DK161022B - Imidazoquinoxaline compounds, their preparation and pharmaceutical preparations which comprise the compounds. - Google Patents
Imidazoquinoxaline compounds, their preparation and pharmaceutical preparations which comprise the compounds. Download PDFInfo
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- DK161022B DK161022B DK258289A DK258289A DK161022B DK 161022 B DK161022 B DK 161022B DK 258289 A DK258289 A DK 258289A DK 258289 A DK258289 A DK 258289A DK 161022 B DK161022 B DK 161022B
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Opfindelsen angår hidtil ukendte terapeutisk aktive imi-dazoquinoxalinforbindelser, en fremgangsmåde til fremstilling af disse, og farmaceutiske præparater, hvori forbindelserne indgår. De nye forbindelser er fordelagtige til 5 psykofarmaceutisk anvendelse f.eks. ved behandling af sygdomme i centralnervesystemet, f.eks., som antikrampemid-ler eller anxiolytica.The invention relates to novel therapeutically active imidazoquinoxaline compounds, a process for their preparation, and pharmaceutical compositions comprising the compounds. The new compounds are advantageous for psychopharmaceutical use e.g. in the treatment of central nervous system diseases, for example, as anticonvulsants or anxiolytics.
Det er velkendt (Squires, R.F. and Braestrup, C. i Nature 10 (London) 266 (1977) 732-734) at specifikke områder i centralnervesystemet hos hvirveldyr udviser en stærk specifik affinitet for 1,4- og 1,5-benzodiazepiner. Disse områder kaldes benzodiazepinreceptorer.It is well known (Squires, R.F. and Braestrup, C. in Nature 10 (London) 266 (1977) 732-734) that specific regions of the central nervous system of vertebrates exhibit a strong specific affinity for 1,4- and 1,5-benzodiazepines. These areas are called benzodiazepine receptors.
15 i US patentskrift nr. 4.440.929 omtales imidazoquinoxalin-forbindelser, der i 3-stillingen er substitueret med en carboxylfunktion. Forbindelserne angives at have cardio-tonisk aktivitet. Det fremgår eller antydes derimod på ingen måde, at de kendte forbindelser har affinitet over-20 for benzodiazepinreceptorer, hvorfor det er overraskende, at de omhandlede forbindelser besidder denne affinitet.15 of U.S. Patent No. 4,440,929 discloses imidazoquinoxaline compounds substituted at the 3-position with a carboxyl function. The compounds are reported to have cardiotonic activity. On the other hand, it is by no means evident or suggested that the known compounds have affinity for benzodiazepine receptors, so it is surprising that the compounds of this invention possess this affinity.
Fra dansk fremlæggelsesskrift nr. 154142 kendes imidazo-quinoxalinforbindelser med affinitet over for benzodiaze-25 pinreceptorer, hvor substituenterne i 5- og/eller 6-stillin-gen er forskellige fra de omhandlede forbindelsers 5-methyl/substituerede methylgrupper. Af de i den efterfølgende Tabel 2 anførte data fremgår det tydeligt, at de hos de omhandlede forbindelser nævnte substituenter bevir-30 ker en uventet, større bindingsaffinitet in vitro end de tilsvarende substituenter hos de kendte forbindelser.Danish Patent Specification No. 154142 discloses imidazo-quinoxaline compounds with affinity for benzodiazepine receptors, wherein the substituents at the 5- and / or 6-position are different from the 5-methyl / substituted methyl groups of the compounds of the present invention. From the data set out in the following Table 2, it is evident that the substituents mentioned in the compounds of the present invention have an unexpected, greater binding affinity in vitro than the corresponding substituents of the known compounds.
I dansk fremlæggelsesskrift nr. 155007 beskrives imidazo-quinazolinforbindelser, der foruden forskelle i 4-/6-stil-35 lingen også adskiller sig fra de omhandlede forbindelser ved at være afledt af imidazoquinazolinskelettet. Disse kendte forbindelser udviser ligeledes en langt ringere 1 \Danish Patent Specification No. 155007 describes imidazo-quinazoline compounds which, in addition to differences in the 4- / 6-position, also differ from the compounds in question by being derived from the imidazoquinazoline backbone. These known compounds also exhibit a far inferior 1
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2 bindingsaffinitet in vitro end de.kemisk set, nærmest beslægtede forbindelser omhandlet af den foreliggende opfindelse, hvilket fremgår af de i Tabel 2 nedenfor anførte data.2 bind affinity in vitro than chemically, most closely related compounds of the present invention, as evidenced by the data set forth in Table 2 below.
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Dansk fremlæggelsesskrift nr. 155524 omhandler kondenserede imidazoderivater ligeledes med affinitet for benzodia-zepinreceptorer. De fra dette skrift farmaceutisk bedst egnede forbindelser er modsat de omhandlede forbindelser 10 afledt af pyridopyrazin, og som det fremgår af Tabel 2 udviser disse forbindelser én i forhold til de omhandlede forbindelser meget svagere bindingsaffinitet in vitro.Danish Patent Specification No. 155524 also deals with condensed imidazo derivatives with affinity for benzodiazepine receptors. The pharmaceutically most suitable compounds of this specification are in contrast to the compounds 10 derived from pyridopyrazine, and as shown in Table 2, these compounds exhibit a much weaker binding affinity in vitro.
Imidazoquinoxalinforbindelserne ifølge opfindelsen har 15 den generelle formel IThe imidazoquinoxaline compounds of the invention have the general formula I
tfr - 20 tf tf hvor 25 R3 er -<χ·-α eller CX^R' hvor R' er Cg^-cykloalkyl; 5 30 R er methyl, som eventuelt er substitueret med C^_^-al-kyl, alkoxycarbonyl, pyridyl, morpholino, Cg_7-cycloalkyl, C2<_g-alkenyl, phenalkyl, C^_g-alkylacyl, alkoxyalkyl, al-koxy, phthalimidophenyl, benzyl eller phenyl, som alle er usubstitueret eller substitueret med halogen, C^g-alkyl, 35 amino, azido eller C^_g-alkoxy; og R^ er H, C^_g-alkyl, halogen eller CF^.tfr - 20 tf tf where R3 is - <χ · -α or CXXR R where R 'is Cgg-cycloalkyl; R is methyl optionally substituted with C 1-6 alkyl, alkoxycarbonyl, pyridyl, morpholino, C 1-7 cycloalkyl, C 2-7 alkenyl, phenalkyl, C 1-6 alkylacyl, alkoxyalkyl, alkoxy, phthalimidophenyl, benzyl or phenyl, all of which are unsubstituted or substituted by halogen, C 1-6 alkyl, amino, azido or C 1-6 alkoxy; and R 1 is H, C 1-6 alkyl, halogen or CF 2.
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Forbindelserne ifølge opfindelsen kan fremstilles ved en fremgangsmåde, der omfatter: a) omsætning af en forbindelse med formlen II 5 10 r lp 5 6The compounds of the invention may be prepared by a process comprising: a) reacting a compound of formula II 5 10 r lp 5 6
hvor R og R har ovenstående betydninger og hvor Y er en afgangsgruppe, med en forbindelse med formlen IIIwherein R and R have the above meanings and where Y is a leaving group, with a compound of formula III
15 CN - CH2 - R3 (III) 3 hvor R har ovenstående betydning, til dannelse af en forbindelse ifølge opfindelsen, ellerCN - CH2 - R3 (III) 3 wherein R is as defined above to form a compound of the invention, or
20 b) omsætning af et reaktivt derivat af en forbindelse med den generelle formel IVB) reacting a reactive derivative of a compound of general formula IV
25 IC/T T (IV) 5 625 IC / T T (IV) 5 6
hvor R og R har ovenstående betydninger, med en forbin-30 delse med den generelle formel Vwherein R and R have the above meanings, with a compound of the general formula V
R'- C(«N0H)NH2 (V) hvor R' har ovenstående betydning, til dannelse af en for- 3 35 bindelse med den generelle formel I hvor R erR '- C (' NOH) NH 2 (V) wherein R 'is as defined above to form a compound of general formula I wherein R is
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4 -o* 5 hvor R' har ovenstående betydning.4 -o * 5 where R 'has the above meaning.
Afgangsgruppen, Y, kan være enhver passende afgangsgruppe og, for eksempel, de i amerikanske patenter nr. 4,031,079 10 eller 4,359,420, omtalte, for eksempel, halogen, alkylthio, d.v.s., methylthio, aralkylthio, N-nitrosoalkylamino, al-koxy, mercapto, -0F(0)(0R)2 hvor R er lavere alkyl eller -0P(0)(NR'R") hvor R‘ og R" hver især repræsenterer lavere alkyl eller phenyl, eller sammen med nitrogenatomet, 15 hvortil de er bundet, repræsenterer et heterocyklisk radikal som for eksempel morpholin, pyrrolidin, piperidin eller methylpiperazin. Omsætningen udføres bedst under alkaliske betingelser, f.eks. ved tilstedeværelse af en base, og blandt baser foretrækkes alkalimetal, f.eks., 20 kalium- eller natrium- alkoxider eller hydrider. Omsætningen udføres bedst i et organisk opløsningsmiddel, som ikke reagerer med reaktanterne og produkterne fra omsætningen under omsætningsbetingelserne, specielt et vandfrit opløsningsmiddel og helst et vandfrit aprotisk opløsningsmid-25 del, såsom dimethylformamid (DMF) el.lign. Temperaturområdet, der anvendes, kan ligge indenfor ethvert område, som lader omsætningen forløbe i passende hastighed og uden unødig forsinkelse eller sønderdeling, og et område fra -40°C til omkring stuetemperatur er således sædvanligvis 30 specielt passende.The leaving group, Y, may be any suitable leaving group and, for example, those mentioned in US Patent Nos. 4,031,079 or 4,359,420, for example, halogen, alkylthio, ie, methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -0F (O) (OR) 2 where R is lower alkyl or -0P (O) (NR'R ") where R 'and R" each represent lower alkyl or phenyl, or together with the nitrogen atom to which they are attached , represents a heterocyclic radical such as, for example, morpholine, pyrrolidine, piperidine or methylpiperazine. The reaction is best performed under alkaline conditions, e.g. in the presence of a base, and among bases, alkali metal is preferred, for example, 20 potassium or sodium alkoxides or hydrides. The reaction is best carried out in an organic solvent which does not react with the reactants and products of the reaction under the reaction conditions, especially an anhydrous solvent and preferably an anhydrous aprotic solvent such as dimethylformamide (DMF) or the like. The temperature range used may be within any range which allows the reaction to proceed at an appropriate rate and without undue delay or decomposition, and a range from -40 ° C to about room temperature is thus usually particularly suitable.
Udgangsstofferne kan fremstilles fra kommercielt tilgængelige organiske forbindelser ved anvendelse af velkendte syntesemetoder.The starting materials can be prepared from commercially available organic compounds using well known synthetic methods.
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De farmaceutiske egenskaber af forbindelserne ifølge opfindelsen kan illustreres ved at bestemme deres evne til ( at fortrænge radioaktivt mærket flunitrazepam fra benzo-diazepinreceptorer.The pharmaceutical properties of the compounds of the invention can be illustrated by determining their ability to (displace radiolabeled flunitrazepam from benzodiazepine receptors.
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Fortrængningsaktiviten af forbindelserne ifølge opfindelsen findes ved at bestemme ED^Q-værdien. ED^Q-værdien angiver den dosis (mg/kg) af en testsubstans, som forårsager, at den specifikke binding af flunitrazepam til ben-10 zodiazepinreceptorer i en levende hjerne reduceres til 50% af kontrolværdien.The displacement activity of the compounds of the invention is found by determining the ED The ED ^ value indicates the dose (mg / kg) of a test substance that causes the specific binding of flunitrazepam to benzodiazepine receptors in a living brain to be reduced to 50% of the control value.
En sådan in vivo test udføres som følger: 3 15 Princip. Tyve minutter efter indgivelse af en dosis H- 3 flunitrazepam ( H-FNM) (200 pCi/kg, i.v.) har den speci- 3 fikke binding af H-FNM til hjerne-benzodiazepinrecepto-rer nået sin maximalværdi. Denne specifikke binding af 3 H-FNM kan delvis eller helt forhindres ved samtidig el-20 ler forudgående indgift af farmakologisk aktive benzodi-azepiner og nogle benzodiazepin-lignende stoffer (Chang and Snyder, Eur.J. Pharmacol. 48, 212-218 (1978)).Such an in vivo test is performed as follows: 3 Principle. Twenty minutes after the administration of a dose of H-3 flunitrazepam (H-FNM) (200 µCi / kg, i.v.), the specific binding of H-FNM to brain benzodiazepine receptors has reached its maximum value. This specific binding of 3 H-FNM can be partially or completely prevented by concomitant or prior administration of pharmacologically active benzodiazepines and some benzodiazepine-like substances (Chang and Snyder, Eur. J. Pharmacol. 48, 212-218 ( 1978)).
Testprocedure. Opløsninger af testsubstanser (2 mg/ml) 25 fremstilles i 5% Duphasol-X (TM Duphar, ricinusolie-ethy-lenoxid derivat til emulgering og opløsning af olie og andre vand- uopløselige substanser) ved ultralyd i 10 min ved hjælp af et Branson B15 microtip ultralydapparat (indstilling 7). Grupper på tre mus (hunner, NMR, 18-22 gram) 30 indsprøjtes intraperitonalt med 100 mg/kg af testsubstansen. Femten minutter efter indgift af testsubstansen til- 3 føres musene 4 pCi intravenøst af H-FNM (70-90 pCi/mol) i 200 μΐ fysiologisk saltvandsopløsning. Tyve minutter 3 efter H-FNM indgivelsen aflives musene ved afhugning af 35 hovedet; forhjernen udtages hurtigt (inden for 30 sek) og homogeniseres i 12 ml iskold 25 mM KH2P04, pH 7,1, ved hjælp af et UltraTurrax homogeniseringsapparat udstyret 6Test Procedure. Solutions of test substances (2 mg / ml) are prepared in 5% Duphasol-X (TM Duphar, castor oil-ethylene oxide derivative for emulsifying and dissolving oil and other water-insoluble substances) by ultrasound for 10 minutes using a Branson B15 microtip ultrasound (setting 7). Groups of three mice (females, NMR, 18-22 grams) 30 are injected intraperitoneally with 100 mg / kg of test substance. Fifteen minutes after administration of the test substance, 3 mice are injected 4 µCi intravenously by H-FNM (70-90 µCi / mol) in 200 µΐ physiological saline solution. Twenty minutes 3 after H-FNM administration, mice are sacrificed by cutting off the head; the foreskin is rapidly removed (within 30 sec) and homogenized in 12 ml of ice-cold 25 mM KH2PO4, pH 7.1, by means of an UltraTurrax homogenizer equipped 6
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med en N 10 aksel. To portioner på 1 ml filtreres straks gennem Whatman GF/C glasfiber filtre og vaskes med 2x5 ml af ovennævnte buffer. Mængderne af radioaktivitet på filtrene bestemmes ved konventionel scintillationstælling.with an N 10 shaft. Two 1 ml portions are immediately filtered through Whatman GF / C fiberglass filters and washed with 2x5 ml of the above buffer. The amounts of radioactivity on the filters are determined by conventional scintillation counting.
5 En gruppe ubehandlede mus fungerer som kontrol. En til tre mus indsprøjtes med 25 pg/kg clonazepam i.p. 30 minut- 3 ter før H-FNM til bestemmelse af mængden af non-specifik 3 H-FNM binding, som skal være mellem 8-15% af den totale binding. Når doser af 100 mg/kg hæmmer mere end 50% af 3 10 den specifikke H-flunitrazepambinding, indgives testsubstanser i doser, som er faktorer af 3,16 gange lavere end 100 mg/kg. ED^q for en testsubstans defineres som den dosis, som hæmmer 50% af den specifikke ^H-FNM binding. Specifik binding er mængden af binding i kontroldyr minus 15 mængden, der bindes i clonazepambehandlede mus.5 A group of untreated mice acts as a control. One to three mice are injected with 25 µg / kg clonazepam i.p. 30 minutes 3 hours before H-FNM to determine the amount of non-specific 3 H-FNM binding, which should be between 8-15% of the total binding. When doses of 100 mg / kg inhibit more than 50% of the specific H-flunitrazepam compound, test substances are administered at doses that are factors of 3.16 times lower than 100 mg / kg. ED 2Q for a test substance is defined as the dose which inhibits 50% of the specific 1 H-FNM bond. Specific binding is the amount of binding in control animals minus the amount of binding in clonazepam-treated mice.
Resultater. ED^q-værdien bestemmes fra dosis-respons kurver. Hvis kun en dosis testsubstans administeres, beregnes ED j-Q-vær dien som følger, under forudsætning af, at 20 hæmningen af specifik binding ligger i området 25-75%: EDqq = (administreret dosis) x - mg/kg r C η o 25 — - 1Results. The ED ^ value is determined from dose-response curves. If only one dose of test substance is administered, the ED jQ value is calculated as follows, assuming that the inhibition of specific binding is in the range of 25-75%: EDqq = (administered dose) x - mg / kg r C η o 25 - - 1
L cx JL cx J
hvor C er specifik binding i kontroldyr og C er speci- U Λ ' fik binding i mus behandlet med testsubstans.where C is specific binding in control animals and C is specific- U Λ 'got binding in mice treated with test substance.
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Testresultater, opnået ved at teste nogle af forbindelserne ifølge opfindelsen, vil fremgå af følgende tabel 1.Test results obtained by testing some of the compounds of the invention will appear from the following Table 1.
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7 TABEL 1.7 TABLE 1.
Forbindelse ED5ø (mg/kg) 5-- 2 0,09 6 0,21 1 1,2 10 9 0,61 11 0,47 7 0,75 8 0,23 21 3,1 15 22 2,3 23 0,14 25 1,0 28 1,6 31 I 2,4 20Compound ED 50 (mg / kg) 5--2 0.09 6 0.21 1 1.2 10 9 0.61 11 0.47 7 0.75 8 0.23 21 3.1 15 22 2.3 23 0 , 14 25 1.0 28 1.6 31 I 2.4 20
For at sammenligne de omhandlede forbindelsers bindings-affinitet in vitro med de kendte, kemisk set, nærmest beslægtede forbindelsers affinitet gennemføres følgende 25 test: 3In order to compare the binding affinity of the compounds in vitro with the affinity of the known chemically related compounds, the following tests are performed: 3
In vitro inhibering af H-flunitrazepambinding 30 3In vitro inhibition of H-flunitrazepam binding 30 3
Princip: H-flunitrazepam binder specifikt og med høj af finitet til hjernemembraner hos alle højere pattedyr. Et stofs evne til at hæmme specifik flunitrazepambinding har helt klart sammenhæng med dets affinit for hjernebenzodi-35 azepinreceptorer (Braestrup, C. and Squires, R.F., Eur.-J.Pharmacol. 48, 263-270 (1978)).Principle: H-flunitrazepam binds specifically and with a high degree of finesse to brain membranes in all higher mammals. The ability of a substance to inhibit specific flunitrazepam binding is clearly related to its affinity for brain benzodiazepine receptors (Braestrup, C. and Squires, R.F., Eur.-J.Pharmacol. 48, 263-270 (1978)).
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Frysetørrede bovin-cortexmembraner har vist sig at have samme bindingskarakteristika som friske rottemembraner (Lund, J., Scan.J.Clin.Lab.Invest., 41, 275-280 (1981)).Freeze-dried bovine cortex membranes have been found to have the same binding characteristics as healthy rat membranes (Lund, J., Scan.J.Clin.Lab.Invest., 41, 275-280 (1981)).
5 Test: Frysetørrede bovin-benzodiazepinreceptorpræparater (Prep. 38912 eller efterfølgende præparationer) suspenderes i 40 ml (10 mg/ml) 25 mM KI^PO^, pH 7,1. 25 μΐ test-præparatopløsning sættes til 0,5 ml receptorsuspension- 3 ækvivalenter efterfulgt af 25 μΐ H-flunitrazepamopløsning 10 (1 nM, slutkoncentration); og blandingen inkuberes i 60 min. i et isbad (in duplo). Efter inkubering filtreres prøverne direkte på Whatman GF/C glasfiberfiltre under sug og vaskes straks med 2 x 10 ml iskold buffer. Mængden af radioaktivitet på filtrene bestemmes ved konventionel 15 væskescintillationstælling. Non-specifik binding bestemmes in duplo med clonazepam (100 ng/ml, slutkoncentration) som testopløsning. Specifik binding er total binding minus non- specifik binding.Test: Freeze-dried bovine benzodiazepine receptor preparations (Prep. 38912 or subsequent preparations) are suspended in 40 ml (10 mg / ml) 25 mM KI Add 25 μΐ of test preparation solution to 0.5 ml of receptor suspension - 3 equivalents, followed by 25 μΐ of H-flunitrazepam solution 10 (1 nM, final concentration); and the mixture is incubated for 60 min. in an ice bath (in duplicate). After incubation, the samples are filtered directly onto Whatman GF / C fiberglass filters under suction and washed immediately with 2 x 10 ml ice-cold buffer. The amount of radioactivity on the filters is determined by conventional liquid scintillation counting. Non-specific binding is determined in duplicate with clonazepam (100 ng / ml, final concentration) as test solution. Specific binding is total binding minus non-specific binding.
20 Metode: Testsubstanser opløses i 10 ml vand eller 96% ethanol (om nødvendigt gjort sur med 25 μΐ IN HC1 og varmet på et dampbad i højest 5 minutter) ved en koncentration på 0,22 mg/ml. Der foretages tre fortyndinger i vand eller 48% ethanol (220 ng/ml, 2,2 pg/ml og 22 pg/ml). Kon-25 centrationer på 10, 100 og 1000 ng/ml (slutkoncentration) sættes til dublerende tests. 25-75% hæmning af specifik binding skal være opnået før IC^q beregnes.Method: Test substances are dissolved in 10 ml of water or 96% ethanol (acidified with 25 μΐ IN HCl if necessary and heated in a steam bath for a maximum of 5 minutes) at a concentration of 0.22 mg / ml. Three dilutions are made in water or 48% ethanol (220 ng / ml, 2.2 pg / ml and 22 pg / ml). Concentrations of 10, 100 and 1000 ng / ml (final concentration) are added for duplicate tests. 25-75% inhibition of specific binding must be achieved before calculating IC
Resultater: Testværdien vil blive givet som ICj-q (koncen-30 tration (ng/ml) af testsubstansen, som hæmmer specifik 3 binding af H-flunitrazepam med 50%).Results: The test value will be given as ICj-q (concentration (ng / ml) of the test substance which inhibits specific 3 binding of H-flunitrazepam by 50%).
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9 10 = (anvendt testsubstanskonc. x -— ng/ml 50 Γ co i — - 1 5 L cx - hvor CQ er specifik binding i kontrolforsøg og er specifik binding i testforsøget.9 10 = (applied test substance conc. X -— ng / ml 50 Γ co i - - 1 5 L cx - where CQ is specific binding in control experiment and is specific binding in test test.
10 TABEL 2TABLE 2
tocTGOST
U I5 R° R3 20 Forbindelse R3 X - Y R^ Z - R^ IQ-q (ng/ml) I Ov C'N 0 "™2^2) C'H 0,64 25 II C - N 0 -O^-^d C - H 1,5 30 2 C " N 0 ~Ui3 C"CF3 °'33 6 C " N 0 C_CF3 0,54 35Compound R3 X - YR ^ Z - R ^ IQ-q (ng / ml) I Ov C'N 0 "™ 2 ^ 2) C'H 0.64 25 II C - N 0 -O C - H 1.5 30 2 C "N 0 ~ U 3 C" CF 3 ° 33 33 C "N 0 C_CF 3 0.54 35
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1010
* N* N
IE, title -\JL· C - N O -CHg C - H 11,0 5 * 2D, title C - N 0 -°¾ C - H 10'° * 2D C_N ° “d c " H 19,4 10 ** 1F N - C -CHg 0 C - H 8,9 ** 2, title N - C -CHg 0 C_0C2H5 14,0 15 ,Ο'ν 10 "(I c - N O -°¾ N - H 9,6 20 *** 9D C - N O -CHg N - H 16,0 CH3 «X» 25 Dansk fremlæggelsesskrift nr. 154142IE, title - \ JL · C - NO -CHg C - H 11.0 5 * 2D, title C - N 0 - ° ¾ C - H 10 '° * 2D C_N ° “dc" H 19.4 10 ** 1F N - C -CHg 0 C - H 8.9 ** 2, title N - C -CHg 0 C_0C2H5 14.0 15, Ο'ν 10 "(I c - NO - ° ¾ N - H 9.6 20 *** 9D C - NO -CHg N - H 16.0 CH3 «X» 25 Danish Publication No. 154142
Dansk fremlæggelsesskrift nr. 155007 Dansk fremlæggelsesskrift nr. 155524 \ 1 30 Som det tydeligt fremgår af Tabel 2, indikerer disse data, at methyl/substitueret methyl i 5-stillingen og ændrede/-uændrede substituenter i 6-stillingen hos de omhandlede forbindelser bevirker en udtalt bindingsaffinitet in vitro, sammenlignet med de fra de danske fremlæggelsesskrifter 35 kendte forbindelsers methyl- og isopropylsubstitution.Danish Patent Specification No. 155007 Danish Patent Specification No. 155524 \ 1 30 As is clear from Table 2, these data indicate that methyl / substituted methyl at the 5-position and altered / unchanged substituents at the 6-position of the compounds of the present invention cause a pronounced binding affinity in vitro, compared with the methyl and isopropyl substitution of known compounds from the Danish publication 35.
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1111
Forbindelserne ifølge opfindelsen kan, sammen med et konventionelt hjælpestof, bærestof eller fortyndingsmiddel, og, om ønsket, i form af et farmaceutisk acceptabelt syreadditionssalt heraf, formuleres til farmaceutiske præpara-5 ter og enhedsdoser deraf, og kan i denne fom anvendes på fast form, f.eks. som tabletter eller fyldte kapsler, eller som væsker, såsom opløsninger, suspensioner, emulsioner, eliksirer, eller kapsler fyldt med forbindelsen, alle til oralt brug, i form af suppositorier til rektal 10 administration; eller i form af sterile injektionsopløsninger til parenteral (inklusiv subkutan) brug. Sådanne farmaceutiske præparater og enhedsdosisformer deraf kan omfatte konventionelle ingredienser i konventionelle forhold, med eller uden yderligere aktive forbindelser eller 15 principper, og sådanne enhedsdosisformer kan omfatte enhver passende effektiv centralnervesystem-sygdomslindren-de mængde af den aktive ingrediens i overensstemmelse med den daglige dosis, der tænkes anvendt. Tabletter indeholdende 1-30 mg og nærmere angivet 1 mg aktiv ingrediens 20 per tablet, er således passende repræsentative enhedsdosisformer.The compounds of the invention may, together with a conventional adjuvant, carrier or diluent, and, if desired, in the form of a pharmaceutically acceptable acid addition salt thereof, be formulated into pharmaceutical preparations and unit doses thereof, and may be used in this form in solid form. eg. as tablets or filled capsules, or as liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the compound, all for oral use, in the form of rectal 10 suppositories; or in the form of sterile injection solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional conditions, with or without additional active compounds or principles, and such unit dosage forms may comprise any suitably effective central nervous system disease-relieving amount of the active ingredient in accordance with the daily dosage which conceivably used. Thus, tablets containing 1-30 mg and more specifically 1 mg of active ingredient 20 per tablet are suitably representative unit dosage forms.
Forbindelserne ifølge denne opfindelse kan således anvendes til formulering af farmaceutiske præparater, f.eks., 25 til oral og parenteral indgivelse til pattedyr inkl. mennesker, i overensstemmelse med konventionelle metoder for galenisk farmaci.Thus, the compounds of this invention can be used to formulate pharmaceutical compositions, for example, for oral and parenteral administration to mammals, incl. humans, in accordance with conventional methods of galenic pharmacy.
Konventionelle hjælpestoffer er farmaceutisk acceptable 30 organiske eller uorganiske bærestoffer, der er egnede til parenteral eller oral indgivelse, og som ikke på skadelig måde reagerer med den aktive forbindelse.Conventional excipients are pharmaceutically acceptable organic or inorganic carriers suitable for parenteral or oral administration and which do not adversely react with the active compound.
Eksempler på sådanne bærestoffer er vand, saltopløsninger, 35 alkoholer, polyethylenglycoler, polyhydroxyethoxyleret ricinusolie, gelatine, laktose, amylose, magnesiumstearat, talkum, kiselsyre, fedtsyremonoglycerider og diglycerider,Examples of such carriers are water, saline, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides.
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12 pentaerythritolfedtsyreestre, hydroxymethylcellulose og polyvinylpyrrolidon.12 pentaerythritol fatty acid esters, hydroxymethyl cellulose and polyvinylpyrrolidone.
De farmaceutiske præparater kan, om ønsket, steriliseres 5 og blandes med hjælpestoffer, f.eks. smøremidler, konserveringsmidler, stabilisatorer, befugtningsmidler, emulgeringsmidler, salte der influerer på det osmotiske tryk, buffere og/eller farvestoffer eller lignende, som ikke på skadelig måde reagerer med den aktive forbindelse.The pharmaceutical compositions can, if desired, be sterilized and mixed with adjuvants, e.g. lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts which influence osmotic pressure, buffers and / or dyes or the like, which do not adversely react with the active compound.
1010
Til parenteral indgivelse er injicérbare opløsninger eller suspensioner specielt velegnede, fortrinsvis vandige opløsninger, hvor den aktive forbindelse er opløst i poly-hydroxyleret ricinusolie.For parenteral administration, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions, where the active compound is dissolved in polyhydroxylated castor oil.
1515
Ampuller er passende enhedsdosisformer.Ampoules are appropriate unit dosage forms.
Til oral indgivelse er tabletter, dragéer eller kapsler med talkum og/eller kulhydrat som bærestof eller bindings-20 middel eller lignende, bedst egnede. Bærestoffet bør være laktose og/eller majsstivelse og/eller kartoffelstivelse.For oral administration, tablets, dragees or capsules with talc and / or carbohydrate as carrier or binding agent or the like are most suitable. The carrier should be lactose and / or corn starch and / or potato starch.
En sirup, eliksir eller lignende kan anvendes, når et sødet bærestof kan bruges. Generelt, i bredere anvendelsesområde, dispenseres forbindelsen ifølge opfindelsen i en-25 hedsdosisformer indeholdende 0,05-100 mg i et farmaceutisk acceptabelt bærestof per enhedsdosis.A syrup, elixir or the like can be used when a sweetened carrier can be used. Generally, in a wider field of application, the compound of the invention is dispensed in unit dosage forms containing 0.05-100 mg in a pharmaceutically acceptable carrier per unit dose.
En typisk tablet, som kan fremstilles ved konventionelle tabletfremstillingsteknikker indeholder: 30A typical tablet that can be prepared by conventional tablet manufacturing techniques contains: 30
Aktiv forbindelse 1,0 mgActive compound 1.0 mg
Lactosum 67,8 mg Ph.Eur.Lactosum 67.8 mg Ph.Eur.
Avicel 31,4 mgAvicel 31.4 mg
Amberlite® IRP 88 1,0 mg 35 Magnesii stearas 0,25 mg Ph.Eur.Amberlite® IRP 88 1.0 mg 35 Magnesii stearas 0.25 mg Ph.Eur.
DK 161022 B j 13 På grund af deres høje grad af affinitet til benzodiazepin-receptorerne, er forbindelserne ifølge opfindelsen yderst nyttige i behandlingen af sygdomme eller forstyrrelser i centralnervesystemet, når de administreres i en mængde, der 5 lindrer, bedrer eller fjerner disse. Den vigtige CNS aktivitet af forbindelserne ifølge opfindelsen omfatter både anti-konvulsive og anxiolytiske virkninger og lav toksicitet, hvilket tilsammen giver et yderst gunstigt terapeutisk index. Forbindelserne ifølge opfindelsen kan således indgives 10 til et individ, f.eks et menneske eller et dyr, der har behov herfor til behandling, lindring, bedring, eller fjernelse af en centralnervesystemslidelse, knyttet til de såkaldte benzodiazepinreceptorer, som kræver en sådan psykofarmaceutisk behandling, d.v.s., specielt krampe 15 og/eller angsttilstande, om ønsket, i form af et farmaceutisk acceptabelt syreadditionssalt heraf (såsom hydrobro-mid, hydroklorid, eller sulfat, som altid fremstillet på den sædvanlige eller konventionelle måde, f.eks. inddam-pning til tørstof af den frie base i opløsning sammen med 20 syren), sædvanligvis i forbindelse med, samtidig med, eller sammen med et farmaceutisk acceptabelt bærestof eller fortyndingsmiddel, specielt og fortrinsvis i form af et farmaceutisk præparat heraf, enten oralt, rektalt, eller parenteralt (inklusiv subkutant), i en psykopharmaceutisk 25 centralnervesystemslindrende effektiv dosis, d.v.s. en antikrampe- og/ eller anxiolytisk mængde, og under alle omstændigheder en mængde, som er effektiv til lindring af en sådan sygdom i centralnervesystemet, på grund af deres benzodiazepinreceptoraffinitet. Passende dosisområder er 30 1-200 milligram daglig, fortrinsvis 1-100 milligram dag lig, og specielt 1-30 milligram daglig, som altid afhængigt af den faktiske måde hvorpå det indgives, i hvilken form det indgives, hvilket symptom behandlingen er rettet mod, det involverede individ og det involverede individs 35 kropsvægt, samt den ansvarlige læges eller dyr lasges præference og erfaring.Due to their high affinity for the benzodiazepine receptors, the compounds of the invention are extremely useful in the treatment of central nervous system disorders or disorders when administered in an amount that alleviates, ameliorates or removes them. The important CNS activity of the compounds of the invention encompasses both anti-convulsive and anxiolytic effects and low toxicity, which together provides an extremely favorable therapeutic index. Thus, the compounds of the invention may be administered to a subject, for example, a human or animal in need of treatment, relief, amelioration, or removal of a central nervous system disorder associated with the so-called benzodiazepine receptors which require such psychopharmaceutical treatment. i.e., especially cramping and / or anxiety states, if desired, in the form of a pharmaceutically acceptable acid addition salt thereof (such as hydrobromide, hydrochloride, or sulfate, as always prepared in the usual or conventional manner, e.g. dry substance of the free base in solution together with the acid), usually in association with, simultaneously with, or together with a pharmaceutically acceptable carrier or diluent, in particular and preferably in the form of a pharmaceutical composition thereof, either orally, rectally, or parenterally ( including subcutaneously), in a psychopharmaceutical central nervous system relieving effective dose, i.e. an anticonvulsant and / or anxiolytic amount, and in any case an amount effective for relieving such a central nervous system disease because of their benzodiazepine receptor affinity. Suitable dosage ranges are 30-1-200 milligrams daily, preferably 1-100 milligrams daily, and especially 1-30 milligrams daily, as always, depending on the actual manner in which it is administered, in which form it is administered, which symptom the treatment is directed to, the individual body and the individual's body weight involved, as well as the preference and experience of the responsible physician or animal.
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1414
Opfindelsen vil nu blive beskrevet yderligere i detaljer med reference til følgende eksempler: 5 EKSEMPEL 1 a. N-phenethyl-2-nitroanilin 10 En omrørt opløsning af 2-fluoronitrobenzen (14,1 g, 0,1 mol) og triethylamin (14 ml, 0,1 mol) i DMF (150 ml) tilsattes phenethylamin (12,1 g, 0,1 mol). Derefter opvarmedes blandingen til 100°C, og reaktionen overvågedes på TLC. Da reaktionen var tilendebragt (2 timer) fjernedes 15 opløsningsmidlet ved inddampning in vacuo. Inddampnings-resten deltes mellem 0,5 N vandig HC1 (100 ml) og æter (100 ml). Den organiske fase vaskedes med vand, tørredes og inddampedes, hvilket gav titelforbindelsen som en gul olie.The invention will now be further described in detail with reference to the following Examples: EXAMPLE 1 a. N-phenethyl-2-nitroaniline 10 A stirred solution of 2-fluoronitrobenzene (14.1 g, 0.1 mole) and triethylamine (14 ml , 0.1 mole) in DMF (150 mL) was added phenethylamine (12.1 g, 0.1 mole). The mixture was then heated to 100 ° C and the reaction monitored on TLC. When the reaction was complete (2 hours), the solvent was removed by evaporation in vacuo. The residue is partitioned between 0.5 N aqueous HCl (100 ml) and ether (100 ml). The organic phase was washed with water, dried and evaporated to give the title compound as a yellow oil.
20 På lignende måde fremstilledes følgende forbindelser ved reaktion mellem l-fluoro-2-nitrobenzen og de tilsvarende aminer: 25 N-(2-morpholinoethyl)-2-nitroanilin. Smp. 42-44°C.Similarly, the following compounds were prepared by reaction of 1-fluoro-2-nitrobenzene with the corresponding amines: 25 N- (2-morpholinoethyl) -2-nitroaniline. Mp. 42-44 ° C.
N-(2-chlorbenzyl)-2-nitroanilin. Smp. 106-107°CN- (2-chlorobenzyl) -2-nitroaniline. Mp. 106-107 ° C
N-(2-methoxybenzyl)-2-nitroanilin. Smp. 114-115°C.N- (2-methoxybenzyl) -2-nitroaniline. Mp. 114-115 ° C.
3030
N-(2-methoxybenzyl)-2-nitroanilin. Smp. 92-93°CN- (2-methoxybenzyl) -2-nitroaniline. Mp. 92-93 ° C
N-(2-pyridylmethyl)-2-nitroanilin. Smp. 87-88°C.N- (2-pyridylmethyl) -2-nitroaniline. Mp. 87-88 ° C.
35 N-(2-chlorbenzyl)-2-chlor-6-nitroanilin, smp. 69-71°CN- (2-chlorobenzyl) -2-chloro-6-nitroaniline, m.p. 69-71 ° C
fremstilledes fra 2,3-dichlornitrobenzen og 2-chlorben-zylchlorid. Rensning på SiO^ (pentan/æter 15:1).was prepared from 2,3-dichloronitrobenzene and 2-chlorobenzyl chloride. Purification on SiO 2 (pentane / ether 15: 1).
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15 ; b. N-ethoxalyl-2-nitro-6-methylanilin15; b. N-Ethoxalyl-2-nitro-6-methylaniline
En omrørt opløsning af 2-nitro-6-methylanilin (10 g, 65 5 mmol) og triethylamin (11 ml, 80 mmol) i THF (80 ml) sattes dråbevis til en opløsning af ethoxalylchlorid (9 ml, 80 mmol). Da tilsætningen var tilendebragt opvarmedes blandingen til reflux. Efter 3 timer afkøledes blandingen til stuetemperatur og det bundfældede triethylammoniumchlorid 10 filtreredes fra. Filtratet inddampedes, hvilket gav råproduktet som en olie. Rensning (Si02/æter:pentan, 1:1) gav den rene titelforbindelse som en olie.A stirred solution of 2-nitro-6-methylaniline (10 g, 65 mmol) and triethylamine (11 ml, 80 mmol) in THF (80 ml) was added dropwise to a solution of ethoxalyl chloride (9 ml, 80 mmol). When the addition was complete, the mixture was heated to reflux. After 3 hours, the mixture was cooled to room temperature and the precipitated triethylammonium chloride 10 was filtered off. The filtrate was evaporated to give the crude product as an oil. Purification (SiO 2 / ether: pentane, 1: 1) afforded the pure title compound as an oil.
På lignende måde fremstilledes de følgende N-ethoxalyl 15 aniliner ved reaktion mellem ethoxalylchlorid og de tilsvarende aniliner: N-ethoxalyl-N-(2-methoxybenzyl)-2-nitroanilin. Olie 20 N-ethoxalyl-N-(4-methoxybenzyl)-2-nitroanilin. Olie N-ethoxalyl-N-(2-pyridylmethyl)-2-nitroanilin. OlieSimilarly, the following N-ethoxalyl anilines were prepared by reaction of ethoxalyl chloride with the corresponding anilines: N-ethoxalyl-N- (2-methoxybenzyl) -2-nitroaniline. Oil N-ethoxalyl-N- (4-methoxybenzyl) -2-nitroaniline. Oil N-ethoxalyl-N- (2-pyridylmethyl) -2-nitroaniline. Oil
N-(2-chlorbenzyl)-N-ethoxalyl-2-nitroanilin. Smp. 98-25 99°CN- (2-chlorobenzyl) -N-ethoxalyl-2-nitroaniline. Mp. 98-25 99 ° C
N-ethoxalyl-N-(2-morpholinoethyl)-2-nitroanilin. Smp. 75-76°C.N-ethoxalyl-N- (2-morpholinoethyl) -2-nitroaniline. Mp. 75-76 ° C.
30 N-benzyl-N-ethoxalyl-2-nitroanilin. Smp. 170-175°CN-benzyl-N-ethoxalyl-2-nitroaniline. Mp. 170-175 ° C
N-(2-chlorbenzyl)-2-chlor-N-ethoxalyl-6-nitroanilin.N- (2-chlorobenzyl) -2-chloro-N-ethoxalyl-6-nitroaniline.
Smp. 101-102°C.Mp. 101-102 ° C.
35 N-ethoxalyl-N-phenethyl-2-nitroanilin. Olie N-cyclopropylmethyl-N-ethoxalyl-2-nitroanilin. OlieN-ethoxalyl-N-phenethyl-2-nitroaniline. Oil N-cyclopropylmethyl-N-ethoxalyl-2-nitroaniline. Oil
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16 C. N-ethoxalyl-N-methyl-2-nitro-6-methylanilin16 C. N-ethoxalyl-N-methyl-2-nitro-6-methylaniline
NaH (1 g, 22 mmol) sattes i portioner til en omrørt opløs-5 ning af N-ethoxalyl-2-nitro-6-methylanilin (5 g, 20 mmol) i DMF (50 ml). Derefter tilsattes methyljodid (2 ml, 22 mmol). Blandingen henstod natten over ved stuetemperatur, hvorefter opløsningsmidlet fjernedes ved inddampning in vacuo. Inddampningsrestsen deltes mellem æter og vand.NaH (1 g, 22 mmol) was added in portions to a stirred solution of N-ethoxalyl-2-nitro-6-methylaniline (5 g, 20 mmol) in DMF (50 ml). Then methyl iodide (2 ml, 22 mmol) was added. The mixture was allowed to stand overnight at room temperature, after which the solvent was removed by evaporation in vacuo. The evaporation residue is shared between ether and water.
10 Den organiske fase vaskedes med vand, tørredes over Na2&0^ og inddampedes, hvilket gav titelforbindelsen som en olie.The organic phase was washed with water, dried over Na 2 O 2 and evaporated to give the title compound as an oil.
På lignende måde fremstilledes følgende forbindelse ved alkylering af det tilsvarende udgangsstof: 15 N-ethoxalyl-N-ethyl-2-nitro-6-methylanilin (olie) fremstilledes fra N-ethoxalyl-2-nitro-6-methylanilin og ethyl-jodid.Similarly, the following compound was prepared by alkylating the corresponding starting material: N-ethoxalyl-N-ethyl-2-nitro-6-methylaniline (oil) was prepared from N-ethoxalyl-2-nitro-6-methylaniline and ethyl iodide.
20 d. N-ethoxalyl-4-chlor-2-trifluororoethylanilinD. N-ethoxalyl-4-chloro-2-trifluorooroethylaniline
En blanding af 2-amino-5-chlorbenzotrifluorid (14,4 ml, 0,1 mol) og triethylamin (14,0 ml, 0,1 mol) opløstes i 25 tør tetrahydrofuran, THF (250 ml). Denne opløsning tilsattes under omrøring en opløsning af ethoxalylchlorid i THF (50 ml). Da tilsætningen var tilendebragt (30 min.) rørtes blandingen ved stuetemperatur i 3 timer, hvorefter det bundfældede triethylammoniumchlorid filtreredes fra, 30 og filtratet inddampedes in vacuo. Dette gav den rå titelforbindelse (24 g) som blege krystaller. Smp. 55-58°C.A mixture of 2-amino-5-chlorobenzotrifluoride (14.4 ml, 0.1 mol) and triethylamine (14.0 ml, 0.1 mol) was dissolved in dry tetrahydrofuran, THF (250 ml). This solution was added with stirring a solution of ethoxalyl chloride in THF (50 ml). When the addition was complete (30 minutes), the mixture was stirred at room temperature for 3 hours, then the precipitated triethylammonium chloride was filtered off and the filtrate was evaporated in vacuo. This gave the crude title compound (24 g) as pale crystals. Mp. 55-58 ° C.
e. N-ethoxalyl-4-chlor-6-nitro-2-trifluoromethyl-aniline. N-Ethoxalyl-4-chloro-6-nitro-2-trifluoromethyl-aniline
En opløsning af N-ethoxalyl-4-chlor-2-trifluoromethylani-lin i koncentreret svovlsyre (125 ml) tilsattes en omrørt 35A solution of N-ethoxalyl-4-chloro-2-trifluoromethylaniline in concentrated sulfuric acid (125 ml) was added to a stirred solution.
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17 blanding af 100% salpetersyre (120 ml) og koncentreret svovlsyre (240 ml). Temperaturen blev holdt mellem 8-10°C under tilsætningen. Efter at tilsætningen var tilendebragt rørtes opløsningen i yderligere 20 min. uden ekstern af-5 køling, hvorefter den hældtes på isvand. Dette gav bund-fældelse af titelforbindelsen som en olie, som krystalliseredes som svagt gule krystaller ved henstand. Krystallerne filtreredes fra og vaskedes omhyggeligt med vand.17 mixture of 100% nitric acid (120 ml) and concentrated sulfuric acid (240 ml). The temperature was maintained between 8-10 ° C during the addition. After the addition was complete, the solution was stirred for an additional 20 min. without external cooling, after which it was poured into ice water. This precipitated the title compound as an oil which crystallized as pale yellow crystals on standing. The crystals were filtered off and washed thoroughly with water.
Smp. 100-101°C.Mp. 100-101 ° C.
10 f. N-ethoxalyl-N-methyl-4-chlor-6-nitro-2-trifluorome-thylanilin 15 En omrørt opløsning af N-ethoxalyl-4-chlor-6-nitro-2-trifluoromethylanilin (11 g, 32,3 mmol) og methyljodid (3,0 ml, 48 mmol) i tør dimethylformamid (DMF, 50 ml) tilsattes portionsvis natriumhydrid (ialt 1,7 g, 39 mmol).10 f. N-ethoxalyl-N-methyl-4-chloro-6-nitro-2-trifluoromethyl-aniline A stirred solution of N-ethoxalyl-4-chloro-6-nitro-2-trifluoromethylaniline (11 g, 32 3 mmol) and methyl iodide (3.0 ml, 48 mmol) in dry dimethylformamide (DMF, 50 ml) was added portionwise sodium hydride (total 1.7 g, 39 mmol).
Ekstern afkøling blev brugt til at holde reaktionstempera-20 turen under 25°C. Omrøring fortsattes ved stuetemperatur i 3 timer, hvorefter opløsningsmidlet fjernedes ved ind-dampning in vacuo. Inddampningsresten deltes derefter mellem æter og vand. Den organiske fase vaskedes to gange med vand, tørredes over Na^SO^ og inddampedes. Denne be-25 handling gav titelforbindelsen som en olie, som viderefor-arbejdedes uden yderligere rensning.External cooling was used to keep the reaction temperature below 25 ° C. Stirring was continued at room temperature for 3 hours, after which the solvent was removed by evaporation in vacuo. The residue is then divided between ether and water. The organic phase was washed twice with water, dried over Na2 SO4 and evaporated. This treatment gave the title compound as an oil which was continued without further purification.
g. 3,4-dihydro-2-hydroxy-3-oxo-4-methyl-5-trifluoromethyl-quinoxalin-1-oxid 30 -g. 3,4-Dihydro-2-hydroxy-3-oxo-4-methyl-5-trifluoromethyl-quinoxaline-1-oxide
En opløsning af N-ethoxalyl-N-methyl-4-chlor-6-nitro-2-trifluoroanilin (12 g, 32 mmol) og triethylamin (5,6 ml, 32 mmol) i 96% ethanol (150 ml) blev hydrogeneret under 35 standardbetingelser med 5% Pd/C (1 g) som katalysator.A solution of N-ethoxalyl-N-methyl-4-chloro-6-nitro-2-trifluoroaniline (12 g, 32 mmol) and triethylamine (5.6 mL, 32 mmol) in 96% ethanol (150 mL) was hydrogenated under standard conditions with 5% Pd / C (1 g) as catalyst.
Efter at reaktionen var tilendebragt, blev katalysatoren filtreret fra, og opløsningsmidlet fjernedes ved inddamp-After the reaction was complete, the catalyst was filtered off and the solvent was removed by evaporation.
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18 ning. Behandling af inddampningsresten med vand/ethylace-tat (150 ml/50 ml) gav produktet som hvide krystaller, som opsamledes ved filtrering. Smp. 196-198°C.18 ning. Treatment of the residue with water / ethyl acetate (150 ml / 50 ml) gave the product as white crystals which were collected by filtration. Mp. 196-198 ° C.
5 På lignende måde fremstilledes følgende 1-oxid quinoxali-ner: 4-benzy1-3,4-dihydro-2-hydroxy-3-oxo-quinoxalin-1-oxid, smp. 170-175°C ved hydrogenering af N-ethoxalyl-N-benzyl-10 2-nitroanilin 3.4- dihydro-2-hydroxy-4-(2-morpholinoethyl)-3-oxo-quinox-alin-l-oxid. Smp. 170-172°C ved hydrogenering af N-ethox-alyl-N-(2-morpholinoethyl)-2-nitroanilin 15 3.4- dihydro-2-hydroxy-3-oxo-4-phenethyl-quinoxalin-l-oxid, smp. 200-201°C ved hydrogenering af N-ethoxalyl-N-phenethyl-2-nitroanilin 20 4-(2-chlorbenzyl)-3,4-dihydro-2-hydroxy-3-oxo-quinoxa- lin-1-oxid, smp. 250-260°C (sønderdeling.) ved hydrogenering af N-ethoxalyl-N-(2-chlorbenzyl)-2-nitroanilin.Similarly, the following 1-oxide quinoxalines were prepared: 4-benzyl-3,4-dihydro-2-hydroxy-3-oxo-quinoxaline-1-oxide, m.p. 170-175 ° C by hydrogenation of N-ethoxalyl-N-benzyl-2-nitroaniline 3,4-dihydro-2-hydroxy-4- (2-morpholinoethyl) -3-oxo-quinox-aline-1-oxide. Mp. 170-172 ° C by hydrogenation of N-ethox-alyl-N- (2-morpholinoethyl) -2-nitroaniline 3,4-dihydro-2-hydroxy-3-oxo-4-phenethyl-quinoxaline-1-oxide, m.p. 200-201 ° C by hydrogenation of N-ethoxalyl-N-phenethyl-2-nitroaniline 4- (2-chlorobenzyl) -3,4-dihydro-2-hydroxy-3-oxo-quinoxaline-1-oxide, mp. 250-260 ° C (dec.) By hydrogenation of N-ethoxalyl-N- (2-chlorobenzyl) -2-nitroaniline.
RaNi anvendtes som katalysator 25 3,4-dihydro-2-hydroxy-4-(4-methoxybenzyl)-3-oxo-quinoxa-lin-l-oxid, smp. 193-194°C ved hydrogenering af N-ethoxa-lyl-N-(4-methoxybenzyl)-2-nitroanilin 3.4- dihydro-2-hydroxy-4-(2-pyridylmethyl)-3-oxo-quinoxa- 30 lin-1-oxid, smp. 220°C (sønderdeling) ved hydrogenering af N-ethoxalyl-N-(2-pyridylmethyl)-2-nitroanilin 3.4- dihydro-2-hydroxy-4-(2-methoxybenzyl)-3-oxo-quinoxa-lin-1-oxid, smp. 243-244°C ved hydrogenering af N-ethoxa- 35 lyl-N-(2-methoxybenzyl)-2-nitroanilin 19RaNi was used as catalyst 3,4-dihydro-2-hydroxy-4- (4-methoxybenzyl) -3-oxo-quinoxaline-1-oxide, m.p. 193-194 ° C by hydrogenation of N-ethoxyl-N-N- (4-methoxybenzyl) -2-nitroaniline 3,4-dihydro-2-hydroxy-4- (2-pyridylmethyl) -3-oxo-quinoxaline lin 1-oxide, m.p. 220 ° C (dec.) By hydrogenation of N-ethoxalyl-N- (2-pyridylmethyl) -2-nitroaniline 3,4-dihydro-2-hydroxy-4- (2-methoxybenzyl) -3-oxo-quinoxa-lin-1- oxide, m.p. 243-244 ° C by hydrogenation of N-ethoxanol-N- (2-methoxybenzyl) -2-nitroaniline 19
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5-chlor-4-(2-chlorbenzyl)-3,4-dihydro-2-hydroxy-3-oxo-quinoxalin-1-oxid, smp. 222-223°C ved hydrogenering af 2-chlor-N-(2-chlorbenzyl)-N-ethoxalyl-6-nitroanilin. RaNi anvendtes som katalysator 5 4-cyclopropylmethyl-3,4-dihydro-2-hydroxy-3-oxo-quinoxa-lin-l-oxid, smp. 205-206°C.5-chloro-4- (2-chlorobenzyl) -3,4-dihydro-2-hydroxy-3-oxo-quinoxaline-1-oxide, m.p. 222-223 ° C by hydrogenation of 2-chloro-N- (2-chlorobenzyl) -N-ethoxalyl-6-nitroaniline. RaNi was used as catalyst 5 4-cyclopropylmethyl-3,4-dihydro-2-hydroxy-3-oxo-quinoxa-lin-1-oxide, m.p. 205-206 ° C.
10 I visse tilfælde stoppede hydrogeneringen ikke ved quinox-alin-l-oxidet, men ved amino eller quinoxalin oxidationstilstanden.10 In some cases, hydrogenation did not stop at the quinox-aline-1 oxide, but at the amino or quinoxaline oxidation state.
h. 4-ethyl-l,2,3,4-tetrahydro-5-methyl-2,3-dioxo-quinoxa-15 linh. 4-Ethyl-1,2,3,4-tetrahydro-5-methyl-2,3-dioxo-quinoxalin
Hydrogenering af N-ethoxalyl-N-ethyl-6-methyl-2-nitroani-lin under standardbetingelser gav N-ethoxalyl-N-ethyl-2-20 amino-6-methylanilin som en olie. Ringslutning til titelforbindelsen blev foretaget i ethanol/1 N HC1 (50 ml/25 ml) ved reflux i 10 min. Produktet bundfældedes efter afkøling og opsamledes ved filtrering. Smp. >300°C.Hydrogenation of N-ethoxalyl-N-ethyl-6-methyl-2-nitroaniline under standard conditions gave N-ethoxalyl-N-ethyl-2-20 amino-6-methylaniline as an oil. Cycle to the title compound was made in ethanol / 1 N HCl (50 ml / 25 ml) by reflux for 10 min. The product was precipitated after cooling and collected by filtration. Mp. > 300 ° C.
25 i. 4-benzyl-l,2,3,4-tetrahydro-2,3-dioxo-quinoxalin4-Benzyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline
En opløsning af 4-benzyl-l,2,3,4-tetrahydro-2,3-dioxo-qui-noxalin-l-oxid (14,6 g, 54 mmol) og triphenylphosphin (21 30 g, 80 mmol) i dimethylformamid (200 ml) rørtes ved 110°C i 24 timer. Opløsningen inddampedes in vacuo, hvorefter inddampningsresten rørtes i methylenchlorid (100 ml). Denne behandling gav den rå titelforbindelse som et krystallinsk bundfald.A solution of 4-benzyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline-1-oxide (14.6 g, 54 mmol) and triphenylphosphine (21 30 g, 80 mmol) in dimethylformamide (200 ml) was stirred at 110 ° C for 24 hours. The solution was evaporated in vacuo and the residue was stirred in methylene chloride (100 ml). This treatment gave the crude title compound as a crystalline precipitate.
Produktet blev renset ved rekrystallisering fra ethanol, smp. 273-274°C.The product was purified by recrystallization from ethanol, m.p. 273-274 ° C.
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20 På lignende måde fremstilledes følgende quinoxaliner fra deres tilsvarende 1-oxider: 1.2.3.4- tetrahydro-2,3-dioxo-4-phenethyl quinoxalin, smp.Similarly, the following quinoxalins were prepared from their corresponding 1-oxides: 1.2.3.4-tetrahydro-2,3-dioxo-4-phenethyl quinoxaline, m.p.
5 105-106°C.Mp 105-106 ° C.
4- (2-chlorbenzyl)-1,2,3,4-tetrahydro-2,3-dioxo-quinoxa-lin, smp. >300°C.4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline, m.p. > 300 ° C.
10 1,2,3,4-tetrahydro-4-(4-methoxybenzyl)-2,3-dioxo-quinoxa- lin, smp. 246-247°C.1,2,3,4-tetrahydro-4- (4-methoxybenzyl) -2,3-dioxo-quinoxaline, m.p. 246-247 ° C.
5- chlor-4-(2-chlorbenzyl)-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin, smp. 234-236°C.5- chloro-4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline, m.p. 234-236 ° C.
15 1.2.3.4- tetrahydro-4-(2-methoxybenzyl)-2,3-dioxo-quinoxalin, smp. 271-272°C.1.2.3.4-tetrahydro-4- (2-methoxybenzyl) -2,3-dioxo-quinoxaline, m.p. 271-272 ° C.
1.2.3.4- tetrahydro-4-(2-morpholinoethyl)-2,3-dioxo-qui-20 noxalin, smp. 233-236°C.1.2.3.4-tetrahydro-4- (2-morpholinoethyl) -2,3-dioxoquinonexaline, m.p. 233-236 ° C.
1.2.3.4- tetrahydro-4-(2-pyridylmethyl)-2,3-dioxo-quinoxalin, smp. 295-297°C.1.2.3.4-tetrahydro-4- (2-pyridylmethyl) -2,3-dioxo-quinoxaline, m.p. 295-297 ° C.
25 4-cyclopropylmethyl-l,2,3,4-tetrahydro-2,3-dioxo-quinoxa lin, smp. 211-213°C.4-cyclopropylmethyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxa lin, m.p. 211-213 ° C.
j. 5-benzyl-3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin (Forbindelse 1) 30 ------j. 5-Benzyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline (Compound 1) ----
En iskold, omrørt opløsning af 4-benzyl-l,2,3,4-tetrahy-dro-2,3-dioxo-quinoxalin (1 g, 4 mmol) i tør DMF (20 ml) tilsattes kalium t-butylat (0,56 g, 5 mmol). Omrøring fort-35 sattes indtil al kalium t-butylatet var opløst. I visse eksperimenter observeredes et kraftigt bundfald af kalium-quinoxalinsaltet.An ice-cold, stirred solution of 4-benzyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline (1 g, 4 mmol) in dry DMF (20 ml) was added potassium t-butylate (0 , 56 g, 5 mmol). Stirring was continued until all the potassium t-butylate was dissolved. In certain experiments, a strong precipitation of the potassium quinoxaline salt was observed.
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2121
Blandingen tilsattes derefter diethylchlorphosphat (0,7 ml, 5 mmol) og omrøring fortsattes ved stuetemperatur i 30 min., hvorefter en forudfremstillet -40°C kold opløsning af kalium t-butylat (0,56 g, 5 mmol) og 5-cyclopro-5 pyl-3-isocyanomethyl-l,2,4-oxadiazol (0,8 g, 5 mmol) i tør DMF (15 ml) tilsattes.The mixture was then added with diethyl chlorophosphate (0.7 ml, 5 mmol) and stirring was continued at room temperature for 30 minutes, after which a pre-prepared -40 ° C cold solution of potassium t-butylate (0.56 g, 5 mmol) and 5-cyclopro 5-pyl-3-isocyanomethyl-1,2,4-oxadiazole (0.8 g, 5 mmol) in dry DMF (15 ml) was added.
Råproduktet krystalliseredes fra det olieagtige bundfald ved behandlling med en blanding af vand (25 ml) og ethyl-10 acetat (10 ml). Krystallerne opsamledes ved filtrering og rensedes ved kolonnekromatografi (Si02/ethylacetat), smp.The crude product was crystallized from the oily precipitate by treatment with a mixture of water (25 ml) and ethyl 10 acetate (10 ml). The crystals were collected by filtration and purified by column chromatography (SiO 2 / ethyl acetate), m.p.
250- 255°C.250 DEG-255 DEG C.
På lignende måde fremstilledes følgende forbindelser fra 15 de tilsvarende guinoxaliner og isonitriler: 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-me-thyl-4-oxo-6-trifluormethyl-imidazo[1,5-a]quinoxalin, smp. 231-234°C ved reaktion mellem 5-cyclopropyl-3-iso-20 cyanomethyl-l,2,4-oxadiazol og l,2,3,4-tetrahydro-4-me-thyl-2,3-dioxo-5-trifluormethyl quinoxalin (Forbindelse 2) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-25 5-phenethyl-imidazo[l,5-a]quinoxalin, smp. 200-201°C ved reaktion mellem 5-cyclopropyl-3-isocyanomethyl-l,2,4-oxa-diazol og l,2,3,4-tetrahydro-2,3-dioxo-5-phenethyl-quinox-alin (Forbindelse 3) 30 5-(2-chlorbenzyl)-3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)- 4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxalin, smp. 243-244°C ved reaktion mellem 5-cyclopropyl-3-isocyanomethyl-l,2,4-oxadiazol og 4-(2-chlorbenzyl)-l,2,3,4-tetrahydro-2,3-dioxo-quinoxalin (Forbindelse 4) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-(4-methoxybenzyl)-4-oxo-imidazo[l,5-a]quinoxalin, smp. 200- 35 22Similarly, the following compounds were prepared from the corresponding guinoxalines and isonitriles: 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5-methyl-4-oxo- 6-trifluoromethyl-imidazo [1,5-a] quinoxaline, m.p. 231-234 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4-methyl-2,3-dioxo-5 -trifluoromethyl quinoxaline (Compound 2) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5-phenethyl-imidazo [1,5-a] quinoxaline, m.p. 200-201 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxa-diazole and 1,2,3,4-tetrahydro-2,3-dioxo-5-phenethyl-quinoxaline ( Compound 3) 5- (2-Chlorobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) 4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline, m.p. 243-244 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline ( Compound 4) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (4-methoxybenzyl) -4-oxo-imidazo [1,5-a] quinoxaline , m.p. 200- 35 22
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203°C ved reaktion mellem 5-cyclopropyl-3-isocyanomethyl- 1.2.4- oxadiazol og 1,2,3,4-tetrahydro-4-(4-methoxybenzyl)- 2.3- dioxo-quinoxalin (Forbindelse 5) 5 3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-4,5-dihydro-5-methyl- 4- oxo-6-trifluormethylimidazo[l,5-a]quinoxalin, smp. 232-233°C ved reaktion mellem 3-cyclopropyl-5-isocyanomethyl- 1.2.4- oxadiazol og l,2,3,4-tetrahydro-4-methyl-2,3-dioxo- 5- trifluormethyl guinoxalin (Forbindelse 6) 10 6- chlor-5-(2-chlorbenzyl)-3-(5-cyclopropyl-l,2,4-oxadiazol- 3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin, smp. 244-245°C ved reaktion mellem 5-cyclopropyl-3-isocyanomethyl- 1.2.4- oxadiazol og 5-chlor-4-(2-chlorbenzyl)-1,2,3,4- 15 tetrahydro-2,3-dioxo-quinoxalin (Forbindelse 7) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo- 5-(2-pyridylmethyl)-imidazo[l,5-a]quinoxalin, smp. 197-198°C ved reaktion mellem 5-cyclopropyl-3-isocyanomethyl-l,2,4-20 oxadiazol og 1,2,3,4-tetrahydro-4-(2-pyridylmethyl)-2,3-dioxo-quinoxalin (Forbindelse 8) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5~dihydro-5-(2-methoxybenzyl)-4-oxo-imidazo[l,5-a]quinoxalin, smp. 201-25 203°C ved reaktion mellem 5-cyclopropyl-3-isocyanomethyl- 1.2.4- oxadiazol og l,2,3,4-tetrahydro-4-(2-methoxybenzyl)- 2.3- dioxo-quinoxalin (Forbindelse 9) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-(2-30 morpholinoethyl)-4-oxo-imidazo[l,5-a]quinoxalin, smp. 187-188°C ved reaktion mellem 5-cyclopropyl-3-isocyanomethyl- 1.2.4- oxadiazol og 1,2,3,4-tetrahydro-4-(2-morpholinoethyl)- 2.3- dioxo-quinoxalin (Forbindelse 10) 35 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-5-cyclopropylmethyl- 4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin, smp. 213-215°C ved reaktion mellem 4-cyclopropylmethyl-l,2,3,4-tetrahydro- 23203 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4- (4-methoxybenzyl) -2,3-dioxo-quinoxaline (Compound 5) (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-5-methyl-4-oxo-6-trifluoromethylimidazo [1,5-a] quinoxaline, m.p. 232-233 ° C by reaction between 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4-methyl-2,3-dioxo-5-trifluoromethyl guinoxaline (Compound 6) 6- chloro-5- (2-chlorobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a ] quinoxaline, m.p. 244-245 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 5-chloro-4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo -quinoxaline (Compound 7) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5- (2-pyridylmethyl) imidazo [1,5- a] quinoxaline, m.p. 197-198 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-20 oxadiazole and 1,2,3,4-tetrahydro-4- (2-pyridylmethyl) -2,3-dioxo-quinoxaline (Compound 8) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (2-methoxybenzyl) -4-oxo-imidazo [1,5-a] quinoxaline, m.p. 201-25 203 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4- (2-methoxybenzyl) -2,3-dioxo-quinoxaline (Compound 9) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (2-30 morpholinoethyl) -4-oxo-imidazo [1,5-a] quinoxaline, m.p. . 187-188 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4- (2-morpholinoethyl) -2,3-dioxo-quinoxaline (Compound 10) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -5-cyclopropylmethyl-4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline, m.p. 213-215 ° C by reaction between 4-cyclopropylmethyl-1,2,3,4-tetrahydro-23
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2,3-dioxo-quinoxalin og 5-cyclopropy1-3-i socyanomethy1- 1.2.4- oxadiazol (Forbindelse 11)2,3-dioxo-quinoxaline and 5-cyclopropyl-3-i-socyanomethyl-1,2,4-oxadiazole (Compound 11)
Ethyl 4,5-dihydro-5,6-dimethyl-4-oxo-imidazo[l,5-a]quinoxa-5 line-3-carboxylat, snip. 190-191°C ved reaktion mellem 1.2.3.4- tetrahydro-4,5-dimethyl-2,3-dioxo-quinoxalin og ethyl isocyanoacetat (Forbindelse 12)Ethyl 4,5-dihydro-5,6-dimethyl-4-oxo-imidazo [1,5-a] quinoxa-5-line 3-carboxylate, snip. 190-191 ° C by reaction between 1.2.3.4-tetrahydro-4,5-dimethyl-2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 12)
Ethyl 5-ethyl-4,5-dihydro-6-methyl-4-oxo-imidazo[l,5-a]qui-10 noxalin-3-carboxylat, smp. 159-160°C ved reaktion mellem 4-ethyl-l,2,3,4-tetrahydro-5-methyl-2,3-dioxo-quinoxalin og ethyl isocyanoacetat (Forbindelse 13)Ethyl 5-ethyl-4,5-dihydro-6-methyl-4-oxo-imidazo [1,5-a] quinoxaline-3-carboxylate, m.p. 159-160 ° C by reaction between 4-ethyl-1,2,3,4-tetrahydro-5-methyl-2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 13)
Ethyl 4,5-dihydro-5-phenethyl-imidazo[l,5-a]quinoxalin-3-15 carboxylat, smp. 179-180°C ved reaktion mellem 1,2,3,4-tetrahydro-2,3-dioxo-4-phenethyl-quinoxalin og ethyliso-cyanoacetat (Forbindelse 14)Ethyl 4,5-dihydro-5-phenethyl-imidazo [1,5-a] quinoxaline-3-carboxylate, m.p. 179-180 ° C by reaction between 1,2,3,4-tetrahydro-2,3-dioxo-4-phenethyl-quinoxaline and ethyl iso-cyanoacetate (Compound 14)
Ethyl 4,5-dihydro-5-(4-methoxybenzyl)-4-oxo-imidazo[l,5-a]-20 quinoxalin-3-carboxylat, smp. 194-195°C ved reaktion mellem 1.2.3.4- tetrahydro-4-(4-methoxybenzyl)-2,3-dioxo-quinoxalin og ethyl isocyanoacetat (Forbindelse 15)Ethyl 4,5-dihydro-5- (4-methoxybenzyl) -4-oxo-imidazo [1,5-a] -quinoxaline-3-carboxylate, m.p. 194-195 ° C by reaction between 1.2.3.4-tetrahydro-4- (4-methoxybenzyl) -2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 15)
Ethyl 5-(2-chlorbenzyl)-4,5-dihydro-4-oxo-imidazo[l,5-a]-25 quinoxalin-3-carboxylat, smp. 203-209°C ved reaktion mellem 4-(2-chlorbenzyl)-1,2,3,4-tetrahydro-2,3-dioxo-quinoxalin og ethyl isocyanoacetat (Forbindelse 16) EKSEMPEL 2 30 3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-4,5-dihydro-5,6-dimethyl-4-oxo-imidazo[l,5-a]quinoxalin (Forbindelse 17) 35 En blanding af ethyl-4,5-dihydro-5,6-dimethyl-4-oxo-imi- dazo[l,5-a)quinoxalin-3-carboxylat (450 mg), cyclopropan- carboxamidoxim (500 mg) og knust molekylesi 4Å (5 g) blevEthyl 5- (2-chlorobenzyl) -4,5-dihydro-4-oxo-imidazo [1,5-a] -quinoxaline-3-carboxylate, m.p. 203-209 ° C by reaction between 4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 16) EXAMPLE 2 3- (3-cyclopropyl) 1,2,4-Oxadiazol-5-yl) -4,5-dihydro-5,6-dimethyl-4-oxo-imidazo [1,5-a] quinoxaline (Compound 17) A mixture of ethyl-4, 5-dihydro-5,6-dimethyl-4-oxo-imidazo [1,5-a) quinoxaline-3-carboxylate (450 mg), cyclopropane-carboxamidoxime (500 mg) and crushed molecular sieve 4Å (5 g)
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i 24 behandlet med en opløsning af natrium (70 mg) i tør ethanol (50 ml). Den omrørte blanding blev refluxét i 3 timer, afkølet og filtreret gennem et filter. Filtratet koncentreredes til et volumen på 10 ml ved inddampning in 5 vacuo, hvorved titelforbindelsen delvist bundfældedes. Tilsætning af vand (50 ml) gav en yderligere udfældning af titelforbindelsen. Krystallerne opsamledes ved filtrering og vaskedes med vand, smp. 223-224°C.in 24 treated with a solution of sodium (70 mg) in dry ethanol (50 ml). The stirred mixture was refluxed for 3 hours, cooled and filtered through a filter. The filtrate was concentrated to a volume of 10 ml by evaporation in 5 vacuo, whereby the title compound partially precipitated. Addition of water (50 ml) gave a further precipitation of the title compound. The crystals were collected by filtration and washed with water, m.p. 223-224 ° C.
10 På lignende måde fremstilledes følgende oxadiazoler ved reaktion mellem cyclopropancarboxamidoxim og de tilsvarende ethylestre. Forbindelsen rensedes ved omkrystallisation fra isopropanol.Similarly, the following oxadiazoles were prepared by reaction of cyclopropane carboxamidoxime with the corresponding ethyl esters. The compound was purified by recrystallization from isopropanol.
15 3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-4,5-dihydro-4-oxo- 5-phenethyl-imidazo[1,5-a]quinoxalin, smp. 235-236°C. (Forbindelse 18) 5- (2-chlorbenzyl)-3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)- 20 4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin, smp. 276-277°C.3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-4-oxo-5-phenethyl-imidazo [1,5-a] quinoxaline, m.p. 235-236 ° C. (Compound 18) 5- (2-Chlorobenzyl) -3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) - 4,5-dihydro-4-oxo-imidazo [1,5-a ] quinoxaline, m.p. 276-277 ° C.
(Forbindelse 19) 3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-4,5-dihydro-5-(2-methoxybenzyl)-4-oxo-imidazo[l,5-a]quinoxalin, smp. 260-25 261°C. (Forbindelse 20) 3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-5-ethyl-4,5-dihydro- 6- methyl-4-oxo-imidazo[l,5-a]quinoxalin, smp. 211-212°C. (Forbindelse 21) 30 35(Compound 19) 3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-5- (2-methoxybenzyl) -4-oxo-imidazo [1,5-a] quinoxaline, m.p. 260-25 261 ° C. (Compound 20) 3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -5-ethyl-4,5-dihydro-6-methyl-4-oxo-imidazo [1,5-a] quinoxaline, m.p. 211-212 ° C. (Compound 21)
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25 EKSEMPEL 3 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-5-ethoxycarbonyl-methyl-4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin (For-5 bindelse 22)EXAMPLE 3 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -5-ethoxycarbonyl-methyl-4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline (For -5 compound 22)
En omrørt opløsning af 3-(5-cyclopropyl-l,2,4-oxadiazol- 3-yl)-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxalin (200 mg) 10 i DMF (10 ml) tilsattes natriumhydrid (50 mg) og efter 10 min ethylmonochloracetat (1 ml). Blandingen omrørtes i yderligere 2 timer, hvorefter opløsningsmidlet fjernedes ved inddampning in vacuo. Inddampningsresten deltes mellem vand (25 ml) og æter (20 ml), og det krystalliske pro-15 dukt filtreredes fra. Smp. 245-246°C.A stirred solution of 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline (200 mg) in DMF (10 ml) was added sodium hydride (50 mg) and after 10 minutes ethyl monochloroacetate (1 ml). The mixture was stirred for an additional 2 hours, after which the solvent was removed by evaporation in vacuo. The residue was partitioned between water (25 mL) and ether (20 mL) and the crystalline product was filtered off. Mp. 245-246 ° C.
Med 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin og de passende halogenider som startmaterialer og DMF som opløsningsmiddel fremstil-20 ledes følgende forbindelser: 3- (5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-(3,3-dimethylallyl)-4-oxo-imidazo[l,5-a]quinoxalin, smp. 133-134°C ved alkylering med 3,3-dimethylallylbromid. (Forbin- 25 delse 23) 5-allyl-3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro- 4- oxo-imidazo[l,5-a]quinoxalin, smp. 188-189°C ved alkylering med allylbromid. (Forbindelse 24) 30 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo- 5- phenacyl-imidazo[l,5-a]quinoxalin, smp. 258-259°C ved alkylering med phenacylbromid (Forbindelse 25) 35 5-acetonyl-3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin, smp. 280-282°C ved alkylering med chloracetone. Omkrystallisering fra iWith 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline and the appropriate halides as starting materials and DMF as solvent The following compounds are prepared: 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (3,3-dimethylallyl) -4-oxo-imidazo [1 , 5-a] quinoxaline, m.p. 133-134 ° C by alkylation with 3,3-dimethylallyl bromide. (Compound 23) 5-Allyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline , m.p. 188-189 ° C by alkylation with allyl bromide. (Compound 24) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5-phenacyl-imidazo [1,5-a] quinoxaline, m.p. . 258-259 ° C by alkylation with phenacyl bromide (Compound 25) 5-Acetonyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [ 1,5-a] quinoxaline, m.p. 280-282 ° C by chloroacetone alkylation. Recrystallization from i
DK 161022 BDK 161022 B
26 methanol (Forbindelse 26) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-5-(2-fluorbenzyl)- 4.5- dihydro-4-oxo-imidazo[l,5-a]quinoxalin, smp. 229-230°C 5 ved benzylering med 2-fluorbenzylchlorid. Omkrystallisering fra toluen (Forbindelse 27) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-(2-methylbenzyl)-4-oxo-imidazo[l,5-a]quinoxalin, smp. 235-10 237°C ved benzylering med 2-methyl-benzylchlorid. Omkrys tallisering fra methanol (Forbindelse 28) 5-(2-bromobenzyl)-3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)- 4.5- dihydro-4-oxo-imidazo[1,5-a]quinoxalin, smp. 236-237°C 15 ved benzylering med 2-bromobenzylbromid (Forbindelse 29) 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl) - 4,5-dihydro-5-(3-methoxybenzyl)-4-oxo-imidazo[l,5-a]quinoxalin, smp. 188-190°C ved benzylering med m-methoxybenzylchlorid. Omkrys-20 tallisering fra toluen (Forbindelse 30) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-5-(2-ethoxyethyl)- 4.5- dihydro-4-oxo-imidazo[l,5-a]quinoxalin, smp. 161-162°C ved alkylering med 2-bromoethylethylæter. Omkrystallisering 25 fra ethanol (Forbindelse 31) 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-5-(4-phthalimidobenzyl)-imidazo[l,5-a]quinoxalin, smp. 195-197°C, omformning til krystaller med smp. 280-282°C ved ben-30 zylering med 4-(phthalimido)benzylchlorid. Omkrystallisering fra dichlormethan acetone, 4:1 (Forbindelse 32) 35 DK 161022 27 EKSEMPEL 4 5-(4-aminobenzyl)-3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-5 4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin (Forbindelse 33)Methanol (Compound 26) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -5- (2-fluorobenzyl) 4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline, m.p. 229-230 ° C by benzylation with 2-fluorobenzyl chloride. Recrystallization from toluene (Compound 27) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (2-methylbenzyl) -4-oxo-imidazo [1,5 -a] quinoxaline, m.p. 235-10 237 ° C by benzylation with 2-methyl-benzyl chloride. Recrystallize from methanol (Compound 28) 5- (2-bromobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) - 4,5-dihydro-4-oxo-imidazo [1,5- a] quinoxaline, m.p. 236-237 ° C by benzylation with 2-bromobenzyl bromide (Compound 29) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) - 4,5-dihydro-5- (3-methoxybenzyl) - 4-oxo-imidazo [1,5-a] quinoxaline, m.p. 188-190 ° C by benzylation with m-methoxybenzyl chloride. Recrystallization from toluene (Compound 30) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -5- (2-ethoxyethyl) 4,5-dihydro-4-oxo-imidazo [1,2] 5-a] quinoxaline, m.p. 161-162 ° C by alkylation with 2-bromoethylethyl ether. Recrystallization from ethanol (Compound 31) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5- (4-phthalimidobenzyl) imidazo [1,2] 5-a] quinoxaline, m.p. 195-197 ° C, conversion to crystals with m.p. 280-282 ° C by benzylation with 4- (phthalimido) benzyl chloride. Recrystallization from dichloromethane acetone, 4: 1 (Compound 32) EXAMPLE 4 5- (4-Aminobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -5,5 -dihydro-4-oxo-imidazo [1,5-a] quinoxaline (Compound 33)
En blanding af 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-5-(4-phthalimidobenzyl)-imidazo[1,5-a]qui-10 noxalin (0,46 g, 0,87 nunol) og hydrazin (2 ml) i ethanol (25 ml) omrørtes ved stuetemperatur i 1,5 time. Bundfaldet opsamledes ved filtrering, vaskedes med ethanol og tørredes, hvilket gav titelforbindelsen, smp. 246-248°C.A mixture of 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5- (4-phthalimidobenzyl) imidazo [1,5-a] qui -10 noxaline (0.46 g, 0.87 nunol) and hydrazine (2 ml) in ethanol (25 ml) were stirred at room temperature for 1.5 hours. The precipitate was collected by filtration, washed with ethanol and dried to give the title compound, m.p. 246-248 ° C.
15 EKSEMPEL 5 5-(4-azidobenzyl)-3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]quinoxalin (Forbindelse 34) 20 -EXAMPLE 5 5- (4-Azidobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline (Compound 34) 20 -
En omrørt opløsning af 5-(4-aminobenzyl)-3-(5-cyclopropyl- 1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[1,5-a]-quinoxalin (0,1 g, 0,25 mmol) i trifluoreddikesyre (3 ml) 25 ved 0°C tilsattes natriumnitrit (0,1 g, 1,4 mmol). Efter 5 min. tilsattes natriumazid (0,16 g, 2,5 mmol). Omrøring fortsattes i 1 time. Derefter tilsattes vand (20 ml), og blandingen extraheredes to gange med dichlormethan (20 ml). De samlede ekstrakter tørredes over natriumsulfat og 30 inddampedes hvilket gav titelforbindelsen som et bleggult tørstof, smp. 183-184°C (sønderdeling). Chromatografisk rensning (Si02)/CH2Cl2-acetone 4:1) gav krystaller med smp. 194-197°C (sønderdeling).A stirred solution of 5- (4-aminobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] Quinoxaline (0.1 g, 0.25 mmol) in trifluoroacetic acid (3 ml) at 0 ° C was added sodium nitrite (0.1 g, 1.4 mmol). After 5 min. sodium azide (0.16 g, 2.5 mmol) was added. Stirring was continued for 1 hour. Then water (20 ml) was added and the mixture was extracted twice with dichloromethane (20 ml). The combined extracts were dried over sodium sulfate and evaporated to give the title compound as a pale yellow solid, m.p. 183-184 ° C (dec.). Chromatographic purification (SiO 2) / CH 2 Cl 2 acetone 4: 1) gave crystals with m.p. 194-197 ° C (dec.).
3535
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK258289A DK161022C (en) | 1988-06-01 | 1989-05-26 | IMIDAZOQUINOXALIN COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK297188A DK297188D0 (en) | 1988-06-01 | 1988-06-01 | IMIDAZOQUINOXAL COMPOUNDS, THEIR PREPARATION AND USE |
| DK297188 | 1988-06-01 | ||
| DK625988 | 1988-11-10 | ||
| DK625988A DK625988D0 (en) | 1988-11-10 | 1988-11-10 | IMIDAZOQUINOXAL COMPOUNDS, THEIR PREPARATION AND USE |
| DK258289A DK161022C (en) | 1988-06-01 | 1989-05-26 | IMIDAZOQUINOXALIN COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS |
| DK258289 | 1989-05-26 |
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| Publication Number | Publication Date |
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| DK258289D0 DK258289D0 (en) | 1989-05-26 |
| DK258289A DK258289A (en) | 1989-12-02 |
| DK161022B true DK161022B (en) | 1991-05-21 |
| DK161022C DK161022C (en) | 1991-10-28 |
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| DK258289A DK161022C (en) | 1988-06-01 | 1989-05-26 | IMIDAZOQUINOXALIN COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS |
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| DK258289A (en) | 1989-12-02 |
| DK258289D0 (en) | 1989-05-26 |
| DK161022C (en) | 1991-10-28 |
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