TW396161B - Analogs of thymosin <alpha>1 - Google Patents
Analogs of thymosin <alpha>1 Download PDFInfo
- Publication number
- TW396161B TW396161B TW083100771A TW83100771A TW396161B TW 396161 B TW396161 B TW 396161B TW 083100771 A TW083100771 A TW 083100771A TW 83100771 A TW83100771 A TW 83100771A TW 396161 B TW396161 B TW 396161B
- Authority
- TW
- Taiwan
- Prior art keywords
- glu
- lys
- val
- thr
- ser
- Prior art date
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- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 title description 13
- 108010046075 Thymosin Proteins 0.000 title description 12
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- OVLIFGQSBSNGHY-KKHAAJSZSA-N Val-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N)O OVLIFGQSBSNGHY-KKHAAJSZSA-N 0.000 claims description 12
- KNZQGAUEYZJUSQ-ZLUOBGJFSA-N Ser-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)N KNZQGAUEYZJUSQ-ZLUOBGJFSA-N 0.000 claims description 11
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- C07K14/575—Hormones
- C07K14/57581—Thymosin; Related peptides
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- A61P37/04—Immunostimulants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
第83100771號專利申請案 A7 中文說明書修正頁(86年12月)B7 五、發明说明()
86.12.2#® 充 經濟部中央樣準局員工消费合作社印製 如賁例1所述在Hamilton PRP-1管柱純化部份此粗肽( 0.150克)K生成46.2毫克焦麩胺釀脫乙睡基胸腺素^^ 。該物質經分析性高效液相層析經發現很均質。胺基分析 结果:24小時水解;Asp, 4.00 (4); Thr, 3.04 (3); Ser, 2.69 (3I;IGIIIIII I (7); Ala, 2.90 (3); Val, 1.80 (3); lie, 1.00 (1); Leu, I.00 (1); Lys, 3.90 (4).經 100 小時水解;Asp, 4.00 (4); Thr, 3.09 (3); Ser, 2.67 (3); Glu, 7.50 (7); Ala, 3.14 (3);
Val, 2.83 (3);IIle, 1.04 (iX^Leu, 1.08 (1); LyS, 4.05 (4)。 質譜儀分析结果顯示該呔具預期的分子量 MIT = 3,177.1; MHa* = 3,200.2(計算之分子量=3,177.4) Ο 實例5
Swiss-Webster小鼠分成五姐處理: 第I I :具內毒素的小鼠(K60毫克/公斤之E. ^〇1i 脂多釀內毒素注射之小鼠),其不纆處理。 第ϋ组:具內毒素的小鼠(Κ60毫克/公斤之R. 脂多醣内毒素注射之小鼠),其在投予内毒素後五分鐘、 二小時及四小時,分3次Κ100微克胸腺素’ cti-Nu醢胺 (Τβ :ι-Η1β-ΗΗ2)注射處理之。 ~ 第I组:具內毒素的小鼠(Κ 60毫克/公斤之E. r»〇n 脂多醣内毒素注射之小鼠),其在投予内毒素後五分鐘、 二小時及四小時*分3次Κ100微克胸腺素 cti-Καβ藤胺 (Τ« :ι-Η1β-ΝΗ2)注射處理之。 -17- 本紙張尺度適用中國國家標準(CNS > λ!規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) 、1Τ Μ 覜濟部中央楳準局貝工消费合作社印製 A6 B6 五、發明説明(1 ) 瑭明费長 葙萌筋18 本發明涉及有W臃腺素Cti之新合成的化合物及其新穎 的合成方法。 生前坊g銳明 臃腺素為衍生自胸腺之多肽免疫修飾因子。實驗証明脾 腺素可誘導T-细胞分化並增強免疫功能。 名為臃腺素部份5之自牛臃腺萃取物•部份纯化的成份 含有一些包括命名為胸腺素αι的成份之胸腺的肽產物。 胸腺素最初分_自胸腺素部份5並已經定序及化學 合成(美画專利號碼 4,079,127、4,148,788與 4,855 307 )° 小鼠、牛與人的脾腺索序列非常類似。脾腺素αι 有28個胺基酸並經証實具調節免疫糸統的活性。膊腺素ct i的免疫活性包括刺激cx -與7 -干擾素的產生,增進巨 噬细胞移動抑制因子的產生、誘導表琨T-妞胞標識物,包 括細胞間素-2受Μ與改菩幫助者T-細胞活性。 本技藝中之可表現類似天然膊腺產物功能之新合成的化 合物。仍然需要是穩定且易於合成的。 雄职摘酉 本發明有關具式(I )的化合物: X-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser- (I)
Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Z 本紙張尺度逋用肀ί國家標準(CNS)f4规格(210X297公釐) ..........Μ.............................................:::..........................裝.......................玎.....................線 (請先閩讀背面之注意事項再填窝本頁) 經濟部+*«準局貝工消费合作社印氟 A6 B6 五、發明説明(2 ) 其中該X為乙醢基或焦麩胺醢基*而Z為-NHfc、-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Aia-Glu-Asn-Pro-NH2 ' -Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-Gly-NHss或- Lys-Glu-Lys-Lys-Glu-Val-Val-GU- Glu-Aia-Glu-Asn其限制條件為,當X為焦麩胺醢 基時· Z 為 _ L y s - G 1 u - L y s - L y s - G 1 u - V a 1 - V a 1 - G 1 u - G 1 u-Ala-Glu-Asn ;而且當X為乙醢基時Z便非-Lys-GIu-Lys-Lys_Glu_Val-Val-Glu-Glu-Ala-Glu-Asn及其製法。 酧住亘播窨施例之說明 本發明之化合物有關脾腺素αχ且是可用Μ治療不同疾 病與回懕免疫系統調節物之指激的免疫糸統調節物。吾人 可用本發明之能賦予免疫力的化合物於兔疫剝奪及免疫Κ 抑的病人體内重姐免疫功能並治療免疫不足的疾病。 經發明之具上述式(I )的化合物特例之一為胸腺素ctt -Ν1β醢胺(序列辨識號碼:1)其中該X為乙酿基而Z為 。根據本發明之進一步的實例為胸腺素oti-Pro醢胺 (序列辨識號碍:2)其中該X為乙藤基而Z為-Lys-GU-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-Pro-NHa K 及脾腺索〇11-卩17釀胺(序列辨識號碼:3)其中該X為乙 醣基而 Z 為-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-AU-Glu-Asn-Gly-NH2 。本發明亦通用於焦麩胺醢基-脫 乙醢基-腌腺素〇^(序列辨識號碼:4) *其中該X為焦您 胺藤基而Z 為- Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu- Asn〇 -4- 本紙張尺度逋用令國家櫟準(0NS)甲4规格(210X297公*) ~ ~ ........................................................-..........................裝......................訂.....................線 {請先閲讀背面之注意事項再填窝本頁) B6 五、發明説明(5 ) 本發明亦包括根據上述式(I )之化合物的新穎中間產物 及前驅物。 中間產物與前驅物之實例包括具式(I)之化合物: Xi-Thr-Lys-Asp-Leu-NHa (II) 其中該 Χι 為1'111",116*'1'^,0111-116-1'[1「,561"-6111-116-Thr, Ser-Ser-Glu-Ile-Thr, Thr-Ser~Ser-Glu-Ile-Thr ♦ Asp-Thr-Ser-Ser-Glu-Ile-Thr» Val-Asp-Thr-Ser-Ser-G iu-Ile-Thr, Ala-Va1-Asp~Thr-Ser-Ser-Glu-I le-Thr» Ala-Ala-Val-Asp-Thr-Ser'Ser-Glu-Ile-Thr^ Asp'Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr,或 Ser^Asp-Ala-Ala*Val-AsP'Thr-Ser-Ser*Glu"I le~Thr * 具式(m )之化合物: X2"Ala"Glu*Asn-Pro-NH2 (III) 經濟部"央櫺準局貝工消费合作社印製 {請先閲讀背面之注意事項再填寫本頁) 其中該 X2 為 Glu, Glu-Glu, Val-Glu-GU, Val-Val-Glu-Glu, Glu-Val-Val-Glu-Glu> Lys-Glu-Val-Val-Glu-Glu ,Lys-Lys-Glu-Val-Val-Glu-Glu* Glu-Lys-Lys-Glu-Val~Val-Glu-Glu, Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu» Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val'Qlu-Glu, Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu» Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys'Glu-Val-Val-G1u-G 1 u, Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu~Lys-Lys-Glu-Val-Val-Glu-Glu, Glu-Ile-Thr-Thr-Lys-Asp-Leu- 本紙張尺度遑用中B國家標準(CNS)f 4规格(210X297公釐) A6 B6 經濟部中央樣準局員工消t合作社印製 五、發明説明(4 ) Lys-Glu-Lys-Lys-Glu-Val-Val-Glu'Glu* Ser-Glu-Ile* Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Ser-Ser*~Glu-Ile-Thr"Thp-Lys-Asp*Leu-Lys" Glu-Lys-Lys-Glu-Val-Val-Glu-Glu* Thr-Ser-Ser-Glu* Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys^Lys-Glu-Val-Val-Glu-Glu» Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys' AsP"Leu~Lys~Glu"Lys-Lys-Glu-Val-Val"Glu-Glu» Val-AsP"Thr-Ser"Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu*Lys~Lys'Glu*Val-Val-Glu-Glu» Ala-Val-Asp^Thr'* Ser*Ser"G1u-I 1e-Thr-Thr-Lys-Asp'Leu^Lys-G 1 u-Lys-Lys-Glu-Val-Val-Glu-Glu, Ala-Ala-Val-Asp^Thr*Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu~Val_Val-Cilu-GIu,或 Ser-Asp-AIa-AIa-Val-Asp-Thr~Ser"Ser-Glu~Ile-Thr-Thr-Lys-AsP"Leu"Lys~Glu-Lys~Lys-Glu-Val-Val-Glu-Glu,與具式(IV)之化合物。 Xa-Aal-Glu-Asn-Gly-NHz (IV) 其中該 Xa為Gul, Glu-Glu, Va卜Glu-GIu, Va卜VahGlu-Glu» Glu-Val-Val-Glu-Glu, Lys-Glu-Val*Val-Glu-Glu ,Lys-Lys-Glu-Val-Val-Glu-Glu, Glu-Lys-Lys-Glu-Val-Val*Glu-Glu, Lys-Glu-Lys-Lys-GIu-Val-Val-GIu* Glu» Leu-Lys-Glu-Lys-Lys-Glu*Val-Val-Glu-Glu» Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu'Glu* Lys- ........................................................:...........................裝......................訂.....................線 <請先閲讀背面之注意事項再填寫本頁> 拿紙張尺度遑用中國家樣準(CNS)甲4规格(210X297公*) A6 B6 經濟部中央樣攀馬貝工消费合作社印製 五、發明説明(5 ) Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Thr-Lys*Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val*Val-GIu**Glu, Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys^Lys-G lu-Va 1 - Va 1 - Glu-Glu, Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-G1u-Lys-Lys-G 1 α-Va 1 - Va 1 -Glu-Glu» Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp*Leu-Lys* Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Thr-Ser-Ser-Glu-Ile-Thr-Thp-Lys-Asp-Leu-Lys-Glu-Lys-Lys-G lu-Va 1 -Val-Glu-GIu» Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys· Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu* Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu, Ala-Val-Asp-Thr-Ser-Sep-Glu-Ile-Thr-Thr-Lys^Asp-Leu-Lys-Clu-Lys-Lys-Glu-Val-Val-Glu-Glu> Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp*Leu-Lys-Glu-Lys-Lys-Glu-Val~Val*Glu-Glu, Asp-AIa-Ala->Val-Asp*Thr-Ser" Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu_Glu,或 Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser - Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys'-Glu-Lys-Lys-Glu'Val-Val-Glu-Glu °本發明之化合物*中間產物與前驅物,此處合稱為胸腺 素肽,而且包括類似物及脾腺素CCi之衍生物,可由任何 -7- ...........................................................................裝.......................玎....................•.線 <請先閲讀背面之注意事項再填寫本頁> 本紙張尺度遑用t覼國家揲準(CNS)f4规格(210x297公釐> A6 B6 經濟部+央楳準局貝工消費合作社印裂 五、發明説明(6 ) 通合的肽合成方法供應。此類化合物K固相肽合成法合成 較佳且最好是在4-甲基二苯基甲胺樹脂上行固相合成。 合成後可用通當方法將肽由樹賭切斷,例如*以酸解。 諸如氫氟酸與三氟甲烷磺酸等酸皆通合。使用三氟甲烷磺 (CF3S〇3H)酸最通合。較佳條件為在三氟乙酸條件下將經 保»之肽樹腊與甲苯醚(約5¾至約25X)及硫甲苯醚(約 5X至約25X)溶液混合,並W約5X至約10X三氟甲烷磺酸 (CF3S〇3H)處理Μ酸解。所用之三氟甲烷磺醭為溶於三氣 乙酸之50S!溶液且與欲切斷之含肽樹脂的量約等比例最佳 〇 本發明Κ下述實例做進一步說明,但非Κ此為限° 實例 實例1 Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu_Ile- Thr-Thr-Lys-Asp-Leu-NH2 胸腺素 a x-Nu醣胺 將4-甲基二苯基甲胺樹脂(2.01克*0.55¾莫耳/克) 放入肽合成焼瓶中並以三次40奄升二氯甲烷洗過。然後以 40奄升ΙΟΧ之三乙胺中和樹脂1分鐘,再一次分鐘’然 後Μ二氲甲烷洗三次。經顯示中和過的樹腊對寧海特寧試 驗有強烈正反應。然後,在含溶於二氮甲烷之奄莫耳 Ν,Ν,-二環己碳二亞胺(DCC,0.618克)條件下以3.0毫 莫耳第三-丁氧羰基-L-硫安酸(Boc-Leu,0.784克)偁 合150分鐮。繼績Μ下述固相合成程序進行合成。[步驟 ..................................................................if..........................裝.......................玎.....................線 {請先閱讀背面之注意事項再填寫本頁> 本紙張尺度逋用中困Η家櫺準(CNS)甲4規格(210X297公釐) 經濟部t夹櫺準局貝工消费合作社印製 B6_' 五、發明説明(7 ) 1至11代表全部合成週期所霈之處理,其中之胺基酸殘基 乃加在附於樹腊之成長中的肽上]: 1) 先以溶於二氛甲烷之50S;三氟乙酸洗之, 2) 在50X三氣乙酸中携拌30分鐘, 3) 以二氛甲烷洗三次, 4) 以溶於二氣甲烷之10X三乙胺預洗遇, 5) 於105K三乙胺中攪拌10分鐘, 6) K二氯甲烷洗三次* 7) 對樹腊行寧海特寧試驗(應為強烈正反應)* 8) Μ ·容於二氯甲烷中之0.9*克Boc-Asp(OBzI) ( 3.0奄 萁耳)及0.618克DCC (3.0¾萁耳)溶液攪拌樹脂 120分艟, 9) Μ溶於二氢甲烷之50X異丙酵洗2次* 10) Κ二氮甲烷洗3次* Π)試驗寧海特寧反應。若為負,行下一合成遇期。若 為正,重播步嫌8至11。 固相肽合成遇期,在每一週期步驟8 ,毎次依序地重覆 使用一個下列胺基酸衍生物直至所要的胺基酸序列為止: Boc-Lys(ClZ), (1.244克);Boc-Thr(Bzl), (0.928克); Boc-Thr(Bzl), (0.928克);Boc-Ile, (0.720克Boc-Glu(OBzl), (1.01 克)ί Boc-Ser(Bzl), (0.886 克);Boc-Ser(Bzl), (0.886克);Boc-Thr(Bzl), (0.928克 Boc-Asp(OBzl), (0.970克);Boc-Val, (0·652克); Boc-Ala, (0.568克);Boc-Ala, (0.568克);Boc-Asp ί請先閲讀背面之注意事項再填寫本頁》 本紙張尺度逋用t鼸鼸家樣準(CNS)甲4规格(210X297公釐) B6 經濟部f央樣準局貝工消费合作社印製 五、發明説明(8 ) (OBzl); (0.970克);Boc-Ser(Bzl), (0.886克);和 Acetic Acid (0.180克)。所得之經保護的乙酸基-十六肽 樹腊,Ac-SerUzD-AspCOBzD-'Ala-Ala-Val-AsptOBzl) -Thr(Bzl)-Ser(Bzl)-Ser(Bzl)-Glu(〇Bzl)-I1e-fhr(Bz1) -Thr(Bzl)-Lys(ClZ)-Asp(OBzl)-Leu-MBHA-樹脂重量為 4.25 克。 將部份此烴保護之十六肤樹脂(1.08克)與2毫升甲苯 醚混合並以10邂升液態HF於〇*C攪拌45分鏟。《量的酸在 0°真空中蒸發除去並K乙醚洗殘渣。肽原料以50奄升· 2S5乙酸铵萃取並WSephadex G-10管柱(0.1荑耳濃度乙 酸)去鼸》冷凍乾嫌呔波峰部份產生0.204克之粗肽釀肢 〇 部份粗肽(100奄克)以Hamilton PRP-1管柱(2.15X 25公分,10微米)銪化並以溶於〇.〇 35奠耳瀟度磷酸鉀, 出5之經過緵衝的53.5克/升異丙醇溶劑洗脫之(流速= 5毫升/分;M227毫微米測定)。收集含鈍肽的部份· 於Sephadex G-10管柱去鹽並冷凍乾燥K產生26鼉克胸腺 素αι-Ν13釀胺。所得物質經高效毛细罨泳後發現同質性 很高。胺基酸分析結果:Asp, 3.00 (3); Thr,2.68 (3); Ser, 2.67 (3); Glu, 1.04 (1); Ala, 1.88 (2); Val, 0.97 (1); lie, 1.01 (1); Leu, 1.02 (1); Les, 1.00 (1)。質譜儀分析结果顯示該化合物具預期的分子 量,MH* = 1,693.8, MNa* = l,716.9(經計算之分子最= 1693.8)。 -10- 本纸張尺度遑用十_钃家樣準(CNS)甲4规格(210X297公釐) {請先閲讀背面之注意事項再填窝本頁) A6 B6 經濟部中央櫺準爲貝工消费合作社印製 五、發明説明(9 ) 實例2 Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile- Thr-Thr~Lys~Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val- Glu-Glu-Ala-Glu-Asn-Pro-NHz 脾腺素 a /Pro醣胺 將4-甲基二苯基甲胺樹脂(1.0克,0.55«荑耳/克) 放入合成肽的焼瓶並以三次20蠹升二氣甲烷洗過。然後Μ 10S;三乙胺中和樹脂1分鏟,再一次10分鐘,再以二氯甲 烷洗三次。中和遇的樹脂對寧海特寧試驗頭琨強烈正反應 。然後在溶於二氣甲烷之1 . 5奄荑耳DCC ( 0 . 309克)條件 下以1 . 5毫其耳Boc-Pro ( 0. 322克)偁合120分鐮。如實 例1所概述者以固相肽合成通期繼績進行合成*在每一通 期步驟8每次依序地使用一儸下列胺基酸衍生物,直至在 樹脂上姐成所要的胺基酸序列為止:B〇c-Asn » (0.348 克加0.405克Η0ΒΤ之二甲基甲麵肢溶液),Boc-GIu (OBzl) (0.506克),Boc-Ala(0.284克),Boc-Glu(OBzl) (0.506克),Boc-Glu(0Bzl)(0.506克),Boc-Val (0.326 克),Boc-Val(0.326克),Boc-Glu(0Bzl)(0.506克), Boc-Lys(ClZ) (0.622克),Boc-Lys(ClZ) (0.622克), Boc-Glu(OBzl) (0.506克),Boa-Lys(ClZ) (0.622克), B 〇 c - L e u (0 . 3 7 4 克),B 〇 c - A s p (0 B z I) (0 . 4 8 6 克),B 〇 c-Lys(CU)(0.602完);Boc-Thr(Bzl)(〇.464克),Boc-Thr (Bzl)(0.464克),Boc-Ile(0.360克),Boc-Glu(OBzl) (0.506克),Boc-Ser(Bzi)(0.443克),B〇c-Ser(8zi) -1卜 本紙張尺度逍用中國家樣準<CNS) T4规格(210X297公釐> ' .........................................................!:..........................装......................訂.....................線 {請先閲讀背面之注意事項再填寫本頁) B6 五、發明説明(10 ) (〇·443克),Boc-Thr(Bzl)(0.464克),Boc-Asp(OBzI) (0.485克),Boc-Val(0.326克),Boc-Ala(0,284克), B o c - A 1 a (0 · 2 8 4 克),B o c - A s p (0 B 2: 1 ) (0 . 4 8 5 克),B o c - S e r (Bzl)(0.443克)及 Acetic Acid(0.090克)與乙酸所得之 經保護的乙醢基-二十九呔樹脂Ac-Ser(Bzl)-Asp(0Bzl) -Ala-Ala-Val-Asp(OBzl)-Thr(Bzl)-Ser(Bzl)-Ser(BEl) -Glu(OBzl)-Ile-Thr(Bzl)-Thr(Bzl)-Lys(ClZ)-Asp (OBzl)-Leu-Lys(C1Z)-Glu(OBzl)-Lys (Clz)-Lys (C1Z)-Glu(OBzl)-Val~Val-Glu(0Bzl)-Glu(OBzl) - Ala-Glu (0821)-/^”卩”48}^-樹脂,重2.89克〇 切斷一部份上述烴保護的肽樹脂(0.9 95克)並如實例 1所述處理以得0.335克粗脚腺素cti-Pro-HIU 。如實例 1所述KHanilton PRP-1管柱姹化K產生51幸克脾腺素α 、-Pro醣胺。所得物質於分析性高效液相磨析與毛细霣泳 後纆發現相當均霣。胺*酸分析:24小時水解;Asp, 4.00 (4); Thr, 3.06 (3); Ser, 2.85 (3); Glu, 6.06 (6); Pro, 1.12 (1); Ala, 2.94 (3); Val, 1.88 (3);
Ile, 0.98 (1); Leu, 1.00 (1); Lys, 3.98 (4). 100 (請先閲讀背面之注意事項再填窝本頁> 經濟部+央櫟準局貝工消#合作社印製 hr hydrolysis; Asp, 4.00 (4); Thr, 2.69 (3); Ser, 2.12 (3); Glu, 6.17 (6); Pro, 1.04 (1); Ala, 3.01 (3); VaU 2.96 (3); lie, 1.08 (1); Leu, 1.08 (1); Lys, 4.12 (4)。質譜儀分析结果顯示該肽具預期的分子 量MH* = 3205.1 (經計算之分子躉= 3204.5)。 實例3 -12- 本纸張尺度遑用中鷗謳家樣準(CNS)甲4规格(210X 297公釐) A6 B6 經濟部t央揉準局貝工消#合作社印製 五、發明説明(11 ) Ac-Ser-Asp-Ala-Ala*Val-Asp-Thr-Ser_Ser-Glu-IIe- Thr-Thr-Lys-Asp~Leu-Lys-Glu-Lys-Lys-Glu*Val-Val- Glu-GIu-Ala-Glu-Asn-Gly-NH2 胸腺素 α i-Gly鼸胺 將4-甲基二苯基甲胺樹腊(1.0克,0.55«其耳/克) 放入合成肽的堍瓶並K三次20奄升二氣甲烷洗之。然後Μ 10Χ三乙胺中和樹脂1分鎗,再一次10分鐘,並以二氣甲 烷洗3次。中和後的樹腊對寧海特寧試驗顬現強烈正反應 。然後在溶於二氣甲垸之1.5奄莫耳DCC (0. 309克)條件 下Κ1.5笔莫耳Boc-Gly(0.26 3克)偁合120分鐘。如實 例1所概逑》K固相肽合成通期繼績進行合成,在每一週 期步驟8 ,每次依序地使用一涸下列胺基酸衍生物直至在 樹脂上姐成所要的肽為止:Boc-Asn , ( 0.348克加上 0.405克Η0ΒΤ之二甲基甲醢胺溶液),Boc- Glu(OBzl) (0.506克),Boc-Ala(0.284克),Boc-GIu (OBzi)(0.506 克),Boc-Glu(0Bzl)(0.506克),Boc-Val (0.326克), Boc-Val(0.326克),Boc-Glu(0Bzl)(0.506克克), Boc-Lys(C1Z)(0.622克),Boc-Lys(ClZ) (0.622克), &〇<:-01(1(0821)(0.506克),8〇<;-1^3((:1艺)(0.6 22克), B 〇 c - L e u (0.3 7 4 克),B 〇 c - A s p (0 B z 1 ) (0 . 4 8 5 克),B 〇 c - L y s (Czl)(0.622克),Boc-Thr(Bzl)(0.464克),Boc-Thr (Bzl) (0.464克),Boc-Ile(0.360克),Boc-Glu(OBzI) (0.506 克),Boc-Ser(Bzl)(0.443 克),Boc-Ser(B2:l) (0.443克),Boc-Thr(Bzl)(0.464克),Boc-Asp(OBzI) -13- 本纸張尺度遑用中國家楳準(CNS)甲4规格(210X2.97公釐) .........一.............................................Π..........................#.......................玎.....................& (請先《讀背面之注意事項再填窝本頁} 經濟#中央樣準局工消费合作杜印製 A6 _B6_ 五、發明説明(12 ) (0.485克),Boc-Val(0.326克),Boc-Ala(0.284克), B 〇 c - A 1 a (0 . 2 8 4 克),B 〇 c - A s ρ (0 B z 1 ) (0 . 4 8 5 克),B 〇 c - S e r (Bzl), (0.443克)及 Acetic Acid(0.090克)。所得之經保 護的乙醢基-二十九肽樹腊Ac-Ser(Bzl)-Asp(OBzl)-Ala -Ala-Val-Asp(OBzl)-Thr(Bzl)-Ser(Bzl)-Ser(Bzl) -Glu(OBzl)-Ile-Thr(Bzl)-Thr(Bzl)-Lys(ClZ)~Asp (OBzl)-Leu-Lys(C1Z)-Glu(OBzl)-Lys (Clz) - Lys (C1Z)-GIu(0Bzl)~Val~Val-Gla(0B2l)_Glu(0Bzl)-Ala-Glu (0821)43^-01^481^樹腊,重2.70克。 將部份上述經保護的肽樹脂(0.996克)混K2毫升甲 笨醚,2奄升硫甲苯継與6毫升三氣乙酸。攫拌之並加入 1 . 1毫升50¾ CF3S〇3H三»乙酸溶液並鑛攪拌35分鏟。然 後倒混合物人100鼉升乙継。以更多新鮮乙醚短暫清洗因 而形成之膠狀沈澱物。然後以50奄升30¾乙酸铵萃取肽物 霣繼之以20奄升水。蒸發萃取物總合量至較小艟稹*以 Sep ha dex G-10管柱去蘸(2. 6 X 85公分* 0. 1莫耳濡度 乙酸)並冷凍乾煉生成0.323克的粗二十九肽。 如實例1所述在Hamilton PUP-1管柱純化此粗肽之一部 份(0. 161克)以生成40.2¾克胸腺素ct i-Gly醢胺。該 物質經分析性高效液栢臛析後經發琨很均質。胺基酸分析 结果:經 24 小時水解;Asp, 4.00 (4); Thr>, 2.96 (3); Ser, 2.75 (3); Glu, 5.97 (6); Gly, 1.03 (1); Ala, 2.96 (3); Val, 1.84 (3); lie,. 1.05 (1); Leu, 1.04 (1); Lys, 3.96 (4),經 100小時水解;Asp, 4.00 U); -14- ..........................................................................ii..........................裝.......................玎.....................線 {誘先閲讀背面之注意事項再填窝本頁一 本紙張尺度遑用中國颶家棋準(CNS)甲4规格(210X297公釐) A6 B6 經濟部中央揉準局Λ工消t合作社印氣 五、發明説明(15 ) Thr, 3.00 (3); Ser, 2.41 (3); Glu, 6.1'8 (6); Gly, 1.03 (1); Ala, 2.87 (3); Val, 2.82 (3); lie, 1.06 (1); Leu, 1.05 (1); Lys, 3.79 (4)。質譜儀分 析结果顯示該肽具預期的分子量♦ ΜΗ * = 31 65.5 (計算之分 子量=3164.4)。 實例4 Glp-Ser~Asp~Ala~Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr~Lys~Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn 焦麩胺醢基-脫乙鼸基胸腺 將4-甲基二苯基甲胺樹脂(1.0克,〇.55奄萁耳/克) 放人合成肽的焼瓶並Μ三次20毫升二氯甲烷洗之。然後Μ 10¾三乙胺中和樹脂1分》,再一次10分鐘,並以二氰甲 烷洗3次。中和後的樹脂對寧海特寧試驗顧琨強烈正反懕 。然後在1.5毫莫耳DCC( 0.309克)條件下以1.5毫荑耳 第三-丁氧羰基-L-天冬胺酸/3-苯基醸( 0.485克)偁 合60分鏟。重複一次偁合反應以使樹脂對寧海持寧試驗呈 負反應。如實例1所概迷》以固相肽合成遇期繼鑛進行合 成,在每一遇期步明8 ,每次依序地使用一個下列胺基酸 衍生物直至在樹腊上姐成所要的肤為止:B〇C-GU(0Bzl) (0.506克),Boc-Ala(0.284克),Boc-Glu (0Bzl)(0.506 克),Boc-Glu(0Bzl)(0.506克),Boc-Va丨(0.326克), Boc-Val(0.326克),Boc-Glu(0Bzl)(0.506克),Boc-Lys (C1Z)(0.622克),Boc-Lys(ClZ)(〇.622克),Boc-GIu V -15* 本紙張尺度遍用tB B家*準(CNS) f 4规格(210X297公翁)~ ! ............................................."..........................装.......................玎.....................線 {請先閲讀背面之注意事項再填寫本頁> A6 B6 經濟部中央櫟準局貝工消费合作社印製 五、發明説明(U ) (OBzl)(0.506克),Boc-Lys(ClZ)(0.622克),Boc-Leu (0.374克),Boc-Asp(0Bzl)(0.485克),Boc-Lys(ClZ) (0.622克),Boc-Thr(Bzl)(0.464克),Boc-Thr (Bzi) (0.464克),Boc-Ile(0.360克),Boc-GU(OBzl) (0·506 克),Β ο c - S e r (Β ζ 1 ) (0.4 4 3 克),Β ο c - S e r* (Β ζ 1 ) (0 . 4 4 3 克 ),Boc-Thr(Bzl)(0.464克),Boc-Asp(OBzl) (0.485克 ),Boc-Val(0.326克),Boc-Ala(0.284克),Boc-Ala (0.284克)· Boc-Asp(OBzl) (0.485.克),Boc-Ser* (ΒζΠ, (0.443¾)¾ benzyloxycarbonyl-L- pyroglutamic acid(Z-Glp)(〇.395克)。與苄氧羰基-L-焦麩胺酸所得之 經保護的乙醢基二十九肽樹脂,Z-Glp-Ser (Bzl)-Asp (OB2I)- Ala-Ala-Val-Asp(〇Bzl)-Thr(Bzl)-Ser(Bzl)-Ser(B2l)-Glu(〇Bzl)-Ile-Thr(Bzl)-Thr(Bzl)-Lys(CIZ)-Asp(OBzl)-Leu-Lys(C1Z)-Glu(OBzl)-Lys (Clz)-Lys (C1Z) -Glu(0Bzl)-Val-Val-Glu(0Bzl)-Glu (OBzl)-Ala-GIu (0821)-為31>“8}^-1?63111)-〇821,重2.67克。 將部份上述経保護的肽樹腊(0.995克)混M2毫升甲 苯踺2.2毫升硫甲苯醚與6毫升三氟乙酸。攪拌之並加入 1.1毫升50¾ CF3S03H三黑乙酸溶液並Ί*攪拌35分鐘。然 後將痗合物倒入100 *升的乙醚。以更多新鮮乙醚短暫洗 因而形成之膠狀沈溅物。然後以50奄升4¾乙酸銨萃取肽物 爾,繼之 KSephadex G-10 管柱(2.6X85 公分,0.1 莫 耳濃度乙酸)去鹽,並冷凍乾燦K提供〇. 229克之粗二十 九肽。 -16- .衣紙張尺度逋用t国围家櫺準(CNS)甲4規格(210X297公釐) ........一...........................................................................裝.......................可.....................線 {請先《讀背面之注意事項再填寫本頁> 第83100771號專利申請案 A7 中文說明書修正頁(86年12月)B7 五、發明说明()
86.12.2#® 充 經濟部中央樣準局員工消费合作社印製 如賁例1所述在Hamilton PRP-1管柱純化部份此粗肽( 0.150克)K生成46.2毫克焦麩胺釀脫乙睡基胸腺素^^ 。該物質經分析性高效液相層析經發現很均質。胺基分析 结果:24小時水解;Asp, 4.00 (4); Thr, 3.04 (3); Ser, 2.69 (3I;IGIIIIII I (7); Ala, 2.90 (3); Val, 1.80 (3); lie, 1.00 (1); Leu, I.00 (1); Lys, 3.90 (4).經 100 小時水解;Asp, 4.00 (4); Thr, 3.09 (3); Ser, 2.67 (3); Glu, 7.50 (7); Ala, 3.14 (3);
Val, 2.83 (3);IIle, 1.04 (iX^Leu, 1.08 (1); LyS, 4.05 (4)。 質譜儀分析结果顯示該呔具預期的分子量 MIT = 3,177.1; MHa* = 3,200.2(計算之分子量=3,177.4) Ο 實例5
Swiss-Webster小鼠分成五姐處理: 第I I :具內毒素的小鼠(K60毫克/公斤之E. ^〇1i 脂多釀內毒素注射之小鼠),其不纆處理。 第ϋ组:具內毒素的小鼠(Κ60毫克/公斤之R. 脂多醣内毒素注射之小鼠),其在投予内毒素後五分鐘、 二小時及四小時,分3次Κ100微克胸腺素’ cti-Nu醢胺 (Τβ :ι-Η1β-ΗΗ2)注射處理之。 ~ 第I组:具內毒素的小鼠(Κ 60毫克/公斤之E. r»〇n 脂多醣内毒素注射之小鼠),其在投予内毒素後五分鐘、 二小時及四小時*分3次Κ100微克胸腺素 cti-Καβ藤胺 (Τ« :ι-Η1β-ΝΗ2)注射處理之。 -17- 本紙張尺度適用中國國家標準(CNS > λ!規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) 、1Τ Μ A6 B6 五、發明説明(16 ) 施予 致死蜊: 量類毒素後之小鼠存活率 0 24 48 72 4 5 小時 小時 小時 小時 天 天 内毒 素 10 4 3 3 3 3 60奄 克 / 公斤 内毒 素 10 5 4 4 4 4 60奄 克 / 公斤 加Tc Ϊ 1 -N: ιβ-ΝΗ 2 100 微 克 3 X 内毒 素 10 8 8 7 7 7 60奄 克 / . 公斤 加T a i -N: 1β-ΝΗ 2 100 微 克 3 X 内毒 素 8 8 8 8 8 8 60毫 克 / 公斤 加[G 1 p ]-, Γ α X 100 微 克 3 X 内毒 素 8 8 8 8 8 8 …................................................N! — ::裝.......................玎.....................線 (請先閲讀背面之注意事項再填窝本頁》 經濟部t央櫺準局员工消费合作社印製 60奄克/公斤 加 Τα i-GIy-NHa 100微克3x -18- 本紙張尺度逋用中_0«國家標準(CNS)甲4规格(210X297公釐) 經濟部中央標準局員工消费合作社印製 A6 B6_ 五、發明説明(17 ) 疼抓SR 16羌 (1) 一般資料: (i )申請者:WANG , SU-SUN (ii)發明名稱:脾腺素類似物 (m )序列數目:4 (iv )有闞住址: (A) 住址:ROTHWELL, FIGG, ERNST, AND KURZ, P.C. (B) 街:555 第 13街,NW SUITE 701E (C) 市:華盛頓 ⑻卅:DC (E) 醑:USA (F) 郵匾號碼:20004 (v )電臞可讀型式: (A) 媒賭型式:磁片 (B) 轚腰:IBM可相容型 (C) 搡作糸統:PC-D0S/MS-D0S (D) 軟趙:Patentin Release #1.0, #1.25版 (vi )目前申講者資料: (A) 申請人數目: (B) 建播日期·· (C) 分類: (vffi)律師/代理人資料: (A)姓名: -19- 本紙張尺度適用fa國家標準(CNS)甲4規格(210X297公釐) ...........-....................................................................裝......................訂 ..............線 (請先閱讀背面之注意事項再填寫本頁) S96161 經濟部t央標準局員工消f合作杜印製 A6 B6 五、發明説明(18 ) (B) 註冊號碼:31 , 414 (C) 參考/備審號碼:1 783-126A (ix)通訊資料: (A) 霣話:202-783-6040 (B) 傅真:202-783-6031 (2)序列辨設號碼:1資料: (i )序列特激: (A) 長度:16個胺基酸 (B) 聖式:胺基酸 (D) 相性:直線 (ii )分子型式:肽 (v )片段型式:N -蟠 (ix )待色: (A) 名/重黏:修飾位置 (B) 位置:1 (D)其他資料:/標示=乙醢基-(ix )特色 (A) 名/重點:修飾位置 (B) 位置:16 (D)其他資料:/檷示=-»胺 (X ί)序列說明:¥列辨識號碼:1 Ser Asp Ala Ala Val Asp Thr Ser Ser Glu lie Thr Thr Lys Asp Leu l 5 i〇 15 -20- ...........................................................i.......................裝......................訂.....................線 <請先閲讀背面之注意事項再坶寫本頁> 本紙張尺度適用t國國家楳準(CNS)甲4规格(210X297公釐) 398161 A6 B6 經濟部中央標準局員工消费合作社印製 五、發明説明(19) (2)序列辨設號碼:2資料: (i )序列特激: (A) 長度:29個胺基酸 (B) 型式:胺基酸 (D)相性:直線 (ii )分子型式:肽 (v ) Η段型式:端 (ix )特色: (A) 名/重點:修飾位置 (B) 位置:1 (D)其他資料·· /檷示=乙醢基-(ix )特色: (A)名/重點:修飾位置 (B )位置·· 2 9 (D)其他資料:/標示胺 (xi)序列說明:序列辨識號碼:2 Asp Le^ ASP Αΐ3 Ma Val ASP Thr Ser Ser Glu Ile Thr Thr L'/s 15 1 5 10 Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn Pro 20 25 (2)序列辨設號碼:3資料: * (i )序列特激: (A) 長度:29個胺基酸. (B) 型式:胺基酸 21 本紙張尺度遴用中國國家樣準(CNS)甲4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) 396161 Α6 Β6 經濟部中央標準局貝工消费合作杜印製 五、發明説明(20 ) ' .(D)相性:直線 (ii )分子型式:肽 (v )片段型式:N-端 (ix )特.色: (A) 名/竃黏:修飾位置 (B) 位置:1 (D)其他資料:/檷示=乙醢基-(ix )待色: (A) 名/重點:修飾位置 (B) 位置:29 (D)其他資料:/棵示=-醢胺 (xi)序列說明:序列辨識號碼:3 Ser Asp Ala Ala Val Asp Thr Ser Ser Glu He Thr Thr Lys Asp Leu 1 5 10 15 Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn Gly 20 25 (2)序列辨設號碼:4資料: .(i )序列待激: (A) 長度:29個胺基酸 (B) 型式:胺基酸 (D)相性:直線 (ii )分子型式:肽 (v )片段型式:C-端 (ix )特色: *22* j紙張尺/t遴用中國國準(CNS)甲4規格(210 X 297公釐) Γ 裝丨.................訂.....................線 (請先閲讀背面之注意事項再填寫本頁) 396161 A6 B6 五、發明説明(21 ) (A) 名/重黏:修飾位置(B) 位置:1(D)其他資料:/註="焦麩胺醢基〃Ui)序列說明:序列辨識號碼:4 Xaa Ser Asp Ala Ala Val Asp Thr Ser Ser Glu lie Thr Thr Lys Asp 1 5 i〇 15 Leu Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn 20 25 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央樣準局貝工消费合作社印製 23' 本.紙張尺度遑用中國國家樣準(CNS)甲4规格(210X297公釐)
Claims (1)
- 第83100771號專利申請累 396161 JS 中文申請專利範圍修正本 六、申請專利範園公告本 經濟部中央標準局貝工消费合作社印製 種化合物•其係選自以下姐成之群·· Ser Asp Ala Ala Val Asp Thr Ser Ser Glu lie Thr Thr Lys 1 5 10 Asp Leu 15 Ser Asp Ala Ala Val Asp Thr Ser Ser Glu He Thr Thr Lys 1 5 10 Asp Leu Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn Pro 15 20 25 Ser Asp Ala Ala Val Asp Thr Ser Ser Glu lie Thr Thr Lys 1 5 10 Asp Leu Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn Gly 15 20 25 Glp Ser Asp Ala Ala Val Asp Thr Ser Ser Glu He Thr Thr 1 5 10 Lys Asp Leu Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn 15 20 25 本纸張尺度逍用中國國家標準(CNS ) A4说格(210X297公釐) i裝 訂¾.. (請先閲讀背面之注意事項再填寫本頁) 第83100771號專利申請累 396161 JS 中文申請專利範圍修正本 六、申請專利範園公告本 經濟部中央標準局貝工消费合作社印製 種化合物•其係選自以下姐成之群·· Ser Asp Ala Ala Val Asp Thr Ser Ser Glu lie Thr Thr Lys 1 5 10 Asp Leu 15 Ser Asp Ala Ala Val Asp Thr Ser Ser Glu He Thr Thr Lys 1 5 10 Asp Leu Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn Pro 15 20 25 Ser Asp Ala Ala Val Asp Thr Ser Ser Glu lie Thr Thr Lys 1 5 10 Asp Leu Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn Gly 15 20 25 Glp Ser Asp Ala Ala Val Asp Thr Ser Ser Glu He Thr Thr 1 5 10 Lys Asp Leu Lys Glu Lys Lys Glu Val Val Glu Glu Ala Glu Asn 15 20 25 本纸張尺度逍用中國國家標準(CNS ) A4说格(210X297公釐) i裝 訂¾.. (請先閲讀背面之注意事項再填寫本頁)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/188,232 US6262230B1 (en) | 1994-01-28 | 1994-01-28 | Analogs of thymosin α1 |
Publications (1)
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TW396161B true TW396161B (en) | 2000-07-01 |
Family
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Family Applications (1)
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TW083100771A TW396161B (en) | 1994-01-28 | 1994-01-31 | Analogs of thymosin <alpha>1 |
Country Status (16)
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US (1) | US6262230B1 (zh) |
EP (2) | EP1688431A3 (zh) |
JP (2) | JPH09508387A (zh) |
AT (1) | ATE315583T1 (zh) |
AU (1) | AU1568995A (zh) |
CA (1) | CA2181477C (zh) |
DE (1) | DE69534740T2 (zh) |
DK (1) | DK0741746T3 (zh) |
ES (1) | ES2259439T3 (zh) |
HK (1) | HK1013296A1 (zh) |
MY (1) | MY114151A (zh) |
PE (1) | PE29797A1 (zh) |
PT (1) | PT741746E (zh) |
TW (1) | TW396161B (zh) |
WO (1) | WO1995020602A2 (zh) |
ZA (1) | ZA95669B (zh) |
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AU2006243344B2 (en) * | 2005-05-04 | 2011-04-21 | Lonza Ag | Solid phase bound thymosin alpha-1 and its synthesis |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA988079A (en) * | 1971-07-01 | 1976-04-27 | Rolf Geiger | Process for the manufacture of peptides |
US4079127A (en) | 1976-10-28 | 1978-03-14 | Board Of Regents Of The University Of Texas | Thymosin alpha 1 |
CH641152A5 (en) * | 1977-04-22 | 1984-02-15 | Hoffmann La Roche | Process for preparing thymosin alpha-1 and an analogue |
US4116951A (en) | 1977-04-22 | 1978-09-26 | Hoffmann-La Roche Inc. | [Asn2 ]-thymosin α1 and analogs thereof |
US4148788A (en) | 1978-01-23 | 1979-04-10 | Hoffmann-La Roche Inc. | Synthesis of thymosin α1 |
DE2919592A1 (de) * | 1979-05-15 | 1981-01-15 | Max Planck Gesellschaft | Verfahren zur herstellung von thymosin- alpha 1 und derivaten davon |
DE3100974A1 (de) * | 1980-01-18 | 1982-01-21 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen | Thymosin(alpha)(pfeil abwaerts)1(pfeil abwaerts)-fragmente enthaltende arzneimittel mit immunregulierender wirkung, und thymosin(alpha)(pfeil abwaerts)1(pfeil abwaerts)-fragmente |
US4612365A (en) * | 1980-03-25 | 1986-09-16 | Max-Planck-Gesellschaft Zur Foederung Der Wissenschaften | Medicaments containing alpha 1-thymosin and having an immuno regulatory action and alpha 1-thymosin fragments |
US4659694A (en) * | 1983-10-27 | 1987-04-21 | Hoffmann-La Roche Inc. | Prothymosin alpha |
US4855407A (en) * | 1985-04-11 | 1989-08-08 | Alpha-1 Biomedicals, Inc. | Solid phase process for synthesizing peptides |
ATE136551T1 (de) * | 1988-05-10 | 1996-04-15 | Alpha 1 Biomedicals Inc | Festphase-verfahren zur gewinnung von thymosin- alpha-1 |
-
1994
- 1994-01-28 US US08/188,232 patent/US6262230B1/en not_active Expired - Fee Related
- 1994-01-31 TW TW083100771A patent/TW396161B/zh not_active IP Right Cessation
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1995
- 1995-01-18 CA CA002181477A patent/CA2181477C/en not_active Expired - Fee Related
- 1995-01-18 DK DK95907463T patent/DK0741746T3/da active
- 1995-01-18 EP EP06000390A patent/EP1688431A3/en not_active Withdrawn
- 1995-01-18 JP JP7520088A patent/JPH09508387A/ja not_active Ceased
- 1995-01-18 AT AT95907463T patent/ATE315583T1/de not_active IP Right Cessation
- 1995-01-18 WO PCT/US1995/000617 patent/WO1995020602A2/en active IP Right Grant
- 1995-01-18 PE PE1995259687A patent/PE29797A1/es not_active Application Discontinuation
- 1995-01-18 DE DE69534740T patent/DE69534740T2/de not_active Expired - Fee Related
- 1995-01-18 PT PT95907463T patent/PT741746E/pt unknown
- 1995-01-18 EP EP95907463A patent/EP0741746B1/en not_active Expired - Lifetime
- 1995-01-18 AU AU15689/95A patent/AU1568995A/en not_active Abandoned
- 1995-01-18 ES ES95907463T patent/ES2259439T3/es not_active Expired - Lifetime
- 1995-01-26 MY MYPI95000180A patent/MY114151A/en unknown
- 1995-01-27 ZA ZA95669A patent/ZA95669B/xx unknown
-
1998
- 1998-12-19 HK HK98114130A patent/HK1013296A1/xx not_active IP Right Cessation
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2006
- 2006-01-25 JP JP2006016059A patent/JP3931194B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
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ES2259439T3 (es) | 2006-10-01 |
PT741746E (pt) | 2006-05-31 |
EP1688431A2 (en) | 2006-08-09 |
EP0741746B1 (en) | 2006-01-11 |
WO1995020602A3 (en) | 1995-10-12 |
JP3931194B2 (ja) | 2007-06-13 |
AU1568995A (en) | 1995-08-15 |
ATE315583T1 (de) | 2006-02-15 |
US6262230B1 (en) | 2001-07-17 |
CA2181477C (en) | 2002-01-01 |
MY114151A (en) | 2002-08-30 |
PE29797A1 (es) | 1997-09-01 |
EP1688431A3 (en) | 2006-11-29 |
JPH09508387A (ja) | 1997-08-26 |
WO1995020602A2 (en) | 1995-08-03 |
HK1013296A1 (en) | 1999-08-20 |
CA2181477A1 (en) | 1995-08-03 |
ZA95669B (en) | 1996-07-29 |
DK0741746T3 (da) | 2006-05-29 |
JP2006160751A (ja) | 2006-06-22 |
DE69534740D1 (en) | 2006-04-06 |
EP0741746A1 (en) | 1996-11-13 |
DE69534740T2 (de) | 2006-11-02 |
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