WO2003091205A1 - Sulfamidophenylalkylamines, production et utilisation de ces dernieres - Google Patents

Sulfamidophenylalkylamines, production et utilisation de ces dernieres Download PDF

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Publication number
WO2003091205A1
WO2003091205A1 PCT/CN2002/000927 CN0200927W WO03091205A1 WO 2003091205 A1 WO2003091205 A1 WO 2003091205A1 CN 0200927 W CN0200927 W CN 0200927W WO 03091205 A1 WO03091205 A1 WO 03091205A1
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WO
WIPO (PCT)
Prior art keywords
methyl
alk
substituted
tetramethylene
ethylene
Prior art date
Application number
PCT/CN2002/000927
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English (en)
Chinese (zh)
Inventor
Hong Liu
Hualiang Jiang
Yiping Wang
Kaixian Chen
Ruyun Ji
Weikang Sun
Original Assignee
Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CNB021169012A external-priority patent/CN100358865C/zh
Application filed by Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority to AU2002357560A priority Critical patent/AU2002357560A1/en
Publication of WO2003091205A1 publication Critical patent/WO2003091205A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the invention relates to the fields of medicinal chemistry and medicinal therapy, in particular to the synthesis of sulfonamide benzamide compounds and their therapeutic use in cardiovascular diseases. Background technique
  • VT rapid ventricular tachycardia
  • VF ventricular fibrillation
  • SCD sudden cardiac death
  • Class I is a sodium channel blocker
  • Class II is a ⁇ -blocker
  • Class III is a potassium channel blocker
  • Class IV is a calcium channel blocker.
  • Class I, II, and IV drugs all have effects that reduce conduction velocity and even cause blockade. These effects can increase the likelihood of reentrant stimuli and thus induce arrhythmias.
  • Class III drugs are characterized by blocking potassium channels, and even highly selectively inhibiting Ikr.
  • the electrophysiological effects only prolong the action potential duration (APD) and effective refractory period (ERP) without slowing the intracardiac conduction velocity Increases the calcium inflow in the 2-phase plateau phase, so it has a mild positive muscle effect.
  • the prolonged effect often has reverse frequency / use dependence: slow heart rate, APD prolongs significantly; heart rate The fast APD prolongation decreases or even disappears. They are used clinically to treat life-threatening recurrent ventricular arrhythmias and have a certain effect on atrial arrhythmias.
  • Research and development of potassium channel antagonists has become the current development direction of antiarrhythmic drugs. Almost all antiarrhythmic drugs reported since 1998 are potassium channel antagonists. They are safer, broader, and more effective than other antiarrhythmic drugs, and are expected to become the first choice of antiarrhythmic drugs.
  • An object of the present invention is to provide a sulfonamide benzamide compound having a highly selective inhibitory effect on a potassium ion channel.
  • the present invention provides a sulfonamide benzylamine compound having the structure of the following general formula (I) or a pharmaceutically acceptable salt thereof:
  • X is 0, S or a single bond
  • Y is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl;
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • a preferred embodiment of the compound of formula (I) of the present invention is the following sulfonamide benzoylamine compound or a pharmaceutically acceptable salt thereof-wherein when X is 0 and Y is 1,2-ethylene,
  • Ri is ⁇ , C r C 4 ⁇ ;
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • Another preferred embodiment of the compound of formula (I) of the present invention is the following sulfonamide benzamide compound or a pharmaceutically acceptable salt thereof:
  • Ri is H, C r C 4 alkyl
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • Yet another preferred embodiment of the compound of formula (I) of the present invention is the following sulfonamide benzamide compound or a pharmaceutically acceptable salt thereof:
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • Yet another preferred embodiment of the compound of formula (I) of the present invention is the following sulfanilamide compound or a pharmaceutically acceptable salt thereof-wherein when X is 0 and Y is 1,3-propylene,
  • Ri is dC 4 alkyl
  • Another preferred embodiment of the compound of formula (I) of the present invention is the following sulfonamide benzamide compound or a pharmaceutically acceptable salt thereof-wherein, when X is S and Y is 1,3-propylene,
  • Ri is C ⁇ ⁇
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • Yet another preferred embodiment of the compound of formula (I) of the present invention is the following sulfonamide benzamide compound or a pharmaceutically acceptable salt thereof- Wherein, when X is a single bond and Y is 1,3-propylene,
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • Yet another preferred embodiment of the compound of formula (I) according to the present invention is the following sulfonamide benzoylamine compound or a pharmaceutically acceptable salt thereof-wherein when X is 0 and Y is tetramethylene,
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • Yet another preferred embodiment of the compound of formula (I) according to the present invention is the following sulfonamide benzamine compound or a pharmaceutically acceptable salt thereof:
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • Yet another preferred embodiment of the compound of formula (I) according to the present invention is the following sulfonamide benzylamine compound or a pharmaceutically acceptable salt thereof:
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl.
  • pharmaceutically acceptable salts include propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, and the like.
  • inorganic bases such as sodium, potassium, calcium, aluminum and ammonium salts, or salts formed with organic bases, such as methylamine salts , Ethylamine salts, ethanolamine salts, etc.
  • the sulfonamide benzoylamine compounds of the present invention or a pharmaceutically acceptable salt thereof can be made into various preparations containing 0.01-99.9% by weight of an active ingredient and an appropriate amount of a pharmaceutically acceptable carrier, such as suitable for oral administration, injection Or in the form of preparations for enteral administration.
  • the medicine containing a therapeutically effective amount of the compound of the present invention can be administered to a subject according to the subject's age (months or weeks), general health, disease severity and duration, route of administration, individual sensitivity to the drug, etc. preparation.
  • the present invention also provides a sulfonamide benzamine compound represented by the following formula (II), wherein the compound of the formula (II) is an intermediate for preparing the compound of the formula (I).
  • the present invention also provides a sulfonamide benzamide compound represented by the following formula (m), wherein the compound of the formula (m) is an intermediate for preparing the compound of the formula
  • 1 2 is 11, (C4 'haloalkyl, -(CH 2 ) n N (-alk-X- Is H, C r C 4 alkyl, and the definitions of X, Y, and alk are the same as those in the general formula (I); and the definitions of X, Y, and alk are the same as those in the general formula (I).
  • the present invention provides the following preparation method of a sulfonamide benzamine compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • X is 0, S or a single bond
  • Y is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl, or tetramethylene which may be substituted by methyl;
  • alk is 1,2-ethylene which may be substituted by methyl, 1,3-propylene which may be substituted by methyl or tetramethylene which may be substituted by methyl,
  • the method mainly includes the following steps:
  • the solvent used is selected from ethanol, methanol, acetonitrile, n-butanol and water
  • the base used is selected from potassium carbonate, sodium carbonate , Sodium hydroxide and potassium hydroxide
  • the polar organic solvent used in step (2) is selected from ethanol, methanol, ethyl acetate and tetrahydrofuran, and the catalyst used is selected from Pd / C, Pt / C, Raney nickel / hydrogen, Raney nickel / hydrazine hydrate system, or iron Powder / acid system, especially iron powder / hydrochloric acid system;
  • the alkylsulfonylating agent used in step (3) is selected from the group consisting of sulfonylsulfonyl chloride, alkylsulfonyl bromide and alkylsulfonic anhydride, and the base used is selected from the group consisting of pyridine, triethylamine, and 4-dimethylaminopyridine. (DMAP), organic bases of diisopropylethylamine, and inorganic bases including sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
  • DMAP diisopropylethylamine
  • steps (1), (2), and (3) can be purified by appropriate methods such as column chromatography and recrystallization, respectively, to obtain pure products.
  • the method for preparing the compound represented by the general formula (IV) is as follows-combining the compound represented by the general formula (V) or a salt thereof with the compound represented by the general formula (VI)
  • a condensation reaction can be performed under basic conditions to obtain a compound represented by the general formula (IV).
  • the reaction is usually carried out in an inert solvent at 20-100 ° C.
  • the solvents used are THF Et 2 0 DMF, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane and the like.
  • the bases used are potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, etc.
  • the obtained compound can be purified by appropriate methods such as column chromatography, recrystallization and the like to obtain a pure product.
  • the preparation method of the compound represented by the general formula (V) is as follows-the compound represented by the general formula ( ⁇ )
  • a substitution reaction can be performed to obtain a compound represented by the general formula (VIII).
  • the halogenated hydrocarbons used are 1 2-dichloroethane, 1 2-bromoacetamidine, 1 3-dichloropropane, 1 3-dibromopropane, 1 4-dichlorobutane, 1 4-dibromobutane ⁇ , etc.
  • the base used is sodium hydrogen, sodium amine, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, etc.
  • the solvents used are DMF THF; EtOH and the like.
  • the reaction is usually carried out at a temperature of -30 to 40 ° C, and generally at 0 to 100 ° C.
  • the obtained compound can be purified by an appropriate method such as column chromatography, recrystallization, etc. to obtain a pure product.
  • NMR spectra were measured on Bruker AM-400, and mass spectra were performed on a MAT-95 mass spectrometer. Elemental analysis was performed by the Analysis Room of Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Melting points were measured on an electrothermal melting point tube or a b-type melting point tube. The thermometer was not calibrated; TLC was performed using silica gel GF 254 (produced by Qingdao Ocean Chemical Plant) and sodium carboxymethyl cellulose at a concentration of 0.8%. Thoroughly stir the aqueous solution, spread the plate, dry it, activate it at 100 ⁇ 110 ° C for 1-2 hours, and store it in a desiccator for later use.
  • Test example 1 isolated rat heart reperfusion arrhythmia model
  • the experimental group was injected with different doses of the compound Id in the tail vein (DMSO was used to prepare the corresponding concentrations in normal saline) 100, 300, 500, 1000, 1500, 2000 g / kg; the control group was given a solvent of 0.2 ml / 10 go 5 minutes after dosing, inject a solution of aconitine at a constant rate of 0.1 ml / min in the tail vein at a constant rate of 10 ⁇ to determine the amount of aconitine (atrial arrhythmia (ventricular premature beats, ventricular tachycardia)). ).
  • the aconitine-induced arrhythmia doses in the control group and the treatment group were compared.
  • Test Example 3 Effect on the threshold of ventricular fibrillation induced by electrical stimulation in rabbits Sodium pentobarbital Anesthesia, endotracheal intubation and artificial respiration.
  • the chest is cut out of the heart pack, two electrodes are placed on the apex (positive) and the epicardium (negative) near the atrioventricular sulcus of the left ventricle, and the two electrodes are about 1 cm away from each other.
  • the exciter is stimulated by a series of pulses, with a frequency of 50 Hz, a wave width of 0.3 ms, a string length of 10 s, and a constant voltage output.
  • the stimulus is stimulated every 3 minutes, and the stimulation intensity is gradually increased until the ECG observation shows ventricular fibrillation (VF).
  • VFT ventricular fibrillation threshold
  • the test drug Id is injected intravenously with a volume of 1 ml / kg and the doses are 0.03, 0.1, 0.3, lrag / kg
  • the positive control group was amiodarone 10nig / kg
  • the negative control group was injected with the same volume of normal saline.
  • stimulation was performed every 3 minutes, as described above.
  • Test drug Compound Id, add DMSO to the required concentration, so that the same volume of drug solution is added to each dose.
  • Test strains Salmonella typhimurium histidine auxotrophy mutant strains; TA97, TA98, TA100, TA102 strains were donated by Professor Ames from University of California (Berkeley). Liquid nitrogen preservation strains.
  • Identification includes: histidine auxotrophy, lipopolysaccharide barrier defect (rfa), ultraviolet repair defects (except ⁇ uvrB, TA102), and R-factor.
  • TA97, TA98, and TA100 with pKMlOl plasmid and ammonia resistance
  • TA102 has pKMlOl and pAQl plasmids, and has anti-ampicillin and tetracycline resistance.
  • Sprague-induced rat liver S 9 was prepared by weighing about 200 grams with Aroclor l254 - Dawley rats, ip Aroclor 1254 (Dainippon Pharmaceutical Co., Ltd.) 500 mg / kg, the fifth day of sacrifice, the liver was removed and rinsed under sterile conditions, Immediately rinse with 0.15M C1 at 4 ° C, and then add 0.15M KC1 in the proportion of 3 ml g wet weight. Homogenize at 4 ° C and centrifuge at 9000xg. Take the supernatant to determine the S 9 protein content according to the Lowry method, cytochrome P450 to determine the Johannesen method, and 2-amino-fluorene to check the S 9 organism. Active, qualified persons stored in liquid nitrogen. Allow the frozen S 9 to thaw slowly before use in the experiment, mix with freshly prepared S 9 each time.
  • DMSO dimethyl methoxysulfoxide
  • Doses are 50, 500, 1000, 2500, 5000 g dishes.
  • the standard plate infiltration method is used to measure the direct effect of drugs without metabolic activation.
  • the test top layer is-
  • Pre-culture is used to measure the mutagenic effect of drug metabolism activation.
  • the composition of the test top layer is:
  • the measured solution of the medicinal solution, the bacterial solution, and the S 9 was first incubated after shaking at 30 ° C and 35 ° C, and then the experiment was performed according to the standard plate infiltration method. Set up 3 dishes for each dose group, and count the number of SD of each colony in the non-drug-recovery or drug-recovery activation system (-S 9 or + S 9 ). data analysis
  • the return mutation value of all test groups was less than 2 times that of the negative control group, which was judged as negative.
  • the return mutation value of any test group is 4 times greater than that of the negative control group, and the conclusions of the pre-test and the main test are considered to be positive.
  • TA97 9-aminoacridine (50 g / dish); TA100: methyl methanesulfonate (1 ⁇ / ⁇ );
  • TA98 P-nitroquinoline (700 g / M.); TA102: mitomycin C (5 g / dish).
  • Table 6 Compounds after action by the S 9 metabolic system
  • TA102 1,2- dihydroxy onion quinone (50 ⁇ ⁇ / dish). Possibility of industrial use
  • the method for preparing a sulfonamide benzoylamine compound of the present invention has the advantages of mild reaction conditions, abundant raw materials and easy availability, simple operation and post-treatment, and the like.
  • the sulfonamide benzamidine compounds of the present invention have strong antiarrhythmic activity on a variety of experimental animal models and can be used as antiarrhythmic drugs. They have a highly selective blocking effect on potassium ion channels.
  • Intravenous injection of the compound of the present invention in mice increases the dose of aconitine-induced arrhythmia, and the intensity of the action increases with the dose of the drug.
  • Intravenous injection of the compound of the present invention in rabbits can significantly increase the threshold of ventricular fibrillation caused by electrical stimulation, and the intensity of the action increases with the dose administered.
  • Intravenous injection of the compound of the present invention in rats can significantly reduce the maintenance time of arrhythmia caused by BaCl 2 , and this effect is dose-dependent.
  • the compound of the present invention has low toxicity, and it has been proved in vitro that it has no effect of inducing gene mutation on Salmonella. Therefore, the compound of the present invention can be used for the preparation of a medicament for treating cardiovascular diseases.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne la sulfamidophénylalkylamine représentée par la formule (I) dans laquelle R1 représente H ou alkyle C1-C4; R2 représente H, haloalkyle, CnH2nCOOCmH2m+1(n=1-4; m=1-4) ou (CH2)nN(-alk-X-naphtyl)(-Y-phényl-NHSO2R1-p)(n=1-4; R1 représente H, alkyle C1-C4; X, Y et alk sont tels que définis ci-dessous); X représente O, S ou une liaison simple; Y représente 1,2-éthylène, 1,3-triméthylène ou 1,4 tétraméthylène, qui sont facultativement substitués par un ou plusieurs méthyle ; et alk représente 1,2-éthylène, 1,3 triméthylène ou 1,4 tétraméthylène, qui sont facultativement substitués par un ou plusieurs méthyle. La présente invention concerne ce composé ou ses sels pharmaceutiquement acceptables. Les expériences pharmacologiques ont confirmé que ces composés sont des inhibiteurs du canal K+ et sont utiles pour le traitement et la prévention de plusieurs types d'arythmie chez des modèles animaux. Formule (I)
PCT/CN2002/000927 2002-04-26 2002-12-30 Sulfamidophenylalkylamines, production et utilisation de ces dernieres WO2003091205A1 (fr)

Priority Applications (1)

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AU2002357560A AU2002357560A1 (en) 2002-04-26 2002-12-30 Sulfamidophenylalkylamines and their production and use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN02116901.2 2002-04-26
CNB021169012A CN100358865C (zh) 2001-07-30 2002-04-26 一类磺酰胺苯烷胺类化合物及其制备方法和用途

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4289787A (en) * 1977-12-19 1981-09-15 Eli Lilly And Company Quaternary ammonium antiarrhythmic drugs
US5079248A (en) * 1986-05-01 1992-01-07 Pfizer Inc. Anti-arrhythmic agents
US5155268A (en) * 1984-05-04 1992-10-13 The Upjohn Company Antiarrhythmic N-aminoalkylene alkyl and aryl sulfonamides
US6265445B1 (en) * 1997-12-11 2001-07-24 Gyogyszerkutato Intezet Kft Antiarrhythmic compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4289787A (en) * 1977-12-19 1981-09-15 Eli Lilly And Company Quaternary ammonium antiarrhythmic drugs
US5155268A (en) * 1984-05-04 1992-10-13 The Upjohn Company Antiarrhythmic N-aminoalkylene alkyl and aryl sulfonamides
US5079248A (en) * 1986-05-01 1992-01-07 Pfizer Inc. Anti-arrhythmic agents
US6265445B1 (en) * 1997-12-11 2001-07-24 Gyogyszerkutato Intezet Kft Antiarrhythmic compounds

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