CN116456980A - 噻唑类化合物在制备治疗和预防癌症药物中的用途 - Google Patents
噻唑类化合物在制备治疗和预防癌症药物中的用途 Download PDFInfo
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- AMIGYDGSJCJWSD-UHFFFAOYSA-N thiocane Chemical compound C1CCCSCCC1 AMIGYDGSJCJWSD-UHFFFAOYSA-N 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000005490 tosylate group Chemical class 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- A61K31/41—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
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
通式(I)的噻唑类化合物,或其药学上可接受的盐、水合物或溶剂合物,及其作为STAT3通路抑制剂的用途。所述化合物对肿瘤细胞的增殖具有强抑制活性,可用于治疗癌症。
Description
本发明提供了噻唑类化合物,及其作为STAT3通路抑制剂的用途,所述化合物对肿瘤细胞的增殖具有强抑制活性,可用于治疗癌症.
STAT3(signal transducer and activator of transcription 3,STAT3)通路是信号转导与转录激活因子蛋白家族的重要成员,具有信号转导和转录活化双重功能。迄今为止,在哺乳动物细胞中已有7个STAT家族成员被报道,分别为STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B和STAT6,其中,STAT3广泛存在于各类细胞和组织中,能够被多种细胞因子激活.
在正常情况下,细胞内存在完善的抑制机制,如活化STAT抑制蛋白(protein inhibitor of activated STAT,PIAS),细胞因子信号抑制子(suppressors of cytokine signaling,SDCS)以及一些酪氨酸蛋白磷酸酯酶(protein tyrosine phosphatases(PTPs),包括SHP-2、PTP1B、PTPeC、TC45、SHP-1),使得STAT3信号通路的活化被严格控制在低水平。但在多种肿瘤细胞中,STAT3则被持续性激活并呈高水平表达,如卵巢癌、胰腺癌、前列腺癌、头颈癌、乳腺癌、白血病及非小细胞肺癌,并与肿瘤的与肿瘤的形成与发展,血管生成与肿瘤免疫抑制密切相关。
因此,抑制过度活化的STAT3通路成为了抗肿瘤治疗的一个重要靶点。而寻找安全性高,有足够的细胞渗透性,药代动力学性质可靠的高效STAT3活化抑制剂具有很高的价值。
发明概述
在一个方面,本发明提供了化合物,及其在制备用于治疗/预防癌症的药物中的用途,其中所述化合物为通式(I)的化合物,或其药学上可接受的盐、水合物或溶剂合物:
其中,
R
1选自H、卤素、-CN、-NO
2、-N
3、-OR
a、-NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
2选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
3选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
4选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、 -S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
5选自H、C
1-6烷基或C
1-6卤代烷基;
R选自H、卤素、-CN或-NO
2;
其中R
a、R
b和R
c各自独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;或者R
b和R
c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基。
在另一个方面,本发明提供了一种在受试者中治疗/预防癌症的方法,其包括向所述受试者给药通式(I)的化合物,或其药学上可接受的盐、水合物或溶剂合物:
其中,
R
1选自H、卤素、-CN、-NO
2、-N
3、-OR
a、-NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
2选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
3选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
4选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
5选自H、C
1-6烷基或C
1-6卤代烷基;
R选自H、卤素、-CN或-NO
2;
其中R
a、R
b和R
c各自独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;或者R
b和R
c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基。
在又一个方面,本发明提供了通式(I)的化合物,或其药学上可接受的盐、水合物或溶剂合物,其用于治疗/预防癌症:
其中,
R
1选自H、卤素、-CN、-NO
2、-N
3、-OR
a、-NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
2选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
3选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
4选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
5选自H、C
1-6烷基或C
1-6卤代烷基;
R选自H、卤素、-CN或-NO
2;
其中R
a、R
b和R
c各自独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;或者R
b和R
c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基.
在另一方面,本发明提供了以下化合物,或其药学上可接受的盐、水合物或溶剂合物:
由随后的具体实施方式、实施例和权利要求,本发明的其他目的和优点将对于本领域技术人员显而易见。
图1A为给药过程中,各组小鼠的肿瘤体积变化曲线;图1B为给药28日后,各组存活小鼠的荷瘤体积值;图1C为给药过程中,各组小鼠的体重变化曲线;图1D为给药28日后,各组存活小鼠的体重值.对于图1A,1C,结果使用Mean±SD表示。对于图1B,1D,每个数据点代表单个动物的具体测量值,横直线代表每组的平均值。使用Statistical Product and Service Solutions(SPSS)软件双尾Student′s t检验计算P值,n.s.:与空白溶剂组相比没有显著性差异;*:P<0.05;**:P<0.01;***:P<0.001;P<0.05时表明与空白溶剂组相比有显著性差异。
发明详述
定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时,既定包括每个值和在所述范围内的子范围。例如“C
1-6烷基”包括C
1、C
2、C
3、C
4、C
5、C
6、C
1-6、C
1-5、C
1-4、C
1-3、C
1-2、C
2-6、C
2-5、C
2-4、C
2-3、C
3-6、C
3-5、C
3-4、C
4-6、C
4-5和C
5-6烷基。
“C
1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团,本文也称为“低级烷基”。在一些实施方案中,C
1-4烷基是特别优选的。所述烷基的实例包括但不限于:甲基(C
1)、乙基(C
2)、正丙基(C
3)、异丙基(C
3)、正丁基(C
4)、叔丁基(C
4)、仲丁基(C
4)、异丁基(C
4)、正戊基(C
5)、3-戊基(C
5)、戊基(C
5)、新戊基(C
5)、3-甲基-2-丁基(C
5)、叔戊基(C
5)和正己基(C
6)。不论烷基前是否修饰有“取代的”,烷基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义.
“C
2-6烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中,C
2-4烯基是优选的.C
2-6烯基的例子包括:乙烯基(C
2)、1-丙烯基(C
3)、2-丙烯基(C
3)、1-丁烯基(C
4)、2-丁烯基(C
4)、丁二烯基(C
4)、戊烯基(C
5)、戊二烯基(C
5)、己烯基(C
6),等等。术语“C
2-6烯基”还包括杂烯基,其中一或多个(例如,1、2、3或4个)碳原子被杂原子(例如,氧、硫、氮、硼、硅、磷)替代。不论烯基前是否修饰有“取代的”,烯基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“C
2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团.在一些实施方案中,C
2-4炔基是优选的。C
2-6炔基的例子包括但不限于:乙炔基(C
2)、1-丙炔基(C
3)、2-丙炔基(C
3)、1-丁炔基(C
4)、2-丁炔基(C
4),戊炔基(C
5)、己炔基(C
6),等等.术语“C
2- 6炔基”还包括杂炔基,其中一或多个(例如,1、2、3或4个)碳原子被杂原子(例如,氧、硫、氮、硼、硅、磷)替代.不论炔基前是否修饰有“取代的”,炔基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。在一些实施方案中,卤素基团是F、Cl或Br.在一些实施方案中,卤素基团是F或Cl。在一些实施方案中,卤素基团是F。
因此,“C
1-6卤代烷基”是指上述“C
1-6烷基”,其被一个或多个卤素基团取代。在一些实施方案中,C
1-4卤代烷基是特别优选的,更优选C
1-2卤代烷基。示例性的所述卤代烷基包括但不限于:-CF
3、-CH
2F、-CHF
2、-CHFCH
2F、-CH
2CHF
2、-CF
2CF
3、-CCl
3、-CH
2Cl、-CHCl
2、2,2,2-三氟-1,1-二甲基-乙基,等等.
“C
3-10环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中,C
3-7环烷基是优选的,C
3-6环烷基是特别优选的,更优选C
5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在环烷基环上,且在这样的情况中,碳的数目继续表示环烷基体系中的碳的数目.示例性的所述环烷基包括但不限于:环丙基(C
3)、环丙烯基(C
3)、环丁基(C
4)、环丁烯基(C
4)、环戊基(C
5)、环戊烯基(C
5)、环己基(C
6)、环己烯基(C
6)、环已二烯基(C
6)、环庚基(C
7)、环庚烯基(C
7)、环庚二烯基(C
7)、环庚三烯基(C
7)、环辛基(C
8)、环辛烯基(C
8)、二环[2.2.1] 庚基(C
7)、二环[2.2.2]辛基(C
8)、环壬基(C
9)、环壬烯基(C
9)、环癸基(C
10)、环癸烯基(C
10)、八氢-1H-茚基(C
9)、十氢萘基(C
10)、螺[4.5]癸基(C
10),等等。不论环烷基前是否修饰有“取代的”,环烷基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“3至10元杂环基”或是指具有环碳原子和1至4个环杂原子的3至10元非芳香环系的基团,其中,每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中,只要化合价允许,连接点可为碳或氮原子.在一些实施方案中,3至7元杂环基是优选的,其为具有环碳原子和1至3个环杂原子的3至7元非芳香环系;在一些实施方案中,3至6元杂环基是特别优选的,其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系;更优选5至6元杂环基,其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系.杂环基还包括其中上述杂环基环与一个或多个环烷基、芳基或杂芳基稠合的环体系,其中连接点在杂环基环上;且在这样的情况下,环成员的数目继续表示在杂环基环体系中环成员的数目.不论杂环基前是否修饰有“取代的”,杂环基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
示例性的包含一个杂原子的3元杂环基包括但不限于:氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl).示例性的含有一个杂原子的4元杂环基包括但不限于:氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于:四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于:二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于:三唑啉基、噁二唑啉基和噻二唑啉基.示例性的包含一个杂原子的6元杂环基包括但不限于:哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于:哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于:六氢三嗪基(triazinanyl).示例性的含有一个杂原子的7元杂环基包括但不限于:氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的包含一个杂原子的8元杂环基包括但不限于:氮杂环辛烷基、氧杂环辛烷基和硫杂环辛烷基。示例性的与C
6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于:二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基,等等。示例性的与C
6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于:四氢喹啉基、四氢异喹啉基,等等。
“C
6-14芳基”是指具有6-14个环碳原子和零个杂原子的单环或多环的(例如,双环或三环)4n+2芳族环体系(例如,具有以环状排列共享的6、10或14个π电子)的基团.在一些实施方案中,芳基具有六个环碳原子(“C
6芳基”;例如,苯基).在一些实施方案中,芳基具有十个环碳原子(“C
10芳基”;例如,萘基,例如,1-萘基和2-萘基)。在一些实施方案中,芳基具有十四个环碳原子(“C
14芳基”;例如,蒽基)。在一些实施方案中,C
6-10芳基是特别优选的,更优选C
6芳基.芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述芳基环上,在这种情况下,碳原子的数目继续表示所述芳基环系统中的碳原子数目.不论芳基前是否修饰有“取代的”,芳基的每个独立地任 选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“5至10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团,其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中,只要化合价允许,连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述杂芳基环上,在这种情况下,碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中,5至6元杂芳基是特别优选的,其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系.不论杂芳基前是否修饰有“取代的”,杂芳基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义.
示例性的含有一个杂原子的5元杂芳基包括但不限于:吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于:咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于:三唑基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于:四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于:吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于:哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于:三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于:氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于:吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基.示例性的6,6-双环杂芳基包括但不限于:萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。
示例性的碳原子上的取代基包括但不局限于:卤素、-CN、-NO
2、-N
3、-SO
2H、-SO
3H、-OH、-OR
aa、-ON(R
bb)
2、-N(R
bb)
2、-N(R
bb)
3 +X
-、-N(OR
cc)R
bb、-SH、-SR
aa、-SSR
cc、-C(=O)R
aa、-CO
2H、-CHO、-C(OR
cc)
2、-CO
2R
aa、-OC(=O)R
aa、-OCO
2R
aa、-C(=O)N(R
bb)
2、-OC(=O)N(R
bb)
2、-NR
bbC(=O)R
aa、-NR
bbCO
2R
aa、-NR
bbC(=O)N(R
bb)
2、-C(=NR
bb)R
aa、-C(=NR
bb)OR
aa、-OC(=NR
bb)R
aa、-OC(=NR
bb)OR
aa、-C(=NR
bb)N(R
bb)
2、-OC(=NR
bb)N(R
bb)
2、-NR
bbC(=NR
bb)N(R
bb)
2、-C(=O)NR
bbSO
2R
aa、-NR
bbSO
2R
aa、-SO
2N(R
bb)
2、-SO
2R
aa、-SO
2OR
aa、-OSO
2R
aa、-S(=O)R
aa、-OS(=O)R
aa、-Si(R
aa)
3、-OSi(R
aa)
3、-C(=S)N(R
bb)
2、-C(=O)SR
aa、-C(=S)SR
aa、-SC(=S)SR
aa、-SC(=O)SR
aa、-OC(=O)SR
aa、-SC(=O)OR
aa、-SC(=O)R
aa、-P(=O)
2R
aa、-OP(=O)
2R
aa、-P(=O)(R
aa)
2、-OP(=O)(R
aa)
2、-OP(=O)(OR
cc)
2、-P(=O)
2N(R
bb)
2、-OP(=O)
2N(R
bb)
2、-P(=O)(NR
bb)
2、-OP(=O)(NR
bb)
2、-NR
bbP(=O)(OR
cc)
2、-NR
bbP(=O)(NR
bb)
2、-P(R
cc)
2、-P(R
cc)
3、-OP(R
cc)
2、-OP(R
cc)
3、-B(R
aa)
2、-B(OR
cc)
2、-BR
aa(OR
cc)、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代;
或者在碳原子上的两个偕氢被基团=O、=S、=NN(R
bb)
2、=NNR
bbC(=O)R
aa、=NNR
bbC(=O)OR
aa、 =NNR
bbS(=O)
2R
aa、=NR
bb或=NOR
cc取代;
R
aa的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个R
aa基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代;
R
bb的每个独立地选自:氢、-OH、-OR
aa、-N(R
cc)
2、-CN、-C(=O)R
aa、-C(=O)N(R
cc)
2、-CO
2R
aa、-SO
2R
aa、-C(=NR
cc)OR
aa、-C(=NR
cc)N(R
cc)
2、-SO
2N(R
cc)
2、-SO
2R
cc、-SO
2OR
cc、-SOR
aa、-C(=S)N(R
cc)
2、-C(=O)SR
cc、-C(=S)SR
cc、-P(=O)
2R
aa、-P(=O)(R
aa)
2、-P(=O)
2N(R
cc)
2、-P(=O)(NR
cc)
2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个Rb
b基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代;
R
cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个R
cc基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代;
R
dd的每个独立地选自:卤素、-CN、-NO
2、-N
3、-SO
2H、-SO
3H、-OH、-OR
ee、-ON(R
ff)
2、-N(R
ff)
2,、-N(R
ff)
3 +X
-、-N(OR
ee)R
ff、-SH、-SR
ee、-SSR
ee、-C(=O)R
ee、-CO
2H、-CO
2R
ee、-OC(=O)R
ee、-OCO
2R
ee、-C(=O)N(R
ff)
2、-OC(=O)N(R
ff)
2、-NR
ffC(=O)R
ee、-NR
ffCO
2R
ee、-NR
ffC(=O)N(R
ff)
2、-C(=NR
ff)OR
ee、-OC(=NR
ff)R
ee、-OC(=NR
ff)OR
ee、-C(=NR
ff)N(R
ff)
2、-OC(=NR
ff)N(R
ff)
2、-NR
ffC(=NR
ff)N(R
ff)
2、-NR
ffSO
2R
ee、-SO
2N(R
ff)
2、-SO
2R
ee、-SO
2OR
ee、-OSO
2R
ee、-S(=O)R
ee、-Si(R
ee)
3、-OSi(R
ee)
3、-C(=S)N(R
ff)
2、-C(=O)SR
ee、-C(=S)SR
ee、-SC(=S)SR
ee、-P(=O)
2R
ee、-P(=O)(R
ee)
2、-OP(=O)(R
ee)
2、-OP(=O)(OR
ee)
2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基、杂芳基,其中,每个烷基、烯基、炔基,碳环基,杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代,或者两个偕R
dd取代基可结合以形成=O或=S;
R
ee的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
gg基团取代;
R
ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个R
ff基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
gg基团取代;
R
gg的每个独立地是:卤素、-CN、-NO
2、-N
3、-SO
2H、-SO
3H、-OH、-OC
1-6烷基、-ON(C
1-6烷基)
2、-N(C
1-6烷基)
2、-N(C
1-6烷基)
3 +X
-、-NH(C
1-6烷基)
2 +X
-、-NH
2(C
1-6烷基)
+X
-、-NH
3 +X
-、-N(OC
1-6烷基)(C
1-
6烷基)、-N(OH)(C
1-6烷基)、-NH(OH)、-SH、-SC
1-6烷基、-SS(C
1-6烷基)、-C(=O)(C
1-6烷基)、-CO
2H、-CO
2(C
1-6烷基)、-OC(=O)(C
1-6烷基)、-OCO
2(C
1-6烷基)、-C(=O)NH
2、-C(=O)N(C
1-6烷基)
2、-OC(=O)NH(C
1-6烷基)、-NHC(=O)(C
1-6烷基)、-N(C
1-6烷基)C(=O)(C
1-6烷基)、-NHCO
2(C
1-6烷基)、-NHC(=O)N(C
1-6烷基)
2、-NHC(=O)NH(C
1-6烷基)、-NHC(=O)NH
2、-C(=NH)O(C
1-6烷基)、-OC(=NH)(C
1- 6烷基)、-OC(=NH)OC
1-6烷基、-C(=NH)N(C
1-6烷基)
2、-C(=NH)NH(C
1-6烷基)、-C(=NH)NH
2、-OC(=NH)N(C
1-6烷基)
2、-OC(NH)NH(C
1-6烷基)、-OC(NH)NH
2、-NHC(NH)N(C
1-6烷基)
2、-NHC(=NH)NH
2、 -NHSO
2(C
1-6烷基)、-SO
2N(C
1-6烷基)
2、-SO
2NH(C
1-6烷基)、-SO
2NH
2、-SO
2C
1-6烷基、-SO
2OC
1-6烷基、-OSO
2C
1-6烷基、-SOC
1-6烷基、-Si(C
1-6烷基)
3、-OSi(C
1-6烷基)
3、-C(=S)N(C
1-6烷基)
2、C(=S)NH(C
1-6烷基)、C(=S)NH
2、-C(=O)S(C
1-6烷基)、-C(=S)SC
1-6烷基、-SC(=S)SC
1-6烷基、-P(=O)
2(C
1-6烷基)、-P(=O)(C
1- 6烷基)
2、-OP(=O)(C
1-6烷基)
2、-OP(=O)(OC
1-6烷基)
2、C
1-6烷基、C
1-6卤代烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
7碳环基、C
6-C
10芳基、C
3-C
7杂环基、C
5-C
10杂芳基;或者两个偕Rgg取代基可结合形成=O或=S;其中,X
-为反离子。
示例性的氮原子上取代基包括但不局限于:氢、-OH、-OR
aa、-N(R
cc)
2、-CN、-C(=O)R
aa、-C(=O)N(R
cc)
2、-CO
2R
aa、-SO
2R
aa、-C(=NR
bb)R
aa、-C(=NR
cc)OR
aa、-C(=NR
cc)N(R
cc)
2、-SO
2N(R
cc)
2、-SO
2R
cc、-SO
2OR
cc、-SOR
aa、-C(=S)N(R
cc)
2、-C(=O)SR
cc、-C(=S)SR
cc、-P(=O)
2R
aa、-P(=O)(R
aa)
2、-P(=O)
2N(R
cc)
2、-P(=O)(NR
cc)
2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者连接至氮原子的两个R
cc基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基,炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代,且其中R
aa、R
bb、R
cc和R
dd如上所述。
术语“药学上可接受的盐”是指,在可靠的医学判断范围内,适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等,并且与合理的益处/危险比例相称的那些盐.药学上可接受的盐在本领域是众所周知的.例如,Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐,例如盐酸、氢溴酸、磷酸、硫酸和高氯酸,或与有机酸形成的盐,例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐,例如,离子交换方法。其它药学上可接受的盐包括:已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、时甲苯磺酸盐、十一烷酸盐、戊酸盐,等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N
+(C
1-4烷基)
4盐.代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐,等等。如果合适的话,其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子,反离子例如卤离子、氢氧根、甲酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
本领域技术人员将理解,有机化合物可以与溶剂形成复合物,其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时,复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成,例如,结晶形式,且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物 且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下,所述溶剂合物将能够分离,例如,当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常,包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定.因此,化合物的水合物可用例如通式R·x H
2O代表,其中R是该化合物,和x是大于0的数。给定化合物可形成超过一种水合物类型,包括,例如,单水合物(x为1)、低级水合物(x是大于0且小于1的数,例如,半水合物(R·0.5 H
2O))和多水合物(x为大于1的数,例如,二水合物(R·2 H
2O)和六水合物(R·6 H
2O)).
给药的“受试者”包括但不限于:人(即,任何年龄组的男性或女性,例如,儿科受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻的成人、中年的成人或年长的成人))和/或非人的动物,例如,哺乳动物,例如,灵长类(例如,食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中,受试者是人.在一些实施方案中,受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
除非另作说明,否则,本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用,它降低疾病、障碍或病症的严重程度,或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”),还包括受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂.例如,本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药,或与另一治疗剂一起呈单一单位剂型同时给药。
在一个具体实施方案中,本发明提供了化合物,及其在制备用于治疗/预防癌症的药物中的用途,其中所述化合物为通式(I)的化合物,或其药学上可接受的盐、水合物或溶剂合物:
其中,
R
1选自H、卤素、-CN、-NO
2、-N
3、-OR
a、-NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
2选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
3选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷基;
R
4选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)R
a、-S(O)
2R
a、-S(O)NR
bR
c、-S(O)
2NR
bR
c、-S(O)
2OR
a、-P(O)R
bR
c、-P(O)
2R
a、-P(O)(NR
bR
c)
2、-P(O)
2NR
bR
c、C
1-6烷基或C
1-6卤代烷 基;
R
5选自H、C
1-
6烷基或C
1-6卤代烷基;
R选自H、卤素、-CN或-NO
2;
其中R
a、R
b和R
c各自独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;或者R
b和R
c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基.
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中R
1选自H、卤素、-CN、-NO
2、-N
3或-OH,优选为H、卤素或-OH,更优选为H或-OH。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中R
2选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)
2OH、C
1-6烷基或C
1-6卤代烷基,优选为H、卤素、-CN、-NO
2、-N
3、C
1-6烷基或C
1-6卤代烷基,更优选为H、卤素、C
1-6烷基或C
1-6卤代烷基。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中R
3选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)
2OH、C
1-6烷基或C
1-6卤代烷基,优选为H、卤素、-CN、-NO
2、-N
3、C
1-6烷基或C
1-6卤代烷基,更优选为H、卤素、-N
3、C
1-6烷基或C
1-6卤代烷基。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中R
4选自H、卤素、-CN、-NO
2、-N
3、-C(O)R
a、-C(O)OR
a、-C(O)NR
bR
c、-S(O)
2OH、C
1-6烷基或C
1-6卤代烷基,优选为H、卤素、-CN、-NO
2、-N
3、C
1-6烷基或C
1-6卤代烷基,更优选为H、卤素、C
1-6烷基或C
1-6卤代烷基。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中R
5为H。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中:
R
1为H或-OH;
R
2为H、卤素、C
1-6烷基或C
1-6卤代烷基;
R
3为H、卤素、-N
3、C
1-6烷基或C
1-6卤代烷基;
R
4为H、C
1-6烷基或C
1-6卤代烷基;
R
5为H。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中R
2和R
3中至少一个为非氢基团.
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中R为卤素,优选为Cl或Br,更优选为Br。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中所述化合物具有通式(I-1)的结构:
其中各基团如上文所定义。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中所述化合物具有以下结构:
或其药学上可接受的盐、水合物或溶剂合物。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中所述癌症为STAT3通路介导的癌症,优选为神经胶质瘤、结肠直肠癌、胃癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌、头颈癌、乳腺癌、白血病或非小细胞肺癌。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中所述癌症位于脑内。
在另一个具体实施方案中,本发明提供了上述化合物及用途,其中所述癌症为转移至脑内或骨组织的转移癌。
在另一个具体实施方案中,本发明提供了以下化合物,或其药学上可接受的盐、水合物或溶剂合物:
不受限于理论,目前认为,5-硝基噻唑类化合物可通过抑制丙酮酸:铁氧还蛋白/黄氧还蛋白氧化还原酶(Pyruvate:ferredoxin/flavodoxin oxidoreductases,PFORs)的酶依赖性电子转移反应,干扰厌氧能量代谢,发挥抗寄生虫及抗厌氧菌活性。5-位的硝基取代基对其发挥以上活性至关重要。具体来说,在生理条件下(pH=7.4),NTZ可以阴离子形式存在(NTZ
-,如下图)。作为丙酮酸或TPP的非竞争性抑制剂,NTZ
-可通过干扰丙酮酸羧基与TPP氨基的相互作用,诱导丙酮酸自PFOR蛋白中释放,而在PFOR催化作用早期发挥作用。
将噻唑环5-位硝基用卤素取代后,由于共振式的破坏,卤素化合物不在具有抗厌氧微生物活性。因此,5-位卤素取代的化合物口服给药后,除了发挥抗肿瘤活性,还具有不显著影响肠道菌群、避免或减少胃肠道菌群紊乱的优点,具有更高的安全性.
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。本发明未描述制备方法的原料或产品均购自商品化产品。
本发明化合物的合成方法如下:
实施例1:TIZ(2-羟基-N-(5-硝基噻唑-2-基)苯甲酰胺)的制备。
将NTZ(2-乙酸基-N-(5-硝基噻唑-2-基)苯甲酰胺)(5mmol)置于50mL圆底烧瓶中,加入15mL浓盐酸,10滴浓硫酸,混合物在50℃下搅拌反应至NTZ完全水解。将混合物过滤,用蒸馏水洗涤固体至中性,乙酸乙酯溶解,无水硫酸钠干燥,过滤浓缩后,柱层析法纯化(二氯甲烷/甲醇梯度洗脱)得淡黄色TIZ固体,产率:92%。
实施例2:化合物3、8-11、13-22、24的一般合成路线(线路1).
路线1.化合物3、8-11、13-22、24的合成
试剂及反应条件:(a)氯化亚砜,吡啶,二氯甲烷;(b)无水四氢呋喃,三乙胺。
(a)将对应的苯甲酸衍生物(1.5mmol,1.0当量)溶于无水二氯甲烷(5mL/mmol),向反应液中加入氯化亚砜(1.8mmol,1.2当量)和两滴吡啶,加热回流至反应完全。旋蒸去除溶剂和过量的氯化亚砜,残留固体溶解于无水四氢呋喃中直接进行下一步反应。
(b)2-氨基-5-硝基噻唑(1.5mmol,1.0当量)溶于无水四氢呋喃(5mL/mmol),并向反应液中加入三乙胺(1.8mmol,1.2当量)。-15℃下,将(a)步所制备苯甲酰氯溶液逐滴加入到上述预冷反应液中。反应液恢复至室温,加热回流过夜,反应至起始原料完全消耗,加水淬灭反应。乙酸乙酯萃取反应液,稀盐酸、饱和食盐水分别洗涤合并的有机相,无水硫酸钠干燥,过滤,减压蒸馏以获得粗品。粗品经柱层析纯化(二氯甲烷/甲醇梯度洗脱)得到目标化合物。
实施例3:化合物1、2、12和25的一般合成路线(路线2)。
路线2.化合物1,2,12,25的合成
试剂及反应条件:(a)氢氧化钠,乙酸酐,水;(b)氯化亚砜,吡啶,二氯甲烷;无水四氢呋喃,三乙胺;(c)浓盐酸,浓硫酸,50℃。
在按照上述方法将苯甲酸衍生物与2-氨基-5-硝基噻唑进行偶联之前,首先利用乙酸酐对相应苯甲酸的酚羟基进行乙酰化保护,并在得到乙酰化保护的偶联产物后,酸性条件下脱保护以获得最终产物。
酚羟基的乙酰化保护。将1.5g氢氧化钠溶解于20mL蒸馏水中并转移至100mL圆底烧瓶。向上述溶液中加入相应的羟基苯甲酸(18.1mmol)并搅拌至完全溶解。最后,在0℃下,向溶液中加入4ml乙酸酐,在室温下搅拌直至反应完成。过滤混合物,得到的白色固体用蒸馏水充分洗涤,干燥,得到乙酰氧基苯甲酸衍生物.
将待脱保护化合物(5mmol)置于50mL圆底烧瓶中,加入15mL浓盐酸,10滴浓硫酸,混合物在50℃下搅拌反应至原料完全水解。将混合物过滤,用蒸馏水洗涤固体至中性,乙酸乙酯溶解,无水硫酸钠干燥,过滤浓缩后,柱层析法纯化(二氯甲烷/甲醇梯度洗脱)得脱保护产物。
实施例4:化合物4-7、23的一般合成路线(线路3)。
路线3.化合物4-7和23的合成
试剂及反应条件:(a)EDCI,HOBt,DIEA,DMF。
化合物以相应的苯甲酸衍生物及2-氨基-5-硝基噻唑为原料,1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDCI)和1-羟基苯并三唑(HOBt)作为缩合试剂,N-二异丙基乙胺(DIEA)提供碱性环境,N,N-二甲基甲酰胺(DMF)为溶剂,通过一步缩合反应得到,并经柱层析分离纯化。
具体来说,将苯甲酸衍生物(1.5mmol,1.0当量)、EDCI(2.25mmol,1.5当量)和HOBT(2.25mmol,1.5当量)溶解于10mLDMF中并在室温下搅拌30分钟。将2-氨基-5-硝基噻唑(1.5mmol,1.0当量)、DIEA(4.5mmol,3.0当量)溶解于10mLDMF中并在室温下搅拌30分钟。然后将上述 反应液混合,室温下搅拌反应至起始原料完全消耗,加水淬灭反应。混合液用乙酸乙酯萃取,合并的有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩后,柱层析法纯化(二氯甲烷/甲醇梯度洗脱)得到目标产物。
实施例5:化合物26的一般合成路线(线路4)。
路线4.化合物26的合成
试剂及反应条件:(a)炔丙基溴,碳酸钾,DMF。
化合物26以化合物15为原料,使用炔丙基溴对化合物15进行N-炔丙基化得到。
具体来说,化合物15(2.00mmol,1.0当量)溶于10mL无水DMF中,0℃下,向溶液中加入碳酸钾(9.44mmol,4.7当量)搅拌30分钟。30分钟后,在冰浴条件下,向反应中逐滴加入炔丙基溴(5.00mmol,2.5当量),恢复反应至室温,继续搅拌反应直到起始原料完全消耗.加水淬灭反应,并用二氯甲烷萃取,饱和食盐水洗涤合并的有机层,无水硫酸钠干燥,过滤浓缩后,粗品通过柱层析法纯化(二氯甲烷/甲醇梯度洗脱)得到化合物26。
实施例6:2-羟基-3-甲基-N-(噻唑-2-基)苯甲酰胺(化合物27)的制备
取3-甲基水杨酸(2mmol,0.305g)于50ml圆底烧瓶中,用8ml DMF溶解,依次加入HATU(2.4mmol,0.910g),NMM(6mmol,660μl)以及2-氨基噻唑(2mmol,0.203g),50℃加热搅拌反应过夜,反应过程中TLC监测。反应结束后加入水(25ml)来淬灭反应,乙酸乙酯萃取(30ml*3),有机相合并,并用饱和食盐水洗(40ml*2),无水硫酸钠干燥,过滤后减压浓缩,柱层析分离(石油醚/乙酸乙酯=15∶1)(v/v),得白色固体0.148g,收率32.0%。
实施例7:4-三氟甲基-N-(5-溴噻唑-2-基)苯甲酰胺(化合物28)的制备
以对三氟甲基苯甲酸和2-氨基-5-溴噻唑为原料,称取4-三氟甲基笨甲酸(4.0mmol,0.76g)于含有10mL DMF的50mL圆底烧瓶中,依次加入PyBoP(4mmol,2.10g),K
2CO
3(8mmol,1.10g),2-氨基-5-溴噻唑(1mmol,0.18g),转至60℃反应24h。TLC监测至反应不再发生后向反应体系中加入水(25mL)来淬灭反应,乙酸乙酯萃取(30mL*3),有机相合并,饱和食盐水洗(40mL*2),无水硫酸钠干燥,过滤,减压浓缩。柱层析分离,收集产物,产物为白色固体,收率54%。
本发明化合物的表征.本发明中所涉及的化合物,均对其熔点进行了测定,并通过核磁氢谱,碳谱及高分辨质谱进行了表征.
2-羟基-N-(5-硝基噻唑-2-基)苯甲酰胺(TIZ)。淡黄色固体.产率:92%。m.p.:209-210℃.
1H NMR(400MHz,DMSO-d
6)δ12.14(br,1H,OH),8.70(s,1H,4’-H),7.91(dd,J=7.9,1.7Hz,1H,ArH),7.54-7.47(m,1H,ArH),7.08-6.98(m,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.43,161.45,157.32,142.35,142.01,135.12,130.57,119.87,117.20,116.42.m/z(ES
-),HRMS calcd for C
10H
6N
3O
4S[M-H]
-,264.0079;found 264.0081.
3-羟基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物1)。淡黄色固体。产率:35%。m.p.:245-246℃.
1H NMR(400MHz,DMSO-d
6)δ13.50(s,1H,NH),9.94(s,1H,OH),8.71(s,1H,4’-H),7.58(dt,J=7.8,1.2Hz,1H,ArH),7.46(t,J=2.1Hz,1H,ArH),7.37(t,J=7.8Hz,1H,ArH),7.07(ddd,J=8.1,2.5,0.9Hz,1H,ArH).
13C NMR(100MHz,DMSO-d
6)δ166.44,162.59,157.59,142.60,142.00,132.07,129.86,120.51,119.03,115.16.m/z(ES
-),HRMS calcd for C
10H
6N
3O
4S[M-H]
-,264.0079;found 264.0081。
4-羟基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物2)。淡黄色固体。产率:69%.m.p.:213-214℃.
1H NMR(400MHz,DMSO-d
6)δ13.31(s,1H,NH),10.52(s,1H,OH),8.70(s,1H,4’-H),8.05(d,J=8.2Hz,2H,ArH),6.91(d,J=8.2Hz,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.65,162.95,162.40,142.74,141.81,130.99,121.13,115.46.m/z(ES
-),HRMS calcd for C
10H
6N
3O
4S[M-H]
-,264.0079;found 264.0082。
N-(5-硝基噻唑-2-基)苯甲酰胺(化合物3)。淡黄色固体。产率:81%。m.p.:218-219℃.
1H NMR(400MHz,DMSO-d
6)δ13.60(s,1H,NH),8.72(s,1H,4’-H),8.13(d,J=7.8Hz,2H,ArH),7.70(t,J=7.3Hz,1H,ArH),7.59(t,J=7.4Hz,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ166.43,162.60,142.61,142.07,133.50,130.79,128.79,128.55.m/z(ES
-),HRMS calcd for C
10H
6N
3O
3S[M-H]
-,248.0130;found 248.0131。
2-甲基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物4)。淡黄色固体。产率:68%。m.p.:182-183℃.
1H NMR(400MHz,DMSO-d
6)δ13.50(s,1H,NH),8.69(s,1H,4’-H),7.64(d,J=7.5Hz,1H,ArH),7.49(t,J=7.5Hz,1H,ArH),7.39-7.32(m,2H,ArH),2143(s,3H,CH
3).
13C NMR(100MHz,DMSO-d
6)δ168.55,162.03,142.65,142.00,137.03,132.26,131.55,131.05,128.50,125.78,19.66.m/z(ES
-),HRMS calcd for C
11H
8N
3O
3S[M-H]
-,262.0286;found 262.0285。
2-硝基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物5).淡黄色固体。产率:62%。m.p.:227-228℃.
1H NMR(400MHz,DMSO-d
6)δ13.83(s,1H,NH),8.70(s,1H,4’-H),8.25(d,J=8.1Hz,1H,ArH),7.95(t,J=7.5Hz,1H,ArH),7.90-7.83(m,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.91,161.41,146.12,142.53,142.36,134.58,132.36,129.81,129.21,124.59.m/z(ES
-),HRMS calcd for C
10H
5N
4O
5S[M-H]
-,292.9981;found 292.9981。
2-氟-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物6)。淡黄色固体。产率:86%。m.p.:188-189℃.
1H NMR(400MHz,DMSO-d
6)δ13.62(s,1H,NH),8.71(s,1H,4’-H),7.81(td,J=7.5,1.7Hz,1H,ArH),7.73-7.66(m,1H,ArH),7.46-7.35(m,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ164.09,161.64,159.50(d,J=252.7Hz),142.59,142.19,134.61(d,J=8.7Hz),130.58,124.74(d,J=3.6Hz),120.94(d,J=12.6Hz),116.53(d,J=21.3Hz).m/z(ES
-),HRMS calcd for C
10H
5FN
3O
3S[M-H]
-,266.0036;found 266.0031.
2-溴-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物7)。淡黄色固体。产率:70%。m.p.:198-199℃.
1H NMR(400MHz,DMSO-d
6)δ13.73(s,1H,NH),8.70(s,1H,4’-H),7.78(d,J=7.5Hz,1H,ArH),7.69(d,J=7.5Hz,1H,ArH),7.58-7.48(m,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ167.01,161.39,142.57,142.37,135.10,133.03,132.69,129.67,127.78,119.18.m/z(ES
-),HRMS calcd for C
10H
5BrN
3O
3S[M-H]
-,325.9235,327.9215;found 325.9233,327.9213。
2-氯-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物8)。淡黄色固体。产率:64%。m.p.:191-192℃.
1H NMR(400MHz,DMSO-d
6)δ13.73(s,1H,NH),8.70(s,1H,4’-H),7.72(d,J=7.4Hz,1H,ArH),7.66-7.58(m,2H,Ar-H),7.54-7.48(m,1H).
13C NMR(100MHz,DMSO-d
6)δ166.15,161.39,142.56,142.35,132.86,132.71,130.43,129.98,129.80,127.35.m/z(ES
-),HRMS calcd for C
10H
5ClN
3O
3S[M-H]
-,281.9740;found 281.9743。
2-羟基-3-甲基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物9)。淡黄色固体.产率:31%.m.p.:181-182℃.
1H NMR(400MHz,DMSO-d
6)δ12.03(br,1H,OH)8.76(s,1H,4’-H),7.92(d,J=6.9Hz,1H,ArH),7.42(d,J=6.9Hz,1H,ArH),6.90(t,J=7.7Hz,1H,ArH),2.22(s,3H,CH
3).
13C NMR(100MHz,DMSO-d
6)δ169.36,162.71,158.00,141.32,141.14,136.18,126.91,126.41,118.90,114.87,15.77.m/z(ES
-),HRMS calcd for C
11H
8N
3O
4S[M-H]
-,278.0236;found 278.0238。
2-羟基-4-甲基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物10)。淡黄色固体。产率:28%。m.p.:216-217℃.
1H NMR(400MHz,DMSO-d
6)δ12.09(br,1H,OH),8.69(s,1H,4’-H),7.85(d,J=8.0Hz,1H,ArH),6.89-6.81(m,2H,ArH),2.32(s,3H,CH
3).
13C NMR(100MHz,DMSO-d
6)δ165.38,161.59,157.52,146.09,142.37,141.85,130.44,121.01,117.35,113.43,21.23.m/z(ES
-),HRMS calcd for C
11H
8N
3O
4S[M-H]
-,278.0236;found 278.0242.
2-羟基-5-甲基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物11)。淡黄色固体。产率:22%。m.p.:209-210℃.
1H NMR(400MHz,DMSO-d
6)
1H NMR(400MHz,DMSO-d
6)δ12.01(br,1H,OH),8.67(s,1H,4’-H),7.74-7.70(m,1H,ArH),7.31(dd,J=8.4,2.4Hz,1H,ArH),6.94(d,J=8.3Hz,1H,ArH),2.26(s,3H,CH
3).
13C NMR(100MHz,DMSO-d
6)δ165.44,161.51,155.21,142.40,141.92,135.83,130.25,128.65,117.11,115.85,19.86.m/z(ES
-),HRMS calcd for C
11H
8N
3O
4S[M-H]
-,278.0236;found 278.0243。
2,4-二羟基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物12)。淡黄色固体。产率:45%。m.p.:243-244℃.
1H NMR(400MHz,DMSO-d
6)δ12.07(s,2H,NH+OH),10.53(s,1H,OH),8.68(s,1H,4’-H),7.86(d,J=9.3Hz,1H,ArH),6.45(m,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ164.73,164.12,161.59,159.84,142.52,141.96,132.56,108.95,107.02,102.8.m/z(ES
-),HRMS calcd for C
10H
6N
3O
5S[M-H]
-,280.0028;found 280.0031。
3-氯-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物13)。淡黄色固体。产率:62%。m.p.:192-193℃.
1H NMR(400MHz,DMSO-d
6)δ13.66(s,1H,NH),8.70(s,1H,4’-H),8.17(t,J=1.8Hz,1H,ArH),8.08-8.03(m,1H,ArH),7.78-7.72(m,1H,ArH),7.60(t,J=7.9Hz,1H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.17,162.36,142.44,142.15,133.53,133.14,132.81,130.70,128.26,127.28.m/z(ES
-),HRMS calcd for C
10H
5ClN
3O
3S[M-H]
-,281.9740;found 281.9749。
4-氯-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物14)。淡黄色固体。产率:72%。m.p.:244-245℃.
1H NMR(400MHz,DMSO-d
6)δ13.66(s,1H,NH),8.71(s,1H,4’-H),8.12(d,J=8.6Hz,2H,ArH),7.65(d,J=8.6Hz,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.48,162.50,142.53,142.14,138.46,130.48,129.62,128.91.m/z(ES
-),HRMS calcd for C
10H
5ClN
3O
3S[M-H]
-,281.9740;found 281.9745。
N-(5-硝基噻唑-2-基)-4-(三氟甲基)苯甲酰胺(化合物15)。淡黄色固体.产率:76%。m.p.:227-228℃.
1H NMR(400MHz,DMSO-d
6)δ13.80(s,1H,NH),8.71(s,1H,4’-H),8.29(d,J=8.2Hz,2H,ArH),7.94(d,J=8.2Hz,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.52,162.36,142.33,142.17,134.70,132.74(q,J
CF=32.2Hz),129.47,125.63(q,J
CF=3.4Hz),123.66(q,J
CF=272.9Hz).m/z(ES
-),HRMS calcd for C
11H
5F
3N
3O
3S[M-H]
-,316.0004;found 316.0008。
4-叠氮-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物16)。淡黄色固体。产率:54%。m.p.:172-173℃.
1H NMR(400MHz,DMSO-d
6)δ13.56(s,1H,NH),8.71(s,1H,4’-H),8.18(d,J=7.7Hz,2H,ArH),7.31(d,J=7.7Hz,2H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.38,162.60,144.72,142.56,142.02,130.57,127.07,119.37.m/z(ES
-),HRMS calcd for C
10H
5N
6O
3S[M-H]
-,289.0144;found 289.0148.
4-甲氧基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物17)。淡黄色固体。产率:41%.m.p.:231-232℃.
1H NMR(400MHz,DMSO-d
6)δ13.40(s,1H,NH),8.70(s,1H,4’-H),8.15(d,J=8.9Hz,2H,ArH),7.11(d,J=8.9Hz,2H,ArH),3.87(s,3H).
13C NMR(100MHz,DMSO-d
6)δ165.56,163.40,162.82,142.63,141.87,130.74,122.72,114.11,55.62.m/z(ES
-),HRMS calcd for C
11H
8N
3O
4S[M-H]
-,278.0236;found 278.0235。
4-(4-甲基哌嗪-1-基)-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物18).淡黄色固体。产率:17%.m.p.:210-211℃.
1H NMR(400MHz,DMSO-d
6)δ11.87(s,1H,NH),8.61(s,1H,4’-H),8.04(d,J=8.6Hz,2H,ArH),7.02(d,J=8.6Hz,2H),3.43(t,J=5.0Hz,4H,CH
2),2.76(t,J=5.0Hz,4H,CH
2),2.45(s,3H,CH
3).m/z(ES
-),HRMS calcd for C
15H
16N
5O
3S[M-H]
-,346.0974;found 346.0972。
4-吗啉基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物19)。淡黄色固体。产率:33%。m.p.:186-187℃.
1H NMR(400MHz,DMSO-d
6)δ13.24(s,1H,NH),8.69(s,1H,4’-H),8.05(d,J=8.8Hz,2H,ArH),7.05(d,J=8.8Hz,2H,ArH),3.73(t,J=4.7Hz,4H,CH
2),3.33(t,J=4.7Hz,4H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ165.39,163.09,154.28,142.87,141.74,130.29,118.97,113.08,65.86,46.64.m/z(ES
-),HRMS calcd for C
14H
13N
4O
4S[M-H]
-,333.0658;found 333.0658。
4-(叔丁基)-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物20)。淡黄色固体。产率:68%。m.p.:179-180℃.
1H NMR(400MHz,DMSO-d
6)δ13.51(s,1H,NH),8.70(s,1H,4’-H),8.08(d,J=8.1Hz,2H,ArH),7.60(d,J=8.1Hz,2H,ArH),1.32(s,9H,CH
3).
13C NMR(100MHz,DMSO-d
6)δ166.10,162.63,156.67,142.60,142.00,128.47,127.95,125.63,34.93,30.77.m/z(ES
-),HRMS calcd for C
14H
14N
3O
3S[M-H]
-,304.0756;found 304.0759.
4-(甲磺酰基)-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物21)。淡黄色固体。产率:56%。m.p.:198-199℃.
1H NMR(400MHz,DMSO-d
6)δ13.84(s,1H,NH),8.75(s,1H,4’-H),8.34(d,J=8.2Hz,2H,ArH),8.13(d,J=8.2Hz,2H,ArH),3.32(s,3H,CH
3).
13C NMR(100MHz,DMSO-d
6)δ165.57,162.42,144.52,142.39,142.15,135.42,129.57,127.22,43.09.m/z(ES
-),HRMS calcd for C
11H
8N
3O
5S
2[M-H]
-,325.9905;found 325.9910。
N-(5-硝基噻唑-2-基)-4-氨基磺酰基苯甲酰胺(化合物22)。淡黄色固体。产率:21%。m.p.:193-194℃.
1H NMR(400MHz,DMSO-d
6)δ13.78(s,1H,NH),8.75(s,1H,4’-H),8.27(d,J=8.3Hz,2H,ArH),7.99(d,J=8.3Hz,2H,ArH),7.59(s,2H,NH
2).
13C NMR(100MHz,DMSO-d
6)δ165.68,162.42,147.89,142.45,142.15,133.79,129.33,125.86.m/z(ES
-),HRMS calcd for C
10H
7N
4O
5S
2[M-H]
-,326.9858;found 326.9872.
N-(5-硝基噻唑-2-基)-4-(N-苯基氨基磺酰基)苯甲酰胺(化合物23)。产率:71%。淡黄色固体。m.p.:175-176℃.
1H NMR(400MHz,DMSO-d
6)δ13.74(s,1H,CONH),10.47(s,1H,SO
2NH),8.72(s,1H,4’-H),8.25-8.18(m,2H,ArH),7.94-7.88(m,2H,ArH),7.27-7.20(m,2H,ArH),7.16-7.07(m,2H,ArH),7.08-7.02(m,1H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.58,162.38,143.30,142.41,142.13,137.20,134.86,129.54,129.27,126.92,124.49,120.39.m/z(ES
-),HRMS calcd for C
16H
11N
4O
5S
2[M-H]
-,403.0171;found 403.0173。
3,4-二氯-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物24)。淡黄色固体。产率:67%。m.p.:202-203℃.
1H NMR(400MHz,DMSO-d
6)δ13.73(s,1H,NH),8.73(s,1H,4’-H),8.40-8.34(m,1H,ArH),8.08-8.01(m,1H,ArH),7.86(d,J=8.4Hz,1H,ArH).
13C NMR(100MHz,DMSO-d
6)δ164.59,162.45,142.55,142.20,136.31,131.73,131.40,131.17,130.51,128.83.m/z(ES
-),HRMS calcd for C
10H
4Cl
2N
3O
3S[M-H]
-,315.9350;found 315.9345。
3,4-二羟基-N-(5-硝基噻唑-2-基)苯甲酰胺(化合物25)。淡黄色固体。产率:48%.m.p.:235-236℃.
1H NMR(400MHz,DMSO-d
6)δ13.24(s,1H,NH),10.07(s,1H,OH),9.49(s,1H,OH),8.67(s,1H,4’-H),7.58(dd,J=8.3,2.1Hz,1H,ArH),7.52(d,J=2.1Hz,1H,ArH),6.85(d,J=8.3Hz,1H,ArH).
13C NMR(100MHz,DMSO-d
6)δ165.81,163.03,151.10,145.47,142.86,141.83,121.48,121.26,116.02,115.30.m/z(ES
-),HRMS calcd for C
10H
6N
3O
5S[M-H]
-,280.0028;found 280.0023。
N-(5-硝基噻唑-2-基)-N-(丙炔基)-4-(三氟甲基)苯甲酰胺(化合物26).淡黄色固体。产率:72%。m.p.:173-174℃.
1H NMR(400MHz,DMSO-d
6)δ9.21(s,1H,4’-H),8.45(d,J=8.2Hz,2H,ArH),7.92(d,J=8.2Hz,2H,ArH),5.23(d,J=2.5Hz,2H,CH
2),3.65(t,J=2.5Hz,1H,C≡CH).
13C NMR(100MHz,DMSO-d
6)δ172.80,165.12,138.32,134.57,133.81,132.38(q,J=31.8Hz),129.94,125.61(q,J=3.7Hz),123.89(q,J=272.7Hz),77.50,76.67,38.91.rn/z(ES
-),HRMS calcd for C
14H
7F
3N
3O
3S[M-H]
-,354.0160;found 354.0162。
2-羟基-3-甲基-N-(噻唑-2-基)苯甲酰胺(化合物27)。m.p.:176.9-177.2℃.
1H NMR(400MHz,DMSO-d
6)δ13.39(bs,1H),12.81(bs,1H),7.92(m,1H),7.58(d,J=4.0Hz,1H),7.33(d,J=4.0Hz,1H),7.24(m,1H),6.82(m,1H),3.09(s,3H).
13C NMR(100MHz,DMSO-d
6)δ159.08,135.44,127.41,126.26,118.61,113.42,60.21,16.17.HRMS(ESI)[M+H
+]calcd 235.0536 found 235.0545。
4-三氟甲基-N-(5-溴噻唑-2-基)苯甲酰胺(化合物28)。m.p.:184.3-184.6℃.
1H NMR(400MHz,DMSO-d
6)δ13.17(s,1H),8.27(d,J=8.2Hz,2H),7.93(d,J=8.2Hz,2H),7.69(s,1H).
13C NMR(101MHz,DMSO-d
6)δ135.83,132.92,132.60,129.66,126.08,126.05,126.01,125.97,125.57,122.86,102.96.HRMS(ESI)[M+H
+]calcd 352.9389 found 352.9401。
生物实施例
1.本发明化合物STAT3通路抑制活性的评价。本发明通过可稳定表达IL-6受体和可与STAT3结合的分泌胚胎碱性磷酸酶报告基因的HEK-Blue IL-6细胞系进行。
具体来说,细胞培养用96孔板中每孔加入IL-6细胞因子(终浓度1ng/mL)20μL、不同浓度的待测化合物20μL及HEK-Blue IL-6细胞悬液(每孔5×10
4个)160μL,每孔共200μL液体;阴性对照组为40μL完全培养基和160μL细胞悬液;阳性对照组为IL-6细胞因子(终浓度1ng/mL)20μL、完 全培养基20μL和细胞悬液160μL。细胞在37℃细胞培养箱孵育20小时后,每孔吸取20μL上清液转移至另一块96孔板中,加入37℃预热的QUANTI-Blue显色液180μL,在37℃孵育1小时后,于655nm波长下进行吸光度检测。为了排除化合物毒性造成细胞数量减少而导致吸光度下降的假阳性干扰,使用四甲基偶氮唑盐微量酶反应比色法(MTT法)对处理后的HEK-Blue细胞活性进行了测试,MTT测试方法按一般测试方法进行。
2.本发明化合物抗细胞增殖活性测试方法。本发明通过四甲基偶氮唑盐微量酶反应比色法(MTT法)对化合物对不同细胞系的抗增殖活性进行了测试。
具体来说,在96孔板中每孔接种5000-6000个细胞,继续培养6小时后,使用不同浓度的化合物或DMSO处理细胞不同时间,每组设置三个复孔。培养结束后,使用多通道移液器移走原含药培养基,每孔加入100μl的四甲基偶氮唑蓝培养基溶液(5mg/ml)。继续在37℃孵育细胞3-4小时,用多通道移液器移走原培养基,每孔加入100μL二甲基亚砜,室温避光振摇15分钟,于570nm波长下进行吸光度检测.
3.本发明所用细胞的培养方法。除另外说明,本发明所用细胞系购买自北京协和细胞资源中心。人宫颈癌细胞系HeLa、人肺腺癌细胞系A549、人恶性黑色素瘤细胞系A375和人胚肾细胞系HEK293T在DMEM中培养.前列腺癌细胞系PC3在F12K培养基中培养.结肠腺癌细胞系HT29在MCCOY′s5a培养基中培养.人恶性胶质母细胞瘤细胞系U87MG在含有非必需氨基酸的MEM中培养。上述培养基中均加入了10%胎牛血清(FBS)、100单位/mL青霉素和100单位/mL链霉素。人急性髓系白血病细胞系HL60在添加了20%胎牛血清(FBS)、100单位/mL青霉素和100单位/mL链霉素的IMDM培养基中培养。HEK-BlueTM-IL6细胞购买自Invivogen公司,并在添加了10%热灭活胎牛血清(FBS;56℃热灭活30分钟)、100单位/mL青霉素、100单位/mL链霉素、100μg/mL Normocin
TM(Invivogen)、1x HEK Blue
TM选择性抗生素(Invivogen)的DMEM培养基中培养。所有细胞在37℃、5%CO
2条件下培养,支原体污染检测呈阴性。
4.本发明所用药代动力学性质评价方法。本发明使用Sprague-Dawley大鼠对化合物NTZ及化合物15的药代动力学性质进行了测试。具体来说,将12只雄性SD大鼠(300-320g)分为4组,每组3只。在进行1天的适应性饲养后,全部大鼠禁食12小时后给药。其中,NTZ受试组分别通过尾静脉注射,按5mg/Kg给药(A组)或通过灌胃,按25mg/Kg给药(B组);化合物15受试组分别通过尾静脉注射,按5mg/Kg给药(C组)或通过灌胃,按25mg/Kg给药(D组)。所给药物溶解在10%二甲基亚砜,40%PEG-400以及50%无菌生理盐水中.对受试动物,在给药前,给药后5分钟,10分钟,20分钟,30分钟,1小时,2小时,4小时,8小时,24小时,32小时,48小时时间点眼眶静脉丛采血,每次采血100μL,血液用肝素钠抗凝,离心获得血浆后-80℃保存。所得血样以化合物14(2ng/mL)为内标,通过LC-MS/MS(
BEH C18 1.7μm,ESI
+,Waters)进行定量分析。数据采用DAS version 2.1.1软件进行拟合,拟合时采用二房室模型。
5.小鼠荷瘤模型中的有效性和安全性。5周龄雌性BALB/c-nu裸鼠右腋皮下接种HeLa细胞(5×10
6个/只)。28天后,平均荷瘤体积达到100mm
3.小鼠被随机分为5组,每组6只,开始进行给药。其中,溶剂组小鼠每日一次灌胃给药100μL0.5%羟甲基纤维素钠(CMC)水溶液;NTZ对照组每 日一次灌胃给药NTZ混悬液(400mg/kg);化合物15分为高、中、低剂量三组,每日一次分别灌胃给药25、5、1mg/kg化合物15的混悬液。给药过程中,溶剂组给药第11、18、21日,NTZ组给药后第18日,15高剂量组给药后第20日,中、低剂量组给药后第27日各有一只小鼠死亡。截至给药28日结束,溶剂组存活小鼠数量为2只,NTZ组及15高、中、低剂量组各为5只。
表1.本发明化合物的结构及其活性数据。
a未测试,
b选择性指数:STAT3通路的抑制%/HEK-Blue
TMIL-6细胞的细胞活力的抑制%。所有值为三次独立实验的平均值。
NTZ为硝唑尼特。
TIZ为替唑尼特。
表2.本发明化合物在HEK 293T和HeLa细胞系中的生长抑制活性。
所有值为三次独立实验的平均值。
WP1066为(2E)-3-(6-溴吡啶-2-基)-2-氰基-N-[(1S)-1-苯基乙基]-2-丙烯酰胺。
表3.NTZ和本发明代表性化合物对不同细胞系的生长抑制活性。
所有值为三次独立实验的平均值.
表4.NTZ和化合物15的药代动力学参数(n=3只大鼠/组)。
at
1/2α:分布相的半衰期,
bt
1/2β:消除相的半衰期,
cVd/F:分布的表观体积,
dCl/F:表观清除速率,单位时间内从中央室清除药物的表观体积,
eAUC
0-∞:浓度时间曲线的曲线下面积,
fT
max:峰浓度到达时间,
gC
max:最大血浆浓度,
gF:绝对生物利用度。
给药后28天内,各组小鼠的平均肿瘤体积-时间曲线如图1A所示。结果表明,每日1mg/kg灌胃给药化合物15即可有效抑制小鼠荷瘤的生长,且效果优于400mg/kg NTZ对照组。同时,随着化合物15给药剂量的加大,抗肿瘤活性呈剂量依赖性升高。给药28日结束时,化合物15高、中、低三种剂量给药组小鼠荷瘤的平均体积均小于NTZ组,同时与溶剂组小鼠的肿瘤体积间存在显著性差异(图1B)。表明化合物15的体内抗肿瘤活性优于NTZ。
在安全性方面,不同浓度化合物15给药均未造成小鼠体重的明显下降(图1C),同时给药28天后,给药组小鼠的平均体重甚至略高于溶剂组(图1D),表明药物具有良好的耐受性.
Claims (14)
- 化合物在制备用于治疗/预防癌症的药物中的用途,其中所述化合物为通式(I)的化合物,或其药学上可接受的盐、水合物或溶剂合物:其中,R 1选自H、卤素、-CN、-NO 2、-N 3、-OR a、-NR bR c、C 1-6烷基或C 1-6卤代烷基;R 2选自H、卤素、-CN、-NO 2、-N 3、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-S(O)R a、-S(O) 2R a、-S(O)NR bR c、-S(O) 2NR bR c、-S(O) 2OR a、-P(O)R bR c、-P(O) 2R a、-P(O)(NR bR c) 2、-P(O) 2NR bR c、C 1-6烷基或C 1-6卤代烷基;R 3选自H、卤素、-CN、-NO 2、-N 3、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-S(O)R a、-S(O) 2R a、-S(O)NR bR c、-S(O) 2NR bR c、-S(O) 2OR a、-P(O)R bR c、-P(O) 2R a、-P(O)(NR bR c) 2、-P(O) 2NR bR c、C 1-6烷基或C 1-6卤代烷基;R 4选自H、卤素、-CN、-NO 2、-N 3、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-S(O)R a、-S(O) 2R a、-S(O)NR bR c、-S(O) 2NR bR c、-S(O) 2OR a、-P(O)R bR c、-P(O) 2R a、-P(O)(NR bR c) 2、-P(O) 2NR bR c、C 1-6烷基或C 1-6卤代烷基;R 5选自H、C 1-6烷基或C 1-6卤代烷基;R选自H、卤素、-CN或-NO 2;其中R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基;或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基。
- 权利要求1的用途,其中R 1选自H、卤素、-CN、-NO 2、-N 3或-OH,优选为H、卤素或-OH,更优选为H或-OH。
- 权利要求1或2的用途,其中R 2选自H、卤素、-CN、-NO 2、-N 3、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-S(O) 2OH、C 1-6烷基或C 1-6卤代烷基,优选为H、卤素、-CN、-NO 2、-N 3、C 1-6烷基或C 1-6卤代烷基,更优选为H、卤素、C 1-6烷基或C 1-6卤代烷基。
- 权利要求1-3中任一项的用途,其中R 3选自H、卤素、-CN、-NO 2、-N 3、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-S(O) 2OH、C 1-6烷基或C 1-6卤代烷基,优选为H、卤素、-CN、-NO 2、-N 3、C 1-6烷基或C 1-6卤代烷基,更优选为H、卤素、-N 3、C 1-6烷基或C 1-6卤代烷基。
- 权利要求1-4中任一项的用途,其中R 4选自H、卤素、-CN、-NO 2、-N 3、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-S(O) 2OH、C 1-6烷基或C 1-6卤代烷基,优选为H、卤素、-CN、-NO 2、-N 3、C 1-6烷基或C 1-6卤代烷基,更优选为H、卤素、C 1-6烷基或C 1-6卤代烷基。
- 权利要求1-5中任一项的用途,其中R 5为H。
- 权利要求1-6中任一项的用途,其中:R 1为H或-OH;R 2为H、卤素、C 1-6烷基或C 1-6卤代烷基;R 3为H、卤素、-N 3、C 1-6烷基或C 1-6卤代烷基;R 4为H、C 1-6烷基或C 1-6卤代烷基;R 5为H.
- 权利要求1-7中任一项的用途,其中R 2和R 3中至少一个为非氢基团。
- 权利要求1-8中任一项的用途,其中R为卤素,优选为Cl或Br,更优选为Br。
- 权利要求1-8中任一项的用途,其中所述化合物具有通式(I-1)的结构:其中各基团如权利要求1-8中任一项所定义。
- 权利要求1的用途,其中所述化合物具有以下结构:或其药学上可接受的盐、水合物或溶剂合物。
- 权利要求1-11中任一项的用途,其中所述癌症为STAT3通路介导的癌症,优选为胶质瘤、结肠直肠癌、胃癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌、头颈癌、乳腺癌、白血病或非小细胞肺癌。
- 权利要求12的用途,其中所述癌症为转移至脑内或骨组织的转移癌.
- 化合物,或其药学上可接受的盐、水合物或溶剂合物:
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