DE3705934A1 - Indolyl derivatives, processes for their preparation, and their use as medicaments - Google Patents
Indolyl derivatives, processes for their preparation, and their use as medicamentsInfo
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- DE3705934A1 DE3705934A1 DE19873705934 DE3705934A DE3705934A1 DE 3705934 A1 DE3705934 A1 DE 3705934A1 DE 19873705934 DE19873705934 DE 19873705934 DE 3705934 A DE3705934 A DE 3705934A DE 3705934 A1 DE3705934 A1 DE 3705934A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
Die Erfindung betrifft Indolyl-Derivate und deren physiologisch verträgliche Säureadditionssalze, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zubereitungen.The invention relates to indolyl derivatives and their physiological compatible acid addition salts, process for their preparation and pharmaceutical compositions containing them Preparations.
Die erfindungsgemäßen Verbindungen besitzen wertvolle pharmakologische Eigenschaften. Sie beeinflussen insbesondere das Zentralnervensystem und eignen sich zum Einsatz in psychopharmazeutischen Präparationen.The compounds of the invention have valuable ones pharmacological properties. They affect in particular the central nervous system and are suitable for use in psychopharmaceutical preparations.
Es ist bekannt, daß bestimmte Stellen im zentralen Nervensystem von Vertebraten eine hohe spezifische Affinität für die Bindung von 1,4- und 1,5-Benzodiazepinen aufweisen. Diese Stellen werden Benzodiazepinrezeptoren genannt.It is known to have specific locations in the central nervous system of vertebrates have a high specific affinity for show the binding of 1,4- and 1,5-benzodiazepines. These sites are called benzodiazepine receptors.
Es wurde nun gefunden, daß Indolyl-Derivate der allgemeinen Formel IIt has now been found that indolyl derivatives of the general Formula I.
worinwherein
R¹Wasserstoff, Halogen, Methyl, Methoxy, R², R³Wasserstoff, Methyl, Ethyl und R⁴Phenyl, Chlorphenyl, Fluorphenyl, Trifluorphenyl, Tolyl, Pyridyl, Thiazolyl, 5-Chlorthiazolyl, 4,5- Trimethylenthiazolyl, Thiazolinyl, Imidazolyl, 5- Methylisoxazolyl, Pyrimidinyl, Pyridazinyl sowie XCarbonyl oder Methylen bedeuten, überraschenderweise eine starke Affinität für die Bindung an Benzodiazepin- Rezeptoren zeigen, obwohl sie sich in ihrer chemischen Struktur deutlich von Benzodiazepinen unterscheiden.R1 hydrogen, halogen, methyl, methoxy, R², R³hydrogen, methyl, ethyl and R⁴phenyl, chlorophenyl, fluorophenyl, trifluorophenyl, Tolyl, pyridyl, thiazolyl, 5-chlorothiazolyl, 4,5- Trimethylene thiazolyl, thiazolinyl, imidazolyl, 5- Methylisoxazolyl, pyrimidinyl, pyridazinyl such as X is carbonyl or methylene, surprisingly a strong affinity for binding to benzodiazepine Receptors show, even though they are in their chemical structure clearly from benzodiazepines differentiate.
In der Erfindung enthalten sind auch die pharmazeutisch verwendbaren Säureadditionssalze von Verbindungen der Formel I.Pharmaceuticals are also included in the invention usable acid addition salts of compounds of the formula I.
Diese werden beispielsweise mit anorganischen Säuren, wie Mineralsäuren, z. B. Schwefelsäure, Phosphorsäure oder Halogenwasserstoffsäuren, z. B. Salzsäure, mit organischen Carbonsäuren, wie Niederalkancarbonsäuren, z. B. Essigsäure, wie gegebenenfalls ungesättigten Dicarbonsäuren, z. B. Oxal-, Malon-, Malein- oder Fumarsäure, oder wie Hydroxycarbonsäuren, z. B. Weinsäure oder Citronensäure, oder mit Sulfonsäuren, wie Niederalkan- oder gegebenenfalls substituierte Benzolsulfonsäuren, z. B. Methan- oder p-Toluolsulfonsäure gebildet.These are, for example, with inorganic acids such as Mineral acids, e.g. B. sulfuric acid, phosphoric acid or Hydrohalic acids, e.g. B. hydrochloric acid, with organic Carboxylic acids, such as lower alkane carboxylic acids, e.g. B. acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. B. Oxalic, malonic, maleic or fumaric acid, or such as hydroxycarboxylic acids, e.g. B. tartaric acid or citric acid, or with Sulfonic acids, such as lower alkane or optionally substituted Benzenesulfonic acids, e.g. B. methane or p-toluenesulfonic acid educated.
Erfindungsgemäße Verbindungen sind beispielsweise:
N-2-Pyridyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-2-Thiazolinyl-5-chlor-3-methoxy-1-methyl-indol-2-carboxamid,
N-2-Imidazolyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-2-Thiazolinyl-3-hydroxy-1-methyl-indol-2-carboxamid,
3-Methoxy-1-methyl-2-(2-thiazolinyl-aminomethyl)-indol-
hydrochlorid,
N-2-Pyridyl-3-hydroxy-1-methyl-indol-2-carboxamid,
N-2-Thiazolyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-2-Thiazolyl-3-hydroxy-1-methyl-indol-2-carboxamid,
N-5-Methylisoxazol-3-yl-3-methoxy-1-methyl-indol-2-carboxamid,
N-4-Chlorphenyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-4-Chlorphenyl-3-hydroxy-1-methyl-indol-2-carboxamid,
N-4-Fluorphenyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-3-Trifluormethylphenyl-3-methoxy-1-methyl-indol-2-
carboxamid,
N-4-Tolyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-2-Pyrimidinyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-2-Pyrimidinyl-3-hydroxy-1-methyl-indol-2-carboxamid,
N-2-Pyridazinyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-2-Thiazolinyl-3-methoxy-1-methyl-indol-2-carboxamid,
N-5-Chlorthiazol-2-yl-3-methoxy-1-methyl-indol-2-carboxamid,
N-4,5-Trimethylenthiazolyl-3-methoxy-1-methyl-indol-2-
carboxamid,
N-2-Thiazolyl-3-methoxy-indol-2-carboxamid,
N-2-Thiazolinyl-1,5-dimethyl-3-methoxy-indol-2-carboxamid,
N-2-Thiazolinyl-1,5-dimethyl-3-methoxy-indol-2-carboxamid,
N-2-Thiazolyl-5-chlor-3-methoxy-1-methyl-indol-2-carboxamid,
N-2-Thiazolyl-3,5-dimethoxy-1-methyl-indol-2-carboxamid,
N-2-Thiazolinyl-3,5-dimethoxy-1-methyl-indol-2-carboxamid,
3-Methoxy-1-methyl-2-(2-thiazolyl-aminomethyl)-indol,
5-Chlor-3-methoxy-1-methyl-2-(2-thiazolinyl-aminomethyl)-
indol,
1,5-Dimethyl-3-methoxy-2-(2-thiazolinyl-aminomethyl)-indol.Compounds according to the invention are, for example:
N-2-pyridyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-thiazolinyl-5-chloro-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-imidazolyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-thiazolinyl-3-hydroxy-1-methyl-indole-2-carboxamide,
3-methoxy-1-methyl-2- (2-thiazolinylaminomethyl) indole hydrochloride,
N-2-pyridyl-3-hydroxy-1-methyl-indole-2-carboxamide,
N-2-thiazolyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-thiazolyl-3-hydroxy-1-methyl-indole-2-carboxamide,
N-5-methylisoxazol-3-yl-3-methoxy-1-methyl-indole-2-carboxamide,
N-4-chlorophenyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-4-chlorophenyl-3-hydroxy-1-methyl-indole-2-carboxamide,
N-4-fluorophenyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-3-trifluoromethylphenyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-4-tolyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-pyrimidinyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-pyrimidinyl-3-hydroxy-1-methyl-indole-2-carboxamide,
N-2-pyridazinyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-thiazolinyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-5-chlorothiazol-2-yl-3-methoxy-1-methyl-indole-2-carboxamide,
N-4,5-trimethylene thiazolyl-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-thiazolyl-3-methoxy-indole-2-carboxamide,
N-2-thiazolinyl-1,5-dimethyl-3-methoxy-indole-2-carboxamide,
N-2-thiazolinyl-1,5-dimethyl-3-methoxy-indole-2-carboxamide,
N-2-thiazolyl-5-chloro-3-methoxy-1-methyl-indole-2-carboxamide,
N-2-thiazolyl-3,5-dimethoxy-1-methyl-indole-2-carboxamide,
N-2-thiazolinyl-3,5-dimethoxy-1-methyl-indole-2-carboxamide,
3-methoxy-1-methyl-2- (2-thiazolylaminomethyl) indole,
5-chloro-3-methoxy-1-methyl-2- (2-thiazolinylaminomethyl) indole,
1,5-dimethyl-3-methoxy-2- (2-thiazolinylaminomethyl) indole.
Die erfindungsgemäßen Verbindungen der Formel I besitzen anxiolytische, sedative und antikonvulsive Wirksamkeit mit hoher Affinität zum Benzodiazepin-Rezeptor. Sie können daher zur Behandlung von chronischer Anxiolyse oder zusammen mit Neuroleptika oder Antidepressiva zur Behandlung von psychotischen oder depressiven Zuständen verwendet werden.The compounds of the formula I according to the invention have anxiolytic, sedative and anticonvulsant effectiveness with high affinity for the benzodiazepine receptor. You can therefore for the treatment of chronic anxiolysis or together with neuroleptics or antidepressants for treatment used by psychotic or depressive conditions will.
Die Darstellung der erfindungsgemäßen Verbindungen erfolgt nach an sich bekannten Verfahren. Dabei sind mehrere Methoden möglich.The compounds according to the invention are shown according to known methods. There are several Methods possible.
- 1. Carbonsäurechloride der Formel II worin R¹, R², R³ die in Formel I angegebenen Bedeutungen haben, werden mit Aminen der Formel R⁴-NH₂ umgesetzt, wobei R⁴ die in Formel I angegebene Bedeutung hat. Dabei gibt man das Säurechlorid der Formel II zu einer Mischung aus dem Amin R⁴-NH₂ und einem tertiären Amin, wie Triethylamin, als Säureakzeptor in einem geeigneten organischen Lösungsmittel, wie Ether, Tetrachlorkohlenstoff, Dichlormethan, Chloroform oder Toluol bei Temperaturen von 0° bis 60°C.1. Carboxylic acid chlorides of the formula II wherein R¹, R², R³ have the meanings given in formula I, are reacted with amines of the formula R⁴-NH₂, where R⁴ has the meaning given in formula I. The acid chloride of the formula II is added to a mixture of the amine R⁴-NH₂ and a tertiary amine, such as triethylamine, as an acid acceptor in a suitable organic solvent, such as ether, carbon tetrachloride, dichloromethane, chloroform or toluene at temperatures from 0 ° to 60 ° C.
- 2. Man läßt Carbonsäuren der Formel III worin R¹, R², R³ die in Formel I angegebenen Bedeutungen haben, in einem geeigneten Lösungsmittel in Gegenwart eines Kondensationsmittels mit Aminen der Formel R⁴-NH₂ reagieren, wobei R⁴ die in Formel I angegebene Bedeutung hat. Besonders günstig in der Anwendung ist das Phosphorazo-Verfahren nach Goldschmidt mit Phosphortrichlorid in Pyridin. Aber auch andere gebräuchliche Reagentien, wie z. B. Dicyclohexylcarbodiimid oder N,N-Carbonyl-diimidazol können mit Erfolg eingesetzt werden.2. Allow carboxylic acids of formula III wherein R¹, R², R³ have the meanings given in formula I, react in a suitable solvent in the presence of a condensing agent with amines of the formula R⁴-NH₂, where R⁴ has the meaning given in formula I. The phosphorazo method according to Goldschmidt with phosphorus trichloride in pyridine is particularly favorable in use. But also other common reagents, such as. B. dicyclohexylcarbodiimide or N, N-carbonyl-diimidazole can be used successfully.
- 3. Aminolyse von Carbonsäuremethylestern der Formel IV worin R¹, R², R³ die in Formel I angegebenen Bedeutungen haben, in einem geeigneten Lösungsmittel mit Aminen der Formel R⁴-NH₂, wobei R⁴ die in Formel I angegebene Bedeutung hat. Bevorzugt wird die allgemeinen Methode von B. Singh (Tetrahedron Letters, 4, 321-322, 1971). Sie wird bei milden Temperaturen in einem aprotischen Lösungsmittel, wie Dimethylsulfoxid, Dimethylformamid oder N-Methyl-2-pyrrolidon, mit Natriumhydrid als Base durchgeführt. Die Ausbeuten liegen dabei zwischen 60 und 90% der Theorie.3. Aminolysis of carboxylic acid methyl esters of the formula IV wherein R¹, R², R³ have the meanings given in formula I, in a suitable solvent with amines of the formula R⁴-NH₂, where R⁴ has the meaning given in formula I. The general method of B. Singh (Tetrahedron Letters, 4, 321-322, 1971) is preferred. It is carried out at mild temperatures in an aprotic solvent, such as dimethyl sulfoxide, dimethylformamide or N-methyl-2-pyrrolidone, with sodium hydride as the base. The yields are between 60 and 90% of theory.
- 4. Die Verbindungen der Formel I mit R=H stellt man am besten durch Etherspaltung aus Verbindungen der Formel I mit R³=Methyl oder Ethyl her. Prinzipiell können zur Etherspaltung alle Methoden verwendet werden, die eine Amidbindung intakt lassen. Ein besonders bevorzugtes Reagenz ist Bortribromid. Dabei werden unter milden Bedingungen eine große Zahl von funktionellen Gruppen nicht angegriffen. Die Reaktion wird gewöhnlich in einem Lösungsmittel, wie Dichlormethan, Toluol oder Pentan, bei Temperaturen von 0°C bis Raumtemperatur bei Reaktionszeiten von 12-15 Stunden ausgeführt.4. The compounds of formula I with R = H are placed on best by ether cleavage from compounds of the formula I with R³ = methyl or ethyl. In principle can all methods are used for ether cleavage which leave an amide bond intact. A particularly preferred one The reagent is boron tribromide. Doing so will be mild Conditions a large number of functional groups not attacked. The reaction is usually in a solvent such as dichloromethane, toluene or Pentane, at temperatures from 0 ° C to room temperature Response times of 12-15 hours executed.
-
5. Verbindungen der Formel I mit X=CH₂ werden durch Reduktion
aus Verbindungen der Formel I mit X=CO erhalten.
Hierzu können alle bekannten Reduktionsverfahren für
Carbonsäureamide angewendet werden. Vorteilhaft ist die
Verwendung von komplexen Metallhydriden, insbesondere
Lithiumaluminiumhydrid in einem Lösungsmittel. Dafür
eignen sich normale und cyclische Ether, wie Diethylether,
Dioxan und Tetrahydrofuran, bei Temperaturen bis
zur Siedetemperatur des Lösungsmittels.
Die erfindungsgemäßen Verbindungen können als Basen oder in Form ihrer Salze Verwendung finden.5. Compounds of formula I with X = CH₂ are obtained by reduction from compounds of formula I with X = CO. All known reduction processes for carboxamides can be used for this. It is advantageous to use complex metal hydrides, in particular lithium aluminum hydride, in a solvent. For this purpose, normal and cyclic ethers, such as diethyl ether, dioxane and tetrahydrofuran, are suitable at temperatures up to the boiling point of the solvent.
The compounds according to the invention can be used as bases or in the form of their salts.
Die vorliegende Erfindung betrifft ebenfalls pharmazeutische Präparate, welche die Verbindungen der Formel I oder pharmazeutisch verwendbare Säureadditionssalze dieser Verbindungen enthalten. Bei den erfindungsgemäßen pharmazeutischen Präparaten handelt es sich um solche zur enteralen wie oralen oder rektalen oder parenteralen Verabreichung, welche die pharmazeutischen Wirkstoffe allein oder zusammen mit einem üblichen pharmazeutisch anwendbaren Trägermaterial enthalten. Vorteilhafterweise liegt die pharmazeutische Zubereitung des Wirkstoffes in Form von Einzeldosen vor, die auf die gewünschte Verabreichung abgestimmt sind, wie z. B. Tabletten, Drag´es, Kapseln, Suppositorien. Bei oraler Applikation liegt die Dosierung der Verbindungen üblicherweise zwischen 0,1-10 mg/kg/Tag, vorzugsweise zwischen 1-5 mg/kg/Tag und kann ein- oder mehrmals, bevorzugt zwei- bis dreimal täglich, verabreicht werden. Die Herstellung der erfindungsgemäßen Verbindungen wird durch die folgenden Beispiele näher erläutert. Die angegebenen Schmelzpunkte wurden mit einem Büchi 510-Schmelzpunktbestimmungsapparat gemessen und sind in °C angegeben und nicht korrigiert. Die IR-Spektren wurden mit einem Nicolet Modell 3600 FT gemessen. Die Massenspektren wurden mit dem Gerät Varian MAT 311-A (70 eV) aufgenommen.The present invention also relates to pharmaceutical Preparations containing the compounds of formula I or pharmaceutically acceptable acid addition salts of these compounds contain. In the pharmaceutical Preparations are enteral such as oral or rectal or parenteral administration, which are the active pharmaceutical ingredients alone or together with a customary pharmaceutically usable carrier material contain. The pharmaceutical is advantageously located Preparation of the active substance in the form of single doses before, which is tailored to the desired administration are, such as B. tablets, drages, capsules, suppositories. In the case of oral administration, the dosage of the compounds lies usually between 0.1-10 mg / kg / day, preferably between 1-5 mg / kg / day and can be taken one or more times, preferably two to three times a day. The preparation of the compounds according to the invention explained in more detail by the following examples. The specified Melting points were measured using a Büchi 510 melting point determination apparatus measured and are given in ° C and not corrected. The IR spectra were recorded with a Nicolet Model 3600 FT measured. The mass spectra were recorded with the Varian MAT 311-A (70 eV) device.
Eine Lösung von 2,2 g 3-Methoxy-1-methyl-indol-2-carbonsäurechlorid
in 20 ml Dichlormethan wird bei ca. 0°C unter
Rühren zu einer Mischung aus 0,9 g 2-Aminopyridin, 4 ml
Triethylamin und 40 ml Dichlormethan zugetropft. Anschließend
wird 12 Stunden bei Raumtemperatur weitergerührt. Die
Lösung wird nacheinander mit zweinormaler Natronlauge und
Wasser gewaschen, über Natriumsulfat getrocknet und im
Vakuum eingedampft. Der hellbeige Rückstand wird mit Ether
ausgerührt und liefert 1,4 g weiße Kristalle von N-2-Pyridyl-
3-methoxy-1-methyl-indol-2-carboxamid vom Fp.
108-110°C.
IR (KBr):1670 cm-1;
MS:M⁺ m/e 281, basepeak m/e 250.A solution of 2.2 g of 3-methoxy-1-methyl-indole-2-carboxylic acid chloride in 20 ml of dichloromethane is stirred at approx. 0 ° C to a mixture of 0.9 g of 2-aminopyridine, 4 ml of triethylamine and 40 ml of dichloromethane was added dropwise. Then stirring is continued for 12 hours at room temperature. The solution is washed successively with two normal sodium hydroxide solution and water, dried over sodium sulfate and evaporated in vacuo. The light beige residue is stirred with ether and gives 1.4 g of white crystals of N-2-pyridyl-3-methoxy-1-methyl-indole-2-carboxamide, mp. 108-110 ° C.
IR (KBr): 1670 cm -1 ; MS: M⁺ m / e 281, basepeak m / e 250.
Zu einer Mischung von 3 g 5-Chlor-3-methoxy-1-methyl-
indol-2-carbonsäure-methylester und 3,7 g 2-Aminothiazolin
in 30 ml Dimethylsulfoxid gibt man portionsweise unter
Eiskühlung 0,57 g 55%ige Natriumhydrid-Dispersion in
Mineralöl. Nach Beendigung der Wasserstoffentwicklung läßt
man ca. 14 Stunden bei Raumtemperatur weiterrühren und
gießt den Ansatz unter Rühren auf Eis. Die Kristalle werden
abgesaugt, an der Luft getrocknet und mit Ether verrieben.
Man erhält 1,2 g weiße Kristalle von N-2-Thiazolinyl-
5-chlor-3-methoxy-1-methyl-indol-2-carboxamid vom
Fp. 190-192°C.
IR (KBr):1697 cm-1;
MS:M⁺ m/e 323, basepeak m/e 292.
To a mixture of 3 g of 5-chloro-3-methoxy-1-methylindole-2-carboxylic acid methyl ester and 3.7 g of 2-aminothiazoline in 30 ml of dimethyl sulfoxide, 0.57 g of 55% sodium hydride is added in portions with ice cooling -Dispersion in mineral oil. After the evolution of hydrogen has ended, stirring is continued for about 14 hours at room temperature and the mixture is poured onto ice while stirring. The crystals are suctioned off, air-dried and triturated with ether. 1.2 g of white crystals of N-2-thiazolinyl-5-chloro-3-methoxy-1-methyl-indole-2-carboxamide, mp. 190-192 ° C., are obtained.
IR (KBr): 1697 cm -1 ; MS: M⁺ m / e 323, basepeak m / e 292.
3,1 g 3-Methoxy-1-methyl-indol-2-carbonsäure und 2 g
2-Amino-imidazolsulfat werden unter gelindem Erwärmen in
30 ml Pyridin gelöst. Darauf wird unter Eiskühlung und
Rühren 1,03 g Phosphortrichlorid in 5 ml Pyridin eingetropft.
Man läßt 30 Minuten bei Raumtemperatur stehen und
erhitzt 3 Stunden bei 100°C. Das Pyridin wird im Vakuum
abdestilliert. Der braune Feststoff wird in Chloroform
aufgenommen und nacheinander mit zweinormaler Salzsäure,
verdünnter Natriumcarbonatlösung und Wasser gewaschen. Der
eingeengte Rückstand wird chromatographisch an Kieselgel/
Chloroform gereinigt und ergibt 0,7 g von N-2-Imidazolyl-
3-methoxy-1-methyl-indol-2-carboxamid vom Fp. 202-204°C.
IR (KBr):1668 cm-1;
MS:M⁺ m/e 270, basepeak m/e 239.
3.1 g of 3-methoxy-1-methyl-indole-2-carboxylic acid and 2 g of 2-amino-imidazole sulfate are dissolved in 30 ml of pyridine with gentle heating. Then 1.03 g of phosphorus trichloride in 5 ml of pyridine is added dropwise with ice cooling and stirring. The mixture is left to stand at room temperature for 30 minutes and heated at 100 ° C. for 3 hours. The pyridine is distilled off in vacuo. The brown solid is taken up in chloroform and washed successively with two normal hydrochloric acid, dilute sodium carbonate solution and water. The concentrated residue is purified by chromatography on silica gel / chloroform and gives 0.7 g of N-2-imidazolyl-3-methoxy-1-methyl-indole-2-carboxamide, mp. 202-204 ° C.
IR (KBr): 1668 cm -1 ; MS: M⁺ m / e 270, basepeak m / e 239.
Zu einer Lösung von Bortribromid (24,9 ml einer 1 molaren
Lösung in Dichlormethan) gibt man bei 0°C unter Stickstoff
tropfenweise eine Lösung von 2,4 g N-2-Thiazolinyl-3-
methoxy-1-methyl-indol-2-carboxamid in 100 ml Dichlormethan.
Nach 20 Stunden bei Raumtemperatur wird mit Eis
gekühlt und unter heftigem Rühren Eiswasser zugegeben. Die
organische Phase wird abgetrennt, mit Wasser gewaschen und
über Natriumsulfat getrocknet. Die eingeengte Lösung wird
chromatographisch an Kieselgel gereinigt. Man erhält 1,6 g
N-2-Thiazolinyl-3-hydroxy-1-methyl-indol-2-carboxamid vom
Fp. 211-213°C.
IR (KBr):1672 cm-1;
MS:M⁺ m/e 275, basepeak m/e 161.
A solution of 2.4 g of N-2-thiazolinyl-3-methoxy-1-methyl-indole-2 is added dropwise to a solution of boron tribromide (24.9 ml of a 1 molar solution in dichloromethane) at 0 ° C. under nitrogen -carboxamide in 100 ml dichloromethane. After 20 hours at room temperature, the mixture is cooled with ice and ice water is added with vigorous stirring. The organic phase is separated off, washed with water and dried over sodium sulfate. The concentrated solution is purified chromatographically on silica gel. 1.6 g of N-2-thiazolinyl-3-hydroxy-1-methyl-indole-2-carboxamide of mp 211-213 ° C. are obtained.
IR (KBr): 1672 cm -1 ; MS: M⁺ m / e 275, basepeak m / e 161.
Zu einer Suspension von 0,6 g Lithiumaluminiumhydrid in
absolutem Tetrahydrofuran wird unter Rühren bei Raumtemperatur
tropfenweise eine Lösung von 1,5 g N-2-Thiazolinyl-
3-methoxy-1-methyl-indol-2-carboxamid in absolutem Tetrahydrofuran
zugegeben. Man läßt 14 Stunden bei Raumtemperatur
weiterrühren. Unter Eiskühlung wird das Reaktionsgemisch
tropfenweise mit Wasser versetzt und mit Ether
ausgeschüttelt. Die organische Phase wird mit Wasser
gewaschen, über Natriumsulfat getrocknet und eingeengt.
Die Base wird direkt in das Hydrochlorid übergeführt und
aus Ethanol umkristallisiert. Man erhält 0,8 g 3-Methoxy-
1-methyl-2-(2-thiazolinyl-aminomethyl)-indol-hydrochlorid
vom Fp. 158-160°C.
IR (KBr):1600 cm-1;
MS:M⁺ m/e 275, basepeak m/e 260.
A solution of 1.5 g of N-2-thiazolinyl-3-methoxy-1-methyl-indole-2-carboxamide in absolute tetrahydrofuran is added dropwise to a suspension of 0.6 g of lithium aluminum hydride in absolute tetrahydrofuran with stirring at room temperature. The mixture is stirred for a further 14 hours at room temperature. With ice cooling, the reaction mixture is added dropwise with water and extracted with ether. The organic phase is washed with water, dried over sodium sulfate and concentrated. The base is converted directly into the hydrochloride and recrystallized from ethanol. 0.8 g of 3-methoxy-1-methyl-2- (2-thiazolinylaminomethyl) indole hydrochloride, mp. 158-160 ° C., is obtained.
IR (KBr): 1600 cm -1 ; MS: M⁺ m / e 275, basepeak m / e 260.
Nach der Methodik der Beispiele 1-5 werden die folgenden Verbindungen der Formel I hergestellt:Following the methodology of Examples 1-5 are the following Compounds of formula I prepared:
Claims (3)
- a) Carbonsäurechloride der Formel II worin R¹, R², R³ die in Formel I angegebenen Bedeutungen haben, in einem geeigneten Lösungsmittel in Gegenwart eines Säureakzeptors mit Aminen R⁴-NH₂ umsetzt, wobei R⁴ die in Formel I angegebene Bedeutung hat,
- b) Carbonsäuren der Formel III worin R¹, R², R³ die in Formel I angegebenen Bedeutungen haben, in einem geeigneten Lösungsmittel in Gegenwart eines Kondensationsmittels mit Aminen R⁴-NH₂ reagieren läßt, wobei R⁴ die in Formel I angegebene Bedeutung hat,
- c) Carbonsäuremethylester der Formel IV worin R¹, R², R³ die in Formel I angegebenen Bedeutungen haben, in einem geeigneten Lösungsmittel der Aminolyse mit Aminen R⁴-NH₂ unterwirft, wobei R⁴ die in Formel I angegebene Bedeutung hat,
- d) Verbindungen der Formel I, worin R¹, R², R⁴ die angegebenen Bedeutungen haben und R³ Methyl oder Ethyl und X=CO ist, in einem geeigneten Lösungsmittel einer Etherspaltung zu Verbindungen der Formel I mit R³=H unterwirft,
- e) Verbindungen der Formel I, worin R¹, R², R³, R⁴ die angegebenen Bedeutungen haben und X=CO ist, in einem geeigneten Lösungsmittel einer Reduktion zu Verbindungen der Formel I mit X=CH₂ unterwirft.
- a) Carboxylic acid chlorides of the formula II wherein R¹, R², R³ have the meanings given in formula I, in a suitable solvent in the presence of an acid acceptor with amines R⁴-NH₂, where R⁴ has the meaning given in formula I,
- b) carboxylic acids of formula III wherein R¹, R², R³ have the meanings given in formula I, can react with amines R⁴-NH₂ in a suitable solvent in the presence of a condensing agent, where R⁴ has the meaning given in formula I,
- c) methyl carboxylate of the formula IV wherein R¹, R², R³ have the meanings given in formula I, subject to aminolysis with amines R⁴-NH₂ in a suitable solvent, where R⁴ has the meaning given in formula I,
- d) compounds of the formula I in which R¹, R², R⁴ have the meanings indicated and R³ is methyl or ethyl and X = CO, in an appropriate solvent, subject to ether cleavage to give compounds of the formula I with R³ = H,
- e) compounds of the formula I in which R¹, R², R³, R⁴ have the meanings given and X = CO, in a suitable solvent, a reduction to compounds of the formula I with X = CH₂.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873705934 DE3705934A1 (en) | 1987-02-25 | 1987-02-25 | Indolyl derivatives, processes for their preparation, and their use as medicaments |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873705934 DE3705934A1 (en) | 1987-02-25 | 1987-02-25 | Indolyl derivatives, processes for their preparation, and their use as medicaments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3705934A1 true DE3705934A1 (en) | 1988-09-08 |
Family
ID=6321673
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19873705934 Withdrawn DE3705934A1 (en) | 1987-02-25 | 1987-02-25 | Indolyl derivatives, processes for their preparation, and their use as medicaments |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE3705934A1 (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0432040A1 (en) * | 1989-12-06 | 1991-06-12 | Sanofi | Heterocyclic derivatives of acylaminothiazole, their preparation and pharmaceutical compositions containing them |
| FR2661677A1 (en) * | 1990-05-04 | 1991-11-08 | Sanofi Sa | Heterocyclic acylaminothiazole derivatives, their preparation and pharmaceutical compositions containing them |
| EP0469984A2 (en) * | 1990-07-31 | 1992-02-05 | Sanofi | N-sulfonyl-indoline derivatives, their preparation and pharmaceutical compositions containing them |
| FR2677356A1 (en) * | 1991-06-05 | 1992-12-11 | Sanofi Sa | SUBSTITUTED ACYLAMINO-2 THIAZOLE-5 HETEROCYCLIC DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| EP0526348A1 (en) * | 1991-08-02 | 1993-02-03 | Sanofi | Indoline derivatives carrying an amide function, their preparation and pharmaceutical compositions containing them |
| US5338755A (en) * | 1990-07-31 | 1994-08-16 | Elf Sanofi | N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present |
| EP0611766A1 (en) * | 1993-02-19 | 1994-08-24 | Sanofi | Polysubstituted 2-amido thiazoles derivatives, process for their preparation, pharmaceutical compositions and utilization for the preparation of a medicament |
| US5481005A (en) * | 1990-07-31 | 1996-01-02 | Sanofi | N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present |
| EP1493733A2 (en) * | 1999-08-20 | 2005-01-05 | Dow AgroSciences LLC | Fungicidal heterocyclic aromatic amides, their compositions and methods of use |
| WO2006023590A1 (en) * | 2004-08-19 | 2006-03-02 | Aventis Pharmaceuticals Inc. | 3-ARYLTHIOINDOLE-2-CARBOXAMIDE DERIVATIVES AND ANALOGS THEREOF AS INHIBITORS OF CASEIN KINASE Iϵ |
| JP2007512264A (en) * | 2003-11-24 | 2007-05-17 | ノボ ノルディスク アクティーゼルスカブ | Heteroarylindolecarboxamides and analogs thereof for use as glucokinase activators in the treatment of obesity |
-
1987
- 1987-02-25 DE DE19873705934 patent/DE3705934A1/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5189049A (en) * | 1989-12-06 | 1993-02-23 | Sanofi | Heterocyclic substituted acylaminothiazoles, their preparation and pharmaceutical compositions containing them |
| USRE37094E1 (en) | 1989-12-06 | 2001-03-13 | Sanofi | Heterocyclic substituted acylaminothiazoles, their preparation and pharmaceutical compositions containing them |
| EP0432040A1 (en) * | 1989-12-06 | 1991-06-12 | Sanofi | Heterocyclic derivatives of acylaminothiazole, their preparation and pharmaceutical compositions containing them |
| FR2661677A1 (en) * | 1990-05-04 | 1991-11-08 | Sanofi Sa | Heterocyclic acylaminothiazole derivatives, their preparation and pharmaceutical compositions containing them |
| EP0469984A2 (en) * | 1990-07-31 | 1992-02-05 | Sanofi | N-sulfonyl-indoline derivatives, their preparation and pharmaceutical compositions containing them |
| EP0469984A3 (en) * | 1990-07-31 | 1992-03-11 | Sanofi | N-sulfonyl-indoline derivatives, their preparation and pharmaceutical compositions containing them |
| US5481005A (en) * | 1990-07-31 | 1996-01-02 | Sanofi | N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present |
| US5338755A (en) * | 1990-07-31 | 1994-08-16 | Elf Sanofi | N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present |
| EP0518731A1 (en) * | 1991-06-05 | 1992-12-16 | Sanofi | Heterocyclic derivatives of substituted 2-acylamino 5-thiazole, their preparation and pharmaceutical compositions containing them |
| US5314889A (en) * | 1991-06-05 | 1994-05-24 | Elf Sanofi | Heterocyclic substituted 2-acylamino-5-thiazoles, their preparation and pharmaceutical compositions containing them |
| FR2677356A1 (en) * | 1991-06-05 | 1992-12-11 | Sanofi Sa | SUBSTITUTED ACYLAMINO-2 THIAZOLE-5 HETEROCYCLIC DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| US5380736A (en) * | 1991-06-05 | 1995-01-10 | Elf Sanofi | Heterocyclic substituted 2-acylamino-5-thiazoles, their preparation and pharmaceutical compositions containing them |
| EP0526348A1 (en) * | 1991-08-02 | 1993-02-03 | Sanofi | Indoline derivatives carrying an amide function, their preparation and pharmaceutical compositions containing them |
| FR2679903A1 (en) * | 1991-08-02 | 1993-02-05 | Sanofi Elf | DERIVATIVES OF N - SULFONYL INDOLINE CARRYING AMIDIC FUNCTION, PREPARATION THEREOF, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME. |
| WO1993003013A1 (en) * | 1991-08-02 | 1993-02-18 | Elf Sanofi | Indoline derivatives having an amide function, their preparation, and pharmaceutical compositions containing them |
| EP0611766A1 (en) * | 1993-02-19 | 1994-08-24 | Sanofi | Polysubstituted 2-amido thiazoles derivatives, process for their preparation, pharmaceutical compositions and utilization for the preparation of a medicament |
| FR2701708A1 (en) * | 1993-02-19 | 1994-08-26 | Sanofi Elf | Polysubstituted 2-amido-4-phenylthiazole derivatives, process for their preparation, pharmaceutical composition and use of these derivatives for the preparation of a medicament |
| EP1493733A2 (en) * | 1999-08-20 | 2005-01-05 | Dow AgroSciences LLC | Fungicidal heterocyclic aromatic amides, their compositions and methods of use |
| EP1493733A3 (en) * | 1999-08-20 | 2005-01-26 | Dow AgroSciences LLC | Fungicidal heterocyclic aromatic amides, their compositions and methods of use |
| JP2007512264A (en) * | 2003-11-24 | 2007-05-17 | ノボ ノルディスク アクティーゼルスカブ | Heteroarylindolecarboxamides and analogs thereof for use as glucokinase activators in the treatment of obesity |
| WO2006023590A1 (en) * | 2004-08-19 | 2006-03-02 | Aventis Pharmaceuticals Inc. | 3-ARYLTHIOINDOLE-2-CARBOXAMIDE DERIVATIVES AND ANALOGS THEREOF AS INHIBITORS OF CASEIN KINASE Iϵ |
| US8008340B2 (en) | 2004-08-19 | 2011-08-30 | Aventis Pharmaceuticals Inc. | 3-arylthioindole-2-carboxamide derivatives and analogs thereof as inhibitors of casein kinase I |
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