DK171841B1 - N-hetero-cyclyl-4-piperidineamines - Google Patents

N-hetero-cyclyl-4-piperidineamines Download PDF

Info

Publication number
DK171841B1
DK171841B1 DK083183A DK83183A DK171841B1 DK 171841 B1 DK171841 B1 DK 171841B1 DK 083183 A DK083183 A DK 083183A DK 83183 A DK83183 A DK 83183A DK 171841 B1 DK171841 B1 DK 171841B1
Authority
DK
Denmark
Prior art keywords
parts
piperidinyl
benzimidazol
fluorophenylmethyl
ethyl
Prior art date
Application number
DK083183A
Other languages
Danish (da)
Other versions
DK83183A (en
DK83183D0 (en
Inventor
Frans Janssens
Raymond Stokbroekx
Marcel Luyckx
Joseph Torremans
Original Assignee
Janssen Pharmaceutica Nv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US06/002,276 external-priority patent/US4219559A/en
Priority claimed from DK129879A external-priority patent/DK169325B1/en
Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv
Priority to DK083183A priority Critical patent/DK171841B1/en
Publication of DK83183A publication Critical patent/DK83183A/en
Publication of DK83183D0 publication Critical patent/DK83183D0/en
Application granted granted Critical
Publication of DK171841B1 publication Critical patent/DK171841B1/en

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Description

i DK 171841 B1in DK 171841 B1

Den foreliggende opfindelse angår hidtil ukendte N-heterocyclyl-4-piperidinaminer, der kan anvendes som mellemprodukter ved fremstilling af andre ligeledes hidtil ukendte N-heterocyclyl-4-piperidinaminer.The present invention relates to novel N-heterocyclyl-4-piperidinamines which can be used as intermediates in the preparation of other similarly novel N-heterocyclyl-4-piperidinamines.

I U.S.A. patentskrift nr. 2.971.005 er beskrevet 2-(phenylmethyl-5 amino)benzimidazoler med lokalanæstetiske og antifibrillatoriske egenskaber, og i U.S.A. patentskrift nr. 2.857.391 er beskrevet et antal 2-(aminomethylJbenzimidazoler. De ved fremgangsmåden ifølge stamansøgning-en, DK patentansøgning nr. 1298/79, fremstillede forbindelser afviger væsentligt herfra, strukturelt ved arten af den 4-piperidinylgruppe, som 10 er bundet til aminonitrogenatomet, og ved, at de besidder uventede anti-histaminiske egenskaber. Der kendes endvidere forbindelsen 1-methyl-N-phenyl-N-phenylmethyl-4-piperidinamin, som er en antihistaminisk forbindelse med trivialnavnet Bamipin (se Merck index, 8. udgave (1968) side 118). De ifølge stamansøgningen fremstillede forbindelser afviger struk-15 turelt væsentligt herfra ved, at de indeholder en lH-benzimidazol-2-yl eller 3H-imidazo[4,5-b]pyridin-2-yl-gruppe bundet til aminonitrogenatomet.IN USA. U.S. Patent No. 2,971,005 discloses 2- (phenylmethyl-5-amino) benzimidazoles having local anesthetic and antifibrillatory properties, and in U.S.A. U.S. Patent No. 2,857,391 discloses a number of 2- (aminomethylbenzimidazoles). The compounds prepared by the process of the parent application, DK Patent Application No. 1298/79, differ substantially therefrom, structurally by the nature of the 4-piperidinyl group to which 10 is attached. the compound 1-methyl-N-phenyl-N-phenylmethyl-4-piperidinamine, which is an antihistaminic compound of the trivial name Bamipin (see Merck index, 8). edition (1968) p. 118) The compounds prepared according to the parent application differ substantially from this in that they contain a 1H-benzimidazol-2-yl or 3H-imidazo [4,5-b] pyridin-2-yl- group attached to the amino nitrogen atom.

De her omhandlede hidtil ukendte N-heterocyclyl-4-piperidinaminer kan gengives ved den i krav 1 viste almene formel (XX), mens de ligele-20 des hidtil ukendte N-heterocyclyl-4-piperidinaminer, der kan fremstilles ud fra disse forbindelser, kan gengives ved den almene formel:The novel N-heterocyclyl-4-piperidinamines disclosed herein can be reproduced by the general formula (XX) of claim 1, while the novel N-heterocyclyl-4-piperidinamines which can be prepared from these compounds are similar. can be reproduced by the general formula:

RR

25 r3 « ri i2 og farmaceutisk acceptable syreadditionssalte deraf, hvori 30 R er hydrogen eller methyl, R1 er hydrogen eller lavere al kyl med 1 til 6 carbonatomer, R2 er hydrogen, al kyl med 1 til 10 carbonatomer, cycloalkyl med 3 til 6 carbonatomer, aryl, mono- eller diphenyl-Clg-lavere alkyl, hvor phenylgruppen eventuelt er substitueret med 1 til 2 ens eller forskelli-35 ge substituenter, som er halogenatomer eller methyl- eller nitrogrupper, RJ er hydrogen, halogen, methyl eller trifluormethyl, 2 DK 171841 B1 L er en lavere al kyl gruppe, som indeholder 1 til 6 carbonatomer og eventuelt er substitueret med en cyano- eller hydroxygruppe eller en C^lavere alkoxygruppe, Cj_^lavere al kyl carbonyl oxygruppe eller en aryl-, aryloxy-, arylthio- eller aminogruppe, diphenyl-Cj_g-lavere al- 5 kyl, di-(halogenphenyl)Cj_glavere alkyl, 3-cyano-3,3-diphenyl propyl, 2- propenyl, 3-aryl-2-propenyl, 3-aryloxy-2-hydroxypropyl eller en gruppe med formlen: Z-CH. , hvor m Zm m et et helt tal fra 1 til 4, og Z er 4-aryl-4,5-dihydro-5-oxo-lH-tetrazol-1-yl, 4-(Cj_^lavere al-10 kyl)-4,5-dihydro-5-oxo-lH-tetrazol-1-yl-2,3-dihydro-l,4-benzodioxy-2-yl, 2,3-dihydro-l,4-benzodioxin-6-yl, 2,3-dihydro-2-oxo-lH-benzimidazol-1-yl, 2,3-dihydro-3-oxo-4H-benzoxazin-4-yl, (10,ll-dihydro-5H-dibenzo-[a,d]cyclohepten-5-yliden)methyl, 4-morpholinyl, arylcarbonyl, arylami-nocarbonyl, Cj^lavere al kylaminocarbonylamino, aryl carbonyl ami no, aryl-15 ami nocarbonyl ami no, Cj_4lavere alkyl carbonyl amino, ami nocarbonyl ami no eller arylamino, hvor, når L er en med en arylgruppe substitueret lavere alkylgruppe med 1 til 6 carbonatomer, arylgruppen betegner phenyl, substitueret phenyl, naphthalenyl, thienyl eller pyrridinyl, hvor nævnte substituerede phenyl indeholder 1 til 3 substituenter, som uafhængigt af 20 hinanden er halogenatomer eller methyl-, Cj 4lavere alkyloxy-, trifluor-methyl-, hydroxy-, nitro- eller aminogrupper, og hvor en af substituen-terne desuden kan være methylthio, Cj^lavere alkyloxy, carbonylmethoxy, phenyl acetyloxy, benzoyloxy, methoxybenzoyloxy, phenylmethoxy, Cj^lavere alkyloxycarbonyloxy, phenylmethoxycarbonyloxy, methyl sulfonyl eller 25 cyanomethoxy, og hvor aryl i alle andre definitioner af L betyder en phenylgruppe, der eventuelt er mono- eller disubstitueret, hvor hver substituent uafhængigt af hinanden er et halogenatom eller en methyl-eller methoxygruppe, og Q er CH eller N.And pharmaceutically acceptable acid addition salts thereof, wherein 30 R is hydrogen or methyl, R 1 is hydrogen or lower alkyl of 1 to 6 carbon atoms, R2 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms , aryl, mono- or diphenyl-C 1-8 lower alkyl, wherein the phenyl group is optionally substituted by 1 to 2 identical or different substituents which are halogen atoms or methyl or nitro groups, R 1 is hydrogen, halogen, methyl or trifluoromethyl, 2 DK 171841 B1 L is a lower alkyl group containing 1 to 6 carbon atoms and optionally substituted with a cyano or hydroxy group or a C 1 lower alkoxy group, C 1-4 lower alkyl carbonyl oxy group or an aryl, aryloxy, arylthio - or amino group, diphenyl-Cj_-lower alkyl, di- (halogenophenyl) Cj-lower alkyl, 3-cyano-3,3-diphenyl propyl, 2-propenyl, 3-aryl-2-propenyl, 3-aryloxy-2 -hydroxypropyl or a group of the formula: Z-CH. wherein m Zm m is an integer from 1 to 4 and Z is 4-aryl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, 4- (C1-6 lower alkyl) -4,5-dihydro-5-oxo-1H-tetrazol-1-yl-2,3-dihydro-1,4-benzodioxy-2-yl, 2,3-dihydro-1,4-benzodioxin-6-yl , 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl, 2,3-dihydro-3-oxo-4H-benzoxazin-4-yl, (10,11-dihydro-5H-dibenzo- [a , d] cyclohepten-5-ylidene) methyl, 4-morpholinyl, arylcarbonyl, arylaminocarbonyl, C arylamino, wherein when L is a lower alkyl group substituted with 1 to 6 carbon atoms, the aryl group represents phenyl, substituted phenyl, naphthalenyl, thienyl or pyrridinyl, wherein said substituted phenyl contains 1 to 3 substituents which are independently halogen atoms or methyl, C 1-4 lower alkyloxy, trifluoro-methyl, hydroxy, nitro or amino groups, and wherein one of the substituents additionally may be methylthio, Cj ^ lower alkyloxy, carbonylmethoxy, phenyl acetyloxy, benzoyloxy, methoxybenzoyloxy, phenylmethoxy, C - or disubstituted where each substituent is independently a halogen atom or a methyl or methoxy group and Q is CH or N.

Forbindelserne med formel (XX) ifølge opfindelsen er mellemproduk-30 ter til fremstilling af de i stamansøgningen, DK patentansøgning nr. 1298/79, omhandlede forbindelser, hvilke forbindelser har fælles nyttig antihistaminisk virkning.The compounds of formula (XX) according to the invention are intermediates for the preparation of the compounds disclosed in the parent application, DK Patent Application No. 1298/79, which compounds have common useful antihistaminic effect.

I de foregående definitioner betyder udtrykket "lavere al kyl" en ligekædet eller forgrenet carbonhydridgruppe med fra 1 til 6 carbonato-35 mer som f.eks. methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl og lignende, udtrykket "alkyl" som 3 DK 171841 B1 anvendt i definitionen af R2 omfatter ligekædede og forgrenede carbon-hydridgrupper med fra 1 til 10 carbonatomer som f.eks. de foran anførte lavere al kyl grupper og højere homologe såsom heptyl, octyl, nonyl og de-cyl, udtrykket "lavere alkenyl" refererer til ligekædede alkenylgrupper 5 med fra 3 til 6 carbonatomer, hvori umættetheden fortrinsvis er i β-st i 11 i ngen, men også kan være i y-, 6-, eller e-stillingen som f.eks.In the foregoing definitions, the term "lower alkyl" means a straight-chain or branched hydrocarbon group having from 1 to 6 carbons, e.g. methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like, the term "alkyl" as used in the definition of R 2 comprises straight and branched hydrocarbon groups having from 1 to 10 carbon atoms, e.g. the above lower alkyl groups and higher homologues such as heptyl, octyl, nonyl and decyl, the term "lower alkenyl" refers to straight chain alkenyl groups 5 having from 3 to 6 carbon atoms, the unsaturation being preferably in β-st for 11 , but may also be in the y, 6, or e position, e.g.

2-propenyl, 2-butenyl, 3-pentenyl, 2-hexenyl og lignende, udtrykket "cycloalkyl" refererer til cycliske carbonhydridgrupper med fra 3 til 6 carbonatomer såsom cyclopropyl, cyclobutyl, cyclopentyl og cyclohexyl, 10 og udtrykket "halogen" er generisk for fluor, chlor, brom og iod.2-propenyl, 2-butenyl, 3-pentenyl, 2-hexenyl and the like, the term "cycloalkyl" refers to cyclic hydrocarbon groups having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the term "halogen" is generic for fluorine, chlorine, bromine and iodine.

Forbindelserne med den almene formel (I) kan i almindelighed afledes af et udgangsmateriale med formlen: 15 (n) r1 uThe compounds of general formula (I) can generally be derived from a starting material of formula:

RR

hvori R, R1, R2, R3, n og Q har de ovenfor anførte betydninger, ved at 20 indføre den ønskede L-substituent på piperidin-nitrogenatomet ved hjælp af i og for sig kendte fremgangsmåder.wherein R, R1, R2, R3, n and Q have the above meanings by introducing the desired L substituent on the piperidine nitrogen atom by methods known per se.

I almindelighed kan indføringen af L i mellemproduktet (II) hensigtsmæssigt udføres ved omsætning af (II) med en passende reaktionsdygtig ester med formlen LY (III), hvori L har den ovenfor anførte betyd-25 ning, og Y betyder en reaktionsdygtig esterrest som f.eks. halogen, fortrinsvis chlor eller brom, eller en sulfonyloxyrest som f.eks. methyl -sulfonyloxy eller 4-methyl phenyl sulfonyloxy og lignende.In general, the introduction of L into the intermediate (II) may conveniently be effected by reacting (II) with a suitable reactive ester of formula LY (III), wherein L has the meaning given above and Y means a reactive ester residue such as .g. halogen, preferably chlorine or bromine, or a sulfonyloxy residue, e.g. methylsulfonyloxy or 4-methylphenyl sulfonyloxy and the like.

Kondensationsreaktionen mellem (II) og (III) udføres hensigtsmæssigt i et inert organisk opløsningsmiddel som f.eks. et aromatisk car-30 bonhydrid, f.eks. benzen, methyl benzen, dimethyl benzen og lignende, en lavere alkanol, f.eks. methanol, ethanol, 1-butanol og lignende, en keton, f.eks. 4-methyl-2-pentanon og lignende, en ether, f.eks. 1,4-di-oxan, Ι,Γ-oxybisethan og lignende, Ν,Ν-dimethylformamid (DMF), nitrobenzen og lignende.The condensation reaction between (II) and (III) is conveniently carried out in an inert organic solvent such as e.g. an aromatic hydrocarbon, e.g. benzene, methyl benzene, dimethyl benzene and the like, a lower alkanol, e.g. methanol, ethanol, 1-butanol and the like, a ketone, e.g. 4-methyl-2-pentanone and the like, an ether, e.g. 1,4-dioxane, Ι, Γ-oxybisethane and the like, Ν, Ν-dimethylformamide (DMF), nitrobenzene and the like.

35 Tilsætning af en passende base som f.eks. et al kalimetalcarbonat- eller hydrogencarbonat eller en organisk base som f.eks. N,N-diethyl- 4 DK 171841 B1 ethanamin eller N-(l-methylethyl)-2-propanamin kan anvendes for at opsamle den syre, som frigøres under reaktionsforløbet. Under visse omstændigheder er tilsætning af et iodidsalt, fortrinsvis et alkalimetal -iodid, passende.Addition of a suitable base, e.g. an al potassium metal carbonate or hydrogen carbonate or an organic base such as e.g. N, N-diethyl-ethanamine or N- (1-methylethyl) -2-propanamine can be used to collect the acid which is released during the course of the reaction. Under certain circumstances, the addition of an iodide salt, preferably an alkali metal iodide, is appropriate.

5 Noget forhøjede temperaturer kan anvendes for at forøge reaktions hastigheden.Slightly elevated temperatures can be used to increase the reaction rate.

Når L i formel (I) betegner en (2,3-dihydro-2-oxo-lH-benzimidanol- l-yl)lavere alkylgruppe, er det hensigtsmæssigt at anvende en reaktionsdygtig ester (III), hvori nitrogenatomet i 3-stillingen af 2,3-dihydro-10 2-oxo-lH-benzimidazol-l-yl-gruppen er substitueret med en passende beskyttende gruppe, fortrinsvis en 1-methylethenylgruppe, og fjerne denne beskyttende gruppe efter afslutning af kondensationsreaktionen. Fjernelsen af den beskyttende gruppe kan ske på i og for sig kendt måde såsom ved sur hydrolyse, når en 1-methylethenylgruppe er involveret.When L in formula (I) represents a (2,3-dihydro-2-oxo-1H-benzimidanol-1-yl) lower alkyl group, it is convenient to use a reactive ester (III) wherein the nitrogen atom at the 3-position of The 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl group is substituted by an appropriate protecting group, preferably a 1-methylethenyl group, and removing this protecting group upon completion of the condensation reaction. The removal of the protecting group may occur in a manner known per se such as by acid hydrolysis when a 1-methylethenyl group is involved.

15 Når L betegner en 2-aryl-2-hydroxyethyl- eller en 3-aryloxy-2-hy- droxypropylgruppe, udføres indføringen af substituenten i mellemproduktet (II) hensigtsmæssigt ved, at man omsætter (II) ved en forhøjet temperatur med en passende oxiran med formlen: 20 «yMOCH^-Δ UV> hvori m er 0 eller 1.When L represents a 2-aryl-2-hydroxyethyl or a 3-aryloxy-2-hydroxypropyl group, the introduction of the substituent into the intermediate (II) is conveniently carried out by reacting (II) at an elevated temperature with an appropriate temperature. oxirane of the formula: 20 «yMOCH ^ -Δ UV> wherein m is 0 or 1.

Omsætningen af formel (II) med (IV) kan udføres i et passende organisk opløsningsmiddel eller eventuelt i fravær af noget opløsningsmid-25 del. Egnede opløsningsmidler, som kan anvendes, omfatter f.eks. aromatiske carbonhydrider såsom benzen, methylbenzen, dimethyl benzen og lignende, halogenerede carbonhydrider som f.eks. trichlormethan, dichlormethan og lignende, lavere al kanoler såsom methanol, ethanol, 2-propanol og lignende alkoholer, og blandinger af sådanne opløsningsmidler. Når pipe-30 ridinderivatet (II) er i form af et syreadditionssalt, er det hensigtsmæssigt til reaktionsblandingen at sætte en passende base som f.eks. natriumcarbonat for at frigøre den frie syre fra saltet.The reaction of formula (II) with (IV) may be carried out in a suitable organic solvent or, optionally, in the absence of any solvent. Suitable solvents which may be used include, e.g. aromatic hydrocarbons such as benzene, methylbenzene, dimethyl benzene and the like, halogenated hydrocarbons such as e.g. trichloromethane, dichloromethane and the like, lower all channels such as methanol, ethanol, 2-propanol and similar alcohols, and mixtures of such solvents. When the piperidine derivative (II) is in the form of an acid addition salt, it is convenient for the reaction mixture to add a suitable base such as e.g. sodium carbonate to release the free acid from the salt.

Forbindelserne med formel (I), hvori L betegner en 2-hydroxyethyl-gruppe, kan fremstilles ved, at man omsætter en passende piperidin med 35 formel (II) med oxiran under anvendelse af samme procedure som beskrevet for omsætningen af (IV) med (II).The compounds of formula (I) wherein L represents a 2-hydroxyethyl group can be prepared by reacting an appropriate piperidine of formula (II) with oxirane using the same procedure as described for the reaction of (IV) with ( II).

5 DK 171841 B1 Når L på fastgørelsestidspunktet til piperidin-nitrogenatomet er en primær eller sekundær alkylgruppe, kan forbindelserne (I) også fremstilles ved reduktiv aminering af et aldehyd eller en keton svarende til alkoholen L-OH med et piperidinderivat med formel (II) på i og for sig 5 kendt måde. En hensigtsmæssig fremgangsmåde består i, at man hydrogenerer en blanding af aldehydet eller ketonen og (II) i et passende organisk opløsningsmiddel i nærværelse af en passende katalysator som f.eks. palladium-på-trækul.When at the time of attachment to the piperidine nitrogen atom, L is a primary or secondary alkyl group, compounds (I) can also be prepared by reductive amination of an aldehyde or ketone corresponding to the alcohol L-OH with a piperidine derivative of formula (II) of 5 known in itself. A convenient process consists of hydrogenating a mixture of the aldehyde or ketone and (II) in a suitable organic solvent in the presence of a suitable catalyst such as e.g. palladium-on-charcoal.

Passende organiske opløsningsmidler omfatter lavere alkanoler såsom 10 methanol, ethanol, propanol og lignende. Hastigheden for hydrogeneringsreaktionen kan øges ved, at den udføres i nærværelse af en passende svag syre som f.eks. eddikesyre. Når piperidinderivatet (II) er i form af et additionssalt med en stærk syre, f.eks. saltsyre eller hydrogenbromidsy-re, er det hensigtsmæssigt dertil at sætte et salt af stærk base med 15 svag syre, f.eks. natriumacetat, for at binde den stærke syre. Når (II) indeholder grupper, der i sig selv er påvirkelige ved katalytisk hydrogenering, f.eks. når R2 betyder en aryl methyl gruppe, kan det være hensigtsmæssigt til reaktionsblandingen at sætte en passende katalysatorgift som f.eks. thiophen.Suitable organic solvents include lower alkanols such as methanol, ethanol, propanol and the like. The rate of the hydrogenation reaction can be increased by being carried out in the presence of a suitably weak acid such as e.g. acetic acid. When the piperidine derivative (II) is in the form of an addition salt with a strong acid, e.g. hydrochloric acid or hydrobromic acid, it is convenient to add a strong base salt with weak acid, e.g. sodium acetate, to bind the strong acid. When (II) contains groups which are themselves susceptible to catalytic hydrogenation, e.g. when R 2 represents an aryl methyl group, it may be appropriate for the reaction mixture to add an appropriate catalyst poison such as e.g. thiophene.

20 Når L betegner en gruppe med formlen hvori m er et helt tal fra og med 2 til og med 4, og Z har den ovenfor anførte betydning, kan forbindelserne med formel (I) også fremstilles ved, at man omsætter (II) med et passende alkenyl deri vat, Z-C ^ -1, på i og for sig kendt måde for udførelse af lignende additionsreaktioner, f.eks. ved omrøring 25 og opvarmning af reaktanterne med hinanden i et passende, for reaktionen inert organisk opløsningsmiddel som f.eks. en lavere alkanol såsom 2-propanol, butanol og lignende.When L represents a group of formula wherein m is an integer from 2 to 4 and Z has the meaning given above, the compounds of formula (I) can also be prepared by reacting (II) with a suitable alkenyl derivative, ZC1-1, in a manner known per se for carrying out similar addition reactions, e.g. by stirring 25 and heating the reactants with each other in a suitable, inert organic solvent reaction, e.g. a lower alkanol such as 2-propanol, butanol and the like.

Når L betegner en 2-(aroylamino)ethylgruppe eller en 2-arylethyl-gruppe kan forbindelserne (I) også opnås ved, at man omsætter (II) med 30 henholdsvis en passende 1-aroyalaziridin eller en passende ethenylaren. Disse omsætninger udføres fortrinsvis i et passende, for reaktionen inert opløsningsmiddel som f.eks. en lavere alkanol, f.eks. methanol, ethanol, propanol, butanol og lignende alkoholer, et aromatisk carbonhy-drid, f.eks. benzen, methyl benzen, dimethyl benzen og lignende, en keton, 35 f.eks. 4-methyl-2-pentanon, en ether, f.eks. 1,4-dioxan, l,l'-oxybis-ethan og lignende, Ν,Ν-dimethylformamid, nitrobenzen og lignende eller 6 DK 171841 B1 en blanding af sådanne opløsningsmidler. Forhøjede temperaturer er hensigtsmæssige for at forøge reaktionshastigheden, og fortrinsvis udføres omsætningen ved tilbagesvalingstemperaturen for reaktionsblandingen.When L represents a 2- (aroylamino) ethyl group or a 2-arylethyl group, compounds (I) can also be obtained by reacting (II) with an appropriate 1-aroyalaziridine or an appropriate ethenylarene, respectively. These reactions are preferably carried out in a suitable reaction-inert solvent, e.g. a lower alkanol, e.g. methanol, ethanol, propanol, butanol and similar alcohols, an aromatic hydrocarbon, e.g. benzene, methyl benzene, dimethyl benzene and the like, a ketone, e.g. 4-methyl-2-pentanone, an ether, e.g. 1,4-dioxane, 1,1'-oxybis-ethane and the like, Ν, Ν-dimethylformamide, nitrobenzene and the like or a mixture of such solvents. Elevated temperatures are suitable for increasing the reaction rate, and preferably the reaction is carried out at the reflux temperature of the reaction mixture.

Forbindelserne med formel (I) kan også fremstilles ved cyclodesul -5 furisering af et passende thiourinstofderivat med formlen ?2The compounds of formula (I) may also be prepared by cyclodesul-5 fururization of a suitable thiourea derivative of formula? 2

R ' NHR 'NH

10 (V)10 (V)

31 I31 I

*3* 3

Denne cyclodesulfuriseringsreaktion kan udføres ved, at man omsæt-15 ter (V) med et passende alkylhalogenid, fortrinsvis iodmethan i et passende, for reaktionen inert organisk opløsningsmiddel, f.eks. en lavere alkanol såsom methanol, ethanol, 2-propanol og lignende. Herudover kan cyclodesulfuri seringsreaktionen udføres ved, at man omsætter (V) med et passende metaloxid eller -salt i et passende opløsningsmiddel i henhold 20 til den fremgangsmåde, som f.eks. er beskrevet i Pharmazie, 31, 348 (1976). For eksempel kan forbindelserne med formel (I) let fremstilles ved, at man omsætter (V) med et passende Hg (11)- eller Pb(II)oxid eller -salt som f.eks. HgO, HgCl2, HgiOAc^, PbO eller PbtOAcJg. I visse tilfælde kan det være hensigtsmæssigt at supplere reaktionsblandingen med 25 en lille smule svovl. Endog methandiiminer, specielt N,N'-methantetrayl-bisfcyclohexanamin] kan anvendes som cyclodesulfuriseringsmidler. Egnede, for reaktionen inerte organiske opløsningsmidler, som med fordel kan anvendes, omfatter lavere al kanoler, f.eks. methanol, ethanol, 2-propa-nol og lignende, halogenerede carbonhydrider, f.eks. dichlormethan og 30 trichlormethan, ethere, f.eks. tetrahydrofuran, 2,2'-oxybispropan og lignende, og blandinger af sådanne opløsningsmidler.This cyclodesulfurization reaction can be carried out by reacting (V) with a suitable alkyl halide, preferably iodomethane, in a suitable organic solvent for the reaction, e.g. a lower alkanol such as methanol, ethanol, 2-propanol and the like. In addition, the cyclodesulfurization reaction can be carried out by reacting (V) with a suitable metal oxide or salt in a suitable solvent according to the process, e.g. are described in Pharmazie, 31, 348 (1976). For example, the compounds of formula (I) can be readily prepared by reacting (V) with a suitable Hg (11) or Pb (II) oxide or salt, e.g. HgO, HgCl2, HgiOAc ^, PbO or PbtOAcJg. In some cases it may be convenient to supplement the reaction mixture with a little sulfur. Even methanedimines, especially N, N'-methanetretrayl-biscyclohexanamine] can be used as cyclodesulfurizers. Suitable, inert organic solvents which can advantageously be used for the reaction include lower alkanols, e.g. methanol, ethanol, 2-propanol and the like, halogenated hydrocarbons, e.g. dichloromethane and trichloromethane, ethers, e.g. tetrahydrofuran, 2,2'-oxybispropane and the like, and mixtures of such solvents.

Amino-substituerede forbindelser kan for eksempel afledes af de tilsvarende nitro- og cyano-substituerede forbindelser ved, at man reducerer sidstnævnte, f.eks. ved katalytisk hydrogenering i nærværelse af 35 en passende katalysator som f.eks. Raney-nikkel og lignende.For example, amino-substituted compounds can be derived from the corresponding nitro- and cyano-substituted compounds by reducing the latter, e.g. by catalytic hydrogenation in the presence of a suitable catalyst, e.g. Raney nickel and the like.

De amino-substituerede forbindelser kan igen N-alkyleres eller acy- 7 DK 171841 B1 leres ved omsætning deraf med et passende alkyleringsmiddel eller acyle-ringsmiddel, f.eks. et halogenid, et alkamiddel eller acyleringsmiddel, f.eks. et halogenid, et alkanoylhalogenid, et alkoxycarbonylhalogenid, et isocyanat og lignende.The amino-substituted compounds can again be N-alkylated or acylated by reaction thereof with a suitable alkylating agent or acylating agent, e.g. a halide, an alkali or acylating agent, e.g. a halide, an alkanoyl halide, an alkoxycarbonyl halide, an isocyanate and the like.

5 Sekundært og tertiært amino-substituerede forbindelser med formel (I) kan fremstilles ved, at man f.eks. substituerer en passende halogensubstitueret forbindelse med den ønskede primære eller sekundære amin.Secondary and tertiary amino-substituted compounds of formula (I) can be prepared by e.g. substitutes an appropriate halogen-substituted compound with the desired primary or secondary amine.

Aminocarbonyl-substituerede forbindelser kan hensigtsmæssigt afledes af de tilsvarende estere ved omsætning af sidstnævnte med ammoniak 10 eller en passende primær eller sekundær amin i et egnet opløsningsmid del.Aminocarbonyl-substituted compounds may conveniently be derived from the corresponding esters by reaction of the latter with ammonia 10 or a suitable primary or secondary amine in a suitable solvent moiety.

Forbindelser med formel (I), som i strukturen indeholder en sulfo-nylgruppe, kan let afledes af de tilsvarende thioforbindelser ved, at man oxiderer sidstnævnte med et passende oxidationsmiddel, f.eks. hydro-15 genperoxid eller lignende.Compounds of formula (I) which contain in the structure a sulfonyl group can be readily derived from the corresponding thio compounds by oxidizing the latter with a suitable oxidizing agent, e.g. hydrogen peroxide or the like.

Ved alle de foregående og efterfølgende fremstil!i nger kan reaktionsprodukterne isoleres fra reaktionsblandingen og - om nødvendigt -yderligere renses på i og for sig kendt måde.In all the foregoing and subsequent preparations, the reaction products can be isolated from the reaction mixture and, if necessary, further purified in a manner known per se.

Forbindelserne med formel (I) kan omdannes til den therapeutisk ak-20 tive ikke-toxiske syreadditionssal tform ved behandling med en passende syre som f.eks. en uorganisk syre såsom hydrohalogenidsyre, f.eks. hy-drogenchlorid, hydrogenbromid og lignende og svovlsyre, salpetersyre, phosphorsyre og lignende, eller en organisk syre som f.eks. eddike-, propan-, 2-hydroxyeddike-, 2-hydroxypropan-, 2-oxopropan-, propandioin-, 25 butandioin-, (Z)-2-butendioin-, (E)-2-butendioin-, 2-hydroxybutandioin-, 2,3-dihydroxybutandioin-, 2-hydroxy-l,2,3-propantricarboxyl-, benzo-, 3-phenyl-2-propan-, α-hydroxybenzeneddike-, methansulfon-, ethansulfon-, benzensul fon-, 4-methylbenzensul fon-, cyclohexansulfam-, 2-hydroxybenzo-, 4-amino-2-hydroxybenzosyre og lignende syrer.The compounds of formula (I) can be converted to the therapeutically active non-toxic acid addition salt by treatment with a suitable acid such as e.g. an inorganic acid such as hydrohalic acid, e.g. hydrogen chloride, hydrogen bromide and the like and sulfuric acid, nitric acid, phosphoric acid and the like, or an organic acid such as e.g. vinegar, propane, 2-hydroxyacetic, 2-hydroxypropane, 2-oxopropane, propanedioin, butanedioin, (Z) -2-butenedioin, (E) -2-butenedioin, 2-hydroxybutanedioin, , 2,3-dihydroxybutanedioin-, 2-hydroxy-1,2,3-propanetricarboxyl-, benzo-, 3-phenyl-2-propane, α-hydroxybenzeneacetic acid, methanesulfone, ethanesulfone, benzenesulphonic acid, methylbenzenesulphonic, cyclohexanesulfame, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acid and similar acids.

30 Omvendt kan saltformen omdannes ved behandling med base til den frie baseform.Conversely, the salt form can be converted by base treatment to the free base form.

Udgangsmaterialerne med formel (II) kan i almindelighed fremstilles ud fra et thiourinstofderivat med formel (X), hvori R, R1, R2, R3 og n har de ovenfor anførte betydninger, og P betyder en passende beskyttende 35 gruppe som f.eks. lavere alkyloxycarbonyl eller phenylmethoxycarbonyl, ved, at man underkaster (X) en cyclodesulfuriseringsreaktion til opnåel- 8 DK 171841 B1 se af et mellemprodukt med formlen (XI) og derefter eliminerer den beskyttende gruppe på sædvanlig måde.The starting materials of formula (II) can generally be prepared from a thiourea derivative of formula (X) wherein R, R 1, R 2, R 3 and n have the meanings given above, and P represents a suitable protecting group such as e.g. lower alkyloxycarbonyl or phenylmethoxycarbonyl by subjecting (X) a cyclodesulfurization reaction to obtain an intermediate of formula (XI) and then eliminating the protecting group in the usual manner.

R2R2

5 B NH R5 B NH R

S V-q IS V-q I

^ Cyclodesulfu- p_^· ‘ \ fr>H3 H risering 10 ( x ) (xi·)^ Cyclodesulfu- p_ ^ · '\ fr> H3 H ris 10 (x) (xi ·)

Fjernelse af be- (Π) skyttende gruppe 15Removal of protecting (Π) protecting group 15

Cyclodesulfuriseri ngen af (X) til opnåelse af (XI) udføres på samme måde som her beskrevet til fremstilling af forbindelserne (I) ud fra (V). Til fjernelse af den beskyttende gruppe P kan anvendes i og for sig kendte metoder. For eksempel kan denne gruppe, når det er en lavere al-20 kyloxycarbonylgruppe, fjernes ved basisk eller fortrinsvis sur hydrolyse under anvendelse af f.eks. hydrogenbromidsyre i iseddikesyre, og når den beskyttende gruppe er en phenylmethoxycarbonylgruppe, fjernes ved basisk eller sur hydrolyse eller ved katalytisk hydrogenering ved anvendelse af en passende katalysator såsom palladium-på-trækul.The cyclodesulfurization of (X) to obtain (XI) is carried out in the same manner as described herein for the preparation of compounds (I) from (V). For removal of the protective group P can be used in methods known per se. For example, when it is a lower alkyloxycarbonyl group, this group can be removed by basic or preferably acidic hydrolysis using e.g. hydrobromic acid in glacial acetic acid and when the protecting group is a phenylmethoxycarbonyl group is removed by basic or acid hydrolysis or by catalytic hydrogenation using a suitable catalyst such as palladium-on-charcoal.

25 Mellemprodukter med formel (XI), hvori R2 er forskellig fra hydro gen, kan også afledes af den tilsvarende forbindelse (XI), hvori R2 er hydrogen, ved indføring af den ønskede R2-substituent på i og for sig kendt måde.Intermediates of formula (XI) wherein R2 is different from hydrogen can also be derived from the corresponding compound (XI) wherein R2 is hydrogen by introducing the desired R2 substituent in a manner known per se.

Thiourinstofderivaterne med formel (X), hvori R1 betyder hydrogen 30 (Xa), kan fremstilles ved, at man omsætter en passende 4-isothiocyanato-piperidin med formel (XII) med en passende benzendiamin eller pyridindi-amin med formel (XIII), f.eks. ved simpel omrøring af reaktanterne med hinanden i et passende organisk opløsningsmiddel som f.eks. en lavere alkanol, f.eks. methanol, ethanol, 2-propanol og lignende.The thiourea derivatives of formula (X) wherein R 1 is hydrogen 30 (Xa) can be prepared by reacting an appropriate 4-isothiocyanato-piperidine of formula (XII) with a suitable benzenediamine or pyridinediamine of formula (XIII), .g. by simply stirring the reactants with each other in a suitable organic solvent, e.g. a lower alkanol, e.g. methanol, ethanol, 2-propanol and the like.

35 DK 171841 B1 P.^y^ , -* w »· (XII) (XIII) r2 /35 DK 171841 B1 P. ^ y ^, - * w »· (XII) (XIII) r2 /

'5 R NH'5 R NH

a fi y% , P-N VnH-C-NhA r3 10 ( X-a )and fi y%, P-N VnH-C-NhA r3 10 (X-a)

Thiourinstofderivaterne med formel (X), hvori R1 har den ovenfor anførte betydning, og R2 betyder hydrogen (Xb), kan fremstilles ved, at man omsætter en passende 4-piperidinamin med formel (XIV) med en 15 passende l-isothiocyanat-2-nitrobenzen med formel (XV), efterfulgt af reduktion af nitrogruppen i den således opnåede forbindelse (XVI) ved hjælp af velkendte nitro-til-amin reduktionsmetoder som f.eks. ved omsætning af (XVI) med nascerende hydrogen eller ved katalytisk hydrogenering under anvendelse af en passende katalysator som f.eks. palladium- 20 på-trækul, platin-på-trækul og lignende eller i nærværelse af mere end én sådan katalysator.The thiourea derivatives of formula (X) wherein R 1 is as defined above and R 2 is hydrogen (Xb) can be prepared by reacting an appropriate 4-piperidinamine of formula (XIV) with a suitable 1-isothiocyanate-2 nitrobenzene of formula (XV), followed by reduction of the nitro group of the thus obtained compound (XVI) by well known nitro-to-amine reduction methods such as e.g. by reaction of (XVI) with nascent hydrogen or by catalytic hydrogenation using a suitable catalyst such as palladium-on-charcoal, platinum-on-charcoal, and the like or in the presence of more than one such catalyst.

25 j—\ 325 j— \ 3

P-N >NH +· —}f- BP-N> NH + · -} f- B

\-VI , S=C=N^) -5- R1 30 (XV ) R O Ν’ Λ n 3 P-N VN-C-NHV/ -A- R nitro-til-amin 35 Y—J I . \——/ reduktion ^ R1 (XVI ) 10 DK 171841 B1\ -VI, S = C = N ^) -5- R1 30 (XV) R O Ν 'Λ n 3 P-N VN-C-NHV / -A- R nitro-to-amine Y-J I. [/ Reduction] R1 (XVI) DK

R Η NR Η N

Ηλ VRÅ 3Ηλ FROM 3

p'L/F^ w"Hp'L / F ^ w "H

5 R5 R

Prækurser-materialerne med formel (XIV) kan fremstilles ved hjælp af i og for sig kendte fremgangsmåder, f.eks. ved reduktiv aminering af den tilsvarende 4-piperidinon. 4-isothiocyanatopiperidinerne med formel (XII) kan igen fremstilles ud fra den tilsvarende forbindelse (XIV), 10 hvori R1 betyder hydrogen i henhold til standardmetoder til fremstilling af isothiocyanater ud fra primære aminer, f.eks. ved omsætning af aminen med carbondisulfid i basisk medium og efterfølgende tilsætning til reaktionsblandingen af et passende lavere alkylcarbonochloridat.The precursor materials of formula (XIV) can be prepared by methods known per se, e.g. by reductive amination of the corresponding 4-piperidinone. The 4-isothiocyanatopiperidines of formula (XII) can again be prepared from the corresponding compound (XIV), wherein R 1 represents hydrogen according to standard methods for preparing isothiocyanates from primary amines, e.g. by reacting the amine with carbon disulfide in basic medium and subsequently adding to the reaction mixture of a suitable lower alkylcarbon chloride.

Udgangsmaterialerne med formel (XII), hvori P betegner en lavere 15 alkyloxycarbonyl- eller phenylmethoxycarbonylgruppe, kan også fremstilles ved, at man omsætter et tilsvarende udgangsmateriale (XII), hvori P betegner phenylmethyl, med et passende carbonochloridat.The starting materials of formula (XII) wherein P represents a lower alkyloxycarbonyl or phenylmethoxycarbonyl group may also be prepared by reacting a corresponding starting material (XII) wherein P represents phenylmethyl with an appropriate carbon chloride.

Udgangsmaterialerne med formel (V) kan fremstilles ved anvendelse af lignende fremgangsmåder som beskrevet ovenfor til fremstilling af 20 thiourinstofderivaterne med formel (X), idet man dog går ud fra en passende 4-piperidinon eller 4-piperidinamin, hvori L-substituenten allerede er til stede på piperidinnitrogenatomet.The starting materials of formula (V) can be prepared using similar procedures as described above to prepare the 20 thiourea derivatives of formula (X), however, starting from an appropriate 4-piperidinone or 4-piperidinamine in which the L substituent is already present. present on the piperidine nitrogen atom.

De oprindelige udgangsmaterialer for hver af de foregående fremgangsmåder er kendte forbindelser, eller de kan fremstilles ved anvend-25 else af i og for sig kendte fremgangsmåder til fremstilling af lignende kendte forbindelser.The original starting materials for each of the foregoing processes are known compounds, or they can be prepared using methods known per se to produce similar known compounds.

F.eks. er fremstillingen af 4-(halogenalkyl)-2H-l,4-benzoxazin-3(4H)-oner, ved N-substitueringsreaktion af 2H-l,4-benzoxazin-3(4H)-on med en dihalogen lavere alkylgruppe beskrevet i belgisk patentskrift nr.Eg. is the preparation of 4- (haloalkyl) -2H-1,4-benzoxazine-3 (4H) -ones, by N-substitution reaction of 2H-1,4-benzoxazin-3 (4H) -one with a dihalogen lower alkyl group described in Belgian patent no.

30 859.415. l,3-dihydro-l-(3-oxobutyl)-2H-benzimidazol-2-on (XIX) kan fremstilles ved, at man underkaster l,3-dihydro-l-(l-methylethenyl)-2H-benz-imidazol-2-on (XVII) og 3-buten-2-on en Michael-addition i nærværelse af en base såsom Ν,Ν-diethylethanamin og lignende og efterfølgende hydrolyse af l,3-dihydro-l-(l-methylethenyl)-3-(3-oxobutyl)-2H-benzimidazol-2-35 on (XVIII).30 859.415. 1,3-dihydro-1- (3-oxobutyl) -2H-benzimidazol-2-one (XIX) can be prepared by subjecting 1,3-dihydro-1- (1-methylethenyl) -2H-benzimidazole -2-one (XVII) and 3-butene-2-one a Michael addition in the presence of a base such as Ν, Ν-diethylethanamine and the like and subsequent hydrolysis of 1,3-dihydro-1- (1-methylethenyl) - 3- (3-oxobutyl) -2H-benzimidazole-2-35 one (XVIII).

11 DK 171841 B1 H2C o o HC-C-N^ffl + CH-=CH-C-CHn Michael-addition 3 ^^ 2 3 -* 5 (xvn) H2C o o11 DK 171841 B1 H2C o o HC-C-N ^ ffl + CH- = CH-C-CHn Michael addition 3 ^^ 2 3 - * 5 (xvn) H2C o

HjC-IS-N^-C^-C^-C-CHj . hydrolyse _^ 1° (XVIII) o o CH2 - CH2 - C - CH3 15 O (XIX)HjC-IS-N ^ -C ^ -C ^ -C-CHj. hydrolysis _ 1 ° (XVIII) o o CH 2 - CH 2 - C - CH 3 O (XIX)

Forbindelserne med formel (I) og de farmaceutisk acceptable syread-ditonssalte deraf er kraftige antihistaminiske midler, og de kan som sådanne anvendes til fremstilling af værdifulde lægemidler til human og 20 animalsk terapi.The compounds of formula (I) and the pharmaceutically acceptable acid additon salts thereof are potent antihistaminic agents and as such can be used to prepare valuable drugs for human and animal therapy.

De værdifulde antihistaminiske egenskaber af forbindelserne med formel (I) blev påvist ved følgende test-metode.The valuable antihistaminic properties of the compounds of formula (I) were demonstrated by the following test method.

BESKYTTELSE AF ROTTER MOD FORBINDELSE 48/80-INDUCERET DØDELIGHED.PROTECTION OF ROTES AGAINST CONNECTION 48/80-INDUCED DEATH.

2525

Forbindelse 48/80, som er en blanding af oligomere opnået ved kondensation af p-methoxy-N-methyl-phenethylamin og formaldehyd, er beskrevet som et kraftigt histamin-frigørende middel (Int. Arch. Allergy, 13, 336 (1958). Beskyttelse mod forbindelse 48/80-induceret dødeligt kreds-30 løbs-kollaps synes at være en simpel metode til kvantitativ vurdering af testforbindelsers antihistaminiske aktivitet. Hanrotter af en indavlet Wistar-stamme, der vejede 240-260 gr., anvendtes i forsøget. Efter sult-ning en nat overførtes rotterne til konditionerede laboratorier (temp. = 21±0C, relativ fugtighed = 65 ± 5 %).Compound 48/80, which is a mixture of oligomers obtained by condensation of p-methoxy-N-methyl-phenethylamine and formaldehyde, is described as a potent histamine-releasing agent (Int. Arch. Allergy, 13, 336 (1958)). Protection against compound 48/80-induced lethal circuit 30 collapse appears to be a simple method for quantitatively assessing the antihistaminic activity of test compounds. Male rats of an inbred Wistar strain weighing 240-260 gr were used in the experiment. starvation one night, the rats were transferred to conditioned laboratories (temp. = 21 ± 0 ° C, relative humidity = 65 ± 5%).

35 Rotterne behandledes subkutant eller oralt med en testforbindelse eller opløsningsmidlet (NaCl-opløsning, 0,9%). En time efter behandling- 12 DK 171841 B1 en injiceredes intravenøst forbindelse 48/80, friskt opløst i vand i en dosis på 0,5 mg/kg (0,2 ml/100 gr legemsvægt).The rats were treated subcutaneously or orally with a test compound or solvent (NaCl solution, 0.9%). One hour after treatment, intravenous compound 48/80, freshly dissolved in water, was injected at a dose of 0.5 mg / kg (0.2 ml / 100 g body weight).

I kontrolforsøg, hvor 250 med opløsningsmiddel behandlede dyr injiceredes med standarddosen af forbindelse 48/80, overlevede ikke mere end 5 2,8 % af dyrene efter 4 timer. Overlevelse efter 4 timer betragtes der for som et sikkert kriterium for en beskyttende virkning af det indgivne lægemiddel.In control experiments where 250 solvent treated animals were injected with the standard dose of compound 48/80, no more than 5 2.8% of the animals survived after 4 hours. Survival after 4 hours is considered a safe criterion for a protective effect of the administered drug.

Forbindelserne med formel (I) og de farmaceutisk acceptable syreadditionssalte deraf viste sig at være meget aktive i ovennævnte test, 10 idet de beskyttede dyrene mod forbindelse 48/80-induceret dødelighed ved orale og subkutane doser på ikke mere end 2,5 mg/kg. Et antal af de omhandlede forbindelser viste sig endog at være effektive ved doser så lave som 0,16 mg/kg.The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof were found to be very active in the above tests, protecting the animals from compound 48/80 induced mortality at oral and subcutaneous doses of not more than 2.5 mg / kg. . A number of the compounds of the present invention were even found to be effective at doses as low as 0.16 mg / kg.

Som følge af de omhandlede forbindelsers værdifulde antihistamini-15 ske aktivitet kan de formuleres til forskellige farmaceutiske præparatformer til administreringsformål. Til fremstilling af de farmaceutiske præparater kombineres en effektiv antihistaminisk mængde af den ønskede forbindelse på base- eller syreadditionssal tform som aktiv bestanddel i intim blanding med en farmaceutisk acceptabel bærer, der kan antage en 20 lang række forskellige former i afhængighed af den ønskede præparationsform til administrering. Disse farmaceutiske præparater er hensigtsmæssige på enhedsdosisform, der fortrinsvis er egnet til administrering oralt, rektalt eller ved parenteral injektion. Til fremstilling af præparater på oral dosisform kan f.eks. anvendes et vilkårligt af de sæd-25 vanlige farmaceutiske medier som f.eks. vand, glycoler, olier, alkoholer og lign. i tilfælde af orale flydende præparater såsom suspensioner, siruper, eliksirer og opløsninger, eller faste bærere såsom stivelser, sukkerarter, kaolin, smøremidler, bindemidler, disintegreringsmidler og lignende i tilfælde af pulvere, piller, kapsler og tabletter.Due to the valuable antihistaminic activity of the compounds of the present invention, they can be formulated into various pharmaceutical formulations for administration purposes. To prepare the pharmaceutical compositions, an effective antihistaminic amount of the desired compound in base or acid addition salt form is combined as an active ingredient in intimate admixture with a pharmaceutically acceptable carrier which can take a wide variety of forms depending upon the desired form of administration for administration. . These pharmaceutical compositions are convenient in unit dosage form which is preferably suitable for oral, rectal or parenteral injection. For the preparation of oral dosage form, e.g. any of the usual pharmaceutical media such as e.g. water, glycols, oils, alcohols and the like. in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets.

30 Som følge af administreringsletheden repræsenterer tabletter og kapsler de mest fordelagtige orale enhedsdosisformer, i hvilket tilfælde der naturligvis anvendes faste farmaceutiske bærere. Til parenterale præparater vil bæreren sædvanligvis omfatte sterilt vand, i det mindste for en stor dels vedkommende, selvom der også kan tilsættes andre be-35 standdele, f.eks. for at lette opløseligheden. Injicerbare opløsninger kan f.eks. fremstilles, hvori bæreren omfatter saltopløsningen, glucose- 13 DK 171841 B1 opløsningen eller en blanding af salt- og glucoseopløsning. Injicerbare suspensioner kan også fremstilles, i hvilket tilfælde der kan anvendes passende flydende bærere, suspensionsmidler og lignende. Syreadditionssalte af (I) er på grund af deres forøgede vandopløselighed i forhold 5 til den tilsvarende baseform selvsagt mere egnede til fremstilling af vandige præparater.Because of the ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are naturally used. For parenteral preparations, the carrier will usually comprise sterile water, at least in large part, although other ingredients, e.g. to facilitate solubility. Injectable solutions may e.g. are prepared wherein the carrier comprises the saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be used. Of course, due to their increased water solubility in relation to the corresponding base form, acid addition salts of (I) are more suitable for the preparation of aqueous preparations.

Det er især fordelagtigt at formulere de ovennævnte farmaceutiske præparater på enhedsdosisform for at lette administreringen og doseringens ensartethed. Enhedsdosisformer refererer her til fysisk diskrete en-10 heder, der er egnede som enhedsdoser, idet hver enhed indeholder en forudbestemt mængde aktiv bestanddel beregnet til at frembringe den ønskede terapeutiske virkning, sammen med den nødvendige farmaceutiske bærer. Eksempler på sådanne enhedsdosisformer er tabletter (herunder kærvdelte eller overtrukne tabletter), kapsler, piller, pulverpakninger, oblat-15 kapsler, injicerbare opløsninger eller suspensioner, teske-portionsaf-vejninger, spiseske-portionsafvejninger og lign. samt særskilte multipler deraf.It is particularly advantageous to formulate the above-mentioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. Unit dosage forms herein refer to physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient intended to produce the desired therapeutic effect, together with the necessary pharmaceutical carrier. Examples of such unit dosage forms are tablets (including slotted or coated tablets), capsules, pills, powder packs, cachets, injectable solutions or suspensions, teaspoon portion balances, tablespoon portion balances and the like. as well as separate multiples thereof.

I de følgende eksempler er alle dele vægtdele, med mindre andet er anført.In the following examples, all parts are parts by weight, unless otherwise stated.

20 A. FREMSTILLING AF MELLEMPRODUKTER Eksempel 1A. Preparation of Intermediate Products Example 1

En blanding af 102 dele ethyl-4-oxo-l-piperidincarboxylat, 50 dele 25 methanamin og 400 dele methanol hydrogeneres ved normalt tryk og ved stuetemperatur med 5 dele palladium-på-trækul katalysator 10%. Efter optagning af den beregnede mængde hydrogen filtreres katalysatoren fra over Hyflo, og filtratet inddampes, hvilket giver 111 dele ethyl 4-(methylamino)-l-piperidincarboxylat som remanens.A mixture of 102 parts of ethyl 4-oxo-1-piperidine carboxylate, 50 parts of 25 methanamine and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off over Hyflo and the filtrate is evaporated to give 111 parts of ethyl 4- (methylamino) -1-piperidine carboxylate as residue.

30 Til en omrørt og afkølet blanding af 4 dele natriumhydroxid i 60 dele vand sættes successivt 7,9 dele carbondisulfid og 17,2 dele ethyl- 4-amino-l-piperidincarboxylat ved en temperatur under 10°C. Omrøringen fortsætter i 30 minutter ved denne temperatur. Så tilsættes dråbevis 10,9 dele ethylcarbonchloridat (exotermisk reaktion: Temperaturen stiger 35 til ca. 35°C). Når dette er bragt til ende, fortsættes omrøringen i 2 timer ved 60°C. Reaktionsblandingen afkøles, og produktet ekstraheres DK 171841 Bl 14 med methylbenzen. Ekstrakten tørres, filtreres og inddampes, hvilket giver 22 dele (100%) ethyl-4-isothiocyanat-l-piperidincarboxylat som remanens.To a stirred and cooled mixture of 4 parts sodium hydroxide in 60 parts water is added successively 7.9 parts carbon disulfide and 17.2 parts ethyl 4-amino-1-piperidinecarboxylate at a temperature below 10 ° C. Stirring is continued for 30 minutes at this temperature. Then 10.9 parts of ethyl carbon chloridate are added dropwise (exothermic reaction: the temperature rises 35 to about 35 ° C). When this is complete, stirring is continued for 2 hours at 60 ° C. The reaction mixture is cooled and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated to give 22 parts (100%) of ethyl 4-isothiocyanate-1-piperidine carboxylate as residue.

Ved at gentage fremgangsmåden fra andet trin kan der også ud fra en 5 passende amin fremstilles: 4-isothiocyanat-l-(phenylmethylJpiperidin, og l-[4,4-bis(4-fluorphenyl)butyl]-4-isothiocyanatpiperidin; smp.By repeating the process of the second step, a suitable amine can also be prepared from: 4-isothiocyanate-1- (phenylmethylpiperidine) and 1- [4,4-bis (4-fluorophenyl) butyl] -4-isothiocyanate piperidine;

92°C.92 ° C.

10 Eksempel 2Example 2

Til en omrørt opløsning af 28,4 dele 4-isothiocyanat-l-(phenylme-thyl)pi peri d i n i 315 dele methylbenzen sættes dråbevis 41 dele (phenyl-methyl)carbonchloridat ved stuetemperatur. Når dette er sket, opvarmes det hele til tilbagesvaling, og omrøring fortsættes natten over ved ti 1 -15 bagesvalingstemperatur. Reaktionsblandingen afkøles, og opløsningsmidlet inddampes. Remanensen renses ved søjlechromatografi over silicagel ved anvendelse af trichlormethan som eluent. De rene fraktioner samles, og eluenten inddampes, hvilket giver 32 dele (97%) (phenylmethyl)-4-iso-thiocyanat-l-piperincarboxylat som remanens.To a stirred solution of 28.4 parts of 4-isothiocyanate-1- (phenylmethyl) pi peri d in n in 315 parts of methylbenzene is added dropwise 41 parts (phenylmethyl) of carbon chloride at room temperature. When this is done, it is all heated to reflux and stirring is continued overnight at ten to 15 reflux temperatures. The reaction mixture is cooled and the solvent is evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated to give 32 parts (97%) (phenylmethyl) -4-isothiocyanate-1-piperine carboxylate as residue.

2020

Eksempel 3Example 3

En blanding af 9,7 dele 4-fluorbenzenmethamin-hydrochlorid, 9,4 dele 2-chlor-3-nitropyridin, 10,6 dele natriumcarbonat, 0,1 del kalium-iodid og 90 dele Ν,Ν-dimethylformamid omrøres 1 time ved 90°C. Reak-25 tionsblandingen afkøles og hældes i vand. Det udfældede produkt frafil-treres og krystalliseres fra 2-propanol, hvilket giver 10,5 dele (71%) N-(4-fluorphenylmethyl)-3-nitro-2-pyridinamin, smeltepunkt 76°C.A mixture of 9.7 parts of 4-fluorobenzene methamine hydrochloride, 9.4 parts of 2-chloro-3-nitropyridine, 10.6 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of Ν, Ν-dimethylformamide is stirred for 1 hour. 90 ° C. The reaction mixture is cooled and poured into water. The precipitated product is filtered off and crystallized from 2-propanol to give 10.5 parts (71%) of N- (4-fluorophenylmethyl) -3-nitro-2-pyridinamine, m.p. 76 ° C.

En blanding af 10,5 dele N-(4-fluorphenylmethyl)-3-nitro-2-pyridin-amin og 200 dele methanol hydrogeneres ved normalt tryk og stuetempera-30 tur med 2 dele Raney-nikkel katalysator. Efter optagning af den beregnede mængde hydrogen frafiltreres katalysatoren, og filtratet inddampes, hvilket giver 9,3 dele (100%) N2-(4-fluorphenylmethyl)-2,3-pyridindiamin som remanens.A mixture of 10.5 parts of N- (4-fluorophenylmethyl) -3-nitro-2-pyridine-amine and 200 parts of methanol is hydrogenated at normal pressure and room temperature with 2 parts of Raney nickel catalyst. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated to give 9.3 parts (100%) of N2- (4-fluorophenylmethyl) -2,3-pyridinediamine as residue.

Ved at følge den samme fremgangsmåde og ved anvendelse af ækviva-35 lente mængder af de passende udgangsmaterialer kan der også fremstilles: N1-(phenylmethyl)-4-(trifluormethyl)-1,2-benzendiamin, og 15 DK 171841 B1 4-chlor-N1-(4-fluorphenylmethyl)-1,2-benzendi amin.By following the same procedure and using equivalent amounts of the appropriate starting materials, N1- (phenylmethyl) -4- (trifluoromethyl) -1,2-benzenediamine can also be prepared, and -N1- (4-fluorophenylmethyl) -1,2-benzenediamine.

Eksempel 4Example 4

En blanding af 34,8 dele l,3-dihydro-l-(l-methylethenyl)-2H-benz-5 imidazol-2-on, 28 dele 3-buten-2-on, 20,2 dele Ν,Ν-diethylethanamin og 270 dele tetrahydrofuran omrøres og tilbagesvales over en week-end. Reaktionsblandingen inddampes, hvilket giver 48,8 dele (100%) 1,3-dihydro- 1-(1-methylethenyl)-3-(3-oxobutyl)-2H-benzimidazol-2-on som remanens.A mixture of 34.8 parts of 1,3-dihydro-1- (1-methylethenyl) -2H-benz-5-imidazol-2-one, 28 parts of 3-buten-2-one, 20.2 parts of Ν, Ν- diethylethanamine and 270 parts of tetrahydrofuran are stirred and refluxed over a week-end. The reaction mixture is evaporated to give 48.8 parts (100%) of 1,3-dihydro-1- (1-methylethenyl) -3- (3-oxobutyl) -2H-benzimidazol-2-one as residue.

En blanding af 48,8 dele l,3-dihydro-l-(l-methylethenyl)-3-(3-oxo-10 butyl)-2H-benzimidazol-2-on, 12 dele 2-propanol mættet med gasformig hydrogenchlorid og 240 dele 2-propanol omrøres i 3 timer ved stuetemperatur. Det udfældede produkt frafiltreres, vaskes med 2,2'-oxybispropan og tørres, hvilket giver 30 dele (73,4%) l,3-dihydro-l-(3-oxobutyl)-2H-benzimidazol-2-on.A mixture of 48.8 parts of 1,3-dihydro-1- (1-methylethenyl) -3- (3-oxo-10-butyl) -2H-benzimidazol-2-one, 12 parts of 2-propanol saturated with gaseous hydrogen chloride and 240 parts of 2-propanol are stirred for 3 hours at room temperature. The precipitated product is filtered off, washed with 2,2'-oxybispropane and dried to give 30 parts (73.4%) of 1,3-dihydro-1- (3-oxobutyl) -2H-benzimidazol-2-one.

1515

Eksempel 5Example 5

Til en omrørt blanding af 9 dele 2H-l,4-benzoxazin-3(4H)-on, 0,9 del Ν,Ν,Ν-triethylbenzenmethanaminiumchlorid, 9 dele natriumhydroxidopløsning 50% og 24 dele vand sættes 10,4 dele l-brom-3-chlorpropan ved 20 30°C. Det hele opvarmes til 90°C, og omrøringen fortsættes i 3 timer ved denne temperatur. Reaktionsblandingen afkøles til ca. 70°C, methylbenzen tilsættes, og det hele røres natten over ved stuetemperatur. Den organiske fase udskilles, tørres, filtreres og inddampes, hvilket giver 10 dele 4-(3-chlorpropyl)-2H-l,4-benzoxazin-3(4H)-on som remanens.To a stirred mixture of 9 parts of 2H-1,4-benzoxazine-3 (4H) -one, 0.9 parts of Ν, Ν, Ν-triethylbenzene methanaminium chloride, 9 parts of sodium hydroxide solution 50% and 24 parts of water are added 10.4 parts of 1- bromo-3-chloropropane at 20 ° C. The whole is heated to 90 ° C and stirring is continued for 3 hours at this temperature. The reaction mixture is cooled to ca. 70 ° C, methyl benzene is added and the whole is stirred overnight at room temperature. The organic phase is separated, dried, filtered and evaporated to give 10 parts of 4- (3-chloropropyl) -2H-1,4-benzoxazin-3 (4H) -one as residue.

2525

Eksempel 6Example 6

En blanding af 10,6 dele ethyl-4-isothiocyanat-l-piperidincarboxy-lat, 11,6 dele 4-chlor-N*-(phenylmethyl)-l,2-benzendiamin og 90 dele tetrahydrofuran omrøres natten over ved stuetemperatur. Reaktionsbiand-30 ingen inddampes, hvilket giver 21 dele (100%) ethyl-4-[([[5-chlor-2-[(phenyl methyl) ami no]-phenyl]amino]thioxomethyl]amino]-l-piperidincarbo-xylat; smp. 162°C.A mixture of 10.6 parts of ethyl 4-isothiocyanate-1-piperidinecarboxylate, 11.6 parts of 4-chloro-N * - (phenylmethyl) -1,2-benzenediamine and 90 parts of tetrahydrofuran is stirred overnight at room temperature. The reaction mixture is evaporated to give 21 parts (100%) of ethyl 4 - [([[5-chloro-2 - [(phenyl methyl) amino] phenyl] amino] thioxomethyl] amino] -1-piperidinecarboxylic acid xylate, mp 162 ° C.

Ved at følge fremgangsmåden i eksempel 6 og under anvendelse af 35 ækvivalente mængder af de passende udgangsmaterialer kan der fremstilles: 16 DK 171841 B1 ethyl-4-{[(2-amino-5-chlorphenyl)aminothioxomethyl]amino}-1-piperi-dincarboxylat; smp. 162,2°C, ethyl-4-{[(2-aminophenyl )aminothioxomethyl ]amino}-l-piperidincarbo-5 xylat som remanens, ethyl-4-{[(2-amino-5-methylphenyl)aminothioxomethyl]amino}-l-piperidincarboxylat som remanens, ethyl-4-[{[{2-(phenylmethyl)amino]-3-pyridinyl)amino]thioxomethyl}-amino]-l-piperidincarboxylat; smp. 146,7°C, 10 ethyl-4-{[{2-[(phenylmethyl)amino]-5-(trifluormethyl)phenyl)amino]- thioxomethylamino}-l-piperidincarboxylat som remanens, ethyl-4-[{[(2-amino-4-fluorphenyl) amino]thioxomethyl}amino]-1-pi peri d i ncarboxylat som remanens, ethyl-4-[{[{5-chlor-2-[(4-fluorphenylmethyl) ami no]phenyl}amino]-15 thioxomethyl}amino]-l-piperidincarboxylat som remanens, (phenyl methyl )-4-[{2-[4-fluorphenylmethyl) ami no]-3-pyridinylami no)-thioxomethylamino]-1-pi peridi ncarboxylat, N-(2-nitrophenyl)-N'-[1 - (2-phenyl ethyl)-4-pi peridinyl]-N'-(phenyl -methyl)thiourinstof; smp. 151,1°C, 20 N-(l-[4,4-bis(4-fluorphenyl) butyl]-4-piperidinyl}-N'-phenylthio- urinstof; smp. 90°C; ethyl -4-[{[(2-amino-3-pyridinyl) ami no]thioxomethyl}amino]-1-pi peri -dincarboxylat; smp. 176,9°C, 4-[{[(2-phenyl ami no)phenyl]ami nothioxomethyl}amino]-1-piperidincar-25 boxylat; smp. 154,2°C og ethyl-4-{[{[2-(4-fluorphenylami no)phenyl]amino)thioxomethyl]ami no)- 1-piperidincarboxylat som remanens.Following the procedure of Example 6 and using 35 equivalent amounts of the appropriate starting materials, it is possible to prepare: 1-ethyl-4 - {[(2-amino-5-chlorophenyl) aminothioxomethyl] amino} -1-piperidine. dincarboxylat; mp. 162.2 ° C, ethyl 4 - {[(2-aminophenyl) aminothioxomethyl] amino} -1-piperidinecarboxylate as residue, ethyl 4 - {[(2-amino-5-methylphenyl) aminothioxomethyl] amino} -1-piperidinecarboxylate as residue, ethyl 4 - [{[{2- (phenylmethyl) amino] -3-pyridinyl) amino] thioxomethyl} amino] -1-piperidinecarboxylate; mp. 146.7 ° C, ethyl 4 - {[{2 - [(phenylmethyl) amino] -5- (trifluoromethyl) phenyl) amino] thioxomethylamino} -1-piperidinecarboxylate as residue, ethyl 4 - [{[( 2-amino-4-fluorophenyl) amino] thioxomethyl} amino] -1-piperidincarboxylate as residue, ethyl 4 - [{[{5-chloro-2 - [(4-fluorophenylmethyl) amino] phenyl} amino ] -15 thioxomethyl} amino] -1-piperidinecarboxylate as residue, (phenyl methyl) -4 - [{2- [4-fluorophenylmethyl) amino] -3-pyridinylamino) thioxomethylamino] -1-piperidinecarboxylate, N - (2-nitrophenyl) -N '- [1- (2-phenylethyl) -4-piperidinyl] -N' - (phenylmethyl) thiourea; mp. 151.1 ° C, 20 N- (1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl} -N'-phenylthiourea; mp 90 ° C; ethyl -4 - [{ [(2-amino-3-pyridinyl) amino] thioxomethyl} amino] -1-piperidinecarboxylate; mp 176.9 ° C, 4 - [{[(2-phenylamino) phenyl] amine nothioxomethyl} amino] -1-piperidinecarboxylate; mp 154.2 ° C and ethyl 4 - {[{[2- (4-fluorophenylamino) phenyl] amino) thioxomethyl] amino] -1-piperidinecarboxylate as residue.

Eksempel 8 30 En blanding af 21,6 dele l-isothiocyanat-2-nitrobenzen og 45 dele tetrahydrofuran omrøres, indtil alle faste stoffer er opløst. Derefter tilsættes 29,5 dele N-(l-methylethyl)-l-(2-phenylethyl)-4-piperidinamin og 160 dele ethanol, og det hele omrøres natten over ved stuetemperatur. Reaktionsblandingen inddampes, og remanensen krystalliseres fra 2-propa-35 nol. Produktet frafiltreres og tørres, hvilket giver 43 dele (84%) N-(l-methylethyl)-Ν'-(2-nitrophenyl)-N-[1 -(2-phenyl ethyl)-4-pi peri dinyl]th i o- 17 DK 171841 B1 urinstof; smp. 100,6°C.Example 8 A mixture of 21.6 parts of 1-isothiocyanate-2-nitrobenzene and 45 parts of tetrahydrofuran is stirred until all solids have dissolved. Then, 29.5 parts of N- (1-methylethyl) -1- (2-phenylethyl) -4-piperidinamine and 160 parts of ethanol are added and the whole is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is crystallized from 2-propanol. The product is filtered off and dried to give 43 parts (84%) of N- (1-methylethyl) -Ν '- (2-nitrophenyl) -N- [1- (2-phenylethyl) -4-piperidinyl] th i o- urea; mp. 100.6 ° C.

Eksempel 9Example 9

Ved at følge fremgangsmåden i eksempel 8 kan der fremstilles føl -5 gende thiourinstofferivater ved omsætning af et passende 4-piperidinamin med et passende l-isothiocyanat-2-nitrobenzen.Following the procedure of Example 8, the following thiourea derivatives can be prepared by reacting an appropriate 4-piperidinamine with an appropriate 1-isothiocyanate-2-nitrobenzene.

ethyl-4-[methyl-{[(2-nitrophenyl) ami no]thioxomethyl}amino]-l-piperidincarboxylat, 10 ethyl-4-{butyl[(2-nitrophenyl) ami nothioxomethyl]ami no}-1-piperidin- carboxylat som remanens, N-ethyl-N'-(2-nitrophenyl)-N-[1-(2-phenyl ethyl)-4-piperi dinyl]-thiourinstof, N-(2-nitrophenyl)-Ν'-[1-(2-phenyl ethyl)-4-piperi dinyl]-Ν'-propyl -15 thiourinstof; smp. 90,3°C, N-cyclopropyl-Ν'-(2-nitrophenyl)-N-[1 -(2-phenyl ethyl)-4-piperidi-nyl]-thiourinstof; smp. 150,1°C og cis + trans-methvl-3-methyl -4-[{[(2-nitrophenyl)amino]thioxome-thyl}amino]-l-piperidincarboxylat; smp. 157,5°C.ethyl 4- [methyl - {[(2-nitrophenyl) amino] thioxomethyl} amino] -1-piperidinecarboxylate, ethyl 4- {butyl [(2-nitrophenyl) amine nothioxomethyl] amino} -1-piperidine hydrochloride carboxylate as residue, N-ethyl-N '- (2-nitrophenyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -thiourea, N- (2-nitrophenyl) -Ν' - [1 - (2-phenylethyl) -4-piperidinyl] -Ν'-propyl-thiourea; mp. 90.3 ° C, N-cyclopropyl-Ν '- (2-nitrophenyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -thiourea; mp. 150.1 ° C and cis + trans-methyl-3-methyl-4 - [{[(2-nitrophenyl) amino] thioxomethyl} amino] -1-piperidinecarboxylate; mp. 157.5 ° C.

2020

Eksempel 10Example 10

En blanding af 43 dele N-(l-methylethyl)-N'-(2-nitrophenyl)-N-[l-2-phenylethyl)-4-piperidinyl]thiourinstof og 800 dele methanol mættes med ammoniak, hydrogeneres ved normalt tryk og ved stuetemperatur med 6 dele 25 palladium-på-trækul katalysator 10% og 6 dele platin-på-trækul katalysator 5%. Efter optagning af den beregnede mængde hydrogen frafiltreres katalysatorerne over Hyflo, og filtratet inddampes, hvilket giver 39 dele (100 %) N-(2-aminophenyl)-N'-(l-methylethyl)-N'[l-(2-phenylethyl)-4-pi peri d i nyl]thiourinstof som remanens.A mixture of 43 parts of N- (1-methylethyl) -N '- (2-nitrophenyl) -N- [1-2-phenylethyl) -4-piperidinyl] thiourea and 800 parts of methanol is saturated with ammonia, hydrogenated at normal pressure and at room temperature with 6 parts 25 palladium-on-charcoal catalyst 10% and 6 parts platinum-on-charcoal catalyst 5%. After taking up the calculated amount of hydrogen, the catalysts are filtered off over Hyflo and the filtrate is evaporated to give 39 parts (100%) of N- (2-aminophenyl) -N '- (1-methylethyl) -N' [1- (2-phenylethyl) ) -4-pi peri di nyl] thiourea as residue.

3030

Eksempel 11Example 11

Ved at følge fremgangsmåden i eksempel 10 og under anvendelse af en ækvivalent mængde af en passende nitroblanding som udgangsmateriale kan der fremstilles: ethyl -4-[{[(2-ami nophenyl)ami no]th i oxomethyl}methy1amino]-l-piperi- 35 18 DK 171841 B1 dincarboxylat, ethyl -4-{[(2-ami nophenyl) ami nothioxomethyl]butyl ami no}-1-pi peridincarboxylat, N-(2-ami nophenyl)-Ν'-[1-(2-phenyl ethyl)-4-pi peri di nyl]thiourinstof, 5 N-(2-ami nophenyl)-Ν'-[1-(2-phenyl ethyl)-4-pi peridinyl]-N'propyl - thiourinstof, N-(2-aminophenyl)-Ν'-cyclopropyl-N'-[1-(2-phenyl ethyl)-4-piperidin-yl]thiourinstof, methyl-4-{[(2-ami nophenyl) ami no]thioxomethylami no}-3-methyl-1-pipe-10 ridincarboxylat, N-(2-ami nophenyl)-Ν'-[1-(2-phenyl ethyl)-4-piperidinyl]-Ν'(phenyl methyl Jthiourinstof som remanens.Following the procedure of Example 10 and using an equivalent amount of a suitable nitro mixture as starting material, it is possible to prepare: ethyl -4 - [{[(2-aminophenyl) amino] th in oxomethyl} methylamino] -1-piperidine B1 dincarboxylate, ethyl -4 - {[(2-aminophenyl) amine nothioxomethyl] butyl amine} -1-pi peridinecarboxylate, N- (2-aminophenyl) -Ν '- [1- (2 -phenyl ethyl) -4-piperidinyl] thiourea, 5 N- (2-aminophenyl) -Ν '- [1- (2-phenylethyl) -4-piperidinyl] -N'propyl - thiourea, N - (2-Aminophenyl) -Ν'-cyclopropyl-N '- [1- (2-phenylethyl) -4-piperidin-yl] thiourea, methyl-4 - {[(2-aminophenyl) amino] thioxomethylamino } -3-methyl-1-pipe-pyridinecarboxylate, N- (2-aminophenyl) -Ν '- [1- (2-phenylethyl) -4-piperidinyl] -Ν' (phenyl methylthiourea as residue.

Eksempel 12 15 En blanding af 23 dele (phenylmethyl)-4-[{2-[(4-fluorphenylmethyl)- amino]-3-pyri dinyl ami no}thioxomethylami no]-1-piperidincarboxylat, 17 dele mercurioxid, 0,1 del svovl og 450 dele tetrahydrofuran omrøres og tilbagesvales i 1 time. Reaktionsblandingen filtreres over Hyflo, og filtratet inddampes. Remanensen krystalliseres fra en blanding af 4-me-20 thyl-2-pentanon og 2,2,-oxybispropan. Produktet frafiltreres og tørres, hvilket giver 20 dele (93 %) (phenylmethyl)-4-[3-(4-fluorphenylmethyl)-3H-imidazo[4,5-b]pyridin-2-ylamino]-1-piperidincarboxylat; smp. 130°C.Example 12 A mixture of 23 parts (phenylmethyl) -4 - [{2 - [(4-fluorophenylmethyl) amino] -3-pyridinylamino} thioxomethylamino] -1-piperidinecarboxylate, 17 parts mercuric oxide, 0.1 part sulfur and 450 parts tetrahydrofuran are stirred and refluxed for 1 hour. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2-oxybispropane. The product is filtered off and dried to give 20 parts (93%) of (phenylmethyl) -4- [3- (4-fluorophenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinecarboxylate; mp. 130 ° C.

Eksempel 13 25 Ved at følge fremgangsmåden i eksempel 12 og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der fremstilles: ethyl-4-[(lH-benzimidazol-2-yl)methylami no]-1-piperidincarboxyl at, 30 ethyl -4-[(lH-benzimidazol-2-yl)butylami no]-1-pi peri dincarboxylat; smp. 225,9°C, ethyl-4-[1-(phenylmethyl )-5-(tri fluormethyl)-lH-benzimidazol-2-yl-amino]-l-piperidinylcarboxylat; smp. 200°C, ethyl-4-(5-fluor-lH-benzimidazol-2-ylami no)-1-piperidincarboxylat; 35 smp. 227,5°C, ethyl-4-[5-chlor-1-(phenyl methyl)-lH-benzimidazol-2-ylami no]-1-pi- 19 DK 171841 B1 peridincarboxylat; smp. 211,9°C, ethyl-4-[3-(phenylmethyl)-3H-imidazo[4,5-b]pyridin-2-ylamino]-l-piperidincarboxylat; smp. 148,6°C, ethyl-4-[5-chlor-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-5 ylamino]-l-piperidincarboxyl; smp. 215,8°C, methyl-4-(lH-benzimidazol-2-ylami no)-3-methyl-1-piperidincarboxylat; smp. 155°C, ethyl-4-[2-(4-fluorphenylmethyl)-3H-imidazo[4,5-b]pyridin-2-ylamino]-piperidincarboxylat; smp. 134,4°C, 10 ethyl-4-[(3H-imidazo[4,5-b]pyridin-2-yl )amino]-l-piperincarboxylat; smp. 216,1°C, ethyl-4-(1-phenol-ΙΗ-benzimidazol -2-yl ami no)-1-piperidincarboxylat; smp. 137°C og ethyl-4-[l-(4-fluorphenyl)-lH-benzimidazol-2-ylamino]-1-piperidin-15 carboxylat; smp. 153°C.Example 13 By following the procedure of Example 12 and using equivalent amounts of the appropriate starting materials, ethyl 4 - [(1H-benzimidazol-2-yl) methylamino] -1-piperidinecarboxyl, 30 ethyl 4 - [(1H-benzimidazol-2-yl) butylamino] -1-piperidinecarboxylate; mp. 225.9 ° C, ethyl 4- [1- (phenylmethyl) -5- (trifluoromethyl) -1H-benzimidazol-2-yl-amino] -1-piperidinylcarboxylate; mp. 200 ° C, ethyl 4- (5-fluoro-1H-benzimidazol-2-ylamino) -1-piperidinecarboxylate; 35 m.p. 227.5 ° C, ethyl 4- [5-chloro-1- (phenyl methyl) -1H-benzimidazol-2-ylamino] -1-piperidinecarboxylate; mp. 211.9 ° C, ethyl 4- [3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinecarboxylate; mp. 148.6 ° C, ethyl 4- [5-chloro-1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinecarboxyl; mp. 215.8 ° C, methyl 4- (1H-benzimidazol-2-ylamino) -3-methyl-1-piperidinecarboxylate; mp. 155 ° C, ethyl 4- [2- (4-fluorophenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] piperidinecarboxylate; mp. 134.4 ° C, ethyl 4 - [(3H-imidazo [4,5-b] pyridin-2-yl) amino] -1-piperine carboxylate; mp. 216.1 ° C, ethyl 4- (1-phenol-ΙΗ-benzimidazol-2-ylamino) -1-piperidinecarboxylate; mp. 137 ° C and ethyl 4- [1- (4-fluorophenyl) -1H-benzimidazol-2-ylamino] -1-piperidine carboxylate; mp. 153 ° C.

Eksempel 14Example 14

En blanding af 28 dele ethyl-4-{[(2-aminophenyl)aminothioxomethyl]-amino}-l-piperidincarboxylat, 112 dele iodmethan og 240 dele etanol om-20 røres og tilbagesvales i 8 timer. Reaktionsblandingen inddampes, og remanensen optages i vand. Det hele al kali seres med ammoniakhydroxid, og produktet ekstraheres med dichlormethan. Ekstrakten tørres, filtreres og inddampes. Remanensen krystalliseres fra en blanding af 2-propanol og 2,2'-oxobispropan. Produktet filtreres fra og tørres, hvilket giver 7 25 dele (28%) ethyl-4-(lH-benzimidazol-2-ylamio)-l-piperidincarboxylat.A mixture of 28 parts of ethyl 4 - {[(2-aminophenyl) aminothioxomethyl] amino} -1-piperidinecarboxylate, 112 parts of iodomethane and 240 parts of ethanol is stirred and refluxed for 8 hours. The reaction mixture is evaporated and the residue is taken up in water. The entire al potassium is extracted with ammonia hydroxide and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol and 2,2'-oxobispropane. The product is filtered off and dried to give 7 parts (28%) of ethyl 4- (1H-benzimidazol-2-ylamio) -1-piperidinecarboxylate.

Ved at følge den samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der fremstilles; ethyl-4-(5-chlor-ΙΗ-benzimidazol-2-ylami no)-1-piperidincarboxylat; 30 smp. 234,1°C og ethyl-4-(5-methyl-ΙΗ-benzimidazol-2-ylamino)-l-piperidincarboxylat. Eksempel 15Following the same procedure and using equivalent amounts of the appropriate starting materials can be prepared; ethyl 4- (5-chloro-ΙΗ-benzimidazol-2-ylamino) -1-piperidinecarboxylate; 30 m.p. 234.1 ° C and ethyl 4- (5-methyl-ΙΗ-benzimidazol-2-ylamino) -1-piperidinecarboxylate. Example 15

En blanding af 19 dele methyl-4-(ΙΗ-benzimidazol-2-ylamino)-3-me-35 thyl-1-piperidincarboxylat, 11 dele l-(chlormethyl)-4-fluorbenzen, 6 dele natriumcarbonat og 135 dele Ν,Ν-dimethylformamid omrøres og opvarmes 20 DK 171841 B1 natten over ved 70°C. Reaktionsblandingen afkøles og hældes på vand. Produktet ekstraheres tre gange med methyl benzen. De kombinerede ekstrakter tørres, filtreres og inddampes. Remanensen renses ved søjlechro-matografi over silicagel under anvendelse af en blanding af trichlorme-5 than og methanol (96:4 efter volumen) som eluent. De rene fraktioner samles, og eluenten inddampes. Remanensen krystalliseres fra en blanding af 2-propanon og 2,2'-oxybispropan. Produktet frafiltreres og tørres, hvilket giver 8 dele (38%) methyl-4-[l-(4-fluorphenylmethyl)-ΙΗ-benzi-midazol-2-ylamino]-3-methyl-1-piperidincarboxylat; smp. 172,5°C.A mixture of 19 parts of methyl 4- (ΙΗ-benzimidazol-2-ylamino) -3-methyl-1-piperidinecarboxylate, 11 parts of 1- (chloromethyl) -4-fluorobenzene, 6 parts of sodium carbonate and 135 parts of Ν, Ν-Dimethylformamide is stirred and heated overnight at 70 ° C. The reaction mixture is cooled and poured onto water. The product is extracted three times with methyl benzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96: 4 by volume) as eluent. The pure fractions are combined and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried to give 8 parts (38%) of methyl 4- [1- (4-fluorophenylmethyl) -ΙΗ-benzimidazol-2-ylamino] -3-methyl-1-piperidinecarboxylate; mp. 172.5 ° C.

1010

Eksempel 16Example 16

Under anvendelse af fremgangsmåden i eksempel 13 kan de følgende 4-(l-R2-lH-benzimidazol-2-ylamino)-l-piperidincarboxylater fremstilles ved at alkylere det tilsvarende 4-(lH-benzimidazol-2-ylamino)-l-piperidin-15 carboxylat med et passende chlorid, bromid eller iodid med formlen R2X:Using the procedure of Example 13, the following 4- (1-R2-1H-benzimidazol-2-ylamino) -1-piperidinecarboxylates can be prepared by alkylating the corresponding 4- (1H-benzimidazol-2-ylamino) -1-piperidine -15 carboxylate having a suitable chloride, bromide or iodide of the formula R2X:

O _ .HO _ .H

(lavere alky])~Q~^~N~"^-N -(R^)(lower alky]) ~ Q ~ ^ ~ N ~ "^ - N - (R ^)

20 R1 IR1 I

R2 21 DK 171841 B1R2 21 DK 171841 B1

Lavere alkyl R R1 R2 (R3)n smeltepunkt C2H5 Η H CH3 · Η 166,7*C .Lower alkyl R 1 R 2 (R 3) n melting point C 2 H 5 Η H CH 3 · Η 166.7 * C.

C2H5 nH H CH3 5(6)-CH3 142,0*CC2H5 nH H CH3 5 (6) -CH3 142.0 * C

C2Hs h H C2Hs hC2Hs h H C2Hs h

C2H5 Η H njC3H? HC2H5 Η H njC3H? H

C2H5 Η H i.C3H7 . HC2H5 Η H i.C3H7. H

C2H5 HH n. C4H9 HC2H5 HH n. C4H9 H

C2Hs Η h a.C5Hu HC2Hs Η h a.C5Hu H

C2H5 Η H n.C6H13 HC2H5 Η H n.C6H13 H

C.,H5 B H n.C7Hls HC., H5 B H n.C7Hls H

c2h5 H H -Q Hc2h5 H H -Q H

C2K5 Η H 4-Br-C6H4-CH2 H - 'C2K5 Η H 4-Br-C6H4-CH2 H - '

C2H. Η H C^g-CI^ 5(6)-CH3 179, 3-CC2H. Η H C ^ g-C ^ 5 5 (6) -CH3 179, 3-C

C2H5 η H C6H5-CH2 hC2H5 η H C6H5-CH2 h

C2H5 H H 2-c1-G6H4’CH2 H 213, 4*CC2H5 H H 2-c1-G6H4'CH2 H 213, 4 * C

C2H- Η H 4-Cl-C6H4-CH2 H 202,6*CC2H- ΗH 4-Cl-C6H4-CH2 H 202.6 * C

Ο,Η^ Η H 4-CH3-C6H4-CH2 K 177,7* C4, Η ^ Η H 4-CH3-C6H4-CH2 K 177.7 * C

C2Hs ' Η H 4-F-C6H4-CH2 HC2Hs' Η H 4-F-C6H4-CH2 H

ί^Η, Η H 2-F-C6H4-CH2· H 176,0*Cί ^ Η, Η H 2-F-C6H4-CH2 · H 176.0 * C

C2H5 H H 4-f-C6H4’CH2 5(6)-CH3 173, 3*CC2H5 H H 4-f-C6H4'CH2 5 (6) -CH3 173, 3 * C

c2H5‘ Η H 4-F-C6H4-CH2 5(6)-F 182, 5*Cc2H5 'Η H 4-F-C6H4-CH2 5 (6) -F 182, 5 * C

C2H5 η H 0^-0¾ 5(6)-F 184, 0eCC2H5 η H 0 ^ -0¾ 5 (6) -F 184, 0eC

CH3 CH3 H C6H5-CH2 . H 191, O'CCH3 CH3 H C6H5-CH2. H 191, O'C

(cia+trans-isomer(CIA + trans isomer

C-H_ Η H 4-NO- -C, H -CH_ HC-H_ Η H 4-NO- -C, H -CH_ H

2 5 2 6 4 2 C_H_ H CH, C,H.-CH- H 25f,0eC(HCl- 2 5 2 6 5 2 salt)2 5 2 6 4 2 C_H_H CH, C, H-CH- H 25f, 0eC (HCl- 2 5 2 6 5 2 salt)

C-H Η H 4-F-2-CH,-C,H,- HC-H Η H 4-F-2-CH, -C, H, - H

2 5 ό o ό CH2 22 DK 171841 B12 5 ό o ό CH2 22 DK 171841 B1

Eksempel 17Example 17

En blanding af 7 dele ethyl-4-{[5(6)-fluor-l-(4-fluorphenylmethyl)-lH-benzimidazol-Z-yl]amino}-l-piperidincarboxylat og 300 dele brombrin-tesyre 48% i iskold eddikesyre omrøres og til bagesval es i 1 time. Reak-5 tionsblandingen inddampes, og remanensen koges i 2-propanol, 2,2'-oxy-bispropan tilsættes, og efter afkøling lader man produktet krystallisere. Det frafiltreres og tørres, hvilket giver 7,2 dele (88,2%) 5(6)-fluor-l-(4-fluorphenylmethyl)-N-(4-piperidinyl)-lH-benzimidazol-2-amin dihydrobromid; smp. 285,6°C.A mixture of 7 parts of ethyl 4 - {[5 (6) -fluoro-1- (4-fluorophenylmethyl) -1H-benzimidazol-Z-yl] amino} -1-piperidinecarboxylate and 300 parts of hydrobromic acid 48% in ice cold acetic acid is stirred and refluxed for 1 hour. The reaction mixture is evaporated and the residue is boiled in 2-propanol, 2,2'-oxy-bispropane is added and after cooling the product is allowed to crystallize. It is filtered off and dried to give 7.2 parts (88.2%) of 5 (6) -fluoro-1- (4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide; mp. 285.6 ° C.

1010

Eksempel 18Example 18

Analogt med foregående eksempler kan de følgende l-R2-N-(4-piperi-dinyl)-lH-benzimidazol-2-aminer fremstilles ved hydrolyse af de tilsvarende methyl- eller ethyl-1-piperidincarboxylater.By analogy to the foregoing examples, the following 1- R2-N- (4-piperidinyl) -1H-benzimidazole-2-amines can be prepared by hydrolysis of the corresponding methyl or ethyl-1-piperidinecarboxylates.

23 DK 171841 B123 DK 171841 B1

-p I-p I

^ r Λ 1^ r Λ 1

C O IC O I

2 · ·2 · ·

CU OO ICU OO I

<u cn i -p <n i Ί! i i i i t ' i i i i i i i » 0) , E cn i w cn i<u cn i -p <n i Ί! i i i i t 'i i i i i i i i »0), E cn i w cn i

I .1 I I ... - i. i i . -........... — . — II .1 I I ... - i. I i. --........... -. - I

0 *0 *

Pi » 1 ! g ! n »8 b β (a A·« ni ta S s s j S · ® o -p 3* X X 2« X ί* X X rt as cd <d !Pi »1! g! n »8 b β (a A ·« ni ta S s s j S · ® o -p 3 * X X 2 «X ί * X X rt if cd <d!

® <—* ·—i <vj<M<vJ(MfMcQCM{vJÆÆXlÆ 43 J® <- * · —i <vj <M <vJ (MfMcQCM {VJÆÆXLÆ 43 J

e OJ to x |.e OJ to x |.

c XXXXXXXXXXX:: X J· υυυυυυυυυυυυ o ; i ! <n 1 S ί i cn 1c XXXXXXXXXXX :: X J · υυυυυυυυυυυυ o; i! <n 1 S ί i cn 1

Ar _5 - * s” IAr _5 - * s ”I

\ ff «η U C? υ J\ ff «η U C? υ J

/ \ p* S ιΑχ’ϊΓιΑχ'χχχχχχχ x · =v5-“ ! r ø-4 i/ \ p * S ιΑχ'ϊΓιΑχ'χχχχχχχ x · = v5- “! r ø-4 i

2—(X__ I2— (X__ I

«—ί^Ί x^ ! U — tn cn } = c- i — <y> — ;«—Ί ^ Ί x ^! U - tn cn} = c- i - <y> -;

* in X «η X S X X* in X «η X S X X

S m »-· m c*· ^ nO i I i <m X S (Μ n OOOOU L J iS m »- · m c * · ^ nO i I i <m X S (Μ n OOOOU L J i

β KSUXUUcUcccc Jβ KSUXUUcUcccc J

i i· i« i »hi.....— — — ' ' ...... — - 1 ...........i i · i «i» hi .....— - - '' ...... - - 1 ...........

t t *"*o5 xxxx-xxxxxxxx x ; ------- *- — ----- 1 1 —....... —-------\t t * "* o5 xxxx-xxxxxxxx x; ------- * - - ----- 1 1 —....... —------- \

__ I__ I

W *γ****γ·*+ι*·+**Ψ**—*^**·*+*~ *r* IW * γ **** γ · * + ι * · + ** Ψ ** - * ^ ** · * + * ~ * r * I

C* *·· , 24 DK 171841 B1 -2 g C o υ wg sL U ^ o^u 0 07 jj O * O 03 O o ' N 5C * * ··, 24 DK 171841 B1 -2 g C o υ wg sL U ^ o ^ u 0 07 jj O * O 03 O o 'N 5

•3 · ' ' 1 ® 1 1 2 ' 1 3 S a ' ' S ' cTS• 3 · '' 1 ® 1 1 2 '1 3 S a' 'S' cTS

_J__Λ_A A Λ S ~ £ O O O O o °ro ri £ C4 (Μ (Μ f\l ri_J__Λ_A A Λ S ~ £ O O O O o ° ro ri £ C4 (Μ (Μ f \ l ri

H Vi X XX X -r SH Vi X XX X -r S

O) O λ·«··^* l·· 7 ^ ** Ih Ih Ih Ih Ih Ih i ^ o ^ ^ M P3 X u.fflfliflJffllBBilCD»; gii «ΟΛββχΧίαχχχυχχχχχ« (0(0 ^X^XX(vJ(vJX(vJr4rJX<vjrJ^(M^X CQ W N NN (Μ (M <** σS 'τ·,TT,T*,T·,Γ*Γ*τ',T’,τ, I' T T* *τ» 5" *t"O) O λ · «·· ^ * l · · 7 ^ ** Ih Ih Ih Ih Ih Ih i ^ o ^^ M P3 X u.fflfliflJffllBBilCD»; gii «ΟΛββχΧίαχχχυχχχχχ« {0 (0 ^ X ^ XX) vJ (vJX (vJr4rJX <vjrJ ^ (M ^ X CQ WN NN) (Μ (M <** σS 'τ ·, TT, T *, T ·, Γ * Γ * τ ', T', τ, I 'TT * * τ »5" * t "

>»H >1h **H l»H **H »HH> »H> 1h ** H l» H ** H »HH

υ . υ υ u u u u u uo oz u u.u'u o u « o*i X X .υ. υ υ u u u u u uo oz u u.u'u o u «o * i X X.

O u fa c fa — — i i * o u u ts* ^ a X· X X X X X X- X X LO m X in ιη ιη- ιλ x xO u fa c fa - - i i * o u u ts * ^ a X · X X X X X X- X X LO m X in ιη ιη- ιλ x x

<M<M

NN N§ <M (Μ «Μ- - ** X X X o -T* x XX xNN N§ <M (Μ «Μ- - ** X X X o -T * x XX x

UU. U ^.rj O <M <M O O N nU (VIUU. U ^ .rj O <M <M O O N nU (VI

* * l_— *r , iXXXi u X X 1 X* * l_— * r, iXXXi u X X 1 X

f ^ u o u * ^ O U J* o c- SE oUX XiiiXXii 7o ' *r ,,^πι νΛ ό in in ' in ό ό in m ^ m M U Ο O <n u UXXXUUXXOxf ^ u o u * ^ O U J * o c- SE oUX XiiiXXii 7o '* r ,, ^ πι νΛ ό in in' in ό ό in m ^ m M U Ο O <n u UXXXUUXXOx

¢5 m — 2 ' l £ i i ό vo ό i i >n Ό ' vO¢ 5 m - 2 'l £ i i ό vo ό i i> n Ό' vO

X ^OOeu'faXfeOUUfafaUU^UX ^ OOeu'faXfeOUUfafaUU ^ U

1 1 1 * ‘ J, ‘ ' TJ* (Μ 'ί Ί<· ^ ’I' ^ ΊΤ-ν (»1 O'1 1 1 * 'J,' 'TJ * (Μ' ί Ί <· ^ 'I' ^ ΊΤ-ν (»1 O '

- X. X- X. X

• K XUXXXXX^XXXZXXXXXX• K XUXXXXX ^ XXXZXXXXXX

__c_ m m__c_ m m

C5 XmXXXXXXXXXXXXXXOOC5 XmXXXXXXXXXXXXXXOO

» I»I

cn m 25 DK 171841 B1cn m 25 DK 171841 B1

4J4J

Λί § u u o, · · ω ° o . , 4J O O 1 1 ,η μ m 6 A Λ to _______ ρ ε rH J-4 Π3 O _Λί § u u o, · · ω ° o. , 4J O O 1 1, η μ m 6 A Λ to _______ ρ ε rH J-4 Π3 O _

Ul'W OUl'W O

U ‘ri'4 P M . p QJ * O « ' fflU 'ri'4 P M. p QJ * O «'ffl

<-< S ffi K<- <S fi K

'Τ’ u Al <M Λ1'Τ' u Al <M Λ1

<u T<u T

fflffl

i Sice

QJ pj U) ns m ___ n X X S ' X α ϋ u o ϋQJ pj U) ns m ___ n X X S 'X α ϋ u o ϋ

X X X XX X X X

a (Μ Εa (Μ Ε

UU

Ε ϋ ο X- ΊX ϋ ο X- Ί

fM ^ νΟ XfM ^ νΟ X

a X ο ϋ νΟ ' , ϋ Al pj «Γ» , Ο 1 ^ h X U* Ο ι ι ι U <}* ^ - . ►** ^ Ρ5 Λ 3* 4*a X ο ϋ νΟ ', ϋ Al pj «Γ», Ο 1 ^ h X U * Ο ι ι ι U <} * ^ -. ► ** ^ Ρ5 Λ 3 * 4 *

ΡΖ X X »Π ECΡΖ X X »Π EC

26 DK 171841 B126 DK 171841 B1

Eksempel 19Example 19

En blanding af 20 dele (phenylmethyl)-4-[3-(4-fluorphenylmethyl)-3H-imidazo[4,5-b]pyridin-2-ylamino]-l-piperidincarboxylat og 160 dele methanol hydrogeneres ved normalt tryk og ved stuetemperatur med 2 dele 5 palladium-på-trækul katalysator 10%. Efter optagning af den beregnede mængde hydrogen frafiltreres katalysatoren, og filtratet inddampes. Remanensen koges i 2,2'-oxobispropan. Det uopløste produkt frafiltreres og omdannes til hydrochloridsalt i 2-propanol. Saltet frafiltreres og tørres, hvilket giver 12 dele 3-(4-fluorphenylmethyl)-N-(4-piperidinyl)-3H- 10 imidazo[4,5-b]pyridin-2-amin dihydrochlorid monohydrat; smp. 269,7°C.A mixture of 20 parts (phenylmethyl) -4- [3- (4-fluorophenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinecarboxylate and 160 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts 5 palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is boiled in 2,2'-oxobispropane. The undissolved product is filtered off and converted to hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 12 parts of 3- (4-fluorophenylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5-b] pyridin-2-amine dihydrochloride monohydrate; mp. 269.7 ° C.

B. FREMSTILLING AF SLUTPRODUKTER Eksempel 20 15 En blanding af 2 dele 2-(bromethoxy)benzen, 3 dele l-(phenylme- thyl)-N-(4-piperidinyl)-lH-benzimidazol-2-amin, 2 dele natriumcarbonat, 0,1 del kaliumiodid og 90 dele Ν,Ν-dimethylformamid omrøres natten over ved 70°C. Reaktionsblandingen afkøles og hældes i vand. Produktet eks-traheres med methyl benzen. Ekstrakten tørres, filtreres og inddampes.B. PREPARATION OF FINAL PRODUCTS Example 20 A mixture of 2 parts of 2- (bromethoxy) benzene, 3 parts of 1- (phenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine, 2 parts of sodium carbonate, 0.1 part potassium iodide and 90 part Ν, Ν-dimethylformamide are stirred overnight at 70 ° C. The reaction mixture is cooled and poured into water. The product is extracted with methyl benzene. The extract is dried, filtered and evaporated.

20 Remanensen omdannes til hydrochloridsalt i 2-propanon. Saltet frafiltreres og tørres, hvilket giver 3,5 dele (70%) N-[l-(2-phenoxyethyl)-4-pi-peridinyl]-l-(phenylmethyl)-lH-benzimidazol-2-amin dihydrochlorid monohydrat; smp. 197,6°C.The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 3.5 parts (70%) of N- [1- (2-phenoxyethyl) -4-piperidinyl] -1- (phenylmethyl) -1H-benzimidazole-2-amine dihydrochloride monohydrate; mp. 197.6 ° C.

25 Eksempel 21Example 21

Ved at følge fremgangsmåden i eksempel 20.og ved anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan de følgende forbindelser fremstilles på fri baseform eller i form af et syreadditionssalt efter omsætning af den frie base med et passende salt.Following the procedure of Example 20. and using equivalent amounts of the appropriate starting materials, the following compounds can be prepared in free base form or in the form of an acid addition salt after reacting the free base with a suitable salt.

_27__ DK 171841 B1 -p i λ: « » ϋϋϋ uoouu u uuu; ^ ··· · · · · · · ···· cn oo aa O' in co τ^ Μ ό oa <a 'f j_27__ DK 171841 B1 -p i λ: «» ϋϋϋ uoouu u uuu; ^ ··· · · · · · ···· cn oo aa O 'in co τ ^ Μ ό oa <a' f j

ao rS ao —Γ n n f in un ^ Jao rS ao —Γ n n f in un ^ J

c, 0s θ' p· Tf Tf —< ni ao σ' o* *· j £ PJ — m - Μ N Μ N pa C4 Μ <M | • —----o---! o O O sfo ni u -C? ^ ν'λ) n n- i " 1 - o . X Ϊ 5 S “ s'1 · ¢) ^ 2 υϊ ®υυυυ — υυ^ι , £ «j X «ο X X X X . εκ-· α> -μ · Æ <Ν| ί Ν Ν Ν Ν — Ν Ν η <Λ Ή q Ο U ιc, 0s θ 'p · Tf Tf - <ni ao σ' o * * · j £ PJ - m - Μ N Μ N pa C4 Μ <M | • —---- o ---! o O O sfo ni u -C? ^ ν'λ) n n- i "1 - o. X Ϊ 5 S" s'1 · ¢) ^ 2 υϊ ®υυυυ - υυ ^ ι, £ «j X« ο XXXX. εκ- · α> -µ · Æ <Ν | ί Ν Ν Ν Ν - Ν Ν η <Λ Ή q Ο U ι

<2 <σ si S S I<2 <σ are S S I

® W jJj {M PJ · „ XXX XXXXX X ΧΧχί a uuu u u u u u u uuu;® W jJj {M PJ · „XXX XXXXX X ΧΧχί a uuu u u u u u u u uuu;

« I«I

...... ......... ......l \ «η „ · a : Ύ « - ί /=r=\ « XXX XXXXX X XXX i $ __—i / V PJ ^ «...... ......... ...... l \ «η„ · a: Ύ «- ί / = r = \« XXX XXXXX X XXX i $ __— i / V PJ

2^2—« X I2 ^ 2— «X I

τα ϋ i X—05 X i · U - w cn ‘ T P“ I —» —· O' —< p. ιοί t n X ΙΛ X X X X I-- *r Ό {~_ J pJ p1 X rn X lo p- Tp mo ( 1 {η U , (S X P4 O ^ U U U U η * i jj U U c U c c c c — X' (j jτα ϋ i X — 05 X i · U - w cn 'TP “I -» - · O' - <p. ιοί tn X ΙΛ XXXX I-- * r Ό {~ _ J pJ p1 X rn X lo p- Tp mo (1 {η U, (SX P4 O ^ UUUU η * i jj UU c U cccc - X '{jj

pa . Ipa. IN

cn i *-» S 1 « ’ χ X x xxxxx x X u x !cn i * - »S 1« 'χ X x xxxxx x X u x!

ta« ta* M ta* ta* ta* ta* ta* ta* ta* ta* *f* Ita «ta * M ta * ta * ta * ta * ta * ta * ta * ta * * f * I

M* *1* hU m* *** »1* n·* ta* ta* ta* ta« »1* ta«M * * 1 * hU m * *** »1 * n · * ta * ta * ta * ta« »1 * ta«

- —1 1 I- —1 1 I

TT

n n <m cg ra <\i ca ra N N n , N N N N N N N N r4 fsl <N <M 1n n <m cg ra <\ i ca ra N N n, N N N N N N N N N r4 fsl <N <M 1

Xta* ta* ta* ta« ta« ta* ta* ta* ta* ta* ta* IXta * ta * ta * ta «ta« ta * ta * ta * ta * ta * ta * I

ta* ta* Pm ta* ta* *1* ta* ta* ta* ta* ta* ita * ta * Pm ta * ta * * 1 * ta * ta * ta * ta * ta * i

J UUU U U U U U CJ .UUU IJ UUU U U U U U CJ .UUU I

III I I I I I I III, m m in minminm m m uv m tIII I I I I I I III, m m in minminm m m uv m t

XXX XXXXX X XXX-IXXX XXXXX X XXX-I

Ό nO «O nO nO O sfl %0 sO vO >0 «Ο IΌ nO «O nO nO O sfl% 0 sO vO> 0« Ο I

1 u u u U U U U U U UUU I1 u u u u U U U U U U UUU I

28 DK 171841 B1 ' i £ 00000000^0000·^ ; C .»···««· .«···· 2 o < 0) -i-i-^c-ToaN^co^j’—OMC'-^O * -P inO'CQCO^C'OO^'CQ^'e'Ø'^·. 2 1 f—I (Vj m Λ4 —< —“ Λ) *— o — ^ N m 1 « S - ' ε c i ----o Λ428 DK 171841 B1 'i £ 00000000 ^ 0000 · ^; C. »···« «·.« ···· 2 o <0) -ii- ^ c-ToaN ^ co ^ j'-OMC '- ^ O * -P inO'CQCO ^ C'OO ^' CQ ^ 'e'Ø' ^ ·. 2 1 f — I (Vj m Λ4 - <- “Λ) * - o - ^ N m 1« S - 'ε c i ---- o Λ4

u o O -So Iu o O -So I

^ <M Λα ^ -Cf Λ3 I^ <M Λα ^ -Cf Λ3 I

ΗΕΐΙυβ(ίβΜθοο-.«Ι JΗΕΐΙυβ (ίβΜθοο -. «Ι J

ΗΪβΟ®^Ββ" "(Τί·—* · <U -P X X *“·“*“ . el χ , Μ H NN (03 (Vi , <0(0 , « in ; t a xxxxxxxxxxx x ! υουοοουοουυ, z o .ΗΪβΟ® ^ Ββ "" (Τί · - * · <U -P X X * “·“ * “. El χ, Μ H NN (03 (Vi, <0 (0,« in; t a xxxxxxxxxxx x x! Υουοοουοουυ, z o.

i —- - - m m i - X X fa · £5 , ^ - υ o i ; « u “ - - 3- : S XXXXXX'iniS^’STXX 1 111 «v in i " "1 nS ' π* η <M (M <M (M <"*- i 5 » X· X XX ~ ! . j* o u o υ «* o ^ ! •*t* X i -i ii μ— X »i« i T να *?< ·*<* «-Λ U i vO U X X ~ X X I I ~ I .i —- - - m m i - X X fa · £ 5, ^ - υ o i; «U« - - 3-: S XXXXXX'iniS ^ 'STXX 1 111 «v in i" "1 nS' π * η <M (M <M (M <" * - i 5 »X · X XX ~! . j * ouo υ «* o ^! • * t * X i -i ii µ— X» i «i T να *? <· * <*« -Λ U i vO UXX ~ XXII ~ I.

n · Ό vO UOOintri . >° in i i^o u « u υ x x u x 1 ΛΙ U X I I I I SO Ό ' von · Ό vO UOOintri. > ° in i i ^ o u «u υ x x u x 1 ΛΙ U X I I I I SO Ό 'vo

« CQOfcXhXStukUUfeU«CQOfcXhXStukUUfeU

iii i ;iii i;

TjTT^ri* (VJ U -rT ^ “ ,TjTT ^ ri * (VJ U -rT ^ «,

” I"I

o ! x ! "« xxxdxxxxxxzzz 'o! x! "" Xxxdxxxxxxzzz '

C IC I

-----------1 CO 1----------- 1 CO 1

(S XXXXXXXXXXXXU L(S XXXXXXXXXXXXU L

Λ4 ^_C4 ΛΙ Λ1 (VJ NNNNNNMM 1 caoaoj(M(Mo4rvioj(M(Mo4ojra i M· *rnm *mm Pr* *T* *T* mm *T* ρψ* »mm M· mm p*m .Λ4 ^ _C4 ΛΙ Λ1 {VJ NNNNNNMM 1 caoaoj {M {Mo4rvioj {M (Mo4ojra i M · * rnm * mm Pr * * T * * T * mm * T * ρψ * »mm M · mm p * m.

>M pm* PM *+* mm mm mm pM mm mm mm »*4 m* 1 I I I I I I I I I I I I I 1 ιηΐπίΛΐηιηιηνηιηιηιηΐΛΐηιη 1 I PM »mm mm *i+ M*· pM pm pM tM pM pM pM pM .> M pm * PM * + * mm mm mm pM mm mm mm »* 4 m * 1 I I I I I I I I I I I I 1 ιηΐπίΛΐηιηιηνηιηιηιηΐΛΐηιη 1 I PM» mm mm * i + M * · pM pm pM tM pM pM pM pM pM.

I %G Ό Ό Ό Ό Ό sQ \Q \Q ^5 Ό vO 1 [-.. luuuouuuoooooo_.I% G Ό Ό Ό Ό Ό sQ \ Q \ Q ^ 5 Ό vO 1 [- .. luuuouuuoooooo_.

29 DK 171841 B1 u o29 DK 171841 B1 u o

SS

o υ ί u *? υ υ o ' cjuooouououoæo c ·'·♦* ····»······ v · 3 <n ® —< —* σ'β«τ>Ό<ο<3θ<Ί'ί'Γ'θο<νΐ^ £1* -4444444444 ^ 4 αι o J n f* a — cn^t— -4cn<ninr*i'4*cv.- in ρ Ν ί Ό ff> w voo^m^c—t— fnoinm ( un 1-1 Ν 4· Μ Η Ν (M(^irt-4>-l»<MlH(\J»1«<Q ΟΙ i ® ” 10 U "" Λ Sm Ο Ο Ο Η- (\J Ο ω Ο 0 Ο ο gT*. > Ο X J* = af af ·Λ® sf^ g x ^ u 2u§-«uG22o2u§2S§2§o υ ί u *? υ υ o 'cjuooouououoæo c ·' · ♦ * ···· »····· v · 3 <n ® - <- * σ'β« τ> Ό <ο <3θ <Ί'ί'Γ ' θο <νΐ ^ £ 1 * -4444444444 ^ 4 αι o J nf * a - cn ^ t— -4cn <ninr * i'4 * cv.- in ρ Ν ί Ό ff> w voo ^ m ^ c — t— fnoinm (about 1-1 Ν 4 · Μ Η Ν {M {^ irt-4> -l »<MlH (\ J» 1 «<Q ΟΙ i ®” 10 U "" Λ Sm Ο Ο Ο Η- {\ J Ο ω Ο 0 Ο ο gT *.> Ο XJ * = of af · Λ® sf ^ gx ^ u 2u§- «uG22o2u§2S§2§

gi X rtXX X X <4 <4 S <4 X X rt at X * Xgive X rtXX X X <4 <4 S <4 X X rt at X * X

<0^ «Μ ^ N N NNJiNJNNÆJNi CM<0 ^ «Μ ^ N N NNJiNJNNÆJNi CM

mm .mm.

„ X XXX XXX XXXXXXXXX"X XXX XXX XXXXXXXXX

σ u υ υ u υυυζυυυυυυυυυσ u υ υ u υυυζυυυυυυυυυ

* I* I

fOfO

«Ν·^ ^ ^ ►*· fy* »y* *m *y* Nr* *y» M«Ν · ^ ^ ^ ► * · fy *» y * * m * y * Nr * * y »M

tob« »i*- »M »i* t±* »1*. »^4 M* **4 *W· M4 Μ Mtob «» i * - »M» i * t ± * »1 *. »^ 4 M * ** 4 * W · M4 Μ M

. (Μ* (M {M {MM. (Μ * (M {M {MM

x* XXX XXx * XXX XX

t ί (MmUUU mmmmmmO Ut ί (MmUUU mmmmmmO U

M S’ I s X ' ‘ ' x x x X X X ' ' « > sT* S’ S5 x x x S’ S’ S’ S’ S’ S’ x a;M S 'I s X' '' x x x X X X '' «> sT * S 'S5 x x x S' S 'S' S 'S' S 'S' x a;

•~_ 4θ U »λ m «λ,^°, ,'0,,'0 m m in m vn in ,:° n0 q. X XX^UCj-i^^^-UU• ~ _ 4θ U »λ m« λ, ^ °,, '0 ,,' 0 m m in m vn in,: ° n0 q. X XX ^ UCj-i ^^^ - UU

V 1 in Μ vO Ό ' ' ' 40 m3 Ό Ό so vO ,' ' r t, S U CJU^^^UUOUUU^»V 1 in Μ vO Ό '' '40 m3 Ό Ό so vO,' 'r t, S U CJU ^^^ UUOUUU ^ »

Λ . 40 III IIΛ. 40 III II

^ 4* u -4* -4* -4* -4» -4*^ 4 * u -4 * -4 * -4 * -4 »-4 *

X XXX XXX X XXXXXXXXXX XXX XXX X XXXXXXXXX

<n m<n m

X XX X

a u xxx xxxxuxxxxxxxxand u xxx xxxxuxxxxxxxx

Μ MΜ M

fM Μ X ' XfM Μ X 'X

x "Τα υ υ U m m rn cn ^ ____ ^^ 'T «Μ <M "Ti "m M "7a U -f4 _T> Γτ ^ *# x x x x x x "r x xxx xx "Τα υ υ U m m rn cn ^ ____ ^^ 'T« Μ <M "Ti" m M "7a U -f4 _T> Γτ ^ * # x x x x x x" r x xxx x

<m X mO Ouooo^ ^»-OOUU<m X mO Ouooo ^^ »- OOUU

*Π 40 ΓΓ I I Cl. 4- - 4 - -- Μ- I £--'--- 4—. —.* Π 40 ΓΓ I I Cl. 4- - 4 - - Μ- I £ --'--- 4—. -.

n (J 0 x χ * « < · υ ουχχχχ J w I -X. CJ ϋ O O O 0 ^ o^uuuu I <M I II π I I « I !« O' I I I I 1 m η mil II m m m m ►- >r m ►*. m m m mn (J 0 x χ * «<· υ ουχχχχ J w I -X. CJ ϋ OOO 0 ^ o ^ uuuu I <MI II π II« I! «o 'IIII 1 m η mil II mmmm ►-> rm ► *. mmmm

X X X ** nJXXXXT^rrXT^XXXXX X X ** nJXXXXT ^ rrXT ^ XXXX

Ό I Ό 3* X -Ο Ό vO Ό . 4 M vQ . - ΌΌΌ 'O-Ό I Ό 3 * X -Ο Ό vO Ό. 4 M vQ. - ΌΌΌ 'O-

__U ΤΓ ϋ U UUUU-UCicOwOUUU__U ΤΓ ϋ U UUUU-UCicOwOUUU

30 DK 171841 B1 i i ij υυυυυυυυυυυυυυυ · " ··············· ·.30 DK 171841 B1 i i ij υυυυυυυυυυυυυυυ · "···········.

5 —<in -«f o cd r- o <vj—< — > in m * min^jvor^oc'm — c-r^c*.on(vjo t ij ^♦iDO^cnin unvoO'^Ti'ir) r- cd — 'J* 1 Η---1-<ρ)Ρ4Ν(νι--ΝΝ-Μ t5 - <in - «fo cd r- o <vj— <-> in m * min ^ jvor ^ oc'm - cr ^ c * .on (vjo t ij ^ ♦ iDO ^ cnin unvoO '^ Ti'ir) r- cd - 'J * 1 Η --- 1- <ρ) Ρ4Ν (νι - ΝΝ-Μ t

E JE J

ω iω i

______ I______ I

o o o O O { i, <m -Γ1 n ^ »rT1 1 m n o X U X X X » •3 0n0«« < x~* ; <u ^ ® *E <*i -* · «'J όη —* —* ·'o o o O O {i, <m -Γ1 n ^ »rT1 1 m n o X U X X X» • 3 0n0 «« <x ~ *; <u ^ ® * E <* i - * · «'J όη - * - * ·'

SeOzSS-uuuzSoogS! WM rtJJXXcdcdXX Γνϊ cd X X cd rt ' nJ «3 Æ r4 <M Æ ,α <M <M Λ*· <Μ Æ <\1 ra Æ Λ 1SeOzSS-uuuzSoogS! WM rtJJXXcdcdXX Γνϊ cd X X cd rt 'nJ «3 Æ r4 <M Æ, α <M <M Λ * · <Μ Æ <\ 1 ra Æ Λ 1

• PQ ω . J• PQ ω. J

“" _ i i i“" _ I i i

CC

i ήΜ* W« ta·· »ww taM M·* ta» Nta *γ» ty« ta» kM Ργ+ »m | l-U H4 *±4 »1»·—·· »*i M-4 M* NM >»W Mm MM ta4 Hta | a uuuoxcxjaauuuuuuo « : j i ?—os c ; —ci ήΜ * W «ta ··» ww taM M · * ta »Nta * γ» ty «ta» kM Ργ + »m | l-U H4 * ± 4 »1» · - ·· »* i M-4 M * NM>» W Mm MM ta4 Hta | a uuuoxcxjaauuuuuuo «: j i? —os c; -c

I cn II cn I

x S XXXXXXXXXXXXXXX' Λ--=-i I _ J «i oa oa oa -4 oa i X1 X XX XX 'x S XXXXXXXXXXXXXXX 'Λ - = - i I _ J «i oa oa oa -4 oa i X1 X XX XX'

j, Gu u o V u Jj, Gu u o V u J

<M '« V ** V _«M _fj V ; 05 S X S X X .-1- S X Xo = S’ X ·<M '«V ** V _« M _fj V; 05 S X S X X.-1- S X Xo = S 'X ·

W « '« «« « '« « S’ '«VIW «'" "" "" "" "S"' "VI

b, fc, * X fa fa s s -f I x u fa XX i i i Ό N i I >0 N »m nO Ό i i Ό •^^uo^^uuouu^^ou ! .....—-....... -— - - *b, fc, * X fa fa s s -f I x u fa XX i i i Ό N i I> 0 N »m nO Ό i i Ό • ^^ uo ^^ uuouu ^^ ou! ..... —- ....... -— - - *

rO IrO I

ro ro ! n <m cm ^T4 'ro ro! n <m cm

U (Ί (Μ N N τ~ «τ' ' ' IU (Ί (Μ N N τ ~ «τ '' 'I

'••w' M »M ta* ta* Μ M 04 a , »o* »L »u J« r -s r λ Μ (vi t OUUUU.EH, o i I · I I ti OJ τΓ1 X.'•• w' M »M ta * ta * Μ M 04 a,» o * »L» u J «r -s r λ Μ (vi t OUUUU.EH, o i I · I I ti OJ τΓ1 X.

^XXXX^OO X X X « i XUUUUXUU U ^ 1 n° II I! II II U · <M CM · = !^ XXXX ^ OO X X X «i XUUUUXUU U ^ 1 n ° II I! II II U · <M CM · =!

. 1 ' I—· ►v *“" *τ· X- _X _Ρ** ·*» r I. 1 'I— · ►v * “" * τ · X- _X _Ρ ** · * »r I

** I M« »Li l-M H« 'IE*-«UC<XXXXn ! OUUUUO vOnoUU ό cj nOnoi i** I M «» Li l-M H «'IE * -« UC <XXXXn! OUUUUO vOnoUU ό cj nOnoi i

Jp · · 1 · *UU' ' U X- U ϋ i X tn m to vn m i · tnui· in . . r-. > uXXXXXfcfaXXfaXfatuU 'Jp · · 1 · * UU '' U X- U ϋ i X tn m to vn m i · tnui · in. . r. > uXXXXXfcfaXXfaXfatuU '

I sO vO ^ ^ vO I I vOO| vO , I I II sO vO ^^ vO I I vOO | vO, I I I

______ ^υΟΟυΟ^^υ U ^ (J »r w * 31 DK 171841 B1 “““““T”"-——————————. i i______ ^ υΟΟυΟ ^^ υ U ^ (J »r w * 31 DK 171841 B1" "" "" T "" --—————————.

4-1 I4-1 I

§υυυυυυυ o u u ί di······· · · · I .§Υυυυυυυ o u u ί di ······ · · · I.

(1) ^ί* CO CQ σ' C— CO Ό in. O O I(1) ^ ί * CO CQ σ 'C— CO Ό in. O O I

4-J — — — -. « - * ^ s I4-J - - - -. «- * ^ s I

i-' O' v « o η in a r~ r- ra · ω C'· σ' ro -«r α ro cm σ' i E <M-h—<M <vi — ·i- 'O' v «o η in a r ~ r- ra · ω C '· σ' ro -« r α ro cm σ 'i E <M-h— <M <vi - ·

W IW I

_____ - - — - - - -.....— 1 ε uf1 ! 0 6 0 χ ; ij a?1 o o, o · fl S s T O O <M O ·_____ - - - - - - -.....— 1 ε uf1! 0 6 0 χ; ij a? 1 o o, o · fl S s T O O <M O ·

m "st. U * N N ϊ ra Jm "st. U * N N ϊ ra J

—* to mS I n . *E i qj *X _ ® O X _* _*· o X ! ^ouu2ouu.S S y !.- * to mS I n. * E i qj * X _ ® O X _ * _ * · o X! ^ ouu2ouu.S S y !.

^χχ^χχ-χχ d d s «^ χχ ^ χχ-χχ d d s «

N N η N N N N M· tM IN N η N N N N M · tM I

1 · ' ! <D —' '1 · '! <D - ''

(Λ U I(Λ U I

(0 5" ' ffl s : ►t* *** h”· ►t» ►r* ►r· i **♦« ►-* hM N** M>* ►·* NM »i« t*+ σουυυυυυυ u u ! m f - = i _r _ x u , m U O i · 5 iiSwsaJs x x 'X ! __:_to------1-! i pU t S : fM 04 44* < t* 5* w. i u u ό ! • « o i vn in tn m t ,(0 5 "'ffl s: ►t * *** h" · ►t »►r * ►r · i ** ♦« ►- * hM N ** M> * ► · * NM »i« t * + σουυυυυυυ uu! mf - = i _r _ xu, m UO i · 5 iiSwsaJs xx 'X! __: _ to ------ 1-! i pU t S: fM 04 44 * <t * 5 * w. iuu ό! • «oi vn in tn mt,

s X X X in Is X X X in I

<vj Ό S m* fsj Ό C4 i * csxxxuuoou u d· ; 7 —- ..... ....— -—— --- 1 ~ i l<vj Ό S m * fsj Ό C4 i * csxxxuuoou u d ·; 7 —- ..... ....— -—— --- 1 ~ i l

1 I U I I ( I1 I U I I (I

ro co ro ro ro co ro iro co ro ro ro co ro i

N (Ί (Μ ιΜ (Μ N ιΊ IN (Ί (Μ ιΜ (Μ N ιΊ I

XXXXXXX OJ « £ £ £ Η E "λι ;XXXXXXX OJ «£ £ £ Η E„ λι;

t » I I I I I , , X It »I I I I I,, X I

i XXXXXXX ^-T --C4 o · uuuuuuu ^ ^ 'r ! "*r d* rf "^f "’o· ϋ ϋ / ^ ! xxxxxxx i i o=( I! !i XXXXXXX ^ -T --C4 o · uuuuuuu ^^ 'r! "* r d * rf" ^ f "'o · ϋ ϋ / ^! xxxxxxx i i o = (I!

sO Ό -43 vO *0 Ό vO \ Jl IsO Ό -43 vO * 0 Ό vO \ Jl I

o< ri o< ri * ; fo fa fa fa fo fa fa A ix J \ m !o <ri o <ri *; fo fa fa fa fo fa fa A ix J \ m!

i i i i i i i 2Γ X X Ji i i i i i i i 2Γ X X J

Ί'Ί’Ί’Ί'νντΤ m _ q IΊ'Ί'Ί'Ί'νντΤ m _ q I

32 DK 171841 B1 U U U ϋ | · · · · <d σ* m >o 'J* -U -P - m o vo c* m <u c r* · n· r* ·* E3 - -* <M — w α ε l-l o 4-(32 DK 171841 B1 U U U ϋ | · · · · <D σ * m> o 'J * -U -P - m o vo c * m <u c r * · n · r * · * E3 - - * <M - w α ε l-l o 4- (

PP

m ’Om 'O

ω o uf* S 3f < »H · m* « u S u 2 . X rt X <4 φ ρα Λ . N Λ m <ϋω o uf * S 3f <»H · m *« u S u 2. X rt X <4 φ ρα Λ. N Λ m <ϋ

CQCQ

συ u o z.συ u o z.

^_c Ί« X X s x nj <vi^ _c Ί «X X s x nj <vi

X XX X

u u . I 1 <m τ1 τ'u u. I 1 <m τ1 τ '

M £ X .XM £ X .X

22 vj O nC22 BC O

'* u « *- · >- af * U Ί* O Tf ni <vl fM (V) <M ni <vl (Vl'* u «* - ·> - of * U Ί * O Tf ni <vl fM (V) <M ni <vl (Vl

XXX XXXX X

U U U^ (JU U U ^ {J

2>sZ2> SZ

III IIII I

in m in min m in m

X X X XX X X X

ni ni Ό (vi o u . u u 33 DK 171841 B1 +j ·£ o o o o ουοηοοουου 3 · ·' · · a··,······never never Ό (vi o u u u u 33 DK 171841 B1 + j · £ o o o o ουοηοοουου 3 · · '· · a ··, ······

Λ -< m 04 04 ^:Hl<lo(nHC0O«lNΛ - <m 04 04 ^: Hl <lo (nHC0O «lN

PJ - - -- - — so o no vocoo-^int'-com-ifcn <» t— -ο σ' o4mcocoo4^**o»-<in E r+ (VI 04 ψ~4 »-·—4<— ω S N o a ^ c 04 ® 0=0 O®®®«®«® ·©® COm 22 ® I 22 ®®®®®®®®®® ja . ja qq ÆjaÆÆjajaÆÆÆÆ 3 0 0" Φ o so i 2 *τ· a) ~ ***PJ - - - - - so o no vocoo- ^ int'-com-ifcn <»t— -ο σ 'o4mcocoo4 ^ ** o» - <in E r + (VI 04 ψ ~ 4 »- · —4 < - ω SN oa ^ c 04 ® 0 = 0 O®®® «®« ® · © ® COm 22 ® I 22®®®®®®®®®®® yes. Yes qq ÆjaÆÆjajaÆÆÆÆ 3 0 0 "Φ o so i 2 * τ · a) ~ ***

w Xw X

g 04 ^ a a a a a aaaaaaaaa u o o u u 0000000002 ___c *2« a a a a oaaaaaaaaa id <o 04 a _o 04 Jl, Q2 M< i i-U 22 —Γ1 ο ϋ ** 04 04 04 ^ ' oi χΛ a a a i a ag 04 ^ a a a a a a aaaaaaaaa u o o u u 0000000002 ___c * 2 «a a a a oaaaaaaaaa id <o 04 a _o 04 Jl, Q2 M <i i-U 22 —Γ1 ο ϋ ** 04 04 04 ^ 'oi χΛ a a a i a a

rj0 o o o o *„ xi^Orj0 o o o o * „xi ^ O

1 m m m m S’ m m m in S^ S’ ^ m t** a a a a^aBaac-kt*1 I 04 vO Ο Οι όόόό,,Τό1 m m m m S 'm m m in S ^ S' ^ m t ** a a a a ^ aBaac-kt * 1 I 04 vO Ο Οι όόόό ,, Τό

X Ο O O O^OOOO^^^OX Ο O O O ^ OOOO ^^^ O

' «Ό rO'«Ό rO

04 - ^*04 g 04 = SL a a 04 ϋ J. O O ^ V, 2 .04 - ^ * 04 g 04 = SL a a 04 ϋ J. O O ^ V, 2.

rt \ \ 04 04 CO 04 U 04 CO , 04 S’ )—\ /—\ a aa^a a ^ a ^o4 ο o oo H uuau ro g S’ ~ *o S’ a /=\ /=^ ctr2v,<^s a a v a a a a . .a o°v_/ W L JL JW ? 9 v η v v ? 1 '-' -' Π^ν/ m m m in i inmma ’o aaaaj^aaaua I, vO vO so vC 22 vO vO sO ( Ό ;* oooooooo^o 34 DK 171841 B1 4J υ υ υ υ.υϋϋϋϋυυ υ υ υ Λ · · « ······«· · # · S >ο ο oo >ο oo <*ι ae κ *. % ** *> ν «.rt \ \ 04 04 CO 04 U 04 CO, 04 S ') - \ / - \ a aa ^ aa ^ a ^ o4 ο o oo H uuau ro g S' ~ * o S 'a / = \ / = ^ ctr2v , <^ saavaaaa. .a o ° v_ / W L JL JW? 9 v η v v? 1 '-' - 'Π ^ ν / mmm in i inmma' o aaaaj ^ aaaua I, vO vO so vC 22 vO vO sO (Ό; * oooooooo ^ o 34 DK 171841 B1 4J υ υ υ υ.υϋϋϋϋυυ υ υ υ Λ · · «······« · · # · S> ο ο oo> ο oo <* ι ae κ *.% ** *> ν «.

af Γ" νβ in I'fTi* CvJ vO PHof Γ "νβ in I'fTi * CvJ vO PH

-P Is- Γ" on M Tf f T)| Γ' vO Μ 0O n t> ifl ^ ^ 0X| ^"4 4“4 ^ *“4 ^4 IB4 ^4 ^4 . 4«4 4^ ω .-P Is- Γ "on M Tf f T) | Γ 'vO Μ 0O n t> ifl ^ ^ 0X | ^" 4 4 “4 ^ *“ 4 ^ 4 IB4 ^ 4 ^ 4. 4 «4 4 ^ ω.

~ on~ on

SS

* ϋ O* ϋ Oh

CL) 1 (vj i—I gj OkCSCoOOUUOOU u u T< rH qq a r)_Q ααααααα α oo ® CL) Ci rt «I vi*/ rtrtrtrtrtrtrt rt rtrt vi .CL) 1 (vj i — I gj OkCSCoOOUUOOU u u T <rH qq a r) _Q ααααααα α oo ® CL) Ci rt «I vi * / rtrtrtrtrtrtrt rt rtrt vi.

>-i ja .0^,0.0.0.0,0.0.0.0 i> -i yes .0 ^, 0.0.0.0,0.0.0.0 i

I O MI O M

14.1 HM14.1 HM

a) +> U - w i—1 fO <0 - ·£* cq cn a s a a a x υ UU ΌΖΖΖΌΖΖΖ z z z "_c ona) +> U - w i — 1 fO <0 - · £ * cq cn a s a a x υ UU ΌΖΖΖΌΖΖΖ z z z "_c on

Cj p* Ηρ Ηρ Η* *ρ *p ►p *-p Hp ►p ►p p* p* m* k«* a·^Cj p * Ηρ Ηρ Η * * ρ * p ►p * -p Hp ►p ►p p * p * m * k «* a · ^

<N N (NJ rvj N N<N N (NJ rvj N N

Stap Hp *p Hp HM M* M *1* P* ο υ υ υ υ υ rJ Tf rf tp ^njovjovj^^fvlovi fJ N r) a a aa a^sEaaaa a a a 40 00 voUUU vOvoU u υ υ υStep Hp * p Hp HM M * M * 1 * P * ο υ υ υ υ υ rJ Tf rf tp ^ njovjovj ^^ fvlovi fJ N r) a a aa a ^ sEaaaa a a a 40 00 voUUU vOvoU u υ υ υ

U OU U ' 1 ' U U 1 1 IIIU OU U '1' U U 1 1 III

1 11 i m in m i i un in m m m n. cijCxj f14aaar1.rx.aa -a a a1 11 i m in m i i un in m m m n. CijCxj f14aaar1.rx.aa -a a a

1 11 |Ό>Ονθ7|ΌΟ vOxOnO1 11 | Ό> Ονθ7 | ΌΟ vOxOnO

rt **<* ^UUU^^UU uuu osj <* a R n a —Τ' u • s*~ a a ^ 0 a g V E υ jjT· υ , u Y*4 i· af1 Vo υ 3? x" v. „ J X x" u S u g -r O u =, s' υ To A V, 'omV R ή V-4 υ υ - ^^paa V 9 λ"\ = '* Γ X 10 £ S a 4^ R R °\9 R ^ =rt ** <* ^ UUU ^^ UU uuu osj <* a R n a —Τ 'u • s * ~ a a ^ 0 a g V E υ jjT · υ, u Y * 4 i · af1 Vo υ 3? x "v." JX x "u S ug -r O u =, s' υ To AV, 'omV R ή V-4 υ υ - ^^ paa V 9 λ" \ =' * Γ X 10 £ S a 4 ^ RR ° \ 9 R ^ =

^ .A y 1 i vo ^ /-N *1 <m a· u-t V" < *r* **« (J^ .A y 1 i vo ^ / -N * 1 <m a · u-t V "<* r * **« (J

on on u·0 ^ x 0 40 /^V " - , a a V t ' «0 g υ u C /> υ H 2 υ U tn ^ a S ' r' r' n 'Λon on u · 0 ^ x 0 40 / ^ V "-, a a V t '« 0 g υ u C /> υ H 2 υ U tn ^ a S' r 'r' n 'Λ

TV a ^ L JTV a ^ L J

___]_^ ^ υ υ E z xy ^_υ n Ό 35 DK 171841 B1 £ υ υ υ. υ ο υ c ······ g Ό Ο ro θ'" <—I U") Οι » . ^ ν > ν Ο η· —* t- CO Ο -ο (Μ m co m τι*___] _ ^ ^ υ υ E z xy ^ _υ n Ό 35 DK 171841 B1 £ υ υ υ. υ ο υ c ····· g Ό Ο ro θ '"<—I U") Οι ». ^ ν> ν Ο η · - * t- CO Ο -ο (Μ m co m τι *

^ ^ pH (\J^^ pH (\ J

<D<D

GG

WW

é o” o n>é o ”o n>

o _ Xo _ X

«+-Ι O«+ -Ι O.

*> 9-, <M-C? 1-1 <"* jr (0 « β O * " (/] tn ® <n , .*> 9-, <M-C? 1-1 <"* yr (0« β O * "(/] tn ® <n ,.

rt <ti rt · ' ro rort <ti rt · 'ro ro

0 Λ Λ Λ -* O O0 Λ Λ Λ - * O O

ii O 2 2ii O 2 2

ί * X Xί * X X

Q)Q)

1 N (Μ N1 N (Μ N

Cl) w (tf m_____Cl) w (tf m_____

X XX X

α z z z z u u roα z z z z z u u ro

«. X X S X X X'. X X S X X X

CJCJ

XX

oisland

(Μ (Μ IM N(Μ (Μ IM N

S X x jr; X <MS X x yr; X <M

(s] u υ u so o K(s) u υ u so o K

i i i n i Ui i i n i U

w m in m , mi X S X Cu X „r m ό ό i m ®w m in m, mi X S X Cu X „r m ό ό i m ®

U ϋ U O UU ϋ U O U

^1 ^NJ _^\1 N N N^ 1 ^ NJ _ ^ \ 1 N N N

X S XX S X

_u _u _u_u _u _u

CO T i VCO T i V

—, ϋ o u-, ϋ o u

(M ni III(M ni III

J S N N (MJ S N N (M

u ^ ^ ^ ' V -xxx X ο o '-O m j ϊ ϋ ϋ ϋ ►r _** ni ro ro rou ^ '^' V -xxx X ο o '-O m j ϊ ϋ ϋ ϋ ►r _ ** ni ro ro ro ro

il X Jil X J

O vO M ro ro ro i U Ci. i i iO vO M ro ro ro i U Ci. i i i

η . · Z Z Zη. · Z Z Z

£ tu οΓ O O Ό£ tu οΓ O O Ό

vO I l-M I I IvO I l-M I I I

_I U O to m ro_ 36 DK 171841 B1_I U O to m ro_ 36 DK 171841 B1

Eksempel 22Example 22

En blanding af 2,4 dele (2-bromethyl)benzen, 6 dele 5(6)fluor-l-(4-fluorphenylmethyl)-N-(4-piperidinyl)-lH-benzimidazol-2-amin dihydrobro-mid, 4 dele natriumcarbonat, 0,2 del kaliumiodid og 240 dele 4-methyl-2-5 pentanon omrøres og tilbagesvales natten over under anvendelse af en vandseparator. Reaktionsblandingen afkøles og hældes på koldt vand. Lagene udskilles, og den vandige fase ekstraheres tre gange med trichlor-methan. De kombinerede organiske faser tørres, filtreres og inddampes. Remanensen renses ved søjlechromatrografi over silicagel under anvendel-10 se af en blanding af trichlormethan og methanol (97:3 efter volumen) som eluent. De rene fraktioner samles, og eluenten inddampes. Remanensen fraskilles ved søjlechromatografi over silicagel under anvendelse af en blanding af ethylacetat og methanol (93:7 efter volumen) som eluent. Den første fraktion (A-isomer) samles, og eluenten inddampes. Remanensen 15 vaskes med en blanding af 2,2'-oxybispropan og petroleumsether og tørres, hvilket giver 1 del (17,5%) 6-fluor-l-(4-fluorphenylmethyl)-N-[l-(phenylethyl)-4-piperidinyl]-lH-benzimidazol-2-amin; smp. 178,1°C.A mixture of 2.4 parts (2-bromethyl) benzene, 6 parts 5 (6) fluoro-1- (4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 4 parts sodium carbonate, 0.2 parts potassium iodide and 240 parts 4-methyl-2-5 pentanone are stirred and refluxed overnight using a water separator. The reaction mixture is cooled and poured onto cold water. The layers are separated and the aqueous phase is extracted three times with trichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. The pure fractions are combined and the eluent is evaporated. The residue is separated by column chromatography over silica gel using a mixture of ethyl acetate and methanol (93: 7 by volume) as eluent. The first fraction (A isomer) is collected and the eluent is evaporated. The residue is washed with a mixture of 2,2'-oxybispropane and petroleum ether and dried to give 1 part (17.5%) of 6-fluoro-1- (4-fluorophenylmethyl) -N- [1- (phenylethyl) -4 piperidinyl] -LH-benzimidazol-2-amine; mp. 178.1 ° C.

Den anden fraktion (B-isomer) opsamles, og eluenten inddampes. Remanensen vaskes med en blanding af 2,2'-oxybispropan og petroleumsether 20 og tørres, hvilket giver 1,2 dele 5-fluor-l-(4-fluorphenylmethyl)-N-[l-(2-phenylethyl)-4-piperidinyl]-lH-benzimidazol-2-amin monohydrat; smp.The second fraction (B isomer) is collected and the eluent is evaporated. The residue is washed with a mixture of 2,2'-oxybispropane and petroleum ether 20 and dried to give 1.2 parts of 5-fluoro-1- (4-fluorophenylmethyl) -N- [1- (2-phenylethyl) -4-piperidinyl ] -1H-benzimidazole-2-amine monohydrate; mp.

188,8°C.188.8 ° C.

Eksempel 23 25 En blanding af 4 dele l-(3-chlorpropyl)-l,3-dihydro-3-(l-methyl- ethenyl)-2H-benzimidazol-2-on, 7 dele l-(phenylmethyl)-N-(4-piperidi-nyl)-lH-benzimidazol-2-amin dihydrobromid, 5 dele natriumcarbonat, 0,1 del kaliumiodid og 135 dele N,N-dimethyl formamid omrøres og opvarmes natten over ved 70°C. Reaktionsblandingen hældes i vand, og produktet 30 ekstraheres med methyl benzen. Ekstrakten tørres, filtreres og inddampes. Remanensen omdannes til hydrochloridsalt i 2-propanol. Efter omrøring i en time inddampes opløsningsmidlet, og remanensen optages i vand. Den frie base frigøres på konventionel måde med ammoniakhydroxid, og produktet ekstraheres med trichlormethan. Ekstrakten tørres, filtreres og ind-35 dampes. Remanensen krystalliseres fra ethanol. Produktet filtreres fra og tørres, hvilket giver 3,3 dele (45,7%) l,3-dihydro-l-[3-{4-[l-(phe- 37 DK 171841 B1 nylmethyl)-lH-benzimidazol-2-ylamino]-l-piperidinyl}propyl]-2H-benzimi-dazol-2-on; smp. 243,1°C.Example 23 A mixture of 4 parts of 1- (3-chloropropyl) -1,3-dihydro-3- (1-methyl-ethenyl) -2H-benzimidazol-2-one, 7 parts of 1- (phenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 5 parts sodium carbonate, 0.1 parts potassium iodide and 135 parts N, N-dimethyl formamide are stirred and heated overnight at 70 ° C. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in 2-propanol. After stirring for one hour, the solvent is evaporated and the residue is taken up in water. The free base is conventionally released with ammonia hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried to give 3.3 parts (45.7%) of 1,3-dihydro-1- [3- {4- [1- (phe-nylmethyl) -1H-benzimidazole-2 ylamino] -l-piperidinyl} propyl] -2H-benzimi-imidazole-2-one; mp. 243.1 ° C.

Ved at følge samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der fremstilles: 5 l-[3-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol -2-ylamino]-l-pipe-ridinyl}propyl]-l,3-dihydro-2H-benzimidazol-2-on; smp. 237,6°C.Following the same procedure and using equivalent amounts of the appropriate starting materials, it is possible to prepare: 1- [3- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-pipe ridinyl} propyl] -l, 3-dihydro-2H-benzimidazol-2-one; mp. 237.6 ° C.

l-[3-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-3-me-thyl-l-piperidinyl}propyl]-l,3-dihydro-2H-benzimidazol-2-on dihydrochlo-10 rid. 2-propanolat; smp. 244,1°C, l-[3-{4-[3-(fluorphenylmethyl)-3H-imidazo[4,5-b]pyridin-2-ylamino]- l-piperidinyl}propyl]-l,3-dihydro-2H-benzimidazol-2-on; smp. 202,4°C, 1.3- dihydro-1-{3-[4-(1-phenyl-lH-benzimidazol-2-ylamino]-l-piperi-dinyl]propyl}-2H-benzimidazol-2-on; smp.l85,3°C.L- [3- {4- [L- (4-fluorophenylmethyl) benzimidazole-2-ylamino] -3-me-thyl-l-piperidinyl} propyl] -l, 3-dihydro-2H-benzimidazol-2 -on dihydrochloride. 2-propanolate; mp. 244.1 ° C, 1- [3- {4- [3- (fluorophenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinyl} propyl] -1,3-dihydro -2H-benzimidazol-2-one; mp. 202.4 ° C, 1,3-dihydro-1- {3- [4- (1-phenyl-1H-benzimidazol-2-ylamino] -1-piperidinyl] propyl} -2H-benzimidazol-2-one; .l85,3 ° C.

15 l-[3-{4-[l-(4-fluorphenyl)-lH-benzimidazol-2-ylamino]-l-piperidin-yl]propyl}-2H-benzimidazol-2-on; smp. 188,9°C og 1.3- dihydro-1-[3-(4-[3-(phenylmethyl)-3H-imidazo[4,5-b]pyridin-2-ylami no]-1-piperidinyl}-propyl]-2H-benzimidazol-2-on; smp. 221,7°C.1- [3- {4- [1- (4-fluorophenyl) -1H-benzimidazol-2-ylamino] -1-piperidin-yl] propyl} -2H-benzimidazol-2-one; mp. 188.9 ° C and 1,3-dihydro-1- [3- (4- [3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinyl} propyl] -2H-benzimidazol-2-one, mp 221.7 ° C.

20 Eksempel 24Example 24

En blanding af 2,3 dele 2-(4-methoxyphenylJethylmethansulfonat, 4,9 dele l-[(4-fluorphenyl)methyl]-N-(4-piperidinyl)-lH-benzimidazol-2-amin dihydrobromid, 3,2 dele natriumcarbonat, 0,1 del kaliumiodid og 90 dele Ν,Ν-dimethylformamid omrøres natten over ved 70°C. Reaktionsblandingen 25 hældes på vand. Produktet ekstraheres med methyl benzen. Ekstrakten vaskes med vand, tørres, filtreres og inddampes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner samles, og eluenten inddampes. Remanensen krystalliseres fra 2,2'-oxybispropan, 30 hvilket giver 2,2 dele (48%) l-(4-fluorphenylmethyl)-N-(l-[2-(4-methoxy-phenyl)ethyl]-4-piperidinyl)-lH-benzimidazol-2-amin; smp. 172,9°C.A mixture of 2.3 parts of 2- (4-methoxyphenylethylmethanesulfonate, 4.9 parts of 1 - [(4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 3.2 parts Sodium carbonate, 0.1 part potassium iodide and 90 parts Ν, Ν-dimethylformamide are stirred overnight at 70 ° C. The reaction mixture is poured onto water. The product is extracted with methyl benzene. The extract is washed with water, dried, filtered and evaporated. over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are combined and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane to give 2.2 parts (48%) of (4-fluorophenylmethyl) -N- (1- [2- (4-methoxy-phenyl) ethyl] -4-piperidinyl) -1H-benzimidazol-2-amine; mp 172.9 ° C.

Eksempel 25Example 25

Ved at følge fremgangsmåden i eksempel 24 og under anvendelse af 35 ækvivalente mængder af de passende udgangsmaterialer kan der opnås følgende blandinger på fri baseform eller i form af et syreadditionssalt 38 DK 171841 B1 efter omsætning af den frie base med en passende syre.Following the procedure of Example 24 and using 35 equivalent amounts of the appropriate starting materials, the following mixtures can be obtained in free base form or in the form of an acid addition salt after reacting the free base with a suitable acid.

RR

at71-(chu-fyimJ 'T)] * \_/ 'N^'Q> i2 2 Base- él- smelte-at71- (chu-fyimJ 'T)] * \ _ /' N ^ 'Q> i2 2 Base-el-melt

Aryl R R Q ler sait_ punkt ___,____;__-forju__ 3.4- (CH30) -C6H3 H 4-F-C6H4-CH2 CH base 69,3*C .Aryl R R Q clay sait_ point ___, ____; __- forju__ 3.4- (CH30) -C6H3 H 4-F-C6H4-CH2 CH base 69.3 * C.

E,5-(CH30)2-C6H3 H 4-F-C6H4-CH2 CH base 127, 9*CE, 5- (CH30) 2-C6H3 H 4-F-C6H4-CH2 CH base 127.9 ° C

4-(C-,H_0)-C,H. H 4-F-C,H -CH, CH base 152,3*C4- (C, H_0) C, H. H 4-F-C, H -CH, CH base 152.3 * C

4-(CH30)-C6H4 H 4-F-C6H4-CH2 N base 149,1*C4- (CH30) -C6H4 H 4-F-C6H4-CH2 N base 149.1 ° C

3- (CHlO)-C,H H 4-F-C,H -CH, CH 2HC1.1/2 242,4*C3- (CH10) -C, H H 4-F-C, H -CH, CH 2HC1.1 / 2 242.4 * C

3 64 ___ . 6 4 2 H^Q3 64 ___. 6 4 2 H ^ Q

2- (CH30)-C6H4 H 4-F-C6H4-CH2 CH base 153, 1*C2- (CH30) -C6H4 H 4-F-C6H4-CH2 CH base 153, 1 * C

4- (CH,0)-C, H. CH, 4-F-C,H -CH, CH 2HC1 184, 0eC4- (CH, O) -C, H. CH, 4-F-C, H -CH, CH 2HC1 184, 0eC

3 6 4 3 6 4 2 [cis+trans- isomer)3 6 4 3 6 4 2 [cis + trans isomer)

3.4*5-(CH,0),-C,H, H 4-F-C,H.-CH, CH 2HC1.1/2 260,2*C3.4 * 5- (CH, O), - C, H, H 4-F-C, H-CH, CH 2HC1.1 / 2 260.2 * C

3 3 6 2 6 4 ώ H203 3 6 2 6 4 ώ H20

3.4- (CH30)2-C6H3 H ’ C6H5-CH2 CH base 149, 8‘C3.4- (CH30) 2-C6H3 H 'C6H5-CH2 CH base 149, 8 ° C

4.(CH O)-C,H CH3 C6H5-CH2 CH ZHCLHjO 198, 4*C4. (CHO) -C, H CH3 C6H5-CH2 CH ZHCLH2O 198, 4 * C

^ 0 * (cis+txans- isomer)(0 cis + txans isomer)

3- (CH30)-C6H4 H C6H5-CH2 CH base 128, 6eC3- (CH30) -C6H4 H C6H5-CH2 CH base 128, 6 ° C

4- (C2H.O)-C6H4 H C6H5-CH2 CH base 128, 5*C4- (C2H.O) -C6H4H C6H5-CH2 CH base 128, 5 ° C

2- (CH„0)-C,H. . H C,H -CH, CH 2HC1. 186, 1*C2- (CH2 O) -C, H. . H C, H -CH, CH 2 HCl. 186, 1 ° C

3.64 65 2 2H^03.64 65 2 2H ^ 0

3- (CH3)-C6H4 H C6H5-CH2 CH 2HC1.H20 235, 7*C3- (CH3) -C6H4 H C6H5-CH2 CH 2HC1.H2O 235.7 ° C

4- (CH30)-C6H4 H C6H5-CH2 CH 2HC1.H20 274, 7*C4- (CH30) -C6H4 H C6H5-CH2 CH 2HC1.H20 274, 7 * C

4-Cl-C6H4 H C6H5-CH2 CH base 183, 9*C4-Cl-C6H4 H C6H5-CH2 CH base 183, 9 ° C

3,4,5-(CH30)3-C6H2 H C6H5-CH2 CH base 156, 6*C3,4,5- (CH30) 3-C6H2 H C6H5-CH2 CH base 156,6 ° C

4-(<^HCI^O)-C6H4 H 4-F-C6H4-CH2 CH base 155, 4*C4 - (<3 HCl 2 O) -C6H4 H 4-F-C6H4-CH2 CH base 155, 4 * C

4-CH30-C6H4 H C6H5 CH base 157, 8eC4-CH30-C6H4 H C6H5 CH base 157, 8 ° C

4-CH30-C6H4 H 4-F-C6H4 CH base 167, 4eC4-CH30-C6H4 H 4-F-C6H4 CH base 167, 4eC

4:-CH30-C6H4 H 4-NOz-C6H4-CH2 CH base 200, leC4: -CH30-C6H4H 4-NO2-C6H4-CH2 CH base 200, leC

39 DK 171841 B139 DK 171841 B1

Aryl R R2 Q ?Jreia!t: Smelte- _________(lim PunktAryl R R2 Q? Jreia! T: Melt _________ (glue point

5 2,4-(CH,0),-C,H- H 4-F-C.H.-CH, CH 2 HC1 190 4‘C2,4- (CH, O), - C, H- H 4-F-C.H.-CH, CH 2 HCl 190 4 ° C

.. 3 2 6 3 · 6 4 2 .1/2H20.. 3 2 6 3 · 6 4 2 .1 / 2H20

4-CH-O-C/Η. H 4-F-2-CH,- CH 2 HBr 264,8*C4-CH-O-C / Η. H 4-F-2-CH, - CH 2 HBr 264.8 ° C

3 6 4 3 · c6h3-ch23 6 4 3 · c6h3-ch2

10 4-CH30-C6H4 H C6Hs-CH2 N base 124,1*C4-CH30-C6H4 H C6H5-CH2 N base 124.1 ° C

3-CH3-4-3-CH3-4-

(C6H5-CH2-0)-C6H3 H 4-F-C6H4-CH2 CH base 145,6'C(C6H5-CH2-O) -C6H3 H 4-F-C6H4-CH2 CH base 145.6 ° C

15 H CH 2HC1* 264,6'C15 H CH 2 HCl * 264.6 ° C

20 Eksempel 26Example 26

En blanding af 2,8 dele [2-(2-thienyl)ethyl]-4-methylbenzensul fonat, 4,9 dele l-[4-fluorphenyl)methyl]-N-(4-piperidinyl)-lH-benzimida-zol-2-amin dihydrobromid, 2,1 dele natriumcarbonat, 0,1 del kaliumiodid og 90 dele N,N-dimethyl formamid omrøres natten over ved 70°C. Reaktions-25 blandingen afkøles og hal des på vand. Produktet ekstraheres med methyl-benzen. Ekstrakten tørres, filtreres og inddampes. Remanensen renses ved søjlechromatografi over silicagel ved anvendelse af en blanding trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen krystalliseres 30 fra 2-propanol. Produktet filtreres fra og tørres, hvilket giver 2,3 dele (53%) l-(4-fluorphenylmethyl)-N-{l-[2-(2-thienyl)ethyl]-4-piperidin-yl)-lH-benzimidazol-2-amin; smp. 151,6°C.A mixture of 2.8 parts of [2- (2-thienyl) ethyl] -4-methylbenzenesulfonate, 4.9 parts of 1- [4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benzimidazole -2-amine dihydrobromide, 2.1 parts sodium carbonate, 0.1 parts potassium iodide and 90 parts N, N-dimethyl formamide are stirred overnight at 70 ° C. The reaction mixture is cooled and poured onto water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried to give 2.3 parts (53%) of 1- (4-fluorophenylmethyl) -N- {1- [2- (2-thienyl) ethyl] -4-piperidin-yl) -1H-benzimidazole -2-amine; mp. 151.6 ° C.

Ved at følge den samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der fremstilles: 35 l-(phenylmethyl)-N-{l-[2-(2-thienyl)ethyl]-4-piperidinyl}-lH-benz- 40 DK 171841 B1 imidazol-2-amin dihydrochlorid monohydrat; snip.259 273°C, l-(4-fluorphenylmethyl)-N-{l-[2-(1-napthaienyl)ethyl]-4-piperidin-yl}-lH-benzimidazol-2-amin; smp. 143,1°C, og 3-(4-fluorphenylmethyl)-N-{1-[2-(2-thienyl)ethyl]-4-piperidinyl}-5 3H-imidazo[4,5-b]pyridin-2-amin; smp.l76,2°C.Following the same procedure and using equivalent amounts of the appropriate starting materials, it is possible to prepare: 1- (phenylmethyl) -N- {1- [2- (2-thienyl) ethyl] -4-piperidinyl} -1H- benzimidazole-2-amine dihydrochloride monohydrate; snip.259 273 ° C, 1- (4-fluorophenylmethyl) -N- {1- [2- (1-napthienyl) ethyl] -4-piperidin-yl} -1H-benzimidazol-2-amine; mp. 143.1 ° C and 3- (4-fluorophenylmethyl) -N- {1- [2- (2-thienyl) ethyl] -4-piperidinyl} -5H-imidazo [4,5-b] pyridin-2 amine; smp.l76,2 ° C.

Eksempel 27Example 27

En blanding af 2,1 dele 2-(ethenylJpyridin, 3,25 dele 1-[(4-fluorphenylJmethyl]-N-(4-piperidinyl)-lH-benzimidazol-2-amin og 80 dele 10 1-butanol omrøres og tilbagesvales natten over. Reaktionsblandingen inddampes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af en blanding af trichlormethan og methanol (97:3 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen krystalliseres fra 2,2,-oxybispropan, hvilket giver 1 del 15 (23%) 1-[(4-fluorphenyl)methyl)-N-{l-[2-(2-pyridi nyl)ethyl]-4-piperidin- yl}-lH-benzimidazol-2-amin; smp. 133,4°C.A mixture of 2.1 parts of 2- (ethenylpyridine, 3.25 parts of 1 - [(4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine and 80 parts of 10-butanol is stirred and refluxed The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as the eluent. The pure fractions are collected and the eluent is evaporated. to give 1 part 15 (23%) of 1 - [(4-fluorophenyl) methyl) -N- {1- [2- (2-pyridinyl) ethyl] -4-piperidinyl} -1H-benzimidazole-2 amine, mp 133.4 ° C.

Ved at følge den samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der også fremstilles: 20 4-[1-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-1-piperidin- propannitril; smp. 166,5°C, 1-(4-fluorphenylmethyl)-Ν-{1-[-[2-(4-pyridi nyl)ethyl]-4-pi peridi n-yl}-lH-benzimidazol-2-amin; smp. 158,2°C, og 3-(4-fluorphenylmethyl)-N-(l-[2-(2-pyridinyl) ethyl]-4-piperidinyl)-25 3H-imidazo[4,5-b]pyridin-2-amin; smp. 157,2°C.Following the same procedure and using equivalent amounts of the appropriate starting materials, it is also possible to prepare: 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidine-propannitrile; mp. 166.5 ° C, 1- (4-fluorophenylmethyl) -Ν- {1 - [- [2- (4-pyridinyl) ethyl] -4-piperidin-1-yl} -1H-benzimidazol-2-amine; mp. 158.2 ° C and 3- (4-fluorophenylmethyl) -N- (1- [2- (2-pyridinyl) ethyl] -4-piperidinyl) -3H-imidazo [4,5-b] pyridine-2 amine; mp. 157.2 ° C.

Eksempel 28Example 28

Til 3,96 dele l-(4-fluorbenzoyl)aziridin, opløst i 16 dele benzen, sættes 3,25 dele af l-[(4-fluorphenyl)methyl]-N-(4-piperidinyl)-lH-benz-30 imidazol-2-amin, 90 dele benzen og 45 dele N,N-dimethyl formamid. Det hele røres og tilbagesvales i 5 timer. Reaktionsblandingen afkøles og hældes på vand. Lagene fraskilles, og den vandige fase ekstraheres med methyl benzen. De kombinerede faser tørres, filtreres og inddampes. Remanensen krystalliseres fra en blanding af 2-propanon og 2,2'-oxybispro-35 pan, hvilket giver 1 del (19%) 4-fluor-N-[2-(4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-1-piperidinyl)ethyl]benzamid; smp. 193,7°C.To 3.96 parts of 1- (4-fluorobenzoyl) aziridine, dissolved in 16 parts of benzene, are added 3.25 parts of 1 - [(4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benz-30 imidazole-2-amine, 90 parts of benzene and 45 parts of N, N-dimethyl formamide. It is all stirred and refluxed for 5 hours. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with methyl benzene. The combined phases are dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 1 part (19%) of 4-fluoro-N- [2- (4- [1- (4-fluorophenylmethyl) -1H) benzimidazole-2-ylamino] -1-piperidinyl) ethyl] benzamide; mp. 193.7 ° C.

41 DK 171841 B141 DK 171841 B1

Med udgang fra 3-(phenylmethyl)-N-(4-piperidinyl)-3H-imidazo[4,5- b]pyridin-2-amin og under anvendelse af samme fremgangsmåde kan der også fremstilles: 5 4-fluor-N-[2-{4-[3-(phenyl methyl)-3H-imidazo[4,5-b]pyridin-2-ylami- no]-l-piperidinyl}ethyl]benzamid; smp. 187,5°C.Starting from 3- (phenylmethyl) -N- (4-piperidinyl) -3H-imidazo [4,5- b] pyridin-2-amine and using the same process, 4-fluoro-N- [2- {4- [3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinyl} ethyl] benzamide; mp. 187.5 ° C.

Eksempel 29Example 29

En blanding af 3,6 dele [(4-methoxyphenoxy)methyl]oxiran, 4,9 dele 10 l-[(4-fluorphenylJmethyl]-N-(4-piperidinyl)-lH-benzimidazol-2-amin dihy-drobromid, 2,1 dele natriumcarbonat, 40 dele methanol og 90 dele benzen omrøres og tilbagesvales natten over. Reaktionsblandingen filtreres, og filtratet inddampes. Remanensen krystalliseres fra en blanding af 2-pro-panon og 2,2'-oxybispropan. Produktet filtreres fra og tørres, hvilket 15 giver 2,6 dele (51%) 4-[l-(4-fluorphenylmethyl)-lHbenzimidazol-2-ylami-no]-a-(4-methoxyphenoxymethyl)-l-piperidinethanol; smp. 174,5°C.A mixture of 3.6 parts of [(4-methoxyphenoxy) methyl] oxirane, 4.9 parts of 10 - [(4-fluorophenyl) methyl] -N- (4-piperidinyl) -1H-benzimidazole-2-amine dihydrobromide, 2.1 parts of sodium carbonate, 40 parts of methanol and 90 parts of benzene are stirred and refluxed overnight, the reaction mixture is filtered and the filtrate is evaporated, the residue is crystallized from a mixture of 2-propane and 2,2'-oxybispropane. The product is filtered off and dried to give 2.6 parts (51%) of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -a- (4-methoxyphenoxymethyl) -1-piperidinethanol; mp 174.5 ° C.

Eksempel 30Example 30

Ved at følge fremgangsmåden i eksempel 29 og under anvendelse af 20 ækvivalente mængder af de passende udgangsmaterialer kan der også fremstilles: a-(phenoxymethyl)-4-{[l-(phenylmethyl)-lH-benzimidazol-2-yl]amino}- 1-piperidinethanol; smp. 146,6°C, 25 4-[l-(4-fl uorphenylmethyl)-lH-benzimidazol-2-ylamino]-tt-(phenoxyme- thyl)-1-piperidinethanol; smp. 181,3°C, 4-[1-(4-f1 uorphenylmethyl)-lH-benzimidazol-2-ylamino]-3-methyl-ar-(phenoxymethyl)-l-piperidinethanol dihydrochlorid monohydrat; smp.Following the procedure of Example 29 and using 20 equivalent amounts of the appropriate starting materials, it is also possible to prepare: α- (phenoxymethyl) -4 - {[1- (phenylmethyl) -1H-benzimidazol-2-yl] amino} - 1-piperidineethanol; mp. 146.6 ° C, 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -t- (phenoxymethyl) -1-piperidinethanol; mp. 181.3 ° C, 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -3-methyl-ar- (phenoxymethyl) -1-piperidinethanol dihydrochloride monohydrate; mp.

163,3 °C, 30 or-(4-methoxyphenoxymethyl)-4-[l-(phenylmethyl)-lH-benzimidazol-2- ylamino]-l-piperidinethanol; smp. 162,7°C, a-(2-butoxyphenoxymethyl)-4-[1-(4-f1uorphenyl methyl)-lH-benzimida-zol-2-ylamino]-l-piperidinethanol; smp. 138,7°C, a-(2,6-dimethoxyphenoxymethyl)-4-[(4-fl uorphenylmethyl)-lHbenzimi-35 dazol-2-ylamino]-l-piperidinethanol; smp. 140°C, 4-[1-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-α-(2methoxy- 42 DK 171841 B1 phenoxymethyl)-l-piperidinethanol; smp. 174°C, l-{4-[3-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol -2-ylamino]-l-piperidinyl}-2-hydroxypropoxy]phenyl}ethanon; smp. 174,7°C, a-(2,6-dimethoxyphenoxymethyl)-4-[1 -(phenyl methyl)-ΙΗ-benzimidazol-5 2-ylamino]-l-piperidinethanol; smp. 122,2°C, 4-[l-(4-fluorphennylmethyl)-lH-benzimidazol-2-ylamino]-a-phenyl-1-piperidinethanol; smp. 184,1°C og a-(phenoxymethy1)-4-[3-(phenyl methyl)-3H-imidazo[4,5-b]pyri din-2-ylamino]-l-piperidinethanol; smp. 136,6°C.163.3 ° C, or- (4-methoxyphenoxymethyl) -4- [1- (phenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol; mp. 162.7 ° C, α- (2-butoxyphenoxymethyl) -4- [1- (4-fluorophenyl methyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol; mp. 138.7 ° C, α- (2,6-dimethoxyphenoxymethyl) -4 - [(4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol; mp. 140 ° C, 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -α- (2methoxy-phenoxymethyl) -1-piperidinethanol; mp. 174 ° C, 1- {4- [3- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} -2-hydroxypropoxy] phenyl} ethanone; mp. 174.7 ° C, α- (2,6-dimethoxyphenoxymethyl) -4- [1- (phenylmethyl) -ΙΗ-benzimidazol-2-ylamino] -1-piperidinethanol; mp. 122.2 ° C, 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -α-phenyl-1-piperidinethanol; mp. 184.1 ° C and α- (phenoxymethyl) -4- [3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-ylamino] -1-piperidinethanol; mp. 136.6 ° C.

1010

Eksempel 31Example 31

Til en omrørt blanding af 40,4 dele l-(4-fluorphenylmethyl)-N-(4-piperidinyl)-lH-benzimidazol-2-amin hydrobromid og 400 dele methanol sættes 8,8 dele oxiran, og omrøringen fortsættes natten over ved stue-15 temperatur. Reaktionsblandingen inddampes, og remanensen optages i vand.To a stirred mixture of 40.4 parts of 1- (4-fluorophenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine hydrobromide and 400 parts of methanol is added 8.8 parts of oxirane and stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is taken up in water.

Det bundfældede produkt filtreres fra og tørres, hvilket giver 29 dele (64%) 4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-l-piperidin-ethanol monohydrobromid; smp. 248.2°C.The precipitated product is filtered off and dried to give 29 parts (64%) of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidine-ethanol monohydrobromide; mp. 248.2 ° C.

20 Eksempel 32Example 32

Til 1 del opløsning af 2 dele thiophen i 40 dele ethanol sættes 1,5 dele formaldehydopløsning 37%, 3 dele l-(phenylmethyl)-N-(4-piperidin-yl)-lH-benzimidazol-2-amin og 120 dele methanol. Det hele hydrogeneres ved normalt tryk og ved stuetemperatur med to dele palladium-på-trækul 25 katalysator 10%. Efter at den beregnede mængde hydrogen er optaget, fra-filtreres katalysatoren over Hyflo, og filtratet inddampes. Remanensen optages i vand, og det hele al kali seres med ammoniumhydroxid. Produktet ekstraheres med dichlormethan. Ekstrakten tørres, filtreres og inddampes. Remanensen konverteres til hydrochloridsalt i 2-propanol. Saltet 30 frafiltreres og tørres, hvilket giver 1,5 dele (36,6%) N-(l-methyl-4-pi-peridinyl)-1-(phenylmethyl)-lHbenzimidazol-2-amin dihydrochlorid monohydrat; smp. 191,1°C.To 1 part solution of 2 parts thiophene in 40 parts ethanol is added 1.5 parts formaldehyde solution 37%, 3 parts 1- (phenylmethyl) -N- (4-piperidin-yl) -1H-benzimidazole-2-amine and 120 parts methanol . It is all hydrogenated at normal pressure and at room temperature with two parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over Hyflo and the filtrate is evaporated. The residue is taken up in water and the whole is potassized with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 1.5 parts (36.6%) of N- (1-methyl-4-piperidinyl) -1- (phenylmethyl) -1H-benzimidazole-2-amine dihydrochloride monohydrate; mp. 191.1 ° C.

Ved at følge den samme fremgangsmåde og under anvendelse af ækvivalente mængder af passende udgangsmaterialer kan der også fremstilles: 35 43 DK 171841 B1 l-(4-fluorphenylmethyl)-N-(1-methyl-4-piperidinyl)-lH-benzimidazol- 2-amin; smp. 145,5°C, N-(1-cyclohexyl-4-piperidinyl)-l-(4-fluorphenylmethyl)-lHbenzimida-zol-2-amin; smp. 168°C, 5 1-(4-fluorphenyl methyl)-N-[1 -(1-methyl-2-phenyl ethyl)-4-piperidin- yl]-lH-benzimidazol-2-amin; smp. 182,4°C, 1-methyl-N-(1-methyl-4-pipen dinyl)-lH-benzimidazol-2-amin dihydro-chlorid dihydrat; smp. 300,6°C, 1-ethyl-N-[1-methylethyl)-4-piperidinyl]-lH-benzimidazol-2-amin; 10 smp. 156,6°C.Following the same procedure and using equivalent amounts of suitable starting materials, it is also possible to prepare: 1- (4-fluorophenylmethyl) -N- (1-methyl-4-piperidinyl) -1H-benzimidazole-2 amine; mp. 145.5 ° C, N- (1-cyclohexyl-4-piperidinyl) -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine; mp. 168 ° C, 1- (4-fluorophenyl methyl) -N- [1- (1-methyl-2-phenylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 182.4 ° C, 1-methyl-N- (1-methyl-4-piperidinyl) -1H-benzimidazole-2-amine dihydrochloride dihydrate; mp. 300.6 ° C, 1-ethyl-N- [1-methylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; 10 m.p. 156.6 ° C.

N-(1-methyl-4-piperidinyl)-l-phenyl-lH-benzimidazol- 2-amin; smp.N- (1-methyl-4-piperidinyl) -1-phenyl-1H-benzimidazol-2-amine; mp.

128,5°C.128.5 ° C.

3-(4-fluorphenylmethyl)-N-(1-methyl-4-piperidinyl)-3H-imidazo[4,5- b]pyridin-2-amin; smp. 153,4°C og 15 N-(1-methyl-4-piperidinyl)-3-(phenylmethyl)-3H-imidazo[4,5-b]- pyridin-2-amin; smp. 141,4°C.3- (4-fluorophenylmethyl) -N- (1-methyl-4-piperidinyl) -3H-imidazo [4,5- b] pyridin-2-amine; mp. 153.4 ° C and N- (1-methyl-4-piperidinyl) -3- (phenylmethyl) -3H-imidazo [4,5-b] pyridin-2-amine; mp. 141.4 ° C.

Eksempel 33Example 33

Til 1 del opløsning af 2 dele thiophen i 40 dele ethanol sættes 2 20 dele cyclohexanon, 3 dele l-(phenylmethyl)-N-(4-piperidinyl)-lH-benzimi-dazol-2-amin, 1 del eddikesyre og 120 dele methanol. Det hele hydrogeneres ved normalt tryk og ved stuetemperatur med 2 dele palladium-på-trækul katalysator 10%. Efter optagning af den beregnede mængde hydrogen frafiltreres katalysatoren over Hyflo, og filtratet inddampes. Remanen-25 sen optages i vand, og det hele alkaliseres med natriumhydroxid. Produktet ekstraheres med tetrahydrofuran. Ekstrakten tørres, filtreres og inddampes. Remanensen krystalliseres fra en blanding af 2,2'-oxybispro-pan og 2-propanol, hvilket giver 1,5 dele (38,5%) N-(l-cyclohexyl-4-pi-peridinyl)-1-(phenylmethyl)-lH-benzimidazol-2-amin; smp. 143°C.To 1 part solution of 2 parts thiophene in 40 parts ethanol are added 2 20 parts cyclohexanone, 3 parts 1- (phenylmethyl) -N- (4-piperidinyl) -1H-benzimidazole-2-amine, 1 part acetic acid and 120 parts methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off over Hyflo and the filtrate is evaporated. The residue is taken up in water and the whole is alkalized with sodium hydroxide. The product is extracted with tetrahydrofuran. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol to give 1.5 parts (38.5%) of N- (1-cyclohexyl-4-piperidinyl) -1- (phenylmethyl) -LH-benzimidazol-2-amine; mp. 143 ° C.

30 Ved at følge den samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der også fremstilles: 1-phenyl-4-{4-[1-(phenyl methyl)-ΙΗ-benzimidazol-2-ylami no]-1-piperidinyl}cyclohexancarbonitril; smp. 106-107°C, 35 4-{4-[l-(4-fluorphenylmethylJ-lH-benzimidazol-2-ylamino]-1- piperidinyl)-l-phenylcyclohexancarbonitril dihydrochlorid; smp. 275°C, DK 171841 Bl 44 l-[3-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-1-pipe-ridinyl}butyl]-l,3-dihydro-2H-benzimidazol-2-on; smp. 234,°C, N-(l-cyclohexyl-4-piperidinyl)-3-(phenylmethyl)-3H-imidazo[4,5- b]pyridin-2-amin; smp. 129,2°C, 5 N-[1-(1-methyl ethyl)-4-pi peridi nyl]-3-(phenylmethyl)-3H-imidazo- [4,5-b]pyridin-2-amin; smp. 136,4°C og 1-(4-fluorphenylmethyl)-N-[l-(2-[(phenylmethyl)amino]ethyl}4-pipe-ridin]-lH-benzimidazol-2-amin; smp.135,6°C.Following the same procedure and using equivalent amounts of the appropriate starting materials, it is also possible to prepare: 1-phenyl-4- {4- [1- (phenyl methyl) -ol-benzimidazol-2-ylamino] -1 piperidinyl} cyclohexanecarbonitrile; mp. 106-107 ° C, 4- {4- [1- (4-fluorophenylmethyl] -1H-benzimidazol-2-ylamino] -1-piperidinyl) -1-phenylcyclohexanecarbonitrile dihydrochloride; mp. 275 ° C, DK 171841 B1 44 1- [3- {4- [1- (4-Fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} butyl] -1,3-dihydro-2H benzimidazole-2-one; mp. 234 ° C, N- (1-cyclohexyl-4-piperidinyl) -3- (phenylmethyl) -3H-imidazo [4,5- b] pyridin-2-amine; mp. 129.2 ° C, 5 N- [1- (1-methylethyl) -4-piperidinyl] -3- (phenylmethyl) -3H-imidazo- [4,5-b] pyridin-2-amine; mp. 136.4 ° C and 1- (4-fluorophenylmethyl) -N- [1- (2 - [(phenylmethyl) amino] ethyl) 4-piperidine] -1H-benzimidazol-2-amine; ° C.

10 Eksempel 34Example 34

En blanding af 39,8 dele N-(Z-aminophenyl)-N'-ethyl-N'-[l-(2-phenylethyl)-4-pi peri di nyl]thiourinstof, 15 dele mercurioxid, 0,1 del svovl og 400 dele methanol omrøres og tilbagesvales natten over. Reaktionsblandingen filtreres varmt over Hyflo, og filtratet inddampes. Re- 15 manensen krystalliseres fra 4-methyl-2-pentanon. Produktet filtreres fra og tørres, hvilket giver 14,5 dele (43%) N-ethyl-N-[l-(2-phenylethyl)-4-piperidinyl]-lH-benzimidazol-2-amin; smp. 204,9°C.A mixture of 39.8 parts of N- (Z-aminophenyl) -N'-ethyl-N '- [1- (2-phenylethyl) -4-piperidinyl] thiourea, 15 parts of mercuric oxide, 0.1 part of sulfur and 400 parts of methanol are stirred and refluxed overnight. The reaction mixture is filtered hot over Hyflo and the filtrate is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried to give 14.5 parts (43%) of N-ethyl-N- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 204.9 ° C.

Ved at følge den samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der også fremstilles: 20 N-[1-(2-phenyl ethyl)-4-piperidinyl]-N-propyl-lH-benzimidazol-2- amin, N-(l-methyl ethyl)-N-[1-(2-phenyl ethyl)-4-piperi dinyl]-lH-benzimida-zol-2-amin; smp. 228,4°C, 25 N-cyclopropyl-N-[1 -(2-phenyl ethyl)-4-piperi dinyl]-lH-benzimidazol- 2-amin; smp. 193,5°C, N-[l-(2-phenyl ethyl)-4-piperidinyl]-N-(phenyl methyl)-lH-benzimida-zol-2-amin; smp. 191,5°C.Following the same procedure and using equivalent amounts of the appropriate starting materials, 20 N- [1- (2-phenyl ethyl) -4-piperidinyl] -N-propyl-1H-benzimidazole-2-amine can also be prepared. , N- (1-methylethyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 228.4 ° C, N-cyclopropyl-N- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 193.5 ° C, N- [1- (2-phenyl ethyl) -4-piperidinyl] -N- (phenyl methyl) -1H-benzimidazol-2-amine; mp. 191.5 ° C.

30 Eksempel 35Example 35

Til en omrørt og afkølet blanding (under 5°C) af 3,3 dele N-methyl-[l-(2-phenylethyl)-4-piperidinyl]-lH-benzimidazol-2-amin, 100 dele dime-thylsulfoxid og 90 dele benzen sættes 0,5 del natriumhydriddispersion 50%. Efter omrøring i 30 minutter tilsættes 1,5 dele l-(chlormethyl)-4- 35 fluor-benzen, og omrøringen fortsættes natten over, medens blandingen tillades at opnå stuetemperatur. Reaktionsblandingen hældes i vand, og 45 DK 171841 B1 produktet ekstraheres med methyl benzen. Ekstrakten tørres, filtreres og inddampes. Remanensen konverteres til hydrochloridsalt i 2-propanon.To a stirred and cooled mixture (below 5 ° C) of 3.3 parts of N-methyl- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazole-2-amine, 100 parts of dimethylsulfoxide and 90 part of benzene is added 0.5 part of sodium hydride dispersion 50%. After stirring for 30 minutes, 1.5 parts of 1- (chloromethyl) -4- 35 fluorobenzene are added and stirring is continued overnight while allowing the mixture to reach room temperature. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in 2-propanone.

Saltet filtreres fra og krystalliseres fra 2-propanol, hvilket giver 2,8 dele (54,4%) l-[(4-fluorphenyl)methyl]-N-methyl-N-[l-(2-phenylethyl)-4-5 piperidinyl]-lHbenzimidazol-2-amin dihydrochlorid; smp. 246,6°C.The salt is filtered off and crystallized from 2-propanol to give 2.8 parts (54.4%) of 1 - [(4-fluorophenyl) methyl] -N-methyl-N- [1- (2-phenylethyl) -4- 5-piperidinyl] -1H-benzimidazole-2-amine dihydrochloride; mp. 246.6 ° C.

Ved at følge samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der også fremstilles: l-[(4-chlorphenyl)methyl]-N-[l-(2-phenylethyl)-4-pi peridi nyl]-N-10 (phenylmethyl)-lH-benzimidazol-2-amin; smp. 138°C, l-[(2-methoxyphenyl)methyl]-N-[l-(2-phenylethyl)-4-piperidinyl]-N-(phenylmethyl)-lH-benzimidazol-2-amin; smp. 148,3°C, l-[(4-methoxyphenyl)methyl3-N-[1-(2-phenyl ethyl)-4-piperidinyl]-N-(phenylmethyl)-lH-benzimidazol-2-amin; smp. 122,4°C, 15 l-[(4-fluorphenylJmethyl]-N-[1- (2-phenyl ethyl)-4-pi peridi nyl]-N- (phenylmethyl)-lH-benzimidazol-2-amin; smp. 108,5°C, 1-(4-bromphenylmethyl)-N-[1-(2-phenyl ethyl)-4-piperidinyl]-N-(phenylmethyl)-lH-benzimidazol-2-amin; smp. 139,3°C, 1 -[(4-methyl phenyl)methyl]-N-[l-(2-phenyl ethyl)-4-p iperidinyl]-N-20 (phenylmethyl)-lH-benzimidazol-2-amin; smp. 123,4°C, 1-(2-chlorphenylmethyl)-N-[l-(2-phenylethyl)-4-piperidinyl]-N-(phenylmethyl)-lH-benzimidazol-2-amin; smp. 105,5°C, 1-butyl-N-[l-(2-phenylethyl)-4-piperidinyl]-N-(phenylmethyl)-1H-benzimidazol-2-amin; smp. 76,5°C og 25 1-ethyl-N-[l-(2-phenylethyl)-4-pi peridinyl]-N-(phenylmethyl)-lH- benzimidazol-2-amin dihydrochlorid dihydrat; smp. 157,2°C.Following the same procedure and using equivalent amounts of the appropriate starting materials, it is also possible to prepare: 1 - [(4-chlorophenyl) methyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -N -10 (phenylmethyl) -1H-benzimidazole-2-amine; mp. 138 ° C, 1 - [(2-methoxyphenyl) methyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; mp. 148.3 ° C, 1 - [(4-methoxyphenyl) methyl3-N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; mp. 122.4 ° C, 1 - [(4-fluorophenyl) methyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; 108.5 ° C, 1- (4-bromophenylmethyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; mp 139, 3 ° C, 1 - [(4-methylphenyl) methyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -N-20 (phenylmethyl) -1H-benzimidazole-2-amine; 123.4 ° C, 1- (2-Chlorophenylmethyl) -N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine; mp 105.5 ° C, 1-butyl-N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazol-2-amine, mp 76.5 ° C and 1-ethyl- N- [1- (2-phenylethyl) -4-piperidinyl] -N- (phenylmethyl) -1H-benzimidazole-2-amine dihydrochloride dihydrate, mp 157.2 ° C.

Eksempel 36Example 36

En blanding af 1,6 dele l-(l-chlorethyl)-4-fluorbenzen, 3,2 dele N-30 [l-(2-phenylethyl)-4-piperidinyl]-lH-benzimidazol-2-amin, 1 del natrium-carbonat, 0,1 del kaliumiodid og 120 dele 4-methyl-2-pentanon omrøres og tilbagesvales natten over med vand-separator. Reaktionsblandingen afkøles, hældes på vand, og lagene adskilles. Den organiske fase tørres, filtreres og inddampes. Remanensen renses ved søjlechromatografi over 35 silicagel under anvendelse af trichlormethan og methanol (98:2 efter volumen) som eluent. Oe rene fraktioner opsamles, og eluenten bortdampes.A mixture of 1.6 parts of 1- (1-chloroethyl) -4-fluorobenzene, 3.2 parts of N-30 [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazole-2-amine, 1 part sodium carbonate, 0.1 part potassium iodide and 120 parts 4-methyl-2-pentanone are stirred and refluxed overnight with water separator. The reaction mixture is cooled, poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over 35 silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. Oe pure fractions are collected and the eluent is evaporated.

46 DK 171841 B146 DK 171841 B1

Remanensen krystalliseres fra 2,2'-oxybispropan. Produktet filtreres fra og tørres, hvilket giver 1,8 dele (40,7%) l-[l-(4-fluorphenyl)-ethyl]-N-[l-(2-phenylethyl)-4-piperidinyl]-lH-benzimidazol-2-amin; smp.The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried to give 1.8 parts (40.7%) of 1- [1- (4-fluorophenyl) ethyl] -N- [1- (2-phenylethyl) -4-piperidinyl] -1H- benzimidazol-2-amine; mp.

161,7°C.161.7 ° C.

55

Eksempel 37Example 37

Ved at følge fremgangsmåderne i eksempler 35 og 36 og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer opnås følgende forbindelser på fri baseform eller i form af et syreadditionssalt 10 efter omsætning af den frie base med en passende syre O^-^OK X)Following the procedures of Examples 35 and 36 and using equivalent amounts of the appropriate starting materials, the following compounds are obtained in free base form or in the form of an acid addition salt 10 after reacting the free base with an appropriate acid (

RR

DK 171841 B1 47 R* R2 Base-eller saltforir SmeltepunktDK 171841 B1 47 R * R2 Base or salt forerene Melting point

H C^Hg-iCH^ base 136tl*CH C ^ Hg-iCH ^ base 136tl * C

H 4-F-C6H4-(CH2)2 base 151,5*0H 4-F-C6H4- (CH2) 2 base 151.5 * 0

H (4-F-C6H )-CH(C6iy 2HCLH20 239,6*CH (4-F-C6H) -CH (C6iy2HCLH2O 239.6 ° C)

H C6H -CHfCH^-CI^ base 144,5*0 H ^^-CH2 base 127,6*0 H C6H5-CH(CH3) 2HC1.H20 239,9*0 H - (4-F-C6H4)2CH base* 172,5*0 H 2-(CH30)-C6H4-CH2 base 128,5*0H 144 - CH 2 base 127.6 * 0 H C 6 H 5 -CH (CH 3) 2 H C 1 H 2 O 239.9 * 0 H - (4-F-C 6 H 4) 2CH base * 172.5 * 0 H 2- (CH30) -C6H4-CH2 base 128.5 * 0

CH3 2-(CH30)-C6H4-CH2 2HN03 169?7*CCH3 2- (CH30) -C6H4-CH2 2HNO3 169.7 ° C

CH3 . 2-Cl-C6H4-CH2 2HC1 251,2*CCH3. 2-C1-C6H4-CH2 2HC1 251.2 * C

CH3 4-Br-C6H4-CH2 .2HCLHzO “ 187,1*0 CH3 4-(CH30)-C6H4-CH2 2HN03 163,5*0CH3 4-Br-C6H4-CH2 .2HCLHzO 187.1 * 0 CH3 4- (CH30) -C6H4-CH2 2HNO3 163.5 * 0

CH3 C&H -CH2 2HC1 243,1*CCH3 C&H -CH2 2HC1 243.1 * C

CH3 4-(CH3)-C6H4-CH2 2HN03 175,3*0 CH, 4-Cl-C,H-CH, 2HC1 251,3*0 3 6 4 2 * CH3 a-c4H9 2HC1 257,9*0 CH3 C2H5 2HC1.H20 243,1*0 C2H5 C6H5-CH2 base 115,8*0CH3 4- (CH3) -C6H4-CH2 2HNO3 175.3 * 0 CH, 4-Cl-C, H-CH, 2HC1 251.3 * 0 3 6 4 2 * CH3 a-c4H9 2HC1 257.9 * 0 CH3 C2H5 2HC1.H2O 243.1 * 0 C2H5 C6H5-CH2 base 115.8 * 0

C2H5 C2H5 base 93,2*CC2H5 C2H5 base 93.2 ° C

"ϊθ3Η ? C6"H -CH2 2HC1.H20 159,4*0 nC3H7aC4H * (COOH)2 177,5*0 nC3H7C2H5 2HC1 160,7*0 iC3H? C2H5 2HC1.1AH20 206,8*0"ϊθ3Η? C6" H -CH2 2HC1.H20 159.4 * 0 nC3H7aC4H * (COOH) 2 177.5 * 0 nC3H7C2H5 2HC1 160.7 * 0 iC3H? C2H5 2HC1.1AH20 206.8 * 0

iC3H? C6H5-CH2 CCOOH)2 215,6’CiC3H? C 6 H 5 -CH 2 CCOOH) 215.6 ° C

1C3H7 nC4H9 (COOH)2 198,0*0 nC.H- C,H_-CH_ 2HC1.2H,0 160,0*0 4 9 o 5 c. u aC4H9 4"Br-c6Ii4-CH2 2HC1.2H^O- 137,2*0 nC.H nC.Hn 2HCL2H,0 138,7*0 4 9 4 9 2 '1C3H7 nC4H9 (COOH) 2 198.0 * 0 nC.H-C, H_-CH_ 2HC1.2H, 0 160.0 * 0 4 9 o 5 c. U aC4H9 4 "Br-c6Ii4-CH2 2HC1.2H ^ O - 137.2 * 0 nC.H nC.Hn 2HCL2H, 0 138.7 * 0 4 9 4 9 2 '

nC.Hn 4-F-C,H.-CH 2HC1.2H,0 135 5*CnC.Hn 4-F-C, H-CH 2HC1.2H, 0 135 5 * C

4 9 o 4 Z Z · -<^J 21101.21^0 123,8*0 48 DK 171841 B14 9 o 4 Z Z · - <^ J 21101.21 ^ 0 123.8 * 0 48 DK 171841 B1

Eksempel 38Example 38

En blanding af 3,2 dele N-[1 -(2-phenylethyl)-4-piperidinyl]-1H-benzimidazol-2-amin, 2,9 dele [2-(2-thienyl)ethyl]-4-methylbenzensulfo-nat, 1 del natriumcarbonat og 135 dele 4-methyl-2-pentanon omrøres og 5 tilbagesvales natten over med vand-separator. Reaktionsblandingen hældes i vand, og lagene udskilles. Den organiske fase tørres, filtreres og inddampes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen kry-10 stalliseres fra en blanding af 2,2'-oxybispropan og 2-propanon, hvilket giver 1 del (23,2%) N-[l-(2-phenylethyl)-4-piperidinyl]-l-[2-(2-thie-nyl)ethyl]-lH-benzimidazol-2-amin; smp. 118,3°C.A mixture of 3.2 parts of N- [1- (2-phenylethyl) -4-piperidinyl] -1H-benzimidazole-2-amine, 2.9 parts of [2- (2-thienyl) ethyl] -4-methylbenzenesulfonic acid overnight, 1 part sodium carbonate and 135 parts of 4-methyl-2-pentanone are stirred and refluxed overnight with water separator. The reaction mixture is poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanone to give 1 part (23.2%) of N- [1- (2-phenylethyl) -4-piperidinyl] -1- [2 - (2-thienyl) ethyl] -LH-benzimidazol-2-amine; mp. 118.3 ° C.

Eksempel 39 15 Til en omrørt og afkøket blanding (under 5°C) af 4 dele N-[l-(2- phenylethyl)-4-piperidinyl]-l-(phenylmethyl)-lH-benzimidazol-2-amin, 100 dele dimethylsulfoxid og 90 dele benzen sættes 0,5 del natriumhydriddis-persion 50%. Efter omrøring i 30 minutter ved en temperatur under 5°C tilsættes 1,3 dele (chlormethyl)benzen, og omrøringen fortsættes i 4 ti-20 mer, mens blandingen tillades at opnå stuetemperatur. Reaktionsblandingen hældes i vand, og produktet ekstraheres med methyl benzen. Ekstrakten tørres, filtreres og inddampes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af en blanding af trichlormethan og methanol (97:3 efter volumen) som eluent. De rene fraktioner opsamles, og 25 eluenten inddampes. Remanensen konverteres til nitratsalt i 2-propanon. Saltet frafiltreres og tørres, hvilket giver 1,5 dele (24%) N-[1-(2-phenyl ethyl)-4-piperidi nyl]-N,1-bis-(phenyl methyl)-lH-benzimidazol -2-amin-dinitrat; smp. 156,9°C.Example 39 To a stirred and boiled mixture (below 5 ° C) of 4 parts of N- [1- (2-phenylethyl) -4-piperidinyl] -1- (phenylmethyl) -1H-benzimidazole-2-amine, 100 parts dimethyl sulfoxide and 90 parts of benzene are added 0.5 parts of sodium hydride dispersion 50%. After stirring for 30 minutes at a temperature below 5 ° C, 1.3 parts (chloromethyl) benzene are added and stirring is continued for 4 hours while allowing the mixture to reach room temperature. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to nitrate salt in 2-propanone. The salt is filtered off and dried to give 1.5 parts (24%) of N- [1- (2-phenylethyl) -4-piperidinyl] -N, 1-bis- (phenylmethyl) -1H-benzimidazole -2- amine dinitrate; mp. 156.9 ° C.

30 Eksempel 40Example 40

Til 1 del af en opløsning af 2 dele thiophen i 40 dele ethanol sættes 3,3 dele l-(4-fluorphenylmethyl)-N-{l-[2-(4-nitrophenyl)ethyl]-4-pi-peridinyl}-lH-benzimidazol-2-amin og 120 dele methanol. Det hele hydrogeneres ved normalt tryk og ved stuetemperatur med 2 dele platin-på-35 trækul katalysator 5%. Efter at den beregnede mængde hydrogen er optaget, frafiltreres katalysatoren, og filtratet inddampes. Remanensen ren- 49 DK 171841 B1 ses ved søjlechromatografi over s il i cage! under anvendelse af en blanding af methylbenzen og methanol (95:5 efter volumen) mættet med ammoniak som eluent. t)e rene fraktioner opsamles, og eluenten inddampes. Remanensen krystalliseres fra 2-propanol, hvilket giver 1,3 dele (42%) N-{l-[2-5 (4-aminophenylethyl]-4-piperidinyl)-l-(4-fluorphenylmethyl)-lH-benzimi -dazol-2-amin; smp. 195,4°C.To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol is added 3.3 parts of 1- (4-fluorophenylmethyl) -N- {1- [2- (4-nitrophenyl) ethyl] -4-piperidinyl} - 1H-benzimidazole-2-amine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over sieve in cage! using a mixture of methylbenzene and methanol (95: 5 by volume) saturated with ammonia as eluent. t) e pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol to give 1.3 parts (42%) of N- {1- [2-5 (4-aminophenylethyl] -4-piperidinyl) -1- (4-fluorophenylmethyl) -1H-benzimidazole -2-amine; mp. 195.4 ° C.

Ved at følge den samme hydrogeneringsfremgangsmåde og med udgang i den tilsvarende ni troforbindelse kan der også fremstilles: 10 1-[(4-aminophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperi - dinyl]-lH-benzimidazol-2-aminmonohydrat; smp. 142,6°C.Following the same hydrogenation process and starting with the corresponding nine faith compound, it is also possible to prepare: 1 - [(4-aminophenyl) methyl] -N- [1- [2- (4-methoxyphenyl) ethyl] -4-piperidine - dinyl] -1H-benzimidazole-2-amine monohydrate; mp. 142.6 ° C.

Eksempel 41Example 41

En blanding af 7,5 dele l-(4-fluorphenylmethyl)-N-[l-{2-[4(phenyl-15 methoxy)phenyl]ethyl)-4-piperidinyl]-lH-benzimidazol-2-amin og 120 dele methanol hydrogeneres ved normalt tryk og ved stuetemperatur med 2 dele palladium-på-trækul katalysator 10%. Efter at den beregnede mængde hydrogen er optaget, frafiitreres katalysatoren, og filtratet inddampes. Remanensen suspenderes i 2,2'-oxybispropan. Produktet frafiitreres og 20 tørres, hvilket giver 5,5 dele (88,5%) 4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamin]-1-piperidinyl}ethyl]phenolhemihydrat; smp.A mixture of 7.5 parts of 1- (4-fluorophenylmethyl) -N- [1- {2- [4 (phenyl-methoxy) phenyl] ethyl) -4-piperidinyl] -1H-benzimidazole-2-amine and 120 parts of methanol are hydrogenated at normal pressure and at room temperature with 2 parts palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is suspended in 2,2'-oxybispropane. The product is filtered off and dried to give 5.5 parts (88.5%) of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamine] -1-piperidinyl} ethyl] phenolhemihydrat; mp.

111,6°C.111.6 ° C.

Ved at følge den samme hydrogeneringsfremgangsmåde og med udgang i l-(4-fluorphenylmethyl)-N-[l-{2-[3-methyl-4-(phenylmethoxy)phenyl]-25 ethyl)-4-piperidinyl]-lH-benzimidazol-2-amin kan der også fremstilles 4-(2-[4-{[l-(4-fluorphenylmethyl)-lH-benzimidazol -2-yl ]amino)-1-piperidin-yl]ethyl}-2-methylphenol dihydrochlorid monohydrat; smp. 277,8°C.Following the same hydrogenation process and starting with 1- (4-fluorophenylmethyl) -N- [1- {2- [3-methyl-4- (phenylmethoxy) phenyl] ethyl] -4-piperidinyl] -1H- benzimidazol-2-amine may also be prepared 4- (2- [4 - {[1- (4-fluorophenylmethyl) -1H-benzimidazol-2-yl] amino) -1-piperidin-yl] ethyl} -2-methylphenol dihydrochloride monohydrate; mp. 277.8 ° C.

En blanding af 8 dele l-(4-fluorphenylmethyl )-N-{l-[2-(3methoxy-phenyl)ethyl]-4-piperidinyl)-lH-benzimidazol-2-amin og 255 dele af en 30 hydrobromideddikeopløsning 48% i eddikesyre omrøres og tilbagesvales i 3 timer. Reaktionsblandingen inddampes, og remanensen optages i vandet.A mixture of 8 parts of 1- (4-fluorophenylmethyl) -N- {1- [2- (3-methoxy-phenyl) ethyl] -4-piperidinyl) -1H-benzimidazole-2-amine and 255 parts of a hydrobromide acetic acid solution 48% in acetic acid is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is taken up in the water.

Den frie base frigøres på konventionel måde med ammoniumhydroxid og eks-traheres med trichlormethan. Ekstrakten tørres, filtreres og inddampes. Remanensen renses to gange ved søjlechromatografi over silicagel under 35 anvendelse af først en blanding af trichlormethan og methanol (98:2 efter volumen) og dernæst en blanding af trichlormethan og methanol (95:5 50 DK 171841 B1 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen konverteres til hydrochloridsalt i 2-propanon. Saltet frafiltreres og tørres, hvilket giver 0,8 del (9%) 3-[2-{4-[l-(4-fluor-phenylmethyl)-lH-benzimidazol-2-ylalimino]-l-piperidinyl)ethyl]phenol 5 dihydrochlorid monohydrat; smp. 209,8°C.The free base is conventionally released with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol (98: 2 by volume) and then a mixture of trichloromethane and methanol (95: 5 50 DK 171841 B1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 0.8 part (9%) of 3- [2- {4- [1- (4-fluoro-phenylmethyl) -1H-benzimidazol-2-ylalimino] -1-piperidinyl) ethyl] phenol Dihydrochloride monohydrate; mp. 209.8 ° C.

Eksempel 42Example 42

En blanding på 1,2 dele 3-brom-l-propen, 4 dele 4-[2-{4-[l-(4-fl uorphenylmethyl)-lH-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]phe-10 nol, 1,4 dele kaliumcarbonat og 160 dele 2-propanon omrøres og tilbagesvales natten over. Reaktionsblandingen filtreres, og filtratet inddampes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af trichlormethan og methanol (98:2 efter volumen) som eluent.A mixture of 1.2 parts of 3-bromo-1-propene, 4 parts of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] pheanol, 1.4 parts potassium carbonate and 160 parts 2-propanone are stirred and refluxed overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent.

De rene fraktioner opsamles, og eluenten inddampes. Remanensen konverte-15 res til hydrochloridsalt i 2-propanon. Saltet frafiltreres og tørres, hvilket giver 1 del (19,9%) l-(4-fluorphenylmethyl)-N-[l-{2-[4-(2-prope-nyloxy)phenyl]ethyl}-4-piperidinyl]-lH-benzimidazol-2-amin dihydrochlorid; smp. 224,7°C.The pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 1 part (19.9%) of 1- (4-fluorophenylmethyl) -N- [1- {2- [4- (2-propenyloxy) phenyl] ethyl} -4-piperidinyl] -1H-benzimidazole-2-amine dihydrochloride; mp. 224.7 ° C.

20 Eksempel 43Example 43

En blanding af 15 dele thionylchlorid, 4 dele 4-[l-(4-fluorphenyl-methyl)-lH-benzimidazol-2-ylamino]-l-piperidinethanol dihydrochlorid og 375 dele trichlormethan omrøres og tilbagesvales natten over. Det udfældede produkt frafiltreres og tørres, hvilket giver 13 dele (83%) N-[1-25 (2-chlorethyl)-4-piperidinyl]-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin dihydrochlorid; smp. > 260°C.A mixture of 15 parts of thionyl chloride, 4 parts of 4- [1- (4-fluorophenyl-methyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol dihydrochloride and 375 parts of trichloromethane is stirred and refluxed overnight. The precipitated product is filtered off and dried to give 13 parts (83%) of N- [1-25 (2-chloroethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine dihydrochloride; mp. > 260 ° C.

Eksempel 44Example 44

En blanding på 0,9 del morpholin, 4,8 dele N-[l-(2-chlorethyl)-4-30 piperidinyl]-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin dihydrochlorid, 3 dele natriumcarbonat, 0,1 del kaliumiodid og 135 dele N,N-dime-thylformamid omrøres og opvarmes natten over ved 70°C. Reaktionsblandingen hældes i vand, og produktet ekstraheres med methyl benzen. Ekstrakten tørres, filtreres og inddampes. Remanensen renses ved søjlechromatografi 35 over silicagel under anvendelse af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten ind- 51 DK 171841 B1 dampes. Remanensen krystalliseres fra en blanding af 2-propanon og 2,2'-oxybispropan, hvilket giver 0,6 del (12,5%) [2{4-[l-(4-fluorphenylme-thyl)-lH-benzimidazol-2-ylamino]-1-pi peridinyl)-ethyl]-4-morpholincarbo-xylat; smp. 144,8°C.A mixture of 0.9 parts of morpholine, 4.8 parts of N- [1- (2-chloroethyl) -4-30 piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine dihydrochloride, 3 parts sodium carbonate , 0.1 part potassium iodide and 135 parts N, N-dimethylformamide are stirred and heated overnight at 70 ° C. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 0.6 part (12.5%) of [2 {4- [1- (4-fluorophenylmethyl) -1H-benzimidazole-2 -ylamino] -1-piperidinyl] ethyl] -4-morpholinecarboxylate; mp. 144.8 ° C.

55

Eksempel 45Example 45

En blanding af 3,6 dele morpholin, 4,8 dele N-[1-(2-chlorethyl)-4-piperidinyl]-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin dihydrochlo-rid, 0,1 del kaliumiodid og 135 dele N,N,-dimethylformamid omrøres og 10 opvarmes natten over ved 70°C. Reaktionsblandingen hældes i vand, og produktet ekstraheres med methyl benzen. Ekstrakten tørres, filtreres og inddampes. Remanensen konverteres til hydrochloridsalt i methanol. Saltet frafiltreres og tørres, hvilket giver 1 del (18,3%) l-(4-fluorphe-nylmethyl )-Ν-{1-[2-(4-morpholinyl) ethyl]-4-piperidinyl)-lH-benzimidazol-15 2-amin trihydrochlorid; smp. + 300°C.A mixture of 3.6 parts of morpholine, 4.8 parts of N- [1- (2-chloroethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine dihydrochloride, 1 part potassium iodide and 135 parts N, N, -dimethylformamide are stirred and heated overnight at 70 ° C. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in methanol. The salt is filtered off and dried to give 1 part (18.3%) of 1- (4-fluorophenylmethyl) -Ν- {1- [2- (4-morpholinyl) ethyl] -4-piperidinyl) -1H-benzimidazole 2-amine trihydrochloride; mp. + 300 ° C.

Eksempel 46Example 46

Til en omrørt blanding af 4,5 dele 4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-l-piperidinethanol, 2 dele N,N-diethylethanamin 20 og 195 dele dichlormethan sættes dråbevis en opløsning af 1,7 dele 4-methoxybenzoylchlorid i dichlormethan. Efter færdiggørelsen fortsættes omrøringen natten over ved stuetemperatur. Vand tilsættes, og lagene udskilles. Den organiske fase tørres, filtreres og inddampes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af en 25 blanding af trichlormethan og methanol (98:2 efter volumen) som eluent.To a stirred mixture of 4.5 parts of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinethanol, 2 parts of N, N-diethylethanamine 20 and 195 parts of dichloromethane is added dropwise to a solution of 1.7 parts of 4-methoxybenzoyl chloride in dichloromethane. After completion, stirring is continued overnight at room temperature. Water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent.

De rene fraktioner opsamles, og eluenten inddampes. Remanensen konverteres til hydrochloridsalt i 2-propanon. Saltet filtreres fra og tørres, hvilket giver 2,5 dele (43,5%) [2-{4-[l-(4-fluorphenylmethyl)-lH-benz-imidazol-2-ylamino]-l-piperidinyl)ethyl]-4-methoxybenzoat dihydrochlorid 30 hemihydrat; smp. 189,2°C.The pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 2.5 parts (43.5%) of [2- {4- [1- (4-fluorophenylmethyl) -1H-benz-imidazol-2-ylamino] -1-piperidinyl) ethyl] -4-methoxybenzoate dihydrochloride hemihydrate; mp. 189.2 ° C.

Ved at følge samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der også fremstilles: (4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol -2-yl amino]-1-pi-35 peridinyl)ethyl]phenyl)benzenacetat; smp. 135,1°C, (4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-1-pi- 52 DK 171841 B1 peridinylJethyl]phenyl}4-methoxybenzoat; smp. 157,1°C, {4-[2-{4-[l-(4-fluorphenylmethyl}-lH-benzimidazol-2-ylamino]-l-pi-peridinyl)ethyl]phenyl}methylcarbonat; smp. 134,5°C og {4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-l-pi-5 peridinyl}ethyl]phenyl}-(phenylmethyl)carbonat; smp. 147,8°C.By following the same procedure and using equivalent amounts of the appropriate starting materials, it is also possible to prepare: (4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-yl amino] -1- (piperidinyl) ethyl] phenyl) benzeneacetate; mp. 135.1 ° C, (4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl] ethyl] phenyl} 4-methoxybenzoate; 157.1 ° C, {4- [2- {4- [1- (4-fluorophenylmethyl} -1H-benzimidazol-2-ylamino] -1-piperidinyl) ethyl] phenyl} methyl carbonate; mp 134, 5 ° C and {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenyl} - (phenylmethyl) carbonate; 147.8 ° C.

Eksempel 47Example 47

En blanding af 1,2 dele chloracetonitril, 6,7 dele 4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylami no]-1-piperidinylJethyl]phe-10 nol, 2,8 dele kaliumcarbonat og 160 dele 2-propanon omrøres og tilbagesvales natten over. Reaktionsblandingen hældes i vand, og produktet eks-traheres med methyl benzen. Ekstrakten tørres, filtreres og inddampes. Remanensen konverteres til hydrochloridsalt i 2-propanon. Saltet filtreres fra og tørres, hvilket giver 7,4 dele (78,6%) {4-[2-{4[l-(4-fluor-15 phenylmethyl)-lH-benzimidazol-2-ylami no]-1-piperidinylJethylJphenoxyJ-acetonitril dihydrochlorid monohydrat; smp. 224,6°C.A mixture of 1.2 parts of chloroacetonitrile, 6.7 parts of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl] ethyl] phenol, 2 , 8 parts potassium carbonate and 160 parts 2-propanone are stirred and refluxed overnight. The reaction mixture is poured into water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and dried to give 7.4 parts (78.6%) of {4- [2- {4 [1- (4-fluoro-phenylmethyl) -1H-benzimidazol-2-ylamino] -1- piperidinylethylphenoxyJ-acetonitrile dihydrochloride monohydrate; mp. 224.6 ° C.

Ved at følge samme fremgangsmåde og under anvendelse af ækvivalente mængder af de passende udgangsmaterialer kan der fremstilles; 20 ethyl-2-{4-[2-{4-[1-(4-f1uorphenyl methyl )-lH-benzimidazol-2-ylami- no]-l-piperidinyl}ethyl]phenoxy}acetat; smp. 109,1°C, methyl-2-{4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylami-no]-l-piperidinyl}ethyl]phenoxy}acetat; smp.l09,8°C, 1-[2-{4-[2-{4-[l-(4-f1uorphenylmethyl )-lH-benzimidazol-2-ylamino]-25 l-piperidinyl}ethyl]phenoxy}acetyl]piperidin dihydrochlorid; smp. 247°C.By following the same process and using equivalent amounts of the appropriate starting materials, it is possible to prepare; Ethyl 2- {4- [2- {4- [1- (4-fluorophenyl methyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenoxy} acetate; mp. 109.1 ° C, methyl 2- {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenoxy} acetate; mp 109.8 ° C, 1- [2- {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -25-piperidinyl} ethyl] phenoxy} acetyl ] piperidine dihydrochloride; mp. 247 ° C.

Eksempel 48Example 48

En blanding af 0,5 del isocyanatomethan, 4,5 dele 4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-1-pi peri di nyl}ethyl]phenol 30 og 135 dele tetrahydrofuran omrøres natten over ved stuetemperatur. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af en blanding af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen krystalliseres fra en blanding af 2-propanon og 2,2'-oxybispropan, hvil -35 ket giver 1 del (20%) {4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol- 2-ylami no]-1-pi peridinylJethyl]phenylJmethylcarbamat; smp. 172,2°C.A mixture of 0.5 parts of isocyanatomethane, 4.5 parts of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenol and 135 parts of tetrahydrofuran are stirred overnight at room temperature. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, which gives 1 part (20%) of {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazole]. 2-ylamino [1-pi peridinyl] ethyl] phenyl] methyl carbamate; mp. 172.2 ° C.

53 DK 171841 B153 DK 171841 B1

Ved additionsomsætning af 4-[2-{4-[l-(4-fluorphenylmethyl)-1H-benzimidazol-2-ylamino]-l-piperidiny1}ethyl]-phenol til 1-isocyanobutan kan der også fremstilles: 5 {4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-l-pi- peridinyl}ethyl]phenyl}butylcarbamat; smp. 142,5°C.By addition reaction of 4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] -phenol to 1-isocyanobutane can also be prepared: 5 {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenyl} butylcarbamate; mp. 142.5 ° C.

Eksempel 49Example 49

En blanding af 9 dele 4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-10 ylamino]-l-piperidinacetonitril og 200 dele methanol, mættet med ammoniak, hydrogeneres ved normalt tryk og ved stuetemperatur med 3 dele Ra-ney-nikkel katalysator. Efter at den beregnede mængde hydrogen er optaget, frafiltreres katalysatoren, og filtratet inddampes. Remanensen konverteres til hydrochloridsalt i 2-propanon. Saltet frafiltreres og kry-15 stalliseres fra en blanding af 2-propanon og methanol, hvilket giver 11 dele N-[l-(2-aminoethyl)-4-piperidinyl]-l-(4-fluorphenylmethyl)-lH-benz-imidazol-2-amin trihydrochlorid; smp. 292,9°C.A mixture of 9 parts of 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidine acetonitrile and 200 parts of methanol, saturated with ammonia, is hydrogenated at normal pressure and at room temperature with 3 parts of Ra ney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from a mixture of 2-propanone and methanol to give 11 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole -2-amine trihydrochloride; mp. 292.9 ° C.

Under anvendelse af den samme hydrogeneringsproces og med udgang i 4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-l-piperidinpropan-20 nitril kan der også fremstilles: N-[l-(3-aminopropyl)-4-piperidinyl]-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin trihydrochlorid monohydrat; smp. 239,3°C.Using the same hydrogenation process and starting with 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinopropanitrile, N- [1- (3-aminopropyl) can also be prepared ) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine trihydrochloride monohydrate; mp. 239.3 ° C.

Eksempel 50 25 En blanding af 1,8 dele l-isothiocyanato-2-nitrobenzen, 3,7 dele N- [1-(2-aminoethyl)-4-pi peridinyl]-l-(4-fluorphenylmethyl)-lH-benzimida-zol-2-amin og 135 dele tetrahydrofuran omrøres natten over ved stuetemperatur. Reaktionsblandingen inddampes. Remanensen renses ved søjlechro-matografi over silicagel under anvendelse af en blanding af trichlorme-30 than og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes, hvilket giver 3,7 dele (67%) N-[2-{4-[l-(4-fl uorphenylmethyl)-lH-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]-N/-(2-nitrophenyl)thiourinstof som remanens.Example 50 A mixture of 1.8 parts of 1-isothiocyanato-2-nitrobenzene, 3.7 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimida -zol-2-amine and 135 parts of tetrahydrofuran are stirred overnight at room temperature. The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 3.7 parts (67%) of N- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] -N / - (2-nitrophenyl) thiourea as residue.

En blanding af 3,7 dele N-[2-{4-[l-(4-fluorphenylmethyl)-lHbenz-35 imidazol-2-ylamino]-l-pioeridinyl}ethyl]-N'-(2-nitrophenyl)thi ourinstof, 7 dele jernpulver, 0,25 del koncentreret saltsyre, 48 dele ethanol og 15 54 DK 171841 B1 dele vand omrøres og tilbagesvales i 1 time. Reaktionsblandingen alkali-seres, og filtratet inddampes, hvilket giver 3,5 dele N-(2-aminophenyl)-N'.[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol -2-ylamino]-1-piperidi-nyljethyl)thiourinstof som remanens.A mixture of 3.7 parts of N- [2- {4- [1- (4-fluorophenylmethyl) -1Hbenz-imidazol-2-ylamino] -1-pioeridinyl} ethyl] -N '- (2-nitrophenyl) thi 7 parts of iron powder, 0.25 parts of concentrated hydrochloric acid, 48 parts of ethanol and 15 parts of water are stirred and refluxed for 1 hour. The reaction mixture is alkalized and the filtrate is evaporated to give 3.5 parts of N- (2-aminophenyl) -N '. [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] - 1-piperidinylethyl) thiourea as residue.

5 En blanding af 3,5 dele N-(2-aminophenyl )-N'-[2-{4-[l-(4fluorphe- nylmethyl)-lH-benzimidazol-2-ylamino]-1-pi peri dinyljethyl]thi ourinstof, 2,2 dele mercuri(Il)oxid, 0,1 del svovl og 80 dele ethanol omrøres og tilbagesvales i 1 time. Reaktionsblandingen filtreres over Hyflo, og filtratet inddampes. Remanensen renses ved søjlechromatografi over si 1 i -10 cage! under anvendelse af en blanding af trichlormethan og methanol (95:5 efter volumen) som eluent. De rene fraktioner opsamles, og eluen-ten inddampes. Remanensen krystalliseres fra 2-propanon, hvilket giver 1,5 dele (44,4%) N-{l-[2-(lH-benzimidazol-2-ylamino)ethyl]-4-piperidi-nyl}-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin; smp. 253,4°C.A mixture of 3.5 parts of N- (2-aminophenyl) -N '- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinylethyl] thi our nitrogen, 2.2 parts of mercuric (II) oxide, 0.1 parts of sulfur and 80 parts of ethanol are stirred and refluxed for 1 hour. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is purified by column chromatography over si 1 in -10 cage! using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanone to give 1.5 parts (44.4%) of N- {1- [2- (1H-benzimidazol-2-ylamino) ethyl] -4-piperidinyl} -1- (4 -fluorphenylmethyl) -LH-benzimidazol-2-amine; mp. 253.4 ° C.

1515

Eksempel 51Example 51

En opløsning af 4,77 dele N-[l-aminoethyl)-4-piperidinyl]-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin trihydrochlorid i methanol mættet med ammoniak omrøres 1 time ved stuetemperatur. Opløsningsmidlet 20 inddampes, og remanensen optages i 135 dele tetrahydrofuran. Derefter tilsættes 6 dele isocyanatomethan, og det hele omrøres natten over ved stuetemperatur. Det udfældede produkt frafiltreres og tørres, hvilket giver 3 dele (70,7%) N-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylami no]-1-pi peri di nyl}ethyl]-Ν'-methyl urinstof hemi hydrat; smp.A solution of 4.77 parts of N- [1-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine trihydrochloride in methanol saturated with ammonia is stirred for 1 hour at room temperature. The solvent 20 is evaporated and the residue is taken up in 135 parts of tetrahydrofuran. Then 6 parts of isocyanatomethane are added and the whole is stirred overnight at room temperature. The precipitated product is filtered off and dried to give 3 parts (70.7%) of N- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl } ethyl] -Ν'-methyl urea hemi hydrate; mp.

25 231,4°C.231.4 ° C.

Eksempel 52Example 52

Til en omrørt blanding af 3,8 dele N-[l-(2-aminoethyl)-4-piperidi-nyl]-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin, 1 del N,N-diethyl-30 ethanamin og 195 dele dichlormethan sættes dråbevis en opløsning af 1,7 dele 4-methoxybenzoylchlorid i dichlormethan. Når det er færdigt, fortsættes omrøringen natten over ved stuetemperatur. Reaktionsblandingen hældes i vand, og lagene udskilles. Den organiske fase tørres, filtreres og inddampes. Remanensen renses ved søjlechromatografi over silicagel 35 under anvendelse af en blanding af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten ind- 55 DK 171841 B1 dampes. Remanensen konverteres til hydrochloridsalt i 2-propanol. Saltet frafiltreres og tørres, hvilket giver 1 del N-[2-{4-[l-(4-fluorphenylme-thyl)-lH-benzimidazol-2-ylamino]-l-piperidinyl}ethyl]-4-methoxy-N-(4-methoxybenzoyl)benzamid dihydrochlorid di hydrat; smp. 161,5°C.To a stirred mixture of 3.8 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine, 1 part N, N-diethyl -30 ethanamine and 195 parts of dichloromethane are added dropwise to a solution of 1.7 parts of 4-methoxybenzoyl chloride in dichloromethane. When done, stirring is continued overnight at room temperature. The reaction mixture is poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel 35 using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 1 part of N- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] -4-methoxy-N- (4-methoxybenzoyl) benzamide dihydrochloride di hydrate; mp. 161.5 ° C.

55

Eksempel 53Example 53

Til en blanding af 2 dele thiophen i 40 dele ethanol sættes 1 del paraformaldehyd, 3,5 dele N-[l-(2-aminoethyl)-4-piperidinyl]-l-(4-fluor-phenylmethyl)-lH-benzimidazol-2-amin og 120 dele methanol. Det hele hy-10 drogeneres ved normalt tryk og ved stuetemperatur med 2 dele pal ladium-på-trækul katalysator 10%. Efter at den beregnede mængde hydrogen er optaget, frafiltreres katalysatoren, og filtratet inddampes. Remanensen optages i vand, og produktet ekstraheres med trichlormethan. Ekstrakten tørres, filtreres og inddampes. Remanensen krystalliseres fra en bland-15 ing af 2-propanon og 2,2'-oxobispropan, hvilket giver 1,5 dele (42%) N-{1-[2-(dimethyl ami no)ethyl]-4-piperidinyl)-l-(4-fluorphenylmethyl)-1H-benzimidazol-2-amin; smp. 166,1°C.To a mixture of 2 parts of thiophene in 40 parts of ethanol is added 1 part of paraformaldehyde, 3.5 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluoro-phenylmethyl) -1H-benzimidazole 2-amine and 120 parts of methanol. The entire hy-10 is dehydrated at normal pressure and at room temperature with 2 parts of pal ladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxobispropane to give 1.5 parts (42%) of N- {1- [2- (dimethylamino) ethyl] -4-piperidinyl) -L- (4-fluorophenylmethyl) -1H-benzimidazol-2-amine; mp. 166.1 ° C.

Eksempel 54 20 Til 1 del af en opløsning af 2 dele thiophen i 40 dele ethanol sæt tes 2,5 dele benzaldehyd, 3,7 dele N-[l-(2-aminoethyl)-4-piperidinyl]-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin og 120 dele methanol. Det hele hydrogeneres ved normalt tryk og ved stuetemperatur med 2 dele pal-ladium-på-trækul katalysator 10%. Efter at den beregnede mængde hydrogen 25 er optaget, frafiltreres katalysatoren over Hyflo, og filtratet inddampes. Remanensen konverteres til hydrochloridsalt i 2-propanon. Saltet frafiltreres og optages i vand. Den frie base frigøres på konventionel måde med ammoniumhydroxid og ekstraheres med dichlormethan. Ekstrakten tørres, filtreres og inddampes. Remanensen krystalliseres fra en bland-30 ing af 2-propanon og 2,2'-oxybispropan, hvilket giver 1,5 dele (27,5%) N-[l-{2-[bi s(phenylmethyl) amino]ethyl}-4-piperidinyl]-l-(4-fluorphenyl-methyl)-lH-benzimidazol-2-amin; smp. 116,4°C.Example 54 To 2.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol are added 2.5 parts of benzaldehyde, 3.7 parts of N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4- fluorophenylmethyl) -1H-benzimidazole-2-amine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen 25 is taken up, the catalyst is filtered off over Hyflo and the filtrate is evaporated. The residue is converted to hydrochloride salt in 2-propanone. The salt is filtered off and taken up in water. The free base is conventionally released with ammonium hydroxide and extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 1.5 parts (27.5%) of N- [1- {2- [bis (phenylmethyl) amino] ethyl} -4-piperidinyl] -L- (4-fluorophenyl-methyl) -LH-benzimidazol-2-amine; mp. 116.4 ° C.

Eksempel 55 35 En blanding af 5,5 dele N-[l-(lH-benzimidazol-2-yl)-4-piperidinyl]- l-(phenylmethyl)-lH-benzimidazol-2-amindinitrat, 1,5 dele l-(chlorme- 56 DK 171841 B1 thyl)-4-fluorbenzen, 5 dele natriumcarbonat, 0,1 del kaliumiodid og 120 dele 4-methyl-2-pentanon omrøres og tilbagesvales natten over under anvendelse af en vandseparator. Reaktionsblandingen hældes i vand, og lagene udskilles. Den organiske fase tørres, filtreres og inddampes. Rema-5 nensen renses ved søjlechromatografi over silicagel under anvendelse af en blanding af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen krystalliseres fra en blanding af 4-methyl-2-pentanon og 2,2'-oxybispropan. Produktet frafiltreres og tørres, hvilket giver 1,5 dele (28,3%) N-{1-10 [1-(4-fluorphenylmethyl)-lH-benzimidazol-2-yl]-4-pi peri di nyl}-1-(phenyl -methyl)-lH-benzimidazol-2-amin; smp. 163,9°C.Example 55 A mixture of 5.5 parts of N- [1- (1H-benzimidazol-2-yl) -4-piperidinyl] -1- (phenylmethyl) -1H-benzimidazole-2-amine dinitrate, 1.5 parts of 1- (chloromethyl) -4-fluorobenzene, 5 parts sodium carbonate, 0.1 parts potassium iodide and 120 parts 4-methyl-2-pentanone are stirred and refluxed overnight using a water separator. The reaction mixture is poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried to give 1.5 parts (28.3%) of N- {1-10 [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-yl] -4-piperidinyl} -1 - (phenyl-methyl) -1H-benzimidazole-2-amine; mp. 163.9 ° C.

Eksempel 56Example 56

En blanding af 3,7 dele l-(4-fluorphenylmethyl)-N-{l-[3-(4-methoxy-15 phenylthio)propyl]-4-piperidinyl}-lH-benzimidazol-2-amin, 2,42 dele hy-drogenperoxidopløsning 30% og 20 dele eddikesyre omrøres og tilbagesvales 1 time. Reaktionsblandingen afkøles og hældes i isvand. Det hele alkali seres med natriumhydroxidopløsning 50%, og produktet ekstraheres med trichlormethan. Ekstrakten vaskes med vand, tørres, filtreres og inddam-20 pes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af en blanding af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen konverteres til ethandioatsalt i methanol og 2-propanol. Saltet frafiltreres og tørres, hvilket giver 0,8 del (16%) l-(4-fluorphenylme-25 thyl)-N-{l-[3-(4-methoxyphenylsulfonyl)propyl]-4-piperidinyl}-lH-benz-imidazol-2-aminethandioat (1:2); smp. 213,1°C.A mixture of 3.7 parts of 1- (4-fluorophenylmethyl) -N- {1- [3- (4-methoxy-phenylthio) propyl] -4-piperidinyl} -1H-benzimidazole-2-amine, 2.42 parts of hydrogen peroxide solution 30% and 20 parts acetic acid are stirred and refluxed for 1 hour. The reaction mixture is cooled and poured into ice water. The entire alkali is extracted with 50% sodium hydroxide solution and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to ethanedioate salt in methanol and 2-propanol. The salt is filtered off and dried to give 0.8 part (16%) of 1- (4-fluorophenylmethyl) -N- {1- [3- (4-methoxyphenylsulfonyl) propyl] -4-piperidinyl} -1H-benz -imidazole-2-aminethanedioate (1: 2); mp. 213.1 ° C.

Eksempel 57Example 57

En blanding af 5 dele ethyl-2-{4-[2- 4-[l-(4-fluorphenylmethyl)-lH-30 benzimidazol-2-ylamino]-l-piperidinyl}ethyl]phenoxy acetat, 70 dele ethanaminopløsning 50% og 40 dele methanol omrøres i 3 timer ved stuetemperatur. Reaktionsblandingen inddampes, og remanensen krystalliseres to gange fra 2-propanol, hvilket giver 1 del (19%) N-ethyl-2-{4-[2-{4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylami no]-1 piperidinyl}-35 ethyl]-phenoxy}acetamid; smp. 160,9°C.A mixture of 5 parts of ethyl 2- {4- [2- 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenoxy acetate, 70 parts of ethanamine solution 50% and 40 parts of methanol are stirred for 3 hours at room temperature. The reaction mixture is evaporated and the residue is crystallized twice from 2-propanol to give 1 part (19%) of N-ethyl-2- {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazole-2 -ylamino [1-piperidinyl} -35-ethyl] -phenoxy} -acetamide; mp. 160.9 ° C.

57 DK 171841 B157 DK 171841 B1

Eksempel 58Example 58

En blanding af 3,5 dele methyl-2-{4-[2- 4-[l-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylamino]-l-piperidinyl}ethyl]phenoxy acetat, 90 dele koncentreret ammoniumhydroxid og 40 dele methanol omrøres i 4 timer ved 5 stuetemperatur. Reaktionsblandingen inddampes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af en blanding af trichlormethan og methanol (95:5 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen krystalliseres fra 2-propanol, hvilket giver 1 del (28,5%) 2-{4-[2-{4-[l-(4-fluorphe-10 nylmethyl)-lH-benzimidazol-2-ylamino]-l-piperidinyl)-ethyl]phenoxy}acet-amido; smp. 180,4°C.A mixture of 3.5 parts of methyl 2- {4- [2- 4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1-piperidinyl} ethyl] phenoxy acetate, 90 parts concentrated ammonium hydroxide and 40 parts of methanol are stirred for 4 hours at 5 room temperature. The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol to give 1 part (28.5%) of 2- {4- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1 piperidinyl) ethyl] phenoxy} acet-amido; mp. 180.4 ° C.

Eksempel 59Example 59

Til en omrørt og afkølet blanding (under 10°C) af 5,04 dele carbon-15 disulfid, 2,06 dele N,N'-methantetraylbis[cyclohexamin] og 45 dele te-trahydrofuran sættes dråbevis en opløsning af 3,7 dele N-[l-(2-amino-ethyl)-4-piperidinyl]-l-(4-fluorphenylmethyl)-lH-benzimidazol-2-amin i tetrahydrofuran. Når det er færdigt, fortsættes omrøringen natten over, mens blandingen får lov til at nå stuetemperatur. Reaktionsblandingen 20 inddampes. Remanensen renses ved søjlechromatografi over silicagel under anvendelse af en blanding af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten iddampes, hvilket giver 4 dele (100%) l-(4-fluorphenylmethyl)-N-[l-(2-isothiocya-natoethyl)-4-piperidinyl]-lH-benzimidazol-2-amin som remanens.To a stirred and cooled mixture (below 10 ° C) of 5.04 parts of carbon disulfide, 2.06 parts of N, N'-methantetraylbis [cyclohexamine] and 45 parts of tetrahydrofuran is added dropwise to a solution of 3.7 parts. N- [1- (2-aminoethyl) -4-piperidinyl] -1- (4-fluorophenylmethyl) -1H-benzimidazole-2-amine in tetrahydrofuran. When done, stirring is continued overnight while the mixture is allowed to reach room temperature. The reaction mixture is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 4 parts (100%) of 1- (4-fluorophenylmethyl) -N- [1- (2-isothiocya-natoethyl) -4-piperidinyl] -1H-benzimidazole-2-amine as residue.

25 En blanding på 2,1 dele N-(4-fluorphenylmethyl)-l,2-benzendiamin, 4 dele l-(4-fluorphenylmethyl)-N-[l-(2-isothiocyanatoethyl)-4-pi peri d i -nyl]-lH-benzimidazol-2-amin og 90 dele tetrahydrofuran omrøres og tilbagesvales i 2 timer. Reaktionsblandingen inddampes, hvilket giver 6 dele (100%) N-{2-[(4-fluorphenylmethyl)ami no]phenyl }-N'-[2-{4-[l-(4fluorphe-30 nylmethyl)-lH-benzimidazol-2-ylamino]-l-piperidinyl}ethyl]thiourinstof som remanens.A mixture of 2.1 parts of N- (4-fluorophenylmethyl) -1,2-benzenediamine, 4 parts of 1- (4-fluorophenylmethyl) -N- [1- (2-isothiocyanatoethyl) -4-piperidinyl ] -1H-benzimidazole-2-amine and 90 parts of tetrahydrofuran are stirred and refluxed for 2 hours. The reaction mixture is evaporated to give 6 parts (100%) of N- {2 - [(4-fluorophenylmethyl) amino] phenyl} -N '- [2- {4- [1- (4fluorophenylmethyl) -1H-benzimidazole 2-ylamino] -1-piperidinyl} ethyl] thiourea as residue.

En blanding af 6 dele N-{2-[(4-fluorphenylmethyl)amino]phenyl}-N'-[2-{4-[1-(4-fluorphenylmethyl)-lH-benzimidazol-2-ylami no]-1-piperidi-nyl]ethyl)thiourinstof, 3,2 dele mercuri(Il)oxid, 0,1 del svovl og 90 35 dele tetrahydrofuran omrøres og tilbagesvales i 3 timer. Reaktionsblandingen filtreres over Hyflo, og filtratet inddampes. Remanensen renses 58 DK 171841 B1 ved søjlechromatografi over silicagel under anvendelse af trichlormethan og methanol (98:2 efter volumen) som eluent. De rene fraktioner opsamles, og eluenten inddampes. Remanensen krystalliseres fra en blanding af 2-propanon og 2,2'-oxybispropan, hvilket giver 1,2 dele (20%) 1-(4-5 fluorphenylmethyl)-N-[1-(2-(1-fluorphenylmethyl)-lH-benzimidazol-2-yl- amino]ethyl)-4-piperidinyl]-lH-benzimidazol-2-amin; smp. 196,9°C.A mixture of 6 parts of N- {2 - [(4-fluorophenylmethyl) amino] phenyl} -N '- [2- {4- [1- (4-fluorophenylmethyl) -1H-benzimidazol-2-ylamino] -1 -piperidinyl] ethyl) thiourea, 3.2 parts of mercuric (II) oxide, 0.1 parts of sulfur and 90 parts of tetrahydrofuran are stirred and refluxed for 3 hours. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 1.2 parts (20%) of 1- (4-5 fluorophenylmethyl) -N- [1- (2- (1-fluorophenylmethyl) - 1H-benzimidazol-2-yl-amino] ethyl) -4-piperidinyl] -1H-benzimidazol-2-amine; mp. 196.9 ° C.

Claims (1)

10 R1 L . R* hvori L1 er hydrogen, lavere alkyloxycarbonyl eller phenylmethoxycarbo- nyl, 15. er hydrogen eller methyl, R1 er hydrogen eller lavere al kyl med 1 til 6 carbonatomer, R2 er hydrogen, alkyl med fra 1 til 10 carbonatomer, aryl, cycloal-kyl med 3 til 6 carbonatomer, mono- eller diphenyl-Cj_g-lavere al kyl, hvor phenylgruppen eventuelt er substitueret med 1 til 2 ens eller 20 forskellige substituenter, som er halogenatomer eller methyl- eller nitrogrupper, R3 er hydrogen, halogen, methyl eller trifluormethyl, og Q er CH eller N.10 R1 L. R * wherein L 1 is hydrogen, lower alkyloxycarbonyl or phenylmethoxycarbonyl, 15. is hydrogen or methyl, R 1 is hydrogen or lower alkyl of 1 to 6 carbon atoms, R 2 is hydrogen, alkyl of from 1 to 10 carbon atoms, aryl, cycloal alkyl of 3 to 6 carbon atoms, mono- or diphenyl-Cj-lower alkyl, wherein the phenyl group is optionally substituted with 1 to 2 identical or 20 different substituents which are halogen atoms or methyl or nitro groups, R 3 is hydrogen, halogen, methyl or trifluoromethyl, and Q is CH or N.
DK083183A 1978-04-03 1983-02-24 N-hetero-cyclyl-4-piperidineamines DK171841B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DK083183A DK171841B1 (en) 1978-04-03 1983-02-24 N-hetero-cyclyl-4-piperidineamines

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US89253478A 1978-04-03 1978-04-03
US89253478 1978-04-03
US227679 1979-01-10
US06/002,276 US4219559A (en) 1979-01-10 1979-01-10 N-Heterocyclyl-4-piperidinamines
DK129879 1979-03-29
DK129879A DK169325B1 (en) 1978-04-03 1979-03-29 Analogous process for the preparation of N-heterocyclyl-4-piperidinamines
DK83183 1983-02-24
DK083183A DK171841B1 (en) 1978-04-03 1983-02-24 N-hetero-cyclyl-4-piperidineamines

Publications (3)

Publication Number Publication Date
DK83183A DK83183A (en) 1983-02-24
DK83183D0 DK83183D0 (en) 1983-02-24
DK171841B1 true DK171841B1 (en) 1997-06-30

Family

ID=27439388

Family Applications (1)

Application Number Title Priority Date Filing Date
DK083183A DK171841B1 (en) 1978-04-03 1983-02-24 N-hetero-cyclyl-4-piperidineamines

Country Status (1)

Country Link
DK (1) DK171841B1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3583613A (en) * 1968-12-03 1971-06-08 Irving Gish Portable and foldable luggage carrier

Also Published As

Publication number Publication date
DK83183A (en) 1983-02-24
DK83183D0 (en) 1983-02-24

Similar Documents

Publication Publication Date Title
DK169325B1 (en) Analogous process for the preparation of N-heterocyclyl-4-piperidinamines
US4219559A (en) N-Heterocyclyl-4-piperidinamines
FI81797C (en) Process for the preparation of a five-membered heterocyclic ring containing therapeutically active N- (bicyclic heterocyclyl) -4-piperidinamine
KR870001510B1 (en) Process for preparation of n-(bicyclic heterocyclyl)-4-piperidinamines
FI77231B (en) ANALOGIFICANT FARING FOR THE PIPING OF PIPERIDES AND OF ANTI-PRESSIVE MEDICINAL PRODUCTS.
DK173674B1 (en) Anti-allergic preparations containing N-heterocyclyl-4-piperidinamines, N-heterocyclyl-4-piperidinamines for use as antiallergic and novel N-heterocyclyl-4-piperidinamines and process for their preparation
JPS61137884A (en) Benzoxazole- and benzothiazoleamine derivative
US4835161A (en) Anti-histaminic compositions containing n-heterocyclyl-4-piperidinamines
JPH0524151B2 (en)
US9493432B2 (en) Cyclopentylbenzamide derivatives and their use for the treatment of psychotic and cognitive disorders
JP2008526895A (en) Imidazole and benzimidazole derivatives useful as histamine H3 antagonists
JPS6231707B2 (en)
DK151017B (en) METHOD OF ANALOGUE FOR PREPARING SUBSTITUTED N- (4-INDOLYL-PIPERIDINO-ALKYL) -BENZIMIDAZOLONES OR PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF
DK171841B1 (en) N-hetero-cyclyl-4-piperidineamines
JPH01228986A (en) ((5 (6)(1h-azole-1-ylmethyl) benzimidazole) carbamate
IE61728B1 (en) Novel n-(4-piperidinyl) bicyclic condensed 2-imidazolamine derivatives
PL147092B1 (en) Process for preparing novel n-/bicycloheterocyclo/-4-piperidinamines
CZ284447B6 (en) 4-/3-(4-oxothiazoledinyl)/butinylamine, process for preparing such compound, pharmaceutical composition containing thereof and its use
JPS6230990B2 (en)
PL146228B1 (en) Method of obtaining novel n-/bicyclic heterocyclilo/-4-piperidinamines containing five-member heterocyclic rings
TH62392A (en) New quinoline and pyridine derivatives
CS234048B2 (en) Method of piperidine derivatives making

Legal Events

Date Code Title Description
B1 Patent granted (law 1993)
PUP Patent expired