SK279453B6 - Esters of thienyl carboxylic acids and amino alcohols, method for producing thereof, intermediates, pharmaceutical compositions containing same and their use - Google Patents
Esters of thienyl carboxylic acids and amino alcohols, method for producing thereof, intermediates, pharmaceutical compositions containing same and their use Download PDFInfo
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Abstract
Description
Oblasť technikyTechnical field
Vynález sa týka esterov tienylkarboxylových kyselín a aminoalkoholov, spôsobu ich výroby, farmaceutických prostriedkov s ich obsahom a ich použitia.The invention relates to thienylcarboxylic acid esters and aminoalcohols, to a process for their preparation, to pharmaceutical compositions containing them and to their use.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Parasympatické nervy zabezpečujú dominantné bronchokonstrikčné neurálne riadenie hladkých svalov dýchacích ciest u ľudí. Cholinergický neurálny tonus je hlavnou reversibilnou zložkou chronických obštrukčných pulmonálnych chorôb (COPD), kde prostredníctvom podráždenia vágu tonusu cez deň tiež prispieva k nočným záchvatom astmy. Čas trvania účinku súčasných anticholinergických liečiv je niekedy nepostačujúca na poskytnutie uspokojivého udržania terapie u pacientov alebo na kontrolu nočnej astmy. Preto je tu klinická potreba vývoja novej anticholinergickej účinnej látky, ktorá má dlhší čas trvania než doteraz známe liečivá.Parasympathetic nerves provide the dominant bronchoconstrictive neural control of airway smooth muscle in humans. Cholinergic neural tone is a major reversible component of chronic obstructive pulmonary disease (COPD), where it also contributes to nocturnal asthma attacks through daytime irritation of tonus vagus. The duration of action of current anticholinergic drugs is sometimes insufficient to provide satisfactory maintenance of therapy in patients or to control nocturnal asthma. Therefore, there is a clinical need for the development of a new anticholinergic active substance which has a longer duration than the known drugs.
Úlohou tohto vynálezu je poskytnúť kvartéme amóniové zlúčeniny, ktoré sú anticholinergickými bronchodilatantmi s dlhotrvajúcim účinkom na liečenie pacientov s reverzibilnou obštrukčnou chorobou dýchacích ciest. Tieto zlúčeniny inhibujú exogénny acetylcholín (Ach)-indukovaný bronchospazmaticky trikrát účinnejšie než napríklad ipratropium bromid, ktorý je známy z doterajšieho stavu techniky a prejavujú sa značne dlhším časom trvania účinku než rovnaká dávka ipratropium bromidu. Čas trvania ochrany proti cholinergickej neurálnej bronchokonštrikcii je najvýznamnejším liečebným účinkom týchto látok.It is an object of the present invention to provide quaternary ammonium compounds which are anticholinergic bronchodilators with a long lasting effect for the treatment of patients with reversible obstructive airways disease. These compounds inhibit exogenous acetylcholine (Ach) -induced bronchospasm three times more efficiently than, for example, ipratropium bromide known in the art and exhibit a considerably longer duration of action than the same dose of ipratropium bromide. The duration of protection against cholinergic neural bronchoconstriction is the most significant therapeutic effect of these agents.
Podstata vynálezuSUMMARY OF THE INVENTION
Podstatu vynálezu tvoria estery tienylkarboxylových kyselín a aminoalkoholov všeobecného vzorca (I)The present invention provides esters of thienylcarboxylic acids and aminoalcohols of formula (I)
R2 R 2
O, kdeO, where
A znamená skupinu všeobecného vzorca (II)A represents a group of formula (II)
kdewhere
Q znamená jednu z dvojväzbových skupín -CH2-CH2, -CH2-CH2-CH2-, -CH=CH-,Q represents one of the divalent groups -CH 2 -CH 2 , -CH 2 -CH 2 -CH 2 -, -CH = CH-,
aand
R znamená alkyl s 1 až 4 atómami uhlíka, prípadne substituovaný atómom halogénu alebo hydroxyskupinou,R is C 1 -C 4 alkyl optionally substituted by halogen or hydroxy,
R' znamená alkyl s 1 až 4 atómami uhlíka a R a R' môžu spolu tvoriť alkylénový zvyšok s 4 až 6 atómami uhlíka, pričom sa pozitívny náboj dusíkového atómu vyrovnaná ekvivalentom aniónu Χθ,R 'is C 1 -C 4 alkyl and R and R' can be taken together to form a C 4 -C 6 alkylene moiety, whereby the positive charge of the nitrogen atom is offset by the anion equivalent Χθ,
R1 znamená tienyl, fenyl, furyl, cyklopentyl alebo cyklohexyl, pričom všetky zvyšky môžu byť substituované metylovými zvyškami, tienyl a fenyl tiež atómami chlóru alebo fluóru,R 1 is thienyl, phenyl, furyl, cyclopentyl or cyclohexyl, each of these radicals to be substituted by methyl radicals, phenyl and thienyl also chlorine or fluorine,
R2 znamená atóm vodíka, hydroxyskupinu, alkoxyskupina alebo alkylovú skupinu, obidve s 1 až 4 atómami vodíku R2 is H, OH, alkoxy or alkyl group, both having 1 to 4 carbon atom
R“ znamená atóm vodíka, atóm fluóru, chlóru alebo metylovú skupinu.R 'represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.
Výhodné zlúčeniny podľa vynálezu sú tie, v ktorých R1 znamená 2-tienyl.Preferred compounds of the invention are those wherein R 1 is 2-thienyl.
Výhodné zlúčeniny podľa vynálezu sú tie, v ktorých R2 znamená hydroxyskupinu.Preferred compounds are those wherein R 2 is hydroxy.
Medzi ďalšie výhodné zlúčeniny podľa vynálezu patria tie, kde A znamenáOther preferred compounds of the invention include those wherein A is
R a X( ) má význam, uvedený v nároku 1 a R' má význam uvedený v nároku 1, s výnimkou atómu vodíka.R and X () are as defined in claim 1 and R 'is as defined in claim 1, except for a hydrogen atom.
Zvlášť výhodné sú zlúčeniny, kde R1 znamená 2-tienyl a A znamená skupinu n n .Especially preferred are compounds wherein R1 is 2-thienyl and A represents a low voltage.
/ CH-- N~CH_ O X vro alebo/ CH-- N ~ CH_O X vro or
vo forme 3α-, kde X<_) znamená ekvivalent aniónu, výhodne Br alebo CH3SO3·.in the form of 3α-, wherein X ()) is an anion equivalent, preferably Br or CH 3 SO 3 ·.
Podstatu vynálezu tvoria aj zlúčeniny všeobecného vzorcaThe present invention also relates to compounds of the general formula
vo forme 3α-, ako metobromidy alebo metometánsulfonáty.in the form of 3α-, such as metobromides or methanesulfonates.
Zlúčeniny podľa vynálezu sa pripravujú tak, že sa ester všeobecného vzorca (IV)The compounds of the invention are prepared by the ester of formula (IV)
R (IV), kde R znamená alkyl s 1 až 4 atómami uhlíka a R1, R2 a R3 majú už uvedený význam, podrobí výmene esterových skupín s aminoalkoholom všeobecného vzorca (V)R (IV), wherein R is C 1 -C 4 alkyl and R 1 , R 2 and R 3 are as previously defined, is subjected to an exchange of ester groups with an amino alcohol of formula (V)
kde Q má už uvedený význam, a Q znamená =NR alebo =NH, v inertnom organickom rozpúšťadle alebo v tavenine, za prítomnosti katalyzátora výmeny esterových skupín a získané zlúčeniny všeobecného vzorca (VI) sawherein Q is as defined above, and Q is = NR or = NH, in an inert organic solvent or melt, in the presence of an ester exchange catalyst, and the compound of formula (VI) obtained is
(VI)(VI)
a) v prípade, že Q znamená =NR, kvartemizujú pôsobením reaktívneho monoderivátu alkánu vzorca Z-(alkyl s 1 až 4 atómami uhlíka), kde Z je ľahko odštiepiteľná skupina, alebo sa(a) when Q is = NR, quartemize by treatment with a reactive mono-derivative of an alkane of the formula Z- (alkyl of 1 to 4 carbon atoms), where Z is a readily cleavable group, or
b) v prípade, že Q znamená =NH, kvartemizujú disubstituovaným alkánom vzorca Z-(alkylén so 4 až 6 atómami uhlíka)-Z bez izolácie medziproduktov.b) when Q is = NH, quaternize with a disubstituted alkane of formula Z- (C 4 -C 6 alkylene) -Z without isolation of the intermediates.
Podstatu vynálezu tvoria aj zlúčeniny všeobecného vzorca (VI), kde Q, Q', Q, Ra, R1 a R2 majú význam uvedený, ako aj adičné soli týchto látok s kyselinami s výnimkou tropínesterov fenyl-2-tienylglykolovej, 2,2'-ditienylglykolovej a3,3'-ditienylglykolovej kyseliny.The present invention also relates to compounds of formula (VI) wherein Q, Q ', Q, R a , R 1 and R 2 are as defined above, as well as acid addition salts thereof, with the exception of phenyl-2-thienylglycolic tropinesters, 2'-dithienylglycolic acid and 3, 3'-dithienylglycolic acid.
Ďalej podstatu vynálezu tvoria aj zlúčeniny všeobecného vzorca (VI), ktorými sú:The present invention also relates to compounds of formula (VI) which are:
Farmaceutický prostriedok s anticholinergickými účinkami, na liečbu ochorení dýchacích ciest a sínusovej bra dykardie, ktorého podstatou je, že obsahuje zlúčeniny podľa vynálezu spolu s pomocnými látkami a/alebo nosičmi.Pharmaceutical composition with anticholinergic effects, for the treatment of respiratory diseases and sinus bradycardia, comprising a compound of the invention together with excipients and / or carriers.
Zlúčeniny podľa vynálezu sa používajú na prípravu farmaceutických prostriedkov s anticholinergickým účinkom, ďalej na liečbu ochorení dýchacích ciest a sínusovej bradykardie.The compounds of the invention are used for the preparation of pharmaceutical compositions with anticholinergic activity, further for the treatment of respiratory diseases and sinus bradycardia.
Na liečebné použitie sú vhodné najmä kvartéme deriváty, zatiaľ čo terciáme zlúčeniny sú vhodné aj ako medziprodukty.Quaternary derivatives are particularly suitable for therapeutic use, while tertiary compounds are also useful as intermediates.
Zlúčeniny podľa vynálezu sú cholinergné látky so silným a dlhodobým účinkom. Pri podaní dávok poriadku pg inhaláciou je možné dosiahnuť doby účinku až 24 hodín. Toxicita je približne rovnaká ako toxicita bežne dodávaného výrobku Ipratropiumbromidu, ale liečebný účinok je silnejší.The compounds of the invention are cholinergic substances with a strong and long-lasting effect. When doses of the order of pg are administered by inhalation, an effect time of up to 24 hours can be achieved. The toxicity is approximately the same as the toxicity of a commercially available Ipratropium bromide product, but the therapeutic effect is stronger.
Zlúčeniny podľa vynálezu sa ako anticholinergné látky môžu použiť na liečenie chronickej obštruktívnej bronchitídy a ľahkej až stredne ťažkej astmy a ďalej na liečenie sínusovej bradykardie, spôsobenej podráždením vagu.The compounds of the invention may be used as anticholinergic agents for the treatment of chronic obstructive bronchitis and mild to moderate asthma, and for the treatment of sinus bradycardia caused by vagal irritation.
Pri ochoreniach dýchacích ciest prichádza do úvahy predovšetkým inhalačné použitie zlúčenín podľa vynálezu, najmä kvartémych zlúčenín, čím je možné vylúčiť do značnej miery akékoľvek vedľajšie účinky. Pri bradykardii sa látky podávajú výhodne vnútrožilovo alebo perorálne. V tomto prípade je výhodné, že zlúčeniny podľa vynálezu nie sú ovplyvňované pohybmi žalúdka a čriev.In respiratory diseases, the inhalation use of the compounds according to the invention, in particular the quaternary compounds, is in particular possible, so that any side effects can be largely avoided. For bradycardia, the agents are preferably administered intravenously or orally. In this case, it is preferred that the compounds of the invention are not affected by gastric and bowel movements.
Pri spracovaní liekovej formy sa k účinným látkam pridávajú známe pomocné látky a/alebo nosiče. Na inhalačné podanie ide napríklad o suspenzie v skvapalnených hnacích plynoch, prostriedky s obsahom lipozómov alebo prolipozómov, injekčné roztoky, tablety, dražé, kapsuly alebo prášky na použitie vo zvyčajných inhalačných prístrojoch.When processing the dosage form, known excipients and / or carriers are added to the active ingredients. For administration by inhalation, for example, suspensions in liquefied propellants, liposome or proliposome formulations, injectable solutions, tablets, dragees, capsules or powders for use in conventional inhaler devices are provided.
Ďalej budú uvedené príklady zloženia liekových foriem. Údaje sú uvedené v % hmotnostných.Examples of the formulation of the dosage forms will be given below. Data are in% by weight.
1. Aerosól v dávkovacom balení účinná látka podľa vynálezu 0,005 sorbitan trioleát 0,1 monofluórtrichlórmetán a difluórdichlórmetán v pomere 2:3 do 1001. Aerosol in a dosage package active ingredient according to the invention 0.005 sorbitan trioleate 0.1 monofluorotrichloromethane and difluorodichloromethane in a ratio of 2: 3 to 100
Suspenzia sa plní do nádobky, opatrenej dávkovacím ventilom. Pri jednom uvedení ventilu do činnosti sa výhodne uvoľní 50 pl suspenzie, roztok môže obsahovať aj vyššiu dávku účinnej látky, napríklad 0,02 % hmotnostných.The suspension is filled into a container fitted with a metering valve. One actuation of the valve preferably releases 50 µl of the suspension, the solution may also contain a higher dose of active ingredient, for example 0.02% by weight.
2. Tablety účinná látka podľa vynálezu0,05 koloidná kyselina kremičitá0,95 mliečny cukor65,00 zemiakový škrob28,00 polyvinylpyrolidón3,00 sodná soľ glykolátu celulózy2,00 stearan horečnatý1,002. Tablets Active ingredient according to the invention 0.05 Colloidal silicic acid0.95 Milk sugar65.00 Potato starch28.00 Polyvinylpyrrolidone 3.00 Sodium cellulose glycolate2.00 Magnesium stearate1.00
Zmes sa spracuje bežným spôsobom na tablety s hmotnosťou 200 mg.The mixture is processed to 200 mg tablets in a conventional manner.
Výhodné vlastnosti zlúčenín podľa vynálezu je možné dokázať napríklad pri brzdení broncholýzy králika, u ktorého bol vyvolaný kŕč vnútrožilovým podaním acetylcholínu. Po vnútrožilovom podaní zlúčenín podľa vynálezu v dávke 3 pg/kg vnútrožilovo bol maximálny účinok po 10 až 40 minútach. Ani po 5 hodinách ešte účinok nepoklesol na polovicu, to znamená, že pokles účinku na polovicu trvá podstatne dlhší čas ako 5 hodín, ako je možné dokázať percentami účinku jednotlivých dávok po 5 hodinách.Advantageous properties of the compounds of the invention can be demonstrated, for example, in inhibiting broncholysis of a rabbit in which a convulsion has been induced by intravenous administration of acetylcholine. Following intravenous administration of the compounds of the invention at 3 µg / kg intravenously, the maximal effect was 10 to 40 minutes. Even after 5 hours, the effect has not yet decreased by half, meaning that the decrease in effect in half lasts considerably longer than 5 hours, as can be shown by the percent action of the individual doses after 5 hours.
zlúčenina zvyšok účinku v %compound residual effect in%
Zlúčenina ACompound A
Zlúčenina CCompound C
Poznámky:notes:
1. V zlúčeninách, v ktorých R1 má odlišný význam od 2-tienylového zvyšku, ide o racemáty.Compounds in which R 1 is different from the 2-thienyl radical are racemates.
2. Ide vždy o 3a-zlúčeniny.2. These are always 3a-compounds.
Na výrobu zlúčenín podľa vynálezu je možné použiť zásadne známe postupy.In principle, known methods can be used to produce the compounds of the invention.
Výmena esterovej skupiny sa uskutočňuje pri vyššej teplote v organickom rozpúšťadle, napríklad toluéne, xyléne, heptáne alebo v tavenine, pričom ako katalyzátor je možné použiť silnú bázu, napríklad metoxid sodíka, etoxid sodíka, hydrid sodíka alebo kovový sodík. Na odstránenie uvoľneného nižšieho alkoholu zo zmesi sa použije znížený tlak alebo azeotropné oddestilovanie alkoholu. Reakcia sa zvyčajne uskutočňuje pri teplote, neprekračujúcej 95 °C. Často prebieha reakcia výhodnejšie v tavenine.The ester group is exchanged at a higher temperature in an organic solvent such as toluene, xylene, heptane or melt, and a strong base such as sodium methoxide, sodium ethoxide, sodium hydride or sodium metal may be used as the catalyst. A reduced pressure or azeotropic distillation of the alcohol is used to remove the released lower alcohol from the mixture. The reaction is usually carried out at a temperature not exceeding 95 ° C. Often, the reaction is preferably carried out in the melt.
Z adičných solí terciámych amínov s kyselinami je možné v prípade potreby získať známym spôsobom voľné bázy pôsobením vhodných zásad. Kvartemizácia sa uskutočňuje vo vhodnom rozpúšťadle, napríklad acetonitrile alebo v zmesi acetonitrilu a metylénchloridu, výhodne pri teplote miestnosti. Ako kvartemizačné činidlo sa výhodne použije zodpovedajúci alkylhalogenid, ako alkylbromid. Produkty, v ktorých Q' má význam NH, slúžia ako východiskové látky pre tie zlúčeniny, v ktoiých R a R' spoločne tvoria alky Iónový zvyšok so 4 až 6 atómami uhlíka. Premenu na terciámu a potom kvartérnu zlúčeninu je potom možné uskutočniť pôsobením 1,4-, 1,5- alebo 1,6-dihalogénalkánu bez izolácie medziproduktu.If desired, free bases can be obtained from the acid addition salts of tertiary amines by treatment with suitable bases in a known manner. The quaternization is carried out in a suitable solvent, for example acetonitrile or in a mixture of acetonitrile and methylene chloride, preferably at room temperature. The quaternizing agent used is preferably a corresponding alkyl halide such as an alkyl bromide. Products in which Q 'has the meaning of NH serve as starting materials for those compounds in which R and R' together form an alkyl ion radical having 4 to 6 carbon atoms. Conversion to tertiary and then quaternary compounds can then be accomplished by treatment with 1,4-, 1,5- or 1,6-dihaloalkane without isolation of the intermediate.
Východiskové látky môžu, pokiaľ ešte neboli opísané, byť získané analogickými spôsobmi ako známe zlúčeniny.The starting materials may, if not already described, be obtained by analogous methods to known compounds.
Napríklad je možné získať: metylester kyseliny di-(2-tienyl)glykolovej z dimetylesteru kyseliny šťavclovej a 2-tienylmagnéziumbromidu, etylester kyseliny di-(2-tienyl)glykolovej z kyseliny (2-tienyljglyoxylovej a 2-tienyllítia, etylester kyseliny hydroxyfenyl-(2-tienyl)octovej z metylesteru kyseliny fenylglyoxylovej a 2-tienylmagnéziumbromidu alebo z metylesteru kyseliny (2-tienyl)glyoxylovej a fenylmagnéziumbromidu.For example, it is possible to obtain: di- (2-thienyl) glycolic acid methyl ester from dimethyl oxalate and 2-thienylmagnesium bromide; 2-thienyl) acetic acid from methylglycellic acid methyl ester and 2-thienylmagnesium bromide or from (2-thienyl) glyoxylic acid methyl ester and phenylmagnesium bromide.
Podobným spôsobom je možné uviesť do reakcie aj metylester kyseliny 2-tienylglyoxylovej a cyklohexyl- alebo cyklopentylmagnéziumbromid.Similarly, 2-thienylglyoxylic acid methyl ester and cyclohexyl or cyclopentylmagnesium bromide can also be reacted.
Takéto aminoalkoholy je možné vyrobiť rôznym spôsobom.Such aminoalcohols can be prepared in various ways.
Výroba pseudoskopínu bola opísaná v publikácii M. Polonovski a ďalší, Bull, Soc. Chim. 43, 79 (1928).The production of pseudoscopy has been described by M. Polonovski et al., Bull, Soc. Chim. 43, 79 (1928).
Pseudotropenol je možné získať frakčnou kryštalizáciou zo zmesi, ktorá bola opísaná v publikáciách V. Hayakawa a ďalší, J. Amer. Chem. Soc. 1978, 100(6), 1786 a R. Noyori a ďalší, J. Amer. Chem. Soc. 1974, 96(10), 3336, je tiež možné tieto zmesi destilovať.Pseudotropenol can be obtained by fractional crystallization from the mixture described by V. Hayakawa et al., J. Amer. Chem. Soc. 1978, 100 (6), 1786 and R. Noyori et al., J. Amer. Chem. Soc. 1974, 96 (10), 3336, it is also possible to distill these mixtures.
Pri použití 2- alebo 3-furylglyoxylnitrilu je možné okrem kyseliny 2- alebo 3-furylglyoxylovej získať aj zvyčajným spôsobom zodpovedajúce metylestery. Z týchto látok je potom možné získať opísaným spôsobom pri použití organických derivátov kovov 2- alebo 3-brómtiofénu aj zodpovedajúce estery kyseliny glykolovej. Organické zlúčeniny kovov, získané z 2-, 3- alebo 4-halogénpyridínu je možné uviesť do reakcie s metylesterom kyseliny 2- alebo 3-tienylglyoxylovej za vzniku zodpovedajúcich esterov kyseliny glykolovej.When 2- or 3-furylglyoxylnitrile is used, in addition to 2- or 3-furylglyoxylic acid, the corresponding methyl esters can be obtained in the customary manner. The corresponding glycolic esters can then also be obtained from these materials using the organic metal derivatives of 2- or 3-bromothiophene as described above. The organic metal compounds obtained from 2-, 3- or 4-halopyridine can be reacted with 2- or 3-thienylglyoxylic acid methyl ester to give the corresponding glycolic acid esters.
Estery kyseliny tienylglykolovej, v ktorých obsahuje tiofénový kruh atóm fluóru v polohe 2 alebo 3, je možné vyrobiť napríklad z 2- alebo 3-fluórtiofénu bromáciou na 2-bróm-3-fluór- alebo 2-bróm-5-fluórtiofén s následným prevedením na organickú zlúčeninu kovu a reakciou s príslušným esterom kyseliny glyoxylovej za získania požadovaného esteru kyseliny glykolovej.Thienylglycolic acid esters in which the thiophene ring contains a fluorine atom in the 2 or 3 position can be prepared, for example, from 2- or 3-fluorothiophene by bromination to 2-bromo-3-fluoro- or 2-bromo-5-fluorothiophene followed by conversion to an organic metal compound and reacting with an appropriate glyoxylic ester to give the desired glycolic ester.
2-Fluórtiofén a 3-fluórtiofén je možné premeniť na estery kyseliny glyoxylovej spôsobom podľa publikácie Unterhalt, Árch. Pharm. 322, 839 (1989) a získané estery je možné, ako už bolo opísané uviesť do reakcie s 2- alebo 3-tienylovými derivátmi na estery kyseliny glykolovej. Vhodnou voľbou zložiek je možné získať symetricky substituované estery kyseliny ditienylglykolovej.2-Fluorothiophene and 3-fluorothiophene can be converted to glyoxylic esters according to Unterhalt, Ar. Pharm. 322, 839 (1989) and the esters obtained can be reacted as described above with 2- or 3-thienyl derivatives to give glycolic acid esters. Symmetrically substituted dithienylglycolic esters can be obtained by suitable choice of components.
SK 279453 Β6SK 279453 Β6
Ďalší postup vedie analogicky ku kondenzácii benzoínu a analogickej reakcii s kyselinou benzylovou.A further procedure leads analogously to the condensation of benzoin and an analogous reaction with benzylic acid.
Praktické uskutočnenie vynálezu bude vysvetlené nasledujúcimi príkladmi.The following examples illustrate the invention.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Skopínester kyseliny di-(2-tienyl)glykolovejDi- (2-thienyl) glycolic acid scopine ester
50,87 g, 0,2 mol metylesteru kyseliny di-(2-tienyl)glykolovej a 31,04 g, 0,2 mol skopínu sa rozpustí v 100 ml absolútneho toluénu a potom sa po niekoľkých podieloch pridá 1,65 g, 0,071 gramatómu sodíka pri teplote kúpeľa 90 °C. Pri teplote 78 až 90 °C a tlaku 0,5.105 Pa (500 mbar) sa z reakčnej zmesi oddestiluje vznikajúci metanol. Po reakčnom čase 5 hodín sa reakčná zmes vmieša do zmesi ľadu a kyseliny chlorovodíkovej. Kyslá fáza sa oddelí, alkalizuje uhličitanom sodným a voľná báza sa extrahuje metylénchloridom. Po vysušení síranom sodným sa metylénchlorid oddestiluje za zníženého a odparok sa nechá prekryštalizovať z acetonitrilu. Vo výťažku 44,7 % teoretického množstva sa týmto spôsobom získa 33,79 g béžového kryštalického produkte s teplotou topenia 149 až 150 °C (acetonitril).50.87 g, 0.2 mol of methyl di- (2-thienyl) glycolic acid ester and 31.04 g, 0.2 mol of scopine are dissolved in 100 ml of absolute toluene and then 1.65 g, 0.071 are added in several portions. of sodium gramamatome at a bath temperature of 90 ° C. At a temperature of 78-90 DEG C. and a pressure of 0.5.10 5 Pa (500 mbar), the reaction mixture was distilled off formed methanol. After a reaction time of 5 hours, the reaction mixture is stirred into a mixture of ice and hydrochloric acid. The acid phase was separated, basified with sodium carbonate and the free base was extracted with methylene chloride. After drying over sodium sulfate, the methylene chloride is distilled off under reduced pressure and the residue is recrystallized from acetonitrile. In a yield of 44.7% of theory, 33.79 g of a beige crystalline product are obtained, m.p. 149 DEG-150 DEG C. (acetonitrile).
Príklad 2Example 2
Skopínester kyseliny di-(2-tienyl)glykolovejDi- (2-thienyl) glycolic acid scopine ester
12,72 g, 0,05 mol metylesteru kyseliny di-(2-tienyl)glykolovej a 7,76 g, 0,05 mol skopínu sa zahrieva v kúpeli s teplotou 70 °C s použitím vodnej vývevy až do roztavenia. Do taveniny sa pridá 2,70 g, 0,05 mol metoxidu sodíka a zmes sa zahrieva s použitím vodnej vývevy 1 hodinu na kúpeli s teplotou 70 °C a potom ešte ďalšiu hodinu na kúpeli s teplotou 90 °C. Stuhnutá tavenina sa pri riadenej teplote zmieša so zmesou 100 ml vody a 100 ml metylénchloridu a metylénchloridová fáza sa opakovane extrahuje vodou a potom zodpovedajúcim množstvom zriedenej kyseliny chlorovodíkovej. Vodné fázy sa zlejú, po pridaní zodpovedajúceho množstva uhličitanu sodného sa metylénchloridom extrahuje skopínester kyseliny di-(2-tienyl)glykolovej a metylénchloridový roztok sa vysuší síranom sodným a bežným spôsobom sa pripraví hydrochlorid. Kryštáliky sa odfiltrujú za odsávania, premyjú sa acetónom a sušia za zníženého tlaku pri 35 °C. Vo výťažku 53,1 % sa získa po prekryštalizovaní z metanolu 10,99 g svetlobéžových kryštálov s teplotou topenia 238 až 241 °C za rozkladu. Z hydrochloridu je možné bežným spôsobom získať voľnú látku.12.72 g, 0.05 mol of di- (2-thienyl) glycolic acid methyl ester and 7.76 g, 0.05 mol of scopine are heated in a 70 ° C bath using a water pump until melting. Sodium methoxide (2.70 g, 0.05 mol) was added to the melt and the mixture was heated using a water pump for 1 hour in a 70 ° C bath and then for an additional hour in a 90 ° C bath. The solidified melt is mixed with a mixture of 100 ml of water and 100 ml of methylene chloride at a controlled temperature, and the methylene chloride phase is repeatedly extracted with water and then with an appropriate amount of dilute hydrochloric acid. The aqueous phases are decanted, after addition of an appropriate amount of sodium carbonate, the di- (2-thienyl) glycolic acid scopine ester is extracted with methylene chloride and the methylene chloride solution is dried over sodium sulphate and the hydrochloride is prepared in a conventional manner. The crystals were filtered off with suction, washed with acetone and dried under reduced pressure at 35 ° C. In a yield of 53.1%, after recrystallization from methanol, 10.99 g of pale beige crystals with a melting point of 238 DEG-241 DEG C. are obtained with decomposition. The free material can be obtained from the hydrochloride in a conventional manner.
Príklad 3Example 3
Skopínester kyseliny di-(2-tienyl)glykolovejDi- (2-thienyl) glycolic acid scopine ester
38,15 g, 0,15 mol metylesteru kyseliny di-(2-tienyl)glykolovej a 23,28 g, 0,15 mol skopínu sa zmieša, pridá sa 0,34 g, 0,015 gramatómu sodíka a zmes sa roztaví s použitím vodnej vývevy na kúpeli s teplotou 90 °C. Reakcia trvá 2,5 hodiny. Potom sa pridá 100 ml absolútneho etanolu a zmes sa mieša pri teplote kúpeľa 90 °C tak dlho, až vznikne roztok. Tento roztok sa potom ochladí na teplotu miestnosti a pridá sa zmes ľadu a kyseliny chlorovodíkovej, ochladenej ľadom. Vykryštalizovaný hydrochlorid bázického esteru sa odfiltruje za odsávania a premyje sa malým množstvom vody a dostatočným množstvom dietyléteru. Fáza filtrátu sa oddelí a vodná fáza sa extrahuje dietyléterom. Odfiltrovaný hydrochlorid sa uvedie do suspenzie v kyslej vodnej fáze a za riadenia teploty sa pridaním uhličitanu sodného premení na voľnú látku, ktorá sa extrahuje metylénchloridom. Metylénchloridové fázy sa vysušia síranom sodným a oddestilujú, získaný kryštalický materiál sa čistí aktívnym uhlím a nechá prekryštalizovať z acetonitrilu. Vo výťažku 70,1 % sa získa 39,71 g svetložltých kryštálov s teplotou topenia 148 až 149 °C.38.15 g (0.15 mol) of di- (2-thienyl) glycolic acid methyl ester and 23.28 g (0.15 mol) of scopine are mixed, 0.34 g (0.015 gram) of sodium are added and the mixture is melted using aqueous vacuum pumps at 90 ° C. The reaction takes 2.5 hours. 100 ml of absolute ethanol are then added and the mixture is stirred at a bath temperature of 90 ° C until a solution is obtained. The solution was then cooled to room temperature and an ice-cooled mixture of ice and hydrochloric acid was added. The crystallized basic ester hydrochloride is filtered off with suction and washed with a little water and a sufficient amount of diethyl ether. The filtrate phase is separated and the aqueous phase is extracted with diethyl ether. The filtered hydrochloride is suspended in the acidic aqueous phase and converted to the free material by addition of sodium carbonate under temperature control, which is extracted with methylene chloride. The methylene chloride phases are dried over sodium sulphate and distilled off, the crystalline material obtained is purified by activated carbon and recrystallized from acetonitrile. 39.71 g of pale yellow crystals with a melting point of 148-149 ° C are obtained in a yield of 70.1%.
Tabuľka ITable I
Zlúčeniny všeobecného vzorcaCompounds of general formula
Poznámka: všetky hydrochloridy sa topia za rozkladu.Note: all hydrochlorides melted with decomposition.
SK 279453 Β6SK 279453 Β6
Príklad 4Example 4
Metobromid skopínesteru kyseliny di-(2-tienyl)glykolovejDi- (2-thienyl) glycolic acid scopine ester metobromide
10,0 g, 0,0265 mol skopínesteru kyseliny di-(2-tienyl)glykolovej sa rozpustí v zmesi 20 ml bezvodého metylénchloridu a 30 ml bezvodého acetonitrilu, pridá sa 12,8 g 0,1325 mol metylbromidu vo forme 50%-ného roztoku v bezvodom acetonitrile a reakčná zmes sa pevne uzavrie do reakčnej nádoby a nechá sa stáť 24 hodín pri teplote miestnosti. V priebehu tohto času sa vytvorí kryštalická zrazenina. Táto zrazenina sa odfiltruje za odsávania, premyje sa metylénchloridom a potom sa suší za zníženého tlaku pri teplote 35 °C. Po vysušení pri teplote 111 °C a prekryštalizovaní zo zmesi metanolu a acetónu sa získa biely kryštalický produkt s teplotou topenia 217 až 218 °C.Di- (2-thienyl) glycolic acid scopine ester (10.0 g, 0.0265 mol) is dissolved in a mixture of 20 ml of anhydrous methylene chloride and 30 ml of anhydrous acetonitrile, and 12.8 g of 0.1325 mol of methyl bromide is added as 50% by weight. solution in anhydrous acetonitrile and the reaction mixture was tightly sealed into a reaction vessel and allowed to stand at room temperature for 24 hours. During this time, a crystalline precipitate forms. The precipitate was filtered off with suction, washed with methylene chloride and then dried under reduced pressure at 35 ° C. After drying at 111 ° C and recrystallization from methanol-acetone, a white crystalline product is obtained with a melting point of 217-218 ° C.
Tabuľka IITable II
Kvartéme zlúčeniny vzorcaQuaternary compounds of formula
obsahuje kryštalický metanolcontains crystalline methanol
Poznámka: všetky zlúčeniny z tejto tabuľky sa topia za rozkladu.Note: all compounds of this table melt with decomposition.
Tabuľka IIITable III
Zlúčeniny vzorcaCompounds of formula
HO-C-CO-OA \HO-C-CO-OA
R1 R 1
C. A R1 teplota topenia‘C hydrochloricC. AR 1 Melting point C hydrochloric
Tabuľka IVTable IV
Zlúčeniny vzorcaCompounds of formula
č. Ano. A
3a-(6p,7p-epoxy)tropanyl3a- (6?, 7? Epoxy) tropanyl
3a-(6,7-dehydro)tropanyt3a- (6,7-dehydro) tropanyt
3a-(6p.7p-epoxy)tropanyl3a (6p.7p-epoxy) tropanyl
3a-(6,7-dehydro)tropanyl3a- (6,7-dehydro) tropanyl
3a-(6p.7p-epoxy)tropanyl3a (6p.7p-epoxy) tropanyl
3a-(6,7-dehydfú)tfôpanyl3a- (6,7-dehydfú) tfôpanyl
R2 teplota topenia ’C hydrochloridR2 melting point 'C hydrochloride
HH
H metyl metyl 210-212,5 metoxy metoxyH methyl methyl 210-212.5 methoxy methoxy
Tabuľka VIITable VII
Zlúčeniny vzorcaCompounds of formula
Tabuľka VTable V
Zlúčeniny vzorcaCompounds of formula
s kryštalickým metanolomwith crystalline methanol
Tabuľka VIIITable VIII
Zlúčeniny vzorcaCompounds of formula
Tabuľka VITable VI
Kvartéme zlúčeniny vzorcaQuaternary compounds of formula
č. A tepľ top. *cno. And warm top. * c
3a-(6p.70-epoxy)tropanyt-metobrornid H3α- (6β, 70-epoxy) tropanyl-metobrornide H
3a-(6,7-dehydro)tropanyl- metobromid H3α- (6,7-dehydro) tropanyl-metobromide H
3a-(6p,7p-epoxy)tropanyl-metobromid metyl3α- (6β, 7β-epoxy) tropanyl metobromide methyl
3a-{6,7-dehydro)tropanyl-metobromid3a {6,7-dehydro) tropanyl-methobromide
3a-tropanylmetobromid metoxy3α-tropanylmetobromide methoxy
3a-(N-metyl)troparyl-rnetobrorn»d metyl 206-208 metoxy3α- (N-methyl) troparyl-methylbromodimethyl 206-208 methoxy
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Free format text: PRODUCT NAME: TIOTROPIUM BROMID; NAT. REGISTRATION NO/DATE: 14/0032/02-S 20020308; FIRST REGISTRATION: NL RVG 26191 20011009 Spc suppl protection certif: DO 3; 2-2002 Filing date: 20020730 |
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SPCE | Expiry of an spc |
Free format text: PRODUCT NAME: TIOTROPIUM BROMID; NAT. REGISTRATION NO/DATE: 14/0032/02-S 20020308; FIRST REGISTRATION: NL RVG 26191 20011009 Spc suppl protection certif: DO 3;2-2002 Expiry date: 20160318 |