DK156391B - ANALOGY PROCEDURE FOR PREPARING 3-AMINOPYR ROLLER DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR PREPARING 3-AMINOPYR ROLLER DERIVATIVES Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
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- 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]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
Description
DK 156391 BDK 156391 B
Den foreliggende opfindelse angâr en analogifremgangsmâde til fremstilling af hidtil ukendte 3-aminopyrrolderivater med 12 3 4The present invention relates to an analogous process for the preparation of novel 3-aminopyrrole derivatives having 12 3 4
den i krav 1 viste almene formel I i hvilken R, R , R , R , Rthe general formula I shown in claim 1 in which R, R, R, R, R
5 og R har de sammesteds angivne betydninger, eller salte deraf 5 med farmaceutisk acceptable syrer.5 and R have the same meanings stated, or salts thereof 5 with pharmaceutically acceptable acids.
En foretrukken gruppe af forbindelserne med formel I er dem hvori R er hydrogen, metyl eller klorsubstitueret benzyl, R er hydrogen, fenyl, fenyl substitueret med metyl, metoxy, 2 fluor eller klor, R er hydrogen, acetyl, metyl eller metyl-3 4 10 sulfonyl, R er hydrogen eller metyl, R er acetyl, propionyl, butyryl, isobutyryl, karbometoxy, karbætoxy, karb- 5 amyl eller benzoyl og R er metyl eller karbamyl, eller hvor 2 3 R og R tilsammen er benzyliden eller klorsubstitueret benz-yliden eller salte deraf med farmaceutisk acceptable syrer.A preferred group of the compounds of formula I are those wherein R is hydrogen, methyl or chloro-substituted benzyl, R is hydrogen, phenyl, phenyl substituted with methyl, methoxy, 2 fluorine or chlorine, R is hydrogen, acetyl, methyl or methyl-4 Sulfonyl, R is hydrogen or methyl, R is acetyl, propionyl, butyryl, isobutyryl, carbomethoxy, carbethoxy, carbamyl or benzoyl and R is methyl or carbamyl, or wherein R 3 and R are together benzylidene or chlorine-substituted benzyl. the ylidene or salts thereof with pharmaceutically acceptable acids.
15 If01ge opfindelsen foretrækkes det særligt at fremstille forbindelsen 3-amino-4-isobutyryl-5-metyl-2-fenyl-pyrrol, der som det fremgâr af omstâende dokumentation har særlig h0j farmakologisk virkning, eller et sait deraf med en farmaceutisk acceptabel syre.According to the invention, it is particularly preferred to prepare the compound 3-amino-4-isobutyryl-5-methyl-2-phenyl-pyrrole, which, as is clear from the present documentation, has a particularly high pharmacological effect, or a site thereof with a pharmaceutically acceptable acid.
20 De omhandlede forbindelser fremstilles ifolge opfindelsen pa den i krav l's kendetegnende del angivne mâde.The compounds of the invention are made in accordance with the invention in the manner specified in claim 1.
De som udgangsmaterialer anvendte aminonitriler kan fremstilles ved i det væsentlige at f0lge den metode der er beskre-vet af Steiger i Organic Synthesis, 22, 13, 1942 og 22, 23, 25 1942.The aminonitriles used as starting materials can be prepared by following essentially the method described by Steiger in Organic Synthesis, 22, 13, 1942 and 22, 23, 1942.
Forbindelserne med den i krav 1 viste formel III er enten produkter der er tilgængelige i handelen eller kan vindes ved naerliggende modifikationer af i handelen værende produkter.The compounds of formula III shown in claim 1 are either commercially available products or can be obtained by nearby modifications of commercially available products.
Reaktionen mellem de i krav 1 viste forbindelser II og 30 III forl0ber normalt under dannelse af et mellemprodukt, der er en forbindelse med âben kæde som repræsenteres med f01gen-de almene formel IV eller dens tautomere iminform.The reaction between the compounds II and 30 III shown in claim 1 normally proceeds to form an intermediate product which is an open-chain compound represented by the general general formula IV or its tautomeric imine.
R4 cn y 35 ,1 - JL 5 IvR4 cn y 35, 1 - JL 5 Iv
RR
22
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Denne forbindelse kan om 0nskes isoleres, renses og karakteriseres ved hjælp af almindelige analysemetoder f0r den ringsluttes til dannelse af slutforbindelserne med formel I. Den kan imidlertid ogsâ anvendes som râmateriale til det efterfolgende ringslut-5 ningstrin uden at det pâvirker de endelige udbytter.This compound may, if desired, be isolated, purified and characterized by ordinary assay methods before being cyclized to form the final compounds of formula I. However, it can also be used as a feedstock for the subsequent cyclization step without affecting the final yields.
Reaktanterne II og III bringes i kontakt med hinanden i i det væsentlige ækvimolære mængder i nærværelse af et vandfrit organisk oplosningsmiddel som med fordel kan vælges blandt benzen, dioxan, tetrahydrofuran, lavere alkanoler og analoge oplosningsmidler. Der 10 kan tilsættes en lille mængde ρ-toluensulfonsyre som katalysator og blandingen koges under tilbagesvaling i en période pâ mellem 2 og 28 timer. Den dannede mellemproduktforbindelse med formel IV kan om onsket isoleres og karakteriseres, eller den kan anvendes som sâdan i det efterfolgende ringslutningstrin som gennemfores i 15 nærværelse af basiske katalysatorer valgt blandt karbonater, hydroxyder, alkoxyder, hydrider og amider af metallerne i gruppe I og II i grundstoffernes periodiske System. Ogsâ i dette til-fælde gennemfores reaktionen i nærværelse af et oplosningsmiddel som fortrinsvis vælges blandt vandfrie lavere alkanoler med hojst 20 4 kulstofatomer. Ringslutningen kan foregâ ved stuetemperatur, men somme tider er det nodvendigt at opvarme eller at tilbagesvale reaktionsblandingen for at accelerere ringslutningsreaktionen som afsluttes indenfor et tidsrum pâ mellem 1 og 3o timer.Reactants II and III are contacted with each other in substantially equimolar amounts in the presence of an anhydrous organic solvent which may advantageously be selected from benzene, dioxane, tetrahydrofuran, lower alkanols and analogous solvents. A small amount of ρ-toluenesulfonic acid can be added as a catalyst and the mixture is refluxed for a period of between 2 and 28 hours. The intermediate compound of formula IV formed may, if desired, be isolated and characterized, or it may be used as such in the subsequent cyclization step carried out in the presence of basic catalysts selected from carbonates, hydroxides, alkoxides, hydrides and amides of the metals of groups I and II of the Periodic Elements of the Elements. Also in this case, the reaction is carried out in the presence of a solvent which is preferably selected from anhydrous lower alkanols having a maximum of 20 4 carbon atoms. The cyclization can take place at room temperature, but sometimes it is necessary to heat or reflux the reaction mixture to accelerate the cyclization reaction which terminates within a period of between 1 and 30 hours.
Det er i nogle tilfælde iagttaget at nâr X betegner en 25 gruppe -C'=C-,kan dannelsen af aminopyrrolderivaterne med formel I foregâ i kun et reaktionstrin. I dette tilfælde sammenblandes ami-nonitrilet. med formel II eller et syreadditiohssalt deraf med en forbindelse med formel III,hvor X er en -C=C- gruppe,i i det væsentlige ækvimolære mængder i nærværelse af et organisk op-30 losningsmiddel som fx en vandfri alkanol med 1-4 kulstofatomer, kloroform, tetrahydrofuran, benzen og analoge og et alkalimetal-eller jordalkalimetalkarbonat eller -hydroxyd som katalysator, og den resulterende blanding koges under tilbagesvaling i ca.It has been observed in some cases that when X represents a group -C '= C-, the formation of the amino pyrrole derivatives of formula I can take place in only one reaction step. In this case, the ammonium nitrile is mixed. of formula II or an acid addition salt thereof having a compound of formula III wherein X is a -C = C group, in substantially equimolar amounts in the presence of an organic solvent such as anhydrous alkanol having 1-4 carbon atoms, chloroform, tetrahydrofuran, benzene and analogs and an alkali metal or alkaline earth metal carbonate or hydroxide as catalyst, and the resulting mixture is refluxed for approx.
3-5 timer.3-5 hours.
35 Slutforbindelserne med formel I udvindes fra reaktionsblan dingen som de frie baser eller i form af salte med farmaceutisk acceptable syrer, idet man anvender konventionel teknik.The final compounds of formula I are recovered from the reaction mixture as the free bases or in the form of salts with pharmaceutically acceptable acids, using conventional techniques.
Denne konventionelle teknik omfatter fjernelse af oplosnings- 3This conventional technique involves removing solution 3
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midlet fra reaktionsblandingen ved inddampning, optagelse af rema-nensen i et oplosningsmiddel, atter inddampning af opl0sningsmidlet og rensning af det vundne faste stof, væske eller olieagtige sub-stans ved omkrystallisation, fraktioneret destination eller destil-5 lation under nedsat tryk. H vis reaktionen direkte resulterer i et krystallinsk fast stof udvindes dette simpelthen ved filtrering og om nodvendigt rensning ved omkrystallisation. Omkrystallisations-oplosningsmidlerne er fortrinsvis lavere alkanoler med 1-4 kulstofatomer, diætylæter eller blandinger deraf.the solvent from the reaction mixture by evaporation, absorption of the residue in a solvent, evaporation of the solvent and purification of the obtained solid, liquid or oily substance by recrystallization, fractional distillation or distillation under reduced pressure. If the reaction directly results in a crystalline solid, this is simply recovered by filtration and, if necessary, purification by recrystallization. The recrystallization solvents are preferably lower alkanols having 1-4 carbon atoms, diethyl ether or mixtures thereof.
10 De ovenfor nævnte salte af forbindelserne med formel I med farmaceutisk acceptable syrer er hovedsagelig repræsenteret af hydrokloridet, hydrobromidet, hydrojodidet, sulfatet, fosfatet, benzoatet, oxalatet, acetatet, metansulfonatet, cyklohexylsul-fonatet og analoge. De vindes let ved behandling af en forbindelse 15 med formel I som den frie base med en i forvejen valgt farmaceutisk acceptabel syre. Omvendt er det ogsâ muligt at genvinde den frie base fra det tilsvarende syreadditionssait ved reaktion med mindst en ækvimolær mængde af et basisk middel.The above-mentioned salts of the compounds of formula I with pharmaceutically acceptable acids are mainly represented by the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, benzoate, oxalate, acetate, methanesulfonate, cyclohexyl sulfonate and analogs. They are readily obtained by treating a compound of formula I as the free base with a pre-selected pharmaceutically acceptable acid. Conversely, it is also possible to recover the free base from the corresponding acid addition site by reaction with at least one equimolar amount of a basic agent.
Ved at gâ frem som ovenfor beskrevet kan man vinde forbin- 2 3 20 delser med formlen I hvori R, R og R er hydrogenatomer eller 2 syreadditionssalte deraf. Hvls der 0nskes substituenter R og 3 R der er forskellige fra hydrogen kan de indf0res ved velkend- te metoder ved omsætning af forbindelser med formel I med pas- sende reaktanter. Sâledes vil fx omsætning med et alkylerings- 25 middel sâsom en blanding af myresyre og formaldehyd eller et alkylhalogenid eller alkylsulfat med 1-4 kulstofatomer give et 2 3 produkt hvori R eller R eller begge er alkylgrupper med 1-4 2 kulstofatomer. Forbindelser hvori R er en alifatisk acylgrup- pe med 2-4 kulstofatomer eller en benzoylgruppe kan vindes ved 30 at omsætte en forbindelse med formel I med halogenider eller anhydrider af alifatiske syrer med 2-4 kulstofatomer eller med 2 3 benzoesyre. Forbindelser hvori R og R tilsammen udg0r benz-yliden eller klorsubstitueret benzyliden kan let fremstilles if0lge kendte reaktioner til opnâelse af schiffske baser ud 35 fra aminer og karbonylforbindelser.Proceeding as described above, compounds of formula I wherein R, R and R are hydrogen atoms or 2 acid addition salts thereof can be obtained. Where substituents R and 3R which are different from hydrogen are desired, they may be introduced by well known methods by reacting compounds of formula I with suitable reactants. Thus, for example, reaction with an alkylating agent such as a mixture of formic acid and formaldehyde or an alkyl halide or alkyl sulfate of 1-4 carbon atoms will give a product in which R or R or both are alkyl groups of 1-4 carbon atoms. Compounds wherein R is an aliphatic acyl group having 2-4 carbon atoms or a benzoyl group can be obtained by reacting a compound of formula I with halides or anhydrides of aliphatic acids with 2-4 carbon atoms or with 2,3 benzoic acid. Compounds in which R and R together form the benzylidene or chlorine-substituted benzylidene can be readily prepared according to known reactions to obtain schiffic bases from amines and carbonyl compounds.
44
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Substitution pâ ring-nitrogenatomet finder soin regel ikke sted under de reaktionsbetingelser der anvendes til indforelse af grupperne K2 og R3 pd nitrogenatomsÎ i 3-5tiilirigsïïi m sigtsmæssig metode til indforelse af de 0nskede substituenter 5 i overenssternmelse med formlen I pâ pyrrolringens kerne-nitrogen- atom indbefatter omsætning med en i forvejen udvalgt forbindelse med formlenI, hvori R er et hydrogenatom, med et udvalgt (C-^) alkylhalogenid eller klorsubstitueret benzylhalogenid i nær- værelse af et stærkt basisk middel, fortrinsvis et alkalimetal 10 eller et alkalimetalhydrid, i et inaktivt organisk oplosningsmid- del som fx dimetylformamid under nitrogenatmosfære. Omsætningen gennemfores ved stuetemperatur· Det onskede aminopyrrol substi- tueret i 1-stillingen isoleres derpâ i gode udbytter fra reak- tionsblandingen. Det mâ forstâs at hvis under disse reaktions- p 3 15 betingelser enten R eller R eller begge betegner hydrogen i den udvalgte forbindelse med formlen I vil ogsâ disse hydrogen-atomer blive erstattet med de ovenfor beskrevne substituenter. Sâledes kan i den vundne forbindelse ogsâ aminogruppen i 3-stil-lingen samtidigt substitueres med fx en eller to (C.^) alkyl-20 grupper. Hvis der imidlertid onskes forbindelser med formel I hvori R og/eller R er hydrogenatomer og som er substitueret pâ kernenitrogenatomet vil det være nodvendigt at beskytte aminogruppen i 3-stillingen, fx ved omsætning med en karbonyl-forbindelse" eller et alkylsulfonyl- eller benzenfenylhalogenid 25 til fremstilling af henholdsvis den tilsvarende schiffske base eller alkylsulfonyl- eller benzensulfonylaminoderivaterne. Derpâ gennemf0res substitueringen i 1-stillingen som angivet ovenfor og en sur hydrolytisk spaltning af beslcyttelsesgruppen giver de enskede forbindelser hvori R og/eller R er hydrogenatomer 30 Metoder der indbefatter sulfonylering af aminogruppen i 3-stillingen giver ogsâ en anvendelig vej. til fremstilling af forbindelser med formel I hvori R er hydrogen, R^ er hydrogen 3 og R er en alkylgruppe med 1-4 kulstofatomer. Denne reaktions-vej bestâr af (C-^) alkylering af aminnitrogenet i en forbin-35 delse med formel I, hvori R er hydrogen, R2 er benzensulfonyl, (CT λ) alkylsulfonyl, toluensulfonyl eller fenacylsulfonyl og 3±— R er hydrogen, ved anvendelse af sædvanlige metoder til al- 2 5Substitution of the ring nitrogen atom does not normally take place under the reaction conditions used to introduce the groups K2 and R3 pd nitrogen atoms into 3-5 suitable directions for introducing the desired substituents 5 in accordance with the formula I of the pyrrole ring nitrogen atom. includes reacting with a pre-selected compound of formula I wherein R is a hydrogen atom, with a selected (C 1-4) alkyl halide or chloro-substituted benzyl halide in the presence of a strong basic agent, preferably an alkali metal or an alkali metal hydride, in an inactive organic solvent such as dimethylformamide under nitrogen atmosphere. The reaction is carried out at room temperature · The desired aminopyrrole substituted in the 1 position is then isolated in good yields from the reaction mixture. It is to be understood that under these reaction conditions, either R or R or both represent hydrogen in the selected compound of formula I, these hydrogen atoms will also be replaced by the substituents described above. Thus, in the compound obtained, the amino group in the 3-position can also be simultaneously substituted by, for example, one or two (C1-6) alkyl groups. However, if compounds of formula I wherein R and / or R are hydrogen atoms and are substituted on the nucleus nitrogen, it will be necessary to protect the amino group at the 3-position, for example by reaction with a carbonyl compound "or an alkylsulfonyl or benzene phenyl halide. The substituent is carried out at the 1-position as indicated above and an acidic hydrolytic cleavage of the decision group gives the individual compounds wherein R and / or R are hydrogen atoms. Methods including ammonium sulfonyl at the 3-position also provides a useful route for the preparation of compounds of formula I wherein R is hydrogen, R 2 is hydrogen 3 and R is an alkyl group of 1-4 carbon atoms. This reaction pathway consists of (C of the amine nitrogen in a compound of formula I wherein R is hydrogen, R 2 is benzenesulfonyl, (CT λ) alk ylsulfonyl, toluenesulfonyl or phenacylsulfonyl and 3 ± - R are hydrogen, using the usual methods of al.
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kylering af aminer. Den ovenfor definerede gruppe R fjernes ved hydrolytisk spaltning med syrer eller i overensstemmelse med den metode der er beskrevet af J.B. Hendrickson og R.cooling of amines. The above-defined group R is removed by hydrolytic cleavage with acids or according to the method described by J.B. Hendrickson and R.
Bergeron, i Tetrahedron Letters, side 345, 1970.Bergeron, in Tetrahedron Letters, page 345, 1970.
5 5 Forbindelserne med formel I hvori R er en karbamylgrup- pe kan vindes ved at en tilsvarende C^_4-karbalkoxyforbindelse mættes med ammoniak i alkoholisk opl0sning.The compounds of formula I wherein R is a carbamyl group can be obtained by saturating a corresponding C 1-4 carbalkoxy compound with ammonia in alcoholic solution.
De ved fremgangsmâden if0lge opfindelsen fremstillede forbindelser har bemærkelsesværdige antiinflammatoriske virk-10 ninger og virkninger som depressanter for centralnervesyste-met.The compounds of the present invention have remarkable anti-inflammatory effects and effects as depressants of the central nervous system.
Et aspekt af den antiflammatoriske virkning vistes ved hjælp af den carrageenin-inducerede odemtest hos rotter som udf0rtes ifolge den metode der er beskrevet af C.A. Winter et al.f 15 Proc. Soc. Exptl. Biol. Med., 111, 544, 1962. Ved repræsentative forsog viste det sig at forbindelserne ifolge omstàende eksempler nr. 1, 2, 3, 6, 11, 12, 13, 14, 16, 17, 19, 23, 33, -36, 37, 39, 43, 44, 45 a), 45 b) , 49 ,50,53 og 54 gav en procentvis formind-skelse af det inducerede odem pâ mellem ca. lo til ca. 8o ved 20 indgift i dosisniveauer pâ mellem l/5o og l/5 af deres LD^-værdier. Under samme forsogsbetingelser er formindskelsen af det inducerede odem fremkaldt af vidt anvendte antiinflammatoriske lægemidler som fx fenylbutazon (4-butyl-l,2-difenylpyrazolidin-3,5-dion), ca.One aspect of the anti-inflammatory action was demonstrated by the carrageenin-induced odor test in rats performed according to the method described by C.A. Winter et al.f. Proc. Soc. Exp. Biol. Med., 111, 544, 1962. By representative experiments it was found that the compounds according to Examples Nos. 1, 2, 3, 6, 11, 12, 13, 14, 16, 17, 19, 23, 33, -36 , 37, 39, 43, 44, 45 a), 45 b), 49, 50.53 and 54 gave a percentage reduction of the induced edema of between ca. laughed at approx. 8o at 20 administration at dose levels between 1 / 5o and 1/5 of their LD 2 values. Under the same experimental conditions, the reduction of the induced edema is caused by widely used anti-inflammatory drugs such as phenylbutazone (4-butyl-1,2-diphenylpyrazolidine-3,5-dione), approx.
45 %, men kun nâr forbindelsen indgives i en dosis der er hojere 25 end 1/4 af dens LD^Q-værdi. Det skal bemærkes at toksisiteterne af de ifslge den foreliggende opfindelse fremstillede aminopyrrol-derivater er meget lav. Sâledes er, med fâ undtagelser, deres LD^Q-værdier aile hojere end looo mg/kg p.o. hos mus, mens den tilsvarende LD^0-værdi for fenylbutazon er ca. 39o mg/kg p.o.45%, but only when the compound is administered at a dose higher than 1/4 of its LD 2 Q value. It should be noted that the toxicities of the aminopyrrole derivatives prepared according to the present invention are very low. Thus, with few exceptions, their LD ^ Q values are all higher than looo mg / kg p.o. in mice, while the corresponding LD 2 O value for phenylbutazone is approx. 39o mg / kg p.o.
30 Toksisiteterne bestemtes ved den metode der er beskrevet af Lichtfield og Wilcoxon i J. Pharm. Exp. Ther., 96, 99, 1949.The toxicities were determined by the method described by Lichtfield and Wilcoxon in J. Pharm. Exp. Ther., 96, 99, 1949.
I folgende tabel gives mere detaljeret rede for den ovenfor omtalte antiinflammatoriske virkning.The following table gives a more detailed account of the anti-inflammatory effect mentioned above.
T a b e 1 6T a b e 1 6
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Forbindelse LD. mg/kg Dosis mg/kg % formindskelse if0lge 5 m P·0, r°tter af induceret 0dem eksempel r 5 2 >looo loo 36,5 2oo 44,3 1 >looo 5 23,4 lo 32,5 2o 39,o 5o 43,8 10 loo 58,9 2oo 76,6 3 >looo loo 4o,6 2oo 53,9 11 >1000 5 23,2 lo 31,9 _ 2o 43,5 5o 5o,7 loo 69,6 2oo 75,4 12 >looo 5 23,o lo 31,1 2o 35,1 20 50 41’9 20 loo 55,4 2oo 67,6 13 >looo 5o 29,6 loo 4o,8 2oo 58,3 14 >looo loo 35,4 - 2oo 47,9 16 5oo 5o 24,3 loo 45,9 17 >looo 5o 24,2 loo 37,3 2oo 44,9 30 23 >1000 20 29,2 5o 43,1 loo 58,5 2oo 71,0 36 VLooo 2o 21,5 5o 38,5 „ loo 49,2 2oo 69,6 37 ^looo loo 24,2 2oo 38,7 43 >looo 5o 23,9 loo 47,9 2oo 68,2 7Compound LD. mg / kg Dose mg / kg% decrease according to 5 m P · 0, rates of induced 0 example R 5 2> looo loo 36.5 2oo 44.3 1> looo 5 23.4 lo 32.5 2o 39, o 5o 43.8 10 loo 58.9 2oo 76.6 3> looo loo 4o, 6 2oo 53.9 11> 1000 5 23.2 lo 31.9 _ 2o 43.5 5o 5o, 7 loo 69.6 2oo 75.4 12> looo 5 23, o lo 31.1 2o 35.1 20 50 41'9 20 loo 55.4 2oo 67.6 13> looo 5o 29.6 loo 4o, 8 2oo 58.3 14> looo loo 35.4 - 2oo 47.9 16 5oo 5o 24.3 loo 45.9 17> looo 5o 24.2 loo 37.3 2oo 44.9 30 23> 1000 20 29.2 5o 43.1 loo 58.5 2oo 71.0 36 VLooo 2o 21.5 5o 38.5 "loo 49.2 2oo 69.6 37 ^ looo loo 24.2 2oo 38.7 43> looo 5o 23.9 loo 47.9 2oo 68.2 7
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LD- mg/kg Dosis mg/kg % Pormmdskelse ifoïge J° p.o. rotter af induceret odem j.j.wxyc p.o. mus r eksempel nr.LD mg / kg Dose mg / kg% Reduction according to J ° p.o. rats of induced odor j.j.wxyc p.o. mouse r example no.
18 500 20 25,3 5 50 36,0 100 45,0 21 500 20 21,0 50 34,1 100 46,0 in 26 >1000 50 26,4 100 34,3 200 48,0 27 >1000 50 26,1 100 35,8 200 46,7 15 29 >1000 50 39,1 100 49,3 200 61,3 30 500 20 21,1 50 32,4 100 44,0 20 33 500 20 20,0 50 33,2 100 44,8 39 >1000 50 16,6 100 31,2 200 45,6 25 56 >1000 50 15,6 100 32,2 200 45,4 44 >looo 2o 23,9 5o 35,2 loo 47,9 30 200 6.9,0 45 a) >looo loo 31,0 2oo 53,1 45 b) >looo 5o ll,o loo 34,3 2oo 52,7 50 >looo loo 38,o 35 2oo 47,6 53 > looo 5o 27,1 loo 41,4 2oo 56,3 fenylbutazon 39o 5o 3318 500 20 25.3 5 50 36.0 100 45.0 21 500 20 21.0 50 34.1 100 46.0 in 26> 1000 50 26.4 100 34.3 200 48.0 27> 1000 50 26 , 1 100 35.8 200 46.7 15 29> 1000 50 39.1 100 49.3 200 61.3 30 500 20 21.1 50 32.4 100 44.0 20 33 500 20 20.0 50 33, 2 100 44.8 39> 1000 50 16.6 100 31.2 200 45.6 25 56> 1000 50 15.6 100 32.2 200 45.4 44> looo 2o 23.9 5o 35.2 loo 47, 9 30 200 6.9,0 45 a)> looo loo 31.0 2oo 53.1 45 b)> looo 5o ll, o loo 34.3 2oo 52.7 50> looo loo 38, o 35 2oo 47.6 53> looo 5o 27.1 loo 41.4 2oo 56.3 phenylbutazone 39o 5o 33
^ ΊΛΛ AC^ ΊΛΛ AC
..... DK 156391 B..... DK 156391 B
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De omhandlede forbindelser er ogsâ udrustede med andre biologiske egenskaber som er meget 0nskelige i kraftige anti-inflammatoriske forbindelser. De bar sâledes udtalte antipyretiske og analgetiske virkninger som er henholdsvis 2, lo og ca. 4 5 gange sâ kraftig som for acetylsalicylsyre. Desuden udviser de omhandlede forbindelser en meget lav ulcerogen virkning som er ca. 5-lo gange mindre end den der iagttages hos andre kendte og i terapien anvendte antiinflammatoriske forbindelser, fx acetylsalicylsyre og fenylbutazon. Analgetisk virkning bestemtes ifolge 10 L.O. Randall og J.J. Selitto, Arch. Int. Pharmacodyn., No. 4* CX1, side 4o9, 1957- Antipyretisk virkning undersogtes ifolge R.H.The compounds of the present invention are also endowed with other biological properties which are highly desirable in potent anti-inflammatory compounds. Thus, they had pronounced antipyretic and analgesic effects which are 2, 1, and 2, respectively. 4 times as strong as for acetylsalicylic acid. In addition, the compounds of the invention exhibit a very low ulcerogenic effect which is approx. 5-fold times less than that observed in other known and used anti-inflammatory compounds, eg acetylsalicylic acid and phenylbutazone. Analgesic effect was determined according to 10 L.O. Randall and J.J. Selitto, Arch. Int. Pharmacodyn., No. 4 * CX1, page 4o9, 1957- Antipyretic action was investigated according to R.H.
Buller et al., J. Pharm. Pharmacol., 9. 128, 1957, mens den ulce-rogene virkning bestemtes ifclge Thuilliet et al., Chim. Therap., 3, 53, 1968.Buller et al., J. Pharm. Pharmacol., 9. 128, 1957, while the ulcerogenic effect was determined by Thuilliet et al., Chim. Therap., 3, 53, 1968.
15 Som tidligere nævnt har de omhandlede forbindelser ogsâ virkning pâ centralnervesystemet. Denne egenskab under-sogtes . ved den generelle metode der er foreslâet af S. Irwin, Psychopharmacologia (Berl.) 13, 222, 1968. Det har vist sig at nogle af de forbindelser der har udvist særligt effektive anti-20 flammatoriske egenskaber, som fx forbindelserne ifolge eksemplerne 1 og 12 ogsâ er udrustet med en god grad af sedativ og myorelaxe-rende virkning. Dette er uden tvivl en yderligere meget gunstig egenskab ved de omhandlede forbindelser, idet en vis sedativ myorelaxerende virkning er nyttig hos patienter der lider af 25 alvorlige inflammatoriske sygdomme. Nogle andre af de omhandlede forbindelser udviser ogsâ meget intéressante ansiolytiske egenskaber.15 As mentioned earlier, the compounds in question also have an effect on the central nervous system. This property was investigated. by the general method proposed by S. Irwin, Psychopharmacologia (Berl.) 13, 222, 1968. It has been found that some of the compounds exhibited particularly effective anti-inflammatory properties, such as the compounds of Examples 1 and 12 is also equipped with a good degree of sedative and myorelaxing effect. This is undoubtedly a further very beneficial property of the compounds of the present invention, as some sedative myorelaxative effect is useful in patients suffering from 25 severe inflammatory diseases. Some other of the compounds of the present invention also exhibit very interesting aniolytic properties.
Disse egenskaber undersogtes ved "pôle climbing avoidance test" hos rotter som udfortes som beskrevet af G. Maffii, J.These properties were investigated by "pôle climbing avoidance test" in rats performed as described by G. Maffii, J.
30 Pharm. Pharmacol., 11, 129, 1959. Repræsentative forsog viste at forbindelserne ifolge omstâende eksempler 26 og 32 er særligt effektive til hæmning af den sekundært betingede reaktion hos rotter (CR,,) ved e.t dosisniveau . som ikke pâvirker den primært betingede reaktion (CR) og den ubetingede reaktion (UR). Det 35 vides at den sekundært betingede reaktion er forbundet med en angsttilstand hos dyret og hæmningen deraf er direkte pâvirket af indgivelsen af angstlindrende forbindelser.Pharm. Pharmacol., 11, 129, 1959. Representative experiments showed that the compounds of Examples 26 and 32 are particularly effective in inhibiting the secondary conditional response in rats (CR,) at one dose level. which does not affect the primary conditional reaction (CR) and the unconditional reaction (UR). It is known that the secondary conditioned reaction is associated with an anxiety state of the animal and its inhibition is directly affected by the administration of anxiety relieving compounds.
Resultaterne er opstillet i folgende tabel hvor ogsâ toksi- 9The results are presented in the following table, where also toxic 9
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citeten af de afprovede forbindelser er angivet. Tabellen viser ogsà at meprobamat (2-metyl-2-propyl-l,3-propandiol-dikarbamat) har betydelig lavere angstlindrende egenskaber end de afpr0vede forbindelser.the citation of the compounds tested is indicated. The table also shows that meprobamate (2-methyl-2-propyl-1,3-propanediol dicarbamate) has significantly lower anxiety relieving properties than the compounds tested.
55
TabelTable
Forbindelse LD mg/kg Dosis mg/kg Hæmning afCompound LD mg / kg Dose mg / kg Inhibition of
if0lge i.p? mus i*p* mus GR2 CR URaccording to i.p? mouse in * p * mouse GR2 CR UR
eksempel nr. Deconditionerede rot- ter/behandlede rotter 26 8oo 3o 4/lo o/lo o/lo 6o 8/lo o/lo o/lo 32 8oo 3o 4/lo o/lo o/lo 5 6o 7/lo o/lo o/lo meprobamat 5oo 3o 3/lo o/lo o/lo 6o 6/lo 2/lo o/loExample No. Deconditioned rats / treated rats 26 8oo 3o 4 / lo o / lo o / lo 6o 8 / lo o / lo o / lo 32 8oo 3o 4 / lo o / lo o / lo 5 6o 7 / lo o / lo o / lo meprobamat 5oo 3o 3 / lo o / lo o / lo 6o 6 / lo 2 / lo o / lo
Idet de foretrukne indgiftsveje er oral og rektal kan ogsâ paranteral indgift anvendes. Til oral indgift oparbejdes forbin-2Q delserne i farmaceutiske dosisformer som fx tabletter, kapsler, elixirer, oplosninger og lignende. Dosisenheden kan indeholde de sædvanlige excipienser, fx stivelse, gummier, fedtsyrer, alkoholer, sukkerstoffer og lignende. Til rektal indgift kan forbindelserne indgives i form af suppositorier blandet med konventionelle vehik-25 1er, som fx kakaosm0r, voks, spermaceti eller polyoxyetylenglykoler og derivater deraf. Dosis ligger fra ca. o,o5 til ca. 2,00 g pr. dagp fortrinsvis indgivet i delte doser.Since the preferred routes of administration are oral and rectal, parenteral administration can also be used. For oral administration, the compounds are processed into pharmaceutical dosage forms such as tablets, capsules, elixirs, solutions and the like. The dosage unit may contain the usual excipients, eg starch, gums, fatty acids, alcohols, sugars and the like. For rectal administration, the compounds may be administered in the form of suppositories mixed with conventional vehicles, such as cocoa butter, wax, spermaceti or polyoxyethylene glycols and derivatives thereof. The dose ranges from approx. o, o5 to approx. 2.00 g per daily dosage is preferably administered in divided doses.
Fremgangsmâden ifolge opfindelsen belyses nærmere i det folgende ved hjælp af nogle eksempler.The process according to the invention is elucidated in the following by means of some examples.
Elcsempel 1 10Example 1 10
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4-acetyl-3-amino-5-metyl-2-fenylpyrrol-hydroklorid 5 a) En oplosning af 2 g (o,ol5 mol) 2-amino-2-£enylacetonitril og 1,4 g (o,ol4 mol) acetylacetone i 3o ml vandfrit benzen koges under tilbagesvaling i 2 timer pâ et oliebad i nærværelse af loo mg p-toluensulfonsyre. Efter afkoling filtreres reaktionsblandin-gen hvorpâ opl0sningsmidlet afdampes hvorved der vindes en olie-10 agtig remanens som destilleres under nedsat tryk. Det vundne mellemprodukt som bestâr af en forbindelse med âben kæde koger ved 15o°C/o,l mgHg.4-Acetyl-3-amino-5-methyl-2-phenylpyrrole hydrochloride 5 a) A solution of 2 g (o, ol5 mole) of 2-amino-2-phenylacetonitrile and 1.4 g (o, ol4 mole) acetylacetone in 3 ml of anhydrous benzene is refluxed for 2 hours in an oil bath in the presence of loo mg of p-toluenesulfonic acid. After cooling, the reaction mixture is filtered and the solvent is evaporated to give an oily residue which is distilled under reduced pressure. The obtained intermediate consisting of an open-chain compound boils at 150 ° C / 0.1 mgHg.
b) o,4o g natrium oploses i 15 ml vandfrit ætanol hvorpâ en oplosning af 2,5 g af den i eksempel 1 a) vundne forbindelse i 15 vandfrit ætanol drâbevis tilsættes og blandingen henstâr ved stuetemperatur i 4 timer. Efter indbobling af tort hydrogenklorid i ætanoloplosningen dannes et bundfald som opsamles ved filtrering og omkrystalliseres ira ætanol/diætylæter. Der vindes 2,o g af den i overskriften angivne forbindelse. Smeltepunkt 242°C (sonderde1ing). 20 Den frie base vindes ved ekstraktion med ætylacetat af en vandig oplosning af hydrokloridet alkaliseret med 5% natriumhydroxyd. Smeltepunkt 22o°C (fra metanol).b) dissolve 4 g of sodium in 15 ml of anhydrous ethanol, to which is added dropwise a solution of 2.5 g of the compound obtained in Example 1 a) in 15 anhydrous ethanol and the mixture is left at room temperature for 4 hours. After incorporation of tort hydrogen chloride into the ethanol solution, a precipitate is formed which is collected by filtration and recrystallized from ethanol / diethyl ether. 2 and g of the compound indicated in the heading are won. Melting point 242 ° C (dec). The free base is obtained by extraction with ethyl acetate from an aqueous solution of the hydrochloride alkalized with 5% sodium hydroxide. Melting point 22 ° C (from methanol).
Eksempel 2 25 ========= 3-amino-4-karbætoxy-5-metyl-2-£enylpyrrol-hydroklorid- a) En oplosning af 6 g (o,o42 mol) 2-amino-2-fenylacetonitril og 5 g (o,o42 mol) ætylacetoacetat i 3o ml vandfrit benzen koges under tilbagesvaling i 4 timer pâ et oliebad i nærværelse af loo 30 mg p-toluensulfonsyre. Efter afkoling filtreres reaktionsblandin- gen hvorpâ oplosningsmidlet afdampes hvorved der vindes en olie-.j agtig remanens som destilleres under nedsat tryk. Den vundne mellemproduktforbindelse med âben kæde har kogepunkt 14o°C/o,o5 mmHg.Example 2 ========= 3-Amino-4-carboxyoxy-5-methyl-2-phenylpyrrole hydrochloride a) A solution of 6 g (0.142 mole) of 2-amino-2 phenylacetonitrile and 5 g (0.142 mole) of ethyl acetoacetate in 30 ml of anhydrous benzene are refluxed for 4 hours in an oil bath in the presence of loo 30 mg of p-toluenesulfonic acid. After cooling, the reaction mixture is filtered and the solvent is evaporated to give an oily residue which is distilled under reduced pressure. The obtained open-chain intermediate compound has a boiling point of 14 ° C / o, 0.5 mmHg.
35 b) o,8o g natrium oploses i 15 ml vandfrit ætanol hvorefter en oplosning af 5 g af den under eksempel 1 b) vundne forbindelse i 35 ml vandfrit ætanol tilsættes drâbevis og blandingen henstâr ved stuetemperatur i 4 timer. Efter indbobling af tort hydrogen i ætanoloplosningen dannes hurtigt et bundfald som filtreres ogB) 0,8 g of sodium is dissolved in 15 ml of anhydrous ethanol and then a solution of 5 g of the compound obtained in Example 1 b) is added dropwise in 35 ml of anhydrous ethanol and the mixture is left at room temperature for 4 hours. After immersion of tort hydrogen in the ethanol solution, a precipitate is rapidly formed which is filtered and
Eksempel 3-30 11Example 3-30 11
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F0lgende forbindelser fremstilles ved at folge den totrins-proces der er beskrevet i eksempel 1 ud fra de relevante forbin-5 delser med formlerne II og III under anvendelse af alkalimetal- alkoxyder eller alkalimetalkarbonater sont de basiske ringslutnings-katalysatorer. Hvis mellemproduktforbindelsen med âben kæde isole-res og karakteriseres er deres kemisk-fysiske egenskaber angivet, ellers mâ det forstâs at disse mellemprodukter ringsluttes direkte 10 til slutforbindelserne.The following compounds are prepared by following the two-step process described in Example 1 from the relevant compounds of formulas II and III using alkali metal alkoxides or alkali metal carbonates, especially the basic cyclization catalysts. If the open chain intermediate compound is isolated and characterized, their chemical-physical properties are indicated, otherwise it will be understood that these intermediates are cyclized directly to the final compounds.
3. 3-amino-4-benzoyl-5-metyl-2-fenylpyrrol-hydroklorid3. 3-Amino-4-benzoyl-5-methyl-2-phenylpyrrole hydrochloride
Ud fra 2-amino-2-£enylacetonitril og benzoylacetone vindes den âbenkædede mellemproduktforbindelse med smeltepunkt 134-135°C 15 (fra diætylæter/hexan). Den i overslcriften angivne forbindelse vindes med et samlet udbytte pâ 6o%. Smeltepunkt 285-29o°C (fra metanol/diætylæter). Den frie base smelter ved 2o3-2o5°C (fra metanol).From 2-amino-2-enylacetonitrile and benzoylacetone, the open-chain intermediate compound is obtained, mp 134-135 ° C (from diethyl ether / hexane). The compound indicated in the heading is obtained with a total yield of 6%. Melting point 285-29 ° C (from methanol / diethyl ether). The free base melts at 20 DEG-250 DEG C. (from methanol).
20 4. 3-amino--4-benzoyl-2-f enylpyrrol-hydroklorid4. 3-Amino-4-benzoyl-2-phenylpyrrole hydrochloride
Den âbenkædede mellemproduktforbindelse med smeltepunkt 88-9o°C (fra hexan) vindes ud fra 2-amino-2-fenylacetonitril og benzoylacetaldehyd. Den i overskriften angivne forbindelse vindes med et samlét udbytte pâ 47% med smeltepunkt 272-274°C (fra aetanol).The open-chain intermediate compound of melting point 88-9 ° C (from hexane) is recovered from 2-amino-2-phenylacetonitrile and benzoylacetaldehyde. The title compound is obtained with a combined yield of 47%, mp 272-274 ° C (from ethanol).
25 5. 4-acetyl-3-amino-2-ætyl-5-metylpyrrol-hydroklorid5. 4-Acetyl-3-amino-2-ethyl-5-methylpyrrole hydrochloride
Ud fra 2-aminobutyronitril og acetylacetone vindes den âbenkædede mellemproduktforbindelse med kogepunkt loo°c/o,o2 mmHg.From 2-aminobutyronitrile and acetylacetone, the open-chain intermediate compound having a boiling point of 10 ° C / o, o2 mmHg is obtained.
30 Det i overskriften angivne produkt vindes med et samlet udbytte pâ 49%. Smeltepunkt 245-248°C (fra ætanol/diætylæter). Den frie base smelter ved 219-221°C (fra metanol).30 The title of the product is obtained with a total yield of 49%. Melting point 245-248 ° C (from ethanol / diethyl ether). The free base melts at 219-221 ° C (from methanol).
6. 3-amino-4-karbætoxy-2-fenylpyrrol-hydroklorid 35 Den i overskriften angivne forbindelse vindes med et samlet udbytte pâ 45% ud fra 2-amino-2-fenylacetonitril og ætylpropynoat. Smeltepunkt 244-245°C (fra ætanol/diætylæter).6. 3-Amino-4-carbethoxy-2-phenylpyrrole hydrochloride The title compound is obtained with a total yield of 45% from 2-amino-2-phenylacetonitrile and ethylpropynoate. Melting point 244-245 ° C (from ethanol / diethyl ether).
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5 7. 4-acetyl-3-amino-2-fenylpyrrol-hydroklorid7. 4-acetyl-3-amino-2-phenylpyrrole hydrochloride
Ud fra 2-amino-2-fenylacetonitril og acetylacetaldehyd vindes den âbenkædede mellemproduktforbindelse med kogepunkt 14o°C/o,o5 mmHg. Den i overskriften angivne forbindelse vindes i et samlet udbytte pâ 56%. Produktet smelter ikke ved op til 335°C.From 2-amino-2-phenylacetonitrile and acetylacetaldehyde, the open-chain intermediate compound having a boiling point of 14 ° C / 0.1 mmHg is obtained. The title specified in the title is obtained in a total yield of 56%. The product does not melt at up to 335 ° C.
10 -8.. 4-acetyl-3-amino-2-(p-metoxyfenyl)-pyrrol10 -8 .. 4-acetyl-3-amino-2- (p-methoxyphenyl) pyrrole
Ud fra 2-amino-2-(p-metoxyfenyl)-acetonitril og acetylacetaldehyd vindes det âbenkædede mellemprodukt med kogepunkt 18o°C/ o,o3 mmHg. Samlet udbytte for den i overskriften angivne forbindel-15 se: 44%, smeltepunkt 198-2oo°C (fra diætylæter).From the 2-amino-2- (p-methoxyphenyl) -acetonitrile and acetylacetaldehyde, the open-chain intermediate with boiling point 18 ° C / o, o3 mmHg is obtained. Total yield of the title compound: 44%, mp 198-250 ° C (from diethyl ether).
9. 3-amino-4-ben2oyl-5-metylpyrrol-hydroklorid9. 3-Amino-4-benzoyl-5-methylpyrrole hydrochloride
Ud fra aminoacetonitril og benzoylacetone vindes den âbenkædede forbindelse med smeltepunkt 111-112°C (fra diætylæter). Samlet 20 udbytte for den i overskriften angivne forbindelse 52%. Smeltepunkt 225-27o°C (fra ætanol/diætylæter).From aminoacetonitrile and benzoylacetone, the monoblend compound is obtained, mp 111-112 ° C (from diethyl ether). A total of 20 yields for the title compound 52%. Melting point 225-27 ° C (from ethanol / diethyl ether).
10. 4-acetyl-3-amino-5-metylpyrrol-hydroklorid10. 4-Acetyl-3-amino-5-methylpyrrole hydrochloride
Ud fra aminoacetonitril og acetylacetone vindes den âbenkædede 25 mellemproduktforbindelse med smeltepunkt 1o6-1o8°C (fra diætylæter). Den i overskriften angivne forbindelse vindes med et samlet udbytte pâ 64%. Smeltepunkt 211-212°C (fra ætanol).From aminoacetonitrile and acetylacetone, the open-chain intermediate compound is obtained, m.p. 10 DEG-110 DEG C. (from diethyl ether). The title given is won with a total yield of 64%. Melting point 211-212 ° C (from ethanol).
.11. 4-ace tyl-3-amino-5-metyl-2-( p-tolyl)-pyrrol 30 Den i overskriften angivne forbindelse vindes i et samlet udbytte pâ 94% ud fra 2-amino-2-(p-tolyl)-acetonitril og acetylacetone. Smeltepunkt 232-234°C (fra ætanol/diætylæter).0.11. 4-Acetyl-3-amino-5-methyl-2- (p-tolyl) pyrrole The title compound is obtained in a total yield of 94% from 2-amino-2- (p-tolyl) - acetonitrile and acetylacetone. Melting point 232-234 ° C (from ethanol / diethyl ether).
Λ2. 4-acetyl-3-amino-2-(p-metoxyfenyl)-5-metylpyrrol 35 Den i overskriften angivne forbindelse vindes med et sam let udbytte pâ 92% ud fra 2-amino-2-(p-metoxyfenyl)-acetonitril og acetylacetone. Smeltepunkt 222-223°C (fra ætanol).Λ2. 4-Acetyl-3-amino-2- (p-methoxyphenyl) -5-methylpyrrole The title compound is obtained with a total yield of 92% from 2-amino-2- (p-methoxyphenyl) acetonitrile and acetylacetone. Melting point 222-223 ° C (from ethanol).
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13. 3-amino-4-3carbætoxy-5-metyl-2-( p-tolyl) -pyrrol-hydroklorid13. 3-Amino-4-3 carbethoxy-5-methyl-2- (p-tolyl) pyrrole hydrochloride
Ud fra 2-amino-2-(p-tolyl)-acetonitril og ætylacetoacetat vindes den âbenkædede mellemproduktforbindelse med kogepunkt 16o°C/ o,o5 mmHg. Samlet udbytte af den i overskriften angivne forbindelse: 5 88%. Smeltepunkt 266-268°C (fra metanol).From 2-amino-2- (p-tolyl) -acetonitrile and ethylacetoacetate, the open-chain intermediate compound having a boiling point of 16 ° C / o, 0.5 mmHg is obtained. Total yield of the title compound: 5 88%. Melting point 266-268 ° C (from methanol).
14. 4-acetyl-3-amino-2-(p-fluorfenyl)-5-metylpyrrol14. 4-Acetyl-3-amino-2- (p-fluorophenyl) -5-methylpyrrole
Ud fra 2-amino-2-(p-fluorfenyl)-acetonitril og acetylacetone vindes den âbenkædede mellemproduktforbindelse med kogepunkt 15o°c/ 10 o,3 mmHg. Samlet udbytte af den i overskriften angivne forbindelse er 47%. Smeltepunkt 211-212°C (fra æt.anol).From 2-amino-2- (p-fluorophenyl) -acetonitrile and acetylacetone, the open-chain intermediate compound having a boiling point of 15 ° C / 10.0.3 mmHg is obtained. Total yield of the title compound is 47%. Melting point 211-212 ° C (from ethanol).
15. 3-amino-4-karbætoxy-2-(p-fluorfenyl)-S-metylpyrrol-hydroklorid15. 3-Amino-4-carbethoxy-2- (p-fluorophenyl) -S-methylpyrrole hydrochloride
Det âbenkædede mellemprodukt vindes ud fra 2-amino-2-(p-fluor-15 fenyl)-acetonitril og ætylacetoacetat. Kogepunkt 22o°c/o,2 mmHg.The open-chain intermediate is recovered from 2-amino-2- (p-fluorophenyl) -acetonitrile and ethylacetoacetate. Boiling point 22 ° C / o, 2 mmHg.
Det i overskriften angivne produkt vindes med et samlet udbytte pâ 53% og med smeltepunkt 258-26o°C (fra ætanol/diætylæter).The title product is obtained with a total yield of 53% and m.p. 258-26 ° C (from ethanol / diethyl ether).
16. 3-amino~4-karbætoxy-5--metylpyrrol-hydroklor id 20 Den âbenkædede mellemproduktforbindelse vindes ud fra amino- acetonitril og ætylacetoacetat med kogepunkt 9o-98°C (fra metanol}. Den i overskriften angivne forbindelse vindes i et samlet udbytte pâ 44% med smeltepunkt 211-214°C (fra metanol).16. 3-Amino ~ 4-carbethoxy-5-methylpyrrole hydrochloride 20 The open-chain intermediate compound is recovered from aminoacetonitrile and ethylacetoacetate with boiling point 90 DEG-98 DEG C. (from methanol). yield 44% with mp 211-214 ° C (from methanol).
25 17. 3-amino-4-isobutyryl-5-metyl--2-f enylpyrrol17. 3-Amino-4-isobutyryl-5-methyl-2-phenylpyrrole
Den âbenkædede mellemproduktforbindelse vindes ud fra 2-amino- 2-fenyl-acetonitril og 5-metylhexan-2,4-dion. Kogepunkt 15o°C/o,3 mmHg. Samlet udbytte af den i overskriften angivne forbindelse er 64%, smeltepunkt 18o-183°C (fra metanol/dietylæter).The open-chain intermediate compound is recovered from 2-amino-2-phenyl-acetonitrile and 5-methylhexane-2,4-dione. Boiling point 15 ° C / o, 3 mmHg. Total yield of the title compound is 64%, mp 18o-183 ° C (from methanol / diethyl ether).
30 18. 3-amino-5-metyl-2-f enyl-4-propionylpyrro.l18. 3-Amino-5-methyl-2-phenyl-4-propionylpyrrol
Ud fra 2-amino-2-fenylacetonitril og iiexan-2,4-dion vindes den âbenkædede mellemproduktforbindelse med kogepunkt 16o°C/o,3 mmHg. Det i overskriften angivne produkt vindes i et samlet udbytte pâ 35 53% med smeltepunkt 166-168°C (fra metanol).From 2-amino-2-phenylacetonitrile and hexane-2,4-dione, the open-chain intermediate compound having a boiling point of 16 ° C / o, 3 mmHg is obtained. The title product is obtained in a total yield of 53%, m.p. 166-168 ° C (from methanol).
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19. 4-acetyl-3-amino-5-metyl-2-(m-tolyl)-pyrrol19. 4-Acetyl-3-amino-5-methyl-2- (m-tolyl) pyrrole
Ud fra 2-amino-2-(m-tolyl)-acetonitril og acetylacetone vin-des den âbenkædede mellemproduktforbindelse med kogepunkt 17o°C/ o,o2imn Hg. Den i overskriften angivne forbindelse vindes i et 5 samlet udbytte pâ 59% med smeltepunkt 195-197°C (fra ætanol).From 2-amino-2- (m-tolyl) -acetonitrile and acetylacetone, the open-chain intermediate compound having a boiling point of 17 ° C / o, o2 µm Hg is obtained. The title compound is obtained in an overall yield of 59%, mp 195-197 ° C (from ethanol).
2 0. 4-acetyl-3-amino-2-ætyl-5-metylpyrrol-hydroklorid2 0. 4-Acetyl-3-amino-2-ethyl-5-methylpyrrole hydrochloride
Den i overskriften angivne forbindelse vindes i et samlet udbytte pâ 73% ud fra 2-aminobutyronitril og acetylacetone. Smel-10 tepunkt 245-248°C (fra metanol).The title compound is obtained in a total yield of 73% from 2-aminobutyronitrile and acetylacetone. Melting point 245-248 ° C (from methanol).
21. 3-amino-4-(p-metoxybenzoyl)-5-metyl-2-fenylpyrrol21. 3-Amino-4- (p-methoxybenzoyl) -5-methyl-2-phenylpyrrole
Den i overskriften angivne forbindelse vindes i et samlet udbytte pâ 43% ud fra 2-amino-2-fenylacetonitril og (p-metoxybenzoyl)-15 acetone. Smeltepunkt 219-221"C (fra ætanol).The title compound is obtained in a total yield of 43% from 2-amino-2-phenylacetonitrile and (p-methoxybenzoyl) -15 acetone. Melting point 219-221 ° C (from ethanol).
22. 4-acetyl-3-amino-2-(p-benzyloxyfenyl)-5-metylpyrrol22. 4-Acetyl-3-amino-2- (p-benzyloxyphenyl) -5-methylpyrrole
Den i overskriften angivne forbindelse vindes med et samlet udbytte pâ 51% ud fra 2-amino-2-(p-benzoloxyfenyl)-acetonitril 20 og acetylacetone. Smeltepunkt 245-25o°C (fra ætanol).The title compound is obtained with a total yield of 51% from 2-amino-2- (p-benzoloxyphenyl) -acetonitrile 20 and acetylacetone. Melting point 245-25 ° C (from ethanol).
23. 4-acetyl-3-amino-2-(p-klorfenyl)-5-metylpyrrol23. 4-Acetyl-3-amino-2- (p-chlorophenyl) -5-methylpyrrole
Den i overskriften angivne forbindelse vindes med et samlet udbytte pâ 67% ud fra 2-amino-2-(p-klorfenyl)-acetonitril og 25 acetylacetone. Smeltepunkt 2o5-2o8°C (fra ætanol).The title compound is obtained with a total yield of 67% from 2-amino-2- (p-chlorophenyl) -acetonitrile and 25-acetylacetone. Melting point 205-288 ° C (from ethanol).
24 3-amino-4-karbatoxy-2-(p-metoxyfenyl)-5-metylpyrrol-hydro-klorid24 3-Amino-4-carbatoxy-2- (p-methoxyphenyl) -5-methylpyrrole hydrochloride
Den i overskriften angivne forbindelse vindes i et samlet 30 udbytte pâ 44% ud fra 2-amino-2-(p-metoxyfenyl)-acetonitril og ætylacetoacetat. Smeltepunkt 234-236°C (fra metanol).The title compound is obtained in a total yield of 44% from 2-amino-2- (p-methoxyphenyl) -acetonitrile and ethylacetoacetate. Melting point 234-236 ° C (from methanol).
s 25. 3-amino°4-benzoyl-2-(p-fluorfenyl)-5-metylpyrrols 25. 3-Amino ° 4-benzoyl-2- (p-fluorophenyl) -5-methylpyrrole
Ud fra 2=amino-2~(p-fluorfenyl)-acetonitril og benzoylacetone 35 vindes den âbenkædede mellemproduktsforbindelse med kogepunkt 12o°C/ , . vindçs o,2 mmHg. Den 1 overskriften angivne forbindelse/ι et samlet udbytte pâ 66% med smeltepunkt 2o9-21o°C (fra ætanol/diætylæter).From 2 = amino-2- (p-fluorophenyl) -acetonitrile and benzoylacetone 35, the open-chain intermediate compound having a boiling point of 12 ° C is obtained. winds o, 2 mmHg. The title compound (1) gives a total yield of 66% with m.p. 20 ° to 21 ° C (from ethanol / diethyl ether).
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26. 4-acety l-3-amino-2-(o-tolyl)-5--metylpyrrol26. 4-Acetyl 1-3-amino-2- (o-tolyl) -5-methylpyrrole
Ud fra 2-amino-2-(o-tolyl)-acetonitril qg acetylacetone vindes den âbenkædede forbindelse med kogepunkt 12o°C/o,2 mmHg.From 2-amino-2- (o-tolyl) -acetonitrile and acetylacetone, the open-chain compound having a boiling point of 120 ° C / o, 2 mmHg is obtained.
Den i overskriften angivne forbindelse vindes i et samlet udbytte 5 pâ 77% med smeltepunkt 258°C (fra metanol).The title compound is obtained in a total yield 5 of 77%, m.p. 258 ° C (from methanol).
27. 3-amino-5-metyl-4-metylkarbamyl-2-fenylpyrrol-hydroklorid27. 3-Amino-5-methyl-4-methylcarbamyl-2-phenylpyrrole hydrochloride
Den i overskriften angivne forbindelse vdndes i et samlet udbytte pâ 55% ud fra 2-amino-2-fenylacetonitr.il og a-acetyl-N-10 metylacetamid·.· Smeltepunkt 247-25o°C (fra ætanol).The title compound is recovered in a combined yield of 55% from 2- amino-2-phenylacetonitrile and α-acetyl-N-10 methylacetamide · Melting point 247-25 ° C (from ethanol).
28» 3-amino-4-(o-klorbenzoyl)-5-metyl-2-fenylpyrrol28 »3-Amino-4- (o-chlorobenzoyl) -5-methyl-2-phenylpyrrole
Den i overskriften angivne forbindelse vindes i et samlet udbytte pâ 51% ud fra 2-amino-2-fenylacetonitril og o-klorben-15 zoylacetone. Smeltepunkt 214-216°C (fra ætanoX).The title compound is obtained in a total yield of 51% from 2-amino-2-phenylacetonitrile and o-chlorobenzoylacetone. Melting point 214-216 ° C (from ethanol).
2 9. 3-amino-4-butyryl-2-fenyl-5-propylpyrrol-hydroklorid9. 3-Amino-4-butyryl-2-phenyl-5-propylpyrrole hydrochloride
Den i overskriften angivne forbindelse vindes i et samlet udbytte pâ' 6o% ud fra 2-amino-2-fenylacetonitril og nonan-4,6-20 dion. Smeltepunkt 228-23o°C med sonderdeling (fra metanol/diætyl- æter).The title compound is obtained in a total yield of 6% from 2-amino-2-phenylacetonitrile and nonan-4,6-20 dione. Melting point 228-23 ° C with probe division (from methanol / diethyl ether).
30. 3-amino-4-butyryl-5-metyl-2-f enylpyrrol-shydroklorid30. 3-Amino-4-butyryl-5-methyl-2-phenylpyrrole hydrochloride
Den i overskriften angivne forbindelse vindes i et samlet 25 udbytte pâ 48% ud fra 2-amino-2-fenylacetonitr.il og heptan-2,4- dion. Smeltepunkt 240-245°C med senderdeling (fra metanol/diætyl-æter).The title compound is obtained in a total yield of 48% from 2- amino-2-phenylacetonitrile and heptane-2,4-dione. Melting point 240-245 ° C with transmitter partition (from methanol / diethyl ether).
Eksempel 31 30 =========== 4-acetyl-3-benzoylamino-5-metyl-2-fenylpyrrol fremstilles ud fra den i eksempel 1 fremstilleâe forbindelse og benzoylklorid. Udbytte 79%. Smeltepunkt 3ol-3o3°C (fra ætanol/vand).Example 31 4-Acetyl-3-benzoylamino-5-methyl-2-phenylpyrrole is prepared from the compound of Example 1 and benzoyl chloride. Yield 79%. Melting point 3ol-300 ° C (from ethanol / water).
Eksempel 32-36 16Examples 32-36 16
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Ud fra eddikesyreanhydrid og et udvalgt aminopyrrolderivat i nærværelse a£ pyridin og ved i det væsentlige at gâ frem som be-5 skrevet af E.E. Royals, Advanced Organic Chemistry, side 616-617,From acetic anhydride and a selected aminopyrrole derivative in the presence of pyridine and by essentially proceeding as described by E.E. Royals, Advanced Organic Chemistry, pages 616-617,
New York, Prentice Hall Inc., 1954, til acylering af aminer, frem-stilles folgende forbindelser: 32. 3-acetylamino~4-karbætoxy-5-metyl-2-fenylpyrrol 10 ved anvendelse af den i eksempel 2 fremstillede forbindelse som aminopyrrolreaktionspartner. üdbytte 89%. Smeltepunkt 213-215°C (fra ætanol).New York, Prentice Hall Inc., 1954, for the acylation of amines, the following compounds are prepared: 32. 3-Acetylamino ~ 4-carbethoxy-5-methyl-2-phenylpyrrole 10 using the compound of Example 2 as an aminopyrrole reaction partner . Yield yield 89%. Melting point 213-215 ° C (from ethanol).
33. 3-acetylamino-4-benzoyl-5-metylpyrrol 15 ved anvendelse af den i eksempel 11 vundne forbindelse som aminopyrrolreaktionspartner. üdbytte 86%. Smeltepunkt 182-183°C (fra ætylacetat/vand).33. 3-Acetylamino-4-benzoyl-5-methylpyrrole 15 using the compound obtained in Example 11 as an aminopyrrole reaction partner. Yield yield 86%. Melting point 182-183 ° C (from ethyl acetate / water).
34. 4-acetyl-3-acetylamino-5-metylpyrrol 20 ved anvendelse af den i eksempel 12 vundne forbindelse som aminopyrrolreaktionspartner. üdbytte 72%. Smeltepunkt 2o6-2o8°C (fra metanol).34. 4-Acetyl-3-acetylamino-5-methylpyrrole 20 using the compound obtained in Example 12 as an aminopyrrole reaction partner. Yield yield 72%. Melting point 2-6 ° C (from methanol).
35. 4-acetyl-3-acetylamino-5-metyl-2-fenylpyrrol 25 ved anvendelse af den i eksempel 1 vundne forbindelse som aminopyrrolreaktionspartner . üdbytte 8o%. Smeltepunkt 215-217°C (fra acetone/bexan).35. 4-acetyl-3-acetylamino-5-methyl-2-phenylpyrrole 25 using the compound obtained in Example 1 as an aminopyrrole reaction partner. Exchanges 8o%. Melting point 215-217 ° C (from acetone / bexane).
36. 3-acetylamino-4-karbætoxy-5-metylpyrrol 30 ved anvendelse af den i eksempel 2o vundne forbindelse som aminopyrrolreaktionspartner. üdbytte 9o%. Smeltepunkt 165-6o°C (fra ætylacetat).36. 3-Acetylamino-4-carbethoxy-5-methylpyrrole 30 using the compound obtained in Example 2o as an aminopyrrole reaction partner. Yield exchange 9%. Melting point 165-6 ° C (from ethyl acetate).
Eksempel .37 17Example .37 17
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4-acetyl-3-metansulfonamido-5-metyl-2-fenylpyrrol4-acetyl-3-methanesulfonamido-5-methyl-2-pyrrole
Til en oplosning af 5 g (0,0278 mol) af xLen i eksempel 1 5 vundne forbindelse i 4o ml pyridin sættes under omroring ved 0°CTo a solution of 5 g (0.0278 mol) of xLene in Example 1 5 obtained in 4o ml of pyridine is added with stirring at 0 ° C.
2,6 g (o,0228 mol) metansulfonylklorid. Omroringen fortsættes i en time hvorpâ opl0Sningen henstâr natten over ved 0°C. Reaktions-blandingen udhældes i lo%s vandig saltsyre og xlet dannende bundfald omkrystalliseres fra vandigt ætanol. Udbytte 4,1 g, smeltepunkt 10 172-175°C.2.6 g (0.228 mol) of methanesulfonyl chloride. Stirring is continued for one hour at which time the solution is left overnight at 0 ° C. The reaction mixture is poured into 100% aqueous hydrochloric acid and xylated precipitate is recrystallized from aqueous ethanol. Yield 4.1 g, mp 10 172-175 ° C.
Eksempel 38 4-karbætoxy-3-metansulfonamido-5-metyl-2-fenylpyrrol 15 fremstilles pâ den i eksempel 37 beskrevne mâde ud fra den i eksempel 2 vundne forbindelse og metansulfonylklorid. Udbytte 83%. Smeltepunkt 173-174°C (fra vandigt ætanol).Example 38 4-Carbethoxy-3-methanesulfonamido-5-methyl-2-phenylpyrrole 15 is prepared in the manner described in Example 37 from the compound obtained in Example 2 and methanesulfonyl chloride. Yield 83%. Melting point 173-174 ° C (from aqueous ethanol).
Eksempel 39 20 =========== 4-acetyl-3-dimetylamino-5-nietyl-2-fenylpyrrol fremstilles ud fra den i eksempel 1 vundne forbindelse ved alky-lering med dimetylsulfat. Udbytte 68%. Smeltepunkt 153-155°C (fra kloroform).Example 39 4 = Acetyl-3-dimethylamino-5-methyl-2-phenylpyrrole is prepared from the compound obtained in Example 1 by alkylation with dimethyl sulfate. Yield 68%. Melting point 153-155 ° C (from chloroform).
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Eksempel 40 4-benzoyl-3-is.opropylamino-5-metyl-2-fenylpyrrolExample 40 4-Benzoyl-3-isopropylamino-5-methyl-2-phenylpyrrole
Den i overskriften angivne forbindelse fremstilles ved at 30 omsætte ækvimolære mængder af den if0lge eksempel 3 vundne for bindelse og isopropylbromid ved stuetemperatur,. Udbytte 31%. Smeltepunkt 132-136°C (fra hexan).The title compound is prepared by reacting equimolar amounts of the compound of Example 3 obtained for bonding and isopropyl bromide at room temperature. Yield 31%. Melting point 132-136 ° C (from hexane).
Eksempel 41 35 4-acetyl-3-formamido-2-(p-metoxyfenyl)-5-metylpyrrol 5 g (o,o2o6 mol) af den i eksempel 12 vundne forbindelse ««ΜΛΜ ^ Γμ «Μ Ί ûre/ MA. -AA _____A _ A Ai JaM AA A A. A A 1 J.AAA A.. J A A _ "1 A. A .A Â .. _ 18Example 41 4-Acetyl-3-formamido-2- (p-methoxyphenyl) -5-methylpyrrole 5 g (o, o2o6 mole) of the compound obtained in Example 12 «ΜΛΜ ^ Γμ« Μ Ί ure / MA. -AA _____A _ A Ai JaM AA A A. A A 1 J.AAA A .. J A A _ "1 A. A .A Â .. _ 18
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koges under tilbagesvaling i l5-2o min. Derpâ afkoles reaktions-blandingen og udïiældes i isvand. Det dannede bundfald opsamles ved filtrering og omkrystalliseres fra metanol. ïïdbytte 2,5 g a£ den i overskriften angivne forbindelse med smeltepunkt 21o-211°C. 5Boil under reflux for l5-2o min. The reaction mixture is then cooled and poured into ice water. The precipitate formed is collected by filtration and recrystallized from methanol. Exchange 2.5 g of the title compound, mp 21o-211 ° C. 5
Eksempel 42 4-karbætoxy-3-formamido-5-metyl-2-fenylpyrrolExample 42 4-Carbethoxy-3-formamido-5-methyl-2-phenylpyrrole
Denne forbindelse freinstilles soin beskrevet i eksempel 41 10 ud fra den i eksempel 2 vundne forbindelse. ïïdbytte 83 %.This compound is released as described in Example 41 10 from the compound obtained in Example 2. Yield 83%.
Smeltepunkt 18o-182°C (fra ætanol/vand).Melting point 18o-182 ° C (from ethanol / water).
Eksempel 43 15 4~acetyl-3-(p~klorbenzylidenamino)-5-metyl--2-fenylpyrrolExample 43 4-Acetyl-3- (p-chlorobenzylideneamino) -5-methyl-2-phenylpyrrole
En opl0sning af 5,o g (o,o234 mol) af den i eksempel 1 vnndne forbindelse i 2oo ml ætanol sættes til en oplosning afA solution of 5 µg (0.2234 moles) of the compound obtained in Example 1 in 20 ml of ethanol is added to a solution of
5,o g (o,o358 mol) p-klorbenzaldehyd i loo ml ætanol ved 45-5o°C hvorefter den resulterende blanding koges under tilbagesvaling 20 i ca. 4 timer. Efter afkoling udhældes reaktionsblandingen i 12oo ml vand mættet med natriumklorid. Der dannes et bundfald som opsamles ved filtrering og omkrystalliseres fra ætanol/vand. ïïdbytte 9,5 g af den i overskriften angivne forbindelse med smeltepunkt 214-215°CP-chlorobenzaldehyde in 100 ml of ethanol at 45-5 ° C, then the resulting mixture is refluxed for 20 minutes at ca. 4 hours. After cooling, the reaction mixture is poured into 1200 ml of water saturated with sodium chloride. A precipitate is formed which is collected by filtration and recrystallized from ethanol / water. Yield 9.5 g of the title compound, mp 214-215 ° C
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Eksempel 44 4-acetyl-3-benzylidenamino-’5-metyl-2-f enylpyrrol fremstilles pâ den i eksempel 43 beskrevne raàde ud fra den i 30 eksempel 1 vundne forbindelse og benzaldehyd. ïïdbytte 87%. Smeltepunkt 173-176°C (fra metanol).Example 44 4-Acetyl-3-benzylideneamino-5-methyl-2-phenylpyrrole is prepared in the manner described in Example 43 from the compound obtained in Example 1 and benzaldehyde. Yield 87%. Melting point 173-176 ° C (from methanol).
Eksempel 45 35 4-acetyl-3-amino°l15-dime tyl-2-fenylpyrro1 a) En opissning af 1,4 g (o,oo467 mol) af den i eksempel 44 vundne forbindelse i 25 ml dimetylformamid sættes drâbevis til 19Example 45 4-Acetyl-3-amino-1,15-dimethyl-2-phenylpyrroline a) An addition of 1.4 g (0.14646 mole) of the compound obtained in Example 44 in 25 ml of dimethylformamide is added dropwise to 19
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en kold suspension af natriumhydrid i lo ml dimetylformamid.a cold suspension of sodium hydride in 100 ml of dimethylformamide.
Den resulterende blanding omrores ved ca. o-5°C i 15 min. hvorpâ der tilsættes 1 ml metyljodid (o,ol61 mol). Omroringen fortsættes i 3o min. ved ca. 0°C og i 3o min. ved stuetemperatur hvorpâ der 5 sættes 15o ml vand til reaktionsblandingen som derefter ekstra-heres med di$tylæter.-Den organiske fase skilles fra og oplos-ningsmidlet afdampes. Den resulterende remanens (1,2 g) omkry-stalliseres fra isopropanol/vand. Smeltepunkt 136-138°C. Pro-duktet er 4-acetyl-3-benzylidenamino-l,5-dimetyl-2-£enylpyrrol.The resulting mixture is stirred at ca. o-5 ° C for 15 min. to which is added 1 ml of methyl iodide (o, ol61 mol). Stirring is continued for 3 min. at about. 0 ° C and for 3 min. at room temperature at which 15 ml of water is added to the reaction mixture, which is then extracted with diethyl ether. The organic phase is separated and the solvent is evaporated. The resulting residue (1.2 g) is recrystallized from isopropanol / water. Melting point 136-138 ° C. The product is 4-acetyl-3-benzylideneamino-1,5-dimethyl-2-phenylpyrrole.
10 b) l,o g (o,oo316 mol) a£ den i eksempel 45 a) fremstillede forbindelse opl0ses i 3o ml lo%s vandig saltsyre og den resulterende oplosning opvarmes til 8o-9o°C i ca. 2 timer. Ved a£-koling og neutralisation med natriumhydroxyd dannes et bundfald som omkrystalliseres fra ætanol/vand. Udbytte o,8 g af den i 15 overskriften angivne forbindelse med smeltepunkt 124-216°C.B) 10 g (0.316 mol) of the compound prepared in Example 45 (a) is dissolved in 30 ml of 100% aqueous hydrochloric acid and the resulting solution is heated to 80 ° C for about 10 minutes. 2 hours. Upon α-carbonation and neutralization with sodium hydroxide, a precipitate is formed which is recrystallized from ethanol / water. Yield 8 g of the title compound, mp 124-216 ° C.
vedby
Det tilsvarende hydroklorid smelter/2o8-2o9°C (fra ætanol/ diætylæter).The corresponding hydrochloride melts / 20 ° -28 ° C (from ethanol / diethyl ether).
Eksempel 46 20 =========== 4-acetyl-3-amino-l-ætyl-5-metyl-2-fenylpyrrolExample 46 =========== 4-acetyl-3-amino-1-ethyl-5-methyl-2-phenylpyrrole
Ved at gâ frem som under punkt a) i eksempel 45 og ved at gâ ud fra den i eksempel 71 vundne forbindelse og ætyljodid 25 vindes 4-acetyl-3-benzylidenamino-l-ætyl-5-metyl-2-fenylpyrrol med smeltepunkt 139-141°C (fra isopropanol/vand). Denne forbindelse hydrolyseres som angivet under b) i eksempel 74 hvorved den i overskriften angivne forbindelse vindes i et samlet udbytte pâ 54% og med smeltepunkt lo7-lo8°C (fra ætanol).Proceeding as under point (a) of Example 45 and starting from the compound and ethyl iodide obtained in Example 71, 4-acetyl-3-benzylideneamino-1-ethyl-5-methyl-2-phenylpyrrole is obtained, m.p. -141 ° C (from isopropanol / water). This compound is hydrolyzed as indicated in b) in Example 74 whereby the title compound is obtained in a total yield of 54% and m.p. 177-118 ° C (from ethanol).
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Eksempel 47 4-acetyl-3-amino-5-metyl-2-fenyl-l-propylpyrrol 35 Ved at gâ ud fra den i eksempel 44 vundne forbindelse og propyljodid og ved at gâ frem som under a) i eksempel 45 vindes 4-acetyl-3-benzylidenamino-5-metyl-2-fenyl-l-propylpyrrol som et olieagtigt stof. Denne forbindelse hydrolyseres som under b) 20Example 47 4-Acetyl-3-amino-5-methyl-2-phenyl-1-propylpyrrole 35 Starting from the compound and propyl iodide obtained in Example 44 and proceeding as under a) in Example 45, 4- acetyl-3-benzylideneamino-5-methyl-2-phenyl-1-propylpyrrole as an oily substance. This compound is hydrolyzed as under b) 20
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i eksempel 45 hvorved den i overskriften angivne forbindelse vindes i et udbytte pâ 5o% og med smeltepunkt 113-115°C (fra ætanol).in Example 45 where the title compound is obtained in a yield of 50% and m.p. 113-115 ° C (from ethanol).
5 Eksempel 48 4-acetyl-3-amino-l-(p-klorbenzyl)-5-metyl-2-fenylpyrrol 4-acetyl-3-benzylidenamino-l-(p-klorbenzyl)-5-mety1-2-10 fenylpyrrol fremstilles ud fra den i eksempel 44 vundne for-bindelse og p-klorbenzylklorid ved at gâ frem som under punkt a) i eksempel 45 . Smeltepunkt 136-137°C (fra ætanol/vand).Example 48 4-Acetyl-3-amino-1- (p-chlorobenzyl) -5-methyl-2-phenylpyrrole 4-acetyl-3-benzylideneamino-1- (p-chlorobenzyl) -5-methyl-2-phenylpyrrole is prepared from the compound obtained in Example 44 and p-chlorobenzyl chloride by proceeding as under point (a) of Example 45. Melting point 136-137 ° C (from ethanol / water).
Denne forbindelse hydrolyseres som under b) i eksempel 74 hvor-ved man vinder den i overskriften angivne forbindelse i et ud-15 bytte pâ 58% og med smeltepunkt 164-166°C (fra ætanol/vand).This compound is hydrolyzed as under b) in Example 74, whereby the title compound is obtained in a yield of 58% and m.p. 164-166 ° C (from ethanol / water).
Eksempel 49 20 4-acetyl-l-(o-klorben2yl)-5-metyl-3-dimetylamino-2-fenylpyrrolExample 49 4-Acetyl-1- (o-chlorobenzyl) -5-methyl-3-dimethylamino-2-phenylpyrrole
Den i overskriften angivne forbindelse fremstilles med et udbytte pâ 67% ud fra den i eksempel 39 vundne forbindelse og o-klorbenzylklorid og ved at gâ frem som under a) i eksempel 45.The title compound is prepared with a yield of 67% from the compound obtained in Example 39 and o-chlorobenzyl chloride and by proceeding as under (a) in Example 45.
Smeltepunkt lo3-lo5°C (fra isopropanol).Melting point lo3-lo5 ° C (from isopropanol).
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Eksempel 50 4-ace ty 1-1- ( p-klorbenzyl ) - 5~me ty1-3-dime ty lamino-2-f e ny lpyrr ο 1 30 Den i overskriften angivne forbindelse vindes i et udbytte pâ 52% ud fra den i eksempel 39 vundne forbindelse og p-klorbenzylklorid og ved at gâ frem som under punkt a) i eksempel 45. Smeltepunkt 118-119°C (frahexan).Example 50 4-ace ty 1-1- (p-chlorobenzyl) -5-dimethyl-3-dime ty lamino-2-Fe new pyrrole ο 1 The title compound is obtained in a yield of 52% from the compound and p-chlorobenzyl chloride obtained in Example 39 and by proceeding as under point a) of Example 45. Melting point 118-119 ° C (frahexane).
35 Eksempel 51 4-k arbæt oxy-3 - ( N-me ty 1-me t ansu lf onamido ) -1,5-dime tyl-2-f enylpyrrol Ud fra den i eksempel 38 vundne forbindelse og metyljodid 21Example 51 4-kb oxy-3- (N-methyl 1-methanesulfonamido) -1,5-dimethyl-2-phenylpyrrole From the compound of Example 38 and methyl iodide 21
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og ved at folge den under punkt a) i eksempel 45 beskrevne procedure vindes den i overskriften angivne forbindelse i et udbytte pâ 71% og med smeltepunkt 138-14o°C (fra ætanol/acetone).and following the procedure described in (a) of Example 45, the title compound is obtained in a yield of 71% and mp 138-14o ° C (from ethanol / acetone).
5 Eksempel 52 4-acety 1-3-( o-karboxyf enyl) -amino-5-metyl-2-f enylpyrrolExample 52 4-Acetyl 1-3- (o-carboxyphenyl) -amino-5-methyl-2-phenylpyrrole
En suspension af 2 g (o,oo934 mol) af den i eksempel 1 10 vundne forbindelse, 1,87 g (o,oo934 mol) o-brombenzoesyre, 2 g natriumacetat og o,5 g kobberpulver i 15o ml vand koges under tilbagesvaling i 4 timer. Efter afkoling henstâr blandingen natten over. Der dannes et bundfald som opsamles ved filtrering og omkrystalliseres fra vandigt metanol. Det i overskriften angivne 15 produkt vindes i et udbytte pâ 1,5 g og med smeltepunkt 260-262°C, Eksempel 53 3-amino-5-karbamyl-4-karbometoxy-2-fenylpyrrol 20 En opl0sning af 5 g (o,o161 mol) 3-amino-4,5-dikarbometoxy- 2- fenylpyrrol-hydroklorid mættes med gasformigt ammoniak hvoref-ter den henstâr i 2 dage. Et produkt udkrystalliseres og opsamles ved filtrering. Udbytte 2,8 g, smeltepunkt 177-179°C (fra metanol/vand).A suspension of 2 g (o, oo934 mole) of the compound obtained in Example 11, 1.87 g (o, oo934 mole) of o-bromobenzoic acid, 2 g of sodium acetate and 0.5 g of copper powder in 15 ml of water is refluxed. for 4 hours. After cooling, the mixture is left to stand overnight. A precipitate is formed which is collected by filtration and recrystallized from aqueous methanol. The title product is obtained in a yield of 1.5 g and m.p. 260-262 ° C, Example 53 3-Amino-5-carbamyl-4-carbomethoxy-2-phenylpyrrole 20 A solution of 5 g (o, o161 mole) of 3-amino-4,5-dicarbomethoxy-2-phenylpyrrole hydrochloride is saturated with gaseous ammonia and then left for 2 days. A product is crystallized and collected by filtration. Yield 2.8 g, mp 177-179 ° C (from methanol / water).
2525
Eksempel 54 3- acetylaniino-4-karboxy-5-metyl-2-f enylpyrrol vindes i et udbytte pâ 49% ved sur hydrolyse af den i eksempel 30 32 vundne forbindelse. Smeltepunkt 258-26o°C (fra ætanol/vand).Example 54 3- Acetylamino-4-carboxy-5-methyl-2-phenylpyrrole is obtained in a yield of 49% by acidic hydrolysis of the compound obtained in Example 30 32. Melting point 258-26 ° C (from ethanol / water).
Eksempel 55 4- karboxy~3-metansulfonamid-5-metyl-2-fenylpyrrol 35 vindes i et udbytte pâ 54% ved sur hydrolyse af den i eksempel 38 vundne forbindelse. Smeltepunkt 269-271°C (fra acetone/vand).Example 55 4- Carboxy ~ 3-methanesulfonamide-5-methyl-2-phenylpyrrole 35 is recovered in a 54% yield by acidic hydrolysis of the compound obtained in Example 38. Melting point 269-271 ° C (from acetone / water).
Eksempel 56 22Example 56 22
DK 156391 BDK 156391 B
4-acetyl-5-metyl-3-metylamino-2-fenylpyrrol 1,5 g (o,oo366 mol) 4-acetyl-5-metyl-3-(N-metylfenacylsul-5 fonamido)-2-fenylpyrrol suspenderes i 1oo ml eddikesyre og 5 ml koncentreret saltsyre ved stuetemperatur hvorpâ der i smâ por-tioner tilsættes 1,1 g zinkpulver. Den resulterende blanding omr0res i 2 timer ved stuetemperatur, zinken fjernes ved filtrer ing og filtratet ekstraheres 2 gange med 2oo ml ætylacetat.4-Acetyl-5-methyl-3-methylamino-2-phenylpyrrole 1.5 g (o, oo366 mol) of 4-acetyl-5-methyl-3- (N-methylphenacylsulfonamido) -2-phenylpyrrole are suspended in 100 ml of acetic acid and 5 ml of concentrated hydrochloric acid at room temperature, to which 1.1 g of zinc powder is added in small portions. The resulting mixture is stirred for 2 hours at room temperature, the zinc is removed by filtration and the filtrate is extracted twice with 20 ml of ethyl acetate.
10 Efter afdampning af ætylacetatet vindes en remanens som optages i ætylæter og filtreres. Der vindes o,3 g af den i overskriften angivne forbindelse med smeltepunkt 174-176°C.After evaporation of the ethyl acetate, a residue is obtained which is taken up in ethyl ether and filtered. O, 3 g of the title compound is obtained, mp 174-176 ° C.
Eksempel 57 15 =========== 4-benzoyl-3-ætylamino-5-metyl-2-fenylpyrrolExample 57 =========== 4-benzoyl-3-ethylamino-5-methyl-2-phenylpyrrole
Denne forbindelse vinder man i et udbytte pâ 44% ud fra 4-benzoyl-3-(N-ætyl-p-toluensulfonamido)-5-metyl-2-fenylpyrrol ved at f01ge den metode der er beskrevet i eksempel 56. Smelte-20 punkt 178-18o°C (fra ætanol/vand).This compound is obtained in a yield of 44% from 4-benzoyl-3- (N-ethyl-p-toluenesulfonamido) -5-methyl-2-phenylpyrrole by following the method described in Example 56. Melting-20 point 178-18 ° C (from ethanol / water).
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3979073A GB1427945A (en) | 1973-08-22 | 1973-08-22 | Aminopyrrole derivatives |
| GB3979073 | 1973-08-22 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK445974A DK445974A (en) | 1975-04-28 |
| DK156391B true DK156391B (en) | 1989-08-14 |
| DK156391C DK156391C (en) | 1990-01-08 |
Family
ID=10411528
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK445974A DK156391C (en) | 1973-08-22 | 1974-08-21 | ANALOGY PROCEDURE FOR PREPARING 3-AMINOPYR ROLLER DERIVATIVES |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS5328914B2 (en) |
| AR (3) | AR210246A1 (en) |
| AT (1) | AT336600B (en) |
| BE (1) | BE819088A (en) |
| CA (1) | CA1050556A (en) |
| CH (1) | CH605741A5 (en) |
| CS (1) | CS188201B2 (en) |
| DD (1) | DD113756A5 (en) |
| DE (4) | DE2439284C2 (en) |
| DK (1) | DK156391C (en) |
| ES (3) | ES429446A1 (en) |
| FI (1) | FI61879C (en) |
| FR (1) | FR2241308B1 (en) |
| GB (1) | GB1427945A (en) |
| HU (1) | HU169728B (en) |
| IE (1) | IE40290B1 (en) |
| IL (1) | IL45368A (en) |
| IN (1) | IN140329B (en) |
| LU (1) | LU70764A1 (en) |
| NL (1) | NL7411092A (en) |
| NO (1) | NO143845C (en) |
| PL (2) | PL96806B1 (en) |
| RO (3) | RO70534A (en) |
| SE (1) | SE394429B (en) |
| SU (1) | SU843738A3 (en) |
| YU (1) | YU36926B (en) |
| ZA (1) | ZA744754B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1492663A (en) * | 1975-02-20 | 1977-11-23 | Lepetit Spa | 4-amino-3-pyrrole carboxamides |
| GB1548398A (en) * | 1975-06-05 | 1979-07-11 | Lilly Industries Ltd | Acylamino pyrroles furans and thiophenes |
| DE3212591A1 (en) * | 1982-04-03 | 1983-10-13 | Gödecke AG, 1000 Berlin | 2-PYRROLIN-3-CARBONITRIL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| JPH0216740U (en) * | 1988-07-21 | 1990-02-02 | ||
| EP0390739B1 (en) * | 1989-03-28 | 1995-08-09 | Ciba-Geigy Ag | Substituted aminopyrroles as stabilisers in chlorinated polymers |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1148908A (en) * | 1965-04-19 | 1969-04-16 | Sumitomo Chemical Co | Indole derivatives and processes for making them |
| GB1187903A (en) * | 1967-09-29 | 1970-04-15 | Sumitomo Chemical Co | Glucuronides of 3-Indolylaliphatic Acid Derivatives and Processes for Producing them |
-
1973
- 1973-08-22 GB GB3979073A patent/GB1427945A/en not_active Expired
-
1974
- 1974-07-27 ZA ZA00744754A patent/ZA744754B/en unknown
- 1974-07-29 IL IL45368A patent/IL45368A/en unknown
- 1974-08-01 YU YU2141/74A patent/YU36926B/en unknown
- 1974-08-08 NO NO742862A patent/NO143845C/en unknown
- 1974-08-08 IE IE1672/74A patent/IE40290B1/en unknown
- 1974-08-16 DE DE2439284A patent/DE2439284C2/en not_active Expired
- 1974-08-16 DE DE2462963A patent/DE2462963C2/en not_active Expired
- 1974-08-16 DE DE2462966A patent/DE2462966C2/en not_active Expired
- 1974-08-16 DE DE2462967A patent/DE2462967C2/en not_active Expired
- 1974-08-16 DD DD180545A patent/DD113756A5/xx unknown
- 1974-08-19 RO RO7491734A patent/RO70534A/en unknown
- 1974-08-19 RO RO7491735A patent/RO70535A/en unknown
- 1974-08-19 RO RO79830A patent/RO72882B/en unknown
- 1974-08-20 LU LU70764A patent/LU70764A1/xx unknown
- 1974-08-20 NL NL7411092A patent/NL7411092A/en unknown
- 1974-08-20 IN IN1864/CAL/1974A patent/IN140329B/en unknown
- 1974-08-21 DK DK445974A patent/DK156391C/en active
- 1974-08-21 JP JP9600974A patent/JPS5328914B2/ja not_active Expired
- 1974-08-21 SU SU742055571A patent/SU843738A3/en active
- 1974-08-21 CH CH1142674A patent/CH605741A5/xx not_active IP Right Cessation
- 1974-08-21 HU HULE754A patent/HU169728B/hu not_active IP Right Cessation
- 1974-08-21 FI FI2462/74A patent/FI61879C/en active
- 1974-08-21 CA CA207,472A patent/CA1050556A/en not_active Expired
- 1974-08-21 SE SE7410636A patent/SE394429B/en not_active IP Right Cessation
- 1974-08-22 AT AT684774A patent/AT336600B/en not_active IP Right Cessation
- 1974-08-22 BE BE147818A patent/BE819088A/en not_active IP Right Cessation
- 1974-08-22 ES ES429446A patent/ES429446A1/en not_active Expired
- 1974-08-22 PL PL1974189700A patent/PL96806B1/en unknown
- 1974-08-22 CS CS745833A patent/CS188201B2/en unknown
- 1974-08-22 PL PL1974173617A patent/PL95235B1/pl unknown
- 1974-08-22 FR FR7428894A patent/FR2241308B1/fr not_active Expired
- 1974-08-27 AR AR255253A patent/AR210246A1/en active
-
1976
- 1976-06-03 AR AR263502A patent/AR210132A1/en active
- 1976-06-03 AR AR263503A patent/AR210133A1/en active
- 1976-07-01 ES ES449425A patent/ES449425A1/en not_active Expired
- 1976-07-01 ES ES449426A patent/ES449426A1/en not_active Expired
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