DE2655009A1 - ISOXAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEANS CONTAINING THESE COMPOUNDS - Google Patents
ISOXAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEANS CONTAINING THESE COMPOUNDSInfo
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- DE2655009A1 DE2655009A1 DE19762655009 DE2655009A DE2655009A1 DE 2655009 A1 DE2655009 A1 DE 2655009A1 DE 19762655009 DE19762655009 DE 19762655009 DE 2655009 A DE2655009 A DE 2655009A DE 2655009 A1 DE2655009 A1 DE 2655009A1
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- methylisoxazole
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
HOECHST AKTIENGESELLSCHAFT 3 2655009HOECHST AKTIENGESELLSCHAFT 3 2655009
Aktenzeichen: . HOE 76/F 29h File number: . HOE 76 / F 29h
Datum: 3. Dezember 1976 Dr.KM/RpDate: December 3, 1976 Dr.KM/Rp
Isoxazolderivate, Verfahren zu ihrer Herstellung und diese Verbindungen
enthaltende Mittel
Zusatz zur Patentanmeldung P 25 24 959.5 (HOE 75/F 149)Isoxazole derivatives, processes for their preparation and compositions containing these compounds
Addition to patent application P 25 24 959.5 (HOE 75 / F 149)
Gegenstand der Hauptanmeldung P 25 24 959.5 (HOE 75/F 149) sind S-Methyl-isoxazol-^-carbonsäureanilide der FormelThe main application P 25 24 959.5 (HOE 75 / F 149) are S-methyl-isoxazole - ^ - carboxylic acid anilides of the formula
12 312 3
worin R , R und R gleich oder verschieden sein können und Alkyl mit 1, 2 oder 3 C-Atomen, Alkoxy mit 1, 2 oder 3 C-Atomen/ Alkylthio mit 1,2 oder 3 C-Atomen, welche Gruppen jeweils vollständig oder teilweise durch gleiche oder verschiedene Ha3.ogen-wherein R, R and R can be the same or different and Alkyl with 1, 2 or 3 carbon atoms, alkoxy with 1, 2 or 3 carbon atoms / alkylthio with 1,2 or 3 carbon atoms, which groups are complete or partially by the same or different Ha3.ogen-
809824/0 029 /2 809824/0 029/2
atome, wie Fluor, Chlor, Brom oder Jod, substituiert sein können, Halogen, wie Fluor, Chlor, Br.ora oder Jod, Nitro, Cyan, Carbalkoxy mit 1, 2 oder 3 C-Atomen in der Alkylgruppe, bedeuten, worinatoms, such as fluorine, chlorine, bromine or iodine, can be substituted, halogen, such as fluorine, chlorine, bromine or iodine, nitro, cyano, carbalkoxy with 1, 2 or 3 carbon atoms in the alkyl group, mean in which
1 21 2
R und R weiterhin Wasserstoff bedeuten, in welchem Fall jedochR and R continue to represent hydrogen, but in which case
3 33 3
R nicht Methyl sein kann, in welchem Fall jedoch R zusätzlich Phenyl, das gegebenenfalls jeweils einfach oder zweifach durch Fluor, Chlor, Brom, Jod, Alkyl mit 1, 2 oder 3 C-Atomen oder Alkoxy mit 1, 2 oder 3 C-Atomen substituiert sein kann, oder Phenoxy, das gegebenenfalls jeweils einfach oder zweifach durch Fluor, Chlor, Brom, Jod, Alkyl mit 1, 2 oder 3 C-Atomen oder Alkoxy mit 1, 2 oder 3 C-Atomen substituiert sein kann, bedeutet,R cannot be methyl, but in which case R can also be phenyl, which is optionally single or double Fluorine, chlorine, bromine, iodine, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1, 2 or 3 carbon atoms can be substituted, or Phenoxy, which is optionally in each case once or twice by fluorine, chlorine, bromine, iodine, alkyl having 1, 2 or 3 carbon atoms or Alkoxy can be substituted by 1, 2 or 3 carbon atoms, means
1 2 31 2 3
oder worin R Wasserstoff bedeutet und R und R gemeinsam eine Methylendioxy-Gruppe oder gemeinsam mit dem sie tragenden Phenylring einen Naphthalinring bedeuten.or in which R is hydrogen and R and R together are one Methylenedioxy group or together with the phenyl ring bearing them mean a naphthalene ring.
In weiterer Ausbilding des Gegenstandes der Hauptanmeldung wurden nun neue pharmakologisch wirksame 5-Methyl-isoxazol-4-carbonsäureamide der Formel IIn a further development of the subject matter of the main application, new pharmacologically active 5-methyl-isoxazole-4-carboxamides have now been introduced of formula I.
NH-RNH-R
(I)(I)
in der R einen ein-, zwei- oder dreikernigen, ungesättigten heterocyclischen Rest mit 3 bis 13 C-Atomen und ein, zwei, drei oder vier Heteroatomen aus der Gruppe Sauerstoff, Schwefel und Stickstoff, wovon höchstens eines von Stickstoff verschieden ist, im Ringsystem bedeutet, das gegebenenfalls mit Alkyl oder Alkoxy mit jeweils ein, zwei oder drei C-Atomen, Halogen, wie Fluor, Chlor, Brom oder Jod, Nitro, Hydroxy, Carboxy, Carbamoyl oder der Oxo-Gruppe vorzugsweise ein-, zwei- oder dreifach substituiert ist, sowie die Additionssalze dieser Verbindungen mit einer physiologisch verträglichen Säure.in which R is a mono-, di- or trinuclear, unsaturated heterocyclic radical with 3 to 13 carbon atoms and one, two, three or four heteroatoms from the group consisting of oxygen, sulfur and nitrogen, of which at most one is different from nitrogen is, in the ring system means that optionally with alkyl or alkoxy each having one, two or three carbon atoms, halogen, such as Fluorine, chlorine, bromine or iodine, nitro, hydroxy, carboxy, carbamoyl or the oxo group, preferably mono-, di- or trisubstituted is, as well as the addition salts of these compounds with a physiologically acceptable acid.
Geeignete Reste R sind beispielsweise Thienyl, Pyridyl, Pyrimidinyl. Pyrazinyl s Pyridazinyl, Imidazolyl, Thiazolyl, Thiazolinyl,Suitable radicals R are, for example, thienyl, pyridyl and pyrimidinyl. Pyrazinyl s pyridazinyl, imidazolyl, thiazolyl, thiazolinyl,
809824/0029 /3 809824/0029 / 3
Oxazolyl, Thiadiazolyl, Benzothiazolyl, Benzoxazolyl, Benzimidazolyl, Chinolyl, Pyrazolyl, Äcridinyl, Tetrazolyl, die gegebenenfalls mit den oben genannten Gruppen substituiert sind.Oxazolyl, thiadiazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, Quinolyl, pyrazolyl, acridinyl, tetrazolyl, the optionally are substituted with the above groups.
Bevorzugt sind Verbindungen der Formel I, worin R einen gegebenenfalls ein-, zwei- oder dreifach mit Halogen, wie Fluor, Chlor, Brom oder Jod substituierten Pyridyl-, einen gegebenenfalls ein-, zwei- oder dreifach mit (C1-C3J-AIlCyI und/oder der Oxo-Gruppe substituierten Pyrimidinyl- oder einen gegebenenfalls mit einer Nitrogruppe substituierten Thiazolylrest darstellt.Preference is given to compounds of the formula I in which R is a pyridyl which is optionally mono-, di- or trisubstituted by halogen, such as fluorine, chlorine, bromine or iodine, or a pyridyl- optionally mono-, di- or trisubstituted by (C 1 -C 3 J -AIlCyI and / or the oxo group-substituted pyrimidinyl or a thiazolyl radical which is optionally substituted by a nitro group.
Das Verfahren zur Herstellung der Verbindungen der Formel I ist dadurch gekennzeichnet, daß man ein 5-Methylisoxazol-4-carbonsäure-Derivat der Formel IIThe process for the preparation of the compounds of the formula I is characterized in that a 5-methylisoxazole-4-carboxylic acid derivative is used of formula II
(II)(II)
in der X ein Halogenatom, vorzugsweise Chlor oder Brom, eine YO- oder ZO-CO-O-Gruppe bedeutet, wobei Y für gegebenenfalls durch Fluor, Chlor, Brom, Jod, Methyl, Äthyl, Methoxy, Äthoxy, Trifluormethyl, Nitro oder Cyan einfach, zweifach oder dreifach substituiertes Phenyl oder für den Acylrest entsprechend der Formel II und Z für (C.-C^)-Alkyl, Benzyl oder Phenyl stehen, mit einem ungesättigten heterocyclischen Amin der Formel IIIin which X is a halogen atom, preferably chlorine or bromine, a YO or ZO-CO-O group, where Y is optionally by fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, ethoxy, Trifluoromethyl, nitro or cyan single, double or triple substituted phenyl or for the acyl radical corresponding to Formula II and Z stand for (C.-C ^) - alkyl, benzyl or phenyl, with an unsaturated heterocyclic amine of the formula III
H2N-R (III)H 2 NR (III)
worin R die zu Formel I angegebene Bedeutung hat, umsetzt.wherein R has the meaning given for formula I, converts.
Die Reaktion wird zweckmäßig in einem Verteilungs- oder Lösungsmittel durchgeführt, das sich gegenüber den Reaktionspartnern indifferent verhält. Hierfür kommen polare Lösungsmittel beispielsweise Nitrile, wie Acetonitril, Äther, wie Diäthyläther,The reaction is conveniently carried out in a partition or solvent carried out, which behaves indifferently towards the reaction partners. Polar solvents are used for this purpose, for example Nitriles, such as acetonitrile, ethers, such as diethyl ether,
80982A/0029 /4 80982A / 0029/4
* 265·* 265
Tetrahydrofuran oder Dioxan und Alkohole, wie Methanol, Äthanol, Propanol oder Isopropanol inf.rage , sowie unpolare Lösungsmittel wie Benzol, Toluol, Cyclohexan.Tetrahydrofuran or dioxane and alcohols such as methanol, ethanol, propanol or isopropanol inf.rage, as well as non-polar solvents such as benzene, toluene, cyclohexane.
Bevorzugtes Herstellungsverfahren ist die Umsetzung des Carbonsäurechlorids der Formel limit einem Amin der Formel III. Dabei ist es vorteilhaft, die Umsetzung in Gegenwart von säurebindenden Mitteln wie Kalium- oder Natriumcarbonat, Alkali- oder Erdalkalihydroxiden oder -alkoholaten, organischen Basen, beispielsweise Triäthylamin, Pyridin, Picolin oder Chinolin oder dem jeweiligen im Überschuß eingesetzten Amin, bei Temperaturen zwischen 0 und 1600C, vorzugsweise zwischen 20 und 800C durchzuführen. Die Reaktionszeiten können wenige Minuten bis zu zwei Stunden betragen .The preferred production process is the reaction of the carboxylic acid chloride of the formula limit with an amine of the formula III. It is advantageous to carry out the reaction in the presence of acid-binding agents such as potassium or sodium carbonate, alkali or alkaline earth metal hydroxides or alcoholates, organic bases, for example triethylamine, pyridine, picoline or quinoline or the respective amine used in excess, at temperatures between 0 and 160 ° C., preferably between 20 and 80 ° C. The reaction times can range from a few minutes to two hours.
Die als Ausgangsstoffe benötigten 5-Methylisoxazol-4-carbonsäure-Derivate der Formel II werden entsprechend DRP 634 286 durch Umsetzung von Äthoxymethylidenacetessigester mit Hydroxylamin zum 5-Methylisoxazol-4-carbonsäureester, saures Verseifen des so erhaltenen Esters, vorzugsweise mit einem Gemisch aus Eisessig und konzentrierter Salzsäure im Verhältnis 1:1, zur 5-Methylisoxazol-4-carbonsäure, überführen dieser Carbonsäure nach üblichen Methoden in die Carbonsäurehalogenide, Ester oder gemischten Anhydride, erhalten. Als Carbonsäure-Derivate der Formel II kommen beispielsweise in Betracht 5-Methylisoxazol-4-carbonsäurephenylester, insbesondere 2,4-Dichlorphenylester und 2,4,6-Trichlorphenylester, weiterhin 5- Methylisoxazol-4-carbonsäureanhydride, insbesondere solche, in denen X den Methoxycarbonyloxyrest, Äthoxycarbonyloxyrest, Phenoxcarbonyloxyrest oder Benzyloxycarbonyloxyrest bedeuten .The 5-methylisoxazole-4-carboxylic acid derivatives required as starting materials of formula II are according to DRP 634 286 by reacting Äthoxymethylidenacetoessigester with hydroxylamine to the 5-methylisoxazole-4-carboxylic acid ester, acidic saponification of the ester thus obtained, preferably with a mixture of glacial acetic acid and concentrated hydrochloric acid in a ratio of 1: 1 to 5-methylisoxazole-4-carboxylic acid, convert this carboxylic acid by customary methods into the carboxylic acid halides, esters or mixed Anhydrides. Suitable carboxylic acid derivatives of the formula II are, for example, 5-methylisoxazole-4-carboxylic acid phenyl ester, in particular 2,4-dichlorophenyl ester and 2,4,6-trichlorophenyl ester, furthermore 5-methylisoxazole-4-carboxylic acid anhydrides, in particular those in which X denotes the methoxycarbonyloxy radical, ethoxycarbonyloxy radical, phenoxcarbonyloxy radical or benzyloxycarbonyloxy radical .
Die erfindungsgemäßen Verbindungen gemäß Formel I sind in der Regel gut kristallisierbare Substanzen. Sie können mit physiologisch verträglichen Säuren in Säureadditionssalze übergeführt werden. Hierfür kommen insbesondere starke Säuren wie Halogenwasserstoff säuren, insbesondere Salzsäure, Schwefel-, Phosphor-, p-Toluolsulfon-, Methansulf on- und Cyclohexylarnidosulfonsäure infrage.The compounds according to the invention according to formula I are generally easily crystallizable substances. You can with physiological compatible acids are converted into acid addition salts. Strong acids such as hydrogen halide are particularly useful for this purpose acids, in particular hydrochloric acid, sulfuric, phosphoric, p-toluenesulphonic, methanesulphonic and cyclohexylarnidosulphonic acid in question.
809824/0029809824/0029
Die 5-Methyl-isoxazol-4-carhonsäureamide der Formel I haben wertvolle pharmakologische Eigenschaften. Insbesondere zeigen sie antiphlogistxsche, antipyretische und analgetische Eigenschaften. Ihre Toxizität ist gering, die Magenverträglichkeit gut.The 5-methyl-isoxazole-4-carhonic acid amides of the formula I have valuable pharmacological properties. In particular, they show anti-inflammatory, anti-pyretic and analgesic properties. Their toxicity is low and gastric tolerance is good.
80982A/002980982A / 0029
Β"*" 26bS009 Β "*" 26bS009
HerstellungsbeispieleManufacturing examples
1. N-(5-Brom-2-pyridyl)-5-Methylisoxazol-4-carboxamid der Formel1. N- (5-Bromo-2-pyridyl) -5-methylisoxazole-4-carboxamide of the formula
a) 0,1 MoI 2-Amino-5-brompyridin der Formel III (17,3 g) gelöst in 200 ml Tetrahydrofuran, werden bei Raumtemperatur tropfenweise mit einer Lösung von 0,05 Mol 5-Methylisoxazol-4-carbonsäurechlorid der Formel II (7,3 g) in 20 ml Tetrahydrofuran unter Rühren versetzt. Nach weiteren 10 Minuten Rühren filtriert man den ausgefallenen Niederschlag ab und dampft das Filtrat unter vermindertem Druck zur Trockene ein. Man erhält 13,6 g (96 % der Theorie) eines farblosen Kristallinen Produktes; Schmelzpunkt aus Äthanol: 168 - 1690C,a) 0.1 mol of 2-amino-5-bromopyridine of the formula III (17.3 g) dissolved in 200 ml of tetrahydrofuran are added dropwise at room temperature with a solution of 0.05 mol of 5-methylisoxazole-4-carboxylic acid chloride of the formula II (7.3 g) in 20 ml of tetrahydrofuran were added with stirring. After stirring for a further 10 minutes, the deposited precipitate is filtered off and the filtrate is evaporated to dryness under reduced pressure. 13.6 g (96% of theory) of a colorless crystalline product are obtained; Melting point from ethanol: 168 - 169 0 C,
b) 0,1 Mol 2-Amino-5-brompyridin der Formel III (17,3 g) und 0,1 Mol C,4-Dichlor)phenyl-5-methylisoxazol-4-carboxylat der Formel II (27,2 g) gelöst in 150 ml Tetrahydrofuran, werden 75 Minuten unter Rückfluß erhitzt. Man bringt anschließend die Lösung unter vermindertem Druck zurTrockene und digeriert die öligen Rückstand mit Cyclohexan.b) 0.1 mol of 2-amino-5-bromopyridine of the formula III (17.3 g) and 0.1 mol of C, 4-dichloro) phenyl 5-methylisoxazole-4-carboxylate of the formula II (27.2 g) dissolved in 150 ml of tetrahydrofuran Heated under reflux for 75 minutes. The solution is then brought to dryness under reduced pressure digested the oily residue with cyclohexane.
Nach Dekantieren wird der Rückstand in 300 ml Chloroform gelöst und mit 200 ml 2 η Salzsäure geschüttelt.After decanting, the residue is dissolved in 300 ml of chloroform and shaken with 200 ml of 2N hydrochloric acid.
Die Chloroformphase wird mit Wasser neutral gewaschen, getrocknet und unter vermindertem Druck zur Trockene gebracht. Man erhält 21,4 g (76 % der Theorie) eines kristallinen Produktes; Schmelzpunkt nach ümkristallisation aus Äthanol: 168 bis 169°C.The chloroform phase is washed neutral with water, dried and brought to dryness under reduced pressure. 21.4 g (76% of theory) of a crystalline product are obtained; Melting point after recrystallization from ethanol: 168 to 169 ° C.
c) 0,1 Mol 2-Amino-5-brompyridin der Formel II (17,3 g) und 0,1 Mol Benzyloxycarbonyl-5-methylisoxazol-4-carboxylat derc) 0.1 mol of 2-amino-5-bromopyridine of the formula II (17.3 g) and 0.1 mol of benzyloxycarbonyl-5-methylisoxazole-4-carboxylate
.Formel II (26,1 g), gelöst in 200 ml Tetrahydrofuran, werden 90 Minuten unter Rückfluß erhitzt. Man bringt die Mischung unter vermindertem Druck zur Trockene und digeriert den Rück-.Formula II (26.1 g) dissolved in 200 ml of tetrahydrofuran Heated under reflux for 90 minutes. The mixture is brought to dryness under reduced pressure and the residue is digested
809824/0029809824/0029
stand mit Cyclohexan. Nach Dekantieren wird der Rückstand in 300 ml Chloroform gelöst und mit 200 ml 2 η Salzsäure geschüttelt. Die Chloroformphase wird mit Wasser neutral gewaschen, getrocknet und unter vermindertem Druck zur Trockene gebracht. Man erhältso 20,6 g (73 % der Theorie) eines kristallinen Produktes; Schmelzpunkt nach Umkristallisieren aus Äthanol 168 bis 1690C.stood with cyclohexane. After decanting, the residue is dissolved in 300 ml of chloroform and shaken with 200 ml of 2 η hydrochloric acid. The chloroform phase is washed neutral with water, dried and brought to dryness under reduced pressure. 20.6 g (73% of theory) of a crystalline product are thus obtained; Melting point after recrystallization from ethanol 168 to 169 0 C.
Nach dem vorstehend angegebenen Verfahren erhält man durch Umsetzung vonAccording to the procedure given above, reaction is obtained from
5-Methylisoxazol-4-carbonsäurechlorid der Formel II mit dem 3-Aminopyridin der Formel III das N-(3-Pyridyl)-5-methylisoxazol-4-carboxamid-hydrochlorid der Formel I.5-methylisoxazole-4-carboxylic acid chloride of the formula II with the 3-aminopyridine of the formula III is N- (3-pyridyl) -5-methylisoxazole-4-carboxamide hydrochloride of formula I.
5-Methylisoxazol-4-carbonsäurechlorid der Formel II mit dem 2-Amino-4-methylthiazol der Formel IIIdas N-(4-Methyl-2-thiazolyl) -B-methylisoxazol^-carboxamid-hydrochlorid der Formel I.5-methylisoxazole-4-carboxylic acid chloride of the formula II with the 2-Amino-4-methylthiazole of the formula III the N- (4-methyl-2-thiazolyl) -B-methylisoxazole ^ -carboxamide hydrochloride der Formula I.
(2,4-Dichlor)phenyl-5-methylisoxazol-4-carboxylat der Formel II mit dem 2-Amino-4-pyridin der Formel III das N-(4-Pyridyl-5-methylisoxazol-4~carboxamid-hydrochlorid der Formel I.(2,4-dichloro) phenyl 5-methylisoxazole-4-carboxylate of the formula II with the 2-amino-4-pyridine of the formula III, the N- (4-pyridyl-5-methylisoxazole-4-carboxamide hydrochloride of formula I.
5-Methylisoxazol-4-carbonsäurechlorid der Formel II mit dem 4-Aminoantipyrin der Formel III das N-(4-Antipyrinyl)-5-methylisoxazol-4-carboxamid-hydrochlorid der Formel I.5-methylisoxazole-4-carboxylic acid chloride of the formula II with the 4-aminoantipyrine of the formula III the N- (4-antipyrinyl) -5-methylisoxazole-4-carboxamide hydrochloride of formula I.
(2,4-Dichlor)phenyl-5-methylisoxazol-4-carboxylat der Formel II mit dem 2-Amino-4-chlorbenzothiazol der Formel III das N- (4-Chlor-2-benzothiazolyl) -S-methylisoxazol^-carboxamid der Formel I.(2,4-dichloro) phenyl 5-methylisoxazole-4-carboxylate of the formula II with the 2-amino-4-chlorobenzothiazole of the formula III the N- (4-chloro-2-benzothiazolyl) -S-methylisoxazole ^ -carboxamide of formula I.
(2,4-Dichlor)phenyl-5-methylisoxazol-4-carboxylat der Formel II mit dem 2-Aminopyridin der Formel III das N-(2-Pyridyl)-5-methylisoxazol-4-carboxamid-hydrochlorid der Formel I.(2,4-dichloro) phenyl 5-methylisoxazole-4-carboxylate of the formula II with the 2-aminopyridine of the formula III, the N- (2-pyridyl) -5-methylisoxazole-4-carboxamide hydrochloride of formula I.
80982A/ÜÜ2980982A / ÜÜ29
5-Methylisoxazol-4-carbonsäurechlorid der Formel II mit dem 2-Ämino-5-brompyridin der Formel Illdas N-(5-Brom-2~pyridyl)-5-methylisoxazol-4-carboxamid der Formel I.5-methylisoxazole-4-carboxylic acid chloride of the formula II with the 2-amino-5-bromopyridine of the formula III the N- (5-bromo-2- pyridyl) -5-methylisoxazole-4-carboxamide of formula I.
5-Methylisoxazol-4-carbonsäurechlorid der Formel II mit dem 6-Amino-1 /-3-dimethyl-2,4~dioxo--1 ,2 ,3 , 4-tetrahydropyrimidin der Formel III das N-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinyl)-5-methylisoxazol-4-carboxamid der Formel I,5-methylisoxazole-4-carboxylic acid chloride of the formula II with the 6-amino-1 / -3-dimethyl-2,4 ~ dioxo-1 , 2 , 3, 4-tetrahydropyrimidine of the formula III the N- (1,3- Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinyl) -5-methylisoxazole-4-carboxamide of the formula I,
5-Methylisoxazol-4-carbonsäurechlorid der Formel II mit dem 2-Amino-5-nitrothiazol der Formel III das N-(5-Nitro-2-thiazolyl)-5-methylisoxazol-4-carboxamid-hydrochlorid der Formel5-methylisoxazole-4-carboxylic acid chloride of the formula II with the 2-amino-5-nitrothiazole of the formula III the N- (5-nitro-2-thiazolyl) -5-methylisoxazole-4-carboxamide hydrochloride the formula
(2,4-Dichlor)phenyl-5-methylisoxazol-4-carboxylat der Formel(2,4-dichloro) phenyl 5-methylisoxazole-4-carboxylate of the formula
II mit dem 2-Amino-2-thiazolin der Formel III das N-(2-Thiazolin-2-yl)-5-methylisoxazol-4-carboxamid-hydrochlorid der Formel I.II with the 2-amino-2-thiazoline of the formula III is N- (2-thiazolin-2-yl) -5-methylisoxazole-4-carboxamide hydrochloride of formula I.
Benzyloxycarbonyl-5-methylisoxazol-4-carboxylat der Formel II mit dem 2-Amino-5-(p-nitrophenyl)sulfonyl-thiazol der FormelBenzyloxycarbonyl-5-methylisoxazole-4-carboxylate of the formula II with the 2-amino-5- (p-nitrophenyl) sulfonyl-thiazole of the formula
III das N-/5- (p-Nitrophenyl) sulfonyl~2-thiazolyl7-4-carboxamid der Formel I.III the N- / 5- (p-nitrophenyl) sulfonyl ~ 2-thiazolyl7-4-carboxamide of formula I.
Benzyloxycarbonyl-5-methylisoxazol-4-carboxylat der Formel II mit dem 2-Aminobenzothiazol der Formel III das N-(2-Benzothiazolyl)-5-methylisoxazol-4-carboxamid-hydrochlorid der FormelBenzyloxycarbonyl-5-methylisoxazole-4-carboxylate of the formula II with the 2-aminobenzothiazole of the formula III the N- (2-benzothiazolyl) -5-methylisoxazole-4-carboxamide hydrochloride the formula
(2,4-Dichlor)phenyl-5-methylisoxazol-4~carboxylat der Formel II mit dem 2-Amino-benzimidazol der Formel in das N-(2-Benzimidazolyl) -S-methylisoxazol^-carboxamid-hydrochlorid der Formel I.(2,4-Dichloro) phenyl-5-methylisoxazole-4- carboxylate of the formula II with the 2-amino-benzimidazole of the formula into the N- (2-benzimidazolyl) -S-methylisoxazole ^ -carboxamide hydrochloride of formula I.
Benzyloxycarbonyl-5-methylisoxazol-4-carboxylat der Formel IIBenzyloxycarbonyl-5-methylisoxazole-4-carboxylate of the formula II
mit dem 2-Amino-5-chlorbenzoxazol der Formel III das N-(5-with the 2-amino-5-chlorobenzoxazole of the formula III the N- (5-
chlor-2-benzoxazolyl)-5-methylisoxazol-4-carboxamid der Formel I.chloro-2-benzoxazolyl) -5-methylisoxazole-4-carboxamide of the formula I.
809824/0029809824/0029
*r . . 265&0Q9* r . . 265 & 0Q9
(2,4-Dichlor)phenyl-5-methylisoxazol-4-carboxylat der formel Ii mit dem 2~Ämino-5-nitropyridin der Formel HI das N-(5-Nitro-2-pyridy2}-5-methylisoxazol-4-carboxamid der Formel I.(2,4-dichloro) phenyl 5-methylisoxazole-4-carboxylate of formula II with the 2 ~ amino-5-nitropyridine of the formula HI the N- (5-nitro-2-pyridy2} -5-methylisoxazole-4-carboxamide of formula I.
Benzyloxycarbonyl-S-methylisoxazol^-carboxylat der Formel II mit dem 2-Amino-3,5-dibrompyridin der Formel III das N-(3,5-Dibrom-2-pyridyl)-5-methylisoxazol-4-carboxamid der Formel I.Benzyloxycarbonyl-S-methylisoxazole ^ -carboxylate of the formula II with the 2-amino-3,5-dibromopyridine of the formula III, the N- (3,5-dibromo-2-pyridyl) -5-methylisoxazole-4-carboxamide of formula I.
Tabelle I; S-Methylisoxazol-^-carbonsäureciinide der Formel ITable I; S-methylisoxazole - ^ - carbonsäureciinide of the formula I.
Nr.No.
*-\_7 x HCl* - \ _ 7 x HCl
χ HClχ HCl
CH,CH,
X HClX HCl
SchmelzpunktCMelting point C.
250-252 (Zers.) 221-223 210-215 (Zers.)250-252 (decomp.) 221-223 210-215 (decomp.)
218-220218-220
Cl ,Cl,
χ HClχ HCl
239-242239-242
9824/00299824/0029
265S009265S009
Fortsetzung TabelleContinuation table
Schmelzpunkt CMelting point C.
J/J /
-CH3 -CH 3
CH-168-169 CH-168-169
χ HClχ HCl
χ HClχ HCl
.Η O.Η O
χ HClχ HCl
χ HClχ HCl
ClCl
26O-265 (Zers.) I85-I87 (Zers.)26O-265 (decomp.) I85-I87 (decomp.)
234-237 (Zers.) 23O-I35 (Zers.) 170-175 (Zers.) 202-203234-237 (decomp.) 23O-I35 (decomp.) 170-175 (decomp.) 202-203
I65-I67I65-I67
80982 4/0029 /11 80982 4/0029 / 11
Claims (5)
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762655009 DE2655009A1 (en) | 1976-12-04 | 1976-12-04 | ISOXAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEANS CONTAINING THESE COMPOUNDS |
| CH1393477A CH608498A5 (en) | 1976-12-04 | 1977-11-15 | Process for the preparation of novel 5-methylisoxazole- 4-carboxamides |
| NL7713151A NL7713151A (en) | 1976-12-04 | 1977-11-29 | ISOXAZOLE DERIVATIVES, THEIR PREPARATION AND MEDICINAL PRODUCTS WITH THESE SUBSTANCES. |
| LU78628A LU78628A1 (en) | 1976-12-04 | 1977-12-02 | |
| IE245277A IE46269B1 (en) | 1976-12-04 | 1977-12-02 | Isoxazole derivatives,process for their manufacture and preparations containing these compounds |
| IT3035277A IT1126219B (en) | 1976-12-04 | 1977-12-02 | ISOSSAZOLIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEANS CONTAINING SUCH COMPOUNDS |
| GB5034777A GB1596383A (en) | 1976-12-04 | 1977-12-02 | Isoxazole derivatives process for their manufacture and preparations containing these compounds |
| AT866377A AT362366B (en) | 1976-12-04 | 1977-12-02 | METHOD FOR PRODUCING NEW 5-METHYL- -ISOXAZOLE-4-CARBONIC ACID AMIDES AND THEIR SALTS |
| CA292,302A CA1102341A (en) | 1976-12-04 | 1977-12-02 | Isoxazole derivatives, process for their manufacture and agents containing these compounds |
| DK538677A DK538677A (en) | 1976-12-04 | 1977-12-02 | ISOXAZOLE DERIVATIVES PROCEDURE FOR THEIR PREPARATION AND MEASURES CONTAINING THESE COMPOUNDS |
| JP14562277A JPS5371070A (en) | 1976-12-04 | 1977-12-03 | Isooxazole derivative and process for preparing same |
| BE183170A BE861503R (en) | 1976-12-04 | 1977-12-05 | NEW ISOXAZOLES DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS |
| FR7736547A FR2372830A2 (en) | 1976-12-04 | 1977-12-05 | ISOXAZOLE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762655009 DE2655009A1 (en) | 1976-12-04 | 1976-12-04 | ISOXAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEANS CONTAINING THESE COMPOUNDS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE2655009A1 true DE2655009A1 (en) | 1978-06-15 |
| DE2655009C2 DE2655009C2 (en) | 1990-03-29 |
Family
ID=5994666
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19762655009 Granted DE2655009A1 (en) | 1976-12-04 | 1976-12-04 | ISOXAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEANS CONTAINING THESE COMPOUNDS |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5371070A (en) |
| AT (1) | AT362366B (en) |
| BE (1) | BE861503R (en) |
| CA (1) | CA1102341A (en) |
| CH (1) | CH608498A5 (en) |
| DE (1) | DE2655009A1 (en) |
| DK (1) | DK538677A (en) |
| FR (1) | FR2372830A2 (en) |
| GB (1) | GB1596383A (en) |
| IE (1) | IE46269B1 (en) |
| IT (1) | IT1126219B (en) |
| LU (1) | LU78628A1 (en) |
| NL (1) | NL7713151A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0016277A1 (en) * | 1978-11-03 | 1980-10-01 | American Cyanamid Company | 2-Carbonyl-3-hydroxy-alkenonitriles, their use as anti-arthritic agents and processes for their preparation |
| EP0012435A3 (en) * | 1978-12-16 | 1980-10-01 | Hoechst Aktiengesellschaft | Isoxazole derivatives, process for their preparation, medicines containing them and intermediates required in this process |
| EP0035285A3 (en) * | 1979-08-17 | 1981-10-14 | American Cyanamid Company | Novel isoxazole carboxylic acid phenyl esters, pharmaceutical compositions containing certain of said esters, and process for preparing said esters |
| DE3247454A1 (en) * | 1982-12-22 | 1984-06-28 | Laboratorios Bago S.A., Buenos Aires | Substituted 3-phenyl-5-methylisoxazole-4-carboxanilides, process for their preparation and pharmaceutical compositions containing these compounds |
| EP0378111A1 (en) * | 1989-01-09 | 1990-07-18 | ZAMBON GROUP S.p.A. | Isoxazole derivatives having anti-serotonin activity, their preparation process and compositions containing them |
| US4983619A (en) * | 1986-08-08 | 1991-01-08 | Lilly Industries Limited | Pharmaceutical compounds |
| EP0440503A1 (en) * | 1990-02-02 | 1991-08-07 | Syntex (U.S.A.) Inc. | 4-Isoxazolecarboxamide derivatives |
| LT3416B (en) | 1990-05-18 | 1995-09-25 | Hoechst Ag | Isoxazole-4-carboxamides, hydroxyalkylidene-cyanoacetamides, drugs containing these compounds and method for the preparation of such drugs |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8619432D0 (en) * | 1986-08-08 | 1986-09-17 | Lilly Industries Ltd | Pharmaceutical compounds |
| US4935434A (en) * | 1988-01-26 | 1990-06-19 | Bristol-Myers Company | Antiarthritic isoxazole-4-carboxamides |
| DE59010701D1 (en) * | 1990-05-18 | 1997-05-22 | Hoechst Ag | ISOXAZOLE-4-CARBONIC ACID AMIDES AND HYDROXYALKYLIDES-CYANACETIC ACID AMIDES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND THE USE THEREOF |
| US7338956B2 (en) * | 2002-08-07 | 2008-03-04 | Sanofi-Aventis Deutschland Gmbh | Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals |
| CN103772376B (en) * | 2012-10-24 | 2017-01-11 | 中国医学科学院医药生物技术研究所 | Substituted benzo-1,3-miscellaneous azole compound and preparation method and application thereof |
| TWI714528B (en) * | 2014-05-14 | 2021-01-01 | 瑞士商諾華公司 | Carboxamide derivatives |
| WO2015173656A1 (en) * | 2014-05-14 | 2015-11-19 | Novartis Ag | Carboxamide derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2208351B2 (en) * | 1971-03-01 | 1976-09-16 | Warner-Lambert Co., Morris Plains, N.J. (V.StA.) | 4-HYDROXY-3- (3-ISOXAZOLOCARBAMOYL) -2H-1,2-BENZOTHIAZINE-1,1-DIOXIDES AND THE METHOD FOR THEIR PRODUCTION |
-
1976
- 1976-12-04 DE DE19762655009 patent/DE2655009A1/en active Granted
-
1977
- 1977-11-15 CH CH1393477A patent/CH608498A5/en not_active IP Right Cessation
- 1977-11-29 NL NL7713151A patent/NL7713151A/en not_active Application Discontinuation
- 1977-12-02 LU LU78628A patent/LU78628A1/xx unknown
- 1977-12-02 DK DK538677A patent/DK538677A/en unknown
- 1977-12-02 AT AT866377A patent/AT362366B/en not_active IP Right Cessation
- 1977-12-02 IT IT3035277A patent/IT1126219B/en active
- 1977-12-02 IE IE245277A patent/IE46269B1/en unknown
- 1977-12-02 CA CA292,302A patent/CA1102341A/en not_active Expired
- 1977-12-02 GB GB5034777A patent/GB1596383A/en not_active Expired
- 1977-12-03 JP JP14562277A patent/JPS5371070A/en active Pending
- 1977-12-05 BE BE183170A patent/BE861503R/en not_active IP Right Cessation
- 1977-12-05 FR FR7736547A patent/FR2372830A2/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2208351B2 (en) * | 1971-03-01 | 1976-09-16 | Warner-Lambert Co., Morris Plains, N.J. (V.StA.) | 4-HYDROXY-3- (3-ISOXAZOLOCARBAMOYL) -2H-1,2-BENZOTHIAZINE-1,1-DIOXIDES AND THE METHOD FOR THEIR PRODUCTION |
Non-Patent Citations (3)
| Title |
|---|
| Arzneimittelforsch. 30, 1980, S. 1314-1325, 33, 1983, S. 1555-1569, 23, 1973, S. 1690-1695 * |
| Drugs of the Future, Vol. III, Nr. 8, 1978, S. 615-617 * |
| Med. Klinik, 77, 1982, 14, 15 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0016277A1 (en) * | 1978-11-03 | 1980-10-01 | American Cyanamid Company | 2-Carbonyl-3-hydroxy-alkenonitriles, their use as anti-arthritic agents and processes for their preparation |
| EP0012435A3 (en) * | 1978-12-16 | 1980-10-01 | Hoechst Aktiengesellschaft | Isoxazole derivatives, process for their preparation, medicines containing them and intermediates required in this process |
| EP0035285A3 (en) * | 1979-08-17 | 1981-10-14 | American Cyanamid Company | Novel isoxazole carboxylic acid phenyl esters, pharmaceutical compositions containing certain of said esters, and process for preparing said esters |
| DE3247454A1 (en) * | 1982-12-22 | 1984-06-28 | Laboratorios Bago S.A., Buenos Aires | Substituted 3-phenyl-5-methylisoxazole-4-carboxanilides, process for their preparation and pharmaceutical compositions containing these compounds |
| US4983619A (en) * | 1986-08-08 | 1991-01-08 | Lilly Industries Limited | Pharmaceutical compounds |
| EP0378111A1 (en) * | 1989-01-09 | 1990-07-18 | ZAMBON GROUP S.p.A. | Isoxazole derivatives having anti-serotonin activity, their preparation process and compositions containing them |
| EP0440503A1 (en) * | 1990-02-02 | 1991-08-07 | Syntex (U.S.A.) Inc. | 4-Isoxazolecarboxamide derivatives |
| LT3416B (en) | 1990-05-18 | 1995-09-25 | Hoechst Ag | Isoxazole-4-carboxamides, hydroxyalkylidene-cyanoacetamides, drugs containing these compounds and method for the preparation of such drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5371070A (en) | 1978-06-24 |
| IE46269B1 (en) | 1983-04-20 |
| CH608498A5 (en) | 1979-01-15 |
| FR2372830A2 (en) | 1978-06-30 |
| DE2655009C2 (en) | 1990-03-29 |
| IT1126219B (en) | 1986-05-14 |
| LU78628A1 (en) | 1978-07-11 |
| BE861503R (en) | 1978-06-05 |
| CA1102341A (en) | 1981-06-02 |
| GB1596383A (en) | 1981-08-26 |
| AT362366B (en) | 1981-05-11 |
| NL7713151A (en) | 1978-06-06 |
| FR2372830B2 (en) | 1980-06-20 |
| DK538677A (en) | 1978-06-05 |
| ATA866377A (en) | 1980-10-15 |
| IE46269L (en) | 1978-06-04 |
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