NO152841B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NEW 4-AROYLIMIDAZOL-2-ONES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NEW 4-AROYLIMIDAZOL-2-ONES Download PDF

Info

Publication number
NO152841B
NO152841B NO801796A NO801796A NO152841B NO 152841 B NO152841 B NO 152841B NO 801796 A NO801796 A NO 801796A NO 801796 A NO801796 A NO 801796A NO 152841 B NO152841 B NO 152841B
Authority
NO
Norway
Prior art keywords
imidazol
straight
carbon atoms
branched lower
dihydro
Prior art date
Application number
NO801796A
Other languages
Norwegian (no)
Other versions
NO801796L (en
NO152841C (en
Inventor
Richard A Schnettler
Richard C Dage
J Martin Grisar
Original Assignee
Richardson Merrell Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26727558&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NO152841(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Richardson Merrell Inc filed Critical Richardson Merrell Inc
Publication of NO801796L publication Critical patent/NO801796L/en
Publication of NO152841B publication Critical patent/NO152841B/en
Publication of NO152841C publication Critical patent/NO152841C/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/70—One oxygen atom

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

Foreliggende oppfinnelse angår en analogifremgangs- The present invention relates to an analogue process

måte ved fremstilling av terapeutisk aktive nye 4-aroylimida-zol-2-oner. way in the preparation of therapeutically active new 4-aroylimidazol-2-ones.

De mest nærliggende publikasjoner antas å være U.S. patentskrift 2 514 380 og 2 441 933 så vel som R. Duschinsky og L. A. Dolan, J. Am. Chem. Soc. 68, 2350-55 (1946); ibid. 70, 657-62 (1948); ibid. 67, 2079-84 (1945); og Y. A. Rozin. E. P. Dorienko og Z. V. Pushkareva, Khim. Geterotsikl. Soedin., The closest publications are believed to be U.S. U.S. Patent Nos. 2,514,380 and 2,441,933 as well as R. Duschinsky and L.A. Dolan, J. Am. Chem. Soc. 68, 2350-55 (1946); ibid. 70, 657-62 (1948); ibid. 67, 2079-84 (1945); and Y.A. Rozin. E. P. Dorienko and Z. V. Pushkareva, Khim. Goat root cycle. Soedin.,

4(4), 698-701 (1968). Disse publikasjoner beskriver fremstilling av og mellomproduktanvendelse av følgende forbindelser: 4-benzoyl-l,3-dihydro - 2H-imidazol-on, 4(4), 698-701 (1968). These publications describe the preparation and intermediate use of the following compounds: 4-benzoyl-1,3-dihydro-2H-imidazol-one,

4-benzoyl-l,3-dihydro-2H-imidazol-2-on 1,3 -diacetat, 4-benzoyl-l,3-dihydro-5-(lavere alkyl)-2H-imidazol-2-on, 4-benzoyl-l,3-dihydro-5-metyl-2H-imidazol-2-on -1,3-diacetat, 1,3-dihydro-4-(3,4-dimetylbenzoyl)-2H-imidazol-2-on — 1,3-diacetat, 1,3-dihydro-4-(hydroksybenzoyl)-2H -imidazol-2-on, 1,3-dihydro-4-(hydroksybenzoyl)-5-(lavere alkyl)-2H-imidazol-2-on t 4-benzoyl-1,3-dihydro-2H-imidazol-2-one 1,3-diacetate, 4-benzoyl-1,3-dihydro-5-(lower alkyl)-2H-imidazol-2-one, 4- benzoyl-1,3-dihydro-5-methyl-2H-imidazol-2-one -1,3-diacetate, 1,3-dihydro-4-(3,4-dimethylbenzoyl)-2H-imidazol-2-one — 1,3-diacetate, 1,3-dihydro-4-(hydroxybenzoyl)-2H-imidazol-2-one, 1,3-dihydro-4-(hydroxybenzoyl)-5-(lower alkyl)-2H-imidazol-2 -on t

1,3-dihydro-4-(3,4-dihydroksybenzoyl)-2H-imidazol-2-on/ 1,3-dihydro-4-(4-nitrobenzoyl)-2H-imidazol-2-on, 1,3-dihydro-4-metyl-5-(4-nitrobenzoyl)-2H-imidazol-2-on, 4-(3-aminobenzoyl)-1,3-dihydro-2H-imidazol-2-on, 4-(4-aminobenzoyl)-1,3-dihydro-2H-imidazol-2-on, 4-(4-aminobenzoyl)-1,3-dihydro-5-metyl-2H-imidazol-2-on, 1,3-dihydro-4-(3,4-dihydroxybenzoyl)-2H-imidazol-2-one/ 1,3-dihydro-4-(4-nitrobenzoyl)-2H-imidazol-2-one, 1,3- dihydro-4-methyl-5-(4-nitrobenzoyl)-2H-imidazol-2-one, 4-(3-aminobenzoyl)-1,3-dihydro-2H-imidazol-2-one, 4-(4-aminobenzoyl )-1,3-dihydro-2H-imidazol-2-one, 4-(4-aminobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one,

men ingen farmasøytisk anvendelse for 4-aroylimidazol-2-oner er tidligere blitt foreslått. but no pharmaceutical application for 4-aroylimidazol-2-ones has previously been suggested.

Oppfinnelsen angår således en analogifremgangsmåte The invention thus relates to an analog method

ved fremstilling av terapeutisk aktive forbindelser av generell formel in the preparation of therapeutically active compounds of general formula

hvori Ar er 2-furyl, 2-tienyl eller fenyl, idet fenylgruppen er monosubstituert i orto-, meta- eller parastilling med X^, in which Ar is 2-furyl, 2-thienyl or phenyl, the phenyl group being monosubstituted in the ortho-, meta- or para-position with X^,

disubstituert i parastilling med X2 eller i orto- eller metastilling med X3; X^ er halogen, rettkjedet eller forgrenet lavere alkyl med 1-4 karbonatomer, rettkjedet eller forgrenet lavere alkoksy med 1-4 karbonatomer, rettkjedet eller forgrenet lavere alkyltio med 1-4 karbonatomer, trifluormetyl, NR^R^, piperidinyl eller morfolinyl, X2 og X3 er halogen, rettkjedet eller forgrenet lavere alkoksy med 1-4 karbonatomer, rettkjedet eller forgrenet lavere alkyl med 2-4 karbonatomer; eller når X^ er i metastilling, kan X2 og X^ sammen være metylendioksy som eventuelt er substituert med én eller to metylgrupper; R er hydrogen, rettkjedet eller forgrenet lavere alkyl med 1-4 karbonatomer, rettkjedet eller forgrenet lavere alkylkårbonyl med 1-4 karbonatomer, eller benzoyl, hver av R^, R_ og R4 er hydrogen eller rettkjedet eller forgrenet lavere alkyl med 1-4 karbonatomer, forutsatt at både R3 og R4 ikke kan være hydrogen, disubstituted in the para position with X2 or in the ortho or meta position with X3; X^ is halogen, straight-chain or branched lower alkyl with 1-4 carbon atoms, straight-chain or branched lower alkoxy with 1-4 carbon atoms, straight-chain or branched lower alkylthio with 1-4 carbon atoms, trifluoromethyl, NR^R^, piperidinyl or morpholinyl, X2 and X3 is halogen, straight-chain or branched lower alkoxy of 1-4 carbon atoms, straight-chain or branched lower alkyl of 2-4 carbon atoms; or when X^ is in the meta position, X2 and X^ together may be methylenedioxy optionally substituted with one or two methyl groups; R is hydrogen, straight or branched lower alkyl of 1-4 carbon atoms, straight or branched lower alkyl carbonyl of 1-4 carbon atoms, or benzoyl, each of R^, R_ and R 4 is hydrogen or straight or branched lower alkyl of 1-4 carbon atoms , provided that both R 3 and R 4 cannot be hydrogen,

og farmasøytisk akseptable salter derav. and pharmaceutically acceptable salts thereof.

Disse forbindelser er anvendbare som antihypertensive midler, kardiotone midler og antitrombosemidler. These compounds are useful as antihypertensive agents, cardiotonic agents and antithrombotic agents.

Eksempler på en rettkjedet eller forgrenet alkylgruppe med fra 1-4 karbonatomer som anvendt her er methyl, ethyl, n-propyl, isopropyl, n-butyl og isobutyl. Examples of a straight-chain or branched alkyl group with from 1-4 carbon atoms as used here are methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

Eksempler på en rettkjedet eller forgrenet Examples of a straight chain or branched

lavere alkoksygruppe med fra 1-4 karbonatomer som anvendt her er metoksy, etoksy, n-propoksy, isopropoksy, n-butoksy og isobutoksy. lower alkoxy group with from 1-4 carbon atoms as used here are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and isobutoxy.

Som anvendt her menes med uttrykket halogen, fluor, As used herein, the term halogen, fluorine,

klor, brom eller jod. Med uttrykket halogenid menes fluorid, klorid, bromid eller jodid. chlorine, bromine or iodine. The term halide means fluoride, chloride, bromide or iodide.

Uttrykket rettkjedet eller forgrenet lavere alkyltio The term straight chain or branched lower alkylthio

med fra 1-4 karbonatomer angir strukturen S-alkyl hvori alkyldelen er en rettkjedet eller forgrenet alkylgruppe med fra 1-4 karbonatomer slik som f.eks. metyl, etyl, n-propyl, isopropyl, n-butyl eller isobutyl. with from 1-4 carbon atoms indicates the structure S-alkyl in which the alkyl part is a straight-chain or branched alkyl group with from 1-4 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

Med uttrykket metylendioksy eventuelt substituert med With the expression methylenedioxy optionally substituted with

en eller to metylgrupper, menes metylendioksy, etylendioksy eller isopropylidendioksy. one or two methyl groups means methylenedioxy, ethylenedioxy or isopropylidenedioxy.

Med uttrykket en benzoylgruppe menes en gruppe av formel -(CO)C6H5. By the term a benzoyl group is meant a group of the formula -(CO)C6H5.

Med uttrykket en rettkjedet eller forgrenet lavere alkylkarbonylgruppe med 1-4 karbonatomer menes en gruppe med strukturen By the expression a straight-chain or branched lower alkylcarbonyl group with 1-4 carbon atoms is meant a group with the structure

hvori alkyldelen er en rettkjedet eller forgrenet lavere alkylgruppe med fra 1-4 karbonatomer, og kan være f.eks. metyl, etyl, n-propyl, isopropyl, n-butyl eller isobutyl. in which the alkyl part is a straight-chain or branched lower alkyl group with from 1-4 carbon atoms, and can be e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

En særlig foretrukken forbindelse er 1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-on A particularly preferred compound is 1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one

Når R er hydrogen i forbindelsene av formel I er flere tautomere former av formel II mulig: When R is hydrogen in the compounds of formula I, several tautomeric forms of formula II are possible:

hvori R^ og Ar er som definert i formel I. Disse sure tauto-merer kan danne farmasøytisk aktive salter av generell formel wherein R 1 and Ar are as defined in formula I. These acidic tautomers can form pharmaceutically active salts of general formula

III III

hvori R^ og Ar er som definert i formel 1, og M er et farma-søytisk akseptabelt alkalimetall slik som natrium eller kalium, jordalkalimetall slik som kalsium eller magnesium, og overgangsmetall slik som sink eller jern, hovedgruppemetall, ammonium eller organisk ammoniumion slik som tetrametyl-ammoniumion. I denne beskrivelse menes med uttrykket imidazol-2-on enhver av tautomerene av formel II, og et farmasøytisk akseptabelt salt av et imidazol-2-on skal omfatte enhver tautomer av formel III. Analogifremgangsmåten ifølge oppfinnelsen er kjennetegnet ved at en forbindelse av formel hvori R^ er som ovenfor angitt, Friedel-Craft acyleres med 1-10 molarekvivalenter av et 2-furoylhalogenid, 2-tienoyl-halogenid, benzoylhalogenid som er monosubstituert i orto-, meta- eller parastilling med X^, eller et disubstituert benzoylhalogenid som er substituert i parastilling med X2 eller i orto- eller metastilling med X^ hvori X^, X» og X^ er som definert ovenfor, i nærvær av fra 1-10 molarekvivalenter av en Lewissyre-katalysator i et egnet løsningsmiddel ved en tempera-tur på 0-100°C i 1-10 timer, og når R skal være forskjellig fra hydrogen, at det resulterende aroylimidazol-2-on acyleres eller alkyleres med et acylhalogenid eller alkyleringsmiddel, alternativt a) hvor X^ er piperidinyl eller morfolinyl, at den således dannede forbindelse hvori X^ er fluor, behandles med fra 1 til 10 molarekvivalenter av piperidin eller morfolin, i et løsningsmiddel i fra 1/2 time til 48 timer ved 0-150°C, b) hvor X^ er en aminogruppe av formel NR-^R^, at en forbindelse av formelen wherein R 1 and Ar are as defined in formula 1, and M is a pharmaceutically acceptable alkali metal such as sodium or potassium, alkaline earth metal such as calcium or magnesium, and transition metal such as zinc or iron, main group metal, ammonium or organic ammonium ion such as tetramethylammonium ion. In this description, the term imidazol-2-one means any of the tautomers of formula II, and a pharmaceutically acceptable salt of an imidazol-2-one shall include any tautomer of formula III. The analog method according to the invention is characterized by a compound of formula in which R^ is as indicated above, Friedel-Craft acylated with 1-10 molar equivalents of a 2-furoyl halide, 2-thienoyl halide, benzoyl halide which is monosubstituted in ortho-, meta- or para position with X^, or a disubstituted benzoyl halide substituted in the para position with X2 or in the ortho or meta position with X^ wherein X^, X" and X^ are as defined above, in the presence of from 1-10 molar equivalents of a Lewis acid catalyst in a suitable solvent at a temperature of 0-100°C for 1-10 hours, and when R is to be different from hydrogen, that the resulting aroylimidazol-2-one is acylated or alkylated with an acyl halide or alkylating agent, alternatively a) where X^ is piperidinyl or morpholinyl, that the thus formed compound wherein X^ is fluorine is treated with from 1 to 10 molar equivalents of piperidine or morpholine, in a solvent for from 1/2 hour to 48 hours at 0-150 °C , b) where X^ is an amino group of formula NR-^R^, that a compound of the formula

reduseres under dannelse av det tilsvarende aminobenzoyl-imidazol-2-on som deretter alkyleres, eller hvor farmasøytisk akseptable salter ønskes, at det således dannede aroylimidazol-2-on omsettes med et egnet metall eller basisk ammoniumsalt. is reduced to form the corresponding aminobenzoyl-imidazol-2-one which is then alkylated, or where pharmaceutically acceptable salts are desired, the thus formed aroylimidazol-2-one is reacted with a suitable metal or basic ammonium salt.

Friedel-Crafts reaksjonen utføres The Friedel-Crafts reaction is carried out

ved å forblande ca. 1 molar ekvivalent av det egnede imidazol-2-on med ca. 1 molar ekvivalent til 10 molar ekvivalenter, fortrinnsvis ca. 2 molar ekvivalenter, av en Lewis-syre-katalysator i et egnet løsningsmiddel, f.eks. petroleumeter, et klorert hydrokarbon slik som karbontetraklorid, etylen-klorid, metylenklorid eller kloroform, et klorert aromatisk løsningsmiddel slik som 1,2,4-triklorbenzen eller o-diklorbenzen, karbondisulfid, eller fortrinnsvis nitrobenzen. by premixing approx. 1 molar equivalent of the suitable imidazol-2-one with approx. 1 molar equivalent to 10 molar equivalents, preferably approx. 2 molar equivalents, of a Lewis acid catalyst in a suitable solvent, e.g. petroleum ether, a chlorinated hydrocarbon such as carbon tetrachloride, ethylene chloride, methylene chloride or chloroform, a chlorinated aromatic solvent such as 1,2,4-trichlorobenzene or o-dichlorobenzene, carbon disulfide, or preferably nitrobenzene.

Ca. 1 molar ekvivalent til 10 molar ekvivalenter, fortrinnsvis ca. 1,1 molarekvivalenter av den egnede aroylforbindelse tilsettes, fortrinnsvis dråpevis til blandingen av imidazol-2-onene, Lewis-syre og løsningsmidlet, og reaksjonen tillates å forløpe i ca. 1/2 time til 100 timer, fortrinnsvis fra 1 time til ca. 10 timer avhengig av reaktantene, løsningsmidlet, og temperaturen som kan være fra -78° til 150°C, fortrinnsvis fra 0° til 100°C og helst rundt 60°C. Det resulterende aroylimidazol-2-on kan isoleres fra reaksjonsblandingen ved hvilken som helst egnet kjent prosedyre, fortrinnsvis ved stopping av reaksjonsblandingen med isvann og deretter fjerning av produktet ved filtrering eller ekstraksjon og løsnings-middelt jerning . About. 1 molar equivalent to 10 molar equivalents, preferably approx. 1.1 molar equivalents of the suitable aroyl compound are added, preferably dropwise, to the mixture of the imidazol-2-ones, Lewis acid and the solvent, and the reaction is allowed to proceed for approx. 1/2 hour to 100 hours, preferably from 1 hour to approx. 10 hours depending on the reactants, the solvent, and the temperature which can be from -78° to 150°C, preferably from 0° to 100°C and preferably around 60°C. The resulting aroylimidazol-2-one can be isolated from the reaction mixture by any suitable known procedure, preferably by quenching the reaction mixture with ice water and then removing the product by filtration or extraction and solvent iron.

Lewis-syrekatalysatorer som er egnet for bruk i Friedel-Craf ts reaksjoner som her beskrevet er f.eks. et metall slik som aluminium, serium, kopper, jern, molybden, wolfram eller sink, en Bronstead-syre slik som fosforsyre, svovelsyre, sulfonsyre eller en hydrohalosyre, slik som saltsyre eller hydrobromsyre, halogensubstituerte eddiksyrer slik som klor-eddiksyre eller trikloreddiksyre, eller et metallisk halogenid slik som borhalogenid, sinkklorid, sinkbromid, berrylklorid, kopperklorid, jern(III)bromid, jern(III)klorid, kvikksølv(II)-klorid, kvikksølv(I)klorid, antimonbromid, antimonklorid, titan(IV)bromid, titan(IV)klorid, titan(III)klorid, aluminium-bromid eller fortrinnsvis aluminiumklorid. Lewis acid catalysts which are suitable for use in the Friedel-Crafts reactions described here are e.g. a metal such as aluminium, cerium, copper, iron, molybdenum, tungsten or zinc, a Bronstead acid such as phosphoric acid, sulfuric acid, sulphonic acid or a hydrohalo acid such as hydrochloric or hydrobromic acid, halogen-substituted acetic acids such as chloroacetic acid or trichloroacetic acid, or a metallic halide such as boron halide, zinc chloride, zinc bromide, beryl chloride, copper chloride, iron(III) bromide, iron(III) chloride, mercury(II) chloride, mercury(I) chloride, antimony bromide, antimony chloride, titanium(IV) bromide, titanium (IV) chloride, titanium (III) chloride, aluminum bromide or preferably aluminum chloride.

Forbindelsene av formel I hvori X^ er i orto- eller para-stilling og er piperidinyl eller morfolinyl fremstilles ifølge a) fra et egnet fluorbenzoylimidazol-2-on av formel VI The compounds of formula I in which X^ is in the ortho or para position and is piperidinyl or morpholinyl are prepared according to a) from a suitable fluorobenzoylimidazol-2-one of formula VI

hvori R og R^ er som definert i formel I og hvor fluoratomet enten er i orto- eller para-stilling. Den egnede forbindelse av formel VI tillates å omsettes med fra 1-10 molar ekvivalenter piperidin eller morfolin. Denne reaksjon kan utføres med eller uten løsningsmiddel, fortrinnsvis er aminet løsningsmiddel såvel som reaktant. Egnedé løsningsmidler, om ønsket, for denne reaksjonen er f.eks. dimetylformamid, dimetylsulfoksyd, petroleum-ether, klorerte hydrokarboner slik som kloroform, metylenklorid eller karbontetraklorid, karbondisulfid, eteriske løs-ningsmidler slik som dietyleter, tetrahydrofuran eller p_-dioksan, aromatiske løsningsmidler slik som benzen, toluen eller xylen, eller alkoholiske løsningsmidler slik som etanol. Reaksjonen tillates å forløpe fra 1/2 time til 48 timer, fortrinnsvis rundt 24 timer avhengig av reaktantene, løsnings-midlet om slikt anvendes, og temperaturen som kan være i fra 0-150°C. Forbindelsene av formel I hvori er en amingruppe av formel -NR^R^ og hvori R^ og R^ er som definert i formel I, fremstilles alternativt ifølge b) fra de tilsvarende nitrosubstituerte benzoylimidazol-2-oner av formel VII wherein R and R^ are as defined in formula I and where the fluorine atom is either in the ortho or para position. The appropriate compound of formula VI is allowed to react with from 1-10 molar equivalents of piperidine or morpholine. This reaction can be carried out with or without solvent, preferably the amine is solvent as well as reactant. Suitable solvents, if desired, for this reaction are e.g. dimethylformamide, dimethyl sulfoxide, petroleum ether, chlorinated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, carbon disulfide, ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane, aromatic solvents such as benzene, toluene or xylene, or alcoholic solvents such as ethanol . The reaction is allowed to proceed from 1/2 hour to 48 hours, preferably around 24 hours depending on the reactants, the solvent if such is used, and the temperature which can be from 0-150°C. The compounds of formula I in which an amine group of formula -NR^R^ and in which R^ and R^ are as defined in formula I, are alternatively prepared according to b) from the corresponding nitro-substituted benzoylimidazol-2-ones of formula VII

hvori R og R-j^ er som definert i formel I. Forbindelsene av formel VII er enten kjent innen faget eller kan fremstilles ved Friedel-Crafts acylering av et imidazol-2-on av formel IV med et nitrosubstituert benzoylhalogenid, fortrinnsvis et wherein R and R-j^ are as defined in formula I. The compounds of formula VII are either known in the art or can be prepared by Friedel-Crafts acylation of an imidazol-2-one of formula IV with a nitro-substituted benzoyl halide, preferably a

nitrosubstituert benzoylklorid etter analoge metoder til de her angitte. Nitrogruppen reduseres til den usubstituerte aminogruppe ved hvilken som helst egnet kjent metode og om ønsket, kan den usubstituerte aminogruppe deretter alkyleres ved hvilken som helst egnet kjent metode. nitro-substituted benzoyl chloride by analogous methods to those indicated here. The nitro group is reduced to the unsubstituted amino group by any suitable known method and, if desired, the unsubstituted amino group can then be alkylated by any suitable known method.

Nitrobenzoylimidazol-2-onene omdannes The nitrobenzoylimidazol-2-ones are converted

til de tilsvarende aminobenzoylimidazol-2-oner ved reduksjon med tinn, sink, jern eller annet egnet aktivt metall i kon-sentrert saltsyreløsning. Ca. 1 molar ekvivalent til 10 molar ekvivalenter av metall anvendes, og reaksjonen tillates a for-løpe i fra 1/2 til 10 timer, fortrinnsvis fra 2-3 timer avhengig av reaktantene og temperaturen som kan være fra 25-150°C, fortrinnsvis rundt 100°C. Alternativt kan nitrobenzoyl-imidazol-2-onene reduseres katalytisk med nikkel, platina, palladium eller andre lignende egnede metaller og molekylært hydrogen. Slike reaksjoner utføres typisk i et alkoholisk løsningsmiddel, fortrinnsvis etanol, men ethvert ikke-reaktivt løsningsmiddel kan anvendes, og mengden av metallkatalysator kan variere fra 0,001 molar ekvivalent til 0,1 molar ekvivalent. Reaksjonen tillates å forløpe i fra 1 minutt til 1 time, fortrinnsvis rundt 10 minutter avhengig av reaktantene, løsningsmidlet og temperaturen som kan være fra 0-100°C, fortrinnsvis rundt 25°C. Alternativt kan nitrobenzoylimidazol-2-onene reduseres med ammoniumbisulfid (NH^SH) i vandig ammoniakk. Ca. 1-10 molar ekvivalenter, fortrinnsvis rundt 3 molar ekvivalenter bisulfid omsettes i 1/2 time til 10 timer, fortrinnsvis rundt 2 timer, avhengig av reaktantene og temperaturen som kan være fra 0-150°C, fortrinnsvis rundt 50°C. Endelig kan nitrobenzoylimidazol-2-onene reduseres til de tilsvarende aminoforbindelser ved hvilken som helst annen kjent metode innen faget. to the corresponding aminobenzoylimidazol-2-ones by reduction with tin, zinc, iron or other suitable active metal in concentrated hydrochloric acid solution. About. 1 molar equivalent to 10 molar equivalents of metal is used, and the reaction is allowed to proceed for from 1/2 to 10 hours, preferably from 2-3 hours depending on the reactants and the temperature which can be from 25-150°C, preferably around 100°C. Alternatively, the nitrobenzoyl-imidazol-2-ones can be catalytically reduced with nickel, platinum, palladium or other similarly suitable metals and molecular hydrogen. Such reactions are typically carried out in an alcoholic solvent, preferably ethanol, but any non-reactive solvent can be used, and the amount of metal catalyst can vary from 0.001 molar equivalent to 0.1 molar equivalent. The reaction is allowed to proceed for from 1 minute to 1 hour, preferably around 10 minutes depending on the reactants, the solvent and the temperature which can be from 0-100°C, preferably around 25°C. Alternatively, the nitrobenzoylimidazol-2-ones can be reduced with ammonium bisulphide (NH^SH) in aqueous ammonia. About. 1-10 molar equivalents, preferably around 3 molar equivalents of bisulphide are reacted for 1/2 hour to 10 hours, preferably around 2 hours, depending on the reactants and the temperature which can be from 0-150°C, preferably around 50°C. Finally, the nitrobenzoylimidazol-2-ones can be reduced to the corresponding amino compounds by any other method known in the art.

Alkyleringen av de usubstituerte aminobenzoyl-imidazol-2-onene kan utføres f.eks. ved omsetning med én eller flere ekvivalenter av et egnet alkylhalogenid av formel R^X og R^X hvori R3 og R^ er som definert i formel I og hvor X er et halogenid. Typisk utføres disse reaksjoner i et løsnings-middel slik som petroleumeter, klorerte hydrokarboner slik som karbontetraklorid, kloroform eller metylenklorid, klorerte aromater slik som 1,2,4-triklorbenzen, o-diklorbenzen eller klorbenzen, karbondisulfid, nitrobenzen, dimetylformamid, dimetylsulfoksyd, eteriske løsningsmidler slik som dietyleter, tetrahydrofuran eller p_-dioksan, aromatiske løsningsmidler slik som benzen,toluen eller xylen, alkoholer slik som metanol, etanol eller propanol, og vandige alkoholer slik som vandig etanol. Disse alkyleringer utføres fortrinnsvis i nærvær av en eller flere ekvivalenter av en "proton-svamp" slik som trietylamin, pyridin, natriumhydroksyd, kalsium-hydroksyd eller kaliumhydroksyd for å nøytralisere ethvert hydrohalogenid etter som det dannes. Alternativt kan de usubstituerte aminobenzoylimidazol-2-oner alkyleres ved hvilket som helst annen egnet kjent prosedyre slik som omsetning med maursyre og formaldehyd under dannelse av en dimetylamin-forbindelse. Enn videre kan et uttall andre substituenter slik som halogen og hydroksy fremstilles fra de nitrosubstituerte benzoylimidazol-2-oner av formel VII via diazoniumionet etter velkjente metoder innen faget. The alkylation of the unsubstituted aminobenzoyl-imidazol-2-ones can be carried out e.g. by reaction with one or more equivalents of a suitable alkyl halide of formula R^X and R^X wherein R 3 and R^ are as defined in formula I and where X is a halide. Typically, these reactions are carried out in a solvent such as petroleum ether, chlorinated hydrocarbons such as carbon tetrachloride, chloroform or methylene chloride, chlorinated aromatics such as 1,2,4-trichlorobenzene, o-dichlorobenzene or chlorobenzene, carbon disulfide, nitrobenzene, dimethylformamide, dimethylsulfoxide, ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane, aromatic solvents such as benzene, toluene or xylene, alcohols such as methanol, ethanol or propanol, and aqueous alcohols such as aqueous ethanol. These alkylations are preferably carried out in the presence of one or more equivalents of a "proton sponge" such as triethylamine, pyridine, sodium hydroxide, calcium hydroxide or potassium hydroxide to neutralize any hydrohalide as it is formed. Alternatively, the unsubstituted aminobenzoylimidazol-2-ones can be alkylated by any other suitable known procedure such as reaction with formic acid and formaldehyde to form a dimethylamine compound. Furthermore, a number of other substituents such as halogen and hydroxy can be prepared from the nitro-substituted benzoylimidazol-2-ones of formula VII via the diazonium ion according to well-known methods in the art.

Om ønsket kan én eller begge av nitrogenatomene i imidazol-2-on-ringen være substituert med en alkylgruppe etter hvilken som helst kjent metode. Slike metoder innbefatter omsetning av det egnede N-usubstituerte aroylimidazol-2-on med en base og et alkyleringsmiddel i nærvær av et ikke-reaktivt løsningsmiddel. Egnede baser for denne reaksjonen kan f.eks. være et hydrid slik som natriumhydrid eller kalsiumhydrid, et karbonat eller dikarbonat slik som natriumkarbonat eller natriumbikarbonat, et fenoksyd slik som natriumfenoksyd, et alkoksyd slik som natriumetoksyd, eller fortrinnsvis et hydroksyd slik som natriumhydroksyd. Egnede alkyl-leringsmidler for denne reaksjonen er f.eks. et alkylhalogenid slik som metylklorid, metylbromid eller methyljodid, eller dialkylsulfat slik som dimetylsulfat. Egnede ikke-reaktive løsningsmidler er f.eks. petroleumeter, klorerte hydrokarboner slik som karbontetraklorid, kloroform eller metylenklorid, klorerte aromater slik som 1,2,4-triklorbenzen, o-diklorbenzen eller klorbenzen, karbondisulf id, nitrobenzen, eteriske l*is-ningsmidler slik som dietyleter, tetrahydrofuran eller p_-dioksan, aromatiske løsningsmidler slik som benzen, toluen eller xylen, eller fortrinnsvis polare aprotiske løsnings-midler slik som dimetylformamid (DtlF) eller dimetylsulf oksyd (DMSO). Reaksjonen tillates å forløpe i fra 1 minutt til 1 time, og temperaturen kan være fra 0-100°C, fortrinnsvis ca. 25°C. Når det ønskes at bare en av imidazol-2-on nitrogenatomene skal være substituert med en alkylgruppe, omsettes det egnede imidazol-2-on med fra 1 molar ekvivalent til 10 molar ekvivalenter av en base, fortrinnsvis i fra 1 molar ekvivalent og med ca. 1 molar ekvivalent av et alkyleringsmiddel. Ved anvendelse av denne prosedyre dannes begge mulige monoalkylerte nitrogenisomerer. Disse isomerer kan skilles etter konvensjonelle metoder innen faget slik som fraksjonert krystallisering, fraksjonert destillasjon eller kromatografi. Når det ønskes at begge nitrogenatomer i imidazol-2-on-ringen skal være alkylsubstituert, omsettes det egnede imidazol-2-on med fra 2 molar ekvivalenter til 10 molarekvivalenter av en base, fortrinnsvis ca. 2 molar ekvivalenter, og fra 2 molar ekvivalenter til 10 molar ekvivalenter av et alkyleringsmiddel, fortrinnsvis ca. 2 molar ekvivalenter. If desired, one or both of the nitrogen atoms in the imidazol-2-one ring may be substituted with an alkyl group by any known method. Such methods involve reacting the appropriate N-unsubstituted aroylimidazol-2-one with a base and an alkylating agent in the presence of a non-reactive solvent. Suitable bases for this reaction can e.g. be a hydride such as sodium hydride or calcium hydride, a carbonate or dicarbonate such as sodium carbonate or sodium bicarbonate, a phenoxide such as sodium phenoxide, an alkoxide such as sodium ethoxide, or preferably a hydroxide such as sodium hydroxide. Suitable alkylating agents for this reaction are e.g. an alkyl halide such as methyl chloride, methyl bromide or methyl iodide, or dialkyl sulfate such as dimethyl sulfate. Suitable non-reactive solvents are e.g. petroleum ether, chlorinated hydrocarbons such as carbon tetrachloride, chloroform or methylene chloride, chlorinated aromatics such as 1,2,4-trichlorobenzene, o-dichlorobenzene or chlorobenzene, carbon disulfide, nitrobenzene, ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane , aromatic solvents such as benzene, toluene or xylene, or preferably polar aprotic solvents such as dimethylformamide (DtlF) or dimethylsulfoxide (DMSO). The reaction is allowed to proceed for from 1 minute to 1 hour, and the temperature can be from 0-100°C, preferably approx. 25°C. When it is desired that only one of the imidazol-2-one nitrogen atoms should be substituted with an alkyl group, the suitable imidazol-2-one is reacted with from 1 molar equivalent to 10 molar equivalents of a base, preferably in from 1 molar equivalent and with approx. . 1 molar equivalent of an alkylating agent. By using this procedure, both possible monoalkylated nitrogen isomers are formed. These isomers can be separated by conventional methods in the field such as fractional crystallization, fractional distillation or chromatography. When it is desired that both nitrogen atoms in the imidazol-2-one ring should be alkyl substituted, the suitable imidazol-2-one is reacted with from 2 molar equivalents to 10 molar equivalents of a base, preferably approx. 2 molar equivalents, and from 2 molar equivalents to 10 molar equivalents of an alkylating agent, preferably approx. 2 molar equivalents.

Om ønsket kan nitrogenatomene i imidazol-2-on-ringen være substituert med en alkylkarbonylgruppe etter kjente metoder innen faget. Slike metoder innbefatter omsetning av de N-usubstituerte aroylimidazol-2-oner ifølge oppfinnelsen med et acylhalogenid, fortrinnsvis et acylklorid slik som acetylklorid, n-propanoylklorid, isopropanoylklorid eller butanoylklorid. Normalt vil acyleringsreaksjoner som gjør bruk av acylhalogenider anvende en syresvamp slik som tri-etylamid eller pyridin for å fjerne ethvert hydrohalogenid etter som det dannes. Enn videre kan den tilsvarende fri syre eller syreanhydrid anvendes i stedet for acylhalogenidene. Acyleringsreaksjoner utføres generelt uten tilsatt løsnings-middel, men kan utføres under anvendelse av ethvert ikke-aktivt løsningsmiddel, f.eks. petroleumeter, klorerte hydrokarboner slik som kloroform, metylenklorid eller karbontetraklorid, karbondisulfid, eteriske løsningsmidler slik som dietyleter, tetrahydrofuran eller p_-dioksan eller aromatiske løs-ningsmidler slik som benzen, toluen eller xylen. Reaksjonene tillates å forløpe i fra 1 minutt til 100 timer, fortrinnsvis fra ca. 1 time til ca. 10 timer og temperaturen kan være fra -78°C til 150°C, fortrinnsvis fra 0-100°C. If desired, the nitrogen atoms in the imidazol-2-one ring can be substituted with an alkylcarbonyl group according to methods known in the art. Such methods include reaction of the N-unsubstituted aroylimidazol-2-ones according to the invention with an acyl halide, preferably an acyl chloride such as acetyl chloride, n-propanoyl chloride, isopropanoyl chloride or butanoyl chloride. Normally, acylation reactions using acyl halides will use an acid sponge such as triethylamide or pyridine to remove any hydrohalide as it is formed. Furthermore, the corresponding free acid or acid anhydride can be used instead of the acyl halides. Acylation reactions are generally carried out without added solvent, but can be carried out using any non-active solvent, e.g. petroleum ether, chlorinated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, carbon disulphide, ethereal solvents such as diethyl ether, tetrahydrofuran or p-dioxane or aromatic solvents such as benzene, toluene or xylene. The reactions are allowed to proceed for from 1 minute to 100 hours, preferably from approx. 1 hour to approx. 10 hours and the temperature can be from -78°C to 150°C, preferably from 0-100°C.

Alkalimetall-, jordalkalimetall-, overgangsmetall-, hovedgruppemetall-, ammonium- eller organisk-ammoniumsalter av aroylimidazol-2-onene kan fremstilles Alkali metal, alkaline earth metal, transition metal, main group metal, ammonium or organo-ammonium salts of the aroylimidazol-2-ones can be prepared

fra et tilsvarende metall eller basisk ammoniumsalt, f.eks. et alkoksyd, slik som natriummetoksyd eller natriumetoksyd, et fenoksyd slik som natriumfenoksyd, hydroksyder slik som natriumhydroksyd eller kaliumhydroksyd eller et karbonat, slik som natriumkarbonat, kaliumkarbonat, sinkkarbonat, magnesiumkarbonat eller natriumhydrogenkarbonat. Disse reaksjoner kan utføres med eller uten løsningsmiddel. Egnede løsningsmidler er f.eks. lavere alkoholer slik som metanol, etanol, isopropanol, n-propanol eller n-butanol, aromatiske løsningsmidler slik som benzen, toluen eller xylen, eteriske løsningsmidler slik som dietyleter, tetrahydrofuran eller p_-dioksan, og halogenerte hydrokarbonløsningsmidler slik som kloroform, metylenklorid eller karbontetraklorid. Aroyl-imidazol-2-on og basen tillates å omsettes i fra 1 minutt til 24 timer avhengig av reaktantene og temperaturen som kan være fra -78-150°C, fortrinnsvis fra 0-25°C. from a corresponding metal or basic ammonium salt, e.g. an alkoxide such as sodium methoxide or sodium ethoxide, a phenoxide such as sodium phenoxide, hydroxides such as sodium hydroxide or potassium hydroxide or a carbonate such as sodium carbonate, potassium carbonate, zinc carbonate, magnesium carbonate or sodium bicarbonate. These reactions can be carried out with or without solvent. Suitable solvents are e.g. lower alcohols such as methanol, ethanol, isopropanol, n-propanol or n-butanol, aromatic solvents such as benzene, toluene or xylene, ethereal solvents such as diethyl ether, tetrahydrofuran or p_-dioxane, and halogenated hydrocarbon solvents such as chloroform, methylene chloride or carbon tetrachloride . The aroyl-imidazol-2-one and the base are allowed to react for from 1 minute to 24 hours depending on the reactants and the temperature which can be from -78-150°C, preferably from 0-25°C.

Aroylkloridene eller deres tilsvarende karboksylsyrer som kreves for Friedel-Crafts-acyleringen ifølge oppfinnelsen, er enten generelt tilgjengelig eller kan fremstilles etter analoge prosedyrer. Imidazol-2-on utgangsmaterialene av formel IV kan fremstilles som beskrevet av R. Duschinsky og L. A. Dolan, J. Am. Chem. Soc. 67, 2079 (1945), R. Duschinsky og L. A. Dolan, J. Am. Chem. Soc. 68, 2350 (1945) eller U.S. patent 2 441 933. The aroyl chlorides or their corresponding carboxylic acids required for the Friedel-Crafts acylation according to the invention are either generally available or can be prepared by analogous procedures. The imidazol-2-one starting materials of formula IV can be prepared as described by R. Duschinsky and L. A. Dolan, J. Am. Chem. Soc. 67, 2079 (1945), R. Duschinsky and L.A. Dolan, J. Am. Chem. Soc. 68, 2350 (1945) or U.S. patent 2,441,933.

Forbindelsene av generell formel I kan anvendes ved behandling av hjertesvikt innbefattet kongestiv hjertesvikt, bakoverrettet hjertesvikt)foroverrettet hjertesvikt, venstre ventrikulær hjertesvikt eller høyre ventikulær hjertesvikt eller ved behandling av enhver annen tilstand som krever styrkning av hjertefunksjonen med et kardiotont middel. I mange henseender utviser disse forbindelser digitalis-lignende virkning. Forbindelsene av generell formel I kan også anvendes ved behandling av hypertensjon innbefattet <p>rimær eller essensiell hypertensjon, hormonelt fremkalt hypertensjon, nyere hypertensjon og kjemisk fremkalt hypertensjon. Endelig kan forbindelsen av generell formel I anvendes som antitrombosemidler. De påvirker koagulasjonen av blod ved å for-hindre aggregering av blodplater, som spiller en dominerende rolle i trombosetilstander både i begynnelsesfase og i den tilstoppende tilstand. Arteriell trombose, særlig i arterier som tilfører blod til hjertemuskelen og hjerne, er en hoved-årsak for død og uførhet. The compounds of general formula I can be used in the treatment of heart failure including congestive heart failure, retrograde heart failure) forward heart failure, left ventricular heart failure or right ventricular heart failure or in the treatment of any other condition requiring enhancement of cardiac function with a cardiotonic agent. In many respects these compounds exhibit digitalis-like action. The compounds of general formula I can also be used in the treatment of hypertension including <p>primary or essential hypertension, hormonally induced hypertension, recent hypertension and chemically induced hypertension. Finally, the compound of general formula I can be used as antithrombotic agents. They affect the coagulation of blood by preventing the aggregation of blood platelets, which play a dominant role in thrombotic states both in the initial phase and in the clogging state. Arterial thrombosis, particularly in arteries that supply blood to the heart muscle and brain, is a major cause of death and disability.

Forbindelsene kan administreres på forskjellig måte The connections can be managed in different ways

for å oppnå den ønskede effekt. Forbindelsene kan administreres alene eller i form av farmasøytiske preparater til den pasient som skal behandles enten oralt eller parenteralt, dvs. intravenøst eller intramuskulært. Mengden av administrert forbindelse vil variere med strengheten av hyperten-sjonen, hjertesvikt eller blodklumping og administreringsmåte. For oral administrering er antihypertensiv effektiv mengde to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the patient to be treated either orally or parenterally, i.e. intravenously or intramuscularly. The amount of compound administered will vary with the severity of the hypertension, heart failure or blood clot and mode of administration. For oral administration, antihypertensive is effective amount

av forbindelse fra 0,1 mg/kg av pasientens kroppsvekt pr. of compound from 0.1 mg/kg of the patient's body weight per

dag til 500 mg/kg kroppsvekt pr. dag og fortrinnsvis fra 50 day to 500 mg/kg body weight per day and preferably from 50

til 150 mg/kg kroppsvekt pr. dag. to 150 mg/kg body weight per day.

For parenteral administrering er den antihypertensivt aktive mengde av forbindelse fra 0,01 mg/kg kroppsvekt pr. For parenteral administration, the antihypertensive active amount of compound is from 0.01 mg/kg body weight per

dag opptil 150 mg/kg kroppsvekt pr. dag og fortrinnsvis fra 1,0 mg/kg kroppsvekt pr. dag til opptil 10,0 mg/kg kroppsvekt pr. dag. For oral eller parenteral administrering er den kardiotont effektive mengde av forbindelse fra 0,1 mg/kg kroppsvekt pr. dag opptil 500 mg/kg kroppsvekt pr. dag og fortrinnsvis fra 0,1 til 10,0 mg/kg kroppsvekt pr. dag. For oral eller parenteral administrering er den effektive antikoagulerende mengde av forbindelser fra 0,1 mg/kg kroppsvekt pr. dag opptil 1000 mg/kg kroppsvekt pr. dag og fortrinnsvis fra 1-100 mg/kg kroppsvekt pr. dag. day up to 150 mg/kg body weight per day and preferably from 1.0 mg/kg body weight per day to up to 10.0 mg/kg body weight per day. For oral or parenteral administration, the cardiotonically effective amount of compound is from 0.1 mg/kg body weight per day up to 500 mg/kg body weight per day and preferably from 0.1 to 10.0 mg/kg body weight per day. For oral or parenteral administration, the effective anticoagulant amount of compounds is from 0.1 mg/kg body weight per day up to 1000 mg/kg body weight per day and preferably from 1-100 mg/kg body weight per day.

For oral administrering kan en enhetsdose inneholde f. For oral administration, a unit dose may contain e.g.

eks. fra 10-100 mg aktiv bestanddel. For parenteral administrering kan en enhetsdose inneholde f.eks. fra 5-50 mg aktiv bestanddel. Gjentagende daglig administrering av forbindelsene kan være ønskelig å ville variere med pasientens tilstand og administreringsmåte. e.g. from 10-100 mg of active ingredient. For parenteral administration, a unit dose may contain e.g. from 5-50 mg of active ingredient. Repeated daily administration of the compounds may be desirable to vary with the patient's condition and method of administration.

Som anvendt her menes med uttrykket pasient et varm-blodig dyr, f.eks. fugler slik som høns og kalkuner, og pattedyr slik som primater, mennesker, sauer, haster, kuer og okser, griser, hunder, katter, rotter og mus. As used here, the term patient means a warm-blooded animal, e.g. birds such as chickens and turkeys, and mammals such as primates, humans, sheep, hamsters, cows and bulls, pigs, dogs, cats, rats and mice.

Det etterfølgende angår bruk av forbindelsene fremstilt ifølge oppfinnelsen som antihypertensive midler, kardiotone midler og antikoagulanter. The following relates to the use of the compounds produced according to the invention as antihypertensive agents, cardiotonic agents and anticoagulants.

A. Anvendelse av 1,3-dihydro-4-(4-metoksybenzoyl)-5-metyl-2H-imidazol-2-on som et antihypertensivt middel. A. Use of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one as an antihypertensive agent.

100 ml/kg av tittelforbindelsen ble administrert oralt til seks spontant hypertensive rotter. Denne dose resulterte i en 40% nedsettelse, på gjennomsnittlig basis, i blodtrykket innen 15 minutter etter administrering. 100 ml/kg of the title compound was administered orally to six spontaneously hypertensive rats. This dose resulted in a 40% reduction, on an average basis, in blood pressure within 15 minutes of administration.

B. Anvendelse av 1,3-dihydro-4-(4-metoksybenzoyl)-5-metyl-2H-imidazol-2-on som et kardiotont middel. B. Use of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one as a cardiotonic agent.

Hjertesvikt ble fremkalt i en hund ved administrering Cardiac failure was induced in one dog by administration

av 20 mg/kg natriumpentobarbitol eller 3 mg/kg propranalol-hydroklorid til blod som gjennomstrømmer hjertet. Etter administrering av en av disse hjertenedsettende midler økes høyre arterietrykk dramatisk og hjerteydelsen (cardiac output) nedsettes sterkt. Administrering av tittelforbindelsen (1 mg/kg) motvirker svikten som indikert ved en motvirkning av høyre arterietrykk og hjerteydelse til nivåer før behandling. C. Anvendelse av 1,3-dihydro-4-(4-metoksybenzoyl)-5-metyl-2H-imidazol-2-on som et antitrombosemiddel. of 20 mg/kg sodium pentobarbitol or 3 mg/kg propranalol hydrochloride to blood flowing through the heart. After administration of one of these cardiac depressants, right arterial pressure is increased dramatically and cardiac output is greatly reduced. Administration of the title compound (1 mg/kg) reverses the failure as indicated by a reversal of right arterial pressure and cardiac output to pretreatment levels. C. Use of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one as an antithrombotic agent.

Når adenosindifosfat tilsettes til sitrert blodplaterik plasma finner det sted en typisk aggregering av blodplater. When adenosine diphosphate is added to citrated platelet-rich plasma, a typical aggregation of platelets takes place.

Hvis imidlertid tittelforbindelsen tilsettes til det sitrerte blodplaterike plasma i konsentrasjoner på 3, 10, 30 og 100 yg/ml og deretter adenosindifosfat tilsettes, inhiberes aggregeringen av 33, 49, 82 og 98%. However, if the title compound is added to the citrated platelet-rich plasma at concentrations of 3, 10, 30 and 100 µg/ml and then adenosine diphosphate is added, aggregation is inhibited by 33, 49, 82 and 98%.

De etterfølgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.

Eksempel 1 Example 1

1,3-dihydro-4-(4-fluorobenzoyl)-5-metyl-2H-imidazol-2-on. 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one.

Til en omrørt blanding av 98,1 g (1 mol) 1,3-dihydro-4-metyl-2H-imidazol-2-on, 266,7 g (2 mol) vannfritt aluminiumklorid og 500 ml nitrobenzen ble dråpevis tilsatt 158,6 g (1 mol) p_-fluorbenzoylklorid i løpet av 10 minutter. Blandingen ble omrørt ved 60-65°C i 6 timer og ble deretter helt over på 2 kg is. Det resulterende bunnfall ble vasket med dietyleter og vann og ble omkrystallisert fra 1,2 liter dimetylformamid under dannelse av 131 g av tittelforbindelsen med smeltepunkt 289-292°C. To a stirred mixture of 98.1 g (1 mol) 1,3-dihydro-4-methyl-2H-imidazol-2-one, 266.7 g (2 mol) anhydrous aluminum chloride and 500 ml nitrobenzene was added dropwise 158, 6 g (1 mol) of p_fluorobenzoyl chloride in the course of 10 minutes. The mixture was stirred at 60-65°C for 6 hours and then poured onto 2 kg of ice. The resulting precipitate was washed with diethyl ether and water and recrystallized from 1.2 liters of dimethylformamide to give 131 g of the title compound, mp 289-292°C.

Eksempel 2 Example 2

1,3-dihydro-4-metyl-5-[4-(1-piperidinyl)benzoyl]-2H-imidazol-2-on. 1,3-dihydro-4-methyl-5-[4-(1-piperidinyl)benzoyl]-2H-imidazol-2-one.

En suspensjon av 11,0 g (0,05 mol) 1,3-dihydro-4-(4-fluorbenzoyl)-5-metyl-2H-imidazol-2-on i 30 ml piperidin ble omrørt ved tilbakeløpstemperatur i 24 timer. Overskudd-piperidinenble fordampet under redusert trykk og residuet ble avkrystallisert to ganger fra en blanding av isopropanol og vann under dannelse av 11,9 g av tittelforbindelsen. Smeltepunkt 260-263°C. A suspension of 11.0 g (0.05 mol) of 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one in 30 ml of piperidine was stirred at reflux temperature for 24 hours. The excess piperidine was evaporated under reduced pressure and the residue recrystallized twice from a mixture of isopropanol and water to give 11.9 g of the title compound. Melting point 260-263°C.

Eksempel 3 Example 3

1,3-dihydro-4-metyl-5-[4-(4-morfolinyl)benzoyl]-2H-imidazol-2-on. 1,3-dihydro-4-methyl-5-[4-(4-morpholinyl)benzoyl]-2H-imidazol-2-one.

Ved å følge den prosedyre som er beskrevet i eksempel 2 men anvende morfolin istedenfor piperidin ble tittelforbindelsen erholdt. Smeltepunkt 283-286°C. By following the procedure described in Example 2 but using morpholine instead of piperidine, the title compound was obtained. Melting point 283-286°C.

Eksempel 4 Example 4

1,3-dihydro-4-[4-(dimetylamino)benzoyl]-5-metyl-2H-imidazol-2-on. 1,3-dihydro-4-[4-(dimethylamino)benzoyl]-5-methyl-2H-imidazol-2-one.

En blanding av 11,0 g (0,05 mol) 1,3-dihydro-4-(4-fluorbenzoyl)-5-metyl-2H-imidazol-2-on, 100 ml 30%-ig vandig løsning av dimetylamin og 200 ml etanol ble oppvarmet i en trykkbombe til 130-135°C i 22 timer. Blandingen ble avkjølt, det faste materiale ble oppsamlet og omkrystallisert fra isopropanol-vann under dannelse av tittelforbindelsen. Smeltepunkt >310°C. X(maks.)(metanol) 364 nm (e = 23,300). A mixture of 11.0 g (0.05 mol) 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one, 100 ml of a 30% aqueous solution of dimethylamine and 200 ml of ethanol was heated in a pressure bomb to 130-135°C for 22 hours. The mixture was cooled, the solid was collected and recrystallized from isopropanol-water to give the title compound. Melting point >310°C. X(max)(methanol) 364 nm (e = 23,300).

Eksempel 5 Example 5

1,3-dihydro-4-mety1-5-[4-(metyltio)benzoyl]-2H-imidazol-2-on. 1,3-dihydro-4-methyl-5-[4-(methylthio)benzoyl]-2H-imidazol-2-one.

En løsning av 25,0 g 4-(mety.ltio)-benzosyre og 22 ml tionylklorid i 50 ml benzen ble kokt under tilbakeløpskjøling i 4 timer. Overskuddreagens og løsningsmiddel ble fordampet og residuet ble destillert azeotropt tre ganger med benzen for å fjerne all tionylklorid. Residuet ble dråpevis tilsatt til en blanding av 11,8 g 1,3-dihydro-4-metyl-2H-imidazol-2-on, 40,0 g vannfritt aluminiumklorid og 100 ml nitrobenzen. Den resulterende blanding ble omrørt ved 60-65°C i 5 timer, helt over på is og det dannede bunnfall ble oppsamlet, vasket med etyleter og vann og omkrystallisert fra isopropanol-vann under dannelse av tittelforbindelsen. Smeltepunkt 255-258°C (spaltning) . A solution of 25.0 g of 4-(methylthio)-benzoic acid and 22 ml of thionyl chloride in 50 ml of benzene was refluxed for 4 hours. Excess reagent and solvent were evaporated and the residue was azeotropically distilled three times with benzene to remove all thionyl chloride. The residue was added dropwise to a mixture of 11.8 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one, 40.0 g of anhydrous aluminum chloride and 100 ml of nitrobenzene. The resulting mixture was stirred at 60-65°C for 5 hours, poured onto ice and the precipitate formed was collected, washed with ethyl ether and water and recrystallized from isopropanol-water to give the title compound. Melting point 255-258°C (decomposition).

Eksempel 6 Example 6

1,3-dihydro-4-(4-metoksybenzoyl)-5-metyl-2H-imidazol-2-on. 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one.

Til 19,6 g 1,3-dihydro-4-metyl-2H-imidazol-2-on og 53,2 g vannfritt aluminiumklorid i 150 ml nitrobenzen ble dråpevis tilsatt 34,2 g p-metoksybenzoylklorid, og blandingen ble helt over på 500 ml 2N-HC1 og is, vasket tre ganger med etyleter hvorpå det resulterende faste materiale ble omkrystallisert fra isopropanol-vann under dannelse av tittelforbindelsen. Smeltepunkt 257-258°C (spaltning). To 19.6 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 53.2 g of anhydrous aluminum chloride in 150 ml of nitrobenzene, 34.2 g of p-methoxybenzoyl chloride was added dropwise, and the mixture was poured onto 500 ml 2N-HCl and ice, washed three times with ethyl ether whereupon the resulting solid was recrystallized from isopropanol-water to give the title compound. Melting point 257-258°C (decomposition).

Eksempel 7 Example 7

1,3-dihydro-4-(4-metoksybenzoyl)-5-metyl-2H-imidazol-2-on, natriumsalt. 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one, sodium salt.

Til 7,0 g 1,3-dihydro-4-(4-metoksybenzoyl)-5-metyl-2H-imidazol-2-on i 100 ml metanol ble tilsatt 1,6 g natriummetoksyd. Blandingen ble oppvarmet på et dampbad inntil denne ble homogen, ble filtrert og fordampet til tørrhet. Det faste residuum ble omkrystallisert fra isopropanol under dannelse av tittelforbindelsen. Smeltepunkt 280-28 2°C (spaltning). To 7.0 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one in 100 ml of methanol was added 1.6 g of sodium methoxide. The mixture was heated on a steam bath until it became homogeneous, was filtered and evaporated to dryness. The solid residue was recrystallized from isopropanol to give the title compound. Melting point 280-28 2°C (decomposition).

Eksempel 8 Example 8

4-benzoyl-l,3-dihydro-5-metylimidazol-2-on. 4-benzoyl-1,3-dihydro-5-methylimidazol-2-one.

Til en løsning av 3,0 g 4-metylimidazol-2-on og 8,0 g aluminiumklorid i 50 ml nitrobenzen ble dråpevis tilsatt 4,6 g benzoylklorid. Løsningen ble oppvarmet til 6 0°C i fire timer, ble helt over i isvann, oppslemmet med eter og det resulterende faste materiale ble filtrert og tørket under dannelse av tittelforbindelsen. Smeltepunkt 250-54°C. To a solution of 3.0 g of 4-methylimidazol-2-one and 8.0 g of aluminum chloride in 50 ml of nitrobenzene, 4.6 g of benzoyl chloride was added dropwise. The solution was heated to 60°C for four hours, poured into ice water, slurried with ether and the resulting solid filtered and dried to give the title compound. Melting point 250-54°C.

Eksempel 9 Example 9

1,3-dihydro-4-metyl-5-tienoyl-2H-imidazol-2-on. 1,3-dihydro-4-methyl-5-thienoyl-2H-imidazol-2-one.

Til en løsning av 7,3 g 4-metylimidazol-2-on og 10,8 g aluminiumklorid i 150 ml nitrobenzen ble tilsatt 12,0 g 2-tienoylklorid. Blandingen ble omrørt ved 6 0°C i 3 timer, ble avkjølt og helt over på isvann. Den organiske delen ble eks-trahert i etylacetat, tørket og det organiske løsningsmiddel ble fordampet under dannelse av tittelforbindelsen. Smeltepunkt 212-215°C. To a solution of 7.3 g of 4-methylimidazol-2-one and 10.8 g of aluminum chloride in 150 ml of nitrobenzene was added 12.0 g of 2-thienoyl chloride. The mixture was stirred at 60°C for 3 hours, cooled and poured into ice water. The organic portion was extracted into ethyl acetate, dried and the organic solvent was evaporated to give the title compound. Melting point 212-215°C.

Eksempel IQ Example IQ

1,3-dihydro-4-(3,4-dimetoksybenzoyl)-2H-imidazol-2-on. 1,3-dihydro-4-(3,4-dimethoxybenzoyl)-2H-imidazol-2-one.

Til en løsning av 6,5 g 1,3-dihydro-4-metyl-2H-imidazol-2-on og 14,6 g aluminiumklorid i 65 ml nitrobenzen ble tilsatt 17,6 g 3,4-dimetoksybenzoylklorid i porsjoner. Blandingen ble omrørt i 3 timer ved 60°C, ble avkjølt og helt over i isvann. Det gummiaktige faste materiale ble filtrert fra og omkrystallisert to ganger fra etylalkohol-vann under dannelse av tittelforbindelsen. Smeltepunkt 257-259°C. To a solution of 6.5 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 14.6 g of aluminum chloride in 65 ml of nitrobenzene, 17.6 g of 3,4-dimethoxybenzoyl chloride was added in portions. The mixture was stirred for 3 hours at 60°C, was cooled and poured into ice water. The gummy solid was filtered off and recrystallized twice from ethyl alcohol-water to give the title compound. Melting point 257-259°C.

Eksempel 11 Example 11

1,3-dihydro-4-(2-furanoyl)-5-metyl-2H-imidazol-2-on. 1,3-dihydro-4-(2-furanoyl)-5-methyl-2H-imidazol-2-one.

Til en oppslemming av 8,9 g 1,3-dihydro-4-metyl-2H-imidazol-2-on og 24,0 g aluminiumklorid i 135 ml nitrobenzen ble dråpevis tilsatt 12,9 g furanoylklorid. Blandingen ble omrørt ved 60°C i tre timer, ble avkjølt og helt over på isvann. Det faste materiale ble deretter filtrert og omkrystallisert To a slurry of 8.9 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 24.0 g of aluminum chloride in 135 ml of nitrobenzene, 12.9 g of furanoyl chloride were added dropwise. The mixture was stirred at 60°C for three hours, was cooled and poured into ice water. The solid material was then filtered and recrystallized

to ganger fra metylalkohol under dannelse av tittelforbindelsen. Smeltepunkt 214-216°C. twice from methyl alcohol to form the title compound. Melting point 214-216°C.

Eksempel 12 Example 12

1,3-dihydro-4-(2-tienoyl)-2H-imidazol-2-on. 1,3-dihydro-4-(2-thienoyl)-2H-imidazol-2-one.

I 50 ml nitrobenzen ble kombinert 13,3 g aluminiumklorid, 4,2 g 1,3-dihydro-2H-imidazol-2-on og 8,1 g tienoylklorid. Blandingen ble omrørt ved 6 0°C i tre timer og helt over på isvann. Det faste materiale ble filtrert fra, vasket med eter og omkrystallisert to ganger fra etanol-vann under dannelse av tittelforbindelsen. Smeltepunkt 339-42°C. In 50 ml of nitrobenzene, 13.3 g of aluminum chloride, 4.2 g of 1,3-dihydro-2H-imidazol-2-one and 8.1 g of thienoyl chloride were combined. The mixture was stirred at 60°C for three hours and poured into ice water. The solid was filtered off, washed with ether and recrystallized twice from ethanol-water to give the title compound. Melting point 339-42°C.

Eksempel 13 Example 13

4-benzoyl-l,3-dihydro-2H-imidazol-2-on. 4-benzoyl-1,3-dihydro-2H-imidazol-2-one.

Til 51 ml nitrobenzen ble tilsatt 1,68 g 1,3-dihydro-2H-imidazol-2-on, 5,3 g aluminiumklorid og 3,1 g benzoylklorid. Blandingen ble omrørt i tre timer ved 6 0°C og ble helt over på isvann. Det faste materiale ble filtrert fra, vasket med eter og omkrystallisert to ganger fra metylalkohol-vann under dannelse av tittelforbindelsen. Smeltepunkt 329-30°C. To 51 ml of nitrobenzene were added 1.68 g of 1,3-dihydro-2H-imidazol-2-one, 5.3 g of aluminum chloride and 3.1 g of benzoyl chloride. The mixture was stirred for three hours at 60°C and poured into ice water. The solid was filtered off, washed with ether and recrystallized twice from methyl alcohol-water to give the title compound. Melting point 329-30°C.

Eksempel 14 Example 14

1,3 -dihydro-4-furanoyl-2H-imidazol-2-on. 1,3-dihydro-4-furanoyl-2H-imidazol-2-one.

Til 50 ml nitrobenzen ble tilsatt 4,2 g 1,3-dihydro-2H-imidazol-2-on, 13,3 g aluminiumklorid og 7,2 g furanoylklorid. Blandingen ble omrørt ved 6 0°C i tre timer og ble helt over i isvann. Det faste materiale ble filtrert fra, vasket med eter og omkrystallisert to ganger fra etanol-vann under dannelse av tittelforbindelsen. Smeltepunkt 318-321°C. To 50 ml of nitrobenzene were added 4.2 g of 1,3-dihydro-2H-imidazol-2-one, 13.3 g of aluminum chloride and 7.2 g of furanoyl chloride. The mixture was stirred at 60°C for three hours and poured into ice water. The solid was filtered off, washed with ether and recrystallized twice from ethanol-water to give the title compound. Melting point 318-321°C.

Eksempel 15 Example 15

1,3-dihydro-4-(3,4-metylendioksybenzoyl)-5-metyl-2H-imidazol-2-on. 1,3-dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl-2H-imidazol-2-one.

Til 5,13 g 1,3-dihydro-4-metyl-2H-imidazol-2-on og To 5.13 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and

7,98 g vannfritt aluminiumklorid i 80 ml nitrobenzen ble dråpevis tilsatt 10,60 g 3,4-metylendioksybenzoylklorid, og blandingen ble helt over på 500 ml 2N-HC1 og is, ble vasket tre ganger med etyleter hvorpå det resulterende faste materiale ble oppsamlet under dannelse av tittelforbindelsen. Smeltepunkt 293-296°C (spaltning). 7.98 g of anhydrous aluminum chloride in 80 ml of nitrobenzene was added dropwise to 10.60 g of 3,4-methylenedioxybenzoyl chloride, and the mixture was poured into 500 ml of 2N-HCl and ice, washed three times with ethyl ether, whereupon the resulting solid was collected during formation of the title compound. Melting point 293-296°C (decomposition).

Eksempel 16 Example 16

1,3-dihydro-4-(4-metoksybenzoyl)-1,3,5-trimetyl-2H-imidazol-2-on. 1,3-dihydro-4-(4-methoxybenzoyl)-1,3,5-trimethyl-2H-imidazol-2-one.

I 120 ml DMSO ble innført 15,2 g pulverformet kaliumhydroksyd, 8,0 g 1,3-dihydro-4-(4-metoksybenzoyl)-5-metyl-2H-imidazol-2-on, natriumsalt og 19,5 g metyljodid. Blandingen ble omrørt ved romtemperatur i 60 minutter og ble helt over i 800 ml vann. Ekstraksjonen med metylenklorid gav et fast materiale som ble krystallisert fra eter. Smeltepunkt 109-111°C. NMR: N-CN3 (6 protoner) ved 3,3 ppm. 15.2 g of powdered potassium hydroxide, 8.0 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one, sodium salt and 19.5 g of methyl iodide were introduced into 120 ml of DMSO . The mixture was stirred at room temperature for 60 minutes and poured into 800 ml of water. The extraction with methylene chloride gave a solid which was crystallized from ether. Melting point 109-111°C. NMR: N-CN3 (6 protons) at 3.3 ppm.

Eksempel 17 Example 17

1,3-dihydro-(1 eller 3)-5-dimetyl-4-(4-metoksybenzoyl)-2H-imidazol-2-on. 1,3-dihydro-(1 or 3)-5-dimethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

Til 2,0 g 1,3-dihydro-4-(4-metoksybenzoyl)-5-metyl-2H-imidazol-2-on i 30 ml DMSO ble tilsatt 0,288 g natriumhydrid og 1,22 g metyljodid. Blandingen ble omrørt ved 22°C i 30 minutter, ble helt over i metylenklorid og vasket med vann. Løsningsmidlet ble tørket og fordampet under dannelse av en olje som med tritureringmed kloroform gav et fast materiale. Det faste materiale ble krystallisert fra metanol, smeltepunkt 225-228°C. To 2.0 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one in 30 ml of DMSO was added 0.288 g of sodium hydride and 1.22 g of methyl iodide. The mixture was stirred at 22°C for 30 minutes, poured into methylene chloride and washed with water. The solvent was dried and evaporated to give an oil which on trituration with chloroform gave a solid. The solid material was crystallized from methanol, mp 225-228°C.

Analyse beregnet for ci2<H>14<N>2°3<:> C <6>3,40, H 5,73, N 11,39. Analysis calculated for ci2<H>14<N>2°3<:> C <6>3.40, H 5.73, N 11.39.

Funnet: C 63,34, H 5,85, N 11,21. Found: C 63.34, H 5.85, N 11.21.

NMR: N-metyl, singlet ved 3,2 ppm. NMR: N-methyl, singlet at 3.2 ppm.

Claims (2)

1. Analogifremgangsmåte ved fremstilling av terapeutisk aktive forbindelser av generell formel hvori Ar er 2-furyl, 2-tienyl eller fenyl, idet fenylgruppen er monosubstituert i orto-, meta- eller parastilling med X^, disubstituert i parastilling med X2 eller i orto- eller metastilling med X^; X^ er halogen, rettkjedet eller forgrenet lavere alkyl med 1-4 karbonatomer, rettkjedet eller forgrenet lavere alkoksy med 1-4 karbonatomer, rettkjedet eller forgrenet lavere alkyltio med 1-4 karbonatomer, trifluormetyl, NR^R^, piperidinyl eller morfolinyl, X2 og X^ er halogen, rettkjedet eller forgrenet lavere alkoksy med 1-4 karbonatomer, rettkjedet eller forgrenet lavere alkyl med 2-4 karbonatomer; eller når X^ er i metastilling, kan X.> og X^ sammen være metylendioksy som eventuelt er substituert med én eller to metylgrupper; R er hydrogen, rettkjedet eller forgrenet lavere alkyl med 1-4 karbonatomer, rettkjedet eller forgrenet lavere alkylkarbonyl med 1-4 karbonatomer, eller benzoyl, hver av R^, R^ og R^ er hydrogen eller rettkjedet eller forgrenet lavere alkyl med 1-4 karbonatomer, forutsatt at både R^ og R^ ikke kan være hydrogen, og farmasøytisk akseptable salter derav, karakterisert ved at en forbindelse av formel hvori R., er som ovenfor angitt, Friedel-Craft acyleres med 1-10 molarekvivalenter av et 2-furoylhalogenid, 2-tienoyl-halogenid, benzoylhalogenid som er monosubstituert i orto-, meta- eller parastilling med X^, eller et disubstituert benzoylhalogenid som er substituert i parastilling med X2 eller i orto- eller metastilling med X^ hvori X^, X2 og X^ er som definert ovenfor, i nærvær av fra 1-10 molarekvivalenter av en Lewissyre-katalysator i et egnet løsningsmiddel ved en tempera-tur på 0-100°C i 1-10 timer, og når R skal være forskjellig fra hydrogen, at det resulterende aroylimidazol-2-on acyleres eller alkyleres med et acylhalogenid eller alkyleringsmiddel, alternativt a) hvor X^ er piperidinyl eller morfolinyl, at den således dannede forbindelse hvori X^ er fluor, behandles med fra 1 til 10 molarekvivalenter av piperidin eller morfolin, i et løsningsmiddel i fra 1/2 time til 48 timer ved 0-150°C, b) hvor X^ er en aminogruppe av formel NR-jR^, at en forbindelse av formelen reduseres under dannelse av det tilsvarende aminobenzoyl-imidazol-2-on som deretter alkyleres, eller hvor farmasøytisk akseptable salter ønskes, at det således dannede aroylimidazol-2-on omsettes med et egnet metall eller basisk ammoniumsalt.1. Analogy method in the preparation of therapeutic active compounds of general formula in which Ar is 2-furyl, 2-thienyl or phenyl, the phenyl group being monosubstituted in the ortho-, meta- or para-position with X^, disubstituted in the para position with X 2 or in the ortho or meta position with X 2 ; X^ is halogen, straight-chain or branched lower alkyl with 1-4 carbon atoms, straight-chain or branched lower alkoxy with 1-4 carbon atoms, straight-chain or branched lower alkylthio with 1-4 carbon atoms, trifluoromethyl, NR^R^, piperidinyl or morpholinyl, X 2 and X 1 are halogen, straight-chain or branched lower alkoxy of 1-4 carbon atoms, straight-chain or branched lower alkyl of 2-4 carbon atoms; or when X^ is in the meta position, X.> and X^ together may be methylenedioxy optionally substituted with one or two methyl groups; R is hydrogen, straight or branched lower alkyl of 1-4 carbon atoms, straight or branched lower alkylcarbonyl of 1-4 carbon atoms, or benzoyl, each of R^, R^ and R^ is hydrogen or straight or branched lower alkyl of 1- 4 carbon atoms, provided that both R^ and R^ cannot be hydrogen, and pharmaceutically acceptable salts thereof, characterized in that a compound of formula in which R., as indicated above, is Friedel-Craft acylated with 1-10 molar equivalents of a 2-furoyl halide, 2-thienoyl halide, benzoyl halide which is monosubstituted in the ortho-, meta- or para-position with X 2 , or a disubstituted benzoyl halide substituted in the para position with X 2 or in the ortho or meta position with X 2 wherein X 2 , X 2 and X 2 are as defined above, in the presence of from 1-10 molar equivalents of a Lewis acid catalyst in a suitable solvent at a temperature of 0-100°C for 1-10 hours, and when R must be different from hydrogen, that the resulting aroylimidazol-2-one is acylated or alkylated with an acyl halide or alkylating agent, alternatively a) where X^ is piperidinyl or morpholinyl, that the thus formed compound in which X^ is fluorine is treated with from 1 to 10 molar equivalents of piperidine or morpholine, in a solvent for from 1/2 hour to 48 hours at 0-150°C, b ) where X^ is an amino group of formula NR -jR^, that one connection of the formula is reduced to form the corresponding aminobenzoyl-imidazol-2-one which is then alkylated, or where pharmaceutically acceptable salts are desired, the thus formed aroylimidazol-2-one is reacted with a suitable metal or basic ammonium salt. 2. Fremgangsmåte ifølge krav 1, for fremstilling av 1,3-dihydro-4-metyl-5-[4-(metyltio)-benzoyl]-2H-imidazol-2-on, karakterisert ved at 1,3-dihydro-4-metyl-2H-imidazol-2-on acyleres med 4-(metyltio)-benzoylklorid.2. Process according to claim 1, for the production of 1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one, characterized in that 1,3-dihydro-4 -methyl-2H-imidazol-2-one is acylated with 4-(methylthio)-benzoyl chloride.
NO801796A 1979-06-18 1980-06-17 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NEW 4-AROYLIMIDAZOL-2-ONES. NO152841C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4980879A 1979-06-18 1979-06-18
US11920780A 1980-02-07 1980-02-07

Publications (3)

Publication Number Publication Date
NO801796L NO801796L (en) 1980-12-19
NO152841B true NO152841B (en) 1985-08-19
NO152841C NO152841C (en) 1985-11-27

Family

ID=26727558

Family Applications (1)

Application Number Title Priority Date Filing Date
NO801796A NO152841C (en) 1979-06-18 1980-06-17 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NEW 4-AROYLIMIDAZOL-2-ONES.

Country Status (20)

Country Link
AT (1) AT375349B (en)
AU (1) AU532783B2 (en)
CA (1) CA1132554A (en)
CH (1) CH646155A5 (en)
DE (1) DE3021792A1 (en)
DK (1) DK160269C (en)
ES (1) ES8105299A1 (en)
FR (1) FR2459233A1 (en)
GB (1) GB2055364B (en)
HK (1) HK61486A (en)
HU (1) HU186736B (en)
IE (1) IE50646B1 (en)
IL (1) IL60243A (en)
IT (1) IT1143922B (en)
MY (1) MY8600709A (en)
NL (2) NL193752C (en)
NO (1) NO152841C (en)
NZ (1) NZ193935A (en)
PH (1) PH18683A (en)
SE (2) SE447107B (en)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH18106A (en) * 1981-02-18 1985-03-21 Merrell Dow Pharma Novel-4-aroylimidazol-2-ones
US4405628A (en) * 1981-03-05 1983-09-20 Merrell Dow Pharmaceuticals Inc. 4-Pyridylimidazolones and method of use
US4329471A (en) * 1981-05-04 1982-05-11 Merrell Dow Pharmaceuticals Inc. 4-(4-Phenyl-1-piperidinyl)methyl-5-acyl-1,3-dihydro-2H-imidazol-2-ones
US4329470A (en) * 1981-05-04 1982-05-11 Merrell Dow Pharmaceuticals Inc. 5-(4-Phenyl 1-piperidinyl)methyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid derivatives
AU549872B2 (en) * 1981-05-04 1986-02-20 Merrell Dow Pharmaceuticals Inc. 4-oxymethyl-5-acyl-1,3-dihydro-2h-imidazol-2-ones
US4371737A (en) * 1981-05-04 1983-02-01 Merrell Dow Pharmaceuticals Inc. 5-Aminomethyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid derivatives
US4381393A (en) * 1981-05-04 1983-04-26 Merrell Dow Pharmaceuticals Inc. 4-Aminomethyl-5-acyl-1,3-dihydro-2H-imidazol-2-ones
US4526981A (en) * 1981-05-04 1985-07-02 Merrell Dow Pharmaceuticals Inc. [1,2-Dihydro-4(5)-acyl-2-oxo-2H-imidazol-4(5)-yl] methyl nitrates
US4367236A (en) 1981-11-04 1983-01-04 Merrell Dow Pharmaceuticals Inc. Method for the treatment of cardiac failure with alkanoylimidazol-2-one derivatives
US4410540A (en) * 1981-11-04 1983-10-18 Merrell Dow Pharmaceuticals Inc. Cardiotonic 4-aroylimidazolidin-2-ones
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
JP2007530566A (en) * 2004-03-22 2007-11-01 ミオゲン インコーポレイティッド (R) -Enoximone sulfoxide and its use in the treatment of PDE-III mediated diseases
CA2560528A1 (en) * 2004-03-22 2005-10-06 Myogen, Inc. (s) - enoximone sulfoxide and its use in the treatment of pde-iii mediated diseases
EP2218442A1 (en) 2005-11-09 2010-08-18 CombinatoRx, Inc. Methods, compositions, and kits for the treatment of ophthalmic disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
US7879802B2 (en) 2007-06-04 2011-02-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP2810951B1 (en) 2008-06-04 2017-03-15 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
ES2624828T3 (en) 2008-07-16 2017-07-17 Synergy Pharmaceuticals Inc. Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
JP6251038B2 (en) 2011-03-01 2017-12-20 シナジー ファーマシューティカルズ インコーポレイテッド Method for preparing guanylate cyclase C agonist
US20150119399A1 (en) 2012-01-10 2015-04-30 President And Fellows Of Harvard College Beta-cell replication promoting compounds and methods of their use
EP2958577A2 (en) 2013-02-25 2015-12-30 Synergy Pharmaceuticals Inc. Guanylate cyclase receptor agonists for use in colonic cleansing
AU2014235209B2 (en) 2013-03-15 2018-06-14 Bausch Health Ireland Limited Guanylate cyclase receptor agonists combined with other drugs
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
AU2014274812B2 (en) 2013-06-05 2018-09-27 Bausch Health Ireland Limited Ultra-pure agonists of guanylate cyclase C, method of making and using same
KR20160042039A (en) 2013-08-09 2016-04-18 알데릭스, 인코포레이티드 Compounds and methods for inhibiting phosphate transport
US20200368223A1 (en) 2019-05-21 2020-11-26 Ardelyx, Inc. Methods for inhibiting phosphate transport
CN114539157B (en) * 2022-03-03 2023-12-22 曲靖师范学院 Method for preparing 4-iodo-N-aryl pyrazole compound by iodine-promoted oxidation method

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2441933A (en) * 1945-07-30 1948-05-18 Hoffmann La Roche Substituted imidazolones and process of making them

Also Published As

Publication number Publication date
SE447107B (en) 1986-10-27
FR2459233A1 (en) 1981-01-09
NZ193935A (en) 1985-05-31
AU532783B2 (en) 1983-10-13
IT8048997A0 (en) 1980-06-17
SE8501452D0 (en) 1985-03-25
NL193752B (en) 2000-05-01
NO801796L (en) 1980-12-19
CH646155A5 (en) 1984-11-15
ES492255A0 (en) 1981-06-01
PH18683A (en) 1985-08-29
NL300015I2 (en) 2000-10-02
NL300015I1 (en) 2000-11-01
ES8105299A1 (en) 1981-06-01
HU186736B (en) 1985-09-30
DE3021792C2 (en) 1989-08-10
HK61486A (en) 1986-08-29
GB2055364A (en) 1981-03-04
IT1143922B (en) 1986-10-29
GB2055364B (en) 1983-06-08
NO152841C (en) 1985-11-27
AT375349B (en) 1984-07-25
DK160269B (en) 1991-02-18
SE8004253L (en) 1980-12-19
IE801162L (en) 1980-12-18
DK160269C (en) 1991-07-22
MY8600709A (en) 1986-12-31
IE50646B1 (en) 1986-06-11
IL60243A (en) 1987-01-30
FR2459233B1 (en) 1983-09-23
NL8003498A (en) 1980-12-22
DE3021792A1 (en) 1981-01-22
DK259080A (en) 1980-12-19
IL60243A0 (en) 1980-09-16
CA1132554A (en) 1982-09-28
AU5911880A (en) 1981-01-08
SE8501452L (en) 1985-03-25
SE464559B (en) 1991-05-13
NL193752C (en) 2000-09-04
ATA314280A (en) 1983-12-15

Similar Documents

Publication Publication Date Title
NO152841B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NEW 4-AROYLIMIDAZOL-2-ONES
Petersen et al. Synthesis and hypotensive activity of N-alkyl-N''-cyano-N'-pyridylguanidines
US4405635A (en) 4-Aroylimidazol-2-ones and their use as pharmaceuticals
JPH0236159A (en) Chemical compounds
JPH0597816A (en) 4-aryl-thiazole or imidazole derivative
JP2004517086A (en) Substituted 2-anilinobenzimidazoles and their use as NHE inhibitors
CS249115B2 (en) Method of new imidazolylphenylamides production
PL145230B1 (en) Method of obtaining novel 2-ketoindolo-1-carbonamides
EP0058435A2 (en) Novel 4-aroylimidazol-2-ones
JPH0223548B2 (en)
US4025508A (en) 6-(Trifluoromethyl)-benzothiadiazines
DK149364B (en) ANALOGY PROCEDURE FOR PREPARATION OF 5- (CHLORPHENYL) -6H-1,3,4-THIADIAZIN-2-AMINES
DE2811477A1 (en) 1,2,4-TRIAZINE-5-ON DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
NO131345B (en)
NO156567B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE ALKANOYLIMIDAZOLE-2 DERIVATIVES.
JPH0616638A (en) Pyridine compound and its medicinal use
US3329677A (en) N-benzhydryloxyphthalimides and pryidinealdehyde o-benzhydryloximes
Seidel et al. Reactions of 2-acetoacetylamine pyridines with triethylorthoformate and zinc chloride
NO148556B (en) ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE TRIAZINONES.
JPH08225537A (en) Imidazole derivative, its acid addition salt permissible as medicine, their production and antiulcer comprising the same derivative or its acid addition salt as active ingredient
US3476748A (en) Substituted 6,7-dihydro-5-h-pyrimidino thiazines
US3592851A (en) 2&#39;-amino-2-benzoyl-benzenesulfonanilides
DK151885B (en) METHOD OF PREPARING PYRIDOOE1,2AAAPYRIMIDIN-3-CARBOXAMIDES OR OPTICALLY ACTIVE ISOMERS OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF
US3209009A (en) Pons ctal
DE3121137A1 (en) Novel pyridazino[4,5-b]indoles, processes for their preparation, their use and also pharmaceutical preparations based on these compounds, intermediates and their preparation