DK164668B - Analogy process for preparing 1,4-dihydropyrid-5- yl(cyclic imidate) esters - Google Patents

Analogy process for preparing 1,4-dihydropyrid-5- yl(cyclic imidate) esters Download PDF

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DK164668B
DK164668B DK181183A DK181183A DK164668B DK 164668 B DK164668 B DK 164668B DK 181183 A DK181183 A DK 181183A DK 181183 A DK181183 A DK 181183A DK 164668 B DK164668 B DK 164668B
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ethyl
dihydro
methyl
oxazolyl
pyridinecarboxylate
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DK181183A
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DK181183A (en
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Graham S Poindexter
Jr Davis L Temple
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Squibb Bristol Myers Co
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iin

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Den foreliggende opfindelse angår en anal ogi fremgangsmåde til fremstilling af hidtil ukendte l,4-dihydropyrid-5-yl-(cykl i sk imidat)estere, hvilke forbindelser besidder biologiske egenskaber.The present invention relates to an analogue and process for the preparation of novel 1,4-dihydropyrid-5-yl (cycle in skimidate) esters, which compounds have biological properties.

En betydelig mængde kendt teknik er fremkommet over det 5 sidste tiår med hensyn til forbindelser af 4-aryl-l,4-dihydropyridin--serien, som har calcium-antagonist-egenskaber og er nyttige til behandling af cardiovaskulære sygdomme. Disse calciumblokerende virkninger synes at mediere vasodilation, som gør disse forbindelser nyttige ved behandlingen af angina og hypertension. Disse struk- 10 turer typificeres af nifedipin (formel 1): (8i H3C02Cvy^J\/C02CH3A considerable amount of prior art has emerged over the last decade with regard to compounds of the 4-aryl-1,4-dihydropyridine series, which have calcium antagonist properties and are useful in the treatment of cardiovascular diseases. These calcium-blocking effects appear to mediate vasodilation, which makes these compounds useful in the treatment of angina and hypertension. These structures are typified by nifedipine (Formula 1): (8i H3CO2Cvy ^ J \ / CO2CH3

15 I15 I

H3C"^\n CH3 fH3C "^ \ n CH3 f

HH

(1) 20 der kemisk betegnes 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbo-methoxy-l,4-dihydropyridin. Nifedipin og nogle beslægtede 4-aryl- 1,4-dihydropyridiner er omhandlet i USA patentskrift nr. 3.485.847, udstedt 23. december 1969. Talrige efterfølgende patenter er blevet 25 udstedt vedrørende 1,4-dihydropyridiner, hvori andre substituent-grupper er blevet anvendt i de forskellige ringstillinger for dihydro-pyridin-delen. Strukturen af disse senere patenterede forbindelser, som er af interesse for den foreliggende opfindelse, kan vises ved formel 2.(1) chemically designated 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbo-methoxy-1,4-dihydropyridine. Nifedipine and some related 4-aryl-1,4-dihydropyridines are disclosed in U.S. Patent No. 3,485,847, issued December 23, 1969. Numerous subsequent patents have been issued for 1,4-dihydropyridines wherein other substituent groups are have been used in the various ring positions of the dihydro-pyridine moiety. The structure of these later patented compounds which are of interest to the present invention can be shown by Formula 2.

30 R3 r4°2O/^\C02r230 R3 r4 ° 2O / ^ \ CO2r2

T TT T

35 r5^ n r1 t35 r5 ^ n r1 t

HH

(2) 2(2) 2

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Bossert, et al., USA patentskrift nr. 3.488.359, udstedt 6.Bossert, et al., U.S. Patent No. 3,488,359, issued 6.

januar 1970, og nr. 3.574.843, udstedt 13. april 1971, beskriver 2 4 forbindelser, hvori ændringen indebærer, at R og R er alkoxy-al kylgrupper.January 1970, and No. 3,574,843, issued April 13, 1971, disclose 24 compounds wherein the change implies that R and R are alkoxyalkyl groups.

5 Murakami, et al., DE-OS nr. 2.407.115 beskriver forbindelser, 2 hvori R er en di substitueret aminoalkyl gruppe.Murakami, et al., DE-OS No. 2,407,115 discloses compounds 2 wherein R is a di-substituted aminoalkyl group.

Kojima, et al., USA patentskrift nr. 4.220.649, udstedt 2.Kojima, et al., U.S. Patent No. 4,220,649, issued 2.

2 september 1980, beskriver forbindelser, hvori R er en pyrrolidin-ring.September 2, 1980, discloses compounds wherein R is a pyrrolidine ring.

10 Loev, et al., USA patentskrift nr. 3.511.847, udstedt 12. maj 3 1970, opremser forbindelser med store variationer i arten af R .10 Loev, et al., U.S. Patent No. 3,511,847, issued May 12, 1970, lists compounds with wide variations in the nature of R.

2 42 4

Endvidere er carboxylgrupperne, som er bundet til R og R , erstattet af carbonylgrupper i beskrivelsen, men der er ikke patentkrav på disse forbindelser, og der er heller ikke beskrevet en frem-15 gangsmåde til syntese deraf.Further, the carboxyl groups bonded to R and R are replaced by carbonyl groups in the specification, but no claims are made on these compounds, nor is a process for synthesizing them.

Teulon, et al., USA patentskrift nr. 4.096.270, udstedt 20.Teulon, et al., U.S. Patent No. 4,096,270, issued 20.

3 juni 1978, beskriver dihydropyridiner, hvori R er en substitueret pyridin-del.June 3, 1978, discloses dihydropyridines wherein R is a substituted pyridine moiety.

Sammenfattende kan disse og andre tidligere patenterede di- 20 hydropyridinforbindelser, som er af interesse for den foreliggende 12 4 5 opfindelse, vises ved formel 2. I almindelighed er R , R , R og R alkylgrupper eller alkylgrupper, som bærer forskellige substituen- 3 ter, f.eks. amino-, ether-, mercaptogrupper, etc. Arten af R varierer betydeligt, men nyttige cardiovaskulære egenskaber synes 25 at blive maksimerede, når denne gruppe er en elektrontiltrækkende aryldel eller heterocyklisk del.In summary, these and other previously patented dihydropyridine compounds of interest to the present invention may be represented by Formula 2. In general, R, R, R and R are alkyl groups or alkyl groups bearing various substituents. , eg. amino, ether, mercapto groups, etc. The nature of R varies considerably, but useful cardiovascular properties appear to be maximized when this group is an electron-attracting aryl moiety or heterocyclic moiety.

Meyers og Gabriel rapporterede i Heterocycles, vol. 11, pp.Meyers and Gabriel reported in Heterocycles, vol 11, pp.

133-138 (1978) en ny syntese af 1,4-dihydropyridiner. Denne syntese anvender oxazoliner som aktiverende grupper for at lette 30 organo-metallisk addition til pyridinringen til dannelse af 1,4-di-hydropyridiner (formel 3).133-138 (1978) a new synthesis of 1,4-dihydropyridines. This synthesis uses oxazolines as activating groups to facilitate 30 organometallic addition to the pyridine ring to form 1,4-dihydropyridines (Formula 3).

I mg* II mg * I

II J eller ><Γ /--II J or> <Γ / -

” --- cKJ”--- cKJ

HH

(3) 3(3) 3

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Ingen anvendelighed blev anført for disse forbindelser, og de blev normalt omdannet til pyridiner under milde oxidative betingelser.No utility was indicated for these compounds and they were usually converted to pyridines under mild oxidative conditions.

Den foreliggende opfindelse tilvejebringer forbindelser med formel (I)The present invention provides compounds of formula (I)

5 R4o OR4o O

V r3 R5 \-/ O-tCHl* ίο Hn _K Γ" f-Λ, ΛιV r3 R5 \ - / O-tCHl * ίο Hn _K Γ "f-Λ, Λι

H r2 R RH r2 R R

(I) 15 og syreadditionssalte af disse forbindelser. I ovenstående formel har R, R^, R2, R3, R4, R5, m og n følgende betydninger. R og R1 er uafhængigt udvalgt blandt hydrogen, C^ ^-alkyl - og Cj ^-alkoxy-Cj 4~ alkyl grupper, hvor alkoxyalkyl refererer til en Cj til alkylenkæde 20 og en Cj til alkylgruppe forbundet med et oxygenatom; R2 er Cj_4-alkyl, phenyl eller thienyl; R3 er cykl oal kyl med 5 til 7 carbonatomer, bicykloalkenyl med 7 til 9 carbonatomer, furanyl, indolyl, pyridyl, thienyl, phenyl, naphthyl eller substitueret phenyl med substituenterne omfattende acetamino, C^-alkyl, Cj^-alkoxy, 25 cyano, halogen, hydroxyl, nitro og trifluormethyl; R4 er Cj^-alkyl eller Cj^-alkoxy-Cj^-alkyl som defineret ovenfor; R^ er Cj_^-alkyl eller phenyl; m er 0 eller 1; og n er 0 eller 1.(I) 15 and acid addition salts of these compounds. In the above formula, R 1, R 2, R 2, R 3, R 4, R 5, m and n have the following meanings. R and R 1 are independently selected from hydrogen, C 1-4 alkyl and C 1-4 alkoxy-C 1-4 alkyl groups, wherein alkoxyalkyl refers to a C 1 to alkylene chain 20 and a C 1 to alkyl group linked to an oxygen atom; R 2 is C 1-4 alkyl, phenyl or thienyl; R 3 is cyclic oalkyl having 5 to 7 carbon atoms, bicycloalkenyl having 7 to 9 carbon atoms, furanyl, indolyl, pyridyl, thienyl, phenyl, naphthyl or substituted phenyl with the substituents comprising acetamino, C halogen, hydroxyl, nitro and trifluoromethyl; R 4 is C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl as defined above; R 1 is C 1-6 alkyl or phenyl; m is 0 or 1; and n is 0 or 1.

De omhandlede forbindelser kan eksistere som optiske isomere, og såvel racematerne af disse isomere som de individuelle racemiske 30 modifikationer falder inden for opfindelsens rammer. Racematerne kan opspaltes i deres individuelle isomere ved hjælp af velkendt teknik, såsom adskillelse af diastereomere salte dannet med optisk aktive syrer, efterfulgt af omdannelse tilbage til de optisk aktive baser.The present compounds may exist as optical isomers, and both the racemates of these isomers as well as the individual racemic modifications fall within the scope of the invention. The racemates can be cleaved into their individual isomers by well-known techniques, such as separation of diastereomeric salts formed with optically active acids, followed by conversion back to the optically active bases.

Til potentiel medicinsk anvendelse foretrækkes de farmaceutisk 35 acceptable syreadditionssalte. De farmaceutisk acceptable syreadditionssalte er sådanne salte, hvori anionen ikke væsentligt bidrager til toxiciteten eller den farmakologiske aktivitet af saltet, 4For potential medical use, the pharmaceutically acceptable acid addition salts are preferred. The pharmaceutically acceptable acid addition salts are those salts in which the anion does not significantly contribute to the toxicity or pharmacological activity of the salt.

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og som sådanne er de farmakologiske ækvivalenter til baserne med ovenstående formel. Syreadditionssaltene opnås enten ved omsætning af en organisk base med formel (I) med en syre, fortrinsvis ved kontakt i opløsning, eller ved hjælp af enhver af de standard metoder, som 5 detaljeret er beskrevet i litteraturen, og som er tilgængelige for enhver fagmand.and as such are the pharmacological equivalents to the bases of the above formula. The acid addition salts are obtained either by reacting an organic base of formula (I) with an acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any skilled person.

De omhandlede forbindelser blev påvist at være calciumion-kanal-blokerende på basis af in vitro farmakologisk testning. For tiden undersøges nogle calcium-kanal-blokerende midler indgående i patienter 10 med koronare hjertesygdomme som følge af de gunstige cardiovaskulære virkninger, som medieres af disse midler.The compounds of this invention were shown to be calcium ion channel blocking on the basis of in vitro pharmacological testing. Currently, some calcium channel blockers are being investigated extensively in patients 10 with coronary heart disease due to the beneficial cardiovascular effects mediated by these agents.

Biologisk testning af de omhandlede forbindelser med formel (I) under anvendelse af et in vitro giatmuskel-vævspræparat viser, at disse forbindelser besidder specifik blokerende virkning på calcium-15 ionkanaler. Denne in vitro test for calciumionkanal-blokering består i at suspendere longitudinale giatmuskel-strimler af marsvineileum i bade indeholdende Tyrode's opløsning, som holdes ved 37°C og udluftes med 95% 0,,-5% COg. Vævene ækvilibreres i 60 min. før starten af alle forsøg. En enkelt reaktion på carbachol opnås og anvendes i alle 20 forsøg som et kontrolmaksimum. Imellem successive doser re- ækvilibreres vævene og vaskes med Tyrode's opløsning hvert 15. min.Biological testing of the subject compounds of formula (I) using an in vitro giat muscle tissue preparation shows that these compounds have specific blocking effect on calcium ion channels. This in vitro test for calcium ion channel blockage consists in suspending longitudinal guinea pig ileum muscle strips in baths containing Tyrode's solution which is maintained at 37 ° C and vented with 95% 0, - 5% COg. The tissues are equilibrated for 60 min. before the start of all trials. A single response to carbachol is obtained and used in all 20 trials as a control maximum. Between successive doses, the tissues are re-equilibrated and washed with Tyrode's solution every 15 min.

For at studere virkningen af forbindelserne udsættes vævene for antagonisten i 10 min. før tilsætningen af carbachol. Til alle forsøg testes kun én antagonist for enhver koncentration og i ethvert væv.To study the effect of the compounds, the tissues are exposed to the antagonist for 10 min. before the addition of carbachol. For all experiments, only one antagonist is tested for any concentration and in any tissue.

25 Resultaterne, der er vist i tabel V, udtrykkes som molære koncentrationer af antagonister, der inhiberer muskel reaktionen med 50%.The results shown in Table V are expressed as molar concentrations of antagonists that inhibit the muscle response by 50%.

Da calcium-antagonisme i almindelighed inhiberer excitation-kontrakti on-kobling i vaskulær glat muskulatur, fremkalder midler 30 af denne type sædvanligvis vasodilation. Testning af udvalgte forbindelser, f.eks. ethyl-5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridincarboxylat ifølge opfindelsen i den gang!ion-blokerede, angiotensin (II)-understøttede rottemodel (Deitchman, et al., J. Pharmacol.Since calcium antagonism generally inhibits excitation-contraction coupling in vascular smooth muscle, agents of this type usually induce vasodilation. Testing selected compounds, e.g. ethyl 5- (4,5-dihydro-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate of the invention at that time , angiotensin (II) supported rat model (Deitchman, et al., J. Pharmacol.

35 Methods, 3, 311-321 (1980)) viste vasodilation med dens ledsagende sænkning af blodtryk.35 Methods, 3, 311-321 (1980)) showed vasodilation with its accompanying lowering of blood pressure.

55

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Endvidere er disse udvalgte forbindelser ifølge den foreliggende opfindelse blevet undersøgt in vitro og in vivo i laboratorieforsøg udviklet til at forudsige et lægemiddels potential til at beskytte hjertevæv mod beskadigelse som følge af ischemi. Disse forsøg ud-5 nytter den kendte relation mellem progressiv udtømning af højenergi--phosphat og påbegyndelsen af lethal cellebeskadigelse i ischemisk myocardium. Resultater fra disse screening-forsøg viser, at disse udvalgte forbindelser besidder anti-ischemi virkning.Furthermore, these selected compounds of the present invention have been studied in vitro and in vivo in laboratory experiments designed to predict the potential of a drug to protect cardiac tissue from damage due to ischemia. These experiments utilize the known relationship between progressive depletion of high-energy phosphate and the onset of lethal cell damage in ischemic myocardium. Results from these screening trials show that these selected compounds possess anti-ischemic activity.

Farmaceutiske præparater på enhedsdosisform indeholder en 10 effektiv, men non-toxisk mængde af en forbindelse med formel (I) og en passende farmaceutisk bærer. Mængden af forbindelsen med formel (I) i præparatet vil variere fra ca. 5 mg til ca. 500 mg.Unit dosage form pharmaceutical compositions contain an effective but non-toxic amount of a compound of formula (I) and a suitable pharmaceutical carrier. The amount of the compound of formula (I) in the composition will vary from ca. 5 mg to approx. 500 mg.

Fagmanden vil forstå, at man ved bestemmelse af mængderne af den aktive bestanddel i sådanne enhedsdosispræparater må tage såvel 15 aktiviteten af den kemiske bestanddel som værtsdyrets størrelse i betragtning.Those skilled in the art will appreciate that in determining the amounts of the active ingredient in such unit dose preparations, both the activity of the chemical component and the size of the host animal must be taken into account.

I almindelighed vil de aktive bestanddele på enhedsdosisform blive kombineret med en farmaceutisk bærer. Denne farmaceutiske bærer kan være enten et fast stof eller en væske. Eksempler på 20 faste bærere kan være lactose, magnesiumstearat, saccharose, talkum, stearinsyre, gelatine, agar, pectin eller akacia. Eksempler på flydende bærere kan være jordnøddeolie, olivenolie eller sesamolie.Generally, the active ingredients in unit dosage form will be combined with a pharmaceutical carrier. This pharmaceutical carrier may be either a solid or a liquid. Examples of solid carriers may be lactose, magnesium stearate, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Examples of liquid carriers may be peanut oil, olive oil or sesame oil.

Tilsvarende kan bæreren eller diluenten indeholde et tidsforsinkelsesmateriale, såsom glycerylmonostearat eller glyceryldistearat alene 25 eller med en voks.Similarly, the carrier or diluent may contain a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.

En lang række forskellige farmaceutiske former kan anvendes.A wide variety of pharmaceutical forms can be used.

Som eksempler på anvendelse af en fast bærer kan præparatet tabletteres, anbringes i hårde gelatinekapsler eller i form af en pastil.As examples of the use of a solid carrier, the composition may be tableted, placed in hard gelatin capsules or in the form of a lozenge.

Mængden af fast bærer vil variere betydeligt, men vil i almindelig-30 hed være ca. 25 mg til ca. 1 g. Når en flydende bærer anvendes, kan præparatet være i form af en blød gelatinekapsel, en flydende suspension eller en steril suspension eller opløsning til parenteral brug.The amount of solid carrier will vary considerably, but will generally be approx. 25 mg to approx. When a liquid carrier is used, the composition may be in the form of a soft gelatin capsule, a liquid suspension or a sterile suspension or solution for parenteral use.

Til behandling via vasodilatation af cardiovaskulære uregel-35 mæssigheder, såsom angina eller hypertension, administreres internt til mennesker eller pattedyr en effektiv non-toxisk mængde af en forbindelse med formel (I). Den aktive bestanddel administreres fortrinsvis på enhedsdosisform, som beskrevet ovenfor. Administre- 6For the treatment via vasodilatation of cardiovascular irregularities, such as angina or hypertension, an effective non-toxic amount of a compound of formula (I) is administered internally to humans or mammals. The active ingredient is preferably administered in unit dosage form, as described above. Admin- 6

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ringsvejen kan være oral og/eller parenteral.the ring pathway may be oral and / or parenteral.

De omhandlede forbindelser fremstilles ved anvendelse af kendte fremgangsmåder på de passende udgangsmaterialer. Specifikt gør den foreliggende opfindelse brug af en fremgangsmåde til frem-5 stilling af forbindelserne med formel (I) i henhold til følgende reaktionsskema.The present compounds are prepared using known methods on the appropriate starting materials. Specifically, the present invention employs a process for preparing the compounds of formula (I) according to the following reaction scheme.

R lithium- R3 ^ 0 [CHlju diisopropyl- 0-[CH]m 0-[CH]m 10 CH3-< tCH2]n -Ϊ52-, LiCH-y [CH ] I [CH2]n »n* ΓΑ* R H2N/R2 CIV) (II) 15 R3R lithium- R3 ^ 0 [CH diisopropyl- 0- [CH] m 0- [CH] m 10 CH3- <tCH2] n -Ϊ52-, LiCH-y [CH] I [CH2] n »n * ΓΑ * R H2N / R2 CIV) (II) R3

i r4°2Vin r4 ° 2V

r3-cho + CH3'cCH2C02R4-*r3-cho + CH3'cCH2CO2R4- *

on H jrSon H jrS

20 3 (III) R5 25 4 f /°'[^3 (III) R5 25 4 f / ° '[^

J I RJ I R

HH

30 (I) 1 2 3 4 5 1 ovenstående skema har R, R , R , R , R , R , m og n samme betydninger som i formel (I). Den foretrukne fremgangsmåde til fremstilling af forbindelserne med formel (I) består i at tilbage- * 35 svale addukt-mel!emprodukterne (II) og (III) i ethanol i sk opløsning i 18 til 24 timer. Fjernelse af opløsningsmidlet giver et materiale, der, såfremt det er et fast stof, renses ved omkrystallisation og, såfremt det er en olie, omdannes til et syreadditionssalt og dernæst 7(I) 1 2 3 4 5 1 The above scheme has R, R, R, R, R, R, m and n having the same meanings as in formula (I). The preferred process for preparing the compounds of formula (I) consists in refluxing the adduct intermediates (II) and (III) in ethanol in so-called solution for 18 to 24 hours. Removal of the solvent gives a material which, if it is a solid, is purified by recrystallization and, if it is an oil, is converted to an acid addition salt and then 7

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renses. Denne lette reaktion finder sted i sædvanligt laboratorie-eller anlægsudstyr under hensigtsmæssige driftsbetingelser. Fremstilling af forbindelser med formel (I) i henhold til fremgangsmåden ifølge opfindelsen omfatter i almindelighed opvarmning af (II) og •5 (III) rent eller i nærværelse af en række forskellige for reaktionen inerte organiske opløsningsmidler. Egnede opløsningsmidler omfatter, men er ikke begrænsede til, benzen, toluen, tetrahydrofuran, di-butylether, butanol, hexanol, methanol, dimethoxyethan, ethylen-glycol, etc. Egnede reaktionstemperaturer er fra ca. 60° til 150°C.cleaned. This light reaction takes place in usual laboratory or plant equipment under appropriate operating conditions. Preparation of compounds of formula (I) according to the process of the invention generally comprises heating (II) and (III) pure or in the presence of a variety of organic solvent inert for the reaction. Suitable solvents include, but are not limited to, benzene, toluene, tetrahydrofuran, di-butyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are from 60 ° to 150 ° C.

10 Ingen katalysator eller kondensationsmiddel kræves.No catalyst or condensing agent is required.

Fremgangsmåden ifølge opfindelsen belyses nærmere i de følgende eksempler. Temperaturerne er udtrykt i °C, og smeltepunkterne er ukorrigerede. Værdierne for de kernemagnetiske resonansspektre (NHR) refererer til kemiske skifteværdier (δ) udtrykt som 15 dele pr. million (dpm) i forhold til tetramethylsilan (TMS) som intern referencestandard. Det relative areal, som er rapporteret for de forskellige skifteværdier i de NMR-spektrale data, svarer til antallet af hydrogenatomer for en bestemt funktionel type i molekylet. Arten af skiftende med hensyn til multiplicitet er angivet som 20 bred singlet (bs), singlet (s), multiplet (m) eller dublet (d).The process according to the invention is illustrated in more detail in the following examples. Temperatures are expressed in ° C and the melting points are uncorrected. The values of the nuclear magnetic resonance spectra (NHR) refer to chemical shift values (δ) expressed as 15 parts per minute. million (ppm) relative to tetramethylsilane (TMS) as internal reference standard. The relative area reported for the different shift values in the NMR spectral data corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of changing in terms of multiplicity is given as 20 broad singlet (bs), singlet (s), multiplet (m) or doublet (d).

Anvendte forkortelser er DMSO-dg (deuterodimethylsul foxid), CDCl^ (deuterochloroform), og er i øvrigt konventionelle. De infrarøde spektralbeskrivel ser (IR) omfatter kun bølgeabsorptionstal (cnf*) med identifikationsværdi for en funktionel gruppe. IR-bestemme!-25 serne foretoges under anvendelse af kaliumbromid (KBr) som diluent. Elementæranalyserne er angivet som vægt%ér.Abbreviations used are DMSO-dg (deuterodimethylsul foxide), CDCl3 (deuterochloroform), and are otherwise conventional. The infrared spectral descriptors (IR) only include wave absorption numbers (cnf *) with identification value for a functional group. The IR determinations were made using potassium bromide (KBr) as diluent. The elemental analyzes are given as% by weight.

SYNTESE AF MELLEMPRODUKTERSYNTHESIS OF INTERMEDIATES

A. Mellemprodukter med formel (II) 30A. Intermediates of Formula (II) 30

Eksempel 1 2-amino-l-(4,5-dih.ydro-2-oxazo1y1)-l-butenExample 1 2-Amino-1- (4,5-dihydro-2-oxazolyl) -1-butene

En opløsning af 2-methyl-2-oxazolin (8,5 g, 0,10 mol) i 100 ml tør tetrahydrofuran (THF) sattes via sprøjte til en omrørt suspen-35 sion af frisk fremstillet 1 ithiumdiisopropyl amid i 50 ml THF. Suspensionen holdtes omrørt under en nitrogenatmosfære ved -78°C i yderligere en time, efter at tilsætningen var tilendebragt. På dette tidspunkt sattes propionitril (10 ml, 0,14 mol) til den omrørte suspen- 8A solution of 2-methyl-2-oxazoline (8.5 g, 0.10 mol) in 100 ml of dry tetrahydrofuran (THF) was added via syringe to a stirred suspension of freshly prepared 1 lithium diisopropyl amide in 50 ml of THF. The suspension was kept stirred under a nitrogen atmosphere at -78 ° C for an additional hour after the addition was complete. At this point, propionitrile (10 mL, 0.14 mol) was added to the stirred suspension

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sion, som dernæst henstod til opvarmning til stuetemperatur under fortsat omrøring. Reaktionsblandingen afkøledes dernæst med 25 ml mættet NH^Cl opløsning. Det organiske lag fraskiltes og vaskedes med vand. Den vandige vaskevæske modekstraheredes med ether, 5 og de organiske dele forenedes og vaskedes med saltvand. Den organiske opløsning tørredes over KgCO^, filtreredes og koncentreredes til 13 g gul væske. Destillation (90-95°C ved 1 mm Hg) gav 6,5 g klar væske som produkt (70% udbytte).sion, which was then allowed to warm to room temperature with continued stirring. The reaction mixture was then cooled with 25 ml of saturated NH 2 Cl solution. The organic layer was separated and washed with water. The aqueous wash liquid was extracted with ether, 5 and the organic portions were combined and washed with brine. The organic solution was dried over KgCO3, filtered and concentrated to 13 g of yellow liquid. Distillation (90-95 ° C at 1 mm Hg) gave 6.5 g of clear liquid as product (70% yield).

10 Eksempel 2 2-amino-l-(4,5-dihydro-4,4-dimethyl-2-oxazol.yl)-l-propenExample 2 2-Amino-1- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1-propene

En opløsning af 4,5-dihydro-2,4,4-trimethyl-2-oxazolin (25 g, 0,22 mol) og tetramethylethylendiamin (25,5 g, 0,22 mol) sattes til en omrørt blanding af lithiumdiisopropyl amid (frisk fremstillet ud fra 15 0,23 mol diisopropylamin og 0,23 mol n-butyllithium i 100 ml tør THF), som holdtes under en nitrogenatmosfære ved -78°C. Den resulterende hvidlige suspension omrørtes ved -78°C i yderligere 2,5 time. En opløsning af acetonitril (15 g, 0,35 mol) i 50 ml THF sattes til den omrørte reaktionsblanding, som dernæst henstod til 20 opvarmning til stuetemperatur. Reaktionsblandingen afkøledes med mættet ammoniumchloridopløsning, og vand tilsattes i en tilstrækkelig mængde til at opløse alle faste stoffer i blandingen. En 100 ml portion ether tilsattes, og de resulterende lag adskiltes. Det organiske lag vaskedes med saltvand og tørredes (KgCOg), filtreredes 25 og koncentreredes i vakuum til dannelse af 24,9 g gul væske.A solution of 4,5-dihydro-2,4,4-trimethyl-2-oxazoline (25 g, 0.22 mol) and tetramethylethylenediamine (25.5 g, 0.22 mol) was added to a stirred mixture of lithium diisopropyl amide (freshly prepared from 0.23 mole of diisopropylamine and 0.23 mole of n-butyllithium in 100 ml of dry THF), which was kept under a nitrogen atmosphere at -78 ° C. The resulting whitish suspension was stirred at -78 ° C for an additional 2.5 hours. A solution of acetonitrile (15 g, 0.35 mol) in 50 mL of THF was added to the stirred reaction mixture, which was then allowed to warm to room temperature. The reaction mixture was cooled with saturated ammonium chloride solution and water was added in a sufficient quantity to dissolve all solids in the mixture. A 100 ml portion of ether was added and the resulting layers separated. The organic layer was washed with brine and dried (KgCO 3), filtered and concentrated in vacuo to give 24.9 g of yellow liquid.

Destillation gav et 10% produktudbytte af enamino-oxazolin, kp.Distillation yielded a 10% product yield of enamino-oxazoline, b.p.

102-105°C ved 4 mm Hg.102-105 ° C at 4 mm Hg.

Eksempel 3 30 2-amino-l-(5,6-dihydro-4,4,6-trimethyl-4H-l,3-oxazin-2-yl)-l-buten Til en opløsning af 11,0 mmol lithiumdiisopropyl amid (11,1 g diisopropylamin, 50 ml 2,4 M n-butyllithium i n-hexan) i 100 ml THF, som holdtes ved -78°C under en nitrogenatmosfære, sattes en opløsning af 5,6-dihydro-4,4,6-trimethyl-4H-l,3-oxazin (14,1 g, 35 0,10 mol) i 100 ml THF. Reaktionsblandingen omrørtes dernæst ved -78° i yderligere 2 timer, på hvilket tidspunkt en opløsning af propionitril (8,3 g, 0,15 mol) i 50 ml THF tilsattes. Reaktionsblandingen henstod til opvarmning til stuetemperatur og afkøledes med 9Example 3 2-Amino-1- (5,6-dihydro-4,4,6-trimethyl-4H-1,3-oxazin-2-yl) -1-butene To a solution of 11.0 mmol lithium diisopropyl amide (11.1 g of diisopropylamine, 50 ml of 2.4 M n-butyllithium in n-hexane) in 100 ml of THF, kept at -78 ° C under a nitrogen atmosphere, was added a solution of 5,6-dihydro-4.4 , 6-trimethyl-4H-1,3-oxazine (14.1 g, 0.10 mol) in 100 ml of THF. The reaction mixture was then stirred at -78 ° for a further 2 hours, at which time a solution of propionitrile (8.3 g, 0.15 mol) in 50 ml of THF was added. The reaction mixture was allowed to warm to room temperature and cooled to 9

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75 ml mættet NH^Cl-opløsning. En 100 ml portion ether tilsattes, det organiske lag fraskiltes, vaskedes med saltvand og tørredes (I^COg).75 ml of saturated NH4 Cl solution. A 100 ml portion of ether was added, the organic layer was separated, washed with brine and dried (1 CO 2).

Efter fjernelse af KgCOj ved filtrering koncentreredes filtratet i vakuum til dannelse af 21,2 g af en gul væske, der destilleredes til 5 et produktudbytte på 15,5 g (79% udbytte) som en bleggul olie, kp.After removal of KgCO 3 by filtration, the filtrate was concentrated in vacuo to give 21.2 g of a yellow liquid distilled to give a product yield of 15.5 g (79% yield) as a pale yellow oil, b.p.

140°C ved 4 mm Hg.140 ° C at 4 mm Hg.

Eksempel 4 2-amino-l-(4,5-dihydro-4-methoxymethy1-4-methyl-2-oxazolyl)-l-buten 10 En opløsning af 4,5-dihydro-2,4-dimethyl-4-hydroxymethyl- -oxazol [10,0 g, 0,78 mol. For syntese af denne hydroxyoxazolin, jvfr. H. Witte og W. Seeliger, Angew. Chem. Int. Ed., vol. 11, 287 (1972); J. Nys og J. Libeer, Bull. Soc. Chim. Belges., vol. .65, 377 (1956)] i 100 ml THF sattes dråbevis til en omrørt suspension af 15 natriumhydrid (3,6 g af en 57% suspension i mineralolie) i 40 ml tør THF under en nitrogenatmosfære ved stuetemperatur. Den resulterende suspension omrørtes i 3 timer under nitrogenatmosfære, og dernæst tilsattes en opløsning af methyliodid (12,1 g, 0,08 mol) i 25 ml THF, og blandingen henstod under omrøring natten over. En 100 20 ml portion ether tilsattes, hvorefter lagene adskiltes, og det organiske lag vaskedes to gange med vand og dernæst med saltvand.Example 4 2-Amino-1- (4,5-dihydro-4-methoxymethyl-4-methyl-2-oxazolyl) -1-butene A solution of 4,5-dihydro-2,4-dimethyl-4-hydroxymethyl - -oxazole [10.0 g, 0.78 mol. For the synthesis of this hydroxyoxazoline, cf. H. Witte and W. Seeliger, Angew. Chem. Int. Ed., Vol. 11, 287 (1972); J. Nys and J. Libeer, Bull. Soc. Chim. Belges., Vol. 65, 377 (1956)] in 100 ml of THF was added dropwise to a stirred suspension of sodium hydride (3.6 g of a 57% suspension in mineral oil) in 40 ml of dry THF under a nitrogen atmosphere at room temperature. The resulting suspension was stirred for 3 hours under a nitrogen atmosphere, then a solution of methyl iodide (12.1 g, 0.08 mol) in 25 ml of THF was added and the mixture was allowed to stir overnight. A 100 ml portion of ether was added, then the layers were separated and the organic layer was washed twice with water and then with brine.

Det organiske lag tørredes (K^CO^), filtreredes og koncentreredes i vakuum til 8,4 g gul residual væske, der ved destillation gav 4,4 g (39% udbytte) klart flydende produkt, kp. 90C ved 10 mm Hg.The organic layer was dried (K 2 CO 2), filtered and concentrated in vacuo to 8.4 g of yellow residual liquid to give, by distillation, 4.4 g (39% yield) of clear liquid product, b.p. 90C at 10 mm Hg.

25 Til en omrørt, afkølet (~78°C) blanding af 1 ithiumdiisopropyl-amid (27 mmol), fremstillet ud fra 2,7 g af aminen, 11,3 ml 2,4 M n-butyllithium i n-hexan) i 10 ml THF sattes en opløsning af det ovenfor fremstillede oxazolin-mel!emprodukt (3,6 g, 25 mm). Den resulterende gule blanding omrørtes ved -78° i 1,5 time, på hvilket 30 tidspunkt propionitril (2,8 g, 0,05 mol) i 10 ml THF tilsattes.To a stirred, cooled (~ 78 ° C) mixture of 1 lithium diisopropyl amide (27 mmol), prepared from 2.7 g of the amine, 11.3 ml of 2.4 M n-butyllithium in n-hexane) To 10 ml of THF was added a solution of the above-prepared oxazoline mixture (3.6 g, 25 mm). The resulting yellow mixture was stirred at -78 ° for 1.5 hours, at which time propionitrile (2.8 g, 0.05 mol) in 10 ml of THF was added.

Denne blanding henstod til opvarmning til stuetemperatur og afkøledes dernæst med en mættet NH^Cl-opløsning. Reaktionsblandingen oparbejdedes dernæst som i de foregående eksempler, og destillation gav 1,2 g (25% udbytte) af produktet enamino-oxazolin, 35 kp. 120° ved 1 mm Hg.This mixture was allowed to warm to room temperature and then cooled with a saturated NH4 Cl solution. The reaction mixture was then worked up as in the previous examples and distillation gave 1.2 g (25% yield) of the product enamino-oxazoline, 35 kp. 120 ° at 1 mm Hg.

Nogle yderligere eksempler på mellemprodukter med formel (II), som kan fremstilles ved anvendelse af den i de foregående eksempler angivne fremgangsmåde, er givet i tabel I.Some additional examples of intermediates of formula (II) which can be prepared using the process set forth in the preceding examples are given in Table I.

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Tabel ITable I

Yderligere mellemprodukter med formel (II) 5 R5 ?5Additional intermediates of formula (II) 5 R5? 5

LiCH2—/ [CH2]n + R2CN —> I t®2]n x-7<, ' P’T^ 10 E E η2Λ2 (IV) (II)LiCH2 - / [CH2] n + R2CN -> I t®2] n x -7 <, 'P'T ^ 10 E E η2Λ2 (IV) (II)

Eks. R R1 R2 m R5 n kp. (°C/0,1 mm) snip. °CEx. R R1 R2 m R5 n kp. (° C / 0.1 mm) snip. ° C

15 5 Me He Et 0 - 1 70-72 6 Me H Et 0 - 1 7 Η H Et 0 - 2 8 Η Η Et 1 Et 1 9 MeOCH2 Me Me 0 - 2 20 10 H Me Ph 0 - 1 11 Me Me CHMe2 0 - 1 80 58-61 12 Me Me CMe3 0 - 1 - 132-133 13 Me Me Ph 0 - 1 - 74-75 14 Me Me 2- 0 - 1 107 69-70 25 thienyl 15 Η H Et 1 Ph 1 175 (ved 2,5 mm) - B. Mellemprodukter med formel (III) 30 Eksempel 1615 5 Me He It 0 - 1 70-72 6 Me H It 0 - 1 7 Η H It 0 - 2 8 Η Η It 1 It 1 9 MeOCH2 Me Me 0 - 2 20 10 H Me Ph 0 - 1 11 Me Me CHMe2 0 - 1 80 58-61 12 Me Me CMe3 0 - 1 - 132-133 13 Me Me Ph 0 - 1 - 74-75 14 Me Me 2- 0 - 1 107 69-70 25 thienyl 15 Η H Et 1 Ph 1 175 (at 2.5 mm) - B. Intermediates of Formula (III) Example 16

Ethyl-e-acetyl-3-nitrocinnamatEthyl E-acetyl-3-nitrocinnamate

En reaktionsblanding indeholdende m-nitrobenzaldehyd (151 g, 1,0 mol), ethylacetoacetat (130 g, 1,0 mol), piperidin (4 ml) og iseddikesyre (12 ml) i 200 ml benzen til bagesval edes i 2,5 timer under 35 fjernelse af vand (19 ml) ved hjælp af en Dean Stark fælde. Den mørkebrune reaktionsopløsning henstod til afkøling til stuetemperatur og vaskedes dernæst med vand adskillige gange og koncentreredes i vakuum til dannelse af et mørkegult fast stof. Dette faste stofA reaction mixture containing m-nitrobenzaldehyde (151 g, 1.0 mol), ethyl acetoacetate (130 g, 1.0 mol), piperidine (4 ml) and glacial acetic acid (12 ml) in benzene (200 ml) for reflux for 2.5 hours under 35 removal of water (19 ml) using a Dean Stark trap. The dark brown reaction solution was allowed to cool to room temperature and then washed with water several times and concentrated in vacuo to give a dark yellow solid. This solid

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n omkrystalli seredes fra ethanol til dannelse af 182 g (69% udbytte) gult fast stof, smp. 103-106°C. Litteratur snip.: S. Ruhemann, J.N was recrystallized from ethanol to give 182 g (69% yield) of yellow solid, m.p. 103-106 ° C. Literature snip .: S. Ruhemann, J.

Chem. Soc., vol. 83, 717 (1903) - smp. 110°C.Chem. Soc., Vol. 83, 717 (1903) - m.p. 110 ° C.

Yderligere eksempler på mellemprodukter med formel (III), som 5 fremstilledes under anvendelse af den i eksempel 16 givne fremgangsmåde, er angivet i tabel II.Further examples of intermediates of formula (III) prepared using the procedure given in Example 16 are given in Table II.

Tabel IITable II

Yderligere mellemprodukter med formel (III) 10 R3 oAdditional intermediates of formula (III) R3 o

r3-cho + CH3CCH2C02R4 -> Tr3-cho + CH3CCH2C02R4 -> T

15 J15 J

(III)(III)

Kp. Smp.Kp. Mp.

Eks. R3 R4 (°C/0,1 mm) (°C) 20 - - - - - 17 m-nitrophenyl i-propyl 18 m-nitrophenyl butyl 19 m-nitrophenyl methoxyethyl 20 m-nitrophenyl dimethyl amino- 25 ethyl 21 p-nitrophenyl ethyl - 59,5-61,5 22 cyklohexyl ethyl 160-170 23 1-naphthyl ethyl 120-130 24 3-indolyl ethyl - 121-122,5 30 25 2-furanyl ethyl 118-120 26 2-thienyl ethyl 110-120 27 3-pyridyl ethyl 145-165 28 2-bicykloheptenyl ethyl 134-140 29 phenyl ethyl 97 35 30 m-cyanophenyl ethyl 130-160 31 o-chlorphenyl ethyl 32 m-hydroxy-p- ethyl nitro-phenyl 12Ex. R3 R4 (° C / 0.1 mm) (° C) 20 - - - - - 17 m-nitrophenyl i-propyl 18 m-nitrophenyl butyl 19 m-nitrophenyl methoxyethyl 20 m-nitrophenyl dimethyl aminoethyl 21 p nitrophenyl ethyl 59.5-61.5 22 cyclohexyl ethyl 160-170 23 1-naphthyl ethyl 120-130 24 3-indolyl ethyl 121-122.5 30 2-furanyl ethyl 118-120 26 2-thienyl ethyl 110 -120 27 3-pyridyl ethyl 145-165 28 2-bicycloheptenyl ethyl 134-140 29 phenyl ethyl 97 35 30 m-cyanophenyl ethyl 130-160 31 o-chlorophenyl ethyl 32 m-hydroxy-p-ethyl nitro-phenyl 12

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Kp. Smp.Kp. Mp.

Eks. R3 R4 (°C/0,1 mm) (°C) 33 o-fluorphenyl ethyl 130 5 34 m-chlorphenyl ethyl 120-123 35 m-trifluormethyl- ethyl 100-110 phenyl 36 p-hydroxy-m- ethyl nitro-phenyl 10 37 o-methoxyphenyl ethyl 38 m-methylphenyl ethyl 140 39 p-hydroxy-m- ethyl - 110-112 methoxyphenyl 40 p-acetamido- ethyl 15 phenyl 41 m-methylsulfonyl- ethyl phenyl 42 m-trifluormethyl- ethyl sulfonylphenyl 20 43 o-chlor-m-nitro- ethyl phenyl 44 o-nitrophenyl methyl 45 m-nitrophenyl methyl - 145-146 46 m-nitrophenyl n-propyl 25 47 m-nitrophenyl 2-chlorethyl - 68-76 SYNTESE AF PRODUKTER Eksempel 48Ex. R3 R4 (° C / 0.1 mm) (° C) 33 o-fluorophenyl ethyl 130 5 34 m-chlorophenyl ethyl 120-123 35 m-trifluoromethylethyl 100-110 phenyl 36 p-hydroxy-m-ethyl nitro phenyl 10 37 o-methoxyphenyl ethyl 38 m-methylphenyl ethyl 140 39 p-hydroxy-m-ethyl - 110-112 methoxyphenyl 40 p-acetamidoethyl phenyl 41 m-methylsulfonylethyl phenyl 42 m-trifluoromethylethyl sulfonylphenyl 20 43 o-chloro-m-nitroethyl phenyl 44 o-nitrophenyl methyl 45 m-nitrophenyl methyl - 145-146 46 m-nitrophenyl n-propyl 47 47 m-nitrophenyl 2-chloroethyl - 68-76 SYNTHESIS OF PRODUCTS Example 48

Ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazol.yl )-6-eth.yl-l,4-dihydro-2-30 -methyl-4-(3-nitrophenyl)-3-pyri di ncarboxylatEthyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-30-methyl-4- (3-nitrophenyl) 3-pyridine carboxylate

En reaktionsblanding bestående af ethyl-a-acetyl-3-nitrocinnamat (eksempel 15; 13,2 g, 50,0 mmol), 2-amino-l-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-l-buten (eksempel 5; 8,4 g, 50,0 mmol) og 75 ml ethanol tilbagesval edes i 19 timer. Blandingen koncentreredes i vakuum til 21,0 g 35 gult fast stof, der omkrystalliseredes fra vandig ethanol til dannelse af 17,4 g (84% udbytte) gule krystaller, smp. 162-163°C.A reaction mixture consisting of ethyl α-acetyl-3-nitrocinnamate (Example 15; 13.2 g, 50.0 mmol), 2-amino-1- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) 1-Butene (Example 5; 8.4 g, 50.0 mmol) and 75 mL of ethanol refluxed for 19 hours. The mixture was concentrated in vacuo to 21.0 g of 35 yellow solid which was recrystallized from aqueous ethanol to give 17.4 g (84% yield) of yellow crystals, m.p. 162-163 ° C.

Analyse beregnet for C22H27N3°5: 63>91» 6,59; N, 10,17.Analysis calculated for C 22 H 27 N 3 ° 5: 63> 91 »6.59; N, 10.17.

Fundet: C, 63,90; H, 6,58; N, 10,13.Found: C, 63.90; H, 6.58; N, 10.13.

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Denne og de øvrige omhandlede dihydro-oxalyl-dihydropyridi nbaser kan let omdannes til deres hydrochloridsalte ved behandling af en isopropyl al kohol opløsning af basen med vandig HC1, efterfulgt af konventionel oparbejdning og rensning. Omdannelse af ovenstående base til dens 5 monohydrochloridsalt gav et gult fast stof, smp. 234-235°.This and the other disclosed dihydro-oxalyl-dihydropyridine bases can be readily converted to their hydrochloride salts by treating an isopropyl alcohol solution of the base with aqueous HCl, followed by conventional work-up and purification. Conversion of the above base to its monohydrochloride salt gave a yellow solid, m.p. 234-235 °.

Analyse beregnet for C22^27^3*VHC1: C, 58,73; H, 6,27; N, 9,34. Fundet: C, 58,76; H, 6,43; N, 9,36.Analysis calculated for C 22 H 27 Cl 3: VHCl H, 6.27; N, 9.34. Found: C, 58.76; H, 6.43; N, 9.36.

NMR (DMSO-dg): 1,21 (6,t [7,0 Hz]); 1,24 (3,s); 1,51 (3,s); 2,39 (3,s); 2,86 (2,m); 4,08 (2,q [7,0 Hz]); 4,58 (2,s); 5,32 10 (1,s); 7,59 (l,t [8,1 Hz]); 7,97 (2,m); 8,28 (l,m); 10,64 (l,bs); 12,60 (l,bs).NMR (DMSO-d 6): 1.21 (6, t [7.0 Hz]); 1.24 (3, s); 1.51 (3, s); 2.39 (3, s); 2.86 (2, m); 4.08 (2, q [7.0 Hz]); 4.58 (2, s); 5.32 (1, s); 7.59 (l, t [8.1 Hz]); 7.97 (2, m); 8.28 (1, m); 10.64 (1, bs); 12.60 (1, bs).

IR (KBr); 1065, 1125, 1230, 1270, 1350, 1440, 1490, 1530, 1585, 1605, 1700 og 2980 cm"1.IR (KBr); 1065, 1125, 1230, 1270, 1350, 1440, 1490, 1530, 1585, 1605, 1700 and 2980 cm "1.

15 Eksempel 49Example 49

Ethyl-5-(4,5-dih.ydro-2-oxazoly1)-6-ethyl-l,4-dihydro-2-methyl-4-(3--nitrophenyl)-3-pyridincarboxylatEthyl 5- (4,5-dih.ydro-2-oxazoly1) -6-ethyl-l, 4-dihydro-2-methyl-4- (3 - nitrophenyl) -3-pyridinecarboxylate

En blanding af 2-amino-l-(4,5-dihydro-2-oxazolyl)-l-buten (eksempel 1; 5,0 g, 35,7 mmol) og ethyl-α-acetyl-3-nitrocinnamat 20 (eksempel 15; 9,4 g, 35,7 mmol) i 75 ml ethanol til bagesval edes 23 timer. Koncentration af reaktionsblandingen i vakuum gav 16,6 g gult fast stof. Omkrystallisering fra ethanol gav 11,3 g (82% udbytte) gult fast stof, smp. 149-150°C.A mixture of 2-amino-1- (4,5-dihydro-2-oxazolyl) -1-butene (Example 1; 5.0 g, 35.7 mmol) and ethyl α-acetyl-3-nitrocinnamate 20 ( Example 15; 9.4 g, 35.7 mmol) in 75 ml of ethanol for reflux for 23 hours. Concentration of the reaction mixture in vacuo gave 16.6 g of yellow solid. Recrystallization from ethanol gave 11.3 g (82% yield) of yellow solid, m.p. 149-150 ° C.

Analyse beregnet for C20H23N3°5: C’ 62>33’ H, 6,02; N, 25 10,91. Fundet; C, 62,23; H, 5,96; N, 10,75.Analysis calculated for C20 H23 N3 ° 5: C '62> 33' H, 6.02; N, 10.91. found; C, 62.23; H, 5.96; N, 10.75.

Omdannelse af ovennævnte base til hydrochloridsaltet gennemførtes ved at behandle en isopropanolopløsning af basen med 10% vandig HC1. Reaktionsopløsningen filtreredes, koncentreredes i vakuum til et gult fast stof og omkrystalli seredes fra methanol, 30 hvilket gav et gult fast stof, smp. 206-207°C.Conversion of the above base to the hydrochloride salt was accomplished by treating an isopropanol solution of the base with 10% aqueous HCl. The reaction solution was filtered, concentrated in vacuo to a yellow solid and recrystallized from methanol to give a yellow solid, m.p. 206-207 ° C.

NMR (CF3COOH); 1,42 (6,t [7,4 Hz]); 2,49 (3,s); 3,01 (2,q [7,4 Hz]); 4,11 (2,t [9,0 Hz]; 4,39 (2,q [7,4 Hz]); 5,17 (s,t [9,0 Hz]); 5,20 (l,s); 7,75 (2,m), 8,12 (l,bs); 8,21 (l,m), 8,36 (l,m); 8,71 (l,bs).NMR (CF 3 COOH); 1.42 (6, t [7.4 Hz]); 2.49 (3, s); 3.01 (2, q [7.4 Hz]); 4.11 (2, t [9.0 Hz]; 4.39 (2, q [7.4 Hz]); 5.17 (s, t [9.0 Hz]); 5.20 (1, s); 7.75 (2, m); 8.12 (1, bs); 8.21 (1, m); 8.36 (1, m); 8.71 (1, bs).

35 IR (KBr): 1070, 1130, 1230, 1260, 1285, 1350, 1435, 1490, 1530, 1590, 1610, 1700 og 2980 cm'1.IR (KBr): 1070, 1130, 1230, 1260, 1285, 1350, 1435, 1490, 1530, 1590, 1610, 1700, and 2980 cm -1.

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Eksempel 50Example 50

Ethyl-5-[4,5-dihydro-4-(methoxymethyl)-4-roethyl-2-oxazolyl]-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridincarbox.yl at,monohydrochlorid 5 En blanding af 2-amino-l-(4,5-dihydro-4-methoxymethyl-4- -methyl-2-oxazolyl)-l-buten (eksempel 4; 0,9 g, 4,6 mmol) og ethyl--a-acetyl-3-nitrocinnamat (eksempel 15; 1,2 g, 4,0 mmol) i 10 ml ethanol tilbagesvaledes i 23 timer. Reaktionsblandingen koncentreredes i vakuum til en gul olie, der repræsenterede det rå produkt.Ethyl-5- [4,5-dihydro-4- (methoxymethyl) -4-roethyl-2-oxazolyl] -6-ethyl-1,4-dihydro-2-methyl-4- (3-nitrophenyl) -3- A mixture of 2-amino-1- (4,5-dihydro-4-methoxymethyl-4- -methyl-2-oxazolyl) -1-butene (Example 4; 0.9 g, 4) (6 mmol) and ethyl α-acetyl-3-nitrocinnamate (Example 15; 1.2 g, 4.0 mmol) in 10 ml of ethanol were refluxed for 23 hours. The reaction mixture was concentrated in vacuo to a yellow oil representing the crude product.

10 Denne rå base omdannedes til hydrochloridsaltet (isopropyl al kohol og 10% vandig HC1), der efter omkrystallisation fra ethanol gav 0,25 g (11,3% udbytte) gult fast stof, smp. 257-258°C (dekomp.).This crude base was converted to the hydrochloride salt (isopropyl alcohol and 10% aqueous HCl) which, after recrystallization from ethanol, gave 0.25 g (11.3% yield) of yellow solid, m.p. 257-258 ° C (decomp.).

Analyse beregnet for CggHggNjOg.HCl: C, 57,56; H, 6,31; N, 8,76. Fundet: C, 57,34; H, 6,25; N, 8,46.Analysis calculated for C CggHggNN₂Og.HCl: C, 57.56; H, 6.31; N, 8.76. Found: C, 57.34; H, 6.25; N, 8.46.

15 NMR (DMSO-dg): 1,22 (6,m); 1,44 (3,s); 2,37 (3,s); 2,78 (2,m); 2,92 (3,s), 3,27 (2,m); 4,10 (2,q [7,4 Hz]); 4,48 (l,d [8,2 Hz]); 4,70 (l,d [8,2 Hz]; 5,31 (l,s), 7,75 (2,m), 8,10 (l,n), 8,28 (l,m); 10,52 (l,bs).NMR (DMSO-d 6): 1.22 (6, m); 1.44 (3, s); 2.37 (3, s); 2.78 (2, m); 2.92 (3, s), 3.27 (2, m); 4.10 (2, q [7.4 Hz]); 4.48 (1, d [8.2 Hz]); 4.70 (1, d [8.2 Hz); 5.31 (1, s), 7.75 (2, m), 8.10 (1, n), 8.28 (1, m); 10.52 (1, bs).

IR (KBr): 1068, 1125, 1225, 1280, 1350, 1440, 1450, 1470, 20 1495, 1532, 1595, 1620, 1642 og 2980 cm'1.IR (KBr): 1068, 1125, 1225, 1280, 1350, 1440, 1450, 1470, 20 1495, 1532, 1595, 1620, 1642 and 2980 cm -1.

Eksempel 51Example 51

Ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-l,4-dihydro-2,6-di-methyl-4-(3-n i trophenyl)-3-pyri di ncarboxy1 at,monohydrochlorid 25 En blanding af 2-amino-l-(4,5-dihydro-4,4-dimethyl-2-oxazo-lyl)-l-propen (eksempel 2; 2,9 g, 18,8 mmol) og ethyl-α-acetyl-3--nitrocinnamat (eksempel 15; 4,9 g, 18,8 mmol) i 20 ml ethanol tilbagesval edes i 18 timer. Reaktionsblandingen koncentreredes i vakuum til en orangefarvet olie, der repræsenterede det rå produkt.Ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-pyridinecarboxy1 monohydrochloride 25 A mixture of 2-amino-1- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1-propene (Example 2; 2.9 g, 18.8 mmol) and ethyl α-acetyl-3-nitrocinnamate (Example 15; 4.9 g, 18.8 mmol) in 20 mL of ethanol reflux for 18 hours. The reaction mixture was concentrated in vacuo to an orange oil representing the crude product.

30 Denne rå base omdannedes til hydrochloridsaltet (isopropanol og 10% vandig HC1), hvilket gav 4,25 g (52% udbytte) gult krystallinsk produkt, smp. 236°C (dekomp.) efter omkrystalli sation fra vandig ethanol.This crude base was converted to the hydrochloride salt (isopropanol and 10% aqueous HCl) to give 4.25 g (52% yield) of yellow crystalline product, m.p. 236 ° C (decomp.) After recrystallization from aqueous ethanol.

Analyse beregnet for ^i^gNsOg.HCl: 57,87; H, 6,02; N, 9,65. Fundet: C, 57,71; H, 6,23; N, 9,62.Analysis calculated for i g gNNOO.HCl: 57.87; H, 6.02; N, 9.65. Found: C, 57.71; H, 6.23; N, 9.62.

35 NMR (DMSO-dg): 1,19 (3,t [6,6 Hz]); 1,24 (3,s); 1,47 (3,s); 2,36 (3,s); 2,44 (3,s); 4,09 (2,q [6,6 Hz]); 4,53 (2,s); 5,20 (1,s); 7,76 (2,m); 8,09 (l,m), 8,25 (l,m); 10,50 (l,bs).NMR (DMSO-d 6): 1.19 (3, t [6.6 Hz]); 1.24 (3, s); 1.47 (3, s); 2.36 (3, s); 2.44 (3, s); 4.09 (2, q [6.6 Hz]); 4.53 (2, s); 5.20 (1, s); 7.76 (2, m); 8.09 (1, m), 8.25 (1, m); 10.50 (1, bs).

IR (KBr): 1025, 1125, 1240, 1260, 1350, 1445, 1485, 1530, 15IR (KBr): 1025, 1125, 1240, 1260, 1350, 1445, 1485, 1530, 15

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1590, 1605, 1700 og 2980 cm-1.1590, 1605, 1700 and 2980 cm -1.

Eksempel 52Example 52

Ethyl-5-(5,6-dihydro-4,4,6-trimethyl-4(H)-l,3-oxazin-2-vl)-6-ethy1- -l,4-dihydro-2-methy1-4-(3-nitrophenyl)-3-p.yridincarboxylat,mono-5 hydrochloridEthyl 5- (5,6-dihydro-4,4,6-trimethyl-4 (H) -1,3-oxazin-2-yl) -6-ethyl-1,4-dihydro-2-methyl 4- (3-nitrophenyl) -3-pyridinecarboxylate, monohydrochloride

En blanding af 2-amino-l-(5,6-dihydro-4,4,6-trimethyl-4H-l,3--oxazin-2-yl)-l-buten (eksempel 3; 4,90 g, 25,0 mmol) og ethyl-a--acetyl-3-nitrocinnamat (eksempel 15; 6,58 g, 25,0 mmol) i 75 ml ethanol tilbagesvaledes i 20 timer. Koncentration i vakuum gav et 10 gult fast stof, der omkrystalli seredes fra ethanol, hvilket gav 8,9 g (81% udbytte) af et gult fast stof, smp. 159-163°C.A mixture of 2-amino-1- (5,6-dihydro-4,4,6-trimethyl-4H-1,3-oxazin-2-yl) -1-butene (Example 3; 4.90 g, 25.0 mmol) and ethyl α-acetyl-3-nitrocinnamate (Example 15; 6.58 g, 25.0 mmol) in 75 ml of ethanol were refluxed for 20 hours. Concentration in vacuo afforded a 10 yellow solid which was recrystallized from ethanol to give 8.9 g (81% yield) of a yellow solid, m.p. 159-163 ° C.

Det ovenfor fremstillede gule faste baseprodukt omdannedes til hydrochloridsaltet på samme måde som i de foregående eksempler, hvilket gav et gult fast monohydrochloridsalt, smp. 259-260°C 15 (dekomp.).The yellow solid base product prepared above was converted to the hydrochloride salt in the same manner as in the previous examples to give a yellow solid monohydrochloride salt, m.p. 259-260 ° C (decomp.).

Analyse beregnet for ^H^f^Og.HCl: C, 60,31; H, 6,75; N, 8,80. Fundet: C, 60,49; H, 6,78; N, 8,59.Calcd. For C H HH f fHCl: C, 60.31; H, 6.75; N, 8.80. Found: C, 60.49; H, 6.78; N, 8.59.

NMR (DMSO-dg): 1,19 (9,m); 1,40 (6,s); 1,90 (2,m); 2,36 (3,s); 2,60 (2,m); 4,06 (2,q [7,0 Hz]); 4,83 (l,m); 4,92 (l,s); 20 7,68 (2,m); 8,09 (2,m), 9,80 (l,bs).NMR (DMSO-d 6): 1.19 (9, m); 1.40 (6, s); 1.90 (2, m); 2.36 (3, s); 2.60 (2, m); 4.06 (2, q [7.0 Hz]); 4.83 (1, m); 4.92 (1, s); 7.68 (2, m); 8.09 (2, m), 9.80 (1, bs).

IR (KBr): 1070, 1105, 1125, 1220, 1265, 1350, 1485, 1530, 1605, 1620, 1695 og 2975 cm'1.IR (KBr): 1070, 1105, 1125, 1220, 1265, 1350, 1485, 1530, 1605, 1620, 1695 and 2975 cm -1.

Yderligere eksempler på de omhandlede forbindelser er angivet i tabel III. Disse yderligere produkter syntetiseredes under anven-25 del se af de i eksempel 48-52 beskrevne fremgangsmåder.Further examples of the compounds of the invention are given in Table III. These additional products were synthesized using the procedures described in Examples 48-52.

Tabel IIITable III

Yderligere produkter med formel (I) 30 R3 R5 H3cA + AN7 RlAdditional products of formula (I) 30 R3 R5 H3cA + AN7 Rl

h2A2 Rh2A2 R

-* i 16- * i 16

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Eks. R R1 R2 R3 R4 m R5 n 53 Η H Et 3-N02Ph Me 0-1 54 Me Me Et 2-furanyl Et 0-1 5 55 Me Me Et 4-N02Ph Et 0-1 56 Me Me Et Ph Et 0 - 1 57 Me Me Et 2-FPh Et 0-1 58 Me Me i-Pr 3-N02Ph Et 0-1 59 Me Me t-Bu 3-N02Ph Et 0-1 10 60 Me Me Ph 3-N02Ph Et 0-1 61 Me Me 2-thienyl 3-N0£Ph Et 0-1 62 Me Me Et 2-Cl-5-N02Ph Et 0-1 63 Me Me Et 3-ClPh Et 0-1 64 Me Me Et 3-CF3Ph Et 0-1 15 65 Me Me Et 2-thienyl - Et 0-1 66 Me Me Et 4-0H-3-Me0Ph Et 0-1 67 Me Me Et 3-MePh Et 0-1 68 Me Me Et 1-naphthyl Et 0-1 69 Me Me Et 3-pyridyl Et 0-1 20 70 Me Me Et 2-ClPh Et 0-1 71 Me Me Et 3-CNPh Et 0-1 72 Me Me Et 2-MeOPh Et 0-1 73 Me Me Et 2-bicyklohep- Et 0-1 tenyl 25 74 Me Me Et cyklohexyl Et 0-1 75 Me Me Et 4-AcNHPh Et 0-1 76 Me Me Et 3-0H-4-N02Ph Et 0-1 77 Me H Me 4-isobutylphenyl Et 1 Ph 1 78 H CH20Me Et 4-propoxyphenyl Et 0-1 30 79 Me Me Et 3-ethyl phenyl MeOCH2CH2 0 - 1 80 Me Me Et 3-CH3S02Ph Me2NCH2CH2 0 - 1 81 Me CH20Me Et 3-CF3S02Ph Et 0-1 82 Me CH20Me Et 4-CF3S02Ph MeOCH2CH2 0 - 1 83 Me Me Et 3-indolyl Et 0-1 35 84 Me Me Et 4-0H-3-N02Ph Et 0-1Ex. R R1 R2 R3 R4 m R5 n 53 Η H Et 3-N02Ph Me 0-1 54 Me Me Et 2-Furanyl Et 0-1 5 55 Me Me Et 4-N02Ph Et 0-1 56 Me Me Et Ph Et 0 - 1 57 Me Me Et 2-FPh Et 0-1 58 Me Me i-Pr 3-N02Ph Et 0-1 59 Me Me t-Bu 3-N02Ph Et 0-1 10 60 Me Me Ph 3-N02Ph Et 0-1 61 Me Me 2-Thienyl 3-N0 £ Ph Et 0-1 62 Me Me Et 2-Cl-5-NO2Ph Et 0-1 63 Me Me Et 3-ClPh Et 0-1 64 Me Me Et 3-CF3Ph Et 0 -1 15 65 Me Me Et 2-Thienyl - Et 0-1 66 Me Me Et 4-0H-3-Me0Ph Et 0-1 67 Me Me Et 3-MePh Et 0-1 68 Me Me Et 1-Naphthyl Et 0 -1 69 Me Me Et 3-Pyridyl Et 0-1 20 70 Me Me Et 2-ClPh Et 0-1 71 Me Me Et 3-CNPh Et 0-1 72 Me Me Et 2-MeOPh Et 0-1 73 Me Et 2-bicyclohep- Et 0-1 tenyl 25 74 Me Me Et cyclohexyl Et 0-1 75 Me Me Et 4-AcNHPh Et 0-1 76 Me Me Et 3-0H-4-NO2Ph Et 0-1 77 Me H Me 4-isobutylphenyl Et 1 Ph 1 78 H CH 2 Ome Et 4-propoxyphenyl Et 0-1 30 79 Me Me Et 3-Ethylphenyl MeOCH2CH2 0 - 1 80 Me Me Et 3-CH3 SO2Ph Me2NCH2CH2 0 - 1 81 Me CH20Me Et 3-CF3SO2Ph Et 0-1 82 Me CH 2 Me Et 4-CF 3 SO 2 Ph MeOCH 2 CH 2 0 - 1 83 Me Me Et 3-indolyl Et 0-1 35 84 Me Me Et 4-0H-3-NO2Ph Et 0-1

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1717

Eks. R R1 R2 R3 R4 m R5 n 85 Η H Et 3-N02Ph i-Pr 0-1 86 Η H Et 3-N02Ph MeOCH2CH2 0 - 1 5 87 Η H Et 3-N02Ph C1CH2CH2 0 - 1 88 Η H Et 3-N02Ph Et 1 Ph 0 89 Η H Et 3-N02Ph H2NCH2CH2 0 - 1Ex. R R1 R2 R3 R4 m R5 n 85 Η H Et 3-NO2Ph i-Pr 0-1 86 Η H Et 3-NO2Ph MeOCH2CH2 0 - 1 5 87 Η H Et 3-NO0Ph C1CH2CH2 0 - 1 88 Η H Et 3- N02Ph Et 1 Ph 0 89 Η H Et 3-N02Ph H2NCH2CH2 0 - 1

De fysiske egenskaber af produkterne ifølge de i tabel III 10 angivne eksempler er i tilgængeligt omfang anført i tabel IV.The physical properties of the products according to the examples set out in Table III 10 are available to an extent in Table IV.

Tabel IVTable IV

Fysiske egenskaber - forbindelser med formel (I) 15 AnalysePhysical Properties - Compounds of Formula (I) Analysis

Eks. Navn Smp. (°C) Beregnet Fundet 53 methyl-5-(4,5-dihydro-2-oxazo- 201-202 C, 55,96 55,99 lyl)-6-ethyl-l,4-dihydro-2-me- H, 5,44 5,60 20 thyl-4-(3-nitrophenyl)-3-pyri- N, 10,31 10,03 din-carboxylat,monohydrochlorid 54 Ethyl-5-(4,5-dihydro-4,4-di- 138,5-140 C, 67,02 66,68 methyl-2-oxazolyl)-6-ethyl-4-(2- H, 7,31 7,36 25 -furanyl)-l,4-dihydro-2-methyl- N, 7,82 7,97 -3-pyridin-carboxylat 55 Ethyl-5-(4,5-dihydro-4,4-di- 246-248 C, 58,73 58,36 methyl-2-oxazolyl)-6-ethyl-1,4- H, 6,28 6,63 30 -dihydro-2-methyl-4-(4-nitro- N, 9,34 9,40 phenyl)-3-pyridincarboxylat, monohydrochlorid 56 Ethyl-5-(4,5-dihydro-4,4-di- 147-149 C, 71,71 71,69 35 methyl-2-oxazolyl)-6-ethyl-1,4- H, 7,66 7,66 -dihydro-2-methyl-4-phenyl-3- N, 7,60 7,48 pyridincarboxylat 57 Ethyl-5-(4,5-dihydro-4,4-di - 175-177 C, 62,48 62,41 40 methyl-2-oxazolyl)-6-ethyl-4- H, 6,68 6,70 -(2-fl uorphenyl)-1,4-di hydro-2- N, 6,63 6,51 methyl-3-pyridincarboxylat, monohydrochlorid 45 58 Ethyl -5-(4,5-di hydro-4,4-di- 216-217 C, 59,55 59,45 methyl-2-oxazolyl)-l,4-dihydro- H, 6,52 6,72 2-methyl-6-(1-methylethyl )-4- N, 9,06 9,41 -(3-nitrophenyl)-3-pyridincarb-oxylat,monohydrochl ori dEx. Name Mp. (° C) Calculated Found 53 methyl-5- (4,5-dihydro-2-oxazo-201-202 C, 55.96 55.99 yl) -6-ethyl-1,4-dihydro-2-methyl H, 5.44 5.60 Thyl-4- (3-nitrophenyl) -3-pyridine, 10.31 10.03 din-carboxylate, monohydrochloride 54 Ethyl 5- (4,5-dihydro-4, 4-di-138.5-140 C, 67.02 66.68 methyl-2-oxazolyl) -6-ethyl-4- (2- H, 7.31 7.36-furanyl) -1,4-methyl dihydro-2-methyl-N, 7.82 7.97 -3-pyridine carboxylate Ethyl 5- (4,5-dihydro-4,4-di-246-248 ° C, 58.73 58.36 methyl 2-oxazolyl) -6-ethyl-1,4-H, 6.28 6.63 -dihydro-2-methyl-4- (4-nitro-N, 9,34 9.40 phenyl) -3- pyridinecarboxylate, monohydrochloride 56 Ethyl 5- (4,5-dihydro-4,4-di-147-149 ° C, 71.71 71.69 methyl-2-oxazolyl) -6-ethyl-1,4-H, 7.66 7.66-dihydro-2-methyl-4-phenyl-3- N, 7.60 7.48 pyridinecarboxylate 57 Ethyl 5- (4,5-dihydro-4,4-di - 175-177 ° C , 62.48, 62.41 (2-methyl-2-oxazolyl) -6-ethyl-4- H, 6.68 6.70 - (2-fluorophenyl) -1,4-dihydro-2- N, 6, 63 6.51 methyl 3-pyridinecarboxylate, monohydrochloride 45 58 Ethyl -5- (4,5-di hydro-4,4-di-216-217 ° C, 59.55 59.45 methyl-2-oxaz olyl) -1,4-dihydro-H, 6.52 6.72 2-methyl-6- (1-methylethyl) -4- N, 9.06 9.41 - (3-nitrophenyl) -3-pyridinecarbyl oxylate, monohydrochl ori d

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1818

AnalyseAnalysis

Eks. Navn Smp. (°C) Beregnet Fundet 59 Ethyl-5-(4,5-dihydro-4,4-di- 155-157 C, 65,29 64,90 5 methyl-2-oxazolyl)-6-(1,1-di- H, 7,08 7,17 methylethyl)-l,4-dihydro-2- N, 9,52 9,17 methyl-4-(3-nitropyridincarb-oxylat 10 60 Ethyl-5-(4,5-dihydro-4,4-di- 112-113 C, 67,67 67,73 methyl-2-oxazolyl)-1,4-dihydro- H, 5,90 5,86 -2-methyl-4-(3-nitrophenyl)-6- N, 9,11 9,04 -phenyl-3-pyridincarboxylat 15 61 Ethyl-5-(4,5-di hydro-4,4-di- 143-145 C, 57,20 57,17 methyl-2-oxazolyl)-l,4-dihydro- H, 5,21 5,31 -2-methyl-4-(3-nitrophenyl)-6- N, 8,34 8,06 -(2-thienyl)-3-pyridincarboxylat, monohydrochiorid 20 62 Ethyl-4-(2-chlor-5-nitrophenyl)- 220-224 C, 54,56 54,59 -5-(4,5-dihydro-4,4-dimethyl-2- H, 5,62 5,70 -oxazolyl)-6-ethyl-l,4-dihydro- N, 8,68 8,58 -2-methyl-3-pyridincarboxylat, 25 monohydrochiorid 63 Ethyl-4-(3-chlorphenyl)-5-(4,5- 170-172,5 C, 65,58 65,62 -dihydro-4,4-dimethyl-2-oxazo- H, 6,75 6,73 lyl)-6-ethyl-l,4-dihydro-2-me- N, 6,95 6,84 30 thyl-3-pyridincarboxylat Cl, 8,80 8,83 64 Ethyl-5-(4,5-dihydro-4,4-di- 78-81 C, 63,30 62,95 methyl-2-oxazolyl)-6-ethyl-l,4- H, 6,24 6,29 dihydro-2-methyl-4-[3-(trifluor- N, 6,42 6,12 35 methyl)phenyl]-3-pyridincarb- oxylat 65 Ethyl-5-(4,5-dihydro-4,4-di- 155-158 C, 64,14 63,92 methyl-2-oxazolyl)-6-ethyl-1,4- H, 7,00 7,06 40 -dihydro-2-methyl-4-(2-thienyl- H, 7,48 7,17 -3-pyridincarboxylat 66 Ethyl-5-(4,5-di hydro-4,4-di- 182-185 C, 66,65 66,28 methyl-2-oxazolyl)-6-ethyl-1,4- H, 7,30 7,32 45 -dihydro-4-(4-hydroxy-3-meth- N, 6,76 6,54 oxyphenyl)-2-methyl-3-pyridincarboxyl at 67 Ethyl-5-(4,5-dihydro-4,4-di- 162-163 C, 72,23 72,01 50 methyl-2-oxazolyl)-6-ethyl-1,4- H, 7,91 7,97 -dihydro-2-methyl-4-(3-methyl- N, 7,33 7,25 phenyl)-3-pyridincarboxylat 55 19Ex. Name Mp. (° C) Calculated Found 59 Ethyl 5- (4,5-dihydro-4,4-di-155-157 C, 65.29 64.90 methyl-2-oxazolyl) -6- (1,1- di-H, 7.08 7.17 methylethyl) -1,4-dihydro-2- N, 9.52 9.17 methyl-4- (3-nitropyridinecarboxylate) Ethyl 5- (4,5- dihydro-4,4-di-112-113 C, 67.67 67.73 methyl-2-oxazolyl) -1,4-dihydro-H, 5.90 5.86 -2-methyl-4- (3- nitrophenyl) -6- N, 9,11 9,04 -phenyl-3-pyridinecarboxylate 61 Ethyl 5- (4,5-dihydro-4,4-di-143-145 C, 57.20 57.17 methyl 2-oxazolyl) -1,4-dihydro-H, 5.21 5.31 -2-methyl-4- (3-nitrophenyl) -6- N, 8.34 8.06 - (2-thienyl) -3-Pyridinecarboxylate, monohydrochloride 62 Ethyl 4- (2-chloro-5-nitrophenyl) - 220-224 ° C, 54.56 54.59 -5- (4,5-dihydro-4,4-dimethyl-2 - H, 5.62 5.70 -oxazolyl) -6-ethyl-1,4-dihydro-N, 8.68 8.58 -2-methyl-3-pyridinecarboxylate, monohydrochloride 63 Ethyl 4- (3- chlorophenyl) -5- (4.5-170-172.5 C, 65.58 65.62-dihydro-4,4-dimethyl-2-oxazolo-H, 6.75 6.73yl) -6-ethyl -1,4-dihydro-2-meth-N, 6.95 6.84 ethyl 3-pyridinecarboxylate Cl, 8.80 8.83 64 Ethyl 5- (4,5-dihydro-4,4-di - 78 -81 C, 63.30 62.95 methyl-2-oxazolyl) -6-ethyl-1,4-H, 6.24 6.29 dihydro-2-methyl-4- [3- (trifluoro-N, 6 , 42 6,12 (methyl) phenyl] -3-pyridinecarboxylate 65 Ethyl 5- (4,5-dihydro-4,4-di-155-158 ° C, 64.14 63.92 methyl-2-oxazolyl ) -6-ethyl-1,4-H, 7,00 7,06 40-dihydro-2-methyl-4- (2-thienyl-H, 7,48 7,17 -3-pyridinecarboxylate 66 Ethyl-5 (4,5-di hydro-4,4-di-182-185 ° C, 66.65 66.28 methyl-2-oxazolyl) -6-ethyl-1,4-H, 7.30 7.32 dihydro-4- (4-hydroxy-3-meth-N, 6.76, 6.54 oxyphenyl) -2-methyl-3-pyridinecarboxyl at 67 Ethyl 5- (4,5-dihydro-4,4-di 162-163 ° C, 72.23, 72.01 methyl-2-oxazolyl) -6-ethyl-1,4-H, 7.91 7.97-dihydro-2-methyl-4- (3-methyl-N , 7.33 7.25 phenyl-3-pyridinecarboxylate 55 19

DK 164668 BDK 164668 B

AnalyseAnalysis

Eks. Navn Smp. (°C) Beregnet Fundet 68 Ethyl-5-(4,5-dihydro-4,4-di- 236-238 C, 68,63 68,79 5 methyl-2-oxazolyl)-6-ethyl-1,4- H, 6,87 6,65 -dihydro-2-methyl-4-(l-naphtha- N, 6,16 5,87 lenyl)-3-pyridincarboxylat,mono-hydrochlorid 10 69 Ethyl-5-(4,5-dihydro-4,4-di- 161,5-163,5 C, 67,94 67,70 methyl-2-oxazolyl)-6-ethyl -1,4- H, 7,39 7,48 -dihydro-2-methyl-4-(3-pyridi- N, 11,32 11,22 nyl)-3-pyridincarboxylat H20, 0,49 0,5 15 70 Ethyl-4-(2chlorphenyl)-5-(4,5- 179-182 C, 60,15 59,78 -dihydro-4,4-dimethyl-2-oxazo- H, 6,43 6,18 lyl)-6-ethyl-l,4-dihydro-2-me- N, 6,38 6,40 thyl-3-pyridincarboxylat,mono- Cl, 16,14 16,13 hydrochlorid 20 71 Ethyl-4-(3-cyanophenyl)-5-(4,5- 179-181 C, 70,21 70,15 -dihydro-4,4-dimethyl2-oxazo- H, 6,92 6,92 lyl)-6-ethyl-l,4-dihydro-2-me- N, 10,68 10,54 thyl-3-pyridincarboxylat 25 72 Ethyl-5-(4,5-dihydro-4,4-di- 230 C, 63,52 63,22 methyl-2-oxazolyl)-6-ethyl-1,4- H, 7,19 7,20 -dihydro-4-(2-methoxyphenyl)- N, 6,45 6,24 -2-methyl-3-pyridincarboxylat, 30 monohydrochlorid 73 Ethyl-4-(bicyklo[2,2]hept-5-en- 165-166,5 C, 71,84 72,22 -2-yl)-5-(4,5-di hydro-4,4-di- H, 8,39 8,34 methyl-2-oxazolyl)-6-ethyl-l,4- N, 7,29 7,33 35 -dihydro-2-methyl-3-pyridincarb oxyl at 74 Ethyl-4-cyklohexyl-5-(4,5-di- 205-208 C, 64,30 64,14 hydro-4,4-dimethyl-2-oxazolyl)- H, 8,59 8,56 40 -6-ethyl-l,4-dihydro-2-methyl - N, 6,82 6,42 -3-pyridincarboxylat,monohydrochlorid 75 Ethyl-5-[4-(acetylamino)phe- 240,5-241 C, 60,62 60,51 45 nyl]-5-(4,5-dihydro-4,4-di- H, 7,10 7,17 methyl-2-oxazolyl)-6-ethyl-1,4- N, 8,84 8,51 -dihydro-2-methyl-3-pyridin- FLO, 2,84 2,70 carboxyl at,monohydrochlorid 50 76 Ethyl-5-(4,5-dihydro-4,4-di- 145,5-146 C, 61,53 61,69 methyl-2-oxazolyl)-6-ethyl-1,4- H, 6,34 6,35 dihydro-4-(3-hydroxy-4-nitro- N, 9,79 9,78 phenyl)-2-methyl-3-pyridincarb-oxylat 55 20Ex. Name Mp. (° C) Calculated Found 68 Ethyl 5- (4,5-dihydro-4,4-di-236-238 ° C, 68.63 68.79 methyl-2-oxazolyl) -6-ethyl-1,4 - H, 6.87 6.65-dihydro-2-methyl-4- (1-naphtha-N, 6.16 5.87 lenyl) -3-pyridinecarboxylate, monohydrochloride 69 Ethyl 5- (4, 5-dihydro-4,4-di-161.5-163.5 C, 67.94 67.70 methyl-2-oxazolyl) -6-ethyl -1,4- H, 7,39 7,48-dihydro -2-methyl-4- (3-pyridin-N, 11,32 11,22 nyl) -3-pyridinecarboxylate H 2 O, 0.49 0.5 70 Ethyl 4- (2-chlorophenyl) -5- (4.5 179-182 C, 60.15 59.78-dihydro-4,4-dimethyl-2-oxazo-H, 6,43 6,18-yl) -6-ethyl-1,4-dihydro-2-methyl N, 6.38 6.40 Thyl-3-pyridinecarboxylate, mono-Cl, 16.14 16.13 hydrochloride 71 Ethyl 4- (3-cyanophenyl) -5- (4,5- 179-181 C, 70 (21, 70,15-dihydro-4,4-dimethyl-2-oxazo-H, 6,92 6,92 yl) -6-ethyl-1,4-dihydro-2-meth-N, 10,68 10,54 thyl -3-Pyridinecarboxylate 72 Ethyl 5- (4,5-dihydro-4,4-di-230 C, 63.52 63.22 methyl-2-oxazolyl) -6-ethyl-1,4-H, 7 , 19 7,20-dihydro-4- (2-methoxyphenyl) - N, 6.45 6.24 -2-methyl-3-pyridinecarboxylate, monohydrochloride 73 Ethyl 4- (bicyclic) lo [2,2] hept-5-ene-165-166.5 C, 71.84 72.22 -2-yl) -5- (4,5-di hydro-4,4-di-H, 8 , 39 8.34 methyl-2-oxazolyl) -6-ethyl-1,4-N, 7.29 7.33-dihydro-2-methyl-3-pyridinecarboxyl at 74 Ethyl-4-cyclohexyl-5 (4,5-di-205-208 C, 64,30 64,14 hydro-4,4-dimethyl-2-oxazolyl) - H, 8.59 8.56 40 -6-ethyl-1,4-dihydro -2-methyl - N, 6.82 6.42 -3-pyridinecarboxylate, monohydrochloride 75 Ethyl 5- [4- (acetylamino) phe-240.5-241 C, 60.62 60.51 Nyl] -5 - (4,5-dihydro-4,4-di-H, 7,10 7,17 methyl-2-oxazolyl) -6-ethyl-1,4-N, 8,84,5,5-dihydro-2 methyl 3-pyridine-FLO, 2.84 2.70 carboxyl, monohydrochloride 50 76 Ethyl 5- (4,5-dihydro-4,4-di-145.5-146 ° C, 61.53 61.69 methyl-2-oxazolyl) -6-ethyl-1,4-H, 6.34 6.35 dihydro-4- (3-hydroxy-4-nitro-N, 9.79 9.78 phenyl) -2-methyl -3-pyridinecarboxylate 55

DK 164668 BDK 164668 B

AnalyseAnalysis

Eks. Navn Smp. (°C) Beregnet Fundet 5 83 Ethyl-5-(4,5-dihydro-4,4-di- 124,5-125 C, 68,32 68,67 methyl-2-oxazolyl)-6-ethyl-l,4- H, 7,57 7,45 -dihydro-4-(lH-indol-3-yl)-2- N, 9,56 9,62 -methyl-3-pyridincarboxylat- H«0, 2,05 1,97 ethanol at,hemi hydrat 10 84 Ethyl-5-(4,5-dihydro-4,4-di- 134,5-135 C, 56,72 56,62 methyl-2-oxazolyl)-6-ethyl-1,4- H, 6,06 6,08 -dihydro-4-(4-hydroxy-3-nitro- N, 9,02 8,82 phenyl)-2-methyl-3-pyridincarb- 15 oxylat,monohydrochlorid 85 1-methylethyl-5-(4,5-di hydro- 160-161 C, 63,17 63,15 -2-oxazolyl)-6-ethyl-l,4-di- H, 6,31 6,38 hydro-2-methyl-4-(3-nitrophe- N, 10,52 10,27 20 nyl-3-pyridincarboxylat 86 2-methoxyethyl-5-(4,5-dihydro- 190-191 C, 55,82 55,65 -2-oxazolyl)-6-ethyl-1,4-di- H, 5,80 5,77 hydro-2-methyl-4-(3-nitrophe- N, 9,30 9,30 25 nyl)-3-pyri di ncarboxylat,mono- hydrochlorid 88 Ethyl-5-(4,5-dihydro-5-phenyl- 193-195 C, 62,72 62,59 -2-oxazolyl)-6-ethyl-1,4-di- H, 5,67 5,65 30 hydro-2-methyl-4-(3-nitrophe- N, 8,44 8,33 nyl)-3-pyridincarboxylat,mono-hydrochloridEx. Name Mp. (° C) Calculated Found 83 Ethyl 5- (4,5-dihydro-4,4-di-124.5-125 ° C, 68.32 68.67 methyl-2-oxazolyl) -6-ethyl-1 , 4- H, 7.57 7.45-dihydro-4- (1H-indol-3-yl) -2- N, 9,56 9,62-methyl-3-pyridinecarboxylate H 2 O, 2.05 1.97 ethanol, hemi hydrate 84 Ethyl 5- (4,5-dihydro-4,4-di-134.5-135 ° C, 56.72 56.62 methyl-2-oxazolyl) -6-ethyl -1,4- H, 6,06 6,08-dihydro-4- (4-hydroxy-3-nitro-N, 9,02 8,82 phenyl) -2-methyl-3-pyridinecarboxylate, monohydrochloride 85 1-methylethyl-5- (4,5-dihydro-160-161 C, 63.17 63.15 -2-oxazolyl) -6-ethyl-1,4-di-H, 6.31 6.38 hydro-2-methyl-4- (3-nitrophen-N, 10.52 10.27 nyl 3-pyridinecarboxylate 86 2-methoxyethyl-5- (4,5-dihydro-190-191 C, 55.82 55 , 65 -2-oxazolyl) -6-ethyl-1,4-di-H, 5.80 5.77 hydro-2-methyl-4- (3-nitrophen-N, 9.30 9.30 nyl) -3-pyridinecarboxylate, monohydrochloride 88 Ethyl 5- (4,5-dihydro-5-phenyl-193-195 ° C, 62.72 62.59 -2-oxazolyl) -6-ethyl-1,4 -di-H, 5.67 5.65 hydro-2-methyl-4- (3-nitrophen-N, 8,44 8,33 nyl) -3-pyridinecarboxylate, monohydrochloride

Dataene i tabellen viser, at forbindelserne med formel I har 35 specifik blokerende virkning på calciumionkanaler.The data in the table shows that the compounds of formula I have specific blocking effect on calcium ion channels.

TABEL VTABLE V

Fascie og toniske kontraktioner af longitudinåle qlatmuskelstriml er af marsvineileum 40 Eks. IC5Q (nm) nr. fascie tonisk 48 20 5 49 10 30 45 52 400 800 53 20 100 54 60 200Fascie and tonic contractions of longitudinal needle muscle strip are of guinea pig 40 Ex. IC5Q (nm) No. fascic tonic 48 20 5 49 10 30 45 52 400 800 53 20 100 54 60 200

Claims (3)

21 DK 164668 B21 DK 164668 B 1. Anal ogi fremgangsmåde til fremstilling af l,4-dihydropyrid-5-yl-(cyklisk imidat)estere med den almene formel (I) « *V / ? • \ 2 ‘ / K1. Analogous Process for Preparation of 1,4-Dihydropyrid-5-yl (Cyclic Imidate) Esters of General Formula (I) • \ 2 '/ K 10. R R eller syreadditionssalte deraf, hvori R og R* er uafhængigt udvalgt blandt hydrogen, Cj_4-alkyl og Cj_4-alkoxy-C14-alkyl, Rg er Cj_4-alkyl, phenyl eller thienyl, 15. er cykl oal kyl med 5 til 7 carbonatomer, bicykloalkenyl med 7 til 9 carbonatomer, furanyl, indolyl, pyridyl, thienyl, phenyl, naphthyl eller substitueret phenyl, hvor substituenterne omfatter acetamino, Cj_4-alkyl, Cj_4-alkoxy, cyano, halogen, hydroxyl, nitro og trif1uormethyl,10. RR or acid addition salts thereof, wherein R and R * are independently selected from hydrogen, C 1-4 alkyl and C 1-4 alkoxy-C 14 alkyl, R 9 is C 1-4 alkyl, phenyl or thienyl, 15. is cyclic or 5 to 7 cycloalkyl. carbon atoms, bicycloalkenyl having 7 to 9 carbon atoms, furanyl, indolyl, pyridyl, thienyl, phenyl, naphthyl or substituted phenyl, wherein the substituents include acetamino, C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro and trifluoromethyl, 20 R^ er C14-alkyl eller Cj_4-alkoxy-Cj_4-alkyl, R5 er Cj_4-alkyl eller phenyl, m er 0 eller 1, og n er 0 eller 1, kendetegnet ved, at man opvarmer en forbindelse med den almene 25 formel (II) R5 iHCHJa [CH0]_ (ΤΠ fVy h2n/r2 12 5 hvori R, R , R , R , m og n har de ovenfor anførte betydninger, med en 35 forbindelse med den almene formel (III) 22 DK 164668 B A r3 R V J Y (III) h3ctN 3 4 5 hvori R og R har de ovenfor anførte betydninger, i fravær eller nærværelse af et inert organisk opløsningsmiddel, til dannelse af en forbindelse med formel (I), hvorefter man om ønsket omdanner en forbindelse med formel (I) til et syreadditionssalt deraf. oR 1 is C 14 alkyl or C 1-4 alkoxy-C 1-4 alkyl, R 5 is C 1-4 alkyl or phenyl, m is 0 or 1, and n is 0 or 1, characterized by heating a compound of the general formula (II) R5 inHCHJa [CH0] _ (ΤΠ fVy h2n / r2125 wherein R, R, R, R, m and n have the above meanings, with a compound of the general formula (III) 22 DK 164668 BA r3 RVJY (III) h3ctN 3 4 5 wherein R and R have the above meanings, in the absence or presence of an inert organic solvent, to form a compound of formula (I) and then, if desired, convert a compound of formula ( I) to an acid addition salt thereof o 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at R er 3Method according to claim 1, characterized in that R is 3 10 C^-alkyl, R er 3-nitrophenyl, m er 0 og n er 1.C is -alkyl, R is 3-nitrophenyl, m is 0 and n is 1. 3. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man ud fra de tilsvarende udgangsmaterialer fremstiller ethyl-5-(4,5-di-hydro - 4,4-d i methyl - 2 - oxazol yl) - 6-ethy 1 -1,4-d i hydro - 2-methy 1 - 4 - (3-n i tro-phenyl)-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazo- 15 lyl) -6-ethyl -4- (2-f uranyl) -1,4-dihydro-2-methyl -3-pyridi ncarboxyl at, ethyl -5- (4,5-di hydro-4,4-dimethyl -2-oxazolyl) -6-ethyl -1,4-di hydro-2-methyl-4-phenyl-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl- 2-oxazolyl)-6-ethyl-4-(2-fluorphenyl)-l,4-dihydro-2-methyl-3-pyridin-carboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-l,4-dihydro-2- 20 methyl-6-(methyl ethyl)-4-(3-nitrophenyl)-3-pyridincarboxyl at, ethyl-5-(4,5-di hydro-4,4-dimethyl-2-oxazolyl)-6-(1,1-dimethyl ethyl)-l,4-dihydro- 2-methyl)-4-(3-nitrophenyl)-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4, 4-dimethyl -2-oxazolyl )-l, 4-di hydro-2-methyl -4- (3-nitrophenyl )-6-phe-nyl-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)- 25 l,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-(2-thienyl)-3-pyridin- carboxylat, ethyl-4-(2-chlor-5-nitrophenyl)-5-(4,5-di hydro-4,4-dimethyl- 2- oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-3-pyridincarboxylat, ethyl-4-(3-chlorphenyl)-5-(4,5-di hydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl- 30 2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-[3-tri f 1 uormethyl)phenyl]-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-thienyl)-3-pyridincarboxylat, ethyl-5-(4,5-di hydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-hydroxy- 3- methoxyphenyl)-2-methyl-3-pyridi ncarboxylat, ethyl-5-(4,5-di hydro-4,4- 35 dimethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-methylphenyl)-3- pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(1-naphthyl)-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-1,4-di hydro-2-methyl-4-(3- 23 DK 164668 B pyridinyl}-3-pyridincarboxylat, ethyl-4-(2-chlorphenyl)-5-(4,5-hydro- 4.4- dimethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridincarb-oxylat, ethyl-4-(3-cyanophenyl)-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)- 6-ethyl-l,4-dihydro-2-methyl-3-pyridincarboxylat, ethyl-5-(4,5-dihydro- 5 4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-4-(2-methoxyphenyl)-2-methyl-3-pyridincarboxylat, ethyl-4-(bicyklo-[2,2,l]hept-5-en-2-yl)-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-3-pyridincarboxylat, ethyl-4-cyklohexyl-5-(4,5-dihydro-4,4-dimethyl-2-oxa-zolyl)-6-ethyl-l,4-dihydro-2-methyl-3-pyridincarboxylat, ethyl-4-[4-10 (acetylamino)phenyl]-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl- 1.4- dihydro-2-methyl-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-4-(3-hydroxy-4-nitrophenyl)-2-methyl-3-pyridincarboxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl )-6-ethyl-1,4-dihydro-4-(lH-indol-3-yl)-2-methyl-3-pyridincarb- 15 oxylat, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-1,4-di-hydro-4-(4-hydroxy-3-nitrophenyl)-2-methyl-3-pyridincarboxylat, methyl- 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-4-(3-nitro-phenyl)-3-pyridincarboxylat,monohydrochlorid, ethyl-5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridincarb-20 oxylat, ethyl-5-[4,5-dihydro-4-(methoxymethyl)-4-methyl-2-oxazolyl]-6-ethyl-l,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridincarboxylat, monohydrochlorid, ethyl-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-1,4-di hydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridincarboxylat»monohy-drochlorid, ethyl-5-(5,6-dihydro-4,4,6-trimethyl-4H-l,3-oxazin-2-yl)-6-25 ethyl-l,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridincarboxylat, 1-me-thylethyl-5-(4,5-di hydro-2-oxazolyl)-6-ethyl-1,4-di hydro-2-methyl-4-(3-nitrophenyl)-3-pyridincarboxylat, 2-methoxyethyl-5-(4,5-dihydro-2-oxazo-lyl)-6-ethyl-l,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridincarboxylat, monohydrochlorid. 30Process according to claim 1, characterized in that ethyl-5- (4,5-di-hydro-4,4-di-methyl-2-oxazolyl) -6-ethyl-1 is prepared from the corresponding starting materials. , 4-di hydro-2-methyl 1-4 - (3-nitro-phenyl) -3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl -4- (2-furanyl) -1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl -5- (4,5-dihydro-4,4-dimethyl-2-carboxylic acid) oxazolyl) -6-ethyl -1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6- ethyl 4- (2-fluorophenyl) -1,4-dihydro-2-methyl-3-pyridine carboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1, 4-dihydro-2- methyl-6- (methyl ethyl) -4- (3-nitrophenyl) -3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) ) -6- (1,1-dimethyl ethyl) -1,4-dihydro-2-methyl) -4- (3-nitrophenyl) -3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4) -dimethyl-2-oxazolyl) -1,4-dihydro-2-methyl-4- (3-nitrophenyl) -6-phenyl-3-pyridinecarboxylate, ethyl 5- (4,5 dihydro-4,4-dimethyl-2-oxazolyl) 1,4-dihydro-2-methyl-4- (3-nitrophenyl) -6- (2-thienyl) -3-pyridine carboxylate, ethyl-4 - (2-chloro-5-nitrophenyl) -5- (4,5-di hydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 4- (3-chlorophenyl) -5- (4,5-di hydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl -5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- [3-trifluoromethyl) phenyl] -3 pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- (2-thienyl) -3-pyridinecarboxylate , ethyl 5- (4,5-di hydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-4- (4-hydroxy-3-methoxyphenyl) -2-methyl 3-Pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- (3-methylphenyl) -3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- (1-naphthyl) -3 pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2- oxazolyl) -6-ethyl-1,4-di hydro-2-methyl-4- (3- pyridinyl} -3-pyridinecarboxylate, ethyl 4- (2-chlorophenyl) -5- (4.5 -hydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 4- (3-cyanophenyl) -5- (4,5-dihydro) -4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2- oxazolyl) -6-ethyl-1,4-dihydro-4- (2-methoxyphenyl) -2-methyl-3-pyridinecarboxylate, ethyl 4- (bicyclo- [2,2,1] hept-5-ene-2 -yl) -5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 4-cyclohexyl-5 (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 4- [4-10 (acetylamino) phenyl ] -5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4 4-Dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-4- (3-hydroxy-4-nitrophenyl) -2-methyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro -4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-d ihydro-4- (1H-indol-3-yl) -2-methyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl -1,4-di-hydro-4- (4-hydroxy-3-nitrophenyl) -2-methyl-3-pyridinecarboxylate, methyl 5- (4,5-dihydro-2-oxazolyl) -6-ethyl-1 4-dihydro-2-methyl-4- (3-nitro-phenyl) -3-pyridinecarboxylate, monohydrochloride, ethyl 5- (4,5-dihydro-2-oxazolyl) -6-ethyl-1,4-dihydro 2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate, ethyl 5- [4,5-dihydro-4- (methoxymethyl) -4-methyl-2-oxazolyl] -6-ethyl 1,4-dihydro-2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate, monohydrochloride, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1,4- di hydro-2,6-dimethyl-4- (3-nitrophenyl) -3-pyridinecarboxylate monohydrochloride, ethyl 5- (5,6-dihydro-4,4,6-trimethyl-4H-1,3- oxazin-2-yl) -6-ethyl-1,4-dihydro-2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate, 1-methylethyl-5- (4,5-dihydro- 2-oxazolyl) -6-ethyl-1,4-di hydro-2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate, 2-methoxyethyl-5- (4,5-dihydro-2-oxazolyl) ) -6-ethyl-l, 4-dihydro-2-methyl -4- (3-nitrophenyl) -3-pyridinecarboxylate, monohydrochloride. 30
DK181183A 1983-04-25 1983-04-25 METHOD OF ANALOGY FOR THE PREPARATION OF 1,4-DIHYDROPYRID-5-YL (CYCLIC IMIDATE) ESTERS DK164668C (en)

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DK181183A DK164668C (en) 1983-04-25 1983-04-25 METHOD OF ANALOGY FOR THE PREPARATION OF 1,4-DIHYDROPYRID-5-YL (CYCLIC IMIDATE) ESTERS

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DK181183D0 (en) 1983-04-25
DK164668C (en) 1992-12-21
DK181183A (en) 1984-10-26

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