CN101123954A - 抗肿瘤剂 - Google Patents

抗肿瘤剂 Download PDF

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CN101123954A
CN101123954A CNA2006800054166A CN200680005416A CN101123954A CN 101123954 A CN101123954 A CN 101123954A CN A2006800054166 A CNA2006800054166 A CN A2006800054166A CN 200680005416 A CN200680005416 A CN 200680005416A CN 101123954 A CN101123954 A CN 101123954A
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replacement
replace
tumor
group
therapeutic agent
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CN101123954B (zh
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神田裕
曾我史朗
中岛孝行
奈良真二
中川启
盐津行正
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KH Neochem Co Ltd
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Kyowa Hakko Kogyo Co Ltd
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • 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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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract

本发明提供一种用于治疗选自造血器官肿瘤和固态肿瘤中的肿瘤的治疗剂，其中含有由下述通式(I)表示的苯甲酰基化合物或其药物前体或其药理学上允许的盐作为有效成分，式中，n表示1～5的整数；R1表示取代或无取代的低级烷氧基、取代或无取代的低级烷氧基羰基、CONR7R8等；R2表示取代或无取代的芳基或者取代或无取代的芳香族杂环基；R3和R5相同或不同，表示氢原子、取代或无取代的低级烷基等；R4表示氢原子、羟基或者卤素；R6表示氢原子、卤素、取代或无取代的低级烷基等。

Description

抗肿瘤剂
【技术领域】
本发明涉及含有苯甲酰基化合物或其药物前体或其药理学上允许的盐作为有效成分的肿瘤治疗剂。
【背景技术】
作为具有抗肿瘤活性的苯甲酰基化合物，已知有下述的化合物A等(参照专利文献1)。
Figure A20068000541600081
另外，还已知在热休克蛋白90(Hsp90)Heat shock protein】类【family】中具有结合活性的苯甲酰基化合物(参照专利文献2)。
【专利文献1】国际公开第01/81288号小册子
【专利文献2】国际公开第2005/000778号小册子
【发明内容】
【发明所要解决的课题】
本发明的目的在于，提供一种含有苯甲酰基化合物或其药物前体或其药理学上允许的盐作为有效成分的肿瘤治疗剂，所述的肿瘤选自造血器官肿瘤和固态肿瘤。
【用于解决课题的手段】
本发明涉及以下的(1)～(21)项。
(1)选自造血器官肿瘤和固态肿瘤的肿瘤的治疗剂，其中含有由通式(I)表示的苯甲酰基化合物或其药物前体或其药理学上允许的盐作为有效成分，
[式中，
n表示1～5的整数；
R1表示取代或无取代的低级烷基、
取代或无取代的低级烷氧基、
取代或无取代的环烷基、
取代或无取代的低级烷氧基羰基、
取代或无取代的杂环烷基、
取代或无取代的芳基、
CONR7R8(式中，R7和R8相同或不同，表示氢原子、取代或无取代的低级烷基、取代或无取代的环烷基、取代或无取代的低级烷酰基、取代或无取代的芳基、取代或无取代的杂环基、取代或无取代的芳烷基、取代或无取代的杂环烷基或者取代或无取代的芳酰基，或者，R7和R8与相邻的氮原子一起，形成取代或无取代的杂环基)
或者
NR9R10(式中，R9和R10各自与上述R7和R8的定义相同)；
R2表示取代或无取代的芳基
或者
取代或无取代的芳香族杂环基；
R3和R5相同或不同，表示
氢原子、
取代或无取代的低级烷基、
取代或无取代的低级链烯基、
取代或无取代的低级烷酰基、
取代或无取代的环烷基、
取代或无取代的芳烷基
或者
取代或无取代的芳酰基；
R4表示氢原子、
羟基
或者
卤素；
R6表示氢原子、
卤素、
氰基、
硝基、
取代或无取代的低级烷基、
取代或无取代的低级链烯基、
取代或无取代的低级炔基、
取代或无取代的低级烷氧基、
取代或无取代的环烷基、
氨基、
低级烷基氨基、
二低级烷基氨基、
羧基、
取代或无取代的低级烷氧基羰基、
取代或无取代的低级烷酰基、
取代或无取代的芳氧基、
取代或无取代的芳基、
取代或无取代的杂环基、
取代或无取代的芳烷基
或者
取代或无取代的杂环烷基；
但是，
(i)当R3和R5为甲基、且R4和R6为氢原子时，
且
(a)当-(CH2)nR1为甲氧基羰基甲基时，
R2不能为选自2，4，6-三甲氧基-5-甲氧基羰基-3-硝基苯基、3-氰基-2，4，6-三甲氧基苯基、5-氰基-2-乙氧基-4，6-二甲氧基-3-硝基苯基、2，6-二甲氧基苯基、2-氯-6-甲氧基苯基以及2-氯-4，6-二甲氧基-5-甲氧基羰基-3-硝基苯基中的基团；
(b)当-(CH2)nR1为乙氧基羰基甲基时，
R2不能为2，4，6-三甲氧基-3-甲氧基羰基苯基；
(c)当-(CH2)nR1为N，N-二甲基氨基甲基时，
R2不能为苯基；
(ii)当R3、R4、R5和R6为氢原子时，
且
(a)当-(CH2)nR1为2-(乙酰氧基甲基)庚基、3-氧代戊基或者戊基时，
R2不能为6-羟基-4-甲氧基-3-甲氧基羰基-2-戊基苯基；
(b)当-(CH2)nR1为3-氧代戊基时，
R2不能为选自3-苄氧基羰基-6-羟基-4-甲氧基-2-戊基苯基和3-羧基-6-羟基-4-甲氧基-2-戊基苯基中的基团；
(c)当-(CH2)nR1为正丙基时，
R2不能为2，4-二羟基-6-[(4-羟基-2-氧代吡喃-6-基)甲基]苯基；
(iii)当R3和R4为氢原子、R5为甲基、且R6为甲氧基羰基、且-(CH2)nR1为戊基时，
R2不能为选自6-[2-(乙酰氧基甲基)庚基]-2，4-二羟基苯基、2，4-二羟基-6-戊基苯基以及2，4-二羟基-6-(3-氧代戊基)苯基中的基团；
(iv)当R3和R5为苄基、R4和R6为氢原子、且-(CH2)nR1为3-氧代戊基时，
R2不能为选自6-苄氧基-4-甲氧基-3-甲氧基羰基-2-戊基苯基和6-苄氧基-3-苄氧基羰基-4-甲氧基-2-戊基苯基中的基团；
(v)当R3为苄基、R4为氢原子、R5为甲基、-(CH2)nR1为戊基、且R6为甲氧基羰基或者苄氧基羰基时，
R2不能为2，4-双(苄氧基)-6-(3-氧代戊基)苯基；
(vi)当R3和R4为氢原子、R5为甲基、-(CH2)nR1为戊基、且R6为羧基或者苄氧基羰基时，
R2不能为2，4-二羟基-6-(3-氧代戊基)苯基；
(vii)当R3、R4和R6为氢原子、R5为正丙基、且-(CH2)nR1为5-(1，1-二甲基丙基)-4-(2-氢苯并三唑-2-基)-2-羟基苯基甲基时，
R2不能为苯基]。
(2)上述(1)中所述的肿瘤治疗剂，其中，R2为取代或无取代的芳香族杂环基、被1～3个取代基取代的芳基或者芳基。
(3)上述(1)中所述的肿瘤治疗剂，其中，R2为被1～3个取代基取代的芳基或者芳基。
(4)上述(1)中所述的肿瘤治疗剂，其中，R2为被1～3个取代基取代的苯基或者苯基。
(5)上述(1)中所述的肿瘤治疗剂，其中，R2为取代或无取代的芳香族杂环基。
(6)上述(1)～(5)任一项中所述的肿瘤治疗剂，其中，R3和R5相同或不同，为氢原子、取代或无取代的低级烷基、取代或无取代的低级烷酰基、取代或无取代的芳酰基或者取代或无取代的低级链烯基。
(7)上述(1)～(5)任一项中所述的肿瘤治疗剂，其中，R3、R4和R5为氢原子。
(8)上述(1)～(7)任一项中所述的肿瘤治疗剂，其中，R1为CONR7R8(式中，R7和R8分别与上述的含义相同)。
(9)上述(1)～(7)任一项中所述的肿瘤治疗剂，其中，R1为CONR7AR8B(式中，R7A和R8A相同或不同，表示氢原子、取代或无取代的低级烷基或者取代或无取代的杂环烷基)。
(10)上述(1)～(7)任一项中所述的肿瘤治疗剂，其中，R1为CONR7BR8B(式中，R7B和R8B与相邻的氮原子一起，形成取代或无取代的杂环基)。
(11)上述(1)～(7)任一项中所述的肿瘤治疗剂，其中，R1为取代或无取代的低级烷氧基。
(12)上述(1)～(11)任一项中所述的肿瘤治疗剂，其中，R6为氢原子、低级烷基、卤素或者芳基。
(13)上述(1)～(11)任一项中所述的肿瘤治疗剂，其中，R6为低级烷基。
(14)上述(1)～(11)任一项中所述的肿瘤治疗剂，其中，R6为乙基。
(15)上述(1)～(14)任一项中所述的肿瘤治疗剂，其中，肿瘤为造血器官肿瘤。
(16)上述(15)中所述的肿瘤治疗剂，其中，造血器官肿瘤为选自白血病、多发性骨髓肿瘤和淋巴肿瘤中的肿瘤。
(17)上述(1)～(14)任一项中所述的肿瘤治疗剂，其中，肿瘤为固态肿瘤。
(18)上述(17)中所述的肿瘤治疗剂，其中，固态肿瘤为选自大肠癌、食道癌、胃癌、肝癌、胰腺癌、胆道癌、膀胱癌、肾癌、前列腺癌、乳腺癌、宫颈癌、子宫体癌、卵巢癌、头颈部癌、肺癌、骨肉肿瘤、黑素瘤、以及脑肿瘤中的肿瘤。
(19)选自造血器官肿瘤和固态肿瘤中的肿瘤的治疗方法，其特征在于，投给有效量的上述(1)中所述由通式(I)表示的苯甲酰基化合物或其药物前体或其药理学上允许的盐。
(20)上述(1)中所述的由通式(I)表示的苯甲酰基化合物或其药物前体或其药理学上允许的盐在制造选自造血器官肿瘤和固态肿瘤中的肿瘤的治疗剂中的应用。
(21)选自造血器官肿瘤和固态肿瘤中的肿瘤的治疗剂，其中含有由通式(IA)表示的苯甲酰基化合物或其药物前体或其药理学上允许的盐作为有效成分：
[式中，nA表示0～10的整数；
R1A表示氢原子、羟基、氰基、羧基、硝基、卤素、取代或无取代的低级烷基、取代或无取代的低级链烯基、取代或无取代的低级炔基、取代或无取代的低级烷氧基、取代或无取代的环烷基、取代或无取代的低级烷氧基羰基、取代或无取代的低级烷酰氧基、取代或无取代的杂环烷基、取代或无取代的芳基、取代或无取代的芳基磺酰基、取代或无取代的杂环基、CONR7R8(式中，R7和R8相同或不同，表示氢原子、取代或无取代的低级烷基、取代或无取代的环烷基、取代或无取代的低级烷酰基、取代或无取代的芳基、取代或无取代的杂环基、取代或无取代的芳烷基、取代或无取代的杂环烷基或者取代或无取代的芳酰基，或者，R7和R8与相邻的氮原子一起，形成取代或无取代的杂环基)或者NR9R10(式中，R9和R10分别与上述R7和R8的含义相同)；
R2A表示取代或无取代的低级烷基、取代或无取代的低级链烯基、取代或无取代的低级炔基、取代或无取代的环烷基、取代或无取代的芳基或者取代或无取代的杂环基；
R3和R5A相同或不同，表示氢原子、取代或无取代的低级烷基、取代或无取代的低级链烯基、取代或无取代的低级烷酰基、取代或无取代的环烷基、取代或无取代的芳烷基或者取代或无取代的芳酰基；
R4A和R6A相同或不同，表示氢原子、羟基、卤素、氰基、硝基、取代或无取代的低级烷基、取代或无取代的低级链烯基、取代或无取代的低级炔基、取代或无取代的低级烷氧基、取代或无取代的环烷基、氨基、低级烷基氨基、二低级烷基氨基、羧基、取代或无取代的低级烷氧基羰基、取代或无取代的低级烷酰基、取代或无取代的芳氧基、取代或无取代的芳基、取代或无取代的杂环基、取代或无取代的芳烷基或者取代或无取代的杂环烷基]。
【发明的效果】
本发明提供一种含有苯甲酰基化合物或其药物前体或其药理学上允许的盐作为有效成分的、选自造血器官肿瘤和固态肿瘤中的肿瘤的治疗剂。
【附图说明】
图1示出化合物33对人慢性骨髓性白血病K562细胞移植小鼠的抗肿瘤效果。横轴表示给药试验开始后的天数，纵轴表示肿瘤体积(mm3)。结果以与小鼠各5只的平均值的标准偏差来表示。
图2示出化合物33对人肺癌NCI-H596细胞移植小鼠的抗肿瘤效果。横轴表示给药试验开始后的天数，纵轴表示肿瘤体积(mm3)。结果以与小鼠各5只的平均值的标准偏差来表示。
图3表示化合物33对人前列腺癌22Rv1细胞移植小鼠的抗肿瘤效果。横轴表示给药试验开始后的天数，纵轴表示肿瘤体积(mm3)。结果以与小鼠各5只的平均值的标准偏差来表示。
【符号说明】
-●-：化合物33给药组
-○-：非给药组
【具体实施方式】
在通式(I)或者(IA)的各基团的定义中，
作为低级烷基、低级烷氧基、低级烷氧基羰基、低级烷基氨基和二低级烷基氨基的低级烷基部分，可列举出例如直链或支链的碳数为1～8的烷基，具体地可列举出甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基等。二低级烷基氨基中的2个低级烷基部分可以相同，也可以不同。
作为低级链烯基，可列举出例如直链或支链的碳数为2～8的链烯基，具体地可列举出乙烯基、烯丙基、1-丙烯基、甲基丙烯酰基、巴豆基、1-丁烯基、3-丁烯基、2-戊烯基、4-戊烯基、2-己烯基、5-己烯基、2-庚烯基、2-辛烯基等。
作为低级炔基，可列举出例如直链或支链的碳数为2～8的炔基，具体地可列举出乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基等。
作为低级烷酰基和低级烷酰氧基的低级烷酰基部分，可列举出例如直链或支链的碳数为1～7的烷酰基，具体地可列举出甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、庚酰基等。
作为环烷基，可列举出例如碳数为3～8的环烷基，具体地可列举出环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
作为芳基、芳基磺酰基、芳氧基和芳酰基的芳基部分，可列举出例如碳数为6～14的单环式、二环式或者三环式的芳基，具体地可列举出苯基、茚基、萘基、蒽基等。
作为芳烷基，可列举出例如碳数为7～15的芳烷基，具体地可列举出苄基、苯乙基、二苯甲基、萘基甲基等。
作为芳香族杂环基，可列举出例如含有至少1个选自氮原子、氧原子和硫原子中的原子的5元或6元的单环性芳香族杂环基、3～8元的环缩合而成的二环或者三环性且含有至少1个选自氮原子、氧原子和硫原子中的原子的稠环性芳香族杂环基等，具体地可列举出吡啶基、吡嗪基、嘧啶基、哒嗪基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基【ナフチリヅニル】、噌啉基【シンノリニル】、吡咯基、吡唑基、咪唑基、三唑基、四唑基、噻吩基、呋喃基、噻唑基、唑基、吲哚基、吲唑基、苯并咪唑基、苯并三唑基、苯并噻唑基、苯并唑基、嘌呤基、苯并二氧戊环基等。
作为杂环基和杂环烷基的杂环基部分，除了上述芳香族杂环基的定义中所列举的基团以外，还可列举出例如脂环式杂环基。作为脂环式杂环基，可列举出例如含有选自氮原子、氧原子和硫原子中至少1个原子的5元或6元的单环性脂环式杂环基、由3～8元的环缩合而成的二环或者三环性且含有选自氮原子、氧原子和硫原子中至少1个原子的稠环性脂环式杂环基等，具体地可列举出吡咯烷基、哌啶子基【ピペリヅノ】、哌嗪基【ピペラヅニル】、吗啉代【モルホリノ】、吗啉基【モルホリニル】、硫代吗啉代、硫代吗啉基、高哌啶子基【ホモピペリヅノ】、高哌嗪基【ホモピペラヅニル】、四氢吡啶基、四氢喹啉基、四氢异喹啉基、四氢呋喃基、四氢吡喃基、二氢苯并呋喃基、氧代哌嗪基、2-氧代吡咯烷基等。
作为与相邻的氮原子一起所形成的杂环基，可列举出例如至少含有1个氮原子的5元或6元的单环性杂环基(该单环性杂环基也可以含有其他的氮原子、氧原子或者硫原子)、由3～8元的环缩合而成的二环或者三环性的、至少含有1个氮原子的稠环性杂环基(该稠环性杂环基也可以含有其他的氮原子、氧原子或者硫原子)等，具体地可列举出吡咯烷基、哌啶子基、哌嗪基、吗啉代、硫代吗啉代、高哌啶子基、高哌嗪基、四氢吡啶基、四氢喹啉基、四氢异喹啉基、氧代哌嗪基、2-氧代吡咯烷基等。
杂环烷基的亚烷基部分与从上述低级烷基的定义中除去一个氢原子而形成的基团的含义相同。
卤素指的是氟、氯、溴、碘各种原子。
作为取代低级烷基、取代低级烷氧基、取代低级烷氧基羰基、取代低级链烯基和取代低级炔基中的取代基(A)，可以相同或不同，可列举出例如取代数为1～3的取代基，具体地可列举出羟基、氧代、氰基、硝基、羧基、氨基、卤素、取代或无取代的低级烷氧基、环烷基、低级烷酰基、低级烷氧基羰基、低级烷基氨基、二低级烷基氨基等。取代基的取代位置没有特殊限定。在取代基(A)中示例的卤素、低级烷氧基、环烷基、低级烷酰基、低级烷氧基羰基、低级烷基氨基和二低级烷基氨基，分别与上述的含义相同。作为在取代基(A)中示例的取代低级烷氧基中的取代基，可以相同或不同，可列举出例如取代数为1～3的取代基，具体地可列举出羟基、卤素等，该卤素与上述的含义相同。在取代基(A)的示例中，作为由上述R7和R8的定义的取代低级烷基中的取代基，可以相同或不同，更优选例如取代数为1～3的羟基、低级烷氧基等。
作为在取代低级烷酰基、取代低级烷酰氧基、取代环烷基、取代芳基、取代苯基、取代芳基磺酰基、取代芳氧基、取代芳烷基、取代芳酰基、取代杂环烷基、取代杂环基、取代芳香族杂环基以及与相邻的氮原子一起所形成的取代杂环基中的取代基(B)，可以相同或不同，可列举出例如取代数为1～3的取代基，具体地可列举出羟基、卤素、硝基、氰基、氨基、羧基、氨基甲酰基、取代或无取代的低级烷基、取代或无取代的低级烷氧基、芳烷氧基、低级烷基磺酰基、低级烷基磺胺酰基、环烷基、低级烷氧基羰基、低级烷基氨基、二低级烷基氨基、低级烷酰基、杂环基、取代或无取代的芳基、取代或无取代的杂环烷氧基、取代或无取代的杂环羰基烷氧基等。取代基的取代位置没有特殊限定。在取代基(B)中示例的卤素、低级烷基、低级烷氧基、环烷基、低级烷氧基羰基、低级烷基氨基、二低级烷基氨基、低级烷酰基、杂环基和芳基，分别与上述的含义相同，低级烷基磺酰基和低级烷基磺胺酰基的低级烷基部分与上述低级烷基的含义相同，芳烷氧基的芳烷基部分与上述芳烷基的含义相同，杂环烷氧基和杂环羰基烷氧基的杂环基部分和亚烷基，分别与从上述杂环基和上述低级烷基的定义中除去一个氢原子而形成的基团的含义相同。作为在取代基(B)中示例的取代低级烷基、取代低级烷氧基和取代芳基中的取代基，可以相同或不同，可列举出例如取代数为1～3的取代基，具体地可列举出羟基、卤素、低级烷氧基、氰基、低级烷基氨基、二低级烷基氨基等，该卤素、低级烷氧基、低级烷基氨基和二低级烷基氨基分别与上述的含义相同。作为在取代基(B)中示例的取代杂环烷氧基和取代杂环羰基烷氧基中的取代基，可以相同或不同，可列举出例如取代数为1～3的取代基，具体地可列举出羟基、卤素、低级烷基、低级烷氧基、杂环基等，此处所示的卤素、低级烷基、低级烷氧基和杂环基分别与上述的含义相同。在取代基(B)的例子中，作为在上述R2的定义中举出的取代芳基和取代苯基中的取代基，可以相同或不同，更优选例如取代数为1～3的卤素、低级烷氧基、低级烷氧基低级烷氧基、取代或无取代的杂环烷氧基等。进而，作为在上述R2的定义中举出的取代苯基中的取代基的取代位置，特别优选苯基的3位和4位或者3位。
以下将由通式(I)和(IA)表示的化合物分别称为化合物(I)和(IA)。对于其他式编号的化合物也同样。
本发明的肿瘤治疗剂中使用的化合物(I)或者(IA)，可采用例如国际公开第2005/000778号小册子中记载的方法或者与其类似的方法来制得。
本发明的肿瘤治疗剂中使用的化合物(I)或者(IA)的具体例示于表1和表2。
应予说明，表中的Ph表示苯基，R2a、R2b和R2c中的基团前面所记载的数字，表示苯基上各自的取代位置。
Figure A20068000541600201
表1-1
Figure A20068000541600202
表1-2
Figure A20068000541600211
表1-3
Figure A20068000541600221
表1-4
Figure A20068000541600231
表1-5
Figure A20068000541600241
表1-6
Figure A20068000541600251
表1-7
Figure A20068000541600261
表1-8
表1-9
表1-10
Figure A20068000541600291
表1-11
Figure A20068000541600301
表1-12
Figure A20068000541600321
表2
Figure A20068000541600322
作为本申请的肿瘤治疗剂中使用的化合物(I)或者(IA)的药物前体(prodrug)，可列举出例如在血液中按照水解等各种机理在体内转变而生成的本发明中所述的化合物(I)或者(IA)的化合物，可以按照本领域技术人员熟知的技术[例如、“J.Med.Chem.”，1997年，第40卷，p.2011-2016；“Drug Dev.Res.”，1995年，第34卷，p.220-230；“Advances in Drug Res.”，1984年，第13卷，p.224-331；Bundgaard著，“Design of Prodrugs”，1985年，Elsevier Press等]来确定。
具体地讲，当化合物(I)或者(IA)在其结构中具有羧基时，作为化合物(I)或者(IA)的药物前体，可列举出该羧基的氢原子被下述基团取代的化合物等，所述基团选自：低级烷基、低级烷酰氧基烷基(例如，低级烷酰氧基甲基、1-(低级烷酰氧基)乙基、1-甲基-1-(低级烷酰氧基)乙基等)、低级烷氧基碳酰氧基烷基(例如、低级烷氧基碳酰氧基甲基、1-(低级烷氧基碳酰氧基)乙基、1-甲基-1-(低级烷氧基碳酰氧基)乙基等)、N-(低级烷氧基羰基)氨基烷基(例如、N-(低级烷氧基羰基)氨基甲基、1-[N-(低级烷氧基羰基)氨基]乙基等)、3-酞酮基、4-巴豆酸内酯基【クロトノラクトニル】、γ-丁内酯-4-基、二低级烷基氨基烷基、氨基甲酰基烷基、二低级烷基氨基甲酰基烷基、哌啶子基烷基、吡咯烷基【ピロリヅノ】烷基、吗啉代烷基等。
另外，当化合物(I)或者(IA)在其结构中具有醇性羟基时，作为化合物(I)或者(IA)的药物前体，可列举出该羟基的氢原子被下述基团取代的化合物等，所述基团选自：低级烷酰氧基烷基、1-(低级烷酰氧基)乙基、1-甲基-1-(低级烷酰氧基)乙基、低级烷氧基碳酰氧基烷基、N-低级烷氧基羰基氨基烷基、琥珀酰基【スクシノイル】、低级烷酰基、α-氨基低级烷酰基等。
另外，当化合物(I)或者(IA)在其结构中具有氨基时，作为化合物(I)或者(IA)的药物前体，可列举出该氨基的1个或者2个氢原子被下述基团取代的化合物等，所述基团选自：低级烷基羰基、低级烷氧基羰基、低级烷基氨基甲酰基、二低级烷基氨基甲酰基等。
此处所示的低级烷基、低级烷氧基碳酰氧基烷基、低级烷氧基碳酰氧基甲基、1-(低级烷氧基碳酰氧基)乙基、1-甲基-1-(低级烷氧基碳酰氧基)乙基、N-(低级烷氧基羰基)氨基烷基、N-(低级烷氧基羰基)氨基甲基、1-[N-(低级烷氧基羰基)氨基]乙基、二低级烷基氨基烷基、二低级烷基氨基甲酰基烷基、低级烷氧基碳酰氧基甲基、低级烷基羰基、低级烷氧基羰基、低级烷基氨基甲酰基以及二低级烷基氨基甲酰基的低级烷基部分与上述低级烷基的含义相同，二低级烷基氨基烷基、二低级烷基氨基甲酰基烷基以及二低级烷基氨基甲酰基中的2个低级烷基部分可以相同，也可以不同。
另外，此处所示的低级烷酰氧基烷基、低级烷酰氧基甲基、1-(低级烷酰氧基)乙基、1-甲基-1-(低级烷酰氧基)乙基、低级烷酰基以及α-氨基低级烷酰基的低级烷酰基部分，与上述低级烷酰基的含义相同。
另外，此处所示的低级烷酰氧基烷基、低级烷氧基碳酰氧基烷基、N-(低级烷氧基羰基)氨基烷基、二低级烷基氨基烷基、氨基甲酰基烷基、二低级烷基氨基甲酰基烷基、哌啶子基烷基、吡咯烷基【ピロリヅノ】烷基以及吗啉代烷基的亚烷基部分，与从上述低级烷基的定义中除去1个氢原子而成的亚烷基的含义相同。
这些化合物(I)或者(IA)的药物前体，可以按照例如“ProtectiveGroups in Organic Synthesis，third edition”、T.W.Greene著，John Wiley&Sons Inc.(1999年)等中记载的方法或者与其类似的方法，由化合物(I)来制备。
化合物(I)或者(IA)或者其药物前体的药理学上允许的盐，包括例如可药用的酸加成盐、金属盐、铵盐、有机胺加成盐、氨基酸加成盐等。
作为化合物(I)或者(IA)或者其药物前体的可药用的酸加成盐，可列举出例如盐酸盐、硫酸盐、硝酸盐、磷酸盐等的无机酸盐；乙酸盐、马来酸盐、富马酸盐、柠檬酸盐等的有机酸盐；作为可药用的金属盐，可列举出例如钠盐、钾盐等的碱金属盐；镁盐、钙盐等的碱土类金属盐、铝盐、锌盐等；作为可药用的铵盐，可列举出例如铵、四甲基铵等的盐；作为可药用的有机胺加成盐，可列举出例如吗啉、哌啶等的加成盐；作为可药用的氨基酸加成盐，可列举出例如甘氨酸、苯基丙氨酸、赖氨酸、天冬氨酸、谷氨酸等的加成盐。
作为采用本发明的肿瘤治疗剂治疗的造血器官肿瘤，可列举出例如急性骨髓性白血病(AML)、急性淋巴性白血病(ALL)、急性骨髓球性白血病(APL)、慢性骨髓性白血病(CML)、慢性淋巴性白血病(CLL)、有毛细胞白血病(HCL)、成人T细胞白血病等的白血病、何杰金氏【ホヅキン】病、非何杰金氏淋巴肿瘤(例如B细胞淋巴肿瘤、T细胞淋巴肿瘤等)等的淋巴肿瘤、多发性骨髓肿瘤等。
作为可用本发明的肿瘤治疗剂来治疗的固态肿瘤，可列举出例如大肠癌、食道癌、胃癌、肝癌、胰腺癌、胆道癌等的消化系统肿瘤、膀胱癌、肾癌、前列腺癌等的泌尿系统癌肿瘤、乳腺癌、宫颈癌、子宫体癌、卵巢癌等的妇科系肿瘤、头颈部癌、肺癌、骨肉肿瘤、黑素瘤、脑肿瘤等。
本发明的肿瘤治疗剂中使用的化合物(I)或者(IA)或者其药物前体、或者其药理学上允许的盐，可以直接单独地给药，但希望作为通常的各种医药制剂来提供。另外，这些医药制剂可用于动物和人。
本发明中所述的医药制剂，作为活性成分，可以单独地含有化合物(I)或者(IA)或者其药物前体、或者其药理学上允许的盐，或者也可以作为与任意的用于其他治疗的有效成分的混合物来含有。另外，这些医药制剂可以通过将活性成分与可药用的一种或者一种以上的载体一起混合，采用制剂学的技术领域中熟知的任意方法来制造。
作为给药途径，希望在治疗时使用最有效的途径，可列举出经口给药、或者例如静脉内等的非经口给药。
作为给药方式，有例如片剂、注射剂等。
适于经口给药的、例如片剂等，可以使用乳糖、甘露糖醇等的赋形剂、淀粉等的崩解剂、硬脂酸镁等的润滑剂、羟丙基纤维素等的粘结剂、脂肪酸酯等的表面活性剂、甘油等的增塑剂等来制造。
适于非经口给药的制剂，优选由含有与接受者的血液等渗的活性化合物的灭菌水性剂构成。例如，在注射剂的场合，通过使用由盐溶液、葡萄糖溶液或者盐水与葡萄糖溶液的混合物构成的载体等来配制注射用的溶液。
另外，这些非经口剂中，也可以添加那些在经口剂中所示例的赋形剂、崩解剂、润滑剂、粘结剂、表面活性剂以及增塑剂、以及选自稀释剂、防腐剂、调味剂类等中的1种或者1种以上的辅助成分。
化合物(I)或者(IA)或者其药物前体、或者其药理学上允许的盐的给药量和给药次数，根据给药方式、患者的年龄、体重、所要治疗的症状的性质或者轻重程度等的不同而异，通常在经口的场合，成人每人0.01mg～1g、优选0.05～50mg按1天1次乃至数次给药。在静脉内给药等非经口给药的场合，成人每人0.001～500mg、优选0.01～100mg按1天1次乃至数次给药。但是，关于这些给药量和给药次数，可以根据上述的各种条件进行变动。
下面，用试验例具体地说明化合物(I)对代表性的肿瘤的治疗效果。
试验例1：对人慢性骨髓性白血病K562细胞的增殖抑制试验
在96孔微型平皿(ヌンク社制)中，向每孔接种1000个的人慢性骨髓性白血病K562细胞，在含有10％牛胎儿血清(FCS)的RPMI1640培养基(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养24小时。将配制成10mmol/L的各试验化合物的二甲亚砜(DMSO)溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1{4-[3-(4-碘苯基)-2-(4-硝基苯基)-2H-5-四唑基]-1，3-苯二磺酸酯}(4-[3-(4-Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1，3-benzene disulfonate)标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL，在5％二氧化碳温育器内、在37℃下培养2小时。使用微型平皿分光光度计(日本モレキュラ一デバイス社制、SpectraMax340PC384)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表3中。从表3看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对人慢性骨髓性白血病K562细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为慢性骨髓性白血病的治疗剂是有用的。
试验例2：对人急性骨髓性白血病MV4；11细胞的增殖抑制试验
在96孔微型平皿(ヌンク社制)中，向每孔接种10000个的人急性骨髓性白血病MV4；11细胞，在含有10％FCS的IMDM培养基(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养24小时。将配制成10mmol/L的各试验化合物的DMSO溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL，在5％二氧化碳温育器内，在37℃下培养1小时。使用微型平皿分光光度计(日本モレキュラ一デバイス社制、SpectraMax340PC384)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表3中。从表3看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对人急性骨髓性白血病MV4；11细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为急性骨髓性白血病的治疗剂是有用的。
试验例3：对人多发性骨髓肿瘤NCI-H929细胞的增殖抑制试验
在96孔微型平皿(ヌンク社制)中，向每孔接种10000个的人多发性骨髓肿瘤NCI-H929细胞，在含有10％FCS的RPMI培养基(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养24小时。将配制成10mmol/L的各试验化合物的DMSO溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL后，在5％二氧化碳温育器内、在37℃下培养2小时。使用微型平皿分光光度计(日本モレキュラ一デバイス社制、SpectraMax340PC384)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表3中。从表3看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对人多发性骨髓肿瘤NCI-H929细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为多发性骨髓肿瘤的治疗剂是有用的。
试验例4：对人T细胞淋巴肿瘤Karpas-299细胞的增殖抑制试验
在96孔微型平皿(ヌンク社制)中，向每孔接种5000个的人T细胞淋巴肿瘤Karpas-299细胞，在含有10％FCS的RPMI培养基(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养5小时。将配制成10mmol/L的各试验化合物的DMSO溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL后，在5％二氧化碳温育器内、在37℃下培养2小时。使用微型平皿分光光度计(日本モレキュラ一デバイス社制、SpectraMax340PC384)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表3中。从表3看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对人T细胞淋巴肿瘤Karpas-299细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为T细胞淋巴肿瘤的治疗剂是有用的。
试验例5：对来自人慢性淋巴性白血病的MEC-1细胞的增殖抑制 试验
在96孔微型平皿(ヌンク社制)中，向每孔接种10000个的来自人慢性淋巴性白血病的MEC-1细胞，在含有10％FCS的RPMI1640培养基(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养1小时。将配制成10mmol/L的各试验化合物的DMSO溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL后，在5％二氧化碳温育器内、在37℃下培养3小时。使用微型平皿分光光度计(モレキュラ一デバイス社制、M-SPmax250)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表3中。从表3看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对来自人慢性淋巴性白血病的MEC-1细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为慢性淋巴性白血病的治疗剂是有用的。
表3
  化合物   肿瘤细胞的存活率(％viability)
  人慢性K562骨髓性白血病细胞   人急性骨髓性白血病MV4；11细胞   人慢性淋巴性白血病MEC-1细胞   人多发性骨髓肿瘤NCI-H929细胞   人T细胞淋巴肿瘤Karpas-299细胞
  13   26   0   7   0   27
  16   4   0   3   0   13
  17   4   0   4   0   16
  32   4   0   4   0   15
  33   4   0   4   0   14
  38   4   0   4   0   14
  41   4   0   4   0   19
  56   5   0   4   0   14
  61   5   0   5   0   13
  69   4   0   4   0   14
  88   4   0   5   0   16
  91   4   0   4   0   16
  95   4   0   4   0   15
  106   4   0   4   0   13
  107   5   0   5   0   14
  122   4   0   4   0   12
  124   4   0   4   0   14
  125   4   0   5   0   15
  134   4   0   6   0   16
  139   4   1   5   0   14
  144   4   0   4   0   15
  149   4   0   5   0   14
  151   4   0   4   0   13
另外，从上述试验例1～5的结果可知，化合物(I)作为例如白血病、淋巴肿瘤、多发性骨髓肿瘤等的造血器官肿瘤的治疗剂是有用的。
试验例6：对人乳腺癌BT-474细胞的增殖抑制试验
在96孔微型平皿(ヌンク社制)中，向每孔接种4000个的人乳腺癌BT-474细胞，在含有10％FCS的Dulbecco改良Eagle培养基【Dulbecco′s Modified Eagle Medium】(DMEM)(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养24小时。将配制成10mmol/L的各试验化合物的DMSO溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL后，在5％二氧化碳温育器内、在37℃下培养2小时。使用微型平皿分光光度计(日本モレキュラ一デバイス社制、SpectraMax340PC384)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表4中。从表4看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对人乳腺癌BT-474细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为乳腺癌的治疗剂是有用的。
试验例7：对人肺癌NCI-H596细胞的增殖抑制试验
在96孔微型平皿(ヌンク社制)中，向每孔接种4000个的人肺癌NCI-H596细胞，在含有10％FCS的RPMI 1640培养基(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养24小时。将配制成10mmol/L的各试验化合物的DMSO溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL后，在5％二氧化碳温育器内、在37℃下培养2小时。使用微型平皿分光光度计(バイオラツド社制、Model 550)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表4中。从表4看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对人肺癌NCI-H596细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为肺癌的治疗剂是有用的。
试验例8：对人肾癌OS-RC-2细胞的增殖抑制试验
在96孔微型平皿(ヌツク社制)中，向每孔接种1000个的人肾癌OS-RC-2细胞，在含有10％FCS的RPMI 1640培养基(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养24小时。将配制成10mmol/L的各试验化合物的DMSO溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL后，在5％二氧化碳温育器内、在37℃下培养2小时。使用微型平皿分光光度计(バイオラツド社制、Model 550)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表4中。从表4看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对人肾癌OS-RC-2细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为肾癌的治疗剂是有用的。
试验例9：对人前列腺癌22Rv1细胞的增殖抑制试验
在96孔微型平皿(ヌンク社制)中，向每孔接种5000个的人前列腺癌22Rv1细胞，在含有10％FCS的RPMI 1640培养基(培养用培养基)中，在5％二氧化碳温育器内、在37℃下预培养24小时。将配制成10mmol/L的各试验化合物的DMSO溶液用培养用培养基稀释，以使其最终浓度成为10μmol/L，将其添加到各个孔中。将各个孔在5％二氧化碳温育器内、在37℃下进一步培养72小时。培养结束后，添加WST-1标识混合物(ロシュ·ダイアグノステイツクス社制)，向每1孔添加10μL后，在5％二氧化碳温育器内、在37℃下培养2小时。使用微型平皿分光光度计(バイオラツド社制、Model 550)，测定在450nm和655nm处的各个孔的吸光度。计算出从各个孔在655nm处的吸光度减去在450nm处的吸光度而得到的值(吸光度差)，以不添加试验化合物的细胞而获得的值作为100％，以不含细胞的孔的值作为0％，通过比较由添加试验化合物的孔得到的吸光度差，计算出试验化合物处理后的细胞存活率(％viability)。
结果示于表4中。从表4看出，作为化合物(I)的代表例，实施试验的化合物组，在10μmol/L的浓度下显示出对人前列腺癌22Rv1细胞的细胞增殖抑制活性。就是说，可以看出，化合物(I)作为前列腺癌的治疗剂是有用的。
表4
  化合物   肿瘤细胞的存活率(％viability)
  人乳腺癌BT-474细胞   人肺癌NCI-H596细胞   人肾癌OS-RC-2细胞   人前列腺癌22Rv1细胞
  13   12   35   66   6
  16   12   19   17   5
  17   10   16   20   5
  32   13   15   17   5
  33   13   20   18   5
  38   13   15   18   4
  41   14   12   18   5
  56   13   20   18   5
  61   12   25   25   5
  69   13   15   16   5
  88   13   14   17   6
  91   13   14   17   5
  95   13   14   18   5
  106   12   12   16   5
  107   13   16   18   5
  122   12   15   15   5
  124   13   15   15   5
  125   14   17   20   5
  134   13   17   21   6
  139   14   16   21   5
  144   13   14   16   5
  149   14   14   20   4
  151   13   28   30   5
另外，从上述试验例6～9的结果可知，化合物(I)作为例如乳腺癌、肺癌、肾癌、前列腺癌等的固态肿瘤的治疗剂是有用的。
试验例10：使用人慢性骨髓性白血病K562细胞移植小鼠模型的 体内抗肿瘤效果
作为造血器官肿瘤的疾病模型，使用将人慢性骨髓性白血病K562细胞移植到免疫功能不全的小鼠身上的实验体系，考察化合物33在体内的抗肿瘤效果。
在癌细胞移植前一天，向Fox C.B-17/Icr-scidJcl小鼠(日本クレア)的腹腔内投与抗asialoGM1抗体各0.3mg/小鼠。将K562细胞在含有10％牛胎儿血清(FCS)的RPMI1640培养基中，在5％二氧化碳温育器内，在37℃下培养，使其增殖，按每只小鼠移植1×107细胞的比例将细胞移植到腹侧皮下。在移植10天后，用游标卡尺测定皮下增殖的肿瘤的长径和短径，按照以下的式子求出肿瘤体积。
Figure A20068000541600451
同时还测定各小鼠的体重，按照肿瘤体积和体重随机将小鼠分为给药组和非给药组2个组，每组5只。将当天定义为给药试验开始第0天，如以下那样开始给药。
将化合物33在给药用溶剂〔由N，N-二甲基乙酰胺(和光纯药社制)、CREMOPHOR EL(sigma-aldrich公司制)和生理食盐水(大塚制药社制)按照容量比1∶1∶8混合而成的溶液〕中按照10mg/mL的浓度进行溶解，在给药开始第0天、第1天、第2天、第7天、第8天、第9天，分别按照小鼠每1g体重给药0.01mL(100mg/kg)的用量，每天2次由尾静脉进行静脉内给药。在给药试验开始4天、7天、10天、14天、17天、22天后，测定药剂非给药组和化合物33给药组的肿瘤体积。
其结果示于图1中。化合物33给药组中，观察到明显的对肿瘤增殖的抑制，可以确认，化合物33对人慢性骨髓性白血病K562细胞移植小鼠也具有体内抗肿瘤效果。从以上结果看出，通过给与化合物(I)，在体内也可以获得对造血器官肿瘤的治疗效果。
试验例11：使用人肺癌NCI-H596细胞移植小鼠模型的体内抗肿 瘤效果
作为固态肿瘤的疾病模型，使用将人肺癌NCI-H596细胞移植到免疫功能不全的小鼠身上的实验体系，考察化合物33在体内的抗肿瘤效果。
将NCI-H596细胞在含有10％牛胎儿血清(FCS)的RPMI1640培养基中，在5％二氧化碳温育器内，在37℃下培养，使其增殖，按每只小鼠移植1×107细胞的比例将细胞移植到BALB/cAJcl-nu小鼠(日本クレア)的腹侧皮下。从形成了肿瘤的小鼠体内摘取肿瘤，将肿瘤组织切成约8mm3的组织片，用外套管针将其移植到实施试验用的BALB/cAJcl-nu小鼠(日本クレア)的腹侧皮下。在移植17天后，用游标卡尺测定皮下增殖的肿瘤的长径和短径，按照以下的式子求出肿瘤体积。
同时还测定各小鼠的体重，按照肿瘤体积和体重随机将小鼠分为给药组和非给药组2个组，每组5只。将当天定义为给药试验开始第0天，如以下那样开始给药。
将化合物33在给药用溶剂〔由N，N-二甲基乙酰胺(和光纯药社制)、CREMOPHOR EL(sigma-aldrich公司制)和生理食盐水(大塚制药社制)按照容量比1∶1∶8混合而成的溶液〕中按照5mg/mL的浓度进行溶解，在给药开始第0天～第4天，连日分别按照小鼠每1g体重给药0.01mL(50mg/kg)的用量，每天2次由尾静脉进行静脉内给药。在给药试验开始4天、7天、10天、14天、17天后，测定药剂非给药组和化合物33给药组的肿瘤体积。
其结果示于图2中。化合物33给药组中，观察到明显的对肿瘤增殖的抑制，可以确认，化合物33对人肺癌NCI-H596细胞移植小鼠也具有体内抗肿瘤效果。从以上结果看出，通过给与化合物(I)，在体内也可以获得对固态肿瘤的治疗效果。
试验例12：使用人前列腺癌22Rv1细胞移植小鼠模型的体内抗肿 瘤效果
作为固态肿瘤的疾病模型，使用将人前列腺癌22Rv1细胞移植到免疫功能不全的小鼠身上的实验体系，考察化合物33在体内的抗肿瘤效果。
将22Rv1细胞在含有10％牛胎儿血清(FCS)的RPMI1640培养基中，在5％二氧化碳温育器内，在37℃下培养，使其增殖，按每只小鼠移植1×107细胞的比例将细胞移植到BALB/cAJcl-hu小鼠(日本クレア)的腹侧皮下。在移植17天后，用游标卡尺测定皮下增殖的肿瘤的长径和短径，按照以下的式子求出肿瘤体积。
Figure A20068000541600471
同时还测定各小鼠的体重，按照肿瘤体积和体重随机将小鼠分为给药组和非给药组2个组，每组5只。将当天定义为给药试验开始第0天，如以下那样开始给药。
将化合物33在给药用溶剂〔由N，N-二甲基乙酰胺(和光纯药社制)、CREMOPHOR EL(sigma-aldrich公司制)和生理食盐水(大塚制药社制)按照容量比1∶1∶8混合而成的溶液〕中按照10mg/mL的浓度进行溶解，在给药开始第0天～第4天，连日分别按照小鼠每1g体重给药0.01mL(100mg/kg)的用量，每天2次由尾静脉进行静脉内给药。在给药试验开始4天、7天、10天、14天、17天后，测定药剂非给药组和化合物33给药组的肿瘤体积。
其结果示于图3中。化合物33给药组中，观察到明显的对肿瘤增殖的抑制，可以确认，化合物33对人前列腺癌22Rv1细胞移植小鼠也具有体内抗肿瘤效果。从以上结果看出，通过给与化合物(I)，在体内也可以获得对固态肿瘤的治疗效果。
【实施例1】
按照常规方法，配制由如下组成构成的片剂。将40g的化合物4、乳糖286.8g和玉米淀粉60g混合，向其中加入羟丙基纤维素的10％水溶液120g。将得到的混合物按照常规方法搅匀，造粒，使其干燥后，整粒，制成压片用颗粒。向其中加入硬脂酸镁1.2g并混合，用一台具有直径为8mm的杵的压片机(クリ一ンプレスコレクト12菊水制作所制)进行压片，得到片剂(每片含有活性成分20mg)。
处方化合物         420mg
    乳糖           143.4mg
    玉米淀粉       30mg
    羟丙基纤维素   6mg
   硬脂酸镁        0.6mg
                                   
                   200mg
【实施例2】
按照常规方法，配制由如下组成构成的片剂。将40g的化合物6、乳糖286.8g和玉米淀粉60g混合，向其中加入羟丙基纤维素的10％水溶液120g。将得到的混合物按照常规方法搅匀，造粒，使其干燥后，整粒，制成压片用颗粒。向其中加入硬脂酸镁1.2g并混合，用一台具有直径为8mm的杵的压片机(クリ一ンプレスコレクト12菊水制作所制)进行压片，得到片剂(每片含有活性成分20mg)。
处方化合物         620mg
    乳糖           143.4mg
    玉米淀粉       30mg
    羟丙基纤维素   6mg
    硬脂酸镁       0.6mg
                                     
                   200mg
【实施例3】
按照常规方法，配制由如下组成构成的注射剂。将1g的化合物7和氯化钠9g溶解于注射用蒸馏水中，使全体成为1000mL。将得到的溶液用0.2μm的一次性【DISPOSABLES】膜滤器进行无菌过滤后，向玻璃小瓶中分别无菌填充2mL，得到注射剂(每1玻璃小瓶中含有活性成分2mg)。
处方化合物          72mg
    氯化钠          18mg
   注射用蒸馏水     适量
                                  
                    2.00mL
【产业上的可利用性】
本发明提供一种含有苯甲酰基化合物或其药物前体或其药理学上允许的盐作为有效成分的用于治疗选自造血器官肿瘤和固态肿瘤中的肿瘤的治疗剂。

Claims (20)

1.选自造血器官肿瘤和固态肿瘤的肿瘤的治疗剂，其中含有由通式(I)表示的苯甲酰基化合物或其药物前体或其药理学上允许的盐作为有效成分，
Figure A2006800054160002C1
[式中，
n表示1～5的整数；
R1表示取代或无取代的低级烷基、
取代或无取代的低级烷氧基、
取代或无取代的环烷基、
取代或无取代的低级烷氧基羰基、
取代或无取代的杂环烷基、
取代或无取代的芳基、
CONR7R8(式中，R7和R8相同或不同，表示氢原子、取代或无取代的低级烷基、取代或无取代的环烷基、取代或无取代的低级烷酰基、取代或无取代的芳基、取代或无取代的杂环基、取代或无取代的芳烷基、取代或无取代的杂环烷基或者取代或无取代的芳酰基，或者，R7和R8与相邻的氮原子一起，形成取代或无取代的杂环基)
或者
NR9R10(式中，R9和R10各自与上述R7和R8的定义相同)；
R2表示取代或无取代的芳基
或者
取代或无取代的芳香族杂环基；
R3和R5相同或不同，表示
氢原子、
取代或无取代的低级烷基、
取代或无取代的低级链烯基、
取代或无取代的低级烷酰基、
取代或无取代的环烷基、
取代或无取代的芳烷基
或者
取代或无取代的芳酰基；
R4表示氢原子、
羟基
或者
卤素；
R6表示氢原子、
卤素、
氰基、
硝基、
取代或无取代的低级烷基、
取代或无取代的低级链烯基、
取代或无取代的低级炔基、
取代或无取代的低级烷氧基、
取代或无取代的环烷基、
氨基、
低级烷基氨基、
二低级烷基氨基、
羧基、
取代或无取代的低级烷氧基羰基、
取代或无取代的低级烷酰基、
取代或无取代的芳氧基、
取代或无取代的芳基、
取代或无取代的杂环基、
取代或无取代的芳烷基
或者
取代或无取代的杂环烷基；
其中，
(i)当R3和R5为甲基、且R4和R6为氢原子时，且
(a)当-(CH2)nR1为甲氧基羰基甲基时，
R2不能为选自2，4，6-三甲氧基-5-甲氧基羰基-3-硝基苯基、3-氰基-2，4，6-三甲氧基苯基、5-氰基-2-乙氧基-4，6-二甲氧基-3-硝基苯基、2，6-二甲氧基苯基、2-氯-6-甲氧基苯基以及2-氯-4，6-二甲氧基-5-甲氧基羰基-3-硝基苯基中的基团；
(b)当-(CH2)nR1为乙氧基羰基甲基时，
R2不能为2，4，6-三甲氧基-3-甲氧基羰基苯基；
(c)当-(CH2)nR1为N，N-二甲基氨基甲基时，
R2不能为苯基；
(ii)当R3、R4、R5和R6为氢原子时，且
(a)当-(CH2)nR1为2-(乙酰氧基甲基)庚基、3-氧代戊基或者戊基时，
R2不能为6-羟基-4-甲氧基-3-甲氧基羰基-2-戊基苯基；
(b)当-(CH2)nR1为3-氧代戊基时，
R2不能为选自3-苄氧基羰基-6-羟基-4-甲氧基-2-戊基苯基和3-羧基-6-羟基-4-甲氧基-2-戊基苯基中的基团；
(c)当-(CH2)nR1为正丙基时，
R2不能为2，4-二羟基-6-[(4-羟基-2-氧代吡喃-6-基)甲基]苯基；
(iii)当R3和R4为氢原子、R5为甲基、且R6为甲氧基羰基、且-(CH2)nR1为戊基时，
R2不能为选自6-[2-(乙酰氧基甲基)庚基]-2，4-二羟基苯基、2，4-二羟基-6-戊基苯基以及2，4-二羟基-6-(3-氧代戊基)苯基中的基团；
(iv)当R3和R5为苄基、R4和R6为氢原子、且-(CH2)nR1为3-氧代戊基时，
R2不能为选自6-苄氧基-4-甲氧基-3-甲氧基羰基-2-戊基苯基和6-苄氧基-3-苄氧基羰基-4-甲氧基-2-戊基苯基中的基团；
(v)当R3为苄基、R4为氢原子、R5为甲基、-(CH2)nR1为戊基、且R6为甲氧基羰基或者苄氧基羰基时，
R2不能为2，4-双(苄氧基)-6-(3-氧代戊基)苯基；
(vi)当R3和R4为氢原子、R5为甲基、-(CH2)nR1为戊基、且R6为羧基或者苄氧基羰基时，
R2不能为2，4-二羟基-6-(3-氧代戊基)苯基；
(vii)当R3、R4和R6为氢原子、R5为正丙基、且-(CH2)nR1为5-(1，1-二甲基丙基)-4-(2-氢苯并三唑-2-基)-2-羟基苯基甲基时，R2不能为苯基]。
2.权利要求1所述的肿瘤治疗剂，其中，R2为取代或无取代的芳香族杂环基、被1～3个取代基取代的芳基或者芳基。
3.权利要求1所述的肿瘤治疗剂，其中，R2为被1～3个取代基取代的芳基或者芳基。
4.权利要求1所述的肿瘤治疗剂，其中，R2为被1～3个取代基取代的苯基或者苯基。
5.权利要求1所述的肿瘤治疗剂，其中，R2为取代或无取代的芳香族杂环基。
6.权利要求1～5任一项中所述的肿瘤治疗剂，其中，R3和R5相同或不同，为氢原子、取代或无取代的低级烷基、取代或无取代的低级烷酰基、取代或无取代的芳酰基或者取代或无取代的低级链烯基。
7.权利要求1～5任一项中所述的肿瘤治疗剂，其中，R3、R4和R5为氢原子。
8.权利要求1～7任一项中所述的肿瘤治疗剂，其中，R1为CONR7R8(式中，R7和R8分别与上述的含义相同)。
9.权利要求1～7任一项中所述的肿瘤治疗剂，其中，R1为CONR7AR8B(式中，R7A和R8A相同或不同，表示氢原子、取代或无取代的低级烷基或者取代或无取代的杂环烷基)。
10.权利要求1～7任一项中所述的肿瘤治疗剂，其中，R1为CONR7BR8B(式中，R7B和R8B与相邻的氮原子一起，形成取代或无取代的杂环基)。
11.权利要求1～7任一项中所述的肿瘤治疗剂，其中，R1为取代或无取代的低级烷氧基。
12.权利要求1～11任一项中所述的肿瘤治疗剂，其中，R6为氢原子、低级烷基、卤素或者芳基。
13.权利要求1～11任一项中所述的肿瘤治疗剂，其中，R6为低级烷基。
14.权利要求1～11任一项中所述的肿瘤治疗剂，其中，R6为乙基。
15.权利要求1～14任一项中所述的肿瘤治疗剂，其中，肿瘤为造血器官肿瘤。
16.权利要求15中所述的肿瘤治疗剂，其中，造血器官肿瘤为选自白血病、多发性骨髓肿瘤和淋巴肿瘤中的肿瘤。
17.权利要求1～14任一项中所述的肿瘤治疗剂，其中，肿瘤为固态肿瘤。
18.权利要求17所述的肿瘤治疗剂，其中，固态肿瘤为选自大肠癌、食道癌、胃癌、肝癌、胰腺癌、胆道癌、膀胱癌、肾癌、前列腺癌、乳腺癌、宫颈癌、子宫体癌、卵巢癌、头颈部癌、肺癌、骨肉肿瘤、黑素瘤、以及脑肿瘤中的肿瘤。
19.选自造血器官肿瘤和固态肿瘤中的肿瘤的治疗方法，其特征在于，投给有效量的权利要求1所述由通式(I)表示的苯甲酰基化合物或其药物前体或其药理学上允许的盐。
20.权利要求1所述的由通式(I)表示的苯甲酰基化合物或其药物前体或其药理学上允许的盐在制造用于治疗选自造血器官肿瘤和固态肿瘤中的肿瘤的治疗剂中的应用。
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