CN1276754C - 胃肠基质肿瘤的治疗 - Google Patents
胃肠基质肿瘤的治疗 Download PDFInfo
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- CN1276754C CN1276754C CNB018178952A CN01817895A CN1276754C CN 1276754 C CN1276754 C CN 1276754C CN B018178952 A CNB018178952 A CN B018178952A CN 01817895 A CN01817895 A CN 01817895A CN 1276754 C CN1276754 C CN 1276754C
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
本发明公开了通式I的化合物4-(4-甲基哌嗪-1-基甲基)-N-[4-甲基-3-[(4-吡啶-3-基)嘧啶-2-基氨基]苯基]-苯甲酰胺或其可药用盐可用于治疗胃肠基质肿瘤。
Description
本发明涉及4-(4-甲基哌嗪-1-基甲基)-N-[4-甲基-3-[(4-吡啶-3-基)嘧啶-2-基氨基]苯基]-苯甲酰胺(以下称为“化合物I”)或其可药用的盐在制备用于治疗胃肠基质肿瘤(GIST)的药物组合物中的用途；还涉及化合物I或其可药用的盐在治疗GIST中的用途；并且涉及治疗患有GIST的温血动物(包括人)的方法，该方法通过给需要这种治疗的所述动物服用有效剂量的化合物I或其可药用的盐进行治疗。
胃肠基质肿瘤(GIST)是最近表征的一种源于胃肠道，最通常源于胃部(占所有GIST的60％到70％)的间充质肿瘤家族。在过去，这些肿瘤被不同地划分为平滑肌瘤、平滑肌母细胞瘤或平滑肌肉瘤。但是现已清楚，基于它们独特的分子发病机制和临床特征，GIST代表了一组截然不同的临床病理疾病。GIST最常出现于中年或老年群体中，平均的疾病表现年龄为50-60岁并且在发病率方面没有表现出明显的性别差异。估计至少10-30％的GIST是可引起腹内扩散和转移(最常见肝脏和腹膜植入(seeding))的恶性肿瘤。恶性GIST的年发病率约每100000人新增0.3例。最常表现的症状是上腹部隐痛。许多(30％)病例是无症状的，而且GIST可以在评价(与肿瘤有关的胃肠出血导致的)贫血的过程中诊断出来。
处理转移的和不能用手术治疗的GIST是主要的难题，因为众所周知GIST对癌症的化学治疗法没有应答。例如，在一项最近的II期临床实验中，18位晚期平滑肌肉瘤患者中的12位(67％)对由氮烯咪胺、丝裂霉素、阿霉素、顺铂和沙格司亭(sargramostim)组成的治疗方案有应答，但21位GIST患者中只有一位(5％)有应答(J.Edmonson，R.Marks，J.Buckner，M.Mahoney，Proc.Am.Soc.Clin.Oncol.1999；
18：541a“晚期恶性胃肠基质肿瘤患者和其它晚期平滑肌肉瘤患者对D-MAP+沙格司亭治疗的应答对比”)。治疗结果与其它化学治疗方案一样是不令人信服的。与临床的化学耐药性一致，与广谱耐药性(MDR)有关的P-糖蛋白和广谱耐药蛋白MRP1在恶性GIST中的表达比在平滑肌肉瘤中更为显著。
现已令人惊讶地证实用化合物I或其可药用的盐能成功地治疗GIST。
化合物I是具有通式I的4-(4-甲基哌嗪-1-基甲基)-N-[4-甲基-3-[(4-吡啶-3-基)嘧啶-2-基氨基]苯基]-苯甲酰胺：
于1993年10月6日公开的欧洲专利申请EP-A-0564409的实施例21以及众多其它国家的同族申请和专利(例如美国专利5521184和日本专利2706682)中描述了化合物I的制备和它的尤其作为抗肿瘤药物的用途。
化合物I的可药用盐是可药用的酸加成盐，象例如化合物I与无机酸(如盐酸，硫酸或磷酸)的加成盐，或化合物I与适宜的有机羧酸或磺酸的加成盐，所述有机羧酸或磺酸为例如脂肪族一元羧酸或脂肪族二元羧酸如三氟乙酸、乙酸、丙酸、羟基乙酸、琥珀酸、马来酸、富马酸、羟基顺丁烯二酸、苹果酸、酒石酸、柠檬酸或草酸，或氨基酸如精氨酸或赖氨酸，芳族羧酸如苯甲酸、2-苯氧基-苯甲酸、2-乙酰氧基-苯甲酸、水杨酸、4-氨基水杨酸，芳香族-脂肪族羧酸如苯乙醇酸或苯基-2-丙烯酸，杂芳族羧酸如烟酸或异烟酸，脂肪族磺酸如甲基、乙基或2-羟乙基磺酸，或芳族磺酸如苯、对甲苯或萘-2-磺酸。
1999年1月28日公开的PCT专利申请WO99/03854中记述了化合物I的单甲基磺酸加成盐(下文以“盐I”表示)和其优选的晶体形式。
以下描述了用盐I治疗患有不可切除的转移性GIST的第一位实体瘤患者的治疗结果。患者具有抗化疗性并且患有快速进行性转移性GIST，除了接受临床试验没有其它治疗选择。已有病历记载，患者在多个部位迅速发展出抗化疗性GIST。按日剂量400mg口服施用盐I。采用包括动态磁共振影像(MRI)和用18氟-氟脱氧葡萄糖作为示踪物的正电子发射断层扫描(PET)的影像研究对治疗效果纵向地进行了评价；此外，评价了肝脏转移性肿瘤的系列活检组织，作为盐I的组织病理学效果的根据。
在开始用盐I治疗后一个月内在具有阴性PET影像的肿瘤中获得了完全代谢应答，此时在磁共振影像中肿瘤体积已经减少了52％，即在开始用盐I治疗后一个月内基于MRI肝脏转移瘤总体积减少了52％。许多肝脏转移瘤变为囊性而且动态MRI显示出显著减少的肿瘤增强，提示肿瘤的生长能力降低。此外，通过一系列肿瘤活检组织的病理学评价证实了这种治疗的抗癌活性。PET扫描揭示：用盐I治疗一个月内肿瘤对18氟-氟脱氧葡萄糖(FDG)的高亲和性吸收呈阴性。用动态MRI检测到的肿瘤的造影增强模式在开始用盐I后两周内急剧地减少，并且许多转移性损伤在随后的跟踪中变为囊性。在一系列针刺活检组织中恶性GIST组织被纤维化和坏死组织代替。随治疗的继续，肝脏损伤的尺寸逐渐收缩并且在PET中发现低代谢区域代替了高代谢的肝脏转移瘤。这些发现提示在MRI扫描上可见的持续残余肝脏损伤很可能几乎没有或完全没有能存活的病变。在治疗的7个月间，持续对这些有益的临床和影像应答作了记录。
重要的是，口服盐I治疗的临床毒性情况非常有利，主要由轻微血球减少和排便频率稍微增加组成。
依据种族、年龄、个体情况、服药方式和所讨论的临床表现，给体重约70公斤的温血动物施用有效剂量的药物，所述剂量为例如约100-1000mg，优选200-600mg特别优选400mg的日剂量。对于患有不可切除的和/或转移性恶性GIST的成人患者，可推荐每天400mg的初始剂量。对于用每天400mg药物治疗后应答不充分的患者可谨慎地考虑提高剂量，并且只要他们能从治疗获益并且不存在会产生限制的毒性，即可以对患者进行治疗。
本发明也涉及给患有GIST的人类对象施用化合物I或其可药用盐的方法，其包括在超过三个月的期间给人类对象每天一次服用药物有效量的化合物I或其可药用的盐。本发明尤其涉及这样的方法，其中施用日剂量200-600mg，特别是400-600mg优选400mg的盐I。
实施例1
A)病史
一位既往健康的50岁的高加索妇女，1996年10月发现轻微腹部不适和上腹部出现一个大肿瘤。采用近侧胃切除从胃部切除了两个直径分别为6.5和10cm的肿瘤，大网膜和结肠系腹膜由于有多个直径1-2mm的转移小瘤而被切除。肿瘤的组织学与(每10个高倍视野中具有超过20个的有丝分裂核的)恶性GIST相匹配。1998年2月切除了一个左上腹部的复发肿瘤，2个肝脏转移瘤和多个小的腹内转移瘤，在1998年9月又切除6个肝转移瘤和1个卵巢转移瘤。1998年11月至1999年3月针对多个肝转移瘤接受了七个周期的IADIC治疗(异环磷酰胺，阿霉素和氮烯咪胺)。其对IADIC无应答，1999年3月剖腹切除了一个大的肠梗阻转移瘤和45个较小转移瘤。随后在1999年4月至2000年2月期间，采用由每日一次400mg酞胺哌啶酮和每日三次皮下施用0.9MUα-干扰素组成的实验方案对她进行治疗以控制持续的肝脏病变。在6个月病情稳定期后，肝脏转移瘤迅速发展并出现几个新的转移瘤，2000年2月在MRI中发现28个肝脏转移瘤和至少2个上腹部转移瘤，导致门静脉和肝静脉受压迫。
2000年3月开始每日一次口服400mg(如实施例2中所述的4个胶囊)剂量的盐I进行治疗。
B)治疗毒性和反应的评估
在每隔2-4周的随访中对治疗毒性进行了评估，并且每间隔1-2星期对血细胞数量和血液化学进行分析。采用动态MRI扫描、18氟-氟脱氧葡萄糖(FDG)正电子发射断层扫描(PET)检查和肝转移瘤的切割针刺活检评估治疗反应。使用1.5T Magnetom Vision(Siemens，Erlangen，德国)进行动态MRI扫描。得到造影剂(0.1mmol/kg钆-DOTA；Dotarem，Guerbet，法国)静脉注射前后的脂抑制T1加权屏气梯度回波横断层影像。在5分钟内连续成像建立增强模式，并在10分钟后进行延迟扫描。使用8-环ECAT 931/08设备(Siemens-CT1 Corp.Knoxville，TN)实施了PDGPET。所用的FDG的剂量为355至375MBq。
C)结果
在MRI中的肿瘤反应
用盐I治疗后几星期内患者的总肿瘤尺寸有相当大的降低。在开始使用盐I的前一天实施的MRI扫描中，8个大的可测量的肝转移瘤的肿瘤面积(以两个双垂直参数的乘积总和计)为112.5cm2。在其后的盐I治疗过程中进行的MRI扫描中，开始用盐I治疗后两星期时总肿瘤大小降至66.9cm2(降低41％)、一个月时降至54.3cm2(降低52％)、两个月时降至41.5cm2(降低63％)、四个月时降至36.2cm2(降低68％)、5.5个月时降至32.5cm2(降低71％)。未见新损伤出现，而且28个肝转移瘤中的6个消失。用盐I治疗前在动态MRI中显示出相当明显的造影增强的转移瘤的周缘表现出急剧减小，并在治疗过程中进行的动态MRI扫描中没有或几乎没有增强，而且许多转移瘤变为囊性。在2000年9月肿瘤继续应答而且患者临床表现仍良好。
正电子发射断层扫描(PET)的影像
在肿瘤的系列FDG PET影像中发现显著的变化，提示盐I的抗肿瘤代谢效应。在开始使用盐I的前四天进行的PET扫描中可看到多个肝转移瘤和与肾盂积水相吻合的FDG向右肾的聚集。在使用盐I后1个月进行的重复PET中肝部未见不正常的FDG吸收并且右肾显示正常的吸收。在开始使用盐I后2个月时进行的PET中，在肝转移瘤位点看到FGD吸收较周围肝脏软组织少的“冷”区域，这与诱导出现的MRI中所看到的转移瘤囊性转变和针刺活检中看到的坏死相一致。
组织学反应
使用盐I后1个月和2个月时从位于腹部的肝转移瘤取出的系列切割针刺活检组织显示GIST细胞密度显著降低、呈黏液样降解并结疤，而且没有明显炎症反应和坏死迹象。
用盐I治疗的耐受性
用盐I治疗总体耐受良好。未见脱发现象而且患者据述仅有与吞服药物胶囊有关的轻微偶见的恶心，持续约15分钟，但与食物同服药物后有所改善。血细胞数变化不显著。她的血红蛋白水平在盐I治疗期间于118g/L和125g/L之间变化(治疗前此值为120g/L)、白细胞数为3.2至4.4×109/L(治疗前为5.5×109/L)、粒细胞数为1.52至2.39×109/L(治疗前为3.2×109/L)以及血小板数为261至365×109/L(治疗前为360×109/L)。未见与药物有关的肝、肾和心脏毒性。主要的主观毒性(均为1级(NCI CTC版2.0))包括排便频率增加(2-4次/天)、偶而腿部肌肉痉挛、轻微短暂的踝水肿、以及在盐I治疗期间左腹部皮肤上诊断出伴有皮疹的带状疱疹感染。在用盐I治疗期间，世界卫生组织(WHO)行为状态评分(performancestatus)从1(存在与癌症有关的症状)改进至0(正常)。
实施例2：含有β晶形的4-(4-甲基-1-哌嗪-1-基甲基)-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-苯甲酰胺甲磺酸盐的胶囊
以下列组成制备含有119.5mg标题化合物(盐I)(相当于100mg化合物I(游离碱))作为活性物质的胶囊：
组成
盐I 119.5mg
纤维素MK GR 92mg
交联聚维酮XL 15mg
微粉硅胶200 2mg
硬脂酸镁 1.5mg
230mg
通过将各组分混合并且将混合物填充至1号硬明胶胶囊中制备胶囊。
实施例3：含有β晶形的4-(4-甲基-1-哌嗪-1-基甲基)-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-苯甲酰胺甲磺酸盐的胶囊
以下列组成制备含有100mg标题化合物(＝盐I)作为活性物质的胶囊：
组成
活性物质 100mg
微晶纤维素 200mg
PVPPXL 15mg
微粉硅胶 2mg
硬脂酸镁 1.5mg
318.5mg
通过将各组分混合并将混合物填充至1号硬明胶胶囊中制备胶囊。
实施例4
在本专利申请的优先权日时，一项包括更多GIST患者的临床研究正在以类似于实施例1所述研究的方式实施。该项研究目前还没有完成，但已有的状况是：可评价疗效的33位患者中有6位还未被评价；剩余27位患者中只有1位显示病情进展；18位患者病情稳定，即降低4-42％；8位患者显示有部分反应，即降低50-66％。
实施例5
在患有不可切除的和/或转移性恶性胃肠基质肿瘤(GIST)的患者中实施了一项开放的、随机多中心的II期临床研究。在该研究中147位患者入组并随机接受为期达24个月的每天一次口服400mg或600mg盐I的治疗。这些患者的年龄在18-83岁之间，并且病理诊断CD 117呈阳性，具有不可切除的和/或转移性恶性GIST。疗效的主要证据基于客观应答比率，并且对应答时间、应答持续期、治疗失败时间和存活率也进行了评价。要求肿瘤在病变的至少一个位点是可测量的并且根据西南肿瘤协作组(SWOG)的标准来表征应答。研究结果源自该研究的中期分析报告并总结在下表中：
最佳肿瘤反应
| 最佳应答 | 400mg(N＝73)n(％) | 600mg(N＝74)n(％) | 所有剂量(N＝147)n(％) |
| 完全应答部分应答病情稳定病情进展病情不可评价未知 | 027(37.0)33(45.2)10(13.7)3(4.1)0 | 032(43.2)28(37.8)8(10.8)4(5.4)2(2.7) | 059(40.1)61(41.5)18(12.2)7(4.8)2(1.4) |
由于对患者的随访有限，并且在试验开始后约一年进行的中期分析时病情稳定的患者的数量可观，因此对这个试验组进行了进一步的评价。在61位“病情稳定”的患者中，在47位患者中观察到显著的肿瘤缩小，有些属于仍未经二次评估证实的部分应答(28位患者)，而其余患者的肿瘤尺寸减小超过25％(19位患者)。因此在将来，随着这些患者用盐I治疗更长的时间段后部分应答的不断被确认或达到，应答者的数量可能增加。
总之，总共118位患者(80％)的肿瘤尺寸在至少一次评估中缩小超过25％。这些患者包括那些被确认(n＝59)和未被确认(n＝28)具有部分应答的患者、肿瘤尺寸缩小超过25％的被确认病情稳定的患者(n＝19)和其它12位肿瘤尺寸在任何肿瘤评估项目中都缩小超过25％的患者。被确认有应答的患者均未出现复发。
对于全部受试人员，开始应答的中位时间是12星期。中期分析(无“区间校正”，no interval censoring)时观察到的应答期为7星期至38星期，中位值近似为14星期。在12星期时治疗未失败的患者数量的估计值为80％，而且此估计值在治疗24星期时为66％。无区间校正情况下，该估计值分别为81％和67％。在汇合群体(全部受治疗患者)中治疗失败时间(区间校正)的中位值为54星期，但该估计值仅基于两位患者的治疗情况因此不是一个可靠的估计。
由于所观察到的死亡数目小而且随访时间相对较短，所以未对总存活率进行统计分析。
在所评价的任一个疗效参数中未见给药组之间存在差异。
Claims (1)
1.具有通式I的4-(4-甲基哌嗪-1-基甲基)-N-[4-甲基-3-[(4-吡啶-3-基)嘧啶-2-基氨基]苯基]-苯甲酰胺
或它的可药用盐在制备用于治疗胃肠基质肿瘤的药物组合物中的用途。
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| JP2005526048A (ja) * | 2002-02-27 | 2005-09-02 | アブ サイエンス | Ｃｎｓ疾患を治療するためのチロシンキナーゼ阻害剤の使用方法 |
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