SK289692A3 - Imidazolylmethyl-pyridine, method of preparation thereof, medicament and pharmaceutical composition containing this pyridine - Google Patents
Imidazolylmethyl-pyridine, method of preparation thereof, medicament and pharmaceutical composition containing this pyridine Download PDFInfo
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Abstract
Description
Imidazoylmetylpyridín, spôsob jeho prípravy, tento pyridín ako liečivo a farmaceutická kompozícia tento pyridín obsahujúcaImidazoylmethylpyridine, a process for its preparation, this pyridine as a medicament and a pharmaceutical composition of this pyridine comprising
Oblasť technikyTechnical field
Vynález sa týka imidazolylmetylpyridínov, spôsobu ich prípravy, týchto pyridínov ako liečiv a farmaceutických kompozícií, ktoré tieto pyridíny obsahujú ako účinnú látku.The invention relates to imidazolylmethylpyridines, to a process for their preparation, to these pyridines as medicaments and to pharmaceutical compositions containing them as an active ingredient.
Doterajší stav techniky európskych patentov 3560 a 337928 sú známe pyridínové deriváty, ktoré sú štruktúrne podobné ďalej navrhnutým zlúčeninám podía vynálezu. V ani jednom z uvedených dvoch patentových dokumentov však nie je zmienka o tom, že by tieto zlúčeniny mali účinok na centrálnu nervovú sústavu.BACKGROUND OF THE INVENTION European patents 3560 and 337928 are known pyridine derivatives which are structurally similar to the compounds of the invention proposed below. However, neither of these two patent documents mentions that these compounds have an effect on the central nervous system.
Teraz sa našlo nové, že zlúčeniny podľa vynálezu neočakávane vykazujú účinok voči centrálnej nervovej sústave a že sú takto použiteľné na liečenie rôznych ochorení centrálnej nervovej sústavy.It has now been found that the compounds of the invention unexpectedly exhibit activity against the central nervous system and that they are thus useful for the treatment of various diseases of the central nervous system.
Podstata vynálezuSUMMARY OF THE INVENTION
Predmetom vynálezu je imidazolylmetylpyridín všeobecného vzorca IThe present invention provides an imidazolylmethylpyridine of formula I
RR
R (I) v ktoromR (I) wherein
R1 znamená alkylovú skupinu obsahujúcu 1 až 4 atómy uhlíka,R 1 represents an alkyl group having 1 to 4 carbon atoms,
R2 a R3 nezávisle jeden na druhom znamenajú atóm vodíka alebo alkylovú skupinu obsahujúcu 1 až 4 atómy uhlíka aR 2 and R 3 independently of one another are hydrogen or alkyl having 1 to 4 carbon atoms and
R4 znamená atóm vodíka alebo alkylovú skupinu obsahujúcu 1 až 4 atómy uhlíka, vo forme voľnej zásady alebo vo forme adičnej soli s kyselinou.R 4 represents a hydrogen atom or a C 1 -C 4 alkyl group, in the form of the free base or in the form of an acid addition salt.
Výhodne je imidazolylmetylpyridínom všeobecného vzorca I [2-(2-metylimidazol-l-yl) metyl] pyridín vo forme voľnej zásady alebo vo forme adičnej soli s kyselinou.Preferably, the imidazolylmethylpyridine of formula I is [2- (2-methylimidazol-1-yl) methyl] pyridine in free base form or in acid addition salt form.
Výhodne vo všeobecnom vzorci IPreferably in Formula I
R1 znamená metylovú skupinu,R 1 represents a methyl group,
R2 znamená atóm vodíka,R 2 is H,
R3 znamená atóm vodíka,R 3 represents a hydrogen atom,
R4 znamená skupinu 6-CH3 aleboR 4 is 6-CH 3 or
R1 znamená metylovú skupinu,R 1 represents a methyl group,
R2 znamená metylovú skupinu,R 2 is methyl,
R3 znamená atóm vodíka,R 3 represents a hydrogen atom,
R4 znamená atóm vodíka aleboR 4 is H or
Rx znamená metylovú skupinu,R x represents a methyl group,
R2 znamená atóm vodíka,R 2 is H,
R3 znamená metylovú skupinu,R 3 represents a methyl group,
R4 znamená atóm vodíka a imidazolylmetylová skupina je v polohe 2 aleboR 4 represents a hydrogen atom and the imidazolylmethyl group is in the 2-position or
Rx znamená metylovú skupinu, / IR x is methyl, / I
R2 znamená etylovú skupinu,R 2 is ethyl,
R3 znamená atóm vodíka,R 3 represents a hydrogen atom,
R4 znamená atóm vodíka.R 4 is hydrogen.
Zlúčeniny podľa vynálezu sa získajú reakciou zlúčeniny všeobecného vzorca II v ktorom R4 má vyššie uvedený význam a X znamená atóm halogénu, so zlúčeninou všeobecného vzorca IIIThe compounds of the invention are obtained by reacting a compound of formula II wherein R 4 is as defined above and X is a halogen atom with a compound of formula III
v ktorom R1, R2 a R3 majú vyššie uvedený význam, a izoláciou získanej zlúčeniny všeobecného vzorca I vo forme voľnej zásady alebo vo forme adičnej soli s kyselinou.wherein R 1 , R 2 and R 3 are as defined above, and isolating the obtained compound of formula I as the free base or in the form of an acid addition salt.
Reakcia zlúčeniny všeobecného vzorca II so zlúčeninou všeobecného vzorca III sa môže uskutočniť známym spôsobom v rozpúšťadle, ktoré je v reakčných podmienkach inertné, napríklad v dimetylformamide alebo nižšom alkohole. Vo všeobecnom vzorci II X výhodne znamená atóm chlóru.The reaction of a compound of formula II with a compound of formula III can be carried out in a manner known per se in a solvent which is inert under the reaction conditions, for example dimethylformamide or a lower alcohol. In formula II, X is preferably a chlorine atom.
Spracovanie reakčnej zmesi a čistenie takto získaných zlúčenín všeobecného vzorca I sa môže tiež uskutočniť známym spôsobom.Treatment of the reaction mixture and purification of the compounds of formula I thus obtained can also be carried out in a manner known per se.
Zlúčeniny všeobecného vzorca I môžu byť prítomné vo forme voľnej zásady alebo vo forme ich adičných solí s kyselinami. Tieto adičné soli sa môžu získať z voľných zásad a naopak známym spôsobom.The compounds of the formula I can be present in the form of the free base or in the form of their acid addition salts. These addition salts can be obtained from the free bases and vice versa in a known manner.
Východiskové zlúčeniny všeobecného vzorca II a všeobecného vzorca III sú buď známymi zlúčeninami alebo sa môžu pripraviť známymi spôsobmi alebo spôsobmi, ktoré sú analogické so známymi spôsobmi.The starting compounds of the formulas II and III are either known compounds or can be prepared by known methods or by methods analogous to known methods.
Zlúčeniny všeobecného vzorca L a ich fyziologicky prijateľné soli, ktoré budú ďalej súhrne označované ako zlúčeniny podľa vynálezu, majú využiteľné farmakologické účinky a môžu sa preto použiť ako farmaceutiká.The compounds of formula (L) and their physiologically acceptable salts, hereinafter referred to collectively as the compounds of the invention, have useful pharmacological effects and can therefore be used as pharmaceuticals.
V cykle spánok/bdenie krysy s dlhodobo ustáleným režimom [metóda opísaná J.M.Vigouret-om a kol. v J.Pharmacol 10, 503 (1978)] spôsobujú zlúčeniny podía vynálezu podané v perorálnej dávke 1 až 100 mg/kg zvýšenie stavu bdelosti predĺžením fázy bdenia. Pre zlúčeninu z príkladu 1 tvorí minimálne účinná dávka pri tomto teste 3 mg/kg pri perorálnom podaní. Pri perorálnej dávke 10 mg/kg zvyšuje táto zlúčenina čas úplného bdenia na 6 hodín, pričom znižuje čas spánku v priebehu rovnakej periódy a klasický spánok o 3 hodiny.In the sleep / wake cycle of a long-term steady-state regimen [the method described by J. M. Vivouret et al. in J.Pharmacol 10, 503 (1978)], the compounds of the invention administered at an oral dose of 1 to 100 mg / kg cause an increase in alertness by prolonging the waking phase. For the compound of Example 1, the minimum effective dose in this test is 3 mg / kg orally. At an oral dose of 10 mg / kg, this compound increases the time to complete waking to 6 hours, reducing sleep time during the same period and classical sleep by 3 hours.
Ak sa okrem toho zlúčeniny podľa vynálezu podajú v perorálnej dávke krysám s bilaterálnymi léziami v miestach Locus coeruleus (LC) a Nucleus basalis Meynert (NBM), potom tieto zlúčeniny významne zlepšujú poznávacie schopnosti merané schopnosťou vyvarovať sa elektrickému šoku v kyvadlovej komore (shuttle box).In addition, when the compounds of the invention are administered orally at rats with bilateral lesions at Locus coeruleus (LC) and Nucleus basalis Meynert (NBM) sites, these compounds significantly improve cognitive ability measured by the ability to avoid electric shock in the shuttle box. .
Táto metóda je obdobná s metódou opísanou V. Haroutunian-om a kol. v Brain Research 507 (1990) 261 - 226. Samci krysy OFA (s telesnou hmotnosťou 300 g) sa anestetizujú pentobarbitalom a umiestnia sa do stereotaxného zariadenia s hornou incíznou tyčinkou umiestnenou 5 mm (LC) alebo 3,3 mm (NBM) pod interaurálnou línou. Lézie sa uskutočnia použitím vysokofrekvenčného generátora lézie pri teplote 60 °C počas 10 sekúnd. Päť týždňov po uskutočnení lézie sa uskutoční testovanie chovania s použitím testu vyvarovania sa elektrického šoku v kyvadlovej komore, ktorý je opísaný A.R. Dravid-om, A.L.Jaton-om a E.B. Van Deusen-om v Experimental Brain Research, Suppl.13, str. 249 (1986). Zlúčenina z príkladu 1 vykazuje pri tomto teste minimálnu účinnú dávku 1 mg/kg pri perorálnom podaní. Pri perorálnej dávke 10 mg/kg táto zlúčenina vyvolá u krýs celkový počet správnych varovných odoziev v porovnaní s kontrolnými pokusnými zvieratami (krysy s predstieranou operáciou).This method is similar to that described by V. Haroutunian et al. in Brain Research 507 (1990) 261-226. Male OFA rats (300 g body weight) are anesthetized with pentobarbital and placed in a stereotaxic device with an upper incision stick placed 5 mm (LC) or 3.3 mm (NBM) below the interaural lazy. Lesions are performed using a high frequency lesion generator at 60 ° C for 10 seconds. Five weeks after the lesion, a behavioral test was performed using the pendulum chamber electric shock avoidance test described by A.R. Dravid, A.L.Jaton and E.B. Van Deusen in Experimental Brain Research, Suppl.13, p. 249 (1986). The compound of Example 1 exhibits a minimum effective dose of 1 mg / kg for oral administration in this test. At an oral dose of 10 mg / kg, this compound elicits a total number of correct warning responses in rats compared to control animals (sham rats).
Zlúčeniny podľa vynálezu sú preto použiteľné na liečenie senilnej demencie, Alzheimerovej choroby a ostatných degeneratívnych ochorení, medzi ktoré patria najmä Huntingtonova chorea, Parkinsonova choroba, Steel-Richardsonov syndróm, neskorá dyskinézia, hyperkinézia, akútne konfúzne poruchy, Downov syndróm, ťažká myasténia a Friedrichova ataxia, a ďalej ako antidepresíva.The compounds of the invention are therefore useful for the treatment of senile dementia, Alzheimer's disease and other degenerative diseases, including in particular Huntington's disease, Parkinson's disease, Steel-Richardson syndrome, late dyskinesia, hyperkinesia, acute confusion disorders, Down's syndrome, severe myasthenia and Friedrich's , and furthermore as antidepressants.
Indikovaná denná dávka sa pohybuje v rozmedzí od asi 1 mg do asi 100 mg zlúčeniny podľa vynálezu, pričom táto dávka sa vhodne podáva napríklad v dielčich dávkach štyrikrát denne.The indicated daily dose is in the range of about 1 mg to about 100 mg of a compound of the invention, which dose is conveniently administered, for example, in divided doses four times a day.
Zlúčenina podľa vynálezu sa môže podávať ľubovoľným z konvenčných spôsobov podania, najmä enterálne, výhodne perorálne, napríklad vo forme tabliet alebo kapsulí, alebo parenterálne, napríklad vo forme injikovateľných roztokov alebo suspenzii.The compound of the invention may be administered by any of the conventional routes of administration, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.
V súlade s vyššie uvedeným vynález tiež zahrňuje zlúčeninu podľa vynálezu na použitie vo funkcii farmaceutiká, napríklad na liečenie senilnej demencie, Alzheimerovej choroby a ostatných degeneratívnych ochorení, akými sú Huntingtonova chorea, Parkinsonova choroba, Steel-Richardsonov syndróm, neskorá dyskinézia, hyperkinézia, akútne konfúzne poruchy, Downov syndróm, ťažká myasténia a Friedrichova ataxia, ako aj na liečenie depresií.In accordance with the above, the invention also includes a compound of the invention for use as a pharmaceutical, for example for the treatment of senile dementia, Alzheimer's disease and other degenerative diseases such as Huntington's disease, Parkinson's disease, Steel-Richardson syndrome, late dyskinesia, hyperkinesis, acute confusion disorders, Down's syndrome, severe myasthenia and Friedrich's ataxia, as well as for the treatment of depression.
Vynález tiež zahrňuje farmaceutickú kompozíciu, ktorej podstata spočíva v tom, že obsahuje zlúčeninu podľa vynálezu spoločne s aspoň jedným farmaceutickým nosičom alebo riedidlom. Takéto farmaceutické kompozície sa môžu pripraviť konvenčným spôsobom. Jednotkové dávkovacie formy obsahujú napríklad od asi 0,25 mg do asi 50 mg zlúčeniny podľa vynálezu.The invention also encompasses a pharmaceutical composition comprising a compound of the invention together with at least one pharmaceutical carrier or diluent. Such pharmaceutical compositions may be prepared in a conventional manner. Unit dosage forms contain, for example, from about 0.25 mg to about 50 mg of a compound of the invention.
V nasledujúcej časti opisu bude vynález bližšie objasnený pomocou konkrétnych príkladov jeho uskutočnenia, pričom tieto príklady majú len ilustračný charakter a nijako neobmedzujú rozsah vynálezu, ktorý je jednoznačne vymedzený formuláciou patentových nárokov. Teploty uvedené v týchto príkladoch v stupňoch Celzia sú nekorigovanými teplotami.In the following, the invention will be explained in more detail by means of specific examples thereof, the examples being illustrative only and in no way limiting the scope of the invention, which is clearly defined by the wording of the claims. The temperatures given in these examples in degrees Celsius are uncorrected temperatures.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1 [2-(2-metylimidazol-l-yl(metyl]pyridínExample 1 [2- (2-methylimidazol-1-yl (methyl) pyridine)
9,7 g (75 mM) 2-(chlórmetyl)pyridínu a 42 g (512 mM) 2-metylimidazolu sa suspenduje v 40 ml dimetylformaldehydu, následne sa získaná suspenzia mieša počas 3 hodín pri teplote 105 °C. Dimetylformamid sa oddestiluje a kryštalický zvyšok sa zriedi etylacetátom a malým množstvom hexánu. Po filtrácii sa materský lúh zahustí odparením a dimetylformamid sa oddestiluje, následne sa po niekoľkonásobnom vytrepaní do vody a metylchloridu získa 10,3 g požadovaného olejového produktu.9.7 g (75 mM) of 2- (chloromethyl) pyridine and 42 g (512 mM) of 2-methylimidazole are suspended in 40 ml of dimethylformaldehyde, followed by stirring at 105 ° C for 3 hours. Dimethylformamide was distilled off and the crystalline residue was diluted with ethyl acetate and a small amount of hexane. After filtration, the mother liquor is concentrated by evaporation and dimethylformamide is distilled off, followed by shaking several times into water and methyl chloride to obtain 10.3 g of the desired oil product.
9,3 g získanej zásady v etanole sa zmieša s 12,7 g kyseliny fumarovej. Rezultujúca bis(zásada)-tris(hydrogénfumarát) kryštalizuje zo zmesi etanolu a etylacetátu, následne sa raz rekryštalizuje zo zmesi etanolu a etylacetátu. Pri chromatografii na tenkej vrstve sa tento produkt prezentuje ako homogénny (jediná škvrna) a s teplotou topenia 109 až 110 °C.9.3 g of the base obtained in ethanol are mixed with 12.7 g of fumaric acid. The resulting bis (base) -tris (hydrogen fumarate) is crystallized from a mixture of ethanol and ethyl acetate, then recrystallized once from a mixture of ethanol and ethyl acetate. Thin layer chromatography shows this product as homogeneous (single spot) and melting at 109-110 ° C.
Postupom, ktorý je analogický s postupom opísaným v príklade 1, sa získajú nasledujúce [2-(imidazol-l-yl)metyl]pyridíny.In a manner analogous to that described in Example 1, the following [2- (imidazol-1-yl) methyl] pyridines were obtained.
Príklady 2 až 4Examples 2-4
+ = fumarát ++ = dihydrochlorid.+ = fumarate ++ = dihydrochloride.
ΊΊ
Príklad 5Example 5
Postupom, ktorý je analogický s postupom opísaným v príklade 1, sa môže získať aj nasledujúci [4-(imidazol-l-yl)metylIpyridín.In a manner analogous to that described in Example 1, the following [4- (imidazol-1-yl) methyl] pyridine can also be obtained.
+ - fumarát+ - fumarate
Claims (6)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4131584A DE4131584A1 (en) | 1991-09-23 | 1991-09-23 | IMIDAZOLYLMETHYL-PYRIDINE, THEIR PRODUCTION AND USE AS A PHARMACEUTICAL |
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| Publication Number | Publication Date |
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| SK279224B6 SK279224B6 (en) | 1998-08-05 |
| SK289692A3 true SK289692A3 (en) | 1998-08-05 |
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| SK2896-92A SK289692A3 (en) | 1991-09-23 | 1992-09-21 | Imidazolylmethyl-pyridine, method of preparation thereof, medicament and pharmaceutical composition containing this pyridine |
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| JPH10165349A (en) * | 1996-12-06 | 1998-06-23 | Matsushita Electric Ind Co Ltd | Dish washer |
| DE10000161A1 (en) * | 2000-01-06 | 2001-07-19 | Boehringer Ingelheim Pharma | Determining test substances that inhibit protease, involves incubating cells expressing fusion protein having substrate with cleavage site for protease and reporter, measuring cleaved reporter and comparing with standard |
| GB0009037D0 (en) * | 2000-04-13 | 2000-05-31 | Novartis Ag | Organic compounds |
| US20080280954A1 (en) * | 2005-07-29 | 2008-11-13 | Vanda Pharmaceuticals, Inc | Method of Improving Wakefulness |
| EP1986659A4 (en) * | 2006-02-13 | 2009-10-21 | Vanda Pharmaceuticals Inc | Stable dosage formulations of imidazolylalkyl-pyridines |
| WO2009097416A1 (en) * | 2008-01-29 | 2009-08-06 | Vanda Pharmaceuticals, Inc. | Imidazolylalkyl- pyridines as dbh inhibitors |
| AU2009303389B2 (en) | 2008-10-17 | 2014-10-16 | Wisconsin Alumni Research Foundation | Method of making biologically active alpha-beta peptides |
| EP2630136A1 (en) * | 2010-10-21 | 2013-08-28 | Universität des Saarlandes | Selective cyp11b1 inhibitors for the treatment of cortisol dependent diseases |
| BR112019024534A2 (en) * | 2017-05-22 | 2020-06-09 | Torrey Pines Inst For Molecular Studies | compositions, methods of use and methods of treatment |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0003732B1 (en) * | 1978-02-01 | 1983-10-19 | The Wellcome Foundation Limited | Imidazole derivatives and salts thereof, their synthesis, and pharmaceutical formulations thereof |
| GB2028317B (en) * | 1978-08-15 | 1982-11-10 | Pfizer Ltd | 2-(imidazol-1-ylmethyl)-pyridine and -quinoline thromboxane synthetase inhibitors |
| US4634711A (en) * | 1985-08-02 | 1987-01-06 | Smithkline Beckman Corporation | Pyridylalkyl imidazole-2-thiols |
| DE3811574A1 (en) * | 1988-03-31 | 1989-10-19 | Schering Ag | N-SUBSTITUTED IMIDAZOLES, METHODS FOR THEIR PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS |
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1991
- 1991-09-23 DE DE4131584A patent/DE4131584A1/en not_active Withdrawn
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1992
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1995
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1996
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed due to non-payment of maintenance fees |
Effective date: 20110921 |