NO326445B1 - Substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines, use of the same, drugs and methods for the preparation of the compounds - Google Patents
Substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines, use of the same, drugs and methods for the preparation of the compounds Download PDFInfo
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- NO326445B1 NO326445B1 NO20042856A NO20042856A NO326445B1 NO 326445 B1 NO326445 B1 NO 326445B1 NO 20042856 A NO20042856 A NO 20042856A NO 20042856 A NO20042856 A NO 20042856A NO 326445 B1 NO326445 B1 NO 326445B1
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- phenyl
- hydrates
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Foreliggende oppfinnelse angår substituerte 2-tio-3,5-dicyano-4-fenyl-6-amino-pyridiner, en fremgangsmåte for deres fremstilling og deres anvendelse for fremstilling av medikamenter, samt medikament inneholdende forbindelsen, eventuelt sammen med minst en ytterligere aktiv forbindelse. The present invention relates to substituted 2-thio-3,5-dicyano-4-phenyl-6-amino-pyridines, a method for their preparation and their use for the preparation of medicinal products, as well as medicinal products containing the compound, possibly together with at least one further active compound .
Adenosin, et nukleosid bestående av adenin og D-ribose, er en endogen faktor som har cellebeskyttende aktivitet, særlig under celleødeleggende betingelser med begrenset oksygen- og substrattilførsel, slik som f.eks. i tilfelle ischemi i forskjellige organer (f.eks. hjerte og hjerne). Adenosine, a nucleoside consisting of adenine and D-ribose, is an endogenous factor that has cell-protective activity, particularly under cell-destructive conditions with limited oxygen and substrate supply, such as e.g. in case of ischemia in different organs (eg heart and brain).
Adenosin dannes intracellulært som et intermediat i løpet av nedbryting av adenosin-5'-monofosfat (AMP) og S-adenosylhomocystein, men kan frigis fra cellen, i hvilket tilfelle den virker som en hormonlignende substans eller neurotransmitter ved binding til spesifikke reseptorer. Adenosine is formed intracellularly as an intermediate during the breakdown of adenosine-5'-monophosphate (AMP) and S-adenosylhomocysteine, but can be released from the cell, in which case it acts as a hormone-like substance or neurotransmitter by binding to specific receptors.
Under normoksiske betingelser, er konsentrasjonen av fritt adenosin i det ekstracellulære mellomrommet svært lav. Under ischemiske eller hypoksiske betingelser blir imidlertid den ekstracellulære konsentrasjonen av adenosin i de berørte organene økt drama-tisk. Således er det f.eks. kjent at adenosin inhiberer blodplateaggregering og øker blod-tilførsel til koronare arterier. Videre virker den på hjertehastigheten, på frigivelse av neuro transmittere og på lymfocyttdifferensiering. Under normoxic conditions, the concentration of free adenosine in the extracellular space is very low. Under ischemic or hypoxic conditions, however, the extracellular concentration of adenosine in the affected organs is increased dramatically. Thus, it is e.g. known that adenosine inhibits platelet aggregation and increases blood supply to coronary arteries. Furthermore, it acts on the heart rate, on the release of neurotransmitters and on lymphocyte differentiation.
Formålet med disse virkningen av adenosin er å øke oksygenlevering til berørte organer og/eller å redusere metabolismen til disse organene for å justere metabolismen til organene til blodtilførsel til organet under ischemiske eller hypoksiske betingelser. The purpose of these actions of adenosine is to increase oxygen delivery to affected organs and/or to reduce the metabolism of these organs in order to adjust the metabolism of the organs to blood supply to the organ under ischemic or hypoxic conditions.
Virkningen til adenosin formidles via spesifikke reseptorer. Pr. i dag er undertypene Al, A2a, A2b og A3 kjent. Virkningene til disse adenosinreseptorene formidles intracellulært ved budbringer cAMP. I tilfelle binding av adenosin til A2a eller A2b reseptorer, blir intracellulært cAMP økt via aktivering av den membranbundede adenyl atcyklasen, mens binding av adenosin til Al eller A3 reseptorer resulterer i en reduksjon av intracellulær cAMP konsentrasjon via inhibering av adenylatcyklase. The effect of adenosine is mediated via specific receptors. As of today, the subtypes Al, A2a, A2b and A3 are known. The effects of these adenosine receptors are mediated intracellularly by the messenger cAMP. In case of binding of adenosine to A2a or A2b receptors, intracellular cAMP is increased via activation of the membrane-bound adenyl at cyclase, while binding of adenosine to A1 or A3 receptors results in a reduction of intracellular cAMP concentration via inhibition of adenylate cyclase.
I henhold til foreliggende oppfinnelse er "adenosinreseptorselektive ligander" substrater som bindes selektivt til en eller flere undertyper av adenosinreseptorene og således enten etterligner virkningen til adenosin (adenosinagonist) eller blokkerer dens virkning (adenosinantagonist). According to the present invention, "adenosine receptor selective ligands" are substrates that bind selectively to one or more subtypes of the adenosine receptors and thus either mimic the action of adenosine (adenosine agonist) or block its action (adenosine antagonist).
I sammenheng med foreliggende oppfinnelse blir adenosinreseptorligander referert til som "selektive" hvis, for det første, de er klart aktive på en eller flere adenosinreseptorundertyper og, for det andre, at aktiviteten som kan observeres på en eller flere adenosinreseptorundertyper anses som svakere (faktor 10 eller mindre), hvis tilstede i det hele tatt, hvorved det, med hensyn til testfremgangsmåtene for virkningsselektivitet, vises til testmetoder beskrevet i avsnitt A.II. In the context of the present invention, adenosine receptor ligands are referred to as "selective" if, first, they are clearly active on one or more adenosine receptor subtypes and, second, that the activity that can be observed on one or more adenosine receptor subtypes is considered weaker (factor 10 or less), if present at all, whereby, with respect to the test methods for selectivity of action, reference is made to test methods described in section A.II.
I henhold til deres reseptorselektivitet kan adenosinreseptorselektive ligander oppdeles i forskjellige kategorier, f.eks. ligander som bindes selektivt til Al eller A2 reseptorene til adenosin og i tilfelle av sistnevnte også f.eks. de som bindes selektivt til A2a eller A2b reseptorene til adenosin. Også mulig er adenosinreseptorligander som bindes selektivt til et antall undertyper av adenosinreseptorene, f.eks. ligander som bindes selektivt til Al og A2, men ikke til A3 reseptorene til adenosin. According to their receptor selectivity, adenosine receptor-selective ligands can be divided into different categories, e.g. ligands that bind selectively to the A1 or A2 receptors of adenosine and in the case of the latter also e.g. those that bind selectively to the A2a or A2b receptors of adenosine. Also possible are adenosine receptor ligands that bind selectively to a number of subtypes of the adenosine receptors, e.g. ligands that bind selectively to A1 and A2, but not to A3 receptors for adenosine.
Den ovenfor nevnte reseptorselektiviteten kan bestemmes ved effekten til substansene på cellelinjer som, etter transfeksjon med det korresponderende cDNA, uttrykker resep-torundertypene det gjelder (se publikasjonen M.E. Olah, H. Ren, J. Ostrowski, K.A. Jacobson, G.L. Stiles, "Cloning, expression, and characterization of the unique bovine Al adenosine receptor. Studies on the ligand binding site by sited-directed mutagene-sis." i J. Biol. Chem. 267 (1992) side 10764-10770). The above-mentioned receptor selectivity can be determined by the effect of the substances on cell lines which, after transfection with the corresponding cDNA, express the receptor subtypes in question (see the publication M.E. Olah, H. Ren, J. Ostrowski, K.A. Jacobson, G.L. Stiles, "Cloning, expression, and characterization of the unique bovine Al adenosine receptor. Studies on the ligand binding site by sited-directed mutagene-sis." in J. Biol. Chem. 267 (1992) page 10764-10770).
Effekten av substansene på slike cellelinjer kan bestemmes med biokjemiske målinger av intracellulær budbringer cAMP (se publikasjonen K.N. Klotz, J. Hessling, J. Hegler, C. Owman, B. Kull, B.B. Fredholm, M.J. Lohse, "Comparative pharmacology og human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells" i Naunyn Schmiedebergs Arch. Pharmacol. 357 (1998) side 1-9). The effect of the substances on such cell lines can be determined with biochemical measurements of the intracellular messenger cAMP (see the publication K.N. Klotz, J. Hessling, J. Hegler, C. Owman, B. Kull, B.B. Fredholm, M.J. Lohse, "Comparative pharmacology and human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells" in Naunyn Schmiedeberg's Arch. Pharmacol. 357 (1998) page 1-9).
I tilfelle Al agonister (kobling foretrukket via Gi proteiner), blir en reduksjon i intracellulær cAMP konsentrasjon observert (foretrukket etter direkte prestimulering av adenylatcyklase med forskolin), i tilfelle Al antagonister blir en økning i intracellulær cAMP konsentrasjon observert (foretrukket etter prestimulering med adenosin eller adenosin-lignende substanser pluss direkte prestimulering med adenylatcyklase med forskolin). Tilsvarende fører A2a og A2b agonister (kobling foretrukket via Gg proteiner) til en økning av A2a og A2b antagonister for å redusere cAMP konsentrasjonen i cellene. I tilfelle A2 reseptorer, er direkte prestimulering av adenylatcyklase med forskolin ikke fordelaktig. In the case of Al agonists (linking preferably via Gi proteins), a decrease in intracellular cAMP concentration is observed (preferably after direct prestimulation of adenylate cyclase with forskolin), in the case of Al antagonists an increase in intracellular cAMP concentration is observed (preferably after prestimulation with adenosine or adenosine-like substances plus direct prestimulation of adenylate cyclase with forskolin). Correspondingly, A2a and A2b agonists (linking preferably via Gg proteins) lead to an increase of A2a and A2b antagonists to reduce the cAMP concentration in the cells. In the case of A2 receptors, direct prestimulation of adenylate cyclase with forskolin is not beneficial.
"Adenosinreseptorspesifikke" ligander kjent fra litteraturen er først og fremst derivater basert på naturlig adenosin (S.-A. Poulsen og R.J. Quinn, "Adenosine receptors: new opportunities for future drugs" i Bioorganic and Medicinal Chemistry 6 (1998) side 619 til 641). Imidlertid har de fleste av adenosinligandene kjente fra litteraturen ulempen med at deres virkning i virkeligheten ikke er reseptorspesifikk, at deres aktivitet er mindre enn den til naturlig adenosin eller at de kun har svak aktivitet etter oral administrasjon. Således er de først og fremst anvendt for eksperimentelle formål. "Adenosine receptor specific" ligands known from the literature are primarily derivatives based on natural adenosine (S.-A. Poulsen and R.J. Quinn, "Adenosine receptors: new opportunities for future drugs" in Bioorganic and Medicinal Chemistry 6 (1998) pages 619 to 641 ). However, most of the adenosine ligands known from the literature have the disadvantage that their action is not actually receptor specific, that their activity is less than that of natural adenosine or that they only have weak activity after oral administration. Thus, they are primarily used for experimental purposes.
I tillegg beskriver WO 00/12510 2-tio-3,5-(Ucyano-4-aiyl-6-aniinopyridiner med en struktur tilsvarende den til forbindelsene ifølge oppfinnelsen. Imidlertid er de farmakokinetiske egenskapene til forbindelsene beskrevet deri mindre fordelaktige; særlig har de dårlig biotilgjengelighet etter oral administrasjon. In addition, WO 00/12510 describes 2-thio-3,5-(Ucyano-4-yl-6-aniinopyridines) with a structure similar to that of the compounds according to the invention. However, the pharmacokinetic properties of the compounds described therein are less favorable; in particular, they have poor bioavailability after oral administration.
Det er nå et formål med foreliggende oppfinnelse å finne eller tilveiebringe forbindelser som ikke har ulempene som er nevnt i teknikkens stand og/eller har forbedret biotilgjengelighet. It is now an object of the present invention to find or provide compounds which do not have the disadvantages mentioned in the prior art and/or have improved bioavailability.
Følgelig angår foreliggende oppfinnelse forbindelser med formel (I) Accordingly, the present invention relates to compounds of formula (I)
n representerer et tall 2,3 eller 4, n represents a number 2,3 or 4,
R<1> representerer hydrogen eller (Ci-GO-alkyl R<1> represents hydrogen or (Ci-GO-alkyl
og and
R<2> representerer pyridyl eller tiazolyl som for sin del kan være substituert med (Ci-GO-alkyl, halogen, amino, dimetylamino, acetylamino, guanidino, pyridylamino, tienyl, furyl, imidazolyl, pyridyl, morfolinyl, tiomorfolinyl, piperidinyl, pipera-zinyl, N-(Ci-C4)-alkylpiperazinyl, pyrrolidinyl, oksazolyl, isoksazolyl, pyrimidi-nyl, pyrazinyl, eventuelt (Ci-C4)-alkylsubstituert tiazolyl eller fenyl som eventuelt er substituert opp til tre ganger med halogen, (Ci-C4)-alkyl eller (C1-C4)-alkoksy, R<2> represents pyridyl or thiazolyl which for its part may be substituted with (Ci-GO-alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, morpholinyl, thiomorpholinyl, piperidinyl, pipera -zinyl, N-(Ci-C4)-alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, optionally (Ci-C4)-alkyl substituted thiazolyl or phenyl which is optionally substituted up to three times with halogen, (Ci- C4)-alkyl or (C1-C4)-alkoxy,
og deres salter, hydrater, hydrater av salter og solvater. and their salts, hydrates, hydrates of salts and solvates.
Avhengig av substitusjonsmønsteret kan forbindelsene med formel (I) eksistere i stereo-isomere former som enten er bilde og speilbilde (enantiomerer) eller ikke bilde og Depending on the substitution pattern, the compounds of formula (I) can exist in stereoisomeric forms which are either image and mirror image (enantiomers) or non-image and
speilbilde (diastereomerer). Oppfinnelsen angår både enantiomerer eller diastereomerer og deres respektive blandinger. De racemiske formene, som diastereomerene, kan sepa-reres på kjent måte til stereospesikt enhetlige komponenter. På samme måte angår foreliggende oppfinnelse også andre tautomerer av forbindelsene med formel (I) og deres salter. mirror image (diastereomers). The invention relates to both enantiomers or diastereomers and their respective mixtures. The racemic forms, such as the diastereomers, can be separated in a known manner into stereospecifically uniform components. In the same way, the present invention also relates to other tautomers of the compounds of formula (I) and their salts.
Salter av forbindelser med formel (I) kan være fysiologisk akseptable salter av forbindelsene ifølge oppfinnelsen med mineralsyrer, karboksylsyrer eller sulfonsyrer. Særlig foretrukket er f.eks. salter med saltsyre, hydrobromsyre, svovelsyre, fosforsyre, metan-sulfonsyre, etansulfonsyre, toluensulfonsyre, benzensulfonsyre, naftalendisulfonsyre, trifluoreddiksyre, eddiksyre, propionsyre, melkesyre, vinsyre, sitronsyre, fumarsyre, maleinsyre eller benzosyre. Salts of compounds of formula (I) can be physiologically acceptable salts of the compounds according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred are e.g. salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, trifluoroacetic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Salter som kan nevnes inkluderer salter med vanlige baser, slike som f.eks. alkalime-tallsalter (f.eks. natriumsalter eller kaliumsalter), jordalkalimetallsalter (f.eks. kalsi-umsalter eller magnesiumsalter) eller ammoniumsalter, avledet fra ammoniakk eller organiske aminer, slik som f.eks. dietylamin, trietylamin, etyldiisopropylamin, prokain, dibenzylamin, N-metyl-morfolin, dihydroabietylamin, 1-efenamin eller metylpiperidin. Salts which may be mentioned include salts with common bases, such as e.g. alkali metal salts (e.g. sodium salts or potassium salts), alkaline earth metal salts (e.g. calcium salts or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as e.g. diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methyl-morpholine, dihydroabiethylamine, 1-ephenamine or methylpiperidine.
Ifølge oppfinnelsen er hydrater eller solvater de formene av forbindelsene med formel (I) som, i fast eller flytende tilstand, ved hydratisering med vann eller koordinering med løsemiddelmolekyler danner en molekylforbindelse eller et kompleks. Eksempler på hydrater er sesquihydrater, monohydrater, dihydrater eller trihydrater. På samme måte er hydrater eller solvater av salter av forbindelsene ifølge oppfinnelsen også egnet. According to the invention, hydrates or solvates are those forms of the compounds of formula (I) which, in solid or liquid state, upon hydration with water or coordination with solvent molecules form a molecular compound or a complex. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. In the same way, hydrates or solvates of salts of the compounds according to the invention are also suitable.
Videre inkluderer oppfinnelsen også prodrugformer av forbindelsene ifølge oppfinnelsen. Ifølge foreliggende oppfinnelse er prodrugformer utgaver av forbindelsene med formel (I) som for sin del kan være biologisk aktive eller inaktive, men som kan omdannes under fysiologiske betingelser, f.eks. metabolittisk eller solvolyttisk) til de korresponderende biologisk aktive formene. Furthermore, the invention also includes prodrug forms of the compounds according to the invention. According to the present invention, prodrug forms are versions of the compounds of formula (I) which for their part can be biologically active or inactive, but which can be converted under physiological conditions, e.g. metabolic or solvolytic) to the corresponding biologically active forms.
I sammenheng med foreliggende oppfinnelse har substituentene, med mindre annet er angitt, følgende betydninger: Halogen representerer generelt fluor, klor, brom eller jod. Foretrukket er fluor, klor eller brom. Svært foretrukket er fluor eller klor. In the context of the present invention, the substituents, unless otherwise stated, have the following meanings: Halogen generally represents fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine are preferred. Very preferred is fluorine or chlorine.
(Ci-C4)-alkyl representerer generelt et rettkjedet eller forgrenet alkylradikal som har 1 til 4 karbonatomer. Eksempler som kan nevnes er: metyl, etyl, n-propyl, isopropyl, n-butyl, sek-butyl, isobutyl og tert-butyl. (C 1 -C 4 )alkyl generally represents a straight chain or branched alkyl radical having 1 to 4 carbon atoms. Examples that can be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.
(Ci-C4)-alkoksy representerer generelt et rettkjedet eller forgrenet alkoksyradikal som har 1 til 4 karbonatomer. Eksempler som kan nevnes er: metoksy, etoksy, n-propoksy, isopropoksy, n-butoksy, sek-butoksy, isobutoksy og tert-butoksy. (C 1 -C 4 )-Alkoxy generally represents a straight or branched chain alkoxy radical having 1 to 4 carbon atoms. Examples that can be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy.
Foretrukket er forbindelser med formel (I) Compounds of formula (I) are preferred
hvori in which
n representerer tallet 2, n represents the number 2,
R<1> representerer hydrogen, metyl eller etyl, R<1> represents hydrogen, methyl or ethyl,
og and
R<2> representerer pyridyl eller tiazolyl som for sin del kan være substituert med metyl, etyl, fluor, klor, amino, dimetylamino, acetylamino, guanidino, 2-pyridylarnino, 4-pyridylamino, tienyl, pyridyl, morfolinyl, piperidinyl, eventuelt metylsubstituert tiazolyl eller fenyl som eventuelt kan være substituert opp til tre ganger med klor eller metoksy, R<2> represents pyridyl or thiazolyl which for its part may be substituted with methyl, ethyl, fluorine, chlorine, amino, dimethylamino, acetylamino, guanidino, 2-pyridylarnino, 4-pyridylamino, thienyl, pyridyl, morpholinyl, piperidinyl, optionally methyl substituted thiazolyl or phenyl which may optionally be substituted up to three times with chlorine or methoxy,
og deres salter, hydrater, hydrater av saltene og solvater. and their salts, hydrates, hydrates of the salts and solvates.
Særlig foretrukket er forbindelser med formel (I) hvori R<1> er hydrogen eller metyl. Particularly preferred are compounds of formula (I) in which R<1> is hydrogen or methyl.
Særlig foretrukket er forbindelser med formel (I) hvori Particularly preferred are compounds of formula (I) in which
n representerer tallet 2, n represents the number 2,
R<1> representerer hydrogen eller metyl R<1> represents hydrogen or methyl
og and
R<2> representerer pyridyl eller tiazolyl som for sin del kan være substituert med metyl, klor, amino, dimetylamino, acetylamino, guanidino, 2-pyridylamino, 4-pyridylamino, tienyl, pyridyl, morfolinyl, 2-metyltiazol-5-yl, fenyl, 4-klorfenyl eller 3,4,5-trimetoksyfenyl, R<2> represents pyridyl or thiazolyl which for its part may be substituted with methyl, chlorine, amino, dimethylamino, acetylamino, guanidino, 2-pyridylamino, 4-pyridylamino, thienyl, pyridyl, morpholinyl, 2-methylthiazol-5-yl, phenyl, 4-chlorophenyl or 3,4,5-trimethoxyphenyl,
og deres salter, hydrater, hydrater av salter og solvater. and their salts, hydrates, hydrates of salts and solvates.
Svært foretrukket er forbindelser fra eksempel 6 med følgende struktur Very preferred are compounds from example 6 with the following structure
og deres salter, hydrater, hydrater av saltene og solvatene. and their salts, hydrates, hydrates of the salts and solvates.
Foreliggende oppfinnelse tilveiebringer også en fremgangsmåte for fremstilling av forbindelser med formel (I), kjennetegnet ved at forbindelsene med formel (II) The present invention also provides a method for the preparation of compounds of formula (I), characterized in that the compounds of formula (II)
hvori in which
n og R<1> er som definert ovenfor, n and R<1> are as defined above,
omsettes med forbindelser med formel (III) reacted with compounds of formula (III)
hvori in which
R er som definert ovenfor og X representerer en egnet utgående gruppe, f.eks. og foretrukket halogen, særlig klor, brom eller jod, eller representerer mesylat, tosy-lat, triflat eller 1-imidazolyl, R is as defined above and X represents a suitable leaving group, e.g. and preferably halogen, especially chlorine, bromine or iodine, or represents mesylate, tosylate, triflate or 1-imidazolyl,
hvis hensiktsmessig under nærvær av en base. if appropriate in the presence of a base.
Fremgangsmåten beskrevet ovenfor kan illustreres f.eks. ved formelskjemaet nedenfor: The procedure described above can be illustrated e.g. by the formula form below:
Egnede løsemidler for fremgangsmåten ifølge oppfinnelsen er alle organiske løsemidler som er inerte under reaksjonsbetingelsene. Disse inkluderer alkoholer, slik som metanol, etanol og isopropanol, ketoner, slik som aceton og metyletylketon, acyliske og cykliske etere, slik som dietyleter og tetrahydrofuran, estere, slik som etylacetat eller butylacetat, hydrokarboner, slik som benzen, xylen, toluen, heksan eller cykloheksan, klorerte hydrokarboner, slik som diklormetan, klorbenzen eller dikloretan, eller andre løsemidler, slik som dimetylformamid, acetonitril, pyridin eller dimetylsulfoksid (DMSO). Vann er også et egnet løsemiddel. Foretrukket er dimetylformamid. Det er også mulig å anvende blandinger av løsemidler nevnt ovenfor. Suitable solvents for the method according to the invention are all organic solvents which are inert under the reaction conditions. These include alcohols, such as methanol, ethanol and isopropanol, ketones, such as acetone and methyl ethyl ketone, acyl and cyclic ethers, such as diethyl ether and tetrahydrofuran, esters, such as ethyl acetate or butyl acetate, hydrocarbons, such as benzene, xylene, toluene, hexane or cyclohexane, chlorinated hydrocarbons, such as dichloromethane, chlorobenzene, or dichloroethane, or other solvents, such as dimethylformamide, acetonitrile, pyridine, or dimethylsulfoxide (DMSO). Water is also a suitable solvent. Dimethylformamide is preferred. It is also possible to use mixtures of solvents mentioned above.
Egnede baser er vanlige uorganiske eller organiske baser. Disse inkluderer foretrukket alkalimetallhydroksider, slik som f.eks. natriumhydroksid eller kaliumhydroksid, eller alkalimetallkarbonater, slik som natriumkarbonat eller kaliumkarbonat, eller alkalimetallbikarbonater, slik som natriumbikarbonat eller kaliumbikarbonat, eller alkalimetal-lalkoksider, slik som natriummetoksid eller kaliummetoksid, natriumetoksid eller ka-liumetoksid eller kalium tert-butoksid, eller amider, slik som natriumamid, litium bis(trimetylsilyl)amid eller litiumdiisopropylamid, eller organometalliske forbindelser, slik som litium eller fenyllitium, eller l,8-diazabicyklo[5,4,0]undek-7-en (DBU) eller l,5-diazabicyklo[4,3,0]non-5-en (DBN), eller aminer, slik som trietylamin eller pyridin. Foretrukket er alkalimetallkarboner og alkalimetallbikarbonater. Suitable bases are common inorganic or organic bases. These preferably include alkali metal hydroxides, such as e.g. sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or alkali metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate, or alkali metal oxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium methoxide or potassium tert-butoxide, or amides, such as sodium amide , lithium bis(trimethylsilyl)amide or lithium diisopropylamide, or organometallic compounds, such as lithium or phenyllithium, or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or 1,5-diazabicyclo[4, 3,0]non-5-ene (DBN), or amines, such as triethylamine or pyridine. Alkali metal carbonates and alkali metal bicarbonates are preferred.
Her kan basen anvendes i en mengde på fra 1 til 10 mol, foretrukket fra 1 til 5 mol, særlig fra 1 til 4 mol, basert på 1 mol av forbindelsen med formel (II). Here, the base can be used in an amount of from 1 to 10 mol, preferably from 1 to 5 mol, in particular from 1 to 4 mol, based on 1 mol of the compound of formula (II).
Reaksjonen finner generelt sted i et temperaturområde på fra -78°C til 140°C, foretrukket i området fra -78°C til 40°C, særlig ved romtemperatur. The reaction generally takes place in a temperature range of from -78°C to 140°C, preferably in the range from -78°C to 40°C, particularly at room temperature.
Reaksjonen kan utføres ved atmosfæretrykk, hevet eller redusert trykk (f.eks. i området fra 0,5 til 5 bar). Generelt blir reaksjonen utført ved atmosfæretrykk. The reaction can be carried out at atmospheric pressure, elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
Forbindelsene med formel (II) er i og for seg kjente og kan fremstilles ved vanlige fremgangsmåter kjente fra litteraturen, f.eks. ved å omsette de tilsvarende benzaldehy-dene med cyanotioacetamid. Referanse kan gjøres særlig til følgende publikasjoner: Dyachenko et al, Russian Journal of Chemistry, bind 33, nr. 7,1997, side 1014 til 1017 og bind 34, nr. 4,1998, side 557 til 563; • Dyachenko et al, Chemistry of Heterocyclic Compounds, bind 34, nr. 2,1998, side 188 til 194; • Qintela et al, European Journal of Medicinal Chemistry, bind 33, 1988, side 887 til 897; The compounds of formula (II) are known in and of themselves and can be prepared by usual methods known from the literature, e.g. by reacting the corresponding benzaldehydes with cyanothioacetamide. Reference may be made in particular to the following publications: Dyachenko et al, Russian Journal of Chemistry, Volume 33, No. 7, 1997, pages 1014 to 1017 and Volume 34, No. 4, 1998, pages 557 to 563; • Dyachenko et al, Chemistry of Heterocyclic Compounds, Vol. 34, No. 2, 1998, pages 188 to 194; • Qintela et al, European Journal of Medicinal Chemistry, Volume 33, 1988, pages 887 to 897;
• Kandeel et al, Zeitschift fur Naturforschung 42b, 107 til 111 (1987). • Kandeel et al, Zeitschift fur Naturforschung 42b, 107 to 111 (1987).
Således er det f.eks. også mulig å fremstille forbindelser med formel (II) fra forbindelser med formel (IV) ved omsetning med et alkalimetallsulfid. Denne fremstillingsfrem-gangsmåten kan f.eks. illustreres ved følgende reaksjonsskjema: Thus, it is e.g. also possible to prepare compounds of formula (II) from compounds of formula (IV) by reaction with an alkali metal sulphide. This production method can e.g. is illustrated by the following reaction scheme:
Alkalimetallsulfidet som anvendes er foretrukket natriumsulfid i en mengde på fra 1 til 10 mol, foretrukket fra 1 til 5 mol, særlig fra 1 til 4 mol, basert på 1 mol av forbindelsen med formel (IV). The alkali metal sulfide used is preferably sodium sulfide in an amount of from 1 to 10 mol, preferably from 1 to 5 mol, in particular from 1 to 4 mol, based on 1 mol of the compound of formula (IV).
Egnede løsemidler er alle organiske løsemidler som er inerte under reaksjonsbetingelsene. Disse inkluderer f.eks. N,N-dimetylformamid, N-metylpyrrolidinon, pyridin og acetonitril. Foretrukket er N,N-dimetylformamid. Det er også mulig å anvende blandinger av løsemidler nevnt ovenfor. Suitable solvents are all organic solvents which are inert under the reaction conditions. These include e.g. N,N-dimethylformamide, N-methylpyrrolidinone, pyridine and acetonitrile. N,N-dimethylformamide is preferred. It is also possible to use mixtures of solvents mentioned above.
Reaksjonen blir generelt utført i et temperaturområde på fra 20°C til 140°C, foretrukket i området fra 20°C til 120°, særlig i området fra 60°C til 100°C. The reaction is generally carried out in a temperature range of from 20°C to 140°C, preferably in the range from 20°C to 120°, particularly in the range from 60°C to 100°C.
Reaksjonen kan utføres ved atmosfærisk, hevet eller redusert trykk (f.eks. i området fra 0,5 til 5 bar). Generelt blir reaksjonen utført ved atmosfæretrykk. The reaction can be carried out at atmospheric, elevated or reduced pressure (eg in the range from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
Forbindelsene med formel (III) er enten kommersielt tilgjengelige eller er kjente for fagmannen eller kan fremstilles ved vanlige fremgangsmåter. The compounds of formula (III) are either commercially available or are known to the person skilled in the art or can be prepared by conventional methods.
Forbindelser med formel (IV) er enten kommersielt tilgjengelige eller er kjente for fagmannen eller kan fremstilles ved vanlige fremgangsmåter. Referanse gjøres her særlig til følgende publikasjoner. • Kambe et al., Synthesis, 531 til 533 (1981); Compounds of formula (IV) are either commercially available or are known to the person skilled in the art or can be prepared by conventional methods. Reference is made here in particular to the following publications. • Kambe et al., Synthesis, 531 to 533 (1981);
• Elnagdi et al., Z. Naturforsch. 47b, 572 til 578 (1991). • Elnagdi et al., Z. Naturforsch. 47b, 572 to 578 (1991).
Den farmasøytiske aktiviteten til forbindelsene med formel (I) kan forklares ved deres virkning som selektive ligander på adenosin Al reseptorer. Her virker de som Al agonister. The pharmaceutical activity of the compounds of formula (I) can be explained by their action as selective ligands on adenosine A1 receptors. Here they act as Al agonists.
Overraskende har forbindelsene med formel (I) et overraskende anvendelig farmakologisk aktivitetsspektrum og er derfor egnet særlig for profylakse og/eller behandling av sykdommer. Surprisingly, the compounds of formula (I) have a surprisingly applicable spectrum of pharmacological activity and are therefore particularly suitable for the prophylaxis and/or treatment of diseases.
Sammenlignet med teknikkens stand, har forbindelsene med formel (I) ifølge foreliggende oppfinnelse forbedrede farmakokinetiske egenskaper, særlig bedre biotilgjengelighet etter oral administrasjon. Compared to the state of the art, the compounds of formula (I) according to the present invention have improved pharmacokinetic properties, in particular better bioavailability after oral administration.
Forbindelsene med formel (I), alene eller i kombinasjon med en eller flere andre aktive forbindelser, er egnet for profylakse og/eller behandling av forskjellige sykdommer, dvs. særlig f.eks. sykdommer i det kardiovaskulære systemet (kardiovaskulære sykdommer). Aktive forbindelser egnet for kombinasjoner er særlig aktive forbindelser for behandling av koronar hjertesykdom, slik som f.eks. særlig nitrater, betablokker, kalsi-umantagonister eller diuretiske forbindelser. The compounds of formula (I), alone or in combination with one or more other active compounds, are suitable for prophylaxis and/or treatment of various diseases, i.e. particularly e.g. diseases of the cardiovascular system (cardiovascular diseases). Active compounds suitable for combinations are particularly active compounds for the treatment of coronary heart disease, such as e.g. in particular nitrates, beta-blockers, calcium antagonists or diuretic compounds.
Innenfor sammenhengen i foreliggende oppfinnelse er kardiovaskulære sykdommer å forstå særlig som f.eks. følgende sykdommer: koronar restenose, slik som f.eks. restenose etter ballongdilatasjon av periferale blodkar, takykardi, arrytmier; perifere og kardiovaskulære forstyrrelser, stabil og ustabil angina pectoris; arteriell og ventrikulær fib-rillering. Within the context of the present invention, cardiovascular diseases are to be understood in particular as e.g. the following diseases: coronary restenosis, such as e.g. restenosis after balloon dilatation of peripheral blood vessels, tachycardia, arrhythmias; peripheral and cardiovascular disorders, stable and unstable angina pectoris; arterial and ventricular fibrillation.
Forbindelsene med formel (I) er videre også særlig egnet f.eks. for å redusere størrelsen til myokardisk areal berørt av et infarkt. The compounds of formula (I) are also particularly suitable, e.g. to reduce the size of the myocardial area affected by an infarct.
Forbindelsene med formel (I) er videre særlig egnet f.eks. for profylakse og/eller behandling av tromboemboliske sykdommer og ischemier, slik som myokardisk infarkt, slag og transitoriske ischemiske anfall. The compounds of formula (I) are furthermore particularly suitable, e.g. for the prophylaxis and/or treatment of thromboembolic diseases and ischaemia, such as myocardial infarction, stroke and transient ischemic attacks.
Videre indikasj onsområder for hvilke forbindelsene med formel (I) er særlig egnet er f.eks. profylakse og/eller behandling av forstyrrelser i det urogenitale området, slik som f.eks. irritabel blære, erektil dysfunksjon og seksuell dysfunksjon hos kvinner, og i tillegg også profylakse og/eller behandling av inflammasjonsforstyrrelser, slik som f.eks. astma og inflammerte dermatoser, av neuroinflammasjonsforstyrrelser i sentralnervesys-temet, slik som f.eks. tilstander etter cerebralt infarkt, Alzheimers sykdom, videre også neurodegenerative lidelser, så vel som smerte og kreft. Further indication areas for which the compounds of formula (I) are particularly suitable are e.g. prophylaxis and/or treatment of disorders in the urogenital area, such as e.g. irritable bladder, erectile dysfunction and sexual dysfunction in women, and in addition also prophylaxis and/or treatment of inflammatory disorders, such as e.g. asthma and inflamed dermatoses, from neuroinflammation disorders in the central nervous system, such as e.g. conditions after cerebral infarction, Alzheimer's disease, further also neurodegenerative disorders, as well as pain and cancer.
Et ytterligere spesielt indikasjonsområdet er f.eks. profylakse og/eller behandling av sykdommer i luftveiene, slik som f.eks. astma, kronisk bronkitt, pulmonær emfysem, bronkiektase, cystisk fibrose (mukoviskidose) og pulmonær hypertensjon. A further special indication area is e.g. prophylaxis and/or treatment of diseases in the respiratory tract, such as e.g. asthma, chronic bronchitis, pulmonary emphysema, bronchiectasis, cystic fibrosis (cystic fibrosis) and pulmonary hypertension.
Endelig er forbindelsene med formel (I) også særlig egnet f.eks. for profylakse og/eller behandling av diabetes, særlig diabetes mellitus. Finally, the compounds of formula (I) are also particularly suitable, e.g. for prophylaxis and/or treatment of diabetes, especially diabetes mellitus.
Foreliggende oppfinnelse angår også anvendelse av forbindelsene med formel (I) for fremstilling av medikamenter for profylakse og/eller behandling av sykdommer i det kardiovaskulære systemet. The present invention also relates to the use of the compounds of formula (I) for the production of drugs for the prophylaxis and/or treatment of diseases in the cardiovascular system.
Videre angår oppfinnelsen anvendelse av forbindelsene med formel (I) for fremstilling av medikamenter for profylakse og/eller behandling av sykdommer av den urogenitale regionen og kreft. Furthermore, the invention relates to the use of the compounds of formula (I) for the production of medicaments for the prophylaxis and/or treatment of diseases of the urogenital region and cancer.
Oppfinnelsen angår likeledes anvendelse av forbindelsene med formel (I) for fremstilling av medikamenter for profylakse og/eller behandling av inflammasjons- og neuroin-flammasjonssykdommer, neurodegenerative sykdommer og smerte. The invention also relates to the use of the compounds of formula (I) for the production of drugs for the prophylaxis and/or treatment of inflammatory and neuroinflammatory diseases, neurodegenerative diseases and pain.
Foreliggende oppfinnelse inkluderer videre medikamenter som innbefatter minst en forbindelse med formel (I), foretrukket sammen med et eller flere farmakologisk akseptable hjelpestoffer eller bærere. The present invention further includes medicaments which include at least one compound of formula (I), preferably together with one or more pharmacologically acceptable excipients or carriers.
Oppfinnelsen omfatter videre medikamenter som omfatter minst en forbindelse med formel (I) og minst en ytterligere aktiv forbindelse. The invention further comprises medicaments comprising at least one compound of formula (I) and at least one further active compound.
Egnet for administrering av forbindelsene med formel (I) er alle vanlige administra-sjonsformer, dvs. oral, parenteral, inhalerbar, nasal, sublingual, rektal, lokal, slik som f.eks. i tilfelle implantater eller stenter, eller ekstern, slik som f.eks. transdermal. I tilfellet parenteral administrasjon, kan det særlig nevnes intravenøs, intramuskulær og sub-kutan administrasjon, f.eks. som et subkutant depot. Foretrukket er oral eller parenteral administrasjon. Særlig foretrukket er oral administrasjon. Suitable for administration of the compounds of formula (I) are all usual forms of administration, i.e. oral, parenteral, inhalable, nasal, sublingual, rectal, local, such as e.g. in the case of implants or stents, or external, such as e.g. transdermal. In the case of parenteral administration, mention may be made in particular of intravenous, intramuscular and subcutaneous administration, e.g. as a subcutaneous depot. Oral or parenteral administration is preferred. Particularly preferred is oral administration.
Her kan de aktive forbindelsene administreres alene eller i form av preparater. Egnede preparater for oral administrasjon er blant annet tabletter, kapsler, pellets, sukkerbelagte Here, the active compounds can be administered alone or in the form of preparations. Suitable preparations for oral administration include tablets, capsules, pellets, sugar-coated
tabletter, piller, granuler, faste og flytende aerosoler, siruper, emulsjoner, suspensjoner og løsninger. Her kan den aktive forbindelsen være til stede i en slik mengde at den te-rapeutiske effekten oppnås. Generelt kan den aktive forbindelsen være tilstede i en konsentrasjon på fra 0,1 til 100 vekt-%, særlig fra 0,5 til 90 vekt-%, foretrukket fra 5 til 80 vekt-%. Spesielt bør konsentrasjonen av aktiv forbindelse være fra 0,5 til 90 vekt-%, dvs. den aktive forbindelsen bør være tilstede i mengder tilstrekkelig til å oppnå det nevnte doseringsområdet. tablets, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. Here, the active compound can be present in such an amount that the therapeutic effect is achieved. In general, the active compound can be present in a concentration of from 0.1 to 100% by weight, in particular from 0.5 to 90% by weight, preferably from 5 to 80% by weight. In particular, the concentration of active compound should be from 0.5 to 90% by weight, i.e. the active compound should be present in amounts sufficient to achieve the aforementioned dosage range.
De aktive forbindelsene kan omdannes på en i og for seg kjent måte til vanlige preparater. Dette oppnås ved anvendelse av inerte, ikke-toksiske farmasøytisk egnede bærere, hjelpestoffer, løsemidler, vehikler, emulsjoner og/eller dispergeringsmidler. The active compounds can be converted in a manner known per se into common preparations. This is achieved by using inert, non-toxic pharmaceutically suitable carriers, excipients, solvents, vehicles, emulsions and/or dispersants.
Hjelpestoffer som kan nevnes er f.eks.: vann, ikke-toksiske organiske løsemidler, slik som f.eks. parafiner, vegetabilske oljer (f.eks. sesamolje), alkoholer (f.eks. etanol, glyserol), glykoler (f.eks. polyetylenglykol), faste bærere, slik som naturlige eller syntetis-ke jordmineraler (f.eks. talkum eller silikater), sukker (f.eks. laktose), emulgatorer, dispergeringsmidler (f.eks. polyvinylpyrrolidon) og glidemidler (f.eks. magnesiumsulfat). Excipients that can be mentioned are, for example: water, non-toxic organic solvents, such as e.g. paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), solid carriers, such as natural or synthetic earth minerals (e.g. talc or silicates), sugars (e.g. lactose), emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and glidants (e.g. magnesium sulfate).
I tilfellet oral administrasjon kan selvfølgelig tabletter også inneholde additiver slike som natriumsitrat, sammen med adjuvanter slik som stivelse, gelatin og lignende. Vandige preparater for oral administrasjon kan videre blandes med smaksforsterkere eller fargestoffer. In the case of oral administration, tablets may of course also contain additives such as sodium citrate, together with adjuvants such as starch, gelatin and the like. Aqueous preparations for oral administration can further be mixed with flavor enhancers or colourants.
Generelt er det fordelaktig å administrere, i tilfelle parenteral administrasjon, mengder på fra ca. 0,1 til ca. 10 000 ug/kg, foretrukket fra ca. 1 til ca. 1 000 ug/kg, særlig fra ca. In general, it is advantageous to administer, in the case of parenteral administration, amounts of from approx. 0.1 to approx. 10,000 ug/kg, preferably from approx. 1 to approx. 1,000 ug/kg, especially from approx.
1 ug/kg til ca. 100 ug/kg, av kroppsvekt, for å oppnå effektive resultater. I tilfelle oral administrasjon, er mengden fra ca. 0,05 til ca. 5 mg/kg, foretrukket fra ca. 0,1 til ca. 5 mg/kg, særlig fra ca. 0,1 til ca. 1 mg/kg, av kroppsvekt. 1 ug/kg to approx. 100 ug/kg, of body weight, to achieve effective results. In case of oral administration, the amount is from approx. 0.05 to approx. 5 mg/kg, preferably from approx. 0.1 to approx. 5 mg/kg, especially from approx. 0.1 to approx. 1 mg/kg, of body weight.
Til tross for dette, kan det likevel være påkrevet å avvike fra de nevnte mengder, avhengig av kroppsvekt, administrasjonsrute, individuell respons ovenfor den aktive forbindelsen, type preparat og tid eller intervall hvorved administrasjon finner sted. Despite this, it may still be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual response to the active compound, type of preparation and time or interval at which administration takes place.
Foreliggende oppfinnelse blir illustrert ved følgende eksempler. The present invention is illustrated by the following examples.
I eksemplene nedenfor, er prosentandeler i hvert tilfelle basert på vekt; deler er vektde-ler, med mindre annet er angitt. In the examples below, percentages in each case are based on weight; parts are parts by weight, unless otherwise stated.
A. Bestemmelse av fysiologisk aktivitet A. Determination of physiological activity
I. Bestemmelse av kardiovaskulær effekt I. Determination of cardiovascular effect
Etter at toraks har blitt åpnet ble hjertet raskt fjernet fra anestesibehandlede rotter og introdusert i en vanlig Langendorff-apparatur. De koronare arteriene ble perfusert ved konstant volum (10 ml/min.) og det resulterende perfusjonstrykket ble avlest ved hjelp av en passende trykksensor. I dette oppsettet tilsvarer en reduksjon i perfusjonstrykk en relaksasjon av de koronare arteriene. Samtidig blir trykket som hjertet utvikler i løpet av hver kontraksjon målt ved hjelp av en ballong, som har blitt introdusert i venstre ven-trikkel, og en andre trykksensor. Hjertefrekvensen, som er hjerteslag i isolasjon, bereg-nes fra antall kontraksjoner pr. tidsenhet. After the thorax has been opened, the heart was quickly removed from anesthetized rats and introduced into a standard Langendorff apparatus. The coronary arteries were perfused at constant volume (10 ml/min) and the resulting perfusion pressure was read using an appropriate pressure sensor. In this setup, a reduction in perfusion pressure corresponds to a relaxation of the coronary arteries. At the same time, the pressure that the heart develops during each contraction is measured using a balloon, which has been introduced into the left vein trickle, and a second pressure sensor. The heart rate, which is the heartbeat in isolation, is calculated from the number of contractions per unit of time.
I dette eksperimentelle oppsettet ble følgende verdier oppnådd for reduksjon i hjertehastighet (den angitte prosentandelen refererer til reduksjon i hjertehastighet i prosent ved den angjeldende konsentrasjonen): In this experimental setup, the following values were obtained for reduction in heart rate (the percentage indicated refers to the reduction in heart rate in percent at the relevant concentration):
II. Bestemmelse av adenosin Al, A2a, A2b og A3 agonisme II. Determination of adenosine A1, A2a, A2b and A3 agonism
a) Bestemmelse av adenosinagonisme indirekte ved hjelp av genekspresjon a) Determination of adenosine anagonism indirectly by means of gene expression
Celler av CHO (kinesisk hamsterovarie) permanent cellelinje ble transfektert stabilt med cDNA for adenosinreseptorundertypene Al, A2a og A2b. Adenosin Al reseptorene kobles til adenylatcyklase ved hjelp av Gi-proteiner, mens adenosin A2a og A2b reseptorer kobles ved hjelp av Gs-proteiner. Korresponderende med dette, blir dannelsen av cAMP i cellen henholdsvis inhibert eller stimulert. Deretter blir ekspresjon av luciferase modifisert ved hjelp av en cAMP-avhengig promoter. Luciferasetesten optimaliseres med hensyn til høy sensitivitet og reproduserbarhet, lav varians og god egnethet for implementering på et robotsystem, ved å variere flere testparametere, slik som celletett-het, varighet på vekstfase og testinkubering, forskolinkonsentrasjon og mediumsam-mensetning. Følgende testprotokoll anvendes for farmakologisk karakterisering av celler og robotassisert substanstestscreening: Forrådskulturer ble dyrket, ved 37°C og under 5% C02, i DMEM/F12-medium som inneholdt 10% FCS (fosterkalveserum) og i hvert tilfelle splittet 1:10 etter 2-3 dager. Testkulturene ble sådd i 384-brønns plater med en andel på fra 1 000 til 3 000 celler pr. brønn og dyrket ved 37°C i ca. 48 timer. Mediet ble deretter erstattet med en fysiologisk natriumkloirdløsning (130 mM natriumklorid, 5 mM kaliumklorid, 2 mM kalsiumklo-rid, 20 mM HEPES, 1 mM magnesiumklorid 6H20, 5 mM NaHC03, pH 7,49. Substansene, som løses i DMSO, fortynnes 1:10 tre ganger med fysiologisk natriumkloridløs-ning og pipetteres til testkulturene (maksimum sluttkonsentrasjon av DMSO i testblan-dingen: 0,5%). På denne måten ble endelige substanskonsentrasjoner på f.eks. 5 uM til 5 nM oppnådd. 10 minutter senere ble forskolin tilsatt til Al-cellene og alle kulturene ble deretter inkubert ved 37°C i 4 timer. Deretter ble 35 ul av en løsning som besto av 50% lysinreagens (30 mM dinattumhydrogenfosfat, 10% glyserol, 3% TritonXlOO, 25 mM TrisHCl, 2 mM ditiotreitol (DTT), pH 7,8) og 50% luciferasesubstratløsning (2,5 mM ATP, 0,5 mM luciferin, 0,1 mM koenzym A, 10 mM tricin, 1,35 mM magnesiumsulfat, 15 mM DTT, pH 7,8) tilsatt til testkulturene og platene ble ristet i ca. 1 minutt og deretter ble luciferaseaktiviteten målt ved anvendelse av et kamerasystem. Adenosina-nalogforbindelse NECA (5-N-etylkarboksamidoadenosin), som bindes til alle adenosinreseptorundertyper med høy affinitet og fremviser en agonistist effekt, anvendes i disse tre eksperimentene som referanseforbindelse (Klotz, K.N., Hessling, J., Hegler, J., Owman, C, Kull, B., Fredholm, B.B., Lohse, M.J., Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells, Naunyn Schmiedebergs Arch Pharmacol., 357 (1998), 1-9). Cells of the CHO (Chinese Hamster Ovary) permanent cell line were stably transfected with cDNA for adenosine receptor subtypes A1, A2a and A2b. Adenosine A1 receptors are connected to adenylate cyclase by means of Gi proteins, while adenosine A2a and A2b receptors are connected by means of Gs proteins. Corresponding to this, the formation of cAMP in the cell is respectively inhibited or stimulated. Then, expression of luciferase is modified using a cAMP-dependent promoter. The luciferase test is optimized with regard to high sensitivity and reproducibility, low variance and good suitability for implementation on a robotic system, by varying several test parameters, such as cell density, duration of growth phase and test incubation, forskolin concentration and medium composition. The following test protocol is used for pharmacological characterization of cells and robot-assisted substance test screening: Stock cultures were grown, at 37°C and under 5% CO2, in DMEM/F12 medium containing 10% FCS (fetal calf serum) and in each case split 1:10 after 2 -3 days. The test cultures were seeded in 384-well plates with a proportion of from 1,000 to 3,000 cells per well. well and cultured at 37°C for approx. 48 hours. The medium was then replaced with a physiological sodium chloride solution (130 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 20 mM HEPES, 1 mM magnesium chloride 6H 2 O, 5 mM NaHCO 3 , pH 7.49. The substances, which are dissolved in DMSO, are diluted 1 :10 three times with physiological sodium chloride solution and pipetted to the test cultures (maximum final concentration of DMSO in the test mixture: 0.5%). In this way, final substance concentrations of, for example, 5 µM to 5 nM were obtained. 10 minutes later forskolin was added to the A1 cells and all cultures were then incubated at 37° C. for 4 hours. Then 35 µl of a solution consisting of 50% lysine reagent (30 mM disodium hydrogen phosphate, 10% glycerol, 3% TritonX100, 25 mM TrisHCl , 2 mM dithiothreitol (DTT), pH 7.8) and 50% luciferase substrate solution (2.5 mM ATP, 0.5 mM luciferin, 0.1 mM coenzyme A, 10 mM tricine, 1.35 mM magnesium sulfate, 15 mM DTT , pH 7.8) was added to the test cultures and the plates were shaken for about 1 minute and then the luciferase activity must lt when using a camera system. Adenosine analog compound NECA (5-N-ethylcarboxamidoadenosine), which binds to all adenosine receptor subtypes with high affinity and exhibits an agonistic effect, is used in these three experiments as a reference compound (Klotz, K.N., Hessling, J., Hegler, J., Owman, C, Kull, B., Fredholm, B.B., Lohse, M.J., Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells, Naunyn Schmiedebergs Arch Pharmacol., 357 (1998), 1-9).
Følgende tabell 1 gir verdiene som oppnås for stimulering av forskjellige adenosinreseptorundertyper ved forskjellige konsentrasjoner av forbindelsen fra eksempel 1 og 6. Tabellen gir %-verdier av de tilsvarende referansestimulusene. De målte verdiene for A2a og A2b reseptorene er verdier i prosent av maksimdsitmulering oppnådd med NECA; de målte verdiene for Al reseptoren er verdier i prosent etterfølgende direkte prestimulering av adenylatcyklasen med 1 umolar forskolin (som tilsvarer 100% verdien). Al-agonister fremviser i henhold til dette en reduksjon i aktivitet av luciferase (målt verdi mindre enn 100%). The following Table 1 gives the values obtained for the stimulation of different adenosine receptor subtypes at different concentrations of the compound from Examples 1 and 6. The table gives % values of the corresponding reference stimuli. The measured values for the A2a and A2b receptors are values in percent of maximal stimulation obtained with NECA; the measured values for the Al receptor are values in percentage following direct prestimulation of the adenylate cyclase with 1 umolar forskolin (which corresponds to the 100% value). A1 agonists accordingly exhibit a reduction in luciferase activity (measured value less than 100%).
b) Bestemmelse av adenosinagonisme direkte ved hjelp av detektering av cAMP Celler av CHO (kinesisk hamsterovarie) permanent cellelinje ble transfektert stabilt med b) Determination of adenosine anagonism directly by detection of cAMP Cells of the CHO (Chinese Hamster Ovary) permanent cell line were stably transfected with
cDNA for adenosinreseptorundertypene Al, A2a, A2b og A3. Binding av substanser til A2a og A2b reseptorundertyper bestemmes ved å måle det intracellulære cAMP-innholdet i disse cellene ved anvendelse av en vanlig radioimmunologisk undersøkelse (cAMP RIA, IBL GmbH, Hamburg, Tyskland). cDNA for adenosine receptor subtypes A1, A2a, A2b and A3. Binding of substances to A2a and A2b receptor subtypes is determined by measuring the intracellular cAMP content in these cells using a standard radioimmunological assay (cAMP RIA, IBL GmbH, Hamburg, Germany).
Når substansene virker som agonister blir binding av substansene uttrykt som en økning i det intracellulære innholdet av cAMP. Adenosinanalogforbindelsen NECA (5-N-etylkarboksamidoadenosin), som binder alle adenosinreseptorundertyper med høy affinitet, men ikke selektivt og fremviser en agonistisk effekt, anvendes som referanseforbindelse i disse eksperimentene (Klotz, K.N., Hessling, J., Hegler, J., Owman, C, Kull, B., Fredholm, B.B., Lohse, M.J., Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells, Naunyn Schmiedebergs Arch Pharmacol. 357 (1998), 1-9). When the substances act as agonists, binding of the substances is expressed as an increase in the intracellular content of cAMP. The adenosine analog compound NECA (5-N-ethylcarboxamidoadenosine), which binds all adenosine receptor subtypes with high affinity but not selectively and exhibits an agonistic effect, is used as a reference compound in these experiments (Klotz, K.N., Hessling, J., Hegler, J., Owman, C, Kull, B., Fredholm, B.B., Lohse, M.J., Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells, Naunyn Schmiedebergs Arch Pharmacol. 357 (1998), 1-9).
Adenosinreseptorene Al og A3 kobles til et Gj-protein, dvs. stimulering av disse reseptorene fører til inhibering av adenylatcyklase og som en konsekvens av dette til en reduksjon i det intracellulære cAMP-nivået. For å identifisere Al/A3-reseptoragonister, ble adenylatcyklasen stimulert med forskolin. Imidlertid inhiberer en ytterligere stimu-leiing av Al/A3-reseptorene adenylatcyklasen, hvilket betyr at A1/A3-reseptoragonistene kan detekteres med et sammenligningsvis lavt innhold av cAMP i cellen. The adenosine receptors A1 and A3 are connected to a Gj protein, i.e. stimulation of these receptors leads to inhibition of adenylate cyclase and, as a consequence, to a reduction in the intracellular cAMP level. To identify A1/A3 receptor agonists, the adenylate cyclase was stimulated with forskolin. However, further stimulation of the A1/A3 receptors inhibits the adenylate cyclase, which means that the A1/A3 receptor agonists can be detected with a comparatively low content of cAMP in the cell.
For å detektere en antagonistisk effekt på adenosinreseptoren, ble rekombinante celler som ble transfektert med den korresponderende reseptoren prestimulert med NECA og effekten av substansen når det gjelder å redusere det intracellulære innholdet av cAMP ledsaget ved denne prestimuleringen ble undersøkt. XAC (xantinaminkongener), som binder til alle adenosinreseptorundertypene med høy affinitet og fremviser en antagonistisk effekt ble anvendt som referanseforbindelse i disse eksperimentene (Muller, C.E., Stein, B., Adenosine receptor antagonists: structures and potential therapeutic applica-tions, Current Pharmaceutical Design, 2 (1996) 501-530). To detect an antagonistic effect on the adenosine receptor, recombinant cells transfected with the corresponding receptor were prestimulated with NECA and the effect of the substance in reducing the intracellular content of cAMP accompanied by this prestimulation was investigated. XAC (xanthine amine congeners), which binds to all adenosine receptor subtypes with high affinity and exhibits an antagonistic effect, was used as a reference compound in these experiments (Muller, C.E., Stein, B., Adenosine receptor antagonists: structures and potential therapeutic applications, Current Pharmaceutical Design , 2 (1996) 501-530).
III. Farmakokinetiske undersøkelser III. Pharmacokinetic studies
Farmakokinetiske data ble bestemt etter administrasjon av forskjellige substanser i.v. eller p.o. som løsninger til mus, rotter og hunder. For dette formålet ble blodprøver sam-let opp opptil 24 timer etter administrasjon. Konsentrasjonene av uforandret substans ble bestemt ved bioanalytiske fremgangsmåter (HPLC eller HPLC-MS) i plasmaprøver som ble oppnådd fra blodprøvene. Farmakokinetiske parametere ble deretter bestemt fra plasmakonsentrasjontidsforløpet som hadde blitt oppnådd på denne måte. Følgende tabell 2 gir bioulgjengeligheten i forskjellige arter. Pharmacokinetic data were determined after administration of various substances i.v. or p.o. as solutions for mice, rats and dogs. For this purpose, blood samples were collected up to 24 hours after administration. The concentrations of unchanged substance were determined by bioanalytical methods (HPLC or HPLC-MS) in plasma samples obtained from the blood samples. Pharmacokinetic parameters were then determined from the plasma concentration time course thus obtained. The following Table 2 gives the bioavailability in different species.
B. Arbeidseksempler B. Work examples
Forkortelser anvendt: Abbreviations used:
DBU l>8-diazabicyklo[5.4.0]undek-7-en DBU 1>8-diazabicyclo[5.4.0]undec-7-ene
DMF dimetylformamid DMF dimethylformamide
ESI elektrosprayionisering (for MS) ESI electrospray ionization (for MS)
HEPES 2-[4-(2-hydroksyetyl)pipei^ino]etansulfonsyre HEPES 2-[4-(2-hydroxyethyl)pipeline]ethanesulfonic acid
HPLC høytrykks, høyytelsesvæskekromatografi HPLC high-pressure, high-performance liquid chromatography
b.p. kokepunkt b.p. boiling point
MS massespektroskopi MS mass spectroscopy
NMR kjernemagnetisk resonansspektroskopi NMR nuclear magnetic resonance spectroscopy
p.a. pro analysi on. pro analysis
RT romtemperatur RT room temperature
Tris 2-arnino-2-hydroksymetyl)-1,3 -propandiol Tris 2-amino-2-hydroxymethyl)-1,3-propanediol
Fremstillingseksempel Manufacturing example
Eksempel 1 Example 1
2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-[(3-pyri^ dikarbonitril 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(3-pyri^dicarbonitrile
Trinn 1: Step 1:
4-(2-metoksyetoksy)benzaldehyd 4-(2-Methoxyethoxy)benzaldehyde
146,5 g (1,2 mol) 4-hydroksybenzaldehyd blir oppløst i DMF, og 20 g (0,12 mol) kali-umjodid, 134,6 g (1,2 mol) kalium tert-butoksid og 170,2 g (1,8 mol) 2-kloretylmetyleter tilsettes. Reaksjonsblandingen røres ved 80°C i 16 timer. For oppar-beiding blir reaksjonsblandingen konsentrert under redusert trykk. Resten tas opp i 11 etylacetat og ekstraheres med 0,51 IN vandig natriumhydroksidløsning. Etylacetatfasen tørkes ved anvendelse av magnesiumsulfat og konsentreres under redusert trykk. Resten 146.5 g (1.2 mol) of 4-hydroxybenzaldehyde is dissolved in DMF, and 20 g (0.12 mol) of potassium iodide, 134.6 g (1.2 mol) of potassium tert-butoxide and 170.2 g (1.8 mol) of 2-chloroethyl methyl ether is added. The reaction mixture is stirred at 80°C for 16 hours. For oppar pickling, the reaction mixture is concentrated under reduced pressure. The residue is taken up in 1 1 ethyl acetate and extracted with 0.51 IN aqueous sodium hydroxide solution. The ethyl acetate phase is dried using magnesium sulphate and concentrated under reduced pressure. The rest
som oppnås etter konsentrasjon destilleres under høyvakuum (kokepunkt: 100°C ved 0,45 mbar). Dette gir 184,2 g (85% av teoretisk) av produktet. which is obtained after concentration is distilled under high vacuum (boiling point: 100°C at 0.45 mbar). This gives 184.2 g (85% of theoretical) of the product.
MS (ESIpos): m/z = 181 (M+H)<+>MS (ESIpos): m/z = 181 (M+H)<+>
'H-NMR (300 MHz, CDC13): 8 = 3,5 (s, 3H), 3,8 (tr, 2H), 4,2 (tr, 2H), 7,0 (d, 2H), 7,8 (d,lH),9,9(s, 1H). 1H NMR (300 MHz, CDCl 3 ): δ = 3.5 (s, 3H), 3.8 (tr, 2H), 4.2 (tr, 2H), 7.0 (d, 2H), 7 .8 (d, 1H), 9.9 (s, 1H).
Trinn 2: Step 2:
2-arrimo-4-[4-(2-metoksyetoksy)fenyl]-6-sulfanylpyridin-3,5-dikarbomtri 2-arrimo-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanylpyridine-3,5-dicarbotri
18 g (100 mmol) 4-(2-metoksyetoksy)benzaldehyd, 10 g (200 mmol) cyanotioacetamid og 20,2 g (200 mmol) N-metylmorfolin i 100 ml etanol varmes til refluks i 3 timer. Etter avkjøling blir de presipiterte krystallene filtrert fra med sug, vasket med litt etanol og tørket under redusert trykk. Dette gir 12 g (31% av teoretisk) av produkt som inneholder 0,5 mol ekvivalent N-metylmorfolin. 18 g (100 mmol) of 4-(2-methoxyethoxy)benzaldehyde, 10 g (200 mmol) of cyanothioacetamide and 20.2 g (200 mmol) of N-methylmorpholine in 100 ml of ethanol are heated to reflux for 3 hours. After cooling, the precipitated crystals are filtered off with suction, washed with a little ethanol and dried under reduced pressure. This gives 12 g (31% of theoretical) of product containing 0.5 mol equivalent of N-methylmorpholine.
MS (ESIpos): m/z = 327 (M+H)<+>MS (ESIpos): m/z = 327 (M+H)<+>
'H-NMR (300 MHz, DMSO-de): 8 = 2,8 (tr, 4H, N-metylmorfolinsignal), 3,3 (s, 3H), 3,7 (m, 2H + 4H N-metylmorfolinsignal), 4,2 (tr, 2H), 7,1 (d, 2H), 7,4 (d, 2H), 7,6 (s, bred, 2H). 'H-NMR (300 MHz, DMSO-de): δ = 2.8 (tr, 4H, N-methylmorpholine signal), 3.3 (s, 3H), 3.7 (m, 2H + 4H N-methylmorpholine signal) , 4.2 (tr, 2H), 7.1 (d, 2H), 7.4 (d, 2H), 7.6 (s, broad, 2H).
Trinn 3: 2-armno-4-[4-(2-metoksyetoksy)fenyl]-6-[(3-pyri^ dikarbonitril Step 3: 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(3-pyri^dicarbonitrile
4,28 g (11,36 mmol; utgangsmaterialet inneholdt 0,5 molekvivalent av N-metylmorfolin; følgelig var renheten 86,6%) 2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-sulfanylpyridin-3,5-karbonitril løses i 40 ml DMF p.a., 3,34 g (39,75 mmol) natriumbikarbonat og 2,48 g (15,1 mmol) 3-pikolylkloridhydroklorid blir deretter tilsatt. Suspensjonen røres ved romtemperatur over natten, 40 ml etanol tilsettes og blandingen blir vannet til ca. 40°C. 19 ml vann blir deretter tilsatt dråpevis. Presipitatet filtreres fra med sug og tørkes under redusert trykk. Dette gir 3,70 g (78% av teori) av produktet. 4.28 g (11.36 mmol; the starting material contained 0.5 mol equivalent of N-methylmorpholine; consequently the purity was 86.6%) 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanylpyridine- 3,5-carbonitrile is dissolved in 40 ml of DMF p.a., 3.34 g (39.75 mmol) of sodium bicarbonate and 2.48 g (15.1 mmol) of 3-picolyl chloride hydrochloride are then added. The suspension is stirred at room temperature overnight, 40 ml of ethanol is added and the mixture is diluted to approx. 40°C. 19 ml of water is then added dropwise. The precipitate is filtered off with suction and dried under reduced pressure. This gives 3.70 g (78% of theory) of the product.
MS (ESIpos): m/z = 418 (M+H)<+>MS (ESIpos): m/z = 418 (M+H)<+>
'H-NMR (300 MHz, DMSO-de): 8 = 3,3 (s, 3H), 3,7 (tr, 2H), 4,2 (tr, 2H), 4,5 (s, 2H), 7,1 (d, 2H), 7,35 (dd, 1H), 7,45 (d, 2H), 7,9 (d tr, 1H), 8,1 (s, bred, 2H), 8,45 (dd, 1H), 8,75 (d, 1H). 1H NMR (300 MHz, DMSO-de): δ = 3.3 (s, 3H), 3.7 (tr, 2H), 4.2 (tr, 2H), 4.5 (s, 2H) , 7.1 (d, 2H), 7.35 (dd, 1H), 7.45 (d, 2H), 7.9 (d tr, 1H), 8.1 (s, wide, 2H), 8 .45 (dd, 1H), 8.75 (d, 1H).
Eksempel 2 Example 2
2-ammo-6-[(2-klor-l,3-itazol-4-yl)metylsulf^ 3,5-dikarbonitril 2-Ammo-6-[(2-chloro-1,3-itazol-4-yl)methylsulf, 3,5-dicarbonitrile
100 mg (0,31 mmol) 2-amino-4-[4-(2-metoksyetoksy)f(myl]-6-sidfanyl-pyranyl-3,5-dikarbonitril løses i 1 ml DMF. 103 mg (1,23 mmol) natriumbikarbonat og 77,2 mg (0,46 mmol) 4-klormetyl-2-klor-l,3-tiazol blir deretter tilsatt. Denne suspensjonen ristes ved romtemperatur over natten og vann tilsettes. Presipitatet filtreres fra med sug, vaskes med etanol og dietyleter og tørkes ved 40°C under redusert trykk. Dette gir 123 mg (88% av teoretisk) av produktet. 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)f(myl)-6-sidphanyl-pyranyl-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 77.2 mg (0.46 mmol) of 4-chloromethyl-2-chloro-1,3-thiazole are then added. This suspension is shaken at room temperature overnight and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure This gives 123 mg (88% of theory) of the product.
MS (ESIpos): m/z = 458 (M+H)<+>MS (ESIpos): m/z = 458 (M+H)<+>
'H-NMR (300 MHz, DMSO-de): 8 = 3,3 (s, 3H), 3,7 (tr, 2H), 4,2 (tr, 2H), 4,5 (s, 2H), 7,1 (d, 2H), 7,45 (d, 2H), 7,8 (s, 1H), 8,05 (s, bred, 2H). 1H NMR (300 MHz, DMSO-de): δ = 3.3 (s, 3H), 3.7 (tr, 2H), 4.2 (tr, 2H), 4.5 (s, 2H) , 7.1 (d, 2H), 7.45 (d, 2H), 7.8 (s, 1H), 8.05 (s, broad, 2H).
Eksempel 3 Example 3
2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-[(2-fenyl-l,3-tiazol-4-yl)metyl-sulfanyl]pyridin-3,5-dikarbonitril 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-phenyl-1,3-thiazol-4-yl)methyl-sulfanyl]pyridine-3,5-dicarbonitrile
100 mg (0,31 mmol) 2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-sulfanyl-pyridin-3,5-dikarbonitril løses i 1 ml DMF. 103 mg (1,23 mmol) natriumbikarbonat og 96,4 mg (0,46 mmol) 4-klormetyl-2-fenyl-1,3 -tiazol blir deretter tilsatt. Suspensjonen ristes ved romtemperatur over natten og vann tilsettes. Presipitatet filtreres fra med sug, vaskes med etanol og dietyleter og tørkes ved 40°C under redusert trykk. Dette gir 149 mg (97% av teoretisk) av produktet. 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-phenyl-1,3-thiazole are then added. The suspension is shaken at room temperature overnight and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40°C under reduced pressure. This gives 149 mg (97% of theoretical) of the product.
MS (ESIpos): m/z = 500 (M+H)<+>MS (ESIpos): m/z = 500 (M+H)<+>
tø-NMR (300 MHz, DMSO-de): 8 = 3,3 (s, 3H), 3,7 (tr, 2H), 4,2 (tr, 2H), 4,5 (s, 2H), 7,1 (d, 2H), 7,5 (m, 5H), 7,8 (s, 1H), 7,9 (m, 2H), 8,05 (s, bred, 2H). melting NMR (300 MHz, DMSO-de): δ = 3.3 (s, 3H), 3.7 (tr, 2H), 4.2 (tr, 2H), 4.5 (s, 2H), 7.1 (d, 2H), 7.5 (m, 5H), 7.8 (s, 1H), 7.9 (m, 2H), 8.05 (s, broad, 2H).
Eksempel 4 Example 4
2-armno-4-[4-(2-metoksyetoksy)fenyl]-6-[(2-tiofen-2-yl)-1,3-tiazol-4-ylJmetylsulfanyllpyirdin-S^-dikarbonitril 2-armino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-thiophen-2-yl)-1,3-thiazol-4-yl]methylsulfanylpyridine-S^-dicarbonitrile
100 mg (0,31 mmol) 2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-sulfanyl-pyridin-3,5-dikarbonitril løses i 1 ml DMF. 103 mg (1,23 mmol) natriumbikarbonat og 96,4 mg (0,46 mmol) 4-klormetyl-2-(tiofen-2-yl)-l,3-tiazol blir deretter tilsatt. Suspensjonen ristes ved romtemperatur over natten og vann tilsettes. Presipitatet filtreres fra med sug, vaskes med etanol og dietyleter og tørkes ved 40°C under redusert trykk. Dette gir 146 mg (84% av teoretisk) av produktet. 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-(thiophen-2-yl)-1,3-thiazole are then added. The suspension is shaken at room temperature overnight and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40°C under reduced pressure. This gives 146 mg (84% of theoretical) of the product.
MS (ESIpos): m/z = 506 (M+H)<+>MS (ESIpos): m/z = 506 (M+H)<+>
<t>ø-NMR (300 MHz, DMSO-de): 8 = 3,3 (s, 3H), 3,7 (tr, 2H), 4,2 (tr, 2H), 4,6 (s, 2H), 7,15 (m, 3H), 7,5 (d, 2H), 7,65 (d, 1H), 7,75 (d, 1H), 7,8 (s, 1H), 8,1 (s, bred, 2H). <t>ø-NMR (300 MHz, DMSO-de): δ = 3.3 (s, 3H), 3.7 (tr, 2H), 4.2 (tr, 2H), 4.6 (s, 2H), 7.15 (m, 3H), 7.5 (d, 2H), 7.65 (d, 1H), 7.75 (d, 1H), 7.8 (s, 1H), 8, 1 (s, wide, 2H).
Eksempel 5 Example 5
2-aniino-4-[4-(2-metoksyetoksy)fenyl]-6-[(2-tiofen-3-yl)-l,3-tiazol-4-yl)metylsulfanyl]pyridin-3,5-dikarbonitril 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-thiophen-3-yl)-1,3-thiazol-4-yl)methylsulfanyl]pyridine-3,5-dicarbonitrile
100 mg (0,31 mmol) 2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-sulfanyl-pyridin-3,5-dikarbonitril løses i 1 ml DMF. 103 mg (1,23 mmol) natriumbikarbonat og 96,4 mg (0,46 mmol) 4-klorrnetyl-2-(tiofen-3 -yl)-1,3 -tiazol blir deretter tilsatt. Suspensjonen 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-(thiophen-3-yl)-1,3-thiazole are then added. The suspension
ristes ved romtemperatur over natten og vann tilsettes. Presipitatet filtreres fra med sug, vaskes med etanol og dietyleter og tørkes ved 40°C under reduser trykk. Dette gir 141 mg (82% av teoretisk) av produktet. is shaken at room temperature overnight and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40°C under reduced pressure. This gives 141 mg (82% of theoretical) of the product.
MS (ESIpos): m/z = 506 (M+H)<+>MS (ESIpos): m/z = 506 (M+H)<+>
<!>H-NMR (300 MHz, DMSO-d*): 8 = 3,3 (s, 3H), 3,7 (tr, 2H), 4,2 (tr, 2H), 4,6 (s, 2H), 7,15 (d, 2H), 7,5 (d, 2H), 7,55 (d, 1H), 7,7 (dd, 1H), 7,8 (s, 1H), 8,1 (s, bred, 2H), 8,15 (d, 1H). <!>H-NMR (300 MHz, DMSO-d*): δ = 3.3 (s, 3H), 3.7 (tr, 2H), 4.2 (tr, 2H), 4.6 (s , 2H), 7.15 (d, 2H), 7.5 (d, 2H), 7.55 (d, 1H), 7.7 (dd, 1H), 7.8 (s, 1H), 8 .1 (s, wide, 2H), 8.15 (d, 1H).
Eksempel 6 Example 6
2-ammo-6-({[2-(4-Uorfenyl)-l,3-tiazol-4-yl]metyl}sulfanyl)-4-[4-(2-hydroksyetoksy)fenyl]pyridm-3,5-dikarbonitril 2-amino-6-({[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-[4-(2-hydroxyethoxy)phenyl]pyridin-3,5- dicarbonitrile
Rute 1: Route 1:
1. trinn: 1 step:
2-ammo-4-[4-(2-hydtoksyetoksy)fenyl]-6-sulf^ 2-Ammo-4-[4-(2-hydoxyethoxy)phenyl]-6-sulf
12,46 g (75 mmol) 4-(2-hydroksyetoksy)benzaldehyd, 15,02 g (150 mmol) cyanotioacetamid og 15,15 g (150 mmol) N-metylmorfolin blir først blandet sammen i 75 ml etanol og varmet til refluks i 3 timer. Etter avkjøling blir reaksjonsløsningen konsentrert under redusert trykk. Resten løses i IN vandig natriumhydroksidløsning og vaskes to ganger 12.46 g (75 mmol) of 4-(2-hydroxyethoxy)benzaldehyde, 15.02 g (150 mmol) of cyanothioacetamide and 15.15 g (150 mmol) of N-methylmorpholine are first mixed together in 75 ml of ethanol and heated to reflux for 3 hours. After cooling, the reaction solution is concentrated under reduced pressure. The residue is dissolved in IN aqueous sodium hydroxide solution and washed twice
med etylacetat. Den vandige natriumhydroksidfasen surgjøres med IN saltsyre og de presipiterte krystallene filtreres fra med sug og tørkes under redusert trykk ved 45°C. Dette gir 12,05 g (51% av teoretisk) av produktet. with ethyl acetate. The aqueous sodium hydroxide phase is acidified with IN hydrochloric acid and the precipitated crystals are filtered off with suction and dried under reduced pressure at 45°C. This gives 12.05 g (51% of theoretical) of the product.
MS (ESIpos): m/z = 313 (M+H)<+>, 330 (M+NH4)<+>MS (ESIpos): m/z = 313 (M+H)<+>, 330 (M+NH4)<+>
'H-NMR (300 MHz, DMSO-de): 8 = 3,7 (t, 2H), 4,1 (t, 2H), 7,1 (d, 2H), 7,4 (d, 2H), 8,0 (brs,2H). 1H NMR (300 MHz, DMSO-de): δ = 3.7 (t, 2H), 4.1 (t, 2H), 7.1 (d, 2H), 7.4 (d, 2H) , 8.0 (brs, 2H).
2. trinn: 2-arrrino-6-({[2-(4-klorf^ hydroksyetoksy)fenyl]pyri^ 2nd step: 2-amino-6-({[2-(4-chlorof^hydroxyethoxy)phenyl]pyri^
6,91 g (22,12 mmol) 2-ammo-4-[4-(2-hydroksyetoksy)f^ dikarbonitril løses i 150 ml DMF. 7,44 g (66,35 mmol) l,8-diazabicyklo[5.4.0]undec-7-en og 10,8 g (44,24 mmol) 4-klormetyl-2-(4-klorfenyl)-l ,3-tiazol blir deretter tilsatt. Suspensjonen røres ved romtemperatur over natten, 50 g silikagel tilsettes og blandingen konsentreres under redusert trykk. Substansblandingen på silikagel renses med kro-matografi på silikagel (mobilfase: toluen til toluen/etylacetat, 1:1 blanding). Dette gir 5,5 g (47% av teoretisk) av produktet. 6.91 g (22.12 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)-dicarbonitrile are dissolved in 150 ml of DMF. 7.44 g (66.35 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 10.8 g (44.24 mmol) 4-chloromethyl-2-(4-chlorophenyl)-1, 3-thiazole is then added. The suspension is stirred at room temperature overnight, 50 g of silica gel is added and the mixture is concentrated under reduced pressure. The substance mixture on silica gel is purified by chromatography on silica gel (mobile phase: toluene to toluene/ethyl acetate, 1:1 mixture). This gives 5.5 g (47% of theoretical) of the product.
MS (ESIpos): m/z = 521 (M+H)<+>MS (ESIpos): m/z = 521 (M+H)<+>
'H-NMR (300 MHz, DMSO-dé): 8 = 3,7 (dt, 2H), 4,1 (t, 2H), 4,6 (s, 2H), 4,9 (t, 1H), 7,1 (d, 2H), 7,4 (d, 2H), 7,5 (d, 2H), 7,9 (m, 3H), 8,1 (br s, 2H). 1H NMR (300 MHz, DMSO-dé): δ = 3.7 (dt, 2H), 4.1 (t, 2H), 4.6 (s, 2H), 4.9 (t, 1H) , 7.1 (d, 2H), 7.4 (d, 2H), 7.5 (d, 2H), 7.9 (m, 3H), 8.1 (br s, 2H).
Rute 2: Route 2:
Alternativt kan produktet også fremstilles uten å isolere 2-amino-4-[4-(2-hydroksyetoksy)fenyl]-6-sulfanyl-3,5-pyridmdikarbonitril ved omsetting av 2-[4-(2-hydroksyetoksy)-benzyliden]malonitril med 2-cyanotioacetamid og 4-klor-metyl-2-(4-klorfenyl)-! ,3-tiazol: Alternatively, the product can also be prepared without isolating 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanyl-3,5-pyrimidinedicarbonitrile by reaction of 2-[4-(2-hydroxyethoxy)-benzylidene] malonitrile with 2-cyanothioacetamide and 4-chloromethyl-2-(4-chlorophenyl)-! ,3-thiazole:
/. trinn: /. steps:
2-[4-(2-hydroksyetoksy)-^ 1 000 g (5,85 mol) av 4-(2-hydroksyetoksy)benzaldehyd og 425 g (6,43 mol) malondi-nitril løses i 5 000 ml isopropylalkohol og 5 g (0,059 mol) piperidin tilsettes. Blandingen varmes til 80°C i 16 timer og avkjøles deretter til 3°C for å isolere produktet. Produktet filtreres fra og vaskes med 400 ml iskald isopropylalkohol. Deretter blir blandingen tørket i vakuum (40 mbar) ved 50°C i 45 timer. 2-[4-(2-Hydroxyethoxy)-^ 1,000 g (5.85 mol) of 4-(2-hydroxyethoxy)benzaldehyde and 425 g (6.43 mol) malondi-nitrile are dissolved in 5,000 ml of isopropyl alcohol and 5 g (0.059 mol) piperidine is added. The mixture is heated to 80°C for 16 hours and then cooled to 3°C to isolate the product. The product is filtered off and washed with 400 ml of ice-cold isopropyl alcohol. The mixture is then dried in vacuum (40 mbar) at 50°C for 45 hours.
Utbytte: 1 206 g (94,6% av teoretisk) av svakt gule krystaller Yield: 1206 g (94.6% of theory) of pale yellow crystals
<*>H (400 MHz, CDC13): 3,95-4,32 (m, 4H), 6,95-7,15 (m, 2H), 7,61 (s, 1H), 7,85-7,95 (m, 1H). <*>H (400 MHz, CDC13): 3.95-4.32 (m, 4H), 6.95-7.15 (m, 2H), 7.61 (s, 1H), 7.85- 7.95 (m, 1H).
2. trinn: 2nd step:
4-klormetyl-2-(4-klorfenyl)-l,3-tiazol 4-Chloromethyl-2-(4-chlorophenyl)-1,3-thiazole
171,65 g (1,0 mol) 4-klortiobenzamid ble løst i 550 ml isopropylalkohol og 133,3 g 171.65 g (1.0 mol) of 4-chlorothiobenzamide was dissolved in 550 ml of isopropyl alcohol and 133.3 g
(1,05 mol) 1,3-dikloraceton ble tilsatt ved en temperatur på maksimum 30°C i løpet av 3 timer. Blandingen ble deretter rørt ved 40°C i 5,5 timer og ved 20°C i 10 timer. For å gi fullstendig reaksjon ble blandingen deretter varmet til 55°C i 7,5 timer. Produktet ble isolert ved avkjøling til 10°C og tilsetting av 950 ml vann. pH-verdien ble justert til 4 til 5 ved anvendelse av natriumhydroksidløsning og produktet ble filtrert fra med sug. (1.05 mol) of 1,3-dichloroacetone was added at a temperature of maximum 30°C over 3 hours. The mixture was then stirred at 40°C for 5.5 hours and at 20°C for 10 hours. To give complete reaction, the mixture was then heated to 55°C for 7.5 hours. The product was isolated by cooling to 10°C and adding 950 ml of water. The pH was adjusted to 4 to 5 using sodium hydroxide solution and the product was filtered off with suction.
Utbytte: 220,9 g (91% av teoretisk) av hvite til svakt gule krystaller. Yield: 220.9 g (91% of theory) of white to slightly yellow crystals.
<*>H (400 MHz, CDC13): 4,90 (s, 2H, CH2), 7,5-7,55 (m, 2H), 7,85 (s, 1H, tiazol), 7,9-7,95 (m, 2H). <*>H (400 MHz, CDC13): 4.90 (s, 2H, CH2), 7.5-7.55 (m, 2H), 7.85 (s, 1H, thiazole), 7.9- 7.95 (m, 2H).
3. trinn: 3rd step:
2-ammo-6-({[2-(4-ldorfenyl)-l,3-uazol-4^ hydroksyetoksy)fenyl]-3,5-pyri<fo 2-Ammo-6-({[2-(4-dorphenyl)-1,3-uazol-4-hydroxyethoxy)phenyl]-3,5-pyri<pho
428,4 g (2,0 mol) 2-[4-(2-hydroksyetoksy)-benzyliden]mdonmtril, 108,4 g (1,05 mol) 2-cyanotioacetamid og 244,1 g (1,0 mol) 4-klormetyl-2-(4-klorfenyl)-1,3-tiazol ble suspendert i 3,4 liter metanol og 556,1 g (3,0 mol) tributylamin ble tilsatt i løpet av 60 minutter. Blandingen ble deretter rørt i 20 timer ved romtemperatur og produktet ble filtrert fra. Etter tørking i vakuum, ble det urene produktet (360,8 g, urent utbytte: 70% av teoretisk) suspendert i 3 liter diklormetan og blandingen ble rørt i 2 timer ved 35°C. Produktet ble filtrert fra og tørket ved høyvakuum. Krystallene, som nå er hvite, kan renses ved anvendelse av rekrystallisering fra tetrahydrofuran/vann (1:1). 428.4 g (2.0 mol) 2-[4-(2-hydroxyethoxy)-benzylidene]mdonimtrile, 108.4 g (1.05 mol) 2-cyanothioacetamide and 244.1 g (1.0 mol) 4 -chloromethyl-2-(4-chlorophenyl)-1,3-thiazole was suspended in 3.4 liters of methanol and 556.1 g (3.0 mol) of tributylamine was added over 60 minutes. The mixture was then stirred for 20 hours at room temperature and the product was filtered off. After drying in vacuo, the crude product (360.8 g, crude yield: 70% of theory) was suspended in 3 liters of dichloromethane and the mixture was stirred for 2 hours at 35°C. The product was filtered off and dried under high vacuum. The crystals, which are now white, can be purified using recrystallization from tetrahydrofuran/water (1:1).
Utbytte: 353,5 g (68% av teoretisk) av hvite krystaller Yield: 353.5 g (68% of theory) of white crystals
MS(EI): m/z = 520,00 MS(EI): m/z = 520.00
Eksempel 7 Example 7
2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-[(2-pyridm^ dikarbonitril 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-pyridin^dicarbonitrile
100 mg (0,31 mmol) 2-arnmo-4-[4-(2-metoksyetoksy)fenyl]-6-sulfanyl-pyridin-3,5-dikarbonitril løses i 1 ml DMF. 103 mg (1,23 mmol) natriumbikarbonat og 75,4 mg (0,46 mmol) 2-pikolylkloirdhydroklorid tilsettes deretter. Suspensjonen ristes ved romtemperatur over natten og vann tilsettes. Presipitatet filtreres fra med sug, vaskes med etanol og dietyleter og tørkes ved 40°C under redusert trykk. Dette gir 104 mg (81% av teoretisk) av produktet. 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 75.4 mg (0.46 mmol) of 2-picolyl chloride hydrochloride are then added. The suspension is shaken at room temperature overnight and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40°C under reduced pressure. This gives 104 mg (81% of theoretical) of the product.
MS (ESIpos): m/z = 418 (M+H)<+>MS (ESIpos): m/z = 418 (M+H)<+>
<*>H NMR (300 MHz, DMSO-de): 8 = 3,3 (s, 3H), 3,7 (tr, 2H), 4,2 (tr, 2H), 4,6 (s, 2H), 7,1 (d, 2H), 7,4 (dd, 1H), 7,45 (d, 2H), 7,65 (d, 1H), 7,75 (tr, 1H), 8,0 (s, bred, 2H), 8,5 (d, 1H). Eksempel 8 2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-[(2-metyl-1,3-itazol-4-yl)metyl-sulfanyl]pyridin-3,5-dikarbonitril <*>H NMR (300 MHz, DMSO-de): δ = 3.3 (s, 3H), 3.7 (tr, 2H), 4.2 (tr, 2H), 4.6 (s, 2H ), 7.1 (d, 2H), 7.4 (dd, 1H), 7.45 (d, 2H), 7.65 (d, 1H), 7.75 (tr, 1H), 8.0 (s, wide, 2H), 8.5 (d, 1H). Example 8 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-methyl-1,3-itazol-4-yl)methyl-sulfanyl]pyridine-3,5-dicarbonitrile
100 mg (0,31 mmol) 2-amino-4-[4-(2-metoksyfenyl)fenyl]-6-sulfanyl-pyridin-3,5-dikarbomtril løses i 1 ml DMF. 103 mg (1,23 mmol) natriumbikarbonat og 90,5 mg (0,61 mmol) av 4-klormetyl-2-metyl-1,3 -tiazol blir deretter tilsatt. Suspensjonen ristes ved romtemperatur over natten og vann tilsettes. Presipitatet filtreres fra med sug og tørkes ved 40°C under redusert trykk. Dette gir 88,8 mg (66,2% av teoretisk) av produktet. 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyphenyl)phenyl]-6-sulfanyl-pyridine-3,5-dicarbomtrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 90.5 mg (0.61 mmol) of 4-chloromethyl-2-methyl-1,3-thiazole are then added. The suspension is shaken at room temperature overnight and water is added. The precipitate is filtered off with suction and dried at 40°C under reduced pressure. This gives 88.8 mg (66.2% of theoretical) of the product.
MS (ESIpos): m/z = 438 (M+H)<+>MS (ESIpos): m/z = 438 (M+H)<+>
Eksemne! 9 Eczema! 9
2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-[(2-amino-l,3-tiazol-4-yl)metyl-sulfanyl]pyridin-3,5-dikarbonitril 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-amino-1,3-thiazol-4-yl)methyl-sulfanyl]pyridine-3,5-dicarbonitrile
100 mg (0,31 mmol) 2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-sulfanyl-pyridin-3,5-dikarbonitril løses i 1 ml DMF. 103 mg (1,23 mmol) natriumbikarbonat og 68,3 mg (0,46 mmol) 4-klormetyl-2-amino-l,3-tiazol blir deretter tilsatt. Suspensjonen ristes ved romtemperatur over natten og vann tilsettes. Filtratet filtreres fra med sug, vaskes med etanol og dietyleter og tørkes ved 40°C under redusert trykk. Dette gir 115,9 mg (86,2% av teoretisk) av produktet. 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 68.3 mg (0.46 mmol) of 4-chloromethyl-2-amino-1,3-thiazole are then added. The suspension is shaken at room temperature overnight and water is added. The filtrate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40°C under reduced pressure. This gives 115.9 mg (86.2% of theoretical) of the product.
MS (ESIpos): m/z = 439 (M+H)<+>MS (ESIpos): m/z = 439 (M+H)<+>
Eksempel 10 Example 10
2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-[(2-(2-pyridyl)-13-ti sulfanyl]pyridm-3,5-dikarbonitril 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-(2-pyridyl)-13-thisulfanyl]pyridin-3,5-dicarbonitrile
50 mg (0,15 mmol) 2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-sulfanyl-pyridin-3,5-dikarbonitril løses i 1 ml DMF. 51,5 mg (0,61 mmol) natriumbikarbonat og 58,6 mg 50 mg (0.15 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 51.5 mg (0.61 mmol) sodium bicarbonate and 58.6 mg
(0,23 mmol) 4-klormetyl-2-(2-pyridyl)-l,3-tiazol blir deretter tilsatt. Suspensjonen ristes ved RT over natten og vann tilsettes. Presipitatet filtreres fra med sug, vaskes med etanol og dietyleter og tørkes ved 40°C under redusert trykk. Dette gir 67,4 mg (87,9% av teoretisk) av produktet. (0.23 mmol) of 4-chloromethyl-2-(2-pyridyl)-1,3-thiazole is then added. The suspension is shaken at RT overnight and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40°C under reduced pressure. This gives 67.4 mg (87.9% of theoretical) of the product.
MS (ESIpos): m/z = 501 (M+H)<+>MS (ESIpos): m/z = 501 (M+H)<+>
Eksempel 11 Example 11
2-anuno-4-[4-(2-hydroksyetoksy)fenyl]-6-{[(2-metyl-l,3-tiazol-4-yl)metyl]-sulfanyl}pyridin-3,5-dikarbonitril 2-anuno-4-[4-(2-hydroxyethoxy)phenyl]-6-{[(2-methyl-1,3-thiazol-4-yl)methyl]-sulfanyl}pyridine-3,5-dicarbonitrile
31,2 mg (0,1 mmol) 2-ammo-4-[4-(2-hy(hx)ksyetoksy)fenyl]-6-sulfanyl-pyridin-3,5-dikarbonitril løses i 0,3 ml DMF. 33,6 mg (0,4 mmol) natriumbikarbonat og 26,7 mg (0,15 mmol) 4-metyl-2-klor-l,3-tiazolhydroklorid blir deretter tilsatt. Suspensjonen ris- 31.2 mg (0.1 mmol) of 2-amino-4-[4-(2-hy(hx)oxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile are dissolved in 0.3 ml of DMF. 33.6 mg (0.4 mmol) of sodium bicarbonate and 26.7 mg (0.15 mmol) of 4-methyl-2-chloro-1,3-thiazole hydrochloride are then added. The rice suspension
tes ved romtemperatur over natten, Alteres og renses med preparativ HPLC [kolonne: Macherey-Nagel VP 50/21 Nucleosil 100-5 Cl 8 Nautilus, 20x50 mm; strømningshas-tighet: 25 ml/min.; gradient (A = acetonitril, B = vann + 0,3% trifluoreddiksyre): 0 min. 10% A; 2,0 min. 10% A; 6,0 min. 90% A; 7,0 min. 90% A; 7,1 min. 10% A; 8,0 min. 10% A; deteksjon: 220 nm]. Konsentrasjon av de angjeldende fraksjonene gir 20,2 mg (47,7% av teoretisk) av produktet. tested at room temperature overnight, altered and purified by preparative HPLC [column: Macherey-Nagel VP 50/21 Nucleosil 100-5 Cl 8 Nautilus, 20x50 mm; flow rate: 25 ml/min.; gradient (A = acetonitrile, B = water + 0.3% trifluoroacetic acid): 0 min. 10% A; 2.0 min. 10% A; 6.0 min. 90% A; 7.0 min. 90% A; 7.1 min. 10% A; 8.0 min. 10% A; detection: 220 nm]. Concentration of the relevant fractions yields 20.2 mg (47.7% of theoretical) of the product.
MS (ESIpos): m/z = 424 (M+H)<+>MS (ESIpos): m/z = 424 (M+H)<+>
Eksempel 12 Example 12
2-amino-6-{[(2-amino-l,3-tiazol-4-yl)metyl]sulfanyl}-4-[4-(2-hydroksyetoksy)-fenyl]pyridin-3,5-dikarbonitril 2-amino-6-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfanyl}-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitrile
31,2 mg (0,1 mmol) 2-ammo-4-[4-(2-hydroksyetoksy)fenyl]-6-sulfanyl-pyridin-3,5-dikarbonitril løses i 0,3 ml DMF. 33,6 mg (0,4 mmol) av natriumbikarbonat og 22,3 mg (0,15 mmol) 4-amino-2-klor-1,3-tiazol blir deretter tilsatt. Suspensjonen ristes ved romtemperatur over natten, filtreres og renses med preparativ HPLC [kolonne: Macherey-Nagel VP 50/21 Nucleosil 100-5 C18 Nautilus, 20x50 mm; strømningshastighet: 25 ml/min.; gradient (A = acetonitril, B = vann + 0,3% trifluoreddiksyre): 0 min. 10% A; 2,0 min. 10% A; 6,0 min. 90% A; 7,0 min. 90% A; 7,1 min. 10% A; 8,0 min. 10% A; deteksjon: 220 nm]. Konsentrasjon av angjeldende fraksjon gir 35,7 mg (84,1% av teoretisk) av produktet. 31.2 mg (0.1 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile are dissolved in 0.3 ml of DMF. 33.6 mg (0.4 mmol) of sodium bicarbonate and 22.3 mg (0.15 mmol) of 4-amino-2-chloro-1,3-thiazole are then added. The suspension is shaken at room temperature overnight, filtered and purified by preparative HPLC [column: Macherey-Nagel VP 50/21 Nucleosil 100-5 C18 Nautilus, 20x50 mm; flow rate: 25 ml/min.; gradient (A = acetonitrile, B = water + 0.3% trifluoroacetic acid): 0 min. 10% A; 2.0 min. 10% A; 6.0 min. 90% A; 7.0 min. 90% A; 7.1 min. 10% A; 8.0 min. 10% A; detection: 220 nm]. Concentration of the relevant fraction yields 35.7 mg (84.1% of theoretical) of the product.
MS (ESIpos): m/z = 425 (M+H)<+>MS (ESIpos): m/z = 425 (M+H)<+>
Eksempel 13 Example 13
2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-({[2-(4-morfolinyl)-l,3-^ metyl}sulfanyl)pyrid^-3,5-dikair)ordtril 2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-({[2-(4-morpholinyl)-1,3-^methyl}sulfanyl)pyridin^-3,5-dicair)orthril
Trinn 1: Step 1:
4-[4-(klormetyl)-1,3-tiazol-2-yl]morfolin 4-[4-(chloromethyl)-1,3-thiazol-2-yl]morpholine
11,51 g (78,76 mmol) 4-morfolinkarbotioamid og 10,00 g (78,76 mmol) dikloraceton i 100 ml etanol varmes under refluks i 1 time. Det fargeløse fastestoffet som presipiterer fra den rosa løsningen blir, etter avkjøling, filtrert fra med sug og vasket to ganger med etanol. Dette gir 12,96 g (75% av teoretisk) av produktet. 11.51 g (78.76 mmol) of 4-morpholinecarbothioamide and 10.00 g (78.76 mmol) of dichloroacetone in 100 ml of ethanol are heated under reflux for 1 hour. The colorless solid that precipitates from the pink solution is, after cooling, filtered off with suction and washed twice with ethanol. This gives 12.96 g (75% of theoretical) of the product.
MS (ESIpos): m/z = 219 (M+H)<+>MS (ESIpos): m/z = 219 (M+H)<+>
Trinn 2: 2-amino-4-[4-(2-metoksyetoksy)fenyl]-6-({[2-(4-morfolinyl)-l,3-tiazol-4-yl]-metyl} sulfanyl)pyridin-3,5-dikarbonitril li TY Step 2: 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-({[2-(4-morpholinyl)-1,3-thiazol-4-yl]-methyl} sulfanyl)pyridin- 3,5-dicarbonitrile li TY
MS (ESIpos): m/z = 509 (M+H)<+>MS (ESIpos): m/z = 509 (M+H)<+>
<*>H NMR (300 MHz, DMSO-de): 8 = 3,3 (m, 7H), 3,7 (m, 6H), 4,2 (tr, 2H), 4,4 (s, 2H), 6,95 (s, 1H), 7,15 (d, 2H), 7,45 (d, 2H), 8,0 (s, bred, 2H). <*>H NMR (300 MHz, DMSO-de): δ = 3.3 (m, 7H), 3.7 (m, 6H), 4.2 (tr, 2H), 4.4 (s, 2H ), 6.95 (s, 1H), 7.15 (d, 2H), 7.45 (d, 2H), 8.0 (s, broad, 2H).
Eksemplene listet i tabell 3 fremstilles analogt med eksempel 13. Klormetyltiazoler anvendt som utgangsmaterialer er enten kommersielt tilgjengelige eller kan fremstilles analogt med trinn 1 i eksempel 13. The examples listed in table 3 are prepared analogously to example 13. Chloromethylthiazoles used as starting materials are either commercially available or can be prepared analogously to step 1 in example 13.
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