TW200940050A

TW200940050A - Polymorphs of N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide)

Info

Publication number: TW200940050A
Application number: TW097145857A
Authority: TW
Inventors: Elena I Kostik; li-jun Sun; Joanna Dziewiszek; Jun Y Choi
Original assignee: Synta Pharmaceuticals Corp
Priority date: 2007-11-28
Filing date: 2008-11-27
Publication date: 2009-10-01
Also published as: WO2009073147A3; WO2009073147A2

Abstract

At least 70% by weight of Compound 1 is the single crystalline form, Form A, Form C, or Form D, of the compound. A pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent, and compound 1, wherein at least 70% by weight of the compound is the single crystalline form, Form A, Form C, or Form D, of the compound. A method of treating a subject with cancer comprises administering to the subject an effective amount of compound 1 or the pharmaceutical composition.

Description

200940050 九、發明說明：【發明所屬之技術領域】本發明係關於化合物1之獨特晶形及包含本文所述之化合物1之晶形的新穎組成物及醫藥組成物。本發明亦係關於治療患有癌症之個體之方法。此外，本發明係關於製備本文所述之晶形之方法。【先前技術】美國專利第MGG，66G號、第6,762 2G4號、第7,〇37 94〇 ©號帛7,001，923號及第6,924,312號中已報導某些雙（硫醯拼酿胺）化合物顯著增強太平洋紫杉醇（pacHtaxel)及太平洋紫杉醇類似物之抗癌活性。尤其地，相對於僅以太平洋紫杉醇治療之患者，與紫杉醇（tax〇1)組合之N_丙二酿基_ 雙甲基-N 硫苯甲酿肼）已展示延長罹患ιν帛轉移性黑色素瘤之患者的疾病進展時間。獲得具有適於大規模生產幻如乾崧填充）N-丙二醯基_雙（\，_甲基·ν，·硫苯甲酿肼）作為藥物之性質的該化合物之晶形將為有利的。【發明内容】目前中請者已發現由以下結構表示之化合物i之若干BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel crystal form of Compound 1 and a novel composition and pharmaceutical composition comprising the crystal form of Compound 1 described herein. The invention is also directed to a method of treating an individual having cancer. Furthermore, the invention relates to a process for the preparation of the crystalline forms described herein. [Prior Art] Certain bis(thioindoles) compounds have been reported in U.S. Patent Nos. MGG, No. 6, No. 6,762, No. 6, No. 7, No. 7, 〇37, 94, 〇, 7, 001, 923, and 6, 924, 312. Enhances the anticancer activity of paclitaxel (pacHtaxel) and paclitaxel analogs. In particular, N-propanol- bis-methyl-N-thiobenzidine in combination with paclitaxel (tax〇1) has been shown to prolong the spread of metastatic melanoma in patients with paclitaxel alone (tax〇1). The time of progression of the patient's disease. It would be advantageous to obtain a crystalline form of the compound having properties suitable for large-scale production of a phantom dry-filled N-propanediyl-bis(\,_methyl·v,·thiobenzazole) as a drug. . SUMMARY OF THE INVENTION At present, a number of compounds i have been found by the following structures.

(化合物1 ) 200940050 在一具體實例中，本發明係針對化合物j，其中至少 70重量％之該化合物為該化合物之單晶形人形。在另一具體實例中，本發明係針對化合物1，其中至少 70重量％之該化合物為該化合物之單晶形c形。在還另一具體實例中，本發明係針對化合物i，其中至少70重量％之該化合物為該化合物之單晶形D形。在還另一具體實例中，本發明係針對化合物i，其中至少70重量％之該化合物為該化合物之單晶形A形之晶體慣態1 〇在還另一具體實例中，本發明係針對化合物1，其中至少70重量％之該化合物為該化合物之單晶形A形之晶體慣態2 〇在還另一具體實例中，本發明係針對包含醫藥上可接受之載劑或稀釋劑及化合物i之醫藥組成物其中至少重量之該化合物為該化合物之單晶形人形。在還另一具體實例中，本發明係針對包含醫藥上可接受之載劑或稀釋劑及化合物i之醫藥組成物，其中至少几重量％之該化合物為該化合物之單晶形c形。在還另一具體實例中，本發明係針對包含醫藥上可接受之載劑或稀釋劑及化合物i之醫藥組成物，其中至少重量％之該化合物為該化合物之單晶形D形。 ^在還另一具體實例中，本發明係針對包含醫藥上可接受之載劑或稀釋劑及化合物i之醫藥組成物，其中至少重量％之該化合物為該化合物之單晶形人形之晶體慣態卜 200940050 在還另-具體實财，本發明係針對包含醫藥上可接受之載劑或稀釋劑及化合物之醫藥組成物，#中至少川重量。/。之該化合物為該化合物之單晶形A形之晶體慣態2。本發明亦包含一種治療患有癌症之個體的方法。該方法包含向該個體投予有效量之本文中揭示的本發明之化合物或醫藥組成物。本發明亦包含-種治療患有癌症之個體的方法，該方法包含向該個體投予有效量之太平洋紫杉醇或太平洋紫杉醇類似物及有效量之本文中揭示的本發明之化合物或醫藥本發明亦包括本文中握^ 、 Y褐不的本發明之化合物或醫藥組成物用於治療癌症之用途。本發明亦包括有效晋$ 士正a & ^ ，句双罝之太千洋紫杉醇或太平洋紫杉醇類似物及有效量之本文中棍+ 於不又Τ揭不的本發明之化合物或醫藥組成物用於治療癌症之用途。本發明亦包括本文中揭示的本發明之化合物或醫藥板成物用於製備供治療個髏癌症用之藥劑的用途。本發明亦包括太平洋紫杉醇或太平洋紫杉醇類似物及本文中揭示之本發明之化合物或醫藥組成物用於製備供治療個體癌症用之藥劑的用途。【實施方式】本發月提供化合物1之獨特晶形及包含本文所述之化合物1之晶形的新穎組成物及醫藥組成物。本發明亦提供 …療患有癌症之個體之方法^此外，本發明提供製備本文 7 200940050 所述之晶形之方法。在本發明之一具體實例中，至少特定重量百分比之化合物1為化合物1之單晶形A形。特定重量百分比包括 70%、72% ' 75%、77%、80%、82%、85%、87%、90%、92%、 95%、97%、99%、99_5%、99.9%或在 70%與 100%之間的百分比。在本發明之一具體實例中，至少特定重量百分比之化合物1為化合物1之單晶形A形之晶體慣態1。特定重量百分比包括 70%、72%、75%、77%、80%、82%、85%、87%、 90%、92%、95%、97%、99%、99.5%、99.9%或在 70%與 100%之間的百分比。在本發明之一具體實例中，至少特定重量百分比之化合物1為化合物1之單晶形A形之晶體慣態2。特定重量百分比包括 70%、72%、75%、77%、80%、82%、85%、87%、 90%、92%、95%、97%、99%、99.5%、99.9%或在 70%與 100%之間的百分比。在本發明之一具體實例中，至少特定重量百分比之化合物1為化合物1之單晶形C形。特定重量百分比包括 70%、72%、75%、77%、80%、82%、85% ' 87%、90%、92%、 95%、97% ' 99%、99.5%、99.9%或在 70%與 100%之間的百分比。在本發明之一具體實例中，至少特定重量百分比之化合物1為化合物1之單晶形D形。特定重量百分比包括 70%、72%、75%、77%、80%、82%、85%、87%、90%、92%、 200940050 95%、97/〇、99%、99.5%、99.9%或在 70%與 1〇0%之間的百分比。如本文中所肖，「結晶」係指具有極其規則化學結構之固體。單晶形意謂呈單晶體或各自具有相同晶形之複數個晶體的化合物1。當化合物1之特定重量百分比為單晶形時，化合物】之其餘部分為非晶形化合物j及/或除該單晶形外之一或多種化合物1晶形的某種組合。當結晶化合物i定義為化合物1之一特定形時，其餘部分係由非晶形及/或不同於所指定之一或多種特定形之晶形組成。單晶形之實例包括化合物1之A、C及D形以及特徵在於如本文中所討論之一或多種性質的單晶形之種類。在一具體實例中，至少70重量％、72重量％、75重量 %、77重量％、80重量％、82重量％、85重量％、87重量％、 90重量％、92重量％、95重量％、97重量％、99重量％、 .99.5重量％、99.9重量％或在7〇重量％與1()()重量％之間的重量百分比之化合物1為化合物i之單晶形D形，且化合物1之其餘部分中至少95%為化合物單晶形八形。在一具體實例中，至少70重量％、72重量％、75重量 /〇、77重量％、80重量％、82重量％、85重量％、87重量重量％、92重量％、95重量％、97重量％、99重量量%。、 99.5重量％、99.9重量％或在70重量％與1〇〇重量％之間的重量百分比之化合物1為化合物j之單晶形〇形，且化合物1之其餘部分中至少95%為化合物單晶形八形。 200940050 在一具體實例中，至少70重量％、72重量％、75重 %、77重量％、8〇重量％、82重量％、85重量％ 87重量。/〇量 90重量。/〇、92重量％、95重量％、97重量％、99重量％*、、 99.5重量％、99.9重量％或在70重量％與1〇〇重量％之間的重$百分比之化合物i為化合物單晶形A形且化人物1之其餘部分中至少95%為化合物i之單晶形D形。σ 在一具體實例中，至少70重量％、72重量％、75重量 /。、77重量％ ' 8〇重量％、82重量❶/。、85重量％、87重量〇/。、 90重量0/〇、92重量％、95重量％、97重量％、99重量〇/〇、 99.5重量％、99 9重量％或在7〇重量％與1〇〇重量％之間的重量百分比之化合物i為化合物j之單晶形Α形且化合物1之其餘部分中至少95%為化合物i之單晶形c形。在本發明之另一具體實例中，醫藥組成物包含醫藥上可接受之載劑或稀釋劑及化合物1，其中至少特定重量百分比之化合物1為化合物i之單晶形。特定百分比包括7〇%、 72%、75%、77%、8〇〇/0、82。/。、85%、87%、90%、92%、95〇/〇、 97%、99%' 99.5%、99.9%或在 70〇/〇與 1〇0%之間的百分比。在一具體實例中，單晶形為化合物A形。在另一具醴實例中’單晶形為化合物1之C形。在另一具體實例中，單晶形為化合物1之D形。在本發明之另一具體實例中，醫藥組成物包含醫藥上可接受之載劑或稀釋劑及化合物1，其中至少特定重量百分比之化合物1為化合物1之A形之單晶體慣態。特定百分比包括 70%、72%、75%、77%、80%、82%、85%、87%、 200940050 90%、92%、95%、97%、99%、99.5。—^ 麵之間的百分比。在一具體實例中，單晶體慣態為化合慣態“在另一具體實例中，單晶體慣態為化α物1之A形之晶體慣態2。在化合物1特定晶形之以下描述中，可特定晶「形」描述本發明之I體實口物^ Ο m 特_特徵亦可=參考:i。："’化合物1之述之晶形之-或多=在…未參考特定「形」下所 A形在本發明之一具體實例中，化合物！之單晶形广此晶形亦特徵在於使用Cu_Ka輕射獲得圖】所干夏如表1所列之Μ角、晶格面距及相對強度之值以射:有末繞射（本文中稱為「XRPD」）n特線粉化合物1之晶形A形特徵為W或3個選自由1〇.7二：中’ 及“七^組成之群組之主要“角父咖峰^ 柳體實例中，化合物；1之晶形A形特徵為以下 —特定具(Compound 1) 200940050 In one embodiment, the invention is directed to compound j wherein at least 70% by weight of the compound is a single crystal human form of the compound. In another embodiment, the invention is directed to Compound 1, wherein at least 70% by weight of the compound is a single crystal c-shape of the compound. In still another embodiment, the invention is directed to compound i wherein at least 70% by weight of the compound is a single crystal form of the compound. In still another embodiment, the invention is directed to compound i, wherein at least 70% by weight of the compound is a single crystal A-shaped crystal habit of the compound 1 还 In yet another specific example, the invention is directed to Compound 1, wherein at least 70% by weight of the compound is a single crystal A-shaped crystal habit of the compound 2 In another embodiment, the invention is directed to a pharmaceutically acceptable carrier or diluent The pharmaceutical composition of Compound i wherein at least the weight of the compound is a single crystal form of the compound. In still another embodiment, the invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and Compound i, wherein at least a few percent by weight of the compound is a single crystal c-shape of the compound. In still another embodiment, the invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and Compound i, wherein at least 5% by weight of the compound is a single crystal form of the compound. In yet another specific embodiment, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and Compound i, wherein at least 5% by weight of the compound is a single crystal form of the compound. State of the art 200940050 In addition to the specific financial, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound, at least a weight of #. /. The compound is a single crystal A-shaped crystal habit 2 of the compound. The invention also encompasses a method of treating an individual having cancer. The method comprises administering to the individual an effective amount of a compound or pharmaceutical composition of the invention disclosed herein. The invention also encompasses a method of treating an individual having cancer, the method comprising administering to the individual an effective amount of paclitaxel or paclitaxel analog and an effective amount of a compound or medicament of the invention disclosed herein. The use of a compound or pharmaceutical composition of the invention, including the present invention, for the treatment of cancer. The present invention also encompasses the effective administration of a compound or pharmaceutical composition of the present invention, which is effective in the treatment of a sedative a & ^, a sorghum, a paclitaxel or a paclitaxel analog, and an effective amount of a stick of the present invention. For the treatment of cancer. The invention also encompasses the use of a compound or pharmaceutical form of the invention disclosed herein for the preparation of a medicament for the treatment of a cancer. The invention also encompasses the use of paclitaxel or paclitaxel analogs and the compounds or pharmaceutical compositions of the invention disclosed herein for the preparation of a medicament for treating cancer in a subject. [Embodiment] This month provides a novel crystal form of Compound 1 and a novel composition and pharmaceutical composition comprising the crystal form of Compound 1 described herein. The present invention also provides a method of treating an individual having cancer. Furthermore, the present invention provides a method of preparing the crystal form described in Japanese Patent No. 200940050. In one embodiment of the invention, at least a specific weight percent of Compound 1 is a single crystal A shape of Compound 1. Specific weight percentages include 70%, 72% '75%, 77%, 80%, 82%, 85%, 87%, 90%, 92%, 95%, 97%, 99%, 99_5%, 99.9% or in The percentage between 70% and 100%. In one embodiment of the invention, at least a specific weight percent of Compound 1 is a single crystal A-shaped crystal habit 1 of Compound 1. Specific weight percentages include 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 90%, 92%, 95%, 97%, 99%, 99.5%, 99.9% or in The percentage between 70% and 100%. In one embodiment of the invention, at least a specific weight percent of Compound 1 is a single crystal A-shaped crystal habit 2 of Compound 1. Specific weight percentages include 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 90%, 92%, 95%, 97%, 99%, 99.5%, 99.9% or in The percentage between 70% and 100%. In one embodiment of the invention, at least a specific weight percent of Compound 1 is a single crystal C shape of Compound 1. Specific weight percentages include 70%, 72%, 75%, 77%, 80%, 82%, 85% '87%, 90%, 92%, 95%, 97% '99%, 99.5%, 99.9% or at The percentage between 70% and 100%. In one embodiment of the invention, at least a specific weight percent of Compound 1 is a single crystal form D of Compound 1. Specific weight percentages include 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 90%, 92%, 200940050 95%, 97/〇, 99%, 99.5%, 99.9% Or a percentage between 70% and 1〇0%. As used herein, "crystalline" refers to a solid having an extremely regular chemical structure. The single crystal form means a compound 1 which is a single crystal or a plurality of crystals each having the same crystal form. When the specific weight percentage of the compound 1 is a single crystal form, the remainder of the compound is an amorphous compound j and/or a combination of one or more crystal forms of the compound 1 other than the single crystal form. When the crystalline compound i is defined as one of the specific forms of the compound 1, the remainder is composed of a crystalline form which is amorphous and/or different from the specified one or more specific forms. Examples of the single crystal shape include the A, C, and D shapes of the compound 1, and the kind of the single crystal shape characterized by one or more properties as discussed herein. In one embodiment, at least 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 90%, 92%, 95% by weight 97% by weight, 99% by weight, .99.5% by weight, 99.9% by weight or a weight percentage of between 7% by weight and 1% by weight of the compound 1 is a single crystal form D of the compound i, and At least 95% of the remainder of Compound 1 is a compound single crystal octagonal. In one embodiment, at least 70% by weight, 72% by weight, 75% by weight, 77% by weight, 80% by weight, 82% by weight, 85% by weight, 87% by weight, 92% by weight, 95% by weight, 97% % by weight, 99% by weight. 99.9% by weight, 99.9% by weight or between 70% by weight and 1% by weight of Compound 1 is a single crystal shape of Compound j, and at least 95% of the remainder of Compound 1 is a compound single Crystal shape eight shape. 200940050 In one embodiment, at least 70% by weight, 72% by weight, 75% by weight, 77% by weight, 8% by weight, 82% by weight, and 85% by weight of 87% by weight. / Quantity 90 weight. /〇, 92% by weight, 95% by weight, 97% by weight, 99% by weight*, 99.9% by weight, 99.9% by weight or a weight % of the compound i between 70% by weight and 1% by weight is a compound At least 95% of the single crystal A shape and the remainder of the character 1 is a single crystal D shape of the compound i. σ In one embodiment, at least 70% by weight, 72% by weight, and 75% by weight. 77% by weight '8〇% by weight, 82% by weight/. , 85% by weight, 87% by weight. 90 wt%/〇, 92 wt%, 95 wt%, 97 wt%, 99 wt〇/〇, 99.5% by weight, 99 9 wt% or a weight percentage between 7 wt% and 1 wt% The compound i is a single crystal shape of the compound j and at least 95% of the remainder of the compound 1 is a single crystal c shape of the compound i. In another embodiment of the invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and Compound 1, wherein at least a particular weight percent of Compound 1 is in the form of a single crystal of Compound i. Specific percentages include 7〇%, 72%, 75%, 77%, 8〇〇/0, 82. /. , 85%, 87%, 90%, 92%, 95%/〇, 97%, 99% '99.5%, 99.9% or a percentage between 70〇/〇 and 1〇0%. In one embodiment, the single crystal form is a compound A shape. In another example, 'single crystal form is the C shape of compound 1. In another embodiment, the single crystal form is the D shape of Compound 1. In another embodiment of the invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and Compound 1, wherein at least a particular weight percent of Compound 1 is the single crystal habit of Form A of Compound 1. Specific percentages include 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 200940050 90%, 92%, 95%, 97%, 99%, 99.5. —^ The percentage between faces. In one embodiment, the single crystal habit is a compounding habit "In another embodiment, the single crystal habit is the crystal habit 2 of the A shape of the alpha species 1. In the following description of the specific crystal form of the compound 1, it may be specified The crystal "shape" describes the solid body of the present invention. 特征 m Special _ characteristics can also be = reference: i. : "' The crystal form of compound 1 - or more = in the absence of reference to a particular "shape" A shape In one embodiment of the invention, the compound! The single crystal shape is also characterized by the use of Cu_Ka light shot to obtain the map. The values of the corners, lattice spacing and relative intensity listed in Table 1 are as follows: there is a final diffraction (referred to herein as The "XRPD") n-line powder compound 1 has a crystal form A shape characterized by W or 3 main ones selected from the group consisting of 1〇.7二:中中和七七^, the main "角父咖峰峰" , compound; 1 crystal form A shape features the following - specific

峰：8.60。、10.76。、14.49。、16.33。、18.74。、19 18。2 XRPD 23.65。及24.12。。應瞭解所指定的2以意謂該指定值=。。。、 11 200940050 表1.圖1之XRPD峰位置（°20) 晶格面距（A) I/Ioa 8.60 10.27 72 10.76 8.21 22 12.40 7.13 4 13.48 6.56 6 14.49 6.11 32 15.24 5.81 6 16.33 5.42 26 17.49 5.07 8 18.74 4.73 100 19.18 4.62 23 19.93 4.45 18 20.92 4.24 69 22.50 3.95 12 23.17 (肩峰） 3.84 4 23.65 3.76 38 24.12 3.69 31 24.76 3.59 5 25.88 3.44 5 27.13 3.28 4 27.72 3.22 19 28.45-28.69 (寬峰） 3.13-3.11 7-6 29.18 3.06 13 30.01-30.28 (寬峰） 2.98-2.95 6-5 30.73 2.91 8 31.81 2.81 4 32.35-33.38 (寬峰） 2.77-2.68 3-4 35.00 2.56 7 36.64 2.45 3 38.73 2.32 6 39.34 2.29 4 a. 1/1。=相對強度 200940050 如本文中所用，「主要XRPD峰」係指相對強度大於 20%之XRPD峰。相對強度係按所關注之峰之峰強度與最大峰之峰強度的比率計算。一在本發明之另一具體實例中，化合物i之A形特徵為展示於圖2(A)之差示掃描熱量測定（本文中稱為「」) 曲線中起㈣191±1.0t：且最大值在196±1〇t：下的吸熱轉變。該曲線繪出熱流為來自於含有A形化合物ι之樣品溫Peak: 8.60. 10.76. 14.49. 16.33. 18.74. , 19 18. 2 XRPD 23.65. And 24.12. . It should be understood that the specified 2 means that the specified value =. . . , 11 200940050 Table 1. XRPD peak position of Figure 1 (°20) Lattice spacing (A) I/Ioa 8.60 10.27 72 10.76 8.21 22 12.40 7.13 4 13.48 6.56 6 14.49 6.11 32 15.24 5.81 6 16.33 5.42 26 17.49 5.07 8 18.74 4.73 100 19.18 4.62 23 19.93 4.45 18 20.92 4.24 69 22.50 3.95 12 23.17 (shoulder) 3.84 4 23.65 3.76 38 24.12 3.69 31 24.76 3.59 5 25.88 3.44 5 27.13 3.28 4 27.72 3.22 19 28.45-28.69 (wide peak) 3.13-3.11 7-6 29.18 3.06 13 30.01-30.28 (wide peak) 2.98-2.95 6-5 30.73 2.91 8 31.81 2.81 4 32.35-33.38 (wide peak) 2.77-2.68 3-4 35.00 2.56 7 36.64 2.45 3 38.73 2.32 6 39.34 2.29 4 a. 1/1. = Relative Strength 200940050 As used herein, "major XRPD peak" refers to an XRPD peak having a relative intensity greater than 20%. The relative intensity is calculated as the ratio of the peak intensity of the peak of interest to the peak intensity of the largest peak. In another embodiment of the present invention, the A-shaped characteristic of Compound i is shown in the differential scanning calorimetry (herein referred to as "") curve of Figure 2(A) (4) 191 ± 1.0 t: and the maximum value The endothermic transition at 196 ± 1 〇 t:. The curve depicts the heat flow from the temperature of the sample containing the A-form compound ι

f的函數。使用每分鐘1(rc之掃描速率自25艺至25(rc對樣品執行DSC。、化5物1之A形特徵亦為展示於圖2(B)之熱解重量 :析（本文中稱為r TGA」）曲線。該曲線繪出樣品之重量為温度之函數’其中自25。〇至25〇t，溫度變化速率昧分鐘1〇。〇該曲線展示當樣品溫度自25。〇變化至17〇艺時’重量損失為約0.47%。令化合物1之A形特徵亦為展示於圖3之爪譜。更特定化合物iiA形在KBr基質（例如，KBr壓片）中庙有（例如）32〇6、1691、1376及1352 cm-丨之汲吸收峰。應瞭解特定m吸收峰意謂特定值土lcm·、化合物ι之a形特徵亦為由展示於圖4之固態丨3c_nmr 化合物1之A形特徵亦為0.2-〇.3g/ml之容積密度。匕口物1之A形特徵亦為在每分鐘之加熱速率下 l.(TC-193± l.(TC 之熔點。匕〇物1之A形特徵亦為展示於圖％之拉曼光譜 13 200940050 (Raman spectrum )。更特定言之，化合物i 如”—…一、拉曼吸收峰二定拉曼吸收峰意謂特定值±1 cm·1。晶體慣態1 在一具艎實你J中’化合物！之A形特徵為晶體慣態i。 A形之晶體慣態1 一般可由化合物i於多種溶劑（諸如，丙嗣、乙酸乙醋、乙醇、四氫咬喃、二氣甲燒或其水性混人物）中之飽和溶液製備。亦可使用乙酸乙醋、乙醇、四^ 呋喃及二氣甲烷含水或不含水之混合物。在一具體實例中。，晶艎慣態1係藉由將化合物i之熱飽和丙酮·水溶液自 50°C以上、-般在耽與贼之間（例如，㈣）的田度冷卻至周圍溫度來製備。通常，以體積計，化合物^熱丙酮-水溶液之水與丙嗣的比率等於或大於ι:ι。通常採用之丙酮及水之量各自獨立地大於每i公斤化合物i 12 L。在-實例中，所採用之丙酮及水之量各自獨立地大於 1公斤化+合物1 14 L，諸如每1公斤化合物1 25 L。、接著使化合物1之熱丙酮·水溶液冷卻至周圍溫戶，且 :所得混合物攪掉—定時段以使八形之晶：雖然授掉時段通常為i天以上（例如，2天或3天以:：。，但應注意該時段可且），奴了易於藉由評估來自所得混合物之— 沈澱的特徵性暂_ —分 (例如’ IR或NMR )來確定。在一眘紅攪拌時段在3-4天之„如士 + 在實例中，室溫且通常在18七以。广η固恤度」意謂 L-25C (例如 ’ 18°C-23°C)之間。在一特定具體實例中，A形之晶體慣態1特徵為諸如針 200940050 狀或棒狀形狀之細長形狀。在另一特定具體實例中，該針狀或棒狀形狀具有小於50微米、通常小於2〇微米之平均晶體大小（主要或最長尺寸）。在還另一特定具體實例中，晶體慣態1為平均大小小於50微米之針狀或棒狀晶體的黏聚物’其中該黏聚物具有1)9〇在100微米與6〇〇微米之間或100微米與500微米之間的粒度分布（PSD ) ^在還另一特定具體實例中，晶體慣態1為平均大小小於5〇微米之針狀或棒狀晶體的黏聚物，其中該黏聚物具有D9〇在6〇與1〇〇〇微米之間的粒度分布（PSD)。在還另一特定具體實例中，至少50重量。/。之晶髏慣態1通過篩網需要大於丨5〇微米之篩網。在一實例中’至少70重量％之晶體慣態1通過篩網需要大於150微米之薛網。在另一實例中，至少80重量％之晶體慣態1通過篩網需要大於150微米之篩網。在還另一實例中’至少90重量％之晶體慣態丨通過篩網需要大於 150微米之篩網。在一具體實例中，小於50重量％之晶體 ^ 慣態1通過1 50微米篩網。在另一具體實例中，小於40重量％之晶體慣態1通過15 0微米篩網。在另一具髏實例中，小於30重量％之晶體慣態1通過150微米篩網。在另一具體實例中，小於20重量％之晶體慣態！通過ι5〇微米篩網。在另一具體實例中，小於10重量％之晶體慣態1通過15〇微米篩網。在一具體實例中，通過500微米篩網之晶體慣態1之重組時間超過25分鐘。如本文中所用’重組時間係在50:50 Cremophor EL/乙醇溶液中於周圍溫度（例如，18-25°C )下量測。重組時間 15 200940050 可根據實施例7中描述之程序量測。舉例而言，藉由將266 mg化合物1溶解於16.7 mL 50:50 Cremophor EL/乙醇溶液中，以232-236 rpm之速度手工振盪或機械振盪來量測重組時間》在另一具體實例中，A形之晶艎慣態1具有大於或等於約4至小於或等於約π之長寬縱橫比（亦即，約4沒從橫比鐵13)。在另一具體實例中，長宽縱橫比為大於或等於約 5至小於或等於約1〇 (亦即，約5鐵橫比識10 )。The function of f. Use a scan rate of 1 per minute (rc scan rate from 25 to 25 (rc performs a DSC on the sample. The A-shaped feature of the 5 object 1 is also shown in the thermogravimetric weight shown in Figure 2 (B): r TGA") curve. The curve plots the weight of the sample as a function of temperature 'where from 25 〇 to 25 〇t, the rate of temperature change 昧 min 1 〇. 〇 This curve shows the change in sample temperature from 25 〇 to 17 The weight loss is about 0.47%. The A-shaped feature of Compound 1 is also shown in Figure 3. The more specific compound iiA shape is in the KBr matrix (for example, KBr tablet).汲6, 1691, 1376, and 1352 cm-丨 absorption peaks. It should be understood that the specific m absorption peak means a specific value of soil lcm·, and the a-shaped characteristic of the compound ι is also represented by the solid 丨3c_nmr compound 1 shown in Fig. 4 The A-shaped feature is also a bulk density of 0.2-〇.3g/ml. The A-shaped characteristic of the mouthwash 1 is also at a heating rate per minute. (TC-193±l. (the melting point of TC. The A-shaped feature of 1 is also shown in Figure Raman Spectrum 13 200940050 (Raman spectrum). More specifically, compound i such as "-... one, Raman suction The peak-density Raman absorption peak means a specific value ±1 cm·1. Crystal habit 1 In a tamping of your J' compound A's characteristic is crystal habit i. A-shaped crystal habit 1 It can be prepared from a saturated solution of compound i in various solvents such as acetamidine, ethyl acetate, ethanol, tetrahydroanion, dioxin or its water-mixed person. Ethyl acetate, ethanol, etc. can also be used. A mixture of furan and di-halogen methane with or without water. In a specific example, the crystal halo 1 is obtained by heating a saturated aqueous solution of the compound i from above 50 ° C, between the cockroach and the thief. (For example, (4)) The field is prepared by cooling to ambient temperature. Usually, the ratio of water to propionate of the compound ^hot acetone-water solution is equal to or greater than ι:ι by volume. The amount of acetone and water usually used is Independently greater than 12 L per 1 kg of compound i. In the example, the amount of acetone and water used is each independently greater than 1 kg of compound + 14 L, such as 1 25 L per 1 kg of compound. The hot acetone solution of Compound 1 is cooled to the surrounding temperature, and: The mixture is stirred up - for a period of time to make the octagonal crystal: although the period of the grant is usually more than i days (for example, 2 days or 3 days with :::, but it should be noted that the time is available), the slave is easy to use Evaluate the characteristic temporary _-points of the precipitate from the resulting mixture (eg 'IR or NMR) to determine. 3-4 days in a cautious red mixing period „如士+ In the example, room temperature and usually at 18 Seven to. Wide η solidity means "between L-25C (eg '18 ° C-23 ° C). In a particular embodiment, the A-shaped crystal habit 1 features an elongated shape such as a needle 200940050 or a rod shape. In another specific embodiment, the needle or rod shape has an average crystal size (primary or longest dimension) of less than 50 microns, typically less than 2 microns. In yet another specific embodiment, the crystal halo 1 is a viscous or rod-like crystal of an average size of less than 50 microns. wherein the binder has 1) 9 Å at 100 microns and 6 microns. Or a particle size distribution (PSD) between 100 microns and 500 microns. In yet another specific embodiment, the crystal halo 1 is a cohesive of needle-like or rod-like crystals having an average size of less than 5 microns. The binder has a particle size distribution (PSD) of D9 〇 between 6 〇 and 1 〇〇〇 micron. In yet another particular embodiment, at least 50 weights. /. The crystal 1 of the crystal is required to pass through the screen to a screen larger than 丨 5 μm. In one example, at least 70% by weight of the crystal habit 1 passes through the screen and requires a network of more than 150 microns. In another example, at least 80% by weight of the crystalline habit 1 requires a screen of greater than 150 microns through the screen. In yet another example, at least 90% by weight of the crystalline habit enthalpy through the screen requires a screen greater than 150 microns. In one embodiment, less than 50% by weight of the crystals ^ habit 1 pass through a 150 micron screen. In another embodiment, less than 40% by weight of the crystal habit 1 passes through a 150 micron screen. In another example, less than 30% by weight of the crystal habit 1 passes through a 150 micron screen. In another specific example, less than 20% by weight of the crystal habit! Pass ι5 〇 micron screen. In another embodiment, less than 10% by weight of the crystal habit 1 passes through a 15 微米 micron screen. In one embodiment, the recombination time through the crystal habit 1 of the 500 micron screen exceeds 25 minutes. The 'recombination time' as used herein was measured in a 50:50 Cremophor EL/ethanol solution at ambient temperature (e.g., 18-25 °C). Recombination time 15 200940050 can be measured according to the procedure described in Example 7. For example, by dissolving 266 mg of Compound 1 in 16.7 mL of a 50:50 Cremophor EL/ethanol solution, manually measuring the recombination time by shaking at 232-236 rpm or mechanically oscillating. In another embodiment, The A-shaped crystal enthalpy habit 1 has an aspect ratio of greater than or equal to about 4 to less than or equal to about π (i.e., about 4 is not from the transverse iron 13). In another embodiment, the aspect ratio has a length to width aspect ratio of greater than or equal to about 5 to less than or equal to about 1 Torr (i.e., about 5 iron cross-sectional ratios of 10).

晶體慣態2 在另一具體實例中’化合物1之A形特徵為晶體慣丨 2。A形之晶體慣態2 —般可由化合物1於多種溶劑（諸如丙酮、乙酸乙酯、乙醇、四氫呋喃、二氣曱烷、DMF或；水性混合物）中之飽和溶液製備。亦可使用丙酮、乙酸丨酯、乙醇、四氫呋喃、DMF及二氣甲烷含水或不含水之〉、合物。舉例而言，可使用乙醇' DMF及水之混合物。在1 具體實例中，晶體慣態2係由化合物i於丙酮及水中之jCrystal Habit 2 In another embodiment, the A-form of Compound 1 is characterized by crystal habit 2 . The A-form crystal habit 2 can be prepared from a saturated solution of Compound 1 in various solvents such as acetone, ethyl acetate, ethanol, tetrahydrofuran, dioxane, DMF or an aqueous mixture. Acetone, decyl acetate, ethanol, tetrahydrofuran, DMF, and di-methane may also be used, with or without water. For example, a mixture of ethanol 'DMF and water can be used. In a specific example, the crystal habit 2 is composed of the compound i in acetone and water.

和溶液製備《通常，以體積計，丙酮為主要部分。在一1 例中，以體積計，丙酮：水之比率大於5:1。在另一實例中> 以體積計，丙嗣：水之比率$ 7:1。在另—具體實例中，晶遣慣態2係由化合物；！之飽和丙酮溶液製備。所採用丙^ 量通常大於每i公斤化合物"2L丙網。在一實例中” 採用丙綢之量大於每1公斤化合物1 呖1 14]^丙_，諸如每公斤化合物1 28 L丙酮。接著將化合物1之丙嗣-水溶液赤合夜或丙酮溶液添加至冷7 16 200940050 中以引起至少一部分化合物！沈澱。通常，添加化合物ι 之溶液之水的溫度低於或等於1(rc (例如，i〇t：或 one)。在-實例中，添加化合物i之溶液之水的溫度低於或等於5。。（例如，(TC)。在添加期間，將所得混合物之溫度維持在低於或等於⑺它之溫度下（例如，在低於或等於5°C之溫度下）。在一特定具體實例中’在將化合物 1之溶液添加至冷水中完成後，接著使所得懸浮液溫至周圍溫度’且在周圍溫度下攪拌一定時段。And solution preparation "Normally, acetone is the main part by volume. In one case, the acetone:water ratio is greater than 5:1 by volume. In another example, the ratio of propylene:water is $7:1 by volume. In another specific example, the crystal habit 2 is composed of a compound; Prepared by saturated acetone solution. The amount of propylene used is usually greater than every 1 kg of compound " 2L. In one example, the amount of acryl is greater than 1 呖 1 14 per 1 kg of compound, such as 1 28 L of acetone per kg of compound. Next, the propionate-water solution of Compound 1 is added to the night or acetone solution to Cold 7 16 200940050 to cause at least a portion of the compound! Precipitation. Typically, the temperature of the water to which the solution of compound ι is added is less than or equal to 1 (rc (for example, i〇t: or one). In the example, compound i is added The temperature of the water of the solution is lower than or equal to 5. (for example, (TC). During the addition, the temperature of the resulting mixture is maintained at a temperature lower than or equal to (7) (for example, at 5 ° or lower) At a temperature of C. In a specific example, 'after the solution of Compound 1 is added to cold water, the resulting suspension is then warmed to ambient temperature' and stirred at ambient temperature for a certain period of time.

通常，添加化合物i之溶液的冷水之量大於ΐ8ι水：丙酮（以體積計），一般大於或等於2:1 (以體積計）。通常’化合物1之溶液至冷水中之添加執行1〇分鐘以上、-般2G分鐘以上之時段。在—實例中，化合物i之溶液至冷水中之添加執行2〇分鐘與4〇分鐘之間的時段。通常將由化合⑼1之溶液及冷水產生之懸浮液在周圍溫度下㈣i小時以上或3小時以上。在―實例中，該時段為3-U小時或6_12小時。在另—實例中，該時段為爪μ 小時。在-特定具體實例中，A形之晶體慣態2特徵為多核放射狀聚集體之黏聚物（球粒）^在另一特定具體實例中，晶體慣態2之晶體具有小於5〇微米（例 >，小於微之平均晶體大+(主要或最長尺寸）。在另—特定具體實例中，晶體慣態2為平均晶體大小小於5〇微米之精細的黏聚物’其中該黏聚物具有D9〇在1〇〇與15〇微:十:：的粒度分布（PSD)。在還另一特定具體實例中，晶體㈣ 17 200940050 2為平均晶體大小小於5〇與虫微水之精細晶體的黏聚％ ^ . 該黏聚物具有D50在60靼聚物’其中 «與100微米之間的單 (PSD)。在還另一特定 '叔度为布 /、體實例中，至少5〇體慣態2通過150微米餘_ 备里重/〇之曰日卞缔網。在—實例中，至少之晶體慣態2通過15〇微半兹_ 重量/〇微水篩網。在另一實例中，至少80 重量％之晶體慣態2通過！ π似r ★ 主ν川少90重量％之晶體慣態2 只』甲至、2通過150微米篩網。在另_Typically, the amount of cold water added to the solution of compound i is greater than ι8ι water: acetone (by volume), typically greater than or equal to 2:1 (by volume). Usually, the addition of the solution of Compound 1 to cold water is carried out for a period of 1 minute or longer, for a period of 2 G minutes or longer. In the example, the addition of the solution of compound i to cold water is carried out for a period of between 2 minutes and 4 minutes. The suspension produced by the combination of the solution of (9) 1 and cold water is usually at room temperature (iv) for more than i hours or more than 3 hours. In the instance, the time period is 3-U hours or 6_12 hours. In another example, the period is the jaws for hours. In a specific embodiment, the crystal habit 2 of the A-shape is characterized by a polynuclear radial aggregate of cohesive particles (pellets). In another specific embodiment, the crystal of the crystal habit 2 has a thickness of less than 5 μm. Example >, smaller than the average crystal size of the micro+ (main or longest dimension). In another specific embodiment, the crystal habit 2 is a fine cohesive polymer having an average crystal size of less than 5 〇 micrometers It has a particle size distribution (PSD) of D9〇 at 1〇〇 and 15〇: Ten:: In yet another specific example, the crystal (4) 17 200940050 2 is a fine crystal with an average crystal size of less than 5 〇 and insect micro water. The cohesive % ^ . The cohesive has a D50 at 60 靼polymer 'where « and 100 microns between the single (PSD). In yet another specific 'unclearness is cloth /, body examples, at least 5 〇 The body habit 2 passes through a 150 micron _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the example, at least 80% by weight of the crystal habit 2 passes! π like r ★ The main ν Chuan 90% by weight of the crystal habit 2 Only 』A to, 2 through 150 micron sieve. In another _

中，至少95重量％之晶體掩能， Λ 1 J 體填態2通過150微米篩網。一般〇而言，相較於晶體慣態i，曰日日體慣態2内聚性較小、可壓性較小且可滲透性較大， * θ 士此 _ 因此，其具有對於乾粉填充而言令人滿意之粉末流動性t。A a i王買。在晶體慣態2之情況下，可實現在周圍溫度下少於或尊於热以八雄 ‘ 凡寻於約1 5分鐘之重組時間。在一實例中，對於通過150微米餘網♦日抽）1 不師網之晶體慣態2而言，在50:5〇At least 95% by weight of the crystal is masked, and Λ 1 J is filled through the 150 micron screen. In general, compared to the crystal habit i, the solar habit 2 of the day is less cohesive, less compressible, and more permeable, * θ 士 _ therefore, it has a filling for dry powder Satisfactory powder fluidity t. A a i Wang bought. In the case of crystal habit 2, it is possible to achieve a recombination time of less than or about the heat at the ambient temperature to the eight males. In one example, for a crystal habit 2 that passes through a 150 micron residual network ♦ daily, 1 is not in the network, at 50:5 〇

Cremophor EL/乙醇中之番細眭„,丨、从士姑夏、-a時間少於或等於約15分鐘，例如少於約1〇分鐘或少於約5分鐘。在-具體實例中，至少 70重量％、80重量％、90重量％或％ s量％之晶體慣態2 ❹ 通過150微米篩網且具有在5〇:5〇 Crem〇ph〇r el/乙醇中少於15分鐘之重組時間。在另一具體實例中，A形之晶體慣態2(多核放射狀聚集體之黏聚物（球粒））具有大於或等於約丨且小於或等於約2之長寬縱橫比（亦即，約i会從橫比鐵2 )。在另一具體實例中，長寬縱橫比為約1.2。在另一具體實例中，至少70重量％ ' 8〇重量％、9〇重量％或95重量％之晶體慣態2通過15〇微米篩網且具有大 18 *200940050 於或等於約1且小於或等於約2之長寬縱橫比。太s 你为一具體實例中’至少70重量％、80重量％、90重量％或％重量 %之晶體慣態2具有在50:50 Cremophor EL/乙醇中少於分鐘之重組時間及大於或等於約1且小於或等於約2之長寬縱橫比。在另一具體實例中，至少7〇重量％、8〇重量〇/ 90重量％或95重量％之晶體慣態2通過15〇微米筛網且具有在50:50 CremophorEL/乙醇中少於15分鐘之重組時門' 大於或等於約1且小於或等於約2之長寬縱橫比曰 © C形，在本發明之一具體實例中，化合物；!之單晶形特形。此晶形特徵亦在於使用Cu_Ka輻射獲得圖5所示具如表2所列之2"、晶格面距及相對強度之值的二、有 ::特定具體實例中’化合物！之晶形c形特徵為卜2、3。或 5 個選自 * 1〇.32。、14 8〇。、21 49。、23 、組成之群組之主要2|9角XRpD峰。在另— '12° 8中’化合物1之晶形c形特徵為以下…角=:例 21.49。、23.〇5。、24.34。及3〇12。。 .15、19.68。、 19 200940050 表2.圈5之XRPD峰位豎（°2Θ) 晶格面距（Α) I/Ioa 5.12 17.24 4 8.64 10.22 86 10.32 8.56 34 11.83 7.48 5 12.94 6.83 14 13.86 6.38 6 14.80 5.98 24 15.70 5.64 26 16.88 5.25 26 17.29 5.13 9 17.64 5.02 15 19.15 4.63 100 19.68 4.51 21 20.39 4.35 11 20.86-21.07 (寬峰） 4.26-4.21 11-13 21.49 4.13 64 21.91 (肩峰） 4.05 7 22.75 3.91 8 23.05 3.86 43 23.64 3.76 12 24.34 3.65 24 25.00-25.81 (寬峰） 3.56-3.45 7-10 26.93 3.31 8 27.75 3.21 4 28.48-28.66 (寬峰） 3.13-3.11 16-12 28.98 3.08 17 29.57 3.02 10 30.12 2.96 24 31.22 2.86 17 32.06 2.79 6 33.53 2.67 6 34.60 2.59 5 36.33 2.47 6 37.90 2.37 6 38.44-38.80 (寬峰） 2.34-2.32 4 31/1。=相對強度 20 200940050 _在本發明之另—具體實例中，化合物1之c形特徵為展不於圏6(A)之差示掃描熱量測^(本文中稱為「dsc」）曲線中在142±1_『C下之放熱轉變及在197±1.(TC下之吸熱轉變。該曲線緣出熱流为來自於含有化合物1之C形之樣品溫度之函數。使用每分鐘10°c之掃描速率自25艺至25(rc 對樣品執行DSC。化合物1之C形特徵亦為展示於圖6(B)之熱解重量 φ 刀析（本文中稱為「TG A」）曲線。該曲線繪出樣品之重量知失％為溫度之函數，其中自25<t至25〇<t，溫度變化速率為每分鐘10。〇該曲線展示當樣品溫度自2yc變化至175它時，重量損失為約0.318% » 在一特定具體實例中，在每分鐘1〇〇c之加熱速率下，化合物1之C形在142 ± l.(TC-150 ± l.(TC下發生放熱轉變且接著在190 ± 1.〇。〇192 ± l.Ot：下熔融。 C形一般可由化合物i於多種溶劑（諸如，丙嗣、乙酸 ❿ 乙酯、乙醇、四氫呋喃、二氣甲烷或其水性混合物）中之飽和溶液製備。亦可使用丙酮、乙酸乙酯、乙醇、四氩吱掩及二氣甲烷含水或不含水之混合物。在一具體實例中，化合物1之C形係藉由將化合物1於二氣甲烧中之飽和溶液緩慢冷卻來製備。 D形在本發明之一具體實例中，化合物1之單晶形特徵為D 形。此晶形特徵亦在於使用Cu-Κα輻射獲得圖7所示具有表3所列之20角、晶格面距及相對強度之值的Xrpd圖。 21 200940050 在一特定具體實例中，化合物1之晶形D形特徵為卜2、3、 4、5、6、7、8、9、10 或 11 個選自由 7.520、13.220、13.90〇、 17.23° > 22.06° ' 22.66° > 23.35° ' 24.97° ' 26.65° ' 28.44° 及29.19°組成之群組之主要20角XRPD峰。在另一特定具體實例中，化合物1之晶形D形特徵為以下主要20角XRPD ： 7.52°' 7.84°' 13.22°' 13.90°' 15.82°' 16.75°' 17.23° ' 18.70° ' 19.71° ' 20.80° ' 22.06° ' 22.66° ' 23.35° > 23.74° ' 24.070、24.310、24.970、26.650、28.440及 29.19° ° 表3.圖7之XRPD峰位置（°2〇晶格面距（A) I/Ioa 6.55 13.49 12 7.52 11.75 96 7.84 11.27 21 11.79 7.50 5 13.22 6.69 97 13.90 6.36 96 15.07 5.87 6 15.82 5.60 46 16.75 5.29 30 17.23 5.14 93 18.70 4.74 73 19.71 4.50 77 20.35 4.36 8 20.80 4.27 60 21.35 4.16 10 22.06 4.03 100 22.66 3.92 23 23.35 3.81 25 23.74 3.75 31 24.07 3.69 55 24.31 3.66 78 24.97 3.56 88 22 200940050Cremophor EL/ethanol is a fine 眭, 丨, from Stuart, -a time less than or equal to about 15 minutes, such as less than about 1 minute or less than about 5 minutes. In the specific example, at least 70% by weight, 80% by weight, 90% by weight or % s by volume of the crystal habit 2 ❹ through a 150 micron sieve and having less than 15 minutes of recombination in 5〇:5〇Crem〇ph〇r el/ethanol In another embodiment, the A-form crystal habit 2 (the multi-core radial aggregate of the binder (spherulites)) has a length to width aspect ratio greater than or equal to about 丨 and less than or equal to about 2 (also That is, about i will be from the transverse iron 2). In another embodiment, the aspect ratio is about 1.2. In another embodiment, at least 70% by weight '8〇% by weight, 9〇% by weight or 95% The % by weight crystal habit 2 passes through a 15 〇 micron screen and has a length to width aspect ratio of 18 * 200940050 at or equal to about 1 and less than or equal to about 2. Too s you are at least 70% by weight in a specific example, 80% by weight, 90% by weight or % by weight of the crystal habit 2 has less than a minute of recombination in 50:50 Cremophor EL/ethanol And an aspect ratio of greater than or equal to about 1 and less than or equal to about 2. In another embodiment, at least 7 〇 wt%, 8 〇 wt 〇 / 90 wt%, or 95 wt% of the crystal habit 2 passes 15 〇Micromesh screen and having a length-to-width aspect ratio 曰© C shape of a recombination gate door of less than 15 minutes in 50:50 CremophorEL/ethanol, greater than or equal to about 1 and less than or equal to about 2, in one of the present invention In the example, the compound has a single crystal shape. The crystal form is also characterized by using Cu_Ka radiation to obtain the values of 2", lattice spacing and relative intensity shown in Table 5 as shown in Table 2: : In a specific example, the compound c-shaped feature of 'Compound! is 2, 3, or 5 selected from *1〇.32., 14 8〇., 21 49., 23, the main group of the group 2| 9-angle XRpD peak. In the other '12° 8', the crystal form c of the compound 1 is characterized by the following: angle =: Example 21.49., 23.〇5, 24.34, and 3〇12. .15, 19.68. , 19 200940050 Table 2. XRPD peak position of circle 5 (°2Θ) lattice spacing (Α) I/Ioa 5.12 17.24 4 8.64 10.22 86 10.32 8.56 34 11.83 7.48 5 12.94 6 .83 14 13.86 6.38 6 14.80 5.98 24 15.70 5.64 26 16.88 5.25 26 17.29 5.13 9 17.64 5.02 15 19.15 4.63 100 19.68 4.51 21 20.39 4.35 11 20.86-21.07 (wide peak) 4.26-4.21 11-13 21.49 4.13 64 21.91 (shoulder ) 4.05 7 22.75 3.91 8 23.05 3.86 43 23.64 3.76 12 24.34 3.65 24 25.00-25.81 (wide peak) 3.56-3.45 7-10 26.93 3.31 8 27.75 3.21 4 28.48-28.66 (wide peak) 3.13-3.11 16-12 28.98 3.08 17 29.57 3.02 10 30.12 2.96 24 31.22 2.86 17 32.06 2.79 6 33.53 2.67 6 34.60 2.59 5 36.33 2.47 6 37.90 2.37 6 38.44-38.80 (wide peak) 2.34-2.32 4 31/1. = relative intensity 20 200940050 - In another embodiment of the invention, the c-shaped characteristic of compound 1 is in the differential scanning calorimetry (referred to herein as "dsc") curve of 圏6(A) The exothermic transition at 142 ± 1 _ "C and the endothermic transition at 197 ± 1. (TC) The heat flow is a function of the temperature of the sample from the C shape containing Compound 1. The use of 10 ° C per minute The scan rate was from 25 to 25 (rc performed on the sample for DSC. The C-shaped feature of Compound 1 is also the thermogravimetric φ knife analysis (herein referred to as "TG A") curve shown in Figure 6 (B). The % weight loss of the sample is plotted as a function of temperature, where from 25 < t to 25 〇 < t, the rate of temperature change is 10 per minute. This curve shows the weight loss when the sample temperature changes from 2yc to 175 it. It is about 0.318% » In a specific example, at a heating rate of 1 〇〇c per minute, the C shape of Compound 1 is 142 ± l. (TC-150 ± l. (There is an exothermic transition under TC and then 190 ± 1. 〇〇 192 ± l. Ot: under melting. C-shape can generally be compound i in a variety of solvents (such as acetamidine, hydrazine acetate Preparation of a saturated solution in ester, ethanol, tetrahydrofuran, di-methane or an aqueous mixture thereof. It is also possible to use acetone, ethyl acetate, ethanol, tetrahydroanthracene and a mixture of dioxane methane with or without water. The C shape of the compound 1 is prepared by slowly cooling the saturated solution of the compound 1 in a two-gas methane. D-form In one embodiment of the present invention, the single crystal shape of the compound 1 is D-shaped. The crystal form is also characterized by the use of Cu-Κα radiation to obtain an Xrpd diagram having the values of the 20 angles, lattice spacing and relative intensities shown in Table 3 as shown in Figure 7. 21 200940050 In a specific embodiment, the crystal form D of Compound 1 The shape features are 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 selected from 7.520, 13.220, 13.90, 17.23 ° > 22.06 ° ' 22.66 ° > 23.35 ° ' 24.97 ° ' The main 20-corner XRPD peak of the group of 26.65° ' 28.44° and 29.19°. In another specific example, the crystalline form D of Compound 1 is characterized by the following main 20-corner XRPD: 7.52°' 7.84°' 13.22°' 13.90°' 15.82°' 16.75°' 17.23° ' 18.70° ' 19.71° ' 20 .80° ' 22.06° ' 22.66° ' 23.35° > 23.74° ' 24.070, 24.310, 24.970, 26.650, 28.440 and 29.19 ° ° Table 3. XRPD peak position of Figure 7 (°2〇 lattice spacing (A) I/Ioa 6.55 13.49 12 7.52 11.75 96 7.84 11.27 21 11.79 7.50 5 13.22 6.69 97 13.90 6.36 96 15.07 5.87 6 15.82 5.60 46 16.75 5.29 30 17.23 5.14 93 18.70 4.74 73 19.71 4.50 77 20.35 4.36 8 20.80 4.27 60 21.35 4.16 10 22.06 4.03 100 22.66 3.92 23 23.35 3.81 25 23.74 3.75 31 24.07 3.69 55 24.31 3.66 78 24.97 3.56 88 22 200940050

相對強度 Ο 在本發明之另一具體實例中，化合物1之〇形特徵為展示於圖8之DSC曲線。DSC曲線展示最大值在“Μ代之吸熱轉變’其引起最大值在n〇±1 〇它之放熱轉變接著 =大值在195±1.GC之吸熱轉變。該曲線綠出熱流為含有化之D形之樣溫度之函數。使用每分鐘1〇。〇之掃描速率自25。(：至25CTC對樣品執行DSC。 +，《物1之D形特徵亦為展示於圖9之以譜。舉例而 :，合物1之D形在KBr&f (例如，KBr^ )中具列如）3221、1708、1666及I376 cm_i之汛吸收峰。 23 200940050 化〇物1之0形特徵亦為展示於圖37之拉曼光譜。舉 ' 例而言，化合你！ 1 + η , 物1之D形具有（例如）1381、10〇4及695 cm·1 之拉曼吸收峰。〇在本發明之另一具體實例中，化合物1之D形特徵為單晶雜結構。該單晶艘結構係由使用M。⑪輻射自化合物 1之D形之合適單晶體獲得之χ射線晶體學資料導出。該晶體結構特徵為具有以下單位晶胞參數之PI 21/nl空間群： « = 14.4 ± 0.1 λ ； 6 = 5.7 ± 0.1 A ； c = 23.9 ± 〇.ι Λ ； ^ =102.1 ± 0.1 〇 ;且 ν = 1920 ± 1 Α3。 ^ ❹ 在一特定具鱧實例中，化合物1之〇形特徵為呈具有以下單位晶胞參數之PI 2 1/nl空間群形式的單晶體結構. α = 14.3994(8)人；6 = 5.7133(3) A ; c = 23 872(3)入· 尽=102.130(3) 0 ;且 V = 1920.1(2) A3。在另一特定具體實例中’化合物1之D形特徵為呈具有下表4之單位晶胞參數之PI 21/nl空間群形式的單晶體結構β ❹ 24 200940050 表4:化合物1之D形之晶體資料及資料收集參數Relative Strength Ο In another embodiment of the invention, the 〇-shaped feature of Compound 1 is the DSC curve shown in Figure 8. The DSC curve shows the maximum value in the "endothermic transition of the deuterium" which causes the maximum value at n 〇 ± 1 〇 its exothermic transition followed by the large value of the endothermic transition at 195 ± 1. GC. The curve green heat flow is contained A function of the temperature of the D-shape. Use 1 每 per minute. The scan rate of 〇 is from 25. (: to 25 CTC to perform DSC on the sample. +, "The D-shaped feature of the object 1 is also shown in Figure 9." And: the D shape of the compound 1 has a 汛 absorption peak such as 3221, 1708, 1666, and I376 cm_i in KBr&f (for example, KBr^). 23 200940050 The 0-shaped feature of the chemical composition 1 is also shown. In the Raman spectrum of Fig. 37, for example, compound you! 1 + η, the D shape of the object 1 has a Raman absorption peak of, for example, 1381, 10〇4, and 695 cm·1. In another embodiment, the D-shaped feature of Compound 1 is a single crystal heterostructure derived from the χ-ray crystallographic data obtained using M.11 radiation from a suitable single crystal of the D shape of Compound 1. The crystal structure is characterized by a PI 21/nl space group with the following unit cell parameters: « = 14.4 ± 0.1 λ ; 6 = 5.7 ± 0.1 A ; c = 23.9 ± 〇.ι Λ ; ^ =102.1 ± 0.1 〇; and ν = 1920 ± 1 Α 3. ^ ❹ In a specific example, the 〇 character of compound 1 is PI 2 with the following unit cell parameters Single crystal structure in the form of 1/nl space group. α = 14.3994(8) person; 6 = 5.7133(3) A ; c = 23 872(3) in · exhaust = 102.130(3) 0 ; and V = 1920.1(2) A3. In another specific example, 'the D-shape of Compound 1 is a single crystal structure in the form of a PI 21/nl space group having the unit cell parameters of Table 4 below. β ❹ 24 200940050 Table 4: D shape of Compound 1 Crystal data and data collection parameters

#is?>A>AA 化式空Q办C C19H20N4O2S2 400.52 P121/nl (第 14 號） 14.3994(8) 5.7133(3) 23.872(3) 102.130(3) 1920.1(2) 4 1.385 0.44x0.23x0.15 150. Μ〇Κ〇(0.71073) 石墨 0.286 經驗* 0.88 > 0.96 Nonius. KappaCCD 0 至 13、0 至 7、-30 至 30 4.98-54.94 0.36 SHELXTL 840.0 其中 P =(F〇2+2 F〇2)/3 26218 4333 0.071 4333 F〇2>2.0s(F〇2) 2776 254 0.00 0.052 0.130 0.957 β， F» A3 z d 計算 > gcnf3#is?>A>AA-style empty Q office C C19H20N4O2S2 400.52 P121/nl (No. 14) 14.3994(8) 5.7133(3) 23.872(3) 102.130(3) 1920.1(2) 4 1.385 0.44x0.23x0 .15 150. Μ〇Κ〇(0.71073) Graphite 0.286 Experience* 0.88 > 0.96 Nonius. KappaCCD 0 to 13, 0 to 7, -30 to 30 4.98-54.94 0.36 SHELXTL 840.0 where P =(F〇2+2 F 〇2)/3 26218 4333 0.071 4333 F〇2>2.0s(F〇2) 2776 254 0.00 0.052 0.130 0.957 β, F» A3 zd Calculation> gcnf3

晶體尺寸，mm U 溫度，K 輻射（波長，A) 單色器線性絕對係數，mm_1 .所應用之吸收校正透射因子：最小，最大繞射計 Λ、众、/範圍 2q範圍，° 馬赛克性（mosaicity)，° 所用程式 P'oiX) 加權 © 1/[s2(F02)+(0.0948P)2+0.0000P]，所收集之資料唯一資料及int 精化中所用之資料 R因子計算中所用之截止點 I>2.0s(I)之資料變數之數目最後循環中之最大位移/esd R(F〇)Crystal size, mm U temperature, K radiation (wavelength, A) Linear absolute coefficient of monochromator, mm_1. Applied absorption correction transmission factor: minimum, maximum diffraction meter, mass, / range 2q range, ° mosaic ( Mosaicity), ° Program P'oiX) Weighted © 1/[s2(F02)+(0.0948P)2+0.0000P], the only data collected and the data used in int refinement. The number of data variables of the cutoff point I>2.0s(I) The maximum displacement in the last loop/esd R(F〇)

Rw(F〇2) 適合度Rw (F〇2) fitness

Otwinowski Ζ·及 Minor. 1997. ·276,307 ° 25 200940050 圖U(A)展示化合物1之D形之單晶體結構的〇rtep 圖式’其中原子係由5〇%概率各向異性熱橢圓體表示。在一特定具體實例中，化合物1之D形特徵為展示於圖ιι(Β) /β結晶办轴向下觀察的堆積圖（packing pattern )。圖11 ( B ) 之化合物1之氫鍵制图展示於圖11(C)。 D形一般可由化合物i於多種溶劑（諸如，丙酮、乙酸乙酯、乙醇、四氫呋喃、二氣甲烷、DMF或其水性混合物）中之飽和溶液製備。亦可使用㈣、乙酸乙酯乙醇四 ❹ 氫夫喃、DMF及二氣甲烷含水或不含水之混合物。舉例而Otwinowski Ζ· and Minor. 1997. ·276,307 ° 25 200940050 Figure U(A) shows the 〇rtep pattern of the D-shaped single crystal structure of Compound 1 where the atomic system is represented by a 5〇% probability anisotropic thermal ellipsoid. In a specific embodiment, the D-shaped feature of Compound 1 is a packing pattern as viewed under the axial direction of Figure ιι ( /) / β. The hydrogen bond pattern of Compound 1 of Figure 11 (B) is shown in Figure 11 (C). The D shape can generally be prepared from a saturated solution of compound i in various solvents such as acetone, ethyl acetate, ethanol, tetrahydrofuran, dioxane, DMF or an aqueous mixture thereof. It is also possible to use (iv) ethyl acetate, ethanol, tetrahydrofuran, DMF and di-methane, with or without a mixture of water. For example

言’可使用乙醇、DMF及水之混合物。在—具趙實例中，D 形係由化合物1之飽和丙酮水溶液製備。通常，以趙積計，丙嗣為主要部分。在—實例中，以體積計，丙酮：水之比率大於5:1。在另—實例中，以體積計，丙酮：水之比率為7:1。視情況，可將—或多個D形晶種添加至丙嗣-水溶液中。在周圍溫度下將水添加至化合物•水溶液中。將所得混合物在周圍溫度下維持足以引起至少一部分化合物】沈 ❹ 殿，時段。在-具體實例中’添加至化合物ι溶液中之水之董與化合物1溶液之丙酮之量相 r ,, m Λ r t 八％ HI之水：丙酮 :積计）（例如，大於或等於2:1(以體積計））。或 ’：加至化合物i溶液中之水之量與化合物1溶液之丙酮之量相比，小於U之水：丙嗣（以溆1.1夕p弓η，積冲）（例如，0.5:1 與1.1之間或0.75:1與1:1之間）。在水添加至化合物i溶液中後，、實例中，在將冷及甲後，將所得混合小時以下（例如小時或2·4小時，拌或授動5 又時段。或者，可 26 200940050 將犯口物攪拌5小時以上（例如，8小時以上、⑺小時以上：8 12小時之間）。在另一具體實例中添加至化合物 1 /合液中之水之量與化合物j溶液之丙酮之量相比，小於 1:1之水(以體積計）’且在添加水後，將所得混合物攪拌或攪動5小時以下（例如，1-5小時或2-4小時）之時段。人在製備化合物1之D形之另—具體實例中藉由將化 ❹合物1之熱飽和丙酮-水溶液自5〇〇c以上（例如，5〇。匚與7〇(；c 之間諸如60 C)之溫度冷卻至周圍溫度來製備〇形。通常化〇物1之熱丙網-水溶液之水：丙酮的比率等於或大於 1:1 (以體積計）。在一特定具體實例中，化合物1之D形具有小於或等於0.1 g/rnL ( H g/mL)之容積密度。在另一特定具體實例中，在每分鐘l〇°C之加熱速率 ^，化合物！之〇形在162±1代164±1代下溶融接〇著在167 士 nc-169 土 ivc下放熱轉變，且接著在190 ± 1.0°C_192± 1.〇。〇下熔融。开v形成聚集體或顆粒之傾向較小，此對製造過程而言為有利的《在-具體實例中，D %大體上不含聚集體或顆粒。在另-具體實例中，低於5()重量％、4()重量％重量％、2〇重量％、10重量％、5重量％或1重量％之D形為聚集體或顆粒。例如可根據實施例4中所述之方法2製備D 形。本發明之其他具體實例係針對特徵為本文中討論之任 27 200940050 何單晶形之上述特徵的組合之化合物j之單晶形。特性化可為針對特定晶形所描述之XRPD、TGA、DSC及單晶體結構’則定中之一或多者的任何組合。舉例而言化合物1之單晶形特徵可為關於在XRPD掃描中主要峰之20角之 XRPD結果的任何組合及/或由自單晶趙結構分析獲得之資料導出的單位晶胞參數中之一或多者之任何組合。使用多種分析技術之單晶形肖性化<組合的實例包括 XRPD掃描中至少一個主要峰㈣位置及藉由相應DSC量〇測觀測到的一或多個熱流轉變期間與最大熱流有關之溫度；XRPD掃描中至少—個主要峰的⑺位置及在相應似量測中在指定溫度範圍内與樣品有關之—或多個重量損失；XRPD掃描中至少一個主要峰㈣位置及藉由相應靴量測觀測到的一或多個熱流轉變期間與最大熱流有關之溫度及在相應TGA量測中在指定溫度範圍内與樣品有關之一或多個重量損失。X，上述實例各自可用單晶形之一或多A mixture of ethanol, DMF and water can be used. In the case of Zhao, the D-form is prepared from a saturated aqueous acetone solution of Compound 1. Usually, in terms of Zhao Ji, Bingyin is the main part. In the example, the ratio of acetone:water is greater than 5:1 by volume. In another example, the acetone:water ratio is 7:1 by volume. Optionally, one or more D-shaped seed crystals may be added to the propionate-water solution. Water is added to the compound aqueous solution at ambient temperature. The resulting mixture is maintained at ambient temperature sufficient to cause at least a portion of the compound to sink. In the specific example, 'the amount of water added to the compound of the compound ι and the amount of acetone of the compound 1 solution r, m Λ rt 8% water of HI: acetone: product) (for example, greater than or equal to 2: 1 (by volume)). Or ': the amount of water added to the solution of the compound i is less than the amount of acetone of the solution of the compound 1, less than the water of U: propyl hydrazine (with 溆 1.1 p p η, accumulate) (for example, 0.5:1 with Between 1.1 or between 0.75:1 and 1:1). After the water is added to the solution of the compound i, in the example, after the cold and the nail are added, the mixture is mixed for less than the hour (for example, hour or 2.4 hours, mixed or administrated for 5 time periods. Or, 26 200940050 will be sin The mouth is stirred for more than 5 hours (for example, 8 hours or more, (7) hours or more: 8 12 hours). In another specific example, the amount of water added to the compound 1 / combined solution and the amount of acetone of the compound j solution In contrast, water less than 1:1 (by volume)' and after the addition of water, the resulting mixture is stirred or agitated for a period of less than 5 hours (eg, 1-5 hours or 2-4 hours). In another embodiment, the heat-saturated acetone-water solution of the chemical composition 1 is from 5 〇〇c or more (for example, 5 〇. 匚 and 7 〇 (; c such as 60 C) The temperature is cooled to the ambient temperature to prepare a dome shape. Generally, the ratio of the water of the hot polypropylene-aqueous solution of the hydrazine 1 to acetone is equal to or greater than 1:1 (by volume). In a specific embodiment, the compound 1 is D. The shape has a bulk density less than or equal to 0.1 g/rnL (H g/mL). In the case of the body, at a heating rate of 1 °C per minute, the compound shape of the compound is fused at 162 ± 1 generation 164 ± 1 generation, and the exothermic transformation is carried out under 167 nc-169 soil ivc, and then 190 ± 1.0 ° C _192 ± 1. 〇. Melting under the arm. The tendency to open v to form aggregates or particles is small, which is advantageous for the manufacturing process. In the specific example, D % is substantially free of aggregates. Or granules. In another embodiment, less than 5 () wt%, 4 () wt% wt%, 2 wt%, 10 wt%, 5 wt% or 1 wt% of the D shape is an aggregate or granule For example, a D-shape can be prepared according to Method 2 as described in Example 4. Other specific examples of the present invention are directed to a single crystal of Compound j characterized by a combination of the above-described features of any of the 27 200940050 single crystal forms discussed herein. The characterization can be any combination of one or more of the XRPD, TGA, DSC, and single crystal structures described for a particular crystal form. For example, the single crystal shape of Compound 1 can be related to the major peaks in an XRPD scan. Any combination of 20-degree XRPD results and/or from a single crystal structure Any combination of one or more of the unit cell parameters derived from the obtained data. Single crystal shape visualization using a variety of analytical techniques. Examples of combinations include at least one major peak (four) position in an XRPD scan and by corresponding DSC Measure the temperature associated with the maximum heat flow during one or more heat flow transitions observed; the (7) position of at least one of the major peaks in the XRPD scan and the sample-related or more in the specified temperature range Weight loss; at least one major peak (four) position in the XRPD scan and the temperature associated with the maximum heat flow during one or more heat flow transitions observed by the corresponding shoe measurements and within the specified temperature range in the corresponding TGA measurement About one or more weight loss. X, each of the above examples may be one or more of a single crystal shape

個單位晶胞參數㈣❹XRPD掃描中至少―個主要峰的 20位置。以上所討論之特性化組合可用於描述化合物ι之任何單晶形（例如’ A形、C形或〇形）。本文中所揭示之單晶形可為溶劑合物或水合物。「溶劑合物」係指結晶期間溶劑分子併人晶格中之晶形。溶劑合物可包括水或非水性溶劑，諸如乙醇、異丙醇、卿〇' 乙酸乙醇胺及EtOAc。併入晶格中之溶劑分子為水的溶劑合物通常稱為「水合物」。水合物包括化學計量水合物以 28 200940050 及含有可變量之水的組成物。或格可大入贫所揭不之單晶形之晶Unit unit cell parameters (4) 20 XRPD scan at least 20 positions of the main peak. The characterization combinations discussed above can be used to describe any single crystal form of the compound ι (e.g., 'A shape, C shape, or 〇 shape). The single crystal form disclosed herein may be a solvate or a hydrate. By "solvent" is meant a crystalline form of a solvent molecule in a human crystal lattice during crystallization. The solvate may include water or a non-aqueous solvent such as ethanol, isopropanol, sulphuric acid ethanolamine and EtOAc. The solvate in which the solvent molecule incorporated into the crystal lattice is water is commonly referred to as "hydrate". Hydrates include stoichiometric hydrates of 28 200940050 and compositions containing variable amounts of water. Or the grid can be enlarged into the crystal of the single crystal

含併入其中之水（亦即’無水）或其他溶劑。在某些特定具體實例中，A形、C rnhycA. v r λ- 小及D形各自獨立地大Contains water (i.e., 'anhydrous') or other solvent incorporated therein. In some specific embodiments, the A shape, the C rnhycA. v r λ- small and the D shape are each independently large

,不含水（無水）或其他溶劑。通常，A形、c形或D 形大體上不含水或其他溶劑意謂每！莫耳化合物ι少於U 莫耳水或任何溶劑；通常每i莫耳化合^少⑨〇 ι莫耳水或任何溶劑；更通常每i莫耳化合物1少於任何溶劑。 ^No water (anhydrous) or other solvents. Usually, the A-shape, the C-shape or the D-shape is substantially free of water or other solvents means each! The molar compound ι is less than U-mole water or any solvent; typically less than 9 moles of water per solvent or any solvent; more typically less than any solvent per mole of compound 1. ^

在本發明之另-具體實例令，醫藥組成物包含醫藥上可接受之載劑或稀釋劑及化合物丨之單晶形。在一特定具體實例中，單晶形為化合物！之A形。在另一特定具體實例中，單晶形為化合物1之C形。在另一特定具體實例中，單晶形為化合物1之D形。A形、c形及D形各自之特徵 (包括特定特徵）係如上所述。合適醫藥上可接受之載劑可含有不抑制所揭示化合物之生物活性的惰性成份。醫藥上可接受之載劑應具有生物相容性，亦即在投予個體後無毒、無發炎性、無免疫原性且不產生其他不當反應。可採用標準醫藥調配技術，諸如 Remington's Pharmaceutical Sciences, Mack Publishing Company，Easton，PA中所述之彼等技術。待投予之化合物之調配物將根據所選投藥途徑而變化（例如，溶液、乳液、膠囊）。用於非經腸投予之合適醫藥載劑包括（例如）無菌水、生理鹽水、抑菌鹽水（含有約0.9% mg/ml苄醇之鹽水）、碟酸鹽緩衝鹽水、漢克斯溶液（Hank's solution )、 29 200940050 林格氏乳酸鹽（Rlnger，s laetate )及其類似物。用於封裝組成物（諸如，在硬明膠或環糊精之塗層中）之方法在此項技術中已知（Baker 等人，「c〇ntr〇iied Release 〇f Bi〇1〇gical Active Agents」，John Wiley and s〇ns, i986)。個艘」為哺乳動物，較佳為人類但亦可為需要獸醫治療：動物’例如伴侣㈣（例如，犬' 貓及其類似動物）家畜（例如’牛、綿羊、豬、馬及其類似動物）及實驗動物（例如’大鼠、小鼠、豚鼠及其類似動物）。本發明之另-具趙實例為一種治療患有癌症之個體之方法。本發明之方法視情況可用於如下所述之多重抗藥性癌症該方法包含投予有效量之本文所述之化合物或醫藥組成物的步驟。其他抗增生或抗癌療法可與本發明之化合物或醫藥組成物組合以治療增生疾病及癌症。可與本發明之抗癌劑組合制之其他療法包括外科手術、放射療法（包括（但不限於)γ輻射、中子束放射療法、電子束放射療法、質子療法、近距離放射療法及全身性放射性同位素）及内刀泌療法。可與本發明之抗癌劑組合使用之其他抗癌劑包括生物反應調節劑（包括（但不限於）干擾素、介白素及腫瘤壞死因子（TNF ))、熱療法及冷療法、削弱任何不良反應之藥劑（例如，止吐藥）及其他經批准之化學治療藥物抗癌劑之特定實例在下文中詳細描述。較佳地，共同投予之抗癌藥物為使微管穩定之藥劑，諸如太平洋紫杉醇或太平洋紫杉醇類似物。如上所指示’本發明之一具體實例係針對治療患有癌 '200940050 症之個體。「治療患有癌症之個體」包括部分或大體上實現以下一或多種結果：使癌症生長或擴散停滯、減輕癌症程度（例如’減小腫瘤大小或減少患病位點的數目）、抑制癌症生長速率及改善或改良臨床症狀或與癌症有關之指標（諸如’組織或血清組份）。可藉由本發明之方法治療或預防之癌症包括（但不限於）人類肉瘤及癌瘤’例如纖維肉瘤、黏液肉瘤、脂肪肉瘤、軟骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、 ***肉瘤、***内皮肉瘤、滑膜瘤、間皮瘤、尤因氏瘤（Ewing’s tumor)、平滑肌肉瘤、橫紋肌肉瘤、結腸癌、胰腺癌、乳癌、卵巢癌、***癌、鱗狀細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌瘤、乳頭狀癌、乳頭狀腺癌、囊腺癌、艟性癌、支氣管癌、腎細胞癌、肝癌、膽管癌、.絨膜癌、精原細胞瘤、胚胎癌、韋爾姆斯氏瘤（wilms， tumor )、子宮頸癌、睾丸腫瘤、肺癌、小細胞肺癌、膀胱 ❹ 癌、上皮癌、神經膠質瘤、星形細胞瘤、髓母細胞瘤、顱因管瘤至管膜瘤、松果艘瘤、血管母細胞瘤、聽神經瘤、少突神經膠質瘤、腦脊膜瘤、黑色素瘤、神經母細胞瘤、視網膜母細胞瘤；白血病，例如急性淋巴細胞白血病及急性艟細胞白血病（脊髓母細胞白血病、前髓細胞白血病、骨髓單核細胞白血病、單核細胞白血病及紅白血病）；慢性白血病（慢性髓細胞（粒細胞）白血病及慢性淋巴細胞白血病）；及真性紅細胞增多症、淋巴瘤（霍奇金氏病 (Hodgkin’s disease)及非霍奇金氏病）、多發性骨髓瘤、 31 200940050 瓦爾登斯特倫氏巨球蛋白血病（Waldenstrobm's macroglobulinemia)及重鍵病。白血病之其他實例包括急性及/或慢性白血病，例如淋巴細胞白血病（例如’如p388 (鼠類）細胞系所例示）、大顆粒淋巴細胞白血病及淋巴母細胞白血病；T細胞白血病’例如T細胞白血病（例如，如CEm、jurkat及HSB-2 (急性）、YAC-1 (鼠類）細胞系所例示）、τ淋巴細胞白企病及T淋巴母細胞白血病；b細胞白血病（例如，如SB (急性）細胞系所例示）及B淋巴細胞白血病；混合細胞 Ο 白血病’例如B細胞及τ細胞白血病及B淋巴細胞及T淋巴細胞白企病，骨趙白企病’例如粒細胞白血病、骨趙細胞白金病（例如’如hl_6〇 (前髓細胞）細胞系所例示）及骨髓性白血病（例如，如K562 (慢性）細胞系所例示）；中性粒細胞白jk病；嗜伊紅血球白血病；單核細胞白血病 (例如，如THP-1 (急性）細胞系所例示）；骨髓單核細胞白血病；内格利氏（Naegeli )型骨髓白血病及非淋巴細胞白血病。白血病之其他實例描述於❹ 第 60 章，Michael C. Perry 編，Williams & Williams (1992)及心化 Cflwcer 仏价⑹第 5 版之第36部分，Bast等人編，b.C. Decker Inc. (2000)中。前述參考文獻之全部教示内容以引用的方式併入本文中。在一具體實例中，咸信所揭示之方法尤其有效治療患有非實體腫瘤（諸如，多發性骨趙瘤）之個體。在另一具體實例中，咸仏所揭示之方法尤其有效針對τ白血病（例 32 200940050 如，如Jurkat及CEM細胞系所例示）；B白血病（例如，如SB細胞系所例示）：前聽細胞（例如，如HL-60細胞系所例示）；子宮肉瘤（例如，如MES-SA細胞系所例示）；單核細胞白血病（例如，如THP -1 (急性）細胞系所例示）；及淋巴瘤（例如，如U937細胞系所例示）。所揭示之方法尤其有效治療癌症具有「多重抗藥性」之個體。最初對抗癌藥物有反應之癌症在該抗癌藥物不再有效治療患有該癌症之個體時變得對該抗癌藥物具有抗 ❹ 性。舉例而言’許多腫瘤最初將對抗癌藥物治療有反應，大小減小或甚至消退，不料竟會形成對該藥物之抗性。抗藥性腫瘤之特徵為儘管投予增加劑量之抗癌藥物，但其仍重新開始生長及/或在看似消退後再出現。對兩種或兩種以上抗癌藥物形成抗性的癌症稱為具有r多重抗藥性」。舉例而言，通常癌症對三種或三種以上抗癌劑、通常五種或五種以上抗癌劑且有時十種或十種以上抗癌劑具有抗性。 ❹ 「有效量」為當向患有癌症之個體投予化合物時實現有益臨床結果之化合物1之量。「有益臨床結果」包括與不進行該治療相比，腫瘤塊減小、轉移減少、與癌症有關之症狀的嚴重程度降低及/或個體壽命延長。向個體投予之化合物之精確量將視疾病或病狀之類型及嚴重程度及個體特徵（諸如，整體健康狀況、年齡、性別、體重及對藥物之耐受性）而定。其亦將視癌症之程度、嚴重程度及類型而定。熟習此項技術者將能夠根據此等及其他因素來域定適當劑量。有效量之所揭示化合物通常在每天約i mg/mm2 33 200940050 與每天約10 g/mm2之間的範圍内’且較佳在每天1〇 mg/mm2 ’ 與約5 g/mm2之間的範圍内《當與另一抗癌劑共同投予時，第二抗癌劑之「有效量」將視所用藥物之類型而定。經批准之抗癌劑的合適劑量係已知的且可由熟習此項技術者根據個體之病狀、所治療之癌症類型及所使用之化合物j之量進行調整。本文中所揭示之化合物或醫藥組成物係藉由任何合適之途徑投予，包括（例如）以膠囊、懸浮液或錠劑經口投予或藉由非經腸投予。非經腸投予可包括（例如）全身性 ❹ 投予’諸如藉由肌肉内、靜脈内、皮下或腹膜内注射。本文中所揭示之化合物及醫藥組成物亦可經口（例如，飲食）、局部、藉由吸入（例如，支氣管内、鼻内、經口吸入或鼻内滴劑）或經直腸投予，其視待治療之癌症類型而定。經口及非經腸投予為較佳投藥模式。視情況’本文中所揭示之化合物及醫藥組成物可與諸如以下各物之其他抗癌劑共同投予：阿黴素（Adriamycin )、放線菌素 D ( Dactinomycin)、博來黴素（Bleomycin) 、〇長春花鹼（Vinblastine )、順鉑（cisplatin )、阿西維辛 (acivicin ):阿柔比星（aclarubicin );鹽酸阿考達唑 (acodazole hydrochloride);阿克羅寧（acr〇nine );阿多來新（adozelesin )，阿地白介素（aldesleukin );六甲密胺（altretamine );安波徽素（ambomycin );乙酸阿美蒽醌（ametantrone acetate);胺魯米特（aminoglutethimide); 安吖啶（amsacrine);阿那曲唑（anastroz〇ie);安麯黴素 34 200940050 (anthramycin);天冬醯胺酶（asparaginase);曲林菌素 (asperlin );阿紮胞苦（azacitidine );阿紮替派（azetepa ); 阿佐黴素（azotomycin );巴馬司他（batimastat);苯佐替派（benzodepa );比卡魯胺（bicalutamide );鹽酸比生群（bisantrene hydrochloride );二甲績酸雙奈法德（bisnafide dimesylate);比折來新（bizelesin);硫酸博來黴素；布嗟那納（brequinar sodium) •，漠匹立明（bropirimine ); 白消安（busulfan);放線菌素 C ( cactinomycin);二甲睾嗣(calusterone );卡醋胺（caracemide );卡貝替姆 (carbetimer );卡銘（carboplatin );卡莫司；丁（ carmustine ); 鹽酸卡柔比星（carubicin hydrochloride ):卡折來新 (carzelesin ):西地芬戈（cedefingol );苯丁酸氮芬 (chlorambucil );西羅黴素（cirolemycin );克拉屈濱 (cladribine ):曱續酸克里奈托（crisnatol mesylate );環填醯胺（cyclophosphamide );阿糖胞苷（cytarabine );達卡巴嗓（dacarbazine );鹽酸道諾黴素（daunorubicin hydrochloride ):地西他濱（decitabine );右奥馬銘 (dexormaplatin );地紮胍寧（dezaguanine );甲續酸地紮脈寧；地吖酿（diaziquone );經道諸紅黴素 (doxorubicin );鹽酸經道諾紅黴素；曲洛昔芬 (droloxifene ):檸檬酸曲洛昔芬；丙酸屈他雄_ (dromostanolone propionate):達佐徽素（duazomycin ); 依達曲沙（edatrexate );鹽酸依氟烏胺酸（eflornithine hydrochloride );依沙蘆星（elsamitrucin );恩洛翻 35 200940050 (enloplatin );恩普胺醋（enpromate );依匹旅咬 (epipropidine ) ;鹽酸表柔比星（epirubicinIn another embodiment of the invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and a single crystal form of the compound. In a specific example, the single crystal is a compound! A shape. In another specific embodiment, the single crystal form is the C shape of Compound 1. In another specific embodiment, the single crystal form is the D shape of Compound 1. The characteristics (including specific features) of each of the A-shape, the c-shape, and the D-shape are as described above. Suitable pharmaceutically acceptable carriers can contain inert ingredients which do not inhibit the biological activity of the disclosed compounds. A pharmaceutically acceptable carrier should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and non-invasive after administration to an individual. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. The formulation of the compound to be administered will vary depending on the route of administration chosen (e.g., solution, emulsion, capsule). Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (salt containing about 0.9% mg/ml benzyl alcohol), discate buffered saline, Hanks' solution ( Hank's solution ), 29 200940050 Ringer's lactate (Rlnger, s laetate ) and its analogues. Methods for encapsulating compositions such as in hard gelatin or cyclodextrin coatings are known in the art (Baker et al., "c〇ntr〇iied Release 〇f Bi〇1〇gical Active Agents John Wiley and s〇ns, i986). A ship is a mammal, preferably a human but may also require veterinary treatment: an animal such as a companion (four) (eg, a dog's cat and its like) livestock (eg 'bovine, sheep, pig, horse and the like) And experimental animals (eg 'rats, mice, guinea pigs and the like). Another example of the invention is a method of treating an individual having cancer. The method of the invention may optionally be used in multi-drug resistant cancers as described below. The method comprises the step of administering an effective amount of a compound or pharmaceutical composition described herein. Other anti-proliferative or anti-cancer therapies can be combined with the compounds or pharmaceutical compositions of the invention to treat proliferative diseases and cancer. Other therapies that can be combined with the anticancer agents of the present invention include surgery, radiation therapy (including but not limited to gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemicity) Radioisotopes) and internal knife therapy. Other anticancer agents that can be used in combination with the anticancer agents of the invention include biological response modifiers (including but not limited to, interferon, interleukin and tumor necrosis factor (TNF)), heat therapy and cold therapy, weakening any Specific examples of adversely acting agents (e.g., antiemetics) and other approved chemotherapeutic agents are described in detail below. Preferably, the co-administered anticancer drug is an agent that stabilizes the microtubule, such as paclitaxel or paclitaxel analog. As indicated above, one specific embodiment of the invention is directed to treating an individual having cancer '200940050'. "Treatment of an individual with cancer" includes partial or substantial achievement of one or more of the following: stagnating cancer growth or spread, reducing the extent of cancer (eg, 'reducing tumor size or reducing the number of diseased sites), inhibiting cancer growth Rate and indicators that improve or improve clinical symptoms or cancer (such as 'tissue or serum component'). Cancers which can be treated or prevented by the methods of the invention include, but are not limited to, human sarcomas and carcinomas such as fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphatic vessels Sarcoma, lymphatic endothelial sarcoma, synovial tumor, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal Cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, spastic cancer, bronchial carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, spermatogonia Tumor, embryonic carcinoma, wilms, tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma , cranial tumor to tubular tumor, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinal Tumor; leukemia, such as acute lymphoblastic leukemia and acute leukocyte leukemia (myeloid leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia and erythroleukemia); chronic leukemia (chronic myeloid cells (granulocytes) Leukemia and chronic lymphocytic leukemia; and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, 31 200940050 Waldenstrom's giant Maldenemia (Waldenstrobm's macroglobulinemia) and double bond disease. Other examples of leukemia include acute and/or chronic leukemias, such as lymphocytic leukemia (eg, as exemplified by p388 (murine) cell lines), large granular lymphocytic leukemia and lymphoblastic leukemia; T cell leukemias such as T cell leukemia (eg, such as CEm, jurkat, and HSB-2 (acute), YAC-1 (murine) cell lines), tau lymphocytic disease, and T lymphoblastic leukemia; b-cell leukemia (eg, such as SB ( Acute cell line exemplified) and B lymphocytic leukemia; mixed cell Ο leukemia 'such as B cell and tau cell leukemia and B lymphocytes and T lymphocytes white disease, bone white disease 'such as granulocyte leukemia, bone Zhao Cellular platinum disease (eg, 'exemplified by hl_6〇 (pre-myeloid cell) cell line) and myeloid leukemia (eg, as exemplified by K562 (chronic) cell line); neutrophil white jk disease; eosinophilic leukemia; Monocytic leukemia (eg, as exemplified by THP-1 (acute) cell lines); bone marrow monocytic leukemia; Naegeli type myeloid leukemia and non- Lymphocyte leukemia. Other examples of leukemia are described in Chapter 60, Michael C. Perry, Williams & Williams (1992), and Cflwcer (6), Part 5, Part 36, Bast et al., bC Decker Inc. (2000) )in. All teachings of the aforementioned references are incorporated herein by reference. In one embodiment, the method disclosed by Yanshin is particularly effective in treating individuals suffering from non-solid tumors, such as multiple bone tumors. In another embodiment, the method disclosed by Saline is particularly effective against tau leukemia (Example 32 200940050, eg, as exemplified by Jurkat and CEM cell lines); B leukemia (eg, as exemplified by SB cell line): pre-hearing cells (for example, as exemplified by the HL-60 cell line); uterine sarcoma (for example, as exemplified by the MES-SA cell line); monocytic leukemia (for example, as exemplified by the THP-1 (acute) cell line); Tumors (e.g., as exemplified by the U937 cell line). The disclosed method is particularly effective in treating individuals with "multiple drug resistance" in cancer. A cancer that initially responds to an anticancer drug becomes resistant to the anticancer drug when the anticancer drug is no longer effective in treating an individual having the cancer. For example, many tumors initially respond to anticancer drug treatments, reduce in size or even subside, and unexpectedly develop resistance to the drug. Drug-resistant tumors are characterized by re-starting growth and/or reappearing after seemingly subside, despite the administration of an increased dose of anti-cancer drug. A cancer that develops resistance to two or more of the above anticancer drugs is said to have r multidrug resistance. For example, cancer is generally resistant to three or more anticancer agents, usually five or more anticancer agents and sometimes ten or more anticancer agents. 「 An "effective amount" is the amount of Compound 1 that achieves a beneficial clinical result when a compound is administered to an individual having cancer. "Beneficial clinical outcome" includes a reduction in tumor mass, a decrease in metastasis, a decrease in the severity of symptoms associated with cancer, and/or an increase in the lifespan of the individual as compared to not performing the treatment. The precise amount of a compound administered to an individual will depend on the type and severity of the disease or condition and the individual characteristics (such as overall health, age, sex, weight, and tolerance to the drug). It will also depend on the extent, severity and type of cancer. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors. An effective amount of the disclosed compound is typically in the range between about i mg/mm 2 33 200940050 per day and about 10 g/mm 2 per day 'and preferably between 1 〇 mg/mm 2 ' and about 5 g/mm 2 per day. "When co-administered with another anticancer agent, the "effective amount" of the second anticancer agent will depend on the type of drug used. Suitable dosages of approved anticancer agents are known and can be adjusted by those skilled in the art depending on the condition of the individual, the type of cancer being treated, and the amount of compound j employed. The compounds or pharmaceutical compositions disclosed herein are administered by any suitable route, including, for example, orally or by parenteral administration in capsules, suspensions or lozenges. Parenteral administration can include, for example, systemic sputum administration, such as by intramuscular, intravenous, subcutaneous or intraperitoneal injection. The compounds and pharmaceutical compositions disclosed herein may also be administered orally (eg, by diet), topically, by inhalation (eg, intrabronchial, intranasal, oral or intranasal drops) or rectally, Depending on the type of cancer to be treated. Oral and parenteral administration are preferred modes of administration. Depending on the situation, the compounds and pharmaceutical compositions disclosed herein can be co-administered with other anticancer agents such as Adriamycin, Dactinomycin, and Bleomycin. , Vinblastine, cisplatin, acivicin: aclarubicin; acadazole hydrochloride; acronin (acr〇nine) ; adozelesin, aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; (amsacrine); anastrozazole (anastroz〇ie); aflatoxin 34 200940050 (anthramycin); asparaginase; asperlin; azacitidine; azacitidine Azetopa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; Bisnafide dimesyl Ate); bizelesin; bleomycin sulfate; brequinar sodium • bropirimine; busulfan; cactinomycin; Calusterone; carracemide; carbetimer; carboplatin; carmust; carmustine; carubicin hydrochloride: card fold New (carzelesin): cedefingol; chlorambucil; cirolemycin; cladribine: cristatol mesylate; Cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride: decitabine; dexormaplatin; Dezaguanine; jiazining; diaziquone; erythromycin (doxorubicin); erythromycin hydrochloride; droloxifene: citric acid Ciclofen; dromostanolone propionate: Dazuo Duazomycin ); edatrexate; eflornithine hydrochloride; elsamitrucin; 恩洛翻35 200940050 (enloplatin); enpromate vinegar (enpromate); Epipoidine; epirubicin hydrochloride (epirubicin)

hydrochloride );厄布洛°坐（erbulozole );鹽酸依索比星 (esorubicin hydrochloride);雌莫司汀(estramustine )；雌莫司汀填酸納；依他琐唾（etanidazole );依託泊苷 (etoposide ):填酸依託泊苷；埃托寧（etoprine );鹽酸法屈0坐（fadrozole hydrochloride );法紫拉濱（fazarabine ); 芬維 A 胺（fenretinide);氮尿苷（floxuridine);氟填酸達拉賓（fludarabine phosphate );氟尿嘴咬（fluorouracil ); IL 西他濱（flurocitabine );破喧酮（fosquidone );福司曲星納（fostriecin sodium) •，吉西他賓（gemcitabine);鹽Hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium; etanidazole; etoposide Etoposide ): acid etoposide; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; Fludarabine phosphate; fluorouracil; IL flurocitabine; fosquidone; fostriecin sodium • gemcitabine ;salt

酸吉西他賓；經基腺（hydroxyurea );鹽酸黃膽素（idarubicin hydrochloride );異環填酿胺（ifosfamide );伊莫福新 (ilmofosine );介白素II(包括重組介白素II或rIL2 )、干擾素a-2a ;干擾素a-2b ;干擾素α-ηΐ ;干擾素α-η3 ;干擾素|8-Ia;干擾素γ-Ib;異丙鉑（iproplatin);鹽酸伊立替康（irinotecan hydrochloride ):乙酸蘭瑞肽（lanreotide acetate);來曲哇（letrozole);乙酸亮丙立德（leuprolide acetate);鹽酸利阿唾（liarozole hydrochloride);洛美曲索納（lometrexol sodium ):洛莫司汀（lomustine ):鹽酸洛索蒽親(losoxantrone hydrochloride );馬索羅盼 (masoprocol );美登素（maytansine ):鹽酸氮芥 (mechlorethamine hydrochloride );乙酸甲地孕酮 (megestrol acetate );乙酸美俞孕嗣（melengestrol 36 *200940050Gemcitabine; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II) Or rIL2), interferon a-2a; interferon a-2b; interferon α-ηΐ; interferon α-η3; interferon|8-Ia; interferon γ-Ib; iproplatin; Irinotecan hydrochloride: lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium ): lomustine: losoxantrone hydrochloride; masoprocol; maytansine: mechlorethamine hydrochloride; megestrol acetate Acetate); acetic acid meyer pregnancy (melengestrol 36 *200940050

acetate);美法命（melphalan);美諾立爾（menogaril); 疏基嗓吟（mercaptopurine );甲胺嗓吟（methotrexate ); 甲胺嗓吟鈉；蔓托寧（metoprine );美妥替〇底（meturedepa ); 米丁度胺（mitindomide);米托卡西（mitocarcin);米托羅米（mitocromin ):米托潔林（mitogillin );米托馬星 (mitomalcin );絲裂黴素（mitomycin );米托司培 (mitosper );米托坦（mitotane );鹽酸米托蒽醌 (mitoxantrone hydrochloride );徽盼酸（mycophenolic acid );諾考達 β坐（nocodazole );諾拉黴素（nogalamycin ); 奥馬銘（ormaplatin );奥昔舒命（oxisuran );培門冬酶 (pegaspargase );培利黴素（peliomycin );奈莫司汀 (pentamustine );硫酸培洛黴素（peplomycin sulfate ); 培填酿胺（perfosfamide );略泊漠烧（pipobroman ) ; 〇辰泊舒凡（piposulfan ):鹽酸0比羅蒽酿（piroxantrone hydrochloride );普卡黴素（plicamycin );普洛美坦 (plomestane ) ; 〇卜吩姆納（porfimer sodium ):泊非黴素 (porfiromycin );潑尼莫司汀（prednimustine );鹽酸丙卡巴肼（procarbazine hydrochloride );嗓吟黴素 (puromycin );鹽酸嘌吟黴素；0比"坐0夫喃菌素 (pyrazofurin );利波腺苷（riboprine );羅穀亞胺 (rogletimide);沙芬戈（safingol);鹽酸沙芬戈；司莫司汀（semustine ) •，辛曲秦（simtrazene );司泊索非納 (sparfosate sodium);司帕黴素（sparsomycin);鹽酸錄螺胺（spirogermanium hydrochloride );螺莫司、汀 37 200940050 〇Acetate); melphalan; menogaril; mercaptopurine; methotrexate; methotrexate; metoprine; Meturedepa; mitindomide; mitocarcin; mitocromin: mitogillin; mitomalcin; mitomycin Mitomycin); mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; noramycin Nogalamycin ); ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate Perfosfamide; pipobroman; piposulfan: piroxantrone hydrochloride; plicamycin; promethate (plomestane); porfimer sodium: porfiromycin; Prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; 0 ratio "pyrazofurin; Lipo adenosine Ribopren); rogletimide; safingol; safingo hydrochloride; semustine • simtrazene; sparfosate sodium; Sparsomycin; spirogermanium hydrochloride; spirulina, Ting 37 200940050 〇

(spiromustine ):螺翻（spiroplatin ):鍵黑黴素 (streptonigrin ):鏈腺黴素（streptozocin );績氣苯腺 (sulofenur );他利黴素（talisomycin );替康蘭納（tecogalan sodium);替加氣（tegafur);鹽酸替洛蒽酿（teloxantrone hydrochloride );替莫泊芬（temoporfin );替尼泊戒 (teniposide );替羅昔隆（teroxirone );睾内醋 (testolactone );嗟咪嗓呤（thiamiprine );硫鳥嗓吟 (thioguanine );嘆替派（thiotepa );嘆嗤0夫林（tiazofurin ); 替拉紮明（tirapazamine ):檸檬酸托瑞米芬（toremifene citrate );乙酸曲托龍（trestolone acetate ):填酸曲西立濱（triciribine phosphate );三甲曲沙（trimetrexate );葡萄糖搭酸三甲曲沙（trimetrexate glucuronate);曲普瑞林 (triptorelin);鹽酸妥布氯嗤（tubulozole hydrochloride); 烏拉莫司汀（uracil mustard);烏瑞替派（uredepa);伐普肽（vapreotide);維替泊芬（verteporfin);硫酸長春花驗（vinblastine sulfate );硫酸長春新驗（vincristine sulfate);長春地辛（vindesine);硫酸長春地辛；硫酸長春匹定（vinepidine sulfate);硫酸長春甘 S旨（vinglycinate sulfate);硫酸長春羅新（vinleurosine sulfate);酒石酸長春瑞賓（vinorelbine tartrate );硫酸長春羅定（vinrosidine sulfate);硫酸長春利定（vinzolidine sulfate);伏羅*坐 (vorozole);折尼始（zeniplatin);淨司他丁（ zinostatin); 逢酸左柔比星（zorubicin hydrochloride )。其他抗癌藥物包括（但不限於）：20-表-1，25二羥維生 38 200940050 素 D3; 5-乙快尿痛咬（5-ethynyluracil );阿比特龍 (abiraterone ):阿柔比星；醯基富稀（acylfulvene );腺環戊醇（adecypenol);阿多來新；阿地白介素；ALL_TK 拮抗劑；六甲密胺；胺莫司汀（ambamustine );艾美多 (amidox );胺構、;r ( amifostine );胺基乙酿丙酸 (aminolevulinic acid);胺柔比星（amrubicin);安0丫咬；阿那格雷（anagrelide );阿那曲嗓；穿心蓮内酯 (andrographolide );血管生成抑制劑；拮抗劑D;拮抗劑 G ;安他利（antarelix );抗背部化形態發生蛋白-1 (anti-dorsalizing morphogenetic protein-1 );抗雄激素 (antiandrogen)，***癌；抗***（antiestrogen )；抗新普拉通（antineoplaston);反義寡核苷酸；甘胺酸阿非迪黴素（aphidicolin glycinate );細胞凋亡基因調節劑；細胞凋亡調控劑；無嘌呤核酸；ara-CDP-DL-PTBA ;精胺酸脫胺酶；奥沙那寧（asulacrine );阿他美坦（atamestane ); 阿莫司汀（atrimustine );阿新司坦汀（axinastatin) 1 ;阿新司坦、汀2;阿新司坦'汀3;阿紮司填（azasetron );阿紮托新（azatoxin);重氮酷胺酸（azatyrosine);漿果赤黴素III衍生物；班蘭諾（balanol);巴馬司他；BCR/ABL 括抗劑；苯并氣（benzochlorins );苯甲醯基星形抱菌素 (benzoylstaurosporine ) ； β 内醢胺衍生物；/3-阿立辛 (beta-alethine );倍他黴素 B ( betaclamycin Β );樺木酸 (betulinic acid) ; bFGF抑制劑；比卡魯胺；比生群；雙氮丙°定基精胺（bisaziridinylspermine);雙奈法德；雙曲 39 200940050(spiromustine): spiroplatin: streptonigrin: streptozocin; sulofenur; talisomycin; tecogalan sodium ; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; Thiamiprine; thioguanine; thiotepa; tiazolefurin; tirapazamine: toremifene citrate; Trestolone acetate: triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tobramycin hydrochloride Bul (tubulozole hydrochloride); uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; Vincristine sulfate Vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; Vinrosidine sulfate; vincrolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include (but are not limited to): 20-Table-1, 25 Dihydroxyvitamin 38 200940050 Prime D3; 5-Ethyynyluracil; Abiraterone: Aroubi Star; acylfulvene; adencypenol; adoline; aldileukin; ALL_TK antagonist; hexamethylene melamine; amemustine; amidox; Amine structure; r ( amifostine ); aminolevulinic acid; amrubicin; ampoules; anagrelide; anastrobine; andrographolide Angiogenesis inhibitor; antagonist D; antagonist G; antaric (antarelix); anti-dorsalizing morphogenetic protein-1; antiandrogen, prostate cancer; Estrogen (antiestrogen); anti-nepranoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptotic gene regulator; apoptosis regulator; Nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; oxazanin (asulac Rine ); atamestane; atrimustine; axistatin 1; ashinstatin, statin 2; ashinstatin 'tin 3; azasitetron; Azatoxin; azatyrosine; baccatin III derivative; balanol; bamastat; BCR/ABL inhibitor; benzochlorins ; benzoylstaurosporine; β-indoleamine derivatives; /3-beta-alethine; betaclamycin ;; betulinic acid; bFGF inhibitor; bicalutamide; biotic group; bisaziridinylspermine; double naifade; hyperbolic 39 200940050

稀A ( bistratene A);比折來新；布魯法特（breflate ); 漠匹立明；布度敛（budotitane ); 丁硫胺酸亞礙胺（buthionine sulfoximine ):妈泊三醇（calcipotriol ) •，卡泊斯汀 C (calphostin C);喜樹驗衍生物（camptothecin derivative ); 金絲雀痘IL-2 ( canarypox IL-2 );卡西他賓；甲酿胺-胺基 -***；羧基醯胺基咪唑；CaRest M3 ; CARN 700 ;軟骨衍生之抑制劑；卡折來新；酪蛋白激酶抑制劑（ICOS);栗樹精胺（castanospermine);殺菌肽 B ( cecropin B);西曲瑞克（cetrorelix);綠素類（chlorlns);氣啥°惡琳確酿胺（chloroquinoxaline sulfonamide );西卡前列素 (cicaprost);順式卟啭（cis-porphyrin);克拉屈濱；克羅米芬類似物（clomifene analogues );克黴峻 (clotrimazole );克立徽素 A ( collismycin A );克立黴素 B ;康布他汀A4 ( combretastatin A4 );康布他汀類似物；康納吉寧（conagenin );卡那貝西汀 816( crambescidin 816);克里奈托（crisnatol);念珠藻環肽（cryptophycin) 8;念珠藻環肽A衍生物；卡拉新A( curacin A );環戊蒽 S昆（cyclopentanthraquinones ):環普蘭姆（cycloplatam )；西匹黴素（cypemycin );阿糖胞苷十八炫基填酸鹽 (cytarabine ocfosfate );溶細胞因子（cytolytic factor ); 細胞抑素（cytostatin );達昔單抗（dacliximab );地西他濱；去氫膜海勒素B( dehydrodidemnin B );地洛瑞林 (deslorelin ):***（dexamethasone );右異環麟醯胺（dexifosfamide);右雷佐生（dexrazoxane);右維拉 •200940050 帕米（dexverapamil);地0丫酿；膜海勒素 B( didemnin B ); 地多西（didox);二乙基降精胺（diethylnorspermine )；二氫-5-氮胞普（dihydro-5-azacytidine ) ; 9-二 °惡黴素 (9-dioxamycin );二苯基螺莫司汀；多可沙諾（docosanol); 多拉司壤（dolasetron ):脫氧氟尿苷（doxifluridine ):曲洛昔芬；屈***紛（dronabinol );多卡米辛SA( duocarmycin SA);依布栖琳（ebselen);依考莫司汀（ecomustine ); 依地福新（edelfosine ):依決洛單抗（edrecolomab );依氣鳥胺酸；欖香婦（elemene );乙喊替氟（emitefur);表柔比星；愛普列特（epristeride );雌莫司汀類似物；雌激素促效劑；***拮抗劑；依他硝唑；磷酸依託泊苷；依西美坦（exemestane );法屈。坐；法紮拉濱；芬維A胺；非格司亭（filgrastim );非那雄安（finasteride ):夫拉平度 (flavopiridol );氟卓斯、;τ ( flezelastine );氟斯特隆 (fluasterone);氟達拉濱（fludarabine);鹽酸氟道諾黴素(fluorodaunorunicin hydrochloride );福紛美克 (forfenimex);福美司坦（formestane );福司曲星；福莫司、;T ( fotemustine );亂德外 *#( gadolinium texaphyrin ); 墙酸鎵；加洛他濱（galocitabine );加尼瑞克（ganirelix ); 明膠酶抑制劑；吉西他賓；麩胱甘肽抑制劑（glutathione inhibitor );赫普蘇姆（hepsulfam );赫瑞古林（heregulin ); 六亞甲基二乙醢胺（hexamethylene bisacetamide );金絲桃素（hypericin);伊班膦酸（ibandronic acid );黃膽素；艾多昔芬（idoxifene );伊決孟酮（idramantone );伊莫 200940050 . 福新；伊洛馬司他（ilomastat ) ; °米°坐0丫咬酮 (imidazoacridones);味啥莫特（imiquimod);免疫刺激肽；胰島素樣生長因子-1受體抑制劑；干擾素促效劑；干擾素；介白素；蛾苄脈（iobenguane );峨多柔比星 (iododoxorubicin) ; 4-甘薯醇（4-ipomeanol );伊羅普拉 (iroplact );伊索拉定（irsogladine );異苯胍。坐 (isobengazole );同功軟海綿素 b( isohomohalicondrin B ); 伊他司瓊（itasetron);傑斯普拉克立德（jaspiakin〇iide); 卡哈拉立德F ( kahalalide F);片螺素-N三乙酸鹽〇 (lamellarin-N triacetate ):蘭瑞肽；雷那黴素 (leinamycin );來格司亭（lenograstim );硫酸香兹多糖 (lentinan sulfate);立托他汀（iept〇lstatin);來曲唾；白血病抑制因子；白血球α干擾素；亮丙立德+***+孕酮；亮丙瑞林（leuprorelin);左旋咪唑（levamis〇ie); 利阿嗤（liarozole )，直鏈多胺類似物；親脂性雙糖肽；親脂性紐化合物；立索克林酿胺7( liss〇clinamide 7 );洛翻 (lobaplatin);蚯蚓磷脂（lombricine);洛美曲索；氣尼〇達明（lonidamine);洛索蒽醌；洛伐他汀（1〇vastatin); 洛索立賓（loxoribine );勒托替康（lurtotecan );錄德〇卜啉（lutetiumtexaphyrin);立索茶；溶解肽（lytic peptide )，美坦新（maitansine );麥洛坦灯 A (mannostatin A ),馬立馬司他（marimastat);馬索羅盼 (masoprocol);馬司非（maspin);基質溶素抑制劑；基質金屬蛋白酶抑制劑；美諾立爾；麥爾巴隆（merbarone ); 42 200940050Bractal A (bistratene A); bracts new; bruflate; pirate; budotitane; buthisine sulfoximine: calcipotriol •, calphostin C; camptothecin derivative; canarypox IL-2; casiparin; amide-amino-three Carbazole; carboxy-guanidinoimidazole; CaRest M3; CARN 700; cartilage-derived inhibitor; cardinalxin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; Cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; Clomifene analogues; clatumrimazole; collismycin A; seromycin B; compretatin A4; compstatin analogue; connaji Conagenin; casabetine 816 (crambescidin 816); crennat (crisnatol); nocturnal ring peptide (cryptophycin) 8; Candida cyclic peptide A derivative; carain A (curacin A); cyclopentanthraquinones: cycloplatam; cypemycin; cytarabine Cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B Deslorelin: dexamethasone; dexifosfamide; dexrazoxane; right vera•200940050 dexverapamil; ground 0 brewing; membrane Didemin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxacillin ( 9-dioxamycin); diphenyl sirolimus; doxosanol; dolasetron: dexifluridine: trooxifen; dronabinol; Duocarmycin SA; ebselen; ecomustine; edifuxin (e Delfosine ): edrecolomab; edionine; elemene; emitefur; epirubicin; epristeride; estramustine Analogs; estrogen agonists; estrogen antagonists; etidazole; etoposide phosphate; exemestane; Sitting; fazarabin; fenretinide; filgrastim; finasteride: flavopiridol; fluraz, τ (flezelastine); Fluasterone); fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; forskestine; florosic; T (fotemustine) ;加德外外*#(gadolinium texaphyrin); gallium wall; galocitabine; ganirelix; gelatinase inhibitor; gemcitabine; glutathione inhibitor ); hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; Idoxifene; idramantone; Imo 200940050. Fuxin; ilomastat; °m° sitting on imidazoacridones; miso mote ( Imiquimod); immunostimulatory peptide; insulin-like growth factor-1 receptor inhibitor; interferon Interferon; interleukin; interleukin; ibbenguane; iododocorubicin; 4-potomeanol; iroplact; isoladine ); isophthalide. Sit (isobengazole); isohomohalicondrin B; itasetron; jaspiakin〇iide; kahalalide F; snail -N triacetate: lanreotide; leinamycin; lenograstim; lentinan sulfate; ritotatin (iept〇lstatin) Leukemia inhibitory factor; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamis 〇ie; liarozole, linear Polyamine analog; lipophilic disaccharide peptide; lipophilic neonatal compound; liss 〇clinamide 7; lopaplatin; lombricine; lomexoxine; Lonidamine; losopressin; lovastatin (1〇vastatin); loxoribine; lurototecan; lutetiumtexaphyrin; lissuocha; (lytic peptide), maitansine; merostatin A, marimastat marimastat); Masuo Luo hope (masoprocol); non-Horse Division (of maspin); stromelysin inhibitors; matrix metalloproteinase inhibitors; US Norwich Seoul; Maier Barron (merbarone); 42 200940050

美替瑞林（meterelin);蛋胺酶（methioninase);甲氧氣普胺（metoclopramide ) ; MIF 抑制劑；米非司酿I (mifepristone );米替福新（miltefosine );米立司亭 (mirimostim );錯配雙鏈 RNA ;米托胍膝（mitoguazone ); 二溴衛矛醇（mitolactol );絲裂黴素類似物；米托萘胺 (mitonafide );米托毒素纖維母細胞生長因子-沙泊寧 (saporin );米托蒽酿；莫法羅汀（mofarotene ) •，莫拉司亭（molgramostim);單株抗體，人類域毛膜***； ® 單磷醯基脂質 A+分支桿菌細胞壁 sk ;莫哌達醇 (mopidamol );多重抗藥性基因抑制劑；基於多重腫瘤抑制劑1之療法；芥類抗癌劑；美卡普羅B( mycaperoxide B ); 分枝桿菌細胞壁提取物；美瑞普隆（myriaporone) ; N-乙醯基地那林（N-acetyldinaline) ; N-取代苯甲醯胺；那法瑞林（nafarelin );納格瑞替（nagrestip );納洛嗣（naloxone ) +喷他佐辛（pentazocine);納普維（napavin);萘特非 (naphterpin ):那托司亭（nartograstim );奈達銘 ❹ (nedaplatin );奈柔比星（nemorubicin );奈立膦酸 (neridronic acid );中性肽鏈内切酶；尼魯醯胺 (nilutamide ) •，尼沙黴素（nisamycin ) •，氧化氣調節劑；墙基氧抗氧化劑；尼曲林（nitrullyn ) ; 06-苄基烏嘌吟 (06-benzylguanine );奥曲肽（octreotide );奥克恩 (okicenone );寡核普酸；奥那司酮（onapristone );昂丹司壤（ondansetron);昂丹司填；奥拉新（oracin);經口細胞因子誘發劑；奥馬始；奥沙特隆（osaterone );奥賽 43 200940050 力銘（oxaliplatin);厄諾黴素（oxaunomycin);帕諾明 (palauamine );標糊酿基根瘤菌素（palmitoylrhizoxin ); 帕米膦酸（pamidronic acid );人參三醇（panaxytriol )；帕諾米芬（panomifene);帕拉貝新（parabactin);帕折普汀（pazelliptine);培門冬酶；皮地新（peidesine);戊聚糖聚硫酸納（pentosan polysulfate sodium);喷司他丁 (pentostatin );喷曲唑（pentrozole );全氟溴烷 (perflubron);培磷醯胺；紫蘇子醇（peruiyi alcohol)；吩嗪黴素（phenazinomycin):苯乙酸鹽；磷酸酶抑制劑；皮西班尼（picibanil );鹽酸毛果芸香鹼（pilocarpine hydrochloride );吡柔比星（pirarubicin ) ; »比曲克辛 (piritrexim):普來司汀（placetin) A ;普來司汀B ;血裝素原活化劑抑制劑；銘錯合物；始化合物；銘-三胺錯合物；卟吩姆納；泊非黴素；潑尼松（prednisone);丙基雙吖啶酮（propyl bis-acridone );***素J2 ;蛋白酶體抑制劑；基於蛋白質A之免疫調節劑；蛋白激酶c抑制劑；微藻蛋白激酶C抑制劑；蛋白酪胺酸磷酸酶抑制劑；嗓吟核普填酸化酶抑制劑；紫紅素（purpurin );咬》坐淋η丫咬 (pyrazoloacridine );吡哆醛化血紅蛋白聚氧伸乙基接合物，raf拮抗劑；雷替曲赛（raltitrexed );雷莫司填 (ramosetron ) ; ras法呢基蛋白質轉移酶抑制劑；ras抑制劑；ras-GAP抑制劑；脫甲基瑞替立汀（retelHptine demethylated);依替膦酸銖 Re 186 ;根瘤菌素（rhiz〇xin); 核糖酶（ribozymes ) ; RII視黃醯胺；羅穀亞胺；羅希吐驗 .200940050 (rohitukine );羅莫肽（romurtide );羅喧美克 (roquinimex );魯濱吉隆 B1 ( rubiginone B1 );魯泊塞 (ruboxyl );沙芬戈；聖特平（saintopin) ; SarCNU ;沙卡弗托 A ( sarcophytol A );沙格司亭（sargramostim); Sdi 1模擬劑；司莫司汀；衰老衍生抑制劑1 ;有義寡核苷酸；信號轉導抑制劑；信號轉導調節劑；單鏈抗原結合蛋白；西佐喝（sizofiran);索布佐生（sobuzoxane):领卡納（sodium borocaptate );苯基乙酸納；索佛羅（solverol); 〇生長調節素結合蛋白；索納明（sonermin );斯帕福斯酸 (sparfosic acid );斯皮卡黴素 D( spicamycin D );螺莫司汀；斯蘭羅皮汀（splenopentin );海綿抑素1 ( spongistatin 1 );角鯊胺（squalamine );幹細胞抑制劑；幹細胞*** 抑制劑；斯皮米德（stipiamide );基質溶素抑制劑；索非羅新（ sulfinosine);超活性血管活性腸肽拮抗劑；蘇拉端素（suradista );蘇拉明（suramin );苦馬豆素（swainsonine ); 合成葡糖胺聚糖；他莫司汀（tallimustine );曱蛾化他莫昔芬（tamoxifen methiodide );牛績莫司汀（tauromustine ); 他紮羅汀（tazarotene ):替康蘭鈉；替加氟；碲旅喃銪 (tellurapyrylium );端粒酶抑制劑；替莫泊芬；替莫嗤胺；替尼泊戒；四氯十氧化物；替β坐明（tetrazomine );嗟立斯汀（thaliblastine );嘆考瑞林（thiocoraline );血小板生成素；血·小板生成素模擬劑；胸腺法新（thymalfasin);胸腺生長素受體促效劑；胸勝曲南（thymotrinan );促甲狀腺激素；乙基錫初紫紅素（tin ethyl etiopurpurin);替拉 45 200940050 紮明；二氣二茂欽（titanocene bichloride );托普升替 (topsentin );托瑞米芬；全能幹細胞因子；轉譯抑制劑；維甲酸（tretinoin ):三乙酿尿普（triacetyluridine ):曲西立濱；三甲曲沙；曲普瑞林；托烧司違（tropisetron ); 妥羅雄腺（turosteride);酷胺酸激酶抑制劑；酷胺酸峨酸抑素（tyrphostin ) ; UBC 抑制劑；烏苯美司（ubenimex ); 尿殖竇衍生之生長抑制因子；尿激酶受體拮抗劑；伐普肽 (vapreotide );凡瑞林B ( variolin B );載體系統，紅血球基因療法；維拉雷瑣（velaresol);凡拉明（veramine ); 凡咬（verdin);維替泊芬（verteporfin);長春瑞賓；維薩汀（vinxaltine);維他欣（vitaxin);伏羅。坐；紮諾特隆（zanoterone );折尼鉑；齊拉考泊（zilascorb );及淨司他丁斯酯（zinostatin stimalamer )。較佳其他抗癌藥物為 5-氟尿嘲咬（5-fluorouracil )及曱醯四氫葉酸 (leucovorin ) 〇可使用之治療性抗體之實例包括（但不限於）： HERCEPTIN® (曲妥珠單抗（Trastuzumab ) ) ( Genentech， CA )，其為一種用於治療患有轉移性乳癌之患者的人化抗 HER2 單株抗體；REOPRO® (阿昔單抗（abciximab )) (Centocor )，其為一種用於預防凝塊形成之血小板上之抗醣蛋白 Ilb/IIIa 受體；ZENAPAX® (達利珠單抗 (daclizumab ) ) ( Roche Pharmaceuticals, Switzerland)，其為一種用於預防急性腎同種異體移植排斥反應之免疫抑制性人化抗CD25單株抗體；PANOREX™，其為一種鼠類 200940050 抗 17-IA 細胞表面抗原 IgG2a 抗體（Glaxo Wellcome/Centocor) ; BEC2，其為一種鼠類抗個體基因型 (GD3 抗原決定基）IgG 抗體（ImClone System ); IMC-C225，其為一種嵌合抗 EGFR IgG 抗體（ImClone System ) ; VITAXIN™，其為一種人化抗aV|83整合素抗體 (Applied Molecular Evolution/Medlmmune ) ; Campath 1H/LDP-03，其為一種人化抗 CD52 IgGl 抗體（Leukosite); Smart M195，其為一種人化抗 CD33 IgG 抗體（Protein 〇 Design Lab/Kanebo) ; RITUXANTM，其為一種嵌合抗 CD20 IgGl 抗體（IDEC Pharm/Genentech，Roche/Zettyaku ); LYMPHOCIDE™，其為一種人化抗 CD22 IgG 抗體 ( Immunomedics ) ; LYMPHOCIDE™ Y-90 (Immunomedics ) ; Lymphoscan (經 Tc-99m 標記；放射成像；Immunomedics) ; Nuvion (針對 CD3 ; Protein Design Labs) ; CM3 為一種人化抗 ICAM3 抗體（ICOS Pharm); IDEC-114 為一種靈長類化抗 CD80 抗體（IDEC w Pharm/Mitsubishi ) ; ZEVALINTM為一種放射性標記之鼠類抗 CD20 抗體（IDEC/Schering AG) ; IDEC-131 為一種人化抗CD40L抗體（IDEC/Eisai) ; IDEC-151為一種靈長類化抗CD4抗體（IDEC) ; IDEC-152為一種靈長類化抗CD23 抗體（IDEC/Seikagaku) ; SMART 抗 CD3 為一種人化抗 CD3 IgG ( Protein Design Lab) ; 5G1.1 為一種人化抗補體因子5 ( C5 )抗體（Alexion Pharm) ; D2E7為一種人化抗 TNF-0：抗體（CAT/BASF); CDP870 為一種人化抗 TNF-α Fab 47 200940050 片段（Celltech) ; IDEC-151為一種靈長類化抗CD4 IgGl 抗體（IDEC Pharm/SmithKline Beecham ) ; MDX-CD4 為一種人類抗 CD4 IgG 抗體（Medarex/Eisai/Genmab ) ； CD20- 抗生蛋白鏈菌素（+生物素-釔90; NeoRx) ; CDP571為一種人化抗TNF-α IgG4抗艎（Celltech) ; LDP-02為一種人 4匕抗《4/37 抗體（LeukoSite/Genentech) ; OrthoClone OKT4A 為一種人化抗 CD4IgG 抗體（OrthoBiotech) ; ANTOVA™ 為一種人化抗 CD40L IgG 抗體（Biogen) ; ANTEGREN™ 為一種人化抗VLA-4 IgG抗體（Elan):且CAT-152為一種人類抗 TGF-jS2 抗體（Cambridge Ab Tech)。可用於本發明之方法及組成物中的化學治療劑包括 (但不限於）烷化劑、抗代謝物、天然產物或激素。可用於在本發明之方法及組成物中治療或預防T細胞惡性疾病之烷化劑的實例包括（但不限於）氮芥類（例如，雙（氣乙基）甲胺（mechloroethamine )、環鱗醯胺、苯丁酸氮芥等）、烷基磺酸鹽（例如，白消安）、亞硝基脲（例如，卡莫司汀、洛莫司汀等）或三氮烯（達卡巴嗪等）。可用於在本發明之方法及組成物中治療或預防T細胞惡性疾病的抗代謝物之實例包括（但不限於）葉酸類似物（例如，曱胺喋呤）或嘧啶類似物（例如，阿糖胞苷）、嘌呤類似物（例如，巯基嘌呤、硫鳥嘌呤、喷司他丁）。可用於本發明之方法及組成物中治療或預防T細胞惡性疾病的天然產物之實例包括（但不限於）長春花生物鹼（例如，長春花驗、長春新驗）、表鬼臼素（epipodophyllotoxin )(例 200940050 如’依託泊苷）、抗生素（例如，道諾黴素、羥道諾紅黴素、博來黴素）、酶（例如，左旋天冬醯胺）或生物反應調節劑（例如，干擾素α)。可用於在本發明之方法及組成物中治療或預防癌症之烷化劑的實例包括（但不限於）氮芥類（例如，雙（氯乙基）曱胺、環磷醯胺、苯丁酸氮芥、美法侖等）、伸乙亞胺（ethylenimine )及甲基三聚氰胺（（例如’、甲基二聚氰胺（hexamethlymelamine)、嘆替派）、烷基磺酸鹽（例如，白消安）、亞硝基脲（例如，卡莫司 >丁、洛莫司汀、鏈脲黴素等）或三氮烯（逹卡巴嗪等）。可用於在本發明之方法及組錢中治療或預防癌症的抗代謝物之實例包括（但不限於）葉酸類似物（例如，甲胺喋呤）或嘧啶類似物（例如，氟尿嘧啶、氟尿苷、阿糖胞苷）、嗓呤類似物（例如，疏基嗓呤、硫鳥噪吟、喷司他丁）。可用於在本發明<方法及組成物中治冑或預防癌症的天然 © f物之實例包括（但不限於）長春花生物鹼（例如，長春花驗、長春新驗）、表先白素（例如，依託泊皆、替尼泊武）、抗生素（例如，放線菌素D、道諾黴素、經道諾紅徽素、博來黴素、普卡黴素、絲裂黴素）、酶（例如’左旋天冬酿胺）或生物反應調節劑（例如，干擾素㈠。可用於在本發明之方法及組成物中治療或預防癌症的激素及拮抗劑之實例包括（但不限於）腎上腺皮質類固醇（例如，潑尼松）、孕酮（例如，己酸經孕_、乙酸甲地孕網、乙酸甲經孕嗣）、***（例如，己稀雌紛（d洲yStilbestrol )、 49 200940050 乙快雄二醇）、抗***（例如，他莫昔芬）、雄激素（例 ' 如，丙酸睾酮（testoster〇ne pr〇pi〇nate)、氟甲睾鲖 (flu〇xymester〇ne ))、抗雄激素（例如，I他胺 (flutamide ))、激性腺素釋放素類似物（例如，亮丙立德）。可用於本發明之方法中及與本發明之組成物一起使用以治療或預防癌症的其他藥劑包括銘配位錯合物（例如，順/ 卡舶）蒽一銅（例如，米托葱酿）、經取代之腺（例如，經基脲）曱基肼衍生物（例如，丙卡巴肼）、腎上線皮質抑制劑（例如，米托坦、胺魯米特）。〇咸信本文中所揭示之化合物及醫藥組成物當與藉由因穩定微管而使細胞停滯纟G2_M期來起作用的抗癌劑共同投予時尤其有效。因此，所揭示之方法較佳包括共同投予藉由此機制起作用的抗癌藥物。藉由因穩定微管而使細胞 #滞在G2.M期來起作用的抗癌劑之實例包括（但不限於）以下市售藥物及研製中藥物：厄布㈣（Erbul_1〇 (亦稱為R 55104)、海兔毒素i〇(D〇iastatjni〇)(亦稱為 DLS-10及NSC-376128 )、羥乙磺酸米伏布林（Miv〇buUn❹ isethionate)(亦稱為 CI_98〇)、長春新鹼、nsc_639829、迪斯德莫來（Discodermolide)(亦稱為 NVP-XX-A-296 )、 ABT-751 (Abbott，亦稱為 E_7010)、海洋素（AU〇rhyrtin) (諸如，海洋素A及海洋素C)、海綿抑素（Sp〇ngistatin) (諸如，海綿抑素1、海綿抑素2、海綿抑素3、海綿抑素 4、海綿抑素5、海綿抑素6、海綿抑素7、海綿抑素8及海綿抑素 9 )、鹽酸西馬多丁（ Cemad〇tin hydr〇chl〇ride )(亦 50 200940050 稱為 LU-103793 及 NSC-D-669356)、埃坡黴素（Epothilone) (諸如，埃坡黴素A、埃坡黴素B、埃坡黴素C (亦稱為脫氧埃坡黴素A或dEpoA)、埃坡黴素D (亦稱為KOS-862、 dEpoB及脫氧埃坡黴素B)、埃坡黴素E、埃坡黴素F、埃坡黴素B N-氧化物、埃坡黴素A N-氧化物、16-氮雜埃坡黴素B、21-胺基埃坡黴素B (亦稱為BMS-310705 ) 、21- 羥基埃坡黴素D(亦稱為脫氧埃坡黴素F及dEpoF) 、26-氟埃坡黴素）、阿瑞他、汀PE( Auristatin PE )(亦稱為 ® NSC-654663 )、索利多汀（Soblidotin)(亦稱為 TZT-1027)、 LS-4559-P ( Pharmacia，亦稱為 LS-4577 ) ' LS-4578 (Pharmacia，亦稱為 LS-477-P)、LS-4477 ( Pharmacia )、 LS-4559 ( Pharmacia) 、RPR-1 12378 ( Aventis )、硫酸長春新驗、DZ-3358 ( Daiichi)、FR-182877 ( Fujisawa，亦稱為 WS-9885B) 、GS-164 ( Takeda)、GS-198 ( Takeda)、 KAR-2 ( Hungarian Academy of Sciences ) 、BSF-223651 (BASF，亦稱為 ILX-651 及 LU-223651 ) 、SAH-49960 (Lilly/Novartis )、SDZ-268970 ( Lilly/Novartis )、AM-97 (Armad/Kyowa Hakko ) 、AM-132 ( Armad ) 、AM-138 (Armad/Kyowa Hakko ) 、IDN-5005 ( Indena )、念珠藻環肽 52 ( Cryptophycin 52)(亦稱為 LY-355703 )、AC-7739 (Ajinomoto,亦稱為 AVE-8063A 及 CS-39.HC1)、AC-7700 (Ajinomoto ，亦稱為 AVE-8062 、AVE-8062A 、 CS-39-L-Ser.HCl 及 RPR-258062A )、維魯醯胺 (Vitilevuamide )、托布辛 A ( Tubulysin A )、卡那德索 51 200940050 (Canadensol )、矢車菊黃素（Centaureidin )(亦稱為 NSC-106969 )、T-l38067( Tularik，亦稱為 T-67、TL-l38067 及 TI-138067)、COBRA-1 (Parker Hughes Institute，亦稱為 DDE-261 及 WHI-261 )、H10( Kansas State University)、 H16 ( Kansas State University )、歐斯丁 A1 ( Oncocidin A1 )Metelin (methioninase); metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim Mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogue; mitonaphine (mitonafide); mitoxantrone fibroblast growth factor-sand Saporin; mitox brewing; mofarotene •, molrasostim; monoclonal antibody, human domain gonadotropin; ® monophosphoryl lipid A+ mycobacterial cell wall Sk; mopidamol; multidrug resistance gene inhibitor; multi-tumor inhibitor 1 based therapy; canine anticancer agent; mecaperoxide B; mycobacterial cell wall extract; Myriaporone; N-acetyldinaline; N-substituted benzamide; nafarelin; nagrestip; naloxone + Pentazocine; napavin; naphterpin: that Nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide • nisha Nisalmycin •, oxidizing gas regulator; wall-based oxygen antioxidant; nitroline (06-benzylguanine); octreotide; okicenone; Oligonucleotide; onasetstone; ondansetron; ondanset filling; oracin; oral cytokine inducer; omasian; osaterone Orsay 43 200940050 oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; ginseng triol ( Panaxytriol ); panomifene; parabactin; pazelliptine; parmozyme; peidesine; pentosan polysulfate sodium ; pentostatin; pentrozole; perfluorobromine n); phosphatamine; peruiyi alcohol; phenazinomycin: phenylacetate; phosphatase inhibitor; picibanil; pilocarpine hydrochloride; Pirarubicin; piritrexim: placetin A; priestine B; vasopressin activator inhibitor; mer complex; initial compound; Amine complex; 卟姆姆纳 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Agent; protein kinase c inhibitor; microalgae protein kinase C inhibitor; protein tyrosine phosphatase inhibitor; sputum nuclear peroxidase inhibitor; purpurin; purpurin 坐丫 bite (pyrazoloacridine Pyridoxal hemoglobin polyoxyethylene ethyl conjugate, raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras -GAP inhibitor; demethylthiolatine (retelHptine dem Ethylated); etidronate Re 186; rhiz〇xin; ribozymes; RII retinol; rotamimine; roxitaxin. 200940050 (rohitukine); romopeptide ); roquinimex; rubiginone B1; ruboxyl; safingo; saintopin; SarCNU; sarcophytol A; Sarlistostim; Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction regulator; single-chain antigen-binding protein; Drink (sizofiran); sobuzoxane: sodium borocaptate; phenylacetate; Solverol; 〇 growth regulator binding protein; sonaming (sonermin); Sparfosic acid; spicamycin D; spiroxetine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; Stem cell division inhibitor; stipiamide; matrix lysin inhibitor; sophomore ( sulfinosine); super active vasoactive intestinal peptide antagonist; suraddista; suramin; swainsonine; synthetic glycosaminoglycan; tallimustine Tamoxifen methiodide; tauromustine; tazarotene: temalanine; tegafur; ura 铕铕 tell (tellurapyrylium); telomerase Inhibitor; temoprofen; temoguanamine; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; platelet production Blood; small plateogenic hormone mimetic; thymalfasin; thymus auxin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin Tira 45 200940050 Zha Ming; Titanocene bichloride; Topsentin; Toremifene; Totipotent Stem Cell Factor; Translation Inhibitor; Retinoic Acid: Triethylene Urea (triacetyluridine): 曲西立滨; 三甲曲沙; Purinetron; tropisetron; turosteride; valine kinase inhibitor; tyrphostin; UBC inhibitor; ubenimex; Urinary sinus-derived growth inhibitory factor; urokinase receptor antagonist; vapreotide; variolin B; vector system, red blood cell gene therapy; velaresol; van lamamine (veramine); verdin; verteporfin; verapamil; vinxaltine; vitaxin; volta. Sit; zanoterone; nitrite; zilascorb; and zinostatin stimalamer. Preferred other anticancer drugs are 5-fluorouracil and leucovorin. Examples of therapeutic antibodies that can be used include, but are not limited to: HERCEPTIN® (tratrozin) Trastuzumab (Genentech, CA), a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO® (abciximab) (Centocor), which is An anti-glycoprotein Ilb/IIIa receptor on platelets for preventing clot formation; ZENAPAX® (daclizumab) (Roche Pharmaceuticals, Switzerland), which is used to prevent acute renal allograft rejection Reactive immunosuppressive humanized anti-CD25 monoclonal antibody; PANOREXTM, a murine 200940050 anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2, a murine anti-individual genotype ( GD3 epitope IgG antibody (ImClone System); IMC-C225, which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXINTM, which is a humanized anti-aV|83 integrin antibody (Applied) Molecular Evolution/Medlmmune); Campath 1H/LDP-03, a humanized anti-CD52 IgG1 antibody (Leukosite); Smart M195, a humanized anti-CD33 IgG antibody (Protein® Design Lab/Kanebo); RITUXANTM, A chimeric anti-CD20 IgG1 antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOCIDETM, a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDETM Y-90 (Immunomedics); Lymphoscan (via Tc-99m) Mark; radiography; Immunomedics; Nuvion (for CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primate anti-CD80 antibody (IDEC w Pharm/Mitsubishi) ZEVALINTM is a radiolabeled murine anti-CD20 antibody (IDEC/Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primate anti-CD4 antibody (IDEC) IDEC-152 is a primatized anti-CD23 antibody (IDEC/Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody Alexion Pharm; D2E7 is a humanized anti-TNF-0: antibody (CAT/BASF); CDP870 is a humanized anti-TNF-α Fab 47 200940050 fragment (Celltech); IDEC-151 is a primate antibody CD4 IgG1 antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-streptavidin (+Biotin-钇90; NeoRx); CDP571 is a Humanized anti-TNF-α IgG4 anti-sputum (Celltech); LDP-02 is a human 4匕 anti-"4/37 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (OrthoBiotech); ANTOVATM is a Humanized anti-CD40L IgG antibody (Biogen); ANTEGRENTM is a humanized anti-VLA-4 IgG antibody (Elan): and CAT-152 is a human anti-TGF-jS2 antibody (Cambridge Ab Tech). Chemotherapeutic agents useful in the methods and compositions of the present invention include, but are not limited to, alkylating agents, antimetabolites, natural products or hormones. Examples of alkylating agents useful in the treatment and prevention of T cell malignancies in the methods and compositions of the present invention include, but are not limited to, nitrogen mustards (e.g., xyethylethamine, ring scales) Indoleamine, chlorambucil, etc.), alkyl sulfonate (eg, busulfan), nitrosourea (eg, carmustine, lomustine, etc.) or triazene (dakacarbazine) Wait). Examples of antimetabolites useful in the treatment or prevention of T cell malignancies in the methods and compositions of the invention include, but are not limited to, folic acid analogs (eg, amidoxime) or pyrimidine analogs (eg, arabinose) Cytidine), purine analogs (eg, mercaptopurine, thioguanine, pentastatin). Examples of natural products useful in the methods and compositions of the invention for treating or preventing T cell malignancies include, but are not limited to, vinca alkaloids (e.g., periwinkle test, Changchun new test), epipodophyllotoxin (epipodophyllotoxin) (Example 200940050 such as 'etoposide), antibiotics (eg, daunorubicin, hydroxydanomycin, bleomycin), enzymes (eg, L-aspartame) or biological response modifiers (eg , interferon alpha). Examples of alkylating agents useful in the treatment or prevention of cancer in the methods and compositions of the invention include, but are not limited to, nitrogen mustards (eg, bis(chloroethyl)guanamine, cyclophosphamide, phenylbutyric acid Nitrogen mustard, melphalan, etc., ethylenimine and methyl melamine (eg 'methyl melamine (hexamethlymelamine), sate), alkyl sulfonate (eg, white An), a nitrosourea (for example, caromozine, butyl, lomustine, streptozotocin, etc.) or triazene (carbazine, etc.) can be used in the method and group money of the present invention. Examples of antimetabolites that treat or prevent cancer include, but are not limited to, folic acid analogs (eg, methotrexate) or pyrimidine analogs (eg, fluorouracil, fluorouridine, cytarabine), purine analogs (e.g., sulfhydryl, thiophene, pentastatin.) Examples of natural sources that can be used to treat or prevent cancer in the <Methods and Compositions of the Invention include, but are not limited to, Changchun Flower alkaloids (eg, Changchun flower test, Changchun new test), table white pigment ( For example, etoposide, teinicarb, antibiotics (eg, actinomycin D, daunorubicin, dioxin, bleomycin, pucamycin, mitomycin), enzymes (eg, 'L-Spirulina Amine') or a biological response modifier (eg, interferon (I). Examples of hormones and antagonists that can be used to treat or prevent cancer in the methods and compositions of the invention include, but are not limited to, the adrenal gland Corticosteroids (eg, prednisone), progesterone (eg, hexanoic acid via pregnancy, methicillin acetate, acetaminophen acetate), estrogen (eg, dilute yStilbestrol, 49) 200940050 B fast androgen), antiestrogens (eg tamoxifen), androgens (eg 'testoster〇ne pr〇pi〇nate', testosterone flumxymester〇ne )), antiandrogens (eg, flutamide), gonadotropin-releasing hormone analogs (eg, leuprolide). Can be used in the methods of the invention and with the compositions of the invention to Other agents for treating or preventing cancer include intermolecular complexes (eg For example, Shun/Carbo) copper (eg, mites), substituted glands (eg, ureido) guanidinium derivatives (eg, procarbazine), suprarenal cortical inhibitors (eg , mitoxantrone, aminamide. The compounds and pharmaceutical compositions disclosed herein are co-administered with an anticancer agent that acts by arresting the cells during the G2_M phase by stabilizing the microtubules. It is particularly effective. Therefore, the disclosed method preferably includes co-administering an anticancer drug that acts by this mechanism. An example of an anticancer agent that acts by stabilizing microtubules to cause cells to lag in the G2.M phase Including (but not limited to) the following commercially available drugs and drugs under development: Erb (four) (Erbul_1〇 (also known as R 55104), sea toxin i〇 (D〇iastatjni〇) (also known as DLS-10 and NSC- 376128), Miv〇buUn❹ isethionate (also known as CI_98〇), vincristine, nsc_639829, Discodermolide (also known as NVP-XX-A-296) ), ABT-751 (Abbott, also known as E_7010), and AU〇rhyrtin (such as Ocean A and Ocean C), Sp〇ngistatin (such as spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, sponge Inhibin 8 and spirostatin 9 ), Cemad〇tin hydr〇chl〇ride (also known as LU-103793 and NSC-D-669356 in 200940050), Epothilone (Epothilone) Such as, epothilone A, epothilone B, epothilone C (also known as deoxyetomycin A or dEpoA), epothilone D (also known as KOS-862, dEpoB and deoxygenated Paclimycin B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21- Amino Epothilone B (also known as BMS-310705), 21-Hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-fluoroepothilone), Aréta , PE ( Auristatin PE ) (also known as ® NSC-654663 ), Soblidotin (also known as TZT-1027), LS-4559-P ( Pharmacia, also known as LS-4577 ) ' LS- 4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RP R-1 12378 (Aventis), Changchun Sulfuric Acid, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 ( Takeda), GS-198 ( Takeda), KAR- 2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/ Kyowa Hakko ) , AM-132 ( Armad ) , AM-138 (Armad/Kyowa Hakko ) , IDN-5005 ( Indena ), Cryptophycin 52 (also known as LY-355703 ), AC-7739 ( Ajinomoto, also known as AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A), Viru Vitilevuamide, Tubulysin A, Candadeso 51 200940050 (Canadensol), Centaureidin (also known as NSC-106969), T-l38067 (Tularik, also known as T -67, TL-l38067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 ( Kansas State University), H16 ( Kansas State University), Oss A1 (Oncocidin A1)

(亦稱為 BTO-956 及 DIME) 、DDE-313 (Parker Hughes Institute )、福吉立德 B ( Fijianolide B )、勞馬立德 (Laulimalide ) ' SPA-2 ( Parker Hughes Institute)、SPA-1 (Parker Hughes Institute，亦稱為 SPIKET-P) 、3-IAABU ❹ (Cytoskeleton/Mt. Sinai School of Medicine，亦稱為 MF-569)、那可辛（Narcosine)(亦稱為 NSC-5366)、納斯卡平（Nascapine ) ' D-24851 ( Asta Medica)、A-105972 (Abbott )、哈米特林（Hemiasterlin ) 、3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine，亦稱為 MF-191) 、TMPN (Arizona State University)、乙酿基丙 _ 酸二茂叙（Vanadocene acetylacetonate ) 、T-138026 Ο (Tularik )、莫薩曲爾（Monsatrol )、伊諾欣（Inanocine ) ^ (亦稱為 NSC-698666 )、3-IAABE ( Cytoskeleton/Mt· Sinai(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide 'SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU ❹ (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nas Nascapine ' D-24851 ( Asta Medica), A-105972 (Abbott ), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 T (Tularik), Monsatrol, Inanocine ^ (also known as NSC- 698666 ), 3-IAABE ( Cytoskeleton/Mt· Sinai

School of Medicine)、A-204197( Abbott)、T-607( Tularik，亦稱為 T-900607) 、RPR-115781 (Aventis)、艾榴塞洛素 (Eleutherobin )(諸如，去甲艾權塞洛素、去乙酿艾權塞洛素、異艾榴塞洛素A及Z-艾榴塞洛素）、卡瑞巴德 (Caribaeoside )、卡瑞巴林（Caribaeolin )、軟海綿素 B (Halichondrin B) ' D-64131( Asta Medica) ' D-68144( Asta 52 200940050School of Medicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607), RPR-115781 (Aventis), Eleutherobin (such as, Aegypso素素, 乙乙艾塞塞素素, 异艾瑞塞罗素 A and Z-艾瑞塞罗素), Caribaeoside, Caribaeolin, Haloperondrin B ) ' D-64131( Asta Medica) ' D-68144( Asta 52 200940050

Medica )、含氣環肽 A ( Diazonamide A ) 、A-293620Medica ), gas-containing cyclic peptide A ( Diazonamide A ), A-293620

(Abbott ) 、NPI-2350 ( Nereus )、箭根薯酮内酯 A (Taccalonolide A ) 、TUB-245 ( Aventis ) 、A-259754 (Abbott )、戴峻他灯（Diozostatin )、（-)-苯基阿斯汀 ((-)-Phenylahistin)(亦稱為 NSCL-96F037 ) 、D-68838 (Asta Medica) 、D-68836 ( Asta Medica)、肌基質蛋白 B (Myoseverin B)、D-43411 ( Zentaris，亦稱為 D-81862)、 A-289099 ( Abbott) ' A-318315 ( Abbott) 、HTI-286 (亦 ❿ 稱為 SPA-110,三氟乙酸鹽）（Wyeth )、D-823 17( Zentaris)、 D-82318 (Zentaris)、SC-12983 (NCI)、瑞伐他汀磷酸鈉 (Resverastatin phosphate sodium)、BPR-0Y-007 ( National Health Research Institutes)及 SSR-25041 1( Sanofi)及 Hsp90 抑制劑，諸如格萊黴素（geldanmycin )、根赤殼菌素 (radicicol )、除莠黴素 A ( herbimycin A )、麥克比星 (macbecin ) I 及 II、新生黴素（novobiocin ) 、17-稀丙基胺基-17-脫甲氧基格萊黴素（17AAG ) 、17-脫甲氧基 ® -17-[2-(二曱基胺基）乙基胺基]格萊黴素（17DMAG )、 CNF-1010、基於嘌呤之Hsp90抑制劑（諸如，PU3、PU24FC1 及PU29FC1)及根赤殼菌素之肟衍生物（諸如，KF25706 及 KF58333 )。太平洋紫杉醇（亦稱為「紫杉醇」）為一種熟知之抗癌藥物，其藉由增強且穩定微管形成而起作用。太平洋紫杉醇之結構展示於圖12中。已知太平洋紫杉醇之許多類似物，包括歐洲紫杉醇（docetaxel)，其結構展示於圊13中。 53 200940050 歐洲紫杉醇亦稱為「泰索帝（TA爾刪）」1他洋紫杉醇類似物之結構展示於圖中。此等化合物具有基本紫杉烧骨架作為共同結構特徵且亦已展示具有因穩定微管而使細胞停滞在⑽期的能力。因此，自圖U-34顯而易見多種取代基可修掷紫杉燒骨架而不會不利地影響生物活性。亦顯而易見太平洋紫杉醇類似物之〇個Μ個或2個環己烷環可在指示位置具有雙鍵。出於清楚之目的，基本紫杉烷骨架展示於以下結構式（VI)中：(Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Benzene Keastin ((-)-Phenylahistin) (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris , also known as D-81862), A-289099 (Abbott) 'A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth), D-823 17 (Zentaris ), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-0Y-007 (National Health Research Institutes), and SSR-25041 1 (Sanofi) and Hsp90 inhibitors , such as genomicin (geldanmycin), radicicol, herbimycin A, macbecin I and II, novobiocin, 17-diamond Amino- 17-demethoxyglycomycin (17AAG), 17-demethoxy® -17-[2-(didecylamino)ethylamino] gleomycin (17DMAG) , CNF-1010, base Hsp90 inhibitors of purine (such as, PU3, PU24FC1, and PU29FC1) and oxime derivatives of radicicol (such as, KF25706 and KF58333). Pacific paclitaxel (also known as "paclitaxel") is a well-known anticancer drug that acts by enhancing and stabilizing microtubule formation. The structure of Pacific Paclitaxel is shown in Figure 12. Many analogs of paclitaxel are known, including docetaxel, the structure of which is shown in 圊13. 53 200940050 European paclitaxel is also known as "Tesote (TA)". The structure of his paclitaxel analogue is shown in the figure. These compounds have a basic yew skeleton as a common structural feature and have also been shown to have the ability to arrest cells in stage (10) due to stabilization of microtubules. Therefore, it is apparent from the figure U-34 that a variety of substituents can be used to rip the yew skeleton without adversely affecting the biological activity. It is also apparent that one or two cyclohexane rings of the paclitaxel analog may have a double bond at the indicated position. For the sake of clarity, the basic taxane skeleton is shown in the following structural formula (VI):

ΟΟ

00

(νι)。由結構式（VI)表示之紫杉烧骨架中之環己烧環省略了雙鍵。&本紫杉@骨架可在一或兩個帛己院S中包括〇或1個雙鍵，如圖6·26及以下結構式（νπ)及（VIII)中所指示。結構式（VI)亦省略了大量原子以指示太平洋紫杉醇類似物間通常發生結構變化之位點。舉例而言，紫杉烧骨架上僅經氧原子取代指示羥基、酿基、烷氧基或另一含氧取代基通常存在於該位點上。紫杉烷骨架上可進行 54 200940050 等及其他取代，而 rfn不會喪失增強及穩定微管形成之能力。因此’術語Γ 4- &十羊紫杉醇類似物」在本文中定義成意謂二有基本太平洋紫杉醇骨架且促進微管形成之化合物。太平洋紫杉醇類似物可調配為奈米粒子膠狀組成物以改良輸液時間且消除用會引起某些患者產生過敏性反應之 Cremophor傳遞藥物的需要。調配為奈米粒子膠狀組成物之太平洋紫杉醇類似物的一實例為ABI_〇〇7，其為一種在鹽水中重組的蛋白質穩定之太平洋紫杉醇之奈米粒子膠狀組成物。通常，本文中所用之太平洋紫杉醇類似物係由結構式 (VII)或（VIII)表示》(νι). The cyclohexane ring in the yew-burning skeleton represented by the structural formula (VI) omits the double bond. & This yew @ skeleton can include 〇 or 1 double bond in one or two 帛院院 S, as indicated in Figure 6.26 and below (νπ) and (VIII). Structural formula (VI) also omits a large number of atoms to indicate sites where structural changes typically occur between the paclitaxel analogs. For example, substitution of only the oxygen atom on the yew skeleton indicates that the hydroxyl group, the aryl group, the alkoxy group or another oxygen-containing substituent is usually present at this site. The taxane skeleton can be subjected to 54 200940050 and other substitutions, and rfn does not lose the ability to enhance and stabilize microtubule formation. Thus the term '4- 4-amphibix analogs' is defined herein to mean a compound that has a basic Pacific paclitaxel backbone and promotes microtubule formation. The Pacific paclitaxel analog can be formulated as a nanoparticle gel-like composition to improve infusion time and eliminate the need for a Cremophor delivery drug that causes an allergic reaction in some patients. An example of a paclitaxel analog formulated as a colloidal composition of nanoparticles is ABI_〇〇7, which is a gelatinous composition of a protein-stabilized paclitaxel nanoparticle recombined in saline. Generally, the paclitaxel analogs used herein are represented by structural formula (VII) or (VIII).

55 20094005055 200940050

Rio為低碳烷基、經取代之低碳烷基、苯基、經取代之 ❹ 笨基、-SR19、_NHR19 或-〇尺19。Rio is a lower alkyl group, a substituted lower alkyl group, a phenyl group, a substituted hydrazine group, -SR19, _NHR19 or - 〇19.

Ri 1為低碳烧基、經取代之低碳烷基、芳基或經取代之芳基。Ri 1 is a lower carbon group, a substituted lower alkyl group, an aryl group or a substituted aryl group.

Ri2為-H、-OH、低碳烷基、經取代之低碳烷基、低碳烷氧基、經取代之低碳烷氧基、-〇-C(〇)-(低碳烷基）、 -o_c(o)-(經取代之低碳烷基）、_〇_ch2-0-(低碳烷基）-S-CH2_0-(低破烧基）。Ri2 is -H, -OH, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, -〇-C(〇)-(lower alkyl) -o_c(o)-(substituted lower alkyl), _〇_ch2-0-(lower alkyl)-S-CH2_0- (low-cracking base).

Ri3 為-H、-CH3 或與 R14 — 起為-CH2-。〇 R14為-H、-OH、低碳烷氧基、-0-C(0)-(低碳烷基）、經取代之低碳烷氧基、-〇-C(0)-(經取代之低碳烷基）、 -o-ch2-o-p(o)(oh)2、-o-ch2-o-(低碳烷基）、-o-ch2-s-(低碳烷基）或與R2〇 —起為一雙鍵。Ri3 is -H, -CH3 or -CH2- with R14. R14 is -H, -OH, lower alkoxy,-0-C(0)-(lower alkyl), substituted lower alkoxy, -〇-C(0)-(substituted Lower alkyl), -o-ch2-op(o)(oh)2, -o-ch2-o-(lower alkyl), -o-ch2-s-(lower alkyl) or R2〇 is a double key.

Ri5為-H、低碳醯基、低碳烷基、經取代之低碳烧基、烷氧基甲基、烷硫基甲基、-0c(0)-0(低碳烧基）、 -0C(0)-0(經取代之低碳炫基）、-〇c(〇)-NH(低碳烧基）或 56 200940050 -OC(0)-NH(經取代之低碳烷基）。Ri5 is -H, lower fluorenyl, lower alkyl, substituted lower alkyl, alkoxymethyl, alkylthiomethyl, -0c(0)-0 (low carbon alkyl), - 0C(0)-0 (substituted low carbon group), -〇c(〇)-NH(low carbon alkyl) or 56 200940050 -OC(0)-NH (substituted lower alkyl).

Rie為苯基或經取代之苯基。 R17為-H、低碳醯基、經取代之低碳醯基、低碳烷基、經取代之低碳烷基、（低碳烷氧基）甲基或（低碳烷基）硫基甲基0Rie is phenyl or substituted phenyl. R17 is -H, lower fluorenyl, substituted lower fluorenyl, lower alkyl, substituted lower alkyl, (lower alkoxy) methyl or (lower alkyl) thio Base 0

Ris為-H、-CH3或與R17及與r17及r18鍵結之碳原子一起形成5或6員非芳族雜環。 R19為低碳烷基、經取代之低碳烷基、苯基、經取代之 ❹苯基。 Κ·2〇為-H或鹵素。Ris is -H, -CH3 or together with R17 and a carbon atom bonded to r17 and r18 form a 5 or 6 membered non-aromatic heterocyclic ring. R19 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, or a substituted indenylphenyl group. Κ·2〇 is -H or halogen.

Rn為-Η、低碳烷基、經取代之低碳烷基、低碳醯基或經取代之低碳醯基。較佳地’結構式（VII )及（VIII )中之變數定義如下： Rio 為苯基、第三丁氧基、-S-CH2-CH-(CH3)2、-S-CH(CH3)3、 -S-(CH2)3CH3、-0-CH(CH3)3、-NH-CH(CH3)3、-ch=c(ch3)2 O 或對氣苯基；Rn為苯基、（CH3)2CHCH2-、-2-呋喃基、環丙基或對甲苯甲醯基；R1；j為_H、-〇H、CH3CO-或-(CH2)2-#-嗎嚇基；R13為甲基，或R13及r14 一起為_CH2-;Rn is -fluorene, lower alkyl, substituted lower alkyl, lower sulfhydryl or substituted lower fluorenyl. Preferably, the variables in 'Structures (VII) and (VIII) are defined as follows: Rio is phenyl, tert-butoxy, -S-CH2-CH-(CH3)2, -S-CH(CH3)3 , -S-(CH2)3CH3, -0-CH(CH3)3, -NH-CH(CH3)3, -ch=c(ch3)2 O or p-phenyl; Rn is phenyl, (CH3) 2CHCH2-,-2-furanyl, cyclopropyl or p-tolylmethylhydrazine; R1;j is _H, -〇H, CH3CO- or -(CH2)2-#-, stimuli; R13 is methyl, Or R13 and r14 together are _CH2-;

Ri4 為·Η、-CH2SCH3 或-CH2-0-P(〇)(〇H)2 ; R15 為 ch3co-; R16 為苯基；R17 為-Η，或 R17 及 r18 — 起為-O-CO-O·; Ris 為-Η ; R2〇為-H 或-F ;且 R21 為-Η、 -C(0)-CHBr-(CH2)i3-CH3 或-C(〇HCH2)14-CH3 ; •c(o)-ch2-ch(oh)-cooh 、 57 200940050 -C(0)-CH2-0-C(0)-CH2CH(NH2)-C0NH2 、 -C(0)-CH2-0--CH2CH2〇CH3 或-C(0)-〇-C(0)-CH2CH3。太平洋紫杉醇類似物亦可鍵結或側接於醫藥上可接受之聚合物’諸如聚丙婦醯胺。此類型聚合物之一實例展示於圖35。如本文中所用之術語「太平洋紫杉醇類似物」包括該等聚合物。在與一或多種其他治療劑（例如，太平洋紫杉醇或太平洋紫杉醇類似物）組合之共同療法中，本文中所揭示之化合物或醫藥組成物可與其他治療劑同時或分開投予。投 ❹ 藥之確切詳情將視兩種物質在彼此存在下之藥物動力學而定，且可包括大體上同時投予兩種物質，及在投予一物質之某一時段内（例如，24小時内）投予另一物質（若藥物動力學合適）。合適給藥方案之設計對熟習此項技術者而言為常規的。在特定具體實例中，將大體上同時投予兩種物質亦即相對於彼此在幾分鐘内投予，或以包含兩種物質之單一組成物投予。所揭示之化合物1之晶形及晶體慣態可根據上述方法 ❹ 製備。在某些特定具體實例中，所揭示之化合物1之晶形 ^晶體慣態可根據實施例1-4中所述之方法製備。化合物i 可根據美國專利第M00,660號、第6,762,204號及第 6’825,235號及美國公開案第2008/0146842號中所述之方法製備此等公開案及申請案之全部教示内容以引用的方式併入本文中。藉由乂下實施例來說明本發明，該等實施例並不意欲 58 200940050 以任何方式加以限制。範例 X射線粉末繞射使用裝備有％範圍為120°之CPS (彎曲位置靈敏型）偵測器的Inel XRG-3000繞射計執行X射線粉末繞射 (XRPD)分析。使用Cu-Κα輻射以0.03〇 20之解析度收集即時資料。管電壓及電流量分別設為40 kV及30 mA。單色器狹縫設為5 mmxl60 /xm。顯示2.5°-40°之20的圖案。藉由將樣品裝填至薄壁玻璃毛細管中來製備樣品以對其進行分析。將各毛細管安裝在經機動化以允許毛細管在資料獲取期間旋轉的測角儀頭上。分析樣品歷時300 sec。使用矽參考標準執行儀器校正。使用File Monkey 3.1_2版將由Inel XRPD儀器產生之任何XRPD檔案轉化為Shimadzu.raw構案。藉由Shimadzu XRD-6100/7000 5.0版軟體處理Shimadzu.raw檔案以自動找到峰位置。「峰位置」意謂峰形強度曲線之最大強度。峰選擇所用之參數展示於資料之各參數集之下半部分中。 Shimadzu XRD-6100/7000「基本方法」1.01版演算法使用以下過程：對所有圖案進行平滑化。扣除背景以得到峰之純相對強度。對於所有圖案，將由50%強度下之Cu Καί ( 1·5406 A) 峰產生之峰減去Cu Κα2 ( 1.5444人）波長之峰。特定XRPD峰資料及XRPD資料之量測條件匯總於表 59 200940050Ri4 is ·Η, -CH2SCH3 or -CH2-0-P(〇)(〇H)2; R15 is ch3co-; R16 is phenyl; R17 is -Η, or R17 and r18 are -O-CO- O·; Ris is -Η; R2〇 is -H or -F; and R21 is -Η, -C(0)-CHBr-(CH2)i3-CH3 or -C(〇HCH2)14-CH3; (o)-ch2-ch(oh)-cooh, 57 200940050 -C(0)-CH2-0-C(0)-CH2CH(NH2)-C0NH2, -C(0)-CH2-0--CH2CH2〇 CH3 or -C(0)-〇-C(0)-CH2CH3. The paclitaxel analog may also be bonded or flanked by a pharmaceutically acceptable polymer such as polyacrylamide. An example of this type of polymer is shown in Figure 35. The term "pacific paclitaxel analog" as used herein includes such polymers. In a combination therapy with one or more other therapeutic agents (e.g., paclitaxel or paclitaxel analogs), the compounds or pharmaceutical compositions disclosed herein can be administered simultaneously or separately with other therapeutic agents. The exact details of the administration of the drug will depend on the pharmacokinetics of the two substances in the presence of each other and may include the administration of the two substances substantially simultaneously, and within a certain period of time during which a substance is administered (eg, 24 hours) Internally, another substance is administered (if the pharmacokinetics are appropriate). The design of a suitable dosing regimen is conventional to those skilled in the art. In a particular embodiment, the two substances will be administered substantially simultaneously, i.e., administered within a few minutes relative to each other, or administered as a single composition comprising both substances. The crystal form and crystal habit of the disclosed Compound 1 can be prepared according to the above method. In certain specific embodiments, the crystalline form of the disclosed Compound 1 can be prepared according to the methods described in Examples 1-4. Compounds i can be prepared by reference to all teachings of the publications and applications in the manner described in U.S. Patent Nos. M00,660, 6,762,204 and 6, '825,235, and U.S. Publication No. 2008/0146842. The manner is incorporated herein. The invention is illustrated by the following examples, which are not intended to be limited in any way. Example X-Ray Powder Diffraction X-ray powder diffraction (XRPD) analysis was performed using an Inel XRG-3000 diffractometer equipped with a CPS (bend position sensitive) detector with a range of 120°. Real-time data were collected using Cu-Κα radiation at a resolution of 0.03 〇 20 . The tube voltage and current are set to 40 kV and 30 mA, respectively. The monochromator slit is set to 5 mmxl60 /xm. A pattern of 20° to 40° is displayed. Samples were prepared for analysis by loading the samples into thin-walled glass capillaries. Each capillary is mounted on a goniometer head that is motorized to allow the capillary to rotate during data acquisition. The sample was analyzed for 300 sec. Perform instrument calibration using the 矽 reference standard. Any XRPD file generated by the Inel XRPD instrument is converted to the Shimadzu.raw structure using File Monkey version 3.1_2. The Shimadzu.raw file was processed by Shimadzu XRD-6100/7000 version 5.0 software to automatically find the peak position. "Peak position" means the maximum intensity of the peak shape intensity curve. The parameters used for peak selection are shown in the lower half of each parameter set of the data. Shimadzu XRD-6100/7000 "Basic Method" Version 1.01 algorithm uses the following procedure: Smooth all patterns. The background is subtracted to obtain the pure relative intensity of the peak. For all patterns, the peak produced by the Cu Καί (1·5406 A) peak at 50% intensity is subtracted from the peak of the Cu Κα2 (1.5444 person) wavelength. The measurement conditions of specific XRPD peak data and XRPD data are summarized in Table 59 200940050

表5:圈1之A形之XRPD圖量測條件= X-射線管目標 =Cu 電壓 = 0.0 (kV) 電流 = 0.0 (mA) 狹縫發散狹縫 = 0.00000 (°) 散射狹縫 = 0.00000 (°) 接收狹縫 = 0.00000 (mm) 掃描驅動軸 = 2Θ/Θ 掃描範圍 =3.009-39.969 掃描模式 = 掃描速度 = 0.0060 (°/min) 取樣間距 = 0.0300 (°) 預置時間 =300.00 ( sec ) 資料處理條件：平滑化 [自動] 平滑化點 =9 B.G.扣除 [自動] 取樣點 =9 重複次數 =30 Kal-a2分離 [手動] Kal a2比率 = 50.0 (%) 峰搜尋 [自動] 差異點 =9 FWHM臨限值 = 0.050 (°) 強度臨限值 =30 (標準密耳（parmil)) 200940050 FWHM 比率(η-1)/η =2 系統誤差校正： [無] 精確峰校正： [無]Table 5: XRPD pattern measurement of circle A's A shape = X-ray tube target = Cu voltage = 0.0 (kV) Current = 0.0 (mA) Slit divergence slit = 0.00000 (°) Scattering slit = 0.00000 ( °) Receiving slit = 0.00000 (mm) Scanning drive axis = 2Θ/Θ Scanning range = 3.009-39.969 Scan mode = Scan speed = 0.0060 (°/min) Sampling interval = 0.0300 (°) Preset time = 300.00 ( sec ) Data processing conditions: Smoothing [Automatic] Smoothing point = 9 BG deduction [Automatic] Sampling point = 9 Repeat number = 30 Kal-a2 separation [Manual] Kal a2 ratio = 50.0 (%) Peak search [Automatic] Difference point = 9 FWHM threshold = 0.050 (°) Strength threshold = 30 (standard mil (parmil)) 200940050 FWHM ratio (η-1) / η = 2 Systematic error correction: [None] Accurate peak correction: [None]

峰資料清單[總數=35] 編號 2Θ d I I/Io FWHM 積分I 1 8.2892 10.65807 648 9 0.14920 5660 2 8.6048 10.26786 5334 72 0.24370 46266 3 10.7629 8.21338 1656 22 0.25510 16960 4 12.4049 7.12964 276 4 0.22080 3125 5 13.4814 6.56266 474 6 0.20350 5436 6 14.4934 6.10662 2376 32 0.22410 20376 7 15.2416 5.80849 443 6 0.22160 3801 8 16.3279 5.42441 1921 26 0.29360 21133 9 17.4870 5.06739 585 8 0.27150 6673 10 18.7433 4.73047 7414 100 0.21570 58711 11 19.1767 4.62453 1710 23 0.29850 18547 12 19.9271 4.45204 1308 18 0.23250 11927 13 20.9248 4.24197 5151 69 0.22510 45299 14 22.5025 3.94799 876 12 0.30930 9526 15 23.1692 3.83588 271 4 0.30760 4066 16 23.6539 3.75836 2801 38 0.26990 25708 17 24.1188 3.68696 2329 31 0.28740 25013 18 24.7592 3.59303 366 5 0.25260 4780 19 25.8834 3.43946 398 5 0.31480 4830 20 27.1324 3.28390 281 4 0.25150 2646 21 27.7156 3.21611 1426 19 0.30930 15851 22 28.4492 3.13482 526 7 0.24300 6279 23 28.6892 3.10914 415 6 0.00000 0 24 29.1844 3.05750 968 13 0.28630 12799 25 30.0092 2.97532 428 6 0.37720 4437 26 30.2792 2.94940 356 5 0.32700 3605 27 30.7289 2.90725 598 8 0.24640 5860 28 31.8144 2.81049 270 4 0.28430 2778 29 32.3492 2.76524 233 3 0.17380 1256 30 32.5592 2.74788 318 4 0.26780 3117 31 33.3759 2.68249 274 4 0.30550 5110 32 34.9993 2.56169 509 7 0.31660 6901 61 200940050 33 36.6432 2.45045 247 3 0.32300 3782 34 38.7328 2.32292 465 6 0.25070 4198 35 39.3422 2.28833 262 4 0.28810 3716 表6 :圈5之 A形之XRPD圈量測條件： X射線管目標 =Cu 電壓 = 0.0 (kV) 電流 = 0.0 (mA) 狹縫發散狹縫 = 0.00000 (°) 散射狹縫 = 0.00000 (°) 接收狹縫 = 0.00000 (mm) 掃描驅動軸 = 2ΘΙΘ 掃描範圍 =3.009-39.969 掃描模式 = 掃描速度 = 0.0060 (°/min) 取樣間距 = 0.0300 (°) 預置時間 =300.00 ( sec ) 資料處理條件：平滑化 [自動] 平滑化點 =9 B.G.扣除 [自動] 取樣點 =11 重複次數 =30 Kal-a2分離 [手動] Kal a2比率 = 50.0(%) 峰搜尋 [自動] 差異點 =9Peak data list [total = 35] No. 2Θ d II/Io FWHM Integral I 1 8.2892 10.65807 648 9 0.14920 5660 2 8.6048 10.26786 5334 72 0.24370 46266 3 10.7629 8.21338 1656 22 0.25510 16960 4 12.4049 7.12964 276 4 0.22080 3125 5 13.4814 6.56266 474 6 0.20350 5436 6 14.4934 6.10662 2376 32 0.22410 20376 7 15.2416 5.80849 443 6 0.22160 3801 8 16.3279 5.42441 1921 26 0.29360 21133 9 17.4870 5.06739 585 8 0.27150 6673 10 18.7433 4.73047 7414 100 0.21570 58711 11 19.1767 4.62453 1710 23 0.29850 18547 12 19.9271 4.45204 1308 18 0.23250 11927 13 20.9248 4.24197 5151 69 0.22510 45299 14 22.5025 3.94799 876 12 0.30930 9526 15 23.1692 3.83588 271 4 0.30760 4066 16 23.6539 3.75836 2801 38 0.26990 25708 17 24.1188 3.68696 2329 31 0.28740 25013 18 24.7592 3.59303 366 5 0.25260 4780 19 25.8834 3.43946 398 5 0.31480 4830 20 27.1324 3.28390 281 4 0.25150 2646 21 27.7156 3.21611 1426 19 0.30930 15851 22 28.4492 3.13482 526 7 0.24300 6279 23 28.6892 3.10914 415 6 0.00000 0 24 29.1844 3.0575 0 968 13 0.28630 12799 25 30.0092 2.97532 428 6 0.37720 4437 26 30.2792 2.94940 356 5 0.32700 3605 27 30.7289 2.90725 598 8 0.24640 5860 28 31.8144 2.81049 270 4 0.28430 2778 29 32.3492 2.76524 233 3 0.17380 1256 30 32.5592 2.74788 318 4 0.26780 3117 31 33.3759 2.68249 274 4 0.30550 5110 32 34.9993 2.56169 509 7 0.31660 6901 61 200940050 33 36.6432 2.45045 247 3 0.32300 3782 34 38.7328 2.32292 465 6 0.25070 4198 35 39.3422 2.28833 262 4 0.28810 3716 Table 6: X-shaped XRPD circle measurement for circle 5: X Tube target = Cu voltage = 0.0 (kV) Current = 0.0 (mA) Slit divergence slit = 0.00000 (°) Scatter slit = 0.00000 (°) Receiving slit = 0.00000 (mm) Scanning drive axis = 2 ΘΙΘ Scanning range =3.009-39.969 Scan mode = Scan speed = 0.0060 (°/min) Sampling interval = 0.0300 (°) Preset time = 300.00 ( sec ) Data processing conditions: Smoothing [Automatic] Smoothing point = 9 BG deduction [Automatic] Sampling point = 11 number of repetitions = 30 Kal-a2 separation [manual] Kal a2 ratio = 50.0 (%) [Auto] = 9 points of difference

62 20094005062 200940050

FWHM臨限值強度臨限值 FWHM 比率(n-l)/n 系統誤差校正：精確峰校正： = 0.050 (°) =30 (標準密耳） =2 [無] [無] 峰資料清單[總數=42] 編號 1Θ d I 1/1〇 FWHM 積分I 1 5.1232 17.23518 158 4 0.28200 2450 2 8.6414 10.22445 3683 86 0.20660 28903 3 10.3206 8.56436 1467 34 0.20060 11768 4 11.8275 7.47637 197 5 0.19120 1648 5 12.9433 6.83426 613 14 0.23020 5410 6 13.8638 6.38249 264 6 0.23170 2126 7 14.8003 5.98067 1017 24 0.19500 7282 8 15.7041 5.63845 1124 26 0.35020 13467 9 16.8791 5.24850 1100 26 0.24490 9496 10 17.2872 5.12550 394 9 0.18250 2613 11 17.6444 5.02254 639 15 0.20560 4678 12 19.1514 4.63058 4271 100 0.22320 35706 13 19.6805 4.50727 893 21 0.23810 9108 14 20.3868 4.35268 471 11 0.24020 4121 15 20.8592 4.25516 459 11 0.34160 6123 16 21.0692 4.21322 555 13 0.00000 0 17 21.4871 4.13221 2732 64 0.20240 23167 18 21.9092 4.05355 287 7 0.23520 3324 19 22.7492 3.90574 322 8 0.13300 2658 20 23.0485 3.85569 1824 43 0.21190 14173 21 23.6412 3.76035 507 12 0.28180 5457 22 24.3430 3.65351 1008 24 0.25920 9377 23 24.9992 3.55907 304 7 0.23120 3504 24 25.2392 3.52577 239 6 0.00000 0 25 25.8129 3.44870 419 10 0.28140 6315 26 26.9277 3.30840 346 8 0.22050 2681 27 27.7507 3.21212 160 4 0.16550 1005 28 28.4792 3.13159 694 16 0.25820 5019 29 28.6592 3.11233 502 12 0.28560 3973 30 28.9817 3.07842 741 17 0.22440 5718 63 200940050 31 29.5730 3.01820 413 10 0.23980 3809 32 30.1205 2.96458 1037 24 0.29920 11894 33 30.9392 2.88797 187 4 0.15000 1392 34 31.2168 2.86292 715 17 0.24840 5472 35 31.4792 2.83965 220 5 0.18440 2060 36 32.0602 2.78950 252 6 0.29120 3423 37 33.5336 2.67023 273 6 0.15200 1518 38 34.6003 2.59031 212 5 0.25900 2851 39 36.3338 2.47060 255 6 0.24830 3795 40 37.9032 2.37184 245 6 0.25820 2635 41 38.4392 2.33999 162 4 0.17820 1257 42 38.7992 2.31910 179 4 0.14180 1534 表7 : 圖7之 A形之XRPD圖量測條件：管線射標壓流 X目電電 =Cu = 0.0 (kV) = 0.0 (mA) 狹縫發散狹縫 = 0.00000 (°) 散射狹縫 = 0.00000 (°) 接收狹縫 = 0.00000 (mm) 掃描驅動軸 = 2Θ/Θ 掃描範圍 =3.009-39.969 掃描模式 = 掃描速度 = 0.0060 (°/min) 取樣間距 = 0.0300 (°) 預置時間 =300.00 ( sec ) 資料處理條件：平滑化 [自動] 平滑化點 =11 64 200940050FWHM threshold intensity threshold FWHM ratio (nl) / n systematic error correction: accurate peak correction: = 0.050 (°) = 30 (standard mil) = 2 [none] [none] peak data list [total = 42 No. 1Θ d I 1/1〇FWHM Integral I 1 5.1232 17.23518 158 4 0.28200 2450 2 8.6414 10.22445 3683 86 0.20660 28903 3 10.3206 8.56436 1467 34 0.20060 11768 4 11.8275 7.47637 197 5 0.19120 1648 5 12.9433 6.83426 613 14 0.23020 5410 6 13.8638 6.38249 264 6 0.23170 2126 7 14.8003 5.98067 1017 24 0.19500 7282 8 15.7041 5.63845 1124 26 0.35020 13467 9 16.8791 5.24850 1100 26 0.24490 9496 10 17.2872 5.12550 394 9 0.18250 2613 11 17.6444 5.02254 639 15 0.20560 4678 12 19.1514 4.63058 4271 100 0.22320 35706 13 19.6805 4.50727 893 21 0.23810 9108 14 20.3868 4.35268 471 11 0.24020 4121 15 20.8592 4.25516 459 11 0.34160 6123 16 21.0692 4.21322 555 13 0.00000 0 17 21.4871 4.13221 2732 64 0.20240 23167 18 21.9092 4.05355 287 7 0.23520 3324 19 22.7492 3.90574 322 8 0.13300 2658 20 23.0485 3.85569 1824 43 0.21190 14173 21 23.6412 3.76035 507 12 0.28180 5457 22 24.3430 3.65351 1008 24 0.25920 9377 23 24.9992 3.55907 304 7 0.23120 3504 24 25.2392 3.52577 239 6 0.00000 0 25 25.8129 3.44870 419 10 0.28140 6315 26 26.9277 3.30840 346 8 0.22050 2681 27 27.7507 3.21212 160 4 0.16550 1005 28 28.4792 3.13159 694 16 0.25820 5019 29 28.6592 3.11233 502 12 0.28560 3973 30 28.9817 3.07842 741 17 0.22440 5718 63 200940050 31 29.5730 3.01820 413 10 0.23980 3809 32 30.1205 2.96458 1037 24 0.29920 11894 33 30.9392 2.88797 187 4 0.15000 1392 34 31.2168 2.86292 715 17 0.24840 5472 35 31.4792 2.83965 220 5 0.18440 2060 36 32.0602 2.78950 252 6 0.29120 3423 37 33.5336 2.67023 273 6 0.15200 1518 38 34.6003 2.59031 212 5 0.25900 2851 39 36.3338 2.47060 255 6 0.24830 3795 40 37.9032 2.37184 245 6 0.25820 2635 41 38.4392 2.33999 162 4 0.17820 1257 42 38.7992 2.31910 179 4 0.14180 1534 Table 7: Figure 7 A-shaped XRPD diagram measurement conditions: Pipeline jet pressure X-ray electric = Cu = 0.0 (kV) = 0.0 (mA) Slit Slit slit = 0.00000 (°) Scatter slit = 0.00000 (°) Receiving slit = 0.00000 (mm) Scanning drive axis = 2Θ/Θ Scanning range = 3.009-39.969 Scan mode = Scan speed = 0.0060 (°/min) Sampling Spacing = 0.0300 (°) Preset time = 300.00 ( sec ) Data processing conditions: Smoothing [Automatic] Smoothing point = 11 64 200940050

B.G扣除取樣點重複次數B.G deduction sampling point repetition number

Kal-a2分離 Kal a2比率蜂搜尋差異點 FWHM臨限值強度臨限值 FWHM 比率(n-l)/n 系統誤差校正：精確峰校正： [自動] =13 =30 [手動] = 50.0 (%) [自動] =9 = 0.050 (°) =30 (標準密耳） =2 [無] [無] 峰資料清單[總數=51] 編號 2Θ d I I/Io FWHM 積分I 1 6.5489 13.48592 316 12 0.31500 4751 2 7.5166 11.75175 2543 96 0.25550 23000 3 7.8392 11.26885 566 21 0.24740 6686 4 11.7899 7.50013 130 5 0.22140 1272 5 13.2235 6.69007 2572 97 0.23750 23386 6 13.9027 6.36472 2536 96 0.23410 21364 7 14.1992 6.23248 89 3 0.07420 705 8 15.0732 5.87300 159 6 0.23010 1705 9 15.8155 5.59898 1222 46 0.25330 11320 10 16.7541 5.28737 783 30 0.26450 7063 11 17.2295 5.14254 2468 93 0.30150 25766 12 17.6792 5.01273 127 5 0.16680 1191 13 18.6959 4.74236 1948 73 0.24660 17358 14 19.3892 4.57432 132 5 0.11840 704 15 19.7124 4.50005 2048 77 0.23740 17531 16 20.3492 4.36064 206 8 0.28240 2329 17 20.7967 4.26781 1587 60 0.30460 16922 18 21.3513 4.15819 271 10 0.24800 2999 19 22.0594 4.02628 2652 100 0.22900 21452 20 22.6592 3.92105 605 23 0.22500 4868 65 200940050 21 23.3492 3.80671 673 25 0.28520 5743 22 23.7392 3.74505 811 31 0.38100 9314 23 24.0692 3.69444 1461 55 0.28120 11218 24 24.3092 3.65851 2079 78 0.30380 20009 25 24.9748 3.56249 2328 88 0.25530 21643 26 25.2992 3.51754 159 6 0.11580 1303 27 25.7492 3.45708 171 6 0.22340 1274 28 26.0897 3.41273 457 17 0.25750 4258 29 26.6485 3.34242 1318 50 0.25180 12015 30 27.5431 3.23586 258 10 0.20650 1844 31 28.4388 3.13595 1067 40 0.27610 10638 32 29.1941 3.05651 2017 76 0.24500 18271 33 29.7900 2.99671 509 19 0.23350 4962 34 30.4592 2.93238 568 21 0.30200 5844 35 30.7592 2.90446 387 15 0.23420 3462 36 31.3217 2.85357 112 4 0.25500 969 37 31.7059 2.81986 380 14 0.25450 3157 38 32.1092 2.78536 156 6 0.18160 1173 39 32.3792 2.76275 223 8 0.27440 1931 40 33.1892 2.69715 117 4 0.13600 629 41 33.5285 2.67062 541 20 0.37660 6972 42 34.3292 2.61014 199 8 0.27420 1922 43 34.7192 2.58171 193 7 0.25560 2081 44 35.6712 2.51496 445 17 0.42630 6493 45 36.5223 2.45828 160 6 0.25590 1373 46 37.1968 2.41524 90 3 0.37130 1130 47 37.9233 2.37063 442 17 0.25520 4021 48 38.2892 2.34881 204 8 0.21300 1700 49 38.9967 2.30781 113 4 0.21500 829 50 39.5034 2.27937 106 4 0.22350 771 51 39.8792 2.25875 127 5 0.11460 614 差示掃描熱量測定及熱解重量分析使用每分鐘10°c之加熱速率自25°c至250°c對A形、C 形及D形之樣品進行差示掃描熱量測定（DSC)及熱解重量分析（TG)。圖 2 ( A) -2 ( B)、圖 6 及圖 8 ( A) -8 ( B) 66 200940050 展示熱分析之結果。 J：.晶體结_構測定 D形之單晶體結構係由使用Μο Κα輻射自化合物^之 D形之合適單晶體獲得的χ射線晶體學資料導出。該晶體結構特徵為1 21 /η 1空間群： « = 14.3994(8) A ； Ζ, = 5.7133(3) A ； c = 23.872(3) A ； =1〇2·130(3) ° ;且 v = 192〇·ι(2) A3。單位晶胞之晶胞參數匯總於上表4中。 ❹ 化合物1之多形艚夕厶气實施例1. f備化合一物1之A形之晶體慣_ 1 將5 g化合物i添加至125 mL丙酮中。將i25 去離。子水添加至此混合物中。在攪拌下將所得混合物加熱至 6〇°C，直至達到透明溶液。接著使所得溶液冷卻至周圍溫度且攪拌4天《使用IR譜檢查a形之晶體慣態i形成是否完成。將所得固體藉由過濾分離且在真空下於4〇。〇下乾燥。藉由過遽過程獲得之針型晶體傾向於在乾燥過程中被壓縮成塊。實施例2 · 備化合物1之A形之晶韓慣_ 9 將化合物1懸浮於丙鲷（14 L/kg)中，且在攪拌下將水（2 L/kg)添加至懸浮液中，直至所有固體在周圍溫度下溶解。將水（30.4 L/kg)添加至結晶容器中且冷卻至〇它。經20-40分鐘將化合#丨之丙酮/水溶液添加至結晶容器中之水甲，同時將溫度維持在5t：以下。在周圍溫度下將所得懸浮液擾動20-24小時。將所得固體用冷5〇%丙嗣水溶液、 67 200940050 接著用正庚烧洗蘇而過據，且在真空下於赃下乾燥。 - 3L施例3_:製備化厶吃—1之c报在回流下將1 g化合物i溶於約27〇社二氣甲院中。將所得溶液經由0·2微米過遽器過渡至另—燒瓶中。將溶液緩慢冷卻至周圍溫度以促進結晶。必要時，進行進一步冷部以實現及完成結晶。將所得固體藉由過遽分離且在真空下於周圍溫度下乾燥。或者，在搜拌下將5g化合物"容於135〇mL二氣甲燒中。將所得溶液經由G·2微米過濾器過m燒瓶中。將〇二液冷卻至GC且授動12·16小時，同時將溶液溫度維持在〇C下將所得固趙藉由過遽分離，用冷（〇⑺。丙輞水溶液及庚烧洗蘇’且在真空下於贼下乾燥以產生3 3 5 g產物。 1 ^ d ¥ A.方法1 在攪拌下將5 g化合物1溶於70 mL( 14 L/kg)丙酮及 10 mL ( 2 L/kg )去離子水中，直至在周圍溫度下達到透明 Ο 合液將6〇 mL ( 12 L/kg )去離子水添加至化合物1之丙水溶液中且將所得混合物攪拌24小時。視情況在添加水之前或與此同時，添加5%(25〇 mg)化合物χ之D形。將固體藉由過濾分離，用冷（G_1G<t) 5()%丙嗣水溶液及庚烷洗滌，且在真空下於5〇〇c下乾燥以產生3 9 14丨§產物。或者’在授拌下將5 g化合物1溶於70 mL ( 14 L/kg) 丙酮及10 mL ( 2 L/kg)去離子水中，直至在周圍溫度下達 68 200940050 到透明溶液。視情況，添加5% (25〇 mg)化合物1之D形作為晶種。在周圍溫度下將130 mL (26 L/kg)去離子水添加至化合物1之丙酮/水溶液中且將所得混合物攪拌8· 12小時’使結晶完成。將所得固體藉由過濾分離，用冷（〇_1〇t：) 50%丙酮水溶液及庚烷洗滌’且在真空下於5〇。〇下乾燥以產生4· 1 -4.3 g產物。 B.方法2 將5 g化合物1添加至125 mL丙酮中。將125 mL去離子水添加至此混合物中。在攪拌下將所得混合物加熱至 6〇°C，直至達到透明溶液。接著使所得溶液冷卻至周圍溫度且授拌2小時。在冷卻過程中，化合物1之〇形之晶體沈澱。將所得固體藉由過濾分離且在真空下於4〇。匚下乾燥。實施例5穩定性研究材料戽設備： 20 mL閃爍管Kal-a2 separation Kal a2 ratio bee search difference point FWHM threshold intensity threshold FWHM ratio (nl) / n systematic error correction: accurate peak correction: [auto] = 13 = 30 [manual] = 50.0 (%) [ Automatic] =9 = 0.050 (°) =30 (standard mil) =2 [none] [none] Peak data list [total = 51] No. 2Θ d II/Io FWHM Integration I 1 6.5489 13.48592 316 12 0.31500 4751 2 7.5166 11.75175 2543 96 0.25550 23000 3 7.8392 11.26885 566 21 0.24740 6686 4 11.7899 7.50013 130 5 0.22140 1272 5 13.2235 6.69007 2572 97 0.23750 23386 6 13.9027 6.36472 2536 96 0.23410 21364 7 14.1992 6.23248 89 3 0.07420 705 8 15.0732 5.87300 159 6 0.23010 1705 9 15.8155 5.59898 1222 46 0.25330 11320 10 16.7541 5.28737 783 30 0.26450 7063 11 17.2295 5.14254 2468 93 0.30150 25766 12 17.6792 5.01273 127 5 0.16680 1191 13 18.6959 4.74236 1948 73 0.24660 17358 14 19.3892 4.57432 132 5 0.11840 704 15 19.7124 4.50005 2048 77 0.23740 17531 16 20.3492 4.36064 206 8 0.28240 2329 17 20.7967 4.26781 1587 60 0.30460 16922 18 21.3513 4.15819 271 10 0 .24800 2999 19 22.0594 4.02628 2652 100 0.22900 21452 20 22.6592 3.92105 605 23 0.22500 4868 65 200940050 21 23.3492 3.80671 673 25 0.28520 5743 22 23.7392 3.74505 811 31 0.38100 9314 23 24.0692 3.69444 1461 55 0.28120 11218 24 24.3092 3.65851 2079 78 0.30380 20009 25 24.9748 3.56249 2328 88 0.25530 21643 26 25.2992 3.51754 159 6 0.11580 1303 27 25.7492 3.45708 171 6 0.22340 1274 28 26.0897 3.41273 457 17 0.25750 4258 29 26.6485 3.34242 1318 50 0.25180 12015 30 27.5431 3.23586 258 10 0.20650 1844 31 28.4388 3.13595 1067 40 0.27610 10638 32 29.1941 3.05651 2017 76 0.24500 18271 33 29.7900 2.99671 509 19 0.23350 4962 34 30.4592 2.93238 568 21 0.30200 5844 35 30.7592 2.90446 387 15 0.23420 3462 36 31.3217 2.85357 112 4 0.25500 969 37 31.7059 2.81986 380 14 0.25450 3157 38 32.1092 2.78536 156 6 0.18160 1173 39 32.3792 2.76275 223 8 0.27440 1931 40 33.1892 2.69715 117 4 0.13600 629 41 33.5285 2.67062 541 20 0.37660 6972 42 34.3292 2.61014 199 8 0.27420 1922 43 34.719 2 2.58171 193 7 0.25560 2081 44 35.6712 2.51496 445 17 0.42630 6493 45 36.5223 2.45828 160 6 0.25590 1373 46 37.1968 2.41524 90 3 0.37130 1130 47 37.9233 2.37063 442 17 0.25520 4021 48 38.2892 2.34881 204 8 0.21300 1700 49 38.9967 2.30781 113 4 0.21500 829 50 39.5034 2.27937 106 4 0.22350 771 51 39.8792 2.25875 127 5 0.11460 614 Differential Scanning Calorimetry and Thermogravimetric Analysis Samples of A, C and D shapes from 25 ° C to 250 ° C using a heating rate of 10 ° C per minute Differential scanning calorimetry (DSC) and thermogravimetric analysis (TG) were performed. Figure 2 (A) -2 (B), Figure 6 and Figure 8 (A) -8 (B) 66 200940050 Shows the results of thermal analysis. J: Crystallization _ DETERMINATION The D-shaped single crystal structure is derived from the χ ray crystallographic data obtained by using Μο Κα radiation from a suitable single crystal of the compound D shape. The crystal structure is characterized by a 1 21 /η 1 space group: « = 14.3994(8) A ; Ζ, = 5.7133(3) A ; c = 23.872(3) A ; =1〇2·130(3) ° ; v = 192〇·ι(2) A3. The unit cell parameters of the unit cell are summarized in Table 4 above.多 Compound 1 polymorphism 实施 Example 1. F-form compound 1 A-form crystal habit _ 1 5 g of compound i was added to 125 mL of acetone. Remove the i25. Subwater is added to this mixture. The resulting mixture was heated to 6 ° C with stirring until a clear solution was reached. The resulting solution was then cooled to ambient temperature and stirred for 4 days. "Is the formation of the crystal form i of the a-shape using IR spectroscopy to complete. The resulting solid was isolated by filtration and dried under vacuum. Dry under the armpits. The needle crystal obtained by the enthalpy process tends to be compressed into a block during the drying process. Example 2 · A-form crystal of Compound 1 was prepared. 9 Compound 1 was suspended in propionium (14 L/kg), and water (2 L/kg) was added to the suspension with stirring until All solids dissolved at ambient temperature. Water (30.4 L/kg) was added to the crystallization vessel and cooled to sputum. The acetone/water solution of the compound #丨 was added to the water in the crystallization vessel over 20-40 minutes while maintaining the temperature at 5t: or less. The resulting suspension was perturbed at ambient temperature for 20-24 hours. The obtained solid was passed through a cold aqueous solution of 5% hydrazine, 67 200940050, followed by washing with n-gum, and dried under vacuum under vacuum. - 3L Example 3_: Preparation of sputum sputum - 1 c report 1 g of compound i was dissolved in about 27 〇二气在在 under reflux. The resulting solution was transferred to a separate flask via a 0.2 micron filter. The solution was slowly cooled to ambient temperature to promote crystallization. If necessary, further cooling is performed to achieve and complete crystallization. The resulting solid was separated by hydrazine and dried under vacuum at ambient temperature. Alternatively, 5 g of the compound " is contained in 135 〇 mL of two gas aeration while searching. The resulting solution was passed through a G. 2 micron filter through an m flask. The ruthenium solution was cooled to GC and allowed to act for 12·16 hours, while maintaining the temperature of the solution at 〇C, the obtained solid was separated by hydrazine, and cooled (〇(7). Dry under thief under vacuum to give 3 3 5 g of product. 1 ^ d ¥ A. Method 1 5 g of Compound 1 was dissolved in 70 mL (14 L/kg) of acetone and 10 mL (2 L/kg) with stirring. Deionized water until a clear chelating solution is reached at ambient temperature 6 〇 mL (12 L/kg) of deionized water is added to the aqueous solution of Compound 1 in propylene and the resulting mixture is stirred for 24 hours, optionally before adding water. Or at the same time, add 5% (25 〇mg) of compound χD. The solid is separated by filtration, washed with cold (G_1G<t) 5 ()% aqueous solution of hydrazine and heptane, and under vacuum Dry at 5 〇〇c to produce 3 丨 14 丨 § product. Or '5 g of Compound 1 dissolved in 70 mL (14 L/kg) acetone and 10 mL (2 L/kg) of deionized water under mixing. Until the ambient temperature reaches 68 200940050 to the clear solution. Depending on the situation, add 5% (25 〇mg) Compound 1 D as a seed. 130 mL (26 L/kg) at ambient temperature Ionic water was added to the acetone/water solution of Compound 1 and the resulting mixture was stirred for 8·12 hours to complete the crystallization. The obtained solid was separated by filtration using cold (〇_1〇t:) 50% aqueous acetone solution and heptane. Washed 'and under vacuum at 5 Torr. Dry under the underarm to give 4·1 - 4.3 g of product. B. Method 2 5 g of compound 1 was added to 125 mL of acetone. 125 mL of deionized water was added to this mixture. The resulting mixture was heated to 6 ° C with stirring until a clear solution was reached. The resulting solution was then cooled to ambient temperature and allowed to mix for 2 hours. During cooling, the crystals of the compound 1 were precipitated. It was separated by filtration and dried under vacuum at 4 Torr. Example 5 Stability Study Materials 戽 Equipment: 20 mL scintillation tube

秤：Mettler Toledo XP 105DR ❹ 穩定性測試樣品批料製備：將100 mg土2%化合物1稱至各20 mL閃爍管中。將瓶蓋上合適之帽蓋且用石堪膜密封以防止水分進入。測試由不同批次合成之測試化合物的穩定性。每一批次製備12個瓶且將其分配至各別穩定性腔室中以便根據以下方案開始其穩定性研究。 69 200940050 穩定性方案時間點(月） 25〇C/60% RH 40〇C/75%RH 0.5 ΝΑ 1瓶(外觀，HPLC) 1 1瓶(外觀，HPLC) 1瓶(外觀，HPLC) 3 1瓶(外觀，HPLC) 1瓶(外觀,HPLC) 6 1瓶(外觀，HPLC) 1瓶(外觀，HPLC) 9 1瓶(外觀，HPLC) ΝΑ 12 1瓶(外觀，HPLC) ΝΑ 24 1瓶(外觀，HPLC) ΝΑ 所有時間點 1瓶(僅IR) 1瓶(僅IR) ΝΑ :不適用；RH :相對濕度測試化合物之穩定性係藉由其外觀及藉由分析方法 (諸如，HPLC及IR)測定。使用一瓶中之材料，在上文列出之兩種條件下，對所有時間點執行IR測試。化合物1含有微量如下所示之化合物2。藉由HPLC分析在各時間點存在之化合物1及2之量。Scale: Mettler Toledo XP 105DR 稳定性 Stability Test Sample Batch Preparation: 100 mg of soil 2% Compound 1 was weighed into each 20 mL scintillation vial. The bottle is capped with a suitable cap and sealed with a stone film to prevent moisture ingress. The stability of the test compounds synthesized from different batches was tested. Twelve bottles were prepared in each batch and dispensed into separate stability chambers to begin their stability studies according to the following protocol. 69 200940050 Stability schedule time point (month) 25〇C/60% RH 40〇C/75%RH 0.5 ΝΑ 1 bottle (appearance, HPLC) 1 1 bottle (appearance, HPLC) 1 bottle (appearance, HPLC) 3 1 Bottle (Appearance, HPLC) 1 bottle (appearance, HPLC) 6 1 bottle (appearance, HPLC) 1 bottle (appearance, HPLC) 9 1 bottle (appearance, HPLC) ΝΑ 12 1 bottle (appearance, HPLC) ΝΑ 24 1 bottle ( Appearance, HPLC) 1 1 bottle at all time points (IR only) 1 bottle (IR only) ΝΑ : Not applicable; RH: Relative humidity test compound stability by its appearance and by analytical methods (such as HPLC and IR ) Determination. An IR test was performed at all time points using the materials in one vial under the two conditions listed above. Compound 1 contained a small amount of Compound 2 shown below. The amounts of Compounds 1 and 2 present at each time point were analyzed by HPLC.

s ο 化合物2) 200940050 穩定性資料列於表1-4中。表1.批次時間(月） 1 在 25° 0 C/604 0.5 V〇 RH * 1 F之穩ί 3 t性資; 6 9 12 外觀淺黃色 NA 淺黃色淺黃色淺黃色淺黃色淺黃色 FT-IR D形 NA D形 D形 D形 D形 D形化合物1 % 99.0 NA 98.8 99.0 99.0 97.5 98 0 化合物2 % 1.30 NA 1.28 1.31 1.28 1.38 1.33 ❹ 表2.批次1 -時間（月） 0L 40〇C/7f 0 5% RH 下 0.5 之穩定 1 i資料 3 6 外觀淺黃色淺黃色淺黃色淺黃色淺黃色 FT-IR D形 D形 D形 D形 D形化合物1 % 99.0 99.7 95.8 98.9 98 4 化合物2 % 1.30 1.28 1.28 1.33 1.31 表3.批次2在25°C/60% RH下之穩定性資料時間（月） 0 0.5 1 3 6 9 12 外觀淺黃色粉末 NA 淺黃色粉末淺黃色粉末淺黃色粉末淺黃色粉末淺黃色粉末 FT-IR D形 NA D形 D形 D形 D形 D形化合物1 % 99.7 NA 98.6 100.2 99.6 98.9 QQ 7 化合物2 % 0.15 NA 0.14 0.15 0.13 0.13 0.13 71 200940050 實施例6溶解性資料量測化合物1之A形及D形的溶解性且資料列於表〇表4.批次2在40〇C/75% RH下之栽定性資料時間（月） 0 0.5 1 3 6 外觀淺黃色粉末淺黃色粉末淺黃邕粉末淺黃色粉末淺黃色粉末 FT-IR D形 D形 D形 D形 D形化合物1 % 99.7 99.6 100.3 100.2 101.7 化合物2 % 0.15 0.14 0.16 0.19 0.18 中表5·化合物1之A形及D形的溶解性s ο Compound 2) 200940050 Stability data is listed in Table 1-4. Table 1. Batch time (months) 1 at 25° 0 C/604 0.5 V〇RH * 1 F stable 3 t character; 6 9 12 Appearance light yellow NA light yellow light yellow light yellow light yellow light yellow FT -IR D-form NA D-shaped D-shaped D-shaped D-shaped D compound 1 % 99.0 NA 98.8 99.0 99.0 97.5 98 0 Compound 2 % 1.30 NA 1.28 1.31 1.28 1.38 1.33 ❹ Table 2. Batch 1 - time (month) 0L 40 〇C/7f 0 5% RH 0.5 stable 1 i data 3 6 Appearance light yellow light yellow light yellow light yellow light yellow FT-IR D shape D shape D shape D shape D compound 1 % 99.0 99.7 95.8 98.9 98 4 Compound 2 % 1.30 1.28 1.28 1.33 1.31 Table 3. Stability of Batch 2 at 25 ° C / 60% RH Data Time (Month) 0 0.5 1 3 6 9 12 Appearance Light Yellow Powder NA Light Yellow Powder Light Yellow Powder Shallow Yellow powder light yellow powder light yellow powder FT-IR D-shaped NA D-shaped D-shaped D-shaped D-shaped D-shaped compound 1 % 99.7 NA 98.6 100.2 99.6 98.9 QQ 7 Compound 2 % 0.15 NA 0.14 0.15 0.13 0.13 0.13 71 200940050 Example 6 The solubility data were measured for the solubility of Compound A in the A and D shapes and the data are listed in Table 4. Batch 2 in 40栽C/75% RH planting data time (month) 0 0.5 1 3 6 Appearance light yellow powder light yellow powder light yellow enamel powder light yellow powder light yellow powder FT-IR D-shaped D-shaped D-shaped D-shaped D-shaped Compound 1 % 99.7 99.6 100.3 100.2 101.7 Compound 2 % 0.15 0.14 0.16 0.19 0.18 Table 5 · Solubility of Form A and Form D of Compound 1

振盪時間 (小時） EtOAc中之溶解性 (mg/ml) EtOH中之溶解性 (mg/ml) 50:50 Cre/EtOH 中之溶解性 (mg/ml)Oscillation time (hours) Solubility in EtOAc (mg/ml) Solubility in EtOH (mg/ml) 50:50 Sol/EtOH Solubility (mg/ml)

Cre · Cremophor ΟCre · Cremophor Ο

72 200940050 製備50:50 Cremophor EL/乙醇且將其經由0.45 μηχ過遽器過濾且用於測試。將266 mg化合物1稱至具有橡膠塞之50 mL玻璃瓶中。藉由注射器及針取16 7 ml經過渡之 50:50 Cremophor EL/乙醇溶液且將其添加至瓶中^將瓶手動振盈或在機械振盪器上以232-236 rpm之速度振盪。使用三個瓶測定重組時間。在不同時間點，對瓶進行目測。 -篩截谢萬（Sieve-cut Test ) 使用Retsch振盪器及150微米篩網以兩個5分鐘時間 ® 間隔執行篩分。視批量而定，使用5 g至20 g樣品。量測接收器中所收集之材料的質量及百分比。光學顯撒街使用裝備有DP7 1彩色相機之〇iympUs BX5 1顯微鏡執打光學顯微術《使用5倍、1〇倍及40倍物鏡檢視樣品。將樣品置〜於玻璃載片上且振實以獲得單層粒子。在用5倍物鏡獲得經振實粉末（tapped powder)之影像後，將一滴矽 ❹油添加至樣品中。將蓋玻片輕輕置於樣品上，且用5倍及 10倍物鏡獲得影像。接著向蓋玻片施壓以使聚集艎破碎，且用5倍及40倍物鏡獲得影像。在周圍溫度下使用軟艎 DP-BSW獲得影像。體慣態1及晶艚惽轉7 根據程序a)製備批料1及2;根據程序b)製備批料3 及4;且根據程序製備批料5_8。 a)將化合物1懸浮於丙酮（14 L/Kg)中。添加水（2 L/Kg)且將所得混合物攪拌以溶解固體。將水（12 73 200940050 添加至澄清溶液中。將溶液攪拌14_丨6小時，直至大部分固體沈澱。將漿料冷卻至lore，歷時2_4小時，以便完全沈澱。將固體藉由過濾分離，用冷50%丙酮水溶液、接著用丙酮：正庚烷（1:2)之冷混合物且最終用正庚烷洗滌。將固體在真空下於50°C下乾燥。 b) 將125 mL丙酮及125 mL水添加至5 g化合物1中。將混合物加熱至60。(：，直至獲得澄清溶液。將溶液冷卻至室溫。固艎在冷卻期間沈澱。將所得混合物攪拌4_6天，直至完全轉變成A形（過濾漿料樣品且藉由ir檢查是否完全 0 轉變成A形）。將固體過濾且在真空下於4〇°c下乾燥。或者，在攪拌下將5g化合物1溶於7〇mL(14 L/kg) 丙酮及10 mL ( 2 L/kg)水中。添加60 mL ( 12 L/kg)水且將所得混合物攪拌4-6天’直至完全轉變成a形（過漶漿料樣品且藉由IR檢查是否完全轉變成A形）。將固體過遽且在真空下於40°C下乾燥。 c) 將化合物1懸浮於丙嗣（14 L/Kg )中。添加水（2 L/Kg )且攪拌以溶解固體以形成化合物1之濃溶液。將水〇 (30.4 L/Kg)冷卻至〇°C且添加至化合物1之濃溶液中，同時將溫度維持在〇-5。(：之間，歷時20-70分鐘。將懸浮液溫至周圍溫度且攪動20-24小時。將固體藉由過濾分離，用冷 50°/。丙酮水溶液且接著用正庚烷洗滌兩次且在真空下於 5〇°C下乾燥。結果結果列於下表6中。 74 200940050 表6.A形之晶體慣態1及晶艘慣態2之特性化批號慣態編號批量粒子外觀通過特定大小篩網之重量，％特定篩截之重組時間 (min) 1 在結晶器中粒化） 107 g 由針型晶體組成之橢圓形至圓形聚集體未通過300 微米篩網 » 25,500 微米篩截 2 1(在結晶器中粒化） 1.67Kg 由針型晶體組成之橢圓形至圓形聚集體未通過300 微米篩網 »25,500 微米篩截 3 1(疏鬆晶體） 5g 細針狀體約23% (阻塞篩網)， 150微米篩網 15,150 微米篩截 4 1(疏鬆晶體） 5g 細針狀體未通過150 微米篩網 (阻塞）。 42%,500 微米篩網 »25,500 微米篩截 5 2(聚集體，在結晶|§ 中形成） 30 g 球粒a 98%, 150 微米篩網 10,150 微米篩截 6 2(聚集體，在結晶中形成） 2.9 Kg 球粒a 98%, 150 微米篩網 5,150 微米篩截 7 2(聚集體，在過濾器乾燥器中重塑） 4.6 kg 橢圓形至圓形聚集體 95%, 150 微米篩網 7,150 微米篩截 8 2(聚集體，在過濾器乾燥器中重塑） 3.7 kg 複雜形狀之聚集體 93%,150 微米篩網 11,150 微米篩截 a.觀測到在結晶器中形成之晶體慣態2之聚集體為多核放射狀聚集體之黏聚物（球粒）。當固體經靜態乾燥時保持該形狀（批料5及6)。然而，當固體在過濾器乾燥器中在連續攪動下乾燥時，粒子發生一定程度的重塑，產生更平滑之形狀（如在批料7及8之狀況下）。然而，在一些狀況下，過濾器中不受控制之重塑可導致聚集體大量破壞， 75 200940050 產生與極大粒子混合之極細粒子。偏振光顯微術展示在結晶器中粒化之晶體慣態丨（批料 1及2)由橢圓形至圓形聚集體及一小部分疏鬆針：粒子(針狀體）組成。聚集體長度在7〇至25〇微米之間變化，且寬度在70至160微米之間變化。疏鬆針狀體具有約3 27微米之長度及約0.7-2微米之寬度（長寬縱橫比為約4_13卜當向分散於油中之樣品上的蓋玻片施壓時，聚集體破裂成：述大小之針狀體。 ❹ 偏振光顯微術展示晶體慣態丨（批料3及4)由細針狀體組成，該等細針狀體具有約4_41微米之長度及約〇 8 4 2 微米之寬度（長寬縱橫比為5_10)β ’ · 偏振光顯微術展示晶體慣態2(批料5及6)由多核射狀聚集體之黏聚物（球粒）組成。聚集體長度在Μ至\ = =，，且寬度在一微来之間變化(長寬縱偏振光顯微術展示當在過濾、器乾燥器中授㈣（〇及8)，晶體慣態2由具有多種形狀（大部分為 ::分，集體組成。聚集體長度在17至且寬度在一微米之間變化(長宽縱橫比為約’ :然已參考本發明之實施例具體實例來特別但熟習此項技術者應瞭解可在不偏離如隨附申 Π:包含之本發明之範訂在形式及細節上作出【圖式簡單說明】圖1為自A形化合W之樣品獲得的XRpD(x射線粉 76 200940050 末繞射）圖。圖2為展示A形化合物i之樣品之熱分析資料的圖： (A )差示掃描熱量測定曲線，（b )熱解重量分析曲線。圖3為在KBr壓片中A形化合物1之樣品的iR(紅外）譜。 ' 圖4為A形化合物1之樣品的固態(核磁共振）譜。圖5為自C形化合物1之樣品獲得的xrpd圖。圖6為展示c形化合物1之樣品之熱分析資料的圖： (A)差示掃描熱量測定曲線，（b)熱解重量分析曲線。圖7為自D形化合物1之樣品獲得的xrpd圖。圖8為展示D形化合物1之樣品的差示掃描熱量測定資料的圖》圖9為在KBr壓片中D形化合物1之樣品的IR(紅外）譜。' 圖10為D形化合物1之樣品的固態13C-NMR(核磁共振）譜。圖11(A)為展示d形化合物1之X射線結構的ORTEP 圖式’其中原子係由50%概率各向異性熱橢圓體表示。圖11 ( B )為沿結晶b軸向下觀察之圖11 ( A)中所示化合物1的堆積圖。囷11(C)展示圖u(B)中所示化合物i的氫鍵制圖。圖12為太平洋紫杉醇（紫杉醇）之結構。圖13為歐洲紫杉醇（泰索帝）之結構。 77 200940050 4'34各自為太平洋訾知磁如圖35為包含側接於聚/ 物之結構。基團的聚含& ?。物主鏈之太平洋紫杉醇類似物圈36 a 物為所示三個單體單元之三聚物。圖卩之樣如的拉曼光譜。叫J /為D形化合 f 之樣品的拉曼光譜。 I主要元件符號說明】無 ❹72 200940050 Prepare 50:50 Cremophor EL/ethanol and filter through a 0.45 μη 遽且 filter for testing. 266 mg of Compound 1 was weighed into a 50 mL glass vial with a rubber stopper. 16 7 ml of the transitioned 50:50 Cremophor EL/ethanol solution was syringed and needled and added to the vial. The vial was manually shaken or shaken on a mechanical shaker at 232-236 rpm. The reconstitution time was determined using three bottles. The bottles were visually observed at different time points. - Sieve-cut Test Screening was performed at two 5 minute intervals ® intervals using a Retsch oscillator and a 150 micron screen. Depending on the batch, use 5 g to 20 g samples. Measure the mass and percentage of material collected in the receiver. Optical display street Use the iympUs BX5 1 microscope equipped with a DP7 1 color camera to perform optical microscopy. Use 5x, 1〇 and 40x objectives to view the sample. The sample was placed on a glass slide and tapped to obtain a single layer of particles. After obtaining an image of the tapped powder with a 5x objective, a drop of 矽 ❹ oil was added to the sample. The coverslip was gently placed on the sample and images were obtained with 5x and 10x objectives. The coverslip was then pressed to break the aggregates and images were obtained with 5x and 40x objectives. Image was obtained using soft 艎 DP-BSW at ambient temperature. Bulk 1 and Wafer 7 Batches 1 and 2 were prepared according to procedure a); batches 3 and 4 were prepared according to procedure b); and batch 5-8 was prepared according to the procedure. a) Compound 1 was suspended in acetone (14 L/Kg). Water (2 L/Kg) was added and the resulting mixture was stirred to dissolve the solid. Water (12 73 200940050 was added to the clear solution. The solution was stirred for 14 丨 6 hours until most of the solid precipitated. The slurry was cooled to lore for 2-4 hours for complete precipitation. The solid was separated by filtration. Cold 50% aqueous acetone, followed by cold mixture of acetone: n-heptane (1:2) and finally washed with n-heptane. The solid was dried under vacuum at 50 ° C. b) 125 mL of acetone and 125 mL Water was added to 5 g of Compound 1. The mixture was heated to 60. (: until a clear solution is obtained. The solution is cooled to room temperature. The solid is precipitated during cooling. The resulting mixture is stirred for 4-6 days until completely converted to Form A (filter sample is filtered and checked by ir for complete 0 conversion) A.) The solid was filtered and dried under vacuum at 4 ° C. Alternatively, 5 g of Compound 1 was dissolved in 7 mL (14 L/kg) of acetone and 10 mL (2 L/kg) of water with stirring. Add 60 mL (12 L/kg) of water and stir the resulting mixture for 4-6 days until completely converted to a-shape (over-slurry slurry sample and checked by IR for complete conversion to A-shape). It was dried under vacuum at 40 ° C. c) Compound 1 was suspended in propionium (14 L/Kg). Water (2 L/Kg) was added and stirred to dissolve the solid to form a concentrated solution of Compound 1. The water hydrazine (30.4 L/Kg) was cooled to 〇 ° C and added to the concentrated solution of Compound 1, while maintaining the temperature at 〇-5. (Between: 20-70 minutes. The suspension was warmed to ambient temperature and agitated for 20-24 hours. The solid was separated by filtration, washed with cold 50 ° / aqueous acetone and then twice with n-heptane and Drying under vacuum at 5 ° C. The results are shown in Table 6. 74 200940050 Table 6. Characters of Form A of Form A and Crystal Inserts 2 Characterization Batch Numbers Habit Numbers Batch Particles Appearance Specific Weight of the size screen, % recombination time for specific sieves (min) 1 granulation in the crystallizer) 107 g Elliptical to circular aggregates consisting of needle crystals not passing through 300 micron mesh » 25,500 micron sieve 2 1 (granulation in the crystallizer) 1.67Kg Elliptical to circular aggregate composed of needle crystals does not pass the 300 micron sieve »25,500 micron sieve 3 1 (loose crystal) 5g fine needles about 23% (blocking screen), 150 micron screen 15, 150 micron sieve 4 1 (loose crystal) 5 g fine needles did not pass through a 150 micron screen (blocking). 42%, 500 micron screen » 25,500 micron sieve 5 2 (aggregate, formed in crystallization | §) 30 g spherule a 98%, 150 micron sieve 10, 150 micron sieve 6 2 (aggregate, in crystallization Form) 2.9 Kg pellet a 98%, 150 micron screen 5,150 micron sieve 7 2 (aggregate, remodeled in filter dryer) 4.6 kg elliptical to circular aggregate 95%, 150 micron screen 7,150 Micron sieve 8 2 (aggregate, remodeled in filter dryer) 3.7 kg aggregate of complex shapes 93%, 150 micron screen 11,150 micron sieve a. Observed crystal habit formed in the crystallizer 2 The aggregates are clays (pellets) of multinuclear radial aggregates. This shape is maintained when the solid is statically dried (batch 5 and 6). However, when the solids are dried in a filter drier under continuous agitation, the particles undergo some degree of remodeling resulting in a smoother shape (as in the case of batches 7 and 8). However, in some cases, uncontrolled remodeling in the filter can result in extensive destruction of aggregates, 75 200940050 Producing very fine particles mixed with the largest particles. Polarized light microscopy shows that the crystal habits of granules (batch 1 and 2) granulated in the crystallizer consist of elliptical to circular aggregates and a small number of loose needles: particles (needles). The length of the aggregate varies from 7 Å to 25 Å and the width varies from 70 to 160 microns. The loose needle has a length of about 3 27 microns and a width of about 0.7-2 microns (a length to width aspect ratio of about 4-13). When a cover slip is applied to a sample dispersed in oil, the aggregate breaks into: The needles of the size ❹ Polarized light microscopy shows that the crystal habits 批 (batch 3 and 4) consist of fine needles with a length of about 4 to 41 microns and about 〇 8 4 2 The width of the micron (length to width aspect ratio is 5_10) β ' · Polarized light microscopy shows that crystal habit 2 (batch 5 and 6) consists of polynuclear ray aggregates (spherulites). Μ to \ = =, and the width varies from one micro (long-width longitudinal polarized light microscopy shows that when given in the filter, the dryer (4) (〇 and 8), the crystal habit 2 has a variety of shapes (Most:: minute, collective composition. The length of the aggregate is between 17 and the width varies between one micron (the aspect ratio is about ': however, it has been specifically referred to with reference to the specific examples of the embodiments of the present invention. The skilled person should understand that the form and details of the invention may be made without departing from the accompanying application: BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph of XRpD (x-ray powder 76 200940050 diffraction) obtained from a sample of Form A. Figure 2 is a graph showing the thermal analysis data of a sample of Compound A of type A: (A) The scanning calorimetry curve is shown, (b) the thermogravimetric analysis curve. Figure 3 is the iR (infrared) spectrum of the sample of the A-form compound 1 in the KBr tablet. ' Figure 4 is the solid state of the sample of the A-form compound 1 (nuclear magnetic Figure 5 is a diagram of the xrpd obtained from a sample of Compound C. Figure 6 is a graph showing the thermal analysis of a sample of Compound C: (A) differential scanning calorimetry curve, (b) heat Figure 7 is a diagram showing the xrpd obtained from the sample of the D compound 1. Fig. 8 is a graph showing the differential scanning calorimetry data of the sample of the D compound 1 Fig. 9 is the D shape in the KBr tablet. IR (infrared) spectrum of a sample of Compound 1. 'Figure 10 is a solid state 13C-NMR (nuclear magnetic resonance) spectrum of a sample of Compound D of Form D. Figure 11 (A) is an ORTEP diagram showing the X-ray structure of Compound 1 of Form d Where the atomic system is represented by a 50% probability anisotropic thermal ellipsoid. Figure 11 (B) is observed along the axial direction of the crystal b Fig. 11 is a stacked view of the compound 1 shown in Fig. 11. (C) shows the hydrogen bond pattern of the compound i shown in Fig. u(B). Fig. 12 shows the structure of paclitaxel (paclitaxel). The structure of paclitaxel in Europe. 77 200940050 4'34 each is known as the Pacific Ocean. Figure 35 is a structure containing a side-by-side structure. The poly-containing & The analog ring 36a is a terpolymer of the three monomer units shown. The Raman spectrum of a sample called J / is a D-form f. I main component symbol description] None ❹

7878

Claims

200940050 、申請專利範圍： 1. 一種由以下結構式表示之化合物200940050, the scope of application for patents: 1. A compound represented by the following structural formula

其中至少7〇重量％之該化合物為該化合物之單晶形A e ❹ 形其中至少90重量其中至少99重量 2. 如申請專利範圍第1項之化合物 %之該化合物為該化合物之單晶形A形 3. 如申請專利範圍第丨項之化合物 %之該化合物為該化合物之單晶形A形 / 4·如中請專利範圍帛1項之化合物，其中該單晶形A >特徵在於至）—個選自由1G 76。、Μ⑼。及Μ η。組成之群組之主要20角X射線粉末繞射峰。 ,5·如申請專利範圍第1項之化合物，其中該單晶形A 形特徵在於至少兩個選自由1〇·76。、14.49。及16.33。組成之群組之主要Μ角X射線粉末繞射峰。 ,6.如申請專利範圍帛1項之化合物，其中該單晶形A ::徵在於10·76。、14.49。及16 33。之主要2" χ射線粉禾繞射峰。 f 7.如申請專利範圍第1項之化合物，其中該單晶形形特徵在於 8.60。、丨〇.76。、14.49。、16.33。、18.74。、1918。、 2 23.65及24.12。之主要20角X射線粉末繞射峰。 79 200940050 8. 如申請專利範圍第i項之化合物，其中該單晶形A 形特徵在於圖1之X射線粉末繞射圖。 9. 一種醫藥組成物，其包含醫藥上可接受之載劑或稀釋劑及由以下結構式表示之化合物：Wherein at least 7% by weight of the compound is a single crystal form of the compound, wherein at least 90% of the compound is at least 99% by weight. The compound of the compound of claim 1 is a single crystal of the compound. A shape 3. The compound of the compound of the ninth aspect of the patent application is a single crystal A shape of the compound / 4. The compound of the patent scope 帛1, wherein the single crystal shape A > To) - one selected from 1G 76. , Μ (9). And Μ η. The main 20-angle X-ray powder diffraction peaks of the group formed. 5. The compound of claim 1, wherein the single crystal shaped A shape is characterized in that at least two are selected from the group consisting of 1 〇 76. 14.49. And 16.33. The main corner of the group consists of X-ray powder diffraction peaks. 6. The compound of claim 1, wherein the single crystal form A: is at 10.76. 14.49. And 16 33. The main 2" χ 粉 powder and the diffraction peak. f. The compound of claim 1, wherein the single crystal shape is characterized by 8.60. , 丨〇.76. 14.49. 16.33. 18.74. 1918. 2, 2, 65 and 24.12. The main 20-angle X-ray powder diffraction peak. 79 200940050 8. The compound of claim i, wherein the single crystal A shape is characterized by the X-ray powder diffraction pattern of FIG. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula:

其中至少70重量％之該化合物為該化合物之單晶形入形。 1〇·如申請專利範圍第9項之醫藥組成物，其中至少9〇重量％之該化合物為該化合物之單晶形A形。 11. 如申請專利範圍第9項之醫藥組成物其中至少％重量％之該化合物為該化合物之單晶形A形。 12. 如申請專利範圍第9項之醫藥組成物其中該單晶形A形特徵在於至少一個選自由1〇 %。、14 49。及μ 組成之群组之主要角χ射線粉末繞射峰。 13. 如申請專利範圍第9項之醫藥組成物其中該單晶形A形特徵在於至少兩個選自由1〇.76。、14.49。及16 組成之群組之主要角χ射線粉末繞射峰。 14. 如申請專利範圍第9項之醫藥組成物丨中該單晶形Α形特徵在於1〇 76〇、14 49〇及16 33〇之主要以角X 線粉末繞射峰。 200940050 15·如申請專利範圍第9項之醫藥組成物，其中該單晶形 A 形特徵在於 8.60。、10.76。、14.49。、16.33。、18.74。、 19·18°、20.92°、23.65°及24.12。之主要20角X射線粉末繞射峰。如申清專利範圍第9項之醫藥組成物，其中該單晶形Α形特徵在於圖1之X射線粉末繞射圖。 17.—種由以下結構式表示之化合物：At least 70% by weight of the compound is a single crystal shape of the compound. The pharmaceutical composition of claim 9, wherein at least 9% by weight of the compound is a single crystal A shape of the compound. 11. The pharmaceutical composition of claim 9 wherein at least 5% by weight of the compound is a single crystal A shape of the compound. 12. The pharmaceutical composition according to claim 9 wherein the single crystal form A is characterized in that at least one selected from the group consisting of 1%. , 14 49. And the main corner of the group consisting of μ χ ray powder diffraction peaks. 13. The pharmaceutical composition according to claim 9 wherein the single crystal form A is characterized in that at least two are selected from the group consisting of 1 〇.76. 14.49. And the main corner of the group consisting of 16 ray powder diffraction peaks. 14. The single crystal shape of the medicinal composition of claim 9 is characterized by a diffraction peak of an angular X-ray powder of 1 〇 76 〇, 14 49 〇 and 16 33 。. The pharmaceutical composition of claim 9, wherein the single crystal A shape is characterized by 8.60. 10.76. 14.49. 16.33. 18.74. , 19·18°, 20.92°, 23.65° and 24.12. The main 20-angle X-ray powder circulates the peak. For example, the pharmaceutical composition of claim 9 is characterized in that the single crystal shape is characterized by the X-ray powder diffraction pattern of Fig. 1. 17. A compound represented by the following structural formula:

s 形其中至少70重量%之該化合物為該化合物之單晶形c 其中至少90重 18. 如申請專利範圍第17項之化合物量％之該化合物為該化合物之單晶形C形其中至少99重 19. 如申請專利範圍第17項之化合物量％之該化合物為該化合物之單晶形c形 ,20.如中請專利範圍第17項之化合物其中該單晶形。形特徵在於至少一個選自由1〇 32。、"Μ。、。Μ。、及30.12。組成之群組之主要2" χ射線粉末繞射峰。 21·如申請專利範圍第17項之化合物，其中形特徵在於至少兩個選自由㈣。、14.8〇。、、21州t C 及3°.12。組成之群组之主要…射線粉末繞射峰2:·。5。 81 200940050 ,22.如申請專利範圍第17項之化合物，其中該單晶形c 形特徵在於至少三個選自由1〇 32。、14 8〇。、2i 49。、U 〇尸及30.12。組成之群组之主要2wX射線粉末繞射峰。 23·如申請專利範圍第17項之化合物，其中該單晶形C 形特徵在於至少四個選自由10.32。、14.80。、21.49。、23 〇5。及30.12。組成之群组之主要20角χ射線粉末繞射峰。 ❹ 24.如申請專利範圍第17項之化合物，其中該單晶形c 形特徵在於 10.32。、14.8〇。、21 49。、23 〇5。及 3〇Μ。之主要2Θ角X射線粉末繞射峰。 ,25.如申請專利範圍帛17項之化合物其中該單晶形c 形特徵在於 8.64。、1G.32。、14.8G。、15.7G。、16.88。、19.15。、 19.68。、21.49。、23 〇5。、24 34。及 3〇 12。之主要 2". X 射線粉末繞射峰。 26. 如申請專利_ 17項之化合物，其中該單晶形c 形特徵在於圖5之χ射線粉末繞射圖。〇 27. 一種醫藥組成物，其包含醫藥上可接受之載劑或稀釋劑及由以下結構式表示之化合物：At least 70% by weight of the compound is a single crystal form of the compound, wherein at least 90 is 18. The compound of the compound of claim 17 is a single crystal form of the compound, wherein at least 99 19. The compound of the compound according to claim 17 is a single crystal c-shaped form of the compound, 20. The compound of claim 17 wherein the single crystal form. The shape is characterized in that at least one is selected from the group consisting of 1 〇 32. , "Μ. ,. Hey. And 30.12. The main 2" χ ray powder diffraction peaks of the group formed. 21. The compound of claim 17, wherein the shape is characterized in that at least two are selected from the group consisting of (d). , 14.8 〇. , 21 states t C and 3 °.12. The main group of the composition... ray powder diffraction peak 2: ·. 5. The compound of claim 17, wherein the single crystal c-shape is characterized in that at least three are selected from the group consisting of 1 〇 32. , 14 8〇. 2i 49. , U corpse and 30.12. The main 2w X-ray powder diffraction peak of the group consisting. 23. The compound of claim 17, wherein the single crystal C-shape is characterized in that at least four are selected from the group consisting of 10.32. 14.80. , 21.49. , 23 〇 5. And 30.12. The main 20-angle X-ray powder diffraction peak of the group consisting. ❹ 24. The compound of claim 17, wherein the single crystal c-shape is characterized by 10.32. , 14.8 〇. 21 51. , 23 〇 5. And 3〇Μ. The main 2 angle X-ray powder diffraction peak. 25. The compound of claim 17, wherein the single crystal c-shape is characterized by 8.64. , 1G.32. , 14.8G. , 15.7G. 16.88. 19.15. , 19.68. , 21.49. , 23 〇 5. 24 34. And 3〇 12. The main 2". X ray powder diffraction peak. 26. The compound of claim 17, wherein the single crystal c-shape is characterized by a diffraction pattern of the ray-ray powder of FIG. 〇 27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula:

其中至少70重量％之該化合物為該化合物之單晶形c 82 200940050 28_如申請專利範圍第27項之醫藥組成物，其中至少 90重量％之該化合物為該化合物之單晶形c形。 29. 如申請專利範圍第27項之醫藥組成物，其中至少 99重量％之該化合物為該化合物之單晶形c形。 30. 如申請專利範圍第27項之醫藥組成物其中該單晶形C形特徵在於至少一個選自由32。、14 8〇。、21 、 23.05及30.12。組成之群组之主要20角χ射線粉末繞射 0 31. 如申請專利範圍第27項之醫藥組成物其中該單晶形C形特徵在於至少兩個選自由ίο」]。、14.80。、2149。、 23.05及3012。組成之群组之主要角χ射線粉末繞射〇 32. 如申請專利範圍第27項之醫藥組成物，其中該單晶形c形特徵在於至少三個選自由ι〇 32。、ΐ4·8〇。、21 49〇、 23.05及3〇12。組成之群组之主要20角χ射線粉末繞射峰。 ,33.如申請專利範圍第巧項之醫藥組成物，其中該單晶形C形特徵在於至少四個選自由1〇 Μ。、μ 8〇。、21 49〇、 23 05及30·12。組成之群组之主要20角X射線粉末繞射 ιΐ^ 〇 4·如申請專利範圍第27項之醫藥組成物，其中該單晶形 C 形特徵在於 10.32。、14.8〇。、21 49。、23 〇5。及 30.12。之主要20角χ射線粉末繞射峰。 35.如申請專利範圍第27項之醫藥組成物，其中該單晶 83 200940050 形 C 形特徵在於 8.64。、10.32。' 14.80。、15.70。、16.88。、 19·15、19.680、21.49。、23.05。、24.34。及 30.12。之主要 20 角X射線粉末繞射峰。 36. 如申請專利範圍第27項之醫藥組成物，其中該單晶形C形特徵在於圖5之X射線粉末繞射圖。 37. 一種由以下結構式表示之化合物： Ο 〇At least 70% by weight of the compound is a single crystal form of the compound c 82 200940050 28 - a pharmaceutical composition according to claim 27, wherein at least 90% by weight of the compound is a single crystal c shape of the compound. 29. The pharmaceutical composition of claim 27, wherein at least 99% by weight of the compound is a single crystal c-shape of the compound. 30. The pharmaceutical composition of claim 27, wherein the single crystal C-shape is characterized in that at least one is selected from the group consisting of 32. , 14 8〇. , 21, 23.05 and 30.12. The main 20-corner ray-ray powder diffraction of the group consisting of 0. The pharmaceutical composition of claim 27, wherein the single crystal-shaped C-shape is characterized in that at least two are selected from the group consisting of ίο]. 14.80. 2149. , 23.05 and 3012. The main composition of the group consisting of the ray-ray powder diffraction 〇 32. The pharmaceutical composition of claim 27, wherein the single crystal-shaped c-shape is characterized in that at least three are selected from the group consisting of ι〇32. Ϊ́4·8〇. 21 49〇, 23.05 and 3〇12. The main 20-corner ray-ray powder diffraction peaks of the group formed. 33. The pharmaceutical composition of claim </ RTI> wherein the single crystal shape is characterized in that at least four are selected from the group consisting of 1 〇. , μ 8〇. 21 49〇, 23 05 and 30·12. The main 20-angle X-ray powder diffraction of the group consisting of ιΐ^ 〇 4. The pharmaceutical composition of claim 27, wherein the single crystal C-shape is characterized by 10.32. , 14.8 〇. 21 51. , 23 〇 5. And 30.12. The main 20-corner ray-ray powder diffraction peak. 35. The pharmaceutical composition of claim 27, wherein the single crystal 83 200940050 C shape is characterized by 8.64. 10.32. ' 14.80. 15.70. 16.88. , 19·15, 19.680, 21.49. 23.05. 24.34. And 30.12. The main 20-angle X-ray powder diffraction peak. 36. The pharmaceutical composition of claim 27, wherein the single crystal C-shape is characterized by the X-ray powder diffraction pattern of Figure 5. 37. A compound represented by the following structural formula: Ο 〇

SS

其中至少70重量％之該化合物為該化合物形 38. 如申請專利範圍第37項之化合物其中至少9〇重量％之該化合物為該化合物之單晶形〇形。〇 39. 如申請專利範圍第37項之化合物，其中至少99重量％之該化合物為該化合物之單晶形d形。 4〇·如申請專利範圍第37項之化合物，其中該單晶形〇形特徵在於至少-個選自由7.52。、13.22。、13.9〇。、17 23。、 22.06°、22.66。、23.35。、24 97。、％以。λ • 26·65 、28.44。及 29 19。组成之群组之主要2Θ角Χ射線粉末繞射峰。 · 仏如申請專利範圍第37項之化合物㈣徵在於至，三個選自由Μ。，。、〗 22·06ο ' 22.66〇、23 •35 24.97、2“5。、28.44。及2919。 84 200940050 組成之群组之主要20角χ射線粉末繞射峰。 A如申請專利範圍第37項之化合物，其中該單晶形d 形特徵在於至少五個選自由7.52。、13.22°、13 9〇〇、17 23〇、 22.06 22.66、23.35°、24.97°、26.65、28 44。及 2919〇組成之群组之主要2Θ角χ射線粉末繞射峰。 ,43.如申請專利範圍第37項之化合物其中該單晶形d 形特徵在於至少七個選自由7.52。、13.22。、13 9〇。、17 23。、 Ο Ο 22.06 22.66、23.35。、24.97。、26.65。、28 44。及 2919。組成之群组之主要2Θ角X射線粉末繞射峰。 44.如中請專利範圍第37項之化合物，其中該單晶形d 形特徵在於至少九個選自由7.52。、13.22。、13 9〇。、17 23。、 22.06°、22.66。、23.35。、24.97。、26.65。、28 44。及 29 19。組成之群组之主要2Θ角Χ射線粉末繞射峰。 . ,45.如中請專利範圍第37項之化合物，其中該單晶形d 形特徵在於選自由 7.52。、13.22。、13.90。、17.23。、22 〇6。、 22·66。、23·35。、24.97。、2“5。、28.44。及 29·19。組成之群组之主要2Θ角X射線粉末繞射峰。 46. 如申請專利範圍第”項之化合物其中 ^r^^7,2〇.7,4〇M3,2〇W3.90〇M5<82^i6^D 17·23。、 18.70。、 19·71。、 20.80。、 22.06。、 22.66。、 23.35。、 23’74。、 24.07。、 24.31。、 24.97。、 26.65。、 28.44。及 29.19。之主要2Θ角X射線粉末繞射峰。 47. 如申請專利範圍第37項之化合物，其形特徵在於圖7之X射線粉末繞射圖。 $ 85 200940050 48 ·如申請專利範圍第37項之化合物，其中該單晶形D 形特徵在於呈P1 21/nl空間群且具有以下單位晶胞參數之單晶體結構.α = 14.4 ± 〇.1 A ; ό = 5.7 ± 0.1 A ; e = 23.9 士 0.1 A ; /3 = 102.1 ± 〇.i 〇 ;且 v = 1920 ± 1 人3。 49. 一種醫藥組成物，其包含醫藥上可接受之載劑或稀釋劑及由以下結構式表示之化合物： S -Ν、At least 70% by weight of the compound is in the form of the compound. 38. The compound of claim 37, wherein at least 9% by weight of the compound is a single crystal shape of the compound. 39. The compound of claim 37, wherein at least 99% by weight of the compound is a single crystal form of the compound. 4. A compound according to claim 37, wherein the single crystal shape is characterized in that at least one is selected from the group consisting of 7.52. 13.22. , 13.9 baht. , 17 23. 22.06°, 22.66. 23.35. , 24 97. , % to. λ • 26·65, 28.44. And 29 19. The main 2 Θ Χ ray powder diffraction peaks of the group formed. · For example, the compound of claim 37 (4) is located in and the three are selected from Μ. ,. , 〖22·06ο ' 22.66〇, 23 • 35 24.97, 2 “5., 28.44. and 2919. 84 200940050 The main 20-corner ray-ray powder diffraction peak of the group. A as claimed in Article 37 a compound, wherein the single crystal form d is characterized by at least five selected from the group consisting of 7.52, 13.22, 139, 17 23, 22.06 22.66, 23.35, 24.97, 26.65, 28 44, and 2919 Å. The main 2 Θ χ 粉末粉末绕绕 , , , , 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 17 23, Ο Ο 22.06 22.66, 23.35., 24.97., 26.65., 28 44. and 2919. The main 2 Θ X-ray powder diffraction peaks of the group. 44. a compound, wherein the single crystal shape d is characterized in that at least nine are selected from the group consisting of 7.52, 13.22, 139, 17, 23, 22.06, 22.66, 23.35, 24.97, 26.65, 28 44. 29 19. The main 2 Θ Χ 粉末绕 powder diffraction peaks of the group consisting of . . , 45. The compound of claim 37, wherein the single crystal shape d is characterized by being selected from the group consisting of 7.52, 13.22, 13.90, 17.23, 22 〇 6., 22.66, 23.35, 24.97, 2 "5. 28.44. And 29·19. The main 2 corner X-ray powder diffraction peaks of the group consisting of. 46. For example, the compound of the scope of the patent application is ^r^^7,2〇.7,4〇M3,2〇W3.90〇M5<82^i6^D 17·23., 18.70., 19· 71., 20.80., 22.06., 22.66., 23.35., 23'74, 24.07, 24.31, 24.97, 26.65, 28.44, and 29.19. Main 2 Θ X-ray powder diffraction peaks. The compound of claim 37, which is characterized by the X-ray powder diffraction pattern of Fig. 7. $85 200940050 48. The compound of claim 37, wherein the single crystal shape is characterized by being P1 a 21/nl space group with a single crystal structure of the following unit cell parameters. α = 14.4 ± 〇.1 A ; ό = 5.7 ± 0.1 A ; e = 23.9 ± 0.1 A ; /3 = 102.1 ± 〇.i 〇; v = 1920 ± 1 person 3. 49. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: S - Ν,

其中至少70重量％之該化合物為該化合物之單晶形D 形。 50. 如申請專利範圍第49項之醫藥組成物，其中至少 90重量°/。之該組成物為該化合物之單晶形〇形。 51. 如申請專利範圍第49項之醫藥組成物，其中至少 99重量。/◦之該組成物為該化合物之單晶形d形。 52·如申請專利範圍第49項之醫藥組成物，其中該單晶形D形特徵在於至少一個選自由7 52。、13 22。、η 、 17.23。、22.〇6。、22 66。、23 35。、24 97。、26 65。、u 料〇及29.19。組成之群组之主要角χ射線粉末繞射峰。 53·如申請專利範圍第49項之醫藥組成物，其中該單晶形D形特徵在於至少三個選自由7.52〇、13 22。、13 %。、 n_230、22.06。、22.66。、23.35。、24.97。、26.65。、28 44〇 86 200940050 及29.19組成之群组之主要20角χ射線粉末繞射峰。 54.如申請專利範圍第49項之醫藥組成物，其中該單晶形D形特徵在於至少五個選自由752〇、1322。、139〇0、 17.23 、 22.06。、 22.66。、 23.35。、 24.97° 、 26.65。、 28.44。及29.19。組成之群组之主要20肖X射線粉末繞射峰。 ,55.如申請專利範圍第竹項之醫藥組成物，其中該單晶形D形特徵在於至少七個選自由7 52。、η 22〇、列〇、 ❹ Ο 17.23 、 22.06。、 22.66。、 23.35。、 24.97。、 26.65。、 28.44。及29.19°組成之群组之主要射線粉末繞射峰。 56.如申請專利範圍第49項之醫藥組成物， 17·23°、22.06°、22.66。、23.35。、24 97。、26 65。、28 44〇及29」9。組成之群组之主要2" χ射線粉末繞射峰。 57·如申請專利範圍第的項之醫藥組成物，盆形〇形特徵在於選自…。、13.22。、13.9〇。：二0曰 —23.35。、24.97。> 組成之群组之主要以角X射線粉末繞射峰。 19 形二申請專利範圍第49項之醫藥組成物其中該單晶特徵在於 7.52。、7.84。、13.22。、13.9〇。、η 16·75〇'Π.23〇.18.7〇0.1971^2〇8〇^ ·； 23.35。、23 74〇〜 22.66、 …。二、^ ^ 之主要20角X射線粉末繞射峰。 59.如申請專利範圍第49項之醫藥組成物，其形特徵在於之X射線粉末繞射^ ~ 87 200940050 60. 如申請專利範圍第49項之醫藥組成物，其中該單晶形D形特徵在於呈Pl 21/nl空間群且具有以下單位晶胞參數之單晶體結構：α = 14.4 ± 〇.1 A;办=5.7 ± 0.1 A; c = 23.9 土 0.1 A ;芦=102.1 ± 〇·ι。；且 ν = 1920 士 1 Α3。 61. 如申請專利範圍第1項之化合物，其中至少7〇重量〇/〇之該化合物為該化合物之單晶形Α形之晶體慣態1。 62. 如申凊專利範圍第61項之化合物，其中至少9〇重量％之該化合物為該化合物之單晶形A形之晶體慣態1。 63. 如申請專利範圍第61項之化合物，其中至少99重 0 量％之該化合物為該化合物之單晶形A形之晶體慣態1。 64. 如申請專利範圍第6丨項之化合物，其中該晶體慣態 1特徵在於針狀形狀。 65. 如申請專利範圍第9項之醫藥組成物，其中至少7〇重量％之該化合物為該化合物之單晶形A形之晶體慣態i。 66. 如申請專利範圍第65項之醫藥組成物，其中至少 90重量％之該組成物為該化合物之單晶形A形之晶體慣熊 1。 ❹ 67. 如申請專利範圍第65項之醫藥組成物，其中至少 99重量％之該組成物為該化合物之單晶形a形之晶體慣熊 1 ° 68. 如申請專利範圍第65項之醫藥組成物，其中該晶體慣態1特徵在於針狀形狀。 69. 如申請專利範圍第1項之化合物，其中至少7〇重量 %之該化合物為該化合物之單晶形A形之晶體慣態2。 88 '200940050 m 70·如申請專利範圍第69項之化合物，其中至少9〇重量％之該化合物為該化合物之單晶形Α形之晶體慣態2。 71_如申請專利範圍第69項之化合物，其中至少99重量％之該化合物為該化合物之單晶形A形之晶體慣態2。 72. 如申請專利範圍第69項之化合物，其中該晶體慣態 2特徵在於多邊形形狀。 73. 如申請專利範圍第69項之化合物，其中該晶體慣態 2具有大於或等於約1且小於或等於約2之長寬縱橫比。 ^ 74.如申請專利範圍第69-73項中任一項之化合物，其中至少70重量％之該晶體慣態2通過1 5〇微米篩網。 75·如申請專利範圍第74項之化合物，其中通過150微米篩網之晶體慣態2具有少於1 5分鐘之重組時間。 76. 如申請專利範圍第9項之醫藥組成物，其中至少7〇重量％之該化合物為該化合物之單晶形A形之晶體慣態2。 77. 如申請專利範圍第76項之醫藥組成物，其中至少 90重量％之該組成物為該化合物之單晶形a形之晶體慣態霸2。 78. 如申請專利範圍第76項之醫藥組成物，其中至少 99重量％之該組成物為該化合物之單晶形A形之晶體慣態 1。 79. 如申請專利範圍第76項之醫藥組成物，其中該晶體慣態2特徵在於多邊形形狀。 80. 如申請專利範圍第76項之醫藥組成物，其中該晶體慣態2具有大於或等於約丨且小於或等於約2之長寬縱橫 89 200940050 比。 81.如申請專利範圍第76-80項中任一項之醫藥組成物，其中至少70重量％之該晶體慣態2通過150微米篩網。 82·如申請專利範圍第81項之醫藥組成物，其中通過 150微米篩網之晶體慣態2具有少於15分鐘之重組時間。 83. 如申請專利範圍第卜8項、第17_26項、第37_48 項 '第61-64項及第69-73項中任一項之化合物，其中該化合物大體上不含水及溶劑。 84. 如申請專利範圍第74項之化合物，其中該化合物大 ❹ 體上不含水及溶劑。 85·如申請專利範圍第75項之化合物，其中該化合物大體上不含水及溶劑。 86. 如申請專利範圍第9_16項、第27_36項、第49-60 項、第65-68項及第76-80項中任一項之醫藥組成物，其中該化合物大體上不含水及溶劑。 87. 如申請專利範圍第81項之醫藥組成物，其中該化合物大體上不含水及溶劑。 ❹ 88. 如申請專利範圍第82項之醫藥組成物，其中該化合物大體上不含水及溶劑。 89. —種如申請專利範圍第18項、第17 26項第p a 項、第61-64項、第69-75項及第83_85項中任一項之化合物的用途，其係用於製備供治療患有癌症之個體用的藥劑。 90. —種如申請專利範圍第9_16項、第27 36項第 49-60項、第65-68項、第76_82項及第86 88項中任一項 90 '200940050 之醫藥組成物的用途，其係用於製備供治療患有癌症之個體用的藥劑。 91·種太平洋紫杉醇（paciitaxel)或太平洋紫杉醇類似物及如申請專利範圍第18項、第17_26項、第W項、第61-64項、帛69_76項及第83-85項中任一項之化合物的用途’其係用於製備供治療患有癌症之個體用的藥劑。 92· —種太平洋紫杉醇或太平洋紫杉醇類似物及如申請 ❹專利範圍第9-16項、第27_36項、第49_6〇項、第65_68 第76 82項及第86-88項中任一項之醫藥組成物的用途其係用於製備供治療患有癌症之個體用的藥劑。 93.如申請專利範圍第89 92中任一項之用途，其中該癌症為黑色素瘤。 ^ 十一、圖式：如次頁 ❹ 91At least 70% by weight of the compound is a single crystal form D of the compound. 50. The pharmaceutical composition of claim 49, wherein at least 90% by weight. The composition is a single crystal shape of the compound. 51. The pharmaceutical composition of claim 49, wherein at least 99% by weight. The composition of the compound is a single crystal d-shape of the compound. 52. The pharmaceutical composition of claim 49, wherein the single crystal shaped D-shape is characterized in that at least one selected from the group consisting of 725. , 13 22. , η, 17.23. 22.226. 22 66. 23 35. , 24 97. 26 65. , u 〇 and 29.19. The main corner of the group consists of ray powder diffraction peaks. 53. The pharmaceutical composition of claim 49, wherein the single crystal shape is characterized in that at least three are selected from the group consisting of 7.52 〇, 13 22 . , 13%. , n_230, 22.06. 22.66. 23.35. 24.97. 26.65. , 28 44〇 86 200940050 and 29.19 group of the main 20-angle X-ray powder diffraction peak. 54. The pharmaceutical composition of claim 49, wherein the single crystal shaped D-shape is characterized by at least five selected from the group consisting of 752 〇, 1322. , 139〇0, 17.23, 22.06. 22.66. 23.35. , 24.97°, 26.65. 28.44. And 29.19. The main 20 Xiao X-ray powder diffraction peaks of the group formed. 55. The pharmaceutical composition of claim 4, wherein the single crystal shape is characterized in that at least seven are selected from the group consisting of 7 52 . , η 22〇, Lennon, ❹ Ο 17.23, 22.06. 22.66. 23.35. , 24.97. 26.65. 28.44. And the main ray powder diffraction peak of the group of 29.19° composition. 56. The pharmaceutical composition of claim 49, 17·23°, 22.06°, 22.66. 23.35. , 24 97. 26 65. 28 44〇 and 29”9. The main 2" χ ray powder diffraction peaks of the group formed. 57. A pharmaceutical composition according to the scope of the patent application, wherein the basin shape is characterized by being selected from. 13.22. , 13.9 baht. : 2 0 — 23.35. 24.97. > The group consisting mainly of angular X-ray powder diffraction peaks. 19 The pharmaceutical composition of claim 49, wherein the single crystal is characterized by 7.52. , 7.84. 13.22. , 13.9 baht. η 16·75〇'Π.23〇.18.7〇0.1971^2〇8〇^ ·; 23.35. , 23 74〇 ~ 22.66, .... Second, ^ ^ The main 20-angle X-ray powder diffraction peak. 59. The pharmaceutical composition according to claim 49, which is characterized in that the X-ray powder is diffracted. The substrate is a medical composition according to claim 49, wherein the single-crystal D-shaped feature It consists of a single crystal structure with a Pl 21/nl space group and the following unit cell parameters: α = 14.4 ± 〇.1 A; do = 5.7 ± 0.1 A; c = 23.9 ± 0.1 A; reed = 102.1 ± 〇·ι. ; and ν = 1920 ± 1 Α 3. 61. The compound of claim 1, wherein at least 7 〇〇 / 〇 of the compound is a single crystal form of the compound. 62. The compound of claim 61, wherein at least 9% by weight of the compound is a single crystal A-shaped crystal habit 1 of the compound. 63. The compound of claim 61, wherein at least 99% by weight of the compound is a single crystal A-shaped crystal habit 1 of the compound. 64. The compound of claim 6 wherein the crystal habit 1 is characterized by a needle shape. 65. The pharmaceutical composition of claim 9, wherein at least 7% by weight of the compound is a single crystal A-shaped crystal habit i of the compound. 66. The pharmaceutical composition of claim 65, wherein at least 90% by weight of the composition is a single crystal A-shaped crystal habitual bear 1 of the compound. ❹ 67. The pharmaceutical composition of claim 65, wherein at least 99% by weight of the composition is a single crystal shaped a-shaped crystal of the compound 1 ° 68. The medicine of claim 65 A composition in which the crystal habit 1 is characterized by a needle shape. 69. The compound of claim 1, wherein at least 7% by weight of the compound is a single crystal A-shaped crystal habit 2 of the compound. 88 '200940050 m 70. The compound of claim 69, wherein at least 9% by weight of the compound is the single crystal form of the compound. 71. A compound according to claim 69, wherein at least 99% by weight of the compound is a single crystal A-shaped crystal habit 2 of the compound. 72. The compound of claim 69, wherein the crystal habit 2 is characterized by a polygonal shape. 73. The compound of claim 69, wherein the crystal habit 2 has an aspect ratio of greater than or equal to about 1 and less than or equal to about 2. The compound of any one of claims 69-73, wherein at least 70% by weight of the crystal habit 2 passes through a 15 μm screen. 75. The compound of claim 74, wherein the crystal habit 2 passing through the 150 micron screen has a recombination time of less than 15 minutes. 76. The pharmaceutical composition of claim 9, wherein at least 7% by weight of the compound is a single crystal A-shaped crystal habit 2 of the compound. 77. The pharmaceutical composition of claim 76, wherein at least 90% by weight of the composition is a single crystal a-shaped crystal habit of the compound. 78. The pharmaceutical composition of claim 76, wherein at least 99% by weight of the composition is a single crystal A-shaped crystal habit 1 of the compound. 79. The pharmaceutical composition of claim 76, wherein the crystal habit 2 is characterized by a polygonal shape. 80. The pharmaceutical composition of claim 76, wherein the crystal habit 2 has a ratio of length to width 89 200940050 greater than or equal to about 丨 and less than or equal to about 2. The pharmaceutical composition according to any one of claims 76 to 80, wherein at least 70% by weight of the crystal habit 2 passes through a 150 micron sieve. 82. The pharmaceutical composition of claim 81, wherein the crystal habit 2 passing through the 150 micron sieve has a recombination time of less than 15 minutes. 83. A compound according to any one of the preceding claims, wherein the compound is substantially free of water and a solvent, as claimed in claim 8, wherein the compound is substantially free of water and a solvent. 84. The compound of claim 74, wherein the compound is substantially free of water and a solvent. 85. The compound of claim 75, wherein the compound is substantially free of water and a solvent. 86. The pharmaceutical composition of any one of claims 9-16, 27-36, 49-60, 65-68, and 76-80, wherein the compound is substantially free of water and solvent. 87. The pharmaceutical composition of claim 81, wherein the compound is substantially free of water and a solvent. ❹ 88. The pharmaceutical composition of claim 82, wherein the compound is substantially free of water and a solvent. 89. Use of a compound as claimed in claim 18, 17 26, pa, 61-64, 69-75 and 83_85, for preparation An agent for treating an individual having cancer. 90. The use of a pharmaceutical composition such as patent application scope 9_16, item 27 36 item 49-60, item 65-68, item 76_82 and item 86 88 of 90 '200940050, It is used to prepare an agent for treating an individual having cancer. 91. A paclitaxel or paclitaxel analog and any one of claims 18, 17_26, W, 61-64, 帛69_76, and 83-85 Use of a compound 'is used to prepare an agent for treating an individual having cancer. 92. A type of paclitaxel or paclitaxel analog and a medicine as claimed in any of claims 9-16, 27_36, 49_6, 65_68 76 82 and 86-88 Use of the composition is for the preparation of a medicament for treating an individual having cancer. The use of any one of the inventions of claim 89, wherein the cancer is melanoma. ^ XI, schema: as the next page ❹ 91