DK169104B1 - Analogous Process for Preparation of N-Substituted 2-Pyridylindoles or Salts thereof - Google Patents
Analogous Process for Preparation of N-Substituted 2-Pyridylindoles or Salts thereof Download PDFInfo
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Description
DK 169104 B1DK 169104 B1
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte N-substituerede 2-pyridyl-indoler med den almene formel yxc -The present invention relates to an analogous process for the preparation of novel N-substituted 2-pyridyl indoles of the general formula
R3 CH2-A-BR3 CH2-A-B
10 hvori Rx betyder lavalkyl, Ar betyder pyridyl, R2 og R3 hver for sig betyder hydrogen, halogen, carboxylavalkyl eller lavalkoxycarbonyllavalkyl, A betyder alkylen med 1-12 C-atomer, phenylen, en direkte binding eller lavalkylen-(thio 15 eller oxy)-phenylen, B betyder carboxy, lavalkoxycarbonyl, carbamoyl eller hydroxymethyl, eller salte deraf.Wherein Rx is low alkyl, Ar is pyridyl, R 2 and R 3 are each independently hydrogen, halogen, carboxylavalkyl or lower alkoxycarbonyllavalkyl, A is alkylene having 1-12 C atoms, phenylene, a direct bond or low alkylene (thio or oxy) -phenylene, B means carboxy, lower alkoxycarbonyl, carbamoyl or hydroxymethyl, or salts thereof.
Fra beskrivelsen til US-patent nr. 3.468.894 er det kendt at anvende 1-usubstituerede 3-methyl-2-(3- eller 4-pyridyl)-20 indoler som diuretiske midler. Endvidere er 2-(2-pyridyl)-indol-3-(eddike- og propion)-syrer beskrevet i f.eks. Pharm. Bull. 4, 16 (1956) eller Chemical Abstracts 64, 1954d (1966). Desuden er eventuelt substituerede 2-(3-pyridyl)-indol-3-eddikesyrer beskrevet som kemiske mellemprodukter i Bull.From the specification of U.S. Patent No. 3,468,894, it is known to use 1-unsubstituted 3-methyl-2- (3- or 4-pyridyl) -20 indoles as diuretic agents. Furthermore, 2- (2-pyridyl) -indole-3- (acetic and propionic) acids are described in e.g. Pharm. Bull. 4, 16 (1956) or Chemical Abstracts 64, 1954d (1966). In addition, optionally substituted 2- (3-pyridyl) -indole-3-acetic acids are described as chemical intermediates in Bull.
25 Soc. Chim. France 1966. 771-772, og Bull. Soc. Chim. France 1969. 4154-4159. Endvidere er fremstillingen af 1-cyanethyl-2-(2-pyridyl)-indol beskrevet i Pharmazie 23 (10) 557-560 (1968).Soc. Chim. France 1966. 771-772, and Bull. Soc. Chim. France 1969. 4154-4159. Furthermore, the preparation of 1-cyanethyl-2- (2-pyridyl) indole is described in Pharmazie 23 (10) 557-560 (1968).
30 Det har overraskende vist sig, at de N-substituerede 2-pyr-idylindoler med den ovenfor anførte formel I udgør en hidtil ukendt klasse yderst virksomme og højspecifikke thromboxan-syntetase-inhibitorer.Surprisingly, it has been found that the N-substituted 2-pyridyl indoles of the above Formula I constitute a novel class of highly effective and highly specific thromboxane synthetase inhibitors.
35 De ovenfor anførte egenskaber bevirker, at de omhandlede N-substituerede 2-pyridylindoler er særligt anvendelige 2 DK 169104 B1 til indgift alene eller i kombination til pattedyr, f.eks. til behandling eller forebyggelse af sygdomme, som har relation til hæmningen af thromboxan-syntetase. Disse sygdomme omfatter cardiovaskulære forstyrrelser, såsom throm-5 bose, atherosclerose, coronarkrampe, arrhytmier, cerebrale iskæmiske anfald, migræne og andre vaskulære hovedsmerter, myocardieinfarkt, angina pectoris, hypertension, åndedrætsforstyrrelser, såsom astma og apnoe, og betændelsessygdomme. Det har også vist. sig; at hæmningen af thromboxan-synte-10 tasen formindsker metastasen ved visse tumorklasser. De omhandlede forbindelser kan derfor være nyttige ved behandlingen af visse former for kræft.The above mentioned properties cause the N-substituted 2-pyridylindoles in question to be particularly useful for administration alone or in combination with mammals, e.g. for the treatment or prevention of diseases related to the inhibition of thromboxane synthetase. These diseases include cardiovascular disorders such as thrombosis, atherosclerosis, coronary artery disease, arrhythmias, cerebral ischemic attacks, migraine and other vascular headaches, myocardial infarction, angina pectoris, hypertension, respiratory disorders such as asthma and apnea and asthma. It has also shown. itself; that the inhibition of the thromboxane synthase decreases metastasis in certain tumor classes. Therefore, the compounds of this invention may be useful in the treatment of certain types of cancer.
Der foretrækkes forbindelser med den ovenfor anførte formel 15 I, hvori R2 er bundet til indolkernen i 5-stillingen.Preferred are compounds of the above Formula 15 I wherein R 2 is bonded to the indole nucleus at the 5-position.
Forbindelser med formlen I, hvori A betyder alkylen med 3-10 carbonatomer, phenylen, lavalkylen-thio-phenylen eller lavalkylen-oxy-phenylen, hver især med 7-10 carbonatomer, 20 er særligt foretrukne.Compounds of formula I wherein A is alkylene having 3-10 carbon atoms, phenylene, lower alkylene-thio-phenylene or lower alkylene-oxy-phenylene, each having 7-10 carbon atoms, are particularly preferred.
Desuden er forbindelserne med formlen I, hvori A betyder alkylen med 1-12 carbonatomer eller phenylen, vigtige.In addition, the compounds of formula I wherein A is alkylene of 1-12 carbon atoms or phenylene are important.
25 De her anvendte almene definitioner har indenfor omfanget af den foreliggende opfindelse følgende betydninger.The general definitions used herein have the following meanings within the scope of the present invention.
En alkylengruppe med 1-12 carbonatomer kan være ligekædet eller forgrenet og er fortrinsvis propyl en, butyl en, pent-30 ylen, hexylen eller heptylen, hvor de nævnte grupper kan være usubstituerede eller substituerede med en eller flere lavalkylgrupper, idet summen af carbonatomerne er højst 12.An alkylene group having 1-12 carbon atoms may be straight or branched and is preferably propyl, butyl, pentylene, hexylene or heptylene, said groups being unsubstituted or substituted by one or more lower alkyl groups, the sum of the carbon atoms being no more than 12.
Ved phenylen forstås 1,2-, 1,3- eller fortrinsvis 1,4-phen-35 ylen.Phenylene means 1,2-, 1,3- or preferably 1,4-phenylene.
3 DK 169104 B13 DK 169104 B1
Pyridyl betyder 2-, 3- eller 4-pyridyl, især 3-pyridyl.Pyridyl means 2-, 3- or 4-pyridyl, especially 3-pyridyl.
Udtrykket "lav" anvendt i forbindelse med de ovenfor og i det følgende anførte organiske grupper, rester eller forbin-5 delser betyder sådanne med højst 7, fortrinsvis 4, især 1, 2 eller 3 carbonatomer.The term "low" used in connection with the organic groups, residues, or compounds listed above and hereinafter means those having at most 7, preferably 4, especially 1, 2 or 3 carbon atoms.
En lavalkylen-(thio eller oxy)-phenylengruppe indeholder i alkylengruppen fortrinsvis 1-4, især 1 eller 2 carbonatomer.A lower alkylene (thio or oxy) phenylene group contains in the alkylene group preferably 1-4, especially 1 or 2 carbon atoms.
10 Lavalkylengruppen kan være ligekædet eller forgrenet.The lower alkylene group may be straight or branched.
En lavalkylgruppe indeholder fortrinsvis 1-4 carbonatomer og betyder f.eks. ethyl, propyl eller butyl, især methyl.A lower alkyl group preferably contains from 1 to 4 carbon atoms and means e.g. ethyl, propyl or butyl, especially methyl.
15 En lavalkoxygruppe indeholder fortrinsvis 1-4 carbonatomer og er f.eks. ethoxy, propoxy eller især methoxy.A lower alkoxy group preferably contains 1-4 carbon atoms and is e.g. ethoxy, propoxy or especially methoxy.
En lavalkoxycarbonylgruppe indeholder fortrinsvis 1-4 carbonatomer i alkoxydelen og betyder f.eks. methoxycarbonyl 20 eller isopropoxycarbonyl, især ethoxycarbonyl.A lower alkoxycarbonyl group preferably contains 1-4 carbon atoms in the alkoxy moiety and means e.g. methoxycarbonyl or isopropoxycarbonyl, especially ethoxycarbonyl.
Halogen er fortrinsvis fluor eller chlor, men kan også være brom eller iod.Halogen is preferably fluorine or chlorine, but may also be bromine or iodine.
25 Salte er fortrinsvis terapeutisk anvendelige salte, f.eks. metalsalte eller ammoniumsalte af forbindelserne med formlen I, som indeholder frit carboxy, især alkalimetal- eller jordalkalimetalsalte, f.eks. natrium-, kalium-, magnesiumeller calciumsalte, i første række let krystalliserende 30 ammoniumsalte. Disse er afledt af ammoniak eller organiske aminer, f.eks. mono-, di- eller tri-lav-(alkyl, cycloalkyl eller hydroxyalkyl)-aminer, lavalkylendiaminer eller (hydr-oxy-lavalkyl eller aryl-lavalkyl)-lavalkylammoniumbaser, såsom methylamin, diethylamin, triethylamin, dicyclohexyl-35 amin,triethanolamin, ethylendiamin, tris-(hydroxymethyl)-aminomethan eller benzyl-trimethylammoniumhydroxid. De 4 DK 169104 B1 nævnte forbindelser med formlen I danner syreadditionssalte. Disse fremstilles fortrinsvis med sådanne syrer, der fører til terapeutisk anvendelige syreadditionssalte. Syrer, som giver terapeutisk anvendelige syreadditionssalte, er f.eks.Salts are preferably therapeutically useful salts, e.g. metal salts or ammonium salts of the compounds of formula I which contain free carboxy, especially alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, primarily light crystallizing ammonium salts. These are derived from ammonia or organic amines, e.g. mono-, di- or tri-low (alkyl, cycloalkyl or hydroxyalkyl) amines, low alkylene diamines or (hydroxy-low alkyl or aryl-low alkyl) -lavalkylammonium bases such as methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) aminomethane or benzyl trimethylammonium hydroxide. The compounds of formula I mentioned form acid acid salts. These are preferably prepared with such acids which lead to therapeutically useful acid addition salts. Acids which provide therapeutically useful acid addition salts are e.g.
5 stærke mineralsyrer, såsom hydrogenhalogenidsyrer, f.eks. hydrogenchloridsyre eller hydrogenbromidsyre, svovlsyre, phosphorsyre, salpetersyre eller perchlorsyre, eller organiske syrer, såsom aliphatiske eller aromatiske carboxylsyrer eller sulfonsyrer, f.eks. myresyre, eddikesyre, prop-10 ionsyre, ravsyre, glycolsyre, mælkesyre, æblesyre, vinsyre, gluconsyre, citronsyre, maleinsyre, fumarsyre, pyrodrue-syre, phenyleddikesyre, benzoesyre, 4-aminobenzoesyre, anthranilsyre, 4-hydroxybenzoesyre, salicylsyre, 4-amino-salicylsyre, pamoesyre, nicotinsyre, methansulfonsyre, 15 ethansulfonsyre, hydroxyethansulfonsyre, benzensulfonsyre, p-toluensulfonsyre, naphthalensulfonsyre, sulfanilsyre eller cyclohexylsulfaminsyre, eller ascorbinsyre.5 strong mineral acids such as hydrogen halide acids, e.g. hydrochloric or hydrobromic, sulfuric, phosphoric, nitric or perchloric, or organic acids such as aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxy acid -salicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulphanilic acid or cyclohexylsulfamic acid, or ascorbic acid.
De omhandlede forbindelser har værdifulde farmakologiske egenskaber, f.eks. cardiovaskulære virkninger, idet de 20 selektivt hæmmer thromboxandanneIsen i pattedyr. Denne hæmning fremkommer som følge af selektiv formindskelse af thromboxan-syntetase-koncentrationen. Forbindelserne er derfor nyttige til behandling af sygdomme, som reagerer på thromboxan-syntetase-hæmning i pattedyr. Sådanne syg-25 domme er i første række cardiovaskulære forstyrrelser, såsom thrombose, arteriosclerose, coronarkramper, cerebrale iskæmiske anfald, migræne og andre vaskulære hovedsmerter, myocardieinfarkt, angina pectoris og hypertension.The compounds of the invention have valuable pharmacological properties, e.g. cardiovascular effects, in that they selectively inhibit mammalian thromboxane formation. This inhibition results from selective reduction of the thromboxane synthetase concentration. Therefore, the compounds are useful in the treatment of diseases which respond to thromboxane synthetase inhibition in mammals. Such diseases are primarily cardiovascular disorders such as thrombosis, arteriosclerosis, coronary cramps, cerebral ischemic attacks, migraine and other vascular headaches, myocardial infarction, angina pectoris and hypertension.
Disse virkninger kan påvises ved in vitro-forsøg eller in 30 vivo-dyreforsøg, fortrinsvis med pattedyr, f.eks. marsvin, mus, rotter, katte, hunde eller aber. De nævnte forbindelser kan indgives enteralt eller parenteralt, fortrinsvis oralt eller subkutant, intravenøst eller intraperitonealt, f.eks. ved hjælp af gelatinekapsler eller i form af stivelsesholdige suspensioner eller vandige opløsninger. Den 5 DK 169104 B1 anvendte dosis kan ligge i området fra omkring 0,01 til 100 mg/kg/dag, fortrinsvis ca. 0,05 til 50 mg/kg/dag, især ca. 0,1 til 25 mg/kg/dag.These effects can be detected by in vitro or in vivo animal studies, preferably with mammals, e.g. guinea pigs, mice, rats, cats, dogs or monkeys. Said compounds may be administered enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. by gelatin capsules or in the form of starchy suspensions or aqueous solutions. The dose used may be in the range of about 0.01 to 100 mg / kg / day, preferably approx. 0.05 to 50 mg / kg / day, in particular approx. 0.1 to 25 mg / kg / day.
In vitro-hæmningen af thromboxan-syntetase-enzymet kan 5 påvises analogt med fremgangsmåden ifølge Sun, Biochem. Bio-phys, Res. Comm. 74, 1432 (1977). Testmetoden gennemføres på følgende måde: 14The in vitro inhibition of the thromboxane synthetase enzyme can be detected analogously to the method of Sun, Biochem. Biophys., Res. Comm. 74, 1432 (1977). The test method is carried out as follows:
C-Arachidonsyre inkuberes med et enzymblandingspræparat bestående af solubiliseret og partielt renset prostaglandin-cyclooxygenase fra sædblærer fra får og af et råt mikro-10 sompræparat af thromboxan-syntetase fra lyserede blodplader fra mennesker. Forsøgsforbindelsen (opløst i en puffer eller om nødvendigt i lidt ethanol) sættes til inkubationsmediet. Ved inkubationsperiodens afslutning (30 minutter) reduceres prostaglandin E2 (PGE2) ved tilsætning af natrium-15 borhydrid til en blanding af prostaglandin F2a og F2PC-Arachidonic acid is incubated with an enzyme blend composition consisting of solubilized and partially purified sheep seminal vesicles prostaglandin cyclooxygenase and a human microplate thromboxane synthase preparation from lysed platelets. The test compound (dissolved in a buffer or, if necessary, in a little ethanol) is added to the incubation medium. At the end of the incubation period (30 minutes), prostaglandin E2 (PGE2) is reduced by the addition of sodium borohydride to a mixture of prostaglandin F2a and F2P.
[PGF2(a+p)]. De radioaktive produkter og overskud af substrat ekstraheres med ethylacetat, og ekstrakten inddampes til tørhed. Remanensen opløses i acetone, sættes dråbevis til tyndtlagsplader og kromatograferes med et opløs-20 ningsmiddelsystem bestående af toluen:acetone:iseddike (100:100:3 (rumfang)]. De radioaktive zoner lokaliseres.[PGF2 (a + p)]. The radioactive products and excess substrate are extracted with ethyl acetate and the extract is evaporated to dryness. The residue is dissolved in acetone, added dropwise to thin-layer plates and chromatographed with a solvent system consisting of toluene: acetone: glacial acetic acid (100: 100: 3 (volume)]. The radioactive zones are located.
Zonerne med thromboxan B2 (TXB2) og PGF2a+3 overføres til scintillationsrør for væsker og tælles. Kvotienten af talværdierne for TxB2/PGF2a+3 beregnes for hver koncentra-25 tion af forsøgsforbindelsen, og IC^-værdien bestemmes grafisk. Denne værdi er den koncentration af forsøgsforbindelsen, ved hvilken kvotienten TxB2/PGF2a+3 reduceres til 50% af kontrolværdien.The zones of thromboxane B2 (TXB2) and PGF2a + 3 are transferred to scintillation tubes for liquids and counted. The quotient of the numerical values of TxB2 / PGF2a + 3 is calculated for each concentration of the test compound and the IC IC value is determined graphically. This value is the concentration of the test compound at which the quotient TxB2 / PGF2a + 3 is reduced to 50% of the control value.
In vitro-virkningen på prostaglandin-cyclo-oxygenase bestem-30 mes ved en modifikation af fremgangsmåden ifølge Takeguchi et al., som er beskrevet i Biochemistry _10, 2372 (1971). Testmetoden er som følger: 6 DK 169104 B1The in vitro effect on prostaglandin cyclo oxygenase is determined by a modification of the method of Takeguchi et al., Described in Biochemistry 10, 2372 (1971). The test method is as follows: 6 DK 169104 B1
Lyofiliserede sædblære-mikrosomer fra får anvendes som prostaglandinsyntetiserende enzympræparat. Der foretages måling af omdannelsen af ^C-arachidonsyre i PGE2. Forsøgsforbindelserne (opløst i en puffer, eller om nødvendigt 5 i lidt ethanol) sættes til inkubationsblandirigen. Prostaglan-dinerne ekstraheres og adskilles ved tyndtlagskromatografi. Pladerne undersøges, de radioaktive zoner, som svarer til PGE2, overføres til scintillationsrør for væsker, og radioaktiviteten bestemmes. IC^Q-værdien for hæmningen 10 bestemmes grafisk. Denne værdi betyder den koncentration af forsøgsforbindelsen, som formindsker mængden af det syntetiserede PGE2 med 50%.Lyophilized semen bladder microsomes are used as prostaglandin synthesizing enzyme preparation. Measurement of the conversion of β-arachidonic acid into PGE2 is performed. The test compounds (dissolved in a buffer or, if necessary, 5 in a little ethanol) are added to the incubation mixture regimen. The prostaglandins are extracted and separated by thin layer chromatography. The plates are examined, the radioactive zones corresponding to PGE2 are transferred to scintillation tubes for liquids and the radioactivity determined. The IC ^ value of inhibition 10 is determined graphically. This value means the concentration of the test compound which reduces the amount of the synthesized PGE2 by 50%.
In-vitro-virkningen på prostacyclin-(PGI2)-syntetase bestemmes analogt med fremgangsmåden ifølge Sun et al., 15 Prostaglandins 14, 1055 (1977). Forsøgsmetoden er som følger: 14 C-Arachidonsyre inkuberes med en enzymblanding bestående af solubiliseret og partielt renset prostaglandin-cyclooxygenase fra sædblærer fra får og af rå PGl^-syntetase i 20 form af en mikrosomfraktion fra aorta fra kvæg.The in vitro effect on prostacyclin (PGI2) synthetase is determined analogously to the method of Sun et al., Prostaglandins 14, 1055 (1977). The test method is as follows: 14 C-Arachidonic acid is incubated with an enzyme mixture consisting of solubilized and partially purified sheep semen bladder prostaglandin cyclooxygenase and of raw PG1 + synthase in the form of a bovine aortic microsomal fraction.
Forsøgsforbindelsen (opløst i en puffer, eller om nødvendigt i lidt ethanol) sættes til inkubationsblandingen. Reaktionsblandingen inkuberes i 100 mM tris*HCl (pH-værdi 7,5) i 30 minutter ved 37°C, syrnes til pH-værdien 3 og 25 ekstraheres med ethylacetat. Ekstrakten inddampes til tørhed, remanensen opløses i acetone og anbringes på tyndtlags-plader og kromatograferes med et af Sun et al. beskrevet opløsningsmiddelsystem. De radioaktive zoner lokaliseres ved hjælp af en detektor. Zonerne svarende til 6-keto-PGF^a 30 (et stabilt slutprodukt fra prostacyclinbiotransformationen) og PGE2 overføres til scintillationsrør for væsker og tæl les. Kvotienten for talværdien 6-keto-PGF^a/PGE2 beregnes for hver koncentration af den anvendte forsøgsforbindelse. ICsQ-værdien for hæmningen bestemmes grafisk. Denne værdi 35 er den koncentration af forsøgsforbindelsen, som reducerer kvotienten 6-keto-PGF1a/PGE2 til 50% af kontrolværdien.The test compound (dissolved in a buffer, or if necessary in a little ethanol) is added to the incubation mixture. The reaction mixture is incubated in 100 mM Tris * HCl (pH 7.5) for 30 minutes at 37 ° C, acidified to pH 3 and extracted with ethyl acetate. The extract is evaporated to dryness, the residue is dissolved in acetone and placed on thin-layer plates and chromatographed with one of Sun et al. described solvent system. The radioactive zones are located by means of a detector. The zones corresponding to 6-keto-PGF2a 30 (a stable end product of the prostacyclin biotransformation) and PGE2 are transferred to scintillation tubes for liquids and counted. The quotient for the numerical value of 6-keto-PGF 2 α / PGE 2 is calculated for each concentration of the test compound used. The ICsQ value for the inhibition is determined graphically. This value is the concentration of the test compound which reduces the quotient 6-keto-PGF1a / PGE2 to 50% of the control value.
7 DK 169104 B1 Hæmningen af syntesen og formindskelsen af thromboxan-plasmakoncentrationen bestemmes in vivo ved indgift af forsøgsforbindelsen til rotter (analogt med den af Tai et al. i Annual. Biochem. 87, 343, 1978, og af Salmon 5 i Prostaglandins 15, 383, 1978, beskrevne fremgangsmåde) på følgende måde:Inhibition of the synthesis and decrease of thromboxane plasma concentration is determined in vivo by administration of the test compound to rats (analogous to that of Tai et al. In Annual. Biochem. 87, 343, 1978, and of Salmon 5 in Prostaglandins 15, 383, 1978, described as follows):
Rotter behandles med forsøgsforbindelsen eller bærematerialet, og 2 timer senere foretages intravenøs injektion af ionophor A 23187 (0,5 mg/kg). 2 minutter efter 10. ionophor-injektionen udtages blod fra dyrene til analyse.Rats are treated with the test compound or vehicle and 2 hours later intravenous injection of ionophore A 23187 (0.5 mg / kg) is made. Two minutes after the 10th ionophore injection, blood is drawn from the animals for analysis.
I en bestemt enkeltmængde af hver plasmaprøve bestemmes thromboxan og fra andre enkeltmængder bestemmes 6-keto-PGF^a, de stabile metaboliter af thromboxan A2 eller prostacyclinet' (PGH^) ved radioimmunoanalyse.In a specific single amount of each plasma sample, thromboxane is determined and from other single amounts 6-keto-PGFβ, the stable metabolites of thromboxane A2 or prostacyclin (PGH₂) is determined by radioimmunoassay.
15 Forbindelserne med formlen I er yderst virksomme og selektive thromboxan-syntetase-inhibitorer. Ved virksomme dosiskoncentrationer og derover optræder der ingen væsentlig hæmning af hverken det fordelagtige prostacyclin-syntetase-enzymsystem eller prostaglandin-cyclooxygenase-20 enzymsystemet. Der sker overraskende en signifikant forøgelse af prostacyclin-koncentrationen.The compounds of formula I are highly effective and selective thromboxane synthetase inhibitors. At effective dose concentrations and above, there is no significant inhibition of neither the beneficial prostacyclin synthetase enzyme system nor the prostaglandin cyclooxygenase enzyme system. Surprisingly, a significant increase in prostacyclin concentration occurs.
ICsQ-værdien for en af de omhandlede forbindelser, f.eks. for 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indol, erThe ICsQ value of one of the compounds of the present invention, e.g. for 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) indole is
_ O_ O
1,2 x 10 mol for thromboxan-syntetase-hæmningen, medens 25 ICj-Q-værdien for hæmningen af prostacyclin-syntetasen og prostaglandin-cyclooxygenasen i begge tilfælde er flere 10'er potenser større, nemlig ca. 1 x 10 ’ mol.1.2 x 10 moles for the thromboxane synthetase inhibition, while the 25 ICj-Q value for the inhibition of the prostacyclin synthetase and the prostaglandin cyclooxygenase in both cases, several 10's potencies are greater, viz. 1 x 10 'mol.
Endvidere er IC^Q-værdien for thromboxan-syntetase-hæmningen 2 x 10-8 mol for 1-(5-carboxypentyl)-5-(2-carboxyethyl)- —8 30 3-methyl-2-(3-pyridyl)-indol og 5 x 10 mol for l-(4-carb- -9 oxybenzyl)-3-methyl-2-(3-pyridyl)-indol, 1 x 10 mol for 1- (5-carboxypentyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol o og 1 x 10 mol for 1-(5-carbamoyl-pentyl)-5-chlor-3-methyl- 2- (3-pyridyl)-indol, 2,6 x 10 8 mol for 1-[2-(4-carboxy- _o 35 phenoxy)-ethyl]-3-methyl-2-(3-pyridyl)-indol og 5,8 x 10 8 DK 169104 B1 mol for 1-[2-(4-carboxyphenylthio)-ethyl]-3-methyl-2-(3-pyridyl)-indol-hydrochlorid.In addition, the IC Q value of the thromboxane synthetase inhibition is 2 x 10-8 moles for 1- (5-carboxypentyl) -5- (2-carboxyethyl) -1,8-3-methyl-2- (3-pyridyl) indole and 5 x 10 moles for 1- (4-carb-9-oxybenzyl) -3-methyl-2- (3-pyridyl) indole, 1 x 10 mole for 1- (5-carboxypentyl) -5-chloro -3-methyl-2- (3-pyridyl) indole and 1 x 10 mol for 1- (5-carbamoyl-pentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole, 2 , 6 x 10 8 moles for 1- [2- (4-carboxy-phenoxy) ethyl] -3-methyl-2- (3-pyridyl) indole and 5.8 x 10 8 mole for 1- [2- (4-carboxyphenylthio) ethyl] -3-methyl-2- (3-pyridyl) indole hydrochloride.
1-(7-Carboxyheptyl)-3-methyl-2-(3-pyridyl)-indol og 1-(5-® carboxypentyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol, som er repræsentative eksempler på de omhandlede forbindelser, formindsker plasmakoncentrationen af thromboxan Έ>2 hos rotter ved en så lav oral dosis som 0,10mg/kg med mere end 50%. Ved denne eller større orale doser konstateres, en overraskende forøgelse af prostacyclin-plasmakoncentra-tionen.1- (7-Carboxyheptyl) -3-methyl-2- (3-pyridyl) indole and 1- (5-carboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole are representative examples of the compounds of this invention, reducing the plasma concentration of thromboxane Έ> 2 in rats at a dose as low as 0.10mg / kg by more than 50%. At this or greater oral doses, a surprising increase in the plasma concentrations of prostacyclin is found.
Som følge af de ovenfor anførte fordelagtige egenskaber er de omhandlede forbindelser yderst værdifulde som specifikke 15 terapeutiske midler til pattedyr og mennesker.Due to the advantageous properties set forth above, the compounds of this invention are extremely valuable as specific mammal and human therapeutic agents.
Hæmningen af den på forskellig måde fremkaldte aggregation af blodplader og thrombocytopeni ved hjælp af de omhandlede forbindelser, f.eks. ved hjælp af 1-(7-carboxyheptyl)-^0 3-methyl-2-(3-pyridyl)-indol, viser forbindelsernes anvendelighed ved thromboemboli. Eksperimentelt betragtes en forlængelse af blødnings tiden hos rotter som tegn på gunstig antithrombotisk virkning. Eksempelvis udviser l-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indol denne virkningThe inhibition of the variously induced platelet aggregation and thrombocytopenia by the compounds of the present invention, e.g. by means of 1- (7-carboxyheptyl) - 3 O-3-methyl-2- (3-pyridyl) indole, shows the utility of the compounds in thromboembolism. Experimentally, prolongation of bleeding time in rats is considered as evidence of beneficial antithrombotic effect. For example, 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) indole exhibits this effect
Λ CΛ C
ved oral indgift til rotter i en dosis på ca. 30 mg/kg.by oral administration to rats at a dose of approx. 30 mg / kg.
Med hensyn til de gunstige virkninger ved åndedrætsforstyrrelser kan henvises til, at de omhandlede forbindelser giver beskyttelse mod pludselig død, der indtræder som følge 30 af lungeobstruktion fremkaldt af arachidonsyre. Således beskytter f.eks. 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)-indol mus mod pludselig død ved en oral indgift i en dosis på 100 mg/kg.With respect to the beneficial effects of respiratory disorders, it may be noted that the compounds of the present invention provide protection against sudden death occurring as a result of pulmonary obstruction caused by arachidonic acid. Thus, e.g. 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) -indole mice against sudden death by oral administration at a dose of 100 mg / kg.
35 DK 169104 Bl 9DK169104 P9
Analogifremgangsmåden ifølge opfindelsen er ejendommelig ved, at man 1) kondenserer en forbindelse med formlen 5 R2 ^R1 ΓΓΤ (v) /ΛΑβ^ΑγThe analogous process according to the invention is characterized in that one) condenses a compound of the formula 5 R2 ^ R1 ΓΓΤ (v) / ΛΑβ ^ Αγ
R3 IR3 I
XX
10 hvori X betyder hydrogen, alkalimetal eller tri-lavalkyl-silyl, og Rlf R2, R3 og Ar har de ovenfor angivne betydninger, med et reaktionsdygtigt funktionelt derivat af en forbindelse med formlen 15 HO - CH2 - A - B (VI) hvori A og B har de ovenfor angivne betydninger, eller 2) ringslutter en forbindelse med formlen 20 r2 yv ™2-riWherein X represents hydrogen, alkali metal or tri-lower alkyl silyl, and R 1f R 2, R 3 and Ar have the meanings given above, with a reactive functional derivative of a compound of formula 15 HO - CH 2 - A - B (VI) wherein A and B has the above meanings, or 2) cyclically terminates a compound of formula 20 r2 yv ™ 2-ri
L |J-N - N = C - ΛΤ (VXDL | J-N - N = C - ΛΤ (VXD
25 R3 CH2'A'BR3 CH2'A'B
hvori Ar, Rj, R2, R3, A og B har de ovenfor angivne betydninger, eller 30 3) cycliserer en forbindelse med formlenwherein Ar, R 1, R 2, R 3, A and B have the above meanings, or 3) cyclizes a compound of formula
Vv-CHAVv-CHA
p i o (vm) 35 - C -Arp i o (vm) 35 - C -Ar
R3 CH2"A-BR3 CH2 "A-B
10 DK 169104 B1 hvori Ar, R^, R2, R3, A og B har de ovenfor angivne betyd-ninger, eller 4) i en forbindelse med formlen 5 RlWherein Ar, R 1, R 2, R 3, A and B have the above meanings, or 4) in a compound of formula 5 R 1
TtjL (ia> .TtjL (ia>.
λΛν/ ArλΛν / Ar
3 CH2~A-C3 CH2 ~ A-C
10 hvori A, Ar, R^, R2 og R3 har de ovenfor angivne betydninger, og C betyder en gruppe, som er forskellig fra B, og som kan omdannes til gruppen B, omdanner gruppen C til gruppen B, eventuelt under forlængelse af kæden A indenfor dennes de-15 finition, eller 5) til fremstilling af forbindelser med formlen I, hvori R^ betyder lavalkyl, Ar betyder pyridyl, R2 og R3 hver for sig betyder hydrogen, halogen, carboxylavalkyl eller lavalkoxy-carbonyl-lavalkyl, A betyder alkylen med 1-12 C-atomer, 20 phenylen eller en direkte binding, og B betyder carboxy, lavalkoxycarbonyl, carbamoyl eller hydroxymethyl, kondenserer en forbindelse med formlen V, hvori X betyder hydrogen, og R^, R2, R3 og Ar har de umiddelbart ovenfor i indledningen til denne variant angivne betydninger, med et 25 reaktionsdygtigt funktionelt derivat af en forbindelse med formlen HO - CH2 - A - B' (Via) 30 hvori A har den ovenfor i indledningen til denne variant angivne betydning, og B' betyder carboxy, lavalkoxycarbonyl, carbamoyl, mono- eller dilavalkyl-carbamoyl, hydroxymethyl, forethret hydroxymethyl, halogenmethyl, trialkoxymethyl eller cyan, og i en dannet forbindelse med formlen 35 11 DK 169104 B1 R2 Rl • Pk 3 CH2-A-B' 10 hvori B' er forskellig fra B som defineret ovenfor i indledningen til denne variant, og R1( R2, R3, A og Ar har de ovenfor i indledningen til denne variant angivne betydninger, omdanner gruppen B' til gruppen B, eventuelt under forlængelse af kæden A indenfor dens definition, 15 idet man, om ønsket eller om nødvendigt, midlertidigt beskytter en forstyrrende reaktionsdygtig gruppe ved alle disse fremgangsmåder, hvorefter man, om nødvendigt, omdanner en fremstillet forbindelse med formlen I til en anden forbindelse med formlen 20 I og/eller, om ønsket eller om nødvendigt, omdanner en fremstillet fri forbindelse til et salt eller et fremstillet salt til den fri forbindelse eller til et andet salt og/eller, om ønsket, adskiller en dannet blanding af isomere eller racemater i de enkelte isomere eller racemater 25 og/eller, om ønsket, opspalter dannede racemater i de optiske antipoder.Wherein A, Ar, R 2, R 2 and R 3 have the meanings given above and C means a group other than B and which can be converted to group B, group C transforms to group B, optionally extending the chain A within its definition, or 5) for the preparation of compounds of formula I wherein R 1 represents lower alkyl, Ar represents pyridyl, R 2 and R 3 each represent hydrogen, halogen, carboxylavalkyl or lower alkoxycarbonyl-lower alkyl, A means alkylene having 1-12 C atoms, phenylene or a direct bond, and B represents carboxy, lower alkoxycarbonyl, carbamoyl or hydroxymethyl, condenses a compound of formula V wherein X represents hydrogen and R 1, R 2, R 3 and Ar have the immediately above in the introduction to this variant, with a reactive functional derivative of a compound of the formula HO - CH 2 - A - B '(Via) 30 wherein A has the meaning given above in the introduction to this variant and B' means carboxy, low alkoxycarbonyl, approx rbamoyl, mono- or dilavalkyl-carbamoyl, hydroxymethyl, etherified hydroxymethyl, halo-methyl, trialkoxymethyl or cyan, and in a compound of formula 35 wherein P 'is different from B as defined above in the introduction to this variant, and R1 (R2, R3, A and Ar have the meanings given above in the introduction to this variant, converting group B 'to group B, optionally extending chain A within its definition, , if desired or if necessary, temporarily protect a disruptive reactive group in all of these processes, whereupon, if necessary, convert a prepared compound of formula I to another compound of formula 20 I and / or, if desired or if necessary, convert a prepared free compound to a salt or a prepared salt to the free compound or to another salt and / or, if desired, separates a formed mixture of isomers or racemates in the individual isomers or racemates 25 and / or, if desired, split racemates into the optical antipodes.
Kondensationen ifølge fremgangsmåde 1) gennemføres fortrinsvis under basiske betingelser, f.eks. med et basisk alka-30 limetalsalt eller et kvaternært ammoniumsalt, f.eks. tetra-butyl-ammoniumhydroxid. Således omdannes f.eks. især forbindelser med formlen V, hvori X betyder hydrogen, fortrinsvis in situ med et reaktionsdygtigt metalliserende middel til reaktionsdygtige organometalmellemprodukter.The condensation according to process 1) is preferably carried out under basic conditions, e.g. with a basic alkali metal salt or a quaternary ammonium salt, e.g. tetra-butyl ammonium hydroxide. Thus, e.g. in particular compounds of formula V wherein X represents hydrogen, preferably in situ with a reactive metallizing agent for reactive organometallic intermediates.
35 12 DK 169104 B1 035 12 DK 169104 B1 0
Man arbejder fortrinsvis med omkring 1 molækvivalent f.eks. af en stærk alkalinetalbase, såsom lithium-diiso-propylamid, natriumhydrid eller kalium-tert-butoxid, i et indifferent opløsningsmiddel, f.eks. dimethylformamid 5 eller tetrahydrofuran, i et temperaturområde fra -50 til 75, fortrinsvis fra -25 til 50°C.It is preferable to use about 1 molar equivalent, e.g. of a strong alkaline metal base, such as lithium diisopropylamide, sodium hydride or potassium tert-butoxide, in an inert solvent, e.g. dimethylformamide 5 or tetrahydrofuran, in a temperature range from -50 to 75, preferably from -25 to 50 ° C.
Kondensationen af den dannede reaktionsdygtige organometal-forbindelse med formlen V med et reaktionsdygtigt funktio-10 nelt derivat af en forbindelse med formlen VI gennemføres i et temperaturområde fra ca. -25 til ca. 50, fortrinsvis fra ca 0 til ca. 30°C. Når B betyder carboxy, carbamoyl, hydroxycarbamoyl eller mono-lavalkyl-carbamoyl, anvender man yderligere f.eks. 1 molækvivalent af metalliserings-15 midlet.The condensation of the formed reactive organometallic compound of formula V with a reactive functional derivative of a compound of formula VI is carried out in a temperature range of from ca. -25 to approx. 50, preferably from about 0 to about 30 ° C. When B is carboxy, carbamoyl, hydroxycarbamoyl or mono-lower alkyl-carbamoyl, further is used e.g. 1 mole equivalent of the metallizing agent.
Udgangsforbindelserne med formlen V, hvori X betyder hydrogen, er enten kendt, f.eks. fra beskrivelsen til 20 US-patent nr. 3.468.894, J. Chem. Soc. 1955, 286¾ ogThe starting compounds of formula V wherein X represents hydrogen are either known, e.g. from the specification to U.S. Patent No. 3,468,894, J. Chem. Soc. 1955, 286¾ and
Bull. Soc. Chim. France 1969, 4154, eller de fremstilles analogt med den velkendte indolsyntese ifølge Fischer ud fra tilsvarende, eventuelt substituerede phenylhydraziner og ketoner med formlen ArCOO^R^ i nærværelse af kondensa-25 tionsmidler, f.eks. ethanolisk saltsyre eller polyphosphor-syre.Bull. Soc. Chim. France 1969, 4154, or they are prepared analogously to the well-known indole synthesis of Fischer from similar, optionally substituted phenylhydrazines and ketones of the formula ArCOO ^ R ^ in the presence of condensing agents, e.g. ethanolic hydrochloric acid or polyphosphoric acid.
Udgangsforbindelser med formlen VI eller de i det følgende omtalte med formlen Via er kendte eller hidtil ukendte for-30 bindeiser. I sidstnævnte tilfælde kan de fremstilles på i og for sig kendt måde, f.eks. som anført i beskrivelsen til US-patent nr. 4.256.757 eller i beskrivelsen til GB-patentansøgning nr. 2.016.452A, eller som beskrevet i de efterfølgende eksempler.Starting compounds of formula VI or those hereinafter referred to as formula Via are known or novel compounds. In the latter case, they can be prepared in a manner known per se, e.g. as disclosed in the specification of U.S. Patent No. 4,256,757 or in the specification of GB Patent Application No. 2,016,452A, or as described in the following Examples.
r 35 0 13 DK 169104 B1r 35 0 13 DK 169104 B1
Ringslutningen af udgangsforbindelserne med formlen VII i-følge fremgangsmåde 2) gennemføres termisk eller fortrinsvis i nærværelse af et surt kondensationsmiddel ifølge den velkendte Fischer-indolsyntese, f.eks. som beskrevet 5 i Heterocyclic Compunds, Indoles Part I, udgivet af W. J. Houlihan, side 232-317- Omsætningen gennemføres fortrinsvis i nærværelse af hydrogenhalogenider, f.eks. ethanolisk saltsyre, eller polyphosphorsyre, eventuelt i et indifferent opløsningsmiddel, ved temperaturer mellem ca. 50 og 10 100°C.The cyclization of the starting compounds of formula VII according to process 2) is carried out thermally or preferably in the presence of an acidic condensing agent according to the well-known Fischer indole synthesis, e.g. as described 5 in Heterocyclic Compunds, Indoles Part I, published by W. J. Houlihan, pages 232-317. The reaction is preferably carried out in the presence of hydrogen halides, e.g. ethanolic hydrochloric acid, or polyphosphoric acid, optionally in an inert solvent, at temperatures between ca. 50 and 10 100 ° C.
Hydrazonudgangsforbindelserne med formlen .VII enten isoleres eller fortrinsvis fremstilles in situ ved kondensation af en keton med formlen Ar-COCH2R-^, hvori Ar og R^ har de ovenfor 15 angivne betydninger, med en substitueret hydrazin med formlen R2 ΪΧ 20 - NH2The hydrazone starting compounds of formula VII are either isolated or preferably prepared in situ by condensation of a ketone of formula Ar-COCH 2 R 4, wherein Ar and R 2 have the meanings given above, with a substituted hydrazine of formula R2 ΪΧ 20 - NH 2
R IR I
3 . CH2-A-B3. CH 2 A-B
hvori A, B, R2 og R^ har de ovenfor angivne betydninger, fortrinsvis i nærværelse af en sur katalysator.wherein A, B, R 2 and R 2 have the meanings given above, preferably in the presence of an acidic catalyst.
2525
Hydrazinudgangsforbindelserne med formlen X fremstilles fortrinsvis f.eks. ved nitrosering af tilsvarende substituerede aniliner med formlen R2 30 (xi)The hydrazine starting compounds of formula X are preferably prepared e.g. by nitrosating similarly substituted anilines of formula R2 30 (xi)
y^V'lrøCH^A-BV'lrøCH ^ y ^ A-B
R3 hvori symbolerne A, B, R2 og R3 har de ovenfor angivne be-35 tydninger, og efterfølgende reduktion af N-nitroso-derivatet, f.eks. med zink i eddikesyre eller under anvendelse af en anden i og for sig kendt fremgangsmåde.R3 wherein the symbols A, B, R2 and R3 have the above meanings and subsequent reduction of the N-nitroso derivative, e.g. with zinc in acetic acid or using another method known per se.
14 DK 169104 B1 0 Når de nævnte mellemprodukter indeholder generende r'eak- tionsdygtige grupper, såsom hydroxy- eller aminogrupper, kan sådanne grupper fortrinsvis midlertidigt beskyttes på velkendt måde på et vilkårligt trin ved hjælp af let fraspaltelige beskyttelsesgrupper, f.eks.iform af estere 5 eller amider.Preferably, when said intermediates contain nuisance-reactive groups such as hydroxy or amino groups, such groups may be temporarily protected in a well-known manner at any step by means of readily cleavable protecting groups, e.g. esters 5 or amides.
Cycliseringen ifølge fremgangsmåde 3) gennemføres under betingelserne for indolsyntesen ifølge Madelung, f.eks. som beskrevet i Heterocyclic Compounds, Indoles Part I, 10 udgivet af W. J. Houlihan, side 385-396. Den intramole- kylære cyclisering gennemføres fortrinsvis i nærværelse af en stærk base, f.eks. natrium-ethoxid, natriumamid eller kalium-tert-butoxid, fordelagtigt ved forhøjet temperatur, f.eks. ca. 300°Q eller i et indifferent højtkogende opløs-15 ningsmiddel, f.eks. tetrahydronaphthalen.The cyclization according to process 3) is carried out under the conditions of the Madelung indole synthesis, e.g. as described in Heterocyclic Compounds, Indoles Part I, 10 published by W. J. Houlihan, pages 385-396. The intramolecular cyclization is preferably carried out in the presence of a strong base, e.g. sodium ethoxide, sodium amide or potassium tert-butoxide, advantageously at elevated temperature, e.g. ca. 300 ° Q or in an inert high boiling solvent, e.g. tetrahydronaphthalen.
Udgangsforbindelserne med formlen VIII fremstilles ved acy-lering af substituerede aniliner med den ovenfor anførte 20 formel XI med en forbindelse med formlen ArCOOH eller et reaktionsdygtigt funktionelt derivat deraf.The starting compounds of formula VIII are prepared by the acylation of substituted anilines of the above formula XI with a compound of formula ArCOOH or a reactive functional derivative thereof.
Omdannelsen af en forbindelse med formlen la ifølge frem-25 gangsmåde 4), hvori C er forskellig fra B, til en forbindelse med formlen I og den fakultative omdannelse af en fremstillet forbindelse med formlen I til en anden omhandlet forbindelse gennemføres under anvendelse af i og for sig kendte kemiske fremgangsmåder og/eller som her be-30 skrevet.The conversion of a compound of formula Ia according to method 4), wherein C is different from B, to a compound of formula I and the optional conversion of a prepared compound of formula I to another object compound is carried out using i and known chemical processes and / or as described herein.
Omdannelige grupper C er fortrinsvis trialkoxymethyl, fores tret hydroxymethyl, forethret hydroxymethyl, halogen-methyl, cyan, 2-oxazolinyl, dihydro-2-oxazolinyl, lav-35 alkanoyloxymethyl, acetyl, methyl, carboxycarbonyl, tri-halogenacetyl, di-lavalkoxymethyl, alkylendioxymethyl, vinyl, alkynyl, forestret carboxy og amideret carboxy.Convertible groups C are preferably trialkoxymethyl, trifluorinated hydroxymethyl, etherified hydroxymethyl, halo-methyl, cyano, 2-oxazolinyl, dihydro-2-oxazolinyl, low-alkanoyloxymethyl, acetyl, methyl, carboxycarbonyl, tri-haloacetyl, di-loweralkoxymethyl, alkyl , vinyl, alkynyl, esterified carboxy and amidated carboxy.
0 15 DK 169104 B10 15 DK 169104 B1
Udgangsforbindelserne med formlen la fremstilles ifølge fremgangsmåde lj til 3) eller som her beskrevet under anvendelse af i og for sig kendt kemiske fremgangsmåder.The starting compounds of formula Ia are prepared according to process Ij to 3) or as described herein using chemical methods known per se.
5 De enkelte definitioner i de ovenfor beskrevne fremgangsmåder har følgende betydning: I et reaktionsdygtigt funktionelt derivat af en alkohol med formlen VI eller Via er hydroxygruppen eksempelvis for-10 estret med en stærk uorganisk eller organisk syre, først og fremmest med en hydrogenhalogenidsyre, f.eks. hydrogen-chloridsyre, hydrogenbromidsyre eller hydrogeniodidsyre, en aliphatisk eller aromatisk sulfonsyre, f.eks. methansul-fonsyre eller p-toluensulfonsyre. Disse forbindelser frem-15 stilles på i og for sig kendt måde.The individual definitions in the processes described above have the following meaning: In a reactive functional derivative of an alcohol of formula VI or Via, for example, the hydroxy group is esterified with a strong inorganic or organic acid, first of all with a hydrogen halide acid, f. eg. hydrogen chloride acid, hydrogen bromic acid or hydrogen iodide acid, an aliphatic or aromatic sulfonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid. These compounds are prepared in a manner known per se.
Trialkoxymethyl betyder fortrinsvis tri(lavalkoxy)-methyl, især triethoxy- eller trimethoxy-methyl.Trialkoxymethyl preferably means tri (lower alkoxy) methyl, especially triethoxy or trimethoxy methyl.
2020
Porethret hydroxymethyl betyder fortrinsvis tertiær lav-alkoxymethyl, lavere alkoxy-alkoxymethyl, f.eks. methoxy-methoxymethyl, 2-oxa- eller 2-thiacycloalkoxymethyl, især 2-tetrahydropyranyloxymethyl.Preferably, pore ether hydroxymethyl means tertiary low-alkoxymethyl, lower alkoxy-alkoxymethyl, e.g. methoxy-methoxymethyl, 2-oxa or 2-thiacycloalkoxymethyl, especially 2-tetrahydropyranyloxymethyl.
2525
Forestret hydroxymethyl betyder fortrinsvis lavalkanoyl-oxymethyl, fordelagtigt halogenmethyl, især chlormethyl, men også brommethyl eller iodmethyl.Preferably, esterified hydroxymethyl means lower alkanoyl oxymethyl, advantageously halogen methyl, especially chloromethyl, but also bromomethyl or iodomethyl.
30 Et alkalimetal betyder fortrinsvis lithium, men kan dog også være kalium eller natrium.An alkali metal preferably means lithium, but may also be potassium or sodium.
Mellemprodukter med formlen la eller Ib, hvori C eller B* betyder halogenmethyl, kan fortrinsvis omsættes på i 35 og for sig kendt måde, fortrinsvis med et alkalimetal” cyanid, f.eks. kaliumcyanid. Derved fås forbindelser med DK 169104 B1 0 16 formlen la eller Ib, hvori kæden er forlænget med et car-bonatom, og C eller B* betyder cyan. Disse kan igen på i og for sig kendt måde omdannes til forbindelser med formlen I, hvori B betyder carboxy, alkoxycarbonyl eller _ carbamoyl.Intermediates of formula Ia or Ib, wherein C or B * is halogenomethyl, may preferably be reacted in a manner known per se, preferably with an alkali metal "cyanide, e.g. potassium cyanide. Thereby, compounds of formula Ia or Ib are obtained in which the chain is extended by a carbon atom and C or B * means cyano. These can again be converted into compounds of the formula I in a manner known per se in which B is carboxy, alkoxycarbonyl or carbamoyl.
5 Således kan forbindelser med formlen la eller Ib , hvori C eller B* betyder cyan (nitriler), omdannes til forbindelser med formlen I, hvori B betyder carboxy, ved hydro-lyse med uorganiske syrer, f.eks. med hydrogenhalogenid-syrer, såsom hydrogenchloridsyre, eller svovlsyre i vandig opløsning, eller fortrinsvis ved hydrolyse med vandige alkalimetalhydroxider, f.eks. kaliumhydroxid, ved tilbagesvalings temperatur.Thus, compounds of formula Ia or Ib wherein C or B * means cyan (nitriles) can be converted to compounds of formula I wherein B represents carboxy by hydrolysis with inorganic acids, e.g. with hydrogen halide acids, such as hydrochloric acid, or sulfuric acid in aqueous solution, or preferably by hydrolysis with aqueous alkali metal hydroxides, e.g. potassium hydroxide, at reflux temperature.
1515
Omdannelsen af de nævnte nitriler til forbindelser med formlen I, hvori B betyder lavalkoxycarbony1, gennemføres fortrinsvis ved behandling med en lavalkanol, f.eks. vandfrit ethanol, i nærværelse af en stærk syre, f.eks. hydrogen-2o chloridsyre, fortrinsvis under tilbagesvaling, med efterfølgende forsigtig hydrolyse med vand.The conversion of said nitriles to compounds of formula I wherein B is lower alkoxycarbonyl is preferably carried out by treatment with a lower alkanol, e.g. anhydrous ethanol, in the presence of a strong acid, e.g. hydrogen-2O chloride acid, preferably under reflux, with subsequent gentle hydrolysis with water.
Omdannelsen af de nævnte nitriler til forbindelser med formlen I, hvori B betyder carbamoyl, gennemføres fortrinsvis 25 ved behandling med et alkalimetalhydroxid, f.eks. fortyndet natriumhydroxid, og hydrogenperoxid, fortrinsvis ved stuetemperatur.The conversion of said nitriles to compounds of formula I wherein B is carbamoyl is preferably carried out by treatment with an alkali metal hydroxide, e.g. dilute sodium hydroxide, and hydrogen peroxide, preferably at room temperature.
Mellemprodukter med formlen la eller Ib, hvori C eller B' 30 betyder halogenmethyl, f.eks. chlormethyl, kan omdannes til forbindelser med formlen I, hvori B betyder carboxy, og kæden er forlænget med 2 carbonatomer, først ved behandling f.eks. med et dilavalkyl-malonat, f.eks. diethyl-malonat, i nærværelse af en base/ f.eks. kaliumcarbonat eller 35 natriumethoxid, i et opløsningsmiddel, såsom dimethyl- formamid, fortrinsvis ved en temperatur mellem 50 og 100°C, 0 17 DK 169104 B1 til substituerede di-lavalkylmalonater. Disse hydrolyseres derpå med en vandig base, f.eks. fortyndet natriumhydroxidopløsning, til den tilsvarende malonsyre, som decarboxyleres under standardbetingelser, f.eks. ved opvarmning i xylenop-5 løsning, til forbindelsen med formlen I, hvori B betyder carboxy. Anvender man i stedet for malonsyre-di-lavalkyl-esteren en cyaneddikesyre-lavalkylester, får man de tilsvarende forbindelser med formlen la eller Ib, hvori C eller B' betyder cyan.Intermediates of formula Ia or Ib, wherein C or B '30 means halo methyl, e.g. chloromethyl may be converted to compounds of formula I wherein B is carboxy and the chain is extended by 2 carbon atoms, first by treatment e.g. with a dilavalkyl malonate, e.g. diethyl malonate, in the presence of a base / e.g. potassium carbonate or sodium ethoxide, in a solvent such as dimethylformamide, preferably at a temperature between 50 and 100 ° C to substituted di-lower alkyl malonates. These are then hydrolyzed with an aqueous base, e.g. dilute sodium hydroxide solution, to the corresponding malonic acid, which is decarboxylated under standard conditions, e.g. by heating in xylene solution, to the compound of formula I wherein B is carboxy. If instead of the malonic acid di-lower alkyl ester, a cyan acetic acid low alkyl ester is used, the corresponding compounds of formula Ia or Ib are obtained in which C or B 'means cyan.
1010
Forbindelser med formlen I, hvori B betyder lavalkoxy-carbonyl, kan amideres med ammoniak, mono- eller dilav-alkylaminer, f.eks. methylamin eller dimethylamin, i et indifferent opløsningsmiddel, f.eks. en lavalkanol, såsom 15 butanol, eventuelt ved forhøjet temperatur, til forbindelser med formlen I, hvori B betyder carbamoyl.Compounds of formula I wherein B is lower alkoxycarbonyl may be amidated with ammonia, mono- or dilavalkylamines, e.g. methylamine or dimethylamine, in an inert solvent, e.g. a lower alkanol such as butanol, optionally at elevated temperature, for compounds of formula I wherein B is carbamoyl.
Omdannelsen af forbindelser med formlen I eller Ib, hvori 20 b eller B' betyder lavalkoxycarbonyl, cyan, usubstitueret mono- eller dilavalkylcarbamoyl, til forbindelser med formlen I, hvori B betyder carboxy, gennemføres fortrinsvis ved hydrolyse med uorganiske syrer, f.eks. med hydrogenhalogenid-syrer eller svovlsyre, eller med vandige baser, fortrinsvis 25 med alkalimetalhydroxider, f.eks. lithium- eller natriumhydroxid .The conversion of compounds of formula I or Ib wherein 20b or B 'means lower alkoxycarbonyl, cyano, unsubstituted mono- or dilavalkylcarbamoyl, into compounds of formula I wherein B represents carboxy is preferably carried out by hydrolysis with inorganic acids, e.g. with hydrogen halide acids or sulfuric acid, or with aqueous bases, preferably with alkali metal hydroxides, e.g. lithium or sodium hydroxide.
Forbindelser med formlen I, hvori B betyder carboxy eller lavalkoxycarbonyl, kan reduceres med simple eller komplekse 30 letmetalhydrider, f.eks. med lithiumaluminiumhydrid, alan eller diboran, til forbindelser med formlen I, hvori B betyder hydroxymethyl. Alkoholerne kan også fremstilles ved egnet solvolyse af mellemprodukter med formlen la, hvori C betyder halogenmethyl, ved behandling f.eks. med et alka-35 limetalhydroxid, f.eks. lithium- eller natriumhydroxid.Compounds of formula I wherein B is carboxy or lower alkoxycarbonyl may be reduced by simple or complex light metal hydrides, e.g. with lithium aluminum hydride, alan or diborane, for compounds of formula I wherein B is hydroxymethyl. The alcohols may also be prepared by suitable solvolysis of intermediates of formula Ia, wherein C is halo methyl, by treatment e.g. with an alkali metal hydroxide, e.g. lithium or sodium hydroxide.
DK 169104 B1 0 18DK 169104 B1 0 18
De ovenfor nævnte alkoholer kan igen omdannes til forbindelser med formlen I, hvori B betyder carboxy, med konventionelle oxidationsmidler/ fortrinsvis med pyridinium-dichrorcat i dimethylformamid ved stuetemperatur.The above-mentioned alcohols can again be converted to compounds of formula I wherein B is carboxy, with conventional oxidizing agents / preferably with pyridinium dichlorocate in dimethylformamide at room temperature.
55
Frie carboxylsyrer kan forestres med lavalkanoler, f.eks. ethanol i nærværelse af en stærk syre, f.eks. svovlsyre, fortrinsvis ved forhøjet temperatur, eller med diazo-lav-alkaner, f.eks. diazomethan, i et opløsningsmiddel, f.eks.Free carboxylic acids can be esterified with lower alkanols, e.g. ethanol in the presence of a strong acid, e.g. sulfuric acid, preferably at elevated temperature, or with diazo-low alkanes, e.g. diazomethane, in a solvent, e.g.
10 ethylether, fortrinsvis ved stuetemperatur, til de tilsvarende estere, nemlig til sådanne forbindelser med formlen I, hvori B betyder lavalkoxycarbonyl.10 ethyl ether, preferably at room temperature, to the corresponding esters, namely to such compounds of formula I wherein B is lower alkoxycarbonyl.
Endvidere kan de frie carboxylsyrer omdannes ved behandling 15 af deres reaktionsdygtige mellemprodukter, f.eks. et acryl-halogenid, såsom et syrechlorid, eller et blandet anhydrid, f.eks. et anhydrid afledt af en halogenkulsyre-lavalkyl-ester, f.eks. chlormyresyre-ethylester, med ammoniak, monoeller dilavalkylaminer i et indifferent opløsningsmiddel, 20 f.eks. methylenchlorid, fortrinsvis i nærværelse af en basisk katalysator, f.eks. pyridin, til forbindelserne med formlen I, hvori B betyder usubstitueret carbamoyl, mono- eller di-(lavalkyl)-carbamoyl.Furthermore, the free carboxylic acids can be converted by treating their reactive intermediates, e.g. an acrylic halide, such as an acid chloride, or a mixed anhydride, e.g. an anhydride derived from a halo-carbonic acid lower alkyl ester, e.g. chloromyric acid ethyl ester, with ammonia, mono or dilavalkylamines in an inert solvent, e.g. methylene chloride, preferably in the presence of a basic catalyst, e.g. pyridine, for the compounds of formula I wherein B is unsubstituted carbamoyl, mono- or di- (lower alkyl) carbamoyl.
2525
Forbindelser med formlen I, hvori B betyder carboxy, kan ved den velkendte Arndt-Eistert-syntese omdannes til forbindelser med formlen I, hvori B betyder carboxy, og kæden indeholder et yderligere carbonatom. Der foretages især 30 behandling af et reaktionsdygtigt funktionelt derivat af den som udgangsmateriale anvendte carboxylsyre, f.eks. syre-chloridet, med diazomethan, f.eks. i diethylether, hvorved der dannes en forbindelse med formlen la, hvori C betyder diazoacetyl. Omdannelse med f.eks. sølvoxid fører til de 35 nævnte carboxylsyrer med formlen I, hvor kæden A indeholder et yderligere carbonatom.Compounds of formula I wherein B is carboxy can, by the well-known Arndt-Eistert synthesis, be converted to compounds of formula I wherein B is carboxy and the chain contains an additional carbon atom. In particular, treatment of a reactive functional derivative of the starting carboxylic acid, e.g. the acid chloride, with diazomethane, e.g. in diethyl ether to form a compound of formula Ia wherein C is diazoacetyl. Conversion with e.g. silver oxide leads to the 35 carboxylic acids of formula I wherein the chain A contains an additional carbon atom.
0 19 DK 169104 B10 19 DK 169104 B1
Grupper, som kan omdannes til en carboxygruppe, er f.éks. forestrede carboxygrupper, anhydridiserede carboxygrupper, herunder tilsvarende grupper af asymmetriske og indre anhy-drider, amiderede carboxygrupper, cyan, amidinogrupper, 5 herunder cycliske amidinogrupper, såsom 5-tetrazolyl, imino-ethergrupper, herunder cycliske iminoethergrupper, såsom f.eks. med lavalkyl substituerede 2-oxazolinyl- eller di-hydro-2-oxazolinylgrupper, endvidere methyl, hydroxymethyl, forethret hydroxymethyl, lavalkanoyloxymethyl, tri-10 alkoxymethyl, acetyl, trihalogenacetyl, halogenmethyl, carboxycarbonyl (C0C00H), formyl (CHO), di-lavalkoxymethyl, alkylendioxymethyl, vinyl, ethynyl eller diazoacetyl. Ved omdannelsen til carboxygruppen kan kæden A samtidig forlænges indenfor dennes definition.Groups that can be converted into a carboxy group are e.g. esterified carboxy groups, anhydrided carboxy groups, including corresponding groups of asymmetric and internal anhydrides, amidated carboxy groups, cyano, amidino groups, including cyclic amidino groups such as 5-tetrazolyl, imino ether groups, including cyclic imino ether groups such as e.g. substituted with lower alkyl 2-oxazolinyl or dihydro-2-oxazolinyl groups, further methyl, hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, halo methyl, carboxycarbonyl (COC00H), formyl (CHO , alkylenedioxymethyl, vinyl, ethynyl or diazoacetyl. At the time of conversion to the carboxy group, the chain A can simultaneously be extended within its definition.
1515
Forestrede carboxygrupper foreligger fortrinsvis i form af lavalkylestere, f.eks. methyl-, ethyl-, n- eller iso-(propyl eller butyl)-ester. Endvidere foreligger de i form af substituerede lavalkylestere, f.eks. ω-amino-, ω-mono- el-2Q ler dimethylamino-, α-carboxy- eller α-carbethoxy- (ethyl, propyl eller butyl)-ester. Andre estere er aryl-lavalkylestere, f.eks. benzyl-, (methyl-, methoxy-, chlor)-substitueret benzyl- og pyridylmethylester, lavalkanoyloxy-lavalkyl-estere, f.eks. pivaloyloxymethylester, 3-phthalidyl- og 25 med methyl, methoxy eller chlor substitueret 3-phthalidyl-ester, som er afledt af tilsvarende 3-hydroxy-phthaisyre-estere, (hydroxy, lavalkanoyloxy, lavalkoxy)-substituerede lavalkoxy-methylestere, f.eks. β-(hydroxy, acetyloxy, methoxy) -ethoxymethylester, bicycloalkoxycarbonyl-lavalkylestere, 30 f.eks. sådanne, der er afledt af bicycliske monoterpenoid-alkoholer, f.eks. usubstituerede eller med lavalkyl substituerede bicyclo[2,2,l]heptyloxycarbonyl-lavalkylestere, fortrinsvis bornyloxycarbonylmethylester, samt halogen-substituerede lavalkylestere, f.eks. trichlorethyl- eller 35 iodethylester.Esterated carboxy groups are preferably in the form of lower alkyl esters, e.g. methyl, ethyl, n or iso (propyl or butyl) ester. Furthermore, they are in the form of substituted lower alkyl esters, e.g. ω-amino, ω-mono or 2Q is dimethylamino, α-carboxy or α-carbethoxy (ethyl, propyl or butyl) ester. Other esters are aryl-lower alkyl esters, e.g. benzyl, (methyl, methoxy, chloro) -substituted benzyl and pyridyl methyl esters, low alkanoyloxy-low alkyl esters, e.g. pivaloyloxymethyl ester, 3-phthalidyl and methyl, methoxy or chloro substituted 3-phthalidyl ester, derived from corresponding 3-hydroxy-phthalic acid esters, (hydroxy, low alkanoyloxy, low alkoxy) -substituted low alkoxy methyl esters, e.g. . β- (hydroxy, acetyloxy, methoxy) ethoxymethyl ester, bicycloalkoxycarbonyl-low alkyl esters, e.g. those derived from bicyclic monoterpenoid alcohols, e.g. unsubstituted or lower alkyl substituted bicyclo [2,2,1] heptyloxycarbonyl low alkyl esters, preferably boron yloxycarbonyl methyl ester, as well as halo-substituted lower alkyl esters, e.g. trichloroethyl or iodoethyl ester.
DK 169104 B1 0 20DK 169104 B1 0 20
Amiderede carboxygrupper er fortrinsvis carboxygrupper i form af usubstituerede amider, N-mono- eller di-lav-alkylamider, f.eks. mono- eller di-methylamider, tertiære amider, som eksempelvis er afledt af pyrrolidin, piperidin 5 eller morpholin, med α-carbolavalkoxy eller carboxy substituerede lavalkylamider, f.eks. mono-N-(carboethoxy-methyl)-amider, og mono-N-(carboxymethyl)-amider, a-carbo-lavalkoxy- eller carboxy-substituerede aryl-lavalkylamider, f.eks. (carboethoxy eller carboxy)-substituerede phenyleth-10 ylamider, samt amino-lavalkylamider, f.eks. β-aminoethylamider og β-(carbobenzyloxy-amino)-ethylamider.Amidated carboxy groups are preferably carboxy groups in the form of unsubstituted amides, N-mono- or di-lower alkylamides, e.g. mono- or dimethylamides, tertiary amides derived, for example, from pyrrolidine, piperidine 5 or morpholine, with α-carbolavalkoxy or carboxy substituted lower alkylamides, e.g. mono-N- (carboethoxy-methyl) amides, and mono-N- (carboxymethyl) -amides, α-carbo-low alkoxy- or carboxy-substituted aryl-low-alkyl amides, e.g. (carboethoxy or carboxy) -substituted phenylethylamides, as well as amino-lower alkylamides, e.g. β-aminoethylamides and β- (carbobenzyloxyamino) ethylamides.
Omdannelsen til carboxygruppen gennemføres på i og for sig kendt måde, f.eks. som beskrevet her eller i de efterføl-15 gende eksempler, f.eks. solvolytisk, såsom hydrolytisk eller acidolytisk, eller reduktivt (forestrede carboxygrupper) . Således omdannes f.eks. trichlorethyl- eller 2-iod-ethylester ved reduktion, f.eks. med zink og en carboxylsyre i nærværelse af vand til carboxylsyren. Benzyleste-20 re eller nitro-benzylestere kan omdannes til carboxygruppen ved katalytisk hydrogenering, i sidstnævnte tilfælde også med kemiske reduktionsmidler, f.eks. natriumdithionit eller med zink og en carboxylsyre. Endvidere kan f.eks. tert-butylestere også spaltes f.eks. med trifluoreddike-25 syre.The conversion to the carboxy group is carried out in a manner known per se, e.g. as described herein or in the following examples, e.g. solvolytic, such as hydrolytic or acidolytic, or reductive (esterified carboxy groups). Thus, e.g. trichloroethyl or 2-iodo ethyl ester by reduction, e.g. with zinc and a carboxylic acid in the presence of water for the carboxylic acid. Benzyl esters or nitrobenzyl esters can be converted to the carboxy group by catalytic hydrogenation, in the latter case also by chemical reducing agents, e.g. sodium dithionite or with zinc and a carboxylic acid. Furthermore, e.g. tert-butyl esters are also cleaved e.g. with trifluoroacetic acid.
Ved reduktionen af gruppen C kan en alkenylen- eller alkyn-ylenkæde A omdannes til den tilsvarende alkylenkæde.By the reduction of group C, an alkenylene or alkynylene chain A can be converted to the corresponding alkylene chain.
30 Endvidere kan forbindelser med formlen la, hvori C betyder acetyl, oxidativt spaltes til de tilsvarende forbindelser med formlen I, hvori B betyder carboxy. Først omdannes udgangsforbindelsen til en forbindelse med formlen la, hvori C betyder trihalogenacetyl,' f.eks. tribrom- eller 35 triiodacetyl, f.eks. ved behandling med natriumhypobromit, hvorefter der spaltes, f.eks. med en vandig base, f.eks. natriumhydroxid.Further, compounds of formula Ia wherein C represents acetyl may be oxidatively cleaved to the corresponding compounds of formula I wherein B represents carboxy. First, the starting compound is converted to a compound of formula Ia wherein C is trihaloacetyl, e.g. tribromo or triiodoacetyl, e.g. by treatment with sodium hypobromite, after which cleavage, e.g. with an aqueous base, e.g. sodium hydroxide.
0 21 DK 169104 B10 21 DK 169104 B1
Udgangsforbindelser med formlen la, hvori C betyder acetyl, kan fremstilles ud fra forbindelser med formlen la, hvori C betyder halogenmethyl, ved behandling med en aceteddike-syre-lavalkylester, f.eks. aceteddikesyreethylester, i nær-5 værelse af en base, f.eks. natriumhydrid, og efterfølgende hydrolyse med en stærk base, f.eks. med vandigt natriumhydroxid.Starting compounds of formula Ia in which C is acetyl can be prepared from compounds of formula Ia in which C is halo methyl by treatment with an acetacetic acid low alkyl ester, e.g. acetic acetic acid ethyl ester, in the vicinity of a base, e.g. sodium hydride, and subsequent hydrolysis with a strong base, e.g. with aqueous sodium hydroxide.
De nævnte forbindelser kan også fremstilles ved kondensa-10 tion af en forbindelse med formlen la, hvori C betyder cyan, med f.eks. et Grignard- eller et andet organometalreagens, f.eks. methylmagnesiumbromid, under standardbetingelser.Said compounds may also be prepared by condensing a compound of formula Ia wherein C is cyano, with e.g. a Grignard or other organometallic reagent, e.g. methyl magnesium bromide, under standard conditions.
Udgangsforbindelser med formlen la, hvori C betyder carb-15 oxycarbonyl (C0C00H), omdannes ved termisk behandling eller ved oxidation til forbindelserne med formlen I, hvori B betyder carboxy. Ved denne omdannelse opvarmes udgangsforbindelsen til en forhøjet temperatur, f.eks. ca. 200°C, i nærværelse af glaspulver, eller den behandles f.eks.Starting compounds of formula Ia, wherein C is carb-oxycarbonyl (COC00H), are converted by thermal treatment or by oxidation to the compounds of formula I wherein B is carboxy. In this conversion, the starting compound is heated to an elevated temperature, e.g. ca. 200 ° C, in the presence of glass powder, or it is treated e.g.
20 med natriumhydrogenperoxid i nærværelse af et basisk middel, f.eks. natriumhydroxid.20 with sodium hydrogen peroxide in the presence of a basic agent, e.g. sodium hydroxide.
Udgangsforbindelserne med formlen la, hvori C betyder C0C00H, kan eksempelvis fremstilles ved kondensation af en forbin-25 delse med formlen la, hvori C betyder halogenmethyl, med f.eks. 2-ethoxycarbonyl-l,3-dithian, og efterfølgende oxida-tiv hydrolyse, f.eks. med N-bromsuccinimid i vandig acetone, og derefter ved behandling med fortyndet vandig natriumhydroxidopløsning.The starting compounds of formula Ia in which C is COCOH may be prepared, for example, by condensing a compound of formula Ia in which C is halo methyl, e.g. 2-ethoxycarbonyl-1,3-dithian, and subsequent oxidative hydrolysis, e.g. with N-bromosuccinimide in aqueous acetone, and then by treatment with dilute aqueous sodium hydroxide solution.
3030
Forbindelser med formlen la, hvori C betyder formyl, di-lav-alkoxy-methyl, eller alkylendioxymethyl (formyl beskyttet i form af en acetal), f.eks. dimethylacetal, oxideres f.eks. med sølvnitrat, pyridiniumdichromat eller ozon til for-35 bindeiserne med formlen I, hvori B betyder carboxy.Compounds of formula Ia, wherein C is formyl, di-low-alkoxymethyl, or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. dimethyl acetal, e.g. with silver nitrate, pyridinium dichromate or ozone to the compounds of formula I wherein B is carboxy.
22 DK 169104 B1 o22 DK 169104 B1 o
Forbindelser med formlen la, hvori C betyder vinyl, omdannes til forbindelserne med fomlen I, hvori B betyder carboxy, idet der først foretages ozonolyse til dannelse af forbindelserne med formlen I, hvori B betyder formyl, som t derefter oxideres til forbindelserne med formlen I, hvoriCompounds of formula Ia, wherein C is vinyl, are converted to the compounds of formula I wherein B represents carboxy, first performing ozonolysis to form the compounds of formula I, wherein B represents formyl, which is then oxidized to the compounds of formula I, in which
OISLAND
B betyder carboxy.B means carboxy.
Udgangsforbindeiser med formlen la, hvori C betyder vinyl, kan også behandles med nikkelcarbonyl og carbonmonoxid under 10 højt tryk, hvorved man får forbindelser med formlen I, hvori B betyder carboxy, og hvor kæden A ved siden af carboxygruppen indeholder en dobbeltbinding.Starting compounds of formula Ia, wherein C means vinyl, can also be treated with nickel carbonyl and carbon monoxide under high pressure to give compounds of formula I wherein B means carboxy and the chain A next to the carboxy group contains a double bond.
Forbindelser med formlen la, hvori C betyder ethynyl, kan 15 behandles med en stærk base, f.eks. butyllithium, derefter kondenseres med carbondioxid eller en halogenmyresyre-lavalkylester, f.eks. chlormyresyreethylester, og derefter hydrolyseres. På denne måde fås forbindelser med formlen I, hvori B betyder carboxy, og kæden A indeholder en tre-20 dobbelt binding i nabostilling til carboxygruppen.Compounds of formula Ia wherein C is ethynyl may be treated with a strong base, e.g. butyl lithium, then condensed with carbon dioxide or a halo formic acid low alkyl ester, e.g. chloromyric acid ethyl ester, and then hydrolyzed. In this way, compounds of formula I wherein B is carboxy are obtained and chain A contains a three to 20 double bond adjacent to the carboxy group.
Forbindelser med formlen la, hvori C betyder halogenmethyl, kan omdannes til de tilsvarende organometalmellemprodukter, f.eks. kobber- eller magnesiumderivater, på i og for sig 25 kendt måde.Compounds of formula Ia wherein C is halo methyl may be converted to the corresponding organometallic intermediates, e.g. copper or magnesium derivatives, in a manner known per se.
Ved kondensation f.eks. af et fremstillet organisk magnesium- (Grignard) -reagens , f.eks. med en forbindelse med formlen la, hvori C f.eks. er omdannet til CI^MgCl, med 30 carbondioxid fås en forbindelse med formlen I, hvori B betyder carboxy, og kæden er forlænget med et carbonatom.For condensation e.g. of a manufactured organic magnesium (Grignard) reagent, e.g. with a compound of formula Ia wherein C is e.g. is converted to Cl 2 MgCl, with 30 carbon dioxide is obtained a compound of formula I wherein B is carboxy and the chain is extended by a carbon atom.
Ved kondensation af det nævnte Grignard-reagens med f.eks. en halogeneddikesyre-lavalkylester, f.eks. bromeddikesyre-35 ethylester, og efterfølgende hydrolyse fås en forbindelse med formlen I, hvori B betyder carboxy, og kæden er forlænget med 2 carbonatomer.By condensing said Grignard reagent with e.g. a haloacetic acid low alkyl ester, e.g. bromoacetic acid ethyl ester, and subsequent hydrolysis is obtained a compound of formula I wherein B is carboxy and the chain is extended by 2 carbon atoms.
0 23 DK 169104 B10 23 DK 169104 B1
Det nævnte Grignard-reagens kan kondenseres i nærværelse af et kobber-I-halogenid, f.eks. kobber-I-chlorid, med en a,3-umættet syre eller en ester, f.eks. med propiolsyre eller acrylsyre, hvorved man får en forbindelse med form-5 len I, hvori B betyder carboxy, og hvor kæden er forlænget med 3 carbonatomer.Said Grignard reagent may be condensed in the presence of a copper I halide, e.g. copper I chloride, with an α, 3-unsaturated acid or an ester, e.g. with propiolic acid or acrylic acid to give a compound of formula I wherein B represents carboxy and the chain is extended by 3 carbon atoms.
Forbindelser med formlen I, hvori A betyder lavalkylen eller en direkte binding, og B betyder hydroxymethyl, som 10 reaktionsdygtigt funktionelt derivat, kan kondenseres med en lavalkanol (eller thiol), eller en phenol (eller thiophenol) (som er substitueret med B på passende måde), fortrinsvis i nærværelse af en stærk base. Der fås forbindelser med formlen I, hvori A betyder lavalkylen-(thio 15 eller oxy)-phenylen, phenylen-(thio eller oxy)-lavalkylen eller lavalkylen-(thio eller oxy)-lavalkylen.Compounds of formula I wherein A represents low alkyl or a direct bond and B represents hydroxymethyl as a reactive functional derivative can be condensed with a low alkanol (or thiol), or a phenol (or thiophenol) (which is substituted with B in appropriate way), preferably in the presence of a strong base. Compounds of formula I are obtained in which A is lower alkylene (thio or oxy) phenylene, phenylene (thio or oxy) low alkylene or low alkylene (thio or oxy) low alkylene.
De ovenfor nævnte reaktioner gennemføres på i og for sig 20 kendt måde, i nærværelse eller fraværelse af fortyndingsmidler, fortrinsvis i sådanne, som er indifferente overfor reagenserne og opløser disse, katalysatorer, kondensationsmidler eller andre ovenfor anførte midler, og/eller i en indifferent atmosfære, under afkølings ved stuetemperatur 25 eller ved forhøjet temperatur, fortrinsvis ved kogepunktet for det anvendte opløsningsmiddel, ved normalt eller forhøjet tryk. De foretrukne opløsningsmidler, katalysatorer og reaktionsbetingelser fremgår af de efterfølgende eksempler.The above reactions are carried out in a manner known per se, in the presence or absence of diluents, preferably in those which are inert to the reagents and dissolve them, catalysts, condensing agents or other agents listed above, and / or in an inert atmosphere. , under cooling at room temperature 25 or at elevated temperature, preferably at the boiling point of the solvent used, at normal or elevated pressure. The preferred solvents, catalysts and reaction conditions are set forth in the following examples.
3030
Fremgangsmåden ifølge opfindelsen omfatter ligeledes sådanne udførelsesformer, ved hvilke et udgangsmateriale dannes under reaktionsbetingelserne, eller hvor en udgangsforbindelse anvendes i form af et salt eller en optisk ren an-35 tipode.The process of the invention also encompasses such embodiments in which a starting material is formed under the reaction conditions or wherein an starting compound is used in the form of a salt or an optically pure antipode.
0 . DK 169104 B1 240. DK 169104 B1 24
Ved fremgangsmåden ifølge opfindelsen anvendes fordelagtigt sådanne udgangsforbindelser, som fører til de ovenfor beskrevne særligt værdifulde forbindelser.In the process of the invention, such starting compounds are advantageously used which lead to the particularly valuable compounds described above.
5 Alt efter valget af udgangsforbindelser og fremgangsmåder kan de hidtil ukendte forbindelser foreligge i form af en af de mulige isomere eller blandinger deraf. De kan f.eks. alt efter tilstedeværelsen af en dobbelt-' binding og antallet af asymmetriske carbonatomer forelig-10 ge som rene optiske isomere, f.eks. som antipoder, eller som blandinger af optiske isomere, f.eks. som racemater, blandinger af diastereomere, blandinger af racemater eller blandinger af geometriske isomere. De ovenfor anførte mulige isomere og deres blandinger er også omfattet af 15 opfindelsen. Mange specifikke isomere kan være foretrukket.Depending on the choice of starting compounds and methods, the novel compounds may be in the form of one of the possible isomers or mixtures thereof. For example, they can depending on the presence of a double bond and the number of asymmetric carbon atoms available as pure optical isomers, e.g. as antipodes, or as mixtures of optical isomers, e.g. such as racemates, mixtures of diastereomers, mixtures of racemates, or mixtures of geometric isomers. The above possible isomers and their mixtures are also encompassed by the invention. Many specific isomers may be preferred.
Fremstillede blandinger af diastereomere, blandinger af racemater eller geometriske isomere kan på basis af komponenternes fysisk-kemiske forskelle på i og for sig kendt måde 20 adskilles i de rene isomere, diastereomere, racemater eller geometriske isomere, f.eks. ved kromatografi og/el-ler fraktioneret krystallisation.Produced mixtures of diastereomers, mixtures of racemates or geometric isomers can be separated into pure isomers, diastereomers, racemates or geometric isomers based on the physicochemical differences known per se in the known manner. by chromatography and / or fractional crystallization.
Dannede racemater kan endvidere adskilles i de optiske anti-25 poder på i og for sig kendt måde, f.eks. ved omsætning af det sure slutprodukt med en optisk aktiv base, som danner salte med den racemiske syre. Disse salte kan f.eks. ved fraktioneret krystallisation adskilles i de diastereomere salte. Fra sidstnævnte kan de optisk aktive syre-antipoder 30 frigøres ved syrning. Basiske racemiske produkter kan adskilles på tilsvarende måde, f.eks. ved adskillelse af de diastereomere salte med en optisk aktiv syre og frigørelse af den optisk aktive base med en base. Racemiske forbindelser kan således spaltes i de optiske antipoder, f.eks.Furthermore, formed racemates can be separated into the optical anti-pods in a manner known per se, e.g. by reacting the acidic final product with an optically active base which forms salts with the racemic acid. These salts may e.g. by fractional crystallization, the diastereomeric salts are separated. From the latter, the optically active acid antipodes 30 can be released by acidification. Basic racemic products can be separated in a similar manner, e.g. by separating the diastereomeric salts with an optically active acid and releasing the optically active base with a base. Thus, racemic compounds can be cleaved in the optical antipodes, e.g.
35 ved fraktioneret krystallisation af d- eller Z~(tartrater, 0 25 DK 169104 B1 mandelater, camphersulfonater), eller af d- eller £-(a-meth-ylbenzylamin, cinchonidin, cinchonin, quinin, quinidin, ephedrin, dehydroabietylamin, brucin eller strychnin)-salte. Af de to antipoder isoleres fortrinsvis den antipode, som 5 har den kraftigste virkning.35 by fractional crystallization of d- or Z ~ (tartrates, mandelates, camphor sulphonates), or of d- or β - (α-methyl-benzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, bruin or strychnine salts. Of the two antipodes, the antipode which has the most potent effect is preferably isolated.
Endelig kan de omhandlede forbindelser fås i fri form eller i form af salte. En fremstillet fri base kan omdannes til det tilsvarende syreadditionssalt, fortrinsvis 10 med syrer, som fører til terapeutisk anvendelige syreadditionssalte, eller med anionbyttere. Dannede salte kan omdannes til de tilsvarende fri baser, f.eks. ved behandling med en stærkere base, såsom med et metalhydroxid eller ammoniumhydroxid eller et basisk salt, f.eks. et 15 alkålimetalhydroxid eller -carbonat, eller en kationbyt-ter. En forbindelse med formlen I, hvori B betyder carb-oxy, kan også omdannes til de tilsvarende metal- eller ammoniumsalte. Disse eller andre salte, f.eks. picraterne, kan også anvendes til rensningen af de dannede frie baser.Finally, the compounds of the present invention are available in free form or in the form of salts. A prepared free base can be converted to the corresponding acid addition salt, preferably 10 with acids leading to therapeutically useful acid addition salts, or with anion exchangers. Formed salts can be converted to the corresponding free bases, e.g. by treatment with a stronger base such as with a metal hydroxide or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchanger. A compound of formula I wherein B is carb-oxy may also be converted to the corresponding metal or ammonium salts. These or other salts, e.g. the picrates, can also be used for the purification of the formed free bases.
2o Baserne omdannes til salte, saltene isoleres, og baserne frigøres fra saltene.The bases are converted to salts, the salts are isolated and the bases released from the salts.
Som følge af det snævre slægtsskab mellem de omhandlede .forbindelser i fri form og i form af deres salte skal der 25 i det foregående og efterfølgende ved de fri forbindelser og saltene eventuelt også forstås de tilsvarende salte eller frie forbindelser.Due to the close relationship between the compounds in free form and in the form of their salts, the previous and subsequent free compounds and the salts may optionally also mean the corresponding salts or free compounds.
Ferbindelserne og deres salte kan også fås i form af hy-30 drater, eller de kan indeholde andre, til krystallisationen anvendte opløsningsmidler.The compounds and their salts can also be obtained in the form of hydrates, or they may contain other solvents used for crystallization.
De farmaceutiske præparater er sådanne, der er egnede til enteral, f.eks. oral eller rektal, og parenteral indgift 35 til pattedyr og mennesker. Præparaterne anvendes til behandling eller forebyggelse af sygdomme, som reagerer på hæmningen af thromboxan-syntetasen. Disse præparater indehol- DK 169104 B1 0 26 der en virksom dosis af en farmakologisk aktiv forbindelse med formlen I eller et farmaceutisk acceptabelt salt deraf alene eller i kombination med et eller flere farmaceutisk acceptable bærematerialer.The pharmaceutical compositions are those suitable for enteral, e.g. oral or rectal, and parenteral administration 35 to mammals and humans. The compositions are used to treat or prevent diseases that respond to the inhibition of thromboxane synthetase. These compositions contain an effective dose of a pharmacologically active compound of formula I or a pharmaceutically acceptable salt thereof alone or in combination with one or more pharmaceutically acceptable carriers.
55
De omhandlede farmakologisk anvendelige forbindelser kan anvendes til fremstilling af farmaceutiske præparater, som indeholder en virksom mængde af det aktive stof sammen med eller i blanding med bærestoffer, som er egnede til 10 enteral eller parenteral indgift. Fortrinsvis anvender man tabletter eller gelatinekapsler, som indeholder den virksomme forbindelse sammen med fortyndingsmidler, f.eks. lactose, dextrose, rørsukker, mannitol, sorbitol, cellulose og/eller glycin, og smøremidler, f.eks. kiseljord, 15 talkum, stearinsyre eller salte deraf, såsom magnesium- eller calciumstearat, og/eller polyethylenglycol. Tabletter indeholder ligeledes bindemidler, f.eks. magnesiumalumi-niumsilicat, stivelsespasta, gelatine, traganth, methylcel-lulose, natriumcarboxymethylcellulose og/eller polyvinyl-20 pyrrolidon og, om ønsket, desintegreringsmidler, f.eks.The disclosed pharmacologically useful compounds can be used for the preparation of pharmaceutical compositions containing an effective amount of the active substance together with or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatine capsules are used which contain the active compound together with diluents, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, e.g.
stivelsesarter, agar, alginsyre eller et salt deraf, såsom natr'iumalginat, og/eller bruseblandinger eller adsorptionsmidler, farvestoffer, smagstoffer og sødemidler. Injektionspræparater er fortrinsvis isotoniske vandige opløsninger 25 eller suspensioner, og suppositorier er i første række fedtemulsioner eller -suspensioner. De farmakologiske præparater kan være steriliserede og/eller indeholde hjælpestoffer, f.eks. konserveringsmidler, stabiliseringsmidler, fugtemidler og/eller emulgeringsmidler, opløsningsfremmende 30 midler, salte til regulering af det osmotiske tryk og/eller puffere. De farmaceutiske præparater, som om ønsket kan indeholde andre farmakologisk værdifulde forbindelser, kan fremstilles på i og for sig kendt måde, f.eks. ved konventionelle blandings-, granulerings- eller dragérings-35 fremgangsmåder, og de indeholder fra ca. 0,1 til ca. 75, 0 27 DK 169104 B1 især fra ca. 1 til ca. 50% aktivt stof. Enkeltdoser til pattedyr med en legemsvægt på omkring 50-70 kg kan indeholde fra 10-100 mg aktiv bestanddel.starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or shower mixtures or adsorbents, dyes, flavors and sweeteners. Injection preparations are preferably isotonic aqueous solutions or suspensions, and suppositories are primarily fat emulsions or suspensions. The pharmacological compositions may be sterilized and / or contain excipients, e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, solvents, salts for controlling the osmotic pressure and / or buffers. The pharmaceutical compositions which, if desired, may contain other pharmacologically valuable compounds can be prepared in a manner known per se, e.g. by conventional mixing, granulating or coating methods and they contain from ca. 0.1 to approx. 75, 0 27 DK 169104 B1 especially from ca. 1 to approx. 50% active substance. Single doses for mammals with a body weight of about 50-70 kg may contain from 10-100 mg of active ingredient.
5 Fremgangsmåden ifølge opfindelsen illustreres nærmere i de efterfølgende eksempler. De anførte dele er vægtdele. Medmindre andet er anført foretages inddampningen af opløsningsmidler under formindsket tryk, f.eks. mellem ca. 15 og ca. 100 mm Hg.The process according to the invention is further illustrated in the following examples. The parts listed are parts by weight. Unless otherwise stated, the evaporation of solvents is carried out under reduced pressure, e.g. between approx. 15 and approx. 100 mm Hg.
1010
Eksempel 1 1640 ml dimethylformamid og 430 g kalium-tert-butoxid anbringes i en 76 1 glasbeholder. Opløsningen omrøres under 15 nitrogen og afkøles til -8°C. I løbet af 0,75 timer tilsættes en opløsning af 682 g 3-methyl-2-(3-pyridyl)-indol i 3280 ml dimethylformamid, hvorved temperaturen holdes under 0°C. Blandingen omrøres i 2 timer ved -10°C, og der tilsættes 1640 ml af en opløsning af 780 g 8-bromoctansyre-20 methylester i dimethylformamid i løbet af 1 time. Reaktionstemperaturen holdes under 0°C. Reaktionsblandingen omrøres 1 2 timer, hvorefter den henstår natten over ved stuetemperatur. Den rustfarvede blanding afkøles derefter til ca.Example 1 1640 ml of dimethylformamide and 430 g of potassium tert-butoxide are placed in a 76 liter glass container. The solution is stirred under nitrogen and cooled to -8 ° C. Over 0.75 hours, a solution of 682 g of 3-methyl-2- (3-pyridyl) indole in 3280 ml of dimethylformamide is added, keeping the temperature below 0 ° C. The mixture is stirred for 2 hours at -10 ° C and 1640 ml of a solution of 780 g of 8-bromooctanoic acid methyl ester in dimethylformamide is added over 1 hour. The reaction temperature is kept below 0 ° C. The reaction mixture is stirred for 2 hours, then left to stand overnight at room temperature. The rust-colored mixture is then cooled to ca.
5°C og behandles med 19.700 ml isvand. Temperaturen stiger 25 til 25°C. Blandingen omrøres i 0,5 timer og ekstraheres med to gange 8.000 ml ether. Ekstrakterne tørres over magnesiumsulfat og inddampes i vakuum. Man får 1- (7-methoxy-carbonylheptyl)-3-methyl-2-(3-pyridyl)-indol i form af en olie. 1293 g af denne olie behandles med 6.530 ml 1 N 30 natriumhydroxidopløsning, og blandingen opvarmes på et dampbad i 2,5 timer til 90°C. Opløsningen afkøles til stuetemperatur og vaskes med tre gange 3.000 ml ether.5 ° C and treated with 19,700 ml of ice water. The temperature rises 25 to 25 ° C. The mixture is stirred for 0.5 hours and extracted twice with 8,000 ml of ether. The extracts are dried over magnesium sulfate and evaporated in vacuo. 1- (7-methoxy-carbonylheptyl) -3-methyl-2- (3-pyridyl) -indole is obtained as an oil. 1293 g of this oil are treated with 6,530 ml of 1 N 30 sodium hydroxide solution and the mixture is heated on a steam bath for 2.5 hours to 90 ° C. The solution is cooled to room temperature and washed with 3,000 ml of ether.
Det vandige lag afkøles til 10°C og indstilles med 3.400 ml 2 N saltsyre på pH-værdien 3,5. Den dannede tunge suspen-35 sion ekstraheres med fire gange 4.000 ml methylenchlorid.The aqueous layer is cooled to 10 ° C and adjusted with 3,400 ml of 2N hydrochloric acid to pH 3.5. The resulting heavy suspension is extracted with four times 4,000 ml of methylene chloride.
DK 169104 B1 0 28DK 169104 B1 0 28
De sammenblandede ekstrakter vaskes en gang med 4.000 ml vand og tørres over magnesiumsulfat. Blandingen filtreres, opløsningsmidlet fordampes ved 60°C, remanensen tritureres med 2.000 ml ether, og produktet tørres. Der fås 1—(7— 5 carboxyheptyl)-3-methyl-2- (3-pyridyl)-indol, smp. 113-115°C. Efter omkrystallisation fra ethanol stiger smeltepunktet til 114-116°C.The combined extracts are washed once with 4,000 ml of water and dried over magnesium sulfate. The mixture is filtered, the solvent evaporated at 60 ° C, the residue triturated with 2,000 ml of ether and the product dried. 1- (7-5 carboxyheptyl) -3-methyl-2- (3-pyridyl) indole, m.p. 113-115 ° C. After recrystallization from ethanol, the melting point rises to 114-116 ° C.
3-Methyl-2-(3-pyridyl)-indol-udgangsmaterialet fremstilles 10 i alt væsentligt under anvendelse af den i USA-patentskrift nr. 3.468.894 beskrevne fremgangsmåde.The 3-methyl-2- (3-pyridyl) indole starting material is prepared substantially using the process described in U.S. Patent No. 3,468,894.
8-Bromoctansyre-methylesteren fremstilles ud fra azelainsy-re i alt væsentligt som beskrevet i USA-patentskrift nr.The 8-Bromoctanoic acid methyl ester is prepared from azelaic acid substantially as described in U.S. Pat.
15 3.852.419 eller ved direkte forestring af 8-bromoctansyren, på følgende måde:3,852,419 or by direct esterification of the 8-bromooctanoic acid, as follows:
En blanding af methanol (4.700 ml), 8-bromoctansyre (912 g) og svovlsyre (912 ml) koges i en egnet reaktionsbeholder 20 ... .A mixture of methanol (4,700 ml), 8-bromooctanoic acid (912 g) and sulfuric acid (912 ml) is boiled in a suitable reaction vessel 20 ....
i 5 timer ved tilbagesvaling og onrøres natten over ved stuetemperatur. Opløsningsmidlet fordampes under formindsket tryk (3 mm Hg), og den olieformige remanens opløses i ether (4.000 ml). Opløsningen vaskes med vand (3 x 2.000 ml), mættet vandig na- triumhydrogencarbonatopløsning (1.000 ml) og mættet van-25 dig natriumchloridopløsning. Etherlaget tørres over magnesiumsulfat og filtreres. Efter afdampning af opløsningsmidlet og destillation af den rå olie får man 8-bromoctan-syremethylesteren, som koger ved 73-76°C/0,05 mm Hg.for 5 hours at reflux and stirring overnight at room temperature. The solvent is evaporated under reduced pressure (3 mm Hg) and the oily residue is dissolved in ether (4,000 ml). The solution is washed with water (3 x 2,000 ml), saturated aqueous sodium hydrogen carbonate solution (1,000 ml) and saturated aqueous sodium chloride solution. The ether layer is dried over magnesium sulfate and filtered. After evaporation of the solvent and distillation of the crude oil, the 8-bromooctanoic acid methyl ester is obtained, which boils at 73-76 ° C / 0.05 mm Hg.
ώΡ = 1,4614.ώΡ = 1.4614.
30 υ30 υ
Eksempel 2Example 2
Til en suspension fremstillet ved fortynding af 4,8 g 50%'s natriumhydrid-suspension i mineralolie med 40 ml dimethyl- formamid sættes dråbevis under nitrogen en opløsning af 35 13,5 g 3-methyl-2-(3-pyridyl)-indol i 80 ml dimethylform-amid. Efter endt tilsætning omrøres den grøngule blanding 0 29 DK 169104 B1 ved stuetemperatur i ca. 1 time. Til reaktionsblandingen sættes dråbevis under afkøling til 0-5°C bromeddikesyre-ethylester (11,2 ml, 0,10 mol), og der omrøres i 4 timer ved stuetemperatur.To a suspension prepared by diluting 4.8 g of 50% sodium hydride suspension in mineral oil with 40 ml of dimethylformamide is added dropwise under nitrogen to a solution of 13.5 g of 3-methyl-2- (3-pyridyl) - indole in 80 ml of dimethylformamide. After the addition is complete, the green-yellow mixture is stirred at room temperature for approx. 1 hour. To the reaction mixture is added dropwise with cooling to 0-5 ° C bromoacetic acid ethyl ester (11.2 ml, 0.10 mol) and stirred for 4 hours at room temperature.
55
Reaktionsblandingen hældes i 1.000 ml isvand, og der ekstraheres med 3 x 300 ml ether. Etherlaget ekstraheres med 3 x 300 ml 1 N saltsyre. Den sure ekstrakt indstilles med koncentreret ammoniumhydroxid på pH-værdien 9-10 og 10 ekstraheres med 3 x 250 ml ether. De sammenblandede ether-ekstrakter tørres over magnesiumsulfat, filtreres og inddampes under formindsket tryk. Man får 1-ethoxycarbonyl-methyl-3-methyl-2-(3-pyridyl)-indo1 i form af en olie.The reaction mixture is poured into 1,000 ml of ice water and extracted with 3 x 300 ml of ether. The ether layer is extracted with 3 x 300 ml of 1 N hydrochloric acid. The acidic extract is adjusted to pH 9-10 with concentrated ammonium hydroxide and extracted with ether (3 x 250 ml). The mixed ether extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. 1-ethoxycarbonyl-methyl-3-methyl-2- (3-pyridyl) -indole is obtained in the form of an oil.
15 Den ovenfor fremstillede olie koges i 500 ml 1 N saltsyre i 4 timer med tilbagesvaling. Efter henstand natten over udskilles et gult fast materiale, som tørres i 12 timer ved 60-80°C/30 mm Hg. Efter omkrystallisation fra ethanol fås l-carboxymethyl-3-methyl-2-(3-pyridyl)-indol-hydrochlo-20 rid, smp. 204-207°C.The oil prepared above is boiled in 500 ml of 1 N hydrochloric acid for 4 hours at reflux. After standing overnight, a yellow solid is separated, which is dried for 12 hours at 60-80 ° C / 30 mm Hg. After recrystallization from ethanol, 1-carboxymethyl-3-methyl-2- (3-pyridyl) -indole hydrochloride is obtained, m.p. 204-207 ° C.
Til fremstilling af den frie aminosyre indstilles pH-vær-dien i hydrolysemediet på 3,5.To prepare the free amino acid, adjust the pH of the hydrolysis medium to 3.5.
25 Eksempel 3-6Examples 3-6
Analogt med de i e'ksempel 1 og 2 beskrevne fremgangsmåder fremstilles forbindelser med formlen II, hvori = CH^, og R^ = H og R^ = OH: 30 Eksem- Ester-udgangs- C H pyr Smp. Qrikrystalliseret pel stof oQ fra 3 Br(CH2)5COOEt* (CH2)5 3-Pyridyl 113-114 Acetonitril 4 Br (CH2)gC0QMe (CH2)g 3-Eyridyl 106-107,5 Acetonitril 5 Br(CH2)4COQMe (CH2)4 3-pyridyl 123-125 Ethanol 35 6 Br (CH2) gCOOEt (O^^ 4-Pyridyl 186-188 Acetonitril * Et = ethyl, Me = methyl 0 30 DK 169104 B1Analogous to the methods described in Examples 1 and 2, compounds of formula II are prepared in which = CH 2 and R 2 = H and R 2 = OH: Eczema-Ester starting C H pyr. Crystallized pellet of oQ from 3 Br (CH2) 5COOEt * (CH2) 5 3-Pyridyl 113-114 Acetonitrile 4 Br (CH2) gCOQMe (CH2) g 3-Eyridyl 106-107.5 Acetonitrile 5 Br (CH2) 4COQMe (CH2 ) 4 3-Pyridyl 123-125 Ethanol 6 Br (CH 2) gCOOEt (O 4 4-Pyridyl 186-188 Acetonitrile * Et = ethyl, Me = methyl 0 DK 169104 B1
De som udgangsforbindelser anvendte 2-(3- og 4-pyridyl)-indoler fremstilles under anvendelse af den i USA-patent-skrift nr. 3.468.894 beskrevne fremgangsmåde.The 2- (3- and 4-pyridyl) indoles used as starting compounds are prepared using the method described in U.S. Patent No. 3,468,894.
5 De som udgangsmaterialer anvendte ethyl- eller methyl-oo-brom-estere er handelsvarer eller kan fremstilles ud fra kommercielle ω-brom-syrer, hvilket illustreres i det følgende for 6-brom-hexansyre-methylesteren. Til en opløsning af 6-brom-hexansyre (10 g) i 50 ml methanol sættes 1,0 ml 10 koncentreret svovlsyre, og blandingen koges i 8 timer med tilbagesvaling. Methanolet fordampes og remanensen opløses i ether. Etheropløsningen befries for syren ved vaskning med vand, hvorpå den tørres over natriumsulfat og inddampes til tørhed. Ved destillation ved 0,8 mm Hg fås 6-brom-15 hexansyre-methylester, som koger ved 85-90°C/0,8 mm Hg.The ethyl or methyl o-bromo esters used as starting materials are commodities or can be prepared from commercial ω-bromo acids, as illustrated below for the 6-bromo-hexanoic acid methyl ester. To a solution of 6-bromo-hexanoic acid (10 g) in 50 ml of methanol is added 1.0 ml of 10 concentrated sulfuric acid and the mixture is refluxed for 8 hours. The methanol is evaporated and the residue is dissolved in ether. The ether solution is freed from the acid by washing with water and then dried over sodium sulfate and evaporated to dryness. Distillation at 0.8 mm Hg gives 6-bromo-hexanoic acid methyl ester, which boils at 85-90 ° C / 0.8 mm Hg.
1- (7-Carboxyheptyl)-3-methyl-2-(2-pyridyl)-indol fremstilles analogt med den i eksempel 1 beskrevne fremgangsmåde.1- (7-Carboxyheptyl) -3-methyl-2- (2-pyridyl) indole is prepared analogously to the procedure described in Example 1.
Den som udgangsmateriale anvendte 3-methyl-2-(2-pyridyl)- 20 indol er beskrevet i J. Chem. Soc. 1955, 2865.The 3-methyl-2- (2-pyridyl) -20 indole used as starting material is described in J. Chem. Soc. 1955, 2865.
De tilsvarende forbindelser med formlen II, hvori R| er hydrogen, Pyr = 2-, 3- eller 4-pyridyl, = fluor, hydro-25 gen eller methyl, og R^ = hydrogen, fremstilles på analog måde under anvendelse af de i eksemplerne 1 og 2 beskrevne fremgangsmåder. Som udgangsforbindelser anvendes de nødvendige ω-brom-estere og de kendte 2-(pyridyl)-indoler.The corresponding compounds of formula II wherein R 1 is hydrogen, Pyr = 2-, 3- or 4-pyridyl, = fluoro, hydrogen or methyl, and R 2 = hydrogen is prepared in an analogous manner using the procedures described in Examples 1 and 2. The starting compounds are used with the necessary ω-bromo esters and the known 2- (pyridyl) indoles.
2- (2-, 3- og 4-Pyridyl)-indolerne er beskrevet i Pharm.The 2- (2-, 3- and 4-Pyridyl) indoles are described in Pharm.
30 Bull. Japan 4, 16 (1956), og 5-(Eluor og methyl)-2-(3-pyr- idyl)-indolerne i Bull. Soc. Chim. France 1969, 4154.30 Bull. Japan 4, 16 (1956), and the 5- (Eluoro and methyl) -2- (3-pyridyl) indoles in Bull. Soc. Chim. France 1969, 4154.
Eksempel 7 og 8Examples 7 and 8
Forbindelserne med formlen II, hvori R^ = CH3, R3 = H, Pyr = 35 3-pyridyl, CmH2m = (CH2)5 og R4 = OH, fremstilles under anvendelse af de i ovenstående eksempler beskrevne fremgangsmåder .The compounds of formula II wherein R 1 = CH 3, R 3 = H, Pyr = 35 3-pyridyl, C m H 2 m = (CH 2) 5 and R 4 = OH are prepared using the methods described in the above examples.
0 31 DK 169104 B10 31 DK 169104 B1
Eksempel Ri, Smp. Salt _^_ 7 5-C1 143-145 8 5-OCH3 175-178 HC1 5Example Ri, m.p. Salt _ ^ _ 7 5-C1 143-145 8 5-OCH3 175-178 HCl 5
Forbindelsen ifølge eksempel 7 fremstilles på følgende måde: Til en suspension fremstillet ved fortynding af 1,39 g 50%'s natriumhydrid-suspension i mineralolie med 30 ml dimethyl-formamid sættes dråbevis under omrøring i en ni trogena tinor-10 sfære ved 0-5°C en opløsning af 6,59 g 5-chlor-3-methyl- 2-(3-pyridyl)-indol (fremstillet som beskrevet i USA-patent-skrift nr. 3.468.894) i 60 ml dimethylformamid. Efter endt tilsætning omrøres suspensionen i 1/2 time ved 0°C, hvorefter der under afkøling til 0°C dråbevis tilsættes en opløs-15 ning af 6,06 g 6-brom-hexansyre-methylester i 10 ml dimethylf ormamid. Reaktionsblandingen henstår til opvarmning til stuetemperatur, hvorefter den omrøres i 5 timer ved stuetemperatur og hældes i 400 ml isvand. Den dannede blanding ekstraheres med 3 x 300 ml ethylacetat. Ekstrakten 20 vaskes med mættet vandig natriumchloridopløsning, tørres over magnesiumsulfat og inddampes til tørhed. Man får 1- (5-methoxycarbonylpentyl) -5-chlor-3-methyl-2- (3-pyridyl)-indol i form af en olie.The compound of Example 7 is prepared as follows: To a suspension prepared by diluting 1.39 g of 50% sodium hydride suspension in mineral oil with 30 ml of dimethylformamide is added dropwise with stirring in a nine trogenic tinor sphere at 0 ° C. 5 ° C a solution of 6.59 g of 5-chloro-3-methyl-2- (3-pyridyl) indole (prepared as described in U.S. Pat. No. 3,468,894) in 60 ml of dimethylformamide. After the addition is complete, the suspension is stirred for 1/2 hour at 0 ° C, and a solution of 6.06 g of 6-bromo-hexanoic acid methyl ester in 10 ml of dimethylformamide is added dropwise with cooling to 0 ° C. The reaction mixture is allowed to warm to room temperature, then stirred for 5 hours at room temperature and poured into 400 ml of ice water. The resulting mixture is extracted with 3 x 300 ml of ethyl acetate. The extract 20 is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. 1- (5-methoxycarbonylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole is obtained as an oil.
25 En opløsning af 3,2 g af den ovenfor fremstillede forbindelse i 30 ml 3 N natriumhydroxidopløsning koges i .17 timer under tilbagesvaling. Efter afkøling frafiltreres det dannede produkt, som opløses i 50 ml vand. Efter syrning med 2 N saltsyre til pH-værdien 4-5 udfældes produktet, 30 som renses ved suspendering i ether. Man får l-(5-carb-oxypentyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol, smp. 143-145°C.A solution of 3.2 g of the compound prepared above in 30 ml of 3 N sodium hydroxide solution is boiled under reflux for 17 hours. After cooling, the resulting product is filtered off, which is dissolved in 50 ml of water. After acidification with 2N hydrochloric acid to the pH 4-5, the product precipitates, which is purified by suspending in ether. 1- (5-carb-oxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole is obtained, m.p. 143-145 ° C.
På tilsvarende måde fremstilles 1-(5-carboxypentyl)-5-35 methoxy-3-methyl-2-(3-pyridyl)-indol i form af en olie.Similarly, 1- (5-carboxypentyl) -5- 35 methoxy-3-methyl-2- (3-pyridyl) indole is prepared in the form of an oil.
Efter behandling med ethanolisk saltsyre i ethanol og krystallisation ved tilsætning af ethylether fås forbin- 0 32 DK 169104 B1 delsen ifølge eksempel 8, nemlig 1-(5-carboxypentyl)-5-meth-oxy-3-methyl-2-(3-pyridyl)-indol-hydrochlorid, som smelter ved 175-178°C.After treatment with ethanolic hydrochloric acid in ethanol and crystallization by the addition of ethyl ether, the compound of Example 8 is obtained, namely 1- (5-carboxypentyl) -5-methoxy-3-methyl-2- (3- pyridyl) -indole hydrochloride, which melts at 175-178 ° C.
5 1- (5-Carboxypentyl) -5-hydroxy-3-methyl-2- (3-pyridyl) -indol fremstilles på følgende måde: En opløsning af 1,70 g 1-(5-carboxypentyl) -5-methoxy-3-methyl-2- (3-pyridyl) -indol koges i 85 ml 48%'s hydrogenbromidsyre i 30 minutter under tilbagesvaling. Reaktionsblandingen inddampes til tørhed, 10 remanensen fortyndes med vand, hvorefter der indstilles på pH-værdien 6 med fortyndet natriumhydroxidopløsning. Bundfaldet isoleres og omkrystalliseres fra en blanding af acetone og ethylacetat. Man får 1-(5-carboxypentyl)- 5-hydroxy-3-methyl-2- (3-pyridyl) -indol.1- (5-Carboxypentyl) -5-hydroxy-3-methyl-2- (3-pyridyl) indole is prepared as follows: A solution of 1.70 g of 1- (5-carboxypentyl) -5-methoxyphenyl 3-methyl-2- (3-pyridyl) indole is boiled in 85 ml of 48% hydrogen bromic acid for 30 minutes under reflux. The reaction mixture is evaporated to dryness, the residue is diluted with water and then adjusted to pH 6 with dilute sodium hydroxide solution. The precipitate is isolated and recrystallized from a mixture of acetone and ethyl acetate. 1- (5-carboxypentyl) -5-hydroxy-3-methyl-2- (3-pyridyl) indole is obtained.
1515
Eksempel 9 og 10Examples 9 and 10
Nedenstående forbindelser med formlen III, hvori C EL· be-The following compounds of formula III wherein C EL ·
P 2PP 2P
tyder gruppen CH2-CH2, og Pyr betyder 3-pyridyl, fremstilles under anvendelse af stort set samme fremgangsmåde som 20 anvendt i eksempel 2. Ved kondensation af 3-methyl-2- (3-pyridyl)-indol-5-propionsyre-ethylesteren med 6-brom-hexansyre-ethylester eller med 8-bromoctansyre-methyl-ester fås estrene ifølge eksempel 9a og 10a. Ved hydrolyse med saltsyre fås de tilsvarende di-syrer ifølge eksempel 25 9 og 10.and the group means 3-pyridyl is prepared using substantially the same procedure as used in Example 2. Condensation of the 3-methyl-2- (3-pyridyl) -indole-5-propionic acid ethyl ester with 6-bromo-hexanoic acid ethyl ester or with 8-bromooctanoic acid methyl ester, the esters of Examples 9a and 10a are obtained. Hydrolysis with hydrochloric acid gives the corresponding diacids of Examples 25 9 and 10.
Eksempel cnH2n SmP· Rg Rg Omkrystalliseret __fra_ 30 9a (CH2) g olie 0C2H5 OC2H5 9 (CH2)^ 143-145 OH OH Acetonitril 10a (CH2)7 olie OCH3 OC2H5 10 (ch2)7 128-130 OH OH Acetonitril 35 l-Carboxyheptyl-3-methyl-2- (4-pyridyl)-indol-5-propion-syre fremstilles på analog måde.Example cnH2n SmP · Rg Rg Recrystallized __from 30 9a (CH2) g oil 0C2H5 OC2H5 9 (CH2) ^ 143-145 OH OH Acetonitrile 10a (CH2) 7 oil OCH3 OC2H5 10 (ch2) 7 128-130 OH OH Acetonitrile 35 Carboxyheptyl-3-methyl-2- (4-pyridyl) -indole-5-propionic acid is prepared in an analogous manner.
o 33 DK 169104 B1o 33 DK 169104 B1
De som udgangsforbindelser anvendte indoler fremstilles på følgende måde: Til en suspension af p-hydrazinohydro-kanelsyre [Manske og Kulka, J.Can. Res. 25 B, 376 (1947), 4,50 g] i 50 ml absolut ethanol sættes under nitrogen ved 5 stuetemperatur og omrøring 10 ml mættet ethanolisk saltsyre. I løbet af ca. 5 minutter fås en opløsning. Til den rødorangefarvede opløsning sættes 3,37 g (0,025 mol) 3-propionylpyridin, reaktionsblandingen opvarmes til tilbagesvaling, hvorefter den holdes i 18 timer under tilbage-10 svaling. Den dannede opløsning afkøles i et isvandbad, og de dannede krystaller af 3-methyl-2-(3-pyridyl)-indol-5-propionsyre-ethylester-hydrochloridet isoleres, smp.The indoles used as starting compounds are prepared as follows: For a suspension of p-hydrazinohydro-cinnamic acid [Manske and Kulka, J. Can. Res. 25 B, 376 (1947), 4.50 g] in 50 ml of absolute ethanol is added under nitrogen at 5 room temperature and stirring 10 ml of saturated ethanolic hydrochloric acid. Over approx. A solution is obtained for 5 minutes. To the red-orange colored solution is added 3.37 g (0.025 mole) of 3-propionylpyridine, the reaction mixture is heated to reflux and then refluxed for 18 hours. The resulting solution is cooled in an ice-water bath and the crystals formed of the 3-methyl-2- (3-pyridyl) -indole-5-propionic acid ethyl ester hydrochloride are isolated, m.p.
249-251°C. Den fri base, dvs. 3-methyl-2-(3-pyridyl)-indol- 5-propionsyre-ethylester fremstilles ved opslæmning af 15 hydrochlorid-saltet i vand, hvorefter der gøres basisk med 3 N natriumhydroxidopløsning, hvorefter der ekstraheres med ether.249-251 ° C. The free base, ie. 3-Methyl-2- (3-pyridyl) -indole-5-propionic acid ethyl ester is prepared by slurrying the hydrochloride salt in water, then basifying with 3N sodium hydroxide solution, then extracting with ether.
På tilsvarende måde fremstilles 3-methyl-2-(4-pyridyl)-in-20 dol-5-propionsyreethylester-hydrochlorid med smp. større end 275°C og den tilsvarende frie base.Similarly, 3-methyl-2- (4-pyridyl) -indole-5-propionic acid ethyl ester hydrochloride is prepared, m.p. greater than 275 ° C and the corresponding free base.
En suspension af 7,5 g 3-methyl-2-(3-pyridyl)-indol-5-propionsyre-ethylester-hydrochlorid i 450 ml 2 N salt-25 syre opvarmes i 2 timer under tilbagesvaling, hvorefter der afkøles, og det faste dannede materiale isoleres, hvorved man får 3-methyl-2-(3-pyridyl)-indol-5-propion~ syre-hydrochlorid, som smelter ved 290°C.A suspension of 7.5 g of 3-methyl-2- (3-pyridyl) -indole-5-propionic acid ethyl ester hydrochloride in 450 ml of 2N hydrochloric acid is heated at reflux for 2 hours, then cooled solid formed material is isolated to give 3-methyl-2- (3-pyridyl) -indole-5-propionic acid hydrochloride, which melts at 290 ° C.
3030
Ved tilsvarende hydrolyse af 3-methy1-2-(4-pyridyl)-indol- 5-propionsyre-ethylester-hydrochlorid fås 3-methyl-2-(4-pyridyl)-indol-5-propionsyre-hydrochlorid, som smelter over 305°C.By corresponding hydrolysis of 3-methyl-2- (4-pyridyl) -indole-5-propionic acid ethyl ester hydrochloride, 3-methyl-2- (4-pyridyl) -indole-5-propionic acid hydrochloride is obtained, which melts above 305 ° C.
35 DK 169104 Bl 0 3435 DK 169104 Pg 0 34
Eksempel 11 a) En opløsning af 1-(4-cyanbenzyl)-3-methyl-2-(3-pyri-dyl)-indol (5,8 g) i 100 ml af en l:l-blanding af 20%'s saltsyre og iseddike koges i 20 timer under tilbagesvaling.Example 11 a) A solution of 1- (4-cyanobenzyl) -3-methyl-2- (3-pyridyl) -indole (5.8 g) in 100 ml of a 1: 1 mixture of 20% s hydrochloric acid and glacial acetic acid are refluxed for 20 hours.
5 Efter afkøling hældes opløsningen i 100 ml isvand, og pH-værdien indstilles med mættet vandig natriumhydrogen-carbonatopløsning på 4,5-5. Det dannede bundfald ekstrahe-res med ethylacetat, ekstrakten vaskes med vand og inddampes til tørhed. Man får 1-(4-carboxybenzyl)-3-methyl-2-10 (3-pyridyl)-indol, smp. 273-275°C.After cooling, the solution is poured into 100 ml of ice water and the pH is adjusted with saturated aqueous sodium hydrogen carbonate solution of 4.5-5. The precipitate formed is extracted with ethyl acetate, the extract is washed with water and evaporated to dryness. 1- (4-carboxybenzyl) -3-methyl-2-10 (3-pyridyl) indole is obtained, m.p. 273-275 ° C.
Det som udgangsmateriale anvendte nitril fremstilles på følgende måde: Til en suspension af 2,9 g (0,06 mol) 50%'s natriumhydrid i mineralolie i 40 ml dimethylformamid sæt-15 tes dråbevis under nitrogen ved 0-5°C i løbet af 20 minutter en opløsning af 10,4 g (0,05 mol) 3-methyl-2-(3-pyridyl)-indol i 60 ml dimethylf ormamid. Reaktionsblandingen omrøres i 1/2 time ved 0-5°C, hvorpå der dråbevis tilsættes 9,8 g (0,05 mol) p-cyan-benzylbromid i 50 ml 20 dimethylformamid. Blandingen omrøres i 1 time ved 0-10°CThe nitrile used as the starting material is prepared as follows: To a suspension of 2.9 g (0.06 mole) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide is added dropwise under nitrogen at 0-5 ° C over of 20 minutes a solution of 10.4 g (0.05 mol) of 3-methyl-2- (3-pyridyl) indole in 60 ml of dimethylformamide. The reaction mixture is stirred for 1/2 hour at 0-5 ° C, then 9.8 g (0.05 mole) of p-cyanobenzyl bromide is added dropwise in 50 ml of dimethylformamide. The mixture is stirred for 1 hour at 0-10 ° C
og derefter ved stuetemperatur i 30 minutter, hvorefter den hældes i 600 ml isvand. Det dannede faste materiale isoleres, tørres, vaskes med petroleumsether og opløses atter i 500 ml ether. Etheropløsningen vaskes først med 25 vand og derpå med mættet vandig natriumhydrogencarbonat-opløsning, tørres over magnesiumsulfat, behandles med aktivt kul og filtreres. Efter inddampning af etheropløsningen til tørhed fås et gult fast materiale. Dette produkt opslæmmes i varm cyclohexan og frafiltreres.and then at room temperature for 30 minutes, after which it is poured into 600 ml of ice water. The solid formed is isolated, dried, washed with petroleum ether and redissolved in 500 ml of ether. The ether solution is first washed with 25 water and then with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, treated with activated carbon and filtered. After evaporation of the ether solution to dryness a yellow solid is obtained. This product is suspended in hot cyclohexane and filtered off.
30 Man får 1-(4-cyanbenzyl)-3-methyl-2-(3-pyridyl)-indol, smp. 127-129°C.1- (4-cyanobenzyl) -3-methyl-2- (3-pyridyl) indole is obtained, m.p. 127-129 ° C.
b) På analog måde fremstilles 1-(4-carboxybenzyl)-5-35 35 DK 169104 B1 chlor-3-methyl-2-(3-pyridyl)-indol-hydrochlorid, srap. 217-220°C.b) Analogously, 1- (4-carboxybenzyl) -5- 35 is prepared chlorine-3-methyl-2- (3-pyridyl) -indole hydrochloride, srap. 217-220 ° C.
Eksempel 12 a) Til en suspension af 0,49 g lithiumaluminiumhydrid i 5 50 ml vandfrit tetrahydrofuran sættes dråbevis i en nitrogenatmosfære ved stuetemperatur en opløsning af 3,92 g 1-(5-methoxycarbonylpentyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol i 30 ml vandfrit tetrahydrofuran. Efter endt tilsætning omrøres suspensionen i 1 time ved 10 stuetemperatur, hvorpå der tilsættes 50 ml mættet vandig ammoniumchloridopløsning. Reaktionsblandingen henstår natten over ved stuetemperatur, og det organiske lag fjernes. Det vandige lag filtreres til fjernelse af salte, hvorpå det ekstraheres med 2 x 50 ml ethylacetat.Example 12 a) To a suspension of 0.49 g of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran is added dropwise in a nitrogen atmosphere at room temperature a solution of 3.92 g of 1- (5-methoxycarbonylpentyl) -5-chloro-3-methyl-2 - (3-pyridyl) indole in 30 ml of anhydrous tetrahydrofuran. After the addition is complete, the suspension is stirred for 1 hour at 10 room temperature, then 50 ml of saturated aqueous ammonium chloride solution is added. The reaction mixture is allowed to stand overnight at room temperature and the organic layer is removed. The aqueous layer is filtered to remove salts and then extracted with 2 x 50 ml of ethyl acetate.
15 De sammenblandede organiske lag vaskes med mættet vandig natriumchloridopløsning, tørres over magnesiumsulfat og inddampes i vakuum. Råproduktet renses ved triturering med hexan/ether og opløses i ethanol. Opløsningen syrnes med ethanolisk saltsyre, og opløsningen fortyndes med 20 vandfri ether til udfældning af det krystallinske produkt. Det dannede 1-(6-hydroxyhexyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol-hydrochlorid-hémihydrat smelter ved 115-118°C.The combined organic layers are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The crude product is purified by trituration with hexane / ether and dissolved in ethanol. The solution is acidified with ethanolic hydrochloric acid and diluted with 20 anhydrous ether to precipitate the crystalline product. The resulting 1- (6-hydroxyhexyl) -5-chloro-3-methyl-2- (3-pyridyl) indole hydrochloride hemihydrate melts at 115-118 ° C.
b) På tilsvarende måde fremstilles 1-(6-hydroxyhexyl)-25 3-methyl-2-(3-pyridyl)-indol i form af en olie.b) Similarly, 1- (6-hydroxyhexyl) -25 3-methyl-2- (3-pyridyl) indole is prepared in the form of an oil.
NMR (CDC13) <S 3,50 (t, 2H) , 3,98 (t, 2H)NMR (CDCl 3) δ S 3.50 (t, 2H), 3.98 (t, 2H)
Eksempel 13Example 13
Til en suspension af 1,52 g 1-(5-carboxypentyl)-5-chlor- 3-methyl-2-(3-pyridyl)-indol i 50 ml toluen sættes 30 dråbevis ved stuetemperatur under nitrogen 0,31 ml thio-nylchlorid. Den dannede blanding koges i 1 time under tilbagesvaling, hvorefter der tilsættes yderligere 0,10 g thionylchlorid, og opløsningen omrøres natten over ved stuetemperatur. Den dannede suspension inddampes til tør-35 hed. Man får den rå 1-(5-chlorcarbonylpentyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol, som anvendes direkte uden 36 DK 169104 B1 yderligere rensning.To a suspension of 1.52 g of 1- (5-carboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole in 50 ml of toluene is added dropwise at room temperature under nitrogen 0.31 ml of chloride. The resulting mixture is refluxed for 1 hour, then an additional 0.10 g of thionyl chloride is added and the solution is stirred overnight at room temperature. The resulting suspension is evaporated to dryness. The crude 1- (5-chlorocarbonylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole is obtained, which is used directly without further purification.
En suspension af 0,86 g af den ovenfor fremstillede 1-(5-chlorcarbonylpentyl)-5-chlor-3-methyl-2-(3-pyri-dyl)-indol i 20 ml koncentreret ammoniumhydroxid omrøres 5 natten over ved stuetemperatur. Ved filtrering af suspensionen og opslæmning af det fremkomne faste materiale i ether fås 1-(5-carbamoylpentyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol, smp. 137-140°C.A suspension of 0.86 g of the above-prepared 1- (5-chlorocarbonylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole in 20 ml of concentrated ammonium hydroxide is stirred overnight at room temperature. Filtration of the suspension and slurry of the resulting solid in ether afforded 1- (5-carbamoylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole, m.p. 137-140 ° C.
Eksempel 14 10 Til en suspension af 2,9 g (0,06 mol) 50%'s natrium- hydrid i mineralolie i 40 ml dimethylformamid sættes dråbevis i løbet af 20 minutter under nitrogen ved 0-5°C en opløsning af 10,4 g 3-methyl-2-(3-pyridyl)-indol i 60 ml dimethylformamid. Blandingen omrøres ved 0-5°C i 30 minut-15 ter, hvorpå der dråbevis tilsættes 17,6 g (0,06 mol) 1-tetrahydropyranyloxy-8-bromoctan i 50 ml dimethylformamid. Blandingen omrøres i 1 time ved 0-10°C og i 30 minutter ved stuetemperatur, hvorefter den hældes i isvand og ekstraheres med ether. Etherekstrakten vaskes med vand, 20 tørres over magnesiumsulfat og inddampes til tørhed. Remanensen opløses i 100 ml 3 N saltsyre, den dannede opløsning henstår i 30 minutter ved stuetemperatur, vaskes med ether, gøres basisk med vandig 3 N natriumhydroxidopløsning og ekstraheres med methylenchlorid. Methylenchlorid-25 opløsningen inddampes til tørhed. Man får 1-(8-hydroxy-octyl)-2-(3-pyridyl)-3-methylindol.Example 14 10 To a suspension of 2.9 g (0.06 mol) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide is added dropwise over 20 minutes under nitrogen at 0-5 ° C, a solution of 10 4 g of 3-methyl-2- (3-pyridyl) indole in 60 ml of dimethylformamide. The mixture is stirred at 0-5 ° C for 30 minutes, to which is added dropwise 17.6 g (0.06 mol) of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of dimethylformamide. The mixture is stirred for 1 hour at 0-10 ° C and for 30 minutes at room temperature, after which it is poured into ice water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting solution is left at room temperature for 30 minutes, washed with ether, basified with aqueous 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness. 1- (8-hydroxy-octyl) -2- (3-pyridyl) -3-methylindole is obtained.
Eksempel 15Example 15
En opløsning af 4 g 1-(7-methoxycarbonylheptyl)-3-methyl-2*-(3-pyridyl)-indol i 40 ml n-butanol mættes med methyl-30 amin og opvarmes i en trykbeholder i 3 dage på et dampbad. Reaktionsblandingen inddampes til tørhed, og produktet omkrystalliseres fra ethylacetat. Man får 1-[7-(N-methyl-carbamoyl)-heptyl]-3-methyl-2-(3-pyridyl)-indol.A solution of 4 g of 1- (7-methoxycarbonylheptyl) -3-methyl-2 * - (3-pyridyl) indole in 40 ml of n-butanol is saturated with methyl 30 amine and heated in a pressure vessel for 3 days on a steam bath . The reaction mixture is evaporated to dryness and the product is recrystallized from ethyl acetate. 1- [7- (N-methyl-carbamoyl) -heptyl] -3-methyl-2- (3-pyridyl) -indole is obtained.
37 DK 169104 B137 DK 169104 B1
Eksempel 16Example 16
Fremstilling af 10.000 tabletter indeholdende 10 mg aktivt stof ifølge eksempel 1 pr. tablet.Preparation of 10,000 tablets containing 10 mg of active substance of Example 1 per tablet.
Bestanddele 5 1-(7-Carboxyheptyl)-3-methyl-2- (3-pyridyl)-indol 100 g Mælkesukker 1157 gIngredients 5 1- (7-Carboxyheptyl) -3-methyl-2- (3-pyridyl) indole 100 g Milk Sugar 1157 g
Majsstivelse 75 gCorn starch 75 g
Polyethylenglycol 6000 75 g 10 Talkumpulver 75 gPolyethylene glycol 6000 75 g 10 Talcum powder 75 g
Magnesiumstearat 18 gMagnesium stearate 18 g
Rent vand q.s.Pure water q.s.
FremgangsmådeCourse of action
Samtlige pulverformige bestanddele sigtes gennem en si med 15 en maskevidde på 0,6 mm. Derefter blandes det aktive stof med mælkesukker, talkum, magnesiumstearat og halvdelen af stivelsen i et egnet blandeapparatur. Den anden halvdel af stivelsen suspenderes i 40 ml vand, og suspensionen sættes til en kogende opløsning af polyethylengly-20 col i 150 ml vand. Den dannede pasta sættes til pulverblandingen, hvorpå der granuleres, eventuelt under tilsætning af en yderligere mængde vand. Granulatet tørres natten over ved 35°C, sigtes gennem en si med en maskevidde på 1,2 mm og presses til tabletter med en diameter 25 på 6,4 mm med delekærv.All powdered components are screened through a screen having a mesh width of 0.6 mm. Then, the active substance is mixed with milk sugar, talc, magnesium stearate and half of the starch in a suitable mixing apparatus. The other half of the starch is suspended in 40 ml of water and the suspension is added to a boiling solution of polyethylene glycol in 150 ml of water. The paste formed is added to the powder mixture and then granulated, optionally with the addition of an additional amount of water. The granulate is dried overnight at 35 ° C, sieved through a sieve with a mesh width of 1.2 mm, and pressed into tablets of 6.4 mm diameter with split groove.
Eksempel 17Example 17
Fremstilling af 10.000 kapsler indeholdende 25 mg aktivt stof ifølge eksempel 11a pr. kapsel.Preparation of 10,000 capsules containing 25 mg of active substance of Example 11a per capsule.
Bestanddele 30 1-(4-Carboxybenzyl)-3-methyl-2- (3-pyridyl)-indol 250 g Mælkesukker 1650 gIngredients 1- 1- (4-Carboxybenzyl) -3-methyl-2- (3-pyridyl) indole 250 g Milk sugar 1650 g
Talkumpulver 100 g 38 DK 169104 B1Talcum powder 100 g 38 DK 169104 B1
FremgangsmådeCourse of action
Samtlige pulverformige bestanddele sigtes gennem en si med en maskevidde på 0,6 mm. Derefter homogeniseres det aktive stof først med talkum og derefter med mælkesukker 5 i et egnet blandeapparatur. Ved hjælp af en påfyldningsmaskine fyldes den dannede blanding i kapsel nr. 3 i en mængde på 200 mg pr. kapsel.All powdered components are screened through a screen having a mesh width of 0.6 mm. Then, the active substance is first homogenized with talc and then with milk sugar 5 in a suitable mixing apparatus. By means of a filling machine, the mixture formed in capsule # 3 is filled to an amount of 200 mg per ml. capsule.
På tilsvarende måde fremstilles tabletter og kapsler med et indhold på ca. 10-100 mg af andre af de omhandlede 10 forbindelser, f.eks. 1-(5-carboxypentyl)-5-(chlor, fluor, methoxy eller methyl)-3-methyl-2-(3-pyridyl)-indol, 1—(5— carboxypenty1)-5,6-dichlor-3-methyl-2-(3-pyridyl)-indol, eller andre af de i eksemplerne nævnte forbindelser.Similarly, tablets and capsules having a content of approx. 10-100 mg of other of the present compounds, e.g. 1- (5-carboxypentyl) -5- (chloro, fluoro, methoxy or methyl) -3-methyl-2- (3-pyridyl) indole, 1- (5-carboxypentyl) -5,6-dichloro-3- methyl 2- (3-pyridyl) indole, or other of the compounds mentioned in the examples.
Eksempel 18 15 En opløsning af 50 mg 1-(5-carbamoylpentyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol i 1 ml 6 N saltsyre koges i 3 timer under tilbagesvaling. Efter afkøling udfældes hydrochloridsaltet. Suspensionen inddampes til tørhed, og remanensen gøres basisk ved tilsætning af mættet van-20 dig natriumhydrogencarbonatopløsning. Opløsningen vaskes med ether og indstilles med 2 N saltsyre på pH-værdien 6-7. Man får den rå fri syre, nemlig 1-(5-carboxypentyl)- 5-chlor-3-methyl-2-(3-pyridyl)-indol, smp. 137-141°C.Example 18 A solution of 50 mg of 1- (5-carbamoylpentyl) -5-chloro-3-methyl-2- (3-pyridyl) -indole in 1 ml of 6N hydrochloric acid is refluxed for 3 hours. After cooling, the hydrochloride salt precipitates. The suspension is evaporated to dryness and the residue is made basic by the addition of saturated aqueous sodium hydrogen carbonate solution. The solution is washed with ether and adjusted with 2N hydrochloric acid to pH 6-7. The crude free acid is obtained, namely 1- (5-carboxypentyl) -5-chloro-3-methyl-2- (3-pyridyl) indole, m.p. 137-141 ° C.
Eksempel 19 25 Til en blanding af 4,17 g 3-methy1-2-(3-pyridyl)-indol, 0,64 g tetra-n-butyl-ammoniumbromid og 1,02 g pulveriseret kaliumhydroxid i 500 ml acetonitril sættes under omrøring ved stuetemperatur under nitrogen 5,06 g p-(2-bromethoxy)-benzoesyre [fremstillet som beskrevet i USA-patentskrif-30 tet nr. 2.790.825]. Suspensionen omrøres i 5 dage. Kalium-bromidet frafiltreres, og filtratet koncentreres til en olie. Denne opløses i ethylacetat og ekstraheres med 3 N saltsyre. Syrelaget isoleres og behandles med 3 N natriumhydroxidopløsning. Den dannede suspension eks-35 traheres med 3 x 100 ml ethylacetat, og det organiske lag fraskilles. Denne tørres over magnesiumsulfat og kon- 39 DK 169104 B1 centreres. Man får 1-[2-(4-ethoxycarbonylphenoxy)-ethyl]-2-(3-pyridyl)-3-methylindo1 i form af en olie.Example 19 To a mixture of 4.17 g of 3-methyl-2- (3-pyridyl) indole, 0.64 g of tetra-n-butyl ammonium bromide and 1.02 g of powdered potassium hydroxide in 500 ml of acetonitrile is stirred. at room temperature under nitrogen 5.06 g of p- (2-bromethoxy) -benzoic acid [prepared as described in U.S. Patent No. 2,790,825]. The suspension is stirred for 5 days. The potassium bromide is filtered off and the filtrate is concentrated to an oil. This is dissolved in ethyl acetate and extracted with 3N hydrochloric acid. The acid layer is isolated and treated with 3 N sodium hydroxide solution. The resulting suspension is extracted with ethyl acetate (3 x 100 ml) and the organic layer is separated. This is dried over magnesium sulfate and concentrated. 1- [2- (4-ethoxycarbonylphenoxy) ethyl] -2- (3-pyridyl) -3-methylindole is obtained in the form of an oil.
Eksempel 20Example 20
En blanding af 4/7 g 1-[2-(4-ethoxycarbonylphenoxy)-ethyl]-5 2-(3-pyridyl)-3-methylindol i 220 ml 2 N saltsyre koges i 6 timer med tilbagesvaling. Efter afkøling gøres opløsningen basisk med 3 N natriumhydroxidopløsning og eks-traheres med ethylacetat. Den basiske opløsning filtreres og indstilles med 5 N saltsyre på pH-værdien 6-7. Det fa-10 ste materiale fraskilles, tørres og omkrystalliseres fra acetone. Man får 1-[2-(4-carboxyphenoxy)-ethyl]-2-(3-pyr-idyl)-3-methylindol, smp. 190-193°C.A mixture of 4/7 g of 1- [2- (4-ethoxycarbonylphenoxy) ethyl] -5 2- (3-pyridyl) -3-methylindole in 220 ml of 2N hydrochloric acid is refluxed for 6 hours. After cooling, the solution is basified with 3N sodium hydroxide solution and extracted with ethyl acetate. The basic solution is filtered and adjusted with 5 N hydrochloric acid to pH 6-7. The solid material is separated, dried and recrystallized from acetone. 1- [2- (4-carboxyphenoxy) ethyl] -2- (3-pyridyl) -3-methylindole, m.p. 190-193 ° C.
Eksempel 21Example 21
En opløsning af 5,9 g p-mercapto-benzoesyre-ethylester 15 (fremstillet ifølge J.Chem. Soc., 1963, 1947-1954) i 30 ml dimethylformamid sættes dråbevis til en grød fremstillet af 1,55 g 50%'s natriumhydrid-mineralolie i 30 ml dimethylformamid. Denne blanding omrøres under nitrogen ved stuetemperatur i 30 minutter. Opløsningen sættes dråbe-20 vis til en opløsning af 9,78 g 1-(2-methylsulfonyloxy-eth-yl)-2-(3-pyridyl)-3-methylindol i 60 ml dimethylformamid ved -10°C. Denne blanding omrøres ved stuetempeatur natten over og hældes i 1000 ml isvand. Blandingen ekstrahe-res flere gange med ether (i alt ca. 1000 ml). Ethereks-25 trakten vaskes med 3 x 200 ml vand, tørres over magnesiumsulfat og inddampes i vakuum. Man får 1-[2-(4-ethoxy-carbonyl-phenylthio)-ethyl]-2-(3-pyridyl)-3-methylindol i fom af en olie. NMR (CDCl^) bekræfter strukturen.A solution of 5.9 g of p-mercapto-benzoic acid ethyl ester 15 (prepared according to J.Chem. Soc., 1963, 1947-1954) in 30 ml of dimethylformamide is added dropwise to a porridge made of 1.55 g of 50% sodium hydride mineral oil in 30 ml of dimethylformamide. This mixture is stirred under nitrogen at room temperature for 30 minutes. The solution is added dropwise to a solution of 9.78 g of 1- (2-methylsulfonyloxy-ethyl) -2- (3-pyridyl) -3-methylindole in 60 ml of dimethylformamide at -10 ° C. This mixture is stirred at room temperature overnight and poured into 1000 ml of ice water. The mixture is extracted several times with ether (a total of about 1000 ml). The ether extract is washed with 3 x 200 ml water, dried over magnesium sulfate and evaporated in vacuo. 1- [2- (4-Ethoxy-carbonyl-phenylthio) -ethyl] -2- (3-pyridyl) -3-methylindole is obtained in the form of an oil. NMR (CDCl3) confirms the structure.
Udgangsforbindelsen fremstilles på følgende måde: Til 30 11,77 g 1-(2-ethoxycarbonyl-ethyl)-2-(3-pyridyl)-3-methyl- indol i 400 ml tør tetrahydrofuran sættes ved 0°C 60 ml 1 M opløsning af lithiumaluminiumhydrid i tetrahydrofuran. Reaktionsblandingen omrøres i 1 time ved stuetemperatur, hvorefter den afkøles i et isbad og tilsættes 2,26 ml vand, 35 2,26 ml 15%'s natriumhydroxidopløsning og 6,78 ml vand i nævnte rækkefølge. Blandingen filtreres og koncentreres 40 DK 169104 B1 i . vakuum. Remanensen opløses i ether, vaskes med mættet natriumhydrogencarbonatopløsning, tørres over magnesiumsulfat og koncentreres i vakuum. Man får den halvfaste 1-(2-hydroxyethyl)-2-(3-pyridyl)-3-methyl-indol, 5 som anvendes direkte i det efterfølgende trin.The starting compound is prepared as follows: To 11.77 g of 1- (2-ethoxycarbonyl-ethyl) -2- (3-pyridyl) -3-methyl-indole in 400 ml of dry tetrahydrofuran is added at 0 ° C 60 ml of 1 M solution. of lithium aluminum hydride in tetrahydrofuran. The reaction mixture is stirred for 1 hour at room temperature, after which it is cooled in an ice bath and added 2.26 ml of water, 2.26 ml of 15% sodium hydroxide solution and 6.78 ml of water in that order. The mixture is filtered and concentrated. vacuo. The residue is dissolved in ether, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The semi-solid 1- (2-hydroxyethyl) -2- (3-pyridyl) -3-methyl-indole is obtained, which is used directly in the subsequent step.
2,70 ml methansulfonylchlorid sættes dråbevis ved -10°C til en opløsning af 7,5 g 1-(2-hydroxyethyl)-2-(3-pyridyl)- 3-methylindol og 10,34 ml triethylamin i 150 ml methylen-chlorid. Blandingen omrøres ved stuetemperatur i 30 minut-10 ter, hvorefter den hældes i 600 ml isvand. Den fremkomne grød ekstraheres med methylenchlorid, ekstrakten vaskes med mættet natriumhydrogencarbonatopløsning, tørres over magnesiumsulfat og inddampes i vakuum. Man får l-(2-methyl-sulfonyloxy-ethyl)-2-(3-pyridyl)-3-methylindol, som anven-15 des direkte i den ovenfor beskrevne reaktion.2.70 ml of methanesulfonyl chloride is added dropwise at -10 ° C to a solution of 7.5 g of 1- (2-hydroxyethyl) -2- (3-pyridyl) -3-methylindole and 10.34 ml of triethylamine in 150 ml of methylene hydrochloride. chloride. The mixture is stirred at room temperature for 30 minutes, then poured into 600 ml of ice water. The resulting porridge is extracted with methylene chloride, the extract is washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo. There is obtained 1- (2-methylsulfonyloxy-ethyl) -2- (3-pyridyl) -3-methylindole, which is used directly in the reaction described above.
Eksempel 22Example 22
En blanding af 6,39 g 1-[2-(4-ethoxycarbonyl-phenylthio)-ethyl]-2-(3-pyridyl)-3-methylindol i 260 ml 2 N saltsyre koges i 6 timer med tilbagesvaling. Efter afkøling ind-20 stilles blandingens pH-værdi på 6-7 med mættet natrium-hydrogencarbonatopløsning (ca. 500 ml). Til blandingen sættes 200 ml ether, og der omrøres i 30 minutter. Det faste materiale fraskilles, vaskes med vand og derpå med ether og opløses i 100 ml absolut ethanol. Opløsningen 25 filtreres, og den varme opløsning behandles med 1,68 mlA mixture of 6.39 g of 1- [2- (4-ethoxycarbonyl-phenylthio) -ethyl] -2- (3-pyridyl) -3-methylindole in 260 ml of 2N hydrochloric acid is refluxed for 6 hours. After cooling, the pH of the mixture is adjusted to 6-7 with saturated sodium hydrogen carbonate solution (about 500 ml). To the mixture is added 200 ml of ether and stirred for 30 minutes. The solid is separated, washed with water and then with ether and dissolved in 100 ml of absolute ethanol. The solution 25 is filtered and the hot solution is treated with 1.68 ml
6,5 N ethanolisk saltsyre. Opløsningen afkøles og fortyndes med ca. 100 ml ether. Det dannede produkt isoleres. Man får 1-[2-(4-carboxyphenylthio)-ethyl]-2-(3-pyridyl) -3-methylindol-hydrochlorid, smp. 222-224°C6.5 N ethanolic hydrochloric acid. The solution is cooled and diluted with ca. 100 ml of ether. The resulting product is isolated. 1- [2- (4-carboxyphenylthio) ethyl] -2- (3-pyridyl) -3-methylindole hydrochloride, m.p. 222-224 ° C
30 Eksempel 23Example 23
En opløsning af lithiumdiisopropylamid (LDA) fremstilles ved tilsætning af n-butyl-lithium (7,66 mmol, 1,6 mol i hexan) til en opløsning af diisopropylamin (7,6 mmol) i 12 ml tetrahydrofuran (THF) ved -20°C. LDA-opløsningen 35 afkøles til -78°C, og der tilsættes dråbevis 1-(5-methoxy-carbonylpentyl)-2-(3-pyridyl)-3-methyl-indol (2,48 g) i 41 DK 169104 B1 24 ml THF i løbet af 5 minutter. Blandingen omrøres ved -78°C i 20 minutter, hvorpå der tilsættes 1,5 g phenyl-selenylchlorid i 12 ml THF. Efter 5 minutters forløb fjernes kølebadet, og blandingen henstår til opvarmning 5 til 0°C. Der tilsættes 60 ml mættet vandig natriumhydrogen-carbonatopløsning, hvorefter der ekstraheres med 3 x 50 ml ether. De sammenblandede organiske ekstrakter vaskes med mættet vandig natriumhydrogencarbonatopløsning og mættet vandig natriumchloridopløsning og tørres over 10 vandfrit magnesiumsulfat. Ved koncentrering i vakuum fås den rå 1-(5-methoxycarbonyl)-5-phenyl-selenyl-2-(3-pyridyl)- 3-methylindol i form af en gul olie. Det rå selenid opløses i 40 ml dichlormethan, og der tilsættes dråbevis 1,8 g (16 mmol) 30%'s hydrogenperoxidi 1,8 ml vand. Efter tilsæt-15 ning af ca. 10% af hydrogenperoxidet indtræder en eksoterm reaktion. Temperaturen stiger til 30°Q indtil tilsætningen er afsluttet. Blandingen omrøres i yderligere 30 minutter, hvorpå der tilsættes 40 ml 5%'s vandig natriumcarbonatop-løsning. Dichlormethanlaget isoleres. Den vandige fase eks-20 traheres med 25 ml dichlormethan. De sammenblandede organiske faser vaskes med 5%'s vandig natriumcarbonatopløsning, vand og mættet vandig natriumchloridopløsning og tørres over vandfrit magnesiumsulfat. Ved koncentrering i vakuum får man 1-(5-methoxycarbonyl-pent-4-enyl)-2-(3-pyridyl)-3-25 methyl-indol i form af en lysegul olie. Der foretages yderligere rensning ved kortvejskromatografi (silicagel) med ethylacetat-hexan (2:3) som eluent. NMR (COClo) 6 5,53 -1 0 (d,lH), 6,65 (m,lH), IR (flydende) 1720 cmA solution of lithium diisopropylamide (LDA) is prepared by adding n-butyl lithium (7.66 mmol, 1.6 mol in hexane) to a solution of diisopropylamine (7.6 mmol) in 12 ml tetrahydrofuran (THF) at -20 ° C. The LDA solution 35 is cooled to -78 ° C, and 1- (5-methoxy-carbonylpentyl) -2- (3-pyridyl) -3-methyl-indole (2.48 g) is added dropwise in 41 DEG 169104 B1 24 ml of THF over 5 minutes. The mixture is stirred at -78 ° C for 20 minutes, then 1.5 g of phenyl selenyl chloride is added in 12 ml of THF. After 5 minutes, the cooling bath is removed and the mixture is allowed to warm to 5 to 0 ° C. Add 60 ml of saturated aqueous sodium hydrogen carbonate solution and then extract with 3 x 50 ml of ether. The mixed organic extracts are washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over 10 anhydrous magnesium sulfate. When concentrated in vacuo, the crude 1- (5-methoxycarbonyl) -5-phenyl-selenyl-2- (3-pyridyl) -3-methylindole is obtained as a yellow oil. The crude selenide is dissolved in 40 ml of dichloromethane and 1.8 g (16 mmol) of 30% hydrogen peroxide 1.8 ml of water are added dropwise. After the addition of approx. 10% of the hydrogen peroxide enters an exothermic reaction. The temperature rises to 30 ° Q until the addition is complete. The mixture is stirred for an additional 30 minutes, then 40 ml of 5% aqueous sodium carbonate solution is added. The dichloromethane layer is isolated. The aqueous phase is extracted with 25 ml of dichloromethane. The mixed organic phases are washed with 5% aqueous sodium carbonate solution, water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration in vacuo gives 1- (5-methoxycarbonyl-pent-4-enyl) -2- (3-pyridyl) -3-25 methyl-indole as a pale yellow oil. Further purification is performed by short-circuit chromatography (silica gel) with ethyl acetate-hexane (2: 3) as eluent. NMR (COCl 3) δ 5.53-1.0 (d, 1H), 6.65 (m, 1H), IR (liquid) 1720 cm
Eksempel 24 30 Til en opløsning af den α,β-umættede ester, nemlig 1—(5— methoxycarbonylpent-4-enyl)-2-(3-pyridyl)-3-methylindol (84 mg) i 1 ml methanol sættes 1 ml 1 N vandig lithium-hydroxidopløsning. Blandingen omrøres natten over ved stuetemperatur, hvorefter den inddampes i vakuum til tørhed.Example 24 To a solution of the α, β-unsaturated ester, namely 1- (5-methoxycarbonylpent-4-enyl) -2- (3-pyridyl) -3-methylindole (84 mg) in 1 ml of methanol is added 1 ml 1 N aqueous lithium hydroxide solution. The mixture is stirred overnight at room temperature, then evaporated in vacuo to dryness.
35 Remanensen opløses i 2 ml vand, og opløsningen vaskes med 5 ml diethylether. Den vandige fase syrnes til pH-vær-dien 6,6-7,0 og ekstraheres med dichlormethan. Den organiske ekstrakt vaskes med mættet vandig natriumchloridopløsning, 42 DK 169104 B1 tørres over magnesiumsulfat og inddampes i vakuum. Der fås en bleggul olie, som størkner efter triturering med chloroform. Man får 1- (5-carboxypent-4-e.iyl)-2- (3-pyridyl) - 3-methylindol, smp. 145-147°C.The residue is dissolved in 2 ml of water and the solution is washed with 5 ml of diethyl ether. The aqueous phase is acidified to pH 6.6-7.0 and extracted with dichloromethane. The organic extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. A pale yellow oil is obtained which solidifies after trituration with chloroform. 1- (5-carboxypent-4-ethyl) -2- (3-pyridyl) -3-methylindole, m.p. 145-147 ° C.
5 Eksempel 25Example 25
Til en opløsning af Collins-reagens, som er fremstillet under nitrogen ved 0-5°C af 5,6 mg chromtrioxid og 8,86 g (112 mmol) pyridin i 150 ml dichlormethan, sættes på én gang 1,8 g 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-indol 10 i dichlormethan (15 ml). Blandingen omrøres i 25 minutter og filtreres gennem "Celite"®. Filtratet anbringes på en silicagelsøjle og elueres med en l:l-blanding af ethyl-acetat og dichlormethan (500 ml). Ved koncentrering i vakuum fås 1-(5-formylpentyl)-2-(3-pyridyl)-3-méthylindol 15 som en bleggul olie. NMR (CDCl^) θ 9,7 (t,lH), IR (flydende) 2710, 1720 cm"1.To a solution of Collins reagent prepared under nitrogen at 0-5 ° C of 5.6 mg chromium trioxide and 8.86 g (112 mmol) of pyridine in 150 ml of dichloromethane is added at once 1.8 g of 1- (6-hydroxyhexyl) -3-methyl-2- (3-pyridyl) indole in dichloromethane (15 ml). The mixture is stirred for 25 minutes and filtered through "Celite" ®. The filtrate is placed on a silica gel column and eluted with a 1: 1 mixture of ethyl acetate and dichloromethane (500 ml). When concentrated in vacuo, 1- (5-formylpentyl) -2- (3-pyridyl) -3-methylindole is obtained as a pale yellow oil. NMR (CDCl3) θ 9.7 (t, 1H), IR (liquid) 2710, 1720 cm -1.
Eksempel 26 328 mg trimethylphosphonoacetat sættes dråbevis under nitrogen til en opløsning af 220 mg kalium-tert-butoxid i 20 5 ml THF ved 0°C. Opløsningen omrøres i 20 minutter ved 0°C, hvorefter den afkøles til -78°C, og der tilsættes dråbevis en opløsning af 1-(5-formyl-pentyl)-2-(3-pyridyl)- 3-methylindol (450 mg) i THF (5 ml). Blandingen holdes i 15 minutter ved -78°C, og afkølingen indstilles. Blandin-25 gen omrøres natten over ved stuetemperatur, fortyndes med 25 ml vand og ekstraheres med 3 x 25 ml diethylether. De sammenblandede ekstrakter vaskes med mættet vandig natrium-hydrogencarbonatopløsning og med mættet vandig natrium-chloridopløsning og tørres over magnesiumsulfat. Efter 30 inddampning i vakuum får man 1-(7-methoxycarbonylhept- 6-enyl)-2-(3-pyridyl)-3-methylindol som en bleggul olie.Example 26 328 mg of trimethylphosphonoacetate is added dropwise under nitrogen to a solution of 220 mg of potassium tert-butoxide in 20 ml of THF at 0 ° C. The solution is stirred for 20 minutes at 0 ° C, then cooled to -78 ° C and a solution of 1- (5-formyl-pentyl) -2- (3-pyridyl) -3-methylindole (450 mg) is added dropwise ) in THF (5 ml). The mixture is kept at -78 ° C for 15 minutes and the cooling is adjusted. The mixture is stirred overnight at room temperature, diluted with 25 ml of water and extracted with 3 x 25 ml of diethyl ether. The mixed extracts are washed with saturated aqueous sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation in vacuo, 1- (7-methoxycarbonylhept-6-enyl) -2- (3-pyridyl) -3-methylindole is obtained as a pale yellow oil.
IR (flydende) 1735 cm-1.IR (liquid) 1735 cm -1.
Eksempel 27Example 27
Vedhydrolyse af 50 mg 1-(7-methoxycarbonylhept-6-enyl)-2-35 (3-pyridyl)-3-methylindol under anvendelse af fremgangamåden ifølge eksempel 24 fås 1-(7-carboxyhept-6-enyl)-2-(3-pyridyl)- 43 DK 169104 B1 3-methylindol. Smp. 144-146°C (omkrystalliseret fra dichlor-methan-hexan).By hydrolysis of 50 mg of 1- (7-methoxycarbonylhept-6-enyl) -2-35 (3-pyridyl) -3-methylindole using the procedure of Example 24, 1- (7-carboxyhept-6-enyl) -2- (3-pyridyl) - 43-methylindole. Mp. 144-146 ° C (recrystallized from dichloromethane-hexane).
Eksempel 28 1-(7-Carboxyhept-6-enyl)-2-(3-pyridyl)-3-methylindol (10 mg) 5 hydrogeneres i 1 ml absolut ethanol med en katalytisk mængde 10%'s palladium-på-kul ved et tryk på 1 atmosfære. Efter 3,5 timer frafiltreres katalysatoren, og der vaskes med nogle ml ethanol. De sammenblandede organiske ekstrakter inddampes i vakuum. Der fås en farveløs olie, som der-10 efter bringes til krystallisation. Man får 1-(7-carboxyhept-yl)-3-methyl-2- (3-pyridyl)-indol, som er identisk med den ifølge eksempel 1 fremstillede forbindelse. Det rå produkt smelter ved 110-113°C.Example 28 1- (7-Carboxyhept-6-enyl) -2- (3-pyridyl) -3-methylindole (10 mg) is hydrogenated in 1 ml of absolute ethanol with a catalytic amount of 10% palladium on carbon at a pressure of 1 atmosphere. After 3.5 hours, the catalyst is filtered off and washed with some ml of ethanol. The combined organic extracts are evaporated in vacuo. A colorless oil is obtained which is then brought to crystallization. There is obtained 1- (7-carboxyhept-yl) -3-methyl-2- (3-pyridyl) indole, which is identical to the compound of Example 1. The crude product melts at 110-113 ° C.
Eksempel 29 15 1-(4-Cyanbutyl)-3-methy1-2-(3-pyridyl)-indol (578 mg) op varmes ved 185°C i 30 minutter med 450 mg pulveriseret natriumhydroxid og 5 ml ethylenglycol. Blandingen hældes i 50 ml vand, vaskes med ether, og blandingen indstilles på pH-værdien 6 med 2 N saltsyre. Den dannede olie ud-20 krystalliserer. Man får 1-(4-carboxybutyl)-3-methyl-2- (3-pyridyl)-indol, som er identisk med den ifølge eksempel 5 fremstillede forbindelse. Smp. 127-129°C.Example 29 1- (4-Cyanbutyl) -3-methyl-2- (3-pyridyl) indole (578 mg) is heated at 185 ° C for 30 minutes with 450 mg of powdered sodium hydroxide and 5 ml of ethylene glycol. The mixture is poured into 50 ml of water, washed with ether and adjusted to pH 6 with 2N hydrochloric acid. The resulting oil crystallizes out. There is obtained 1- (4-carboxybutyl) -3-methyl-2- (3-pyridyl) indole, which is identical to the compound of Example 5. Mp. 127-129 ° C.
Udgangsforbindelsen fremstilles på følgende måde: En opløsning af 3-methyl-2-(3-pyridyl)-indol (2,09 g) i 12 ml DMF 25 sættes til en suspension af 50%'s natriumhydrid-mineralolie i 6 ml DMF ved 0°C. Blandingen omrøres i 30 minutter ved 0°C, hvorpå den behandles med en opløsning af 1,78 g 5-bromvaleronitril i 4 ml DMF. Blandingen omrøres ved stuetemperatur natten over, hældes i 125 ml vand og ekstraheres 30 med 2 x 50 ml ether. Ekstrakten vaskes med 3 x 20 ml vand og tørres over magnesiumsulfat. Man får 1-(4-cyanbutyl)-3-methyl-2-(3-pyridyl)-indol i form af en olie.The starting compound is prepared as follows: A solution of 3-methyl-2- (3-pyridyl) indole (2.09 g) in 12 ml of DMF is added to a suspension of 50% sodium hydride mineral oil in 6 ml of DMF at 0 ° C. The mixture is stirred for 30 minutes at 0 ° C, then treated with a solution of 5-bromovaleronitrile 1.78 g in 4 ml of DMF. The mixture is stirred at room temperature overnight, poured into 125 ml of water and extracted with 2 x 50 ml of ether. The extract is washed with 3 x 20 ml of water and dried over magnesium sulfate. 1- (4-cyanbutyl) -3-methyl-2- (3-pyridyl) indole is obtained in the form of an oil.
Eksempel 30Example 30
En blanding af 578 mg 1-(4-cyanbutyl)-3-methyl-2-(3-pyr-35 idyl)-indol, 173 mg natriumazid, 142 mg ammoniumchlorid 44 DK 169104 B1 og 5 mg lithiumchlorid i 2 ml DMF opvarmes natten over ved 120°C. Efter afkøling filtreres blandingen, og filtratet fortyndes med ca. 25 ml vand. Opløsningen indstilles med 3 N natriumhydroxidopløsning på pH-værdien 10-11, og opløs-5 ningen vaskes med ether til fjernelse af uomsat nitril.A mixture of 578 mg of 1- (4-cyanbutyl) -3-methyl-2- (3-pyridyl) indole, 173 mg of sodium azide, 142 mg of ammonium chloride and 5 mg of lithium chloride in 2 ml of DMF is heated. overnight at 120 ° C. After cooling, the mixture is filtered and the filtrate is diluted with ca. 25 ml of water. The solution is adjusted with 3 N sodium hydroxide solution to pH 10-11 and the solution is washed with ether to remove unreacted nitrile.
Den vandige fase indstilles med 2 N saltsyre på pH-værdien 5-6 og ekstraheres med ether. Etherekstrakten vaskes med vand, tørres over magnesiumsulfat og inddampes i vakuum.The aqueous phase is adjusted to pH 5-6 with 2N hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated in vacuo.
Den faste remanens opslæmmes i petroleumsether og isole-10 res. Man får 1-[4-(5-tetrazolyl)-butyl]-3-methyl-2-(3-pyridyl)-indol, smp. 177-179°C.The solid residue is suspended in petroleum ether and isolated. 1- [4- (5-tetrazolyl) butyl] -3-methyl-2- (3-pyridyl) indole is obtained, m.p. 177-179 ° C.
Eksempel 31Example 31
En opløsning af 3-methyl-2- (3-pyridyl)-indol (2,08 g) i 12 ml DMF sættes under nitrogen ved 10-15°C til en suspen-15 sion af 0,528 g 50%'s natriumhydrid-mineralolie i 6 ml DMF. Efter endt tilsætning omrøres blandingen ved stuetemperatur i 30 minutter, hvorpå der dråbevis tilsættes 2,39 g 3-(p-chlormethyl-phenyl)-2-methyl-acrylsyre-ethylester i 5 ml DMF. Den dannede blanding omrøres natten over ved stuetemperatur 20 og hældes i 100 ml vand. Den fremkomne blanding ekstraheres med 2 x 50 ml ethylacetat. De organiske lag vaskes med 100 ml mættet vandig natriumchloridopløsning, tørres over magnesiumsulfat og inddampes. Man får 1-[p-(2-ethoxycarbonylpropen-1-yl)-benzyl]-3-methyl-2-(3-pyridyl)-indol.A solution of 3-methyl-2- (3-pyridyl) -indole (2.08 g) in 12 ml of DMF is added under nitrogen at 10-15 ° C to a suspension of 0.528 g of 50% sodium hydride solution. mineral oil in 6 ml DMF. After the addition is complete, the mixture is stirred at room temperature for 30 minutes, then 2.39 g of 3- (p-chloromethyl-phenyl) -2-methyl-acrylic acid ethyl ester in 5 ml of DMF is added dropwise. The resulting mixture is stirred overnight at room temperature 20 and poured into 100 ml of water. The resulting mixture is extracted with 2 x 50 ml of ethyl acetate. The organic layers are washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. 1- [p- (2-ethoxycarbonylpropen-1-yl) -benzyl] -3-methyl-2- (3-pyridyl) -indole is obtained.
25 Ved hydrolyse med 2 N saltsyre fås 1-[p-(2-carboxypropen-l-yl)-benzyl]-3-methyl-2-(3-pyridyl)-indol.Hydrolysis with 2N hydrochloric acid gives 1- [p- (2-carboxypropen-1-yl) -benzyl] -3-methyl-2- (3-pyridyl) -indole.
Udgangsforbindelsen fremstilles på følgende måde: En suspension af 10,0 g 50%'s natriumhydrid i mineralolie i en 350 ml friskdestilleret dimethoxyethan (DME) omrøres under 30 nitrogen ved 10°C, hvorpå der i løbet af ca. 40 minutter tilsættes triethyl-2-phosphonopropionat. Blandingen omrøres i 30 minutter ved 10°C. Under omrøring i yderligere 1,5 timer stiger opløsningens temperatur til stuetemperatur.The starting compound is prepared as follows: A suspension of 10.0 g of 50% sodium hydride in mineral oil in a 350 ml of freshly distilled dimethoxyethane (DME) is stirred under 30 nitrogen at 10 ° C and then stirred for approx. For 40 minutes, triethyl 2-phosphonopropionate is added. The mixture is stirred for 30 minutes at 10 ° C. With stirring for an additional 1.5 hours, the temperature of the solution rises to room temperature.
Denne opløsning overføres under nitrogen med en kanyle 35 til en 500 ml tildrypningstragt, hvorefter den dråbevis sættes til en opløsning af 33,53 g terephthalaldehyd i 45 DK 169104 B1 475 ml tør DME i løbet af 1 time ved 22-34°C. Efter endt tilsætning omrøres reaktionsblandingen mekanisk ved stuetemperatur i 2 timer, hældes i 100 ml vand og ekstraheres med 4 x 500 ml ether. Etherekstrakten vaskes med 700 ml 5 mættet vandig natriumchloridopløsning, tørres over magnesiumsulfat, filtreres og koncentreres i vakuum. Der fås en gul olie, som delvis krystalliserer ved henstand. Den rå blanding renses ved suspendering i en blanding af petroleumsether og ethylacetat (93:7). Efter fjernelse 10 af uomsat dialdehyd koncentreres filtratet i vakuum.This solution is transferred under nitrogen with a cannula 35 to a 500 ml dropping funnel and then dropwise added to a solution of 33.53 g of terephthalaldehyde in dry DME over 1 hour at 22-34 ° C. After completion of the addition, the reaction mixture is mechanically stirred at room temperature for 2 hours, poured into 100 ml of water and extracted with 4 x 500 ml of ether. The ether extract is washed with 700 ml of 5 saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. A yellow oil is obtained, which partially crystallizes on standing. The crude mixture is purified by suspending in a mixture of petroleum ether and ethyl acetate (93: 7). After removal of unreacted dialdehyde 10, the filtrate is concentrated in vacuo.
Der fås en blanding, som renses yderligere ved højtryksvæskekromatografi under anvendelse af en blanding af petroleumsether og ethylacetat (93:7). Man får den rene 4-formyl-a-methylkanelsyre-ethylester. En opløsning 15 af 34,80 g af dette aldehyd i 820 ml absolut ethanol behandles med 12,11 g granuleret natriumborhydrid ved stuetemperatur under nitrogen. Den dannede blanding omrøres i 3 timer ved stuetemperatur (eller indtil borhydridet er opløst), koncentreres til et rumfang på ca. 200 ml, for-20 tyndes med 400 ml vand og ekstraheres med 3 x 200 ml ether. Etherekstrakten vaskes med 100 ml vand og med mættet vandig natriumchloridopløsning, tørres over magnesiumsulfat, filtreres, hvorefter filtratet koncentreres i vakuum. Man 'får 3- (p-hydroxymethylphenyl)-2-methyl-acrylsyre-ethyl-25 ester. Til en opløsning af dette produkt i 350 ml methyl-enchlorid sættes dråbevis ved stuetemperatur 11,53 ml thio-nylchlorid i løbet af 25 minutter. Den klare farveløse opløsning omrøres i 2 timer. Opløsningen vaskes med 100 ml vand, 200 ml mættet vandig natriumhydrogencarbonatopløsning, 30 100 ml vand og 100 ml mættet vandig natriumchloridopløs ning. Det organiske lag tørres og inddampes. Man får 3-(p-chlormethyl-phenyl)-2-methyl-acrylsyre-ethylester, som anvendes uder yderligere rensning.A mixture is obtained which is further purified by high-pressure liquid chromatography using a mixture of petroleum ether and ethyl acetate (93: 7). The pure 4-formyl-α-methylcinnamic acid ethyl ester is obtained. A solution 15 of 34.80 g of this aldehyde in 820 ml of absolute ethanol is treated with 12.11 g of granulated sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred for 3 hours at room temperature (or until the borohydride is dissolved), concentrated to a volume of approx. 200 ml, dilute with 400 ml of water and extract with 3 x 200 ml of ether. The ether extract is washed with 100 ml of water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. There is obtained 3- (p-hydroxymethylphenyl) -2-methyl-acrylic acid ethyl ester. To a solution of this product in 350 ml of methylene chloride is added dropwise at room temperature 11.53 ml of thionyl chloride over 25 minutes. The clear colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated aqueous sodium bicarbonate solution, 30 ml of water and 100 ml of saturated aqueous sodium chloride solution. The organic layer is dried and evaporated. There is obtained 3- (p-chloromethyl-phenyl) -2-methyl-acrylic acid ethyl ester which is used without further purification.
Eksempel 32 35 1-(5-Formylpentyl)-3-methyl-2-(3-pyridyl)-indol (127 mg) opløses i 0,66 ml DMF, og der tilsættes 298 mg pyridinium-dichromat i én portion. Blandingen omrøres natten over ved stuetemperatur, fortyndes med 25 ml af en blanding af 46 DK 169104 B1 ether og ethylacetat (4:1) og filtreres. Det faste materiale vaskes med varm chloroform, og de sammenblandede filtrater koncentreres i vakuum. Der fås et mørkebrunt gummiagtigt materiale, som opslæmmes med en blanding af 5 ether og ethylacetat (4:1) og ekstraheres med 2 ml 0,1 N vandig natriumhydroxidopløsning. Den vandige ekstrakt indstilles på pH-værdien 5,5-6,0 og ekstraheres med chloroform. Chloroformekstrakten tørres og koncentreres i vakuum. Der fås en gul olie. Ved tyndtlagskromatografi (silicagel, 10 ethylacetat-hexan (1:1)) viser tilstedeværelsen af den ønskede syre. Ved yderligere kromatografi på silicagel under anvendelse af en blanding af ethylacetat og hexan (1:1) som eluent fås den ønskede l-'(5-carboxypentyl)-3-methyl-2-(3-pyridyl)-indol, som er identisk med den ifølge 15 eksempel 3 fremstillede forbindelse.Example 32 1- (5-Formylpentyl) -3-methyl-2- (3-pyridyl) indole (127 mg) is dissolved in 0.66 ml of DMF and 298 mg of pyridinium dichromate is added in one portion. The mixture is stirred overnight at room temperature, diluted with 25 ml of a mixture of ether and ethyl acetate (4: 1) and filtered. The solid is washed with hot chloroform and the combined filtrates are concentrated in vacuo. A dark brown rubbery material is obtained which is slurried with a mixture of 5 ether and ethyl acetate (4: 1) and extracted with 2 ml of 0.1 N aqueous sodium hydroxide solution. The aqueous extract is adjusted to pH 5.5-6.0 and extracted with chloroform. The chloroform extract is dried and concentrated in vacuo. A yellow oil is obtained. By thin layer chromatography (silica gel, 10 ethyl acetate-hexane (1: 1)), the presence of the desired acid shows. Further chromatography on silica gel using a mixture of ethyl acetate and hexane (1: 1) as eluent gives the desired 1- (5-carboxypentyl) -3-methyl-2- (3-pyridyl) indole, which is identical with the compound of Example 3 prepared.
Eksempel 33Example 33
Til en opløsning af 692 mg natriumhydroxid i 4 ml vand sættes 0,344 ml brom under afkøling med et isbad. Den dannede opløsning sættes til 400 mg 1-(5-oxohexyl)-3-meth-20 yl-2-(3-pyridyl)-indol, og blandingen omrøres i 2 timer ved stuetemperatur. Blandingen vaskes med ether. Den vandige opløsning filtreres og indstilles på pH-værdien 5,6 med 2 N saltsyre. Man isolerer det faste hvide råprodukt, som smelter i området 108-120°C. Ved adskillelse 25 under anvendelse af tyndtlagskromatografi (silicagel, methylenchlorid-methanol (9:1)) fås 1-(4-carboxybutyl)-3-methyl-2-(3-pyridyl)-indol, som er identisk med den ifølge eksempel 5 fremstillede forbindelse.To a solution of 692 mg of sodium hydroxide in 4 ml of water is added 0.344 ml of bromine under cooling with an ice bath. The resulting solution is added to 400 mg of 1- (5-oxohexyl) -3-methyl-2- (3-pyridyl) indole and the mixture is stirred for 2 hours at room temperature. The mixture is washed with ether. The aqueous solution is filtered and adjusted to pH 5.6 with 2N hydrochloric acid. The solid white crude product which melts in the range 108-120 ° C is isolated. Separation 25 using thin layer chromatography (silica gel, methylene chloride-methanol (9: 1)) gives 1- (4-carboxybutyl) -3-methyl-2- (3-pyridyl) indole identical to that of Example 5 compound.
Udgangsforbindelsen fremstilles på følgende måde: l-(4-30 Cyanbutyl)-3-methyl-2-(3-pyridyl)-indol (1,5 g) i 15 ml ether sættes til en opløsning af 0,0103 mol methylmagne-siumbromid i 15 ml e.ther. Blandingen koges i 3 timer under tilbagesvaling. Efter afkøling tilsættes dråbevis 10 ml 6 N saltsyre, og blandingen opvarmes i flere timer under 35 tilbagesvaling. Reaktionsblandingen vaskes med ether og indstilles med 3 N natriumhydroxidopløsning på pH-værdien 10-11. Efter ekstraktion med ether og fordampning af opløs- 47 DK 169104 B1 ningsmidlet får man 1-(5-oxohexyl)~3-methyl-2-(3-pyridyl)-indol. IR 1720 cm"1, NMR (CDC13) δ 2,0.The starting compound is prepared as follows: 1- (4-30 Cyanbutyl) -3-methyl-2- (3-pyridyl) indole (1.5 g) in 15 ml of ether is added to a solution of 0.0103 mol of methyl magnesium bromide. in 15 ml e.ther. The mixture is refluxed for 3 hours. After cooling, 10 ml of 6N hydrochloric acid is added dropwise and the mixture is heated under reflux for several hours. The reaction mixture is washed with ether and adjusted with 3 N sodium hydroxide solution to pH 10-11. After extraction with ether and evaporation of the solvent, 1- (5-oxohexyl) ~ 3-methyl-2- (3-pyridyl) indole is obtained. IR 1720 cm "1, NMR (CDCl13) δ 2.0.
Eksempel 34 1- (7-Carboxyheptyl)-5-chlor-3-methyl-2-(3-pyridyl)-indol-5 hydrochlorid (421 mg) opløst i 7 ml tetrahydrofuran opvarmes og behandles med 202 mg (0,278 ml) triethylamin. Denne opløsning sættes dråbevis til en opløsning af 108 mg (0,096 ml) chlormyresyreethylester i 1 ml tetrahydrofuran, og der afkøles til 0-5°C. Reaktionsblandingen omrøres i 1 ti-10 me ved denne temperatur og filtreres til fjernelse af triethylamin-hydrochloridet. Filtratet behandles med en opløsning af 69 mg hydroxylamin-hydrochlorid og 40 mg natriumhydroxid i 10 ml methanol. Denne blanding omrøres i 0,5 timer, hvorefter den koncentreres i vakuum. Remanen-15 sen behandles med 25 ml ether-methanol (10:1) og filtreres. Filtratet inddampes i vakuum. Der fås en tyktflydende olie, som opløses i acetone og behandles med 6,5 N ethanolisk saltsyre. Man får 1-(7-hydroxycarbamoyl-heptyl)-3-methyl- 2- (3-pyridyl)-indol-hydrochlorid, smp. 170-173°C.Example 34 1- (7-Carboxyheptyl) -5-chloro-3-methyl-2- (3-pyridyl) -indole-hydrochloride (421 mg) dissolved in 7 ml of tetrahydrofuran is heated and treated with 202 mg (0.278 ml) of triethylamine. . This solution is added dropwise to a solution of 108 mg (0.096 ml) of chloroformic acid ethyl ester in 1 ml of tetrahydrofuran and cooled to 0-5 ° C. The reaction mixture is stirred for 1 hour at this temperature and filtered to remove the triethylamine hydrochloride. The filtrate is treated with a solution of 69 mg of hydroxylamine hydrochloride and 40 mg of sodium hydroxide in 10 ml of methanol. This mixture is stirred for 0.5 hours and then concentrated in vacuo. The residue is treated with 25 ml of ether-methanol (10: 1) and filtered. The filtrate is evaporated in vacuo. A viscous oil is obtained which is dissolved in acetone and treated with 6.5 N ethanolic hydrochloric acid. 1- (7-hydroxycarbamoyl-heptyl) -3-methyl-2- (3-pyridyl) -indole hydrochloride is obtained, m.p. 170-173 ° C.
20 Eksempel 35 0,14 ml 7,1 N ethanolisk saltsyre sættes til 236 mg N-phen-yl-N-(5-methoxycarbonylpentyl)-hydrazin i 2 ml absolut v ethanol, hvorpå der tilsættes 135 mg 3-propionylpyridin. Blandingen koges natten over med tilbagesvaling. Derefter 25 tilsættes yderligere 0,62 ml ethanolisk saltsyre, og der opvarmes i yderligere 24 timer med tilbagesvaling. Efter afkøling filtreres blandingen, og filtratet inddampes i vakuum. Remanensen udrøres i 10 ml vand og indstilles med 1 N natriumhydroxidopløsning på pH-værdien 10-11. Denne 30 blanding ekstraheres med ether. Ekstrakten vaskes med vand, tørres over magnesiumsulfat og inddampes. Der fås en olie, som er 1-(5-ethoxycarbonylpentyl)-3-methyl-2-(3-pyridyl)-indol.Example 35 0.14 ml of 7.1 N ethanolic hydrochloric acid is added to 236 mg of N-phenyl-N- (5-methoxycarbonylpentyl) hydrazine in 2 ml of absolute v ethanol, to which 135 mg of 3-propionylpyridine is added. The mixture is refluxed overnight. Then, an additional 0.62 ml of ethanolic hydrochloric acid is added and heated for a further 24 hours at reflux. After cooling, the mixture is filtered and the filtrate is evaporated in vacuo. The residue is stirred in 10 ml of water and adjusted with 1 N sodium hydroxide solution to pH 10-11. This mixture is extracted with ether. The extract is washed with water, dried over magnesium sulfate and evaporated. An oil is obtained which is 1- (5-ethoxycarbonylpentyl) -3-methyl-2- (3-pyridyl) indole.
Denne ester hydrolyseres med 10 ml 2 N saltsyre under til-35 bagesvaling, hvorefter blandingen indstilles på pH-værdien ca. 6 med mættet vandig natriumhydrogencarbonatopløsning og 48 DK 169104 B1 ekstraheres med ether. Ved oparbejdning af den organiske ekstrakt fås 1-(5-carboxypentyl)-3-methyl-2-(3-pyridyl)-indol, som er identisk med den ifølge eksempel 3 fremstillede forbindelse. Smeltepunktet for råproduktet er 5 111-113°C.This ester is hydrolyzed with 10 ml of 2N hydrochloric acid under reflux and the mixture is adjusted to pH approx. 6 with saturated aqueous sodium hydrogen carbonate solution and extracted with ether. By working up the organic extract, 1- (5-carboxypentyl) -3-methyl-2- (3-pyridyl) -indole, which is identical to the compound of Example 3, is obtained. The melting point of the crude product is 511-113 ° C.
Udgangsforbindelsen fremstilles på følgende måde: 2,79 g (2,73 ml) anilin, 6,27 g β-bromhexansyre-methylester og 12,24 g (0,09 mol) natriumacetat-trihydrat opvarmes i 15 ml absolut ethanol natten over ved 80-100°C. Efter 10 afkøling hældes blandingen i 75 ml isvand og ekstraheres med ether. Den organiske ekstrakt vaskes med vand, tørres over magnesiumsulfat og inddampes i vakuum. Man får N-(5-methoxycarbonylpentyl)-anilin.The starting compound is prepared as follows: 2.79 g (2.73 ml) of aniline, 6.27 g of β-bromohexanoic acid methyl ester and 12.24 g (0.09 mol) of sodium acetate trihydrate are heated in 15 ml of absolute ethanol overnight at 80-100 ° C. After 10 cooling, the mixture is poured into 75 ml of ice water and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate and evaporated in vacuo. N- (5-methoxycarbonylpentyl) -aniline is obtained.
En opløsning af 1,4 g natriumnitrit i 5 ml vand sættes 15 dråbevis ved 0-10°C til en blanding af 4,42 g N-(5-methoxy-carbonylpentyl)-anilin, 2,9 ml koncentreret saltsyre og is, som er nødvendig til afkøling til den nævnte temperatur. Blandingen omrøres derefter i 1 time ved stuetemperatur og ekstraheres med ether. Ekstrakten vaskes med vand, tørres 20 over magnesiumsulfat og inddampes i vakuum. Man får N-nitroso-N-(5-methoxycarbonylpentyl)-anilin i form af en olie.A solution of 1.4 g of sodium nitrite in 5 ml of water is added dropwise at 0-10 ° C to a mixture of 4.42 g of N- (5-methoxy-carbonylpentyl) -aniline, 2.9 ml of concentrated hydrochloric acid and ice. which is necessary for cooling to said temperature. The mixture is then stirred for 1 hour at room temperature and extracted with ether. The extract is washed with water, dried over magnesium sulfate and evaporated in vacuo. N-nitroso-N- (5-methoxycarbonylpentyl) -aniline is obtained in the form of an oil.
3,6 g af det ovenfor fremstillede nitrosoderivat i 4 ml iseddike sættes dråbevis til 3,94 g zinkpulver i 6 ml vand.3.6 g of the above-prepared nitroso derivative in 4 ml of glacial acetic acid is added dropwise to 3.94 g of zinc powder in 6 ml of water.
25 Efter den eksoterme reaktion op til en temperatur på 35°CAfter the exothermic reaction up to a temperature of 35 ° C
omrøres blandingen i 2 timer ved stuetemperatur. Zinket fra-filtreres, filtratet vaskes med ether, indstilles på pH-værdien 10-11 med 40%'s natriumhydroxidopløsning og ekstraheres med ether. Ekstrakten tørres over magnesiumsulfat 30 og inddampes i vakuum. Der fås en rå olie. Efter kortvejskromatografi på silicagel med hexan-eddikesyre (5:1) får man N-phenyl-N-(5-methoxycarbonylpentyl)-hydrazin med en renhed på ca. 80%. Dette produkt anvendes direkte ved den ovenfor beskrevne Fischer-cyclisering.the mixture is stirred for 2 hours at room temperature. The zinc is filtered off, the filtrate is washed with ether, adjusted to pH 10-11 with 40% sodium hydroxide solution and extracted with ether. The extract is dried over magnesium sulfate 30 and evaporated in vacuo. A crude oil is obtained. After short-circuit chromatography on silica gel with hexane-acetic acid (5: 1), N-phenyl-N- (5-methoxycarbonylpentyl) -hydrazine is obtained having a purity of approx. 80%. This product is used directly in the Fischer cyclization described above.
49 DK 169104 B149 DK 169104 B1
Eksempel 36Example 36
Man opløser 1-[7,7-(bis-methoxycarbonyl)-heptyl]-3-methyl-2-(3-pyridyl)-indol (273 mg) i methanol (0,5 ml), hvorpå der tilsættes 1,95 ml 1 N vandig lithiumhydroxidopløsning.1- [7,7- (bis-methoxycarbonyl) -heptyl] -3-methyl-2- (3-pyridyl) -indole (273 mg) is dissolved in methanol (0.5 ml), and 1.95 is added. ml 1 N aqueous lithium hydroxide solution.
5 Blandingen omrøres i 1 time ved stuetemperatur, hvorefter den koges i 2,5 timer under tilbagesvaling. Den klare opløsning inddampes til tørhed, remanensen opløses i vand, og opløsningen indstilles på pH-værdien 6-6,2. Der dannes et gult, gummiagtigt fast materiale, som ekstraheres 10 i chloroform. Ekstrakten tørres over magnesiumsulfat og inddampes. Man får rå 1-[7,7-(bis-carboxy)-heptyl]-3-methyl-2-(3-pyridyl)-indol. NMR (CDCl^) δ 10,60 (2H).The mixture is stirred for 1 hour at room temperature, then it is refluxed for 2.5 hours. The clear solution is evaporated to dryness, the residue is dissolved in water and the solution is adjusted to pH 6-6.2. A yellow, gummy solid is formed which is extracted in chloroform. The extract is dried over magnesium sulfate and evaporated. Crude 1- [7,7- (bis-carboxy) -heptyl] -3-methyl-2- (3-pyridyl) indole is obtained. NMR (CDCl3) δ 10.60 (2H).
En prøve af den rå dicarboxylsyre (28 mg) opvarmes i 30 minutter i p-xylen (3 ml), som indeholder 0,1 ml 0,1 N 15 saltsyre. Den klare opløsning henstår til afkøling til stuetemperatur. Der udfældes et gummiagtigt materiale, som ekstraheres med natriumhydroxid. Den vandige fase isoleres, indstilles på pH-værdien 6-6,2 og ekstraheres med en blanding af ethylacetat og ether (8:2). den organiske 20 fase tørres over magnesiumsulfat og inddampes. Der fås en farveløs olie, som størkner efter henstand. Man får l-(7-carboxyheptyl)-3-methy1-2-(3-pyridyl)-indol, som ifølge NMR- og TLC-værdier er identisk med forbindelsen fremstillet ifølge eksempel 1.A sample of the crude dicarboxylic acid (28 mg) is heated for 30 minutes in p-xylene (3 ml) containing 0.1 ml of 0.1 N hydrochloric acid. The clear solution is allowed to cool to room temperature. A rubbery material is precipitated which is extracted with sodium hydroxide. The aqueous phase is isolated, adjusted to pH 6-6.2 and extracted with a mixture of ethyl acetate and ether (8: 2). the organic phase is dried over magnesium sulfate and evaporated. A colorless oil is obtained which solidifies upon standing. There is obtained 1- (7-carboxyheptyl) -3-methyl-2- (3-pyridyl) indole, which according to NMR and TLC values is identical to the compound prepared according to Example 1.
25 Udgangsforbindelsen fremstilles på følgende måde: Ved 0°CThe starting compound is prepared as follows: At 0 ° C
sættes 0,36 ml thionylchlorid til 1,37 g 1-(6-hydroxyhexyl)- 3-methyl-2-(3-pyridyl)-indol, og blandingen omrøres i 1 time ved stuetemperatur. Derefter sættes mættet vandig natrium-hydrogencarbonatopløsning til blandingen, som ekstraheres 30 med dichlormethan. Ekstrakten vaskes med mættet vandig natriumchloridopløsning og tørres over magnesiumsulfat.0.36 ml of thionyl chloride is added to 1.37 g of 1- (6-hydroxyhexyl) -3-methyl-2- (3-pyridyl) indole and the mixture is stirred for 1 hour at room temperature. Then saturated aqueous sodium hydrogen carbonate solution is added to the mixture, which is extracted with dichloromethane. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate.
Efter inddampning i vakuum fås det rå chlorid i form af en olie. Ved rensning ved kromatografi på silicagel (methylen-chlorid/ethylacetat (19:1)) fås 1-(6-chlorhexyl)-3-methyl-35 2-(3-pyridyl)-indol i form af en lysegul olie. NMR (CDCl^) δ 3,30 (t,2H), 3,92 (t,2H).After evaporation in vacuo, crude chloride is obtained in the form of an oil. Purification by chromatography on silica gel (methylene chloride / ethyl acetate (19: 1)) gives 1- (6-chlorohexyl) -3-methyl-2- (3-pyridyl) indole in the form of a pale yellow oil. NMR (CDCl3) δ 3.30 (t, 2H), 3.92 (t, 2H).
50 DK 169104 B1 1-(6-Chlorhexyl)-3-methyl-2-(3-pyridyl)-indol (0,5 g) sættes til en blanding af 792 mg dimethylmalonat, 790 mg kaliumcarbonat og 11,6 ml dimethylformamid, og blandingen opvarmes under nitrogen i 18 timer ved 80-90°C. Blandingen 5 hældes i 80 ml isvand, og der syrnes med 1 N saltsyre og vaskes med ether. Det vandige lag indstilles på pH-værdien 6 og ekstraheres med ether. Ekstrakten tørres over magnesiumsulfat og inddampes til en gul olie. Ved rensning ved præparativt tyndtlagskromatigrafi (chloroform-ethylacetat 10 (9:1)) får man 1-[7,7-(bis-methoxycarbonyl)-heptyl]-3- methyl-2-(3-pyridyl)-indol. NMR (CDCl^)* 63,32 (t,lH), 3,78 (s,6H), 4,03 (t, 2H) . IR (flydende) 1750 cm ·*·.1- (6-Chlorhexyl) -3-methyl-2- (3-pyridyl) indole (0.5 g) is added to a mixture of 792 mg of dimethyl malonate, 790 mg of potassium carbonate and 11.6 ml of dimethylformamide. and the mixture is heated under nitrogen for 18 hours at 80-90 ° C. The mixture 5 is poured into 80 ml of ice water and acidified with 1N hydrochloric acid and washed with ether. The aqueous layer is adjusted to pH 6 and extracted with ether. The extract is dried over magnesium sulfate and evaporated to a yellow oil. Purification by preparative thin layer chromatography (chloroform-ethyl acetate 10 (9: 1)) gives 1- [7,7- (bis-methoxycarbonyl) -heptyl] -3-methyl-2- (3-pyridyl) indole. NMR (CDCl3) δ 63.32 (t, 1H), 3.78 (s, 6H), 4.03 (t, 2H). IR (liquid) 1750 cm · * ·.
Eksempel 37 1-(6-Chlorhexyl)-3-methy1-2-(3-pyridyl)-indol (165 mg) i 15 2 ml tør THF sættes dråbevis til 12 mg magnesiumspåner i 2 ml tør THF under nitrogen. Til initiering af reaktionen tilsættes en iodkrystal under tilsætningen. Efter endt tilsætning koges blandingen i 4 timer under tilbagesvaling, hvorefter den afkøles til 0°C. Under omrøring i 20 15 minutter ledes tør carbondioxidgas til reaktionsbehol deren. Den uklare blanding hældes i 5 ml 1 N natriumhydro-xidopløsning og ekstraheres med ether. Den vandige fase indstilles på pH-værdien 6-6,2, og der ekstraheres med ethylacetat. Den organiske fase tørres over magnesiumsul-25 fat og inddampes til tørhed i vakuum. Råproduktet smelter ved 106-107°C. Produktet er 1-(6-carboxyhexyl)-3-methyl- 2-(3-pyridyl)-indol, hvis TLC- og NMR-værdier er identiske med værdierne for forbindelsen fremstillet ifølge eksempel 4.Example 37 1- (6-Chlorohexyl) -3-methyl-2- (3-pyridyl) indole (165 mg) in 2 ml of dry THF is added dropwise to 12 mg of magnesium shavings in 2 ml of dry THF under nitrogen. To initiate the reaction, an iodine crystal is added during the addition. After the addition is complete, the mixture is refluxed for 4 hours, then cooled to 0 ° C. With stirring for 20 minutes, dry carbon dioxide gas is fed to the reaction vessel. The cloudy mixture is poured into 5 ml of 1 N sodium hydroxide solution and extracted with ether. The aqueous phase is adjusted to pH 6-6.2 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The crude product melts at 106-107 ° C. The product is 1- (6-carboxyhexyl) -3-methyl-2- (3-pyridyl) indole, whose TLC and NMR values are identical to those of the compound prepared according to Example 4.
30 Eksempel 38 1-(Prop-2-ynyl)-3-methyl-2-(3-pyridyl)-indol (90 mg) opløses under nitrogen i 2 ml THF, og den dannede opløsning afkøles til -78°C. Der tilsættes dråbevis en opløsning af 0,024 ml (1,6 mol i hexan) n-butyllithium i løbet af 1 mi-35 nut. Den orangefarvede blanding omrøres i yderligere 10 minutter ved -78°C, hvorpå der tilsættes 0,031 ml chlor-myresyremethylester. Blandingen henstår til opvarmning til 51 DK 169104 B1 stuetemperatur, hvorefter den hældes i mættet vandig natrium-chloridopløsning, og der ekstraheres med ether. Ekstrakten vaskes med vand og tørres over magnesiumsulfat. Ved ind-dampning i vakuum fås en olie, som renses ved præparativt 5 tyndtlagskromatografi. Som opløsningsmiddel anvendes 1:1-blanding af ethylacetat og hexan. 1-(3-Methoxycarbonyl-prop-2-ynyl)-3-methyl-2-(3-pyridyl)-indol isoleres i form af en olie. NMR (CDC13) 6 3,73 (s,3H), 4,83 (s,2H). IR (CHC13) 1715, 2245 cm"1.Example 38 1- (Prop-2-ynyl) -3-methyl-2- (3-pyridyl) -indole (90 mg) is dissolved under nitrogen in 2 ml of THF and the resulting solution is cooled to -78 ° C. A solution of 0.024 ml (1.6 mole in hexane) of n-butyllithium is added dropwise over 1 minute. The orange mixture is stirred for a further 10 minutes at -78 ° C, then 0.031 ml of chloro-formic acid methyl ester is added. The mixture is allowed to warm to room temperature, after which it is poured into saturated aqueous sodium chloride solution and extracted with ether. The extract is washed with water and dried over magnesium sulfate. Evaporation in vacuo gives an oil which is purified by preparative thin layer chromatography. As the solvent, 1: 1 mixture of ethyl acetate and hexane is used. 1- (3-Methoxycarbonyl-prop-2-ynyl) -3-methyl-2- (3-pyridyl) indole is isolated in the form of an oil. NMR (CDCl 3) δ 3.73 (s, 3H), 4.83 (s, 2H). IR (CHCl3) 1715, 2245 cm -1.
10 Udgangsforbindelsen fremstilles på følgende måde: 53 mg natriumhydrid i form af en 50%'s mineraloliedispersion vaskes under nitrogen med petroleumsether. Det vaskede natriumhydrid suspenderes i 2 ml tør DMF, og der tilsættes dråbevis 3-methyl-2-(3-pyridyl)-indol (208 mg) i DMF (2 ml).The starting compound is prepared as follows: 53 mg sodium hydride in the form of a 50% mineral oil dispersion is washed under nitrogen with petroleum ether. The washed sodium hydride is suspended in 2 ml of dry DMF and 3-methyl-2- (3-pyridyl) indole (208 mg) in DMF (2 ml) is added dropwise.
15 Blandingen omrøres i yderligere 30 minutter, hvorpå der dråbevis tilsættes propargylbromid. Reaktionsblandingen omrøres i yderligere 2 timer, hvorefter den hældes i isvand, der syrnes med 1 N saltsyre og ekstraheres med ether. Den vandige fase gøres basisk med natriumhydrogen-20 carbonat og ekstraheres med ether. Etherekstrakten vaskes med vand og mættet vandig natriumchloridopløsning og tørres over magnesiumsulfat. Ved inddampning i vakuum fås 1-(prop-2-ynyl)-3-methyl-2-(3-pyridyl)-indol. NMR (CDCl^) 6 2,20 (s,4H), 4,70 (d,2HJ = 3 Hz), IR (flydende) 3200, 25 2120 cm 1. Smeltepunktet er 104-105°C efter rensning ved kortvejskromatografi under anvendelse af en l:l-blanding af ethylacetat og hexan.The mixture is stirred for an additional 30 minutes, then propargyl bromide is added dropwise. The reaction mixture is stirred for an additional 2 hours, then poured into ice water, acidified with 1N hydrochloric acid and extracted with ether. The aqueous phase is made basic with sodium hydrogen carbonate and extracted with ether. The ether extract is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation in vacuo gives 1- (prop-2-ynyl) -3-methyl-2- (3-pyridyl) indole. NMR (CDCl3) δ 2.20 (s, 4H), 4.70 (d, 2HJ = 3 Hz), IR (liquid) 3200, 2120 cm 1. The melting point is 104-105 ° C after purification by short-circuit chromatography under using a 1: 1 mixture of ethyl acetate and hexane.
Eksempel 39Example 39
Ved behandling af 33 mg 1-(3-methoxycarbonylprop-2-ynyl)-30 3-methyl-2-(3-pyridyl)-indol i 1 ml methanol med 0,3 ml 1 N lithiumhydroxidopløsning ved stuetemperatur fås 1—(3— carboxyprop-2-ynyl)-3-methy1-2-(3-pyridyl)-indol. IR 1720 -1 cm DK 169104 B1 52By treating 33 mg of 1- (3-methoxycarbonylprop-2-ynyl) -30 3-methyl-2- (3-pyridyl) indole in 1 ml of methanol with 0.3 ml of 1 N lithium hydroxide solution at room temperature, 1- (3) is obtained. - carboxyprop-2-ynyl) -3-methyl-2- (3-pyridyl) indole. IR 1720 -1 cm DK 169104 B1 52
Eksempel 40Example 40
Analogt med de i de ovenstående eksempler beskrevne fremgangsmåder fremstilles nedenstående forbindelser med formlen II, hvori = CH^, Pyr = 3-pyridyl og = OH.Analogous to the methods described in the above examples, the following compounds of formula II are prepared wherein = CH 2, Pyr = 3-pyridyl and = OH.
5 Forbin- Ri Ri C H~ Salt Smp. °C5 Forbin- Ri Ri C H ~ Salt Mp. ° C
delse 2_3 m 2m___ 40/1 5-C1 H (CH2)7 HCl 173-176 40/2 5-OCH3 Η (CH2)s HBr 188-189 40/3 5-C1 6-C1 (CH2)5 HCl 178-180 10 40/4 5-F H (cH2)5 HCl 216-219 40/5 5-CH3 H (CH2) 5 HC1 185-188 40/6 5“CH3 H (CH2)7 - 124-125 40/7 Η H (ch2)10 - 100-102 40/8 5-0-CH2-0-6 (CH2)5 15 40/9 5-OH Η (<3Η2)5 “ 168-170 40/10 5-SCH3 H (CH2)5 " 135-137part 2_3 m 2m___ 40/1 5-C1 H (CH2) 7 HCl 173-176 40/2 5-OCH3 Η (CH2) s HBr 188-189 40/3 5-C1 6-C1 (CH2) 5 HCl 178- 180 10 40/4 5-FH (cH2) 5 HCl 216-219 40/5 5-CH3 H (CH2) 5 HCl 185-188 40/6 5 “CH3 H (CH2) 7 - 124-125 40/7 Η H (ch2) 10 - 100-102 40/8 5-0-CH2-0-6 (CH2) 5 15 40/9 5-OH Η (<3Η2) 5 “168-170 40/10 5-SCH3 H ( CH2) 5 "135-137
De som udgangsmaterialer anvendte N-usubstituerede indoler er kendte forbindelser. Den hidtil ukendte udgangsforbindelse for forbindelsen 40/10, nemlig 5-methylthio-3-methyl-20 2-(3-pyridyl)-indol smelter ved 160-162°C.The N-unsubstituted indoles used as starting materials are known compounds. The novel starting compound for compound 40/10, namely 5-methylthio-3-methyl-2- (3-pyridyl) indole, melts at 160-162 ° C.
Forbindelsen 40/9 fremstilles ved hydrogenolyse af l-(5-carboxypentyl)-5-benzyloxy-3-methyl-2-(3-pyridyl)-indol, smp. 176-178°C. Den som udgangsforbindelse anvendte 5-benzyloxy-3-methyl-2-(3-pyridyl)-indol smelter ved 164-166°C.Compound 40/9 is prepared by hydrogenolysis of 1- (5-carboxypentyl) -5-benzyloxy-3-methyl-2- (3-pyridyl) indole, m.p. 176-178 ° C. The 5-benzyloxy-3-methyl-2- (3-pyridyl) -indole used as the starting compound melts at 164-166 ° C.
25 Eksempel 41Example 41
Analogt med de i de ovenstående eksempler beskrevne fremgangsmåder fremstilles nedenstående forbindelser med formlen I,, hvori R^ = CH3, Ar = 3-pyridyl og B = COOH.By analogy with the methods described in the above examples, the following compounds of formula I, wherein R 1 = CH 3, Ar = 3-pyridyl and B = COOH are prepared.
Forbin- R_ R_ A BConnect- R_ R_ A B
30 delse_ -5_30 part_ -5
41/1 Η H C=C-(CH2)3 COOH41/1 Η H C = C- (CH2) 3 COOH
41/2 Η H CH2S(CH2)2 COOH41/2 Η H CH 2 S (CH 2) 2 COOH
41/3 Η H (CH2)20(CH2)2 COOH41/3 Η H (CH2) 20 (CH2) 2 COOH
41/4 Η H (CH2)20(CH2)3 COOH41/4 Η H (CH2) 20 (CH2) 3 COOH
53 DK 169104 B153 DK 169104 B1
De alkylerende udgangsforbindelser for forbindelserne 41/2, 41/3 og 41/4 fremstilles ifølge J. Org. Chem. 3_4, 2955 (1969), US-patentskrift nr. 3.984.459 eller Chem. Abstr.The alkylating starting compounds for compounds 41/2, 41/3 and 41/4 are prepared according to J. Org. Chem. 3, 4, 2955 (1969), U.S. Patent No. 3,984,459 or Chem. Abstr.
83, 166177b.83, 166177b.
5 Virkning på thromboxan-syntetase fra blodplader fra mennesker_5 Effect on thromboxane synthetase from human platelets_
Afprøvningen gennemføres under anvendelse af den tidligere beskrevne fremgangsmåde. Denne in vitrohæmning af thrombo-xan-syntetase-enzymet påvises analogt med fremgangsmåden 10 ifølge Sun, Biochem. Biophys. Res. Comm. 7£, 1432 (1977).The test is performed using the method described previously. This in vitro inhibition of the thromboxane synthetase enzyme is demonstrated analogously to the method of Sun, Biochem. Biophys. Res. Comm. 7, 1432 (1977).
Resultaterresults
Forbindelse IC50 ifølge eksempel Thromboxan-syntetase 3 0,003 15 1 0,012 2 1,800 4 0,008 5 0,007 9 0,021 20 10 0,069 11 0,050 6 3,400 7 0,001 12 0,260 25 13 0,013Compound IC50 of Example Thromboxane Synthetase 3 0.003 15 1 0.012 2 1.800 4 0.008 5 0.007 9 0.021 20 10 0.069 11 0.050 6 3.400 7 0.001 12 0.260 25 13 0.013
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US4675332A (en) * | 1984-12-10 | 1987-06-23 | Warner-Lambert Company | Acidic tetrazolyl substituted indole compounds and their use as antiallergy agents |
US4609733A (en) * | 1984-12-27 | 1986-09-02 | Ciba-Geigy Corporation | 3-keto-substituted-N-pyridylindoles |
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US6828344B1 (en) * | 1998-02-25 | 2004-12-07 | Genetics Institute, Llc | Inhibitors of phospholipase enzymes |
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