DK168377B1 - N- (1H-indol-4-yl) benzamide derivatives and their salts, process for their preparation, and pharmaceutical compositions containing them - Google Patents
N- (1H-indol-4-yl) benzamide derivatives and their salts, process for their preparation, and pharmaceutical compositions containing them Download PDFInfo
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Abstract
Description
DK 168377 B1DK 168377 B1
Opfindelsen angår nogle hidtil ukendte derivater af N-(1H-indol-4-yl)-benzamid samt deres salte og lægemidler med indhold heraf.The invention relates to some novel derivatives of N- (1H-indol-4-yl) -benzamide, as well as their salts and drugs containing them.
Derivater af N-(1H-indol-4-yl)-benzamid er beskrevet i eruopæisk patentansøgning 5 nr. 86401528.4, som er publiceret 11 MAR 1987 under nr. EP 213984 A1. Disse derivater har følgende almene formel: R3 ^ /R1 10 B o 0^· 15 hvor R og R-j indbyrdes uafhængigt repræsenterer et hydrogenatom, en lineær alkylgruppe med 1-5 carbonatomer, en forgrenet alkylgruppe med 3-5 carbonatomer, en cykloalkylgruppe med 3-7 carbonatomer, en cykloalkylalkylgruppe med 4-7 carbonatomer eller en aralkylgruppe med 7-12 carbonatomer, eventuelt substitueret med 1, 2 eller 3 grupper, som vælges blandt 20 halogen, methyl, ethyl, methoxy, ethoxy, trifluormethyl, methylthio, amino og nitro, eller R og Ri kan sammen danne en mættet eller umættet heterocyklisk gmppe, som eventuelt indeholder et andet heteroatom, som vælges blandt oxygen, svovl og nitrogen, idet nitrogenatomet eventuelt er substitueret med en alkylgruppe med 1-5 carbonatomer, phenyl, substitueret phenyl eller naphthyl eller med en aralkylgruppe med 7-12 carbonatomer, R3 betegner et hydro-25 genatom, en alkylgruppe med 1-5 carbonatomer, en alkoxygruppe med 1-3 carbonatomer, et chlor-, brom- eller iodatom, en nitrogruppe eller en aminogruppe, eventuelt substitueret med en alifatisk acylgruppe med 2-5 carbonatomer eller en alkylgruppe med 1-5 carbonatomer, hvor a sammen med b betegner en oxogruppe eller sammen med c en carbon-carbon-binding, hvor b betegner et hydrogenatom ellersammen med a en oxogruppe, hvor c betegner et hydrogena-30 tom eller sammen med a en carbon-carbon-binding, A betegner en kæde - (CH2)n -, hvor n -(CH,)m -CH -CH, - kan antage værdierne 2, 3,4 eller 5, eller betegner en kæde | hvor mDerivatives of N- (1H-indol-4-yl) -benzamide are disclosed in European Patent Application 5 No. 86401528.4 published March 11, 1987 under No. EP 213984 A1. These derivatives have the following general formula: wherein R 3 and R 10 independently represent a hydrogen atom, a linear alkyl group of 1-5 carbon atoms, a branched alkyl group of 3-5 carbon atoms, a cycloalkyl group of 3 -7 carbon atoms, a cycloalkylalkyl group of 4-7 carbon atoms or an aralkyl group of 7-12 carbon atoms, optionally substituted with 1, 2 or 3 groups selected from halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio, amino and nitro, or R and R 1 may together form a saturated or unsaturated heterocyclic group optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, the nitrogen atom being optionally substituted with an alkyl group having 1-5 carbon atoms, phenyl, substituted phenyl or naphthyl or with an aralkyl group of 7-12 carbon atoms, R3 represents a hydrogen atom, an alkyl group of 1-5 carbon atoms, an alkoxy group of 1-3 carbon atoms, a chloro, bromo or iodine atom, a nitro group or an amino group, optionally substituted with an aliphatic acyl group having 2-5 carbon atoms or an alkyl group having 1-5 carbon atoms, where a together with b represents an oxo group or together with c represents a carbon-carbon bond where b represents a hydrogen atom, together with a an oxo group, where c represents a hydrogen atom or together with a a carbon-carbon bond, A represents a chain - (CH2) n -, where n - (CH2) m -CH -CH - may assume the values 2, 3, 4 or 5, or denote a chain | how m
OHOH
kan antage værdierne 1,2 eller 3, B betegner en kæde -CO-NH- eller -NH-CO-, R2 betegner et hydrogenatom, en lineær alkylgruppe med 1-5 carbonatomer eller en forgrenet alkylgruppe med 3-5 carbonatomer.may assume the values 1,2 or 3, B represents a chain -CO-NH- or -NH-CO-, R 2 represents a hydrogen atom, a linear alkyl group of 1-5 carbon atoms or a branched alkyl group of 3-5 carbon atoms.
35 DK 168377 B1 235 DK 168377 B1 2
Disse forbindelser vides at være i besiddelse af interessante farmakologiske egenskaber og især bemærkelsesværdige anti-arytmiegenskaber. Foreliggende opfindelse omhandler hidtil ukendte forbindelser, som falder ind under den generelle formel fra førnævnte europæiske patentansøgning, hvilke hidtil ukendte forbindelser ligeledes har særdeles interessante anti-aryt-5 miegenskaber.These compounds are known to possess interesting pharmacological properties and especially remarkable antiarrhythmic properties. The present invention relates to novel compounds which fall within the general formula of the aforementioned European patent application, which novel compounds also have extremely interesting antiarrhythmic properties.
Den foreliggende opfindelse angår altså N-(1H-indol-4-yl)-benzamidderivater med formlen (I) samt disses additionssalte med syrer:The present invention thus relates to N- (1H-indol-4-yl) -benzamide derivatives of formula (I) and their addition salts with acids:
XX
Υ-Λ /CH3Υ-Λ / CH3
VV
H OH H CH3 6?H OH H CH3 6?
HH
hvor den ene af substituenteme X og Y betegner en alkylgruppe med 1-5 carbonatomer, en alkoxygruppe med 1-3 carbonatomer, et chlor-, brom- eller iodatom, en nitrogruppe eller en 20 aminogruppe, der eventuelt er substitueret med en alifatisk acylgruppe med 2-5 carbonatomer eller med en eller to alkylgrupper med 1-5 carbonatomer, og hvor den anden substituent betegner et hydrogenatom, dog betegner Y ikke en methoxygruppe, og X betegner ikke et chloratom.wherein one of the substituents X and Y represents an alkyl group of 1-5 carbon atoms, an alkoxy group of 1-3 carbon atoms, a chlorine, bromine or iodine atom, a nitro group or an amino group optionally substituted by an aliphatic acyl group having 2-5 carbon atoms or with one or two alkyl groups having 1-5 carbon atoms and the other substituent represents a hydrogen atom, however, Y does not represent a methoxy group and X does not represent a chlorine atom.
Når X eller Y betegner en alkylgruppe, foretrækkes en methyl- eller ethylgruppe, men de kan 25 også betegne en n-propyl-, isopropyl-, n-butyl-, isobutyl-, tert.-butyl- eller n-pentylgruppe.When X or Y represents an alkyl group, a methyl or ethyl group is preferred, but they may also represent an n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl group.
Når X eller Y betegner en alkoxygruppe, foretrækkes en methoxy-, ethoxy-, n-propoxy- eller isopropoxygruppe.When X or Y represents an alkoxy group, a methoxy, ethoxy, n-propoxy or isopropoxy group is preferred.
30 Når X eller Y betegner en aminogruppe, substitueret med en eller to alkylgrupper, foretrækkes methyl- eller ethyigrupper.When X or Y represents an amino group substituted by one or two alkyl groups, methyl or ethyl groups are preferred.
Additionssaltene med uorganiske eller organiske syrer kan f.eks. være de salte, som dannes med saltsyre, hydrogenbromidsyre, salpetersyre, svovlsyre, phosphorsyre, eddikesyre, myresy-35 re, propionsyre, benzoesyre, maleinsyre, fumarsyre, ravsyre, vinsyre, citronsyre, oxalsyre, glyoxylsyre, asparaginsyre og alkansulfonsyre såsom methan- eller ethansulfonsyre, arylsul-fonsyrer såsom benzen- eller p-toluensulfonsyre og arylcarboxylsyrer.The addition salts with inorganic or organic acids may e.g. be the salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid and alkanoic acid, , arylsulfonic acids such as benzene or p-toluenesulfonic acid and aryl carboxylic acids.
DK 168377 B1 3DK 168377 B1 3
Opfindelsen vedrører især sådanne forbindelser med formlen I samt disses additionssalte med syrer, hvor X betegner en methoxy-, nitro-, amino- eller acetylaminogruppe, og Y betegner et hydrogenatom, samt forbindelser, hvor Y betegner et chioratom eller en nitro-, amino- eller acetylaminogruppe, og X betegner et hydrogenatom, og ganske særligt vedrører opfindelsen 2-5 (3-((1,1 -dimethylethyl)-amino)-2-hydroxypropoxy)-N-(1 H-indol-4-yl)-5-nitrobenzamid samt den ne forbindelses additionssalte med syrer.The invention relates in particular to such compounds of formula I as well as their addition salts with acids wherein X represents a methoxy, nitro, amino or acetylamino group and Y represents a hydrogen atom, and compounds wherein Y represents a chlorine atom or a nitro, amino or acetylamino group, and X represents a hydrogen atom, and more particularly, the invention relates to 2-5 (3 - ((1,1-dimethylethyl) amino) -2-hydroxypropoxy) -N- (1H-indol-4-yl) - 5-nitrobenzamide as well as the addition compound salts with acids.
Forbindelser med formlen I kan ifølge den foreliggende opfindelse fremstilles ved en metode i lighed med den i europæisk patentansøgning nr. 86401528.4 beskrevne.Compounds of formula I can be prepared according to the present invention by a method similar to that described in European Patent Application No. 86401528.4.
1010
Fremgangsmåden til fremstilling af forbindelser ifølge den foreliggende opfindelse er ejendommelig ved, at man lader en forbindelse med formlen II:The process for preparing compounds of the present invention is characterized by leaving a compound of formula II:
XX
15 "0-OH15 "O-OH
Ao "Ao "
H-NH-N
Λη) 20Λη) 20
HH
hvor X og Y har den førnævnte betydning, reagere med et halogenid med formlen III:wherein X and Y have the aforementioned meaning, react with a halide of formula III:
Hal -CH2 -CH - CH2Hal -CH2 -CH - CH2
\ / III\ / III
OISLAND
25 under dannelse af en forbindelse med formlen IV:25 to form a compound of formula IV:
XX
Αχ 30 YVcH2-OT-Ci,2 pO 0Y 30 YVcH2-OT-Ci, 2 pO 0
H-HH-H
ifSri 35ifSri 35
HH
DK 168377 B1 4 som man lader reagere med tert.-butylamin under dannelse af en forbindelse med formlen I, som om ønsket kan udsættes for en uorganisk eller organisk syre under dannelse af et syreadditionssalt .Which is reacted with tert-butylamine to give a compound of formula I which, if desired, can be exposed to an inorganic or organic acid to form an acid addition salt.
5 Når X eller Y betegner en alkyl- eller alkoxygruppe eller et chlor-, brom- eller iodatom i forbindelsen med formlen II, foretrækkes et chloratom som Hal i forbindelsen med formlen III.When X or Y represents an alkyl or alkoxy group or a chlorine, bromine or iodine atom in the compound of formula II, a chlorine atom such as Hal in the compound of formula III is preferred.
Reaktionen mellem forbindelserne med formlerne II og III foretrækkes forløbende i nærvær af en base, såsom kalium- eller natriumcarbonat, natriumhydroxid eller kaliumhydroxid.The reaction of the compounds of formulas II and III is preferably preferred in the presence of a base such as potassium or sodium carbonate, sodium hydroxide or potassium hydroxide.
10 Når X eller Y i forbindelsen med formlen II betegner en nitrogruppe, foretrækkes et bromatom som Hal i forbindelsen med formlen III. Reaktionen forløber så under opvarmning med tilbagesvaling af forbindelsen med formlen IV.When X or Y in the compound of formula II represents a nitro group, a bromine atom such as Hal in the compound of formula III is preferred. The reaction then proceeds under reflux of the compound of formula IV.
15 Reaktionen mellem derivatet med den almene formel IV og tert.-butylamin foregår ved anvendelse af et opløsningsmiddel, f.eks. en alifatisk alkohol som methanol eller ethanol.The reaction of the derivative of the general formula IV with tert-butylamine is carried out using a solvent, e.g. an aliphatic alcohol such as methanol or ethanol.
Når man ønsker at fremstille en forbindelse med formlen I, hvor X eller Y betegner en eventuelt substitueret aminogruppe, kan man reducere forbindelsen med formlen I, hvor X eller Y 20 betegner en nitrogruppe og i givet fald lade dette aminoderivat reagere med et derivat af en substituent, som man ønsker at opnå.When one wishes to prepare a compound of formula I wherein X or Y represents an optionally substituted amino group, one may reduce the compound of formula I wherein X or Y 20 represents a nitro group and, where appropriate, react this amino derivative with a derivative of a substituent which one wishes to obtain.
De tilsvarende operative betingelser er kendt af fagfolk.The corresponding operating conditions are known to those skilled in the art.
25 Udgangsforbindelser med den almene formel II kan fremstilles ved en reaktion mellem 4-ami-noindol og en tilsvarende substitueret hydroxybenzoesyre.Starting compounds of the general formula II can be prepared by a reaction of 4-aminoindole with a corresponding substituted hydroxybenzoic acid.
De forbindelser, som ligger til grund for den foreliggende opfindelse, er i besiddelse af nogle meget interessante farmakologiske egenskaber. De er især i besiddelse af bemærkelsesværdi-30 ge anti-arytmiegenskaber, og visse forbindelser har anti-calciumvirkning.The compounds which form the basis of the present invention possess some very interesting pharmacological properties. In particular, they possess remarkable antiarrhythmic properties and certain compounds have anti-calcium action.
Disse egenskaber illustreres længere fremme i den eksperimentelle del.These properties are illustrated further in the experimental section.
Disse egenskaber retfærdiggør udnyttelsen af N-(1H-indol-4-yl)-benzamidderivateme med den 35 almene formel (I), såvel som deres salte, som lægemidler.These properties justify the utilization of the N- (1H-indol-4-yl) -benzamide derivatives of the general formula (I), as well as their salts, as drugs.
Forbindelserne ifølge opfindelsen finder anvendelse f.eks. ved behandling af arytmier.The compounds of the invention apply e.g. in the treatment of arrhythmias.
DK 168377 B1 5DK 168377 B1 5
Den sædvanlige dosis kan f.eks. være fra 50 mg til 1 g pr. dag, afhængig af den benyttede forbindelse og den pågældende patient og den optrædende lidelse. Forbindelsen ifølge eksempel 1 kan indgives ad oral vej til mennesker i en daglig dosis på 200-800 mg til behandling af ventrikulær og supraventrikulær arytmi samt ledarytmi svarende til 3-12 mg pr. kg le-5 gemsvægt.The usual dose may be e.g. be from 50 mg to 1 g per day. per day, depending on the compound used and the patient in question and the occurring disorder. The compound of Example 1 can be administered by oral route to humans at a daily dose of 200-800 mg for the treatment of ventricular and supraventricular arrhythmia and joint arrhythmia corresponding to 3-12 mg per day. kg of body weight.
Opfindelsen angår derfor ligeledes farmaceutiske præparater, der som aktiv bestanddel indeholder i det mindste et N-(1H-indol-4-yl)-benzamidderivat med ovennævnte formel I eller et additionssalt deraf med farmaceutisk acceptable syrer.The invention therefore also relates to pharmaceutical compositions containing as active ingredient at least one N- (1H-indol-4-yl) benzamide derivative of the above formula I or an addition salt thereof with pharmaceutically acceptable acids.
1010
Som lægemidler kan forbindelserne med formlen I og deres farmaceutisk acceptable additionssalte inkorporeres i farmaceutiske præparater beregnet til indgift ad fordøjelsesvejen eller ad parenteral vej.As drugs, the compounds of formula I and their pharmaceutically acceptable addition salts can be incorporated into pharmaceutical compositions intended for administration by the digestive or parenteral route.
15 Disse farmaceutiske præparater kan f.eks. være faste eller flydende og foreligge i de i den humane medicin normalt benyttede farmaceutiske former som f.eks. uoversukrede eller over-sukrede piller, gelatinepræparater, granulater, stikpiller og injektionspræparater. De fremstilles efter gængse metoder. Den eller de aktive bestanddele kan inkorporeres deri sammen med i sådanne farmaceutiske præparater normalt benyttede tilsætningsstoffer såsom talkum, gummi 20 arabicum, lactose, stivelse, magnesiumstearat, kakaosmør, vandige eller ikke-vandige bærestoffer, fedtstoffer af animalsk eller vegetabilsk oprindelse, paraffinderivater, glycoller og diverse fugte-, dispergerings- eller emulgeringsmidler samt konserveringsmidler.These pharmaceutical compositions may e.g. be solid or liquid and are present in the pharmaceutical forms normally used in human medicine, e.g. unsweetened or over-sugared pills, gelatin preparations, granules, suppositories and injection preparations. They are manufactured by conventional methods. The active ingredient (s) may be incorporated therein together with additives normally used in such pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fats of animal or vegetable origin, paraffin derivatives, glycols and various wetting, dispersing or emulsifying agents and preservatives.
Nedenstående eksempler illustrerer opfindelsen.The following examples illustrate the invention.
2525
Eksempel 1: 2-(3-((1,1-dimethylethyl)-amino)-2-hydroxypropoxy)-N-(1H-indol-4-yl)-5-nitrobenz-amid og chlorhydratet herafExample 1: 2- (3 - ((1,1-dimethylethyl) amino) -2-hydroxypropoxy) -N- (1H-indol-4-yl) -5-nitrobenzamide and its chlorohydrate
Man opvarmer under tilbagesvaling i løbet af 1 time 9,8 g 2-hydroxy-5-nitro-N-(1H-indol-4-yl)-30 benzamid med 40 ml epibromhydrin. Overskuddet af epibromhydrin fjernes ved 60 °C under formindsket tryk, man optager resten i 100 ml ethanol og 40 ml tert.-butylamin og opvarmer med tilbagesvaling i 2 timer. Overskydende opløsningsmiddel og reagens fjernes ved 60 °C under reduceret tryk, og man får 78 g råprodukt. Oprensningen sker ved to på hinanden følgende chromatografier på silicagel (elueringsmiddel ved den første: Chloroform : methanol: 35 triethylamin (8:1:1); elueringsmiddel ved den anden: Chloroform : acetone : triethylamin (5:4:1)). Man får 4,4 g af forbindelsen i basisk form med smeltepunkt 208 °C.At reflux, 9.8 g of 2-hydroxy-5-nitro-N- (1H-indol-4-yl) -benzamide is heated over 1 hour with 40 ml of epibromohydrin. The excess epibromohydrin is removed at 60 ° C under reduced pressure, the residue is taken up in 100 ml of ethanol and 40 ml of tert-butylamine and heated at reflux for 2 hours. Excess solvent and reagent are removed at 60 ° C under reduced pressure to give 78 g of crude product. The purification is performed by two successive chromatographs on silica gel (eluent at the first: chloroform: methanol: triethylamine (8: 1: 1); eluent at the second: chloroform: acetone: triethylamine (5: 4: 1)). 4.4 g of the compound is obtained in basic form, m.p. 208 ° C.
DK 168377 B1 6DK 168377 B1 6
Dannelse af chlorhvdratChlorine hydrate formation
Man opløser med tilbagesvaling 3,5 g af den ovenfor fremstillede base i en liter isopropanol og 250 ml methanol, tilsætter en mættet opløsning af saltsyre i ethylacetat indtil en sur pH-værdi.Reflux 3.5 g of the above-prepared base is dissolved in 1 liter of isopropanol and 250 ml of methanol, a saturated solution of hydrochloric acid in ethyl acetate is added to an acidic pH.
Man opvarmer 30 min med tilbagesvaling, inddamper til ca. 500 ml, isafkøler, filtrerer og tørrer 5 ved 50 °C under formindsket tryk. Man får 2,85 g af det forventede produkt med smeltepunkt 260 °C.Reflux for 30 minutes, evaporate to approx. 500 ml, ice-cooler, filter and dry at 50 ° C under reduced pressure. 2.85 g of the expected product is obtained, m.p. 260 ° C.
Analyse:Analysis:
Beregnet: C% 57,08 H% 5,88 N% 12,10 Cl% 7,66 10 Fundet: 56,8 6,1 12,0 7,4Calculated: C% 57.08 H% 5.88 N% 12.10 Cl% 7.66 Found: 56.8 6.1 12.0 7.4
Fremstilling af 2-hvdroxv-5-nitro-N-(1 H-indol-4-vQ-benzamidPreparation of 2-hydroxy-5-nitro-N- (1H-indole-4-yl-benzamide)
Man opvarmer under tilbagesvaling i løbet af 3 timer 6 g 4-aminoindol, 150 ml tetrahydrofuran, 8,4 g 5-nitrosalicylsyre og 12,5 g dicyklohexylcarbodiimid. Man afkøler, filtrerer, tilsætter 15 200 ml ethylacetat og fjerner ureageret 4-aminoindol ved vask med 1N saltsyre, tørrer, filtrerer, inddamper til tørhed ved 50 °C under formindsket tryk. Tilbage bliver 20 g af en forbindelse, som man uddriver med en blanding af chloroform og methanol (50:50), filtrerer, tørrer ved formindsket tryk, og man får 7,5 g af den forventede forbindelse med et smeltepunkt på over 260 “C.At reflux over 6 hours, 6 g of 4-aminoindole, 150 ml of tetrahydrofuran, 8.4 g of 5-nitrosalicylic acid and 12.5 g of dicyclohexylcarbodiimide are heated. Cool, filter, add 15 200 ml of ethyl acetate and remove unreacted 4-aminoindole by washing with 1N hydrochloric acid, dry, filter, evaporate to dryness at 50 ° C under reduced pressure. Back, 20 g of a compound which is expelled with a mixture of chloroform and methanol (50:50) are filtered, dried at reduced pressure and give 7.5 g of the expected compound with a melting point above 260 ° C .
2020
Eksempel 2: 5-amino-2-(3-((1,1-dimethylethyl)-amino)-2-hydroxypropoxy)-N-(1 H-indol-4-yl)- benzamidExample 2: 5-Amino-2- (3 - ((1,1-dimethylethyl) amino) -2-hydroxypropoxy) -N- (1H-indol-4-yl) benzamide
Man opvarmer under tilbagesvaling i løbet af 1 time 142 mg af den i eksempel 1 fremstillede 25 forbindelse, 5 ml methanol, en knivspids Raney-nikkel og 0,2 ml hydrazinhydrat. Man filtrerer, fjerner methanolen ved 50 °C under formindsket tryk og får 128 mg af den forventede forbindelse.At reflux, 142 mg of the compound of Example 1, 5 ml of methanol, a pinch of Raney nickel and 0.2 ml of hydrazine hydrate are heated over 1 hour. Filter, remove the methanol at 50 ° C under reduced pressure and obtain 128 mg of the expected compound.
UV-spektrum (ethanol):UV spectrum (ethanol):
Max. 219 nm ^443 30 Max. 310 nm ^230 UV-spektrum (ethanol; 0,1 N HCI):Max. 219 nm ^ 443 Max. 310 nm ^ 230 UV spectrum (ethanol; 0.1 N HCl):
Max. 299 nm E/ 208 ε = 8.200Max. 299 nm E / 208 ε = 8,200
Vendepunkt 275 og 332 nm 35 --- DK 168377 B1 7Turning point 275 and 332 nm 35 --- DK 168377 B1 7
Eksempel 3: 5-acetylamino-2-(3-((1,1-dimethylethyl)-amino)-2-hydroxypropoxy)-N-(1H-indol-4-yl)-5-benzamid og neutralt oxalat herafExample 3: 5-Acetylamino-2- (3 - ((1,1-dimethylethyl) amino) -2-hydroxypropoxy) -N- (1H-indol-4-yl) -5-benzamide and neutral oxalate thereof
Trin A: 5-amino-2-hydroxy-N-(1 H-indol-4-yl)-benzamid 5 En suspension bestående af 6 g 5-nitro-2-hydroxy-N-(1H-indol-4-yl)-benzamid fra eksempel 1, 600 ml methanol og 15 ml 64% hydrazinhydrat opvarmes under tilbagesvaling i løbet af 2 timer 1 nærvær af 6 g Raney-nikkel. Man filtrerer den fremkomne opløsning, fjerner opløsningsmidlet ved 50 eC under formindsket tryk, opstemmer det resterende stof i en chloroform-methanol-blanding (1:1), frafiltrerer den udkrystalliserede forbindelse, tørrer og opsamler 4 g af den for- 10 ventede forbindelse med et smeltepunkt over 260 °C.Step A: 5-Amino-2-hydroxy-N- (1H-indol-4-yl) -benzamide A suspension consisting of 6 g of 5-nitro-2-hydroxy-N- (1H-indol-4-yl) ) -benzamide of Example 1, 600 ml of methanol and 15 ml of 64% hydrazine hydrate are refluxed over 2 hours in the presence of 6 g of Raney nickel. The resulting solution is filtered, the solvent is removed at 50 ° C under reduced pressure, the residue is precipitated in a chloroform-methanol mixture (1: 1), the crystallized compound is filtered off, dried and collected 4 g of the expected compound with a melting point above 260 ° C.
Trin B: 5-acetylamino-2-acetoxy-N-(1 H-indol-4-yl)-benzamid 2,6 g af den i foregående trin fremstillede forbindelse nedkøles, opslemmet i 70 ml tetrahydro-furan, til 0-5 °C, herefter tilsættes 4,7 ml eddikesyreanhydrid, og blandingen henstår 3 timer 15 ved stuetemperatur. Opløsningsmidlet fjernes ved 50 CC under formindsket tryk, det resterende stof opstemmes i en chloroform-methanolblanding (1:1), man filtrerer og får efter tørring ved 80 °C 2,7 g af det forventede produkt med smeltepunkt 263 °C.Step B: 5-acetylamino-2-acetoxy-N- (1H-indol-4-yl) -benzamide 2.6 g of the compound prepared in the previous step is cooled, suspended in 70 ml of tetrahydrofuran, to 0-5 ° C, then 4.7 ml of acetic anhydride is added and the mixture is allowed to stand for 3 hours at room temperature. The solvent is removed at 50 ° C under reduced pressure, the residue is precipitated in a chloroform-methanol mixture (1: 1), filtered and, after drying at 80 ° C, 2.7 g of the expected product is obtained, mp 263 ° C.
Trin C: 5-acetylamino-2-hydroxy-N-(1 H-indol-4-yl)-benzamld 20 Til en suspension bestående af 1,5 g af den i det foregående trin fremkomne forbindelse og 150 ml methanol sættes ved stuetemperatur 1,5 g natriumborhydrid, hvorefter der opvarmes i 2 timer med tilbagesvaling. Methanolen fjernes delvist ved 50 °C under formindsket tryk, der fortyndes med 200 ml vand og 200 ml ethylacetat, hvorefter der ekstraheres med ethylacetat.Step C: 5-Acetylamino-2-hydroxy-N- (1H-indol-4-yl) -benzamide To a suspension consisting of 1.5 g of the compound obtained in the previous step and 150 ml of methanol is added at room temperature 1.5 g of sodium borohydride, then heat for 2 hours at reflux. The methanol is partially removed at 50 ° C under reduced pressure, diluted with 200 ml of water and 200 ml of ethyl acetate, then extracted with ethyl acetate.
Man tørrer, fjerner opløsningsmidlerne ved 50 °C under formindsket tryk og opsamler 1,35 g af 25 den forventede forbindelse, som benyttes uomdannet i det efterfølgende trin.Dry, remove the solvents at 50 ° C under reduced pressure and collect 1.35 g of the expected compound, which is used unchanged in the subsequent step.
Trin D: 5-acetylamino-2-((2-oxiranyl)-methoxy)-N-(1H-indol-4-yl)-benzamid Man opvarmer under tilbagesvaling i løbet af 2 timer 3,5 g af den forbindelse, der er fremstillet i trin C, 150 ml acetone, 1,6 g kaliumcarbonat og 9 ml epibromhydrin. Man tilsætter påny 9 ml 30 epibromhydrin og fortsætter tilbagesvalingen i 20 timer. Man filtrerer, vasker med acetone, fjerner opløsningsmidlet ved 50 eC og formindsket tryk, genopslemmer det resterende stof i ether, filtrerer, tørrer ved 80 °C og får 3,4 g af den forventede forbindelse tilbage med et smeltepunkt på 230 °C.Step D: 5-Acetylamino-2 - ((2-oxiranyl) -methoxy) -N- (1H-indol-4-yl) -benzamide Refluxing over 3.5 hours gives 3.5 g of the compound which is prepared in Step C, 150 ml of acetone, 1.6 g of potassium carbonate and 9 ml of epibromohydrin. 9 ml of 30 epibromohydrin is added again and the reflux is continued for 20 hours. Filter, wash with acetone, remove the solvent at 50 ° C and reduce pressure, resuspend the remaining substance in ether, filter, dry at 80 ° C and recover 3.4 g of the expected compound with a melting point of 230 ° C.
35 Trin E: 5-acetylamino-2-(3-(1,1-dimethylethyl)-amino)-2-hydroxy-propoxy)-N-(1H-indol-4-yl)- benzamid og neutralt oxalat herafStep E: 5-Acetylamino-2- (3- (1,1-dimethylethyl) amino) -2-hydroxy-propoxy) -N- (1H-indol-4-yl) benzamide and its neutral oxalate
Man opvarmer under tilbagesvaling i løbet af 1 time 3,4 g af en forbindelse, der fremkommer som ovenfor beskrevet, i 200 ml ethanol og 20 ml tert.-butylamin. Man fjerner opløsningsmid- DK 168377 B1 8 lerne ved 50 °C og formindsket tryk, chromatograferer det resterende stof på silicagel (elueringsmiddel: chloroform: methanol: triethylamin = 8:1:1) og opsamler 3,9 g af den forventede base.Reflux over 3.4 hours of a compound obtained as described above is heated in 200 ml of ethanol and 20 ml of tert-butylamine. The solvent was removed at 50 ° C and reduced pressure, chromatographed on the residue on silica gel (eluent: chloroform: methanol: triethylamine = 8: 1: 1) and collected 3.9 g of the expected base.
5 Fremstilling af oxalatetPreparation of the Oxalate
Man opløser 2,7 g base i 200 ml ethanol og tilsætter 330 mg oxalsyre. Man filtrerer, tørrer ved 80 °C under formindsket tryk og får 2,2 g af det forventede oxalat med smeltepunkt over 260 °C.Dissolve 2.7 g of base in 200 ml of ethanol and add 330 mg of oxalic acid. Filter, dry at 80 ° C under reduced pressure to give 2.2 g of the expected oxalate having a melting point above 260 ° C.
Analyse: Yt C2H204 = 423,549 10 Beregnet: C% 62,10 H% 6,46 N% 11,59Analysis: Surface C2H2O4 = 423.549 Calculated: C% 62.10 H% 6.46 N% 11.59
Fundet: 61,9 6,2 11,5Found: 61.9 6.2 11.5
Eksempel 4: 2-(3-((1,1-dimethylethyl)-amino)-2-hydroxypropoxy)-N-(1 H-indol-4-yl)-4-methoxy-benzamid og benzoatet heraf 15Example 4: 2- (3 - ((1,1-dimethylethyl) amino) -2-hydroxypropoxy) -N- (1H-indol-4-yl) -4-methoxy-benzamide and its benzoate
Trin A: 4-methoxy-2-((2-oxiranyl)-methoxy)-N-(1 H-indol-4-yl)-benzamid Man arbejder efter en fremgangsmåde i analogi med eksempel 3, trin D, men ud fra 5 g 4-me-thoxy-2-hydroxy-N-(1H-indol-4-yl)-benzamid, 150 ml acetone, 2,45 g kaliumcarbonat og 14 ml epichlorhydrin. Man får 7,3 g af den forventede forbindelse med smeltepunkt 157 eC.Step A: 4-Methoxy-2 - ((2-oxiranyl) -methoxy) -N- (1H-indol-4-yl) -benzamide A process is analogous to Example 3, step D, but starting from 5 g of 4-methoxy-2-hydroxy-N- (1H-indol-4-yl) benzamide, 150 ml of acetone, 2.45 g of potassium carbonate and 14 ml of epichlorohydrin. 7.3 g of the expected compound are obtained, with a melting point of 157 eC.
2020
Trin B: 2-(3-((1,1-dimethylethyl)-amino)-2-hydroxypropoxy)-N-(1 H-indol-4-yl)-4-methoxybenza-mid og benzoatet herafStep B: 2- (3 - ((1,1-dimethylethyl) amino) -2-hydroxypropoxy) -N- (1H-indol-4-yl) -4-methoxybenzamide and its benzoate
Man arbejder efter en fremgangsmåde i analogi med eksempel 3, trin E, men ud fra 6 g af den i ovenstående trin A fremstillede forbindelse, 100 ml ethanol, 9,2 ml tert.-butylamin med tilba-25 gesvaling i 3 timer. Man får 6,1 g af den forventede base, som man opløser i 300 ml isopropa-nol med tilbagesvaling, og derefter tilsættes 1,8 g benzoesyre. Man inddamper delvis, isafkøler, filtrerer, tørrer under formindsket tryk og får 5,1 g af det forventede benzoat. Efter omkrystallisation i ethanol fås et smeltepunkt på 195 °C.One works according to a procedure analogous to Example 3, Step E, but from 6 g of the compound prepared in Step A above, 100 ml of ethanol, 9.2 ml of refluxed tert-butylamine for 3 hours. 6.1 g of the expected base are dissolved in 300 ml of reflux isopropanol and then 1.8 g of benzoic acid is added. Partially evaporated, ice-cooled, filtered, dried under reduced pressure to give 5.1 g of the expected benzoate. After recrystallization in ethanol, a melting point of 195 ° C is obtained.
30 Analyse. ^23^29^3θφ CyHg02 — 532,629Analysis. ^ 23 ^ 29 ^ 3θφ CyHg02 - 532,629
Beregnet: C% 67,53 H% 6,61 N% 7,87Calculated: C% 67.53 H% 6.61 N% 7.87
Fundet: 67,5 6,7 8,0Found: 67.5 6.7 8.0
Fremstilling af 4-methoxv-2-hvdroxv-N-(1H-indol-4-vn-benzamid. som anvendes i begyndelsen 35 af eksempel 4.Preparation of 4-methoxy-2-hydroxy-N- (1H-indol-4-yl-benzamide) used at the beginning of Example 4.
Man opvarmer 3,96 g 4-amino-1H-indol, 70 ml tetrahydrofuran, 5 g 2-hydroxy-4-methoxyben-zoesyre og 6,2 g dicyklohexylcarbodiimid. Man fjerner opløsningsmidlet ved 50 eC under formindsket tryk, genopslemmer det resterende stof i ethylacetat og fjerner ureageret 4-aminoin- DK 168377 B1 9 dol ved vask med 2N saltsyre. Man fjerner ethylacetatet under reduceret tryk, genopslemmer det resterende stof i ether og tørrer ved 50 °C. Man får 7,1 g af den forventede forbindelse med et smeltepunkt på 190 °C.3.96 g of 4-amino-1H-indole, 70 ml of tetrahydrofuran, 5 g of 2-hydroxy-4-methoxybenzoic acid and 6.2 g of dicyclohexylcarbodiimide are heated. The solvent is removed at 50 DEG C. under reduced pressure, resuspended in ethyl acetate and unreacted 4-aminoin-dol by washing with 2N hydrochloric acid. The ethyl acetate is removed under reduced pressure, resuspended in ether and dried at 50 ° C. 7.1 g of the expected compound are obtained with a melting point of 190 ° C.
5 Eksempel 5: 5-chlor-2-(3-((1,1-dimethylethyl)-amino)-2-hydroxypropoxy)-N-(1H-indol-4-yl)- benzamid og det neutrale oxalat herafExample 5: 5-Chloro-2- (3 - ((1,1-dimethylethyl) amino) -2-hydroxypropoxy) -N- (1H-indol-4-yl) benzamide and its neutral oxalate
Trin A: 5-chlor-1 -((2-oxiranyl)-methoxy)-N-(1 H-indol-4-yl)-benzamid Man arbejder efter en fremgangsmåde i analogi med eksempel 3, trin D, men ud fra 3 g 5-10 chlor-2-hydroxy-N-(1H-indol-4-yl)-benzamid, 100 ml acetone, 1,47 g kaliumcarbonat og 8,3 ml epichlorhydrin. Man får 3,35 g af den forventede forbindelse med smeltepunkt 175 °C.Step A: 5-Chloro-1 - ((2-oxiranyl) -methoxy) -N- (1H-indol-4-yl) -benzamide A process is analogous to Example 3, step D, but starting from 3 g of 5-10 chloro-2-hydroxy-N- (1H-indol-4-yl) benzamide, 100 ml of acetone, 1.47 g of potassium carbonate and 8.3 ml of epichlorohydrin. 3.35 g of the expected compound is obtained, mp 175 ° C.
Trin B: 5-chlor-2-(3-((1,1-dimethylethyl)-amino)-2-hydroxypropoxy)-N-(1 H-indol-4-yl)-benzamid og det neutrale oxalat heraf 15 Man arbejder efter en fremgangsmåde i analogi med eksempel 3, trin E, men ud fra 3 g af den i trin A fremstillede forbindelse, 60 ml ethanol, 4,6 ml tert.-butylamin. Man får 2,6 g af den forventede base og derefter 2,4 g af oxaiatet. Smeltepunktet er over 260 °C.Step B: 5-Chloro-2- (3 - ((1,1-dimethylethyl) amino) -2-hydroxypropoxy) -N- (1H-indol-4-yl) benzamide and its neutral oxalate works according to a procedure analogous to Example 3, Step E, but from 3 g of the compound prepared in Step A, 60 ml of ethanol, 4.6 ml of tert-butylamine. 2.6 g of the expected base and then 2.4 g of the oxaiate are obtained. The melting point is above 260 ° C.
Analyse: C^H^rCIN^O^, % ~ 460,941 20 Beregnet: C% 59,93 H% 5,90 N% 9,12 Cl% 7,69Analysis: C ^H ^RCIN ^O ^,% ~ 460,941 Calculated: C% 59.93 H% 5.90 N% 9.12 Cl% 7.69
Fundet: 60,2 5,8 9,1 7,9Found: 60.2 5.8 9.1 7.9
Fremstilling af 5-chlor-2-hvdroxv-N-f1 H-indol-4-vlVbenzamid. som anvendtes i starten af eksempel 5.Preparation of 5-chloro-2-hydroxy-N-1H-indol-4-ylbenzamide. which was used at the beginning of Example 5.
25 Man opvarmer 3,96 g 4-amino-1H-indol i 75 ml tetrahydrofuran med 5,16 g 5-chlorsalicylsyre og 6,2 g dicyklohexylcarbodiimid med tilbagesvaling i 2 timer; der tilsættes på ny 0,62 g dicy-klohexylcarbodiimid, opvarmes igen med tilbagesvaling i 1 time, afkøles, filtreres, og opløsningsmidlet fjernes ved 50 °c og formindsket tryk. Man genopslemmer det resterende stof i ethylacetat, vasker med 2N saltsyre, tørrer og fjerner ethylacetaten ved 50 eC og formindsket 30 tryk. Efter chromatografi af det resterende stof på silicagel (elueringsmiddel: chloroform: ethylacetat = 9:1) opsamler man 3,9 g af den forventede forbindelse med smeltepunkt 248 °C.3.96 g of 4-amino-1H-indole is heated in 75 ml of tetrahydrofuran with 5.16 g of 5-chlorosalicylic acid and 6.2 g of reflux dicyclohexylcarbodiimide for 2 hours; 0.62 g of dicyclohexylcarbodiimide is again added, refluxed for 1 hour, cooled, filtered and the solvent removed at 50 ° C and reduced pressure. The remaining substance is resuspended in ethyl acetate, washed with 2N hydrochloric acid, dried and removed from ethyl acetate at 50 ° C and reduced to 30 pressures. After chromatography of the residue on silica gel (eluent: chloroform: ethyl acetate = 9: 1), 3.9 g of the expected compound are obtained, mp 248 ° C.
10 DK 168377 B110 DK 168377 B1
Eksempel 6Example 6
Man fremstiller tabletter efter recepten:Tablets are made according to the recipe:
Forbindelse fra eksempel 1..........................................................................................50 mg 5 Tilsætningsstof til dannelse af en tablet på................................................................100 mg (detaljer vedrørende tilsætningsstof: lactose, stivelse, talkum, magnesiumstearat)Compound of Example 1 .............................................. ............................................ 50 mg 5 Additive for Formation of a tablet on .............................................. .................. 100 mg (additive details: lactose, starch, talc, magnesium stearate)
Farmakologisk undersøgelse 10 11 Anti-arvtmivirknina på rottePharmacological study 10 11 Rat anti-inheritance virus in rat
Man åbner luftrøret på hanrotter på 300-350 g, som er anæstetiseret ad intraperitoneal ved ved hjælp af 1,20 g/kg urethan, og underkaster dem kunstigt åndedræt (40-50 indåndinger på 3 ml pr. minut).The trachea is opened on 300-350 g male rats anesthetized by intraperitoneal using 1.20 g / kg urethane and subjected to artificial respiration (40-50 inhalations of 3 ml per minute).
15 Man anbringer subcutant nåle til registrering af rottemes elektrokardiogram på Dll-aflednings-signalet.Subcutaneous needles are applied to record the rat electrocardiogram on the D11 diversion signal.
Man indgiver de produkter, som skal undersøges, ad intravenøs eller oral vej.The products to be examined are administered by intravenous or oral route.
20 5 minutter efter indgiften af forbindelsen foretager man perfusion af halsvenen på rotterne med 10 pg/min af en aconitinopløsning, og man noterer tidspunktet for fremkomsten af forstyrrelser i hjerterytmen (10 pg aconitin svarer tili perfusion med 0,2 ml opløsning).20 minutes after administration of the compound perfusion of the jugular vein of rats is performed with 10 µg / min of an aconitin solution and the timing of the onset of cardiac arrhythmias is noted (10 µg aconitin corresponds to perfusion with 0.2 ml solution).
Resultaterne udtrykkes i procent forlængelse af tiden for fremkomsten af forstyrrelser i hjerte-25 rytmen i forhold til kontroldyr og i afhængighed af dosis af den undersøgte forbindelse.The results are expressed as a percentage extension of the time of onset of cardiac arrhythmias relative to control animals and depending on the dose of the compound under study.
De resultater, som fremgår af tabellen nedenfor, viser, at forbindelserne ifølge opfindelsen har bemærkelsesværdige anti-arytmiegenskaber.The results shown in the table below show that the compounds of the invention have remarkable antiarrhythmic properties.
Forbindelse ifølge eksem- Dosis Procentforlængelse af tiden pel (mg/kg) (ved intravenøs indgift) 1 2,5 + 77% 1 + 39% 0,5 +17% 4 2,5 + 38% 1 +10% 30 DK 168377 B1 11 21 Prøve for anti-calciumaktivitet in vitroCompound according to Eczema Dose Percentage elongation of time pel (mg / kg) (by intravenous administration) 1 2.5 + 77% 1 + 39% 0.5 + 17% 4 2.5 + 38% 1 + 10% 30 DK 168377 B1 11 21 Test for anti-calcium activity in vitro
Spiralskåme halearterier på rotter forbindes med spændingsfølere og holdes i beholdere på 25 ml Krebs' stødpude med natriumbicarbonat (NaCI: 120,8 mM, KCI: 5,9 mM, MgCI2:1,2 mM, NaH2P04: 1,2 mM, NaHC03: 15,5 mM, glucose: 12,6 mM) ved 37 °C, som holdes under en 5 atmosfære af en blanding af: 02:95% og C02: 5%.Spiral tail arteries in rats are connected to voltage sensors and kept in 25 ml Krebs buffer with sodium bicarbonate (NaCl: 120.8 mM, KCI: 5.9 mM, MgCl2: 1.2 mM, NaH2 PO4: 1.2 mM, NaHCO3: 15.5 mM, glucose: 12.6 mM) at 37 ° C, which is kept under a 5 atmosphere of a mixture of: 02: 95% and CO 2: 5%.
Præparaterne depolariseres med en stødpudeopløsning med en koncentration på 100 mM med hensyn til K+-ioner (NaCI: 26,7 mM, KCI: 100 mM, MgCI2: 1,2 mM, NaH2P04: 1,2 mM, NaHC03:15,5 mM, glucose: 12,6 mM).The preparations are depolarized with a buffer solution at a concentration of 100 mM with respect to K + ions (NaCl: 26.7 mM, KCI: 100 mM, MgCl 2: 1.2 mM, NaH 2 PO 4: 1.2 mM, NaHCO 3: 15.5 mM , glucose: 12.6 mM).
10 I et rumfang på 250 pi tilsætter man calciumchiorid til frembringelse af en serie med tiltagende Ca2+-koncentrationer, gående fra 0,1 til 3,0 mM, og man noterer de derved frembragte arterie-kontraktioner, der således udgør en kontrolserie. Man gentager operationen med serien af Ca2+-ioner hvert kvarter, og hver serie følges af 4 vaskninger.In a volume of 250 µl calcium chloride is added to produce a series of increasing Ca 2+ concentrations ranging from 0.1 to 3.0 mM and the resulting artery contractions thus forming a control series are noted. The operation is repeated with the series of Ca 2+ ions every quarter, and each series is followed by 4 washes.
15 Når der er opnået en stabil reaktion, gentages operationen med serien af Ca2+-ioner under tilstedeværelse af forskellige koncentrationer af den forbindelse, der skal undersøges, indtil en stabil reaktion er opnået.When a stable reaction is obtained, the operation is repeated with the series of Ca 2+ ions in the presence of various concentrations of the compound to be investigated until a stable reaction is obtained.
20 Arteriekontraktioneme afhænger af en indtræden af Ca2+-ioneme i de glatte muskelceller og fremkaldes af de glatte musklers depolarisation ved hjælp af K+-ioneme og ved hjælp af virkningen af noradrenalin, der frigøres på det præsynaptiske niveau. Hvis man starter på operationen igen med arterier, som er denerveret ved hjælp af 6-OH-dopamin, undertrykker man noradrenalinets egenvirkning.The artery contractions depend on the entry of the Ca 2+ ions into the smooth muscle cells and are induced by the smooth muscle depolarization by the K + ions and by the effect of noradrenaline released at the presynaptic level. If you start the operation again with arteries denervated by 6-OH-dopamine, the self-efficacy of norepinephrine is suppressed.
2525
Resultaterne udtrykkes ved hjælp af Cl50 (inhiberende koncentration 50), hvilket er den koncentration, som med 50% inhibererden kontraktion, som skyldes K+-ioneme.The results are expressed by Cl50 (inhibitory concentration 50), which is the concentration that with 50% inhibitory contraction caused by the K + ions.
Man konstaterer ved hjælp af resultaterne i tabellen nedenfor, at forbindelserne ifølge den 30 foreliggende opfindelse har en stærk anti-calciumvirkning.It is found by the results in the table below that the compounds of the present invention have a strong anti-calcium effect.
Forbindelse ifølge eksempel__Clgn i pM_ 4 8 5 5,4 DK 168377 B1 12 3) Undersøgelse af akut toxitetCompound of Example__Clgn in pM_ 4 8 5 5.4 DK 168377 B1 12 3) Acute toxicity study
Man har vurderet den dødelige dosis DLq af forbindelsen ifølge eksempel 1 efter indgift ad oral vej på mus.The lethal dose of DLq of the compound of Example 1 has been assessed after oral administration in mice.
5 Med DLq betegner man den maksimale dosis, som ikke fremkalder nogen dødeiigehd i løbet af 7 dage.5 DLq is used to denote the maximum dose that does not cause any death within 7 days.
Den opnåede DLger på 200 mg/kg.The obtained DLger of 200 mg / kg.
Claims (5)
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| Application Number | Priority Date | Filing Date | Title |
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| FR8700151 | 1987-01-09 | ||
| FR8700151A FR2609464B1 (en) | 1987-01-09 | 1987-01-09 | NOVEL N- (1H-INDOL 4-YL) BENZAMIDE DERIVATIVES AND THEIR SALTS, THEIR USE AS MEDICAMENTS, AND THE COMPOSITIONS CONTAINING THEM |
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| EP (1) | EP0275221B1 (en) |
| JP (1) | JPS63188664A (en) |
| KR (1) | KR880008988A (en) |
| AT (1) | ATE62673T1 (en) |
| AU (1) | AU619728B2 (en) |
| DE (1) | DE3862380D1 (en) |
| DK (1) | DK168377B1 (en) |
| ES (1) | ES2029033T3 (en) |
| FI (1) | FI85140C (en) |
| FR (1) | FR2609464B1 (en) |
| GR (1) | GR3002185T3 (en) |
| HU (1) | HU201910B (en) |
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| DE4119611A1 (en) * | 1991-06-14 | 1992-12-17 | Bayer Ag | AGENTS FOR CONTROLLING PESTS BASED ON SUBSTITUTED OXAZOLIDINONE, NEW SUBSTITUTED OXAZOLIDINONE, THEIR PRODUCTION AND USE |
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| US4853408A (en) * | 1985-04-23 | 1989-08-01 | Roussel Uclaf | 4-phenylpropyl-indoles having antiarythmic activity |
| FR2583047B1 (en) * | 1985-06-05 | 1988-01-08 | Roussel Uclaf | PROCESS FOR THE PREPARATION OF INDOLE 4-PHENYLPROPYL DERIVATIVES AND INTERMEDIATES |
| FR2584713B1 (en) * | 1985-07-11 | 1988-09-09 | Roussel Uclaf | NOVEL CARBOXAMIDE INDOLE DERIVATIVES, SALTS THEREOF, PROCESS AND INTERMEDIATES FOR THEIR PREPARATION, APPLICATION AS MEDICAMENTS AND COMPOSITIONS CONTAINING THEM |
| ATE97403T1 (en) * | 1986-12-19 | 1993-12-15 | Roussel Uclaf | INDOL CARBOXAMIDE DERIVATIVES AND THEIR SALTS, PROCESSES AND INTERMEDIATE PRODUCTS FOR THE MANUFACTURE, MEDICINAL USE AND COMPOSITIONS CONTAINING THEM. |
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1987
- 1987-01-09 FR FR8700151A patent/FR2609464B1/en not_active Expired - Lifetime
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1988
- 1988-01-05 ZA ZA8837A patent/ZA8837B/en unknown
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- 1988-01-08 FI FI880064A patent/FI85140C/en not_active IP Right Cessation
- 1988-01-08 ES ES198888400036T patent/ES2029033T3/en not_active Expired - Lifetime
- 1988-01-08 JP JP63001420A patent/JPS63188664A/en active Pending
- 1988-01-08 EP EP88400036A patent/EP0275221B1/en not_active Expired - Lifetime
- 1988-01-08 HU HU8854A patent/HU201910B/en not_active IP Right Cessation
- 1988-01-08 AU AU10129/88A patent/AU619728B2/en not_active Ceased
- 1988-01-08 IE IE3988A patent/IE60779B1/en not_active IP Right Cessation
- 1988-01-08 DE DE8888400036T patent/DE3862380D1/en not_active Expired - Fee Related
- 1988-01-09 KR KR1019880000113A patent/KR880008988A/en not_active Application Discontinuation
-
1991
- 1991-06-26 GR GR90400513T patent/GR3002185T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2609464A1 (en) | 1988-07-15 |
| IE60779B1 (en) | 1994-08-10 |
| HUT45491A (en) | 1988-07-28 |
| EP0275221A3 (en) | 1988-08-24 |
| DE3862380D1 (en) | 1991-05-23 |
| AU619728B2 (en) | 1992-02-06 |
| ES2029033T3 (en) | 1992-07-16 |
| GR3002185T3 (en) | 1992-12-30 |
| FI880064A (en) | 1988-07-10 |
| FI85140B (en) | 1991-11-29 |
| FI880064A0 (en) | 1988-01-08 |
| IE880039L (en) | 1988-07-09 |
| DK3288A (en) | 1988-07-10 |
| HU201910B (en) | 1991-01-28 |
| EP0275221B1 (en) | 1991-04-17 |
| KR880008988A (en) | 1988-09-13 |
| DK3288D0 (en) | 1988-01-06 |
| JPS63188664A (en) | 1988-08-04 |
| ATE62673T1 (en) | 1991-05-15 |
| EP0275221A2 (en) | 1988-07-20 |
| AU1012988A (en) | 1988-07-14 |
| FI85140C (en) | 1992-03-10 |
| FR2609464B1 (en) | 1990-12-07 |
| ZA8837B (en) | 1989-03-29 |
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