NO124643B

NO124643B -

Info

Publication number: NO124643B
Application number: NO315069A
Authority: NO
Inventors: Tsung-Ying Shen; G Walford; C Dorn
Original assignee: Merck & Co Inc
Priority date: 1967-07-26
Filing date: 1969-07-31
Publication date: 1972-05-15

Description

Analogifremgangsmåte ved fremstilling Analogy method in manufacturing

av anti-inflammatoriske aralkylthioaminsyrer. of anti-inflammatory aralkylthioamic acids.

Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av visse (3 -aralkylthio -substituert -a-aminosyrer og deres estere og amider, og også fremstillingen av mono-, di- og tri-(aralkyl)-thio-substituert-a-aminosyrer og derivater derav. The present invention relates to an analogous method for the production of certain (3-aralkylthio-substituted-α-amino acids and their esters and amides, and also the production of mono-, di- and tri-(aralkyl)-thio-substituted-α-amino acids and derivatives hence.

Ved foreliggende fremgangsmåte fremstilles ant i-inflammatoriske forbindelser av den generelle formel: In the present method, anti-inflammatory compounds of the general formula are produced:

hvor R er hydrogen, halogen-laverealkyl, hydroxy, halogen, lavere-alkylthlo, laverealkoxy, hitro, laverealkyl eller methylendioxy, where R is hydrogen, halo-lower alkyl, hydroxy, halogen, lower alkyl thlo, lower alkoxy, hydrogen, lower alkyl or methylenedioxy,

R^er hydrogen., laverealkyl eller fenyl, R^ is hydrogen, lower alkyl or phenyl,

R2er hydroxy, lavere alkoxy, lavere alkoxy-lavere alkoxy, amino, lavere alkylamino, di-lavere alkylamino, eller OZ, hvor Z er et kation, R 2 is hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, amino, lower alkylamino, di-lower alkylamino, or OZ, where Z is a cation,

R^og R^ er hydrogen eller laverealkyl, R^ and R^ are hydrogen or lower alkyl,

R^og R^er hydrogen, laverealkyl eller laverealkanoyl, og når R^er hydrogen, kan R^også være guanyl; og R^ and R^ are hydrogen, lower alkyl or lower alkanoyl, and when R^ is hydrogen, R^ may also be guanyl; and

R^og R£ er hydrogen, laverealkyl, fenyl, nafthyl, thlenyl, pyrldyl eller' substituert fenyl hvori substituentene er R^ ^) • > idet Rg og R'k kan være like eller forskjellige, R^ and R£ are hydrogen, lower alkyl, phenyl, naphthyl, thlenyl, pyrldyl or' substituted phenyl in which the substituents are R^ ^) • > wherein Rg and R'k may be the same or different,

med folgende unntagelser: with the following exceptions:

(1) når Rg og R^ er fenyl, er minst én av R, R-^, R^, R^, R^og R^-forskjellig fra hydrogen; (2) når R£ er fenyl og R er hydrogen eller én alkoxygruppe, er minst en av R-^, R-^, R^, , R^og Rg forskjellig fra hydrogen; (3) når R^ er hydrogen og R er hydrogen, én alkoxy- eller nitro-gruppe eller ett halogenatom, er minst én av R-^, R^, R^, R^, R^og R^forskjellig fra hydrogen; (1) when Rg and R^ are phenyl, at least one of R, R-^, R^, R^, R^, and R^ is other than hydrogen; (2) when R 1 is phenyl and R 1 is hydrogen or one alkoxy group, at least one of R 1 , R 1 , R 1 , , R 1 , and R 8 is different from hydrogen; (3) when R₂ is hydrogen and R₂ is hydrogen, one alkoxy or nitro group or one halogen atom, at least one of R₂, R₂, R₂, R₂, R₂ and R₂ is different from hydrogen;

(^f) og når R^er alkanoyl, er minst én av R, R^, R^, R^, R^, Rg og R^ forskjellig fra hydrogen. (^f) and when R^ is alkanoyl, at least one of R, R^, R^, R^, R^, Rg, and R^ is different from hydrogen.

Disclaimerne har til hensikt å begrense fremgangsmåteforbind-elsene overfor forbindelser som er kjent fra bl.a. U.S. patenter og 2.900.375, nederlandsk patentansokning 650081+9 og Canadian Journal of Chemistry, Vol.<>>+3 (1965) , 206 - 210. The disclaimers are intended to limit the process compounds to compounds known from e.g. U.S. patents and 2,900,375, Dutch patent application 650081+9 and Canadian Journal of Chemistry, Vol.<>>+3 (1965) , 206 - 210.

I sin mere foretrukne form er oppfinnelsen rettet på fremstillingen av forbindelsene ifolge formel A med folgende spesielt foretrukne substituenter: R er hydrogen, halogen, trifluormethyl, methylthio eller methoxy, R-^ er hydrogen, methyl eller fenyl, In its more preferred form, the invention is directed to the preparation of the compounds according to formula A with the following particularly preferred substituents: R is hydrogen, halogen, trifluoromethyl, methylthio or methoxy, R-^ is hydrogen, methyl or phenyl,

R2er hydroxy, ethoxy eller OM hvor M er en farmasoytisk godtagbar metallion som natrium, magnesium, calcium, aluminium, kobber, zink eller cholin, R2 is hydroxy, ethoxy or OM where M is a pharmaceutically acceptable metal ion such as sodium, magnesium, calcium, aluminium, copper, zinc or choline,

R^og R^ er hydrogen, methyl eller fenyl, R^ and R^ are hydrogen, methyl or phenyl,

R^og R^er hydrogen, methyl eller guanyl, og R^ and R^ are hydrogen, methyl or guanyl, and

R^og R£ er hydrogen, fenyl, nafthyl eller substituert fenyl, R^ and R^ are hydrogen, phenyl, naphthyl or substituted phenyl,

og Rg og R£ kan være like eller forskjellige. and Rg and R£ may be the same or different.

De mest foretrukne forbindelser som fremstilles ifølge oppfinnelsen, har formel A hvor: The most preferred compounds produced according to the invention have formula A where:

R er halogen, R is halogen,

R2er hydroxy, R2 is hydroxy,

R^,R3,R^, R^ og R^er hydrogen, og R 1 , R 3 , R 2 , R 3 and R 3 are hydrogen, and

R^og R£ er hydrogen, fenyl eller halogenfenyl, og disse forbindelser er foretrukket på grunn av sin særlig sterke aktivitet. R^ and R^ are hydrogen, phenyl or halophenyl, and these compounds are preferred because of their particularly strong activity.

Representative forbindelser fremstilt ifølge oppfinnelsen er som følger: S-(3,4-diklorbenzyl)-L-cystein, smp. 195 - 202°C, S-(3,4-diklorbenzyl)-a-methyl-DL-cystein, smp. 217 - 219°C, S-(3,4-diklorbenzyl)-a-fenyl-DL-cystein, smp. 230 - 233°C, S-tris-(4-fluorfenyl)-methyl-L-cystein, smp. 153~156°C, S-(p-klorfenyldifenylmethyl)-L-cystein, smp. l6o - l62°C, S-(a-nafthyldifenylmethyl)-L-cystein, smp. 155 - 158°C, S-(2'-thienyldifenylmethyl)-L-cystein, smp. 165 - l66°C, S-(4'-pyridyldifenylmethyl)-L-cystein, smp. 245°C (spaltn.), S-(a-nafthylfenylmethyl)-L-cystein, smp. 189 - 191°C. Representative compounds prepared according to the invention are as follows: S-(3,4-dichlorobenzyl)-L-cysteine, m.p. 195 - 202°C, S-(3,4-dichlorobenzyl)-α-methyl-DL-cysteine, m.p. 217 - 219°C, S-(3,4-dichlorobenzyl)-α-phenyl-DL-cysteine, m.p. 230 - 233°C, S-tris-(4-fluorophenyl)-methyl-L-cysteine, m.p. 153~156°C, S-(p-chlorophenyldiphenylmethyl)-L-cysteine, m.p. 160 - 162°C, S-(a-naphthyldiphenylmethyl)-L-cysteine, m.p. 155 - 158°C, S-(2'-thienyldiphenylmethyl)-L-cysteine, m.p. 165 - 166°C, S-(4'-pyridyldiphenylmethyl)-L-cysteine, m.p. 245°C (dec.), S-(α-naphthylphenylmethyl)-L-cysteine, m.p. 189 - 191°C.

Det har vist seg at forbindelsene av ovenstående struktur har en høy grad av anti-inflammatorisk aktivitet og er virksomme til å forhindre og inhibere forsinkede typer sensibilitet. Forbindelsene fremstilt ifølge oppfinnelsen har en gunstig grad av aktivitet og er av verdi ved behandling av arthritiske og dermatologiske lidelser som er responsive for behandling med anti-inflammatoriske midler. Til disse formål kan forbindelsene administreres i tabletter eller kapsler, eller andre farmasøytiske preparater, idet den optimale dose avhenger av aktiviteten av den spesielle forbindelse som anvendes, og graden og typen av infeksjon som behandles. Skjønt den optimale dose vil avhenge av den spesielle forbindelse og den spesielle lidelse som behandles, kan orale doser på 10 - 5000 mg pr. dag anvendes med fordel, men doser på 50 - lOOO mg foretrekkes i alminnelighet . It has been shown that the compounds of the above structure have a high degree of anti-inflammatory activity and are effective in preventing and inhibiting delayed types of sensitivity. The compounds produced according to the invention have a favorable degree of activity and are of value in the treatment of arthritic and dermatological disorders which are responsive to treatment with anti-inflammatory agents. For these purposes, the compounds may be administered in tablets or capsules, or other pharmaceutical preparations, the optimum dose depending on the activity of the particular compound used, and the degree and type of infection being treated. Although the optimal dose will depend on the particular compound and the particular disorder being treated, oral doses of 10 - 5000 mg per day is used with advantage, but doses of 50 - 100 mg are generally preferred.

a-aminosyreforbindelsene fremstilt ifølge oppfinnelsen kan også anvendes i farmasøytiske preparater med forskjellige salicylater, som aspirin. Disse preparater kan inneholde 0,1 - 8,0 g aspirin og 0,5 - 10,0 g a-aminosyreforbindelse. Fortrinnsvis inneholder disse preparater ca. 250 mg av a-aminosyreforbindelsen og ca. 300 mg aspirin, sammen med excipienser. Disse excipienser kan f.eks. være inerte fortynningsmidler som calciumcarbonat, natriumcarbonat, The α-amino acid compounds produced according to the invention can also be used in pharmaceutical preparations with various salicylates, such as aspirin. These preparations may contain 0.1 - 8.0 g of aspirin and 0.5 - 10.0 g of α-amino acid compound. Preferably, these preparations contain approx. 250 mg of the α-amino acid compound and approx. 300 mg aspirin, together with excipients. These excipients can e.g. be inert diluents such as calcium carbonate, sodium carbonate,

lactose, calciumfosfat eller natriumfosfat, granulerings- og des-integreringsmidler, f.eks. roaisstivelser eller alginsyre, binde-midler, f.eks. stivelse, gelatin eller acacin, og smøremidler, f.eks. magnesiumstearat, stearinsyre eller talcum. lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, e.g. roe starches or alginic acid, binders, e.g. starch, gelatin or acacin, and lubricants, e.g. magnesium stearate, stearic acid or talc.

De ant ireumatiske egenskaper av penicillamin er beskrevet i litteraturen. Mekanismen av virkningen forståes fremdeles ikke helt. I henhold til A. Lorber [Nature, 210, 1235 (June 18, 1966)] er chelering med toverdige metaller, som kobber, og deltagelsen av den frie sulfhydrylgruppe i en utbytningsdissosiasjon med disulfid-bundet immune globuliner in vivo to mulige virkemåter. Det er vel-kjent at den frie sulfhydrylgruppe i alminnelighet foretrekkes frem-for thioethere som metallkompleksdannende bindinger, og thioethere er ikke istand til å danne disulfidbindinger in vivo. Det var således uventet å finne at en rekke aralkylthioethere, som man ikke vet danner sulfhydrylstoffskifteprodukter in vivo, virkelig har bedre antireumatisk aktivitet enn penicillamin. The antirheumatic properties of penicillamine are described in the literature. The mechanism of action is still not fully understood. According to A. Lorber [Nature, 210, 1235 (June 18, 1966)], chelation with divalent metals, such as copper, and the participation of the free sulfhydryl group in a yield dissociation with disulfide-bonded immune globulins in vivo are two possible modes of action. It is well known that the free sulfhydryl group is generally preferred to thioethers as metal complex-forming bonds, and thioethers are not able to form disulfide bonds in vivo. It was thus unexpected to find that a number of aralkylthioethers, which are not known to form sulfhydryl metabolism products in vivo, really have better antirheumatic activity than penicillamine.

Foreliggende oppfinnelse er følgelig rettet på en fremgangsmåte ved fremstilling av nye aralkylthioethere som har denne uventede anti-inflammatoriske egenskap. The present invention is therefore directed to a method for the production of new aralkylthioethers which have this unexpected anti-inflammatory property.

Forbindelsen med formel A foreligger som racemater eller deres optisk aktive -1 eller +d form og kan anvendes som racematene eller de optisk aktive former. The compound of formula A exists as racemates or their optically active -1 or +d form and can be used as the racemates or the optically active forms.

Ved foreliggende fremgangsmåte omsettes et a-substituert benzylhalogenid med det passende cystein ved forhøyede temperaturer, fortrinnsvis ved eller nær tilbakeløpstemperaturen for systemet, i et oppløsningsmiddel (fortrinnsvis et polart oppløsningsmiddel som dimethylformamid, flytende ammoniakk, etc.). Følgende ligning illustrerer denne fremgangsmåte: In the present method, an α-substituted benzyl halide is reacted with the appropriate cysteine at elevated temperatures, preferably at or near the reflux temperature of the system, in a solvent (preferably a polar solvent such as dimethylformamide, liquid ammonia, etc.). The following equation illustrates this procedure:

hvor R, R1, R^, R^, R^, R^, Rg og R£ er som ovenfor angitt, og X er halogen. where R, R1, R^, R^, R^, R^, Rg and R^ are as indicated above, and X is halogen.

En alminnelig metode for fremstilling av a-t ris-(aryl)-thio-substituert-a-aminosyrer er å kondensere en passende triarylalkohol med (3-mercapto-a-aminosyrer direkte i nærvær av en Lewis-syre, som BF^-etherat i iseddik ved forhøyede temperaturer., A common method for the preparation of α-tris-(aryl)-thio-substituted-α-amino acids is to condense an appropriate triaryl alcohol with (3-mercapto-α-amino acids) directly in the presence of a Lewis acid, such as BF^-etherate in glacial acetic acid at elevated temperatures.,

En bekvem metode for fremstilling av en R^-a-dimethylaminosyre er ved omsetning.av den tilsvarende a-aminoforbindelse med formaldehyd i nærvær av hydrogen over palladium. Alternativt er, når en R^-a-alkylaminosyre ønskes, en annen egnet fremgangsmåte omsetningen av en passende a-aminosyre med ammoniakk og natrium og et spor av ferriklorid. Det således dannede produkt behandles med p-toluensulfonylklorid under dannelse av en a-toluensulfonylaminosyrefor-bindelse. Denne forbindelse omsettes så med en base og et alkyl-halogenid, fulgt av natrium og ammoniakk og et passende arylmethyl-halogenid under dannelse av det ønskede a-aminosyre-sluttprodukt med den passende a-alkylsubstituent. A convenient method for the preparation of an R^-α-dimethylamino acid is by reaction of the corresponding α-amino compound with formaldehyde in the presence of hydrogen over palladium. Alternatively, when an R 1 -α-alkylamino acid is desired, another suitable method is the reaction of a suitable α-amino acid with ammonia and sodium and a trace of ferric chloride. The product thus formed is treated with p-toluenesulfonyl chloride to form an a-toluenesulfonyl amino acid compound. This compound is then reacted with a base and an alkyl halide, followed by sodium and ammonia and an appropriate arylmethyl halide to form the desired α-amino acid end product with the appropriate α-alkyl substituent.

Racematene kan overføres til deres -1 eller +d form ved en hvilken som helst konvensjonell metode, som dannelse av et salt av den racemiske aminosyre med en optisk aktiv base eller syre, som a-fenethylamin eller vinsyre. Disse optisk aktive salter kan skilles ved fraksjonert krystallisasjon og igjen overføres til den optisk aktive a-aminosyre ved behandling med syre eller base. The racemates can be converted to their -1 or +d form by any conventional method, such as forming a salt of the racemic amino acid with an optically active base or acid, such as α-phenethylamine or tartaric acid. These optically active salts can be separated by fractional crystallization and again transferred to the optically active α-amino acid by treatment with acid or base.

En vanlig syntesemetode som er særlig nyttig ved fremstilling av de optisk aktive isomere av a-aminosyrene, er den reduserende transaminering av en a-ketosyre med et optisk aktivt amin. Denne fremgangsmåte er mere utførlig beskrevet i J. Org. Chem. 3_2_>1790 - 1794 (1967)- Den beskrevne metode kan videre også anvendes ved fremstilling av den racemiske a-aminosyre ved reduserende transaminering av en a-ketosyre med ammoniakk. Fremgangsmåten beskrevet A common synthesis method which is particularly useful in the preparation of the optically active isomers of the α-amino acids is the reductive transamination of an α-keto acid with an optically active amine. This method is described in more detail in J. Org. Chem. 3_2_>1790 - 1794 (1967)- The described method can also be used in the preparation of the racemic α-amino acid by reductive transamination of an α-keto acid with ammonia. The procedure described

i ovennevnte publikasjon, anvender palladium-på-trekull som reduk-sjonsmiddel, men andre kjemiske reduksjonsmidler kan likeledes anvendes . in the above-mentioned publication, uses palladium-on-charcoal as reducing agent, but other chemical reducing agents can also be used.

De ønskede estere og amider fåes ifølge oppfinnelsen ved for-estring av den tilsvarende frie syre under anvendelse av den passende alkohol for å få den ønskede estergruppe eller ved amidering av esterforbindelsen med det passende amin for å få den ønskede amid-gruppe. Hvilke som helst velkjente reaksjonsbetingelser kan anvendes ved fremstilling av disse estere eller amider, som omsetning av a-aminosyren med alkohol i nærvær av mineralsyre ved forhøyet tempera-tur eller omsetning av en a-aminosyreester (som en alkylester) med ammoniakk eller et passende R2~amin ved temperaturer ved eller under værelset emperat ur. The desired esters and amides are obtained according to the invention by esterification of the corresponding free acid using the appropriate alcohol to obtain the desired ester group or by amidation of the ester compound with the appropriate amine to obtain the desired amide group. Any well-known reaction conditions can be used in the preparation of these esters or amides, such as reaction of the α-amino acid with alcohol in the presence of mineral acid at elevated temperature or reaction of an α-amino acid ester (such as an alkyl ester) with ammonia or a suitable R2 ~amine at temperatures at or below room temperature.

Ønskede estere og amider kan dessuten fremstilles direkte ved foreliggende fremgangsmåte. Desired esters and amides can also be produced directly by the present process.

En annen bekvem metode for fremstilling av en R^-a-dimethyl-aminoester eller -amid er ved omsetning av den tilsvarende a-aminoforbindelse med formaldehyd i nærvær av hydrogen over palladium eftersom a-dimethylaminosyren dannes. Another convenient method for the preparation of an R 2 -α-dimethyl amino ester or amide is by reacting the corresponding α-amino compound with formaldehyde in the presence of hydrogen over palladium since the α-dimethylamino acid is formed.

a-guanidino-aminosyreforbindelsene fremstilles ifølge oppfinnelsen ved omsetning av den passende a-aminosyreforbindelse med S-methylisothioureasulfat i nærvær av ammoniakk. The α-guanidino-amino acid compounds are prepared according to the invention by reacting the appropriate α-amino acid compound with S-methylisothioureasulfate in the presence of ammonia.

Følgende eksempler skal gies for å illustrere oppfinnelsen ytterligere. The following examples shall be given to further illustrate the invention.

Eksempel 1 Example 1

S-( p- kldrfenyldifenylmethyl)- L- cystein S-(p-kldrphenyldiphenylmethyl)-L-cysteine

Til en omrørt blanding av 6,05 g (0,05 mol) L-cystein i ca. 150 ml flytende ammoniakk som koker under tilbakeløp, tilsettes por-sjonsvis 15,6 g (0,05 mol) klor-(p-klorfenyl)-difenylmethan. Reaksjonsblandingen ble omrørt inntil man fikk en klar oppløsning hvorpå ammoniakken fikk lov til å fordampe.Blandingen ble så behandlet med vann og produktet fraskilt fra den vandige blanding og vasket omhyggelig med koldt vann-ether, og filtrert. Produktet ble oppsamlet ved filtrering og hadde smeltepunkt l6o - l62°C. To a stirred mixture of 6.05 g (0.05 mol) L-cysteine for approx. 15.6 g (0.05 mol) of chloro-(p-chlorophenyl)-diphenylmethane are added in portions to 150 ml of liquid ammonia which boils under reflux. The reaction mixture was stirred until a clear solution was obtained whereupon the ammonia was allowed to evaporate. The mixture was then treated with water and the product separated from the aqueous mixture and washed carefully with cold water-ether, and filtered. The product was collected by filtration and had a melting point of 160 - 162°C.

Eksempel 2 Example 2

S-t ris-(m-fluorfenyl)-methyl-p-ethyl-DL-cystein-methylester-hydroklorid S-t rice-(m-fluorophenyl)-methyl-p-ethyl-DL-cysteine methyl ester hydrochloride

Til 200 ml vannfri methanol ble tilsatt 44,6 g (0,10 mol) S-t ris-(m-fluorfenyl)-methyl-p-ethyl-DL-cystein. En langsom strøm av tørr hydrogenkloridgass ble innført mens blandingen ble holdt ved svak tilbakeløpskokning under omrøring i 3 timer. Den dannede opp-løsning ble inndampet i vakuum, og residuet ble krystallisert fra en blanding av methanol og ether, hvilket ga S-tris-(m-fluorfenyl)-methyl-p-ethyl-DL-cystein-methylester-hydroklorid. To 200 ml of anhydrous methanol was added 44.6 g (0.10 mol) S-tris-(m-fluorophenyl)-methyl-p-ethyl-DL-cysteine. A slow stream of dry hydrogen chloride gas was introduced while the mixture was maintained at gentle reflux with stirring for 3 hours. The resulting solution was evaporated in vacuo, and the residue was crystallized from a mixture of methanol and ether, giving S-tris-(m-fluorophenyl)-methyl-p-ethyl-DL-cysteine methyl ester hydrochloride.

Eksempel 3 Example 3

S- tris-( m- fluorfenyl)- methyl- P- ethyl- DL- cysteinamid- hydroklorid S- tris-(m- fluorophenyl)- methyl- P- ethyl- DL- cysteinamide hydrochloride

Til 250 ml methanol mettet ved 0°C med ammoniakk ble tilsatt 49,6 g (0,10 mol) S-tris-(m-fluorfenyl)-methyl-p-ethyl-DL-cystein-methyléster-hydroklorid. Den dannede oppløsning fikk"lov til å stå i 4 dager ved 20°C. OpplØsningsmidlet ble fordampet i vakuum og residuet krystallisert fra en blanding av alkohol og ether, hvilket ga S-tris-(m-fluorfenyl)-methyl-p-ethyl-DL-cysteinamid-hydroklbrid. To 250 ml of methanol saturated at 0°C with ammonia was added 49.6 g (0.10 mol) of S-tris-(m-fluorophenyl)-methyl-p-ethyl-DL-cysteine methyl ester hydrochloride. The resulting solution was allowed to stand for 4 days at 20°C. The solvent was evaporated in vacuo and the residue crystallized from a mixture of alcohol and ether to give S-tris-(m-fluorophenyl)-methyl-p-ethyl -DL-cysteinamide hydrochloride.

Eksempel- 4 Example- 4

S- t ris -( m- fluorfenyl)- methyl- g- ethyl- N, N- dimethyl- DL- cystein S- tri -( m- fluorophenyl)- methyl- g- ethyl- N, N- dimethyl- DL- cysteine

En blanding av 11,1 g (0,025 mol) S-t ris-(m-fluorfenyl)-methyl-P-ethyl-DL-cystein og 9,0 ml 40%-ig vandig formaldehyd i 200 ml A mixture of 11.1 g (0.025 mol) S-tris-(m-fluorophenyl)-methyl-P-ethyl-DL-cysteine and 9.0 ml of 40% aqueous formaldehyde in 200 ml

vann ble hydrogenert i nærvær av 11 g 10%-ig palladium-på-trekull, water was hydrogenated in the presence of 11 g of 10% palladium-on-charcoal,

og den teoretiske mengde hydrogen ble opptatt ved rystning over natten ved værelsetemperatur. Katalysatoren ble fjernet ved filtrering og filtratet inndampet i vakuum. and the theoretical amount of hydrogen was taken up by shaking overnight at room temperature. The catalyst was removed by filtration and the filtrate evaporated in vacuo.

Residuet ble tatt opp i kokende aceton, og S-tris-(m-fluor-fenyl)-methyl-p-ethyl-N,N-dimethyl-DL-cystein avsattes ved avkjøling. The residue was taken up in boiling acetone, and S-tris-(m-fluoro-phenyl)-methyl-p-ethyl-N,N-dimethyl-DL-cysteine was deposited on cooling.

Eksempel 5 Example 5

a-guanidino-p-[S-tris-(m-fluorfenyl)-met hylthio]- valeriansyre α-guanidino-p-[S-tris-(m-fluorophenyl)-methylthio]-valeric acid

En oppløsning av 26,7 g (0,06 mol) S-tris-(m-fluorfenyl)-methyl-p-ethyl-DL-cystein i 100 ml vann og 30 ml konsentrert vandig ammoniakk ble behandlet med 27,8 g (0,10 mol) S-methylisothioureasulfat tilsatt i små porsjoner under kraftig omrøring i løpet av ca. 30 minutter. Den dannede oppløsning ble omrørt i 20 timer ved værelsetemperatur. Det krystalliserte produkt ble oppsamlet efter grundig avkjøling av reaksjonsblandingen og ble vasket med vann og alkohol. Krystallisasjon fra en blanding av vann og alkohol ga ren a-guanidino-p-[S-t ris-(m-fluorfenyl)-methylthio]-valeriansyre. A solution of 26.7 g (0.06 mol) of S-tris-(m-fluorophenyl)-methyl-p-ethyl-DL-cysteine in 100 ml of water and 30 ml of concentrated aqueous ammonia was treated with 27.8 g ( 0.10 mol) S-methylisothiourea sulfate added in small portions with vigorous stirring during approx. 30 minutes. The resulting solution was stirred for 20 hours at room temperature. The crystallized product was collected after thorough cooling of the reaction mixture and was washed with water and alcohol. Crystallization from a mixture of water and alcohol gave pure α-guanidino-p-[S-tris-(m-fluorophenyl)-methylthio]-valeric acid.

Eksempel 6 Example 6

S- t ris-( m- f luorf enyl) - met hy 1 - g - et hy 1- N - met hyl - DL- cy st ein S- t ris-( m- f luorf enyl) - met hy 1 - g - et hy 1- N - met hyl - DL- cy st ein

I. Di- p- toluensulfonyl- 3- ethy1- DL- cystin I. Di-p-toluenesulfonyl-3-ethyl-DL-cystine

Til en oppløsning av 0,05 mol S-t ris - (m-f luorf enyl) -methyl-f3 - ethyl-DL-cystein i 400 ml flytende ammoniakk ble tilsatt små stykker natriummetall, langsomt og under omrøring, inntil en varig blåfarge viser seg. Fargen fjernes såvidt med ammoniumklorid, og derpå tilsettes ytterligere ammoniumklorid, ekvivalent med den anvendte mengde natrium. Reaksjonsblandingen fikk stå over natten for å tillate ammoniakken å fordampe. Residuet ble oppløst i vann og oppløsningen ekstrahert omhyggelig med ether. pH av den vandige fase ble innstilt på ca. 8, et spor av ferriklorid ble tilsatt og oppløsningen inndampet til lite volum hvorpå 3-ethyl-DL-cystin krystallase rte. To a solution of 0.05 mol of S-tris-(m-fluorophenyl)-methyl-f3-ethyl-DL-cysteine in 400 ml of liquid ammonia was added small pieces of sodium metal, slowly and with stirring, until a permanent blue color appeared. The color is almost removed with ammonium chloride, and then further ammonium chloride, equivalent to the amount of sodium used, is added. The reaction mixture was allowed to stand overnight to allow the ammonia to evaporate. The residue was dissolved in water and the solution carefully extracted with ether. The pH of the aqueous phase was adjusted to approx. 8, a trace of ferric chloride was added and the solution evaporated to a small volume whereupon 3-ethyl-DL-cystine crystallase reacted.

En oppløsning av 14,8 g (0,05 mol) (3-ethyl-DL-cystin i lOO ral A solution of 14.8 g (0.05 mol) (3-ethyl-DL-cystine in lOO ral

I N vandig natriumhydroxyd ble omrørt kraftig mens en oppløsning av 38 g p-toluensulfonylklorid i 100 ml ether ble tilsatt i 10 porsjoner med 15 minutters mellomrom. Før hver porsjon ble der tilsatt 10. ml 2 N vandig natriumhydroxydoppløsning. Når tilsetningen var av-sluttet , ble blandingen omrørt i ytterligere 30 minutter. Ether-skiktet ble fjernet, og det vandige skikt ble ekstrahert med 100 ml frisk ether. Oppløst ether ble fjernet fra vannfasen ved oppvarmning, og derpå ble den varmeopoppløsning syret ved tilsetning av konsentrert saltsyre under kraftyg rysting. Di-p-toluensulfonyl-Ø-ethyl-DL-cystin krystalliserte og ble, efter omhyggelig avkjøling, oppsamlet ved filtrering. I N aqueous sodium hydroxide was stirred vigorously while a solution of 38 g of p-toluenesulfonyl chloride in 100 ml of ether was added in 10 portions at 15 minute intervals. Before each portion, 10 ml of 2 N aqueous sodium hydroxide solution was added. When the addition was complete, the mixture was stirred for a further 30 minutes. The ether layer was removed and the aqueous layer was extracted with 100 ml of fresh ether. Dissolved ether was removed from the water phase by heating, and then the heated solution was acidified by the addition of concentrated hydrochloric acid under vigorous shaking. Di-p-toluenesulfonyl-Ø-ethyl-DL-cystine crystallized and, after careful cooling, was collected by filtration.

II . S- t ris -( m- fluorfenyl)- methyl- fl- ethyl- N- methyl- DL- cystein II. S- tri -( m- fluorophenyl)- methyl- fl- ethyl- N- methyl- DL- cysteine

Til 5,5 g (0,0091 mol) di-p-toluensulfonyl-|3-ethyl-DL-cystin, oppløst i 55 ml 1 N vandig natriumhydroxydoppløsning, ble tilsatt. 2,3 ml methyljodid. Efter oppvarmning til ca. 70°C ble blandingen rystet kraftig inntil methyljodidskiktet forsvant. Efter at opp-løsningen var avkjølt, ble den ekstrahert med ether.Vannskiktet ble dekket med 100 ml ether og syret sterkt med saltsyre.Vannskiktet ble så reekstrahert med små porsjoner ether inntil det ga negativ prøve på disulfid. De forenede etherekstrakter ble vasket med vann inneholdende en liten mengde natriumbisulfit , og inndampet i vakuum. Residuet ble tatt opp i ca. 200 ml flytende ammoniakk, og natrium ble tilsatt i små stykker under omrøring inntil en permanent blå farge forble. Overskudd av natrium ble ødelagt med ammoniumklorid [i noen tilfelle hvor arylmethylhalogenidet ikke er så reaktivt at solvolyse er hovedreaksjonen i flytende ammoniakk (spesielt med tri-tylhalogenider), må fremgangsmåten modifiseres på dette punkt ved å tillate ammoniakken å fordampe og erstatte den med dimethylformamid],°g 6,7 g (0,02 mol) klor-tris-(m-fluorfenyl)-methan tilsettes langsomt. Ammoniakken får lov til å fordampe, og 5o ml isvann tilsettes ''til residuet. Den dannede oppløsning ekstraheres to ganger med ether og syres så til pH ca. 6 med saltsyre. Bunnfallet av S-tris-(m-fluorfenyl)-methyl-3-ethyl-N-methyl-DL-cystein ble oppsamlet ved filtrering og vasket efter hverandre med vann, alkohol og ether. To 5.5 g (0.0091 mol) of di-p-toluenesulfonyl-|3-ethyl-DL-cystine, dissolved in 55 ml of 1 N aqueous sodium hydroxide solution, was added. 2.3 ml methyl iodide. After heating to approx. 70°C, the mixture was shaken vigorously until the methyl iodide layer disappeared. After the solution had cooled, it was extracted with ether. The aqueous layer was covered with 100 ml of ether and strongly acidified with hydrochloric acid. The aqueous layer was then re-extracted with small portions of ether until it gave a negative test for disulfide. The combined ether extracts were washed with water containing a small amount of sodium bisulphite, and evaporated in vacuo. The residue was taken up in approx. 200 ml of liquid ammonia, and sodium was added in small portions with stirring until a permanent blue color remained. Excess sodium was destroyed with ammonium chloride [in some cases where the arylmethyl halide is not so reactive that solvolysis is the main reaction in liquid ammonia (especially with trityl halides), the procedure must be modified at this point by allowing the ammonia to evaporate and replacing it with dimethylformamide] ,°g 6.7 g (0.02 mol) of chloro-tris-(m-fluorophenyl)-methane is added slowly. The ammonia is allowed to evaporate, and 50 ml of ice water is added to the residue. The resulting solution is extracted twice with ether and then acidified to a pH of approx. 6 with hydrochloric acid. The precipitate of S-tris-(m-fluorophenyl)-methyl-3-ethyl-N-methyl-DL-cysteine was collected by filtration and washed successively with water, alcohol and ether.

Claims

1. Analogy method for the production of therapeutically active α-amino acid compounds of the formula:

where R is hydrogen, halo-lower alkyl, hydroxy, halogen, lower alkylthio, lower alkoxy, nitro, lower alkyl or methylenedioxy, R^ is hydrogen, lower alkyl or phenyl, is hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, amino, lower alkylamino, di-lower alkylamino, or OZ, where Z is a cation, R^ and R^ are hydrogen or lower alkyl, R^ and R^ are hydrogen, lower alkyl or lower alkanoyl, and when R^ is hydrogen, R^ may also be guanyl; and R^ and R'g are hydrogen, lower alkyl, phenyl, naphthyl, thienyl, pyridyl or substituted phenyl in which the substituents are R(]__^)5, Rg and R'g may be the same or different, with the following exceptions:

(1) when R^ and R^ are phenyl, at least In of R, R-p R^, R<1>^»R^°S R5 is different from hydrogen:,

(2) when R₂ is phenyl and R₂ is hydrogen or an alkoxy group, at least one of R₂ R₂, R₂, R₂, R₂ and R₂ is different from hydrogen;

(3) when R'g is hydrogen and R is hydrogen, In alkoxy or nitro group or one halogen atom, at least one of Rp R^, R^, R^, R^9g Rg is different from hydrogen; (k) and when R^ is alkanoyl, at least one of R, R^, R^, R^, R^, R^ and R^ is different from hydrogen, characterized in that an α-substituted benzyl halide of the formula:

where R, R^ and R^ are as indicated above, and X is halogen, is reacted with a cysteine compound of the formula:

where Rp R^, R^, R)+ and R^ are as indicated above, R^ is hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, amino, lower alkylamino or di-lower alkylamino, and the compound obtained, if desired , is transferred to the free acid, a salt, an ester or an amide thereof in a manner known per se, and/or that in the resulting compound where R^ and/or R^ is H, other desired R^- and/or R^--substituents in a manner known per se.

2. Procedure according to claim 1, characterized in that starting materials are used where R is halogen, R^, R^, Rp R^ and R^ are all hydrogen, R^ is hydroxy, and R^ and R^ are hydrogen, phenyl or halophenyl.