NO135064B - - Google Patents

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Publication number
NO135064B
NO135064B NO1234/68A NO123468A NO135064B NO 135064 B NO135064 B NO 135064B NO 1234/68 A NO1234/68 A NO 1234/68A NO 123468 A NO123468 A NO 123468A NO 135064 B NO135064 B NO 135064B
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halogen
lower alkyl
indolyl
alkyl
methoxy
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NO1234/68A
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Norwegian (no)
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NO135064C (en
Inventor
Shen Tsung-Ying
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Merck & Co Inc
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Priority claimed from US28693563 external-priority patent/US3161654A/en
Priority claimed from US296451A external-priority patent/US3201414A/en
Priority claimed from US314503A external-priority patent/US3242185A/en
Application filed by Merck & Co Inc filed Critical Merck & Co Inc
Publication of NO135064B publication Critical patent/NO135064B/no
Publication of NO135064C publication Critical patent/NO135064C/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Description

Foreliggende oppfinnelse angår utgangsmaterialer for fremstilling av terapeutisk aktive N-acylerte 3-indolyl-lavere alifatiske syrer, og estere og salter derav, og disse utgangsmaterialer er karakterisert ved den generelle formel: The present invention relates to starting materials for the production of therapeutically active N-acylated 3-indolyl-lower aliphatic acids, and esters and salts thereof, and these starting materials are characterized by the general formula:

hvor R1 er fenyl, bifenylyl, eller nafthyl som kan være substituert med hydroxyl, lavere alkyl, lavere alkoxy, carbo-lavere alkoxy, lavere alkanoyl, lavere alkanoyloxy, fenyl, fenoxy , benzyl, benzyloxy, benzoyl, amino, mono- eller di-lavere alkylamino, lavere alkanoylamido, N,N-di-(lavere alkyl)-carboxamido, aminomethyl, , nit ro, cyano, halogen, halogen-lavere alkyl, halogen-lavere alkoxy, halogen-lavere alkanoyl, mercapto, lavere alkylthio, halogen-lavere alkylthio, fenylthio, benzylthio, benzoylthio, lavere alkylsulfonyl, lavere alkylsulfinyl eller di-(lavere alkyl)-sulfamoyl, R,, er hydrogen eller lavere alkyl, R^ er hydrogen eller lavere alkyl og R^ er hydrogen, hydroxyl, lavere alkyl, lavere alkenyl, lavere alkoxy, di-lavere alkylamino, lavere alkanoylamido, N-lavere alkyl-lavere alkanoylamido, di-lavere alkylaminomethy1, halogen, nitro, cyano, mercapto, benzylthio, di-lavere alkylsulfamoyl, morfolinyl, N-methyl-piperazinyl, N-pyrrolidyl eller N-azacyclopropy1. where R1 is phenyl, biphenylyl, or naphthyl which may be substituted with hydroxyl, lower alkyl, lower alkoxy, carbo-lower alkoxy, lower alkanoyl, lower alkanoyloxy, phenyl, phenoxy, benzyl, benzyloxy, benzoyl, amino, mono- or di- lower alkylamino, lower alkanoylamido, N,N-di-(lower alkyl)-carboxamido, aminomethyl, , nitro, cyano, halogen, halogen-lower alkyl, halogen-lower alkoxy, halogen-lower alkanoyl, mercapto, lower alkylthio, halogen -lower alkylthio, phenylthio, benzylthio, benzoylthio, lower alkylsulfonyl, lower alkylsulfinyl or di-(lower alkyl)-sulfamoyl, R,, is hydrogen or lower alkyl, R^ is hydrogen or lower alkyl and R^ is hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, di-lower alkylamino, lower alkanoylamido, N-lower alkyl-lower alkanoylamido, di-lower alkylaminomethy1, halogen, nitro, cyano, mercapto, benzylthio, di-lower alkylsulfamoyl, morpholinyl, N-methyl- piperazinyl, N-pyrrolidyl or N-azacyclopropy1.

Disse utgangsmaterialer er vel egnet for fremstilling av terapeutisk aktive N-acylerte 3-indolyl-lavere alifatiske syrer med den generelle formel: These starting materials are well suited for the production of therapeutically active N-acylated 3-indolyl-lower aliphatic acids with the general formula:

hvor R^, R2> R^ og R,- er som ovenfor angitt, og estere og salter derav som også er terapeutisk aktive, jfr. norsk patent nr. 116.466. where R^, R2 > R^ and R,- are as stated above, and esters and salts thereof which are also therapeutically active, cf. Norwegian patent no. 116,466.

Det foretrukne utgangsmateriale ifølge foreliggende oppfinnelse er t-butyl-(l-p-klorbenzoyl-2-methyl-5-methoxy-3-indolyl)-acetat, idet dette utgangsmateriale gir den foretrukne terapeutisk aktive frie syre. The preferred starting material according to the present invention is t-butyl-(1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)-acetate, this starting material giving the preferred therapeutically active free acid.

De ovenfor nevnte terapeutisk aktive forbindelser av formel II har en sterk anti-inflammatorisk aktivitet og kan brukes til å hindre og hemme dannelse av granulomavev. Enkelte av forbindelsene har denne aktivitet i sterk grad og er verdifulle ved behandling av arthritis og dermatologiske sykdommer og lignende tilstander som responderer på behandling med anti-inflamma-toriske midler. The above-mentioned therapeutically active compounds of formula II have a strong anti-inflammatory activity and can be used to prevent and inhibit the formation of granuloma tissue. Some of the compounds have this activity to a strong degree and are valuable in the treatment of arthritis and dermatological diseases and similar conditions that respond to treatment with anti-inflammatory agents.

Et viktig trekk ved disse terapeutisk aktive forbindelser er aroylgruppen på nitrogenatomet i 1-stillingen. Denne gruppe kan innføres ved acylering av en passende substituert 3_indolyl-lavere alifatisk syre eller en ester derav. I de tilfelle hvor den frie syre ønskes som sluttprodukt, kan esteren omdannes til denne frie syre under passende reaksjonsbetingelser. Det har vist seg at 1-aroy1-substituenten lett lar seg hydrolysere under be-tingelser som vanligvis brukes ved forsåpning av en ester til den frie syre. Av denne grunn må der utvises forsiktighet ved omdann-elsen av l-aroyl-3-indolyl-carboxylsyreesteren til den tilsvarende frie syre. Det har vist seg at det er fordelaktig å anvende t-butylesteren, som lar seg fjerne selektivt, f.eks. ved oppvarmning til over 210°C, eller ved oppvarmning ved 25-HO°C i nærvær av en katalytisk mengde av en organisk sulfonsyre eller annen syre, eller ved oppvarmning til over 25°C i et inert oppløsningsmiddel An important feature of these therapeutically active compounds is the aroyl group on the nitrogen atom in the 1-position. This group can be introduced by acylation of a suitably substituted 3_indolyl-lower aliphatic acid or an ester thereof. In those cases where the free acid is desired as the final product, the ester can be converted into this free acid under suitable reaction conditions. It has been shown that the 1-aroyl1-substituent can easily be hydrolysed under conditions that are usually used when saponifying an ester to the free acid. For this reason, care must be taken when converting the 1-aroyl-3-indolyl carboxylic acid ester to the corresponding free acid. It has been found to be advantageous to use the t-butyl ester, which can be removed selectively, e.g. by heating above 210°C, or by heating at 25-HO°C in the presence of a catalytic amount of an organic sulphonic acid or other acid, or by heating above 25°C in an inert solvent

i nærvær av en sterk syre (norsk patent 116.466). in the presence of a strong acid (Norwegian patent 116,466).

Av de ovenfor nevnte grunner er derfor t-butylest erne med formel I ovenfor gunstige utgangsmaterialer for fremstilling av de frie syrer uten å påvirke 1-substituenten på indolringen. For the reasons mentioned above, the t-butyl esters of formula I above are therefore favorable starting materials for the preparation of the free acids without affecting the 1-substituent on the indole ring.

Eksempel 1 Example 1

t- butyl- 1- p- klorbenzoy1- 2- methy1- 5- methoxy- 3- indolylacet at t- butyl- 1- p- chlorobenzoy1- 2- methyl1- 5- methoxy- 3- indolylacet at

(A) 2-methyl-5-methoxy-3-indolyleddiksyre-anhydrid. (A) 2-methyl-5-methoxy-3-indolylacetic anhydride.

10 g (0,049 mol) dicyclohexylcarbodiimid oppløses i en opp-løsning av 22 g 2-methyl-5-methoxy-3-indolyleddiksyre (O,10 mol) i 200 ml tetrahydrofuran, og oppløsningen hensettes ved romtemperatur i 2 timer. Det utfelte urinstoff fjernes ved filtrer-ing, og filtratet inndampes i vakuum til et residuum og vaskes med "Skellysolve B". Det tilbakeblivende, oljeaktige anhydrid anvendes uten rensning i det neste trinn. 10 g (0.049 mol) of dicyclohexylcarbodiimide are dissolved in a solution of 22 g of 2-methyl-5-methoxy-3-indolylacetic acid (0.10 mol) in 200 ml of tetrahydrofuran, and the solution is allowed to stand at room temperature for 2 hours. The precipitated urea is removed by filtration, and the filtrate is evaporated in vacuum to a residue and washed with "Skellysolve B". The remaining oily anhydride is used without purification in the next step.

(B) t-butyl-2-methyl-5-methoxy-3-indolylacetat. (B) t-butyl 2-methyl-5-methoxy-3-indolyl acetate.

25 ml t-butylalkohol og 0,3 g smeltet zinkklorid tilsettes 25 ml of t-butyl alcohol and 0.3 g of molten zinc chloride are added

anhydridet fra A ovenfor. Oppløsningen oppvarmes under tilbake-løp i l6 timer, og overskudd av alkohol fjernes under vakuum. Residuet oppløses i ether, vaskes flere ganger med mettet bicar-bonatoppløsning, vann og mettet saltoppløsning. Efter tørring over magnesiumsulfat behandles oppløsningen med trekull, inndampes og vaskes flere ganger med "Skellysolve B" for fullstendig fjernelse av alkohol. Den tilbakeblivende, oljeaktige ester, the anhydride from A above. The solution is heated under reflux for 16 hours, and excess alcohol is removed under vacuum. The residue is dissolved in ether, washed several times with saturated bicarbonate solution, water and saturated salt solution. After drying over magnesium sulphate, the solution is treated with charcoal, evaporated and washed several times with "Skellysolve B" for complete removal of alcohol. The residual, oily ester,

18 g tilsvarende 93%, anvendes uten rensning. 18 g corresponding to 93%, used without purification.

(C) t-butyl-1-p-klorbenzoyl-2-methyl-5-methoxy-3-indolylacetat. (C) t-butyl 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl acetate.

En oppløsning av 18 g (0,065 mol) ester i 450 ml tørt A solution of 18 g (0.065 mol) ester in 450 ml dry

dimethylformamid kjøles til 4°C i et isbad, og 4,9 g (0,098 mol) natriumhydrid i 50%'s suspensjon tilsettes i porsjoner. Efter 15 minutter tilsettes 15 g p-klorbenzoylklorid (0,085 mol) dråpevis i løpet av IO minutter, og blandingen omrøres i 9 timer uten fornyelse av isbadet. Blandingen blir så helt over i en liter 5%'s eddiksyre, ekstrahert med en blanding av ether og benzen, vasket grundig med vann, bicarbonat, mettet salt, tørret over magnesiumsulfat, behandlet med trekull og inndampet til ef residuum som delvis krystalliserer. Dette rystes med ether, der filtreres, og filtratet inndampes til et residuum (17 g) som størkner efter kjøling natten over. Råproduktet kokes med 300 ml dimethylformamide is cooled to 4°C in an ice bath, and 4.9 g (0.098 mol) of sodium hydride in 50% suspension is added in portions. After 15 minutes, 15 g of p-chlorobenzoyl chloride (0.085 mol) are added dropwise over 10 minutes, and the mixture is stirred for 9 hours without renewing the ice bath. The mixture is then poured into a liter of 5% acetic acid, extracted with a mixture of ether and benzene, washed thoroughly with water, bicarbonate, saturated salt, dried over magnesium sulphate, treated with charcoal and evaporated to a residue which partially crystallizes. This is shaken with ether, then filtered, and the filtrate is evaporated to a residue (17 g) which solidifies after cooling overnight. The raw product is boiled with 300 ml

"Skellysolve B", kjøles til romtemperatur, væsken dekanteres fra noe gummiaktig materiale, behandles med trekull, inndampes til lOO ml og hensettes for krystallisasjon. Det således erholdte produkt (10 g) omkrystalliseres fra 50 ml methanol og gir 4,5 g analytisk rent t-butyl-1-p-klorbenzoyl-2-methyl-5-methoxy-3-indolylacetat med smp. 103 - 104°C. "Skellysolve B", cooled to room temperature, the liquid decanted from some rubbery material, treated with charcoal, evaporated to lOO ml and set aside for crystallization. The product thus obtained (10 g) is recrystallized from 50 ml of methanol and gives 4.5 g of analytically pure t-butyl-1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl acetate with m.p. 103 - 104°C.

Eksempel 2 Example 2

t- butyl- l- p- methylthiobenzoyl- 2- methyl- 5- methoxy- 3- indolyl- a-propionat t- butyl- l- p- methylthiobenzoyl- 2- methyl- 5- methoxy- 3- indolyl- a-propionate

(A) 2-methyl-5-methoxy-3-indolyl-a-propionsyre-anhydrid. (A) 2-methyl-5-methoxy-3-indolyl-α-propionic anhydride.

9 g (0,O44 mol) dicyclohexylcarbodiimid oppløses i en opp-løsning av 21 g (0,09 mol) 2-methyl-5-methoxy-3-indolyl-a-propion-syre og 200 ml tetrahydrofuran, og oppløsningen hensettes i 2 timer ved romtemperatur. Det utfelte urinstoff fjernes ved fil-trering, og filtratet inndampes i vakuum til et residuum og vaskes med "Skellysolve B". Det tilbakeblivende, oljeaktige anhydrid anvendes uten rensning. 9 g (0.044 mol) of dicyclohexylcarbodiimide are dissolved in a solution of 21 g (0.09 mol) of 2-methyl-5-methoxy-3-indolyl-α-propionic acid and 200 ml of tetrahydrofuran, and the solution is placed in 2 hours at room temperature. The precipitated urea is removed by filtration, and the filtrate is evaporated in vacuum to a residue and washed with "Skellysolve B". The remaining oily anhydride is used without purification.

(B) t-butyl-2-methyl-5-methoxy-3-indolyl-a-propionat. (B) t-butyl-2-methyl-5-methoxy-3-indolyl-α-propionate.

25 ml t-butylalkohol og 0,3 9 sammensmeltet zinkklorid tilsettes ovennevnte anhydrid. Oppløsningen oppvarmes under tilba.ke-løp i 16 timer, og overskuddet av alkohol fjernes i vakuum. Residuet oppløses i ether, vaskes flere ganger med mettet bicarbonat, vann og mettet saltoppløsning. Efter tørring over mag-nesiumsulf at behandles oppløsningen med trekull, inndampes og vaskes flere ganger med "Skellysolve B" for fullstendig fjernelse av alkohol. Den tilbakeblivende, oljeaktige ester (14 g) anvendes uten rensning. (C) t-butyl-l-p-methylthiobenzoy1-2-methy1-5-methoxy-3-indoly1-a-propionat. 20 g (0,69 mol) av den ovenfor under B erholdte ester opp-løst i 450 ml tørt dimethylformamid kjøles til 4°C under omrøring i et isbad, og 5,2 g natriumhydrid (0,10 mol, 5% suspensjon) tilsettes i porsjoner. Blandingen omrøres i 10 minutter, hvorpå 17 g p-methylthiobenzoylklorid (smp. 5l°C, 0,091 mol) tilsettes i porsjoner i løpet av 10 minutter, og blandingen omrøres i 7 timer ved romtemperatur uten fornyelse av isbadet. Blandingen blir så helt over i en liter 5%<*>s eddiksyre, ekstrahert med ether, 25 ml of t-butyl alcohol and 0.3 g of fused zinc chloride are added to the above-mentioned anhydride. The solution is heated under reflux for 16 hours, and the excess alcohol is removed in vacuo. The residue is dissolved in ether, washed several times with saturated bicarbonate, water and saturated salt solution. After drying over magnesium sulphate, the solution is treated with charcoal, evaporated and washed several times with "Skellysolve B" to completely remove alcohol. The remaining oily ester (14 g) is used without purification. (C) t-butyl-1-p-methylthiobenzoyl-2-methyl-5-methoxy-3-indolyl-α-propionate. 20 g (0.69 mol) of the ester obtained above under B dissolved in 450 ml of dry dimethylformamide is cooled to 4°C with stirring in an ice bath, and 5.2 g of sodium hydride (0.10 mol, 5% suspension) added in portions. The mixture is stirred for 10 minutes, after which 17 g of p-methylthiobenzoyl chloride (m.p. 51°C, 0.091 mol) is added in portions over 10 minutes, and the mixture is stirred for 7 hours at room temperature without renewing the ice bath. The mixture is then poured into a liter of 5%<*>s acetic acid, extracted with ether,

vasket grundig med vann, bicarbohat, mettet saltoppløsning, tørret over magnesiumsulfat, behandlet med trekull og inndampet i vakuum til et residuum, vekt 33 g. Dette oppløses i ether, blandes med 100 g syrevasket aluminiumoxyd, hvorpå der inndampes til tørrhet i vakuum og kromatograferes fra "Skellysolve B" i en kolonne inne-holdende 300 g syrevasket aluminiumoxyd. Efter vaskning med "Skellysolve B" elueres produktet med 5% ether i "Skellysolve B", washed thoroughly with water, bicarbonate, saturated salt solution, dried over magnesium sulfate, treated with charcoal and evaporated in vacuo to a residue, weight 33 g. This is dissolved in ether, mixed with 100 g of acid-washed aluminum oxide, then evaporated to dryness in vacuo and chromatographed from "Skellysolve B" in a column containing 300 g of acid-washed aluminum oxide. After washing with "Skellysolve B", the product is eluted with 5% ether in "Skellysolve B",

hvilket gir t -butyl-1-p-met hy lthiobenzoy 1 -2 -met hy 1-5-methoxy -3-indolyl-a-propionat i form av en gul olje (11 g, 36%). giving t -butyl-1-p-meth hy lthiobenzoy 1 -2 -meth hy 1-5-methoxy -3-indolyl-α-propionate as a yellow oil (11 g, 36%).

Eks empel 3 Example 3

t- butyl- l- p- klorbenzoy1- 2- methy1- 5- methoxy- 3- indoly1- g- propionat t- butyl- l- p- chlorobenzoy1- 2- methyl1- 5- methoxy- 3- indoly1- g- propionate

(A) Til en oppløsning av 20,O g (0,07 mol) t-butyl-a-(2-methyl-5-methoxy-3~indolyl)-propionat i 270 ml dimethylformamid settes i (A) To a solution of 20.0 g (0.07 mol) t-butyl-α-(2-methyl-5-methoxy-3-indolyl)-propionate in 270 ml of dimethylformamide is added

små porsjoner 7,0 g (0,14 mol) 51% natriumhydrid i mineralolje under nitrogen med omrøring og iskjøling. Efter 15 minutter ble 17,5 g (0,10 mol) p-klorbenzoylklorid tilsatt dråpevis, hvorved et hvitt bunnfall utskiltes nesten øyeblikkelig. Blandingen omrøres ved 0°C i 2 timer og hensettes i et koldt rom natten over. Neste morgen filtreres blandingen og fortynnes med ether. En halvpart av oppløsningen vaskes med vann, natriumbicarbonat, derpå igjen med vann og tørres over natriumsulfat. Den tørrede oppløsning inndampes til en sirup som kromatograf eres på 4-00 g syrevasket aluminiumoxyd. Efter at mineralolje og spor av forurensninger er eluert med petrolether og 5% ether i petrolether, erholdes det ønskede produkt, t-butyl-l-p-klorbenzoyl-2-methyl-5-methoxy-3-indolyl-a-propionat, i form av en gul olje ved eluering med 10% small portions 7.0 g (0.14 mol) 51% sodium hydride in mineral oil under nitrogen with stirring and ice cooling. After 15 minutes, 17.5 g (0.10 mol) of p-chlorobenzoyl chloride was added dropwise, whereby a white precipitate separated almost immediately. The mixture is stirred at 0°C for 2 hours and left in a cold room overnight. The next morning, the mixture is filtered and diluted with ether. Half of the solution is washed with water, sodium bicarbonate, then again with water and dried over sodium sulphate. The dried solution is evaporated to a syrup which is chromatographed on 4-00 g of acid-washed aluminum oxide. After mineral oil and traces of impurities are eluted with petroleum ether and 5% ether in petroleum ether, the desired product, t-butyl-l-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl-α-propionate, is obtained in the form of a yellow oil by elution with 10%

ether i petrolether. Den annen halvpart behandles på lignende måt e. ether in petroleum ether. The other half is treated in a similar way e.

Claims (2)

1. Kjemisk forbindelse for anvendelse som utgangsmateriale ved fremstilling av terapeutisk aktive N-acylerte 3-indolyl-lavere alifatiske syrer med den generelle formel: og estere og salter derav, hvor R^ er fenyl, bifenylyl eller nafthyl som kan være substituert med hydroxyl, lavere alkyl, lavere alkoxy, carbo-lavere alkoxy, lavere alkanoyl, lavere alkanoyloxy, fenyl, fenoxy, benzyl, benzyloxy, benzoyl, amino, mono- eller di-lavere alkylamino, lavere alkanoylamido, N,N-di-(lavere alkyl)-carboxamido, aminomethyl, nitro, cyano, halogen, halogen-lavere alkyl, halogen-lavere alkoxy, halogen-lavere alkanoyl, mercapto, lavere alkylthio, halogen-lavere alkylthio, fenylthio, benzylthio, benzoylthio, lavere alkylsulfonyl, lavere alkylsulfinyl eller di-(lavere alkyl)-sulfamoyl, R^ er hydrogen eller lavere alkyl, R^ er hydrogen eller lavere alkyl, og R,- er hydrogen, hydroxyl, lavere alkyl, lavere alkenyl, lavere alkoxy, di-lavere alkylamino, lavere alkanoylamido, N-lavere alkyl-lavere alkanoylamido, di-lavere alkylaminomethyl, halogen, nitro, cyano, mercapto, benzylthio, di-lavere alkylsulfamoyl, morfolinyl, N-methylpiperaziny1, N-pyrrolidyl eller N-azacyclo-propyl, karakterisert ved at den er en forbindelse med den generelle formel: hvor 1^, R2> R og R^ er som ovenfor angitt.1. Chemical compound for use as starting material in the preparation of therapeutically active N-acylated 3-indolyl-lower aliphatic acids of the general formula: and esters and salts thereof, where R^ is phenyl, biphenylyl or naphthyl which may be substituted with hydroxyl, lower alkyl, lower alkoxy, carbo-lower alkoxy, lower alkanoyl, lower alkanoyloxy, phenyl, phenoxy, benzyl, benzyloxy, benzoyl, amino, mono- or di-lower alkylamino, lower alkanoylamido, N,N-di-(lower alkyl)-carboxamido, aminomethyl, nitro, cyano, halogen, halogen-lower alkyl, halogen-lower alkoxy, halogen-lower alkanoyl, mercapto, lower alkylthio, halogen-lower alkylthio, phenylthio , benzylthio, benzoylthio, lower alkylsulfonyl, lower alkylsulfinyl or di-(lower alkyl)-sulfamoyl, R^ is hydrogen or lower alkyl, R^ is hydrogen or lower alkyl, and R,- is hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, di-lower alkylamino, lower alkanoylamido, N-lower alkyl-lower alkanoylamido, di-lower alkylaminomethyl, halogen, nitro, cyano, mercapto, benzylthio, di- lower alkylsulfamoyl, morpholinyl, N-methylpiperaziny1, N-pyrrolidyl or N-azacyclo-propyl, characterized in that it is a compound with the general formula: where 1^, R2 > R and R^ are as indicated above. 2. Forbindelse ifølge krav 1, karakterisert ved at den er t-butyl-(1-p-klor-benzoyl-2-methyl-5-methoxy-3-indolyl)-acetat.2. Connection according to claim 1, characterized in that it is t-butyl-(1-p-chloro-benzoyl-2-methyl-5-methoxy-3-indolyl)-acetate.
NO1234/68A 1961-03-22 1968-04-01 NO135064C (en)

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US9743461A 1961-03-22 1961-03-22
US16461562A 1962-01-05 1962-01-05
NO14373562 1962-03-21
US28693563 US3161654A (en) 1962-01-05 1963-06-11 alpha-(1-aroyl-3-indolyl) alkanoic acids
US296451A US3201414A (en) 1963-07-22 1963-07-22 New 1-heteroacyl-3-indolyl aliphatic acids
US31045463A 1963-09-20 1963-09-20
US31047763A 1963-09-20 1963-09-20
US314503A US3242185A (en) 1963-10-07 1963-10-07 Lower aliphatic acids, salts and derivatives thereof
US32386363A 1963-11-04 1963-11-04
US321328A US3275644A (en) 1962-01-05 1963-11-04 Certain 1-azolylindol-3-ylaliphatic acids
US321686A US3275645A (en) 1962-01-05 1963-11-06 N-(1-acyl-3-indolyl)-acids
US437338A US3338921A (en) 1962-01-05 1965-01-26 Thenoic and furoic acids
US442152A US3328423A (en) 1962-01-05 1965-03-23 alpha-(3-indolyl)-cyclopropyl lower aliphatic acids
US528020A US3316267A (en) 1962-01-05 1966-02-15 Indolyl acids

Publications (2)

Publication Number Publication Date
NO135064B true NO135064B (en) 1976-10-25
NO135064C NO135064C (en) 1977-02-02

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NO1234/68A NO135064C (en) 1961-03-22 1968-04-01
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CH (8) CH450420A (en)
CY (1) CY348A (en)
DE (3) DE1795543C3 (en)
DK (5) DK111959B (en)
FI (2) FI41158B (en)
GB (1) GB997638A (en)
MY (1) MY6600092A (en)
NO (2) NO135064C (en)
SE (5) SE315592B (en)

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HU176215B (en) 1978-01-27 1981-01-28 Chinoin Gyogyszer Es Vegyeszet Process for preparing a cyclodextrin-indomethacin inclusion complex with a ratio of at about 2:1
US7135495B2 (en) 2000-03-09 2006-11-14 Ono Pharmaceutical Co., Ltd. Indole derivatives
CA2459515A1 (en) * 2001-09-07 2003-03-20 Kazuhiko Torisu Indole derivatives
US20230218644A1 (en) 2020-04-16 2023-07-13 Som Innovation Biotech, S.A. Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus
CN113248419A (en) * 2021-06-09 2021-08-13 云南中医药大学 Synthesis method of novel HuR inhibitor 1-benzenesulfonyl-3-phenylindole-4, 5-dione
CN115417804A (en) * 2022-09-16 2022-12-02 天津药明康德新药开发有限公司 Synthesis method of 7-methyl-1H-indole-5-carboxylic acid

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NO122372B (en) 1971-06-21
DE1795543A1 (en) 1972-01-13
CH445491A (en) 1967-10-31
MY6600092A (en) 1966-12-31
NO135064C (en) 1977-02-02
CH445492A (en) 1967-10-31
SE315592B (en) 1969-10-06
CH445490A (en) 1967-10-31
CH426822A (en) 1966-12-31
CH449018A (en) 1967-12-31
CH450420A (en) 1968-01-31
SE315281B (en) 1969-09-29
SE314984B (en) 1969-09-22
DK114975B (en) 1969-08-25
DE1620031B1 (en) 1971-04-08
CY348A (en) 1966-06-03
DE1620030B1 (en) 1970-03-05
CH445493A (en) 1967-10-31
DK120637B (en) 1971-06-28
DK120340B (en) 1971-05-17
FI41158B (en) 1969-06-02
CH450419A (en) 1968-01-31
DK116737B (en) 1970-02-09
GB997638A (en) 1965-07-07
SE315282B (en) 1969-09-29
DK111959B (en) 1968-10-28
DE1795543C3 (en) 1980-06-04
FI41159B (en) 1969-06-02
DE1795543B2 (en) 1979-09-20
SE315593B (en) 1969-10-06

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