CN1196703C - 作为cdk2抑制剂的吡唑并苯并二氮䓬 - Google Patents
作为cdk2抑制剂的吡唑并苯并二氮䓬 Download PDFInfo
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- CN1196703C CN1196703C CNB008065543A CN00806554A CN1196703C CN 1196703 C CN1196703 C CN 1196703C CN B008065543 A CNB008065543 A CN B008065543A CN 00806554 A CN00806554 A CN 00806554A CN 1196703 C CN1196703 C CN 1196703C
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- Prior art keywords
- benzodiazepine
- pyrazolo
- phenyl
- chloro
- nitro
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- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 title abstract description 12
- QBCJSMSLBBCZGU-UHFFFAOYSA-N pyrazolo[3,4-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=NN=C3C=CC2=C1 QBCJSMSLBBCZGU-UHFFFAOYSA-N 0.000 title abstract description 5
- 102000015792 Cyclin-Dependent Kinase 2 Human genes 0.000 title abstract 2
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 125
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims description 119
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- -1 saturated cyclic aliphatic hydrocarbon Chemical class 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 19
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 239000000651 prodrug Substances 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 239000002207 metabolite Substances 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 8
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- XQPYSCCJJWMMIP-UHFFFAOYSA-N 5-(2-fluorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical group N=1C(C)=CN=C2C3=CN=NC3=CC=C2C=1C1=CC=CC=C1F XQPYSCCJJWMMIP-UHFFFAOYSA-N 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
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- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- XTHFLXPPCJCRCV-UHFFFAOYSA-N 5-(2-fluorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC=C1N=NC=C12 XTHFLXPPCJCRCV-UHFFFAOYSA-N 0.000 claims description 3
- OEDUIFSDODUDRK-UHFFFAOYSA-N 5-phenyl-1h-pyrazole Chemical compound N1N=CC=C1C1=CC=CC=C1 OEDUIFSDODUDRK-UHFFFAOYSA-N 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- SPVSGXHYZOLHFK-UHFFFAOYSA-N 1H-1,4-benzodiazepine-3-carbaldehyde Chemical compound N1C=C(N=CC2=C1C=CC=C2)C=O SPVSGXHYZOLHFK-UHFFFAOYSA-N 0.000 claims description 2
- RIFZWNMWLMAWOZ-UHFFFAOYSA-N 1h-1,4-benzodiazepine-3-carbonitrile Chemical compound C1=NC(C#N)=CNC2=CC=CC=C21 RIFZWNMWLMAWOZ-UHFFFAOYSA-N 0.000 claims description 2
- IBXVHHWYEXKPQL-UHFFFAOYSA-N 2-[5-(2-fluorophenyl)-2H-pyrazolo[3,4-i][1,4]benzodiazepin-1-yl]ethanol Chemical compound OCCN1CC=NC(=C2C1=C1C(C=C2)=NN=C1)C1=C(C=CC=C1)F IBXVHHWYEXKPQL-UHFFFAOYSA-N 0.000 claims description 2
- UHLHKEDGAYUSTO-UHFFFAOYSA-N 3-methyl-7-nitro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1 UHLHKEDGAYUSTO-UHFFFAOYSA-N 0.000 claims description 2
- CQCCAQYYDLMFBY-UHFFFAOYSA-N 5-(2-fluorophenyl)-3-(hydroxymethyl)pyrazolo[3,4-i][1,4]benzodiazepine-7-carbonitrile Chemical group N=1C(CO)=CN=C2C3=CN=NC3=C(C#N)C=C2C=1C1=CC=CC=C1F CQCCAQYYDLMFBY-UHFFFAOYSA-N 0.000 claims description 2
- DCCPWWJJFVJDKB-UHFFFAOYSA-N 5-(2-fluorophenyl)-3-methyl-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F DCCPWWJJFVJDKB-UHFFFAOYSA-N 0.000 claims description 2
- ZOYUTSBNHKSWFH-UHFFFAOYSA-N 5-(2-fluorophenyl)-7-iodo-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(I)C=C2C=1C1=CC=CC=C1F ZOYUTSBNHKSWFH-UHFFFAOYSA-N 0.000 claims description 2
- DSCKBFOEVNZHSD-UHFFFAOYSA-N 5-(2-fluorophenyl)-7-iodopyrazolo[3,4-i][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC(I)=C1N=NC=C12 DSCKBFOEVNZHSD-UHFFFAOYSA-N 0.000 claims description 2
- YMWYFETZSIACMI-UHFFFAOYSA-N 5-(2-fluorophenyl)-7-nitropyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1F YMWYFETZSIACMI-UHFFFAOYSA-N 0.000 claims description 2
- QHRSESMSOJZMCO-UHFFFAOYSA-N 5-methyl-3-phenyl-1h-pyrazole Chemical compound N1C(C)=CC(C=2C=CC=CC=2)=N1 QHRSESMSOJZMCO-UHFFFAOYSA-N 0.000 claims description 2
- VDFDWUJTYQVVKI-UHFFFAOYSA-N 7-bromo-3-methyl-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(Br)C=C2C=1C1=CC=CC=C1 VDFDWUJTYQVVKI-UHFFFAOYSA-N 0.000 claims description 2
- XOAWOGAPHMLLFE-UHFFFAOYSA-N 7-chloro-3-methyl-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(Cl)C=C2C=1C1=CC=CC=C1 XOAWOGAPHMLLFE-UHFFFAOYSA-N 0.000 claims description 2
- VIRZTGGBXATKRK-UHFFFAOYSA-N 7-chloro-5-(2-fluorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(Cl)C=C2C=1C1=CC=CC=C1F VIRZTGGBXATKRK-UHFFFAOYSA-N 0.000 claims description 2
- HQYMNMKHMKIDEA-UHFFFAOYSA-N 7-chloro-5-(2-fluorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC(Cl)=C1N=NC=C12 HQYMNMKHMKIDEA-UHFFFAOYSA-N 0.000 claims description 2
- FDXOEZIOEKWNEC-UHFFFAOYSA-N 7-chloro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C(Cl)=CC2=C1C1=CC=CC=C1 FDXOEZIOEKWNEC-UHFFFAOYSA-N 0.000 claims description 2
- YYNADVCNWNNESS-UHFFFAOYSA-N 7-fluoro-3-methyl-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(F)C=C2C=1C1=CC=CC=C1 YYNADVCNWNNESS-UHFFFAOYSA-N 0.000 claims description 2
- HNNKBZNZOZXPSW-UHFFFAOYSA-N 7-fluoro-5-(2-fluorophenyl)-3-methylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(F)C=C2C=1C1=CC=CC=C1F HNNKBZNZOZXPSW-UHFFFAOYSA-N 0.000 claims description 2
- SAYYEHPNKHRUPG-UHFFFAOYSA-N 7-fluoro-5-(2-fluorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine Chemical compound FC1=CC=CC=C1C1=NC=CN=C2C1=CC(F)=C1N=NC=C12 SAYYEHPNKHRUPG-UHFFFAOYSA-N 0.000 claims description 2
- IZGJNHSAHZFTKD-UHFFFAOYSA-N 7-iodo-3-methyl-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N=1C(C)=CN=C2C3=CN=NC3=C(I)C=C2C=1C1=CC=CC=C1 IZGJNHSAHZFTKD-UHFFFAOYSA-N 0.000 claims description 2
- VYCSQLMGSOJUFC-UHFFFAOYSA-N 7-nitro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1 VYCSQLMGSOJUFC-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- KXODDHVDMALSCS-UHFFFAOYSA-N ethyl 5-(2-fluorophenyl)pyrazolo[3,4-i][1,4]benzodiazepine-7-carboxylate Chemical compound N1=CC=NC2=C3C=NN=C3C(C(=O)OCC)=CC2=C1C1=CC=CC=C1F KXODDHVDMALSCS-UHFFFAOYSA-N 0.000 claims description 2
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- RIRZYXPHINXCOM-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)-7-nitro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=C(C=2C=C3OCOC3=CC=2)C=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1 RIRZYXPHINXCOM-UHFFFAOYSA-N 0.000 claims 1
- FNKKKRDENFXAQL-UHFFFAOYSA-N 3-(1h-imidazol-2-yl)-7-nitro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C=CC=CC=2)N=C1C1=NC=CN1 FNKKKRDENFXAQL-UHFFFAOYSA-N 0.000 claims 1
- KIIGCLAYQHXZPJ-UHFFFAOYSA-N 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-nitro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound N1=C(C=2C=C3OCCOC3=CC=2)C=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C1C1=CC=CC=C1 KIIGCLAYQHXZPJ-UHFFFAOYSA-N 0.000 claims 1
- KBYINRVXHADDMT-UHFFFAOYSA-N 3-(2-fluorophenyl)-7-nitro-5-phenylpyrazolo[3,4-i][1,4]benzodiazepine Chemical compound C1=NC2=C3C=NN=C3C([N+](=O)[O-])=CC2=C(C=2C=CC=CC=2)N=C1C1=CC=CC=C1F KBYINRVXHADDMT-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/22—Sulfur atoms
Abstract
具有式(I)结构的新的吡唑并苯并二氮䓬及其药物可接受的盐,其中R<sup>1</sup>、R<sup>2</sup>、R<sup>3</sup>和R<sup>4</sup>如上文所定义,它能够抑制依赖于细胞周期蛋白的激酶(CDK),特别是CDK2,它是用于治疗或控制细胞增殖疾病的抗增殖药物,特别是用来治疗或控制乳腺癌、结肠癌、肺癌和前列腺癌。
Description
本发明涉及能抑制依赖于细胞周期蛋白的激酶(CDK),特别是CDK2的新型吡唑并苯并二氮。这些化合物和它们药物可接受的盐以及所述化合物的前体为抗增生剂,被用于治疗或控制细胞增生疾病,特别是癌症。本发明还涉及含有这些化合物的药物组合物,以及用于治疗和/或预防癌症的方法,特别是治疗或控制实体肿瘤。本发明的化合物特别用于治疗或控制乳腺癌、结肠癌、肺癌和前列腺癌。本发明还涉及用于制备上述抗增生剂的中间体。
不受控制的细胞增生是癌症的特点。癌症肿瘤细胞通常是直接或间接调控细胞分裂周期遗传基因受到某种程度的损伤。
依赖于细胞周期蛋白的激酶(CDK)是对控制细胞周期特别重要的酶。这些酶能调节细胞周期不同阶段间的转变,如从G1阶段进化到S阶段(活性DNA合成的时期),或从G2阶段进化到M阶段,在该阶段出现有丝分裂和细胞分裂。
CDK由起催化作用的CDK亚基和起调节作用的细胞周期蛋白亚基组成。细胞周期蛋白亚基是CDK活性的关键调节器,其中每种CDK与细胞周期蛋白特定的亚型相作用:例如细胞周期蛋白A(CDK1,CDK2)。不同的激酶/细胞周期蛋白对调控细胞周期特定阶段的进程。
细胞周期控制系统失常暗示着癌细胞会不受控制地生长。能抑制CDK的化合物用作抗增生治疗药物已得到很多文献的验证。
本发明涉及能抑制一种或多种CDK活性,特别是CDK2活性的吡唑并苯并二氮。这些化合物被用于治疗癌症,特别是实体肿瘤。具体地,本发明的化合物特别用于治疗或控制乳腺癌、结肠癌、肺癌和前列腺癌。本发明还涉及用于制备上述抗增生剂的中间体。
本发明的化合物为下式I的化合物:
其中
R1为氢,-NO2,-CN,-卤素,-OR5,-R6OR7,-COOR7,-CONR8R9,-NR10R11,-NHCOR12,-NHSO2R13,或任选被羟基和/或卤素取代的直链低级烷基;
R2和R4分别独立为氢,-卤素,-NO2,-CF3,或直链低级烷基;
R3为氢,环烷基,芳基,杂环,杂芳基,-COOR7,-CN,烯基,-CONR8R9,炔基,或任选被羟基、-OR9、F和/或芳基取代的低级烷基;
R5为任选被卤素取代的低级烷基;
R6为低级烷基;
R7为氢或低级烷基;
R8和R9分别独立为氢或其本身任选被羟基和/或NH2取代的低级烷基;或者R8和R9可以形成任选被羟基、-NH2、和/或低级烷基取代的五元或六元杂环;
R10、R11和R12分别独立为氢或低级烷基;
R13为任选被卤素和/或-NR14R15取代的低级烷基;以及
R14和R15分别独立为氢或任选被卤素取代的低级烷基;或者-NR14R15为杂环。
并且,本发明涉及式I化合物的前体药物和药物活性代谢物,以及上述化合物的药物可接受的盐。
本发明还进一步涉及式I化合物、或式I化合物的前体药物和药物活性代谢物、以及上述化合物的药物可接受的盐作为药物的应用;本发明还涉及含有药物有效量的任何一种或多种上述化合物或其药物可接受的盐或前体药物,和药物可接受的载体或赋型剂。
本发明还涉及式I化合物、或式I化合物的前体药物和药物活性代谢物、以及上述化合物的药物可接受的盐在制备用于治疗实体肿瘤,具体是乳腺癌、结肠癌、肺癌和前列腺癌,更具体是乳腺癌或结肠癌的药物中的应用。
在本文中,下列术语具有如下定义。
“芳基”指具有5至10个原子并由1或2个环组成的芳香基。芳基的例子包括苯基和1-或2-萘基。
“烯基”指含有双键的具有2-6个碳原子,优选2-4个碳原子的直链或支链、取代或未取代的脂肪族不饱和烃。典型的烯基包括乙烯、丙烯、异丙烯、丁烯等。优选的烯基为直链烯基。
“炔基”指含有叁键的具有2-6个碳原子,优选2-4个碳原子的直链或支链、取代或未取代的脂肪族不饱和烃。典型的烯基包括乙炔等。优选的炔基为直链炔基。
“环烷基”指含有3至8个原子的非芳香的部分或完全饱和的环状脂肪烃。环烷基的例子包括环丙基、环丁基、环戊基和环己基。
“有效量”指至少一种式I化合物或其药物可接受的盐、前体药物或代谢物的量,其能够明显抑制包括人肿瘤细胞系的肿瘤细胞的增生。
“卤素”指氟,氯,溴或碘。优选的卤素为氟和氯。
“杂芳基”是具有5至10个原子、1或2个环、并含有一个或多个杂原子的芳香基。杂芳基的例子有2-、3-或4-吡啶基,四唑基,噁二唑基,吡嗪基,喹啉基,吡咯基和咪唑基。
“杂原子”指选自N、O和S的原子。
“杂环”指3-至10-元非芳香的部分或完全饱和的烃基,如四氢喹啉基,其含有一个或两个环,至少一个杂原子。
“IC50”指抑制50%的具体测定的活性所需要的特定的吡唑并苯并二氮的浓度,IC50尤其可以采用下文实施例4所描述的方法所测定。
“低级烷基”指具有1至6个、优选1至4个碳原子的直链或支链、取代或未取代的饱和脂肪烃。典型的低级烷基包括甲基,乙基,丙基,异丙基,丁基,叔丁基,2-丁基,戊基,己基等。
“药物可接受的盐”指保留了式I化合物的生物效力和性质,并与合适的非毒性有机或无机酸或有机或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐的例子包括从无机酸如盐酸、氢溴酸、氢碘酸、硫酸、氨磺酸、磷酸和硝酸衍生的盐,和从有机酸如对甲苯磺酸、水杨酸、甲磺酸、草酸、琥珀酸、柠檬酸、苹果酸、乳酸、富马酸等衍生的盐。碱加成盐的例子包括从铵、钾、钠和季铵的氢氧化物(例如氢氧化四甲基铵)衍生的盐。
“药学上可接受的”如药学上可接受的载体、赋形剂、前体药物等,指药理学上可接受的、并对给药具体化合物的患者基本上无毒性。
“药学活性代谢物”指药学上可接受并且有效的式I化合物的代谢产物。
“前体药物”指在生理条件下或通过溶剂分解可以转化为任何式I化合物或转化为式I化合物的药物可接受的盐的化合物。当对患者给药时,前体药物可以是无活性的,但其在体内转化为式I的活性化合物。
“取代的”如取代的烷基,除非另外说明,指取代基可以在一个或多个位置存在,在每个位置取代基独立地选自具体的选项。
化合物
在一个实施方案中,本发明涉及具有下式的化合物:
和式I化合物的前体药物和药物活性代谢物,以及上述化合物的药物可接受的盐,其中R1至R15如上所定义。
在式I化合物的一个优选实施方案中,R1为氢,NO2,CN,CONH2,卤素或未取代的低级烷基。优选的低级烷基为甲基和乙基。更优选地,R1为NO2,CN,或CONH2。R1优选在7-位或8-位。
在式I化合物的另一个优选实施方案中,R1在2’位,为氢或卤素。
在式1化合物的另一个优选实施方案中,R3为未取代的低级烷基,羟基低级烷基,环烷基,杂环,或杂芳基。优选的低级烷基为甲基、乙基和羟基甲基。优选的环烷基为未取代的C3-C5。
在式I化合物的另一个优选实施方案中,R4在4’位,为氢或卤素,更优选R4为氢。
在式I化合物的另一个优选实施方案中,R5和R6独立为甲基或乙基,它们每一个可以任选被卤素取代。更具体地,R5为三氟甲基。
在式I化合物的另一个优选实施方案中,R7为氢、甲基或乙基。
在式I化合物的另一个优选实施方案中,R8和R9分别独立为氢、甲基、乙基或羟乙基。当R8和R9形成杂环时,优选的杂环基团为六元、未取代、最优选包括两个杂原子的基团。最优选的杂原子选自O和N。
在式I化合物的另一个优选实施方案中,R10、R11和R12分别独立为氢、甲基或乙基。
在式I化合物的另一个优选实施方案中,R13为可以任选被卤素取代的低级烷基,最优选R13为甲基、乙基或三氟甲基。
在式I化合物的另一个优选实施方案中,R14和R15分别独立为氢、甲基、乙基或杂环。优选的杂环为包括至少一个氮原子的3-7元环。
下列的中间体也是按照本发明的其它优选化合物的例子:
其中R1、R2和R4如上所定义。
其中,在以上各式中,每个R1、R2、R3和R4如上文所定义。这些中间体用于合成式I化合物。
本文公开的和通过上式所包括的化合物可以表现出互变异构或结构异构现象。本发明还包括这些化合物的任何互变异构或结构异构型,或者这些异构型的混合物,并且不限于以上结构式所示的任何一种互变异构或结构异构型。
式I化合物的合成
本发明的化合物可以通过本领域公知的方法制备。在实施例中给出了用于合成这些化合物的适当方法。一般地,这些化合物可以按照下面给出的合成路线进行制备。
合成路线1
R3=H
a)Lawesson试剂反应(已知的对于大多数取代基的反应)
b)与Me2N-CH(OEt)2反应
c)与肼反应。
化合物可以通过商业来源获得,或通过本领域公知的方法合成。
合成路线2
R3不为H
a)Lawesson试剂反应(已知对于大多数取代基的反应)
d)在碱存在下、优选在哌啶存在下与R3-CHO反应
c)与肼反应
e)二氢吡唑氧化成吡唑(在空气中、DMSO、RT-150℃的条件下,或在空气和碱(Cs2CO3/DMF)存在下)。
合成路线2
R3不为H的其它合成路线
a)Lawesson试剂反应(已知对于大多数取代基的反应)
f)在碱、优选在二氮杂双环十一碳烷或2,2,6,6-四甲基哌啶存在下,与R3-CHO反应
g)通过弱酸处理(对甲苯磺酸吡啶鎓、醋酸吡啶鎓等)或在吡啶存在下与三甲基氯硅烷回流,进行脱水
c)与肼反应
e)二氢吡唑氧化成吡唑(在空气中、DMSO、室温-150℃的条件下,或在空气和碱(Cs2CO3/DMF)存在下)。
反应路线4
R1或R3官能团的转变
其中R1’可以是如上述定义的R1的任何基团,同样地,其中R3’可以是如上述定义的R3的任何基团。
如上面反应路线4所示例,应用已知方法通过对已存在的官能团进行化学修饰,可以获得几种取代基。例如,当所需的R1=NH2,该取代可以通过还原相应的硝基获得。同样地,当所需的R1=NHR’(其中R’=-COR12,-SO2R13,或-R10R11),该取代可以通过相应的R1=NH2化合物与酸性卤化物或酸酐反应获得。当所需的R1=CONRR”(其中R=氢或低级烷基,R”=低级烷基),该取代可以通过在钯催化剂存在下,R1=I的相应化合物与一氧化碳和伯或仲胺反应获得。
另外,如果起始原料中的R3为CO2Et,标准的化学修饰可以用于制备具有下式相应R3基团的化合物:
CH2OH(还原);CHO(部分还原);CH2NMe2(醛的还原氨化);CH2OMe(醇的烷化);CH=CH2(醛的烯化);CONRR”(其中R=H或低级烷基,R”=H或低级烷基,与相应的胺HNRR”进行氨解,其中R=H或低级烷基,R”=H或低级烷基);CONHNHR(其中R=H、低级烷基或芳基)(肼解-与肼反应);CN(酰胺CONH2的脱水)。
在上述反应路线中,化合物1可以商业购买,例如从Sigma购买,或者通过本领域公知的方法容易地合成。因此,化合物2可以通过Sternbach等J.Org.Chem.29:231(1964)的方法或通过与Lawesson试剂进行反应,从相应的内酰胺(化合物1)制备。
组合物/配方
在另外的实施方案中,本发明涉及一种药物组合物,所述组合物包括至少一种式I化合物或其前体药物,或者式I化合物或其前体药物的药物可接受的盐。
这些组合物可以口服给药,例如以片剂、包衣片、糖衣丸、硬或软明胶胶囊、溶液剂、乳剂、混悬液的的形式。它们还可以直肠给药,例如以栓剂的形式,或非胃肠给药,例如以注射液的形式。
包含式I化合物、这类化合物的前体药物或其盐的本发明药物组合物可以用本专业已知的方法生产,例如通过常规混合、制胶囊、溶解、制粒、乳化、捕集、制糖丸、或冻干法制备。这些药物制剂可以用治疗惰性的无机或有机载体配制。乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐可以用作片剂、包衣片剂、糖丸和硬胶囊的载体。软胶囊的合适载体有植物油、蜡、脂肪。根据活性物质的性质,在软胶囊的情况下通常不用载体。生产溶液剂或糖浆所用的载体是水、多元醇、蔗糖、转化糖和葡萄糖。注射液的合适载体是水、醇、多元醇、甘油、植物油、磷脂和表面活性剂。栓剂的合适载体是天然或硬化的油、蜡、脂肪和半固体多元醇。
该药物制剂还可以含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、改变渗透压的盐、缓冲剂、包衣剂或抗氧化剂。它们也可以含有其它有治疗价值的物质,包括式I化合物之外的其它活性成分。
剂量
如上所述,式I化合物、其前体药物、和其盐、以及含有这些化合物的药物组合物用于治疗或控制细胞增生疾病,特别是肿瘤疾病。这些化合物和含有所述化合物的配方特别治疗或控制实体肿瘤,如例如乳腺癌和结肠癌。
按照本发明化合物的治疗有效量指能够有效预防、减缓或改善被治疗患者疾病症状或延长治疗患者生存时间的量。本领域普通技术人员可以确定治疗有效量。
式I化合物的治疗有效量或剂量可以在很宽的限制内变化,并可以在各种具体情况下根据个体需要进行调节。一般说来,在对体重约70kg的成人口服或肠胃外给药的情况下,日剂量约10mg至约10000mg,优选约200mg至约1000mg将是合适的,尽管当特殊情况时上限可以被超过。日剂量可以分单剂量或多剂量给药,或者对于肠胃外给药,可以连续灌注。
实施例
本发明的化合物可以按照已知技术合成,如例如上面给出的一般合成路线。下列实施例描述了用于制备本发明化合物和配方的优选方法。
在下列实施例中,在ppm水平给出了相对于四甲基硅烷的NMR数据,溶剂和光谱数据如下所述。
实施例1:按照反应路线1制备的吡唑
步骤a:内酰胺(化合物1)与Lawesson试剂反应,制备硫代内酰胺(Thiolactam)(化合物2)
1.1化合物A1:R1=H,R1=F,R4=H
在75℃下,向5.085g(20mmol)内酰胺1(其中R1=H,R1=F,R4=H)的50mL二甲氧基乙烷中,加入8.9g(22mmol)Lawesson试剂(2,4-双(4-甲氧基苯基)-1,3-二硫代-2,4-二phosphetane-2,4-二硫化物;Pedersen,B.S.;Scheibye,S.;Nilsson,N.H.;Lawesson,S.-O.,Bull.Soc.Chim.Belg.,1978,87:223.)。将混合物搅拌30分钟,冷却,倒入10%碳酸氢钠水溶液中。将该水性混合物用二氯甲烷萃取,将萃取液用水洗涤,无水硫酸钠干燥,在减压下过滤并浓缩。将残渣在二氯甲烷-甲醇中重结晶,得到4.0g化合物A1(硫代内酰胺2)。
1H nmr:(DMSO-d6,300mHz)12.56(s,1H,NH),7.10-7.65(in,8H),4.59(s,2H)。
1.2化合物A2:R1=F,R2=R4=H
化合物A2按照与上述制备化合物A1相同的方法进行制备。1H nmr:(DMSO-d6,300mHz)12.50(s,1H,NH),7.37-7.56(m,7H),7.06(dd,J=3,9Hz,1H),4.60(br s,2H)。
步骤b:硫代内酰胺2与DMF乙缩醛反应,制备二甲基氨基亚甲基衍生物3:
1.3化合物A3:R1=Cl,R2=Cl,R4=H
0.999g(3.1mmol)硫代内酰胺2(R1=Cl,R2=Cl,R4=H)的10mL四氢呋喃和10mL二甲基甲酰胺二乙基乙缩醛的溶液在室温下搅拌2小时。在减压下除去挥发物,留下桔红色固体残渣。从己烷-乙酸乙酯中结晶,得到0.716g化合物A3(衍生物3,其中R1=Cl,R2=Cl,R4=H),其为红色固体,mp 196~198℃1H nmr:(DMSO-d6,400mHz)10.21(s,1H),7.84(s,1H),7.43-7.56(m,4H),7.32(dd,J=3,9Hz,1H),7.00(d,J=9Hz,1H),6.60(d,J=3Hz,1H),3.27(s,6H)。
步骤c:二甲基氨基亚甲基衍生物3转化为吡唑4
1.4化合物A4:R1=Cl,R2=Cl,R3=R4=H
5-(2-氯苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮
向0.265g(0.71mmol)在10mL干燥二氯甲烷的溶液中加入大约39.8毫升(1.27mmole)无水肼。将混合物在氩气下搅拌85分钟,然后溶在二氯甲烷中,用水洗涤,无水硫酸钠干燥,在减压下过滤并浓缩,得到0.219g化合物A4(吡唑,其中R1=Cl,R2=Cl,R4=H)棕褐色固体。分析样品通过薄层硅胶过滤,用乙酸乙酯洗脱,然后在乙酸乙酯中重结晶。mp>300℃1H nmr:(DMSO-d6,400mHz)12.07(s,1H,NH),8.03(s,1H,NH),7.58(s,1H),7.4-7.5(m,4H),7.17(dd,J=2,9Hz,1H),6.79(d,J=9Hz,1H),6.25(s,1H)。
下列吡唑(化合物4)按照上述合成路线1步骤a-c所描述进行制备:
1.5化合物A5:R1=NO2,R2=Cl,R3=H,R4=H
5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)9.16(s,1H,NH),7.90(dd,J=2,8Hz,1H),7.4-7.6(m,5H),7.08(d,J=2Hz,1H),6.75(d,J=8Hz,1H).
1.6化合物A6:R1=Cl,R2=H,R3=H,R4=H
5-苯基-7-氯-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,200mHz)7.97(s,1H,NH),7.62(s,1H),7.35-7.60(m,5H),7.29(dd,J=2,9Hz,1H),6.93(d,J=9Hz,1H),6.60(d,J=2Hz,1H).
1.7化合物A7:R1=Cl,R2=F,R3=H,R4=H
5-(2-氟苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)12.10(s,1H,NH),8.01(s,1H),7.60(s,1H),7.5(m,2H),7.18-7.33(m,3H),6.83(d,J=8Hz,1H),6.47(s,1H).
1.8化合物A8:R1=Cl,R2=Cl,R3=H,R4=Cl
5-(2,4-二氯苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)12.09(s,1H,NH),8.05(s,11H,NH),7.68(s,1H),7.56(s,1H),7.52(d,J=10Hz,1H),7.48(d,J=10Hz,1H),7.19(dd,J=2,9Hz,1H),6.78(d,J=9Hz,1H),6.27(d,J=2Hz,1H).
1.9化合物A9:R1=H,R2=H,R3=H,R4=H
5-苯基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.04(s,1H),7.77(s,1H),7.58(s,1H),7.32-7.47(m,5H),7.22(dt,J=2,8Hz,1H),6.92(d,J=8Hz,1H),6.76(d,J=8Hz,1H),6.67(dd,J=1,8Hz,1H).
1.10化合物A10:R1=H,R2=F,R3=H,R4=H
5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,200mHz)12.00(s,1H,NH),7.79(s,1H),7.32-7.56(m,3H),7.00-7.32(m,3H),6.78(d,J=6Hz,1H),6.64(t,J=6Hz,1H),6.48(d,J=6Hz,1H).
1.11化合物A11:R1=F,R2=F,R3=H,R4=H
5-(2-氟苯基)-7-氟-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,200mHz)12.10(s,1H,NH),7.85(s,1H),7.4-7.7(m,3H),7.18-7.39(m,2H),7.05(m,1H),6.86(m,1H),6.26(br d,J=8Hz,1H).
1.12化合物A12:R1=CH3O,R2=Cl,R3=H,R4=H
5-(2-氯苯基)-7-甲氧基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,200mHz)12.00(s,1H,NH),7.35-7.60(m,5H),6.81(d,J=8Hz,1H),6.75(d,J=8Hz,1H),5.89(s,1H),3.46(s,3H).
1.13化合物A13:R1=NO2,R2=F,R3=H,R4=H
5-(2-氟苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.14(s,1H,NH),9.06(s,1H,NH),7.89(dd,J=2,9Hz,1H),7.55(s,1H),7.4-7.5(m,2H),6.76(d,J=9Hz,1H).
1.14化合物A14:R1=CH3SO2,R2=H,R3=H,R4=H
5-苯基-甲磺酰基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)12.18(s,1H,NH),8.54(s,1H,NH),7.72(dd,J=2,9Hz,1H),7.64(s,1H),7.43(m,5H),7.14(d,J=2,Hz,1H),7.06(d,J=9Hz,1H),3.01(s,3H).
1.15化合物A15:R1=CN,R2=F,R3=H,R4=H
5-(2-氟苯基)-7-氰基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.16(s,1H,NH),8.63(s,1H,NH),7.59(s,1H),7.4-7.58(m,3H),7.2-7.37(m,2H),6.82(dd,J=2,8Hz,1H),6.78(s,1H).
1.16化合物A16:R1=NO2,R2=H,R3=H,R4=H
5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)12.19(s,1H,NH),8.96(s,1H,NH),8.03(dd,J=2,9Hz,1H),7.62(s,1H),7.35-7.5(m,6H),6.94(d,J=9Hz,1H).
1.17化合物A17:R1=NO2,R2=CF3,R3=H,R4=H
5-(2-三氟甲基苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.12(s,1H,NH),9.18(s,1H,NH),7.45-7.9(m,6H),7.00(s,1H),6.71(d,J=9Hz,1H).
1.18化合物A18:R1=CO2CH3,R2=H,R3=H,R4=H
5-苯基-7-甲氧甲酰基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.15(s,1H,NH),8.42(s,1H,NH),7.78(dd,J=2,9Hz,1H),7.62(s,1H),7.35-7.45(m,5H),7.29(d,J=2Hz,1H),6.93(d,J=9Hz,1H),3.66(s,3H).
1.19化合物A19:R1=I,R2=F,R3=H,R4=H
5-(2-氟苯基)-7-碘-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.09(s,1H,NH),7.99(s,1H,NH),7.58(s,1H),7.4-7.55(m,3H),7.19-7.35(m,2H),6.76(s,1H),6.62(d,J=8Hz,1H).
1.20化合物A20:R1=CO2Et,R2=F,R3=H,R4=H
5-(2-氟苯基)-7-乙氧甲酰基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.08(s,1H,NH),8.50(s,1H,NH),7.62(d,J=8Hz,1H),7.57(s,1H),7.4-7.5(m,2H),7.18-7.35(m,2H),7.14(s,1H),6.80(d,J=8Hz,1H),4.15(q,J=6Hz,2H),1.17(t,J=6Hz,3H).
1.21化合物A21:R1=H,R2=Cl,R3=H,R4=H
5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.95(s,1H),8.40(s,1H),7.84(s,1H),7.53(s,1H),7.38-7.48(m,4H),7.09(t,J=8Hz,1H),6.78(d,J=8Hz,1H),6.61(t,J=8Hz,1H),6.34(d,J=8Hz,1H).
实施例2:按照合成路线2和3将硫代内酰胺2转化成取代的吡唑7
2.1化合物B1:R1=NO2,R2=Cl,R3=吡咯基,R4=H;合成路线2
3-(2-吡咯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
0.995g(3mmol)硫代内酰胺2(R1=NO2,R2=Cl,R3=吡咯基,R4=H)、0.571g(6mmol)吡咯-2-醛、0.383g(4.5mmol)(Aldrich)哌啶和10mL二甲氧基乙烷的混合物氩气下搅拌2小时。将混合物置于乙酸乙酯中,连续用0.1M硫酸、水和盐水洗涤,无水硫酸钠干燥,过滤,减压下浓缩。通过硅胶色谱分离相应的烯烃(用己烷/乙酸乙酯(1∶1)洗脱)红色固体(0.309g),直接用于下一步。将烯烃5(0.309g)溶解于6mL二甲亚砜中,在氩气下与72.5mg(2.2mmol)肼反应。20分钟后,将混合物置于乙酸乙酯中,连续用水和盐水洗涤,无水硫酸钠干燥,过滤,减压下浓缩,得到二氢吡唑6(0.296g)。将6的混合物溶解于二甲亚砜中,在空气中130℃下加热2小时,冷却,置于乙酸乙酯中,连续用水和盐水洗涤。萃取物用无水硫酸钠干燥,过滤,减压下浓缩。通过硅胶色谱(用己烷/乙酸乙酯25/75洗脱)纯化产物化合物B1。
1H nmr:(DMSO-d6,300mHz)12.12(s,1H,NH),10.39(s,1H,NH),9.07(s,1H,NH),7.96(dd,J=2,8Hz,1H),7.4-7.65(m,4H),7.15(d,J=2Hz,1H),6.90(s,1H),6.79(d,J=8Hz,1H),6.48(s,1H),6.12(d,J=2Hz,1H).
2.2化合物B2:R1=NO2,R2=Cl,R3=CO2Et,R4=H;合成路线3
3-乙氧甲酰基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
5.0g(15.1mmol)硫代内酰胺2(R1=NO2,R2=Cl)、6mL 50%乙醛酸乙酯的甲苯溶液、4.5mL(31mmol)二氮杂双环十一碳烷和100mL二甲氧基乙烷的混合物氩气、室温下搅拌30分钟。将混合物用0.005M H2SO4酸化,乙酸乙酯萃取。得到的萃取物用无水硫酸钠干燥,过滤,减压下浓缩。通过硅胶色谱(用己烷/乙酸乙酯60/40洗脱)洗脱,得到非对映异构体的混合物(5.6g)羟醛加成物8。
将4.7g(10.8mmol)上面得到的羟醛加成物8、100mL吡啶和6.9mL(54.4mmol)三甲基氯硅烷的混合物在室温下搅拌10分钟,然后在120℃下加热1.5小时。将混合物冷却,加入到1L乙酸乙酯中,连续用水和盐水洗涤。乙酸乙酯层用无水硫酸钠干燥。在减压下过滤和蒸发掉挥发性物质后,通过硅胶过滤粗品残渣,用己烷/乙酸乙酯(1∶1)洗脱,得到4.3g烯烃5。
将上述得到的4.3g烯烃5的210mL二氯甲烷溶液用0.68mL(21.6mmol)无水肼搅拌30分钟。然后将混合物置于水中分配,水相用二氯甲烷萃取。合并萃取液,用无水硫酸钠干燥,减压下过滤和浓缩。将二氢吡洛6的混合物中含有的残渣溶解于50mL二甲亚砜中,在空气中130℃下加热3小时。将反应混合物冷却,加入到乙酸乙酯中,用水洗涤。用无水硫酸钠干燥有机层,减压下过滤和浓缩。通过硅胶色谱分离产物,己烷/乙酸乙酯(40/60)洗脱,得到0.580g化合物B2(R1=NO2,R2=Cl,R3=CO2Et,R4=H)。
1H nmr:(DMSO-d6,400mHz)13.33(s,1H),9.15(s,1H),8.02(dd,J=2,9Hz,11-1),7.46-7.55(m,4H),7.18(d,J=2Hz,1H),6.89(d,J=9Hz,1H),4.25(q,J=7Hz,2H),1,27(t,J=7Hz,3H).
按照上述合成路线2或3制备下列吡唑(化合物7):
2.3化合物B3:R1=NO2,R2=Cl,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.85(s,1H,NH),9.04(s,1H,NH),7.83(dd,J=2,9Hz,1H),7.39-7.52(m,4H),7.05(d,J=2Hz,1H),6.69(d,J=9Hz,1H),1.98(s,3H).
2.4化合物B4:R1=NO2,R2=Cl,R3=CH2CH3,R4=H;(合成路线2)
3-乙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.91(s,1H,NH),9.05(s,1H,NH),7.85(dd,J=2,8Hz,1H),7.35-7.58(m,4H),7.04(d,J=2Hz,1H),6.71(d,J=8Hz,1H),2.41(q,J=7Hz,2H),1.06(t,J=7Hz,3H).
2.5化合物B5:R1=NO2,R2=Cl,R3=CH2CH2Ph,R4=H;(合成路线2)
3-(2-苯基乙基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,200mHz)11.95(s,1H,NH),9.05(s,1H,NH),7.82(dd,J=2,8Hz,1H),7.05-7.60(m,10H),6.70(d,J=8Hz,1H),2.82(m,2H),2.64(m,2H).
2.6化合物B6:R1=NO2,R2=Cl,R3=i-Pr,R4=H;(合成路线2)
3-(1-甲基乙基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.90(s,1H,NH),9.02(s,1H,NH),7.84(dd,J=2,9Hz,1H),7.35-7.55(m,4H),7.04(d,J=2Hz,1H),6.74(d,J=9Hz,1H),2.86(sept,j=9Hz,1H),1.14(d,J=9Hz,6H).
2.7化合物B7:R1=CN,R2=F,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-3-腈
1H nmr:(DMSO-d6,300mHz)12.05(s,1H,NH),8.55(s,1H,NH),7.45(m,3H),7.25(m,2H),6.78(d,J=8Hz,1H),6.71(s,1H),2.03(s,3H).
2.8化合物B8:R1=NO2,R2=Cl,R3=CH2Ph,R4=H;(合成路线2)
3-(苯基甲基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.08(s,1H,NH),9.08(s,1H),7.85(d,J=9Hz,1H),7.40-7.56(m,4H),7.16-7.34(m,5H),7.06(brs,1H),6.71(d,J=9Hz,11H),3.71(s,2H).
2.9化合物B9:R1=CO2Et,R2=F,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氟苯基)-7-乙氧甲酰基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.81(s,1H),8.37(s,1H),7.59(dd,J=2,9Hz,1H),7.39-7.51(m,2H),7.16-7.31(m,2H),7.09(s,1H),6.74(d,J=9HZ,1H),4.08(q,J=7Hz,2H),2.04(s,3H),1.12(t,J=7Hz,3H).
2.10化合物B10:R1=NO2,R2=Cl,R3=5-(4-Me)-吡唑基,R4=H;(合成路线2)
3-(4-甲基吡唑-5-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)12.58(s,1H),9.26(s,1H),8.75(brs,1H),7.95(d,J=8Hz,1H),7.42-7.6(m,5H),7.12(s,1H),6.81(d,J=8Hz,1H),2.32(s,3H).
2.11化合物B11:R1=NO2,R2=Cl,R3=CH2-iPr,R4=H;(合成路线2)
3-(2-甲基丙基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)11.91(s,1H),9.06(s,1H),7.87(dd,J=2,9Hz,1H),7.4-7.56(m,4H),7.08(d,J=2Hz,1H),6.74(d,J=9Hz,1H),2.28(d,J=7Hz,2H),1.89(n,J=7Hz,1H),0.88(d,J=7Hz,6H).
2.12化合物B12:R1=NO2,R2=Cl,R3=CF3,R4=H;(合成路线3)
3-三氟甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(CDCl3+DMSO-d6,300mHz)7.98(dd,J=2,9Hz,1H),7.2-7.6(m,6H),7.02(br s,1H),6.62(d,J=9Hz,1H).
2.13化合物B13:R1=NO2,R2=Cl,R3=1-噻唑基,R4=H;(合成路线3)
3-(1-噻唑基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)13.08(s,1H),9.21(s,1H),7.88-7.92(m,2H),7.84(d,J=3Hz,1H),7.42-7.62(m,4H),7.12(d,J=2Hz,1H),6.79(d,J=8Hz,1H).
2.14化合物B14:R1=NO2,R2=Cl,R3=4-咪唑基,R4=H;(合成路线2)
3-(4-咪唑基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)12.33(s,1H),12.29(s,1H),9.07(s,1H),7.90(dd,J=2,9Hz,1H),7.76(S.1H),7.44-7.63(m,4H),7.35(s,1H),7.11(d,J=2Hz,1H),6.78(d,J=9Hz,1H).
2.15化合物B15:R1=NO2,R2=Cl,R3=2-吡唑基,R4=H;(合成路线2)
3-(2-吡唑基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)13.11(s,1H),12.48(s,1H),9.12(s,1H),7.93(d,J=9Hz,1H),7.76(s,1H),7.39-7.60(m,4H),7.11(s,1H),6.78(d,J=9Hz,1H),6.59(s,1H).
2.16化合物B16:R1=NO2,R2=Cl,R3=3-吡唑基,R4=H;(合成路线2)
3-(3-吡唑基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)13.09(s,1H),12.31(s,1H),9.13(s,1H),7.80-8.05(m,4H),7.40-7.62(m,3H),7.13(s,1H),6.78(d,J=9Hz,1H).
2.17化合物B17:R1=NO2,R2=Cl,R3=CH(Me)CH2Me,R4=H;(合成路线2)
3-(1-甲基丙基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.90(s,1H),9.04(s,1H),7.85(dd,J=2,9Hz,1H),7.38-7.55(m,4H),7.05(d,J=2Hz,1H),6.72(d,J=9Hz,1H),2.65(m,1H),1.52(m,2H),1.13(d,J=7Hz,3H),0.79(t,J=8Hz,3H).
2.18化合物B18:R1=MeO,R2=Cl,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氯苯基)-7-甲氧基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.69(s,1H),7.34-7.50(m,5H),6.77(dd,J=2,9Hz,1H),6.72(d,J=9Hz,1H),5.86(d,J=9Hz,1H),5.86(d,J=2Hz,1H),3.44(s,3H),2.05(s,3H).
2.19化合物B19:R1=Cl,R2=H,R3=CH3,R4=H;(合成路线2)
3-甲基-5-苯基-7-氯-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)11.85(s,1H),7.90(s,1H),7.46-7.52(m,2H),7.39-7.44(m,3H),7.29(dd,J=2,9Hz,1H),6.92(d,J=9Hz,1H),6.62(d,J=2Hz,1H),2.16(s,3H).
2.20化合物B20:R1=Cl,R2=Cl,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氯苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.78(s,1H),7.95(s,1H),7.38-7.55(m,4H),7.17(dd,J=2,9Hz,1H),6.75(d,J=9Hz,1H),6.22(d,J=2Hz,1H),2.03(s,3H).
2.21化合物B21:R1=H,R2=F,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.75(s,1H),7.69(s,1H),7.36-7.52(m,2H),7.04-7.30(m,3H),6.77(d,J=8Hz,1H),6.63(t,J=8Hz,1H),6.50(d,J=8Hz,1H),2.07(s,3H).
2.22化合物B22:R1=F,R2=H,R3=CH3,R4=H;(合成路线2)
3-甲基-5-苯基-7-氟-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.85(s,1H),7.70(s,1H),7.46-7.55(m,2H),7.35-7.43(m,2H),7.11(dt,J=3,9Hz,1H),6.92(dd,J=5,9Hz,1H),6.41(dd,J=3,10Hz,1H),2.14(s,3H).
2.23化合物B23:R1=NO2,R2=Cl,R3=苯基,R4=H;(合成路线2)
3-苯基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)12.65(s,1H),9.18(s,1H),7.95(dd,J=2,9Hz,1H),7.78(d,J=8Hz,2H),7.32-7.63(m,7H),7.14(d,J=2Hz,1H),6.85(d,J=9Hz,1H).
2.24化合物B24:R1=NO2,R2=Cl,R3=正丙基,R4=H;(合成路线2)
3-丙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)11.91(s,1H),9.06(s,1H),7.86(d,J=8Hz,1H),7.41-7.53(m,4H),7.08(s,1H),6.72(d,J=8Hz,1H),2.38(t,J=8Hz,2H),1.54(tq,J=8,7Hz,2H),0.88(t,J=7Hz,3H).
2.25化合物B25:R1=NO2,R2=Cl,R3=环丙基,R4=H;(合成路线2)
3-环丙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,400mHz)11.72(s,1H),9.05(s,1H),7.87(dd,J=2,9Hz,51H),7.41-7.55(m,4H),7.08(d,J=2Hz,1H),6.72(d,J=9Hz,1H),1.79(p,J=7Hz,1H),0.88(d,J=7Hz,4H).
2.26化合物B26:R1=F,R2=F,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氟苯基)-7-氟-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.82(s,1H),7.76(s,1H),7.41-7.58(m,2H),7.18-7.35(m,2H),7.05(dt,J=3,9Hz,1H),6.84(dd,J=6,9Hz,1H),6.25(dd,J=3,9Hz,1H),2.08(s,3H).
2.27化合物B27:R1=NO2,R2=H,R3=CH3,R4=H;(合成路线2)
3-甲基-5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮
2.28化合物B28:R1=H,R2=H,R3=CH3,R4=H;(合成路线2)
3-甲基-5-苯基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.78(s,1H),7.66(s,1H),7.47(m,2H),7.39(m,3H),7.20(dt,J=1,8Hz,1H),6.88(d,J=8Hz,1H),6.75(t,J=8Hz,1H),6.68(dt,J=1,8Hz,1H),2.14(s,3H).
2.29化合物B29:R1=I,R2=F,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氟苯基)-7-碘-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.81(s,1H),7.90(s,1H),7.39-7.57(m,3H),7.18-7.36(m,2H),6.75(s,1H),6.59(d,J=9Hz,1H),2.07(s,3H).
2.30化合物B30:R1=H,R2=Cl,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮
2.31化合物B31:R1=NO2,R2=F,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氟苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.90(s,1H),9.00(s,1H),7.87(dd,J=3,9Hz,1H),7.47(m,21-1),7.18-7.32(m,3H),6.73(d,J=9Hz,1H),2.02(s,3H).
2.32化合物B32:R1=Cl,R2=F,R3=CH3,R4=H;(合成路线2)
3-甲基-5-(2-氟苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.81(s,1H),7.96(s,1H),7.40-7.55(m,2H),7.17-7.32(m,3H),6.79(d,J=9Hz,1H),6.42(s,1H),2.08(s,3H).
2.33化合物B33:R1=I,R2=H,R3=CH3,R4=H;(合成路线2)
3-甲基-5-苯基-7-碘-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.82(s,1 H),7.85(s,1H),7.36-7.55(m,6H),6.91(d,J=2Hz,1H),6.70(d,J=9Hz,1H),2.15(s,3H).
2.34化合物B34:R1=Br,R2=H,R3=CH3,R4=H;(合成路线2)
3-甲基-5-苯基-7-溴-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)7.89(s,1H),7.49(m,2H),7.38(m,4H),6.85(d,J=9Hz,1H),6.74(d,J=2Hz,1H),2.15(s,3H).
2.35化合物B35:R1=CN,R2=F,R3=-CH2OH,R4=H;(合成路线2)
3-羟基甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-腈
实施例3:按照合成路线4进行官能团修饰
参照上述合成路线4,通过现有官能团的转化,可以很容易地得到某些化合物。下面进一步举例描述了一些官能团转化。
A.碘被羰基取代:R1=I到R1=CONRR’
3.1化合物C1:R1=CON(-CH2CH2-O-CH2CH2-),R2=F,R3=H,R4=H5-(2-氟苯基)-7-吗啉基羰基-吡唑并[3,4][1,4]苯并二氮
搅拌0.0712g(0.17mmol)吡唑4(R1=I,R2=F,R3=H,R4=H)、0.0082g(0.0012mmol)双三苯膦二氯化钯催化剂、1mL吗啉的混合物,在一氧化碳的的大气下加热(75℃)90分钟。冷却混合物,然后通过反相硅胶色谱纯化(应用水-乙腈梯度洗脱),得到0.06g化合物C1(吡唑4,其中R1=CON(-CH2CH2-O-CH2CH2-),R2=F,R3=H,R4=H)。
1H nmr:(DMSO-d6,300mHz)12.05(s,1H,NH),8.18(s,1H,NH),7.59(s,1H),7.4-7.5(m,2H),7.18-7.35(m,3H),6.84(d,J=9Hz,1H),3.25(m,8H).
下列化合物应用上述方法A制备
3.2化合物C2:R1=CONHCH2CH2OH,R2=F,R3=H,R4=H
N-(2-羟基乙基)-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺
1H nmr:(DMSO-d6,300mHz)12.08(5,1H,NH),8.20(s,1H,NH),8.16(m,1H,NH),7.61(d,J=9Hz,1H),7.57(s,1H),7.4-7.5(m,2H),7.14-7.3(m,2H),7.11(s,1H),6.89(d,J=9Hz,1H),4.63(m,1H,OH),3.40(m,2H),3.18(m,2H).
3.3化合物C3:R1=CON(CH2CH2OH)2,R2=F,R3=H,R4=H
N,N-双-(2-羟基乙基)-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺
1H nmr:(DMSO-d6,300mHz)12.10(s,1H,NH),8.11(s,1H,NH),7.59(s,1H),7.4-7.52(m,2H),7.15-7.3(m,3H),6.80(d,J=9Hz,1H),6.58(s,1H),4.65(m,2H,OH),3.30(m,8H).
B.硝基还原到氨基:R1=NO2到R1=NH2
3.4化合物C4:R1=NH2,R2=Cl,R3=CH3,R4=H
3-甲基-5-(2-氟苯基)-7-氨基-吡唑并[3,4][1,4]苯并二氮
将0.20g(0.57mmol)的吡唑7(R1=NO2,R2=Cl,R3=CH3,R4=H)的8mL乙醇溶液在室温、氢气下与阮内镍(0.5mL 50%在水中的稀浆,使用前用乙醇洗涤)搅拌。4小时后,减压过滤、浓缩混合物,得到0.177g化合物4(氨基衍生物7,其中(R1=NO2,R2=Cl,R3=CH3,R4=H)。mp.260-263℃。
1H nmr:(DMSO-d6,300mHz)11.62(s,1H),7.38-7.47(m,4H),7.07(s,s,1H),6.53(d,J=8Hz,1H),6.38(dd,J=2,9Hz,1H),5.74(d,J=2Hz,1H),4.52(s,2H),2.06(s,3H).
下列化合物应用上述方法B制备:
3.5化合物C5:R1=NH2,R2=Cl,R3=H,R4=H
5-(2-氟苯基)-7-氨基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(CD3OD,300mHz)7.35-7.55(m,5H),6.72(dd,J=3,7Hz,1H),6.62(d,J=7Hz,1H),6.13(d,J=3Hz,1H).
3.6化合物C6:R1=NH2,R2=Cl,R3=i-Pr,R4=H
3-(1-甲基乙基)-5-(2-氯苯基)-7-氨基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)11.65(2,1H),7.38-7.4(m,4H),7.08(s,1H),6.75(d,J=8Hz,1H),6.39(dd,J=2,8Hz,1H),5.74(d,J=2Hz,1H),2.98(sept,J=7Hz,1H),1.18(d,J=7Hz,6H).
C.氨基化合物的衍生化(Derivitization):R1=NH2到R1=NHR’(如上面合成路线4所定义)
3.7化合物C7:R1=NHAc,R2=Cl,R3=CH3,R4=H
N-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-乙酰胺
0.323g(1mmol)吡唑7(R1=NH2,R2=Cl,R3=CH3,R4=H)在20mL二氯甲烷中的混悬液与0.112g(1.1mmol)乙酸酐在惰性气体、室温下反应。然后将混合物用乙酸乙酯稀释,连续用水和盐水洗涤。用乙酸乙酯萃取水层,合并萃取液,用无水硫酸钠干燥,减压下浓缩并过滤。应用硅胶色谱分离产物,采用己烷-乙酸乙酯(30/70)洗脱,得到0.175g化合物C7。
1H nmr:(DMSO-d6,300mHz)11.71(s,1H),9.56(s,1H),7.56(s,1H),7.38-7.57(m,5H),6.67(d,J=8Hz,1H),6.57(d,J=2Hz,1H),2.05(s,3H),1.83(s,3H).
按照上述方法C制备化合物7的方法,制备下列化合物:
3.8化合物C8:R1=丙烯酰NH,R2=Cl,R3=CH3,R4=H
N-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-丙烯酰胺(propenamide)
1H nmr:(DMSO-d6,300mHz)11.71(s,1H),9.78(5,1H),7.63(s,1H),7.52(dd,J=2,9Hz,1H),7.35-7.50(m,4H),6.71(d,J=9Hz,1H),6.69(d,J=2Hz,1H),6.23(dd,J=10,18Hz,1H),6.08(dd,J=2,18Hz,1H),5.60(dd,J=2,10Hz,1H),2.05(s,3H).
3.9化合物C9:R1=CH3SO2NH,R2=Cl,R3=CH3,R4=H
N-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-甲磺酰胺
0.323g(1mmol)吡唑7(R1=NH2,R2=Cl,R3=CH3,R4=H)、0.122g(1mmol)4-二甲基氨基吡啶和5mL四氢呋喃的混合物在惰性气体、室温下搅拌2小时。将混合物用乙酸乙酯稀释,连续用水和盐水洗涤,应用乙酸乙酯从水相中再萃取。合并乙酸乙酯萃取液,用无水硫酸钠干燥,减压下浓缩并过滤。应用硅胶色谱分离产物,采用己烷-乙酸乙酯(10/90)洗脱,得到0.244g化合物C9(吡唑7,其中R1=CH3SO2NH,R2=Cl,R3=CH3,R4=H)(在乙酸乙酯中重结晶)mp 196-198℃。
1H nmr:(DMSO-d6,300mHz)11.74(s,1H),9.12(s,1H),7.71(s,1H),7.36-7.46(m,4H),6.94(dd,J=2,8Hz,1H),6.72(d,J=8Hz,1H),6.31(d,J=2Hz,1H),2.70(s,3H),2.05(s,3H).
D.R3=CO2Et到R3=CONRR’的氨解
3.10化合物C10:R1=NO2,R2=Cl,R3=CONH2,R4=H
5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-酰胺
0.15g(0.36mmol)吡唑7(R1=NO2,R2=Cl,R3=CO2Et,R4=H)与氨水(15mL)在乙醇(50mL)中的溶液在室温下搅拌48小时。在减压下除去挥发物质,通过硅胶色谱纯化产物。应用乙酸乙酯-异丙醇(95/5)洗脱,得到0.074g化合物C10固体(吡唑7’,其中R1=NO2,R2=Cl,R3=CONH2,R4=H)mp>340℃,(在乙酸乙酯中重结晶)。
1H nmr:(DMSO-d6,400mHz)12.95(brs,1H),9.23(brs,1H),7.92(d,J=8Hz,1H),7.81(s,1H),7.45-7.61(m,4H),7.21(s,1H),7.08(s,1H),6.75(d,J=8Hz,1H).
按照上述方法D制备化合物10的方法,制备下列化合物:
3.11化合物C11:R1=NO2,R2=Cl,R3=CONMe2,R4=H
N,N-二甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-酰胺
1H nmr:(DMSO-d6,300mHz)12.65(s,1H),9.18(s,1H),7.91(d,J=9Hz,1H),7.41-7.55(m,4H),7.08(s,1H),6.75(d,J=9Hz,1H),3.01(5,3H),2.88(s,3H).
3.12化合物C12:R1=NO2,R2=Cl,R3=CONHNH2,R4=H
N-氨基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-酰胺
1H nmr:(DMSO-d6,300mHz)13.02(s,1H),9.19(s,1H),8.58(t,J=5Hz,1H),7.91(dd,J=2,9Hz,1H),7.41-7.62(m,4H),7.09(d,J=2Hz,1H),6.75(d,J=9Hz,1H),4.54(d,J=5Hz,2H).
E.R3=CO2Et到R3=CHO和R3=CH2OH的还原
3.13化合物C13:R1=NO2,R2=Cl,R3=CHO,R4=H;和
化合物C14:R1=NO2,R2=Cl,R3=CH2OH,R4=H
0.48g(1.17mmol)吡唑7(R1=NO2,R2=Cl,R3=CO2Et,R4=H)与30mL四氢呋喃在-15℃、惰性气体下用1.52mL的1M氢化铝锂的四氢呋喃溶液处理30分钟。将混合物用乙酸乙酯稀释,连续用硫酸钾水溶液和盐水洗涤,应用乙酸乙酯从水相中再萃取。合并乙酸乙酯萃取液,用无水硫酸钠干燥,减压下浓缩并过滤。应用硅胶色谱分离产物,采用己烷-乙酸乙酯洗脱,得到0.21g化合物C13(吡唑7’,其中R1=NO2,R2=Cl,R3=CHO,R4=H)红色固体,和0.11g化合物C13(吡唑7’,其中R1=NO2,R2=Cl,R3=CH2OH,R4=H)红色固体。
化合物C13:
5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-醛
1H nmr:(DMSO-d6,300mHz)13.29(s,1H),9.66(s,1H),9.27(s,1H),7.96(dd,J=2,9Hz,1H),7.45-7.59(m,4H),7.13(d,J=2Hz,1H),6.79(d,J=9Hz,1H).
化合物C14:
3-羟基甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
1H nmr:(DMSO-d6,300mHz)12.11(s,1H),9.08(s,1H),7.85(dd,J=2,9Hz,1H),7.42-7.50(m,4H),7.06(d,J=2Hz,1H),6.71(d,J=9Hz,1H),5.23(t,J=5Hz,1H),4.27(d,J=5Hz,2H).
F.醛的还原氨化:R3=CHO到R3=CH2NR2
3.14化合物C15:R1=NO2,R2=Cl,R3=CH2NMe2,R4=H
3-(N,N-二甲基氨基甲基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
0.142g(0.39mmol)吡唑7(R1=NO2,R2=Cl,R3=CO2Et,R4=H)、0.0631g(0.78 mmol)二甲胺盐酸盐、0.11mL(0.78mmol)三乙胺、0.165g(1mmol)三乙酸基硼氢化物、0.2的4A分子筛和20mL二氯甲烷的混悬液在惰性气体下搅拌3小时。过滤混合物,用乙酸乙酯稀释,连续用硫酸钾水溶液和盐水洗涤,应用乙酸乙酯从水相中再萃取。合并乙酸乙酯萃取液,用无水硫酸钠干燥,减压下浓缩并过滤。应用反相硅胶色谱(应用水-乙腈-三氟乙酸进行梯度洗脱)进行纯化,得到0.147g化合物C15(吡唑7’,其中R1=NO2,R2=Cl,R3=CH2NMe2,R4=H)三氟乙酸盐。
1H nmr:(DMSO-d6,300mHz)12.54(s,1H),9.92(s,1H),9.25(s,1H),7.91(dd,J=2,8Hz,1H),7.45-7.55(m,4H),7.10(d,J=2Hz,1H),6.76(d,J=8Hz,1H),4.08(s,2H),2.75(s,6H).
G.醇的烷基化:R3=CH2OH到R3=CH2OCH3
3.15化合物C16:R1=NO2,R2=Cl,R3=CH2OCH3,R4=H
0.075g(0.2mmol)吡咯7(R1=NO2,R2=Cl,R3=CH2OH,R4=H)、0.2g硅胶和20mL四氢呋喃的混合物用重氮甲烷在乙醚中的溶液(50mL,大约9.2mmol)搅拌。2小时后,在减压下过滤混合物并干燥。通过硅胶色谱纯化产物,用己烷-乙酸乙酯洗脱,得到红色固体的化合物C16(吡咯7’,其中R1=NO2,R2=Cl,R3=CH2OCH3,R4=H)。
1H nmr:(DMSO-d6,300mHz)12.27(s,1H),9.11(s,1H),7.86(dd,J=2,9Hz,1H),7.43-7.50(m,4H),7.06(d,J=2Hz,1H),6.72(d,J=9Hz,1H),4.20(s,2H),3.25(s,3H).
H.醛的亚甲基化(Methylenation):R3=CHO到R3=CHCH2
3.16化合物C17:R1=NO2,R2=Cl,R3=CHCH2,R4=H
3-次乙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮
在-78℃、惰性气体下,向通过在5mL四氢呋喃中的0.109g(0.31mmol)甲基三苯基溴化鏻和0.29mL 1M叔丁氧化钾的四氢呋喃溶液反应得到的亚甲基三苯基正膦中,加入0.080g(0.22mmol)的吡咯7(R1=NO2,R2=Cl,R3=CHO,R4=H),将混合物保温回流,搅拌过夜,其后将混合物冷却至室温,乙酸乙酯稀释,连续用水和盐水洗涤。应用无水硫酸钠干燥乙酸乙酯萃取物,在减压下过滤混合物并干燥。通过硅胶色谱纯化产物,用己烷-乙酸乙酯(70/30)洗脱,得到0.043g红色固体的化合物C17(吡咯7’,其中R1=NO2,R2=Cl,R3=CHCH2,R4=H)。
1H nmr:(DMSO-d6,300mHz)12.33(s,1H),9.11(s,1H),7.88(dd,J=2,9Hz,1H),7.40-7.50(m,4H),7.08(d,J=2Hz,1H),6.74(d,J=9Hz,1H),6.40(dd,J=12,18Hz,1H),5.85(d,J=18Hz,1H),5.36(d,J=12Hz,1H).
I.酰胺的脱水:R3=CONH2到R3=CN
3.17化合物C18:R1=NO2,R2=Cl,R3=CN,R4=H
5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-腈
0.47g(1.23mmol)吡咯7(R1=NO2,R2=Cl,R3=CONH2,R4=H)、0.34g(2.46mmol)碳酸钾、0.94g(6.15mmol)磷酰氯和20mL乙腈的混合物在惰性气体下加热至回流4小时。将混合物冷却至室温,乙酸乙酯稀释,连续用饱和碳酸氢钠水溶液、水和盐水洗涤,用乙酸乙酯再萃取水相。应用无水硫酸钠干燥。合并的乙酸乙酯萃取物,在减压下过滤混合物并干燥。通过硅胶色谱纯化产物,用己烷-乙酸乙酯(70/30)洗脱,得到0.24g橙色固体的化合物C18(吡咯7’,其中R1=NO2,R2=Cl,R3=CN,R4=H)(从二氯甲烷重结晶得到)。mp 193-196℃。
IR(KBr)2240cm-1.1H nmr:(DMSO-d6,300mHz)9.36(s,1H),7.96(dd,J=2,9Hz,1H),7.48-7.58(m,4H),7.11(d,J=2Hz,1H),6.77(d,J=9Hz,1H).
J.腈的水解R1=CN至R3=CONH2
3.18化合物C19:R1=CONH2,R2=F,R3=CH3,R4=H
3-甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺
向0.5g(1.6mmol)吡咯7(R1=CN,R2=F,R3=CH3,R4=H)在79mL二甲亚砜的溶液中,加入47mL冰冻的过氧化氢(30%水溶液)和24mL 1M氢氧化钠。反应完全后,将混合物用乙酸乙酯萃取,萃取液连续用水和盐水洗涤,然后用无水硫酸钠干燥。将混合物在减压下过滤混合物并干燥。通过硅胶色谱纯化(用乙酸乙酯/甲醇(95∶5)洗脱),得到0.5g黄色固体的化合物C19(吡咯7’,其中R1=CONH2,R2=F,R3=CH3,R4=H)。mp 323-324℃。
1H nmr:(DMSO-d6,300mHz)11.79(s,1H),8.08(s,1H),7.64(s,1H),7.58(dd,J=2,9Hz,1H),7.38-7.52(m,2H),7.02-7.30(m,4H),6.73(d,J=9Hz,1H),2.05(s,3H).
在上述实施例1-3中没有特别列出的其它化合物也是采用上述方法制备。这些用“D”表示的化合物列在下表I-IV中。
实施例4:抗增殖活性
本发明化合物的抗增殖活性如下所证明。这些效果表明本发明化合物可用于治疗癌症,特别是治疗实体肿瘤,如乳腺癌和结肠癌。
CDK2闪光板试验
为了测定CDK2活性的抑制,将纯化过的重组成视网膜细胞瘤(Rb)蛋白涂在96孔闪光板上(New England Nuclear,Boston,MA)。Rb是通过CDK2进行磷酸化的天然物质(Herwig和Strauss,Eurr.J.Biochem.,Vol.246(1997)pp.581-601,在本文引用作为参考)。从昆虫细胞提取物中部分纯化重组活性人细胞周期蛋白E/CDK2复合物。将这些活性细胞周期蛋白E/CDK2以及33P-ATP和测试化合物的稀释液加入到Rb涂布的闪光板上。将该板在振荡下室温温育25分钟,然后洗涤,并在Topcount闪烁计数器(Packard Instrument Co.,DowneersGrove,IL)上计数。试验化合物的稀释液在各种试验中被重复试验。Rb磷酸化抑制百分数(其为CDK2活性抑制的衡量标准)根据下式确定:
100×[1-(试验化合物-非特异性数)/(总数-非特异性数)]
其中“试验化合物”指重复试验每分钟的平均计数,“非特异性数”指当不加入细胞周期蛋白E/CDK2时的每分钟平均计数,而“总数”指不加入化合物时每分钟的平均计数。
上述体外试验的结果在下表IA至1C中给出。
表1A
Cdk2的抑制IC50范围0.01-0.99uM
化合物编号 | R1(7位) | R2(2’位)* | R3 | R4(4’位) |
A5 | NO2 | Cl | H | H |
A13 | NO2 | F | H | H |
A15 | CN | F | H | H |
A16 | NO2 | H | H | H |
A17 | NO2 | CF3 | H | H |
A20 | CO2Et | F | H | H |
A21 | H | Cl | H | H |
B1 | NO2 | Cl | 2-吡咯基 | H |
B3 | NO2 | Cl | CH3 | H |
B4 | NO2 | Cl | CH2CH3 | H |
B6 | NO2 | Cl | i-Pr | H |
B7 | CN | F | CH3 | H |
B9 | CO2Et | F | CH3 | H |
B10 | NO2 | Cl | 5-(4-Me)-吡唑基 | H |
B12 | NO2 | Cl | CF3 | H |
B13 | NO2 | Cl | 1-噻唑基 | H |
B14 | NO2 | Cl | 4-咪唑基 | H |
B15 | NO2 | Cl | 2-吡唑基 | H |
B16 | NO2 | Cl | 3-吡唑基 | H |
B17 | NO2 | Cl | CH(Me)CH2Me | H |
B18 | MeO | Cl | CH3 | H |
B19 | Cl | H | CH3 | H |
B20 | Cl | Cl | CH3 | H |
B21 | H | F | CH3 | H |
B22 | F | H | CH3 | H |
B23 | NO2 | Cl | Ph | H |
B24 | NO2 | Cl | 丙基 | H |
B25 | NO2 | Cl | 环丙基 | H |
B26 | F | F | CH3 | H |
B27 | NO2 | H | CH3 | H |
B28 | H | H | CH3 | H |
B29 | I | F | CH3 | H |
B30 | H | Cl | CH3 | H |
B31 | NO2 | F | CH3 | H |
B32 | Cl | F | CH3 | H |
B35 | CN | F | CH2OH | H |
C1 | CON-吗啉酰胺 | F | H | H |
C2 | CONHCH2CH2OH | F | H | H |
C4 | NH2 | Cl | CH3 | H |
C6 | NH2 | Cl | i-Pr | H |
C7 | AcNH | Cl | CH3 | H |
C8 | 丙烯酰NH | Cl | CH3 | H |
C9 | MsNH | Cl | CH3 | H |
C10 | NO2 | Cl | CONH2 | H |
C12 | NO2 | Cl | CONHNH2 | H |
C13 | NO2 | Cl | CHO | H |
C14 | NO2 | Cl | CH2OH | H |
C16 | NO2 | Cl | CH2OMe | H |
C17 | NO2 | Cl | CH=CH2 | H |
C18 | NO2 | Cl | CN | H |
C19 | CONH2 | F | CH3 | H |
D1 | NO2 | m-NO2 ** | H | H |
D2 | NO2 | CF3 | CH3 | H |
D3 | Me2NSO2NH | Cl | CH3 | H |
D4 | ClCH2NHSO2NH | Cl | CH3 | H |
D5 | 吗啉基ISO2NH | Cl | CH3 | H |
D6 | NO2 | Cl | 2-硫代苯基 | H |
D7 | NO2 | Cl | 2-呋喃基 | H |
D8 | NO2 | Cl | 2-(3-Me)-硫代苯基 | H |
D9 | NO2 | Cl | 3-吡啶基 | H |
D10 | NO2 | Cl | 4-吡啶基 | H |
D11 | NO2 | Cl | p-MeSPh | H |
D12 | NO2 | Cl | p-CF3OPh | H |
D13 | NO2 | Cl | o,m-亚甲基二氧-Ph | H |
D14 | NO2 | Cl | p-OH-o-MeOPh | H |
D15 | NO2 | Cl | 3-硫代苯基 | H |
D16 | NO2 | Cl | p-Ph-Ph | H |
D17 | NO2 | Cl | m-NO2Ph | H |
D18 | NO2 | H | 环丙基 | H |
D50 | CONH2 | F | H | H |
D51 | CON-吗啉酰胺amide | F | CH3 | H |
D52 | CONHCH2CH2OH | F | CH3 | H |
D53 | CONHCH2CH2-N-吗啉基 | F | CH3 | H |
*除非另有说明
**3’位
在其余表中,R1,R2,R3和R4的取代位与上述表1A相同
表1B
Cdk2的抑制
IC50
范围0.01-0.99um
化合物编号 | R1 | R2 | R3 | R4 |
A6 | Cl | H | H | H |
A7 | Cl | F | H | H |
A9 | H | H | H | H |
A10 | H | F | H | H |
A11 | F | F | H | H |
A14 | CH3SO2 | H | H | H |
A18 | CO2CH3 | H | H | H |
A19 | I | F | H | H |
B2 | NO2 | Cl | CO2Et | H |
B5 | NO2 | Cl | CH2CH2Ph | H |
B8 | NO2 | Cl | CH2Ph | H |
B11 | NO2 | Cl | CH2-iPr | H |
B33 | I | H | CH3 | H |
C3 | CON(CH2CH2OH)2 | F | H | H |
C5 | NH2 | Cl | H | H |
C11 | NO2 | Cl | CONMe2 | H |
D19 | NO2 | Cl | 2-苯并呋喃基 | H |
D20 | NO2 | Cl | 2-吲哚基 | H |
D21 | NO2 | Cl | 2-N-Me-吡咯基 | H |
D22 | CO2H | F | H | H |
D23 | NO2 | Cl | m-OH-Ph | H |
D24 | NO2 | Cl | p-MePh | H |
D25 | NO2 | Cl | m-CNPh | H |
D26 | NO2 | Cl | 2-(5-Me)-硫代苯基 | H |
D27 | NO2 | H | 3-吡啶基 | H |
D28 | NO2 | Cl | p-Me2NPh | H |
D29 | NO2 | Cl | o-CNPh | H |
D30 | NO2 | Cl | m-MePh | H |
D31 | NO2 | Cl | m-EtO-Ph | H |
D32 | NO2 | Cl | 2-(5-Et)-呋喃基 | H |
D33 | NO2 | Cl | 2-萘基 | H |
D34 | NO2 | H | 2-咪唑基 | H |
D35 | CO2Na | H | H | H |
D37 | NO2 | Cl | o-MePh | H |
表1C
Cdk2的抑制IC50范围10-30uM
化合物编号 | R1 | R2 | R3 | R4 |
A4 | Cl | Cl | H | H |
D38 | NO2 | Cl | 1-噁二唑基 | H |
D39 | NO2 | Cl | o-NO2Ph | H |
D40 | NO2 | Cl | o-CF3Ph | H |
D41 | NO2 | Cl | m-CF3Ph | H |
D42 | NO2 | Cl | o-MeOPh | H |
D43 | NO2 | Cl | 4-N-吡唑基 | H |
D44 | NO2 | Cl | m-PhOPh | H |
D45 | NO2 | H | m,p-亚甲基二氧-Ph | H |
D46 | NO2 | H | m,p-亚乙基二氧-Ph | H |
D47 | NO2 | H | o-F-Ph | H |
基于细胞的检测
从American Type Cell Culture Collection(ATOC;Rockvilie,MD)购买雌激素受体阴性上皮乳腺癌系(MDA-MB435),在ATCC推荐的介质中培养。为了分析测试化合物对这些细胞生长的影响,将该细胞在96孔组织培养板上每孔2000细胞进行铺板,然后在37℃、5%CO2下温育过夜。第二天,将测试化合物溶解于100%二甲基亚砜(DMSO)中,制成10mM储备液。将每种化合物用足够量的无菌介质稀释,得到最终浓度120μM。然后将该化合物连续用1.2%DMSO稀释。将四分之一最终体积的稀释化合物转移至96孔培养板上。重复检测该测试化合物。将DMSO加入到一组“对照细胞”中,使每孔中DMSO的浓度达到0.3%。加入没有细胞的孔作为“空白”。加入没有抑制剂的孔作为“无抑制剂对照”。将该板再重新置于培养箱中,加入测试化合物后,如下进行分析。
将3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑溴鎓(噻唑兰;MTT)加入到每孔上,得到最终浓度1mg/mL。然后将该板在37℃下温育3小时。在将含MTT介质吸出前,将该板在1000rpm下离心5分钟。然后取出含MTT介质,将100μL 100%乙醇加入到每孔中,以溶解最终的甲代谢物。为了保证能够完全溶解,将该板在室温下振摇15分钟。570nm下在微量滴定板读数器(Molecular Dynamics)上读出吸收度读数,650nm下读数作为对照。通过所有孔的值减去空白孔(没有细胞)的吸收度,然后1.00减去每个测试化合物重复测定的平均值与对照平均值的比值,得到百分比抑制。通过绘出浓度的对数值/百分比抑制,进行线性回归,确定抑制浓度(IC50)。
上述MDA-MB-435基于细胞检测的结果在下表IIA-IIC中给出。
表IIA
MDA-MB435(乳腺)的抗增生活性检测IC50范围0.01-1uM
化合物编号 | R1 | R2 | R3 | R4 |
B3 | NO2 | Cl | CH3 | H |
B4 | NO2 | Cl | CH2CH3 | H |
B6 | NO2 | Cl | i-Pr | H |
B7 | CN | F | CH3 | H |
B22 | F | H | CH3 | H |
B25 | NO2 | Cl | 环丙基 | H |
B29 | NO2 | H | CH3 | H |
B31 | NO2 | F | CH3 | H |
B35 | CN | F | CH2OH | H |
C4 | NH2 | Cl | CH3 | H |
C7 | AcNH | Cl | CH3 | H |
C8 | 丙烯酰NH | Cl | CH3 | H |
C9 | MsNH | Cl | CH3 | H |
C13 | NO2 | Cl | CHO | H |
C14 | NO2 | Cl | CH2OH | H |
C17 | NO2 | Cl | CH=CH2 | H |
D3 | Me2NSO2NH | Cl | CH3 | H |
表IIB
MDA-MB435(乳腺)的抗增生活性检测IC50范围1.1-9.99uM
化合物号码 | R1 | R2 | R3 | R4 |
A15 | CN | F | H | H |
B9 | CO2Et | F | CH3 | H |
B10 | NO2 | Cl | 5-(4-Me)-吡唑基 | H |
B12 | NO2 | Cl | CF3 | H |
B14 | NO2 | Cl | 4-咪唑基 | H |
B16 | NO2 | Cl | 3-吡唑基 | H |
B18 | MeO | Cl | CH3 | H |
B19 | Cl | H | CH3 | H |
B20 | Cl | Cl | CH3 | H |
B21 | H | F | CH3 | H |
B30 | H | Cl | CH3 | H |
C6 | NH2 | Cl | i-Pr | H |
C16 | NO2 | Cl | CH2OMe | H |
D4 | ClCH2NHSO2NH | Cl | CH3 | H |
D5 | 吗啉基 | Cl | CH3 | H |
D51 | CON-吗啉酰胺 | F | CH3 | H |
D52 | CONHCH2CH2OH | F | CH3 | H |
D53 | CONHCH2CH2-N-吗啉基 | F | CH3 | H |
表IIC
MDA-MB435(乳腺)的抗增生活性检测IC50范围10-30uM
化合物编号 | R1 | R2 | R3 | R4 |
A5 | NO2 | Cl | H | H |
A13 | NO2 | F | H | H |
B2 | NO2 | Cl | CO2Et | H |
B5 | NO2 | Cl | CH2CH2Ph | H |
B8 | NO2 | Cl | CH2Ph | H |
B13 | NO2 | Cl | 1-噻唑基 | H |
B15 | NO2 | Cl | 2-吡唑基 | H |
B24 | NO2 | Cl | 丙基 | H |
C5 | NH2 | Cl | H | H |
C10 | NO2 | Cl | CONH2 | H |
C15 | NO2 | Cl | CH2NMe2 | H |
C18 | NO2 | Cl | CN | H |
D38 | NO2 | Cl | 1-噁二唑基 | H |
从ATCC获得结肠腺癌SW80和结肠癌HCT-116,按照上述与MDA-MB-435基于细胞检测相同的方案进行检测,只是进行以下修改。细胞系SW480以每孔1000细胞进行铺板,在加入测试化合物后6天后进行检测。细胞系HCT-116以每孔1000细胞进行铺板,在加入测试化合物后4天后进行检测。
上述基于SW480(结肠)和HCT-116(结肠)检测的结果分别在下表IIIA-IIIC和IVA-IVC中给出。
表IIIA
SW480(结肠)抗增生活性检测IC50范围0.01-1uM
化合物编号 | R1 | R2 | R3 | R4 |
B3 | NO2 | Cl | CH3 | H |
B4 | NO2 | Cl | CH2CH3 | H |
B6 | NO2 | Cl | i-Pr | H |
B7 | CN | F | CH3 | H |
B10 | NO2 | Cl | 5-(4-Me)-吡唑基 | H |
B21 | H | F | CH3 | H |
B26 | F | F | CH3 | H |
B27 | NO2 | H | CH3 | H |
B31 | NO2 | F | CH3 | H |
B35 | CN | F | CH2OH | H |
C1 | CON-吗啉酰胺 | F | H | H |
C4 | NH2 | Cl | CH3 | H |
C7 | AcNH | Cl | CH3 | H |
C8 | AcryloylNH | Cl | CH3 | H |
C9 | MsNH | Cl | CH3 | H |
C14 | NO2 | Cl | CH2OH | H |
C19 | CONH2 | F | CH3 | H |
D2 | NO2 | CF3 | CH3 | H |
D51 | CON-吗啉酰胺 | F | CH3 | H |
D52 | CONHCH2CH2OH | F | CH3 | H |
D53 | CONHCH2CH2-N-吗啉基 | F | CH3 | H |
表IIIB
SW480(结肠)抗增生活性检测IC50范围1.1-9.99uM
化合物编号 | R1 | R2 | R3 | R4 |
A5 | NO2 | Cl | H | H |
A13 | NO2 | F | H | H |
A15 | CN | F | H | H |
B1 | NO2 | Cl | 2-吡咯基 | H |
B9 | CO2Et | F | CH3 | H |
B18 | MeO | Cl | CH3 | H |
B19 | Cl | H | CH3 | H |
B20 | Cl | Cl | CH3 | H |
B22 | F | H | CH3 | H |
B25 | NO2 | Cl | 环丙基 | H |
B29 | I | F | CH3 | H |
B30 | H | Cl | CH3 | H |
B32 | Cl | F | CH3 | H |
D3 | Me2NSO2NH | Cl | CH3 | H |
D4 | ClCH2NHSO2NH | Cl | CH3 | H |
D5 | 吗啉基ISO2NH | Cl | CH3 | H |
D50 | CONH2 | F | H | H |
表IIIC
SW480(结肠)抗增生活性检测IC50范围10-30uM
R1 | R2 | R3 | R4 | |
A9 | H | H | H | H |
A10 | H | F | H | H |
A11 | F | F | H | H |
A21 | H | Cl | H | H |
B5 | NO2 | Cl | CH2CH2Ph | H |
B8 | NO2 | Cl | CH2Ph | H |
B23 | NO2 | Cl | Ph | H |
B24 | NO2 | Cl | Propyl | H |
B33 | I | H | CH3 | H |
C5 | NH2 | Cl | H | H |
C12 | NO2 | Cl | CONHNH2 | H |
D6 | NO2 | Cl | 2-硫代苯基 | H |
D7 | NO2 | Cl | 2-呋喃基 | H |
D9 | NO2 | Cl | 3-吡啶基 | H |
D10 | NO2 | Cl | 4-吡啶基 | H |
D20 | NO2 | Cl | 2-吲哚基 | H |
B34 | Br | H | CH3 | H |
D37 | NO2 | Cl | o-MePh | H |
D40 | NO2 | Cl | o-CF3Ph | H |
D48 | NO2 | Cl | 1-萘基 | H |
表IVA
HCT16(结肠)抗增生活性检测IC50范围0.01-1uM
化合物编号 | R1 | R2 | R3 | R4 |
B3 | NO2 | Cl | CH3 | H |
B4 | NO2 | Cl | CH2CH3 | H |
表IVB
HCT16(结肠)抗增生活性检测IC50范围1.1-9.99uM
化合物序号 | R1 | R2 | R3 | R4 |
A15 | CN | F | H | H |
B1 | NO2 | Cl | 2-吡咯基 | H |
B6 | NO2 | Cl | i-Pr | H |
B7 | CN | F | CH3 | H |
B9 | CO2Et | F | CH3 | H |
B10 | NO2 | Cl | 5-(4-Me)-吡唑基 | H |
B25 | NO2 | Cl | 环丙基 | H |
C12 | NO2 | Cl | CONHNH2 | H |
D50 | CONH2 | F | H | H |
表IVC
HCT16(结肠)抗增生活性检测IC50范围10-30Um
化合物序号 | R1 | R2 | R3 | R4 |
A5 | NO2 | Cl | H | H |
A9 | H | H | H | H |
A10 | H | F | H | H |
A13 | NO2 | F | H | H |
A14 | CH3SO2 | H | H | H |
A16 | NO2 | H | H | H |
A21 | H | Cl | H | H |
B5 | NO2 | Cl | CH2CH2Ph | H |
B8 | NO2 | Cl | CH2Ph | H |
B23 | NO2 | Cl | Ph | H |
B24 | NO2 | Cl | 丙基 | H |
C1 | CON-吗啉酰胺 | F | H | H |
C2 | CONHCH2CH2OH | F | H | H |
C5 | NH2 | Cl | H | H |
D6 | NO2 | Cl | 2-硫代苯基 | H |
D7 | NO2 | Cl | 2-呋喃基 | H |
D8 | NO2 | Cl | 2-(3-Me)-硫代苯基 | H |
D9 | NO2 | Cl | 3-吡啶基 | H |
D10 | NO2 | Cl | 4-吡啶基 | H |
D11 | NO2 | Cl | p-MeSPh | H |
D12 | NO2 | Cl | p-CF3OPh | H |
D13 | NO2 | Cl | o,m-亚甲基二氧-Ph | H |
D14 | NO2 | Cl | p-OH-o-MeOPh | H |
D18 | NO2 | H | 环丙基 | H |
D19 | NO2 | Cl | 2-苯并呋喃基 | H |
D20 | NO2 | Cl | 2-吲哚基 | H |
D37 | NO2 | Cl | o-MePh | H |
D41 | NO2 | Cl | m-CF3Ph | H |
D43 | NO2 | Cl | 4-N-吡咯基Ph | H |
D48 | NO2 | Cl | 1-苯基 | H |
D49 | NO2 | Cl | 4-异喹啉基 | H |
实施例5:片剂配方
项目 | 成分 | Mg/片 | |||||
1 | 化合物1* | 5 | 25 | 100 | 250 | 500 | 750 |
2 | 无水乳糖 | 103 | 83 | 35 | 19 | 38 | 57 |
3 | 交联羧甲基纤维素钠 | 6 | 6 | 8 | 16 | 32 | 48 |
4 | Povidone K30 | 5 | 5 | 6 | 12 | 24 | 36 |
5 | 硬脂酸镁 | 1 | 1 | 1 | 3 | 6 | 9 |
总重量 | 120 | 120 | 150 | 300 | 600 | 900 |
*化合物1代表本发明化合物。
生产工艺:
1.将项目1,2和3在合适的混合器中混合15分钟。
2.将步骤1的粉末混合物用20%Povidone K30溶液(项目4)制粒。
3.在50℃干燥步骤2的颗粒。
4.将步骤3的颗粒通过合适的整粒(milling)装置。
5.将项目5加入磨碎后的步骤4的颗粒中,并混合3分钟。
6.将步骤5的颗粒在合适的压片机上压片。
实施例6:胶囊配方
项目 | 成分 | mg/胶囊 | ||||
1 | 化合物1* | 5 | 25 | 100 | 250 | 500 |
2 | 无水乳糖 | 159 | 123 | 148 | -- | -- |
3 | 玉米淀粉 | 25 | 35 | 40 | 35 | 70 |
4 | 滑石 | 10 | 15 | 10 | 12 | 24 |
5 | 硬脂酸镁 | 1 | 2 | 2 | 3 | 6 |
总重量 | 200 | 200 | 300 | 300 | 600 |
*化合物1代表本发明化合物。
生产工艺:
1.将项目1,2和3在合适的混合器中混合15分钟。
2.加入项目4和5并混合3分钟。
3.填充到胶囊内。
实施例7:注射液/乳剂
项目 | 成分 | mg/ml |
1 | 化合物1* | 1mg |
2 | PEG 400 | 10-50mg |
3 | 磷脂 | 20-50mg |
4 | 豆油 | 1-5mg |
5 | 甘油 | 8-12mg |
6 | 水加至 | 1ml |
*化合物1代表本发明化合物。
生产工艺:
1.将项目1溶于项目2中。
2.将项目3,4和5加入项目6并混合至分散,然后均化。
3.将步骤1的溶液加入步骤2的混合物中,并均化至分散液透明。
4.无菌滤过0.2μm滤纸并填充到小瓶内。
实施例8:注射液/乳剂
项目 | 成分 | mg/ml |
1 | 化合物1* | 1mg |
2 | Glycofurol | 10-50mg |
3 | 磷脂 | 20-50mg |
4 | 豆油 | 1-5mg |
5 | 甘油 | 8-12mg |
6 | 水 | 加至1ml |
*化合物1代表本发明化合物。
生产工艺:
1.将项目1溶于项目2中。
2.将项目3,4和5加入项目6并混合至分散,然后均化。
3.将步骤1的溶液加入步骤2的混合物中,并均化至分散液透明。
4.无菌滤过0.2μm滤纸并填充到小瓶内。
尽管通过参考特定和优选的方案举例来说明本发明,本专业技术人员应该理解各种改变和修饰都可以通过本发明的常规实验和实践而进行。因此,本发明不限于前面的说明,而由权利要求书和其等同替换来限定。
Claims (18)
1.一种下式I的化合物,和式I化合物的前体药物和药物活性代谢物,以及上述化合物的药物可接受的盐:
其中
R1为氢,-NO2,-CN,-卤素,-OR5,-R6OR7,-COOR7,-CONR8R9,-NR10R11,-NHCOR12,-NHSO2R13,或任选被羟基和/或卤素取代的直链低级烷基;
R2和R4分别独立为氢,-卤素,-NO2,-CF3,或直链低级烷基;
R3为氢,环烷基,芳基,杂环,杂芳基,-COOR7,-CN,烯基,-CONR8R9,炔基,或任选被羟基、-OR9、F和/或芳基取代的低级烷基;
R5为任选被卤素取代的低级烷基;
R6为低级烷基;
R7为氢或低级烷基;
R8和R9分别独立为氢或其本身任选被羟基和/或-NH2取代的低级烷基;或者R8和R9可以形成任选被羟基、-NH2、和/或低级烷基取代的五元或六元杂环;
R10、R11和R12分别独立为氢或低级烷基;
R13为任选被卤素和/或-NR14R15取代的低级烷基;以及
R14和R15分别独立为氢或任选被卤素取代的低级烷基;或者-NR14R15为杂环,
其中:
“环烷基”指含有3至8个原子的非芳香的部分或完全饱和的环状脂肪烃;
“芳基”指具有5至10个原子并由1或2个环组成的芳香基;
“杂环”指3-至10-元非芳香的部分或完全饱和的烃基,其含有一个或两个环和至少一个选自N、O和S的杂原子;
“杂芳基”是具有5至10个原子、1或2个环、并含有一个或多个杂原子的芳香基;
“烯基”指含有双键的具有2-6个碳原子的直链或支链、取代或未取代的脂肪族不饱和烃;和
“低级烷基”指具有1至6个碳原子的直链或支链、取代或未取代的饱和脂肪烃。
2.按照权利要求1的化合物,其中R1为氢,NO2,CN,CONH2,卤素或低级烷基,“低级烷基”如权利要求1所定义。
3.按照权利要求1或2的化合物,其中R1为NO2,CN,或CONH2。
4.按照权利要求1的化合物,其中R1在2’位,为氢或卤素。
5.按照权利要求1的化合物,其中R3为低级烷基,羟基低级烷基,环烷基,杂环,或杂芳基,“低级烷基”、“环烷基”、“杂环”和“杂环基”如权利要求1所定义。
6.按照权利要求1的化合物,其中R3为甲基、乙基和羟基甲基。
7.按照权利要求1的化合物,其为3-甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮。
8.按照权利要求1的化合物,其为3-甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-腈。
9.按照权利要求1的化合物,其为3-甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺。
10.按照权利要求1的化合物,其为3-羟基甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-腈。
11.按照权利要求1的式I化合物,其为:
5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
5-(2-氯苯基)-7-氨基-吡唑并[3,4][1,4]苯并二氮,
5-苯基-7-氯-吡唑并[3,4][1,4]苯并二氮,
5-(2-氟苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮,
5-(2-氯苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮,
5-(2,4-二氯苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮,
5-苯基-吡唑并[3,4][1,4]苯并二氮,
5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮,
5-(2-氟苯基)-7-氟-吡唑并[3,4][1,4]苯并二氮,
5-(2-氯苯基)-7-甲氧基-吡唑并[3,4][1,4]苯并二氮,
5-(2-氟苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
5-苯基-甲磺酰基-吡唑并[3,4][1,4]苯并二氮,
5-(2-氟苯基)-7-氰基-吡唑并[3,4][1,4]苯并二氮,
5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮,
5-(3-硝基苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
5-(2-三氟甲基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
5-苯基-7-甲氧甲酰基-吡唑并[3,4][1,4]苯并二氮,
(5-苯基-吡唑并[3,4][1,4]苯并二氮-7-基)-羧酸钠盐,
5-(2-氟苯基)-7-碘-吡唑并[3,4][1,4]苯并二氮,
5-(2-氟苯基)-7-乙氧甲酰基-吡唑并[3,4][1,4]苯并二氮,
N-(2-羟基乙基)-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺,
5-(2-氟苯基)-7-吗啉基羰基-吡唑并[3,4][1,4]苯并二氮,
N,N-双-(2-羟基乙基)-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺,
(5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-羧酸,
5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺,或
5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮。
12.按照权利要求1的式I化合物,其为:
3-乙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-苯基乙基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(1-甲基乙基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(1-甲基乙基)-5-(2-氯苯基)-7-氨基-吡唑并[3,4][1,4]苯并二氮,
3-(苯基甲基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氯苯基)-7-乙氧甲酰基-吡唑并[3,4][1,4]苯并二氮,
3-(2-甲基丙基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-三氟甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-羟基甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
N-(2-羟基乙基)-3-甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺,
3-(N,N-二甲基氨基甲基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(1-甲基丙基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-甲氧基甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-次乙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氯苯基)-7-甲氧基-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氯苯基)-7-氨基-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-苯基-7-氯-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氯苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮,
N-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-乙酰胺,
N-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-甲磺酰胺,
N-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-丙烯酰胺,
3-甲基-5-苯基-7-氟-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氟苯基)-7-碘-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氟苯基)-7-吗啉基羰基-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氟苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-苯基-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氟苯基)-7-氯-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-三氟甲基苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
N’-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-4-N,N-二甲基胺基磺酰胺,
N’-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-4-N-氯甲基胺基磺酰胺,
N’-(3-甲基-5-(2-氯苯基)-吡唑并[3,4][1,4]苯并二氮-7-基)-4-吗啉基磺酰胺,
N-[2-(4-吗啉基)乙基]-3-甲基-5-(2-氟苯基)-吡唑并[3,4][1,4]苯并二氮-7-酰胺,
3-甲基-5-苯基-7-碘-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-苯基-7-溴-吡唑并[3,4][1,4]苯并二氮,
3-甲基-5-(2-氟苯基)-7-氟-吡唑并[3,4][1,4]苯并二氮,
3-环丙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-环丙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,或
3-丙基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮。
13.按照权利要求1的式I化合物,其为:
3-乙氧甲酰基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-酰胺,
N,N-二甲基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-酰胺,
N-氨基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-酰胺,
5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-醛,或
5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮-3-腈。
14.按照权利要求1的式I化合物,其为:
3-(4-甲基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(4-二甲基氨基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-氰基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-苯基-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-甲基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-硝基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-三氟甲基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-三氟甲基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(1-萘基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-甲氧基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(4-(甲基硫)苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(4-三氟甲氧基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(4-羟基-2-甲氧基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-羟基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-((1,1’-联苯基)-4基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-萘基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-硝基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-苯氧基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-氰基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-乙氧基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-甲基苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,或
3-(2-氟苯基)-5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮。
15.按照权利要求1的式I化合物,其为:
3-(4-甲基吡唑基-5-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(1-噻唑基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(1,3,4-噁二唑-2-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(4-咪唑基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-吡唑基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-吡唑基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-噻吩基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-呋喃基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-甲基噻吩-2-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-甲基噻吩-2-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(吲哚-2-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(1-甲基-1H-吡咯-2-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-吡啶)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(4-(1-吡咯基)苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-吡咯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(4-异喹啉基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-苯并呋喃基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(3-噻吩基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(5-甲基噻吩-2-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-咪唑基)-5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2-吡啶基)-5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(1,3-苯并间二氧杂环戊烯-5-基)-5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2,3-二氢-1,4-苯并二氧芑-6-基)-5-苯基-7-硝基-吡唑并[3,4][1,4]苯并二氮,
3-(2,3-亚甲基二氧苯基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮,或
3-(5-乙基呋喃-2-基)-5-(2-氯苯基)-7-硝基-吡唑并[3,4][1,4]苯并二氮。
17.一种药物组合物,包括作为活性成分的权利要求1-15中任何一个的化合物和药物可接受的载体或赋型剂。
18.权利要求1-15中任何一个的化合物在制备用于治疗或控制乳腺癌、结肠癌、肺癌和前列腺癌的医药中的应用。
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CNB2004100682242A Expired - Fee Related CN1279029C (zh) | 1999-04-21 | 2000-04-14 | 作为cdk2抑制剂的吡唑并苯并二氮䓬 |
CNB008065543A Expired - Fee Related CN1196703C (zh) | 1999-04-21 | 2000-04-14 | 作为cdk2抑制剂的吡唑并苯并二氮䓬 |
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CNB2004100682242A Expired - Fee Related CN1279029C (zh) | 1999-04-21 | 2000-04-14 | 作为cdk2抑制剂的吡唑并苯并二氮䓬 |
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US (3) | US6440959B1 (zh) |
EP (1) | EP1185529B1 (zh) |
JP (1) | JP3746680B2 (zh) |
KR (1) | KR100481757B1 (zh) |
CN (2) | CN1279029C (zh) |
AR (1) | AR023542A1 (zh) |
AT (1) | ATE279413T1 (zh) |
AU (1) | AU768667B2 (zh) |
BR (1) | BR0009887A (zh) |
CA (1) | CA2367704C (zh) |
CO (1) | CO5170444A1 (zh) |
CZ (1) | CZ20013738A3 (zh) |
DE (1) | DE60014893T2 (zh) |
DK (1) | DK1185529T3 (zh) |
ES (1) | ES2228522T3 (zh) |
HK (1) | HK1046278B (zh) |
HR (1) | HRP20010742A2 (zh) |
HU (1) | HUP0300318A3 (zh) |
IL (1) | IL145764A0 (zh) |
JO (1) | JO2248B1 (zh) |
MA (1) | MA26782A1 (zh) |
NO (1) | NO20015065D0 (zh) |
NZ (1) | NZ514523A (zh) |
PE (1) | PE20010054A1 (zh) |
PL (1) | PL200933B1 (zh) |
PT (1) | PT1185529E (zh) |
RU (1) | RU2249593C2 (zh) |
SI (1) | SI1185529T1 (zh) |
TR (1) | TR200103016T2 (zh) |
TW (1) | TW585866B (zh) |
WO (1) | WO2000064900A1 (zh) |
YU (1) | YU73101A (zh) |
ZA (1) | ZA200108016B (zh) |
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NZ532463A (en) * | 2001-11-13 | 2007-02-23 | Dimensional Pharm Inc | Substituted 1,4-benzodiazepines and uses thereof for the treatment of cancer |
FR2847253B1 (fr) * | 2002-11-19 | 2007-05-18 | Aventis Pharma Sa | Nouveaux derives de pyridazinones a titre de medicaments et compositions pharmaceutiques les renfermant |
PL378116A1 (pl) * | 2003-02-27 | 2006-03-06 | Abbott Laboratories | Heterocykliczne inhibitory kinazy |
EP1802625B1 (en) * | 2004-10-13 | 2008-06-18 | F. Hoffmann-Roche AG | Disubstituted pyrazolobenzodiazepines useful as inhibitors for cdk2 and angiogesis, and for the treatment of breast, colon, lung and prostate cancer |
KR20080055914A (ko) * | 2005-10-14 | 2008-06-19 | 에프. 호프만-라 로슈 아게 | 5-(2-클로로페닐)-1,2-디히드로-7-플루오로-8-메톡시-3-메틸-피라졸로[3,4-b][1,4] 벤조디아제핀의 투여 섭생 |
KR20090045233A (ko) | 2006-07-10 | 2009-05-07 | 파이온 유케이 리미티드 | 속효형 벤조디아제핀 염 및 이의 중합체 형태 |
KR20100073454A (ko) * | 2008-12-23 | 2010-07-01 | 국립암센터 | 트란스글루타미나제 억제제로 사용되는 신규한 피라졸로디아제핀계 화합물, 이의 제조방법 및 이를 포함하는 조성물 |
EP2305647A1 (en) | 2009-09-18 | 2011-04-06 | PAION UK Limited | Process for preparing 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4 H-imidazo[1,2-a][1,4]benzodiazepine-4-yl] propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process |
EP2450039A1 (en) | 2010-11-08 | 2012-05-09 | PAION UK Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
US9321737B2 (en) * | 2012-02-02 | 2016-04-26 | Senex Biotechnology Inc | CDK8-CDK19 selective inhibitors and their use in anti-metastatic and chemopreventative methods for cancer |
CN103288830A (zh) * | 2012-02-24 | 2013-09-11 | 中国科学院大连化学物理研究所 | 一种合成手性二氢-5H-吡咯并[2,1-c][1,4]-苯并二氮杂卓的方法 |
CN102603743B (zh) * | 2012-02-24 | 2014-05-28 | 南京天易生物科技有限公司 | 抗肿瘤的氮杂苯并[f]薁衍生物其制备方法及其用途 |
CN103288828A (zh) * | 2012-02-24 | 2013-09-11 | 中国科学院大连化学物理研究所 | 一种合成手性二氢-6H-吲哚并[2,1-c][1,4]-苯并二氮杂卓的方法 |
AR094963A1 (es) | 2013-03-04 | 2015-09-09 | Ono Pharmaceutical Co | Reacción de oxidación excelente en el índice de conversión |
CN106608877B (zh) * | 2015-10-21 | 2018-11-13 | 新发药业有限公司 | 一种依鲁替尼中间体4-氨基-3-(4-苯氧基)苯基-1H-吡唑并[3,4-d]嘧啶的制备方法 |
CN109906220A (zh) * | 2016-11-01 | 2019-06-18 | 豪夫迈·罗氏有限公司 | 用于治疗cns相关疾病的1,3-二氢-1,4-苯并二氮杂*-2-硫酮化合物 |
BR112019008295B1 (pt) | 2016-12-13 | 2024-03-12 | TransThera Sciences (Nanjing), Inc | Composto inibidor de multiquinase, forma cristalina do composto de fórmula iii, formulação/composição farmacêutica, seus usos, métodos para a preparação da forma cristalina e do composto de fórmula iii e intermediário para a preparação do composto de fórmula iii |
CN109020980B (zh) * | 2017-06-09 | 2020-11-20 | 华东师范大学 | 一类抗肿瘤作用的吡唑并嘧啶二氮*衍生物 |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
US11472791B2 (en) | 2019-03-05 | 2022-10-18 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors |
WO2020205560A1 (en) | 2019-03-29 | 2020-10-08 | Incyte Corporation | Sulfonylamide compounds as cdk2 inhibitors |
WO2020223558A1 (en) * | 2019-05-01 | 2020-11-05 | Incyte Corporation | Tricyclic amine compounds as cdk2 inhibitors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
JP2023509260A (ja) | 2019-08-14 | 2023-03-08 | インサイト・コーポレイション | Cdk2阻害剤としてのイミダゾリルピリミジニルアミン化合物 |
CN115298177A (zh) | 2019-10-11 | 2022-11-04 | 因赛特公司 | 作为cdk2抑制剂的双环胺 |
AU2021267622A1 (en) * | 2020-05-08 | 2022-12-15 | Transthera Sciences (Nanjing), Inc. | Synthesis method for anti-tumor compound and intermediate thereof |
TW202237585A (zh) | 2020-11-27 | 2022-10-01 | 瑞士商瑞森製藥公司 | Cdk抑制劑 |
WO2022149057A1 (en) | 2021-01-05 | 2022-07-14 | Rhizen Pharmaceuticals Ag | Cdk inhibitors |
CN115322196A (zh) * | 2021-05-10 | 2022-11-11 | 药捷安康(南京)科技股份有限公司 | 多激酶抑制剂的药物组合物及其用途 |
WO2024030399A2 (en) * | 2022-08-02 | 2024-02-08 | Lab1636, Llc | Use of a gaba-a pam for reduction of tactile hypersensitivity |
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WO1998014450A1 (en) | 1996-10-02 | 1998-04-09 | Novartis Ag | Pyrimidine derivatives and processes for the preparation thereof |
US6350786B1 (en) * | 1998-09-22 | 2002-02-26 | Hoffmann-La Roche Inc. | Stable complexes of poorly soluble compounds in ionic polymers |
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