WO2010111948A1 - Composés d'arylméthylamine, procédés de préparation et utilisations à des fins pharmaceutiques de ces composés - Google Patents

Composés d'arylméthylamine, procédés de préparation et utilisations à des fins pharmaceutiques de ces composés Download PDF

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WO2010111948A1
WO2010111948A1 PCT/CN2010/071455 CN2010071455W WO2010111948A1 WO 2010111948 A1 WO2010111948 A1 WO 2010111948A1 CN 2010071455 W CN2010071455 W CN 2010071455W WO 2010111948 A1 WO2010111948 A1 WO 2010111948A1
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group
compound
atom
ring
pharmaceutically acceptable
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尤启冬
杨倩
汪小涧
汤依群
陈春林
郭小可
金英华
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中国药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of arylmethylamine compounds, a process for the preparation thereof, and a pharmaceutical preparation thereof and a medical use thereof. Background technique
  • Arrhythmia is a major disease that seriously threatens people's health and quality of life. According to incomplete statistics, about a million people die each year due to failure to effectively control primary or secondary arrhythmia, and the patient population is becoming younger. Therefore, the market size of antiarrhythmic drugs It is expanding year by year.
  • Antiarrhythmic drugs can be divided into four categories according to their different mechanisms of action.
  • the main clinical applications are class III antiarrhythmic drugs, potassium channel blockers, including dofetilide, sotalol, etc.
  • the mechanism of action of the drug is to specifically block the fast-delayed rectifier potassium channel current ( ⁇ ), and the other two components of the delayed rectifier potassium channel ( ⁇ )—slow-delay rectifier potassium channel current (IKS) and ultra-fast delayed rectifier potassium.
  • the channel current ( ⁇ ⁇ ) has no blocking effect, and its electrophysiological effect is to prolong the myocardial action potential time course and effective refractory period.
  • arrhythmia disease should be considered as a combined result of a variety of ion channel properties, and its treatment should not be limited to the regulation of a single ion channel.
  • the present invention closely follows the development trend of antiarrhythmic drugs, designs and synthesizes a class of compounds having an arylmethylamine structure, and pharmacological tests prove that the compounds of the present invention have certain blocking activities for I KUR , ⁇ and IKS ,
  • the compounds and their pharmaceutical preparations can be used to treat a range of diseases caused by abnormal potassium channel function, for example, arrhythmia, ischemic injury and the like.
  • the compounds of the invention have the general formula:
  • Ar represents a benzene ring, a pyridine ring or a 5- or 6-membered aromatic ring containing 0 to 2 selected from a nitrogen atom, a sulfur atom or an oxygen atom;
  • Ar also indicates
  • Y represents a nitrogen atom or a carbon atom, which represents a nitrogen atom, and ⁇ represents a benzyl group, a phenyl group or a C group.
  • Ar also denotes wherein Y represents a nitrogen atom or a carbon atom, and 2 represents an oxygen atom or a sulfur atom;
  • X represents a nitrogen atom or a carbon atom.
  • L represents -CO-, -SO2-, -NH-, -CONH-, -(CH 2 ) n O-, -(CH 2 ) n N-, -(CH 2 ) n O- or -(CH 2 ) n CONH-, where n is an integer from 1 to 4.
  • R represents a mono- or poly-substitution, and a poly-substitution means a di-, tri- or tetra-substituent; the substituent is selected from the group consisting of halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, ⁇ C 4
  • the alkyl group, the oxime group of ⁇ 0», the amino fluorenyl group of ⁇ , the alkylamino group of ⁇ , the acyl group of ⁇ , the amide group of ⁇ , the alkoxycarbonyl group of ⁇ , and the benzene ring are connected to ⁇ a 3 ⁇ 4 alkyl group or a d-C 4 alkoxy group bonded to a benzene ring; the substituent may also be selected from a 5- or 6-membered impurity having 1 to 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom Ring-bonded ⁇ C 4 thiol or alkoxy.
  • the present invention also includes stereoisomers of the compound of the formula (I), hydrates thereof or pharmaceutically acceptable salts thereof.
  • Ar preferably represents a benzene ring, a benzoxazole ring, a benzimidazole ring, a 1-benzylbenzimidazole ring, a 1-phenylbenzimidazole ring or a benzo[1,3]dioxolane.
  • L preferably represents -CH 2 CH 2 0-, -CH 2 N -, -CH 2 CH 2 N -, -C CONH -, -CONH -, -NH -, -CO- or -so 2 -.
  • R preferably denotes a para-substituted or o- or para-disubstituted; the substituent is selected from halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, methoxy, ester or amide .
  • the invention also discloses a process for the preparation of the compound of the formula (I).
  • the compound ( ⁇ ) is reacted with anhydrous piperazine to obtain the compound (111), and the compound ( ⁇ ) is reacted with Ar-CH 2 -Cl to obtain a compound of the formula (I).
  • the reaction temperature of the reaction of the compound ( ⁇ ) with anhydrous piperazine is preferably 10 to 40 ° C, and the reaction time is preferably 2 to 12 hours.
  • the solvent used for the reaction is preferably anhydrous ethanol or methanol, and 40% hydrobromic acid is preferably added to the reaction liquid.
  • the reaction temperature of the reaction of the compound (III) with Ar-CH 2 -Cl is preferably 60 to 90 ° C, and the reaction time is preferably 2 to 2. 4 hours.
  • the solvent used for the reaction is preferably acetonitrile, hydrazine, hydrazine-dimethylformamide (DMF) or chloroform, and a base such as triethylamine or potassium carbonate is preferably added to the reaction liquid.
  • the preparation method of the compound includes:
  • the preparation method of the compound includes -R
  • Ar-C-Cl is reacted with 4-piperidone or 4-piperidinecarboxylic acid to obtain compound (IV) or compound (V), and Ar, R, and L are as defined above; compound (IV) or compound (V) is respectively Reaction with an R-substituted phenylalkylamine gives a compound of the formula (I).
  • the reaction temperature at which Ar-CH 2 -CI is reacted with 4-piperidone or 4-piperidinecarboxylic acid is preferably 60 to 90 ° C, and the reaction time is preferably 4 to 12 hours.
  • the solvent used for the reaction is preferably acetonitrile, chloroform, tetrahydrofuran or DMF, and a base such as triethylamine or potassium carbonate is preferably added to the reaction liquid.
  • the reaction temperature of the reaction of the compound (IV) with the R-substituted phenylhydrazine amine is preferably 140 to 160 ° C, and the reaction time is preferably 4 to 8 hours.
  • the solvent used for the reaction is preferably toluene or xylene, and then a reducing agent such as sodium borohydride, lithium aluminum hydride or the like is further added to the reaction liquid.
  • the reaction temperature of the reaction of the compound (V) with the R-substituted phenylalkylamine is preferably 10 to 40 ° C, and the reaction time is preferably 2 to 4 hours.
  • the solvent used for the reaction is preferably tetrahydrofuran, chloroform or dichloromethane, and an acylating condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or hydrazine is added to the reaction solution.
  • a base such as triethylamine or 4-dimethylaminopyridine (DMAP) is preferably added to the ruthenium-dicyclohexylcarbodiimide (DCC).
  • the compound of the formula (I) can be purified by a usual separation method such as recrystallization, column chromatography or the like.
  • the compound of the present invention may be added into a pharmaceutically acceptable carrier to prepare a common pharmaceutical preparation, such as a tablet, a capsule, a powder, a syrup, a liquid, a suspension, an injection, and may be added to a fragrance, a sweetener, a liquid or Common pharmaceutical excipients such as solid fillers or thinners.
  • the compound of the present invention can be administered clinically by means of oral administration or injection.
  • the compound of the present invention is used in a clinical dose of 0.01 mg to 1000 mg/day, and may be deviated from this range depending on the severity of the condition or the dosage form.
  • the invention has the advantages that the compound has certain blocking activity on the delayed rectifier potassium channels I KUR , ⁇ and IKS , and the compound and the pharmaceutical preparation thereof can be used for treating the abnormal function of the potassium ion channel.
  • the preparation method provided by the invention has the characteristics of mild reaction conditions, abundant raw materials, easy operation and post-treatment.
  • the guinea pig cardiomyocytes were isolated by acute enzymatic hydrolysis, and the whole cell patch clamp (model: HEKA, EPC-10) was used to delay the rectifying current in the fast-acting component and the slow-acting component.
  • the data collected from the representative structure of the present invention was dissolved in the perfusion solution of the measured current and collected in at least 10 mi.
  • the data was analyzed in Pulse-fit software, and the IC 5Q values of each compound on kr and IKS were calculated. The results are shown in Table 2.
  • guinea pig cardiomyocytes The guinea pig is stunned, the heart is taken quickly, placed in a calcium-free Tyrode solution at 4 °C, trimmed and placed on a Langendorff device, perfused with calcium-free bench solution for 5 min, containing 1 mg/ml Type II collagenase, 0.1 mg/ml Protease, 0.5% BSA, CaCl 2 150nmol/L low calcium Tyrode solution perfusion heart, until the heart becomes soft, relax, remove the heart, cut the ventricle into fresh enzyme Incubate at 37 °C in the solution, gently stir for 5-10 min, pour out the supernatant, and dilute with TyC solution containing CaCb lmmol L, this is the first cell storage solution; , the third cell storage solution. The perfusate was saturated with 5% C0 2 + 95% 0 2 . The cells were used after 2 h.
  • Whole-cell patch clamp technique Take the cell liquid into the cell pool, wait until the cells are attached, perfuse with extracellular fluid, flow rate 2 ml/min, select cells with calcium tolerance, clear stripes, use 3D manipulator to move the electrode to Cell surface, negative The pressure causes the electrode tip to form a high-resistance sealing on the cell surface, and further absorbs the cell membrane with a negative pressure, so that the electrode liquid and the intracellular fluid are turned on to form a whole cell state, and after performing capacitance and series impedance compensation, voltage clamp recording is performed. .
  • the signal is guided by the Ag/AgCl electrode, amplified by the patch clamp amplifier, and the computer distributes the set excitation pulse to the cell, and the electrical signal generated by the cell is converted by the converter and stored in the computer.
  • All stimulation signal control, current data sampling and analysis were performed by pulse V8.60.
  • the same concentration was diluted with water and added to the extracellular fluid. The highest concentration of ethanol was 0.1%.
  • the preliminary results of this study showed that the concentration had no effect on the experimental results.
  • the recording was performed after the recording current was stabilized for 10 minutes, and the current after 10 minutes of administration was recorded, and the experiment was carried out at 25 to 30 °C.
  • Stimulus parameters ⁇ , I KS records: Record the wake values of the two currents. Perfused with extracellular fluid containing 0.1 mmol L CdCl 2 , maintaining a voltage of -50 mV, depolarizing to 60 mV for 500 ms, maintaining the voltage to a 50 mV for 1000 ms, recording I Ks ; then clamping the voltage at - 50mV 1000ms, record 1 & .
  • Modeling method Male Sprague-Dawley rats (250-280g) 30, continuous tail vein injection of calcium chloride acetylcholine (CaCl 2 -ACh) mixture (10mL / Kg, where CaCl 2 10mg / ml, ACh ⁇ ⁇ ⁇ 7 days of modeling; rats were randomly divided into a model group and a drug-administered group on the fourth day of modeling. The rats in the administration group were intraperitoneally injected at a dose of 2.5 mg g 5 minutes before the fourth day of modeling.
  • CaCl 2 -ACh calcium chloride acetylcholine
  • mice Male Sprague-Dawley rats (body weight 270-300 g) were randomly divided into control group, low-dose and high-dose administration groups, 4 in each group, and low-dose administration group (dose 2.5 mg g/day, Intraperitoneal injection for 3 days), high-dose administration group (dose 5 mg Kg/day, intraperitoneal injection for 3 days), normal control rats were intraperitoneally injected with physiological saline l m IJKg per day. After the end of the administration, the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate and fixed in the supine position. The right common carotid artery and the left external jugular vein were separated.
  • a curved polyethylene cannula with a length of about 12 cm was inserted, and a 6 cm long cotton thread was inserted in the middle.
  • the heparin physiological saline solution (25 U/mL) was filled with a polyethylene tube. Cavity, one end of the tube was inserted into the left external jugular vein, the heparin was accurately injected by a polyethylene tube, and then the other end of the polyethylene tube was inserted into the right common carotid artery. Open the arterial clip and the blood flows from the right common carotid artery into the polyethylene tube and back to the left external jugular vein.
  • the blood flow was interrupted after 15 minutes of open blood flow, and 1.8 mL of blood was taken from the right common carotid artery.
  • the prothrombin time (PT) value was determined by leaving the sample. Quickly remove the cotton thread and weigh it. The total weight minus the weight of the cotton thread will result in a wet weight of the thrombus.
  • the compound of the present invention CPUYY18 (corresponding to Example 18) was intraperitoneally injected for three days, prolonging the blood prothrombin time (PT) of rats and inhibiting platelet thrombosis in a certain extent (see Fig. 3). .
  • mice Male SD rats (body weight 270-300 g) were randomly divided into a model group, a drug-administered group, and a control group. On days 1 to 3 of the experiment, rats were anesthetized with 10% chloral hydrate (0.3 mL/100 g), and an electrocardiogram was recorded after anesthesia. A mixture of CaCl 2 -ACh (10 mg/mL CaCl 2 + 6.6 ug/mL Ach mixed at a dose of 0.1 mL/100 g) was injected into the tail vein to record the duration of atrial fibrillation.
  • the atrial fibrillation time began with a typical atrial fibrillation electrocardiogram (P wave disappeared, f wave appeared) after the injection of mixed liquid to restore the 6 consecutive sinus rhythm as a sign of atrial fibrillation disappearance, the whole process of electrocardiogram monitoring.
  • the animals were randomly divided into groups on the fourth day.
  • the drug-administered group was intraperitoneally injected with the corresponding dose of the drug 10 minutes before the start of modeling, and the same operation was repeated, and the above operation was repeated until the seventh day.
  • the rats were sacrificed.
  • the left atrial muscle of the rats was taken and hung in a bath filled with oxygen-saturated constant temperature KH solution.
  • the preload was lg, 1.5 times the threshold potential stimulation at 1 Hz for about 1 hour, and the experiment was started after the specimen was stabilized.
  • the effective refractory period ERP of the myocardium was determined by the continuous double stimuli method using the BL-420F biofunctional system. The number of all experimental cases was not less than 6, and the difference between the two groups was used to perform statistical analysis between groups.
  • the above experimental results show that the arylmethylamine compound of the present invention has a certain blocking activity for the delayed rectifier potassium channel currents I K , kr and I Ks , and at an effective dose (2.5 mg/Kg):
  • the expression level of connexin Cx43 in tremor animal can improve the electrical signal transmission between cardiomyocytes; prolong prothrombin time (PT) in rats, and inhibit plate thrombosis in rats to some extent; can effectively shorten arrhythmia persistence Time, prolonging the effective refractory period (ERP) of cardiomyocytes, thus showing a therapeutic effect on arrhythmias.
  • PT prothrombin time
  • EBP effective refractory period
  • the drug and its medicinal preparation can be used for treating a series of diseases caused by abnormal function of potassium ion channels, for example, diseases such as arrhythmia and ischemic injury.
  • Figure 1 is the standard curve of protein quantification
  • Figure 2 is the effect of compound CPUYY18 on myocardial Cx43 protein expression in atrial fibrillation rats (A: Western original map; B: grayscale quantitative map)
  • Figure 3 shows the in vivo anticoagulant effect of compound CPUYY18 and its effect on platelet thrombosis (A: platelet wet weight; B: prothrombin time PT)
  • Figure 4 shows the in vivo antiarrhythmic effect of compound CPUYY18 (A: effect of CPUYY18 on atrial fibrillation time in rats; B: effect of CPUYY18 on rat atrial ERP)
  • O-phenylenediamine (0.06 mol) was dissolved in 100 mL of methanol, potassium carbonate (0.03 mol) was added, and stirred at room temperature. Under a nitrogen atmosphere, a solution of benzyl bromide (0.015 mol) in 15 mL of methanol was added dropwise, stirred at room temperature for 10 h, filtered, and concentrated. The next reaction is directly carried out by treatment.
  • N 1 -Benzyl phenylenediamine (0.014 mol) was dissolved in 100 mL of 5N hydrochloric acid, chloroacetic acid (0.016 mol) was added, and refluxed for 4 h.
  • N-(4-Methoxyphenyl)piperidine-4-carboxamide hydrochloride (0.0034 mol) was added 15 mL of acetonitrile, 0.007 mol of potassium carbonate, and refluxed for 1 h.
  • 2-Chloromethylbenzoxazole (0.0034 mol) was added and refluxed for 2 h.
  • the reaction solution was poured into water, extracted with ethyl acetate (30 mL ⁇ 3 ⁇ ) and dried over anhydrous sodium sulfate.

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Abstract

La présente invention concerne des composés d'arylméthylamine (I), Ar, X, L et R étant tels que définis dans la description. L'invention concerne également des procédés de préparation ainsi que des compositions pharmaceutiques et des utilisations correspondantes. Les composés d'arylméthylamine décrits dans l'invention peuvent être utilisés pour traiter une série de maladies provoquées par une anomalie du fonctionnement du canal potassique, telle que l'arythmie ou des lésions ischémiques.
PCT/CN2010/071455 2009-03-31 2010-03-31 Composés d'arylméthylamine, procédés de préparation et utilisations à des fins pharmaceutiques de ces composés WO2010111948A1 (fr)

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WO2020115045A1 (fr) * 2018-12-05 2020-06-11 Esteve Pharmaceuticals, S.A. Dérivés de 1h-benzo[d]imidazole substitués ayant une activité multimodale dirigée contre la douleur et des états pathologiques associés à la douleur

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Publication number Priority date Publication date Assignee Title
FR2967674A1 (fr) * 2010-11-23 2012-05-25 Pf Medicament Derives d'heteroarylsulfonamides, leur preparation et leur application en therapeutique humaine
WO2012069503A1 (fr) * 2010-11-23 2012-05-31 Pierre Fabre Medicament Dérivés d'hétéroarylsulfonamides, leur préparation et leur application en thérapie humaine
JP2014502268A (ja) * 2010-11-23 2014-01-30 ピエール、ファーブル、メディカマン ヘテロアリールスルホンアミド誘導体、それらの製造およびヒト治療におけるそれらの応用
US8846930B2 (en) 2010-11-23 2014-09-30 Pierre Fabre Medicament Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy
US9156834B2 (en) 2010-11-23 2015-10-13 Pierre Fabre Medicament Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy
KR101838326B1 (ko) 2010-11-23 2018-03-13 피에르 파브르 메디카먼트 헤테로아릴술폰아미드 유도체, 이의 제조방법 및 인간치료에서의 용도
WO2020115045A1 (fr) * 2018-12-05 2020-06-11 Esteve Pharmaceuticals, S.A. Dérivés de 1h-benzo[d]imidazole substitués ayant une activité multimodale dirigée contre la douleur et des états pathologiques associés à la douleur

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