CN110141664A - A kind of pharmaceutical composition for treating acute myeloid leukemia - Google Patents
A kind of pharmaceutical composition for treating acute myeloid leukemia Download PDFInfo
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- CN110141664A CN110141664A CN201910452580.0A CN201910452580A CN110141664A CN 110141664 A CN110141664 A CN 110141664A CN 201910452580 A CN201910452580 A CN 201910452580A CN 110141664 A CN110141664 A CN 110141664A
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- pharmaceutical composition
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- pyridine
- pyrazolo
- pyrimidine
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- 210000004180 plasmocyte Anatomy 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 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 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000003612 virological effect Effects 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
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
Abstract
The present invention relates to a kind of pharmaceutical composition for treating leukaemia, active constituent is homoharringtonine and Wee1 kinase inhibitor in the pharmaceutical composition, and wherein the weight ratio of homoharringtonine and Wee1 kinase inhibitor is 1:10-10:1.Pharmaceutical composition of the invention is for treating leukaemia, especially for the significant in efficacy of chronic myelogenous leukemia or acute myeloid leukemia.The present invention provides a kind of completely new thinking for the administering drug combinations scheme of exploitation treatment leukaemia.
Description
Technical field
The present invention relates to drug fields, and in particular to a kind of pharmaceutical composition for treating leukaemia.
Background technique
Leukaemia is a kind of stock in the cancer of marrow, refers to that a large amount of immature blood cell precursors cells are uncontrolled
Infinite multiplication is accumulated and infiltrates its hetero-organization and organ, while inhibiting the generation of normal plasma cell.Leukaemic is in the early stage
Symptom is easy to be ignored because unobvious, common sympton include out of strength, anaemia, palpitaition, shortness of breath and liver, spleen, enlargement of lymph nodes and
Skeleton pain etc..Leukaemic usually will appear complication caused by hematopoiesis function disorder simultaneously, comprising: bleeding, fever, difficulty
Control the symptoms such as sexy dye, high leukocyte count, expiratory dyspnea, obnubilation or organ failure.The definite disease of leukaemia
Because currently not it is clear that possible inducement includes viral factor, chemical factor, radiation factor and inherent cause etc., such as suction
Cigarette, ionising radiation, certain chemical reagent (such as benzene) and Down's syndrome, there is the also category people at highest risk of family's leukaemia history.
Leukaemia is divided into acute leukemia and chronic leukemia according to the speed of disease.Acute leukemia is characterized in
Immature haemocyte quantity increases sharply, and since so many abnormal cell is piled up in marrow, prevents marrow from manufacturing normal
Haemocyte.Along with the fast development of disease, malignant cell constantly accumulates spreads to blood and the gradually other tissues of infiltration again
And organ, therefore, acute leukemia must obtain medical treatment as early as possible.Chronic leukemia is characterized in having relative maturity but still different
Normal excessive leukocyte accumulation, usually developing causes some months or several years abnormal white cell production rate to be higher than normal white cell,
Therefore abnormal cell accumulation is more and more.Leukaemia then can be divided into lymphoid leukemia according to the source of diseased cells and medullary system is white
Blood disease.Generally speaking, the cell type in source is suddenly mitigated in conjunction with the state of an illness, leukaemia can be divided into four types: acute lymphoblastic system is white
Blood disease (ALL), acute myeloid leukemia (AML), chronic lymphatic system leukaemia (CLL) and chronic myelogenous leukemia (CML).
Acute myeloid leukemia (AML) is a kind of heterogeneous hematopoietic tissue malignant proliferative disorders, is adult haematological malignant
Most common type in tumour, and recently as reasons such as atmosphere pollution, the morbidity of AML has the tendency that increasing year by year.With
Modern hematology basis and clinical continuous development, are constantly improve the diagnosis of AML, parting, classification, in the diagnosis of AML
It is also more accurate and careful with prognosis layering aspect, the therapeutic strategy more individuation of selection is layered according to prognosis, but in its treatment neck
There is not new breakthrough in domain yet.
In the past 30 years, the AML induction scheme based on cytarabine and anthracycline chemotherapy medicine is still occupied an leading position, and is changed
The complete remission rate (CR) for the treatment of only maintains 50~70%, 5 years survival rates also only in 20-30% or so.Although a part of patient
It can benefit from increasingly mature hematopoietic stem cell transplantation technology, but transplantation donor limited source, transplant -related toxicities and concurrent
It rejects after disease, transplanting and the objective factors such as recurrence limits implantation technique in the extensive use of AML patient, refractory and recurrence AML
It is still the problem for perplexing countless blood work persons.Therefore, research institution both domestic and external is always in insistent exploratory development AML
Optimal treatment strategy.
Targeted drug (the all-trans retinoic acid in AML specific type-acute promyelocytic leukemia (APL) in recent years
(ATRA) and or arsenious acid) application make its from the highest AML of the death rate be changed into it is clinical largely cure AML (90% with
On CR rate and 85% long-term disease-free survival)；The target of BCR-ABL fusion is directed to equally in chronic myelocytic leukemia
It is applied to clinical to drug tyrosine kinase inhibitor one, two generations and achieves curative effect well；To make the target for gene
It is had become a hot topic of research to drug, but is not yet found to have the fusion of this feature in the other types AML in addition to APL,
And its mechanism often relates to a variety of caryogram or gene unconventionality, keeps the research and development for AML gene target drug extremely difficult.
At the same time, the research institution both domestic and external drug target new in constantly research AML, in view of epigenetics
Change AML importance fall ill and mechanism increasingly clearly, also shown for the small molecule compound of epigenetic mark
Effective anti-AML activity, such as the low acetylation inhibitor of dnmt rna inhibitor, histone synthesis and carry out clinical I
Or the II phase tests, and achieves certain research achievement, show its with great application prospect, therefore be directed to epigenetic mark
Therapy target be one of focus of Recent study.
Homoharringtonine (HHT) is the anti-tumor drug with Chinese characteristics extracted from Chinese Plants.It is high
Harringtonine is present in Cephalotaxus Cephalotaxus plant, and 1963 by Paudler etc. for the first time from Japanese caephalotaxus sinensis
Cephalotaxine (Cephaloyaxine) is isolated in C.drupaceasieb.etcZucc and cepehalotaxus fortunei C.fortuneiHook.f..
1969, Powell etc. isolated homoharringtonine for the first time from Cephalotaxus harringtonia (Knightex Forbes) Kochcv. F. Astigiata, determined that its structure is (2R) -2- hydroxyl -2-
(4- hydroxy-4-methyl amyl) succinic acid (methyl), and find that it has apparent activity to mouse lymph leukemia P388.
Homoharringtonine is readily soluble in methanol, ethyl alcohol or chloroform, slightly soluble in water or ether, thus it is speculated that its oral absorption
It is poor, it prompts that modification main ingredient should be taken during pharmacy, the auxiliary materials such as solubilizer is added or the means such as suspension are made to changing
The oral absorption problem of kind HHT.
Homoharringtonine is applied to the history of existing more than 30 years of the treatment of AML at home.Homoharringtonine is being treated
In AML mainly by the way of drug combination, with HA (HHT, cytarabine) scheme, (HHT, cytarabine and Accra are mould by HAA
Element) based on scheme and HAD (HHT, cytarabine and daunorubicin) scheme.In addition, there are also some drug combinations to show unique characteristics
Method improves treatment tolerance for example, HIA (darubicin+HHT+ cytarabine) scheme can reduce Cardiovascular Toxicity
Property；HIA combines Decitabine and treats recurrent and refractory AML；HAAG (HHT+ Aclarubicin+cytarabine+granular leukocyte colony stimulation
The factor)+Decitabine (DAC) be used for progressive stage acute myeloid leukemia；The treatment of HAAG Combined with Chinese Herbal, can mitigate gerontal patient
Chemotherapy adverse effect reduces patient suffering's degree；HHT combines her cloth and combines for Buddhist nun to the white blood of FLT3-ITD saltant type acute myeloid
Disease has significant curative effect.
In nearest Blood Research Institute the United Nations, Zhejiang University other researchs and Clinical Institutions apply combined based on HHT Ah
The induction scheme of sugared cytidine and/or dutriomycin achieves good curative effect to the treatment of AML, while because its is more economical
Toxicity is lower and has great application prospect.
The study on mechanism of the anti-AML of homoharringtonine shows that HHT can change the activity of Telomerase, lower MCL-1
And survivin, the phosphorylation for inhibiting PI3K/AKT signal and JAK2-STAT5 access, there is research acting on AMLHL-60 to HHT
Gene expression analysis shows that HHT can also significantly lower c-myc gene after cell strain.
Wee1 kinases is one of the important member of serine/threonine protein kitase family, is risen in the entire cell cycle
To a variety of important function, such as ensure DNA replication dna accuracy and chromatin integrality, the starting of retardance DNA replication dna and G2 phase to M phase turn
It changes.Ataxia-telangiectasia mutated gene ATM and ATM and Rad3 GAP-associated protein GAP ATR is the core of DNA damage response
Response kinases.Wee1 kinases plays key effect in above-mentioned DNA damage response access.After DNA damage is identified, by phosphoric acid
Change the Wee1 kinases of activation for the Thr15 phosphorylation on cdc2, to inhibit cdc2 active, makes cell cycle arrest, Zan Bujin
Enter mitosis, is repaired to complete DNA.
In cell cycle progression, p53 albumen is by ATM-Chk2-p53 approach in G1/S phase and G2/M phase to DNA damage
It is checked, monitors the integrality of genome.When cell damages, p53 will activate p2 gene expression, p21 albumen meeting
It is acted on corresponding CDK-cyclins complex, causes the retardance of each checkpoint, repair damaged cell.If p53 gene is sent out
Raw mutation or missing, cannot control the proliferation of cell, lead to cell carcinogenesis.Research shows that being more than that 50% tumour all exists
P53 gene delection or mutation cause the defect of cell cycle G1/S checkpoint, so that the duplication and damage of DNA of tumor cell are repaired
Multiple process relys more on the checkpoint G2/M.As the Key kinases of the checkpoint G2/M, Wee1 kinases is answered in DNA of tumor cell damage
It is particularly important during answering, this makes Wee1 kinases in many tumours in high expression status.Inhibit the work of Wee1 kinases
Property after, inhibition of phosphorylation do not occur for cdc2, and DNA damage just enters the M phase without repairing in time, causes genomic instability and dye
Colour solid missing, causes mitosis disaster, leads to apoptosis of tumor cells.On the other hand, the p53 gene function of normal cell is being just
Often, DNA damage can be checked respectively in the phase checkpoint G1/S and G2/M, when the active quilt of the Wee1 kinases of normal cell
When inhibition, missing functionally can be compensated by the DNA damage repair mechanism that p53 is relied on, and normal cell is enable to deposit
It is living.Therefore, theoretically inhibit Wee1 kinase activity that can selectively kill p53 gene defect tumour cell, without influencing just
Normal cell is a kind of ideal oncotherapy approach.
Traditional chemotherapeutics such as platinum class, camptothecin and nucleoside analog acts on DNA synthesis process, causes DNA's
Synthesis damage, radiotherapy equally can result in the coup injury of DNA of tumor cell.Since Wee1 kinases is DNA damage response
Key kinases in access inhibit its activity that can theoretically enhance the antitumor action and radiotherapy of classic chemotherapy drug
Effect.In addition, PARP inhibitor is equally to act on DNA damage repair process, meeting is possible to the combination of Wee1 kinase inhibitor
Enhance oncotherapy effect.On the other hand, other act on the anti-tumor drug of non-DNA target point (such as taxol and monoclonal antibody class are anti-
Tumour medicine) also there is relevant clinical research carrying out with the connection of Wee1 kinase inhibitor.
The document that homoharringtonine is combined treatment leukaemia with Wee1 kinase inhibitor is had not been reported at present.
Summary of the invention
Present invention seek to address that aforementioned technical problem, provides a kind of pharmaceutical composition of novel therapeutic leukaemia, for clinic
The administering drug combinations scheme of upper exploitation treatment leukaemia provides a kind of completely new thinking.
Above-mentioned purpose of the invention is realized by following technological means.
The present invention provides a kind of pharmaceutical composition for treating leukaemia, and active constituent is high cepehalotaxus fortunei in the pharmaceutical composition
Ester alkali and Wee1 kinase inhibitor.
Preferably, the Wee1 kinase inhibitor is selected from following compounds:
(a) 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl) pyridine-2- base)-6- (4- (4- methylpiperazine-1-yl) phenylamino
Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(b) 2- ethyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenylamino
Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(c) 2- propyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenylamino
Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(d) 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl
Amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(e) 2- cyclopropyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl
Amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(f) 2- butyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenylamino
Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(g) 2- cyclobutyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl
Amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one.
Preferably, the weight ratio of homoharringtonine and Wee1 kinase inhibitor is 1:10-10 in aforementioned pharmaceutical compositions:
1。
It is furthermore preferred that the weight ratio of homoharringtonine and Wee1 kinase inhibitor is 1:5-5 in aforementioned pharmaceutical compositions:
1。
It is further preferred that the weight ratio of homoharringtonine and Wee1 kinase inhibitor is 4 in aforementioned pharmaceutical compositions:
1 or 3:1.
Most preferably, homoharringtonine and Wee1 kinase inhibitor (a) 2- methyl-1-(6- in aforementioned pharmaceutical compositions
(2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] is phonetic
The weight ratio of pyridine -3 (2H) -one is 4:1.
Most preferably, homoharringtonine and Wee1 kinase inhibitor (d) 2- allyl -1- in aforementioned pharmaceutical compositions
(6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d]
The weight ratio of pyrimidine -3 (2H) -one is 3:1.
Preferably, aforementioned pharmaceutical compositions further comprise pharmaceutically acceptable auxiliary material.
Preferably, aforementioned pharmaceutical compositions are solid pharmaceutical preparation.
It is furthermore preferred that above-mentioned solid pharmaceutical preparation is tablet, capsule or lyophilized preparation.
The present invention also provides application of the aforementioned pharmaceutical compositions in the drug of preparation treatment leukaemia.
Preferably, the leukaemia is chronic myelogenous leukemia or acute myeloid leukemia.
The present invention also provides application of the aforementioned pharmaceutical compositions in the drug that preparation inhibits K562 cell Proliferation.
The present invention also provides application of the aforementioned pharmaceutical compositions in the drug that preparation inhibits HL-60 cell Proliferation.
It is that the present invention generates the utility model has the advantages that
Inventor has found that the combination of homoharringtonine and Wee1 kinase inhibitor is for treatment leukaemia tool under study for action
There is significant effect.More surprisingly, two kinds of active components match in appropriate weight range, and treatment leukaemia is produced
It has given birth to and has been difficult to expected excellent effect.
Specific embodiment
Below with reference to embodiment, the present invention will be further explained, and embodiments of the present invention are not limited thereto.Under
It states experimental method used in embodiment unless otherwise specified, is conventional method.
Embodiment 1
Weigh homoharringtonine 1.6g, 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl) pyridine-2- base)-6- (4- (4- first
Base piperazine -1- base) phenyl amino) -1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 0.4g, tartaric acid 1g be dissolved in right amount respectively
In hot water for injection, then tartaric acid solution is slowly added into homoharringtonine and 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl)
Pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one it is mixed
It closes in solution, is stirred continuously, dissolve active constituent all, lactose 10g, mannitol 15g, stirring and dissolving, with 4% is then added
NaOH tune pH to 4, benefit inject water to 1000ml, are sterile filtered, and filtrate is sub-packed in the west of the control by sterilizing by 1ml/ branch
It in woods bottle, sets and is freeze-dried in freeze dryer for 24 hours, the sterilized butyl rubber plug of gland rolls aluminium lid, checks, packs to obtain the final product.
Embodiment 2
Weigh homoharringtonine 1g, 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl) pyridine-2- base)-6- (4- (4- methyl
Piperazine -1- base) phenyl amino) -1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 1g, tartaric acid 1g be dissolved in appropriate heat note respectively
It penetrates and uses in water, then tartaric acid solution is slowly added into homoharringtonine and 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl) pyridine-
2- yl) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one mixed solution
In, it is stirred continuously, dissolves active constituent all, lactose 10g, mannitol 15g, stirring and dissolving, with 4%NaOH tune is then added
PH to 4, benefit inject water to 1000ml, are sterile filtered, and filtrate is sub-packed in the control cillin bottle by sterilizing by 1ml/ branch,
It sets and is freeze-dried in freeze dryer for 24 hours, the sterilized butyl rubber plug of gland rolls aluminium lid, checks, packs to obtain the final product.
Embodiment 3
Weigh homoharringtonine 1.8g, 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl) pyridine-2- base)-6- (4- (4- first
Base piperazine -1- base) phenyl amino) -1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 0.2g, tartaric acid 1g be dissolved in right amount respectively
In hot water for injection, then tartaric acid solution is slowly added into homoharringtonine and 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl)
Pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one it is mixed
It closes in solution, is stirred continuously, dissolve active constituent all, lactose 10g, mannitol 15g, stirring and dissolving, with 4% is then added
NaOH tune pH to 4, benefit inject water to 1000ml, are sterile filtered, and filtrate is sub-packed in the west of the control by sterilizing by 1ml/ branch
It in woods bottle, sets and is freeze-dried in freeze dryer for 24 hours, the sterilized butyl rubber plug of gland rolls aluminium lid, checks, packs to obtain the final product.
Embodiment 4
Weigh homoharringtonine 1.5g, 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4-
Methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 0.5g, tartaric acid 1g be dissolved in respectively it is suitable
In calorimetric water for injection, then tartaric acid solution is slowly added into homoharringtonine and 2- allyl -1- (6- (2- hydroxyl propyl- 2-
Base) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one
It in mixed solution, is stirred continuously, dissolves active constituent all, lactose 10g, mannitol 15g is then added, stirring and dissolving is used
4%NaOH tune pH to 4, benefit inject water to 1000ml, are sterile filtered, and filtrate is sub-packed in the control by sterilizing by 1ml/ branch
It in cillin bottle, sets and is freeze-dried in freeze dryer for 24 hours, the sterilized butyl rubber plug of gland rolls aluminium lid, checks, packs to obtain the final product.
Embodiment 5
Weigh homoharringtonine 1g, 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- first
Base piperazine -1- base) phenyl amino) -1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 1g, tartaric acid 1g be dissolved in appropriate heat respectively
In water for injection, then tartaric acid solution is slowly added into homoharringtonine and 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl)
Pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one it is mixed
It closes in solution, is stirred continuously, dissolve active constituent all, lactose 10g, mannitol 15g, stirring and dissolving, with 4% is then added
NaOH tune pH to 4, benefit inject water to 1000ml, are sterile filtered, and filtrate is sub-packed in the west of the control by sterilizing by 1ml/ branch
It in woods bottle, sets and is freeze-dried in freeze dryer for 24 hours, the sterilized butyl rubber plug of gland rolls aluminium lid, checks, packs to obtain the final product.
Embodiment 6
Weigh homoharringtonine 1.8g, 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4-
Methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] (2H) -one of pyrimidine -3 0.2g, tartaric acid 1g be dissolved in respectively it is suitable
In calorimetric water for injection, then tartaric acid solution is slowly added into homoharringtonine and 2- allyl -1- (6- (2- hydroxyl propyl- 2-
Base) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one
It in mixed solution, is stirred continuously, dissolves active constituent all, lactose 10g, mannitol 15g is then added, stirring and dissolving is used
4%NaOH tune pH to 4, benefit inject water to 1000ml, are sterile filtered, and filtrate is sub-packed in the control by sterilizing by 1ml/ branch
It in cillin bottle, sets and is freeze-dried in freeze dryer for 24 hours, the sterilized butyl rubber plug of gland rolls aluminium lid, checks, packs to obtain the final product.
Test example 1: inhibiting effect of the pharmaceutical composition of the present invention to K562 cell Proliferation
1, test method
(1) cell culture and test grouping
K562 cell routine is incubated in the RPMI1640 culture medium containing 10% inactivated fetal bovine serum, at 37 DEG C, containing 5%
CO2, saturated humidity incubator in cultivate.Liquid passage is changed within every two days, logarithmic growth phase cell is used for subsequent experimental.When test
Each test group is added drug concentration and is respectively as follows: homoharringtonine group and Wee1 kinase inhibitor a group (i.e. Wee1 kinase inhibitor
(a), 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl) pyridine-2- base)-6- (4- (4- methylpiperazine-1-yl) phenyl amino)-1H-
Pyrazolo [3,4-d] pyrimidine -3 (2H) -one) drug concentration setting be 2 μm of ol/L, joint group 1 is 1.6 μm of ol/L high tricuspids
+ 0.4 μm of ol/LWee1 kinase inhibitor a of China fir ester alkali (i.e. the concentration ratio of homoharringtonine and Wee1 kinase inhibitor a is 4:
1), joint group 2 be+0.2 μm of ol/LWee1 kinase inhibitor a of 1.8 μm of ol/L homoharringtonines (i.e. homoharringtonine with
The concentration ratio of Wee1 kinase inhibitor a is 9:1), joint group 3 is+1 μm of ol/LWee1 kinases suppression of 1 μm of ol/L homoharringtonine
Preparation a (i.e. the concentration ratio of homoharringtonine and Wee1 kinase inhibitor a are 1:1) observes each test group culture for 24 hours and 48h
Cell growth condition afterwards.
(2) cell Proliferation viability examination
Each experimental group cell is taken, adjustment cell number is 5 × 105/ ml is inoculated in 96 orifice plates, and 100 microlitres/hole, every group 6
A multiple holes, 37 DEG C, 5%CO2Under the conditions of overnight incubation, rear every hole is added 10 μ lCCK-8 solution, continues in incubator and be incubated for
2h measures absorbance value (A value) of each hole at wavelength 450nm with microplate reader.Experiment is repeated 3 times, cell proliferation inhibition rate
(%)=(1- experimental group average A-value/control group average A-value) × 100%.
2, test result
Each test group inhibits the test result of K562 cell Proliferation to be shown in Table 1.
Influence of the pharmaceutical composition of the present invention of table 1 to K562 cell Proliferation is inhibited
1 test result of table shows that homoharringtonine and Wee1 kinase inhibitor a can generate the proliferation of K562 cell
Inhibiting effect, and be more and more obvious with the extension of time.It is worth noting that, when homoharringtonine and Wee1 kinases press down
When preparation a is combined, the inhibited proliferation of K562 cell is significantly increased, wherein the inhibitory effect of joint group 1 is best.
Test example 2: inducing action of the pharmaceutical composition of the present invention to HL-60 Apoptosis
1, test method
(1) cell culture and test grouping
It is counted after the HL-60 cell Trypan Blue that cell culture fluid is cultivated for the RPMI-1640 containing 10% calf serum
Number refuses dye living cells >=98% or more person and is suitable for experiment.Every hole inoculation 1 × 10 in 24 porocyte culture plates6The HL- of/mL
60 cells, 37 DEG C, 5%CO2Under the conditions of preculture for 24 hours.Each test group addition drug concentration is respectively as follows: high cepehalotaxus fortunei ester when test
Alkali group and Wee1 kinase inhibitor d group (i.e. Wee1 kinase inhibitor (d), 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyrrole
Pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one) drug
Concentration setting is 2 μm of ol/L, and joint group 1 is+0.5 μm of ol/LWee1 kinase inhibitor d of 1.5 μm of ol/L homoharringtonines
(i.e. the concentration ratio of homoharringtonine and Wee1 kinase inhibitor d is 3:1), joint group 2 is 1.8 μm of ol/L homoharringtonines
+ 0.2 μm of ol/LWee1 kinase inhibitor d (i.e. the concentration ratio of homoharringtonine and Wee1 kinase inhibitor d is 9:1), joint
Group 3 is+1 μm of ol/LWee1 kinase inhibitor d of 1 μm of ol/L homoharringtonine (i.e. homoharringtonine and Wee1 kinase inhibition
The concentration ratio of agent d is 1:1).Above-mentioned each test group is in 37 DEG C, 5%CO2Under the conditions of cultivate respectively for 24 hours with collect cell after 48h,
It is resuspended after washing 2 times with PBS, adjustment cell concentration is 1 × 106/ mL, above-mentioned experiment are repeated 3 times.
(2) Apoptosis detects
Using FITC-annexinV/PI method, the 100 μ L of cell suspension of above-mentioned each test group effect different time is taken, is added
10 μ LFITC-annexinV, are resuspended cell after 37 DEG C of incubation 10min, PBS washings, 50 μ L of PI terminate liquid are added, uses fluidic cell
Instrument detection.Calculate the effect of each test group for 24 hours with the HL-60 apoptosis rate of 48h.
2, test result
The test result of each test group HL-60 cells Apoptosis is shown in Table 2.
The influence of the pharmaceutical composition HL-60 cells Apoptosis of the present invention of table 2
2 test result of table shows that homoharringtonine and Wee1 kinase inhibitor d can occur HL-60 cells cell
Apoptotic effect, and be more and more obvious with the extension of time.It is worth noting that, when homoharringtonine and Wee1 kinases press down
When preparation d is combined, the inducing action of HL-60 Apoptosis is significantly increased, wherein the inhibitory effect of joint group 1 is best.
Claims (10)
1. a kind of pharmaceutical composition for treating leukaemia, which is characterized in that active constituent is high tricuspid in described pharmaceutical composition
China fir ester alkali and Wee1 kinase inhibitor.
2. pharmaceutical composition according to claim 1, which is characterized in that the Wee1 kinase inhibitor is selected from following chemical combination
Object:
(a) 2- methyl-1-(6- (2- hydroxyl propyl- 2- yl) pyridine-2- base)-6- (4- (4- methylpiperazine-1-yl) phenyl amino)-
1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(b) 2- ethyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -
1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(c) 2- propyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -
1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(d) 2- allyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenylamino
Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(e) 2- cyclopropyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenylamino
Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(f) 2- butyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenyl amino) -
1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one；
(g) 2- cyclobutyl -1- (6- (2- hydroxyl propyl- 2- yl) pyridine -2- base) -6- (4- (4- methylpiperazine-1-yl) phenylamino
Base) -1H- pyrazolo [3,4-d] pyrimidine -3 (2H) -one.
3. pharmaceutical composition according to claim 1 or 2, which is characterized in that wherein homoharringtonine and Wee1 kinases
The weight ratio of inhibitor is 1:10-10:1.
4. pharmaceutical composition according to claim 3, which is characterized in that wherein homoharringtonine and Wee1 kinase inhibition
The weight ratio of agent is 1:5-5:1.
5. pharmaceutical composition according to claim 4, which is characterized in that wherein homoharringtonine and Wee1 kinase inhibition
The weight ratio of agent is 4:1 or 3:1.
6. pharmaceutical composition according to claim 1-5, which is characterized in that described pharmaceutical composition is further wrapped
Include pharmaceutically acceptable auxiliary material.
7. pharmaceutical composition according to claim 1-6, which is characterized in that described pharmaceutical composition is solid system
Agent.
8. pharmaceutical composition according to claim 7, which is characterized in that the solid pharmaceutical preparation is tablet, capsule or jelly
Dry preparation.
9. application of the described in any item pharmaceutical compositions of claim 1-8 in the drug of preparation treatment leukaemia.
10. application according to claim 9, which is characterized in that the leukaemia is chronic myelogenous leukemia or acute marrow
It is leukaemia.
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