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CN105963300A - Novel application of PIKfyve inhibitor for resisting radiation injury - Google Patents

Novel application of PIKfyve inhibitor for resisting radiation injury Download PDF

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Publication number
CN105963300A
CN105963300A CN201510109560.5A CN201510109560A CN105963300A CN 105963300 A CN105963300 A CN 105963300A CN 201510109560 A CN201510109560 A CN 201510109560A CN 105963300 A CN105963300 A CN 105963300A
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compound
pyrimidine
base
pyridine
morpholinyl
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CN105963300B (en
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余祖胤
邢爽
熊国林
何新华
从玉文
罗庆良
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Institute of Radiation Medicine of CAMMS
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Institute of Radiation Medicine of CAMMS
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Abstract

The invention belongs to the technical field of medicine, and a novel application of a PIKfyve inhibitor for resisting radiation injury, and mainly relates to a medical application of the PIKfyve inhibitor in prevention and treatment of nuclear/radiation injury and radiation injury during tumor radiotherapy. Accurately, the invention relates to usage of the PIKfyve inhibitor for preventing and/or treating various radiation injuries by individually using or combing other treatment methods.

Description

The new application of PIKfyve inhibitor Antiradiation injury
Technical field
The invention belongs to pharmaceutical technology field, about the Antiradiation injury new application of PIKfyve inhibitor, mainly it is at core/spoke Penetrate the preventing and treating of damage and medical application in radiation damage preventing and treating that tumour radiotherapy causes.More particularly, the present invention is closed In individually or jointly other Therapeutic Method, application PIKfyve inhibitor prevents and/or treats various radiation damage.
Background technology
Nuclear energy and nuclear technology are the widest in the application of the every field such as industrial and agricultural production, health care, scientific research and Defence business General, they, while bringing huge interests to the mankind, there is also potential threat.Nuclear war, relate to nuclear terror raid, earthquake or Tsunamis etc. cause nuclear power station generation nuclear leakage, and in the work such as civilian radioactive source, medical exposure by poor management or operation is lost Wait by mistake and all may result in personnel by roentgenization.Can send out when body is at short notice by heavy dose of (＞ 1Gy) ionization radiation irradiation Raw acute radiation sickness (Acute Radiation Sickness, ARS), or it is referred to as acute radiation injury syndrome (Acute Radiation Syndrome disease, ARS).Acute radiation sickness is a kind of systemic disease, according to the difference of damaged organ, be divided into BM form, Visible peristalsis visible intestinal peristalsis and brain type three type；According to by being divided into acute, subacute and chronic according to time length difference radiation sickness.Acute radiation is died of illness Rate of dying is high, cures difficulty, and the current exposure dosage patient more than 8Gy there is no the precedent brought back to life.Additionally, tumor patient accepts In radiation therapy process, ray also results in damage to normal cell while killing tumor cell, the most therefore limits radiation The actual application for the treatment of.Therefore, in order to Antiradiation injury, provide safety guarantee to the efficient application of nuclear energy with nuclear technology, need Antiradiation injury medical science to be greatly developed.
Phosphatidylinositols-3-phosphoric acid 5-kinases (PIKfyve) is the lipid kinase of a 240kDa, can be specifically with endosome Phosphatidylinositols-3-phosphoric acid (PI3P) is that substrate catalysis produces phosphatidylinositols-3,5-phosphoric acid (PI (3,5) P2).PIKfyve and PI (3,5) the P2 signal path of mediation participates in maintaining intracellular interior body/lysosome form, glucose transport, retrovirus to sprout, Autophagy and ion channel activity etc..The research of nearly 2 years discloses PIKfyve important function in innate immune reaction, PIKfyve The multiple proinflammatory cytokines that can lower the mediation of TLR signal path after activity suppression is expressed.Research shows, PIKfyve inhibitor STA 5326 (STA) suppresses its phosphate transferase activity, and then specific inhibition Toll receptor (TLR) directly in conjunction with PIKfyve The IL-12/IL-23 of mediation expresses, and suppresses helper T cell subgroup Th1 type to react.Due to immune system and inflammation Reaction critical role in the acute radiation sickness course of disease, it is presumed that improve inflammatory and immune response to be probably the weight of preventing and treating radiation damage Want approach.Based on this, we have discovered that PIKfyve specific inhibitor STA 5326 and YM201636 is to acute radiation Damage mice has significant preventive and therapeutic effect.This finds still to belong to the first, and related content has no report.
To sum up, the invention provides the new application of a compounds i.e. PIKfyve inhibitor Antiradiation injury.
Summary of the invention
About the Antiradiation injury new application of PIKfyve inhibitor, mainly it is controlled in core/radiation damage treatment and tumour radiotherapy Treat the medical application in the radiation damage preventing and treating caused.More particularly, the present invention about individually or jointly other Therapeutic Method, Application PIKfyve inhibitor prevents and/or treats various radiation damage.
Inventor it has been investigated that: the bone marrow depression caused by ionizing radiation and associated disease are had by PIKfyve inhibitor There are prevention and/or therapeutical effect.The present invention produces accordingly.
Concrete discovery according to the present invention, it is provided that
1. acute radiation sickness such as slight bone marrow form acute radialion sickness, the moderate BM form acute radiation that treatment a variety of causes causes Disease, ablative type acute radiation sickness, Extremely severe bone marrow form of acute radiation sickness and the method for visible peristalsis visible intestinal peristalsis radiation sickness, the method includes shining The PIKfyve inhibitor of administering therapeutic effective dose at least 1 day at least 1 day and/or after irradiating before penetrating, the most defined hereinbelow Compound 1 to compound 24.
2. the method for bone marrow depression that treatment roentgenization causes, the method include pre-irradiation at least 1 day and/or after irradiating extremely The PIKfyve inhibitor of administering therapeutic effective dose, the compound of the most as defined below 1 to 24 in few 1 day.
3. the method for the treatment of bone marrow depression caused by tumour radiotherapy, the method includes pre-irradiation at least 1 day, radiates and control During treatment and/or irradiate after the PIKfyve inhibitor of at least 1 day administering therapeutic effective dose, the most as defined below 1 to 24 Compound.
4. treatment be combined, with chemotherapy or surgical operation, the radiotherapy carried out caused by the method for bone marrow depression, the method Including during pre-irradiation at least 1 day, radiotherapy and/or irradiate after at least 1 day administering therapeutic effective dose PIKfyve inhibitor, Compound 1 to compound 24 the most as defined below.
These bone marrow depression are, by and large, treat with PIKfyve inhibitor and the individuality that can benefit includes, are scheduled to out Begin or accepting radiotherapy.The individuality can benefited especially in this treatment includes there is bone marrow depression person or may easily occur Bone marrow depression person.Such as, these individualities may just accept, may accept, or accepted radiotherapy.
A side according to the present invention and, treat because the method for the bone marrow depression caused by radiation includes, to needing these treatments The PIKfyve inhibitor of individual drug treatment effective dose.
In some instantiation, PIKfyve inhibitor was administered at least one day before first dose of individual body radiation therapy.
In some other instantiations, PIKfyve inhibitor was controlled before first dose individual of radiotherapy at least one day to radiation Treat and be administered in the period of at least one day after stopping.
In some instantiation, by PIKfyve inhibitor individual body radiation therapy, before chemotherapeutical first dose at least one day Interior administration.
Other instantiation includes, by PIKfyve inhibitor during radiotherapy, chemotherapy in be administered.
PIKfyve inhibitor is usually amino-metadiazine compound, such as the compound of structure formula (I).
Wherein: X and Y is the alkyl containing 1-5 the substituted C6-C20 of hetero atom respectively, aryl, alkoxyl, aryloxy group, Or substituted amino；W is substituted amino, can be connected cyclization with X, it is also possible to do not exist；Z is alkoxyl, substituted Amino or substituted sulfydryl, Z can be connected cyclization with Y, it is also possible to is not connected with Y；U is oxygen atom or methylene.
On the other hand, wherein: X and Y can also be containing 1-5 the substituted alkyl of hetero atom respectively, aryl, alkoxyl, Aryloxy group, or substituted amino；W is substituted amino, can be connected cyclization with X, it is also possible to do not exist；Z is alkoxyl, Substituted amino or substituted sulfydryl；U is oxygen atom, methylene.
Another further aspect, wherein X and Y is the alkyl containing 1-5 the substituted C10-C16 of hetero atom respectively, alkoxyl, virtue Base, or substituted amino；W is substituted amino, can be connected cyclization with X, it is also possible to do not exist；Z is hydrogen atom；U For oxygen atom.
Or, wherein X and Y is the alkoxyl containing 1-5 the substituted C10-C16 of hetero atom respectively, aryl, or substituted Amino；W is substituted amino, can be connected cyclization with X, it is also possible to do not exist；Z is hydrogen atom；U is oxygen atom.
Include but not limited to the compound of following compound 1 to compound 24.
(E)-4-(6-(2-(3-chlorobenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 1)
(E)-4-(6-(2-(3-fluorobenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 2)
(E)-4-(6-(2-(3-allyl iodide diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 3)
(E)-4-(6-(2-(3-methylbenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 4)
(E)-4-(6-(2-(3-bromobenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 5)
The bromo-N ' of 3--(6-morpholinyl-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) benzoyl hydrazine (compound 6)
3-methyl-N '-(6-morpholinyl-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) benzoyl hydrazine (compound 7)
3-methyl-N '-(6-morpholinyl-2-(2-(pyridine-2-base) ethylamino-) pyrimidine-4-yl) benzoyl hydrazine (compound 8)
3-methyl-N '-(6-morpholinyl-2-(phenethylamine base) pyrimidine-4-yl) benzoyl hydrazine (compound 9)
N '-(6-morpholinyl-2-(phenethylamine base) pyrimidine-4-yl)-3-pyridinecarboxylic hydrazine (compound 10)
N '-(6-morpholinyl-2-(phenethylamine base) pyrimidine-4-yl)-Isoniazid (compound 11)
4-morpholinyl-N-phenethyl-pyridine [3 ', 2 ': 4,5] furan [3,2-d] pyrimidine-2-amine (compound 12)
Buddhist nun can amide (compound 13) for N-(3-(4-morpholinyl-pyridine [3 ', 2 ': 4,5] furan [3,2-d] pyrimidine-2-base) phenyl)
Buddhist nun can amide (compound 14) for 6-amino-N-(3-(4-morpholinyl-pyridine [3 ', 2 ': 4,5] furan [3,2-d] pyrimidine-2-base) phenyl)
(E)-4-(5-(2-(3-methylbenzene methene) diazanyl)-2-Phenylpyrazole also [1,5-a] pyrimidin-7-yl) morpholine (compound 15)
(E)-4-(5-(2-(3-methylbenzene methene) diazanyl)-2-(4-pyridine radicals) pyrazolo [1,5-a] pyrimidin-7-yl) morpholine (compound 16)
3-methyl-N '-(7-morpholinyl-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine-5-base) benzoyl hydrazine (compound 17)
The chloro-N ' of 3--(7-morpholinyl-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine-5-base) benzoyl hydrazine (compound 18)
(E)-4-(5-(2-(3-chlorobenzene methene) diazanyl)-2-(4-pyridine radicals) pyrazolo [1,5-a] pyrimidin-7-yl) morpholine (compound 19)
The fluoro-N ' of 3--(7-morpholinyl-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine-5-base) benzoyl hydrazine (compound 20)
(E)-5-(2-(3-methylbenzene methene) hydrazine)-7-(piperidin-1-yl)-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine (compound 21)
3-methyl-N '-(7-piperidin-1-yl-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine-5-base) benzoyl hydrazine (compound 22)
(E)-4-(6-(2-(3-methylbenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) piperidines (compound 23)
Buddhist nun can amide (compound 24) for 6-amino-N-(3-(4-piperidin-1-yl-pyridine [3 ', 2 ': 4,5] furan [3,2-d] pyrimidine-2-base) phenyl)
Should be appreciated that compound described herein can be direct active substance, or can be prodrug.Such as, compound is permissible Form for phosphorylation.
In the case of providing every kind of cited patent applications or scientific publications, the theme relevant to compound is merged in this herein Apply for reference.Also include its officinal salt, corresponding racemate, diastereomer, enantiomer, make a variation mutually The corresponding crystalline modifications of structure body and above-claimed cpd (in the presence of), the disclosedest solvate, hydrate and polymorphic Thing.Can as described in the cited the description in document prepare respectively and use combine as the present invention in the compound of active component.This The combination of two or more single active component as implied above, i.e. drug regimen in the scope of the invention is also included in bright scope The active component of three kinds or more can be included.Additionally, the first activating agent and coagent are not identical compositions.Such as this paper institute With, be administered preferably belong to be administered orally, drug administration by injection.
Detailed description of the invention
This specification discloses prevention and/or the method for the treatment of ionization radiation injury.
Possibility will be by radioactive exposure to have this colony needed to include, such as first strike, the core dirty bomb attack of terrorism, or i.e. To enter radiocontamination region, before (possible) radioactive exposure, a few hours or at least 1 day accept the PIKfyve inhibitor of effective dose Prophylactic treatment.
The wounded of the exposure dose that individuals in need includes having been subjected to causing hemopoietic to damage or accident patient, in being subject to After according at once, accept the PIKfyve inhibitor for treating of effective dose in a few hours or at least 1 day.
This specification also discloses treatment because of the method for the bone marrow depression caused by X-ray therapy.
X-ray therapy (radiation therapy) and radiotherapy (radiotherapy) are used interchangeably in herein, and include external exposure (external irradiation) and internal radiation (internal irradiation), also refer to referred to as brachytherapy (brachytherapy), intracavity near Connect brachytherapy (interstitial brachytherapy) between treatment (intracavitary brachytherapy), or tissue.Can take into account Radioactive source includes pure gamma (pure Gamma), pure beta (pure Beta), and mixing radiation.
Used herein, term " chemotherapy " and " chemotherapeutant " are used interchangeably, and mean to manifest anticancer effect and The chemotherapeutant being used in the treatment of malignant tumor or medicine.
Used herein, the bone marrow depression caused by radiation includes that the local such as total irradiation or breast pulmonary, pelvis, trunk is shone Penetrate caused radiation injury.Irradiation often results in acute radiation sickness or bone marrow hematogenesis suppression.Symptom can include vomiting, hematopoietic cell Minimizing, anemia, thrombocytopenia, leukopenia, hematopoietic cell proliferation obstacle, thrombocytopenic are hemorrhage etc..
The present invention again additionally aspect about with PIKfyve inhibitor for treating individuals in need (such as, mammals, the mankind, horse, Canis familiaris L., cat) method.Confirm whether individuality has these demands treated, individuality itself can be depended on or healthy irradiation protects professional's Pass judgment on, and can be subjective (such as, view) or objective (such as, can measure by test or diagnostic method).
Individuals in need includes accepting radiocurable individuality, the most individually accept radiotherapy or combine other can Cause the chemotherapy of bone marrow depression.This needs to be revealed in individuality and accepts radiotherapy, chemotherapy or (several) Before the combination for the treatment of；The combination that individuality is accepting radiotherapy, chemotherapy or (several) are treated；Individuality accepts to put Penetrate treatment, after combination that chemotherapy or (several) are treated.Such as, individuality may be about to, may, or connect It is subject to, radiation therapy in combination chemotherapy.
Used herein, therapeutically effective amount it is meant that when administered to a human or non-human subject, effectively provides treatment benefit (ratio Such as, the improvement to symptom) amount, such as, be effectively improved the amount of Anemia.
According to some instantiation, PIKfyve inhibitor can be used for various therapeutic scheme, and these schemes can be according to individual and treatment class Type and change.
PIKfyve inhibitor can before treatment, period, and/or be administered afterwards.Such as, can be first at individual radiotherapy It is administered at least one day before agent, is administered during radiotherapy, is administered at least one day after radiotherapy stops.
Preferably before myelosuppresive therapy, during treatment and after treatment, it is administered PIKfyve inhibitor.Such as, from putting After before penetrating treatment, chemotherapeutical first dose and combined treatment at least one day stops to radiotherapy, after chemotherapy stops It is administered in the period of at least one day.
According to particular embodiment, PIKfyve inhibitor can be administered together in conjunction with other compound, such as, chemotherapeutant, anti- Inflammatory agent, antipyretic, radiosensitizer, radioprotector, urinary tract agent, antiemetic, and/or diarrhea.Such as, Cisplatin (cisplatin), carboplatin (carboplatin), Docetaxel (docetaxel), Paclitaxel (paclitaxel), fluorine are urinated Pyrimidine (flurouracil), capecitabine (capecitabine), gemcitabine (gelncitabine), irinotecan (irinotecan), Hycamtin (topotecan), etoposide (etoposide), mitomycin (mitomycin), gefitinib (geftinib), length Spring new alkali (vincristine), vinblastine (vinblastine), amycin (doxorubicin), cyclophosphamide (cyclophosphamide), celecoxib (celecoxib), rofecoxib (rofecoxib), valdecoxib (valdccoxib), cloth Ibuprofen (ibuprofen), naproxen (naproxen), ketoprofen (ketoprofen), dexamethasone (dexamethasone), sprinkle Buddhist nun pine (prednisone), prednisolone (prednisolone), hydrocortisone (hydrocortisone), acetaminophen (acetaminophen), MISOPROSTOL stone Xiao azoles (misonidazole), amifostine (amifostine), Tamsulosin (tamsulosin), Phenazopyridine (phenazopyridine), ondansetron (ondansetron), granisetron (granisetron), alosetron (alosctron), palonosetron (palonosetron), promethazine (promethazine), prochlorperazine (prochlorperazine), Trimethoxy benzene vinegar amine (trimethobenzamide), aprepitant (aprcpitant), diphenoxylate add atropine (diphenoxylate with Atropine), balsalazide (balsalizide), and/or loperamide (loperamide).
The method disclosed herein, the PIKfyve inhibitor to individuals in need drug treatment effective dose, with protection individuality antagonism Systemic injury caused by radiation is also useful.Such as, preventative taking can be administered before patient accepts radiation.
Accompanying drawing explanation
The impact on 8.5Gy gamma-rays total irradiation C57 mouse survival of Fig. 1 .STA pre-irradiation 1h gavage
Result shows, irradiation control group mice starts none survival in death, two weeks occur after irradiating on the 10th day, and STA Group mice then starts death occur from the 14th talent, survival 40% when 30 days.
The impact on 6.5Gy gamma-rays total irradiation C57 mouse peripheral blood cell number of Fig. 2 .STA pre-irradiation 1h gavage
Result shows, compared with irradiation control group, pre-irradiation 1h is to mice single oral gavage STA5326 10,20 and 30mg/kg All can promote that peripheral blood platelet count, RBC number are recovered；And along with dosage increases, this effect presents becoming of enhancing Gesture, promotees recovery effects with 30mg/kg group the most obvious
Fig. 3. the impact on 6.5Gy gamma-rays total irradiation C57 mouse peripheral blood cell number of the various dose STA pre-irradiation 1h gavage
Compared with irradiation control group, pre-irradiation 1h respectively give C57 mouse stomach 20mg/kg, 30mg/kg, 40mg/kg and During 50mg/kg STA5326, each group mice peripheral leukocytes recovery trend is without significant difference, but 30 and 40mg/kg administration groups Mouse peripheral blood platelet and erythrocytic recovery trend are basically identical and be substantially better than irradiation control group, 20mg/kg and 50mg/kg Organize inconspicuous with the difference of irradiation control group.
The impact on 6.5Gy gamma-rays total irradiation C57 mouse peripheral blood cell number of Fig. 4 .STA pre-irradiation different time gavage
In pre-irradiation 24h, single oral gavage STA 30mg/kg all can promote that the hematopoietic cell of 6.5Gy gamma-rays total irradiation mice is extensive Multiple, the action effect being wherein administered with pre-irradiation 3h is the most obvious.
The impact on 8.5Gy gamma-rays total irradiation C57 mouse survival of Fig. 5 .STA pre-irradiation 3h gavage
Comparing with irradiation control group, STA5326 20mg/kg group mouse survival rate is without significantly improving, but mice starts the death time Postpone；And STA 30mg/kg and 40mg/kg is administered the time-to-live not only extending dead Mus, and 30 days survival rates improve 50% (irradiation control group is 0).
The impact on 6.5Gy gamma-rays total irradiation C57 Bone Marrow Hematopoietic Stem Cells of Mice of Fig. 6 .STA pre-irradiation 3h gavage
In STA group mice 3h bone marrow after irradiation live single nucleated cell quantity apparently higher than irradiation control group；Analyze Lin-c-kit+Sca-l-Cell and Lin-c-kit+Sca-l+Content shows, the quantity irradiating latter 14 days these two kinds of cells of STA group is the highest In irradiation control group.
The different time gavage impact on 6.5Gy gamma-rays total irradiation C57 mouse peripheral blood cell number after Fig. 7 .STA irradiation
Result shows, after irradiation, in 24h, single oral gavage STA 30mg/kg all can promote 6.5Gy gamma-rays total irradiation mice Hematopoietic cell recovers, especially notable to the rush restitution of platelet and RBC number, wherein makees with 24h administration group after irradiating The most obvious by effect.
The impact on 6.5Gy gamma-rays total irradiation C57 mouse peripheral blood cell number of Fig. 8 .STA pre-irradiation 3h lumbar injection
It was found that 3h can improve outside mice to C57 mouse peritoneal injection STA5326 30mg/kg before 6.5Gy total irradiation The minimum of all blood leukocytes, and promote the recovery of platelet and RBC number.
The impact on 8.5Gy gamma-rays total irradiation C57 mouse survival of Fig. 9 .STA pre-irradiation 3h lumbar injection
The all death (irradiation control group) in 30 days after irradiation of 8.5Gy total irradiation C57 mice, and at pre-irradiation 3h single Lumbar injection STA5326 30mg/kg can make the current deposit rate of mice improve 90%.
Specific embodiment
1, STA5326 pre-irradiation 1 hour single oral gavage can improve lethal exposure mouse survival rate.
For the Study On The Radioprotective of preliminary observation STA5326, healthy male adult C57 mice is divided into irradiation control group and STA administration group, often group 10.STA group mice in the STA5326 (0.2ml/ Mus) of pre-irradiation 1h single oral gavage 20mg/kg, Irradiation control group gavage PEG400 0.2ml/ Mus.Mice exposure dosage is60Co gamma-rays whole body once irradiating 8.5Gy, irradiates Close rate is 61.6cGy/min, observes the survival condition of mice, Continuous Observation 30 days after irradiation twice daily.Result shows, Irradiation control group mice starts none survival in death, two weeks occur after irradiating on the 10th day, and STA group mice is then from the 14th Talent starts death occur, 40% (Fig. 1) of surviving when 30 days.
At 1 hour single oral gavage of pre-irradiation, 2, STA5326 can promote that Irradiated Mice hematopoietic cell recovers
After roentgenization, body hemopoietic function sustains damage, and blood cell count reduces rapidly, and leukocyte, platelet counts fall sharply The infection caused and hemorrhage complication usually cause the minimizing of patient death, erythrocyte number and content of hemoglobin to cause anemia also Can not be ignored.In order to observe the STA impact on exposure body hemopoietic function, we use 6.5Gy60Whole body of Co gamma-rays Irradiate (exposure dose rate 61.6cGy/min) C57 mice and set up the hemopoietic system damage model that acute exposure causes.Mice is divided into Irradiate comparison and STA 10mg/kg, 20mg/kg and 30mg/kg totally four groups, often group 8.Tri-administration group mices of STA are respectively At pre-irradiation 1h single oral gavage 10mg/kg, 20mg/kg and 30mg/kgSTA5326, irradiation control group gavage 0.2ml/ Mus PEG400.After irradiating, different time takes tail vein detection peripheral blood cells number.Result shows, compared with irradiation control group, Pre-irradiation 1h all can promote the recovery of mouse peripheral blood cell to mice single oral gavage STA532610,20 and 30mg/kg, Especially human peripheral blood platelet count, RBC number rush restitution notable；And along with dosage increase, this effect in The trend now strengthened, promotees hemocyte recovery effects the most substantially (Fig. 2) with 30mg/kg group.
3, the STA5326 of various dose are in the impact on Irradiated Mice Radiation in jury of the 1 hour single oral gavage of pre-irradiation
The STA5326 further looking at various dose is administered 6.5Gy in pre-irradiation single oral gavage60Co γ body line total irradiation (is shone Penetrate close rate 60.0cGy/min) mouse hematopoetic cell recover impact.Experiment finds, compared with irradiation control group, and pre-irradiation When 1h gives C57 mice (n=8) gavage 20mg/kg, 30mg/kg, 40mg/kg and 50mg/kgSTA5326 respectively, each group Mice peripheral leukocytes recovery trend is without significant difference, but 30 and 40mg/kg administration group mouse peripheral blood platelet and erythrocyte Recovery trend basically identical and be substantially better than irradiation control group, the difference of 20mg/kg and 50mg/kg group and irradiation control group is not Substantially (Fig. 3).
4, STA5326 are administered the impact on Irradiated Mice Radiation in jury in the prevention of pre-irradiation different time
On above-mentioned experiment basis, with 6.5Gy60Co gamma-rays total irradiation (exposure dose rate 60.0cGy/min) mice is mould Type, observes STA and is administered the impact on irradiated mice Radiation in jury at pre-irradiation different time.C57 mice is divided into irradiation Comparison and STA administration group, wherein the administration time of STA be set to pre-irradiation 24h (-24h), pre-irradiation 12h (-12h), Pre-irradiation 3h (-3h) and pre-irradiation 1h (-1h) totally 4 groups, often group 8.STA administration group is respectively in the pre-irradiation corresponding time Single oral gavage STA5326 30mg/kg (0.2ml/ Mus), the PEG400 of irradiation control group gavage 0.2ml/ Mus.Detection mice periphery Hemocyte, result shows, in pre-irradiation 24h, single oral gavage STA 30mg/kg all can promote that 6.5Gy gamma-rays total irradiation is little The hematopoietic cell of Mus recovers, and the action effect being wherein administered with pre-irradiation 3h is the most obvious (Fig. 4).
5, STA5326 significantly improve fatal dose in the administration of pre-irradiation 3h single oral gavage irradiates mouse survival rate
Above-mentioned it was experimentally observed that STA when pre-irradiation is administered with irradiate 3h give about to irradiated mice hemopoietic system recover Facilitation is the most obvious, in order to confirm the Study On The Radioprotective of STA, and this laboratory observation 8.5Gy60Co gamma-rays (irradiates Close rate 60.0cGy/min) before total irradiation 3h to C57 mice gavage respectively STA5326 20mg/kg, 30mg/kg and 40mg/kg (n=10), observes the mice survival condition of 30 days.As it is shown in figure 5, compare with irradiation control group, STA5326 20mg/kg group mouse survival rate is without significantly improving, but mice starts death time postponement；And STA 30mg/kg and 40mg/kg It is administered the time-to-live not only extending dead Mus, and 30 days survival rates improve 50% (irradiation control group is 0).
6, STA5326 are administered the impact on Irradiated Mice marrow hemopoietic stem cells at pre-irradiation 3h single oral gavage
Have been demonstrated that STA5326 is administered at pre-irradiation 3h single oral gavage and can remarkably promote the recovery of Irradiated Mice hematopoietic cell, And the survival rate of fatal dose irradiation mice can be improved.Based on this, we have further looked at STA5326 prevention and have been administered being shone Penetrate the impact of mouse hematopoietic stem cell.The male C57 of 40 healthy adult is divided into irradiation control group and STA group, often organizes 20 Only.STA group mice is in pre-irradiation 3h single oral gavage STA5326 30mg/kg (0.2ml/ Mus), and irradiation control group gavages PEG400 0.2ml/ Mus.Mice all accepts 6.5Gy60Co gamma-rays total irradiation.Respectively 3 little to, 1,10 and 14 days every groups the most after irradiation Put to death 5 mices, collect femur bone marrow cell, to use stream after LinFITC, c-kit APC and Sca-1 PE-Cy7 labeled cell The content of hematopoietic stem/progenitor cells in formula cell instrument detection medullary cell.As shown in Figure 6, in STA group mice 3h bone marrow after irradiation Live single nucleated cell quantity apparently higher than irradiation control group；Analyze Lin-c-kit+Sca-1-Cell and Lin-c-kiy+Sca-1+ Content shows, the quantity irradiating latter 14 days these two kinds of cells of STA group is above irradiation control group.This result shows, STA shines It is administered before penetrating and can not only protect Irradiated Mice medullary cell, moreover it is possible to stimulate convalescent period hematopoietic stem cell to generate.
7, the STA5326 different time single oral gavage administration impacts on Irradiated Mice Radiation in jury after irradiation
Specify that STA pre-irradiation be administered Mice After Acute Irradiation Injury is had obvious protective action after, for studying STA further It is administered after irradiation acute radiation injury with or without therapeutical effect, by 6.5Gy60Co gamma-rays total irradiation (exposure dose rate 60.0cGy/min) C57 mice is divided into irradiation control group and STA treatment group, wherein STA component be 1h (+1h) after irradiating, 3h (+3h) after irradiation, irradiate after 12h (+12h), irradiate after 24h (+24h).STA administration group is the most corresponding Time single oral gavage STA5326 30mg/kg (0.2ml/ Mus), the PEG400 of irradiation control group gavage 0.2ml/ Mus.Detection mice Peripheral hemogram result shows, after irradiation, in 24h, single oral gavage STA 30mg/kg all can promote that 6.5Gy gamma-rays total irradiation is little The hematopoietic cell of Mus recovers, especially notable to the rush restitution of platelet and RBC number, is wherein administered with 24h after irradiating Group action effect is the most substantially (Fig. 7).
8, STA5326 can promote Irradiated Mice Radiation in jury in pre-irradiation single intraperitoneal injection administration in 3 hours, and make fatal dose Irradiate mice current deposit rate and improve 90%.
The studies above finds that STA gastric infusion after pre-irradiation and irradiation is possible not only to promote irradiation mouse hemopoietic functional rehabilitation, Also significantly improve fatal dose and irradiate the survival rate of mice, extend the time-to-live.This experiment changes the administering mode of STA into abdomen Chamber injection further looks at its Radioprotective Effect to mice.It was found that 3h is to C57 mice abdomen before 6.5Gy total irradiation Chamber injection STA5326 30mg/kg can improve the minimum of mouse peripheral blood leukocyte, and promotes platelet and RBC number Recover (Fig. 8).Prompting, STA intraperitoneal injection has Study On The Radioprotective equally to the hemopoietic system of mice.Cause with 8.5Gy Dead dose irradiation mice is that the result of study of model shows, pre-irradiation 3h single intraperitoneal injection STA5326 30mg/kg can make mice Current deposit rate improve 90% (Fig. 9).

Claims (5)

  1. The medical usage of the 1.PIKfyve inhibitor such as Antiradiation injury of the amino-metadiazine compound of structure formula (I), for there being it The individual internal prevention needed and/or the method for the treatment of damage caused by ionizing radiation.
    Wherein: X and Y is the alkyl containing 1-5 the substituted C6-C20 of hetero atom respectively, aryl, alkoxyl, aryloxy group, Or substituted amino；W is substituted amino, can be connected cyclization with X, it is also possible to do not exist；Z is alkoxyl, takes The amino in generation or substituted sulfydryl, Z can be connected cyclization with Y, it is also possible to is not connected with Y；U is oxygen atom or methylene Base.
  2. 2. the medicinal usage of the Antiradiation injury of the compound as described in right 1, wherein X and Y is containing 1-5 hetero atom respectively Substituted alkyl, aryl, alkoxyl, aryloxy group, or substituted amino；W is substituted amino, can be connected with X Cyclization, it is also possible to do not exist；Z is alkoxyl, substituted amino or substituted sulfydryl；U is oxygen atom, methylene.
  3. 3. the medicinal usage of the Antiradiation injury of the compound as described in right 2, wherein X and Y is containing 1-5 hetero atom respectively The alkyl of substituted C10-C16, alkoxyl, aryl, or substituted amino；W is substituted amino, can connect with X It is connected into ring, it is also possible to do not exist；Z is hydrogen atom；U is oxygen atom.
  4. 4. the medicinal usage of the Antiradiation injury of the compound as described in right 3, wherein X and Y is containing 1-5 hetero atom respectively The alkoxyl of substituted C10-C16, aryl, or substituted amino；W is substituted amino, can be connected cyclization with X, Can not also exist；Z is hydrogen atom；U is oxygen atom.
  5. 5. the medicinal usage of the Antiradiation injury of the compound as described in right 4, includes but not limited to following compound.
    (E)-4-(6-(2-(3-chlorobenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 1)
    (E)-4-(6-(2-(3-fluorobenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 2)
    (E)-4-(6-(2-(3-allyl iodide diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 3)
    (E)-4-(6-(2-(3-methylbenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 4)
    (E)-4-(6-(2-(3-bromobenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) morpholine (compound 5)
    The bromo-N ' of 3--(6-morpholinyl-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) benzoyl hydrazine (compound 6)
    3-methyl-N '-(6-morpholinyl-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) benzoyl hydrazine (compound 7)
    3-methyl-N '-(6-morpholinyl-2-(2-(pyridine-2-base) ethylamino-) pyrimidine-4-yl) benzoyl hydrazine (compound 8)
    3-methyl-N '-(6-morpholinyl-2-(phenethylamine base) pyrimidine-4-yl) benzoyl hydrazine (compound 9)
    N '-(6-morpholinyl-2-(phenethylamine base) pyrimidine-4-yl)-3-pyridinecarboxylic hydrazine (compound 10)
    N '-(6-morpholinyl-2-(phenethylamine base) pyrimidine-4-yl)-Isoniazid (compound 11)
    4-morpholinyl-N-phenethyl-pyridine [3 ', 2 ': 4,5] furan [3,2-d] pyrimidine-2-amine (compound 12)
    Buddhist nun can amide (compound 13) for N-(3-(4-morpholinyl-pyridine [3 ', 2 ': 4,5] furan [3,2-d] pyrimidine-2-base) phenyl)
    Buddhist nun can amide (compound 14) for 6-amino-N-(3-(4-morpholinyl-pyridine [3 ', 2 ': 4,5] furan [3,2-d] pyrimidine-2-base) phenyl)
    (E)-4-(5-(2-(3-methylbenzene methene) diazanyl)-2-Phenylpyrazole also [1,5-a] pyrimidin-7-yl) morpholine (compound 15)
    (E)-4-(5-(2-(3-methylbenzene methene) diazanyl)-2-(4-pyridine radicals) pyrazolo [1,5-a] pyrimidin-7-yl) morpholine (compound 16)
    3-methyl-N '-(7-morpholinyl-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine-5-base) benzoyl hydrazine (compound 17)
    The chloro-N ' of 3--(7-morpholinyl-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine-5-base) benzoyl hydrazine (compound 18)
    (E)-4-(5-(2-(3-chlorobenzene methene) diazanyl)-2-(4-pyridine radicals) pyrazolo [1,5-a] pyrimidin-7-yl) morpholine (compound 19)
    The fluoro-N ' of 3--(7-morpholinyl-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine-5-base) benzoyl hydrazine (compound 20)
    (E)-5-(2-(3-methylbenzene methene) hydrazine)-7-(piperidin-1-yl)-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine (compound 21)
    3-methyl-N '-(7-piperidin-1-yl-2-(pyridin-4-yl) pyrazoles [1,5-a] pyrimidine-5-base) benzoyl hydrazine (compound 22)
    (E)-4-(6-(2-(3-methylbenzene alkene diazanyl)-2-(2-(pyridine-2-base) ethyoxyl) pyrimidine-4-yl) piperidines (compound 23)
    Buddhist nun can amide (compound 24) for 6-amino-N-(3-(4-piperidin-1-yl-pyridine [3 ', 2 ': 4,5] furan [3,2-d] pyrimidine-2-base) phenyl)
    Should be appreciated that compound described herein can be direct active substance, or can be prodrug.Such as, compound is permissible Form for phosphorylation.
    In the case of providing every kind of cited patent applications or scientific publications, the theme relevant to compound is merged in this herein Apply for reference.Also include its officinal salt, corresponding racemate, diastereomer, enantiomer, make a variation mutually The corresponding crystalline modifications of structure body and above-claimed cpd (in the presence of), the disclosedest solvate, hydrate and polymorphic Thing.Can as described in the cited the description in document prepare respectively and use combine as the present invention in the compound of active component.This The combination of two or more single active component as implied above, i.e. drug regimen in the scope of the invention is also included in bright scope The active component of three kinds or more can be included.Additionally, the first activating agent and coagent are not identical compositions.Such as this paper institute With, be administered preferably belong to be administered orally, drug administration by injection.
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CN113683596A (en) * 2021-08-17 2021-11-23 上海应用技术大学 Pyrimidine tankyrase 2 inhibitor and preparation method and application thereof

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