CN106432159A - Novel benzofuran derivative as well as preparation method and application thereof - Google Patents
Novel benzofuran derivative as well as preparation method and application thereof Download PDFInfo
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- CN106432159A CN106432159A CN201610553240.3A CN201610553240A CN106432159A CN 106432159 A CN106432159 A CN 106432159A CN 201610553240 A CN201610553240 A CN 201610553240A CN 106432159 A CN106432159 A CN 106432159A
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- butyl
- compound shown
- methanesulfonamido
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- benzoyl
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- 0 CCCCC(C1C2CC1)=Cc1c2ccc(*)c1 Chemical compound CCCCC(C1C2CC1)=Cc1c2ccc(*)c1 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
Abstract
The invention belongs to the field of medicines, and in particular relates to a novel benzofuran derivative or a pharmaceutical salt thereof, a preparation method of the derivative, a medicinal composition containing the derivative, and application of the derivative and the medicinal composition in preparing anti-arrhythmia agents and treating related diseases.
Description
Technical field
The invention belongs to field of medicaments, specifically, the present invention relates to benzofuran derivative or its officinal salt, institute
The preparation method stating derivative, the pharmaceutical composition comprising described derivative and described derivative and pharmaceutical composition are in system
Purposes in standby antiarrhythmic drug and therapy-related disease.
Background technology
Amiodarone belongs to benzofuran derivative, for the prophylactic treatment of VA, auricular fibrillation etc., as
Antiarrhythmic drug is applied to more than 40 years of clinic.Due to containing 2 atomic iodine in amiodarone molecular structure, account for it and relatively divide
The 37.2% of protonatomic mass, after treating 2~3 months, dysthyreosis in about 5%~28% patient.Amiodarone is long-term
Medication occurs the risk of bad reaction to increase, wherein most commonly seen with pulmonary toxicity, and incidence is 1%~17%, how to use continuous
Interstitial pneumonia or hylactic pneumonia occurred after 3~December of medicine.
Amiodarone, dronedarone and go butyl dronedarone structure as follows:
Dronedarone (Dronedarone, SR33589) is the anti-rhythm of the heart of III class of French Sanofi-Aventis company exploitation
Not normal medicine, on July 1st, 2009 ratifies listing in the U.S., and December 16 in 2009 Huo European Union EMEA approval is it is adaptable to atrial fibrillation
(AF) and auricular flutter disease (AFL) patient the rhythm of the heart control, maintain sinus rhythm and slow down ventricular rhythm, clinic is mainly used in controlling
Treat arrhythmia cordis.Dronedarone is the derivative of the structure benzofuran similar with amiodarone (Amiodarone), has and amine
As iodine ketone, electro physiology effect, eliminates the toxic and side effect of iodine simultaneously, improves pharmacokinetics.But compared with amiodarone
Dronedarone and go butyl dronedarone negative inotropic action stronger, increased Patients with Cardiac Failure and organic heart disease people uses
The death rate, and list after serious hepatic disorder occurs.
Patent in our company's application《Benzofuran derivative, its preparation method and application》(application number:
201410267113.8) describe series of new benzofuran derivative in, water-soluble, metabolic stability is better than certainly how reaching
Grand, and action intensity is better than amiodarone.We are modified further to compound structure on this basis, result of study table
Bright, compound antiarrhythmic effect of the present invention is better than amiodarone, and vitro stability is better than dronedarone, and heart is born
Property myodyamia effect is suitable with amiodarone, is significantly better than dronedarone, is expected to become the new anti-heart having validity and security concurrently
Rule market medicine.
Content of the invention
First purpose of the present invention there are provided benzofuran derivative or its officinal salt representated by formula I:
Wherein:
R1 and R2 independence selected from H, halogen, alkyl, alkoxyl, trifluoro ethoxy, methanesulfonamido;
A is the alkyl or cycloalkyl containing N;
N is 1~4;
Preferably, R1It is selected from:The tert-butyl group or methanesulfonamido, R2For H.
Preferably, group A is selected from:Diethylamine, dibutyl amine or cyclopropylamine.
Preferably, n is selected from 2 or 3.
The salt of benzofuran derivative of the present invention, be above-mentioned structure shown in formula I benzofuran derivative with organic
Acid or salt formed by inorganic acid.
Compound representated by formula I can form pharmaceutical salts, such as sulfate, phosphate, hydrochloride, hydrogen bromine with inorganic acid
Hydrochlorate;Can also with organic acid formed pharmaceutical salts, for example acetate, oxalates, citrate, succinate, gluconate,
Tartrate, tosilate, benzene sulfonate, mesylate, benzoate, lactate, maleate, fumarate etc..
It is preferably hydrochloride.
It is further preferred that the compounds of this invention is:
2- butyl -3- [3- methanesulfonamido -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- methylsulfonyl ammonia
Base benzofuran hydrochloride (I 1);
2- butyl -3- [3- methanesulfonamido -4- [2- (diethylamino) ethyoxyl] benzoyl] -5- methanesulfonamido
Benzofuran hydrochloride (I 2);
2- butyl -3- [the 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- methanesulfonamido benzene
And furans hydrochloride (I 3);
2- butyl -3- [the 3- tert-butyl group -4- [2- (diethylamino) ethyoxyl] benzoyl] -5- methanesulfonamido benzo
Furans hydrochloride (I 4);
2- butyl -3- [the 3- tert-butyl group -4- [3- (piperidin-1-yl) propoxyl group] benzoyl] -5- methanesulfonamido benzo
Furans hydrochloride (I 5);
2- butyl -3- [3,5- di-t-butyl -4- [3- (piperidin-1-yl) propoxyl group] benzoyl] -5- methanesulfonamido
Benzofuran hydrochloride (I 6).
Above-claimed cpd, its corresponding structural formula is as follows:
Second object of the present invention is the system of benzofuran derivative representated by offer formula I or its officinal salt
Preparation Method.
Preparation method of the present invention, comprises the following steps:
(1) compound shown in formula II and compound shown in formula III is made to react chemical combination shown in production IV in the basic conditions
Thing:
(2) compound shown in formula IV is made to pass through compound shown in hydrolysis production V:
(3) compound and oxalyl chloride shown in formula V is made to react compound shown in production VI:
(4) make compound shown in formula VI and compound shown in formula VII shown in production VIII in the presence of aluminum trichloride (anhydrous)
Compound:
(5) make the compound shown in substitution reaction production Ⅹ under proper condition of compound shown in formula Ⅸ:
(6) compound shown in formula Ⅹ and compound shown in formula III is made to react chemical combination shown in production VIII in the basic conditions
Thing:
(7) nitro making compound shown in formula VIII reduces compound shown in production Ⅺ:
(8) compound shown in formula Ⅺ and mesyl chloride is made to react compound shown in production I in the basic conditions:
Third object of the present invention is to provide a kind of pharmaceutical composition, containing representated by least one formula I
Benzofuran derivative or its officinal salt.
As needed, the pharmaceutical composition of the present invention can also add one or more pharmaceutically acceptable carrier or tax
Shape agent.
The pharmaceutical composition of the present invention, the benzofuran derivative representated by formula I or weight hundred shared by its officinal salt
Divide ratio can be 0.1-99.9%, remaining is pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention can be prepared into any pharmaceutically useful formulation, and these formulations include:Tablet, sugar coated tablet
Agent, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, mouth containing agent, granule, electuary,
Pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, ointment, emplastrum, creme, spray,
Drops, patch.The preparation of the present invention, preferably peroral dosage form, such as:Capsule, tablet, oral liquid, granule, pill, dissipate
Agent, sublimed preparation, paste etc..
Method of administration of the present invention can be administered orally, non-bowel or local be administered, preferred oral and injection form administration.It is suitable to
Medicinal oral Preparation can be tablet, capsule, granule or other be suitable to medicinal liquid form preparation such as solution,
Emulsion, suspending agent etc..Preferably oral formulations are tablets, and described tablet can be made coating, enteric, sustained release or quantitation and release
The form put.
The pharmaceutical composition of the present invention, the preparation of its oral administration can contain conventional excipient, such as adhesive, filling
Agent, diluent, tablet agent, lubricant, disintegrant, colouring agent, flavor enhancement and wetting agent, can be coated to tablet if necessary.
Applicable filler includes cellulose, mannitol, lactose and other similar fillers.Suitable disintegrant bag
Include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycollate.Suitable lubricant includes, for example firmly
Fatty acid magnesium.Suitable pharmaceutically acceptable wetting agent includes lauryl sodium sulfate.
Can be by mixing, filling, the method that compressing tablet etc. is commonly used prepares solid oral composition.Repeatedly mixed and can be made work
Property material be distributed in those compositions entirely using a large amount of fillers.
The form of oral liquid can be for example aqueous or oily suspensions, solution, emulsion, syrup or elixir,
Or can be a kind of dry products that can be compounded with water or other suitable carrier before use.This liquid preparation can contain
Conventional additive, such as suspending agent, such as sorbierite, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl are fine
Dimension element, aluminium stearate gel or hydrogenated edible fats, emulsifying agent, such as lecithin, anhydro sorbitol monooleate or Arab
Glue;Non-aqueous carrier (they can include edible oil), such as apricot kernel oil, fractionated coconut oil, the oily ester of the ester of such as glycerine,
Propane diols or ethanol;Preservative, such as para hydroxybenzene methyl esters or propylparaben or sorbic acid, and if necessary,
Conventional flavouring agent or colouring agent can be contained.
For injection, the fluid unit dosage form of preparation contains active material and the sterile carrier of the present invention.According to carrier
And concentration, this compound can be suspended or dissolve.The preparation of solution is dissolved in a kind of load typically by by active material
In body, filter sterilization before being loaded into a kind of suitable bottle or ampoule, then seal.For example a kind of local anaesthesia of auxiliary material
Agent, preservative and buffer can also be dissolved in this carrier.In order to improve its stability, can be by this after loading bottle
Plant composition frost, and under vacuo water is removed.
The pharmaceutical composition of the present invention, optionally adds suitable pharmaceutically acceptable load when being prepared into medicament
Body, described pharmaceutically acceptable carrier is selected from:Mannitol, sorbierite, sodium pyrosulfite, sodium hydrogensulfite, sodium thiosulfate, salt
Sour cysteine, TGA, methionine, injection Vitamin B_6 DTA disodium, Ethylenediaminetetraacetic Acid Calcium Salt, the alkali-metal carbonate of monovalence, acetic acid
Salt, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, wheat
Bud sugar, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and its
Derivative, alginates, gelatin, polyvinylpyrrolidone, glycerine, POLYSORBATE 80, agar, calcium carbonate, calcium bicarbonate, surface-active
Agent, polyethylene glycol, cyclodextrin, beta-schardinger dextrin, phospholipid material, kaolin, talcum powder, calcium stearate, magnesium stearate etc..
The compounds of this invention or its officinal salt can be with independent or administrations in the form of pharmaceutical composition.Medicine group of the present invention
Compound can be made into various suitable dosage forms according to method of administration.Using one or more physiologically acceptable carrier, comprise to assign
Shape agent and auxiliary agent, they are conducive to for reactive compound being processed into the preparation that can pharmaceutically use.Suitable dosage form
Depending on selected method of administration, can be prepared according to general knowledge well known in the art.
Fourth object of the present invention is to provide benzofuran derivative or its officinal salt preparing anti-rhythm of the heart mistake
Application in normal medicine.
5th purpose of the present invention is to provide using benzofuran derivative or its officinal salt as active component
Application in preparing antiarrhythmic medicine for the pharmaceutical composition.
Related indication corresponding to arrhythmia cordis of the present invention includes:Paroxysmal or permanent atrial fibrillation (AF) or
Auricular flutter (AFL), recent AF/AFL outbreak, with cardiovascular risk disease (include hypertension, diabetes, previously cardiovascular unexpected,
Atrium sinistrum diameter >=50mm or left ventricular ejection fraction [LVEF]<40%), sinus rhythm or the rhythm of the heart can conversion disease or a combination thereofs.
Benzofuran derivative of the present invention or its officinal salt, its water solubility is substantially better than how hydrochloric acid certainly reaches
Grand, and vitro stability and antiarrhythmic effect are superior to dronedarone hydrochloride.In addition, medicine of the present invention is more steady
Fixed, side effect is less, and quality is relatively reliable.
Brief description
Fig. 1 is the action diagram to guinea pig isolated heart convergent force for the medicine
Fig. 2 is the impact figure to ouabain arrhythmogenic effect dosage for the medicine
Specific embodiment
Below by specific embodiment, technical scheme is further described, the enforcement wherein enumerating
Example is the description of the invention, and limits its protection domain never in any form.
Embodiment 1 2- butyl -3- [3- methanesulfonamido -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5-
Methanesulfonamido benzofuran (I 1)
Step 1:2- butyl -3- (3- nitro -4- hydroxy benzoyl) -5- nitrobenzofuran
2- butyl -3- (4- hydroxy benzoyl) -5- nitrobenzofuran (5.00g, 14.7mmol) is dissolved in 100mL bis-
In chloromethanes, drip red fuming nitric acid (RFNA) (5ml, 72.5mmol), room temperature reaction 40min, add water and dichloromethane extraction, dichloromethane phase
Concentrate, obtain yellow solid 5.5g, yield 97%.
Step 2:2- butyl -3- [3- nitro -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- nitro benzo
Furans
2- butyl -3- (3- nitro -4- hydroxy benzoyl) -5- nitrobenzofuran (5.0g, 13.0mmol) is added
In 150ml acetonitrile, add potassium carbonate (7.18g, 52.0mmol) and KI (1.22g, 7.37mmol), be heated to reflux 20min,
Add N- (3- chloropropyl) di-n-butylamine (8.03g, 39.0mmol), back flow reaction 12h, reactant liquor is cooled to room temperature, filter, filter
Cake is washed with a small amount of acetonitrile, and filtrate is concentrated, and residue is through silica gel column separating purification (eluant, eluent, petroleum ether: ethyl acetate=10
: 1, v: v), obtain 5.62g faint yellow solid, yield is 78%.
Step 3:2- butyl -3- [3- amino -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- amino benzo
Furans
By 2- butyl -3- [3- nitro -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- nitrobenzofuran
(0.50g, 1.30mmol) is dissolved in 50ml methyl alcohol, adds 0.13g palladium carbon, by reaction system charge and discharge hydrogen three times, in logical hydrogen
Under the conditions of room temperature reaction 6h.By reacting liquid filtering, filter cake is washed with a small amount of methyl alcohol, and filtrate concentrates, and obtains yellow oily liquid
0.46g, yield 98%.
Step 4:2- butyl -3- [3- methanesulfonamido -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- first
Sulfonamido benzofuran
By 2- butyl -3- [3- amino -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- aminobenzofur
(0.48g, 1.02mmol) is dissolved in 20ml dichloromethane, adds sodium acid carbonate (0.26g, 3.05mmol), in the condition of stirring
Under be slowly added to the dichloromethane solution of mesyl chloride (0.22g, 1.52mmol), react 6h under room temperature.By reactant liquor water
(30ml × 2) wash, organic layer anhydrous sodium sulfate drying, filter, concentrate, residue through silica gel column separating purification (eluant, eluent,
Dichloromethane: methyl alcohol=50: 1, v: v), obtain 0.43g faint yellow solid, yield is 76%, LC-MS:m/z 650.3[M+H]+.
Step 5:2- butyl -3- [3- methanesulfonamido -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- first
Sulfonamido benzofuran hydrochloride (I 1)
By 2- butyl -3- [3- methanesulfonamido -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- methylsulfonyl
Aminobenzofur (0.65g, 1.0mmol) is dissolved in 10ml acetonitrile, the hydrochloric acid solution 0.35ml of dropping 3mol/L, stirs under room temperature
Mix 30min, reactant liquor reduced pressure concentration is obtained 0.68g light yellow solid, yield is 99%, LC-MS:m/z 650.3[M+H]+.
1H NMR(400MHz,DMSO-d6):δ=0.81 (t, J=7.2Hz, 3H), 0.93 (t, J=7.6Hz, 6H), 1.23
(q, J=7.6Hz, 2H), 1.35 (q, J=7.2Hz, 4H), 1.65-1.67 (m, 6H), 2.18 (s, 2H), 2.81 (t, J=
7.2Hz, 2H), 2.89 (s, 3H), 2.99 (s, 3H), 3.08 (s, 4H), 4.24 (s, 2H), 7.22 (d, J=8.4Hz, 2H),
7.32 (s, 1H), 7.63 (d, J=8.8Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.74 (s, 1H), 9.17 (s, 1H), 9.61
(s, 1H), 9.83 (s, 1H).
Embodiment 2 2- butyl -3- [3- methanesulfonamido -4- [2- (diethylamino) ethyoxyl] benzoyl] -5- first
Sulfonamido benzofuran hydrochloride (I 2)
Replace N- (3- chloropropyl) di-n-butylamine as raw material with 2- chloroethyl diethylamine, synthetic method is with described in embodiment 1
The preparation method of compound, LC-MS:m/z 580.2[M+H]+.
1H NMR(400MHz,DMSO-d6):δ=0.81 (t, J=7.2Hz, 3H), 1.19-1.29 (m, 9H), 1.62-
1.69 (m, 2H), 2.82 (t, J=7.2Hz, 2H), 2.90 (s, 3H), 3.02 (s, 3H), 3.27 (t, J=7.2Hz, 2H), 3.61
(s, 2H), 4.48 (s, 2H), 7.21 (d, J=8.8Hz, 1H), 7.27 (d, J=8.8Hz, 1H), 7.31 (s, 1H), 7.63 (d, J
=8.8Hz, 1H), 7.69 (d, J=8.0Hz, 1H), 7.79 (s, 1H), 9.22 (s, 1H), 9.61 (s, 1H), 9.80 (s, 1H).
Embodiment 3 2- butyl -3- [the 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- first sulphur
Acylamino- benzofuran (I 3)
Step 1:3- tertiary butyl-4-hydroxy benzoic acid
3,5- di-tert-butyl-4-hydroxybenzoic acid (10.0g, 40mmol) is added in 100mL dichloromethane, is dividedly in some parts
Alchlor (7.86g, 60mmol), is heated to 35 DEG C of reaction 1.5h, and water quenching on the rocks is gone out, point liquid, and organic phase concentrates, and obtains 7.5g light
Yellow solid, yield 96%.
Step 2:3- tertiary butyl-4-hydroxy methyl benzoate
3- tertiary butyl-4-hydroxy benzoic acid (4.0g, 21mmol) is dissolved in 100ml methyl alcohol, drips thionyl chloride
(12.0g, 100mmol), is heated to reflux 2h.Reactant liquor is cooled to room temperature, is evaporated to thick solid, plus a small amount of methyl alcohol is dilute
Release, add water, filter, filter cake is washed with a small amount, and dries, and obtains 4.2g white solid, yield 97%.
Step 3:The 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] methyl benzoate
According to the method described in step 2 in embodiment 1, simply by 2- butyl -3- (3- nitro -4- hydroxy benzoyl) -
5- nitrobenzofuran is changed to 3- tertiary butyl-4-hydroxy methyl benzoate, and yield is 60%.
Step 4:The 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] benzoic acid
The 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] methyl benzoate (2.0g, 5.3mmol) is dissolved in 20mL
In methyl alcohol, add 60mL NaOH (3M) solution, 2h is stirred at room temperature, adjust pH value to 4~5 with 3N hydrochloric acid solution, add second
Acetoacetic ester extracts (80mL*3), point liquid, and organic phase anhydrous sodium sulfate drying is concentrated to dryness, obtains light yellow solid 1.83g, receives
Rate 95%.
Step 5:The 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] chlorobenzoyl chloride
By the 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] benzoic acid (1.0g, 2.75mmol), it is dissolved in 50ml
In dichloromethane, add oxalyl chloride (1.0g, 8.0mmol) and 2~3 DMF catalysis, reaction 1h is stirred at room temperature, system is reduced pressure
Concentrate, obtain white solid 1.1g, yield 100%.
Step 6:2- butyl -3- [the 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- nitrobenzene
And furans
2- butyl -5- nitrobenzofuran (0.67g, 3.05mmol) is dissolved in 50ml dichloromethane, ice bath is cooled to 0
DEG C, add the 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] chlorobenzoyl chloride (1.2g, 3.05mmol) and anhydrous tri-chlorination
Aluminium (0.61g, 4.58mmol), reacts 17h under room temperature.Reactant mixture is added in 100ml water, point liquid, organic layer water
(50ml × 2) wash, anhydrous sodium sulfate drying, filter, and concentrate, silica gel post separation (eluant, eluent, dichloromethane:Methyl alcohol=20:1,
v:V), obtain yellow oily liquid 0.95g, yield is 54%.
Step 7:2- butyl -3- [the 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- aminobenzene
And furans
According to the method described in step 3 in embodiment 1, simply by 2- butyl -3- [3- nitro -4- [3- (di-n-butyl ammonia
Base) propoxyl group] benzoyl] -5- nitrobenzofuran is changed to 2- butyl -3- [the 3- tert-butyl group -4- [3- (di-n-butyl amino)
Propoxyl group] benzoyl] -5- nitrobenzofuran, yield is 99%.
Step 8:2- butyl -3- [the 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- methylsulfonyl
Aminobenzofur
According to the method described in step 4 in embodiment 1, simply by 2- butyl -3- [3- amino -4- [3- (di-n-butyl ammonia
Base) propoxyl group] benzoyl] -5- aminobenzofur is changed to 2- butyl -3- [the 3- tert-butyl group -4- [3- (di-n-butyl amino)
Propoxyl group] benzoyl] -5- aminobenzofur, yield is 83%, LC-MS:m/z 613.4[M+H]+.
Step 9:2- butyl -3- [3- methanesulfonamido -4- [2- (diethylamino) ethyoxyl] benzoyl] -5- first sulphur
Acylamino- benzofuran hydrochloride (I 3)
According to the method described in step 5 in embodiment 1, simply by 2- butyl -3-, [[(two just for 3- for 3- methanesulfonamido -4-
Butylamino) propoxyl group] benzoyl] -5- methanesulfonamido benzofuran is changed to 2- butyl -3- [the 3- tert-butyl group -4- [3- (two
N-butylamino) propoxyl group] benzoyl] -5- methanesulfonamido benzofuran, yield 100%, LC-MS:m/z 613.4[M+
H]+.
1H NMR(400MHz,DMSO-d6):δ=0.81 (t, J=7.2Hz, 3H), 0.93 (t, J=7.6Hz, 6H), 1.23
(q, J=7.6Hz, 2H), 1.35 (q, J=7.2Hz, 4H), 1.37 (s, 9H), 1.65-1.67 (m, 6H), 2.18 (s, 2H),
2.81 (t, J=7.2Hz, 2H), 2.89 (s, 3H), 3.08 (s, 4H), 4.24 (s, 2H), 7.22 (d, J=8.4 Hz, 2H),
7.32 (s, 1H), 7.63 (d, J=8.8Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.74 (s, 1H), 9.61 (s, 1H), 9.83
(s,1H).
Embodiment 4 2- butyl -3- [the 3- tert-butyl group -4- [2- (diethylamino) ethyoxyl] benzoyl] -5- methylsulfonyl
Aminobenzofur hydrochloride (I 4)
Replace N- (3- chloropropyl) di-n-butylamine as raw material with 2- chloroethyl diethylamine, synthetic method is with described in embodiment 3
The preparation method of compound, LC-MS:m/z 543.3[M+H]+.
1H NMR(400MHz,DMSO-d6):δ=0.81 (t, J=7.2Hz, 3H), 1.19-1.29 (m, 9H), 1.35 (s,
9H), 1.62-1.69 (m, 2H), 2.82 (t, J=7.2Hz, 2H), 3.02 (s, 3H), 3.27 (t, J=7.2Hz, 2H), 3.61
(s, 2H), 4.48 (s, 2H), 7.21 (d, J=8.8Hz, 1H), 7.27 (d, J=8.8Hz, 1H), 7.31 (s, 1H), 7.63 (d, J
=8.8Hz, 1H), 7.69 (d, J=8.0Hz, 1H), 7.79 (s, 1H), 9.61 (s, 1H), 9.80 (s, 1H).
Embodiment 5 2- butyl -3- [the 3- tert-butyl group -4- [3- (piperidin-1-yl) propoxyl group] benzoyl] -5- methylsulfonyl
Aminobenzofur hydrochloride (I 5)
Replace N- (3- chloropropyl) di-n-butylamine as raw material with N- (3- chloropropyl) piperidines, synthetic method is with embodiment 3 institute
State the preparation method of compound, LC-MS:m/z 569.3[M+H]+.
1H NMR(400MHz,DMSO-d6):δ=0.80 (t, J=7.2Hz, 3H), 1.23 (q, J=7.6Hz, 2H), 1.36
(s, 9H), 1.65-1.81 (m, 7H), 2.28 (s, 2H), 2.80 (t, J=7.2Hz, 2H), 2.89 (s, 3H), 2.92 (s, 2H),
(3.18 s, 2H), 3.35 (s, 2H), 4.21 (t, J=6.4Hz, 2H), 7.13 (d, J=8.4Hz, 1H), 7.21 (d, J=
8.4Hz, 1H), 7.30 (s, 1H), 7.63 (d, J=8.8Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.74 (s, 1H), 9.61
(s, 1H), 9.83 (s, 1H).
Embodiment 6 2- butyl -3- [3,5- di-t-butyl -4- [3- (piperidin-1-yl) propoxyl group] benzoyl] -5- first
Sulfonamido benzofuran hydrochloride (I 6)
Replace 3- tertiary butyl-4-hydroxy benzoic acid for raw material with 3,5- di-tert-butyl-4-hydroxybenzoic acid, synthetic method is same
The preparation method of compound, LC-MS described in embodiment 5:m/z 625.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ=0.80 (t, J=7.2Hz, 3H), 1.23 (q, J=7.6Hz, 2H), 1.36
(s, 18H), 1.65-1.81 (m, 7H), 2.28 (s, 2H), 2.80 (t, J=7.2Hz, 2H), 2.89 (s, 3H), 2.92 (s, 2H),
3.18 (s, 2H), 3.35 (s, 2H), 4.21 (t, J=6.4Hz, 2H), 7.13 (d, J=8.4Hz, 1H), 7.21 (d, J=
8.4Hz, 1H), 7.30 (s, 1H), 7.70 (s, 2H), 9.61 (s, 1H), 9.83 (s, 1H).
Test case
Biological assessment
The inhibitory action to hERG potassium channel for test case 1 the compounds of this invention
Experimental procedure:
(1) cell (recombinant HEK 293 cell system expression people hERG (ether-a-go-go related gene) collected
Potassium channel) suspension is placed in cell pool, every 30s pressure-vaccum cell once, to avoid cell settlement or agglomerating.Mechanical arm is automatically injected
Intracellular fluid, cell suspension is simultaneously injected sealing-in chip by extracellular fluid.Cell is attached on hole under negative pressure must attract at random, so
Pass through the rupture of diaphragm that suction makes to be attached on hole afterwards, form whole-cell recording technique pattern.
(2) Whole-cell recording completes according to the standardization program that patchmaster formulates.When whole-cell recording technique is stable
After start administration (experimental group be the compounds of this invention;Control group is amiodarone), each drug concentration acts on and detecting to after stablize
Next concentration, independent 3 cells of duplicate detection during recording.
(3) Whole-cell recording full cell hERG potassium current recording method is as follows:Clamping voltages remove best by -80mV
+ 40mV maintains 500 milliseconds, is then maintained at rapidly -40mV and maintains 500 milliseconds, records tail current, and every 10 seconds repeated acquisition
Data.Data is acquired and is stored in PatchMaster software by HEKA EPC-10Quatro amplifier.
All electro physiology are tested all at room temperature (25 DEG C).
Quality control:
(1), in the whole process tested, the following standard side of all data fit is adopted:
(2) sealing-in resistance Rseal before rupture of membranes in whole experiment>1GΩ.
(3) current attenuation is less than 1%/min in negative control group
(4) leakage current is less than 100pA.
(5) series resistance Rs in whole experiment<20MΩ.
(6) before being administered, electric current is more than 400pA.
Data analysis:
(1) all data are represented with the means standard deviation of n cell.
(2) standardized current amplitude is fitted by below equation:1(1-(c(IC50)-1)h)-1.In equation, c is
Drug concentration, IC50For the drug concentration of ceiling effect 50%, h is hill coefficient.Nanion Technologies is passed through in matching
The software for data analysis integrated completes.
Experimental result:
Compound of the present invention is detected according to as above scheme, and result is shown in following table, wherein:
A represents that IC50 exists>In the range of 10 μM;
B represents IC50 in the range of 1 μM -10 μM;
C represents IC50 in the range of 0 μM -1 μM
Following table summarizes the inhibitory action to hERG potassium channel for the compound.
Compound | hERG IC50(nM) |
Amiodarone | C |
I 1 | C |
I 2 | C |
I 3 | C |
I 4 | B |
I 5 | B |
I 6 | B |
The effect to guinea pig isolated heart convergent force for test case 2 compound of the present invention
Dronedarone, amiodarone belongs to Group III antiarrhythmic drug, and amiodarone class medicine is for the ion channel of heart
There is extensive inhibitory action, document report dronedarone and amiodarone all can suppress cardiac sodium channel with concentration dependent,
Calcium channel, and multiple potassium channel, such as IKr, IKs, Ito, IK1 etc..Document report dronedarone has negative inotropic action,
Have a strong impact on the Clinical practice scope of dronedarone.
In this research, we utilize langendorff Perfused isolated heart technology, detect compound of the present invention and amine
The negative inotropic action to heart of iodine ketone and dronedarone.Thus evaluate and relatively compound of the present invention and amiodarone and
The difference that dronedarone affects on normal isolated myocardium convergent force.
Experimental procedure:
Cavy body weight 350-400g, male and female do not limit.Lumbar injection yellow Jackets (30mg kg-1), heparin (250u
kg-1).Anesthesia come into force after, first cut off abdominal cavity, then cut off thoracic cavity through diaphram in thoracic cavity both sides, haemostatic clamp clamps front wall, turn over to
Head, completely reveals heart, gently pinches base of heart (as far as possible avoiding extruding heart) with thumb and forefinger, gently lifts, cut
Heart, retains longer sustainer as far as possible.Heart is put rapidly in the cleaning fluid of room temperature (18-22 DEG C), rapid row aorta is inserted
Pipe, recovers coronary artery perfusion.Heart overhangs on Langendorff perfusion device, with 60mmHg pressure row heart perfusion retrogradely.Fill
The Krebs-Henseleit buffer solution that flow liquid closes for oxygen, temperature is maintained at 37 DEG C.An osculum is cut at atrium sinistrum, will be with breast
The pressure-measuring pipe of glue capsule inserts left ventricle through mitral orifice, connects pressure transducer, and regulation intracapsular pressure is 10mmHg.
MedLab3000 physiological signal collection analysis system record left ventricular pressure power changes, and analysis obtains left ventricular contraction pressure
(left ventricular systolic pressure, LVSP, unit mmHg), left ventricular end-diastolic pressure (left
Ventricular end-diastolic pressure, LVEDP, unit mmHg), maximal ascending rate of internal pressure of left ventricle (+
Dp/dtmax, unit mmHg/s), maximal descending rate of internal (- dp/dtmax, unit mmHg/s) and heart rate (heart
Rate, HR, unit beats/s) etc. data.Administration after stablizing 20 minutes (compound of the present invention, amiodarone and certainly how to reach
Grand), each concentration is administered at least 40 minutes, heart left chamber systolic pressure and maximum climbing speed, the diastole of left room before and after record administration
The end of term presses, systolic pressure, the change of diastolic pressure.
Experimental result:
Under 1 μM of mass action, compound of the present invention is minimum to the negative inotropic action of guinea pig myocardium convergent force, with amine
Quite, dronedarone has significant negative inotropic action to iodine ketone.
The effect to guinea pig isolated heart convergent force for the medicine
By each group sample be administered after with administration before Control group data make than be standardized process after, column diagram is such as
Shown in Fig. 1.
Test case 3 compound causes the effect of rabbit arrhythmia model to ouabain
The purpose of this experiment is comparative studies compound of the present invention and intravenous amiodarone administration induces rabbit to ouabain
The effect of arrhythmia model, thus evaluate the antiarrhythmic effect of compound of the present invention.
Experimental procedure:
Fasting 12h before animal used as test experiment, free water, experiment concrete operations are as follows:
(1) rabbit is weighed, and 25% urethane is through auricular vein injecting anesthetic, and arranges venous detaining needle;
(2) rabbit lies on the back and is fixed on operating table;
(3) powerlab system record standard limbs II lead electrocardiogram (position is right fore, left hind, left hind);
(4) after continuous monitoring electrocardiogram 15min, amiodarone or test medicine 5ml are disposably injected by venous detaining needle,
Blank control group injects 5% glucose injection 5ml;
(5) after continuous monitoring electrocardiogram 30min, connect syringe pump, ouabain solution is continuously given in the way of drip-feed
Medicine, injection speed is 15 μ g/min (0.1ml/min);
(6) continuous monitoring electrocardiogram record VPB (VP), Ventricular Tachycardia (VT), ventricular fibrillation (VF) occur
And heartbeat stop time and ouabain consumption.
Experimental result:
The impact to ouabain arrhythmogenic effect dosage for the medicine
Compound | Dosage | VPB | Ventricular Tachycardia | Quiver in room |
Control group | - | 0.283±0.0346 | 0.349±0.0469 | 0.462±0.0415 |
I2 | 5mg/kg | 0.428±0.0620** | 0.543±0.0192 | 0.637±0.0426 |
Amiodarone | 15mg/kg | 0.413±0.0295*** | 0.47±0.0256* | 0.643±0.0302*** |
Dronedarone | 2mg/kg | 0.371±0.0662* | 0.576±0.0738 | 0.683±0.0822* |
*p<0.05,**p<0.01,***p<0.001, vs. control group
Compound of the present invention dramatically increases the dosage needed for ouabain leads to arrhythmia cordis to occur as seen from the above table,
Drug effect concentration is 5mg/kg, and effect is better than amiodarone.Its action intensity is as shown in Figure 2.
Due to being limited by application documents length, in above-mentioned experiment, the present invention only enumerates section Example as experiment
Medicine, but in fact, other compounds of the present invention also can obtain same or like effect.
Claims (10)
1. a kind of benzofuran derivative with general formula I or its officinal salt:
Wherein:
R1And R2Independent selected from H, halogen, alkyl, alkoxyl, trifluoro ethoxy, methanesulfonamido;
A is the alkyl or cycloalkyl containing N;
N is 1~4.
2. benzofuran derivative according to claim 1 or its officinal salt are it is characterised in that described group A
Selected from diethylamine, dibutyl amine or cyclopropylamine, n is selected from 2 or 3.
3. benzofuran derivative according to claim 1 or its officinal salt are it is characterised in that described R1It is selected from
The tert-butyl group or methanesulfonamido, R2For H.
4. according to any one of claim 1-3 benzofuran derivative or its officinal salt it is characterised in that described
Salt is benzofuran derivative and organic acid or the salt formed by inorganic acid of Formulas I structure.
5. benzofuran derivative according to claim 4 or its officinal salt are it is characterised in that described salt selects
From:Sulfate, disulfate, phosphate, hydrophosphate, hydrochloride, hydrobromate, acetate, oxalates, citrate, amber
Amber hydrochlorate, gluconate, tartrate, tosilate, benzene sulfonate, mesylate, benzoate, lactate, horse
Come hydrochlorate, fumarate, preferably hydrochloride.
6. benzofuran derivative according to claim 1 or its officinal salt are it is characterised in that described compound
It is selected from:
2- butyl -3- [3- methanesulfonamido -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- methanesulfonamido benzene
And furans hydrochloride (I 1);
2- butyl -3- [3- methanesulfonamido -4- [2- (diethylamino) ethyoxyl] benzoyl] -5- methanesulfonamido benzo
Furans hydrochloride (I 2);
2- butyl -3- [the 3- tert-butyl group -4- [3- (di-n-butyl amino) propoxyl group] benzoyl] -5- methanesulfonamido benzo furan
Mutter hydrochloride (I 3);
2- butyl -3- [the 3- tert-butyl group -4- [2- (diethylamino) ethyoxyl] benzoyl] -5- methanesulfonamido benzofuran
Hydrochloride (I 4);
2- butyl -3- [the 3- tert-butyl group -4- [3- (piperidin-1-yl) propoxyl group] benzoyl] -5- methanesulfonamido benzofuran
Hydrochloride (I 5);
2- butyl -3- [3,5- di-t-butyl -4- [3- (piperidin-1-yl) propoxyl group] benzoyl] -5- methanesulfonamido benzo
Furans hydrochloride (I 6).
7. the preparation method of the benzofuran derivative described in claim 1 or its officinal salt, comprises the following steps:
(1) compound shown in formula II and compound shown in formula III is made to react compound shown in production IV in the basic conditions:
(2) compound shown in formula IV is made to pass through compound shown in hydrolysis production V:
(3) compound and oxalyl chloride shown in formula V is made to react compound shown in production VI:
(4) compound shown in formula VI and the chemical combination shown in production VIII in the presence of aluminum trichloride (anhydrous) of compound shown in formula VII are made
Thing:
(5) make the compound shown in substitution reaction production Ⅹ under proper condition of compound shown in formula Ⅸ:
(6) compound shown in formula Ⅹ and compound shown in formula III is made to react compound shown in production VIII in the basic conditions:
(7) nitro making compound shown in formula VIII reduces compound shown in production Ⅺ:
(8) compound shown in formula Ⅺ and mesyl chloride is made to react compound shown in production I in the basic conditions:
8. a kind of pharmaceutical composition, using benzofuran derivative described in any one of claim 1-6 or its officinal salt as
Medicinal active ingredient.
9. the pharmaceutical composition described in claim 7, is adding one or more pharmaceutically acceptable carrier or excipient
After make any pharmaceutically useful formulation,
Wherein, pharmaceutically acceptable carrier is selected from:Mannitol, sorbierite, sodium pyrosulfite, sodium hydrogensulfite, thiosulfuric acid
Sodium, cysteine hydrochloride, TGA, methionine, injection Vitamin B_6 DTA disodium, Ethylenediaminetetraacetic Acid Calcium Salt, the alkali-metal carbonate of monovalence,
Acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, wood sugar
Alcohol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose
And its derivative, alginates, gelatin, polyvinylpyrrolidone, glycerine, POLYSORBATE 80, agar, calcium carbonate, calcium bicarbonate, surface work
Property agent, polyethylene glycol, cyclodextrin, beta-schardinger dextrin, phospholipid material, kaolin, talcum powder, calcium stearate, magnesium stearate;
Wherein, formulation includes:Tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule
Agent, oral liquid, mouth containing agent, granule, electuary, pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution, injection, bolt
Agent, ointment, emplastrum, creme, spray, drops, patch, preferably peroral dosage form, such as:Capsule, tablet, oral
Liquid, granule, pill, powder, sublimed preparation, paste.
10. benzofuran derivative described in any one of claim 1-7 or its officinal salt are preparing antiarrhythmic medicine
Application in thing.
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