WO1994013622A1 - Derives de l'aralkyldiamine et medicaments antiarythmiques contenant ces derives - Google Patents

Derives de l'aralkyldiamine et medicaments antiarythmiques contenant ces derives Download PDF

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Publication number
WO1994013622A1
WO1994013622A1 PCT/DE1993/001145 DE9301145W WO9413622A1 WO 1994013622 A1 WO1994013622 A1 WO 1994013622A1 DE 9301145 W DE9301145 W DE 9301145W WO 9413622 A1 WO9413622 A1 WO 9413622A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
aralkyldiamine
diethylamino
phenylpent
alkyl
Prior art date
Application number
PCT/DE1993/001145
Other languages
German (de)
English (en)
Inventor
Gerd Petrik
Siegfried Rhein
Martin Elsner
Original Assignee
Helopharm W. Petrik Gmbh & Co. Kg.
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
Application filed by Helopharm W. Petrik Gmbh & Co. Kg. filed Critical Helopharm W. Petrik Gmbh & Co. Kg.
Priority to EP94900743A priority Critical patent/EP0673362A1/fr
Priority to AU55600/94A priority patent/AU5560094A/en
Publication of WO1994013622A1 publication Critical patent/WO1994013622A1/fr

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
    • C07C275/48—Y being a hydrogen or a carbon atom
    • C07C275/54—Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas

Definitions

  • the invention relates to new aralkyldiamine derivatives, processes for their preparation and medicaments containing these compounds.
  • Class I compounds such as, for example, flecainide (INN) (N- (2-piperidylmethyl) -2,5-bis (2,2,2-trifluoroethoxy) benzamide), lidocaine (INN) (2-diethylamino-2 ' , 6'-acetoxylidide) and propafenone (INN) (2 '- [2-hydroxy-3- (propylamino) propoxy] -3-phenylpr ⁇ piophenon), act locally on the nerve and myocardial membranes and thereby slow the conduction of stimuli, which in turn reduces the forwarding of premature heartbeats. In addition, the tendency of damaged cells to send out premature heartbeats is suppressed.
  • the class II compounds are the so-called ⁇ -blockers.
  • Propranolol (INN) (1-isopropylamino-3- (1-naphthyloxy) -2-propanol) may be mentioned here as an example.
  • Class III compounds such as amiodarone (INN) (2-butyl-3-benzofuranyl) - [4- (2-diethylaminoethoxy) -3,5-diiodophenyl] ketone) or sotalol (INN) (4 '- (l-Hydroxy-2-isopropylaminoethyl) methanesulfonanidide) have little or no influence on the conduction of the stimulus. In fact, they are largely independent of the stimulus conduction. These connections extend the duration of the action potential of the heart muscle and thereby lengthen the time interval in which the heart muscle is not excitable. They neither slow the stimulus conduction nor the excitability of the cells of the heart.
  • WO-88/02362 are aryl-N-aminoalkyl-4- (sulfonamido) benzamides of the general formula
  • the compounds of class III are particularly suitable for the treatment of cardiac arrhythmias, since they do not influence the conduction of stimuli or the excitability of the cardiac cells.
  • the class III antiarrhythmics used to date have a number of side effects, some of which are considerable. These include, for example, nausea, vomiting, feeling of fullness, constipation, headache, dizziness, visual disturbances, sleep disturbances, sensitivity to sunlight, skin hyperpigmentation, sinus bradycardia, prolongation of the AV conduction time and pulmonary fibrosis.
  • side effects make their use in medical practice considerably more difficult. There is therefore an urgent need for compounds which do not have these side effects or only have them to a minor extent.
  • this object is achieved by creating new aralkyldiamine derivatives of the general formula I
  • R ** L is a hydrogen atom or a benzoyl radical, the phenyl radical optionally being substituted by a halogen atom, a nitro group, an amino group, an alkyl or alkoxy group having up to four C atoms, a phenoxy group or a benzoyl group,
  • R 2 is a hydroxymethyl, aminomethyl, aminocarboxymethyl or aminooxycarboxymethyl group
  • R 3 and R 4 are the same or different and represent hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl or hydroxyalkyl radicals each having up to 6 carbon atoms, alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl radicals each having up to 9 C atoms, or phenylalkyl or phenoxyalkyl radicals with up to 6 C atoms in the alkyl part, where the phenyl radical is optionally substituted by an alkyl or alkoxy radical with up to 3 C atoms each,
  • n is an integer between 1 and 8.
  • R *** ⁇ is a p-nitrobenzoyl radical
  • R j L is a p-nitrobenzoyl radical
  • R 2 is a piperidinomethyl, morpholinomethyl, phenethylamino, methylamino methyl, ethylaminomethyl, diethylaminomethyl, dimethylaminomethyl, benzylaminomethyl, Alaninomethyl, anilinomethyl, p-toluidomethyl, pyrrolidinomethyl, piperazinomethyl, hydroxymethyl, acetoxymethyl, butyryloxymethyl, benzoyloxymethyl, N, N, N-dimethylglycyloxymethyl, N, N-diethylglycyloxymethyl -Dipropylglycyloxymethyl, nicotinoyloxymethyl, phenylalanyloxymethyl or le
  • the invention further relates to a process for the preparation of the compounds of the formula I according to the invention, which is characterized in that an A in the formula II
  • the compounds according to the invention can be prepared by using various reactants and processes.
  • Scheme A shows some reaction routes leading to the compounds according to the invention.
  • the primary amine (a) is optionally reacted with a carboxylic acid halide to give the acid amide (b).
  • the amide or amine (b) is reacted in a Mannich reaction with formaldehyde and a corresponding primary, secondary or aromatic amine in a manner known per se to give the N-Mannich bases (c) according to the invention. If the amide or amine (b) is reacted with formaldehyde alone, the hydroxymethyl derivatives (d) according to the invention are obtained. Further reaction of the hydroxymethyl derivatives (d) with carboxylic acid, aminocarboxylic acid and N, N-dialkylaminocarboxylic acid halides in a manner known per se provides the compounds (e) according to the invention. These correspond to Formula I.
  • Scheme B shows a way of producing the amines according to formula II, starting from omega-chlorocarboxylic acids (a), which are reacted in a manner known per se with an excess of thionyl chloride to give the corresponding acid chlorides (b) .
  • These acid chlorides are subjected to a Friedel-Crafts reaction with benzene and aluminum trichloride as Friedel-Crafts catalyst and the above-mentioned chlorophenones (c) are formed.
  • the omega-chlorophenones (c) are with appropriate primary, secondary or aromatic amines converted to the omega-aminophenones (d).
  • the keto group of the omega-aminophenones can be converted into the corresponding free amine (s) under the conditions of reductive amination, for example by reduction with sodium cyanoboranate in the presence of ammonium acetate.
  • These amines correspond to the general formula II.
  • the invention further relates to a process for the preparation of the compounds of the formula I in enantiomerically pure form, which is characterized in that an amine of the formula Ha
  • the compounds of the invention can be prepared in an analogous manner, as described in Scheme A, with the proviso that the amine (a) is an amine of the formula Ha.
  • the starting compounds for the preparation of the compounds according to the invention in enantiomerically pure form, the amines of the formula Ila, can be prepared from suitable precursors by enantioselective synthesis.
  • the amines of the formula Ila can also be obtained from the amines of the formula II by racemate resolution by processes and methods known per se.
  • the amines of the general formula II are usually in the form of racemates or mixtures of enantiomeric or diastereomeric forms.
  • the amines of the formula Ila can be prepared by fractional crystallization using suitable diastereomeric salts with enantiomerically pure acids. Suitable acids are, for example, tartaric acid, o-tolyltartaric acid, benzoyltartaric acid or camphorsulfonic acid.
  • the resolution can also be resolved chromatographically by separation on chiral sorbents or with chiral solvents or solvent mixtures or a combination of these processes.
  • the present invention also relates to medicaments for oral, intravenous, intramuscular and rectal application which, in addition to the customary carriers, auxiliaries and diluents, contain a compound of the formula I. These new compounds are made available for the treatment of cardiac arrhythmias.
  • aralkyldiamine derivatives according to the invention are prepared with the customary solid or liquid carriers or diluents and the pharmaceutical-technical auxiliaries usually used for the desired type of application in a suitable dosage in a manner known per se.
  • the preferred preparations are dosage forms which are suitable for oral administration. Dosage forms of this type are, for example, capsules, tablets, film-coated tablets, dragees, pills, powders, solutions or suspensions or depot forms.
  • Parenteral forms of preparation such as injection solutions, are also suitable. Suppositories can also be mentioned as an application form.
  • Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier, such as milk sugar, sorbitol or microcrystalline cellulose, and encapsulating it in gelatin capsules.
  • an inert carrier such as milk sugar, sorbitol or microcrystalline cellulose
  • Corresponding tablets can be mixed, for example, by mixing the active ingredient with known auxiliaries, for example inert fillers such as dextrose, sugar, sorbitol, mannitol, corn starch, disintegrants such as polyvinyl pyrrolidone or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents for achieving a depot effect such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, and compressing the mixture.
  • the tablets can optionally also consist of several layers.
  • film tablets can be obtained by coating the cores produced analogously to the tablets with film formers, such as, for example, polymethacrylates or methyl celluloses.
  • film formers such as, for example, polymethacrylates or methyl celluloses.
  • Coated tablets are produced accordingly by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example polyvinylpyrrolidone, gum arabic, talc, sugar, titanium dioxide or shellac.
  • agents commonly used in tablet coatings for example polyvinylpyrrolidone, gum arabic, talc, sugar, titanium dioxide or shellac.
  • Solutions and suspensions with the active ingredient according to the invention can additionally contain taste-improving agents such as saccharin, cyclamate or sugar as well as flavorings such as vanillin, citrus extracts or peppermint oils. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.
  • Parenteral administration forms such as injection solutions, are prepared in a manner known per se by dissolving the compound according to the invention in water or physiological saline.
  • Suitable suppositories can be prepared by mixing the compound according to the invention with carriers provided for this purpose, such as cocoa butter, neutral fats or polyethylene glycol or their derivatives.
  • the therapeutic agents When used systemically, the therapeutic agents preferably contain the compounds according to the invention in a single dose of 10 to 500 mg and are administered daily in one or more doses depending on the type and severity of the disease.
  • the aralkyldiamine derivatives according to the invention have an antiarrhythmic effect.
  • the compounds of the general formula I can be used for the treatment of cardiac arrhythmias, in particular arrhythmias of the re-entrant type and in particular of disease states which are known as chronic ventricular tachycardias.
  • the effectiveness of the compounds according to the invention is based on the property of prolonging the action potential of the myocard. Substances with these properties are classified according to the Vaughan-Williams classification in class III of the antiarrhythmic substances.
  • the antiarrhythmic properties can be investigated using various in vivo and in vitro methods.
  • myocardial tissues from guinea pigs dogs or rabbits are suitable for measuring the resting and action potentials. Measurements are made, for example, on Purkinje fibers of rabbits or dogs, on auricular muscle fibers or papillary muscles of guinea pigs.
  • In vivo measurements are carried out on anesthetized pigs or dogs. For this purpose, re-entrant arrhythmias and / or atrial fibrillation are generated, for example by programmed electrical stimulation, and the antiarrhythmic effectiveness of the compounds according to the invention is determined.
  • the compounds according to the invention have a good anti-arrhythmic class III effect.
  • the compounds according to the invention are more effective in QT prolongation than the known class III antiarrhythmic agent D-sotalol.
  • the new substances are suitable for the treatment of otherwise therapy-resistant arrhythmias, in particular they eliminate ventricular tachycardias which occur after myocardial infarction and are based on a "re-entry , 1 mechanism" (Cardic Arrhythmia Ed. P. Brugada, HJJ Wellens , Futura Publishing Co., Mount Kisko, New York 1987).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne de nouveaux dérivés de l'aralkyldiamine de formule générale (I), qui ont une action antiarythmique, des procédés pour leur préparation et des médicaments contenant ces composés. Dans la formule générale (I), R1 désigne un atome d'hydrogène ou un reste benzoyle, le reste phényle pouvant le cas échéant être substitué par un atome d'halogène, un groupe nitro, un groupe amino, un groupe alkyle ou alcoxy ayant un maximum de quatre atomes de C, un groupe phénoxy ou un groupe benzoyle, R2 désigne un groupe hydroxyméthyle, aminométhyle, aminocarboxyméthyle ou amino-oxycarboxyméthyle, R3 et R4 sont identiques ou différents et désignent des atomes d'hydrogène, des restes alkyle, cycloalkyle, alcényle, alkinyle ou hydroxyalkyle avec chacun un maximum de 6 atomes de C, des restes alcoxyalkyle, alkylthio alkyle ou dialkylaminoalkyle avec chacun un maximum de 9 atomes de C, ou des restes phénylalkyle ou phénoxyalkyle ayant un maximum de 6 atomes de C dans la partie alkyle, le reste phényle éta nt éventuellement substitué par un reste alkyle ou alcoxy ayant chacun un maximum de 3 atomes de C, et n est un nombre entier compris entre 1 et 8.
PCT/DE1993/001145 1992-12-09 1993-11-29 Derives de l'aralkyldiamine et medicaments antiarythmiques contenant ces derives WO1994013622A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP94900743A EP0673362A1 (fr) 1992-12-09 1993-11-29 Derives de l'aralkyldiamine et medicaments antiarythmiques contenant ces derives
AU55600/94A AU5560094A (en) 1992-12-09 1993-11-29 Aralkyldiamine derivatives and antiarrythmic drugs containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19924242396 DE4242396C2 (de) 1992-12-09 1992-12-09 Aralkyldiaminderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
DEP4242396.1 1992-12-09

Publications (1)

Publication Number Publication Date
WO1994013622A1 true WO1994013622A1 (fr) 1994-06-23

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PCT/DE1993/001145 WO1994013622A1 (fr) 1992-12-09 1993-11-29 Derives de l'aralkyldiamine et medicaments antiarythmiques contenant ces derives

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EP (1) EP0673362A1 (fr)
AU (1) AU5560094A (fr)
DE (1) DE4242396C2 (fr)
WO (1) WO1994013622A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3069731A1 (fr) 2005-11-14 2016-09-21 Labrys Biologics Inc. Antagonistes d'anticorps dirigés contre un peptide associé au gène de la calcitonine et procédés les utilisant

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988002362A1 (fr) * 1986-10-02 1988-04-07 Schering Aktiengesellschaft Aryl-n-aminoalkyl-4-(sulfonamido)benzamides, agents antiarhytmiques et leurs compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988002362A1 (fr) * 1986-10-02 1988-04-07 Schering Aktiengesellschaft Aryl-n-aminoalkyl-4-(sulfonamido)benzamides, agents antiarhytmiques et leurs compositions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 114, no. 1, 7 January 1991, Columbus, Ohio, US; abstract no. 191k, M. I. CHERKASHIN ET AL.: "Polymeric effect on antiarrythmic and anesthetic activity of aliphatic-aromatic aminoamides" page 17; *
DOKL. AKAD. NAUK. SSSR, vol. 313, no. 3, 1990 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3069731A1 (fr) 2005-11-14 2016-09-21 Labrys Biologics Inc. Antagonistes d'anticorps dirigés contre un peptide associé au gène de la calcitonine et procédés les utilisant

Also Published As

Publication number Publication date
DE4242396A1 (de) 1994-06-16
AU5560094A (en) 1994-07-04
EP0673362A1 (fr) 1995-09-27
DE4242396C2 (de) 1995-01-05

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