DE3407505A1 - Novel benzothiazinecarboxamides having antiarthritic activity - Google Patents
Novel benzothiazinecarboxamides having antiarthritic activityInfo
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- DE3407505A1 DE3407505A1 DE19843407505 DE3407505A DE3407505A1 DE 3407505 A1 DE3407505 A1 DE 3407505A1 DE 19843407505 DE19843407505 DE 19843407505 DE 3407505 A DE3407505 A DE 3407505A DE 3407505 A1 DE3407505 A1 DE 3407505A1
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- benzothiazine
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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
Abstract
Description
Titel: Neue Benzothiazin-carbonsäureamide mitTitle: New benzothiazine carboxamides with
antiarthritischer Wirksamkeit Beschreibung Die Erfindung betrifft neue Benzothiazin-carbonsäureamide und deren physiologisch verträgliche Additionssalze, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zubereitungen und ihre Verwendung bei der Prophylaxe und Therapie rheumatischer Erkrankungen, besonders bei Arthrose. Antiarthritic Efficacy Description The invention relates to new benzothiazine carboxamides and their physiologically compatible addition salts, Process for their preparation and pharmaceutical compositions containing these compounds Preparations and their use in the prophylaxis and therapy of rheumatic Diseases, especially osteoarthritis.
3-Carbamoyl-l , 2-benzothiazin-1 , 1-dioxide mit einem heterocyclischen Substituenten am Amid-Stickstoff wurden zum erstenmal im US-Patent 3,591,584 beschrieben. Da die Substanzen gute antiinflammatorische und analgetische Eigenschaften zeigen, werden einige in der Therapie von Erkrankungen des rheumatischen Formenkreises verwendet, obwohl sie die Nachteile aller bekannten nichtsteroidalen Therapeutika wie Magenunverträglichkeit mit Ulcusbildung oder gastrointestinalen Irritationen aufweisen.3-carbamoyl-l, 2-benzothiazine-1, 1-dioxide with a heterocyclic Substituents on the amide nitrogen were first described in U.S. Patent 3,591,584. Since the substances show good anti-inflammatory and analgesic properties, some are used in the therapy of rheumatic diseases, although they have the disadvantages of all known nonsteroidal therapeutics such as gastric intolerance with ulcer formation or gastrointestinal irritation.
Es wurde nun gefunden, daß Benzothiazincarbasäureamide der Formel I worin R1 einen 5- oder 6-gliedrigen aromatischen oder teilhydrierten, gegebenenfalls mit einem 5- oder 6-gliedrigen Ring anellierten Heterocyclyl-, Heterocyclylalkyl-, Heterocyclylarylrest mit 1-3 Heteroatomen der Elemente Stickstoff und Schwefel bedeutet, der gegebenenfalls durch Halogen, Hydroxy, Oxo, C1,3-Alkyl, C1,3-Alkoxy, Mercapto, C1,3-Alkylthio, C1,3-Alkoxycarbonyl, Alkoxycarbonylaklylthio, C36-Cycloalkyl substituiert ist und deren pharmazeutisch verträgliche Salze wertvolle pharmakologische Eigenschaften aufweisen.It has now been found that Benzothiazincarbasäureamide of the formula I wherein R1 is a 5- or 6-membered aromatic or partially hydrogenated, optionally with a 5- or 6-membered ring fused heterocyclyl, heterocyclylalkyl, heterocyclylaryl radical with 1-3 heteroatoms of the elements nitrogen and sulfur, which is optionally replaced by halogen, hydroxy, Oxo, C1,3-alkyl, C1,3-alkoxy, mercapto, C1,3-alkylthio, C1,3-alkoxycarbonyl, alkoxycarbonylaklylthio, C36-cycloalkyl and the pharmaceutically acceptable salts thereof have valuable pharmacological properties.
Ausgenommen von der Erfindung sind Verbindungen der Formel I, bei denen R1 2-Pyridyl, 2-Tniazolyl oder 3-Pyrazolyl bedeutet.Compounds of the formula I are excluded from the invention where R1 is 2-pyridyl, 2-triazolyl or 3-pyrazolyl.
Bevorzugt sind Verbindungen der Formel I, bei denen R1 2-(2-Thiazolinyl), 2-(4,5-Trimethylen-thiazolyl), 2-(4,5-Tetramethylen-thiazolyl), 2-(4-Ethoxycarbonyl-thiazolyl), 2-(5-Chlor-thiazolyl), 2-Picolyl, 3-Picolyl, 4-(l-Imidazolyl)-phenyl, 5-(3-Methyl-isothiazolyl), 2-(1-Methyl-4-hydroxy-imidazolyl), 2-(1,3,4-Thiadiazolyl), 2-(5-Cyclopropyl-1,3,4-thiadiazolyl), 2-(5-Mercapto-1,3,4-thiadiazolyl), 2-(5-Methylthio-1,3,4-thiadiazolyl), 2-(5-Ethoxycarbonylethylthio-1,3,4-thiadiazolyl), 3-(4-Hydroxychinolyl), 3-(Dihydro-l-methyl-4-oxo-benzo/bZpyridyl), bedeutet.Preferred compounds of the formula I are those in which R1 is 2- (2-thiazolinyl), 2- (4,5-trimethylene-thiazolyl), 2- (4,5-tetramethylene-thiazolyl), 2- (4-ethoxycarbonyl-thiazolyl), 2- (5-chloro-thiazolyl), 2-picolyl, 3-picolyl, 4- (l-imidazolyl) -phenyl, 5- (3-methyl-isothiazolyl), 2- (1-methyl-4-hydroxy-imidazolyl), 2- (1,3,4-thiadiazolyl), 2- (5-cyclopropyl-1,3,4-thiadiazolyl), 2- (5-mercapto-1,3,4-thiadiazolyl), 2- (5-methylthio-1,3,4-thiadiazolyl), 2- (5-ethoxycarbonylethylthio-1,3,4-thiadiazolyl), 3- (4-hydroxyquinolyl), 3- (dihydro-l-methyl-4-oxo-benzo / bZpyridyl), means.
In der Erfindung enthalten sind auch pharmazeutisch verwendbare Additionssalze von Verbindungen der Formel I.Also included in the invention are pharmaceutically acceptable addition salts of compounds of the formula I.
Die Hydroxylgruppe des Benzothiazins besitzt als Enol saure Eigenschaften und kann mit Basen pharmazeutisch verträgliche Salze bilden. Dazu können anorganische und organische Basen Verwendung finden, beispielsweise Natrium-, Kalium-, Lithium- und Calciumhydroxid bzw. Triethanolamin, Triethylamin, Diethylamin.As an enol, the hydroxyl group of benzothiazine has acidic properties and can form pharmaceutically acceptable salts with bases. Inorganic and organic bases are used, for example sodium, potassium, lithium and calcium hydroxide or triethanolamine, triethylamine, diethylamine.
Verbindungen der Formel I, die einen basischen Heterocyclus enthalten, können pharmazeutisch verwendbare Säureadditionssalze ergeben. Diese werden beispielsweise mit starken anorganischen Säuren, wie Mineralsäuren, z.B.Compounds of the formula I which contain a basic heterocycle, can give pharmaceutically acceptable acid addition salts. These are for example with strong inorganic acids such as mineral acids, e.g.
Schwefelsäure, Phosphorsäure oder Halogenwasserstoffsäuren, z.B. Salzsäure, mit starken organischen Carbonsäuren, wie Niederalkancarbonsäuren, z.B. Essigsäure, wie gegebenenfalls ungesättigte 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.Sulfuric acid, phosphoric acid or hydrohalic acids, e.g. hydrochloric acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, e.g. acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. oxalic, malonic, maleic or Fumaric acid, or such as hydroxycarboxylic acids, e.g. tartaric acid or citric acid, or with sulfonic acids, such as lower alkanoic or optionally substituted benzenesulfonic acids, e.g. methane or p-toluenesulphonic acid is formed.
Erfindungsgemäße Verbindungen sind beispielsweise: N-E2-(2-Thiazolinyl)2-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-l , l-dioxid N-E2-(4,5-Trimethylen-thiazolyl)7-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-Z2-(4,5-Tetramethylen-thiazolyl)g-4-hydroxy-2-methyl-2H-1, 2-benzothiazin-3-carboxamid-l, l-dioxid N-[2-(4-Ethoxycarbonyl-thiazolyl)2-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-l,l-dioxid N-T2- ( 5-Chlor-thiazolyl )7-4-hydroxy-2-methyl-2H-l , 2-benzothiazin-3-carboxamid-l, l-dioxid N- (2-Picolyl ) -4-hydroxy-2-methyl-2H-1, 2-benzothiazin-3-carboxamid-l,l-dioxid N-(3-Picolyl)-4-hydroxy-2-methyl-2EI-1,2-benzothiazin-3-carboxamid-l,l-dioxid N-|4-(1-Imidazolyl)-phenyl|-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-r5-(3-Methyl-isothiazolyl)7-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-f2- (4-Hydroxy-l-methyl-imidazolyl )7-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-[2-(1,3,4-Thiadiazolyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-[2-(5-Cyclopropyl-1,3,4-thiadiazolyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-f2- ( 5-Mercapto-l 3, 4-thiadiazolyl )7-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-[2-(5-Methylthio-1,3,4-thiadiazolyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-g2-(5-Ethoxycarbonylethylthio-1,3,4-thiadiazolyl)7-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid N-g3-(4-Hydroxy-chinolyl)7-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-l , l-dioxid N-E3-(Dihydro-l-methyl-4-oxo-benzozbvpyridyl/-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Die Verbindungen der Formel I weisen wertvolle pharmakologische Eigenschaften auf. Insbesondere besitzen sie eine ausgeprägte antiinflammatorische Wirkung, die sich durch Reduktion des durch Carragenin erzeugten Pfotenödems und im Adjuvans-Arthritis-Modell nachweisen läßt. Sie eignen sich daher besonders zur Therapie von rheumatischen Krankheiten, wie z.B. Arthrosen.Examples of compounds according to the invention are: N-E2- (2-thiazolinyl) 2-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1 , 1-Dioxide N-E2- (4,5-trimethylene-thiazolyl) 7-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N-Z2- (4,5-tetramethylene-thiazolyl) g-4-hydroxy-2-methyl-2H-1, 2-benzothiazine-3-carboxamide-1, l-dioxide N- [2- (4-ethoxycarbonyl-thiazolyl) 2-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N-T2- (5-chloro-thiazolyl) 7-4-hydroxy-2-methyl-2H-l, 2-benzothiazine-3-carboxamide-l, l-dioxide N- (2-picolyl) -4-hydroxy-2-methyl-2H-1, 2-benzothiazine-3-carboxamide-l, l-dioxide N- (3-picolyl) -4-hydroxy-2-methyl-2EI-1,2-benzothiazine-3-carboxamide-1,1-dioxide N- | 4- (1-imidazolyl) -phenyl | -4-hydroxy -2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N-r5- (3-methyl-isothiazolyl) 7-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N-f2- (4-Hydroxy-1-methyl-imidazolyl) 7-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N- [2- (1,3,4-thiadiazolyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N- [2- (5-Cyclopropyl-1,3,4-thiadiazolyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N-f2- (5-mercapto-1,3,4-thiadiazolyl) 7-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N- [2- (5-methylthio-1,3,4-thiadiazolyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N-g2- (5-ethoxycarbonylethylthio-1,3,4-thiadiazolyl) 7-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide N-g3- (4-Hydroxy-quinolyl) 7-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1 , 1-Dioxide N-E3- (Dihydro-1-methyl-4-oxo-benzoin-pyridyl / -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide The compounds of the formula I have valuable pharmacological properties. In particular, they have a pronounced anti-inflammatory effect by reducing the paw edema produced by carrageenin and in the adjuvant arthritis model can be proven. They are therefore particularly suitable for the therapy of rheumatic diseases Diseases such as osteoarthritis.
Die Darstellung der erfindungsgemäßen Verbindungen erfolgt unter an sich bekannten Bedingungen. Beim Verfahren 1 wird ein Benzothiazin-carbonsäureester der Formel II, worin R2 eine Methyl- oder Ethylgruppe bedeutet, mit einem Amin der Formel R1-NH2 umgesetzt, wobei R1 die in Formel I angegebene Bedeutung besitzt. Die Aminolyse des Esters wird am vorteilhaftesten bei der Siedetemperatur des Lösungsmittels durchgeführt, wobei der entstehende Alkohol azeotrop oder durch Verwendung eines Molekularsiebs entfernt wird. Bevorzugte Lösungsmittel für die Reaktion sind Xylol und Toluol bei Temperaturen von 110-1500C, vorzugsweise 120-l400C.The compounds according to the invention are prepared under conditions known per se. In process 1, a benzothiazine carboxylic acid ester of the formula II, where R2 is a methyl or ethyl group, reacted with an amine of the formula R1-NH2, where R1 has the meaning given in formula I. The aminolysis of the ester is most advantageously carried out at the boiling point of the solvent, the alcohol formed being removed azeotropically or by using a molecular sieve. Preferred solvents for the reaction are xylene and toluene at temperatures of 110-1500C, preferably 120-1400C.
Das Verfahren 2 geht von Sulfonamidestern der allgemeinen Formel III aus, die unter Basenkatalyse zu den 4-Hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-l, 1-dioxiden cyclysiert werden.Process 2 is based on sulfonamide esters of the general formula III, which are cyclized with base catalysis to the 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides.
Die Umsetzung wird in einem Lösungsmittel bei Temperaturen von 60-1200C durchgeführt. Als Lösungsmittel eignen sich protische und aprotische, beispielsweise Methanol, Dioxan, Tetrahydrofuran, Dimethylformamid. Als Basen kommen Alkalihydride, -amide, oder -alkoholate in Betracht.The reaction is carried out in a solvent at temperatures of 60-1200C carried out. Suitable solvents are protic and aprotic, for example Methanol, dioxane, tetrahydrofuran, dimethylformamide. Alkali hydrides are used as bases, -amides or alcoholates into consideration.
Die vorliegende Erfindung betrifft ebenfalls pharmazeutische Präparate, welche Verbindungen der Formel I enthalten. Bei den erfindungsgemäßen pharmazeutischen Präparaten handelt es sich um solche zur enteralen wie oralen oder rektalen sowie 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.The present invention also relates to pharmaceutical preparations, which compounds of formula I contain. In the pharmaceutical according to the invention Preparations are those for enteral such as oral or rectal as well parenteral administration containing the active pharmaceutical ingredients alone or together with a conventional, pharmaceutically applicable carrier material. Advantageously if the pharmaceutical preparation of the active ingredient is available in the form of single doses, tailored to the desired administration, e.g.
Tabletten, Dragees, Kapseln, Suppositorien, Granulate, Lösungen, Emulsionen oder Suspensionen. Bei oraler Applikation liegt die Dosierung der Verbindungen üblicherweise zwischen 10 - 1000 mg pro Tag, vorzugsweise zwischen 30 -300 mg und kann ein- oder mehrmals, bevorzugt zwei- bis dreimal täglich, verabreicht werden.Tablets, coated tablets, capsules, suppositories, granulates, solutions, emulsions or suspensions. In the case of oral administration, the dosage of the compounds is usually between 10-1000 mg per day, preferably between 30-300 mg and can be one or be administered several times, preferably two to three times a day.
Die Herstellung der erfindungsgemäßen Verbindungen wird durch die folgenden Beispiele näher erläutert. Die angegebenen Schmelzpunkte wurden mit einem Büchi 510-Schmelzpunktbestimmungsapparat gemessen und sind mit OC angegeben und nicht korrigiert. Die IR-Spektren wurden mit dem Gerät Perkin Elmer 257 und die Massenspektren mit dem Gerät Varian MAT-311-A (70 eV) aufgenommen.The preparation of the compounds according to the invention is carried out by the following examples are explained in more detail. The specified melting points were with a Büchi 510 melting point apparatus and are indicated with OC and not corrected. The IR spectra were recorded using the Perkin Elmer 257 and the Mass spectra recorded with the Varian MAT-311-A (70 eV) device.
Beispiel 1 N-[2-(4,5-Trimethylen-thiazolyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-l,l-dioxid Eine Lösung von 2,7 g 4-Hydroxy-2-methyl-2H-1,2-benzothiazin-3-carbonsäure-methylester-l,l-dioxid und 1,4 g 2-Amino-4,5-trimethylen-thiazol in 160 ml Xylol wird unter Rückfluß erhitzt, wobei langsam Xylol abdestilliert. Die Lösungsmittelmenge wird dabei durch kontinuierliches Zutropfen konstant gehalten. Nach ca. 15 Stunden wird zur Trockne eingeengt. Der Rückstand wird säulenchromatographisch an Kieselgel gereinigt. Die mit Chloroform eluierte Hauptfraktion ergibt mit Ether verrieben 1,9 g hellgelbe Kristalle von N-[2-(4,5-Trimethylen-thiazolyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid vom Schmelzpunkt 246-247°C.Example 1 N- [2- (4,5-Trimethylene-thiazolyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide A solution of 2.7 g of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 1.4 g of 2-amino-4,5-trimethylene-thiazole in 160 ml of xylene is heated under reflux, slowly distilling off xylene. The amount of solvent is thereby by continuous Dropping kept constant. After about 15 hours, it is concentrated to dryness. Of the The residue is purified by column chromatography on silica gel. The one with chloroform Eluted main fraction gives 1.9 g of light yellow crystals of, triturated with ether N- [2- (4,5-trimethylene-thiazolyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with a melting point of 246-247 ° C.
IR (KBr): 1634 cm'l MS: M+ 377 Beispiel 2 N-F2- (4, 5-Tetramethylen-thiazolyl £/-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Ein Gemisch aus 2,7 g 4-Hydroxy-2-methyl-2H-1,2-benzothiazin-3-carbonsäure-methylester-l,l-dioxid und 1,54 g 2-Amino-4,5-tetramethylen-thiazol und 150 ml Xylol wird unter Rühren 11 Stunden auf Siedetemperatur gehalten unter gleichzeitigem Abdestillieren des Lösungsmittels. Die Lösung wird unter Rühren abgekühlt, der Feststoff abfiltriert und mit Methanol und Ether gewaschen. Man erhält 1,1 g gelbe Kristalle von N-g2-(4,5-Tetramethylen-thiazolyl)g-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamidl,l-dioxid vom Schmelzpunkt 252-2540C.IR (KBr): 1634 cm -1 MS: M + 377 Example 2 N-F2- (4, 5-tetramethylene-thiazolyl £ / -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide A mixture of 2.7 g of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 1.54 g of 2-amino-4,5-tetramethylene-thiazole and 150 ml of xylene is added with stirring Maintained at boiling temperature for 11 hours while distilling off the Solvent. The solution is cooled while stirring, and the solid is filtered off and washed with methanol and ether. 1.1 g of yellow crystals of N-g2- (4,5-tetramethylene-thiazolyl) -g-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamido-1-dioxide are obtained of melting point 252-2540C.
IR (KBr): 1633 cm'l MS: M+ 391 Beispiel 3 N-S2-(1,3,4-Thiadiazolyl)|-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-l, l-dioxid Zu 1,85 g 2-Methoxycarbonyl-phenylsulfonyl-N-2-( 1,3,4-thiadiazolyl)-sarkosinamid in 50 ml Tetrahydrofuran werden 0,24 g Natriumhydrid gegeben und 54 Stunden unter Rückfluß erhitzt. Das Lösungsmittel wird abgezogen und der Rückstand zwischen Wasser und Chloroform verteilt. Die Wasserphase wird abgetrennt, mit 2-normaler Salzsäure angesäuert und dreimal mit je 10 ml Chloroform extrahiert. Die organische Phase wird gewaschen, über Natriumsulfat getrocknet, eingeengt und liefert 564 mg Rückstand, der aus Methylenchlorid/Cyclohexan umkristallisiert wird. Man erhält 260 mg von N-[2-(1,3,4-Thiadiazolyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid vom Schmelzpunkt 229-2310C.IR (KBr): 1633 cm -1 MS: M + 391 Example 3 N-S2- (1,3,4-thiadiazolyl) | -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1, 1-dioxide To 1.85 g of 2-methoxycarbonyl-phenylsulfonyl-N-2- (1,3,4-thiadiazolyl) sarcosinamide in 50 ml of tetrahydrofuran 0.24 g of sodium hydride are added and 54 hours under Heated to reflux. The solvent is evaporated and the residue between water and chloroform distributed. The water phase is separated off with 2N hydrochloric acid acidified and extracted three times with 10 ml of chloroform each time. The organic phase is washed, dried over sodium sulfate, concentrated and gives 564 mg of residue, which is recrystallized from methylene chloride / cyclohexane. 260 mg of N- [2- (1,3,4-thiadiazolyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of melting point 229-2310C.
IR (KBr): 1631 cm-l MS: M+ 338 Beispiel 4 Nach der Methodik der Beispiele 1 bis 3 wurden die folgenden Verbindungen hergestellt: N-l2-(2-Thiazolinyl)g-4-hydroxy-2-methyl-2H-1,2-benzOthiazin-3-carboxamid-l, 1-dioxid Fp. 310-3120C N-[2-(4-Ethoxycarbonyl-thiazolyl)-4-hydroxy-2-methyl-2H-1, 2-benzothiazin-3-carboxamid-l, l-dioxid Fp. 263-264"C N-g2-(5-Chlorthiazolyl)l-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1, l-dioxid Fp. 235-2360C N-[2-(5-Mercapto-1,3,4-thiadiazolyl)l-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp. 276-278°C N-[2-(5-Methylthio-1,3,4-thiadiazolyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp. 280°C (Zers.) N-[2-(5-Cyclopropyl-1,3,4-thiadiazolyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp. 212-214°C N-B2-(5-Ethoxyearbonylethylthio-1,3,4-thiadiazolyl)2-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp 232-231°C N-e5-(3-Methyl-isothiazolyl)7-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-l,l-dioxid Fp. 257-2580C N-(2-Picolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp. 196-199°C N-(3-Picolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp. 171-173°C N-f2- (4-Hydroxy-l-methyl-imidazolyl )j-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp. 241-243°C N-[4-(1-Imidazolyl)-phenyl]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp. 255-257°C N-O3-(4-Hydroxy-chinolyl)g-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-l,l-dioxid Fp. 335-3360C N-[3-(Dihydro-1-methyl-4-oxo-benzo[b]pyridyl)]-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid-1,1-dioxid Fp. 288-2900CIR (KBr): 1631 cm -1 MS: M + 338 Example 4 According to the methodology of the examples 1 to 3 the following compounds were prepared: N-12- (2-thiazolinyl) g-4-hydroxy-2-methyl-2H-1,2-benzOthiazine-3-carboxamide-1, 1-dioxide m.p. 310-3120C N- [2- (4-ethoxycarbonyl-thiazolyl) -4-hydroxy-2-methyl-2H-1, 2-benzothiazine-3-carboxamide-l, l-dioxide m.p. 263-264 "C N-g2- (5-chlorothiazolyl) 1-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide -1, I-dioxide m.p. 235-2360C N- [2- (5-mercapto-1,3,4-thiadiazolyl) 1-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide Mp 276-278 ° C. N- [2- (5-Methylthio-1,3,4-thiadiazolyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1 -dioxide Mp 280 ° C (dec.) N- [2- (5-Cyclopropyl-1,3,4-thiadiazolyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1 , 1-dioxide Mp. 212-214 ° C N-B2- (5-ethoxyearbonylethylthio-1,3,4-thiadiazolyl) 2-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1- dioxide Mp 232-231 ° C N-e5- (3-methyl-isothiazolyl) 7-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide M.p. 257-2580C N- (2-picolyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide Mp 196-199 ° C N- (3-picolyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide Mp 171-173 ° C N-f2- (4-Hydroxy-1-methyl-imidazolyl) j-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide M.p. 241-243 ° C N- [4- (1-imidazolyl) -phenyl] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide Mp. 255-257 ° C N-O3- (4-hydroxy-quinolyl) g-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide M.p. 335-3360C N- [3- (Dihydro-1-methyl-4-oxo-benzo [b] pyridyl)] -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1 , 1-dioxide M.p. 288-2900C
Claims (5)
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| DE19843407505 DE3407505A1 (en) | 1984-03-01 | 1984-03-01 | Novel benzothiazinecarboxamides having antiarthritic activity |
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| DE19843407505 DE3407505A1 (en) | 1984-03-01 | 1984-03-01 | Novel benzothiazinecarboxamides having antiarthritic activity |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01228975A (en) * | 1988-03-09 | 1989-09-12 | Nippon Hai Potsukusu:Kk | Benzothiazine-1,1-dioxide derivative, its production and medical composition containing the same |
| WO1991007970A1 (en) * | 1989-11-30 | 1991-06-13 | Nippon Hypox Laboratories Incorporated | Medicine containing thiazine dioxide derivative |
| US5677282A (en) * | 1995-06-07 | 1997-10-14 | Proscript, Inc. | Amino acid amides of 1,3,4-thiadiazoles as matrix metalloproteinase |
| WO1998025949A1 (en) * | 1996-12-09 | 1998-06-18 | Proscript, Inc. | Substituted 5-amino-1,3,4-thiadiazole-2-thiones |
| WO2000006550A1 (en) * | 1998-07-31 | 2000-02-10 | Nippon Soda Co., Ltd. | Phenylazole compounds, process for producing the same and drugs for hyperlipemia |
| US7354944B2 (en) | 2004-10-18 | 2008-04-08 | Amgen Inc. | Thiadiazole compounds and methods of use |
| US7553837B2 (en) | 2003-08-01 | 2009-06-30 | Nippon Soda Co., Ltd. | Phenylazole compounds production process and antioxidants |
| US7652155B2 (en) | 2003-04-14 | 2010-01-26 | Nippon Soda Co., Ltd. | Diamine derivative, production process therefor and antioxidant |
| US7897619B2 (en) | 2007-07-17 | 2011-03-01 | Amgen Inc. | Heterocyclic modulators of PKB |
| US7919504B2 (en) | 2007-07-17 | 2011-04-05 | Amgen Inc. | Thiadiazole modulators of PKB |
-
1984
- 1984-03-01 DE DE19843407505 patent/DE3407505A1/en not_active Withdrawn
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01228975A (en) * | 1988-03-09 | 1989-09-12 | Nippon Hai Potsukusu:Kk | Benzothiazine-1,1-dioxide derivative, its production and medical composition containing the same |
| EP0413051A1 (en) * | 1988-03-09 | 1991-02-20 | Nippon Hypox Laboratories Incorporated | Benzothiazine-1,1-dioxide derivatives |
| WO1991007970A1 (en) * | 1989-11-30 | 1991-06-13 | Nippon Hypox Laboratories Incorporated | Medicine containing thiazine dioxide derivative |
| US5677282A (en) * | 1995-06-07 | 1997-10-14 | Proscript, Inc. | Amino acid amides of 1,3,4-thiadiazoles as matrix metalloproteinase |
| WO1998025949A1 (en) * | 1996-12-09 | 1998-06-18 | Proscript, Inc. | Substituted 5-amino-1,3,4-thiadiazole-2-thiones |
| US6342516B1 (en) | 1998-07-31 | 2002-01-29 | Nippon Soda Co., Ltd. | Phenylazole compounds, process for producing the same and drugs for hyperlipemia |
| WO2000006550A1 (en) * | 1998-07-31 | 2000-02-10 | Nippon Soda Co., Ltd. | Phenylazole compounds, process for producing the same and drugs for hyperlipemia |
| US7652155B2 (en) | 2003-04-14 | 2010-01-26 | Nippon Soda Co., Ltd. | Diamine derivative, production process therefor and antioxidant |
| US7553837B2 (en) | 2003-08-01 | 2009-06-30 | Nippon Soda Co., Ltd. | Phenylazole compounds production process and antioxidants |
| US7354944B2 (en) | 2004-10-18 | 2008-04-08 | Amgen Inc. | Thiadiazole compounds and methods of use |
| US7700636B2 (en) | 2004-10-18 | 2010-04-20 | Amgen Inc. | Thiadiazole compounds and methods of use |
| US7919514B2 (en) | 2004-10-18 | 2011-04-05 | Amgen Inc. | Thiadiazole compounds and methods of use |
| US7897619B2 (en) | 2007-07-17 | 2011-03-01 | Amgen Inc. | Heterocyclic modulators of PKB |
| US7919504B2 (en) | 2007-07-17 | 2011-04-05 | Amgen Inc. | Thiadiazole modulators of PKB |
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