CN111499619A - Medicine for treating hepatic fibrosis and preparation method thereof - Google Patents
Medicine for treating hepatic fibrosis and preparation method thereof Download PDFInfo
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Abstract
The compound can obviously reduce the expression of TGF- β 1 and α -SMA mRNA of a hepatic fibrosis rat, obviously relieve the hepatic fibrosis degree and show good treatment effect on the hepatic fibrosis.
Description
Technical Field
The invention relates to the field of medical chemistry, in particular to a medicament for treating hepatic fibrosis. The invention also relates to the use of said medicament and to a method for the production thereof.
Background
Hepatic fibrosis is a pathophysiological process, which refers to abnormal proliferation of connective tissue in the liver caused by various pathogenic factors. Any liver injury has a liver fibrosis process in the process of liver repair and healing, and if the injury factor cannot be removed for a long time, the fibrosis process can be continuously developed into cirrhosis and even liver cancer for a long time, so that the health of a patient is seriously threatened.
Hepatic injury from various etiologies results in HSC activation, accelerated proliferation of activated HSCs, and combined secretion of large amounts of Extracellular Matrix (ECM) deposited in the liver, forming fibrosis, HSCs are activated, displaying a highly fibrotic (myofibroblast) phenotype from a quiescent vitamin a-rich state after they are activated, increased contractile force of activated HSCs is attributed to expression of cytoskeletal proteins and α smooth muscle actin (α -SMA), α -SMA expression is used as a marker of HSC activation.
Transforming Growth Factor- β 1(Transforming Growth Factor- β 1, TGF- β 1) is the major fibroblast Growth Factor, and the TGF- β 1 pathway is the major pathway for activating HSCs to promote ECM production (WA L TON K L, et al. targeting TGF- β media SMAD signalling for the prevention of fibrosis [ J]Frontiers inpharmacology,2017,8: 461). The balance between ECM synthesis and degradation is controlled by Matrix Metalloproteinases (MMPs) and their inhibitors TIMPs, MMP proteins promote ECM degradation, TIMP proteins inhibit ECM degradation by inhibiting MMP activity (hemman S,
GRAF, RODERFE L D M, equivalent, expression of MMPs and TIMPs in liver fibrosis-a system viewing with specific tissues in journal of Hepatology,2007,46(5):955 cake 975. overexpression of TGF- β 1 can inhibit MMPs expression and promote TIMPs expression, thereby leading to ECM deposition and formation of liver fibers (Wangle et al. Chinese herbal effective ingredient research progress for regulating TGF- β 1/Smads signal channel against hepatic fibrosis. Chinese herbal journals 2019,44(4):666 674) -therefore regulating TGF- β 1 signal channel has an important role in reversing the development of hepatic fibrosis (MIYAWA K, et al. two way facial tissue in- β culturing. TGF-11912): 11912).
Benzopyran compounds are heterocyclic compounds with pharmaceutical activity widely existing in natural products and drug molecules, and most of the benzopyran compounds have flavone, isoflavone and the like (Dongzhou and the like, coumarin derivative synthesis and research progress, chemical world, 2009(8):494 497). The benzopyran compounds have various types, and have various pharmacological activities according to the types and positions of substituents on mother nucleus, such as treating liver diseases and tumors, inhibiting bacteria, resisting oxidation, etc. JP5349800B2 discloses a benzopyran compound and application thereof in treating liver diseases, particularly liver fibrosis, and WO2016072946A1 discloses another benzopyran compound and application thereof in treating fibrosis, but the benzopyran compounds have the problems of poor treatment effect, high toxic and side effects and the like.
In order to overcome the problems in the prior art, the application provides a novel benzopyran compound, which has good therapeutic effect on hepatic fibrosis.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a medicament with good treatment effect on hepatic fibrosis.
In one embodiment, the present invention provides a benzopyran-based compound having the structure shown in formula I:
in formula I:
R1selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;
Ra、Rbeach independently selected from C1-C6 alkyl, C1-4 alkoxy C1-C4 alkyl, C1-4 alkylamino C1-4 alkyl, di (C1-4 alkyl) amino C1-4 alkyl, or Ra、RbTogether with the N atom to which they are attached form a 5 or 6 membered heterocycloalkyl;
R2-R5each independently selected from hydrogen, halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, and C6-C14 aryl, wherein the C6-C14 aryl is optionally substituted by one or more of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino.
The compound shown in the formula I also comprises a stereoisomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I, a stereoisomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof, as described herein, and a pharmaceutically acceptable adjuvant, carrier or excipient.
In yet another embodiment, the present invention provides the use of a compound of formula I, a stereoisomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof, for the manufacture of a medicament for the treatment of liver fibrosis.
Advantageous effects
Test results show that the compound can obviously reduce the expression of TGF- β 1 and α -SMAmRNA of a liver fibrosis rat, obviously reduce the degree of liver fibrosis and show good treatment effect on the liver fibrosis.
Detailed Description
The present invention is described in more detail below to facilitate an understanding of the present invention.
It should be understood that the terms or words used in the specification and claims should not be construed as having meanings defined in dictionaries, but should be interpreted as having meanings that are consistent with their meanings in the context of the present invention on the basis of the following principles: the concept of terms may be defined appropriately by the inventors for the best explanation of the invention.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
As used herein, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. The term includes straight and branched chain alkyl groups, preferably including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and the like.
As used herein, the term "aryl" refers to an aromatic carbocyclic group of 6 to 14, preferably 6 to 10, carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl), which may or may not be aromatic, provided that the point of attachment is at an aromatic carbon atom. The term includes phenyl and naphthyl and the like.
As used herein, the term "heterocycloalkyl" refers to a 3 to 14-membered, preferably 3 to 6-membered, most preferably 5 or 6-membered, saturated cyclic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring. The term includes pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, homopiperidinyl, morphininyl, thiomorpholinyl, piperazinyl, or homopiperazinyl groups and the like.
As used herein, the term "compound" refers to the general formulae disclosed herein, compounds encompassed by any subgenera of these general formulae, as well as any particular compound having the general formulae and subgenera general formulae, including stereoisomers, pharmaceutically acceptable salts, prodrugs, or solvates thereof.
As used herein, the term "stereoisomer" refers to a chirally different compound comprising one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
As used herein, the term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions known in the art, representative pharmaceutically acceptable salts include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate, acetate, butyrate, adipate, heptanoate, hexanoate, maleate, fumarate, citrate, benzoate, benzenesulphonate, aspartate, camphorate, camphorsulphonate, digluconate, cyclopentanepropionate, ethanesulphonate, lactate, methanesulphonate, nicotinate, oxalate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate and p-toluenesulphonate.
As used herein, the term "prodrug" refers to a compound that is capable of being converted in vivo to an active compound. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrugs of the present invention may be esters, and in the present invention esters may be used as prodrugs of benzene esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
As used herein, the term "solvate" refers to those compounds combined with a stoichiometric or non-stoichiometric amount of solvent. Preferred solvents are volatile, non-toxic and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
The invention provides a compound shown as a formula I, a stereoisomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof:
in formula I:
R1selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;
Ra、Rbeach independently selected from C1-C6 alkyl, C1-4 alkoxy C1-C4 alkyl, C1-4 alkylamino C1-4 alkyl, di (C1-4 alkyl) amino C1-4 alkyl, or Ra、RbTogether with the N atom to which they are attached form a 5 or 6 membered heterocycloalkyl;
R2-R5each independently selected from hydrogen, halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, and C6-C14 aryl, wherein the C6-C14 aryl is optionally substituted by one or more of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino.
In one embodiment of the present invention, said R1Selected from hydrogen.
In one embodiment of the present invention, said Ra、RbEach independently selected from C1-C4 alkyl.
In one embodiment of the present invention, said RaSelected from C1-C6 alkyl, said RbSelected from C1-4 alkylamino C1-4 alkyl, di (C1-4 alkyl) amino C1-4 alkyl.
In one embodiment of the present invention, said Ra、RbTogether with the N atom to which they are attached form a piperidinyl or morpholinyl group.
In the inventionIn one embodiment, R is2-R5Each independently selected from hydrogen, halogen, nitro, C1-C6 alkyl.
In one embodiment of the present invention, said R2-R5Each independently selected from hydrogen, F, nitro, C1-C4 alkyl.
The following compounds are preferred in the present invention:
in addition, the invention provides a pharmaceutical composition, which comprises the compound shown in the formula I, the stereoisomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, and a pharmaceutically acceptable adjuvant, carrier or excipient.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert adjuvant, carrier or excipient, including: (a) fillers, for example, starch, glucose, lactose, sucrose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (d) wetting agents, such as cetyl alcohol and glycerol monostearate; and (e) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the form of capsule, tablet or pill, the dosage form may also contain buffering agents, for example, organic acids such as citric acid, tartaric acid and lactic acid, inorganic acids such as phosphoric acid and hydrochloric acid, alkali hydroxides such as sodium hydroxide and calcium hydroxide, and amines such as triethanolamine, diethanolamine and diisopropanolamine. In addition, deodorant, dispersant, preservative, perfume, etc. may be used as necessary.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Carriers and solvents that can be used are water and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention will be administered in therapeutically effective amounts by any of the recognized modes of administration of agents that serve similar utilities. The compounds of the present invention may be administered as a single daily dose, or the total daily dose may be divided into two, three or four daily doses.
For the present invention, suitable dosage levels are generally from about 0.001 to 100mg per kg body weight of the patient per day, which may be administered in single or multiple doses. Preferably, the dosage level is from about 0.01 to about 25mg/kg per day; more preferably, from about 0.05 to about 10mg/kg per day. Suitable dosage levels may be about 0.01 to 25mg/kg per day, about 0.05 to 10mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range, the dose may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0mg/kg per day. For oral administration, the formulations are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, in particular 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered in a treatment regimen of 1 to 4 times per day, preferably once per day or twice per day.
It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. A therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
The invention also relates to a process for preparing a pharmaceutical composition comprising a compound of formula I, a stereoisomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof, as defined herein, and a pharmaceutically acceptable adjuvant, carrier or excipient, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the compounds of the invention may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The invention relates to a compound shown in a formula I, and application of a stereoisomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof.
The compound shown in the formula I, the stereoisomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof can obviously reduce the expression of TGF- β 1 and α -SMAmRNA of a rat with hepatic fibrosis, obviously reduce the degree of the hepatic fibrosis and show good treatment effect on the hepatic fibrosis.
In one embodiment, the invention provides the use of the compound shown in formula I, a stereoisomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof in the preparation of a medicament for treating liver fibrosis.
In yet another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula I.
In general, the compounds of the present invention may be prepared by a process as described herein, wherein the substituents are as defined in the compounds of formula I, unless otherwise specified, said process comprising:
step 1
Reacting the compound shown in the formula II with trimethylsilyl acetylene in the presence of organic base, a palladium catalyst and a copper catalyst to obtain a compound shown in the formula III;
step 2
Reacting a compound shown in a formula III with a compound shown in a formula IV in the presence of an organic base, a palladium catalyst and a copper catalyst to obtain a compound shown in a formula V;
step 3
Hydrolyzing the compound of formula V in the presence of a base to a compound of formula VI; step 4
Reacting a compound represented by formula VI with a compound represented by formula VII in the presence of a base and a condensing agent to obtain a compound represented by formula I;
wherein R is selected from C1-4 alkyl, and X is selected from chlorine or bromine.
In one embodiment, the organic base described in steps 1 and 2 comprises triethylamine, trimethylamine, diisopropylethylamine, pyridine.
In one embodiment, the palladium catalyst described in steps 1 and 2 comprises PdCl2、Pd(PPh3)4、Pd(PPh3)2Cl2。
In one embodiment, the copper catalyst described in steps 1 and 2 comprises CuI, CuCl, Cu2O。
In one embodiment, the base of step 3 comprises NaOH, KOH, NaOMe, NaOEt, KOMe, KOEt.
In one embodiment, the base of step 4 comprises Na2CO3、K2CO3Triethylamine, trimethylamine, diisopropylethylamine and pyridine.
In one embodiment, the condensing agent of step 4 comprises PyBOP, PyAOP, HBTU, TBTU.
The compounds of the present invention may be prepared by a number of methods well known to those skilled in the art of synthesis. The compounds of the invention may be prepared, for example, using the reactions and techniques listed below, together with methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent suitable for the reagents and materials used and for the conversion to be effected. Furthermore, in the synthetic methods described below, it is to be understood that all proposed reaction conditions (including choice of solvent, reaction atmosphere, reaction temperature, experimental duration and work-up procedures) are selected as standard conditions for the reaction, which should be readily ascertained by one skilled in the art of organic synthesis. Not all compounds falling within a given class may be compatible with certain reaction conditions required in certain of the described methods. These limitations on substituents compatible with reaction conditions will be apparent to those skilled in the art and alternative methods may be used.
Example 1: 6- ((7-fluoro-6-methyl-1H-indol-3-yl) ethynyl) -N, N-dimethylchroman-4-carboxamide (Compound 1)
Step 1 methyl 6-iodochroman-4-carboxylate (31.81g,100mmol) was dissolved in ethyl acetate (280m L) and Pd (PPh) was added3)2Cl2(0.70g,1mmol), CuI (0.19g,1mmol) and triethylamine (30ml), and the temperature was reduced to 0 ℃ under the protection of nitrogen and stirred for 30 min. Trimethylsilylacetylene (TMSA,15ml) was then added and the temperature was raised to 70 ℃ for 12 h. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure and eluted with cyclohexane/dichloromethane (v/v. 3/1)Column chromatography gave 6-ethynylchroman-4-carboxylic acid methyl ester (17.08g, 79.0%). ESI-MS: 217[ M + H]+
Step 2 methyl 6-ethynylchromane-4-carboxylate (10.81g,50mmol) is dissolved in NMP (150m L) and 3-bromo-7-fluoro-6-methyl-1H-indole (11.40g,50mmol), Pd (PPh) is added3)2Cl2(0.35g,0.5mmol), CuI (0.095g,0.5mmol) and triethylamine (15ml), were heated to 80 ℃ under nitrogen and stirred overnight, the reaction was cooled and filtered, and H was introduced2O (1L), the solid was filtered off and the ethanol recrystallized to give methyl 6- ((7-fluoro-6-methyl-1H-indol-3-yl) ethynyl) -chroman-4-carboxylate (13.70g, 75.4%). ESI-MS: 364[ M + H ]. The results of the purification of the residue were combined]+
Step 3 methyl 6- ((7-fluoro-6-methyl-1H-indol-3-yl) ethynyl) -chroman-4-carboxylate (10.90g,30mmol) was dissolved in ethanol (120M L), NaOH (2.4g, 60mmol) was added, reflux stirred overnight, cooled to room temperature, 1% HCl was added to adjust the pH to 4 the precipitated solid was filtered off, washed with water and recrystallized from methanol to give 6- ((7-fluoro-6-methyl-1H-indol-3-yl) ethynyl) -chroman-4-carboxylic acid (9.86g, 94.2%). ESI-MS 350[ M + H ]: 350[ M + H ] -]+
And 4, step 4: 6- ((7-fluoro-6-methyl-1H-indol-3-yl) ethynyl) -chroman-4-carboxylic acid (0.70g,2mmol) is dissolved in tetrahydrofuran (10ml) and dimethylamine hydrochloride (0.16g, 2mmol), diisopropylethylamine (1.09g,10mmol) and PyBOP (0.62g,1.2mmol) are added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, dissolved in ethyl acetate (20ml), and washed with water 3 times and anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Column chromatography with petroleum ether/dichloromethane (v/v-5/1) and recrystallisation from ethanol gave the title compound as a white solid (0.47g, 62.0%).
ESI-MS：377[M+H]+
Elemental analysis: theoretical value C, 73.39; h, 5.62; f, 5.05; n, 7.44; o,8.50
Found C, 73.02; h, 5.37; f, 5.15; n, 7.65; o,8.81
Hydrogen spectrum (400MHz, DMSO-d6)8.01(s,1H),7.75(d,1H, J ═ 7.5Hz),7.44(d,1H, J ═ 7.5Hz),7.32(s,1H),6.92(d,1H, J ═ 7.5Hz),6.73(d,1H, J ═ 7.5Hz),4.13-4.30(m,2H),3.60(t,1H, J ═ 7.0Hz),2.90(s,6H),2.33(s,3H),2.15-2.42(m, 2H).
Example 2: n- (2- (dimethylamino) ethyl) -N-methyl-6- ((7-fluoro-6-methyl-1H-indol-3-yl) ethynyl) chroman-4-carboxamide (Compound 2)
6- ((7-fluoro-6-methyl-1H-indol-3-yl) ethynyl) -chroman-4-carboxylic acid (0.70g,2mmol), prepared in step 3 of example 1, was dissolved in tetrahydrofuran (10ml) and N, N, N' -trimethylethylenediamine dihydrochloride (0.35g, 2mmol), diisopropylethylamine (1.09g,10mmol) and PyBOP (0.62g,1.2mmol) were added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, dissolved in ethyl acetate (20ml), and washed with water 3 times and anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Column chromatography on petroleum ether/ethyl acetate (v/v-10/1) followed by recrystallization from ethanol afforded the title compound as an off-white solid (0.51g, 58.3%).
ESI-MS：434[M+H]+
Elemental analysis: theoretical value C, 72.03; h, 6.51; f, 4.38; n, 9.69; o,7.38
Found C, 72.14; h, 6.76; f, 4.22; n, 9.80; o,7.08
Hydrogen spectrum (400MHz, DMSO-d6)8.01(s,1H),7.75(d,1H, J ═ 7.5Hz),7.44(d,1H, J ═ 7.5Hz),7.32(s,1H),6.92(d,1H, J ═ 7.5Hz),6.73(t,1H, J ═ 7.5Hz),4.13-4.30(m,2H),3.60(t,1H, J ═ 7.0Hz),2.85(s,3H),2.72(t,2H, J ═ 7.1Hz),2.65(s,6H),2.58(t,2H, J ═ 7.1Hz),2.33(s,3H),2.15-2.42(m, 2H).
Example 3: 6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) -N, N-dimethylchroman-4-carboxamide (Compound 3)
Step 1 methyl 6-ethynylchromane-4-carboxylate (10.81g,50mmol), prepared in step 1 of example 1, was dissolved in NMP (150m L) and 3-bromo-6-methyl-5-nitro-1H-indole (11.40g,50mmol), Pd(PPh3)2Cl2(0.35g,0.5mmol), CuI (0.095g,0.5mmol) and triethylamine (15ml), were heated to 85 ℃ under nitrogen and stirred overnight, the reaction was cooled and filtered, and H was introduced2O (1L), the solid was filtered off and methanol recrystallized to give methyl 6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) -chroman-4-carboxylate (14.17g, 72.6%). ESI-MS: 391[ M + H ] -]+
Step 2 methyl 6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) -chroman-4-carboxylate (11.71g,30mmol) was dissolved in ethanol (120M L), NaOH (2.4g, 60mmol) was added, reflux stirred overnight, cooled to room temperature, 1% HCl was added to adjust the pH to 4 the precipitated solid was filtered off, washed with water and recrystallized to give 6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) -chroman-4-carboxylic acid (10.87g, 96.3%). ESI-MS: 377[ M + H ] -% ]]+
And step 3: 6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) -chroman-4-carboxylic acid (0.75g,2mmol) is dissolved in tetrahydrofuran (10ml) and dimethylamine hydrochloride (0.16g, 2mmol), diisopropylethylamine (1.09g,10mmol) and PyBOP (0.62g,1.2mmol) are added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, dissolved in chloroform (25ml), and washed with water 3 times and anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Column chromatography with petroleum ether/chloroform (v/v-8/1) and recrystallization from methanol gave the title compound as a bright white solid (0.56g, 69.3%).
ESI-MS：404[M+H]+
Elemental analysis: theoretical value C, 68.47; h, 5.25; n, 10.42; o,15.86
Found C, 68.11; h, 5.45; n, 10.33; o,16.11
Hydrogen spectrum (400MHz, DMSO-d6)8.42(s,1H),8.01(s,1H),7.75(s,1H),7.44(d,1H, J ═ 7.5Hz),7.38(s,1H),6.91(d,1H, J ═ 7.5Hz),4.10-4.27(m,2H),3.60(t,1H, J ═ 7.0Hz),2.90(s,6H),2.33(s,3H),2.14-2.41(m, 2H).
Example 4: n- (2- (dimethylamino) ethyl) -N-methyl-6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) chroman-4-carboxamide (Compound 4)
6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) -chroman-4-carboxylic acid (0.75g,2mmol), prepared in example 3, step 2, was dissolved in tetrahydrofuran (10ml) and N, N, N' -trimethylethylenediamine dihydrochloride (0.35g, 2mmol), diisopropylethylamine (1.09g,10mmol) and PyBOP (0.62g,1.2mmol) were added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, dissolved in chloroform (25ml), and washed with water 3 times and anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Column chromatography on cyclohexane/ethyl acetate (v/v-7/1) and recrystallisation from ethanol gave the title compound as a white solid (0.51g, 58.3%).
ESI-MS：461[M+H]+
Elemental analysis: theoretical value C, 67.81; h, 6.13; n, 12.17; o,13.90
Found C, 67.62; h, 6.27; n, 12.08; o,14.03
Hydrogen spectrum (400MHz, DMSO-d6)8.41(s,1H),7.99(s,1H),7.74(s,1H),7.44(d,1H, J ═ 7.5Hz),7.38(s,1H),6.92(d,1H, J ═ 7.5Hz),4.13-4.30(m,2H),3.60(t,1H, J ═ 7.0Hz),2.84(s,3H),2.70(t,2H, J ═ 7.1Hz),2.64(s,6H),2.57(t,2H, J ═ 7.1Hz),2.34(s,3H),2.15-2.41(m, 2H).
Example 5: (6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) chroman-4-yl) (morphininyl) methanone (Compound 5)
6- ((6-methyl-5-nitro-1H-indol-3-yl) ethynyl) -chroman-4-carboxylic acid (0.75g,2mmol), prepared in example 3, step 2, was dissolved in tetrahydrofuran (10ml) and morpholine hydrochloride (0.25g, 2mmol), diisopropylethylamine (1.09g,10mmol) and PyBOP (0.62g,1.2mmol) were added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, dissolved in toluene (25ml), and washed with water 3 times and anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. Column chromatography on n-ethane/ethyl acetate (v/v-8/1) and recrystallization from methanol afforded the title compound as an off-white solidCompound (0.63g, 70.5%).
ESI-MS：446[M+H]+
Elemental analysis: theoretical value C, 67.41; h, 5.20; n, 9.43; o,17.96
Found C, 67.88; h, 5.10; n, 9.37; o,17.65
Hydrogen spectrum (400MHz, DMSO-d6)8.41(s,1H),8.00(s,1H),7.75(s,1H),7.43(d,1H, J ═ 7.5Hz),7.38(s,1H),6.95(d,1H, J ═ 7.5Hz),4.13-4.30(m,2H),3.58-3.67(m,5H),3.45-3.49(m,4H),2.35(s,3H),2.14-2.40(m, 2H).
Test example: therapeutic action of Compounds of the invention on hepatic fibrosis
Selecting SPF male SD rat (body mass 200 + -20 g)52, reserving 10 for control, and injecting 50% CCl subcutaneously into the rest rats4(1: 1 mixing with olive oil) 2ml/kg of the dilution, and the control group was given the same volume of olive oil 2 times per week for 8 consecutive weeks. After 8 weeks, 2 rats were killed by cervical dislocation after anesthesia, and the right liver tissue was taken for pathological section examination, and the rat liver cells were swollen, part of the liver cells were denatured and necrotic, fibrous connective tissue was proliferated, and the liver tissue was divided into a wide range of pseudolobules by the proliferated fibrous tissue, suggesting success of molding.
40 successfully modeled rats were randomly divided into a model group and an administration group (compound 1 group, compound 4 group and compound 5 group) according to body mass, 10 rats in each group were injected with the corresponding drug 1 time/d subcutaneously for 4 weeks, the administration dose was 30mg/kg, the control group and the model group were administered with the same volume of physiological saline, after 12 hours of the last administration, the rats were sacrificed by cervical dislocation after anesthesia, the left lobe of the liver was taken, a proper amount of liver tissue was weighed, 9 times the volume of physiological saline was added, mechanical homogenization was carried out in ice bath at 4 ℃, 3000r/min, centrifugation was carried out for 10min, and then the supernatant was taken for use, expression of TGF- β 1 and α -SMA mRNA was measured by RT-PCR, GAPDH was used as an internal reference, and the primer sequences are shown in table 1.
TABLE 1 RT-PCR primer sequences
In addition, the right liver lobe of the rat was fixed and embedded, stained with hematoxylin-eosin and Masson fiber collagen, followed by histopathological examination of the liver, and liver fibrosis was graded according to the pathological diagnosis standard for western' an national viral hepatitis in 2000. Liver fibrosis is divided into 5 stages: 1. normal tissue, with a very small amount of normal fibrous connective tissue in the zone of the sink, score 0; 2. collagen fibers around the central veins and the areas of the venules are proliferated, a small amount of fiber bundles extend from the central veins and the portal veins of the venules, no fiber intervals are formed, and the structure of the venules is still preserved for 1 minute; 3. fibers of the central venous region and the portal venous region extend to the periphery to form incomplete intervals, most of leaflet structures are preserved for 2 minutes; 4. a large amount of collagen fibers are proliferated, a small amount of thin collagen fibers are formed at complete intervals, and the leaflet structure is damaged by 3 minutes; 5. thickening at full intervals, pseudolobules formation, 4 points.
As a result:
1. RT-PCR result analysis shows that the expression of TGF- β 1 and α -SMA of the model group rats is obviously increased compared with the normal group, and the expression of TGF- β 1 and α -SMA can be obviously reduced and CCl is obviously slowed down after 4 weeks of administration of the compound 1 group, the compound 4 group and the compound 5 group compared with the model group4Hepatic fibrosis model rat liver injury process.
TABLE 2 Effect on rat TGF- β 1, α -SMA expression
Note: a: relative expression, calculating the relative expression of the rest groups with the measured value of the model group as 1.00;
in comparison with the normal group,*P<0.01，**P<0.005; in comparison to the set of models,#P<0.01，##P<0.005
2. the grading result of the hepatic fibrosis degree shows that the hepatic fibrosis degree and grading of the model group are obviously increased compared with those of the normal group; compared with the model group, after the compound 1 group, the compound 4 group and the compound 5 group are administrated for 4 weeks, the degree and grading of hepatic fibrosis can be obviously relieved, and the compound provided by the invention has a good treatment effect after being treated for 4 weeks.
TABLE 3 Effect on hepatic fibrosis staging scores in rats
Note: a: compared to the normal group; b: compared with model group
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (10)
1. A compound of formula I, a stereoisomer, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof:
in formula I:
R1selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;
Ra、Rbeach independently selected from C1-C6 alkyl, C1-4 alkoxy C1-C4 alkyl, C1-4 alkylamino C1-4 alkyl, di (C1-4 alkyl) amino C1-4 alkyl, or Ra、RbTogether with the N atom to which they are attached form a 5 or 6 membered heterocycloalkyl;
R2-R5each independently selected from hydrogen, halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, and C6-C14 aryl, wherein the C6-C14 aryl is optionally substituted by one or more of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkylamino.
2. A compound of claim 1, wherein R isa、RbEach independently selected from C1-C4 alkyl。
3. A compound of claim 1, wherein R isaSelected from C1-C6 alkyl, said RbSelected from C1-4 alkylamino C1-4 alkyl, di (C1-4 alkyl) amino C1-4 alkyl.
4. A compound of claim 1, wherein R isa、RbTogether with the N atom to which they are attached form a piperidinyl or morpholinyl group.
5. A compound of claim 1, wherein R is2-R5Each independently selected from hydrogen, halogen, nitro, C1-C6 alkyl.
6. The compound of claim 1, wherein the compound is selected from the group consisting of:
7. a pharmaceutical composition comprising a compound of formula I according to claim 1, a stereoisomer, a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable adjuvant, carrier or excipient.
8. Use of a compound of formula I according to claim 1, a stereoisomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof, for the preparation of a medicament for the treatment of liver fibrosis.
9. A process for the preparation of a compound of formula I according to claim 1, characterized in that it comprises:
step 1
Reacting the compound shown in the formula II with trimethylsilyl acetylene in the presence of organic base, a palladium catalyst and a copper catalyst to obtain a compound shown in the formula III;
step 2
Reacting a compound shown in a formula III with a compound shown in a formula IV in the presence of an organic base, a palladium catalyst and a copper catalyst to obtain a compound shown in a formula V;
step 3
Hydrolyzing the compound of formula V in the presence of a base to a compound of formula VI;
step 4
Reacting a compound represented by formula VI with a compound represented by formula VII in the presence of a base and a condensing agent to obtain a compound represented by formula I;
wherein R is selected from C1-4 alkyl, and X is selected from chlorine or bromine.
10. The method of claim 9, wherein the organic base in steps 1 and 2 comprises triethylamine, trimethylamine, diisopropylethylamine, pyridine,
the palladium catalyst of steps 1 and 2 comprises PdCl2、Pd(PPh3)4、Pd(PPh3)2Cl2，
The copper catalyst in the steps 1 and 2 comprises CuI, CuCl and Cu2O，
The alkali in the step 3 comprises NaOH, KOH, NaOMe, NaOEt, KOMe and KOEt,
the base in step 4 comprises Na2CO3、K2CO3Triethylamine, trimethylamine, diisopropylethylamine, pyridine,
the condensing agent in the step 4 comprises PyBOP, PyAOP, HBTU and TBTU.
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| US8975247B2 (en) * | 2009-03-18 | 2015-03-10 | The Board Of Trustees Of The Leland Stanford Junion University | Methods and compositions of treating a flaviviridae family viral infection |
| CN105801550A (en) * | 2009-11-05 | 2016-07-27 | 理森制药股份公司 | Novel benzopyran kinase modulators |
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| US8975247B2 (en) * | 2009-03-18 | 2015-03-10 | The Board Of Trustees Of The Leland Stanford Junion University | Methods and compositions of treating a flaviviridae family viral infection |
| CN105801550A (en) * | 2009-11-05 | 2016-07-27 | 理森制药股份公司 | Novel benzopyran kinase modulators |
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