CN107362166A - Tetrahydropyridine simultaneously application of (3) ketone compounds of [4,5] thieno [2,3] pyrimidine 4 in pharmacy - Google Patents
Tetrahydropyridine simultaneously application of (3) ketone compounds of [4,5] thieno [2,3] pyrimidine 4 in pharmacy Download PDFInfo
- Publication number
- CN107362166A CN107362166A CN201710644518.2A CN201710644518A CN107362166A CN 107362166 A CN107362166 A CN 107362166A CN 201710644518 A CN201710644518 A CN 201710644518A CN 107362166 A CN107362166 A CN 107362166A
- Authority
- CN
- China
- Prior art keywords
- compound
- application
- thieno
- pyrimidine
- wee1
- 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.)
- Granted
Links
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 title claims abstract description 15
- -1 ketone compounds Chemical class 0.000 title claims abstract description 5
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 101150040313 Wee1 gene Proteins 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 6
- 229940043355 kinase inhibitor Drugs 0.000 claims description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 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 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 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
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 2
- 229940001468 citrate Drugs 0.000 claims description 2
- 150000004675 formic acid derivatives Chemical class 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
- 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229950004288 tosilate Drugs 0.000 claims description 2
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims 2
- 201000002313 intestinal cancer Diseases 0.000 claims 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 11
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 8
- 102000020233 phosphotransferase Human genes 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 229940000406 drug candidate Drugs 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- 238000012216 screening Methods 0.000 abstract 1
- 229940125904 compound 1 Drugs 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000002775 capsule Substances 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
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000011278 mitosis Effects 0.000 description 3
- 230000012746 DNA damage checkpoint Effects 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000004668 G2/M phase Effects 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 230000010337 G2 phase Effects 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 108010042653 IgA receptor Proteins 0.000 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100034014 Prolyl 3-hydroxylase 3 Human genes 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
- 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
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 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
- 230000003287 optical effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provide it is a kind of with tetrahydropyridine simultaneously (3) ketone compounds of [4,5] thieno [2,3] pyrimidine 4 be active component pharmaceutical composition, and its application in Wee1 micromolecular inhibitors are prepared.Drug candidate target spot of the Wee1 kinases as oncotherapy, its inhibitor, which combines some chemotherapeutics, can strengthen its antitumor activity.So far, only 1 Wee1 micromolecular inhibitor enters clinical experimental stage, shows that the compound of the invention tumor cell line different to five kinds shows good inhibitory activity through anti tumor activity in vitro screening.It can be used to develop new Wee1 micromolecular inhibitors, a kind of new selection is provided for therapeutic field of tumor, there is good application value.
Description
Technical field
The present invention relates to pharmaceutical technology field, and more particularly to a kind of tetrahydropyridine, simultaneously [4,5-] thieno [2,3-] is phonetic
Pyridine -4 (3) -one class compound, the pharmaceutical composition using the compound as active component, and the compound and pharmaceutical composition
Application in the cancer therapy drug over-expressed for suppressing Wee1 kinases is prepared.The compound on tumor cell strain, which has, to be suppressed
Effect, can be as the lead compound of development of new antineoplastic.
Background technology
Wee1 protein kinases are found in fission yeast cell first, belong to serine, Serineprotein kinase family, high
Degree is conservative and is widely present in eucaryote.It is a kind of cyclin, mainly the cell cycle the S phases or
The G2/M phases are activated.It can cell cycle regulation protein dependent kinase 1 (CDK1) phosphorylation state, so as to adjust CDK1 with
The activity of cell periodic protein B (cyclinB) compound is so as to realizing the regulation and control of cell cycle, and to DNA damage checkpoint
With important adjustment effect.Wee1 protein kinases pass through the acting regulatory mitosis of 3 cytoscopy points, i.e. cell G2/M
Phase checkpoint, cell size checkpoint and DNA Damage checkpoint.Studies have shown that is all examined in multiclass malignant cell
Measure Wee1 kinases and overexpression be present, indicate the candidate targets that Wee1 kinases is treatment of cancer.
At present, the inhibitor based on Wee1 kinases mainly has three kinds, is MK-1775, PD0407824 respectively,
PD0166285.Wherein MK-1775 combines other chemotherapeutic drug therapy oophoromas, is currently in clinical II phase conceptual phase, and
PD0166285 and PD0407824 inhibitor is not tested also in patients.Wee1 inhibitor by suppress Wee1 activity and
Play antitumor action so that tumour cell enters the M phases in advance from S phases or G2 phases, it is impossible to completes DNA synthesis and reparation, table
It is now cellular histone resulting anomaly, two pole spindles form obstacle, and Chromosome spread exists, finally exits mitosis, draw
Natural death of cerebral cells is sent out, is referred to as " mitosis disaster ".Wee1 some inhibitor have application to clinical stage, in antineoplaston
Wide application prospect is tentatively illustrated, Wee1 kinase inhibitors suppress being used in combination for medicine with DNA and are likely to anticancer
A kind of more effective therapeutic strategy of disease.Thus, it is found that more efficient, the stronger Wee1 micromolecular inhibitors of specificity are controlled in tumour
There is Great significance in treatment.Therefore, it is necessary to find more efficient, the Wee1 micromolecular inhibitors of high specificity.At present, exist
In treatment of cancer, the research report of such compound is had no.
At present, there are no in the prior art on tetrahydropyridine simultaneously [4,5-] thieno [2,3-] pyrimidine -4 (3) -one class
Report of the compound as the pharmaceutical composition of active ingredient, also preparing Wee1 kinases without the compound and its pharmaceutical composition
Application report in inhibitor and antineoplastic.
The content of the invention
A kind of the present invention is intended to provide tetrahydropyridine simultaneously [4,5-] thieno [2,3-] pyrimidine -4 (3) -one class compound
(1), compound 1 and the pharmaceutical composition of pharmaceutical carrier or excipient containing treating cancer effective dose, compound 1 and medicine group
The preparation method of compound, the application of compound 1 or its pharmaceutical composition in Wee1 kinase inhibitor drugs are prepared.
In order to realize the above-mentioned purpose of the present invention, the invention provides following technical scheme：
Pharmaceutical composition, wherein tetrahydropyridine shown in the following structural formula containing therapeutically effective amount simultaneously [4,5-] thieno
[2,3-] pyrimidine -4 (3) -one class compound (1) or its pharmaceutical salts, and at least one pharmaceutically acceptable carrier,
Pharmaceutical composition as mentioned, wherein described compound tetrahydropyridine simultaneously [4,5-] thieno [2,3-] pyrimidine -4
(3) pharmaceutical salts of -one class (1) be hydrochloride, hydrobromate, nitrate, mesylate, sulfate, phosphate, succinate,
Malate, fumarate, maleate, tosilate, tartrate, citrate, formates, acetate, second two
Hydrochlorate, trifluoroacetate, fluoroform sulphonate.
Invention also provides compound tetrahydropyridine simultaneously [4,5-] thieno [2,3-] pyrimidine -4 (3) -one class chemical combination
The application of thing (1) or its pharmaceutical salts in Wee1 kinase inhibitors are prepared.
And compound tetrahydropyridine simultaneously [4,5-] thieno [2,3-] pyrimidine -4 (3) -one class compound (1) or its medicine
With application of the salt in antineoplastic is prepared.
Apply as mentioned, wherein described tumour is leukaemia, liver cancer, lung cancer, breast cancer, colon cancer.
In addition, the application present invention also offers described pharmaceutical composition in Wee1 kinase inhibitors are prepared.
And application of the described pharmaceutical composition in antineoplastic is prepared.
Apply as mentioned, wherein described tumour is leukaemia, liver cancer, lung cancer, breast cancer, colon cancer.
The compounds of this invention is measured to five kinds of leukaemia, liver cancer, lung cancer, breast cancer and colon cancer through biological activity test
The IC50 of tumor cell line.As a result show that compound 1 has certain Vitro Tumor Growth inhibitory activity.
When the compounds of this invention is used as on medicine, it can directly use or be used in the form of pharmaceutical composition.The medicine
Compositions contain 0.1~99%, and preferably 0.5%~95% the compounds of this invention, remaining is pharmaceutically acceptable salt,
Or pharmaceutical acceptable carrier and/or excipient nontoxic to humans and animals.
The amount of application of the compounds of this invention can be according to route of administration, the age of patient, body weight, the type for the disease treated
Change with the order of severity etc., its daily dose can be 0.01~10mg/kg body weight, preferably 0.1~5mg/kg body weight.Can be once
Or repeatedly apply.
It orally can use its solid or liquid preparation, such as pulvis, tablet, sugar-coat agent, capsule, solution, syrup, dripping pill.
Injection can use its solid or liquid preparation, such as powder-injection, solution type injection.
Brief description of the drawings：
Fig. 1 be compound tetrahydropyridine simultaneously [4,5-] thieno [2,3-] pyrimidine -4 (3) -one class compound (1) to five kinds
The IC50 of different tumor cell lines suppresses figure.
Embodiment：
In order to be better understood from the essence of the present invention, below in conjunction with the accompanying drawings, with regard to formula (1) compound 1 and its biology
Activity Results illustrate its application in field of medicaments.
Embodiment 1：
The compounds of this invention is purchased from Dutch specs companies (network address：http://www.specs.com/), number in its storehouse
For：AO-476/42169315.
Embodiment 2：
Measure of the compounds of this invention 1 to the half growth inhibitory concentration IC50 of five kinds of different tumor cell lines：
1st, experimental principle and step
MTS is MTT analogs, and succinate dehydrogenase can be metabolized reduction MTS in living cells mitochondria, generate solubility
Formazan (Formazan) compound, can be directly dissolved in culture medium., only need to be by a small amount of CellTiter during detection
Aqueous One Solution reagent are directly added into the culture medium of cultivation plate hole, 1-4h are incubated, then with ELIASA
Read 490nm absorbance.Optical density OD (490nm) value of the compound is directly proportional to number of viable cells.Detection is with cis-platinum
With taxol as positive control.The IC50 values of compound are calculated by concentration effect growth curve and determined.
Room temperature, static 90 minutes, melt CellTiter completelyAqueous One Solution reagent.Choosing
Select five kinds of different tumor cell lines of optimal cell concentration, including HL-60, SMMC-7721, A-549, MCF-7 and SW480.Point
Do not spread in 96 well culture plates, per the μ L of hole 100,37 DEG C, 5%CO2In the environment of be incubated 24h, be separately added into 20 μ LCellTiterContinue to be incubated 2h after Aqueous One Solution reagent, absorbance is read in 490nm.And set the positive right
According to group cis-platinum and taxol.
2nd, reagent and instrument
Reagent：CellTiterAQueous One Solution Cell Proliferation Assay
Instrument：CO2Incubator (Thermo), superclean bench (Thermo), chemiluminescence ELIASA (Thermo)
3rd, experimental result
1) inhibiting rate：Inhibiting rate=(1-ASample/APositive control) * 100%
As shown in Fig. 1, table 1, wherein percentage represents when compound reaction density is 50 μM pair the inhibitory activity of compound 1
The inhibiting rate of five kinds of different tumor cell lines.
IC50 (μM) of the compound of table 1 to different tumor cell lines
Embodiment 3：
Compound 1,4% ethanol solution of sulfuric acid is added, pH=4, is filtered, dries, sulphate cpd 1 is made.
Embodiment 4：
Compound 1,4% hydrochloric acid solution is added, pH=4, is filtered, dries, hydrochloride compound 1 is made.
Embodiment 5：
Compound 1,4% tartaric acid solution is added, pH=4, is filtered, dries, tartrate compound 1 is made.
Embodiment 6：
Compound 1,4% citric acid solution is added, pH=4, is filtered, dries, citrate compound 1 is made.
Embodiment 7：
Capsule：Compound 1 or salt 10mg, lactose 187mg, magnesium stearate 3mg obtained by embodiment 2-5.
Preparation method：Compound or its salt and cosolvent are mixed, sieving, uniformly mixing, obtained mixture is loaded
Hard gelatin capsule, each capsule weight 200mg, active component content 10mg.
Claims (8)
1. pharmaceutical composition, wherein tetrahydropyridine shown in the following structural formula containing therapeutically effective amount simultaneously [4,5-] thieno
[2,3-] pyrimidine -4 (3) -one class compound (1) or its pharmaceutical salts, and at least one pharmaceutically acceptable carrier,
2. pharmaceutical composition as claimed in claim 1, wherein described compound tetrahydropyridine simultaneously [4,5-] thieno [2,
3-] pyrimidine -4 (3) -one class (1) pharmaceutical salts for hydrochloride, hydrobromate, nitrate, mesylate, sulfate, phosphate,
Succinate, malate, fumarate, maleate, tosilate, tartrate, citrate, formates, second
Hydrochlorate, oxalate, trifluoroacetate, fluoroform sulphonate.
3. compound tetrahydropyridine simultaneously making by [4,5-] thieno [2,3-] pyrimidine -4 (3) -one class compound (1) or its pharmaceutical salts
Application in standby Wee1 kinase inhibitors.
4. compound tetrahydropyridine simultaneously making by [4,5-] thieno [2,3-] pyrimidine -4 (3) -one class compound (1) or its pharmaceutical salts
Application in standby antineoplastic.
5. application as claimed in claim 4, it is characterised in that described tumour is leukaemia, liver cancer, lung cancer, breast cancer, knot
Intestinal cancer.
6. application of the pharmaceutical composition in Wee1 kinase inhibitors are prepared described in claim 1.
7. application of the pharmaceutical composition described in claim 1 in antineoplastic is prepared.
8. application as claimed in claim 7, it is characterised in that described tumour is leukaemia, liver cancer, lung cancer, breast cancer, knot
Intestinal cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710644518.2A CN107362166B (en) | 2017-08-01 | 2017-08-01 | Application of tetrahydropyrido [4,5- ] thieno [2,3- ] pyrimidine-4 (3) -ketone compound in pharmacy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710644518.2A CN107362166B (en) | 2017-08-01 | 2017-08-01 | Application of tetrahydropyrido [4,5- ] thieno [2,3- ] pyrimidine-4 (3) -ketone compound in pharmacy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107362166A true CN107362166A (en) | 2017-11-21 |
| CN107362166B CN107362166B (en) | 2020-07-17 |
Family
ID=60310240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710644518.2A Expired - Fee Related CN107362166B (en) | 2017-08-01 | 2017-08-01 | Application of tetrahydropyrido [4,5- ] thieno [2,3- ] pyrimidine-4 (3) -ketone compound in pharmacy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107362166B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110141664A (en) * | 2019-05-28 | 2019-08-20 | 宁波市鄞州人民医院 | A kind of pharmaceutical composition for treating acute myeloid leukemia |
| CN113018298B (en) * | 2021-03-09 | 2022-05-03 | 四川轻化工大学 | Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof |
| CN114558002A (en) * | 2022-03-15 | 2022-05-31 | 四川轻化工大学 | Application of compound in preparing medicine for treating tumor |
-
2017
- 2017-08-01 CN CN201710644518.2A patent/CN107362166B/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| ESSAM KH. AHMED: "Syntheses of some new azolopyrido[4",3":4,5]thieno[2,3-d]pyrimidines", 《HETEROATOM CHEMISTRY》 * |
| ESSAM KH. AHMED等: "Synthesis of new pyrido[4,3:4,5]thieno[2,3:4,5]pyrimido[2,1-B][1,3,4]thiadiazine derivatives", 《PHOSPHORUS, SULFUR AND SILICON》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110141664A (en) * | 2019-05-28 | 2019-08-20 | 宁波市鄞州人民医院 | A kind of pharmaceutical composition for treating acute myeloid leukemia |
| CN113018298B (en) * | 2021-03-09 | 2022-05-03 | 四川轻化工大学 | Inhibitor for treating promyelocytic leukemia and pharmaceutical composition thereof |
| CN114558002A (en) * | 2022-03-15 | 2022-05-31 | 四川轻化工大学 | Application of compound in preparing medicine for treating tumor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107362166B (en) | 2020-07-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11684620B2 (en) | Pharmaceutical compositions comprising N-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine | |
| CN103874689B (en) | The combination of AKT inhibitor compound and Wei Luofeini and using method | |
| JP5719770B2 (en) | Icotinib hydrochloride, compound, crystallographic form, concomitant drug and its use | |
| CN110382483A (en) | Condensed N- heterocyclic compound and its application method | |
| CN103997894A (en) | Treatment of breast cancer | |
| WO2018218963A1 (en) | Pharmaceutically acceptable salt of egfr inhibitor, crystal form thereof, preparation method therefor and application thereof | |
| CN105848682A (en) | Pharmaceutical combinations | |
| CN108653282B (en) | Application of benzothiazole and benzopyrrole compounds in preparation of antitumor drugs | |
| CN102712601A (en) | A compound, a process for its preparation, a pharmaceutical composition, use of a compound, a method for modulating or regulating serine/threonine kinases and a serine/threonine kinases modulating agent | |
| CN110461853A (en) | Benzothiophene estrogenic agents | |
| CN107362166A (en) | Tetrahydropyridine simultaneously application of (3) ketone compounds of [4,5] thieno [2,3] pyrimidine 4 in pharmacy | |
| RU2657783C2 (en) | Combination cancer therapy using azabicyclo compound | |
| EP3279201B1 (en) | Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor | |
| RU2678455C1 (en) | N-(3-(5-(4-chlorophenyl)-1n-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulphonamide crystalline form, active component, pharmaceutical composition and medicine | |
| CN102083829A (en) | Improved Raf inhibitors | |
| CN104662022A (en) | Means and method for treating solid tumours | |
| CN103732601B (en) | The one class treatment platinum compounds of cell proliferation disorders, its preparation method and application | |
| CN104230912B (en) | Quinoline, Its Preparation Method And Use | |
| CN109824693B (en) | BRD4 inhibitor and application thereof in tumor treatment medicine | |
| KR20120099219A (en) | Combination | |
| CN105209032A (en) | Treatment of cancer and other conditions using a transcription factor modulator | |
| CN104650086A (en) | Ponatinib hydrochloride compound | |
| CN104327083A (en) | Substituted-indanyl amide-type compounds and pharmaceutically acceptable salt and preparation method and application thereof | |
| CN110023318A (en) | The crystal form of compound | |
| WO2023222011A1 (en) | Combination drug for treating triple-negative breast cancer |
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: 20200717 |