SK3962001A3 - Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments - Google Patents
Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments Download PDFInfo
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Abstract
Description
Benzoylguanidínové deriváty, spôsob ich výroby, farmaceutický prostriedok s ich obsahom a ich použitieBenzoylguanidine derivatives, process for their preparation, pharmaceutical composition containing them and their use
Oblasť technikyTechnical field
Tento vynález sa týka benzoylguanidínových derivátov, spôsobu ich výroby, farmaceutického prostriedku s ich obsahom a ich použitia na prípravu lieku.The present invention relates to benzoylguanidine derivatives, a process for their preparation, a pharmaceutical composition containing them and their use in the preparation of a medicament.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Známe sú podobné zlúčeniny tohto typu z nemeckého patentu 196 01 303.8. Prekvapivo sa zistilo, že zlúčeniny podľa vynálezu, na rozdiel od derivátov benzoylguanidínu známych už predtým z problematiky, majú prednosť, že okrem nečakane vyššej účinnosti majú aj tú výhodu, že sú dostupné aj ústnym podaním.Similar compounds of this type are known from German patent 196 01 303.8. Surprisingly, it has been found that the compounds of the invention, in contrast to the benzoylguanidine derivatives already known from the prior art, have the advantage that, in addition to the unexpectedly higher efficacy, they also have the advantage of being available by oral administration.
Podstata vynálezuSUMMARY OF THE INVENTION
Podstatou vynálezu sú benzoylguanidínové deriváty všeobecného vzorca IThe present invention provides benzoylguanidine derivatives of formula (I)
v ktoromin which
R1 znamená C-i-Ce alkyl, heteroaryl nesubstituovaný alebo jednoducho alebo viacnásobne substituovaný rozvetvenou alebo nerozvetvenou C1-C4 alkylovou skupinou, cykloalkylovou skupinou, rozvetvenou alebo nerozvetvenou C1-C4 alkoxyskupinou, NH2 skupinou alebo jednou primárnou alebo sekundárnou aminoskupinou, trifluórmetylovou skupinou, kyanoskupinou alebo nitroskupinou alebo halogénom, ····R 1 represents C 1 -C 6 alkyl, heteroaryl unsubstituted or singly or multiply substituted with branched or unbranched C 1 -C 4 alkyl, cycloalkyl, branched or unbranched C 1 -C 4 alkoxy, NH 2 or one primary or secondary amino, trifluoromethyl, nitro or cyano or cyano or halogen, ····
-2aryl nesubstituovaný alebo jednoducho alebo viacnásobne substituovaný rozvetvenou alebo nerozvetvenou C1-C4 alkylovou skupinou, rozvetvenou alebo nerozvetvenou C1-C4 alkoxyskupinou, NH2 skupinou alebo primárnou alebo sekundárnou aminoskupinou, trifluórmetylovou skupinou, hydroxyskupinou, kyanoskupinou alebo nitroskupinou alebo halogénom alebo 5- alebo 6-členným heteroarylovým zvyškom, ktorý môže obsahovať jeden, dva, tri, štyri alebo päť heteroatómov zo skupiny obsahujúcej dusík, kyslík alebo síru, a môžu byť rovnaké alebo rôzne, alkylaryl nesubstituovaný alebo jednoducho alebo viacnásobne substituovaný v arylovej a/alebo alkylovej časti rozvetvenou alebo nerozvetvenou C1-C4 alkylovou skupinou, rozvetvenou alebo nerozvetvenou C1-C4 alkoxyskupinou, NH2 skupinou alebo primárnou alebo sekundárnou aminoskupinou, trifluórmetylovou skupinou, kyanoskupinou alebo nitroskupinou alebo halogénom, voliteľne vo forme jednotlivých tautomérov alebo voliteľne enantiomérov a ich zmesí, ako aj vo forme voľných zásad alebo zodpovedajúcich kyslých adičných solí s farmakologicky prijateľnými kyselinami.-2aryl unsubstituted or singly or multiply substituted by branched or unbranched C 1 -C 4 alkyl, branched or unbranched C 1 -C 4 alkoxy, NH 2 or primary or secondary amino, trifluoromethyl, hydroxy, cyano or nitro or 5-halo or 5-halo or 5-halo; a heteroaryl radical which may contain one, two, three, four or five heteroatoms from the group consisting of nitrogen, oxygen or sulfur, and may be the same or different, alkylaryl unsubstituted or mono- or polysubstituted in the branched or unbranched aryl and / or alkyl moiety -C4 alkyl, branched or unbranched C1-C4 alkoxy, NH2 or primary or secondary amino, trifluoromethyl, cyano or nitro or halogen, optionally in the form of individual tautomers or optionally enantiomers and mixtures thereof, as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
Výhodné podľa vynálezu sú zlúčeniny všeobecného vzorca I, v ktorom R1 znamená nesubstituovaná fenylové jadro alebo fenylové jadro substituované fluórom alebo metylovou skupinou, trifluórmetylovou skupinou, metoxyskupinou, alebo pyrolylovým zvyškom, aleboPreferred are the compounds of formula I, wherein R1 is an unsubstituted phenyl ring or a phenyl ring substituted by fluorine or by a methyl, trifluoromethyl, methoxy, or pyrrolyl radical, or
Osobitne výhodné sú nasledovné zlúčeniny: metánsulfonát 4-(4-(2-pyrolylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoylguanidínuParticularly preferred are the following compounds: 4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine methanesulfonate
x CH3SO3Hx CH3SO3H
-34-(4-(4-fluórfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoylguanidín-metánsulfonát • ·-34- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine methanesulfonate • ·
X CH3SO3HX CH3SO3H
C1-C4 alkyl pripadne CrCe alkyl všeobecne znamená rozvetvený alebo nerozvetvený uhľovodíkový zvyšok s 1 až 4, prípadne až 8 atómami uhlíka, ktoré môžu byť voliteľne substituované jedným alebo viacerými atómami halogénu (halogénov), výhodne fluórom, ktoré môžu byť rovnaké alebo rozdielne. Ako príklady možno uviesť nasledujúce uhľovodíkové zvyšky:C 1 -C 4 alkyl or C 1 -C 6 alkyl generally denotes a branched or unbranched hydrocarbon radical having 1 to 4 or up to 8 carbon atoms, which may be optionally substituted by one or more halogen atoms (preferably halogens), preferably fluorine, which may be the same or different. Examples are the following hydrocarbon residues:
metyl, etyl, propyl, 1-metyletyl (izopropyl), n-butyl, 1-metylpropyl, 2-metylpropyl, 1,1dimetyletyl, pentyl, 1-metylbutyl, 2-metylbutyl, 3-metylbutyl, 1,1-dimetylpropyl, 1,2dimetylpropyl, 2,2-dimetylpropyl, 1-etylpropyl, hexyl, 1-metylpentyl, 2-metylpentyl, 3metylpentyl, 4-metylpentyl, 1,1-dimetylbutyl, 1,2-dimetylbutyl, 1,3-dimetylbutyl, 2,2dimetylbutyl, 2,3-dimetylbutyl, 3,3-dimetylbutyl, 1-etylbutyl, 2-etylbutyl, 1,1,2-trimetylpropyl, 1,2,2-trimetylpropyl, 1-etyl-1-metylpropyl a 1-etyl-2-metylpropyl. Výhodné sú, pokiaľ nie je uvedené inak, zvyšky nižších alkylov s 1 až 4 atómami uhlíka, ako je napríklad metyl; etyl, propyl, /zo-propyl, n-butyl, 1-metylpropyl, 2-metylpropyl alebo 1,1-dimetyletyl.methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2dimethylbutyl 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2 methylpropyl. Unless otherwise indicated, lower alkyl radicals having 1 to 4 carbon atoms, such as methyl; ethyl, propyl, iso -propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
Alkoxy všeobecne znamená alkylovú skupinu s priamym alebo rozvetveným reťazcom pripojenú cez atóm kyslíka. Výhodný je zvyšok nižších alkoxyskupín s 1 až 4 atómami uhlíka. Osobitne výhodná je metoxyskupina.Alkoxy generally means a straight or branched chain alkyl group attached through an oxygen atom. Preferred is the radical of lower alkoxy groups having 1 to 4 carbon atoms. Methoxy is particularly preferred.
Aryl znamená všeobecne aromatický zvyšok so 6 až 10 atómami uhlíka - aj v zlúčeninách, pričom aromát môže byť substituovaný jednou alebo viacerými nižšími alkylovými skupinami, trifluórmetylovými skupinami, kyanoskupinami, alkoxyskupinami, nitroskupinami, aminoskupinami a/alebo jedným alebo viacerým atómami halogénov, ktoré môžu byť rovnaké alebo rôzne; výhodný arylový zvyšok je voliteľne substituovaný fenylový zvyšok, pričom ako substituenty sú výhodnéAryl generally represents an aromatic radical having 6 to 10 carbon atoms - also in the compounds, wherein the aromatic may be substituted by one or more lower alkyl, trifluoromethyl, cyano, alkoxy, nitro, amino and / or one or more halogen atoms, which may be the same or different; the preferred aryl radical is an optionally substituted phenyl radical, with substituents being preferred
halogény, ako je napríklad fluór, chlór alebo bróm, kyanoskupina aj hydroxylová skupina, ako halogén je podľa vynálezu osobitne výhodný fluór. Arylový substituent, výhodne fenyl, môže byť ďalej substituovaný 5- alebo 6-členným heteroarylovým zvyškom, ktorý môže obsahovať jeden, dva, tri, štyri alebo päť heteroatómov zo skupiny obsahujúcej dusík, kyslík alebo síru, ktoré môžu byť rovnaké alebo rôzne.halogens such as fluorine, chlorine or bromine, cyano and hydroxyl, such as halogen according to the invention, fluorine is particularly preferred. The aryl substituent, preferably phenyl, may be further substituted with a 5- or 6-membered heteroaryl radical which may contain one, two, three, four or five heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, which may be the same or different.
Aralkyl všeobecne znamená arylový zvyšok so 7 až 14 atómami uhlíka, ktorý je napojený cez alkylénový reťazec, pričom aromát môže byť substituovaný jedným alebo viacerými nižšími alkylovými skupinami, alkoxyskupinami, nitroskupinami, aminoskupinami a/alebo jedným alebo viacerými atómami halogénov, ktoré môžu byť rovnaké alebo rôzne. Výhodné sú aralkylové zvyšky s 1 až 6 atómami uhlíka v alifatickej časti a so 6 atómami uhlíka v aromatickej časti.Aralkyl generally means an aryl radical of 7 to 14 carbon atoms which is linked through an alkylene chain, wherein the aromatic may be substituted by one or more lower alkyl, alkoxy, nitro, amino and / or one or more halogen atoms, which may be the same or Differently. Preferred are aralkyl radicals having 1 to 6 carbon atoms in the aliphatic moiety and having 6 carbon atoms in the aromatic moiety.
Ako výhodné aralkylové zvyšky, pokiaľ nie je uvedené inak, možno uviesť benzyl, fenetyl a fenylpropyl.Preferred aralkyl radicals, unless otherwise indicated, include benzyl, phenethyl and phenylpropyl.
Halogén znamená, pokiaľ nie je uvedené inak, fluór, chlór, bróm, jód, a výhodne fluór, chlór alebo bróm.Halogen means, unless otherwise indicated, fluorine, chlorine, bromine, iodine, and preferably fluorine, chlorine or bromine.
Amino znamená, pokiaľ nie je uvedené inak, skupinu NH2, ktorá môže byť voliteľne substituovaná jedným alebo dvoma CrCe alkylovými, arylovými alebo aralkylovými zvyškami, a môžu byť rovnaké alebo rôzne.Amino means, unless otherwise indicated, an NH 2 group which may be optionally substituted with one or two C 1 -C 6 alkyl, aryl or aralkyl radicals, and may be the same or different.
Podľa toho alkylamino znamená napríklad metylamino, etylamino, propylamino, 1-metylénetylamino, butylamino, 1-metylpropylamino, 2-metylpropylamino alebo 1,1-dimetyletylamino.Accordingly, alkylamino means, for example, methylamino, ethylamino, propylamino, 1-methylethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.
Podľa toho dialkylamino znamená napríklad dimetylamino, dietylamino, dipropylamino, dibutylamino, di-(1-metyletyl)amino, di(1-metylpropyl)amino, di-2metylpropylamino, etylmetylamino, metylpropylamino.Accordingly, dialkylamino means, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, di- (1-methylethyl) amino, di (1-methylpropyl) amino, di-2-methylpropylamino, ethylmethylamino, methylpropylamino.
Cykloalkyl všeobecne znamená nasýtený alebo nenasýtený cyklický uhľovodíkový zvyšok s 5 až 9 atómami uhlíka, ktorý voliteľne môže byť substituovaný jedným atómom halogénu alebo viacerými atómami halogénu, výhodne fluóru, ktoré môžu byť rovnaké alebo rôzne. Výhodné sú cyklické uhľovodíky s 3 až 6 atómami uhlíka. Ako príklady možno uviesť cyklopropyl, cyklobutyl, cyklopentyl, cklopentenyl, cyklohexyl, cyklohexenyl, cykloheptyl, cykloheptenyl, cykloheptadienyl, cyklooktyl, cyklooktenyl, cyklooktadienyl a cyklononinyl.Cycloalkyl generally means a saturated or unsaturated cyclic hydrocarbon radical of 5 to 9 carbon atoms, which may optionally be substituted by one halogen atom or by more halogen atoms, preferably fluorine, which may be the same or different. Preferred are cyclic hydrocarbons having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and cyclononinyl.
···· • ·· ···· ·· ··· ··· ··· • · · · ··· · · • ···· ···· ··· ·· · · · ·· ··· ·· ··· ·· ·································································································· ··· ·· ··· ·· ·
-5Heteroaryl podľa vyššie uvedenej definície všeobecne znamená 5- až 6členné jadro, ktoré ako heteroatóm môže obsahovať kyslík, síru a/alebo dusík a na ktorom môže byť nakondenzované ďalšie aromatické jadro. Výhodné sú 5- a 6členné aromatické jadrá, ktoré obsahujú jeden atóm kyslíka, jeden atóm síry a/alebo až dva atómy dusíka a ktoré sú voliteľne benzokondenzované.-5-Heteroaryl as defined above generally means a 5- to 6-membered nucleus which, as a heteroatom, may contain oxygen, sulfur and / or nitrogen and on which an additional aromatic nucleus may be fused. Preferred are 5- and 6-membered aromatic cores which contain one oxygen atom, one sulfur atom and / or up to two nitrogen atoms and which are optionally benzofused.
Ako osobitné heterocyklické systémy možno uviesť napríklad akridinyl, akridonyl, alkylpyridinyl, antrachinonyl, askorbyl, azaazulenyl, azabenzantracenyl, azabenzantrenyl, azachryzenyl, azacyklazinyl, azaindolyl, azanaftacenyl, azanaftalenyl, azaprenyl, azatrifenylenyl, azepinyl, azinoindolyl, azinopyrolyl, benzakridinyl, benzazapinyl, benzofuryl, benzonaftyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl, benzochinolinyl, benzochinolizinyl, benzotiepinyl, benzotiofenyl, benzylizochinolinyl, bipyridinyl, buty rola kto nyl, kaprolaktamyl, karbazolyl, karbolinyl, katechinyl, chromenopyronyl, chromonopyranyl, kumarinyl, kumaronyl, dekahydrochinolinyl, dekahydrochinolonyl, diazaantracenyl, diazafenantrenyl, dibenzazapinyl, dibenzofuranyl, dibenzotiofenyl, dichromylenyl, dihydrofuranyl, dihydroizokumarinyl, dihydroizochinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridonyl, dihydropyronyl, dihydrotiopyranyl, diprylenyl, dioxantylenyl, oenantolaktamyl, flavanyl, fl a vo nyl, fluoranyl, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanochinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoizochinolinyl, hydrofuranyl, hydrofuranonyl, hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrolyl, hydrochinolinyl, hydrotiochromenyl, hydrotiofenyl, indolizidinyl, indolizinyl, indolonyl, izatinyl, izatogenyl, izobenzofurándionyl, izobenzfuranyl, izochromanyl, izoflavonyl, izoindolinyl, izoindolobenzazapinyl, izoindolyl, izochinolinyl, izochinuklidinyl, laktamyl, laktonyl, maleimidyl, monoazabenzonaftenyl, naftalenyl, naftimidazopyridíndionyl, naftindolizíndionyl.naftodihydropyranyl, naftofuranyl, naftyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl, fenantrachinonyl, ftalidizochinolinyl, ftalimidyl, ftalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyrándionyl, pyranopyridinyl, pyranochinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridíntionyl, pyridinonaftalenyl, pyridinopyridinyl, pyridinyl, pyridokolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrolyl, pyridochinolinyl, pyronyl, pyrokolinyl, ···· · ·· ···· ·· ··· ··· ··· • · · · ··· · · • ···· ···· ·· ··· ·· ··· ·· 9 Specific heterocyclic systems include, for example, acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzantracenyl, azabenzantrenyl, azachryzenyl, azacyclazinyl, azaindolyl, azanaphthenyl, azanaphthenyl, azaprenyl, azaprenyl, azepiphenylenyl, azatriphenylenyl, azatriphenylenyl, azatriphenylenyl, azatriphenylenyl, azatriphenylenyl, azatriphenylenyl; , benzopyranonyl, benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl, benzothiepinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl, caprolactamyl, carbazolyl, carbolinyl, catechinyl, chromenopyronyl, chromonopyranocynyl, coumarolinyl, coumarininyl, coumarininyl, coumarininyl, coumarininyl, coumarininyl, coumarinolinyl, coumarin dibenzofuranyl, dibenzothiophenyl, dichromylenyl, dihydrofuranyl, dihydroisocoumarinyl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridonyl, dihydropyronyl, dihydrothiopyranyl, diprylenyl, dioxantylenyl, oenantolactamyl, flanyl, lactanyl, flavanyl, flavanyl, flavanyl, flavanyl uoranyl, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydrofuranonyl, hydroindolyl, hydropyraninyl, indopynyl, hydropyolyl, hydroquinolinyl, hydroquinol, izobenzofurándionyl, izobenzfuranyl, isochromanyl, izoflavonyl, isoindolinyl, izoindolobenzazapinyl, isoindolyl, isoquinolinyl, izochinuklidinyl, laktamyl, lactonyl, maleimidyl, monoazabenzonaftenyl, naphthalenyl, naftimidazopyridíndionyl, naftindolizíndionyl.naftodihydropyranyl, naftofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl, fenantrachinonyl, phthalidisoquinolinyl, phthalimidyl, phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyridionyl, pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridinothionyl, pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrolyl, pyridoquinolinyl, pyronyl, pyrokolinyl, ··· ························· · · · · ······························ 9
-6pyrolidinyl, pyrolizidinyl, pyrolizinyl, pyrolodioazinyl, pyrolonyl, pyrolopyrimidinyl, pyrolochinolonyl, pyrolyl, chinakridonyl, chinolinyl, chinolizidinyl, chinolizinyl, chinolonyl, chinuklidinyl, rodaminyl, spirokumaranyl, sukcinimidyl, sulfolanyl, sulfolenyl, tetrahydrofuranyl, tetrahydroizochinolinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrotiapyranyl, tetrahydrotiofenyl, tetrahydrotiopyranonyl, tetrahydrotiopyranyl, tetronyl, tiafenyl, tiachromanyl, tiadekalinyl, tianaftenyl, tiapyranyl, tiapyronyl, tiazolopyridinyl, tienopyridinyl, tienopyrolyl, tienotiofenyl, tiepinyl, tiochromenyl, tiokumarinyl, tiopyranyl, triazaantracenyl, triazinoindolyl, triazolopyridinyl, tropanyl, xantenyl, xantonyl, xanthydrolyl, adeninyi, aloxanyl, aloxazinyl, antranilyl, azabenzantrenyl, azabenzonaftenyl, azanaftacenyl, azafenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, kyselina barbiturová, benzazinyl, benzimidazoltionyl, benzimidazolonyl, benzizotiazolyl, benzizoxazolyl, benzocinolinyl, benzodiazocinyl, benzodioxolanyl; benzodioxolyl, benzopyridazinyl, benzotiazepinyl, benzotiazinyl, benzotiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinolinyl, depsidinyl, diazafenantrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzotiazinyl, dihydrooxazolyl, dihydropyridazinyl, dihydropyrimidinyl, dihydrotiazinyl, dioxanyl, dioxenyl, dioxepinyl, dioxinonyl, dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, ditiolanyl, ditiolenyl, ditiolyl, flavinyl, furopyrimidinyl, glykokyamidinyl, guaninyl, hexahydropyrazinoizochinolinyl, hexahydropyridazinyl, hydantoinyl.hydroimidazolyl, hydroparazinyl, hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, imidazolinyl, imidazolyl, imidazochinazolinyl, imidazotiazolyl, indazolbenzopyrazolyl, indoxazenyl, inozinyl, izoaloxazinyl, izotiazolyl, izoxazolidinyl, izoxazolinonyl, izoxazolinyl, izoxazolonyl, izoxazolyl, lumazinyl.metyltyminyl, metyluracilyl, morfolinyi, naftimidazolyl, oroticyl, oxatianyl, oxatiolanyl, oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl, oxazolyl, perhydrocinolinyl, perhydropyroloazinyl, perhydropyrolotiazinyl, perhydrotiazinonyl, perimidinyl, fenazinyl, fenotiazinyl, fenoxatiinyl, fenoxazinyl, fenoxazonyl, ftalazinyl, piperazíndionyl, piperazinodionyl, polychinoxalinyl, pteridinyl, pterinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidíntionyl,-6pyrrolidinyl, pyrrolizidinyl, pyrrolizinyl, pyrrolodioazinyl, pyrrolonyl, pyrrolopyrimidinyl, pyrroloquinolonyl, pyrrolyl, quinacridonyl, quinolizinyl, quinolizinyl, quinolonyl, tetrahydrofluorinyl, rhodaminyl, spirocoumarinylsulfonyl, succinimidyl, succinimidyl, succinimidyl, succinimidyl, succinimidyl, succinimidyl, succinimidyl, succinolyl , tetrahydrothiopyranonyl, tetrahydrothiopyranyl, tetronyl, thiaphenyl, thiachromanyl, thiadecalinyl, thianaphenyl, thiapyranyl, thiapyronyl, thiazolopyridinyl, thienopyridinyl, thienopyrolyl, thienothiophenyl, thiopinyl, thiochromenyl, thiocyanol, triazanolinyl, thiopyranolinyl, thiopyranolinyl, thiopyranolinyl, thiopyranolinyl, thiopyranol, , aloxanyl, aloxazinyl, anthranilyl, azabenzantrenyl, azabenzonaphthenyl, azanaftacenyl, azafenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolthionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzisoxazolyl, linyl, benzodiazocinyl, benzodioxolanyl; benzodioxolyl, benzopyridazinyl, benzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinolinyl, depsidinyl, diazafenantrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydro-benzothiazinyl, dihydro-benzothiazinyl, dihydro-benzothiazinyl, dihydro-benzothiazinyl, dihydro-benzothiazinyl, dihydro-benzothiazinyl dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, dithiolanyl, ditiolenyl, dithiolyl, flavinyl, furopyrimidinyl, glykokyamidinyl, guaninyl, hexahydropyrazinoizochinolinyl, hexahydropyridazinyl, hydantoinyl.hydroimidazolyl, hydroparazinyl, tetrahydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, imidazolinyl, imidazolyl, imidazochinazolinyl, imidazothiazolyl, indazolbenzopyrazolyl, indoxazenyl, inozinyl, isoaloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl, lumazinylmethylthyminyl, methyluracilyl, morpholinyl, naphthimidazolyl, oroticyl, oxatianyl, oxatiolanyl, oxazinonyl, oxazo lidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl, oxazolyl, perhydrocinolinyl, perhydropyrroloazinyl, perhydropyrolothiazinyl, perhydrothiazinonyl, perimidinyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl, phenoxazinyl pyrazinyl, pyrazolidinyl, pyrazolidonyl, pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinothionyl,
pyrimidinyl, pyrimidonyl, pyrimidoazepiny, pyrimidopteridinyl, pyrolobenzodiazepinyl, pyrolodiazinyl, pyrolopyrimidinyl, chinazolidnyl, chinazolinonyl, chinazolinyl, chinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydrochinoxalinyl, tetrahydrotiazolyl, tiazepinyl, tiazinyl, tiazolidinonyl, tiazolidinyl, tiazolinonyl, tiazolinyl, tiazolobenzimidazolyl, tiazolyl, tienopyrimidinyl, tiazolidinonyl, tyminyl, triazolopyrimidinyl, uracilyl, xantinyl.xylitolyl, azabenzonaftenyl, benzofuroxantyl, benzotiadiazinyl, benzotriazepinonyl, benzot ri azoly I, benzoxadiazinyl, dioxadiazinyl, ditiadazolyl, ditiazolyl, furazanyl, furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl, oxadiazolyl, oxatiazinonyl, oxatriazolyl, pentazinyl, pentazolyl, pentazinyl, polyoxadiazolyl, sydonyl, tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, tiadiazinyl, tiadiazolinyl, tiadiazolyl, tiadioxazinyl, tiatriazinyl, tiatriazolyl, tiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolíndionyl, triazolinyl, triazolyl, trioxanyl, trifenodioxazinyl, trifenoditiazinyl, tritiadiazepinyl, tritianyl alebo trioxolanyl.pyrimidinyl, pyrimidonyl, pyrimidoazepines, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl, quinazolidnyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydropyridazinyl, tetrahydropyridazinyl, tetrahydropyridazinyl, tetrahydropyridazinyl, tetrahydropyridazinyl, tetrahydropyridazinyl, tetrahydropyridazinyl thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl, thiazolidinonyl, thyminyl, triazolopyrimidinyl, uracilyl, xantinyl.xylitolyl, azabenzonaphthenyl, benzofuroxanthyl, benzothiadiazinyl, benzotriazepinonyl, benzothiazole, furadiazinyl, dioxadiazolyl, dioxox, thiazolyl, dioxadiazol, , oxathiazinonyl, oxatriazolyl, pentazinyl, pentazolyl, pentazinyl, polyoxadiazolyl, sydonyl, tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, thiadiazinyl, thiadiazolinyl, thiadiazolyl, thiadioxazinyl, thiatriazinyl, thiatriazolyl, triazazolyl pinyl, triazinoindolyl, triazinyl, triazolinedione, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, trithiadiazepinyl, tritianyl or trioxolanyl.
Zlúčeniny tohto typu sú už známe z nemeckého patentu 196 01 303.8.Compounds of this type are already known from German patent 196 01 303.8.
Takéto zlúčeniny možno použiť kvôli ich účinku ako inhibítory bunkovej výmeny Na+/H+ ako účinné látky v liečivách alebo môžu nájsť uplatnenie ako medziprodukty na prípravu takých účinných látok. Zlúčeniny podľa vynálezu pôsobia proti arytmiám, ktoré sa vyskytujú napríklad pri hypoxiách. Sú ďalej použiteľné pri ochoreniach, ktoré súvisia s ischémiami (príklady: srdcová, mozgová, gastrointestinálna - ako napríklad mezenteriálna trombóza/embólia - pľúcna, obličková ischémia, ischémia pečene, ischémia kostrového svalstva). Zodpovedajúce ochorenia sú napríklad koronárna choroba srdca, srdcový infarkt, angína pektoris, stabilná angína pektoris, ventrikulárne arytmie, subventrikulárne arytmie, srdcová nedostatočnosť, ďalej na podporu bypasových operácií, na podporu operácií na otvorenom srdci, na podporu operácií, pri ktorých je potrebné prerušenie zásobovania srdca krvou a na podporu transplantácií srdca - embólie v pľúcnom obehu, akútne alebo chronické zlyhanie obličiek, chronická nedostatočnosť obličiek, mozgová porážka, reperfúzne škody pri opätovnom prekrvovaní oblastí mozgu po spriechodnení upchatých ciev a akútne a chronické poruchy prekrvenia mozgu. V tomto prípade sú uvedené zlúčeniny užitočné aj v kombinácii s trombolytickými prostriedkami ako je napríklad t-PA, streptokináza a urokináza.Such compounds can be used as active ingredients in medicaments because of their effect as Na + / H + cell exchange inhibitors or can find use as intermediates for the preparation of such active ingredients. The compounds according to the invention act against arrhythmias which occur, for example, in hypoxia. They are further useful in diseases associated with ischemia (examples: cardiac, cerebral, gastrointestinal - such as mesenterial thrombosis / embolism - pulmonary, renal ischemia, liver ischemia, skeletal muscle ischemia). Corresponding diseases are, for example, coronary heart disease, heart attack, angina pectoris, stable angina pectoris, ventricular arrhythmias, subventricular arrhythmias, cardiac insufficiency, support for bypass operations, support for open heart operations, support for operations requiring disruption of supply of the heart by blood and to support heart transplantation - embolism in the pulmonary circulation, acute or chronic renal failure, chronic renal insufficiency, stroke, reperfusion injury in re-perfusion of brain areas after blockage of obstructed blood vessels and acute and chronic cerebral vascular disorders. In this case, the compounds are also useful in combination with thrombolytic agents such as t-PA, streptokinase and urokinase.
-8Pri reperfúzii ischemického srdca (napríklad po záchvate angíny pektoris alebo v prípade srdcového infarktu) sa môžu vyskytnúť ireverzibilné poškodenia na kardiomyocytoch v postihnutých oblastiach. Zlúčeniny podľa vynálezu pôsobia v takom prípade okrem iných aj kardioprotektívne.-8In the reperfusion of the ischemic heart (for example after angina pectoris or in case of a heart attack), irreversible damage to cardiomyocytes may occur in the affected areas. In this case, the compounds according to the invention also act cardioprotectively.
Do oblasti použitia ischémie je potrebné začleniť aj zabránenie škodám na transplantátoch (napríklad ako ochranu transplantátu - ako napríklad pečene, obličiek, srdca alebo pľúc - pred, počas a po implantácii, ako aj pri skladovaní transplantátov), ktoré sa môžu vyskytnúť v súvislosti s transplantáciou. Zlúčeniny sú okrem toho ochranne pôsobiace liečivá pri výkonoch angioplastických operačných zákrokov na srdci a na periférnych cievach.Preventing transplant damage (such as protecting the transplant - such as the liver, kidneys, heart or lungs - before, during and after implantation, as well as storing transplants) that may occur in transplantation should also be included in the field of ischemia use . In addition, the compounds are protective drugs for the treatment of angioplastic surgeries on the heart and peripheral vessels.
Pri esenciálnej hypertónii a diabetickej nefropatii je bunková výmena sodíkových protónov zvýšená. Zlúčeniny podľa vynálezu sú preto vhodné ako inhibítory tejto výmeny na preventívnu liečbu týchto ochorení.In essential hypertonia and diabetic nephropathy, the cellular exchange of sodium protons is increased. The compounds of the invention are therefore useful as inhibitors of this exchange for the preventive treatment of these diseases.
Zlúčeniny podľa vynálezu sa ďalej vyznačujú silno inhibičným účinkom na proliferáciu buniek. Preto sú tieto zlúčeniny ako liečivá zaujímavé u tých ochorení, u ktorých proliferácia buniek hrá primárnu alebo sekundárnu úlohu a môžu sa použiť ako prostriedky na liečbu nádorových ochorení, benígnych nádorov, alebo napríklad hypertrofie prostaty, aterosklerózy, orgánových hypertrofií a hyperplázií, fibrotických ochorení a diabetických neskorých komplikácií.The compounds of the invention are further characterized by a potent cell proliferation inhibitory effect. Therefore, these compounds are of interest as drugs in those diseases in which cell proliferation plays a primary or secondary role and can be used as agents for the treatment of cancer, benign tumors, or, for example, prostate hypertrophy, atherosclerosis, organ hypertrophy and hyperplasia, fibrotic diseases and diabetic late complications.
Ďalej je o zlúčeninách tohto typu známe, že môžu mať priaznivý vplyv na krvnú hladinu sérových lipoproteínov.Furthermore, compounds of this type are known to have a beneficial effect on the blood level of serum lipoproteins.
Prekvapivo sa zistilo, že zlúčeniny vzorca I, na rozdiel od derivátov benzoylguanidínu známych už predtým z problematiky, majú prednosť, že okrem nečakane vyššej účinnosti majú aj tú výhodu, že sú dostupné aj ústnym podaním.Surprisingly, it has been found that the compounds of the formula I, in contrast to the benzoylguanidine derivatives previously known in the art, have the advantage that, in addition to the unexpectedly higher efficacy, they also have the advantage of being available by oral administration.
Účinné látky podľa všeobecného vzorca I možno použiť ako vodný injekčný roztok (napríklad na vnútrožilové, vnútrosvalové alebo podkožné podanie), ako tabletu, ako čapík, ako masť, ako náplasť na transdermálnu aplikáciu, ako aerosól na inhalačné použitie pľúcnou cestou, alebo ako nosový spray.The active compounds of the formula I can be used as an aqueous injectable solution (e.g. for intravenous, intramuscular or subcutaneous administration), as a tablet, as a suppository, as an ointment, as a patch for transdermal application, as an aerosol for inhalation by pulmonary route or as nasal spray. .
V ďalšom sa uvádza niekoľko príkladov farmaceutických preparátov s udanou účinnou látkou:The following are some examples of pharmaceutical formulations with the indicated active ingredient:
Tabletytablets
Účinná látka všeobecného vzorca I 20,0 mgActive ingredient of the formula I 20.0 mg
Stearan horečnatý 1,0 mgMagnesium stearate 1.0 mg
Kukuričný škrob 62,0 mgCorn starch 62.0 mg
Laktóza 83,0 mgLactose 83.0 mg
Polyvinylpyrolidón 1,6 mgPolyvinylpyrrolidone 1.6 mg
Roztok pre injekcieSolution for injection
Účinná látka všeobecného vzorca I 0,3 gActive ingredient of the formula I 0.3 g
Chlorid sodný 0,9 gSodium chloride 0.9 g
Voda pre injekcie do 100 mlWater for injections up to 100 ml
Roztok možno sterilizovať štandardnými spôsobmi.The solution can be sterilized by standard methods.
Vodný roztok na nosové alebo inhalačné použitieAqueous solution for nasal or inhalation use
Účinná látka všeobecného vzorca I 0,3 gActive ingredient of the formula I 0.3 g
Chlorid sodný 0,9 gSodium chloride 0.9 g
Benzalkóniumchlorid 0,01 mgBenzalkonium chloride 0.01 mg
Deionizovaná voda do 100 mlDeionized water to 100 ml
Uvedený roztok je vhodný na nosovú aplikáciu v sprayi alebo v kombinácii so zariadením, ktoré produkuje aerosól s veľkosťou častíc výhodne medzi 2 až 6 μηπ, na použitie cez pľúca.Said solution is suitable for nasal application in a spray or in combination with a device that produces an aerosol with a particle size preferably between 2 to 6 μηπ, for use via the lung.
Kapsuly na inhaláciuCapsules for inhalation
Zlúčeniny všeobecného vzorca I sa naplnia do kapsúl z tvrdej želatíny v mikronizovanej forme (veľkosť častíc v podstate medzi 2 a 6 μιτι), voliteľne s pridaním mikronizovaných nosičov ako je napríklad laktóza. Na inhaláciu slúžia obvyklé zariadenia pre práškovú inhaláciu. Každá kapsula sa naplní napríklad s 0,2 až 20 mg účinnej látky všeobecného vzorca I a 0 až 40 mg laktózy.The compounds of formula I are filled into hard gelatin capsules in micronized form (particle size substantially between 2 and 6 μιτι), optionally with the addition of micronized carriers such as lactose. Conventional powder inhalation devices are used for inhalation. Each capsule is filled with, for example, 0.2 to 20 mg of active compound of the formula I and 0 to 40 mg of lactose.
···· · ·· ···· ·· • ·· · ·· · • · · · ··· · ····· ··················
-10·· ··· ·· ··· ··-10 ·· ··· ·· ··· ··
Aerosól na inhaláciuAerosol for inhalation
Účinná látka všeobecného vzorca I 1 dielActive ingredient of the formula I 1 part
Sójový lecitín 0,2 dielySoya lecithin 0.2 parts
Zmes hnacích plynov do 100 dielovPropellant mixture up to 100 parts
Zmes sa plní výhodne do aerosólových kontajnerov pomocou dávkovacieho ventilu. Dávkovač sa nastaví tak, aby dávka obsahovala 0,5 mg. Pre ostatné dávky uvedeného rozsahu sa výhodne použijú zmesi s vyšším alebo nižším podielom účinnej látky.The mixture is preferably filled into aerosol containers by means of a metering valve. The dispenser is adjusted so that the dose contains 0.5 mg. For other doses of the above range, mixtures with a higher or lower proportion of the active ingredient are preferably used.
Masť (zloženie v g/100 g masti)Ointment (composition in g / 100 g ointment)
Účinná látka všeobecného vzorca I 2 gActive ingredient of the formula I 2 g
Koncentrovaná kyselina chlorovodíková 0,011 gConcentrated hydrochloric acid 0.011 g
Nátriumpyrosulfit 0,05 gSodium pyrosulfite 0.05 g
Zmes z rovnakých dielov cetylalkoholu a stearylalkoholu 20 gMixture of equal parts of cetyl alcohol and stearyl alcohol 20 g
Biela vazelína 5 gWhite petrolatum 5 g
Umelý bergamotový olej 0,075 gArtificial bergamot oil 0.075 g
Destilovaná voda do 100Distilled water up to 100
Z jednotlivých zložiek sa obvyklým spôsobom pripraví masť.An ointment is prepared from the individual components in the usual manner.
Spôsoby prípravy zlúčenín podľa vynálezu sú v problematike všeobecne známe a zlúčeniny podľa vynálezu možno preto získať napríklad reakciou esterov kyseliny 4-(1-piperazinyl)-3-trifluórmetyl-benzoovej všeobecného vzorca IIMethods for preparing the compounds of the invention are generally known in the art, and the compounds of the invention can therefore be obtained, for example, by reacting the 4- (1-piperazinyl) -3-trifluoromethyl-benzoic esters of formula II
so zlúčeninou všeobecného vzorca III,with a compound of formula III,
R1C(O)Q (III) v ktorom Q znamená odstupujúcu skupinu substituovateľnú dusíkom piperazínu, voliteľne v prítomnosti pomocných látok, výhodne karbonyldiimidazolu, sa získa výsledný derivát kyseliny benzoovej všeobecného vzorca IVR 1 C (O) Q (III) in which Q represents a nitrogen-substituted leaving group substituted with piperazine, optionally in the presence of excipients, preferably carbonyldiimidazole, yields the resulting benzoic acid derivative of formula IV
ktorý sa suspenduje vo vhodnom, výhodne bezvodom rozpúšťadle, výhodne dimetylformamide a nechá sa zreagovať so zmesou roztoku alebo suspenzie zásady, výhodne hydridu sodného vo vhodnom bezvodom rozpúšťadle, výhodne dimetylformamide, so soľou guanidínu, výhodne s hydrochloridom guanidínu a reakčný produkt sa vyizoluje.which is suspended in a suitable, preferably anhydrous solvent, preferably dimethylformamide, and reacted with a mixture of a solution or suspension of a base, preferably sodium hydride, in a suitable anhydrous solvent, preferably dimethylformamide, with a guanidine salt, preferably guanidine hydrochloride.
Súčasný vynález sa vysvetľuje nasledujúcimi príkladmi.The present invention is illustrated by the following examples.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Metylester kyseliny 4-fluór-3-trifluórmetyl-benzoovej4-Fluoro-3-trifluoromethyl-benzoic acid methyl ester
35,4 g (170 mmol) kyseliny 4-fluór-3-(trifluórmetyl)-benzoovej v 250 ml metanolu sa za chladenia ľadom pri -5 °C nechá zreagovať počas 25 minút so 68 ml SOCI2. Po úplnom pridaní sa reakčná zmes ohrieva do spätného toku ešte 3 hodiny. Reakčný roztok sa ochladí na izbovú teplotu a vo vákuu sa odparí. Olejovitý zvyšok sa rozmieša s 200 ml dietyléteru a vyextrahuje sa s vodou, nasýteným roztokom NaHCO3 a opäť s vodou. Zlúčené organické fázy sa vysušia nad síranom horečnatým a odparia sa vo vákuu.35.4 g (170 mmol) of 4-fluoro-3- (trifluoromethyl) -benzoic acid in 250 ml of methanol are treated with 68 ml of SOCl2 for 25 minutes under ice-cooling at -5 ° C. After complete addition, the reaction mixture was refluxed for 3 hours. The reaction solution was cooled to room temperature and evaporated in vacuo. The oily residue is stirred with 200 ml of diethyl ether and extracted with water, saturated NaHCO3 solution and again with water. The combined organic phases are dried over magnesium sulphate and evaporated in vacuo.
Výťažok: 29,0 g (77 %) ·*·· · ·· ··· · ··· ··· · · · • · · · ··· · · ··· · · · · · ·· ·«· ·· ··· ·· ·Yield: 29.0 g (77%) * 77 77 77 77 77 77 77 77 77 77 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 29 «· ·· ··· ·· ·
-12Metylester kyseliny 4-(4-benzyl-1 -piperazinyl)-3-trifluórmetyl-benzoovej g (31,5 mmol) metylesteru kyseliny 4-fluór-3-trifluórmetyl-benzoovej sa rozpustí v 60 ml suchého dimetylsulfoxidu (DMSO) a nechá sa zreagovať s 5,55 g (31,5 mmol) ZV-benzylpiperazínu a 4,35 g (31,5 mmol) uhličitanu vápenatého. Zmes sa mieša 12 hodín pri 90 °C. Po vychladení sa reakčná zmes vyleje do 200 ml vody a trikrát sa vyextrahuje s etylesterom kyseliny octovej. Zlúčené organické fázy sa premyjú vodou a nasýteným roztokom chloridu sodného, vysušia sa nad síranom horečnatým a oddestilujú sa vo vákuu. Zvyšok sa chromatografuje zmesou heptánu esteru (esterov) kyseliny octovej na silikagéli.4- (4-Benzyl-1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester g (31.5 mmol) of 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester was dissolved in 60 mL of dry dimethylsulfoxide (DMSO) and allowed to stand. was reacted with 5.55 g (31.5 mmol) of N -benzylpiperazine and 4.35 g (31.5 mmol) of calcium carbonate. The mixture was stirred at 90 ° C for 12 hours. After cooling, the reaction mixture is poured into 200 ml of water and extracted three times with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and distilled off in vacuo. The residue is chromatographed with a mixture of acetic acid heptane (s) on silica gel.
Výťažok: 3,93 g (33 %)Yield: 3.93 g (33%)
Metylester kyseliny 4-(1-piperazinyl)-3-trifluórmetyl-benzoovej4- (1-Piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester
20,2 g (53,3 mmol) metylesteru kyseliny 4-(4-benzyl-1-piperazinyl)-3-trifluórmetyl-benzoovej sa rozpustí v 200 ml metanolu a nechá sa zreagovať s paládiom nad aktívnym uhlím počas 1,4 hodiny pri 70 °C a hydrogenuje sa za tlaku vodíka 5 barov. Roztok sa odsaje cez celit a oddestiluje sa vo vákuu.20.2 g (53.3 mmol) of methyl 4- (4-benzyl-1-piperazinyl) -3-trifluoromethyl-benzoate were dissolved in 200 ml of methanol and treated with palladium on charcoal for 1.4 hours at 70 ° C and hydrogenated under a hydrogen pressure of 5 bar. The solution was aspirated through celite and distilled off in vacuo.
Výťažok: 14,85 g (97 %)Yield: 14.85 g (97%)
Všeobecný návod na kopuláciu metylesteru kyseliny 4-(1-piperazinyl)-3-trifluórmetyl-benzoovej s kyselinou benzoovou mmol zodpovedajúcej karbónovej kyseliny sa rozpustí v 30 ml absolútneho tetrahydrofuránu (THF) a nechá sa zreagovať pod ochranným plynom pri 0 °C s 810 mg (5 mmol) karbonyldiimidazolu a mieša sa 2 hodiny pri izbovej teplote (približne 25 °C). Následne sa pridá 1,44 g metylesteru kyseliny (5 mmol) 4-(1-piperazinyl)-3trifluórmetyl-benzoovej a ďalej sa mieša približne počas 12 hodín. Roztok sa vo vákuu odparí dosucha a rozmieša sa esterom kyseliny octovej. Po premytí nasýteným roztokom NaHCO3, nasýteným roztokom NaCl a vodou sa organické fázy vysušia nad MgSO4 a odparia sa vo vákuu. Po vykryštalizovaní vo vhodnomGeneral instructions for coupling 4- (1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester with benzoic acid mmol of the corresponding carbonic acid are dissolved in 30 ml of absolute tetrahydrofuran (THF) and reacted under shielding gas at 0 ° C with 810 mg (5 mmol) carbonyldiimidazole and stirred for 2 hours at room temperature (about 25 ° C). Subsequently, 1.44 g of methyl 4- (1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester (5 mmol) is added and stirring is continued for approximately 12 hours. The solution was evaporated to dryness in vacuo and stirred with acetic acid ester. After washing with saturated NaHCO3, saturated NaCl and water, the organics dried over MgSO4 and evaporated in vacuo. After crystallization in an appropriate
rozpúšťadle alebo po chromatografovaní na silikagéli vo vhodnom eluente sa získajú nasledujúce zlúčeniny:solvent or after chromatography on silica gel in a suitable eluent, the following compounds are obtained:
1. Metylester kyseliny 4-(4-(3-metoxyfenylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoovej1. 4- (4- (3-Methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)Column chromatography: acetic acid ester (s) / heptane (2: 1)
Výťažok: 81 %Yield: 81%
2. Metylester kyseliny 4-(4-(2-pyrolylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoovej2. 4- (4- (2-Pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Vykryštalizovanie z metanoluCrystallization from methanol
Výťažok: 75 %Yield: 75%
Teplota topenia: 149 °CM.p .: 149 ° C
3. Metylester kyseliny 4-(4-(4-fluórfenylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoovej3. 4- (4- (4-Fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)Column chromatography: acetic acid ester (s) / heptane (2: 1)
Výťažok: 77 %Yield: 77%
4. Metylester kyseliny 4-(4-(2-metoxyfenylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoovej4. 4- (4- (2-Methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)Column chromatography: acetic acid ester (s) / heptane (2: 1)
Výťažok: 79 %Yield: 79%
5. Metylester kyseliny 4-(4-(3-trifluórmetylfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoovej5. 4- (4- (3-Trifluoromethylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)Column chromatography: acetic acid ester (s) / heptane (2: 1)
Výťažok: 83 %Yield: 83%
6. Metylester kyseliny 4-(4-fenylkarbonyl-1-piperazinyl)-3-trifluórmetyl-benzoovej Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)6. 4- (4-Phenylcarbonyl-1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester Column chromatography: Acetic acid ester (es) / heptane (2: 1)
Výťažok: 87 %Yield: 87%
-14··»· ·· ···· ·· • · · · · · • · ··· · · • · · · · · ·· ···-14 ··· ·······························
7. Metylester kyseliny 4-(4-(2-furylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoovej Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)7. 4- (4- (2-Furylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester Column chromatography: acetic acid ester (es) / heptane (2: 1)
Výťažok: 75 %Yield: 75%
8. Metylester kyseliny 4-(4-(3-metylfenylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoovej8. 4- (4- (3-Methylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)Column chromatography: acetic acid ester (s) / heptane (2: 1)
Výťažok: 79 %Yield: 79%
9. Metylester kyseliny 4-(4-(4-(1-pyryl)fenylkarbonyl-1-piperazinyl)-3-trifluórmetylbenzoovej9. 4- (4- (4- (1-Pyryl) phenylcarbonyl-1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester)
Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)Column chromatography: acetic acid ester (s) / heptane (2: 1)
Výťažok: 87 %Yield: 87%
10. Metylester kyseliny 4-(4-(2-pyridylkarbonyl)-1 -piperazinyl)-3-trifluórmetylbenzoovej10. 4- (4- (2-Pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Stĺpcová chromatografia: ester (estery) kyseliny octovej/heptán (2:1)Column chromatography: acetic acid ester (s) / heptane (2: 1)
Výťažok: 73 %Yield: 73%
Všeobecný návod na prípravu acylguanidínu zo zodpovedajúcich metylesterov karbónových kyselínGeneral guidance on the preparation of acylguanidine from the corresponding methyl esters of carbonic acids
5,09 g (127,2 mmol) 60%-ného NaH v bielom oleji sa premyje dvakrát éterom a zleje sa. Pridá sa 200 ml absolútneho DMF a za miešania a v ochrannom plyne sa v malých dávkach pridá 12,15 g (127,2 mmol) hydrochlorid guanidínu. Po miešaní 1 hodinu sa pridá 21,2 mmol zodpovedajúceho metylesteru a roztok sa mieša ďalšie 2 hodiny približne pri teplote 120 °C. Následne sa reakčná zmes nechá vychladnúť na izbovú teplotu, pŕefiltruje sa a filtrát sa vo vákuu odparí. Po chromatografii na silikagéli s vhodným elučným činidlom a po prekonvertovaní éterickou kyselinou chlorovodíkovou alebo inými farmakologicky prijateľnými kyselinami na zodpovedajúce soli sa získajú nasledujúce zlúčeniny (v nasledujúcich štruktúrnych5.09 g (127.2 mmol) of 60% NaH in white oil were washed twice with ether and decanted. 200 ml of absolute DMF is added and guanidine hydrochloride (12.15 g, 127.2 mmol) is added in small portions under stirring and shielding gas. After stirring for 1 hour, the corresponding methyl ester (21.2 mmol) was added and the solution was stirred at about 120 ° C for a further 2 hours. The reaction mixture was then allowed to cool to room temperature, filtered and the filtrate evaporated in vacuo. Chromatography on silica gel with a suitable eluent and conversion with ethereal hydrochloric acid or other pharmacologically acceptable acids to the corresponding salts yields the following compounds (in the following
-15vzorcoch sa kvôli prehľadnosti atómy vodíka vynechali, pokiaľ boli naviazané na atóm uhlíka alebo dusíka a pokiaľ nie sú potrebné pre pochopenie vynálezu):(15) for the sake of clarity of the hydrogen atom, they have been omitted if attached to a carbon or nitrogen atom and unless necessary for an understanding of the invention):
Príklad 1Example 1
Hydrochlorid 4-(4-(3-metoxyfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoylguanidínu ···· · ·· ···· ·· ··· ··· ··· • · · · ··· · · • · · · · ···· ··· · · ··· ·· ··· ·· ··· ·· ·4- (4- (3-Methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine hydrochloride ················· · · · · · · · · · · · · · · · · · · ·
x HCl z metylesteru kyseliny 4-(4-(3-metoxyfenylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoovejx HCl from 4- (4- (3-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Stĺpcová chromatografia: ester kyseliny octovej/metanol (5:1)Column chromatography: acetic acid / methanol (5: 1)
Výťažok: 71 %Yield: 71%
MS: (M+H)+ = 450 (voľná zásada)MS: (M + H) < + > = 450 (free base)
Príklad 2Example 2
4-(4-(2-Pyrolylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoylguanidín-metánsulfonát4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine methanesulfonate
X CH3SO3H z metylesteru kyseliny 4-(4-(2-pyrolylkarbonyl)-1-piperazinyl-3-trifluórmetyl-benzoovejX CH3SO3H from 4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl-3-trifluoromethyl-benzoic acid methyl ester)
Stĺpcová chromatografia: ester kyseliny octovej/metanol (5:1)Column chromatography: acetic acid / methanol (5: 1)
Výťažok: 66 %Yield: 66%
Teplota topenia: 246 °CMelting point: 246 ° C
MS: (M+H)+ = 409 (voľná zásada)MS: (M + H) < + > = 409 (free base)
-16Príklad 3-16Example 3
4-(4-(4-Fluórfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoylguanidín-metánsulfonát4- (4- (4-Fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine methanesulfonate
X CH3SO3H z metylesteru kyseliny 4-(4-(4-fluórfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoovejX CH3SO3H from 4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Stĺpcová chromatografia: ester kyseliny octovej/metanol (5:1)Column chromatography: acetic acid / methanol (5: 1)
Výťažok: 40 %Yield: 40%
Teplota topenia: 140 °CMelting point: 140 ° C
MS: (M+H)+ = 438 (voľná zásada)MS: (M + H) < + > = 438 (free base)
Príklad 4Example 4
Hydrochlorid 4-(4-(2-metoxyfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoylguanidínu4- (4- (2-Methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine hydrochloride
z metylesteru kyseliny 4-(4-(2-metoxyfenylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoovejfrom methyl 4- (4- (2-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoate
Stĺpcová chromatografia: ester kyseliny octovej/metanol (5:1)Column chromatography: acetic acid / methanol (5: 1)
Výťažok: 71 %Yield: 71%
Teplota topenia: 219 °C (rozklad)Melting point: 219 ° C (decomposition)
MS: (M+H)+ = 450 (voľná zásada)MS: (M + H) < + > = 450 (free base)
-17Príklad 5-17Example 5
Hydrochlorid 4-(4-(3-trifluórmetylfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoyl-guanidínu4- (4- (3-Trifluoromethylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoyl-guanidine hydrochloride
x HCI z metylesteru kyseliny 4-(4-(3-trifluórmetylfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoovejx HCl from 4- (4- (3-trifluoromethylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester
Stĺpcová chromatografia: ester kyseliny octovej/metanol (5:1)Column chromatography: acetic acid / methanol (5: 1)
Výťažok: 25 %Yield: 25%
Teplota topenia: 140 °C (rozklad)Melting point: 140 ° C (decomposition)
MS: (M+H)+ = 488 (voľná zásada)MS: (M + H) < + > = 488 (free base)
Príklad 6Example 6
Hydrochlorid 4-(4-fenylkarbonyl-1-piperazinyl)-3-trifluórmetyl-benzoylguanidínu4- (4-Phenylcarbonyl-1-piperazinyl) -3-trifluoromethyl-benzoylguanidine hydrochloride
z metylesteru kyseliny 4-(4-fenylkarbonyl-1-piperazinyl)-3-trifluórmetyl-benzoovej Stĺpcová chromatografia: ester kyseliny octovej/metanol (5:1)from methyl 4- (4-phenylcarbonyl-1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester Column chromatography: acetic acid / methanol (5: 1)
Výťažok: 64 %Yield: 64%
Teplota topenia: 214 °C214 ° C
MS: (M+H)+ = 420 (voľná zásada)MS: (M + H) < + > = 420 (free base)
-18Príklad 7-18Example 7
Metánsulfonát 4-(4-(2-furylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoylguanidínu4- (4- (2-Furylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine methanesulfonate
X CH3SO3H z metylesteru kyseliny 4-(4-(2-furylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoovej Vykryštalizovanie z éteru Výťažok: 19 %X CH3SO3H from 4- (4- (2-furylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester Crystallization from ether Yield: 19%
Teplota topenia: 190 °C (rozklad)Melting point: 190 ° C (decomposition)
MS: (M+H)+ = 410 (voľná zásada)MS: (M + H) < + > = 410 (free base)
Príklad 8Example 8
Metánsulfonát 4-(4-(3-metylfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoylguanidínu4- (4- (3-Methylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine methanesulfonate
x CH3SO3H z metylesteru kyseliny 4-(4-(3-metylfenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoovejCH3SO3H from 4- (4- (3-methylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester
Vykryštalizovanie z metanolu/esteru kyseliny octovejCrystallization from methanol / acetic acid ester
Výťažok: 76 %Yield: 76%
Teplota topenia: 199 °CMelting point: 199 ° C
MS: (M+H)+ = 434 (voľná zásada)MS: (M + H) < + > = 434 (free base)
Príklad 9Example 9
Dimetánsulfonát zoylguanidínuZoylguanidine dimethanesulfonate
4-(4-(4-( 1-pyrolyl)fenylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-ben-4- (4- (4- (1-pyrrolyl) phenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzene
x 2 CH3SO3H z metylesteru kyseliny 4-(4-(4-(1-pyryl)fenylkarbonyl)-1-piperazinyl)-3-trifluórmetylbenzoovejx 2 CH3SO3H from 4- (4- (4- (4- (1-pyryl) phenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester)
Vykryštalizovanie z metanoluCrystallization from methanol
Výťažok: 48 %Yield: 48%
Teplota topenia: 150 °C (rozklad)Melting point: 150 ° C (decomposition)
MS: (M+H)+ = 485 (voľná zásada)MS: (M + H) < + > = 485 (free base)
Príklad 10Example 10
Dimetánsulfonát 4-(4-(2-pyridylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoylguanidínu4- (4- (2-Pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine dimethanesulfonate
x 2 CH3SO3H z metylesteru kyseliny 4-(4-(2-pyridylkarbonyl)-1-piperazinyl)-3-trifluórmetyl-benzoovejx 2 CH3SO3H from 4- (4- (2-pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester
Stĺpcová chromatografia: ester kyseliny octovej/metanol (5:1)Column chromatography: acetic acid / methanol (5: 1)
Výťažok: 34 %Yield: 34%
Teplota topenia: 115 °C (rozklad)Melting point: 115 ° C (decomposition)
MS: (M+H)+ = 421 (voľná zásada) ·· ···· • · • ···MS: (M + H) + = 421 (free base) ·· ···· · · · ···
-20···· ·· ·· ···-20 ········································
Farmakoiogické údajePharmaco-biological data
Inhibícia výmeny Na+/H+ v bunkách ľudského črevného karcinómu (HT-29):Inhibition of Na + / H + Exchange in Human Intestinal Carcinoma Cells (HT-29):
Bunky HT-29 sa kultivovali pri 37 °C a 5 % CO2 v rastovom médiu. Po 3 až 5 dňoch sa rastové médium odstránilo, bunky sa premyli a označili sa so 7,5 μΜ BCECF-AM (pH-senzitívne fluorescenčné farbivo) pri 37 °C bez CO2. Po 30 minútach sa bunky premyli a okyslili sa nasledujúcim médiom: 70 mM cholínchloridu, 20 mM NH4CI, 1 mM MgCI2, 1,8 mM CaCI2, 5 mM glukózy a 15 mM HEPES, pH 7,5.HT-29 cells were cultured at 37 ° C and 5% CO 2 in growth medium. After 3-5 days the growth medium was removed, the cells were washed and labeled with 7.5 μΜ BCECF-AM (pH-sensitive fluorescent dye) at 37 ° C without CO2. After 30 minutes, the cells were washed and acidified with the following media: 70 mM choline chloride, 20 mM NH 4 Cl, 1 mM MgCl 2 , 1.8 mM CaCl 2 , 5 mM glucose and 15 mM HEPES, pH 7.5.
Po 6 minútach pri 37 °C bez CO2 sa bunky premyli a inkubovali sa 5 minút v premývacom médiu: 120 mM cholínchloridu, 5 mM KCI, 1 mM MgCb, 1,8 mM CaCb, 5 mM glukózy a 15 mM MOPS, pH 7,0.After 6 minutes at 37 ° C without CO 2, the cells were washed and incubated for 5 minutes in wash medium: 120 mM choline chloride, 5 mM KCl, 1 mM MgCl 2, 1.8 mM CaCl 2, 5 mM glucose and 15 mM MOPS, pH 7, 0th
Premývacie médium sa odstránilo a pridalo sa kontrolné médium s testovacou zlúčeninou alebo bez nej: 120 mM NaCl, 5 mM KCI, 1 mM MgCI2, 1,8 mM CaCb 5 mM glukózy, 15 mM MOPS, pH 7,0.Wash medium was removed and control medium with or without test compound was added: 120 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 1.8 mM CaCl 2 5 mM glucose, 15 mM MOPS, pH 7.0.
Bunky sa inkubovali 4 minúty pri 37 °C bez CO2 a merali sa fluorometricky (CytoFluor 2350). Fluorescencia farbiva BCECF sa merala pri excitačnej vlnovej dĺžke 485 nm (pH-senzitívne) a 440 nm (nie pH-senzitívne) a pri emisnej vlnovej dĺžke 530 nm. Cytoplazmatické pH sa vypočíta z pomeru fluorescencií pri 485 a 440 nm. Pomer fluorescencie sa kalibruje nigericínom odmeraním fluorescenčného signálu po vyrovnaní vonkajšieho a vnútorného pH.Cells were incubated for 4 minutes at 37 ° C without CO 2 and measured by fluorometry (CytoFluor 2350). The BCECF dye fluorescence was measured at an excitation wavelength of 485 nm (pH-sensitive) and 440 nm (not pH-sensitive) and at an emission wavelength of 530 nm. The cytoplasmic pH is calculated from the fluorescence ratio at 485 and 440 nm. The fluorescence ratio is calibrated by nigericin by measuring the fluorescence signal after balancing the external and internal pH.
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-21 Zlúčeniny podľa vynálezu okrem toho prekvapivo vykazujú veľmi dobrú biologickú dostupnosť a dlhé polčasy po ústnom podaní. Sú to vlastnosti, ktoré sa výborne hodia na ústnu aplikáciu.In addition, the compounds of the invention surprisingly show very good bioavailability and long half-lives after oral administration. These properties are excellent for oral administration.
Farmakologicko-kinetické údajePharmacological-kinetic data
Na výskum sa použili samčie potkany vážiace približne 200 g (nie nalačno). Na vnútrožilovú aplikáciu sa látky rozpustili v okyslenom vodnom roztoku (pH 3). Jednotlivé dávkové injekcie (0,5 mg/kg vnútrožilovo, 2,5 mg/kg ústne) sa injikovali do chvostovej žily (0,2 ml/200 g) alebo sa kanylou podali do žalúdka (1 ml/200 g).Male rats weighing approximately 200 g (not fasted) were used for the research. For intravenous administration, the substances were dissolved in an acidified aqueous solution (pH 3). Single dose injections (0.5 mg / kg intravenously, 2.5 mg / kg orally) were injected into the tail vein (0.2 ml / 200 g) or cannulated into the stomach (1 ml / 200 g).
Na stanovenie aplikovanej dávky sa analyzovali aplikačné roztoky. Z retroorbitálneho cievneho plexa sa za krátkej anestézie halothánom a pomocou heparinizovaných sklených kapilár odobrali alikvotné časti 0,5 ml krvi podľa nasledujúcej schémy:Application solutions were analyzed to determine the application rate. Aliquots of 0.5 ml of blood were removed from the retroorbital vascular plexus under brief anesthesia with halothane and heparinized glass capillaries according to the following scheme:
- po vnútrožilovej aplikácii: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h;after intravenous administration: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h;
- po ústnej aplikácii: 15 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 32 h.- after oral administration: 15 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 32 h.
Vzorky sa centrifugovali a plazma sa skladovala pri -20 °C až do analýzy. Príprava vzoriek sa uskutočňuje tekuto-tekutou extrakciou pomocou jedného interného štandardu. Extrakty plazmy sa analyzovali pomocou HPLC s reverznou fázou, ktorá bola spojená s elektrosprayovým tandemovým hmotnostným spektrometrom.Samples were centrifuged and plasma was stored at -20 ° C until analysis. Sample preparation is performed by liquid-liquid extraction using one internal standard. Plasma extracts were analyzed by reverse phase HPLC, which was coupled to an electrospray tandem mass spectrometer.
Farmakokinetické údaje sa stanovili zo zodpovedajúcich plazmatických koncentrácií bezkompartmentovou analýzou s použitím programu TopFit (Heinzel, G., Woloszczak, R., Thomann, P. TopFit 2.0 - Pharmacokinetic and pharmacodynamic data analysis, systém for the PC, Gustáv Fischer Veria g, Stuttgart, Jena, New York, 1993).Pharmacokinetic data were determined from the corresponding plasma concentrations by non-compartmental analysis using the TopFit program (Heinzel, G., Woloszczak, R., Thomann, P. TopFit 2.0 - Pharmacokinetic and pharmacodynamic data analysis, PC system, Gustav Fischer Veriag, Stuttgart, Jena, New York, 1993).
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-22Na nemeckú patentovú prihlášku č. 198 43 489, ktorej prioritu súčasná patentová prihláška vyžaduje, sa týmto v plnom rozsahu odvoláva.German patent application no. 198 43 489, the priority of which the present patent application requires, is hereby fully repealed.
Claims (9)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843489A DE19843489B4 (en) | 1998-09-22 | 1998-09-22 | Benzoylguanidine derivatives having advantageous properties, processes for their preparation and their use in the preparation of medicaments, and pharmaceutical compositions containing them |
| PCT/EP1999/006857 WO2000017176A2 (en) | 1998-09-22 | 1999-09-16 | Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments |
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| CZ (1) | CZ300158B6 (en) |
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| DE10106970A1 (en) * | 2001-02-15 | 2002-08-29 | Boehringer Ingelheim Pharma | New benzoylguanidine salt |
| US6730678B2 (en) * | 2001-02-15 | 2004-05-04 | Boehringer Ingelheim Pharma Kg | Benzoylguanidine salt and hydrates thereof |
| DE10144030A1 (en) * | 2001-09-07 | 2003-03-27 | Boehringer Ingelheim Pharma | Composition containing 4-piperazino-benzoylguanidine derivative, useful e.g. for treating cardiac infarction, containing component to improve local tolerance, e.g. beta-cyclodextrin derivative or polymer |
| US6982256B2 (en) | 2001-09-07 | 2006-01-03 | Boehringer Ingelheim Pharma Kg | Tolerance of 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine in intravenous administration |
| FR2871157A1 (en) * | 2004-06-04 | 2005-12-09 | Aventis Pharma Sa | BIARYL AROMATIC PRODUCTS, COMPOSITIONS CONTAINING SAME AND USE THEREOF |
| JP2011527677A (en) * | 2008-07-08 | 2011-11-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Pyrrolidinyl and piperidinyl compounds useful as NHE-1 inhibitors |
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| MM4A | Patent lapsed due to non-payment of maintenance fees |
Effective date: 20160916 |