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 PDF

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SK279453B6
SK279453B6 SK4523-90A SK452390A SK279453B6 SK 279453 B6 SK279453 B6 SK 279453B6 SK 452390 A SK452390 A SK 452390A SK 279453 B6 SK279453 B6 SK 279453B6
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thienyl
tropanyl
methyl
formula
fluoro
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SK4523-90A
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SK452390A3 (en
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Rolf Banholzer
Rudolf Bauer
Richard Reichl
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Boehringer Ingelheim Kg
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Abstract

Disclosed are esters of thienyl carboxylic acids and amino alcohols of the general formula (I) wherein A denotes a group of the formula (II); Q is one of the double-bond groups -CH2-CH2, -CH2-CH2-CH2-, -CH=CH-; R is alkyl with 1 to 4 carbons, optionally halogen- or hydroxygroup-substituted; R' is alkyl and R and R' may together form an alkylene residual; R1 is thienyl, phenyl, furyl, cyclopentyl or cyclohexyl, whereas all the residuals can be substituted by methyl residuals, thienyl and phenyl by fluorine or chlorine; R2 is hydrogen, hydroxygroup, alkoxygroup or an alkyl group; and Ra is hydrogen, fluorine, chlorine or a methyl group. A method for the preparation of the said compounds and pharmaceutical compositions exhibiting anticholinergic activity for the treatment of diseases related to the respiratory tract and sinus bradycardia are further disclosed.

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%

A A 76 76 B B 76 76 C C 81 81 D D 61 61 E E 68 68 F F 73 73 G G 69 69 Zlúčenina vzorca Compound of formula \ S \ WITH 1 ÍO-C-CO-A 1 IO-C-CO-A

Zlúčenina ACompound A

-0—/ CH3-JÍä-CH3 -0- / CH 3 -J a-CH 3 0 0 2-tienyl 2-thienyl \ 1 \ 1 / / / L / L -0 —/ CH3-lŕ&-CH3 -0 - / CH 3 and CH 3 -LR 0 / 0 / 3-fenyl 3-phenyl -0__/ CH3-Jŕ&-CH3 -O &lt; 3 &gt; 2-tienyl 2-thienyl -0__/ CH3 -tŕS'-CHq \ I-O + / CH 3 - 3-tienyl 3-thienyl Bŕ9 br9 -0 / CH3 (CH3) 2-O / CH 3 (CH 3 ) 2 cyMopent cyMopent BiP BiP -0_CH3-f^-CH2-CH2F-O-CH 3 -f-CH 2 -CH 2 F cyklopent cyclopent

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.

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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

č. no. A A báza base teplota topenia *C hydfochtorid melting point * C hydfochtorid 1 1 3a-(6|3,7|i-epoxy)tropanyl 3a- (6 | 3.7 | i-epoxy) tropanyl 2-tienyl 2-thienyl 149-150 149-150 238-241 238-241 2 2 3a-tropanyl 3-tropanyl 2-tienyl 2-thienyl 167-168 167-168 253 253 3 3 3a-|6.7-dehydro)tropanyl 3a | 6.7-dehydro) tropanyl 2-tienyl 2-thienyl 164-165 164-165 4 4 3a-(N-0-flu6retyi)nor1ropaľtyl 3a- (N-0-flu6retyi) nor1ropaľtyl 2-tienyl 2-thienyl 236 236 5 5 3a-(N-izoprcpýl)granatanyl 3a- (N-isopropyloxy) granatanyl 2-lienyl 2-lienyl 232 232 6 6 3a -(N-izopropyt)nortropanyl 3a - (N-Isopropyl) nortropanyl 2-lienyl 2-lienyl 250 250 7 7 3a-(6p,7p-epoxy)-N-izopropylnor Iropanyl 3a- (6?, 7? Epoxy) -N-izopropylnor Iropanyl 2-tienyí 2-thienyl 206 206 8 8 3a-(60.70-epoxy)-N-etyl· nortropanyi 3α- (60.70-epoxy) -N-ethylnorthropanyl 2-tienyl 2-thienyl 212-213 212-213 9 9 3a-(A-etyl)nortropanyl 3a- (S-ethyl) nortropanyl 2-tienyl 2-thienyl 256-7 256-7 10 10 3a-(N.N-metyl)granatar>yf 3a- (N, N-methyl) granatart> yf 2-tienyl 2-thienyl 241 241 11 11 3a-(60,70-epoxy}-N-p-fluór- etylnortropanyl 3a (60,70-epoxy} -N-p-fluoro- etylnortropanyl 2-tienyl 2-thienyl 18B-190 18B-190 12 12 3a-(60.70-epoxy)-N-npropytnortropanyl 3a (60.70-epoxy) -N-npropytnortropanyl 2-tienyl 2-thienyl 104-106 104-106 13 13 3a-(6p,70-epoxy>-N-n-birtyl· nortropanyl 3a- (6?, 70-epoxy> N-n-birtyl · nortropanyl 2-tienyl 2-thienyl 225-227 225-227 14 14 3a-(6a.7p-epoxy)trapanyi 3a (6a.7p-epoxy) trapanyi •fenyl • phenyl 248-247 248-247 15 15 3a-tropanyl 3-tropanyl fenyl phenyl 243-244 243-244 16 16 3a-(N-p-fluóretyl)nortfopanyl 3a- (N-p-fluoro-ethyl) nortfopanyl fenyl phenyl 219-220 219-220 17 17 3a-(6,7-dehydro)tropanyl 3a- (6,7-dehydro) tropanyl fenyl phenyl 181-1B3 181-1B3 18 18 3a-(N-etyl)nortropanyl 3a- (N-ethyl) nortropanyl fenyl phenyl 231-232 231-232 19 19 3a-(N-izopropyl)nortfopanyl 3a- (N-isopropyl) nortfopanyl fenyl phenyl 24Ô-247 24o-247 20 20 3a-tropanyl 3-tropanyl cykbhexyl cykbhexyl 260 260 21 21 3a-(N-0-flvóretyl)nortropanyl 3a- (N-0-flvóretyl) nortropanyl cyklohexyl cyclohexyl 203-204 203-204 22 22 3a-(60,70-epoxy)tropanyl 3a (60,70-epoxy) tropanyl cyklopentyl cyclopentyl 237 237 23 23 3a-1ropanyl 3-1ropanyl cyklopentyl cyclopentyl 280 280 24 24 3a-(N-0-flučretyl)nortropanyl 3a- (N-0-flučretyl) nortropanyl cyklopentyl cyclopentyl 182-183 182-183 25 25 3a-(N-etyl)nortropanyl 3a- (N-ethyl) nortropanyl cyklopentyl cyclopentyl 227-228 227-228 26 26 3a-(N-izopropyl)nortfopany( 3a- (N-isopropyl) nortfopany ( cyklopentyl cyclopentyl 174-175 174-175 27 27 3a-(60,7 p-epcxy)lt opanyl 3α- (60.7 β-epoxy) 1 -tanyl 2-lienyl 2-lienyl 240-242 240-242 28 28 3a-tropanyt 3-tropanyt 2-lienyl 2-lienyl 217-219 217-219 29 29 3a-(6,7-dehydro)tropanyl 3a- (6,7-dehydro) tropanyl 2-lienyl 2-lienyl 233-235 233-235 30 30 3a-(6,7-dehydro)1ropanyl 3a- (6,7-dehydro) 1ropanyl 3-lienyl 3-lienyl 247-248 247-248 31 31 3α-(6β,7 p-e poxyjtropa n yl 3α- (6β, 7β-e poxy) triphenyl 3-lienyl 3-lienyl 242-243 242-243 32 32 3a-(60,70-epoxy)tropanyl 3a (60,70-epoxy) tropanyl 2-furyl 2-furyl 33 33 3a-(6,7-dehydro)tropanyl 3a- (6,7-dehydro) tropanyl 2-furyl 2-furyl 34 34 3a-tropanyl 3-tropanyl 2-furyl 2-furyl 35 35 3a-tropanyl 3-tropanyl 2-pyridyl 2-pyridyl 36 36 3a-(6070-epoxy)tropanyl 3a- (6070-epoxy) tropanyl 2-pyridyl 2-pyridyl 37 37 3a-(6,7-dehydro)tropanyl 3a- (6,7-dehydro) tropanyl 2-pyridyl 2-pyridyl 36 36 3a-Iropanyl 3-Iropanyl 3-tienyt 3-thienyl 39 39 3a-(6,7-dehydro)tntpanyl 3a- (6,7-dehydro) tntpanyl cyklopentyl cyclopentyl 40 40 30460,70-6 poxyjlropanyl 30460,70-6 poxyjlropanyl cyklohexyl cyclohexyl 41 41 3a-(6,7-dehydro)tropanyt 3a- (6,7-dehydro) tropanyt cyklohexyl cyclohexyl

Poznámka: všetky hydrochloridy sa topia za rozkladu.Note: all hydrochlorides melted with decomposition.

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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

6. 6th A A R1 R1 tepl. top. *C temp. top. * C 26 26 3a-(N-p-fluóretyl)nortropanyl-metotroniid 3a- (N-p-fluoro-ethyl) nortropanyl-metotroniid cyklohexyl cyclohexyl 280 280 27 27 3a-tropanyl-P-fluóretylbromid 3-tropanyl-P-fluoroethyl bromide cyklohexyl cyclohexyl 233-234 233-234 26 26 Sa-tropanylmetotromid Sa-tropanylmetotromid cyklopeniyl cyklopeniyl 260 260 29 29 3a-tropanytetyiartHTiia 3-tropanytetyiartHTiia cyklopeniyl cyklopeniyl 235-236 235-236 30 30 3a-(N-etyl)rDrtrapanyl-rTietobromid 3a- (N-ethyl) rDrtrapanyl-rTietobromid cyklopeniyl cyklopeniyl 251-252 251-252 31 31 3a-(N-izopropyl)nortropanyi-melob-omid 3a- (N-isopropyl) nortropanyi-MELOB-omid cyklopeniyl cyklopeniyl 244-245 244-245 32 32 3a-tropany'-p-‘lLioretyl-bwiid 3-p-tropany''lLioretyl-bwiid cyklopeniyl cyklopeniyl 189-190 189-190 33 33 3n-(N-p-fluĎretyl)nortropany1>metobromid 3N (N-p-fluĎretyl) nortropany1> methobromide cyklopeniyl cyklopeniyl 266-267 266-267 34 34 3a-(6.7-dehydro)rortrop8nyl-metarnetán 3a- (6,7-dehydro) rortrop8nyl-metarnetán sulíonát sulfonate 2-tienyt 2-thienyl 225-226 225-226 35 35 30-(6B,7|J-epDxy)tropar,yl-metobtDmid 30- (6B, 7 | J-epDxy) TROPAR, Y-metobtDmid 2-tienyl 2-thienyl 21B-22D 21B-22D 36 36 3(J-lropanylmetoi:tcmíd 3 (J-lropanylmetoi: tcmíd 2-tienyl 2-thienyl 243-244 243-244 37 37 3[)-(6.7-dehydro)ltopanykmetobromid 3 [) - (6,7-dehydro) ltopanykmetobromid 2-tienyl 2-thienyl 211-214 211-214 38 38 3a-(6,7-dehydro)trcpanyl-metobromid 3a- (6,7-dehydro) trcpanyl-methobromide 3-tienyt 3-thienyl 182-183’ 182-183 ' 39 39 3a-(65.7p-epoxy)tropanyl-metobromid 3a (65.7p-epoxy) tropanyl-methobromide 3-tienyl 3-thienyl 217-218 217-218 40 40 (+)-enantiomérč. 1 (+) - enantiomérč. 1 41 41 (-)-er>aniiomér č. 1 (-) - eri anomer no. 1 42 42 3a-(6|J,7fl-cpoxy’4ropanyl-metobromid 3a- (6 | J, 7fl-cpoxy'4ropanyl-methobromide 2-ftjryl 2-ftjryl 43 43 3a-(6,7<lehydrr>)tropanyl-metobromid 3a- (6,7 <lehydrr>) tropanyl-methobromide 2-furyl 2-furyl 44 44 3a-tropafiylmetobromid 3-tropafiylmetobromid 2-furyl 2-furyl 45 45 3a-(65,7p-epoxy)tropanyl-metobromid 3a (65,7p-epoxy) tropanyl-methobromide 2-pyridyl 2-pyridyl 46 46 3a-(6,7-dehydro)lropanyl-metobromid 3a- (6,7-dehydro) lropanyl-methobromide 2-pyridyl 2-pyridyl 47 47 3a-tropanylmel3bromid 3-tropanylmel3bromid 2-pyridyl 2-pyridyl 48 48 3a-tropanylrTiet3brcmid 3-tropanylrTiet3brcmid 3-tienyl 3-thienyl 49 49 3a-(6,7-dehydro)lropanyl-rretobromid3a- (6,7-dehydro) l-r opanyl rretobromid cyklopeniyl cyklopeniyl 50 50 3tx-{66,7p-epoxy)iropanyl-rnetobromid 3tx- {66,7p-epoxy) iropanyl-rnetobromid cyklohexyl cyclohexyl 51 51 3a-(6,7-dehydro)lropanyl-fnelobromicl 3a- (6,7-dehydro) lropanyl-fnelobromicl cyklohexyl cyclohexyl 52 52 3B-(63.7p-epoxy)tropanyl-n)etoDromd 3B- (63.7p-epoxy) n-tropanyl) etoDromd cykiopentyl cyclopentyl

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

č. no. A A R1 R1 lepí. top. sticks. top. 1 1 3a-(Sp7ŕ^poxy)tropanylmetobromW 3a- (Sp7ŕ ^ propoxy) tropanylmetobromW 2-tienyt 2-thienyl 217-218 217-218 2 2 3a-tropanyl-metobromid 3-tropanyl-methobromide 2-lienyl 2-lienyl 263-264 263-264 3 3 3a-(6,7-dehydro)tropanyl-metobromid 3a- (6,7-dehydro) tropanyl-methobromide 2-tienyl 2-thienyl 191-192 191-192 4 4 3a-(N-p-fluóretyl)nortrapanylrnetobromid 3a- (N-p-fluoro-ethyl) nortrapanylrnetobromid 2-tienyl 2-thienyl 242-243 242-243 5 5 3a-tropanyk|J-flu6rmetobromid 3-tropanyk | J flu6rmetobromid 2-tienyl 2-thienyl 214-215 214-215 5 5 3a-(N-i2opropyl)granatanyknetobromid 3a- (N-i2opropyl) granatanyknetobromid 2-tienyl 2-thienyl 242-243 242-243 7 7 3a-(N-Í20DropyI)nortropanyl-metobromid 3a- (N-Í20DropyI) nortropanyl-methobromide 2-tienyl 2-thienyl 229-230 229-230 S WITH 3a-(6['l,7(!-epoxyj-N-izopropylnortropanylmeiobromid3a- (6 [l, 7 (? - N-epoxyj izopropylnortropanylmeiobromid 2-tienyl 2-thienyl 223-224 223-224 9 9 3a-(Sf>.7|3-epoxy)-etyl-oortropanylmetobroriid 3a- (S f> .7 | 3-epoxy) -ethyl oortropanylmetobroriid 2-tienyl 2-thienyl 215-216 215-216 10 10 3a-(N-elyl}nortropanyl-metobromid 3a- (N-ethyl} nortropanyl-methobromide 2-tienyl 2-thienyl 260-261 260-261 11 11 3a-(N-metyl)granatanyl-metobromid 3a- (N-methyl) granatanyl-methobromide 2-tienyl 2-thienyl 246-247 246-247 12 12 3a-(ep.7p-epoxy)-N-p-fluór-etylnortropanyl- metobromid 3a (ep.7p-Epoxy) -N-p-fluoro-etylnortropanyl- methobromide 2-tienyl 2-thienyl 182-183 182-183 13 13 3a-(6P,7p-epoxy)-N-n-propyl-noi1ropanyl· metobromid 3α- (6β, 7β-epoxy) -N-n-propyl-nitropropyl metobromide 2-tienyl 2-thienyl 209-210 209-210 14 14 3a-tropanyl-P-hydioxyetylbromid 3-tropanyl-P-hydioxyetylbromid 2-tienyf 2-tienyf 231-232 231-232 15 15 3a-(6p,7p-epoxy propány Imetobromid 3α- (6β, 7β-epoxy propanes Imetobromide fenyl phenyl 217-218 217-218 16 16 3a-tropanylmelobromld 3-tropanylmelobromld fenyl phenyl 273-274 273-274 17 17 3a-(N-p-flu6rety1)nortropanylnic1obromid 3a- (N-p-flu6rety1) nortropanylnic1obromid fenyl phenyl 215 215 18 18 3a-(6,7-dehydm)tropanyt-metobromÍd 3a- (6,7-dehydm) tropanyt-methobromide fenyl phenyl 170-171 170-171 19 19 3a-(N-ety()noítropanyŕ-melobroniid 3a- (N-ethyl () noítropanyŕ-melobroniid fenyl phenyl 249-250 249-250 20 20 3a-(N-ízopropyl)nortropanyl -metobromid 3α- (N -isopropyl) nortropanyl-metobromide fenyl phenyl 259-260 259-260 21 21 3a-tropanyletylbromid 3-tropanyletylbromid fenyl phenyl 248-249 248-249 22 22 3a-(N-etyJ)fiortropanyt-etyibromid 3a- (N-ethyl-) fiortropanyt-etyibromid fenyl phenyl 244-245 244-245 23 23 3a-(6p,7p-epoxy(tropanyf-etylbromid 3a- (6?, 7? Epoxy (tropanyf-ethyl bromide fenyl phenyl 226 226 24 24 3a-tropanyl-P-fIuórbfornid 3-tropanyl-P-fIuórbfornid fenyi phenyl 241 241 25 25 3a-tropanylmeiobromid 3-tropanylmeiobromid cykloheKyl cykloheKyl 278 278

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

t T 3«-(65,7p-epoxy)tropanyl 3 '- (65,7p-epoxy) tropanyl fenyl phenyl 246-247 246-247 2 2 3a-(6,7-dehydro)tropanyi 3a- (6,7-dehydro) tropanyi fenyl phenyl 261-262 261-262 3 3 3a-(65.7p-epoxy)tropanyl 3a (65.7p-epoxy) tropanyl 3-tienyi 3-thienyl 4 4 3ari6,7-dehydro}tropanyl 3ari6,7-dehydro} tropanyl 3-tienyl 3-thienyl 5 5 3a-troparyl 3-troparyl 3-tienyl 3-thienyl 6 6 3a-(N-metyl)<|ranatanyl 3a- (N-methyl) <| ranatanyl 3-tienyl 3-thienyl

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

ô. about. A A R1 R1 tepl.top. *< tepl.top. * < 1 1 3a-(6p.7p-epoxy)tropanyi-metobromid 3a (6p.7p-epoxy) tropanyi-methobromide fenyl phenyl 211-212 211-212 2 2 3a-(6,7-dehydro)tropanyl-metobromid 3a- (6,7-dehydro) tropanyl-methobromide fenyl phenyl 158-160* 158-160 * 3 3 3a-(60,7p-epoxy)tropanyl-metobromid 3a (60,7p-epoxy) tropanyl-methobromide 3-tienyl 3-thienyl 4 4 3a-(6,7-dehydro)tropanyl-metobromjd 3a- (6,7-dehydro) tropanyl-metobromjd 3-tienyl 3-thienyl 5 5 3a-tropanyinietobromid 3-tropanyinietobromid 3-tienyl 3-thienyl 6 6 3a-(N-rTielyl)granatany[-metobromid 3a- (N-rTielyl) granatany [-metobromid 3-tienyl 3-thienyl

s kryštalickým metanolomwith crystalline methanol

č. no. A A R1 R 1 R9 R9 1 1 3a-(6p,7p-epoxy)tropanyl 3a- (6?, 7? Epoxy) tropanyl 2-tienyl 2-thienyl 5-metyl 5-methyl 2 2 3a-(6,7-dehydro)tropanyl 3a- (6,7-dehydro) tropanyl 2-tienyl 2-thienyl 5-metyl 5-methyl 3 3 3a-tropanyi 3-tropanyi 2-tieryl 2-tieryl 5-metyl 5-methyl 4 4 3a-(6P,7p-epoxy)tropanyl 3a (6P, 7P-epoxy) tropanyl 2-(5-metyl)-lienyl 2- (5-methyl) -lienyl S-metyl S-methyl 5 5 3a-(6,7-dehydro)tropanyl 3a- (6,7-dehydro) tropanyl 2-'5-metyl)-tíenyl 2-'5-methyl) thienyl 5-metyl 5-methyl 5 5 3a-tropanyl 3-tropanyl 2-(5-metyl)-1>enyl 2- (5-methyl) -1> phenyl 5-metyl 5-methyl 7 7 3a-(6p,7p-epoxy)trcpanyl 3a- (6?, 7? Epoxy) trcpanyl 2-tieryl 2-tieryl 5-fluôr 5-fluoro B B 3o-(6.7-dehydro)tropanyi 3 O- (6,7-dehydro) tropanyi 2-tienyl 2-thienyl 5-fluór 5-fluoro 9 9 3a-tropanyl 3-tropanyl 2-tienyl 2-thienyl 5-fluór 5-fluoro 10 10 3ct-(6p,7p-epoxy)tropanyl 3ct- (6?, 7? Epoxy) tropanyl 2-{5-fluór-tienyl) 2- {5-fluoro-thienyl) 5-fluór 5-fluoro 11 11 3a-(6,7-dehydro)lropanyl 3a- (6,7-dehydro) lropanyl 2-(5-fluór-tienyl) 2- (5-fluoro-thienyl) 5-fluór 5-fluoro 12 12 3a-tropanyl 3-tropanyl 2-;5-tluór-‘Jenyl)2, 5-tluó -'Jenyl R) 5-fluór 5-fluoro

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

Claims (12)

PATENTOVÉ NÁROKYPATENT CLAIMS č. no. A A R1 R1 Ra R a 1 1 3a-(6p,7p-epoxy)tropanyl-metobromid 3a- (6?, 7? Epoxy) tropanyl-methobromide 2-tienyl 2-thienyl 5-metyl 5-methyl 2 2 3a-(6,7-dehydro)tropanyl-metobromid 3a- (6,7-dehydro) tropanyl-methobromide 2-tienyl 2-thienyl 5-metyl 5-methyl 3 3 3a-tropanyl metobromid 3α-tropanyl metobromide 2-tienyl 2-thienyl 5-metyl 5-methyl 4 4 3u (6p.7p-epoxyXropanyl-metobromid 3u (6β, 7β-epoxyXropanyl-metobromide) 2-(5-metyl)-lienyl 2- (5-methyl) -lienyl 5-metyl 5-methyl 5 5 3tt-(o,7-dehYdro)tropanyl-metobromid 3tt- (a, 7-dehydro) tropanyl-methobromide 2-(5-m6ty!)-tienyl 2- (5-m6ty!) - thienyl 5-metyl 5-methyl 6 6 3a-tropanylmetobromid 3-tropanylmetobromid 2-(5-me1yl)-tienyl 2- (5-me1yl) thienyl 5-metyl 5-methyl 7 7 3a-(6P,7p-epoxy)trapanyl-metobromid 3a (6P, 7P-epoxy) trapanyl-methobromide 2-tienyl 2-thienyl 5-fluôr 5-fluoro 8 8 3u-(6,7-dehydro)tropanyl-metobromid 3u- (6,7-dehydro) tropanyl-methobromide 2-tienyl 2-thienyl 5-fluór 5-fluoro 9 9 3a-trcpanylmetobromid 3-trcpanylmetobromid 2-tienyl 2-thienyl 5-fluôr 5-fluoro 10 10 3a-(6p,7p-epoxy)tropanyl-nnetobromid 3a- (6?, 7? Epoxy) tropanyl-nnetobromid 2-(5-fluór) tienyl 2- (5-fluoro) thienyl 5-fluór 5-fluoro 11 11 3a-(6,7-dehydro)tropanyl-metobroínid 3a- (6,7-dehydro) tropanyl-metobroínid 2-(5-fluór)tienyl 2- (5-fluoro) thienyl 5-fluór 5-fluoro 12 12 3<r-UopanylmetobTomkí 3 <r UopanylmetobTomkí 2-(5-fluôr)tienyl 2- (5-fluoro) thienyl 5-fluôr 5-fluoro
1. Zlúčeniny všeobecného vzorca (I)1. Compounds of formula (I) 0), kde0) where A znamená skupinu všeobecného vzorca (II) kdeA represents a group of formula (II) wherein Q znamená jednu z dvojväzbových skupínQ represents one of the bivalent groups -CH2-CH2, -CH2-CH2-CH2-, -CH=CH-,-CH 2 -CH 2 , -CH 2 -CH 2 -CH 2 -, -CH = CH-, -CH - CH“ a-CH - CH 'a 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, R1 znamená alkyl s 1 až 4 atómami uhlíka a R a R1 môžu spolu tvoriť alkylénový zvyšok so 4 až 6 atómami uhlíka, pričom sa pozitívny náboj dusíkového atómu vyrovnaná ekvivalentom aniónu X( ),R 1 is C 1 -C 4 alkyl and R and R 1 may together form an C 4 -C 6 alkylene moiety, whereby the positive charge of the nitrogen atom is offset by the anion X equivalent () , 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, alkoxyskupinu alebo alkylovú skupinu, obidve s 1 až 4 atómami uhlíkaR 2 is hydrogen, hydroxy, alkoxy or alkyl group, both having 1 to 4 carbon atoms Ra znamená atóm vodíka, atóm fluóru, chlóru alebo metylovú skupinu.R a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group. 2. Zlúčeniny podľa nároku 1, kde R1 znamená 2-tienyl.Compounds according to claim 1, wherein R 1 is 2-thienyl. 3. Zlúčeniny podľa nároku 1 alebo 2, kde R2 znamená hydroxyskupinu.Compounds according to claim 1 or 2, wherein R 2 is hydroxy. 4. Zlúčeniny podľa nároku 1, 2 alebo 3, kde A znamenáCompounds according to claim 1, 2 or 3, wherein A represents -( rL.'5 \) :<a \____I/- (rL. ' 5 '): < a \ ____ I / -/ J;p.·3:<- / J; p. · 3 : < \I\ I R a X<_) má význam, uvedený v nároku 1 a R1 má význam uvedený v nároku 1, s výnimkou atómu vodíka.R and X (1) are as defined in claim 1 and R 1 is as defined in claim 1, except for a hydrogen atom. 5. Zlúčeniny podľa nároku 1 až 4, kde R1 znamená 2-tienyl a A znamená skupinu vo forme 3α-, kde X'’ znamená ekvivalent aniónu, výhodne Br alebo CH3SO3·.Compounds according to claims 1 to 4, wherein R 1 represents 2-thienyl and A represents a group in the form 3α-, wherein X '' represents an anion equivalent, preferably Br or CH 3 SO 3 ·. 6. Zlúčeniny všeobecného vzorca podľa nároku 1, vo forme 3α-, ako metobromidy alebo metometánsulfonáty.Compounds of formula I according to claim 1, in the form of 3α-, such as metobromides or methanesulfonates. 7. Spôsob výroby zlúčenín podľa nárokov 1 až 6, vyznačujúci sa tým, že sa ester všeobecného vzorca (IV) r1-C-CO-ORA process for the preparation of the compounds according to claims 1 to 6, characterized in that the ester of the general formula (IV) r 1-C-CO-OR R2 ('V), kde R” znamená alkyl s 1 až 4 atómami uhlíka a R1, R2 a R3 majú význam uvedený v nároku 1, podrobí výmene esterových skupín s aminoalkoholom všeobecného vzorca (V)R 2 ( 'V) wherein R' is C 1 -C 4 alkyl and R 1, R 2 and R 3 are as defined in Claim 1, is subjected to the transesterification with an amino alcohol of formula (V) Q má význam uvedený v nároku 1 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) saQ is as defined in claim 1 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 a) v prípade, že Q znamená =NR, kvartemizujú pôsobením reaktívneho monoderivátu alkánu vzorca Z-(alkyl s 1 až 4 atómami uhlíka), kde Zje ľahko odštiepiteľnú 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), wherein Z is an easily cleavable group, or b) prípade, že Q znamená =NH, kvartemizujú disubstituovaným alkánom vzorca Z-(alkylén s 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. 8. Medziprodukt všeobecného vzorca (VI), kde Q, Q, Ra, R1 a R2 majú význam uvedený v nároku 1, ako aj adičné soli týchto látok s kyselinami s výnimkou tropínesterov fény 1-2-ticnylglykolo vej, 2,2'-ditienylglykolovej a 3,3'-ditienylglykolovej kyseliny na prípravu zlúčeniny vzorca (I) podľa nároku 1.An intermediate of formula (VI), wherein Q, Q, R a , R 1 and R 2 are as defined in claim 1, as well as acid addition salts thereof with the exception of the tropinesters of the 1-2-ticnyl glycolic acid, 2, 2'-dithienylglycolic and 3,3'-dithienylglycolic acid for the preparation of a compound of formula (I) according to claim 1. 9. Medziprodukt podľa nároku 8, všeobecného vzorca (VI), ktorým je aleboAn intermediate according to claim 8, which is or 10. Farmaceutický prostriedok s anticholinergickými účinkami, na liečbu ochorení dýchacích ciest a sínusovej bradykardie, vyznačujúci sa tým, že obsahuje zlúčeniny podľa nárokov 1 až 6 spolu s pomocnými látkami a/alebo nosičmi.Pharmaceutical composition with anticholinergic effects, for the treatment of respiratory diseases and sinus bradycardia, characterized in that it contains the compounds according to claims 1 to 6 together with adjuvants and / or carriers. 11. Použitie zlúčenín podľa nárokov 1 až 6 na prípravu farmaceutických prostriedkov s anticholinergickým účinkom.Use of the compounds according to claims 1 to 6 for the preparation of pharmaceutical compositions having anticholinergic activity. 12. Použitie zlúčenín podľa 1 až 6 na prípravu farmaceutických prostriedkov na liečbu ochorení dýchacích ciest a sínusovej bradykardie.Use of the compounds according to 1 to 6 for the preparation of pharmaceutical compositions for the treatment of respiratory diseases and sinus bradycardia.
SK4523-90A 1989-09-16 1990-09-17 Esters of thienyl carboxylic acids and amino alcohols, process for their preparation, intermediate products, pharmaceutical compositions containing same and their use SK452390A3 (en)

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HU9200857D0 (en) 1992-05-28
JPH0730074B2 (en) 1995-04-05
UA41272C2 (en) 2001-09-17
DD297647A5 (en) 1992-01-16
RU2073677C1 (en) 1997-02-20
IL95691A0 (en) 1991-06-30
AU6431890A (en) 1991-04-18
CZ452390A3 (en) 1998-11-11
DE10299026I2 (en) 2004-07-01
KR910006272A (en) 1991-04-29
YU47800B (en) 1996-01-09
PH31617A (en) 1999-01-12
NZ235306A (en) 1997-06-24
IE903342A1 (en) 1991-04-10
SK452390A3 (en) 1998-11-04

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