NO134743B

NO134743B -

Info

Publication number: NO134743B
Application number: NO3374/71A
Authority: NO
Inventors: R K Razdan; W R Thompson
Original assignee: Beecham Group Ltd
Priority date: 1970-09-14
Filing date: 1971-09-10
Publication date: 1976-08-30
Also published as: FR2106490A1; SE372943B; ZA716039B; ES394980A1; NL7112521A; DK135994C; AT308108B; IE35636L; CA965421A; DK135994B; AU3336571A; DE2145320A1; FR2106490B1; GB1360009A; IE35636B1; CH559209A5; BE772492A; NO134743C

Description

Forbindelser som fremstilles ved fremgangsmåten i henhold til oppfinnelsen, er i besittelse av nyttig kardiovaskulær og sentralnervesystem-aktivitet, som f.eks. anti-hypertensiv aktivitet, dvs. aktivitet mot forhøyet blodtrykk. Compounds produced by the method according to the invention possess useful cardiovascular and central nervous system activity, such as e.g. anti-hypertensive activity, i.e. activity against elevated blood pressure.

I britisk patentskrift 1.162.784 er det beskrevet visse pyridylbenzopyraner omfattende slike av den generelle formel (Ia). De tilsvarende estere og etere av den generelle formel (Ib) er beskrevet i britisk patentskrift 1.314.428, og tilsvarende estere og basiske etere av den generelle formel (le) er beskrevet i britisk patentskrift 1.314.427. In British patent specification 1,162,784, certain pyridylbenzopyrans are described, including those of the general formula (Ia). The corresponding esters and ethers of the general formula (Ib) are described in British patent document 1,314,428, and the corresponding esters and basic ethers of the general formula (le) are described in British patent document 1,314,427.

(Ia) X' = OH eller et salt herav (Ia) X' = OH or a salt thereof

(Ib) X' = forestret eller foretret hydroksyl (Ib) X' = esterified or etherified hydroxyl

(Ic) X' = hydroksyl forestret eller foretret med en basisk eter- eller estergruppe. (Ic) X' = hydroxyl esterified or etherified with a basic ether or ester group.

R* er en lavere alkylgruppe og R 2 er en hydrokarbon-gruppe som inneholder fra 1 til 20 karbona tomer. ■ : ... R* is a lower alkyl group and R 2 is a hydrocarbon group containing from 1 to 20 carbon atoms. ■ : ...

Visse forbindelser av den generelle formel (i) har vist seg å være i besittelse av sentralnervesystem-(SNS-)aktivitet. Det har vist seg at beslektede forbindelser i hvilke 4-pyridyl-gruppen er blitt redusert til tetrahydropyridyl er i besittelse av anti-hypertensiv aktivitet. Certain compounds of general formula (i) have been shown to possess central nervous system (CNS) activity. Related compounds in which the 4-pyridyl group has been reduced to tetrahydropyridyl have been shown to possess anti-hypertensive activity.

Ved hjelp av fremgangsmåten i henhold til oppfinnelsen tilveiebringes nye benzopyraner av den generelle formel By means of the method according to the invention, new benzopyrans of the general formula are provided

(II) (II)

hvor R er en uforgrenet eller forgrenet alkylgruppe med 4-9 karbonatomer, R^ er en lavere alkyl-, lavere alkenyl- eller aryl-lavere-alkylgruppe med 1-20 karbonatomer, og X er en hydroksylgruppe, en saltdannet hydroksylgruppe eller en gruppe OR,. where R is a straight or branched alkyl group of 4-9 carbon atoms, R^ is a lower alkyl, lower alkenyl or aryl-lower alkyl group of 1-20 carbon atoms, and X is a hydroxyl group, a salt-formed hydroxyl group or a group OR ,.

hvor R_ er alkyl med 1-6 karbonatomer, eller OCOR^ hvor R,, er where R_ is alkyl with 1-6 carbon atoms, or OCOR^ where R,, is

5 6 6 5 6 6

alkyl med 1-6 karbonatomer som eventuelt er substituert med en amino- eller mono- eller dialkylaminogruppe med 2-6 karbonatomer. alkyl with 1-6 carbon atoms which is optionally substituted with an amino or mono- or dialkylamino group with 2-6 carbon atoms.

Hensiktsmessige grupper R2 omfatter butyl-, heksyl-, butenyl-, butynyl- og lignende grupper, samt slike grupper som n-heptyl-, 2-oktyl-, 3-metyl-2-oktyl- og lignende grupper. Fortrinnsvis er R2 n-amyl. Suitable groups R2 include butyl, hexyl, butenyl, butynyl and similar groups, as well as such groups as n-heptyl, 2-octyl, 3-methyl-2-octyl and similar groups. Preferably, R 2 is n-amyl.

Hensiktsmessige grupper R^ omfatter aryl-, alifatiske og cykloalifatiske hydrokarbongrupper og kombinasjoner av disse som kan være mettede eller umettede og rettkjedede eller forgrenede grupper når dette er ønskelig. Innenfor definisjonen av R^ om-fattes således alifatiske grupper med 1-20 karbonatomer og særlig lavere alifatiske grupper med 1-6 karbonatomer, aryl-lavere alifatiske og cykloalifatisk-lavere alifatiske, hvor den cykloalifatiske del har 3-8 karbonatomer. Således kan f.eks. R^ være allyl, benzyl, fenyletyl, propargyl, cyklopropylmetyl foruten slike grupper som er anført som hensiktsmessige grupper for R2-Foretrukkede -grupper omfatter allyl-, benzyl- og fenyletyl-grupper. Suitable groups R 1 include aryl, aliphatic and cycloaliphatic hydrocarbon groups and combinations thereof which may be saturated or unsaturated and straight-chain or branched groups when this is desired. Thus, within the definition of R^ are included aliphatic groups with 1-20 carbon atoms and in particular lower aliphatic groups with 1-6 carbon atoms, aryl-lower aliphatic and cycloaliphatic-lower aliphatic, where the cycloaliphatic part has 3-8 carbon atoms. Thus, e.g. R 2 be allyl, benzyl, phenylethyl, propargyl, cyclopropylmethyl, besides such groups which are listed as appropriate groups for R 2 - Preferred groups include allyl, benzyl and phenylethyl groups.

Hensiktsmessige grupper x omfatter hydroksylgruppen eller et sålt, en ester eller eterderivat derav. Passende salter omfatter slike av alkali- og jordalkalimetaller, idet natrium- Suitable groups x include the hydroxyl group or a salt, an ester or ether derivative thereof. Suitable salts include those of the alkali and alkaline earth metals, sodium

og kaliumsalter er å foretrekke. Passende ester-og eterderivater kan fremstilles for å endre de fysikalske eller farmasøytiske egenskaper ved forbindelsen, f.eks. for å endre oppløselighets-egenskapene på en ønsket måte. Passende forestrede derivater omfatter slike som dannes av en enkel enverdig syre, f.eks. slike som dannes av eddiksyre eller benzoesyre, slike som dannes av flerverdige syrer, f.eks. en monoester av ravsyre eller fosfor-syre, eller slike som dannes av amino-substituerte syrer, f.eks. en ester av fenylglycin eller 2-dietylaminopropionsyre og lignende. Passende forestrede derivater kan omfatte usubstituerte etere, f.eks. metyl- eller etyleteren, eller substituerte etere, f.eks. basiske etere som 2-dietylaminoetyleteren. and potassium salts are preferred. Appropriate ester and ether derivatives can be prepared to change the physical or pharmaceutical properties of the compound, e.g. to change the solubility properties in a desired way. Suitable esterified derivatives include those formed from a simple monovalent acid, e.g. those formed from acetic acid or benzoic acid, those formed from polyvalent acids, e.g. a monoester of succinic or phosphoric acid, or those formed from amino-substituted acids, e.g. an ester of phenylglycine or 2-diethylaminopropionic acid and the like. Suitable esterified derivatives may include unsubstituted ethers, e.g. the methyl or ethyl ether, or substituted ethers, e.g. basic ethers such as 2-diethylaminoethyl ether.

Når den forestrede eller foretrede gruppe oppviser sure eller basiske substituenter, så kan det dannes salter av disse substituenter. Således kan det dannes syre-addisjonssalter av aminosubstituerte grupper, f.eks. hydrokloridet av en dietyl-aminoeter eller en dietylaminoester. When the esterified or etherified group exhibits acidic or basic substituents, salts can be formed from these substituents. Thus, acid addition salts of amino-substituted groups can be formed, e.g. the hydrochloride of a diethyl amino ether or a diethyl amino ester.

Foretrukkede grupper X omfatter hydroksylgruppen og dens alkalimetallsalter. Preferred groups X include the hydroxyl group and its alkali metal salts.

Fremgangsmåten i henhold til oppfinnelsen for fremstilling av forbindelsene av den generelle formel (II) går ut på en reduksjon av en forbindelse av den generelle formel lii The process according to the invention for the preparation of the compounds of the general formula (II) involves a reduction of a compound of the general formula lii

hvor B 0 er et anion, og R^ i R3 og X er som tidligere definert, where B 0 is an anion, and R^ in R 3 and X are as previously defined,

med unntagelse av at X ikke kan være en OCOR^-gruppe hvorved reduksjonen foretas med et borhydrid; og at eventuelt deretter den således dannede forbindelse av formel (III) omsettes med et acyleringsderivat av en syre R-COOH slik at man får den tilsvarende forbindelse av formel (III) hvor X er en OCOR^o-gruppe. with the exception that X cannot be an OCOR^ group whereby the reduction is carried out with a borohydride; and that optionally then the thus formed compound of formula (III) is reacted with an acylation derivative of an acid R-COOH so that the corresponding compound of formula (III) is obtained where X is an OCOR^o group.

Reduksjonen med borhydrid utføres i et oppløsnings-middel som f.eks. en vandig alkohol ved romtemperatur. The reduction with borohydride is carried out in a solvent such as e.g. an aqueous alcohol at room temperature.

Et foretrukket borhydrid er natriumborhydrid. A preferred borohydride is sodium borohydride.

Foretrukkede oppløsningsmidler omfatter vandig etanol og vandig metanol, særlig en 3:l-blanding av etanol og vann. Preferred solvents include aqueous ethanol and aqueous methanol, particularly a 3:1 mixture of ethanol and water.

Generelt kan det anvendes lavere temperaturer, rom-temperaturer eller høye temperaturer for reaksjonen, men det har vist seg at reaksjonen er fullført i løpet av passende kort tid, f.eks. 1 time eller mindre hvis det anvendes romtemperatur. In general, lower temperatures, room temperatures or high temperatures can be used for the reaction, but it has been found that the reaction is completed within a suitably short time, e.g. 1 hour or less if room temperature is used.

Om ønskes kan arten av gruppen x varieres etter reduksjonsreaksjonen ved én eller flere eventuelt ønskede reak-sjoner. Således kan f.eks. en forbindelse hvor X er en eter-gruppe dannes av den tilsvarende hydroksyforbindelse ved en eller annen standardarbeidsmåte for foretring etter dannelse av hydroksy-forbindelsen ved reduksjon av et pyridinderivat (III). Alterna-tivt kan naturligvis en forbindelse i hvilken X er en foretret hydroksylgruppe fremstilles direkte ved fremgangsmåten ifølge oppfinnelsen, hvis X er den foretrede hydroksylgruppe i pyridin-derivatet (III) . If desired, the nature of the group x can be varied after the reduction reaction by one or more possibly desired reactions. Thus, e.g. a compound where X is an ether group is formed from the corresponding hydroxy compound by some standard procedure for etherification after formation of the hydroxy compound by reduction of a pyridine derivative (III). Alternatively, of course, a compound in which X is an etherified hydroxyl group can be prepared directly by the method according to the invention, if X is the etherified hydroxyl group in the pyridine derivative (III).

På lignende måte kan gruppen R3 modifiseres eller erstattes ved vanlige arbeidsmåter etter reduksjonsprosessen. F.eks. kan en benzylgruppe fjernes ved hydrogenering og erstattes med en alternativ gruppe R^• In a similar way, the group R3 can be modified or replaced by common methods after the reduction process. E.g. a benzyl group can be removed by hydrogenation and replaced with an alternative group R^•

Det kvaternære salt av den generelle formel (III) kan fremstilles fra den tilsvarende pyridylforbindelse (I) ved en hvilken som helst passende fremgangsmåte. En særlig hensikts-messig fremgangsmåte er reaksjonen av pyridylforbindelsen (i) The quaternary salt of the general formula (III) can be prepared from the corresponding pyridyl compound (I) by any suitable method. A particularly suitable method is the reaction of the pyridyl compound (i)

med en forbindelse R^B, hvor B er et klor-, brom- eller jodatom, with a compound R^B, where B is a chlorine, bromine or iodine atom,

•eller en gruppe som SC^CH^ og lignende, som lett erstattes ved •or a group such as SC^CH^ and the like, which is easily replaced by

en nukleofil ombytningsreaksjon. En slik reaksjon kan finne sted i et vanlig oppløsningsmiddel som aceton, eter, dimetylformamid eller lignende ved lav temperatur, romtemperatur eller forhøyede temperaturer. Generelt er det fordelaktig å arbeide ved forhøyede temperaturer, f.eks. ved tilbakeløpstemperatur, for å lette reak-sjons forløpet. a nucleophilic exchange reaction. Such a reaction can take place in a common solvent such as acetone, ether, dimethylformamide or the like at low temperature, room temperature or elevated temperatures. In general, it is advantageous to work at elevated temperatures, e.g. at reflux temperature, to facilitate the course of the reaction.

Når laboratoriedyr undersøkes med forbindelser fremstilt innenfor rammen av denne oppfinnelsen, har det vist seg at disse er i besittelse av kardiovaskulær aktivitet, og særlig har det vist seg at de senker blodtrykket hos hypertensive dyr. Ved hjelp av fremgangsmåten ifølge oppfinnelsen kan det således tilveiebringes farmasøytiske preparater som inneholder en forbindelse av den generelle formel (II) sammen med ett eller flere farmasøy-tisk aksepterbare bærestoffer, fortynningsstoffer eller andre hjelpemidler. Slike preparater kan ha en form som er egnet for oral bruk (f.eks. piller, tabletter eller kapsler) for parenteral bruk (f.eks. i oppløsning i sterilt vann for injeksjon) eller ved hjelp av suppositorier. When laboratory animals are tested with compounds prepared within the scope of this invention, these have been shown to possess cardiovascular activity, and in particular have been shown to lower blood pressure in hypertensive animals. By means of the method according to the invention, it is thus possible to provide pharmaceutical preparations containing a compound of the general formula (II) together with one or more pharmaceutically acceptable carriers, diluents or other auxiliaries. Such preparations may be in a form suitable for oral use (eg pills, tablets or capsules) for parenteral use (eg in solution in sterile water for injection) or by means of suppositories.

De farmasøytiske preparater som inneholder forbindelsen (II) kan om ønskes også inneholde andre anti-hypertensive midler eller diuretika. På lignende måte kan to forbindelser av formel (II) brukes sammen hvis det er ønskelig. En slik sammensetning kan være nødvendig for å oppnå en eller annen ønsket aktivitets-profil eller lignende. The pharmaceutical preparations containing the compound (II) may, if desired, also contain other anti-hypertensive agents or diuretics. Similarly, two compounds of formula (II) may be used together if desired. Such a composition may be necessary to achieve some desired activity profile or the like.

De følgende eksempler skal tjene til å klargjøre oppfinnelsen. The following examples shall serve to clarify the invention.

Eksempel 1 Example 1

7- n- amyl- 4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)-2, 2- dimetyl- 2H- kromen- 5- ol. 7-n-amyl-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-2H-chromen-5-ol.

7-n-amyl-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol 7-n-amyl-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol

(6,46 g, 0,02 mol) og benzylbromid (5,13 g, 0,03 mol) ble behandlet under tilbakeløp i aceton (20 ml) i fire timer. Blandingen ble avkjølt,og det rå salt ble oppsamlet ved filtrering, vasket med aceton og tørket. Omkrystallisering fra vandig .etanol ga 4-(7-h-amyl-5- hydroksy-2,2-dimetyl-2H-kromen-4-yl-l-benzylpyridiniumbromid (6.46 g, 0.02 mol) and benzyl bromide (5.13 g, 0.03 mol) were refluxed in acetone (20 mL) for four hours. The mixture was cooled and the crude salt was collected by filtration, washed with acetone and dried. Recrystallization from aqueous ethanol gave 4-(7-h-amyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl-1-benzylpyridinium bromide

(9 ,40 gV. 95%) med smp. 251-252°C.. ' (9 .40 gV. 95%) with m.p. 251-252°C.. '

Dette benzylpyridinbromid (9,40 g) ble oppløst i en blanding av metanol (60 ml) og vann (20 ml) og natriumborhydrid (1,45 g ble tilsatt i små deler i løpet av en halv time til den omrørte oppløsning ved romtemperatur. Når tilsetningen var fullstendig, ble blandingen omrørt ved romtemperatur i 1 time, fortyn-net med vann og ekstrahert med eter. Eterekstrakten ble vasket med vann, tørket (MgSO^) og inndampet under redusert, trykk for å gi et oljeaktig residuum som krystalliserte fra lettbensin (kp. 60-80°C) for å gi 7-n-amyl-4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-2H-kromen-5-ol (6,35 g, 80%) med smp. 103-104°C. This benzylpyridine bromide (9.40 g) was dissolved in a mixture of methanol (60 ml) and water (20 ml) and sodium borohydride (1.45 g) was added in small portions over half an hour to the stirred solution at room temperature. When the addition was complete, the mixture was stirred at room temperature for 1 hour, diluted with water and extracted with ether. The ether extract was washed with water, dried (MgSO 4 ) and evaporated under reduced pressure to give an oily residue which crystallized from light gasoline (b.p. 60-80°C) to give 7-n-amyl-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-2H-chromene -5-ol (6.35 g, 80%) with mp 103-104°C.

Eksempel 2 Example 2

7- n- amyl- 2, 2- dimetyl- 4- l-( 2- fenyletyl)- 1, 2, 5, 6- tetrahydropyrid- 4- yl- 2H- kromen- 5- ol. 7-n-amyl-2,2-dimethyl-4-1-(2-phenylethyl)-1,2,5,6-tetrahydropyrid-4-yl-2H-chromen-5-ol.

(6,46 g, 0,02 mol) og 2-fenyletylbromid (5,55 g, 0,03 mol) ble behandlet under tilbakeløp sammen i aceton (20 ml) i seks timer. Ved opparbeidelse som angitt i eksempel 1 fikk man 4-(7-n-amyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl)-1-(2-fenyletyl)-pyridinbro-mid (9,17 g, smp. 257-258°C (fra vandig etanol). (6.46 g, 0.02 mol) and 2-phenylethyl bromide (5.55 g, 0.03 mol) were refluxed together in acetone (20 mL) for six hours. By working up as indicated in example 1, 4-(7-n-amyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl)-1-(2-phenylethyl)-pyridine bromide (9 .17 g, mp 257-258°C (from aqueous ethanol).

Dette fenyletylpyridinbromid (9,17 g) ble redusert under anvendelse av natriumborhydrid (1,40 g) ved fremgangsmåten som er beskrevet i eksempel 1 for å gi 7-n-amyl-4-1-(2-fenyletyl)-1,2,5,6-tetrahydropyrid-4-yl -2H-kromen-5-ol (5,73 g, 72%), smp. 132-133°C (fra lettbensin).. This phenylethylpyridine bromide (9.17 g) was reduced using sodium borohydride (1.40 g) by the procedure described in Example 1 to give 7-n-amyl-4-1-(2-phenylethyl)-1,2 ,5,6-tetrahydropyrid-4-yl-2H-chromen-5-ol (5.73 g, 72%), m.p. 132-133°C (from light petrol)..

Eksempel 3 Example 3

7-n-amyl-4-( 1- etyl- l, 2, 5, 6- tetrahydropyrid- 4- yl) - 2, 2-dimetyl- 2H- kromen- 5- ol 7-n-amyl-4-(1-ethyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-2H-chromen-5-ol

7-n-amyl-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (5,oo g) 0,015 mol) og etylbromid (6,8o g, 0,062 mol) ble behandlet under tilbakeløp sammen i aceton (70 ml) i seks timer. Opparbeidelse som eksempel 1 gav 4-(7-n-amyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl)-1-etylpyridinbromid-hemihydrat (5,68 g, 84%) smp. 168-170°C (fra aceton). 7-n-amyl-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (5.00 g, 0.015 mol) and ethyl bromide (6.80 g, 0.062 mol) were treated under reflux together in acetone (70 mL) for six hours. Workup as in Example 1 gave 4-(7-n-amyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl)-1-ethylpyridine bromide hemihydrate (5.68 g, 84%) m.p. 168-170°C (from acetone).

Dette etylpyridinbromid (5,36 g) ble redusert under anvendelse av natriumborhydrid (0,80 g) ved fremgangsmåten som er beskrevet i eksempel 1, for å gi 7-n-amyl-4-(1-etyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-2H-kromen-5-ol (3,10 g, 72%), smp. This ethyl pyridine bromide (5.36 g) was reduced using sodium borohydride (0.80 g) by the procedure described in Example 1 to give 7-n-amyl-4-(1-ethyl-1,2,5 ,6-tetrahydropyrid-4-yl)-2,2-dimethyl-2H-chromen-5-ol (3.10 g, 72%), m.p.

150-151°C (fra vandig etanol). 150-151°C (from aqueous ethanol).

Eksempel 4 Example 4

7- n- amyl- 2, 2- dimetyl- 4-( 1- metyl- 1, 2, 5, 6- tetrahydropyrid- 4- yl)- 2H- kromen- 5- ol 7- n- amyl- 2, 2- dimethyl- 4-( 1- methyl- 1, 2, 5, 6- tetrahydropyrid- 4- yl)- 2H- chromen- 5-ol

7-n-amyl-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (5,00 g, 0,015 mol) og metyljodid (4,40 g, 0,031 mol) ble behandlet sammen i aceton (70 ml) i to timer. Opparbeidelse som i eksempel 1 gav 4-(7-n-amyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl)-1-metylpyridinjodid-hemihydrat (4,52 g, 64%), smp. 184-186°C (fra aceton). 7-n-Amyl-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (5.00 g, 0.015 mol) and methyl iodide (4.40 g, 0.031 mol) were treated together in acetone (70 ml) for two hours. Workup as in Example 1 gave 4-(7-n-amyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl)-1-methylpyridine iodide hemihydrate (4.52 g, 64%), m.p. . 184-186°C (from acetone).

Dette metylpyridinjodid (4,30 g) ble redusert under anvendelse av natriumborhydrid (0,50 g) ved fremgangsmåten som er beskrevet i eksempel 1 for å gi 7-n-amyl-2,2-dimetyl-4-(1-metyl-1,2,5,6-tetrahydropyrid-4-yl)-2H-kromen-5-ol (1,21 g, 40%), smp. 160-161°C (fra vandig etanol). This methylpyridine iodide (4.30 g) was reduced using sodium borohydride (0.50 g) by the procedure described in Example 1 to give 7-n-amyl-2,2-dimethyl-4-(1-methyl- 1,2,5,6-tetrahydropyrid-4-yl)-2H-chromen-5-ol (1.21 g, 40%), m.p. 160-161°C (from aqueous ethanol).

Eksempel 5 Example 5

4-( l- allyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)-7-n-amyl-2H-kromen- 5- ol 4-(1-allyl-1,2,5,6-tetrahydropyrid-4-yl)-7-n-amyl-2H-chromen-5-ol

7-n-amyl-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (5,00 g, 0,015 mol) og allylbromid (3,76 g, 0,031 mol) ble behandlet under tilbakeløp i aceton (70 ml) i to timer. Opparbeidelse som beskrevet i eksempel 1, gav 1-allyl-4-(7-n-amyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl) -pyridinbromid (6,00 g, 88%), smp. 188-1'96°C (fra acetonetylacetat). 7-n-Amyl-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (5.00 g, 0.015 mol) and allyl bromide (3.76 g, 0.031 mol) were treated under reflux in acetone (70 mL) for two hours. Workup as described in Example 1 gave 1-allyl-4-(7-n-amyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl)-pyridine bromide (6.00 g, 88%) , m.p. 188-1'96°C (from acetone ethyl acetate).

Dette allylpyridinbromid (5,96 g) ble redusert under anvendelse av natriumborhydrid (1,57 g) ved fremgangsmåten som er beskrevet i eksempel 1, for å gi 4-(1-allyl-l,2,5,6-tetrahydropyrid-4-yl)-7-n-amyl-2,2-dimetyl-2H-kromen-5-ol (3,41 g, 69%), smp. 96-97°C (etter mykning ved 55-56°C) (fra metylcyanid). This allylpyridine bromide (5.96 g) was reduced using sodium borohydride (1.57 g) by the procedure described in Example 1 to give 4-(1-allyl-1,2,5,6-tetrahydropyrid-4 -yl)-7-n-amyl-2,2-dimethyl-2H-chromen-5-ol (3.41 g, 69%), m.p. 96-97°C (after softening at 55-56°C) (from methyl cyanide).

Eksempel 6 Example 6

7- n- amyl- 2, 2- dimetyl- 4-( 1- n- propyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 2H- kromen- 5- ol 7- n- amyl- 2, 2- dimethyl- 4-( 1- n- propyl- 1, 2, 5, 6- tetrahydropyrid- 4- yl)- 2H- chromen- 5-ol

(3,23 g, 0,01 mol) og n-propylbromid (4,92 g, 0,04 mol) ble behandlet under tilbakeløp i aceton (50 ml) i ti timer. Oppløsningen ble derpå konsentrert til 25 ml og eter ble tilsatt for å bevirke at det skilles ut en krystallinsk utfelning. Det faste stoff ble filtrert fra, vasket med eter og tørket. Omkrystallisering fra aceton-eter gav 4-(7-n-amyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl)-l-n-propyl -pyridinb"romid v(3,36 g, 76%), smp. 209-2i'2°c . ,; (3.23 g, 0.01 mol) and n-propyl bromide (4.92 g, 0.04 mol) were treated under reflux in acetone (50 mL) for ten hours. The solution was then concentrated to 25 ml and ether was added to cause a crystalline precipitate to separate. The solid was filtered off, washed with ether and dried. Recrystallization from acetone-ether gave 4-(7-n-amyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl)-1-n-propyl-pyridine bromide (3.36 g, 76% ), mp 209-21'2°c.,;

Dette propylpyridinbromid (,324 g) ble' redusert'under anvendelse av natriumborhydrid (,0,80 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 7-n-amyl-2,2-dimetyl-4-(1-n-propyl-l,2,5,6-tetrahydropyrid-4-yl)-2H-kromen-5-ol (1,71 g, 64%) av smp. 118-119°c (fra vandig etanol). This propylpyridine bromide (.324 g) was reduced using sodium borohydride (.0.80 g) by the procedure described in Example 1 to give 7-n-amyl-2,2-dimethyl-4-(1-n- propyl-1,2,5,6-tetrahydropyrid-4-yl)-2H-chromen-5-ol (1.71 g, 64%) of m.p. 118-119°c (from aqueous ethanol).

Eksempel 7 Example 7

7- n- amyl- 2, 2- dimetyl- 4-( 1- difenylmetyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 2H- kromen- 5- ol. 7-n-amyl-2,2-dimethyl-4-(1-diphenylmethyl-1,2,5,6-tetrahydropyrid-4-yl)-2H-chromen-5-ol.

(3,23 g, 0,01 mol) og difenylmetylklorid (2,10 g, 0,01 mol) ble behandlet sammen under tilbakeløp i aceton (50 ml), som inneholdt en krystall av kaliumjodid, i to døgn. Opparbeidelse som i eksempel 6 gav - 4-(7-n-amyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl)-1-difenylmetylpyridinklorid (0,41 g, 8%) av smp. 212-215°C (fra aceton-eter). (3.23 g, 0.01 mol) and diphenylmethyl chloride (2.10 g, 0.01 mol) were treated together under reflux in acetone (50 mL), containing a crystal of potassium iodide, for two days. Workup as in example 6 gave - 4-(7-n-amyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl)-1-diphenylmethylpyridine chloride (0.41 g, 8%) of m.p. 212-215°C (from acetone-ether).

Dette difenylmetylpyridinklorid (0,30 g) ble redusert under anvendelse av natriumborhydrid (0,10 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 7-n-amyl-2,2-dimetyl-4-(1-difenylmetyl-l ,2,5,6-tetrahydropyrid-4-yl)-2H-kromen-5-ol (0,13 g, 47%) This diphenylmethylpyridine chloride (0.30 g) was reduced using sodium borohydride (0.10 g) by the procedure described in Example 1 to give 7-n-amyl-2,2-dimethyl-4-(1-diphenylmethyl-1, 2,5,6-tetrahydropyrid-4-yl)-2H-chromen-5-ol (0.13 g, 47%)

av smp. 69-71°C. of m.p. 69-71°C.

Eksempel 8 Example 8

2, 2- dimetyl- 7-( 3- metyl- 2- oktyl)- 4-[ 1-( 2- fenyletyl)-1, 2, 5, 6- tetrahydropyrid- 4- yl]- 2H- kromen- 5- ol 2,2-dimetyl-7-(3-metyl-2-oktyl)-4-(4-pyri dyl)-2H-kromen-5-ol (10,00 g, 0,026 mol) og 2-fenyletylbromid (18,50 g, 0,100 mol) ble behandlet under tilbakeløp sammen i tørr eter (80 ml) i 24 timer. Blandingen ble avkjølet og råsaltet ble oppsamlet ved filtrering, vasket med eter og tørket. Omkrystallisering fra vandig etanol gav 4-[5-hydroksy-2,2-dimetyl-7-(3-metyl-2-oktyl)-2H-kromen-4-yl]-1-(2-fenyletyl)-pyridinbromidmonohydrat (11,60 g, 77%), av smp. 204-205°C. 2, 2- dimethyl- 7-( 3- methyl- 2- octyl)- 4-[ 1-( 2- phenylethyl)-1, 2, 5, 6- tetrahydropyrid- 4- yl]- 2H- chromen- 5- ol 2,2-dimethyl-7-(3-methyl-2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol (10.00 g, 0.026 mol) and 2-phenylethyl bromide (18 .50 g, 0.100 mol) were refluxed together in dry ether (80 mL) for 24 h. The mixture was cooled and the crude salt was collected by filtration, washed with ether and dried. Recrystallization from aqueous ethanol gave 4-[5-hydroxy-2,2-dimethyl-7-(3-methyl-2-octyl)-2H-chromen-4-yl]-1-(2-phenylethyl)-pyridine bromide monohydrate (11 .60 g, 77%), of m.p. 204-205°C.

Dette fenyletylpyridinbromid (11,60 g) ble redusert under anvendelse av natriumborhydrid (1,50 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 2,2-dimetyl-7-(3-metyl-2-oktyl)-4-[1-(2-fenyletyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-kromen-5-ol (4,40 g, 46%} av smp„ 100-102°C. This phenylethylpyridine bromide (11.60 g) was reduced using sodium borohydride (1.50 g) by the procedure described in Example 1 to give 2,2-dimethyl-7-(3-methyl-2-octyl)-4-[ 1-(2-Phenylethyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-chromen-5-ol (4.40 g, 46%} of mp 100-102°C.

Eksempel 9 Example 9

4-(1-allyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl- 4-(1-allyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-

7-( 3- metyl- 2- oktyl)- 2H- kromen- 5- ol 7-(3-methyl-2-octyl)-2H-chromen-5-ol

2,2-dimety1-7-(3-me tyl-2-oktyl)-4-(4-pyr i dy1)-2H-kromen 5-ol (11,40 g,0,03 mol) og allylbromid(7,20 g, 0,06 mol) ble behandlet sammen under tilbakeløp i aceton (50 ml) i 8 timer. Opparbeidelse som i eksempel 1 gav 1-allyl-4-[5-hydroksy-2,2-dimetyl-7-(3-metyl-2-oktyl)-2H-kromen-4-yl]-pyridinbromid (10,50 g,70%) av smp. 208-2lO°C (fra aceton-etanol). 2,2-dimethyl-7-(3-methyl-2-octyl)-4-(4-pyr yl dy1)-2H-chromene 5-ol (11.40 g, 0.03 mol) and allyl bromide (7 .20 g, 0.06 mol) were treated together under reflux in acetone (50 mL) for 8 h. Workup which in example 1 gave 1-allyl-4-[5-hydroxy-2,2-dimethyl-7-(3-methyl-2-octyl)-2H-chromen-4-yl]-pyridine bromide (10.50 g .70%) of m.p. 208-210°C (from acetone-ethanol).

Dette allylpyridinbromid (10,45 g) ble redusert under anvendelse av natriumborhydrid (1,60 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(1-allyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-7-3-metyl-2-oktyl)-2H-kromen-5-ol (3,20 g,37%) av smp. 85-86°C (fra metylcyanid). This allylpyridine bromide (10.45 g) was reduced using sodium borohydride (1.60 g) by the procedure described in Example 1 to give 4-(1-allyl-1,2,5,6-tetrahydropyrid-4-yl) -2,2-dimethyl-7-3-methyl-2-octyl)-2H-chromen-5-ol (3.20 g, 37%) of m.p. 85-86°C (from methyl cyanide).

Eksempel 10 Example 10

4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2- dimetyl- 7-( 3- metyl- 2- oktyl)- 2H- kromen- 5- ol 4-( 1- benzyl- 1, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2- dimethyl- 7-( 3- methyl- 2- octyl)- 2H- chromen- 5-ol

2,2-dimetyl-7-(3-metyl-2-oktyl)-4-(4-pyridyl)-2H-kromen-5-ol (7-25 g, 0,019 mol) og benzylklorid (5,00 g, 0,040 mol) ble behandlet under tilbakeløp sammen i aceton (50 ml), som inneholdt en krystall av natriumjodid, i fire timer. Opparbeidelse som i eksempel 1 gav 1-benzyl-4-[5-hydroksy-2,2-dimetyl-7-(3-metyl-2-oktyl)-2H-kromen-4-yl]pyridinkloridmonohydrat (7,98 g, 72%) av smp. 242-243°C (fra vandig etanol). 2,2-dimethyl-7-(3-methyl-2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol (7-25 g, 0.019 mol) and benzyl chloride (5.00 g, 0.040 mol) were refluxed together in acetone (50 mL), containing a crystal of sodium iodide, for four hours. Workup which in example 1 gave 1-benzyl-4-[5-hydroxy-2,2-dimethyl-7-(3-methyl-2-octyl)-2H-chromen-4-yl]pyridine chloride monohydrate (7.98 g, 72%) of m.p. 242-243°C (from aqueous ethanol).

Dette benzylpyridinklorid (7,69 g) ble redusert under anvendelse av natriumborhydrid (1,50 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-7-(3-metyl-2-oktyl)-2H-kromen-5-ol (3,10 g, 44%) som et amorft fast stoff (renset ved kolonnekromatografi på kiselsyregel under anvendelse av kloroform som elueringsmiddel. This benzylpyridine chloride (7.69 g) was reduced using sodium borohydride (1.50 g) by the procedure described in Example 1 to give 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -2,2-dimethyl-7-(3-methyl-2-octyl)-2H-chromen-5-ol (3.10 g, 44%) as an amorphous solid (purified by column chromatography on silica gel using chloroform as eluent.

Eksempel 11 Example 11

2, 2- dimetyl- 7-( 2- oktyl)- 4-[ l-( 2- fenyletyl)- 1, 2, 5, 6-tetrahydropyrid- 4- yl]- 2H- kromen- 5- ol. 2, 2-dimethyl-7-(2-octyl)-4-[1-(2-phenylethyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-chromen-5-ol.

2,2-dimetyl-7-(2-oktyl)-4-(4-pyridyl)-2H-kromen-5-ol (12,00 g, 0,03 mol) og 2-fenyletylbromid (9,30 g, 0,05 mol) ble behandlet under tilbakeløp sammen i aceton (50 ml) i 8 timer. Opparbeidelse som i eksempel 1 gav 4-[5-hydroksy-2,2-dimetyl-7-(2-oktyl)-2H-kromen-4-yl]-1-(2-fenyletyl)-pyridinbromid-dihydrat (14,70 g, 82%) av smp. 226-228°C (fra vandig metanol). 2,2-dimethyl-7-(2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol (12.00 g, 0.03 mol) and 2-phenylethyl bromide (9.30 g, 0.05 mol) were refluxed together in acetone (50 mL) for 8 h. Preparation which in example 1 gave 4-[5-hydroxy-2,2-dimethyl-7-(2-octyl)-2H-chromen-4-yl]-1-(2-phenylethyl)-pyridine bromide dihydrate (14, 70 g, 82%) of m.p. 226-228°C (from aqueous methanol).

Dette fenyletylpyridinbromid (14,00 g) ble redusert under anvendelse av natriumborhydrid:(1,70) ved fremgangsmåten beskrevet i eksempel 1 for å gi 2,2-dimetyl-7-(2-oktyl)-4-[1-(2-fenyletyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-kromen-5-ol (8,70 g, 77%) av smp. 99-100°C (fra lettbensin). This phenylethylpyridine bromide (14.00 g) was reduced using sodium borohydride: (1.70) by the procedure described in Example 1 to give 2,2-dimethyl-7-(2-octyl)-4-[1-(2 -phenylethyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-chromen-5-ol (8.70 g, 77%) of m.p. 99-100°C (from light petrol).

Eksempel 12 Example 12

4-( 1- allyl- 1, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2- dimetyl- 7-( 2- oktyl)- 2H- kromen- 5- ol 4-( 1- allyl- 1, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2- dimethyl- 7-( 2- octyl)- 2H- chromen- 5-ol

2,2-dimetyl-7-(2-oktyl)-4-(4-pyridyl)-2H-kromen-5-ol (12,00 g, 0,033 mol) og allylbromid (6,00 g, 0,050 mol) ble behandlet under tilbakeløp sammen i aceton (50 ml) i 8 timer. Opparbeidelse som i eksempel 1 gav 1-allyl-4-[5-hydroksy-2,2-dimetyl-7-(2-oktyl)-2H-kromen-4-yl]pyridinbromid (12,70 g, 81%) av smp. 178-180°C (fra vandig metanol. 2,2-Dimethyl-7-(2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol (12.00 g, 0.033 mol) and allyl bromide (6.00 g, 0.050 mol) were refluxed together in acetone (50 mL) for 8 h. Workup which in Example 1 gave 1-allyl-4-[5-hydroxy-2,2-dimethyl-7-(2-octyl)-2H-chromen-4-yl]pyridine bromide (12.70 g, 81%) of m.p. 178-180°C (from aqueous methanol.

Dette allylpyridinbromid (12,70) ble redusert under This allylpyridine bromide (12.70) was reduced under

anvendelse av natriumborhydrid (2,00 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(1-allyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-7-(2-oktyl)-2H-kromen-5-ol (2,00 g, 24% av smp. 72-73°C (fra lett bensin). using sodium borohydride (2.00 g) by the procedure described in Example 1 to give 4-(1-allyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-7-(2 -octyl)-2H-chromen-5-ol (2.00 g, 24% of m.p. 72-73°C (from light gasoline).

Eksempel 13 Example 13

4-( l- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2- dimetyl-7-( 2- oktyl)- 2H- kromen- 5- ol 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-7-(2-octyl)-2H-chromen-5-ol

2,2-dimetyl-7-(2-oktyl)-4-(4-pyridyl)-2H-kromen-5-ol (,3,65g, 0,01 mol) og benzylklorid (2,50 g, 0,02 mol) ble tilbake-løpsbehandlet sammen i aceton (90 ml), som inneholdt en krystall av natriumjodid, i 8 timer. Opparbeidelse som i eksempel 1 gav 1-benzyl-4-[5-hydroksy-2,2-dimetyl-7-(2-oktyl)-2H-kromen-4-yl]-pyridinklorid (4,88 g, 99%) av smp. 235-238°C (fra vandig etanol). 2,2-dimethyl-7-(2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol (.3.65g, 0.01 mol) and benzyl chloride (2.50g, 0, 02 mol) were refluxed together in acetone (90 mL), containing a crystal of sodium iodide, for 8 h. Workup that in example 1 gave 1-benzyl-4-[5-hydroxy-2,2-dimethyl-7-(2-octyl)-2H-chromen-4-yl]-pyridine chloride (4.88 g, 99%) of m.p. 235-238°C (from aqueous ethanol).

Dette benzylpyridinklorid (4,00 g) ble redusert under anvendelse av natriumborhydrid (0,70 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-7-(2-oktyl)-2H-kromen-5-ol (3,01 g, 81%)av smp. 103-104°C (fra metylcyanid). This benzylpyridine chloride (4.00 g) was reduced using sodium borohydride (0.70 g) by the procedure described in Example 1 to give 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -2,2-dimethyl-7-(2-octyl)-2H-chromen-5-ol (3.01 g, 81%) of m.p. 103-104°C (from methyl cyanide).

Eksempel 14 Example 14

4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 7-( n- heptyl)-2, 2- dimetyl- 2H- kromen- 5- ol 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-7-(n-heptyl)-2,2-dimethyl-2H-chromen-5-ol

7-(n-heptyl)-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (700 g, 0,02 mol) og benzylklorid (5,00 g, 0,04 mol) ble tilbake-løpsbehandlet sammen i aceton (50 ml), inneholdende en krystall av 7-(n-heptyl)-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (700 g, 0.02 mol) and benzyl chloride (5.00 g, 0.04 mol ) were refluxed together in acetone (50 mL), containing a crystal of

natriumjodid, i tre timer. Opparbeidelse som i eksempel 1 gav 1-benzyl-4-[7-(n-heptyl)-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl]-pyridinkloridmonohydrat (9,80 g, 97%) av smp. 228°C (fra vandig etanol). sodium iodide, for three hours. Workup which in example 1 gave 1-benzyl-4-[7-(n-heptyl)-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl]-pyridine chloride monohydrate (9.80 g, 97%) of m.p. 228°C (from aqueous ethanol).

Dette benzylpyridinklorid (9,30 g) ble redusert under anvendelse av natriumborhydrid (1,50 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(l-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-7-(n-heptyl)-2,2-dimetyl-2H-kromen-5-ol (6,75 g) 78%, som et amorft fast stoff (renset ved kolonnekromatografi på kiselsyregel under anvendelse av kloroform som elueringsmiddel. This benzylpyridine chloride (9.30 g) was reduced using sodium borohydride (1.50 g) by the procedure described in Example 1 to give 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -7-(n-heptyl)-2,2-dimethyl-2H-chromen-5-ol (6.75 g) 78%, as an amorphous solid (purified by column chromatography on silica gel using chloroform as eluent.

Eksempel 15 Example 15

7-( n- heptyl)- 2, 2- dimetyl- 4-[ 1-( 2- fenyletyl)- 1, 2, 5, 6-tetrahydropyrid- 4- yl]- 2H- kromen- 5- ol. 7-(n-heptyl)-2,2-dimethyl-4-[1-(2-phenylethyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-chromen-5-ol.

7-(n-heptyl)-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (1,00 g, 0,003 mol) og 2-fenyletylbromid (2,00 g, et stort overskudd) ble tilbakeløpsbehandlet sammen i aceton (20 ml) i tre timer. Opparbeidelse som i eksempel 1 gav 4-[ 7-(n-he±yl)-5-hydrok-sy-2,2-dimetyl-2H-kromen-4-yl]-1-(2-fenyletyl)-pyridinbromid (1,00 g, 59%) av smp. 264-266°C (fra vandig etanol). 7-(n-heptyl)-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (1.00 g, 0.003 mol) and 2-phenylethyl bromide (2.00 g, a large excess) were refluxed together in acetone (20 mL) for three hours. Preparation which in example 1 gave 4-[7-(n-he±yl)-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl]-1-(2-phenylethyl)-pyridine bromide ( 1.00 g, 59%) of m.p. 264-266°C (from aqueous ethanol).

Dette fenyletylpyridinbromid (0,90 g) ble redusert un- This phenylethylpyridine bromide (0.90 g) was reduced un-

der anvendelse av natriumborhydrid (0,50 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 7-(n-heptyl)-2,2-dimetyl- 4-[1-(2-fenyletyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-kromen-5-ol (0,62 g, 81%) av smp. 114-114,5°C (fra metylcyanid). where using sodium borohydride (0.50 g) by the method described in Example 1 to give 7-(n-heptyl)-2,2-dimethyl-4-[1-(2-phenylethyl)-1,2,5, 6-tetrahydropyrid-4-yl]-2H-chromen-5-ol (0.62 g, 81%) of m.p. 114-114.5°C (from methyl cyanide).

Eksempel 16 Example 16

4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2- dimetyl-7- ( n- nonyl)- 2H- kromen- 5- ol 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-7-(n-nonyl)-2H-chromen-5-ol

2,2-dimetyl-7-(n-nonyl)-4-(4-pyridyl)-2H-kromen-5-ol 2,2-dimethyl-7-(n-nonyl)-4-(4-pyridyl)-2H-chromen-5-ol

(7,80 g, 0,02 mol) og benzylbromid (7,00 g, 0,04 mol) ble tilbake-løpsbehandlet sammen i aceton (120 ml) i fire timer. Opparbeidelse som i eksempel 1 gav 1-benzyl-4-[5-hydroksy-2,2-dimetyl-7-(n-nonyl)-2H-kromen-4-yl]-pyridinbromidmonohydrat (9,35 g, 87%) av smp. 210-212°C (fra vandig etanol). (7.80 g, 0.02 mol) and benzyl bromide (7.00 g, 0.04 mol) were refluxed together in acetone (120 mL) for four hours. Workup which in example 1 gave 1-benzyl-4-[5-hydroxy-2,2-dimethyl-7-(n-nonyl)-2H-chromen-4-yl]-pyridine bromide monohydrate (9.35 g, 87%) of m.p. 210-212°C (from aqueous ethanol).

Dette benzylpyridinbromid (8,36 g) ble redusert under anvendelse av natriumborhydrid (1,20 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-7-(n-nonyl)-2H-kromen-5-ol (5,50 g, 76%) som et amorft fast stoff (renset ved kolonnekromatografi på kiselsyre-•rf;:-/ gel:. -under anvendelse av kloroform som elueringsmiddel) . This benzylpyridine bromide (8.36 g) was reduced using sodium borohydride (1.20 g) by the procedure described in Example 1 to give 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -2,2-dimethyl-7-(n-nonyl)-2H-chromen-5-ol (5.50 g, 76%) as an amorphous solid (purified by column chromatography on silica gel :.-using chloroform as eluent) .

Eksempel 17 Example 17

2, 2- dimetyl- 7-( n- nonyl)- 4-[ 1-( 2- fenyletyl)- 1, 2, 5, 6-tetrahydropyrid- 4- yl]- 2H- kromen- 5- ol 2,2-dimetyl-7-(n-nonyl)-4-(4-pyridyl)-2H-kromen-5-ol (7,80 g, 0,02 mol) og 2-fenyletylbromid (7,40 g, 0,04 mol) ble tilbakeløpsbehandlet sammen i aceton (120 ml) i 7 timer. Opparbeidelse som i eksempel 1 gav 4-[5-hydroksy-2,2-dimetyl-7-(n-nonyl-2H-kromen-4-yl]-1-(2-fenyletyl)pyridinbromid (8,29 g, 74%) av smp. 237-240°C (fra vandig etanol). 2, 2- dimethyl- 7-( n- nonyl)- 4-[ 1-( 2- phenylethyl)- 1, 2, 5, 6-tetrahydropyrid- 4- yl]- 2H- chromen- 5-ol 2,2 -dimethyl-7-(n-nonyl)-4-(4-pyridyl)-2H-chromen-5-ol (7.80 g, 0.02 mol) and 2-phenylethyl bromide (7.40 g, 0.04 mol) were refluxed together in acetone (120 mL) for 7 h. Workup which in example 1 gave 4-[5-hydroxy-2,2-dimethyl-7-(n-nonyl-2H-chromen-4-yl]-1-(2-phenylethyl)pyridine bromide (8.29 g, 74 %) of mp 237-240°C (from aqueous ethanol).

Dette fenyletylpyridinbromid (5,00 g) ble redusert under anvendelse av natriumborhydrid (1,50 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 2,2-dimetyl-7-(n-nonyl)-4-[l-(2-fenyletyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-kromen-5-ol (3 ,44 g, 80%) av smp. 107-108°C (fra metylcyanid. This phenylethylpyridine bromide (5.00 g) was reduced using sodium borohydride (1.50 g) by the procedure described in Example 1 to give 2,2-dimethyl-7-(n-nonyl)-4-[l-(2 -phenylethyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-chromen-5-ol (3.44 g, 80%) of m.p. 107-108°C (from methyl cyanide.

Eksempel 18 Example 18

4-( l- allyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2- dimetyl-7- ( n- nonyl)- 2H- kromen- 5- ol 4-(1-allyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-7-(n-nonyl)-2H-chromen-5-ol

2,2-dimetyl-7-(n-nonyl-4-(4-pyridyl)-2H-kromen-5-ol (5,00 g, 0,013 mol) og allylbromid (3,25 g, 0,027 mol) ble tilba-keløpsbehandlet sammen i aceton (100 ml) i 8 timer. Opparbeidelse som i eksempel 1 gav 1-allyl-4-[5-hydroksy-2,2-dimetyl-7-(n-nonyl)-2H-kromen-4-yl]-pyridinbromid (5,79 g, 83%) av smp. 155-157°C (fra aceton-etylacetat). 2,2-Dimethyl-7-(n-nonyl-4-(4-pyridyl)-2H-chromen-5-ol (5.00 g, 0.013 mol) and allyl bromide (3.25 g, 0.027 mol) were added -coelated together in acetone (100 ml) for 8 hours. Workup which in example 1 gave 1-allyl-4-[5-hydroxy-2,2-dimethyl-7-(n-nonyl)-2H-chromen-4- yl]-pyridine bromide (5.79 g, 83%) of mp 155-157°C (from acetone-ethyl acetate).

Dette allylpyridinbromid (4,61 g) ble redusert under anvendelse av natriumborhydrid (0,57 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(1-allyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-7-(n-nonyl)-2H-kromen-5-ol (2,20 g, 57%) av smp. 82-84°C (renset ved kolonnekromatografi på kiselsyregel under anvendelse av kloroform som elueringsmiddel). This allylpyridine bromide (4.61 g) was reduced using sodium borohydride (0.57 g) by the procedure described in Example 1 to give 4-(1-allyl-1,2,5,6-tetrahydropyrid-4-yl) -2,2-dimethyl-7-(n-nonyl)-2H-chromen-5-ol (2.20 g, 57%) of m.p. 82-84°C (purified by column chromatography on silica gel using chloroform as eluent).

Eksempel 19 Example 19

4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2, 7- tri-metyl- 2H- kromen- 5- ol 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2,7-tri-methyl-2H-chromen-5-ol

2,2,7-trimetyl-4-(4-pyridyl)-2H-kromen-5-ol (5,34 g, 0,02 mol) og benzylbromid (7,2.4 g, 0,04 mol) ble oppvarmet sammen i dimetylformamid (80 ml) ved 100°C i 6 timer. Man lot oppløsningen avkjøle seg, den ble derpå helt i eter (200 ml) og det rå salt ble filtrert fra, vasket med eter og tørket. Omkrystallisering fra etanol-etylacetat gav 1-benzyl-4-(5-hydroksy-2,2,7-trimetyl- 2,2,7-trimethyl-4-(4-pyridyl)-2H-chromen-5-ol (5.34 g, 0.02 mol) and benzyl bromide (7.2.4 g, 0.04 mol) were heated together in dimethylformamide (80 ml) at 100°C for 6 hours. The solution was allowed to cool, it was then poured into ether (200 ml) and the crude salt was filtered off, washed with ether and dried. Recrystallization from ethanol-ethyl acetate gave 1-benzyl-4-(5-hydroxy-2,2,7-trimethyl-

2H-kromen-4-yl)-pyridinbromid (8,39 g, 95%) av smp. 270-271°C. 2H-chromen-4-yl)-pyridine bromide (8.39 g, 95%) of m.p. 270-271°C.

Dette benzylpyridinbromid (7,37 g) ble redusert under anvendelse av natriumborhydrid. (2,00 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2,7-trimetyl-2H-kromen-5-ol (3,36 g, 58%) åv smp. 71-73°C (fra lettbensin). This benzylpyridine bromide (7.37 g) was reduced using sodium borohydride. (2.00 g) by the procedure described in Example 1 to give 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2,7-trimethyl-2H-chromene-5 -ol (3.36 g, 58%) of m.p. 71-73°C (from light petrol).

Eksempel 20 Example 20

4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 7-( n- butyl)-2, 2,- dimetyl- 2H- kromen- 5- ol 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-7-(n-butyl)-2,2,-dimethyl-2H-chromen-5-ol

Konsentrert svovelsyre (84 ml) ble tilsatt dråpevis til en omrørt blanding av etyl-isonikotinoylacetat (35,00 g, 0,18 mol) og 5-n-butylresorsinol (30,00 g, 0,18 mol) ved 0°C. Ved slutten Concentrated sulfuric acid (84 mL) was added dropwise to a stirred mixture of ethyl isonicotinoyl acetate (35.00 g, 0.18 mol) and 5-n-butylresorcinol (30.00 g, 0.18 mol) at 0°C. At the end

av tilsetningen ble tilsatt fosforylklorid (15 ml), og blandingen of the addition was added phosphoryl chloride (15 ml), and the mixt

ble omrørt ved romtemperatur i 18 timer. Blandingen ble derpå helt i et overskudd av mettet natriumbikarbonatoppløsning. Det rå kumarin som skilte seg ut ble ekstrahert i kloroform. De forenede ekstrakter ble tørket (MgSO^O og inndampet. Det gjenværende faste stoff ble krystallisert fra metylcyanid for å gi 7-n-butyl-5-hydro-xy-4-(4-pyridyl)kumarin (27,46 g, 53%) av smp. 193-195°C. was stirred at room temperature for 18 hours. The mixture was then poured into an excess of saturated sodium bicarbonate solution. The crude coumarin that separated was extracted in chloroform. The combined extracts were dried (MgSO 4 O and evaporated. The remaining solid was crystallized from methyl cyanide to give 7-n-butyl-5-hydroxy-4-(4-pyridyl)coumarin (27.46 g, 53 %) of mp 193-195°C.

Dette kumarin (10,00 g, 0,034 mol) ble tilsatt porsjonsvis i løpet av en halv time til IM oppløsning av metyllithium i eter (200 ml, 0,200 mol) under nitrogen ved -10°C.Oppløpningen ble derpå omrørt ved -10°C i 1 time. Fortynnet saltsyre (100 ml) ble tilsatt forsiktig og man lot blandingens temperatur få anledning til å stige til 25°C. Etter nøytralisering med natriumbikarbonat-oppløsning ble eteren fraskilt og det vandige lag ble ekstrahert med eter. De forenede eterekstrakter ble tørket (MgSO^) og inndampet for å gi 1-(4-n-butyl-2,6-dihydroksyfenyl)-3-metyl-1-(4-pyridyl)but-l-en-3-ol (11,11 g) som et gult fast stoff. Dette rå triol ble behandlet under tilbakeløp i iseddik (150 ml) il time. Oppløsningen ble derpå helt i vann (100 ml) og nøytralisert med natriumbikarbonatoppløsning. Det rå kromenol ble filtrert fra, vasket med vann og tørket. Omkrystallisering fra metylcyanid gav 7-(n-butyl)-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (7,80 g, 74%) av smp. 194-194,5°C. This coumarin (10.00 g, 0.034 mol) was added portionwise over half an hour to a 1M solution of methyllithium in ether (200 mL, 0.200 mol) under nitrogen at -10°C. The mixture was then stirred at -10° C for 1 hour. Dilute hydrochloric acid (100 ml) was added carefully and the temperature of the mixture was allowed to rise to 25°C. After neutralization with sodium bicarbonate solution, the ether was separated and the aqueous layer was extracted with ether. The combined ether extracts were dried (MgSO 4 ) and evaporated to give 1-(4-n-butyl-2,6-dihydroxyphenyl)-3-methyl-1-(4-pyridyl)but-1-en-3-ol (11.11 g) as a yellow solid. This crude triol was treated under reflux in glacial acetic acid (150 mL) for 1 hour. The solution was then poured into water (100 ml) and neutralized with sodium bicarbonate solution. The crude chromenol was filtered off, washed with water and dried. Recrystallization from methyl cyanide gave 7-(n-butyl)-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (7.80 g, 74%) of m.p. 194-194.5°C.

Dette kromenol (5,00 g, 0,016 mol) og benzylbromid (5,00 g, 0,34 mol) ble sammen behandlet under tilbakeløp i aceton (100 ml) i 2 timer. Opparbeidelse som angitt i eksempel 1 gav 1-benzyl-4-[7-(n-butyl)-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl]pyridinbromid (6,47 g, 84%) av smp. 262-263°c (fra vandig etanol). This chromenol (5.00 g, 0.016 mol) and benzyl bromide (5.00 g, 0.34 mol) were treated together under reflux in acetone (100 mL) for 2 hours. Workup as indicated in Example 1 gave 1-benzyl-4-[7-(n-butyl)-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl]pyridine bromide (6.47 g, 84%) of m.p. 262-263°c (from aqueous ethanol).

Dette benzylpyridinbromid (5,66 g) ble redusert under anvendelse av natriumborhydrid (1,00 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(l-benzyl-12,,5,6-tetrahydropyrid-4-yl)-7-(n-butyl)-2,2-dimetyl-2H-kromen-5-ol (3,63 g, 76%) av smp. 136-137°C (fra lettbensin). This benzylpyridine bromide (5.66 g) was reduced using sodium borohydride (1.00 g) by the procedure described in Example 1 to give 4-(1-benzyl-12,5,6-tetrahydropyrid-4-yl)- 7-(n-butyl)-2,2-dimethyl-2H-chromen-5-ol (3.63 g, 76%) of m.p. 136-137°C (from light petrol).

Eksempel 21 Example 21

4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 3-( n- heksyl)-2, 2- dimetyl- 2H- kromen- 5- ol 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3-(n-hexyl)-2,2-dimethyl-2H-chromen-5-ol

Konsentrert svovelsyre (112 ml) ble tilsatt dråpevis til en omrørt blanding av etyl-isonikotinoylacetat (39,90 g, 0,206 mol) og 5-n-heksylresorcinol (40,00 g, 0,206 mol) ved 0°C. Ved slutten av tilsetningen ble tilsatt fosforylklorid (64 ml) og blandingen ble omrørt ved romtemperatur i 24 timer. Opparbeidelse som beskrevet i eksempel 20 gav 7-n-heksyl-5-hydroksy-4-(4-pyridyl)-kumarin (55,20 g, 84%) av smp. 138-140°C (fra metylcyanid). Concentrated sulfuric acid (112 mL) was added dropwise to a stirred mixture of ethyl isonicotinoyl acetate (39.90 g, 0.206 mol) and 5-n-hexylresorcinol (40.00 g, 0.206 mol) at 0°C. At the end of the addition, phosphoryl chloride (64 ml) was added and the mixture was stirred at room temperature for 24 hours. Workup as described in Example 20 gave 7-n-hexyl-5-hydroxy-4-(4-pyridyl)-coumarin (55.20 g, 84%) of m.p. 138-140°C (from methyl cyanide).

Dette kumarin (9,69 g, 0,03 mol) ble tilsatt porsjonsvis This coumarin (9.69 g, 0.03 mol) was added portionwise

i løpet av ' en halv time til IM oppløsning av metyllithium i eter (160 ml, 0,16 mol) under nitrogen ved -10°C. Opparbeidelse som beskrevet i eksempel 20 gav 1-(4-n-heksyl-2,6-dihydroksyfenyl)-3- metyl-1-(4-pyridyl)but-l-en-3-ol (8,00 g) som et gult fast stoff. Dette rå triol ble tilbakeløpsbehandlet i iseddik (120 ml) 1 time. Opparbeidelse som beskrevet i eksempel 20 gav 7-(n-heksyl)-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (4,61 g, 45%) av smp. 142-144°C (fra metylcyanid). over half an hour to 1M solution of methyllithium in ether (160 ml, 0.16 mol) under nitrogen at -10°C. Workup as described in Example 20 gave 1-(4-n-hexyl-2,6-dihydroxyphenyl)-3-methyl-1-(4-pyridyl)but-1-en-3-ol (8.00 g) as a yellow solid. This crude triol was refluxed in glacial acetic acid (120 mL) for 1 hour. Workup as described in Example 20 gave 7-(n-hexyl)-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (4.61 g, 45%) of m.p. 142-144°C (from methyl cyanide).

Dette kromenol (2,55 g, 0,0075 mol) og benzylbromid This chromenol (2.55 g, 0.0075 mol) and benzyl bromide

(2,57 g, 0,0150 mol) ble tilbakeløpsbehandlet sammen i aceton (50 ml) i 16 timer. Opparbeidelse som i eksempel 1 gav 1-benzyl-4- (7-n-heksyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl)pyridinbromid-monohydrat (3,50 g, 91%)' av smp. 223-225°C (fra aceton-eter). (2.57 g, 0.0150 mol) were refluxed together in acetone (50 mL) for 16 h. Workup which in example 1 gave 1-benzyl-4-(7-n-hexyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl)pyridine bromide monohydrate (3.50 g, 91%)' of m.p. 223-225°C (from acetone-ether).

Dette benzylpyridinbromid (3,40 g) ble redusert under anvendelse av natriumborhydrid (0,60 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-3-(n-heksyl)-2,2-dimetyl-2H-kromen-5-ol (2,00 g, 69%) som en gul gummiaktig substans (renset ved kolonnekromatografi på kiselsyregel under anvendelse av 4:1 petroleumeter (60-80°):dietyleter som elueringsmiddel) . This benzylpyridine bromide (3.40 g) was reduced using sodium borohydride (0.60 g) by the procedure described in Example 1 to give 4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3-(n-hexyl)-2,2-dimethyl-2H-chromen-5-ol (2.00 g, 69%) as a yellow gummy substance (purified by column chromatography on silica gel using 4:1 petroleum ether ( 60-80°):diethyl ether as eluent) .

Eksempel 22 Example 22

5- acetoksy- 7-( n- amyl)- 4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)- 2, 2- dimetyl- 2H- kromen. 5-acetoxy-7-(n-amyl)-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-2H-chromene.

7-(n-amyl)-4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-2H-kromen-5-ol (4,17 g, 0,01 mol), vannfritt natriumacetat (0,82 g, 0,01 mol) og eddiksyreanhydrid (20 ml) ble sammen tilbakeløpsbehandlet i 4 timer. Etter avkjøling ble blandingen helt i vann (300 ml) og omrørt for å ødelegge overskudd av eddiksyreanhydrid. Oppløsningen ble gjort basisk med natrium-karbonatoppløsning og ekstrahert med eter. Eterekstraktene ble tørket (MgS04) og inndampet for å gi 5-acetoksy-7-(n-amyl)-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-2H-kromen (3 ,51 g, 76%) som en gul gummiaktig substans (renset ved kolonnekromatografi på kiselsyregel under anvendelse av dietyleter som elueringsmiddel) . 7-(n-amyl)-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-2H-chromen-5-ol (4.17 g, 0 .01 mol), anhydrous sodium acetate (0.82 g, 0.01 mol) and acetic anhydride (20 mL) were refluxed together for 4 hours. After cooling, the mixture was poured into water (300 mL) and stirred to destroy excess acetic anhydride. The solution was basified with sodium carbonate solution and extracted with ether. The ether extracts were dried (MgSO 4 ) and evaporated to give 5-acetoxy-7-(n-amyl)-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl -2H-chromium (3.51 g, 76%) as a yellow gummy substance (purified by column chromatography on silica gel using diethyl ether as eluent).

Eksempel 2 3 Example 2 3

7-( n- amyl)- 4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)-2, 2,- dimetyl- 2H- kromen- 5- yl- 3- dietylaminobutyrat- di-hydroklor iddihydr at. 7-( n- amyl)- 4-( 1- benzyl- 1, 2, 5, 6- tetrahydropyrid- 4- yl)-2, 2,- dimethyl- 2H- chromen- 5- yl- 3- diethylaminobutyrat-di -hydrochlor dihydr at.

7-(n-amyl)-4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-2H-kromen-5-ol (4,17 g, 0,01 mol) og 3-dietylamino-smørsyrehydroklorid (1,95 g, 0,01 mol) ble omrørt sammen i mety-lenklorid (100 ml). Dicykloheksylkarbodiimid (2,10 g, 0,01 mol) ble derpå tilsatt og blandingen omrørt ved romtemperatur i 5 døgn. Den resulterende utfelning av dicykloheksylurinstoff ble filtrert fra og filtratet ble konsentrert til det halve volum. Tilsetning av eter til den konsentrerte oppløsning forårsaket utskillelse av det rå salt (3,19 g, 48%). To omkrystalliseringer fra butanon gav 7-(n-amyl)-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimetyl-2H-kromen-5-yl 3-dietylaminobutyrat-dihydroklorid-dihydrat av smp. 165-169°C. 7-(n-amyl)-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-2H-chromen-5-ol (4.17 g, 0 .01 mol) and 3-diethylaminobutyric acid hydrochloride (1.95 g, 0.01 mol) were stirred together in methylene chloride (100 mL). Dicyclohexylcarbodiimide (2.10 g, 0.01 mol) was then added and the mixture stirred at room temperature for 5 days. The resulting precipitate of dicyclohexylurea was filtered off and the filtrate was concentrated to half volume. Addition of ether to the concentrated solution caused precipitation of the crude salt (3.19 g, 48%). Two recrystallizations from butanone gave 7-(n-amyl)-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-2,2-dimethyl-2H-chromen-5-yl 3- diethylaminobutyrate dihydrochloride dihydrate of m.p. 165-169°C.

Eksempel 24 Example 24

7-( n- amyl)- 4-( 1- benzyl- l, 2, 5, 6- tetrahydropyrid- 4- yl)-5- metoksy- 2, 2- dimetyl- 2H- kromen. 7-(n-amyl)-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-5-methoxy-2,2-dimethyl-2H-chromene.

7-8n-amyl)-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (6,46 g, 0,02 mol) ble oppløst i benzen (50 ml). Natriumhydrid (0,80 g av en 60% dispersjon i olje; 0,02 mol) ble derpå tilsatt porsjonsvis til den omrørte blanding ved romtemperatur. Når ut-viklingen av hydrogen var opphørt, ble tilsatt metyljodid (1,25 ml, 2,84 g, 0,02 mol) til den omrørte suspensjon og blandingen ble 7-8n-Amyl)-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (6.46 g, 0.02 mol) was dissolved in benzene (50 mL). Sodium hydride (0.80 g of a 60% dispersion in oil; 0.02 mol) was then added portionwise to the stirred mixture at room temperature. When evolution of hydrogen had ceased, methyl iodide (1.25 mL, 2.84 g, 0.02 mol) was added to the stirred suspension and the mixture was

opphetet under tilbakeløp i 1 time. Etter kjøling ble tilsatt vann (30 ml) for å oppløse det dannede natriumjodid og de to lag heated under reflux for 1 hour. After cooling, water (30 ml) was added to dissolve the sodium iodide formed and the two layers

ble skilt fra hverandre. Benzenlaget ble inndampet og den dyprøde restolje ble renset ved kolonnekromatografi (på kiselsyregel under anvendelse av en 1:1 blanding av 60-80°C petroleumeter-dietyleter som elueringsmiddel) for å gi 7-(n-amyl-5-metoksy-2,2-dimetyl-4-(4-pyridyl)-2H-kromen (3,10 g, 46%) som en gul gummiaktig substans. were separated from each other. The benzene layer was evaporated and the deep red residual oil was purified by column chromatography (on silica gel using a 1:1 mixture of 60-80°C petroleum ether-diethyl ether as eluent) to give 7-(n-amyl-5-methoxy-2, 2-Dimethyl-4-(4-pyridyl)-2H-chrome (3.10 g, 46%) as a yellow gummy substance.

Denne metyleter (3,00 g, 0,009 mol) og benaylbromid (1,171 g, 0,010 mol) ble sammen tilbakeløpsbehandlet i aceton (50 ml) i 3 døgn. Opparbeidelse som i eksempel 1 gav 4-(7-amyl-5-metoksy-2,2-dimetyl-2H-kromen-4-yl)-1-benzylpyridinbromidmono-hydrat (3,19 g, 71%) av smp. 113-116°C (fra acetoneter). This methyl ether (3.00 g, 0.009 mol) and benayl bromide (1.171 g, 0.010 mol) were refluxed together in acetone (50 mL) for 3 days. Workup as in example 1 gave 4-(7-amyl-5-methoxy-2,2-dimethyl-2H-chromen-4-yl)-1-benzylpyridine bromide monohydrate (3.19 g, 71%) of m.p. 113-116°C (from acetones).

Dette benzylpyridinbromid (2,90 g) ble redusert under anvendelse av natriumborhydrid (0,80 g) ved fremgangsmåten beskrevet i eksempel 1 for å gi 7-(n-amyl)-4-(1-benzyl-l,2,5,6-tetrahydropyrid-4-yl)-5-metoksy-2,2-dimetyl-2H-kromen (1,58 g, 64%) som en gul gummiaktig substans (renset ved kolonnekromatografi på kiselsyregel under anvendelse av dietyleter som elueringsmiddel). This benzylpyridine bromide (2.90 g) was reduced using sodium borohydride (0.80 g) by the procedure described in Example 1 to give 7-(n-amyl)-4-(1-benzyl-1,2,5, 6-tetrahydropyrid-4-yl)-5-methoxy-2,2-dimethyl-2H-chromene (1.58 g, 64%) as a yellow gummy substance (purified by column chromatography on silica gel using diethyl ether as eluent).

Eksempel 25 Example 25

Visse forbindelser av den generelle formel (IV) viste seg å ha anti-hypertensiv aktivitet i metakortikoid hypertensive rotter. Rottene ble dosert med 100 mg/kg oralt og fallet i det systologiske blodtrykk ble bestemt 4 og 24 timer etter administre-ringen. 2-metyldopa er innført i den følgende tabell for sammen-ligningsformål. Certain compounds of the general formula (IV) were shown to have anti-hypertensive activity in metacorticoid hypertensive rats. The rats were dosed with 100 mg/kg orally and the drop in the systological blood pressure was determined 4 and 24 hours after the administration. 2-methyldopa is included in the following table for comparison purposes.

Eksempel 25 Example 25

7- n- amyl- 2> 2- dimetyl- 4- f1-( 2- naftylmetyl)- 1, 2, 5, 6-tetrahydropyrid- 4- yll - 2H- kromen- 5- ol. 7-n-amyl-2>2-dimethyl-4-f1-(2-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-yl-2H-chromen-5-ol.

(5,00g), 2-(brommetyl)naftalen (3,31g) og aceton (70ml) ble oppvarmet sammen under tilbakeløpskjøling i 1 1/2 time. Blandingen ble så konsentrert til det halve volum og fikk avkjøle seg. Det blekgule, krystallinske faste stoff ble filtrert, vasket med aceton og tørket under vakuum slik at man fikk 4-(7-n-amyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl)-1-(2-naftylmetyl)pyridiniumbromid (5,70g),smp. 259-260°. (5.00g), 2-(bromomethyl)naphthalene (3.31g) and acetone (70ml) were heated together under reflux for 1 1/2 hours. The mixture was then concentrated to half volume and allowed to cool. The pale yellow crystalline solid was filtered, washed with acetone and dried under vacuum to give 4-(7-n-amyl-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl)-1- (2-naphthylmethyl)pyridinium bromide (5.70g), m.p. 259-260°.

Dette kvaternære salt (5,34g) ble oppløst i en blanding av 250 ml etanol og 75 ml vann. Overskudd av natriumborhydrid (tilnærmet l,00g) ble tilsatt porsjonsvis i løpet av en halv time til den omrørte løsning ved omgivelsestemperatur, og til slutt ble blandingen omrørt i ytterligere en halv time for å sikre fullstendig omsetning. This quaternary salt (5.34g) was dissolved in a mixture of 250ml ethanol and 75ml water. Excess sodium borohydride (approximately 1.00g) was added portionwise over half an hour to the stirred solution at ambient temperature, and finally the mixture was stirred for another half hour to ensure complete reaction.

300 ml vann ble så tilsatt, og blandingen ble ekstrahert grunding med eter (4 x 250 ml). Den samlede eterekstrakt ble vasket med vann, tørket over vannfritt natriumsulfat og inndampet til tørrhet under redusert trykk. Den faste inndampningsrest (4,19g) ble rekrystallisert ut fra 60-80° petroleter slik at man fikk 3,10g tetrahydropyridin som farveløse mikrokrystaller med smp. 131-132°. 300 mL of water was then added and the mixture was extracted trituration with ether (4 x 250 mL). The combined ether extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The solid evaporation residue (4.19g) was recrystallized from 60-80° petroleum ether so that 3.10g of tetrahydropyridine was obtained as colorless microcrystals with m.p. 131-132°.

Eksempel 26 Example 26

7- n- amyl- 2, 2- dimetyl- 4-|" 1-( 1- naftylmetyl) - 1, 2, 5, 6-tetrahydropyrid- 4- yll-2H-kromen-5-ol. 7-n-amyl-2,2-dimethyl-4-|"1-(1-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-yl-2H-chromen-5-ol.

(5,00g), 1-(klormetyl)naftalen (3,00g), en krystall av kalium- (5.00g), 1-(chloromethyl)naphthalene (3.00g), a crystal of potassium

jodid og 70 ml aceton ble oppvarmet sammen under tilbakeløps-kjøling i én time. Løsningen ble deretter konsentrert til det halve volum og fikk henstå ved omgivelsestemperatur i 16 timer slik at man fikk et gult, krystallinsk utfellingsprodukt av 4-(7-n-amyl-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl)-1-(1-naftylmetyl)-pyridiniumklorid (5,06g), smp. 259-261°. iodide and 70 ml of acetone were heated together under reflux for one hour. The solution was then concentrated to half volume and allowed to stand at ambient temperature for 16 hours to give a yellow, crystalline precipitate of 4-(7-n-amyl-5-hydroxy-2,2-dimethyl-2H-chromene-4) -yl)-1-(1-naphthylmethyl)-pyridinium chloride (5.06g), m.p. 259-261°.

Dette kvaternære salt (5,00g) ble oppløst i en blanding av 120 ml etanol og 40 ml vann, og overskudd av natriumborhydrid ble tilsatt porsjonsvis til den omrørte løsning ved omgivelsestemperatur. Opparbeidelse som beskrevet i eksempel 1 ga 4,08 g av tetrahydropyridi.net med smp. 51-53 (krystalliserte med vanskelighet ut fra benzen/60-80° petroleter). This quaternary salt (5.00g) was dissolved in a mixture of 120ml ethanol and 40ml water, and excess sodium borohydride was added portionwise to the stirred solution at ambient temperature. Workup as described in example 1 gave 4.08 g of tetrahydropyridinium with m.p. 51-53 (crystallized with difficulty from benzene/60-80° petroleum ether).

Eksempel 27 Example 27

7- n- amyl- 2, 2- dimetyl- 4~ rl-( 2- fi- naftyletyl)- 1, 2, 5, 6-tetrahydropyrid- 4- yll- 2H- kromen- 5- ol. 7- n- amyl-2, 2- dimethyl- 4~ rl-( 2- fin- naphthylethyl)- 1, 2, 5, 6- tetrahydropyrid- 4- yl- 2H- chromen- 5-ol.

7-n-amyl-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (3,56g), 2-(Æ-naftyl)etylbromid (2,74g) og aceton (50 ml) ble oppvarmet sammen under tilbakeløpskjøling i 14 timer. Tørr dietyleter ble så tilsatt til den avkjølte løsning, og det resulterende utfe llingsprodukt ble filtrert fra og rekrystallisert ut fra etanol/eter slik at man fikk 4-(7-n-amyl-5-hydroksy-2,2dimetyl-2H-kromen-4-yl)-l-[2-(fi-naftyl)etyl]-pyridiniumbromid (3,57g) 7-n-amyl-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (3.56g), 2-(Æ-naphthyl)ethyl bromide (2.74g) and acetone (50 ml) were heated together under reflux for 14 h. Dry diethyl ether was then added to the cooled solution, and the resulting precipitate was filtered off and recrystallized from ethanol/ether to give 4-(7-n-amyl-5-hydroxy-2,2dimethyl-2H-chromene- 4-yl)-1-[2-(tri-naphthyl)ethyl]-pyridinium bromide (3.57g)

smp. 229-230°. m.p. 229-230°.

Dette kvaternære salt (3,46g) ble oppløst i en blanding av 195 ml etanol og 65 ml vann, og overskudd av natriumborhydrid ble tilsatt porsjonsvis til den omrørte løsning ved omgivelsestemperatur. Opparbeidelse som beskrevet i eksempel ga 1,92 g av tetrahydropyridinet, smp. 159-161°(utfra 60-80° petroleter). This quaternary salt (3.46g) was dissolved in a mixture of 195ml ethanol and 65ml water, and excess sodium borohydride was added portionwise to the stirred solution at ambient temperature. Workup as described in the example gave 1.92 g of the tetrahydropyridine, m.p. 159-161° (based on 60-80° petroleum ether).

Eksempel 28 Example 28

7-( 2- heksyl) 2, 2- dimetyl- 4-[ l-( 2- naftylmetyl)- 1, 2, 5, 6-tetrahydropyrid- 4- yll- 2H- kromen- 5- ol. 7-(2-hexyl)2,2-dimethyl-4-[1-(2-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-yl-2H-chromen-5-ol.

7-(2-heksyl)-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (5,00g), 2-brommetylnaftalen (3,54g) og aceton (70 ml) ble oppvarmet sammen under tilbakeløpskjøling i 6 timer. Det resulterende blekgule utfellingsprodukt ble filtrert fra og tørket slik at man fikk 4-[7-(2-heksyl)-5-hydroksy-2,2,dimetyl-2H-kromen-4-yl]-1-(2-naftylmetyl)pyridiniumbromid (8,20g) smp. 236-239°. 7-(2-hexyl)-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (5.00g), 2-bromomethylnaphthalene (3.54g) and acetone (70ml) were heated together under reflux for 6 hours. The resulting pale yellow precipitate was filtered off and dried to give 4-[7-(2-hexyl)-5-hydroxy-2,2,dimethyl-2H-chromen-4-yl]-1-(2-naphthylmethyl) pyridinium bromide (8.20g) m.p. 236-239°.

Dette kvaternære salt (8,l0g) ble oppløst i 150 ml etanol og 50 ml vann, og overskudd av natriumborhydrid ble tilsatt porsjonsvis til den omrørte løsning ved omgivelsestemperatur. Opparbeidelse som beskrevet i eksempel 1 ga 4,11 g av tetrahydropyridinet, smp. 153-154° (utfra 60-80°petroleter). This quaternary salt (8.10g) was dissolved in 150 ml of ethanol and 50 ml of water, and excess sodium borohydride was added portionwise to the stirred solution at ambient temperature. Workup as described in example 1 gave 4.11 g of the tetrahydropyridine, m.p. 153-154° (based on 60-80° petroleum ether).

Eksempel 29 Example 29

7-( 2- heksyl)- 2, 2- dimetyl- 4- rl-( 1- naftylmetyl)- 1, 2, 5, 6-tetrahydropyrid- 4- yl1- 2H- kromen- 5- ol. 7-(2-hexyl)-2,2-dimethyl-4- 1-(1-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-yl1-2H-chromen-5-ol.

7-(2-heksyl)-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (5,00g), 1-klormetylnaftalen (2,64g) og aceton (70 ml) ble oppvarmet sammen under tilbakeløpskjøling i 6 timer. Det resulterende gule utfellingsprodukt ble filtrert fra og tørket slik at 7-(2-hexyl)-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (5.00g), 1-chloromethylnaphthalene (2.64g) and acetone (70ml) were heated together under reflux for 6 hours. The resulting yellow precipitate was filtered off and dried so that

man fikk 4-[7-(2-heksyl)-5-hydroksy-2,2-dimetyl-2H-kromen-4-yl]-1-(1-naftylmetyl)pyridiniumklorid (5,13g), smp. 258-260°. 4-[7-(2-hexyl)-5-hydroxy-2,2-dimethyl-2H-chromen-4-yl]-1-(1-naphthylmethyl)pyridinium chloride (5.13g), m.p. 258-260°.

Dette kvaternære salt (5,13g) ble oppløst i 300 ml etanol og 100 ml vann, og overskudd av natriumborhydrid ble tilsatt porsjonsvis til den omrørte løsning ved omgivelsestemperatur. Opparbeidelse som beskrevet i eksempel 1 gav 2,38g av tetrahydropyridinet, smp. 98-100° (utfra 60-80° petroleter). This quaternary salt (5.13g) was dissolved in 300 ml of ethanol and 100 ml of water, and excess sodium borohydride was added portionwise to the stirred solution at ambient temperature. Workup as described in example 1 gave 2.38g of the tetrahydropyridine, m.p. 98-100° (based on 60-80° petroleum ether).

Eksempel 30 Example 30

5- acetoksy- 7- n- amyl- 2, 2- dimetyl- 4-[ l-( 2- naftylmetyl)-1, 2, 5, 6- tetrahydropyrid- 4- y11- 2H- kromen. 5-acetoxy-7-n-amyl-2,2-dimethyl-4-[1-(2-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-y11-2H-chromene.

7-n-amyl-2,2-dimetyl-4-[l-(2-naftyImetyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-kromen-5-ol (l,52g; fremstilt som beskrevet i eksempel 1), vannfritt natriumacetat (0,27g) og eddiksyreanhydrid (10 ml) ble oppvarmet sammen under tilbakeløps-kjøling i 4 timer. Løsningen ble så hellet ned i 150 ml isvann og gjort basisk med mettet natriumbikarbonatløsning. Den basiske løsning ble ekstrahert med eter, og eterekstraktene ble tørket over natriumsulfat. Inndampning til tørrhet i vakuum gav en gummi som ble renset ved hjelp av søylekromatografi på silikagel under anvendelse av dietyleter/60-80° petroleterblandinger som elueringsmiddel slik at man fikk l,05g av acetatet som en halmfarvet viskøs olje. 7-n-amyl-2,2-dimethyl-4-[1-(2-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-yl]-2H-chromen-5-ol (1.52g; prepared as described in Example 1), anhydrous sodium acetate (0.27g) and acetic anhydride (10ml) were heated together under reflux for 4 hours. The solution was then poured into 150 ml of ice water and basified with saturated sodium bicarbonate solution. The basic solution was extracted with ether, and the ether extracts were dried over sodium sulfate. Evaporation to dryness in vacuo gave a gum which was purified by column chromatography on silica gel using diethyl ether/60-80° petroleum ether mixtures as eluent to give 1.05g of the acetate as a straw colored viscous oil.

Eksempel 31 Example 31

7-( n- amyl)- 4- fl-( 2- naftylmetyl)- 1, 2, 5, 6- tetrahydropyrid-4- yl1- 2, 2- dimetyl- 2H- kromen- 5- yl- 4- dietylaminobutyrat-dihydroklorid. 7 -n -amy 1 -2 , 2 -d ime ty 1 -4 - [ 1 - (2 -na f ty Ime ty 1) -1, 2 , 5 ,6 - tetrahydropyrid-4-yl]-2H-kromen-5-ol (4,56g; fremstilt som beskrevet i eksempel 1), 4-dietylarainosmørsyrehydroklorid (l,96g), dicykloheksylkarbondiimid (2,l0g) og diklormetan (150 ml) ble omrørt sammen i 10 dager. Løsningen ble så konsentrert til 40 ml, og tørr eter ble tilsatt. Det resulterende utfellingsprodukt ble filtrert og rekrystallisert ut fra etanol/eter slik at man fikk den basiske ester som et dihydroklorid (2,89g) smp. 126-130°. 7-( n- amyl)- 4- fl-( 2- naphthylmethyl)- 1, 2, 5, 6- tetrahydropyrid-4- yl1- 2, 2- dimethyl- 2H- chromen- 5- yl- 4- diethylaminobutyrat- dihydrochloride. 7 -n -amy 1 -2 , 2 -di ime ty 1 -4 - [ 1 - (2 -na f ty Ime ty 1) -1, 2 , 5 ,6 - tetrahydropyrid-4-yl]-2H-chromene -5-ol (4.56g; prepared as described in Example 1), 4-diethylarainobutyric acid hydrochloride (1.96g), dicyclohexylcarbondiimide (2.10g) and dichloromethane (150ml) were stirred together for 10 days. The solution was then concentrated to 40 mL, and dry ether was added. The resulting precipitate was filtered and recrystallized from ethanol/ether to give the basic ester as a dihydrochloride (2.89g) m.p. 126-130°.

Eksempel 32 Example 32

7-( n- amyl)- 5- metoksy- 2, 2- dimetyl- 4- rl-( 2- naftylmetyl)-1, 2, 5, 6- tetrahydropyrid- 4- yl1- 2H- kromen. 7-(n-amyl)-5-methoxy-2,2-dimethyl-4- 1-(2-naphthylmethyl)-1,2,5,6-tetrahydropyrid-4-yl1-2H-chromene.

7-n-amyl-2,2-dimetyl-4-(4-pyridyl)-2H-kromen-5-ol (6,36g) ble oppløst i 50 ml benzen, og natriumhydrid (0,88g av 7-n-amyl-2,2-dimethyl-4-(4-pyridyl)-2H-chromen-5-ol (6.36g) was dissolved in 50 ml of benzene, and sodium hydride (0.88g of

en 60% dispersjon i mineralolje) ble tilsatt porsjonsvis. a 60% dispersion in mineral oil) was added portionwise.

Blandingen ble omrørt i. 15 minutter, og en løsning av jodmetan (3,14g) i benzen (20 ml) ble tilsatt dråpevis. Ved slutten av tilsetningen ble blandingen behandlet under tilbakeløpskjøling i 1,5 timer. Etter avkjøling ble blandingen hellet ned i 130 ml vann og ekstrahert med eter. De kombinerte organiske ekstrakter ble tørket over natriumsulfat og inndampet i vakuum. Den rå restolje ble renset ved hjelp av søylekromatografi på silikagel under anvendelse av dietyleter/60-80° petroleter som elueringsmiddel slik at man fikk 7-n-amyl-5-metoksy-2,2-dimetyl-4-(4-pyridyl)-2H-kromen som 4,15 g av en gul olje. The mixture was stirred for 15 minutes and a solution of iodomethane (3.14g) in benzene (20ml) was added dropwise. At the end of the addition, the mixture was refluxed for 1.5 hours. After cooling, the mixture was poured into 130 ml of water and extracted with ether. The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude residual oil was purified by column chromatography on silica gel using diethyl ether/60-80° petroleum ether as eluent to give 7-n-amyl-5-methoxy-2,2-dimethyl-4-(4-pyridyl) -2H-chromium as 4.15 g of a yellow oil.

Dette 4-(4-pyridyl)-2H-kromen (4,15g), 2-brommetylnaftalen (2,87g) og aceton (50 ml) ble oppvarmet sammen under tilbakeløpskjøling i 13 timer. This 4-(4-pyridyl)-2H-chrome (4.15g), 2-bromomethylnaphthalene (2.87g) and acetone (50ml) were heated together under reflux for 13 hours.

Så ble tørr dietyleter tilsatt til den avkjølte løs-ning, og det resulterende utfellingsprodukt av 4-(7-n-amyl-5-metoksy-2,2-dimetyl-2H-kromen-4-yl)-l-(2-naftyImetyl) pyridinium-bromid (4,55g, smp. 93-95°) ble filtrert og tørket. Dry diethyl ether was then added to the cooled solution, and the resulting precipitate of 4-(7-n-amyl-5-methoxy-2,2-dimethyl-2H-chromen-4-yl)-1-(2- naphthylmethyl)pyridinium bromide (4.55g, m.p. 93-95°) was filtered and dried.

Dette kvaternære salt (4,55g) ble oppløst i 120 ml etanol og 40 ml vann, og overskudd av natriumborhydrid ble tilsatt porsjonsvis til den omrørte løsning ved omgivelsestemperatur. Opparbeidelse som beskrevet i eksempel 1 gav 2,44 g av tetrahydropyridinet som en gummi (renset ved hjelp av søylekromatografi på silikagel under anvendelse av dietyleter/60-80° petroleter som elueringsmiddel). This quaternary salt (4.55g) was dissolved in 120ml of ethanol and 40ml of water, and excess sodium borohydride was added portionwise to the stirred solution at ambient temperature. Workup as described in Example 1 gave 2.44 g of the tetrahydropyridine as a gum (purified by means of column chromatography on silica gel using diethyl ether/60-80° petroleum ether as eluent).

Eksempel 33 Example 33

Farmakologi Pharmacology

Metakortikoid-hypertensjon ble indusert i rotter ved metoden til Green o.a. [Amer. J. Physiol., 170, 94 (1952)]. Alle forbindelser ble suspendert i metylcéllulose og administrert oralt til grupper på minst 3 metakortikoid-hypertensive rotter med en dose av 100 mg/kg. Blodtrykket ble målt indirekte på bevisste, hemmede rotter ved metoden til Friedman o.a. [Proe. Soc. Exper. Biol. Med., 70, 670 (1949)]. Følgende resultater ble oppnådd for forbindelser av formelen: Metacorticoid hypertension was induced in rats by the method of Green et al. [Amer. J. Physiol., 170, 94 (1952)]. All compounds were suspended in methylcellulose and administered orally to groups of at least 3 metacorticoid-hypertensive rats at a dose of 100 mg/kg. Blood pressure was measured indirectly on conscious, restrained rats by the method of Friedman et al. [Pro. Soc. Exper. Biol. Med., 70, 670 (1949)]. The following results were obtained for compounds of the formula:

Claims

Analogous process for the preparation of a compound of formula (II) or a salt thereof:

where is a straight or branched alkyl group of 4-9 carbon atoms, R^ is a lower alkyl, lower alkenyl or aryl-lower alkyl group of 1-20 carbon atoms, and X is a hydro

syl group, a salt-formed hydroxyl group or a group OR^ where Rj. is alkyl with 1-6 carbon atoms, or OCORg where R& is alkyl with 1-6 carbon atoms which is optionally substituted with an amino- or mono- or dialkylamino group with 2-6 carbon atoms, characterized in that a compound of formula (III):

wherein the groups R 2 , R 3 and X are as defined for formula (n) with the exception that X cannot be an OC 0 R 8 group, and B<&> represents an anion, is reduced by a borohydride; and that optionally then the thus formed compound of formula (III) is reacted with an acylation derivative of an acid RgCOOH so that the corresponding compound of formula (III) is obtained where x is an OCOR6 group.