TW201420102A - Combination therapy - Google Patents
Combination therapy Download PDFInfo
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- TW201420102A TW201420102A TW102136618A TW102136618A TW201420102A TW 201420102 A TW201420102 A TW 201420102A TW 102136618 A TW102136618 A TW 102136618A TW 102136618 A TW102136618 A TW 102136618A TW 201420102 A TW201420102 A TW 201420102A
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
Description
本發明係關於醫藥組合,其包含(a)至少一種靶向/降低蛋白質或脂質激酶活性之受體酪胺酸激酶(RTK)抑制劑化合物,該化合物選自由以下組成之群:式I化合物或其互變異構物、式II化合物或其互變異構物、式III化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物;及(b)一或多種CYP17抑制劑或其醫藥上可接受之鹽,例如(3β)-17-(吡啶-3-基)雄甾-5,16-二烯-3-醇(阿比特龍,abiraterone)、乙酸阿比特龍、1-(2-氯-吡啶-4-基)-3-(4-甲基-吡啶-3-基)-咪唑啶-2-酮、酮康唑(ketoconazole)或VN/124-1(TOK-001);此組合在治療或預防增殖性疾病(例如***癌)中之用途;及治療罹患增殖性疾病之個體之方法,其包含投與治療有效量之此組合。 The present invention relates to a pharmaceutical combination comprising (a) at least one receptor tyrosine kinase (RTK) inhibitor compound that targets/reduces protein or lipid kinase activity, the compound being selected from the group consisting of: a compound of formula I or a tautomer thereof, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or And (b) one or more CYP17 inhibitors or pharmaceutically acceptable salts thereof, for example, (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (A Bitron, abiraterone), abiraterone acetate, 1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one, ketoconazole (ketoconazole) or VN/124-1 (TOK-001); use of the combination for treating or preventing a proliferative disease (such as prostate cancer); and a method for treating an individual suffering from a proliferative disease, comprising administering a therapeutically effective This combination of quantities.
利用醫學去勢(例如利用LHRH激動劑)之標準一線雄激素去除療法(ADT)最初誘導80%至90%的晚期***癌患者之緩解。在醫學去勢惡化後,通常可利用習用二線激素消融療法(包括非類固醇抗雄激素(例如比卡魯胺(bicalutamide))、酮康唑及DES)將患者「重新誘導」為緩解。成功地施加一系列的雄激素消融療法達成12至33個月之中值無惡化存活期,此時抗去勢表型佔優勢。***癌優先轉移至骨骼,該***癌在其中誘發可產生顯著疼痛、全身症狀、貧血及死亡之成 骨性反應。直至最近,在用完標準雄激素消融療法後,除細胞毒性化學療法外,轉移性抗去勢***癌(mCRPC)患者幾乎別無選擇。然而,遺憾的是,化學療法僅產生適度存活益處且與顯著毒性相關。 Standard first-line androgen removal therapy (ADT) using medical castration (eg, using LHRH agonists) initially induces remission in 80% to 90% of patients with advanced prostate cancer. After the deterioration of medical castration, patients can usually be "re-induced" into remission by conventional second-line hormone ablation therapy (including non-steroidal antiandrogens (such as bicalutamide), ketoconazole, and DES). Successfully applied a series of androgen ablation therapy to achieve a median of 12 to 33 months without worsening survival, when the anti-castrated phenotype dominated. Prostate cancer is preferentially transferred to the bone, which induces significant pain, systemic symptoms, anemia, and death. Bone reaction. Until recently, in addition to cytotoxic chemotherapy, patients with metastatic anti-castration prostate cancer (mCRPC) had little choice after using standard androgen ablation therapy. However, unfortunately, chemotherapy only produces moderate survival benefits and is associated with significant toxicity.
直至最近,當關於基礎***癌生物學之深入瞭解促使合理整合涉及抗去勢疾病發展之關鍵促生長途徑之新穎「靶向」藥劑時,對推進除化學療法以外之療法選項之努力所取得的成功甚少。自轉譯研究已顯現三個主要觀點: Until recently, when the in-depth understanding of basic prostate cancer biology led to the rational integration of novel "targeted" agents involved in key growth-promoting pathways for the development of anti-castration disease, the success of efforts to advance treatment options other than chemotherapy Very little. Self-translating research has revealed three main points:
1)在抗去勢疾病演變期間,雄激素生物合成自內分泌源(睪丸及腎上腺)轉移至腫瘤-骨微環境內之旁分泌/自分泌源。雄激素之腫瘤內產生(以及內分泌)受到諸如阿比特龍等新穎CYP17抑制劑有效抑制。 1) During the evolution of anti-castration disease, androgen biosynthesis is transferred from endocrine sources (test pills and adrenal glands) to paracrine/autocrine sources in the tumor-bone microenvironment. Intratumoral production of androgen (and endocrine) is effectively inhibited by novel CYP17 inhibitors such as abiraterone.
2)參與正常***脂質體發育之雄激素受體(AR)獨立性「間質-上皮」生長信號傳導途徑在抗去勢疾病演變期間頻繁地變得失調。此等途徑之實例包括c-Met、NOTCH及FGF信號傳導。該等途徑呈現小分子治療劑之新穎靶標。 2) Androgen Receptor (AR) independence involved in normal prostate liposome development The "mesenchymal-epithelial" growth signaling pathway frequently becomes dysregulated during the development of anti-castration disease. Examples of such pathways include c-Met, NOTCH, and FGF signaling. These pathways present novel targets for small molecule therapeutics.
3)阻斷間質-上皮交互作用途徑之藥劑之相對適度有效性表明,持久腫瘤內雄激素信號傳導係驅動骨中抗去勢生長之優勢存活途徑。此推理線路已引出以下假設,對腫瘤內雄激素信號傳導進行有效抑制應為靶向間質-上皮交互作用途徑之小分子治療劑之合理組合策略的關鍵態樣。 3) The relatively modest effectiveness of agents that block the interstitial-epithelial interaction pathway suggests that prolonged intratumoral androgen signaling drives the dominant survival pathway for anti-castration growth in bone. This line of reasoning has led to the hypothesis that effective inhibition of androgen signaling in tumors should be a key aspect of a rational combination strategy for small molecule therapeutics that target the interstitial-epithelial interaction pathway.
阿比特龍最近已經FDA批準用於治療已在隨機處理III期研究中顯示延長總體存活後預先接受多西他賽(docetaxel)之mCRPC患者。在12.8個月之中值隨訪後,阿比特龍-普賴松(prednisone)組之總體存活長於安慰劑-普賴松組(14.8個月對10.9個月;危害比,0.65;95%信賴區間,0.54至0.77;P<0.001)。儘管有該等令人鼓舞之結果,但多達1/3患者似乎對阿比特龍並無反應且剩餘70%最終將惡化。對腫瘤浸潤之骨髓生檢之分子病理學分析揭示,AR之均勻強烈的核表現連同 >10% CYP17腫瘤表現與較長治療停止時間(>4個月)相關聯。總之,該等發現表明,雄激素受體(AR)獨立性生長途徑促進在投與阿比特龍後抗去勢生長。 Abirate has recently been approved by the FDA for the treatment of mCRPC patients who have previously received docetaxel after a prolonged overall survival in a randomized phase III study. After a median follow-up of 12.8 months, the overall survival of the abiraterone-prednisone group was longer than that of the placebo-Pryson group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval) , 0.54 to 0.77; P < 0.001). Despite these encouraging results, as many as one-third of patients seem to have no response to Abitrone and the remaining 70% will eventually deteriorate. Molecular pathology analysis of bone marrow biopsy for tumor infiltration reveals that AR has a uniform and strong nuclear performance along with >10% CYP17 tumor performance was associated with longer treatment cessation (>4 months). Taken together, these findings indicate that the androgen receptor (AR) independent growth pathway promotes anti-castration growth after administration of abiraterone.
式I、式II及式III化合物抑制各種蛋白質激酶,例如受體酪胺酸激酶(RTK)。受體酪胺酸激酶(RTK)係調控成人組織之發育性細胞生長及分化、重塑及再生之跨膜多肽。已知稱為生長因子或細胞介素之多肽配體活化RTK。信號傳導RTK涉及配體結合及受體之外部結構域中之構象轉變,從而導致其二聚化。配體結合至RTK使特定酪胺酸殘基發生受體轉磷酸並且隨後活化用於使細胞質受質之磷酸化之催化結構域。 The compounds of Formula I, Formula II, and Formula III inhibit various protein kinases, such as the receptor tyrosine kinase (RTK). Receptor tyrosine kinase (RTK) is a transmembrane polypeptide that regulates the developmental cell growth, differentiation, remodeling and regeneration of adult tissues. A polypeptide ligand known as a growth factor or interleukin is known to activate RTK. Signaling RTK is involved in ligand binding and conformational transitions in the outer domain of the receptor, resulting in its dimerization. Binding of the ligand to the RTK causes the specific tyramine residue to undergo transphosphorylation and subsequent activation of the catalytic domain for phosphorylation of the cytoplasmic material.
兩個RTK亞家族對血管內皮具有特異性。該等包括血管內皮生長因子(VEGF)亞家族及Tie受體亞家族。III類RTK包括血管內皮生長因子受體1(VEGFR-1)、血管內皮生長因子受體2(VEGFR-2)及血管內皮生長因子受體3(VEGFR-3)。 Two RTK subfamilies are specific for vascular endothelium. These include the vascular endothelial growth factor (VEGF) subfamily and the Tie receptor subfamily. Class III RTKs include vascular endothelial growth factor receptor 1 (VEGFR-1), vascular endothelial growth factor receptor 2 (VEGFR-2), and vascular endothelial growth factor receptor 3 (VEGFR-3).
受抑制之酪胺酸激酶包括Cdc2激酶(細胞***週期2激酶)、Fyn(與SRC、FGR、YES有關之FYN致癌基因激酶)、Lck(淋巴球特異性蛋白質酪胺酸激酶)、c-Kit(幹細胞因子受體或肥大細胞生長因子受體)、p60src(最初鑑別為勞斯(rous)肉瘤病毒之v-src致癌基因之酪胺酸激酶)、c-ABL(代表最初自艾德森(Adelson)白血病病毒分離之致癌基因產物之酪胺酸激酶)、VEGFR3、PDGFRα(血小板源生長因子受體α)、PDGFRβ(血小板源生長因子受體β)、FGFR3(纖維母細胞生長因子受體3)、FLT-3(fms樣酪胺酸激酶-3)或Tie-2(具有lg及EGF同源結構域之酪胺酸激酶)。 Inhibited tyrosine kinases include Cdc2 kinase (cell division cycle 2 kinase), Fyn (FYN oncogene kinase associated with SRC, FGR, YES), Lck (lymphocyte-specific protein tyrosine kinase), c-Kit (stem cell factor receptor or mast cell growth factor receptor), p60src (originally identified as the tyrosine kinase of the v-src oncogene of the rous sarcoma virus), c-ABL (representing the original from Adelson ( Adelson) tyrosine kinases of oncogene products isolated from leukemia virus, VEGFR3, PDGFRα (platelet-derived growth factor receptor alpha), PDGFRβ (platelet-derived growth factor receptor beta), FGFR3 (fibroblast growth factor receptor 3) ), FLT-3 (fms-like tyrosine kinase-3) or Tie-2 (tyrosine kinase with lg and EGF homology domains).
已發現包含以下之醫藥組合藉由抑制FGF(促成阿比特龍抗性之AR獨立性信號傳導途徑)來改良CYP17抑制劑(例如阿比特龍)之抗腫瘤活性:(a)至少一種靶向/降低蛋白質或脂質激酶活性之受體酪胺酸 激酶(RTK)抑制劑化合物,該化合物選自由以下組成之群:式I化合物或其互變異構物、式II化合物或其互變異構物、式III化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物;及(b)一或多種CYP17抑制劑或其醫藥上可接受之鹽。 It has been found that a combination of the following drugs improves the anti-tumor activity of a CYP17 inhibitor (eg, abiraterone) by inhibiting FGF, an AR-independent signaling pathway that contributes to abiraterone resistance: (a) at least one targeting/ Receptor tyrosine that reduces protein or lipid kinase activity A kinase (RTK) inhibitor compound selected from the group consisting of a compound of formula I or a tautomer thereof, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof, the compound a pharmaceutically acceptable salt, a pharmaceutically acceptable salt of the tautomer or a mixture thereof; and (b) one or more CYP17 inhibitors or a pharmaceutically acceptable salt thereof.
本發明係關於醫藥組合,其包含(a)至少一種選自由以下組成之群之RTK抑制劑化合物:式I化合物或其互變異構物、式II化合物或其互變異構物、式III化合物或其互變異構物,該化合物之醫藥上可接受之鹽、互變異構物之醫藥上可接受之鹽或其混合物;及(b)一或多種CYP17抑制劑或其醫藥上可接受之鹽;例如(3β)-17-(吡啶-3-基)雄甾-5,16-二烯-3-醇(阿比特龍)、乙酸阿比特龍、1-(2-氯-吡啶-4-基)-3-(4-甲基-吡啶-3-基)-咪唑啶-2-酮、酮康唑或VN/124-1(TOK-001);其用於同時、單獨或依序投與,特定而言用於治療或預防增殖性疾病。 The invention relates to a pharmaceutical combination comprising (a) at least one RTK inhibitor compound selected from the group consisting of a compound of formula I or a tautomer thereof, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of a tautomer or a mixture thereof; and (b) one or more CYP17 inhibitors or a pharmaceutically acceptable salt thereof; For example (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (abiraterone), abiraterone acetate, 1-(2-chloro-pyridin-4-yl) --3-(4-Methyl-pyridin-3-yl)-imidazolidine-2-one, ketoconazole or VN/124-1 (TOK-001); for simultaneous, separate or sequential administration In particular, it is used to treat or prevent proliferative diseases.
本發明亦係關於組合,例如包含以下之醫藥組合之組合製劑:(a)至少一種選自由以下組成之群之RTK抑制劑化合物:式I化合物或其互變異構物、式II化合物或其互變異構物、式III化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物;及(b)一或多種CYP17抑制劑或其醫藥上可接受之鹽,例如(3β)-17-(吡啶-3-基)雄甾-5,16-二烯-3-醇(阿比特龍)、乙酸阿比特龍、1-(2-氯-吡啶-4-基)-3-(4-甲基-吡啶-3-基)-咪唑啶-2-酮、酮康唑或VN/124-1(TOK-001)。 The invention also relates to a combination, for example a combination preparation comprising the following pharmaceutical combinations: (a) at least one RTK inhibitor compound selected from the group consisting of a compound of formula I or a tautomer thereof, a compound of formula II or An isomer, a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof; and (b) one or more CYP17 inhibitors Or a pharmaceutically acceptable salt thereof, for example, (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (abiraterone), abiraterone acetate, 1-( 2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one, ketoconazole or VN/124-1 (TOK-001).
本發明尤其係關於可用於治療或預防有需要之個體之增殖性疾病本發明之組合。 The invention relates in particular to combinations of the invention which are useful in the treatment or prevention of proliferative disorders in an individual in need thereof.
本發明亦係關於用於製備用以治療或預防有需要之個體之增殖性疾病之醫藥組合物或藥劑的本發明組合。 The invention also relates to a combination of the invention for the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disorder in an individual in need thereof.
除非另有明確說明,否則本文所用一般術語定義為以下含義:除非另有說明,否則術語「包含」及「包括」在本文中以開放式及非限制性含義使用。 Unless otherwise expressly stated, the general terms used herein are defined to have the following meanings: unless otherwise indicated, the terms "include" and "include" are used herein in the open and non-limiting sense.
除非本文另有說明或上下文明顯矛盾,否則在闡述本發明之上下文(尤其在下文申請專利範圍之上下文)中術語「一(a及an)」、「該」及類似指示物皆應視為涵蓋單數與複數二者。當化合物、鹽及諸如此類以複數形式使用時,此亦指單一化合物、鹽或諸如此類。 Unless otherwise stated herein or clearly contradicted by the context, the terms "a", "the" and "the" Both singular and plural. When a compound, a salt, and the like are used in the plural, this also means a single compound, a salt or the like.
術語「載劑」係指與化合物一起投與之稀釋劑、佐劑或媒劑。此等醫藥載劑可為無菌液體,例如水及油,包括彼等石油、動物、植物或合成來源之油,例如花生油、大豆油、礦物油、芝麻油及諸如此類。較佳採用水或水性溶液鹽水溶液及水性右旋糖及甘油溶液作為載劑,尤其用於可注射溶液。適宜醫藥載劑闡述於「Remington's Pharmaceutical Sciences」(E.W.Martin)中。 The term "carrier" refers to a diluent, adjuvant or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids such as water and oil, including oils of such petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferred as carriers, especially for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" (E.W. Martin).
本文所用術語「組合」或「醫藥組合」定義呈一個劑量單位形式之固定組合,或用於組合投與之非固定組合(或部分之套組),其中式I、式II或式III之化合物及組合配偶體(例如如下文所解釋之CYP17抑制劑藥物,亦稱作「治療劑」或「助劑」)可同時獨立地投與或在時間間隔內單獨投與,其中該等時間間隔尤其允許組合配偶體顯示協作效應,例如協同效應。本文所用術語「組合投與」或諸如此類意指涵蓋向有需要之單一個體(例如患者)投與所選組合配偶體,且意欲包括不必以相同投與途徑或同時投與試劑之治療方案。術語「固定組合」意指將活性成份(例如式(I)、式II或式III之化合物)與組合配偶體二者以單一實體或劑量形式同時投與患者。術語「非固定組合」或 「部分之套組」意指將活性成份(例如式I、式II或式III之化合物)與組合配偶體二者作為單獨實體同時、並行或依序且無具體時間限制地投與患者,其中此投與可在患者體內提供該兩種化合物之治療有效濃度。後者也適用於雞尾酒療法,例如投與三種或更多種活性成份。 The term "combination" or "pharmaceutical combination" as used herein, is defined as a fixed combination in the form of a dosage unit or a combination of non-fixed combinations (or portions) of a compound of formula I, formula II or formula III. And the combination partner (for example, a CYP17 inhibitor drug, also referred to as a "therapeutic agent" or "auxiliary agent" as explained below) can be administered simultaneously or separately at intervals, wherein the intervals are particularly Allows the combined partner to display synergistic effects, such as synergies. The term "combination administration" or the like as used herein is meant to encompass the administration of a selected combination partner to a single individual (eg, a patient) in need thereof, and is intended to include a treatment regimen that does not necessarily require the same administration route or concurrent administration of the agent. The term "fixed combination" means that the active ingredient (eg, a compound of Formula (I), Formula II or Formula III) and a combination partner are administered to a patient simultaneously in a single entity or dosage form. The term "non-fixed combination" or "Partial kit" means that the active ingredient (eg, a compound of Formula I, Formula II or Formula III) and a combination partner are administered to a patient as separate entities simultaneously, in parallel or sequentially and without specific time constraints, wherein This administration provides a therapeutically effective concentration of the two compounds in the patient. The latter also applies to cocktail therapy, for example by administering three or more active ingredients.
本文所用術語「CYP17抑制劑」係關於抑制細胞色素P450 17-α-羥化酶17-20裂解酶(CYP17)(在類固醇激素生物合成中起關鍵作用之多功能酶)之化合物。該術語包括(但不限於)(3β)-17-(吡啶-3-基)雄甾-5,16-二烯-3-醇(阿比特龍)、乙酸阿比特龍(阿比特龍已論述於諸如以下等專利中:WO 200900132、WO 2008024485、WO 2006021776、WO 09509178、WO 09320097)、1-(2-氯-吡啶-4-基)-3-(4-甲基-吡啶-3-基)-咪唑啶-2-酮、酮康唑及VN/124-1(TOK-001)。 The term "CYP17 inhibitor" as used herein relates to a compound which inhibits cytochrome P450 17-α-hydroxylase 17-20 lyase (CYP17), a multifunctional enzyme that plays a key role in steroid hormone biosynthesis. The term includes, but is not limited to, (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (abiraterone), abiraterone acetate (Abitron has been discussed In patents such as: WO 200900132, WO 2008024485, WO 2006021776, WO 09509178, WO 09320097), 1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl) )-Imidazolidin-2-one, ketoconazole and VN/124-1 (TOK-001).
1-(2-氯-吡啶-4-基)-3-(4-甲基-吡啶-3-基)-咪唑啶-2-酮 1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one
本文所用術語「RTK抑制劑」包括(但不限於)蛋白質酪胺酸激酶及/或絲胺酸及/或蘇胺酸激酶抑制劑或脂質激酶抑制劑,例如:i)靶向、降低或抑制血管內皮生長因子受體(VEGF)活性之化合物,例如靶向、降低或抑制VEGF活性之化合物,尤其抑制VEGF受體 之化合物,例如但不限於7H-吡咯并[2,3-d]嘧啶衍生物(AEE788);BAY 43-9006;揭示於WO 00/09495中之異膽鹼化合物,例如(4-第三丁基-苯基)-94-吡啶-4-基甲基-異喹啉-1-基)-胺(AAL881);及ii)靶向、降低或抑制血小板源生長因子受體(PDGFR)活性之化合物,例如靶向、降低或抑制PDGFR活性之化合物,尤其抑制PDGF受體之化合物,例如N-苯基-2-嘧啶-胺衍生物,例如伊馬替尼(imatinib)、SU101、SU6668及GFB-111;iii)靶向、降低或抑制纖維母細胞生長因子受體(FGFR)活性之化合物;iv)靶向、降低或抑制Trk受體酪胺酸激酶家族活性之化合物;v)靶向、降低或抑制FLT3受體酪胺酸激酶家族活性之化合物;及vi)靶向、降低或抑制C-kit受體酪胺酸激酶(PDGFR家族之一部分)活性之化合物,例如靶向、降低或抑制c-Kit受體酪胺酸激酶家族活性之化合物,尤其抑制c-Kit受體之化合物,例如伊馬替尼;及vii)靶向、降低或抑制蛋白質-酪胺酸激酶活性之化合物,例如甲磺酸伊馬替尼(GLEEVEC);酪胺酸磷酸化抑制劑(tyrphostin)或嘧啶基胺基苄醯胺及其衍生物(TASIGNA)。酪胺酸磷酸化抑制劑較佳係低分子量(Mr<1500)化合物或其醫藥上可接受之鹽,尤其選自亞苄基丙二腈類之化合物或S-芳基苯丙二腈或雙基質喹啉類化合物,更尤其為任一選自由以下組成之群之化合物:酪胺酸磷酸化抑制劑A23/RG-50810、AG 99、酪胺酸磷酸化抑制劑AG 213、酪胺酸磷酸化抑制劑AG 1748、酪胺酸磷酸化抑制劑AG 490、酪胺酸磷酸化抑制劑B44、酪胺酸磷酸化抑制劑B44(+)對映異構物、酪胺酸磷酸化抑制劑AG 555、AG 494、酪胺酸磷酸化抑制劑AG 556、AG957及阿達福丁(adaphostin)(4-{[(2,5-二羥基苯基)甲基]胺基}-苯甲酸金剛烷基酯、 NSC 680410、阿達福丁);術語「醫藥組合物」在本文中定義為指欲投與個體(例如,哺乳動物或人類)以便預防或治療影響該哺乳動物之特定疾病或病況的含有至少一種治療性劑之混合物或溶液。 The term "RTK inhibitor" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or sulphate kinase inhibitors or lipid kinase inhibitors, for example: i) targeting, reducing or inhibiting A compound of vascular endothelial growth factor receptor (VEGF) activity, such as a compound that targets, decreases or inhibits VEGF activity, particularly a compound that inhibits the VEGF receptor, such as, but not limited to, 7H-pyrrolo[2,3-d]pyrimidine derivative (AEE788); BAY 43-9006; a heterocholine compound disclosed in WO 00/09495, such as (4-t-butyl-phenyl)-94-pyridin-4-ylmethyl-isoquinoline- a 1-amino)-amine (AAL881); and ii) a compound that targets, decreases or inhibits platelet-derived growth factor receptor (PDGFR) activity, such as a compound that targets, decreases or inhibits PDGFR activity, particularly inhibits PDGF receptor Compounds such as N -phenyl-2-pyrimidine-amine derivatives such as imatinib, SU101, SU6668 and GFB-111; iii) targeting, reducing or inhibiting fibroblast growth factor receptor (FGFR) Active compound; iv) a compound that targets, decreases or inhibits the activity of the Trk receptor tyrosine kinase family; v) targets a compound that reduces or inhibits the activity of the FLT3 receptor tyrosine kinase family; and vi) a compound that targets, reduces or inhibits the activity of the C-kit receptor tyrosine kinase (part of the PDGFR family), such as targeting, reducing or inhibiting a compound active in the c-Kit receptor tyrosine kinase family, particularly a compound that inhibits the c-Kit receptor, such as imatinib; and vii) a compound that targets, decreases or inhibits protein-tyrosine kinase activity, such as Imatinib sulfonate (GLEEVEC); tyrphostin or pyrimidinyl benzamide and its derivatives (TASIGNA). The tyrosine phosphorylation inhibitor is preferably a low molecular weight (M r <1500) compound or a pharmaceutically acceptable salt thereof, especially a compound selected from the group consisting of benzalmalononitrile or S-aryl phenylmalononitrile or A bi-substrate quinoline compound, more particularly a compound selected from the group consisting of tyrosine phosphorylation inhibitor A23/RG-50810, AG 99, tyrosine phosphorylation inhibitor AG 213, tyrosine Phosphorylation inhibitor AG 1748, tyrosine phosphorylation inhibitor AG 490, tyrosine phosphorylation inhibitor B44, tyrosine phosphorylation inhibitor B44(+) enantiomer, tyrosine phosphorylation inhibitor AG 555, AG 494, tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantane The base, NSC 680410, adafodine); the term "pharmaceutical composition" is defined herein to mean the inclusion of an individual (eg, a mammal or a human) in order to prevent or treat a particular disease or condition affecting the mammal. A mixture or solution of at least one therapeutic agent.
術語「醫藥上可接受」在本文中定義為指彼等在合理的醫學判斷範圍內適於與哺乳動物(例如哺乳動物或人類)組織接觸,無過度毒性、刺激性、過敏反應及其他問題併發症、與合理之益處/風險比相稱之化合物、材料、組合物及/或劑型。 The term "pharmaceutically acceptable" is defined herein to mean that they are suitable for contact with mammalian (eg mammalian or human) tissues within reasonable medical judgment without excessive toxicity, irritation, allergic reactions and other problems. A compound, material, composition, and/or dosage form that is commensurate with a reasonable benefit/risk ratio.
本發明所用術語「共投與」或「組合投與」定義為涵蓋向單一患者投與所選治療劑,且意欲包括該等藥劑未必以相同投與途徑或同時投與之治療方案。 The term "co-administered" or "combined administration" as used in the present invention is defined to encompass the administration of a selected therapeutic agent to a single patient, and is intended to include treatment regimens that are not necessarily administered by the same administration route or concurrently.
本文所用術語「治療(treating或treatment)」包含減輕、減弱或減緩個體之至少一種症狀或實現疾病惡化之延遲之治療。例如,治療可為諸如癌症等病症之一或若干種症狀之減退或病症之完全根除。在本發明之含義內,術語「治療」亦表示阻止、延遲發作(即,疾病臨床表現前之時期)及/或降低疾病發生或惡化之風險。術語「保護」在本文中用於指預防、延遲個體之疾病之發生或持續或加劇、或治療該疾病或視需要所有該等情形。 The term "treating or treating" as used herein encompasses treatment that reduces, attenuates, or slows down at least one symptom of an individual or delays the progression of the disease. For example, the treatment can be a reduction in one or several symptoms such as cancer or a complete eradication of the condition. Within the meaning of the present invention, the term "treatment" also means preventing, delaying the onset (i.e., the period prior to the clinical manifestation of the disease) and/or reducing the risk of developing or worsening the disease. The term "protection" is used herein to mean preventing, delaying the onset or persistence or aggravation of an individual's disease, or treating the condition or all such conditions as needed.
本文所用術語「預防(prevent、preventing或prevention)」包含預防與所預防狀態、疾病或病症相關或由其引起之至少一種症狀。 The term "prevent, prevention, or prevention" as used herein encompasses the prevention of at least one symptom associated with or caused by a prevented state, disease or condition.
術語「聯合治療活性」或「聯合治療效應」意指治療劑可以較佳在所欲治療溫血動物、尤其人類中仍顯示(較佳協同)交互作用(聯合治療效應)之時間間隔單獨給予(以長期交錯方式、尤其順序特定方式)。無論何種情形皆尤其可藉由跟蹤血液濃度來測定,此表明該兩種化合物至少在某些時間間隔期間皆存於所欲治療人類之血液中。 The term "combination therapeutic activity" or "combination therapeutic effect" means that the therapeutic agent can preferably be administered separately at intervals of time (better synergistic) interaction (combination therapy effect) in the warm-blooded animal, especially human, to be treated ( In a long-term staggered manner, especially in a sequential manner). In any case, it can be determined, inter alia, by tracking blood concentrations, which indicates that the two compounds are present in the blood of the human being treated, at least during certain time intervals.
術語治療劑組合之「醫藥有效量」或「臨床有效量」係相對於 用該組合治療之病症之基線臨床上可觀察到之體徵及症狀足以提供可觀察到之改良的量。 The term "pharmaceutically effective amount" or "clinically effective amount" of a combination of therapeutic agents is relative to The clinically observable signs and symptoms at the baseline of the condition treated with the combination are sufficient to provide an observable improved amount.
本文所用術語「個體」或「患者」包括能夠罹患或患有癌症或直接或間接涉及癌症之任何病症之動物。個體之實例包括哺乳動物,例如,人類、犬、奶牛、馬、豬、綿羊、山羊、貓、小鼠、兔、大鼠及轉基因非人類動物。在較佳實施例中,個體係人類,例如,罹患、易患或可能能夠罹患癌症之人類。 The term "individual" or "patient" as used herein includes an animal that is capable of suffering from or suffering from cancer or any condition that directly or indirectly involves cancer. Examples of individuals include mammals, for example, humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In a preferred embodiment, a system of humans, for example, a human suffering from, susceptible to, or likely to be able to develop cancer.
術語「約」或「大約」應具有在給定值或範圍之10%內、更佳在5%內之含義。 The term "about" or "approximately" shall have the meaning within 10%, more preferably within 5% of a given value or range.
通常,在提及諸如氫或H等某一元素時,意指包括該元素之所有同位素。例如,若R基團定義為包括氫或H,則其亦包括氘及氚。 Generally, when referring to an element such as hydrogen or H, it is meant to include all isotopes of that element. For example, if the R group is defined to include hydrogen or H, it also includes ruthenium and osmium.
片語「未經取代之烷基」係指不含有雜原子之烷基。因此,該片語包括直鏈烷基,例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一基、十二基及諸如此類。該片語亦包括直鏈烷基之具支鏈異構物,包括(但不限於)以舉例方式提供之以下基團:-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH(CH2CH3)2、-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、-CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、-CH(CH3)CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2、-CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3)及其他。該片語亦包括環狀烷基,例如環烷基,例如環丙基、環丁基、環戊基、環己基、環庚基及環辛基,且此等環經如上文所定義之 直鏈及具支鏈烷基取代。該片語亦包括多環狀烷基,例如但不限於金剛烷基、降莰基及二環[2.2.2]辛基,且此等環經如上文所定義之直鏈及具支鏈烷基取代。因此,片語未經取代之烷基包括一級烷基、二級烷基及三級烷基。未經取代之烷基可鍵結至母體化合物中之一或多個碳原子、氧原子、氮原子及/或硫原子。優選未經取代之烷基包括具有1至20個碳原子之直鏈及具支鏈烷基及環狀烷基。更優選之此等未經取代之烷基具有1至10個碳原子,而甚至更優選之此等基團具有1至5個碳原子。最優選之未經取代之烷基包括具有1至4個或1至3個碳原子之直鏈及具支鏈烷基且包括甲基、乙基丙基及-CH(CH3)2。 The phrase "unsubstituted alkyl" means an alkyl group which does not contain a hetero atom. Thus, the phrase includes straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl and the like. . The phrase also includes branched isomers of linear alkyl groups including, but not limited to, the following groups provided by way of example: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )( CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH(CH 3 (CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 3 , -CH 2 CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH( CH 3 )CH(CH 3 ) 2 , -CH(CH 2 CH 3 )CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ) and others. The phrase also includes cyclic alkyl groups such as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and such rings are straight as defined above Chains and branched alkyl substitutions. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantyl, norbornyl and bicyclo [2.2.2] octyl, and such rings are straight and branched as defined above. Substituted. Thus, the unsubstituted alkyl group includes a primary alkyl group, a secondary alkyl group, and a tertiary alkyl group. The unsubstituted alkyl group may be bonded to one or more of the carbon, oxygen, nitrogen and/or sulfur atoms of the parent compound. Preferred unsubstituted alkyl groups include straight chain and branched alkyl groups having from 1 to 20 carbon atoms and cyclic alkyl groups. More preferably, such unsubstituted alkyl groups have from 1 to 10 carbon atoms, and even more preferably such groups have from 1 to 5 carbon atoms. The most preferred unsubstituted alkyl group includes straight chain and branched alkyl groups having 1 to 4 or 1 to 3 carbon atoms and includes methyl, ethylpropyl and -CH(CH 3 ) 2 .
片語「經取代烷基」係指如上文所定義其中一或多個鍵結至碳或氫之鍵由鍵結至非氫及非碳原子之鍵替代的未經取代之烷基,該等非氫及非碳原子例如(但不限於)鹵化物中之鹵素原子,例如F、Cl、Br及I;諸如以下等基團中之氧原子:羥基、烷氧基、芳氧基及酯基;諸如以下等基團中之硫原子:硫醇基、烷基及芳基硫化物基團、碸基、磺醯基及亞碸基;諸如以下等基團中之氮原子:胺、醯胺、烷基胺、二烷基胺、芳基胺、烷基芳基胺、二芳基胺、N-氧化物、醯亞胺及烯胺;諸如以下等基團中之矽原子:三烷基矽烷基、二烷基芳基矽烷基、烷基二芳基矽烷基及三芳基矽烷基;及各種其他基團中之其他雜原子。經取代烷基亦包括其中一或多個鍵結至碳或氫原子之鍵由鍵結至諸如以下等雜原子之鍵替代之基團:羰基、羧基及酯基中之氧;諸如以下等基團中之氮:亞胺、肟、腙及腈。優選之經取代烷基尤其包括其中一或多個鍵結至碳或氫原子之鍵由一或多個鍵結至氟原子之鍵替代的烷基。經取代烷基之一個實例係三氟甲基及含有三氟甲基之其他烷基。其他烷基包括彼等一或多個鍵結至碳或氫原子之鍵由鍵結至氧原子之鍵替代者,從而使得經取代烷基含有羥基、烷氧基、 芳氧基或雜環基氧基。仍其他烷基包括具有以下基團之烷基:胺、烷基胺、二烷基胺、芳基胺、(烷基)(芳基)胺、二芳基胺、雜環基胺、(烷基)(雜環基)胺、(芳基)(雜環基)胺或二雜環基胺。 The phrase "substituted alkyl" refers to an unsubstituted alkyl group as defined above wherein one or more bonds bonded to carbon or hydrogen are replaced by a bond bonded to a bond other than a hydrogen and a non-carbon atom. Non-hydrogen and non-carbon atoms such as, but not limited to, halogen atoms in halides such as F, Cl, Br and I; oxygen atoms in groups such as: hydroxy, alkoxy, aryloxy and ester groups a sulfur atom in a group such as a thiol group, an alkyl group and an aryl sulfide group, a fluorenyl group, a sulfonyl group, and a fluorenylene group; a nitrogen atom such as the following: an amine, a guanamine , alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, quinones and enamines; ruthenium atoms in groups such as: trialkyl Alkyl, dialkylarylalkyl, alkyldiarylalkyl and triarylalkyl; and other heteroatoms in various other groups. The substituted alkyl group also includes a group in which one or more bonds bonded to a carbon or hydrogen atom are replaced by a bond bonded to a hetero atom such as a carbonyl group, a carboxyl group, and an ester group; Nitrogen in the group: imine, hydrazine, hydrazine and nitrile. Preferred substituted alkyl groups include, in particular, alkyl groups in which one or more bonds bonded to a carbon or hydrogen atom are replaced by one or more bonds bonded to a fluorine atom. An example of a substituted alkyl group is a trifluoromethyl group and other alkyl groups containing a trifluoromethyl group. Other alkyl groups include those in which one or more bonds bonded to a carbon or hydrogen atom are replaced by a bond bonded to an oxygen atom such that the substituted alkyl group contains a hydroxyl group, an alkoxy group, An aryloxy or heterocyclic oxy group. Still other alkyl groups include alkyl groups having the following groups: amines, alkylamines, dialkylamines, arylamines, (alkyl)(aryl)amines, diarylamines,heterocyclylamines, (alkanes) ()heterocyclyl)amine, (aryl)(heterocyclyl)amine or diheterocyclylamine.
片語「未經取代之芳基」係指不含有雜原子之芳基。因此,舉例而言,該片語包括(但不限於)諸如苯基、聯苯基、蒽基及萘基等基團。儘管片語「未經取代之芳基」包括含有縮合環之基團,例如萘,但其不包括具有鍵結至一個環成員之其他基團(例如烷基或鹵基)之芳基,此乃因諸如甲苯基等芳基在本文中視為經取代芳基,如下文所述。優選之未經取代之芳基係苯基。在一些實施例中,未經取代之芳基具有6至14個碳原子。未經取代之芳基可鍵結至母體化合物中之一或多個碳原子、氧原子、氮原子及/或硫原子。 The phrase "unsubstituted aryl" means an aryl group which does not contain a hetero atom. Thus, for example, the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, and naphthyl. Although the phrase "unsubstituted aryl" includes a group containing a fused ring, such as naphthalene, it does not include an aryl group having another group bonded to a ring member (for example, an alkyl group or a halogen group). It is because an aryl group such as a tolyl group is referred to herein as a substituted aryl group, as described below. A preferred unsubstituted aryl phenyl group. In some embodiments, the unsubstituted aryl has 6 to 14 carbon atoms. The unsubstituted aryl group can be bonded to one or more of the carbon atoms, oxygen atoms, nitrogen atoms and/or sulfur atoms in the parent compound.
片語「經取代芳基」相對於未經取代之芳基具有與經取代烷基相對於未經取代之烷基相同之含義。然而,經取代芳基亦包括其中一個芳香族碳鍵結至上述一個非碳或非氫原子之芳基且亦包括其中芳基之一或多個芳香族碳鍵結至如本文所定義經取代或未經取代之烷基、烯基或炔基之芳基。此包括以下鍵結排列:芳基之兩個碳原子鍵結至烷基、烯基或炔基之兩個原子以界定稠環系統(例如二氫萘基或四氫萘基)。因此,片語「經取代芳基」尤其包括(但不限於)諸如甲苯基及羥基苯基等基團。 The phrase "substituted aryl" has the same meaning as the unsubstituted alkyl group with respect to the unsubstituted alkyl group with respect to the unsubstituted alkyl group. However, substituted aryl also includes an aryl group in which one aromatic carbon is bonded to one of the above non-carbon or non-hydrogen atoms and also includes one or more aromatic carbons in which the aryl group is bonded to a substituent as defined herein. Or an unsubstituted alkyl, alkenyl or alkynyl aryl group. This includes the following bond arrangement: two carbon atoms of the aryl group are bonded to two atoms of an alkyl, alkenyl or alkynyl group to define a fused ring system (e.g., dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase "substituted aryl" includes, but is not limited to, groups such as tolyl and hydroxyphenyl.
片語「未經取代之烯基」係指直鏈及具支鏈及環狀基團,例如彼等針對如上文所定義未經取代之烷基所述者,只是在兩個碳原子之間存在至少一個雙鍵。實例尤其包括(但不限於)乙烯基、-CH=CH(CH3)、-CH=C(CH3)2、-C(CH3)=CH2、-C(CH3)=CH(CH3)、-C(CH2CH3)=CH2、環己烯基、環戊烯基、環己二烯基、丁二烯基、戊二烯基及己二烯基。在一些實施例中,未經取代之烯基具有2至8個碳原子。 The phrase "unsubstituted alkenyl" refers to straight-chain and branched and cyclic groups, such as those described above for unsubstituted alkyl groups as defined above, only between two carbon atoms. There is at least one double bond. Examples include (but are not limited to) ethenyl, -CH = CH (CH 3) , - CH = C (CH 3) 2, -C (CH 3) = CH 2, -C (CH 3) = CH (CH 3 ), -C(CH 2 CH 3 )=CH 2 , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl. In some embodiments, the unsubstituted alkenyl group has 2 to 8 carbon atoms.
片語「經取代烯基」相對於未經取代之烯基具有與經取代烷基相對於未經取代之烷基相同之含義。經取代烯基包括其中非碳或非氫原子鍵結至以雙鍵結至另一碳之碳的烯基及彼等其中一個非碳或非氫原子鍵結至不參與鍵結至另一碳之雙鍵之碳的烯基。 The phrase "substituted alkenyl" has the same meaning as the unsubstituted alkyl group with respect to the unsubstituted alkyl group. Substituted alkenyl groups include alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon bonded to another carbon and one of the non-carbon or non-hydrogen atoms is bonded to not participate in bonding to another carbon The alkenyl group of the carbon of the double bond.
片語「未經取代之炔基」係指直鏈及具支鏈基團,例如彼等針對如上文所定義未經取代之烷基所述者,只是在兩個碳原子之間存在至少一個三鍵。實例尤其包括(但不限於)-C≡C(H)、-C≡C(CH3)、-C≡C(CH2CH3)、-C(H2)C≡C(H)、-C(H)2C≡C(CH3)及-C(H)2C≡C(CH2CH3)。在一些實施例中,未經取代之炔基具有2至8個碳原子。 The phrase "unsubstituted alkynyl" refers to both straight-chain and branched-chain groups, such as those described above for an unsubstituted alkyl group as defined above, except that at least one is present between two carbon atoms. Three keys. Examples include, but are not limited to, -C≡C(H), -C≡C(CH 3 ), -C≡C(CH 2 CH 3 ), -C(H 2 )C≡C(H),- C(H) 2 C≡C(CH 3 ) and -C(H) 2 C≡C(CH 2 CH 3 ). In some embodiments, the unsubstituted alkynyl group has 2 to 8 carbon atoms.
片語「經取代炔基」相對於未經取代之炔基具有與經取代烷基相對於未經取代之烷基相同之含義。經取代炔基包括其中非碳或非氫原子鍵結至以三鍵結至另一碳之碳的炔基及彼等其中非碳或非氫原子鍵結至不參與鍵結至另一碳之三鍵之碳的炔基。 The phrase "substituted alkynyl" has the same meaning as the unsubstituted alkynyl group with respect to the unsubstituted alkyl group with respect to the unsubstituted alkyl group. Substituted alkynyl groups include alkynyl groups wherein a non-carbon or non-hydrogen atom is bonded to a carbon bonded to another carbon and wherein none of the non-carbon or non-hydrogen atoms are bonded to participate in bonding to another carbon Alkynyl group of a triple bond carbon.
片語「未經取代之雜環基」係指芳香族與非芳香族環化合物,包括單環、二環及多環化合物,例如(但不限於)含有3個或更多個環成員之奎寧環基,其中一或多個環成員為雜原子,例如(但不限於)N、O及S。儘管片語「未經取代之雜環基」包括稠合雜環,例如苯并咪唑基,但其不包括具有鍵結至一個環成員之其他基團(例如烷基或鹵基)之雜環基,此乃因諸如2-甲基苯并咪唑基等化合物為經取代雜環基。雜環基之實例包括(但不限於):含有1至4個氮原子之不飽和3至8員環,例如(但不限於)吡咯基、吡咯啉基、咪唑基、吡唑基、吡啶基、二氫吡啶基、嘧啶基、吡嗪基、噠嗪基、***基(例如4H-1,2,4-***基、1H-1,2,3-***基、2H-1,2,3-***基等)、四唑基(例如1H-四唑基、2H四唑基等);含有1至4個氮原子之飽和3至8員環,例如(但不限於)吡咯啶基、咪唑啶基、六氫吡啶基、六氫吡嗪基;含有1 至4個氮原子之稠合不飽和雜環基,例如(但不限於)吲哚基、異吲哚基、吲哚啉基、吲嗪基、苯并咪唑基、喹啉基、異喹啉基、吡唑基、苯并***基;含有1至2個氧原子及1至3個氮原子之不飽和3至8員環,例如(但不限於)噁唑基、異噁唑基、噁二唑基(例如1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,5-噁二唑基等);含有1至2個氧原子及1至3個氮原子之飽和3至8員環,例如(但不限於)嗎啉基;含有1至2個氧原子及1至3個氮原子之不飽和稠合雜環基,例如,苯并噁唑基、苯并噁二唑基、苯并噁嗪基(例如2H-1,4-苯并噁嗪基等);含有1至3個硫原子及1至3個氮原子之不飽和3至8員環,例如(但不限於)噻唑基、異噻唑基、噻二唑基(例如1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基等);含有1至2個硫原子及1至3個氮原子之飽和3至8員環,例如(但不限於)四氫噻唑基;含有1至2個硫原子之飽和及不飽和3至8員環,例如(但不限於)噻吩基、二氫二硫雜環己二烯基(dihydrodithiinyl)、二氫二亞硫醯基(dihydrodithionyl)、四氫噻吩、四氫噻喃;含有1至2個硫原子及1至3個氮原子之不飽和稠合雜環,例如(但不限於)苯并噻唑基、苯并噻二唑基、苯并噻嗪基(例如2H-1,4-苯并噻嗪基等)、二氫苯并噻嗪基(例如2H-3,4-二氫苯并噻嗪基等);含有氧原子之不飽和3至8員環,例如(但不限於)呋喃基;含有1至2個氧原子之不飽和稠合雜環,例如苯并二噁茂基(例如1,3-苯并二噁茂基等);含有氧原子及1至2個硫原子之不飽和3至8員環,例如(但不限於)二氫氧硫雜環己二烯基(dihydrooxathiinyl);含有1至2個氧原子及1至2個硫原子之飽和3至8員環,例如1,4-氧硫;含有1至2個硫原子之不飽和稠環,例如苯并噻吩基、苯并二硫雜環己二烯基(benzodithiinyl);及含有氧原子及1至2個硫原子之不飽和稠合雜環,例如苯并氧硫雜環己二烯基(benzoxathiinyl)。雜環基亦包括上述彼等,其中環中之一或多個S原子係雙鍵鍵結至一或兩個氧原子(亞碸及 碸)。例如,雜環基包括四氫噻吩氧化物及四氫噻吩1,1-二氧化物。優選雜環基含有5或6環成員。更優選之雜環基包括嗎啉、六氫吡嗪、六氫吡啶、吡咯啶、咪唑、吡唑、1,2,3-***、1,2,4-***、四唑、噻吩、硫嗎啉、硫嗎啉(其中硫嗎啉之S原子鍵結至一或多個O原子)、吡咯、高六氫吡嗪、噁唑啶-2-酮、吡咯啶-2-酮、噁唑、奎寧環、噻唑、異噁唑、呋喃及四氫呋喃。 The phrase "unsubstituted heterocyclic group" means aromatic and non-aromatic ring compounds, including monocyclic, bicyclic and polycyclic compounds such as, but not limited to, quinone containing 3 or more ring members. A ring group in which one or more ring members are heteroatoms such as, but not limited to, N, O and S. Although the phrase "unsubstituted heterocyclic group" includes a fused heterocyclic ring, such as a benzimidazolyl group, it does not include a heterocyclic ring having another group bonded to a ring member (for example, an alkyl group or a halogen group). The reason is that a compound such as 2-methylbenzimidazolyl is a substituted heterocyclic group. Examples of heterocyclic groups include, but are not limited to, unsaturated 3 to 8 membered rings containing from 1 to 4 nitrogen atoms such as, but not limited to, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl , dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1, 2,3-Triazolyl, etc.), tetrazolyl (eg 1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms, such as, but not limited to, pyrrole Pyridyl, imidazolidinyl, hexahydropyridyl, hexahydropyrazinyl; fused unsaturated heterocyclic group containing from 1 to 4 nitrogen atoms, such as, but not limited to, fluorenyl, isodecyl, hydrazine Porphyrin group, pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, pyrazolyl, benzotriazolyl; unsaturated 3 containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms To an 8-membered ring, such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2,5-oxadiazolyl, etc.; a saturated 3 to 8 membered ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, but not limited to, morpholinyl; An unsaturated fused heterocyclic group of 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, a benzoxazolyl group, a benzooxadiazolyl group, a benzoxazinyl group (for example, 2H-1,4- a benzoxazinyl group, etc.; an unsaturated 3 to 8 membered ring containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms, such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (eg 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.; containing 1 to 2 a sulfur atom and a saturated 3 to 8 membered ring of 1 to 3 nitrogen atoms, such as, but not limited to, a tetrahydrothiazolyl group; a saturated and unsaturated 3 to 8 membered ring containing 1 to 2 sulfur atoms, for example (but Not limited to) thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; containing 1 to 2 sulfur atoms and 1 to An unsaturated fused heterocyclic ring of three nitrogen atoms, such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (eg, 2H-1,4-benzothiazinyl, etc.) , a dihydrobenzothiazinyl group (for example, 2H-3,4-dihydrobenzothiazinyl, etc.); an unsaturated 3 to 8 membered ring containing an oxygen atom, for example (but Not limited to) furanyl; unsaturated fused heterocyclic ring containing 1 to 2 oxygen atoms, such as benzodioxanyl group (for example, 1,3-benzodioxanyl group, etc.); containing oxygen atom and 1 to 2 sulfur Atomic unsaturation 3 to 8 membered rings, such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 members containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms Ring, such as 1,4-oxosulfur An unsaturated fused ring containing 1 to 2 sulfur atoms, such as a benzothienyl group, a benzodithiinyl group; and an unsaturated condensed group containing an oxygen atom and 1 to 2 sulfur atoms; A heterocyclic ring such as benzoxathiinyl. Heterocyclyl groups also include those described above, wherein one or more S atoms in the ring are double bonded to one or two oxygen atoms (anthracene and fluorene). For example, a heterocyclic group includes a tetrahydrothiophene oxide and a tetrahydrothiophene 1,1-dioxide. Preferably, the heterocyclic group contains a 5 or 6 ring member. More preferred heterocyclic groups include morpholine, hexahydropyrazine, hexahydropyridine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, Thimorpholine, thiomorpholine (wherein the S atom of thiomorpholine is bonded to one or more O atoms), pyrrole, homohexahydropyrazine, oxazolidin-2-one, pyrrolidin-2-one, evil Azole, quinuclidine ring, thiazole, isoxazole, furan and tetrahydrofuran.
片語「經取代雜環基」係指如上文所定義其中一或多個環成員鍵結至非氫原子的未經取代之雜環基,例如上文針對經取代烷基及經取代芳基所述者。實例尤其包括(但不限於)2-甲基苯并咪唑基、5-甲基苯并咪唑基、5-氯苯并噻唑基、N-烷基六氫吡嗪基(例如1-甲基六氫吡嗪基、六氫吡嗪-N-氧化物、N-烷基六氫吡嗪N-氧化物)、2-苯氧基-噻吩及2-氯吡啶基。另外,經取代雜環基亦包括其中鍵結至非氫原子之鍵鍵結至為經取代及未經取代之芳基、取代及未經取代之芳烷基或未經取代之雜環基一部分之碳原子的雜環基。實例包括(但不限於)1-苄基六氫吡啶基、3-苯基硫嗎啉基、3-(吡咯啶-1-基)-吡咯啶基及4-(六氫吡啶-1-基)-六氫吡啶基。諸如N-烷基取代之六氫吡嗪基(例如N-甲基六氫吡嗪基)、經取代嗎啉基及六氫吡嗪N-氧化物基團(例如六氫吡嗪N-氧化物及N-烷基六氫吡嗪N-氧化物)等基團係一些經取代雜環基之實例。諸如經取代六氫吡嗪基(例如N-烷基取代之六氫吡嗪基,例如N-甲基六氫吡嗪及諸如此類)、經取代嗎啉基、六氫吡嗪N-氧化物基團及N-烷基六氫吡嗪N-氧化物基團等基團係一些尤其適宜作為R6或R7基團之經取代雜環基之實例。 The phrase "substituted heterocyclic group" refers to an unsubstituted heterocyclic group wherein one or more ring members are bonded to a non-hydrogen atom as defined above, for example, above substituted alkyl and substituted aryl Said. Examples include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzothiazolyl, N-alkylhexahydropyrazinyl (eg 1-methylhexa) Hydropyrazinyl, hexahydropyrazine-N-oxide, N-alkylhexahydropyrazine N-oxide), 2-phenoxy-thiophene and 2-chloropyridyl. Further, the substituted heterocyclic group also includes a bond in which a bond to a non-hydrogen atom is bonded to a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group or an unsubstituted heterocyclic group. a heterocyclic group of a carbon atom. Examples include, but are not limited to, 1-benzylhexahydropyridyl, 3-phenylthiomorpholinyl, 3-(pyrrolidin-1-yl)-pyrrolidinyl, and 4-(hexahydropyridin-1-yl) )-hexahydropyridyl. Such as N-alkyl substituted hexahydropyrazinyl (eg N-methylhexahydropyrazinyl), substituted morpholinyl and hexahydropyrazine N-oxide groups (eg hexahydropyrazine N-oxidation) The group such as N-alkyl hexahydropyrazine N-oxide) is an example of some substituted heterocyclic groups. Such as substituted hexahydropyrazinyl (eg N-alkyl substituted hexahydropyrazinyl, such as N-methylhexahydropyrazine and the like), substituted morpholinyl, hexahydropyrazine N-oxide Groups such as a group and an N-alkylhexahydropyrazine N-oxide group are some examples of substituted heterocyclic groups which are particularly suitable as the R 6 or R 7 group.
片語「未經取代之雜環基烷基」係指如上文所定義其中未經取代之烷基之氫鍵或碳鍵經鍵結至如上文所定義之雜環基之鍵替代的未經取代之烷基。例如,甲基(-CH3)係未經取代之烷基。若甲基之氫原子由鍵結至雜環基之鍵替代,例如若甲基之碳鍵結至吡啶之碳2(一 個碳鍵結至吡啶之N)或吡啶之碳3或4,則該化合物係未經取代之雜環基烷基。 The phrase "unsubstituted heterocyclylalkyl" means a bond as defined above wherein the hydrogen bond or carbon bond of the unsubstituted alkyl group is bonded to a bond of a heterocyclic group as defined above. Substituted alkyl. For example, methyl (-CH 3 ) is an unsubstituted alkyl group. If the hydrogen atom of the methyl group is replaced by a bond bonded to the heterocyclic group, for example, if the carbon of the methyl group is bonded to the carbon 2 of the pyridine (a carbon bonded to the N of the pyridine) or the carbon 3 or 4 of the pyridine, The compound is an unsubstituted heterocyclylalkyl group.
片語「經取代雜環基烷基」相對於未經取代之雜環基烷基具有與經取代芳烷基相對於未經取代之芳烷基相同之含義。然而,經取代雜環基烷基亦包括其中非氫原子鍵結至雜環基烷基之雜環基中之雜原子(例如(但不限於)六氫吡啶基烷基之六氫吡啶環中之氮原子)的基團。另外,經取代雜環基烷基亦包括其中該基團之烷基部分之碳鍵或氫鍵由鍵結至經取代及未經取代之芳基或經取代及未經取代之芳烷基之鍵替代的基團。實例包括(但不限於)苯基-(六氫吡啶-1-基)-甲基及苯基-(嗎啉-4-基)-甲基。 The phrase "substituted heterocyclylalkyl" has the same meaning as the unsubstituted arylalkyl group with respect to the unsubstituted aralkyl group relative to the unsubstituted heterocyclylalkyl group. However, the substituted heterocyclylalkyl group also includes a hetero atom in which a non-hydrogen atom is bonded to a heterocyclic group of a heterocyclylalkyl group (for example, but not limited to, a hexahydropyridylalkyl group in a hexahydropyridine ring). a group of nitrogen atoms). Further, the substituted heterocyclylalkyl group also includes a carbon bond or a hydrogen bond in which the alkyl moiety of the group is bonded to a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group. A group substituted by a bond. Examples include, but are not limited to, phenyl-(hexahydropyridin-1-yl)-methyl and phenyl-(morpholin-4-yl)-methyl.
片語「經取代雜環基氧基」係指其中鍵結至氫原子之鍵由鍵結至如上文所定義以其他方式經取代之雜環基之環原子之鍵替代的羥基(-OH)。 The phrase "substituted heterocyclic oxy" refers to a hydroxy group (-OH) in which a bond bonded to a hydrogen atom is replaced by a bond bonded to a ring atom of a heterocyclic group which is otherwise substituted as defined above. .
片語「未經取代之芳氧基烷基」係指如上文所定義其中碳鍵或氫鍵由鍵結至氧原子之鍵替代的未經取代之烷基,該氧原子鍵結至如上文所定義未經取代之芳基。 The phrase "unsubstituted aryloxyalkyl" refers to an unsubstituted alkyl group as defined above wherein a carbon bond or a hydrogen bond is replaced by a bond bonded to an oxygen atom, the oxygen atom bonded to the above An unsubstituted aryl group is defined.
片語「經取代芳氧基烷基」係指如上文所定義其中鍵結至芳氧基烷基之烷基之碳基或氫基之鍵鍵結至非碳及非氫原子(如上文針對經取代烷基所述)或其中芳氧基烷基之芳基之如上文所定義芳基取代的未經取代之芳氧基烷基。 The phrase "substituted aryloxyalkyl" refers to a bond of a carbon or a hydrogen radical as defined above wherein the alkyl group bonded to the aryloxyalkyl group is bonded to a non-carbon and a non-hydrogen atom (as set forth above) An unsubstituted aryloxyalkyl group substituted by an aryl group as defined above wherein the alkyl group of the aryloxyalkyl group is substituted.
片語「未經取代之雜環基氧基烷基」係指如上文所定義其中碳鍵或氫鍵由鍵結至氧原子之鍵替代的未經取代之烷基,該氧原子鍵結至如上文所定義未經取代之雜環基。 The phrase "unsubstituted heterocyclyloxyalkyl" refers to an unsubstituted alkyl group as defined above wherein a carbon bond or a hydrogen bond is replaced by a bond bonded to an oxygen atom, the oxygen atom bonded to An unsubstituted heterocyclic group as defined above.
片語「經取代雜環基氧基烷基」係指如上文所定義其中鍵結至雜環基氧基烷基之烷基之碳基或氫基之鍵鍵結至非碳及非氫原子(如上文針對經取代烷基所述)或其中雜環基氧基烷基之雜環基之如上文 所定義雜環基取代的未經取代之雜環基氧基烷基。 The phrase "substituted heterocyclic oxyalkyl" refers to a bond or a hydrogen group bonded to a heterocyclyloxyalkyl group as defined above to a non-carbon and non-hydrogen atom. (as described above for the substituted alkyl group) or a heterocyclic group of the heterocyclyloxyalkyl group as above A heterocyclic group-substituted unsubstituted heterocyclic oxyalkyl group as defined.
片語「未經取代之雜環基烷氧基」係指如上文所定義其中碳鍵或氫鍵由鍵結至氧原子之鍵替代(該氧原子鍵結至母體化合物)且其中未經取代之烷基之另一碳鍵或氫鍵鍵結至如上文所定義未經取代之雜環基的未經取代之烷基。 The phrase "unsubstituted heterocyclylalkoxy" means a carbon bond or a hydrogen bond as defined above, which is replaced by a bond bonded to an oxygen atom (the oxygen atom is bonded to the parent compound) and wherein it is unsubstituted Another carbon bond or hydrogen bond of the alkyl group is bonded to the unsubstituted alkyl group of the unsubstituted heterocyclic group as defined above.
片語「經取代雜環基烷氧基」係指如上文所定義其中鍵結至雜環基烷氧基之烷基之碳基或氫基之鍵鍵結至非碳及非氫原子(如上文針對經取代烷基所述)或其中雜環基烷氧基之雜環基之如上文所定義雜環基取代的未經取代之雜環基烷氧基。此外,經取代雜環基烷氧基亦包括其中鍵結至基團之烷基部分之碳鍵或氫鍵可經一或多個其他經取代及未經取代之雜環取代的基團。實例包括(但不限於)吡啶-2-基嗎啉-4-基甲基及2-吡啶-3-基-2-嗎啉-4-基乙基。 The phrase "substituted heterocyclylalkoxy" refers to a bond to a non-carbon and a non-hydrogen atom, as defined above, wherein the carbon or hydrogen group bonded to the alkyl group of the heterocyclylalkoxy group is bonded An unsubstituted heterocyclylalkoxy group substituted with a heterocyclic group as defined above for the substituted heteroalkyl group or a heterocyclic group of the heterocyclylalkoxy group. Further, the substituted heterocyclylalkoxy group also includes a group in which a carbon bond or a hydrogen bond bonded to the alkyl moiety of the group may be substituted with one or more other substituted and unsubstituted heterocyclic rings. Examples include, but are not limited to, pyridin-2-ylmorpholin-4-ylmethyl and 2-pyridin-3-yl-2-morpholin-4-ylethyl.
片語「未經取代之烷氧基烷基」係指如上文所定義其中碳鍵或氫鍵由鍵結至氧原子之鍵替代的未經取代之烷基,該氧原子鍵結至如上文所定義未經取代之烷基。 The phrase "unsubstituted alkoxyalkyl" refers to an unsubstituted alkyl group as defined above wherein a carbon bond or a hydrogen bond is replaced by a bond bonded to an oxygen atom, the oxygen atom bonded to the above An unsubstituted alkyl group is defined.
片語「經取代烷氧基烷基」係指如上文所定義其中鍵結至烷氧基烷基之烷基及/或烷氧基之碳基或氫基之鍵鍵結至非碳及非氫原子的未經取代之烷氧基烷基,如上文針對經取代烷基所述。 The phrase "substituted alkoxyalkyl" refers to a bond or a bond between a carbon group or a hydrogen group of an alkyl group and/or an alkoxy group bonded to an alkoxyalkyl group as defined above to a non-carbon and a non-carbon. An unsubstituted alkoxyalkyl group of a hydrogen atom as described above for a substituted alkyl group.
關於羥基、胺基及巰基之術語「經保護」係指該等官能基之受彼等熟習此項技術者已知之保護基團保護而免於發生不期望反應的形式,該保護基團例如彼等於Protective Groups in Organic Synthesis,Greene,T.W.;Wuts,P.G.M.,John Wiley & Sons,New York,NY(第3版,1999)中所述者,其可使用其中所述之程序添加或去除。受保護羥基之實例包括(但不限於)矽烷基醚,例如彼等藉由羥基與諸如(但不限於)以下等試劑反應而獲得者:第三丁基二甲基-氯矽烷、三甲基氯矽烷、三異丙基氯矽烷、三乙基氯矽烷;經取代甲基醚及乙基醚,例 如(但不限於)甲氧基甲基醚、甲硫基甲基醚、苄氧基甲基醚、第三丁氧基甲基醚、2-甲氧基乙氧基甲基醚、四氫吡喃醚、1-乙氧基乙基醚、烯丙基醚、苄基醚;酯,例如(但不限於)苯甲醯基甲酸酯、甲酸酯、乙酸酯、三氯乙酸酯及三氟乙酸酯。受保護胺基之實例包括(但不限於)醯胺,例如,甲醯胺、乙醯胺、三氟乙醯胺及苄醯胺;醯亞胺,例如酞醯亞胺及二硫琥珀醯亞胺;及其他。受保護巰基之實例包括(但不限於)硫醚,例如S-苄基硫醚及S-4-吡啶甲基硫醚;經取代S-甲基衍生物,例如半硫、二硫及胺基硫縮醛;及其他。 The term "protected" with respect to hydroxy, amine and thiol refers to a form of such functional groups that are protected from undesired reactions by protecting groups known to those skilled in the art, such as Equivalent to those described in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY (3rd edition, 1999), which can be added or removed using the procedures described therein. Examples of protected hydroxy groups include, but are not limited to, decyl ethers, such as those obtained by reacting a hydroxy group with a reagent such as, but not limited to, the following: tert-butyldimethyl-chlorodecane, trimethyl Chlorodecane, triisopropylchlorodecane, triethylchloromethane; substituted methyl ether and ethyl ether, examples Such as (but not limited to) methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, tert-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydrogen Pyryl ether, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzalkonate, formate, acetate, trichloroacetic acid Ester and trifluoroacetate. Examples of protected amine groups include, but are not limited to, decylamines, for example, formamide, acetamide, trifluoroacetamide, and benzamide; quinone imines such as quinone imine and dithiosuccinimide Amine; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl sulfide and S-4-pyridylmethyl sulfide; substituted S-methyl derivatives such as hemisulfur, disulfide and amine groups Thioacetal; and others.
本發明醫藥組合包括(a)至少一種選自由以下組成之群之RTK抑制劑化合物:式I化合物或其互變異構物、式II化合物或其互變異構物、式III化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物。 The pharmaceutical combination of the invention comprises (a) at least one RTK inhibitor compound selected from the group consisting of a compound of formula I or a tautomer thereof, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof A pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof.
RTK抑制劑化合物可選自式I化合物、該化合物之互變異構物、該化合物之鹽、該互變異構物之鹽或其混合物,其中式I化合物具有下式:
其中:R1、R2、R3及R4可相同或不同,且獨立地選自H、Cl、Br、F、I、-OR10基團、-NR11R12基團、經取代或未經取代之一級、二級或三 級烷基、經取代或未經取代之芳基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜環基或經取代或未經取代之雜環基烷基;R5、R6、R7及R8可相同或不同,且獨立地選自H、Cl、Br、F、I、-OR13基團、-NR14R15基團、-SR11基團、經取代或未經取代之一級、二級或三級烷基、經取代或未經取代之芳基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜環基、經取代或未經取代之雜環基烷基、經取代或未經取代之烷氧基烷基、經取代或未經取代之芳氧基烷基或經取代或未經取代之雜環基氧基烷基;R10及R13可相同或不同,且獨立地選自經取代或未經取代之烷基、經取代或未經取代之芳基、經取代或未經取代之雜環基、經取代或未經取代之雜環基烷基、經取代或未經取代之烷氧基烷基、經取代或未經取代之芳氧基烷基或經取代或未經取代之雜環基氧基烷基;R11及R14可相同或不同,且獨立地選自經取代或未經取代之烷基、經取代或未經取代之芳基或經取代或未經取代之雜環基;R12及R15可相同或不同,且獨立地選自經取代或未經取代之烷基、經取代或未經取代之芳基或經取代或未經取代之雜環基;且R16選自經取代或未經取代之烷基、經取代或未經取代之芳基或經取代或未經取代之雜環基。 Wherein: R 1 , R 2 , R 3 and R 4 may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -OR 10 groups, -NR 11 R 12 groups, substituted or Unsubstituted primary, secondary or tertiary alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted a heterocyclic group or a substituted or unsubstituted heterocyclylalkyl group; R 5 , R 6 , R 7 and R 8 may be the same or different and independently selected from H, Cl, Br, F, I, - OR 13 group, -NR 14 R 15 group, -SR 11 group, substituted or unsubstituted one, two or three alkyl groups, substituted or unsubstituted aryl group, substituted or not Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted alkoxy An alkyl group, a substituted or unsubstituted aryloxyalkyl group or a substituted or unsubstituted heterocyclic oxyalkyl group; R 10 and R 13 may be the same or different and independently selected from substituted or unsubstituted Substituted alkyl group Or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl group, substituted or unsubstituted alkoxyalkyl group, substituted or unsubstituted Substituted aryloxyalkyl or substituted or unsubstituted heterocyclyloxyalkyl; R 11 and R 14 may be the same or different and independently selected from substituted or unsubstituted alkyl, substituted Or unsubstituted aryl or substituted or unsubstituted heterocyclic group; R 12 and R 15 may be the same or different and independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted An aryl group or a substituted or unsubstituted heterocyclic group; and R 16 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group .
RTK抑制劑化合物亦可選自式II化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物,其中式II化合物具有下式:
其中:R7係經取代或未經取代之雜環基。在一些實施例中,R7係選自經取代或未經取代之六氫吡啶基、六氫吡嗪基或嗎啉基之經取代或未經取代之雜環基。在其他實施例中,R7係經取代或未經取代之N-烷基六氫吡嗪基。在其他實施例中,R7係經取代或未經取代之N-烷基六氫吡嗪基,且N-烷基六氫吡嗪基之烷基包含1至4個碳原子。 Wherein: R 7 is a substituted or unsubstituted heterocyclic group. In some embodiments, R 7 is selected from substituted or unsubstituted heterocyclic groups of substituted or unsubstituted hexahydropyridyl, hexahydropyrazinyl or morpholinyl. In other embodiments, R 7 N- alkyl-based by-hexahydro-pyrazinyl, substituted or non-substituted. In other embodiments, R 7 N- alkyl-hexahydro-line by a substituted or unsubstituted pyrazinyl group, the N- alkyl and the alkyl group of the piperazine containing from 1 to 4 carbon atoms.
RTK抑制劑化合物亦可選自式III化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物,其中式III化合物具有下式:
式III化合物包括4-胺基-5-氟-3-[5-(4-甲基六氫吡嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮(化合物A)及(4-胺基-5-氟-3-[6-(4-甲基六氫吡嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮)(化合物B)。 The compound of formula III includes 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl)-1H-benzoimidazol-2-yl]quinoline-2 (1H) -ketone (Compound A) and (4-Amino-5-fluoro-3-[6-(4-methylhexahydropyrazin-1-yl)-1H-benzimidazol-2-yl]quinoline- 2(1H)-keto) (Compound B).
在較佳實施例中,本發明醫藥組合包括至少一種式I化合物或其 互變異構物、式II化合物或其互變異構物、式III化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物,該式III化合物係化合物A。 In a preferred embodiment, the pharmaceutical combination of the invention comprises at least one compound of formula I or a tautomer, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof The compound of formula III is compound A.
在另一較佳實施例中,本發明醫藥組合包括至少一種式I化合物或其互變異構物、式II化合物或其互變異構物、式III化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物,該式III化合物係化合物B。 In another preferred embodiment, the pharmaceutical combination of the invention comprises at least one compound of the formula I or a tautomer thereof, a compound of the formula II or a tautomer thereof, a compound of the formula III or a tautomer thereof, a pharmaceutical of the compound An acceptable salt, a pharmaceutically acceptable salt of the tautomer or a mixture thereof, the compound of formula III being Compound B.
式I之RTK抑制劑化合物或其互變異構物、式II化合物或其互變異構物、式III化合物或其互變異構物、該化合物之醫藥上可接受之鹽、該互變異構物之醫藥上可接受之鹽或其混合物;其調配物及其製備方法闡述於(例如)WO2002/222598、WO2003/087095、WO2005/046589、WO2006/127926、WO2006/124413、WO2007/064719、WO2009/115562及WO2012/001074中,該等案件以全文引用方式併入本文中。 An RTK inhibitor compound of the formula I or a tautomer thereof, a compound of the formula II or a tautomer thereof, a compound of the formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, the tautomer A pharmaceutically acceptable salt or a mixture thereof; a formulation thereof and a process for the preparation thereof are described, for example, in WO2002/222598, WO2003/087095, WO2005/046589, WO2006/127926, WO2006/124413, WO2007/064719, WO2009/115562 and These cases are incorporated herein by reference in their entirety in WO 2012/001074.
本發明化合物可以游離形式或醫藥上可接受之鹽形式投與。 The compounds of the invention may be administered in free form or as a pharmaceutically acceptable salt.
除非另有說明,否則本文所用「醫藥上可接受之鹽」包括無機鹼鹽、有機鹼鹽、無機酸鹽、有機酸鹽或鹼性或酸性胺基酸鹽。作為無機鹼鹽,本發明包括(例如)諸如鈉或鉀等鹼金屬鹽;諸如鈣及鎂或鋁等鹼土金屬鹽;及氨鹽。作為有機鹼鹽,本發明包括(例如)三甲胺鹽、三乙胺鹽、吡啶鹽、甲基吡啶鹽、乙醇胺鹽、二乙醇胺鹽及三乙醇胺鹽。作為無機酸鹽,本發明包括(例如)鹽酸、氫溴酸、硝酸、硫酸及磷酸之鹽。作為有機酸鹽,本發明包括(例如)甲酸鹽、乙酸鹽、三氟乙酸鹽、富馬酸鹽、草酸鹽、酒石酸鹽、馬來酸鹽、乳酸鹽、檸檬酸鹽、琥珀酸鹽、蘋果酸鹽、甲磺酸鹽、苯磺酸鹽及對甲苯磺酸鹽。作為鹼性胺基酸鹽,本發明包括(例如)精胺酸鹽、離胺酸鹽及鳥胺酸鹽。酸性胺基酸包括(例如)天冬胺酸及麩胺酸。 As used herein, "pharmaceutically acceptable salts" include inorganic base salts, organic base salts, mineral acid salts, organic acid salts or basic or acidic amino acid salts. As the inorganic base salt, the present invention includes, for example, an alkali metal salt such as sodium or potassium; an alkaline earth metal salt such as calcium and magnesium or aluminum; and an ammonia salt. As the organic base salt, the present invention includes, for example, a trimethylamine salt, a triethylamine salt, a pyridinium salt, a methylpyridine salt, an ethanolamine salt, a diethanolamine salt, and a triethanolamine salt. As the inorganic acid salt, the present invention includes, for example, a salt of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. As the organic acid salt, the present invention includes, for example, formate, acetate, trifluoroacetate, fumarate, oxalate, tartrate, maleate, lactate, citrate, succinate , malate, methanesulfonate, besylate and p-toluenesulfonate. As the basic amino acid salt, the present invention includes, for example, arginine, anisoamine, and aguanine. Acidic amino acids include, for example, aspartic acid and glutamic acid.
式I化合物之單乳酸鹽以各種多晶型物形式(包括(例如)單水合物形式及無水形式)存在。若相同物質組合物(包括其單水合物及溶劑合物)以產生特定結晶形式所特有的不同熱力學及物理性質之不同晶格佈置結晶,則產生多晶型物。 The monolactates of the compounds of formula I exist in various polymorphic forms including, for example, monohydrate forms and anhydrous forms. Polymorphs are produced if the same composition of matter (including its monohydrates and solvates) is crystallized in a different crystal lattice to produce different thermodynamic and physical properties characteristic of a particular crystalline form.
適於本發明之化合物A及化合物B之其他醫藥上可接受之鹽包括WO2005/04658中所揭示之鹽。 Other pharmaceutically acceptable salts suitable for the compounds A and B of the present invention include the salts disclosed in WO2005/04658.
除非文中另有說明或明確指示,否則在提及可用於本發明醫藥組合中之治療劑時,包括化合物之游離鹼及化合物之所有醫藥上可接受之鹽。 Unless otherwise stated or expressly indicated herein, reference is made to the therapeutic agents useful in the pharmaceutical compositions of the invention, including the free base of the compound and all pharmaceutically acceptable salts of the compound.
該等藉由編號、通用名或商品名標識之化合物的結構可自標準綱要「默克索引(The Merck Index)」之現行版本或自(例如)國際專利(Patents International)(例如IMS World Publications)等數據庫獲得。其相應內容以引用方式併入本文中。 The structure of such compounds identified by number, generic or trade name may be from the current version of the standard "The Merck Index" or from, for example, Patents International (eg IMS World Publications) Wait for the database to get. The corresponding content is hereby incorporated by reference.
在本文中給出專利申請案之引文之各種情況下,與化合物有關之標的物以引用方式併入本申請案中。可分別按照所引用文件中所述來製備及投與在本發明之醫藥組合中用作治療劑之化合物。同樣包含其中所揭示其醫藥上可接受之鹽、對應外消旋異構物、非對映同分異構物、對映異構物、互變異構物以及上文所揭示化合物之對應晶體變體(若存在),例如,溶劑合物、水合物及多晶型物。兩種如上文所述單獨治療劑之組合亦在本發明之範圍內,即,在本發明範圍內之醫藥組合可包括三種或更多種治療劑。 In each case where the citation of the patent application is given herein, the subject matter related to the compound is incorporated herein by reference. Compounds useful as therapeutic agents in the pharmaceutical compositions of the present invention can be prepared and administered as described in the cited documents, respectively. Also included are the pharmaceutically acceptable salts, corresponding racemic isomers, diastereomeric isomers, enantiomers, tautomers, and corresponding crystal modifications of the compounds disclosed above disclosed therein. Body, if present, for example, solvates, hydrates, and polymorphs. Combinations of two separate therapeutic agents as described above are also within the scope of the invention, i.e., a pharmaceutical combination within the scope of the invention may include three or more therapeutic agents.
根據本發明,優選組合配偶體係(a)選自由以下組成之群之RTK抑制劑化合物:4-胺基-5-氟-3-[5-(4-甲基六氫吡嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮(化合物A)及(4-胺基-5-氟-3-[6-(4-甲基六氫吡嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮)(化合物B),或其醫藥上可接受之鹽,及(b)(3β)-17-(吡啶-3-基)雄甾-5,16-二烯-3-醇或其醫藥 上可接受之鹽。較佳地,該等化合物以治療有效劑量投與,其在組合時,提供有益效應。投與可為同時或依序。 According to the present invention, it is preferred that the combined mate system (a) is selected from the group consisting of RTK inhibitor compounds consisting of 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl) -1H-benzimidazol-2-yl]quinoline-2(1H)-one (Compound A) and (4-Amino-5-fluoro-3-[6-(4-methylhexahydropyrazine) -1-yl)-1H-benzimidazol-2-yl]quinoline-2(1H)-one) (Compound B), or a pharmaceutically acceptable salt thereof, and (b)(3β)-17- (pyridin-3-yl)androst-5,16-dien-3-ol or its medicine Acceptable salt. Preferably, the compounds are administered in a therapeutically effective amount which, when combined, provides a beneficial effect. The vote can be simultaneous or sequential.
在一個實施例中,增殖性病症係癌症。本文所用術語「癌症」意指廣譜腫瘤,包括所有實體瘤及血液惡性病。此等腫瘤之實例包括(但不限於)以下之良性或惡性腫瘤:腦及中樞神經系統、肺(特定而言小細胞肺癌及非小細胞肺癌)、膀胱、***、胃、胰腺、***、頭及頸、腎(renal,kidney)、輸尿管、卵巢、***、結腸直腸、食道、睪丸、婦科(例如,卵巢、子宮肉瘤、輸卵管癌、子宮內膜癌、宮頸癌、***癌或***)、甲狀腺、胰腺、骨、皮膚、黑素瘤、直腸、肛門、結腸、睪丸、霍奇金氏病(Hodgkin's disease)、小腸、內分泌系統(例如,甲狀腺、副甲狀腺或腎上腺)、軟組織及骨肉瘤、尿道、陰莖、白血病、淋巴瘤、多發性骨髓瘤、膽、肝、神經纖維瘤病、急性骨髓性白血病(AML)、骨髓增生異常症候群(MDS)及卡波氏肉瘤(Kaposi's sarcoma)。 In one embodiment, the proliferative disorder is cancer. The term "cancer" as used herein refers to a broad spectrum of tumors, including all solid tumors and hematological malignancies. Examples of such tumors include, but are not limited to, benign or malignant tumors: brain and central nervous system, lung (specifically small cell lung cancer and non-small cell lung cancer), bladder, prostate, stomach, pancreas, breast, head And neck, kidney (renal, kidney), ureter, ovary, prostate, colorectal, esophagus, testicular, gynecology (for example, ovary, uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer or vulva), thyroid , pancreas, bone, skin, melanoma, rectum, anus, colon, testicular, Hodgkin's disease, small intestine, endocrine system (eg, thyroid, parathyroid or adrenal gland), soft tissue and osteosarcoma, urethra , penis, leukemia, lymphoma, multiple myeloma, gallbladder, liver, neurofibromatosis, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and Kaposi's sarcoma.
根據又一態樣,本發明提供用於投與人類之協同組合,其包含(a)選自由以下組成之群之RTK抑制劑化合物:4-胺基-5-氟-3-[5-(4-甲基六氫吡嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮(化合物A)及(4-胺基-5-氟-3-[6-(4-甲基六氫吡嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮)(化合物B)或其醫藥上可接受之鹽,及(b)(3β)-17-(吡啶-3-基)雄甾-5,16-二烯-3-醇或其醫藥上可接受之鹽,其中各組份之劑量範圍對應於在適宜腫瘤模型(例如,下文實例中所述之腫瘤模型)中觀察到之協同範圍,該等範圍主要用於鑑別協同交互作用。 According to still another aspect, the present invention provides a synergistic combination for administration to humans comprising (a) an RTK inhibitor compound selected from the group consisting of 4-amino-5-fluoro-3-[5-( 4-methylhexahydropyrazin-1-yl)-1H-benzoimidazol-2-yl]quinoline-2(1H)-one (Compound A) and (4-Amino-5-fluoro-3- [6-(4-Methylhexahydropyrazin-1-yl)-1H-benzoimidazol-2-yl]quinoline-2(1H)-one) (Compound B) or a pharmaceutically acceptable salt thereof And (b) (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol or a pharmaceutically acceptable salt thereof, wherein the dose range of each component corresponds to The synergistic range observed in a suitable tumor model (e.g., the tumor model described in the Examples below) is primarily used to identify synergistic interactions.
本發明之一個目標係提供包含針對增殖性疾病聯合治療有效之量之醫藥組合物,其包含本發明組合。在此組合物中,組合配偶體(a)及(b)可藉由任何適宜途徑以單一調配物或單位劑型投與,同時但單獨地投與,或依序地投與。該單位劑型亦可為固定組合。 One object of the present invention is to provide a pharmaceutical composition comprising an amount effective in combination therapy for proliferative diseases comprising a combination of the invention. In this composition, the combination partners (a) and (b) can be administered in a single formulation or unit dosage form by any suitable route, but administered separately, or sequentially. The unit dosage form can also be a fixed combination.
用於單獨投與兩種組合配偶體或用於以固定組合(即,單一蓋倫製劑(galenical)組合物)投與之包含本發明組合的醫藥組合物可以本身已知之方式製備且為彼等適於經腸(例如經口或直腸)及非經腸投與包括人類在內之哺乳動物(溫血動物)者,其包含治療有效量之單獨至少一種藥理學活性組合配偶體(例如如上文所指示)或該配偶體與一或多種尤其適於經腸或非經腸施加之醫藥上可接受之載劑之組合。 Pharmaceutical compositions comprising the combination of the two, or a combination comprising a combination of the invention, for administration in a fixed combination (i.e., a single galenical composition) may be prepared in a manner known per se and are Suitable for enteral (eg, oral or rectal) and parenteral administration to a mammal, including a human, a warm-blooded animal, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone (eg, as above) Indicated) or a combination of the partner and one or more pharmaceutically acceptable carriers which are particularly suitable for enteral or parenteral administration.
新穎醫藥組合物可含有約0.1%至約99.9%、較佳約1%至約60%之治療劑。 The novel pharmaceutical compositions may contain from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of the therapeutic agent.
用於經腸或非經腸投與之組合療法之適宜醫藥組合物係(例如)彼等呈單元劑型者,例如糖包衣錠劑、錠劑、膠囊或栓劑或安瓿。若不另外指明,則該等係以本身已知之方式製備,例如藉助各種習用混合、粉碎、直接壓縮、造粒、糖包衣、溶解、凍乾製程或彼等熟習此項技術者容易明瞭之製作技術製備。應瞭解,組合配偶體含於各劑型之個別劑量內之單位含量本身無需構成有效量,此乃因必需有效量可藉由投與複數個劑量單位來達成。 Suitable pharmaceutical compositions for combination therapy by enteral or parenteral administration are, for example, those in unit dosage form, such as sugar-coated lozenges, lozenges, capsules or suppositories or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulation, sugar coating, dissolving, lyophilization processes or those skilled in the art. Production technology preparation. It will be appreciated that the unit content of the combination partner contained within individual dosages of each dosage form need not constitute an effective amount per se, since the necessary effective amount can be achieved by administering a plurality of dosage units.
含有藥劑組合或藥劑組合之個別藥劑之單位劑型可呈包封於膠囊(例如明膠膠囊)內之微錠劑形式。為此,可使用用於醫藥調配物中之明膠膠囊,例如稱為CAPSUGEL之硬明膠膠囊(自Pfizer獲得)。本發明單位劑型可視情況進一步包含用於醫藥之其他習用載劑或賦形劑。此等載劑之實例包括(但不限於)崩解劑、結合劑、潤滑劑、滑動劑、穩定劑及填充劑、稀釋劑、著色劑、矯味劑及防腐劑。熟習此項技術者藉由常規實驗即可針對劑型之特定期望性質來選擇上述載劑中之一或多種而無需任何過多工作量。所用各載劑之量可在業內習用範圍內變化。以下皆以引用方式併入本文中之參考文獻揭示用於調配口服劑型之技術及賦形劑。參見The Handbook of Pharmaceutical Excipients,第4版,Rowe等人編輯,American Pharmaceuticals Association(2003);及Remington:the Science and Practice of Pharmacy,第20版,Gennaro編輯,Lippincott Williams & Wilkins(2003)。 The unit dosage form containing the individual agent or combination of agents may be in the form of a micro-tablet enclosed in a capsule, such as a gelatin capsule. For this purpose, gelatin capsules for use in pharmaceutical formulations, such as hard gelatin capsules known as CAPSUGEL (available from Pfizer) can be used. The unit dosage form of the invention may optionally comprise other conventional carriers or excipients for use in medicine. Examples of such carriers include, but are not limited to, disintegrants, binders, lubricants, slip agents, stabilizers and fillers, diluents, colorants, flavoring agents, and preservatives. One or more of the above carriers can be selected by a person skilled in the art by routine experimentation with respect to the particular desired properties of the dosage form without any excessive effort. The amount of each carrier used can vary within the range of practice in the art. The following references, which are hereby incorporated by reference, disclose the entire disclosure of the disclosure of the disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of See The Handbook of Pharmaceutical Excipients , 4th edition, edited by Rowe et al., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro ed., Lippincott Williams & Wilkins (2003).
可藉由在造粒之前或造粒期間將一或多種習用載劑納入初始混合物中或藉由在口服劑型中組合一或多種習用載劑與包含藥劑組合或藥劑組合之個別藥劑之顆粒將該等可選其他習用載劑納入口服劑型中。在後一實施例中,經組合混合物可經進一步摻和,例如經由V形摻和器摻和,且隨後壓縮或模製成錠劑(例如單片錠劑),藉由膠囊囊封,或填充至藥囊中。 One or more conventional carriers may be included in the initial mixture prior to or during granulation or by combining one or more conventional carriers in an oral dosage form with granules of individual agents comprising a combination of agents or agents. Other optional carriers are included in the oral dosage form. In the latter embodiment, the combined mixture may be further blended, for example, via a V-shaped blender, and then compressed or molded into a tablet (eg, a tablet), encapsulated by a capsule, or Fill into the sachet.
醫藥上可接受之崩解劑之實例包括(但不限於)澱粉;黏土;纖維素;海藻酸鹽;樹膠;交聯聚合物,例如交聯聚乙烯基吡咯啶酮;交聯羧甲基纖維素鈉(cross-linked sodium carboxymethylcellulose或croscarmellose sodium),例如來自FMC之ACDI-SOL;及交聯羧甲基纖維素鈣;大豆多糖;及瓜爾膠(guar gum)。崩解劑可以組合物之約0重量%至約10重量%之量存在。在一個實施例中,崩解劑以組合物之約0.1重量%至約5重量%之量存在。 Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starch; clay; cellulose; alginates; gums; crosslinked polymers such as crosslinked polyvinylpyrrolidone; crosslinked carboxymethyl fibers Cross-linked sodium carboxymethylcellulose or croscarmellose sodium, such as ACDI-SOL from FMC; and croscarmellose calcium; soybean polysaccharide; and guar gum. The disintegrant can be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1% to about 5% by weight of the composition.
醫藥上可接受之結合劑之實例包括(但不限於)澱粉;纖維素及其衍生物,例如微晶纖維素(例如,來自FMC(Philadelphia,PA)之AVICEL PH)、羥丙基纖維素、羥乙基纖維素及來自Dow Chemical公司(Midland,MI)之羥丙基甲基纖維素METHOCEL;蔗糖;右旋糖;玉米糖漿;多糖;及明膠。結合劑可以組合物之約0重量%至約50重量%(例如,2-20重量%)之量存在。 Examples of pharmaceutically acceptable binding agents include, but are not limited to, starch; cellulose and its derivatives, such as microcrystalline cellulose (eg, AVICEL PH from FMC (Philadelphia, PA)), hydroxypropyl cellulose, Hydroxyethyl cellulose and hydroxypropyl methylcellulose METHOCEL from Dow Chemical Company (Midland, MI); sucrose; dextrose; corn syrup; polysaccharide; and gelatin. The binding agent can be present in an amount from about 0% to about 50% by weight (e.g., from 2 to 20% by weight) of the composition.
醫藥上可接受之潤滑劑及醫藥上可接受之滑動劑之實例包括(但不限於)膠體二氧化矽、三矽酸鎂、澱粉、滑石粉、磷酸鈣、硬脂酸鎂、硬脂酸鋁、硬脂酸鈣、碳酸鎂、氧化鎂、聚乙二醇、粉狀纖維素及微晶纖維素。潤滑劑可以組合物之約0重量%至約10重量%之量存 在。在一個實施例中,潤滑劑可以組合物之約0.1重量%至約1.5重量%之量存在。滑動劑可以約0.1重量%至約10重量%之量存在。 Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable slip agents include, but are not limited to, colloidal cerium oxide, magnesium tristearate, starch, talc, calcium phosphate, magnesium stearate, aluminum stearate , calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The lubricant may be present in an amount from about 0% to about 10% by weight of the composition. in. In one embodiment, the lubricant can be present in an amount from about 0.1% to about 1.5% by weight of the composition. The slip agent can be present in an amount from about 0.1% to about 10% by weight.
醫藥上可接受之填充劑及醫藥上可接受之稀釋劑之實例包括(但不限於)粉糖、可壓縮糖、葡聚糖結合劑、糊精、右旋糖、乳糖、甘露醇、微晶纖維素、粉狀纖維素、山梨醇、蔗糖及滑石粉。填充劑及/或稀釋劑例如可以組合物之約0重量%至約80重量%之量存在。 Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, powdered sugar, compressible sugars, glucan binding agents, dextrin, dextrose, lactose, mannitol, microcrystals Cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent may be present, for example, in an amount from about 0% to about 80% by weight of the composition.
在一個實施例中,本發明亦係關於本發明之組合,其用於製備用以治療或預防有需要之個體之增殖性疾病之醫藥組合物或藥劑。 In one embodiment, the invention is also directed to a combination of the invention for the manufacture of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disorder in an individual in need thereof.
在又一實施例中,本發明係關於選自由以下組成之群之RTK抑制劑化合物與至少一種抗***、尤其氟維司群(fulvestrant)或其醫藥上可接受之鹽之組合的用途:4-胺基-5-氟-3-[5-(4-甲基六氫吡嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮(化合物A)及(4-胺基-5-氟-3-[6-(4-甲基六氫吡嗪-1-基)-1H-苯并咪唑-2-基]喹啉-2(1H)-酮)(化合物B)或其醫藥上可接受之鹽,其用於製備用以治療或預防有需要之個體之增殖性疾病之醫藥組合物或藥劑。 In a further embodiment, the invention relates to the use of a combination of an RTK inhibitor compound selected from the group consisting of at least one antiestrogenic, in particular fulvestrant, or a pharmaceutically acceptable salt thereof: 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl)-1H-benzoimidazol-2-yl]quinoline-2(1H)-one (compound) A) and (4-Amino-5-fluoro-3-[6-(4-methylhexahydropyrazin-1-yl)-1H-benzimidazol-2-yl]quinoline-2 (1H) a ketone) (Compound B) or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disorder in an individual in need thereof.
根據本發明,治療有效量之本發明組合之各組合配偶體可同時或依序且以任一順序投與,且該等組份可單獨或以固定組合形式投與。例如,本發明之治療增殖性疾病之方法可包含同時或以任一順序依序以聯合治療有效量、較佳以協同有效量(例如,以對應於本文所述量之每日或間歇劑量)(i)投與呈游離形式或醫藥上可接受之鹽形式之第一藥劑(a)及(ii)投與呈游離形式或醫藥上可接受之鹽形式之藥劑(b)。本發明組合之個別組合配偶體可在療法進程期間於不同時間單獨投與或以分次或單一組合形式同時投與。此外,術語「投與」亦涵蓋使用組合配偶體之前藥,該前藥於活體內轉化成原樣組合配偶體。因此,本發明應理解為涵蓋所有該等同時或交替治療之方案且術語「投與」應相應地理解。 In accordance with the present invention, a therapeutically effective amount of each of the combination partners of the combinations of the invention can be administered simultaneously or sequentially and in any order, and the components can be administered separately or in a fixed combination. For example, a method of treating a proliferative disorder of the invention can comprise a therapeutically effective amount, preferably in a synergistically effective amount (eg, in a daily or intermittent dose corresponding to the amounts described herein), either simultaneously or in any order. (i) administration of the first agent (a) and (ii) in the form of a free form or a pharmaceutically acceptable salt (b) in the form of a free form or a pharmaceutically acceptable salt. The individual combination partners of the combinations of the invention may be administered separately at different times during the course of the therapy or simultaneously in a divided or single combination. In addition, the term "administering" also encompasses the use of a combination partner's prodrug, which is converted in vivo to the original combination partner. Therefore, the present invention should be understood to cover all such simultaneous or alternating treatments and the term "administration" should be understood accordingly.
用於本發明組合中之各組合配偶體之有效劑量可端視所用特定化合物或醫藥組合物、投與模式、所治療之病況及所治療病況之嚴重程度而變化。因此,本發明組合之劑量方案應根據多種因素(包括投與途徑及患者之腎及肝功能)來選擇。具有一般技能之臨床醫師或醫師可容易地確定減緩、對抗或阻止該病況惡化所需單一治療劑之有效量並開出處方。 The effective dosage of each combination partner for use in the combination of the invention will vary depending upon the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Thus, the dosage regimen of the combination of the invention should be selected based on a variety of factors, including the route of administration and the kidney and liver function of the patient. A clinician or physician with general skill can readily determine the effective amount of a single therapeutic agent needed to slow, counter or prevent the progression of the condition and prescribe.
本發明組合之組合配偶體(a)及(b)產生功效且無毒性之最佳比率、個別及組合劑量及濃度係基於治療劑對於靶部位之可利用性之動力學,且係使用彼等熟習此項技術者已知之方法測定。 The optimal ratios, individual and combined doses and concentrations of the combination partners (a) and (b) of the present invention to produce efficacy and non-toxicity are based on the kinetics of the availability of the therapeutic agent to the target site, and are used It is determined by methods known to those skilled in the art.
各個體可根據經驗使用已知方法確定各組合配偶體用於治療增殖性疾病之最佳劑量,且其將取決於多種因素,包括(但不限於)疾病進展程度;個體之年齡、體重、總體健康狀況、性別及飲食;投與時間及途徑;及個體正在服用之其他藥劑。最佳劑量可使用業內所熟知之常規測試及程序來確定。 Each individual can empirically determine the optimal dosage of each combination partner for the treatment of a proliferative disease using known methods, and it will depend on a variety of factors including, but not limited to, the extent of disease progression; the age, weight, and overall of the individual. Health status, gender and diet; time and route of administration; and other medications the individual is taking. The optimal dosage can be determined using routine testing and procedures well known in the art.
可與載劑材料組合以產生單一劑型之各組合配偶體的量將端視所治療個體及特定投與模式而變化。在一些實施例中,含有本文所述藥劑組合之單位劑型將含有通常在單獨投與藥劑時投與之量之該組合之各藥劑。 The amount of each combination partner that can be combined with the carrier material to produce a single dosage form will vary depending on the individual being treated and the particular mode of administration. In some embodiments, a unit dosage form containing a combination of agents described herein will contain each of the agents typically administered in the amounts administered when the agent is administered separately.
劑量頻率可端視所用化合物及所欲治療或預防之特定病況而變化。一般而言,較佳使用足以提供有效療法之最低劑量。通常可使用適於所治療或預防病況之分析來監測患者之治療有效性,該等分析應為彼等熟習此項技術者所熟悉。 The dosage frequency can vary depending on the compound employed and the particular condition being treated or prevented. In general, it is preferred to use a minimum dose sufficient to provide an effective therapy. The patient's therapeutic effectiveness can generally be monitored using an assay suitable for treating or preventing the condition, and such analysis should be familiar to those skilled in the art.
本發明進一步提供市售包裝,其包含作為治療劑之本發明組合以及其同時、單獨或依序使用之說明書,該包裝用於延遲有需要之個體之增殖性疾病之惡化或治療該疾病。 The invention further provides a commercially available package comprising a combination of the invention as a therapeutic agent and instructions for its simultaneous, separate or sequential use for delaying the progression or treatment of a proliferative disorder in an individual in need thereof.
以下實例闡釋上文所述之本發明;然而,其並不意欲以任一方 式限制本發明之範圍。本發明醫藥組合之有益效應亦可藉由熟習此項相關技術者原本已知之其他測試模型來測定。 The following examples illustrate the invention described above; however, it is not intended to be either The scope of the invention is limited. The beneficial effects of the pharmaceutical compositions of the present invention can also be determined by other test models known to those skilled in the art.
使用人類***癌異種移植物實施之臨床前研究支持FGF信號傳導促成AR獨立性抗去勢疾病之演變之假設。MDA PCa 118b係自晚期抗去勢病人獲得之骨轉移的***癌異種移植物。分子病理學分析揭示,MDA PCa 118b細胞不表現AR,但過度表現高FGF9量。MDA PCa 118b細胞在活體外誘導共培養之成骨細胞之增殖且在免疫缺陷小鼠之骨中以FGF9依賴方式誘導強成骨性反應。在細胞注射後5週對MDA PCa 118b正位骨腫瘤之MRI分析證實,用FGF9中和抗體治療之小鼠產生顯著小於對照之腫瘤。該等引起關注之臨床數據提示利用TKI258在人類mCRPC患者中測試FGF抑制。 Preclinical studies using human prostate cancer xenografts support the hypothesis that FGF signaling contributes to the evolution of AR-independent anti-castration disease. MDA PCa 118b is a metastatic prostate cancer xenograft obtained from advanced anti-castration patients. Molecular pathology analysis revealed that MDA PCa 118b cells did not exhibit AR but overexpressed high FGF9 levels. MDA PCa 118b cells induce proliferation of co-cultured osteoblasts in vitro and induce strong osteogenic responses in the FGF9-dependent manner in the bone of immunodeficient mice. MRI analysis of MDA PCa 118b orthotopic bone tumors 5 weeks after cell injection confirmed that mice treated with FGF9 neutralizing antibody produced tumors significantly smaller than the control. These clinical data of concern suggest the use of TKI258 to test FGF inhibition in human mCRPC patients.
正在進行之TKI258臨床研究包括抗去勢***癌及骨轉移(mCPRC)患者,目標在於在骨髓生檢樣品中評估bFGF信號傳導標記物。患者每天經口接受500mg,持續5天,之後為2天休息期。每個週期為28天且每56天(8週)評價反應。患者持續服用TKI258直至疾病惡化、毒性不可接受或撤回同意。迄今已登記40名患者中之17名。中值年齡為68歲,所有患者皆具有骨轉移,41%患者亦具有淋巴結及/或內臟轉移,且82%患者已預先接受至少一種細胞毒性化學療法方案。中值隨訪為63天且尚未達到中值PFS。最常見之療法相關毒性為1/2級,包括疲勞(37%)、噁心(50%)及腹瀉(50%)。3級毒性比較罕見,包括疲勞(12%)及呼吸困難(12%)。迄今尚無4級毒性。在8週時間點,9/17(52%)患者表現穩定疾病,2/17(10%)在淋巴結中表現PR,2/17(10%)因放射照相惡化而中斷研究,3/17(18%)患者因臨床惡化而中斷研究,且1/17(6%)退出。到目前為止,17患者中之4名(25%)經歷4 個月之持久反應且3名積極接受治療。對腫瘤浸潤之骨髓生檢初步分子病理學分析揭示TKI258誘導之對FGFR1及其下游靶標磷酸-MAPK之下調。 The ongoing TKI258 clinical study includes patients with anti-castrated prostate cancer and bone metastases (mCPRC) with the goal of assessing bFGF signaling markers in bone marrow biopsy samples. The patient received 500 mg orally every day for 5 days, followed by a 2-day rest period. The reaction was evaluated every 28 days and every 56 days (8 weeks). The patient continues to take TKI258 until the disease worsens, the toxicity is unacceptable, or the consent is withdrawn. To date, 17 of the 40 patients have been registered. The median age was 68 years, all patients had bone metastases, 41% had lymph node and/or visceral metastases, and 82% had pre-accepted at least one cytotoxic chemotherapy regimen. The median follow-up was 63 days and the median PFS had not been reached. The most common treatment-related toxicity is 1/2, including fatigue (37%), nausea (50%), and diarrhea (50%). Grade 3 toxicity is rare, including fatigue (12%) and difficulty breathing (12%). There is no grade 4 toxicity to date. At the 8-week time point, 9/17 (52%) patients showed stable disease, 2/17 (10%) showed PR in the lymph nodes, and 2/17 (10%) discontinued the study due to radiographic deterioration, 3/17 ( 18% of patients discontinued the study due to clinical deterioration and 1/17 (6%) withdrew. So far, 4 out of 17 patients (25%) have experienced 4 months of long-term response and 3 active treatment. Preliminary molecular pathology analysis of bone marrow biopsy for tumor infiltration revealed TKI258-induced down-regulation of FGFR1 and its downstream target phospho-MAPK.
基於該等有前景之初步結果,探索以下臨床假設:TI258將藉由抑制促成阿比特龍抗性之AR獨立性信號傳導途徑FGF來改良阿比特龍之抗腫瘤活性。 Based on these promising preliminary results, the following clinical hypothesis was explored: TI258 will improve the anti-tumor activity of abiraterone by inhibiting the AR-independent signaling pathway FGF that contributes to abiraterone resistance.
在此研究中,將確定TKI258與阿比特龍之組合在人轉移性抗去勢***癌中之安全性及臨床效果。主要終點係: In this study, the safety and clinical efficacy of the combination of TKI258 and abiraterone in human metastatic anti-castration prostate cancer will be determined. Primary endpoint:
1)評價TKI258與阿比特龍之組合在此患者組中之耐受性及安全性。 1) To evaluate the tolerability and safety of the combination of TKI258 and abiraterone in this patient group.
2)無惡化存活期(PFS)係主要終點。PFS將為定義為自進入研究至首次出現以下中任一者之時間的複合終點: 2) Non-deteriorating survival (PFS) is the primary endpoint. PFS will be a composite endpoint defined as the time from entry into the study to the first occurrence of any of the following:
‧藉由RECIST準則所確定可量測疾病之惡化。為了視為可量測,基線淋巴結、內臟轉移及軟組織轉移最長尺寸上必須2cm。可疑RECIST惡化必須在>6週後藉由跟蹤掃描來確認。 ‧ The deterioration of the disease can be measured by the RECIST guidelines. In order to be considered measurable, baseline lymph nodes, visceral metastases, and soft tissue metastases must be the longest dimension 2cm. Suspected RECIST deterioration must be confirmed by tracking scans after >6 weeks.
‧藉由骨掃描所確定兩個或更多個可歸因於***癌(而非發紅)之新區域或藉由CT掃描或MRI所確定新/增加大小之溶解性病灶。骨掃描之可疑惡化必須藉由其他成像模式(例如,CT或MRI)及/或在6週後實施確認性骨掃描來確認。 • Two or more new regions attributable to prostate cancer (rather than redness) or new/increased size of soluble lesions as determined by CT scan or MRI as determined by bone scan. Suspicious deterioration of bone scans must be performed by other imaging modalities (eg, CT or MRI) and/or A confirmatory bone scan was performed 6 weeks later to confirm.
‧需要涉及一個以上部位之姑息性放射 ‧ need to involve more than one part of palliative radiation
‧對任何腫瘤性骨病灶實施之手術或後凸成型術 ‧Surgical or kyphoplasty for any tumorous bone lesion
‧癌症相關性臨床惡化,如由治療醫師所確定。 ‧ Cancer-related clinical deterioration, as determined by the treating physician.
不會單獨使用PSA惡化來界定惡化。 PSA deterioration will not be used alone to define the deterioration.
3)收集及彙集(bank)血液及組織樣品用於以後之假設生成性研 究。 3) Collecting and pooling blood and tissue samples for future hypothesis Research.
1)總體存活期 1) Overall survival
2)放射性反應 2) Radioactive reaction
3)生物標記物調節(例如PSA、CTC、血清細胞介素分佈、骨特異性鹼性磷酸酶、尿n-端肽) 3) Biomarker regulation (eg PSA, CTC, serum interleukin distribution, bone-specific alkaline phosphatase, urinary n-terminal peptide)
4)腫瘤藥效動力學量度(使用轉移性組織試樣對FGF及雄激素-受體(AR)信號傳導途徑實施分子病理學分析)。 4) Tumor pharmacodynamic measurement (molecular pathology analysis of FGF and androgen-receptor (AR) signaling pathways using metastatic tissue samples).
在起始II期研究部分之前,將利用劑量遞增I期方案來獲得安全性數據並選擇TKI258與阿比特龍之組合之最佳開始劑量。 Prior to the Phase II study, a dose escalation Phase I protocol will be used to obtain safety data and select the optimal starting dose for the combination of TKI258 and Abiraterone.
如下文所示,3至6名患者群組將使用28天週期用TKI258及阿比特龍治療。TKI258之開始劑量(等級0)將為每天經口200mg,其中5天服用,2天停用,且阿比特龍之劑量將為每天經口1000mg。普賴松將以5mg經口每天兩次投與。 As shown below, groups of 3 to 6 patients will be treated with TKI258 and abiraterone using a 28-day cycle. The starting dose of TKI258 (grade 0) will be 200 mg per day, of which 5 days will be taken, 2 days will be discontinued, and the dose of abiraterone will be 1000 mg per day. Presson will be administered twice daily with 5mg oral.
在週期1期間在各劑量等級下必須滿足如表1中所述之劑量遞增準則以便在下一給藥等級下登記並治療患者。 The dose escalation criteria as described in Table 1 must be met at each dose level during Cycle 1 to register and treat the patient at the next dosing level.
應用3+3設計,由3名患者組成之第一群組將以劑量等級0治療。演算法如下:(1)若3名患者皆未經歷DLT,則由3名患者組成之下一群組將以下一更高劑量等級治療。(2)若3名患者中之1名發生DLT,則其他3名患者將以同一劑量等級治療。若在該劑量下不再發生DLT,即 總共6名患者中之1名發生DLT,則由3名患者組成之下一群組繼續劑量遞增。(3)在任一給定劑量下,若3名患者中之1名以上或6名患者中之1名以上經歷DLT,則劑量等級超過MTD,且若以該劑量治療之患者不到6名,則另外3名患者將以下一更低劑量治療。MTD係其中6名患者中之1名或更少患有DLT的最高研究劑量。 Using the 3+3 design, the first group consisting of 3 patients will be treated with dose level 0. The algorithm is as follows: (1) If all 3 patients have not experienced DLT, the next group consisting of 3 patients will be treated with the following higher dose level. (2) If one of the 3 patients develops DLT, the other 3 patients will be treated at the same dose level. If DLT no longer occurs at this dose, ie A DLT occurred in 1 of a total of 6 patients, and a group consisting of 3 patients continued to increase in dose. (3) At any given dose, if more than one of the three patients or more than one of the six patients experience DLT, the dose level exceeds the MTD, and if less than 6 patients are treated at that dose, The other 3 patients will be treated with the following lower dose. One of the 6 patients with MTD was the highest studied dose of DLT.
在各給定劑量等級下,將存在一週間隙以評估第一名患者之納入與接下來2名患者之納入之間的毒性。 At each given dose level, there will be a one-week gap to assess the toxicity between the inclusion of the first patient and the inclusion of the next two patients.
為使DLT符合要求,應使臨床不良事件(AE)或實驗室異常與藥物相關,如由治療醫師、主要研究者或資助者所評價。DLT將在第一個治療週期界定(根據NCI-CTCAE v 4分級量表)。發生在第一週期之任何藥物相關3級或4級毒性(排除藉由標準療法控制之噁心、嘔吐或腹瀉)視為劑量限制性毒性(DLT),該毒性不包括與繼發性鹽皮質激素過量症候群(包括高血壓、低鉀血症及液體過剩)有關之預期毒性。與鹽皮質激素濃度升高有關之毒性將利用鹽皮質激素受體拮抗劑(依普利酮(eplerenone)50至200mg/d)管控。若鹽皮質激素拮抗作用不逆轉該等毒性,則僅利用每天用0.5mg***(dexamethasone)治療來抑制ACTH。 In order for the DLT to meet the requirements, clinical adverse events (AEs) or laboratory abnormalities should be associated with the drug, as evaluated by the treating physician, primary investigator, or sponsor. The DLT will be defined during the first treatment cycle (according to the NCI-CTCAE v 4 grading scale). Any drug-related grade 3 or 4 toxicity that occurs during the first cycle (excluding nausea, vomiting, or diarrhea controlled by standard therapy) is considered dose-limiting toxicity (DLT), which does not include secondary mineralocorticoids. Expected toxicity associated with excess syndrome (including hypertension, hypokalemia, and fluid excess). Toxicity associated with elevated mineralocorticoid concentrations will be controlled using a mineralocorticoid receptor antagonist (eplerenone 50 to 200 mg/d). If mineralocorticoid antagonism does not reverse these toxicities, ACTH is only inhibited by treatment with 0.5 mg dexamethasone daily.
在選擇TKI258與阿比特龍之最佳開始劑量後,將開始II期研究部分。大約40名患者將接受研究治療直至滿足以下準則中之任一者: After selecting the optimal starting dose for TKI258 and Abiraterone, the Phase II study will begin. Approximately 40 patients will receive study treatment until one of the following criteria is met:
‧疾病惡化 ‧ Disease worsens
‧毒性不可接受 ‧ toxicity is unacceptable
‧患者決定退出 ‧The patient decided to quit
‧涉及一個以上部位之姑息性放射 ‧ palliative radiation involving more than one part
‧根據研究者之判斷,進一步治療將不符合患者之最佳利益。 ‧ According to the investigator's judgment, further treatment will not be in the best interests of the patient.
患者總數:60 Total number of patients: 60
治療組患者數:NA Number of patients in the treatment group: NA
中心數:MDACC Number of centers: MDACC
納入標準 Inclusion criteria
1)患者或其合法授權代表必須提供書面知情同意書。 1) The patient or his or her legally authorized representative must provide written informed consent.
2)年齡18 2) Age 18
3)ECOG性能狀態2 3) ECOG performance status 2
4)***腺癌之組織學證據 4) Histological evidence of prostate adenocarcinoma
5)轉移性抗去勢***癌 5) Metastatic anti-castration prostate cancer
6)患者必須具有手術或正在進行之化學去勢(利用LHRH激動劑或LHRH拮抗劑),其中基線睪酮濃度<50ng/dL。 6) The patient must have surgery or ongoing chemical castration (using an LHRH agonist or LHRH antagonist) with a baseline ketone concentration <50 ng/dL.
7)患者必須具有經記錄之惡化性疾病證據,如藉由以下中之任一者所界定: 7) The patient must have evidence of a documented degenerative disease, as defined by any of the following:
‧PSA惡化:獲得最少2個上升值(3次量測),間隔最少7天,其中最後結果為至少2.0ng/mL ‧PSA deterioration: get at least 2 ascents (3 measurements) with a minimum of 7 days, with the final result being at least 2.0ng/mL
‧新或增加之非骨疾病(RECIST) ‧New or increased non-bone disease (RECIST)
‧陽性骨掃描具有2個或更多個新病灶(PCWG2)。患者必須具有藉由骨掃描及/或CT/MRI所確定之轉移性***癌證據(即,軟組織、內臟、淋巴結)。若淋巴結、內臟及/或軟組織轉移係轉移之唯一證據,則至少一個病灶之直徑必須2cm。 ‧ Positive bone scan with 2 or more new lesions (PCWG2). Patients must have evidence of metastatic prostate cancer (ie, soft tissue, viscera, lymph nodes) as determined by bone scan and/or CT/MRI. If the only evidence of lymph node, visceral and/or soft tissue metastasis is transferred, then at least one lesion must have a diameter 2cm.
8)登記前14天內有以下治療前實驗室數據:絕對嗜中性球計數(ANC)1,500/ml 8) The following pre-treatment laboratory data within 14 days prior to enrollment: absolute neutrophil count (ANC) 1,500/ml
血小板100,000/ml Platelet 100,000/ml
總膽紅素正常上限,由於捷倍耳氏症候群(Gilbert’s syndrome)所致之孤立性高膽紅素血症除外 Total bilirubin Normal upper limit, except for isolated hyperbilirubinemia due to Gilbert's syndrome
SGPT、(ALT)及/或SGOT(AST)1.5×ULN。(若患者具有肝轉移,則2.5×ULN) SGPT, (ALT) and / or SGOT (AST) 1.5 x ULN. (If the patient has liver metastases, then 2.5×ULN)
9)患者之肌酸酐廓清率30ml/min,使用Cockroft-Gault公式得到。 9) Patient's creatinine clearance rate 30 ml/min, obtained using the Cockroft-Gault formula.
10)配偶為有生育能力之女性之男性必須願意同意在治療時及之後的至少3個月使用有效避孕。 10) Men whose spouse is a fertile woman must be willing to agree to use effective contraception at the time of treatment and at least 3 months after treatment.
11)患者可能已接受雄激素消融療法(例如比卡魯胺、酮康唑、DES)及/或「靶向」療法(例如酪胺酸激酶抑制劑)之前治療,但必須在起始研究治療前之前治療藥物之5×半衰期停止該等療法。 11) Patients may have received prior treatment with androgen ablation therapy (eg bicalutamide, ketoconazole, DES) and/or "targeted" therapy (eg tyrosine kinase inhibitor), but must be treated initially Pre-treatment drugs The therapy was stopped with a 5 x half-life.
12)患者可能已接受至多2種用於治療轉移性抗去勢疾病之前細胞毒性化學療法方案。至少一種方案必須含有多西他賽。 12) Patients may have received up to 2 cytotoxic chemotherapy regimens for the treatment of metastatic anti-castration disease. At least one option must contain docetaxel.
1)患者具有小細胞***癌之組織學證據 1) Histopathological evidence of small cell prostate cancer in patients
2)用TKI258或阿比特龍進行前治療 2) Pre-treatment with TKI258 or Abitron
3)在第一次給予研究藥物之日期後14天內進行放射治療(包括對轉移性病灶之姑息性放射治療)或在28天內進行大手術(例如,腹部、骨盆、胸部、矯形或神經開放式手術)。 3) Radiation therapy (including palliative radiotherapy for metastatic lesions) or major surgery within 28 days (eg, abdomen, pelvis, chest, orthopedics or nerves) within 14 days of the date of the first study drug administration Open surgery).
4)在登記後28天內有釤-153,或在登記後12週(336天)內有鍶-89。已接受2劑量或更多劑量之親骨放射性同位素之患者不合格。 4) There is 钐-153 within 28 days after registration, or 锶-89 within 12 weeks (336 days) after registration. Patients who have received 2 or more doses of osteoporotic radioisotopes are unqualified.
5)目前正進行另一治療性臨床試驗之治療 5) Currently undergoing treatment for another therapeutic clinical trial
6)即將發生之骨轉移併發症(骨折及/或臍帶壓迫)。允許適當治療或穩定之骨折及/或臍帶壓迫。 6) Imminent bone metastasis complications (fracture and/or umbilical cord compression). Allow proper treatment or stable fracture and/or umbilical cord compression.
7)存在需要醫學幹預之正在進行之尿路梗阻(例如,尿瀦留、腎水腫)。允許適當治療之尿路梗阻。 7) There is an ongoing urinary tract obstruction requiring medical intervention (eg, urinary retention, renal edema). Urinary tract obstruction that allows proper treatment.
8)患者患有不受控之間發性疾病(例如,不受控之糖尿病、不受控之高血壓)。 8) The patient has an uncontrolled disease (eg, uncontrolled diabetes, uncontrolled hypertension).
9)患者患有另一嚴重醫學或精神疾病,根據研究者之觀點,該疾病可能潛在地干擾患者提供知情同意書之能力或干擾完成根據此方案之治療。 9) The patient has another serious medical or psychiatric disorder that, depending on the investigator, may potentially interfere with the patient's ability to provide informed consent or interfere with the completion of treatment according to the protocol.
10)患者患有第二活動性惡性病,根據研究者之觀點,該惡性病可能潛在地干擾患者參與及/或完成此試驗之能力。 10) The patient has a second active malignant disease, which according to the investigator may potentially interfere with the patient's ability to participate in and/or complete the trial.
18歲 18 years old
患者將接受研究治療直至滿足以下準則中之任一者: The patient will receive study treatment until one of the following criteria is met:
‧疾病惡化 ‧ Disease worsens
‧毒性不可接受 ‧ toxicity is unacceptable
‧患者決定退出 ‧The patient decided to quit
‧涉及一個以上部位之姑息性放射 ‧ palliative radiation involving more than one part
‧根據研究者之判斷,進一步治療將不符合患者之最佳利益。 ‧ According to the investigator's judgment, further treatment will not be in the best interests of the patient.
基於吾人先前對於患者之經驗 Based on my previous experience with patients
研究里程碑日期 Research milestone date
必須輸入月及年 Must enter the month and year
NCC研究代碼分配所需之FPFV、LPFV及CSR日期 FCCV, LPFV and CSR dates required for NCC study code allocation
研究開始(FPFV):2012年8月 Research Beginning (FPFV): August 2012
招募結束(LPFV):2014年9月 End of Recruitment (LPFV): September 2014
研究結束(LPLV):2015年3月 End of Study (LPLV): March 2015
完成臨床研究報告(CSR):初步摘要數據將於2014年1月呈送 Completion of Clinical Research Report (CSR): preliminary summary data will be presented in January 2014
公開日期:2015年12月 Open date: December 2015
此係評價TKI258與阿比特龍之組合用於治療轉移性抗去勢***癌患者之安全性及功效的I/II期實驗室試驗。主要結果係無惡化存 活期(PFS)。基於4個月之歷史平均PFS,平均>6個月之平均存活時間可視為抗疾病活性之有前景之證據。所計劃試樣大小約為60名患者(以完成I期及II期試驗部分),預期每月3名患者之增加速率。基於利用仔細選擇之候選者(根據骨掃描有髂參與證據)獲得之歷史經驗,預期約60%患者生檢將為陽性。不採用依照PSA反應之概率之提前停止規則,此乃因不瞭解,對間質-上皮交互作用途徑之組合抑制是否會導致PSA降低(反之,用阿比特龍主要靶向上皮隔室可導致可預測之PSA降低)。因此,可能為以下情形:PSA未下降,但延長PFS。假定該等患者之短PFS及每月3名患者之預期增加速率,則實施依照所觀察到之PFS時間之提前停止規則亦不可行。基於標準療法之20% 3級或4級毒性之歷史比率,將使用Thall及Sung之方法(1998)來監測毒性。未經調整之PFS時間將使用Kaplan及Meier之方法(1958)以及以下3種潛在預後共變量之效應利用邏輯斯諦回歸(logistic regression)來估計:藉由4週骨髓生檢所確定之FGF及AR信號傳導之抑制、骨標記物(a)尿NTX及(b)骨特異性鹼性磷酸酶之調節以及FGF及AR信號傳導關於FGF R-1、FGF R-3、FGF 9、AR及CYP17之基線標記。 This is an evaluation of the I/II laboratory trial of the combination of TKI258 and abiraterone for the safety and efficacy of patients with metastatic anti-castration prostate cancer. The main result is no deterioration Current (PFS). Based on a historical average PFS of 4 months, an average survival time of >6 months can be considered promising evidence of anti-disease activity. The planned sample size is approximately 60 patients (to complete Phase I and Phase II trials) and is expected to increase the rate of 3 patients per month. Based on historical experience gained with carefully selected candidates (based on evidence of participation in bone scans), it is expected that approximately 60% of patients will be positive for biopsy. Does not use the early stop rule according to the probability of PSA reaction, because it is not known whether the combination inhibition of the interstitial-epithelial interaction pathway will lead to a decrease in PSA (in contrast, the primary targeting of the epithelial compartment with abiraterone may result in The predicted PSA is reduced). Therefore, it may be the case that the PSA has not decreased but the PFS has been extended. Given the short PFS of these patients and the expected rate of increase for three patients per month, it is not feasible to implement an early stop rule in accordance with the observed PFS time. Thall and Sung methods (1998) will be used to monitor toxicity based on a historical ratio of 20% Grade 3 or Grade 4 toxicity of standard therapy. Unadjusted PFS time will be estimated using the Kaplan and Meier method (1958) and the effects of the following three potential prognostic covariates using logistic regression: FGF as determined by 4-week bone marrow biopsy Inhibition of AR signaling, bone markers (a) urinary NTX and (b) regulation of bone-specific alkaline phosphatase and FGF and AR signaling on FGF R-1, FGF R-3, FGF 9, AR and CYP17 Baseline mark.
基於標準療法之20% 3級或4級毒性之歷史比率,將假定p=Prob(3級或4級)遵循β先驗參數(0.20,0.80)。使用Thall及Suung之方法,基於所觀察到之毒性數據,若Pr(p>0.20|數據)>0.95,則將提前停止對試驗之增加,此規則係在大小為5之連續群組後應用。若[3級或4級毒性患者數]/[所評估患者數]大於或等於3/5、5/10、7/15、8/20、9/25、11/30、12/35,則此規則指示停止試驗。 Based on a historical ratio of 20% grade 3 or grade 4 toxicity of standard therapy, it will be assumed that p=Prob (level 3 or grade 4) follows the beta prior parameter (0.20, 0.80). Using the Thall and Suung methods, based on the observed toxicity data, if Pr (p > 0.20 | data) > 0.95, the increase in the test will be stopped early, this rule is applied after a continuous group of size 5. If [number of patients with grade 3 or 4 toxicity] / [number of patients evaluated] is greater than or equal to 3/5, 5/10, 7/15, 8/20, 9/25, 11/30, 12/35, then This rule indicates that the test is stopped.
所有已接受任一劑量之TKI258之研究患者皆可評估安全性。 All patients who had received any dose of TKI258 were able to assess safety.
由研究者視為臨床上顯著之不良事件(包括實驗室不良事件)將根據National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE)(第4版)分級並匯總。 Clinically significant adverse events (including laboratory adverse events) that the investigator considers will be based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (4th edition) are graded and summarized.
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