CA2078470A1 - Benzylamine derivatives and drugs containing these - Google Patents

Benzylamine derivatives and drugs containing these

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Publication number
CA2078470A1
CA2078470A1 CA002078470A CA2078470A CA2078470A1 CA 2078470 A1 CA2078470 A1 CA 2078470A1 CA 002078470 A CA002078470 A CA 002078470A CA 2078470 A CA2078470 A CA 2078470A CA 2078470 A1 CA2078470 A1 CA 2078470A1
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Prior art keywords
mmol
preparation
alkyl
methyl
chloride
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Abandoned
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CA002078470A
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French (fr)
Inventor
Wilfried Lubisch
Sabine Schult
Rudolf Binder
Dietmar Seemann
Manfred Raschack
Roland Reinhardt
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BASF SE
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Individual
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Publication of CA2078470A1 publication Critical patent/CA2078470A1/en
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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
    • C07D295/08—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 bound oxygen or sulfur atoms
    • C07D295/096—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon 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
    • C07C233/80—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 a carbon atom of a six-membered aromatic ring
    • 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
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • 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
    • 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
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • 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
    • C07D295/135—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 separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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

Abstract

O.Z. 0050/42710 Abstract of the Disclosure: Phenylbenzylamines of the formula I

I

where A is , and -O(CH2)m- (with N
or O bonded to the 1,2-phenylene) R1 is H and C1-C4-alkyl, X is N and C-R2, R2 is NO2, CN, NHSO2CH3, CF3, OCF3 and , Y is NR1R3 and N(CH2)n, n is 4, 5 and 6, R3 is H, C1-C4-alkyl, and

Description

2~7~7~

- O.Z. 0050/42710 Novel benzylamine derivative~ and drua~
containina the~e The present invention relates to novel substituted benzylamine derivatives and to drugs contain-ing these a~ active ingredient.
The present invention relates to benzylamine derivatives of the formula I
~`~CH2-y ~A~X

where ll1l Rl A is -N - C- -N502- and -(CH2)m~ (with N
or O bonded to the 1,2-phenylene) Rl is H and C1-C4-alkyl, X is N and C-R2, R2 iq NO2, CN, NHSO~CH3, CF3, OCF3 and N~
Y iq NRlR3 and N~CH2) D ~
n i~ 4, 5 and 6, Rl R4 R3 i~ H, c1-C~-alkyl, ~(CH2)m ~ and - (CH2 ) m~
m iq 1, 2 and 3 and R4 is H, OCH3 and Cl-C~-alkyl, and the physiologically tolerated salts thereof.
The compounds according to the invention can be prepared in various conventional ways.
Those shown in Scheme 1, the amine HY is alky-lated with 2-nitrobenzyl chloride II under conventional conditions in polar solvents, preferably in alcohols, in the pre~ence of bases such as potassium carbonate, at about 25-lOO-C, resulting in the benzylamine III. III can likewise be obtained by reductive amination of 2-nitro-benzaldehyde VI with the amine HY in polar solvent-q, preferably alcohols, in the pre~ence of sodium cyanoboro-hydride. III is reduced in a conventional way to the aniline IV, using as reducing agent hydrogen in the pre~ence of a catalyst ~uch as Pd/carbon, Pt/carbon or Raney nickel or reagentq which are listed, for example, .. . : ' ~

2~78~70 - 2 - O.Z. 0050/42710 in Houben-Weyl, Methoden der organischen Chemie, Vol.
11/1, Chapter IV, eg. Sn/HCl, Fe~HCl and Na2S2O~. IV is reacted with acid chlorides o o x~3z-c 1 ( Z = --C--, --I--under conventional condition~ (dissolved in organic solvents such as methylene chloride or tetrahydrofuran in the presence of a base such as sodium hydroxide solution, aqueous potassium carbonate solution or triethylamine at from -10 to 25C). The amideR or sulfonamides V according to the invention are obtained. The aniline IV can likewise be obtained from the benzaldehyde VI. Following this, VI is reacted with an amine R3NH2 in ~olution, preferably in alcohols, at 25-100C. The resulting imine VII is reduced in a conventional way, preferably with sodium borohydride in alcohol at room temperature, to the secondary amine VIII. Alkylation of VIII to give III is carried out either with a halide R'-Hal (Hal=Cl, Br and I) in solvents such as alcohol~ at 25-150C or by reduc-tive amination with an aldehyde Rl-CHO in the presence of reducing agents ~uch as sodium cyanoborohydride in solvents such as alcohol~ at 0-60C.
III is then reduced to IV as described above.

2~7~7~

_ 3 _ o.z. 0050/42710 Scheme l:

2 reduction ~CHO
rl \ HY -~
~ III ! R3NH2 reduction ~Hat ~ NR3 VrI
R I-CH~ red IV ~ 2 \ ¦ reduction x~z~ ~NHR 3 ~Y
~NH--Z~X

Synthesis of compounds XII according to the invention i8 depicted in Scheme 2. Salicylaldehyde is alkylated with aralkyl compound X~3JL

where L i~ a leaving group such as Cl or 0-tosylate. The reaction is carried out in Rolution, preferably in alcohols or dimethylformamide, in the presence of bases such as potassium carbonate. The aldehyde IX can be converted into the final product XII by reductive amina-tion, which is carried out in solvents such as alcohols in the presence of reducing agents such as sodium cyanoborohydride, HY.

2~8~70 - 4 - o.Z. 0050/42710 Scheme 2:

CHO ~ (CH2)m-L C~O R3NHz ~R3 OH ~ (CH2)m ~ X ~ CH2)m ~ X
1 reduction / IX X
2 chlorinatio~ \ reduction ~ CH2)m ~ X , reduction ~ tion reduction XIII \ H

\ HY ~ O(CH2)m ~ X
Hal or XI
\ / RI-CHO~reduction ~Y
~o(cH2)m~x Reaction of the aldehyde IX with the amine R3NH2, which is carried out in alcohols at from 25 to 100C, results in the imine X which on reduction with sodium borohydride in solvents such as alcohols gives the amine XI. The conversion of XI into the final product XII is carried out either by alkylation with a halide Rl-Hal (Hal = chlorine, bromine and iodine) in polar ~olvents such as alcohols or dimethylformamide at from 25 to 150C, or by reductive amination with an aldehyde RlCHO in solvents such a8 ~lcohols in the presence of reducing agent~ such as sodium cyanoborohydride.
The benzaldehyde derivative IX can be converted into the benzyl chloride XIII by reduction, preferably with sodium borohydride in alcohols, and subsequent chlorination with or without ~olvent with chlorinating agents such a~ thionyl chloride. The subsequent alkyla-tion of the amine HY with the chloride XIII to give the compound XII according to the invention is carried out in alcohols or dimethylformamide in the presence of bases 2~78A7~

- 5 - O.Z. 0050/42710 such as potassium carbonate.
If required, the resulting benzylamine deriva-tives are converted into the acid addition salt of a physiologically tolerated acid. A list of conventional physiologically tolerated acid~ iR to be found in Fortschritte der Arzneimittelforschung, 1966, Birkhauser Verlag, Vol. 10, pages 224 to 285, Germany, Switzerland.
The acid addition salts are as a rule obtained in a conventional manner by mixing the free base or solu-tions thereof with the appropriate acid or solutionsthereof in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dioxane. It is possible to use mixture~ of the said solvents to improve crystallization.
Furthermore, pharmaceutically acceptable aqueous solutions of acid addition compounds of the benzylamine derivatives of the formula I can be prepared by diRsolving the free bases in an aqueous acid solution.
The benzylamine derivatives according to the invention are class III antiarrhythmics. In addition, they have affinity for the sigma receptor and therefore have an antipsychotic, anxiolytic, anticonvulsant and neuroprotective action. We have additionally found that the compounds block the ATP-sen~itive R channel.
The present invention therefore also relates to therapeutic compositions for topical and, in particular, systemic administration which contain a compound of the formula I as active ingredient in addition to the conven-tional vehicles and/or other pharmaceutical aids, and to the use of a compound of the formula I for producing a drug.
The therapeutical compositions or formulations are produced using the COnVQntiOnal liquid or solid vehicles or diluents and the conventional pharmaceutical ancillary substances appropriate for the required mode of 2~7~7~
- 6 - O.Z. 0050/42710 administration and in a dosage suitable for administra-tion, in a conventional manner, for example, mixing the active ingredient with the conventional solid or liquid vehicles and ancillary substances for such products.
The compositions can be admini~tered orally, parenterally or topically. Examples of formulations of this type are uncoated or (film-)coated tablets, cap-sules, pills, powders, solutions or suspensions, infusion or in~ection solutions, and pastes, ointments, gels, creams, lotions, dusting powders, solutions or emulsions and sprays.
The therapeutic compositions can contain the compounds to be used according to the invention in a concentration of from 0.001 to 1%, preferably from 0.001 to 0.1%, for topical administration and preferably in a single do~e of from 0.1 to 50 mg per kg of bodyweight for systemic administration, and can be administered in one or more doses each day depending on the nature and ~everity of the disorders.
Example~ of conventional pharmaceutical ancillary substances for topical administration are alcohols, such as ethanol, isopropanol, ethoxylated castor oil or ethoxylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, liquid paraffin, petrolatum, lanolin, polyethylene glycol, polypropylene glycol, salts of stearic acid and ethoxylated fatty alcohol, and for systemic administration of lactose, propylene glycol and ethanol, starch, talc, polyvinylpyrrolidone. The products can contain antioxidants, for example tocopherol and butylated hydroxyanisole or butylated hydroxytoluene, or flavoring~, stabilizers, emulsifiers,lubricants etc. The requirement is that all the ~ubstances used in the production of pharmaceutical formulations are toxicologi-cally acceptable and comparable with the active ingre-dients.
The therapeutic actions can be demonstrated using the following models:

20~7~
- 7 - O.Z. 0050/42710 Antiarrhythmic action The action of the benzylamine derivatives as repolarization inhibitors can be demonstrated by ECG
measurements. In this connection, the cardiac cycle is divided into systole (contraction of the heart), also called QT interval, and diastole (relaxation of the heart and filling of the ventricles with blood). Repolarization inhibitors increase the QT interval while causing a negligible change in the atrioventricular conduction time (PQ interval) and the period of isometric contraction (QRS time, from start of systole to the opening of the semilunar valves).
The activity of the compounds according to the invention as repolarization inhibitors can be inves-tigated in animal experiments by ECG measurements for example on the guinea pig heart (see Basic Res. Cardiol.
82 (1987) 437; J. Pharmacol. Nethods 21 (1989) 195).
Comparison of the activities of several substances is based, for example, on the dose of the substance at which there is a 20% increase from the initial QT interval (ED20s). This is done by plotting the logarithm of the doses of the particular substances against the experimen-tally found relative changes in the QT interval, and linear regression is used to determine the equation of a line from which the ED20~ can then be calculated.
Male Duncin-Hartley guinea pigs weighing from 300 to 350 g were used as experimental animals. 30 min after a~ministration of 1250 I.U. of heparin~kg bodyweight into the abdominal cavity, the animals were sacrificed by a blow to the back of the neck. The carotid arteries were severed for exsanguination and then the thoracic cavity was opened, and the heart was dissected out and attached to a perfusion apparatus. Langendorff perfusion was carried out with oxygen-enriched Rrebs-Henseleit solution at 37C (NaCl 6896 mg/l; RCl 350 mg/l; MgSO~ 285 mg~l;
CaCl2 370 mg/l; RH2PO~ 161 mg/l; NaHCO3 2090 mg/l; glucose 2000 mg~l). The perfusion volume per unit time was 2~ ~8~
- 8 - O.Z. 0050/42710 ad~usted to from 4 to 6 ml/min for a total volume of 100 ml, and the perfusion pre-Qsure was ad~usted to from 60 to 70 mm Hg. Circulating perfuqion was carried out after equilibration for 30 min.
The ECG recordingq were made using two silver electrodes attached to the surface of the heart in a upper region of the left coronary artery and on the rear of the heart at valve level. The PQ and QT intervals and the QRS time, and the heart rate, were measured.
The substance was administered cumulatively into the perfusate at intervals of 15 min.
Binding to the sigma receptor Sigma receptors were discovered a few years ago.
They open up new possibilities for the therapy of various diseases (cf. C.D. Ferris et al., J. Neurochemistry, 57 (1991) 729-737). For example, sigma ligands might be employed as antipsychotics, anticonvulsants, anxiolytics and neuroprotectives. A number of compounds such as haloperidol and 3MY 14802 are reported to have affinity for the sigma receptor (B.L. Largent et al., J.
Pharmacol. Exp. Ther. 2 (1986) 739-748), but these compounds also have affinity for other receptors such as the dopaminertic and serotoninertic receptors. This is why new compounds with a specific action on the sigma receptor are -Qought. The affinities of the compounds according to the invention for the sigma receptors were measured by means of the displacement of 3H-ditolylguani-dine (binding assay).
The affinity constants RI which were determined from the displacement experiments using iterative fitting programs have been reported as a measure of the potency of the compounds.
The binding assay used (binding of [3H]-ditolyl-guanidine) detects haloperidol-sensitive sigma receptors which have a high affinity for haloperidol but only low affinity for phencyclidine and for opioids.

2~78~7~

- g - O.Z. 0050/42710 Methods:
~) Membrane preparation Rat cerebra were homogenized in 10 times the volume of homogenization buffer (50 mmol/l tris(hydroxy-methyl)aminomethane, 0.1 mmol/l ethylenediaminetetra-acetate, pH=7.7) using a Polytron homogenizer (20 sec).
The pellet obtained after centrifugation at 40000 revolu-tions per min for 15 minutes was resuspended and the suspension again centrifuged at 40000 revolutions per min for 15 minutes. The resulting pellet was resuspended in 5 times the volume of homogenization buffer and stored in liquid nitrogen until used further.
~) Sigma binding essay The test substance and membranes (0.3 mg of protein) were incubated in 0.3 ml of incubation buffer (5 mmol/l tris(hydroxymethyl)aminomethane, 0.1 mmol/l ethylenediaminetetraacetate, pH=7.7) at 37C for 45 minutes. Addition of 100,000 dpm t3H]-ditolylguanidine (54.5 Ci/mmol) was followed by incubation for 1 hour. The membranes were filtered off through GF/B filter~ (dunn-Labortechnik, Asbach) and washed with a washing buffer (5 mmol/l tris(hydroxymethyl)aminomethane, 0.1 mmol/l ethylenediaminetetraacetate, pH-7.4) at 37-C. The radio-activity remaining on the filters was measured by liquid scintillation counting. The binding data were analyzed using iterative fitting programs.
A~P-dependent R~ current The ATP-dependent R~ current (A. Noma, Nature 305 (1983) 147-148) was measured using the patch clamp technique in the whole cell configuration (O.P. Hamill et al., Pfl~gers Arch. 391 (1981) 85-100) on isolated guinea pig ventricular myocytes. The I/V plot of the total R~
current of the ventricular cells was recorded with the voltage increasing from -100 mV to 60 mV. The ATP-dependent R~ current was activated either with dinitro-phenol (W.J. Lederer et al., J. Physiol. (London) 413 (1989) 329-349) or with cromakalim (D. Escande et al., 2~73l~
- 10 - O.Z. 0050~42710 Biochem. Biophys. Res. Comm. 154 (1988) 620-625). The sulfonylurea glibenclamide (S.J.H. Ashcroft et al., Cellular Signalling 2 (1990) 197-214) is a selective blocker of the ATP-dependent R+ current in ventricular cells and ~ cells. Glibenclamide has been shown in vitro and in vivo to have antiarrhythmic and antifibrillatory actions (S.S. Bekheit et al., Am. Heart J. 119 (1990) 1025-33; C.D. Wolleben et al., J. Mol. Cell. Cardiol. 21 tl989) 783-88). In addition, glibenclamide reduces the ischemic extracellular Kt accumulation (S.S. Bekheit et al., loc. cit.). These effects demonstrate the potential of ~tATP channel blockers for antiarrhythmic/antiischemic therapy. Since glibenclamide has a considerably stronger action on ~ cells (S.J.H. Ashcroft et al., loc. cit.), it is unsuitable for cardiac applications. New types of blockers of this ion channel are therefore desirable. A
new type of blocker, which is not a sulfonylurea, of this ion channel is 5-hydroxydecanoate, but this has no effect until the concentration is about 100 ~M (J. Mol. Cell.
Cardiol. 21, Suppl. 2, (1989) 9).
PREPARATION OF PRECURSORS
PREPARA$ION 1:
20.0 g (0.12 mol) of 2-nitrobenzyl chloride, 14.2 g (0.12 mol) of benzylmethylamine and 34.2 g of potassium carbonate were stirred in 300 ml of ethanol at 60C for 5 h. The precipitate was then filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene, and ethereal hydrogen chloride solution was added. The precipitated oil was crystallized from a little acetone. 26.2 g of benzyl-methyl(2-nitrobenzyl)amine hydrochloride were obtained.
Melting point 184-186C.
PREPM ATION 2:
26 g (0.10 mol) of the base of the product from Preparation 1 were hydrogenated in 250 ml of methanol in the presence of 1 g of platinum/carbon (5%) in a conven-tional manner. 20.6 g of 2-aminobenzyl(benzyl)methylamine 2~78~7~

- 11 - O.Z. 0050/42710 were obtained aQ an oil. lH-NMR (CDCl3: 6 = 2.1 (s, 3H), 3.4 (8, 2H), 3.5 (~, 2H), 4.7 (broad, 2H, NH) and 6.6-7.4 (9H) ppm.
PREPARATION 3:
15.8 g (0.12 mol) of methyl(2-phenylethyl)amine, 20.0 g (0.12 mol) of 2-nitrobenzyl chloride and 34 g of potassium carbonate were reacted as for Preparation 1.
29 g of methyl(2-nitrobenzyl)-2-phenylethylamine were obtained and immediately reacted further aQ crude product. lH-NMR (CDCl3: ~ = 2.2 (s, 3H), 2.6-2.7 (m, 2H), 2.7-2.9 (m, 2H) and 7.0-7.8 (9H) ppm.
PREPARATION 4:
26 g (96.2 mmol) of the crude product from Preparation 3 were hydrogenated on Pt/carbon (5~) in methanol as in Preparation 2. 22.4 g of the oily 2-amino-benzyl(methyl)-2-phenylethylamine were obtained. lH-NMR
(D~-DMSO): ~ = 2.1 (s, 3H), 2.5-2.7 (m, 2H), 2.7-2.9 (m, 2H), 3.4 (~, 2H), 5.0 (2H, NH), 6.5 (t, lH), 6.6 (d, lH), 6.9-7.0 (2H) and 7.1-7.3 (5H) ppm.
PREPARATION 5:
20.6 g (0.08 mol) of 2-(4-nitrobenzyloxy)benz-aldehyde were dissolved in a mixture of 200 ml of isopro-panol and 50 ml of methanol and then 200 ml of water and 6.0 g (0.16 mol) of sodium borohydride were successively added. After stirring at room temperature for 16 hours, the crystals were filtered off with ~uction. 16.4 g of 2-(4-nitrobenzyloxy)benzyl alcohol were obtained. Melting point 123-C.
PREPARATION 6:
34.0 g (0.13 mol) of the product from Preparation 5 were suspendQd in 350 ml of methylene chloride, and 15 ml of thionyl chloride were added. The mixture was refluxed for 2 h and then concentrated under reduced pre~sure. 36.9 g of 2-(4-nitrobenzyloxy)benzyl chloride were obtained. Melting point 111C.

'' 2 ~ 7 ~
- 12 - O.Z. OOSO/42710 PREPARATION 7:
2.5 g (10 mmol) of 2-t4-cyanobenzyloxy)benz-aldehyde and 1.2 g (10 mmol) of 4 (2-aminoethyl)pyridine in 50 ml of ethanol were refluxed for 8 h. The mixture S was then concentrated under reduced pressure, and the residue was recrystallized from cyclohexane with a little toluene. 2.4 g of N-(2-(4-cyanobenzyloxy)phenyl)methy-lene-2-(4-pyridyl)ethylamine were obtained.
1H-NMR (CDCl3) ~ = 3.0 (t, 2H); 3.9(t, 2H); 5.1(s, 2H);
6.9(d, lH); 7.0(t, lH); 7.1(d, 2H); 7.4(dt, lH); 7.5(d,2H);
7.7(d,2H); 8.0(dd,1H); 8.5(d,2H) and 8.6(s,1H)ppm.

1.9 g (8.4 mmol) of the product from Preparation 2 were dissolved in 50 ml of methylene chloride. SO ml of 2 M sodium hydroxide solution and then, at 0-5C, drop-wise 1.9 g (10.2 mmol) of 4-nitrobenzyl chloride dis-solved in methylene chloride were added, the mixture was stirred for 1 h and the organic phase was separated off and then washed with H20, dried and mixed with ethereal hydrogen chloride solution. The residue from evaporation was boiled with a little acetone. 2.9 g of N-(2-(N-ben-zyl-N-methylaminomethyl)phenyl)-4-nitrobenzamide hydro-chloride were obtained; melting point 230C.

3.0 g (12.5 mmol) of the product from Preparation 4 were reacted with 2.4 g (14.5 mmol) of 4-cyanobenzoyl chloride as in example 1. 2.4 g of 4-cyano-N-(2-(N-methyl-N-(2-phenylethyl)aminomethyl)phenyl)benzamide were obtained. Melting point 128-C (isopropanol).

3.0 q (12.5 mmol) of the products from Preparation 4 and 2.5 g (25 mmol) of triethylamine were dissolved in 100 ml of anhydrous tetrahydrofuran. At 0-5C, 2.75 g (12 mmol) of 4-methanesulfonylaminobenzyl chloride dissolved in tetrahydrofuran were added drop-wise. The reaction mixture was stirred for 2-3 h and then concentrated under reduced pressure. The residue was 2~7~7~
-- 13 - O.Z. 0050/42710 recystallized from a little isopropanol. 3.8 g of 4-methanesulfonylamino-N-(2-(N-methyl-N-(2-phenylethyl)-aminomethyl)phenyl)benzamide were obtained. Nelting point 153C.

3.0 g (10.8 mmol) of the product from Preparation 6, 1.3 g (10.8 mmol) of benzylmethylamine and 2 g of potassium carbonate were reacted as for Preparation 1.
The product was crystallized as fumarate from ethanol.
4.1 g of benzyl(methyl)-2-(4-nitrobenzyloxy)benzylamine fumarate were obtained. Melting point 157~C.
EXANPLE S
4.0 g (14.4 mmol) of the product from Preparation 6, 2.0 g (14.8 mmol) of methyl(2-phenylethyl)amine and 2 g of potassium carbonate were reacted as for prepara-tion 1. 3.6 g of methyl(2-(4-nitrobenzyloxy)benzyl)-2-phenylethylamine hydrochloride were obtained. Melting point 195C.

3.0 g (12.7 mmol) of 2-(4-cyanobenzyloxy)benz-aldehyde, 1.7 g (12.7 mmol) of methyl(2-phenylethyl)amine and 0.76 g (12.7 mmol) of glacial acetic acid were dissolved in isopropanol and stirred at room temperature.
0.8 g (12.7 mmol) of sodium cyanoborohydride was added a little at a time, and the mixture was stirred for a further 16 h. It was then concentrated under reduced pressure, the residue was partitioned between 2 M sodium hydroxide solution and ether, and the organic phase was dried. The ether phase was mixed with ethereal hydrogen chloride solution and the precipitated product was recrystallized from isopropanol. 2.4 g of 2-(4-cyano-benzyloxy)benzyl(methyl)2-phenylethylamine hydrochloride were obtained. Melting point 185C.

2.4 g (7.0 mmol) of the product from Preparation 7 were dissolved in 100 ml of ethanol and, at room temperature, 0.27,g (7.1 mmol) of sodium borohydride was .

2~7g~7~

- 14 - O.Z. 0050/42710 added a little at a time. The reaction mixture was stirred for 16 h and then concentrated under reduced pressure. The residue was partitioned between methylene chloride and water, and the organic phase was dried and concentrated under reduced pressure. 2.5 g of 2-(4-cya-nobenzyloxy)benzyl-2-(4-pyridyl)ethylaminewereobtained.
H-NMR (D2O) ~ = 3.2-3.8(4H); 4.4(9,2H); 5.3(s,2H);
7.1(2H); 7.3-7.8(6H) and 8.8(2H) ppm.

2.4 g (7 mmol) of the product from Example 7, 3 g of 37% strength formalin solution, 0.42 g of glacial acetic acid and 0.46 g of sodium cyanoborohydride were reacted as in Example 6. The precipitated oil was crys-tallized as oxalate from acetone. 1.6 g of 2-(4-cya-nobenzyloxy)benzyl(methyl)-2-(4-pyridyl)ethylamine oxalate were obtained. Melting point 161-162C.

15.0 g (54 mmol) of the product from Preparation 6 and 5.3 ml (54 mmol) of piperidine were stirred in a mixture of 50 ml of triethylamine and 200 ml of dimethyl-formamide at room temperature for 16 h. The reaction mixture was diluted with a large amount of water and extracted with ether. The organic phase was dried and mixed with ethereal hydrogen chloride solution, when the product precipitated. 12.5 g of N-(2-(4-nitrobenzyloxy)-benzyl)piperidine hydrochloride were obtained. Melting point 216C.

3.0 g (15.8 mmol) of N-(2-aminobenzyl)piperidine and 3.1 g (16.7 mmol) of 4-nitrobenzoyl chloride were reacted as in Example 1. 3.4 g of 4-nitro-N-(2-(N-piperi-dinylmethyl)phenyl)benzamide were obtained. Melting point 162C.

2.0 g (8.4 mmol) of 2-(4-cyanobenzyloxy)benz-aldehyde, 1.0 g (8.2 mmol) of 4-methylamino-2-picoline, 0.5 g of glacial acetic acid and 0.53 g of sodium 2~78~79 - 15 - O.Z. 0050/42710 cyanoborohydride were reacted in methanol as in example 6. The resulting oil was crystallized as fumarate from isopropanol. 2.3 g of 2-(4-cyanobenzyloxy)benzyl(methyl)-2-picol-4-ylamine fumarate. Melting point 155-156C.

3.0 g (12.5 mmol) of the product from Preparation 4 and 3.0 g (13.5 mmol) of 4-nitrophenylsulfonyl chloride were reacted as in Example 3. The result was a yellow solid which was recrystallized from toluene. 2.9 g of N-(2-(N-methyl-N-(2-phenylethyl)aminomethyl)phenyl)-4-nitrophenylsulfonamide were obtained. Melting point 151-152C.

Claims (3)

1. A phenylbenzylamine of the formula I

I

where A is , and -0(CH2)m- (with N
or O bonded to the 1,2-phenylene) R1 is H and C1-C4-alkyl, X is N and C-R2, R2 is NO2, CN, NHSO2CH3, CF3, OCF3 and , Y is NR1R3 and N(CH2) n n is 4, 5 and 6, R3 is H, C1-C4-alkyl, and m is 1, 2 and 3 and R4 is H, OCH3 and C1-C4-alkyl, and the physiologically tolerated salts thereof.
2. A drug for systemic administration which contains from 0.1 to 50 mg/kg of bodyweight of a compound as claimed in claim 1 as active ingredient per single dose in addition to conventional pharmaceutic ancillary substances.
3. A drug for topical administration which contains from 0.001 to 0.1% by weight of a compound as claimed in claim 1 as active ingredient in addition to conventional pharmaceutical ancillary substances.
CA002078470A 1991-09-26 1992-09-17 Benzylamine derivatives and drugs containing these Abandoned CA2078470A1 (en)

Applications Claiming Priority (2)

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DE4132013A DE4132013A1 (en) 1991-09-26 1991-09-26 NEW PHENYLBENZYLAMINE AND MEDICINAL PRODUCTS CONTAINING THEM

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EP1524267A1 (en) * 2003-10-15 2005-04-20 Newron Pharmaceuticals S.p.A. Substituted benzylaminoalkylene heterocycles

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