TWI292752B - Retroviral protease inhibiting compounds - Google Patents

Retroviral protease inhibiting compounds Download PDF

Info

Publication number
TWI292752B
TWI292752B TW94141039A TW94141039A TWI292752B TW I292752 B TWI292752 B TW I292752B TW 94141039 A TW94141039 A TW 94141039A TW 94141039 A TW94141039 A TW 94141039A TW I292752 B TWI292752 B TW I292752B
Authority
TW
Taiwan
Prior art keywords
compound
amino
solution
group
acid
Prior art date
Application number
TW94141039A
Other languages
Chinese (zh)
Other versions
TW200611691A (en
Inventor
L Sham Hing
W Norbeck Daniel
Xiaoqi Chen
A Betebenner David
J Kempf Dale
R Herrin Thomas
N Kumar Gondi
L Condon Stephen
J Cooper Arthur
A Dickman Daniel
M Hannick Steven
Kolaczkowski Lawrence
A Oliver Patricia
J Plata Daniel
J Stengel Peter
J Stoner Eric
J Tien Jieh-Hen
Liu Jih-Hua
M Patel Ketan
Original Assignee
Abbott Lab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=25029611&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TWI292752(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US08/753,201 external-priority patent/US5914332A/en
Application filed by Abbott Lab filed Critical Abbott Lab
Publication of TW200611691A publication Critical patent/TW200611691A/en
Application granted granted Critical
Publication of TWI292752B publication Critical patent/TWI292752B/en

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

1292752 九、發明說明: 這是1995年12月13日建檔之美國專利申請案第 08/572,226號的部份接續申請案。 【發明所屬之技術領域】 本發明係關於抑制反轉錄病毒蛋白酶的新穎化合物和組 合物,以及方法,特別是抑制人類免疫不全病毒(HIV)蛋白 酶,一種抑制反轉錄病毒感染的組合物和方法,特別是HIV 感染,製造該化合物以及在該方法中所使用之合成中間物 的方法。 【先前技術】 反轉錄病毒是那些在其生活史中,利用核糖核酸(RNA) 中間物和RNA-依賴性之脫氧核糖核酸(DNA)聚合酶,反轉 錄酶的病毒。反轉錄病毒包括但不限於反轉錄病毒科的 RNA病毒,以及肝DNA病毒屬(Hepadnavirus)和花椰菜花葉 病毒(Caulimovirus)科的DNA病毒。反轉錄病毒在人類、動 物和植物引起各種的疾病狀態。從病理學觀點來看一些較 重要的反轉錄病毒,包括人類免疫不全病毒(HIV-1和 HIV-2),它們在人類引起後天免疫不全徵候群,人類T-細 胞親淋巴性病毒I、II、IV和V,它們引起人類的急性細胞 白血病,以及牛和貓的白血病病毒,它們引起家畜的白血 病。 蛋白酶是在特定肽鍵之處切開蛋白質的酵素。許多生物 學的功能藉著蛋白酶及其互補蛋白酶抑制劑來控制或調 節。例如,蛋白酶腎浩素切開肽血管收縮素原,產生肽血1292752 IX. INSTRUCTIONS: This is part of the continuation application of US Patent Application No. 08/572,226, filed on December 13, 1995. TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds and compositions for inhibiting retroviral proteases, and methods, and in particular, to human immunodeficiency virus (HIV) proteases, a composition and method for inhibiting retroviral infection, In particular, HIV infection, a method of producing the compound and a synthetic intermediate used in the method. [Prior Art] Retroviruses are viruses that reverse the enzymatic activity in their life history using ribonucleic acid (RNA) intermediates and RNA-dependent deoxyribonucleic acid (DNA) polymerases. Retroviruses include, but are not limited to, RNA viruses of the retroviridae family, as well as DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause various disease states in humans, animals and plants. From a pathological point of view, some of the more important retroviruses, including human immunodeficiency virus (HIV-1 and HIV-2), cause acquired immunodeficiency syndrome in humans, human T-cell lymphotropic virus I, II , IV and V, which cause acute cellular leukemia in humans, as well as leukemia viruses in cattle and cats, which cause leukemia in livestock. A protease is an enzyme that cleaves a protein at a specific peptide bond. Many biological functions are controlled or regulated by proteases and their complementary protease inhibitors. For example, the protease lycopene cuts the peptide angiotensinogen to produce peptide blood.

O:\106\106749.DOC 1292752 =素p血管收縮素1再進-步被蛋白酶血管收縮素轉變 酵素(ACE)切開,形成低血壓肽血管收縮素η。已知腎、^ :抑制劑和ACE可在活艘内降低高血壓。反轉錄病毒:蛋 疾病的治療 白輙的抑制劑,將可提供由反轉錄病毒引起之 劑。 編碼蛋白酶之反轉錄病毒的基因組,是引起一或多個諸 如Μ和職基因產物之類多蛋白前驅物之蛋白水解加工的 原因。參見WeUink,反轉錄病毒 蛋白酶最常將gag前驅物加工成核蛋白,亦將碰前驅物加 工成反轉錄酶和反轉錄病毒蛋白酶。此外,反轉錄病毒蛋 白酶疋具有序列專一性的。參見Pearl,胸⑽迦482 (1987)。 ~~' 對於感染性病毒粒子的集合而言,由反轉錄病毒之蛋白 酉母正確地加工前驅物多蛋白是必須的。已經顯示,在活體 外的大麦生成產生蛋白酶_不全的病毒,導致缺乏感染性之 不成熟核心形式的產生。參見Crawford, J. Virol. 51 899 (1985) ; Katoh等人,virology 145 280 (1985)。因此反轉錄 病毒之蛋白酶抑制作用,對於抗病毒之治療提供了誘人的 目標。參見 Mitsuya,Nature 325 775 (1987)。 目如關於病毒性疾疾之治療,通常涉及投予抑制病毒 DNA合成的化合物。目前對於AIDS之治療則涉及投予諸如 3’_疊氮基脫氧胸腺核苷(AZT)、2,,3,-二脫氧胞嘧啶核苷 (DDC)、2丨,3、二脫氧肌苷(dDI)、d4T和3TC之類的化合物, 以及治療因為HIV感染導致之免疫抑制所引起之投機性感O:\106\106749.DOC 1292752 = Prime p vasopressin 1 is further stepped by the protease vasoconstrictor enzyme (ACE) to form a hypotensive peptide vasoconstrictor η. Kidneys, inhibitors, and ACE are known to reduce high blood pressure in living vessels. Retrovirus: Treatment of Egg Diseases Inhibitors of sputum will provide antiretroviral agents. The genome of a retrovirus that encodes a protease is responsible for proteolytic processing of one or more polyprotein precursors such as Μ and gene products. See WeUink, retroviral proteases most often process gag precursors into nuclear proteins, and also process precursors into reverse transcriptase and retroviral proteases. In addition, retroviral proteases are sequence specific. See Pearl, Chest (10) Ga. 482 (1987). ~~' For the collection of infectious virions, it is necessary to correctly process the precursor polyprotein by the retroviral protein aphid. It has been shown that barley production outside the living body produces a protease-incomplete virus that results in the production of an immature core form that lacks infectivity. See Crawford, J. Virol. 51 899 (1985); Katoh et al., Virology 145 280 (1985). Therefore, the protease inhibition of retroviruses provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987). For the treatment of viral diseases, it is usually involved in administering a compound that inhibits viral DNA synthesis. Current treatments for AIDS involve the administration of, for example, 3'-azido-deoxythymidine (AZT), 2,3,-dideoxycytidine (DDC), 2,3,dideoxyinosine ( Compounds such as dDI), d4T and 3TC, and the speculative sex caused by immunosuppression caused by HIV infection

O:\106\106749.DOC 1292752 染的化合物。在治療及/或逆轉該疾病上,目前的aids療法 中沒有一個已被證實是完全有效的。此外,在目前用來治 療AIDS的化合物中,許多會引起不利的副作用,包括低血 小板計數、腎毒性和骨髓血細胞減少症。 最近,在美國已經核准用HIV蛋白酶抑制劑律特納菲 (ritonavir)、沙奎納菲(saquinavir)和印地納菲(丨“比…⑺來 治療HIV的感染。然而,對於改善HIV蛋白酶抑制劑有持續 的需要。 【發明内容】 根據本發明,有一種式I化合物:O:\106\106749.DOC 1292752 Dyed compound. None of the current aids therapy has proven to be fully effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects, including low plate count, nephrotoxicity, and bone marrow cytopenia. Recently, HIV protease inhibitors ritonavir, saquinavir, and indinavir have been approved in the United States for the treatment of HIV infection. However, to improve HIV protease inhibition There is a continuing need for the agent. SUMMARY OF THE INVENTION According to the present invention, there is a compound of formula I:

其中1和112分別選自包括低碳數烷基、環烷基烷基和芳 烷基; • r3為低碳數烷基、羥烷基或環烷基烷基; r4為芳基或雜環; R5為Wherein 1 and 112 are respectively selected from the group consisting of a lower alkyl group, a cycloalkylalkyl group and an aralkyl group; • r3 is a lower alkyl group, a hydroxyalkyl group or a cycloalkylalkyl group; and r4 is an aryl group or a heterocyclic group. ; R5 is

O:\106\106749.DOC 1292752O:\106\106749.DOC 1292752

C)C)

O:\106\106749.DOC -10- 1292752 ΟO:\106\106749.DOC -10- 1292752 Ο

其中η為1、2或3, m為1、2或3, m’為1或2, X為〇、s或ΝΗ, Υ為-CH2- ' -Ο-、-S-或-N(R6)- ’其中R6為氫、低碳數烧基、 環烧基、環烧基烧基、芳基或芳烧基,Y’,為_CH2-或 -N(R6”)-,其中RV’為氫、低碳數烷基、環烷基、環烷基烷 基、芳基或芳烷基,Y’為-N(R6>,其中r6,為氫、低碳數烷 基、環烷基、環烷基烷基、芳基或芳烷基,且Z為〇、S或 NH ; 且 a) -0-, b) · S - ’ c) -N(R7)-,其中R7為氫、低碳數烷基、環烷基或環烷基 烷基, d) -0-伸烷基-, e) -S -伸烧基- f) -S(0)-伸烷基 _, O:\106\106749.DOC 11 1292752 g) -s(o)2-伸烷基-, h) -N(R7)-伸烷基-,其中R7如同上文之定義, i) -伸烧基- Ο- ’ j) -伸烧基- S-’ k) 伸烷基-N(R7)-,其中R7如同上文之定義, l) 伸烷基,或 m) 伸烯基; 或其在藥學上可接受之鹽、酯或藥物前驅物。 • 較佳的化合物是其中I和R2為芳烷基,R3為低碳數烷Where η is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is 〇, s or ΝΗ, Υ is -CH2- ' -Ο-, -S- or -N(R6 )- 'wherein R6 is hydrogen, lower carbon number, cycloalkyl, cycloalkyl, aryl or aryl, Y', is _CH2- or -N(R6")-, where RV' Is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y' is -N(R6>, wherein r6 is hydrogen, lower alkyl, cycloalkyl a cycloalkylalkyl group, an aryl group or an aralkyl group, and Z is hydrazine, S or NH; and a) -0-, b) · S - ' c) -N(R7)-, wherein R7 is hydrogen, Lower alkyl, cycloalkyl or cycloalkylalkyl, d) -0-alkylene-, e) -S -alkylene-f) -S(0)-alkylene_, O: \106\106749.DOC 11 1292752 g) -s(o)2-alkyl-, h)-N(R7)-alkylene-, wherein R7 is as defined above, i) - extendable group - Ο- ' j) - an extended alkyl group - S-' k) alkyl-N(R7)-, wherein R7 is as defined above, l) an alkyl group, or m) an alkenyl group; or Acceptable salts, esters or drug precursors. • Preferred compounds are those wherein I and R2 are aralkyl and R3 is a lower alkane.

基,R4為芳基,R5為 XBase, R4 is aryl, R5 is X

、.^N 一' (〇Η2)η^, .^N a ' (〇Η2) η^

b)b)

XX

O:\106\106749.DOC -12- 1292752O:\106\106749.DOC -12- 1292752

R6·. e) 其中X、Y、Y,、Y”、z、R6”、n、㈤和m,如同上文之定義, 且Li為-伸烧基的式i化合物。 更佳的化合物是其中心和化2為苄基,或1為芊基且仏2為 低碳數烷基,R3為低碳數烷基,汉4為勾以兩個低碳數烷基 來取代的苯基’並可視需要以第三個選自包括低碳數烧 基、羥基、胺基和_素之取代基來取代之,或是b)以兩個 低碳數烧基來取代的说σ定基或u密咬基,並可視需要以第三 個選自包括低碳數烷基、羥基、胺基和_素之取代基來取 代之,R5為R6.. e) wherein X, Y, Y, Y", z, R6", n, (5) and m, as defined above, and Li is a - extendable compound of formula i. More preferred compounds are those in which the center 2 is a benzyl group, or 1 is a fluorenyl group and 仏 2 is a lower alkyl group, R 3 is a lower alkyl group, and Han 4 is a two lower alkyl group. Substituted phenyl' may be substituted with a third substituent selected from the group consisting of a lower carbon group, a hydroxyl group, an amine group and a _ element, or b) substituted with two lower carbon number groups. Said sigma base or u-density base, and may be substituted with a third substituent selected from the group consisting of a lower alkyl group, a hydroxyl group, an amine group and a _ element, R5 is

a) 其中η為1或2,X為Ο或S,且Y為-CH2或-NH-,a) where η is 1 or 2, X is Ο or S, and Y is -CH2 or -NH-,

Z b) O:\106\106749.DOC -13- 1292752Z b) O:\106\106749.DOC -13- 1292752

其中m為1或2,X為Ο,Y為-CH2-且Z為Ο, X \人 L λζWhere m is 1 or 2, X is Ο, Y is -CH2- and Z is Ο, X \人 L λζ

C) id· Z 其中m’為1,X為0,Z為〇且γ為,C) id· Z where m' is 1, X is 0, Z is 〇 and γ is

(ch2w 其中m’為1 ’ X為Ο ’ Y"為·ΝΗ-且丫,為_NH_,或(ch2w where m' is 1 ′ X is Ο ’ Y" is ΝΗ- and 丫, _NH_, or

XX

其中X為Ο且R6n為氫 且 再更佳的化合物是其中尺㈣為亨基,或Ri為爷基且〜 為異丙基,R3為低碳數烷基,^為 2,6-二甲基苯基’其可視需要以第三個選自包括低碳數烷 基和鹵素的取代基所取代,汉5為 a)Wherein X is hydrazine and R6n is hydrogen and a more preferred compound is wherein the ruthenium (4) is a Henyl group, or Ri is a aryl group and ~ is an isopropyl group, R3 is a lower alkyl group, and ^ is a 2,6-dimethyl group. The phenyl group can be optionally substituted with a third substituent selected from the group consisting of a lower alkyl group and a halogen, and Han 5 is a)

O:\106\106749.DOC 14- 1292752 其中η為1或2,X為Ο或S,且丫為_CH2或-NH-,O:\106\106749.DOC 14- 1292752 where η is 1 or 2, X is Ο or S, and 丫 is _CH2 or -NH-,

其中m’為1,X為0,Z為0且Y為-NH-, \入" d) (CH2)m.Where m' is 1, X is 0, Z is 0 and Y is -NH-, \入" d) (CH2)m.

其中 m’為 1,X為 Ο,Y,’為-NH_X Y,為-NH-,或 XWhere m' is 1, X is Ο, Y, ' is -NH_X Y, is -NH-, or X

^hT^N-Re- e) 其中X為0且R6n為氫 且 1^為-〇-CH2-的式I化合物。 最佳的化合物是其中心和化2為芊基,或1為芊基且112為 異丙基,R3為低碳數烧基,R4為2,6 -二甲基苯基,其可視需 要以第三個選自包括低碳數院基和鹵素的取代基所取代, O:\106\106749.DOC - 15- 1292752 R5為^hT^N-Re-e) A compound of formula I wherein X is 0 and R6n is hydrogen and 1^ is -〇-CH2-. The most preferred compound is its center and 2 is a fluorenyl group, or 1 is a fluorenyl group and 112 is an isopropyl group, R3 is a low carbon number alkyl group, and R4 is a 2,6-dimethylphenyl group, which may optionally be The third is selected from a substituent including a low carbon number and a halogen, O:\106\106749.DOC - 15- 1292752 R5 is

X (CH2)n^ a) 其中n為1或2,X為0或S,且Y為-CH2或-NH-,X (CH2)n^ a) wherein n is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

其中m*為1,X為Ο,Z為Ο且Y為-NH-, \人"Where m* is 1, X is Ο, Z is Ο and Y is -NH-, \人"

〇 (CHzW 其中m1為1,X為〇,γ”為-NH-且Y,為-NH-,或〇 (CHzW where m1 is 1, X is 〇, γ" is -NH- and Y is -NH-, or

XX

d) 其中X為Ο且R6”為氫 且 L!為-O-CH2-的式I化合物。 最為優異的化合物是其中1^和112為苄基,或心為苄基且 R2為異丙基’ R3為低碳數烧基,以為2,6-二甲基苯基,其可 視需要以第三個選自包括低碳數烧基和函素的取代基所取 O:\106\106749.DOC -16- 1292752 代,r5為 xd) a compound of the formula I wherein X is hydrazine and R6" is hydrogen and L! is -O-CH2-. The most excellent compounds are those in which 1 and 112 are benzyl, or the heart is benzyl and R2 is isopropyl. 'R3 is a low carbon number alkyl group, which is 2,6-dimethylphenyl group, which may be taken as a third substituent selected from the group consisting of a low carbon number group and a functional element. O: \106\106749. DOC -16-1292752 generation, r5 is x

(CH2)nV 其中η為1或2,X為Ο或S,且Y為-CH2或-NH-, 且 1^為-0-CH2-的式I化合物。 極佳和最佳之式I化合物的實例,係選自包括: (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-[2S-(l-四氫-嘧啶-2-酮基)-3-甲基丁醯基]胺基-1,6-二苯 基己烷; (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(l-咪唑啶-2-酮基)-3,3-二甲基丁醯基)胺基-1,6-二 苯基己烷; (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(卜咪唑啶-2-亞硫醯基)-3 -甲基丁醯基)胺基-1,6-二 苯基己烷; (2S,3S,5S)-2-(2,4,6-三甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(l-咪唑啶-2-酮基)-3-甲基丁醯基)胺基-1,6-二苯基 己烧; (28,38,5 8)-2-(4-氟-2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(卜咪唑啶-2-酮基)-3-甲基丁醯基)胺基-1,6-二苯基 己烧; O:\106\106749.DOC -17- 1292752 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(l-吡咯啶-2-酮基)-3-曱基丁醯基)胺基-1,6-二苯基 己烷; (2S,3S,5S)-2-(2,6-二曱基苯氧乙醯基)胺基-3-羥基 •5-(2S-(l-吡咯啶-2,5-二酮基)-3-曱基丁醯基)胺基-1,6-二 苯基己烷; (28,38,58)-2-(反-3-(2,6-二曱基苯基)丙烯醯基)胺基-3-羥基-5-(2S-(l-四氫嘧啶-2-酮基)-3-曱基丁醯基)胺基-1,6-二苯基己烷; (28,3 8,5 8)-2-(3-(2,6-二甲基苯基)丙醯基)胺基-3-羥基 -5-(2S-(l-四氫嘧啶-2-酮基)-3-甲基丁醯基)胺基-1,6-二苯 基己烷; (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(l-四氫嘧啶-2,4-二酮基)-3 -甲基丁醯基)胺基-1,6-二苯基己烷; (2S,3S,5S)-2-(2,6_二曱基苯氧乙醯基)胺基-3-羥基 -5-(2S-(4-氮雜-1-四氫嘧啶-2-酮基)-3 -甲基丁醯基)胺基 -1,6-二苯基己烷; (2S,3S,5S)-2-(2,6-二曱基苯氧乙醯基)胺基-3-羥基 -5-(2S-(1-四氫嘧啶-2-酮基)-3-甲基丁醯基)胺基-1-苯基-6-甲基庚烷; · (2S,3S,5S)-2-(2,6-二曱基苯氧乙醯基)胺基-3-羥基 -5-(2S-(l-四氫嘧啶-2,4-二酮基)-3 -曱基丁醯基)胺基-1-苯 基-6-曱基庚烷;以及 O:\106\106749.DOC -18- 1292752 (2S,3S,5S)-2-(2,6-二曱基苯氧乙醯基)胺基i輕義 -5-(2S-(4-氮雜-4,5-脫氫-1·嘧啶-2_酮基)_弘曱基丁醯基 基-1,6-二苯基己烷; 或其在藥學上可接受的鹽、酯或藥物前驅物。 極優異之式I化合物為(2S,3S,5S)_2_(2,6_:曱基苯氣乙醯 基)胺基-3-羥基-5_[2S_(1-四氫嘧啶_2•酮基)_3_甲基丁醯基 胺基-1,6-二苯基己炫;或其藥學上可接受之鹽、酉旨或藥] 前驅物。 ^ 在某些狀況下,最好是能夠製備非晶形固體狀之 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基_3、輕義 -5-[2S-(l-四氫嘧啶_2_酮基)_3_甲基丁醯基]胺基-丨,6、二^ 基己烷(或其藥學上可接受之鹽、酯或藥物前驅物)。這類= 非晶形固體,可藉著將(2S,3S,5S)-2-(2,6_:甲基苯氣乙醯 基)胺基-3-羥基-5-[2S-(l-四氫嘧啶-2-酮基)-3·曱基丁醯義] 胺基-1,6-二苯基己烷溶解於有機溶劑(例如乙醇、異丙醇 丙酮、乙腈及其類似物)中,然後再將該溶液加至水中來^掣 備之。較佳的是將(2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺 基-3-羥基-5-[2S-(l-四氫嘧啶-2-酮基)-3-甲基丁醯基]鞍義 _1,6-二苯基己烷溶解於乙醇中(從約2到約4毫升/克),並將 該乙醇系溶液加入水中(從約1〇到約1〇〇毫升/克)並加以攪 拌,以提供非晶形之(2S,3S,5S)_2-(2,6_二甲基苯氧乙醯基) 胺基-3-羥基_5-[28_(1_四氫嘧啶_2_酮基甲基丁醯基]胺 基*—苯基己烧。 本發明的其他具體實施例包括mv蛋白酶抑制化合物,(CH2)nV A compound of formula I wherein n is 1 or 2, X is hydrazine or S, and Y is -CH2 or -NH-, and 1^ is -0-CH2-. Examples of excellent and optimal compounds of formula I are selected from the group consisting of: (2S, 3S, 5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5- [2S-(l-tetrahydro-pyrimidin-2-one)-3-methylbutanyl]amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6 -Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)-3,3-dimethylbutanyl)amino-1,6- Diphenyl hexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(imidazolidin-2-ene) (2,3,5,6-diphenylhexane; (2S,3S,5S)-2-(2,4,6-trimethylphenoxyethyl) Amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutanyl)amino-1,6-diphenylhexan; (28,38,5 8 )-2-(4-fluoro-2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(i-imidazolidin-2-one)-3-methylbutanyl Amino-1,6-diphenylhexanone; O:\106\106749.DOC -17- 1292752 (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl) Amino-3-hydroxy-5-(2S-(l-pyrrolidin-2-one)-3-indolylbutenyl)amino-1,6-diphenyl Hexane; (2S,3S,5S)-2-(2,6-diamidinophenoxyethyl)amino-3-hydroxy•5-(2S-(l-pyrrolidine-2,5-di Keto)-3-mercaptobutyl)amino-1,6-diphenylhexane; (28,38,58)-2-(trans-3-(2,6-dimercaptophenyl)propene Mercapto)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one)-3-mercaptobutyryl)amino-1,6-diphenylhexane; (28, 3 8,5 8)-2-(3-(2,6-Dimethylphenyl)propanyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one) (-3-methylbutanyl)amino-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3- Hydroxy-5-(2S-(l-tetrahydropyrimidin-2,4-dione)-3-methylbutanyl)amino-1,6-diphenylhexane; (2S,3S,5S)- 2-(2,6-dimercaptophenoxyethyl)amino-3-hydroxy-5-(2S-(4-aza-1-tetrahydropyrimidin-2-one)-3-methyl (2S,3S,5S)-2-(2,6-diamidinophenoxy)amino-3-hydroxy-5-(2S -(1-tetrahydropyrimidin-2-one)-3-methylbutanyl)amino-1-phenyl-6-methylheptane; (2S,3S,5S)-2-(2,6 -dimercaptophenoxy Mercapto)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2,4-dione)-3indolylbutenyl)amino-1-phenyl-6-fluorenyl Alkane; and O:\106\106749.DOC -18-1292752 (2S,3S,5S)-2-(2,6-dimercaptophenoxyethyl)amino i-yi-5-(2S- (4-Aza-4,5-dehydro-1.pyrimidin-2-one)-曱曱丁丁醯基-1,6-diphenylhexane; or a pharmaceutically acceptable salt or ester thereof Or drug precursors. The extremely excellent compound of formula I is (2S,3S,5S)_2_(2,6_:mercaptophenoxyethyl)amino-3-hydroxy-5_[2S_(1-tetrahydropyrimidin-2-one) _3_methylbutyrylamido-1,6-diphenylhexanyl; or a pharmaceutically acceptable salt, hydrazine or drug thereof] precursor. ^ In some cases, it is preferred to be able to prepare (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3 in the form of an amorphous solid. -[2S-(l-tetrahydropyrimidin-2-yl)-3-methylbutenyl]amino-indole, 6, dimethyl hexane (or a pharmaceutically acceptable salt, ester or drug precursor thereof) . This type of = amorphous solid can be obtained by (2S,3S,5S)-2-(2,6-:methylphenidinyl)amino-3-hydroxy-5-[2S-(l-four Hydrogen pyrimidin-2-one)-3-mercaptobutyl hydrazine] Amino-1,6-diphenylhexane is dissolved in an organic solvent such as ethanol, isopropanolacetone, acetonitrile and the like, and then Add this solution to the water to prepare it. Preferred is (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-[2S-(l-tetrahydropyrimidin-2- Keto)-3-methylbutanyl] saddle-1,6-diphenylhexane is dissolved in ethanol (from about 2 to about 4 ml/g) and the ethanolic solution is added to water (from about 1) Raise to about 1 mL/g) and stir to provide amorphous (2S,3S,5S)_2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5 -[28_(1_tetrahydropyrimidin-2-onemethylbutanyl)amino*-phenylhexan. Other embodiments of the invention include mv protease inhibiting compounds,

O:\106\106749.DOC -19- 1292752 其包括式II之取代基:O:\106\106749.DOC -19- 1292752 which includes substituents of formula II:

II 〇 其中R3為低碳數烷基、羥烷基或環烷基烷基;且 R5為II 〇 wherein R 3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; and R 5 is

O:\106\106749.DOC -20-O:\106\106749.DOC -20-

X 1292752X 1292752

XX

其中η為1、2或3,m為1、2或3,m’為1或2,X為0、S或NH, Y為-CH2-、-Ο-、-S-或-N(R6)-,其中R6為氫、低碳數烷基、 環烷基、環烷基烷基、芳基或芳烷基,Y”為-CH2-或 O:\106\106749.DOC -21 - 1292752 W(R0”)- ’其中R6”為氫、低碳數烷基、環烷基、環烷基烷 基、芳基或芳烷基,Y,為,其中R6,為氫、低碳數烷 基、環烷基、環烷基烷基、芳基或芳烷基,且2為0、S或 NH 〇 較佳的化合物是含有式II取代基之HIV蛋白酶抑制化合 物,在式II中R3為低碳數烷基,且R5為Where η is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is 0, S or NH, Y is -CH2-, -Ο-, -S- or -N(R6 )-, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y" is -CH2- or O:\106\106749.DOC-21- 1292752 W(R0")- 'wherein R6" is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, Y, wherein R6 is hydrogen, lower alkyl Preferred compounds having a base, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an aralkyl group, and 2 being 0, S or NH 〇 are HIV protease inhibiting compounds containing a substituent of formula II, wherein R3 is Low carbon number alkyl, and R5 is

a) (CH2)n^a) (CH2)n^

O:\106\106749.DOC -22- 1292752O:\106\106749.DOC -22- 1292752

e) 其中X、Y、Y,、Y”、Z、R6”、n、❿和m,均如同上文之定 義。 更佳的化合物是含有式II取代基之HIV蛋白酶抑制化合 物,在式II中R3為低碳數烷基,且115為e) where X, Y, Y, Y", Z, R6", n, ❿ and m are as defined above. A more preferred compound is an HIV protease inhibiting compound containing a substituent of formula II wherein R3 is a lower alkyl group and 115 is

Y (CH2)n- a) 其中n為1或2,X為p或S,且γ為-CH2或-NH-,Y (CH2)n- a) wherein n is 1 or 2, X is p or S, and γ is -CH2 or -NH-,

b) 其中m為1或2,X為Ο,Y為-CH2-且Z為Ο,b) where m is 1 or 2, X is Ο, Y is -CH2- and Z is Ο,

c) 其中m’為1,χ為〇,Z為Ο且丫為_ ΝΗ· O:\106\106749.DOC -23 - 1292752 d) 其中m’為1,X為Ο,Y”為-NH-且Y’為-NH-,或c) where m' is 1, χ is 〇, Z is Ο and 丫 is _ ΝΗ· O:\106\106749.DOC -23 - 1292752 d) where m' is 1, X is Ο, Y" is -NH - and Y' is -NH-, or

X e)X e)

其中X為O,且R6n為氫。 再更佳化合物是含有式II取代基之HIV蛋白酶抑制化合Wherein X is O and R6n is hydrogen. A further preferred compound is an HIV protease inhibiting compound containing a substituent of formula II.

物,在式II中R3為異丙基,且R5為 X (CH2)n^ a) 其中η為1或2,X為0或S,且Y為-CH2或-NH-,R3 is isopropyl in formula II, and R5 is X(CH2)n^ a) wherein η is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

其中m為1或2,X為Ο,Y為-CH2-且Z為Ο,Where m is 1 or 2, X is Ο, Y is -CH2- and Z is Ο,

XX

其中m’為1,X為Ο,Z為Ο且Y為-NH-, O:\106\106749.DOC -24- ⑧ 1292752Where m' is 1, X is Ο, Z is Ο and Y is -NH-, O:\106\106749.DOC -24- 8 1292752

(CH2W d) 其中m’為1,X為Ο,Y”為-NH-且Y’為-NH-,或(CH2W d) wherein m' is 1, X is Ο, Y" is -NH- and Y' is -NH-, or

X tf n-r6- e)X tf n-r6- e)

其中X為O,且R6n為氫。 最佳的化合物是含有式II取代基之HIV蛋白酶抑制化合Wherein X is O and R6n is hydrogen. The most preferred compound is an HIV protease inhibitory compound containing a substituent of formula II.

物,在式II中R3為異丙基,且R5為 X (CH2)n^ a) 其中η為1或2,X為0或S,且Y為-CH2或-NH-,R3 is isopropyl in formula II, and R5 is X(CH2)n^ a) wherein η is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

XX

\ΛΥ L λζ b) (CH2)m· 其中m’為1,X為Ο,Z為O且Y為-NH-,\ΛΥ L λζ b) (CH2)m· where m' is 1, X is Ο, Z is O and Y is -NH-,

XX

(CH2C O:\106\106749.DOC -25- ⑧ 1292752 其中m’為1,X為Ο,γ”為_NH-且γ,為_NH•,或(CH2C O:\106\106749.DOC -25- 8 1292752 where m' is 1, X is Ο, γ" is _NH- and γ, is _NH•, or

d) 其中X為Ο,且R6”為氫。 最優異之化合物是含有式II取代基之mv蛋白醃抑制化 合物,在式II中R3為異丙基,且&5為d) wherein X is hydrazine and R6" is hydrogen. The most preferred compound is a mv protein salt-suppressing compound containing a substituent of formula II, wherein R3 is isopropyl and & 5 is

其中η為1或2,X為〇或S且Y為-CH2或-NH-。 這類HI V蛋白酶抑制化合物的實例包括: 順-N-第三-丁基-十氫-2-[2(R)-羥基-4-苯基-3(SH2S-(1-四氫吡啶-2-酮基)-3-曱基丁醯基)胺丁基]_(4aS,8aS)_異喹 啉-3(S)-羧醯胺; 順-N-第三-丁基-十氫_2-[2(R)-經基冰p塞吩基 -3(S)-(2S-(1-四氫外b咬-2-酮基)-3-曱基丁醢基)胺丁 基]-(4aS,8aS)-異喳啉-3(S)-羧醯胺;以及 4-胺基-1^((2同侧,3 8)-2-羥基-4-苯基-3-(28-(1_四氫嘧咬 -2-酮基)-3-曱基丁醯基胺基)-丁基)-N-異丁基-苯磺醯胺; 及其類似物; 或其在藥學上可接受的鹽類。 這類含有式II之取代基的HI V蛋白酶抑制化合物,可藉著 O:\106\106749.DOC -26- 1292752 將具有胺基(-NH2或-NHR*,其中R*為低碳數烷基)、羥基 (-0H)或硫醇基(-SH)的適當中間物或前驅物,偶聯到式Η 化合物或其鹽或其已活化之酯衍生物上來製備之·· HO-C^^RcWherein η is 1 or 2, X is 〇 or S and Y is -CH2 or -NH-. Examples of such HI V protease inhibiting compounds include: cis-N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(SH2S-(1-tetrahydropyridine- 2-keto)-3-mercaptobutylamino)aminobutyl]-(4aS,8aS)_isoquinoline-3(S)-carboxamide; cis-N-tert-butyl-decahydro-2 -[2(R)-radio-based p-sepeno-3(S)-(2S-(1-tetrahydro-exo-b-but-2-yl)-3-indolylbutanyl)amine butyl]-( 4aS,8aS)-isoindoline-3(S)-carboxamide; and 4-amino-1((2 ipsilateral, 3 8)-2-hydroxy-4-phenyl-3-(28- (1_tetrahydropyrimidin-2-one)-3-mercaptobutylamino)butyl)-N-isobutyl-benzenesulfonamide; and analogs thereof; or pharmaceutically acceptable thereof Salt. Such a HI V protease inhibiting compound containing a substituent of formula II may have an amine group (-NH2 or -NHR*, wherein R* is a lower alkyl number by O:\106\106749.DOC -26-1292752) A suitable intermediate or precursor of a hydroxy group (-0H) or a thiol group (-SH) is coupled to a compound of the formula guanidine or a salt thereof or an activated ester derivative thereof to prepare a HO-C^ ^Rc

II 〇II 〇

III 其中R3為低礙數烧基、羥院基或環烧基烧基;且 R5為III wherein R3 is a low-permeability alkyl group, a hydroxyl-based group or a cycloalkyl group; and R5 is

O:\106\106749.DOC -27-O:\106\106749.DOC -27-

X 1292752X 1292752

其中η為1、2或3,m為1、2或3,m,為!或2,又為〇、s或 NH ’ Y為_CH2-、_〇_、各或_N(R6)_,其中&為氫、低碳數 烷基、環烷基、環烷基烷基、芳基或芳烷基,γ"為_cH2_ 或-Ν〇ν,)_,其中I”為氫、低碳數烷基、環烷基、環烷^ 烷基、芳基或芳烷基,γ,為-N(R6,)_,其中I,為氫、低碳數Where η is 1, 2 or 3, and m is 1, 2 or 3, m, for! Or 2, 〇, s or NH ' Y is _CH2-, _〇_, each or _N(R6)_, wherein & is & hydrogen, lower alkyl, cycloalkyl, cycloalkyl Alkyl, aryl or aralkyl, γ" is _cH2_ or -Ν〇ν,)_, wherein I" is hydrogen, lower alkyl, cycloalkyl, cycloalkylene, aryl or aralkyl Base, γ, is -N(R6,)_, where I is hydrogen, low carbon number

O:\106\106749.DOC -28- 1292752 烷基、環烷基、環烷基烷基、芳基或芳烷基,且z為ο、s 或NH。 較佳的化合物是式III化合物或其已活化之酯衍生物,其O: \106\106749.DOC -28- 1292752 alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl, and z is ο, s or NH. Preferred compounds are compounds of formula III or activated ester derivatives thereof,

中R3為低碳數烷基且r5為 XWhere R3 is a lower alkyl group and r5 is X

, (CH2)nV, (CH2)nV

XX

e) 其中X、γ、γ·、γ”、z、R6”、η、m和m’均如同上文之定義。 -29-e) wherein X, γ, γ·, γ", z, R6", η, m and m' are as defined above. -29-

O:\106\106749.DOC 1292752 更佳的化合物是式III化合物或其已活化之酯衍生物O:\106\106749.DOC 1292752 A more preferred compound is a compound of formula III or an activated ester derivative thereof.

中R3為低碳數烧基且R5為 XMedium R3 is a low carbon number base and R5 is X

(CH2)nV a) 其中η為1或2,X為Ο或S,且Y為-CH24-NH-,(CH2)nV a) wherein η is 1 or 2, X is Ο or S, and Y is -CH24-NH-,

XX

.)—(CH2)m Ύ/ b) Ζ 其中m為1或2,Χ為0, Υ為-CH2-且Ζ為Ο,.)—(CH2)m Ύ/ b) Ζ where m is 1 or 2, Χ is 0, Υ is -CH2- and Ζ is Ο,

其中m’為1,X為0, Ζ為0,且Υ為-ΝΗ-,Where m' is 1, X is 0, Ζ is 0, and Υ is -ΝΗ-,

XX

(CH2W 其中m’為1,X為Ο,Υπ為-ΝΗ-且丫’為-ΝΗ-,或(CH2W where m' is 1, X is Ο, Υπ is -ΝΗ- and 丫' is -ΝΗ-, or

XX

e) 其中X為0且R6’’為氫。 O:\106\106749.DOC -30- 1292752 再更佳的化合物是式III化合物或其已活化之酯衍生物,e) wherein X is 0 and R6'' is hydrogen. O:\106\106749.DOC -30- 1292752 A more preferred compound is a compound of formula III or an activated ester derivative thereof,

其中R3為異丙基且R5為 XWherein R3 is isopropyl and R5 is X

a) 其中η為1或2,X為0或S,且Y為-CH2或-NH-,a) where η is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

其中m為1或2,X為Ο,Y為-CH2-且Z為0,Where m is 1 or 2, X is Ο, Y is -CH2- and Z is 0.

c) zc) z

其中m1為1,X為Ο,Z為Ο,且Y為-NH-, XWhere m1 is 1, X is Ο, Z is Ο, and Y is -NH-, X

(CH2)m·(CH2)m·

其中m’為1,X為Ο,· Y”為-NH-且Y’為-NH-,或 X - R6m e) 其中X為O且R6n為氫。 O:\106\106749.DOC -31 - 1292752 最佳的化合物是式III化合物或其已活化之酯衍生物Wherein m' is 1, X is Ο, · Y" is -NH- and Y' is -NH-, or X - R6m e) wherein X is O and R6n is hydrogen. O:\106\106749.DOC -31 - 1292752 The most preferred compound is a compound of formula III or an activated ester derivative thereof

中R3為異丙基且r5為 XR3 is isopropyl and r5 is X

YY

(CH2)nV a) 其中η為1或2,X為Ο或S,且Y為-CH24-NH-,(CH2)nV a) wherein η is 1 or 2, X is Ο or S, and Y is -CH24-NH-,

X \火 L λ2 b) (CH2)m·X \火 L λ2 b) (CH2)m·

其中m’為1,X為Ο,Z為Ο,且Y為-NH-, 其中以為1,X為Ο,Y”為-NH-且Y’為-NH-,或Wherein m' is 1, X is Ο, Z is Ο, and Y is -NH-, wherein 1, X is Ο, Y" is -NH- and Y' is -NH-, or

X R6··X R6··

d) 其中X為0且r6”為氫。 最優異之化合物是其中r3為異丙基且r5為d) wherein X is 0 and r6" is hydrogen. The most excellent compound is where r3 is isopropyl and r5 is

XX

O:\106\106749.DOC -32- 1292752 的式m化合物或其已活化之醋衍生物,其中…或2, χ 為0或S ’且Υ為-CH】或-ΝΗ-。 本發明之化合物可包括不對稱取代的碳原子。其結果意 指本發明化合物所有的立體異構物均包含在本發明;,: 括消旋混合物、非對映立體異構物的混合物,以及本發日= 化合物的單一非對映立體異構物。O: \106\106749.DOC -32- 1292752 A compound of formula m or an activated vinegar derivative thereof, wherein ... or 2, χ is 0 or S ' and Υ is -CH or -ΝΗ-. The compounds of the invention may include asymmetrically substituted carbon atoms. The results mean that all stereoisomers of the compounds of the invention are included in the invention;: a mixture of racemic mixtures, diastereoisomers, and a single diastereoisomer of the compound Things.

,S”和"R”構型一詞,如同*IupAC 1974推薦書第e節,基 礎立體化學(Fundamental Stereochemistry),Pure AiJ, "S" and "R" configuration, as in *IupAC 1974 Recommendation, Section e, Fundamental Stereochemistry, Pure AiJ

Chem. (1976) 45, 13-30所定義的。 當在本文中使用,,N-保護基,,或,,N_保護的,,一詞,意指那 些基團企圖保護胺基酸或肽的沁終端,或是保護胺基在合 成過程中對抗不想要的反應。在Greene* Wuts,"在有機合 成中的保護基(Protective Groups In 0rganic Synthesis)n, (John Wiley & Sons,New York (1991))中揭示 了經常使用的 N-保護基,藉此將其合併於此以作為參考。N_保護基包括 醯基,諸如甲醯基、乙醯基、丙醯基、三甲基乙醯基、第 一-丁基乙醯基、2-氯乙醯基、2-溴乙醯基、三氟乙醯基、 二氯乙醯基、酞醯基、鄰_硝苯氧基乙醯基、α _氯丁醯基、 本甲醯基、4-氯苯曱醯基、4-溴苯甲醯基、4-硝苯甲醯基及 其類似物;績醢基,諸如苯續醢基、對-甲苯續醯基及其類 似物;胺基甲酸形成的基團,諸如芊氧羰基、對〜氯芊氧幾 基、對-甲氧苄氧羰基、對-硝苄氧羰基、2-硝苄氧羰基、對 -溴芊氧羰基、3,4-二曱氧基芊氧幾基、3,5_二曱氧基苄氧幾 基、2,4-二甲氧基苄氧羰基、4-曱氧基苄氧羰基、2-硝基_4,5_ 〇:\Η)6\] 06749.DOC -33- 1292752 一甲氧基爷氧幾基、3,4,5 -三曱氧基字氧獄基、1-(對-聯笨 基-1-甲基乙氧羰基、α,α-二甲基-3,5-二曱氧基苄氧幾 基、二苯甲氧羰基、第三-丁氧羰基、二異丙基曱氧羰基、 異丙氧羰基、乙氧羰基、曱氧羰基、烯丙氧羰基、2,2,2-三氯乙氧羰基、苯氧羰基、4-硝苯氧羰基、苐基-9-甲氧幾 基、環戊氧羰基、金剛烧氧羰基、環己氧羰基、苯硫幾基 及其類似物;烷基,諸如苄基、三苯曱基、苄氧甲基及其 類似物;以及矽烷基,諸如三甲矽烷基及其類似物。較佳 的Ν-保護基為甲醯基、乙醢基、苯甲醯基、三甲基乙醯基、 第二-丁基乙醯基、苯續醯基、苄基、第三-丁氧羰基(B〇c) 和苄氧羰基(Cbz)。 當在本文中使用’’已活化之酯衍生物” 一詞時,意指醯基 鹵,諸如醯基氣,而已活化之酯類包括但不限於甲酸和乙 酸衍生的酐類,衍生自烷氧羰基鹵化物之酐類,諸如異丁 氧Ik基氟及其類似物’ N-經基玻轴酿亞胺衍生之g旨類、 經基酞醯亞胺衍生之酯類、N_羥基苯并三唑衍生之_類、 N-羥基-5-降冰片烯-2,3-二羧醯胺衍生之酯類、2,4,5_三氯 酚衍生之酯類、苯硫酚衍生之酯類、丙基膦酸衍生之酐類, 及其類似物。 當在本文中使用”烷醯基”一詞,意指R^c(〇)_,其中R】9 為低碳數烷基。 田在本文中使用”伸烯基” 一詞時,意指衍生自含有從2到 10個碳原子,並含有至少一傰碳_碳雙鍵之直線或支鏈烴的 二價基團。伸烯基之實例包括_CH=CH_、_c H=CH_、 O:\106\106749.DOC -34- 1292752 -c(ch3)=ch-、-CH2CH=CHCH2-及其類似物。 當在本文中使用”烷氧基”和”硫代烷氧基,,一詞時,分別意 指11150-和R15s-,其中Rl5為低碳數烷基。 當在本文中使用"烷氧烷氧基,,一詞時,意指R22〇_R23〇_, 其中R22為如同上文定義之低碳數烷基,且r23為伸烷基。烷 氧烷氧基之代表性實例包括甲氧甲氧基、乙氧甲氧基、第 三-丁氧甲氧基及其類似物。 當在本文中使用"烷氧基烷基"一詞時’意指烷氧基附加 在低碳數烷基基團上。 當在本文中使用"烷氧羰基"一詞時,意指R20c(o)_,其中 R20為烷氧基。 當在本文中使用”烷胺基"一詞時,意指_NHR16,其中r】6 為低碳數烧基。 當在本文中使用"烷胺基羰基,,一詞時,意指R2iC(〇)_’其 中R21為烷胺基。 當在本文中使用"伸烧基"-詞時,意指藉著移除兩個氮 原子,衍生自含有從丨到…個碳原子之直線或支鏈之飽和烴 的二價基團,例如亞甲基(偶_)、丨,2_伸乙基(_CH2CH2_)、 1,1-伸乙基(-ch=ch3)、1,3-伸丙基(_CH2CH2CH2_)、2 2_二 甲伸丙基(-CH2C(CH3)2CH2-),及其類似物。 當在本文中使用"胺羰基” 一詞時,意指4(0^%。 當在本文中使用••芳基"-詞時,意指含有6到12個碳房子 之單-或二環的碳環系統,並具有—或兩個芳香族環,包括 但不限於苯基、茶基、四氫審基、氫印基、雖基及其類似 O:\106\106749.DOC •35- 1292752 物。芳基可以是未經取代的,或以一、二或三個分別選自 低碳數烷基、鹵素、鹵化烷基、_化烷氧基、烷氧基、烷 氧羰基、硫代烷氧基、胺基、烷胺基、二烷胺基、胺羰基、 缄基、硝基、羧醛、羧基和羥基的取代基來取代之。 當在本文中使用”芳烷基,,一詞時,意指先前定義之芳基 附加在低碳數烷基基團上,例如芊基及其類似物。 當在本文中使用,’環烷基”一詞時,意指具有3到8個碳原 子之脂肪族環系統,包括但不限於環丙基、環戊基、環己 基及其類似物。 S在本文中使用”環烷基烷基"一詞時,意指環烷基附加 在低碳數烷基基團上,包括但不限於環己甲基。 當在本文中使用”二烷胺基”一詞時,意指_NRi6Ri7,其中 Rl6和R17分別選自低碳數烷基。 當在本文中使用"二烷胺基幾基"一詞時,意指R22C(〇)_, 其中尺22意指二烷胺基。 意指-C卜-Br、-I或-F。 一詞時,意指R180-,其中 $時,意指低碳數烷基中 例如氯甲基、氣乙基、三 當在本文中使用”鹵素”一詞, 當在本文中使用” _化烷氧基 尺18為_化烷基。 當在本文中使用”鹵化烷基,,一 有一或多個氫原子被鹵素置換 氟甲基及其類似物。 當在本文中使用”雜環”時,意指含有―個選自氧、氮和 硫之雜原子的任何3_或4_員環;或是含有一、二或三個分別 選自包括氮、氧和硫之雜原子的5_、6_或7_員環,或是含有Chem. (1976) 45, 13-30. As used herein, the term N-protecting group, or, N-protected, means that those groups attempt to protect the terminal of the amino acid or peptide, or to protect the amine group during synthesis. Fight against unwanted reactions. The frequently used N-protecting group is disclosed in Greene* Wuts, "Protective Groups In 0rganic Synthesisn, (John Wiley & Sons, New York (1991)) It is hereby incorporated by reference. The N-protecting group includes a mercapto group such as a methyl group, an ethyl group, a propyl group, a propyl group, a trimethylethyl group, a first-butyl ethyl group, a 2-chloroethyl group, a 2-bromoethyl group. , trifluoroethyl fluorenyl, dichloroethyl fluorenyl, fluorenyl, o-nitrophenoxy acetyl, α chloropyridinyl, methionyl, 4-chlorophenyl fluorenyl, 4-bromobenzyl Sulfhydryl, 4-nitrobenzhydryl and the like; a fluorenyl group, such as a phenyl fluorenyl group, a p-toluene fluorenyl group and the like; a group formed by an aminocarboxylic acid, such as a fluorenyloxy group, a pair ~Chlorooxyloxy, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromoindoleoxycarbonyl, 3,4-dimethoxyoxyoxyl, 3 ,5-dimethoxybenzyloxymethyl, 2,4-dimethoxybenzyloxycarbonyl, 4-decyloxybenzyloxycarbonyl, 2-nitro-4,5_〇:\Η)6\] 06749 .DOC -33- 1292752 monomethoxy-oxyl, 3,4,5-trimethoxyoxyl, 1-(p-phenyl-l-methylethoxycarbonyl, α,α - dimethyl-3,5-dimethoxybenzyloxymethyl, diphenylmethoxycarbonyl, tert-butoxycarbonyl, diisopropyloximeoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, Anthraceneoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxy group, cyclopentyloxycarbonyl, diamond A carbonyl group, a cyclohexyloxycarbonyl group, a benzothio group, and the like; an alkyl group such as a benzyl group, a triphenylsulfonyl group, a benzyloxymethyl group, and the like; and a decyl group such as a trimethyl decyl group and the like. Preferred oxime-protecting groups are methyl fluorenyl, ethyl fluorenyl, benzhydryl, trimethyl ethane, second-butyl acetyl, benzoxyl, benzyl, and third-butoxy Carbonyl (B〇c) and benzyloxycarbonyl (Cbz). When the term ''activated ester derivative' is used herein, it means fluorenyl halide, such as sulfhydryl, and activated esters include but It is not limited to formic acid and acetic acid-derived anhydrides, anhydrides derived from alkoxycarbonyl halides, such as isobutoxy-Ik-based fluorine and its analogs, N-based, glass-based, and imine-derived, Terpene-derived esters, N-hydroxybenzotriazole-derived, N-hydroxy-5-norbornene-2,3-dicarboxyguanamine-derived esters, 2,4,5_ Trichlorophenol-derived esters, benzene Phenol-derived esters, propylphosphonic acid-derived anhydrides, and the likes. As used herein, the term "alkyl fluorenyl" means R^c(〇)_, where R9 is a low carbon The term "alkenyl" as used herein refers to a divalent derived from a straight or branched hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. Examples of the group-extended alkenyl group include _CH=CH_, _c H=CH_, O:\106\106749.DOC-34-1292752-c(ch3)=ch-, -CH2CH=CHCH2- and the like. When the terms "alkoxy" and "thioalkoxy" are used herein, they mean 11150- and R15s-, respectively, wherein R15 is lower alkyl. When "alkoxyalkoxy," is used herein, it is meant R22〇_R23〇_, wherein R22 is lower alkyl as defined above, and r23 is alkylene. Representative examples of alkoxyalkoxy include methoxymethoxy, ethoxymethoxy, 1,3-butoxymethoxy and the like. When "alkoxyalkyl" is used herein, it is meant that an alkoxy group is appended to a lower alkyl group. When the term "alkoxycarbonyl" is used herein, it is meant R20c(o)_, wherein R20 is alkoxy. When the term "alkylamino" is used herein, it means _NHR16, wherein r6 is a lower carbon number. When "alkylaminocarbonyl is used herein, the term means R2iC(〇)_' wherein R21 is an alkylamino group. When "extension base" is used herein, it means that by removing two nitrogen atoms, it is derived from a carbon atom containing from ... a divalent group of a straight or branched saturated hydrocarbon, such as methylene (even), anthracene, 2_ethylidene (_CH2CH2_), 1,1-extended ethyl (-ch=ch3), 1, 3-extended propyl (_CH2CH2CH2_), 2 2 dimethyl propyl propyl (-CH2C(CH3)2CH2-), and analogs thereof. When the term "amine carbonyl" is used herein, it means 4 ( 0^%. When the term "•aryl" is used herein, it means a mono- or bicyclic carbocyclic system containing 6 to 12 carbon houses and has - or two aromatic rings, including However, it is not limited to phenyl, tea base, tetrahydrocarbyl, hydrogen imprinted, although the base and the like O: \ 106 \ 106749. DOC • 35 - 1292752. The aryl group may be unsubstituted, or Two or three are respectively selected from a lower alkyl group, a halogen, Alkyl, alkoxy, alkoxy, alkoxycarbonyl, thioalkoxy, amine, alkylamino, dialkylamino, amine carbonyl, decyl, nitro, carboxaldehyde, carboxyl and Substituted by a hydroxy group. As used herein, the term "aralkyl" means that the previously defined aryl group is appended to a lower alkyl group, such as a fluorenyl group and the like. As used herein, the term 'cycloalkyl," is taken to mean an aliphatic ring system having from 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkylalkyl" as used herein, means that a cycloalkyl group is appended to a lower alkyl group, including but not limited to cyclohexylmethyl. "Dialkylamino" is used herein. The term means _NRi6Ri7, wherein Rl6 and R17 are each selected from lower alkyl. When the term "dialkylamino" is used herein, it means R22C(〇)_, wherein The ruler 22 means a dialkylamino group. It means -C-Br, -I or -F. In the term, it means R180-, wherein $, means a lower alkyl group such as a chloromethyl group, Ethyl, tri-alternative is used herein as the term "halogen", as used herein, "- alkoxy aryl 18 is _ alkyl. As used herein, "halogenated alkyl", one or more The hydrogen atom is replaced by a halogen with a fluoromethyl group and the like. When "heterocycle" is used herein, it means any 3 or 4 membered ring containing one hetero atom selected from the group consisting of oxygen, nitrogen and sulfur; Is a 5-, 6- or 7-membered ring containing one, two or three heteroatoms each selected from nitrogen, oxygen and sulfur, or

O:\106\106749.DOC -36- 1292752 4個氮原子的5_員環;並包括含有一 、一 個氧原子;一個硫 一、二或三個氮原子;一 瓜原千,一個氮和一個硫屈一 一個氧原子,·在不相鄰位置上 ”,個氮和 置上的一個氧和一個硫在、虱原子,在不相鄰位 子;在相鄰位置上的兩=二ΓΓ位置上的兩個硫原 的氮原子和一個1U氮原子,兩個相鄰 個硫原子,兩個不相鄰的氮原子和一 子’兩個不相鄰的敷原子和—個氧原子的5_、6_或7_員 5-員環具有0_2個雙鍵,而6_和7韵具有^個雙鍵^視 需要將氮雜原子四級錄化。”雜環"―詞亦包括雙環基團, 其中使任何-個上述的雜環與苯環或環己院環或其他雜環 融合(例如+ 朵基、如林基、異如林基、四氫如林基、苯并 吱:、雙四氫呋喃或苯并嘧吩及其類似物)。雜環類包括氮 雜裒丁燒基、P比洛基、峨嘻琳基、p比洛σ定基、峨嗤基、叶匕 唑啉基、吡唑啶基、咪唑基、咪唑啉基、咪唑啶基、吡啶 基、六氫吡啶基、高六氫吡啶基、吡畊基、六氫吡畊基、 嘴咬基、嗒畊基、呤唑基、嘮唑啶基、異噚唑基、異吟唑 啶基、嗎啉基、Ρ塞唑基、嘧唑啶基、異嘧唑基、異嘍唑啶 基、啕哚基、Ρ奎琳基、異ρ奎琳基、苯并咪唑基、苯并違σ坐 基、苯并Ρ号唑基、呋喃基、嘧吩基、四氫呋喃基、四氫嘧 吩基、嘍唑啶基、異嘧唑基、三唑基、四唑基、異呤唑基、 4二唾基、噻二唑基、吡咯基、嘧啶基和苯并嘧吩基。雜 環類亦包括式O:\106\106749.DOC -36- 1292752 A 5-membered ring of four nitrogen atoms; and includes one or one oxygen atom; one sulfur, one or two or three nitrogen atoms; one melon, one nitrogen and one One sulphur is one oxygen atom, in a non-adjacent position, one nitrogen and one oxygen and one sulphur in, 虱 atoms, in non-adjacent positions; two = two 在 in adjacent positions The position of the two sulphur atoms of the nitrogen atom and a 1U nitrogen atom, two adjacent sulfur atoms, two non-adjacent nitrogen atoms and one of the 'two non-adjacent atoms and one oxygen atom The 5_, 6_ or 7_ member 5-membered ring has 0_2 double bonds, and the 6_ and 7 rhymes have ^ double bonds. ^The nitrogen hetero atom is required to be recorded in four stages. The heterocyclic ring is also included. a bicyclic group wherein any one of the above heterocyclic rings is fused to a benzene ring or a cyclohexyl ring or other heterocyclic ring (for example, a phenyl group, such as a linyl group, a hydrazino group, a tetrahydro group such as a linoleyl group, a benzopyrene group) :, bistetrahydrofuran or benzothiophene and its analogs). Heterocycles include azaindole, P. loperyl, sulfonyl, p. piroxicam, fluorenyl, oxazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazole Pyridyl, pyridyl, hexahydropyridyl, homohexahydropyridyl, pyridinyl, hexahydropyrrole, ocaltidine, hydrazine, carbazolyl, oxazolidinyl, isoxazolyl, iso Oxazolidine, morpholinyl, oxazolyl, pyrazolyl, isoxazolyl, isoxazolidinyl, fluorenyl, hydrazinoyl, iso-r-quineyl, benzimidazolyl, Benzoindolizin, benzoxazolyl, furyl, pyrenyl, tetrahydrofuranyl, tetrahydropyrimenyl, oxazolidinyl, isoxazolyl, triazolyl, tetrazolyl, isoindole Azolyl, 4 dithyl, thiadiazolyl, pyrrolyl, pyrimidinyl and benzopyrhenyl. Heterocycles also include

O:\106\106749.DOC -37- 1292752 之化合物,其中X*g_CH2_、-NH-或-〇-,γ*為_c(0)_或 [•C(Rn)Hv其中R”為氫或(VC4烷基,且v為1、2或3,而Z* 為或-NH-,像是1,3-苯并二氧代基、1,4-苯并二氧六環 基及其類似物。 雜環類可以是未經取代的,或是以一、二、三或四個分 別選自包括經基、鹵素、氧代( = Q)、烧基亞胺基(R*N=,其 中R*為低碳數烧基)、胺基、烷胺基、二烧胺基、烷氧基、 烧氧烷氧基、鹵烷基、環烷基、芳基、芳烷基、 -C〇〇H、-S03H和低碳數烧基的取代基來取代。此外,雜 環中含有的氮,可以是N-保護的。 當在本文中使用”羥烷基”一詞時,意指低碳數烷基基團 附加在經基上。 當在本文中使用"低碳數烷基,,一詞時,意指含有丨到6個 碳原子之直鏈或支鏈的烷基基團,包括但不限於甲基、乙 基、正-丙基、異_丙基、正-丁基、異_丁基、第二_丁基、 第二-丁基、正-戊基、i -甲丁基、2,2-二甲丁基、2 -曱戊基、 2,2 - —曱丙基、正-己基及其類似物。 當在本文中使用"硫代烷氧基烷基”一詞時,意指硫代烷 氧基附加在低碳數烷基基團上。 可按照在計劃MV中所示的來製備本發明之式^匕合物。 如同在計劃I中所略述的,可利用標準肽偶聯試劑和方法將 中間物i和1 (其中?1為冰保護基,例如第三_丁氧羰基)偶 聯,例如在1-羥基苯并三唑和諸如二環己基碳化二亞胺 (DCC)或N-乙基-Ν’-二曱胺基丙基碳化二亞胺(EDAC)及其 O:\106\106749.DOC -38^ 1292752 類似物之類的二醯亞胺的存在下,使丄與之反應而獲得i。另 外也可以使中間物L的鹽或已活化酯之衍生物(例如醯基 氯,藉著使羧酸與亞硫醯氣反應來製備)與中間物足反應。 可將化合物i脫去N_保護,得到化合物生。i的N—脫保護作 用中,其中P】(特別是其中Pl為第三_丁氧羰基)是一個酸性 不穩定的N-保護基,會導致不純物的形成,是因為醯基 R4-Li-C(0)-從胺基移至羥基的結果。可藉著執行下列的脫 保護作用來減少或排除該不純物的形成:〇)在二氯甲烷中 使用二氟乙酸,或(2)在大約室溫下,在乙酸中使用濃氫氯 酸(從約2莫耳當量到約6莫耳當量,較佳的是從約2莫耳當量 到約4莫耳當量)。較佳的N_脫保護作用之方法,包括在從約 〇°C到約5°C的溫度下,使化合物主(其中Pl為第三_丁氧羰基) 在乙腈(從約2到約1 〇公升/每公斤化合物d中與濃氫氯酸(從 約10到約20莫耳當量)反應。然後可使化合物5或其已活化之 酯衍生物與化合物生偶聯,而得到式j化合物(也就是6)。 在計劃IIA中展示另一種方法。可將化合物κ其中匕為… 保護基,例如芊氧羰基)偶聯到化合物坌,或其已活化之酉旨 衍生物(例如醯基氯,藉著使羧酸與亞硫醯氣反應來製備), 而得到[。可將化合物及脫去N-保護而得到9。可將化合物9 與化合物1或其已活化之酯衍生物偶聯,而得到式j化合物 (也就是互)。 計劃IIB顯示另一種較佳的方法,其中係在惰性溶劑中 (例如醋酸乙酯、二甲基甲醯胺、THF、乙腈、醋酸異丙酉旨 或甲苯及其類似物),在從約0°C至約50°C的溫度下,使N_ O:\I06\106749.DOC -39- 1292752 保護的胺基醇域3為氫且?4祕保護基,或p々p4都是n_ 保護基,較佳的是p3和?4均為爷基),與從約i到社3莫耳 =1的缓酸s或其鹽或已活化之酯衍生物(例如醯基氯,藉 著使缓酸在醋酸乙s旨或THF中與亞硫醯氯,或在甲苯腕F 及其類似物中與草醯氣反應來製備),在從約1〇到約4〇莫 耳當量(較佳的是從約2.5到約35莫耳當量的有機胺鹼(例 如咪唑、1-甲基咪唑、2_甲基咪唑、2_異丙基咪唑、"基 咪唑、4-硝基咪唑、吡啶、N,N_二甲胺基吡啶、^4-三唑、 ㈣、3_甲基㈣、三乙胺或N_甲基嗎4及其類似物),或 從、1到、力20莫耳當1之無機鹼(例如碳酸鈉或碳酸氫鈉及 其類似物)的存在下進行反應,而得到化合物赵。較佳的有 機胺鹼包括咪唑和三唾。 Μ的脫芊基化作用(例如,使用氫和氫化作用催化劑,或 Pd/c和甲酸鹽(例如甲酸銨及其類似物),或pd/c和甲酸及其 類似物)提供了 可藉著利用有機羧酸(例如s_焦穀胺酸、 琥珀酸或反丁烯二酸及其類似物)之催化作用,有利地將化 合物2純化。較佳的有機羧酸是s_焦穀胺酸。 使化合物艺(或化合物的有機羧酸鹽)與從約1〇到約 莫耳當量的羧酸1或其已活化之酯衍生物(例如醯基氣),在 (1)伙約4到約8莫耳當量(較佳的是從約5到約7莫耳當量)的 無機鹼(例如 NaHC03、Na2C03、KHC03、K2C03、NaOH或 KOH及其類似物)的存在下,在惰性溶劑(例如丨··丨的醋酸乙 酯/水,或醋酸異丙酯/水,或甲苯/水或THF/水及其類似物) 中’在大約室溫下進行反應,或是(2)在從約1.〇到約4〇莫 O:\106\106749.DOC -40- 1292752 耳當量(較佳的是從約2·5到約3.5莫耳當量)之有機胺鹼(例 如味σ坐、1-甲基哺°坐、2-甲基ϋ米嗤、2-異丙基味唆、4-曱基 咪唾、4-瑣基味。坐、ρ比α定、]Sf,N-二曱胺基ρ比咬、1,2,4-三嗤、 峨咯、3-甲基吡咯、三乙胺或N-曱基嗎啉及其類似物)的存 在下,在惰性溶劑(例如醋酸乙酯、醋酸異丙酯、THF、甲 苯、乙腈、二甲基曱醯胺及其類似物)中,在從約〇〇c到5〇 °C的溫度下進行反應,而提供化合物6。 在本發明的較佳具體實施例中(展示於計劃ΙΠ中),中間 化合物i具有化合物垃之化學式(I如同有關式〗化合物的定 義’且最好是異丙基)。可以計劃ΠΙ中所示的各種方法來製 備化合物U。在一個方法中,藉著與適當的氣化甲酸酯及 其類似物反應,將胺基酸辽(以自由羧酸或羧酸酯(也就是 低石厌數烧基醋)之形式)轉變為胺基甲酸g旨q (R,,為苯基、低 奴數烧基取代的苯基、鹵素取代的苯基、硝基取代的苯基、 二氟甲基苯基及其類似物)。使胺基甲酸酯U與從約1〇到約 1·5莫耳當量的胺丄i或其酸加成鹽⑴為釋離基,例如ci、 Br、I或磺酸鹽,如f烷磺酸鹽、三氟磺酸鹽、對_甲苯磺酸 鹽、苯磺酸鹽及其類似物),在惰性溶劑(例如、甲基第 三-丁醚、二甲氧基乙烷、THF/水、二甲氧基乙烷/水、曱 苯或庚烷及其類似物)中,在從約2·5到約3·5莫耳當量之含 量的驗(例如Li〇H、Na0H、Li2C〇3、Na2C〇3、苯氧化裡或 苯氧化鈉及其類似物)的存在下進行反應,提供了脲过。可 將脲ϋ分離,並藉著在惰性溶劑(例如THF、二甲氧基乙烷、 甲基第三-丁醚、甲苯或庚烷及其類似物)中,使其與從約2〇Compound of O:\106\106749.DOC -37- 1292752, wherein X*g_CH2_, -NH- or -〇-, γ* is _c(0)_ or [•C(Rn)Hv where R" is hydrogen Or (VC4 alkyl, and v is 1, 2 or 3, and Z* is or -NH-, such as 1,3-benzodioxo, 1,4-benzodioxanyl and The heterocyclic ring may be unsubstituted or may be selected from one, two, three or four, respectively, including a trans group, a halogen, an oxo (=Q), an alkyl imino group (R*N= , wherein R* is a lower carbon number), an amine group, an alkylamino group, a dialkylamine group, an alkoxy group, a pyroxyalkoxy group, a haloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group, Substituted by a substituent of C〇〇H, -S03H and a lower carbon number. Further, the nitrogen contained in the heterocyclic ring may be N-protected. When the term "hydroxyalkyl" is used herein, Refers to a lower alkyl group attached to a thiol group. As used herein, "lower alkyl," means a straight or branched alkyl group having up to 6 carbon atoms. a group, including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, second-butyl, Di-butyl, n-pentyl, i-methylbutyl, 2,2-dimethylbutyl, 2-indolyl, 2,2-propenyl, n-hexyl and the like. The term "thioalkoxyalkyl" as used herein, means that a thioalkoxy group is attached to a lower alkyl group. The formula of the invention can be prepared as shown in the scheme MV. ^Calculate. As outlined in Scheme I, intermediates i and 1 (wherein ?1 is an ice protecting group, such as a third-butoxycarbonyl group) can be coupled using standard peptide coupling reagents and methods, For example, in 1-hydroxybenzotriazole and such as dicyclohexylcarbodiimide (DCC) or N-ethyl-quinone-diaminopropylcarbodiimide (EDAC) and its O:\106\ 106749.DOC -38^ 1292752 In the presence of a diimine such as an analog, the hydrazine is reacted with it to obtain i. Alternatively, a salt of the intermediate L or a derivative of an activated ester (for example, decyl chloride) may be used. By reacting a carboxylic acid with sulfite gas to prepare a reaction with an intermediate. The compound i can be deprotected by N_ to give a compound. In the N-deprotection of i, P] (especially Where Pl is Tri-butoxycarbonyl) is an acid-labile N-protecting group which results in the formation of impurities due to the transfer of the thiol group R4-Li-C(0)- from the amine group to the hydroxyl group. Deprotection to reduce or eliminate the formation of impurities: 〇) use difluoroacetic acid in dichloromethane, or (2) use concentrated hydrochloric acid in acetic acid at about room temperature (from about 2 moles equivalent) Up to about 6 mole equivalents, preferably from about 2 mole equivalents to about 4 mole equivalents. A preferred method of N-deprotection comprises reacting a compound (wherein P1 is a third-butoxycarbonyl group) in acetonitrile (from about 2 to about 1) at a temperature of from about 〇 ° C to about 5 ° C. 〇 liters per kg of compound d is reacted with concentrated hydrochloric acid (from about 10 to about 20 mole equivalents). Compound 5 or its activated ester derivative can then be coupled to the compound to provide a compound of formula j. (ie, 6). Another method is shown in Scheme IIA. The compound κ can be conjugated to a protecting group, such as an anthraceneoxycarbonyl group, to the compound oxime, or an activated derivative thereof (eg, fluorenyl) Chlorine, prepared by reacting a carboxylic acid with sulfite gas, gives [. The compound can be deprotected by N-protection to give 9. Compound 9 can be coupled with Compound 1 or its activated ester derivative to provide a compound of formula j (i.e., mutual). Scheme IIB shows another preferred method wherein it is in an inert solvent (e.g., ethyl acetate, dimethylformamide, THF, acetonitrile, isopropyl acetate or toluene and the like) at about from about 0. From °C to about 50 ° C, the N-O:\I06\106749.DOC -39-1282952 protected amino alcohol domain 3 is hydrogen and? 4 secret protecting groups, or p々p4 are n_ protecting groups, preferably p3 and ? 4 is a genus), with a slow acid s or a salt thereof or an activated ester derivative (for example, decyl chloride) from about i to 3 mil = 1 by means of a slow acid in acetic acid or THF Prepared by reacting with sulphur chloride or in toluene wrist F and its analogs with grass cockroaches), from about 1 Torr to about 4 Torr molar equivalents (preferably from about 2.5 to about 35 moles) Equivalent organic amine base (eg imidazole, 1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole, "imidazole, 4-nitroimidazole, pyridine, N,N-dimethylamino Pyridine, ^4-triazole, (tetra), 3-methyl(tetra), triethylamine or N-methyl?4 and its analogs), or an inorganic base (eg, carbonic acid) from 1 to 20 mils The reaction is carried out in the presence of sodium or sodium hydrogencarbonate and its analogs to give the compound Zhao. Preferred organic amine bases include imidazole and tris. Deamination of hydrazine (for example, using hydrogen and a hydrogenation catalyst, Or Pd/c and formate salts (such as ammonium formate and its analogs), or pd/c and formic acid and their analogs) are provided by the use of organic carboxylic acids (eg s_pyroglutamic acid, succinic acid or Anti-butene The catalytic action of the acid and its analogs advantageously enriches compound 2. The preferred organic carboxylic acid is s-pyroglutamic acid. The compound art (or organic carboxylate of the compound) is from about 1 〇 to about 莫The equivalent of carboxylic acid 1 or its activated ester derivative (e.g., sulfhydryl gas) is from about 4 to about 8 mole equivalents (preferably from about 5 to about 7 mole equivalents) in (1). In the presence of an inorganic base such as NaHC03, Na2C03, KHC03, K2C03, NaOH or KOH and the like, in an inert solvent (eg ethyl acetate/water of 丨··, or isopropyl acetate/water, or toluene) /water or THF/water and its analogues) 'react at about room temperature, or (2) at from about 1. 〇 to about 4 〇Mo:\106\106749.DOC -40-1292752 Equivalent (preferably from about 2. 5 to about 3.5 molar equivalents) of an organic amine base (e.g., sigma, 1-methyl sputum, 2-methyl glutinous rice, 2-isopropyl odor唆, 4-曱基咪 saliva, 4-triosyl taste. Sit, ρ ratio α,] Sf, N-diamine group ρ than bite, 1,2,4-tris, 峨, 3- Preservation of pyrrole, triethylamine or N-mercaptomorpholine and its analogues In the following, in an inert solvent (such as ethyl acetate, isopropyl acetate, THF, toluene, acetonitrile, dimethyl decylamine and the like), at a temperature of from about 〇〇c to 5 〇 ° C The reaction provides Compound 6. In a preferred embodiment of the invention (shown in the scheme), the intermediate compound i has the chemical formula of the compound (I is as defined in the formula) and is preferably isopropyl. Compound U can be prepared by various methods as shown in the scheme. In one method, the amino acid (free carboxylic acid or carboxylic acid) can be reacted by reacting with a suitable gasified formate and its analogs. The ester (that is, in the form of low-stone antibacterial vinegar) is converted to the carbamic acid g. q (R, phenyl, low sulfonic acid substituted phenyl, halogen substituted phenyl, nitro substituted Phenyl, difluoromethylphenyl and the like). The urethane U and the amine 丄i or its acid addition salt (1) from about 1 Torr to about 1.5 moles are excipients, such as ci, Br, I or sulfonates, such as f-alkanes Sulfonate, trifluorosulfonate, p-toluenesulfonate, besylate and the like) in an inert solvent (eg, methyl third-butyl ether, dimethoxyethane, THF/ In water, dimethoxyethane/water, toluene or heptane and the like, in the range of from about 2. 5 to about 3.5 molar equivalents (eg Li〇H, NaOH, Li2C) The reaction is carried out in the presence of ruthenium 3, Na2C〇3, benzene oxide or sodium phenoxide and the like to provide urea. The urea oxime can be isolated and made in an inert solvent (e.g., THF, dimethoxyethane, methyl tert-butyl ether, toluene or heptane, and the like), from about 2 Torr.

O:\106\106749.DOC -41 - 1292752 到約5 · 〇莫耳當量之含量存在的驗(例如第三-丁氧基钾、氫 化納、氫化鉀或二甲胺基吡啶及其類似物)進一步反應,或 葱i轉變為環脲垃。如果辽之胺基酸醋是起始物質,則再 將該酯水解而提供羧酸垃。 或者是藉著使胺基酸JJ_ (以自由羧酸或羧酸酯之形式), 在惰性溶劑(例如THF、二甲氧基乙烷、曱基第三-丁醚、甲 苯或庚烷及其類似物)中,在鹼的存在下,與從約1〇到約h5 莫耳當量之異氰酸鹽ii(Q為釋離基,例如,或續 酸鹽,如甲烷磺酸鹽、三氟磺酸鹽、對·甲苯磺酸鹽、苯磺 酸鹽及其類似物)進行反應,而將其轉變為脲 另外,也可以藉著使胺基酸辽(以自由羧酸或羧酸酯之形 式),在惰性溶劑(例如THF、二甲氧基乙烷、甲基第三-丁 醚、曱苯或庚烷及其類似物)中,在從約1〇到約4 〇莫耳當 量之含量的鹼(例如NaH或第三_丁氡基鉀及其類似物)的存 在下,與從約^到約K5莫耳當量的胺u或其N_經保護之衍 生物(Q為釋離基,例如C1、汾或丨,或磺酸鹽,如甲烷磺酸 鹽、三氟續酸鹽、對·甲苯績酸鹽、苯石黃酸鹽及其類似物) 進行反應,而將其轉變為二胺如果使用^的冰經保護 衍生物,則需要N-脫保護作用。二胺&與羰基同等物^(例 女光氣羰基一咪唑及其類似物,其中Q,和Q”為釋離基, 士 Cl Br I、-〇-低碳數烷基、〇_芳基或咪唑基及其類似 物),在惰性溶劑(例如THF、二甲氧基乙烷、甲基第三-丁 醚、甲苯或庚烷及其類似物)中,在從約2〇到約4 〇莫耳合 量之含量的驗(NaH或第三·丁氧基鉀及其類似物)的存在^O:\106\106749.DOC -41 - 1292752 to the test of the content of about 5 · 〇 molar equivalent (such as potassium - potassium butoxide, sodium hydride, potassium hydride or dimethyl pyridine and its analogues Further reaction, or onion i is converted to cyclic urea. If the amino acid vinegar of Liao is the starting material, the ester is hydrolyzed to provide a carboxylic acid waste. Or by using an amino acid JJ_ (in the form of a free carboxylic acid or a carboxylic acid ester) in an inert solvent such as THF, dimethoxyethane, decyl-tert-butyl ether, toluene or heptane and In the analog), in the presence of a base, with from about 1 Torr to about h5 molar equivalents of isocyanate ii (Q is a cleavage group, for example, or a sulphonate such as methane sulfonate, trifluoro The sulfonate, p-toluenesulfonate, besylate and the like are reacted to convert it to urea. Alternatively, the amino acid can be used as a free carboxylic acid or a carboxylic acid ester. Form), in an inert solvent such as THF, dimethoxyethane, methyl tert-butyl ether, terpene or heptane and the like, at a molar ratio of from about 1 Torr to about 4 Torr. In the presence of a base such as NaH or a third potassium butyl sulfonate and the like, and an amine u or an N-protected derivative thereof from about 0 to about K5 molar equivalents (Q is a cleavage group, For example, C1, hydrazine or hydrazine, or a sulfonate such as methanesulfonate, trifluoroate, p-toluene, benzoate, and the like, are reacted and converted If the ice is protected diamine derivative of ^, N- deprotection is required. Diamine & carbonyl equivalents (such as phosgene carbonyl-imidazole and its analogs, wherein Q, and Q" are ex-ion groups, CCl Br I, -〇-lower alkyl, 〇_芳Or imidazolyl and analogs thereof, in an inert solvent such as THF, dimethoxyethane, methyl tert-butyl ether, toluene or heptane and the like, at from about 2 Torr to about 4 The presence of 〇 molar content (NaH or third potassium butoxide and its analogues)

O:\106\106749.DOC -42- 1292752 所進行的反應,得到環脲过。如果之胺基酸酯是起始物 處’再將該酉旨水解而提供了缓酸1〇。 另外也可以如計劃IV中所示,使化合物11 (以自由羧酸或 叛酸酯(也就是低碳數烷基酯))根據j. Am. Chem. Soc. 21, 2599 (1950)與丙醯腈反應,得到胺腈丛。或者以3-氯丙腈 來置換丙烯腈而提供21。胺腈丛的N_保護作用像胺基甲酸 一樣(Rm為低碳數烧基或苯基或鹵烧基(例如2_氣乙基、2-漠乙基及其類似物)及其類似物),係使用標準條件(例如胺 與適當之純的氯化甲酸酯(C1C(0)OR3〇,其中r3〇為低碳數烷 基、本基、鹵烧基及其類似物),或是在惰性溶劑(例如水、 THF及其類似物)中,在無機驗(例如Na〇H、KOH、K2C03 及其類似物)或有機驗(例如烧基胺或二烧基胺及其類似物) 及其類似物存在下的反應)提供化合物u。19在催化劑(例如 Ni-Al合金(鹼性的)或阮内鑷(中性或鹼性的)或扒〇2 (酸性 的)及其類似物)的存在下’在惰性溶劑(例如水或甲酵或乙 醇或丁HF及其類似物)中的氫化作用,提供了環脲垃。在較 佳的方法中,在Ni-Al合金催化劑的存在下,在惰性溶劑(例 如水或曱醇或乙醇或THF及其類似物)中,在從約 莫耳菖1之含量的驗(例如KOH或NaOH或LiOH或有機胺驗 及其類似物)的存在下,將化合物以氫化而提供環脲尬。如 果11的胺基酸酯為起始物質,再將該酯水解而提供羧酸M。 或者將化合物U之氫化作用(如同上文對化合物这之描 述)所提供之二胺M轉變為如同先前描述的化合物^。如果 11的胺基酸酯為起始物質,再將該酯水解而提供羧酸M。 O:\106\106749.DOC -43 -The reaction carried out by O:\106\106749.DOC -42-1292752 gives the cyclic urea. If the amino acid ester is the starting material, then the hydrolysis is carried out to provide a buffer acid. Alternatively, compound 11 (as a free carboxylic acid or a decanoic acid ester (ie, a lower alkyl number)) can be used as described in Scheme IV, according to j. Am. Chem. Soc. 21, 2599 (1950) and C. The guanonitrile is reacted to obtain an aminonitrile cluster. Alternatively, acrylonitrile is replaced by 3-chloropropionitrile to provide 21. The N-protection of the aminonitrile cluster is the same as that of the urethane (Rm is a low carbon number or a phenyl or a halogen group (for example, 2-gas ethyl, 2-diethyl and the like) and the like ) using standard conditions (such as an amine with a suitable pure chloroformate (C1C(0)OR3〇, where r3〇 is a lower alkyl, a benzyl, a halogen group, and the like), or In inert solvents (such as water, THF and the like), in inorganic tests (such as Na〇H, KOH, K2C03 and their analogs) or organic tests (such as alkyl or dialkyl amines and their analogues) The reaction in the presence of an analog thereof) provides the compound u. 19 in the presence of a catalyst (eg Ni-Al alloy (alkaline) or bismuth (neutral or basic) or 扒〇2 (acidic) and its analogues] in an inert solvent (eg water or Hydrogenation in methylation or ethanol or butyl HF and its analogs provides cyclic urea. In a preferred method, in the presence of a Ni-Al alloy catalyst, in an inert solvent such as water or methanol or ethanol or THF and the like, in the test from the content of about 1 Torr (for example, KOH) The compound is hydrogenated to provide cyclic urea oxime in the presence of NaOH or LiOH or an organic amine assay and the like. If the amino acid ester of 11 is the starting material, the ester is hydrolyzed to provide the carboxylic acid M. Alternatively, the diamine M provided by the hydrogenation of compound U (as described above for the compound) is converted to a compound as previously described. If the amino acid ester of 11 is the starting material, the ester is then hydrolyzed to provide the carboxylic acid M. O:\106\106749.DOC -43 -

1292752 計劃i1292752 Plan i

55

O:\106\106749.DOC -44- 1292752O:\106\106749.DOC -44- 1292752

計劃IIAPlan IIA

RR

r5R5

O:\106\106749.DOC -45- 6 1292752O:\106\106749.DOC -45- 6 1292752

計劃IIBPlan IIB

nh2Nh2

P3=P4=::t:P3=P4=::t:

11

O:\106\106749.DOC -46 - 6O:\106\106749.DOC -46 - 6

1292752 計劃in1292752 Plan in

O:\106\106749.DOC 1292752 計劃ινO:\106\106749.DOC 1292752 Plan ιν

計劃I VPlan I V

CN N( H2N\ /C02H RaCN N( H2N\ /C02H Ra

R3 nh2 hnx^co2h NH丫^C〇2H r3 18R3 nh2 hnx^co2h NH丫^C〇2H r3 18

VV

〇R30 · C02H ia〇R30 · C02H ia

r3IS n HN\^V^^C〇2H o r3 本發明化合物之製備作用的關鍵中間物,包括如同上述 之式III化合物和式IV化合物:r3IS n HN\^V^^C〇2H o r3 A key intermediate for the preparation of the compounds of the invention, including a compound of formula III and a compound of formula IV as described above:

O:\106\106749.DOC -48, 1292752 或其鹽類, 其中P3和P4分別選自氫或N-保護基;O:\106\106749.DOC -48, 1292752 or a salt thereof, wherein P3 and P4 are each independently selected from hydrogen or an N-protecting group;

RdaR2分別選自包括低碳數烷基、環烷基烷基和芳烷基; R3為低碳數烷基、羥烷基或環烷基烷基;且 R5為RdaR2 is respectively selected from the group consisting of a lower alkyl group, a cycloalkylalkyl group and an aralkyl group; R3 is a lower alkyl group, a hydroxyalkyl group or a cycloalkylalkyl group; and R5 is

(CH2)m(CH2)m

e) (CH2W O:\106\106749.DOC -49- 1292752e) (CH2W O:\106\106749.DOC -49- 1292752

οο

其中η為1、2或3, m為1、2或3, m,為1或2, X為〇、S或 NH,Y為-Ch2_、-〇-、_S_或-N(R6)-,其中 R6為氫、低碳數 烧基、環烷基、環烷基烷基、芳基或芳烷基,γ”為_CH2-或-N(R6”)-,其中為氫、低碳數烷基、環烷基、環烷基 烷基、芳基或芳烷基,Y’為-N(R6,)-,其中r6,為氫、低碳數 烷基、環烷基、環烷基烷基、芳基或芳烷基,且2為〇、s 或NH 〇 較佳的化合物是其中P3和I為氫或苄基,心和1為芳烷 基,R3為低碳數烷基,且汉5為 O:\106\106749.DOC -50-Where η is 1, 2 or 3, m is 1, 2 or 3, m, is 1 or 2, X is 〇, S or NH, and Y is -Ch2_, -〇-, _S_ or -N(R6)- Wherein R6 is hydrogen, a lower carbon alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group or an aralkyl group, and γ" is _CH2- or -N(R6")-, wherein is hydrogen, low carbon a number of alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl groups, Y' is -N(R6,)-, wherein r6 is hydrogen, lower alkyl, cycloalkyl, naphthenic Preferred are alkyl, aryl or aralkyl groups, and 2 is preferably 〇, s or NH 〇 wherein P3 and I are hydrogen or benzyl, core and 1 are aralkyl, and R3 is lower alkyl. , and Han 5 is O:\106\106749.DOC -50-

X X1292752X X1292752

其中X、Y、Y,、Y’,、Z、R6"、η、m和m’均如同上文之定 義的式IV化合物。 更佳的化合物是其中1^和以2和芊基,或1為苄基而為 低碳數烷基,R3為低碳數烷基,且R5為 O:\106\106749.DOC •51 - 1292752 、Ν^γWherein X, Y, Y, Y', Z, R6 ", η, m and m' are as defined above for the compound of formula IV. More preferred compounds are those wherein 1^ and 2 and fluorenyl, or 1 is benzyl and are lower alkyl, R3 is lower alkyl, and R5 is O:\106\106749.DOC •51 - 1292752, Ν^γ

(CH2)nV a) 其中n為1或2,X為0或S,且Y為-CH2或-NH-,(CH2)nV a) wherein n is 1 or 2, X is 0 or S, and Y is -CH2 or -NH-,

b) zb) z

其中m為1或2,X為0,Y為-CH2-且Z為Ο, X \人 L λζ c) (CH2)m· 其中m’為1,X為Ο,Z為0且γ為-, \Λυ”Where m is 1 or 2, X is 0, Y is -CH2- and Z is Ο, X \人L λζ c) (CH2)m· where m' is 1, X is Ο, Z is 0 and γ is - , \Λυ"

d) (CH2w 其中m’為1,X為0,Y”為-NH-且Y’為·νη_,或d) (CH2w where m' is 1, X is 0, Y" is -NH- and Y' is ·νη_, or

Ν · Rs·· Ν e) 其中X為Ο,且R0n為氫的式IV化合物。 再更佳的化合物是其中心和以2和苄基,或Rl為苄基且&2 為異丙基,R3為低碳數烷基,且R5為 -52-Ν · Rs·· Ν e) A compound of the formula IV wherein X is deuterium and R0n is hydrogen. A still more preferred compound is its center and is 2 and benzyl, or R1 is benzyl and & 2 is isopropyl, R3 is lower alkyl, and R5 is -52-

O:\106\106749.DOC 1292752O:\106\106749.DOC 1292752

a) 其中n為1或2,X為0或S,且丫為_Ch24 -NH-,a) where n is 1 or 2, X is 0 or S, and 丫 is _Ch24 -NH-,

其中m為1或2’ X為0’ Y為-CH2-且Z為Ο,Where m is 1 or 2' X is 0' Y is -CH2- and Z is Ο,

其中m’為1 ’ X為0’ Ζ為〇且乂為Where m' is 1 'X is 0' Ζ is 〇 and 乂

(CH2W 其中m*為1 ’ X為0’ Y’’為-NH-且γ,為,或(CH2W where m* is 1 'X is 0' Y'' is -NH- and γ is, or

X hT^N-Re- e) 其中X為Ο,且RV·為氫的式IV化合物。 最佳的化合物是其中心和仏2和苄基,或Ri為芊基且心為 異丙基,R3為低碳數烷基,且r5為 O:\106\106749.DOC •53- 1292752X hT^N-Re- e) A compound of formula IV wherein X is deuterium and RV· is hydrogen. The most preferred compound is its center and 仏2 and benzyl, or Ri is fluorenyl and the core is isopropyl, R3 is lower alkyl, and r5 is O:\106\106749.DOC •53- 1292752

a) 其中η為1或2,X為Ο或S,且Y為_CH2或-ΝΗ·a) where η is 1 or 2, X is Ο or S, and Y is _CH2 or -ΝΗ·

〇)〇)

其中m,為1,X為Ο,Y"為_NH-且,或 X rr^N-Re·* ❿Where m is 1, X is Ο, Y" is _NH- and, or X rr^N-Re·* ❿

(CH2)m· d) 其中X為Ο,且RV·為氫的式IV化合物。 最優異的化合物是其中心和义2為苄基,或心為芊基且 為異丙基,R3為低碳數烷基,且以5為(CH2)m·d) A compound of the formula IV wherein X is deuterium and RV· is hydrogen. The most excellent compound is its center and meaning 2 is benzyl, or the heart is fluorenyl and isopropyl, R3 is lower alkyl, and 5 is

其中η為1或2, X為0或S,且Y為-Ch2或_NH-的式IV化合物a compound of formula IV wherein η is 1 or 2, X is 0 or S, and Y is -Ch2 or _NH-

O:\106\106749.DOC -54 - ⑧ 1292752 式ιν化合物的較佳鹽類是有機羧O:\106\106749.DOC -54 - 8 1292752 The preferred salt of the compound of formula ιν is an organic carboxy group.

酸鹽【實施方式J 酸鹽 焦穀胺 下列實例對本發明$ 的 月之新穎化合物的製 解釋。 角知供進一步 (2S,3S,5S)_(2,6- -5-[2S-(l-味唾唆' 乙烷 氧乙醢基)鞍基_3_經基 酮基)·”基-丙酿基】胺基二苯基 A· N’N-一下基-(l)-苯基丙胺酸爷酯 將含有L-苯基丙胺酸⑽公斤’ 975莫耳)、碳酸鉀⑽ 公斤’ 3220莫耳)、水(675公升)、乙醇(34〇公升)和爷基氯(川 公斤、3275莫耳)的溶液,加熱至卯土㈠它1〇·24小時。將該 反應混合物冷卻至60。(:,並移除下方的水層。在有機物中 加入庚烷(850公升)和水(385公升),攪拌並分離出層次。然 後以水/甲醇混合物(150公升/150公升)沖洗有機物一次。然 後搾乾有機物,得到油狀的想要產物,將其帶到下一個步 驟中,不需純化。 IR (純的)3090, 3050, 3030, 1730, 1495, 1450, 116〇 公分 -1,iHNMRQOO 兆赫茲,CDC13) (5 7.5-7.0 (m5 20H)5 5.3 (d5 1H,J = 13·5赫茲),5.2 (d5 1H,J = 13.5赫茲),4.0 (d5 2H,J = 1 5赫狄),3.8 (t,2H,J = 8.4赫么么),3.6 (d,2H,J一 15赫兹),3·2 (dd,1H,J = 8·4, 14.4赫茲),13C NMR (300 兆赫茲,CDCl3) (5 172.0, 139.2, 138.0, 135·98·2, 128.1, 128.1, 126.9, O:\106\106749.DOC -55- 1292752 126.2, 66.0, 62.3, 54.3, 35·6 〇 ]d -79〇(c = 〇·9, DMF)。 Β· (4S)-4-(N,N-二苄胺基)-3-氧代_5_苯基_戊腈 在氮氣之下,將在520毫升四氫呋喃和42〇毫升乙腈中含 有實例1Α之產物(也就是苄酯)(大約〇·45莫耳)的溶液冷卻 至-4CTC。將第二個在850毫升四氫呋喃中含有胺化鈉(48 7 克,1·25莫耳)的溶液冷卻至_4(rc。在胺化鈉溶液中慢慢地 加入75毫升乙腈,並在-40。〇下再攪拌所得的溶液15分鐘。 然後在-40°C下,將胺化鈉/乙腈溶液慢慢地加至苄酯溶液 中。在-40 C下授拌已混合的溶液1小時,然後以11 $〇毫升 的25% (體重/體重)擰檬酸溶液使其中止。使所得的淤漿回 ✓孤至周圍溫度,並分離出有機物。然後以35〇毫升(重 量/體積)氣化鈉溶液沖洗該有機物,再以9〇〇毫升庚烷稀釋 之。然後以900毫升5% (重量/體積)之氣化鈉溶液沖洗該有 機物三次’以900毫升10%的甲醇系水溶液沖洗兩次,以9〇0 毫升1 5%的曱醇系水溶液沖洗一次,然後再以9〇〇毫升2〇% 的甲醇系水溶液沖洗一次。搾乾有機物,並將所得的.物質 溶解於700毫升的熱乙醇中。當冷卻室溫時,想要的產物便 沉澱出來。過濾而得到想要的產物,從L_苯基丙胺酸中產 量為 59%。IR (CHC13) 3090, 3050, 3030, 2250,1735, 1600, 1490,1450,1370, 13〇〇,1215 公分-1,4 NMR (CDC13)占 7.3 (m,15H),3.9 (d5 1H,J = 19.5 赫茲),3.8 (d5 2H,J = 13·5 赫茲),3.6 (d,2H,J = 13.5赫茲),3.5 (dd,1H,J = 4.0, 10.50 赫兹),3.2 (dd5 1H,J = ι〇·5, 13·5赫茲),3.0 (dd,1H,J = 4·0,Acid Salt [Embodiment J. Acid Coke Glutamine The following examples illustrate the preparation of the novel compounds of the present invention.角知供 further (2S,3S,5S)_(2,6- -5-[2S-(l-味唆唆' ethoxyethoxyethyl) saddle-based _3_pyridyl)) - propyl aryl] Aminodiphenyl A·N'N-Phenyl-(l)-phenylalanine monoester will contain L-phenylalanine (10) kg '975 moles), potassium carbonate (10) kg' A solution of 3220 moles, water (675 liters), ethanol (34 liters liters) and stearyl chloride (Chuan kilograms, 3275 moles), heated to alumina (1) for 1 〇 24 hours. The reaction mixture was cooled to 60. (:, and remove the water layer below. Add heptane (850 liters) and water (385 liters) to the organics, stir and separate the layers. Then rinse with water/methanol mixture (150 liters / 150 liters) Organic matter once. The organics are then dried to give the desired product as an oil which is taken to the next step without purification. IR (pure) 3090, 3050, 3030, 1730, 1495, 1450, 116 〇 - 1, iHNMRQOO megahertz, CDC13) (5 7.5-7.0 (m5 20H) 5 5.3 (d5 1H, J = 13.5 Hz), 5.2 (d5 1H, J = 13.5 Hz), 4.0 (d5 2H, J = 1 5 Hz), 3.8 (t, 2H, J = 8.4 Hz ()), 3.6 (d, 2H, J-15 Hz), 3·2 (dd, 1H, J = 8·4, 14.4 Hz), 13C NMR (300 megahertz, CDCl3) (5 172.0, 139.2, 138.0, 135·98·2, 128.1, 128.1, 126.9, O:\106\106749.DOC -55- 1292752 126.2, 66.0, 62.3, 54.3, 35·6 〇]d -79〇(c = 〇·9, DMF) Β·(4S)-4-(N,N-Dibenzylamino)-3-oxo-5-phenyl-pentanenitrile under nitrogen, will contain examples in 520 ml of tetrahydrofuran and 42 ml of acetonitrile A solution of the product of hydrazine (ie benzyl ester) (about 〇·45 mol) was cooled to -4 CTC. The second solution containing sodium aminate (48 7 g, 1.25 mol) in 850 ml of tetrahydrofuran. Cool to _4 (rc. Slowly add 75 ml of acetonitrile to the sodium azide solution and stir the resulting solution for 15 minutes at -40 ° C. Then azide/acetonitrile at -40 ° C The solution was slowly added to the benzyl ester solution. The mixed solution was mixed at -40 C for 1 hour, and then the solution was stopped with 25% (body weight/body weight) of 11% 体重ml. The slurry is returned to the ambient temperature and the organic matter is separated. The organics were then rinsed with 35 mL (v/v) sodium hydride solution and diluted with 9 mL heptane. The organics were then rinsed three times with 900 ml of a 5% (w/v) sodium sulphate solution. Rinse twice with 900 ml of 10% methanolic aqueous solution and rinse once with 9 〇 0 ml of a 1 5% decyl alcohol solution. It was then rinsed once with 9 ml of a 2% methanol aqueous solution. The organic matter was dried and the resulting material was dissolved in 700 ml of hot ethanol. When cooled at room temperature, the desired product precipitates. Filtration gave the desired product, which yielded 59% from L-phenylalanine. IR (CHC13) 3090, 3050, 3030, 2250, 1735, 1600, 1490, 1450, 1370, 13〇〇, 1215 cm-1,4 NMR (CDC13) 7.3 (m, 15H), 3.9 (d5 1H, J = 19.5 Hz), 3.8 (d5 2H, J = 13·5 Hz), 3.6 (d, 2H, J = 13.5 Hz), 3.5 (dd, 1H, J = 4.0, 10.50 Hz), 3.2 (dd5 1H, J = ι〇·5, 13·5 Hz), 3.0 (dd, 1H, J = 4·0,

O:\106\106749.DOC -56- 1292752 13.5 赫兹),3.G ⑷田’ J = 19.5 赫兹),13C NMR (300 兆赫 CDC13) ^ 197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4 〇 [, ]D -96»(〇 = 〇·5, DMF) 〇 C· (5S)-2-胺基_5_(N,N-二苄胺基广4_氧代-M二苯基 己-2-稀 將氣化苄基鎂(378公斤,在_中2]^,7〇8莫耳)加至O:\106\106749.DOC -56- 1292752 13.5 Hertz), 3.G (4) Field 'J = 19.5 Hz), 13C NMR (300 MHz CDC13) ^ 197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4 〇[, ]D -96»(〇= 〇·5, DMF) 〇C· (5S)-2-amino _5_(N,N-dibenzylamino Wide 4_oxo-M diphenylhex-2-carbene will be vaporized benzyl magnesium (378 kg, in _ 2 2), 7 〇 8 mol)

、在四氫吱,南(288公升)中之實例⑺的腈產物⑼公 斤,244莫耳)溶液中。將該溶液回溫至周圍溫度並攪拌之, 直到分析顯示沒有起始物質為止。然後再將該溶液冷卻至5 °c,並慢慢地移至15%檸檬酸(465公斤)的溶液中。利用額 外的四氫呋喃(85公升)沖洗原先的容器,並將該沖洗液加至 該檸檬酸中止容器中。分離出有機物並以1〇〇/〇氯化鈉(235 公斤)沖洗,再搾乾該固體。再度從乙醇(289公升)中搾乾該 產物,然後溶解於8(TC的乙腈(581公升)中。在冷卻至室溫 後,攪拌12小時。過濾所得的產物,並在3〇〇c的真空烘箱 中脫水,得到大約95公斤的想要產物。熔點1〇1_1〇2〇c,IR (CDC13) 363G,350G,311G,3G6G,3G3G,223G,1620,1595, 1520,1495,1450公分-1,1只]^]\411(3 00兆赫茲,€00:13)(19.8 (br s,1H),7·2 (m,20H),5.1 (s,1H),4.9 (br s,1H),3.8 (d, 2H,J = 14.7 赫茲),3.6 (d5 2H,J = 14.7 赫茲),3.5 (m,3H), 3.2 (dd’ 1H,J = 7.5,14.4赫茲),3.0 (dd,1H,J = 6.6,14·4赫 茲),13C NMR (CDC13) d 198.0,162.8,140.2,140.1,136.0, 129.5,129.3,128.9,128.7,128.1,128.0,127.3, 126·7 O:\106\106749.DOC -57- 1292752 125.6,96·9,66.5, DMF) 〇 54·3, 42·3, 32.4In the solution of the nitrile product (9) metric, 244 moles of the example (7) in tetrahydroanthracene, south (288 liters). The solution was warmed to ambient temperature and stirred until the analysis showed no starting material. The solution was then cooled to 5 ° C and slowly transferred to a solution of 15% citric acid (465 kg). The original container was rinsed with additional tetrahydrofuran (85 liters) and the rinse was added to the citric acid suspension container. The organics were separated and washed with 1 〇〇 / 〇 sodium chloride (235 kg) and then dried. The product was again dried from ethanol (289 liters) and then dissolved in 8 (TC acetonitrile (581 liters). After cooling to room temperature, stirring for 12 hours. The resulting product was filtered and at 3 〇〇c Dehydration in a vacuum oven yielded about 95 kg of the desired product. Melting point 1〇1_1〇2〇c, IR (CDC13) 363G, 350G, 311G, 3G6G, 3G3G, 223G, 1620, 1595, 1520, 1495, 1450 cm - 1,1 only]^]\411 (3 00 megahertz, €00:13) (19.8 (br s, 1H), 7·2 (m, 20H), 5.1 (s, 1H), 4.9 (br s, 1H), 3.8 (d, 2H, J = 14.7 Hz), 3.6 (d5 2H, J = 14.7 Hz), 3.5 (m, 3H), 3.2 (dd' 1H, J = 7.5, 14.4 Hz), 3.0 (dd , 1H, J = 6.6, 14·4 Hz), 13C NMR (CDC13) d 198.0, 162.8, 140.2, 140.1, 136.0, 129.5, 129.3, 128.9, 128.7, 128.1, 128.0, 127.3, 126·7 O:\106 \106749.DOC -57- 1292752 125.6,96·9,66.5, DMF) 〇54·3, 42·3, 32.4

[α JD ]47°(c = 〇·5, 苄胺基>3_羥基-二[α JD ]47°(c = 〇·5, benzylamino)>3_hydroxy-di

D· (2S,3S,5S)-5->S^|-2-(JV,]V 苯基已燒 二==Γ(157公升)中之'氫化納(“公斤,-、耳)的良汙液冷卻至低於_10±5。 (41·6公斤,433莫耳地加入f烷磺酸 。〇以下一 、 w σ成作用期間將溫度維持在0 ★。—旦完成加成作用,慢慢地將水(6公升,333莫 貫例1C之產物(20公斤,43莫 、 旲斗)和四虱呋喃(6 1公升)的溶 液加入,同時在加成作用期間中將溫度維持在代以下。在 0±5 C下授拌該混合物至少〗9小時。 /)在分離燒槪中加入蝴氫化納(6.6公彳,Μ莫耳)和四 氫呋喃(157公升)。在冷卻至_5±5。。之後,加入三氟乙酸 (24·8公斤,218莫耳),同時將溫度維持在15°C以下。在15 ±5°C下攪拌該溶液30分鐘,然後將其加至步驟丨所得的反應 混合物中,保持溫度在2〇t以下。在2〇±5它下攪拌,直到 反應完成為止。然後將該溶液冷卻至1〇±51,並以3Ν ν&〇η (195公斤)使其中止。在與第三_丁基甲醚(162公升)一起攪 拌後分離出有機層,並以〇·5Ν NaOH (200公斤)沖洗_次, 以20%重量/體積之含水氯化銨(195公斤)沖洗一次,並以 25。/◦含水氯化鈉(160公斤)沖洗兩次。搾乾有機物而得到油 狀之想要產物,直接在下一個步驟中使用它。 IR (CHC13) 35 10, 3400, 3 110, 3060, 3030,1630,公分-1, 1HNMR(3 00兆赫茲,CDC13)(5 7.2 (m5 20H)5 4.1 (d? 2H? O:\106\106749.DOC -58- 1292752 卜13.5赫茲),,3.65(111,111),3.5((1,211,1=13.5赫茲),3.1 (m,2H),2.8 (m,1H),2.65 (m,3H),1·55 (m,1H),1·30 (m, 1H),13CNMR (300 兆赫茲,CDC13) δ 140.8, 140.1,138.2, 129.4,129.4,128.6,128.4,128·3,128·2, 126·8,126.3, 125.7,72·0,63.6,54·9,53.3,46.2,40.1,30·2。 Ε· (2S,3S,5S)-2-(N,N-二爷胺基)_3-經基-5-(第三-丁氧 羰基胺基)-1,6-二苯基己烷 將BOC酐(65公斤,373莫耳)和1〇%碳酸鉀(550公斤)加至 在1\4丁6£(1096公升)中之[28,3 8,5 8]-2-队1^二芊胺基-3-經 基-5-胺基·1,6-二苯基己烧(大約1〇5公斤,226莫耳)的溶液 中。攪拌該混合物直到反應完成為止(大約1小時)。移出底 層並以水(665公升)沖洗有機物。然後搾乾該溶液而得到油 狀的想要產物。300赫茲公分' b NMR (CDC13) 5 1.40 (s,9H),1·58 (s5 2H),2·45-2·85 (m,4H),3.05 (m,1H),3·38 (d,2H),3.6 (m,1H),3.79 (m,1H),3·87 (d,2H),4.35 (s5 1H),4·85 (s,廣闊的,1H),7.0-7.38 (m5 20H)。 F-l· (2S,3S,5S)-2_胺基_3_羥基-5-(第三-丁氧羰基胺 基)-1,6-·—苯基己烧 在經過攪拌、在曱醇(350毫升)中之[2S,3S,5S]-2-N,N_: 苄胺基-3-羥基-5-第三-丁氧羰基胺基-1,6-二苯基己烷(12 克,21.3毫莫耳)的溶液中,將入甲酸銨(8·〇5克,128毫莫 耳,6.0當量)和10%鈀碳(2.4克)。在60°C和氮氣之下攪拌該 溶液三小時,然後在75°C下攪拌12小時。加入額外的甲酸 銨(6克)和10%鈀碳〇·5克),以及1毫升冰醋酸。使該反應在 O:\106\106749.DOC -59- 1292752D·(2S,3S,5S)-5->S^|-2-(JV,]V phenyl burned two == Γ (157 liters) of 'sodium hydride ("kg, -, ear) The good dirty liquid is cooled to less than _10±5. (41·6 kg, 433 m is added to the f alkane sulfonic acid. 〇 The following one, w σ during the action to maintain the temperature at 0 ★. - Complete the addition For the purpose, slowly add water (6 liters, 333 gram of the product of 1C (20 kg, 43 Mo, hopper) and tetrahydrofuran (6 1 liter), while the temperature during the addition Maintain the following. Mix the mixture for at least 9 hours at 0 ± 5 C. /) Add the hydrogenated sodium (6.6 metric liters, Μ molar) and tetrahydrofuran (157 liters) to the separated simmer. _5±5. After that, add trifluoroacetic acid (24·8 kg, 218 mol) while maintaining the temperature below 15 ° C. Stir the solution at 15 ± 5 ° C for 30 minutes, then add it To the reaction mixture obtained in the step ,, keep the temperature below 2 〇t. Stir under 2 〇 ± 5 until the reaction is completed. Then cool the solution to 1 〇 ± 51, and 3 Ν ν & 195 kg) make it After stirring, the organic layer was separated after stirring with the third butyl butyl ether (162 liters), and washed with 〇·5Ν NaOH (200 kg) _ times to 20% by weight/volume of aqueous ammonium chloride (195 kg). Rinse once and rinse twice with 25% aqueous sodium chloride (160 kg). Dry the organics to give the desired product as an oil, which was used directly in the next step. IR (CHC13) 35 10, 3400, 3 110, 3060, 3030, 1630, centimeters -1, 1H NMR (3 00 megahertz, CDC13) (5 7.2 (m5 20H) 5 4.1 (d? 2H? O:\106\106749.DOC -58- 1292752 卜 13.5 Hertz), 3.65 (111, 111), 3.5 ((1, 211, 1 = 13.5 Hz), 3.1 (m, 2H), 2.8 (m, 1H), 2.65 (m, 3H), 1·55 (m , 1H), 1·30 (m, 1H), 13CNMR (300 MHz, CDC13) δ 140.8, 140.1, 138.2, 129.4, 129.4, 128.6, 128.4, 128·3, 128·2, 126·8, 126.3, 125.7,72·0,63.6,54·9,53.3,46.2,40.1,30·2. Ε· (2S,3S,5S)-2-(N,N-di-arylamino)_3-carbo-5 -(T-butoxycarbonylamino)-1,6-diphenylhexane to BOC anhydride (65 kg, 373 mol) and 1% potassium carbonate (5 50 kg) is added to [28,3 8,5 8]-2-team 1^diamido-3-yl-5-amino-1 in 1\4 butyl 6 (1096 liters). A solution of 6-diphenylhexanone (about 1 〇 5 kg, 226 mol). The mixture was stirred until the reaction was completed (about 1 hour). Remove the bottom layer and rinse the organics with water (665 liters). The solution is then dried to give the desired product as an oil. 300 Hz centimeters ' b NMR (CDC13) 5 1.40 (s, 9H), 1·58 (s5 2H), 2·45-2·85 (m, 4H), 3.05 (m, 1H), 3·38 (d , 2H), 3.6 (m, 1H), 3.79 (m, 1H), 3·87 (d, 2H), 4.35 (s5 1H), 4·85 (s, broad, 1H), 7.0-7.38 (m5 20H). Fl·(2S,3S,5S)-2_Amino_3_hydroxy-5-(tris-butoxycarbonylamino)-1,6-·-phenylhexanone is stirred, in sterol ( [2S,3S,5S]-2-N,N_: benzylamino-3-hydroxy-5-tris-butoxycarbonylamino-1,6-diphenylhexane (12 g) In a solution of 21.3 millimoles, ammonium formate (8·5 g, 128 mmol, 6.0 equivalent) and 10% palladium carbon (2.4 g) were added. The solution was stirred at 60 ° C under nitrogen for three hours and then at 75 ° C for 12 hours. Additional ammonium formate (6 grams) and 10% palladium carbonium (5 grams) were added, along with 1 ml of glacial acetic acid. The reaction is made at O:\106\106749.DOC -59-1292752

迴流溫度下於2小時内完成。然後將該反應混合物冷卻至室 溫’並通過矽藻土墊過濾之。以甲醇(75毫升)沖洗濾餅,並 在減低的壓力下將混合的濾液濃縮。將殘餘物溶解於1N NaOH(300毫升)中,並萃取至二氯甲烷(2 X 2〇〇毫升)中。 以鹽水(250毫升)沖洗混合的有機層,並覆以硫酸鈉脫水。 在減低的壓力下濃縮該溶液,得到淡色油狀的想要產物, 它慢慢地在靜置之下形成結晶(5克)。可藉著閃爍層析法完 成該產物的進一步純化作用(矽膠,在二氣曱烷中的5%曱 醇)。300兆赫茲 iHNMR(CDCl3) 5 142(s,9h), 158加, 1H),1.70 (m,1H),2 2〇 (s,寬闊的,2H),厶52 ⑼,ih), 2·76-2·95 (m,4Η),3·5〇 (m,1H),3 % (m,1H),4 8〇 (d,寬 闊的,1H),7.15-7.30 (m,10H)。 F_2· (2S,3S,5S)-2-胺基羥基第三_ 丁氧羰基胺基 -1,6_二苯基己垸號珀酸酯It was completed in 2 hours at reflux temperature. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite. The filter cake was rinsed with methanol (75 mL) and the combined filtrate was concentrated under reduced pressure. The residue was dissolved in 1N EtOAc (3 mL) andEtOAcEtOAc The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. The solution was concentrated under reduced pressure to give the desired product as a pale oil which slowly crystallised (5 g). Further purification of the product (gelatin, 5% decyl alcohol in dioxane) can be accomplished by flash chromatography. 300 MHz iH NMR (CDCl3) 5 142 (s, 9h), 158 plus, 1H), 1.70 (m, 1H), 2 2 〇 (s, broad, 2H), 厶52 (9), ih), 2·76 -2·95 (m, 4Η), 3·5〇 (m, 1H), 3% (m, 1H), 4 8〇 (d, broad, 1H), 7.15-7.30 (m, 10H). F_2·(2S,3S,5S)-2-Aminohydroxy 3rd-butoxycarbonylamino-1,6-diphenylhexyl benzoate

將5〇/〇鈀碳(24公斤)的甲醇系淤漿(285毫升)加入在甲醇 (437公升)中之[2S,3S,5S]-2-N,N-二苄胺基羥基巧_第三· 氧1^基胺基-1,6_一苯基己烧(大約127公斤,225莫耳)的 溶液中。在其中加入在甲醇_公升)中之甲酸銨(84公升, U32莫耳)的溶液。將該溶液加熱至75艽6_12小時,然後冷 部至至概。利用塗覆有助㈣(石夕藻土)的據紙,從該反應混 合物中過據固體’並利用熱和真空(高達7 〇 t )從該反應混合 物中除去甲醇。將殘餘物溶解於醋酸異丙酯(4400公斤)中, 加熱(40C)’然後以1〇%碳酸鈉溶液(725公斤)沖洗,最後再 以水(665公升)沖洗。兩個沖洗步驟均在40°C下進行,並將Adding 5 〇/〇 palladium carbon (24 kg) in methanol (285 ml) to [2S,3S,5S]-2-N,N-dibenzylamino hydroxy _ in methanol (437 liters) Third · Oxygen 1 -ylamino-1,6-monophenylhexan (about 127 kg, 225 mol) solution. A solution of ammonium formate (84 liters, U32 mole) in methanol liters was added thereto. The solution was heated to 75 艽 6_12 hours and then cooled to the approximate extent. Methanol was removed from the reaction mixture by heat and vacuum (up to 7 Torr) using a paper coated with (4) (Shiyoshizao). The residue was dissolved in isopropyl acetate (4400 kg), heated (40 C) and then rinsed with 1% sodium carbonate solution (725 kg) and finally rinsed with water (665 liters). Both rinsing steps are carried out at 40 ° C and will

O:\I06\106749.DOC -60- 1292752 產物保存在溶液中。在真空中利用熱(高達7(rc)來移除溶 劑。然後加入異丙醇(475公升),並汽提以移除殘餘的溶劑。 將異丙醇(1200公升)加至殘餘物中,並攪拌直到其均質化為 止。在该溶液中加入在異丙醇(12〇〇公升)中的琥珀酸(15_4〇 公斤)溶液。將該溶液套管加熱至70°C,以便溶解所有的固 體’然後容許慢慢地將其冷卻至室溫,並攪拌6小時。然後 過渡該溶液,得到白色固體狀之想要產物(55-8〇公斤)。 溶點:145-146。C。1HNMR··(Me2SO-d6,3 00兆赫茲)(5 〇·97 (d,3H,IPA),1.20 (s,9H),1.57 (t,2H),2.20 (s,2H,琥 ί白酸),2.55 (m5 2H),2.66 (m,2H),2.98 (m,1H),3.42 (m, 1H),3.70 (m,1H),3·72 (m,1H,IPA),6.60 (d,1H,醯胺 NH),7·0-7·3 (m,10H)。 4 NMR (CD3OD,300 兆赫茲)5 1·11 (d,3H,J = 7赫兹, IPA),1·29 (s,9H),1.70 (m5 2Η),2·47 (s5 2H,琥珀酸),2·65 (m,2H),2.85 (m5 2H),3.22 (m,1H),3.64 (m,1H),3·84 (m5 1H),7·05_7·35 (m,10H) 〇 G· 2,6-二甲苯氧基乙酸乙酯 將溴乙酸乙酯(18·2毫升,164毫莫耳)和碳酸鉋(58克,176 毫莫耳)加至在二氧六環(600毫升)中之2,6-二曱酚(8.0克, 6 6耄莫耳)的溶液中。加熱該反應混合物至迴流丨$小時,冷 卻至室溫’過渡並在真空中濃縮。藉著石夕膠管柱層析法純 化(5%到20%在己烧中之乙醚),得到想要的化合物(8〇〇/〇)。 300兆赫茲NMR (CDC13) 5 1.35 (t,J = 7.5赫茲),2.30 (s,6H),4.31 (q,J = 7·5赫茲,2H)5 4.40 (s,2H),7.0 (m,3H)。 O:\106\106749.DOC -61 - 1292752 t H. 2,6-二曱苯氧基乙酸 在0°C下將5.3克的氫氧化鋰加至在甲醇(17〇亳升)和水 (56毫升)中之得自實例1〇的化合物(5.15克,24.7毫莫耳)、容 液中,並在室溫下攪拌該溶液1.5小時,並在真空中濃縮。 以0·5Μ HC1將殘餘物酸化,並以醋酸乙酯(3〇〇毫升)萃取。 將有機層脫水並濃縮之,得到白色的固體(4·〇5克,91%)。 300兆赫茲!H NMR (CDC13) δ 2.30 (s,6Η),4.48 (s 2Η) 7.0 (m,3H)。 I· (28,38,58)-2-(2,6-二甲苯氧基乙醯基)胺基_3_經基 -5_(第三-丁氧羰基胺基)4,6-二苯基己烷 利用標準EDAC偶聯程序將得自實例ip的胺與得自實例 1H的酸偶聯,得到想要的化合物(78%)。3〇〇兆赫茲1hnmr (CDC13) 5 1.40 (S,9H),1.65 (m,3H),2.18 (S,6H),2.78 (m,2H),2.98 (d,J = 9赫茲,2H),3.75 (m,1H),3.90 (m,1H) 4.15 (m,1H),4.20 (s,2H),4·60 (m,1H),7.0 (m,3H),7·25 (m,10H)。質譜:(m=H)+ = 547。 J· 2-N-(苄氧羰基)胺基_乙醛 在-78°C下將1.34毫升草醯氯逐滴加至在2〇毫升CH2cl2中 之1·45毫升DMSO的溶液中。在-78°C下15分鐘之後,加入 在40毫升CHAl2中之N-Cbz-胺基乙醇的溶液。在_78。〇下j 5 分鐘和〇°C下2分鐘之後,將該溶液冷卻至_78它,並逐滴加 入三乙胺(6.14毫升)。在_78。(:下攪拌該溶液3〇分鐘,並將 其倒入50毫升冰冷的1〇%含水檸檬酸中,再以乙醚(15〇毫 升)萃取。以鹽水沖洗混合的有機層,並以無水的n^s〇4O:\I06\106749.DOC -60-1292752 The product is stored in solution. The heat was removed in vacuo (up to 7 (rc) to remove the solvent. Then isopropanol (475 liters) was added and stripped to remove residual solvent. Isopropanol (1200 liters) was added to the residue, And stirred until homogenization. A solution of succinic acid (15_4 〇 kg) in isopropanol (12 liters liter) was added to the solution. The solution cannula was heated to 70 ° C to dissolve all solids. 'It was then allowed to cool slowly to room temperature and stirred for 6 hours. Then the solution was allowed to pass to give the desired product (55-8 〇 kg) as a white solid. Melting point: 145-146 C. 1HNMR· · (Me2SO-d6, 300 megahertz) (5 〇·97 (d, 3H, IPA), 1.20 (s, 9H), 1.57 (t, 2H), 2.20 (s, 2H, succinic acid), 2.55 (m5 2H), 2.66 (m, 2H), 2.98 (m, 1H), 3.42 (m, 1H), 3.70 (m, 1H), 3·72 (m, 1H, IPA), 6.60 (d, 1H) , guanamine NH), 7·0-7·3 (m, 10H). 4 NMR (CD3OD, 300 MHz) 5 1·11 (d, 3H, J = 7 Hz, IPA), 1·29 (s , 9H), 1.70 (m5 2Η), 2·47 (s5 2H, succinic acid), 2·65 (m, 2H), 2.85 (m5 2H), 3.22 (m,1H), 3.64 (m,1H),3·84 (m5 1H),7·05_7·35 (m,10H) 〇G· 2,6-xylyleneoxyacetate ethyl bromoacetate Ester (18.2 ml, 164 mmol) and carbonic acid planer (58 g, 176 mmol) added to 2,6-dioxol (8.0 g, 6 6 in dioxane (600 ml) The reaction mixture was heated to reflux for 小时$ hr, cooled to room temperature 'transition and concentrated in vacuo. Purified by Shixi hose column chromatography (5% to 20% in hexane) The diethyl ether) gave the desired compound (8 〇〇 / 〇). 300 MHz NMR (CDC13) 5 1.35 (t, J = 7.5 Hz), 2.30 (s, 6H), 4.31 (q, J = 7· 5 Hz, 2H) 5 4.40 (s, 2H), 7.0 (m, 3H). O: \106\106749.DOC -61 - 1292752 t H. 2,6-diphenoxyacetic acid at 0 ° C 5.3 g of lithium hydroxide was added to the compound from Example 1 (5.15 g, 24.7 mmol) in methanol (17 liters) and water (56 mL), in a solution, and at room temperature. The solution was stirred for 1.5 hours and concentrated in vacuo. The residue was acidified with EtOAc EtOAc (EtOAc) ML). The organic layer was dried and concentrated to give a white solid (4·5 g, 91%). 300 megahertz! H NMR (CDC13) δ 2.30 (s, 6 Η), 4.48 (s 2 Η) 7.0 (m, 3H). I·(28,38,58)-2-(2,6-xyloxyethenyl)amino-3-3-yl-amino-5-(tris-butoxycarbonylamino) 4,6-diphenyl The amine from Example ip was coupled with the acid from Example 1H using a standard EDAC coupling procedure to give the desired compound (78%). 3 〇〇 megahertz 1hnmr (CDC13) 5 1.40 (S, 9H), 1.65 (m, 3H), 2.18 (S, 6H), 2.78 (m, 2H), 2.98 (d, J = 9 Hz, 2H), 3.75 (m,1H), 3.90 (m,1H) 4.15 (m,1H), 4.20 (s,2H),4·60 (m,1H),7.0 (m,3H),7·25 (m,10H) ). Mass spectrum: (m = H) + = 547. J· 2-N-(benzyloxycarbonyl)amino-acetaldehyde 1.34 ml of oxalic acid chloride was added dropwise to a solution of 1·45 ml of DMSO in 2 mL of CH 2 Cl 2 at -78 °C. After 15 minutes at -78 °C, a solution of N-Cbz-aminoethanol in 40 ml of CHAl2 was added. At _78. After 5 minutes at 〇j and 2 minutes at 〇 °C, the solution was cooled to _78, and triethylamine (6.14 ml) was added dropwise. At _78. (The solution was stirred for 3 minutes, poured into 50 ml of ice-cold 1% aqueous citric acid, and extracted with diethyl ether (15 mL). The combined organic layer was washed with brine and dried with anhydrous ^s〇4

O:\106\106749.DOC -62- 1292752 脫水;過濾並在真空中濃縮。藉著矽膠管柱層析法將粗產 物純化(10% EtOAc/CH^Cl2),得到想要的化合物(42%)。3〇〇 兆赫兹hNMMCDCIO 5 (s,2H),5·40 (br s,1H),7.36 (m5 5H),9·66 (s,1H)。質譜: (Μ+ΝΗ4)+ = 21卜 Κ· Ν-(苄氧叛基胺基)-乙基纈胺酸甲酯 將纈胺酸甲酯氫氣化物(〇·72克,4.29毫莫耳)、醋酸鈉(〇.7 克’ 8·58毫莫耳)和氰基硼氫化鈉(〇·54克,8·58毫莫耳)加至 在17耄升曱醇中’得自實例ij之駿(O ja克,4·29毫莫耳) 的溶液中。在室溫下攪拌該混合物過夜,並在真空中蒸發 溶劑。將殘餘物溶解於醋酸乙酯(1〇〇毫升)中,並以飽和的 NaHC03 (10毫升)沖洗,再以醋酸乙酯(2 χ 5〇毫升)萃取液 層。以鹽水沖洗混合的有機層,並以無水的硫酸鈉將其脫 水’過濾並在真空中濃縮。藉著矽膠管柱層析法(2〇0/〇 EtOAc/CHWl2)純化殘餘物,得到想要的化合物(6〇%)。3〇〇 兆赫兹NMR (CDC13)占 0·91 (d,J = 3赫茲,3H),0·94 (d, J = 3赫茲,3H),1.90 (m,1H),2.55 (m,1H),2.80 (m5 1H), 2.98 (d,J = 6赫茲,ih),3·20 (m,1H),3.30 (m,1H),3.71 (s, 3H), 5.10 (s,2H),5·27 (br s,1H),7.37 (m,5H)。質譜: (M+H)+ = 309。 L· 2S-(1_咪唑啶-2-酮基)-3-甲基丁酸甲酯 藉著氫解作用移除實例1K中之化合物的Cbz-保護,並以 一當篁在CHzCl2中的1,1_羰基二咪唑來處理粗產物,得到想 要的化合物(64%),3 00兆赫茲 iHNMR^CDCh) 5 0.95 (d,O: \106\106749.DOC -62- 1292752 Dehydrated; filtered and concentrated in vacuo. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) 3〇〇 megahertz hNMMCDCIO 5 (s, 2H), 5·40 (br s, 1H), 7.36 (m5 5H), 9·66 (s, 1H). Mass spectrometry: (Μ+ΝΗ4)+ = 21 Κ· Ν-(benzyloxy-demethylamino)-ethyl methionine methyl hydrazide hydrogenate (〇·72 g, 4.29 mmol) Sodium acetate (〇.7 g '8·58 mmol) and sodium cyanoborohydride (〇·54 g, 8.58 mmol) were added to 17 liters of sterol' from the example ij Chun (O ja gram, 4.29 millimoles) in solution. The mixture was stirred at room temperature overnight and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (1 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 3 〇〇 megahertz NMR (CDC13) occupies 0·91 (d, J = 3 Hz, 3H), 0·94 (d, J = 3 Hz, 3H), 1.90 (m, 1H), 2.55 (m, 1H) ), 2.80 (m5 1H), 2.98 (d, J = 6 Hz, ih), 3·20 (m, 1H), 3.30 (m, 1H), 3.71 (s, 3H), 5.10 (s, 2H), 5·27 (br s, 1H), 7.37 (m, 5H). Mass Spectrum: (M+H)+ = 309. Methyl L. 2S-(1-imidazolidin-2-one)-3-methylbutanoate was removed by hydrogenolysis to remove the Cbz-protection of the compound of Example 1K and was used in CHzCl2 1,1_carbonyldiimidazole was used to treat the crude product to give the desired compound (64%), 300 Hz iHNMR^CDCh) 5 0.95 (d,

O:\106\106749.DOC •63- 1292752 =7.5赫茲),〇·98 (d,卜 7·5赫茲,3H),2.15 (m,1Η),3·47 (m5 3H),3.71 (s,3H),3.73 (m,1H),4.23 (d,J = 10.5赫兹, 1H),4·81 (br s,1H),質譜:(M+H)+ = 2〇1。 Μ· 2S-(1-咪唑啶基)-3•甲基丁酸 在〇 c下將氫氧化鋰單水合物(20當量)加至在2·5毫升水 和5耄升二氧六環中,得自實例1L之化合物(151毫克,0.75 毫莫耳)的溶液中。在〇°C下攪拌該溶液j • 5小時,並在室溫O:\106\106749.DOC •63- 1292752 =7.5 Hz), 〇·98 (d, Bu 7.5 Hz, 3H), 2.15 (m, 1 Η), 3·47 (m5 3H), 3.71 (s , 3H), 3.73 (m, 1H), 4.23 (d, J = 10.5 Hz, 1H), 4·81 (br s, 1H), mass spectrum: (M+H)+ = 2〇1. Μ· 2S-(1-imidazolidinyl)-3•methylbutyric acid was added to lithium hydroxide monohydrate (20 equivalents) in ·5 ml of water and 5 liters of dioxane under 〇c , a solution of the compound from Example 1L (151 mg, 0.75 mmol). Stir the solution at 〇 ° C for 5 hours and at room temperature

下1小時。以IN HC1將其酸化,以Et〇Ac (1〇〇毫升+2 χ 5〇 毫升)萃取,以硫酸鈉將其脫水,並在真空中蒸發經過過濾 的溶液’得到想要的化合物(88%)。3〇〇兆赫茲iH NMR (DMSO-d6) 5 0.85 (d,J = 12赫茲,3Η),0.92 (d,J = 12赫 兹,3H),2·05 (m,1H),3.25 (m,2H),3.30 (m,1H),3.50 (m, 1H),3·90 (d,J = 15赫茲,1H),6.40 (br s,1H),12.60 (br s, 1H)。質譜:(M+H)+ = 187。 Ν· (2S,3S,5S)-2-(2,6。甲苯氧基乙醯基)胺基_3省基 -5-胺基-1,6-二苯基己基 在4·5克得自實例II之化合物中。加入ch2C12和三氟乙酸 各40毫升。將該溶液留在室溫下1小時。在真空中濃縮該溶 液,得到想要的化合物(100%)。300兆赫茲4>^11(00€13) (5 1·48 (m,1H),1.62 (m5 1H),2.05 (m,1H),2.24 (s,6H), 2.50 (m,1H),2.80 (m,1H),3.0-3.10 (m,4H),3.90 (d,J = 10 赫茲,111),4.17(111,出),4.26(八6951=13.5赫茲,211),7.0 (m,3H),7.10 (m,2H),7·30 (m,7H),7.41 (d,J = 10赫茲, 1H)。質譜:(M+H)+ = 447。 O:\106\106749.DOC -64- 1292752 Q· (2S’3S,SS)-2_(2,6C甲苯氧基乙醯基)胺基_3•羥基 米唾唆_2_嗣基)_3_曱基_丁醢基]胺基心,6_二 己烷 利用標準偶聯程序[在DMF中的1-(3-二甲胺基丙基)冬乙 η 一 2妝j,使得自實例IN的胺基化合物與得自實例 1]^的S欠偶聯’得到想要的化合(80%)。300兆赫茲4 NMR (CDCl3) 5 〇·83 (d,J = 6赫兹,3H),0·86 (d5 J = 6H, 3H), U5 (m,2h),2.16 (m,1Η),2·18 (s,6H),2.76 (m,2H),2.97 (d,J = 7·5赫兹,2H),3.14 (m,2H),3.30 (m,2H),3.70 (d,J = 1-赫纸,1H),3.75 (m,1H),4.20 (m,4H), 4.50 (br s,1H), 6·70 (d,J = 7·5赫茲,1H),7·0 (m,3H),7.25 (m,10H)。質 譜:(M+H)+ = 615。 實例2 (2S,3S,5S)-2-(2,6-二甲苯氧基乙醯基)胺基-3-羥基 四氫嘧啶-2-酮基)-3-甲基丁醯基】胺基-1,6-二苯 基己烷 A· 2S_(1-四氫嘧啶-2-酮基)-3-甲基丁酸 利用實例1J到1M中描述的程序,但是以N-Cbz-3-胺基丙 醇來代替實例1J中的N-Cbz-胺基乙酵,得到想要的化合 物。300兆赫茲NMR (DMSO-d3) δ 0.82 (d,J = 7赫茲, 3H),0.93 (d,J = 7赫茲,3H),1.77 (m,2H),2.10 (m,1H), 3·1〇-3·23 (m,4H),4.42 (d,J = 10.5赫茲,1H),6.37 (br s, 1H)。質譜:(M+H)+ = 201。 Β· (28,38,58)-2-(2,6_二甲苯氧基乙醯基)胺基-3-羥基 O:\106\106749.DOC -65- 1292752 -5-[2S-(1-四氫嘧啶-2-酮基)-3-甲基丁醯基]胺基-1ί6-二苯 基己燒 利用標準程序(在DMF中之EDAC),使得自實例ιΝ之胺基 化合物與得自實例2Α之酸偶聯,得到想要的化合物(7〇。/〇)。 300 兆赫茲NMR (CDC13) 5 0.80 (d,J = 4.5赫兹,3Η), 0·83 (d,J = 4.5赫茲,3H),1·50 (m5 1H),1.65-1.72 (m,6H), 2.20 (s,6H),2.68 (m,1H),2.82 (m,2H),3.0 (d,J = 7·5赫茲, 1H),3·05 (m,4H),3.77 (s,1H),4.07 (d,J = 4·5赫茲,iH), 4·20 (m,4H),4.50 (br s,1H),6·78 (br d,1H),7.0 (m5 3H), 7·25 (m,l〇H)。質譜··(M+H)+ = 629。 實例3 (2S,3S,5S)-2-(2,6-二曱苯氧基乙醯基)胺基-經基 -5-[2S-(3-噚唑啶-2-酮基)-3-甲基丁醯基]胺基二苯基 己烷 A· 2S-(3-嘮唑啶-2-酮基)-3-甲基丁酸曱酯 在L-纈胺酸甲酯氫氯化物(7·6毫莫耳)的溶液中,加入在 乙醇中之環氧乙烷的溶液(1 ·5當量)。將該溶液維持在〇艺下 〇·5小時,然後在室溫下18小時,在此時加入〇 〇1當量的 BF3 · EhO。直接使新鮮的環氧乙烷在該溶液中起泡3到4分 鐘。在8小時之後將該溶液濃縮至無水,並將殘餘物溶解於 CH2Ci2中並冷卻至o°c。在該溶液中加入12當量的三乙胺 和1 ·0當ϊ的二光氣。1小時之後,在真空中移除溶劑,並 以水(30毫升)沖洗殘餘物,並以CH2Cl2 (3 χ 5〇毫升)萃取, 脫水並濃縮之。藉著矽膠管柱層析法(5% Et〇Ac/CH2Ci2)純Next hour. It was acidified with IN HCl, extracted with EtOAc (1 mL, EtOAc, EtOAc, EtOAc) ). 3 〇〇 megahertz iH NMR (DMSO-d6) 5 0.85 (d, J = 12 Hz, 3 Η), 0.92 (d, J = 12 Hz, 3H), 2·05 (m, 1H), 3.25 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 3.90 (d, J = 15 Hz, 1H), 6.40 (br s, 1H), 12.60 (br s, 1H). Mass spectrum: (M+H)+ = 187. Ν·(2S,3S,5S)-2-(2,6.Tolyloxyethyl)amino-3-3-phenyl-5-amino-1,6-diphenylhexyl at 4·5 g From the compound of Example II. Add 40 ml of each of ch2C12 and trifluoroacetic acid. The solution was left at room temperature for 1 hour. The solution was concentrated in vacuo to give the desired compound (100%). 300 MHz 4>^11(00€13) (5 1·48 (m, 1H), 1.62 (m5 1H), 2.05 (m, 1H), 2.24 (s, 6H), 2.50 (m, 1H), 2.80 (m, 1H), 3.0-3.10 (m, 4H), 3.90 (d, J = 10 Hz, 111), 4.17 (111, out), 4.26 (eight 6951 = 13.5 Hz, 211), 7.0 (m, 3H), 7.10 (m, 2H), 7·30 (m, 7H), 7.41 (d, J = 10 Hz, 1H). Mass Spectrum: (M+H)+ = 447. O:\106\106749.DOC -64- 1292752 Q·(2S'3S,SS)-2_(2,6C-tolyloxyethyl)amino-3-3-hydroxymethane 唆_2_mercapto)_3_mercapto-butanyl]amino group Heart, 6-dihexane using standard coupling procedure [1-(3-dimethylaminopropyl)-wine in a DMF, a makeup j, such that the amine compound from Example IN was obtained from Example 1 The S coupling of '^' gives the desired compound (80%). 300 MHz 4 NMR (CDCl3) 5 〇·83 (d, J = 6 Hz, 3H), 0·86 (d5 J = 6H, 3H), U5 (m, 2h), 2.16 (m, 1 Η), 2 · 18 (s, 6H), 2.76 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 3.14 (m, 2H), 3.30 (m, 2H), 3.70 (d, J = 1 - Her paper, 1H), 3.75 (m, 1H), 4.20 (m, 4H), 4.50 (br s, 1H), 6·70 (d, J = 7.5 Hz, 1H), 7·0 (m , 3H), 7.25 (m, 10H). Mass spectrum: (M+H)+ = 615. Example 2 (2S,3S,5S)-2-(2,6-xyloxyethenyl)amino-3-hydroxytetrahydropyrimidin-2-one)-3-methylbutanyl]amino- 1,6-Diphenylhexane A· 2S_(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid using the procedure described in Examples 1J to 1M, but with N-Cbz-3-amine Instead of the N-Cbz-aminoglycol in Example 1J, the desired compound was obtained. 300 MHz NMR (DMSO-d3) δ 0.82 (d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz, 3H), 1.77 (m, 2H), 2.10 (m, 1H), 3· 1〇-3·23 (m, 4H), 4.42 (d, J = 10.5 Hz, 1H), 6.37 (br s, 1H). Mass spectrum: (M+H)+ = 201. Β·(28,38,58)-2-(2,6-xyloxyethoxymethyl)amino-3-hydroxy O:\106\106749.DOC -65- 1292752 -5-[2S-( 1-tetrahydropyrimidin-2-one)-3-methylbutanyl]amino-1ί6-diphenylhexanhydride using standard procedures (EDAC in DMF), derived from the amine compound of the example ιΝ Example 2 Acid coupling of hydrazine gave the desired compound (7 〇./〇). 300 MHz NMR (CDC13) 5 0.80 (d, J = 4.5 Hz, 3 Η), 0·83 (d, J = 4.5 Hz, 3H), 1·50 (m5 1H), 1.65-1.72 (m, 6H) , 2.20 (s, 6H), 2.68 (m, 1H), 2.82 (m, 2H), 3.0 (d, J = 7.5 Hz, 1H), 3·05 (m, 4H), 3.77 (s, 1H) ), 4.07 (d, J = 4·5 Hz, iH), 4·20 (m, 4H), 4.50 (br s, 1H), 6.78 (br d, 1H), 7.0 (m5 3H), 7 · 25 (m, l〇H). Mass Spectrum··(M+H)+ = 629. Example 3 (2S,3S,5S)-2-(2,6-Dioxaphenoxyethenyl)amino-carbyl-5-[2S-(3-oxazolidine-2-one)- 3-methylbutylidene]aminodiphenylhexane A·2S-(3-oxazolidine-2-one)-3-methylbutyrate oxime ester in L-proline methyl ester hydrochloride ( A solution of ethylene oxide in ethanol (1.5 eq.) was added to the solution of 7.6 mmol. The solution was maintained at 〇 5 hours, and then at room temperature for 18 hours, at which time 1 equivalent of BF3 · EhO was added. Fresh ethylene oxide is bubbled directly in the solution for 3 to 4 minutes. After 8 hours the solution was concentrated to dryness and the residue was dissolved in CH.sub.2. To this solution was added 12 equivalents of triethylamine and 1 +/- dioxin. After 1 hour, the solvent was removed in vacuo and the residue was washed with water (30 ml), and extracted with CH2Cl2 (3 χ 5 mM), dehydrated and concentrated. Pure by gel column chromatography (5% Et〇Ac/CH2Ci2)

O:\106\106749.DOC -66- 1292752 化粗產物,得到想要的化合物(42%,2步驟)。3〇〇兆赫茲〗H NMR(CDCl3) δ 〇.98 (d,J = 4 〇赫兹,3H) i 〇(d j = 4 〇 赫茲,3H),2.16 (m,1H),3.60 (m,2H),3·73 (s,3H),4.20 (d, J 1 〇赫故,1H),4.37 (m,2H),質譜:(m+h)+ = 202。 Β· 2S-(3-哼唑啶-2-酮基)-3_曱基_丁酸 利用貫例1M中描述的程序將得自實例3 A之曱酯水解,得 到想要的化合物。300兆赫茲iHNMR(DMSO-d6) (5 0.90 (d5 J = 6赫兹,3H),0.95 (d,J = 6赫茲,3H),2·1 (m,1H),3·55 (m,1H),3.70 (m,1H),3·88 (d,J = 9赫兹,ih)5 4.30 (m,2H), 13.0 (br,s,1H)。質譜:(M+NH4)+ = 205。 C· (2S,3S,5S)-2-(2,6c T苯氧基乙醯基)胺基-3-羥基 -5-[2S-(3-噚唑啶-2-酮基)-3-曱基丁醯基】胺基4,6-二苯基 己烷 利用標準偶聯程序(在DMF中之EDAC),使得自實例1N之 胺與得自實例3B之酸偶聯,得到想要的化合物。300兆赫茲 NMR (CDC13) 5 0.83 (d,J = 4·5赫茲,3H),0.87 (d,J = 4-5赫茲,3H),1·75 (m,1H),2·10 (m5 1H),2.20 (s,6H),2·65 (m,1H),2·85 (m,1H),3.0 (m,3H),3.30 (m,1H),3.60 (m, 2H),3·77 (m,1H),4·20 (m,4H),6·25 (br d,J = 6赫茲,1H), 7·〇 (m,3H),7.25 (m,10H)。質譜:(M+H)+ = 616。 實例4 (2S,3S,5S)-2](3R,3aS,6aR)_雙-四氫呋喃氧基]胺基-3-羥 基-5-[2S-(3-甲基-1-咪唑啶-2-酮基)-3-甲基丁醯基】胺基 -1,6-^一苯基己烧 O:\106\106749.DOC 67· 1292752 A· 2S-(3-甲基-1-咪唑啶-2-酮基)-3-甲基丁酸甲酯 將在4.5毫升DMF中之150毫克得自實例1L之化合物的溶 液,加至在0.5毫升DMF中之45毫克(60%的油分散體)氫化 鈉懸浮液中。在室溫下20分鐘之,加入(1.5當量,0.07毫升) 的甲基碘。在1小時中完成該反應。以飽和的NH4C1溶液使 該反應中止,並以乙醚(1〇〇毫升+50毫升X2)萃取,在真空 中脫水並濃縮之。藉著矽膠管柱層析法(20% EtOAc/CH2Cl2)純化粗產物,得到想要的化合物(61%)。300 兆赫茲 4 NMR (CDC13) δ 0.95 (d,J = 6赫茲,3Η),0·97 (d,J = 6赫茲,3H),2·15 (m5 1H),2.80 (s,3H),3.32 (m,3H), 3.60 (m,1H),3·70 (s,3H),4.25 (d,J = 10.5赫茲,1H)。質 譜:(M+H)+ = 215。 Β· 2S-(3-甲基-1-咪唑啶_2-酮基)-3-甲基丁酸 利用在實例1Μ中描述的程序,將得自實例4 a的甲酯水 解’得到想要的化合物。300兆赫兹4 NMR (DMSO-d6) 6 0.85 (d,J = 6赫兹,3H),0.92 (d,J = 6赫茲,3H),2.05 (m, 1H),2·65 (s,3H),3·25 (m5 3H), 3·42 (m,1H),3.90 (d,J = 10 赫茲,1H)。質譜:(M+H)+ = 201。 C· (3R,3aS,6aR)-雙-四氫吱喃-(4_硝苯基)碳酸鹽 將三乙胺(0.26毫升,1 ·85毫莫耳)和氣甲酸對4肖苯酯(34 i 毫克,1·69毫莫耳)加至在10毫升CH2cl2中之3R_羥基 -(3aS,6aR)-雙-四氫呋喃[J· Med· Chem. 3弋 25〇6_25()8 (1994)](200毫克,ί·54毫莫耳)的溶液中。將該溶液保持在 室溫下3天,以CH2C12(100毫升)稀釋,並以飽和的NaHc〇3 O:\106\106749.DOC -68 - 1292752 (15毫升)沖洗。在真空中將有機層脫水並濃縮。藉著石夕膠管 柱層析法5% EtOAc/CH2Cl2)純化,得到想要的化合物 (42%)。3 00兆赫茲]Η NMR (CDC13) 5 2·0 (m,l H),2.20 (m,1H),3.18 (m5 1H),4.0 (m,3H),4.17 (m,1H),5.27 (m, 1H),5·80 (d,J = 6赫茲),7·40 (d,J = 7.5 赫茲,2H),8.30 (d,J =7.5赫茲,2H)。質譜:(M+NH4)+ = 313。 D· (28,38,58)-2-[(3贝,338,631〇-雙-四氫呋味氧基】胺基 -3-羥基-5-(第三-丁氧羰基)胺基-l,6-二苯基己烷O:\106\106749.DOC -66- 1292752 The crude product was obtained to give the desired compound (42%, 2 steps). 3 〇〇 MHz Hz H NMR (CDCl3) δ 〇.98 (d, J = 4 〇 Hertz, 3H) i 〇 (dj = 4 〇 Hertz, 3H), 2.16 (m, 1H), 3.60 (m, 2H) ), 3·73 (s, 3H), 4.20 (d, J 1 〇 赫, 1H), 4.37 (m, 2H), mass spectrum: (m+h)+ = 202. 2S-(3-oxazolidine-2-one)-3-mercapto-butyric acid The oxime ester from Example 3 A was hydrolyzed using the procedure described in Example 1M to give the desired compound. 300 MHz iH NMR (DMSO-d6) (5 0.90 (d5 J = 6 Hz, 3H), 0.95 (d, J = 6 Hz, 3H), 2·1 (m, 1H), 3·55 (m, 1H) ), 3.70 (m, 1H), 3·88 (d, J = 9 Hz, ih) 5 4.30 (m, 2H), 13.0 (br, s, 1H). Mass Spectrum: (M+NH4)+ = 205. C·(2S,3S,5S)-2-(2,6c T-phenoxyethyl)amino-3-hydroxy-5-[2S-(3-oxazolidine-2-one)-3 - mercaptobutyryl]amino 4,6-diphenylhexane The amine from Example 1N was coupled with the acid from Example 3B using standard coupling procedures (EDAC in DMF) to give the desired compound. 300 MHz NMR (CDC13) 5 0.83 (d, J = 4·5 Hz, 3H), 0.87 (d, J = 4-5 Hz, 3H), 1.75 (m, 1H), 2·10 ( M5 1H), 2.20 (s, 6H), 2·65 (m, 1H), 2·85 (m, 1H), 3.0 (m, 3H), 3.30 (m, 1H), 3.60 (m, 2H), 3·77 (m,1H),4·20 (m,4H),6·25 (br d,J = 6 Hz, 1H), 7·〇(m,3H), 7.25 (m,10H). :(M+H)+ = 616. Example 4 (2S,3S,5S)-2](3R,3aS,6aR)_bis-tetrahydrofuranyloxy]amino-3-hydroxy-5-[2S-(3 -methyl-1-imidazolidin-2-one)-3-methylbutanyl Amino-1,6-^-phenylhexanyl O:\106\106749.DOC 67· 1292752 A· 2S-(3-methyl-1-imidazolidin-2-one)-3-methyl Methyl butyrate A solution of 150 mg of the compound from Example 1L in 4.5 mL of DMF was added to a 45 mg (60% oil dispersion) sodium hydride suspension in 0.5 mL DMF. After 20 minutes, (1.5 eq., 0.07 mL) of methyl iodide was added. The reaction was completed in 1 hour. The reaction was quenched with saturated NH4C1 solution and extracted with diethyl ether (1 mL, 50 mL) It was dehydrated and concentrated in vacuo. EtOAc was purified eluted elut elut elut elut elut elut elut elut J = 6 Hz, 3 Η), 0·97 (d, J = 6 Hz, 3H), 2·15 (m5 1H), 2.80 (s, 3H), 3.32 (m, 3H), 3.60 (m, 1H) , 3·70 (s, 3H), 4.25 (d, J = 10.5 Hz, 1H). Mass spectrum: (M+H)+ = 215. Β· 2S-(3-methyl-1-imidazolidin-2-one)-3-methylbutanoic acid was hydrolyzed from the methyl ester of Example 4 a using the procedure described in Example 1 得到compound of. 300 MHz 4 NMR (DMSO-d6) 6 0.85 (d, J = 6 Hz, 3H), 0.92 (d, J = 6 Hz, 3H), 2.05 (m, 1H), 2·65 (s, 3H) , 3·25 (m5 3H), 3·42 (m, 1H), 3.90 (d, J = 10 Hz, 1H). Mass spectrum: (M+H)+ = 201. C·(3R,3aS,6aR)-bis-tetrahydrofuran-(4-nitrophenyl)carbonate triethylamine (0.26 ml, 1.85 mmol) and benzoic acid to 4 choline ester (34 i mg, 1.69 mmol) added to 3R_hydroxy-(3aS,6aR)-bis-tetrahydrofuran in 10 ml of CH2Cl2 [J· Med·Chem. 3弋25〇6_25()8 (1994)] (200 mg, ί·54 mmol) in solution. The solution was kept at room temperature for 3 days, diluted with CH.sub.2Cl.sub.2 (100 mL). The organic layer was dehydrated and concentrated in vacuo. Purification by silica gel column chromatography 5% EtOAc/EtOAc (EtOAc) 3 00 MHz Η NMR (CDC13) 5 2·0 (m, l H), 2.20 (m, 1H), 3.18 (m5 1H), 4.0 (m, 3H), 4.17 (m, 1H), 5.27 ( m, 1H), 5·80 (d, J = 6 Hz), 7.40 (d, J = 7.5 Hz, 2H), 8.30 (d, J = 7.5 Hz, 2H). Mass spectrum: (M+NH4)+ = 313. D·(28,38,58)-2-[(3 shell, 338,631〇-bis-tetrahydrofuranoxy)amino-3-hydroxy-5-(tris-butoxycarbonyl)amino-l ,6-diphenylhexane

將得自實例1F之化合物(130毫克,0.34毫莫耳),加至在 3.4毫升DMF中之得自實例4C之碳酸鹽(100毫克,〇·34毫莫 耳)的溶液中。將該溶液保持在室溫下過夜,然後在真空中 濃縮’藉著矽膠管柱層析法(2%到5% MeOH/ CH2C12)純化 粗產物,得到想要的化合物。3〇〇兆赫茲4 NMR (CDC13) δ 1.40 (s,9Η),1.64 (m,3Η),2.76 (m,2Η),2.87 (m,2H),3.66-4.0 (m,7H),4.53 (m,1H),5.06 (m,2H),5.68 (d,J = 6赫茲,1H),7·10_7·28 (m,10H)。質言昝:(M+NH4)+ = 558 〇 Ε· (2S,3S,5S)-2-[(3R,3aS,6aR)_雙-四氮呋喃氧基]胺基 -3-羥基-5-胺基-1,6-二苯基己烷 將5毫升三氟乙酸加至5毫升ch2C12中、得自實例4D之化 合物(170毫克,〇·31毫莫耳)的溶液中。在〇·25小時之後, 在真空中移除溶劑。將殘餘物溶解於1〇〇毫升Et〇Ac*,並 以飽和的NaHC03沖洗,然後再以鹽水沖洗,脫水並濃縮, 得到想要的化合物(91%)。300兆赫茲4 NMR (CDC13) 5 O:\106\106749.DOC •69- 1292752 L27-1.60 (m,4H),1.75 (m,2H),2.47 (m,1Η),2·80 (m,1H), 2·88 (m,2H),3.0 (m,2H),3.80 (m,4H),4.0 (m,1H),5.10 (m,1H),5·30 (d,J = 10.5赫茲,1H),5.70 (d,J = 6赫茲,1H), 7-05-7.25 (m,10H)。質譜··(M+H)+ = 441。 F· (28,38,58)-2-[(311,338,631〇-雙-四氫呋喃氧基]胺基 經基-5-[2S-(3-甲基-1-咪唑啶-2-酮基)-3-甲基丁醢基]胺 基-1,6-二苯基己烷 利用標準偶聯程序(在DMF中之EDAC),使得自實例4B之 魏酸與得自實例4E之胺基化合物偶聯,得到想要的化合 物。300兆赫茲 iHNMR(CDCi3) 5 〇.82(d,J = 3赫兹,3H), 0.85 (d,J =赫茲,3H)5 1.65 (m,1H),2.77 (s,3H),2·85 (m, 3Η),3·17 (m5 2Η),3·47 (m,1Η),3.60 (m,2Η),3·75 (m,1Η), 3·87 (ηι,1H),4.0 (m,1H),4.20 (m,1H),5.05 (m,2H),5.68 (d,J = 6赫兹,ih),6.45 (br d,J = 7.5赫茲,1H),7.20 (m, 10H)。質譜:(M+H)+ = 623。 實例5 (2§’38,58)-2-[(311,338,631〇-雙-四氫呋喊氧基]胺基小經 基-5_[2S-(1-咪唑啶-2_酮基甲基丁醯基】胺基4,“二苯 基已燒 利用標準偶聯程序(EDAC/DMF),使得自實例4E之胺基 化合物與得自實例1M之羧酸偶聯,得到想要的化合物。3〇〇 兆赫兹 lHNMR(CDCl3)占 〇.85(d,J = 7赫茲,3Η),〇·88 (d,卜赫兹,3Η),1·70 (m,2Η)5 2.18 (m,1Η),2·8〇 (m,3Η), 2.95 (m,1Η),3.20 (m,4Η),3·6〇 (m,3Η),3 75 (m,2Η),4 〇The compound from Example 1F (130 mg, 0.34 mmol) was added to a solution of the carbonate from Example 4C (100 mg, < The solution was kept at room temperature overnight and then concentrated in vacuo. The crude material was purified by silica gel column chromatography (2% to 5% MeOH / CH2 C12) to give the desired compound. 3 〇〇 megahertz 4 NMR (CDC13) δ 1.40 (s, 9 Η), 1.64 (m, 3 Η), 2.76 (m, 2 Η), 2.87 (m, 2H), 3.66-4.0 (m, 7H), 4.53 ( m, 1H), 5.06 (m, 2H), 5.68 (d, J = 6 Hz, 1H), 7·10_7·28 (m, 10H).质言昝:(M+NH4)+ = 558 〇Ε· (2S,3S,5S)-2-[(3R,3aS,6aR)_bis-tetrazirfuryloxy]amino-3-hydroxy-5 -Amino-1,6-diphenylhexane 5 ml of trifluoroacetic acid was added to a solution of the compound of Example 4D (170 mg, 〇 31 mmol) from 5 ml of ch2C12. After 25 hours, the solvent was removed in vacuo. The residue was dissolved in 1 mL of EtOAc (EtOAc) (EtOAc) elute 300 MHz 4 NMR (CDC13) 5 O:\106\106749.DOC •69- 1292752 L27-1.60 (m,4H),1.75 (m,2H),2.47 (m,1Η),2·80 (m, 1H), 2·88 (m, 2H), 3.0 (m, 2H), 3.80 (m, 4H), 4.0 (m, 1H), 5.10 (m, 1H), 5·30 (d, J = 10.5 Hz) , 1H), 5.70 (d, J = 6 Hz, 1H), 7-05-7.25 (m, 10H). Mass spectrum··(M+H)+ = 441. F·(28,38,58)-2-[(311,338,631〇-bis-tetrahydrofuranyloxy)amino group via-5-[2S-(3-methyl-1-imidazolidin-2-one) -3-methylbutanyl]amino-1,6-diphenylhexane using standard coupling procedures (EDAC in DMF) such that the formic acid from Example 4B and the amine compound from Example 4E To obtain the desired compound. 300 MHz iHNMR (CDCi3) 5 〇.82 (d, J = 3 Hz, 3H), 0.85 (d, J = Hertz, 3H) 5 1.65 (m, 1H), 2.77 ( s, 3H), 2·85 (m, 3Η), 3·17 (m5 2Η), 3·47 (m, 1Η), 3.60 (m, 2Η), 3·75 (m, 1Η), 3·87 (ηι, 1H), 4.0 (m, 1H), 4.20 (m, 1H), 5.05 (m, 2H), 5.68 (d, J = 6 Hz, ih), 6.45 (br d, J = 7.5 Hz, 1H ), 7.20 (m, 10H). Mass Spectrum: (M+H)+ = 623. Example 5 (2§'38,58)-2-[(311,338,631〇-bis-tetrahydrofuranyloxy)amine Amino--5-[2S-(1-imidazolidin-2-ylenylmethylbutanyl)amine 4, "Diphenyl has been burned using a standard coupling procedure (EDAC/DMF) to give an amine from Example 4E The base compound was coupled with the carboxylic acid from Example 1M to give the desired compound. lHNMR (CDCl3) accounts for 85.85 (d, J = 7 Hz, 3 Η), 〇·88 (d, Buchs, 3 Η), 1·70 (m, 2 Η) 5 2.18 (m, 1 Η), 2· 8〇(m,3Η), 2.95 (m,1Η), 3.20 (m,4Η),3·6〇(m,3Η),3 75 (m,2Η),4〇

O:\106\106749.DOC -70- 1292752 (m, 1H)? 4.20 (m, ΙΗ^ λ ac /O:\106\106749.DOC -70- 1292752 (m, 1H)? 4.20 (m, ΙΗ^ λ ac /

),4·45 (s,1H),5_10 (m,2H),5.67 (d,J 二 6赫茲,1H)5 6·60 (d τ — ” <从 # 、 ⑼,J — 7·5赫茲,1H),7·20 (m,i〇H)。質 譜:(M+H)+ = 609。 實例6 (2明,58)-2册|嚷唾基)甲氧幾基)胺基) -5-((2S-(l-咪 嗤咬-2-酮基)-3-甲基丁酿基)胺基經基“,心二苯基己烷 A· 2-氣-2-甲醯基乙酸乙醋 在冷部至0C、裝有第三_丁氧基鉀(〇·5莫耳,5〇〇毫升在 THF中的1Μ浴液)和5〇〇毫升無水THF的三頸2公升圓底燒 瓶中在3】時之内從添加漏斗逐滴加入在2〇〇亳升中 之氯化乙酸乙酯(0·5莫耳,53·5毫升)和甲酸乙酯(〇·5莫耳、 40.4毫升)的溶液。在加成作用完成之後,攪拌該反應混合 物1小時,並容許將其靜置過夜。以二乙醚稀釋所得的固 體,並在冰浴中冷卻。然後利用6NHC1使pH值降低至大約 3。分離出有機相,以二乙醚沖洗液層3次。將混合的醚部 份覆以NaSCU脫水,並在真空中濃縮。將粗製之想要化合物 儲存在_30°C下,並可直接使用不需進一步純化。 B· 嘧唑-5-羧酸乙酯 在圓底燒瓶中加入250毫升無水丙酮、7.5克(0.123莫耳) 硫代甲醯胺和18.54克(0.123莫耳)2-氯-2-甲醯基乙酸乙 酯。將該反應加熱至迴流2小時。在真空中移除溶劑,並藉 著層析法(Si02,6公分 o.d·管柱,1〇〇% CHC13,Rf = 0.25) 純化殘餘物,而得到11.6克(60%)淡黃色油狀的想要化合 物。NMR (CDC13) δ 1.39 (t,J = 7赫茲,3Η),4.38 (q5 J = 7 O:\106\106749.DOC •71- 1292752 赫茲,2H),8·50 (s,1Η),8·95 (s5 1H)。 C. 5-(羥甲基)嘧唑 在預先冷卻(冰浴)、含有在250毫升THF中之氫化鋁鋰 (2.89克,76毫莫耳)的三頸500毫升燒瓶中,在1.5小時之内 逐滴加入在100毫升THF中之嘧唑-5-羧酸乙酯(11.82克, 75.68毫莫耳),以避免過度起泡。攪拌該反應額外的1小時, 並以2.9毫升的水、2·9毫升的15% NaOH和8.7毫升的水小心 地處理之。過濾固態的鹽類,並將濾液置於一邊。在1 〇〇 毫升醋酸乙酯中將粗製之鹽類加熱至迴流30分鐘。過濾所 得的混合物,並混合兩種濾液,覆以Na2S04脫水,並在真 空中濃縮。藉著矽膠層析法純化該產物,連續以在氯仿中 之0%-2%-4%曱醇洗脫,得到想要的化合物,Rf_ 〇·3 (在氯 仿中的40/〇曱醇),其在靜置時固化,產量75。/〇。NMR (CDC13) 5 4.92 (s,2H),7.78 (s,1H),8.77 (s,1H)。質譜:(M+H)+ = 116 〇 D· ((5_ρ塞唑基)甲基)-4-(4-硝苯基)碳酸酯 將在100毫升二氯甲烷中之3·11克(27毫莫耳)的5-(羥甲 基)違唾和過量Ν-甲基嗎4的溶液冷卻至〇。〇,並以8·2克(4 1 宅莫耳)氣甲酸4 -硝’基苯自旨來處理之。在授拌1小時之後,以 CHCI3稀釋該反應混合物,連續以1N 、飽和的含水), 4·45 (s, 1H), 5_10 (m, 2H), 5.67 (d, J 2 6 Hz, 1H) 5 6·60 (d τ — ” < from # , (9), J — 7·5 Hertz, 1H), 7·20 (m, i〇H). Mass Spectrum: (M+H)+ = 609. Example 6 (2, 58) -2 嚷 嚷 嚷 )) methoxy) amide -5-((2S-(l-Mispin-2-one)-3-methylbutyryl)amino group via ", heart diphenyl hexane A · 2- gas-2-A Ethyl mercaptoacetate in the cold part to 0C, with a third _butoxy potassium (〇·5 mol, 5 〇〇 ml of a 1 Μ bath in THF) and 5 〇〇 ml of anhydrous THF three neck 2 Ethyl acetate (0.5 mol, 53.5 ml) and ethyl formate (〇·5) in 2 liters were added dropwise from the addition funnel in a liter round bottom flask. Mol, 40.4 ml) solution. After completion of the addition, the reaction mixture was stirred for 1 hour and allowed to stand overnight. The resulting solid was diluted with diethyl ether and cooled in an ice bath. The pH was lowered to about 3. The organic phase was separated and the layer was washed three times with diethyl ether. The mixed ether portion was dried over NaSCU and concentrated in vacuo. The crude desired compound was stored at -30 ° C and used without further purification. B. Pyrazole-5-carboxylic acid ethyl ester was added to a round bottom flask with 250 ml of anhydrous acetone, 7.5 g (0.123). Mole) thiocarbamide and 18.54 g (0.123 mol) of ethyl 2-chloro-2-methyl decylacetate. The reaction was heated to reflux for 2 h. solvent was removed in vacuo and purified by chromatography The residue was purified by EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) , J = 7 Hz, 3 Η), 4.38 (q5 J = 7 O: \106\106749.DOC • 71- 1292752 Hertz, 2H), 8·50 (s, 1Η), 8.95 (s5 1H). C 5-(Hydroxymethyl)pyrazole in a three-neck 500 ml flask containing pre-cooled (ice bath), lithium aluminum hydride (2.89 g, 76 mmol) in 250 mL THF, within 1.5 hours Ethyl pyrimide-5-carboxylate (11.82 g, 75.68 mmol) in 100 ml of THF was added dropwise to avoid excessive foaming. The reaction was stirred for an additional 1 hour with 2.9 ml of water, 2 · 9 ml of 15% NaOH and 8 7 ml of water was carefully treated. The solid salts were filtered and the filtrate was set aside. The crude salt was heated to reflux for 30 minutes in 1 mL of ethyl acetate. The resulting mixture was filtered and the two filtrates were combined, dried over Na 2 SO 4 and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 0% to 2% to 4% decyl alcohol in chloroform to give the desired compound, Rf 〇·3 (40/nonol in chloroform) It solidifies upon standing and yields 75. /〇. NMR (CDC13) 5 4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass Spectrum: (M+H)+ = 116 〇D·((5_ρ塞zolyl)methyl)-4-(4-nitrophenyl)carbonate 31.1 g in 100 ml of dichloromethane (27 A solution of 5-(hydroxymethyl)-inhibited and excess Ν-methyl?4 in millimolar is cooled to hydrazine. 〇, and treated with 8·2 g (4 1 house Moer) gas formic acid 4-n-nitrobenzene. After 1 hour of mixing, the reaction mixture was diluted with CHCI3, continuously with 1 N, saturated water.

NaHC03,以及飽和的鹽水沖洗,覆以NaS〇4脫水,並在真 空中濃縮。藉著矽膠層析法(Si〇2,1-2% MeOH/ CHC13,在 4% KleOH/CHCl3 中 Rf = 0·5)純化殘餘物,產生 5·9克(78〇/〇) 汽色固體狀之想要產物。NMR (CDCI3) 5 53 (s 2Η) O:\106\106749.DOC -72- 1292752 7·39 (dt,J = 9, 3赫兹,2H),8.01 (s,1Η),8·29 (dt,J = 9, 3赫 兹,2H),8.90(S,1H)。質譜:(m+h)+ = 281。 Ε· (2S,3S,5S)i胺基_2_(N_((5-p塞嗤基)甲氧幾基)胺 基)-3-羥基-i,6-二苯基己烷 利用知自實例4D之程序,使得自實例11?之胺基化合物與 待自實例6D之碳酸酯偶聯,接著利用TFA/CH2Cl2移除B〇卜 保濩基,得到想要的化合物。3〇〇兆赫茲!H NMR (CDd)占 13-1.6 (m,2H),2·40 (dd,J = 14, 8赫兹,1H),2·78 (dd,J = 5 赫兹,1H),2_88 (d,J = 7赫兹,2H),3·01 (m,1H),3·72 (br q, 1H),3.81 (br d,J = l〇赫兹,1H),5·28 (s,2H),5 34 (br d,;= 9赫兹,1H),7·07 (br d,J = 7赫茲,2H),7.15-7.35 (m,8H), 7.87 (s,1H),8·80 (s, 1H)。質譜:(m+H)+ = 426。 F· (2S,3S,5S)-2-[(N-((5- p塞嗤基)甲氧幾基)胺 基)-5-((2 S-(l-喃嗤咬-2-綱基)-3-甲基丁醯基)胺基)_3_經基 _1,6-二苯基己烷 利用標準程序.(在DMF中之EDAC),使得自實例6E之胺基 化合物與得自實例1M之羧酸偶聯,得到想要的化合物 (52%)。300兆赫茲 4 NMR (CDC13) 5 0.82 (d,J = 7.5赫茲, 3H),〇·85 (d,j = 7·5赫茲,3H),(m,2H),2 15 (m,1H), 2·7〇 (m,3H),2.85 (d, 7.5赫茲,2Η),3·08 (m,1H),3.18 (m, 1H),3.30 (m,2H),3.60 (m,3H),3·80 (m5 1H),4.16 (m5 1H), 4·40 (s5 1H),5.16 (d,J = 9赫茲,1H),5.24 (s,2H),6.60 (d,J =9赫茲,1H),7.20 (m,10H),7.83 (s5 1H)5 8·80 (s,1H)。質 谱·(M+H)+ = 594。 O:\106\106749.DOC -73- 1292752 實例7 (2S,3S,5S)-2_(N-((5-噻唑基)甲氧羰基)胺基)_3_羥基 -5-(2S-(l-咪唑啶_2_酮基)-3,3-二曱基丁醯基)胺基-l,6-二 苯基己烷 A· 2S-(1-咪唑啶-2-酮基)-3,3-二甲基丁酸 利用在實例1J到1M中描述的程序,但是以L-第三-丁基-亮胺酸甲酯來代替L-纈胺酸甲酯,得到想要的化合物。300 兆赫茲 4 NMR (DMSO-d6) δ 1 ·0 (s,9Η),3.22 (t,J = 7.5 赫效,2H),3·55 (q,J = 7.5赫兹,1H),3.65 (q,J = 7.5赫兹, 1H),4.14 (s,1H),6·40 (s,1H),12.62 (br s,1H)。質譜: (M+H)+ = 201。 Β· (2S,3S,5S)-2-(N-((5-嘧唑基)-甲氧羰基)胺基)-3-羥基 -5-(2S_(l-咪唑啶-2-酮基)-3,3-二甲基丁醯基)胺基-1,6-二 苯基己烷 利用標準程序(在DMF中之EDAC)將得自實例6E之胺基 化合物與得自實例7 A之羧酸偶聯,得到想要的化合物 (77%)。300兆赫茲1HNMR(CDC13) δ 1.0 (s5 9H)5 1.68 (m5 2H),2.60-2.80 (m,3H),2.85 (d,J = 7·5赫茲,1H),3·10 (m, 1H),3.30 (m,1H),3.50 (m,1H),4.56 (s,1H),5·15 (d5 J = 7·5赫茲,1H),5.25 (ABq,1H),6.50 (d,J = 7赫茲,1H),7.20 (m,10H),7·83 (s5 1H)5 8.80 (s,1H)。質譜:(M+H)+ = 609。 實例8 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(l-咪唑啶-2-酮基)-3,3-二甲基丁醯基)胺基-1,6-二 O:\106\106749.DOC -74- 1292752 苯基己烷 利用標準程序(在DMF中之EDAC)將得自實例IN之胺基 化合物與得自實例7 A之羧酸偶聯,得到想要的化合物 (80%)。300兆赫茲 4 NMR (CDC13) δ 1 ·0 (s,9Η),2· 1 8 (s, 6Η),2.68 (m,1Η),2.80 (m,1Η),2·98 (m,3Η),3·10 (m,1Η), 3.27 (q,J = 7赫茲,ih),3.53 (m,1H),3.77 (m,1H),4.0 (s, 1H),4.20 (m,4H),6.72 (m,1H),7.0 (m,3H),7.10-7.25 (m, l〇H)。質譜:(M+H)+ = 629。 實例9 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(2S_(l-咪唑啶-2-亞硫醯基)-3-甲基丁醯基)胺基-1,6-二 苯基己烷 A· 2S-(1-咪唑啶-2-亞硫醯基)-3-甲基丁酸 利用類似在實例1J到1M中描述的程序,但是以1,1-硫代 罗炭基二咪唑來代替1,1-羰基-二咪唑,得到想要的化合物。 3〇〇兆赫茲咕 NMR (DMSO-d6) δ 0.87 (d,J = 6赫茲,3H), 〇·9ό (d,J = 6赫茲,3H),2.11 (m,1H),3.45 (m,2H),3.62 (m, 1H),3·80 (q5 j = 9赫茲,1H),4·80 (d,j = 10赫茲,1H),8·30 (s,1H),12·75 (br s,1H)。 Β· (28,38,58)-2-(2,6-二曱基苯氧乙醯基)胺基-3-羥基 咪唑啶-2-亞硫醯基)-3-甲基丁醯基)胺基-1,6-二 苯基己燒 利用標準程序(在DMF中之EDAC)將得自實例1N之胺基 化合物與得自實例9 A之羧酸偶聯,得到想要的化合物 -75-NaHC03, washed with saturated brine, dehydrated with NaS〇4 and concentrated in the air. The residue was purified by silica gel chromatography (Si2, 1-2% MeOH/CHC13, Rf = 0·5 in 4% KleOH/CHCl3) to yield 5·9 g (78 〇/〇). The desired product. NMR (CDCI3) 5 53 (s 2Η) O:\106\106749.DOC -72- 1292752 7·39 (dt, J = 9, 3 Hz, 2H), 8.01 (s, 1Η), 8·29 (dt , J = 9, 3 Hz, 2H), 8.90 (S, 1H). Mass spectrum: (m+h)+ = 281. Ε·(2S,3S,5S)iamino-2-(N_((5-p)-methoxy)amino)-3-hydroxy-i,6-diphenylhexane The procedure of Example 4D was such that the amine compound from Example 11 was coupled with the carbonate to be obtained from Example 6D, followed by removal of the B oxime group using TFA/CH 2 Cl 2 to give the desired compound. 3 megahertz! H NMR (CDd) accounts for 13-1.6 (m, 2H), 2·40 (dd, J = 14, 8 Hz, 1H), 2·78 (dd, J = 5 Hz, 1H), 2_88 (d, J) = 7 Hz, 2H), 3·01 (m, 1H), 3·72 (br q, 1H), 3.81 (br d, J = l〇 Hertz, 1H), 5·28 (s, 2H), 5 34 (br d,;= 9 Hz, 1H), 7·07 (br d, J = 7 Hz, 2H), 7.15-7.35 (m, 8H), 7.87 (s, 1H), 8·80 (s, 1H). Mass spectrum: (m+H)+ = 426. F·(2S,3S,5S)-2-[(N-((5- p)-methoxy)methoxy)amino)-5-((2 S-(l- 嗤 嗤 bit-2-纲))-3-methylbutylidene)amino)_3_transyl-1,6-diphenylhexane using standard procedures (EDAC in DMF), such that the amine compound from Example 6E is derived from The carboxylic acid of Example 1M was coupled to give the desired compound (52%). 300 MHz 4 NMR (CDC13) 5 0.82 (d, J = 7.5 Hz, 3H), 〇·85 (d, j = 7.5 Hz, 3H), (m, 2H), 2 15 (m, 1H) , 2·7〇(m,3H), 2.85 (d, 7.5 Hz, 2Η), 3·08 (m,1H), 3.18 (m, 1H), 3.30 (m, 2H), 3.60 (m, 3H) ,3·80 (m5 1H), 4.16 (m5 1H), 4·40 (s5 1H), 5.16 (d, J = 9 Hz, 1H), 5.24 (s, 2H), 6.60 (d, J = 9 Hz) , 1H), 7.20 (m, 10H), 7.83 (s5 1H) 5 8·80 (s, 1H). Mass spectrum (M+H)+ = 594. O:\106\106749.DOC -73- 1292752 Example 7 (2S,3S,5S)-2_(N-((5-thiazolyl)methoxycarbonyl)amino)_3_hydroxy-5-(2S-( L-imidazolidin-2-yl)-3,3-dimercaptobutyl)amino-l,6-diphenylhexane A· 2S-(1-imidazolidin-2-one)-3, 3-Dimethylbutyric acid was carried out using the procedure described in Examples 1J to 1M, but replacing L-proline methyl ester with L-tris-butyl-leucine methyl ester to give the desired compound. 300 MHz 4 NMR (DMSO-d6) δ 1 ·0 (s, 9 Η), 3.22 (t, J = 7.5 Hz, 2H), 3·55 (q, J = 7.5 Hz, 1H), 3.65 (q , J = 7.5 Hz, 1H), 4.14 (s, 1H), 6·40 (s, 1H), 12.62 (br s, 1H). Mass Spectrum: (M+H)+ = 201. Β·(2S,3S,5S)-2-(N-((5-pyrazolyl)-methoxycarbonyl)amino)-3-hydroxy-5-(2S_(l-imidazolidin-2-one) -3,3-Dimethylbutanyl)amino-1,6-diphenylhexane The amino group compound from Example 6E was combined with the carboxy group from Example 7 A using standard procedures (EDAC in DMF). Acid coupling gave the desired compound (77%). 300 MHz 1H NMR (CDC13) δ 1.0 (s5 9H) 5 1.68 (m5 2H), 2.60-2.80 (m, 3H), 2.85 (d, J = 7.5 Hz, 1H), 3·10 (m, 1H) ), 3.30 (m, 1H), 3.50 (m, 1H), 4.56 (s, 1H), 5·15 (d5 J = 7.5 Hz, 1H), 5.25 (ABq, 1H), 6.50 (d, J = 7 Hz, 1H), 7.20 (m, 10H), 7·83 (s5 1H) 5 8.80 (s, 1H). Mass spectrum: (M+H)+ = 609. Example 8 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one)- 3,3-Dimethylbutanyl)amino-1,6-diO:\106\106749.DOC -74- 1292752 Phenylhexane The amine from Example IN was obtained using standard procedures (EDAC in DMF) The base compound was coupled with the carboxylic acid from Example 7 A to give the desired compound (80%). 300 MHz 4 NMR (CDC13) δ 1 ·0 (s, 9Η), 2· 1 8 (s, 6Η), 2.68 (m, 1Η), 2.80 (m, 1Η), 2·98 (m, 3Η) ,3·10 (m,1Η), 3.27 (q,J = 7 Hz, ih), 3.53 (m,1H), 3.77 (m,1H), 4.0 (s, 1H), 4.20 (m,4H), 6.72 (m, 1H), 7.0 (m, 3H), 7.10-7.25 (m, l〇H). Mass Spectrum: (M+H)+ = 629. Example 9 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S_(l-imidazolidin-2-sulfinyl) -3-methylbutyryl)amino-1,6-diphenylhexane A·2S-(1-imidazolidin-2-sulfinyl)-3-methylbutanoic acid was similarly used in Examples 1J to 1M The procedure described in the above, but replacing 1,1-carbonyl-diimidazole with 1,1-thiocarbyldiimidazole gives the desired compound. 3〇〇 megahertz NMR (DMSO-d6) δ 0.87 (d, J = 6 Hz, 3H), 〇·9ό (d, J = 6 Hz, 3H), 2.11 (m, 1H), 3.45 (m, 2H), 3.62 (m, 1H), 3·80 (q5 j = 9 Hz, 1H), 4·80 (d, j = 10 Hz, 1H), 8·30 (s, 1H), 12·75 ( Br s, 1H). Β·(28,38,58)-2-(2,6-Dimercaptophenoxyethyl)amino-3-hydroxyimidazolidin-2-sulfinyl)-3-methylbutanyl)amine Base-1,6-diphenylhexanhydride The amine compound from Example 1N was coupled with the carboxylic acid from Example 9A using standard procedures (EDAC in DMF) to give the desired compound-75-

O:\106\1.06749.DOC © 1292752 (53%)。3 00兆赫茲1HNMR(CDCl3)5 0·82(d,J = 6赫兹, 3H),0·93 (d,J = 6赫茲,3H),1.75 (m5 1H),2.20 (s5 6H),2.65 (m,1H),2.84 (m,1H),3.0 (m,3H),3·25 (m,1H),3.40 (m, 2H),3·54 (d,J =赫茲,ih),3·78 (m,1H),4.22 (m,4H), 4.56 (d,J = 10.5赫茲,1H),5.65 (s,1H),6.60 (d,J =赫茲, 1H),7·0 (m,3H),7.25 (m,10H)。質譜:(M+H)+ = 631。 實例10 (2S,3S,5S)-2_(4_胺基-2,6-二甲基苯氧乙醯基)胺基-3-羥 基-5-(2S-(l-咪唑啶-2-酮基)-3-甲基丁醯基)胺基-1,6-二苯 基己烷 A. 2,6_二甲基-4-硝基苯氧乙酸乙酯 慢慢地將50毫升三氟乙酸,加至在1〇〇毫升二氣甲烷中之 10.5克(54.6毫莫耳)的2,6-二甲苯氧基乙酸乙酯和7.5克(109 毫莫耳)亞硝酸鈉的溶液中。在加成作用之後,該反應混合 物變成固體。加入額外的3 5毫升三氟乙酸。在室溫下攪拌 該反應混合物3小時之後,細心地使其分配在飽和的碳酸氫 鈉溶液和二氣曱烷之間。以鹽水沖洗混合的有機萃取物, 並覆以無水的硫酸鈉脫水,過濾並在減低的壓力下將其蒸 發至無水。使殘餘物在30%醋酸乙酯和己烷中再結晶,得 到4.75克(36%)淡育色柱狀的2,6 -二甲基-4 -瑣基苯氧乙酸乙 酯。300兆赫茲咕 NMR (CDC13) δ 1 ·34 (3Η,t5 J = 7.5赫 茲),2.39 (6H,s),4·31 (2H,q,J = 7·5赫茲),7.93 (2H,s)。 Β· 2,6-二甲基-4-硝基苯氧基乙酸 將1¾:升3Ν的氫氧化納加至在1〇毫升甲醇中之0962克 O:\106\106749.DOC -76- 1292752 (4.06毫莫耳)2,6_二甲基-4-硝基苯氧基乙酸乙酯的溶液 中。在室溫下攪拌該反應混合物30分鐘之後,以3N HC1酸 化’並使其分配在水和二氯曱烷之間,以鹽水沖洗混合的 有機萃取物,並覆以無水的硫酸鈉脫水,過濾並在減低的 壓力下蒸發至無水,得到〇·82克(97%)淡黃色固體狀的2,6-一甲基-4_确基苯氧基乙酸。300兆赫茲NMR (d3-DMSO) δ 2·35 (6H,s)5 4·55 (2Η,s),7.97 (2Η,s),13·02 (1Η,br)。 C· (2S,3S,5S)-2-(第三_丁氧羰基)胺基羥基 -5-(2S-(l-咪唑啶-2-酮基)-3-甲基丁醯基)胺基-i,6-二苯基 己烷 利用標準程序(在DMF中之EDAC),將(2S,3S,5S)-2-(第三 -丁氧羰基)胺基-3-羥基-5-胺基-1,6-二苯基己烷與得自實例 1M之羧酸偶聯,得到想要的化合物(1〇〇%)。3〇〇兆赫茲ιΗ NMR (CDCI3) δ 0.83 (d,J = 6赫兹,3Η),0.87 (d,J = 6赫 兹,3H),1·40 (s,9H),1.70 (m,2H),2.16 (m,1H),2·58-2·80 (m,4H)3 3.10-3.30 (m,4H),3.65 (m,2H),4.20 (m5 1H),4·38 (s,1H),4.83 (d,J =赫茲,1H),6.53 (d5 J = 9赫茲,1H),7.20 (m,10H)。質譜:(M+H)+ = 553。 D· (2S,3S,5S)-2-胺基-3-經基-5-(2S-(l-味嗤 -2·嗣 基)-3-曱基丁醯基)胺基-1,6-二苯基己烷 藉著標準程序(TFA/CH2C12)將得自實例10C之化合物脫 去Boc-保護基,得到想要的產物。300兆赫茲NMR (CDCI3) 5 0.87 (d,J = 6赫茲,3H),0.90 (d,J =: 6赫茲, 3H),1.33 (dd,J = 4.5,9.0赫茲,1H),2.18 (m,1H),2·50 (m, O:\106\106749.DOC -77- 1292752 1H),2.80 (m,5H),3·20 (m,4H),3.72 (d,J = 10赫茲,1H), 4·3〇 (m,1H),4.50 (s,1H),6.67 (d,J = 7赫茲 5 1H),7.20 (m, 1〇H)。質譜··(m+H)+ = 453。 Ε· (2S,3S,5S)-2-(4-硝基-2,6-二甲苯氧基乙醯基)胺基 -3-羥基-5-(2S-(l-咪唑啶-2-酮基)-3-甲基丁醯基)胺基-1,6-一求基己烧 利用標準程序(在DMF中之EDAC)將得自實例10D之胺基 化合物與得自實例10B之羧酸偶聯,得到想要的化合物。3 〇〇 兆赫茲NMR (CDC13) 5 0.83 (d,J = 7赫兹,3H),0·86 (d,J = 7赫茲,3Η),1·70 (m,3Η),2·18 (m,2Η),2.28 (s,6Η), 2·75 (m,3H),2.95-3.30 (m,6H), 3.67 (d,J = 10.5赫茲,1H), 3·75 (m,1H),3·82 (d,J = 4赫茲,1H),4.25 (m,5H),6.55 (d, J = 7赫茲,1H),7.20 (m,10H),7.92 (s,2H)。質譜:(M+H)+ =660 〇O:\106\1.06749.DOC © 1292752 (53%). 3 00 MHz 1H NMR (CDCl3) 5 0·82 (d, J = 6 Hz, 3H), 0·93 (d, J = 6 Hz, 3H), 1.75 (m5 1H), 2.20 (s5 6H), 2.65 (m,1H), 2.84 (m,1H), 3.0 (m,3H),3·25 (m,1H), 3.40 (m, 2H),3·54 (d,J=hertz,ih),3 · 78 (m, 1H), 4.22 (m, 4H), 4.56 (d, J = 10.5 Hz, 1H), 5.65 (s, 1H), 6.60 (d, J = Hertz, 1H), 7·0 (m , 3H), 7.25 (m, 10H). Mass spectrum: (M+H)+ = 631. Example 10 (2S,3S,5S)-2_(4_Amino-2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2- Keto)-3-methylbutanyl)amino-1,6-diphenylhexane A. Ethyl 2,6-dimethyl-4-nitrophenoxyacetate slowly 50 ml of trifluoroacetic acid It was added to a solution of 10.5 g (54.6 mmol) of ethyl 2,6-xyloxyacetate and 7.5 g (109 mmol) of sodium nitrite in 1 mL of di-methane. After the addition, the reaction mixture became a solid. An additional 35 ml of trifluoroacetic acid was added. After the reaction mixture was stirred at room temperature for 3 hours, it was carefully partitioned between a saturated sodium hydrogen carbonate solution and dioxane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was recrystallized from 30% ethyl acetate and hexane to yield 4.75 g (yield: 36%) of ethylamine 2,6-dimethyl-4-bromophenoxyacetate. 300 MHz NMR (CDC13) δ 1 ·34 (3Η, t5 J = 7.5 Hz), 2.39 (6H, s), 4·31 (2H, q, J = 7.5 Hz), 7.93 (2H, s ). Β·2,6-Dimethyl-4-nitrophenoxyacetic acid, adding 13⁄4: liter of 3 Torr of sodium hydroxide to 0962 g of 1 mM methanol O:\106\106749.DOC -76-1292752 (4.06 mmol) in a solution of 2,6-dimethyl-4-nitrophenoxyacetic acid ethyl acetate. After stirring the reaction mixture for 30 minutes at room temperature, it was acidified with 3N HCl and partitioned between water and dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure afforded EtOAc (EtOAc: EtOAc) 300 MHz NMR (d3-DMSO) δ 2·35 (6H, s) 5 4·55 (2Η, s), 7.97 (2Η, s), 13·02 (1Η, br). C·(2S,3S,5S)-2-(Third-butoxycarbonyl)aminohydroxy-5-(2S-(l-imidazolidin-2-one)-3-methylbutanyl)amine- i,6-Diphenylhexane (2S,3S,5S)-2-(Thr-Butoxycarbonyl)amino-3-hydroxy-5-amino group using standard procedures (EDAC in DMF) -1,6-Diphenylhexane was coupled with the carboxylic acid from Example 1M to give the desired compound (1%). 3 〇〇 Hz ι NMR (CDCI3) δ 0.83 (d, J = 6 Hz, 3 Η), 0.87 (d, J = 6 Hz, 3H), 1·40 (s, 9H), 1.70 (m, 2H) , 2.16 (m, 1H), 2·58-2·80 (m, 4H) 3 3.10-3.30 (m, 4H), 3.65 (m, 2H), 4.20 (m5 1H), 4·38 (s, 1H) ), 4.83 (d, J = Hertz, 1H), 6.53 (d5 J = 9 Hz, 1H), 7.20 (m, 10H). Mass spectrum: (M+H)+ = 553. D·(2S,3S,5S)-2-amino-3-carbyl-5-(2S-(l-miso-2·indolyl)-3-mercaptobutyl)amino-1,6- The compound from Example 10C was removed from the Boc-protecting group by diphenylhexane by standard procedures (TFA/CH2C12) to give the desired product. 300 MHz NMR (CDCI3) 5 0.87 (d, J = 6 Hz, 3H), 0.90 (d, J =: 6 Hz, 3H), 1.33 (dd, J = 4.5, 9.0 Hz, 1H), 2.18 (m , 1H), 2·50 (m, O:\106\106749.DOC -77-129272 1H), 2.80 (m, 5H), 3·20 (m, 4H), 3.72 (d, J = 10 Hz, 1H), 4·3〇(m,1H), 4.50 (s,1H), 6.67 (d, J = 7 Hz 5 1H), 7.20 (m, 1〇H). Mass spectrum··(m+H)+ = 453. Ε·(2S,3S,5S)-2-(4-nitro-2,6-xyloxyethenyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2- Keto)-3-methylbutanyl)amino-1,6-monohexanone The amine based compound from Example 10D and the carboxylic acid couple from Example 10B were obtained using standard procedures (EDAC in DMF). Combine to get the desired compound. 3 〇〇 megahertz NMR (CDC13) 5 0.83 (d, J = 7 Hz, 3H), 0·86 (d, J = 7 Hz, 3 Η), 1·70 (m, 3 Η), 2·18 (m , 2Η), 2.28 (s, 6Η), 2·75 (m, 3H), 2.95-3.30 (m, 6H), 3.67 (d, J = 10.5 Hz, 1H), 3·75 (m, 1H), 3·82 (d, J = 4 Hz, 1H), 4.25 (m, 5H), 6.55 (d, J = 7 Hz, 1H), 7.20 (m, 10H), 7.92 (s, 2H). Mass spectrometry: (M+H)+ = 660 〇

Fe (2S,3S,5S)_2-(4-胺基_2,6-二甲苯氧基乙醯基)胺基 -3-羥基-5-(2S-(l-咪唑啶-2-酮基)-3-甲基丁醢基)胺基-丨,“ 二苯基己烷 將69宅克得自實例ι〇Ε之化合物的溶液,加至在5毫升甲 醇中之7¾克10〇/〇 Pd/C的懸浮液中。在氫氣壓下激烈地攪拌 該反應混合物(將充滿氫氣的汽球附接在三-向活栓上)。ι 小時之後,由TLC分析確認反應完成;濾掉催化劑並在真 空中濃細濾液。藉著矽膠管層析法(2%到5% Me〇H/ci^cl2) 純化粗產物,得到想要的化合物(65%)。3〇〇兆赫茲1hnmr (CDC13) 5 〇·82 (d,J =赫兹,3H),〇 87 (d,J = 6赫兹, O:\106\106749.DOC -78- 1292752 3Η),1·70 (m,2H),2·1〇 (s,6H),2.15 (m,2H),2.72 (m,2H), 2·97 (d,j = 7 5赫茲,2H),3.08 (m,1H),3·15 (m,1H),3·30 (m,2H),3 45 (br s5 2H),3·66 (d,J == l〇赫兹,1H),3.72 (m, 1H),3.90 (d,J 二 3赫茲,1H),4.10-4.20 (m,4H),4.30 (s, 1H),6.33 (s,2H),6.57 (d,J = 9赫茲,1H),7.20 (m5 10H)。 質譜:(M+H)+ 二 630。 實例11 (2S,3S,5S)-2-(2,4,6-三甲苯氧基乙醯基)胺基-3-羥基 -5-(2S-(i_咪唑啶_2·酮基)-3-甲基丁醯基)胺基-1,6-二苯基 己烷 Α· 2,4,6-三甲苯氣基乙酸 利用得自實例1G和1 H之程序,但是以2,4,6-三甲紛來代 替2,6、二甲酴,得到想要的化合物。300兆赫兹4 NMR (CDC13) ^ 2.25 (s,9H),4·43 (s,2H),6.84 (s5 2H)。質譜: (M+H)+ = 195 ° B. (28,38,58)-2-(2,4,6_三甲苯氧基乙醯基)胺基-3-羥 基-5-(2S-(l-咪唑啶-2-酮基)-3-甲基丁醯基)胺基-1,6-二苯 基已烷 利用標準程序(在DMF中之EDAC)將得自實例l〇D之胺基 化合物與得自實例11A之羧酸偶聯,得到想要的化合物 (51%)。300兆赫茲】H NMR (CDC13)占 〇·82 (d,J = 6赫茲, 3H),〇·85 (d,J = 6赫茲,3H),1.70 (m5 4H),2.13 (s,6H),2·25 (s,3H),2.75 (m,2H),2.97 (d,J = 7赫茲,1H),3·13 (m, 2H), 3.28 (m,2H),3.68 (d,J = 10赫茲,ih),3.72 (m,1H),4.16 O:\106\106749.DOC -79- 1292752 (m,4H),4 40 · (br s,1H),6.67 (d,J = 8赫兹,1H)5 6.80 (s, 2H)’ 7 9rw v 5 • (m,1〇H)。質譜:(m+H)+ = 629。 實例12 )2 (4_敦_2,6 -二甲苯氧基乙醯基)胺基經基 -5-j§ /-I 喊 _ _咪唑啶_2_酮基卜3_曱基丁醯基)胺基二苯基 A· 氟-2,6-二曱苯氧基乙酸 于貢例10和1^之程序,但是以4-氟_2,6-二曱酚來 代替2 6- -田π、 ’ 一 f紛’得到想要的化合物。3〇〇兆赫茲iH nmr (CD3CD&gt;i Λ •26 (s,6Η),4.37 (s,2Η),6.73 (d,J = 9赫兹, 2H)。質譜:M+ = 198。 , Β· (2S,3S,5S)_2-(4-氟-2,6-二甲苯氧基乙醯基)胺基 羥基4-(2S-(l-咪唑啶_2_酮基)_3-甲基丁醯基)胺基^,卜二 苯基已烷 將知自實例10D之胺基化合物與得自實例12A之羧酸偶 聯传到想要的化合物。300兆赫茲^ NMR (CDC13) 5 0·83 (d,J = 6赫兹,3H),〇·86 (d,J = 6赫兹,3H),! 72 (m, 2H),2·15 (s,6H),2.20 (m5 1H),2.76 (m,2H),2·98 (d J = 7 赫兹,2H),3」2 (m,2H),3.30 (m,2H)5 3·67 (d,j = 1〇赫兹, 1H),3·72 (m,1H),4.13 (ABq,J = 8·9赫兹,2H),4·2〇 (m, 2H),4.37 (s,1H),6·64 (d,J = 9赫兹,1H),6·7〇 (d,j =赫兹, 2H),7.20 (m, 10H)。質譜:(m+H)+ = 633。 實例13 (28,38,58)-2-(4,6-二甲基嘧啶-5-氧基乙醯基)胺基-3-羥 O:\106\106749.DOC 8〇 1292752 基-S-(2S-(1-咪唑啶-2-酮基)-3-甲基丁醯基)胺基-1,6-二苯 基己烷 Α· 4,6-二甲基嘧啶-5-氧基乙酸 利用得自實例1G和1Η之程序,但是以5-羥基-4,6-二甲基 喷°定(根據Chem· Ber. 93,1998頁,1960製備)來代替2,6-二 甲盼’得到想要的化合物。300兆赫茲NMR (DMSO-d6) δ 2·45 (s,6Η),4.55 (s,2Η),8.50 (s,1Η)。質譜:Μ+ = 183。 Β· (28,38,58)_2-(4,6-二甲基嘧啶_5-氧基乙醯基)胺基 -3-經基_5^2S-(1-咪唑啶酮基甲基丁醢基)胺基 二苯基己烷 將得自實例10D之胺基化合物與得自實例13A之羧酸偶 聯’得到想要的化合物。300兆赫茲4 NMR (CDC13) 5 0.82 (d5 J = 6赫茲,3H),0·85 (d,J = 6赫茲,3H),1.70 (m, 2H),2·15 (m,1H),2·40 (s,6H),2.75 (m,2H),2.97 (d,J = 7 赫兹,2H),3·12 (m,2H),3.30 (m,2H),3.66 (d,J = 10赫兹, 1H), 3.74 (m,ih),3·88 (d,J =赫兹,iH),4.20 (m,4H), 6·62 (d,J = 9赫兹,1H),7.0 (d,J = 9赫兹,m),7.20 (m, l〇H),8.70 (s,1H)。質譜:(M+H)+ = 617。 實例14 (28,38,58)-2-(2,4-二曱基吡啶_3-氧基乙醯基)胺基-3-羥 基-5-(2S-(l-咪唑啶-2-酮基)-3,3-二甲基丁醯基)胺基 一本基己燒 A. 2.4-二甲基吡啶基-3-氧基乙酸 利用得自實例1G和1H之程序,但是以2,4_二甲基-3_羥基 O:\106\106749.DOC -81 - 1292752 叶匕啶(根據J· Med· Chem· 35, 3667-3671頁,1992來製備)來 代替2,6-二甲酚,得到想要的化合物。3〇〇兆赫茲iH NMR (DMSO_d6) δ 2.26 (s? 3H)? 2.42 (s? 3H)5 4.44 (s5 2H), 7.08 (d,J = 5赫茲,1H),8.07 (d,J = 5赫茲,1H)。質譜:(M+H)+ = 182 ° B· (28,38,58)-2-(2,4-二甲基吡啶_3-氧基乙醯基)胺基 -3-經基-5-(第三-丁氧羰基)胺基-u-二苯基己烷 利用標準程序(在DMF中之EDAC)將得自實例10F之胺基 化合物與得自實例14A之羧酸偶聯,得到想要的化合物。300 兆赫茲 NMR (CDC13) δ 1.40 (s,9Η),1·70 (m,2Η), 2.18 (s,3H),2.40 (s,3H),2.77 (m,2H),2·98 (d,J = 7赫兹, 2H),3.75-3.95 (m,3H),4.20 (s,2H),4.22 (m5 1H),4.60 (br d,1H),7.0 (d,J = 5赫茲,1H),7.10 (m,3H),7.25 (m,7H), 8.16 (d,J = 5赫茲,1H)。質譜:(M+H)+ = 548。 C· (28,38,58)-2-(2,4-二甲基吡啶-3-氧基乙醯基)胺基 -3-羥基-5-胺基-1,6-二苯基己烷 利用標準程序(TFA/CH2C12)將得自實例14B之化合物脫 去Boc-保護基,得到想要的化合物。300兆赫茲4 NMR (CDC13) δ 1.45 (m,1Η),1·62 (m,1Η),2·23 (s5 3Η),2·45 (s,3H),2.50 (m,1H),2.80 (m,1H),3.0 (m5 2H), 3·12 (m5 1H),3.90 (m,1H),4·18 (m,1H),4.25 (ABq,J = 9, 12赫茲, 2H),6·98 (d,J = 5赫茲,1H),7.10 (m,2H),7.30 (m,8H), 8.17 (d5 J = 5赫茲,1H)。質譜··(M+H)+ = 448。 D· (28,38,58)-2-(2,4-二甲基吡啶-3_氧基乙醯基)胺基 O:\106\106749.DOC -82 - 1292752 -3-經基_5-(2S-(1-咪唑啶酮基兴3,弘二曱基丁醯基)胺基 -1,6·二苯基己烷 利用標準程序(在DMF中之EDAC)將得自實例14C之胺基 化合物與得自實例7A之羧酸偶聯,得到想要的化合物。3〇〇 兆赫茲NMR (CDC13) δ 1.0 (s,9Η),1.70 (m,3Η),2·18 (s,3H),2.42 (s,3H),2.75 (m,2H)5 3·0 (m,4H),3.30 (m, 1H),3.55 (m,1H),3.80 (m,1H),4.05 (s,1H),4.20 (m,4H), 4.60 (s,ih)5 6.70 (d,J = 7赫茲,1H),6.97 (d,J = 5赫兹, 1H),7.15 (m,3H),7.25 (m5 7H),8.17 (d5 J =赫茲,1H)。質 譜·(M+H)+ = 630。 實例15 (28,38,58)-2-(2,4_二甲基外|;咬-3-氧基乙酿基)胺基-3-輕 基-5-(2S-(l-咪唑啶_2_酮基曱基丁醯基)胺基4,“二苯 基己烷 利用標準程序(在DMF中之EDAC)將得自實例14C之胺基 化合物與得自實例1M之羧酸偶聯,得到想要的化合物。30〇 兆赫茲 4 NMR (CDC13) 5 0.82 (d,J =赫茲,3H),0·86 (d,J = 6赫茲,3Η),1.75 (m,3Η)5 2.15 (m,1Η),2.18 (s,3Η), 2.40 (s,3H),2.75 (m,2H),2·97 (d,J = 7.5赫茲,2H),3·20 (m,4Η),3.70 (d5 J = 10赫茲,1Η),3.75 (m,1Η),4.20 (m5 6H),4.52 (s,1H),3.75 (m,1H),4·20 (m,6H),4·52 (s,1H), 6.80 (d,J = 7赫茲,1H),6.96 (d,J = 4.5赫茲,1H),7·20 (m, 10H),8.17 (d,J = 4.5赫茲,1H)。質譜:(M+H)+ = 616。 實例16 O:\106\106749.DOC -83- 1292752 (28,38,58)-2-(2,6-二甲基硫代苯氧乙醯基)胺基_3-羥基 _s-(2S-(l-咪唑啶_2_酮基)-3-甲基丁醯基)胺基-1&gt;6_二苯基 已烷 Α· 2,6-二甲基硫代苯氧基乙酸 利用得自實例1G和1Η之程序,但是以2,6-二甲基苯硫酚 來代替2,6-二甲酚,得到想要的化合物。300兆赫茲4 NMR (CDC13) δ 2.5 6 (s,6Η),3.40 (s,2Η),7.10 (m,3Η)。質譜: M+ = 197 〇 ®· (28,38,58)-2-(2,6-二甲基硫代苯氧乙醯基)胺基_3_ 經基-5-(2S-(l-咪唑啶-2-酮基)-3-甲基丁醯基)胺基_;ι,6-二 苯基已燒 將得自實例16Α之羧酸與得自實例10D之胺基化合物偶 聯’得到想要的化合物。3〇〇兆赫茲iH NMR (CDC13) 5 〇·82 (d5 J =赫茲,3H),0.86 (d,J = 6赫茲,3H),2.15 (m, 旧),2.52 (s,6H),2.70 (m,4H),3.10 (m,2H),3·30 (m,4H), 3.60 (m,2H),4.0 (m,1H),4.10 (m,1H),4.22 (s,1H),6.39 (d,J = 7赫茲,1H),6.58 (d,J = 9赫茲,1H),7.20 (m,13H)。 質譜:(M+H)+ = 631。 實例17 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基I羥基 -5-(2S-(l_吡咯啶-2-酮基)_3_甲基丁醯基)胺基^二苯基 己烷 Α· 4-溴丁醯基綠胺酸甲酯 將1.36毫升(16.8毫莫耳)的吡啶加至在3〇毫升CH2Cl2中Fe (2S,3S,5S)_2-(4-Amino-2,6-xyloxyethenyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one) -3-methylbutylidene)amino-indole, "diphenylhexane. A solution of 69 housek from the compound of the example ι〇Ε was added to 7⁄4 g of 10 〇/〇Pd/ in 5 ml of methanol. In the suspension of C. The reaction mixture was vigorously stirred under a hydrogen pressure (the hydrogen-filled balloon was attached to the three-way stopcock). After 1 hour, the reaction was confirmed by TLC analysis; the catalyst was filtered off and vacuumed. The concentrated filtrate was purified by hydrazine gel chromatography (2% to 5% Me 〇H / ci^Cl2) to give the desired compound (65%). 3 〇〇 megahertz 1hnmr (CDC13) 5 〇·82 (d, J = Hertz, 3H), 〇87 (d, J = 6 Hz, O: \106\106749.DOC -78- 1292752 3Η), 1·70 (m, 2H), 2·1 〇(s,6H), 2.15 (m,2H), 2.72 (m,2H), 2·97 (d,j = 7 5 Hz, 2H), 3.08 (m, 1H), 3·15 (m, 1H) ),3·30 (m,2H),3 45 (br s5 2H),3·66 (d,J == l〇 Hertz, 1H), 3.72 (m, 1H), 3.90 (d, J 2 3 Hz , 1H), 4.10-4.20 (m, 4H), 4.30 (s 1H), 6.33 (s, 2H), 6.57 (d, J = 9 Hz, 1H), 7.20 (m5 10H) Mass Spectrum: (M+H) + 630. Example 11 (2S, 3S, 5S)-2 -(2,4,6-trimethyloxyethoxymethyl)amino-3-hydroxy-5-(2S-(i-imidazolidin-2-yl)-3-methylbutanyl)amino-1 , 6-diphenylhexane oxime 2,4,6-trimethylbenzene acetoxy acetic acid using the procedures obtained from Examples 1G and 1 H, but replacing 2,6, dimethyl with 2,4,6-trimethyl酴, the desired compound is obtained. 300 MHz 4 NMR (CDC13) ^ 2.25 (s, 9H), 4·43 (s, 2H), 6.84 (s5 2H). Mass Spectrum: (M+H)+ = 195 ° B. (28,38,58)-2-(2,4,6-Trimethyloxyethenyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2-one) -3-Methylbutanyl)amino-1,6-diphenylhexane The amine compound from Example 1D was coupled to the carboxylic acid from Example 11A using standard procedures (EDAC in DMF). , to obtain the desired compound (51%). 300 megahertz] H NMR (CDC13) 〇·82 (d, J = 6 Hz, 3H), 〇·85 (d, J = 6 Hz, 3H), 1.70 (m5 4H), 2.13 (s, 6H), 2·25 (s, 3H), 2.75 (m, 2H), 2.97 (d, J = 7 Hz, 1H), 3· 13 (m, 2H), 3.28 (m, 2H), 3.68 (d, J = 10 Hz, ih), 3.72 (m, 1H), 4.16 O: \106\106749.DOC -79- 1292752 (m, 4H ), 4 40 · (br s, 1H), 6.67 (d, J = 8 Hz, 1H) 5 6.80 (s, 2H)' 7 9rw v 5 • (m, 1〇H). Mass spectrum: (m+H)+ = 629. Example 12) 2 (4_Den-2,6-xyloxyethenyl)amino group via group -5-j§ /-I shouting _ _ imizidine 2 keto keto 3 曱 曱 醯 ) ) Aminodiphenyl A·fluoro-2,6-dioxaphenoxyacetic acid is used in the procedures of Examples 10 and 1^, but 4-fluoro-2,6-diinol is used instead of 2 6- , 'One f' to get the desired compound. 3 〇〇 megahertz iH nmr (CD3CD>i Λ •26 (s,6Η), 4.37 (s,2Η), 6.73 (d, J = 9 Hz, 2H). Mass spectrum: M+ = 198. , Β· (2S ,3S,5S)_2-(4-Fluoro-2,6-xyloxyethenyl)aminohydroxy 4-(2S-(l-imidazolidin-2-yl)-3-methylbutenyl)amine The amine compound from Example 10D was coupled to the desired compound from the carboxylic acid from Example 12A. 300 MHz NMR (CDC13) 5 0·83 (d, J = 6 Hz, 3H), 〇 · 86 (d, J = 6 Hz, 3H), ! 72 (m, 2H), 2·15 (s, 6H), 2.20 (m5 1H), 2.76 (m, 2H) ), 2·98 (d J = 7 Hz, 2H), 3" 2 (m, 2H), 3.30 (m, 2H) 5 3·67 (d, j = 1 〇 Hz, 1H), 3·72 ( m,1H), 4.13 (ABq, J = 8·9 Hz, 2H), 4·2〇(m, 2H), 4.37 (s, 1H), 6·64 (d, J = 9 Hz, 1H), 6·7〇(d,j=hertz, 2H), 7.20 (m, 10H). Mass spectrum: (m+H)+ = 633. Example 13 (28,38,58)-2-(4,6-II Methylpyrimidin-5-oxyethylidene)amino-3-hydroxyO:\106\106749.DOC 8〇1292752 s-(2S-(1-imidazolidin-2-one)-3- Methylbutenyl)amino-1 , 6-diphenylhexane oxime 4,6-dimethylpyrimidin-5-oxyacetic acid using the procedure from Example 1G and 1 ,, but with 5-hydroxy-4,6-dimethyl spray (According to Chem. Ber. 93, page 1998, prepared in 1960) instead of 2,6-dimethyl </ br> to obtain the desired compound. 300 MHz NMR (DMSO-d6) δ 2·45 (s, 6 Η), 4.55 (s, 2Η), 8.50 (s, 1Η). Mass Spectrum: Μ+ = 183. Β· (28,38,58)_2-(4,6-Dimethylpyrimidin-5-oxyethyl)amine Benzyl-3-transyl- 5^2S-(1-imidazolidinonemethylbutanyl)aminodiphenylhexane. The amine compound from Example 10D was coupled with the carboxylic acid from Example 13A. Desired compound. 300 MHz 4 NMR (CDC13) 5 0.82 (d5 J = 6 Hz, 3H), 0·85 (d, J = 6 Hz, 3H), 1.70 (m, 2H), 2·15 ( m,1H),2·40 (s,6H),2.75 (m,2H),2.97 (d,J = 7 Hz, 2H), 3·12 (m, 2H), 3.30 (m, 2H), 3.66 (d, J = 10 Hz, 1H), 3.74 (m, ih), 3.88 (d, J = Hertz, iH), 4.20 (m, 4H), 6·62 (d, J = 9 Hz, 1H ), 7.0 (d, J = 9 Hz, m), 7.20 (m, l〇H), 8.70 (s, 1H). Mass Spectrum: (M+H)+ = 617. Example 14 (28,38,58)-2-(2,4-Dimercaptopyridine-3-methoxyethenyl)amino-3-hydroxy-5-(2S-(l-imidazolidin-2- Keto)-3,3-dimethylbutanyl)amine-based hexyl burned A. 2.4-dimethylpyridyl-3-oxyacetic acid using the procedures from Examples 1G and 1H, but with 2,4 _Dimethyl-3_hydroxy O:\106\106749.DOC -81 - 1292752 Leaf acridine (prepared according to J. Med. Chem. 35, 3667-3671, 1992) to replace 2,6-dimethyl Phenol gives the desired compound. 3〇〇 megahertz iH NMR (DMSO_d6) δ 2.26 (s? 3H)? 2.42 (s? 3H)5 4.44 (s5 2H), 7.08 (d, J = 5 Hz, 1H), 8.07 (d, J = 5 Hertz, 1H). Mass spectrometry: (M+H)+ = 182 ° B·(28,38,58)-2-(2,4-dimethylpyridine-3-methoxyethenyl)amino-3-carbyl-5 -(T-Butoxycarbonyl)amino-u-diphenylhexane The amine compound from Example 10F was coupled with the carboxylic acid from Example 14A using standard procedures (EDAC in DMF). The compound you want. 300 MHz NMR (CDC13) δ 1.40 (s, 9 Η), 1·70 (m, 2 Η), 2.18 (s, 3H), 2.40 (s, 3H), 2.77 (m, 2H), 2·98 (d , J = 7 Hz, 2H), 3.75-3.95 (m, 3H), 4.20 (s, 2H), 4.22 (m5 1H), 4.60 (br d, 1H), 7.0 (d, J = 5 Hz, 1H) , 7.10 (m, 3H), 7.25 (m, 7H), 8.16 (d, J = 5 Hz, 1H). Mass spectrum: (M+H)+ = 548. C·(28,38,58)-2-(2,4-dimethylpyridin-3-yloxyethyl)amino-3-hydroxy-5-amino-1,6-diphenyl The alkane was subjected to the removal of the Boc-protecting group from the compound from Example 14B using standard procedures (TFA/CH2C12) to afford the desired compound. 300 MHz 4 NMR (CDC13) δ 1.45 (m, 1 Η), 1·62 (m, 1 Η), 2·23 (s5 3 Η), 2·45 (s, 3H), 2.50 (m, 1H), 2.80 (m, 1H), 3.0 (m5 2H), 3·12 (m5 1H), 3.90 (m, 1H), 4·18 (m, 1H), 4.25 (ABq, J = 9, 12 Hz, 2H), 6·98 (d, J = 5 Hz, 1H), 7.10 (m, 2H), 7.30 (m, 8H), 8.17 (d5 J = 5 Hz, 1H). Mass spectrum··(M+H)+ = 448. D·(28,38,58)-2-(2,4-dimethylpyridin-3-ethoxyethyl)amino group O:\106\106749.DOC -82 - 1292752 -3-base group_ 5-(2S-(1-Imidazolidinone) 3,6-diphenylhexane The amine group from Example 14C was obtained using standard procedures (EDAC in DMF). The compound was coupled with the carboxylic acid from Example 7A to give the desired compound. 3 NMR (CDC13) δ 1.0 (s, 9 Η), 1.70 (m, 3 Η), 2·18 (s, 3H) , 2.42 (s, 3H), 2.75 (m, 2H) 5 3·0 (m, 4H), 3.30 (m, 1H), 3.55 (m, 1H), 3.80 (m, 1H), 4.05 (s, 1H) ), 4.20 (m, 4H), 4.60 (s, ih) 5 6.70 (d, J = 7 Hz, 1H), 6.97 (d, J = 5 Hz, 1H), 7.15 (m, 3H), 7.25 (m5) 7H), 8.17 (d5 J = Hertz, 1H). Mass spectrum · (M+H) + = 630. Example 15 (28, 38, 58) -2- (2,4_ dimethyl outside |; bite-3 -oxyethyl aryl)amino-3-carbyl-5-(2S-(l-imidazolidin-2-oxoninoindolyl)amine 4, "diphenylhexane using standard procedures (in DMF) EDAC) The amine-based compound from Example 14C was coupled with the carboxylic acid from Example 1M to give the desired compound. Megahertz 4 NMR (CDC13) 5 0.82 (d, J = Hertz, 3H), 0·86 (d, J = 6 Hz, 3 Η), 1.75 (m, 3 Η) 5 2.15 (m, 1 Η), 2.18 (s , 3Η), 2.40 (s, 3H), 2.75 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 3·20 (m, 4Η), 3.70 (d5 J = 10 Hz, 1Η) ), 3.75 (m, 1Η), 4.20 (m5 6H), 4.52 (s, 1H), 3.75 (m, 1H), 4·20 (m, 6H), 4·52 (s, 1H), 6.80 (d , J = 7 Hz, 1H), 6.96 (d, J = 4.5 Hz, 1H), 7·20 (m, 10H), 8.17 (d, J = 4.5 Hz, 1H). Mass Spectrum: (M+H)+ = 616. Example 16 O:\106\106749.DOC -83- 1292752 (28,38,58)-2-(2,6-Dimethylthiophenoxyethyl)amino-3-3-hydroxyl S-(2S-(l-imidazolidin-2-yl)-3-methylbutanyl)amino-1&gt;6-diphenylhexane oxime·2,6-dimethylthiophenoxyacetic acid Using the procedure from Examples 1G and 1Η, but replacing 2,6-xylenol with 2,6-dimethylthiophenol, the desired compound was obtained. 300 MHz 4 NMR (CDC13) δ 2.5 6 (s, 6 Η), 3.40 (s, 2 Η), 7.10 (m, 3 Η). Mass spectrometry: M+ = 197 〇®·(28,38,58)-2-(2,6-dimethylthiophenoxyethyl)amino _3_ benzyl-5-(2S-(l-imidazole) Pyridin-2-one)-3-methylbutanyl)amino}; i,6-diphenyl was calcined. The carboxylic acid from Example 16 was coupled with the amine compound from Example 10D. compound of. 3〇〇 megahertz iH NMR (CDC13) 5 〇·82 (d5 J = Hertz, 3H), 0.86 (d, J = 6 Hz, 3H), 2.15 (m, old), 2.52 (s, 6H), 2.70 (m, 4H), 3.10 (m, 2H), 3·30 (m, 4H), 3.60 (m, 2H), 4.0 (m, 1H), 4.10 (m, 1H), 4.22 (s, 1H), 6.39 (d, J = 7 Hz, 1H), 6.58 (d, J = 9 Hz, 1H), 7.20 (m, 13H). Mass spectrum: (M+H)+ = 631. Example 17 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-1hydroxy-5-(2S-(l-pyrrolidin-2-one)_3_A Isobutyl]aminophenyldiphenylhexane oxime 4-methylbromobutyryl chloroglycolate 1.36 ml (16.8 mmol) of pyridine was added to 3 mM CH2Cl2

O:\106\106749.DOC -84 - 1292752 之1.08克(8·4毫莫耳)L-纈胺酸甲酯的溶液中,冷卻至〇°c再 加入1·55克(8.4毫莫耳)的心溴丁醯氯。在〇°C下攪拌該溶液 40分鐘,並在室溫下1小時。以飽和的NaHC03、鹽水沖洗 該溶液,並以無水的Na2S04脫水,過濾並在真空中濃縮。 藉著矽膠管柱層析法(5% EtOAc/CHAU)純化粗產物,得到 1.82克(77%)的想要產物。300兆赫茲4 NMR (CDC13) 5 0.92 (d,J = 6赫茲,3H),〇·96 (d5 J = 6赫茲,3H), 2.20 (m, 3H),2.46 (m,2H),3.50 (m5 2H),3·76 (s5 3H),4.58 (dd,J = 4·7赫茲,1H),5·97 (br d,J =7赫茲,1H)。質譜:(M+H)+ = 297 〇 Β· 2S-(1-吡咯啶-2·酮基)-3-曱基丁酸 將在DMF/CH^Cl2混合物中之i.49克(5·3毫莫耳)得自實例 17A之化合物的溶液冷卻至〇。〇,並加入〇 234克當量) 在礦物油中的60%氫化鈉。慢慢地將該混合物回溫至室 溫’並攪拌過夜。將該混合物倒入飽和的氯化錄中,並以 醋酸乙酯萃取,脫水並在真空中濃縮。如同實例1H利用氫 氧化鋰將粗產物水解,得到想要的化合物。300兆赫茲ιΗ NMR (CDC13) 5 0.96 (d,J = 7赫茲,3H),1.06 (d,J = 7赫 兹,3H)5 2·10 (m,2H),2.40 (m,1H),2.50 (t,J = 7赫茲,2H), 3.56 (m,2H),4·14 (d,J = l〇赫茲,m)。質譜:(m+H)+ = 186。 C· (2S,3S,5S)-2-(2,6。T基苯氧乙醯基)胺基_3_羥基 _5_(2S-(1-吡咯啶-;2-酮基)_3_曱基丁醯基)胺基β1,6-二苯基 己烧 O:\106\106749.DOC •85- 1292752 利用標準程序(在DMF中之EDAC)將得自實例17B之羧酸 與得自實例1N之胺偶聯,得到想要的化合物。300兆赫茲 NMR (CDCls) 5 〇·77 (d5 J = 7赫茲,3H),0.83 (d,J = 7赫 兹,3H)5 1.75 (m,3H),2·10 (m,1H),2·20 (s5 6H),2.25 (m, iH),2.65 (m,1H),2·85 (m,1H), 3·0 (d,J = 7赫茲,2H),3.20 (m,1H),3·77 (m,2H),3·88 (d,J = 10赫茲,1H),4.20 (m, 3H),6·30 (d,J = 7赫茲,1H),6.98 (m5 3H),7.20 (m,10H)。 質譜:(M+H)+ = 614。 實例18 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(l-吡咯啶-2,5-二酮基)-3-甲基丁醯基)胺基-1,6-二 苯基己烷 A· 2S-(1-吡咯啶-2,5-二酮基)-3-甲基丁酸芊酯 將1當量的琥珀酐加至在6毫升氯仿中之700毫克(3 ·38毫 莫耳)之L-纈胺酸芊酯的溶液中。在室溫下1小時之後,在 真空中移除溶劑,並將該殘餘物溶解於20毫升DMF中。在 該溶液中加入0.52克Ν-羥基苯并三唑、0.68克EDAC和0·52 毫升三乙胺。在室溫下24小時之後,加入20毫克4-二甲胺 基吡啶基。將該溶液留在室溫下3天。在標準處理之後,藉 著石夕膠管柱層析法純化粗產物,得到〇·25克的想要產物 (26%)。300兆赫茲NMR (CDC13) 5 〇·84 (d,J = 7赫兹, 3H),1.12(d,J = 7赫茲,3H),2.70(m,1Η),2·71 (s,4H),4.45 (d,J = 9赫茲,1H),5·15 (s,2H),7.30 (m,5H)。 Β· 2S-(1-吡咯啶-2,5-二酮基)-3-甲基丁酸O:\106\106749.DOC -84 - 1292752 in a solution of 1.08 g (8.4 m mmol) of L-proline methyl ester, cooled to 〇 ° C and then added 1.55 g (8.4 mmol) ) The heart of bromobutane chloride. The solution was stirred at 〇 ° C for 40 minutes and at room temperature for 1 hour. The solution was washed with saturated NaHC03, brine and dried over anhydrous Na2SO. The crude product was purified by EtOAc EtOAc (EtOAc) elute 300 MHz 4 NMR (CDC13) 5 0.92 (d, J = 6 Hz, 3H), 〇·96 (d5 J = 6 Hz, 3H), 2.20 (m, 3H), 2.46 (m, 2H), 3.50 ( M5 2H), 3·76 (s5 3H), 4.58 (dd, J = 4·7 Hz, 1H), 5.97 (br d, J = 7 Hz, 1H). Mass spectrometry: (M+H)+ = 297 〇Β· 2S-(1-pyrrolidin-2-yl)-3-mercaptobutyric acid i.49 g in a mixture of DMF/CH^Cl2 (5· A solution of 3 mmol of the compound from Example 17A was cooled to hydrazine. 〇, and add 234 234 g equivalent) 60% sodium hydride in mineral oil. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was poured into a saturated chlorinated mixture and extracted with ethyl acetate, dried and concentrated in vacuo. The crude product was hydrolyzed using lithium hydroxide as in Example 1H to give the desired compound. 300 MHz NMR (CDC13) 5 0.96 (d, J = 7 Hz, 3H), 1.06 (d, J = 7 Hz, 3H) 5 2·10 (m, 2H), 2.40 (m, 1H), 2.50 (t, J = 7 Hz, 2H), 3.56 (m, 2H), 4·14 (d, J = l 〇 Hertz, m). Mass spectrum: (m+H)+ = 186. C·(2S,3S,5S)-2-(2,6.T-phenoxyethyl)amino-3_hydroxy_5_(2S-(1-pyrrolidine-;2-keto)_3_曱 醯 醯 )) amino-β1,6-diphenylhexan O:\106\106749.DOC •85- 1292752 The carboxylic acid from Example 17B was obtained from Example 1N using standard procedures (EDAC in DMF). The amine is coupled to give the desired compound. 300 MHz NMR (CDCls) 5 〇·77 (d5 J = 7 Hz, 3H), 0.83 (d, J = 7 Hz, 3H) 5 1.75 (m, 3H), 2·10 (m, 1H), 2 ·20 (s5 6H), 2.25 (m, iH), 2.65 (m, 1H), 2·85 (m, 1H), 3·0 (d, J = 7 Hz, 2H), 3.20 (m, 1H) ,3·77 (m,2H),3·88 (d,J = 10 Hz, 1H), 4.20 (m, 3H), 6·30 (d, J = 7 Hz, 1H), 6.98 (m5 3H) , 7.20 (m, 10H). Mass spectrum: (M+H)+ = 614. Example 18 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-pyrrolidine-2,5-dione) Ethyl 3-methylbutylidene)amino-1,6-diphenylhexane A·2S-(1-pyrrolidine-2,5-dione)-3-methylbutyrate decyl ester 1 Equivalent succinic anhydride was added to a solution of 700 mg (3.38 mmol) of L-validine phthalate in 6 ml of chloroform. After 1 hour at room temperature, the solvent was removed in vacuo and the residue was dissolved in 20 mL DMF. To the solution were added 0.52 g of hydrazine-hydroxybenzotriazole, 0.68 g of EDAC and 0.52 ml of triethylamine. After 24 hours at room temperature, 20 mg of 4-dimethylaminopyridinyl group was added. The solution was left at room temperature for 3 days. After the standard work, the crude product was purified by chromatography eluting with silica gel column chromatography to afford the desired product (26%). 300 MHz NMR (CDC13) 5 〇·84 (d, J = 7 Hz, 3H), 1.12 (d, J = 7 Hz, 3H), 2.70 (m, 1 Η), 2·71 (s, 4H), 4.45 (d, J = 9 Hz, 1H), 5·15 (s, 2H), 7.30 (m, 5H). Β· 2S-(1-pyrrolidine-2,5-dione)-3-methylbutyric acid

O:\106\106749.DOC •86- (ί 1292752 在氫氣壓下(充滿虱氣的球)’激烈地攪拌在5 〇毫升曱 醇中之0.245克得自貫例1 8Α之產物和3〇毫克1〇%鈀碳的混 合物1小時。濾掉催化劑,並在真空之下移除溶劑,得到168 晕克想要的化合物。300兆赫兹NMR丨CDCI1J 3 (d,J = 6赫兹,3Η),1.13 (d,J = 6赫茲,3Η),2·65 (m,1Η), 2·8〇 (s,4Η),4.45 (d,J = 8赫茲,1Η)。質譜:(μ+η)+ = 200。 C· (2S,3S,5S)-2_(2,6^甲基苯氧乙醯基)胺基-3-羥基 -5-(2S-(l-吡咯啶_2,5_二酮基)_3_曱基丁醯基)胺基4,6-二 苯基已烷 利用標準程序(在DMF中之EDAC)將得自實例18B之羧酸 與得自實例1N之胺偶聯,得到想要的產物(75%)。300兆赫 兹1H NMR (CDC13) 5 0.70 (d,J = 4赫茲,3H),0.72 (d,J = 4赫茲,3H),1.70 (m,1H),2.20 (s,6H),2.45 (m,2H),2.60 (s,4H),2.80 (m5 2H),3.0 (m,2H),3·76 (m,lH),4·20 (m, 6H),7.0 (m5 3H),7·20 (m,10H)。質譜:(M+H)+ = 628。 實例19 (2S,3S,5S)-2-(反_3_(2,6-二甲苯基)丙烯酿基)胺基-3-羥 基-5-(2S-(l-四氫嘧啶-2-酮基)-3-曱基丁醯基)胺基二 苯基己烷 A. 2,6-二甲基苯甲醛 藉著標準斯溫(Swern)氧化作用程序(草醯氯/DMSO)將 2,6-二曱基苯曱醇氧化,得到想要的化合物。300兆赫茲iH NMR (CDC13) δ 2.62 (s,6Η),7.10 (m,2Η),7·33 (t,J = 7 赫茲,1H),10.63 (s,1H)。質譜:(M+H)+ = 135 O:\106\106749.DOC -87- 1292752 Β· 反_3_(2,6_二甲苯基)丙烯酸曱酯 將36毫克氫化鈉(在油中60%)加至在15毫升THF中之膦 酸乙酸三曱酯(149毫克,0.82毫莫耳)的溶液中。15分鐘之 後,右入在2毫升THF中之100毫克得自實例19Α的化合物。 在2小時之後,小心地以使使該反應中止,並以醋酸乙酯(70 毫升)萃取,脫水並濃縮之。藉著矽膠管柱層析法(己烷 /EtOAc 95:5)純化粗產物,得到想要的化合物(75%)。300 兆赫茲NMR (CDC13) δ 2.35 (s,6Η),3.82 (s,3Η),6·07 (d,J = 16赫茲,1H),7.10 (m,3H),7.85 (d,J = 16赫兹, 1H)。質譜··(M+NH4)+ = 191。 C. 反-3_(2,6-二曱苯基)丙烯酸 在甲醇和水的混合物中利用氫氧化鋰將得自實例丨〇B之 曱酯水解,得到想要的化合物(84%)。300兆赫茲4 NMR (CDC13) δ 2.38 (s5 6Η),6·13 (d,J = 16赫茲,1Η),7·10 (m, 3H),7.96 (d,J = 16赫茲,1H)。質譜:(M+H)+ = 194。 D· (28,38,58)-2-(反-3-(2,6-二甲苯基)丙烯醯基)胺基 •3-經基-5-(第二-丁氧幾基)胺基-1,6-二苯基己燒 利用標準程序(EDAC/DMF)將得自實例19C之羧酸與得 自實例1F之胺偶聯,得到想要的化合物(84%)。300兆赫茲 ]H NMR (CDC13) δ 1·40 (s5 9Η),1.68 (m5 1Η),2·34 (s5 6H),2.75 (m5 2H),2.96 (m5 2H),3.72 (m,1H),3·85 (m,1H), 4.08 (m,2H),4.60 (m,1H),5.88 (d,J = 10赫茲,1H),5.94 (d,J = 16赫茲,1H),7.10 (m,5H),7.25 (m,8H),7·72 (d,J = 16赫茲,1H)。質譜:(M+H)+ = 543。 O:\106\106749.DOC -88· 1292752 Ε· (2 S,3S,5 S)-2-(反-3-(2,6 -二甲苯基)丙稀醯基)胺基 -3-羥基-5-(2S-(l-四氫嘧啶-2_酮基)-3-甲基丙醯基)胺基 -1,6_二苯基己烷O:\106\106749.DOC •86- (ί 1292752 under hydrogen pressure (ball filled with helium)' vigorously stirred 0.245 g in 5 〇 ml of sterol from the product of Example 8 和 and 3 〇 A mixture of 1 in gram of palladium on carbon was used for 1 hour. The catalyst was filtered off and the solvent was removed under vacuum to give 168 </ RTI> desired compound. 300 MHz NMR 丨CDCI1J 3 (d, J = 6 Hz, 3 Η) , 1.13 (d, J = 6 Hz, 3 Η), 2·65 (m, 1 Η), 2·8 〇 (s, 4 Η), 4.45 (d, J = 8 Hz, 1 Η). Mass spectrum: (μ+η ) + = 200. C· (2S,3S,5S)-2_(2,6^methylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-pyrrolidine_2,5) The carboxylic acid from Example 18B was coupled with the amine from Example 1N using standard procedures (EDAC in DMF) using a standard procedure (EDAC in DMF). The desired product (75%) was obtained. 300 MHz 1H NMR (CDC13) 5 0.70 (d, J = 4 Hz, 3H), 0.72 (d, J = 4 Hz, 3H), 1.70 (m, 1H), 2.20 (s,6H), 2.45 (m,2H), 2.60 (s,4H), 2.80 (m5 2H), 3.0 (m,2H),3·76 (m,lH),4·20 (m, 6H) ), 7.0 (m5 3H), 7·20 (m, 10H) Mass Spectrum: (M+H)+ = 628. Example 19 (2S,3S,5S)-2-(trans_3_(2,6-dimethylphenyl)propenyl)amino-3-hydroxy-5- (2S-(l-tetrahydropyrimidin-2-one)-3-mercaptobutyryl)aminodiphenylhexane A. 2,6-dimethylbenzaldehyde by standard Swern oxidation Procedure (Grass Chlorine/DMSO) oxidize 2,6-dimercaptophenyl alcohol to give the desired compound. 300 MHz iH NMR (CDC13) δ 2.62 (s, 6 Η), 7.10 (m, 2 Η), 7·33 (t, J = 7 Hz, 1H), 10.63 (s, 1H). Mass spectrum: (M+H)+ = 135 O:\106\106749.DOC -87- 1292752 Β· 反_3_(2 , 6-dimethylphenyl) decyl acrylate. 36 mg of sodium hydride (60% in oil) was added to a solution of phosphonic acid tridecyl acetate (149 mg, 0.82 mmol) in 15 ml of THF. After a minute, 100 mg of the compound from Example 19A was taken in 2 ml of THF. After 2 hours, the reaction was quenched carefully, extracted with ethyl acetate (70 mL), dried and concentrated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) 300 MHz NMR (CDC13) δ 2.35 (s, 6Η), 3.82 (s, 3Η), 6·07 (d, J = 16 Hz, 1H), 7.10 (m, 3H), 7.85 (d, J = 16 Hertz, 1H). Mass spectrum··(M+NH4)+ = 191. C. Trans-3_(2,6-diphenylphenyl)acrylic acid The oxime ester from Example 丨〇B was hydrolyzed using lithium hydroxide in a mixture of methanol and water to give the desired compound (84%). 300 MHz 4 NMR (CDC13) δ 2.38 (s5 6Η), 6·13 (d, J = 16 Hz, 1 Η), 7·10 (m, 3H), 7.96 (d, J = 16 Hz, 1H). Mass spectrum: (M+H)+ = 194. D·(28,38,58)-2-(trans-3-(2,6-dimethylphenyl)propenyl)amino-3-carbyl-5-(second-butoxymethyl)amine The carboxylic acid from Example 19C was coupled with the amine from Example 1F using the standard procedure (EDAC/DMF) to afford the desired compound (84%). 300 megahertz]H NMR (CDC13) δ 1·40 (s5 9Η), 1.68 (m5 1Η), 2·34 (s5 6H), 2.75 (m5 2H), 2.96 (m5 2H), 3.72 (m, 1H) , 3·85 (m, 1H), 4.08 (m, 2H), 4.60 (m, 1H), 5.88 (d, J = 10 Hz, 1H), 5.94 (d, J = 16 Hz, 1H), 7.10 ( m, 5H), 7.25 (m, 8H), 7.72 (d, J = 16 Hz, 1H). Mass spectrum: (M+H)+ = 543. O:\106\106749.DOC -88· 1292752 Ε· (2 S,3S,5 S)-2-(trans-3-(2,6-dimethylphenyl)propanyl)amino-3- Hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one)-3-methylpropenyl)amino-1,6-diphenylhexane

移除得自實例19D之化合物的Boc-保護基 (TFA/CH2Ch),並利用標準程序(EDAC/DMF)將所得的胺與 得自實例2A之羧酸偶聯,得到想要的化合物(73%)。300兆 赫茲1H NMR (CDC13) 5 〇·82 (d,J = 6赫茲,3H),〇·87 (d,J =6赫茲,3H),1.50 (m5 1H),1.70 (m,2H),2.20 (m5 1H),2·33 (s,6H),2.68 (m,1H),2·78 (m,1H),2·85 (m,1H),3·〇5 (m, 5H),3.73 (m,1H),4·17 (m,1H),4.30 (d,J = 3赫茲,1H), 4.60 (s,1H),5.95 (d,J = 15赫茲,1H),6·0 (d,J =9赫茲,ih), 6.80 (d,J = 7赫茲,1H),7.25 (m,13H),7.70 (d,J = 15赫兹, 1H)。質譜:(M+H)+ = 625。 實例20 (2S,3S,5S)_2-(3-(2,6-二甲苯基)丙醯基)胺基-3-羥基 -5-(2S-(l-四氫嘧啶-2-酮基)-3-甲基丁醯基)胺基-1,6-二苯 基己烷 A. 3-(2,6-二甲苯基)丙酸甲酯 在氫氣壓(汽球壓力)下激烈地攪拌在25毫升甲醇和40毫 升10% Pd/C中之400毫克得自實例19B之化合物的溶液3小 時。濾掉催化劑,並在真空中濃縮濾液,得到想要的產物 (98%)。3 00兆赫茲 4 NMR (CDC13) 5 2.35 (s,6H),2·45 (m,2Η),2.98 (m,2Η),3.22 (s,3Η),7.02 (s,3Η)。質譜: (M+H)+ = 210 0 O:\106\106749.DOC -89- 1292752 Β· ^(2,6-二曱苯基)丙酸 在甲酉予和水中,和用氫氧化鋰得自實例20A之曱酯水解, ~到想要的化合物(93%)。3〇〇兆赫茲lH nmr (Cdc13) 5 2·36 (s,6H),2.50 (m,2H),3.0 (m,2H),7.03 (s,3H)。質譜: (M+NH4)、196。 C· (28,38,58)_2-(3-(2,6-二甲苯基)丙醯基)胺基-3-羥基 (第三-丁氧羰基)胺基-1,6-二苯基己烷 利用標準偶聯程序(EDAC/DMF)將得自實例20B之羧酸 與得自實例1F之胺偶聯,得到想要的化合物。3〇〇兆赫茲ιΗ NMR (CDC13) δ 1.40 (s? 9Η)5 1.55 (m5 2Η)5 2.20 (m5 2Η)? 2.30 (s,6Η),2.74 (m,2Η),2.85 (m,4Η),3·66 (m,1Η),3·82 (m,1H),3·95 (m5 2H),4.57 (br d5 1H),5.66 (d5 J = 9赫兹, 1H),7.0 (s,3H),7·22 (m,10H)。質譜:(M+H)+ = 545。 D· (28,38,58)-2-(3-(2,6-二甲苯基)丙醯基)胺基-3-羥基 5_(2S-(1-四氫嘧啶-2-酮基)-3-甲基丁醯基)胺基-u-二苯 基己烷 利用在CHCh中之三氟乙酸,移除得自實例2〇c之化合物 B〇c-保護基,並利用標準偶聯程序(EDAC/DMF)將所得的胺 與得自實例2A之羧酸偶聯,得到想要的化合物。3〇〇兆赫茲 4 NMR (CDC13)占 0.82 (d,J = 6赫茲,3H),0.86 (d,J = 6 赫茲,3H),1.55 (m5 2H),1.65 (m,1H),1.70 (s,3H),2.20 (m5 3H),2·30 (s,6H),2.65 (m,1H),2.75 (m,1H),2·86 (m,5H), 3.10 (m,3H),3·68 (m,1H),4.10 (m,4H),4.63 (s5 1H),5.75 (d,J = 7赫茲,1H),6.76 (d,J = 7赫茲 5 1H),7.0 (m,3H),7.20 -90·The Boc-protecting group (TFA/CH2Ch) from the compound from Example 19D was removed, and the obtained amine was coupled with the carboxylic acid from Example 2A using standard procedures (EDAC/DMF) to give the desired compound (73). %). 300 MHz 1H NMR (CDC13) 5 〇·82 (d, J = 6 Hz, 3H), 〇·87 (d, J = 6 Hz, 3H), 1.50 (m5 1H), 1.70 (m, 2H), 2.20 (m5 1H), 2·33 (s, 6H), 2.68 (m, 1H), 2·78 (m, 1H), 2·85 (m, 1H), 3·〇5 (m, 5H), 3.73 (m,1H),4·17 (m,1H), 4.30 (d,J = 3 Hz, 1H), 4.60 (s,1H), 5.95 (d, J = 15 Hz, 1H), 6·0 (d, J = 9 Hz, ih), 6.80 (d, J = 7 Hz, 1H), 7.25 (m, 13H), 7.70 (d, J = 15 Hz, 1H). Mass spectrum: (M+H)+ = 625. Example 20 (2S,3S,5S)_2-(3-(2,6-Dimethylphenyl)propanyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidin-2-one) )-3-methylbutanyl)amino-1,6-diphenylhexane A. Methyl 3-(2,6-dimethylphenyl)propionate is vigorously stirred under hydrogen pressure (balloon pressure) A solution of 400 mg of the compound from Example 19B in 25 ml of methanol and 40 ml of 10% Pd/C was used for 3 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the desired product (98%). 3 00 MHz 4 NMR (CDC13) 5 2.35 (s, 6H), 2·45 (m, 2 Η), 2.98 (m, 2 Η), 3.22 (s, 3 Η), 7.02 (s, 3 Η). Mass spectrometry: (M+H)+ = 210 0 O:\106\106749.DOC -89- 1292752 Β·^(2,6-diphenylene)propionic acid in formazan and water, and lithium hydroxide The oxime ester from Example 20A was hydrolyzed to the desired compound (93%). 3 〇〇 megahertz lH nmr (Cdc13) 5 2·36 (s, 6H), 2.50 (m, 2H), 3.0 (m, 2H), 7.03 (s, 3H). Mass spectrometry: (M+NH4), 196. C·(28,38,58)_2-(3-(2,6-Dimethylphenyl)propanyl)amino-3-hydroxy(tris-butoxycarbonyl)amino-1,6-diphenyl The carboxylic acid from Example 20B was coupled with the amine from Example 1F using a standard coupling procedure (EDAC/DMF) to give the desired compound. 3〇〇MHz Hertz NMR (CDC13) δ 1.40 (s? 9Η)5 1.55 (m5 2Η)5 2.20 (m5 2Η)? 2.30 (s,6Η), 2.74 (m,2Η), 2.85 (m,4Η) ,3·66 (m,1Η),3·82 (m,1H),3·95 (m5 2H),4.57 (br d5 1H),5.66 (d5 J =9 Hz, 1H),7.0 (s,3H ), 7·22 (m, 10H). Mass spectrum: (M+H)+ = 545. D·(28,38,58)-2-(3-(2,6-Dimethylphenyl)propanyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-one) 3-methylbutylidene)amino-u-diphenylhexane The compound B〇c-protecting group from Example 2〇c was removed using trifluoroacetic acid in CHCh and using standard coupling procedures ( EDAC/DMF) The resulting amine was coupled with the carboxylic acid from Example 2A to give the desired compound. 3〇〇 megahertz 4 NMR (CDC13) accounted for 0.82 (d, J = 6 Hz, 3H), 0.86 (d, J = 6 Hz, 3H), 1.55 (m5 2H), 1.65 (m, 1H), 1.70 ( s, 3H), 2.20 (m5 3H), 2·30 (s, 6H), 2.65 (m, 1H), 2.75 (m, 1H), 2·86 (m, 5H), 3.10 (m, 3H), 3·68 (m, 1H), 4.10 (m, 4H), 4.63 (s5 1H), 5.75 (d, J = 7 Hz, 1H), 6.76 (d, J = 7 Hz 5 1H), 7.0 (m, 3H), 7.20 -90·

O:\106\106749.DOC ⑧ 1292752 (m,10H)。質譜:(M+H)+ = 627。 實例21 (2S,3S,5S)-2-(2,6-二甲基-4-擬基苯氧乙酿基)胺基-3-經 基-5-(2S-(l-四氫嘧啶-2-酮基)-3-曱基丁醯基)胺基-1,6-二 苯基己烷 Α· 2,6-二甲基_4_第三-丁基二甲矽烷氧基酚 將200毫克的Pd/C (20%)加至在5毫升甲醇中之2.5克(14.7 毫莫耳)2,6-二甲基苯醌的溶液中。在1大氣壓的氫氣下, 攪拌該反應混合物過夜。在矽藻土墊上移除Pd/C,並在減 低的壓力下蒸發溶劑至無水,得到2.0克(100%)淡黃色油狀 的2,6-二甲基二氫苯醌。 在0°C下,連續將1.2克(17·6毫莫耳)咪唑和2.2克(14.7毫 莫耳)第三-丁基二甲矽烷基氣加至在1〇毫升二氣甲烷中之O:\106\106749.DOC 8 1292752 (m, 10H). Mass spectrum: (M+H)+ = 627. Example 21 (2S,3S,5S)-2-(2,6-Dimethyl-4-methylphenoxyethyl)amino-3-carbyl-5-(2S-(l-tetrahydropyrimidine) -2-keto)-3-indolyl decyl)amino-1,6-diphenylhexane oxime 2,6-dimethyl-4_tris-butyl dimethyl decyloxyphenol will be 200 Mg of Pd/C (20%) was added to a solution of 2.5 g (14.7 mmol) of 2,6-dimethylphenylhydrazine in 5 ml of methanol. The reaction mixture was stirred overnight under 1 atmosphere of hydrogen. The Pd/C was removed on a pad of diatomaceous earth and the solvent was evaporated to dryness under reduced pressure to give 2.0 g (100%) of 2,6-dimethyldihydrophenylhydrazine as a pale yellow oil. 1.2 g (17·6 mmol) of imidazole and 2.2 g (14.7 mTorr) of tri-butyldimethylcarbazine were continuously added to 1 ml of di-methane in 0 ° C at 0 ° C.

2.0克(14.7毫莫耳)2.6-二曱基二氫苯醌的溶液中。按照TLC 的指示’在反應完成之後,使其分配在二氣曱烷和3Ν氯化 氫與鹽水之1:1混合物之間。以鹽水沖洗有機層,覆以硫酸 納脫水’過濾並在減低的壓力下蒸發至無水。利用5%醋酸 乙酯:己烷進行矽膠層析法,得到18克(49%)白色固體狀 之2,6-二曱基-4-第三-丁基二甲矽烷氧基酚。3〇〇兆赫茲Vh NMR (CDC13) 5 〇·16 (s,6H),0.98 (s,9H),2·19 (s,6H), 4·22 (s’ 1Η),6·48 (s5 2Η)。質譜:(Μ+Η)+ = 253。 Β· 2,6_二甲基-4-第三-丁基二甲矽烷氧基苯氧乙酸乙酯 以2·0克(1.43耄莫耳)碳酸鉀和83〇微升(7·5毫莫耳)溴化 乙酸乙醋來處理在5毫升二甲基曱醯胺中之18克(71毫莫 O:\106\106749.DOC •91- 1292752 耳)2,6-二甲基-4-第二-丁基二曱矽烷氧基酚的溶液。將所 得的溶液加熱至70°C 4小時。在冷卻至室温後,使該反應混 合物分配到醋酸乙酯和3N氯化氫之間。以稀釋之鹽水沖洗 混合的有機層,覆以硫酸鎂脫水,過濾並在真空中蒸發。 利用5 %醋酸乙S旨·己烧進行碎膠層析法,得到2 · 〇 3克(8 5 % ) 淡黃色油狀之2,6-二甲基-4-第三-丁基二甲矽烷氧基苯氧 乙酉夂乙酉日。300兆赫热NMR (CDCI3) (5 017 (s 6H) 〇·97 (s5 9H),1·33 (t,3H,J = 6·3赫茲),2.22 (s,6H),4.30 (q, 2H,J = 6·3赫茲),4.35 (s,2H),6·57 (s,2H)。質譜:(M+H)+ =3 5 6 0 C· 2,6-二甲基羥基苯氧乙酸2.0 g (14.7 mmol) of a solution of 2.6-dimercaptodihydrophenylhydrazine. After the completion of the reaction according to the instruction of TLC, it was partitioned between dioxane and a 1:1 mixture of 3 Torr of hydrogen chloride and brine. The organic layer was washed with brine, dried over sodium sulfate and filtered and evaporated to dryness under reduced pressure. Chromatography using 5% ethyl acetate:hexane gave 18 g (yield: 49%) of 2,6-didecyl-4-tris-butyl dimethyl methoxy phenol. 3〇〇 megahertz Vh NMR (CDC13) 5 〇·16 (s,6H), 0.98 (s,9H),2·19 (s,6H), 4·22 (s' 1Η),6·48 (s5 2Η). Mass spectrum: (Μ+Η)+ = 253. Β·2,6-Dimethyl-4-tris-butyldimethyloxyalkyloxyphenoxyacetate with 2·0 g (1.43 耄 mol) potassium carbonate and 83 〇 microliters (7.5 mM Treatment of 18 g (71 mmol Mo:\106\106749.DOC •91-1292752 ears) 2,6-dimethyl-4 in 5 ml of dimethyl decylamine by bromoacetic acid ethyl acetate a solution of a second-butyldioxyloxyphenol. The resulting solution was heated to 70 ° C for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and 3N hydrogen chloride. The combined organic layers were washed with diluted brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Using 5% acetonitrile to purify the gel to obtain 2 · 〇 3 g (85 %) of 2,6-dimethyl-4-tris-butyl dimethyl矽 alkoxyphenoxyacetam. 300 MHz Thermal NMR (CDCI3) (5 017 (s 6H) 〇·97 (s5 9H), 1·33 (t, 3H, J = 6.3 Hz), 2.22 (s, 6H), 4.30 (q, 2H) , J = 6·3 Hz), 4.35 (s, 2H), 6·57 (s, 2H). Mass Spectrum: (M+H)+ = 3 5 6 0 C· 2,6-Dimethylhydroxyphenoxy Acetic acid

將4毫升3N氫氧化鈉,加至在1〇毫升甲醇中之2〇3克(6〇 晕莫耳)2,6-二甲基-4-第三-丁基二甲矽烷氧基苯氧乙酸乙 醋的溶液中。在室溫下攪拌該反應混合物3〇分鐘之後,以 3NHC1將其酸化。容許再攪拌該反應額外的1小時,然後使 其分配在水和二氯甲烷之間。以鹽水沖洗混合的有機萃取 物’並覆以無水的硫酸鈉脫水,過濾並在減低的壓力下蒸 發至無水。與己烷一起研磨,得到910毫克(77%)白色固體 狀之2,6_二甲基-4-羥基苯氧乙酸。300兆赫茲〗h NMR (CD3〇D) (5 2.18 (S5 6H),4.31 (s,2H),6.41 (s,2H)。質 譜:(M+H)+ = 214。 D· (2S,3S,5S)_2-(2,6‘甲基I經基苯氧乙醯基)胺基 經基-5-(第三_丁氧羰基)胺基Ll,卜二苯基己烷 利用標準偶聯程序(EDAC/DMF),將得自實例21C之羧酸Add 4 ml of 3N sodium hydroxide to 2 〇 3 g (6 〇 莫 耳) 2,6-dimethyl-4-tris-butyl dimethyl decyloxyphenoxyl in 1 mL of methanol In a solution of ethyl acetate. After the reaction mixture was stirred at room temperature for 3 minutes, it was acidified with 3NHC1. The reaction was allowed to stir for an additional 1 hour and then partitioned between water and dichloromethane. The combined organic extracts were rinsed with brine and dehydrated with anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. It was triturated with hexane to give 910 mg (77%) of 2,6-dimethyl-4-hydroxyphenoxyacetic acid as a white solid. 300 megahertz h NMR (CD3〇D) (5 2.18 (S5 6H), 4.31 (s, 2H), 6.41 (s, 2H). Mass spectrum: (M+H)+ = 214. D· (2S, 3S , 5S) 2 - (2, 6 'methyl I phenoxyphenoxy) amino group via 5--5 (tris-butoxycarbonyl) amine group L1, diphenyl hexane using standard coupling Procedure (EDAC/DMF), carboxylic acid from Example 21C

O:\106\106749.DOC 1292752 與得自實例IF之胺偶聯,得到想要的化合物。3〇〇兆赫茲ιΗ NMR (CDC13) 5 1.40 (s,9H),1.68 (m,2H),2.07 (s5 6H), 2·77 (d,J = 6赫茲,2H),2·98 (m,2H),3.74 (m,1H),3.90 (m, 1H),4.10 (m,3H),4.58 (m,1H),5.20 (m,1H),6.44 (s,2H), 7·10-7·30 (m5 10H)。 Ε· (28,38,58)-2-(2,6-二甲基-4-羰基苯氧乙醯基)胺基 -3-羥基-5-(2S-(l -四氫嘧啶_2-酮基)甲基丁醯基)胺基 -1,6-二苯基己烷 _ 利用TFA/CH2C12,移除得自實例21D之化合物的Boc_保護O:\106\106749.DOC 1292752 is coupled with an amine from Example IF to give the desired compound. 3 〇〇 Hz ι NMR (CDC13) 5 1.40 (s, 9H), 1.68 (m, 2H), 2.07 (s5 6H), 2·77 (d, J = 6 Hz, 2H), 2·98 (m , 2H), 3.74 (m, 1H), 3.90 (m, 1H), 4.10 (m, 3H), 4.58 (m, 1H), 5.20 (m, 1H), 6.44 (s, 2H), 7·10- 7·30 (m5 10H). Ε·(28,38,58)-2-(2,6-Dimethyl-4-carbonylphenoxyethyl)amino-3-hydroxy-5-(2S-(l-tetrahydropyrimidine_2 -keto)methylbutenyl)amino-1,6-diphenylhexane_ Boc_protection of the compound from Example 21D was removed using TFA/CH2C12

基,並利用標準偶聯程序(EDAC/DMF)將所得的胺與得自實 例2A之羧酸偶聯,得到想要的化合物。3〇〇兆赫茲〗H NMR (CDC13) (5 0.78 (d,J = 5赫茲,3H),0·81 (d,J = 5赫兹, 3H),1·47 (m,1H),2·03 (s,6H),2.18 (m,1H),2.62 (m5 1H), 2.80 (m,2H),3·05 (m,6H),3.78 (m5 1H),4·12 (m5 6H),4.37 (m,1H),4.71 (s,1H),6.47 (s,2H),6·94 (br d,1H),7·20 (m, 10H)。質譜:(M+H)+ = 645。 ® 實例22 (2S,3S,5S)_2_pK(±)-l,l-·一 氣代-2_異丙基-3 -四氮 p塞吩氧 基)胺基-3-經基-5-(2S-(l-四氫喷咬·2-酮基)·3-甲基丁醯基) 胺基-1,6-二苯基已烷 Α. 順(±)-2-異丙基-3-羥基四氫嘧吩 小心地將乙醇鈉(16.75克,0.246莫耳)分成數次加至在 200毫升乙醇中的3-酼基丙酸乙酯(27.25毫升,0.246莫耳) 溶液中。然後將所得的懸浮液冷卻至-20°C,並在2小時内 O:\106\106749.DOC -93- 1292752 逐滴加入在5〇毫升乙醇中之2_溴異戊酸乙酯(5〇克,〇.239 莫耳)°在加成作用完成之後,將該反應加溫至周圍溫度, 並授拌3小時。將該混合物倒入600毫升醋酸乙酯和6〇〇毫升 飽和的ΝΗαΐ中。移出醋酸乙酯層,並以醋酸乙酯萃取液層 (2 X 200毫升)。將混合的有機層覆以硫酸鈉脫水,過據並 在真空中濃縮,得到橘色的油。將該油溶解於500毫升的甲 苯中,並加入乙醇鈉(16·75克,〇·246莫耳)。將該反應混合 物加熱至迴流6小時,冷卻至室溫,然後倒入冰冷的in HC1 (235毫升)溶液中,並以醋酸乙酯(3 χ ι5〇毫升)萃取。將混 合的有機層覆以硫酸鈉脫水,過濾並濃縮成油,將其直接 使用在下一個步驟中,不需進一步純化。 將該粗產物加至5〇〇毫升含水10%硫酸中,並將所得的混 合物加熱至迴流數小時,然後冷卻至室溫並以6Ν氫氧化鈉 中和’再以醋酸乙酯(3 X 300毫升)萃取之。將混合的有機 層脫水,過濾並在真空中濃縮,得到暗葡萄色的油。藉著 在75-80 °C下的真空蒸镏純化粗產物(酮)。300兆赫茲4 NMR (CDC13) 5 0.93 (d,J = 9赫茲,3H),1·03 (d,J = 9赫 茲,3H),2·32 (m,1H),2.55-2.70 (m,2H),2.93 (t,J = 7.5赫 茲,2H),3.38 (d,J = 4赫茲,1H)。質譜:(M+H)+ = 145。 在20分鐘内,將氫化二異丁基鋁(86毫升,1M在THF中) 逐滴加至在0°C下,經過攪拌之在125毫升CH2C12中上述之 酮的溶液中。容許該反應混合物回溫至室溫,然後藉著小 心地加入IN HC1 (2 55毫升)使其中止。以乙醚(3x150毫升) 萃取該反應混合物,並以飽和的碳酸氫鈉、鹽水沖洗混合 O:\106\106749.DOC •94- 1292752 的醚溶液,再覆以硫酸鎮脫水。在真空中濃縮該溶液,並 藉著矽膠管柱層析法(10% EtOAc/己烷)純化所得的油。300 兆赫茲NMR (CDC13) 5 1·〇3 (d,J = 7赫茲,3H),1.08 (d,J = 7赫茲,3H),1·80 (d,J = 9赫茲,1H),1.90 (m,2H), 2.24 (m,1H),2.90-3.10 (m,3H),4.36 (m,1H)。質譜··(M+H)+ =147 〇 B· 順(±)-2-(異丙基-3-嘧吩基)-2-(2-吡啶基)碳酸酯 將二異丙基乙胺(4.65毫升,26.7毫莫耳)和二-(2-吡啶基) 碳酸酯(5.42克,25.1毫莫耳)加至在40毫升CH2C12中之得自 實例22A的產物(2·29克,15·7毫莫耳)中。在室溫下18小時 之後’以氣仿稀釋該反應混合物,並連續以1 〇%檸檬酸、 飽和的碳酸氫鈉、鹽水沖洗,然後覆以硫酸鈉脫水;過濾 並在真空中濃縮。藉著矽膠管柱層析法(2〇% EtOAc/己烷) 純化粗產物’得到想要的化合物。3〇〇兆赫茲NMR (CDC13) δ 1·〇5· (d,J = 7赫兹,3Η),1.08 (d5 J = 7赫兹, 3H),1·90 (m,1H),2.05 (m,2H),2.58 (dd,J = 6, 15赫兹, 2H),3·1〇 (m,2H),3·28 (dd5 J = 3,12赫茲,1H),5·47 (m, 1H),7.12 (m,1H),7·27 (m,1H),7·80 (m,1H),8.41 (m5 1H)。質谱:= 268。 C· (2S,3S,5S&gt;-2_(順(±)·2-異丙基-3-四氫嘧吩氧基)胺 基_3-經基-5-(第三-丁氧羰基)胺基_1,6_二苯基己烷 將得自實例1F的胺(791毫克,2.06毫莫耳)加至在5毫升 CHAl2中之得自實例mb之化合物(5〇〇毫克,[π毫莫耳) 的溶液中。在室溫下攪拌該反應,直到耗盡所有得自實例The resulting amine was coupled with the carboxylic acid from Example 2A using standard coupling procedures (EDAC/DMF) to give the desired compound. 3 〇〇 Hz H NMR (CDC13) (5 0.78 (d, J = 5 Hz, 3H), 0·81 (d, J = 5 Hz, 3H), 1·47 (m, 1H), 2· 03 (s,6H), 2.18 (m,1H), 2.62 (m5 1H), 2.80 (m,2H),3·05 (m,6H), 3.78 (m5 1H),4·12 (m5 6H), 4.37 (m,1H), 4.71 (s,1H), 6.47 (s,2H),6·94 (br d,1H),7·20 (m, 10H). Mass Spectrum: (M+H)+ = 645 ® Example 22 (2S,3S,5S)_2_pK(±)-l,l-·One gas-2-isopropyl-3-tetrazine p-secenyloxy)amino-3-carbyl-5- (2S-(l-tetrahydropurine·2-keto)·3-methylbutanyl)amino-1,6-diphenylhexane oxime. cis(±)-2-isopropyl-3- Hydroxytetrahydropyrimidine Sodium ethoxide (16.75 g, 0.246 mol) was carefully added in several portions to a solution of ethyl 3-mercaptopropionate (27.25 mL, 0.246 mol) in 200 mL of ethanol. The resulting suspension was then cooled to -20 ° C and 2 - bromoisovalerate in 5 mL of ethanol was added dropwise over 2 hours at O: \ 106 \ 106 749. DOC - 93 - 1292752 (5 〇克,〇.239 摩尔)° After the addition was completed, the reaction was warmed to ambient temperature and allowed to mix for 3 hours. The mixture was poured into 600 ml of ethyl acetate and 6 ml of saturated ΝΗαΐ. The ethyl acetate layer was removed and the layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, dried and concentrated in vacuo to give an orange oil. The oil was dissolved in 500 ml of toluene and sodium ethoxide (16.75 g, 〇·246 mol) was added. The reaction mixture was heated to reflux for 6 hr then cooled to EtOAc EtOAc EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The crude product was added to 5 mL of aqueous 10% sulfuric acid, and the resulting mixture was heated to reflux for several hours, then cooled to room temperature and neutralized with 6 Ν sodium hydroxide and then ethyl acetate (3 X 300) ML) extracted. The combined organic layers were dried, filtered and concentrated in vacuo to give a dark oil. The crude product (ketone) was purified by vacuum distillation at 75-80 °C. 300 MHz 4 NMR (CDC13) 5 0.93 (d, J = 9 Hz, 3H), 1·03 (d, J = 9 Hz, 3H), 2·32 (m, 1H), 2.55-2.70 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 3.38 (d, J = 4 Hz, 1H). Mass spectrum: (M+H)+ = 145. Diisobutylaluminum hydride (86 ml, 1 M in THF) was added dropwise to a solution of the above-mentioned ketone in 125 ml of CH2C12 at 0 °C. The reaction mixture was allowed to warm to room temperature and then quenched by the addition of IN HCl (2 55 mL). The reaction mixture was extracted with diethyl ether (3.times.150 mL). EtOAc (EtOAc) The solution was concentrated in vacuo and the obtained oil was purified eluting with EtOAc EtOAc 300 MHz NMR (CDC13) 5 1·〇3 (d, J = 7 Hz, 3H), 1.08 (d, J = 7 Hz, 3H), 1·80 (d, J = 9 Hz, 1H), 1.90 (m, 2H), 2.24 (m, 1H), 2.90-3.10 (m, 3H), 4.36 (m, 1H). Mass spectrometer··(M+H)+ =147 〇B· cis(±)-2-(isopropyl-3-sulfenyl)-2-(2-pyridyl)carbonate diisopropylethylamine (4.65 ml, 26.7 mmol) and bis-(2-pyridyl) carbonate (5.42 g, 25.1 mmol) were added to the product from Example 22A in 40 mL CH2C12 (2·29 g, 15 · 7 millimoles). After 18 hours at room temperature, the reaction mixture was diluted with a gas-like mixture and washed successively with 1% citric acid, saturated sodium hydrogen carbonate, brine, and then dried over sodium sulfate; filtered and concentrated in vacuo. The crude product was purified by hydrazine column chromatography (2% EtOAc/hexanes) to afford the desired compound. 3 〇〇 megahertz NMR (CDC13) δ 1·〇5· (d, J = 7 Hz, 3 Η), 1.08 (d5 J = 7 Hz, 3H), 1·90 (m, 1H), 2.05 (m, 2H), 2.58 (dd, J = 6, 15 Hz, 2H), 3·1〇(m, 2H), 3·28 (dd5 J = 3, 12 Hz, 1H), 5·47 (m, 1H) , 7.12 (m, 1H), 7·27 (m, 1H), 7·80 (m, 1H), 8.41 (m5 1H). Mass Spectrum: = 268. C·(2S,3S,5S&gt;-2_(cis(±)·2-isopropyl-3-tetrahydropyrimenyloxy)amino-3-3-ylamino-5-(tri-butoxycarbonyl) Amino-1,6-diphenylhexane The amine from Example 1F (791 mg, 2.06 mmol) was added to the compound from Example mb in 5 mL of CHAl2 (5 mg, [π] In a solution of millimolar. Stir the reaction at room temperature until all the examples are exhausted

O:\106\106749.DOC -95- 1292752 22B的化合物為止。卩氯仿稀釋該反應混合物,並以⑽摔 檬酸、飽和的碳酸氬鈉、鹽水沖洗,然後利用硫酸鈉脫水: 過濾並在真空中濃縮。藉著矽膠管柱層析法(2% MeOH/C^Cl2)純化粗產物,得到想要的化合物(73%)。3⑽ 兆赫茲咕 NMR (CDC13) 5 0.83_L05 (m,6H),14〇 9H),1·90 (m,3H),2·20 (m,1H),2·75 (m,2H),2.85 (m,4H), 2.95-3.15 (m,3H),3.67-3.90 (m,4H),4·55 (m,iH),5·1〇 (m, 1H),5.30 (m5 1H),7.10-7.26 (m,l〇H)。質譜:(M+H)+ = 557。 D· (2S,3S,5S)-2-(順(±)-l,i-二氧代 _2_ 異丙基 _3_ 四氫噻吩 氧基)胺基-3-經基_5_(第三-丁氧羰基)胺基,6_二苯基已炫 將過硫酸氫鉀製劑(〇x〇ne)(839毫克,1.37毫莫耳)和碳酸 氫鈉(152毫克,1.82毫莫耳)加至在1〇毫升丙酮和〇·5毫升水 中之得自實例22C之化合物(523毫克,0.91毫莫耳)的溶液 中。攪拌所得的溶液2小時,在此時有白色的沉澱物出現。 以含水的亞硫酸氫納使該反應中止,並以醋酸乙g旨(2 X 1 〇〇 毫升)萃取之,以硫酸鈉脫水,過濾並在真空中濃縮。藉著 矽膠管柱層析法(2% MeOH/CK^Cl2)純化粗產物,得到422 毫克的產物。300兆赫茲 4 NMR (CDC13) 5 1.20 (m,6H) 1.40 (s,9H),1·60 (m,4H),2.10-2.32 (m,4H),2·67 (m5 2H), 2.75 (m,2H),2.85 (m,2H),3.15 (m,2H),3.70-3.90 (m,3H) 4.56 (m,1H),5.30 (m,2H),7.10-7.30 (m,l〇H)。 Ε· (2S,3S,5S)-2-(順(±)-l,l_ 二氧代-2-異丙基 _3_ 四氫噻 吩氧基)胺基-3-羥基-5-(2S-(l-四氫嘧啶-2-酮基)_3-甲基丁 醯基)胺基-1,6-二苯基己烷 O:\106\106749.DOC -96- 1292752 利用TFA/CH2C12移除自實例22D之化合物的B〇c_保護 基,並將所得的胺與得自實例2 A之羧酸偶聯,得到想要的 化合物(820/o)。3 00兆赫茲1HNMR(CDCl3)5 0.82(m,6l·l) 1·(Μ·20 (m,6H),1.60 (m,2H),2.07 (m,1H),2.25 (m5 2H), 2·65-3·20 (m,12H),3·70 (m,1H),3·90 (m,1H),4.1〇-4·2〇 (m,2H),5.07 (m,1H),5.37 (m,1H),5·87-5·98 (m,1H), 6.95-7.05 (m,1H),7.20 (m,i〇H)。質譜:(m+H)+ = 671。 實例23 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基I羥基 -5-(2S-(l_二氫嘧啶_2,4_二酮基)_3_甲基丁醯基)胺基 一笨基己烧 Α· N-(2-乙氧基丙烯醯基甲氧羰基甲丙基)脲 將3.90克(0.02 6莫耳)的氰酸銀加至在18毫升甲苯中之 1.74克(0.013莫耳)的2-乙氧丙烯醯氯中。將該混合物加熱至 迴流0·75小時。容許該混合物回溫至室溫,並容許沉澱物 /儿降。回收上清液(9.6毫升),並加入18毫升的無水DMF* 5 笔#Et2〇,冷部至-15°C 45分鐘,並留在冰箱中過夜。在真 二中蒸發〉谷劑,並藉著矽膠管柱層析法(2% Me〇H/CH2C12) 、、、屯化殘餘物,得到1 ·59克想要的化合物(9〇 2%)。3〇〇兆赫茲 H NMR (CDC13) δ G.96 (d5 I = 7赫兹,3H),i 〇 (d,j = 7 赫紙,311),1.37〇,1 = 7.5赫兹,311),2 25 (111,111),3.74(8, 3H),3.97 (q5 J = 7·5赫兹,2H),4·42 ⑽,j = 4 5, 8 〇赫兹, 1H),5·25 (d,J = 12赫兹,1H),7·68 (d,j = i2赫兹,1H),8·55 (s, 1H),9.10 (d,j = 8赫兹,1H)。質譜··(M+H)+ = 273。O:\106\106749.DOC -95-1292752 The compound of 22B. The reaction mixture was diluted with hydrazine chloroform and washed with (10) succinic acid, saturated sodium bicarbonate, brine and then dehydrated with sodium sulfate: filtered and concentrated in vacuo. The crude product was purified by EtOAc EtOAc (EtOAc) 3(10) megahertz NMR (CDC13) 5 0.83_L05 (m, 6H), 14〇9H), 1·90 (m, 3H), 2·20 (m, 1H), 2·75 (m, 2H), 2.85 (m,4H), 2.95-3.15 (m,3H), 3.67-3.90 (m,4H),4·55 (m,iH),5·1〇(m, 1H), 5.30 (m5 1H), 7.10 -7.26 (m, l〇H). Mass Spectrum: (M+H)+ = 557. D·(2S,3S,5S)-2-(cis(±)-l,i-dioxo-2_isopropyl_3_tetrahydrothienyloxy)amino-3-carbyl_5_(third -butoxycarbonyl)amine, 6-diphenyl hexanide potassium peroxodisulphate (〇x〇ne) (839 mg, 1.37 mmol) and sodium bicarbonate (152 mg, 1.82 mmol) plus To a solution of the compound from Example 22C (523 mg, 0.91 mmol) in 1 mL of acetone and EtOAc. The resulting solution was stirred for 2 hours at which time a white precipitate appeared. The reaction was quenched with aqueous sodium hydrogen sulphate and extracted with EtOAc (EtOAc (EtOAc). The crude product was purified by silica gel column chromatography (2% MeOH / EtOAc) to afford 422 mg. 300 MHz 4 NMR (CDC13) 5 1.20 (m, 6H) 1.40 (s, 9H), 1·60 (m, 4H), 2.10-2.32 (m, 4H), 2·67 (m5 2H), 2.75 ( m, 2H), 2.85 (m, 2H), 3.15 (m, 2H), 3.70-3.90 (m, 3H) 4.56 (m, 1H), 5.30 (m, 2H), 7.10-7.30 (m, l〇H ). Ε·(2S,3S,5S)-2-(cis(±)-l,l_dioxo-2-isopropyl_3_tetrahydrothiophenoxy)amino-3-hydroxy-5-(2S- (l-tetrahydropyrimidin-2-one)_3-methylbutanyl)amino-1,6-diphenylhexane O:\106\106749.DOC -96- 1292752 Removal from TIA/CH2C12 The B〇c_ protecting group of the compound of 22D, and the obtained amine was coupled with the carboxylic acid from Example 2A to give the desired compound (820/o). 3 00 MHz 1H NMR (CDCl3) 5 0.82 (m, 6 l·l) 1·(Μ·20 (m, 6H), 1.60 (m, 2H), 2.07 (m, 1H), 2.25 (m5 2H), 2 ·65-3·20 (m,12H),3·70 (m,1H),3·90 (m,1H),4.1〇-4·2〇(m,2H),5.07 (m,1H), 5.37 (m,1H),5·87-5·98 (m,1H), 6.95-7.05 (m,1H), 7.20 (m,i〇H). Mass Spectrum: (m+H)+ = 671. 23 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-1hydroxy-5-(2S-(l-dihydropyrimidine_2,4-dione) _3_Methylbutylidene) Amino-p-phenylene oxime·N-(2-ethoxypropenylmethoxycarbonylpropyl)urea 3.90 g (0.02 6 mol) of silver cyanate is added to 1.74 g (0.013 mol) of 2-ethoxypropenyl chloride in 18 ml of toluene. The mixture was heated to reflux for 0.77 hours. The mixture was allowed to warm to room temperature and allowed to precipitate. The supernatant (9.6 ml) was recovered, and 18 ml of anhydrous DMF* 5 pen #Et2 加入 was added, and the cold portion was -15 ° C for 45 minutes, and left in the refrigerator overnight. Evaporate in the true two granules, and By gel column chromatography (2% Me〇H/CH2C12), 1.59 g of the desired compound (9 〇 2%). 3 〇〇 Hz H NMR (CDC13) δ G.96 (d5 I = 7 Hz, 3H), i 〇 (d, j = 7 Her paper, 311), 1.37〇, 1 = 7.5 Hz, 311), 2 25 (111, 111), 3.74 (8, 3H), 3.97 (q5 J = 7.5 Hz, 2H), 4·42 (10), j = 4 5, 8 〇 Hertz, 1H), 5·25 (d, J = 12 Hz, 1H), 7·68 (d, j = i2 Hertz, 1H), 8·55 (s, 1H), 9.10 (d, j = 8 Hz, 1H). Mass spectrum··(M+H)+ = 273.

O:\106\106749.DOC -97- 1292752 Β· 2S-(1-二氫嘧啶_2,4_二酮基)-3-甲基丁酸 使在10毫升2N硫酸中之174毫克(0.64毫莫耳)得自實例 23 A之化合物的溶液迴流2小時,冷卻至室溫並將其留在冰 箱中過夜。濃縮該混合物,並以醋酸乙酯(2 X 1〇〇毫升)萃 取殘餘物,在真空中脫水和濃縮,得到122毫克想要的化合 物。300兆赫茲咕 NMR (CDC13) 5 1.06 (d,J = 7赫茲,3H), 1.13 (d,J = 7赫茲,3H),2.25 (m,1H),5·04 (d,J = 1〇赫茲, 1H)5 5·74 (d,J = 7赫茲,1H),7·50 (d5 J = 10赫茲,ιΗ),8 43 (s5 1H) 〇 C· (28,38,58)-2-(2,6-二甲基苯氧乙醯基)胺基_3_經基 -5-(2S-(l_二氫嘧啶-2,4-二酮基)-3_甲基丁醯基)胺基 二苯基己烷 利用標準偶聯程序(在DMF中之EDAC)將得自實例23B之 羧酸與得自實例1N之胺偶聯,得到想要的化合物。300兆赫 兹1H NMR (CDC13) 5 0.81 (d,J = 7赫茲,3H),0.92 (d,J = 7赫兹,3H),2.18 (s,6H),2·23 (m,1H),2·63 (m,1H),2_85 (m,1H),3·0 (m,2H),3.78 (m,1H),4·20 (m5 4H),4·58 (d5 J = 10赫兹,1H)5 5.68 (dd,J = 1.5, 7.5赫茲,1H),7·0_7·25 (m, 13H),7.50 (d,J = 7.5赫茲,1H),9·50 (s,1H)。質譜:(M+H)+ =640 ° 實例24 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-[2S-(l-四氫嘧啶-2-酮基)-3-甲基丁醯基】胺基-i,6-二苯 基己烷的另一種製備法 O:\106\106749.DOC -98- 1292752 Α· 2,6-二曱基苯氧乙酸 將在1000毫升Η20中之2,6-二甲酚(102.8克,0.842莫耳) 和氯化乙酸(159.6克,1.68莫耳),加入3-公升附有機械攪拌 和水-冷冷凝器的3 -頸圓底燒瓶中。經由添加漏斗將溶解於 500毫升水中之NaH(134·9克,3·37莫耳)的溶液慢慢地加至 上述的混合物中,並加熱至迴流。在2小時之後。在該反應 混合物中加入額外的氯化乙酸(79·4克,〇·84莫耳)和NaOH溶 液(67·2克,在2〇〇毫升水中之168莫耳)。在19小時之後, 在該反應混合物中加入額外的氯化乙酸(39.8克,〇·42莫耳) 和NaOH溶液(33.6克,在1〇〇毫升水中之〇·84莫耳),並持續 迴流’直到耗盡起始的酚為止。在冰水浴中冷卻該反應燒 瓶,並以濃HC1將其酸化至pH=l,引起沉澱物的形成。在 冰浴中攪拌所得的淤漿1小時,然後將其過濾。將固體溶解 於熱(100 C )水中再將其冷,使產物結晶成白色的板狀,炫 點=136-137\:,產量=78.8克,52%, Β· (28,38,58)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-(第三-丁氧羰基胺基)_1,6_二苯基己烷 將草醯氯(36.3毫升,〇·42莫耳)加至在5〇〇毫升曱苯中之 2,6-二甲基苯氧乙酸(50克,〇·28莫耳)的淤漿中,接著再加 入5滴DMF,並在室溫下攪拌3〇分鐘,然後在55。〇下15小 時。在鉍轉式八化器上移除甲苯,並在真空中移除殘餘的 揮發物,獲得黃褐色油狀之2,6-二甲基苯氧乙醯氯,55克, 100%。 將[2S,3S,5S]-2-胺基-3-羥基-5-第三-丁氧羰基胺基_丨,6_ O:\106\106749.DOC -99- 1292752 一笨基己烷χ 0·5琥珀酸鹽(U1.9克,〇·25莫耳)裝入2公 升、附有機械攪拌的3-頸圓底燒瓶中。加入NaHC03 (1〇6 克’ 1.26莫耳)、600毫升H20和600毫升EtOAc,並激烈地攪 拌’直到所有的固體均溶解為止(丨5分鐘)。減慢攪拌,並經 由添加漏斗以窄流將2,6_二甲基苯氧乙醯氣和Et〇Ac (1〇〇 毫升)加入。在擾拌30分鐘之後,耗盡起始物質(HpLC分 析)’並分離出層次。以EtOAc萃取液層,混合有機層,並 以200毫升1M NaOH、200毫升的10% HC1、200毫升鹽水沖 洗’覆以MgS〇4脫水,過濾並濃縮,得到白色固體狀之想 要產物。 C· (28,38,58)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5_(第三-丁基羰基胺基二苯基己烷 混合(28,38,58)-2-(2,6-二甲基苯氧乙醯基)胺基_3_羥基 -5-(第三-丁氧羰基胺基)_丨,6_二苯基己烷(1751克,〇.32莫 耳)和500毫升CH2C12,並加以攪拌。加入cf3C02H (249毫 升’ 3·2莫耳)並攪拌20-25分鐘,然後將該反應混合物倒入 含有1000毫升水和200毫升CH2C12的分液漏斗中。小心地搖 盪所得的混合物,並分離出層次。再次以5〇〇毫升的水沖洗 有機層’然後以3 X 500毫升NaHC03沖洗,最後以500毫升 鹽水沖洗。將有機溶液覆以MgS04脫水,過濾並濃縮,得 到金黃色的油,將其抽吸成一團泡珠,將3〇〇毫升二乙醚加 至粗產物中,並劇烈地搖盪至溶解。在數分鐘内固體開始 形成結晶’且該混合物變成黏稠狀。加入足夠的二乙醚使 該混合物得以攪拌,並在室溫下搜拌該混合物1小時。過濾 O:\106\106749.DOC -100- 1292752 該固體並將其風乾,得到115克白色針狀的想要產物,產量 81%。 將HC1/二乙醚之溶液加至濾液中,使殘餘的產物以H(:l 鹽之形式沉澱出來。藉著過濾收集略帶淡紅色的固體,小 心地將該固體保持在充滿%之中,同時以乙醚使其潮濕。 在脫水之時,將該胺鹽移至分液漏斗中,並以和 NaHC〇3 (含水的)萃取之。以鹽水沖洗有機層,覆以MgS〇4 脫水,濃縮並以上述方式處理,得到額外的15克想要產物, 總產量為91 %。 D· N-羰基苄氧基-3-胺基丙醇 在12公升3-頸圓底燒瓶中,加入乙酸異丙酯(6·5公升)。 在冰水浴中將溶劑冷卻至〇。(:,並一次加入3_胺基_丨_丙酮 (1.14公斤,15」莫耳,2.15當量)。在這個迅速攪拌的溶液 中,於2小時内逐滴加入氯化甲酸芊酯(1·2〇公斤,叉们莫 耳,1.0當量),同時將燒瓶的内部溫度維持在⑺它到^艺之 間。在加成作用完成之後,容許在1〇。〇到15。〇之間攪拌該 反應混合物額外的〇·3小時,在這段時間之後一次加入水 (3.5公升)’然後分配該溶液,並以額外2 X 3·5公升的水沖 洗。將有機層覆以碳酸鉀脫水並濃縮之,得到固體,將其 浴解於過量的乙酸異丙酯中,並藉著將該化合物加至庚烷 中而使其從溶液中沉澱出來。在氮氣下過濾固體,得到12〇 公斤(82%)無色固體狀之想要產物。 Ε· Ν-羰基苄氧基-3-胺基丙搭 混合335毫升二甲亞砜和9公升的二氯甲烷,並冷卻至_48O:\106\106749.DOC -97- 1292752 Β· 2S-(1-dihydropyrimidin-2,4-dione)-3-methylbutyric acid 174 mg (0.64) in 10 ml of 2N sulfuric acid A solution of the compound from Example 23A was refluxed for 2 hours, cooled to room temperature and left in the refrigerator overnight. The mixture was concentrated, and the residue was crystalljjjjjjjjjjjj 300 MHz NMR (CDC13) 5 1.06 (d, J = 7 Hz, 3H), 1.13 (d, J = 7 Hz, 3H), 2.25 (m, 1H), 5·04 (d, J = 1〇) Hertz, 1H)5 5·74 (d, J = 7 Hz, 1H), 7·50 (d5 J = 10 Hz, ιΗ), 8 43 (s5 1H) 〇C· (28,38,58)-2 -(2,6-dimethylphenoxyethyl)amino-3-3-ylamino-5-(2S-(l-dihydropyrimidin-2,4-dione)-3-methylbutanyl) Aminodiphenylhexane The carboxylic acid from Example 23B was coupled with the amine from Example 1N using standard coupling procedures (EDAC in DMF) to afford the desired compound. 300 MHz 1H NMR (CDC13) 5 0.81 (d, J = 7 Hz, 3H), 0.92 (d, J = 7 Hz, 3H), 2.18 (s, 6H), 2·23 (m, 1H), 2 · 63 (m, 1H), 2_85 (m, 1H), 3·0 (m, 2H), 3.78 (m, 1H), 4·20 (m5 4H), 4·58 (d5 J = 10 Hz, 1H ) 5 5.68 (dd, J = 1.5, 7.5 Hz, 1H), 7·0_7·25 (m, 13H), 7.50 (d, J = 7.5 Hz, 1H), 9·50 (s, 1H). Mass Spectrum: (M+H)+ = 640 ° Example 24 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-[2S-( Another preparation method of l-tetrahydropyrimidin-2-one)-3-methylbutanyl]amino-i,6-diphenylhexane O:\106\106749.DOC -98- 1292752 Α· 2 , 6-Dimercaptophenoxyacetic acid will be added to 3-liter of 2,6-xylenol (102.8 g, 0.842 mol) and chlorinated acetic acid (159.6 g, 1.68 mol) in 1000 ml of hydrazine 20 Mechanically stirred and water-cooled condenser in a 3-neck round bottom flask. A solution of NaH (134·9 g, 3.37 mol) dissolved in 500 ml of water was slowly added to the above mixture via an addition funnel and heated to reflux. After 2 hours. Additional chlorinated acetic acid (79. 4 g, 〇·84 mol) and NaOH solution (67. 2 g, 168 mol in 2 mL of water) were added to the reaction mixture. After 19 hours, additional chlorinated acetic acid (39.8 g, 〇·42 mol) and NaOH solution (33.6 g, 8484 mol in 1 mL of water) were added to the reaction mixture and reflux was continued. 'Until the starting phenol is exhausted. The reaction flask was cooled in an ice water bath and acidified to pH = 1 with concentrated HCl to cause formation of a precipitate. The resulting slurry was stirred in an ice bath for 1 hour and then filtered. The solid was dissolved in hot (100 C) water and then allowed to cool to crystallize the product into a white plate. Hyun = 136-137::, yield = 78.8 g, 52%, Β· (28, 38, 58) -2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-(tris-butoxycarbonylamino)-1,6-diphenylhexane 36.3 ml, 〇·42 mol) was added to a slurry of 2,6-dimethylphenoxyacetic acid (50 g, 〇·28 mol) in 5 ml of decylbenzene, followed by 5 drops. DMF and stir at room temperature for 3 minutes, then at 55. Leave it for 15 hours. The toluene was removed on a helium-transformer and the residual volatiles were removed in vacuo to afford 2,6-dimethylphenoxyethylamine chloride, 55 g, 100%. [2S,3S,5S]-2-Amino-3-hydroxy-5-tris-butoxycarbonylamino 丨,6_O:\106\106749.DOC -99-1292752 0.5 succinate (U 1.9 g, 〇 25 mol) was placed in a 2 liter 3-neck round bottom flask with mechanical stirring. Add NaHC03 (1 〇 6 g ' 1.26 mol), 600 ml H20 and 600 ml EtOAc and stir vigorously until all the solids were dissolved (丨5 min). Stirring was slowed and 2,6-dimethylphenoxyacetam and Et〇Ac (1 mL) were added via a funnel in a narrow stream. After 30 minutes of scramble, the starting material (HpLC analysis) was depleted and the layers were separated. The layers were extracted with EtOAc. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj C·(28,38,58)-2-(2,6-Dimethylphenoxyethyl)amino-3-hydroxy-5-(tris-butylcarbonylaminodiphenylhexane mixed ( 28,38,58)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5-(tris-butoxycarbonylamino)-indole, 6-diphenyl Hexane (1751 g, 〇.32 mol) and 500 ml of CH2C12, and stirred. Add cf3C02H (249 ml '3.2 mol) and stir for 20-25 minutes, then pour the reaction mixture into 1000 ml Water and 200 ml CH2C12 separatory funnel. Carefully shake the resulting mixture and separate the layers. Rinse the organic layer again with 5 mL of water. Then rinse with 3 X 500 mL NaHC03 and finally rinse with 500 mL of saline. The organic solution was dehydrated with MgS04, filtered and concentrated to give a golden oil, which was then taken up into a blister, and 3 liters of diethyl ether was added to the crude product and shaken vigorously to dissolve. The solid began to crystallize within a minute' and the mixture became viscous. Sufficient diethyl ether was added to stir the mixture and the mixture was stirred at room temperature for 1 hour. O:\106\106749.DOC -100- 1292752 The solid was air-dried to give 115 g of the desired product as white needles with a yield of 81%. A solution of HC 1 / diethyl ether was added to the filtrate to give a residual product. Precipitate in the form of H (:1 salt). By collecting a slightly reddish solid by filtration, carefully keep the solid in %, while moistening with ether. At the time of dehydration, the amine salt Transfer to a separatory funnel and extract with NaHC〇3 (aqueous). Wash the organic layer with brine, dehydrate with MgS〇4, concentrate and treat in the above manner to give an additional 15 g of desired product. The yield was 91%. D. N-carbonylbenzyloxy-3-aminopropanol In a 12 liter 3-neck round bottom flask, isopropyl acetate (6.5 liter) was added. The solvent was cooled in an ice water bath. To: (:, and add 3_amino-indole-acetone (1.14 kg, 15 mol), 2.15 equivalents at a time. In this rapidly stirred solution, add decyl chloroformate dropwise over 2 hours. (1·2〇 kg, fork Moer, 1.0 equivalent), while maintaining the internal temperature of the flask (7) it to ^ Yizhi After the completion of the addition, allow the reaction mixture to be stirred for an additional 〇·3 hours between 〇 and 15 ,, after which time water (3.5 liters) is added once and then the solution is dispensed. Rinse with an additional 2 X 3 · 5 liters of water. The organic layer was dehydrated with potassium carbonate and concentrated to give a solid which was taken in an excess of isopropyl acetate. The alkane was precipitated from the solution. The solid was filtered under nitrogen to give 12 g (yield: 82%) of desired product as colorless solid. Ε· Ν-carbonylbenzyloxy-3-aminopropene mixed 335 ml of dimethyl sulfoxide and 9 liters of dichloromethane, and cooled to _48

O:\106\106749.DOC • 101 - Ϊ292752 t。在25分鐘内加入313毫升的草_,以便維持溫度低於 -40t&gt;冷卻至-48°C,並加入溶解於i公升二氯甲烷中之5〇〇 克N-Cbz-3-胺基-1-丙醇,以便維持溫度低於_4〇。〇。在_45 °c下攪拌額外的i小時。以能夠將溫度維持在_4〇t以下的 速度加人1325毫升三乙胺。在_40t:下撥摔額外的15分鐘之 後,容許將該混合物回溫至-3〇t,然後加入2 5公升2〇%含 水的磷酸二氫鉀。攪拌丨小時,然後分離出層次,以鹽水沖 洗有機層,並以硫酸鎂將其脫水。將所得的醛保留在_2〇。〇 的溶液中,直到需要為止。 F· N-(N-(芊氧羰基-3-胺基)丙基)纈胺酸甲酯 在5公升3-頸圓底燒瓶中加入實例24E之粗產物(未經過 層析的)⑴5克,0.555莫耳,u當量),接著加入水(4〇〇毫 升)和甲醇(测毫升)。在整個反應過程中,將該反應混合 物維持在25。(:。在該溶液變成均質化之後,一次加入(s)_ 纖胺酸甲醋氫氯化物(90.2克,0.538莫耳,〇97當量),接著 按順序迅速加入乙酸鈉三水合物〇51克,ln莫耳,2.〇當 量)和氰基蝴氫化納(73.2克’ 117莫耳,21當量容許在 室溫下攪拌該反應混合物〇·5小時,並在真空中濃縮,以便 移除所有存在的甲醇。在該溶液中,加入飽和的含水碳酸 氨納(400毫升),並以乙酸異丙酯(1公升)萃取該混合物。以 水(2 X 400毫升)沖洗有機層,覆以硫酸鈉脫水並濃縮之, 侍到150克的粗產物,將其溶解於乙酸異丙酯(3〇〇毫升)和庚 (2400毫升)中。使無水的HCi在其中起泡,並在該溶液中 有油狀的固體沉澱出來。拋棄固體以外的液體,並將其溶O:\106\106749.DOC • 101 - Ϊ292752 t. 313 ml of grass _ was added over 25 minutes to maintain the temperature below -40 t &gt; cooled to -48 ° C and 5 g of N-Cbz-3-amino group dissolved in i liters of methylene chloride was added - 1-propanol in order to maintain the temperature below _4 〇. Hey. Stir for an additional i hours at _45 °c. 1325 ml of triethylamine was added at a rate capable of maintaining the temperature below _4 〇t. After an additional 15 minutes of _40t:, the mixture was allowed to warm to -3 Torr, and then 2 5 liters of 2% water-containing potassium dihydrogen phosphate was added. After stirring for a few hours, the layers were separated, and the organic layer was washed with brine and dried over magnesium sulfate. The resulting aldehyde was retained at _2 Torr. In a solution of 〇 until needed. Methyl F. N-(N-(indolylcarbonyl-3-amino)propyl) decanoate The crude product of Example 24E (not chromatographed) was added to a 5 liter 3-neck round bottom flask (1) 5 g , 0.555 mol, u equivalent), followed by water (4 mL) and methanol (ml). The reaction mixture was maintained at 25 throughout the course of the reaction. (: After the solution became homogenized, (s)_glycine methyl acetate hydrochloride (90.2 g, 0.538 mol, 〇97 equivalent) was added in one portion, followed by rapid addition of sodium acetate trihydrate 按51 in order.克, ln 莫, 2. 〇 equivalent) and cyano hydride (73.2 g '117 m, 21 eq. allowed to stir the reaction mixture at room temperature for 5 hours and concentrated in vacuo to remove All methanol was present. In this solution, saturated aqueous sodium bicarbonate (400 ml) was added, and the mixture was extracted with isopropyl acetate (1 liter). The organic layer was washed with water (2×400 ml) and covered with The sodium sulfate was dehydrated and concentrated, and 150 g of a crude product was dissolved in isopropyl acetate (3 ml) and hept (2400 ml). Anhydrous HCi was foamed therein and in the solution An oily solid precipitates out. Discard the liquid other than the solid and dissolve it.

O:\106\I06749.DOC 1292752 解於一氯甲统(3公升)中。以水(6Ο 0 ^:升)和飽和的含水碳酸 氫鈉(600毫升)沖洗該溶液,並覆以硫酸鈉脫水。在真空中 濃縮,得到105克(59%)淡黃色油狀之想要產物。 G· Ν-(3-胺基)丙基纈胺酸甲酯 在3公升燒瓶中加入實例24F的產物(120克,0.372莫耳) 和甲醇(1公升)。容許該溶液在阮内鎳(18〇克)的存在下授拌 1小時。在藉著過濾移除阮内鎳之後,加入pd(0H)2 (24克), 並容許在6 0镑/平方英对的氫氣壓力下搜拌該溶液12小 時。以氮氣吹掃該溶液,並再度在60磅/平方英吋的氫氣壓 力下額外的1小時。過濾該溶液並濃縮之,得到63克的油 (90%)。在該油中加入甲苯(120毫升),並再次於真空中濃縮 該溶液,得到想要的產物。 H· 2S-(1-四氫嘧咬_3_酮基)-3-甲基丁酸甲酯 在附有攪拌棒的5公升3-頸圓底燒瓶中加入實例24G之粗 產物(150克,0.8莫耳)和二氣曱烷(3.2公升)。在25分鐘内慢 慢地分批加入羰基二咪唑(232克,1.44莫耳,1.8當量)。容 許該溶液在周圍溫度下攪拌40小時。在1小時之内加入水 (200毫升),並小心地攪拌,直到沒有更多的氣體發生為止。 在正在攪拌的溶液中慢慢地加入35% HC1之溶液,直到該溶 液變成酸性為止。然後使該溶液分配,並以水(2 X 3 00毫升) 沖洗。將有機層覆以硫酸納脫水並將其濃縮,得到12 6克 (74%)無色固體之想要產物。 I· 2S-(l_ra氫嘧啶-2_酮基)-3_曱基丁酸曱酯 在附有攪拌棒的12公升3 -頸圓底燒瓶中,加入實例24H之 O:\106\106749.DOC -103 - 1292752 產物(126克’ 〇·588莫耳)、水(ι_3公升)和THF (3.9公升)。將 該溶液在冰浴中冷卻至〇〇c,並一次加入氫氧化鋰單水合物 (74克’ 1.76莫耳,3·〇當量),迅速地加以攪拌。容許在〇。〇 下授拌該溶液14小時。然後藉著慢慢地加入5〇%含水磷酸 將其酸化至pH 11,並在真空中移除thf。以乙酸異丙酯(2 公升)沖洗液相,接著藉著慢慢地加入35%含水HCu$pH值 酸化。然後以醋酸乙酯(5 χ 2·2公升)萃取液層。濃縮混合的 有機層’得到白色固體狀之想要產物(1〇5克)。然後藉著加 入乙酸異丙酯(500毫升)和乙醇(15毫升)純化該化合物,並 將該溶液煮沸,並加以迅速地攪拌,直到5 〇毫升的溶劑蒸 發為止。將該溶液冷卻至〇。(^並過濾之,得到92克(75%)純 的想要產物。 J· (28,38,58)-2_(2,6-二甲基苯氧乙醯基)胺基-3_羥基 -5-[2S-(l-四氫嘧啶-2-酮基&gt;-3-甲基丁醯基】胺基-:ι,6_二苯 基己烷 在2公升3-頸圓底燒瓶中,混合實例24C (100克,0.22莫 耳)、實例241之產物(44.8克,0.22莫耳)和750毫升DMF,並 在冰/水浴中冷卻該混合物。加入HOBT (90.9克,〇·67莫 耳)、EDAC (86克,0·45莫耳)和三乙胺(62.5毫升,〇·45莫 耳),並移開冰浴,容許攪拌該反應混合物,並加溫至室溫 5小時。以1000毫升IPAC稀釋該反應,並以1〇00毫升水使其 中止。搖盪該混合物並分離之,以1 X 400毫升IPAC萃取液 層,以1 X 400毫升10% HC1、1 X 500毫升NaHC03沖洗有機 物,以100毫升己烷稀釋,然後以4 X 500毫升水,1 χ 5〇〇 O:\106\106749.DOC -104- 1292752 晕升鹽水沖洗,覆以MgS04脫水,過濾並濃縮之,得到白 色泡沫狀之想要產物。 實例25 (2S,3S,5S)_2-(2,6-二甲基苯氧乙醢基)胺基_3_經基 -5_[2S-(1·四氫嘧啶·2,4-二酮基)-3-甲基丁醯基]胺基-1,6-二苯基己烷 Α· N-(2-甲氧羰基)乙基_L-纈胺酸第三-丁酯 將9.0毫升丙烯酸甲酯加至在1〇毫升曱醇中之173克£_纈 胺酸酸第三-丁酯的溶液中。將該溶液加熱至迴流過夜。再 加入另外0.9克毫升丙烯酸甲酯,並持續迴流24小時。在真 空中蒸發溶劑’並藉著矽膠管柱層析法(20〇/〇在己烷中之醋 酸乙S旨)純化粗產物,得到2·435克想要的產物(93 9%)。3〇〇 兆赫兹!H NMR (CDC13) 5 0.91 (d,J = 3.5赫茲,3Η),0.93 (d,J = 3·5赫茲,3H),1.47 (s,9H),1.85 (m,1H),2.47 (t,J = 7赫兹,2H),2.68 (m,1H),2.81 (d5 J = 6赫兹,1H),2·95 (m, 1H),3.68 (s,3H)。質譜:(m+H)+ = 260。 Β· N-(2-缓基醯胺基)乙基綠胺酸第三-丁醋 將在10.8毫升水中之〇·415克氫氧化鋰單水合物加至在5 毫升THF中之1.86克得自實例25Α之產物的溶液中。在4〇分 鐘後,加入10.8毫升IN HC1。將反應混合物蒸發至無水, 並加入無水的吡啶,並蒸發至無水兩次。將該殘餘物溶解 於25毫升乙腈中,並加入〇·62毫升無水吡啶。在該溶液中 加入2.02克Ν,Ν’-二琥珀醯亞胺碳酸酯。攪拌該反應混合物 3.5小時。在真空中移除溶劑,並加入9〇毫升1111?,接著加 O:\106\106749.DOC -105- 1292752 入1.43毫升濃氫氧化銨。容許該反應進行過夜。過渡該反 應此合物並在真空中濃縮濾液。將殘餘物溶解於醋酸乙酯 中,並以碳酸氫納、鹽水沖洗,独無水的硫酸納將其脫 水。在濾掉脫水劑之後,在真空中濃縮濾液,並藉著矽膠 管柱層析法(5% MeOH在C^C〗2中),得到丨.19克(68%)想要 的化合物。300 兆赫兹 iHNMR(CDC13) 5 0.95(d,j = 7 赫 茲,3H),0.97 (d,J = 7赫茲,3H),1.48 (s,9H),1.93 (m,1H), 2·37 (m,2H),2·65 (m,1H),2.95 (m,2H),5·30 (br s,1H), 7·85 (br s,1H)。質譜:(M+H)+ = 245。 C· 2S-(1-四氫嘧啶-2,4-二酮基)-3-甲基丁酸第三·丁酯 將在10毫升THF中之0.92克得自實例25B之產物的溶液 和1.83克羧基二咪唑(CDI)迴流26小時。然後再加入ι·83克 CDI,並再度迴流該溶液72小時。在真空中蒸發溶劑,並將 殘餘物溶解於醋酸乙酯中,以水、飽和的碳酸氫鈉、稀氫 氣酸沖洗,然後再以鹽水沖洗。將有機層脫水、過濾並在 真空中濃縮。藉著矽膠管柱層析法(2%到5%在CH2C12中之 MeOH)純化粗產物,得到0.54克(52%)想要的化合物。300 兆赫茲咕 NMR (CDC13) 5 0·96 (d,J = 7赫茲 5 3H),1.05 (d,J = 7赫茲,3H),1.48 (s,9H),2.20 (m,1H),2.66 (m,2H), 3·43 (m5 1H),3.75 (m,1H),4.63 (d5 J = 9赫茲,1H),7·35 (br s,1H)。質譜:(M+H)+ = 271。 D. 2S-(1-四氮嘧啶-2,4-二酮基)_3-甲基丁酸 在〇°C下攪拌在5毫升三氟乙酸中之0.53克得自實例25C 之化合物的溶液1.25小時。在真空中蒸發溶劑,脫水並藉 O:\106\106749.DOC -106- 1292752 著矽膠管柱層析法MeOH/4% HOAc在CH2C12中)純化, 得到0·36克想要的化合物。300兆赫茲NMR (DMSO-d6) δ 0·86 (d,J = 7赫茲,3Η),0.97 (d,J = 7赫茲,3Η),2.15 (m, 1H),3·40 (m,4H),4.39 (d,J = 10赫茲,1H)。質譜:(M+H)+ =215 ° Ε· (28,38,58)-2_(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-[2s-(i-四氫嘧啶j,4·二酮基甲基丁醯基】胺基-l6_ 二苯基己烷 利用標準偶聯程序(在DMF中之EDAC)將得自實例in之 胺基化合物與得自實例25D之酸偶聯,得到想要的化合物 (68%)。300兆赫茲111應尺((:0(::13)(5〇83((1,:[:=7赫兹, 3H),0.88 (d5 J = 7赫茲,3H), uo (m,2H),2 2〇 (s,6H),2 4〇 (m,1H),2.58 (m,1H),2.80 (m,1H),2.92 (m,1H),3.05 (m, 3H)5 3.65 (d,J = 5赫兹,1H),3·83 (m,1H),4 2〇 (m,5H), 6_18 (d,J = 9赫茲,ih),7.0-7.38 (m5 14H)。質譜:(M+H)+ = 643 〇 實例26 (2S,3S,5S)-2-(2,6·二曱基苯氧乙醯基)胺基·3羥基 -5-[2S-(4-氮雜4•四氫嘧啶酮基)_3甲基丁醯基]胺基 -1,6-二苯基己烷 Α· N(l)-第三-丁氧羰基以(2)_烯丙基胼 將19.0克碳酸鉀加至在5〇毫升乙腈中之ms克第三丁 氧裁基保護之肼的溶液中,接著力nX119t# 將該反應混合物加熱至迴流總共3小時,過渡並在真空中濃O:\106\I06749.DOC 1292752 is dissolved in monochloromethane (3 liters). The solution was washed with water (6 Ο 0 ^: liter) and saturated aqueous sodium hydrogen carbonate (600 mL) and dried over sodium sulfate. Concentration in vacuo gave 105 g (yield: 59%) of desired product as pale yellow oil. G. Ν-(3-Amino)propyl proguanilate The product of Example 24F (120 g, 0.372 mol) and methanol (1 liter) were placed in a 3 liter flask. The solution was allowed to mix for 1 hour in the presence of Raney nickel (18 g). After the Raney nickel was removed by filtration, pd(0H)2 (24 g) was added, and the solution was allowed to mix for 20 hours under a hydrogen pressure of 60 pounds per square inch. The solution was purged with nitrogen and again at an additional 1 hour under a pressure of 60 psig of hydrogen. The solution was filtered and concentrated to give 63 g of oil (90%). Toluene (120 ml) was added to the oil, and the solution was concentrated again in vacuo to give the desired product. H. 2S-(1-tetrahydropyrimidine-3-yl)-3-methylbutanoate was added to a 5 liter 3-neck round bottom flask with a stir bar. , 0.8 moles) and dioxane (3.2 liters). Carbonyldiimidazole (232 g, 1.44 mol, 1.8 equivalents) was added in portions slowly over 25 minutes. The solution was allowed to stir at ambient temperature for 40 hours. Water (200 ml) was added over 1 hour and carefully stirred until no more gas was produced. A solution of 35% HCl was slowly added to the stirring solution until the solution became acidic. The solution was then dispensed and rinsed with water (2 x 3 00 mL). The organic layer was dehydrated with sodium sulfate and concentrated to give 12 6 g (yield: 74%) of desired product. I. 2S-(l_rahydropyrimidin-2-yl)-3-mercaptobutyrate was added to a 12 liter 3-neck round bottom flask with a stir bar, and the addition of Example 24H to O:\106\106749. DOC -103 - 1292752 product (126 g '〇·588 mol), water (ι_3 liter) and THF (3.9 liter). The solution was cooled to 〇〇c in an ice bath, and lithium hydroxide monohydrate (74 g &lt;RTIgt;&lt;/RTI&gt;&gt; Allowed. The solution was mixed for 14 hours. It was then acidified to pH 11 by slowly adding 5 % aqueous phosphoric acid and thf was removed in vacuo. The liquid phase was rinsed with isopropyl acetate (2 liters) and then acidified by slowly adding 35% aqueous HCu $ pH. The layer was then extracted with ethyl acetate (5 χ 2·2 liter). The mixed organic layer was concentrated to give the desired product (1 g, 5 g) as a white solid. The compound was then purified by the addition of isopropyl acetate (500 ml) and ethanol (15 ml), and the solution was boiled and stirred rapidly until 5 ml of solvent was evaporated. The solution was cooled to hydrazine. (^ and filtered to give 92 g (75%) of pure desired product. J·(28,38,58)-2_(2,6-dimethylphenoxyethyl)amino-3-hydroxyl -5-[2S-(l-tetrahydropyrimidin-2-one]&gt;-3-methylbutanyl]amino-: i,6-diphenylhexane in a 2 liter 3-neck round bottom flask, Mix Example 24C (100 g, 0.22 mol), product of Example 241 (44.8 g, 0.22 Mo) and 750 mL of DMF, and cool the mixture in ice/water bath. Add HOBT (90.9 g, 〇·67 mol) EDAC (86 g, 0.45 mol) and triethylamine (62.5 ml, 〇·45 mol), and removed the ice bath, allowed to stir the reaction mixture, and warmed to room temperature for 5 hours. The reaction was diluted with 1000 ml of IPAC and quenched with 1 00 ml of water. The mixture was shaken and separated, extracted with 1 X 400 ml of IPAC, rinsed with 1 X 400 ml of 10% HCl, 1 X 500 ml of NaHC03 The organic matter was diluted with 100 ml of hexane, then washed with 4×500 ml of water, 1 χ 5〇〇O:\106\106749.DOC -104- 1292752, diluted with saline, dehydrated with MgS04, filtered and concentrated to give White foamy product. Example 25 (2S,3S,5S)_2-(2,6-Dimethylphenoxyethyl fluorenyl)amino _3_ carbyl-5_[2S-(1·tetrahydropyrimidin-2,4-dione 3-methylbutylidene]amino-1,6-diphenylhexane oxime N-(2-methoxycarbonyl)ethyl-L-proline acid tert-butyl ester 9.0 ml of acrylic acid The ester was added to a solution of 173 g of the third-butyl phthalate in 1 ml of methanol. The solution was heated to reflux overnight. An additional 0.9 g of methyl acrylate was added and reflux was continued. The crude product was purified by evaporating the solvent in vacuo <RTI ID=0.0>(</RTI> </RTI> <RTIgt; 3 〇〇 Hz! H NMR (CDC13) 5 0.91 (d, J = 3.5 Hz, 3 Η), 0.93 (d, J = 3.5 Hz, 3H), 1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J = 7 Hz, 2H), 2.68 (m, 1H), 2.81 (d5 J = 6 Hz, 1H), 2·95 (m, 1H), 3.68 (s, 3H). :(m+H)+ = 260. Β· N-(2-carboylamino)ethyl lysine 3 -butyric acid will be added to 10.15 ml of water · 415 g of lithium hydroxide monohydrate To 5 ml 1.86 g of the solution from the product of Example 25 was obtained in THF. After 4 minutes, 10.8 ml of IN HC1 was added. The reaction mixture was evaporated to dryness and anhydrous EtOAc was evaporated. The residue was dissolved in 25 ml of acetonitrile and EtOAc (EtOAc) EtOAc. To the solution was added 2.02 g of hydrazine, Ν'-disuccinimide carbonate. The reaction mixture was stirred for 3.5 hours. The solvent was removed in vacuo and 9 mL of 1111? was added, followed by O:\106\106749.DOC -105-1292752 and 1.43 mL of concentrated ammonium hydroxide. The reaction was allowed to proceed overnight. The reaction was partitioned and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate and brine, and then evaporated from anhydrous sodium sulfate. After filtering off the dehydrating agent, the filtrate was concentrated in vacuo and purified by EtOAc EtOAc EtOAc EtOAc 300 MHz iH NMR (CDC13) 5 0.95 (d, j = 7 Hz, 3H), 0.97 (d, J = 7 Hz, 3H), 1.48 (s, 9H), 1.93 (m, 1H), 2·37 ( m, 2H), 2·65 (m, 1H), 2.95 (m, 2H), 5·30 (br s, 1H), 7·85 (br s, 1H). Mass spectrum: (M+H)+ = 245. C. 2S-(1-tetrahydropyrimidin-2,4-dione)-3-methylbutanoic acid tert-butyl ester 0.92 g of a solution obtained from the product of Example 25B in 1 ml of THF and 1.83 Carboxydimethylimidazole (CDI) was refluxed for 26 hours. Then, 83 g of CDI was added, and the solution was again refluxed for 72 hours. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate washed with water, sat. NaHCO? The organic layer was dried, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (2% to 5% MeOH in CH2 C12) to afford 0.54 g (52%) of desired compound. 300 MHz NMR (CDC13) 5 0·96 (d, J = 7 Hz 5 3H), 1.05 (d, J = 7 Hz, 3H), 1.48 (s, 9H), 2.20 (m, 1H), 2.66 (m, 2H), 3·43 (m5 1H), 3.75 (m, 1H), 4.63 (d5 J = 9 Hz, 1H), 7·35 (br s, 1H). Mass spectrum: (M+H)+ = 271. D. 2S-(1-tetraapyrimidine-2,4-dione)-3-methylbutyric acid 0.53 g of a solution of the compound from Example 25C, stirred in 5 mL of trifluoroacetic acid at EtOAc. hour. The solvent was evaporated in vacuo, purified and purified eluting with EtOAc EtOAc EtOAc EtOAc 300 MHz NMR (DMSO-d6) δ 0·86 (d, J = 7 Hz, 3 Η), 0.97 (d, J = 7 Hz, 3 Η), 2.15 (m, 1H), 3·40 (m, 4H) ), 4.39 (d, J = 10 Hz, 1H). Mass spectrometry: (M+H)+ =215 ° Ε·(28,38,58)-2_(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-[2s-(i -tetrahydropyrimidine j,4·diketomethylbutanyl]amino-l6_diphenylhexane The amine compound from Example in was obtained from Example 25D using a standard coupling procedure (EDAC in DMF). The acid is coupled to give the desired compound (68%). 300 MHz Hz 111 ((:0(::13)(5〇83((1,:[:==7 Hertz, 3H), 0.88 ( D5 J = 7 Hz, 3H), uo (m, 2H), 2 2 〇 (s, 6H), 2 4 〇 (m, 1H), 2.58 (m, 1H), 2.80 (m, 1H), 2.92 ( m,1H),3.05 (m, 3H)5 3.65 (d,J = 5 Hz, 1H), 3·83 (m,1H), 4 2〇(m,5H), 6_18 (d, J = 9 Hz , ih), 7.0-7.38 (m5 14H). Mass Spectrum: (M+H)+ = 643 〇 Example 26 (2S,3S,5S)-2-(2,6·Dimercaptophenoxyethyl)amine 3-Hydroxy-5-[2S-(4-aza-4•tetrahydropyrimidinyl)_3methylbutyryl]amino-1,6-diphenylhexaneΑ·N(l)-third- Butoxycarbonyl is added to a solution of m. Focus nX119t # The reaction mixture was heated to reflux for 3 hours in total, and concentrated in vacuo to a transition

O:\106\106749.DOC •107- 1292752 縮。將殘餘物溶解於醋酸乙酯中,以飽和的碳酸氫鈉沖洗, 並以無水的硫酸鈉將其脫水再過濾之。在真空中濃縮之 後,藉著矽膠管柱層析法(20% Et0Ac/己烷)純化粗產物, 得到4.47克想要的產物。3〇〇兆赫茲iH nmr (CDC1J占 1·45 (s,9H),3.46 (m,2H),4.0 (br s,1H),5.10 (m,2H),5.83 (m5 1H),6.0 (br s,1H)。質譜:(m+H)+ = 173。 Β· N(l)-第二-丁氧羰基_]^(2)_稀丙基4(2卜苄氧羰基肼 將4.69克芊氧羰基氧基琥珀醯亞胺加至在15毫升中 之4 · 8克付自貫例2 6 A之化合物的溶液中。在室溫下攪拌該 反應混合物72小時,並在真空中蒸發溶劑。將殘餘物溶解 於醋酸乙酯中,以飽和的碳酸氫鈉沖洗,並以無水的硫酸 納將其脫水。藉著矽膠管柱層析法(2〇%到5〇% EtOAc,在 己烧中)純化在濃縮後獲得的粗產物,得到5·27克想要的化 合物。300 兆赫茲 ^hnmrkdcd 5 _l43(brs,9H),415 (br s,2H),5.18 (s,2H),5·20 (m,2H),5.82 (m,1H),6.39 (br s,1H),7·36 (m5 5H)。質譜··(M+H)+ = 307。 C· N(l)-第三_丁氧羰基-N(2)-甲醯基甲基_N(2)_爷氧幾 基月井 利用無水的冰/丙嗣浴將在1〇〇宅升甲醇中之6·5克得自實 例26Β之化合物的溶液冷卻。使臭氧在其中起泡1 ·75小時, 直到持續呈淡藍色為止。使空氣通過該溶液丨〇分鐘,然後 加入15.6亳升二甲硫,並容許該反應混合物逐漸地回溫至 室溫過夜。在真空中蒸發溶劑,並將殘餘物溶解於醋酸乙 酉旨中,再以水沖洗,然後以鹽水沖洗數次。以無水的硫酸 O:\106\106749.DOC -108- 1292752 納將有機層脫水,㈣並在真空中濃縮,得到7 2克想要的 化合物。300兆赫茲NMR (CDCl3) 3上肩伽% 9H), 4-35 (m, 2H), 5.20 (s, 2H), 6.65 (br s, 1H), 7.36 (s, 5H), 9.70 (br s,1H)。質譜··(M+NH4)+ =: 326。 D· N-【2_(N_(2)-卞氧羰基-N-(l)-第三-丁氧羰基肼基】乙 基纈胺酸甲酯 將3.55克L-纈胺酸甲酯氫氯化物加至在1〇〇毫升甲醇中 之7.2克得自實例26C之化合物的溶液中,接著加入'μ克乙 酸鈉和1.33克氰基棚氫钱。在室溫下料該反應混合物 過仪。過濾該混合物並在真空中濃縮。藉著矽膠管柱層析 法(2% MeOH在ChCh中)純化粗產物,得到5·8克想要的化 合物。300兆赫兹 iHNMR(CDCl3) d 〇9〇((1,; = 6赫兹, 6H),1·43 (br s,9H),1.87 (m,1H),2·6(Μ·0 (m,4H),3.72 (s, 3Η),5.18 (s,2Η),7.37 (m,5Η)。質譜:(Μ+Η)+ = 424。 Ε· 2S-[4-苄氧羰基氮雜四氫嘧啶酮基)_3_甲基丁 酸甲酯 在至溫下’在氛氣之下授拌在20毫升HC1和二氧六環中之 2.4克得自實例26D之化合物的溶液1小時。在真空中蒸發溶 劑’並以飽和的碳酸氫鈉沖洗殘餘物,並以醋酸乙酿萃取 之。將有機層脫水,過濾並在真空中濃縮。將粗產物物溶 解於28毫升CH/h中,並加入0.56克羰基二咪唑。將該溶 液留在室溫下48小時。移除溶劑並藉著矽膠管柱層析法 (10%到30% EtOAc在CH2C12中),得到〇·78克想要的化合 物。300兆赫茲NMR (CDC13) (5 0.90 (d,J = 7赫兹,3Η), O:\106\106749.DOC -109- 1292752 〇·98 (d,J = 7赫茲,3h),2.17 (m,1Η),3·34 (m,1Η),3·61 (m, 2H),3.72 (s,3H),3·98 (m,1H),4.71 (d,J = 10赫茲,1H), 5.20 (s,2H),6.72 (br s,1H),7.38 (m,5H)。質譜:(M+H)+ = 350 ° F· 2S-(4-苄氧羰基氮雜四氫嘧啶酮基)-3_甲基丁酸 在含水的二氧六環中,利用氫氧化鋰將0.78克得自實例 26E之化合物水解,得到〇·35克想要的化合物。3〇〇兆赫茲lH NMR (CDCl3) 6 〇·85 (d,J = 7赫茲 5 3H),1.04 (d5 J = 7赫 热,3H),2·40 (m,出),3.40 (m,1H), 3.50 (m,1H),3.80 (m, 2H),3·95 (d,J 叫 〇赫兹,1H),5 2〇 (s,2H),7 3〇 (s,m), 7·36 (s,5H)。質譜··(M+H)+ = 336。 G· (28’38,58)-2_(2,6-二甲基苯氧乙醯基)胺基_3_羥基 -5-[2S-(下氧羰基氮雜四氫嘧啶_2_酮基卜3_甲基丁醯基】 fe基-1,6-一苯基已燒 利用標準偶聯程序(EDAC/DMF)將得自實例…之胺基化 曰物一得自實例26F之酸偶聯,得到想要的化合物(36%)。 3㈣赫兹 iHNMR(CDa3H G 72(d,卜 7赫兹,3Η), 0.83 (d? J = 7# , 3H)5 2.20 (s5 6H)5 2.65 (m5 1H)5 2.83 (m5 )’ -10 (m,4H)5 3.90 (m? 1H)5 6.65 (m5 1H)3 7.0-7.35 (m,18H)。質譜:(M+H)+== 764。 (2S’3S’5S)_2-(2,6_: f基苯氧乙醯基)胺基j·羥基 _5_[2S-(4-氮雜四氫嘧 風策咬-2-_基)_3_甲基丁醯基】胺基 •Μ-二苯基己烷 利用 10〇/。|巴碳作為催化劑,藉O:\106\106749.DOC •107- 1292752 Shrink. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. After concentrating in vacuo, the crude material was purified by EtOAc EtOAc (EtOAc) 3 〇〇 megahertz iH nmr (CDC1J occupies 1.45 (s, 9H), 3.46 (m, 2H), 4.0 (br s, 1H), 5.10 (m, 2H), 5.83 (m5 1H), 6.0 (br s,1H). Mass Spectrum: (m+H)+ = 173. Β·N(l)-Second-butoxycarbonyl _]^(2)_Dilyl 4 (2 benzyloxycarbonyl hydrazine will be 4.69 g The oxocarbonyloxysuccinimide was added to a solution of 4·8 g of the compound of Example 6 6 in 15 ml. The reaction mixture was stirred at room temperature for 72 hours, and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. EtOAc EtOAc EtOAc The crude product obtained after concentration is purified to give 5.27 g of the desired compound. 300 megahertz, hnmrkdcd 5 _l43 (brs, 9H), 415 (br s, 2H), 5.18 (s, 2H), 5 · 20 (m, 2H), 5.82 (m, 1H), 6.39 (br s, 1H), 7·36 (m5 5H). Mass spectrometer··(M+H)+ = 307. C· N(l)- The third _butoxycarbonyl-N(2)-methylidylmethyl_N(2)_Yu Oxygen-based moon well is treated with an anhydrous ice/acrylic bath. Kede The solution of the compound of Example 26 was cooled. The ozone was bubbled therein for 1.75 hours until it continued to light blue. Air was passed through the solution for a minute, then 15.6 liters of dimethyl sulfide was added, and the reaction mixture was allowed. Gradually warm to room temperature overnight. Evaporate the solvent in vacuo, and dissolve the residue in ethyl acetate, rinse with water, then rinse several times with brine, with anhydrous sulfuric acid O:\106\106749.DOC -108- 1292752 The organic layer is dehydrated, (iv) and concentrated in vacuo to give 72 g of the desired compound. 300 MHz NMR (CDCl3) 3 on shoulder gamma 9H), 4-35 (m, 2H), 5.20 (s, 2H), 6.65 (br s, 1H), 7.36 (s, 5H), 9.70 (br s, 1H). Mass spectrometer··(M+NH4)+ =: 326. D· N-[2_( N-(2)-oxime oxycarbonyl-N-(l)-tris-butoxycarbonylindenyl]ethyl amide methyl ester 3.55 g of methyl L-proline hydrochloride was added to 1 〇〇 7.2 g of a solution of the compound from Example 26C in MeOH was added, followed by 'μg sodium acetate and 1.33 g of cyano hydride. The reaction mixture was passed at room temperature. The mixture was filtered and Concentrated. By silica gel column chromatography (2% MeOH in ChCh) affording crude product was 5. 8 g of the desired compound. 300 MHz iH NMR (CDCl3) d 〇9〇 ((1,; = 6 Hz, 6H), 1.43 (br s, 9H), 1.87 (m, 1H), 2·6 (Μ·0 (m, 4H), 3.72 (s, 3Η), 5.18 (s, 2Η), 7.37 (m, 5Η). Mass Spectrum: (Μ+Η)+ = 424. Ε· 2S-[4-Benzyloxycarbonyl azatetrahydropyrimidine Methyl keto)_3_methylbutanoate was stirred at ambient temperature under stirring in a solution of 2.4 g of the compound from Example 26D in 20 ml of HCl and dioxane for 1 hour. The solvent was evaporated and the residue was washed with EtOAc EtOAc (EtOAc) The carbonyl carbodiimidazole was left at room temperature for 48 hours. The solvent was removed and purified by column chromatography (10% to 30% EtOAc in CH2 C12) 300 MHz NMR (CDC13) (5 0.90 (d, J = 7 Hz, 3 Η), O:\106\106749.DOC -109- 1292752 〇·98 (d, J = 7 Hz, 3h), 2.17 (m ,1Η),3·34 (m,1Η),3·61 (m, 2H), 3.72 (s,3H),3·98 (m,1H),4.71 (d, J = 10 Hz, 1H), 5.20 (s, 2H), 6.72 (br s, 1H), 7.38 (m, 5H). Mass Spectrum: (M+H)+ = 350 ° F· 2S-(4 -Benzyloxycarbonyl azatetrahydropyrimidinyl)-3_methylbutyric acid In aqueous dioxane, 0.78 g of the compound from Example 26E was hydrolyzed using lithium hydroxide to give 〇·35 g. Compound: 3 〇〇 megahertz lH NMR (CDCl3) 6 〇·85 (d, J = 7 Hz 5 3H), 1.04 (d5 J = 7 Hz, 3H), 2·40 (m, out), 3.40 (m,1H), 3.50 (m,1H), 3.80 (m, 2H),3·95 (d,J is called Hertz, 1H), 5 2〇(s,2H),7 3〇(s,m ), 7·36 (s, 5H). Mass Spectrum··(M+H)+ = 336. G·(28'38,58)-2_(2,6-Dimethylphenoxyethyl)amino _3_Hydroxy-5-[2S-(lower oxycarbonylazatetrahydropyrimidine-2-ketoben-3-methylbutyryl) fe-l-1,6-monophenyl has been burned using standard coupling procedure (EDAC) /DMF) An acid-coupled oxime from Example ... was obtained from the acid coupling of Example 26F to give the desired compound (36%). 3(d) Hertz iHNMR (CDa3H G 72 (d, Bu 7 Hz, 3 Η), 0.83 (d? J = 7# , 3H) 5 2.20 (s5 6H) 5 2.65 (m5 1H) 5 2.83 (m5 )' -10 (m ,4H)5 3.90 (m? 1H)5 6.65 (m5 1H)3 7.0-7.35 (m,18H). Mass Spectrum: (M+H)+== 764. (2S'3S'5S)_2-(2, 6_: f-phenoxyethyl oxime) amine group j. hydroxy _5_[2S-(4-azatetrahydropyrimidin-2-one)_3_methylbutanyl]amino-indole-diphenyl The hexane utilizes 10 〇 /. | bar carbon as a catalyst, borrowed

著氫解作用將得自實例26GHydrogenolysis will be derived from Example 26G

O:\106\106749.DOC 1292752 之化合物的芊氧獄基保護基移除’得到想要的化合物。3〇〇 兆赫茲NMR (CDC13) δ 〇·83 (d,J = 4·5赫茲,3Η),0.86 (d,J = 4.5赫茲,3Η),1·80 (m,1Η),2.20 (s,6Η),2.58 (m, 1Η),2·67 (m,1Η),2·90 (m,2Η),3.0 (m,1Η),3 8〇 (m,1Η), 4.20 (m,3Η),6·72 (m,1Η),7.0 (m,2Η),7·20 (m,11Η)。質 譜:(M+H)+ = 630。 實例27 (2S,3S,5S)-2»(2,6-二曱基苯氧乙醯基)胺基_3_經基 -5-[2S-(l-四氫嘧啶_2_酮基)-3_甲基丁醯基】胺基苯基 甲基庚烷 A· (2S,3S,5S)-2_胺基-3-經基_5-(第三-丁氧幾基胺 基)_1_苯基_6_甲基庚烷 依據在實例1A到實例1F-1中描述的程序,但是在實例1C 中以氣化芊基鎂來取代氯化異丙基鎂,得到想要的化合 物。300兆赫茲 iHNMR(CDC13) 5 〇.88(d,J = 7赫茲,3H), 〇·92 (d5 J = 7赫兹,3H),1.43 (s,9H),1·50-1·80 (m,4H), 2·55 (m,1H),2.90 (m,1H),3.0 (m,1H), 3·54 (m,2H),(62 (m,1H),7.30 (m,5H)。質譜:(m+h)+ = 337。 Β· (28,38,58)_2-(2,6-二甲基苯氧乙醯基)胺基_3_羥基 -5-(第三-丁氧羰基胺基)β1_苯基_6_甲基庚烷 利用標準EDAC偶聯程序,將得自實例27Α之胺基化合物 與得自實例1Η之酸偶聯,得到想要的化合物。3〇〇兆赫茲a NMR (CDC13) 5 0.85 (d,J = 7赫兹,3Η),〇 9〇 (d : = 7赫 热,3H),1.43 (s5 9H),1·7〇 (m,2H),2.20 (s,6H),3·〇3 (d5 J 1O:\106\106749. The deoxyl base protecting group of the compound of DOC 1292752 is removed to give the desired compound. 3 〇〇 Hz NMR (CDC13) δ 〇 · 83 (d, J = 4·5 Hz, 3 Η), 0.86 (d, J = 4.5 Hz, 3 Η), 1·80 (m, 1 Η), 2.20 (s ,6Η), 2.58 (m, 1Η), 2·67 (m, 1Η), 2·90 (m, 2Η), 3.0 (m, 1Η), 3 8〇 (m, 1Η), 4.20 (m, 3Η) ), 6·72 (m, 1Η), 7.0 (m, 2Η), 7·20 (m, 11Η). Mass spectrum: (M+H)+ = 630. Example 27 (2S,3S,5S)-2»(2,6-Dimercaptophenoxyethyl)amino-3-3-ylamino-5-[2S-(l-tetrahydropyrimidin-2-yl) -3-methylbutenyl]aminophenylmethylheptane A·(2S,3S,5S)-2-amino-3-carbyl-5-(tris-butoxyamino)_1 _Phenyl-6-methylheptane was subjected to the procedure described in Example 1A to Example 1F-1, but in Example 1C, propylmagnesium chloride was replaced by vaporized fluorenyl magnesium to give the desired compound. 300 MHz iH NMR (CDC13) 5 〇.88 (d, J = 7 Hz, 3H), 〇·92 (d5 J = 7 Hz, 3H), 1.43 (s, 9H), 1.50-1·80 ( m, 4H), 2·55 (m, 1H), 2.90 (m, 1H), 3.0 (m, 1H), 3·54 (m, 2H), (62 (m, 1H), 7.30 (m, 5H) Mass spectrometry: (m+h)+ = 337. Β· (28,38,58)_2-(2,6-dimethylphenoxyethyl)amino-3_hydroxy-5- (third - Butoxycarbonylamino) β1_phenyl-6-methylheptane The amine compound from Example 27 was coupled with the acid from Example 1 using standard EDAC coupling procedures to give the desired compound. 3 〇〇 Hz a NMR (CDC13) 5 0.85 (d, J = 7 Hz, 3 Η), 〇 9 〇 (d : = 7 Hz, 3H), 1.43 (s5 9H), 1.7 〇 (m, 2H), 2.20 (s, 6H), 3·〇3 (d5 J 1

O:\106\106749.DOC -111· 1292752 8赫茲,2H),3·4 1 “ ⑽,1H),3.80 (m,1H),4·20 (m5 2H),4·22 〇,ZH),4.55 (m (M+H)+= 499。’ ),7·0 (m,3H), 7.30 (m,5H)。質譜: c· (2S,3S,SS)〈〜 ^ _5_胺基-1-笼#· (2,6-二甲基苯氧乙醯基)胺基-3-羥基 甲基庚烷 將得自實例27B之化合物的第三-丁 利用實例1N之程序 氧羰基保護基移除,〜1O:\106\106749.DOC -111· 1292752 8 Hz, 2H), 3·4 1 “ (10), 1H), 3.80 (m, 1H), 4·20 (m5 2H), 4·22 〇, ZH) , 4.55 (m (M+H)+= 499.' ), 7·0 (m, 3H), 7.30 (m, 5H). Mass Spectrum: c· (2S,3S,SS)<~ ^ _5_Amino 1-Cage#·(2,6-Dimethylphenoxyethyl)amino-3-hydroxymethylheptane The third-but of the compound from Example 27B was subjected to the procedure of Example 1N for oxycarbonyl protection. Base removal, ~1

ΓΓηηι λ ^ 、传到想要的化合物。300兆赫茲】H NMRΓΓηηι λ ^ , passed to the desired compound. 300 MHz] H NMR

Cl3) 3 0 9 , ld,J = 3赫茲,3H),0·94 (d,J = 3赫茲, 3H),1·60 (m,4H) ^ Λ 2·20 (s,6H),2.85 (m,2H),3.0 (m,1H), 3·85 (m,1H),4.2fw _ (m,2H),7·0 (m,2H),7.35 (m,6H)。質 谱:(m+h)、399。 (,S’sS)-2-(2,6-二甲基苯氧乙醯基)胺基羥基 5 [2S-(1-四氫’唆j嗣基)冬甲基丁醯基基_ _ 曱基庚烷 利用標準偶聯程序(EDAC/DMF),將得自實例27C之胺基 曰物侍自貫例2A之酸偶聯,得到想要的化合物。3〇〇 NMR (CDCI3) 5 0.88 (m, i2H)? 1.67 (m? 2H)? 1·90 (m,1H),2.20 (s,6H),3·0 (d,J = 8赫兹,2H),3 22 (m, 4H)5 3.67 (m5 1H)5 3.77 (m5 1H)5 4.20 (Sj 2H)5 4.40 (m5 1H)5 4·76 (m,1H),7.0 (m,3H),7.30 (m,5H)。質譜:(m+h)+ = 581 〇 實例28 (2S,3S,5S)-2-(2,6-二曱基苯氧乙醯基)胺基羥基 5-[2s-(i_四氫嘧啶_2,“二酮基分3_甲基丁醯基】胺基苯Cl3) 3 0 9 , ld, J = 3 Hz, 3H), 0·94 (d, J = 3 Hz, 3H), 1·60 (m, 4H) ^ Λ 2·20 (s, 6H), 2.85 (m, 2H), 3.0 (m, 1H), 3·85 (m, 1H), 4.2fw _ (m, 2H), 7·0 (m, 2H), 7.35 (m, 6H). Mass spectrum: (m+h), 399. (,S'sS)-2-(2,6-dimethylphenoxyethyl hydrazino)aminol hydroxy 5 [2S-(1-tetrahydro'唆j嗣yl)-glycolylmethyl fluorenyl _ _ fluorenyl The heptane was coupled with the acid of Example 27C from the acid of Example 2C using standard coupling procedures (EDAC/DMF) to afford the desired compound. 3〇〇NMR (CDCI3) 5 0.88 (m, i2H)? 1.67 (m? 2H)? 1·90 (m,1H), 2.20 (s,6H),3·0 (d, J = 8 Hz, 2H ),3 22 (m, 4H)5 3.67 (m5 1H)5 3.77 (m5 1H)5 4.20 (Sj 2H)5 4.40 (m5 1H)5 4·76 (m,1H), 7.0 (m,3H), 7.30 (m, 5H). Mass Spectrum: (m+h)+ = 581 〇 Example 28 (2S,3S,5S)-2-(2,6-Dimercaptophenoxyethyl)aminol 5-[2s-(i_tetrahydro) Pyrimidine_2, "diketo 3-3-methylbutanyl]aminobenzene

O:\106\106749.DOC -112- 1292752 基·6-甲基庚烷 2用標準偶聯程序(EDAC/DMF),將得自實例27C之胺基 化合:與得自實例25D之酸偶聯,得到想要的化合物。300 死赫兹 4_仰(:13) 5 G.83(dj = 7赫兹,6H), 〇 92 J = 7# || , 6H), 1&gt;73 (m, 2H), 2.18 (s, 6H), 2.3〇 (m, 1H), 2-62 (m, 2H), 3.03 (m5 2H), 3.45 (m, lH), .3.55 (m, m), 4.72 (’ 2H),4.20 (m,4H),6.40 (br d,J = 9赫兹,m),7 〇 (m, 3H),7·30 (m,5H),7.62 (br s,1H)。質譜:(M+H)+ = 595。 實例29 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基_3_羥基 -5_[2s-(i-六氫吡畊j,%二酮基&gt;3_甲基丁醯基】胺基 二苯基己烧 A· 2S_(4·苄氧羰基-1_六氫吡畊-2,3-二酮基)-i,6-甲基 丁酸曱酯 將0.79克草醯二咪唑加至在2〇毫升甲苯和1〇毫升乙腈中 之〇_77克N-(苄氧羰基胺基)_乙基_L_纈胺酸曱酯的溶液 中。將該反應混合物保持在50°C下24小時,並加入〇·2克的 草醯二咪唑。將該反應混合物保持在5(rc下另72小時。在 真空中蒸發溶劑,並藉著矽膠管柱層析法(1〇% Et0Ae,在 CH2C12中)純化粗產物’得到想要的化合物。3〇〇兆赫茲 NMR (CDC13) 5 0.95 (d,J = 7赫茲,3H), [03 (d,j = 7赫 兹,3H)5 2·20 (m5 1H),3.60 (m,1H),3.73 (s,3H),3.85 (m, 1H),4.0 (m,1H),4.10 (m,1H),4.90 (d,J = 10赫茲,ih), 5.36 (s,2H),7.20 (m,5H)。質譜:(M+H)+ = 380。 -113-O:\106\106749.DOC -112- 1292752 hexa-methylheptane 2 The amine group from Example 27C was combined using standard coupling procedures (EDAC/DMF): with the acid couple from Example 25D Combine to get the desired compound. 300 dead Hertz 4_Yang (:13) 5 G.83 (dj = 7 Hz, 6H), 〇92 J = 7# || , 6H), 1&gt;73 (m, 2H), 2.18 (s, 6H) , 2.3〇(m, 1H), 2-62 (m, 2H), 3.03 (m5 2H), 3.45 (m, lH), .3.55 (m, m), 4.72 (' 2H), 4.20 (m, 4H) ), 6.40 (br d, J = 9 Hz, m), 7 〇 (m, 3H), 7·30 (m, 5H), 7.62 (br s, 1H). Mass spectrum: (M+H)+ = 595. Example 29 (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5_[2s-(i-hexahydropyrazine j, % diketone &gt;3_Methylbutyryl]Aminodiphenylhexa Burn A· 2S_(4·Benzyloxycarbonyl-1_hexahydropyrazine-2,3-dione)-i,6-methylbutyrate The ester was added to a solution of 7777 g of N-(benzyloxycarbonylamino)-ethyl_L_valerium phthalate in 2 mL of toluene and 1 mL of acetonitrile in 2 mL of toluene and 1 mL of acetonitrile. The reaction mixture was kept at 50 ° C for 24 hours, and 2 g of oxazolidine diimidazole was added. The reaction mixture was kept at 5 (rc for another 72 hours). The solvent was evaporated in vacuo and passed through a silicone tube. Column chromatography (1% Et0Ae in CH2C12) was used to purify the crude product to give the desired compound. 3 〇〇 Hz NMR (CDC13) 5 0.95 (d, J = 7 Hz, 3H), [03 (d , j = 7 Hz, 3H) 5 2·20 (m5 1H), 3.60 (m, 1H), 3.73 (s, 3H), 3.85 (m, 1H), 4.0 (m, 1H), 4.10 (m, 1H) ), 4.90 (d, J = 10 Hz, ih), 5.36 (s, 2H), 7.20 (m, 5H). Mass Spectrum: (M+H)+ = 380. -113-

O:\106\106749.DOC 1292752 Β· Μ·^1·六氫吡**井-2,3-二酮基)-3-甲基丁酸甲酯 藉著氣解作用’利用10% Pd/C作為催化劑,將得曰自實例 29Α之化合物的爷氧幾基保護基移除,得到想要化合物。则 兆赫兹 Wnmmcdcu 5 〇.95 (d,J = 7赫兹,3η) ι 〇3 (d,J = 7赫兹,3Η),2.20 (m,1Η),3.50 (m,3Η),3 74 (s,3Η), 3.83 (m,1H),5.0 (d,J = l〇赫茲,1H), 7·3〇 (br s,1H)。質 譜:(M+H)+ = 229。 C· (28,38,58)_2_(2,6_二甲基苯氧乙醯基)胺基_3_羥基 -5-[2S-(l-六氫吡畊_2,3_二酮基)_弘曱基丁醯基】胺基 二苯基己烧 利用貫例1M之程序將得自實例29B之甲酯水解,並利用 標準EDAC偶聯程序將所得的酸與得自實例1N的胺基化合 物偶聯,得到想要的化合物。3〇〇兆赫茲iH NMR (CDCl3)占 0.82 (d,J = 6赫兹,3H),〇·85 (d,j = 6赫兹,3H),! 8〇 (m, 2H),2·18 (m,1H),2.20 (s,6H),2.65 (m,1H),2.82-3.0 (m, 4H),3.30 (m5 3H),3.70 (m,1H),3·82 (m,1H),4 22 (m,3H), 4.54 (d,J = 10赫兹,1H),6.30 (br,s,1H),6.65 (br d,1H), 7.0-7.30 (m,13H)。質譜:(M+H)+ = 643。 實例30 (2S,3S,5S)_2_(2,6-二甲基苯氧乙醯基)胺基冬羥基 -5-[2S-(4-氮雜-4,5_脫氫_r_噃啶-2_酮基卜3_甲基丁醯基]胺 基-1,6-二苯基己烷 A· 2S-(4-氮雜脫氫_1_嘧啶_2_酮基)-3_甲基丁酸 從實例26F之水解產物混合物中,在管柱層析(5〇/〇 O:\106\106749.DOC -114- 1292752O:\106\106749.DOC 1292752 Β· Μ·^1·hexahydropyrazole ** well, 2,3-dione)-3-methylbutyric acid methyl ester by virtue of '10% Pd /C as a catalyst, the oxiranyl protecting group from the compound of Example 29 was removed to give the desired compound. Then megahertz Wnmmcdcu 5 〇.95 (d, J = 7 Hz, 3η) ι 〇3 (d, J = 7 Hz, 3 Η), 2.20 (m, 1 Η), 3.50 (m, 3 Η), 3 74 (s , 3Η), 3.83 (m, 1H), 5.0 (d, J = l〇 Hertz, 1H), 7·3〇 (br s, 1H). Mass spectrum: (M+H)+ = 229. C·(28,38,58)_2_(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5-[2S-(l-hexahydropyrazine-2,3-dione The methyl ester from Example 29B was hydrolyzed using the procedure of Example 1M and the resulting acid was combined with the amine from Example 1N using standard EDAC coupling procedures. The compound is coupled to give the desired compound. 3〇〇 megahertz iH NMR (CDCl3) accounts for 0.82 (d, J = 6 Hz, 3H), 〇·85 (d, j = 6 Hz, 3H),! 8〇(m, 2H), 2·18 (m, 1H), 2.20 (s, 6H), 2.65 (m, 1H), 2.82-3.0 (m, 4H), 3.30 (m5 3H), 3.70 (m, 1H), 3·82 (m, 1H), 4 22 (m, 3H), 4.54 (d, J = 10 Hz, 1H), 6.30 (br, s, 1H), 6.65 (br d, 1H), 7.0 -7.30 (m, 13H). Mass spectrum: (M+H)+ = 643. Example 30 (2S,3S,5S)_2_(2,6-Dimethylphenoxyethyl)amino-hydroxy-5-[2S-(4-aza-4,5-dehydro-r_噃Pyridin-2-ketoben-3-methylbutylidene]amino-1,6-diphenylhexane A·2S-(4-azadehydro-1-pyrimidin-2-one)-3_A From the hydrolyzate mixture of Example 26F, in the column chromatography (5 〇 / 〇 O: \ 106 \ 106749. DOC - 114 - 1292752

MeOH/5% Ac〇H,在CH2Clj)之後分離出想要的產物,產 ϊ 12·5%。300兆赫茲 iH nmR (CD3OD) 5 〇·93 (d,J = 7赫 兹,3H),1·〇4 (d5 J = 7赫茲,3H),2·20 (m,1Η),3·92 (dd,j = 15, 3赫兹,1H),4 〇 ⑽,j = 15, 3赫茲,1H),4·5〇 (d,】=1〇 赫兹,1H),6.95 (t,J = 3赫茲,1H)。質譜:(M+H)+ = 334。 Β· (28,38,58)-2-(2,6_二甲基苯氧乙醯基)胺基_3_羥基 _5-[2S-(4-氮雜-4,5-脫氫-1-嘧啶-2-酮基)-3-甲基丁醯基】胺 基-1,6-二苯基己烷 利用標準偶聯程序(EDAC/DMF),將得自實例in之化合 物與得自實例30A之酸偶聯,得到想要的化合物(7〇%)。3〇〇 兆赫兹 hNMRWDClD 5 0.80(d,J = 7赫茲,3Η),0·85 (d5 J = 7赫茲,3Η),1.75 (m5 2Η),2.15 (m,1Η),2.20 (s,6Η), 2.62 (m,l H),2.85 (m,1H),3.02 (m,2H),3.55 (m,2H),3.80 (m,1H),4.20 (m,4H),6.38 (br d,1H),6.72 (t,J = 3赫兹, iH),7.0 (m,3H),7.22 (m,10H),7.63 (s,1H)。質譜:(M+H)+ =628 o 實例31 順-N-第三-丁基-十氩 _2_[2(R)-羥基 _4_ 苯基-3(s)_(2S-(l-四氫嘧啶-2_酮基)-3_曱基丁醯基)胺基丁基卜(4aS,8aS)-異 喳啉-3(S)-羧醯胺 可利用標準偶聯程序(在DMF中之EDAC),藉著將實例2A 之產物與順第三-丁基-十氫-2-[2(R)-羥基-4-苯基-3(S)-胺丁基]-(4aS,8aS)-異喳啉-3(S)-羧醯胺(揭示於PCT專利申 請案第W09426749號和1993年3月23曰發布之美國專利第 O:\106\106749.DOC -115- 1292752 5,196,438號中,將兩者合併於此以作為參考)偶聯,來製備 標題化合物。 實例32 順-N_第三-丁基-十氫·2]2(R卜羥基_心苯硫基 -3〇(28-(1-四氫嘧啶-2_酮基)-3-甲基丁醯基)胺基丁 基J-(4aS,8aS)-異喹啉-3(S)-羧醯胺 可利用標準偶聯程序(在DMF中之EDAC),藉著將實例2A 之產物與順-N-第三-丁基-十氫-2_[2(R)_羥基苯硫基 •3(S)_胺丁基]-(4aS,8aS)-異喹啉_3(S)-羧醯胺(揭示於1995 年4月13曰公告之PCT專利申請案第w〇95/〇9843號和1996 年1月16曰發布之美國專利第5,484,926號中,將兩者合併於 此以作為參考)偶聯,來製備標題化合物。 實例33 4-胺基·义((2順,3S)-24基|苯基小⑽♦四氫嘧啶j 酮基)-3-甲基丁醯基胺基)丁基異丁基_苯磺醯胺 可利用標準偶聯程序(在DMF中之eda 之產物與4-W㈣基-4·苯基-3.胺基)_ 丁 基)-Ν-異丁基·苯磺醯胺(揭示於1994年3月η日公告之ρ^τ 專利申請案第W〇94/05639號中,將其合併於此以料參 偶聯,來製備標題化合物。 實例34 Α·另一種製備(28,38,58)-2-(2,6-二甲基苯氧乙醯基) 胺基絲基己垸的方法 在裝叹有機械授拌子、j_KemS度探針、滴液添加漏斗和MeOH/5% Ac〇H, after CH2Clj), the desired product was isolated, yielding 12.5%. 300 MHz iH nmR (CD3OD) 5 〇·93 (d, J = 7 Hz, 3H), 1·〇4 (d5 J = 7 Hz, 3H), 2·20 (m, 1 Η), 3.92 ( Dd,j = 15, 3 Hz, 1H), 4 〇(10), j = 15, 3 Hz, 1H), 4·5〇(d,]=1〇Hz, 1H), 6.95 (t, J = 3 Hz , 1H). Mass spectrum: (M+H)+ = 334. Β·(28,38,58)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy-5-[2S-(4-aza-4,5-dehydrogenation 1-pyrimidin-2-one)-3-methylbutanyl]amino-1,6-diphenylhexane The compound obtained from the example in is obtained from a standard coupling procedure (EDAC/DMF). The acid coupling of Example 30A gave the desired compound (7 %). 3〇〇 megahertz hNMRWDClD 5 0.80 (d, J = 7 Hz, 3 Η), 0·85 (d5 J = 7 Hz, 3 Η), 1.75 (m5 2 Η), 2.15 (m, 1 Η), 2.20 (s, 6 Η) ), 2.62 (m, l H), 2.85 (m, 1H), 3.02 (m, 2H), 3.55 (m, 2H), 3.80 (m, 1H), 4.20 (m, 4H), 6.38 (br d, 1H), 6.72 (t, J = 3 Hz, iH), 7.0 (m, 3H), 7.22 (m, 10H), 7.63 (s, 1H). Mass spectrum: (M+H)+ = 628 o Example 31 cis-N-tert-butyl-deca-argon_2_[2(R)-hydroxy_4_phenyl-3(s)_(2S-(l- Tetrahydropyrimidin-2-keto)-3-mercaptobutyryl)aminobutyl bromide (4aS,8aS)-isoindoline-3(S)-carboxamide can be prepared using standard coupling procedures (in DMF) EDAC) by the product of Example 2A with cis-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-aminobutyl]-(4aS,8aS -isoindoline-3(S)-carboxamide (expressed in PCT Patent Application No. W09426749 and March 23, 1993, U.S. Patent No. 0: \106\106749.DOC -115-1282952 5,196,438 The title compound was prepared by coupling the two together for reference. Example 32 cis-N_T-butyl-decahydro-2]2 (R-hydroxyl-phenylphenylthio-3〇(28-(1-tetrahydropyrimidin-2-one)-3-methyl) Butyl) Aminobutyl J-(4aS,8aS)-isoquinoline-3(S)-carboxamide can be prepared by standard coupling procedure (EDAC in DMF) by using the product of Example 2A with cis- N-tert-butyl-decahydro-2_[2(R)-hydroxyphenylthio-3(S)-aminobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxyindole Amine (disclosed in PCT Patent Application No. WO 95/A No. 9843, issued Apr. 13, 1995, and U.S. Patent No. 5,484,926, issued Jan. Coupling to prepare the title compound. Example 33 4-Amino-((2 cis,3S)-24-yl}phenyl small (10) ♦tetrahydropyrimidin y yl)-3-methylbutyrylamino)butyl Isobutyl-benzenesulfonamide can be subjected to standard coupling procedures (product of eda in DMF and 4-W(tetra)yl-4·phenyl-3.amino)-butyl)-indole-isobutyl·benzene Sulfonamide (disclosed in ρ^τ Patent Application No. W〇94/05639, published on Mar. Method for preparing (28,38,58)-2-(2,6-dimethylphenoxyethyl fluorenyl) amino-based hexanyl oxime with mechanical stir-mix, j_KemS degree probe, drip Add funnel and

O:\106\106749.DOC 1292752 無水氮線路的1公升3_頸燒瓶中,裝入3〇〇克(54.87毫莫耳) 實例II之產物和12〇毫升乙腈。將所得的淤漿冷卻至, 並慢地加入54.1克(549毫莫耳)37%的含水氫氣酸,在加 成作用期間’維持内部溫度不超過+5它。在〇-5它下攪拌該 反應混合物,並定期取出試樣,藉著HPLC (Zorbax管柱, 移動相=1:1乙腈/〇.1%含水磷酸,流速=1.5毫升/分鐘,在2〇5 毫微米處檢測)分析起始物質的消耗。 在攪拌3小時之後完成該反應。藉著慢慢地加入1〇5毫升 20%含水氫氧化鈉使該反應中止。在加成作用期間再度維 持内部溫度不超過+51。一旦證實該反應混合物的pH值為 驗性’便將該溶液回溫至室溫。加入醋酸乙酯(丨8〇毫升)並 加以授拌,在沉降之後分離出下層的液相並將其拋棄。然 後以105毫升1 〇%含水氣化鈉沖洗有機相一次。 使標題化合物從12毫升/克的1:2醋酸乙酯/庚烧中結晶 (產置 80-85%)。 B·另一種製備(28,38,58)-2-(2,6-二甲基苯氧乙醯基) fe基-3-經基-5-胺基-1,6-二苯基己燒的方法 在附V有機械擾掉棒和溫度計的圓底3 -頸之1公升燒瓶 中,加入實例II之產物(51.6克,0.095莫耳)和1〇〇毫升冰醋 酸。在所得的懸浮液中一次加入3 5 %含水的HC1 (10 · 5毫 升,0.103莫耳)。容許在N2氣壓下攪拌該溶液3小時,在此 時加入額外的10.5毫升35%含水的HCM。在額外的15小時之 後’將反應燒瓶浸入冰浴中,並以維持該燒槪之内部溫度 低於30°C的速度加入NaOH溶液(16毫升,0.;i98莫耳)。加入 O:\106\W6749.DOC . Π7-Γ5 1292752 水(200¾升),並以4 χ 200毫升的乙酸異丙酯來萃取該混合 物。以2.5MNaOH(2x20毫升)、100毫升η2〇、鹽水沖洗混 合的有機層,覆以NadO4脫水,過濾並在真空中濃縮,產 生39.7克(94%)無色固體狀之(粗)產物,經*Ηριχ超過%% 的純度。可藉著將產物溶解於200毫升異丙醇中,在蒸氣浴 中加熱,容許冷卻至0-5X:並加以攪拌,來一步純化產物, 產生32.2克(76%)想要的產物,熔點=131t:。 實例35 另一種製備2S-1(1-四氫嘧啶_2_酮基夂甲基丁酸的方法 Α· N-苯氧羰基丄-纈胺酸 可根據1996年6月28曰申請之美國專利甲請案第 08/08/671,893號中揭示的程序來製備义苯氧羰基_L_纈胺 酸’將其合併於此以作為參考,且其包括下列方法。 在裝射有架空攪拌子、冷卻器、pH值探針和熱電偶的反 應态中,加入氯化鋰(15·6克,386莫耳)、L-纈胺酸(26.0公 斤,222莫耳)、中性礬土(8」公斤,15〇篩目,AldHch)和156 公斤的蒸餾水。攪拌這不均勻的混合物,並冷卻至—土$ 。(:。以ίο%含水的氫氧化鋰將13]9[值調整到1〇1。將預先冷卻 (-20C)的氯化甲酸苯酯(36·6公斤,234莫耳)加入,同時將 溫度維持在-9°C以下,並在反應期間利用連續加入1〇%含水 的氳氧化鋰來控制pH值(將PH值維持在9·5到1〇·5的範圍 内,目標是10.0)。 在大約-14 C下攪拌該反應2小時。通過矽藻土過濾該反 應混合物,並以42公斤的蒸餾水沖洗濾餅。以甲基第三-丁O:\106\106749.DOC 1292752 A 1 liter 3 neck flask of anhydrous nitrogen line was charged with 3 gram (54.87 millimoles) of the product of Example II and 12 liters of acetonitrile. The resulting slurry was cooled to and slowly added 54.1 grams (549 millimoles) of 37% aqueous hydrogen acid to maintain the internal temperature no more than +5 during the addition. The reaction mixture was stirred under 〇-5, and the sample was periodically taken out by HPLC (Zorbax column, mobile phase = 1:1 acetonitrile / hydrazine. 1% aqueous phosphoric acid, flow rate = 1.5 ml / min, at 2 Torr) Detection at 5 nm) Analyze the consumption of starting materials. The reaction was completed after stirring for 3 hours. The reaction was quenched by the slow addition of 1 〇 5 ml of 20% aqueous sodium hydroxide. The internal temperature is again maintained no more than +51 during the addition. Once the pH of the reaction mixture was confirmed to be inferior, the solution was warmed to room temperature. Ethyl acetate (丨 8 mL) was added and mixed, and after the sedimentation, the lower liquid phase was separated and discarded. The organic phase was then rinsed once with 105 ml of 1% aqueous sodium hydride. The title compound was crystallized from 12 mL/g of 1:2 ethyl acetate / hexane (yield 80-85%). B. Another preparation of (28,38,58)-2-(2,6-dimethylphenoxyethyl) felyl-3-yl-5-amino-1,6-diphenyl Method of Burning The product of Example II (51.6 g, 0.095 mol) and 1 ml of glacial acetic acid were added to a 3-liter 1 liter flask with a mechanically disturbed rod and thermometer. To the resulting suspension, 35% aqueous HCl (10. 5 ml, 0.103 mol) was added in one portion. The solution was allowed to stir for 3 hours under N2 pressure, at which time an additional 10.5 mL of 35% aqueous HCM was added. The reaction flask was immersed in an ice bath after an additional 15 hours, and a NaOH solution (16 ml, 0.; i98 mol) was added at a rate to maintain the internal temperature of the crucible below 30 °C. Add O:\106\W6749.DOC. Π7-Γ5 1292752 water (2003⁄4 liters) and extract the mixture with 4 χ 200 ml of isopropyl acetate. The combined organic layers were washed with aq. EtOAc (EtOAc) (EtOAc) Ηριχ is more than %% pure. The product can be purified in one step by dissolving the product in 200 ml of isopropanol, heating in a steam bath, allowing to cool to 0-5X: and stirring to yield 32.2 g (76%) of desired product. 131t:. Example 35 Another method for preparing 2S-1 (1-tetrahydropyrimidin-2-one oxime methylbutyric acid) Α·N-phenoxycarbonyl hydrazine-proline acid can be applied for according to the US patent filed on June 28, 1996. The procedure disclosed in U.S. Patent Application Serial No. 08/08/671,893, the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in the the the the the the the the Lithium chloride (15·6 g, 386 mol), L-proline (26.0 kg, 222 mol), neutral alumina in the reaction state of the sub, cooler, pH probe and thermocouple (8" kg, 15 〇 mesh, AldHch) and 156 kg of distilled water. Stir this uneven mixture and cool to - soil $. (: ίο% aqueous lithium hydroxide will be 13] 9 [value adjustment To 1〇1. Pre-cooled (-20C) phenyl chloroformate (36·6 kg, 234 mol) was added while maintaining the temperature below -9 °C, and continuously added 1 在 during the reaction. % aqueous lithium niobate to control the pH (maintain the pH in the range of 9.5 to 1 〇·5, the target is 10.0). Stir the reaction for 2 hours at about -14 C. Pass through the diatomaceous earth The reaction mixture was filtered, and washed with distilled water with 42 kg of filter cake with methyl tertiary - butyl

O:\106\106749.DOC -118- 1292752 驗(65公斤)萃取含水的濾液,以移除殘餘的酚。然後將液相 冷卻至0-5°C,並與200公斤甲苯混合。利用25% (重量/重量) 硫酸將經過攪拌的兩相溶液調整成1)11值1.8_2.〇。在不超過 40 C下濃縮甲苯層,至大約120公升,過滤(30公斤甲苯沖 洗)’然後再度在不超過4 〇 °C下濃縮成大約12 0公升。 在所得的溶液中加入44.2公斤的庚烷,並將所得的溶液 加熱至40 C ± 1 (TC 15分鐘。移除熱源,將該溶液播種,並攪 拌過夜。產物在反應器的壁上結晶,並將其再懸浮於8〇公 斤的甲苯中,在不超過50°C下再濃縮成大約13〇公升,然後 加入45.2公斤的庚烷。然後將所得的溶液加熱至4(rc±1〇t: 至少15分鐘,然後以20°C以下/小時之速率將其冷卻至18〇c ±5 C。在不低於12小時之後,將所得的白色淤漿冷卻至14 °C±5°C,並攪拌3小時以上。過濾白色的淤漿,並以41公斤 1:1的甲苯/庚烷沖洗該固體。在不超過5(rc之下使該固體產 物脫水,得到白色粉末狀之想要產物(47·8公斤)。 Β· 2 S-(l-四氫喷咬-2-酮基)-3-甲基丁酸 將在THF(250毫升)中之N-苯氧羰基纈胺酸(25克, 〇·1〇6莫耳)和3-氯丙胺氫氯化物(15·2克,〇116莫耳)的混合 物冷卻至2°C。在正在攪拌的懸浮液中加入氫氧化鈉(127 克,0.31 8莫耳)。在大約35分鐘之後,發生慢慢的放熱至1〇 C。在10 C以下攪拌該反應2小時。在1 〇分鐘之内加入在丨2 5 毫升THF中之第三-丁醇鉀(29·6克,〇·265莫耳),接著以2〇 耄升THF沖洗。在加成作用期間内,容許該反應混合物的 溫度昇高到20°C。在室溫下攪拌該反應混合物19小時。 O:\106\106749.DOC -119- 1292752 以200毫升蒸餾水使該反應混合物中止,然後利用26 2克 的〉辰氫氯酸將其酸化至pH 9,保持溫度在30°C以下。分離 出液層’並以另外的125毫升THF沖洗之。在已分離之液層 中加入乙醇3A (75毫升),並以12.3克的濃氫氯酸將該混合 物酸化至pH&lt;3,保持溫度在25 °C以下。以醋酸乙酯(250毫 升和150毫升)萃取已經酸化之混合物兩次。在旋轉式汽化 器上,在低於50°C的溫度下將混合的有機層蒸發至無水。 以250毫升醋酸乙酯沖洗殘餘的固體,在迴流溫度下,將殘 餘的固體溶解於150毫升乙醇3A中,並通過覆有助濾劑的5 克Darc〇-G60墊將其過濾,接著以5〇毫升熱乙醇沖洗。在旋 轉式八化器上’在低於50°c的溫度下將濾液蒸發至無水。 在殘餘中加入醋酸乙酯(75毫升),並迴流3〇分鐘。將該懸浮 液冷卻至10°C以下2小時。藉著過濾收集固體,並以2〇毫升 冰冷的醋酸乙酯(5-8。〇沖洗。在4〇°C下脫水72小時之後, 獲得白色固體狀之想要產物(15·6克,74%)。 實例36 另一種製備2S-(1-四氫嘧啶-;2_酮基卜3-甲基丁酸 將苯氧羰基纈胺酸(25〇克,1〇5莫耳;根據在1996年6 月28日提出申請之美國專利申請案第〇8/671,893號中揭示 的程序,將其合併於此以作為參考)和3_氯丙胺氫氯化物 (151克丨·16莫耳)在THF (2·5公升)中之混合物冷卻至2°c。 在正在攪拌的懸浮液中加入氫氧化鈉(127克,3·2莫耳)。在 大約45分鐘後,發生迅速的放熱至1〇{t。在丨巧艺下攪拌該 反應2小時。加入額外的3_氯丙胺(1〇克,〇〇8莫耳),並持O:\106\106749.DOC -118- 1292752 (65 kg) The aqueous filtrate was extracted to remove residual phenol. The liquid phase was then cooled to 0-5 ° C and mixed with 200 kg of toluene. The stirred two-phase solution was adjusted to 1) 11 value 1.8_2. 利用 using 25% (w/w) sulfuric acid. The toluene layer was concentrated at no more than 40 C, to about 120 liters, filtered (30 kg of toluene washed) and then concentrated again to about 12 liters at no more than 4 °C. 44.2 kg of heptane was added to the resulting solution, and the resulting solution was heated to 40 C ± 1 (TC for 15 minutes. The heat source was removed, the solution was sown, and stirred overnight. The product crystallized on the wall of the reactor, Resuspended in 8 kg of toluene, concentrated to about 13 liters at not more than 50 ° C, then added 45.2 kg of heptane. The resulting solution was then heated to 4 (rc ± 1 〇t) : at least 15 minutes, then cool to 18 ° C ± 5 C at a rate of less than 20 ° C / hour. After not less than 12 hours, the resulting white slurry is cooled to 14 ° C ± 5 ° C, Stir for more than 3 hours. Filter the white slurry and rinse the solid with 41 kg of 1:1 toluene/heptane. Dehydrate the solid product under no more than 5 rc to give the desired product as a white powder. (47·8 kg) Β· 2 S-(l-tetrahydropiped-2-one)-3-methylbutyric acid N-phenoxycarbonyl decanoic acid in THF (250 ml) 25 g, 〇·1〇6 mol) and a mixture of 3-chloropropylamine hydrochloride (15. 2 g, 〇116 mol) were cooled to 2 ° C. Add to the stirred suspension Sodium hydroxide (127 g, 0.31 8 mol). After about 35 minutes, a slow exotherm occurred to 1 C. The reaction was stirred for 2 hours below 10 C. Add in 1 2 5 within 1 min. The third potassium butoxide (2.96 g, 〇·265 mol) in THF was washed with 2 liters of THF. During the addition, the temperature of the reaction mixture was allowed to rise to 20 °. C. The reaction mixture was stirred at room temperature for 19 hours. O:\106\106749.DOC -119- 1292752 The reaction mixture was quenched with 200 ml of distilled water and then acidified with 26 2 g of HCl. pH 9, keeping the temperature below 30 ° C. The liquid layer was separated and rinsed with an additional 125 ml of THF. Ethanol 3A (75 ml) was added to the separated liquid layer, and 12.3 g of concentrated hydrochloric acid was added. The mixture was acidified to pH &lt; 3, keeping the temperature below 25 ° C. The acidified mixture was extracted twice with ethyl acetate (250 mL and 150 mL). On a rotary evaporator, at a temperature below 50 ° C. The combined organic layers were evaporated to dryness. The residual solid was washed with ethyl acetate (250 mL) The residual solid was dissolved in 150 ml of ethanol 3A at reflux temperature and filtered through a 5 g pad of Darc(R)-G60 coated with a filter aid, followed by rinsing with 5 ml of hot ethanol. The filtrate was evaporated to dryness at a temperature below 50 ° C. Ethyl acetate (75 mL) was added to the residue and refluxed for 3 min. The suspension was cooled to below 10 ° C for 2 hours. The solid was collected by filtration and washed with 2 mL of ice cold ethyl acetate (5-8. 〇 rinse. After dehydration at 4 ° C for 72 hours, the desired product was obtained as a white solid (15·6 g, 74%). Example 36 Another preparation of 2S-(1-tetrahydropyrimidine-; 2-ketopropyl 3-methylbutanoic acid phenoxycarbonyl decanoic acid (25 g, 1 〇 5 mol; according to June 1996) The procedure disclosed in U.S. Patent Application Serial No. 8/671,893, the entire disclosure of which is incorporated herein by reference in its entirety in the entire entire entire entire entire entire entire entire entire entire entire entire entire content • Mix the mixture in 5 liters to 2 ° C. Add sodium hydroxide (127 g, 3.2 mol) to the stirring suspension. After about 45 minutes, a rapid exotherm occurs to 1 〇{t Stir the reaction for 2 hours under 丨巧艺. Add additional 3 chloropropylamine (1 gram, 〇〇 8 mole) and hold

O:\106\106749.DOCO:\106\106749.DOC

(D ' 120- 1292752 ,稅拌1小時。然後在3 〇分鐘之内加入在1 · 2 $公升thf中之 第一 丁醇鉀(296克,2.6莫耳)的溶液,接著以1〇〇毫升THF 沖洗。在加成作用期間中,容許使該反應混合物的溫度昇 高到20°C,在室溫下攪拌該反應混合物12-16小時。 以2 a升蒸鶴水使该反應混合物中止,並冷卻至12。〇,然 後利用258克(2.6莫耳)的濃氫氣酸將其酸化至?]9[ 9,保持溫 度低於30 C。分離出液層。在已分離之液層中加入乙醇3 a (625宅升)並以116克(1 ·2莫耳)的漠氫氣酸將該混合物酸化 至ρΗ&lt;3,保持溫度低於25艺。將經過酸化的混合物以醋酸 乙酉曰(2.5公升和1.5公升)萃取兩次。在旋轉式汽化器上,在 低於50°C的溫度下將混合的有機層蒸發至無水。藉著與醋 酉文乙S曰(4 X 1公升)一起蒸餾,重複將殘餘的固體脫水。將 殘餘的固體溶解於75〇毫升甲醇中,並以脫色碳(1〇克(D '120- 1292752, mix for 1 hour. Then add a solution of potassium butoxide (296 g, 2.6 m) in 1 · 2 $ liters of thf within 3 , minutes, followed by 1 〇〇 Flushing with THF. During the addition, the temperature of the reaction mixture was allowed to rise to 20 ° C, and the reaction mixture was stirred at room temperature for 12-16 hours. The reaction mixture was quenched by steaming 2 g of crane water. And cooled to 12. 〇, and then acidified to 258 [9] with 258 g (2.6 mol) of concentrated hydrogen acid. 9. Keep the temperature below 30 C. Separate the liquid layer. Add in the separated liquid layer. Ethanol 3 a (625 liters) and acidified to a pH of &lt;3 with 116 grams (1.2 moles) of hydrazine acid, maintaining the temperature below 25 art. The acidified mixture was treated with acetamidine acetate (2.5 Extraction twice and 1.5 liters. The mixed organic layer was evaporated to dryness on a rotary evaporator at a temperature below 50 ° C. Distilled with vinegar 曰 曰 S (4 X 1 liter) , the residual solid was repeatedly dehydrated. The residual solid was dissolved in 75 ml of methanol and decolorized. Carbon (1 gram

DarC〇-G60墊)處理,在室溫下過夜。藉著通過矽藻土過濾 來移除妷。在旋轉式汽化器上,在低於5〇。〇的溫度下將濾 液蒸發至無水。將醋酸乙酯(1.5公升)加至殘餘物中,並在 方疋轉式A化器上移除大約5〇〇毫升。將該懸浮液冷卻至工〇 t以下&gt;1小時。藉著過濾收集固體,並以2 χ 1〇〇毫升冷的 醋酸乙酯(5_8。〇沖洗。在50t下脫水72小時之後,獲得想 要的產物。 實例37 另一種製備2S-(1-四氫嘧啶酮基)-3-甲基丁酸的方法 Α· 羧曱基-N(沒)氰乙基纈胺酸 在附有機械攪拌子的5公升3_頸燒瓶中,加入(s)_纈胺酸Treatment with DarC〇-G60 pad) overnight at room temperature. Remove cockroaches by filtering through diatomaceous earth. On a rotary evaporator, below 5 〇. The filtrate was evaporated to dryness at a temperature of hydrazine. Ethyl acetate (1.5 liters) was added to the residue and about 5 mL was removed on a square-turn converter. The suspension was cooled to below 1 hour &gt; 1 hour. The solid was collected by filtration and washed with 2 mL of cold ethyl acetate (5.sup.5). After dehydration at 50t for 72 hours, the desired product was obtained. Example 37 Preparation of 2S-(1-4- Method for Hydropyrimidinyl)-3-methylbutyric acid 曱· Carboxymethyl-N(n)cyanoethylproline in a 5 liter 3-neck flask with mechanical stirrer, added (s)_ Proline

O:\106\106749.DOC -121 - 1292752 (170.1克,:[·45莫耳)和水145毫升。以冰水浴將該溶液冷卻 至〇C並在20分鐘内逐滴加入在18〇毫升水中之當量 ΚΟΗ (93克的88%固態K〇H)的溶液。在加成作用完成之 後,逐滴加入丙烯腈1〇 (95·5毫升)並激烈地攪拌,同時將 該燒瓶的内部溫度維持在5t:以下。容許在之間攪拌 该溶液4.5小時。加入水(6〇〇毫升),並將酸鹼度計插入該溶 液中。逐滴加入氯化甲酸甲酯1〇當量(112毫升),同時利用 10%含水的ΚΟΗ將該溶液的ΡΗ值維持在9.5到10.5之間。在 〇·5小時之内進行該加成作用。然後以濃HC1和磷酸將該溶 液酸化至pH 2,並接著以2公升乙酸異丙酯萃取之。在真空 之下濃縮有機層,得到201克(60%)無色的油,其在靜置之 下會固化。熔點65-66°C。在25°C下旋光度鈉D線為-0.44 (c =4.3,乙醇)。IR (公分-1,CDC13) 2960, 1740, 1710, 1470。 1HNMR(3 00兆赫茲,CDCl3);((5TMS,0·00)pPm0·93(d,O:\106\106749.DOC -121 - 1292752 (170.1 g,: [·45 mol) and water 145 ml. The solution was cooled to 〇C in an ice water bath and a solution of the equivalent hydrazine (93 g of 88% solid K 〇H) in 18 liters of water was added dropwise over 20 minutes. After the completion of the addition, acrylonitrile 1 〇 (95·5 ml) was added dropwise and vigorously stirred while maintaining the internal temperature of the flask at 5 t: or less. The solution was allowed to stir between 4.5 hours. Water (6 ml) was added and a pH meter was inserted into the solution. Methyl chloroformate 1 〇 equivalent (112 ml) was added dropwise while maintaining the enthalpy of the solution between 9.5 and 10.5 with 10% aqueous hydrazine. This addition is carried out within 5 hours. The solution was then acidified to pH 2 with concentrated HCl and phosphoric acid and then extracted with 2 liters of isopropyl acetate. The organic layer was concentrated under vacuum to give 201 g (yield: 60%) of colorless oil which solidified upon standing. 65-66 ° C melting point. The optical rotation sodium D line at -25 ° C was -0.44 (c = 4.3, ethanol). IR (cm-1, CDC13) 2960, 1740, 1710, 1470. 1H NMR (3 00 megahertz, CDCl3); ((5TMS, 0·00) pPm0·93 (d,

3H, J = 7赫茲),1.07 (d5 3H, J = 6赫茲),2.16-2.36 (m,1H), 2·62-2·86 (m,2H),3.62 (t,2H,J = 7.5赫茲),3·77 (s5 1.2H 旋轉體),3·82 (s5 1·8Η,旋轉體),4·15_4·30 (m5 1Η), 9.76-9.96 (brs,1Η)〇 ms (CDI/NH3) 246,185,146,125。 FABhrms :關於(M+H)+之計算值:229.1 188 ;實驗值: 229.1 185 ° Β· 2S-(1-四氫嘧啶-2-酮基)·3-曱基丁酸 在2公升壓力瓶中加入實例37Α之產物(190克,0.833莫 耳)、水(900毫升)和ΚΟΗ (3當量,140克)。在周圍溫度下, 在該溶液中加入鎳鋁合金(阮内-型)75克。注意到這是未經 O:\106\106749.DOC -122- 1292752 活化之形式。將該溶液密封在壓力彈中並放置在60磅/平方 英对的氫氣壓下。將所得的溶液加熱至1 00。(3 4小時。將該 溶液冷卻至周圍溫度之後,將其過濾,以900毫升二氯甲烷 沖洗’接著酸化至pH 1。以2 X 900毫升二氣甲烷萃取含水 的溶液。將混合的有機層濃縮,得到12〇克的粗產物,使其 在乙酸異丙酯中形成淤漿,得到7〇克的標題化合物。 實例38 另一種製備(28,38,58)-2-(2,6-二甲基苯氧乙醯基)胺基 -3-羥基-5-[2S-(1-四氫嘧啶-2_酮基)_3_甲基丁醯基]胺基 -1,6-二苯基己烧的方法 A-1· 2S-(1-四氫嘧啶酮基广甲基丁醯氣 使2S-(1-四氫嘧啶_2_酮基)_3&lt;_甲基丁酸(17·6克,87·9毫莫 耳)在THF (240毫升)中形成淤漿,並冷卻至&lt;5。〇。在5分鐘 内加入亞硫醯氣(14.3克,12〇毫莫耳)(放熱的)。在2〇&lt;t下 攪拌該淤漿70分鐘,直到*HpLC得知完成為止(在甲醇中 使试樣中止)。藉著旋轉汽化作用移除THF ;加入庚烷(9〇 笔升)’並藉著旋轉汽化作用移除,得到潮濕的固體塊。使 該物質在DMF (85毫升)中形成淤漿。 Α·2·另一種製備2S-(1-四氫嘧啶酮基卜3-甲基丁醯 氯的方法 使2S-(1-四氫噹啶_2_酮基)_3_甲基丁酸(39·6克,198毫莫 耳)在THF (590¾升)中形成淤漿,並冷卻至。在5分鐘之 内加入亞硫醯氣(28.3克,238毫莫耳)(放熱的)。在2〇。〇下 攪拌該淤漿2小時。在旋轉式汽化器上移除τΗρ :加入3H, J = 7 Hz), 1.07 (d5 3H, J = 6 Hz), 2.16-2.36 (m, 1H), 2·62-2·86 (m, 2H), 3.62 (t, 2H, J = 7.5) Hertz), 3·77 (s5 1.2H rotating body), 3·82 (s5 1·8Η, rotating body), 4·15_4·30 (m5 1Η), 9.76-9.96 (brs, 1Η)〇ms (CDI/ NH3) 246, 185, 146, 125. FABhrms: Calculated for (M+H)+: 229.1 188; Experimental value: 229.1 185 ° Β· 2S-(1-tetrahydropyrimidin-2-one)·3-mercaptobutyric acid in a 2 liter pressure bottle The product of Example 37 (190 g, 0.833 mol), water (900 ml) and hydrazine (3 eq., 140 g) were added. At the ambient temperature, 75 g of a nickel-aluminum alloy (in-situ type) was added to the solution. Note that this is not activated by O:\106\106749.DOC -122-1292752. The solution was sealed in a pressure bomb and placed under a pressure of 60 psig of hydrogen. The resulting solution was heated to 100. (3 4 hours. After cooling the solution to ambient temperature, it was filtered, rinsed with 900 ml of dichloromethane) and then acidified to pH 1. The aqueous solution was extracted with 2 X 900 ml of di-methane. Concentration gave 12 g of crude product which was crystallised in EtOAc to afford 7 g of the title compound. Dimethylphenoxyethyl)amino-3-hydroxy-5-[2S-(1-tetrahydropyrimidin-2-yl)-3-ylmethylbutanyl]amino-1,6-diphenyl Method A-1·2S-(1-tetrahydropyrimidinone-based polymethylbutazone is used to make 2S-(1-tetrahydropyrimidin-2-one)_3&lt;_methylbutyric acid (17·6 g) , 87·9 mmoles) formed a slurry in THF (240 mL) and cooled to &lt;5. 〇. Add sulphur sulphur gas (14.3 g, 12 〇 millimolar) within 5 minutes (exothermic The slurry was stirred at 2 Torr &lt;t for 70 minutes until *HpLC was known to be complete (the sample was stopped in methanol). THF was removed by rotary vaporization; heptane was added (9 liters of pen liters) )' and removed by rotary vaporization, getting wet Block. This material was slurried in DMF (85 ml). Α···Another method for preparing 2S-(1-tetrahydropyrimidin-3-yl 3-methylbutane chloride to make 2S-(1- Tetrahydro-acridin-2-(one)-3-ylbutyric acid (39·6 g, 198 mmol) was slurried in THF (5903⁄4 L) and cooled to. Add sulphur in 5 min. Helium (28.3 g, 238 mmol) (exothermic). Stir the slurry for 2 hours at 2 Torr. Remove τΗρ from the rotary evaporator:

O:\106\106749.DOC -123- 1292752 固體塊。 (200毫升),並在旋轉式汽化器上移除,得到潮濕的 使該物質在DMF (225毫升)中形成淤漿。 Β_1· (2S,3S,5S)韻,N-二爷胺基 j經基 _s_[2s_g_ 四氫 嘧啶-2-酮基)-3_甲基丁醯基]胺基二苯基乙烷 將(2S,3S,5S)-2-N,N-二爷胺基-3,基胺基」,6_二苯基 己烷(大約83毫莫耳;1996年2月13日提出申請之美國專利 第5,491,253號,將其合併於此以作為參考)和咪唑(8.2克, 120毫莫耳)溶解於醋酸乙酯(35〇毫升,Κ]ρ&lt;〇·ι%)中,並冷 卻至2°C。加入實例38A4已形成淤漿之產物(放熱的,最大 溫度為l〇°C ),接著以DMF (15毫升)沖洗。攪拌該反應,開 始是冰冷的,然後容許慢慢地加溫至室溫,再攪拌過夜。 以100毫升水使該反應中止,並攪拌30分鐘。分離出有機 層,並以3 X 125毫升的5% NaCl沖洗。過濾有機溶液,並 在旋轉式汽化器上濃縮成黏稠的糖漿,62克。HPLC純度約 為85%(高峰區)。異構體含量約11·2%。 CIMS (NH3) m/z 647 (Μ+Η)+。 NMR (300 兆赫茲,CDC13) δ 7.35-7.10 (m,1〇Η), 7.13-7.06 (m,1H),6.87 (br d,1H),5.22 (br s5 1H),4·28 (d, 1H),4.20-4.05 (m,1H),3.95 (d,2H),3.65-3.56 (m,1H), 3.37 (d,2H)5 3.12-2.89 (m,5H),2.83-2.53 (m,4H)? 2.23-2.08 (m,1H),1.74-1.40 (m,4H),0.87-0.75 (m5 6H)。 】3C NMR (75 兆赫茲,CDC13) 5 170.0,156.6,140.2, 139.1,138.4,129.3,129.1,128.9,128.4,128.3,127·1, 126.0,125.8,69.1,64.0,63.1 (br),54.2, 49.2,41.2, 40.5, O:\106\106749.DOC -124- 1292752 40.0, 39·7, 31.5, 25.4, 21.6, 19.5, 18.6。 Β-2·另一種製備(28,38,58)_2_]^,]^二苄胺基_3_羥基 5 [2 S (1_四氫,咬酮基)-3-甲基丁醯基】胺基6-二苯 基己烧的方法 將(28,3 8,5 8)-2-&gt;1,;^-二苄胺基-3-羥基-5-胺基-1,6-二苯基 己烷(大約180毫莫耳;1996年2月13日提出申請之美國專利 第5,491,253號’將其合併於此以作為參考)和喃唾(38· 1克, 560毫莫耳)溶解於醋酸乙酯(675毫升,KF&lt;〇1%)中,並冷 卻至1 C。在3 0分鐘内慢慢地加入實例3 8 A-2已形成淤漿的 產物(放熱的,最大溫度為6°C),接著以醋酸乙酯(225毫升) 沖洗。在冰冷環境下攪拌該反應1 ·5小時,然後容許慢慢地 加溫至大約27°C,並攪拌約20小時。 以HC1的稀溶液(在225毫升水中的36.75克濃HC1)使該反 應中止’並攪拌20分鐘。過渡兩相的混合物,以1 〇〇毫升醋 酸乙酯沖洗。分離出有機層,並以3 X 125毫升5% NaCl沖 洗。分離出有機層,並以3 X 225毫升5% NaCl和2 X 225毫 升5% NaHC03沖洗。藉著旋轉汽化作用濃縮該有機溶液, 得到黏稠糖漿狀之想要產物。 C· (2S,3S,5S)-2-胺基-3-羥基-5-【2S_(l-四氩嘧啶-2-酮 基&gt;-3-甲基丁醯基】胺基-1,6-二苯基己烷 將實例38B之粗產物(約83毫莫耳)溶解於甲醇(260毫升) 中。加入Pd/C (50%潮濕的Pearlemanfs催化劑,1〇·4克濕重) 和曱酸銨(15·1克,239毫莫耳),並將該混合物加溫至50°C。 在2.5小時之後,藉著TLC得知反應完成。將該混合物冷卻 O:\106\106749.DOC -125- 1292752 至35°C ’並藉著通過矽藻土過濾移除催化劑,接著以甲醇 (250毫升)沖洗。在旋轉式汽化器上濃縮混合的濾液。將殘 餘物溶解於二氧六環(15〇毫升)中並加溫。在旋轉式汽化器 上移除二氧六環,得到60克黃色的油。HPLC純度約為88.2% (南峰區)’異構體含量&gt;7· 9% (然而從主要的高峰處未分離 出一個異構體)。 CIMS (NH3) m/z 467 (M+H)+ 4 NMR (300兆赫茲,CD3OD) δ 7:35-7.10 (m,1〇Η), 4.40-4.20 (m,ιη)5 4.25 (d,1Η),3.68-3.57 (m,1Η), 3.20·3·09 (m,2H),3.08-2.90 (m,3H),2.90-2.74 (m,2H), 2.65-2.49 (m,2H),2.20-2.04 (m,1H),1.92-1.78 (m,1H), 1.78-1.60 (m5 2H)3 1.60-1.45 (m5 1H), 0.88-0.77 (m5 6H) 13C NMR (75 兆赫茲,CD3OD) 5 17L3,158·4,140.5, 139.8, 130·6, 130.4, 129.5, 129·3, 127.3, 127.0, 71.5, 63.9, 57.1,49·1,41.8,41.6,41·4,40.7,40.5,26.9,22.5,20.0, 18.9 】Η NMR (300兆赫茲,CD3〇d)占 7 35 7 13 (m,1〇Η), 5·35 (s,1Η),4·4(Μ·23 (m,2Η),3.60.3.52 (m,1Η), 3·25-2·65 (m,8H),2.58-2.45 (dd,1H),2.30-2.10 (πι,1H), 1.90-1.65 (m,3H),1.65-1.50 (m,1H),0.91 (d,3H),0.84 (d, 3H) 13C NMR (75兆赫茲,CDC13) 5 ι71·2,156.6,139.1, 138.5,129.3,129.2,128.5,128.2,126.3,126.0,71.6,63·1 (br),56.3, 48.7, 41·65 41.0, 40.6,後〇, 39.6, 25·5, 21.7, O:\106\106749.DOC -126- 1292752 19.7, 18.7 D· (2S,3S,5S)-2-胺基-3-羥基 _5_[2S_(1-四氫嘧啶 _2_ 酮 基)_3_甲基丁醯基]胺基-1,6-二苯基己烷(s卜焦穀胺酸鹽 將實例38C之粗產物溶解於二氧六環(37〇毫升,KF== 〇·〇7%濕度)中。加入S-焦穀胺酸(1〇·3克,8〇毫莫耳),並將 懸浮液加溫至50°C,得到澄清的溶液。在攪拌丨小時之後, 以少量產物鹽的結晶來播種該溶液。慢慢地沉澱出鹽。將 該淤漿慢慢地冷卻,並在室溫下攪拌過夜。藉著過濾分離 產物,並以二氧六環(100毫升)沖洗。濕濾餅重12〇克。在6〇 °C的真空烘箱中,以氮氣吹掃使產物脫水。產生35·2克灰 白色的粉末。HPLC純度&gt;98% (高峰區包括焦穀胺酸)。異 •構體含量約為1% (然而從主要的高峰處未分離出一個異構 體)。O:\106\106749.DOC -123- 1292752 Solid block. (200 ml) and removed on a rotary evaporator to obtain a wet slurry of the material in DMF (225 mL). Β_1·(2S,3S,5S) rhyme, N-di-aryl amino group j via _s_[2s_g_tetrahydropyrimidin-2-one)-3-methylbutanyl]aminodiphenylethane (2S , 3S,5S)-2-N,N-di-arylamino-3,ylamino",6-diphenylhexane (approximately 83 millimolar; US patent application filed on February 13, 1996) 5,491,253, which is incorporated herein by reference) and imidazole (8.2 g, 120 mmol) dissolved in ethyl acetate (35 mM, Κ]ρ &lt;〇·ι%) and cooled to 2 °C. The product of Form 38A4 which had formed a slurry (exothermic, maximum temperature of 10 °C) was added, followed by rinsing with DMF (15 mL). The reaction was stirred and started to be ice-cold, then allowed to slowly warm to room temperature and stirred overnight. The reaction was quenched with 100 ml of water and stirred for 30 minutes. The organic layer was separated and washed with 3 X 125 mL of 5% NaCl. The organic solution was filtered and concentrated on a rotary evaporator to a thick syrup, 62 g. The HPLC purity was approximately 85% (peak zone). The isomer content is about 11.2%. CIMS (NH3) m/z 647 (Μ+Η)+. NMR (300 MHz, CDC13) δ 7.35-7.10 (m, 1 〇Η), 7.13-7.06 (m, 1H), 6.87 (br d, 1H), 5.22 (br s5 1H), 4·28 (d, 1H), 4.20-4.05 (m, 1H), 3.95 (d, 2H), 3.65-3.56 (m, 1H), 3.37 (d, 2H) 5 3.12-2.89 (m, 5H), 2.83-2.53 (m, 4H)? 2.23-2.08 (m, 1H), 1.74-1.40 (m, 4H), 0.87-0.75 (m5 6H). 3C NMR (75 MHz, CDC13) 5 170.0, 156.6, 140.2, 139.1, 138.4, 129.3, 129.1, 128.9, 128.4, 128.3, 127·1, 126.0, 125.8, 69.1, 64.0, 63.1 (br), 54.2, 49.2, 41.2, 40.5, O:\106\106749.DOC -124- 1292752 40.0, 39·7, 31.5, 25.4, 21.6, 19.5, 18.6. Β-2·Another preparation (28,38,58)_2_]^,]^dibenzylamino _3_hydroxy 5 [2 S (1_tetrahydro, ketone)-3-methylbutanyl]amine The method of 6-diphenylhexanal is (28,3 8,5 8)-2-&gt;1,;^-dibenzylamino-3-hydroxy-5-amino-1,6-diphenyl Hexane (approximately 180 millimoles; U.S. Patent No. 5,491,253, filed on Feb. 13, 1996, which is incorporated herein by reference) Dissolved in ethyl acetate (675 mL, KF &lt; 1%) and cooled to 1 C. The slurry of the Example 3 8 A-2 was slowly added over 30 minutes (exothermic, maximum temperature 6 ° C) and then rinsed with ethyl acetate (225 mL). The reaction was stirred for 1.5 hours in an ice-cold environment, then allowed to slowly warm to about 27 ° C and stirred for about 20 hours. The reaction was stopped with a dilute solution of HC1 (36.75 g of concentrated HCl in 225 ml of water) and stirred for 20 minutes. The mixture of the two phases was washed with 1 ml of ethyl acetate. The organic layer was separated and washed with 3 X 125 mL 5% NaCI. The organic layer was separated and washed with 3 X 225 mL 5% NaCl and 2 X 225 liters 5% NaHC03. The organic solution was concentrated by rotary vaporization to obtain the desired product as a viscous syrup. C·(2S,3S,5S)-2-Amino-3-hydroxy-5-[2S_(l-tetrahydropyrimidin-2-one]&gt;-3-methylbutanyl]amino-1,6- Diphenylhexane The crude product of Example 38B (about 83 mmol) was dissolved in methanol (260 mL). Pd/C (50% moist Pearlemanfs catalyst, 1 〇 4 g wet weight) and citric acid were added. Ammonium (15.1 g, 239 mmol), and the mixture was warmed to 50 ° C. After 2.5 hours, the reaction was completed by TLC. The mixture was cooled to O:\106\106749.DOC - 125- 1292752 to 35 ° C ' and remove the catalyst by filtration through diatomaceous earth, followed by washing with methanol (250 ml). The mixed filtrate was concentrated on a rotary evaporator. The residue was dissolved in dioxane (15 〇 ml) and warm. Remove the dioxane on a rotary evaporator to obtain 60 g of yellow oil. HPLC purity is about 88.2% (Nanfeng District) 'isomer content> 7.9 9% (however No isomer was isolated from the main peak. CIMS (NH3) m/z 467 (M+H)+ 4 NMR (300 MHz, CD3OD) δ 7:35-7.10 (m,1〇Η) , 4.40-4.20 (m,ιη)5 4.25 (d,1Η), 3.68-3.57 ( m,1Η), 3.20·3·09 (m,2H), 3.08-2.90 (m,3H), 2.90-2.74 (m,2H), 2.65-2.49 (m,2H), 2.20-2.04 (m,1H) ), 1.92-1.78 (m, 1H), 1.78-1.60 (m5 2H)3 1.60-1.45 (m5 1H), 0.88-0.77 (m5 6H) 13C NMR (75 megahertz, CD3OD) 5 17L3,158·4, 140.5, 139.8, 130·6, 130.4, 129.5, 129·3, 127.3, 127.0, 71.5, 63.9, 57.1, 49·1, 41.8, 41.6, 41·4, 40.7, 40.5, 26.9, 22.5, 20.0, 18.9 】 Η NMR (300 MHz, CD3〇d) accounted for 7 35 7 13 (m, 1〇Η), 5·35 (s, 1Η), 4·4 (Μ·23 (m, 2Η), 3.60.3.52 ( m,1Η), 3·25-2·65 (m,8H), 2.58-2.45 (dd,1H), 2.30-2.10 (πι,1H), 1.90-1.65 (m,3H),1.65-1.50 (m , 1H), 0.91 (d, 3H), 0.84 (d, 3H) 13C NMR (75 MHz, CDC13) 5 ι71·2, 156.6, 139.1, 138.5, 129.3, 129.2, 128.5, 128.2, 126.3, 126.0, 71.6 , 63·1 (br), 56.3, 48.7, 41·65 41.0, 40.6, Houyi, 39.6, 25·5, 21.7, O:\106\106749.DOC -126- 1292752 19.7, 18.7 D· (2S, 3S,5S)-2-Amino-3-hydroxy-5-[2S_(1-tetrahydropyrimidin-2-yl)-3-methylbutenyl]amine- 1,6-Diphenylhexane (s-pyroglutamine) The crude product of Example 38C was dissolved in dioxane (37 mL, KF == 〇·〇 7% moisture). S-pyroglutamic acid (1 〇·3 g, 8 〇 mmol) was added, and the suspension was warmed to 50 ° C to give a clear solution. After stirring for a few hours, the solution was sown with a small amount of product salt crystals. The salt is slowly precipitated. The slurry was slowly cooled and stirred at room temperature overnight. The product was isolated by filtration and washed with dioxane (100 mL). The wet cake weighs 12 grams. The product was dewatered by purging with nitrogen in a vacuum oven at 6 °C. Produced 35. 2 grams of grayish white powder. HPLC purity &gt; 98% (peak zone includes pyroglutamic acid). The isotactic content is about 1% (however, one isomer is not separated from the main peak).

熔點 135-141°CMelting point 135-141°C

[a]D25 = -21.9〇(c=2.55 CH3OH) CIMS (NH3) m/z 467 (關於驗的m+H)+,I47 (關於焦穀胺 酸的M+NH4)+,13 0 (關於焦穀胺酸的m+H)+ IR(Kbr) 1586, 1655, 1682 公分-1 4 NMR (400兆赫茲,DMSO-d6) (5 7.62 (s5 ιΗ) 7 54 (d,1H),7·32-7·06 (m,10H),6.33 (s,1H),4·26 (d,lH)5 4.11-3.99 (m,1H),3.82 (dd,1H),3·57-3·48 (m,1H) 3.27-3.19 (m,1H),3.08-2.95 (m,2H),2.92-2.70 (m,5H) 2.53-2.43 (m,1H),2.26-2.14 (m,1H),2.13-1.99 (m 2H) 1.99-1.87 (m,2H),1.72-1.61 (m,2H),1.61-1.49 (m ipj) O:\106\106749.DOC -127· 1292752 1.46-1.35 (m,1H),0.70 (d,3H),0·64 (d,3H)。 13C NMR (100 兆赫茲,DMSO-d6) δ 176.9, 176· 1,169.2, 155.5, 138.8, 137.7, 129.3, 128.3, 127.8, 126.4, 125.5, 66.9, 61.5,56.9,55.3,46.8,40·2,39.6,39.4,38.8,37.4,29.8, 25.4, 25.3, 21.6, 19.6, 18.7 ° 4 NMR (300兆赫茲,CD3OD) 5 7.32-7.03 (m,10H), 4β23-4·12 (m,1H),4·12 (d,1H),3.98 (dd,1H),3.71-3.63 (m, 1H),3.46-3.37 (m,1H),3.11-2.98 (m, 2H),2·97-2·80 (m5 4H),2.70-2.59 (m,1H),2.49-2.38 (m,1H),2.38-2.12 (m, 3H),2.07-1.92 (m,2H),1.75-1.63 (m,2H),1.63-1.50 (m, 1H),1·45·1·32 (m,1H),0.74-0.65 (m,6H)。 13C NMR (75 兆赫茲,CD3OD) δ 181.0, 179.6? 171.65 158.4, 139.5, 137·3, 130.5, 130.0, 129.4, 128.3, 127·2, 68.1, 64.0,59·6, 57·7,48.8,41.7,41.1,40.7,40·6, 37.9,31.1, 26.9, 26.9, 22.5, 20.1,18.9 ° 4 NMR (300 兆赫茲,D20) δ 7.30-6.97 (m,10Η), 4.16-4.03 (m,1H),3.99-3.91 (m,2H),3.71-3.63 (m,1H), 3.43-3.35 (m,1H),3.00-2.68 (m,6H),2.40-2.13 (m,5H), 1.88-1.72 (m,3H),1.68-1.56 (m,1H),1.52-1.37 (m,1H), 1.32-1.18 (m,1H),0.60-0.52 (m,6H)。 13C NMR (75 兆赫茲,D20) δ 1 8 1.6, 1 80· 1, 171 ·0, 157.3,137.9,135.2,129.3,129.2,129.1,128·4,127.6, 126.4,67.3,62.6,58.2,56.7, 47.5,40·1,39.4,39.2,38.7, 35.7, 29.6, 25.3, 25.2, 20.5, 18.5, 17.6 ° O:\106\106749.DOC -128- 1292752 Ε· (28,38,58)-2-(2,6-二曱基苯氧乙醯基)胺基_3-羥基 -5-[2S-(l-四氫嘧啶-I酮基)_夂甲基丁醯基】胺基二苯 基己烷 使貫例1H之產物(7.26克,40·3毫莫耳)在醋酸乙酯(22毫升) 中形成淤漿,並加入亞硫醯氯(5·75克,48·3毫莫耳),接著加 入一滴DMF。將該混合物加溫到5(rc,並攪拌5小時。將所 得的醯基氣溶液冷卻至22t,並適用於後續的偶聯反應。 在燒瓶中混合實例38D之產物(20克,31.7毫莫耳,對於二 氧六環的含量加以修正)、碳酸氫鈉(16·5克,197毫莫耳)、 醋酸乙酯(150毫升)和水(150毫升),並攪拌直到實例之產 物已經溶解為止(一些鹽殘留不溶解)。在5分鐘内加入上述製 備之醯基氯的溶液,接著以醋酸乙酯(5毫升)沖洗。加成作用 是溫和放熱的(最大溫度為23t)。攪拌該混合物過夜。 分離出有機層,並以5%碳酸氫鈉(1〇〇毫升)和水(1〇〇毫 升)沖洗。在旋轉式汽化器上移除溶劑。將殘餘物溶解於醋 酸乙酯(100毫升)中並過濾之,以醋酸乙酯(5〇毫升)沖洗。 在方疋轉式Ά化器上從混合的遽液中移除溶劑。將殘餘物溶 解於熱醋酸乙醋(105毫升)中’並加入庚烧(1〇5毫升);產物 開始迅速地結晶。將該游漿冷卻,並在2 〇 _ 2 3 °C下擾掉5小 時。藉著過濾收集產物,並以1/1 (體積/體積)醋酸乙酯/庚 燒(30毫升)沖洗。在70°C的真空烘箱下使產物脫水,得到 18.8克白色粉末狀的想要產物。 實例39 製備非晶形之(28,38,58)-2-(2,6_二曱基苯氧乙酿基)胺基 O:\106\106749.DOC -129- 1292752 -3-羥基-5-[2 S-(l-四氫嘧贫-2-酮基)-3-甲基丁醯基]胺基 1,6-一苯基己烧 A·將實例38E之產物(2.5克)溶解於8毫升的無水乙醇 中。將該溶液慢慢地逐滴加至250毫升9°C的冷水中,並激 烈地攪拌。立刻出現白色的固體。持續攪拌15分鐘,並藉 著過濾收集該固體。在50°C下真空脫水12小時,得到2 32 克非晶形固體狀之想要產物。 B•將實例38E之產物(2.5克)溶解於6毫升的無水乙醇 中。將該溶液慢慢地逐滴加至3 1毫升7-9°C的冷水中,並激 烈地授拌。出現白色的固體。持續攪拌2〇分鐘,並藉著過 濾收集該固體。在5〇t:下真空脫水12小時,得到2·24克非 晶形固體狀之想要產物。 C·將實例38Ε之產物(0·5克)溶解於8毫升的異丙醇中。將 忒浴液慢慢地逐滴加至丨〇〇毫升1(M5°C的冷水中,並激烈 地攪拌。出現白色的固體。持續攪拌2〇分鐘,並藉著過濾 收集該固體。風乾而得到0.48克非晶形固體狀之想要產物: D.將實例38E之產物(0.5克)溶解於8毫升丙酮和〇 2毫升 =、X乙醇中。將该溶液慢慢地逐滴加至1 〇〇毫升1 〇_ 1 $的 冷水中’並激烈地授拌。出現白色的固體。持續搜摔^ 〇分 鐘,並藉著過遽收集該固體。風乾而得到〇46克非晶形固 體狀之想要產物。 E·將實例38E之產物(0·5克)溶解於2毫升乙腊中。將該溶 液慢慢地逐滴加至100毫升1〇_说的冷水中,並激烈地攪 “出見白色的固體。持續授掉2〇分鐘,並藉著過遽收集[a]D25 = -21.9〇(c=2.55 CH3OH) CIMS (NH3) m/z 467 (for m+H) +, I47 (for M+NH4 of pyroglutamic acid)+, 13 0 (About M+H)+ IR(Kbr) of pyroglutamic acid 1586, 1655, 1682 cm-1 4 NMR (400 MHz, DMSO-d6) (5 7.62 (s5 ιΗ) 7 54 (d,1H),7· 32-7·06 (m,10H),6.33 (s,1H),4·26 (d,lH)5 4.11-3.99 (m,1H),3.82 (dd,1H),3·57-3·48 (m,1H) 3.27-3.19 (m,1H), 3.08-2.95 (m,2H), 2.92-2.70 (m,5H) 2.53-2.43 (m,1H), 2.26-2.14 (m,1H),2.13 -1.99 (m 2H) 1.99-1.87 (m,2H),1.72-1.61 (m,2H),1.61-1.49 (m ipj) O:\106\106749.DOC -127· 1292752 1.46-1.35 (m,1H ), 0.70 (d, 3H), 0·64 (d, 3H). 13C NMR (100 MHz, DMSO-d6) δ 176.9, 176·1, 169.2, 155.5, 138.8, 137.7, 129.3, 128.3, 127.8, 126.4, 125.5, 66.9, 61.5, 56.9, 55.3, 46.8, 40·2, 39.6, 39.4, 38.8, 37.4, 29.8, 25.4, 25.3, 21.6, 19.6, 18.7 ° 4 NMR (300 MHz, CD3OD) 5 7.32- 7.03 (m,10H), 4β23-4·12 (m,1H),4·12 (d,1H),3.98 (dd,1H),3.71-3.63 (m, 1H), 3.46-3.37 (m,1H) ) , 3.11-2.98 (m, 2H), 2·97-2·80 (m5 4H), 2.70-2.59 (m, 1H), 2.49-2.38 (m, 1H), 2.38-2.12 (m, 3H), 2.07 -1.92 (m, 2H), 1.75-1.63 (m, 2H), 1.63-1.50 (m, 1H), 1·45·1·32 (m, 1H), 0.74-0.65 (m, 6H). 13C NMR (75 MHz, CD3OD) δ 181.0, 179.6? 171.65 158.4, 139.5, 137·3, 130.5, 130.0, 129.4, 128.3, 127·2, 68.1, 64.0, 59·6, 57·7, 48.8, 41.7, 41.1 , 40.7, 40·6, 37.9, 31.1, 26.9, 26.9, 22.5, 20.1, 18.9 ° 4 NMR (300 MHz, D20) δ 7.30-6.97 (m, 10 Η), 4.16-4.03 (m, 1H), 3.99 -3.91 (m, 2H), 3.71-3.63 (m, 1H), 3.43-3.35 (m, 1H), 3.00-2.68 (m, 6H), 2.40-2.13 (m, 5H), 1.88-1.72 (m, 3H), 1.68-1.56 (m, 1H), 1.52-1.37 (m, 1H), 1.32-1.18 (m, 1H), 0.60-0.52 (m, 6H). 13C NMR (75 MHz, D20) δ 1 8 1.6, 1 80· 1, 171 · 0, 157.3, 137.9, 135.2, 129.3, 129.2, 129.1, 128·4, 127.6, 126.4, 67.3, 62.6, 58.2, 56.7 , 47.5,40·1,39.4,39.2,38.7, 35.7, 29.6, 25.3, 25.2, 20.5, 18.5, 17.6 ° O:\106\106749.DOC -128- 1292752 Ε· (28,38,58)-2 -(2,6-diamidinophenoxyethyl)amino-3-3-hydroxy-5-[2S-(l-tetrahydropyrimidin-l keto)-indolylmethylbutanyl]aminodiphenyl The product of Example 1H (7.26 g, 40·3 mmol) was slurried in ethyl acetate (22 mL) and sulphur sulphur chloride (5·75 g, 48·3 mmol) was added. Then add a drop of DMF. The mixture was warmed to 5 (rc and stirred for 5 hours. The resulting hydrazine-based gas solution was cooled to 22t and applied to the subsequent coupling reaction. The product of Example 38D was mixed in a flask (20 g, 31.7 mmol) Ears, corrected for dioxane content), sodium bicarbonate (16.5 g, 197 mmol), ethyl acetate (150 ml) and water (150 ml), and stirred until the product of the example has dissolved So far (some salts remain insoluble). A solution of the above-prepared decyl chloride was added over 5 minutes, followed by rinsing with ethyl acetate (5 mL). The addition was mildly exothermic (maximum temperature 23 t). The mixture was separated overnight. The organic layer was separated and washed with 5% sodium hydrogen carbonate (1 mL) and water (1 mL). The solvent was removed on a rotary evaporator. The residue was dissolved in ethyl acetate (100) In ML), filter and rinse with ethyl acetate (5 mL). Remove the solvent from the mixed mash on a square tweezer. Dissolve the residue in hot ethyl acetate (105 ml) In 'and add geng (1 〇 5 ml); The material began to crystallize rapidly. The slurry was cooled and disturbed for 5 hours at 2 〇 _ 2 3 ° C. The product was collected by filtration and burned with 1/1 (v/v) ethyl acetate/g ( 30 ml) rinse. The product was dehydrated in a vacuum oven at 70 ° C to give 18.8 g of the desired product as a white powder. Example 39 Preparation of amorphous (28, 38, 58) -2- (2, 6 - 2 Nonylphenoxyethyl)amino group O:\106\106749.DOC -129- 1292752 -3-hydroxy-5-[2 S-(l-tetrahydropyrimidin-2-one)-3-methyl The product of Example 38E (2.5 g) was dissolved in 8 ml of absolute ethanol. The solution was slowly added dropwise to 250 ml of 9 ° C. In cold water, stirring vigorously. A white solid appeared immediately. Stirring was continued for 15 minutes, and the solid was collected by filtration, and dehydrated under vacuum at 50 ° C for 12 hours to obtain 2 32 g of the desired product as an amorphous solid. B. The product of Example 38E (2.5 g) was dissolved in 6 mL of anhydrous ethanol. The solution was slowly added dropwise to 31 ml of cold water at 7-9 ° C and vigorously stirred. Solid Stirring was continued for 2 minutes, and the solid was collected by filtration, and dehydrated under vacuum for 5 hours at 5 Torr: to obtain 2,24 g of the desired product as an amorphous solid. C. The product of Example 38 (0·5) (g) dissolved in 8 ml of isopropanol. The bath was slowly added dropwise to 丨〇〇ml 1 (M5 ° C in cold water and stirred vigorously. A white solid appeared. Stirring continuously 2 〇 The solid was collected by filtration and dried to give 0.48 g of the desired product as an amorphous solid: D. The product of Example 38E (0.5 g) was dissolved in 8 ml of acetone and EtOAc (2 ml). The solution was slowly added dropwise to 1 〇〇 ml of 1 〇 _ 1 $ of cold water' and vigorously mixed. A white solid appeared. Continue to search for ^ 〇 minutes and collect the solid by sputum. It was air-dried to obtain the desired product of 46 g of amorphous solid. E. The product of Example 38E (0.5 g) was dissolved in 2 mL of EtOAc. The solution was slowly added dropwise to 100 ml of 1 〇 of cold water and stirred vigorously to "see a white solid. Continue to give up for 2 minutes and collect by sputum.

O:\106\106749.DOC 1292752 έ亥固體。風乾而得到0·46克非晶形固體狀之想要產物。 實例40 氣丙基胺基羰基&gt;纈胺酸甲酯 將異氰酸3-氯丙酯(0·3ΐ毫升,3 〇毫莫耳)加至在thF (10 笔升)中之L-纈胺酸甲酯氫氯化物(〇·5克,3〇毫莫耳)和三乙 月女(0.42¾升,3.0毫莫耳)的淤漿中。在室溫下攪拌該反應 混合物4小時,然後加入含水的碳酸氫鈉使其中止。以醋酸 乙酯萃取已經中止的反應混合物。分離出有機層,脫水並 蒸發,得到想要的產物。 實例41 (2S,3S,5S)-2-(2,6-二曱基苯氧乙醯基)胺基•羥基 -5-[2S-(l-四氫-4-羥基·嘧啶_2_酮基)_3_甲基丁醯基]胺基 -1,6-二苯基己烷 使在二氯甲烷中之實例25E之產物的溶液與硼氫化鈉反 應’得到想要的產物。 Λ (2S,3S,5S)-2-(2,6-二甲基苯氧乙酼基)胺基·3_羥』 •5-[2S-(l-四氫-6-經基_吻唆_2•酮基)_3_曱基了酿基]胺3 -1,6-二苯基己烷 在371下,將已經完成在乙醯基部份之羰基基團上以&quot; (50_’6.0微居里)標示之(28,38,5外2_(2,6_二甲基苯氧2 醯基)胺基-3-經基-5-[2S.(1.四氫冬經基_哺咬_2·嗣基X 甲基丁醯基]胺基_1’6_二苯基己燒的3⑽毫升培養物,與; 鼠肝臟微粒體(0.5毫克/毫升微粒體蛋白質)和勵四_產/ O:\106\106749.DOC -131- 1292752 系統一起培養6〇分鐘。藉著加入300毫升乙腈使該代謝反應 停止。在真空中將以3000 RPM離心1〇分鐘之後獲得的上清 液蒸發至無水。在2毫升HPLC流動相中,重建該殘餘物。 在周圍溫度下,利用Alltech Ultrasphere 5微米C18筒型保護 管柱連結的Bechman Ultrasphere 5微米10x150毫米C18管 柱’元成想要產物的分離。以2 · 8宅升/分離之流速,在5 7 分鐘内’利用在緩衝溶液(25 mM乙酸銨,以曱酸將pH值調 整到4.8)中25-55%乙腈的直線梯度作為管柱洗脫液。 篩選HIV蛋白酶之抑制劑的螢光生成分析 可藉著下列方法來決定本發明化合物的抑制效力。 將本發明之化合物溶解於DMSO中,並將一小等份再以 DMSO溶解成1〇〇倍,為測試所希望的終濃度。該反應在6χ 5〇毫米,總體積300毫升的試管中進行。在反應緩衝溶液中 各成伤的終濃度為:125 mM乙酸納,1Μ氯化鈉,5 mM二 硫蘇糖醇,0.5毫克/毫升牛血清白蛋白,13 螢光生成 受酶質,2% (體積/體積)二甲亞颯,ρΗ4·5。在加入抑制劑 之後,將反應混合物置於螢光計小隔間的支架上,並在3〇 °c下培養數分鐘。藉著加入一小等份冰冷的mv蛋白酶反應 開始。記錄螢光強度(激發340毫微米,放射49〇毫微米)作為 時間的函數。前6到8分鐘定出反應速率。所觀察到的速率, 與每單位時間被切開之受酶質的莫耳數成正比。抑制百分 比為100χ( 1-(抑制劑存在的速率)/(缺乏抑制劑之速率》。 螢光生成受酶質·· Dabcyi_Gaba_Ser_G〗n_Asn 丁^pr〇_ Ile-Val-Gln-EDANS,其中 DABCYL=心(心二甲胺基 '苯基)O:\106\106749.DOC 1292752 έ海solid. It was air-dried to obtain the desired product of 0.46 g of an amorphous solid. Example 40 Gas propylaminocarbonyl &gt; methyl methionate 3-chloropropyl isocyanate (0.3 mM, 3 〇 millimolar) was added to L-缬 in thF (10 liters) Methyl aminate hydrochloride (〇·5 g, 3 〇 mmol) and a slurry of three-month-old female (0.423⁄4 liter, 3.0 mmol). The reaction mixture was stirred at room temperature for 4 hours and then quenched by the addition of aqueous sodium hydrogen carbonate. The reaction mixture which had been discontinued was extracted with ethyl acetate. The organic layer was separated, dehydrated and evaporated to give the desired product. Example 41 (2S,3S,5S)-2-(2,6-Dimercaptophenoxyethyl)amino-hydroxy-5-[2S-(l-tetrahydro-4-hydroxypyrimidine_2_ Keto)]3-methylbutylidene]amino-1,6-diphenylhexane The solution of the product of Example 25E in dichloromethane was reacted with sodium borohydride to give the desired product. Λ (2S,3S,5S)-2-(2,6-Dimethylphenoxyethyl)amino-3_hydroxy] •5-[2S-(l-tetrahydro-6-carbyl)唆_2•keto)_3_indenyl]amine 3 -1,6-diphenylhexane at 371, will have been completed on the carbonyl group of the ethyl thiol moiety &quot; (50_ '6.0 microcurie' labeled (28, 38, 5 outer 2_(2,6-dimethylphenoxy 2 fluorenyl)amino-3-carbyl-5-[2S.(1. tetrahydro winter 3(10) ml culture of __哺_2·嗣基 X methylbutylidene]amino-1'6-diphenylhexanide, and; rat liver microsomes (0.5 mg/ml microsomal protein) and Reed IV _Production / O:\106\106749.DOC -131- 1292752 The system was incubated for 6 minutes. The metabolic reaction was stopped by adding 300 ml of acetonitrile. The supernatant obtained after centrifugation at 3000 RPM for 1 minute in a vacuum The liquid was evaporated to dryness. The residue was reconstituted in 2 mL of HPLC mobile phase. Bechman Ultrasphere 5 micron 10 x 150 mm C18 column was used at ambient temperature with Alltech Ultrasphere 5 micron C18 cartridge protection column. Separation of the product. Use at a flow rate of 2 · 8 liters / separation in 5 7 minutes A linear gradient of 25-55% acetonitrile in a buffer solution (25 mM ammonium acetate, pH adjusted to 4.8 with citric acid) was used as a column eluent. Fluorescence generation analysis of inhibitors for screening HIV proteases can be performed by The method determines the inhibitory potency of the compounds of the invention. The compound of the invention is dissolved in DMSO and a small aliquot is dissolved in DMSO to 1 fold to determine the desired final concentration. The reaction is at 6 χ 5 〇. Millimeter, in a total volume of 300 ml test tube. The final concentration of each wound in the reaction buffer solution: 125 mM sodium acetate, 1 Μ sodium chloride, 5 mM dithiothreitol, 0.5 mg / ml bovine serum albumin , 13 fluorescein produced by enzyme, 2% (v/v) dimethyl hydrazine, ρ Η 4 · 5. After the addition of the inhibitor, the reaction mixture was placed on the scaffold of the luminometer compartment and at 3 〇 Incubate for several minutes at ° c. Start by adding a small aliquot of ice-cold mv protease. Record the fluorescence intensity (excitation 340 nm, emission 49 〇 nm) as a function of time. The first 6 to 8 minutes to determine the reaction Rate. observed rate, with unit time The number of moles of the enzyme to be cut is directly proportional. The percentage of inhibition is 100 χ (1-(the rate of inhibitor presence) / (the rate of lack of inhibitor). Fluorescence generates enzymes ·· Dabcyi_Gaba_Ser_G〗 n_Asn 〇_ Ile-Val-Gln-EDANS, where DABCYL=heart (heart dimethylamino 'phenyl)

O:\106\106749.DOC -132· 1292752 偶氮苯甲酸,Gaba=r -胺基丁酸,且EDANS = 5-((2-胺乙基) 胺基)-奈-1 -續酸。 表1 實例之化合物 抑制百分比 抑制劑濃度 (毫微莫耳) 1P 92.6 0.5 2B 93.2 0.5 3C 86.9 0.5 4F 49.7 0.5 5 80.8 0.5 6F 61.4 0.5 7B 67.1 0.5 8 55.6 0.5 9B 62.6 0.5 10F 81.0 0.5 11B 91.1 0.5 12B 76.8 0.5 13B 56.2 1.0 14D 52.7 0.5 15 48 0.5 17C 87.2 0.5 18C 57.8 0.5 19E 68.5 0.5 22E 71.8 0.5 23C 86.0 0.5 25E 100 0.5 26H 94.6 0.5 27D 92.9 0.5 28 86.6 0.5 29C 72.6 0.5 30B 91.0 0.5 O:\106\106749.DOC -133- 1292752 抗病毒之活性 根據下列的程序,可在MT4細胞上測定本發明化合物抗 -HIV的活性。以0.003之感染複數(MOI),利用hivIIIB不含 •細胞的上清液(以已知之50%組織培養感染劑量(tcid5G)預 先冷凍)感染MT4細胞一小時。在一小時的感染之後,沖洗 細胞兩次以移除殘餘的病毒,再懸浮於培養基中,並以每 孔1 X 104個細胞的量,與各種半_對數稀釋之化合物一起播 種在96-孔組織培養盤上。在毒性和細胞對照組中包括未感 染的細胞。利用帶有10〇/〇胎牛血清的RPM]; 164〇 (Gibc〇)作 為培養基。在培養基中加入各種濃度的人類血清(Sigma) 50%、25%和12.5%,得到60%、35%和22.5%總血清的終濃 度。在37°C下在培養器中培養所有的分析盤5天。在所有的 孔中,以每孔25微升加入MTT (Sigma,5毫克/毫升儲藏在 PBS中),培養4小時。以每孔50微升的量,加入帶有〇〇2N 在水中之HC1的20% SDS,以溶解細胞。為了完全溶解,將 培養盤培養過夜,在570/650毫微米波長處,在微滴定培養 盤項取器上讀取’定出細胞光密度(Q D·)。藉著下列公式對 抑制百分比分析原始數據: O.D·測試孔-〇.D·病毒對照組 χ1〇〇 Ο · D ·細胞對照組-〇 · d ·病毒對照組 糟者中點效力方程式(Chou,1975,Proc. Int. Cong Pharmacol·第六版,619頁)計算50%有效濃度(EC50),定出 化合物的效力。利用未感染的MT4細胞計算50%致死濃度 (LC50) 〇 O:\106\106749.DOC -134- 1292752 在這些條件之下,獲得下列的數據(n=4重複確定): 表2 實例之化合物 IC5〇 (μΜ,0%血漿) LC5〇 (μΜ) 1P 0.01 41.32 2B 0.016 17.78 3C 0.025 49.5 4F 0.101 &gt;100 5 0.368 &gt;100 6F 0.193 &gt;100 7B 0.204 &gt;100 8 0.019 17.78 9B 0.272 19.33 10F 0.047 91.97 11B 0.19 18.16 12B 0.093 19.11 14D 0.053 &gt;100 15 0.119 &gt;100 17C 0.051 18.96 18C 0.329 19.1 19E 0.395 17.95 20D 0.283 24.08 25E 0.012 22.88 26H 0.015 33.0 27D 0.03 56.23 28 0.011 72.2 29C 0.427 5 6 30B 0.003 18 O:\106\106749.DOC -135 - 1292752 可使用以衍生自無機或有機酸之鹽類形式的本發明化合 物。這些鹽類包括但不限於下列··乙酸鹽、己二酸鹽、藻 酸鹽、檸檬酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、二 硫酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡萄糖酸鹽、 環戊烧丙酸鹽、十二烧基硫酸鹽、乙科酸鹽、葡萄庚酸 鹽、甘油磷酸鹽、半硫酸鹽(hemisulfate)、庚酸鹽 '己酸鹽、 反丁烯二酸鹽、氫氣化物、氮漠化物、氯蛾化物、域基 乙烷磺酸鹽(羥乙磺酸鹽)乳酸鹽、順丁婦二 、 鹽、终驗酸鹽、2制酸鹽、草酸鹽、帕馬酸鹽二 果膠酯酸鹽、過硫酸鹽、3_苯基丙酸鹽、苦味酸鹽、新戊 酸鹽、丙酸鹽、號轴酸鹽、酒石酸鹽、硫氮酸鹽、對-甲苯 續酸鹽和十-烧酸鹽。亦可利用諸如低碳數烧基_,像是 甲基、乙基、丙基和丁基氣、漠和埃;硫酸二烧基醋,像 瓜酉夂一曱g日、一乙酯、二丁醋和二戊醋,長鏈的函化物, 如癸基、十二烧基、十四燒基和硬脂酸基氯、演和埃,芳 烷基鹵’如下基溴和苯乙基溴及其他的製劑將鹼性的含氮 基團四級化。藉此而獲得水或油_溶性,或可分散之產物。 形成藥學上可接受之酸加成鹽可使用之酸類的實例,包 括諸如氫氯酸、硫酸和磷酸之類的無機酸,以及諸如草酸、 順丁稀二酸、琥拍酸和择檬酸之類的有機酸。其他的鹽類 包括與驗金屬或驗土金屬,如納、鉀、約絲,或是與有 機驗一起形成的鹽類。 *本發明化合物之較佳鹽類包括氫氯化物;甲烷磺酸鹽、 石男酸鹽、膦酸鹽和經乙石黃酸鹽。O:\106\106749.DOC -132· 1292752 Azobenzoic acid, Gaba=r-aminobutyric acid, and EDANS = 5-((2-aminoethyl)amino)-na-1-supply acid. Table 1 Example Compound Percent Inhibitor Concentration (nanomol) 1P 92.6 0.5 2B 93.2 0.5 3C 86.9 0.5 4F 49.7 0.5 5 80.8 0.5 6F 61.4 0.5 7B 67.1 0.5 8 55.6 0.5 9B 62.6 0.5 10F 81.0 0.5 11B 91.1 0.5 12B 76.8 0.5 13B 56.2 1.0 14D 52.7 0.5 15 48 0.5 17C 87.2 0.5 18C 57.8 0.5 19E 68.5 0.5 22E 71.8 0.5 23C 86.0 0.5 25E 100 0.5 26H 94.6 0.5 27D 92.9 0.5 28 86.6 0.5 29C 72.6 0.5 30B 91.0 0.5 O:\106\106749 .DOC -133- 1292752 Antiviral Activity The anti-HIV activity of the compounds of the invention can be determined on MT4 cells according to the following procedure. MT4 cells were infected for one hour at a multiplicity of infection (MOI) of 0.003 using a supernatant containing no cells of hivIIIB (pre-frozen at a known 50% tissue culture infectious dose (tcid5G)). After one hour of infection, the cells were washed twice to remove residual virus, resuspended in culture medium, and seeded in 96-well with various semi-log dilutions of compound at a dose of 1 X 104 cells per well. Tissue culture on the plate. Uninfected cells were included in the toxicity and cell control groups. RPM with 10〇/fetal bovine serum was used; 164〇 (Gibc〇) was used as the medium. Various concentrations of human serum (Sigma) at 50%, 25%, and 12.5% were added to the medium to give final concentrations of 60%, 35%, and 22.5% total serum. All assay plates were incubated in the incubator for 5 days at 37 °C. MTT (Sigma, 5 mg/ml in PBS) was added to 25 μl of each well in all wells and cultured for 4 hours. 20% SDS with 〇〇2N in water HCl was added in an amount of 50 microliters per well to lyse the cells. For complete dissolution, the plates were incubated overnight and read at the 570/650 nm wavelength to determine the optical density (Q D·) of the cells on the microtiter plate reader. The original data were analyzed for percent inhibition by the following formula: OD·test well-〇.D·virus control group χ1〇〇Ο · D · cell control group 〇·d · virus control group bad midpoint potency equation (Chou, 1975, Proc. Int. Cong Pharmacol. Sixth Edition, p. 619) Calculate the 50% effective concentration (EC50) to determine the potency of the compound. 50% lethal concentration (LC50) was calculated using uninfected MT4 cells 〇O:\106\106749.DOC -134- 1292752 Under these conditions, the following data were obtained (n=4 repeat determination): Table 2 Examples of compounds IC5〇(μΜ,0% plasma) LC5〇(μΜ) 1P 0.01 41.32 2B 0.016 17.78 3C 0.025 49.5 4F 0.101 &gt;100 5 0.368 &gt;100 6F 0.193 &gt;100 7B 0.204 &gt;100 8 0.019 17.78 9B 0.272 19.33 10F 0.047 91.97 11B 0.19 18.16 12B 0.093 19.11 14D 0.053 &gt;100 15 0.119 &gt;100 17C 0.051 18.96 18C 0.329 19.1 19E 0.395 17.95 20D 0.283 24.08 25E 0.012 22.88 26H 0.015 33.0 27D 0.03 56.23 28 0.011 72.2 29C 0.427 5 6 30B 0.003 18 O :\106\106749.DOC -135 - 1292752 The compounds of the invention may be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to, the following acetates, adipates, alginates, citrates, aspartates, benzoates, besylate, disulfates, butyrates, Camphorate, camphor sulfonate, digluconate, cyclopentate propionate, dodecyl sulfate, beta acid salt, grape heptanoate, glycerol phosphate, hemisulfate, g Acidate 'hexanoate, fumarate, hydrogenate, nitrogen desert, chloro moth, domain ethane sulfonate (metrate) lactate, cis-butan, salt, terminal Acid salt, acid salt, oxalate salt, pimamate dipeptidate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, number Axate, tartrate, sulphate, p-toluene and decanoate. It is also possible to use, for example, a low carbon number base, such as methyl, ethyl, propyl and butyl gases, indifferent arsenic; sulphuric acid dialkyl vinegar, like guar 酉夂 g, g ethyl ester, two Butane vinegar and dipentyl vinegar, long-chain complexes, such as fluorenyl, dodecyl, tetradecyl and stearic acid chlorides, and aralkyl, arylalkyl halides such as bromine and phenethyl bromide And other formulations quaternize the basic nitrogen-containing groups. Thereby, water or oil-soluble or dispersible products are obtained. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and such as oxalic acid, cis-butane diacid, succinic acid and citric acid. a class of organic acids. Other salts include metals that are associated with metal or soil tests, such as sodium, potassium, or hexagrams, or with organic tests. Preferred salts of the compounds of the invention include hydrochlorides; methanesulfonates, sulphates, phosphonates and ethyl sulphates.

O:\106\106749.DOC -136- 1292752 也可以以i旨類之形式來使用本發明之化合物。這類酯類 的貫例包括其中在本發明化合物中之羥基,已經利用下列 殘基將其醯基化的化合物:經保護或未經保護之胺基酸 殘基、磷酸官能、半琥珀酸鹽殘基、式R*C(0)-或R*C(S)-之醯基殘基,其中R*為氫、低碳數烷基、鹵烷基、烷氧基、 硫代烧氧基、烷氧烷基、硫代烷氧烷基或!|烷氧基,或是 式 Ra_C(Rb)(Rd)_C(〇)-或 Ra-C(Rb)(Rd)-C(S)-之醯基殘基,其 中Rb*Rd分別選自氫或低碳數烷基,且心為 -N(Re)(Rf)、〇Re或-SRe,其中Re和Rf分別選自氫、低礙 數烧基和_烷基,或式Ri8gNH(CH2)2-NHCH2c(〇)-或 R180NH(CH2)2〇CH2C(〇)-之胺-醢基殘基,其中R18〇為氫、低 碳數烷基、芳烷基、環烧基烷基、鏈烧醯基、苯甲醯基或 α -胺醯基。特別感興趣之胺基酸.類為甘胺酸和離胺酸; 然而也可以使用其他的胺基酸殘基,包括其中胺醯基為 ^(COCI^NR^Rmi的那些,其中r·和以加分別選自氫和低 石反數烧基,或基團_NR2〇〇R2〇 1形成雜環中所含有的氮。這些 酯類擔任本發明化合物之藥物前驅物的職務,並在胃腸道 中增加這些物質的溶解度。這些酯類也可以增加該化合物 之靜脈内投藥的溶解度。其他的藥物前驅物包括其中在本 發明化合物上之羥基,利用_CH(Rg)0C(0)R181或 -CH(Rg)OC(S)R181之取代基將其官能化的化合物,其中 Rm為低碳數烷基、鹵烷基、烷氧基、硫代烷氧基或鹵烷氧 基’且Rg為氫、低碳數烧基、鹵烧基、烧氧獄基、胺幾基、 烧胺基獄基或二烧胺基幾基。可根據Schreiber之程序 O:\106\106749.DOC -137- 1292752 (Tetrahedron Lett· 1983, 24 α ,^,2363),错者在甲醇中將相對應 之甲基丙稀酯的臭氧分解,接荽7祕μ + … 肝操者以乙酸酐處理,來製備、言O: \106\106749.DOC -136- 1292752 The compounds of the invention may also be used in the form of i. Specific examples of such esters include those in which the hydroxyl group in the compound of the present invention has been thiolated with the following residues: protected or unprotected amino acid residues, phosphoric acid functions, hemisuccinates a residue, a fluorenyl residue of the formula R*C(0)- or R*C(S)-, wherein R* is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkyloxy , alkoxyalkyl, thioalkoxyalkyl or !|alkoxy, or of the formula Ra_C(Rb)(Rd)_C(〇)- or Ra-C(Rb)(Rd)-C(S)- a thiol residue, wherein Rb*Rd is independently selected from hydrogen or a lower alkyl group, and the core is -N(Re)(Rf), 〇Re or -SRe, wherein Re and Rf are each selected from hydrogen, low a number of alkyl and _alkyl groups, or an amine-fluorenyl residue of the formula Ri8gNH(CH2)2-NHCH2c(〇)- or R180NH(CH2)2〇CH2C(〇)-, wherein R18〇 is hydrogen, low carbon number An alkyl group, an aralkyl group, a cycloalkyl group, a chain decyl group, a benzepyl group or an a-amino group. Amino acids of particular interest are glycine and lysine; however, other amino acid residues may be used, including those wherein the amine group is ^(COCI^NR^Rmi, where r· and The nitrogen contained in the heterocycle is formed by adding a group selected from hydrogen and a low stone inverse alkyl group, or the group _NR2〇〇R2〇1. These esters serve as drug precursors for the compounds of the present invention, and The solubility of these substances is increased in the gastrointestinal tract. These esters may also increase the solubility of the compound for intravenous administration. Other drug precursors include a hydroxyl group in the compound of the present invention, using _CH(Rg)0C(0)R181 or a compound in which a substituent of -CH(Rg)OC(S)R181 is functionalized, wherein Rm is a lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy group and Rg It is hydrogen, a low carbon number base, a halogen group, an oxygenated prison base, an amine group, an amine base or a dialkylamino group. According to the Schreiber procedure O:\106\106749.DOC-137 - 1292752 (Tetrahedron Lett. 1983, 24 α , ^, 2363), the wrong person decomposes the corresponding methyl acrylate in methanol, 7 μ + ... liver secret operation by acetic anhydride, prepared, made

類藥物前驅物。 S 在活體内代謝本發明之藥物前驅物,而得到本發明之化 合物。藥物前驅物醋類的製備,係藉著使本發明化合物鱼 :活化之胺醢基、磷醯基、半琥拍醯基或如同上述之醯基 街生物反應來完成之。然後將所得的產物脫保護,得到相 ,的藥物前驅物醋類。本發明之藥物前驅㈣旨類,也可: 藉著經基與(函院基)酯類之燒基化作用、利用雙你酿基 縮盤之乙醯基轉移作用’或經基與已活化之酸的縮二乍 用,接著是中間物半縮醛之酯化作用來製備之。 本發明之化合物可用來抑制反轉錄病毒的蛋白酶,特別 在活體外或活體内的HIV蛋白酶(尤其是在哺乳動物,特別 是在=類)、°本發明之化合物也可以用來在活體内抑制反轉 錄病毋’尤其是人類免疫不全病毒(Ηιν)β本發明之化合物 也可以用來治療或預防由反轉錄病毒引起的疾病,特別是 後天免疫不全症候群’或是在人類或其他哺乳動物身上的 HIV感染。 、單或刀開之劑篁,投予人類或其他哺乳動物的每曰 總^量^可以是例如從G.謝到则毫克/每公斤體重每天的 用量’較常見的是G1$彳鳩克/每公斤體重每天。劑量單位 。物可3有攻樣含量的幾分之_,以便調製每日劑量。 可以將活性成份的含量與載劑物質混合,.產生單一劑量 形式’其將依據待治療之宿主和特定的投藥方式來改變。Drug-like precursors. S The drug precursor of the present invention is metabolized in vivo to obtain a compound of the present invention. The pharmaceutical precursor vinegar is prepared by subjecting the compound of the present invention to an activated amine sulfhydryl group, a phosphonium group, a semi-anthracene group or a thiol-like biological reaction as described above. The resulting product is then deprotected to give the phase, the drug precursor vinegar. The drug precursor of the present invention (4) is also intended to be: by the alkylation of a base group and a (fossil-based) ester, and by the use of a thiol-transfer of the double-branched base, or the base and activated The diestering of the acid is followed by the esterification of the intermediate hemiacetal. The compounds of the present invention can be used to inhibit retrovirus proteases, particularly HIV proteases in vitro or in vivo (especially in mammals, especially in the class), and the compounds of the invention can also be used to inhibit in vivo. Retroviral 毋 'In particular, human immunodeficiency virus (Ηιν) β The compounds of the invention may also be used to treat or prevent diseases caused by retroviruses, particularly acquired immunosuppression syndrome' or in humans or other mammals. HIV infection. For a single or a knife, the total amount of each dose administered to a human or other mammal can be, for example, from G. Thanks to the amount of milligrams per kilogram of body weight per day. The more common is G1$. / per kg body weight per day. Dosage unit. The object 3 has a fraction of the sample content to prepare the daily dose. The level of active ingredient may be combined with the carrier materials to produce a single dosage form which will vary depending upon the host to be treated and the particular mode of administration.

O:\106\106749.DOC 1292752 瞭解到供任何特定患者使用之 依據各種因专,4化 竹μ里將 _ u素’包括所使用之特定化合物的活性、年齡、 體重、-般健康狀況'性別、飲食、投藥時間、投藥途徑、 速率、藥物組成以及接受治療之疾病的嚴重程度。 盖:&amp;明之化合物可以劑量單位調配物之形式,含有傳統 無毒性之藥學上可接受之想要的載劑、佐劑和媒劑,以: 二非經腸投藥、舌下、藉著吸入喷霧、直腸或局部方式 才又藥。局部投藥亦可涉及經皮投藥的使用,諸如經皮貼片 =離子電滲透療法裝置。當在本文中使料經腸-詞時, ^括皮下主射、靜脈内、肌肉内、胸骨内注射或輸液技術。 可/射的製’例如可根據已知的技藝,利用適當之分 政w或濕满劑及懸浮劑,來調配無菌可注射的含水或含油 懸汗液。無菌可注射的製品也可以是在無毒性非經腸可接 受之稀釋劑或溶劑中的無菌可注射溶液或懸浮液,例如在 1,3曰-丙二醇中之溶液。在可接受的媒劑和溶劑中,可以使用 φ 的疋水、林格氏液和等張的氣化鈉溶液。此外,在傳統上 可使用無菌的固定油作為溶劑或懸浮介質。為了此一目 的,任何溫和的固定油都可以使用,包括單酸甘油醋或甘 油二醋。此外’發現在可注射物的製備中使用脂肪酸,如 油酸。 供直腸投藥之藥物使用的坐劑,可藉著將藥物與適當之 無刺激性賦形劑,諸如可可油和聚乙二醇混合來製備之, 其在吊λ下固化,但是在直腸溫度下液化,並因此在直腸 中將會融化並釋放於該藥物。O:\106\106749.DOC 1292752 Understand the basis for the use of any specific patient, the specificity, age, weight, and general health of the specific compound used. Gender, diet, time of administration, route of administration, rate, composition of the drug, and severity of the disease being treated. Capsules: &amp; Compounds can be in the form of dosage unit formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles which are pharmaceutically acceptable, for the purpose of: parenteral administration, sublingual, by inhalation Spray, rectal or topical medicine. Topical administration may also involve the use of transdermal administration, such as a transdermal patch = iontophoresis device. When the intestine-word is used herein, it includes subcutaneous, intra-venous, intramuscular, intrasternal injection or infusion techniques. The sterilizable injectable aqueous or oleaginous suspension can be formulated, for example, according to known techniques, using appropriate scoring w or wet fullness and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, a solution in 1,3 - propylene glycol. Among the acceptable vehicles and solvents, φ water, Ringer's solution and isotonic sodium vapor solution can be used. In addition, sterile fixed oils have conventionally been employed as a solvent or suspending medium. For this purpose, any mild fixed oil can be used, including monoglyceride or glycerin. Furthermore, it has been found that fatty acids such as oleic acid are used in the preparation of injectables. A suppository for use in a medicament for rectal administration may be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol, which cures under hang λ but at rectal temperature Liquefaction, and thus will melt and release in the rectum.

O:\W6\W6749.DOC -139- 1292752 供口服使用的固體劑量形式可包括膠囊、錠劑、丸劑、 散劑和顆粒。在這類固體劑量形式中,可將活性化合:與 至少一種諸如蔗糖、乳糖或澱粉之類的惰性稀釋劑混合。 這類劑量形式也可以包括惰性稀釋以外的添加物質,就像 在一般的慣例中,例如像硬脂酸鎂之類的潤滑劑。在膠囊、 _和丸劑的案例中,劑量形式也可以含有緩衝劑。^劑 和丸劑可額外地以腸衣膜來製備之。 供口服使用之液體劑量形式,可包括藥學上可接受之乳 劑、溶液、懸浮液、糖漿和酊劑,含有在此項技藝中常用 的惰性稀釋劑,如水。這類組合物也可以包含佐劑,如濕 潤劑、乳化劑和懸浮劑,以及增甜劑、調味劑和香料。 本發明之化合物也可以以微脂粒之形式投藥。如同此項 技藝中已熟知的,微脂粒通常衍生自磷脂類或其他脂質物 質。藉著將單-或多-層之水合液晶分散在含水介質中,形成 微脂粒。可以使用任何無毒性、生理學上可接受並可代謝, 能夠形成微脂粒的脂質。以微脂粒形式存在的本發明組合 物’除了本發明化合物之外,還可以含有穩定劑、防腐劑、 賦形劑及其類似物。較佳的脂質為天然和合成的兩種鱗脂 類和磷脂醯膽鹼(卵磷脂)。 形成微脂粒的方法是此項技藝中已熟知的。參見例如O:\W6\W6749.DOC -139- 1292752 Solid dosage forms for oral use can include capsules, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound can be combined with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also include additional materials other than inert diluents, as in conventional practice, such as a lubricant such as magnesium stearate. In the case of capsules, _ and pills, the dosage form may also contain a buffer. The agent and the pill can be additionally prepared as an enteric film. Liquid dosage forms for oral use may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water conventionally employed in the art. Such compositions may also contain adjuvants such as moisturizers, emulsifying and suspending agents, as well as sweetening, flavoring, and flavoring agents. The compounds of the invention may also be administered in the form of vesicles. As is well known in the art, vesicles are typically derived from phospholipids or other lipid materials. The vesicles are formed by dispersing the mono- or multi-layer hydrated liquid crystal in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming vesicles can be used. The composition of the present invention in the form of vesicles may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic vesicles and phospholipids (lecithin). Methods of forming vesicles are well known in the art. See for example

Prescott編著,Methods in Cell Biology,第 XIV冊,Academic Press, New York,Ν_Υ· (1976),第 33 頁以下。 本發明化合物的一些較佳之劑量形式,揭示於美國專利 申請案第08/754,390號,於1996年11月21日以Lipari,L.A. O:\106\106749.DOC -140- 1292752Edited by Prescott, Methods in Cell Biology, Book XIV, Academic Press, New York, Ν_Υ· (1976), p. 33 below. Some preferred dosage forms of the compounds of the present invention are disclosed in U.S. Patent Application Serial No. 08/754,390, issued November 21, 1996, to Lipari, L.A.O:\106\106749.DOC-140-1292752

Al-Razzak,S· Ghosh和R· Ga〇之名提出申請,名叫 Pharmaceutical Composition,將其合併於此以作為參考。 本發明化合物較佳的劑量形式包括⑷按總溶液之重量 計,以從約1%到約5〇% (較佳的是從約5%到約3〇%)之含量 存在的式I化合物,和(b)按總溶液之重量計,以從約〇%到 約20% (較佳的是從約5%到約丨〇%)含量存在之多氧基3 $萬 麻油的溶液,存在藥學上可接受之有機溶劑中,其包括⑴ 按總溶液之重量計,以從約2〇%到約99% (較佳的是從約 30〇/〇到約70〇/〇,·更佳的是從約4〇%到約65%)含量存在的油 酸,或(ii)⑴按總溶液之重量計,以從約2〇%到約99% (較 # ^ ^ ^ ^ 300/o^J ^ 70〇/〇 ; ^ ^ ^ ^ ^ „ 4〇0/〇ilJ ^ 65〇/〇)^ ^ 存在的油I,與(2)按總溶液之重量計,以從約〇%到i2% (較 佳的疋、力10 /〇)含里存在的乙醇或丙二醇或其混合物的混合 物。在本發明更佳的具體實施例中,將該溶液包膠於軟而 有彈性之明膠膠囊(SEC)中,或硬明膠膠囊中。 本發明最佳的組合物,包括⑷按總溶液之重量計,以大 約鄕含量存在的式ί化合物,和(b)按總溶液之重量計,以 大灼10/。之 '里存在之多氧基35蓖麻油的溶液,在藥學上 可接受之有機溶劑中,其包括⑴按總溶液之重量計,以大 約50M量存在的油酸’與(2)按總溶液之重量言十,以大約 10% a里存在的乙醇的混合物。在本發明最佳的具體實施 例中將該岭液包膠於軟而有彈性之明膠膠囊⑽q中,或 更月膠膠囊中’且該溶液亦包含按總溶液之重量計,以從 、、、勺0.01%到約〇·08% (較佳的是按總溶液之重量計,從約An application is made by Al-Razzak, S. Ghosh and R. Ga., entitled Pharmaceutical Composition, which is incorporated herein by reference. Preferred dosage forms of the compounds of the invention include (4) a compound of formula I in an amount of from about 1% to about 5% by weight, preferably from about 5% to about 3% by weight, based on the total solution, And (b) in the presence of a weight of the total solution, in a solution of from about 〇% to about 20%, preferably from about 5% to about 丨〇%, of the polyoxy 3 10,000 sesame oil present in the presence of pharmacy The acceptable organic solvent comprises (1) from about 2% by weight to about 99% by weight of the total solution (preferably from about 30 〇/〇 to about 70 〇/〇, preferably). Is oleic acid present in an amount from about 4% to about 65%), or (ii) (1) from about 2% to about 99% by weight of the total solution (more than ^^^^300/o^ J ^ 70〇/〇; ^ ^ ^ ^ ^ „ 4〇0/〇ilJ ^ 65〇/〇)^ ^ The presence of oil I, and (2) from the weight of the total solution, from about 〇% to i2 % (preferably 疋, force 10 / 〇) contains a mixture of ethanol or propylene glycol or a mixture thereof. In a more preferred embodiment of the invention, the solution is encapsulated in a soft and flexible gelatin capsule ( In SEC), or in hard gelatin capsules. The best composition of the invention, package (4) based on the weight of the total solution, a compound of the formula ί, which is present in an amount of about 鄕, and (b) a solution of the polyoxyl 35 castor oil in the presence of 10% by weight of the total solution, The pharmaceutically acceptable organic solvent comprises (1) oleic acid ' and (2) in an amount of about 50 M by weight of the total solution, and 10% by weight of the total solution, and about 100% of the ethanol present in a. Mixture. In a preferred embodiment of the invention, the linger is encapsulated in a soft and flexible gelatin capsule (10)q, or more in a gelatin capsule&apos; and the solution is also included as a weight of the total solution to ,,, spoon, 0.01% to about 〇·08% (preferably based on the weight of the total solution, from about

O:\106\106749.DOC -141 - 1292752 Ο · 01 %到約Ο · Ο 5 %)之含量存在的抗氧化劑(較佳的是bht (丁基化之羥基甲苯))。 在下文中提供這類組合物之實例及其製備方法。 成份 重量% 實例2B之化合物(自由鹼) 30 乙醇(USP,200標準強度) 10 多氧基35蓖麻油(Cremophor® EL) 10 油酸,6321,NF 50 丁基化之羥基甲苯(BHT),NF 0.01 上述組合物之製備: 以氮氣吹掃混合水槽。在該槽中混合油酸(499·9克)和乙 醇(100克)。將丁基化之羥基甲苯(〇」克)裝入該槽中,並混 合直到該溶液澄清為止。將實例2B之化合物(3〇〇克)慢慢地 裝入該槽中,並混合直到該溶液澄清為止。在該槽中加入 多氧基35蓖麻油(1〇〇克)並混合之。將所得的溶液填裝至軟 而有彈性之膠囊(〇·333克溶液/SEC)中,得到1〇〇毫克實例 2B之化合物/SEC的劑量,或是0.667克/SEC,得到200毫克 實例2B之化合物/SEC的劑量。 在將本發明之化合物作為唯一活性醫藥製劑來投藥的同 時’也可以將其與一或多種免疫調節劑、抗病.毒劑、其他 抗感染劑或疫苗混合使用。可以與本發明化合物混合投予 的其他抗病毒劑,包括AL_72卜召干擾素、聚甘露乙酸酯、 反轉錄酶抑制劑(例如二脫氧胞嘧啶核茹(ddc ;沙西塔必 (zalcitabine))、二脫氧肌苷(ddI;迪達諾信(dida_n〇sine))、O: \106\106749.DOC -141 - 1292752 Ο · 01 % to about Ο · Ο 5 %) The presence of an antioxidant (preferably bht (butylated hydroxytoluene)). Examples of such compositions and methods for their preparation are provided below. Ingredient% by weight Example 2B compound (free base) 30 Ethanol (USP, 200 standard strength) 10 Polyoxyl 35 castor oil (Cremophor® EL) 10 Oleic acid, 6321, NF 50 Butylated hydroxytoluene (BHT), NF 0.01 Preparation of the above composition: The mixed water tank was purged with nitrogen. Oleic acid (499·9 g) and ethanol (100 g) were mixed in the tank. Butylated hydroxytoluene (〇克) was charged into the tank and mixed until the solution was clear. The compound of Example 2B (3 g) was slowly charged into the tank and mixed until the solution was clear. Polyoxyl 35 castor oil (1 g) was added to the tank and mixed. The resulting solution was filled into a soft and flexible capsule (〇·333 g solution/SEC) to give a dose of 1 mg of the compound of Example 2B/SEC, or 0.667 g/SEC, to give 200 mg of Example 2B. The dose of compound / SEC. While the compound of the present invention is administered as the sole active pharmaceutical preparation, it can also be used in combination with one or more immunomodulators, anti-viral agents, other anti-infective agents or vaccines. Other antiviral agents that can be administered in combination with the compounds of the invention, including AL_72, interferon, polymannose acetate, reverse transcriptase inhibitors (eg, dideoxycytosine ruthenium (ddc; zalcitabine)) , dideoxyinosine (ddI; dida_n〇sine),

O:\106\106749.DOC -142- 1292752 BCH-189、AzdU、卡波菲(carbovir)、ddA、d4C、d4T (斯 塔謬定(stavudine))、3TC (拉米謬定(lamivudine))、 DP-AZT、FLT (氟胸腺核 #)、BCH -189、5-鹵素-3,· 口塞-二脫 氧胞嘧啶核甞、PMEA、雙-POMPMEA、易得謬定 (zidovudine)(AZT) ' 莕菲拉平(nevirapine)、迪菲如定 (delviridine)、MSA-300、楚菲定(trovirdine)及其類似物), 非-核甞反轉錄酶抑制劑(例如R82193、L-697,661、 BI-RG-5 87 (莕菲拉平),反轉錄病毒之蛋白酶抑制劑(例如 HIV蛋白酶抑制劑,像是律特納菲(ritonavir)、Ro 31-8959 (沙奎納菲(saquinavir))、SC-52151、VX-478、AG 1343 (内 非納菲(nelfinavir))、BMS 186,318、SC-55389a、BILA 1096 BS、DMP-323、DMP-450、KNI-227、KNI-272、U-140690、 N-(2(R)-羥基-1(S)-氫茚基)-2(R)-苯甲基-4(S)-經基 -5-(1-(4-(3 -p比σ定甲基)-2(S)-Nf -第三-丁基魏酿胺基)-六氮外匕 口井基))-戊烧醯胺(MK-639 ;印地納菲(indinavir))、5(S)_Boc-胺基-4(s)_羥基-6-苯基-2(R)-苯甲基己醯基-(L)-纈胺酸 -(L)-苯丙胺酸-嗎啉-4-基醯胺、1-莕氧乙醯基-/5-曱硫基-丙胺酸-(2S,3S)-3-胺基-2-羥基-4-丁醯基-1,3-嘧唑啶-4-第 三-丁 基醯胺(也就是 1-萘氧乙醯基 -Mta-(2S,3S)-AHPBA-Thz-NH-tBu)、5-異喳啉氧基乙醯基-冷-甲硫基-丙胺酸-(2S,3S)-3-胺基-2-羥基-4-丁醯基-1,3-嘧 唑啶-4-第三-丁基醯胺(也就是iQoa-Mta-Apns-Thz-NHtBu) 及其類似物),HEPT化合物(L,697,639、R82150、U-87201E 及其類似物),HIV整合酶抑制劑(易特菲(Zintevir)及其類似 O:\106\106749.DOC -143- 1292752 物),TAT抑制劑(例如RO-24-7429及其類似物),膦醯基甲 酸三納、HPA-23、艾弗洛尼信(eflonithine)、肽T、網織素 (Reticulose)(核石粦蛋白)、安薩黴素(ansamycin) LM 427、三 甲翠賽特(trimetrexate)、UA001、三氮 σ坐核嘗(ribavirin)、 干擾素、歐色特諾素(oxetanocin)、歐色特諾素-G、賽可 巴特(cyclobut)-G、賽可巴特-A、ara-M、BW882C87、佛斯 卡内特(foscarnet)、BW256U87、BW348U87、L-693,989、 BV ara-U、CMV三株抗體、FIAC、HOE-602、HPMPC、 MSL-109、Tl-23、三福瑞定(trifluridine)、維達瑞必 (vidarabine)、飛西可非(famciclovir)、盤西可菲 (penciclovir)、阿賽可菲(acyclovir)、根西可菲 (ganciclovir)、卡斯特諾斯普明(castanospermine)、 rCD4/CD4-IgG、CD4-PE40、丁基-DNJ、金絲桃素 (hypericin)、氧雜肉豆蔻酸、硫酸葡聚糖和多硫酸戊聚糖。 可以與本發明化合物混合投予的免疫調節劑,包括布普羅 明(bropirimine)、安普禮根(Ampligen)、抗-人類α干擾素抗 體、菌落刺激因子、CL246,738、Imreg-1、Imreg-2、二乙 基二硫代胺基曱酸鹽、介白素-2、α-干擾素、肌苷普倫諾 貝克斯(pranobex)、曱硫胺酸腦菲肽、胞壁醯基-三肽、 TP-5、促紅血球生成素、納崔酉同(naltrexone)、腫瘤壞死因 子、点干擾素、7干擾素、介白素-3、介白素-4、自體的 CD8 +輸液、α干擾素免疫球蛋白、IGF-1、抗-Leu-3A、自 體接種、生物刺激、體外的光泳現象、環孢多肽、納巴黴 素(rapamycin)、FK-565、FK-506、G-CSF、GM-CSF、高熱、 O:\106\106749.DOC -144- 1292752 異平諾信(isopinosine)、IVIG、HIVIG、被動免疫療法和白 疫苗的高度免疫。可以與本發明化合物混合投予的其他抗 感染劑包括異硫代羥酸五脒。各種HIV或AIDS疫苗中的任 何一個(例如 gpl20 (重組的)、Env2-3 (gpl20)、HIVAC-le (gpl20)、gpl60 (重組的)、VaxSyn HIV-1 (gpl60)、免疫-Ag (gpl60)、HGP-3 0、HIV-免疫原、p24 (重組的)、VaxSyn HIV-1 (p24)均可以與本發明之化合物混合使用。 其他可與本發明化合物混合使用的製劑為安薩黴素LM 427、無嘌呤核酸、ABPP、AI-721、卡瑞塞(carrisyn)、 AS-101、阿佛醇(avarol)、阿易美松(azimexon)、秋水仙素、 化合物Q、CS-85、N-乙醯基半胱胺酸、(2-氧代嘍唑啶-4-羧醯鹽)、D-青黴素、二苯基内醯脲、EL-10、保紅血球生 成素、梭鏈孢酸、葡聚糖、HPA-23、人類生長荷爾蒙、羥 氣奎(hydroxchloroquine)、艾司卡登(iscador)、L_ 歐服洛沙 西(ofloxacin)及其他p奎諾酮(quinolone)抗生素、磨兹多糖、 碳酸鋰、MM-1、單月桂脂、MTP-PE、納崔酮、神經營養 素(neurotropin)、臭氧、PAI、人參(panax ginseng)、己基可 可驗(pentofylline)、己酉同可可驗(pentoxifylline)、肽 T、松 毯萃取物、聚干露乙酸醋、網織素、律多原(retrogen)、三 氮嗤核嘗、核糖酵素(ribozymes)、RS-47、Sdc-28、石夕鶴酸 鹽、THA、胸腺體液因子、胸腺生成素(thymopentin)、胸 腺素片段5、胸腺素α 1、胸腺刺激素(thymostimulin)、 UA00 1、尿口密口定核普、維生素B 12和伍伯謀格(wobemugos) 0 其他可與本發明化合物混合使用的製劑為抗真菌劑,如 O:\106\106749.DOC -145 - 1292752 兩性黴素(amphotericin) B、氯三苯甲口米 °坐(clotrimazole)、 5-氟胞。密咬(flucytosine)、氟可那唾(fluconazole)、易錯可 那峻(itraconazole)、凱多可那嗤(ketoconazole)和制黴菌素 及其類似物。 其他可與本發明化合物混合使用的製劑為抗細菌劑,如 硫酸氨基經丁基卡那黴素(amikacin)、阿際色黴素 (azithromycin)、西普洛薩素(ciprofloxacin)、特蘇洛薩素 (tosufloxacin)、克拉如色黴素(clarithromycin)、克風敏 (clofazimine)、乙烯二氨基二丁醇(ethambutol)、異煙肼 (isoniazid)、p比嗪醯胺(pyrazinamide)、利福必丁(rifabutin)、 利福平(rifampin)、鏈黴素和TLC G_65及其類似物。 其他可與本發明化合物混合使用的製劑為抗贅生物劑, 如α干擾素、COMP(環磷醯胺、長春新鹼、胺甲碟呤和脫 氫可的松)、鬼臼乙叉武(etoposide)、mB ACOD (胺甲碟呤、 博菜黴素、阿黴素(doxorubicin)、環鱗醯胺、長春新驗和地 塞米松)、PRO-MACE/MOPP (脫氫可體松、胺甲碟呤(w/白 菲(leucovin)救援)、阿黴素、環麟醢胺、紅豆杉醇(taxol)、 鬼臼乙叉武/氮芥(mechlorethamine)、長春新驗、脫氫可的 松和普魯爷耕(procarbazine))、長春新驗、長春花驗、血管 抑制素(angioinhibins)、多硫酸戊聚糖、血小板因子4和 SP-PG及其類似物。 其他可與本發明化合物混合使用的製劑為治療神經學疾 病的藥物,如肽T、哌醋甲酯(ritann)、鋰、艾拉菲爾(elavil)、 二苯乙内醯踩(phenyt〇in)、氨甲醯苯革(carbamazipine)、慢O:\106\106749.DOC -142- 1292752 BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine) , DP-AZT, FLT (fluorothymidine #), BCH-189, 5-halogen-3, · sputum-dideoxycytosine quinone, PMEA, bis-POMPMEA, zidovudine (AZT) 'Nevirapine, delviridine, MSA-300, trovirdine and its analogues), non-nuclear reverse transcriptase inhibitors (eg R82193, L-697, 661, BI) -RG-5 87 (荇菲拉平), a protease inhibitor of retrovirus (eg HIV protease inhibitors such as ritonavir, Ro 31-8959 (saquinavir), SC -52151, VX-478, AG 1343 (nelfinavir), BMS 186, 318, SC-55389a, BILA 1096 BS, DMP-323, DMP-450, KNI-227, KNI-272, U-140690, N-(2(R)-hydroxy-1(S)-hydroindenyl)-2(R)-benzyl-4(S)-radio-5-(1-(4-(3 -p ratio) σ定methyl)-2(S)-Nf-Third-Butyl-Wilylamine)-hexa-nitrogen oxime base))-pentyl decylamine (MK-639; Indina (indinavir)), 5(S)_Boc-amino-4(s)-hydroxy-6-phenyl-2(R)-benzylglycidyl-(L)-proline-(L)- Phenylalanine-morpholin-4-ylguanamine, 1-oxoethoxyethyl-/5-decylthio-alanine-(2S,3S)-3-amino-2-hydroxy-4-butanyl-1 , 3-pyrazolidine-4-t-butyl decylamine (also known as 1-naphthyloxyethyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu), 5-isoporphyrinoxy Ethyl thiol-cold-methylthio-alanine-(2S,3S)-3-amino-2-hydroxy-4-butenyl-1,3-pyrazolidine-4-tris-butyl decylamine (ie iQoa-Mta-Apns-Thz-NHtBu) and its analogues), HEPT compounds (L, 697, 639, R82150, U-87201E and their analogues), HIV integrase inhibitors (Zintevir) and It is similar to O:\106\106749.DOC -143- 1292752), TAT inhibitors (such as RO-24-7429 and its analogues), tris-phosphonocarboxylate, HPA-23, Aphrodite ( Eflonithine), peptide T, reticulose (nuclear prion protein), ansamycin ALS 427, trimetrexate, UA001, ribavirin, interference Oxetanocin Oplotox-G, cyclobut-G, sekbat-A, ara-M, BW882C87, foscarnet, BW256U87, BW348U87, L-693, 989, BV ara-U , CMV three antibodies, FIAC, HOE-602, HPMPC, MSL-109, Tl-23, trifluridine (trifluridine), vidarabine (vidarbine), fexiciclovir, panxicofi (penciclovir), acyclovir, ganciclovir, castanospermine, rCD4/CD4-IgG, CD4-PE40, butyl-DNJ, hypericin (hypericin), oxacin myristic acid, dextran sulfate, and pentosan polysulfate. An immunomodulatory agent that can be administered in combination with a compound of the present invention, including bropirimine, Ampligen, anti-human interferon alpha antibody, colony stimulating factor, CL246, 738, Imreg-1, Imreg -2, diethyldithioamino decanoate, interleukin-2, alpha-interferon, inosine pranobex, glucosinolate phenanthrene, cell wall thiol Tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis factor, interferon, interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, alpha Interferon immunoglobulin, IGF-1, anti-Leu-3A, autologous inoculation, biostimulation, in vitro photophoresis, cyclosporin, rapamycin, FK-565, FK-506, G -CSF, GM-CSF, hyperthermia, O:\106\106749.DOC -144- 1292752 High immunity to isopinosine, IVIG, HIVIG, passive immunotherapy and white vaccine. Other anti-infective agents which may be administered in admixture with the compounds of the present invention include guanidinium isothioate. Any of a variety of HIV or AIDS vaccines (eg, gpl20 (recombinant), Env2-3 (gpl20), HIVAC-le (gpl20), gpl60 (recombinant), VaxSyn HIV-1 (gpl60), immune-Ag (gpl60) ), HGP-3 0, HIV-immunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with the compound of the present invention. Other preparations which can be used in combination with the compound of the present invention are ansamycin LM 427, sputum-free nucleic acid, ABPP, AI-721, carrisyn, AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N-Ethylcysteine, (2-oxooxazolidin-4-carboxyindole), D-penicillin, diphenyl carbazide, EL-10, erythropoietin, fusidic acid , dextran, HPA-23, human growth hormone, hydroxchloroquine, iscador, L_ oxalox and other quinolone antibiotics Polysaccharides, lithium carbonate, MM-1, monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng, hexyl Pentofylline, pentoxifylline, peptide T, pineapple extract, polyglycol acetate, reticulum, retrogen, triazide, ribozymes ), RS-47, Sdc-28, shisha, THA, thymic fluid factor, thymopentin, thymosin fragment 5, thymosin α 1, thymostimulin, UA00 1, urinary tract Mouth saponin, vitamin B 12 and wobemugos 0 Other preparations which can be used in combination with the compound of the present invention are antifungal agents, such as O:\106\106749.DOC-145-1292752 Amphotericin (amphotericin) B, clotrimazole, 5-fluorocell, flucytosine, fluconazole, itraconazole, ketoconazole And nystatin and its analogs. Other preparations which can be used in combination with the compound of the present invention are antibacterial agents such as ammonium sulphate, amikacin, azithromycin, xipro Ciprofloxacin, tesulosin (tosuf) Loxacin), clarithromycin, clofazimine, ethambutol, isoniazid, ppyrazinamide, rifabutidine Rifabutin), rifampin, streptomycin and TLC G_65 and analogs thereof. Other formulations which can be used in admixture with the compounds of the present invention are anti-biological agents such as interferon alpha, COMP (cyclophosphamide, vincristine, amine saxophone and dehydrocortisone), scorpion scorpion ( Etoposide), mB ACOD (amino sputum, broccoli, doxorubicin, cyclosporin, vinca citrate and dexamethasone), PRO-MACE/MOPP (dehydrocortisone, amine) A dish (w/ leucovin rescue), doxorubicin, cyclamate, taxol, mechlorethamine, new test, dehydrogenation Pine and procarbazine, Changchunxin, vinca, angiostatin, pentosan polysulfate, platelet factor 4 and SP-PG and their analogues. Other preparations which can be used in combination with the compounds of the present invention are medicaments for the treatment of neurological diseases, such as peptide T, ritann, lithium, elavil, diphenylacetamidine (phenyt〇in). ), carbamazipine, slow

O:\106\106749.DOC 1292752 心利(mexitetine)、肝素和阿拉伯糖胞替及其類似物。 其他可與本發明化合物混合使用的製劑為抗-原蟲劑,如 丙硫咪°坐(albendazole)、阿際色黴素、克拉如色黴素、克林 達黴素、皮質類固醇、氨苯颯(dapsone)、DIMP、艾弗洛尼 信、566C80、凡思達(fansidar)、吱喃峻酮(furazolid〇ne)、 L,671,329、雷σ坐如瑞(letrazuril)、甲石肖嗤 (metronidazole)、巴龍黴素、培佛薩素(pefloxacin)、戊燒月米 (pentamidine)、皮利崔欣(piritrexim)、伯氨 4 (primaquine)、 乙氨α密σ定(pyrimethamine)、生長激素釋放之抑制因子、螺 旋黴素、續胺嘧咬(sulfadiazine)、三曱氧苄二氨嘴。定、 TMP/SMX、三甲翠赛特(trimetrexate)和WR 6026及其類似 物0 在與本發明化合物混合的抑制或治療HIV或AIDS之製劑 中,較佳的是反轉錄酶抑制劑,尤其是AZT (易得謬定)、 ddl (迪達諾定)、ddC (沙西塔必)、d4T (斯塔謬定)、3TC (拉 米謬定)、莕菲拉平、迪菲如定、楚菲定、PMEA、雙 -POMPMEA和 MSA-300。 與本發明化合物混合的抑制或治療HIV或AIDS之其他較 佳的製劑,特別是ABT-538 (律特納菲)及相關的化合物,揭 示在1996年7月30日公告之美國專利第5,541,206號,和1996 年2月13日公告之美國專利第5,491,253號,將其合併於此以 作為參考,N-(2(R)-羥基-1(S)-氫茚基)-2(R)-苯甲基-4(S)-羥基-5-( 1-(4-(3-吡啶甲基(第三-丁墓羰醯胺)-六 氫吡畊基))-戊烷醯胺(也就是印地納菲)及相關的化合物, O:\106\106749.DOC -147- 1292752 揭示在1993年5月12日公告之歐洲專利申請案第541168號 和1995年5月9曰公告之美國專利第5,413,999號,將其合併 於此以作為參考;N-第三-丁基-十氫_2-[2(R)·羥基-4_苯基 -3(S)_[[N-(2_喳啉基幾基)-L-天冬醯胺醯基]胺基]丁 基]-(4aS,8aS)-異喳啉-3(S)-羧醯胺(也就是沙奎納菲)及相 關的化合物,揭示在1993年3月23曰公告之美國專利第 5,196,438號,將其合併於此以作為參考;5(s)_B〇c_胺基 -4(S) -經基-6-苯基-2(R)-苯曱基己醯基_(l)_綠胺酸- (l) -苯 丙胺酸-嗎11 林-4-基酿胺及相關的化合物,揭示在1993年3月 17曰公告之歐洲專利申請案第532466號,將其合併於此以 作為參考;1-莕氧乙醯基-/5 -甲硫基-丙胺酸_(2S,3S)-3_胺基 -2-羥基-4-丁醯基-1,3-嘧唑啶-4-第三-丁基醯胺(也就是^ 奈氧乙酿基- Mta-(2S,3 S)-AHPB A-Thz-NH-tBu),5-異 p套琳氧 基乙醯基-泠-甲硫基-丙胺酸-(2S,3S)-3-胺基-2-羥基-4-丁 醯基-1,3- p塞峻咬-4-第三-丁基醯胺(也就是 iQoa-Mta-Apns-Thz-NHtBu)及相關的化合物,揭示在1992 年6月17日公告之歐洲專利申請案第490667號,和Chem. Pharm· Bull·处(8) 2251 (1992)中,將其合併於此以作為參 考;[1S-[1R*(R*),2S*]]-NM3-[[[(1 山二曱乙基)胺基頂 基](2-曱丙基)胺基]-2-羥基小(苯甲基)丙基]_2·[(2_峻琳基 羰基)胺基]丁烷二醯胺(也就是SC-52151)及相關的化合 物,揭示於1992年5月29日公告之PCT專利申請案第 W092/08701號,以及1993年11月25日公告之pCT專利申請 案第W093/23368號中,將其合併於此以作為參考; O:\106\106749.DOC -148- 1292752O:\106\106749.DOC 1292752 Mexitetine, heparin and arabinose and their analogues. Other preparations which can be used in admixture with the compounds of the invention are anti-protozoal agents, such as albendazole, azithromycin, caromycin, clindamycin, corticosteroids, ammonia Da (dapsone), DIMP, Aflonini, 566C80, fansidar, furazolid〇ne, L,671,329, Lei σ 瑞 瑞 (letrazuril), 甲石肖Metronidazole, paromomycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine , inhibitor of growth hormone release, spiramycin, sulfadiazine, trioxazole diamine. Determination, TMP/SMX, trimetrexate and WR 6026 and analogs thereof. In the preparation for inhibiting or treating HIV or AIDS mixed with the compound of the present invention, a reverse transcriptase inhibitor is preferred, especially AZT (easy to get set), ddl (Didanodine), ddC (shaxita must), d4T (Stadend), 3TC (Lami set), 荇Fiilaping, Diffy Ruding, Chu Fei Ding, PMEA, dual-POMPMEA and MSA-300. Other preferred formulations for inhibiting or treating HIV or AIDS, in combination with a compound of the invention, in particular ABT-538 (Rhinenafi) and related compounds, disclose U.S. Patent No. 5,541, issued July 30, 1996, No. 206, and U.S. Patent No. 5,491,253, issued toK.S. (R)-Benzyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-trihydropyridinyl)-pentane Indoleamine (also known as Indinavir) and related compounds, O:\106\106749.DOC -147- 1292752, discloses European Patent Application No. 541168 and May 9, 1995, published on May 12, 1993. U.S. Patent No. 5,413,999, issued toK. _[[N-(2_ oxalinyl)-L-aspartate oxime]amino]butyl]-(4aS,8aS)-isoindoline-3(S)-carboxamide ( That is, Shaquinafi) and related compounds, which are disclosed in US Pat. No. 5,196,438, issued March 23, 1993, incorporated herein by reference. ;5(s)_B〇c_Amino-4(S)-ylamino-6-phenyl-2(R)-benzoindolyl-(l)-physic acid-(l)-amphetamine酸-?11 lin-4-ylamine and related compounds are disclosed in European Patent Application No. 532,466, issued March 17, 1993, which is incorporated herein by reference in its entirety in -/5 -Methylthio-alanine _(2S,3S)-3-amino-2-hydroxy-4-butenyl-1,3-pyrazolidine-4-tris-butylamine (also known as ^ Nitoxyethyl-Mta-(2S,3 S)-AHPB A-Thz-NH-tBu), 5-iso-p-decyloxyethyl-fluorenyl-methylthio-alanine-(2S, 3S)-3-Amino-2-hydroxy-4-butanyl-1,3-p-Secret-4-III-butyl decylamine (also known as iQoa-Mta-Apns-Thz-NHtBu) and related Compounds are disclosed in European Patent Application No. 490,667, issued Jun. 17, 1992, and in Chem. Pharm. Bull. (8) 2251 (1992), incorporated herein by reference. 1R*(R*),2S*]]-NM3-[[[(1 山 曱 曱 ) ) ) ) ) ] ] ] ] ] ] ] ] ] ] 曱 曱 曱 曱Propyl]_2·[(2_junolinylcarbonyl)amino]butanediamine (also known as SC-52151) and related PCT Patent Application No. W092/08701, filed on May 29, 1992, and hereby incorporated herein by reference, in ; O:\106\106749.DOC -148- 1292752

(也就是VX-478)及相關的化合物,揭示在1994年3月17曰 公告之PCT專利申請案第WO94/05639號中,將其合併於此 以作為參考;(i.e., VX-478) and related compounds are disclosed in PCT Patent Application No. WO94/05639, the entire disclosure of which is incorporated herein by reference.

(也就是DMP-323)或(ie DMP-323) or

(也就是DMP-450) 及相關的化合物,揭示於1993年4月15日公告之PCT專利 申請案第WO93/07128號中,將其合併於此以作為參考;(i.e., DMP-450) and related compounds are disclosed in PCT Patent Application No. WO 93/07128, filed on Apr. 15, 1993, which is hereby incorporated by reference.

(也就是AG1343 (内非納菲)), O:\106\106749.DOC -149- 1292752 揭示在1995年4月13曰公告之PCT專利申請案第 WO95/09843號,以及1996年1月16日公告之美國專利第 5,484,926號中,將其合併於此作為參考;(ie, AG1343 (inner Philippine)), O:\106\106749.DOC -149- 1292752 Revealing PCT Patent Application No. WO95/09843, published on April 13, 1995, and January 16, 1996 U.S. Patent No. 5,484,926, the disclosure of which is incorporated herein by reference.

(也就是 BMS 186,318) 揭示於1994年1月26日公告之歐洲專利申請案第580402 號中,將其合併於此以作為參考;(i.e., BMS 186, 318), which is hereby incorporated by reference in its entirety in its entirety in its entirety the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire

(也就是 SC-55389a) 揭示在人類反轉錄病毒及相關感染的第二次全國會議, (Washington,D.C.,1月 29 日至 2月 2 日,1995年)88會期; 以及(ie SC-55389a) Revealed at the Second National Conference on Human Retroviruses and Related Infections (Washington, D.C., January 29-February 2, 1995) 88 sessions;

O:\106\106749.DOC -150- 1292752 (也就是BILA 1096 BS)和相關的化合物,揭示在1993年9 月15日公告之歐洲專利申請案第56〇268號中,將其合併於 此以作為參考;以及O:\106\106749.DOC-150-1292752 (also known as BILA 1096 BS) and related compounds, which are incorporated herein by reference in its European Patent Application No. 56-268, filed on Sep. For reference; and

(也就是U-140690)和相關 的化合物,揭示於1995年Π月16日公告之PCT專利申請案第 W095/30670號中,將其合併於此以作為參考;或上述任何 一者之藥學上可接受的鹽。 在最佳的組合中,本發明化合物與律特納菲混合一起投 予。這樣的組合對於抑制人類的HIV蛋白酶是特別有用的。 這樣的組合對於抑制或治療人類的HIV感染也是特別有用 白曰勺。當在這樣的組合中使用本發明化合物時,可以分開劑 量之形式,以相同或不同次數來投予本發明化合物,或是 將它們調配成含有兩種化合物的單一組合物。(i.e., U-140 690) and related compounds are disclosed in PCT Patent Application No. W095/30, 670, filed Jan. Acceptable salt. In the most preferred combination, the compound of the invention is administered in combination with a tertna phenanthrene. Such combinations are particularly useful for inhibiting human HIV protease. Such a combination is also particularly useful for inhibiting or treating HIV infection in humans. When the compound of the present invention is used in such a combination, the compounds of the present invention may be administered in the form of separate doses, in the same or different number of times, or they may be formulated into a single composition containing the two compounds.

號1f揭示的,將其合併於此以作為束考, 口服使用之液體劑量 ^國專利第5,484,801 ~ ’(b)包膠的固體或No. 1f, which is incorporated herein by reference, for use as a liquid test, liquid dosage for oral administration, Patent No. 5,484,801 ~ '(b) encapsulated solid or

O:\106\106749.DOC -151 - 1292752 半-固體之劑量形式,如同在1995年3月23日公告之PCT專利 申請案第WO95/07696號和1995年3月13日提出申請之美國 專利序列第08/402,690號中所揭示的,將其合併於此以作為 參考,以及(c)包膠之固體劑量形式,如同在1995年4月13 曰公告之PCT專利申請案第WO95/09614號和1996年9月24 曰公告之美國專利第5,559,158號,將其合併於此以作為參 考。 律特納菲較佳之劑量形式的其他實例,揭示於美國專利 申請案第〇8/754,3 90號,於1996年11月21日以1^?&amp;1^,1^八· Al-Razzak,S. Ghosh和R. Gao之名提出申請,名叫 Pharmaceutical Composition,將其合併於此以作為參考。 律特納菲的較佳組合物包括〇)按總溶液之重量計,以從 約1%到約30% (較佳的是從約5%到約25%)之含量存在的律 特納菲,和(b)按總溶液之重量計,以從約0%到約20% (較 佳的是從約5%到約10%)含量存在之聚氧基35蓖麻油的溶 液,在藥學上可接受有機溶劑中,其包括⑴按總溶液之重 量計,以從約15%到約99% (較佳的是從約30%到約70% ;更 佳的是從約40%到約65%)之含量存在的油酸,或(ii)(l)按總 溶液之重量計,以從約15%到約99% (較佳的是從約30%到 約70°/。;更佳的是從約40%到約65%)之含量存在的油酸,與 (2)按總溶液之重量計,以從約0%到12% (較佳的是約10%) 之含量存在的乙醇或丙二醇或其混合物的混合物。在本發 明最佳的具體實施例中,將該溶液包膠到軟而有彈性之明 膠膠囊(SEC),或硬明膠膠囊中,且該溶液也可以包含按總 O:\106\106749.DOC -152- 1292752 溶液之重量計,以從約0·01%到約0·08% (較佳的是按總溶 液之重量計,從約0·01%到約0·05%)之含量存在的抗氧化: (較佳的是ΒΗΤ (丁基化之羥基曱苯))。 在下文中提供這類組合物之實例及其製備方法。 成份 重量% 律特納菲(自由鹼) 20 乙醇(USP,200標準強度) 10 多氧基35蓖麻油(Cremophor® EL) 5 油酸,6321,NF 65 丁基化之羥基甲苯(BHT),NF 0.01 上述組合物之製備: 以氮氣吹掃混合水槽。在該槽中混合油酸(649·9克)和乙 酵(1〇〇克)。將該混合物加溫至大約m (mi),並保 持在該溫度下。將丁基化之羥基甲苯(01克)裝入該槽中, 並混合直到該溶液澄清為止。將律特納菲(200克)慢慢地裝 入該槽中,並混合直到該溶液澄清為止。在該槽中加入多 氧基35蓖麻油(50克)並混合之。中斷加熱並容許該溶液冷卻 至周圍溫度(20-3 0°C )。將所得的溶液填裝至軟而有彈性之 膠囊(0.5克溶液/SEC)中,得到ι〇〇毫克律特納菲/SEc的劑 畺’或是1.0克/SEC ’得到200毫克律特納菲/seC的劑量。 律特納菲(自由驗) 2〇 乙醇(USP,200標準強度) 1〇 多氧基35蓖麻油(Cremophor® EL) j〇 O:\106\106749.DOC -153 . 1292752 油酸,6321,NF 6〇 丁基化之羥基曱苯(ΒΗΤ),NF 0.01 上述組合物之製備··O:\106\106749.DOC -151 - 1292752 The semi-solid dosage form, as disclosed in PCT Patent Application No. WO95/07696, filed on March 23, 1995, and the US patent filed on March 13, 1995 PCT Patent Application No. WO95/09614, the entire disclosure of which is incorporated herein by reference in its entirety, in its entirety, in its entirety, in And U.S. Patent No. 5,559,158, the disclosure of which is incorporated herein by reference. Further examples of the preferred dosage forms of the law of Turner Philip are disclosed in U.S. Patent Application Serial No. 8/754,396, filed on November 21, 1996, at 1 &lt;1&lt;1&gt; The application for the name of Razzak, S. Ghosh and R. Gao, entitled Pharmaceutical Composition, is hereby incorporated by reference. A preferred composition of the law of Tertena contains rhodium phenanthrene in an amount of from about 1% to about 30%, preferably from about 5% to about 25%, by weight of the total solution. And (b) a solution of polyoxy 35 castor oil present in an amount of from about 0% to about 20%, preferably from about 5% to about 10% by weight of the total solution, in pharmacy In an acceptable organic solvent, it comprises (1) from about 15% to about 99% by weight of the total solution, preferably from about 30% to about 70%; more preferably from about 40% to about 65. The oleic acid present in the amount of %), or (ii) (l) is from about 15% to about 99% by weight of the total solution (preferably from about 30% to about 70%); more preferably The oleic acid is present in an amount from about 40% to about 65%), and (2) is present in an amount of from about 0% to about 12%, preferably about 10% by weight of the total solution. A mixture of ethanol or propylene glycol or a mixture thereof. In a preferred embodiment of the invention, the solution is encapsulated into a soft, flexible gelatin capsule (SEC), or a hard gelatin capsule, and the solution may also contain a total of O:\106\106749.DOC -152- 1292752 The weight of the solution is present in an amount from about 0. 01% to about 0.08% (preferably from about 0. 01% to about 0. 05% by weight of the total solution). Antioxidant: (preferably ΒΗΤ (butylated hydroxy benzene)). Examples of such compositions and methods for their preparation are provided below. Ingredient% by weight Lunafifene (free base) 20 Ethanol (USP, 200 standard strength) 10 Polyoxyl 35 castor oil (Cremophor® EL) 5 Oleic acid, 6321, NF 65 Butylated hydroxytoluene (BHT), NF 0.01 Preparation of the above composition: The mixed water tank was purged with nitrogen. In the tank, oleic acid (649·9 g) and yeast (1 g) were mixed. The mixture was warmed to about m (mi) and held at this temperature. Butylated hydroxytoluene (01 g) was charged to the tank and mixed until the solution was clear. Lawnerafil (200 g) was slowly loaded into the tank and mixed until the solution was clear. Polyoxyl 35 castor oil (50 g) was added to the tank and mixed. The heating was interrupted and the solution was allowed to cool to ambient temperature (20-3 0 ° C). The resulting solution was filled into a soft and flexible capsule (0.5 g solution/SEC) to give ι 〇〇 特 纳 纳 纳 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / Philippine / seC dose. Lawnerife (free test) 2 〇 ethanol (USP, 200 standard strength) 1 〇 polyoxy 35 castor oil (Cremophor® EL) j〇O: \106\106749.DOC -153 . 1292752 oleic acid, 6321, NF 6 〇butylated hydroxy benzene (ΒΗΤ), NF 0.01 Preparation of the above composition··

以氮氣吹掃混合水槽。在該槽中混合油酸(599.9克)和乙 醇(100克)。將該混合物加溫至大約33°C (29-37°C ),並保持 在該溫度下。將丁基化之羥基曱苯(01克)裝入該槽中,並 混合直到該溶液澄清為止。將律特納菲(200克)慢慢地裝入 該槽中,並混合直到該溶液澄清為止。在該槽中加入多氧 基35蓖麻油(100克)並混合之。中斷加熱並容許該溶液冷卻 至周圍溫度(20-30°C )。將所得的溶液填裝至軟而有彈性之 膠囊(〇·5克溶液/SEC)中,得到1〇〇毫克律特納菲/SEC的劑 量’或是1.0克/SEC,得到200毫克律特納菲/SEC的劑量。 包含律特納菲和式I化合物之較佳單一劑量形式的實 例’揭示於美國專利申請案第08/754,39〇號,於1996年u 月 21 日以 Lipari,L.A. Al-Razzak,S. Ghosh和 R· Gao之名提 出申w,名叫Pharmaceutical Composition,將其合併於此 以作為參考。 包含律特納菲和式〗化合物之單一劑量形式的較佳組合 物包括(a)按總溶液之重量計,以從約1%到約(較佳 的是從約5%到約25%)之含量存在的律特㈣,和按總溶液 之重里片’以從約1%到約5〇%(較佳的是從約州到約⑽%) 3里存在的式I化合物的混合物,與(b)按總溶液之重量計, 乂大、勺10/〇 3里存在之聚氧基35蓖麻油的溶液,在藥學上 可接受有機溶劑中,其包括⑴按總溶液之重量計,以從約 -154-Purge the mixing tank with nitrogen. Oleic acid (599.9 g) and ethanol (100 g) were mixed in the tank. The mixture was warmed to about 33 ° C (29-37 ° C) and maintained at this temperature. Butylated hydroxyindole (01 g) was charged to the tank and mixed until the solution was clear. Lawnerafil (200 g) was slowly loaded into the tank and mixed until the solution was clear. Polyoxyl 35 castor oil (100 g) was added to the tank and mixed. The heating was interrupted and the solution was allowed to cool to ambient temperature (20-30 ° C). The resulting solution was filled into a soft and flexible capsule (〇·5 g solution/SEC) to give a dose of 1 gram of law Tenapee/SEC or '1.0 g/SEC to give 200 mg Nafie/SEC dose. An example of a preferred single dosage form comprising a compound of the genital phenanthrene and a compound of the formula I is disclosed in U.S. Patent Application Serial No. 08/754,39, filed on May 21, 1996, to Lipari, LA Al-Razzak, S. The name of Ghosh and R. Gao is called Shen, called Pharmaceutical Composition, which is incorporated herein by reference. Preferred compositions comprising a single dosage form of a law of tumfene and a formula include (a) from about 1% to about (preferably from about 5% to about 25%) by weight of the total solution. a mixture of the content of the formula (IV), and a mixture of the compound of the formula I in a weight ratio of from about 1% to about 5% (preferably from about 约 to about (10)%) of the total solution (b) a solution of polyoxyl 35 castor oil present in the mashed/spooned 10/〇3, based on the weight of the total solution, in a pharmaceutically acceptable organic solvent, including (1) by weight of the total solution, From about -154-

O:\106\106749.DOCO:\106\106749.DOC

1292752 10%到約8 8% (較佳的是從約40%到約65%)之含量存在的油 酸’與(ii)按總溶液之重量計,以大約10%含量存在的乙醇 的混合物。在本發明最佳的具體實施例中,將該溶液包膠 到軟而有彈性之明膠膠囊(SEC),或硬明膠膠囊中,且該溶 液也可以包含按總溶液之重量計,以從約〇 〇1%到約〇.〇8〇/〇 (較佳的是按總溶液之重量計,從約〇·〇丨%到約〇 之含 量存在的抗氧化劑(較佳的是BHT (丁基化之羥基曱苯》。 在下文中提供這類組合物之實例及其製備方法。 成份 重量% 律特納菲(自由鹼) 5 實例2B之化合物(自由鹼) 30 乙醇(USP,200標準強度) 10 多氧基3 5蓖麻油(Cremophor® EL) 10 油酸,6321,NF 45 丁基化之羥基曱苯(BHT),NF 0.01 成份 重量% 律特納菲(自由鹼) 15 實例2B之化合物(自由鹼) 15 乙醇(USP,200標準強度) 10 多氧基35蓖麻油(Cremophor® EL) 10 油酸,6321,NF 50 丁基化之羥基曱苯(BHT),NF 0.01 O:\106\106749.DOC -155- 1292752 成份 重量% 律特納菲(自由鹼) 15 實例2B之化合物(自由鹼) 15 乙醇(USP,200標準強度) 10 多氧基35蓖麻油(Cremophor® EL) 5 油酸,6321,NF 55 丁基化之羥基甲苯(BHT),NF 0.01 上述組合物之製備: 以氮氣吹掃混合水槽。在該槽中混合油酸(549.9克)和乙 醇(100克)。將丁基化之羥基曱苯((^丨克)裝入該槽中,並混 合直到該溶液澄清為止。將律特納菲(丨5 〇克)慢慢地裝入該 槽中,並混合直到該溶液澄清為止。將實例2B之化合物(15〇 克)慢慢地裝入該槽中,並混合直到該溶液澄清為止。在該 槽中加入多氧基3 5蓖麻油(1 〇 〇克)並混合之。將所得的溶液 填裝至軟而有彈性之膠囊〇·〇克溶液/SEC)中,得到律特納 菲和實例2B之化合物各150毫克/SEC的劑量。 成份 重量% 律特納菲(自由驗) 15 實例2B之化合物(自由鹼) 5 乙醇(USP,200標準強度) 10 多氧基35蓖麻油(Cremophor® EL) 10 油酸,6321,NF 60 丁基化之羥基曱苯(BHT),NF 0.01 以單一或分開之劑量投予人類或其他哺乳動物宿奋 &lt;律 O:\106\106749.DOC -156· I292752 特納菲(與本發明化合物一起投予)的每日總劑量,可以是例 如··從約0.001到300毫克/每公斤體重每天的含量,較常見 的疋0 · 1到1 〇毫克律特納菲。劑量單位組合物可含有這類劑 星的幾分之一,以便製造每曰劑量。 在含有律特納菲和實例2B化合物之混合物的組合物中, 律特納菲和實例23化合物之比例(重量/重量)的範圍,是從 約1:16到約5:1 (較佳的是從約ι:6到約3:丨)之間。 在其他最佳的組合中,將本發明化合物與律特納菲及一 或多個反轉錄酶抑制劑(較佳的是一或多個選自包括AZT (易得+疋)、ddl (迪達諾定)、ddC (沙西塔必)、d4T (斯塔 4疋)和3TC (拉米謬定)的化合物)一起投予。這類組合對於 抑制或治療人類的HIV感染是特別有用的。當在這類組合中 使用時,本發明化合物和律特納菲,以及一或多個反轉錄 酉母抑制劑’可以分開製劑之形式,以相同或不同的次數來 投予,或是將它們調製成含有兩或多個化合物的組合物。 特佳的冶療組合包括與律特納菲、αζτ和3tc混合在一起的 式1化合物(尤其是實例2B之化合物)。 將會瞭解到可與本發明化合物混合,用來抑制、治療或 預防剔㈤贿感染的製劑,並不限於上文列舉的那些, 但是原則上包含任何可用來治療或預防MDS或HIV感染的 ▲混合投藥時’可將治療劑調製成以相同次數或不同 數給予的分開組合物,或是以單—組合物之形式來給予试 治療劑。1292752 10% to about 8 8% (preferably from about 40% to about 65%) in the presence of oleic acid' and (ii) a mixture of ethanol present at a level of about 10% by weight of the total solution . In a preferred embodiment of the invention, the solution is encapsulated into a soft, flexible gelatin capsule (SEC), or a hard gelatin capsule, and the solution may also comprise, by weight of the total solution, from about 〇〇1% to about 〇.〇8〇/〇 (preferably, based on the weight of the total solution, from about 〇·〇丨% to about 〇, the antioxidant is present (preferably BHT (butyl) Examples of such compositions and methods for their preparation are provided below. Ingredient % by weight Lunfifin (free base) 5 Example 2B compound (free base) 30 Ethanol (USP, 200 standard strength) 10 Polyoxy 3 5 castor oil (Cremophor® EL) 10 Oleic acid, 6321, NF 45 Butylated hydroxy benzene (BHT), NF 0.01 Ingredient % Lutneufi (free base) 15 Example 2B compound (Free base) 15 Ethanol (USP, 200 standard strength) 10 Polyoxyl 35 castor oil (Cremophor® EL) 10 Oleic acid, 6321, NF 50 Butylated hydroxy benzene (BHT), NF 0.01 O: \106 \106749.DOC -155- 1292752 Ingredient Weight % Lunafifi (free base) 15 Examples 2B compound (free base) 15 ethanol (USP, 200 standard strength) 10 polyoxyl 35 castor oil (Cremophor® EL) 5 oleic acid, 6321, NF 55 butylated hydroxytoluene (BHT), NF 0.01 combination Preparation of the mixture: Purge the mixing tank with nitrogen. Mix oleic acid (549.9 g) and ethanol (100 g) in the tank. Put the butylated hydroxy benzene ((丨克) into the tank, and Mix until the solution is clear. Lawnerafil (丨5 gram) is slowly charged into the tank and mixed until the solution is clear. The compound of Example 2B (15 gram) is slowly loaded. In the tank, and mix until the solution is clear. Add polyoxy 3 5 castor oil (1 gram) to the tank and mix it. Fill the resulting solution into a soft and flexible capsule 〇·〇 In grams of solution / SEC), a dose of 150 mg / SEC of each of the compound of the law of the phenanthrene and the compound of Example 2B was obtained. Ingredient % by weight of the ruthenium phenanthrene (free test) 15 Example 2B of the compound (free base) 5 ethanol (USP, 200 standard strength) 10 polyoxyl 35 castor oil (Cremophor® EL) 10 oil , 6321, NF 60 Butylated hydroxyindole (BHT), NF 0.01 is administered to humans or other mammals in a single or separate dose. *O:\106\106749.DOC -156· I292752 Turner The total daily dose of phenanthrene (administered with the compound of the present invention) may be, for example, from about 0.001 to 300 mg per kg of body weight per day, the more common 疋 0 · 1 to 1 〇 mg of law Tenaf . Dosage unit compositions can contain a fraction of the dosage of such agents to produce a dosage per amp. In the composition comprising a mixture of the law of tertnaphene and the compound of Example 2B, the ratio of the compound of the law of the Tenerife and the compound of Example 23 (weight/weight) ranges from about 1:16 to about 5:1 (preferably It is between about ι:6 and about 3:丨). In other preferred combinations, the compounds of the invention are combined with a tertnaphene and one or more reverse transcriptase inhibitors (preferably one or more selected from the group consisting of AZT (easy to get 疋), ddl (di Danodin), ddC (Shasita), d4T (Star 4) and 3TC (Lamidine) are administered together. Such combinations are particularly useful for inhibiting or treating HIV infection in humans. When used in such combinations, the compound of the invention and the law of tumnafe, and one or more reverse transcriptional apron inhibitors' may be administered in the form of separate formulations, administered in the same or different times, or they may be administered It is prepared into a composition containing two or more compounds. A particularly preferred combination of treatments comprises a compound of formula 1 (particularly the compound of Example 2B) mixed with tertnafi, αζτ and 3tc. Formulations which can be combined with the compounds of the present invention for inhibiting, treating or preventing tick infections are not limited to those listed above, but in principle include any which can be used to treat or prevent MDS or HIV infection. When administered in combination, the therapeutic agent can be formulated into separate compositions administered in the same number or different numbers, or the test therapeutic agent can be administered in the form of a mono-composition.

O:\106\106749.DOC -157 · 1292752O:\106\106749.DOC -157 · 1292752

前文是本發明的主I 明,並未企圖將本發明限制在 已揭不之化合物中。人 ^ 化和改轡勺人—止圖將對熟諳此藝者而言’明顯的變 利1 + 13本發明的範圍和十生質内,在附錄的申噴專 利乾圍中將其加以定義。 曱°月專The foregoing is a subject of the invention and is not intended to limit the invention to the disclosed compounds. The person and the person who changed the spoon--the map will be obvious to the artist. The obvious scope of the invention is 1 + 13 within the scope of the invention and within the genus, it is defined in the appendix of the patent application .曱°月专

O:\106\106749.DOC -158-O:\106\106749.DOC -158-

Claims (1)

96. -· ^96. -· ^ 中文申請專利範圍替換本(96年9月) 十、申請專利範圍: 1. 一種下式之化合物:Chinese patent application scope replacement (September 96) X. Patent application scope: 1. A compound of the following formula: HO-C .1 其中113為Cu烷基;且HO-C .1 wherein 113 is a Cu alkyl group; R5為 '(CH2)n」,其中n為1,2或3,X為-Ο-或-S-,且Y為 •CH2-、-0-、-S-或-N(R6)-,其中 R6為氫或 Cw烷基; 或其鹽。 2. 根據申請專利範圍第1項之化合物,其為2S-(1-四氫嘧啶-2-酮基)-3-甲基丁酸,或其鹽。 3. 一種製備(28,38,58)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基 -5-胺基-1,6-二苯基己烷或其鹽的方法,其包括使 (2S,3S,5S)-2-(2,6-二甲基苯氧乙醯基)胺基-3-羥基-5-第三-丁氧羰基胺基-1,6-二苯基己烷在二氯曱烷中與三氟乙酸反 應,在乙腈中與含水氫氯酸反應,或是在乙酸中與含水氫氯 酸反應。 4. 一種製備下式化合物或其鹽的方法:R5 is '(CH2)n", where n is 1, 2 or 3, X is -Ο- or -S-, and Y is •CH2-, -0-, -S- or -N(R6)-, Wherein R6 is hydrogen or Cw alkyl; or a salt thereof. 2. A compound according to the first aspect of the patent application, which is 2S-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid, or a salt thereof. 3. Preparation of (28,38,58)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane or A method of the salt thereof, which comprises (2S,3S,5S)-2-(2,6-dimethylphenoxyethyl)amino-3-hydroxy-5-tris-butoxycarbonylamino- 1,6-Diphenylhexane is reacted with trifluoroacetic acid in dichloromethane, with aqueous hydrochloric acid in acetonitrile or with aqueous hydrochloric acid in acetic acid. 4. A method of preparing a compound of the formula: or a salt thereof: 〇 «3 其中R3為Ci_6烷基,且Q為釋離基,該方法包括 (a)使下式之化合物或其鹽: 106749-960929.doc ,.1292752〇 «3 wherein R3 is Ci_6 alkyl and Q is a cleavage group, the method comprising (a) a compound of the formula: or a salt thereof: 106749-960929.doc, .1292752 co2h H2N 其中R3如同上述之定義,與下式化合物反應: CfeC=NCo2h H2N wherein R3 is as defined above and reacts with a compound of the formula: CfeC=N QQ 其中Q如同上述之定義;或 (b)使下式之化合物或其鹽: RM0-&lt;0)C-HNWherein Q is as defined above; or (b) a compound of the formula: or a salt thereof: RM0-&lt;0)C-HN C02H 其中R3如同上述之定義,且R”為苯基、Cm烷基取代之苯基、 鹵素取代之苯基、硝基取代之苯基或三氟甲基苯基,與下式 化合物反應: 其中Q如同上述之定義。 5·根據申請專利範圍第4項之方法,其中心為(::“烷基而q為氯 6.根據申請專利範圍第4項之方法,其中&amp;為異丙基而q為氯 106749-960929.docC02H wherein R3 is as defined above, and R" is phenyl, Cm alkyl substituted phenyl, halogen substituted phenyl, nitro substituted phenyl or trifluoromethylphenyl, reacted with a compound of the formula: Q is as defined above. 5. According to the method of claim 4, the center is (:: "alkyl and q is chlorine. 6. According to the method of claim 4, wherein &amp; is isopropyl And q is chlorine 106749-960929.doc
TW94141039A 1996-11-21 1997-02-13 Retroviral protease inhibiting compounds TWI292752B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/753,201 US5914332A (en) 1995-12-13 1996-11-21 Retroviral protease inhibiting compounds

Publications (2)

Publication Number Publication Date
TW200611691A TW200611691A (en) 2006-04-16
TWI292752B true TWI292752B (en) 2008-01-21

Family

ID=25029611

Family Applications (4)

Application Number Title Priority Date Filing Date
TW89115157A TWI259178B (en) 1996-11-21 1997-02-13 Retroviral protease inhibiting compounds
TW96136647A TWI330638B (en) 1996-11-21 1997-02-13 Process for the preparation of retroviral protease inhibiting compounds
TW86101654A TW494097B (en) 1996-11-21 1997-02-13 Retroviral protease inhibiting compounds
TW94141039A TWI292752B (en) 1996-11-21 1997-02-13 Retroviral protease inhibiting compounds

Family Applications Before (3)

Application Number Title Priority Date Filing Date
TW89115157A TWI259178B (en) 1996-11-21 1997-02-13 Retroviral protease inhibiting compounds
TW96136647A TWI330638B (en) 1996-11-21 1997-02-13 Process for the preparation of retroviral protease inhibiting compounds
TW86101654A TW494097B (en) 1996-11-21 1997-02-13 Retroviral protease inhibiting compounds

Country Status (2)

Country Link
BR (1) BR1100397A (en)
TW (4) TWI259178B (en)

Also Published As

Publication number Publication date
TWI259178B (en) 2006-08-01
TWI330638B (en) 2010-09-21
TW494097B (en) 2002-07-11
BR1100397A (en) 2000-04-11
TW200611691A (en) 2006-04-16
TW200817349A (en) 2008-04-16

Similar Documents

Publication Publication Date Title
JP5597689B2 (en) Retroviral protease inhibitor compounds
TWI292752B (en) Retroviral protease inhibiting compounds
CA2238977A1 (en) Retroviral protease inhibiting compounds
KR100220876B1 (en) Anti-viral compounds
AU2007231810B2 (en) Retroviral protease inhibiting compounds
MXPA98004741A (en) Retrovira protease inhibitors compounds
MXPA98004734A (en) Retrovi protease inhibitor compounds

Legal Events

Date Code Title Description
MK4A Expiration of patent term of an invention patent