CH623044A5 - Process for the preparation of novel anilino-2-oxazolines - Google Patents
Process for the preparation of novel anilino-2-oxazolines Download PDFInfo
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- CH623044A5 CH623044A5 CH1516475A CH1516475A CH623044A5 CH 623044 A5 CH623044 A5 CH 623044A5 CH 1516475 A CH1516475 A CH 1516475A CH 1516475 A CH1516475 A CH 1516475A CH 623044 A5 CH623044 A5 CH 623044A5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
- C07D239/96—Two oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/28—Nitrogen atoms not forming part of a nitro radical
Description
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Anilino-2-oxazoline und ihrer pharmazeutisch annehmbaren Salze. The invention relates to a process for the preparation of new anilino-2-oxazolines and their pharmaceutically acceptable salts.
Es wurde gefunden, dass gewisse neue Anilino-2-oxazoli-ne, die als Substituenten eine Hydroxylpolyhalogenisopropyl- io gruppe enthalten, eine wertvolle therapeutische Wirkung, insbesondere eine wertvolle antihypertensive Wirkung aufweisen. It has been found that certain new anilino-2-oxazolines, which contain a hydroxylpolyhalogenisopropyl-io group as substituents, have a valuable therapeutic effect, in particular a valuable antihypertensive effect.
Die neuen Anilino-2-oxazoline entsprechen der allgemeinen Formel 15 The new anilino-2-oxazolines correspond to the general formula 15
cf3 cf3
cfci2 cfci2
1 1
1 1
-c-OH , -c-OH,
1 1
1 1
-c-OH 1 -c-OH 1
1 1
cf2c1 cf2c1
1 1
cf2ci cf2ci cf2ci cf2ci
1 1
1 1
-c-OH 1 -c-OH 1
oder or
1 1
cf2c1 cf2c1
xso-ch2-ch2 xso-ch2-ch2
Der Ausdruck «Halogen» umfasst Fluor, Chlor, Brom und Jod. The term "halogen" includes fluorine, chlorine, bromine and iodine.
In der mit Rf bezeichneten Gruppe kann die Komponente -CY3 beispielsweise -CH3 oder die Gruppe CFY2, z.B. -CFC12, CF2C1 und CF3, sein. Repräsentativ für Rf sind die Gruppen In the group denoted by Rf the component -CY3 can be, for example, -CH3 or the group CFY2, e.g. -CFC12, CF2C1 and CF3. The groups are representative of Rf
CF3 CF3
I I.
-C-OH und insbesondere -C-OH and in particular
I I.
CF2H CF2H
cf3 cf3
I I.
-c-oh. -c-oh.
I I.
CF3 CF3
25 Der Ausdruck «pharmazeutisch annehmbare Salze» wird in seinem normalen bekannten Sinn gebraucht und umfasst pharmazeutisch unbedenkliche Additionssalze sowohl von organischen als auch anorganischen Säuren, z.B. Maleinsäure, Phthalsäure, Bernsteinsäure, Weinsäure, Zitronensäure, Apfel-30 säure, Zimtsäure, Schwefelsäure, Salzsäure, Bromwasserstoffsäure und Phosphorsäure. 25 The term "pharmaceutically acceptable salts" is used in its normal well-known sense and includes pharmaceutically acceptable addition salts of both organic and inorganic acids, e.g. Maleic acid, phthalic acid, succinic acid, tartaric acid, citric acid, malic acid, cinnamic acid, sulfuric acid, hydrochloric acid, hydrobromic acid and phosphoric acid.
R ist vorzugsweise Methyl sowie X2 und X6 vorteilhaft Niederalkyl. R is preferably methyl and X2 and X6 are advantageously lower alkyl.
Als Beispiel für die bevorzugten Verbindungen gemäss der 35 Erfindung wird 2-[4-(Hexafluor-2-hydroxy-2-propyl)-N--methylanilino]-2- oxazolin gen annt. An example of the preferred compounds according to the invention is 2- [4- (hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-oxazoline gene.
Substituierte Anilino-2-oxazoline werden in den U.S. Patentschriften Nr. 3 453 284,3 499 083 und 3 499 084 und in den belgischen Patentschriften 704 392,704 393 und 704 396 be-40 schrieben. In diesen Oxazolinen des Standes der Technik ist jedoch das Stickstoffatom des Anilins unsubstituiert und der entscheidende para-Polyfluorisopropylphenylsubstituent wird nicht nahegelegt. Die Verbindungen werden zudem als auf das Zentralnervensystem wirkende Beruhigungsmittel beschrie-45 ben. Ferner sind Polyfluorisopropyl-substituierte Aniline, zum Teil mit blutdrucksenkender Wirkung, beschrieben worden (z.B. U.S.-Patentschriften Nr. 3 405 177; 3 541 152; 3 594418; 3 772 273 und Gilbert, J. Org. Chem. Bd. 30[1965]1001). Substituted anilino-2-oxazolines are described in U.S. Patent Nos. 3,453,284.3,499,083 and 3,499,084 and in Belgian Patents 704,392,704,393 and 704,396 be-40. In these prior art oxazolines, however, the nitrogen atom of the aniline is unsubstituted and the crucial para-polyfluoroisopropylphenyl substituent is not suggested. The compounds are also described as sedatives that act on the central nervous system. Furthermore, polyfluoroisopropyl-substituted anilines, some with an antihypertensive effect, have been described (for example US Pat. Nos. 3,405,177; 3,541,152; 3,596,418; 3,772,273 and Gilbert, J. Org. Chem. Vol. 30 [1965 ] 1001).
Das erfindungsgemässe Verfahren zur Herstellung der so neuen Anilino-2-oxazoline der allgemeinen Formel I ist dadurch gekennzeichnet, dass man ein N-Phenylharnstoffderivat der allgemeinen Formel The process according to the invention for the preparation of the new anilino-2-oxazolines of the general formula I is characterized in that an N-phenylurea derivative of the general formula
N.CO.NH CH .CH .Q N.CO.NH CH .CH .Q
(IV) (IV)
O-CH, O-CH,
65 worin R, Rf, X2, X5 und X6 die oben angegebene Bedeutung haben und Qx eine bei den angewendeten Reaktionsbedingungen als HQt austretende Gruppe ist, einer intramolekularen Kondensation unterwirft und die Verbindung der For- 65 wherein R, Rf, X2, X5 and X6 have the meaning given above and Qx is a group which emerges as HQt under the reaction conditions used, is subjected to intramolecular condensation and the compound of the form
623 044 623 044
4 4th
mei I in freier Form oder als pharmazeutisch annehmbares Säureadditionssalz isoliert. Qt ist z.B. eine Sulfonsäureester-gruppe oder ein Halogenatom, vorzugsweise Chlor. Eine so erhaltene Verbindung der Formel I, in der R Wasserstoff ist, wird gewünschtenfalls nach den Methoden der N-Alkylierung in eine Verbindung der Formel I, in der R Niederalkyl, Alkoxy-Niederalkyl oder Dialkoxy-Niederalkyl bedeutet, umgewandelt und das hiebei gebildete Oxazolin der allgemeinen Formel I in freier Form oder als pharmazeutisch annehmbares Säureadditionssalz isoliert. mei I isolated in free form or as a pharmaceutically acceptable acid addition salt. Qt is e.g. a sulfonic acid ester group or a halogen atom, preferably chlorine. A compound of the formula I thus obtained in which R is hydrogen is, if desired, converted into a compound of the formula I in which R is lower alkyl, alkoxy-lower alkyl or dialkoxy-lower alkyl by the methods of N-alkylation, and the oxazoline formed thereby of general formula I isolated in free form or as a pharmaceutically acceptable acid addition salt.
Die Kondensation kann in typischer Weise durchgeführt werden, indem der N-Phenylharnstoff auf eine Temperatur, die zweckmässig im Bereich von 50° bis 100°C liegt, in einem wässerigen Medium, z.B. einem wässerigen alkoholischen Medium, das mehr als etwa 10% Wasser enthält, erhitzt wird. The condensation can typically be carried out by heating the N-phenylurea to an appropriate temperature in the range of 50 ° to 100 ° C in an aqueous medium, e.g. an aqueous alcoholic medium containing more than about 10% water.
Die gegebenenfalls vorgesehene N-Alkylierung kann in üblicher Weise durchgeführt werden, beispielsweise durch Umsetzen des geeigneten Alkylhalids oder Alkylsulfonatesters mit der Verbindung der Formel I. The N-alkylation which may be provided can be carried out in a customary manner, for example by reacting the suitable alkyl halide or alkyl sulfonate ester with the compound of the formula I.
Das Ausgangsmaterial der allgemeinen Formel IV kann in an sich bekannter Weise hergestellt werden, z.B. durch Umsetzen von aromatischen Aminen der allgemeinen Formel mit einem reaktionsfähigen Derivat einer Carbaminsäure der allgemeinen Formel The starting material of the general formula IV can be prepared in a manner known per se, e.g. by reacting aromatic amines of the general formula with a reactive derivative of a carbamic acid of the general formula
Qx • CH2 • CH2 • NH • COOH, Qx • CH2 • CH2 • NH • COOH,
worin R, Rf, Qa, X2, X5 und X6 die oben angegebenen Bedeutungen haben, und Isolieren des hiebei gebildeten Phenyl-harnstoffs der allgemeinen Formel IV. wherein R, Rf, Qa, X2, X5 and X6 have the meanings given above, and isolating the phenylurea of the general formula IV formed thereby.
Vorzugsweise ist das reaktionsfähige Derivat der Carbaminsäure ein Isocyanat der Formel qi • ch2 • ch2 - nco . The reactive derivative of carbamic acid is preferably an isocyanate of the formula qi • ch2 • ch2 - nco.
Zweckmässig wird die Reaktion in einem inerten Medium, z.B. in einem nicht polaren Lösungsmittel durchgeführt, wobei Äther, insbesondere Diäthyläther, und aromatische Kohlenwasserstoffe als Beispiele genannt seien. Die angewandte Temperatur und Reaktionszeit lassen sich für jeden einzelnen Fall leicht ermitteln. Im allgemeinen wird in Abhängigkeit von der Art der Reaktionsteilnehmer bei einer Temperatur im Bereich von Umgebungstemperatur bis zur Rückflusstempe-ratur und für eine Zeit von einer oder mehreren Stunden bis zu etwa 1 Tag gearbeitet. The reaction is conveniently carried out in an inert medium, e.g. carried out in a non-polar solvent, ether, in particular diethyl ether, and aromatic hydrocarbons being mentioned as examples. The temperature and reaction time used can easily be determined for each individual case. In general, depending on the nature of the reactants, the process is carried out at a temperature in the range from ambient to the reflux temperature and for a time from one or more hours to about 1 day.
Das aromatische Amin der allgemeinen Formel II kann durch geeignete Einführung der erforderlichen Hydroxypoly-halogenisopropylgruppe, z.B. durch Umsetzung des entsprechenden Polyhalogenketons oder dessen Hydrat mit einem in geeigneter Weise substituierten Anilin, hergestellt werden [siehe beispielsweise E.E. Gilbert, J. Org. Chem. 30 (1965) 1001]. The aromatic amine of the general formula II can be obtained by appropriately introducing the required hydroxypolyhaloisopropyl group, e.g. by reacting the corresponding polyhalogen ketone or its hydrate with an appropriately substituted aniline [see for example E.E. Gilbert, J. Org. Chem. 30 (1965) 1001].
Die Herstellung von Verbindungen der allgemeinen Formel I wird in den folgenden Beispielen beschrieben. Hiebei veranschaulicht Beispiel 1 die Herstellung des Ausgangsmaterials und Beispiel 2 die Herstellung der endgültigen Verbindungen der Formel I. The preparation of compounds of general formula I is described in the following examples. Hiebei illustrates Example 1 the preparation of the starting material and Example 2 the preparation of the final compounds of formula I.
Beispiel 1 example 1
5 N-(2-Chloräthyl)-N'-[4-(hexaßuor-2-hydroxy-2-propyl)-phenyl]-N'-methylharnstoff 5 N- (2-chloroethyl) -N '- [4- (hexassuor-2-hydroxy-2-propyl) phenyl] -N'-methylurea
Man mischt 4,1 g (15 mMol) 4-(Hexafluor-2-hydroxy-2--propyl)-N-methylanilin [E.E. Gilbert, J. Org. Chem. 30 "io (1965) 1001] und 1,9 g (18 mMol) 2-Chloräthylisocyanat in 40 ml Diäthyläther. Man lässt das Gemisch über Nacht stehen, engt auf 6 g eines beigefarbenen Farbstoffs ein, kristallisiert durch Auflösen in Diäthyläther um, gibt Hexan zu und dampft dann den Diäthyläther ab, bis Ausfallung erfolgt, und erhält 15 5,5 g des gewünschten Produktes als weisslichen Feststoff vom Schmelzpunkt 120 bis 121°C. 4.1 g (15 mmol) of 4- (hexafluoro-2-hydroxy-2-propyl) -N-methylaniline are mixed [E.E. Gilbert, J. Org. Chem. 30 "(1965) 1001] and 1.9 g (18 mmol) of 2-chloroethyl isocyanate in 40 ml of diethyl ether. The mixture is left to stand overnight, concentrated to 6 g of a beige-colored dye, crystallizes by dissolving in diethyl ether, adds hexane and then evaporates the diethyl ether until precipitation occurs, and 15 5.5 g of the desired product is obtained as an off-white solid with a melting point of 120 to 121 ° C.
Beispiel 2 Example 2
2-[4-(Hexafluor-2-hydroxy-2-propyl)-N-methyl-anilino] -2-oxazolin 2- [4- (Hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-oxazoline
Man löst 10,0 g (26 mMol) N-(2-Chloräthyl)-N'-[4-(hexa-fluor-2-hydroxy-2-propyl)-phenyl]-N'-methylharnstoff in einem Gemisch von 50 ml Methanol und 100 ml Wasser. Man 25 erhitzt 1 h auf dem Dampfbad. Man engt ein und verteilt zwischen wässeriger ln-Natriumbicarbonatlkösung und Diäthyläther und extrahiert dann mit 200 ml ln-Salzsäure. Man gibt Natriumbicarbonat zu und extrahiert dann mit 200 ml Diäthyläther, trocknet den Ätherextrakt und engt ein, wobei man 30 7,8 g der gewünschten Verbindung als weissen Feststoff vom Schmelzpunkt 188-190°C erhält. 10.0 g (26 mmol) of N- (2-chloroethyl) -N '- [4- (hexafluoro-2-hydroxy-2-propyl) phenyl] -N'-methylurea are dissolved in a mixture of 50 ml of methanol and 100 ml of water. The mixture is heated on the steam bath for 1 h. The mixture is concentrated and partitioned between aqueous sodium bicarbonate solution and diethyl ether and then extracted with 200 ml of hydrochloric acid. Sodium bicarbonate is added and the mixture is then extracted with 200 ml of diethyl ether, the ether extract is dried and concentrated, giving 30 7.8 g of the desired compound as a white solid with a melting point of 188-190 ° C.
Die Salze können nach üblichen Verfahren, z.B. durch Behandlung einer Lösung der freien Base in einem geeigneten organischen Lösungsmittel, z.B. Äther, mit der gewünschten 35 Säure, z.B. Salzsäure, und anschliessendes Abfiltrieren des ausgefällten Salzes hergestellt werden. The salts can be prepared by conventional methods, e.g. by treating a solution of the free base in a suitable organic solvent, e.g. Ether, with the desired 35 acid, e.g. Hydrochloric acid, and then filtering off the precipitated salt.
In analoger Weise, wie in den vorstehenden Beispielen beschrieben, können die folgenden repräsentativen Verbindungen der Formell hergestellt werden: 40 2-[4-(l,3-Dichlor-2-hydroxy-tetrafluor-2-propyl)-N-propyl-anilino]-2-oxazolin 2-[4-(Hexafluor-2-hydroxy-2-propyl)-anilino]-2-oxazolin 2-[N-2,6-Trimethyl-4-(hexafluor-2-hydroxy-2-propyl)--anilino]-2-oxazolinhydrochlorid 45 2-[4-(Hexafluor-2-hydroxy-2-propyl)-N-methylanilino-5--methyl]-2-oxazolin In an analogous manner to that described in the preceding examples, the following representative compounds of the formula can be prepared: 40 2- [4- (1,3-dichloro-2-hydroxy-tetrafluoro-2-propyl) -N-propyl-anilino ] -2-oxazoline 2- [4- (hexafluoro-2-hydroxy-2-propyl) anilino] -2-oxazoline 2- [N-2,6-trimethyl-4- (hexafluoro-2-hydroxy-2- propyl) anilino] -2-oxazoline hydrochloride 45 2- [4- (hexafluoro-2-hydroxy-2-propyl) -N-methylanilino-5-methyl] -2-oxazoline
2-[4-(Chlor-2-hydroxypentafluor-2-propyl)-N-methyl- 2- [4- (chloro-2-hydroxypentafluoro-2-propyl) -N-methyl-
anilino]-2-oxazolin 2-[2-(Hexafluor-2-hydroxy-2-propyl)-N-methylanilino]-50 -2-oxazolin anilino] -2-oxazoline 2- [2- (hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -50 -2-oxazoline
2-[4-(Tetrafluor-l,3-dichlor-2-hydroxy-2-propyl)-N-methyl- 2- [4- (tetrafluoro-l, 3-dichloro-2-hydroxy-2-propyl) -N-methyl-
anilino]-2-oxazolinhydrochlorid 2-[4-(Hexafluor-2-hydroxy-2-propyl)-2-chlor-N-methyl-anilino]-2- oxazolinhydrochlorid 55 2-[4-(Hexafluor-2-hydroxy-2-propyl)-N-n-propylanilino]-2-- oxazolinbisulfat 2-[4-(l,l,l-Trifluor-2-hydroxy-2-propyl)-N-methylanilino]- anilino] -2-oxazoline hydrochloride 2- [4- (hexafluoro-2-hydroxy-2-propyl) -2-chloro-N-methyl-anilino] -2-oxazoline hydrochloride 55 2- [4- (hexafluoro-2-hydroxy- 2-propyl) -Nn-propylanilino] -2-- oxazoline bisulfate 2- [4- (l, l, l-trifluoro-2-hydroxy-2-propyl) -N-methylanilino] -
-2-oxazolinbisulfat 2-[2,6-Dichlor-4-(hexafluor-2-hydroxy-2-propyl)-N-methyl-6o anilino]-2-oxazolinbisulfat -2-oxazoline bisulfate 2- [2,6-dichloro-4- (hexafluoro-2-hydroxy-2-propyl) -N-methyl-6o anilino] -2-oxazoline bisulfate
2-[2,6-Diisopropyl-4-(hexafluor-2-hydroxy-2-propyl)-N--methylanilino]-2-oxazolinbisulfat 2- [2,6-diisopropyl-4- (hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-oxazoline bisulfate
2-[2,6-Diäthyl-4-(hexafluor-2-hydroxy-2-propyl)-N-methyl-anilino]-2-oxazolinbisuIfat 65 2-[2-Chlor-4-(hexafluor-2-hydroxy-2-propyl)-N,6-dimethyl-anilino]-2-oxazolinbisulfat 2-[4-(Hexafluor-2-hydroxy-2-propyl)-2-methoxy-N-methyl-anilino]-2-oxazolinphosphat, Methanolsolvat 2- [2,6-diethyl-4- (hexafluoro-2-hydroxy-2-propyl) -N-methyl-anilino] -2-oxazoline bisulfate 65 2- [2-chloro-4- (hexafluoro-2-hydroxy- 2-propyl) -N, 6-dimethyl-anilino] -2-oxazoline bisulfate 2- [4- (hexafluoro-2-hydroxy-2-propyl) -2-methoxy-N-methyl-anilino] -2-oxazoline phosphate, methanol solvate
5 5
623 044 623 044
2-[2-Fluor-4-(hexafluor-2-hydroxy-2-propyl)-N-methyl-anilino]-2-oxazolinbisulfat 2- [2-fluoro-4- (hexafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-oxazoline bisulfate
2-[4-(Hexafluor-2-hydroxy-2-propyl)-2,5-dimethyl-N--methylanilino]-2-oxazolinbisulfat 2- [4- (Hexafluoro-2-hydroxy-2-propyl) -2,5-dimethyl-N-methylanilino] -2-oxazoline bisulfate
2-[4-(Hexafluor-2-hydroxy-2-propyl)-2,6-dimethoxy-N- 5 -methylanilino]-2-oxazolinbisulfat 2-[N-Äthyl-4-(hexafluor-2-hydroxy-2-propyl)-anilino]--2-oxazolinsulfat und 2- [4- (Hexafluoro-2-hydroxy-2-propyl) -2,6-dimethoxy-N- 5 -methylanilino] -2-oxazoline bisulfate 2- [N-ethyl-4- (hexafluoro-2-hydroxy-2 -propyl) -anilino] - 2-oxazoline sulfate and
2-[4-(Hexafluor-2-hydroxy-2-propyl)-N,2-dimethylanilino]--2-oxazolinhydrochlorid. io 2- [4- (Hexafluoro-2-hydroxy-2-propyl) -N, 2-dimethylanilino] - 2-oxazoline hydrochloride. io
Wenn in einer pharmazeutischen Formulierung 2-[4-(He-xafluor-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazolin verwendet wird, werden 10 mg pro Tablette oder Kapsel als geeignete Menge des aktiven Ingredienz angesehen. When 2- [4- (He-xafluoro-2-hydroxy-2-propyl) -N-methylanilino] -2-oxazoline is used in a pharmaceutical formulation, 10 mg per tablet or capsule is considered a suitable amount of the active ingredient.
15 15
Für die Behandlung der Hypertension oder des Bluthochdrucks ist eine Anzahl von Mitteln bekannt. Einige dieser Mittel, z.B. Reserpin, bewirken bei einigen Patienten eine Senkung des Bluthochdruckes, verursachen jedoch bei anderen Patienten unerwünschte bekannte Nebenwirkungen. 20 A number of agents are known for the treatment of hypertension or high blood pressure. Some of these means, e.g. Reserpine, may reduce high blood pressure in some patients, but cause undesirable known side effects in other patients. 20th
Anderen bekannten Mitteln fehlt ausreichende Wirksamkeit, oder sie führen dazu, dass sich Toleranz gegenüber dem Arzneimittel ausbildet. Other known agents lack sufficient efficacy or cause tolerance to the drug to develop.
Es wurde gefunden, dass die Verbindungen der allgemeinen Formel I eine wertvolle und vorteilhafte blutdruck- 25 senkende Wirkung haben. Ferner wurde festgestellt, dass repräsentative Verbindungen besonders wirksam als Antihypertonika sind, während sie gleichzeitig gewisse nachteilige Nebenwirkungen, die mit bekannten Antihypertonika verbunden sind, vermeiden oder mildern. Auf der Grundlage von Laboratoriumversuchen kann gesagt werden, dass die effektive Dosis, die ED50, bei oraler Verabreichung einer Verbindung der allgemeinen Formel I typischerweise im Bereich von 0,01 .bis 20 mg/kg Körpergewicht des Empfangers pro Tag liegt. Für die Verbindung des Beispiels 2 würde die tägliche Dosis in der Humantherapie bei etwa 0,6 bis 10 mg liegen. Was die Toxizität anbelangt, so war die vorstehend genannte Verbindung bei einer Dosis von 100 mg/kg nicht letal. It has been found that the compounds of the general formula I have a valuable and advantageous hypotensive effect. It has also been found that representative compounds are particularly effective as antihypertensive agents, while at the same time avoiding or mitigating certain adverse side effects associated with known antihypertensive agents. Based on laboratory tests, it can be said that the effective dose, the ED50, for oral administration of a compound of general formula I is typically in the range of 0.01 to 20 mg / kg body weight of the recipient per day. For the compound of Example 2, the daily dose in human therapy would be about 0.6 to 10 mg. In terms of toxicity, the above compound was not lethal at a dose of 100 mg / kg.
Die erforderliche Tagesdosis kann in einer einzigen Gabe oder in verteilten Gaben verabreicht werden. Die zu verabreichende genaue Dosis hängt natürlich davon, wo die betreffende Verbindung innerhalb der vorstehend genannten Dosierungsbereiche liegt, sowie vom Alter und Gewicht des Empfängers ab. The required daily dose can be administered in a single dose or in divided doses. The exact dose to be administered will, of course, depend on where the compound in question is within the dosage ranges mentioned above and the age and weight of the recipient.
Die Verbindungen der allgemeinen Formel I können allein oder in Kombination mit anderen Arzneimitteln z.B. zum Lockern des ß- adrenergischen Systems mit Propanolalhydro-chlorid, verabreicht werden. Die Verbindungen werden oral verabreicht. In jedem Fall wird ein geeigneter pharmazeutischer Träger verwendet, der in Abhängigkeit von den physikalischen Eigenschaften der Verbindung in der Arzneimittelzubereitung gewählt wird. Der Träger darf mit der zu verabreichenden Verbindung nicht chemisch reagieren. Die die aktiven Ingredienten enthaltenden Zubereitungen können typischerweise in Form von Tabletten, Kapseln, Sirup, Elixieren oder Suspensionen vorliegen. The compounds of general formula I can be used alone or in combination with other drugs e.g. to loosen the ß-adrenergic system with propanolal hydrochloride. The compounds are administered orally. In any case, a suitable pharmaceutical carrier is used, which is selected depending on the physical properties of the compound in the pharmaceutical preparation. The carrier must not react chemically with the compound to be administered. The preparations containing the active ingredients can typically be in the form of tablets, capsules, syrups, elixirs or suspensions.
Claims (10)
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES442992A ES442992A1 (en) | 1974-12-02 | 1975-11-26 | Para-polyfluoroisopropyl-anilino-2-oxazoline compounds, pharmaceutical compositions and method of treating hypertension |
US05/668,385 US4081547A (en) | 1974-12-02 | 1976-03-19 | Para-polyfluoroisopropyl-anilino-2-oxazoline compounds, pharmaceutical compositions and method of treating hypertension |
US05/683,104 US4093742A (en) | 1974-12-02 | 1976-05-04 | Anti-hypertensive polyhaloisopropyl-substituted arylureas |
US05/688,219 US4058612A (en) | 1974-12-02 | 1976-05-20 | 6-(Polyhaloisopropyl)quinazoline-2,4-diones |
ES457806A ES457806A1 (en) | 1974-12-02 | 1977-04-14 | Para-polyfluoroisopropyl-anilino-2-oxazoline compounds, pharmaceutical compositions and method of treating hypertension |
ES457807A ES457807A1 (en) | 1974-12-02 | 1977-04-14 | Para-polyfluoroisopropyl-anilino-2-oxazoline compounds, pharmaceutical compositions and method of treating hypertension |
US05/872,130 US4159335A (en) | 1974-12-02 | 1978-01-25 | Substituted anilino-2-thiazolines |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52860374A | 1974-12-02 | 1974-12-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
CH623044A5 true CH623044A5 (en) | 1981-05-15 |
Family
ID=24106378
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH1516475A CH623044A5 (en) | 1974-12-02 | 1975-11-21 | Process for the preparation of novel anilino-2-oxazolines |
Country Status (26)
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JP (1) | JPS5182239A (en) |
AR (2) | AR219478A1 (en) |
AT (1) | AT357557B (en) |
AU (1) | AU501512B2 (en) |
BE (1) | BE835899A (en) |
CA (1) | CA1063112A (en) |
CH (1) | CH623044A5 (en) |
CS (1) | CS188259B2 (en) |
DD (1) | DD124730A5 (en) |
DE (1) | DE2552933A1 (en) |
DK (1) | DK535275A (en) |
FI (1) | FI753332A (en) |
FR (1) | FR2346000A1 (en) |
GB (1) | GB1507340A (en) |
HU (1) | HU175541B (en) |
IE (1) | IE42759B1 (en) |
IL (1) | IL48557A (en) |
IT (1) | IT1051024B (en) |
LU (1) | LU73888A1 (en) |
NL (1) | NL7513804A (en) |
NO (1) | NO146497C (en) |
PH (1) | PH14474A (en) |
PL (2) | PL99122B1 (en) |
SE (2) | SE7513331L (en) |
SU (2) | SU655311A3 (en) |
ZA (1) | ZA757457B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS52111541A (en) * | 1976-02-19 | 1977-09-19 | Scherico Ltd | Substituted ureido compound and medical composition containing it as active ingredient |
US4107303A (en) | 1976-06-24 | 1978-08-15 | E. I. Du Pont De Nemours And Company | Antihypertensive hexafluorohydroxyisopropyl benzazepines and benzazocines |
DE2839462A1 (en) * | 1978-09-11 | 1980-03-27 | Basf Ag | AROYL UREAS |
US6316503B1 (en) * | 1999-03-15 | 2001-11-13 | Tularik Inc. | LXR modulators |
AU2003208952B2 (en) | 2002-01-30 | 2008-04-24 | Amgen Inc. | Heterocyclic arylsulfonamidobenzylic compounds |
AU2003210811B2 (en) | 2002-01-30 | 2008-08-14 | Amgen Inc. | Arylsulfonamidobenzylic compounds |
US20030199578A1 (en) * | 2002-04-19 | 2003-10-23 | Turner Sean C. | Naphthalene amides as potassium channel openers |
CN107108485B (en) * | 2014-10-24 | 2020-06-12 | 小野药品工业株式会社 | KCNQ 2-5 channel activator |
JP6197971B1 (en) * | 2016-04-22 | 2017-09-20 | 小野薬品工業株式会社 | KCNQ2-5 channel-related disease prevention and / or treatment agent |
Family Cites Families (5)
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US3453284A (en) * | 1966-01-19 | 1969-07-01 | Du Pont | Certain 2-(substituted-anilino)-2-oxazolines |
FR1543535A (en) * | 1966-09-27 | 1968-10-25 | Bayer Ag | Manufacturing process of 2-phenylamino-2-oxazolines |
FR1543534A (en) * | 1966-09-27 | 1968-10-25 | Bayer Ag | Manufacturing process of 2-phenylimino-oxazolidines |
DE1670752A1 (en) * | 1966-09-27 | 1970-12-23 | Bayer Ag | Process for the preparation of 2-phenylamino-oxazolines |
DE1670751A1 (en) * | 1966-09-27 | 1970-12-23 | Bayer Ag | Process for the preparation of 2-phenylamino-2-oxazolines |
-
1975
- 1975-11-21 CH CH1516475A patent/CH623044A5/en not_active IP Right Cessation
- 1975-11-25 BE BE162139A patent/BE835899A/en unknown
- 1975-11-26 FR FR7536178A patent/FR2346000A1/en active Granted
- 1975-11-26 GB GB48640/75A patent/GB1507340A/en not_active Expired
- 1975-11-26 DE DE19752552933 patent/DE2552933A1/en not_active Withdrawn
- 1975-11-26 PH PH17810A patent/PH14474A/en unknown
- 1975-11-26 AT AT898575A patent/AT357557B/en not_active IP Right Cessation
- 1975-11-26 SE SE7513331A patent/SE7513331L/en not_active Application Discontinuation
- 1975-11-26 AR AR261362A patent/AR219478A1/en active
- 1975-11-26 CA CA240,512A patent/CA1063112A/en not_active Expired
- 1975-11-26 FI FI753332A patent/FI753332A/fi not_active Application Discontinuation
- 1975-11-26 IE IE2578/75A patent/IE42759B1/en unknown
- 1975-11-26 ZA ZA757457A patent/ZA757457B/en unknown
- 1975-11-26 AU AU86989/75A patent/AU501512B2/en not_active Ceased
- 1975-11-26 NL NL7513804A patent/NL7513804A/en not_active Application Discontinuation
- 1975-11-26 NO NO753984A patent/NO146497C/en unknown
- 1975-11-27 LU LU73888A patent/LU73888A1/xx unknown
- 1975-11-27 DK DK535275A patent/DK535275A/en not_active Application Discontinuation
- 1975-11-27 IL IL48557A patent/IL48557A/en unknown
- 1975-11-27 JP JP50141811A patent/JPS5182239A/ja active Pending
- 1975-12-01 PL PL1975185156A patent/PL99122B1/en unknown
- 1975-12-01 SU SU752194050A patent/SU655311A3/en active
- 1975-12-01 PL PL1975193580A patent/PL102327B1/en unknown
- 1975-12-01 HU HU75SCHE549A patent/HU175541B/en unknown
- 1975-12-01 CS CS758133A patent/CS188259B2/en unknown
- 1975-12-01 DD DD189793A patent/DD124730A5/xx unknown
- 1975-12-02 IT IT29923/75A patent/IT1051024B/en active
-
1976
- 1976-10-20 AR AR265154A patent/AR218436A1/en active
- 1976-10-26 SU SU762414458A patent/SU685146A3/en active
-
1980
- 1980-06-11 SE SE8004364A patent/SE8004364L/en unknown
Also Published As
Publication number | Publication date |
---|---|
ATA898575A (en) | 1979-12-15 |
AU501512B2 (en) | 1979-06-21 |
IT1051024B (en) | 1981-04-21 |
IE42759L (en) | 1976-06-02 |
NL7513804A (en) | 1976-06-04 |
LU73888A1 (en) | 1976-09-06 |
HU175541B (en) | 1980-08-28 |
AT357557B (en) | 1980-07-25 |
CA1063112A (en) | 1979-09-25 |
PL102327B1 (en) | 1979-03-31 |
SU685146A3 (en) | 1979-09-05 |
IL48557A0 (en) | 1976-01-30 |
SE7513331L (en) | 1976-06-03 |
FR2346000B1 (en) | 1978-11-17 |
SU655311A3 (en) | 1979-03-30 |
PL99122B1 (en) | 1978-06-30 |
BE835899A (en) | 1976-05-25 |
DD124730A5 (en) | 1977-03-09 |
PH14474A (en) | 1981-08-07 |
NO753984L (en) | 1976-06-03 |
NO146497C (en) | 1982-10-13 |
AU8698975A (en) | 1977-06-02 |
FR2346000A1 (en) | 1977-10-28 |
DE2552933A1 (en) | 1976-06-10 |
IE42759B1 (en) | 1980-10-08 |
AR219478A1 (en) | 1980-08-29 |
ZA757457B (en) | 1976-11-24 |
NO146497B (en) | 1982-07-05 |
GB1507340A (en) | 1978-04-12 |
JPS5182239A (en) | 1976-07-19 |
AR218436A1 (en) | 1980-06-13 |
FI753332A (en) | 1976-06-03 |
CS188259B2 (en) | 1979-02-28 |
DK535275A (en) | 1976-06-03 |
IL48557A (en) | 1979-05-31 |
SE8004364L (en) | 1980-06-11 |
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