NO152128B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3-BENZOYLPHENYL ACETAMIDES - Google Patents

ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3-BENZOYLPHENYL ACETAMIDES Download PDF

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NO152128B
NO152128B NO802834A NO802834A NO152128B NO 152128 B NO152128 B NO 152128B NO 802834 A NO802834 A NO 802834A NO 802834 A NO802834 A NO 802834A NO 152128 B NO152128 B NO 152128B
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amino
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mol
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phenylacetamide
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NO802834L (en
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James Robert Shanklin Jr
Dwight Allan Shamblee
David Allen Walsh
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Robins Co Inc A H
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms

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Description

Foreliggende oppfinnelse angår analogifremgangsmåter ved fremstilling av visse nye 2-amino-3-benzoylfenylacetamider og heterocycliske derivater derav med anti-inflammatorisk, antipyretisk, analgetisk og blodplateaggregerings-inhiberende virkning, som oppviser minimale uønskede bivirkninger av gastrisk irritasjon ved oral administrasjon til levende dyr. The present invention relates to analogous methods for the production of certain new 2-amino-3-benzoylphenylacetamides and heterocyclic derivatives thereof with anti-inflammatory, antipyretic, analgesic and platelet aggregation-inhibiting action, which exhibit minimal unwanted side effects of gastric irritation when administered orally to live animals.

2-amino-3-benzoylfenyleddiksyrer, estere og metallsalter derav med anti-inflammatorisk aktivitet og blodplateaggreger-ingsinhiberende egenskaper er kjent fra U.S. patent 4 045 576. 2-amino-3-benzoylphenylacetic acids, esters and metal salts thereof with anti-inflammatory activity and platelet aggregation inhibitory properties are known from U.S. Pat. patent 4,045,576.

Sydafrikansk patent 68/4682 angår benzoylfenylacetamider generisk med en rekke substituenter i forskjellige still-inger på fenylgruppen. Ingen av de spesifikt angitte forbindelser er aminofenylacetamider. South African patent 68/4682 concerns benzoylphenylacetamides generically with a number of substituents in different positions on the phenyl group. None of the specifically stated compounds are aminophenylacetamides.

Stort sett har tidligere sterkt anti-inflammatoriske droger vist seg å ha alvorlige bivirkninger med hensyn til gastrisk blødning og ulcerering når administrert oralt til dyr i det effektive område. Forbindelsene som fremstilles ifølge foreliggende oppfinnelse, har vist seg å ha den fordel at de har ekstremt lave forekomster av gastrisk irritasjon når administrert i området effektivt for å redusere inflammasjon sammenlignet med indomethacin og de mindre irriterende 2-amino-3-benzoylfenyleddiksyrer angitt i U.S. patent 4 045 576. For the most part, previously strongly anti-inflammatory drugs have been shown to have serious side effects with respect to gastric bleeding and ulceration when administered orally to animals in the effective range. The compounds prepared according to the present invention have been shown to have the advantage of having extremely low incidences of gastric irritation when administered in the area effective for reducing inflammation compared to indomethacin and the less irritating 2-amino-3-benzoylphenylacetic acids listed in U.S. Pat. patent 4,045,576.

Forbindelsene som fremstilles ifølge foreliggende oppfinnelse, er 2-amino-3-benzoylfenylacetamider med den generelle formel: The compounds produced according to the present invention are 2-amino-3-benzoylphenylacetamides with the general formula:

hvor where

R er hydrogen eller lavere alkyl, R is hydrogen or lower alkyl,

R 1 og R 2er hydrogen, lavere alkyl, cycloalkyl, fenyl eller fenyl substituert med lavere alkyl, lavere alkoxy, halogen, R 1 and R 2 are hydrogen, lower alkyl, cycloalkyl, phenyl or phenyl substituted with lower alkyl, lower alkoxy, halogen,

1 2 1 2

nitro og/eller trifluormethyl, eller R og R kan sammen med det tilstøtende nitrogen danne en heterocyclisk gruppe, nitro and/or trifluoromethyl, or R and R together with the adjacent nitrogen can form a heterocyclic group,

X er hydrogen, lavere alkyl, lavere alkoxy, halogen eller trifluormethyl, X is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl,

Y er hydrogen, lavere alkyl, lavere alkoxy, halogen, trifluormethyl, lavere alkylthio, lavere alkyloxythio eller lavere alkyldioxythio, Y is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylthio, lower alkyloxythio or lower alkyldioxythio,

Am er primær amino (-NH2), methylamino eller dimethylamino, og n er 1, 2 eller 3, Am is primary amino (-NH2), methylamino or dimethylamino, and n is 1, 2 or 3,

De nye forbindelser med formel I har verdifulle farma-kologiske egenskaper og er nyttige når de administreres innvendig i effektiv mengde til å lindre inflammasjon, lindre smerte i dyr som lider av smerte, inhibere blodplateaggregering og bekjempe temperaturstigning i levende dyr, The new compounds of formula I have valuable pharmacological properties and are useful when administered internally in an effective amount to relieve inflammation, relieve pain in animals suffering from pain, inhibit platelet aggregation and combat temperature rise in live animals,

men med minimale bivirkninger sammenlignet med noen andre sterke anti-inflammasjonsmidler. Illustrerende for den anti-inf lammatoriske aktivitet med minimale bivirkninger er forbindelsen ifølge eksempel 3; dvs. 2-amino-3-(4-klorbenzoyl)-fenylacetamid som ble funnet å ha omtrent samme styrke som indomethacin, men oppviste omtrent bare 1/100 så meget irritasjon på maven som indomethacin. Ennvidere ble forbindelsen ifølge eksempel 2, nemlig 2-amino-3-benzoylfenylacetamid, funnet å være 8 ganger mer aktiv som anti-inf lammatorisk middel enn det tilsvarende 4-amino-3-benzoylfenylacetamid samtidig som den utviste bare 1/10 av den mageirritasjon som det tilsvarende ethyl-2-amino-3-benzoyl-fenylacetat. but with minimal side effects compared to some other strong anti-inflammatories. Illustrative of the anti-inflammatory activity with minimal side effects is the compound according to example 3; ie, 2-amino-3-(4-chlorobenzoyl)-phenylacetamide which was found to be about the same potency as indomethacin, but only about 1/100 as much gastric irritation as indomethacin. Furthermore, the compound of Example 2, namely 2-amino-3-benzoylphenylacetamide, was found to be 8 times more active as an anti-inflammatory agent than the corresponding 4-amino-3-benzoylphenylacetamide while exhibiting only 1/10 of the gastric irritation as the corresponding ethyl 2-amino-3-benzoyl-phenylacetate.

Den anti-inflammatoriske aktivitet ble påvist i labora-toriedyr under anvendelse av en modifikasjon av Evans-Blue Carrageenan Pleural Effusion Assay of Sancilio, L. F., The anti-inflammatory activity was demonstrated in laboratory animals using a modification of the Evans-Blue Carrageenan Pleural Effusion Assay of Sancilio, L. F.,

J. Pharmacol. Exp. Ther. 168, 199-204 (1969). J. Pharmacol. Exp. Ther. 168, 199-204 (1969).

Forbindelsene med formel I oppviser inhibering av plateaggregering i forsøksmetoden beskrevet av Born, J. of Phys. 162, 67-68 p. (1962) og Evans et al., J. of Expt. Med. 128, 877-894 (1968). Forsøksdrogene administreres til rotter, og efter 2 timer tappes blod fra rottene, og et platerikt plasma erholdes. Collagen ble tilsatt til det platerike plasma for å indusere plateaggregering, og sammenligninger ble gjort mellom kontrollprøver og prøver fra behandlede dyr. The compounds of formula I show inhibition of plaque aggregation in the test method described by Born, J. of Phys. 162, 67-68 pp. (1962) and Evans et al., J. of Expt. With. 128, 877-894 (1968). The test drugs are administered to rats, and after 2 hours blood is drawn from the rats, and a platelet-rich plasma is obtained. Collagen was added to the platelet-rich plasma to induce platelet aggregation, and comparisons were made between control samples and samples from treated animals.

Forbindelsene med formel I virker også som analgetica som bestemt ved Bradykinin Analgetic Test Method ifølge Dickerson et al., Life Sei. 4, 2063-2069 (1965) som modifisert av Sancilio og Cheung, Fed. Proe. 35, 774 (1976). The compounds of formula I also act as analgesics as determined by the Bradykinin Analgesic Test Method of Dickerson et al., Life Sci. 4, 2063-2069 (1965) as modified by Sancilio and Cheung, Fed. Pro. 35, 774 (1976).

Antipyretisk aktivitet av forbindelsene med formel I fremgår av senkningen av den febrile respons i hypertermiske dyr uten å påvirke den rektale temperatur eller normotermiske dyr. Hypertermisk respons bevirket av subcutan injeksjon av Brewer<1>s gjær i rotter overvinnes ved oral administrasjon av så lite som 4-8 mg/kg av forbindelser med formel I, og ingen betydningsfull forandring i rektal temperatur hos normotermiske rotter iakttaes. Antipyretic activity of the compounds of formula I is evident from the lowering of the febrile response in hyperthermic animals without affecting the rectal temperature or normothermic animals. Hyperthermic response induced by subcutaneous injection of Brewer<1>'s yeast in rats is overcome by oral administration of as little as 4-8 mg/kg of compounds of formula I, and no significant change in rectal temperature in normothermic rats is observed.

De etterfølgende terapeutiske data illustrerer den aktivitet som utvises av de nye forbindelser. The following therapeutic data illustrate the activity exhibited by the new compounds.

(2) Forbindelsen ifølge eksempel 3 nedsatte effektivt den rektale temperatur i hypertermiske rotter ved en oral dose på 4 mg/kg administrert 3-5 timer etter administrering. (3) Collagenindusert blodplateaggregering ble inhibert ved 4 mg/kg oral dose av: (2) The compound of Example 3 effectively decreased the rectal temperature in hyperthermic rats at an oral dose of 4 mg/kg administered 3-5 hours after administration. (3) Collagen-induced platelet aggregation was inhibited at a 4 mg/kg oral dose of:

forbindelse iflg. eks. 2: -66% connection according to e.g. 2: -66%

forbindelse iflg. eks. 3: -78% connection according to e.g. 3: -78%

forbindelse iflg. eks. 7: -80% connection according to e.g. 7: -80%

Det er således et mål ved foreliggende oppfinnelse å fremskaffe nye forbindelser for behandling av levende dyr og særlig pattedyr i den hensikt å lindre inflammasjon og smerte, inhibere blodplateaggregering og behandle febere alt med et minimum av uønskede bivirkninger i det gastriske og intestinale område. It is thus an aim of the present invention to provide new compounds for the treatment of living animals and especially mammals with the aim of alleviating inflammation and pain, inhibiting platelet aggregation and treating fever, all with a minimum of unwanted side effects in the gastric and intestinal area.

I definisjoner av symboler i formlene og hvor de ellers opptrer i beskrivelsen, har uttrykkene følgende betydninger. In definitions of symbols in the formulas and where else they appear in the description, the expressions have the following meanings.

Uttrykket "lavere alkyl" er her anvendt for å omfatte rett-kjedede og forgrenede radikaler med inntil 8 carbonatomer og er eksemplifisert ved slike grupper som methyl, ethyl, propyl, isopropyl, butyl, sek-butyl, t-butyl, amyl, isoamyl, hexyl, heptyl og octyl. Uttrykket "lavere alkoxy" har formelen -0-lavere alkyl. The term "lower alkyl" is used here to include straight-chain and branched radicals with up to 8 carbon atoms and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl, isoamyl, hexyl, heptyl and octyl. The term "lower alkoxy" has the formula -O-lower alkyl.

Uttrykket "halogen" er her anvendt for å betegne fluor, klor, brom og jod, fortrinnsvis fluor, klor og brom. The term "halogen" is used here to denote fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

Uttrykket "cycloalkyl" er her anvendt for å omfatte først og fremst cycliske alkylgrupper med 3-12 carbonatomer, og innbefatter slike grupper som cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl og lignende. The term "cycloalkyl" is used here to include primarily cyclic alkyl groups with 3-12 carbon atoms, and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Uttrykket heterocyclisk gruppe refererer til radikaler som morfolino, pyrrolidino, piperidino, piperazino og lignende . The term heterocyclic group refers to radicals such as morpholino, pyrrolidino, piperidino, piperazino and the like.

Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at The analogy method according to the invention is characterized in that

(a) en forbindelse med formel I hvor R, R 1 , R 2, Am, X og n er som ovenfor angitt, og Y er hydrogen, lavere alkyl, lavere alkoxy, halogen eller trifluormethyl, fremstilles ved å redusere en forbindelse med formelen: (a) a compound of formula I wherein R, R 1 , R 2 , Am, X and n are as above, and Y is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, is prepared by reducing a compound of the formula :

hvor where

R<3> er fenyl eller lavere alkyl, eller R<3> is phenyl or lower alkyl, or

(b) en forbindelse med formel I hvor R, R , R , Am, X og n er som ovenfor angitt, og Y er lavere alkylthio, fremstilles ved å omsette en forbindelse med formel: (b) a compound of formula I wherein R, R , R , Am, X and n are as above, and Y is lower alkylthio, is prepared by reacting a compound of formula:

1 2 1 2

hvor R, R , R og Am er som ovenfor angitt, med en forbindelse med formelen: where R, R , R and Am are as above, with a compound of the formula:

NaS-lavere alkyl, NaS-lower alkyl,

eller or

(c) en forbindelse med formel I, hvor Y er lavere alkyloxythio eller lavere alkyldioxythio, fremstilles ved å oxydere en forbindelse-med formelen: (c) a compound of formula I, where Y is lower alkyloxythio or lower alkyldioxythio, is prepared by oxidizing a compound of the formula:

hvor R, R 1 , R 2 og Am er som ovenfor angitt, eller where R, R 1 , R 2 and Am are as indicated above, or

1 2 (d) en forbindelse med formel I hvor R, R , R , X, Y og n er som ovenfor angitt, og Am er dimethylamino, fremstilles ved å dimethylere en forbindelse med formel I hvor Am er amino. 1 2 (d) a compound of formula I where R, R , R , X, Y and n are as indicated above, and Am is dimethylamino, is prepared by dimethylating a compound of formula I where Am is amino.

Fremgangsmåtealternativ (a) kan illustreres ved følg-ende reaksjonsskjerna: Method alternative (a) can be illustrated by the following reaction core:

1 2 hvor R, R , R , X, Y og n er som ovenfor angitt. Fremgangsmåtealternativ (b) illustreres ved følgende reak-sjonsrekke: mens fremgangsmåtealternativ (c) illustreres ved følgende reaksjoner: 1 2 where R, R , R , X, Y and n are as indicated above. Process alternative (b) is illustrated by the following reaction sequence: while process alternative (c) is illustrated by the following reactions:

Forbindelsene med formel I hvor Am er dimethylamino, The compounds of formula I where Am is dimethylamino,

kan ifølge fremgangsmåtealternativ (d) fremstilles ved å omsette den tilsvarende 2-aminoforbindelse med natriumcyano-borhydrid, formaldehyd, acetonitril og eddiksyre. can be prepared according to process alternative (d) by reacting the corresponding 2-amino compound with sodium cyanoborohydride, formaldehyde, acetonitrile and acetic acid.

Fremstillingen av mellomprodukter med formel II er mere fullstendig beskrevet i Fremstilling 6-15. I alminnelighet fremstilles disse mellomprodukter ved først å omsette de passende 2-aminobenzofenoner med t-butylhypoklorit og det passende thioacetamid koldt (-60° til -70°C) fulgt av tilsetning av triethylamin. The preparation of intermediates of formula II is more fully described in Preparation 6-15. In general, these intermediates are prepared by first reacting the appropriate 2-aminobenzophenones with t-butyl hypochlorite and the appropriate thioacetamide cold (-60° to -70°C) followed by the addition of triethylamine.

Mellomproduktene med formel II reduseres med Raney-nikkel til forbindelser med formel I i oppløsningsmiddel unn-tatt når Y er -S-lavere alkyl som tetrahydrofuran og isoleres ved å fjerne oppløsningsmidlet og krystallisere. Forbindelser med formel I fremstilles som illustrert i den foregående ligning på grunn av forstyrrelse av Raney-nikkel på -S-lavere alkyl i reduksjonstrinnet. The intermediates of formula II are reduced with Raney nickel to compounds of formula I in solvent except when Y is -S-lower alkyl such as tetrahydrofuran and isolated by removing the solvent and crystallizing. Compounds of formula I are prepared as illustrated in the preceding equation due to interference of Raney nickel on -S-lower alkyl in the reduction step.

Fremstilling 1 Production 1

4-[ 2-( methylthioacetyl)]- morfolin 4-[2-(methylthioacetyl)]-morpholine

En blanding av 40,2 g (0,3 mol) ethyl-methylthioacetat og 130 g (1,5 mol) morfolin ble oppvarmet under tilbakeløp i 70 timer. Fraksjonert destillasjon ved nedsatt trykk ga 45 g (86%) av produktet med kokepunkt 104-105°C/0,05 mm Hg ved annen destillasjon. A mixture of 40.2 g (0.3 mol) ethyl methylthioacetate and 130 g (1.5 mol) morpholine was heated under reflux for 70 hours. Fractional distillation at reduced pressure gave 45 g (86%) of the product with boiling point 104-105°C/0.05 mm Hg by second distillation.

Analyse: Beregn, for <C>7H13N02S: C 47,98; H 7,48; N 7,99 Analysis: Calculate, for <C>7H13N02S: C 47.98; H 7.48; N 7.99

Funnet: C 47,55; H 7,59; N 8,18 Found: C 47.55; H 7.59; N 8,18

Fremstilling 2 Manufacturing 2

2- methylthio- N- methylacetamid 2-methylthio-N-methylacetamide

En blanding av 134 g (1,0 mol) ethyl-methylthioacetat A mixture of 134 g (1.0 mol) ethyl methyl thioacetate

og 310 g (10,0 mol) methylamin ble oppvarmet i en bombe ved 150°C i 72 timer. Overskudd av amin og ethanolen dannet ble fjernet ved destillasjon, og den gjenværende tynne sirup ble destillert, hvorved man fikk 112 g (94%) av tittelforbindelsen som en farveløs væske med kokepunkt 76-78°C/0,4 mm Hg. Analyse: Beregn, for C^HgNOS: C 40,31; H 7,61; N 11,75 and 310 g (10.0 mol) methylamine was heated in a bomb at 150°C for 72 hours. Excess amine and the ethanol formed were removed by distillation, and the remaining thin syrup was distilled to give 112 g (94%) of the title compound as a colorless liquid, bp 76-78°C/0.4 mm Hg. Analysis: Calculate, for C 2 H 2 NOS: C 40.31; H 7.61; N 11.75

Funnet: C 39,78; H 7,69; N 11,88 Found: C 39.78; H 7.69; N 11.88

Fremstilling 3 Manufacturing 3

2- methylthio- N, N- dimethylacetamid 2-methylthio-N,N-dimethylacetamide

En blanding av 134 g (1,0 mol) ethyl-methylthioacetat A mixture of 134 g (1.0 mol) ethyl methyl thioacetate

og 360 g (8,0 mol) dimethylamin ble oppvarmet i en bombe ved 150°C i 90 timer. Overskudd av amin og ethanolen fremstilt ble fjernet ved destillasjon, og residuet ble destillert, hvorved man fikk 129 g (97%) av tittelforbindelsen som en klar, farveløs væske med kokepunkt 76-77°C/0,5 mm Hg. and 360 g (8.0 mol) of dimethylamine was heated in a bomb at 150°C for 90 hours. Excess amine and the ethanol produced were removed by distillation, and the residue was distilled to give 129 g (97%) of the title compound as a clear, colorless liquid, bp 76-77°C/0.5 mm Hg.

Analyse: Beregn, for C^H^NOS: C 4 5,08; H 8,32; N 10,51 Analysis: Calculate, for C^H^NOS: C 4 5.08; H 8.32; N 10.51

Funnet: C 43,88; H 8,41; N 10,60 Found: C 43.88; H 8.41; N 10.60

Fremstilling 4 Manufacturing 4

2-( 2- propylthio)- acetamid 2-(2-propylthio)-acetamide

Til en blanding av 4 6,7 g (0,5 mol) 2-kloracetamid i To a mixture of 4 6.7 g (0.5 mol) 2-chloroacetamide i

200 ml absolutt ethanol ble tilsatt i en langsom strøm en oppløsning av 38,1 g (0,5 mol) 2-propanthiol i 100 ml absolutt ethanol og 40 g 50%-ig vandig natriumhydroxyd. 200 ml of absolute ethanol was added in a slow stream to a solution of 38.1 g (0.5 mol) of 2-propanethiol in 100 ml of absolute ethanol and 40 g of 50% aqueous sodium hydroxide.

Blandingen ble oppvarmet under tilbakeløp i 1 time og derpå filtrert. Filtratet ble inndampet under nedsatt trykk, residuet ble oppløst i methylenklorid, og oppløsningen ble tørret over magnesiumsulfat. Blandingen ble filtrert, og filtratet ble igjen inndampet. Ved henstand krystalliserte det sirupsaktige residuum. Omkrystallisasjon fra isopropylether ga 59,0 g (89%) av hvite små plater som smeltet ved 52-54°C. Analyse: Beregn, for C^H^NOS: C 4 5,08; H 8,32; N 10,51 The mixture was heated under reflux for 1 hour and then filtered. The filtrate was evaporated under reduced pressure, the residue was dissolved in methylene chloride, and the solution was dried over magnesium sulfate. The mixture was filtered, and the filtrate was again evaporated. On standing, the syrupy residue crystallized. Recrystallization from isopropyl ether gave 59.0 g (89%) of white small plates melting at 52-54°C. Analysis: Calculate, for C^H^NOS: C 4 5.08; H 8.32; N 10.51

Funnet: C 45,05; H 8,32; N 10,55 Found: C 45.05; H 8.32; N 10.55

Fremstilling 5 Manufacturing 5

2-( 1- propylthio)- acetamid 2-(1-propylthio)-acetamide

Ved å anvende fremgangsmåten i metode 4, men ved å anvende en like stor molarmengde 1-propanthiol istedenfor 2-propanthiol, fikk man 61,2 g (92%) av tittelforbindelsen. De hvite krystaller smeltet ved 49,5-51,0°C. By applying the procedure in method 4, but by using an equal molar amount of 1-propanethiol instead of 2-propanethiol, 61.2 g (92%) of the title compound was obtained. The white crystals melted at 49.5-51.0°C.

Analyse: Beregn, for C^H^NOS: C 45,08; H 8,32; N 10,51 Analysis: Calculate, for C^H^NOS: C 45.08; H 8.32; N 10.51

Funnet: C 44,97; H 8,24; N 10,40 Found: C 44.97; H 8.24; N 10.40

Fremstilling 6 Production 6

2- amiho- 3- benzoyl- 5- klor- ct- ( methylthio) - fenylacetamid 2- amiho- 3- benzoyl- 5- chloro- ct-( methylthio)- phenylacetamide

Til en kold (-70°C) oppløsning av 12,77 g (0,055 mol) 2-amino-5-klorbenzofenon i 300 ml methylenklorid under nitrogenatmosfære, ble tilsatt 6,0 g (0,0552 mol) t-butylhypoklorit i 20 ml methylenklorid. Efter ytterligere 15 minutters om-røring ble en suspensjon av 5,8 g (0,055 mol) et-(methylthio)-acetamid i 150 ml-methylenklorid tilsatt. Blandingen ble omrørt ved -65°C i 1 time. 5,6 g (0,055 mol) triethylamin ble tilsatt, og oppløsningen fikk lov til å oppvarmes til værelsetemperatur. Reaksjonsblandingen ble ekstrahert med flere porsjoner vann, og det organiske skikt ble tørret over magnesiumsulfat. Volumet av oppløsningen ble redusert i vakuum til ca. 200 ml, og produktet krystalliserte som et gult, fast stoff med smp. 173,5-174,5°C. Utbytte var 6,86 g (37,3%). To a cold (-70°C) solution of 12.77 g (0.055 mol) of 2-amino-5-chlorobenzophenone in 300 ml of methylene chloride under a nitrogen atmosphere was added 6.0 g (0.0552 mol) of t-butyl hypochlorite in 20 ml of methylene chloride. After a further 15 minutes of stirring, a suspension of 5.8 g (0.055 mol) of et-(methylthio)-acetamide in 150 ml of methylene chloride was added. The mixture was stirred at -65°C for 1 hour. 5.6 g (0.055 mol) of triethylamine was added and the solution was allowed to warm to room temperature. The reaction mixture was extracted with several portions of water, and the organic layer was dried over magnesium sulfate. The volume of the solution was reduced in vacuo to approx. 200 ml, and the product crystallized as a yellow solid with m.p. 173.5-174.5°C. Yield was 6.86 g (37.3%).

Analyse: Beregn, for C16H15<N>202SC1: C 57,40; H 4,52; N 8,37 Analysis: Calculate, for C16H15<N>202SC1: C 57.40; H 4.52; N 8.37

Funnet: C 57,38; H 4,50; N 8,51 Found: C 57.38; H 4.50; N 8.51

Fremstilling 7 Manufacturing 7

2- amino- 3- benzoyl- ct- ( methylthio) - fenylacetamid 2- amino- 3- benzoyl- ct-( methylthio)- phenylacetamide

Til en kold (-70°C) oppløsning av 19,7 g (0,10 mol) 2-amino-benzofenon i 300 ml methylenklorid under nitrogenatmosfære, ble tilsatt en oppløsning av 11,5 g (0,10 mol) 95%-ig t-butylhypoklorit i 30 ml methylenklorid efter 10 minutter fulgt av en oppløsning av 10,5 g (0,1 mol) methyl-thioacetamid i 300 ml tetrahydrofuran. Temperaturen ble holdt ved eller under -55°C under disse tilsetninger. Efter ytterligere 1 time ved -60°C fikk blandingen lov til å oppvarmes til værelsetemperatur, og bunnfallet ble oppsamlet ved filtrering. Bunnfallet ble oppslemmet i 200 ml methylenklorid, og 11 g (0,11 mol) triethylamin ble tilsatt. Blandingen ble omrørt i 5 minutter. Oppløsningen ble vasket to ganger med 100 ml vann, og den organiske fase ble tørret over magnesiumsulfat og inndampet under nedsatt trykk. Residuet ble vasket med diethylether og tørret, hvorved man fikk 13,0 g (43%) av et lysegult pulver med smp. 153-155°C. Analyse: Beregn, for C16H16<N>2°2S: C 63'98' H 5»37? N 9'33 To a cold (-70°C) solution of 19.7 g (0.10 mol) of 2-amino-benzophenone in 300 ml of methylene chloride under a nitrogen atmosphere, was added a solution of 11.5 g (0.10 mol) of 95% -ig of t-butyl hypochlorite in 30 ml of methylene chloride after 10 minutes followed by a solution of 10.5 g (0.1 mol) of methylthioacetamide in 300 ml of tetrahydrofuran. The temperature was maintained at or below -55°C during these additions. After a further 1 hour at -60°C, the mixture was allowed to warm to room temperature, and the precipitate was collected by filtration. The precipitate was slurried in 200 ml of methylene chloride, and 11 g (0.11 mol) of triethylamine was added. The mixture was stirred for 5 minutes. The solution was washed twice with 100 ml of water, and the organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was washed with diethyl ether and dried, whereby 13.0 g (43%) of a pale yellow powder with m.p. 153-155°C. Analysis: Calculate, for C16H16<N>2°2S: C 63'98' H 5»37? N 9'33

Funnet: C 63,64; H 5,39; N 9,25 Found: C 63.64; H 5.39; N 9.25

Fremstilling 8 Manufacturing 8

2-amino-3-( 4- klorbenzoyl)- a-( fenylthio)- fenylacetamid 2-amino-3-(4-chlorobenzoyl)-α-(phenylthio)-phenylacetamide

Til en kold (-70°C) oppløsning av 34,6 g (0,15 mol) 2-amino-4'-klorbenzofenon i 500 ml methylenklorid ble tilsatt 17,3 g (0,15 mol) 95%-ig t-butylhypoklorit, fulgt efter 10 minutter av en oppløsning av 25,0 g (0,15 mol) fenylthioacetamid i 400 ml tetrahydrofuran som ble tilsatt i løpet av 20 minutter. Temperaturen ble holdt ved -64°C eller lavere under disse tilsetninger. Efter 2 timer ble 20 g (0,2 mol) triethylamin tilsatt, og blandingen fikk lov til å oppvarmes til værelsetemperatur. Blandingen ble inndampet, og residuet ble fordelt mellom vann og methylenklorid. Materialet som var uoppløselig i begge faser, ble oppsamlet ved filtrering, vasket med 20%-ig vandig ethanoloppløsning og tørret, hvorved man fikk 36 g (61%) lysegult pulver med smp. 189-191°C. To a cold (-70°C) solution of 34.6 g (0.15 mol) 2-amino-4'-chlorobenzophenone in 500 ml methylene chloride was added 17.3 g (0.15 mol) 95% -butyl hypochlorite, followed after 10 minutes by a solution of 25.0 g (0.15 mol) of phenylthioacetamide in 400 ml of tetrahydrofuran which was added over 20 minutes. The temperature was maintained at -64°C or lower during these additions. After 2 hours, 20 g (0.2 mol) of triethylamine was added, and the mixture was allowed to warm to room temperature. The mixture was evaporated, and the residue was partitioned between water and methylene chloride. The material which was insoluble in both phases was collected by filtration, washed with 20% aqueous ethanol solution and dried, whereby 36 g (61%) of light yellow powder with m.p. 189-191°C.

Analyse: Beregn, for C^H^I^O^Cl: C 63,55; H 4,32; N 7,06 Analysis: Calculate, for C^H^I^O^Cl: C 63.55; H 4.32; N 7.06

Funnet: C 63,73; H 4,36; N 7,16 Found: C 63.73; H 4.36; N 7.16

Fremstilling 9 Production 9

4-[ 2-( 2- amino- 3- benzoylfenyl)- 2-( methylthio)- acetyl]- morfolin 4-[ 2-( 2- amino- 3- benzoylphenyl)- 2-( methylthio)- acetyl]- morpholine

Til en kold (-65°C) oppløsning av 9/9 g (0,05 mol) 2-aminobenzofenon og 8,8 g (0,05 mol) 4-(a-methylthio)-acetyl-morfolin i 200 ml methylenklorid ble dråpevis tilsatt en opp-løsning av 5,8 g (0,05 mol) 95%-ig t-butylhypoklorit i 20 ml methylenklorid. Efter ytterligere 1 time ved -60°C ble 5,1 g (0,05 mol) triethylamin tilsatt, og blandingen fikk lov til å oppvarmes til værelsetemperatur. Oppløsningen ble vasket to ganger med 100 ml vann, tørret over magnesiumsulfat og inndampet under nedsatt trykk. Residuet ble kromatografert på 600 g silicagel under eluering først med diisopropylether og til slutt med 10% aceton i diisopropylether. Eluatet ble inndampet, residuet oppløst i 150 ml ethanol og oppløs-ningen helt i 400 ml vann. Det uoppløste faste stoff ble oppsamlet og krystallisert fra diethylether og tørret. Utbytte var 12,3 g (62%) gule krystaller med smp. 119-121°C. Analyse: Beregn, for <C>2oH22N2°3S: C 64'84; H 5'99' N 7,56 To a cold (-65°C) solution of 9/9 g (0.05 mol) of 2-aminobenzophenone and 8.8 g (0.05 mol) of 4-(α-methylthio)-acetyl-morpholine in 200 ml of methylene chloride a solution of 5.8 g (0.05 mol) of 95% t-butyl hypochlorite in 20 ml of methylene chloride was added dropwise. After a further 1 hour at -60°C, 5.1 g (0.05 mol) of triethylamine was added and the mixture was allowed to warm to room temperature. The solution was washed twice with 100 ml of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on 600 g of silica gel, eluting first with diisopropyl ether and finally with 10% acetone in diisopropyl ether. The eluate was evaporated, the residue dissolved in 150 ml of ethanol and the solution completely in 400 ml of water. The undissolved solid was collected and crystallized from diethyl ether and dried. Yield was 12.3 g (62%) yellow crystals with m.p. 119-121°C. Analysis: Calculate, for <C>2oH22N2°3S: C 64'84; H 5'99' N 7.56

Funnet: C 65,01; H 5,99; N 7,57 Found: C 65.01; H 5.99; N 7.57

Fremstilling 10 Production 10

2- amino- 3- benzoyl- 5- klor- a- [( 4- klorfenyl)- thio]- fenylacetamid 2- amino- 3- benzoyl- 5- chloro- a- [( 4- chlorophenyl)- thio]- phenylacetamide

Til en kold (-70°C) oppløsning av 20 g (0,0863 mol) 2-amino-5-klorbenzofenon i 500 ml methylenklorid under nitrogen ble tilsatt en oppløsning av 9,48 g (0,088 mol) t-butylhypoklorit i 50 ml methylenklorid. Efter ytterligere omrør-ing i 15 minutter ble en oppløsning av 17,35 g (0,0863 mol), a-(4-klorfenylthio)-acetamid i 500 ml av en 50/50 blanding av tetrahydrofuran og methylenklorid tilsatt. Blandingen ble omrørt ved -70°C i 2 timer, 8,72 g (0,0863 mol) triethylamin ble tilsatt, og den omrørte oppløsning fikk lov til å oppvarmes til værelsetemperatur i løpet av 2 timer. Reaksjonsblandingen ble ekstrahert med flere porsjoner vann, og det organiske skikt ble tørret over magnesiumsulfat. Volumet av væsken ble redusert til ca. 500 ml. 500 ml methylenklorid ble tilsatt for å felle produktet som efter filtrering og tørring veiet 16,62 g (44,7%). Det gule, faste stoff smeltet ved 198-200°C. To a cold (-70°C) solution of 20 g (0.0863 mol) of 2-amino-5-chlorobenzophenone in 500 ml of methylene chloride under nitrogen was added a solution of 9.48 g (0.088 mol) of t-butyl hypochlorite in 50 ml methylene chloride. After further stirring for 15 minutes, a solution of 17.35 g (0.0863 mol), α-(4-chlorophenylthio)-acetamide in 500 ml of a 50/50 mixture of tetrahydrofuran and methylene chloride was added. The mixture was stirred at -70°C for 2 hours, 8.72 g (0.0863 mol) of triethylamine was added, and the stirred solution was allowed to warm to room temperature over 2 hours. The reaction mixture was extracted with several portions of water, and the organic layer was dried over magnesium sulfate. The volume of the liquid was reduced to approx. 500 ml. 500 ml of methylene chloride was added to precipitate the product which after filtration and drying weighed 16.62 g (44.7%). The yellow solid melted at 198-200°C.

Analyse: Beregn, for <c>2iHi6N2°2<S>C12: C 58'48; H 3'74' N 6'49 Analysis: Calculate, for <c>2iHi6N2°2<S>C12: C 58'48; H 3'74' N 6'49

Funnet: C 58,49; H. 3,77; N 6,67 Found: C 58.49; H. 3.77; N 6.67

Fremstilling 11 Production 11

2- amino- 3- benzoyl- 5- klor- ct- ( fenylthio) - fenylacetamid 2- amino- 3- benzoyl- 5- chloro- ct-( phenylthio)- phenylacetamide

Til en kold (-70°C) oppløsning av 80,72 g (0,349 mol) 2-amino-5-klorbenzofenon i 1,5 1 methylenklorid, under nitrogen, ble tilsatt 39,1 g (0,360 mol) t-butylhypoklorid i 100 ml methylenklorid. Efter omrøring i 10 minutter ble en oppløsning av 59,1 g (0,354 mol) a-(fenylthio)-acetamid i 1,5 1 tetrahydrofuran tilsatt. Blandingen ble omrørt i 1,25 timer ved -65°C, 37,5 g (0,371 mol) triethylamin ble tilsatt, og oppløsningen fikk lov til å oppvarmes til værelsetemperatur. Reaksjonsblandingen ble ekstrahert med flere porsjoner vann, og det organiske skikt ble tørret over vann-fritt natriumsulfat.. Volumet av oppløsningen ble redusert i vakuum, og gult, fast stoff feltes og ble så omkrystallisert fra acetonitril som et gult, krystallinsk, fast stoff med smp. 190-191°C (spaltn.). To a cold (-70°C) solution of 80.72 g (0.349 mol) of 2-amino-5-chlorobenzophenone in 1.5 L of methylene chloride, under nitrogen, was added 39.1 g (0.360 mol) of t-butyl hypochloride in 100 ml methylene chloride. After stirring for 10 minutes, a solution of 59.1 g (0.354 mol) α-(phenylthio)-acetamide in 1.5 1 tetrahydrofuran was added. The mixture was stirred for 1.25 hours at -65°C, 37.5 g (0.371 mol) of triethylamine was added, and the solution was allowed to warm to room temperature. The reaction mixture was extracted with several portions of water and the organic layer was dried over anhydrous sodium sulfate. The volume of the solution was reduced in vacuo and a yellow solid precipitated and was then recrystallized from acetonitrile as a yellow crystalline solid with m.p. 190-191°C (dec.).

Analyse: Beregn, for C21H17<N>2<0>2<S>C1: C 63,55; H 4,32; N 7,06 Analysis: Calculate, for C21H17<N>2<0>2<S>C1: C 63.55; H 4.32; N 7.06

Funnet: C 63,62; H 4,29; N 7,08 Found: C 63.62; H 4.29; N 7.08

Fremstilling 12 Production 12

2- amino- 3- benzoyl- a-( fenylthio)- fenylacetamid 2-amino-3-benzoyl-a-(phenylthio)-phenylacetamide

Ved å følge fremgangsmåten i metode 11, men ved å anvende ekvimolare mengder av 2-aminobenzofenon istedenfor 2-amino-5-klorbenzofenon, fåes tittelforbindelsen i 57% utbytte. Omkrystallisert fra methylenklorid-diethylether-hexan smeltet forbindelsen ved 153-154°C. By following the procedure in method 11, but by using equimolar amounts of 2-aminobenzophenone instead of 2-amino-5-chlorobenzophenone, the title compound is obtained in 57% yield. Recrystallized from methylene chloride-diethyl ether-hexane the compound melted at 153-154°C.

Analyse: Beregn, for <C>21<H>18<N>2<0>2<S:> C 69,59; H 5,01; N 7,73 Analysis: Calculate, for <C>21<H>18<N>2<0>2<S:> C 69.59; H 5.01; N 7.73

Funnet: C 69,33; H 5,00; N 7,76 Found: C 69.33; H 5.00; N 7.76

Fremstilling 13 Production 13

2- amino- 3- benzoyl- a-( methylthio)- N- methylfenylacetamid 2-amino-3-benzoyl-a-(methylthio)-N-methylphenylacetamide

En oppløsning av 29,6 g (0,15 mol) 2-aminobenzofenon i 350 ml methylenklorid ble avkjølt til -70°C, og 17,9 g A solution of 29.6 g (0.15 mol) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70°C, and 17.9 g

(0,15 mol) 2-methylthio-N-methylacetamid i 20 ml methylen- (0.15 mol) of 2-methylthio-N-methylacetamide in 20 ml of methylene-

klorid ble tilsatt. Til blandingen ved -70°C ble dråpevis tilsatt en oppløsning av 17,2 g (0,15 mol) 95%-ig t-butylhypoklorit i 30 ml methylenklorid. Temperaturen ble holdt ved eller under -65°C i 1,5 timer, derpå ble 15,1 g (0,15 mol) triethylamin tilsatt hurtig. Oppløsningen fikk lov til å oppvarmes til værelsetemperatur og ble vasket med vann. Den organiske oppløsning ble inndampet, og residuet krystalliserte når det ble blandet med isopropylether. Det faste stoff ble omkrystallisert fra isopropylalkohol, hvorved man fikk 31 g (65%) gule nåler med smp. 149,0-150,0°C. chloride was added. A solution of 17.2 g (0.15 mol) of 95% t-butyl hypochlorite in 30 ml of methylene chloride was added dropwise to the mixture at -70°C. The temperature was maintained at or below -65°C for 1.5 hours, then 15.1 g (0.15 mol) of triethylamine was added rapidly. The solution was allowed to warm to room temperature and was washed with water. The organic solution was evaporated and the residue crystallized when mixed with isopropyl ether. The solid was recrystallized from isopropyl alcohol, whereby 31 g (65%) of yellow needles with m.p. 149.0-150.0°C.

Analyse: Beregn, for <C>17<H>18<N>2°2<S:> C 64'94' H 5'77' N 8'91 Analysis: Calculate, for <C>17<H>18<N>2°2<S:> C 64'94' H 5'77' N 8'91

Funnet: C 65,24; H 5,83; N 8,99 Found: C 65.24; H 5.83; N 8.99

Fremstilling 14 Production 14

2- amino- 3- benzoyl- a-( methylthio)- N, N- dimethylfenylacetamid 2-amino-3-benzoyl-a-(methylthio)-N,N-dimethylphenylacetamide

En oppløsning av 29,6 g (0,15 mol) 2-aminobenzofenon i 350 ml methylenklorid ble avkjølt til -70°C, og 20,0 g A solution of 29.6 g (0.15 mol) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70°C, and 20.0 g

(0,15 mol) 2-methylthio-N,N-dimethylacetamid ble tilsatt. (0.15 mol) of 2-methylthio-N,N-dimethylacetamide was added.

Til blandingen ved -70°C ble dråpevis tilsatt en oppløsning A solution was added dropwise to the mixture at -70°C

av 17,2 g (0,15 mol) 95%-ig t-butylhypoklorit i 30 ml methylenklorid. Temperaturen ble holdt ved eller under -65°C i I, 5 timer, og derpå ble 15,1 g (0,15 mol) triethylamin tilsatt hurtig. Oppløsningen fikk lov til å oppvarmes til værelsetemperatur og ble så vasket med vann. Den organiske oppløsning ble inndampet, og residuet krystalliserte ved blanding med isopropylether. Det faste stoff ble omkrystallisert fra isopropylalkohol, hvilket ga 39,8 g (81%) skarpt gule krystaller med smp. 153-155°C. of 17.2 g (0.15 mol) of 95% t-butyl hypochlorite in 30 ml of methylene chloride. The temperature was maintained at or below -65°C for 1.5 hours, and then 15.1 g (0.15 mol) of triethylamine was added rapidly. The solution was allowed to warm to room temperature and then washed with water. The organic solution was evaporated, and the residue crystallized by mixing with isopropyl ether. The solid was recrystallized from isopropyl alcohol, yielding 39.8 g (81%) of bright yellow crystals, m.p. 153-155°C.

Analyse: Beregn, for C18<H>20N2°2S: C 65'83' H 6'14'" N 8'53 Analysis: Calculate, for C18<H>20N2°2S: C 65'83' H 6'14'" N 8'53

Funnet: C 65,87; H 6,15; N 8,52 Found: C 65.87; H 6.15; N 8.52

Fremstilling 15 Production 15

2- amino- 3-( 4- fluorbenzoyl)- a-( n- propylthio)- fenylacetamid 2- amino- 3-( 4- fluorobenzoyl)- a-( n- propylthio)- phenylacetamide

En oppløsning av 21,5 g (0,1 mol) 4'-fluor-2-aminobenzofenon i 400 ml methylenklorid ble avkjølt til -70°C, og II, 5 g (0,1 mol) 95%-ig t-butylhypoklorit ble tilsatt i A solution of 21.5 g (0.1 mol) of 4'-fluoro-2-aminobenzophenone in 400 ml of methylene chloride was cooled to -70°C, and II, 5 g (0.1 mol) of 95% t- butyl hypochlorite was added i

løpet av 15 minutter, idet temperaturen ble holdt under -6 6°C. during 15 minutes, the temperature being kept below -6 6°C.

Til denne oppløsning ble tilsatt en oppløsning av 13,3 g 2-n-propylthioacetamid i 50 ml methylenklorid i løpet av 10 minutter. Oppløsningen ble omrørt i 1 time ved -65°C til -70°C og fikk så lov til å oppvarmes til 0°C ved hvilken temperatur 10,2 g (0,1 mol) triethylamin ble tilsatt. Oppløs-ningen ble omrørt i 10 minutter og derpå vasket med vann. To this solution was added a solution of 13.3 g of 2-n-propylthioacetamide in 50 ml of methylene chloride over 10 minutes. The solution was stirred for 1 hour at -65°C to -70°C and then allowed to warm to 0°C at which temperature 10.2 g (0.1 mol) of triethylamine was added. The solution was stirred for 10 minutes and then washed with water.

Den organiske oppløsning ble tørret over magnesiumsulfat. Efter inndampning under nedsatt trykk ble residuet krystallisert fra isopropylalkohol og tørret, hvilket ga 19,5 g (56%) gule krystaller som smeltet ved 140-142°C. The organic solution was dried over magnesium sulfate. After evaporation under reduced pressure, the residue was crystallized from isopropyl alcohol and dried, yielding 19.5 g (56%) of yellow crystals melting at 140-142°C.

Analyse: Beregn, for ClgH19N202SF: C 62,41; H 5,53; N 8,09 Analysis: Calculate, for ClgH19N202SF: C 62.41; H 5.53; N 8.09

Funnet: C 62,34; H 5,58; N 8,04 Found: C 62.34; H 5.58; N 8.04

Fremstilling 16 Production 16

På samme måte som angitt i fremstilling 8, ble 2-amino-3-(2-fluorbenzoyl)-a-(fenylthio)-fenylacetamid, 2-amino-3-(4-trifluormethylbenzoyl)-a-(fenylthio)-fenylacetamid, Similarly to Preparation 8, 2-amino-3-(2-fluorobenzoyl)-α-(phenylthio)-phenylacetamide, 2-amino-3-(4-trifluoromethylbenzoyl)-α-(phenylthio)-phenylacetamide,

2-amino-3-(2,4-diklorbenzoyl)-a-(fenylthio)-fenylacetamid og 2-amino-3-(2,4-difluorbenzoyl)-a-(fenylthio)-fenylacetamid fremstilt fra fenylthioacetamid, t-butylhypoklorit og 2-amino-2'-fluorbenzofenon, 2-amino-3-(2,4-dichlorobenzoyl)-α-(phenylthio)-phenylacetamide and 2-amino-3-(2,4-difluorobenzoyl)-α-(phenylthio)-phenylacetamide prepared from phenylthioacetamide, t-butyl hypochlorite and 2-amino-2'-fluorobenzophenone,

2-amino-4<1->trifluormethylbenzofenon, 2-amino-4<1->trifluoromethylbenzophenone,

2-amino-2<1>,4'-diklorbenzofenon og 2-amino-2<1>,4'-dichlorobenzophenone and

2-amino-2<1>,4'-difluorbenzofenon. 2-amino-2<1>,4'-difluorobenzophenone.

Fremstilling 17 Production 17

2- amino- 3- benzoyl- 5- klor- a-( methylthio)- N- methylfenylacetamid 2- amino- 3- benzoyl- 5- chloro- a-( methylthio)- N- methylphenylacetamide

Til en oppløsning av 38,3 g (0,166 mol) 2-amino-5-klorbenzofenon i 1 liter methylenklorid avkjølt til -70°C under en nitrogenatmosfære ble tilsatt 18,05 g (0,16 7 mol) t-butylhypoklorit. Oppløsningen ble omrørt i 15 minutter, og derpå ble en oppløsning av 20,3 g (0,171 mol) 2-methylthio-N-methylacetamid i 100 ml methylenklorid tilsatt. Oppløs-ningen ble omrørt ved -70°C i 2 timer, og 25 ml triethylamin ble tilsatt. Under omrøring fikk oppløsningen lov til å oppvarmes til værelsetemperatur fulgt av ekstraksjon med vann og tørring av det organiske skikt med magnesiumsulfat. Volumet av oppløsningen ble redusert til ca. 400 ml, ether ble tilsatt og oppløsningen anbrakt i kjøleskap ved ca. 0°C over natten. Det faste stoff som krystalliserte, ble tørret under høyvakuum i ca. 4 timer ved 50°C. Vekten av produktet var 31,56 g (54,6%) som smeltet ved 170-171°C. To a solution of 38.3 g (0.166 mol) of 2-amino-5-chlorobenzophenone in 1 liter of methylene chloride cooled to -70°C under a nitrogen atmosphere was added 18.05 g (0.16 7 mol) of t-butyl hypochlorite. The solution was stirred for 15 minutes, and then a solution of 20.3 g (0.171 mol) of 2-methylthio-N-methylacetamide in 100 ml of methylene chloride was added. The solution was stirred at -70°C for 2 hours, and 25 ml of triethylamine was added. While stirring, the solution was allowed to warm to room temperature followed by extraction with water and drying of the organic layer with magnesium sulfate. The volume of the solution was reduced to approx. 400 ml, ether was added and the solution placed in a refrigerator at approx. 0°C overnight. The solid that crystallized was dried under high vacuum for approx. 4 hours at 50°C. The weight of the product was 31.56 g (54.6%) which melted at 170-171°C.

Analyse: Beregn, for C17H17N202SC1: C 58,53; H 4,91; N 8,03 Analysis: Calculate, for C17H17N202SC1: C 58.53; H 4.91; N 8.03

Funnet: C 58,68; H 4,91; N 8,13 Found: C 58.68; H 4.91; N 8,13

Fremstilling 18 Production 18

3- benzoyl- 2-( N- methylamino)- a-( methylthio)- fenylacetamid 3-benzoyl-2-(N-methylamino)-α-(methylthio)-phenylacetamide

Når i henhold til fremgangsmåten ved fremstilling 7, 2-N-methylaminobenzofenon anvendes i ekvimolar mengde istedenfor 2-aminobenzofenon, fåes tittelforbindelsen. When, according to the procedure in preparation 7, 2-N-methylaminobenzophenone is used in an equimolar amount instead of 2-aminobenzophenone, the title compound is obtained.

De etterfølgende eksempler illustrerer oppfinnelsen. Eksempel 1 The following examples illustrate the invention. Example 1

2- amino- 3- benzoyl- 5- klorfenylacetamid 2- amino- 3- benzoyl- 5- chlorophenylacetamide

En blanding av 21,34 g (0,0639 mol) 2-amino-3-benzoyl-5-klor-a-(methylthio)-fenylacetamid og overskudd av Raney-nikkel i en blanding av 900 ml absolutt ethanol og 200 ml dimethylformamid ble omrørt ved værelsetemperatur i 45 minutter. Blandingen ble filtrert gjennom "Celite" for å fjerne Raney-nikkelet. Oppløsningsmidlet ble fjernet under vakuum, hvorved man fikk et gult, fast stoff som når det hadde krystallisert, smeltet ved 213,5-215,0°C (spaltn.). A mixture of 21.34 g (0.0639 mol) of 2-amino-3-benzoyl-5-chloro-α-(methylthio)-phenylacetamide and excess Raney nickel in a mixture of 900 ml of absolute ethanol and 200 ml of dimethylformamide was stirred at room temperature for 45 minutes. The mixture was filtered through Celite to remove the Raney nickel. The solvent was removed under vacuum, whereby a yellow solid was obtained which, when crystallized, melted at 213.5-215.0°C (dec.).

Analyse: Beregn, for ci5H13<N>2°3C1: c 62,40; H 4,54; N 9,70 Analysis: Calculate, for c15H13<N>2°3C1: c 62.40; H 4.54; N 9.70

Funnet: C 62,35; H 4,58; N 9,74 Found: C 62.35; H 4.58; N 9.74

Eksempel 2 Example 2

2- amino- 3- benzoylfenylacetamid 2- amino- 3- benzoylphenylacetamide

Til en omrørt oppløsning av 9,7 g (0,032 mol) 2-amino-3- benzoyl-a-(methylthio)-fenylacetamid i 100 ml tetrahydrofuran ble tilsatt 80 g våt Raney-nikkel (vasket 3 ganger med vann og 3 ganger med tetrahydrofuran). Efter 10 minutter ble blandingen filtrert for å fjerne Raney-nikkel, og filtratet ble inndampet under vakuum. Residuet ble krystallisert fra isopropylalkohol, hvorved man fikk 6,0 g (73%) gule nåler med smp. 178,5-180,0°C. 80 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran). After 10 minutes, the mixture was filtered to remove Raney nickel, and the filtrate was evaporated under vacuum. The residue was crystallized from isopropyl alcohol, whereby 6.0 g (73%) of yellow needles with m.p. 178.5-180.0°C.

Analyse: Beregn, for C15H14N202: C 70'85' H 5»55; N 11,02 Analysis: Calculate, for C15H14N202: C 70'85' H 5»55; N 11.02

Funnet: C 70,53; H 5,53; N 11,04 Found: C 70.53; H 5.53; N 11.04

Eksempel 3 Example 3

2- aminc— 3-( 4- klorbenzoyl)- fenylacetamid 2- aminc— 3-( 4- chlorobenzoyl)- phenylacetamide

Til en omrørt oppløsning av 28,5 g (0,077 mol) 2-amino-3- (4-klorbenzoyl)-a-(fenylthio)-fenylacetamid i 1 liter tetrahydrofuran ble tilsatt 230 g våt Raney-nikkel (vasket 3 ganger med vann og 3 ganger med tetrahydrofuran). Efter To a stirred solution of 28.5 g (0.077 mol) 2-amino-3-(4-chlorobenzoyl)-α-(phenylthio)-phenylacetamide in 1 liter tetrahydrofuran was added 230 g wet Raney nickel (washed 3 times with and 3 times with tetrahydrofuran). After

15 minutter ble blandingen filtrert, og filtratet ble inndampet under nedsatt trykk; hvorved man fikk 17,4 g (84%) 15 minutes, the mixture was filtered, and the filtrate was evaporated under reduced pressure; whereby 17.4 g (84%) were obtained

gult, krystallinsk, fast stoff. Omkrystallisasjon fra isopropylalkohol fulgt av omkrystallisasjon to ganger fra absolutt ethanol ga gule nåler med smp. 212-215°C. yellow, crystalline, solid. Recrystallization from isopropyl alcohol followed by recrystallization twice from absolute ethanol gave yellow needles of m.p. 212-215°C.

Analyse: Beregn, for C^<H>^N^Cl: C 62,40; H 4,54; N 9,70 Analysis: Calculate, for C^<H>^N^Cl: C 62.40; H 4.54; N 9.70

Funnet: C 62,76; H 4,58; N 9,83 Found: C 62.76; H 4.58; N 9.83

Eksempel 4 Example 4

4- [ 2-( 2- amino- 3- benzoylfenyl)- acetyl]- morfolin 4- [ 2-( 2- amino- 3- benzoylphenyl)- acetyl]- morpholine

Til en omrørt oppløsning av 18,5 g (0,05 mol) 4-[2-(2-amino-3-benzoylfenyl)-2-(methylthio)-acetyl]-morfolin i 300 ml tetrahydrofuran ble tilsatt 150 g våt Raney-nikkel. Efter 15 minutter ble blandingen filtrert og filtratet inndampet under nedsatt trykk. Efter omkrystallisasjon av residuet fra isopropylalkohol fikk man 13,3 g (82%) skarpt gule krystaller, med smp. 156,5-158,5°C. To a stirred solution of 18.5 g (0.05 mol) 4-[2-(2-amino-3-benzoylphenyl)-2-(methylthio)-acetyl]-morpholine in 300 ml of tetrahydrofuran was added 150 g of wet Raney - nickel. After 15 minutes, the mixture was filtered and the filtrate evaporated under reduced pressure. After recrystallization of the residue from isopropyl alcohol, 13.3 g (82%) of bright yellow crystals were obtained, with m.p. 156.5-158.5°C.

Analyse: Beregn, for c19H2qN2°3: C 70,35; H 6,22; N 8,64 Analysis: Calculate, for c19H2qN2°3: C 70.35; H 6.22; N 8.64

Funnet: C 70,24; H 6,21; N 8,63 Found: C 70.24; H 6.21; N 8.63

Eksempel 5 Example 5

2- amino- 3- benzoyl- N- methylfenylacetamid 2- amino- 3- benzoyl- N- methylphenylacetamide

En oppløsning av 22,5 g (0,072 mol) 2-amino-3-benzoyl-ct- (methylthio) -N-methylf enylacetamid i 400 ml tetrahydrof uran ble behandlet med 160 g våt Raney-nikkel (vasket 3 ganger med vann og 3 ganger med tetrahydrofuran) i 10 minutter. Blandingen ble filtrert, og filtratet ble inndampet. Residuet ble krystallisert fra isopropylalkohol, hvorved man fikk 17,2 g (89%) gule nåler med smp. 145-146°C. A solution of 22.5 g (0.072 mol) of 2-amino-3-benzoyl-ct-(methylthio)-N-methylphenylacetamide in 400 ml of tetrahydrofuran was treated with 160 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran) for 10 minutes. The mixture was filtered and the filtrate was evaporated. The residue was crystallized from isopropyl alcohol, whereby 17.2 g (89%) of yellow needles with m.p. 145-146°C.

Analyse: Beregn, for <C>16H16N2°2: C 71'62' H 6/°l; N 10,44 Analysis: Calculate, for <C>16H16N2°2: C 71'62' H 6/°l; N 10.44

Funnet: C 71,76; H 6,05; N 10,52 Found: C 71.76; H 6.05; N 10.52

Eksempel 6 Example 6

2- amino- 3- benzoyl- N, N- dimethylfenylacetamid 2-amino-3-benzoyl-N,N-dimethylphenylacetamide

En oppløsning av 33,0 g (0,1 mol) 2-amino-3-benzoyl-a-(methylthio)-N,N-dimethylfenylacetamid i 500 ml tetrahydrofuran ble behandlet med 240 g våt Raney-nikkel (vasket 3 ganger med vann og 3 ganger med tetrahydrofuran) i 10 minutter. Blandingen ble filtrert, og filtratet ble inndampet. Residuet ble krystallisert fra isopropylalkohol, hvilket ga 27,2 g (96%) gule nåler, med smp. 123-124°C. A solution of 33.0 g (0.1 mol) of 2-amino-3-benzoyl-α-(methylthio)-N,N-dimethylphenylacetamide in 500 ml of tetrahydrofuran was treated with 240 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran) for 10 minutes. The mixture was filtered and the filtrate was evaporated. The residue was crystallized from isopropyl alcohol, yielding 27.2 g (96%) of yellow needles, m.p. 123-124°C.

Analyse: Beregn, for C,^<H>lo<N>„<0>o<:> C 72,32; H 6,43; N 9,92 Analysis: Calculate, for C,^<H>lo<N>„<0>o<:> C 72.32; H 6.43; N 9.92

X / lo z zX / lo z z

Funnet: C 72,34; H 6,42; N 9,98 Found: C 72.34; H 6.42; N 9.98

Eksempel 7 Example 7

2- amino- 3-( 4- fluorbenzoyl)- fenylacetamid 2-amino-3-(4-fluorobenzoyl)-phenylacetamide

En oppløsning av 24,2 g (0,07 mol) 2-amino-3-(4-fluor-benzoyl) -a- (n-propylthio) -f enylacetamid i 300 ml tetrahydrofuran ble behandlet med 250 g våt Raney-nikkel (vasket 3 ganger med vann og 3 ganger med tetrahydrofuran). Blandingen ble omrørt i 1 time og filtrert. Filtratet ble inndampet under vakuum, og residuet ble omkrystallisert fra 95%-ig ethylalkohol, hvorved man fikk 14,8 g (78%) gule nåler som smeltet ved 184-186°C. A solution of 24.2 g (0.07 mol) of 2-amino-3-(4-fluoro-benzoyl)-α-(n-propylthio)-phenylacetamide in 300 ml of tetrahydrofuran was treated with 250 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran). The mixture was stirred for 1 hour and filtered. The filtrate was evaporated under vacuum, and the residue was recrystallized from 95% ethyl alcohol, whereby 14.8 g (78%) of yellow needles were obtained which melted at 184-186°C.

Analyse: Beregn, for C15H13<N>2<0>2<F:> C 66'17' H 4'81; N 10,29 Analysis: Calculate, for C15H13<N>2<0>2<F:> C 66'17' H 4'81; N 10.29

Funnet: C 66,32; H 4,81; N 10,48 Found: C 66.32; H 4.81; N 10.48

Eksempel 8 Example 8

På samme måte som angitt i eksempel 2, ble 2-amino-3-(2-fluorbenzoyl)-fenylacetamid, In the same manner as stated in Example 2, 2-amino-3-(2-fluorobenzoyl)-phenylacetamide,

2-amino-3-(2,4-diklorbenzoyl)-fenylacetamid, 2-amino-3-(2,4-dichlorobenzoyl)-phenylacetamide,

2-amino-3-(2,4-difluorbenzoyl)-fenylacetamid og 2-amino-3-(4-trifluormethylbenzoyl)-fenylacetamid fremstilt fra 2-amino-3-(2,4-difluorobenzoyl)-phenylacetamide and 2-amino-3-(4-trifluoromethylbenzoyl)-phenylacetamide prepared from

2-amino-3-(2-fluorbenzoyl)-a-(fenylthio)-fenylacetamid, 2-amino-3-(2,4-diklorbenzoyl)-a-(fenylthio)-fenylacetamid, 2-amino-3-(2,4-difluorbenzoyl)-a-(fenylthio)-fenylacetamid og 2-amino-3-(2-fluorobenzoyl)-a-(phenylthio)-phenylacetamide, 2-amino-3-(2,4-dichlorobenzoyl)-a-(phenylthio)-phenylacetamide, 2-amino-3-(2 ,4-difluorobenzoyl)-α-(phenylthio)-phenylacetamide and

2-amino-3-(4-trifluormethylbenzoyl)-a-(fenylthio)-fenylacetamid. 2-Amino-3-(4-trifluoromethylbenzoyl)-α-(phenylthio)-phenylacetamide.

Eksempel 9 Example 9

En løsning av 6,0 g (0,07 mol) kaliummethylmercaptid i 50 ml dimethylsulfoxyd ble tilsatt til en løsning av 13,6 g (0,05 mol) 2-amino-3-(4-fluorbenzoyl)-fenylacetamid i 100 ml dimethylsulfoxyd. En rød blanding ble erholdt som ble omrørt i 45 minutter og ble deretter helt over i 1,5 1 vann. Et gult, fast materiale ble dannet som ble oppsamlet ved filtrering og omkrystallisert fra 95% ethanol under dannelse av 13,7 g (91,5%) 2-amino-3-[4-methylthio)-benzoyl]-fenylacetamid som et gult pulver med smp. 178-180°C. A solution of 6.0 g (0.07 mol) of potassium methylmercaptide in 50 ml of dimethylsulfoxide was added to a solution of 13.6 g (0.05 mol) of 2-amino-3-(4-fluorobenzoyl)-phenylacetamide in 100 ml dimethylsulfoxide. A red mixture was obtained which was stirred for 45 minutes and then poured into 1.5 L of water. A yellow solid was formed which was collected by filtration and recrystallized from 95% ethanol to give 13.7 g (91.5%) of 2-amino-3-[4-methylthio)-benzoyl]-phenylacetamide as a yellow powder with m.p. 178-180°C.

2-amino-5-methyl-3-[4-(methylthio)-benzoyl]-fenylacetamid ble erholdt som klare, gule nåler med smp. 187,5-189,5°C fra 2-amino-3-(4-fluorbenzoyl)-5-methylfenylacetamid under anvendelse av den ovenfor beskrevne generelle prosedyre. 2-amino-5-methyl-3-[4-(methylthio)-benzoyl]-phenylacetamide was obtained as clear, yellow needles with m.p. 187.5-189.5°C from 2-amino-3-(4-fluorobenzoyl)-5-methylphenylacetamide using the general procedure described above.

Eksempel 10 2- amino- 3-( 4- oxymethylthiobenzoyl)- fenylacetamid Example 10 2-amino-3-(4-oxymethylthiobenzoyl)-phenylacetamide

Tittelforbindelsen ble fremstilt ved å omsette 1 mol 2-amino-3-(4-methylthiobenzoyl)-fenylacetamid med 1 mol natriummetaperjodat og isolere på passende måte.- The title compound was prepared by reacting 1 mol of 2-amino-3-(4-methylthiobenzoyl)-phenylacetamide with 1 mol of sodium metaperiodate and isolating appropriately.-

Eksempel 11 Example 11

2- amino- 3-( 4- dioxymethylthiobehzoyl)- fenylacetamid 2-amino-3-(4-dioxymethylthiobehzoyl)-phenylacetamide

Tittelforbindelsen ble fremstilt ved å omsette 1 mol 2-amino-3-(4-methylthiobenzoyl)-fenylacetamid med 2 mol natriummetaperjodat og isolering på passende måte. The title compound was prepared by reacting 1 mole of 2-amino-3-(4-methylthiobenzoyl)-phenylacetamide with 2 moles of sodium metaperiodate and isolating appropriately.

Eksempel 12 Example 12

2- amino- 3- benzoyl- 5- klor- N- methylfenylacetamid 2- amino- 3- benzoyl- 5- chloro- N- methylphenylacetamide

En oppløsning av 28,33 g (0,081 mol) 2-amino-3-benzoyl-5-klor-a-(methylthio)-N-methylacetamid i 1 liter tetrahydrofuran ble behandlet med overskudd av Raney-nikkel ved værelsetemperatur i 2 timer. Oppløsningen ble filtrert gjennom "Celite". Raney-nikkel-residuet ble vasket med aceton, og vaskevæskene filtrert. De forenede organiske filtrater ble tørret over magnesiumsulfat, og volumet ble redusert til ca. 300 ml. Overskudd av ether ble tilsatt, og oppløsningen fikk lov til å stå ved værelsetemperatur i 1 time fulgt av kjøleskapsavkjøling over natten. Det gule, faste stoff ble oppsamlet og tørret og veiet 20,94 g (85,68%) og smeltet ved 179-180°C. A solution of 28.33 g (0.081 mol) of 2-amino-3-benzoyl-5-chloro-α-(methylthio)-N-methylacetamide in 1 liter of tetrahydrofuran was treated with excess Raney nickel at room temperature for 2 hours. The solution was filtered through "Celite". The Raney nickel residue was washed with acetone and the washings filtered. The combined organic filtrates were dried over magnesium sulfate, and the volume was reduced to approx. 300 ml. Excess ether was added and the solution was allowed to stand at room temperature for 1 hour followed by refrigerator cooling overnight. The yellow solid was collected and dried and weighed 20.94 g (85.68%) and melted at 179-180°C.

Analyse: Beregn, for C16H15N202C1: C 63'48? H 4,99; N 9,25 Analysis: Calculate, for C16H15N202C1: C 63'48? H 4.99; N 9.25

Funnet: C 63,44; H 4,99; N 9,27 Found: C 63.44; H 4.99; N 9.27

Eksempel 13 Example 13

3- benzoyl- 2-( N- methylamino)- fenylacetamid 3-benzoyl-2-(N-methylamino)-phenylacetamide

Når i fremgangsmåten ifølge eksempel 2, 3-benzoyl-2-(N-methylamino)-a-(methylthio)-fenylacetamid anvendes istedenfor 2-amino-3-benzoyl-a-(methylthio)-fenylacetamid, fåes tittelforbindelsen. When in the method according to example 2, 3-benzoyl-2-(N-methylamino)-α-(methylthio)-phenylacetamide is used instead of 2-amino-3-benzoyl-α-(methylthio)-phenylacetamide, the title compound is obtained.

Eksempel 14 Example 14

3- benzoyl- 2-( N, N- dimethylamino)- fenylacetamid 3-benzoyl-2-(N,N-dimethylamino)-phenylacetamide

En oppløsning av 12,7 g (0,05 mol) 2-amino-3-benzoylfenylacetamid i 150 ml acetonitril ble behandlet i 4 timer med 16 ml (0,2 mol) 37%-ig formalin, 6,4 g (0,1 mol) natrium-cyånoborhydrid og 2 ml iseddik med en 15-minutters omrørings-periode mellom hver behandling. Blandingen ble til slutt helt i fortynnet natriumhydroxyd og ekstrahert 3 ganger med diethylether. Etherekstraktene ble forenet, tørret over magnesiumsulfat og inndampet. Produktet ble isolert ved kolonnekromatografi. A solution of 12.7 g (0.05 mol) of 2-amino-3-benzoylphenylacetamide in 150 ml of acetonitrile was treated for 4 hours with 16 ml (0.2 mol) of 37% formalin, 6.4 g (0 .1 mol) of sodium cyanoborohydride and 2 ml of glacial acetic acid with a 15-minute stirring period between each treatment. The mixture was finally poured into dilute sodium hydroxide and extracted 3 times with diethyl ether. The ether extracts were combined, dried over magnesium sulfate and evaporated. The product was isolated by column chromatography.

Eksempel 15 Example 15

2-amino-3-(4-klorbenzoyl)-5-fluorfenylacetamid, 2-amino-3-(4-chlorobenzoyl)-5-fluorophenylacetamide,

smp. 230-233,5°C ble fremstilt fra 2-amino-3-(4-klorbenzoyl)-5-fluor-a-(propylthio)-fenylacetamid under anvendelse av den prosedyre som er beskrevet i eksempel 2. m.p. 230-233.5°C was prepared from 2-amino-3-(4-chlorobenzoyl)-5-fluoro-α-(propylthio)-phenylacetamide using the procedure described in Example 2.

2- amino-5-fluor-3-(4-fluorbenzoyl)-fenylacetamid, 2-amino-5-fluoro-3-(4-fluorobenzoyl)-phenylacetamide,

smp. 220-223°C, ble fremstilt fra 2-amino-5-fluor-3-(4-fluor-benzoyl) -a- (propylthio) -f enylacetamid under anvendelse av prosedyren beskrevet i eksempel 2. m.p. 220-223°C, was prepared from 2-amino-5-fluoro-3-(4-fluoro-benzoyl)-α-(propylthio)-phenylacetamide using the procedure described in Example 2.

Effektive mengder av en hvilken som helst av de foregående farmakologisk aktive forbindelser kan administreres til levende dyr på forskjellige måter, f.eks. oralt som i kapsler eller tabletter, parenteralt i form av sterile opp-løsninger eller suspensjoner, og i noen tilfelle intravenøst i form av sterile oppløsninger. Ved fremstilling av preparatene inkorporeres den aktive bestanddel i en passende bærer, f.eks. en farmasøytisk bærer. Passende farmasøytiske bærere som er nyttige, innbefatter stivelse, gelatin, glucose, magnesiumcarbonat, lactose, malt og lignende. Flytende preparater kan også anvendes, og passende flytende farmasøytiske bærere innbefatter ethylalkohol, propylen-glycol, glycerol, glucosesirup og lignende. Effective amounts of any of the foregoing pharmacologically active compounds may be administered to live animals by various means, e.g. orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. When preparing the preparations, the active ingredient is incorporated into a suitable carrier, e.g. a pharmaceutical carrier. Suitable pharmaceutical carriers useful include starch, gelatin, glucose, magnesium carbonate, lactose, malt and the like. Liquid preparations may also be used, and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerol, glucose syrup and the like.

De farmakologisk aktive forbindelser kan med fordel anvendes i enhetsdoser på fra 0,1 til 250 mg eller mere, av-hengig av størrelsen av dyret. Eksempelvis kan et stort dyr som en hest, kreve tabletter på 500-1000 mg aktiv bestanddel. Enhetsdosen kan gies et passende antall ganger daglig slik at dagsdosen kan variere fra 0,3 til 450 mg. 5 til 25 mg synes å være optimum pr. enhetsdose. The pharmacologically active compounds can advantageously be used in unit doses of from 0.1 to 250 mg or more, depending on the size of the animal. For example, a large animal such as a horse may require tablets of 500-1000 mg of active ingredient. The unit dose can be given an appropriate number of times a day so that the daily dose can vary from 0.3 to 450 mg. 5 to 25 mg seems to be optimum per unit dose.

Det er bare nødvendig at den aktive bestanddel utgjør en effektiv mengde, dvs. slik at en passende effektiv dose vil oppnåes i overensstemmelse med den anvendte doseform. De nøyaktige individuelle doser såvel som dagsdosene vil selv-sagt bli bestemt i henhold til standard medisinske prinsipper under avgjørelse av en lege eller veterinær. It is only necessary that the active ingredient constitutes an effective amount, i.e. so that a suitable effective dose will be obtained in accordance with the dosage form used. The exact individual doses as well as the daily doses will of course be determined according to standard medical principles under the judgment of a doctor or veterinarian.

De aktive midler kan kombineres med andre farmakologisk aktive midler, eller med puffere, antisyrer eller lignende, for administrasjon, og forholdet av den aktive bestanddel i preparatene kan variere sterkt. The active agents can be combined with other pharmacologically active agents, or with buffers, antacids or the like, for administration, and the ratio of the active ingredient in the preparations can vary greatly.

Claims (3)

1. Analogifremgangsmåte ved fremstilling av terapeutisk aktive forbindelser med formelen: hvor R er hydrogen eller lavere alkyl,1. Analogy method for the preparation of therapeutically active compounds with the formula: where R is hydrogen or lower alkyl, 1 2 R og R er hydrogen, lavere alkyl, cycloalkyl, fenyl eller fenyl substituert med lavere alkyl, lavere alkoxy, halogen, nitro og/eller trifluormethyl, eller R 1 og R 2 kan sammen med det tilstøtende nitrogen danne en heterocyclisk gruppe, X er hydrogen, lavere alkyl, lavere alkoxy, halogen eller trifluormethyl, Y er hydrogen, lavere alkyl, lavere alkoxy, halogen, trifluormethyl, lavere alkylthio, lavere alkyloxythio eller lavere alkyldioxythio, Am er primær amino (-NI^), methylamino eller dimethylamino, og n er 1, 2 eller 3, karakterisert ved at 1 2 (a) en forbindelse med formel I hvor R, R , R , Am, X og n er som ovenfor angitt, og Y er hydrogen, lavere alkyl, lavere alkoxy, halogen eller trifluormethyl, fremstilles ved å redusere en forbindelse med formelen: hvor R 3 er fenyl eller lavere alkyl, eller 1 2 (b) en forbindelse med formel I hvor R, R , R , Am, X og n er som ovenfor angitt, og Y er lavere alkylthio, fremstilles ved å omsette en forbindelse med formel: 1 2 hvor R, R , R og Am er som ovenfor angitt, Eted en forbindelse med formelen: NaS-lavere alkyl, eller (c) en forbindelse med formel I, hvor Y er lavere alkyloxythio eller lavere alkyldioxythio, fremstilles ved å oxydere en forbindelse med formelen: 1 2 hvor R, R , R og Am er som ovenfor angitt, eller (d) en forbindelse med formel I hvor R, R 1 , R 2, X, Y og n er som ovenfor angitt, og Am er dimethylamino, fremstilles ved å dimethylere en forbindelse med formel I hvor Am er amino.1 2 R and R are hydrogen, lower alkyl, cycloalkyl, phenyl or phenyl substituted with lower alkyl, lower alkoxy, halogen, nitro and/or trifluoromethyl, or R 1 and R 2 can together with the adjacent nitrogen form a heterocyclic group, X is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, Y is hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylthio, lower alkyloxythio or lower alkyldioxythio, Am is primary amino (-NI^), methylamino or dimethylamino, and n is 1, 2 or 3, characterized in that 1 2 (a) a compound of formula I where R, R , R , Am, X and n are as indicated above, and Y is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, is prepared by reduce a compound with the formula: where R 3 is phenyl or lower alkyl, or 1 2 (b) a compound of formula I where R, R , R , Am, X and n are as indicated above, and Y is lower alkylthio, is prepared by reacting a compound of formula : 1 2 where R, R , R and Am are as indicated above, Eted a compound of the formula: NaS-lower alkyl, or (c) a compound of formula I, where Y is lower alkyloxythio or lower alkyldioxythio, is prepared by oxidizing a compound of the formula: 1 2 where R, R , R and Am are as above, or (d) a compound of formula I where R, R 1 , R 2 , X, Y and n are as above, and Am is dimethylamino, is prepared by dimethylating a compound of formula I wherein Am is amino. 2. Fremgangsmåte ifølge krav 1 ved fremstilling av 2-amino-3-benzoylfenylacetamid, karakterisert ved at 2-amino-3-benzoyl-a-(methylthio)-fenylacetamid omsettes med Raney-nikkel.2. Process according to claim 1 for the production of 2-amino-3-benzoylphenylacetamide, characterized in that 2-amino-3-benzoyl-α-(methylthio)-phenylacetamide is reacted with Raney nickel. 3. Fremgangsmåte ifølge krav 1 ved fremstilling av 2-amino-3-(4-klorbenzoyl)-fenylacetamid, karakterisert ved at 2-amino-3-(4-klor-benzoyl) -o- (fenylthio) -fenylacetamid omsettes med Raney-nikkel .3. Method according to claim 1 for the production of 2-amino-3-(4-chlorobenzoyl)-phenylacetamide, characterized in that 2-amino-3-(4-chloro-benzoyl)-o-(phenylthio)-phenylacetamide is reacted with Raney -nickel.
NO802834A 1979-09-26 1980-09-25 ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-3-BENZOYLPHENYL ACETAMIDES NO152128C (en)

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IL61945A (en) * 1980-02-19 1984-09-30 Robins Co Inc A H 2-amino-3-(hydroxy(phenyl)methyl)phenylacetic acids,esters and amides and pharmaceutical compositions containing them
US6066671A (en) * 1997-12-19 2000-05-23 Alcon Laboratories, Inc. Treatment of GLC1A glaucoma with 3-benzoyl-phenylacetic acids, esters, or amides
US6646001B2 (en) 1997-12-19 2003-11-11 Alcon Manufacturing, Ltd. Use of non-steroidal anti-inflammatory agents in combination with prostaglandin FP receptor agonists to treat glaucoma and ocular hypertension
GB9727523D0 (en) * 1997-12-31 1998-02-25 Pharmacia & Upjohn Spa Alpha-aminoamide derivatives useful as analgesic agents
AR030345A1 (en) * 2000-08-14 2003-08-20 Alcon Inc METHOD OF TREATMENT OF DISORDERS RELATED TO ANGIOGENESIS
MXPA04002009A (en) 2001-09-03 2004-07-08 Newron Pharm Spa Pharmaceutical composition comprising gabapentin or an analogue thereof and an $g(a)-aminoamide and its analgesic use.
EP1438956A1 (en) 2003-01-16 2004-07-21 Newron Pharmaceuticals S.p.A. Alpha-aminoamide derivatives useful as antimigraine agents
CZ2009367A3 (en) * 2009-06-08 2010-06-16 Farmak, A.S. Process for preparing 2-amino-3-benzoylphenylacetamide (nepafenac) with minimum of by-products
CN112794809B (en) * 2019-11-14 2023-12-29 南京济群医药科技股份有限公司 Preparation method of high-purity nepafenac intermediate

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IL61945A (en) * 1980-02-19 1984-09-30 Robins Co Inc A H 2-amino-3-(hydroxy(phenyl)methyl)phenylacetic acids,esters and amides and pharmaceutical compositions containing them

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GB2059963B (en) 1983-04-20
SE8006668L (en) 1981-03-27
FR2465710B1 (en) 1984-10-12
IN151313B (en) 1983-03-26
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IN156255B (en) 1985-06-08
PT71839A (en) 1980-10-01
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FI803002A (en) 1981-03-27
ZA805476B (en) 1981-11-25
IN156254B (en) 1985-06-08
GR70049B (en) 1982-07-26
FR2465710A1 (en) 1981-03-27
IT8024948A0 (en) 1980-09-26
KR830004210A (en) 1983-07-06
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ATA474580A (en) 1983-08-15
KE3307A (en) 1983-08-19
IL60999A (en) 1984-05-31
DK154136B (en) 1988-10-17
KR840000763B1 (en) 1984-06-08
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JPH0141616B2 (en) 1989-09-06
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IE50268B1 (en) 1986-03-19
FI72967B (en) 1987-04-30
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PH22628A (en) 1988-10-28
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