CN108186647A - A kind of medical usage of compound - Google Patents
A kind of medical usage of compound Download PDFInfo
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- CN108186647A CN108186647A CN201810149854.4A CN201810149854A CN108186647A CN 108186647 A CN108186647 A CN 108186647A CN 201810149854 A CN201810149854 A CN 201810149854A CN 108186647 A CN108186647 A CN 108186647A
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
Abstract
The present invention relates to purposes of 2 methyl 1 [3 (4 morpholinyl) third] 5 phenyl N [3 (trifluoromethyl) benzene] 1H pyrroles, 3 formamide with Formulas I structure in the drug for treating liver cancer is prepared.The compound of formula I of the present invention can effectively inhibit the growth of liver cancer cells, and therapeutic effect is played to liver cancer.
Description
Technical field
The invention belongs to pharmaceutical fields.In particular it relates to 2- methyl-1s-[3- (4- morpholinyls) third] -5- phenyl -
The medical usage of N- [3- (trifluoromethyl) benzene] -1H- pyrrole-3-carboxamides.
Background technology
Primary carcinoma of liver is one of ten big malignant tumours that the World Health Organization announces, male's incidence and women morbidity
Rate is divided in the world arranges the 5th and the 7th, occupies third position in the lethal illness of cancer.The whole world new hair and dead every year
Die case accounts for about all malignant tumours 5.4%.In the U.S., the incidence of the primary carcinoma of liver as caused by hepatitis C infection by
Year rises.Chronic hbv-infection, hepatitis c virus infection, alcoholic liver disease, nonalcoholic fatty liver and the related disease of metabolism
Sick (hemochromatosis) etc. can lead to the generation of liver cancer.About 85% liver cancer patient is by progressivity liver fibrosis and/or liver
Hardening develops and causes.Hepatitis B is still the main carcinogenic cause of disease in the world.China is a hepatopathy big country, according to system
As soon as counting existing more than hundred million hepatopathy crowd, i.e. there is a hepatopath in every ten people, wherein especially with hepatitis b virus infected
Caused hepatic sclerosis and then to develop into liver cancer the most prominent.According to the global tumour statistical analysis of World Health Organization 2005, at present
Annual liver cancer number of newly suffering from is 626000, death toll 598000.It is estimated that in global range 2,000,000,000 people suffer from hepatitis B, 200,000,000
People suffers from hepatitis C.Second Cancer death disease will be become by being also anticipated that simultaneously to the year two thousand thirty primary carcinoma of liver.Newly suffer from liver cancer
Patient 55% is happened at China.
At present, with the development and progress of medicine, the therapeutic effect of primary carcinoma of liver obtains a degree of improvement, 5 years
Survival rate reaches 40-70%.Complex treatment has become the basic principle of liver cancer treatment, hepatectomy and liver transfer operation including surgery
Operation, interventional treatment include RF ablation, micro-wave therapeutic and through artery chemoembolizations etc..Part targeted drug has been applied to
Clinic, such as Sorafenib (Sorafenib), Sutent.But because of the high invasion and high relapse rate of primary carcinoma of liver,
Still seriously affect the therapeutic effect of such patient.The discovery of new cancer treatment drug is expected to provide new way for the treatment of liver cancer
Diameter and means.
Invention content
2- methyl-1s-[3- (4- morpholinyls) third] -5- phenyl-N- [3- (trifluoromethyl) benzene] -1H- pyrrole-3-carboxamides
Also known as HC 067047, molecular formula C26H28F3N3O2, there is structure shown in following formula I：
The purpose of the present invention is to provide the 2- methyl-1s with Formulas I structure-[3- (4- morpholinyls) third] -5- phenyl-N-
[3- (trifluoromethyl) benzene] -1H- pyrrole-3-carboxamides (also known as HC 067047) or its pharmaceutically acceptable salt or solvent close
Purposes of the object in the drug for treating liver cancer is prepared.
In some embodiments, above-mentioned liver cancer is differentiated liver cancer.
The so-called pharmaceutically acceptable salt of the present invention, refer to that compound of formula I and acid or alkali formed non-toxic to organism or
The salt of hypotoxicity.The acid can be inorganic acid or organic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, anti-chemistry
Acid, citric acid, lactic acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, p-methyl benzenesulfonic acid etc..It is described
Alkali can be inorganic base or organic base, institute into salt be, for example, alkali metal salt, such as Li salt, Na salt or K salt；Alkali salt, such as Ca
Salt and Mg salt；Or ammonium salt or substituted ammonium salt, such as, front three ammonium salt.
The so-called solvate of the present invention, refers to compound of formula I or its salt and one or more pharmaceutically acceptable solvents
The compound that molecule is formed.The solvent molecule can be water or alcohol, such as ethyl alcohol.
Preferably, one or more pharmaceutically acceptable auxiliaries are further included in the drug.
The so-called pharmaceutic adjuvant of the present invention, refer to the conventional use of pharmaceutically acceptable solid-state of this field institute, liquid or other
The additives such as carrier, excipient, diluent, colorant, the plasticizer of form.Such as magnesium carbonate, magnesium stearate, calcium phosphate, silicon
Diatomaceous earth, microcrystalline cellulose, hydroxymethyl cellulose and salt, talcum, lactose, glucose, mannitol, sucrose, pectin, dextrin, shallow lake
Powder, gelatin, cellulosic material, low melt wax, cocoa butter etc..
Preferably, at least one other drug combination of the drug with being used to treat liver cancer.Further, it is described another
Outer drug is selected from Sorafenib, Sutent or combination.Further, the other drug is Sorafenib.
Preferably, the drug is the drug that tumor cells of hepatocellular carcinoma can be inhibited to grow and/or be proliferated.
Preferably, the drug is can to inhibit the drug that tumor cells of hepatocellular carcinoma migrates and/or invasion are shifted.
The drug prepared by above-mentioned compound of formula I or pharmaceutical composition of the present invention may be used oral medication, be administered to
Medicine (such as intramuscular injection, intravenous injection, intraperitoneal injection), subcutaneous administration, inhalation, the common administering mode of rectally；And
It can be with manufacturing cost field common dosage forms, such as tablet, capsule, suppository, powder needle, injection, aerosol.
In a preferred embodiment of the invention, the compound of structure shown in above-mentioned Formulas I of the invention uses drug administration by injection
Mode is calculated according to the weight (kg) of people, and preferably dosage is 50 μ g/kg, and administering mode is intraperitoneal injection, administration frequency
1 times/day of rate.The dosage of animal is 50 μ g/kg, and administering mode is intraperitoneal injection, 1 times/day of administration frequency.
When treating liver cancer using formula Compound I, the drug can significantly inhibit proliferation and the growth of liver cancer cells,
A new way is provided for liver cancer treatment.
Description of the drawings
Fig. 1 shows the Scid-Huh7- subcutaneous tumors relative volumes of control group and therapy intervention group in embodiment 1.
Fig. 2 shows the cloning efficiencies of control group, activator group and inhibitor group in embodiment 2.
Fig. 3 shows the cell migration rate of control group, activator group and inhibitor group in embodiment 3.
Specific embodiment
Technical scheme of the present invention is described in further details below in conjunction with specific embodiment.It should be appreciated that these realities
It is for illustratively illustrating the basic principles, principal features and advantages of the present invention, the specific implementation used in embodiment to apply example
Condition can make the appropriate adjustments in the range of this field, and protection scope of the present invention should not be limited by the examples.
In an embodiment of the present invention, using the following raw material：
Four week old nude mice NOD/SCID of female (non-obese patients with type Ⅰ DM/severe combined immunodeficiency mouse), purchased from Beijing
Company of tonneau China is tieed up, all mouse are fed in the refined two hospitals Experimental Animal Center SPF ranks Mouse feeder in Hunan, environment temperature
Degree is stablized at 18~22 DEG C, and humid control is 50~60%.NOD/SCID mouse feed the plastics in nontoxic no-special pathogen
It in mouse box, is raised with standard particle feed and pure water and keeps its 12 circadian rhythm 24 round the clock, required environment is satisfied by national real
Test the care of animal and guide for use requirement, it is all operation obtain the animal welfare committee of Xiangye No. 2 Hospital of Central South University approval and
Supervision；
Hepatoma cell strain Huh7, purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank；
Inhibitor HC 067047,2- methyl-1-[3- (4- morpholinyls) third]-5- phenyl-N- [3- (trifluoromethyl) benzene]-
1H- pyrrole-3-carboxamides, purchased from Abcam companies, specification：25mg, article No.：ab145868；
DMSO, purchased from Sigma-Aldrich companies；V900090-500ML；Purity 99%；
DMEM high glucose complete mediums, purchased from Luo Gen Hyclone companies of the U.S.；
Fetal calf serum FBS, 10099-141, purchased from Grand Island Gibco companies of the U.S.；
Trypsase, SH30042.01, purchased from Luo Gen Hyclone companies of the U.S.；
Phosphate buffered saline (PBS) (PBS), SH20256.01B, purchased from U.S. Lip river root Hyclone；
Agonist GSK1016790A, N- ((1S) -1- [4- ((2S) -2- { [(2,4- dichlorophenyl) sulfonyl] amino } -
3- hydroxypropanoyls) -1- piperazinyls] carbonyl } -3- methyl butyls) -1- benzothiophene -2- formamides, purchased from Sigma-
Aldrich；
Vernier caliper, the production of Guang Lu measurers factory, 0-150mm electronic digital displays；
Varioskan Flash multi-function microplate readers, Thermo.
1 nude mice model of embodiment is tested
By 5 × 106A hepatoma cell strain Huh7 cells are injected to the right side abdomen of nude mice NOD/SCID (totally 12) respectively, so
Standard is raised as described above afterwards.Measuring the line of apsides of subcutaneous tumor respectively using vernier caliper, (line of apsides need to hang down
Directly), with 1/2 × length x width2Tumor size is determined, when tumour is formed to volume about 80mm3When mouse is randomly divided into control
Group and therapy intervention group, every group each 6.
By 067047 drug administration by injection of HC to mouse, the variation of tumour is observed, specific administering mode is：
Therapy intervention group：
25mg HC 067047 are dissolved in 2.5ml DMSO, the mother liquor of a concentration of 21.2mM is made.It is used during experiment
DMSO dilutes mother liquor, to form injection drug, intraperitoneal constant volume injection is carried out to this group of mouse, dosage is 100 μ L, i.e. 50 μ gHC
067047/ (kg weight), 1 times/day.
Control group：
In intraperitoneal injection DMSO blank solvents, constant volume injection, dosage is 100 μ L, 1 times/day.
Tumor size is with volume=1/2 × length x width2Detection.Mouse is put to death at the 6th week, compare survival rate and is swollen
Knurl accumulates size.The experimental result of the present embodiment is as follows：
The Scid-Huh7- subcutaneous tumors of 1 control group of table and therapy intervention group (nude mice NOD/SCID-Huh7 cell strains-subcutaneous
Knurl) relative volume
aThere was no significant difference by N.S,bSince most mouse are dead after pharmaceutical intervention 32 days, therefore the unmeasured 5th, 6 week
Data
In table 1, P values represent the difference between control group and the Scid-HepG2- subcutaneous tumors relative volumes of therapy intervention group
It is different.The tumor size of administration first day is 100%.
2- methyl-1s-[3- (4- morpholinyls) third] -5- phenyl-N- [3- have been injected it can be seen from the result of table 1 and Fig. 1
(trifluoromethyl) benzene] -1H- pyrrole-3-carboxamides the subcutaneous tumor volume change of mouse it is significantly slower, show 2- methyl-1s -
[3- (4- morpholinyls) third] -5- phenyl-N- [3- (trifluoromethyl) benzene] -1H- pyrrole-3-carboxamides, which have Huh7 tumours, to be controlled
Treatment acts on.
Embodiment 2：Plates of cells colony formation
I. cloning efficiency is tested
1st, took the logarithm respectively the afternoon day before yesterday Huh7 liver cancer cells in growth period, with 0.25% trypsin digestion and blow and beat into
Individual cells complete cell count；
2nd, by cell suspension in the DMEM complete mediums of 10% fetal calf serum mixing, adjust cell density, by every group
Cell is inoculated in 6 orifice plates, and gently rotate respectively with every hole 2ml culture mediums, 1500 cells/well density respectively, makes cell
It is uniformly dispersed, is placed in containing 5%CO237 DEG C of incubators in overnight incubation；
3rd, morning next day is different dense according to needed for experimental design uses the DMEM complete mediums containing 10% fetal calf serum to prepare
The drug of gradient is spent, 3 multiple holes of every group of concentration, agonist GSK1016790A and inhibitor HC067047 group concentration are respectively 0.1
μm ol/L and 1 μm of ol/L.Gently 6 orifice plate upper strata culture mediums are sucked out, respective concentration drug is added in, is placed in 37 DEG C, 5%CO2
And it is cultivated 1~2 week in the cell incubator of saturated humidity；
4th, often observation when occurring macroscopic clone in culture dish, terminates culture.Liquid is discarded supernatant, it is small with PBS
The heart embathes 2 times, and 4% paraformaldehyde 2mL is added to fix cell 15 minutes.Then fixer is removed, adds appropriate 0.5% violet staining liquid
Dye 10~15 minutes, then slowly washes away dyeing liquor with clear water, is air-dried, counting is taken pictures.
5th, 6 orifice plate bottoms are superimposed a transparent film with grid, with the naked eye directly count clone, counted and be more than 50
Clone's number of cell.Finally calculate cloning efficiency.By parallel three groups of the progress of above-mentioned experiment, a group 1-3 is denoted as, as a result by table 2-3
And shown in Fig. 2.
Cloning efficiency=(clone's number/inoculating cell number) × 100%
Clone's number of each group in 2 embodiment 1 of table
The cloning efficiency of each group in 3 embodiment 1 of table
Brief summary：By upper table and Fig. 2 it is found that HC 067047 can effectively inhibit the Clone formation of hepatoma cell strain.
II. cell invasion ability test
Using 24 orifice plates in 3422#8.0 μm of aperture of Corning companies in this experiment.
1st, by Huh7 liver cancer cells serum starvation 12-24h, the influence of serum is further removed；
2nd, it using 0.25% trypsin digestion and cell, terminates centrifugation after digesting and discards culture solution, washed 1-2 times, made with PBS
It is resuspended with serum free medium, completes cell count, adjustment cell density to 2.5 × 105A/mL；
3rd, agonist GSK1016790A and inhibitor HC067047 group concentration are respectively 0.1 μm of ol/L and 1 μ in testing
Mol/L, in addition blank control group, totally 7 groups, every group of 3 multiple holes, totally 21 holes；
4th, 7 EP pipes are taken, the first pipe is blank control group, adds in 200 μ l cell suspensions, i.e. 5000 cells；Remaining 6 pipe
Interior each addition 600 μ l (200 μ l × 3 multiple holes) cell suspension, i.e. 5000 × 3 cells, 5 are centrifuged under 800rpm/min rotating speeds
Minute, upper strata serum free medium in each EP pipes is removed, rejoins the various serum free mediums containing respective concentration drug,
After abundant mixing, Transwell upper stratas cell is entered with every 200 μ l kinds of hole；
5th, room adds in the DMEM complete mediums that 500 μ l contain 10% fetal calf serum under 24 hole Transwell plates；In 37
DEG C, 5%CO2And the cell incubator routine culture 48h of saturated humidity；
6th, each room matrigel and upper indoor cell are wiped with cotton swab, cell is carefully embathed with PBS 2 times, add 4% poly first
Aldehyde 2mL fixes cell 15 minutes.Then fixer is removed, appropriate 0.5% violet staining liquid is added to contaminate 10~15 minutes, then with clear
Water slowly washes away dyeing liquor, is air-dried, and counts and takes pictures under microscope, by parallel three groups of the progress of above-mentioned experiment, is denoted as a group 4-6,
Specific cell migration number result result is as shown in table 4 and Fig. 3.
The migrating cell number of each group in 4 embodiment 2 of table
Brief summary：HC 067047 can effectively inhibit the migration of liver cancer cells to invade.
Claims (10)
1. 2- methyl-1s-[3- (4- morpholinyls) third] -5- phenyl-N- [3- (trifluoromethyl) benzene] -1H- pyrroles with Formulas I structure
Cough up -3- formamides
Or the purposes of its pharmaceutically acceptable salt or solvate in the drug for treating liver cancer is prepared.
2. purposes according to claim 1, which is characterized in that further included in the drug one or more pharmaceutically acceptable auxiliary
Material.
3. purposes according to claim 1 or 2, which is characterized in that the pharmaceutically acceptable salt is the compound of formula I
Acid salt or basic salt；
It is preferred that the acid salt is inorganic acid salt or acylate, more preferable hydrochloride, hydrobromate, nitrate, sulfate, phosphorus
Hydrochlorate, anti-chemical hydrochloric acid, citrate, lactate, formates, maleate, acetate, fumarate, succinate, winestone
It is one or more in hydrochlorate, mesylate or tosilate；
It is preferred that the basic salt is inorganic base salts or organic alkali salt, more preferable alkali metal salt, alkali salt, ammonium salt or substituted
Ammonium salt；The further preferred basic salt includes one or more in Li salt, Na salt, K salt, Ca salt, Mg salt or front three ammonium salt.
4. purposes according to claim 1 or 2, which is characterized in that solvent molecule in the solvate is water or alcohol,
The alcohol is preferably ethyl alcohol.
5. purposes according to claim 2, which is characterized in that the pharmaceutically acceptable auxiliaries include pharmaceutically acceptable carrier,
It is one or more in excipient, diluent, colorant, plasticizer；It is preferred that magnesium carbonate, magnesium stearate, calcium phosphate, diatomite,
It is microcrystalline cellulose, hydroxymethyl cellulose and salt, talcum, lactose, glucose, mannitol, sucrose, pectin, dextrin, starch, bright
It is one or more in glue, cellulosic material, low melt wax or cocoa butter.
6. according to the purposes described in any one of aforementioned claim, wherein the drug is tumor cells of hepatocellular carcinoma can be inhibited to give birth to
Long and/or proliferation drug.
7. according to the purposes described in any one of aforementioned claim, wherein the drug is tumor cells of hepatocellular carcinoma can be inhibited to move
Move and/or invade the drug of transfer.
8. according to the purposes described in any one of aforementioned claim, wherein the drug passes through oral, injection, subcutaneous, sucking
Or rectally.
9. purposes according to claim 8, wherein the drug administration by injection is selected from intramuscular injection, intravenous injection or abdominal cavity note
It penetrates.
10. according to the purposes described in any one of aforementioned claim, wherein the dosage form of the drug be selected from tablet, capsule,
Suppository, powder needle, injection or aerosol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810149854.4A CN108186647B (en) | 2018-02-13 | 2018-02-13 | Medical application of compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810149854.4A CN108186647B (en) | 2018-02-13 | 2018-02-13 | Medical application of compound |
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| Publication Number | Publication Date |
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| CN108186647A true CN108186647A (en) | 2018-06-22 |
| CN108186647B CN108186647B (en) | 2020-04-07 |
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| CN201810149854.4A Active CN108186647B (en) | 2018-02-13 | 2018-02-13 | Medical application of compound |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012144661A1 (en) * | 2011-04-20 | 2012-10-26 | Shionogi & Co., Ltd. | Aromatic heterocyclic derivative having trpv4-inhibiting activity |
-
2018
- 2018-02-13 CN CN201810149854.4A patent/CN108186647B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012144661A1 (en) * | 2011-04-20 | 2012-10-26 | Shionogi & Co., Ltd. | Aromatic heterocyclic derivative having trpv4-inhibiting activity |
Non-Patent Citations (1)
| Title |
|---|
| RYCHKOV, GY ET AL: "Expression and Function of TRP Channels in Liver Cells", 《ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY》 * |
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