SK42299A3 - N-(benzothiazol-2-yl) piperidine-1-ethanamine derivatives, their preparation and application in therapeutics - Google Patents
N-(benzothiazol-2-yl) piperidine-1-ethanamine derivatives, their preparation and application in therapeutics Download PDFInfo
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Abstract
Description
Oblasť technikyTechnical field
Predkladaný vynález sa týka derivátov N-(2-benzotiazolyl)-1-piperidínetánamínu, spôsobu ich výroby a farmaceutických prostriedkov, ktoré ich obsahujú.The present invention relates to N- (2-benzothiazolyl) -1-piperidineaethanamine derivatives, a process for their preparation and pharmaceutical compositions containing them.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Zlúčeniny s podobnou chemickou štruktúrou sú opísané v európskych patentových prihláškach č. 0 184 257 a 0 199 400 a v dokumente Annales Pharmaceutiques Frangaises, vol. 35, č. 7, Júl 1977, strany 295-307. Žiadny z týchto dokumentov neopisuje zlúčeniny podľa vynálezu, a taktiež sa netýka zlúčenín majúcich afinitu k D4 dopamínergickým receptorom.Compounds with a similar chemical structure are described in European patent applications no. 0 184 257 and 0 199 400 and in Annales Pharmaceutiques Frangaises, vol. 35, no. 7, July 1977, pp. 295-307. None of these documents disclose compounds of the invention, nor does it relate to compounds having affinity for D4 dopaminergic receptors.
Podstata vynálezuSUMMARY OF THE INVENTION
Predkladaný vynález sa týka zlúčenín vzorca IThe present invention relates to compounds of formula I
kde n je celé číslo 0, 1, 2 alebo 3;wherein n is an integer of 0, 1, 2 or 3;
R1 je atóm vodíka, atóm halogénu, metylová skupina alebo metoxyskupina;R 1 is a hydrogen atom, a halogen atom, a methyl group or a methoxy group;
R2 je atóm vodíka alebo metylová skupina aR 2 is H or methyl, and
R3 je atóm vodíka alebo jeden alebo dva atómy halogénu.R 3 is a hydrogen atom or one or two halogen atoms.
Zlúčeniny podlá vynálezu môžu existovať vo forme voľnej bázy alebo vo forme adičnej soli s kyselinami.The compounds of the invention may exist in the form of the free base or in the form of an acid addition salt.
V súlade s predkladaným vynálezom sa môžu zlúčeniny vzorca I pripraviť podľa spôsobu ilustrovaného schémou, ktorá nasleduj e.In accordance with the present invention, compounds of Formula I may be prepared according to the method illustrated by the scheme that follows.
V prípade zlúčenín, kde R2 je atóm vodíka a podľa schémy 1, zlúčenina vzorca II, kde R1 je definované vyššie, reaguje s chlóracetylchloridom vzorca III za podobných podmienok, ako sa opisuje v Bull. Soc. Chim. France 1962, 736-737, to znamená v aprotickom rozpúšťadle, napríklad v dioxáne, pri teplote 20 až 100° C.In the case of compounds wherein R 2 is a hydrogen atom and according to Scheme 1, a compound of formula II, wherein R 1 is as defined above, is reacted with chloroacetyl chloride of formula III under similar conditions to those described in Bull. Soc. Chim. France 1962, 736-737, i.e. in an aprotic solvent such as dioxane at a temperature of 20 to 100 ° C.
Získa sa amid vzorca IV, ktorý reaguje s piperidínom vzorca V, kde n a R3 sú definované vyššie, v aprotickom rozpúšťadle, napríklad v N,N-dimetylformamide, pri teplote 50 až 80° C a v prítomnosti anorganickej bázy, napríklad uhličitanu draselného. Získa sa amid vzorca VI, ktorý sa nakoniec redukuje na amín všeobecného vzorca I (R2 je atóm vodíka) pomocou jednoduchého alebo komplexného redukčného činidla, ako je hydrid alkalického kovu alebo iný kovový hydrid, napríklad lítiumalumíniumhydrid, hydrid boru, komplex hydrid bóru/tetrahydrofurán alebo komplex hydrid bóru/metylsulfid alebo hydrid hliníka, v aromatickom alebo éterickom inertnom rozpúšťadle, napríklad v toluéne, xyléne, dietyléteri, tetrahydrofuráne alebo dioxáne, pri teplote 30 až 140° C v závislosti od rozpúšťadla.An amide of formula IV is obtained, which is reacted with a piperidine of formula V, wherein R 3 is as defined above, in an aprotic solvent, for example N, N-dimethylformamide, at a temperature of 50 to 80 ° C and in the presence of an inorganic base such as potassium carbonate. To give an amide of formula VI, which is finally reduced to an amine of formula I (R2 is hydrogen) with a simple or complex reducing agent, such as an alkali metal hydride or other metal hydride, e.g. lithium aluminum hydride, boron hydride, a boron hydride complex / tetrahydrofuran or a boron hydride / methylsulfide or aluminum hydride complex, in an aromatic or ethereal inert solvent such as toluene, xylene, diethyl ether, tetrahydrofuran or dioxane, at a temperature of 30 to 140 ° C depending on the solvent.
Schéma 1Scheme 1
R1 R 1
(II)(II)
HMHM
'(CH2)n\ŕ^ŕ5\ +R3 (V)'(CH 2) n \ r ^ t 5 \ + R 3 (V)
(I, R2 = CH3)(I, R 2 = CH 3)
V prípade zlúčenín všeobecného vzorca I, kde R2 je metylová skupina a podía schémy 2, zlúčenina všeobecného vzorca II, kde R2 je definované vyššie, reaguje najskôr so zmesou anhydridu kyseliny octovej a kyseliny mravčej použitím podobných podmienok, ako sa opisuje v Tetrahedron Lett. 23(33), 3315-3318 (1982) a v J. Med. Chem. 9, 830-832 (1966), to znamená v inertnom rozpúšťadle, napríklad v tetrahydrofuráne, pri teplote 20 až 40° C a N-formylový medziprodukt, ktorý sa takto pripraví, sa potom redukuje tak, ako sa už uviedlo vo vzťahu k zlúčenine vzorca VI, čím sa získa N-metyl-2-benzotiazolamín všeobecného vzorca VII.The compounds of the formula I, wherein R 2 is methyl, and of Scheme 2, the compound of formula II wherein R 2 is as defined above, is reacted first with an acid anhydride of acetic and formic acid using similar conditions as described in Tetrahedron Lett . 23 (33), 3315-3318 (1982) and in J. Med. Chem. 9, 830-832 (1966), i.e. in an inert solvent, for example tetrahydrofuran, at 20 to 40 ° C, and the N-formyl intermediate thus prepared is then reduced as previously described in relation to the compound. of formula VI to give N-methyl-2-benzothiazolamine of formula VII.
Oddelene piperidínová zlúčenina všeobecného vzorca V, kde n a R1 sú definované vyššie, reaguje s l-bróm-2-chlóretánom použitím štandardných podmienok pre tento typ reakcií, to znamená v polárnom rozpúšťadle, napríklad v Ν,Ν-dimetylformamide, v prítomnosti anorganickej bázy, napríklad uhličitanu draselného, pri teplote 50 až 80° C.Separately, the piperidine compound of formula V, where R 1 is as defined above, is reacted with 1-bromo-2-chloroethane using standard conditions for this type of reaction, i.e. in a polar solvent, for example Ν, Ν-dimethylformamide, in the presence of an inorganic base. e.g. potassium carbonate, at a temperature of 50 to 80 ° C.
Získa sa chlórovaný derivát všeobecného vzorca IX, ktorý nakoniec reaguje s N-metyl-2-benzotiazolamínom vzorca VII v polárnom rozpúšťadle, napríklad v Ν,Ν-dimetylformamide, v prítomnosti anorganickej bázy, napríklad uhličitanu draselného, pri teplote 80 až 100° C, čím sa získa zlúčenina všeobecného vzorca I (R2 je metylová skupina).There is obtained a chlorinated derivative of the general formula IX which is finally reacted with N-methyl-2-benzothiazolamine of the general formula VII in a polar solvent, for example in Ν, Ν-dimethylformamide, in the presence of an inorganic base such as potassium carbonate at 80 to 100 ° C; to give a compound of formula I (R 2 is methyl).
Schéma 2Scheme 2
Východiskové zlúčeniny všeobecného vzorca II sú komerčne dostupné.The starting compounds of formula II are commercially available.
Východiskové zlúčeniny vzorca V sú komerčne dostupné alebo sa opisujú v patentových prihláškach EP-0109317 a EP-0524846.The starting compounds of formula V are commercially available or described in patent applications EP-0109317 and EP-0524846.
Príklady, ktoré nasledujú, podrobne ilustrujú prípravu niektorých zlúčenín podlá vynálezu. Elementárna analýza, IČ a NMR spektrá zodpovedajú štruktúram požadovaných zlúčenín.The examples that follow illustrate in detail the preparation of some of the compounds of the invention. Elemental analysis, IR and NMR spectra are consistent with the structures of the desired compounds.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Čísla zlúčenín uvedených v zátvorkách zodpovedajú číslam uvedeným v tabulke.The numbers of the compounds in brackets correspond to those in the table.
Príklad 1 (zlúčenina č. 1)Example 1 (Compound No. 1)
N-(2-Benzotiazolyl)-4-fenyl-l-piperidínetánamínN- (2-benzothiazolyl) -4-phenyl-l-piperidineethanamine
1.1 N-(2-Benzotiazolyl)-2-chlóracetamid hydrochlorid g (0,1 mol) 2-benzotiazolamínu a 200 ml dioxánu sa umiestni do 1 1 banky s okrúhlym dnom, zmes sa mieša do úplného rozpustenia, pridá sa roztok 11,3 g (0,1 mol) chlóracetylchloridu a zmes sa zohrieva na olejovom kúpeli na teplotu 50° C počas 24 hodín. Pridá sa ďalších 5,6 g (0,05 mol) chlóracetylchloridu rozpusteného v 50 ml dioxánu a v zohrievaní na teplotu 50° C sa pokračuje cez noc. Zmes sa nechá vychladnúť a zrazenina sa odfiltruje, premyje malým množstvom dioxánu a potom petroléterom a vysuší sa v prítomnosti oxidu fosforečného. Získa sa 25,49 g produktu, ktorý sa bez ďalšieho čistenia použije v ďalšom kroku.1.1. N- (2-Benzothiazolyl) -2-chloroacetamide hydrochloride g (0.1 mol) of 2-benzothiazolamine and 200 ml of dioxane are placed in a 1 l round-bottom flask, stirred until complete dissolution, and a solution of 11.3 is added. g (0.1 mol) of chloroacetyl chloride and the mixture was heated in an oil bath at 50 ° C for 24 hours. An additional 5.6 g (0.05 mol) of chloroacetyl chloride dissolved in 50 ml of dioxane was added and heating at 50 ° C was continued overnight. The mixture was allowed to cool and the precipitate was filtered off, washed with a small amount of dioxane and then with petroleum ether and dried in the presence of phosphorus pentoxide. 25.49 g of product are obtained, which product is used as is in the following stage.
1.2 N-(2-Benzotiazolyl)-4-fenyl-l-piperidínacetamid1.2 N- (2-Benzothiazolyl) -4-phenyl-1-piperidineacetamide
2,63 g (0,01 mol) hydrochloridu N-2-(benzotiazolyl)-2-chlóracetamidu, 1,61 g (0,01 mol) 4-fenylpiperidínu, 2,76 g uhličitanu draselného a 80 ml N,N-dimetylformamidu sa umiestni do 500 ml banky s okrúhlym dnom a zmes sa zohrieva počas2.63 g (0.01 mol) of N-2- (benzothiazolyl) -2-chloroacetamide hydrochloride, 1.61 g (0.01 mol) of 4-phenylpiperidine, 2.76 g of potassium carbonate and 80 ml of N, N- of dimethylformamide is placed in a 500 ml round bottom flask and the mixture is heated for
3,5 hodiny na teplotu 50° C. Zmes sa nechá vychladnúť, pridá sa 160 ml vody a zrazenina sa odfiltruje a vysuší. Získa sa 3,15 g produktu, ktorý sa použije bez ďalšieho čistenia v ďalšom kroku.The mixture is allowed to cool, 160 ml of water are added and the precipitate is filtered off and dried. 3.15 g of product are obtained, which product is used as is in the following stage.
1.3 N-(2-Benzotiazolyl)-4-fenyl-l-piperidínetánamín1.3. N- (2-Benzothiazolyl) -4-phenyl-1-piperidineethanamine
430 mg (0,0112 mol) lítiumalumíniumhydridu a potom 60 ml tetrahydrofuránu sa umiestni do 500 ml banky s okrúhlym dnom a suspenzia sa zohreje na teplotu varu. Prikvapkajú sa 2 g (0,0056 mol) N-(2-benzotiazolyl)-4-fenyl-l-piperidínacetamidu rozpusteného v 30 ml tetrahydrofuránu a v zohrievaní sa pokračuje počas ďalších 15 minút. Zmes sa ochladí, pridá sa 56 ml etylacetátu a 22 ml vody, organická vrstva sa po rozsadení oddelí, rozpúšťadlá sa odparia pri zníženom tlaku a olejovitý zvyšok sa vysuší pri zníženom tlaku. Získa sa 2,48 g surového produktu, ktorý sa prečistí pomocou chromatografie na kolóne silikagélu, pričom sa eluuje zmesou 9 : 1 dichlórmetán a metanol, čím sa získa 1,6 g svetložltého oleja, ktorý kryštalizuje. Po rekryštalizácii z 2-propanolu a vysušení pri zníženom tlaku sa vyizoluje 0,81 g zlúčeniny.430 mg (0.0112 mol) of lithium aluminum hydride and then 60 ml of tetrahydrofuran are placed in a 500 ml round bottom flask and the suspension is heated to boiling. 2 g (0.0056 mol) of N- (2-benzothiazolyl) -4-phenyl-1-piperidineacetamide dissolved in 30 ml of tetrahydrofuran are added dropwise and heating is continued for a further 15 minutes. The mixture was cooled, 56 ml of ethyl acetate and 22 ml of water were added, the organic layer was separated after settling, the solvents were evaporated under reduced pressure and the oily residue was dried under reduced pressure. 2.48 g of crude product are obtained, which is purified by silica gel column chromatography, eluting with a 9: 1 mixture of dichloromethane and methanol, to give 1.6 g of a pale yellow oil which crystallizes. After recrystallization from 2-propanol and drying under reduced pressure, 0.81 g of compound is isolated.
Teplota topenia: 140-141° C.M.p .: 140-141 ° C.
Príklad 2 (zlúčenina č. 3)Example 2 (Compound No. 3)
Etándioát N-(2-benzotiazolyl)-4-[(4-fluórfenyl)metyl]-1-piperidínetánamínuN- (2-Benzothiazolyl) -4 - [(4-fluorophenyl) methyl] -1-piperidineaethanamine ethanedioate
2.1 N-(2-Benzotiazolyl)-4-(4-fluórfenyl)metyl-l-piperidínacetamid2.1. N- (2-Benzothiazolyl) -4- (4-fluorophenyl) methyl-1-piperidineacetamide
2,26 g (0,0086 mol) hydrochloridu N-(2-benzotiazolyl)-2-chlóracetamidu, 2,29 g (0,01 mol) hydrochloridu 4-[(4-fluórfenyl)metyl]piperidínu, 4,14 g (0,03 mol) uhličitanu draselného a 80 ml N,N-dimetylformamidu sa umiestni do 500 ml banky s okrúhlym dnom a zmes sa zohrieva počas 2,5 hodiny na teplotu 50° C. Zmes sa nechá vychladnúť, pridá sa 240 ml vody, zmes sa ochladí v ladovom kúpeli a biela zrazenina sa odfiltruje, dôkladne sa premyje vodou a vysuší sa v prítomnosti oxidu fosforečného. Získa sa 2,9 g produktu, ktorý sa rekryštalizuje z 30 ml etanolu. Po vysušení sa získa 2,42 g zlúčeniny.2.26 g (0.0086 mol) of N- (2-benzothiazolyl) -2-chloroacetamide hydrochloride, 2.29 g (0.01 mol) of 4 - [(4-fluorophenyl) methyl] piperidine hydrochloride, 4.14 g (0.03 mol) of potassium carbonate and 80 ml of N, N-dimethylformamide are placed in a 500 ml round bottom flask and the mixture is heated at 50 ° C for 2.5 hours. The mixture is allowed to cool, 240 ml of water are added. The mixture was cooled in an ice bath and the white precipitate was filtered off, washed thoroughly with water and dried in the presence of phosphorus pentoxide. 2.9 g of product are obtained, which product is recrystallized from 30 ml of ethanol. After drying, 2.42 g of compound is obtained.
Teplota topenia: 141-142° C.M.p .: 141-142 ° C.
2.2 Etándioát N-(2-benzotiazolyl)-4-[(4-fluórfenyl)metyl]-1-piperidínetánamínu2.2 N- (2-Benzothiazolyl) -4 - [(4-fluorophenyl) methyl] -1-piperidineaethanamine ethanedioate
1,3 g (0,00349 mol) N-(2-benzotiazolyl)-4-[(4-fluórfenyl)-metyl]-1-piperidínacetamidu sa rozpustí v 25 ml suchého tetra8 hydrofuránu a v dusíkovej atmosfére sa umiestni do 250 ml trojhrdlovej banky s okrúhlym dnom, pridá sa 1,09 ml, čo sú 3 ekvivalenty, komplexu borán/metylsulfid a zmes sa zohrieva počas 4 hodín na teplotu varu. Zmes sa nechá vychladnúť na teplotu miestnosti, pridá sa zmes 53 ml 2N kyseliny chlorovodíkovej a 25 ml metanolu a zmes sa zohrieva znovu na teplotu varu počasDissolve 1.3 g (0.00349 mol) of N- (2-benzothiazolyl) -4 - [(4-fluorophenyl) methyl] -1-piperidineacetamide in 25 ml of dry tetrahydrofuran and place in a 250 ml three-necked flask under nitrogen. round bottom flasks, 1.09 ml, 3 equivalents, of borane / methylsulfide complex is added and the mixture is heated at reflux for 4 hours. The mixture is allowed to cool to room temperature, a mixture of 53 ml of 2N hydrochloric acid and 25 ml of methanol is added and the mixture is again heated to boiling point for
1,5 hodiny a nechá sa stáť cez noc. K zmesi sa pridáva koncentrovaný hydroxid sodný až kým sa pH nezmení na alkalické a zmes sa extrahuje trikrát etylacetátom. Organická vrstva sa premyje vodou, vysuší sa nad síranom sodným a prefiltruje sa a filtrát sa odparí pri zníženom tlaku. Získa sa 1,6 g olejovitého produktu, ktorý sa prečistí pomocou chromatografie na kolóne silikagélu, pričom sa eluuje zmesou 95 : 5 dichlórmetán a metanol. Získa sa 0,83 g nepriehľadného oleja, ktorý sa rozpustí v 2-propanole s jedným ekvivalentom kyseliny šťaveľovej. Po rekryštalizácii, filtrácii a sušení sa vyizoluje 0,73 g zlúčeniny .1.5 hours and allowed to stand overnight. Concentrated sodium hydroxide is added to the mixture until the pH becomes alkaline and the mixture is extracted three times with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. 1.6 g of an oily product are obtained, which product is purified by silica gel column chromatography, eluting with a 95: 5 mixture of dichloromethane and methanol. 0.83 g of an opaque oil is obtained, which is dissolved in 2-propanol with one equivalent of oxalic acid. After recrystallization, filtration and drying, 0.73 g of compound is isolated.
Teplota topenia: 155-156° C.M.p .: 155-156 ° C.
Príklad 3 (Zlúčenina č. 4)Example 3 (Compound No. 4)
Etándioát N-(2-benzotiazolyl)-N-metyl-4-(fenylmetyl)-1-piperidínetánamínuN- (2-benzothiazolyl) -N-methyl-4- (phenylmethyl) -1-piperidineaethanamine ethanedioate
3.1 N-Metyl-2-benzotiazolamín3.1 N-Methyl-2-benzothiazolamine
10,2 ml anhydridu kyseliny octovej sa umiestni do banky s okrúhlym dnom, za miešania sa prikvapká 4,3 ml kyseliny mravčej a zmes sa zohrieva počas 2 hodín na teplotu 50° C. Zmes sa ochladí na teplotu miestnosti, pridá sa 10 ml suchého tetrahydrofuránu, prikvapká sa roztok 11,25 g (0,075 mol) 2-benzotiazolamínu v 30 ml suchého tetrahydrofuránu tak, aby teplota neprekročila 40° C a zmes sa nechá stáť počas 2 dní. Rozpúšťadlo sa odparí pri zníženom tlaku a kryštalický zvyšok sa dvakrát premyje petroléterom a vysuší sa v prítomnosti oxidu fosforečného. Získa sa 13 g medziproduktu N-(2-benzotiazolyl)formamidu. Pripraví sa suspenzia 0,854 g (0,0224 mol) lítiumalumínium9 hydridu v 50 ml tetrahydrofuránu a zohreje sa na teplotu varu a pridá sa roztok 2 g (0,0112.mol) formylového medziproduktu v 100 ml tetrahydrofuránu a v zohrievaní sa pokračuje počas 30 minút. Zmes sa ochladí, pridá sa 100 ml etylacetátu, prikvapká sa 38 ml vody, organická vrstva sa po rozsadení oddelí a odparí sa pri zníženom tlaku a zvyšok sa kryštalizuje z petroléteru, odfiltruje sa a vysuší sa v prítomnosti oxidu fosforečného. Získa sa 1,5 g zlúčeniny.Place 10.2 ml of acetic anhydride in a round-bottomed flask, add dropwise with stirring 4.3 ml formic acid and heat the mixture at 50 ° C for 2 hours. Cool the mixture to room temperature, add 10 ml dry tetrahydrofuran, a solution of 11.25 g (0.075 mol) of 2-benzothiazolamine in 30 ml of dry tetrahydrofuran is added dropwise so that the temperature does not exceed 40 ° C and the mixture is allowed to stand for 2 days. The solvent was evaporated under reduced pressure and the crystalline residue was washed twice with petroleum ether and dried in the presence of phosphorus pentoxide. 13 g of intermediate N- (2-benzothiazolyl) formamide are obtained. A suspension of 0.854 g (0.0224 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran is prepared and heated to boiling and a solution of 2 g (0.0112 mol) of the formyl intermediate in 100 ml of tetrahydrofuran is added and heating is continued for 30 minutes. The mixture is cooled, 100 ml of ethyl acetate are added, 38 ml of water are added dropwise, the organic layer is separated after settling and evaporated under reduced pressure and the residue is crystallized from petroleum ether, filtered off and dried in the presence of phosphorus pentoxide. 1.5 g of compound are obtained.
3.2 1-(2-Chlóretyl)-4-(fenylmetyl)piperidín3.2 1- (2-Chloroethyl) -4- (phenylmethyl) piperidine
2,5 g (0,02 mol) 4-(fenylmetyl)piperidínu rozpusteného v 50 ml N,N-dimetylformamidu sa umiestni do banky s okrúhlym dnom, pridá sa 2,86 g (0,02 mol) l-bróm-2-chlóretánu a 2,76 g (0,02 mol) uhličitanu draselného a zmes sa energicky mieša počas 1 hodiny pri teplote miestnosti. Zmes sa vyleje do 250 ml ľadovej vody a extrahuje sa dvakrát 150 ml etylacetátu. Organická vrstva sa premyje solankou a rozpúšťadlo sa odparí pri zníženom tlaku. Získa sa 7 g olejovitého produktu, ktorý sa prečistí pomocou chromatografie na kolóne silikagélu, pričom sa eluuje etylacetátom. Získa sa 2,1 g čistého produktu vo forme oleja.2.5 g (0.02 mol) of 4- (phenylmethyl) piperidine dissolved in 50 ml of N, N-dimethylformamide are placed in a round-bottomed flask and 2.86 g (0.02 mol) of 1-bromo-2 are added. chloroethane and 2.76 g (0.02 mol) of potassium carbonate, and the mixture was stirred vigorously for 1 hour at room temperature. The mixture was poured into 250 ml of ice-water and extracted twice with 150 ml of ethyl acetate. The organic layer was washed with brine and the solvent was evaporated under reduced pressure. 7 g of an oily product are obtained, which product is purified by silica gel column chromatography, eluting with ethyl acetate. 2.1 g of pure product are obtained in the form of an oil.
3.3 Etándioát N-(2-benzotiazolyl)-N-metyl-4-(fenylmetyl)-1-piperidínetánamínu g (0,00421 mol) 1-(2-chlóretyl)-4-(fenylmetyl)piperidínu sa rozpustí v 25 ml N,N-dimetylformamidu, pridá sa 0,7 g (0,00426 mol) N-metyl-2-benzotiazolamínu a 0,8 g uhličitanu draselného a zmes sa zohrieva počas 1 hodiny na teplotu 100° C. Zmes sa ochladí v ľadovom kúpeli, pridá sa 50 ml vody, zmes sa extrahuje dvakrát 100 ml etylacetátu a organická vrstva sa premyje solankou a odparí sa. Získa sa olejovitý zvyšok, ktorý sa prečistí pomocou dvoch následných chromatografii na kolóne silikagélu, pričom najskôr sa eluuje zmesou 90 : 10 dichlórmetán a metanol a potom etylacetátom. Získa sa 0,3 g zlúčeniny, 0,1 g z nej sa prevedie dó formy oxalátu v etanole.3.3. N- (2-Benzothiazolyl) -N-methyl-4- (phenylmethyl) -1-piperidineaethanamine ethanedioate g (0.00421 mol) of 1- (2-chloroethyl) -4- (phenylmethyl) piperidine is dissolved in 25 ml of N , N-dimethylformamide, 0.7 g (0.00426 mol) of N-methyl-2-benzothiazolamine and 0.8 g of potassium carbonate are added and the mixture is heated at 100 ° C for 1 hour. The mixture is cooled in an ice bath. 50 ml of water are added, the mixture is extracted twice with 100 ml of ethyl acetate and the organic layer is washed with brine and evaporated. An oily residue is obtained, which is purified by two successive silica gel column chromatography, eluting first with dichloromethane / methanol 90: 10 and then with ethyl acetate. 0.3 g of compound is obtained, 0.1 g of which is converted into the oxalate form in ethanol.
Teplota topenia: 164-166° C.Melting point: 164-166 ° C.
Príklad 4 (zlúčenina č. 11)Example 4 (Compound No. 11)
N- (2-Benzotiazolyl)-4-[2-(4-fluórfenyl)etyl]-1-piperidínetánamínN- (2-Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidinoethanamine
4.1 N-(2-Benzotiazolyl)-4-[2-(4-fluórfenyl)etyl]-1-piperidínacetamid4.1. N- (2-Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidineacetamide
2,63 g (0,01 mol) hydrochloridu N-(2-benzotiazolyl)-2-chlóracetamidu, 2,44 g (0,01 mol) hydrochloridu 4-[2-(4-fluórfenyl)etyl]piperidínu, 4,14 g (0,03 mol) uhličitanu draselného a 80 ml N,N-dimetylformamidu sa umiestni do 500 ml banky s okrúhlym dnom a zmes sa zohrieva počas 3,5 hodiny na teplotu 50° C. Zmes sa nechá vychladnúť, pridá sa 240 ml vody a zmes sa extrahuje 300 ml etylacetátu. Organická vrstva sa premyje vodou a potom nasýteným roztokom chloridu sodného, vysuší sa nad síranom sodným a prefiltruje sa a filtrát sa potom odparí pri zníženom tlaku. Získa sa hnedý olejovitý produkt, ktorý sa požije bez ďalšieho čistenia v nasledovnom kroku.2.63 g (0.01 mol) of N- (2-benzothiazolyl) -2-chloroacetamide hydrochloride, 2.44 g (0.01 mol) of 4- [2- (4-fluorophenyl) ethyl] piperidine hydrochloride, 4, 14 g (0.03 mol) of potassium carbonate and 80 ml of N, N-dimethylformamide are placed in a 500 ml round-bottom flask and the mixture is heated at 50 ° C for 3.5 hours. The mixture is allowed to cool, 240 ml are added. ml of water and extracted with 300 ml of ethyl acetate. The organic layer was washed with water and then with saturated sodium chloride solution, dried over sodium sulfate and filtered, and then the filtrate was evaporated under reduced pressure. A brown oily product is obtained which is used without further purification in the next step.
4.2 N-(2-Benzotiazolyl)-4-[2-(4-fluórfenyl)etyl]-1-piperidínetánamín4.2. N- (2-Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidinoethanamine
0,96 g (0,025 mol) lítiumalumíniumhydridu a 140 ml suchého tetrahydrofuránu sa umiestni v dusíkovej atmosfére do 500 ml trojhrdlovej banky s okrúhlym dnom, suspenzia sa zohreje na teplotu varu a prikvapká sa 5,0 g (0,01 mol) N-(2-benzotiazolyl) -4- [2- (4-fluórfenyl)etyl]-1-piperidínacetamidu rozpusteného v 60 ml suchého tetrahydrofuránu a v zohrievaní sa pokračuje počas 30 minút. Zmes sa ochladí, pridá sa 140 ml etylacetátu a 51 ml vody, organická vrstva sa oddelí, rozpúšťadlá sa odparia pri zníženom tlaku a zvyšok sa prečistí pomocou chromatografie na kolóne silikagélu, pričom sa eluuje zmesou 9 : 1 dichlórmetán a metanol. Získa sa 1,6 g oleja, ktorý kryštalizuje. Po rekryštalizácii zo zmesi etanol a voda a vysušení pri zníženom tlaku sa vyizoluje 1,23 g požadovanej zlúčeniny.0.96 g (0.025 mol) of lithium aluminum hydride and 140 ml of dry tetrahydrofuran are placed under nitrogen in a 500 ml three-necked round-bottomed flask, the suspension is heated to boiling and 5.0 g (0.01 mol) of N- (dropwise) are added dropwise. 2-Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidineacetamide dissolved in 60 mL dry tetrahydrofuran and heating was continued for 30 minutes. The mixture was cooled, 140 ml of ethyl acetate and 51 ml of water were added, the organic layer was separated, the solvents were evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with 9: 1 dichloromethane: methanol. 1.6 g of an oil are obtained, which crystallizes. After recrystallization from ethanol-water and drying under reduced pressure, 1.23 g of the desired compound is isolated.
Teplota topenia: 107-108° C.Melting point: 107-108 ° C.
Tabuľka, ktorá nasleduje, ilustruje chemické štruktúry a fyzikálne vlastnosti niekoľkých zlúčenín podľa vynálezu. V kolónke „soľ značka znamená zlúčeninu v základnom stave, „ox. znamená oxalát alebo etándioát a „fum. znamená fumarát alebo (£)-2-buténdioát. Molárny pomer kyselina/báza je uvedený v zátvorkách.The table that follows illustrates the chemical structures and physical properties of several compounds of the invention. In the column " salt " means oxalate or ethanedioate and "fum. means fumarate or (E) -2-butenedioate. The molar acid / base ratio is shown in brackets.
Tabuľkatable
Zlúčeniny podlá vynálezu sa podrobili testom, pomocou ktorých sa demonštrovala ich účinnosť ako terapeuticky aktívnych látok.The compounds of the invention were tested to demonstrate their efficacy as therapeutically active agents.
Študovala sa ich neuroprotektívna aktivita na modeli permanentnej fokálnej ischémie produkovanej intraluminálnou oklúziou strednej mozgovej tepny u potkanov podlá spôsobu, ktorý sa opisuje v Stroke 20, 84-91 (1989).Their neuroprotective activity was studied in a model of permanent focal ischemia produced by intraluminal occlusion of the middle cerebral artery in rats according to the method described in Stroke 20, 84-91 (1989).
Za anestézie sodnou soľou metohexitonu sa pterigopalatinná tepna, krčná tepna a lavá vonkajšia krčná tepna podviažu a do vnútornej krčnej tepny sa zavedie polyamidové vlákno s dĺžkou asi 18 mm, čo zodpovedá vzdialenosti oddeľujúcej miesto začiatku vnútornej krčnej tepny a strednej mozgovej tepny.Under anesthesia with sodium salt of metohexiton, the pterigopalatin artery, carotid artery and left external carotid artery are ligated and a polyamide fiber about 18 mm in length is inserted into the inner carotid artery, corresponding to the distance separating the origin of the inner carotid artery and the middle cerebral artery.
Študované zlúčeniny sa podávajú vnútrožilovo po uzatvorení.Study compounds are administered intravenously after closure.
hodín po uzatvorení strednej mozgovej tepny sa zvieratá usmrtia a vyberie sa mozog.hours after the cerebral artery occlusion, the animals are sacrificed and the brain removed.
Objem mozgového infarktu sa hodnotí z meranej plochy nekrózy v 6 koronárnych sekciách 2,3,5-trifenyltetrazóliumchloridom. Napríklad zlúčenina č. 11 v uvedenej tabulke významne znižuje objem infarktu z asi 48 % pri dávke 1 mg/kg pri vnútrožilovom podávaní v časoch 10 minút, 1,5 hodiny, 3 hodiny a 6 hodín po uzatvorení.The volume of cerebral infarction is evaluated from the measured area of necrosis in 6 coronary sections with 2,3,5-triphenyltetrazolium chloride. For example, compound no. 11 in the above table significantly reduces infarct volume from about 48% at a dose of 1 mg / kg by intravenous administration at 10 minutes, 1.5 hours, 3 hours and 6 hours after occlusion.
Zlúčeniny podlá vynálezu sa podrobili aj testu celkovej mozgovej ischémie u myší.The compounds of the invention were also subjected to a total brain ischemia test in mice.
Ischémia sa spôsobila srdcovou zástavou vyvolanou rýchlym vnútrožilovým podaním chloridu horečnatého. Pri tomto teste sa meria „čas prežitia, čo je interval medzi podaním injekcie chloridu horečnatého a posledným pozorovateľným dýchacím pohybom u každej myši. Tento posledný pohyb sa považuje za poslednú známku fungovania centrálnej nervovej sústavy. K zástave dychu dôjde asi 19 sekúnd po injekcii chloridu horečnatého.Ischemia was caused by cardiac arrest induced by rapid intravenous administration of magnesium chloride. In this test, the survival time, which is the interval between the injection of magnesium chloride and the last observable breathing movement in each mouse, is measured. This last movement is considered to be the last sign of central nervous system functioning. Respiratory arrest occurs about 19 seconds after the injection of magnesium chloride.
Študovala sa skupina 10 samcov myší (Charles River CD1) . Myši sa pred testom kŕmili a podávala sa im voda podlá potreby.A group of 10 male mice (Charles River CD1) were studied. Mice were fed prior to the test and given water as needed.
Čas prežitia sa meral 10 minút po intraperitoneálnom podaní zlúčeniny podlá vynálezu. Výsledky sú uvedené vo forme rozdielu medzi časom prežitia nemeraným v skupine 10 myší, ktorým sa podala zlúčenina, a časom prežitia nameraným v skupine 10 myší, ktoré dostali iba kvapalný nosič. Vzťahy medzi úpravou času prežitia a dávkou zlúčeniny sú zaznamenané graficky podľa semilogaritmickej krivky.Survival time was measured 10 minutes after intraperitoneal administration of a compound of the invention. The results are presented as the difference between the survival time not measured in the group of 10 mice receiving the compound and the survival time measured in the group of 10 mice receiving only the liquid carrier. Relationships between survival time adjustment and compound dose are plotted graphically according to the semi-logarithmic curve.
Z tejto krivky sa vypočíta „trojsekundová účinná dávka (ED3--), čo je dávka (v mg/kg), ktorá poskytne predĺženie času prežitia o 3 sekundy vzhladom na kontrolnú skupinu 10 neošetrených myší. Predĺženie času prežitia o 3 sekundy je tak štatisticky významné, ako aj reprodukovateľné. Hodnoty ED3·- najaktívnejších zlúčenín podľa vynálezu sú nižšie než 5 mg/kg pri intraperitoneálnom spôsobe podania.From this curve, a "three-second effective dose (ED 3--)", which is the dose (in mg / kg) that gives an increase in survival time of 3 seconds relative to a control group of 10 untreated mice, is calculated. An increase in survival time of 3 seconds is both statistically significant and reproducible. The values ED 3; - the most active compounds of the invention are less than 5 mg / kg via the intraperitoneal route of administration.
Zlúčeniny podľa vynálezu sa podrobili aj in vitro štúdii na afinitu k D4 dopamínergickým receptorom získaným transfekciou ľudských D4.4 receptorov do CHO buniek, čo sa v podstate opisuje v Van Tol a kol., Náture 350, 610-614 (1991) a Van Tol a kol.,The compounds of the invention have also been subjected to an in vitro study of the affinity for D 4 dopaminergic receptors obtained by transfecting human D4.4 receptors into CHO cells, essentially as described in Van Tol et al., Nature 350, 610-614 (1991) and Van Tol et al.,
Náture 358, 149-152 (1992).Nature 358, 149-152 (1992).
V deň pokusu sa membránové prostriedky (Receptor Biology, Inc., Glen Echio, MD20812, USA) skladované pri teplote - 80° C rýchlo rozmrazili a potom sa zriedili 20-násobkom objemu inkubačného pufra (50 mM Trís-HCl, 120 mM chlorid sodný, 5 mM chlorid draselný, 2 mM chlorid vápenatý, 5 mM chlorid horečnatý, pH = 7,5) .On the day of the experiment, membrane formulations (Receptor Biology, Inc., Glen Echio, MD20812, USA) were thawed at -80 ° C rapidly and then diluted with 20-fold volume of incubation buffer (50 mM Tris-HCl, 120 mM sodium chloride). , 5 mM potassium chloride, 2 mM calcium chloride, 5 mM magnesium chloride, pH = 7.5).
Suspenzia membrán (100 μΐ, 78 μg membrán) sa inkubuje pri teplote 25° C počas 60 minút v prítomnosti 0,5 nM [3H] spiperonu (špecifická aktivita 17 až 20 Ci/mmol, New England Nuclear/Du Pont de Nemours, Boston, MA, USA) v konečnom objeme 1 ml inkubačného pufra v prítomnosti alebo v neprítomnosti testovanej zlúčeniny.The membrane suspension (100 μΐ, 78 μg membranes) is incubated at 25 ° C for 60 minutes in the presence of 0.5 nM [ 3 H] spiperone (specific activity 17 to 20 Ci / mmol, New England Nuclear / Du Pont de Nemours, Boston, MA, USA) in a final volume of 1 ml incubation buffer in the presence or absence of test compound.
Inkubácia sa ukončí pomocou filtrácie, pričom sa použijú Whatman GB/B® filtre vopred spracované polyetylénimínom (0,5 %) .The incubation is terminated by filtration using Whatman GB / B® filters pretreated with polyethyleneimine (0.5%).
Každá reakčná skúmavka sa trikrát prepláchne 3 ml Tris-NaCl pufra (50 mM Tris-HCl, 120 mM chlorid sodný, pH = 7,5).Each reaction tube is rinsed three times with 3 ml of Tris-NaCl buffer (50 mM Tris-HCl, 120 mM sodium chloride, pH = 7.5).
Filtre sa vysušia v peci pri teplote 120° C počas 5 minút. Pomocou kvapalinovej scintigrafie sa určí zvyšková rádioaktivita na filtroch. Nešpecifické väzby sa určia v prítomnosti 1 μΜ haloperidolu.The filters are dried in an oven at 120 ° C for 5 minutes. Residual radioactivity on the filters is determined by liquid scintigraphy. Non-specific binding is determined in the presence of 1 μΜ haloperidol.
Pre každú koncentráciu študovanej zlúčeniny sa vypočíta percentuálna inhibícia špecifickej väzby [3H]spiperonu a potom sa určí IC50, koncentrácia, ktorá inhibuje 50 % väzieb.For each concentration of study compound, the percent inhibition of the specific binding of [ 3 H] spiperone is calculated and then the IC 50 , the concentration that inhibits 50% of the binding, is determined.
Hodnoty IC50 zlúčenín podľa vynálezu sa pohybujú v rozsahu 3 až 30 nM.IC 50 values of the compounds of the invention range from 3 to 30 nM.
Výsledky testov ukazujú, že zlúčeniny podľa predkladaného vynálezu majú in vivo neuroprotektívne vlastnosti, a že bránia in vitro špecifickej väzbe [3H] spiperonu k ľudským D4.4 dopamínergickým receptorom.The test results show that the compounds of the present invention have neuroprotective properties in vivo and prevent the in vitro specific binding of [ 3 H] spiperone to human D 4 . 4 dopaminergic receptors.
Môžu sa teda použiť na jednej strane na liečbu a prevenciu mozgovocievnych porúch ischemického alebo hypoxického pôvodu (mozgový infarkt, kraniálna alebo miechová trauma, srdcová alebo dýchacia zástava, prechodná ischemická slabosť), zeleného očného zákalu, progresívnych neurodegeneratívnych porúch (starecká demencia, ako je Alzheimerova choroba, cievne demencie, Parkinsonova choroba, Huntingtonova choroba, olivopontocerebrálna atrofia, amiotrofná laterálna skleróza, neurodegeneratívne poruchy vírusového pôvodu a podobne) a aj na prevenciu mozgových ischemických príhod spojených so srdcovou a cievnou chirurgiou alebo endovaskulárnou liečbou.Thus, they can be used on the one hand to treat and prevent cerebrovascular disorders of ischemic or hypoxic origin (cerebral infarction, cranial or spinal cord trauma, cardiac or respiratory arrest, transient ischemic weakness), glaucoma, progressive neurodegenerative disorders such as Alzheimer's dementia, disease, vascular dementia, Parkinson's disease, Huntington's disease, olivopontocerebral atrophy, amiotrophic lateral sclerosis, neurodegenerative disorders of viral origin and the like) and also to prevent cerebral ischemic events associated with cardiac and vascular surgery or endovascular therapy.
Na druhej strane sa môžu zlúčeniny podľa vynálezu použiť na liečbu psychózy, najmä schizofrénie (deficientnej a produktívnej formy) a akútnych a chronických extrapyramídových symptómov vyvolaných neuroleptikami alebo pochádzajúcich z Parkinsonovej choroby, na liečbu rôznych foriem úzkosti, záchvatov panického strachu, fóbií, obsesívnych porúch, na liečbu rôznych foriem depresie, vrátane psychotickej depresie, na liečbu závislosti na drogách a alkohole a porúch hypotalamohypofyzálnej funkcie a na liečbu porúch rozpoznávania spojených s vekom alebo Alzheimerovou chorobou.On the other hand, the compounds of the invention may be used to treat psychosis, particularly schizophrenia (deficient and productive forms) and acute and chronic extrapyramidal symptoms induced by neuroleptics or originating from Parkinson's disease, to treat various forms of anxiety, panic attacks, phobias, obsessive disorders, for the treatment of various forms of depression, including psychotic depression, for the treatment of drug and alcohol dependence and hypothalamic pituitary disorders, and for the treatment of cognitive disorders associated with age or Alzheimer's disease.
Zlúčeniny podľa predkladaného vynálezu môžu byť prítomné vo všetkých farmaceutický prijateľných dávkovacích formách v kombinácii s vhodnými prísadami na enterálne, parenterálne alebo transdermálne podávanie, napríklad vo forme tabliet, dražé, toboliek vrátane tvrdých želatínových toboliek, roztokov alebo suspenzií na orálne podávanie alebo injekčné podávanie, čapíkov, náplastí a podobne, obsahujúcich dávky, ktoré zodpovedajú dennej dávke 1 až 500 mg aktívnej látky.The compounds of the present invention may be present in all pharmaceutically acceptable dosage forms in combination with suitable excipients for enteral, parenteral or transdermal administration, for example in the form of tablets, dragees, capsules including hard gelatin capsules, solutions or suspensions for oral administration or injection, suppositories , patches and the like, containing doses corresponding to a daily dose of 1 to 500 mg of the active ingredient.
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| FR9611925A FR2753970B1 (en) | 1996-10-01 | 1996-10-01 | N- (BENZOTHIAZOL-2-YL) PIPERIDINE-1-ETHANAMINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| PCT/FR1997/001692 WO1998014444A1 (en) | 1996-10-01 | 1997-09-26 | N-(benzothiazol-2-yl) piperidine-1-ethanamine derivatives, their preparation and application in therapeutics |
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| US6107313A (en) * | 1998-10-02 | 2000-08-22 | Combichem, Inc. | Dopamine receptor antagonists |
| JP3886897B2 (en) | 2000-06-21 | 2007-02-28 | エフ．ホフマン−ラ ロシュ アーゲー | Benzothiazole derivatives |
| US7087761B2 (en) | 2003-01-07 | 2006-08-08 | Hoffmann-La Roche Inc. | Cyclization process for substituted benzothiazole derivatives |
| SG131946A1 (en) * | 2003-10-24 | 2007-05-28 | Hoffmann La Roche | Ccr3 receptor antagonists |
| EA011279B1 (en) | 2004-05-24 | 2009-02-27 | Ф. Хоффманн-Ля Рош Аг | 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2yl)-amide |
| CN101056857B (en) | 2004-11-05 | 2010-12-01 | 弗·哈夫曼-拉罗切有限公司 | Process for preparation of isonicotinic acid derivatives |
| BRPI0609719B8 (en) | 2005-03-23 | 2021-05-25 | Hoffmann La Roche | acetylenyl-pyrazole-pyrimidine derivatives as mgbur2 antagonists |
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- 1997-09-26 IL IL12890297A patent/IL128902A/en not_active IP Right Cessation
- 1997-09-26 EE EEP199900135A patent/EE9900135A/en unknown
- 1997-09-26 NZ NZ334553A patent/NZ334553A/en unknown
- 1997-09-26 CZ CZ991126A patent/CZ112699A3/en unknown
- 1997-09-26 KR KR1019990702753A patent/KR20000048767A/en not_active Application Discontinuation
- 1997-09-26 CA CA002266510A patent/CA2266510A1/en not_active Abandoned
- 1997-09-26 BR BR9711842A patent/BR9711842A/en not_active Application Discontinuation
- 1997-09-26 HU HU9904091A patent/HUP9904091A3/en unknown
- 1997-09-26 CO CO97056315A patent/CO4650030A1/en unknown
- 1997-09-26 JP JP10516272A patent/JP2001501217A/en active Pending
- 1997-09-26 PL PL97332648A patent/PL332648A1/en unknown
- 1997-09-26 CN CN97198112A patent/CN1230959A/en active Pending
- 1997-09-26 SK SK422-99A patent/SK42299A3/en unknown
- 1997-09-30 ZA ZA9708772A patent/ZA978772B/en unknown
- 1997-09-30 AR ARP970104493A patent/AR009105A1/en not_active Application Discontinuation
- 1997-09-30 TW TW086114229A patent/TW438800B/en active
-
1999
- 1999-03-22 BG BG103271A patent/BG103271A/en unknown
- 1999-03-30 NO NO991581A patent/NO991581L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9904091A2 (en) | 2000-05-28 |
| EE9900135A (en) | 1999-12-15 |
| NO991581D0 (en) | 1999-03-30 |
| CO4650030A1 (en) | 1998-09-03 |
| KR20000048767A (en) | 2000-07-25 |
| WO1998014444A1 (en) | 1998-04-09 |
| HUP9904091A3 (en) | 2000-07-28 |
| IL128902A (en) | 2001-07-24 |
| TW438800B (en) | 2001-06-07 |
| BR9711842A (en) | 1999-08-24 |
| CZ112699A3 (en) | 1999-06-16 |
| BG103271A (en) | 2000-05-31 |
| NO991581L (en) | 1999-06-01 |
| IL128902A0 (en) | 2000-02-17 |
| FR2753970A1 (en) | 1998-04-03 |
| TR199900634T2 (en) | 1999-06-21 |
| AU722147B2 (en) | 2000-07-20 |
| CA2266510A1 (en) | 1998-04-09 |
| EP0929550A1 (en) | 1999-07-21 |
| AU4463897A (en) | 1998-04-24 |
| NZ334553A (en) | 2000-11-24 |
| AR009105A1 (en) | 2000-03-08 |
| FR2753970B1 (en) | 1998-10-30 |
| ZA978772B (en) | 1998-03-27 |
| JP2001501217A (en) | 2001-01-30 |
| CN1230959A (en) | 1999-10-06 |
| PL332648A1 (en) | 1999-09-27 |
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