CN101812007B - 氨基吡咯类化合物及其制备方法 - Google Patents
氨基吡咯类化合物及其制备方法 Download PDFInfo
- Publication number
- CN101812007B CN101812007B CN2010101579032A CN201010157903A CN101812007B CN 101812007 B CN101812007 B CN 101812007B CN 2010101579032 A CN2010101579032 A CN 2010101579032A CN 201010157903 A CN201010157903 A CN 201010157903A CN 101812007 B CN101812007 B CN 101812007B
- Authority
- CN
- China
- Prior art keywords
- pyrroles
- methane amide
- carbonyl
- sulfonamido
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 Aminopyrrole compound Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 229940073608 benzyl chloride Drugs 0.000 claims description 14
- KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 abstract description 43
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 abstract description 3
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 2
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- 229930192474 thiophene Natural products 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 62
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 230000002194 synthesizing effect Effects 0.000 description 31
- 239000002994 raw material Substances 0.000 description 30
- KMVZDSQHLDGKGV-UHFFFAOYSA-N 2-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=CC=C1S(Cl)(=O)=O KMVZDSQHLDGKGV-UHFFFAOYSA-N 0.000 description 28
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 11
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 11
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 11
- 229960002448 dasatinib Drugs 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 10
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 10
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 208000032839 leukemia Diseases 0.000 description 6
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 5
- 229960002411 imatinib Drugs 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 229950004385 flunamine Drugs 0.000 description 4
- DHOQOKWZEBHCJT-UHFFFAOYSA-N fluorobenzene;methanamine Chemical compound NC.FC1=CC=CC=C1 DHOQOKWZEBHCJT-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 206010025482 malaise Diseases 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 125000005002 aryl methyl group Chemical group 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- TUOAXVJCEPMJTF-UHFFFAOYSA-N cumene;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.CC(C)C1=CC=CC=C1 TUOAXVJCEPMJTF-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 210000004214 philadelphia chromosome Anatomy 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032800 BCR-ABL1 positive blast phase chronic myelogenous leukemia Diseases 0.000 description 1
- 229940118364 Bcr-Abl inhibitor Drugs 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000004860 Blast Crisis Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- IIGKCFXOBRMPQC-UHFFFAOYSA-N CC(C)(C)NC(c1ccc(NC(c2ccccc2)=O)[nH]1)=O Chemical compound CC(C)(C)NC(c1ccc(NC(c2ccccc2)=O)[nH]1)=O IIGKCFXOBRMPQC-UHFFFAOYSA-N 0.000 description 1
- YOWOTEDNNMIHQP-UHFFFAOYSA-N CC(C)c(cc1)ccc1S(Nc1ccc(C(NCc(cccc2)c2F)=O)[nH]1)(=O)=O Chemical compound CC(C)c(cc1)ccc1S(Nc1ccc(C(NCc(cccc2)c2F)=O)[nH]1)(=O)=O YOWOTEDNNMIHQP-UHFFFAOYSA-N 0.000 description 1
- ACXKVGFTKRODDU-UHFFFAOYSA-N CC(C)c(cc1)ccc1S(Nc1ccc(C(NCc2ccccc2)=O)[nH]1)(=O)=O Chemical compound CC(C)c(cc1)ccc1S(Nc1ccc(C(NCc2ccccc2)=O)[nH]1)(=O)=O ACXKVGFTKRODDU-UHFFFAOYSA-N 0.000 description 1
- BIXDJBYRFMNLEH-UHFFFAOYSA-N CN(CC1)CCN1C(c1ccc(NS(c2ccc[s]2)(=O)=O)[nH]1)=O Chemical compound CN(CC1)CCN1C(c1ccc(NS(c2ccc[s]2)(=O)=O)[nH]1)=O BIXDJBYRFMNLEH-UHFFFAOYSA-N 0.000 description 1
- 0 Cc(cccc1*)c1S(Nc1ccc(C(NCc2ccccc2)O)[n]1)(=O)=O Chemical compound Cc(cccc1*)c1S(Nc1ccc(C(NCc2ccccc2)O)[n]1)(=O)=O 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- YQIOLXTXHRAWHH-UHFFFAOYSA-N O=C(c1ccc(NC(c2ccccc2)=O)[nH]1)NC1CC1 Chemical compound O=C(c1ccc(NC(c2ccccc2)=O)[nH]1)NC1CC1 YQIOLXTXHRAWHH-UHFFFAOYSA-N 0.000 description 1
- ONEKWPZSMZCXSN-UHFFFAOYSA-N O=C(c1ccc(NC(c2ccccc2)=O)[nH]1)NCc1ccccc1 Chemical compound O=C(c1ccc(NC(c2ccccc2)=O)[nH]1)NCc1ccccc1 ONEKWPZSMZCXSN-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000003995 blood forming stem cell Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 230000002559 cytogenic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- UTVVREMVDJTZAC-UHFFFAOYSA-N furan-2-amine Chemical compound NC1=CC=CO1 UTVVREMVDJTZAC-UHFFFAOYSA-N 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 125000002496 methyl group Chemical class [H]C([H])([H])* 0.000 description 1
- 210000004493 neutrocyte Anatomy 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明公开了一种氨基吡咯类化合物,其结构式为式(1):式(1)中,R1为取代的苯甲酰基、取代的苯磺酰基或噻吩磺酰基;R2为取代烷基、环烷基、取代的芳甲基或取代的杂环基。本发明还同时公开了该氨基吡咯类化合物的制备方法。该氨基吡咯类化合物能用于制备抗肿瘤/癌症药物。
Description
技术领域
本发明涉及一类抗肿瘤化合物及其制备方法。
背景技术
白血病是一种常见的肿瘤疾病,其发病率约为每10万人中3-4人,居于肿瘤疾病发病率的第六位。中国的白血病发病率与其它亚洲国家相近,但高于欧美国家,其中以慢性粒细胞性白血病(Chronic Myeloid Leukaemia,CML)多见。慢性粒细胞性白血病是一种与染色体9和22相互易位所产生的费城染色体相关的造血干细胞紊乱。这种染色体易位导致嵌合蛋白产物Bcr-Abl产生,它是Abl酪氨酸激酶的一种组合性活性形式。慢性粒细胞性白血病是一种渐进式疾病,它的发展经历了慢性期(chronic),渐快阶段期(accelerated)和突发危机期(blast crisis),其中突发危机期是最成熟的阶段。慢性粒细胞性白血病具有很高的难治性,三分之二病人的突发危机期的表现型为骨髓细胞性的,而余下三分之一病人的突发危机期的表现型为淋巴细胞性的。
口服Abl激酶抑制剂Imatinib和注射免疫调节剂干扰素都能在慢性粒细胞性白血病病人中产生持久性的响应。但Imatinib在治疗慢性期慢性粒细胞性白血病中是最有效的,其完整的血液响应率为95%,完整的细胞遗传学响应率为39%。
虽然Imatinib在治疗慢性期慢性粒细胞性白血病时非常有效,但是已经出现了Imatinib的耐药性,例如突发危机阶段2年期的耐药性发生率为80%。
Dasatinib是由美国BRISTOL-SQUIBB公司研发的一种口服的酪氨酸激酶抑制剂。其结构式如下:
该药于2006年6月上市,是第二代Bcr-Abl抑制剂,用于治疗由Bcr-Abl激酶突变引起的白血病,用于对既往治疗失败或不耐受的成人慢性髓性白血病的所有病期患者,同时还用于治疗对其他疗法耐药或不耐受的费城染色体阳性的急性淋巴细胞性白血病成人患者。Dasatinib属于多靶点酪氨酸激酶抑制剂,其最常见的严重副反应是发热、胸膜积液(在84位受治疗者中有15位出现体液潴留、胃肠道症状和出血事件)、发热性中性白细胞减少、胃肠道出血、肺炎、血小板减少、呼吸困难、贫血、腹泻和心脏衰竭等(FDA,OncologyDrug Advisory Committee,Briefing Document,Dasatinib,NDA 21-986.June 02,2006)。Dasatinib的生物利用度低(在临床前的动物实验中,小鼠为14%,狗为34%,猴子为15%),蛋白结合率为95%(Louis J.Lombardo,Journal of Medicinal Chemistry.2004,47,6658-6661)。Dasatinib的生物利用度过低是导致其对患者个体治疗差异大,副作用高于Imatinib的一个重要原因,另外,低生物利用度也限制了它在抗肿瘤疾病中更广泛的应用。
为了提高Dasatinib的疗效,降低副作用,以其为先导化合物,对其结构进行改造以发现具有疗效更好、副作用更小的新结构类型Bcr-Abl抑制剂,以发现新的抗肿瘤化合物。
发明内容
本发明要解决的技术问题是提供一种氨基吡咯类化合物,该氨基吡咯类化合物能用于制备抗肿瘤药物。
为了解决上述技术问题,本发明提供一种氨基吡咯类化合物,其结构式为式(1):
式(1)中,R1为取代的苯甲酰基、取代的苯磺酰基或噻吩磺酰基;R2为取代烷基、环烷基、取代的芳甲基或取代的杂环基。
作为本发明的氨基吡咯类化合物的改进:苯甲酰基为未取代的或经卤素取代,苯磺酰基为未取代的或经卤素/C1-C6烷基取代;烷基为C1-C6烷基;环烷基为C3-C6环烷基,芳甲基为未取代的或卤素取代苯甲基/呋喃甲基;杂环基为未取代的或经C1-C6烷基/苯甲基取代的六元杂环基,六元杂环为吗啉或哌嗪。
作为本发明的氨基吡咯类化合物的进一步改进,氨基吡咯类化合物为以下任意一个:
1)5-(2-氯苯甲酰氨基)-1H-吡咯-2-甲酸甲酯;
2)5-(2-氯苯甲酰氨基)-1H-吡咯-2-甲酸
3)5-(2-氯苯甲酰氨基)-N-(4-氟苄基)-1H-吡咯-2-甲酰胺
4)5-(2-氯苯甲酰氨基)-N-(4-氯苄基)-1H-吡咯-2-甲酰胺
5)N-苄基-5-(2-氯苯甲酰氨基)-1H-吡咯-2-甲酰胺
6)2-氯-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯甲酰胺
7)5-(2-氯苯甲酰氨基)-N-(2-氟苄基)-1H-吡咯-2-甲酰胺
8)5-(2-氯苯甲酰氨基)-N-(呋喃-2-甲基)-1H-吡咯-2-甲酰胺
9)2-氯-N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)苯甲酰胺
10)N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)-2-氯苯甲酰胺
11)N-叔丁基-5-(2-氯苯甲酰氨基)-1H-吡咯-2-甲酰胺
12)5-苯甲酰氨基-1H-吡咯-2-甲酸甲酯
13)5-苯甲酰氨基-1H-吡咯-2-甲酸
14)5-苯甲酰氨基-N-(4-氟苄基)-1H-吡咯-2-甲酰胺
15)5-苯甲酰氨基-N-(4-氯苄基)-1H-吡咯-2-甲酰胺
16)5-苯甲酰氨基-N-苄基-1H-吡咯-2-甲酰胺
17)N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯甲酰胺
18)5-苯甲酰氨基-N-(2-氟苄基)-1H-吡咯-2-甲酰胺
19)5-苯甲酰氨基-N-(呋喃-2-甲基)-1H-吡咯-2-甲酰胺
20)N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)苯甲酰胺
21)N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)苯甲酰胺
22)5-苯甲酰氨基-N-叔丁基-1H-吡咯-2-甲酰胺
23)5-苯甲酰氨基-N-异丁基-1H-吡咯-2-甲酰胺
24)5-苯甲酰氨基-N-环丙基-1H-吡咯-2-甲酰胺
25)5-苯甲酰氨基-N-环戊基-1H-吡咯-2-甲酰胺
26)N-(5-(4-乙基哌嗪-1-羰基)-1H-吡咯-2-基)苯甲酰胺
27)5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酸甲酯
28)5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酸
29)N-(4-氟苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
30)N-(4-氯苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
31)N-苄基-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
32)4-异丙基-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯磺酰胺
33)N-(2-氟苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
34)N-(呋喃-2-甲基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
35)4-异丙基-N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)苯磺酰胺
36)N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)-4-异丙基苯磺酰胺
37)N-叔丁基-5-(4-异丙基苯磺氨基)-1H-吡咯-2-甲酰胺
38)N-环丙基-5-(4-异丙基苯磺氨基)-1H-吡咯-2-甲酰胺
39)N-异丁基-5-(4-异丙基苯磺氨基)-1H-吡咯-2-甲酰胺
40)N-环戊基-5-(4-异丙基苯磺氨基)-1H-吡咯-2-甲酰胺
41)5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酸甲酯
42)5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酸
43)5-(2,6-二氯苯磺酰氨基)-N-(4-氟苄基)-1H-吡咯-2-甲酰胺
44)N-(4-氯苄基)-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺
45)N-苄基-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺
46)5-(2,6-二氯苯磺酰氨基)-N-(2-氟苄基)--1H-吡咯-2-甲酰胺
47)2,6-二氯-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯磺酰胺
48)2,6-二氯-N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)苯磺酰胺
49)N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)-2,6-二氯苯磺酰胺
50)5-(2,6-二氯苯磺酰氨基)-N-(呋喃-2-甲基)-1H-吡咯-2-甲酰胺
51)N-环戊基-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺
52)N-叔丁基-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺
53)N-环丙基-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺
54)5-(噻吩-2-磺酰氨基)-1H-吡咯-2-甲酸甲酯
55)5-(噻吩-2-磺酰氨基)-1H-吡咯-2-甲酸
56)N-(4-氟苄基)-5-(噻吩-2-磺酰氨基)-1H-吡咯-2-甲酰胺
57)N-(4-氯苄基)-5-(噻吩-2-磺酰氨基)-1H-吡咯-2-甲酰胺
58)N-苄基-5-(噻吩-2-磺酰氨基)-1H-吡咯-2-甲酰胺
59)N-(2-氯苄基)-5-(噻吩-2-磺酰氨基)-1H-吡咯-2-甲酰胺
60)N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)噻吩-2-磺酰胺
61)N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)噻吩-2-磺酰胺
62)N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)噻吩-2-磺酰胺
本发明还同时提供了上述氨基吡咯类化合物的制备方法,其反应方程式如下:
作为本发明的氨基吡咯类化合物的制备方法的改进,其包括如下步骤:
1)、在冰浴中,取化合物1溶于CH2Cl2中,再加入三乙胺,当温度下降到-5~5℃,将取代磺酰氯或酰氯缓慢滴加到上述体系中,室温反应,加入饱和NaHCO3进行洗涤,CH2Cl2层旋转蒸发被除去后,硅胶柱层析,得化合物2;
2)、取化合物2,用甲醇∶水为5∶1体积比的溶液溶解;加入LiOH·H2O,室温反应完全;旋蒸除去甲醇后,用1N的HCl调pH直至产生固体,过滤,干燥得化合物3;
3)、在冰浴条件下,取EDC.HCl、HOBt溶于CH2Cl2中,加入化合物3,滴加取代胺,室温反应;加入饱和NaHCO3进行洗涤,CH2Cl2层旋转蒸发除去后,硅胶柱层析,得氨基吡咯类化合物。
本发明以Dasatinib为先导化合物,对其结构进行改造,合成了通式(I)所示的一类新化合物,以发现疗效更好、副作用更小的抗肿瘤化合物。本发明的氨基吡咯类化合物具有抗肿瘤/癌症的作用。例如对以下癌症具有作用:白血病、急性粒细胞性白血病、慢性粒细胞性白血病、慢性淋巴性白血病、急性淋巴性白血病、脊髓发育不良、多发性骨髓瘤、何杰金氏病或非何杰金氏淋巴瘤、小细胞或非小细胞性肺癌、胃癌、肠癌或结肠直肠癌、前列腺癌、卵巢癌、乳腺癌、脑癌、泌尿道癌、肾癌、膀胱癌、恶性黑素瘤、肝癌、子宫癌或者胰腺癌。实际使用时,本发明的用法及用量等同Dasatinib。
具体实施方式
以下通过具体的实施例进一步说明本发明是如何实现的:
实施例1、5-(2,6-二氯苯磺酰氨基)-N-(4-氟苄基)-1H-吡咯-2-甲酰胺(XW4-1)的合成,依次进行以下步骤:
1)、在冰浴中,取5-氨基-1H-吡咯-2-甲酸甲酯0.428g(3.06mmol)溶于CH2Cl230ml,再往溶液中加入0.402g(3.98mmol)三乙胺,当温度下降到0℃左右,将0.977g(3.98mmol)2,6-二氯苯磺酰氯溶于10ml CH2Cl2溶液缓慢滴加到上述体系中,冰浴反应0.5h之后进行室温(10~30℃)反应,4h之后停止反应,加入饱和NaHCO3进行洗涤,CH2Cl2层旋转蒸发被除去后,硅胶柱层析(石油醚∶乙酸乙酯=1∶4),得0.452g的5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酸甲酯,收率:42.3%。
2)、取5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酸甲酯0.452g(1.299mmol),用甲醇∶水为5∶1(体积比)的混合溶液50ml溶解;然后再称取LiOH·H2O 0.5g,用25ml的水溶解完毕后,缓慢加入到上述体系中。室温搅拌过夜(16h)后,反应完毕。旋蒸除去甲醇后,用1N的HCl调pH直至析出黄色固体,过滤,得0.433g 5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酸,收率:99.5%。
3)、在冰浴条件下,取0.08g(0.42mmol)EDC.HCl和HOBt 0.067g(0.50mmol)溶于15ml的CH2Cl2中,搅拌一段时间(10min)后;将0.095g(0.283mmol)5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酸加到上述体系中,搅拌5min后,往体系中滴加0.053g(0.42mmol)4-氟苄胺,冰浴中反应1h后,转到室温反应,5h后反应完毕。加入饱和NaHCO3进行洗涤,CH2Cl2层旋转蒸发除去后,硅胶柱层析(石油醚∶乙酸乙酯=1∶10的体积比),得0.081g5-(2,6-二氯苯磺酰氨基)-N-(4-氟苄基)-1H-吡咯-2-甲酰胺,收率;43.0%;1H-NMR(500MHz,DMSO-d6):δ11.35(s,1H),10.03(s,1H),8.57(t,J=6.0Hz,1H),7.58-7.60(m,2H),7.50-7.53(m,1H),7.26-7.29(m,2H),7.10-7.14(m,2H),6.58-6.59(m,1H),6.55-6.56(m,1H),4.33(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+442.02.
实施例2、N-苄基-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺(XW4-7)的合成:
步骤1)和步骤2)同实施例1。
在冰浴条件下,取0.08g(0.42mmol)EDC.HCl和HOBt 0.067g(0.50mmol)溶于15ml的CH2Cl2中,搅拌一段时间(10min)后;将0.095g(0.283mmol)5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酸缓慢滴加到上述体系中,搅拌5min后,往体系中滴加0.074g(0.42mmol)N-苄基哌嗪,冰浴中反应1h后,转到室温反应,5h后反应完毕。加入饱和NaHCO3进行洗涤,CH2Cl2层旋转蒸发除去后,硅胶柱层析(石油醚∶乙酸乙酯=1∶10的体积比),得0.081g N-苄基-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺,收率:62%。δ11.35(s,1H,1-NH),10.00(s,1H),8.57(t,J=6.0Hz,1H),7.58-7.60(m,2H),7.50-7.53(m,1H),7.20-7.31(m,5H),6.59-6.60(m,1H),6.55-6.56(m,1H),4.36(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+424.03。
实施例3
5-(2-氯苯甲酰氨基)-N-(4-氟苄基)-1H-吡咯-2-甲酰胺(XW1-1)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,以4-氟苄胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:81.4%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.25(s,1H),10.35(s,1H,5-NH),8.61(t,J=6.0Hz,1H),7.50-7.54(m,1H),7.50-7.54(m,1H),7.45-7.49(m,1H),7.40-7.44(m,1H),7.31-7.34(m,2H),7.13-7.16(m,2H),7.12-7.13(m,1H),6.91-6.92(m,1H,H-4),4.39(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+372.21.
实施例4
5-(2-氯苯甲酰氨基)-N-(4-氯苄基)-1H-吡咯-2-甲酰胺(XW1-2)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,以4-氯苄胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:76.6%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.26(s,1H),10.36(s,1H),8.64(t,J=6.0Hz,1H),7.51-7.54(m,1H),7.51-7.54(m,1H),7.45-7.49(m,1H),7.41-7.44(m,1H),7.38(d,J=8.5Hz,2H),7.31(d,J=8.5Hz,2H),7.16-7.17(m,1H),6.92-6.93(m,1H),4.40(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+388.19.
实施例5
N-苄基-5-(2-氯苯甲酰氨基)-1H-吡咯-2-甲酰胺(XW1-3)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,其余同实施例1(原料之间的配比关系按照摩尔比),收率:58.8%,得化合物1H-NMR(500MHz,DMSO-d6):δ11.25(s,1H),10.35(s,1H),8.61(t,J=6.0Hz,1H),7.50-7.54(m,1H),7.50-7.54(m,1H),7.45-7.49(m,1H),7.41-7.44(m,1H),7.21-7.34(m,5H),7.16-7.17(m,1H),6.92-6.93(m,1H,H-4),4.42(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+354.23.
实施例6
2-氯-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯甲酰胺(XW1-4)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,以吗啉代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:86%,所得化合物1H-NMR(500MHz,DMSO-d6):δ11.29(s,1H),10.33(s,1H),7.50-7.54(m,1H),7.50-7.54(m,1H),7.46-7.49(m,1H),7.41-7.44(m,1H),7.19-7.20(m,1H),6.53-6.54(m,1H),3.68(t,J=4.0Hz,4H),3.62(t,J=4.0Hz,4H);ESI-MS m/z[M+H]+334.21.
实施例7
5-(2-氯苯甲酰氨基)-N-(2-氟苄基)-1H-吡咯-2-甲酰胺(XW1-5)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,以2-氟苄胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:73.7%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.26(s,1H),10.36(s,1H),8.58(t,J=6.0Hz,1H),7.51-7.54(m,1H),7.51-7.54(m,1H),7.46-7.49(m,1H),7.41-7.44(m,1H),7.33-7.36(m,1H),7.28-7.31(m,1H),7.16-7.18(m,1H),7.16-7.18(m,1H),7.15-7.16(m,1H),6.95-6.96(m,1H),4.46(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+372.21.
实施例8
5-(2-氯苯甲酰氨基)-N-(呋喃-2-甲基)-1H-吡咯-2-甲酰胺(XW1-6)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,以2-呋喃甲胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:82.2%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.24(s,1H),10.35(s,1H,5-NH),8.52(t,J=6.0Hz,1H),7.56(d,J=3.0Hz,1H),7.50-7.54(m,1H),7.50-7.54(m,1H),7.45-7.49(m,1H),7.40-7.43(m,1H),7.16-7.17(m,1H),6.89-6.90(m,1H),6.38-6.39(m,1H),6.23(d,J=3.0Hz,1H),4.40(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+344.20.
实施例9
2-氯-N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)苯甲酰胺(XW1-7)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,以N-甲基哌嗪代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:75.2%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.30(s,1H,1-NH),10.36(s,1H),7.51-7.55(m,1H),7.51-7.55(m,1H),7.46-7.50(m,1H),7.41-7.44(m,1H),7.18-7.19(m,1H),6.51-6.52(m,1H),3.67(t,J=5.0,4H),2.33(t,J=5.0Hz,4H),2.20(s,3H);ESI-MS m/z[M+H]+347.24.
实施例10
N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)-2-氯苯甲酰胺(XW1-8)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,以N-苯甲基哌嗪代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:82.2%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.29(s,1H),10.35(s,1H),7.49-7.544(m,1H),7.49-7.54(m,1H),7.45-7.49(m,1H),7.40-7.43(m,1H),7.25-7.33(m,5H),7.17-7.18(m,1H),6.49-6.50(m,1H),3.67(t,J=5.0Hz,4H),3.50(s,2H),2.39(t,J=5.0Hz,4H);ESI-MSm/z[M+H]+423.24.
实施例11
N-叔丁基-5-(2-氯苯甲酰氨基)-1H-吡咯-2-甲酰胺(XW1-9)的合成:
以2-氯苯甲酰氯代替2,6-二氯苯磺酰氯,以叔丁胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:39.3%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.11(s,1H),10.32(s,1H),7.50-7.54(m,1H),7.50-7.54(m,1H),7.46-7.49(m,1H),7.41-7.44(m,1H),7.38(s,1H),7.11-7.12(m,1H),6.85-6.86(m,1H),1.36(s,9H);ESI-MS m/z[M+H]+320.22
实施例12
5-苯甲酰氨基-N-(4-氟苄基)-1H-吡咯-2-甲酰胺(XW2-1)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以4-氟苯甲胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:82.8%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.26(s,1H),10.29(s,1H),8.64(t,J=6.0,1H),7.93(d,J=7.0Hz,2H),7.49-7.55(m,3H),7.32-7.35(m,2H),7.25-7.26(m,1H),7.13-7.17(m,2H),7.00-7.01(m,1H),4.41(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+338.28.
实施例13
5-苯甲酰氨基-N-(4-氯苄基)-1H-吡咯-2-甲酰胺(XW2-2)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以4-氯苄胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:73.7%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.27(s,1H),10.30(s,1H),8.66(t,J=6.0Hz,1H),7.93(d,J=7.0Hz,2H),7.49-7.56(m,3H),7.39(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),7.25-7.26(m,1H),7.00-7.01(m,1H),4.41(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+354.25.
实施例14
5-苯甲酰氨基-N-苄基-1H-吡咯-2-甲酰胺(XW2-3)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,其余同实施例1(原料之间的配比关系按照摩尔比),收率:72.8%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.22(s,1H),10.26(s,1H),8.59(t,J=6.0Hz,1H),7.93(d,J=7.0Hz,2H),7.49-7.55(m,3H),7.23-7.34(m,5H),7.32(d,J=8.0Hz,2H),7.25-7.26(m,1H),7.00-7.01(m,1H),4.43(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+320.28.
实施例15
N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯甲酰胺(XW2-4)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以吗啉代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:39.6%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.26(s,1H),10.24(s,1H),7.93(d,J=7.0Hz,2H),7.49-7.57(m,3H),7.29-7.30(m,1H),6.65-6.66(m,1H),3.70(t,J=4.5Hz,4H),3.63(t,J=4.5Hz,4H);ESI-MSm/z[M+H]+300.23.
实施例16
5-苯甲酰氨基-N-(2-氟苄基)-1H-吡咯-2-甲酰胺(XW2-5)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以2-氟苯甲胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:71.7%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.23(s,1H),10.25(s,1H),8.56(t,J=6.0Hz,1H),7.92(d,J=7.0Hz,2H),7.48-7.54(m,3H),7.33-7.37(m,1H),7.27-7.31(m,1H),7.24-7.25(m,1H),7.14-7.18(m,2H),7.01-7.02(m,1H),4.47(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+338.28.
实施例17
5-苯甲酰氨基-N-(呋喃-2-甲基)-1H-吡咯-2-甲酰胺(XW2-6)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以2-呋喃甲胺胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:78.5%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.22(s,1H),10.25(s,1H),8.51(t,J=6.0Hz,1H),7.93(d,J=7.0Hz,2H),7.56(d,J=3.0Hz,1H),7.48-7.55(m,3H),7.25-7.26(m,1H),6.97-6.98(m,1H),6.38-6.39(m,1H),6.24(d,J=3.0Hz,1H),4.41(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+310.23.
实施例18
N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)苯甲酰胺(XW2-8)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以N-苄基哌嗪代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:82.6%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.25(s,1H),10.25(s,1H),7.93(d,J=7.0Hz,2H),7.48-7.56(m,3H),7.25-7.35(m,5H),7.28-7.29(m,1H),6.61-6.62(m,1H),3.70(t,J=5.0Hz,4H),3.52(s,2H),2.41(t,J=5.0Hz,4H);ESI-MS m/z[M+H]+389.37.
实施例19
5-苯甲酰氨基-N-异丁基-1H-吡咯-2-甲酰胺(XW2-9)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以异丁胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:49.0%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.17(s,1H),10.26(s,1H),8.04(t,J=6.0,1H),7.93(d,J=7.0Hz,2H),7.49-7.55(m,3H),7.21-7.22(m,1H),6.96-6.97(m,1H),3.03(t,J=6.0Hz,2H),1.78-1.82(m,1H),0.88(d,J=6.0Hz,6H);ESI-MS m/z[M+H]+286.29.
实施例20
5-苯甲酰氨基-N-叔丁基-1H-吡咯-2-甲酰胺(XW2-10)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以叔丁胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:40.8%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.09(s,1H),10.22(s,1H),7.92(d,J=7.0Hz,2H),7.49-7.56(m,3H),7.34(s,1H),7.20-7.21(m,1H),6.93-6.94(m,1H),1.36(s,9H);ESI-MS m/z[M+H]+286.29.
实施例21
5-苯甲酰氨基-N-环丙基-1H-吡咯-2-甲酰胺(XW2-11)的合成:
以苯甲酰氯代替2,6-二氯苯磺酰氯,以环丙胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:45.1%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.14(s,1H),10.22(s,1H),8.03(s,1H),7.92(d,J=7.0Hz,2H),7.48-7.54(m,3H),7.20-7.21(m,1H),6.93-6.94(m,1H),2.74-2.80(m,1H),0.64-0.68(m,2H),0.53-0.55(m,2H);ESI-MS m/z[M+H]+270.06.
实施例22
N-(4-氟苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺(XW3-1)的合成:
以4-异丙基磺酰氯代替2,6-二氯苯磺酰氯,以4-氟苯甲胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:75.8%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.23(s,1H),9.54(s,1H),8.53(t,J=6.0Hz,1H),7.62(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.27-7.30(m,2H),7.10-7.13(m,2H),6.56-6.57(m,1H),6.45-6.46(m,1H),4.34(d,J=6.0Hz,2H),2.90-2.96(m,J=7.0Hz,1H),1.19(d,J=7.0Hz,6H);ESI-MS m/z[M+H]+416.08.
实施例23
N-(4-氯苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺(XW3-2)的合成:
以4-异丙基苯磺酰氯代替2,6-二氯苯磺酰氯,以4-氯苯甲胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:72.1%%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.24(s,1H),9.55(s,1H),8.55(t,J=6.0Hz,1H),7.62(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.36(d,J=8.5Hz,2H),7.27(d,J=8.5Hz,2H),6.56-6.57(m,1H),6.45-6.46(m,1H),4.34(d,J=6.0Hz,2H),2.89-2.97(m,J=7.0Hz,1H),1.19(d,J=7.0Hz,6H);ESI-MS m/z[M+H]+432.04.
实施例24
N-苄基-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺(XW3-3)的合成:
以4-异丙基苯磺酰氯代替2,6-二氯苯磺酰氯,以苯甲胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:83.6%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.22(s,1H),9.54(s,1H),8.52(t,J=6.0Hz,1H),7.62(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H),7.20-7.31(m,5H),6.57-6.58(m,1H),6.45-6.46(m,1H),4.36(d,J=6.0Hz,2H),2.89-2.97(m,J=7.0Hz,1H),1.19(d,J=7.0Hz,6H);ESI-MSm/z[M+H]+398.08.
实施例25
4-异丙基-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯磺酰胺(XW3-4)的合成:
以4-异丙基磺酰氯代替2,6-二氯苯磺酰氯,以吗啉代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:76.2%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.28(s,1H),9.45(s,1H),7.61(d,J=8.5Hz,2H),7.40(d,J=8.5Hz,2H),6.50-6.51(m,1H),6.00-6.01(m,1H),3.56(s,8H),2.90-2.99(m,J=7.0Hz,1H),1.20(d,J=7.0,6H,H-8′,9′);ESI-MS m/z[M+H]+378.09.
实施例26
N-(2-氟苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺(XW3-5)的合成:
以4-异丙基磺酰氯代替2,6-二氯苯磺酰氯,以2-氟苄胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:73.5%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.24(s,1H),9.55(s,1H),8.50(t,J=6.0Hz,1H),7.62(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.27-7.31(m,2H),7.12-7.17(m,1H),6.59-6.60(m,1H),6.46-6.47(m,1H),4.40(d,J=6.0Hz,2H),2.89-2.98(m,J=7.0Hz,1H),1.19(d,J=7.0Hz,6H);ESI-MS m/z[M+H]+416.08.
实施例27
4-异丙基-N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)苯磺酰胺(XW3-7)的合成:
以4-异丙基磺酰氯代替2,6-二氯苯磺酰氯,以N-甲基哌嗪代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:70.7%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.25(s,1H),9.43(s,1H),7.62(d,J=8.0,2H),7.41(d,J=8.0Hz,2H),6.51-6.52(m,1H),5.95-5.96(m,1H),3.53(t,J=5.0Hz,4H),2.92-2.98(m,J=7.0Hz),2.26(t,J=5.0Hz,4H),2.18(s,3H),1.19(d,J=7.0Hz,6H);ESI-MSm/z[M+H]+391.13.
实施例28
N-(4-氯苄基)-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺(XW4-2)的合成:
以4-氯苯甲胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比)收率:35.0%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.36(s,1H),10.03(s,1H),8.59(t,J=6.0Hz,1H),7.58-7.60(m,2H),7.50-7.53(m,1H),7.36(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),6.58-6.60(m,1H),6.55-6.56(m,1H),4.33(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+458.00.
实施例29
N-苄基-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺(XW4-3)的合成:
以苄胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比)收率:62.4%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.35(s,1H,1-NH),10.00(s,1H,5-NH),8.57(t,J=6.0,1H,1′″-NH),7.58-7.60(m,2H,H-3′,5′),7.50-7.53(m,1H,H-4′),7.20-7.31(m,5H,H-2″,3″,4″,5″,6″),6.59-6.60(m,1H,H-3),6.55-6.56(m,1H,H-4),4.36(d,J=6.0,2H,H-1′″);ESI-MS m/z[M+H]+424.03.
实施例30
2,6-二氯-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯磺酰胺(XW4-5)的合成:
以苄胺代替N-苄基哌嗪,其余同实施例1(原料之间的配比关系按照摩尔比),收率:76.6%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.38(s,1H),10.03(s,1H),7.59-7.61(m,2H),7.51-7.54(m,1H),6.56-6.57(m,1H),6.09-6.10(m,1H),3.56(s,8H);ESI-MS m/z[M+H]+404.02.
实施例31
N-(2-氟苄基)-5-(噻吩-2-磺酰氨基)-1H-吡咯-2-甲酰胺(XW5-4)的合成:
以2-噻吩磺酰氯代替2,6-二氯苯磺酰氯,以2-氟苯甲胺代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:27.1%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.37(s,1H),9.76(s,1H),8.57(t,J=6.0Hz,1H),7.87(dd,J=5.0Hz,1.0Hz,1H),7.45(dd,J=3.5Hz,1.0Hz,1H),7.28-7.33(m,2H),7.14-7.18(m,2H),7.10-7.13(m,1H),6.62-6.63(m,1H),6.53-6.54(m,1H),4.42(d,J=6.0Hz,2H);ESI-MS m/z[M+H]+379.96.
实施例32
N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)噻吩-2-磺酰胺(XW5-7)的合成:
以2-噻吩磺酰氯代替2,6二氯苯磺酰氯,以吗啉代替苄胺,其余同实施例1(原料之间的配比关系按照摩尔比),收率:40.5%。所得化合物1H-NMR(500MHz,DMSO-d6):δ11.42(s,1H),9.71(s,1H),7.89(dd,J=5.0Hz,1.5Hz,1H),7.45(dd,J=4.0Hz,1.5Hz,1H),7.12-7.14(m,1H),6.57-6.58(m,1H),6.07-6.08(m,1H),3.58(s,8H);ESI-MS m/z[M+H]+341.95.
生物活性试验:
用MTT法对本发明所示化合物和Dasatinib进行白血病K562细胞株增殖抑制活性对比实验。以DMSO作为对照溶剂。
实验步骤:
1)收集对数期生长的细胞,调节细胞悬液浓度1×104/孔(96孔板)。
2)加入化合物,使终浓度达到30μmol/L。
3)置37℃,5%CO2孵育44小时,倒置显微镜下观察。
4)每孔加入20μl MTT溶液(5mg/ml,即0.5%MTT),继续培养4h。
5)用转子离心6min,小心吸掉上清,每孔加入150ul二甲基亚砜,置摇床上低速振荡10min,在酶联免疫检测仪OD570nm(630nm校准)测量各孔的吸光值。
抑制率(IR%)=(1-TOD/COD)×100%
TOD:给药组OD均值 COD:溶剂对照组OD均值
实验结果见下表1:
表1
化合物编号 | 抑制率 | 化合物编号 | 抑制率 | 化合物编号 | 抑制率 |
xw1-1 | 11.02% | xw2-4 | 27.13% | xw3-7 | 14.39% |
xw1-2 | 18.96% | xw2-5 | 10.43% | xw3-12 | 21.30% |
xw1-3 | 28.32% | xw2-6 | 12.80% | xw4-1 | 44.45% |
xw1-4 | 29.98% | xw2-8 | 0.80% | xw4-2 | 20.81% |
xw1-5 | 27.84% | xw2-9 | 18.58% | xw4-3 | 31.88% |
xw1-6 | 21.80% | xw2-10 | 7.51% | xw4-5 | 29.89% |
xw1-7 | 26.30% | xw2-11 | 3.82% | xw4-7 | 44.20% |
xw1-8 | 33.89% | xw3-1 | 2.81% | xw5-4 | 23.92% |
xw1-9 | 8.65% | xw3-2 | 32.51% | xw5-7 | 26.78% |
xw2-1 | 7.35% | xw3-3 | 26.97% | Dasatinib | 36.5% |
xw2-2 | 3.91% | xw3-4 | 5.16% | ||
xw2-3 | 13.15% | xw3-5 | 35.20% |
结果显示,大多数化合物具有抑制白血病K562细胞株增殖活性,其中化合物xw4-1和化合物xw4-7的活性高于上市药Dasatinib。
最后,还需要注意的是,以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (1)
1.一种氨基吡咯类化合物,其特征在于:所述氨基吡咯类化合物为以下任意一个:
5-(2-氯苯甲酰氨基)-N-(4-氟苄基)-1H-吡咯-2-甲酰胺
5-(2-氯苯甲酰氨基)-N-(4-氯苄基)-1H-吡咯-2-甲酰胺
N-苄基-5-(2-氯苯甲酰氨基)-1H-吡咯-2-甲酰胺
2-氯-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯甲酰胺
5-(2-氯苯甲酰氨基)-N-(2-氟苄基)-1H-吡咯-2-甲酰胺
5-(2-氯苯甲酰氨基)-N-(呋喃-2-甲基)-1H-吡咯-2-甲酰胺
2-氯-N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)苯甲酰胺
N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)-2-氯苯甲酰胺
N-叔丁基-5-(2-氯苯甲酰氨基)-1H-吡咯-2-甲酰胺
5-苯甲酰氨基-N-(4-氟苄基)-1H-吡咯-2-甲酰胺
5-苯甲酰氨基-N-(4-氯苄基)-1H-吡咯-2-甲酰胺
5-苯甲酰氨基-N-苄基-1H-吡咯-2-甲酰胺
N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯甲酰胺
5-苯甲酰氨基-N-(2-氟苄基)-1H-吡咯-2-甲酰胺
5-苯甲酰氨基-N-(呋喃-2-甲基)-1H-吡咯-2-甲酰胺
N-(5-(4-苄基哌嗪-1-羰基)-1H-吡咯-2-基)苯甲酰胺
5-苯甲酰氨基-N-叔丁基-1H-吡咯-2-甲酰胺
5-苯甲酰氨基-N-异丁基-1H-吡咯-2-甲酰胺
5-苯甲酰氨基-N-环丙基-1H-吡咯-2-甲酰胺
N-(4-氟苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
N-(4-氯苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
N-苄基-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
4-异丙基-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯磺酰胺
N-(2-氟苄基)-5-(4-异丙基苯磺酰氨基)-1H-吡咯-2-甲酰胺
4-异丙基-N-(5-(4-甲基哌嗪-1-羰基)-1H-吡咯-2-基)苯磺酰胺
5-(2,6-二氯苯磺酰氨基)-N-(4-氟苄基)-1H-吡咯-2-甲酰胺
N-(4-氯苄基)-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺
N-苄基-5-(2,6-二氯苯磺酰氨基)-1H-吡咯-2-甲酰胺
2,6-二氯-N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)苯磺酰胺
N-(4-氟苄基)-5-(噻吩-2-磺酰氨基)-1H-吡咯-2-甲酰胺
N-(5-(吗啉-4-羰基)-1H-吡咯-2-基)噻吩-2-磺酰胺
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010101579032A CN101812007B (zh) | 2010-04-27 | 2010-04-27 | 氨基吡咯类化合物及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010101579032A CN101812007B (zh) | 2010-04-27 | 2010-04-27 | 氨基吡咯类化合物及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101812007A CN101812007A (zh) | 2010-08-25 |
CN101812007B true CN101812007B (zh) | 2011-11-23 |
Family
ID=42619392
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010101579032A Expired - Fee Related CN101812007B (zh) | 2010-04-27 | 2010-04-27 | 氨基吡咯类化合物及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101812007B (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1541214A (zh) * | 2001-07-25 | 2004-10-27 | 新化合物 | |
CN101622229A (zh) * | 2007-02-26 | 2010-01-06 | 参天制药株式会社 | 具有脲基和氨基羰基作为取代基的新型吡咯衍生物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2642762A1 (en) * | 2006-02-16 | 2007-08-30 | Schering Corporation | Pyrrolidine derivatives as erk inhibitors |
-
2010
- 2010-04-27 CN CN2010101579032A patent/CN101812007B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1541214A (zh) * | 2001-07-25 | 2004-10-27 | 新化合物 | |
CN101622229A (zh) * | 2007-02-26 | 2010-01-06 | 参天制药株式会社 | 具有脲基和氨基羰基作为取代基的新型吡咯衍生物 |
Non-Patent Citations (2)
Title |
---|
武慧等.Bcr - Abl酪氨酸激酶抑制剂治疗慢性粒细胞白血病的研究进展.《内蒙古医学院学报》.2008,第30卷55-58. |
武慧等.Bcr- Abl酪氨酸激酶抑制剂治疗慢性粒细胞白血病的研究进展.《内蒙古医学院学报》.2008,第30卷55-58. * |
Also Published As
Publication number | Publication date |
---|---|
CN101812007A (zh) | 2010-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105899490B (zh) | 嘧啶fgfr4抑制剂 | |
JP6321821B2 (ja) | 2,3,4,6−4置換ベンゼン−1,5−ジアミン誘導体、その製造方法および医薬品における使用 | |
CN105646454B (zh) | 含异羟肟酸片段的2-芳胺基嘧啶类衍生物及制备和应用 | |
CN105001208A (zh) | 一种表皮生长因子受体egfr抑制剂及其制备方法与用途 | |
CN101163684A (zh) | 具有酪氨酸激酶抑制作用的喹唑啉衍生物 | |
CN107383004B (zh) | 2-氨基咪唑并吡啶类衍生物及制备和应用 | |
WO2016124160A1 (zh) | 作为egfr抑制剂的嘧啶并嘧啶二酮衍生物及其应用 | |
CN105585565B (zh) | 含2-苯胺基-4-噻唑基吡啶衍生物及其制法和药物组合物与用途 | |
WO2016023330A1 (zh) | 喹唑啉衍生物 | |
CN103382182B (zh) | 苯基脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途 | |
WO2014029726A1 (en) | Novel phenyl-pyridine/pyrazine amides for the treatment of cancer | |
CN107739368B (zh) | N-取代-5-((4-取代嘧啶-2-基)氨基)吲哚类衍生物及其制备方法和用途 | |
CN114685382A (zh) | 具有HDACs抑制活性的喹唑啉-4-胺衍生物及其制备方法与用途 | |
WO2017144025A1 (zh) | 作为EGFR抑制剂的嘧啶并[4,5-d][1,3]噁嗪-2-酮衍生物及其应用 | |
CN103288804A (zh) | 一种尼洛替尼的制备方法 | |
CN101812007B (zh) | 氨基吡咯类化合物及其制备方法 | |
CN108715589B (zh) | 一种用作caspase-3激活剂的香豆素类衍生物及其应用 | |
CN101875617B (zh) | 烷氧基取代芳环的氨甲酰基类芳酸化合物及其制法和用途 | |
CN115141197B (zh) | 一种3-芳杂环取代苯基衍生物及其制备方法与用途 | |
CN109734700A (zh) | 含苯甲酰哌啶结构的smo抑制剂及其制备方法与用途 | |
CN108997176A (zh) | 一种4-氯-n-取代苯基-3-磺酰氨基苯甲酰胺类化合物及其制备和抗肿瘤应用 | |
CN104974109A (zh) | 含噻唑的丙炔酰胺类衍生物及其制法和药物组合物与用途 | |
CN103435554A (zh) | 2-苯氨基苯并咪唑类化合物及其用途 | |
CN107311933A (zh) | 一类苯并咪唑衍生物,及其制备方法和用途 | |
ES2881960T3 (es) | Inhibidores de proteina quinasa |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20111123 Termination date: 20120427 |