EP0736005A1 - Amides d'acide aminocarboxylique, leur procede de preparation et leur utilisation comme medicaments anti-arythmiques - Google Patents

Amides d'acide aminocarboxylique, leur procede de preparation et leur utilisation comme medicaments anti-arythmiques

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Publication number
EP0736005A1
EP0736005A1 EP95900625A EP95900625A EP0736005A1 EP 0736005 A1 EP0736005 A1 EP 0736005A1 EP 95900625 A EP95900625 A EP 95900625A EP 95900625 A EP95900625 A EP 95900625A EP 0736005 A1 EP0736005 A1 EP 0736005A1
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EP
European Patent Office
Prior art keywords
diethylamino
benzamide
nitro
dicyclohexyl
carbamoylmethyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP95900625A
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German (de)
English (en)
Inventor
Wolfgang Sauer
Rudolf Schindler
Carla RÜGER
Hildegard Poppe
Degenhard Marx
Reni Bartsch
Natalja Kaverina
Sergey Seredenin
Valentin Lyskowzev
Arkadij Lichoscherstov
Sergey Borisenko
Sergey Kryzhanovsky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva GmbH
Original Assignee
Arzneimittelwerk Dresden GmbH
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Publication of EP0736005A1 publication Critical patent/EP0736005A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • 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
    • 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
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to new aminocarboxamides of the general formula I.
  • R 1 , R 1 , R 3 , R 4 , R 5 and n and m have the following meanings:
  • R 1 , R 2 is hydrogen, straight-chain or branched C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl,
  • Halogen, cyano, nitro, trifluoromethyl, aminocarbonyl, mesylamino or acylamino can be mono- or disubstituted
  • Phenylalkyl in which the alkyl chain can contain 1-3 carbon atoms and the phenyl ring can be mono- or disubstituted by methyl, methoxy, halogen, nitro, cyano, aminocarbonyl or acylamido
  • Morpholine piperidine, where the piperidine can be mono- or disubstituted with a C 1 -C 2 alkyl group or a phenyl or benzyl group, pyrrolidine, piperazine, which in the 4-position is a C 1 -C 4 alkyl, phenyl, May contain benzyl or acyl group,
  • R 6 H, NHCO 2 CH 2 CH 3
  • R 7 straight-chain or branched C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, such as
  • Cyclohexyl phenyl, which can be mono- or disubstituted by straight-chain C 1 -C 6 alkyl, C 1 -C 2 alkoxy, halogen, cyano, nitro, trifluoromethyl, aminocarbonyl, sulfonamido, toluenesulfonamido, methanesulfonamido or acylamino,
  • Phenylalkyl in which the alkyl chain can contain 1-3 carbon atoms and the phenyl ring can be mono- or disubstituted by methyl, methoxy, halogen, nitro, cyano, aminocarbonyl or acylamido and
  • R 8 can be hydrogen, C 1 -C 2 alkyl, nitro, acylamino
  • Piperidine, pyrrolidine, morpholine, piperazine, which can contain a C 1 -C 4 -alkyl, phenyl or benzyl group in the 4-position n 1 - 5
  • the medicines used to treat irregular heartbeat are:
  • Class I sodium antagonists which are further divided into classes I A , I B and I C
  • Class III potassium channel blockers (repolarization inhibitors)
  • class I C antiarrhythmic drugs are not capable like the
  • Proarrhythmogenic properties of class I antiarrhythmics which can be attributed to a prolongation of the rate of excitation conduction, which favors the development of reentry antiythmias, are regarded as a cause for this.
  • Class III antiarrhythmics which are known as repo
  • the invention is therefore based on the object of new compounds with improved
  • these new compounds are aminocarboxamides of the general formula I in which R 1 to R 5 , n and m have the abovementioned meaning and their physiologically tolerated acid addition salts.
  • the compounds of the general formula I can be prepared by the following processes:
  • Primary or secondary amines of the general formula II, in which R 1 and R 2 have the meaning given above, are mixed with ⁇ -haloalkanecarboxylic acid halides of the general formula III, in which X and Y each represent a halogen atom, preferably a chlorine or a bromine atom and n the has the above meaning, at temperatures from 0 ° C to the reflux temperature of the solvent used in inert organic solvents or in two-phase
  • Solvent mixtures such as water / toluene, water / cyclohexane or water / diethyl ether in the presence of acid acceptors such as.
  • Suitable inert organic solvents are, for example, ethers such as dioxane or tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene or xylene, halogenated aliphatic or aromatic hydrocarbons such as chloroform, 1,2-dichloroethane, carbon tetrachloride or chlorobenzene, aliphatic hydrocarbons such as cyclohexane or Heptane or dipolar aprotic solvents such as dimethylformamide, acetonitrile or dimethyl sulfoxide.
  • ethers such as dioxane or tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated aliphatic or aromatic hydrocarbons such as chloroform, 1,2-dichloroethane, carbon tetrachloride or chlorobenzene
  • aliphatic hydrocarbons such as cyclo
  • Suitable inert solvents are, for example, alcohols, such as ethanol, n-propanol or isopropanol, ethers, such as dioxane or tetrahydrofuran, aromatic hydrocarbons, such as benzene, toluene or xylene, halogenated aliphatic or aromatic hydrocarbons, such as chloroform, 1, 2-dichloroethane, Carbon tetrachloride or chlorobenzene, aliphatic hydrocarbons such as cyclohexane or heptane or dipolar aprotic solvents such as dimethylformamide, acetonitrile or dimethyl sulfoxide.
  • alcohols such as ethanol, n-propanol or isopropanol
  • ethers such as dioxane or tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • a particular embodiment of the present invention consists in that an excess of the compound of formula V is used as solvent.
  • the temperature can vary within wide limits between room temperature and 150 ° C.
  • the compounds of general formula VI are with carboxylic acid halides or
  • Suitable acid acceptors are, for example, alkali carbonates, alkali hydrogen carbonates or tertiary organic amines such as triethylamine, pyridine or NN-dimethylaniline.
  • inert solvents which can be used are ethers such as dioxane or tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene or xylene, halogenated aliphatic or aromatic hydrocarbons such as chloroform, 1, 2-dichloroethane, carbon tetrachloride or chlorobenzene, aliphatic hydrocarbons cyclohexane or heptane or dipolar aprotic solvents, such as dimethylformamide, acetonitrile or dimethyl sulfoxide, can be used.
  • ethers such as dioxane or tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated aliphatic or aromatic hydrocarbons such as chloroform, 1, 2-dichloroethane, carbon tetrachloride or chlorobenzene
  • the temperature can vary between -5 ° C and + 120 ° C.
  • Halogen carboxylic acids of the general formula IX in which X is a halogen atom, preferably chlorine or bromine and n has the meaning given above, in an inert solvent, for example alcohols, ethers of aromatic and halogenated aliphatic hydrocarbons, if appropriate in the presence of an acid-binding agent, preferably at temperatures between 20 and 150 ° C, with an alkylenediamine of the general formula V, with the meanings defined above for R 4 , R 5 and m, to give compounds of the general formula X, in which R 4 R 5 n and m have the abovementioned meaning.
  • an inert solvent for example alcohols, ethers of aromatic and halogenated aliphatic hydrocarbons, if appropriate in the presence of an acid-binding agent, preferably at temperatures between 20 and 150 ° C, with an alkylenediamine of the general formula V, with the meanings defined above for R 4 , R 5 and m, to give compounds of the general formula X,
  • aminocarboxamides of the general formula I with inorganic or organic acids, such as
  • Oxalic acid, tartaric acid, citric acid, fumaric acid, maleic acid, lactic acid or succinic acid implemented in a conventional manner.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the general formula I or salts thereof with physiologically tolerable inorganic or organic acids and optionally pharmaceutically usable excipients and auxiliaries.
  • the compounds of general formula I can be administered orally, parenterally, intravenously or transdermally in the free form of a salt with a physiologically acceptable acid.
  • Tablets, dragees, capsules, plasters, solutions, ampoules or suppositories are therefore particularly suitable as application forms. They can be produced by methods which are generally known and customary in pharmaceutical practice.
  • the dosage of the pharmaceutical preparations depends on the age, condition and weight of the patient and on the form of administration.
  • the daily dose of active substance for intravenous use is between
  • the compounds of general formula I according to the invention are new antiarrhythmics, in particular class III according to Vaughan-Williams (J. Clin. Pharmacol. 24, 129-147, 1984).
  • Substance EC 20 (confidence interval) [10 -6 mol / l]
  • Example 8 about 15 0.73
  • Refractory period (ERP) Refractory period (ERP) to a greater extent than the comparison substances Sematilid, a
  • the new compounds are particularly effective in the treatment of tachycardia arrhythmias, while the comparison substances d / l sotalol and sematilide show only a weak effect in tachyan hythmy.
  • Action potential duration is shown in Table 2.
  • the new compounds result in a dose-dependent and significant prolongation of the APD 90 without significantly changing the conduction time and the maximum spreading speed.
  • the effect when stimulated with 1 Hz is greater than that of the comparative drugs Sotalol and Sematilid.
  • the new compounds are therefore particularly suitable for the treatment of A ⁇ hythmien, which go hand in hand with disturbances of the repolansation phase of the heart rhythm.
  • the compounds of the general formula I have a strong antifibrillation activity.
  • the compound according to example 8 has a dose effect
  • Another significant advantage of the new compounds according to the invention is their significantly greater therapeutic range compared to class I comparison substances such as lidocaine and quinidine. As shown in Table 3, the therapeutic index of the compound according to Example 8 is
  • the therapeutic index (Tl) was calculated from the quotient of the 50% lethal dose (LD 50 ) on the rat in the case of intravenous administration to the 50% effective dose (ED 50 ) on the aconitin antihythmy of the awake rat in the case of intravenous administration.
  • Lidocaine 7.8 39.4 5.0 The investigations of the antiarrhythmic effect on the aconitin arrhythmia of the awake rat and the determination of the acute toxicity on the rat were described by Senova, ZP et al.,
  • Guinea pigs of male or female sex with a body mass of approx. 400 g are killed by a blow to the neck and exsanguinated.
  • the heart was quickly removed and fixed in a preparation bath soaked in carbogen. After opening the right ventricle, the
  • Glucose 10.0.
  • the solution had a temperature of 35 ° C and was continuously flowed through by a gas mixture of 95% oxygen and 5% CO 2 .
  • the papillary muscles were stimulated via bipolar platinum electrodes using the TUR RS 21 "electrostimulator.
  • the measured value was recorded using the Mark VII linear camcorder.
  • the stimulus threshold (in mA) was determined after a 10-minute pause at a frequency of 1 Hz or 3 Hz with a stimulus width of 0.1. 5 ms determined, doubled and kept constant over the entire test period.
  • the refractory period was determined using a standardized stimulation program (individual stimuli). The distance between the basic stimulus and the extra stimuli was automatically increased by 2 ms after each beat until the effective refractory period was reached. The effective refractory period was defined as the smallest interval between basic stimulus and extra stimulation (in ms) that results in a measurable contraction.
  • Base values were applied to the test substances in the bath liquid. After an exposure time of 1 hour, the effective refractory period was determined again.
  • the mean values with standard deviation were calculated from 3-6 individual values at a test concentration.
  • the averages of 3-4 test concentrations were used to calculate the effective concentration, which was a 20%
  • the papillary muscle was positioned on a bipolar Ag-AgCI electrode.
  • the stimulus threshold (mV) was determined at a frequency of 1 Hz. With continuous stimulation at 1 Hz or 3 Hz and double stimulation threshold, an adaptation time of 1h followed. The width of the rectangular pulses was 1 ms.
  • the action potentials were recorded using glass microelectrodes (Kwik-Fil TM, K-Series Borosilicate Glass Capillaries, Sarasota, Florida 34240), which were filled with 3 mol / l KCI and one
  • the signals were amplified with an electrode amplifier (Hugo-Sachs Elektronik KG, type 309), visualized on an oscilloscope (Hitachi Denshi Models VC-6025A) and digitized on an online analyzer coupled to a dot matrix printer.
  • the parameters RP resting potential [mV]
  • OV overshoot potential [mV]
  • V max maximum spreading speed [V / s]
  • tue conduction time [ms]
  • APD 90 action potential duration at 90% repolarization [ ms]
  • the substance effect was assessed after 1 hour exposure in the superfusion medium compared to the base value.
  • the deviation in percent ( ⁇ %) was calculated by taking the mean changes and the standard deviation from the percentage changes in the individual tests (s) were calculated.
  • Significant changes (p ⁇ 0.05) were marked with *.
  • the liquid phases are decanted, the oil adhering to the flask wall is stirred with 200 ml of toluene and 100 ml of water at 50 ° C. for about 2 hours until everything goes into solution.
  • the combined toluene phases are shaken with 300 ml of water, then shaken with 150 ml of 10% hydrochloric acid and the toluene phase is shaken with 200 ml of water.
  • the hydrochloric acid and the last aqueous phase are mixed with 300 ml of toluene together with oil adhering to the bottom of the flask and adjusted to pH 13-14 with 10% sodium hydroxide solution.
  • the residue is taken up in 1 l of water, adjusted to pH 12 with sodium hydroxide solution, with twice each 500 ml of toluene extracted, the combined toluene phases shaken twice with 250 ml of water, dried with sodium sulfate, filtered and distilled to dryness in vacuo.
  • the phases are separated, the aqueous phase is shaken twice with 70 ml of toluene each, the combined toluene phases are shaken out with 80 ml of water, the toluene phase is dried with sodium sulfate, filtered and distilled to dryness.
  • the benzene solution is separated off, shaken out with water, the desired product extracted with 1: 5 dilute hydrochloric acid from the benzene phase, made basic with 1: 5 diluted ammonia solution and extracted with benzene. After washing the benzene phase with water, the benzene is distilled off. The residue is recrystallized from 70% ethanol.
  • the benzene solution is separated off, shaken out with water and the desired product is extracted from the benzene phase with 1: 5 dilute hydrochloric acid.
  • the hydrochloric acid phase is made basic with 1: 5 diluted ammonia solution and extracted with benzene.
  • the residue is recrystallized from 70 percent ethanol.
  • N, N-dicyclohexyl-2- (3-morpholin-4-yl-propyl) -acetamide is prepared from 2-chloro-N, N-dicyclohexylacetamide and 3-morpholino-1-propylamine analogously to Example 8.
  • N, N-dicyclohexyl-2- (2-piperidin-1-yl-ethylamino) acetamide is prepared from 2-chloro-N, N-dicyclohexylacetamide and 2-piperidinoethylamine analogously to Example 8.
  • the residue is recrystallized from dilute ethanol (80 ml of ethanol and 30 ml of water).
  • the hydrochloric acid phase is made basic with 1: 3 diluted ammonia solution and extracted with benzene. After washing the benzene solution with water, the benzene is distilled off and the residue is distilled in vacuo.
  • Reaction mixture is stirred for 6 seconds at room temperature, then mixed with 150 ml of water and stirred for 4 hours at room temperature.
  • the benzene phase is separated off, shaken out with water and the benzene is distilled off.
  • reaction mixture is stirred in the hydrogen atmosphere for 3 hours, the catalyst is filtered off and the methanol is distilled off.
  • the precipitate is filtered off, washed with dilute ammonia solution and with water and in
  • 4-Amino-N- (benzyl-methyl-carbamoyimethyl) -N- (3-diethylamino-propyl) -benzamide becomes N- (benzyl-methyl-carbamoylmethyl) -N- (3-diethylamino-propyl) -4-nitro -benzamide as prepared in Example 17. 5.9 g (0.0143 mol) of 4-amino-N- (benzyl-methyl-carbamoylmethyl) -N- (3-diethylamino-propyl) -benzamide and 7.45 g (0.073 mol) of acetic anhydride are dissolved in 50 ml of benzene Heated at reflux for 6 hours and then distilled to dryness.
  • the benzene phase is separated off, shaken out with water and distilled to dryness.
  • the residue (5.2 g) is dissolved in 20 ml of isopropanol.
  • the precipitate is filtered off and recrystallized from isopropanol and ether. Yield 4.8 g (75% of theory)
  • Methanesulfonyl chloride added and heated under reflux for 6 hours. After cooling, 50 ml of water are added and the mixture is stirred for 2 hours. A solution of 4.8 g (0.035 mol) of potassium carbonate in 20 ml of water is then added and the mixture is stirred for 3 hours. The chloroform phase is separated off and distilled to dryness. The residue is mixed with dilute ammonia solution and extracted with benzene. After washing the benzene phase with water, the benzene is distilled off. The residue is dissolved in 70 ml of methanol and 60 ml of triethylamine and heated under reflux for 6 hours. It is then distilled to dryness, the residue is mixed with water and extracted with benzene.
  • the reaction mixture is concentrated three times with 20 ml of saturated potassium carbonate solution and then twice with 10 ml. HCI extracted.
  • the combined hydrochloric acid phases are shaken once with 20 ml of chloroform, made basic with concentrated NH 3 solution, extracted twice with 20 ml of chloroform and the combined chloroform phases once with 20 ml of water.
  • the chloroform phases are dried over Na 2 SO 4 and, after concentration, give a crystalline residue of 2.4 g, which is recrystallized from 5 ml of isopropanol.
  • the crystalline residue is mixed with acetonitrile, warmed to complete dissolution and carefully cooled. HCI gas is passed into this solution until an acidic reaction occurs. The hydrochloride partially crystallizes out. The reaction mixture is concentrated and the residue is recrystallized from isopropanol.
  • the residue is dried again at 140 ° C. and 0.8-1 Torr. An oily residue is obtained, which is used for the subsequent acylation reaction without further purification.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

De nouveaux composés constituent des médicaments anti-arythmiques, notamment de la classe III, et peuvent être utilisés pour traiter des perturbations du rythme cardiaque, compte tenu de leur grand spectre d'action thérapeutique. Ces composés ont la formule (I), dans laquelle R1, R2, R3, R4, R5, n et m ont la notation suivante: R1, R2 désignent hydrogène, alcoyle C1-C8 à chaîne droite ou ramifiée, cycloalcoyle C3-C8, cyclohexyle, phényle substitué le cas échéant une ou deux fois par alcoyle C1-C4 à chaîne droite, alcoxy C1-C2, halogène, cyano, nitro, trifluorométhyle, aminocarbonyle, mesylamino ou acylamino; ou phénylalcoyle, la chaîne alcoyle pouvant contenir 1 à 3 atomes de carbone et le cycle phényle pouvant être substitué une ou deux fois par méthyle, méthoxy, halogène, nitro, cyano, aminocarbonyle ou acylamido. Le groupe (a) désigne morpholine, pyrrolidine, pipéridine substituée le cas échéant une ou deux fois par un groupe alcoyle C1-C2 ou par un groupe phényle ou benzyle, pipérazine contenant le cas échéant un groupe alcoyle C1-C4, phényle, benzyle ou acyle en 4e position, ou (b) ou (c), où R6 peut désigner H, NHCO2CH2CH3; R3 désigne les groupes CO-R7, (d), (e) ou (f), dans lesquels R7 désigne alcoyle C1-C8 à chaîne droite ou ramifiée, cycloalcoyle C3-C7, cyclohexyle, phényle substitué le cas échéant une ou deux fois par alcoyle C1-C4 à chaîne droite, alcoxy C1-C2, halogène, cyano, nitro, trifluorométhyle, aminocarbonyle, sulfonamido, sulfonamido de toluène, sulfonamido de méthane ou acylamino; phénylalkyle où la chaîne alkyle peut contenir 1-3 atomes de C et le cycle phényle peut être substitué une ou deux fois par méthyle, méthoxy, halogène, nitro, cyano, aminocarbonyle ou acylamido; R8 désigne hydrogène, alcoyle C1-C2, nitro, acylamino; R4, R5 désignent alcoyle C1-C6 à chaîne droite ou ramifiée, cyclohexyle, phényle, phénylalcoyle, le groupe alcoyle pouvant contenir 1 à 3 atomes de C; le groupe (g) désigne pipéridine, pyrrolidine, morpholine, pipérazine contenant le cas échéant un groupe alcoyle C1-C4, un groupe phényle ou un groupe benzyle en 4e position; n vaut de 1 à 5 et_m vaut de 2 à 4.
EP95900625A 1993-12-24 1994-11-12 Amides d'acide aminocarboxylique, leur procede de preparation et leur utilisation comme medicaments anti-arythmiques Withdrawn EP0736005A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4344648 1993-12-24
DE4344648A DE4344648A1 (de) 1993-12-24 1993-12-24 Neue Aminocarbonsäureamide, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
PCT/DE1994/001343 WO1995018099A1 (fr) 1993-12-24 1994-11-12 Amides d'acide aminocarboxylique, leur procede de preparation et leur utilisation comme medicaments anti-arythmiques

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EP0736005A1 true EP0736005A1 (fr) 1996-10-09

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RU2164512C1 (ru) * 1999-07-27 2001-03-27 Всероссийский научный центр по безопасности биологически активных веществ Производные аминокислот, проявляющие антиаритмическую активность
GB0125445D0 (en) * 2001-10-23 2001-12-12 Ferring Bv Protease Inhibitors
RU2500666C2 (ru) * 2011-11-14 2013-12-10 Федеральное государственное бюджетное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Российской академии медицинских наук Замещенные n-[2-(1-адамантиламино)-2-оксоэтил]-n-(аминоалкил)амиды нитробензойных кислот
RU2624438C2 (ru) * 2014-02-17 2017-07-04 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Бис(метоксибензиламиноалкил)амины, обладающие кардиотропной активностью

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US4259259A (en) * 1979-11-15 1981-03-31 Texaco Development Corp. Preparation of β-aminopropionamides
US4544654A (en) * 1984-03-20 1985-10-01 Schering A.G. Substituted sulfonamidobenzamides, antiarrhythmic agents and compositions thereof
US4855497A (en) * 1985-04-02 1989-08-08 Chugai Seiyaku Kabushiki Kaisha Novel diamine derivatives
JP3429338B2 (ja) * 1992-07-27 2003-07-22 杏林製薬株式会社 新規なアリールグリシンアミド誘導体及びその製造法

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WO1995018099A1 (fr) 1995-07-06
DE4344648A1 (de) 1995-06-29
RU2134683C1 (ru) 1999-08-20
CA2179810A1 (fr) 1995-07-06

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