CN106551938B - A kind of medicine for treating NASH and its application - Google Patents

Abstract

The present invention relates to a kind of medicine for treating NASH, the medicine includes：Effective dose has structural formula compound described herein and its pharmaceutically acceptable salt；And pharmaceutically acceptable carrier, wherein R1 are H, halogen；R2 independently selected from：H, (1 6C) alkyl, (3 6C) cycloalkyl, (2 7C) Heterocyclylalkyl, (1 6C) alkyl amino, two [(1 6C) alkyl] amino, (2 7C) heterocyclalkylamino or (3 6C) cycloalkyl amino, each optionally substituted by one or more groups selected from (1 2C) alkyl, fluorine, hydroxyl or (1 2C) alkoxy；R3 independently selected from：H, halogen, (1 3C) alkyl, (1 2C) alkoxy, hydroxyl (1 2C) alkyl, (3 4C) cycloalkyl, (2 3C) alkenyl or cyano group.The medicine of the present invention can optimize various biochemical indicators in serum, and liver nonhazardous is acted on.

Description

A kind of medicine for treating NASH and its application

Technical field

The present invention relates to field of medicaments, specifically, the present invention relates to a kind of medicine for treating NASH and It is applied.

Background technology

Wine except non-alcohol fatty liver (nonalcoholic fatty liver disease, NAFLD) refers to Being integrated by principal character clinical pathology of diffusivity liver cell Macrovesicular steatosis caused by essence and other clear and definite damage liver factors Sign, including simple fatty liver and the fat hepatitis (NASH) and hepatic sclerosis by its differentiation.Recently as living standard Improvement and living-pattern preservation, the incidence of disease of NASH constantly raise, have source investigation show the U.S., west Europe, Japanese general population NAFLD illness rates be 10%~24%, and obesity patient NAFLD illness rates then be up to 57.5%~ 74%.NAFLD would is that a kind of following liver diseases of incidence of disease highest, and treatment NAFLD will be that many decades hepatopathy section will cure from now on Raw facing challenges.NASH there is no the preferable medicine of curative effect at present, and some treatments are only to improve insulin to support It is anti-, the balance of organismic internal environment lipid-metabolism, energetic supersession and polyphenoils is safeguarded, promotes body to be maintained at adaptation reaction rank Section, delay, prevent the disease progression of fatty liver hepatopathy.Clinically the preventing and treating to non-alcoholic fatty liver disease is with dietary adjustments, conjunction Based on reason motion and pharmaceutical intervention.The medicine for the treatment of non-alcoholic fatty liver disease mainly has melbine, vitamin etc..Diformazan is double Guanidine is insulin sensitizer, by improving the sugar tolerance and hyperinsulinemia of patient, reduce internal blood plasma free fatty acid and Plasma triglyceride level, but side effect is obvious, it is very big to gastrointestinal irritation, intentionally, the gerontal patient of renal dysfunction There is the danger that lactic acidosis occurs.Vitamin medicaments such as vitamin A, E etc., have antioxidation, can be by suppressing The formation of oxyradical prevents liver cell to be damaged, but easily accumulation produces toxicity in vivo after heavy dose of supplement, aggravates liver on the contrary Dirty burden.Other many are directed to the blood lipid-lowering medicine of hyperlipidemia, and blood fat can be promoted to focus more on liver and be metabolized, on the contrary easily Promote accumulation of the lipid in liver, and further damage liver function.So the treatment of safe and effective effect affirmative is also lacked at present The medicine of NASH, find and seem and be highly desirable with liver protection, reducing blood lipid, the medicine of lipotropy.

The content of the invention

It is an object of the invention to provide a kind of medicine for treating NASH.

In order to realize the purpose of the present invention, the present invention provides a kind of medicine for treating NASH, the medicine Comprising：Effective dose has following structural compound and its pharmaceutically acceptable salt；And pharmaceutically acceptable carrier：

Wherein

R1 is H, halogen；

R2 independently selected from：H, (1-6C) alkyl, (3-6C) cycloalkyl, (2-7C) Heterocyclylalkyl, (1-6C) alkyl amino, Two [(1-6C) alkyl] amino, (2-7C) heterocyclalkylamino or (3-6C) cycloalkyl amino, each optionally by one or more The individual group substitution selected from (1-2C) alkyl, fluorine, hydroxyl or (1-2C) alkoxy；

R3 independently selected from：H, halogen, (1-3C) alkyl, (1-2C) alkoxy, hydroxyl (1-2C) alkyl, (3-4C) cycloalkanes Base, (2-3C) alkenyl or cyano group.

Preferably, R1 is Cl.

Preferably, R2 is H.

Preferably, R3 is H.

The present invention also provides a kind of method for treating the NASH in individual in need, and it is included to described Individual applies the described medicine of therapeutically effective amount.

The present invention also provides the compound with following structural in the medicine for preparing treatment NASH Using：

Wherein

R1 is H, halogen；

R2 independently selected from：H, (1-6C) alkyl, (3-6C) cycloalkyl, (2-7C) Heterocyclylalkyl, (1-6C) alkyl amino, Two [(1-6C) alkyl] amino, (2-7C) heterocyclalkylamino or (3-6C) cycloalkyl amino, each optionally by one or more The individual group substitution selected from (1-2C) alkyl, fluorine, hydroxyl or (1-2C) alkoxy；

R3 independently selected from：H, halogen, (1-3C) alkyl, (1-2C) alkoxy, hydroxyl (1-2C) alkyl, (3-4C) cycloalkanes Base, (2-3C) alkenyl or cyano group.

Preferably, R1 is Cl.

Preferably, R2 is H.

Preferably, R3 is H.

Before further describing the invention, it should be appreciated that the invention is not restricted to described embodiment, because they Certainly may change.It should also be understood that the purpose of terms used herein is only description embodiment, it is not used to be construed as limiting, Because the scope of the present invention is only limited by the appended claims.

Unless otherwise indicated, all scientific and technical terminologies used herein are understood with one skilled in the art of the present invention Usual implication it is identical.All reference is incorporated into full for all patents referred to herein, application, published application and other publications Herein.If it is opposite that definition listed in this paper patent, application and other publications is included in definition in the part with reference Or it is inconsistent, the definition in the part, which will overwhelm, quotes the definition for including this paper.

Herein and the singulative used in appended claims "one", " one kind " and " described " include plural indicate Thing, unless the context.It should also be noted that claims can be formulated as excluding any optional key element.Equally, This explanation application makees reference claim element and relatively uses this kind of removing property term, such as " only having ", " only ", or make With the antecedent basis of " negative " limitation.

Terms used herein "comprising", " containing " and " comprising " are used with its opening, infinite implication.

To provide conciser description, without using term " about " before some quantitative expressions herein.It should be understood that either No clearly to use term " about ", each content herein represents the numerical value actually given, and it is also represented by being based on ability The approximation for the given numerical value that domain ordinary skill can rationally infer, including due to this kind of caused by experiment and/or measuring condition The equivalent value and approximation of given numerical value.No matter when as a percentage during yield, this kind of yield is represented in specific chemistry Measure and can be obtained the maximum amount of ratio with same entity for calculating the entity quality of yield than under the conditions of.Percents Concentration represent quality ratio, unless otherwise indicated.

Unless otherwise indicated, all scientific and technical terminologies used herein are understood with one skilled in the art of the present invention Usual implication it is identical.Although it can also use and implement or test this hair with similar or equivalent any method described herein and material It is bright, but preferable method and material are described below.All publications being mentioned above are totally incorporated herein by reference, and cited Publication, which is associated, comes these methods of disclosure and description and/or material.

Unless otherwise indicated, the methods and techniques of embodiment of the present invention typically follow conventional method well known in the art and entered Described in the bibliography of row simultaneously such as some in generals or particularly, the bibliography is quoted and discussed through this specification. See, e.g., Loudon, OrganicChemistry (《Organic chemistry》), fourth edition；New York：Oxford University Press (OxfordUniversityPress), 2002,360-361,1084-1085 page；Smith and March, March ' sAdvancedOrganicChemistry：Reactions, Mechanisms, andStructure (《Numb chi is advanced to organise Learn：Reaction, mechanism and structure》), the 5th edition, Wei Li scientific companies (Wiley-Interscience), 2001.

It is used to name the nomenclature of motif compound in the embodiments herein to illustrate herein.The nomenclature typically uses city Available AutoNom softwares (the MDL companies of Andrew in the sage of California) are sold, version 12.0.2 is obtained.

It should be understood that for clarity, some features of the invention described in the content of single each embodiment are also It may be incorporated in single embodiment and provide.Conversely, in the content of single embodiment Short Description it is of the invention Each feature can also be provided separately or be provided in the form of any suitable sub-portfolio.With the chemical base represented by changeable-shaped All combinations of the related embodiment of group are specific to be included in the scope of the invention and by being disclosed herein, just as herein individually and Compound (that is, separable, table of each and each combination down to such combination comprising itself for stable compound is clearly disclosed The compound for detection biological activity of seeking peace).In addition, chemical group listed in describing the embodiment of such changeable-shaped All sub-portfolios are also specifically included in the scope of the invention and by being disclosed herein, just as disclosing individually and clearly chemical base herein Each and each such sub-portfolio of group.

" pharmaceutically acceptable salt " is intended to indicate that the free acid of compound illustrated herein or the salt of alkali, its do not have toxicity, It can biologically tolerate or biologically be suitable to be administered to object.Generally referring to, S.M.Berge etc., “PharmaceuticalSalts(《Pharmaceutical salts》) " J.Pharm.Sci., 1977,66,1-19.It is preferable pharmaceutically acceptable Salt be pharmaceutically effectively and be adapted for contact with object tissue without excessive toxicity, stimulate or it is anaphylactoid those.Herein Described compound can have group acid enough, the enough group of alkalescence, two kinds of functional group or each more than a kind of Type, and therefore with a variety of inorganic or organic base, and inorganic and organic acid reaction to form pharmaceutically acceptable salt.

The example of pharmaceutically acceptable salt includes sulfate, pyrosulfate, disulfate, sulphite, bisulfite Salt, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetic acid Salt, propionate, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propiolate, oxalic acid Salt, malonate, succinate, suberate, sebacate, fumarate, maleate, Isosorbide-5-Nitrae-acetylenedicarboxylic acid salt, 1,6- Hexyndioic acid salt, benzoate, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxy Yl benzoic acid salt, phthalate, sulfonate, metilsulfate, propyl sulfonic acid salt, benzene sulfonate, xylenesulfonate, Naphthalene -1- sulfonate, naphthalene-2-sulfonic acid salt, phenyl acetate salt, phenylpropionic acid salt, PB, citrate, lactate, γ - Hydroxybutyric acid salt, glycollate, tartrate and mandelate.The list of other suitable pharmaceutically acceptable salts is found in Remington′sPharmaceuticalSciences(《Remington pharmaceutical science》), the 17th edition, Easton, PA Mack Publishing Company (MackPublishingCompany), 1985.

It may also include and one or more can pharmaceutically connect for the pharmaceutical composition of therapeutic purposes, including compound described herein The excipient received.Pharmaceutically acceptable excipient refers to no toxicity and is biologically suitable to the material being administered to object.It is this kind of Excipient promotes the administration process of compound described herein and compatible with active component.The example of pharmaceutically acceptable excipient Including stabilizer, lubricant, surfactant, diluent, antioxidant, binding agent, colouring agent, swelling agent, emulsifying agent or tune Taste agent.In a preferred embodiment, the pharmaceutical composition of the invention is aseptic composite.It can be used known to those skilled in the art Or the complex technique that can be used prepares pharmaceutical composition.

The present invention also relates to aseptic composite, including meet the country for determining said composition and the composition of local code.

The conventional method prepared according to a variety of formulations are used in this area, pharmaceutical composition and compound described herein can match somebody with somebody Solution, emulsion, supensoid agent or the dispersant being made as in appropriate drug solvent or supporting agent, or pill, tablet, lozenge, suppository, Wafer, sugar-coat agent, granule, powder agent, the powder agent for reconstruction or the capsule together with solid carriers.The medicine of the present invention Composition can be given by appropriate route of delivery, such as oral, parenteral, rectum, intranasal, part or through eye approach, or lead to Cross suction.Preferably, said composition is formulated as being used for administered intravenously or orally.

For being administered orally, compound of the invention can (such as tablet or capsule) or solution, emulsion in solid form Or the form of supensoid agent provides.To prepare Orally administered composition, compound of the invention can be prepared to form such as daily about 0.01 To about 50mg/kg or daily about 0.05 to about 20mg/kg or daily about 0.1 to about 10mg/kg dosage.Other dosage include Daily about 0.1mg to 1g, daily about 1mg to about 10mg, daily about 10mg to about 50mg, daily about 50mg to about 250mg or every Its about 250mg to 1g.Oral tablet may include and compatible pharmaceutically acceptable excipient (such as diluent, disintegrant, bonding Agent, lubricant, sweetener, flavor enhancement, colouring agent and preservative) mixing active component.Suitable inert filler includes carbonic acid Sodium and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorb Sugar alcohol etc..Exemplary fluids oral vehicle includes ethanol, glycerine, water etc..Starch, polyvinylpyrrolidone (PVP), starch second Alkyd sodium, microcrystalline cellulose and alginic acid are exemplary disintegrants.Bonding agent may include starch and gelatin.If it does, lubrication Agent can be magnesium stearate, stearic acid or talcum.If desired, certain material (such as glycerin monostearate or two can be used Tristerin) coating tablet is with the absorption in delaying stomach and intestine road, or uses enteric coating peridium.

Capsule for oral administration includes hard and Perle.To prepare hard gelatin capsule, can by active component with Solid, semisolid or liquid diluent mixing.Perle can be by by active component and water, oil (such as peanut oil or olive Olive oil), atoleine, the mixture of the list of short chain fatty acids and two glyceride, the mode of polyethylene glycol 400 or mixed with propylene glycol Prepare.

Liquid for oral administration can be the form of supensoid agent, solution, emulsion or syrup, or can face The dry products rebuild with preceding water or other suitable supporting agents.This kind of fluid composition is optional to be included：Pharmaceutically acceptable tax Shape agent, as suspending agent (such as D-sorbite, methylcellulose, mosanom, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, Aluminium stearate gel etc.)；Non-aqueous supporting agent, such as oily (such as apricot kernel oil or fractionated coconut oil), propane diols, ethanol or water；It is anti- Rotten agent (such as methyl p-hydroxybenzoate or propylparaben or sorbic acid)；Wetting agent (such as lecithin)；And (such as Fruit needs) flavor enhancement or colouring agent.

The composition of the present invention can be formulated as suppository and be used for rectally.(including intravenous, muscle is used for parenteral Interior, intraperitoneal, intranasal or subcutaneous route), reagent of the invention can be buffered to suitable pH with aseptic aqueous solution agent or supensoid agent With isotonicity or by it is parenteral it is acceptable it is oily in the form of provide.Suitable aqueous carrier includes Ringer's solution and isotonic Sodium chloride.This kind of form can be that unit dosage form (such as ampoule or disposable injection device), multiple dose form (such as can be from The middle medicine bottle for taking out suitable dose) or solid form or available for the pre-concentration liquid for preparing injectable formulation.At several minutes to number In it time, the scope of exemplary infusion dosage is the reagent mixed with drug-carrier of about 1 to 1000 μ g/kg/ minutes.

For intranasal, suction or oral administration, the spray agent for for example also including suitable carrier can be used to give this hair Bright pharmaceutical composition.

For local use, the compound of the present invention is preferably formulated as emulsifiable paste or ointment or the class suitable for being locally administered Like supporting agent.For local administration, the compound of the present invention can be mixed with drug-carrier, concentration is the pact that medicine accounts for supporting agent 0.1% to about 10%.Another pattern for giving the reagent of the present invention is to reach the effect of transdermal delivery using patch formulation.

Terms used herein " treatment " or " processing " include " preventative " and " therapeutic " treatment." preventative " treatment, which refers to, to be pushed away The symptom or reduce disease or symptom development or recurrence that slow disease, the development of disease symptomses or medical conditions, suppression are likely to occur Risk." therapeutic " treatment includes reducing existing disease, the order of severity of symptom or illness or suppresses its deterioration.Therefore, control Treat the deterioration for including improving or preventing existing disease symptomses, the essence system for preventing other symptoms, improving or preventing symptom System reason, suppress imbalance or disease, such as prevent imbalance or advancing of disease, mitigation imbalance or disease, promote imbalance or disease Regression, mitigate illness caused by disease or imbalance or stop disease or the symptom of imbalance.

Term " object " refers to the mammalian subject for needing the treatment, such as people.

In the treatment method according to the present invention, " effective dose " refers to be controlled needed for the object acquisition for being enough to make this kind for the treatment of of needs Treat the amount or dosage of benefit.The present invention compound effective dose or dosage can by conventional method (as modeling, dosage escalation or Clinical test) determine, wherein consider conventional factors, such as the pattern or approach of administration or medicine delivery, the medicine of reagent are for power The judgement of the order of severity and process, the health status of object, the state of an illness and body weight and the doctor in charge that learn, infect.Exemplary dose The scope of amount is daily per Kilogram subject body weight about 1ug to 2mg active agent, preferably from about 0.05 to 100mg/kg/ days or about 1 To 35mg/kg/ days or about 0.1 to 10mg/kg/ days.In other embodiments, the scope of exemplary dose is about 1mg to about 1g/ days, or about 1-500,1-250,1-100,1-50,50-500 or 250-500mg/ days.Accumulated dose can be with single or separated Dosage device (such as BID, TID, QID) is given.

Once the disease of patient improves, you can regulating dosage is used for preventative or maintaining treatment.For example, the agent of administration Amount or frequency or both can change to be down to symptom keeps the required level for treating or preventing effect.Certainly, if symptom Mitigate to proper level, can stop treating.But during any symptom recurrence, patient can require that the interval in long-term basis is controlled Treat.Patient may also need to the long-term treatment on the basis of long time-histories.

Retouched by reference to specific embodiment with the schematic synthetic schemes of general preparative methods in this article and afterwards State Exemplary chemical entity useful in the method for the present invention.Those skilled in the art will appreciate that to obtain herein more Kind compound, can suitably be selected parent material, so as to which the reaction scheme protected by suitably with or without makes With final required substituent to generate required product.Or, it may be necessary to or want in final required substituting group position Upper use can pass through the proper group that reaction scheme is carried and can substituted in due course by required substituent.In addition, this area skill The order that art personnel should be understood that the conversion shown in following scheme and arbitrarily can hold with specific side base function phase is carried out.It is general Each reaction described in scheme is preferably carried out under about 0 DEG C to the reflux temperature of organic solvent used.All material generally may be used Bought at market supply business.

The medicine of the present invention can shorten the prothrombin time of aborting rat, thrombin time, and plasma fibrinogen increases Add, show that there is anastalsis to postabortal uterine hemorrhage.

Brief description of the drawings

Fig. 1 is liver histopathology figure, wherein A：Normal group；B：Model control group；C、D、E：Medicine of the present invention is low, Middle and high dosage group；F：Positive controls.

Embodiment

Below by way of the description of embodiment, the invention will be further described, but this is not the limit to the present invention System, those skilled in the art according to the present invention basic thought, various modifications may be made or improve, but without departing from this The basic thought of invention, within the scope of the present invention.

Experimental example

The structural formula of medical compounds of the present invention is：

Take 60 (200 ± 20) g, SPF levels of male SD rat.It is randomly divided into 6 groups, respectively Normal group, model pair According to group, the basic, normal, high dosage group of medicine of the present invention and positive controls (Essentiale N/Essentiale Forte N, purchased from Sanofi-Aventis company).It is normal right Then raised according to group with basal feed feeding, model control group, the basic, normal, high dosage group of medicine of the present invention and positive controls with high fat (the high lipid food formula of expecting：The weight % of cholesterol 2, the weight % of lard 10, the weight % of basal feed 88) feeding, continuously feed 16 Week.After feeding 2 weeks, Normal group, model control group are with physiological saline 10ml/ (kgd) gavage；Positive controls will easily be apt to Multiplexing distilled water is configured to 10.2g/L solution, daily gavage 10ml/kg；The basic, normal, high dosage group of medicine of the present invention fills daily Stomach gives 10mg/kg, 20mg/kg and 40mg/kg.Continuous gavage 14 weeks.After experiment terminates, 3% yellow Jackets (0.15ml/ 100g) intraperitoneal injection of anesthesia, heart are directly taken a blood sample, and are put to death rapid complete separation liver after rat, are taken lobus dexter liver group 3mm × 3mm × 6mm, 24h is fixed with 4% paraformaldehyde, step by step dehydration of alcohol, routine paraffin wax Bao Li, carry out disease under microscope after HE is dyed Reason observation.As a result Fig. 1 is seen.

HE coloration results are shown：The liver tissues of rats structural integrity of Normal group is clear, and lobuli hepatis structure is clear, and liver is thin Born of the same parents' rope marshalling；Compared with Normal group, model control group liver changes in severe fatty liver sample, and lobuli hepatis structure is owed Clearly, hepatic cell cords and sinus hepaticus structure disturbance, the fat vacuole that visible diffusivity differs in size in liver cell endochylema；With model comparison Group is compared, and administration group liver organization lobuli hepatis structure is gradually recovered, and hepatic cell cords and sinus hepaticus structure are gradually clear, liver cell lactones Fat vacuole gradually decreases.

The each group rat serum specimen centrifuge collected is separated into serum, serum paddy third is determined using automatic clinical chemistry analyzer Transaminase (ALT), glutamic-oxalacetic transaminease (AST), T-CHOL (CHOL), triglycerides (TG), high density lipoprotein level from (HDL-C), Low-density lipoprotein from (LDL-C), super sensitive C-reactive egg oneself (CRP).As a result see the table below.

With model group than * P<0.05, * * P<0.01

Compared with Normal group, each index level of model control group ALT, AST, CHOL, TG, LDL-C, CRP substantially rises Height, HDL-C is horizontal to be declined；And compared with model control group, the basic, normal, high dosage group each group of medicine of the present invention increases with drug dose Add, Serum ALT, AST, CHOL, TG, LDL-C, CRP value gradually decrease, and HDL-C values gradually increase；And medicine high dose of the present invention Compared with positive controls, each index level of ALT, AST, CHOL, TG, LDL-C, CRP is decreased obviously group, the horizontal rises of HDL-C.

Claims (4)

1. application of the compound with following structural in the medicine for preparing treatment NASH：

Wherein

R1 is H, halogen；

R2 independently selected from：H, (1-6C) alkyl, (3-6C) cycloalkyl, (2-7C) Heterocyclylalkyl, (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (2-7C) heterocyclalkylamino or (3-6C) cycloalkyl amino, it is each optionally one or more Group substitution selected from (1-2C) alkyl, fluorine, hydroxyl or (1-2C) alkoxy；

R3 independently selected from：H, halogen, (1-3C) alkyl, (1-2C) alkoxy, hydroxyl (1-2C) alkyl, (3-4C) cycloalkyl, (2-3C) alkenyl or cyano group.

2. application according to claim 1, it is characterised in that R1 is Cl.

3. application according to claim 1, it is characterised in that R2 is H.

4. application according to claim 1, it is characterised in that R3 is H.