CA2074211A1

CA2074211A1 - Arylalkylamine derivatives

Info

Publication number: CA2074211A1
Application number: CA002074211A
Authority: CA
Inventors: Rudi A. Alisch; Frank R. Schulze; Armin Buschauer; Walter Schunack
Original assignee: Individual
Current assignee: GSK Consumer Healthcare SARL
Priority date: 1991-07-22
Filing date: 1992-07-20
Publication date: 1993-01-23
Also published as: EP0526395A1; FI923306A0; NO922896D0; JPH05262761A; CZ227292A3; IL102572A0; HUT66576A; FI923306A; NO922896L; US5212187A; HU9202388D0; KR930002314A; ZA925466B; TW211571B; IE922363A1; AU2031692A

Abstract

Arylalkylamine derivatives Abstract Arylalkylamine derivatives of the general formula

Description

3- l sm/AlzyM 45 ArYlalkYlamine derivatives The invention relates to arylaLkylamine derivatives which, owing to their antagonistic action against histamine Hl- and H2-receptors, can be used for the prophylaxis and treatment of disorders in which histamine is involved.

A large number of active ingredients that are used in anaesthesia and surgery, as well as surgery per se, may cause a massive release of histamine from mast cells. The liberation of histarnine and the subsequent activation of histamine Hl- and H2-receptors may lead to a clinical picture of anaphylactic or anaphylactoid reaction in varying degrees of severity, from local erythema formation to systemic urticaria with serious decrease in blood pressure, cardiac arrythmia and potentially fatal bronchospasms.

The stimulation of histamine Hl-receptors is, inter alia, a cause of the contraction of smooth muscles, for example the bronchia, and of com~lex cardiovascular effects, for example the contraction or dilatation of vessels, an increase in the permeability of the venule endothelium with exudation and haemoconcentration, prolonging of the atrio-ventricular transmission of stimuli to the extent of an AV block. The activation of the H2-receptors results, inter alia, in an increase in the heart rate, promotion or induction of tachycardiac cardiac irregularity and increased vasodilation. In addition, H2-receptors of the parietal cells of the gastric mucosa bring about an increase in acid secretion with the risk of pulmonary damage resulting from acid aspiration and the formation of stress ulcers.

A significant reduction in those reactions can be achieved by the combined administration of a histamine Hl-receptor-antagonist and a histamine H2-receptor-antagonist before surgery (Lorenz, W.; Doenicke, A. (1985), "Hl- and H2-blockade: A prophylactic principle in anaesthesia and surgery against histamine-release responses of any degree of severity", N. Engl. Reg. Allergy Proc. 6, 37-57. Tryba, M.; Zevounou, F.; Zenz, M.
(1986), "Prevention of histamine-induced cardiovascular reactions during the induction of anaesthesia following premedication with Hl- + H2-antagonists i.m.", Br. J. Anaesth. 58, 478-482).

Owing to its above-mentioned effects on H1- and Hrreceptors, histamine is also involved in various disorders, such as inflammatory skin disorders; pruritus (itching) of various origins, for example pruritus induced by solar radiation, atopic dermatitis and allergic dermatological disorders in general; urticaria, allergies, allergic asthma; rhinitis and allergic disorders of the respiratory organs in general; conjunctivitis and allergic opthalmic disorders in general; and mastocytosis.

The problem underlying the invention is therefore to provide compounds that are suitable for inhibiting the effects of histamine on both the Hl- and the H2-receptors, and that are therefore suitable, for example, for treating the above-mentioned histamine-induced disorders.

The invention relates to arylalkylamine derivatives of the general formula I

R~ I 3 H H
~E' \(C~H ) ~ \(c~) R2 (I), Q

wherein R1 is a substituted or unsubstituted aryl, heteroaryl, aryl-CI-C3alkyl or hetero-aryl-CI-C3alkyl group, a hydrogen atom or a Cl-C3alkyl group, A is a nitrogen atom or a CH group, E is the grouping -(CH2)p-, -O-(CH2)p-, -S-(CH2)p- or \F~(CH2)p-wherein p may be 2, 3 or 4, Q is a nitrogen atom or a CH group, R2 is an unsubstituted or basically substituted aryl, heteroaryl, aryl-C1-C3alkyl or heteroaryl-C1-C3alkyl group, R3 is a hydrogen atom or a C1-C3alkyl group, preferably a methyl group, X is an oxygen atom, a sulfur atom, the grouping N-CN or CH-NO2, m may be 2, 3, 4, 5, 6, 7 or 8 and n may be 1, 2, 3 or 4 and Y is a sulfur atom, an oxygen atom or a methylene group, and to pharmaceutically acceptable salts thereof, also to processes for the preparation of those compounds, to pharmaceutical compositions comprising those compounds and to the use of those compounds for the therapeutic treatment of the human or animal body or for the preparation of pharmaceutical compositions.

Cl-C3alkyl is, for example, methyl. Halogen is, for example, fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Phenyl-CI-C3alkyl is, for example, benzyl.

The radical R2 is preferably piperidino-Cl-C3alkyl-phenyl, guanidino-thiazolyl-Cl-C3alkyl, Cl-C3aLkyl-imidazolyl-Cl-C3alkyl or (N,N-di-Cl-C3alkylamino-Cl-C3alkyl)-furanyl-Cl-C3alkyl.

The compounds of formula I according to the invention are distinguished by a novel overall pharmacological activity that has not been described hitherto. The novel structural class according to the invention exhibits both a histamine Hl-antagonistic component of action and a histamine H2-antagonistic component of action. The following pharmaco-logical results demonstrate this. Suitable for differentiating the two types of action are, for example, in vitro tests on isolated spontaneously beating guinea pig right atrium (H2) and on isolated guinea pig ileum (Hl) (Black, J. W.; Duncan, W. A. M.; Durant, G. J., Ganellin, C. R.; Parsons, M. E. (1972), "Definition and Antagonism of Histamine Hrreceptors", Nature 236,385-390). The concentration/action curves for determining the pharmacological parameters (-log KB) are recorded using a cumulative technique accord-ing to van Rossum, J. M. (1963), "Cumulative Dose-Response Curves. II. Technique for the Making of Dose-Response Curves in Isolated Organs and the Evaluation of DrugParameters", Arch. Int. Pharmacodyn. Ther. 143, 299-307.

Pharmacological data (determined from isolated guinea pig ileum and atrium, respectively) Hl-antagonism H2-antagonism ileum atrium Compounds -log KB -log KB
Example 1 7.20 5.64 Example 9 7.93 6.30 Exarnple 10 8.19 5.83 Example 17 8.30 . 6.78 Example 18 8.43 6.90 Example 20 8.38 7.51 Example 23 8.30 7.90 Example 30 8.21 6.68 Example 35 7.86 7.40 Example 36 8.27 7.57 Example 37 8.13 6.91 Example 48 7.70 7.22 Example 50 8.15 5.19 Example 55 8.14 6.43 . . .
Example 60 8.06 6.41 Example 66 7.95 6.74 Example 70 8.02 6.87 Example 72 7.75 7.35 Example 75 7.91 6.91 Example 79 8.61 6.61 Example 84 8.44 6.52 Example 85 8.15 7.02 Example 88 8.74 6.66 Example 89 8.76 6.76 Example 94 8.80 6.85 Example 96 8.51 8.28 Example 103 7.61 5.92 Example 104 7.97 5.87 Example 105 7.44 7.54 _ - " -.. . .: .
- ' . ~. ., . .. .
- ..
.

Preference is given to the arylalkylamine derivatives of formula I wherein Rl is phenyl, furyl, thienyl, phenyl-CI-C3alkyl or (furyl, thienyl or pyridyl)-CI-C3alkyl, the phenyl ring and the heteroaryl ring in each case being unsubstituted or mono- or di-substituted by halogen, C~-C3alkyl andlor by Cl-C3alkoxy, or Rl is hydrogen or C1-C3alkyl, A is a nitrogen atom or a CH group, E is the grouping -(CH2)p-, -O-(CH2)p-, -S-(CH2)p- or (CH2)p---\

wherein p is 2, 3 or 4, Q is a nitrogen atom or a CH group, R2 is piperidino-CI-C3alkyl-phenyl, guanidino-thiazolyl-CI-C3alkyl, Cl-C3alkyl-imidazolyl-CI-C3alkyl or (N,N-di-Cl-C3alkylamino-CI-C3alkyl)-furanyl-Cl-C3alkyl, R3 is hydrogen or Cl-C3alkyl, X is an oxygen atom, a sulfur atom, the grouping N-CN or CH-NO2, m is 2, 3, 4, 5, 6, 7 or 8 and n is 1, 2, 3 or 4, and Y is a sulfur atom, an oxygen atom or a methylene group, and to the stereoisomeric forms, the hydrates and the physiologically acceptable salts thereof.

In a preferred group of compounds of formula I according to the invention, Rl is a phenyl ring that is unsubstituted or mono- or di-substituted, preferably monosubstituted, by halogen atoms, such as fluorine, chlorine or bromine atoms, preferably chlorine atoms, or by Cl-C3aLkyl groups, preferably methyl or ethyl groups, or by Cl-C3alkoxy groups, such as methoxy or ethoxy groups, or a heteroaryl ring, such as a furyl or a thienyl ring, preferably a phenyl ring. Where the phenyl ring denoted by R1 is monosubstituted, the substituent is preferably bonded in the para-position, a para-chlorine substitution being preferred. In the case of disubstitution, 3,4-, 3,5- and 2,4-disubstitution, especially 3,4-disubstitution, are preferred. A is a CH group or a nitrogen atom, Q is a nitrogen atom or a CH group. E, R2, R3, X, Y, m, n and p are as defined above.
.

In a further preferred group of compounds of formula I according to the invention, Rl is a benzyl group or a heteroarylmethyl group, such as a furylmethyl, thienylmethyl or pyridyl-methyl group, each of which is unsubstituted or mono-or di-substituted, preferably mono-substituted, by halogen atoms, such as fluorine, chlorine or bromine atoms, preferably fluorine or chlorine atoms, or by Cl-C3alkyl groups, preferably methyl or ethyl groups, or 207421~

by Cl-C3aLkoxy groups, such as methoxy or ethoxy groups, preferably methoxy groups, a benzyl group being preferred. Where the benzyl group denoted by Rl is monosubstituted, the substituent is preferably bonded in the para-position, a para-fluorine or para-methoxy substitution being preferred. In the case of disubstitution, 3,4-, 3,5- and 2,4-disubstitution, especially 3,4-disubsdtution, are preferred. Q is a nitrogen atom, A is a nitrogen atom and E is the grouping -CH2-CH2 . R2, R3, X, Y, m, n and p are as defined above.

Special preference is given to the arylalkylamine derivatives of formula I wherein Rl is phenyl or phenyl-CI-C3alkyl, wherein the phenyl ring in each case is unsubstituted or substituted by halogen, C~-C3alkyl or by Cl-C3alkoxy, or is hydrogen or Cl-C3alkyl, A is a nitrogen atom or a CH group, E is the grouping -(CH2)p-, -O-(CH2)p-, -S-(CH2)p- or (CH2)p-wherein p is 2 or 3, Q is a nitrogen atom or a CH group, R2 is piperidino-CI-C3alkyl-phenyl, guanidino-thiazolyl-CI-C3alkyl, Cl-C3aLkyl-imidazolyl-CI-C3alkyl or (N,N-di-Cl-C3alkylamino-CI-C3alkyl)-furanyl-Cl-C3aLkyl, R3 is hydrogen or Cl-C3alkyl, X is an oxygen atom, a sulfur atom, the grouping N-CN or CH-NO2, m may be 2, 3, 4, 5, 6, 7 or 8 and n may be 1, 2, 3 or 4, and Y is a sulfur atom or an oxygen atom, and to the stereo-isomeric forms, the hydrates and the physiologically acceptable salts thereof.

Very special preference is given to the arylalkylamine derivatives of formula I wherein R
is phenyl that is unsubstituted or substituted by halogen or by Cl-C3alkyl, phenyl-Cl-C3alkyl substituted in the phenyl ring by halogen or by Cl-C3alkoxy, or is Cl-C3alkyl, A is a nitrogen atom or a CH group, E is the grouping -(CH2)p-, -O-(CH2)p-, -S-(CH2)p- or 207421~

(CH2)p-\ ~

~ 3 wherein p is 2, Q is a nitrogen atom or a CH group, R2 is 3-piperidinomethyl-phenyl, 2-guanidino-thiazol-4-ylmethyl, 5-methyl-imidazol-4-ylmethyl or 5-(N,N-dimethylamino-methyl)-furan-2-ylmethyl, R3 is Cl-C3alkyl, X is an oxygen atom, a sulfur atom, the grouping N-CN or CH-NO2, m may be 2, 3, 4, 5, 6, 7 or 8 and n may be 2, 3 or 4, and Y is a sulfur atom or an oxygen atom, and to the stereoisomeric forms, the hydrates and the physiologically acceptable salts thereof.

In a further preferred group of compounds of formula I according to the invention, Rl is a hydrogen atom or a Cl-C3alkyl group, preferably a methyl group, A is a CH group, Q is a nitrogen atom and E is the grouping (CH2) p-r>
:~9 R2, R3, X, Y, m, n and p are as defined above.

In a preferred group of compounds of formula I according to the invention, R2 is the grouping 5-methylimidazol-4-ylmethyl and Rl, R3, A, E, Q, X, Y, m, n and p are as defined above.

In a further preferred group of compounds of formula I according to the invention, R2 is the grouping ~ . .

' ' ~ ,; . ', ''' . .:

207~211 S~

(= 2-guanidino-thiazol-4-ylmethyl) and Rl, R3, A, E, Q, X, Y, m, n and p are as defined above.

In a further preferred group of compounds of formula I according to the invention, R2 is the grouping S-(N,N-dimethylaminomethyl)-furan-2-ylmethyl and R1, R3, A, E, Q, X, Y, m, n and p are as defined above.

In a further preferred group of compounds of formula I according to the invenlion, R2 is the grouping 3-piperidinomethyl-phenyl and R1, R3, A, E, Q, X, Y, m, n and p are as defined above.

The invention also relates to all stereoisomeric forms and hydrates of the above-described compounds of the general formula I.

The invention relates especially to the specific compounds described in the Examples and to salts, especially pharmaceudcally acceptable salts, thereof.

The compounds according to the invention can be prepared in a manner known per se, for example as follows:

a) for the preparation of a compound of formula I wherein X is an oxygen atom or a sulfur atom, or the grouping N-CN or CH-NO2, (al) a compound of formula II

Rl l3 H
f~ ~E' \(CH~) ~ (II), ~Q X

, 207~211 wherein Rl, R3, A, E, Q and m are as defined above and Z is a methylthio, a mercapto or a phenoxy group, is reacted with a compound of the general formula III

H2N ~Y~
(CH2) n R2 (III), wherein R2, Y and n are as defined above, preferably in equimolar amounts in a polar solvent, such as an alcohol, for example methanol, ethanol or isopropyl alcohol, or in acetonitrile, dimethyl sulfoxide, dimethylformamide or pyridine, preferably aceto-nitrile, for example at room temperature or at the reflux temperature of the solvent in question, or (a2) a compound of formula IV

~ (CH2) n 2 (IV), wherein R2, Y and n are as defined above and Z is a methylthio, a mercapto or a phenoxy group, is reacted, preferably in equimolar amounts, with a compound of the general formula V
Rl 1 IR3 ~ E (CH2) m (V), wherein Rl, R3, A, E, Q and m are as defined in claim 1, preferably in a polar solvent as mentioned above, or b) for the preparation of a compound of formula I wherein X is an oxygen atom or a sulfur atom, (bl) a compound of formula VI

207g211 - lo -E (CH2) m (YI), ~Q

wherein Rl, R3, A, E, Q and m are as defined above, is reacted, preferably in equimolar amounts, with a compound of formula III wherein R2, Y and n are as defined above, preferably in an inert solvent, for example dimethylformamide or an ether, especially tetrahydrofuran, for example at room temperature or at the reflux temperature of the solvent in question, or (b2) a compound of formula VII

X = C = N - (CH2)o - Y - R2 (VII), wherein R2, Y and n are as defined above, is reacted, preferably in equimolar amounts, with a compound of formula V

~ ~CH2) m (V), wherein Rl, R3, A, E, Q and m are as defined above, preferably in an inert solvent as mentioned above, for example dimethylfor namide or an ether, especially tetrahydro-furan, for example at room temperature or at the reflux temperature of the solvent in question;

and, if desired, a resulting compound of formula I is converted into a different compound of formula I, and/or, if desired, a resulting salt is converted into the free compound or into a different salt, and/or, if desired, a resulting free compound of formula I having salt-forming properties is converted into a salt, especially a physiologically acceptable salt.

Where appropriate, the compounds obtained in accordance with process a) or b) are chromatographed in a manner known per se and/or purifled by a different method, for 207~211 example by recrystallisation.

In addition to the stereoisomeric compounds and the hydrates of the compounds of the general formula I, the invention relates also to the physiologically acceptable salts of those compounds. Those salts may be formed, for example, with mineral acids, such as hydro-chloric, hydrobromic or hydriodic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulfuric acid, or with organic acids, such as formic acid, acetic acid, propionic acid, phenylacetic acid, tartaric acid, citric acid, fumaric acid, methanesulfonic acid or embonic acid.

Free compounds of formula I having salt-forming properties that are obtainable according to the process can be converted into their salts in a manner known per se, compounds having basic properties for example by treatment with acids or suitable derivatives thereof.

In view of the close relationship between the compounds of formula I in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood as including the corresponding salts or free compounds, as appropriate and expedient.

The reactions indicated above can be carried out under reaction conditions known per se, in the absence or, customarily, in the presence of solvents or diluents, preferably those that are inert towards the reagents used and are solvents thereof, in the absence or presence of catalysts, condensation agents or neutralising agents and, depending on the nature of the reaction and/or the reactants, at reduced, normal or elevated temperature, for example at a temperature in the range of from approximately -70C to approximately 190C, prefeMbly from approximately -20C to approximately 150C, for example at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under a nitrogen atmosphere.

The starting materials used in the process of the present invention are preferably those which result in the compounds described at the beginning as being especially valuable.

The invention relates also to those forms of the process in which a compound obtainable as interrnediate at any stage of the process is used as starting material and the remaining steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example a salt, thereof.

For the purpose of administration, the compounds according to the invention can be formulated in any desired manner. The invention therefore relates also to pharmaceutical composidons that comprise at least one compound according to the invention for use in human or veterinary medicine. Such medicaments can be prepared using one or morepharmaceutical carriers or diluents.

The compounds according to the invention can therefore be formulated, for example, for oral, buccal, topical, parenteral or rectal administradon, oral administradon being preferred.

For buccal administration the medicament may be in the form of, for example, tablets or wafers that have been formulated in conventional manner.

The compounds according to the invention can be formulated for parenteral administra-tion, for example by bolus injecdon or by continuous infusion. Injection formulations may be, for example, in unit dose forms in the form of ampoules, or in repeat dose containers with added preservative.

The medicaments may also be in the form of, for example, suspensions, solutions or emulsions in oily or aqueous carriers, and they may comprise formulation excipients, such as suspension, stabilising and/or dispersing agents.

Alternatively, the active ingredient may also be in powder form intended for reconsdtudon with a suitable carrier, for example sterile, pyrogen-free water, before use.
.
The compounds according to the invention may be formulated, for example, also as rectal preparations, for example suppositories or retention enemas, which comprise, for example, suppository bases, such as cocoa butter or other glycerides.

For topical administration the compounds according to the invention may be formulated as, for example, ointments, creams, gels, lotions, powders or sprays.

For oral administradon to a warm-blooded animal weighing approximately 70 kg, a suitable daily dose of compounds according to the invention is from S mg to I g, prefer-ably from S to 250 mg, depending on the condition of the patient, divided into, for .
..

207~211 example, from 1 to 4 single doses. In individual cases it may be necessary to depart from the mentioned amounts, according to the individual response to the active ingredient or to the way in which it is formulated and to the time or frequency of administration. For example, there are cases in which it is possible to use less than the above-mentioned minimum amount, while in other cases the upper limit mentioned has to be exceeded.

The Examples that follow illustrate the present invention; "furfuryl" denotes "furan-2-ylmethyl" .

Example 1: N-r2-rN-r3-(4-chloroDhenvl)-3-(2-pvridvl)propyll-N-methYlaminolethYll-N'-cvano-N"-r4-r3-(piperidinomethvl)phenoxvlbutYIlouanidine A mixture of 0.X g (2.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine (A) and 0.8 g (2 mmol) of N-cyano-O-phenyl-N'-[4-[3-(piperidino-methyl)phenoxy]butyl]isourea (B) is heated under reflux for 12 hours in 20 ml of absolute acetonitrile. The batch is then freed of solvent in vacuo and the reaction product is isolated by means of preparative thick-layer chromatography (silica gel 60 PF254; ethyl acetate/methanol 95+5, ammonia atmosphere). The title compound is obtained in the form of a viscous oil; MS (+FAB method): rn/z (rel. int. [%]) = 616 ([M+H]+, 9), 230 (100); IR (KBr): 2163 cm~l (C-N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 135C with decomposition.

The starting materials are prepared as follows:

(A) A solution of 3-(4-chlorophenyl)-3-(2-pyridyl)propaneamine [A. Buschauer, Arch.
Pharm. (Weinheim) 322, 165-171 (1989)] (0.15 mol) in 100 ml of ether is provided with an underlayer of 100 ml of 10 % NaOH and stirred vigorously while cooling with ice.
Chloroformic acid ethyl ester is slowly added dropwise until no further precipitation occurs at the drip point. The organic phase is washed neutral with water, dried over Na2SO4, concentrated by evaporation in vacuo and dried intensively by means of relatively lengthy evacuation in an oil-pump vacuum. The resulting oil is sufficiently pure for further reaction. 0.12 mol of the reaction product is dissolved in 100 ml of absolute THF and the solution is added dropwise to a stirred and ice-cooled suspension of 9.4 g (0.24 mol) of LiAlH4 in 150 ml of THF and the batch is heated under reflux for a further two hours. After cooling and the addition of water-saturated ether, approximately 10 ml of 10 % NaOH are added to the batch, which is then stirred overnight. The precipitate is filtered off with suction and the clear filtrate is concentrated by evaporation in vacuo. The crude product, 3-(4-chlorophenyl)-3-(2-pyridyl)-N-methyl-1-propanamine [analogous to A. Buschauer, J. Med. Chem. 32, 1963 (1989)], is purified by column chromatography (ethyl acetate/ammoniacal methanol 99+1) and, in a batch size of 10-30 mmol, is then stirred for 2 hours at 60C with an equivalent amount of chloroacetonitrile, a spatula tip of potassium iodide and twice the molar excess of Na2CO3 in 20 ml of a mixture of equal parts of acetonitrile and DMF. When the reaction is complete (TLC monitoring, FM VI), 20 ml of water are added to the batch, which is extracted several times with toluene. The combined organic extracts are washed with water, dried over Na2SO4 and decolorised for column chromatography (CC) using a small amount of silica gel. Concentration by evaporation in vacuo yields the reaction product, 2-[N-[3-(4-chlorophenyl)-3-(2-pyridyl)-propyl]-N-methylamino]acetonitrile of adequate purity in a yield of approximately 80 %.
The nitrile thus produced is dissolved in ether, added dropwise to an ice-cooled stirred suspension of LiAlH4 (1.5 equivalents) in absolute ether (total volume approx. 50 ml) and left for 2 hours at room temperature. When reaction of the educt is complete, water-saturated ether and 2-3 ml of 10 % NaOH are added to the batch, which is stirred at room temperature overnight. After removal of the inorganic phases by suction-filtration, the filtrate is concentrated by evaporation in vacuo and the resulting amine, if sufficiently pure, is reacted further or is isolated by means of preparative thick-layer chromatography.

(B) 4.6 g (0.2 mol) of sodium are dissolved in anhydrous ethanol and 38.24 g (0.2 mol) of 3-piperidinomethylphenol [DEA-2 917 026, Glaxo] are added thereto. After the dropwise addition of 20.71 g (0.2 mol) of 4-chlorobutyronitrile in ethanol, the batch is heated under reflux overnight with the exclusion of moisture. It is then allowed to cool, is filtered, and concentrated to dryness in vacuo. The resulting oil is taken up in ether and washed with 10 % NaOH and water. Drying over Na2SO4 and concentrating yield 35.5 g (0.14 mol) of 4-(3-piperidinomethylphenoxy)butyronitrile in the form of an oil that can be used in the subsequent reaction without further purification. While cooling with ice and stirring, 59.9 mmol of 4-(3-piperidinomethylphenoxy)butyronitrile are introduced slowly into a suspension of 2.98 g (78.4 mmol) of LiAlH4 in 140 ml of anhydrous ether. After stirring for 40 min at room temperature the batch is hydrolysed, while cooling with ice, with 10 ml of water-saturated ether and 7 ml of 10 % NaOH. Stirring is continued for 30 min, and then the batch is suction-filtered and the precipitate is washed several times with ether.
The filtrate is washed with water, dried over Na2SO4, filtered and concentrated to dryness in vacuo to yield 4-(3-piperidinomethylphenoxy)butaneamine in the form of a low-207~211 viscosity brown oil that can be used in the subsequent reaction without further purifica-tion. The equimolar amount of 4-(3-piperidinomethylphenoxy)butaneamine is added while stirring to a suspension of N-cyanodiphenylimidocarbonate in 100 ml of diethyl ether.
After stirring for approx. 15 min, the product, N-cyano-O-phenyl-N'-[4-(3-piperidino-methylphenoxy)butyl]isourea, precipitates copiously, or it crystallises when the solution is concentrated. The product is suction-filtered, washed with diethyl ether and dried.
Example 2: N-rS-rN-r3-(4-chlorophenYI)-3-(2-pYridyl)propYll-N-methylaminolpent N'-cYano-N''-r3-r3-(piperidinomethyl)phenoxYlpro~yll ~uanidine Preparation is effected analogously to Example 1, using 1.09 g (3.15 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine and 1.23 g (3.1 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example I yields the purified title compound in the form of a viscous oil; IR (KBr): 2163 cm-l (C--N).

Example 3: N-r4-rN-r3-(4-chlorophenYI)-3-(2-pYridvl)Propyll-N-methvlaminolbut N'-cYano-N''-r3-r3-(~iperidinomethyl)phenoxvlpropyll uanidine Preparation is effected analogously to Example 1, using 0.99 g (3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 1.17 g(3 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 98+2) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%]) = 630 ([M+H]+, 7), 230 (lO0); IR
(KBr): 2164 cm~l (C-=N).

Example 4: N-r3-rN-r3-(4-chlorophenYI)-3-(2-pYridYl)propvll-N-methylamin propYll-N'-cyano-N"-r3-r3-(piperidinomethvl)phenoxylpropYll uanidine Preparation is effected analogously to Example 1, using 0.5 g (1.57 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and 0.6 g (1.5 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): rn/z (rel. int.[%]) = 616 ([M+H]+, 1), 230 (100).

, 207~211 Example 5: N-r2-~N-r3-(4-chlorophenyll-3-(2-pvridvl)propvll-N-methylaminoleth N'-cvano-N"-r3-r3-(piperidinomethvl)phenoxvlpropvllPuanidine Preparation is effected analogously to Example 1, using 0.7 g (2.3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.85 g(2.2 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS
(+FAB-method): m/z (rel. int.[%]) = 602 ([M+H]+,5), 230 (100); IR (KBr): 2165 cm~l (C-=N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 85C with decomposition.

Example 6. N-cvano-N'-r4-rN-r3-(4-fluorophenvl)-3-(2-Pvridvl)PropYll-N-methylamin butvll-N"-r3-r3-(piperidinomethvl)phenoxYlpropvllPuanidine Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 0.99 g(2.5 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purifled title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int.[%l) = 614 ([M+H]+, 3),214 (50.2), 154 ([m-NO2-benzylOH], 100); IR (KBr): 2163 cm~l (C_N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 105- 110C with decomposition.

Example 7: N-cvano-N'-r3-rN-r3-(4-fluoroPhenyl)-3-(2-PYridvl)propvll-N-methylamin propvll-N"-r3-r3-(piperidinomethYl)PhenoxYlpropYll.Puanidine Preparation is effected analogously to Example 1, using 0.8 g (2.7 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and 1.04 g (2.6 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int.[%]) = 600 ([M+H]+ 22.4), 214 (100); IR (KBr): 2164 cm~l (C_N).

2o7~2l~

Example 8: N-cYano-N'-r2-rN-r3-(4-fluorophenYI)-3-(2-pvridvl)propYll-N-methvlamin ethYll-N~-r3-r3-(piperidinomethvl)phenoxylpropyll~uanidine Preparadon is effected analogously to Example 1, using 0.7 g (2.4 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.95 g(2.4 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified dtle compound in the form of a viscous oil; MS (+FAB method): m/z (rel.int.[%]) = 586 ([M+H]+, 1), 214 (100).

Example 9. N-cYano-N'-r4-LN13-phenvl-3-~2-pYridYl~propyll-N-methylamin-olbut N"-r3-r3-(piperidinomethvl)phenoxYlpropYIl~?uanidine Preparadon is effected analogously to Example 1, using 0.7 g (2.3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,4-butanediamine and 0.89 g (2.3 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as stardng materials. Working up by chromatography analogously to Example 1 yields the purifled dtle compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%]) = 596 ([M+H]+ 7), 196 (100).

Example 10: N-cYano-N'-r3-rN-r3-phenvl-3-(2-PvridYl)propyll-N-methvlaminolpr N"-r3-r3-(piperidinomethYl)phenoxvlpropvll uanidine Preparadon is effected analogously to Example 1, using 0.57 g (2 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified dtle compound in the form of a viscous oil; IR (KBr): 2164 cm-l (C-N).

Example 11: N-cvano-N'-r2-rN-r3-phenYI-3-(2-pYridYl)propyll-N-methylaminoleth N"-r3-r3-(piperidinomethYl)phenoxYlpropYllguanidine Preparadon is effected analogously to Example 1, using 0.7 g (2.6 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,2-ethanediamine and 1 g (2.5 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials.
Working up by chromatography (eluant: ethyl acetate) analogously to Example 1 yields " 2074211 the purified title compound in the form of a viscous oil; MS (+FAB method): mlz (rel.
int.[%]) = 568 ([M+H~+ 3),196 (100).

Example 12: N-cYano-N'-r2-rr(2-~uanidino-4-thiazolYI)methYllthiolethvll-N~-r2 rN-r3-phenvl-3-(2-pyridvl)propyll-N-methylaminolethyllouanidine Preparation is effected analogously to Example 1, using 0.8 g (3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl~-1,2-ethanediamine and 1.01 g (2.7 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl~thio]ethyl~-O-phenyl-isourea as starting materials.
Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%]) = 551 ([M+H]+, 2), 196 (100); IR (KBr): 2164 cm~l (C=N). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: 115-116C
wlth decomposition.

Example 13: N-cvano-N'-r2-rr(2-~uanidino-4-thiazolyl)methyllthiolethyll-N''-r3-rN-r3-phenvl-3-(2-pYridYl)propyll-N-methylaminolpropyll ouanidine Preparation is effected analogously to Example 1, using 0.85 g (3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine and 1.12 g (3 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as startingmaterials. Working up by chroma~ography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 565 (lM+Hl+, 2), 196 (100); IR (KBr): 2162 cm~l (C_N). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/isopropanol; m.p.:
110-112C with decomposition.

Example 14: N-cvano-N'-r4-rN-r3-(4-fluorophenYI~-3-(2-pYridvl)propYll-N-meth~
aminolbutvll-N"-r2-rr(2-~ua!lidino-4-thiazolyl)methYllthiolethvll~uanidine Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 0.95 g(2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl- -isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%]) = 597 ([M+H]+ l), 214 .

20742il (100); IR (KBr): 2162 cm-l (C3N).

Example 15: N-r2-rN-r3-(4-chlorophenyl)-3-(2-pvridvl)proPvll-N-methYlaminolethvll-N'-cvano-N"-r2-rr(2-guanidino4-thiazolYl)methYIlthiolethYllguanidine Preparation is effected analogously to Example 1, using 0.8 g (2.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.98 g(2.6 mmol) of N-cyano-N'-t2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purifled title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 585 ([M+H]+, 6), 230 (100); IR (KBr): 2164 cm~l (C3N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 160C with decomposition.

Example 16: N-r3-rN-r3-(4-chlorophenyll-3-(2-pYridYl)propYll-N-methylaminolpr N'-cYano-N -r2-rr(2- .uanidino-4-thiazolYl)methyl~lthiolethY11o~uanidine Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-t3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and 0.94 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 599 ([M+H]+, 7), 230 (100); IR (KBr): 2161 cm~l (C3N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 160C with decomposition.

Example 17: N-r4-rN-r3-(4-chlorophenyl)-3-(2-PYridYl)propyll-N-methyl-aminolbut N'-cYano-N'-r2-rr(2-~uanidino-4-thiazolvl)methYIlthiolethYllpuanidine Preparation is effected analogously to Example 1, using 0.7 g (2.1 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 0.79 g(2.1 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foarn; MS (+FAB method): m/z (rel. int.[%]) = 613 ([M+H]+, 2), 230 (100).

. . - .

Example 18: N-r5-rN-r3-(4-chlorophenvl)-3-(2-pYridYI)proPyll-N-methylaminolpent N'-cyano-N"-r2-rr(2-~uanidino-4-thiazolvl)methyllthiolethyll uanidine Preparadon is effected analogously to Example 1, using 0.75 g (2.1 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyll-N-methyl-1,5-pentanediamine and 0.81 g (2.1 mmol) of N-cyano-N'-~2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 627 ([M+H]+, 3), 230 (100); IR (KBr): 2162 cm~l (C_N). For analytical purposes a sample is convened into the maleic acid salt and recrystallised from ether/ethanol; m.p.:
87-90C.

Example 19: N-r6-rN-r3-(4-chlorophenyl)-3-(2-pYridYI)propYll-N-methylaminolhe N'-cyano-N" -r2-rr(2-~uanidino-4-thiazolvl)methYllthiolethYllg~uanidine Preparation is effected analogously to Example 1, using 0.5 g (1.4 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,6-hexanediamine and 0.52 g(1.4 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): mtz (rel. int.[%]) = 641 ([M+H]+, 5), 230 (47), 154 (100); IR (KBr): 2161 cm~l (C_N).

Example 20: N-r7-rN-r3-(4chlorophenYI)-3-(2-pvridYI)propvll-N-methYlaminolhept N'-cvano-N"-r2-rr(2-Puanidino-4-thiazolYI)methvllthiolethYllouanidine Preparation is effected analogously to Example 1, using 0.7 g (1.9 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine and 0.7 g(1.9 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloridelmethanol 95+5) analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 655 ([M+H]+ 2), 230 (18), 154 (100); lR (KBr): 2161 cm~l (C=N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/-isopropanol; m.p.: from 150C with decomposition.

Example 21: N-cvano-N'-r2-rr(2-guanidino-4-thiazolYl)methyllthiolethYll-N'~-r4-rN-r2-rr(4-methvlphenyl)phenvl-methyllthiolethvllN-methylaminolbutyll~uanidine Preparation is effected analogously to Example 1, using 0.87 g (2.5 mmol) of N-methyl-N-12-[[(4-methylphenyl)phenyl-methyllthio]ethyl]-1,4-butanediamine and 0.95 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-iso-urea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%]) = 624 ([M+H]+, 6), 181 (100); IR (KBr): 2161 cm~l (C_N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 134-140C with decomposition.

Example 22: N-r3-rN-r3-(4-fluorophenvl3-3-(2-p~-ridYl)pro~YIl-N-methYlaminolproPvll-N'-r3-r3-(piperidinomethyl)phenoxYlpropvll-2-nitro-l,l-ethenediamine A mixture of 0.74 g (2.5 mmol) of N-13-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and an equimolar amount of 1-methylthio-1-[3-[3-(piperidinomethyl)-phenoxy]propyl]amino-2-nitro-ethene is heated under reflux for 12 hours in 20 ml of acetonitrile. The batch is then freed from solvent and the title compound is isolated in the form of a viscous oil by means of preparative thick-layer chromatography (eluant: ethyl acetate/methanol 9+1, ammoniacal atmosphere); MS (+FAB method): m/z (rel. int.[%]) =
619 ([M+H]+ 2), 214 (100). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 102C with decomposition.

Example 23: N-r7-rN-r3-(4-chlorophenYI)-3-(2-pvridvl)propYll-N-methYlaminolhept N'-r2-rr(2-guanidino-4-thiazolYI)methYllthiolethyll-2-nitro- 1.1 -ethenediamine Preparation is effected analogously to Example 22, using 0.83 g (1.7 mmol) of 1-~7-[N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methylamino]heptyl]amino- 1 -methyl-thio-2-nitro-ethene and 0.5 g (2.1 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FABmethod): m/z (rel. int.[%]) = 674 ([M+H]+ 0.6), 230 (100).

Example 24: N-r2-rN-r3-(4-chlorophenyl)-3-l2-pvridyl)propyll-N-methylaminoleth N' -r4-r3-(piperidinomethYl)phenoxYlbutYllurea Preparation is effected analogously to Example 63, using 0.8 g (2.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.69 g (2.7 mmol) of 4-[3-(piperidinomethyl)phenoxy]-butaneamine as starting materials. Working up by chromatography (eluant: methylene chloride) analogously to Example 63 yields the purified dtle compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%]) = 592 ([M+H]+, 2), 230 (100); IR (KBr):
1632 cm~l (C=O). For analytical purposes a sample is converted into the O,O'-ditoluoyl-tartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 124C with decomposition.

Example 2S: N-rS-rN-r3-(4-chloro~h~Q-(2-pvridvl)propYll-N-methYlaminolpentyll-N'-r3-r3-(piperidinomethvl)phenoxylpropyllurea Preparation is effected analogously to Example 63, using 1.29 g (3.6 mmol) of N-t3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 1.04 g (4.2 mmol) of 3-[3-(piperidinomethyl)-phenoxy~propaneamine as starting materials. Working up by chromatography (eluant:
methylene chloride) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+EI-80 eV): m/z (rel. int.[%]) = 619 ([M]+.,<l), 230 (17) 203 (100);
IR (KBr): 1634 cm~l (C=O).

Example 26: N-r4-rN-L~4-chlorophenyl~-3-(2-pvridvl)~ropyll-N-methylaminolbutYll-N'-r3-r3-(piperidinomethvl)PhenoxYlpropvllurea Preparation is effected analogously to Example 63, using 0.7 g (2.1 mmol) of N-[3-(~chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.7 g (2.8 mmol) of 3-[3-(piperidinomethyl)-phenoxy]propaneamine as starting materials. Working up by chromatography (eluant:
methylene chloride/methanol 95+5) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%]) = 606 ([M+H]+, 4), 230 (100); IR (KBr): 1643 cm~l (C=O).

207~21~

Exarnple 27: N-r3-rN-r3-(4-chlorophenYI)-3-(2-pvridYl)proPvll-N-methylaminolpr N'-r3-r3-(piperidinomethyl)phenoxvlpropyllurea Preparation is effected analogously to Example 63, using 0.7 g (2.2 mmol) of N-13-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl- 1,3-propanediamine, an equimolaramount of l,l'-carbonyldiimidazole and 0.55 g (2.2 mmol) of 3-13-(piperidinomethyl)-phenoxy]propaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of an oil. For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/-isopropanol; m.p.: (ether/ethanol): from 65C with decomposition.

Example 28: N-r2-rN-r3-(4-chlorollhenvl~3-(2-pYridYl)propYll-N-methylam~
ethyll-N'-r3-r3-(piperidinnme~hvl~phenoxylpropy!lurea Preparation is effected analogously to Example 63, using 0.92 g (3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.88 g (3.5 mmol) of 3-[3-(piperidinomethyl)-phenoxy]propaneamine as starting materials. Working up by chromatography (eluant:
ethyl acetate) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%]) = 578 ([M+H]~, 2), 230 (38), 78 (100); IR
(KBr): 1637 cm~l (C=O). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 99-105C.

Example 29: N-r4-rN-r3-(4-fluorophenYI)-3-(2-PYridvl)propyll-N-methylaminolbut N'-r3-r3-(piperidinomethvl)phenoxYlpropYllurea Preparation is effected analogously to Example 63, using 0.7 g (2.2 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl- 1,4-butanediamine, an equimolar amount of l,1'-carbonyldiimidazole and 0.6 g (2.4 mmol) of 3-[3-(piperidinomethyl)phenoxy]-propaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 95+5) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): mlz (rel. int.[%]) = 590 ([M+H]~ 17), 214 (100);
IR (KBr): 1631 cm~l (C=O).

~ -.

207~211 Example 30: N-r3-rN-r3-(4-fluorophenYI)-3-(2-pvridYI)propYIl-N-methvlaminolpropvll-N'-r3-r3-(piperidinomethyl)phenoxylpropvllurea Preparadon is effected analogously to Example 63, using 0.78 g (2.6 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.65 g (2.6 mmol) of 3-[3-(piperidinomethyl)phenoxy]-propaneamine as stardng materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%]) = 576 ([M+H]~,7), 214 (100);
IR (KBr): 1649 cm~l (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: 65-67C.

Example 31: N-r2-~N-r3-(4-fluorophenyl2~3-(2-PYridyl)propvll-N-methYlaminol~thyll-N'-r3-r3-(piperidinomethYl)phenoxvlpropvllurea Preparadon is effected analogously to Example 63, using 1 g (3.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of l,l'-carbonyldumidazole and 0.9 g (3.6 mmol) of 3-[3-(piperidinomethyl)-phenoxy]propaneamine as stardng materials. Working up by chromatography (eluant:methylene chloride) analogously to Example 63 yields the purified title compound in the form of an oil; MS (EI-80 eV): m/z (rel. int.[%]) = 561 ([M] '., 3), 84 (70), 214 (100). For analydcal purposes a sample is converted into the hydrochloride and recrystallised from ether/ethanol; m.p.: l l l-115C.

Example 32: N-r4-rN-r3-phenvl-3-(2-pvridYl)propvll-N-methYIaminolbutYll-N7-~3 r3-(piperidinomethyl)phenoxylpropyllurea Preparadon is effected analogously to Example 63, using 0.7 g (2.3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,4-butanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.7 g (2.8 mmol) of 3-[3-(piperidinomethyl)phenoxy]-propaneamine. Working up by chromatography analogously to Example 63 yields the purified dtle compound in the form of an oil; MS (EI-80 eV): m/z (rel. int.[%]) = 571 ([Ml+, 4), 84 (22), 169 (100).

Examl~le 33: N-r3-rN-r3-phenvl-3-(2-pYridYI)propvll-N-methYlaminolpropyll-N~-r3 r3-(piperidinomethvl)phenoxvlpropyllurea Preparadon is effected analogously to Example 63, using 0.74 g (2.6 mmol) of N-methyl-N-13-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.65 g (2.6 mmol) of 3-[3-(piperidinomethyl)phenoxyl-propaneamine as stardng materials. Working up by chromatography (eluant: ethyl acetatetmethanol 9+1) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): mtz (rel. int.[%]) = 558 ([M+H]+, 11), 196 (100);
IR (KBr): 1639 cm~l (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: from 70C with decomposition.

Example 34: N-r2-rN-r3-phenYl-3-(2-pYridYl)propyll-N-methylaminolethyll-N~-l3-r3 (piPeridinomethyl)phenoxylpropyllurea Preparadon is effected analogously to Example 63, using 0.33 g (1.2 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,2-ethanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.4 g (1.6 mmol) of 3-[3-(piperidinomethyl)phenoxy]-propaneamine in 10 ml of absolute tetrahydrofuran as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 63 yields the purified title compound in the form of an oil; MS (EI-80 eV): mtz (rel. int.[%]) = 543 ([M]+, 1), 84 (100). For analytical purposes a sample is converted into the hydrochloride and recrystal-lised from ether/ethanol; m.p.: from 130C with decomposition.

Example 35: N-r8-rN-r3-(4-chloroPhenvl)-3-(2-pvridvl)propYIl-N-methYlaminoloct N-r2-rr(2-.uanidino-4-thiazolyl)methvllthiolethyllurea Preparadon is effected analogously to Example 63, using 0.6 g (1.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,8-octanediamine, an equimolar amount of l,1'-carbonyldiimidazole and 0.4 g (1.7 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromato-graphy (eluant: chloroformtmethanol 9+1) analogously to Example 63 yields the purified dtle compound in the form of a dry foam; MS (+FAB method, DMSOtMNBA): mtz (rel.
int.[%]) = 645 ([M+H]+,<l), 234 (100); IR (KBr): 1638 cm~l (C=O). For analyticalpurposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 135-140C.

,:

Example 36: N-r7-rN-r3-(4-ehlorophenYll-3-(2-pvridYI)propyll-N-methYlaminolheptY
N'-r2-rr(2-ouanidino-4-thiazolyl)methyllthiolethyllurea Preparation is effected analogously to Example 63, using 0.73 g (1.9 mmol) of N-[3-(4-ehlorophenyl)-3-(2-pyridyl)propyl~-N-methyl-1,7-heptanediamine, an equimolar amount of l,l'-earbonyldiimidazole and 0.45 g (2 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]-thio]ethaneamine [DE-A-2 817 078, ICI; C.A. 90. 87452d (1979)] as starting materials.
Working up by ehromatography (eluant: methylene chloride/methanol 9+1) analogously to Example 63 yields the puri~led title compound in the form of a dry foam;
MS (+FAB method): m/z (rel. int.[%]) = 631 ([M+H]+, 3), 230 (31), 154 (100); IR (KBr):
1605 cm~l (C=O). For analytieal purposes a sample is eonverted into the O,O'-ditoluoyl-tartarie aeid salt and reerystallised from ether/isopropanol; m.p.: 132-134C with decomp-osition.

The starting material is prepared as follows:

As described in Example 1, a solution of 3-(4-chlorophenyl)-3-(2-pyridyl)propaneamine is reaeted to form 3-(4-ehlorophenyl)-3-(2-pyridyl)-N-methyl-l-propaneamine [A. Busehauer, J. Med. Chem. 32, 1963 (1989)] which, after purification by column chromatography (ethyl acetate/ammoniacal methanol 99+1), in a batch size of 10-30 mmol is stirred for 2 hours at 60C together with an equivalent amount of 7-bromo-heptanonitrile and twice the molar excess of Na2CO3 in 20 ml of acetonitrile. When the reaction is eomplete (TLC monitoring), 20 ml of water are added to the batch, whieh is extracted several times with toluene. The combined organic extracts are washed with water, dried over Na2SO4 and deeolorised for eolumn ehromatography using a smallamount of siliea gel. Coneentration by evaporation in vaeuo yields the reaction product, 7-[N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methylamino]-heptanonitrile of adequate purity. The nitrile thus produced is dissolved in ether, added dropwise to an ice-cooled stirred suspension of LiAlH4 (1.5 equivalents) in absolute ether (total volume approx.
50 ml) and left for 2 hours at room temperature. When reaction of the educt is complete, water-saturated ether and 2-3 ml of 10 % NaOH are added to the batch, which is stirred at room temperature overnight. After removal of the inorganic phases by suction-filtration, the filtrate is eoncentrated by evaporation in vacuo and the resulting N-[3-(4-chloro-phenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine, if sufficiently pure, is reacted further or is isolated by means of preparative thick-layer chromatography.

207~211 Example 37: N-r6-lN-r3-(4-chlorophenvl~-3-(2-pYridYl)Propvll-N-methylaminolhe N'-r2-rr(2-guanidino-4-thiazolYl)methvllthiolethvllurea Preparation is effected analogously to Example 63, using 0.9 g (2.5 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,6-hexanediamine, an equimolar amount of l,1'-carbonyldiimidazole and 0.6 g (2.6 mmol) of 2-[[(2-guanidino-4-thia-zolyl)methyl]thio~ethaneamine as starting materials. Working up by chromatography (eluant: methylene chloride) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%]) = 617 ([M+H~+ ,6),230 (100), 155 (28); IR (KBr): 1641 cm-l (C=O).

Example 38: N-r5-rN-r3-(4-chlorophenYI)-3-~2-pYridYl)provll-N-methylaminolpent Ni-r2-rr(2-~uanidino-4-thiazolyl~methvllthiolethvllurea Preparation is effected analogously to Example 63, using 1.04 g (3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.75 g (3.3 mmol) of 2-[[(2-guanidino-4-thia-zolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: chloroform/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foarn; MS (+FAB method): m/z (rel. int.[%]) = 603 ([M+H]+, 1), 155 (18), 230 (100); IR (KBr): 1640 cm~l (C=O).

Example 39: N-r4-rN-r3-(4-chlorophenYI)-3-(2-pYridYl)propyll-N-methvlaminolbut N'-r2-rr(2-ouanidino-4-thiazolvl)methYIlthiolethyllurea Preparation is effected analogously to Example 63, using 0.75 g (2 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.54 g (2.3 mmol) of 2-[[(2-guanidino-4-thia-zolyl)methyllthio]ethaneamine as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): rn/z (rel. int.[%]) = 589 ([M+H]+, 2), 230 (100); IR (KBr): 1650 cm~l (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: from 90C
with decomposition.

207~211 Example 40: N-r3-rN-r3-(4-chlorophenvl)-3-(2-pYridvl)propYll-N-methYlaminolpr N'-r2-rr(2-guanidino-4-thiazolyl)methvllthiolethYllurea Preparation is effected analogously to Example 63, using 0.9 g (2.8 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl- 1,3-propanediamine, an equimolar amount of l,1'-carbonyldiimidazole and 0.73 g (3.1 mmol) of 2-[[(2-guanidino-4-thiazolyl)-methyllthio]ethaneamine as starting materials. Working up by chromatography (eluant:
ethyl acetate/methanol 85+15) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 575 ([M+Hl+, 3), 155 (22), 230 (100); IR (KBr): 1646 cm~l (C=O).

Example 41: N-~2-rN-r3-(4-chlorophenyl)-3-(2-pvridYl)propYll-N-methylaminoleth N'-r2-rr(2-guanidino-4-thiazolvl)methyllthiolethvllurea Preparation is effected analogously to Example 63, using 0.9 g (2.9 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyll-N-methyl-1,2-ethanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.75 g (3.2 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]-thiolethaneamine as starting materials. Working up by chromatography (eluant:
methylene chloride/methanol 95+5) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%]) = 561 ([M+H]+, 3), 155 (26), 230 (100); IR (KBr): 1650 cm~l (C=O). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/-isopropanol; m.p.: from 140C with decomposition.

Example 42: N-r7-rN-r3-(4-fluorophenYI)-3-(2-pYridYl)propvll-N-methylaminolhept N'-r2-rr(2-~uanidino-4-thiazolYl)methYllthiolethYllurea Preparation is effected analogously to Example 63, using 0.9 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.65 g (2.8 mmol) of 2-[[(2-guanidino-4-thia-zolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: methylene chloride) analogously to Example 63 yields the purified title compound in the forrn of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 615 ([M+H]+ 2), 214 (100); IR (KBr): 1632 cm~l (C=O).

207~211 Example 43: N-~rN-r3-(4-fluorophenvl)-3-(2-pvridYl)propvll-N-methVlaminOlbut N' -r2-rr(2-guanidino-4-thiazolyl)methyllthiolethvllurea Preparation is effected analogously to Example 63, using 0.95 g (3.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyll-N-melhyl-1,4-butanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.82 g (3.5 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]-thio]ethaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 573 ([M+H]+ 2), 214 (100); IR (KBr): 1632 cm~l (C=O). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from etherAsopropanol; m.p.: from 120C with decomposition.

Example 44: N-r2-rr(2-~uanidino-4-thiazolvl)methyllthiolethYll-N'-r7-rN-r3-phenYI-3-(2-Dvridvl)propyll-N-methvlaminolheptyllurea Preparadon is effected analogously to Example 63, using 0.85 g (2.5 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,7-heptanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.65 g (2.8 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]-thio]ethaneamine as starting materials. Working up by chromatography (eluant:
methylene chloride) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%]) = 597 ([M+H]+, 7), 196 (100); IR
(KBr): 1655 cm~l (C=O).

Example 45: N-r2-rr(2-guanidino-4-thiazolyl)methYIlthiolethYll-N~-r4-rN-r3-phen 3-(2-pvridYl)propYll-N-methYIaminolbutvllurea Preparation is effected analogously to Example 63, using 0.89 g (3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,4-butanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.75 g (3.2 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]-thio]ethaneamine as starting materials. Working up by chromatography (eluant: chloro-form/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 555 ([M+H]+ 1), 196 (100);
IR (KBr): 1610 cm~l (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: from 80C with decomposition.

' ~

Example 46: N-r2-rr(2-Puanidino-4-thiazolyl)methvllthiolethyll-N'-r3-rN-r3-phenYI-3-(2-pvridvl)propvll-N-methYlaminolpropyllurea Preparation is effected analogously to Example 63, using 0.85 g (3 mmol) of N-methyl-N-t3-phenyl-3-(2-pyridyl)propyl]- 1,3-propanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.75 g (3.2 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl~-thio]ethaneamine as starting materials. Working up by chromatography (eluant: chloro-form/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%]) = 541 ([M+H]+, 2), 196 (100); IR
(KBr): 1650 cm~l (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: 95-98C.

Example 47: N-r2-rF(2-~uanidino-4-thiazolvl)methYllthiolethvll-N'-r2-rN-r3-phen~YI-3-(2-pYridvl)propvll-N-meth~ laminolethYllurea Preparation is effected analogously ~o Example 63, using 1 g (3.7 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,2-ethanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 1.15 g (5 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl~-thio]ethaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 527 ([M+H]+ 3), 196 (100).

Example 48: N-r7-rN-r3-(4-chlorophenYI)-3-(2-pYridYl)propvll-N-methvlaminolhept N-r2-rr(2-.uanidino-4-thiazolvl)methYllthiolethvllthiourea Preparation is effected analogously to Example 99, using 0.84 g (2.2 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine and 0.56 g (2.4 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starling materials. Working up by chromatography (eluant: chloroform/methanol 9+1) analogously to Example 99yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%]) = 647 ([M+H]+, 7), 230 (100).

Example 49: N-r4-rN-r3-(4-chlorophenyl~-3-(2-pvridvl)propy!l-N-methVlaminolbutvll-N'-r2-rr(5-methvlimidazol-4-vl)methvllthiole~hYllurea Preparation is effected analogously to Example 63, using 0.8 g (2.4 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl- 1,4-butanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.5 g (2.9 mmol) of 2-[~(5-methylimidazol-4-yl)methyl]-thio]ethaneamine [R.W. Brimblecombe et al., J. Int. Med. Res. 3, 86 (1975)] as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analog-ously to Example 63 yields the puri~led title compound in the form of a crystalline solid that is recrystallised from ether; m.p.: 97-98C; MS (+FAB method): m/z (rel. int.[%]) =
529 ([M+H]+, 10), 230 (100); IR (KBr): 1643 cm~l (C=O).

Example 50: N-r3-rN-r3-(4-chlorophenYl)-3-(2-Pvridyl)propvll-N-methvlaminolpropV
N'-r2-rr(5-methvlimidazol-4-vl)methvllthiolethyllurea Preparation is effected analogously to Example 63, using 0.8 g (2.5 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine, an equimolar amount of l,l'-carbonyldiimidazole and 0.5 g (2.9 mmol) of 2-[[(5-methylimidazol-4-yl)methyl]-thio]ethaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a crystalline solid; m.p.(ether): 102-104C; MS (+FAB method): m/z (rel.
int.[%]) = 515 ([M+H]+, 10), 95 (75), 230 (100).

Example 51: N-r2-rN-[3-(4-chloroQhenyl~-3-(2-pvridvl)propyll-N-methvlaminolethvll-N'-r2-rr(5-methylimidazol-4-Yl~methvllthiolethvllurea Preparation is effected analogously to Example 63, using 0.8 g (2.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.5 g (2.8 mmol) of 2-[[(5-methylimidazol-4-yl)methyl]-thio]ethaneamine as starting materials. Working up by chromatography (eluant: ethyl acetatelmethanol 9+1) analogously to Example 63 yields the puri~led title compound in the form of a crystalline solid; m.p.(ether): 114C; MS (+FAB method): mlz (rel. int.[%]) = 501 ([M+H]+, 15), 95 (63), 230 (100); IR (KBr): 1640 cm~l (C=O).

207~211 Example 52: N-cYano-N'-~2-rN-~2-rN-(4-methoxvbenzYI)-N-(2-pvridYl)aminoleth N-methvlaminolethvll-N"-I3-r3-(piperidinomethyl)phenoxYlpropvll uanidine Preparation is effected analogously to Example 1, using 0.53 g (1.7 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equi-molar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil which crystallises from absolute ether at -20C; MS (EI 70 eV): m/z (rel. int. [%]) = 612 ([M]+. 1); IR (KBr): 2164 cm~l (C-N);
m.p.: 88C (ether).

The starting material is prepared as follows:

11.23 g (43.64 mmol) of 2-[N-(2-aminoethyl)-N-(4-methoxybenzyl)-amino]pyridine [USP 4 532 246 (20.12.1983); C.A. 102, 6208v (1984)] are dissolved in ether and provided with an underlayer of 10 % sodium hydroxide solution. While stirring and cooling with ice-water, 4.73 g (43.64 mmol) of chloroformic acid ethyl ester are added dropwise to the two-phase system in such a manner that the cloudiness so produced first has to dissolve before further ester can be added dropwise. When the reaction is complete the phases are separated, the ethereal phase is dried with Na2SO4 and the ether is distilled off under a weak vacuum to yield N-(4-methoxybenzyl)-N-(2-pyridyl)-2-aminoethane-amino acid ethyl ester in the form of a colourless oil. While cooling with ice and stirring, the oil, dissolved in 20 ml of absolute THF, is introduced slowly into a suspension of 2.28 g (60 mmol) of LiAlH4 in 100 ml of absolute ether. The reaction batch is stirred for 30 min at room temperature and then heated under reflux for a further 1 hour. After cooling, the batch is hydrolysed, while cooling with ice, with water-saturated ether and the dropwise addition of a small amount of 10 % sodium hydroxide solution, until theexothermic reaction has ceased and a white precipitate forms. The batch is stirred for a further 30 min and suction-filtered and the precipitate is washed several times with ether.

The filtrate is washed with water, dried over Na2SO4 and concentrated to dryness in vacuo to yield N-(4-methoxybenzyl)-N-(2-pyridyl)-N'-methyl-1,2-ethanediamine which is then heated for 2 hours at 80C with the equimolar amount of chloroacetonitrile, three times the molar amount of Na2CO3 and a spatula tip of KI in 60 ml of anhydrous DMF. The reaction batch is cooled to room temperature and then water is added until the precipitate has dissolved. The batch is extracted wtih toluene. The combined organic phases are - ;

207421~

dried with MgSO4 and the toluene is distilled off in vacuo. The resulting brownish oil is dissolved in 20 ml of absolute THF and while cooling with ice and stirring is introduced slowly into a suspension of twice the molar amount of LiAlH4 in 50 ml of absolute ether.
After stirring for 30 min, the batch is hydrolysed, while cooling with ice, with water-saturated ether and the dropwise addition of a small amount of 10 % sodium hydroxide solution until the exothermic reaction has ceased and a white precipitate forms. The batch is stirred for a further 30 min and suction-filtered and the precipitate is washed several times with ether. The filtrate is washed with water, dried over Na2SO4 and concentrated to dryness in vacuo to yield N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)àmino]ethyl]-N-methyl-1,2-ethanediamine of sufficient purity for the subsequent reaction.
Example 53: N-cvano-N'-r3-rN-r2-[N-(4-methoxvbenzYl)-N-(2-pYridYl)aminole~
N-methvlaminolpropYll-N"-r3-r3-(piperidinomethYI)phenoxvlpropyllguanidine Preparation is effected analogously to Example 1, using 0.52 g (1.6 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]iso-urea as starting materials. Working up by chromatography analogously to Example 1 yields the purifled title compound in the form of a viscous oil which crystallises from absolute ether at -20C; MS (+FAB method): m/z (rel. int. [%]) = 627 ([M+H]~, 6), 241 (11), 121 (100); IR (KBr): 2165 cm~l (C-N); m.p.: 62-65C (ether).

Example 54: N-cvano-N'-r4-rN-r2-rN-(4-methoxYbenzYI)-N-(2-pYridyl)aminoleth N-methylaminolbutYll-N"-r3-r3-(piperidinomethyl)phenoxylpropyll,guanidine Preparation is effected analogously to Example 1, using 0.53 g (1.5 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equi-molar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil. For analytical purposes a sample is converted into the tartaric acid salt and recrystallised from ether/ethanoVisopropanol; MS
(+FAB method): mtz (rel. int. [%]) = 641 ([M+H]+, 1), 241 (7), 121 (100); IR (KBr):
2166 cm~l (C~N); m.p.: 106-108C (ether/ethanoVisopropanol).

., Example S5: N-cYano-N'-r6-rN-r2-rN-(4-methoxvbenzvl)-N-(2-pYridYl)amino1eth N-methvlaminolhexvll-N"-r3-r3-(piperidinomethvl)phenoxvlpropyll uanidine Preparation is effected analogously to Example 1, using 0.56 g (1.52 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equi-molar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. ~%]) = 669 ([M+H]+, 5), 121 (100); IR (KBr): 2163 cm~l (C_N). For analytical purposes a sample is converted into the tartaric acid salt in an ether/ethanol solvent mixture; m.p.: 79C (ether/ethanol).

Example 56: N-cyano-N'-r2-rN-r2-rN-~4-fluorobenzvl)-N-(2-pvridvl)aminolethvll-N-methvlaminolethvll-N"-r3-r3-(piperidinomethYl)phenoxvlpropvllouanidine Preparation is effected analogously to Example 1, using 0.30 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino~ethyl]-N-methyl-1,2-ethanediamine and the equi-molar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatogMphy analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. l%]) = 601 ([M+H]+, 7),76 (100); IR (KBr): 2169 cm~l (C_N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from ethanoVpetroleum ether; m.p.: 106C (ethanoVpetroleum ether).

Example 57: N-cvano-N'-r3-rN-r2-rN-(4-fluorobenzvl)-N-(2-PvridYI)aminolethvll-N-methvlaminolpropYll-N"-r3-r3-(piperidinomethyl)phenoxYlpropvllouanidine Preparation is effected analogously to Example 1, using 0.63 g (2.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equi-molar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. [%]) = 615 ([M+H]+, 14), 229 (100), 109 (96); IR (KBr): 2167 cm~l (C=N). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanoVether solvent mixture; m.p.: 65-68C (ethanoVether).

207421~

Example 58: N-cvano-N'-r4-rN-r2-rN-(4-fluorobenzvl)-N-(2-pYridYl)aminolethY
N-methylaminolbutvll-N"-r3-r3-(piperidinomethvl)phenoxylpropYll uanidine Preparadon is effected analogously to Example 1, using 0.33 g (1.0 mmol) of N-[2-[N-~4-fluorobenzyl)-N-(2-pyridyl)aminolethyl]-N-methyl-1,4-butanediamine and lhe equi-molar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl~isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. [%]) = 629 ([M+H]+,5), 229 (84), 109 (100); IR (KBr): 2166 cm~l (C-=N). For further analysis, a ponion of the compound is converted into the tartaric acid salt and recrystal-lised from ethanol/acetonitrile/isopropanol; m.p. 84-86C (ethanol/acetonitrile/-isopropanol).

Example 59: N-cvano-N'-r5-rN-r2-rN-(4-fluorobenzvl)-N-(2-Pvridvl)aminolethYll-N-methvlaminolpentyll-N"-r3-r3-(piperidinomethyl)phenoxvlpropvllouanidine Preparation is effected analogously to Example 1, using 0.54 g (1.6 mmol) of N-12-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,5-pentanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. %]) ~ 643 ([M+H]+, 7), 229 (54), 154 ([m-NO2-benzylOH] 100); IR (KBr): 2165 cm~l (CEN).
For further analysis, a ponion of the compound is converted into the tartaric acid salt which forms a dry foam under reduced pressure.

Example 60: N-cyano-N'-r6-rN-r2-rN-(4-fluorobenzYl)-N-(2-pvridvl)aminolethYll-N-methylaminolhexvll-N"-r3-r3-(piperidinomethYl)phenoxYlpropYll~uanidine Preparation is effected analogously to Example 1, using 0.33 g (0.9 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equi-molar amount of N-cyano-O-phenyl-N'-[3-(3-(piperidinomethyl)phenoxy]propyllisourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. [%]) = 657 ([M+H]+, 11), 229 (100); IR (KBr): 2164 cm~1 (C-N). For further analysis, a ponion of the compound is convened into the tartaric acid salt in an ethanoV-ether solvent mixture; m.p.: 58C (ethanol/ether).

207~211 Example 61: N-cvano-N'-~7-rN-~2-rN-(4-fluorobenzvl)-N-(2-pvridvl)aminolethYll-N-methv!aminolheDtvll-N~ ' -r3-r3-(piperidinomethvl)phenoxvlpropvllguanidine Preparation is effected analogously to Example 1, using 0.48 g (1.3 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equi-molar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purifled title compound in the form of a viscous oil; MS (+E'AB method): m/z (rel.
int. [%]) = 671 (lM+H]+, 3), 229 (100); IR (KBr): 2164 cm~l (C_N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanoVether; m.p.: 96-98C (isopropanol/ether).

Example 62: N-cYano-N'-r3-rN-r2-rN-(4-fluorobenzvl)-N-(2-pvridvl)aminolethYll-N-methylaminolpropvll-N"-r4-r3-(pipeAdinomethyl)phenoxvlbutvll uanidine Preparation is effected analogously to Example 1, using 0.50 g (1.6 mmol) of N-[2-[N-(1 fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equi-molar amount of N-cyano-O-phenyl-N'-[4-[3-(piperidinomethyl)phenoxy]butyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. [%]) = 629 ([M+H]+, 18), 229 (9X), 109 (100); IR (KBr): 2164 cm~l (C-N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanoVether; m.p.: 102-105C (isopropanoVether).

Example 63: N-r2-rN-12-rN-(4-methoxYbenzvl)-N-(2-pvridvl)aminolethvll-N-methvl-aminolethyll-N'-r3-r3-(piperidinomethyl)phenoxvlpropvllurea 0.53 g (1.7 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]-ethyl]-N-methyl-1,2-ethanediamine is dissolved in 2.5 ml of absolute THF and, while stirring, is added dropwise in the course of 30 minutes to a solution, cooled to 0C, of 0.27 g (1.7 mmol) of l,l'-carbonyldiimidazole in 9 ml of absolute THF in such a manner that the temperature of the reaction batch remains at 0C. Stirring of the solution at 0C is continued until the arnine has reacted completely to form the isocyanate (TLC monitoring). An equimolar solution of 3-[3-(piperidinomethyl)phenoxy]propylamine in 5 ml of absolute THF is added dropwise to the isocyanate solution. The reaction batch is stirred at room temperature for " 207~211 24 hours. Water is then added to the batch, which is stirred for 30 minutes and extracted with methylene chloride. The organic phases are combined and dried with Na2SO4 and the solvent is distilled off under reduced pressure. The residue is purified by rotation chromatography to yield the purified title compound in the form of a viscous oil.
MS (+FAB method): m/z (rel. int. [%]) = 589 ([M+H]+, 1), 241 (10), 121 (100) IR (KBr):
1639 cm~l (C=O).

Example 64: N-r3-rN-r2-rN-(4-methoxvbenzvl)-N-(2-pvridYl)aminolethYIl-N-methY
aminolpropvll-N~-r3-r3-(pi~eridinomethvl)phenoxylpropyllurea Preparadon is effected analogously to Example 63, using 0.54 g (1.65 mmol) of N-[2-~N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amounts of l,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]-propylamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. ~%]) = 603 ([M+H]+, 10), 121 (100); IR (KBr): 1639 cm~l (C=O).
For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 120C (isopropanol/ether).

Example 65: N-r4-rN-r2-rN-(4-methoxvbenzvl)-N-(2-pYridYI)aminolethYll-N-meth aminolbutvll-N' -r3-r3-(piperidinomethvl)phenoxvlpropYllurea Preparation is effected analogously to Example 63, using 0.55 g (1.6 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equi-molar amounts of l,l'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propyl-amine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 617 ([M+H]+, 1), 121 (100); IR (KBr): 1603 cm~1 (C=O). For further analysis, a portion of the compound is converted into the picric acid salt and recrystallised from ethanol; m.p.: 68-72C (ethanol).

Example 66: N-r6-rN-r2-rN-(4-methoxvbenzvl)-N-(2-pYridvl)aminolethvll-N-methYI-aminolhexyll-N'-r3-r3-(piperidinomethvl)phenoxvlpropvllurea Preparation is effected analogously to Example 63, using 0.58 g (1.5 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl- 1,6-hexanediamine and the equi-molar amounts of 1,1 '-carbonyldiimidazole and 3-[3-(piperidinomethyl~phenoxy]propyl-amine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. l%]) = 645 ([M+H]+,8), 121 (100); IR (KBr): 1635 cm~l (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/-ether solvent mixture; m.p.: 75C (ethanoVether).
Example 67: N-r2-rN-r2-rN-(4-fluorobenzvl)-N-(2-PvridYI)aminolethYll-N-methylamin ethvll-N'-r3-r3-(piperidinomethyl)phenoxYlpropYllurea Preparadon is effected analogously to Example 63, using 0.42 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equi-molar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propyl-amine as stardng materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 577 ([M+H]+, 12), 229 (99), 109 (100); IR (KBr): 1640 cm~l (C=O). For further analysis, a ponion of the compound is converted into the tartaric acid salt and recrystallised from isopropanoUether/petroleum ether; m.p.: 68C (isopropanoVether/-petroleum ether).

Example 68: N-r3-rN-r2-rN-(4-fluorobenzvl)-N-(2-r)Yridvl)aminolethYIl-N-methYlamin propvll-N'-r3-r3-(piperidinomethYl)phenoxvlpropvllurea Preparadon is effected analogously to Example 63, using 0.63 g (2.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equi-molar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propyl-amine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 591 ([M+H]+,7), 229 (86), 109 (100). For further analysis, a portion of the compound is converted into the hydrochloric acid salt and is extracted from ether in the form of a dry foam by stirring; m.p.: 123-125C (ether).

Example 69: N-r4-rN-r2-rN-(4-fluorobenzvl)-N-(2-pYridYl)aminolethYll-N-methylamin butYll-N'-r3-r3-(piPeridinomethvl)phenoxYlpropyllurea Preparadon is effected analogously to Example 63, using 0.45 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equi-molar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propyl-amine as starting materials. Chromatographic working-up analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 605 ([M+H]+, 8), 109 (100); IR (KBr): 1641 cm^l (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystal-lised from isopropanol/ether/petroleum ether; m.p.: 69C (isopropanollether/petroleum ether).

Example 70: N-rS-rN-r2-rN-(4-fluorobenzvl)-N-(2-pYridYI)aminolethvll-N-methYlamin Pentvll-N~-r3-r3-(piperidinomethvl)phenoxvlpropyllurea Preparation is effected analo~ously to Example 63, using 0.51 g (1.5 mmol) of N-[2-lN-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,5-pentanediamine and the equi-molar amounts of l,l'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propyl-amine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 619 ([M+H]+, 3),77 (100); IR (KBr): 1634 cm~l (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystal-lised from isopropanoVether/petroleum ether; m.p.: 63C (isopropanol/ether/petroleum ether).

Example 71: N-r6-rN-r2-~N-(4-fluorobenzyl)-N-(2-pvridYI)aminolethYll-N-methvlamin hexv!l-N'-r3-r3-(piperidinomethvl)phenoxvlproDvllurea Preparation is effected analogously to Example 63, using 0.50 g (1.4 mmol) of N-[2-[N-(~fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equi-molar amounts of l,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propyl-amine as starting materials. Chromatographic working-up analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 633 ([M+H]+, 1), 154 ([m-NO2-benzylOH] 100); IR (KBr): 1640 cm~l (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 65-69C (ethanol/ether).

Example 72: N-r7-rN-r2-rN-(4-fluorobenzvl)-N-(2-pvridvl)aminolethvll-N-methv!aminol-heptvU-N'-r3~(piperidinomethvl)phenoxYlpropvllurea Preparation is effected analogously to Example 63, using 0.59 g (1.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equi-molar amounts of l,l'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propyl-amine as starting materials. Working up by chromatography analogously to Example 63 yields the purified dtle compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 647 ([M+H]+,7), 229 (100); IR (KBr): 1634 cm~l (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanoVether; m.p.: 112C (isopropanoVether).

Example 73: N-r3-rN-r2-rN-(4-fluorobenzvl)-N-(2-pvridvl)aminolethYll-N-methvlaminol-propylLN' -r4-r3-(piperidinomethYl)phenoxvlbutvllurea Preparation is effected analogously to Example 63, using 0.42 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equi-molar amounts of l,l'-carbonyldiimidazole and 4-[3-(piperidinomethyl)phenoxy]butyl-amine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. t%]) = 605 ([M+H]+. 14), 229 (100); IR (KBr): 1631 cm l (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrysta11ised from isopropanoVether; m.p.: 115C (isopropanoVether).

Example 74: N-r2-rN-r2-~N-(4-methoxYbenzvl)-N-(2-pvridvl)aminolethYll-N-methvl-aminolethvll-N'-r3-r3-(piperidinomethvl)Phenoxvlpropvll-2-nitro-l.l-ethenediamine Preparadon is effected analogously to Example 22, using 0.85 8 (2.7 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equi-molar amount of l-methylthio-1-[3-[3-(piperidinomethyl)phenoxy]propyl]amino-2-nitro-ethene as starting materials. Chromatographic working-up analogously to Exarnple 22 yields the purified tdtle compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 632 ([M+H]+, 8), 121 (100). For further analysis, a pordon of the compound is converted into the tartaric acid salt and recrystallised from isopropanoVether;
m.p.: 102-104C (isopropanoVether).

, .

. :

Example 75: N-r6-rN-r2-rN-(4-methoxvbenzvl)-N-(2-pYridvl)aminolethYIl-N-methY
aminolhexvll-N'-r3-r3-(pi~eridinomethvl)phenoxvlpropvll-2-nitro- 1.1 -ethenediamine Preparation is effected analogously to Example 22, using 0.54 g (1.45 mmol) of N-[2-~N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equi-molar amount of 1 -methylthio- 1 -13-[3-(piperidinomethyl)phenoxy]propyl]amino-2-nitro-ethene as starting materials. Working up by chromatography analogously to Example 22 yields the purifled title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 688 ([M+H]+, S), 121 (100). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture;
m.p.: 73C (ethanoVether).

Examp!e 76: N-cvano-N'-l2-rr(2-Puanidino-4-thiazolvl)methYllthiolethYll-N~-r2-rN-r2-rN-(4-methoxvbenzvl)-N-(2-pyridyl)aminolethyll-N-methylaminolethyll ~uanidine Preparation is effected analogously to Example 1, using 0.53 g (1.7 mmol) of N-l2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equi-molar amount of N-cyano-N'-[2-~[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil which crystallises from absolute ether at -20C and is recrystallised from ethanol/ether; M5 (+FAB method): m/z (rel. int. l%]) = 596 ([M+H]+, 1), 121 (100); IR (KBr): 2163 cm~l (C_N); m.p.: 56-58C
(ethanol/ether) .

Example77:N-cvano-N'-r2-rr(2- uanidino-4-thiazolvl)methYllthiolethYll-N''-r3-rN-r2-rN-(4-methoxvbenzvl)-N-(2-pyridyl)aminolethvll-N-methvlaminolpropyll~uanidine Preparation is effected analogously to Example 1, using 0.52 ~ (1.6 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl- 1,3-propanediamine and theequimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil that crystallises from ether at -20C; MS ~+FAB method): m/z (rel. int. [%]) = 610 ([M+H]+, 1), 121 (100); IR (KBr): 2161 cm~l (C=N); m.p.: 54C (ether).

207~211 Example 78: N-cvano-N'-r2-rr(2-~uanidino-4-thiazolvl)methvllthiolethvll-N''-r4-rN-r2-rN-(4methoxybenzyl)-N-(2-Dvridyllaminolethvll-N-methvlaminolbutyll~uanidine Preparation is effected analogously to Example 1, using 0.54 g (1.6 mol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl- 1,4-butanediamine and the equi-molar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio~ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purif~ed title compound in the form of a dry foam.
MS (+FAB method): m/z (rel. int. [%~) = 624 ([M+H~+, 1), 121 (100) IR (KBr): 2163 cm-(C-N) Example 79: N-cYano-N'-r2-rr(2-guanidino-4-thiazolvl)methYIlthiolethvll-N''-r6-rN-r2-rN-(4-methoxvbenzyl)-N-(2-pvridvl)aminolethvll-N-methvlaminolhexvllouanidine Preparation is effected analogously to Example 1, using 0.57 g (1.5 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino~ethyl~-N-methyl-1,6-hexanediamine and the equi-molar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil that crystallises from ether at -20C; MS (+FAB method): m/z (rel. int. [%]) = 652 ([M+H]+, 12), 121 (100); IR
(KBr): 2162 cm-l (C_N); m.p.: 52VC (ether).

Example 80: N-cvano-N'-f2-rN-r2-rN-(4-fluorobenzvl)-N-(2-pvridYl)aminolethYll-N-methvlaminolethvll-N"-r2-rr(2-guanidino-4-thiazolvl)methvllthiolethvllouanidine Preparation is effected analogously to Example 1, using 0.30 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl~-N-methyl-1,2-ethanediamine and the equi-molar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio~ethyl~-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example I
yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 584 ([M+H]+,3), 109 (100); IR (KBr): 2165 cm~l (C_N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystal-lised from isopropanoVether; m.p.: 109C (isopropanoVether).

Example 81: N-cvano-N'-r3-rN-r2-rN-(4-fluorobenzYl)-N-(2-pvridYI)aminOlethyll-N-methvlaminolpropYll-N"-12-r[(2-guanidino-4-thiazolyl)methYllthiolethyll~uanidine Preparation is effected analogously to Example 1, using 0.53 g (1.67 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl~-N-methyl-1,3-propanediamine and the equi-molar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil.
MS (+FAB method): m/z (rel. int. [%]) = 598 ([M+H]+, 6), 109 (100); IR (KBr):
2163 cm~l (C=N); C2,H36FN1lS2 (597.80).

Example 82: N-cvano-N'-r4-rN-r2-rN-(4-fluorobenzYl)-N-(2-pYridYl)aminolethyll-N-methvlaminolbutyll-N' '-r2-rr(2-ouanidino-4-thiazolvl)methYIlthiolethYllouanidine Preparation is effected analogously to Example 1, using 0.33 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equi-molar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purifled title co-npound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 612 ([M+H]+, 49), 229 (100); IR (KBr): 2165 cm~l (C_N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an ethanoVether solvent mixture; m.p.: 137C (ethanoVether).

Example 83: N-cyano-N'-[5-rN-~L~fluorobenzyl)-N-(2-pYridYI)aminolethvll-N-methYlaminolpentYIl-N''-r2-rr(2-ouanidino-4-thiazolvl)methyllthiolethyllouanidine Preparation is effected analogously to Example 1, using 0.51 g (1.5 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,5-pentanediamine and the equi-molar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example I
yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 626 ([M+Hl+,3), 154 ([m-NO2benzylOH] 100); IR (KBr): 2162 cm~~(CEN). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from isopropanoVpetroleum ether; m.p.: 103C (isopropanoV-petroleum ether).

....

Example 84: N-cvano-N'-r6-rN-r2-rN-(4-fluorobenzvl)-N-(2-pYAdvl)aminolethYll-N-methvlaminolhexyll-N"-r2-rr(2-~uanidino-4-thiazolyl)methyllthiolethyllguanidine Preparation is effected analogously to Example 1, using 0.50 g (1.4 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)aminolethyl]-N-methyl- 1,6-hexanediamine and the equi-molar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-0-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purifled title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%]) = 639 ([M+H]+, 9), 229 (100); IR (KBr): 2162 cm-l (C_N). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanoV-ether solvent mixture; m.p.: 75C (ethanoVether).

Example 85: N-cyano-~[~N-r2-LN-(4-fluorobenzvl)-N-(2-p~ridvl)aminolethyll-N-methylaminolheptvll-N"-r~-rr(2-gua ino-4-thiazolyl)methyllthiolethvllguanidine Preparation is effected analogously to Example 1, using 0.57 g (1.53 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equi-molar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]~hio]ethyl]-0-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): rfl/z (rel. int. [%]) = 654 ([M+Hl+, 2), 91 (100); IR (KBr): 2163 cm~l (C=N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an ethanoVether solvent mixture; m.p. 118C (ethanoVether).

Example 86: N-r2-rr(2-guanidino-4-thiazolYl)methYllthiolethvll-N'-r2-rN-r2-rN-(4-methoxvbenzvl)-N-(2-pYridyl)aminolethyll-N-methvlaminolethyllurea Preparation is effected analogously to Example 63, using 0.53 g (1.7 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl- 1,2-ethanediamine and the equi-molar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. [%]) = 572 ([M+H]+, 1), 121 (100); IR (KBr): 1644 cm~l (C=O).
For further analysis, a portion of the compound is converted into the picric acid salt and recrystallised from ethanol; m.p.: 84C (ethanol).

207~21~

Exam~le 87: N r2-rr(2-guanidino-4-thiazolvl)methyllthiolethvll-N'-r3-rN-r2-rN-(4-methoxybenzyl)-N-(2-pyridyl)aminolethyll -N-methYlaminolproPyllurea Preparation is effected analogously to Example 63, using 1.00 g (3.0 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino~ethyl]-N-methyl-1,3-propanediamine and the equimolar amounts of l,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]-thioIethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. [%]) = 586 ([M+H]+, 4), 121 (100); IR (KBr): 1717 cm~l (C=O).
For further analysis, a portion of the compound is converted into the picric acid salt and recrystallised from ethanol; m.p.: 106-109C (ethanol).

Example 88: N-r2-rr(2-~uanidino-4-thiazolYl)methYIlthiolethvll-N'-r4-rN-r2-rN-(4-methoxybenzyl)-N-(2-pyridyl)aminnle~hyll-N-methylaminolbutyllurea Preparation is effected analogously to Example 63, using 0.54 g (1.58 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equi-molar amounts of 1,1 '-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. [%]) = 600 ([M+H]+, 1), 121 (100); IR (KBr): 1599 cm~l (C=O).
For further analysis, a portion of the compound is converted into the picric acid salt and recrystallised from ethanol; m.p.: 104-106C (ethanol).

Example 89: N-r2~ 2-~uani no-4-thiazo yl~methvllthiolethYll-N'-L6-rN-r2-rN-(4-methoxybenzyl)-N-(2-pyridyl)aminolethyll-N-methylaminolhexyllurea Preparation is effected analogously to Example 63, using 0.74 g (2.0 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equi-molar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. [%]) = 628 ([M+H]+, 4), 121 (100); IR (KBr): 1597 cm~l (C=O).
For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanoVether solvent mixture; m.p.: 60C (ethanoVether).

ExamDle 90: N-r2-rN-r2-rN-(4~ uorobenzyl)-N-(2-~yridyl)aminolethyll-N-methylamin ethvll-N'-r2-rr(2-~uanidino-4-thiazolvl)methyllthiolethvllurea Preparation is effected analogously to Example 63, using 0.29 g (0.97 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equi-molar amounts of l,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. [%]) = 560 ([M+H]+, 8),78 (100); IR (KBr): 1659 cm~l (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an elhanoVether solvent mixture; m.p.: 132C (ethanoVether).

Example 91: N-r3-rN-r2-rN-(4-fluorobenzvi)-N-(2-pYridvl)aminolethYll-N-methylamin propyll-N'-r2-rr(2-guanidino-4-thiazolyl)methYllthiolethYllurea Preparation is effected analogously to Example 63, using 0.33 g (1.05 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equi-molar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purifed title compound in the form of a dry foam.
MS (+FAB method): m/z (rel. int. [%]) = 574 ([M+H]+, 9), 109 (100) IR (KBr): 1682 cm~
(C=O).

Example 92: N-r4-rN-r2-rN-(4-fluorobenzvl)-N-(2-pYridYI)aminolethYll-N-methylamin butYll-N'-r2-rr(2-~uanidino-4-thiazolvl)methYIlthiolethYllurea Preparation is effected analogously to Example 63, using 0.20 g (0.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equi-molar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil.
MS (+FAB method): m/z (rel. int. [%]) = 588 ([M+H]+, 2), 109 (100); IR (KBr):
1685 cm~l (C=O); C27H38FNgOS2 (587.90).

207421~

Example 93: N-r5-rN-r2-rN-(4-fluorobenzvl)-N-(2-pvridvl)aminolethVll-N-methYlaminO
pentvll-N'-r2-rr(2-guanidino-4-thiazolyl)methvllthiolethvllurea Preparation is effected analogously to Example 63, using 0.51 g (1.5 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl~-N-methyl-1,5-pentanediamine and the equi-molar amounts of l,l'-carbonyldiimidazole and 2-[1(2-guanidino-4-thiazolyl)methyl]thio~-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. [%]) = 602 ([M+H]+,3),77 (100); IR (KBr): 1687 cm~l (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from isopropanol/ether; m.p.: 91-93C (isopropanol/ether).

Example 94: N-r6-rN-r2-rN-(4-fluorobenzvl)-N-(2-pYridvl)aminolethvll-N-methvl-aminolhexYIl-N-r2-rr(2-,g,uanidino-4-thiazolvl)methvllthiolethyllurea Preparation is effected analogously to Example 63, using 0.50 g (1.4 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equi-molar amounts of l,l'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): mlz (rel. int. [%]) = 616 ([M+H]+, 12), 229 (100); IR (KBr): 1640 cm~l (C=O).
For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanollether solvent mixture; m.p.: 95C (ethanol/ether).

Example 95: N-r7~N-r2-rN-(4-fluorobenzYl)-N-(2-pYridyl~aminolethYll-N-methylamin heptvll-N'-r2-rr(2-Puanidino-4-thiazolYI?methvllthiolethYllurea Preparation is effected analogously to Example 63, using 0.59 g (1.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl- 1,7-heptanediamine and the equi-molar amounts of l,l'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]-ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. [%]) = 630 ([M+H]+,3), 109 (100); IR (KBr): 1666 cm~l (C=O).
For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanoVether; m.p.: 125C (isopropanol/ether).

Example 96: N-r2-rr(2-~uanidino-4-thiazolvl)methvllthiolethvll-N'-r6-~N-r2-rN-(4-methoxvbenzvl)-N-(2-pvridvl)aminolethyll-N-methylaminolhexyll-2-nitro- 1.1 -ethene-diamlne Preparation is effected analogously to Example 22, using 0.41 g (1.8 mmol) of2-t[(2-guanidino-4-thiazolyl)methyl]thio3ethaneamine and the equimolar amount of 1 -[6-[N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methylamino]hexyl]-amino-l-methylthio-2-nitro-ethene. Working up by chromatography analogously to Example 22 yields the purified title compound in the form of a viscous oil; MS (+FAB
method): m/z (rel. int. [%]) = 671 ([M+H]~, 1), 121 (100). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanoUether solvent mixture;
m.p.: 60C (ethanol/ether).

The starting material is prepared as follows:

N-(4-methoxybenzyl)-N'-methyl-N-(2-pyridyl)-1,2-ethanediamine is reacted with the equimolar amount of 6-bromohexanonitrile and three times the molar amount of Na2CO3 in 60 ml of anhydrous acetonitrile while heating under reflux for 3 hours. The reaction batch is cooled to room temperature and water is added until the precipitate has dissolved.
The batch is extracted with toluene. The combined organic phases are dried with MgSO4 and the toluene is distilled off in vacuo to yield N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-6-aminohexanonitrile in the form of a brownish oil.
The oil is dissolved in 20 ml of absolute THF and, while cooling with ice and stirring, is introduced slowly into a suspension of twice the molar amount of LiAlH4 in 50 ml of absolute ether. The batch is stirred for 30 minutes and then, while cooling with ice, is hydrolysed with water-saturated ether and the dropwise addition of a small amount of 10 % sodium hydroxide solution until the exothermic reaction has ceased and a white precipitate forms. The batch is stirred for a further 30 minutes and then suction-filtered and the precipitate is washed several times with ether. The filtrate is washed with water, dried over Na2SO4 and concentrated to dryness in vacuo. The resulting crude product is purified by thick-layer chromatography, using methylene chloride containing 1 % (V/V) methanol as eluant, to yield N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-i,6-hexanediamine of sufficient purity for the subsequent reaction. 0.43 g (1.16 mmol) of that amine is heated under reflux for 4 hours with 0.19 g (1.16 mmol) of 1,1-dimethylthio-2-nitroethene [R. Gomper, H. Schafer, Chem. Ber. 100. 599 (1967)] in 20 ml of absolute acetonitrile. When the reaction is complete (TLC monitoring:

, ~. , .
. :
-;:, ,~

chloroforrn/methanol 95/5 V/V), the solvent is distilled off in vacuo. I'he resulting product, 1-[6-[N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methylamino]-hexyl~amino-l-methylthio-2-nitroethene, is sufficiently pure for the subsequent reaction.
Example 97: N-r4-rN-r2-(diphenylmethoxY)ethvll-N-methYIaminolbutY
N'-r2-rr(2-,~uanidino-4-thiazolvl)methYllthiolethYllurea Preparation is effected analogously to Example 63, using 0.37 g (1.2 mmol) of N-[2-(diphenylmethoxy)ethyl]-N-methyl-1,4-butanediamine and the equimolar amounts of l,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl~methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. [%]) = 570 ([M+H]+, I 1), 167 (100); IR (KBr): 1644 cm~l (C=O). For furtheranalysis, a portion of the compound is conver~ed into the tartaric acid salt and recrystal-lised from acetonitrile/isopropanoUpetroleum ether; m.p.: 101C (acetonitrile/-isopropanoUpetroleum ether).

Example 98: N-r4-rN-(3',3'-diphenvlpropYl)-N-methYIaminolbutYll-N~-r2-rr(2 ~uanidino-4-thiazolYl)methYllthiolethYllurea Preparation is effected analogously to Example 63, using 0.53 g (1.8 mmol) of N-(3',3'-diphenylpropyl)-N-methyl-1,4-butanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as staning materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. [%]) = 554 ([M+H]+, 2), 91 (100); IR (KBr): 1643 cm~l (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an ethanoVether solvent mixture; m.p.: 136C (ethanoUether).

Example 99: N-r2-rr(2-~uanidino-4-thiazolvl)methvllthiolethvll-N'-r6-rN-r2-rN-(4-methoxvbenzYI)-N-(2-pYridYl)aminolethvll-N-methYlaminolhexyllthiourea 0.48 g (1.3 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and 0.27 g (1.3 mmol) of dicyclohexylcarbodiimide are dissolved at -10C in absolute ether with 0.5 ml of carbon disulfide, the temperature is increased in the course of 3 hours to 20C and the batch is stirred for a further 12 hours. The solid that - so -precipitates is filtered off and the filtrate is concentra~ed in vacuo. 0.30 g (1.3 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]e~haneamine dissolved in a small amount of absolute ethanol is added to the concentrated residue and the reaction batch is heated under reflux for 2 hours. It is then concentrated in vacuo and the residue is purified by rotation chromatography to yield the purified title compound in the form of a viscous oil;
MS (+FAB method): m/z (rel. int. [%]) = 644 ([M+H]+, 1), 121 (100). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from acetonitrile/isopropanoVpetroleum ether; m.p.: 78C (acetonitrilelisopropanol/petroleum ether).
Example 100: N-cvano-N'-r2-rr5-r(dimethYlamino)methvllfurfurYIlthiolethvll-N~-r3-rN-1 2-rN-(4-methoxybenzyl)-N-(2-pvridyl)aminolethyll-N-methylaminolpropyll ouanidine Preparation is effected analogously to Example 1, using 0.55 g (1.6 mmol) of N-[2-~N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-N'-[2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethyl]-O-phenyl-isourea. Working up by chromatography analogously to Example 1 yields thepurified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel.
int. [%]) = 593 ([M+H]+, 4), 121 (100); IR (KBr): 2163 cm~l (C_N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from isopropanoVether; m.p.: 74C (isopropanoVether).

The starting material is prepared as follows:

While stirring, the equimolar amount of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]-ethaneamine [J. Bradshaw et al., Br. J. Pharmacol. 66, 464P (1979)] is added to a suspension of approx. 0.1 mol of N-cyanodiphenylimidocarbonate in 100 ml of diethyl ether. After approx. 15 minutes' stirring, the product, N-cyano-N'-[2-[[5- [(dimethyl-amino)methyl]furfuryl]thio]ethyl]-O-phenyl-isourea, precipitates copiously, or it crystallises after concentration of the solution. The product is suction-filtered, washed with diethyl ether and dried.

Example 101: N-r2-rr5-r(dimethylamino)methyllfurfuryllthiolethvll-N'-r2-rN-r2-rN44-fluorobenzvl)-N-(2-pvridyl)aminolethyll-N-methylaminolethyllurea Preparation is effected analogously to Example 63, using 0.56 g (1.8 mmol) of N-[2-[N-207~211 (4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amounts of l,l'-carbonyldiimidazole and 2-[[5-[(dimethylamino)methyl]-furfuryl]thio]ethylamine as stardng materials. Working up by chromatography analog-ously to Example 1 yields the purified title compound in the form of a viscous oil;
MS (+FAB method): m/z (rel. int. [%]) = 543 ([M+H]+, 14), 109 (100); IR (KBr):
1641 cm~1 (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanoVether; m.p.: 90C
(isopropanoVether).

Example 102: N-r2-rr5-r(dimethvlamino)methvl1furfurvllthio1ethYll-N'-r3-rN-r2-rN-(4-fluorobenzvl)-N-~2-pvridvl)aminolethYll-N-methvlaminolpropYllurea Preparadon is effected analogously to Example 63, using 0.57 g (1.8 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amounts of l,l'-carbonyldiimidazole and 2-[[5-[(dimethylamino)methyl]-furfuryl]thio]ethylamine as starting materials. Working up by chromatography analog-ously to Example 1 yields the purified title compound in the form of a viscous oil;
MS (+FAB method): m/z (rel. int. l%]) = 557 ([M+H]+, 1), 109 (100); IR (KBr):
1600 cm~l (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an ethanol/ether solvent mixture; m.p.: 102C (ethanoV-ether).
.

Example 103: N-r2-rr5-r(dimethYlamino)methvllfurfurvllthiolethvll-N'-r4-rN-r2-rN-(4-fluorobenzvl)-N-(2-pvridvl)aminolethvll-N-methvlaminolbutvllurea Preparadon is effected analogously to Example 63, using 0.50 g (1.5 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amounts of l,l'-carbonyldiimidazole and 2-[[5-[(dimethylamino)methyl]-furfuryl]thio]ethylamine as starting materials. Working up by chromatography analog-ously to Example 1 yields the purifiPd title compound in the form of a viscous oil;
MS (+FAB method): m/z (rel. int. ~%]) = 571 ([M+H]+, 17), 109 (100); IR (KBr):
1640 cm~l (C=O). For further analysis, a pordon of the compound is converted into the tartaric acid salt in an ethanoVether solvent mixture; m.p.: 74C (ethanoVether).

Example 104: N-r2-rr5-r(dimethYlamino)methyllfurfurYIlthiolethYll-N~-r3-~N-r2-rN-(4 fluorobenzyl)-N-(2-pvridvl)aminolethyll-N-methvlaminolpropyll-2-nitro- 1,1 -ethene-diamine Preparation is effected analogously to Example 22, using 0.54 g (1.7 mmol) of N-12-lN-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of 1-[2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethyl]amino-1-methylthio-2-nitroethene as starting materials. Working up by chromatography analog-ously to Example 22 yields the purified title compound in the form of a viscous oil;
MS (+FAB method): m/z (rel. int. [%]) = 600 ([M+H]+, 12), 109 (100). For furtheranalysis, a portion of the compound is converted into the tartaric acid salt in an ethanoV-ether solvent mixture; m.p.: 63C (ethanol/ether).

Example 105: N-r2-rr(2-~uanidino-4-thiazolvl)methvllthiolethvll-N'-r6-rN-methvl-N-r2-r 1 -(2-pvridyl)ethYllinden-2-vllethYlaminolhexvll-2-nitro- 1.1 -ethenediamine Preparation is effected analogously to Example 22, using 0.60 g (2.6 mmol) of 2-~[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine and the equimolar amounl of1-1[6-[N-methyl-N-[[2-[1 -(2-pyridyl)ethyl]inden-2-yl]ethyl]amino]hexyl]amino- 1 -methyl-thio-2-nitro-ethene as starting materials. Working up by chromatography analogously to Example 22 yields the purified title compound in the form of a dry foam; MS (+FAB
method): m/z (rel. int. [%]) = 678 (lM+H]+, 11), 93 (100).

The starting material is prepared as follows:

4.0 g (9.8 mmol) of dimethindene maleate are dissolved in water. The solution is rendered aL~caline with 2N sodium hydroxide solution and extracted by shaking four times with n-hexane. The combined organic phases are dried with Na2SO4 and the solvent is distilled offin vacuo. The free base is dissolved in 10 ml of absolute 1,2-dichloroethane and a spatula tip of Na2CO3 (anhydrous) is added to that solution. The mixture is cooled to 0C
and at that temperature 2.79 g (19.6 mmol) of a-chloroethylchloroformate are added dropwise. The batch is then heated under reflux for 12 hours. After cooling, excess Na2CO3 is filtered off and the solvent is distilled off in vacuo. The oily residue is heated under reflux overnight in methanol, CO2 being evolved. The methanol is finally distilled off in vacuo to yield 2.7 g of N-methyl-2-[3-[1-(2-pyridyl)ethyl]inden-2-yl]ethaneamine [S. Radler, Dissertation, Westfalische Wilhelms-Universitat Munster (1989)] in the form 207~211 of the hydrochloride, which is a colourless oil, which is reacted using 6-bromohexano-nitrile and by subsequent treatment with LiAlH4 analogously to the process indicated in Example 96 to form N-methyl-N-[2-[3-[1-(2-pyridyl)ethyl]inden-2-yl]ethyl]-1,6-hexane-diamine and then (by reaction with l,l-dimethylthio-2-nitroethene) 1-[[6-[N-methyl-N-[[2-[1-(2-pyridyl)ethyl]inden-2-yl]ethyl]amino]hexyl]amino- 1-methylthio-2-nitro-ethene.

Example 106: N-r7-rN-r3-(4-chlorophenvl)-3-(2-pvridvl)propYll-N-methYIaminolhePtN'-r3-r3-(piperidinomethyl)phenoxvlpropY11-2-nitro- 1.1 -ethenediamine A mixture of 0.73 g (1.9 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine and an equimolar amount of 1-methylthio-1-[3-[3-(piperidinomethyl)-phenoxy]propyllamino-2-nitro-ethene is heated under reflux for 12 hours in 20 ml of acetonitrile. The batch is then freed of solvent and the title compound is isolated in the form of a viscous oil by means of preparative thick-layer chromatography (eluant: ethyl acetate/methanol 9+ 1, ammonia atmosphere); MS (+FAB method): m/z (rel. int. [%]) =
691 ([M+H]+ 12), 230 (100).

Example 107: An ointment comprising 0.05 percent by weight active ingredient, for example N-~3-[N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methylamino]propyl]-N'-[3-[3-(piperidinomethyl)phenoxylpropyl]urea, is prepared as follows:

Composition Percent by wei~ht active ingredient O.Os vaseline 45.00 paraffin oil 19.60 cetyl alcohol s.oO
beeswax 5 0O
sorbitan sesquioleate 5.00 p-hydroxybenzoate 0.20 water,demineralised 20.15 The fatty substances and emulsifiers are melted together. The preservative is dissolved in water and the solution is incorporated into the fatty melt at elevated temperature by emulsification. After cooling, a suspension of the active ingredient in a portion of the fatty melt is incorporated into the emulsion.

2o7~2ll Example 108: Tablets, each comprising S0 mg of active ingredient, for example N-[7-[N-t3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methylamino]heptyl] -N'-[2-[[(2-guanidino-4thiazolyl)methyl]thio]ethyl]urea, are prepared as follows:

Composition (10 000 tablets) active ingredient 500.0 g lactose 500-0 g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly dispersed) 20.0 g ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of the potato starch and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a -sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silica are added and the mixture is compressed to form tablets each weighing 145 mg and comprising 50 mg of active ingredient, which may, if desired, be provided with breaking notches for flner adaptation of the dose.

' - :.~ ' . .

Claims

1. An arylalkylamine derivative of the general formula I

(I) wherein R1 is a substituted or unsubstituted aryl, heteroaryl, aryl-C1-C3alkyl or hetero-aryl-CI-C3alkyl group, a hydrogen atom or a C1-C3alkyl group, A is a nitrogen atom or a CH group, E is the grouping -(CH2)p-, -O-(CH2)p-, -S-(CH2)p- or wherein p may be 2, 3 or 4, Q is a nitrogen atom or a CH group, R2 is an unsubstituted or basically substituted aryl, heteroaryl, aryl-C1-C3alkyl or heteroaryl-C1-C3alkyl group, R3 is a hydrogen atom or a C1-C3alkyl group, X is an oxygen atom, a sulfur atom, the grouping N-CN or CH-NO2,m may be 2,3,4,5,6,7 or 8 and n maybe 1,2,3 or 4 and Y
is a sulfur atom, an oxygen atom or a methylene group, or a stereoisomeric form, a hydrate or a physiologically acceptable salt thereof.

2. An arylaLkylamine derivadve of formula I according to claim 1, wherein R1 is phenyl, furyl, thienyl, phenyl-C1-C3alkyl or (furyl, thienyl or pyridyl)-C1-C3alkyl, the phenyl ring and the heteroaryl ring in each case being unsubstitutcd or mono- or di-subsdtuted by halogen, C1-C3alkyl and/or by C1-C3alkoxy, or R1 is hydrogen or C1-C3alkyl, A is a nitrogen atom or a CH group, E is the grouping -(CH2)p-, -O-(CH2)p-, -S-(CH2)p- or wherein p is 2, 3 or 4, Q is a nitrogen atom or a CH group, R2 is piperidino-C1-C3alkyl-phenyl, guanidino-thiazolyl-C1-C3alkyl, C1-C3aLkyl-imidazolyl-C1-C3alkyl or (N,N-di-C1-C3alkylamino-C1-C3alkyl)-furanyl-CI-C3alkyl, R3 is hydrogen or C1-C3alkyl, X is an oxygen atom, a sulfur atom or the grouping N-CN or CH-NO2, m is 2, 3, 4, 5, 6, 7 or 8 and n is 1, 2, 3 or 4, and Y is a sulfur atom, an oxygen atom or a methylene group, or a stereo-isomeric form, a hydrate or a physiologically acceptable salt thereof.

3. An arylalkylamine derivative according to claim 1, wherein R1 is a phenyl, furyl or thienyl ring, each of which is unsubstituted or mono- or di-substituted by halogen atoms or by Cl-C3aL~cyl or Cl-C3alkoxy groups, A is a CH group or a nitrogen atom, Q is a nitrogen atom or a CH group, and E, R2, R3, X, Y, m, n and p are as defined in claim 1.

4. An arylalkylamine derivative according to claim 1, wherein R1 is a benzyl, furylmethyl, thienylmethyl or pyridylmethyl group, each of which is unsubstituted or mono- ordi-substituted by halogen atoms or by C1-C3alkyl or C1-C3alkoxy groups, A is a nitrogen atom, Q is a nitrogen atom, and E, R2, R3, X, Y, m, n and p are as defined in claim 1.

5. An arylalkylamine derivative of formula I according to claim 1, wherein R1 is phenyl or phenyl-CI-C3alkyl, wherein the phenyl ring in each case is unsubstituted or substituted by halogen, Cl-C3alkyl or by C1-C3alkoxy, or is hydrogen or C1-C3alkyl, A is a nitrogen atom or a CH group, E is the grouping -(CH2)p-, -O-(CH2)p-, -S-(CH2)p- or wherein p is 2 or 3, Q is a nitrogen atom or a CH group, R2 is piperidino-C1-C3alkyl-phenyl, guanidino-thiazolyl-C1-C3alkyl, C1-C3alkyl-imidazolyl-C1-C3alkyl or (N,N-di-C1-C3alkylamino-C1-C3alkyl)-furanyl-C1-C3alkyl, R3 is hydrogen or C1-C3alkyl, X is an oxygen atom, a sulfur atom or the grouping N-CN or CH-NO2, m may be 2, 3, 4, 5, 6, 7 or 8 and n may be 1, 2, 3 or 4, and Y is a sulfur atom or an oxygen atom, or a stereo-isomeric form, a hydrate or a physiologically acceptable salt thereof.

6. An arylalkylamine derivative of formula I according to claim 1, wherein R1 is phenyl that is unsubstituted or substituted by halogen or by C1-C3alkyl, phenyl-C1-C3alkyl subsdtuted in the phenyl ring by halogen or by C1-C3alkoxy. or is C1-C3alkyl, A is a nitrogen atom or a CH group, E is the grouping -(CH2)p-, -O-(CH2)p-, -S-(CH2)p- or wherein p is 2, Q is a nitrogen atom or a CH group, R2 is 3-piperidinomethyl-phenyl, 2-guanidino-thiazol-4-ylmethyl, 5-methyl-imidazol-4-ylmethyl or 5-(N,N-dimethylamino-methyl)-furan-2-ylmethyl, R3 is C1-C3alkyl, X is an oxygen atom, a sulfur atom or the grouping N-CN or CH-NO2, m may be 2, 3, 4, 5, 6, 7 or 8 and n may be 2, 3 or 4, and Y is a sulfur atom or an oxygen atom, or a stereoisomeric form, a hydrate or a physiologically acceptable salt thereof.

7. An arylalkylamine derivative according to claim 1, wherein R1 is a hydrogen atom or a C1-C3alkyl group, A is a CH group and Q is a nitrogen atom, E is the grouping and R2, R3, X, Y, m, n and p are as defined in claim 1.

8. An arylalkylamine derivative according to claim 1, wherein R2 is the grouping5-methylimidazol-4-ylmethyl and Rl, R3, A, E, Q, X, Y, m, n and p are as defined in claim 1.

9. An arylalkylamine derivative according to claim 1, wherein R2 is the grouping2-guanidino-thiazol-4-ylmethyl and Rl, R3, A, E, Q, X, Y, m, n and p are as defined in claim 1.

10. An arylalkylamine derivative according to claim 1, wherein R2 is the grouping 5-(N,N-dimethylaminomethyl)-furan-2-ylmethyl and Rl, R3, A, E, Q, X, Y, m, n and p are as defined in claim 1.

11. An arylalkylamine derivative according to claim 1, wherein R2 is the grouping 3-piperidinomethyl-phenyl and R1, R3, A, E, Q, X, Y, m, n and p are as defined in claim 1.

12. N-[7-[N-13-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methylamino]heptyl]-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]urea according to claim 1 or a pharma-ceutica11y acceptable salt thereof.

13. N-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N'-16-[N-[2-[N-(4-methoxy-benzyl)-N-(2-pyridyl)amino]ethyl]-N-methylamino]hexyl]-2-nitro-1, 1 -ethenediamine according to claim 1 or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and at least one pharmaceutically acceptable carrier.

15. A pharmaceutical composition according to claim 14 comprising N-[7-[N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methylamino]heptyl]-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]urea or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition according to claim 14 comprising N-[2-[[(2-guan-idino-4-thiazolyl)methyl]thio]ethyl]-N' -[6-[N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)-amino]ethyl]-N-methylamino]hexyl]-2-nitro-1,1-ethenediamine or a pharmaceutically acceptable salt thereof.

17. A compound according to any one of claims 1 to 13 for use in a method for the thera-peutic treatment of the animal or human body.

18. A compound according to any one of claims 1 to 13 for use in the treatment of disorders that respond to the inhibition of histamine H1- and H2-receptors.

19. The use of a compound according to any one of claims 1 to 13 for the preparation of a pharmaceutical composition.

20. The use of a compound according to any one of claims 1 to 13 for the preparation of a pharmaceutical composition for the treatment of disorders that respond to the inhibition of histamine H1- and H2-receptors.

21. A process for the preparation of a compound of formula I according to claim 1, or a stereoisomer, a hydrate or a physiologically acceptable salt thereof, wherein a) for the preparation of a compound of formula I wherein X is an oxygen or a sulfur atom or the grouping N-CN or CH-NO2, (al) a compound of formula II

wherein R1, R3, A, E, Q and m are as defined in claim 1 and Z is a methylthio, amercapto or a phenoxy group, is reacted with a compound of the general formula III

(III), wherein R2, Y and n are as defined in claim 1, or (a2) a compound of formula IV

(IV), wherein R2, Y and n are as defined in claim 1 and Z is a methylthio, a mercapto or a phenoxy group, is reacted with a compound of the general formula V

(V), wherein R1, R3, A, E, Q and m are as defined in claim 1, or b) for the preparation of a compound of formula I wherein X is an oxygen or a sulfur atom, (bl) a compound of formula VI

(VI), wherein R1, R3, A, E, Q and m are as defined in claim 1, is reacted with a compound of formula III wherein R2, Y and n are as defined in claim 1, or (b2) a compound of formula VII
X = C = N - (CH2)n - Y - R2 (VII), wherein R2, Y and n are as defined in claim 1, is reacted with a compound of formula V
(V), wherein R1, R3, A, E, Q and m are as defined in claim 1, and, if desired, a resulting compound of formula I is converted into a different compound of formula I, and/or, if desired, a resulting salt is converted into the free compound or into a different salt, and/or, if desired, a resulting free compound of formula I having salt-forming properties is converted into a salt.