CN108653282B - 苯并噻唑类及苯并吡咯类化合物在制备抗肿瘤药物中的应用 - Google Patents
苯并噻唑类及苯并吡咯类化合物在制备抗肿瘤药物中的应用 Download PDFInfo
- Publication number
- CN108653282B CN108653282B CN201810683777.0A CN201810683777A CN108653282B CN 108653282 B CN108653282 B CN 108653282B CN 201810683777 A CN201810683777 A CN 201810683777A CN 108653282 B CN108653282 B CN 108653282B
- Authority
- CN
- China
- Prior art keywords
- preparation
- compounds
- application
- cancer
- pharmaceutical composition
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 13
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 229940041181 antineoplastic drug Drugs 0.000 title claims description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 239000006188 syrup Substances 0.000 claims description 3
- 235000020357 syrup Nutrition 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003094 microcapsule Substances 0.000 claims description 2
- 239000012053 oil suspension Substances 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000007901 soft capsule Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 1
- 101150040313 Wee1 gene Proteins 0.000 abstract description 18
- 229940043355 kinase inhibitor Drugs 0.000 abstract description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 239000012623 DNA damaging agent Substances 0.000 abstract 1
- 230000004663 cell proliferation Effects 0.000 abstract 1
- 230000005918 in vitro anti-tumor Effects 0.000 abstract 1
- 238000012216 screening Methods 0.000 abstract 1
- 229940126585 therapeutic drug Drugs 0.000 abstract 1
- 210000004881 tumor cell Anatomy 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- -1 sugar coating Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 102000009728 CDC2 Protein Kinase Human genes 0.000 description 3
- 108010034798 CDC2 Protein Kinase Proteins 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 230000012746 DNA damage checkpoint Effects 0.000 description 2
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 2
- 208000009849 Female Genital Neoplasms Diseases 0.000 description 2
- 230000004668 G2/M phase Effects 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 208000029584 urinary system neoplasm Diseases 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000006274 Brain Stem Neoplasms Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- 102000002427 Cyclin B Human genes 0.000 description 1
- 108010068150 Cyclin B Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 230000010337 G2 phase Effects 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000015021 Meningeal Neoplasms Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 101710150974 Regulator of chromosome condensation Proteins 0.000 description 1
- 102100039977 Regulator of chromosome condensation Human genes 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 241000235347 Schizosaccharomyces pombe Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- ROAYSRAUMPWBQX-UHFFFAOYSA-N ethanol;sulfuric acid Chemical compound CCO.OS(O)(=O)=O ROAYSRAUMPWBQX-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000022006 malignant tumor of meninges Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- JWWVWJOIKZNCSU-UHFFFAOYSA-N methanesulfonic acid;2,2,2-trifluoroacetic acid Chemical compound CS(O)(=O)=O.OC(=O)C(F)(F)F JWWVWJOIKZNCSU-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000006618 mitotic catastrophe Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical class N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 208000010916 pituitary tumor Diseases 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供苯并噻唑类化合物和苯并吡咯类化合物，以其为活性成分的药物组合物，及其作为Wee1激酶抑制剂，和在制备抗癌治疗药物中的应用。Wee1已被证实与DNA损伤药物连用可增强其抗肿瘤活性。本发明提供了苯并噻唑类化合物和苯并吡咯类化合物在制备Wee1抑制剂中的应用。该系列化合物经过体外抗肿瘤细胞活性筛选实验，证实其有明显的抗肿瘤细胞增殖活性。
Description
技术领域
本发明涉及医药技术领域，具体地涉及苯并噻唑类及苯并吡咯类化合物，以它们为活性成分的药物组合物，和它们在制备Wee1激酶抑制剂中的应用，以及它们在制备抗肿瘤药物中的应用。
背景技术
Wee1蛋白激酶首先在裂殖酵母细胞中发现，属于丝氨酸、苏氨酸蛋白激酶家族，高度保守并广泛存在于真核生物中。它是一种细胞周期调节蛋白，主要在细胞周期的S期或G2/M期被激活。它能调控细胞周期蛋白依赖性激酶1(CDK1)的磷酸化状态，从而调节CDK1与细胞周期蛋白B(cyclinB)复合物的活性从而实现对细胞周期的调控，且对DNA损伤检查点具有重要的调节作用。Wee1蛋白激酶通过3个细胞检查点的作用调控有丝分裂，即细胞G2/M期检查点、细胞大小检查点和细胞DNA损伤检查点。研究显示，在多类恶性肿瘤细胞中都检测到Wee1激酶存在过表达，表明了Wee1激酶是癌症治疗的一个候选靶点。
目前，基于Wee1激酶的抑制剂主要有三种，分别是MK-1775，PD0407824，PD0166285。其中MK-1775联合其他化疗药物治疗卵巢癌，目前处于临床Ⅱ期研究阶段，而PD0166285和PD0407824抑制剂还未在患者中进行实验。Wee1抑制剂通过抑制Wee1的活性而发挥抗肿瘤作用，使得肿瘤细胞从S期或G2期提前进入M期，不能完成DNA的合成和修复，表现为细胞组蛋白合成异常，二极纺锤体形成障碍，染色体分散存在，最终退出有丝分裂，引发细胞调亡，称作“有丝分裂灾难”。Wee1抑制剂已应用到临床阶段，在抗肿瘤治疗中初步展示了广阔的应用前景，Wee1激酶抑制剂与DNA抑制药物的联合使用很可能是对抗癌症的一种更有效的治疗策略。因此，发现更高效，特异性更强的Wee1小分子抑制剂在肿瘤治疗中具有重大现实意义。
目前，现有技术中未见有关于苯并噻唑类和苯并吡咯类化合物及其药物组合物在制备Wee1激酶抑制剂和抗肿瘤药物中的相关报道。
发明内容
本发明旨在提供苯并噻唑类和苯并吡咯类化合物I和Ⅱ，以其为活性成分的药物组合物，其制备方法，以及其在制备Wee1激酶抑制剂和抗肿瘤药物中的应用。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
药物组合物，其中含有治疗量的下结构式(I)和(Ⅱ)所示的苯并噻唑类及苯并吡咯类衍生物或其药学上可接受的盐，和至少一种药学上可接受的载体
如所述的药物组合物，其中所述的苯并噻唑类及苯并吡咯类化合物的药学上可接受的盐是指化合物与酸所成的盐或酸性质子被金属离子所取代的钠盐、钾盐、镁盐及钙盐；所述的与酸形成的盐为盐酸盐、氢溴酸盐、甲磺酸盐、硫酸盐、磷酸盐、乙酸盐、三氟乙酸盐、三氟甲磺酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、富马酸盐、琥珀盐或苹果酸盐。
如所述的药物组合物在制备Wee1激酶抑制剂中的应用。
如所述的药物组合物在制备抗肿瘤药物中的应用，其特征在于所述的肿瘤为头颈部肿瘤、呼吸系统肿瘤、消化系统肿瘤、泌尿系统肿瘤、骨骼系统肿瘤、妇科肿瘤、血液系统肿瘤及其他类型肿瘤。
如所述的药物组合物在制备抗肿瘤药物中的应用，其特征在于其中所述的头颈部肿瘤为甲状腺癌、鼻咽癌、脑膜癌、听神经瘤、垂体瘤、口腔癌、颅咽管瘤、丘脑和脑干肿瘤、血管源性肿瘤或颅内转移瘤；所述的呼吸系统肿瘤为肺癌；所述的消化系统肿瘤为肝癌、胃癌、食管癌、大肠癌、直肠癌、结肠癌或胰腺癌；所述的泌尿系统肿瘤为肾癌、膀胱癌、前列腺癌或睾丸癌；所述的骨骼系统肿瘤为骨癌；所述的妇科肿瘤为乳腺癌、宫颈癌或卵巢癌；所述的血液系统肿瘤为白血病、恶性淋巴瘤或多发性骨髓瘤。
如所述的药物组合物在制备抗肿瘤药物中的应用。其特征在于其中所述的其他类型肿瘤为恶性黑色素瘤、神经胶质瘤或皮肤癌。
如所述的药物组合物，其特征在于作为适宜口服或注射给药的制剂形式。
如所述的药物组合物，其中所述的口服给药的制剂形式为片剂、缓释片、控释片、锭剂、硬或软胶囊、滴丸、微丸、水性或混油悬剂、乳剂、可分散的散剂或颗粒剂、口服溶液、糖浆剂或酏剂，所述的注射给药的制剂形式为灭菌的水性或油性溶液、无菌粉末、脂质体、乳剂、微乳剂、纳米乳或微囊。
本发明此外还提供了所述的药物组合物在制备Wee1激酶抑制剂中的应用。
以及，所述的药物组合物在制备抗肿瘤药物中的应用。如所述的应用，其中所述的肿瘤为白血病、肝癌、肺癌、乳腺癌、结肠癌。
本发明化合物经抗肿瘤活性试验，测得对白血病、肝癌、肺癌、乳腺癌和结肠癌五种肿瘤细胞株的IC50。结果表明化合物Ⅰ和Ⅱ具有一定的体外肿瘤生长抑制活性。
本发明化合物用作药物上时，可以直接使用或者以药物组合物的形式使用。该药物组合物含有0.1～99％，优选0.5％～95％的本发明化合物，其余为药学上可以接受的盐，或对人和动物无毒的可药用载体和/或赋形剂。
本发明化合物的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等变化，其日剂量可以是0.01～10mg/kg体重，优选0.1～5mg/kg体重。可以一次或多次施用。
口服可用其固体或液体制剂，如粉剂、片剂、糖衣剂、胶囊、溶液、糖浆、滴丸等。
注射可用其固体或液体制剂，如粉针剂、溶液形注射剂等。
附图说明
附图1为本发明苯并噻唑类化合物Ⅰ对肺癌A546细胞株的IC50曲线图，
附图2为本发明化合物Ⅱ对人白血病Jurkat细胞株的IC50曲线图。
具体实施方式
下面结合附图，用本发明的下述实施例对本发明的实质性内容进行详细叙述，但并不以此来限定本发明。
实施例1：
本发明化合物部分购自IBScreen公司，化合物Ⅰ和Ⅱ在库中相应的编号为：STOCK1S-28804；STOCK6S-58881。
化合物I和II的结构式如下所示：
实施例2：
本发明化合物对五种不同肿瘤细胞株的半数生长抑制浓度IC50的测定：
1、实验原理及步骤
MTS为MTT类似物，活细胞线粒体中琥珀酸脱氢酶能够代谢还原MTS，生成可溶性的甲臜(Formazan)化合物，可直接溶解于培养基中。检测时，只需将少量的CellTiter
Aqueous One Solution reagent直接加入培养板孔的培养基中，孵育1-4h，然后以酶标仪读取490nm的吸光度值。该化合物的光密度OD(490nm)值与活细胞数目成正比。检测以顺铂和紫杉醇作为阳性对照。化合物的IC50值通过浓度效应生长曲线计算确定。
室温，静置90分钟，完全融化CellTiter
Aqueous One Solution reagent。选择最适细胞浓度的五种不同肿瘤细胞株，包括Jurkat，SMMC-7721，A-549，MCF-7和SW480。分别铺入96孔培养板中，每孔100μL，37℃，5％CO2的环境下孵育24h，分别加入20μLCellTiter
Aqueous One Solution reagent后继续孵育2h，在490nm读取吸光度值。并设置阳性对照组顺铂和紫杉醇。
2、试剂及仪器
试剂：CellTiter
AQueous One Solution Cell Proliferation Assay 仪器：CO2培养箱(Thermo)，超净工作台(Thermo)，化学发光酶标仪(Thermo)
3、数据处理
在Excel中按如下公式(1)计算得到化合物对单胺氧化酶B的抑制率。公式(1):
抑制率：抑制率＝(1-A样品/A阳性对照)*100％
在GraphPad Prism 5按如下公式(2)计算得到化合物对肿瘤细胞株抑制的IC50值。
公式(2):
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
Y是抑制率，X是化合物浓度。
4、实验结果
化合物Ⅰ和Ⅱ对不同肿瘤细胞株的IC50如表1所示。
表1化合物对不同肿瘤细胞株的IC50(μM)
实施例3：
化合物I或II，加入4％的硫酸乙醇溶液，pH＝4，过滤，干燥，制成硫酸盐化合物。
实施例4：
化合物I或II，加入4％的盐酸溶液，pH＝4，过滤，干燥，制成盐酸盐化合物。
实施例5：
化合物I或II，加入4％的酒石酸溶液，pH＝4，过滤，干燥，制成酒石酸盐化合物。
实施例6：
化合物I或II，加入4％的柠檬酸溶液，pH＝4，过滤，干燥，制成柠檬酸盐化合物。
实施例7：
胶囊剂：化合物I或II或实施例3-6所得的盐10mg，乳糖187mg，硬脂酸镁3mg。
制备方法：将化合物I或II或其盐与助溶剂混和，过筛，均匀混合，把得到的混合物装入硬明胶胶囊，每个胶囊重200mg，活性成分含量为10mg。
实施例8：
片剂：将化合物I或II或实施例3-6制得的盐10mg，加入乳糖180mg，淀粉55mg等辅料混合均匀，并用水将其润湿后制成颗粒并干燥，再加入硬脂酸镁5mg混匀后压片，每片约重250mg。
实施例9：
安瓿剂：将化合物I或II或实施例3-6制得的盐2mg，氯化钠10mg，溶解于适量的注射用水中，过滤所得溶液，在无菌条件下装入安瓿瓶中。
实施例10：
注射用冻干剂：将化合物I或II或实施例3-6制得的盐10mg，碳酸氢钠2mg，甘露醇252mg。
制备方法：将碳酸氢钠、甘露醇，加注射用水溶解，加活性炭吸附30min除热原，过滤去除活性炭，在滤液中加入化合物或其盐，超声处理使溶解，用1N盐酸调节pH为5.0-7.0，微孔滤膜滤过，加注射用水，分装，冷冻干燥，上塞，轧盖，即得。
实施例11：
胶囊剂：将化合物I或II或实施例3-6制得的盐10mg，乳糖187mg，硬脂酸镁3mg。
制备方法：将化合物I或II或其盐与助溶剂混合，过筛，均匀混合，把得到的混合物装入硬明胶胶囊，每个胶囊重200mg，活性成分含量为10mg。
Claims (4)
1.药物组合物在制备抗肿瘤药物中的应用，其特征在于所述的肿瘤为白血病、肝癌、肺癌、乳腺癌、结肠癌，其中含有治疗量的如下结构式(I)和(Ⅱ)所示的苯并噻唑类及苯并吡咯类衍生物或其药学上可接受的盐，和至少一种药学上可接受的载体，
2.如权利要求1所述的药物组合物在制备抗肿瘤药物中的应用，其中所述的苯并噻唑类及苯并吡咯类化合物的药学上可接受的盐是指化合物与酸所成的盐；所述的与酸形成的盐为盐酸盐、氢溴酸盐、甲磺酸盐、硫酸盐、磷酸盐、乙酸盐、三氟乙酸盐、三氟甲磺酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、富马酸盐、琥珀盐或苹果酸盐。
3.如权利要求1所述的药物组合物在制备抗肿瘤药物中的应用，其特征在于其制剂为口服或注射给药的制剂形式。
4.如权利要求3所述的药物组合物在制备抗肿瘤药物中的应用，其中所述的口服给药的制剂形式为片剂、锭剂、硬或软胶囊、滴丸、微丸、水性或混油悬剂、乳剂、可分散的散剂或颗粒剂、口服溶液、糖浆剂或酏剂，所述的注射给药的制剂形式为灭菌的水性或油性溶液、无菌粉末、脂质体、乳剂或微囊。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810683777.0A CN108653282B (zh) | 2018-06-28 | 2018-06-28 | 苯并噻唑类及苯并吡咯类化合物在制备抗肿瘤药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810683777.0A CN108653282B (zh) | 2018-06-28 | 2018-06-28 | 苯并噻唑类及苯并吡咯类化合物在制备抗肿瘤药物中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108653282A CN108653282A (zh) | 2018-10-16 |
| CN108653282B true CN108653282B (zh) | 2020-08-14 |
Family
ID=63773162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810683777.0A Expired - Fee Related CN108653282B (zh) | 2018-06-28 | 2018-06-28 | 苯并噻唑类及苯并吡咯类化合物在制备抗肿瘤药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108653282B (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110141664B (zh) * | 2019-05-28 | 2021-06-08 | 宁波市鄞州人民医院 | 一种治疗急性髓系白血病的药物组合物 |
| CN112999221B (zh) * | 2021-03-22 | 2022-04-12 | 苏州大学 | 一种三氮唑类化合物在制备抗肿瘤药物中的应用 |
| CN114558002A (zh) * | 2022-03-15 | 2022-05-31 | 四川轻化工大学 | 化合物在制备治疗肿瘤药物中的应用 |
| CN115778962B (zh) * | 2022-11-28 | 2024-09-17 | 中国医学科学院肿瘤医院 | 治疗男性食管癌患者的药物及其相关应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7605155B2 (en) * | 2002-09-04 | 2009-10-20 | Schering Corporation | Substituted pyrazolo[1,5-a]pyrimidines as protein kinase inhibitors |
| AR060635A1 (es) * | 2006-04-27 | 2008-07-02 | Banyu Pharma Co Ltd | Derivados de 1,2-dihidro-3h-pirazolo[3,4-d]pirimidin-3-ona, composiciones farmaceuticas que los comprenden y su uso en el tratamiento del cancer |
-
2018
- 2018-06-28 CN CN201810683777.0A patent/CN108653282B/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN108653282A (zh) | 2018-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108653282B (zh) | 苯并噻唑类及苯并吡咯类化合物在制备抗肿瘤药物中的应用 | |
| EP3849537B1 (en) | Combination therapies | |
| EP2719697B1 (en) | Pyridonaphthyridine pi3k/mtor dual inhibitors and preparation and use thereof | |
| CN101778563A (zh) | 调节细胞凋亡的组合物和方法 | |
| BR112019005337A2 (pt) | terapia combinada | |
| SG188207A1 (en) | Combination anti - cancer therapy | |
| EP2826780B1 (en) | Thieno[2,3-d]pyridazine derivatives and therapeutic use thereof for protein kinase inhibition | |
| WO2017129094A1 (zh) | 一种egfr/her2受体酪氨酸激酶抑制剂在制备治疗her2突变癌症药物中的用途 | |
| JP2025503139A (ja) | 固形腫瘍の治療のためのユビキチン特異的プロセシングプロテアーゼ１（ｕｓｐ１）阻害剤 | |
| EP3279201B1 (en) | Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor | |
| CN107362166B (zh) | 四氢吡啶并[4,5-]噻吩并[2,3-]嘧啶-4(3)-酮类化合物在制药中的应用 | |
| CN112979753B (zh) | 一种靶向c-Met的多肽及其应用 | |
| CN106794180A (zh) | 联合疗法 | |
| CN113143913A (zh) | 一种桉烷型倍半萜类化合物在制备抗胰腺癌药物中的应用 | |
| CN105213366B (zh) | 藤黄酮化合物的医药用途及其药物组合物 | |
| CN111821303B (zh) | 沃替西汀及其盐在制备抗肿瘤药物中的应用 | |
| WO2023222011A1 (zh) | 一种治疗三阴乳腺癌的联合用药物 | |
| CN108175768A (zh) | 伊马替尼和拉帕替尼联合用药在氟维司群获得性耐药细胞抑制剂中的应用 | |
| CA3189152A1 (en) | Combination therapies with olig2 inhibitors | |
| CN113082019A (zh) | 一种愈创木烷型倍半萜类化合物在制备治疗胰腺癌药物中的应用 | |
| EP1667719B1 (en) | Treatment of gastrointestinal stromal tumors with imatinib and midostaurin | |
| CN105434432B (zh) | N-羟基邻苯二甲酰亚胺类化合物在制备抗肿瘤药物中的应用 | |
| CN114748479A (zh) | 一种预防和/或治疗癌症的药物组合物 | |
| CN104825455B (zh) | 依鲁替尼的用途 | |
| CN106619622A (zh) | 以丙酰胺类化合物为活性成分的药物组合物和其在制药中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200814 |