NO772893L - DIHYDRO-OXO-NICOTIC ACIDS AND PROCEDURES FOR THEIR PREPARATION - Google Patents

DIHYDRO-OXO-NICOTIC ACIDS AND PROCEDURES FOR THEIR PREPARATION

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Publication number
NO772893L
NO772893L NO772893A NO772893A NO772893L NO 772893 L NO772893 L NO 772893L NO 772893 A NO772893 A NO 772893A NO 772893 A NO772893 A NO 772893A NO 772893 L NO772893 L NO 772893L
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Norway
Prior art keywords
dihydro
oxo
formula
residue
nicotinic acid
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NO772893A
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Norwegian (no)
Inventor
Rudi Weyer
Volker Hitzel
Ernold Granzer
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Hoechst Ag
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Publication of NO772893L publication Critical patent/NO772893L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

Description

Oppfinnelsen vedrører dihydro-okso-nikotinsyrer med den generelle formel I The invention relates to dihydro-oxo-nicotinic acids of the general formula I

som som fri forbindelser eller i form av deres fysiologisk tålbare salter eller estere har verdifulle farmakologiske egenskaper . which as free compounds or in the form of their physiologically tolerable salts or esters have valuable pharmacological properties.

I den generelle formel betyr In the general formula means

R alkyl med 3 til 8 karbonatomer, alkenyl med 3 til R alkyl with 3 to 8 carbon atoms, alkenyl with 3 to

6 karbonatomer, 6 carbon atoms,

cykloalkyl, cykloalkenyl, alkylcykloalkyl, alkylcykloalkenyl, cykloalkylalky1, cykloalkenylalkyl, alkylcykloalkylalkyl eller alkylcykloalkenylalkyl med hver 5 til 9 karbonatomer, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, cycloalkylalky1, cycloalkenylalkyl, alkylcycloalkylalkyl or alkylcycloalkenylalkyl each having 5 to 9 carbon atoms,

alkoksyalkyl med 3-6 C-atomer, idet alkyldelen Alkoxyalkyl with 3-6 C atoms, being the alkyl part

minst inneholder 2 C-atomer, contains at least 2 C atoms,

metoksycyklohéksyl, klorcykloheksy1, bicykloheptyl, bicykloheptenyl, bicykloheptylmetyl, bicykloheptenylmetyl, notri- methoxycyclohexyl, chlorocyclohexy1, bicycloheptyl, bicycloheptenyl, bicycloheptylmethyl, bicycloheptenylmethyl, notri-

cyklyl, cyclyl,

en rest med formel a remainder with formula

■ hvori Y betyr en alkylenrest med 1-3 C-atomer, R betyr alkyl eller alkoksy med hver 1 til 4 karbonatomer, halogen, trifluormetyl eller sammen med R^ eller R betyr metylendioksygruppen, ■ in which Y means an alkylene residue with 1-3 C atoms, R means alkyl or alkoxy with each 1 to 4 carbon atoms, halogen, trifluoromethyl or together with R^ or R means the methylenedioxy group,

5 6- 5 6-

R , R betyr hydrogen, alkyl eller alkoksy med hver 1 til 4 karbonatomer eller halogen, en rest med formel R , R means hydrogen, alkyl or alkoxy each having 1 to 4 carbon atoms or halogen, a residue of formula

hvori Y betyr en alkylenrest med 1-3 C-atomer, R^ betyr hydrogen, alkyl eller alkoksy med hver 1 til 4 C-atomer, halogen, trifluormetyl og R Q betyr hydrogen, alkyl eller alkoksy med hver 1 til 4 C-atomer eller halogen, en rest med formel hvori R-q7 betyr en rest med formel in which Y means an alkylene radical with 1 to 3 C atoms, R^ means hydrogen, alkyl or alkoxy with each 1 to 4 C atoms, halogen, trifluoromethyl and R Q means hydrogen, alkyl or alkoxy with each 1 to 4 C atoms or halogen, a residue of formula wherein R-q7 means a residue of formula

eller en naftylmetylrest, or a naphthylmethyl residue,

12 3 12 3

R , R ,R^ betyr hver hydrogen, alkyl med 1 til 4 R , R , R^ each mean hydrogen, alkyl of 1 to 4

12 3 12 3

karbonatomer eller halogen, idet R , R og R^ kan værelike eller forskjellige. carbon atoms or halogen, R , R , and R 2 may be the same or different.

Forbindelser, hvori R<4>, R og R betyr hydrogen er allerede omtalt (J. Org. Chem. 28, 1443 (1963)). En farmakologisk virkning av disse forbindelser nevnes imidlertid ikke. Compounds in which R<4>, R and R are hydrogen have already been discussed (J. Org. Chem. 28, 1443 (1963)). However, a pharmacological effect of these compounds is not mentioned.

Oppfinnelsens gjenstand er derfor ved siden av dihydroksy-oksonikotinsyrene med formel I, deres fysiologisk tålbare salter og estere også fremgangsmåter til deres fremstilling. Videre vedrører oppfinnelsen farmasøytiske preparater som inneholder en forbindelse med formel I eller en forbindelse The object of the invention is therefore, in addition to the dihydroxy-oxonicotinic acids of formula I, their physiologically tolerable salts and esters, also methods for their preparation. Furthermore, the invention relates to pharmaceutical preparations containing a compound of formula I or a compound

med formel Ia with formula Ia

12 hvori R , R og R-' har overnevnte betydning og R betyr en rest med formel 12 in which R , R and R-' have the above meaning and R means a residue with formula

hvori Y har overnevnte betydning, eller deres salter eller estere eller består av disse samt deres anvendelse som resp, i legemiddel eller legemidler. in which Y has the above meaning, or their salts or esters or consist of these as well as their use as, respectively, in a medicine or medicines.

Foretrukket er innen oppfinnelsens ramme slike forbindelser, hvori R betyr en substituert benzylrest eller Preferred within the scope of the invention are such compounds, in which R means a substituted benzyl radical or

1 2 3 1 2 3

fenyletylrest. R , R og R betyr fortrinnsvis hydrogen og også metyl. phenylethyl residue. R , R and R preferably mean hydrogen and also methyl.

Fremgangsmåten til fremstilling av pyridinkarbok-sylsyre med den generelle formel I erkarakterisert vedat The process for the preparation of pyridine carboxylic acid with the general formula I is characterized thereby

a) et amin med den génerelle formel II a) an amine of the general formula II

hvori R har overnevnte betydning omsettes med et malonsyrederivat med den generelle formel III, eller dets ringslutnings-produkt med den generelle formel IV hvori R 1 , R 2 og R-3^ hver betyr hydrogen eller alkyl med 1 til 4 C-atomer, eventuelt cykliseres deri dannede aminoallylidenmalonester og den dannede forbindelse halogeneres eventuelt, eller b) et amin med overnevnte generelle formel II RNH2kondenseres med et malonsyrederivat med den generelle formel V hvori R<1>betyr hydrogen eller alkyl med 1 til 4 C-atomer til et malonhalvamid med formel VI dette omsettes med dimetylformamidacetal og den dannede forbindelse halogeneres eventuelt, eller c) en pyridonkarboksylsyre med den generelle formel VII eller dens salter eller estere omsettes med en forbindelse med den generelle formel RX, hvori X betyr et halogenatom, fortrinnsvis- klor eller en sulfonyloksyrest, eller d) i et pyridonderivat med den generelle formel VIII in which R has the above-mentioned meaning is reacted with a malonic acid derivative of the general formula III, or its ring closure product of the general formula IV in which R 1 , R 2 and R-3^ each means hydrogen or alkyl with 1 to 4 C atoms, optionally the aminoallylidene malone ester formed therein is cyclized and the compound formed is optionally halogenated, or b) an amine of the above-mentioned general formula II RNH2 is condensed with a malonic acid derivative of the general formula V in which R<1> denotes hydrogen or alkyl with 1 to 4 C atoms to a malonhalamide with formula VI this is reacted with dimethylformamide acetal and the compound formed is optionally halogenated, or c) a pyridone carboxylic acid of the general formula VII or its salts or esters is reacted with a compound of the general formula RX, in which X means a halogen atom, preferably chlorine or a sulfonyloxy acid residue , or d) in a pyridone derivative of the general formula VIII

hvori R, R"*", R^ og R^ har overnevnte betydning og Z betyr en til wherein R, R"*", R^ and R^ have the above meaning and Z means one more

en karboksylgruppe overførbar rest, omdannes denne til en karbok- . a carboxyl group transferable residue, this is converted into a carboxy- .

sylgruppe needle group

i. in.

og ifølge fremgangsmåte a) til d) eventuelt dannede syrer forestres eller overføres i salter resp. dannede estere forsåpes. and according to method a) to d) any acids formed are esterified or transferred into salts or formed esters are saponified.

De for fremstilling av forbindelsene ifølge oppfinnelsen ifølge metode a) anvendte alkoksyallyliden-malonestere fåes ved kondensasjon av malonester.med malonaldehydacetal og overføres etter kjent metode med aminene R-NR^.i mellomtrinnet The alkoxyallylidene malon esters used for the preparation of the compounds according to the invention according to method a) are obtained by condensation of malon esters with malonaldehyde acetal and are transferred according to a known method with the amines R-NR^ in the intermediate step

og dette omdannes fortrinnsvis med baser i pyridonkarboksylsyrene. and this is preferably converted with bases in the pyridone carboxylic acids.

Istedenfor de anvendte alkoksyallyliden-malonestere kan også de tilsvarende substituerte pyronsyrederivater IV, som likeledes fåes av alkoksyallyliden-malonestrene etter kjente metoder, ved oppvarmning med aminer RNH2overføres i forbindelsene ifølge oppfinnelsen. Instead of the alkoxyallylidene malonesters used, the corresponding substituted pyronic acid derivatives IV, which are likewise obtained from the alkoxyallylidene malonesters by known methods, can also be transferred by heating with amines RNH2 into the compounds according to the invention.

Alkylrestene, som forbindelsene med formlene III, IV og V har, kan varieres etter ønske, da de kan avspaltes ved reaksjon. The alkyl residues, which the compounds of the formulas III, IV and V have, can be varied as desired, as they can be split off by reaction.

Ved fremstilling etter metode b) omsettes den substituerte malonester ved oppvarmning med aminene RNH~2 til malon-esterhalvamid. Halvamidet cykliseres ved reaksjon med dimetylformamidacetal, fortrinnsvis i nærvær av baser til pyridonkarbok- In preparation according to method b), the substituted malon ester is converted by heating with the amines RNH~2 to malon ester half amide. The half-amide is cyclized by reaction with dimethylformamide acetal, preferably in the presence of bases to pyridone carbox-

sylsyrederivat. syllic acid derivative.

Ifølge fremgangsmåte c) anvendes den ved nitrogen-atomet usubstituerte pyridonkarboksylsyre i form av et salt eller en ved karboksylgruppen beskyttet forbindelse og bringes i nærvær av syrebindende midler til reaksjon med halogenid RX eller sulfonsyreesteren av alkoholen ROH. According to method c) the pyridone carboxylic acid unsubstituted at the nitrogen atom is used in the form of a salt or a compound protected by the carboxyl group and brought into the presence of acid-binding agents to react with the halide RX or the sulphonic acid ester of the alcohol ROH.

Til fremstillingen ifølge fremgangsmåte d) kan resten Z på kjent måte enten omdannes hydrolytisk eller oksydativt til en karboksylgruppe. Som rester som kan omdannes hydrolytisk til en karboksylgruppe er det fortrinnsvis å nevne nitril- resp. karbamoylgruppen. Forsåpningen kan foregå såvel i surt som også i alkalisk medium, eventuelt over mellomtrinnet med iminoeteren. På oksydativ måte kan det til en karboksylgruppe eksempelvis omdannes hydroksymetyl-, aminometyl-, formyl- og acylgruppen ved innvirkning av oksydasjonsmidler, fortrinnsvis av permanganat, kromat eller hypoklorit resp. også sølvoksyd eller luftoksygen. For the preparation according to method d), the residue Z can be converted either hydrolytically or oxidatively into a carboxyl group in a known manner. As residues that can be converted hydrolytically into a carboxyl group, it is preferable to mention nitrile or the carbamoyl group. The saponification can take place both in an acidic and in an alkaline medium, optionally via the intermediate step with the iminoether. In an oxidative way, the hydroxymethyl, aminomethyl, formyl and acyl group can be converted to a carboxyl group, for example, by the action of oxidizing agents, preferably permanganate, chromate or hypochlorite or also silver oxide or atmospheric oxygen.

De anvendte nitriler fåes ved kondensasjon av N-R-substituerte cyanacetamider med 1,3-diketoner. En annen måte til fremstilling av nitrilene består i alkylering av ved nitro-genet usubstituerte 1,2-dihydro-2-okso-nikotinsyrenitriler. The nitriles used are obtained by condensation of N-R-substituted cyanoacetamides with 1,3-diketones. Another way to prepare the nitriles consists in the alkylation of 1,2-dihydro-2-oxo-nicotinic acid nitriles unsubstituted at the nitrogen gene.

Ifølge fremgangsmåte a) og b) fåes forbindelser, som i pyridonringen ikke inneholder halogen. Ved omsetning med halogen eller halogeneringsmidler som SC^C^ kan halogen (klor) innføres. According to methods a) and b), compounds are obtained which do not contain halogen in the pyridone ring. When reacting with halogen or halogenating agents such as SC^C^, halogen (chlorine) can be introduced.

Forbindelsene ifølge oppfinnelsen kan overføres i fysiologisk tålbare salter. Slike salter er alkali-,~jordalkali-salter eller salter med egnede aminer. The compounds according to the invention can be transferred in physiologically tolerable salts. Such salts are alkali, alkaline earth salts or salts with suitable amines.

Fremstillingen av disse salter foregår på i og for seg kjent måte, eksempelvis ved omsetning med de fri baser eller karbonater. The production of these salts takes place in a manner known per se, for example by reaction with the free bases or carbonates.

Pyridonkarboksylsyrene kan også etter kjente fremgangsmåter overføres i estere. Til forestring egner det seg prinsippielt alle alkoholer, fortrinnsvis anvendes imidlertid lavere alkoholer som metanol, etanol, propanol eller også glykol, etanolamin resp. glykoleter. The pyridone carboxylic acids can also be converted into esters according to known methods. In principle, all alcohols are suitable for esterification, preferably, however, lower alcohols are used such as methanol, ethanol, propanol or also glycol, ethanolamine or glycol ether.

Forbindelsene ifølge oppfinnelsen har verdifulle terapeutiske egenskaper og utmerker seg ved en lipidsenkende virkning. The compounds according to the invention have valuable therapeutic properties and are distinguished by a lipid-lowering effect.

Den lipidsenkende virkning kan fastslås i forskjellige forsøksmodeller. I standardprøve får hanrotter med normalt The lipid-lowering effect can be determined in different experimental models. In the standard test, male rats score normally

serumlipidinnhold i 8 dager preparatet i en dosering på 100 mg/ serum lipid content for 8 days the preparation in a dosage of 100 mg/

kg oralt med sluksonde. kg orally with a feeding tube.

Før og etter behandlingen uttas blod og i serum bestemmes konsentrasjonen av kolesterol etter metoden av Lauber og Richterich og triglycerider etter metoden av Eggstein og Kreutz. De dannede verdier sammenlignes med utgangskonsentra-sjonen og dessuten av en kontrollgruppe. Before and after the treatment, blood is taken and in serum the concentration of cholesterol is determined according to the method of Lauber and Richterich and triglycerides according to the method of Eggstein and Kreutz. The values formed are compared with the starting concentration and also with a control group.

Noen av forbindelsene viser dessuten en blodsukkersenkende virkning. Some of the compounds also show a blood sugar-lowering effect.

Den blodsukkersenkende virkning av forbindelsene ifølge oppfinnelsen kan fastslås, idet man administrerer forbindelsene i doser på 100 mg/kg på normalt ernærte kaniner og bestemmer blodsukkeret over et lengre tidsrom etter metoden av Hagedorn-Jensen eller med autoanalysør. The blood sugar-lowering effect of the compounds according to the invention can be determined by administering the compounds in doses of 100 mg/kg to normally fed rabbits and determining the blood sugar over a longer period of time according to the method of Hagedorn-Jensen or with an autoanalyzer.

Forbindelsene ifølge oppfinnelsen skal fortrinnsvis tjene til fremstilling av oralt administrerbare preparater med lipidsenkende virkning til behandling av lipidstoffvekselfor-styrrelser og/eller Diabetes mellitus og kan appliseres som sådanne eller i form av deres salter eller estere resp. i nærvær av stoffer som tjener til saltdanneIse. The compounds according to the invention should preferably serve for the production of orally administrable preparations with lipid-lowering effects for the treatment of lipid metabolism disorders and/or diabetes mellitus and can be applied as such or in the form of their salts or esters or in the presence of substances that serve to form salt ice.

De nye forbindelser kan enten anvendes alene eller blandet med farmakologisk godtagbare bærere. Derved foretrekkes en oral anvendelsesform. The new compounds can either be used alone or mixed with pharmacologically acceptable carriers. Thereby, an oral application form is preferred.

Som medisinske preparater kommer det fortrinnsvis As medicinal preparations it comes preferably

i betraktning tabletter, som ved siden av fremgangsmåteproduktene inneholder vanlige bærere og hjelpestoffer som talkum, stivelse, melkesukker,«tragant og magnesiumstearat. considering tablets, which, in addition to the process products, contain usual carriers and excipients such as talc, starch, milk sugar, tragacanth and magnesium stearate.

Et preparat som inneholder de omtalte forbindelser som virksomt stoff, f.eks. en tablett eller et pulver med eller uten tilsetninger er hensiktsmessig bragt i en egnet dosert form. Som dosis er det da å velge en slik som er tilpasset virkningen A preparation containing the mentioned compounds as active substance, e.g. a tablet or a powder with or without additives is conveniently brought into a suitable dosage form. The dose is then to choose one that is adapted to the effect

av det anvendte virksomme stoff og den ønskede effekt. Hensiktsmessig utgjør doseringen pr. enhet ca. 0,1 til 2 g, fortrinnsvis 0,5 til 1 g,.imidlertid kan det også anvendes høyere- eller lavere-liggende doseringsenheter, som eventuelt må deles eller mang-foldiggjøres før applikasjon, of the active substance used and the desired effect. Appropriately, the dosage per unit approx. 0.1 to 2 g, preferably 0.5 to 1 g, however, higher or lower dosage units can also be used, which may have to be divided or multiplied before application,

Dihydro-okso-nikotinsyrene ifølge oppfinnelsen kan anvendes såvel alene som også i kombinasjon med andre midler. The dihydro-oxo-nicotinic acids according to the invention can be used both alone and in combination with other agents.

Som egnede stoffer for en slik kombinasjon: Kretsløpsmidler i videste betydning, spesielt imidlertid koronardilatatorer som kromonar eller prenylamin og blodsukkersenkende stoffer som reserpin, alfa-metyl-dopa eller klonidin, andre lipidsenkere eller geriatrika, psykofarmaka som f.eks. klordiazepoksyd, diazepam eller meprobamat samt vitaminer. Por behandling av Diabetes mellitus kommer det ikke bare i betraktning blodsukkersenkende sulfonylurinstoffer som ytterligere virksomme stoffer, men også forbindelser av forskjellig kjemisk oppbygning, som eksempelvis biguanider, spesielt fenyletyl-biguanid eller dimetyl-biguanid. As suitable substances for such a combination: Circulatory agents in the broadest sense, but especially coronary dilators such as chromonar or prenylamine and blood sugar-lowering substances such as reserpine, alpha-methyl-dopa or clonidine, other lipid-lowering or geriatric drugs, psychopharmaceuticals such as e.g. chlordiazepoxide, diazepam or meprobamate and vitamins. For the treatment of diabetes mellitus, it is not only blood sugar-lowering sulphonylureas that come into consideration as additional active substances, but also compounds of different chemical structure, such as biguanides, especially phenylethyl biguanide or dimethyl biguanide.

De følgende eksempler viser noen av de tallrike fremgangsmåtevarianter, som kan anvendes til fremstilling av forbindelsene ifølge oppfinnelsen uten dermed å begrense oppfinnelsens gjenstand. The following examples show some of the numerous process variants which can be used to produce the compounds according to the invention without thereby limiting the object of the invention.

Eksempel 1. Example 1.

1- ( 4- klorbenzyl) - 1, 2- dihydro- 2- okso- nikotinsyre . 1-(4-chlorobenzyl)-1,2-dihydro-2-oxo-nicotinic acid.

18,1 g 3-etoksy-allyliden-malonsyredietylester opp-løses i 30 ml absolutt etanol og blandes ved værelsestemperatur med 10,6 g 4-klorbenzylamin. Temperaturen øker noe, deretter begynner etter ca. en time en krystallutskillelse. Man frasuger etter henstand natten over og tørker. Den dannede 3-(4-klor-benzylamino)-allyliden-malonsyredietylester (smeltepunkt 117 - 119°C) innføres i en oppløsning av natriumetylat fremstillet av 250 ml absolutt etanol og 8 g natrium. Det oppsto en klar opp-løsning og kort tid senere utskiller reaksjonsproduktet seg. Etter flere timers henstand frasuges, stoffet oppløses i vann, oppløsningen filtreres og surgjøres med fortynnet saltsyre. Etter frasugning, gjenutfelling fra fortynnet ammoniakk og omkrystallisering fra metanol-DMF får man 1-(4-klorbenzyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 191-193°C. 18.1 g of 3-ethoxy-allylidene-malonic acid diethyl ester is dissolved in 30 ml of absolute ethanol and mixed at room temperature with 10.6 g of 4-chlorobenzylamine. The temperature rises slightly, then begins after approx. one hour a crystal discharge. One vacuums off after standing overnight and dries. The formed 3-(4-chloro-benzylamino)-allylidene-malonic acid diethyl ester (melting point 117 - 119°C) is introduced into a solution of sodium ethylate prepared from 250 ml of absolute ethanol and 8 g of sodium. A clear solution was formed and a short time later the reaction product separated. After a period of several hours, suction is taken off, the substance is dissolved in water, the solution is filtered and acidified with dilute hydrochloric acid. After extraction, reprecipitation from dilute ammonia and recrystallization from methanol-DMF, 1-(4-chlorobenzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 191-193°C is obtained.

På analog måte får man Analogously, you get

1-(4-mety1-benzyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 163 - 165°C (fra metanol-DMF) 1-(4-methyl-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 163 - 165°C (from methanol-DMF)

1-(3,4-diklor-benzy1)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 219 - 220°C (fra etanol-DMF). 1-(3,4-dichloro-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 219 - 220°C (from ethanol-DMF).

Eksempel 2. Example 2.

1-( 4- metoksy- benzyl)- 1, 2- dihydro- 2- okso- nikotinsyre . 1-(4-Methoxy-benzyl)-1,2-dihydro-2-oxo-nicotinic acid.

18,1 g 3-etoksyallyliden-malonsyredietylester opp-løses i 30 ml absolutt etanol og blandes med 9,1 g 4-metoksy-benzylamin. Temperaturen øker til ca, 40°, deretter begynner en krystallutskillelse. 18.1 g of 3-ethoxyallylidene-malonic acid diethyl ester are dissolved in 30 ml of absolute ethanol and mixed with 9.1 g of 4-methoxy-benzylamine. The temperature rises to approx. 40°, then crystal precipitation begins.

Man lar det stå noen timer, frasuger og tørker. 3-(4-metoksy-benzylamino)-allyliden-malonat (smeltepunkt 122 123°C) innføres i en natriumetylatoppløsning, fremstillet av 8 g natrium og 150 ml etanol. Etter flere timers henstand for-tynnes reaksjonsblandingen med vann, filtreres, filtratet sur-gjøres med fortynnet saltsyre, det utfelte produkt frasuges og omkrystalliseres fra metanol. Den dannede 1-(4-metoksy-benzyl)-l,2-dihydro-2-okso-nikotinsyre smelter ved l4l - l42°C. You leave it for a few hours, vacuum and dry. 3-(4-Methoxy-benzylamino)-allylidene malonate (melting point 122-123°C) is introduced into a sodium ethylate solution, prepared from 8 g of sodium and 150 ml of ethanol. After standing for several hours, the reaction mixture is diluted with water, filtered, the filtrate is acidified with dilute hydrochloric acid, the precipitated product is filtered off with suction and recrystallized from methanol. The 1-(4-methoxy-benzyl)-1,2-dihydro-2-oxo-nicotinic acid formed melts at 141-142°C.

På analog måte får man Analogously, you get

l-(2-klor-benzyl)-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 165 - l67°C (fra fortynnet isopropanol) 1-(2-chloro-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 165 - 167°C (from diluted isopropanol)

1-(3-metyl-benzy1)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 186 - 188°C (fra fortynnet etanol) 1-(3-methyl-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 186 - 188°C (from diluted ethanol)

1-(3-klor-benzyl)-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 191 - 193°C (fra fortynnet etanol) 1-(3-chloro-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 191 - 193°C (from diluted ethanol)

1-(2-{2,5-dimetyl-fenylJ - etyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 168 - 170°C (fra etanol). 1-(2-{2,5-dimethyl-phenyl-ethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 168 - 170°C (from ethanol).

Eksempel 3» Example 3»

1-( 1- fenyl- etyl)- 1, 2- dihydro- 2- okso- nikotinsyre L 1-( 1- phenyl- ethyl)- 1, 2- dihydro- 2- oxo- nicotinic acid L

18,1 g 3-etoksy-allyliden-malonsyre-dietylester blandes i 30 ml absolutt etanol med 9 g alfa-fenyletylamin. 18.1 g of 3-ethoxy-allylidene-malonic acid diethyl ester are mixed in 30 ml of absolute ethanol with 9 g of alpha-phenylethylamine.

Etter kort temperaturøkning og flere timers henstand blandes oppløsningen med oppløsningen av 7 g natrium i 250 ml absolutt etanol og hensettes igjen noen timer. Deretter fjerner man oppløsningsmidlet under nedsatt trykk, blander residuet med vann, filtrerer, surgjør med fortynnet saltsyre og frasuger det utfelte produkt. Etter gjenutfelling fra fortynnet ammoniakk og omkrystallisering fra metanol smelter den dannede l-(l-fenyletyl)-l,2-dihydro-2-okso-nikotinsyre ved 126 - 128°C, After a short increase in temperature and several hours' rest, the solution is mixed with the solution of 7 g of sodium in 250 ml of absolute ethanol and left to rest for a few hours. The solvent is then removed under reduced pressure, the residue is mixed with water, filtered, acidified with dilute hydrochloric acid and the precipitated product is filtered off with suction. After reprecipitation from dilute ammonia and recrystallization from methanol, the formed 1-(1-phenylethyl)-1,2-dihydro-2-oxo-nicotinic acid melts at 126 - 128°C,

På analog måte får man Analogously, you get

1-(2-metoksy-benzyl)-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 127 - 129°C (fra fortynnet etanol) 1-(2-Methoxy-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 127 - 129°C (from dilute ethanol)

1-butyl-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 102 - 103 C 1-butyl-1,2-dihydro-2-oxo-nicotinic acid of melting point 102 - 103 C

(fra etanol) (from ethanol)

1-heksyl-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 86 - 88°C 1-hexyl-1,2-dihydro-2-oxo-nicotinic acid of melting point 86 - 88°C

(fra etanol) (from ethanol)

1- ( 2- -£3, 4-dimetoksy-fenyl} -etyl) -1, 2-dihy dro-2-oks o-nikot insyre av smeltepunkt 165 - l66°C (fra etanol) 1-(2- -£3,4-dimethoxy-phenyl}-ethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 165 - 166°C (from ethanol)

1-(cykloheksylmetyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 189°C (fra etanol) 1-(cyclohexylmethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 189°C (from ethanol)

1-cykloheksyl-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 182°C 1-cyclohexyl-1,2-dihydro-2-oxo-nicotinic acid of melting point 182°C

(fra etanol) (from ethanol)

1-tert.-butyl-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 129°C 1-tert-butyl-1,2-dihydro-2-oxo-nicotinic acid of melting point 129°C

(fra etanol) (from ethanol)

1- ( 2- -{4-klor-f enyllf-etyl) -1, 2-dihy dro-2-oks o-nikot ins yre av smeltepunkt l64°C (fra etanol) 1- ( 2- -{4-chloro-phenyl-ethyl)-1, 2-dihydro-2-oxo-nicotinic acid of melting point 164°C (from ethanol)

1-propyl-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 119°C 1-propyl-1,2-dihydro-2-oxo-nicotinic acid of melting point 119°C

(fra etanol) (from ethanol)

1-(4-metyl-cykloheksyl)-1}2-dihydro-2-okso-nikotinsyre av smeltepunkt l63°C (fra etanol) 1-(4-methyl-cyclohexyl)-1}2-dihydro-2-oxo-nicotinic acid of melting point 163°C (from ethanol)

1-isopropyl-la2-dihydro-2-okso-nikotinsyre av smeltepunkt 117°C 1-isopropyl-1a2-dihydro-2-oxo-nicotinic acid of melting point 117°C

(fra etanol) (from ethanol)

1-oktyl-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 75 - 77°C 1-octyl-1,2-dihydro-2-oxo-nicotinic acid of melting point 75 - 77°C

(fra etanol) (from ethanol)

1-(2 - {4-metyl-fenyl}-etyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 190°C-(fra etanol) 1-(2-{4-methyl-phenyl}-ethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 190°C-(from ethanol)

1-allyl-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 120°C 1-allyl-1,2-dihydro-2-oxo-nicotinic acid of melting point 120°C

(fra etanol) (from ethanol)

1-norbornylmetyl-lj2-dihydro-2-okso-nikotinsyre av smeltepunkt 96°C (fra etanol) 1-norbornylmethyl-lj2-dihydro-2-oxo-nicotinic acid of melting point 96°C (from ethanol)

1-(2-£3,4-diklor-fenyl}-etyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 220°C (fra etanol) 1-(2-£3,4-dichloro-phenyl}-ethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 220°C (from ethanol)

1-(3-fenyl-propyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 107°C (fra etanol) 1-(3-phenyl-propyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 107°C (from ethanol)

1-(2,4-dimetoksy-benzyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 137°C (fra etanol) 1-(2,4-dimethoxy-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 137°C (from ethanol)

1-(2-metoksy-etyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 92°C (fra etanol) 1-(2-Methoxy-ethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 92°C (from ethanol)

1-(3,4,5-trimetoksy-benzy1)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 200°C (fra etanol/dimetylformamid) 1-(3,4,5-trimethoxy-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 200°C (from ethanol/dimethylformamide)

1- (2- -[2-brom-4 3 5-dimetoksy-f enylj -etyl) -1, 2 -di hy dro-2-oks o-nikotinsyre av smeltepunkt 187 - l88°C (fra etanol) 1- (4-fluor-benzyl)-l,2-dihydro-'2-okso-nikotinsyre av smeltepunkt 213-2l4°C (fra etanol/dimetylformamid) 1- (2--[2-bromo-4 3 5-dimethoxy-phenylj-ethyl)-1, 2-dihydro-2-oxo-nicotinic acid of melting point 187 - 188°C (from ethanol) 1- (4-Fluoro-benzyl)-1,2-dihydro-'2-oxo-nicotinic acid of melting point 213-214°C (from ethanol/dimethylformamide)

1-(335-dimetyl-benzyl)-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 229 - 230°C (fra etanol/dimetylformamid) 1-(335-dimethyl-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 229 - 230°C (from ethanol/dimethylformamide)

1-(4-tert.buty1-benzyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 146 - l48°C (fra etanol) 1-(4-tert.butyl-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 146 - 148°C (from ethanol)

1-(3,4-metylendioksy-benzyl)-lJ2-dihydro-2-okso-nikotinsyre av smeltepunkt 173°C (fra etanol/dimetylformamid) 1-(3,4-methylenedioxy-benzyl)-1H2-dihydro-2-oxo-nicotinic acid of melting point 173°C (from ethanol/dimethylformamide)

1- (2-naf ty 1-mety 1)-1., 2-dihydro-2-okso-nikotinsyre av smeltepunkt 192 - 193°C (fra etanol/dimetylformamid) 1-(2-naphthyl-1-methyl)-1.,2-dihydro-2-oxo-nicotinic acid of melting point 192 - 193°C (from ethanol/dimethylformamide)

1-(4-trifluormetyl-benzyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 192°C (fra etanol) 1-(4-trifluoromethyl-benzyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 192°C (from ethanol)

1-(2-tieny1-mety1)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 125 - 126°C (fra etanol) 1-(2-thienyl-methyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 125 - 126°C (from ethanol)

1-(fifenylmetyl)-1j2-dihydro-2-okso-nikotinsyre av smeltepunkt 163°C (fra etanol) 1-(Phiphenylmethyl)-1j2-dihydro-2-oxo-nicotinic acid of melting point 163°C (from ethanol)

1-(4-metylfenyl-fenylmetyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt l63°C (fra etanol) 1-(4-methylphenyl-phenylmethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 163°C (from ethanol)

1-(fenyl-pyrid-4-y1-mety1)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 135°C (fra metanol) 1-(Phenyl-pyrid-4-yl-methyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 135°C (from methanol)

1-(4 j 4'-diklor-difehylmetyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 228°C (fra etanol) 1-(4j 4'-dichloro-diphenylmethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 228°C (from ethanol)

1-(fenyl-pyrid-3-yl-metyl)-13 2-dihydro-2-okso-nikotinsyre av smeltepunkt 138°C (fra etanol) 1-(Phenyl-pyrid-3-yl-methyl)-13 2-dihydro-2-oxo-nicotinic acid of melting point 138°C (from ethanol)

1-(fenyl-pyrid-2-y1-mety1)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt l67°C (fra etanol) 1-(Phenyl-pyrid-2-yl-methyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 167°C (from ethanol)

1-(4,4'-dimetoksy-difenylmetyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 176°C (fra etanol) 1-(4,4'-dimethoxy-diphenylmethyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 176°C (from ethanol)

1-(1-naftyl-metyl)-1,2-dihydro-2-okso-nikotinsyre av smeltepunkt 173°C (fra etanol) 1-(1-Naphthyl-methyl)-1,2-dihydro-2-oxo-nicotinic acid of melting point 173°C (from ethanol)

1-(3,4-dimetyl-benzyl)-l32-dihydro-2-okso-nikotinsyre av smeltepunkt 223-224°C (fra etanol). 1-(3,4-dimethyl-benzyl)-132-dihydro-2-oxo-nicotinic acid of melting point 223-224°C (from ethanol).

Eksempel 4. Example 4.

1-( 4- klor- benzy1)- 1, 2- dihydro- 2- okso- nikotinsyre- etylester. 1-(4-chloro-benzy1)-1,2-dihydro-2-oxo-nicotinic acid ethyl ester.

10 g 1-( 4-klor-benzyl)-1, 2-dihydro.-2--okso-nikotinsyre kokes i 150 ml etanol med 2 ml konsentrert svovelsyre i 10 g of 1-(4-chloro-benzyl)-1,2-dihydro.-2--oxo-nicotinic acid are boiled in 150 ml of ethanol with 2 ml of concentrated sulfuric acid in

6 timer under tilbakeløpskjøler. 6 hours under reflux cooler.

Det i første rekke ikke oppløste stoff går derved langsomt i oppløsning. Man inndamper under nedsatt trykk, blander residuet med natriumbikarbonatoppløsning, frasuger og omkrystalliserer fra fortynnet etanol. Den dannede 1-(4-klorbenzyl ) -1 , 2-dihydro-2-okso-nikotinsyre-ety lester smelter ved 83 - 85°C. The primarily undissolved substance thereby slowly dissolves. Evaporate under reduced pressure, mix the residue with sodium bicarbonate solution, suction off and recrystallize from diluted ethanol. The 1-(4-chlorobenzyl)-1,2-dihydro-2-oxo-nicotinic acid ethyl ester formed melts at 83-85°C.

Eksempel 5-1- ( 4- klor- benzyl-)- l, 2- dihydro- 4 , 6- dimetyl- 2- okso- nikotinsyre . a) 1-(4-klor-benzyl)-1}2-dihydro-4,6-dimety1-2-okso-nikotinsyre-nitril. 28 g cyaneddiksyre-4-klorbenzylamid (fremstillet ved omsetning av cyaneddiksyreetylester med 4-klor-benzylamin; smeltepunkt 127 - 128°C (fra etanol)), 13,5 g pentan-2,4-dion og 7 ml piperidin oppvarmes i 5 timer i 300 ml etanol under tilbakeløp. Etter avkjøling frasuger man og får 1-(4-klorbenzyl ) -1 , 2-dihydro-4,6-dimety1-2-okso-nikotinsyrenitril av smeltepunkt 171 - 172°C. b) 1-(4-klor-benzyl)-1,2-dihydro-4,6-dimety1-2-okso-nikotinsyre . 5 g 1-(4-klor-benzyl)-1,2-dihydro-4,6-dimetyl-2-okso-nikotinsyrenitril oppvarmes under omrøring i en oppløsning av 100 ml konsentrert svovelsyre i 50 ml vann i 6 timer ved 100°C. Etter avkjøling heller man på is, oppløser det utskilte faste stoff i fortynnet ammoniakkoppløsning, filtrerer og sur-gjør oppløsningen med fortynnet saltsyre. Den således dannede 1-(4-klor-benzyl)-1,2-dihydro-4,6-dimety1-2-okso-nikotinsyre omkrystalliseres fra etanol og smelter ved 168 - l69°C. Example 5-1-(4-chloro-benzyl-)-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid. a) 1-(4-chloro-benzyl)-1}2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid nitrile. 28 g of cyanoacetic acid-4-chlorobenzylamide (prepared by reaction of cyanoacetic acid ethyl ester with 4-chloro-benzylamine; melting point 127 - 128°C (from ethanol)), 13.5 g of pentane-2,4-dione and 7 ml of piperidine are heated for 5 hours in 300 ml ethanol under reflux. After cooling, suction is obtained and 1-(4-chlorobenzyl)-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid nitrile of melting point 171 - 172°C is obtained. b) 1-(4-chloro-benzyl)-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid. 5 g of 1-(4-chloro-benzyl)-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid nitrile are heated with stirring in a solution of 100 ml of concentrated sulfuric acid in 50 ml of water for 6 hours at 100° C. After cooling, pour onto ice, dissolve the separated solid in dilute ammonia solution, filter and acidify the solution with dilute hydrochloric acid. The 1-(4-chloro-benzyl)-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid thus formed is recrystallized from ethanol and melts at 168-169°C.

På analog måte vil man av cyaneddiksyre-2-fenyletyl-amid (smeltepunkt 93 - 95°C) og pentan-2,4-dion få l-(2-fenyletyl)-1,2-dihydro-4,6-dimety1-2-okso-nikotinsyrenitril av smeltepunkt 183°C (fra etanol) og ved forsåpning l-(2-fenyletyl)-l,2-dihydro-4,6-dimety1-2-okso-nikotinsyre av smeltepunkt 144 - l45°C (fra etanol), In an analogous way, from cyanoacetic acid-2-phenylethyl-amide (melting point 93 - 95°C) and pentane-2,4-dione, 1-(2-phenylethyl)-1,2-dihydro-4,6-dimethyl- 2-oxo-nicotinic acid nitrile of melting point 183°C (from ethanol) and by saponification 1-(2-phenylethyl)-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid of melting point 144 - 145°C ( from ethanol),

av cyaneddiksyre-butylamid (smeltepunkt 68°C) og pentan-2,4-dion få 1-buty1-1,2-dihydro-4,6-dimety1-2-okso-nikotin-syrenitril av smeltepunkt 97°C (fra etanol) og ved forsåpning 1-buty1-1,2-dihydro-4,6-dimety1-2-okso-nikotinsyre av smeltepunkt 90 - 91°C (fra etanol), of cyanoacetic acid-butylamide (melting point 68°C) and pentane-2,4-dione obtain 1-buty1-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid nitrile of melting point 97°C (from ethanol ) and by saponification 1-butyl1-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid of melting point 90 - 91°C (from ethanol),

av cyaneddiksyre-4-metylbenzylamid (smeltepunkt of cyanoacetic acid-4-methylbenzylamide (m.p

128 - 129°C) og pentan-2,4-dion få 1-(4-mety1-benzyl)-1,2-dihydro-4,6-dimetyl-2-okso-nikotinsyrenitril av smeltepunkt l60°C (fra etanol) og ved forsåpning 1-(4-mety1-benzyl)-1,2-dihydro-4,6-dimetyl-2-okso-nikotinsyre av smeltepunkt' 185 - 128 - 129°C) and pentane-2,4-dione obtain 1-(4-methyl-benzyl)-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid nitrile of melting point 160°C (from ethanol ) and by saponification 1-(4-methyl-benzyl)-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid of melting point' 185 -

187°C (fra etanol). 187°C (from ethanol).

Eksempel 6. Example 6.

5- brom- l- butyl- l, 2- dihydro- 2- okso- nikotinsyre. 5-bromo-1-butyl-1,2-dihydro-2-oxo-nicotinic acid.

10 g 1-butyl-l,2-dihydro-2-okso-nikotinsyre oppløses i 100 ml iseddik og blandes ved værelsestemperatur dråpevis med 3 ml brom. Etter flere timers henstand oppvarmes 1 time ved 10 g of 1-butyl-1,2-dihydro-2-oxo-nicotinic acid are dissolved in 100 ml of glacial acetic acid and mixed at room temperature dropwise with 3 ml of bromine. After a delay of several hours, firewood is heated for 1 hour

40°C. Man fortynner suspensjonen med vann, frasuger utfellingen og omkrystalliserer fra etanol. 5-brom-l-butyl-l, 2-dihy'dro-2-okso- 40°C. The suspension is diluted with water, the precipitate is sucked off and recrystallized from ethanol. 5-bromo-1-butyl-1,2-dihydro-2-oxo-

nikotinsyre smelter ved 151°C. nicotinic acid melts at 151°C.

På analog måte får man Analogously, you get

5-brom-l-butyl-l,2-dihydro-4,6-dimety1-2-okso-nikotinsyre av smeltepunkt 93°C (fra fortynnet etanol). 5-bromo-1-butyl-1,2-dihydro-4,6-dimethyl-2-oxo-nicotinic acid of melting point 93°C (from dilute ethanol).

Eksempel 7- Example 7-

1- heksyl- l, 2- dihydro- 2- okso- riikotinsyre, 1- hexyl- 1, 2- dihydro- 2- oxoriicotinic acid,

6,9 g 1,2-dihydro-2-okso-nikotinsyre blandes i 6.9 g of 1,2-dihydro-2-oxo-nicotinic acid are mixed in

100 ml tetrahydrofuran og 100 ml dimetylformamid porsjonsvis med 3,6 g natriumhydrid. Etter kort etteromrøringstid tildrypper man 16,5 g n-heksylbromid og omrører 3 timer under tilbakeløp. 100 ml of tetrahydrofuran and 100 ml of dimethylformamide in portions with 3.6 g of sodium hydride. After a short post-stirring period, 16.5 g of n-hexyl bromide are added dropwise and stirred for 3 hours under reflux.

Etter inndampning i vakuum tilsetter man 50 ml 2 N natronlut og 50 ml etanol .og forsåper den dannede ester ved 3 timers tilbakeløpskokning, Etter fjerning av alkoholen sur-gjøres den dannede fase og det utfelte produkt omkrystalliseres fra toluen/diisopropyleter. 1-heksyl-l,2-dihydro-2-okso-nikotinsyre smelter ved 85 - 87°C. After evaporation in a vacuum, 50 ml of 2 N caustic soda and 50 ml of ethanol are added and the formed ester is saponified by refluxing for 3 hours. After removal of the alcohol, the formed phase is acidified and the precipitated product is recrystallized from toluene/diisopropyl ether. 1-hexyl-1,2-dihydro-2-oxo-nicotinic acid melts at 85 - 87°C.

På analog måte vii man In an analogous way vii man

av 1,2-dihydro-2-okso-nikotinsyre få 1-butyl-l,2-dihydro-2-okso-nikotinsyre av smeltepunkt 102 - 103°C (etanol), of 1,2-dihydro-2-oxo-nicotinic acid obtain 1-butyl-1,2-dihydro-2-oxo-nicotinic acid of melting point 102 - 103°C (ethanol),

av 1,2-dihydro-6-metyl-2-okso-nikotinsyre få 1-butyl-l,2-dihydro-6-metyl-nikotinsyre av smeltepunkt 8l - 82°C (eddikester). of 1,2-dihydro-6-methyl-2-oxo-nicotinic acid obtain 1-butyl-1,2-dihydro-6-methyl-nicotinic acid of melting point 8l - 82°C (acetic ester).

Eksempel 8. Example 8.

1- butyl- l, 2- dihydr0- 6- mety1- 2- okso- nikotinsyre. 1-butyl-1,2-dihydro-6-methyl-2-oxo-nicotinic acid.

4,75 g 1-butyl-l,2-dihydro-6-metyl--2-okso-nikotin-syrenitril (fremstillet ved omsetning av 1,2-dihydro-6-mety1-2-okso-nikotinsyrenitril med nV:butylbromid i DMP/THP under til-setning av kaliumkarbonatj smeltepunkt 51 - 52°C) holdes under tilbakeløp under omrøring i en blanding av 50 ml 2 N natronlut og 50 ml etanol i 4 timer. Etter avdestillering av alkoholen fortynner man med vann og surgjør med fortynnet saltsyre. Den således utfelte 1-butyl-l,2-dihydro-6-metyl-2-okso-nikotinsyre frasuges og omkrystalliseres etter tørkning fra eddikester. 4.75 g of 1-butyl-1,2-dihydro-6-methyl-2-oxo-nicotinic acid nitrile (prepared by reacting 1,2-dihydro-6-methyl-2-oxo-nicotinic acid nitrile with nV:butyl bromide in DMP/THP with the addition of potassium carbonatej melting point 51 - 52°C) is kept under reflux with stirring in a mixture of 50 ml of 2 N caustic soda and 50 ml of ethanol for 4 hours. After the alcohol has been distilled off, it is diluted with water and acidified with dilute hydrochloric acid. The thus precipitated 1-butyl-1,2-dihydro-6-methyl-2-oxo-nicotinic acid is filtered off with suction and recrystallized after drying from acetic acid.

Den smelter ved 96 - 98°C, It melts at 96 - 98°C,

Eksempel 9, Example 9,

1-( 4- klorbenzyl)- 1, 2- dihydro- 2- okso- nikotinsyre, 1-(4-chlorobenzyl)-1,2-dihydro-2-oxo-nicotinic acid,

1 g 1-(4-klorbenzyl)-1,2-dihydro-2-okso-3-hydroksymetyl-pyridin (smeltepunkt 115 - 117°C) oppbevares i en oppløs-ning av 4 g kaliumdikromat i 5,5 ml konsentrert svovelsyre og 10 ml vann i 3 dager ved værelsestemperatur, Etter fortynning med vann ekstraheres med metylenklorid, denne oppløsning tørkes og inndampes og residuet omkrystalliseres fra metanol-DMF, Den således dannede 1-(4-klorbenzyl)-1,2-dihydro-2-okso-nikotinsyre smelter ved 191 - 193°C 1 g of 1-(4-chlorobenzyl)-1,2-dihydro-2-oxo-3-hydroxymethyl-pyridine (melting point 115 - 117°C) is stored in a solution of 4 g of potassium dichromate in 5.5 ml of concentrated sulfuric acid and 10 ml of water for 3 days at room temperature, After dilution with water, extract with methylene chloride, this solution is dried and evaporated and the residue is recrystallized from methanol-DMF, The 1-(4-chlorobenzyl)-1,2-dihydro-2- oxo-nicotinic acid melts at 191 - 193°C

Claims (6)

1. Dihydro-okso-nikotinsyrer med den generelle formel I1. Dihydro-oxo-nicotinic acids of the general formula I hvori R betyr alkyl med 3 til 8 karbonatomer, alkenyl med 3 til 6 karbonatomer, cykloalkyl, cykloalkenyl, alkylcykloalkyl, alkylcykloalkenyl, cykloalkylalkyl, cykloalkenylalkyl, alkylcykloalkylalkyl eller alkylcykloalkenylalky1 med hver 5 til 9 karbonatomer, alkoksyalkyl med 3-6 C-atomer, idet alkyldelen minst inneholder 2 C-atomer, metoksycykloheksyl, klorcykloheksyl, bicykloheptyl, bicykloheptenyl, bicyklohepty1-metyl, bicykloheptenylmetyl, nortricyklyl, en rest med formel hvori Y betyr en alkylenrest med 1-3 C-atomer, R^ betyr alkyl eller alkoksy med hver 1 til 4 karbonatomer, halogen, trifluormetyl eller sammen med R5 eller R metylendioksygruppen R->, R betyr hydrogen, alkyl eller alkoksy med hver 1 til 4 karbon-auumer ener naiogen, en rest med formel hvori Y betyr en alkylenrest med 1 til 3 C-atomer, R<7>be tyr hydrogen, alkyl eller alkoksy med hver 1 til 4 C-atomer, halogen, trifluormetyl og R obetyr hydrogen, alkyl eller alkoksy med hver 1 til 4 C-atomer eller halogen, en rest med formel hvori R 9 betyr en rest med formel eller en naftylmetylrest, R 1 , R ? , R^ ~* > betyr hver hydrogen, alkyl med 1 til 4 karbonatomer eller halogen, idet R 1 , R p og R; "7 kan være like eller forskjellige, samt deres fysiologisk tålbare salter og estere. in which R means alkyl with 3 to 8 carbon atoms, alkenyl with 3 to 6 carbon atoms, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, alkylcycloalkylalkyl or alkylcycloalkenylalkyl1 each with 5 to 9 carbon atoms, alkoxyalkyl with 3-6 C atoms, the alkyl part at least contains 2 C atoms, methoxycyclohexyl, chlorocyclohexyl, bicycloheptyl, bicycloheptenyl, bicyclohepty1-methyl, bicycloheptenylmethyl, nortricyclyl, a residue of formula in which Y means an alkylene residue with 1-3 C atoms, R^ means alkyl or alkoxy with each 1 to 4 carbon atoms, halogen, trifluoromethyl or together with R5 or R the methylenedioxy group R->, R means hydrogen, alkyl or alkoxy with each 1 to 4 carbon aumer one nitrogen, a residue of formula in which Y means an alkylene residue with 1 to 3 C atoms , R<7>be means hydrogen, alkyl or alkoxy each having 1 to 4 C atoms, halogen, trifluoromethyl and R denotes hydrogen, alkyl or alkoxy with each 1 to 4 C atoms or halogen, a residue of formula in which R 9 means a residue of formula or a naphthylmethyl residue, R 1 , R ? , R^ ~* > each means hydrogen, alkyl of 1 to 4 carbon atoms or halogen, wherein R 1 , R p and R; "7 may be the same or different, as well as their physiologically tolerable salts and esters. 2. Fremgangsmåte til fremstilling av dihydro-okso-nikotinsyrer ifølge krav 1,karakterisert vedat a) et amin med den generelle formel II hvori R har den ovenfor angitte betydning omsettes med et malonsyrederivat med den generelle formel III, eller dets ringslut- ningsprodukt med den generelle formel IV hvori R 1, R 2 og R "5 hver betyr hydrogen eller alkyl med 1 til 4 C-atomer, den dannede aminoallylidenmalonester cykliseres eventuelt og den dannede forbindelse halogeneres eventuelt, eller b) et amin med overnevnte generelle formel II RNH2kondenseres med et malonsyrederivat med den generelle formel V hvori R<1>betyr hydrogen eller alkyl med 1 til 4 C-atomer til et malonhalvamid med formel VI, dette omsettes med dimetylformamidacetal og den dannede forbindelse halogeneres eventuelt, eller • c) en pyridonkarboksylsyre med den generelle formel VII eller dens salter eller estere omsettes med en forbindelse med den generelle formel RX, hvori X betyr et halogenatom, fortrinnsvis klor, eller en sulfonyloksyrest, eller d) i et pyridonderivat med den generelle formel VIII 12 ^ hvori R, R , R og R; har overnevnte betydning og Z betyr en til en karboksylgruppe overførbar rest, overføres denne i en karboksylgruppe og ifølge fremgangsmåte a) til d) eventuelt dannede syrer forestres eller overføres i salter resp. de dannede estere forsåpes. 2. Process for the production of dihydro-oxo-nicotinic acids according to claim 1, characterized in that a) an amine of the general formula II in which R has the above meaning is reacted with a malonic acid derivative of the general formula III, or its ring closure product with the general formula IV in which R 1 , R 2 and R "5 each means hydrogen or alkyl with 1 to 4 C atoms, the aminoallylidene malone ester formed is optionally cyclized and the compound formed is optionally halogenated, or b) an amine of the above general formula II RNH 2 is condensed with a malonic acid derivative of the general formula V in which R<1> denotes hydrogen or alkyl with 1 to 4 C atoms to a malonhalamide of formula VI, this is reacted with dimethylformamide acetal and the compound formed is optionally halogenated, or • c) a pyridone carboxylic acid with the general formula VII or its salts or esters are reacted with a compound of the general formula RX, in which X means a halogen atom, preferably chlorine, or a sulphonyloxy acid residue, or d) in a pyridone derivative of the general formula VIII 12 ^ in which R, R , R and R; has the above meaning and Z means a residue transferable to a carboxyl group, this is transferred into a carboxyl group and according to method a) to d) any acids formed are esterified or transferred into salts resp. the formed esters are saponified. 3. Legemiddel bestående av en resp. inneholdende en dihydro-okso-nikotinsyre åv den i krav 1 angitte formel I eller formel Ia 12^ hvori R , R og R^ har den i krav 1 angitte betydning og R betyr en rest med formel hvori Y har den overnevnte betydning, eller resp. en av deres salter eller ett resp. en av deres estere. 3. Medicine consisting of a resp. containing a dihydro-oxo-nicotinic acid of the formula I specified in claim 1 or formula Ia 12^ in which R, R and R^ have the meaning specified in claim 1 and R means a residue of formula in which Y has the above-mentioned meaning, or resp. . one of their salts or one resp. one of their esters. 4. Fremgangsmåte til fremstilling av•et legemiddel ifølge krav 3,karakterisert vedat en dihydro-okso-nikotinsyre med den i krav 1 angitte formel I eller formel Ia, et av dets salter eller et av dens estere bringes i en ad-ministrer ingsform. 4. Process for producing a drug according to claim 3, characterized in that a dihydro-oxo-nicotinic acid with the formula I or formula Ia stated in claim 1, one of its salts or one of its esters is brought into an administration form. 5. Anvendelse av dihydro-okso-nikotinsyre med den i krav 1 angitte formel I eller formel Ia, deres salter eller estere som resp. i legemiddel eller legemidler. 5. Use of dihydro-oxo-nicotinic acid with the formula I or formula Ia specified in claim 1, their salts or esters as resp. in medicine or medicines. 6. Fremgangsmåte til behandling av stoffvekselfor-styrrelser,karakterisert vedat man administrerer en virksom mengde av en forbindelse med formel Iaifølge krav 1 eller formel Ia, et av dens salter eller en av dens estere.6. Method for treating metabolic disorders, characterized by administering an effective amount of a compound of formula I according to claim 1 or formula Ia, one of its salts or one of its esters.
NO772893A 1976-08-20 1977-08-19 DIHYDRO-OXO-NICOTIC ACIDS AND PROCEDURES FOR THEIR PREPARATION NO772893L (en)

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US4220648A (en) * 1979-01-22 1980-09-02 The Upjohn Company Antidiabetic 1,2-dihydro-2-oxo-6-neopentyl-nicotinic acids
US4645766A (en) * 1981-10-19 1987-02-24 The Upjohn Company 1,2-dihydro-2-oxo-3-hydroxymethyl pyridines, compositions and use
JPS59194824A (en) * 1983-04-19 1984-11-05 Ube Ind Ltd Resin molding machine
EP0417143A1 (en) * 1988-06-03 1991-03-20 The Upjohn Company Cyclic lactams for cholesterol and atherosclerosis control
AU6979091A (en) * 1989-12-22 1991-07-24 Upjohn Company, The Pyridinones useful as antiatherosclerotic agents
ES2072015T3 (en) * 1990-08-21 1995-07-01 Upjohn Co DERIVATIVES OF THE BISPHOSPHONIC ACID AS AN ANTI-ARTHRITIC AGENT.
CZ403592A3 (en) * 1992-02-20 1993-12-15 Hoechst Ag Arylcarbonylaminoalkyldihydrooxopyridines, process of their preparation and their use
US5814645A (en) * 1993-03-24 1998-09-29 Bayer Aktiengesellschaft Arylor hetaryl substituted nitrogen heterocycles and their use as pesticides
DE4309552A1 (en) * 1993-03-24 1994-09-29 Bayer Ag Substituted nitrogen heterocycles
CA2469435A1 (en) * 2001-12-21 2003-07-24 X-Ceptor Therapeutics, Inc. Modulators of lxr
US7482366B2 (en) 2001-12-21 2009-01-27 X-Ceptor Therapeutics, Inc. Modulators of LXR

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