CN1366881A - 用雌激素激动剂/拮抗剂治疗某些癌症的方法 - Google Patents
用雌激素激动剂/拮抗剂治疗某些癌症的方法 Download PDFInfo
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- CN1366881A CN1366881A CN02102519A CN02102519A CN1366881A CN 1366881 A CN1366881 A CN 1366881A CN 02102519 A CN02102519 A CN 02102519A CN 02102519 A CN02102519 A CN 02102519A CN 1366881 A CN1366881 A CN 1366881A
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract
本发明提供用雌激素激动剂/拮抗剂治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法。本发明还提供用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的含有雌激素激动剂/拮抗剂的试剂盒。
Description
发明领域
本发明提供治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法,包括将治疗有效量的雌激素激动剂/拮抗剂对患有肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的患者给药。本发明还提供用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的试剂盒,该试剂盒包含药物组合物和说明书,该药物组合物包含雌激素激动剂/拮抗剂,该说明书是关于用该药物组合物治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法。
发明背景
癌症现在仍然是最可怕的疾病之一,人们已经花费了很多努力和资金,试图发现治疗癌症的方法。本发明提供了治疗某些癌症的方法,也就是肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌。
肝癌有两种主要类型。第一种类型是癌症从身体另一部位转移的结果。在这种类型的肝癌中,来自身体另一部位的癌细胞移行至肝脏,在那里开始生长和形成肿瘤。转移至肝脏的癌细胞一般来自肺、乳房、结肠、胰腺或胃部的癌症。
肝癌的第二种普遍类型称为原发性肝癌。这种类型由几种亚型癌症组成,例如肝细胞癌、纤维层癌、胆管癌、成肝细胞瘤和血管肉瘤,其中肝细胞癌是最常见的肝癌类型。
卵巢癌是第二种最常见和最致命的妇科恶性肿瘤。卵巢癌主要影响绝经前和绝经后的妇女。
硬纤维瘤也称侵袭性纤维瘤病,是致密的结缔组织肿瘤。
神经胶质瘤是一种脑部肿瘤,占颅内肿瘤的45%。
胰腺癌有若干种类,包括导管腺癌、囊腺癌、管内乳头状粘液性肿瘤、胰岛瘤、Zollinger-Ellison综合征(已知也称胃泌素瘤)、致泻瘤和胰高血糖素瘤。
肾细胞癌约占癌症的百分之二。
上面列举的癌症都可以通过将治疗有效量的雌激素激动剂/拮抗剂对患者给药加以治疗。
他莫昔芬治疗卵巢癌、肝细胞癌、硬纤维瘤、恶性神经胶质瘤、胰腺癌和黑素瘤的用途公开在Gelman,Edward P.“他莫昔芬用于治疗除乳腺癌和子宫内膜癌以外的恶性肿瘤”《肿瘤学专题讨论会》24卷1期增刊I,1997年2月,pp SI-65-SI70。
发明概述
本发明提供治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法,该方法包括将治疗有效量的雌激素激动剂/拮抗剂对患有肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的患者给药的步骤。
在该方法的优选实施方式中,该雌激素激动剂/拮抗剂是式(I)化合物:其中:
A选自CH2和NR;
B、D和E独立地选自CH和N;
Y是
(a)苯基,可选地被1-3个独立地选自R4的取代基取代;
(b)萘基,可选地被1-3个独立地选自R4的取代基取代;
(c)C3-C8环烷基,可选地被1-2个独立地选自R4的取代基取代;
(d)C3-C8环烯基,可选地被1-2个独立地选自R4的取代基取代;
(e)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的五元杂环,可选地被1-3个独立地选自R4的取代基取代;
(f)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的六元杂环,可选地被1-3个独立地选自R4的取代基取代;或
(g)由五或六元杂环与苯环稠合而成的二环体系,所述杂环含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子,可选地被1-3个独立地选自R4的取代基取代;
Z1是
(a)-(CH2)pW(CH2)q-;
(b)-O(CH2)pCR5R6-;
(c)-O(CH2)pW(CH2)q-;
(d)-OCHR2CHR3-;或
(e)-SCHR2CHR3-;
G是
其中n是0、1或2;m是1、2或3;Z2是-NH-、-O-、-S-或-CH2-;可选地在相邻的碳原子上与一个或两个苯环稠合,并且可选地在碳上独立地被一至三个、且可选地在氮上独立地被化学上适合的选自R4的取代基取代;或
(c)含有五至十二个碳原子的二环胺,它是桥连的或稠合的,并且可选地被1-3个独立地选自R4的取代基取代;或者
Z1和G联合可以是W是
(k)-C≡C-;R是氢或C1-C6烷基;R2和R3独立地是
(a)氢;或
(b)C1-C4烷基;R4是
(a)氢;
(b)卤素;
(c)C1-C6烷基;
(d)C1-C4烷氧基;
(e)C1-C4酰氧基;
(f)C1-C4烷硫基;
(g)C1-C4烷基亚磺酰基;
(h)C1-C4烷基磺酰基;
(i)羟基(C1-C4)烷基;
(j)芳基(C1-C4)烷基;
(k)-CO2H;
(l)-CN;
(m)-CONHOR;
(n)-SO2NHR;
(o)-NH2;
(p)C1-C4烷基氨基;
(q)C1-C4二烷基氨基;
(r)-NHSO2R;
(s)-NO2;
(t)-芳基;或
(u)-OH;
R5和R6独立地是C1-C8烷基或者一起构成C3-C10碳环;
R7和R8独立地是
(a)苯基;
(b)饱和或不饱和的C3-C10碳环;
(c)含有至多两个选自-O-、-N-和-S-的杂原子的C3-C10杂环;
(d)H;
(e)C1-C6烷基;或者
(f)与R5或R6构成3至8元含氮环;
线性或环状R7和R8可以可选地被至多三个独立地选自C1-C6烷基、卤素、烷氧基、羟基和羧基的取代基取代;
由R7和R8所构成的环可以可选地与苯环稠合;
e是0、1或2;
m是1、2或3;
n是0、1或2;
p是0、1、2或3;
q是0、1、2或3;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
G是或
R4是H、OH、F或Cl;
B和E独立地选自CH和N;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该方法的另一种优选实施方式中,该雌激素激动剂/拮抗剂是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该方法的另一种优选实施方式中,该雌激素激动剂/拮抗剂是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇,D-酒石酸盐。
在该方法的另一种优选实施方式中,该雌激素激动剂/拮抗剂是4-羟基他莫昔芬、屈洛昔芬、托瑞米芬、星克罗曼、艾多昔芬、、雷洛昔芬、6-(4-羟基苯基)-5-[4-(2-哌啶-1-基乙氧基)苄基]萘-2-醇、{4-[2-(2-氮杂二环并[2.2.1]庚-2-基)乙氧基]苯基}-[6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基]甲酮、EM-652、EM-800、GW 5638、GW 7604或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该方法的另一种优选实施方式中,该雌激素激动剂/拮抗剂是式(V)或(VI)化合物:其中:
R1B选自H、OH、-O-C(O)-C1-C12烷基(直链或支链)、-O-C1-C12烷基(直链或支链或环状)、卤素或C1-C4卤代醚;
R2B、R3B、R4B、R5B和R6B独立地选自H、OH、-O-C(O)-C1-C12烷基(直链或支链)、-O-C1-C12烷基(直链或支链或环状)、卤素、C1-C4卤代醚、氰基、C1-C6烷基(直链或支链)或三氟甲基;
XA选自H、C1-C6烷基、氰基、硝基、三氟甲基和卤素;
s是2或3;
a)R7B和R8B独立地选自H、C1-C6烷基或苯基,该苯基可选地被CN、C1-C6烷基(直链或支链)、C1-C6烷氧基(直链或支链)、卤素、-OH、-CF3或-OCF3取代;或者
b)R7B和R8B连结构成含有一个氮杂原子的五元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
c)R7B和R8B连结构成含有一个氟杂原子的六元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
d)R7B和R8B连结构成含有一个氮杂原子的七元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
e)R7B和R8B连结构成含有一个氮杂原子的八元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
f)R7B和R8B连结构成含有6-12个碳原子的饱和二环杂环,它是桥连或稠合的,并且含有一个氮杂原子,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该方法的另一种优选实施方式中,该雌激素激动剂/拮抗剂是式(Va)化合物:
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该方法的另一种优选实施方式中,该雌激素激动剂/拮抗剂是下式(III)(EM-652)或式(IV)(EM-800)化合物:或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
本发明还提供由消费者使用的试剂盒,用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌,该试剂盒包含:
(a)药物组合物,包含雌激素激动剂/拮抗剂;和
(b)说明书,描述使用该药物组合物治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法。
A选自CH2和NR;
B、D和E独立地选自CH和N;
Y是
(a)苯基,可选地被1-3个独立地选自R4的取代基取代;
(b)萘基,可选地被1-3个独立地选自R4的取代基取代;
(c)C3-C8环烷基,可选地被1-2个独立地选自R4的取代基取代;
(d)C3-C8环烯基,可选地被1-2个独立地选自R4的取代基取代;
(e)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的五元杂环,可选地被1-3个独立地选自R4的取代基取代:
(f)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的六元杂环,可选地被1-3个独立地选自R4的取代基取代;或
(g)由五或六元杂环与苯环稠合而成的二环体系,所述杂环含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子,可选地被1-3个独立地选自R4的取代基取代;
Z1是
(a)-(CH2)pW(CH2)q-;
(b)-O(CH2)pCR5R6-;
(c)-O(CH2)pW(CH2)q-;
(d)-OCHR2CHR3-;或
(e)-SCHR2CHR3-;G是
(a)-NR7R8;
其中n是0、1或2;m是1、2或3;Z2是-NH-、-O-、-S-或-CH2-;可选地在相邻的碳原子上与一个或两个苯环稠合,并且可选地在碳上独立地被一至三个、且可选地在氮上独立地被化学上适合的选自R4的取代基取代;或
(c)含有五至十二个碳原子的二环胺,它是桥连的或稠合的,并且可选地被1-3个独立地选自R4的取代基取代;或者
(a)-CH2-;
(b)-CH=CH-;
(c)-O-;
(d)-NR2-;
(g)-CR2(OH)-;
(h)-CONR2-;
(k)-C≡C-;R是氢或C1-C6烷基;R2和R3独立地是
(a)氢;或
(b)C1-C4烷基;R4是
(a)氢;
(b)卤素;
(c)C1-C6烷基;
(d)C1-C4烷氧基;
(e)C1-C4酰氧基;
(f)C1-C4烷硫基;
(g)C1-C4烷基亚磺酰基;
(h)C1-C4烷基磺酰基;
(i)羟基(C1-C4)烷基;
(j)芳基(C1-C4)烷基;
(k)-CO2H;
(l)-CN;
(m)-CONHOR;
(n)-SO2NHR;
(o)-NH2;
(p)C1-C4烷基氨基;
(q)C1-C4二烷基氨基;
(r)-NHSO2R;
(s)-NO2;
(t)-芳基;或
(u)-OH;R5和R6独立地是C1-C8烷基或者一起构成C3-C10碳环;R7和R8独立地是
(a)苯基;
(b)饱和或不饱和的C3-C10碳环;
(c)含有至多两个选自-O-、-N-和-S-的杂原子的C3-C10杂环;
(d)H;
(e)C1-C6烷基;或者
(f)与R5或R6构成3至8元含氮环;
线性或环状R7和R8可以可选地被至多三个独立地选自C1-C6烷基、卤素、烷氧基、羟基和羧基的取代基取代;
由R7和R8所构成的环可以可选地与苯环稠合;
e是0、1或2;
m是1、2或3;
n是0、1或2;
p是0、1、2或3;
q是0、1、2或3;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该试剂盒的另一种优选实施方式中,该雌激素激动剂/拮抗剂是式(IA)化合物:其中:
B和E独立地选自CH和N;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该试剂盒的另一种优选实施方式中,该雌激素激动剂/拮抗剂是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该试剂盒的另一种优选实施方式中,该雌激素激动剂/拮抗剂是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇,D-酒石酸盐。
在该试剂盒的另一种优选实施方式中,该雌激素激动剂/拮抗剂是4-羟基他莫昔芬、屈洛昔芬、托瑞米芬、星克罗曼、艾多昔芬、雷洛昔芬、6-(4-羟基苯基)-5-[4-(2-哌啶-1-基乙氧基)苄基]萘-2-醇、{4-[2-(2-氮杂二环并[2.2.1]庚-2-基)乙氧基]苯基}-[6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基]甲酮、EM-652、EM-800、GW 5638、GW 7604或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
R1B选自H、OH、-O-C(O)-C1-C12烷基(直链或支链)、-O-C1-C12烷基(直链或支链或环状)、卤素或C1-C4卤代醚;
R2B、R3B、R4B、R5B和R6B独立地选自H、OH、-O-C(O)-C1-C12烷基(直链或支链)、-O-C1-C12烷基(直链或支链或环状)、卤素、C1-C4卤代醚、氰基、C1-C6烷基(直链或支链)或三氟甲基;
XA选自H、C1-C6烷基、氰基、硝基、三氟甲基和卤素;
s是2或3;
a)R7B和R8B独立地选自H、C1-C6烷基或苯基,该苯基可选地被CN、C1-C6烷基(直链或支链)、C1-C6烷氧基(直链或支链)、卤素、-OH、-CF3或-OCF3取代;或者
b)R7B和R8B连结构成含有一个氮杂原子的五元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
c)R7B和R8B连结构成含有一个氮杂原子的六元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
d)R7B和R8B连结构成含有一个氮杂原子的七元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
e)R7B和R8B连结构成含有一个氮杂原子的八元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
f)R7B和R8B连结构成含有6-12个碳原子的饱和二环杂环,它是桥连或稠合的,并且含有一个氮杂原子,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
在该试剂盒的另一种优选实施方式中,试剂盒进一步包含另外一种可用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的化合物。
发明的详细说明
本发明提供治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法,该方法包括将治疗有效量的雌激素激动剂/拮抗剂对患有肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的患者给药的步骤。本发明还提供用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的试剂盒,该试剂盒包含药物组合物和说明书,该药物组合物含有雌激素激动剂/拮抗剂,该说明书描述使用该药物组合物治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法。
术语“治疗”包括预防性和缓解性治疗或者起预防或缓解的治疗作用。
术语“患者”表示动物,特别是哺乳动物。优选的患者是人。
“雌激素激动剂/拮抗剂”是这样一种化合物,它影响一部分而非全部与雌激素作用相同的受体,在有些情况下,它拮抗或阻滞雌激素。已知也称“选择性雌激素受体调节剂”(SERM)。雌激素激动剂/拮抗剂还可以称为抗雌激素,不过它们对某些雌激素受体具有某些雌激素活性。雌激素激动剂/拮抗剂因此不是普遍所称的那些“纯粹的抗雌激素”。也能起到激动剂作用的抗雌激素称为I型抗雌激素。I型抗雌激素激活雌激素受体,与之在核内长时间紧密结合,但是削弱了受体的补充作用(Clark等《类固醇》1973,22:707;Capony等《分子细胞内分泌学》1975,3:233)。
“治疗有效量”是雌激素激动剂/拮抗剂在对患有肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的患者给药时为治疗癌症的一种或多种疾患或症状而提供的剂量。优选的剂量是在雌激素激动剂/拮抗剂给药之后减少肿瘤大小的剂量。
本发明的雌激素激动剂/拮抗剂可以全身给药或局部给药。关于全身用药,按照常规方法将雌激素激动剂/拮抗剂配制成肠胃外(例如静脉内、皮下、肌内、腹膜内、鼻内或透皮)或肠内(例如口服或直肠)释放的剂型。静脉内给药可以是一系列注射或长时间的连续输注。注射或其他不连续间隔的给药途径,可以从每周一次至每日一至三次或多次不等。
A选自CH2和NR;
B、D和E独立地选自CH和N;
Y是
(a)苯基,可选地被1-3个独立地选自R4的取代基取代;
(b)萘基,可选地被1-3个独立地选自R4的取代基取代;
(c)C3-C8环烷基,可选地被1-2个独立地选自R4的取代基取代;
(d)C3-C8环烯基,可选地被1-2个独立地选自R4的取代基取代;
(e)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的五元杂环,可选地被1-3个独立地选自R4的取代基取代;
(f)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的六元杂环,可选地被1-3个独立地选自R4的取代基取代;或
(g)由五或六元杂环与苯环稠合而成的二环体系,所述杂环含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子,可选地被1-3个独立地选自R4的取代基取代:
Z1是
(a)-(CH2)pW(CH2)q-;
(b)-O(CH2)pCR5R6-;
(c)-O(CH2)pW(CH2)q-;
(d)-OCHR2CHR3-;或
(e)-SCHR2CHR3-;G是
(a)-NR7R8;
其中n是0、1或2;m是1、2或3;Z2是-NH-、-O-、-S-或-CH2-;可选地在相邻的碳原子上与一个或两个苯环稠合,并且可选地在碳上独立地被一至三个、且可选地在氮上独立地被化学上适合的选自R4的取代基取代;或
(c)含有五至十二个碳原子的二环胺,它是桥连的或稠合的,并且可选地被1-3个独立地选自R4的取代基取代;或者
(a)-CH2-;
(b)-CH=CH-;
(c)-O-;
(d)-NR2-;
(e)-S(O)n-;
(g)-CR2(OH)-;
(h)-CONR2-;
(k)-C≡C-;R是氢或C1-C6烷基;R2和R3独立地是
(a)氢;或
(b)C1-C4烷基;R4是
(a)氢;
(b)卤素;
(c)C1-C6烷基;
(d)C1-C4烷氧基;
(e)C1-C4酰氧基;
(f)C1-C4烷硫基;
(g)C1-C4烷基亚磺酰基;
(h)C1-C4烷基磺酰基;
(i)羟基(C1-C4)烷基;
(j)芳基(C1-C4)烷基;
(k)-CO2H;
(l)-CN;
(m)-CONHOR;
(n)-SO2NHR;
(o)-NH2;
(p)C1-C4烷基氨基;
(q)C1-C4二烷基氨基;
(r)-NHSO2R;
(s)-NO2;
(t)-芳基;或
(u)-OH;R5和R6独立地是C1-C8烷基或者一起构成C3-C10碳环;R7和R8独立地是
(a)苯基;
(b)饱和或不饱和的C3-C10碳环;
(c)含有至多两个选自-O-、-N-和-S-的杂原子的C3-C10杂环;
(d)H;
(e)C1-C6烷基;或者
(f)与R5或R6构成3至8元含氮环;
线性或环状R7和R8可以可选地被至多三个独立地选自C1-C6烷基、卤素、烷氧基、羟基和羧基的取代基取代;
由R7和R8所构成的环可以可选地与苯环稠合;
e是0、1或2;
m是1、2或3;
n是0、1或2;
p是0、1、2或3;
q是0、1、2或3;
和其旋光与几何异构体;及其无毒的药学上可接受的酸加成盐、N-氧化物、酯、季铵盐和前体药物。
R4是H、OH、F或Cl;
B和E独立地选自CH和N;
和其旋光与几何异构体;及其无毒的药学上可接受的酸加成盐、N-氧化物、酯、季铵盐和前体药物。
本发明方法和试剂盒尤其优选的化合物是:
顺式-6-(4-氟苯基)-5-[4-(2-哌啶-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇;
(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇;
顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇;
顺式-1-[6’-吡咯烷基乙氧基-3’-吡啶基]-2-苯基-6-羟基-1,2,3,4-四氢萘;
1-(4’-吡咯烷基乙氧基苯基)-2-(4”-氟苯基)-6-羟基-1,2,3,4-四氢异喹啉;
顺式-6-(4-羟基苯基)-5-[4-(2-哌啶-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇;
1-(4’-吡咯烷基乙氧基苯基)-2-苯基-6-羟基-1,2,3,4-四氢异喹啉及其药学上可接受的盐。
尤其优选的(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇的盐是D-酒石酸盐。
其他优选的雌激素激动剂/拮抗剂公开在美国专利No.5,047,431中。这些化合物的结构这里是由下式(II)所代表的:其中
R1A和R2A可以是相同或不同的,是H、甲基、乙基或苄基;
和其旋光或几何异构体;及其药学上可接受的盐、N-氧化物、酯、季铵盐和前体药物。优选的化合物是屈洛昔芬。
另外优选的雌激素激动剂/拮抗剂是:公开在美国专利No.4,536,516中的化合物;4-羟基他莫昔芬(也就是其中2-苯基部分具有4位羟基的他莫昔芬)和其他公开在美国专利No.4,623,660中的化合物;雷洛昔芬(盐酸[6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基][4-[2-(1-哌啶基)乙氧基]苯基]甲酮)和其他公开在美国专利No.4,418,068、5,393,763、5,457,117、5,478,847和5,641,790中的化合物;托瑞米芬((Z)-2-[4-(4-氯-1,2-二苯基-1-丁烯基)苯氧基]-N,N-二甲基乙胺的2-羟基-1,2,3-丙三羧酸盐(1∶1))和其他公开在美国专利No.4,696,949和4,996,225中的化合物;星克罗曼(1-[2-[[4-(甲氧基-2,2-二甲基-3-苯基苯并二氢吡喃-4-基)苯氧基]乙基]吡咯烷)和其他公开在美国专利No.3,822,287中的化合物;艾多昔芬(1-[4-[[1-(4-碘苯基)-2-苯基-1-丁烯基]苯氧基]乙基]吡咯烷)和其他公开在美国专利No.4,839,155中的化合物;6-(4-羟基苯基)-5-[4-(2-哌啶-1-基乙氧基)苄基]萘-2-醇和其他公开在美国专利No.5,484,795中的化合物;以及{4-[2-(2-氮杂二环并[2.2.1]庚-2-基)乙氧基]苯基}-[6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基]甲酮和其他公开在国际专利申请WO 95/10513中的化合物。其他优选的化合物包括GW 5638和GW 7604,其合成描述在Willson等《医药化学杂志》1994,37:1550-1552中。
进一步优选的雌激素激动剂/拮抗剂包括EM-652(这里是如式(III)所代表的)和EM-800(这里是如式(IV)所代表的)。EM-652和EM-800的合成和各种对映体的活性描述在Gauthier等《医药化学杂志》1997,40:2117-2122中。
进一步优选的雌激素激动剂/拮抗剂包括TSE 424和其他公开在美国专利No.5,998,402、美国专利No.5,985,910、美国专利No.5,780,497、美国专利No.5,880,137和欧洲专利申请EP 0802183 A1中的化合物,包括这里由下式(V)和(VI)所代表的化合物:其中:
R1B选自H、OH或其C1-C12酯(直链或支链)或C1-C12烷基醚(直链或支链或环状)、或卤素;或C1-C4卤代醚,包括三氟甲基醚和三氯甲基醚;
R2B、R3B、R4B、R5B和R6B独立地选自H、OH或其C1-C12酯(直链或支链)或C1-C12烷基醚(直链或支链或环状)、卤素;C1-C4卤代醚,包括三氟甲基醚和三氯甲基醚;氰基、C1-C6烷基(直链或支链)或三氟甲基;
XA选自H、C1-C6烷基、氰基、硝基、三氟甲基和卤素;
s是2或3;
YA选自:
b)五元饱和、不饱和或部分饱和的杂环,含有至多两个选自-O-、-NH-、-N(C1-C4烷基)-、-N=和-S(O)u-的杂环子,其中u是0-2的整数,并且可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、C1-C4烷基氨基、二(C1-C4)烷基氨基、-NHSO2R1B、-NHCOR1B、-NO2和可选被1-3个(C1-C4)烷基取代的苯基;
c)六元饱和、不饱和或部分饱和的杂环,含有至多两个选自-O-、-NH-、-N(C1-C4烷基)-、-N=和-S(O)u-的杂环子,其中u是0-2的整数,并且可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、C1-C4烷基氨基、二(C1-C4)烷基氨基、-NHSO2R1B、-NHCOR1B、-NO2和可选被1-3个(C1-C4)烷基取代的苯基;
d)七元饱和、不饱和或部分饱和的杂环,含有至多两个选自-O-、-NH-、-N(C1-C4烷基)-、-N=和-S(O)u-的杂环子,其中u是0-2的整数,并且可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、C1-C4烷基氨基、二(C1-C4)烷基氨基、-NHSO2R1B、-NHCOR1B、-NO2和可选被1-3个(C1-C4)烷基取代的苯基;或
e)含有6-12个碳原子的二环杂环,它是桥连或稠合的,含有至多两个选自-O-、-NH-、-N(C1-C4烷基)-、-N=和-S(O)u-的杂环子,其中u是0-2的整数,并且可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、C1-C4烷基氨基、二(C1-C4)烷基氨基、-NHSO2R1B、-NHCOR1B、-NO2和可选被1-3个(C1-C4)烷基取代的苯基;
和其旋光与几何异构体;及其无毒的药学上可接受的酸加成盐、N-氧化物、酯、季铵盐和前体药物。
本发明优选的化合物是具有上述通式(V)或(VI)结构的那些,其中:
R1B选自H、OH或其C1-C12酯或烷基醚、和卤素;
R2B、R3B、R4B、R5B和R6B独立地选自H、OH或其C1-C12酯或烷基醚、卤素、氰基、C1-C6烷基、或三卤甲基,优选为三氟甲基,其条件是若R1B是H,则R2B不是OH;
XA选自H、C1-C6烷基、氰基、硝基、三氟甲基和卤素;YA是其中R7B和R8B独立地选自H、C1-C6烷基,或者被-(CH2)w-结合,其中w是2至6的整数,构成一个环,该环可选地被至多三个选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONH(C1-C4烷基)、-NH2、C1-C4烷基氨基、C1-C4二烷基氨基、-NHSO2(C1-C4烷基)、-CO(C1-C4烷基)和-NO2;
和其旋光与几何异构体;及其无毒的药学上可接受的酸加成盐、N-氧化物、酯、季铵盐和前体药物。
上述由连结的R7B和R8B所构成的环可以包括但不限于氮丙啶、氮杂环丁烷、吡咯烷、哌啶、环己胺或环庚胺环。
优选的上述结构式(V)和(VI)化合物是,其中R1B是OH;R2B至R6B是如上所定义的;XA选自Cl、NO2、CN、CF3或CH3;YA是其中R7B和R8B一起连结成-(CH2)t-,其中t是4至6的整数,构成一个环,该环可选地被至多三个选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONH(C1-C4烷基)、-NH2、C1-C4烷基氨基、二(C1-C4)烷基氨基、-NHSO2(C1-C4)烷基、-NHCO(C1-C4)烷基和-NO2;
和其旋光与几何异构体;及其无毒的药学上可接受的酸加成盐、N-氧化物、酯、季铵盐和前体药物。
另一种优选的化合物是TSE-424,这里是由下式(Va)所代表的:
本发明的雌激素激动剂/拮抗剂可以以药学上可接受的盐的形式给药。该盐适宜如有机化学中用的通常是通过使碱性化合物与适合的酸反应而形成。盐通常在适当温度下快速生成,收率高,并经常是这样制备的,作为合成的最后一步,仅从适合的酸性洗液中分离化合物即可。成盐的酸是溶解在适当的有机溶剂或含水有机溶剂中的,例如链烷醇、酮或酯。另一方面,如果需要化合物呈游离碱的形式,按照通常的做法从最后的碱性洗涤步骤中分离之。优选用于制备盐酸盐的工艺是将游离碱溶于适合的溶剂,将该溶液经过分子筛充分干燥,然后向其中通入氯化氢气体。优选的(-)顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇的盐是D-(-)-酒石酸盐。也将得到认可的是雌激素激动剂/拮抗剂有可能以无定形的形式用药。
“药学上可接受的盐”一词包括药学上可接受的酸加成盐和药学上可接受的阳离子盐。“药学上可接受的阳离子盐”是用以定义但不限于这样的盐,例如碱金属盐(例如钠和钾)、碱土金属盐(例如钙和镁)、铝盐、铵盐和与有机胺所生成的盐,有机胺例如苯乍生(benzathine)(N,N’-二苄基乙二胺)、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)、苄乙胺(N-苄基苯乙胺)、二乙胺、哌嗪、氨丁三醇(2-氨基-2-羟甲基-1,3-丙二醇)和普鲁卡因。“药学上可接受的酸加成盐”是用以定义但不限于这样的盐,例如盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、琥珀酸盐、柠檬酸盐、甲磺酸盐和对-甲苯磺酸盐。
本领域普通技术人员将认可的是,某些本发明的雌激素激动剂/拮抗剂要含有一个或多个这样的原子,它们可以处于特定的立体化学、互变异构或几何异构构型,产生立体异构体、互变异构体和构型异构体。所有这样的互变异构体和异构体及其混合物都包括在本发明中。还包括本发明化合物的水合物和溶剂化物。
本发明还包括同位素标记的雌激素激动剂/拮抗剂,要不是一个或多个原子被原子质量或质量数不同于在自然界中通常发现的原子质量或质量数的原子所代替,它们在结构上等同于上文所公开的那些。可以结合在本发明化合物中的同位素实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别例如2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其他原子的其他同位素的本发明化合物、其前体药物和所述化合物与所述前体药物的药学上可接受的盐均属于本发明的范围。某些同位素标记的本发明化合物、例如其中结合有放射性同位素例如3H和14C的那些可用于药物和/或底物组织分布的测定。氚、即3H、和碳-14、即14C同位素是特别优选的,因为它们易于制备和检测。此外,用较重的同位素取代,例如氘、即2H,由于代谢稳定性更高而能够赋予某些治疗上的优点,例如体内半衰期延长或所需剂量减少,因此在某些情况下可能是优选的。同位素标记的本发明化合物及其前体药物的制备,一般可以进行已知的或标准的操作,并且可用易于得到的同位素标记试剂代替非同位素标记试剂。
本领域普通技术人员将认可的是,具有可使用羟基的生理活性化合物可以以药学上可接受的酯的形式给药。本发明化合物可以有效地用羟基上所生成的酯。正如药物化学中长期已知的,有可能通过酯基的适当选择来调整化合物的作用速率或持续时间。
当本发明化合物含有酯时,某些酯基是优选的。包括式I、IA、II、III、IV、V、Va或VI化合物在内的雌激素激动剂/拮抗剂可以在如上文所定义的各种位置含有酯基,其中这些基团是如-COOR所代表的,R是C1-C14烷基、C1-C3氯代烷基、C1-C3氟代烷基、C5-C7环烷基、苯基或被C1-C4烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基一取代或二取代的苯基。
本发明化合物对患者给药的剂量是可以在相当宽范围内变化的,由主治医师进行判断。应当注意,当以盐、例如月桂酸盐的形式给药时,调整化合物的剂量可能是必要的,因为其成盐部分具有一定的分子量。按照本发明给药的化合物的特定剂量将由环境因素决定,例如包括所用的化合物、给药途径和所治疗疾病的严重性。
下列剂量是针对体重约65kg至约70kg的普通人而言的。根据患者的病史,熟练的医务人员能容易地确定体重超出65kg至70kg范围的患者所需剂量。这里所述全部剂量都是雌激素激动剂/拮抗剂的游离碱形式的每日剂量。通过有关种类的分子量的简单比例换算,容易计算游离碱形式的其他形式、例如盐或水合物的剂量。
雌激素激动剂/拮抗剂的有效给药速率的一般范围从约0.001mg/天至约200mg/天。优选的速率范围从约0.010mg/天至约100mg/天。当然,在实践中经常在当天的不同时段将每日剂量的化合物按比例用药。不过,在任何既定情况下,化合物的给药量将取决于这样一些因素,例如具体雌激素激动剂/拮抗剂的效力、化合物的溶解度、所使用的制剂和给药途径。
制剂方法是本领域熟知的,例如公开在《Remington:药剂科学与实践》Mack Publishing Company,Easton,Pa.,第19版(1995)。用于本发明的药物组合物可以是无菌的、非致热的液体溶液或悬液、包衣胶囊剂、栓剂、冻干粉剂、透皮贴剂的剂型或本领域已知的其他剂型。
胶囊剂是这样制备的,将化合物与适合的稀释剂混合,再将适量混合物填充在胶囊内。常用稀释剂包括惰性粉状物质,例如很多不同种类的淀粉,粉状纤维素、尤其是结晶与微晶纤维素,糖类、例如果糖、甘露糖醇和蔗糖,谷粉和类似的可食用粉末。
片剂是通过直接压制、湿法造粒或干法造粒制备的。它们的配方中除所述的化合物外通常加有稀释剂、粘合剂、润滑剂和崩解剂。典型的稀释剂例如包括各种类型的淀粉、乳糖、甘露糖醇、高岭土、磷酸钙或硫酸钙、诸如氯化钠等无机盐和粉状的糖。粉状纤维素衍生物也是有用的。典型的片剂粘合剂是这样的物质,例如淀粉、明胶和诸如乳糖、果糖、葡萄糖等糖类。天然与合成的树胶也是适宜的,包括阿拉伯胶、藻酸盐、甲基纤维素、聚乙烯吡咯烷酮等。聚乙烯醇、乙基纤维素和蜡类也可以充当粘合剂。
润滑剂在片剂中可能是必要的,可防止药片与冲头在冲模中粘连。润滑剂选自滑性的固体,例如滑石、硬脂酸镁与硬脂酸钙、硬脂酸和氢化植物油。
片剂崩解剂是当片剂变湿后促进片剂崩解以释放化合物的物质。它们包括淀粉、粘土、纤维素、藻胶和树胶,特别是可以用玉米与马铃薯淀粉、甲基纤维素、琼脂、膨润土、木纤维素、粉状天然海绵、阳离子交换树脂、藻酸、瓜尔胶、柑橘果浆和羧甲基纤维素,也可以用月桂基硫酸钠。
片剂经常包以糖衣作为着色剂和密封剂,或者包以成膜性保护剂,以改变片剂的溶解性质。化合物还可以被配制成咀嚼片,正如本领域现已成熟的做法,在制剂中使用大量口感良好的物质,例如甘露糖醇。
当需要将化合物作为栓剂给药时,可以使用典型的基质。可可脂是传统的栓剂基质,加入蜡类改性可以略微升高它的熔点。水可混溶性栓剂基质具体包括各种分子量的聚乙烯醇,具有广泛用途。
适当的配制可以延迟或延长化合物的效果。例如,可以制备化合物的缓溶颗粒,再加入片剂或胶囊剂中。可以制备若干种不同溶解速率的颗粒再将颗粒混合物填充胶囊由此来改进配制技术。片剂或胶囊剂可以包以抵抗溶解的膜以达到预期的溶解时间。局部用制剂可以被设计成延迟和/或延长化合物的经皮吸收。即使肠胃外制剂也可以制成长效型,也就是将化合物溶解或悬浮在油性或经过乳化的载体中,使其仅在血清中缓慢分散。
术语“前体药物”表示体内转化形成本发明化合物的化合物。转化作用可以通过各种机理发生,例如在血液中水解。前体药物的用途讨论参见T.Higuchi和W.Stella“作为新颖的释放体系的前体药物”《A.C.S.座谈会丛书》第14卷,和《药物设计中的生物可逆性载体》Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987。
例如,如果本发明化合物含有羧酸官能团,那么前体药物可以包含用这样一种基团代替酸基氢原子所生成的酯,该基因例如(C1-C8)烷基、(C2-C12)烷酰氧基甲基、具有4至9个碳原子的1-(烷酰氧基)乙基、具有5至10个碳原子的1-甲基-1-(烷酰氧基)乙基、具有3至6个碳原子的烷氧羰基氧基甲基、具有4至7个碳原子的1-(烷氧羰基氧基)乙基、具有5至8个碳原子的1-甲基-1-(烷氧羰基氧基)乙基、具有3至9个碳原子的N-(烷氧羰基)氨基甲基、具有4至10个碳原子的1-(N-(烷氧羰基)氨基)乙基、3-苯并[c]呋喃酮基、4-巴豆内酯基、γ-丁内酯-4-基、二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(例如β-二甲氨基乙基)、氨基甲酰基-(C1-C2)烷基、N,N-二(C1-C2)烷基氨基甲酰基-(C1-C2)烷基和哌啶子基-、吡咯烷基-或吗啉代(C2-C3)烷基。
类似地,如果本发明化合物包含醇官能团,那么用以下这样一种基团代替醇基的氢原子可以生成前体药物。该基因例如(C1-C6)烷酰氧基甲基、1-((C1-C6)烷酰氧基)乙基、1-甲基-1-((C1-C6)烷酰氧基)乙基、(C1-C6)烷氧羰基氧基甲基、N-(C1-C6)烷氧羰基氨基甲基、琥珀酰基、(C1-C6)烷酰基、α-氨基(C1-C4)烷酰基、芳基酰基与α-氨基酰基、或α-氨基酰基-α-氨基酰基,其中每个α-氨基酰基独立地选自天然存在的L-氨基酸、P(O)(OH)2、-P(O)(O(C1-C6)烷基)2或葡糖基(碳水化合物的半缩醛形式除去羟基所得基团)。
如果本发明化合物包含胺官能团,那么用这样一种基团代替胺基氢原子可以生成前体药物,例如RX-羰基、RXO-羰基、NRXRX’羰基,其中RX和RX’各自独立地是(C1-C10)烷基、(C3-C7)环烷基、苄基,或者RX-羰基是天然α-氨基酰基或天然α-氨基酰基-天然α-氨基酰基;-C(OH)C(O)OYX,其中YX是H、(C1-C6)烷基或苄基,-C(OYX0)YX1,其中YX0是(C1-C4)烷基,YX1是(C1-C6)烷基、羧基(C1-C6)烷基、氨基(C1-C4)烷基或一-N-或二-N,N-(C1-C6)烷基氨基烷基,-C(YX2)YX3,其中MX2是H或甲基,YX3是一-N-或二-N,N-(C1-C6)烷基氨基、吗啉代、哌啶-1-基或吡咯烷-1-基。
有利的是,本发明还提供由消费者使用的试剂盒,用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌。该试剂盒包含a)药物组合物,包含雌激素激动剂/拮抗剂;和b)说明书,描述使用该药物组合物治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法。
本申请所称的“试剂盒”包括用于含有药物组合物的一个容器,还可以包括分开的几个容器,例如分开的小瓶或分开的箔包。容器可以是本领域已知的任意常规形状或形式,由药学上可接受的材料制成,例如纸或纸板盒、玻璃或塑料瓶或罐、可重新密封的袋(例如盛放片剂的“替换物”,用于放置在不同的容器内)、或泡眼包装(blister pack),用于治疗时从该泡眼中压出单个剂量。所用容器可以与所涉及的实际剂型有关,例如常规纸板盒一般不会用于盛放液体悬液。可行的是一种以上容器可以一起用在单一包装中上市销售单一剂型。例如,片剂可以包含在小瓶内,小瓶进而包含在盒子内。
这种试剂盒的实例是所谓的泡眼包装。泡眼包装在包装工业中是熟知的,广泛用于药物单位剂型(片剂、胶囊剂等)的包装。泡眼包装一般由相对坚硬的材料薄片组成,其上覆盖有一层箔,优选为透明的塑料材料。在包装过程期间,在塑料箔中形成凹陷。凹陷的大小和形状与所要包装的药片或胶囊一致。下一步,将药片或胶囊置于凹陷内,在与形成凹陷相反的方向将相对坚硬的材料薄片用塑料箔密封。结果,将药片或胶囊密封在塑料箔与薄片之间的凹陷内。优选的是,薄片的强度要使药片或胶囊在用手向凹陷施加压力时位于凹陷处的薄片会形成破口,这样就可以从泡眼包装中取出药片或胶囊。
可能需要提供书面提示,例如药片或胶囊旁边的数字。该书面提示为医师、药师或其他健康护理人员、或患者提供这样的信息,由此这些数字对应于所指定药片或胶囊应按照给药方案摄取,或者提供一个含有相同类型信息的卡片。这样的书面说明的另一个实例是印在卡片上的日历,例如“第一周,星期一、星期二......”等......“第二周,星期一、星期二......”等。提示的其他变例将是显而易见的。“每日剂量”可以是单一药片或胶囊,或者是若干药片或胶囊,在给定的一天内服用。
试剂盒的另一种具体实施方式是分配器,它被设计用来每次分配一份每日剂量。优选地,分配器带有提示,以便进一步有利于顺应给药方案。这种提示的一个实例是机械计数器,它指示已被分配的每日剂量数。这种提示的另一个实例是电池驱动的微型芯片存储器,与液晶读数器连接,或者是声音提醒信号,例如读出已经服用的最后一次每日剂量的日期和/或提醒所要服用的下一次剂量。
本发明的试剂盒除了雌激素激动剂/拮抗剂以外还可以包括另外一种或多种药学活性化合物。该另外的化合物优选的是另一种雌激素激动剂/拮抗剂或另一种可用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的化合物。该另外一种或几种化合物可以按照与雌激素激动剂/拮抗剂相同或不同的剂型给药。同样,该另外的化合物可以与雌激素激动剂/拮抗剂同时或不同时给药。
用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌并且可以与本发明的雌激素激动剂/拮抗剂结合使用的化合物包括5-氟尿嘧啶;顺铂;紫杉醇;onconase;托泊替康;六甲胺;异环磷酰胺;阿霉素;依托泊苷;博莱霉素;亚硝基脲类,例如卡莫司汀、洛莫司汀、丙卡巴肼、司莫司汀和长春新碱;氨甲蝶呤;卡铂;放线菌素D;和链佐星。本发明的雌激素激动剂/拮抗剂还可以与放射疗法结合使用。
这里引用的全部文献、包括专利和专利申请在此均作为参考文献引用。
Claims (11)
A选自CH2和NR;
B、D和E独立地选自CH和N;
Y是
(a)苯基,可选地被1-3个独立地选自R4的取代基取代;
(b)萘基,可选地被1-3个独立地选自R4的取代基取代;
(c)C3-C8环烷基,可选地被1-2个独立地选自R4的取代基取代;
(d)C3-C8环烯基,可选地被1-2个独立地选自R4的取代基取代;
(e)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的五元杂环,可选地被1-3个独立地选自R4的取代基取代;
(f)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的六元杂环,可选地被1-3个独立地选自R4的取代基取代;或
(g)由五或六元杂环与苯环稠合而成的二环体系,所述杂环含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子,可选地被1-3个独立地选自R4的取代基取代;
Z1是
(a)-(CH2)pW(CH2)q-;
(b)-O(CH2)pCR5R6-;
(c)-O(CH2)pW(CH2)q-;
(d)-OCHR2CHR3-;或
(e)-SCHR2CHR3-;G是
(a)-NR7R8;
其中n是0、1或2;m是1、2或3;Z2是-NH-、-O-、-S-或-CH2-;可选地在相邻的碳原子上与一个或两个苯环稠合,并且可选地在碳上独立地被一至三个、且可选地在氮上独立地被化学上适合的选自R4的取代基取代;或
(c)含有五至十二个碳原子的二环胺,它是桥连的或稠合的,并且可选地被1-3个独立地选自R4的取代基取代;或者
(a)-CH2-;
(b)-CH=CH-;
(c)-O-;
(d)-NR2-;
(g)-CR2(OH)-;
(h)-CONR2-;
(k)-C≡C-;R是氢或C1-C6烷基;R2和R3独立地是
(a)氢;或
(b)C1-C4烷基;R4是
(a)氢;
(b)卤素;
(c)C1-C6烷基;
(d)C1-C4烷氧基;
(e)C1-C4酰氧基;
(g)C1-C4烷硫基;
(g)C1-C4烷基亚磺酰基;
(h)C1-C4烷基磺酰基;
(i)羟基(C1-C4)烷基;
(j)芳基(C1-C4)烷基;
(k)-CO2H;
(l)-CN;
(m)-CONHOR;
(n)-SO2NHR;
(o)-NH2;
(p)C1-C4烷基氨基;
(q)C1-C4二烷基氨基;
(r)-NHSO2R;
(s)-NO2;
(t)-芳基;或
(u)-OH;R5和R6独立地是C1-C8烷基或者一起构成C3-C10碳环;R7和R8独立地是
(a)苯基;
(b)饱和或不饱和的C3-C10碳环;
(c)含有至多两个选自-O-、-N-和-S-的杂原子的C3-C10杂环;
(d)H;
(e)C1-C6烷基;或者
(f)与R5或R6构成3至8元含氮环;
线性或环状R7和R8可以可选地被至多三个独立地选自C1-C6烷基、卤素、烷氧基、羟基和羧基的取代基取代;
由R7和R8所构成的环可以可选地与苯环稠合;
e是0、1或2;
m是1、2或3;
n是0、1或2;
p是0、1、2或3;
q是0、1、2或3;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
3.权利要求1的用途,其中该雌激素激动剂/拮抗剂是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
4.权利要求1的用途,其中该雌激素激动剂/拮抗剂是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇的D-酒石酸盐。
5.雌激素激动剂/拮抗剂化合物在制备治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的药物中用途,所用的该化合物选自:
A)4-羟基他莫昔芬、屈洛昔芬、托瑞米芬、星克罗曼、艾多昔芬、雷洛昔芬、6-(4-羟基苯基)-5-[4-(2-哌啶-1-基乙氧基)苄基]萘-2-醇、{4-[2-(2-氮杂二环并[2.2.1]庚-2-基)乙氧基]苯基}-[6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基]甲酮、EM-652、EM-800、GW 5638、GW 7604或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物;
R1B选自H、OH、-O-C(O)-C1-C12烷基(直链或支链)、-O-C1-C12烷基(直链或支链或环状)、卤素或C1-C4卤代醚;
R2B、R3B、R4B、R5B和R6B独立地选自H、OH、-O-C(O)-C1-C12烷基(直链或支链)、-O-C1-C12烷基(直链或支链或环状)、卤素、C1-C4卤代醚、氰基、C1-C6烷基(直链或支链)或三氟甲基;
XA选自H、C1-C6烷基、氰基、硝基、三氟甲基和卤素;
s是2或3;
a)R7B和R8B独立地选自H、C1-C6烷基或苯基,该苯基可选地被CN、C1-C6烷基(直链或支链)、C1-C6烷氧基(直链或支链)、卤素、-OH、-CF3或-OCF3取代;或者
b)R7B和R8B连结构成含有一个氮杂原子的五元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
c)R7B和R8B连结构成含有一个氮杂原子的六元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
d)R7B和R8B连结构成含有一个氮杂原子的七元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
e)R7B和R8B连结构成含有一个氮杂原子的八元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
f)R7B和R8B连结构成含有6-12个碳原子的饱和二环杂环,它是桥连或稠合的,并且含有一个氮杂原子,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物;或
6.一种由消费者使用的试剂盒,用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌,该试剂盒包含:
A选自CH2和NR;
B、D和E独立地选自CH和N;
Y是
(a)苯基,可选地被1-3个独立地选自R4的取代基取代;
(b)萘基,可选地被1-3个独立地选自R4的取代基取代;
(c)C3-C8环烷基,可选地被1-2个独立地选自R4的取代基取代;
(d)C3-C8环烯基,可选地被1-2个独立地选自R4的取代基取代;
(e)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的五元杂环,可选地被1-3个独立地选自R4的取代基取代;
(f)含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子的六元杂环,可选地被1-3个独立地选自R4的取代基取代;或
(g)由五或六元杂环与苯环稠合而成的二环体系,所述杂环含有至多两个选自-O-、-NR2-和-S(O)n-的杂原子,可选地被1-3个独立地选自R4的取代基取代;
Z1是
(a)-(CH2)pW(CH2)q-;
(b)-O(CH2)pCR5R6-;
(c)-O(CH2)pW(CH2)q-;
(d)-OCHR2CHR3-;或
(e)-SCHR2CHR3-;
G是
(a)-NR7R8;
其中n是0、1或2;m是1、2或3;Z2是-NH-、-O-、-S-或-CH2-;可选地在相邻的碳原子上与一个或两个苯环稠合,并且可选地在碳上独立地被一至三个、且可选地在氮上独立地被化学上适合的选自R4的取代基取代;或
(c)含有五至十二个碳原子的二环胺,它是桥连的或稠合的,并且可选地被1-3个独立地选自R4的取代基取代;或者
(a)-CH2-;
(b)-CH=CH-;
(c)-O-;
(d)-NR2-;
(g)-CR2(OH)-;
(h)-CONR2-;
(k)-C≡C-;R是氢或C1-C6烷基;R2和R3独立地是
(a)氢;或
(b)C1-C4烷基;R4是
(a)氢;
(b)卤素;
(c)C1-C6烷基;
(d)C1-C4烷氧基;
(e)C1-C4酰氧基;
(f)C1-C4烷硫基;
(g)C1-C4烷基亚磺酰基;
(h)C1-C4烷基磺酰基;
(i)羟基(C1-C4)烷基;
(j)芳基(C1-C4)烷基;
(k)-CO2H;
(l)-CN;
(m)-CONHOR;
(n)-SO2NHR;
(o)-NH2;
(p)C1-C4烷基氨基;
(q)C1-C4二烷基氨基;
(r)-NHSO2R;
(s)-NO2;
(t)-芳基;或
(u)-OH;
R5和R6独立地是C1-C8烷基或者一起构成C3-C10碳环;
R7和R8独立地是
(a)苯基;
(b)饱和或不饱和的C3-C10碳环;
(c)含有至多两个选自-O-、-N-和-S-的杂原子的C3-C10杂环;
(d)H;
(e)C1-C6烷基;或者
(f)与R5或R6构成3至8元含氮环;
线性或环状R7和R8可以可选地被至多三个独立地选自C1-C6烷基、卤素、烷氧基、羟基和羧基的取代基取代;
由R7和R8所构成的环可以可选地与苯环稠合;
e是0、1或2;
m是1、2或3;
n是0、1或2;
p是0、1、2或3;
q是0、1、2或3;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物;和
(b)说明书,描述使用该药物组合物治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法。
8.权利要求6的试剂盒,其中该雌激素激动剂/拮抗剂是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物。
9.权利要求6的试剂盒,其中该雌激素激动剂/拮抗剂是(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-醇的D-酒石酸盐。
10.一种由消费者使用的试剂盒,用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌,该试剂盒包含:
(a)药物组合物,包含雌激素激动剂/拮抗剂化合物,该化合物选自:
A)4-羟基他莫昔芬、屈洛昔芬、托瑞米芬、星克罗曼、艾多昔芬、雷洛昔芬、6-(4-羟基苯基)-5-[4-(2-哌啶-1-基乙氧基)苄基]萘-2-醇、{4-[2-(2-氮杂二环并[2.2.1]庚-2-基)乙氧基]苯基}-[6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基]甲酮、EM-652、EM-800、GW 5638、GW 7604或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物;
R1B选自H、OH、-O-C(O)-C1-C12烷基(直链或支链)、-O-C1-C12烷基(直链或支链或环状)、卤素或C1-C4卤代醚;
R2B、R3B、R4B、R5B和R6B独立地选自H、OH、-O-C(O)-C1-C12烷基(直链或支链)、-O-C1-C12烷基(直链或支链或环状)、卤素、C1-C4卤代醚、氰基、C1-C6烷基(直链或支链)或三氟甲基;
XA选自H、C1-C6烷基、氰基、硝基、三氟甲基和卤素;
s是2或3;
YA是其中:
a)R7B和R8B独立地选自H、C1-C6烷基或苯基,该苯基可选地被CN、C1-C6烷基(直链或支链)、C1-C6烷氧基(直链或支链)、卤素、-OH、-CF3或-OCF3取代;或者
b)R7B和R8B连结构成含有一个氮杂原子的五元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
c)R7B和R8B连结构成含有一个氮杂原子的六元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
d)R7B和R8B连结构成含有一个氮杂原子的七元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
e)R7B和R8B连结构成含有一个氮杂原子的八元饱和杂环,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;或者
f)R7B和R8B连结构成含有6-12个碳原子的饱和二环杂环,它是桥连或稠合的,并且含有一个氮杂原子,该杂环可选地被1-3个独立地选自下组的取代基取代:氢、羟基、卤素、C1-C4烷基、三卤甲基、C1-C4烷氧基、三卤甲氧基、C1-C4酰氧基、C1-C4烷硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、羟基(C1-C4)烷基、-CO2H、-CN、-CONHR1B、-NH2、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-NHSO2R1B、-NHCOR1B、-NO2或可选被1-3个(C1-C4)烷基取代的苯基;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物;
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物;或
D)下式(III)(EM-652)或式(IV)(EM-800)化合物:
或其旋光或几何异构体;或其药学上可接受的盐、N-氧化物、酯、季铵盐或前体药物;和
(b)说明书,描述使用该药物组合物治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的方法。
11.权利要求6的试剂盒,其中该试剂盒进一步包含另外一种可用于治疗肝癌、卵巢癌、硬纤维瘤、神经胶质瘤、胰腺癌或肾细胞癌的化合物。
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- 2002-01-23 MY MYPI20020265A patent/MY141605A/en unknown
- 2002-01-24 CA CA002369264A patent/CA2369264A1/en not_active Abandoned
- 2002-01-25 KR KR1020020004389A patent/KR20020063127A/ko not_active Application Discontinuation
- 2002-01-25 CN CN02102519A patent/CN1366881A/zh active Pending
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112105607A (zh) * | 2018-01-22 | 2020-12-18 | 雷迪厄斯制药公司 | 雌激素受体调节化合物 |
CN109758450A (zh) * | 2019-03-06 | 2019-05-17 | 天津医科大学 | 一种抗肿瘤新化合物、及其制备方法和用途 |
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HU0200264D0 (en) | 2002-03-28 |
HUP0200264A2 (en) | 2002-10-28 |
CA2369264A1 (en) | 2002-07-26 |
AU781168B2 (en) | 2005-05-12 |
HUP0200264A3 (en) | 2004-04-28 |
NZ516821A (en) | 2003-09-26 |
US6821989B2 (en) | 2004-11-23 |
EP1226823A2 (en) | 2002-07-31 |
MY141605A (en) | 2010-05-31 |
HK1046102A1 (zh) | 2002-12-27 |
EP1226823A3 (en) | 2003-04-16 |
PL351866A1 (en) | 2002-07-29 |
NZ526560A (en) | 2004-12-24 |
KR20020063127A (ko) | 2002-08-01 |
AU9712101A (en) | 2002-08-01 |
IL147695A0 (en) | 2002-08-14 |
JP2002316932A (ja) | 2002-10-31 |
ZA200200596B (en) | 2003-07-23 |
US20030130276A1 (en) | 2003-07-10 |
US20050065165A1 (en) | 2005-03-24 |
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