TW568910B - Epothilon derivatives, processes for their production and their use - Google Patents
Epothilon derivatives, processes for their production and their use Download PDFInfo
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- TW568910B TW568910B TW088107412A TW88107412A TW568910B TW 568910 B TW568910 B TW 568910B TW 088107412 A TW088107412 A TW 088107412A TW 88107412 A TW88107412 A TW 88107412A TW 568910 B TW568910 B TW 568910B
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- 238000000034 method Methods 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000006239 protecting group Chemical group 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- -1 monocyclic heteroaromatics Chemical class 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 230000002079 cooperative effect Effects 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 238000006619 Stille reaction Methods 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 6
- 125000004434 sulfur atom Chemical group 0.000 claims 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 238000006069 Suzuki reaction reaction Methods 0.000 claims 1
- 125000002355 alkine group Chemical group 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims 1
- 150000002466 imines Chemical class 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 239000011814 protection agent Substances 0.000 abstract description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000219495 Betulaceae Species 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane Chemical compound CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 125000005382 boronyl group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229930006728 pinane Natural products 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
568910 A7 B7五、發明説明（1 )本發明係關於環氧噻唑酮衍生物類，其製法及其在醫藥品及植物防護劑製造上之用途。本發明特別係關於如下 式2至式6之環氧噻唑酮衍生物類及關於其在醫藥品及植 物防護劑之用途。 經濟部智慧財產局員工消費合作社印製
««I,代:£|~^ etLK丨 (請先閲讀背面之注意事項再填寫本頁) ο ο
2B 0) (H
P 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 568910 A7 B7
(請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 568910 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明（3) 在上式中： R1為氫原子或為CrC8-烷基，宜為CrC6-烷基，特別 佳為Ci-C4-烧基’尤其是甲基、乙基、丙基或丁基。 R2為單環芳基，例如5-或6-元之芳基（如苯環）或 乙稀基，其中任一基可在鄰-及/或間-及/或對-位被一、 二、三、四或五，特別是一或二個，鹵素原子及/或⑽4及/ 或NR5R6基及/或烧基及或烯基及/或炔基取代，其中r4、r5 及R6各自獨立且定義與R1相同，但與Ri無關，或 R2為5-或6-元單環雜芳基，其環上可具有一或更 多，特別是一或二個〇及/或N及/或s原子及/或可具有⑽4 及/或NR5R6基及/或烧基及/或稀基及/或炔基為取代基， 其中R4，R5及R6之定義如上所述。在R2之定義中，特別佳者 為(^-(：6-烷基或(：2-(：6-烯基及-炔基，特別是C^C4__烷基 或C2-Cr烯基及-炔基。烷基中，特別佳者為甲基、乙美、 丙基及丁基且雜芳基中為6元之雜芳基。
Ha 1為鹵素原子，例如漠或峨，
X - Y 為式-CH2CH-OP或-CH=CH-之基，且 P為保護基，例如TMS 根據本發明之化合物可由下列方法製得·· (請先閲讀背面之注意事項再填寫本頁) 訂
568910 A7 B7 五、發明説明（4 ) 如DE 195 42 986中所述，各基如上之定義。在該反應 中，可使用特別是如下之條件（i)、（iii)及選擇地使用 [在（i)後](ii): (i) (a)在溶劑如二氯甲烷中之〇3，及 (b)引起還原作用，例如加入Me2S ; (ii) (a)(CH3C0)20，HC02H，NEt3，DMAp ; (b) DBU ;及 (c) MeOH ， NH3 ;及 (iii) Me3SiC卜 NEt3. 式（3)化合物可藉式（2)化合物與式HC[B(〇R)2]yt^ 物’如三（伸乙基二經基氧蝴基）甲烧反應而製得；R可 為如上述定義之燒基或烯基。 在反應中可選擇地使用強鹼，如Ci-Cf烷基-鋰化合 物（如丁基經）或二烧基胺-經化合物（如二甲基胺 鐘化合物）。该反應一般在低溫下進行，例如，溫度低於一 30°C，溫度宜為低於-50°C，特別佳之溫度為至少在一78 C ’其他反應條件可參考D· Schummer，G. H0fle in Tetrahedron 1995, 51，11219。 例如，在-78°C時，式（2)化合物與三（伸乙基二羥基 氧硼基）曱烷及丁基鋰反應形成式（3)化合物。 式（4)化合物可藉著將式（3)化合物與.碘_基或N 一溴 -琥珀醯亞胺選擇地在極性溶劑中，例如乙腈中反應而製 得。其他反應條件可參考如下文獻：N A. Petasis，I A. (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（2l〇X297公羡） 568910 A7 B7 五、發明説明（5 ) Zavialor， Tetrahedron Lett· 1996,37,567· 為了製造式（5)化合物，可將式（3)化合物與式化 合物在鈐木框架内藉偶合反應而製得，其中p定義如上所 述且z可為鹵素原子或為式—os〇2CF3，一 CH=CHI，一 CH=CHOS〇2CF3基，R2-Z基可特別具有下列結構式： &
『專I IT 其中Α為〇，s，Ν或C原子，且〇Ί，C-之取代基相對應在|津1 如上所述之OR4，NR5R6及烷基，烯基及/或炔基。 一 特別較佳之’’C”取代基為^吒厂烷基或c2-c6-烯基及/ 或-炔基，特別是(：〗-(：4-烷基或c2-c4-稀基及/或—炔基。烷 基中，特別佳者為甲基、乙基、丙基及丁基。 或者，式（5)化合物可將式（4)化合物與^、㈤^藉 Stille偶合反應而製得，其中R2定義同上且R3為q—^一烷 基，宜為(：厂(：4-烷基且特別佳者為甲基，乙基，丙基或丁 CI -Ce·院基 經濟部智慧財產局員工消費合作社印製 基。此外，R2-S11R33化合物可為如下任一結構式： W 「，〇-K取代基 h-，0.,n.，c·取代基Hi 氣“j 察專 568910 A7 ___ _B7_ 五、發明説明（7 ) 製備含三（伸乙基二羥基氧硼基）甲烷（0. 30克，1· 5毫 莫耳）於CH2C12/THF(1:1; 4毫升）之溶液，並在惰性氣體 中冷卻至-78°C。在該溫度下，10分鐘内逐滴加入丁基鋰 (在己烷中之1· 6M溶液；〇· 73毫升，1· 2毫莫耳）。2小時 後，加入含丙酮2(81毫克，0· 15毫莫耳）之CHzCh/THF溶液 (1:1，2毫升）溶液，加熱至室溫並攪拌17小時。在加入 MeOH (2毫升）後，將澄清的反應溶液用製備性高效液相 層析法（Lichroprep RP-18，CH3CN/H2〇 75:25)純化。可 製得57毫克（65%)為E/Z異構混合物（6 : 4)形式之烯基硼 酸3。 所挑選出來的典型數據為：LC-MS(ESI-MS): 585(M++H) ; ^-NMR : (300MHz，CD30D):E-異構物： 1.91(S, 3H), 5.16 (d, 1H, 10 Hz), 5.49 (s, 1H), 2-異構物：1.85((1，311，1.1112)，4.93(3，11〇，5.26 (d, 1H, 9. 6 Hz). 乙稀块衍生物4之合成 (亦參閱 N.APetasis，Ι·Α，Zavialor，Tetrahedron
Lett· 1996, 37, 567) 範例（RkHX-Y^CI^CHOTMS) ·· 在室溫下，N-碘基琥珀醯亞胺（6· 0毫克，27微莫耳） 在惰性氣體及不見光下，加入烯基硼酸3(12毫克，21微莫 耳；E/Z 9:1)於CH3CN(150微升）之溶液中並攪拌3小時。 -9 - 本紙張尺度適用中國國家標準（CNS ) A4規格（21GX297公褒） ^^ (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 568910 A7 B7 五、發明説明（β ) ' '
濃縮後，以製備性薄層色層分離法（si〇2，CH2(:l2/Me()iI 25:5)純化殘質。藉分離E/z-異構混合物形式可分 離出9毫克（66%)峨基乙烯衍生物4。 所挑選出來的典型數據為：LC-MS(ESNM幻： 667CM++H) ; NMR : (300 MHz, CDC13) ; E—異構物： 1·82 (d，3H，1·1Ηζ)，5.36 (d，lH，11 Ηζ)，6.43 (s，1H)。Z-異構物：i 84 (d，3H，1. 1 Hz)，5· 54 (d，1H，10· 5 Hz)，6. 09 (s，1H)。 稀基蝴酸3之鈐木偶合 (亦參閱A, Suzuki，Acc· Chem· Res· 1982，15，178; A. Torrado, S. Lopez, R. Alvarez, A. R. De Lera Synthesis, 1995,285) 範例（RkH，X_Y=CH2CHOTMS，R2=Ph): 經濟部智慧財產局員工消費合作社印製 將含烯基硼酸3( 12毫克，21微莫耳，E/Z 2:8)及乙醇亞 銘（在EtOH中之2M溶液；12微升，24微莫耳）於THF(150微升) 之;谷液’在至溫撥摔15分鐘’然後在3 0分鐘内逐滴加入含 苯基碘（4· 0微升，6· 0毫克，29微莫耳）及四（三苯基膦基） 鈀（7· 1毫克，6· 2微莫耳）於THF( 150微升）之溶液且再攪拌 30分鐘。用製備性薄層色層分離法（Si〇2;CH2Cl2/Et20 95:5)純化後，可得到無色固體形式之環氧噻唑酮苯類似 物5 (10毫克，79%，E/Z 2:8)。 所挑選出來的典型數據為：LC-MS(ESI-MS) : 617 -10 - 本紙張尺度適用中國國家標準（CNS )八4規格（210X297公釐） — 經濟部智慧財產局員工消費合作社印製 568910 A7 B7 五、發明説明（9 ) (M.+ H) ;1!!-NMR: ( 300 MHZ，CDC13) :E_異構物：1.87 (d，3H，1· 4 Ηζ)，5· 35 (d，1H，10. 7Hz)，6· 54 (s，1H)， Z-異構物：1. 80 (d，3H，1. 5 Hz)，5. 61 (d，1H，10· 2
Hz)，6.41 (s，1H)。 碘基乙烯基衍生物4之Stille偶合： (亦參閱K.C.Nicolaou，Υ· He, F· Roschangar, N. P. King, D. Vourloumis，T. Li Angew. Chem. 1998, 1 10,（1/2)，89) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）
Claims (1)
- 568910 8 8 8 8 A B c D 六、申請專利範圍 "一’今 修正補充 :我I 專利申請案第88107412號 、| ROC Patent Appln. No. 88107412 ™— -W後無劃線之申請專利範圍中文本-附件（一） Amended Claims in Chinese - Enel. (I) (民國92年11月1日送呈） (Submitted on November ^ , 2003) 1. 一種製造式(3)化合物之方法 10 (H〇)fD Λ r'(3) 15 其中R1為氫原子或(^-至C8-烷基，X-Y 為式-CH2CH-OP 或-CH=CH-基，及 P為保護基，其特徵在於以式(2)化合物與式HC[B(OR)2]3化合物進 行反應， 20 經濟部智慧財產局員工消費合作社印製 R1(2) 25 各基團係如上述所定義且R之定義如R1，但與R1無 關。2.—種製造式(4)化合物之方法， -12 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 88140B-接 568910 A8 B8 C8 D8 六、申請專利範圍 R110 15 ⑷ 其中 R1為氫原子或Q-至C8-烷基， X-Y 為式 _CH2CH-OP 或-CH=CH-基，及 P為保護基， 且Hal為鹵素原子，如溴或碘， 其特徵在於以式(3)化合物與N-碘基-或N-溴基-琥珀 酸亞胺進行反應， (H〇)ae(3) 經濟部智慧財產局員工消費合作社印製 20 各基團係如上述所定義。 3.—種製造式(5)化合物之方法(5) 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 568910 六、申請專利範圍 Α8 Β8 C8 D8 其中 R為氫原子或（:广至c8-烷基， X-Y 為式-CH2CH_〇P 或 _CH=CH-基，及 p為保護基，且 R2為單環芳基或乙烯基，其中各基可在鄰_及/或間_及/ 或對位被鹵素原子及/或〇R4及/或NR5R6及/或烷 基、締基及/或炔基所取代，或為5_或6_員單環雜芳 基’其環上可含有一或多個〇及/或N及/或S原子 及/或可以OR4及/或NR5R6及/或烷基、烯基及/或炔 基作為取代基，其中R4，R5，R6基各自獨立而其定 義如上述R1之定義，但與Ri無關， 其特徵在於以式(3)化合物與式r2-Z化合物藉鈴木偶 合進行反應，經濟部智慧財產局員工消費合作社印製 其中R2係如上述所定義且Ζ可為鹵素原子或式_ 0S02CF3，-CH=CHI，-CH=CHOS〇2CF3 之基。 4· 一種製造式(5)化合物之方法， -14 - 本紙張尺度適用中國國家標準(CNS)A4規格（21〇Χ297公釐） 568910 六、申請專利範圍 R’其中 R1為氫原子或CV至C8-烷基， X-Y 為式-CH2CH-OP 或-CH=CH-基，及 P為保護基，且 10 R2為單環芳基或乙烯基，其中各基可在鄰-及/或間-及/ 或對位被鹵素原子及/或OR4及/或NR5R6及/或烷基、 烯基及/或炔基所取代，或為5-或6-員單環雜芳基， 其環上可含有一或多個Ο及/或N及/或S原子及/或 可以OR4及/或NR5R6及/或烷基、烯基及/或炔基作為 15 取代基，其中R4，R5，R6基各自獨立而其定義如上 述R1之定義，但與R1無關， 其特徵在於以式(4)化合物 R1經濟部智慧財產局員工消費合作社印製 其中 R1為氫原子或Cr至C8-烷基， -15 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 8 8 8 8 A B c D 經濟部智慧財產局員工消費合作社印製 568910 六、申請專利範圍 X-Y 為式-CH2CH-OP 或 _CH=CH-基，及 P為保護基， 且Hal為鹵素原子，如漠或埃， 與r2-SNR33藉Stille偶合進行反應，其中R2係如前 5 述申請專利範圍中任一項所定義且R3為CrC6••燒 基，宜為Cm-烷基，特別佳為甲基、乙基、丙基或丁 基。 5.—種製造式(6)化合物之方法， 10 。丫 0 0 ⑹ 其中 15 R1為氫原子或CV至C8-烷基， X-Y 為式-CH2CH-OP 或-CH=CH-基，及 R2為單環芳基或乙烯基，其中各基可在鄰-及/或間-及/ 或對位被鹵素原子及/或OR4及/或NR5R6及/或燒 基、浠基及/或炔基所取代，或為5-或6-員單環雜芳 2〇 基，其環上可含有一或多個Ο及/或N及/或S原子 及/或可以OR4及/或NR5R6及/或烷基、烯基及/或炔 基作為取代基，其中R4，R5，R6基各自獨立而其定 義如上述R1之定義，但與R1無關， 其特徵在於將式(5)化合物中之保護基去除-16 - 568910 六、申請專利範圍 A8 B8 C8 D8 10 R1其中Ι^、Ι12、Χ_Υ及P係如上述所定義 6·—種製造式(6)化合物之方法， (5) Λ⑹ 其中 R1為氫原子或Cr至c8-烷基， 15 經濟部智慧財產局員工消費合作社印製 20 X-Y 為式 _CH2CH-OP 或 _ch=CH-基，及 R為單環芳基或乙烯基，其中各基可在鄰-及/或間_及/ 或對位被鹵素原子及/或〇R4&/4 nr5r6及/或燒 基、烯基及/或炔基所取代，或為5_或6-員單環雜芳 基，其環上可含有一或多個0及/或N及/或S原子及 /或可以OR4及/或NR5R6及/或烷基、烯基及/或炔基 作為取代基，其中R4，R5，R6基各自獨立而其定義 如上述R1之定義，但與Ri無關， 其特徵在於其包含如申請專利範圍第1、3及5項中 所揭示之方法步驟，各基團係如前述申請專利範圍之 -17 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐） 568910 A8 B8 C8 D8 六、申請專利範圍 定義。 7.—種製造式(6)化合物之方法， R1經濟部智慧財產局員工消費合作社印製 其中 R1為氫原子或Q-至C8-烷基， 10 X-Y 為式-CH2CH-OP 或-CH=CH_基，及 R2為單環芳基或乙烯基，其中各基可在鄰-及/或間-及/ 或對位被鹵素原子及/或OR4及/或NR5R6及/或烷 基、烯基及/或炔基所取代，或為5-或6-員單環雜芳 基，其環上可含有一或多個Ο及/或N及/或S原子 15 及/或可以OR4及/或NR5R6及/或烷基、烯基及/或炔 基作為取代基，其中R4，R5，R6基各自獨立而其定 義如上述R1之定義，但與R1無關， 其特徵在於其包含如申請專利範圍第1、2、4及5項 中所揭示之方法步驟，各基團係如前述申請專利範圍 20 之定義。 -18 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）
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| DE19820599A DE19820599A1 (de) | 1998-05-08 | 1998-05-08 | Epothilonderivate, Verfahren zu deren Herstellung und deren Verwendung |
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| EP (1) | EP1077980B1 (zh) |
| JP (1) | JP2002514649A (zh) |
| KR (1) | KR20010052325A (zh) |
| AR (1) | AR018344A1 (zh) |
| AT (1) | ATE234842T1 (zh) |
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| CA (1) | CA2330812A1 (zh) |
| DE (2) | DE19820599A1 (zh) |
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| IL (1) | IL139480A0 (zh) |
| TW (1) | TW568910B (zh) |
| WO (1) | WO1999058534A2 (zh) |
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| US6204388B1 (en) | 1996-12-03 | 2001-03-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| WO1999001124A1 (en) | 1996-12-03 | 1999-01-14 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| GB9810659D0 (en) | 1998-05-18 | 1998-07-15 | Ciba Geigy Ag | Organic compounds |
| US6518421B1 (en) | 2000-03-20 | 2003-02-11 | Bristol-Myers Squibb Company | Process for the preparation of epothilone analogs |
| SI1483251T1 (sl) | 2002-03-12 | 2010-03-31 | Bristol Myers Squibb Co | C cian epotilonski derivati |
| DE10355223A1 (de) * | 2003-11-26 | 2005-06-30 | Institut für Pflanzenbiochemie (IPB) | Neue Makrocyclen zur Behandlung von Krebserkrankungen |
| EP1674098A1 (en) | 2004-12-23 | 2006-06-28 | Schering Aktiengesellschaft | Stable and tolerable parental formulations of highly reactive organic drug substances with low or no solubility in water |
| EP2634252B1 (en) | 2005-02-11 | 2018-12-19 | University of Southern California | Method of expressing proteins with disulfide bridges |
| US20110104664A1 (en) | 2006-03-31 | 2011-05-05 | Bristol-Myers Squibb Company | Biomarkers and methods for determining sensitivity to micortubule-stabilizing agents |
| US8008256B2 (en) * | 2006-05-01 | 2011-08-30 | University Of Southern California | Combination therapy for treatment of cancer |
| EP2065054A1 (en) | 2007-11-29 | 2009-06-03 | Bayer Schering Pharma Aktiengesellschaft | Combinations comprising a prostaglandin and uses thereof |
| DE102007059752A1 (de) | 2007-12-10 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Funktionalisierte, feste Polymernanopartikel enthaltend Epothilone |
| EP2070521A1 (en) | 2007-12-10 | 2009-06-17 | Bayer Schering Pharma Aktiengesellschaft | Surface-modified nanoparticles |
| WO2010056901A2 (en) | 2008-11-13 | 2010-05-20 | University Of Southern California | Method of expressing proteins with disulfide bridges with enhanced yields and activity |
| EP2210584A1 (en) | 2009-01-27 | 2010-07-28 | Bayer Schering Pharma Aktiengesellschaft | Stable polymeric composition comprising an epothilone and an amphiphilic block copolymer |
| AU2011255647A1 (en) | 2010-05-18 | 2012-11-15 | Cerulean Pharma Inc. | Compositions and methods for treatment of autoimmune and other diseases |
| US9764038B2 (en) | 2011-12-23 | 2017-09-19 | Innate Pharma | Enzymatic conjugation of antibodies |
| WO2014009426A2 (en) | 2012-07-13 | 2014-01-16 | Innate Pharma | Screening of conjugated antibodies |
| US10036010B2 (en) | 2012-11-09 | 2018-07-31 | Innate Pharma | Recognition tags for TGase-mediated conjugation |
| EP2968582B1 (en) | 2013-03-15 | 2020-07-01 | Innate Pharma | Solid phase tgase-mediated conjugation of antibodies |
| EP3010547B1 (en) | 2013-06-20 | 2021-04-21 | Innate Pharma | Enzymatic conjugation of polypeptides |
| JP6744212B2 (ja) | 2013-06-21 | 2020-08-19 | イナート・ファルマ・ソシエテ・アノニムＩｎｎａｔｅ Ｐｈａｒｍａ Ｐｈａｒｍａ Ｓ．Ａ． | ポリペプチドの酵素的結合 |
| WO2019092148A1 (en) | 2017-11-10 | 2019-05-16 | Innate Pharma | Antibodies with functionalized glutamine residues |
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| DE4138042C2 (de) | 1991-11-19 | 1993-10-14 | Biotechnolog Forschung Gmbh | Epothilone, deren Herstellungsverfahren sowie diese Verbindungen enthaltende Mittel |
| US5351146A (en) * | 1993-03-01 | 1994-09-27 | At&T Bell Laboratories | All-optical network architecture |
| US5781537A (en) * | 1995-07-07 | 1998-07-14 | International Business Machines Corporation | Setting up, taking down and maintaining connections in a communications network |
| DK1186606T4 (da) | 1995-11-17 | 2011-12-05 | Biotechnolog Forschung Gmbh | Epothilonderivater, deres fremstilling og anvendelse |
| DE19542986A1 (de) | 1995-11-17 | 1997-05-22 | Biotechnolog Forschung Gmbh | Epothilon-Derivate und deren Verwendung |
| DK1367057T3 (da) | 1996-11-18 | 2009-01-19 | Biotechnolog Forschung Gmbh | Epothiloner E og F |
| US6380394B1 (en) | 1996-12-13 | 2002-04-30 | The Scripps Research Institute | Epothilone analogs |
| US6304349B1 (en) * | 1998-06-30 | 2001-10-16 | Lucent Technologies Inc. | WDM optical communications networks and methods for provisioning |
| US6445844B1 (en) * | 1999-09-15 | 2002-09-03 | Xros, Inc. | Flexible, modular, compact fiber optic switch |
| US7092633B2 (en) * | 2000-11-14 | 2006-08-15 | University Of Texas System Board Of Regents | System and method for configuring optical circuits |
| US6982951B2 (en) * | 2000-12-21 | 2006-01-03 | At&T Corp. | Method for selecting a restoration path in a mesh network |
| US7212495B2 (en) * | 2001-02-21 | 2007-05-01 | Polytechnic University | Signaling for reserving a communications path |
| AU2002305113A1 (en) * | 2001-03-29 | 2002-10-15 | Atoga Systems, Inc. | Open ring architectures for optical wdm networks |
| US20020194339A1 (en) * | 2001-05-16 | 2002-12-19 | Lin Philip J. | Method and apparatus for allocating working and protection bandwidth in a telecommunications mesh network |
| AU2002351589A1 (en) * | 2001-06-27 | 2003-03-03 | Brilliant Optical Networks | Distributed information management schemes for dynamic allocation and de-allocation of bandwidth |
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- 1998-05-08 DE DE19820599A patent/DE19820599A1/de not_active Withdrawn
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- 1999-05-07 DE DE59904632T patent/DE59904632D1/de not_active Expired - Lifetime
- 1999-05-07 AT AT99926300T patent/ATE234842T1/de not_active IP Right Cessation
- 1999-05-07 KR KR1020007012437A patent/KR20010052325A/ko not_active Ceased
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- 1999-05-07 JP JP2000548338A patent/JP2002514649A/ja not_active Withdrawn
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- 1999-05-10 AR ARP990102186A patent/AR018344A1/es not_active Application Discontinuation
- 1999-05-14 TW TW088107412A patent/TW568910B/zh not_active IP Right Cessation
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Also Published As
| Publication number | Publication date |
|---|---|
| EP1077980B1 (de) | 2003-03-19 |
| EP1077980A2 (de) | 2001-02-28 |
| US20040259922A1 (en) | 2004-12-23 |
| KR20010052325A (ko) | 2001-06-25 |
| CA2330812A1 (en) | 1999-11-18 |
| AU754212B2 (en) | 2002-11-07 |
| ATE234842T1 (de) | 2003-04-15 |
| US6982280B1 (en) | 2006-01-03 |
| IL139480A0 (en) | 2001-11-25 |
| WO1999058534A3 (de) | 2000-01-13 |
| DE59904632D1 (de) | 2003-04-24 |
| HUP0102283A2 (hu) | 2001-10-28 |
| AR018344A1 (es) | 2001-11-14 |
| DE19820599A1 (de) | 1999-11-11 |
| WO1999058534A2 (de) | 1999-11-18 |
| JP2002514649A (ja) | 2002-05-21 |
| ES2195577T3 (es) | 2003-12-01 |
| HUP0102283A3 (en) | 2002-03-28 |
| AU4361199A (en) | 1999-11-29 |
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