-8761 )之Ham’ sF12培養基)中培養60分鐘。其 次再以含20mM HEPES缓衝液(ΡΗ7·4)及2· 5mM羧苯磺二丙 胺Hanks液洗淨1次,並在分析前均同樣浸於Hanks液中。 將其置入螢光藥劑選別系統(濱松光學公司製造, FDSS-2000、FDSS-6000)之分析盤中,在30秒無刺激下測 定,再加入本發明化合物之溶液。5分鐘之後再加入lpA (最 終?辰度· 10 0nM)’以3秒間隔測定添加前後細胞内妈離子 濃度(激發波長為340nm及380nm,螢光波長為5〇〇nm)。將 本發明化合物溶於DMS0中成最終濃度lnM至1〇 a μ後加 入。LPA可使用卜油醯基(18 : 1)-LPA化物(Sigma公司製 造)或1-亞麻烯酿基(18 ·· 3)-LPA化物。卜亞麻烯醯基化物 316588 188 200521108 (18 ·· 3)-LPA可以使用以以下2種方法之任1種合成、精 製者。(1)由18 : 3-LPC(亞麻烯醯基化物(18 : 3)-溶血磷 脂膽鹼)(Sedary公司製造)經pld(磷脂酶D)合成之方法, 或以(2)由18 ·· 3-PC(亞麻烯醯基化物(18 : 3)_磷脂膽鹼) (Avanti P〇lar Lipids 公司製造)經 PLA2 合成 18 : 3-LPC, 之後再由PLD合成LPA之方法。EDG-2拮抗活性是以在添 加不含本發明化合物之DMS0之孔中之LPA(最終濃度: 1 OOnM)尖峰值當做控制組值,並與經化合物處理之細胞 在LPA添加前之值與在添加後之值之差(B)相比,再以以下 之數學式計算其抑制率(% )。 (A-B ) 抑制率(% ) = ----- X 1 0 〇
A ICso值係顯示50%抑制率之本發明化合物之濃度。 其結果本發明化合物在1〇/zM以下之濃度即顯示有抑 制作用。例如實施例20(2)化合物之ICw值為〇〇4〇βΜ。 在大鼠體内(in vivo)對尿道内壓之作用: 雄性 CD(SD)IGS 大鼠(日本 Charles River c〇.,使用 8 至^週齡)以胺基甲酸酯(1. 2g/kg)皮下投藥麻醉。再自其 ^ 4正中切開後’插人化合物投藥用頸動脈導管、血磨測 L用動脈導管。其次再自其下腹部正_切開,自其和骨下 ,紮尿這。再自切開之膀胱頂部將尿道内壓測定用尿道導 管插入尿道内後’結紮固定膀胱頸部。尿道導管、動脈導 316588 】89 200521108 力傳感器後測定各尿道内厂堅、血壓。其次再調 ,迢内壓為2〇_g左右並靜止維持至其安定(約2〇分 ,)。之後再由導管自靜脈内投予試驗化合物,在測定血 堅尿運内壓20分鐘後,再自靜脈内投予—戍巴比妥系 麻醉劑,求其尿道内壓之死後基線。即待尿道内壓降至底 亚保持安定,該點即為其死後基線值。 試驗化合物以各投予量投予。其呈色劑(vehicie)為
Mey Ion ·生理食鹽水=1 : 3溶液。為了證明在活體内試驗
a物之有效H ’將技與化合物後大鼠尿道内壓之變化盘 投與f劑者比較。試驗化合物對尿道内壓作用之評估,是 由才又市後每經2分鐘之測定值減去投藥前之尿道内壓值來 计並將卩返日才間之變化(對基線之展道内壓下降量)作成 圖0 由結果可知,溶劑投與群於投藥後,尿道之内壓幾乎 無交化,而本發明化合物投與群,尿道内壓則明顯下降。 例如声、施例20(2)化合物之〇.1呢/|^至1呢/|^投與群之 尿道内壓明顯下降,其之最大下降量達尿道内壓絕對值(投 樂前尿道内壓-死後基線值)之約3〇至40%,效果甚強。 生物利用性(81〇8¥311313]^1七7,]^)之測定: 本發明化合物投與至SD大鼠(8週鋅程度)後,定時由 頸靜脈採血並測定血漿中本發明化合物之濃度,由其變化 計算本化合物經口投藥後之生物利用性。BA以(經口投藥 時之AUC/靜脈内投藥時之AUCx 100)(%)表示,AUC以血中 濃度-時間曲線下面積(ng · hr/ml)表示。 190 316588 200521108 式⑴所表示之本發明化合物作為^ 以下所示之各種試驗系、生物學實施例 :以 等經適當改良後可實施之方法^載之方法及此 化合物在動態學方面,例如血中半"^表不之本發明 ^ ., L 千衣期、在消化管内之安 ,:經口吸收性、生物利隸等點均優良,此可由例如 =之生物湘性(評估及改善之科學)」(現代醫療社, 1998年7月6日發行)中所載之方法等容易地評估。 製劑例1 : —將U-K2S)-2-[(S)-經基(3,4,5_三甲氧基苯基)甲基]0 ^5-苯基戊基丨苯基)乙酸(實施例2〇(2)化合物,5〇. k)、 鲮甲基纖維素鈣(2g)、硬脂酸鎂(lg)及微精纖維素(47g) 依一般之方法混合後打錠,即可製成1〇⑽顆錠劑,其一錠 中含活性成份5Omg。 製劑例2 將(4-{(2S)- 2-[(S)-羥基(3, 4, 5-三甲氧基苯基)甲基] —5-苯基戊基}苯基)乙酸(實施例2q(2)化合物,2〇g)、甘 路糖醇(2〇〇g)、蒸餾水(丨qL)依一般之方法混合後再經除塵 濾膜過濾,再各以5m 1裝於注射瓶中,經高壓爸加熱滅菌, 再依一般方法冷凍乾燥,即可製成1 000瓶注射劑,其一瓶 中含活性成份2 〇 m g。 式(I)所表示之本發明化合物及其鹽、及其藥物前體可 與LPA受體(特別是EDG—2)拮抗,因此可作為預防及/或治 療各種疾病之藥品。 191 316588
Claims (1)
- 200521108 、申請專利範圍·· 種式(I )所示之^卜人 甘^ & ,^。物、其之鹽、彼等之溶劑合物 或彼荨之樂物前體·· ΟΗ(i) |式中& A及裱β各自獨立’表示可有取代基之環基; 之=各,立,表示結合鍵或主鏈為原子數1至8 美.及環£各自獨立,表示可有取代基之環 ;:叮“鍵或主鏈為原子數1至3個之間隔基;z 、不可經保護之酸性基;t表示整數〇或i卜 .Π:::利範圍第1項之化合物’其中,式⑴所示之 口物為具光學活性之如式(I_A)所示之化合物:Μ-Ζ [式中之〆^為y5 -配位,其他記號表 OH 0·Α) 示與申請專利範圍 第1項中所記載者相同之意義]。 3 ·如申凊專利範圍第1項之化合物, 代基之苯環者。 4 ^為可有取 4‘如申請專利範圍帛)項之化合物’其中,κ為可經取代 316588 192 200521108 之Cl -4稀基者。 5·如申請專利範圍第 代基之茚滿環者。 項之化合物,其中 環Β為可有取 6. 如申請專利範圍第1項之化合物,其中,Q為可經取代 之伸甲基或可經取代之伸乙基者。 7. 如申請專利範圍帛1項之化合物,其中,環D為可有取 代基之苯環、可有取代基之吡唑環或可有取代基之吡咯 環者。 8.如申請專利範圍第!項中之化合物,其中,2為吒〇诎 _C〇NHS〇2Rl基(Rl基表示可經取代之脂族烴基或可有取 代基之環基)或四唆基者。 9·如申請專利範圍第1項之化合物,其中,M—為可經取代之伸曱基、可經取代之 伸乙基、可經取代之伸丙基或可經取代之伸乙烯基者。 10 ·如申凊專利範圍第1項之化合物,其中,環A為可有取 代基之苯環;環B為可有取代基之茚滿環;環D為可有 取代基之苯環、可有取代基之吡唑環或可有取代基之吡M—為可經取代之伸曱基、可經 取代之伸乙基、可經取代之伸丙基或可經取代之仰乙烯 基;Z為-C00H、-CONHSOA1基(R1表示可取代之脂族烴 193 316588 200521108 基或可有取代基之環基)或四唾基者。 11·如申請專利範圍第1項之化合物,係選自(1)U-[(2S, 3S)-2-(2, 3-二氫-1H-茚-2-基甲基)一3一(3, 5 —二甲氧基 - 4-甲基苯基)一3-羥基丙基]—1H—吡咯—3-基丨乙酸、(2) (卜{(2S)-2-[(S)-(3, 5-二甲氧基一4-甲基苯基)(羥基) 甲基]-5-ti蕃吩-3-基戊基咯—3-基)乙酸、(3) {1一 [(2S,3S)-2-(1,3-苯并二氧雜環戊烯一2一基甲基)一3一 (3, 5-二甲氧基-4-甲基苯基)一3一羥基丙基]qη一吼咯 - 3-基}乙酸、(4){1 - [(2S,3S)-2 -(2,3-二氫-1}1-茚-2- 基甲基)-3-羥基-3-(3, 4, 5-三f氧基笨基)丙基]—1H一 吡咯-3-基}乙酸、(5){1-[(23,33)-3-(4-乙醯基-3,5- 二甲氧基苯基)-2-(2, 3-二氫-1Η-茚-2-基甲基)-3-羥 基丙基]- 1Η-吼咯-3-基}乙酸、(6){1 - [(2S,3S)-2 -(2, 3-二氫-1H-茚-2-基甲基)-3-(4-乙基-3, 5-二曱氧 基苯基)- 3-羥基丙基]-1H-吼咯-3-基}乙酸、(7)3 - {1 - [(2S,3S )-2-(2, 3-二氫-1H-萌-2-基曱基)-3-(3, 5-二 甲氧基-4-曱基苯基)-3-羥基丙基]-1Η-吼咯-3-基}丙 酸、(8)3-{1-[(2S,3S)-2-(2, 3-二氫-1Η-茚-2-基曱基) - 3-羥基-3-(3, 4, 5-三曱氧基苯基)丙基]-1 η-吡咯-3-基}丙酸、(9)3-{1-[(2S,3S)-3-(4-乙醯基-3, 5-二曱氧 基本基)-2 -(2,3 - 一氮-1H -印-2-基曱基)-3-經基丙基] -111-吡咯-3-基}丙酸、(1〇)3-{1-[(23,33)-2-(2,3-二 氫-1H-茚-2-基曱基)-3-(4-乙基-3, 5-二曱氧基苯基) -3-羥基丙基]- 1H - □比咯-3-基}丙酸、(11)2 - {1- 194 316588 200521108 [(2S,3S)-2-(2, 3-二氫-n2_基甲基)_3_(3, 5_二 f氧基―4一甲基苯基)-3-經基丙基]各-3_基}_N_ (甲基續醯基)乙醯胺、(12)[卜[(2S,3S)-2-(2,3-二氫 鲁萌-2-基甲基)_3_(3, 5_二甲氧基_4—甲基苯基 I基丙基]4 (甲氧基羰基)吡咯_3一基]乙酸、(η) N-(3-{l-[C2S, 38)-2-(2,3-^^-^-^-2-^^^)-3- (3, 5-二甲氧基-4一甲基苯基)_3_羥基丙基]_ih_吡咯 -3-基}丙醯基)—2一甲基苯磺醯胺、(14)(2e)_3_丨卜 [(2S,3S)-2-(2, 3-二氫-1H-萌-2-基甲基)_3_(3, 5_二 甲氧基-4-甲基笨基)'3_經基丙基]_1H一吼略_3_基}丙 稀酸、(15)2-{l-[(2s,3s)_2_(2,3_m2_基甲 基)-3-(3,5-二甲氧基_4_?基苯基)_3_羥基丙基]_111— 吡咯-3-基}-2-甲基丙酸、及(16)(2趵_3_{1_[(23,35) _2 —(2’ 3_二氫一1H一茚-2-基甲基)-3-(3, 5-二曱氧基_4_ 曱基苯基)-3-羥基丙基]-1H_吡咯_3_基卜2_甲基丙烯 酸所成組群中者。 12· —種醫藥組成物,包含申請專利範圍第丨項之如式Q) 斤示之化a物、其之鹽或彼等之溶劑合物或彼等之藥物 前體者。 η 1 3 j申,專利範圍第1 2項之醫藥組成物,其中,該醫藥 組成物係LPA受體拮抗劑。 14.如申叫專利範圍第13項之醫藥組成物,其中,Lpa受 體為EDG-2。 1 5· 士申明專利範圍第12項之醫藥組成物,其中,該醫藥 316588 195 200521108 蛆成物係泌尿乐為官疾病、癌症相關疾病、增殖性疾 病、炎症•免疫系統疾病、分泌失調導致之疾病、腦關 聯疾病或慢性疾病之預防及/或治療劑。 16· —種預防及/或治療哺乳動物之由E])G_2媒介之疾病之 方法,其特徵為將有效量之申請專利範圍第丨項之化合 物、其之鹽或彼等之溶劑合物或彼等之藥物前體投與至 哺乳動物者。 ㈣彼等之溶劑合物或彼等之藥物前體之用途,係用於 製造由EDG-2媒介之疾病之預防及/或治療華劑。、 18. 一一17. —種申請專利範圍第丨項之式(1)所示之化合物、其之 3巧Λ 1)所示之 之藥物前體與, α 1封阻劑、抗膽鹼劑、 :劑之藥劑所組合而成 316588 196 200521108 七、指定代表圖:無 (一) 本案指定代表圖為:第()圖。 (二) 本代表圖之元件符號簡單說明: 八、本案若有化學式時,請揭示最能顯示發明特徵的化學式:5 316588
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JPWO2004002530A1 (ja) * | 2002-06-26 | 2005-10-27 | 小野薬品工業株式会社 | 慢性疾患治療剤 |
AU2003241836A1 (en) * | 2002-10-03 | 2004-04-23 | Ono Pharmaceutical Co., Ltd. | Lpa receptor antagonists |
EP1695955B1 (en) | 2003-12-19 | 2011-10-12 | Ono Pharmaceutical Co., Ltd. | Compounds having lysophosphatidic acid receptor antagonism and uses thereof |
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CA2733671C (en) | 2008-08-27 | 2018-01-02 | Arena Pharmaceuticals, Inc. | Substituted tricyclic acid derivatives as s1p1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders |
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WO2011037192A1 (ja) | 2009-09-25 | 2011-03-31 | アステラス製薬株式会社 | 置換アミド化合物 |
GB2474748B (en) | 2009-10-01 | 2011-10-12 | Amira Pharmaceuticals Inc | Polycyclic compounds as lysophosphatidic acid receptor antagonists |
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EP4148045A1 (en) | 2010-01-27 | 2023-03-15 | Arena Pharmaceuticals, Inc. | Intermediate compounds for the preparation of (r)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b] indol-3-yl)acetic acid and salts thereof |
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JP5776695B2 (ja) * | 2010-09-24 | 2015-09-09 | アステラス製薬株式会社 | 置換アミド化合物 |
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