TW201121547A - Pharmaceutical composition for the treatment of proliferative diseases - Google Patents
Pharmaceutical composition for the treatment of proliferative diseases Download PDFInfo
- Publication number
- TW201121547A TW201121547A TW98144691A TW98144691A TW201121547A TW 201121547 A TW201121547 A TW 201121547A TW 98144691 A TW98144691 A TW 98144691A TW 98144691 A TW98144691 A TW 98144691A TW 201121547 A TW201121547 A TW 201121547A
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- group
- cancer
- tumor
- formula
- Prior art date
Links
Abstract
Description
201121547 六、發明說明： 【發明所屬之技術領域】 本發明涉及增生性疾病、尤其是腫瘤的治療方法及其 醫藥組合物，特別是涉及一種含有式〗化合物或其可藥用 鹽與抗增生劑併用的醫藥組合物。 【先前技術】 國際癌症協會（National Cancer Institute)估計，僅在美 國，每三個人中就有一人在其一生中會遭遇癌症。患有癌 •症的人中約50%至60%的人會死於該疾病。這種疾病的廣 泛發生對改善腫瘤尤其是惡性腫瘤的治療方案提出了迫切 需求。 目前已發現了多種癌症，並已對應研製了許多抗癌劑 來消滅體内的癌症。根據它們的作用機理進行分類，列舉 如下： 一種類型的化療劑被稱為金屬配位基錯合物。認為這 種類型的化療形式主要是使DNA發生鏈内和鏈間交聯， ^ 從而阻止了細胞的複製。其結果是開始抑制並然後逆轉了 腫瘤的生長。另一種類型的化療劑被稱為烷化劑。這些化 合物透過向分裂的癌細胞的DNA中插入外來的組合物或 分子，破壞癌細胞的正常功能並阻止其增生。另一種類型 的化療劑是抗腫瘤物質。這種類型的物質可預防、殺死或 阻斷癌細胞的生長和擴散。還有非類固醇型芳香酶抑制 劑、雙官能烷化劑等等抗癌劑。 紫杉醇則代表了一類促進微管蛋白聚合作用的抗微管 劑，抑制細胞有絲分裂。已經表明Tax〇17 (紫杉醇）在體[s] 3 201121547 • 内具有極好的抗腫瘤活性並已將其用於各種癌症的治療， l括乳癌、卵巢癌和肺癌。但目前，已有一些腫瘤對紫杉 醇形成了抗藥性^ 血管生成在生命的各種過程中發揮了重要作用，例如 胚胎發育、傷口癒合以及雌性生殖功能。但異常的血管生 成都和疾病有聯繫，例如糖尿病導致的視網膜病、牛皮癣、 癌症類風濕性關節炎、動脈粥樣化。新血管的形成及其 滲透性主要是透過血管内皮生長因子（VEGF)調節的，而腫 ® 瘤血管的生成有兩個不同的受體：VEGF-Rl (fms_iike酪氨 酸激酶，Flt-Ι)和VEGF_R2(激酶轄區，KDR/胎兒肝臟激酶 1 Flk 1)。VEGF ICDR受體是血管内皮細胞特有的（參照： Farrara et al. Endocr. Rev. 1992, 13, 18 ； Neufield et al. FASEBJ· 1999，13, 9)。 VEGF和更多特殊的veGF-A在人類中以三種異構體 (透過改變連結）的形式存在，它們的命名是根據胺基酸基 團的數位來決定的：VEGF 121，VEGF 165和VEGF189。這 籲二種異構體根據與肝素的結合和擴散性有不同的官能性。 胎盤生長因子（P1GF)僅與VEGF-Rl/Flt-Ι結合。 VEGF 的表達是由缺氧（Shweiki 等，Nature 1992，359， 843)和細胞介素、生長因子多樣性引起的，例如介白素j， 介白素-6，表皮生長因子和轉變生長因子^；、轉變生長因 子β。 VEGF受體膜邊界存在於活躍的内皮細胞表面，並控 制了細胞内酿氨酸激酶結構域，這對於細胞内訊息的傳導 是很必要的°有理論說VEGF二聚體是由兩個受體分子聚IS} 4 201121547 • 合而成，它引起了受體細胞内部分自身磷酸化隨之SH2抑 制性蛋白質的連接。磷脂酶C，磷脂醯肌醇-3激酶和鳥苦三 碟酸酶活性蛋白質（GAP)的後續磷酸化已被證明。 很多人類腫瘤，特別是神經膠質瘤和癌顯示出較高程 度的VEGF及其受體。由此引出的假說是VEgf是由腫瘤 細胞釋放出來的，它刺激了毛細血管的成長、以局部内泌 素的形式增生腫瘤内皮細胞並透過增加血液的供給加快了 腫瘤的生長。增加了的VEGF現象可以解釋神經膠質瘤病 鲁 人為什麼會發生大腦水腫。對VEGF現象或者vegf活性 被抑制的研究可以直接證明VEGF所起的作用就是體内腫 瘤血管生成因素。它的成功在於抗VEGF抗體、抑制訊息 轉導顯性一陰性VEGF-2突變體、反義VEGF RNA技術。 所有的方法均可以減少神經膠質瘤細胞系或其他體内腫瘤 細胞系的生長，進而抑制腫瘤血管生成。有三個主要機制 在抗腫瘤的血管生成抑制劑活性方面起著重要作用：丨、抑 φ制脈管的生長，特別是毛細血管，這樣由於細胞死亡和增 生之間存在平衡，最終沒有純淨的腫瘤生長。2、由於流 進、流出腫瘤的血液缺乏從而阻止了腫瘤細胞的轉移。3、 抑制内皮細胞的增生，從而避免周圍組織中的内皮細胞的 局部内泌素效應。 目前已陸續研發出了一些酪氨酸激酶抑制劑，透過抑 制VEGF活性，抑制腫瘤血管生長，從而治療腫瘤等增生 性疾病。近年來最令人矚目的藥物包括諾華(n〇削⑷/先 靈公司研發的治療結直腸癌# VEGFR抑制齊丨Vatalanib (PTK787 )，以及阿斯利康公司治療復發/難治性非小細[S} 5 201121547 胞肺癌的VEGFR和表皮生長因子受體（EGFR)雙標的抑 制劑ZacHma (ZD_6474)。VEGF抑制劑日漸成為一種非常 ’、有應用刖景的新型非細胞毒抗腫瘤藥物。與抑制腫瘤生 長的傳統細胞毒性藥物相比，以新生血管生成為標的之户 療藥物具有更高的特異性、更低的毒性，以及有利於克： 腫瘤的耐樂性’並且可用於多種腫瘤的治療。 【發明内容】. 本發明的一個目的县 扣供式1化合物或其可藥用鹽在 製備治療增生性疾病的藥物中的 ^ ^ 刃甲的用途，其中所述的藥物與 至少一種抗增生劑協同使用。 、201121547 6. Technical Field of the Invention: The present invention relates to a method for treating a proliferative disease, particularly a tumor, and a pharmaceutical composition thereof, and particularly to a compound containing the formula or a pharmaceutically acceptable salt thereof and an anti-proliferative agent A pharmaceutical composition for use in combination. [Prior Art] The National Cancer Institute estimates that in the United States alone, one out of every three people will experience cancer during their lifetime. About 50% to 60% of people with cancer can die from the disease. The widespread occurrence of this disease places an urgent need on treatment options for improving tumors, especially malignant tumors. A variety of cancers have been discovered and many anticancer agents have been developed to eliminate cancer in the body. Classification according to their mechanism of action is listed below: One type of chemotherapeutic agent is referred to as a metal ligand complex. It is believed that this type of chemotherapy is primarily responsible for intra- and inter-strand cross-linking of DNA, thereby preventing cell replication. The result is that inhibition begins and then reverses tumor growth. Another type of chemotherapeutic agent is known as an alkylating agent. These compounds break through the normal function of cancer cells and prevent their proliferation by inserting foreign compositions or molecules into the DNA of dividing cancer cells. Another type of chemotherapeutic agent is an anti-tumor substance. This type of substance prevents, kills or blocks the growth and spread of cancer cells. There are also non-steroidal aromatase inhibitors, bifunctional alkylating agents and the like. Paclitaxel represents a class of anti-microtubule agents that promote the polymerization of tubulin, inhibiting cell mitosis. Tax 〇 17 (paclitaxel) has been shown to have excellent antitumor activity in vivo [s] 3 201121547 • and has been used in the treatment of various cancers, including breast cancer, ovarian cancer and lung cancer. However, at present, some tumors have developed resistance to paclitaxel. angiogenesis plays an important role in various processes of life, such as embryonic development, wound healing, and female reproductive function. However, abnormal blood vessel growth is associated with diseases such as retinopathy caused by diabetes, psoriasis, rheumatoid arthritis, and atheroma. The formation of new blood vessels and their permeability are mainly regulated by vascular endothelial growth factor (VEGF), and the formation of tumor vasculature has two different receptors: VEGF-Rl (fms_iike tyrosine kinase, Flt-Ι) And VEGF_R2 (Kinase Region, KDR/Fetal Liver Kinase 1 Flk 1). The VEGF ICDR receptor is unique to vascular endothelial cells (see: Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al. FASEBJ. 1999, 13, 9). VEGF and more specific veGF-A exist in humans in the form of three isoforms (via altered linkages), which are named according to the number of amino acid groups: VEGF 121, VEGF 165 and VEGF189. This calls for the two isomers to have different functionalities depending on the binding and diffusivity to heparin. Placental growth factor (P1GF) binds only to VEGF-Rl/Flt-Ι. VEGF expression is caused by hypoxia (Shweiki et al, Nature 1992, 359, 843) and interleukin, growth factor diversity, such as interleukin j, interleukin-6, epidermal growth factor and transforming growth factor ^ ;, transforming growth factor beta. The VEGF receptor membrane border exists on the surface of active endothelial cells and controls the intracellular tyrosine kinase domain, which is essential for the transmission of intracellular messages. It is theorized that VEGF dimers are composed of two receptors. Molecular poly IS} 4 201121547 • Combined, it causes partial phosphorylation of the receptor cells followed by attachment of SH2 inhibitory proteins. Phospholipase C, phospholipid 醯 inositol-3 kinase and subsequent phosphorylation of avian triplatease active protein (GAP) have been demonstrated. Many human tumors, particularly gliomas and carcinomas, show a high degree of VEGF and its receptors. The hypothesis is that VEgf is released by tumor cells, which stimulates the growth of capillaries, proliferates tumor endothelial cells in the form of local endocrine hormones, and accelerates tumor growth by increasing blood supply. The increased VEGF phenomenon can explain why gliomas cause brain edema. Studies on the inhibition of VEGF or vegf activity can directly demonstrate that VEGF plays a role in tumor angiogenesis in vivo. Its success lies in anti-VEGF antibodies, inhibition of signal transduction dominant-negative VEGF-2 mutants, and antisense VEGF RNA technology. All methods can reduce the growth of glioma cell lines or other in vivo tumor cell lines, thereby inhibiting tumor angiogenesis. There are three main mechanisms that play an important role in the activity of anti-tumor angiogenesis inhibitors: the growth of vasopressors and vasculature, especially capillaries, so that there is no pure tumor due to the balance between cell death and proliferation. Growing. 2. The lack of blood flowing in and out of the tumor prevents the metastasis of tumor cells. 3. Inhibit the proliferation of endothelial cells, thereby avoiding the local endocrine effect of endothelial cells in surrounding tissues. At present, some tyrosine kinase inhibitors have been developed to inhibit tumor growth by inhibiting VEGF activity and treating proliferative diseases such as tumors. The most notable drugs in recent years include Novartis (n) (N) (Survey), the treatment of colorectal cancer # VEGFR, Qitai Vatalanib (PTK787), and AstraZeneca's treatment of relapsed/refractory non-small [S } 5 201121547 VEGFR and epidermal growth factor receptor (EGFR) double-labeled inhibitor ZacHma (ZD_6474) in lung cancer. VEGF inhibitors are becoming a very new, non-cytotoxic antitumor drug with anti-tumor effect. Compared with traditional cytotoxic drugs, the angiogenesis drugs with higher angiogenesis have higher specificity, lower toxicity, and benefit gram: tumor's typhoid' and can be used for the treatment of various tumors. SUMMARY OF THE INVENTION One object of the present invention is the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a proliferative disease, wherein the medicament and at least one anti-proliferative agent are used. Use synergistically.
式formula
在製備治療增生性疾病的藥物中的用it，其中所述藥物含 有至少一種抗增生劑。It is used in the preparation of a medicament for treating a proliferative disease, wherein the medicament contains at least one anti-proliferative agent.
本發明的另一個目的是提供式I化合物或其可藥用踏 其中所述的抗增生劑是在式I化合物投藥之前、同時 或者之後投藥，·所述的增生性疾病是腫瘤，較佳為實體瘤:m 6 201121547 更較佳為膀胱癌、胰腺癌、^ 奶跟媢、别列腺癌、肺癌、肝癌、消化 系統腫瘤和乳腺癌，其中喵 τ 4化糸統腫瘤較佳為結腸癌、結 腸直腸癌、晚期結腸癌，肺 那癌較佳為非小細胞肺癌。 其中所述的增生性疾、忘β# 展病疋對其他治療手段產生抗性的 難治療的腫瘤。 其中抗增生劑選自微管穩定劑，微管破壞劑、烷化劑、 抗代謝劑、抗腫瘤酶、拓撲異構酶抑制劑、單株抗體、細 胞週期抑制劑和鉑配位化合物，較佳選自蒽環素 (anthracycline)類藥物、替尼泊皆（Tinip〇gan)、米托葱醌 (Mit〇Xantrone)、長春花屬藥物、長春新鹼（vincdstine)、 長春瑞賓（Navelbine®)、喜樹鹼類（Campt〇thecin)、抗生素 類抗腫瘤藥、紫杉烷類化合物、disc〇derm〇lide、蝶啶藥物 (pteridine)、diynene、芳香酶抑制劑（Aroinatase inhibitor)、 二笨氧胺（Tamoxifen)、來曲唾（Letrozole)、鬼白毒素 (podophyllotoxin)、多柔比星（d〇xorubicin)、氨柔比星 (amrubicin)、胺甲葉酸（Methotrexate)、阿拉伯糖基胞略咬 (cytarabine)、6-疏 〇票吟（6-mercaptopurine)、6-硫代鳥嗓吟 (6-Thioguanine)、吉西他濱（Gemcitabine Hydrochloride)、 CPT-11、拓撲替康（TopotecanHydrochloride)、依妥普赛 (Etoposide)、奥沙利銘（Oxaliplatin)、順翻（Cisplatin)、卡 銘定（Carboplatin)、亞葉酸約（Calcium Folinate)、5 -氣尿喊 咬（5-Fluorouridine)、氟尿普（Fluorouridine)、環碟醯胺 (Cytoxan®)、 異環峨醢胺（Ifosfamide)、 甲苄肼 (Procarbazine)、干擾素（interferon)、介白素（interlukin)、 GCSF、胸腺素（Thymosin)、阿巴斯汀（Ebastine)、赫賽汀[S] 7 201121547 (Herceptin )、阿瓦斯汀（Avastin )、利妥昔單株抗體 (Rituximab中文名美羅華）、C225以及其可藥用鹽、溶 劑化物和水合物。其中紫杉烧類化合物較佳選自紫杉烧、 紫杉醇、多西他赛（Docetaxel)，抗生素類抗腫瘤藥較佳選 自阿黴素（Adriamycin)、絲裂黴素（mitomycin)、表阿徽素 (epiadriamycin)、博萊黴素（Blenmycin)、埃博黴素 (Epothilone)。 其中所述式I化合物可藥用鹽選自甲磺酸鹽 # (methanesulfonic acid salt)、鹽酸鹽（hydrochloride)、三氟 醋酸鹽（trifluoroacetic acid salt)、氫溴酸鹽（hydrobromic acid salt)、硫酸鹽（sulfate)、硝酸鹽（nitrate)、鱗酸鹽 (phosphate)、琥珀酸鹽（succinate)、馬來酸鹽（maieic acid salt)、醋酸鹽（acetate)、富馬酸鹽（fumarate)、檸檬酸鹽 (citrate)、枸櫞酸鹽（citrate；)、酒石酸鹽（tartrate)、苯磺酸 鹽（benzene sulfonate)。 本發明的再一個目的是提供一種用於治療增生性疾病 鲁的醫藥組合物，其包含式I化合物或其可藥用鹽、至少_ 種前述的抗增生劑、以及可藥用載體。 本發明提供了一種用於治療抗增生性疾病的協同方 法，其中所述的增生性疾病包括腫瘤，該方法包括給需要 該類治療的哺乳動物包括人使用協同治療有效量的：（1)至 少一種抗増生劑和（2)式I(N_[4_(1_氰基環戊基）苯基]2(4_ 比疋f基）氨基_3_ η比咬甲酿胺）的化合物或其可藥用鹽。 201121547Another object of the present invention is to provide a compound of formula I or a pharmaceutically acceptable anti-proliferative agent thereof, which is administered before, simultaneously with or after administration of a compound of formula I, wherein said proliferative disorder is a tumor, preferably Solid tumor: m 6 201121547 is more preferably bladder cancer, pancreatic cancer, breast achilles tendon, adenocarcinoma, lung cancer, liver cancer, digestive system tumor and breast cancer, of which 喵τ 4 糸 肿瘤 tumor is preferably colon cancer Colorectal cancer, advanced colon cancer, lung cancer is preferably non-small cell lung cancer. Among them, the proliferative disease, the forgetting β# disease, the refractory tumor which is resistant to other treatment means. The anti-proliferative agent is selected from the group consisting of a microtubule stabilizer, a microtubule disrupting agent, an alkylating agent, an antimetabolite, an antitumor enzyme, a topoisomerase inhibitor, a monoclonal antibody, a cell cycle inhibitor, and a platinum coordination compound. Goodly selected from anthracycline, Tinip〇gan, Mit〇Xantrone, Vinca, vincdstine, and Narberbine® ), camptothecin (Campt〇thecin), antibiotic antineoplastic agents, taxanes, disc〇derm〇lide, pteridine, diynene, aroinatase inhibitor, two stupid Tamoxifen, Letrozole, podophyllotoxin, d〇xorubicin, amrubicin, methotrexate, arabinose Cytarabine, 6-mercaptopurine, 6-Thioguanine, Gemcitabine Hydrochloride, CPT-11, Topotecan Hydrochloride, ET-Pop Etoposide, O'Sullivan (O Xaliplatin), Cisplatin, Carboplatin, Calcium Folinate, 5-Fluorouridine, Fluorouridine, Cytoxan® ), Ifosfamide, Procarbazine, interferon, interlukin, GCSF, Thymosin, Ebastine, Herceptin [S] 7 201121547 (Herceptin), Avastin, rituximab antibody (Rituximab Chinese name), C225, and pharmaceutically acceptable salts, solvates and hydrates thereof. The taxane-like compound is preferably selected from the group consisting of yew-burning, paclitaxel, and docetaxel. The antibiotic-like antitumor agent is preferably selected from the group consisting of Adriamycin, mitomycin, and opiate. Epiadriamycin, Blenmycin, Epothilone. Wherein the pharmaceutically acceptable salt of the compound of formula I is selected from the group consisting of methanesulfonic acid salt, hydrochloride, trifluoroacetic acid salt, hydrobromic acid salt, Sulfate, nitrate, phosphate, succinate, maieic acid salt, acetate, fumarate, Citrate, citrate; tartrate, benzene sulfonate. A further object of the present invention is to provide a pharmaceutical composition for treating a proliferative disease comprising a compound of formula I or a pharmaceutically acceptable salt thereof, at least one of the aforementioned anti-proliferative agents, and a pharmaceutically acceptable carrier. The present invention provides a synergistic method for treating an antiproliferative disease, wherein the proliferative disease comprises a tumor, the method comprising administering to a mammal in need of such treatment, including a human, a synergistic therapeutically effective amount: (1) at least An anti-neoplastic agent and (2) a compound of the formula I (N_[4_(1-cyanocyclopentyl)phenyl]2(4_ 疋f-yl)amino_3_ η ratio) Use salt. 201121547
組合物’纟包含至少-種抗增生劑、和式i的化合物或其 可藥用鹽、以及可藥用載體。 。 在本發明的一個較佳實施方案中，該抗增生劑是與式 I化合物一起投藥或是在其投藥之前或之後進行投藥。 式I化合物是酪氨酸激酶抑制劑，其製備方法參照 CN1502608A中的記载，該化合物主要是透過抑制腫瘤新 生血官生成而發揮其抗腫瘤作用，因此，其抗腫瘤療效主 要表現為腫瘤不生長或腫瘤生長延緩（gr〇wth arrest 〇r reduced growth)，而不易完全消除腫瘤。要完全消除腫瘤， 一般需要合用傳統的細胞毒性藥物。 適用於本發明方法和組合物的式I化合物的可藥用鹽 非限制性地包括，與各種有機酸和無機酸形成的鹽，其中 所述的有機酸和無機酸如鹽酸（hydrochl〇ric acid)、經基曱 〜酉夂（hydroxylmethanesulfonic acid)、氫溴酸（hydrobromic acid)、甲磺酸（methanesuifonic acid)、硫酸（sulfuric acid)、 醋I (acetic acid)、三氟醋酸（trifluoroacetic acid)、馬來酸 (maleic acid)、苯磺酸（benzenesulfonic acid)、甲苯磺酸 (toluene sulfonic acid)、項胺酸（sulfamic acid)、乙醇酸 (glycolic acid)、硬脂酸（stearic acid)、乳酸（lactic acid)、[S】 9 201121547 蘋果酸（malic acid)、撲酸（pamoic acid)、對氨基苯磺酸（P- anilinesulfonic acid)、2-乙酸基笨曱酸（2_acetylbenzoic acid)、富馬酸（fumaric acid)、甲苯磺酸（methylbenzene-sulfonic acid)、甲續酸（methanesulfonic acid)、乙烧二續酸 (ethanedisulfonic acid)、草酸（oxalic acid)、經乙基橫酸 (hydroxyethanesulphonic acid)，並包括各種其他可藥用的 鹽，如确酸鹽（nitrate)、填酸鹽（phosphate)、蝴酸鹽（borate)、 酒石酸鹽（tartrate)、枸櫞酸鹽（citrate)、號拍酸鹽 Φ (succinate)、苯曱酸鹽（benzoate)、抗壞血酸鹽（ascorbate)、 水楊酸鹽（salicylate)等等。對於陰離子部分而言可以考慮 用陽離子如季録離子（quaternary ammonium cation)作為可 藥用的抗衡離子。The composition '纟 contains at least one anti-proliferative agent, and a compound of formula i or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. . In a preferred embodiment of the invention, the anti-proliferative agent is administered with the compound of formula I or administered before or after administration. The compound of the formula I is a tyrosine kinase inhibitor, and the preparation method thereof is described in CN1502608A. The compound mainly exerts its anti-tumor effect by inhibiting the neonatal blood production of the tumor, and therefore, the anti-tumor effect mainly manifests as a tumor. Growth or tumor growth delay (gr〇wth arrest 〇r reduced growth), but not easy to completely eliminate the tumor. To completely eliminate tumors, it is generally necessary to use traditional cytotoxic drugs. Pharmaceutically acceptable salts of the compounds of formula I suitable for use in the methods and compositions of the present invention include, without limitation, salts formed with various organic and inorganic acids, such as hydrochloric acid (hydrochl〇ric acid). ), via hydroxylmethanesulfonic acid, hydrobromic acid, methanesuifonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, Maleic acid, benzenesulfonic acid, toluene sulfonic acid, sulfamic acid, glycolic acid, stearic acid, lactic acid Lactic acid), [S] 9 201121547 malic acid, pamoic acid, p-anilinesulfonic acid, 2-acetylbenzoic acid, fumaric acid (fumaric acid), methylbenzene-sulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesul Phonic acid), and includes various other pharmaceutically acceptable salts, such as nitrate, phosphate, borate, tartrate, citrate, Succinate succinate, benzoate, ascorbate, salicylate, and the like. For the anion moiety, a cation such as a quaternary ammonium cation can be considered as a pharmaceutically acceptable counter ion.
較佳的式I化合物的鹽包括甲磺酸鹽（methanesulfonie acid salt)。此外，式I化合物的可藥用鹽可以是與鹼金屬 如鈉、鉀和鋰形成的鹽；與鹼土金屬如鈣和鎂形成的鹽；與 有機驗如—J哀己基胺（dicyclohexylamine)、三丁基胺 (tributylcarbinolamine)、以及吡啶（pyrr〇le)形成的鹽；與胺 基酸如精胺酸（arginine)、賴胺酸（lysine)形成的鹽等等。 本發明的可藥用鹽可以用常用的化學方法來合成。— 般而s，該鹽可以透過在適宜的溶劑或溶劑組合物中將游 離驗或酸與化學計算量的或與過量的所需的成鹽無機或有 機酸或鹼進行反應來進行製備。 因此，在-個較佳的實施方案中，本發明的化療 包括將式ί與其它的抗癌劑併用投藥。當與至少 的抗癌劑併用時，這真所八 、 行、裏所么開的式工化合物表現出優良的⑸ 10 201121547 抗腫瘤活性。 這裏所用的術語「抗腫瘤劑」'「抗癌劑」與「化療 劑」和/或「抗增生劑」是同義的，指的是可以預防癌症或 過度增生細胞增殖的化合物。抗增生劑可以透過如下途徑 來防止癌細胞增殖：（1)干擾細胞複製DNA的能力和（2)誘導 癌細胞的細胞死亡和/或細胞凋亡。Preferred salts of the compounds of formula I include methanesulfonie acid salts. Further, the pharmaceutically acceptable salt of the compound of the formula I may be a salt formed with an alkali metal such as sodium, potassium and lithium; a salt formed with an alkaline earth metal such as calcium and magnesium; and an organic test such as dicyclohexylamine, three a salt formed from tributylcarbinolamine and pyrr〇le; a salt formed with an amino acid such as arginine or lysine, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods. Typically, the salt can be prepared by reacting a free or acid with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or solvent composition. Thus, in a preferred embodiment, the chemotherapy of the present invention comprises administering the formula together with other anticancer agents. When used in combination with at least an anticancer agent, the formula compound of the formula, which is excellent in (5) 10 201121547, exhibits excellent antitumor activity. The term "anti-tumor agent" and "anti-cancer agent" as used herein is synonymous with "chemotherapeutic agent" and/or "anti-proliferative agent" and refers to a compound which can prevent cancer or hyperproliferative cell proliferation. Anti-proliferative agents can prevent cancer cell proliferation by: (1) interfering with the ability of the cell to replicate DNA and (2) inducing cell death and/or apoptosis of cancer cells.
可以用作抗增生劑的化合物包括如下類別的化合物： 烧化劑（非限制性地包括氮4 (nitrogen mustard)、氮丙 啶（aziridine)衍生物、烷基磺酸酯（aikylsulfonate)、亞硝基 脲（nitrosourea)和三氮烯（triazene)):尿嘧啶氮芥 (uramustine)、Chlormethine、環碟酿胺（Cytoxan®)、異環 填酿胺（ifosfamide)、苯丙氨酸氮芥（phenylalanine mustard)、氮芥苯丁酸（chlorambucil)、派泊溴烷 (pipobroman)、 曲他胺（triethylenemelamine)、 Triethylenethiophosphoramine、硫酸布他卡因（busulfan)、 卡莫司汀（carmustine)、環己亞硝（lomustine)、鏈黴佐菌素 (streptozocin)、達卡巴唤（dacarbazine)和替莫0坐胺 (temozolomide) 〇 抗代謝物（非限制性地包括，葉酸拮抗劑（antifolate)、 喷咬類似物、嘌呤類似物和腺苷去胺酶抑制劑（adenosine deaminase inhibitors))·•胺甲葉酸（methotrexate)、5-氟尿嘧 咬（5-fluorouracil)、氟尿苦（fiu〇r〇Uridine)、阿拉伯糖基胞 0密咬（cytarabine)、6-疏基嘌吟（6-mercaptopurine)、6-硫代 鳥嘌吟（6-thioguanine)、構酸氟達拉濱（fludarabine phosphate)、喷司他丁（pentostatin)、和吉西他濱（gemcitabine [ η 201121547 hydrochloride) ° 天然產物及其衍生物（例如，長春花屬生物鹼、抗腫瘤 的抗生素、酶、淋巴因數和表鬼臼毒素（epip〇d〇phyll〇t〇xin)): 長春花鹼（catharanthine)、長春新鹼（vincristine)、 Vindesine、博萊黴素（blenmycin)、放線菌素 D(actin〇mycin D)、道紅鏈絲菌素（daunorubicin)、多柔比星（d〇x〇rubicin)、 表多柔比星（epidoxorubiein)、去曱基道紅鏈絲菌素 (demethyldaunorubicin)、Ara-C，紫杉醇（紫杉醇可以以 鲁 TAXOL®的形式透過商業途徑獲得）、多西他赛 (docetaxel)、光輝黴素（mithramycin)、去氧助間型黴素 (deoxycoformycin)、絲裂黴素-c(mitomycin C)、L-天冬醯 胺酶（L-asparaginase)、干擾素（尤其是IFN_a)、依託泊苷 (yituobogan)、和坦尼坡賽（teniposide)。 單株抗體（非限制性的包括CD抗原的單株抗體， HER2/ERBB2的單株抗體、抗EGFR的單株抗體、抗VEGFR 的單株抗體）：伊馬替尼（imatinib)、利妥昔單株抗體 鲁 (rituximab )、曲妥單株抗體（transtuzumab )、阿倫單 株抗體（alemtuzumab) '西妥昔單株抗體（cetuximab， C225 )、阿瓦斯汀（avastin)、郝賽汀（herceptin)等。 其他抗增生的細胞毒性物質有navelbene、CPT-11、 anastrazole、letrazole、capecitabine、reloxafine、環雄醯 胺（Cytoxan®)、異環磷醯胺（if0samide)、和 droloxafine。 術語「放射治療」非限制性地包括可以由所用的外源 如光線或植入的小型放射源來釋放x_射線或7射線。 微管影響劑干擾了細胞的有絲分裂並且在現有技術中[s】 12 201121547 眾所周知地具有抗增生的細胞毒素活性。本發明用的微管 影響劑非限制性地包括，異秋水仙鹼（allocolchicine) (NSC 406042)、Halichondrin B(NSC609395)、秋水仙驗（NSC 757)、秋水仙鹼衍生物（例知，NSC 33410)、dolastatin 10(NSC 376128)、美坦素（NSC 153858)、rhizoxin (NSC332598)、 紫杉醇（TAXOL®，NSC 125973)、TAXOL®衍生物（例如， 衍生物（例如，NSC 608832)、硫代秋水仙鹼NSC 361792)、 三苯甲基半胱胺酸（NSC 83265)、硫酸長春花鹼（NSC • 49842)、硫酸長春新鹼（NSC67574)、天然和合成的埃博黴 素（epothilone)’非限制性地包括埃博黴素A(epothilone A)、 埃博黴素 B(epothilone B)、埃博黴素 C(epothilone C)、埃 博黴素 D(epothilone D)、去氧埃博黴素 A(deoxyepothilone A)、去氧埃博黴素 B(deoxyepothiloneB)。 另外的抗腫瘤物質包括，discodermolide(見Service， (1996) Science, 274: 2009)雌莫司 ί丁（estramustine)、嘆氨醋 噠唑（nocodazole)、MAP4等等。該類物質的實例還在科學 ® 和專利文獻中進行了描述，可參照，例如，Bui inski (1997) J. Cel 1. Sc i. 1 10: 3055-3064;Panda (1997) Proc. Nat l.Acad. Sci.USA 94:10560-10564;Muhlradt (1997) CancerCompounds which can be used as anti-proliferative agents include the following classes of compounds: Burning agents (including, but not limited to, nitrogen mustard, aziridine derivatives, aikylsulfonate, nitroso Urea (nitrosourea and triazene): uramustine, Chlormethine, Cytoxan®, ifosfamide, phenylalanine mustard ), chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, bubuan, carmustine, cyclohexylnitrite Lomustine), streptozocin, dacarbazine, and temozolomide anti-metabolites (including, without limitation, folic acid antagonists, squirting analogs, Indole analogs and adenosine deaminase inhibitors) • methotrexate, 5-fluorouracil, fiu〇r〇Uridine, Cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentastatin Pentostatin, and gemcitabine [ η 201121547 hydrochloride ) ° natural products and their derivatives (eg, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxin (epip〇d〇phyll) 〇t〇xin)): catharanthine, vincristine, Vindesine, blenmycin, actin〇mycin D, daunorubicin ), doxorubicin (d〇x〇rubicin), epidoxorubiein, demethyldaunorubicin, Ara-C, paclitaxel (paclitaxel can be in the form of TAXOL®) Commercially available), docetaxel, mithramycin, deoxycoformycin, mitomycin C, and L-aspartate (L-asparaginase), interferon (especially IFN_a), Teniposide (yituobogan), and Tenney slope race (teniposide). Monoclonal antibodies (unrestricted monoclonal antibodies including CD antigen, monoclonal antibodies to HER2/ERBB2, monoclonal antibodies against EGFR, monoclonal antibodies against VEGFR): imatinib, rituximab The antibody rituximab, transtuzumab, alemtuzumab 'cetuximab (C225), avastin, herceptin, and the like. Other anti-proliferative cytotoxic substances are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, Cytoxan®, ifosfamide, and droloxafine. The term "radiation therapy" includes, without limitation, x-rays or 7-rays that can be released by an external source such as light or an implanted small source of radiation. Microtubule-influencing agents interfere with mitosis of cells and are known to have anti-proliferative cytotoxic activity in the prior art [s] 12 201121547. The microtubule affecting agent used in the present invention includes, without limitation, allocolchicine (NSC 406042), Halichondrin B (NSC609395), colchicine (NSC 757), colchicine derivatives (known as NSC). 33410), dolastatin 10 (NSC 376128), vasplatin (NSC 153858), rhizoxin (NSC332598), paclitaxel (TAXOL®, NSC 125973), TAXOL® derivatives (eg, derivatives (eg, NSC 608832), thio Colchicine NSC 361792), Tritylcysteine (NSC 83265), Vinblastine Sulfate (NSC • 49842), Vincristine Sulfate (NSC67574), Natural and Synthetic Epothilone (epothilone) Non-limiting includes epothilone A, epothilone B, epothilone C, epothilone D, Epothilium Deoxyepothilone A, deoxyepothilone B. Additional anti-tumor substances include discodermolide (see Service, (1996) Science, 274: 2009) estramustine, nocodazole, MAP4, and the like. Examples of such materials are also described in Scientific® and the patent literature, for example, for example, Bui inski (1997) J. Cel 1. Sc i. 1 10: 3055-3064; Panda (1997) Proc. Nat l .Acad. Sci.USA 94:10560-10564; Muhlradt (1997) Cancer
Res.57:3344-3346;Nicolaou (1997) Nature3 87:268-272;Res. 57: 3344-3346; Nicolaou (1997) Nature 3 87: 268-272;
Vasquez (1997)Mol. Biol. Cell. 8: 973-985; Panda(1996) J. Biol.Chem 271:29807-29812。Vasquez (1997) Mol. Biol. Cell. 8: 973-985; Panda (1996) J. Biol. Chem 271: 29807-29812.
LSI 在希望使異常增生的細胞靜止的情況中，還可以與本 發明的化療方法併用或在本發明的化療方法之前將激素 (hormone)和類固醇類物質（包括合成類似物）投藥于患 13 201121547 者：17a-炔雌醇（17a-ethinylestradiol)、乙蒽酌· (diethylstilbestrol)、睾酮（testosterone)、潑尼松、氟經甲 基睾酿I (fluoxymesterone)、丙酸屈他雄酮（dromostanoloneIn the case where LSI is desired to quiescently aberrantly proliferating cells, hormones (hormone) and steroids (including synthetic analogs) may also be administered to the patient 13 in combination with the chemotherapeutic method of the present invention or before the chemotherapeutic method of the present invention. : 17a-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone
propionate)、睾内酯（testolactone)、醋酸美皆斯妥（megestrol acetate)、甲基培尼皮質醇（methylprednisolone)、甲基睪固 酮（methyltestosterone)、培尼皮質醇（prednisolone)、氟羥 培尼皮質醇（fluoxyprednisolone)、hlorotrianisene、經助孕 m (hydroxyprogesterone) ' 氨魯米特（aminoglutethimide)、 雌 莫司汀 （estramustine)、 醋酸 曱經孕 _ (medroxyprogesterone acetate)、亮丙瑞林（ieuproreiin)、氟 塔醢胺（flutamide)、托瑞米芬（toremifene)、醋酸性瑞林（relin acetate) ° 還適用於本發明併用化療方法的物質有抗血管劑如基 質金屬蛋白酶抑制劑、和其他VEGF抑制劑，如抗_VEGF 抗體並且還包括一些小分子如ZD6474、SU1248和 SU6668。還可以使用得自Genetech的抗-Her2抗體。一種 適宜的EGFR抑制劑是EKB569(一種不可逆的抑制劑）(> 還 包括對EGFR具有免疫特定性的Imcl〇ne抗體㈡乃和爪 抑制劑。 還適用於作為抗增生的細胞抑制劑的冑， 其可以治療非增生性的雄激素依賴性的癌。細胞抑制劑的 另一類實例還有可以抑制雌激素依賴性乳癌的增生和生長 的抗雌激素的他莫昔芬、 1 Xlfen)。細胞增生性訊息轉導 的抑制劑是細胞抑制劑°其實例有表皮生長因子抑制劑、 Her-2抑制劑、MEK-丨激酶抑制劑、ΜΑρκ激酶抑制劑、％ m 14 201121547 抑制劑、Src激酶抑制劑、以及pD(3F抑制劑。 所述的某些抗增生劑是抗生血管和抗血管物質，其可 以阻斷實體瘤的血流’透過剝奪癌細胞的營養而使癌細胞 靜止。還可以使用閹割，其也可以治療非增生的雄激素依 賴J·生癌症。用除手術破壞血流外的其他方法來進行鐵餓療 法是細胞抑制劑的另一種實例。一類特別較佳的抗血管細 胞抑制劑是combretastatins。其他細胞抑制劑的實例包括 MET激酶抑制劑、MAp激酶抑制劑、非受體和受體酪氨 •酸激酶抑制劑、整合蛋白訊息抑制劑、和胰島素類生長因 子受體抑制劑。 本發明提供了用於協同治療各種癌症的方法，所述的 癌症非限制性地包括如下的癌症：膀胱癌（包括快速和轉移 |·生膀胱癌）、乳癌、結腸癌（包括結腸直腸癌）、腎癌、肝癌、 肺癌（包括小細胞和非小細胞肺癌和肺腺癌）、卵巢癌、前 列腺癌、睾丸癌、泌尿生殖道癌、淋巴系統癌、直腸癌、 喉癌、胰腺癌（包括外分泌的胰腺癌）、食道癌、胃癌、膽 籲囊癌、頸癌、甲狀腺癌和皮膚癌（包括鱗狀細胞癌）。 淋巴系的造血腫瘤，包括白血病、急性淋巴細胞白血 病、急性成淋巴細胞白血病、細胞淋巴瘤、丁_細胞淋巴 瘤、何傑金氏淋巴瘤、非-何傑金氏淋巴瘤、毛細胞淋巴瘤、 組織細胞淋巴瘤、和Burketts淋巴瘤。 脊趙系的造血腫瘤，包括急性和慢性骨髓性白血病、 脊髓發育不良綜合症、骨髓性白血病、和早幼粒細胞白血 病。 中樞和周邊神經系統的腫瘤’包括星形細胞瘤、成神[S] 15 201121547 經細胞瘤、神經膠質瘤、和許旺氏細胞瘤。 間質細胞瘤’包括纖維肉瘤、橫紋肌肉瘤、和骨肉瘤； 和其他腫瘤’包括黑素瘤、色素性乾皮病（xen〇derma pigmentosum)、角化棘皮瘤、精原細胞瘤、曱狀腺濾泡癌、 和畴胎癌。 更較佳地’本發明被用來治療快速或轉移性膀胱癌、 胰腺癌、前列腺癌、非小細胞肺癌、結腸直腸癌、肝癌、 月癌以及乳癌的癌症。 籲 在本發明一個較佳的實施方案中，提供了對癌性腫瘤 進行協同治療的方法。本發明的協同方法可以有利地降低 腫瘤的發育、減少腫瘤負荷、或使哺乳動物主體的腫瘤消 退。 用於將這些化療劑中的大部分化療劑安全有效地進行 投藥的方法對所屬技術領域中具有通常知識者而言是公知 的°此外’在標準文獻中也對其投藥方法進行了描述，例 如，在 ‘‘Physicians’ Desk Reference”（PDR)中對許多化 療劑的投藥進行了描述，例如，在1996版pdr中進行了 私述（1^(1化丑1£。〇11〇111^(3〇111卩&117，：\1〇1^316，>〇 07645- 1742，USA);其公開的内容在這裏被引入作為參考。 本發明還包括可用於治療癌症的醫藥組合物，包含將 治療有效量的本發明的組合進行投藥，在投藥時可以將本 發明的組合與可藥用的載體或稀釋劑一起進行投藥或不與 可藥用載體或稀釋劑結合來進行投藥。本發明的具有協同 作用的醫藥組合物包含抗增生劑、式〗的化合物、以及可 藥用的載體。本發明的組合物還可以進一步包含一種或多[s] 16 201121547 種可藥用的其他組分如明礬、穩定劑、抗菌劑、緩衝劑、 著色劑、矯味劑、輔劑等等。 本發明的抗腫瘤劑、式ϊ化合物和組合物可以口服投 藥或非腸道投藥，其中所述的非腸道投藥包括靜脈内投 藥、肌内投藥、腹膜内投藥、皮下投藥、直腸投藥和局部 投藥。 對於口服應用而言，本發明的抗腫瘤劑、式I化合物 和組合物可以以例如片劑或膠囊劑、粉劑、可分散顆粒、 ❿ 或扁膝囊、或水性溶液或混懸液的形式來進行投藥。在用 於口服的片劑中’常用的載體包括乳糖、玉米澱粉、碳酸 鎖、滑石粉、和蔗糖，並且還常使用潤滑劑如硬脂酸鎂。 對於用於口服投藥的膠囊而言，可用的載體包括乳糖、玉 米澱粉、碳酸鎂、滑石粉、和蔗糖。當用水性混懸液來進 行口服投藥時，通常可以添加乳化劑和/或混懸劑。 此外，還可以向口服組合物中加入甜味劑和/或矯味 劑。對於肌内、腹膜内、皮下和靜脈内的應用而言，通常 使用活〖生成分的無菌溶液，並且應當對溶液的pH進行適 當的調節和緩衝。對於靜脈内的應用而言，為了使製劑等 張應當控制溶質的總濃度。 &對於本發明栓劑的製備而言，首先將低熔點的壤如脂 1 -文甘油S日或椰子油混合物溶化，然後將活性成分均句地 _ ’例如透過授拌來將活性成分進行分散。然 後將溶化了的均勻混合物方便地傾倒在一定型號的模具 中’使之冷卻固化。 液體製劑包括溶液、混懸液和乳劑。該類製劑的實例m 17 201121547 是非腸道注射用的水或水/丙二醇溶液。液體製劑還可包括 用於鼻内投藥的溶液。 適於吸入的氣霧劑製劑可以包括溶液和粉末形式的固 體’其可以與可藥用載體如惰性可壓縮氣體併用。 還包括希望在使用前不久即將其轉換成用於口服或非 腸道投藥的液體製劑的固體製劑。該類液體形式包括溶 液、混懸液和乳液。 這裏所述的式I化合物以及抗腫瘤劑還可以進行經皮 • 投藥。該經皮投藥的組合物可以是膏、洗劑、氣霧劑和/或 乳劑的形式並且可以被包含在現有技術中經皮投藥常用的 骨架或儲庫型經皮貼劑中。 本發明的組合還可以與其他眾所周知的治療併用，所 選擇的其他治療可以特別有益地對抗所治療的病症。 如果以固定劑量進行配製，則可以在如下所述的劑量 範圍内使用本發明併用組合物的活性組分。作為另一種供 替代的選擇，抗腫瘤物質、以及式j化合物可以以如下所 φ 述的劑量範圍單獨投藥》 在本發明的一個較佳實施方案中，抗腫瘤物質是以如 下所述的劑量範圍在如下所述劑量範圍的< χ的化合物的 投藥之後進行投藥或與其同時進行投藥。 表1列出了較佳的化療組合和本發明方法所用劑量的 實例。 【表 劑量mg/m2(每個劑量) 10-1500 mg/m2 化合物 18 201121547Propionate), testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, flupontine Alcohol (fluoxyprednisolone), hlorotrianisene, hydroxyprogesterone 'aminoglutethimide, estramustine, medroxyprogesterone acetate, ieuproreiin, fluoride Flutamide, toremifene, relin acetate ° Also suitable for use in the present invention and chemotherapeutic agents are anti-vascular agents such as matrix metalloproteinase inhibitors, and other VEGF inhibitors. For example, anti-VEGF antibodies and also include some small molecules such as ZD6474, SU1248 and SU6668. Anti-Her2 antibodies from Genetech can also be used. A suitable EGFR inhibitor is EKB569 (an irreversible inhibitor) (> also includes Imcl〇ne antibodies (II) that are immunospecific for EGFR and claw inhibitors. Also suitable for use as an anti-proliferative cytostatic agent It can treat non-proliferative androgen-dependent cancer. Another class of cytostatics is tamoxifen, an anti-estrogen that inhibits the proliferation and growth of estrogen-dependent breast cancer, 1 Xlfen). Inhibitors of cell proliferative signal transduction are cytostatic agents. Examples are epidermal growth factor inhibitors, Her-2 inhibitors, MEK-丨 kinase inhibitors, ΜΑρκ kinase inhibitors, % m 14 201121547 inhibitors, Src kinases. Inhibitors, as well as pD (3F inhibitors. Some of the anti-proliferative agents are anti-angiogenic and anti-vascular substances that block the blood flow of solid tumors. 'By depriving cancer cells of nutrients and making cancer cells still. Using castration, it can also treat non-proliferative androgen-dependent J. cancer. Ironstroke therapy is another example of cytostatics by other methods other than surgery to destroy blood flow. A particularly preferred class of anti-angiogenic cells The inhibitor is combrestatin. Examples of other cytostatics include MET kinase inhibitors, MAp kinase inhibitors, non-receptor and receptor tyrosine kinase inhibitors, integrin message inhibitors, and insulin-like growth factor receptor inhibition. The present invention provides a method for the synergistic treatment of various cancers, including, without limitation, cancers such as bladder cancer (including fast) And metastasis | · bladder cancer), breast cancer, colon cancer (including colorectal cancer), kidney cancer, liver cancer, lung cancer (including small cell and non-small cell lung cancer and lung adenocarcinoma), ovarian cancer, prostate cancer, testicular cancer, Genitourinary tract cancer, lymphatic system cancer, rectal cancer, laryngeal cancer, pancreatic cancer (including exocrine pancreatic cancer), esophageal cancer, gastric cancer, gallbladder cancer, cervical cancer, thyroid cancer, and skin cancer (including squamous cell carcinoma) Hematopoietic tumors of the lymphoid system, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, cellular lymphoma, D-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymph Tumor, histiocytic lymphoma, and Burketts lymphoma. Hematopoietic tumors of the vertebral lineage, including acute and chronic myeloid leukemia, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia. Central and peripheral nervous system Tumors include astrocytoma, sacred [S] 15 201121547 Transcellular cell, glioma, and Schwannoma. Interstitial cell tumors Fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and other tumors including melanoma, xen〇derma pigmentosum, keratoacanthoma, seminoma, squamous follicular carcinoma, and domains Fetal cancer. More preferably, the present invention is used to treat cancers of rapid or metastatic bladder cancer, pancreatic cancer, prostate cancer, non-small cell lung cancer, colorectal cancer, liver cancer, lunar cancer, and breast cancer. In a preferred embodiment, a method of synergistic treatment of a cancerous tumor is provided. The synergistic method of the present invention can advantageously reduce tumor development, reduce tumor burden, or cause tumor regression in a mammalian subject. Methods for safe and effective administration of most chemotherapeutic agents in the agent are well known to those of ordinary skill in the art. Further, 'the method of administration is also described in the standard literature, for example, in ''Physicians' The administration of many chemotherapeutic agents is described in the 'Table Reference' (PDR), for example, in the 1996 edition of the drr (1^(1) . 〇11〇111^(3〇111卩&117,:\1〇1^316, >〇 07645-1742, USA); the disclosure of which is incorporated herein by reference. The invention further encompasses a pharmaceutical composition useful for treating cancer comprising administering a therapeutically effective amount of a combination of the invention, which may be administered with or without a pharmaceutically acceptable carrier or diluent when administered. A pharmaceutically acceptable carrier or diluent is combined for administration. The synergistic pharmaceutical composition of the present invention comprises an anti-proliferative agent, a compound of the formula, and a pharmaceutically acceptable carrier. The composition of the present invention may further comprise one or more [s] 16 201121547 pharmaceutically acceptable other components such as alum, a stabilizer, an antibacterial agent, a buffer, a coloring agent, a flavoring agent, an adjuvant, and the like. The antitumor agent, the guanidine compound and the composition of the present invention can be administered orally or parenterally, wherein the parenteral administration includes intravenous administration, intramuscular administration, intraperitoneal administration, subcutaneous administration, rectal administration, and topical administration. Dosing. For oral use, the antitumor agents, compounds of formula I and compositions of the invention may be in the form of, for example, tablets or capsules, powders, dispersible granules, sputum or sacs, or aqueous solutions or suspensions. Do the administration. The commonly used carriers in tablets for oral administration include lactose, corn starch, carbonated lock, talc, and sucrose, and a lubricant such as magnesium stearate is also often used. For capsules for oral administration, useful carriers include lactose, corn starch, magnesium carbonate, talc, and sucrose. When an aqueous suspension is used for oral administration, an emulsifier and/or a suspension may usually be added. In addition, sweeteners and/or flavoring agents may also be added to the oral compositions. For intramuscular, intraperitoneal, subcutaneous, and intravenous applications, sterile solutions of live fractions are typically used and the pH of the solution should be suitably adjusted and buffered. For intravenous applications, the total concentration of solutes should be controlled in order for the formulation to be isotonic. & For the preparation of the suppository of the present invention, the low melting point soil such as the lipid 1-glycerin S day or coconut oil mixture is first melted, and then the active ingredient is uniformly dispersed, for example, by mixing to dissolve the active ingredient. . The melted homogeneous mixture is then conveniently poured into a mold of a certain type to allow it to cool and solidify. Liquid preparations include solutions, suspensions and emulsions. An example of such a formulation m 17 201121547 is a water or water/propylene glycol solution for parenteral injection. Liquid preparations may also include solutions for intranasal administration. Aerosol formulations suitable for inhalation may include solutions and solids in powder form which may be used in combination with a pharmaceutically acceptable carrier such as an inert compressible gas. Also included are solid preparations which are intended to be converted shortly before use into liquid preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of formula I described herein as well as antitumor agents can also be administered transdermally. The transdermal compositions can be in the form of a cream, lotion, aerosol, and/or emulsion and can be included in a conventional dermal or depot-type transdermal patch for transdermal administration in the prior art. Combinations of the invention may also be combined with other well known therapies, and other treatments selected may be particularly beneficial against the condition being treated. If formulated in a fixed dose, the active ingredients of the compositions of the present invention may be employed in the dosage range described below. As an alternative, the anti-tumor substance, and the compound of formula j can be administered separately in a dosage range as described below. In a preferred embodiment of the invention, the anti-tumor substance is in a dosage range as described below. Administration is carried out after administration of the < χ compound in the dose range described below or at the same time as it is administered. Table 1 lists examples of preferred combinations of chemotherapy and dosages employed in the methods of the invention. [Table dose mg/m2 (each dose) 10-1500 mg/m2 compound 18 201121547
+順始 5-150 mg/m2 式I的化合物 10-1500 mg/m2 +卡鉑 5-1000 mg/m2 式I的化合物 10-1500 mg/m2 +放射治療 200-8000 cGy 式I的化合物 10-1500 mg/m2 +CPT-11 5-400 mg/m2 式I的化合物 10-1500 mg/m2 +紫杉醇 40-250 mg/m2 式I的化合物 10-1500 mg/m2 +紫杉醇 40-250 mg/m2 +卡始 5-1000 mg/m2 式I的化合物 10-1500 mg/m2 + 5FU並可以任選地 5-5000 mg/m2 +亞葉酸 5-1000 mg/m2 式I的化合物 10-1500 mg/m2 +埃博黴素 1-500 mg/m2 式I的化合物 10-1500 mg/m2 +吉西他濱 100-3000 mg/m2 式I的化合物 10-1500 mg/m2 + UFT並可以任選地 50-800 mg/m2 +亞葉酸 5-1000 mg/m2 19 201121547+ cis-5-150 mg/m2 Compound of formula I 10-1500 mg/m2 + carboplatin 5-1000 mg/m2 Compound of formula I 10-1500 mg/m2 + radiotherapy 200-8000 cGy Compound 10 of formula I -1500 mg/m2 + CPT-11 5-400 mg/m2 Compound of formula I 10-1500 mg/m2 + paclitaxel 40-250 mg/m2 Compound of formula I 10-1500 mg/m2 + paclitaxel 40-250 mg/ M2 + card start 5-1000 mg/m2 Compound of formula I 10-1500 mg/m2 + 5FU and optionally 5-5000 mg/m2 + leucovorin 5-1000 mg/m2 Compound 10-1500 mg of formula I /m2 + epothilone 1-500 mg/m2 Compound of formula I 10-1500 mg/m2 + gemcitabine 100-3000 mg/m2 Compound of formula I 10-1500 mg/m2 + UFT and optionally 50- 800 mg/m2 + leucovorin 5-1000 mg/m2 19 201121547
式I的化合物 10-1500 mg/m2 +吉西他濱 100-3000 mg/m2 +順始 5-150 mg/m2 式I的化合物 10-1500 mg/m2 +UFT 50-800 mg/m2 +亞葉酸 5-1000 mg/m2 式I的化合物 10-1500 mg/m2 +順在白 5-150 mg/m2 +紫杉醇 4-250 mg/m2 式I的化合物 10-1500 mg/m2 +順在白 5-150 mg/m2 +5FU 5-5000 mg/m2 式I的化合物 10-1500 mg/m2 +Oxaliplatin (奥沙利銘） 5-500 mg/m2 +CPT—11 4-400 mg/m2 式I的化合物 10-1500 mg/m2 +5FU 5-5000 mg/m2 + CPT-11並可以任選地 4-400 mg/m2 +亞葉酸 5-1000 mg/m2 式I的化合物 10-1500 mg/m2 +5FU 5-5000 mg/m2 +放射治療 20-8000 cGy 式I的化合物 10-1500 mg/m2 +放射治療 200-8000 cGy +5FU 5-5000 mg/m2 20 201121547 +順钻 5-150 mg/m2 式I的化合物 10-1500 mg/m2 +Oxaliplatin (奥沙利始） 5-500 mg/m2 +5FU並可以任選地 5-5000 mg/m2 +亞葉酸 5-1000 mg/m2 式I的化合物 10-1500 mg/m2 +紫杉醇 40-250 mg/m2 +CPT-11 4-400 mg/m2 式I的化合物 10-1500 mg/m2 +紫杉醇 40-250 mg/m2 +5—FU 5-5000 mg/m2 式I的化合物 10-1500 mg/m2 +UFT 50-800 mg/m2 + CPT-11並可以任選地 4-400 mg/m2 +亞葉酸 5-1000 mg/m2Compound of formula I 10-1500 mg/m2 + gemcitabine 100-3000 mg/m2 + cis-5-150 mg/m2 Compound of formula I 10-1500 mg/m2 + UFT 50-800 mg/m2 + leucovorin 5- 1000 mg/m2 Compound of formula I 10-1500 mg/m2 + cis-white 5-150 mg/m2 + paclitaxel 4-250 mg/m2 Compound of formula I 10-1500 mg/m2 + cis-white 5-150 mg /m2 +5FU 5-5000 mg/m2 Compound of formula I 10-1500 mg/m2 + Oxaliplatin (Oxalibine) 5-500 mg/m2 + CPT-11 4-400 mg/m2 Compound 10 of formula I 1500 mg/m2 +5FU 5-5000 mg/m2 + CPT-11 and optionally 4-400 mg/m2 + leucovorin 5-1000 mg/m2 Compound of formula I 10-1500 mg/m2 +5FU 5- 5000 mg/m2 + radiotherapy 20-8000 cGy Compound of formula I 10-1500 mg/m2 + radiotherapy 200-8000 cGy +5FU 5-5000 mg/m2 20 201121547 + boring 5-150 mg/m2 Formula I Compound 10-1500 mg/m2 + Oxaliplatin (Oxaligin) 5-500 mg/m2 +5FU and optionally 5-5000 mg/m2 + leucovorin 5-1000 mg/m2 Compound 10-1500 of formula I Mg/m2 + paclitaxel 40-250 mg/m2 + CPT-11 4-400 mg/m2 Compound of formula I 10-1500 mg/m2 + paclitaxel 40-250 mg/m2 +5-FU 5- 5000 mg/m2 Compound of formula I 10-1500 mg/m2 + UFT 50-800 mg/m2 + CPT-11 and optionally 4-400 mg/m2 + leucovorin 5-1000 mg/m2
在上面的表1中，"5FU”表示5-氟尿嘧啶，“亞葉酸 可以以亞葉酸鈣的形式來進行使用，"UFT”是莫耳比為1: 4 的替加敗：尿癌咬。 並且“埃博黴素”較佳地是在WO 99/02514或WO 00/50423中所描述的化合物，兩篇文獻在這裏被整體引入 作為參考。 雖然表1提供了式I化合物以及本發明某些抗癌劑的 劑量範圍的實例，但是當製備本發明的醫藥組合物時，臨 床醫師可以根據所治療患者的病症所提供的資訊來使用較pi L ^ i 21 201121547 佳劑量。例如，式1化合物可以較佳地以每天l〇0-800mg/m2 的劑量來進行投藥。順鉑的較佳劑量為每3個星期75_12〇 mg/m2。卡鉑的較佳劑量為 200-600 mg/m2,或 〇.5_8mg/mlx min的AUC，最較佳的是4 6 mg/ml χ min的。當該方 法使用放射治療時，較佳的劑量範圍為200-6000 CGY。In Table 1 above, "5FU" means 5-fluorouracil, "folinic acid can be used in the form of calcium leucovorin, "UFT" is a molar ratio of 1:4 for the addition of a urinary cancer bite And "epothilone" is preferably a compound described in WO 99/02514 or WO 00/50423, both of which are incorporated herein by reference in its entirety. Examples of dosage ranges for certain anticancer agents, but when preparing the pharmaceutical compositions of the present invention, the clinician can use a better dose than pi L ^ i 21 201121547 based on information provided by the condition of the patient being treated. The compound 1 can be preferably administered at a dose of from 10 to 800 mg/m 2 per day. The preferred dose of cisplatin is 75_12 〇 mg/m 2 every 3 weeks. The preferred dose of carboplatin is 200-600 mg / M2, or AUC of _5_8 mg/mlx min, most preferably 4 6 mg/ml χ min. When the method uses radiation therapy, the preferred dosage range is 200-6000 CGY.
cPT-n的較佳劑量為1G(M25 mg/m2，每週—次。紫杉醇 的卓乂佳劑里為每21 & 130_225 mg/m2。吉西他濱的較佳劑 量為80-1500 mg/m2 ,每週投藥一次。較佳地，當與亞葉 酸併用投藥時，所用UFT的劑量範圍為每天则·彻 mg/ml亞葉酸的較佳劑量為1〇_6〇〇mg/m2,每週投藥一次。 所用的實際劑量可以根據患者的需要和所治療病症的 嚴重程度來進行變化。對特定情況而言，決定適宜劑量是 所層技術領域中具有通常知識者的一般知識。一般而言， 用低於該化合物最佳劑量的較小劑量來開始治療。其後， 逐步少量的增加劑詈首$猶）呈+ # & S训削篁罝至獲得在該情況下的最佳作用。為 了方便起見，可以將總的日劑量分成幾份 的話可以在該天中以各部分的形式進行投藥。 ，某些癌症可以用式1化合物和多種抗癌劑來有效地進 行治療。這種三重或四重併用可以提供更高的功效。當使 用三重和四重併用時可以使用上述的劑量。因此，在上面 表1中的其他該類組合可以包括將式1化合物與⑴米托葱 酿+潑尼松⑼多柔比星+卡峨（3) h⑽ptin +他莫昔芬的 組合。在任何一種上述組合中都可以用υρτ替代5孙 [S] 當使用本發明的方法或組合物時，還可以根據需要在 L床治療中使用如止吐劑等治療藥物。 22 201121547 本發明包括一種用來協同治療癌症的方法，其中可以 對於式I化合物同時或相繼進行投藥1此，雖然 '特疋的治療而言該包含抗腫瘤物質和式j厶物 的藥物製劑對於該組合的投藥而言报有利，但：：二 抗腫瘤物質優先投藥可能是有利的。還應當清楚 :疋本發明中抗腫瘤物質…化合物的組合可以盘其他 治療癌症（較佳地是癌性腫瘤）的方法併用，其中所述的其The preferred dose of cPT-n is 1G (M25 mg/m2, weekly-times. The dosage of paclitaxel is 130/amp; 130_225 mg/m2. The preferred dose of gemcitabine is 80-1500 mg/m2. It is administered once a week. Preferably, when administered in combination with folinic acid, the dose of UFT used is in the range of 1 〇 6 〇〇 mg / m 2 per day, preferably mg / ml of leucovorin, administered weekly. Once. The actual dose used can vary depending on the needs of the patient and the severity of the condition being treated. For a particular situation, determining the appropriate dosage is a general knowledge of those of ordinary skill in the art of the layer. In general, A smaller dose than the optimal dose of the compound is used to initiate the treatment. Thereafter, a small amount of the increasing dose of the dagger is presented as + # & S training to obtain the best effect in this case. For the sake of convenience, the total daily dose can be divided into several portions, and the administration can be carried out in the form of each part on the day. Some cancers can be effectively treated with a compound of formula 1 and a variety of anticancer agents. This triple or quadruple combination can provide higher efficacy. The above dosages can be used when using triple and quadruple. Thus, other such combinations in Table 1 above may include a combination of a compound of formula 1 with (1) mitoxantrone + prednisone (9) doxorubicin + carp (3) h (10) ptin + tamoxifen. In any of the above combinations, υρτ can be used instead of 5 grandchild [S] When the method or composition of the present invention is used, a therapeutic drug such as an antiemetic agent can also be used in the treatment of L bed as needed. 22 201121547 The present invention encompasses a method for the synergistic treatment of cancer, wherein a compound of formula I can be administered simultaneously or sequentially, although the 'medical formulation containing the antitumor substance and the formula j is for the treatment of The administration of this combination is advantageous, but:: It may be advantageous to preferentially administer the secondary anti-tumor substance. It should also be clear that: the combination of anti-tumor substances in the present invention can be used in combination with other methods for treating cancer, preferably cancerous tumors, wherein
=療癌症的方法非限制性地包括放射治療和手術。還應 虽清楚的是如果有的話，細胞抑制劑和靜止劑可以與其他 協同治療中的任何-種或所有的協同治療相繼投 時 投藥。 本發明的組合還可以與選擇用I更有效地對抗所治療 病症的其他眾所周知的治療物質共同投藥0當多種組合製 劑不口適時，本發明的組合或者可以相繼與公知的可藥用 物質一起使用。 化療劑和/或放射治療可以根據現有技術中眾所周知的 治療方案來進行使用。化療劑和/或放射治療的投藥可以根 據所治療的疾病和已知的該化療劑和/或放射治療對該疾病 的作用來進行變化，這對所屬技術領域中具有通常知識者 而言是顯而易見的。根據熟練臨床醫師的常識，治療方案（例 如投藥劑量和投藥次數）還可以根據觀測到的所投藥的治療 劑（即抗腫瘤物質或放射治療）對患者的作用以及觀測到的 疾病對所投藥的治療物質的回應來進行變化β 在本發明的方法令，式I化合物可以與抗增生劑和/或 放射治療同時進行投藥或相繼進行投藥。因此，化療劑和[s] 23 201121547 式i化合物、或放射治療和式丨化合物不一定都要同時投 藥或基本同時進行投藥。熟練的臨床醫師可以很好的判定 出同時投藥或基本同時投藥的優點。 一般而言，式1化合物、以及化療劑不一定是在同一 種醫藥組合物中來進行投藥的，因為不同的物理和化學特 性，其可以或必需透過不同的投藥途徑來進行投藥。例如， 式I化合物可以口服投藥以產生並維持其良好的血液水 準，而化療劑可以靜脈内投藥。在可能的情況中，對投藥 途徑和以同-種醫藥組合物的形式進行投藥的合理性的判 定是熟練臨床醫師十分公知的。可以根據現有技術中所碟 立的方案來決定最初的投藥’然後以所觀測到的作用為基 礎’熟練的臨床醫師可以改變投藥劑量、方式以及投藥次= Methods of treating cancer include, but are not limited to, radiation therapy and surgery. It should also be clear that cytostatics and quiescent agents, if any, can be administered in succession with any or all of the other synergistic treatments. Combinations of the invention may also be co-administered with other well-known therapeutic substances that are more effective against the condition being treated with I. When the various combination preparations are not suitable, the combination of the invention may be used sequentially with known pharmaceutically acceptable substances. . Chemotherapeutic agents and/or radiation therapy can be used according to treatment regimens well known in the art. Administration of chemotherapeutic agents and/or radiation therapy can vary depending on the disease being treated and the effect of the known chemotherapeutic agent and/or radiation therapy on the disease, as will be apparent to those of ordinary skill in the art. of. According to the common knowledge of the skilled clinician, the treatment regimen (for example, the dose and the number of administrations) can also be based on the observed effects of the administered therapeutic agent (ie, anti-tumor substance or radiation therapy) on the patient and the observed disease. Response of the therapeutic substance to change β In the method of the present invention, the compound of formula I can be administered simultaneously or sequentially with an anti-proliferative agent and/or radiation therapy. Therefore, the chemotherapeutic agent and the compound of the formula [s] 23 201121547, or the radiation therapy and the compound of the formula, do not necessarily have to be administered simultaneously or substantially simultaneously. A skilled clinician can well determine the advantages of simultaneous or substantially simultaneous administration. In general, the compound of formula 1 and the chemotherapeutic agent are not necessarily administered in the same pharmaceutical composition, and because of the different physical and chemical properties, it may or may not be administered by a different route of administration. For example, a compound of formula I can be administered orally to produce and maintain a good blood level, while a chemotherapeutic agent can be administered intravenously. Wherever possible, the determination of the rationality of the route of administration and administration in the form of the same pharmaceutical composition is well known to the skilled clinician. The initial administration can be determined according to the protocol set forth in the prior art and then based on the observed effects. The skilled clinician can change the dosage, mode, and dosage.
式1化合物以及抗增生的 特定選擇將取決於主治醫師的 和適當的治療方案。 細胞毒素物質或放射治 珍斷以及對患者病症的 療的 判斷 或基本同時地進行投藥，則：：:……治療不能同時 仃杈樂則可以改變A I化合物、以及化 療劑和/或放射治療投藥的初 m T7U人a ㈣始-人序。因此，例如，可以首 :進…化合物的投藥，然後進 療的投藥；或可以首先推耔am /次敦射化 藥，然後…化和/或放射治療的投 可以重複ϋ行這種交##4 /、在—料—治療方案令 情況進行評㈣* 所治療的疾病和患者的 丨月况進仃》子估後，投藥的次 療物質重複投藥的次數& ^療方案期間各治 S3 數的匈定是熟練的臨床醫師所公知的[ 24 201121547 技能。例如，可以首先進行抗腫瘤劑和/或放射治療的投藥， 尤其是：果使用細胞毒素物質時更是如此。然後，該治療 繼續進仃式I化合物的投藥並且然後可以根據需要進行或 不進行細胞抑制劑的投藥，直至該治療方案結束。 因此，根據經驗和知識，隨著治療的進行，執業醫師 可以根據各患者的需要而對用於該治療組分（治療劑，即式〗 化合物、抗腫瘤劑、或放射治療）投藥的各方案進行修改。 在判斷在投藥劑量下治療是否有效時， 籲師會考慮患者的-般健康情況以及更明確的徵兆如相關疾 病症狀的緩解、腫瘤生長的抑制、腫瘤的實際收縮量、或 轉移的抑制。可以用標準的方法對腫瘤的大小進行測量， 其中所述的標準方法如放射學研究，例如CAT或MRI掃 描，並且可以用連續測定來判斷腫瘤的生長是否被阻止或 甚至被逆轉。還可以用疾病相關症狀如疼痛的緩解以及總 體情況的改善來幫助對治療的效力進行判斷。 透過實驗測定發現，式ϊ化合物或其可藥用鹽如果與 其他抗增生性藥物併用時，能夠提高治療效果，特別是針 對微管影響劑、抗代謝劑、抗生素類抗腫瘤藥、鉑配位化 合物這幾類化合物。 【實施方式】 為了幫助進一步對本發明進行理解，給出如下的實施 例來對本發明進行更詳細的說明。不能認為本發明的範圍 會受實施例的限制，本發明包括申請專利範圍第所定義的 全部主題物質。 【貫施例1】製備化合物A (式Ϊ化合物的曱續酸鹽）[门 25 201121547 在5L反應瓶中，投入式！化合物17〇g(〇 428m〇i)， 曱烷磺酸42.5g (〇.442mol)， 95〇/〇異丙醇水溶液2 55L ， 在氮氣保護並避光條件下攪拌加熱至全溶，得淡黃色透明 溶液，趁熱過濾，冷卻析晶至室溫後過濾，異丙醇洗，真 空乾燥，得白色針狀晶體180.2g(〇.365mol)，收率85.4%。 在5L反應瓶中，投入化合物a 18〇 2g、％%異丙醇 水溶液2.52L，氮氣保護並避光條件下攪拌加熱至全溶， 趁熱過濾，濾液冷卻析晶至室溫，過濾，異丙醇洗，真空 籲乾燥’得白色針狀晶體161.5g，收率89.6%。熔程：193.5 〜195。(：。 【貫施例2】化合物A單用或與奥沙利鉑合用對人結 腸癌Ls 1 74t裸小鼠移植瘤的療效 說明.化合物A即為式I化合物的甲項酸鹽，下同。 1、 實驗動物： BALB/cA-nude裸小鼠，半，5_6周齡，購自上海斯萊 克實驗動物有限責任公司。合格證號：SCXK (滬）2004 響-0005。飼養環境：SPF級。 2、 實驗步驟： 動物經1周適應後，皮下接種人結腸癌Lsl74t瘤塊組 織’待Μ瘤生長至150-300mm3後’將動物隨機分組（d〇)投 藥。化合物A和PTK787均為75mg/kg，口服投藥（灌胃）， d〇_d13 ’每天1次，共14次；奥沙利鉑6mg/kg，靜脈注 射，d0，d4，d8，共3次。合用時，化合物A和pTK787分 [S] 別與奥沙利鉑合用，投藥劑量和投藥方案不變。每週測2 —3次瘤體積，稱鼠重，記錄資料。腫瘤體積（ν)計算公 26 201121547 式為. V= l/2xaxb2 其中 a、b分別表示長、寬。 3、結果： 化合物A、奥沙利鉑單用對人結腸癌Lsl74t的生長均 有一定程度的抑制，其中化合物A療效最好，優於奥沙利 鉑，維持時間相對較長。PTK787，化合物A與奥沙利鉑 合用後，二者均能增效奥沙利鉑的作用；化合物A +奥沙 利鉑的療效明顯好於PTK787 +奥沙利鉑，化合物A的增效 φ 作用明顯優於PTK787。具體實驗結果參照表2。 【表2】化合物A、 奥沙利鉑單用或與PTK787合用 對人結腸癌Ls 174t裸小鼠移植瘤的療效 組別 (投藥） 劑量 (mg/ kg) 動物數 d0 dn 去瘤後體重 (克） d0 dn TV x 士 SD d0 dn RTV x土 SD T/C (%) 對照 12 12 20.5 16.6 204±63 2983±732 15.6±5.22 化合物A (p.o) 75 6 6 20.8 18.6 192士54 1662±349 9.21 士 2.94 59.0° PTK787(p.o)+ 奥沙利链(i.v) 75 6 6 5 21.6 16.2 223±49 1689±323 8.06±2.17 51.7a 化合物A (p.o) +奧沙利鉑(i.v) 75 6 6 6 20.5 16.6 208±63 1154士291 5.85±1.92 37.5^ b 奥沙利I6(i.v) 6 6 6 20.9 15.8 221士79 2157土376 10.6±3.86 68.5a d0 :分籠投藥時間；dn :第1次投藥後14天；aP<0.05 vs對照；bP<0.05 vs奥沙利韵。 【實施例3】化合物A單用或與5-Fu合用對人結腸癌 Lsl74t裸小鼠移植瘤的療效 1、實驗動物： BALB/cA-nude裸小鼠，早，5-6周齡，購自上海斯萊 克實驗動物有限責任公司。合格證號：SCXK (滬）2004 ί S1 27 201121547 —0005。飼養環境：SPF級。 2、 實驗步驟： 動物經1周適應後，皮下接種人結腸癌Lsl74t瘤塊組 織，待腫瘤生長至150-300mm3後，將動物隨機分組（d0)投 藥。化合物A和PTK7 87均為75mg/kg，口服投藥（灌胃）， d0-dl3，每天 1 次，共 14 次；5-Fu 50mg/kg，腹腔注射，d0, d4, d8，共3次。合用時，化合物A和PTK787分別與5-Fu 合用，投藥劑量和投藥方案不變。每週測2 — 3次瘤體積， • 稱鼠重，記錄資料。腫瘤體積（V )計算公式為： V = l/2xaxb2 其中a、b分別表示長、寬。 3、 結果： 化合物A、 5-Fu單用對人結腸癌Lsl74t的生長均有 一定程度的抑制，其中化合物A療效最好，與5-Fu相當。 化合物A、PTK787與5-Fu合用後，二者均能增效5-Fu的 作用；化合物A +5-Fu的療效優於PTK787 + 5-Fu，化合物 A對5-Fu的增效作用比PTK787更明顯。具體實驗結果參 籲照表3。 【表3】化合物A、5-Fu單用或與PTK787合用對人 結腸癌Ls 1 74t裸小鼠移植瘤的療效 組別 對照 劑量 mg/kg 鼠數(只） DO D14 11 11 去瘤後體重(g) DO D14 18.6 14.3 TV (X士 SD) DO D14 168土21 2488±622 RTV (x±SD) 14.8±3.0 T/C % 化合物 A 75 5 5 18.4 17.0 182士18 1580±333 8.9±2.7 6〇.r 化合物 75 5 5 19.3 16.8 194土16 1130±258 5.9±1.8* 39.9^ A + 5-Fu 50 PTK787 75 5 5 19.3 17.5 156±29 1380士 673 8.5±3.4 57.4a + 5-Fu 50 5-Fu 50 5 5 18.7 14.3 181±25 1567±210 9.2 土 2.0 62.5a P<0.01 vs對照；bP<0·05 vs化合物A或5-Fu單用。 28 201121547 【實施例4】化合物A單用或與奥沙利鉑合用對人結 腸癌HT-29裸小鼠移植瘤的療效 1、實驗動物： BALB/cA-mide裸小鼠’早’5-6周齡，購自上海斯萊 克實驗動物有限責任公司。合格證號：SCXK (濃）20〇4 -0005。飼養環境：SPF級》 2、實驗步驟： 動物經1周適應後，皮下接種人結腸癌HT_29瘤塊組 織，待腫瘤生長至300-600mm3後，將動物隨機分組（d〇)投 藥。化合物A和PTK787均為75mg/kg ’ 口服投藥（灌胃）， d〇-dl7,每天！次，共18次；奥沙利麵6叫心，靜脈注 射，d0，d4，d8，共3次。合用時’化合物a和ρτΚ787分 別與奥沙利鉑合用，投藥劑量和投藥方案不變。每週測2 3人瘤體積，稱鼠重，s己錄資料。腫瘤體積（ν)計算公 式為： 〇分別录示長 '寬 3、結果： [S1 本次實驗的目的主要是評價並比較化合物A、奥沙; 翻與PTK787合用對晚期結腸癌模型的療效，因此，、本: 實驗投藥開始時腫瘤體積較大，平均在4〇〇mm3以上，> 於晚期踵瘤模型。奥沙利翻是一線治療晚期結腸癌的主」 樂物’因此，選用奥沙❹作為併用藥。可以看出，奥$ 利麵已經達到其最大耐受劑量，在此劑量下，奥沙糊 夠抑制結腸癌則的生長(p<〇.〇5 vs㈣；化合物A PTK787分別與奥沙利韵合用後，療效均有不同程度地^ 29 201121547 高，二者均顯示出良好的合用基礎；其中尤以化合物A提 高療效較明顯，合用後的療效明顯優於單用化合物A或奥 沙利鉑時的療效。具體實驗結果參照表4。 【表4】化合物A、奥沙利鉑單用或與PTK787合用 對人結腸癌HT-29裸小鼠移植瘤的療效 組別 劑量 動物數 去瘤後體 TV RTV T/C (%) (投藥） (mg/ 重（克） x 士 SD X 士 SD kg) d0 dn d0 dn d0 dn 對照 12 12 19.5 17.5 445±1〇6 2110士577 4.90 土 1.29 化合物A 75 6 6 19.1 17.9 435±51 1215土255 2.79±0,52 56.9a (ρ·ο) PTK787(p.o)+ 75 6 6 19.3 16.7 489±72 1363士228 2.83±0.58 57.8a 奧沙利始(i.v) 化合物A 6 75 6 6 19.7 16.6 520±67 1047士256 2.03±0.51 41.4^ (p.o)+奥沙利 ίό(ϊ.ν) 6 奥沙利舶(i.v) 6 6 6 18.7 14.6 431±79 1351 士 110 3.23士0.65 65.9° d0 ： 分籠投藥時間； dn · 第1次投藥後 19天； aP<0.05 vs對照 ；bP<0 .05 VS 奥沙利始。 【實施例5】化合物A單用或與阿黴素（ADR)、多西 他賽合用對人非小細胞肺癌NCI-H460裸小鼠移植瘤的療 • 效 1、 實驗動物： BALB/cA-nude裸小鼠，早，5-6周齡，購自上海斯萊 克實驗動物有限責任公司。合格證號：SCXK (滬）2004 -0005。飼養環境：SPF級。 2、 實驗步驟： 動物經1周適應後，皮下接種人非小細胞肺癌NCI-H460瘤塊組織，待腫瘤生長至100— 300mm3後，將動物 隨機分組（d0)。投藥劑量化合物A、PTK787均為150mg/kg， 30 201121547 句口服投藥（灌胃），d0-dl3天，每天1次，共14次。多西 他赛单用12mg/kg，d0，d4，d8，靜脈注射，共3次；阿黴 素單用l〇mg/kg ’ d0，靜脈注射，共i次。合用時，投藥 劑量和投藥時間與單用相同。每週測2 — 3次瘤體積，稱 鼠重，記錄資料。腫瘤體積（V )計算公式為： V- l/2xaxb2 其中a、b分別表示長、寬。 3、結果：The particular choice of compound of formula 1 and anti-proliferation will depend on the attending physician's and appropriate treatment regimen. The cytotoxic substances or the radiological diagnosis and the judgment of the treatment of the patient's condition or the administration of the drug at the same time, then:::...the treatment can not change the AI compound, as well as the chemotherapeutic agent and / or radiation therapy The beginning of the m T7U person a (four) the beginning - the human order. Therefore, for example, you can first: enter the compound of the drug, and then the drug for the treatment; or you can first push the am / time to the drug, and then ... and the radiation therapy can be repeated. #4 /, in the material-treatment plan to evaluate the situation (4) * the disease and the patient's sputum in the case of the disease, after the sub-estimation, the number of times the drug is administered repeatedly, the number of times the drug is administered repeatedly The S3 number of Hungarian is known to skilled clinicians [24 201121547 skills. For example, administration of an antitumor agent and/or radiation therapy may be performed first, especially if the cytotoxic substance is used. The treatment is then continued with administration of the compound of formula I and the cytostatic agent can then be administered as needed or not until the end of the treatment regimen. Therefore, based on experience and knowledge, as the treatment progresses, the practitioner can apply the treatment component (therapeutic agent, compound, antitumor agent, or radiation therapy) according to the needs of each patient. to modify. In determining whether the treatment is effective at the dose, the squad will consider the patient's general health and more specific signs such as relief of symptoms associated with the disease, inhibition of tumor growth, actual contraction of the tumor, or inhibition of metastasis. Tumor size can be measured by standard methods such as radiological studies, such as CAT or MRI scans, and continuous assays can be used to determine if tumor growth is prevented or even reversed. Disease-related symptoms such as pain relief and improvement in overall condition can also be used to help judge the efficacy of the treatment. It has been found through experiments that the guanidine compound or its pharmaceutically acceptable salt can improve the therapeutic effect when used in combination with other anti-proliferative drugs, especially for microtubule affecting agents, antimetabolites, antibiotic antitumor drugs, and platinum coordination. Compounds of these classes. [Embodiment] In order to further understand the present invention, the following embodiments are given to explain the present invention in more detail. The scope of the present invention is not to be construed as being limited by the examples, and the present invention includes all subject matter defined in the scope of the claims. [Scheme 1] Preparation of Compound A (Ceramic acid salt of a hydrazine compound) [Gate 25 201121547 In a 5L reaction bottle, input type! Compound 17〇g(〇428m〇i), 42.5g (〇.442mol) of decanesulfonic acid, 2 55L of 95〇/〇 isopropanol aqueous solution, heated to full solubility under nitrogen protection and protected from light, light The yellow transparent solution was filtered while hot, cooled and crystallized to room temperature, filtered, washed with isopropyl alcohol and dried in vacuo to give white needle crystals (yield: s. In a 5 L reaction flask, a compound a 18 〇 2 g, a %% isopropyl alcohol aqueous solution of 2.52 L was placed, and the mixture was heated under nitrogen to be completely dissolved in the dark, and filtered while hot, and the filtrate was cooled to room temperature, filtered, and filtered. The propanol was washed and vacuum-dried to obtain 161.5 g of white needle crystals, and the yield was 89.6%. Melting range: 193.5 ~ 195. (:. 2) Example 2: Compound A alone or in combination with oxaliplatin for the treatment of human colon cancer Ls 1 74t nude mice xenografts. Compound A is the formate salt of the compound of formula I, 1. Experimental animals: BALB/cA-nude nude mice, half, 5-6 weeks old, purchased from Shanghai Slack Laboratory Animals Co., Ltd. Certificate No.: SCXK (Shanghai) 2004 Ring-0005. Feeding environment: SPF 2. Experimental procedure: After 1 week of adaptation, the animals were subcutaneously inoculated with human colon cancer Lsl74t tumor tissue 'after the tumor was grown to 150-300 mm3', and the animals were randomly divided into groups (d〇). Compound A and PTK787 were both. 75mg/kg, oral administration (gavage), d〇_d13 '1 time a day, 14 times; oxaliplatin 6mg/kg, intravenous, d0, d4, d8, a total of 3 times. In combination, compound A And pTK787 [S] is not combined with oxaliplatin, the dosage and administration schedule are unchanged. The tumor volume is measured 2-3 times a week, the weight of the mouse is weighed, and the data is recorded. The tumor volume (ν) is calculated as 26 201121547 V= l/2xaxb2 where a and b represent length and width, respectively. 3. Results: Compound A, oxaliplatin alone The growth of intestinal cancer Lsl74t was inhibited to a certain extent, and compound A was the best, better than oxaliplatin, and the maintenance time was relatively long. PTK787, compound A and oxaliplatin combined, both can be synergistic The effect of oxaliplatin; compound A + oxaliplatin was significantly better than PTK787 + oxaliplatin, and the synergistic effect of compound A was significantly better than PTK787. The specific experimental results are shown in Table 2. [Table 2] Compounds A, oxaliplatin alone or in combination with PTK787 for human colon cancer Ls 174t nude mice xenografts (dosing) dose (mg / kg) number of animals d0 dn post-tumor weight (g) d0 dn TV x Shi SD d0 dn RTV x soil SD T/C (%) Control 12 12 20.5 16.6 204±63 2983±732 15.6±5.22 Compound A (po) 75 6 6 20.8 18.6 192 士 54 1662±349 9.21 士2.94 59.0° PTK787(po)+ Oxali chain (iv) 75 6 6 5 21.6 16.2 223±49 1689±323 8.06±2.17 51.7a Compound A (po) + oxaliplatin (iv) 75 6 6 6 20.5 16.6 208± 63 1154士291 5.85±1.92 37.5^ b Oxali I6(iv) 6 6 6 20.9 15.8 221士79 2157 soil 376 10.6±3.86 68.5a d0 : divided into cages Time; dn: 14 days after the first administration; aP < 0.05 vs control; bP < 0.05 vs Oxley rhyme. [Example 3] Compound A alone or in combination with 5-Fu for human colon cancer Lsl74t nude mice xenografts 1. Experimental animals: BALB/cA-nude nude mice, early, 5-6 weeks old, purchased Since Shanghai Slack Laboratory Animals LLC. Certificate No.: SCXK (Shanghai) 2004 S S1 27 201121547 —0005. Feeding environment: SPF level. 2. Experimental procedure: After 1 week of adaptation, the animals were subcutaneously inoculated with human colon cancer Lsl74t tumor tissue. After the tumor grew to 150-300 mm3, the animals were randomly divided into groups (d0). Compound A and PTK7 87 were both 75 mg/kg, orally administered (stomach), d0-dl3, once a day for 14 times; 5-Fu 50 mg/kg, intraperitoneal injection, d0, d4, d8, 3 times in total. When used in combination, Compound A and PTK787 were combined with 5-Fu, respectively, and the dosage and administration schedule were unchanged. Measure the tumor volume 2 to 3 times a week, • Weigh the rats and record the data. The tumor volume (V) is calculated as: V = l/2xaxb2 where a and b represent length and width, respectively. 3. Results: Compound A and 5-Fu alone inhibited the growth of human colon cancer Lsl74t to a certain extent, and compound A had the best effect, which was equivalent to 5-Fu. Compound A, PTK787 and 5-Fu can enhance the effect of 5-Fu after combination; the effect of compound A +5-Fu is better than that of PTK787 + 5-Fu, and the synergistic effect of compound A on 5-Fu PTK787 is more obvious. The specific experimental results are referred to Table 3. [Table 3] Compound A, 5-Fu alone or in combination with PTK787 for human colon cancer Ls 1 74t nude mice xenografts, control dose, mg/kg, number of mice (only) DO D14 11 11 weight after tumor removal (g) DO D14 18.6 14.3 TV (X Shi SD) DO D14 168 soil 21 2488 ± 622 RTV (x ± SD) 14.8 ± 3.0 T / C % Compound A 75 5 5 18.4 17.0 182 ± 18 1580 ± 333 8.9 ± 2.7 6〇.r compound 75 5 5 19.3 16.8 194 soil 16 1130±258 5.9±1.8* 39.9^ A + 5-Fu 50 PTK787 75 5 5 19.3 17.5 156±29 1380 673 8.5±3.4 57.4a + 5-Fu 50 5-Fu 50 5 5 18.7 14.3 181±25 1567±210 9.2 Soil 2.0 62.5a P<0.01 vs control; bP<0·05 vs. Compound A or 5-Fu alone. 28 201121547 [Example 4] Effect of Compound A alone or in combination with oxaliplatin on human colon cancer HT-29 nude mice xenografts 1. Experimental animals: BALB/cA-mide nude mice 'early' 5- 6 weeks old, purchased from Shanghai Slack Laboratory Animals Co., Ltd. Certificate No.: SCXK (concentrated) 20〇4 -0005. Breeding environment: SPF level 2. Experimental procedure: After 1 week of adaptation, the animals were subcutaneously inoculated with human colon cancer HT_29 tumor tissue. After the tumor grew to 300-600 mm3, the animals were randomly divided into groups (d〇). Both Compound A and PTK787 are 75 mg/kg ‘ Oral Administration (Gavage), d〇-dl7, daily! Times, a total of 18 times; Osali face 6 call heart, intravenous injection, d0, d4, d8, a total of 3 times. When used together, compound a and ρτΚ787 were combined with oxaliplatin, and the dosage and administration schedule were unchanged. The tumor volume of 2 3 people was measured every week, and the rats were weighed. The tumor volume (ν) is calculated as: 〇 Record length 'width 3, respectively. Results: [S1 The purpose of this experiment is mainly to evaluate and compare compound A, Osa; and the effect of combination with PTK787 on advanced colon cancer model, Therefore, this: The tumor volume at the beginning of the experimental administration is larger, with an average of more than 4〇〇mm3, > in the advanced tumor model. Oxali is the first line of treatment for advanced colon cancer. Therefore, oxalatine is used as a combination. It can be seen that O. sinensis has reached its maximum tolerated dose. At this dose, Osa paste inhibits the growth of colon cancer (p<〇.〇5 vs (4); Compound A PTK787 is combined with Oxali rhyme, respectively. Afterwards, the curative effect was high in different degrees, 2011 21547, both of which showed a good basis for combination; especially in the case of compound A, the curative effect was more obvious, and the effect after combination was significantly better than that of compound A or oxaliplatin alone. The specific experimental results are shown in Table 4. [Table 4] Compound A, oxaliplatin alone or in combination with PTK787 for human colon cancer HT-29 nude mice xenografts TV RTV T/C (%) (dosing) (mg/weight (g) x SD SD X SD kg) d0 dn d0 dn d0 dn Control 12 12 19.5 17.5 445±1〇6 2110士577 4.90 Earth 1.29 Compound A 75 6 6 19.1 17.9 435±51 1215 soil 255 2.79±0,52 56.9a (ρ·ο) PTK787(po)+ 75 6 6 19.3 16.7 489±72 1363士228 2.83±0.58 57.8a Oxali beginning (iv ) Compound A 6 75 6 6 19.7 16.6 520±67 1047士256 2.03±0.51 41.4^ (po)+Oxaliίό(ϊ.ν) 6 Oxley (iv) 6 6 6 18.7 14.6 431±79 1351 ± 110 3.23 ± 0.65 65.9 ° d0 : splitting time; dn · 19 days after the first dose; aP < 0.05 vs control; bP < 0 . 05 VS Oxali begins. [Example 5] Compound A alone or in combination with doxorubicin (ADR) and docetaxel for the treatment of human non-small cell lung cancer NCI-H460 nude mice xenografts1 Experimental animals: BALB/cA-nude nude mice, early, 5-6 weeks old, purchased from Shanghai Slack Laboratory Animals Co., Ltd. Certificate No.: SCXK (Shanghai) 2004-0005. Feeding environment: SPF level. 2 Experimental procedure: After 1 week of adaptation, the animals were subcutaneously inoculated with NCI-H460 tumor tissue of non-small cell lung cancer. After the tumor grew to 100-300 mm3, the animals were randomly divided into groups (d0). The doses of compound A and PTK787 were all administered. 150mg/kg, 30 201121547 sentence oral administration (gavage), d0-dl3 days, once a day, a total of 14 times. Docetaxel alone was administered intravenously for 12 times with 12 mg/kg, d0, d4, and d8; amylomycin alone was administered with l〇mg/kg ‘d0, intravenously for a total of i times. When used together, the dosage and administration time are the same as for single use. The tumor volume was measured 2-3 times a week, the rats were weighed, and the data were recorded. The tumor volume (V) is calculated as: V- l/2xaxb2 where a and b represent length and width, respectively. 3. Results:
瞭解化合物A與傳統細胞毒藥物合用時的療效及毒性 有較大的臨床意義。本實驗選用臨床上常用的細胞毒藥物 阿黴素和多西他賽進行研究。阿黴素是拓撲異構酶π抑制 劑，小鼠靜脈投藥的最大耐受量為1〇mg/kg;多西他賽是 $微管藥物，小鼠靜脈投藥的最大耐受劑量為i2mg/kg〇 =面實驗發現化合物A 200mg/kg投藥時小鼠仍能較佳耐 受，但考慮到與細胞毒類藥物合用α及療效㈣的敏感性 問題，我們把化合物Α的劑量減少到15〇mg/kg，並將其與 阿黴素和多西他賽的最大耐受劑量進行合用。 可以看出，阿黴素已經達到了其最大耐受劑量，化合 物A和PTK787與其合用均沒有增加其毒性，相反地，如 表5中所示化合物Α似乎具有改善其毒性的效果。化合物 A阿黴素單用即明顯抑制人肺癌的生長（p<〇 vs。對照）’合用後’療效賴提高；合用時療效均 於早樂（P<G.0l vs #藥），根據計算，合用具有協同作用。 與ptK787比較，化合物A與⑽素合㈣的 於打k787(p<g.G5)。具體實驗結果參照表5。月顯優 ί S1 可以看出，多西他賽已經達到其毒性劑量。同樣地， 31 201121547 化合物A和PTK787與其合用均沒有增加其毒性，相反地， 如表6中所示化合物A似乎具有改善其毒性的效果。化合 物A、多西他赛單用即明顯抑制人肺癌NCI-H460的生長 (P<0.01 vs對照）。與阿黴素類似，化合物a、PTK787與 多西他賽合用後，療效明顯提高；合用時療效均明顯大於 單藥（Ρ<0·01 vs單藥），根據計算，合用具有協同作用。與 ΡΤΚ787比較，化合物Α與多西他赛合用時的療效明顯優 於PTK787(P<0.01)。具體實驗結果參照表6。 # 【表5】化合物A，ADR單用或與ΡΤΚ787合用對人非 小細胞肺癌NCI-H460裸小鼠移植瘤的療效_ 組別 ^)1 石物數~~去瘤後體重 TV RTV T/C (%)It is of great clinical significance to understand the efficacy and toxicity of Compound A in combination with traditional cytotoxic drugs. In this experiment, the clinically commonly used cytotoxic drugs, doxorubicin and docetaxel, were used for the study. Doxorubicin is a topoisomerase π inhibitor. The maximum tolerated dose of intravenous administration in mice is 1〇mg/kg. Docetaxel is a microtubule drug. The maximum tolerated dose for intravenous administration in mice is i2mg/ The kg〇=face test found that the compound A was still better tolerated when the drug was administered at 200 mg/kg. However, considering the sensitivity of the combination of cytotoxic drugs with α and efficacy (4), we reduced the dose of the compound 〇 to 15〇. Mg/kg and combine it with the maximum tolerated dose of doxorubicin and docetaxel. It can be seen that doxorubicin has reached its maximum tolerated dose, and neither Compound A nor PTK787 has increased its toxicity. Conversely, the compound oxime shown in Table 5 seems to have an effect of improving its toxicity. Compound A doxorubicin alone significantly inhibited the growth of human lung cancer (p<〇vs. control) 'after combination' efficacy improvement; combined use of the effect in early music (P < G.0l vs # medicine), according to calculation , the combination has a synergistic effect. Compound A was combined with (10) and (4) to k787 (p<g.G5) compared to ptK787. The specific experimental results are shown in Table 5. Yue Xianyou ί S1 It can be seen that docetaxel has reached its toxic dose. Similarly, 31 201121547 Compound A and PTK787 did not increase their toxicity, and conversely, Compound A as shown in Table 6 appeared to have an effect of improving its toxicity. Compound A and docetaxel alone significantly inhibited the growth of human lung cancer NCI-H460 (P<0.01 vs control). Similar to doxorubicin, compound a, PTK787 and docetaxel combined significantly improved efficacy; combined efficacy was significantly greater than single drug (Ρ < 0 · 01 vs single drug), according to calculations, synergy. Compared with ΡΤΚ787, the combination of compound 多 and docetaxel was superior to PTK787 (P<0.01). The specific experimental results are shown in Table 6. # [Table 5] Compound A, ADR alone or in combination with ΡΤΚ787 for human non-small cell lung cancer NCI-H460 nude mice xenografts _ group ^) 1 stone number ~ ~ after tumor weight TV RTV T / C (%)
(mg/kg (克） x±SD x±SD d0 dn d0 dn dO dn 對照 12 19.1 17.4 74±12 1360±419 18.5±5.4 化合物A 12 150 6 6 18.0 17.2 82±22 625±137 8.0±2.6 43.2^ 化合物A + 150 6 6 18.7 17.8 78±7 254±71 3.3±0.9 17.8-^ ADR PTK787 + 10 150 6 6 18.8 17.1 79±8 380±148 4.9 士 2.3 26.5^ ADR ADR 10 10 6 6 18.0 16.8 63±14 523±155 8.6±3.3 46.5a d0 :分籠投藥時間；dn : 第1次投藥後 14天。 aP<0.01 vs 對照；b P<0.01 vs化合物 A 150 m g/kg單用時；e P<0.01 vs ADR 單用時；dp<〇.〇5 vs PTK787+ADR 組。 【表6】化合物A，多西他賽單用或與PTK787合用對 人非小細胞肺癌NCI-H460裸小鼠移植瘤的療效 組別 劑量 (mg/kg 動物數 去瘤後體重 (克） TV x土 SD RTV x士SD T/C (%) ) dO dn dO dn d0 dn 對照 12 19.1 17.4 74±12 1360±419 18.5±5.4 化合物A 150 12 6 6 18.0 17.2 82±22 625±137 8.0±2.6 43.2^ 化合物A + 150 6 6 19.2 14.9 84±12 176±58 2.2±1.0 11.9^ IS] 32 201121547 多西他賽 12 PTK787 + 150 6 6 18.2 13.5 72±7 279±92 3.9士 1.4 21.1^ 多西他賽 12 多西他賽 12 6 6 18.0 12.8 76±12 552±116 7.4±2.2 40.0a do:分籠投藥時間；dn:第1次投藥後14天。aP<0.01 vs 對照；bP<〇·〇 1 vs 化合物 A 1 50 mg/kg 單用時；CP<0.01 vs 多 西他赛單用時；dP<〇.〇5 vs PTK7 87 +多西他賽組。(mg/kg (g) x±SD x±SD d0 dn d0 dn dO dn Control 12 19.1 17.4 74±12 1360±419 18.5±5.4 Compound A 12 150 6 6 18.0 17.2 82±22 625±137 8.0±2.6 43.2 ^ Compound A + 150 6 6 18.7 17.8 78±7 254±71 3.3±0.9 17.8-^ ADR PTK787 + 10 150 6 6 18.8 17.1 79±8 380±148 4.9 ± 2.3 26.5^ ADR ADR 10 10 6 6 18.0 16.8 63 ±14 523±155 8.6±3.3 46.5a d0 : time of administration in cages; dn: 14 days after the first administration. aP<0.01 vs control; b P<0.01 vs compound A 150 mg/kg when used alone; e P< 0.01 vs ADR alone; dp<〇.〇5 vs PTK787+ADR group. [Table 6] Compound A, docetaxel alone or in combination with PTK787 for human non-small cell lung cancer NCI-H460 nude mice Tumor efficacy group dose (mg/kg number of animals after tumor weight (g) TV x soil SD RTV x SD T/C (%) ) dO dn dO dn d0 dn control 12 19.1 17.4 74±12 1360±419 18.5±5.4 Compound A 150 12 6 6 18.0 17.2 82±22 625±137 8.0±2.6 43.2^ Compound A + 150 6 6 19.2 14.9 84±12 176±58 2.2±1.0 11.9^ IS] 32 201121547 Docetaxel 12 PTK787 + 150 6 6 18.2 13.5 72±7 279±92 3.9 ± 1.4 21.1^ Docetaxel 12 Docetaxel 12 6 6 18.0 12.8 76±12 552±116 7.4±2.2 40.0a do: splitting time; dn: 14 days after one administration. aP<0.01 vs control; bP<〇·〇1 vs compound A 1 50 mg/kg when used alone; CP<0.01 vs docetaxel alone; dP<〇.〇5 vs PTK7 87 + Docetaxel group.
ESI 33ESI 33
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW098144691A TWI528960B (en) | 2009-12-24 | 2009-12-24 | Pharmaceutical composition for the treatment of proliferative diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW098144691A TWI528960B (en) | 2009-12-24 | 2009-12-24 | Pharmaceutical composition for the treatment of proliferative diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201121547A true TW201121547A (en) | 2011-07-01 |
| TWI528960B TWI528960B (en) | 2016-04-11 |
Family
ID=45045652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW098144691A TWI528960B (en) | 2009-12-24 | 2009-12-24 | Pharmaceutical composition for the treatment of proliferative diseases |
Country Status (1)
| Country | Link |
|---|---|
| TW (1) | TWI528960B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2777519C2 (en) * | 2017-12-06 | 2022-08-05 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Use of parp inhibitor in treatment of chemotherapy-resistant ovarian cancer or breast cancer |
-
2009
- 2009-12-24 TW TW098144691A patent/TWI528960B/en active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2777519C2 (en) * | 2017-12-06 | 2022-08-05 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Use of parp inhibitor in treatment of chemotherapy-resistant ovarian cancer or breast cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| TWI528960B (en) | 2016-04-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2010031265A1 (en) | Pharmaceutical composition for the treatment of proliferative diseases | |
| RU2429838C2 (en) | Combined chemotherapy | |
| US11938124B2 (en) | Combination therapy for treatment of cancer | |
| TW200533339A (en) | Therapeutic synergy of anti-cancer compounds | |
| CN101849943A (en) | Use the improved treatment for anemia of HIF alpha stabilizers | |
| TW201206441A (en) | New combination therapy in treatment of oncological and fibrotic diseases | |
| TWI685341B (en) | Use of combination of apatinib and c-met inhibitor in the preparation of medicament for treating tumor | |
| TWI762784B (en) | Use of cdk4/6 inhibitor in combination with egfr inhibitor for preparation of medicament for treating tumor diseases | |
| JP2003533485A5 (en) | ||
| EP2254570B1 (en) | Combination comprising paclitaxel for treating ovarian cancer | |
| ES2946472T3 (en) | Antitumor agent and enhancer of antitumor effect | |
| KR20220003560A (en) | A quinoline compound or a pharmaceutically acceptable salt thereof for the treatment of Ewing's sarcoma | |
| JP7008025B2 (en) | Anti-tumor agent, anti-tumor effect enhancer and anti-tumor kit | |
| MXPA06013902A (en) | Method for treating abnormal cell growth. | |
| WO2016032882A1 (en) | Inhibition of mk2 in the treatment of cancer | |
| MX2007013830A (en) | Combination therapy. | |
| TW202002989A (en) | Antitumor agent, antitumor effect potentiator and antitumor kit | |
| US20230226040A1 (en) | Combination therapy comprising an fgfr inhibitor and a kras inhibitor | |
| JP2020528418A (en) | Combination therapy with BET inhibitors and Bcl-2 inhibitors | |
| TW201343169A (en) | Methods of treating cancer using Aurora kinase inhibitors | |
| TW202019412A (en) | Combination of poziotinib with cytotoxic agent and/or other molecularly targeted agent and use thereof | |
| CN111989092A (en) | Combination therapy of BET inhibitors and proteasome inhibitors | |
| NZ533940A (en) | Combinations comprising epothilones and anti-metabolites | |
| TW202227090A (en) | Pharmaceutical compositions of tetracyclic quinolone analogs and their salts | |
| TW201121547A (en) | Pharmaceutical composition for the treatment of proliferative diseases |