CN107903252A - Triazole derivative and its application in the medicine for preparing treatment liver diseases - Google Patents
Triazole derivative and its application in the medicine for preparing treatment liver diseases Download PDFInfo
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- CN107903252A CN107903252A CN201711047043.5A CN201711047043A CN107903252A CN 107903252 A CN107903252 A CN 107903252A CN 201711047043 A CN201711047043 A CN 201711047043A CN 107903252 A CN107903252 A CN 107903252A
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- Prior art keywords
- compound
- alkyl
- acid
- liver
- hydrate
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of triazole compound for being used to treat liver diseases.The compound is compound, its pharmaceutically acceptable salt, hydrate, solvate or metabolite shown in formula I.The compound can be used in being prepared into treatment and/or prevent the medicine of liver diseases.
Description
Technical field
The invention belongs to biomedicine technical field, is related to triazole derivative and its is preparing treatment liver diseases
Application in medicine.
Background technology
Liver diseases are the common disease and frequently-occurring disease in China, including fatty liver, various acute, chronic hepatitis, liver fibrosis, liver
The series of disease such as hardening, liver cancer, these hepatopathys are mostly by obesity, medicine, excessive consumption of alcohol, B-mode and Hepatitis C Virus sense
Dye etc. causes.Estimate according to the World Health Organization, every year due to death toll caused by various types of hepatitis be about 1,400,000 to
1500000, the 7th is occupied in various diseases.And the World Health Organization alerts, hepatitis, which will exceed AIDS quickly, becomes the mankind the
6 big Health Killers.China has become the country for paying most social cost for hepatitis, hepatic sclerosis and liver cancer in the world.According to me
The statistics of disease prevention and control center of state：China increases virus hepatitis newly per annual report and falls ill patient up to more than 1,000,000, its
Middle hepatitis B patient accounting maintains 80% or so；National hepatitis B virus surface antigen carrier surpasses 1.2 hundred million people, accounts for country's total population
8%~10%, account for nearly the 1/3 of global HBV carrier number；And as many as nearly 1,000,000 people of annual hepatitis B new infections person.
According to rice Intranet, China hepatopathy medication market total scale is risen to 2015 by 233.28 hundred million yuan in 2010
Year 537.005 hundred million yuan, 2014 and 2015 China's hepatosis treating medicine market in general scales be respectively 459.61 hundred million yuan with
537.05 hundred million yuan, growth rate 16.85%；It is expected that hepatosis treating medicine market total scale will keep the annual growth of 15-20%.
Wherein, fatty liver (Fatty liver) this indication is directed to, it is domestic at present also without medicine official listing.State
The seal oil omega-3 polyunsaturated fatty acids of interior Zhejiang Jin Nuokang biologies, application listing are in registration phase.In addition, shellfish courage difficult to understand
Sour (obeticholic acid) obtains U.S. FDA approval on May 27th, 2016, and first granted indication is primary to treat
Property biliary cirrhosis, its be used for the indication of non-alcoholic fatty liver at present US and European be in 3 phases clinic, in day
This is in 2 phase clinical investigation phases.Liver fibrosis (Liver fibrosis) is directed to, has carried out the medicine of this indication at present
Totally 46：Wherein listed 2, registration 1,3 phases are 2 clinical, 2 phases are 8 clinical, 1 phase is 4 clinical, preclinical 28, stop grinding 1
It is a.The two marketed drugs are respectively biological agent gamma- interferon, the Traditional Chinese Medicine Fuzheng of Shanghai Huanghai Sea pharmacy of star medicine again
Huayu Capsule.Hepatic sclerosis (cirrhosis) is directed to, through further screening, it is primary to have marketing data and segment indication
Property biliary cirrhosis (Primary Biliary Cirrhosis, PBC) medicine totally 2, be respectively urso, Austria
Shellfish cholic acid.In addition, it is related to treatment or the diagnostic medicine totally 14 that " hepatocellular carcinoma or liver tumour " at home and abroad lists：More soft ratio
The U.S. appropriate former times monoclonal antibody of star, iodine [131I], cis-platinum, Miboplatin, 18F- fluorocholine chloride, DW-166HC, Immuncell-LC, restructuring
Human Inter Leukin-2, arsenious acid, Gadoxetic acid disodium, Zinostatin stimalamer, Gadoversetamide, pirarubicin and Sorafenib.
Wherein this 14 medicines except Miboplatin, 18F- fluorocholine chloride, DW-166HC, Immuncell-LC and Zinostatin this
This 5 kinds of ester is introduced into Chinese market, remaining 9 kinds in Discussion on Chinese Listed.Having 2 kinds in 9 kinds of medicines, (Gadoxetic acid disodium, gadolinium are not filled in
Amine) it is used for medical imaging diagnosis use, there was only the targeted therapy that Sorafenib is used for liver cancer at present, it is reported that taking Suo Lafei
The adverse reaction that the liver cancer patient of Buddhist nun occurs is more.
In order to reach the therapeutic effect for being preferably directed to liver diseases such as fatty liver, hepatic sclerosis, liver fibrosis, liver cancer etc.,
To better meet the clinical demand with market, thus it is safer, efficient for treating liver diseases there is an urgent need to develop going out
Medicine.
The content of the invention
The technical problems to be solved by the invention are that do not have suitable medicine, Yi Jike to solve existing indication
The defects of taking existing clinical medicine, and a kind of new triazole compound is provided, which can be used for liver diseases
Such as the treatment and/or prevention of fatty liver, hepatic sclerosis, liver fibrosis, liver cancer etc..
The present invention provides a kind of compound shown in formula I, its pharmaceutically acceptable salt, hydrate, solvate,
Metabolite,
Wherein, the R1For selected from phenyl, pyridine radicals, cyclohexyl or cyclopenta, each of which is optionally by 1-3 R4Take
Generation；Or R1For optionally by 1-2 R4Or the cyclopropyl of phenyl substitution；It is preferred that R1For selected from by 1-3 R4Substituted phenyl；
The R2For selected from C1-4Alkyl, halo C1-4Alkyl, unsubstituted C3-8Cycloalkyl or optionally substituted C3-8
Cycloalkyl；It is preferred that R2For selected from cyclopropyl, cyclobutyl or cyclopenta；
The R3For selected from H, C1-10Alkyl, C3-8Cycloalkyl, C2-10Alkenyl, C2-10Alkynyl, aryl, heteroaryl or heterocycle
Base, all substituents are alternatively by 1,2 or 3 selected from halogen, oxo, C1-6Alkyl, C3-8Cycloalkyl, heterocyclic radical, phenyl, benzene oxygen
Base, halogen ,-CN ,-O-R5、-C(O)-R5、-OC(O)-R5-C(O)-O-R5、-N(R5)-C(O)-O-R6、-N(R5)-C(O)-R6、-
N(R5)-C(O)-N(R5)(R6) and-C (O)-N (R5)(R6) substituent substitution, wherein alkyl, cycloalkyl, heterocyclic radical, phenyl,
With phenoxy group alternatively C is selected from by 1,2 or 31-6Alkyl, C3-8Cycloalkyl, C1-6The substituent of alkoxy, hydroxyl and halogen takes
Generation；
The R4For selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy ,-SR7Or ring
Propyl group；
The R5And R6Independently selected from by hydrogen, C1-6Alkyl or C3-8Cycloalkyl forms；Or R5And R6When with they institute
Heterocycle is formed when the nitrogen of connection links together；
According to some embodiments of the present invention, preferably R3For selected from H, C1-10Alkyl or C3-8Cycloalkyl；
According to some embodiments of the present invention, more preferably R3For selected from H, methyl, ethyl, isopropyl, the tert-butyl group or ring third
Base；
The R7For selected from C1-6Alkyl, preferably R7For selected from methyl, ethyl, isopropyl or the tert-butyl group；
X is selected from O or NH, and preferably X is selected from O.
Thus, throughout this manual, those skilled in the art can be to R described in compound shown in Formulas I1~R7And X
Group and its substituent make choice, with provide it is described in the embodiment of the present invention, stablize Formulas I shown in compound or its
Pharmaceutically acceptable salt, hydrate, solvate or metabolite.
According to an embodiment of the invention, compound shown in Formulas I of the present invention, for following any compound：
Compound of formula I of the present invention can be prepared according to the chemical synthesis process of this area routine, its step and bar
Part refers to this area similar the step of reacting and condition.Reaction dissolvent used in each reactions steps of the present invention does not have
Especially limitation, any solvent that can be dissolved starting material to a certain extent and not suppress reaction are included in the present invention.
In addition, many similar changes of this area, equivalent substitution, or it is equal to solvent described in the invention, solvent combination, and solvent
The different proportion of combination, is accordingly to be regarded as the scope of the present invention.
The present invention gives a kind of method of compound described in formula I, its synthetic route are as follows：
Carboxylic acid shown in Formulas I-a reacts with the amine shown in Formulas I-b under conditions of acid amides is suitably formed.For example, to
The mixing of compound of the atent solvent as shown in the Formulas I-a in n,N-Dimethylformamide (DMF) and the compound shown in Formulas I-b
In thing, addition (2- (7- azepine -1H- benzotriazole -1- bases) -1,1,3,3- tetramethylurea hexafluorophosphates (HATU) and alkali,
Typically N-methylmorpholine, and at about room temperatures by mixture keep about 3-18 is small when.When the completion of the reaction, after progress
Processing obtains the product of compound shown in Formulas I.
The compounds of this invention also can be separated and purified according to standard technique well known to those skilled in the art.Such as pure
A kind of particularly useful technology is preparative liquid chromatography when changing compound, it is flowed out using mass spectrum as detection from chromatographic column
Pure compound means.
Preparative LC-MS be for purify small organic molecule, compound as described herein standard effective ways.Can be with
Change liquid chromatogram (LC) and the method for mass spectrum (MS), so that crude product preferably separates and improve detections of the MS to sample.Prepare
The optimization of type gradient LC methods, which is related to, changes pillar, volatility eluant, eluent and conditioning agent and gradient.These methods are in optimization preparative
LC-MS methods are well-known in field, are adopted and are used to purifying compound.This kind of method is described in the following references：
RosentreterU, Huber U.；Optimal fraction collecting in preparative LC/MS；J Comb
Chem.；2004；6 (2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C.,
Development of a custom high-throughput preparative liquidchromatography/mass
spectrometer platform for the preparativepurification and analytical analysis
of compound libraries；J Comb Chem.；2003；5(3)；322-9.
Compound shown in Formulas I of the present invention, it can add the work such as formulation carrier or excipient as active ingredient
The additive of addition is allowed so that preparation is made for pharmaceuticals additive.Tablet, granule, capsule, interior may be appropriately used
Take the oral administration preparation for the form that liquid preparation etc. is suitable for from alimentary canal absorption, the warp such as injection, suppository and patch, paste
The non-oral administration agent such as skin absorbent, and solid pharmaceutical preparation, liquid preparation, needs from the such as circulation, keeping quality Shi Yong Time
Solid solvent is dissolved etc. to any form of form of generally use in the past in appropriate solvent.In addition, in order to improve this chemical combination
The bioavilability and stability of thing, can also use the administration system for including the preparation techniques such as microcapsules, micropowder, inclusion
System.
The present invention provides a kind of pharmaceutical composition, it includes the compound of formula I, its pharmaceutically acceptable salt, water
Compound, solvate or metabolite, and pharmaceutic adjuvant；The compound of formula I, its pharmaceutically acceptable salt, hydration
The dosage of thing, solvate or metabolite can be therapeutically effective amount.
Although reactive compound may be administered alone in compound of formula I of the present invention, it is preferred that as pharmaceutical composition
The form of (such as preparation) provides, and the composition includes at least one reactive compound of the invention and one or more can medicine
With carrier, auxiliary agent, excipient, diluent, filler, buffer, stabilizer, preservative, lubricant or people in the art
Other materials known to member and optional other treatment or prevention agent.Thus, present invention also offers medicine as defined above
Compositions and the method for preparing pharmaceutical composition, this method are included at least one reactive compound and one as defined above
Kind or a variety of pharmaceutical acceptable carrier, excipient, buffer, auxiliary agent, stabilizer or other materials as described herein mix.
In the pharmaceutical composition, the compound of formula I, its pharmaceutically acceptable salt, hydrate, solvation
The dosage of thing or metabolite, can be therapeutically effective amount.
The pharmaceutic adjuvant can be those auxiliary materials widely used in medicine production field.Auxiliary material is mainly used for offer one
A safe and stable and functional pharmaceutical composition, can also provide method, and active ingredient is with institute after making subject's receiving administration
Expected rate dissolution, or promote subject to receive active ingredient after composition is administered and effectively absorbed.
Present invention also offers the compound of formula I, its pharmaceutically acceptable salt, hydrate, solvate or metabolism
Product, the application in the medicine for preparing treatment and/or prevention liver diseases.The liver diseases include but not limited to fat
Liver, hepatic sclerosis, liver fibrosis, liver cancer etc..
Unless otherwise prescribed, all technical terms and scientific terminology used herein have claimed theme fields
Standard implication.If to Mr. Yu's term there are multiple definition, then to be defined herein as standard.When Referral URL or other identifier or
Address, it should be appreciated that such identifier can change, and the customizing messages on internet can change, but mutual by searching for
Networking can find equal information.Reference this type of information can be obtained and open propagated.
It should be understood that above-mentioned general explanation and following detailed description are merely illustrative of, to the present invention and from
This limitation.The singulative being used in the present invention, such as " one kind " or "one", including plural, unless otherwise prescribed.This
Outside, term " comprising " is open limits and non-enclosed.
Unless otherwise indicated, the present invention using mass spectrum, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology or
The conventional method of pharmacology detection, each step and condition can refer to the operating procedure and condition of this area routine.Unless otherwise specified,
The present invention is using the standard name of analytical chemistry, Synthetic Organic Chemistry and medical chemistry and standard laboratory step and technology.
In some cases, standard technique is used for chemical synthesis, chemical analysis, medicine preparation, formula and medicine delivery and patient
Treatment.
Used term " pharmaceutically acceptable " in the present invention, is for those compounds, material, composition
And/or for formulation, within the scope of reliable medical judgment, being contacted suitable for the tissue with human and animal makes for they
With without excessive toxicity, irritation, allergic reaction or other problems or complication, with rational interests/Hazard ratio phase
Claim.
Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that there is specific substitution
It is prepared by the compound of base and the acid of relative nontoxic or alkali., can when in the compound of the present invention containing relatively acid functional group
To pass through the side for using the alkali of sufficient amount to be contacted with the neutral form of this kind of compound in pure solution or suitable atent solvent
Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.
, can be by pure solution or suitable atent solvent when in the compound of the present invention containing relatively alkaline functional group
The mode contacted with the sour neutral form with this kind of compound of sufficient amount obtains acid-addition salts.Pharmaceutically acceptable acid addition
The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus
A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include
As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, butanedioic acid, suberic acid, fumaric acid, lactic acid, mandelic acid,
Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include amino acid (such as
Arginine etc.) salt, and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical
Salts”,Journal of Pharmaceutical Science 66:1-19(1977)).Some specificization of the present invention
Compound contains alkalescence and acid functional group, so as to be converted into any alkali or acid-addition salts.Preferably, in a usual manner
Salt is contacted with alkali or acid, then separate parent compound, thus the neutral form of raw compounds again.The parent fo of compound with
The difference of the form of its various salt is some physical properties, such as the different solubility in polar solvent.
" pharmaceutically acceptable salt " used in the present invention belongs to the derivative of the compounds of this invention, wherein, by with acid
The parent compound is modified into salt or with the mode of alkali into salt.The example of pharmaceutically acceptable salt includes but not limited to：Alkali
Inorganic acid or the alkali metal of acylate, acid group such as carboxylic acid or organic salt of base such as amine etc..Pharmaceutically acceptable salt
Include the quaternary ammonium salt of conventional avirulent salt or parent compound, such as the salt that nontoxic inorganic acid or organic acid are formed.
Conventional avirulent salt includes but not limited to those salt derived from inorganic acid and organic acid, the inorganic acid or organic acid
Selected from Aspirin, 2- ethylenehydrinsulfonic acids, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid,
Citric acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid,
Hydrochloric acid, hydriodate, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, methane
Sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, sub- acetic acid, butanedioic acid, ammonia
Base sulfonic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.
" pharmaceutically acceptable salt " of the present invention can pass through conventional chemical by the parent compound containing acid group or base
Method synthesizes.Under normal circumstances, the preparation method of such salt is：In the mixture of water or organic solvent or both, via
The appropriate alkali or acid of these compounds and stoichiometry of free acid or alkali form are reacted to prepare.It is generally preferable that ether, second
The non-aqueous medias such as acetoacetic ester, ethanol, isopropanol or acetonitrile.
Some compounds of the present invention can exist with nonsolvated forms or solvation form, including hydrate forms.
In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.The present invention's is some
Compound can exist with polycrystalline or amorphous form.
The compound of the present invention can include the original of unnatural proportions on one or more atoms for forming the compound
Daughter isotope.For example, radioisotope labeled compound can be used, such as tritium (3H), iodine-125 (125I) or C-14 (14C).
The present invention compound all isotopics conversion, no matter radioactivity whether, be included within the scope of the present invention.
For medicine or pharmacologically active agents, term " effective dose " or " therapeutically effective amount " refer to nontoxic but can reach
To the medicine of Expected Results or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition
" effective dose " refer to when another active material is combined in said composition for the required dosage that achieves the desired results.Have
The definite of effect amount varies with each individual, and age and ordinary circumstance depending on acceptor, also depend on specific active material, closed in case
Suitable effective dose can be determined by those skilled in the art according to routine test.
Term " active ingredient ", " therapeutic agent ", " active material " or " activating agent " refers to a kind of chemical entities, it can have
The therapeutic purpose disorder of effect ground, disease or illness.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise
Content.
According to an embodiment of the invention, triazole compound preparation of the present invention is convenient, production cost is relatively low.
According to an embodiment of the invention, triazole compound of the present invention, it can significantly inhibit NASH morbid state
The balloon sample enlargement of liver cell, and reduce CD68 Positive area rates.Have for nonalcoholic fatty liver disease (NASH)
There is the effect of good, and effect is better than existing medicine.
According to an embodiment of the invention, triazole compound of the present invention, it is to rat hepatocytes degeneration necrosis
Degree mitigates, and can obviously reduce rat annulus hyperplasia degree, has obvious effect of anti hepatic fibrosis, and dosage is small, peace
Quan Xinggao.
According to an embodiment of the invention, triazole compound of the present invention, has resisting liver cancer activity, to human liver cancer
The growth of Cell Line HepG2, Hep3b and SMMC-7721 has good inhibiting effect.
According to an embodiment of the invention, triazole compound of the present invention, it is right in heart hERG experiments
HERG passages do not have obvious inhibitory action, show good cardiac safety.
So compound of the present invention can be as the medicine of liver diseases, for treating and/or preventing liver disease
Disease, such as treating and/or preventing the liver diseases such as fatty liver, hepatic sclerosis, liver fibrosis, liver cancer.Of the present invention three
Nitrogen azole compounds, available for the medicine for being prepared into treatment and/or prevention liver diseases.
Embodiment
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or bar are not specified in embodiment
Part, carried out according to the described technology of document in the art or condition or according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available.
The embodiment provides compound shown in Formulas I or its pharmaceutically acceptable salt, hydrate, solvation
Thing or metabolite, compound shown in formula Ι or its pharmaceutically acceptable salt, hydrate, solvate or metabolism production
The purposes of the compound of the method and intermediate of thing, pharmaceutical composition, and the present invention in medicine preparation.
The preparation of 1 compound I-1 of embodiment
By compound I-a1 (440mg, 1.05mmol), compound I-b1 (203mg, 1.0mmol), (2- (7- azepines -1H-
Benzotriazole -1- bases) -1,1,3,3- tetramethylurea hexafluorophosphate (HATU) (456mg, 1.2mmol) and N-methylmorpholine (13
μ L, 1.2mmol) add in DMF, when 70 DEG C of stirrings 8 of insulation are small.It is concentrated under reduced pressure and removes solvent, residue is suspended in acetonitrile,
And solid product is separated by filtering, is washed with water (80mL), acetonitrile (80mL), acetone (80mL) and done under vacuo
It is dry, it is product Compound I-1 so as to obtain the off-white powder (yield 62%) of 374mg.(LC/MS：[M+H]+605)。
The preparation of 2~embodiment of embodiment, 5 compound I-2~I-5
The preparation method of compound I-2~I-5, is tested in the way of similar to embodiment 1, but what is used rises
Beginning raw material compound is different.Reaction is finished, and separation product respectively obtains compound I-2~I-5, and product is tested through LC/MS
Card.
Compound I-2 (LC/MS：[M+H]+523)。
Compound I-3 (LC/MS：[M+H]+568)。
Compound I-4 (LC/MS：[M+H]+565)。
Compound I-5 (LC/MS：[M+H]+549)。
Effect of 6 compound of the present invention of embodiment in ldl receptor gene rejects mouse NASH models
The present invention has inquired into higher fatty acid/high courage of the fatty liver and incidence of hepatitis in the known characteristic morbid state with NASH
Sterol diet (Western diet) load ldl receptor gene rejecting mouse (Yoshimatsu M. etc.,
Int.J.Exp.Path., 85,335-43 (2004)) in effect.
Use animal：Male LDL receptor gene knockout mice is used in experiment.During 13 weeks since about 8 week old,
It is freely absorbed higher fatty acid/High cholesterol diet, make to suffer from NASH.Higher fatty acid/High cholesterol diet load is carried out to mouse,
Implement blood sampling and body weight determination after 1 week.
According to making between group not have discrepant mode to be divided into following groups in lipid and weight in blood plasma：Control group (0.5% first
Base cellulose aqueous solution), compound 0.25mg/kg gives group (medicine group of the present invention) and fenofibrate shown in formula I-1
Special 100mg/kg gives group.
Medicine is given：Administration capacity is 5ml/kg weight, and 1 day 1 time oral administration, 0.5% methyl is given to control group
Cellulose aqueous solution, gives group to medicine group of the present invention, fenofibrate and gives compound and Fei Nuo shown in formula I-1 respectively
The liquid of Bei Te.Administration phase is 12 weeks.
Observe and check method：After administration, liver is extracted under yellow Jackets (50mg/kg) anesthesia, using more
After polyformaldehyde is fixed, Hematoxylin-eosin stained preparation and the immunostaining sample to CD68 are made.Contaminated using Hematoxylin-eosin
Colour code sheet, under the conditions of blind examination, by the balloon sample enlargement of liver cell according to following standard (Kleiner etc., Hepatology 41,
1313-21,2005) score, it is shown in Table 1.Measured by image analysis system (WinROOF) in the liver under the conditions of blind examination
CD68 Positive area rates.
Table 1
| Grade | Scoring |
| Without balloon sample enlargement cell | 0 |
| Balloon sample enlargement cell is few | 1 |
| Balloon sample enlargement cell is more or notable | 2 |
The results show：(1) in the 0.25mg/kg administrations of medicine group of the present invention, confirm to significantly inhibit the balloon sample of liver cell
Enlargement.In the 100mg/kg of fenofibrate gives group, confirm there is the tendency for suppressing balloon sample enlargement, but statistically not
Significantly.(2) in the 0.25mg/kg administrations of medicine group of the present invention, the CD68 Positive area rates in liver significantly reduce (drop
Low rate 85.5%).And the CD68 Positive area rates reduced rate of fenofibrate group is 75%.
The result shows that：Medicine group of the present invention is to suppressing the balloon sample enlargement effect of the liver cell of NASH morbid state and reducing
In CD68 Positive area rates, fenofibrate is superior to.
Compound shown in 7 Formulas I of the present invention of embodiment is lacking the KK-A of diet load using methionine/choliney
Effect in nonalcoholic fatty liver disease (NASH) model of mouse
This experiment discussion is known to lack diet (MCD diet) load by carrying out methionine/choline to experimental animal
The MCD diet loads of the pathogenesis of fatty liver for the characteristic morbid state for making there is NASH KK-Ay mouse (Nakano S. etc.,
Hepatol Res., 38 (10), 1026-39,2008) effect in.
Use animal：Male KK-Ay mouse are used in an experiment, start to allow mouse freely to absorb MCD drinks in about 12 week old
Food 16 weeks, makes to suffer from NASH.
Group is formed：In the way of weight does not have difference between group, it is divided into following groups：(MCD is drunk for normal diet group, control group
Food load), compound 0.25mg/kg shown in formula I-2 gives group (of the present invention group) and Bezafibrate 60mg/kg gives
Group.
Medicine is given：Given and carried out by mixed feeding.Control group is set freely to absorb the MCD diet of not drug containing, make the present invention
Group, which is freely absorbed, to be contained the MCD diet of compound shown in 0.00025% Formulas I -2, Bezafibrate is given group freely to absorb and is contained
The MCD diet of 0.06% Bezafibrate.Administration phase is 16 weeks.
Observation and inspection method：After giving, liver is extracted under yellow Jackets (50mg/kg) anesthesia, using more
After polyformaldehyde is fixed, Hematoxylin-eosin stained preparation is made.Under the conditions of blind examination, evaluation fatty liver scoring (Steatosis
score).The grade of fat deposition (Grade) is observed with enlargement ratio 100 again, according to its grade according to following standard by fat
Liver scores with 0 to 3, is shown in Table 2.
Table 2
| Grade | Scoring |
| Less than 5% | 0 |
| 5% with up to less than 33% | 1 |
| 33% with up to less than 66% | 2 |
| More than 66% | 3 |
As a result：In of the present invention group, the fatty liver scoring of whole examples is all 0, i.e. fat deposition almost disappears.In benzene
The 60mg/kg of Zha Beite is given in group, although fat deposition to be suppressed to the degree identical with normal diet group, is not arrived
The degree almost to disappear up to the fat deposition as of the present invention group.It follows that compared with Bezafibrate, institute of the present invention
State the fat deposition that compound shown in Formulas I more strongly suppresses one of NASH morbid state.The result shows that：Shown in Formulas I of the present invention
KK-A of the compound in the MCD diet loads of the animal pattern of NASHyIn mouse, show that the fat deposition of liver substantially reduces.Cause
This, compound of the invention is high as mammiferous non-alcohol fatty liver including humans, particularly severe degree
Nonalcoholic fatty liver disease prevention and/or therapeutic agent be useful.Compound shown in Formulas I of the present invention can be used for making
It is standby into treatment nonalcoholic fatty liver disease
(NASH) preventing/treating medicine, and its effect of drugs is better than existing medicine Bezafibrate.
Influence of the compound to Hepatic Fibrosis fibroplasia degree shown in 8 Formulas I of the present invention of embodiment
SPF grades of Wistar rats 46, weight 190g-220g, half male and half female.Rat be divided at random Normal group,
Model control group, positive control drug group, medicine group of the present invention, totally 4 groups.In addition to Normal group, other each groups rat skin first
The lower pure CCl of injection45ml/kg weight, is changed to that the CCl that concentration is 40% is subcutaneously injected later4Peanut oil solution 3ml/kg weight,
Every 3 days 1 time, totally 6 weeks.Feed normal solid feed, free water.
After modeling, the corresponding tested material of following dosage is given：By weight, positive drug group rat oral gavage colchicin
5mg·kg-1·d-1, compound 1mgkg shown in medicine group rat oral gavage Formulas I -4 of the present invention of the present invention-1·d-1, normally
Control group and model control group rat give the distilled water of same volume.Gavage 1 time daily, is used in conjunction 10 weeks, each group is after the last administration
When fasting 12 is small, weigh, through yellow Jackets intraperitoneal injection of anesthesia, take rat right leaflet liver, about 0.5 cm thick liver of clip
Tissue, neutral buffered formalin are fixed, and paraffin embedding, cuts into slices as 5 μ m thicks.Through multistage dehydration of alcohol, dimethylbenzene is transparent, makees HE
Dyeing, sirius red dye, and pathological tissue photo is shot under light microscopic, observe the situation of change of proliferation of fibrous tissue degree.Pass through
Found after observation pathological section：
Normal group：Lobuli hepatis structure complete display in liver tissues of rats, hepatic cell cords marshalling, no liver cell become
Necrosis, no cell infiltration, no fibroplasia；
Model control group：The visible liver cell of liver tissues of rats is disorganized, the denaturation of liver cell vacuole sample, necrosis, portal area
A large amount of proliferations of fibrous tissue are simultaneously dispersed in inflammatory cell infiltration, and the visible proliferation of fibrous tissue of most of rat extends to lobuli hepatis,
Separate lobuli hepatis and form pseudolobuli；
Positive drug group：Rat hepatocytes degeneration necrosis mitigates, the visible pseudolobuli of partial rat；
Medicine group of the present invention：Rat hepatocytes degeneration necrosis mitigates, the visible pseudolobuli of partial rat.
Light Microscopic observation, for proliferation of fibrous tissue situation with " ++++" for most serious, "-" is no fibroplasia.Normal control
Group liver tissues of rats section display is formed without liver fibrosis, and model group fibroplasia is obvious, illustrates model modeling success.Specifically
It the results are shown in Table 3.
3 each group rat tissue collagen fiber hyperplasia grading comparable situation of table
The result shows that：Medicine group of the present invention mitigates rat hepatocytes degeneration necrosis degree, can obviously reduce rat annulus
Hyperplasia degree.The medicine of compound shown in Formulas I of the present invention has obvious effect of anti hepatic fibrosis.It is and of the present invention
The ability of the anti-hepatic fibrosis of compound shown in Formulas I -4 is better than colchicin, and dosage is smaller than colchicin, security
It is high.
Experimental example 11：Using compound shown in mtt assay bounds evaluation I-5 to the growth inhibition effect of human hepatoma cell strain
1. method：Cell in growth logarithmic phase：HepG2 cell lines, Hep3b and SMMC-7721 with 1.5 ×
104Concentration kind is in 96 orifice plates.Original culture medium is sucked after cell culture 24h is adherent.Experiment is divided into blank control group, medicine
Treatment group.Blank group replaces 1640 culture mediums containing 10% hyclone；Drug-treated group, which is replaced, contains concentration for 100 μM, 50 μM,
The culture medium of 10 μM, 1 μM, 0.1 μM, 0.01 μM and 0.001 μM of Houttuynoid C.After cultivating 48h, concentration 5mg/ is added
The MTT of mL, continues to be put in CO2Incubator culture 4h, sucks 100 μ L of supernatant then along nutrient solution top, adds 100 μ L
10min is placed in DMSO, dark place, using microplate reader (Sunrise Products) measure light absorption value (wavelength 570nm), and according to suction
Light value calculates cell survival, and each processing sets 6 repeating holes.Cell survival rate (%)=Δ ODDrug-treated/ΔODBlank control×
100。
2. result：Compound shown in Formulas I -5 to HepG2 cell lines, Hep3b and
The growth of SMMC-7721 has significant inhibitory action.The compound suppresses HepG2 cell lines, Hep3b
With the IC of SMMC-7721 growths50Value is respectively：9nM、19nM、26nM.
Shown by above-described embodiment, compound is to HepG2 cell lines and SMMC-7721 shown in Formulas I of the invention
Growth there is good inhibiting effect.Thus prove, compound shown in Formulas I of the invention has resisting liver cancer activity, can be used for
Prepare medicines resistant to liver cancer.
20 heart hERG of embodiment is tested
Influence of the compound of the present invention to hERG potassium-channels is detected using manual patch clamp methods, as a result table
Compound described in bright 1-5 of the embodiment of the present invention, it is equal to the inhibitory action of hERG electric currents at highest test concentrations (30 μM)
Not up to IC50, i.e. IC50>30μM.So as to illustrate in the range of the detectable concentration of this experiment described in 1-5 of the embodiment of the present invention
Test sample compound there is no obvious inhibitory action to hERG passages.5 test samples show good in this trial stretch
Good cardiac safety.Amitriptyline (Amitriptyline) be the most widely used blocking hERG electric currents tool drug it
One, therefore positive reference substance, its IC are used as in this research50For 3.16 μM of (notes：In this research, positive reference substance
The IC50 that Amitriptyline suppresses hERG electric currents is 3.16 μM.This result is consistent with the result with document report
(Blockade of the HERG human cardiac K+channel by the antidepressant drug
amitriptyline.British Journal of Pharmacology.Jo,SH et al.,(2000).)).This shows this
Secondary experiment the result is that believable.
So compound of the present invention can be as the medicine of liver diseases, for treating and/or preventing liver disease
Disease, such as treating and/or preventing the liver diseases such as fatty liver, hepatic sclerosis, liver fibrosis, liver cancer.Of the present invention three
Nitrogen azole compounds, available for the medicine for being prepared into treatment and/or prevention liver diseases.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means to combine the embodiment or example particular features, structures, materials, or characteristics described
It is contained at least one embodiment of the present invention or example.In the present specification, schematic expression of the above terms differs
Surely identical embodiment or example are referred to.Moreover, particular features, structures, materials, or characteristics described can be any
Combined in an appropriate manner in one or more embodiments or example.
Although the embodiment of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, those of ordinary skill in the art are not departing from the principle of the present invention and objective
In the case of above-described embodiment can be changed within the scope of the invention, change, replace and modification.
Claims (7)
- A kind of 1. compound, its pharmaceutically acceptable salt, hydrate, solvate or metabolite shown in formula I；Wherein, the R1For selected from phenyl, pyridine radicals, cyclohexyl or cyclopenta, each of which is optionally by 1-3 R4Substitution；Or Person R1For optionally by 1-2 R4Or the cyclopropyl of phenyl substitution；The R2For selected from C1-4Alkyl, halo C1-4Alkyl, unsubstituted C3-8Cycloalkyl or optionally substituted C3-8Cycloalkanes Base；The R3For selected from H, C1-10Alkyl, C3-8Cycloalkyl, C2-10Alkenyl, C2-10Alkynyl, aryl, heteroaryl or heterocyclic radical, own Substituent is alternatively by 1,2 or 3 selected from halogen, oxo, C1-6Alkyl, C3-8Cycloalkyl, heterocyclic radical, phenyl, phenoxy group, halogen Element ,-CN ,-O-R5、-C(O)-R5、-OC(O)-R5-C(O)-O-R5、-N(R5)-C(O)-O-R6、-N(R5)-C(O)-R6、-N (R5)-C(O)-N(R5)(R6) and-C (O)-N (R5)(R6) substituent substitution, wherein alkyl, cycloalkyl, heterocyclic radical, phenyl, With phenoxy group alternatively C is selected from by 1,2 or 31-6Alkyl, C3-8Cycloalkyl, C1-6The substituent of alkoxy, hydroxyl and halogen takes Generation；The R4For selected from halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxy, halo C1-6Alkoxy ,-SR7Or ring third Base；The R5And R6Independently selected from by hydrogen, C1-6Alkyl or C3-8Cycloalkyl forms；Or R5And R6When connected to them Heterocycle is formed when nitrogen links together；The R7For selected from C1-6Alkyl；The X is selected from O or NH.
- 2. compound shown in Formulas I as claimed in claim 1, its pharmaceutically acceptable salt, hydrate, solvate or generation Thank to product, it is characterised in thatThe R1For selected from by 1-3 R4Substituted phenyl；The R2For selected from cyclopropyl, cyclobutyl or cyclopenta；The R3For selected from H, C1-10Alkyl or C3-8Cycloalkyl；The R7For selected from methyl, ethyl, isopropyl or the tert-butyl group；The X is selected from O.
- 3. compound shown in Formulas I as claimed in claim 2, its pharmaceutically acceptable salt, hydrate, solvate or generation Thank to product, it is characterised in thatThe R3For selected from H, methyl, ethyl, isopropyl, the tert-butyl group or cyclopropyl.
- 4. compound shown in Formulas I as claimed in claim 1, its pharmaceutically acceptable salt, hydrate, solvate or generation Thank to product, it is characterised in that compound shown in Formulas I of the present invention, for following any compound：
- 5. a kind of pharmaceutical composition, it includes such as compound of formula I according to any one of claims 1 to 4, it can pharmaceutically connect Salt, hydrate, solvate or the metabolite received, and pharmaceutic adjuvant；The compound of formula I, its is pharmaceutically acceptable Salt, hydrate, the dosage of solvate or metabolite can be therapeutically effective amount.
- 6. such as compound of formula I according to any one of claims 1 to 4, its pharmaceutically acceptable salt, hydrate, solvation Thing or metabolite, or pharmaceutical composition as claimed in claim 5 is in the medicine for preparing treatment and/or prevention liver diseases Application.
- 7. application as claimed in claim 6, it is characterised in that the liver diseases are fatty liver, hepatic sclerosis, liver fiber Change or liver cancer.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015187499A1 (en) * | 2014-06-03 | 2015-12-10 | Gilead Sciences, Inc. | Use of an ask1 inhibitor for the treatment of liver disease, optionally in combination with a loxl2 inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015187499A1 (en) * | 2014-06-03 | 2015-12-10 | Gilead Sciences, Inc. | Use of an ask1 inhibitor for the treatment of liver disease, optionally in combination with a loxl2 inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| R.B. 西尔弗曼 编: "《有机药物化学》", 31 January 2008 * |
| 孟令芝等编著: "《有机波谱分析》", 31 July 2016 * |
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