CN107308172A - A kind of antineoplastic containing aryl ketones phosphate compound and its application - Google Patents

A kind of antineoplastic containing aryl ketones phosphate compound and its application Download PDF

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Publication number
CN107308172A
CN107308172A CN201710537834.XA CN201710537834A CN107308172A CN 107308172 A CN107308172 A CN 107308172A CN 201710537834 A CN201710537834 A CN 201710537834A CN 107308172 A CN107308172 A CN 107308172A
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aryl ketones
phosphate compound
antineoplastic
medicine
phosphate
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郭玮
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Shenzhen Ruike Biological Technology Co Ltd
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Shenzhen Ruike Biological Technology Co Ltd
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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention discloses a kind of antineoplastic containing aryl ketones phosphate compound, including aryl ketones phosphate compound or derivatives thereof, the medicine with regulation intracellular cAMP concentration level.The antineoplastic itself, be made up of the medicine that can adjust intracellular cAMP concentration level and aryl ketones phosphate compound of therapeutically effective amount or derivatives thereof.The component can cooperate with aryl ketones phosphate compound to suppress the growth of tumour, reduce the effective dose of aryl ketones phosphate compound, and then increase the curative effect of aryl ketones phosphate compound and reduce the toxic side effect of aryl ketones phosphate compound.The medicinal antineoplastic and preparation of the present invention, the medicine that can be treated as kinds of tumors.

Description

A kind of antineoplastic containing aryl ketones phosphate compound and its application
Technical field
The invention belongs to pharmaceutical technology field, more particularly, to a kind of antineoplastic containing aryl ketones phosphate compound Thing and its application.
Background technology
In various diseases, cancer is causing death ground one of principal disease.Counted according to the World Health Organization, cancer is one The number dead because of cancer is in the situation of cumulative year after year, 2008 in the individual global main cause of death, worldwide Year number of cancer deaths is up to 7,600,000 (account for all death tolls 13%), it is contemplated that to the year two thousand thirty, global number of cancer deaths will Increase by 45%.Also indicated that in report, the same with developed country in developing country, cancer is into a Major health problem. Lung cancer, breast cancer, colorectal cancer, stomach cancer, liver cancer and cervix cancer are most several cancers of incidence of disease highest.Cancer front three The cause of the death and front three common cancer are different, and the cancer front three cause of the death is：Lung cancer, accounts for the 17.8% of all cancer mortalities, stomach Cancer 10.4%, liver cancer 8.8%.
The main method for the treatment of malignant tumour includes at present：Operative treatment, the chemotherapy of cancer therapy drug, radiotherapy and BRM and other treatments.Wherein chemotherapy occupies irreplaceable in leukaemia, advanced malignant tumor treatment Status.But, due to the poor selectivity of anti-malignant tumor medicine, toxic side effect is big, causes malignant tumor patient immunologic function low Under, quality of life reduction, this causes the use of chemotherapeutics to be subject to certain restrictions.In addition, the generation of multidrug resistance is also limited The use of chemotherapeutics is made.Therefore, studying efficient, low toxicity the antineoplastic of a new generation and improving treatment method turns into The pole for working as business for the treatment of malignant tumor.Wherein, strengthen the anti-malignant tumor activity of medicine by drug combination and reduce medicine Toxicity is a kind of development trend.
The content of the invention
First purpose of the present invention is to provide a kind of antineoplastic containing aryl ketones phosphate compound.
Second object of the present invention is to provide a kind of preparation of antineoplastic.
Third object of the present invention is to provide a kind of antineoplastic for containing aryl ketones phosphate compound as swollen Medicinal application in knurl treatment.
Fourth object of the present invention is to provide a kind of preparation of antineoplastic as the application of medicine in oncotherapy.
To reach above-mentioned purpose, the present invention uses following technical scheme：
A kind of antineoplastic containing aryl ketones phosphate compound, including aryl ketones phosphate compound or its derivative Thing, the medicine with regulation intracellular cAMP concentration level.
Further, the aryl ketones phosphate compound is
Wherein, R1Selected from H, C1-C6Alkyl, C1-C6Alkoxy, cyano group or halogen；R2For ethyoxyl.
Further, the medicine with regulation intracellular cAMP concentration level is adenyl cyclase activator Forskolin and its derivative, Pimobendane theophylline and its derivative are one or two kinds of；Preferably, the aryl Ketone phosphate compound and the mass ratio of medicine with regulation intracellular cAMP concentration level are：1:1-1000.
Further, the mass ratio 1 of the aryl ketones phosphate compound and adenyl cyclase activator Forskolin: 1.5-2。
Further, the mass ratio of the aryl ketones phosphate compound and Pimobendane theophylline is 1:25-50.
Further, the anti-malignant tumor medicine has the medicine for adjusting intracellular cAMP concentration level to be one or more With the combination of aryl ketones phosphate compound.
A kind of preparation of antineoplastic, using the antineoplastic as active component, and is aided with acceptable medicinal Carrier.
Further, the preparation is tablet, oral liquid or capsule.
A kind of antineoplastic is used as the medicinal application in oncotherapy.
A kind of preparation of antineoplastic as the medicine in oncotherapy application.
The antineoplastic containing aryl ketones phosphate compound of the present invention, due to there is regulation using effective ratio Medicine and aryl ketones phosphate compound of intracellular cAMP concentration level or derivatives thereof are constituted；It is intracellular with adjusting The medicine of cAMP concentration levels can cooperate with aryl ketones phosphate compound to suppress the growth of tumour, reduce aryl ketones phosphate chemical combination The consumption of thing, and then increase the curative effect and reduction aryl ketones phosphate compound toxic side effect of aryl ketones phosphate compound.
The medicine that the preparation of the antineoplastic of the present invention can be treated as kinds of tumors.
It is further noted that, if not otherwise specified, any scope described in the present invention includes end value and end value Between any numerical value and any subrange for being constituted with any number between end value or end value.
Beneficial effects of the present invention are as follows：
The present invention relates to a kind of antineoplastic that therapeutically effective amount is bestowed to patient, the antineoplastic itself, by The medicine that can adjust intracellular cAMP concentration level and aryl ketones phosphate compound of therapeutically effective amount or derivatives thereof composition. The component can cooperate with aryl ketones phosphate compound to suppress the growth of tumour, reduce the effective agent of aryl ketones phosphate compound Amount, and then increase the curative effect of aryl ketones phosphate compound and reduce the toxic side effect of aryl ketones phosphate compound.This hair Bright medicinal antineoplastic and preparation, can be treated (such as lung cancer in non-cellule type and prostate cancer) as Several Kinds of Malignancy Medicine.
Embodiment
In order to illustrate more clearly of the present invention, with reference to preferred embodiment, the present invention is described further.Ability Field technique personnel should be appreciated that following specifically described content is illustrative and be not restrictive, and this should not be limited with this The protection domain of invention.
A kind of antineoplastic containing aryl ketones phosphate compound, including aryl ketones phosphate compound or its derivative Thing, the medicine with regulation intracellular cAMP concentration level.
The known medicine that can adjust intracellular cAMP levels has：1. the material of direct activated adenyl cyclase, for example Forskolin；2. the material of cAMP phosphodiesterases, such as theophylline are suppressed；These medicines being capable of inducing apoptosis of tumour cell, suppression Tumor cell proliferation processed, its mechanism of action is the level by raising intracellular cAMP, and then activated protein kinase A (proteinkinase A, PKA), then the propagation of cell is influenceed by the transcription or expression of modulin phosphorylation or gene And apoptosis.
Wherein, Forskolin (structural formula is as follows) is external 1970s first from India's Labiatae Coleus The diterpene-kind compound extracted in plant Coleus forskohlii (coleus forskohlii) root, with cardiac stimulant, hypotensive, relieving asthma, The effects such as anti-inflammatory, platelet aggregation-against, reduction intraocular pressure.Research thinks that Forskolin, by direct exciting adenyl cyclase, is carried The intracellular cyclic adenosine monophosphate of high Various Tissues (cAMP) concentration, so as to participate in various kinds of cell function point analysis, is played extensively in vivo Adjustment effect.The external crude extract using forskolin is as a kind of health products, for losing weight.In India Shri In the human trial that C.B.Patel is done in research center, there are 60 obese patients to take part in the research.These patients are every Its 500mg bfore meals in two times Forslean (including 10%forskolin), continuously takes 12 weeks.At the end of research, The body weight of these patients obtains obvious decline, averagely have dropped 2.3%.Under study for action, there is not any toxic side effect, this It is very small to the toxicity of human body to show forskolin.
Theophylline is a kind of Pimobendane, by suppressing cAMP phosphodiesterases, reduces cAMP degraded, rise Intracellular cAMP level.Theophylline and its derivative (such as aminophylline, diprophylline) have been widely used for clinic now Treatment, is mainly used in treatment bronchial astehma, asthmatic bronchitis, obstructive emphysema and cardiac edema, angina pectoris Deng.Theophylline energy relaxing smooth muscle, excited cardiac muscle, excited maincenter, and have diuresis.The effect of its relaxing smooth muscle is in convulsion The bronchus of contraction state is more prominent.To acute and chronic asthma, no matter orally, injection or rectally, it is effective in cure.To panting Property chronic bronchitis, due to it can excited skeletal muscle, breathing myotility can be strengthened and mitigate the sense of patient respiratory muscular fatigue Feel.
Aryl ketones phosphate compound is divided into four classes：(I) alkyl-substituted aryl ketones phosphate；(II) virtue of halogen substitution Base ketone phosphate；(III) the aryl ketones phosphate of alkoxy substitution；(IV) the aryl ketones phosphate of cyano group substitution.It is following with second The aryl ketones phosphate of epoxide substitution is studied, and its structure is such as shown in (formula 3).
Aryl ketones phosphate compound, which has, suppresses tumor cell proliferation and transferance, with CAI and its derivative Compare, its toxic side effect is very low, therefore as a kind of new type antineoplastic medicine.Some face with ongoing both at home and abroad Bed experiment suppresses the growth, invasion and attack and transfer of tumour in which also demonstrate that aryl ketones phosphate compound energy wide spectrum.Aryl ketones phosphoric acid Ester compounds are most apparent advantage is that its adverse reaction is slight, and incidence is relatively low.From the inhibition to tumour, to swollen The direct repression of oncocyte is poor.Although proliferative effect of the aryl ketones phosphate compound except directly suppressing tumour cell Outside, also with the tumor neovasculature effect of suppression, but its overall clinical tumor-inhibiting action still is below cell toxicity medicament.Cause How this, keep the advantage of aryl ketones phosphate compound low toxicity and increase its antitumaous effect, just very important as one Problem.
The method have the characteristics that have found a kind of advantage that can keep aryl ketones phosphate compound can strengthen it again The drug regimen of antitumor action.
The present invention has found that aryl ketones phosphate compound any of the above-described can be adjusted combining on the basis of research and experiment After the medicine for saving intracellular cAMP levels, antineoplastic becomes apparent to the inhibition of tumour, and combination medical instrument has Synergistic Effect.
The antineoplastic of the present invention is with aryl ketones phosphate compound of 1 mass or derivatives thereof and 1~1000 matter The drug regimen of the regulation intracellular cAMP levels of amount.Some specific antineoplastics are illustrated in the embodiment of the present invention, are 1 mass Include aryl ketones phosphate compound or derivatives thereof and the theophylline antineoplastic of 25-50 mass, or be the virtue of 1 mass The antineoplastic of base ketone phosphate compound or derivatives thereof and the Forskolin of 1.5-2 mass.
In the present invention, above-mentioned antineoplastic is respectively provided with significantly to SH-SY5Y, Bel-7402 and HeLa cell line proliferation Suppress.
Below by way of the effect of specific embodiment and the above-mentioned antineoplastic of experimental verification.
Embodiment 1
This example verifies that the antineoplastic suppression SH-SY5Y of Forskolin or theophylline and aryl ketones phosphate compound is thin The cooperative effect of born of the same parents' propagation.
Experiment material：
People's neuroblastoma SH-SY5Y cell lines.
Forskolin and theophylline are purchased from Sigma.
DMSO is purchased from Chemical Reagent Co., Ltd., Sinopharm Group.
The synthetic method of aryl ketones phosphate compound is shown in patent publication No. CN105330690B.Structure is as follows：
Experimental method：The good SH-SY5Y tumour cells of growth in vitro are collected, with the RPMI1640 containing 10% calf serum Culture medium is configured to 5 × 104/ ml cell suspensions, in being inoculated with 12 well culture plates, (contain 5 × 10 per hole 1ml4Individual oncocyte), put 37 DEG C, 6%CO2Culture discards former culture medium in incubator after 24 hours, adds the RPMI1640 containing respective concentration medicine complete Culture medium 1ml, every group of three holes, while counting three hole cell quantities as cell quantity when starting to be administered.Continue to cultivate 48 hours After discard culture medium, cell is collected in the digestion of 0.05 pancreatin -0.02EDTA digestive juices, in using blood cell counting plate under inverted microscope Count cell quantity.Inhibition rate of tumor cell calculation formula is as follows：100% × (solvent control group cell quantity-administration group cell Quantity)/(solvent control group cell quantity-start cell quantity during administration)
Experimental result：It the results are shown in Table 1.
Histamine result of the different pharmaceutical of table 1 to SH-SY5Y tumor cell proliferations
As a result show, suppression of the 5 μm of ol/L aryl ketones phosphate compound to SH-SY5Y cell line proliferations is used alone Rate is 66.4%；It is only 6.6% to the inhibiting rate of SH-SY5Y cell line proliferations that 1 μm of ol/L Forskolin, which is used alone, individually It is only 18.7% to the inhibiting rate of SH-SY5Y cell line proliferations using 100 μm of ol/L theophylline；When same dose aryl ketones phosphate When compound and Forskolin use in conjunction, the inhibiting rate to cell line proliferation is 75.1%, and aryl ketones phosphoric acid is relatively used alone Ester compounds rise 8.7%, and Forskolin is relatively used alone and rises 68.5%；When same dose aryl ketones phosphate chemical combination When thing and 100 μm of ol/L theophylline use in conjunction, the inhibiting rate to cell line proliferation is 84.7%, and aryl ketones phosphoric acid is relatively used alone Ester compounds rise 18.3%, and theophylline is relatively used alone and rises 66%；Thus provable Forskolin and theophylline are to aryl ketones Phosphate compound suppresses the cooperative effect of SH-SY5Y cells propagation.
Embodiment 2
This example verifies that Forskolin and theophylline suppress the collaboration effect of HeLa cells propagation to aryl ketones phosphate compound Should.
Experiment material is human cervical carcinoma cell system HeLa, other reagents and experimental method be the same as Example 1.Experimental result is shown in Table 2.
The histamine result that the different pharmaceutical of table 2 is bred to HeLa cells
As a result show, 10 μm of ol/L inhibiting rate of the aryl ketones phosphate compound to HeLa cell line proliferations is used alone For 33.17%；It is only 14.9% to the inhibiting rate of HeLa cell line proliferations that 10 μm of ol/L Forskolin, which are used alone, individually should It is only 21.4% to the inhibiting rate of HeLa cell line proliferations with 100 μm of ol/L theophylline, when same dose aryl ketones phosphate chemical combination When thing and Forskolin use in conjunction, the inhibiting rate to cell line proliferation is 68.9%, and aryl ketones Phosphation is relatively used alone Compound rises 35.73%, and Forskolin is relatively used alone and rises 54%；When same dose aryl ketones phosphate compound During with 100umol/L theophylline use in conjunction, the inhibiting rate to cell line proliferation is 61.1%, and aryl ketones phosphate is relatively used alone Compound rises 27.93%, and theophylline is relatively used alone and rises 39.7%；Thus provable Forskolin and the theophylline of arriving is to virtue Base ketone phosphate compound suppresses the cooperative effect of HeLa cells propagation.
Embodiment 3
This example verifies that Forskolin and theophylline suppress the collaboration of Bel-7402 cells propagation to aryl ketones phosphate compound Effect.
Experiment material is Bel7402 Bel-7402, other reagents and experimental method be the same as Example 1.Experimental result is shown in Table 3.
The histamine result that the different pharmaceutical of table 3 is bred to Bel-7402 cells
As a result show, suppression of the 10 μm of ol/L aryl ketones phosphate compound to Bel-7402 cell line proliferations is used alone Rate processed is 53.8%；It is 18.8% to the inhibiting rate of Bel-7402 cell line proliferations that 10 μm of ol/L Forskolin, which are used alone, It is only 25.61% to the inhibiting rate of Bel-7402 cell line proliferations that 100 μm of ol/L theophylline, which are used alone, when same dose aryl ketones When phosphate compound and Forskolin use in conjunction, the inhibiting rate to cell line proliferation is 56.1%, and aryl is relatively used alone Ketone phosphate compound rises 2.3%, and Forskolin is relatively used alone and rises 37.3%；When same dose aryl ketones phosphoric acid When ester compounds and 100umol/L theophylline use in conjunction, the inhibiting rate to cell line proliferation is 66.8%, and aryl is relatively used alone Ketone phosphate compound rises 13%, and theophylline is relatively used alone and rises 41.19%；Thus it is provable to arrive Forskolin and tea Alkali suppresses the cooperative effect of Bel-7402 cells propagation to aryl ketones phosphate compound.
Embodiment 4
The example verifies that Forskolin and theophylline suppress mouse transplanting Lewis ' LC tumours to aryl ketones phosphate compound and given birth to Long cooperative effect.
Experiment material：BALB/C Strains of Mouse, is II grades of experimental animals.Body weight 18-22g, each 20 of male and female, purchased from China Academy of Medical Sciences Experimental Animal Center.
Experimental method：Under sterile working, Lewis ' LC tumour knurl knot of the well-grown without ulceration is taken, health is selected without bad Dead tumor tissues, are put into mill after shredding, and add appropriate physiological saline (NS), grind to form the unicellular homogenate of tumour, After being counted under mirror, 1 × 10 is adjusted to NS7The concentration of/ml cells, in the right armpit subcutaneous vaccination of mouse, every injection oncocyte liquid 2 ×106/0.2ml.Administration weighs tumor tissue weight and observes various medicines and antineoplastic to mouse transplantability after 8 days The inhibitory action of Lewis ' LC tumour growths.Inhibition rate of tumor growth calculation formula is as follows：
(the average knurl weight of the average knurl weight/control group of 1- treatment groups) × 100%, experimental result：It the results are shown in Table 4.
The different pharmaceutical of table 4 is to Lewis ' LC inhibition rate of tumor growth results
Animal vivo test result shows that gavage gives dosage and mouse is moved for 30mg/kg aryl ketones phosphate compound The tumour inhibiting rate of plant property Lewis ' LC tumours is 44.2%.When with 10mg/kgforskolin together gastric infusions, mouse is moved The tumour inhibiting rate of plant property Lewis ' LC tumours rises to 63.2%, rises 19%, shows obvious synergy.When with 100mg/kg theophylline together gastric infusion when, 60.3%, rising are risen to the tumour inhibiting rates of mouse transplantability Lewis ' LC tumours 25%, show obvious synergy.
Above example and test result indicates that, by increasing capacitance it is possible to increase the adenyl cyclase activator of intracellular cAMP levels Forskolin, Pimobendane theophylline can cooperate with increase aryl ketones phosphate compound to SH-SY5Y, Bel- The depression effect of 7402 and HeLa cell line proliferations；Increase aryl ketones phosphate compound can be cooperateed with to mouse transplantability The Suppressive effect of Lewis ' LC tumour growths.In fact, the antineoplastic of the present invention can be used as the wide for the treatment of malignant tumor Spectrality medicine.The antineoplastic of the present invention is specifically enumerated above, wherein the medicine and aryl ketones phosphorus of rise intracellular cAMP levels Two kinds of components of ester compound are that can play the medicinal ingredient of synergistic function.Antineoplastic of the present invention should also include Pharmaceutically acceptable salt class such as hydrochloride, chloride, chelate and metabolite；The antineoplastic of the present invention can also be wrapped Include those pharmaceutical carriers, the particularly pharmaceutically acceptable systemic vectors for oral administration.The present invention also includes two class medicinal ingredients The combination of metabolite.Antineoplastic of the present invention may also include the shape for slowly discharging one or more medicinal active ingredients Formula.The medicinal antineoplastic of the present invention can be made into solid or liquid forms, such as particle suspension or based on PEG Solution.Preferable oral form, but it is also possible to which parenteral mode is administered.
The antineoplastic and preparation with the present invention of sufficient dosage are imposed to tumor patient, can mitigate and treat a variety of Corresponding tumour.
In the present invention, it is related to the pharmaceutical dosage unit forms for systematic administration, it is moved effective for treatment lactation Thing, including the mankind." dosage unit form " refers to physically scattered unit, suitable for being taken to be not as single as animal, each Unit contains enough active components of scheduled volume, by reach that systemic administration adjusts the method for pharmacy of the composition, can Calculate and obtain required effect.
The liquid oral that the implementation of dosage unit form of the invention corresponding is tablet, capsule, be present in liquid-carrier Preparation.The solid diluent or carrier of Solid oral pharmaceutical unit form are selected from lipid, carbohydrate, protein, solid mineral Material：Such as starch, sucrose, kaolin, Dicalcium Phosphate, gelatin, Arabic gum, corn steep liquor, cornstarch, talcum powder.Glue Capsule, it is no matter hard or soft, conventional diluent and excipient can be used to be made, such as edible oil, calcium carbonate, calcium stearate, Magnesium stearate etc..The aqueous solution or aqueous solution are can be made into for oral liquid pharmaceutical formulation, preferably contains suspending agent.Such as Sodium carboxymethylcellulose, methylcellulose, Arabic gum, polyvinylpyrrolidone, polyvinyl alcohol etc..
For the treatment of mammal corresponding with the inventive method, one be made up of the exact dose of necessary active material Kind effective dosage, itself if according to implement the characteristic of clinical treatment, the order of severity of the patient's condition, the species of mammal, the age, Body weight and situation impose form of medication adaptable therewith and the preparation determined, it will have very good effect.When needs are given accurately In the case of dosage, a test dose can be given in advance, then observe clinical response with the exact dose needed for determining.Total comes Say, the effective dose of administration is to by medicine person body weight about daily 0.35mg/kg to about 10mg/kg.
Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not pair The restriction of embodiments of the present invention, for those of ordinary skill in the field, may be used also on the basis of the above description To make other changes in different forms, all embodiments can not be exhaustive here, it is every to belong to this hair Row of the obvious changes or variations that bright technical scheme is extended out still in protection scope of the present invention.

Claims (10)

1. a kind of antineoplastic containing aryl ketones phosphate compound, it is characterised in that：Including aryl ketones phosphate chemical combination Thing or derivatives thereof, the medicine with regulation intracellular cAMP concentration level.
2. antineoplastic according to claim 1, it is characterised in that the aryl ketones phosphate compound is
Wherein, R1Selected from H, C1-C6Alkyl, C1-C6Alkoxy, cyano group or halogen；R2For ethyoxyl.
3. antineoplastic according to claim 1, it is characterised in that described that there is regulation intracellular cAMP concentration level Medicine be adenyl cyclase activator Forskolin and its derivative, Pimobendane theophylline and its derivative One or both of；Preferably, the aryl ketones phosphate compound and the medicine with regulation intracellular cAMP concentration level The mass ratio of thing is：1:1-1000.
4. antineoplastic according to claim 3, it is characterised in that the aryl ketones phosphate compound and adenylate Cyclase activators Forskolin mass ratio 1:1.5-2.
5. antineoplastic according to claim 3, it is characterised in that the aryl ketones phosphate compound and di(2-ethylhexyl)phosphate The mass ratio of lipase inhibitor theophylline is 1:25-50.
6. antineoplastic according to claim 3, it is characterised in that the anti-malignant tumor medicine is one or more The combination of medicine and aryl ketones phosphate compound with regulation intracellular cAMP concentration level.
7. a kind of preparation of the antineoplastic as described in claim 1-6 is any, it is characterised in that made with the antineoplastic For active component, and it is aided with acceptable pharmaceutical carrier.
8. the preparation of antineoplastic according to claim 7, it is characterised in that the preparation is tablet, oral liquid or glue Capsule.
9. the medicinal application in oncotherapy is used as according to any antineoplastics of right 1-6.
10. a kind of preparation of the antineoplastic as claimed in claim 7 is used as the application of the medicine in oncotherapy.
CN201710537834.XA 2017-07-04 2017-07-04 A kind of antineoplastic containing aryl ketones phosphate compound and its application Pending CN107308172A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1660434A (en) * 2005-01-19 2005-08-31 中国医学科学院基础医学研究所 Combination of medication for anti malignant tumours and application
CN105330690A (en) * 2015-10-19 2016-02-17 赵丽娜 Synthetic method of drug intermediate aryl ketone phosphate ester compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1660434A (en) * 2005-01-19 2005-08-31 中国医学科学院基础医学研究所 Combination of medication for anti malignant tumours and application
CN105330690A (en) * 2015-10-19 2016-02-17 赵丽娜 Synthetic method of drug intermediate aryl ketone phosphate ester compound

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