DE1643913B1 - Derivatives of 3-amino-1,2-propanediol - Google Patents

Derivatives of 3-amino-1,2-propanediol

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Publication number
DE1643913B1
DE1643913B1 DE19671643913 DE1643913A DE1643913B1 DE 1643913 B1 DE1643913 B1 DE 1643913B1 DE 19671643913 DE19671643913 DE 19671643913 DE 1643913 A DE1643913 A DE 1643913A DE 1643913 B1 DE1643913 B1 DE 1643913B1
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Germany
Prior art keywords
propargyloxy
found
hydrochloride
calculated
analysis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
DE19671643913
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German (de)
Inventor
Colette Douzon
Claude Fauran
Claude Gouret
Gerard Huguet
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Synthelabo SA
Original Assignee
Delalande SA
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Publication of DE1643913B1 publication Critical patent/DE1643913B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Description

CH,CH,

-N-N

in der R1 ein Wasserstoffatom, Q_3-Alkyl-, Cyclohexyl- oder Benzylrest und R2 ein Wasserstoffatom, Q_4-Alkyl-, Allyl-, Benzyl-, Chlorbenzyl-, Phenäthyl- oder ein gegebenenfalls durch ein oder mehrere Chloratome, durch Chlor und Methyl, durch Fluor, durch Methyl und/oder i-Propyl- oder Trifluormethyl- oder Carboxyl- oder Methoxy- oder Methoxycarbonylrest(en) substituierter Phenylrest ist, oder R1 und R2 zusammen mit dem Stickstoffatom, an das sie gebunden sind, eine Pyrrolidino-, Piperidino-, Methylpiperazino-, Äthoxycarbonylpiperazino-, Morpholino- oder Tetrahydrochinolinogruppe bilden, und ihre Säureadditions- und quartären Ammoniumsalze.in which R 1 is a hydrogen atom, Q_ 3 -alkyl, cyclohexyl or benzyl radical and R 2 is a hydrogen atom, Q_ 4 -alkyl, allyl, benzyl, chlorobenzyl, phenethyl or optionally one or more chlorine atoms Chlorine and methyl, phenyl radical substituted by fluorine, by methyl and / or i-propyl or trifluoromethyl or carboxyl or methoxy or methoxycarbonyl radical (s), or R 1 and R 2 together with the nitrogen atom to which they are bonded , form a pyrrolidino, piperidino, methylpiperazino, ethoxycarbonylpiperazino, morpholino or tetrahydroquinolino group, and their acid addition and quaternary ammonium salts.

Die Erfindung betrifft therapeutisch wirksame von 3-Amino-l,2-propandiol abgeleitete Verbindungen der allgemeinen FormelThe invention relates to therapeutically active compounds derived from 3-amino-1,2-propanediol general formula

Formelformula

(I)(I)

CH2- 0-CH2-C=CH
CH-OH R1
CH2 NCH 2 - 0 CH 2 -C = CH
CH-OH R 1
CH 2 N

R2 R 2

in der R1 ein Wasserstoffatom, Q-3-Alkyl-, Cyclohexyl- oder Benzylrest und R2 ein Wasserstoffatom, C1 _4-Alkyl-, Allyl-, Benzyl-, Chlorbenzyl-, Phenäthyl- oder ein gegebenenfalls durch ein oder mehrere Chloratome, durch Chlor und Methyl, durch Fluor, durch Methyl und/oder i-Propyl- oder Trifluormethyl- oder Carboxyl- oder Methoxy- oder Methoxycarbonylrest(en) substituierter Phenylrest ist, oder R1 und R2 zusammen mit dem Stickstoffatom, an das sie gebunden sind, eine Pyrrolidino-, Piperidino-, Methylpiperazino-, Äthoxycarbonylpiperazino-, Morpholino- oder Tetrahydrochinolinogruppe bilden, und ihre Säureadditions- und quartären Ammoniumsalze.in which R 1 is a hydrogen atom, Q-3-alkyl, cyclohexyl or benzyl radical and R 2 represents a hydrogen atom, C 1 _ 4 alkyl, allyl, benzyl, chlorobenzyl, phenethyl group or an optionally by one or more Chlorine atoms, phenyl radical substituted by chlorine and methyl, by fluorine, by methyl and / or i-propyl or trifluoromethyl or carboxyl or methoxy or methoxycarbonyl radical (s), or R 1 and R 2 together with the nitrogen atom to which they are bound, form a pyrrolidino, piperidino, methylpiperazino, ethoxycarbonylpiperazino, morpholino or tetrahydroquinolino group, and their acid addition and quaternary ammonium salts.

Da die Verbindungen der allgemeinen Formel (I) einerseits basischen Charakter haben, sind auch die Säureadditionssalze, die sich mit organischen oder anorganischen Säuren ergeben können, Gegenstand der Erfindung, und da sie andererseits einen quaternisierbaren Stickstoff enthalten, umfaßt die Erfindung auch die quatemären Ammoniumsalze, die die Amine der Formel (I) bilden können, insbesondere mit den Alkylhalogeniden.Since the compounds of the general formula (I) on the one hand have a basic character, the Acid addition salts that can result with organic or inorganic acids, subject matter of the invention and, on the other hand, containing a quaternizable nitrogen, the invention embraces also the quaternary ammonium salts which the amines of the formula (I) can form, in particular with the Alkyl halides.

Das Verfahren zur Herstellung der Verbindungen der Formel (I) ist folgendermaßen, daß man etwa 1 Mol l-Propargyloxy-2,5-epoxypropan der Formel NHThe process for preparing the compounds of formula (I) is as follows, employing about 1 mole of l-propargyloxy-2,5-epoxypropane of the formula NH

(HI)(HI)

worin R1 und R2 die oben angegebene Bedeutung besitzen, einwirken läßt, während mindestens einer Stunde am Sieden hält und dann das gesuchte Derivat mittels üblicher Methoden, wie Verdampfen des Lösungsmittels bei vermindertem Druck, gewinnt.wherein R 1 and R 2 have the meaning given above, allowed to act, kept boiling for at least one hour and then the derivative sought by means of conventional methods, such as evaporation of the solvent under reduced pressure, wins.

Man kann auch die Aminolösung zuerst zum Sieden bringen und dann das 1-Propargyloxy-2,3-epoxypropan tropfenweise zugeben.You can also bring the amino solution to the boil first and then the 1-propargyloxy-2,3-epoxypropane add drop by drop.

Die Herstellung der Säureadditionssalze der Verbindungen der allgemeinen Formel (I) wird durch Einwirkung der gewählten anorganischen oder organischen Säure auf die Base, wobei gegebenenfalls in einem organischen Lösungsmittel gearbeitet wird, mittels an sich bekannter Methoden durchgeführt. Das gebildete Salz wird nach üblichen Methoden gewonnen und gereinigt, beispielsweise durch FiI-trieren und Umkristallisieren.The preparation of the acid addition salts of the compounds of the general formula (I) is carried out by Action of the selected inorganic or organic acid on the base, where appropriate is carried out in an organic solvent by means of methods known per se. The salt formed is obtained and purified by customary methods, for example by filtration and recrystallization.

Die quatemären Ammoniumsalze werden durch die Einwirkung eines Alkylhalogenids auf die Amine der Formel (I) hergestellt, indem man in einem geeigneten organischen Lösungsmittel und bei der Siedetemperatur des Reaktionsmediums arbeitet. Die so gebildeten Salze werden durch Verdampfen des Lösungsmittels und Umkristallisieren gewonnen.The quaternary ammonium salts are formed by the action of an alkyl halide on the amines of formula (I) prepared by in a suitable organic solvent and at the boiling point of the reaction medium is working. The salts thus formed are removed by evaporation of the solvent and recrystallization.

55 Beispiel 1
l-Propargyloxy-3-isopropylaminopropanol-2 55 Example 1
1-propargyloxy-3-isopropylaminopropanol-2

CH2
O
CHCH 2
O
CH

CH2-O-CH2 CH 2 -O-CH 2

(H)(H)

-C=CH-C = CH

unter Sieden auf etwa 1 bis 3 Mol eines vorher in einem geeigneten Lösungsmittel gelösten Amins der Nach dem Auflösen von 1 Mol (59 g) Isopropylamin in 20OmI Methanol erwärmt man zum Sieden und gibt unter Rühren tropfenweise 0,3 Mol (34 g) 1-Propargyloxy - 2,3 - epoxypropan zu. Dann wird noch 1 Stunde erwärmt, das Methanol verdampft und das Produkt bei vermindertem Druck destilliert (Ausbeute 70%).while boiling to about 1 to 3 mol of an amine previously dissolved in a suitable solvent After 1 mol (59 g) of isopropylamine has been dissolved in 20OmI of methanol, the mixture is heated to the boil and add 0.3 mol (34 g) 1-propargyloxy-2,3-epoxypropane dropwise with stirring. Then still will Heated for 1 hour, the methanol evaporated and the product distilled under reduced pressure (yield 70%).

Kp. 0,07 mm Hg: 90 bis 92°C.Bp 0.07 mm Hg: 90 to 92 ° C.

Analyse: C9H17NO2.Analysis: C 9 H 17 NO 2 .

Berechnet ... C 63,13, H 10,01, N 8,18%;
gefunden .... C 63,35, H 10,10, N 8,16%.Calculated ... C 63.13, H 10.01, N 8.18%;
found .... C 63.35, H 10.10, N 8.16%.

3 43 4

Das Hydrochlorid wird hergestellt, indem man zu Beispiel4The hydrochloride is prepared by following Example 4

der Base eine 10 n-Chlorwasserstoffsäurelösung gibt. l-Propargyloxy-S-dicyclohexylamino-propanol^the base is a 10N hydrochloric acid solution. l-propargyloxy-S-dicyclohexylamino-propanol ^

Das durch Abkühlen ausknstallisierende Salz wird r &j j j j ν ν The salt which crystallizes out on cooling becomes r & j jjj ν ν

abgesaugt und aus Essigsäureäthylester umkristalli- Eine Mischung von 0,3 Mol (55 g) Dicyclohexyl-suctioned off and recrystallized from ethyl acetate A mixture of 0.3 mol (55 g) dicyclohexyl

siert;F. = 84° C (Kofler). 5 amin und 0,3 Mol (34 g) l-Propargyloxy^-epoxy-sated; F. = 84 ° C (Kofler). 5 amine and 0.3 mol (34 g) l-propargyloxy ^ -epoxy-

propan in Lösung in 100 ml Methanol wird 5 Stundenpropane in solution in 100 ml of methanol is 5 hours

Analyse: C9H18NO2Cl. unter gutem Rühren zum Sieden erhitzt. Dann wirdAnalysis: C 9 H 18 NO 2 Cl. heated to the boil with thorough stirring. Then it will be

Berechnet ... C 52,04, H 8,74, N 6,74, Cl 17,07%; das Lösungsmittel verdampft und das Produkt destilgefunden .... C 52,16, H 8,82, N 6,77, Cl 17,05%. liert (Ausbeute 70%).Calculated ... C 52.04, H 8.74, N 6.74, Cl 17.07%; the solvent evaporated and the product found to be distilled .... C 52.16, H 8.82, N 6.77, Cl 17.05%. lated (yield 70%).

ίο Kp. 0,03 mm Hg: 164 bis 166° C.ίο Bp. 0.03 mm Hg: 164 to 166 ° C.

Beisoiel 2 Analyse:C18H31NO2.Example 2 Analysis: C 18 H 31 NO 2 .

v Berechnet ... C 73,67, H 10,55, N 4,77%; v Calculated ... C 73.67, H 10.55, N 4.77%;

l-Propargyloxy-3-phenylaminopropanol-2 gefunden .... C 73,78, H 10,66, N 4,68%.Found 1-propargyloxy-3-phenylaminopropanol-2 ... C 73.78, H 10.66, N 4.68%.

Man erwärmt 1 Mol Anilin (93 g), gelöst in 200 ml Das Hydrochlorid wird hergestellt, indem manHeat 1 mole of aniline (93 g) dissolved in 200 ml. The hydrochloride is prepared by:

Methanol, zum Sieden und gibt dann tropfenweise trockenes Chlorwasserstoffgas in eine Lösung der 0,5 Mol (56 g) l-Propargyloxy-2,3-epoxypropan zu. Base in wasserfreiem Äther einperlt. Nach Umkri-Man hält noch 2 Stunden am Sieden, verjagt dann stallisieren aus einer Mischung von Aceton und das Lösungsmittel und destilliert das Produkt (Aus- 20 Essigsäureäthylester hat das Produkt einen F. = 135° C beute 73%). (Kofler).Methanol, to the boil, and then add dry hydrogen chloride gas dropwise to a solution of the 0.5 mole (56 g) of 1-propargyloxy-2,3-epoxypropane. Base pearls in anhydrous ether. According to Umkri-Man keeps boiling for another 2 hours, then chased away from a mixture of acetone and the solvent and the product is distilled (from ethyl acetate the product has a mp = 135 ° C prey 73%). (Kofler).

Kp. 0,1 mm Hg: 155 bis 158°C. . , _ __ XT_ _Bp 0.1 mm Hg: 155 to 158 ° C. . , _ __ XT _ _

Analyse: C18H32NO2Cl.Analysis: C 18 H 32 NO 2 Cl.

Analyse: C12H15NO2. Berechnet ... C 65,53, H 9,77, N 10,75%;Analysis: C 12 H 15 NO 2 . Calculated ... C 65.53, H 9.77, N 10.75%;

Berechnet ... C 70,22, H 7,37, N 6,82%; 25 gefunden .... C 65,51, H 9,75, N 10,75%.Calculated ... C 70.22, H 7.37, N 6.82%; 25 found .... C 65.51, H 9.75, N 10.75%.

gefunden .... C 70,17, H 7,48, N 6,74%.found .... C 70.17, H 7.48, N 6.74%.

Beispiel 5Example 5

e x s p *e l-Propargyloxy-O-morpholinpropanol-^ exsp * e l-propargyloxy-O-morpholine propanol- ^

l-Propargyloxy-3-diisopropylamino-propanol-2 Man bringt eine Mischung von 0,3 Mol (26 g)l-Propargyloxy-3-diisopropylamino-propanol-2 One brings a mixture of 0.3 mol (26 g)

Morpholin und 100 ml Methanol zum Sieden und gibtMorpholine and 100 ml of methanol to the boil and there

ManbringtO,3 Mol(31g)Isopropylaminundl00ml dann langsam 0,3 Mol (34 g) 1-Propargyloxy-Add 0.3 mol (31 g) isopropylamine and 100 ml then slowly 0.3 mol (34 g) 1-propargyloxy-

Methanol zum Sieden und fügt dann langsam 0,3 Mol 2,3-epoxypropan zu. Dann wird noch 1 Stunde zumMethanol to the boil and then slowly adds 0.3 mol of 2,3-epoxypropane. Then another hour becomes

(34 g) l-Propargyloxy-2,3-epoxypropan zu. Dann wird 35 Rückfluß erhitzt, das Lösungsmittel verjagt und dasAdd (34 g) 1-propargyloxy-2,3-epoxypropane. Then reflux is heated, the solvent driven off and that

noch 5 bis 6 Stunden zum Rückfluß erhitzt, das Produkt destilliert (Ausbeute 75%).heated to reflux for a further 5 to 6 hours, the product is distilled (yield 75%).

Methanol wird verjagt und das Produkt destilliert Kp. 0,01 mm Hg: 115 bis 1200C.Methanol is chased away and the product is distilled, boiling point 0.01 mm Hg: 115 to 120 ° C.

(Ausbeute 70%X Analyse-C10H17NO3.(Yield 70% X analysis-C 10 H 17 NO 3 .

Kp. 0,1 mm Hg: 95 bis 100°C. ^J^ » Q ^ R ^ N .Bp 0.1 mm Hg: 95 to 100 ° C. ^ J ^ » Q ^ R ^ N.

Analyse: C12H23NO2. gefunden .... C 60,28, H 8,48, N 6,93%. .Analysis: C 12 H 23 NO 2 . found .... C 60.28, H 8.48, N 6.93%. .

Berechnet ... C 67,56, H 10,87, N 6,56%;Calculated ... C 67.56, H 10.87, N 6.56%;

gefunden .... C 67,54, H 10,80, N 6,44%. Das Hydrochlorid wird hergestellt, indem man diefound .... C 67.54, H 10.80, N 6.44%. The hydrochloride is made by making the

in Aceton gelöste Base mit alkoholischem Chlorwasser-base dissolved in acetone with alcoholic chlorinated water

45 stoff behandelt. Das Salz wird aus Essigsäureäthyl-45 fabric treated. The salt is made from ethyl acetate

Das Hydrochlorid wird hergestellt, indem man die ester umkristallisiert; F. = 1060C.The hydrochloride is made by recrystallizing the esters; F. = 106 0 C.

Base in Aceton löst und das Salz mittels eines geringen Analvse "C H NO ClDissolve the base in acetone and remove the salt by means of a slight analysis "C H NO Cl

Überschusses an 12n-Chlorwasserstoffsäure fallt. Es ^l1018 ^3*-Λλ*· tt-7™ ,Ifni ™ λ = ™«, Excess of 12N hydrochloric acid falls. Es ^ l 1018 ^ 3 * - Λ λ * · tt-7 ™, Ifni ™ λ = ™ «,

wird aus Essigsäureäthylester umkristallisiert; Β^<*η<* . -. C 50,95, H 7,70, N 5,94, C 5,04/„;is recrystallized from ethyl acetate; Β ^ <* η <*. -. C 50.95, H 7.70, N 5.94, C 5.04 / ";

F. = 860C (Kofler) 50 gefunden .... C 51,12, H 7,90, N 5,94, Cl 14,93%.F. = 86 0 C (Kofler) 50 found .... C 51.12, H 7.90, N 5.94, Cl 14.93%.

Analyse: C12H24NO2Cl. Das Jodmethylat wird hergestellt, indem man dieAnalysis: C 12 H 24 NO 2 Cl. The iodine methylate is produced by the

Berechnet... C 57,70, H 9,69, N 5,61, Cl 14,19%; Base und einen geringen Überschuß MethyljodidCalculated ... C 57.70, H 9.69, N 5.61, Cl 14.19%; Base and a small excess of methyl iodide

gefunden C 57,58, H 9,55, N 5,45, Cl 14,17%. 5 Stunden lang zum Sieden erhitzt. Die Lösung wirdFound C 57.58, H 9.55, N 5.45, Cl 14.17%. Heated to the boil for 5 hours. The solution will be

55 im Vakuum konzentriert und dann in den Kühlschrank55 concentrated in vacuo and then in the refrigerator

gebracht, wo das quaternäre Salz kristallisiert. Es wirdbrought to where the quaternary salt crystallizes. It will

Das Jodmethylat wird hergestellt, indem man die aus Essigsäureäthylester umkristallisiert; F. = 8O0C.The iodine methylate is prepared by recrystallizing it from ethyl acetate; F. = 8O 0 C.

Base und einen geringen Überschuß Methyljodid inBase and a small excess of methyl iodide in

Aceton 10 Stunden lang zum Rückfluß erhitzt. DasAcetone heated to reflux for 10 hours. That

aus der kalten Acetonlösung ausfallende Produkt wird 60 5f^7i H ,Q1 M411 o 14n7 rThe product precipitating from the cold acetone solution becomes 60 5f ^ 7 i H , Q1 M411 o 14n7 r

in einem großen Volumen Petroläther kristallisiert; Γ j.crystallized in a large volume of petroleum ether; Γ j.

■p _ sn° r1 rRfnfwi geiunaen: ■ p _ sn ° r 1 rRfnfwi geiunaen:

t. - öu L, ^onerj t. - öu L, ^ onerj

Analyse: C13H26NO2J.Analysis: C 13 H 26 NO 2 J.

Berechnet: 65 Die in den nachfolgenden Tabellen I, II und IIICalculated: 65 The values in Tables I, II and III below

C 43,95, H 7,38, N 3,94, O9,01, J 35,71%; zusammengefaßten Verbindungen werden nach demC 43.95, H 7.38, N 3.94, O9.01, J 35.71%; summarized connections are after the

gefunden: in den obigen Beispielen beschriebenen Verfahrenfound: procedures described in the examples above

C 44,00, H 7,53, N 4,01, O 9,25, J 35,67%. hergestellt.C 44.00, H 7.53, N 4.01, O 9.25, J 35.67%. manufactured.

Tabelle ITable I.

Verb.Verb. R.R. R2 R 2 HH SalzeSalts SummenformelMolecular formula Molekular
gewichtMolecular
weight Kp. °C/mm HgBp ° C / mm Hg F. 0CF. 0 C „20"20th 11 HH C3H7(H)C 3 H 7 (H) C6H11NO2 C 6 H 11 NO 2 129,156129.156 140/15140/15 1,48061.4806 22 HH C3H7(Ii)C 3 H 7 (Ii) C9H17NO2 C 9 H 17 NO 2 171,23171.23 90 bis 95/0,190 to 95 / 0.1 1,46071.4607 ' 3'3 HH C4H9(Ii)C 4 H 9 (Ii) HClHCl C9H18NO2ClC 9 H 18 NO 2 Cl 207,70207.70 7878 44th HH CH2 = CH-CH3 CH 2 = CH-CH 3 C10H19NO2 C 10 H 19 NO 2 185,26185.26 110 bis 115/0,1110 to 115 / 0.1 1,46091.4609 55 HH CH2 = CH-CH3 CH 2 = CH-CH 3 C9H15NO2 C 9 H 15 NO 2 169,22169.22 110 bis 112/0,1110 to 112 / 0.1 1,48041.4804 66th HH CH2 C6H5 CH 2 C 6 H 5 HClHCl C9H16NO2ClC 9 H 16 NO 2 Cl 205,68205.68 7878 77th HH — CH2-4(Cl)C6H4 - CH 2 -4 (Cl) C 6 H 4 C13H7NO2 C 13 H 7 NO 2 219,27219.27 155 bis 160/0,2155 to 160 / 0.2 1,53501.5350 88th HH (CH2)2 — C6H5 (CH 2 ) 2 - C 6 H 5 C13H16ClNO2 C 13 H 16 ClNO 2 253,72253.72 152 bis 155/0,05152 to 155 / 0.05 1,54501.5450 99 HH -2(Cl)C6H4 -2 (Cl) C 6 H 4 C14H19NO2 C 14 H 19 NO 2 233,30233.30 150/0,04150 / 0.04 1,53221.5322 1010 HH -4(Cl)C6H4 -4 (Cl) C 6 H 4 C12H14ClNO2 C 12 H 14 ClNO 2 239,70239.70 150 bis 154/0,05150 to 154 / 0.05 1,56301.5630 1111th HH -3(CF3)C6H4 -3 (CF 3 ) C 6 H 4 C12H14ClNO2 C 12 H 14 ClNO 2 239,70239.70 165 bis 170/0,1165 to 170 / 0.1 1212th HH -3(Cl) 4(CH3)C6H3 -3 (Cl) 4 (CH 3 ) C 6 H 3 C13H14F3NO2 C 13 H 14 F 3 NO 2 273,25273.25 155 bis 160/0,2155 to 160 / 0.2 1313th HH -3(F)C6H4 -3 (F) C 6 H 4 C13H16ClNO2 C 13 H 16 ClNO 2 253,72253.72 175 bis 180/0,05175 to 180 / 0.05 1414th HH C12H14FNO2 C 12 H 14 FNO 2 223,24223.24 155 bis 160/0,1155 to 160 / 0.1

(Fortsetzung)(Continuation)

CC. HH berechnetcalculated ClCl ElementaranalyseElemental analysis CC. HH gefundenfound ClCl FF. Verb.Verb. 55,7955.79 8,588.58 NN 55,6855.68 8,508.50 NN 63,1263.12 10,0110.01 10,8510.85 FF. 63,3063.30 9,869.86 11,0611.06 11 52,0452.04 8,738.73 8,188.18 17,0717.07 52,1352.13 8,688.68 8,398.39 17,1617.16 22 64,8364.83 10,3410.34 6,746.74 65,0265.02 10,1810.18 6,696.69 33 63,8863.88 8,948.94 7,567.56 63,9163.91 8,938.93 7,407.40 44th 52,5552.55 7,847.84 8,288.28 17,2317.23 52,4452.44 7,927.92 8,578.57 17,2317.23 55 71,2071.20 7,827.82 6,816.81 71,1371.13 7,687.68 6,676.67 66th 61,5461.54 6,366.36 6,396.39 61,3661.36 6,596.59 6,316.31 77th 72,0772.07 8,218.21 5,525.52 72,0572.05 8,318.31 5,585.58 88th 60,1360.13 5,895.89 6,006.00 60,3260.32 5,675.67 5,995.99 99 60,1360.13 5,895.89 5,845.84 60,4960.49 5,845.84 5,645.64 1010 57,1457.14 5,165.16 5,845.84 57,2557.25 5,355.35 5,905.90 21,1821.18 1111th 61,5461.54 6,366.36 5,135.13 61,5061.50 6,416.41 5,075.07 1212th 64,5664.56 6,326.32 5,525.52 20,820.8 64,6364.63 6,456.45 5,505.50 8,648.64 1313th 6,276.27 6,446.44 1414th 8,518.51

(Fortsetzung)(Continuation)

Verb.Verb. RiRi R2 R 2 SalzeSalts SummenformelMolecular formula Molekular
gewichtMolecular
weight Kp. °C/mm HgBp ° C / mm Hg F. 0CF. 0 C „20"20th 1515th HH -3(OCH3)C6H4 -3 (OCH 3 ) C 6 H 4 C13H17NO3 C 13 H 17 NO 3 235,27235.27 180/0,05180 / 0.05 1616 HH -4(OCH3)C6H4 -4 (OCH 3 ) C 6 H 4 C13H17NO3 C 13 H 17 NO 3 235,27235.27 195/0,001195 / 0.001 1717th HH — 2,5(OCH3)2C6H3 - 2.5 (OCH 3 ) 2 C 6 H 3 C14H19NO4 C 14 H 19 NO 4 265,30265.30 210/0,001210 / 0.001 1818th HH -3,4(Cl)2C6H3 -3.4 (Cl) 2 C 6 H 3 C12H13Cl2NO2 C 12 H 13 Cl 2 NO 2 247,15247.15 195 bis 200/0,05195 to 200 / 0.05 1919th HH -3(Cl)C6H4 -3 (Cl) C 6 H 4 Q2H14ClNO2 Q 2 H 14 ClNO 2 239,70239.70 175 bis 180/0,3175 to 180 / 0.3 2020th HH -4(CF3)C6H4 -4 (CF 3 ) C 6 H 4 C13H14F3NO2 C 13 H 14 F 3 NO 2 273,25273.25 150 bis 160/0,7150 to 160 / 0.7 2121 HH -4(COOH)C6H4 -4 (COOH) C 6 H 4 C13H15NO4 C 13 H 15 NO 4 249,26249.26 142142 2222nd HH -2(CH3) 5(1-C3H7)C6H3 -2 (CH 3 ) 5 (1-C 3 H 7 ) C 6 H 3 C16H23NO2 C 16 H 23 NO 2 261,35261.35 150 bis 160/0,2150 to 160 / 0.2 2323 HH -2(COOCH3)C6H4 -2 (COOCH 3 ) C 6 H 4 C14H17NO4 C 14 H 17 NO 4 263,28263.28 190 bis 195/0,05190 to 195 / 0.05

(Fortsetzung)(Continuation)

CC. HH berechnetcalculated ClCl ElementaranalyseElemental analysis CC. HH gefundenfound ClCl FF. Verb.Verb. 66,3666.36 7,287.28 NN 66,4166.41 7,317.31 NN 66,3666.36 7,287.28 5,955.95 FF. 66,1966.19 7,257.25 5,975.97 1515th 63,3863.38 7,227.22 5,955.95 63,4563.45 7,387.38 6,066.06 1616 52,5752.57 4,784.78 5,285.28 52,4152.41 4,814.81 5,455.45 1717th 60,1360.13 5,895.89 5,115.11 60,0060.00 5,775.77 5,155.15 1818th 57,1457.14 5,165.16 5,84 .5.84. 57,3057.30 5,035.03 5,915.91 20,6820.68 1919th 62,6462.64 6,076.07 5,135.13 62,6362.63 6,026.02 5,235.23 2020th 73,5373.53 8,878.87 5,625.62 20,820.8 73,3373.33 8,958.95 5,645.64 2121 63,8663.86 6,516.51 5,365.36 63,7563.75 6,616.61 5,525.52 2222nd 5,325.32 5,545.54 2323

Tabelle IITable II

Verb.Verb. R1 R 1 R2 R 2 SalzeSalts SummenformelMolecular formula Molekular
gewichtMolecular
weight Kp. oC/mmHgKp. O C / mmHg F. 0CF. 0 C „20"20th 2424 CH3 CH 3 CH3 CH 3 C8H15NO2 C 8 H 15 NO 2 157,21157.21 70 bis 73/0,0370 to 73 / 0.03 2525th CH3 .CH 3 . CH3 CH 3 HClHCl C8H16NO2ClC 8 H 16 NO 2 Cl 193,67193.67 hygr.hygr. 2626th C2H5 C 2 H 5 C2H5 C 2 H 5 Q0H19NO2 Q 0 H 19 NO 2 185,26185.26 80 bis 85/0,580 to 85 / 0.5 1,46011.4601 2727 C3H7(n)C 3 H 7 (n) C3H7 (n)C 3 H 7 (n) Q2H13NO2 Q 2 H 13 NO 2 213,31213.31 100 bis 105/0,5100 to 105 / 0.5 1,45061.4506 2828 CH2C6H5 CH 2 C 6 H 5 CH2C6H5 CH 2 C 6 H 5 C20H23NO2 C 20 H 23 NO 2 309,39309.39 185 bis 195/0,03185 to 195 / 0.03 1,55561.5556

(Fortsetzung)(Continuation)

CC. berechnetcalculated ElementaranalyseElemental analysis NN CC. gefundenfound NN Verb.Verb. 61,1261.12 HH 8,918.91 62,0162.01 HH 8,728.72 49,6149.61 9,629.62 18,3018.30 49,0649.06 10,0910.09 18,1618.16 2424 64,8364.83 8,338.33 7,567.56 64,7264.72 8,288.28 7,407.40 2525th 67,5667.56 10,3410.34 6,566.56 67,7767.77 10,2210.22 6,496.49 2626th 77,6477.64 10,8710.87 4,534.53 77,8377.83 10,9710.97 4,674.67 2727 7,497.49 7,317.31 2828

Tabelle IIITable III

Verb.Verb. /■Λ
N ΐ
\ / ■ Λ
N ΐ
\ NG N G SalzeSalts SummenformelMolecular formula Molekular
gewichtMolecular
weight Kp. °C/mm HgBp ° C / mm Hg F. 0CF. 0 C „20"20th R2--'R 2 - ' /—Ί/ —Ί
\ I\ I 2929 1O 1 O C10H17NO2 C 10 H 17 NO 2 183,24183.24 105 bis 110/0,25105 to 110 / 0.25 1,48061.4806 3030th HClHCl Q0H18NO2ClQ 0 H 18 NO 2 Cl 219,71219.71 8484 3131 N N-CH3 N N-CH 3 JCH3 JCH 3 Q1H20NO2JQ 1 H 20 NO 2 J 325,18325.18 8686 3232 C11H19NO2 C 11 H 19 NO 2 197,27197.27 100/0,05100 / 0.05 1,48051.4805 3333 HClHCl Q1H20NO2ClQ 1 H 20 NO 2 Cl 233,73233.73 8787 3434 Q1H20N2O2 Q 1 H 20 N 2 O 2 212,29212.29 118 bis 120/0,2118 to 120 / 0.2 1,49051.4905

Fortsetzungcontinuation

1010

Verb.Verb. \J\ J SalzeSalts SummenformelMolecular formula Molekular
gewichtMolecular
weight Kp. °C/mm HgBp ° C / mm Hg F. 0CF. 0 C »I20 »I 20 3535 N N-CH3 N N-CH 3 2HCl2HCl C11H22N2O2Cl2 C 11 H 22 N 2 O 2 Cl 2 285,22285.22 150150 3636 N N-COOC2H5 N N-COOC 2 H 5 C13H22N2O4 C 13 H 22 N 2 O 4 270,32270.32 165 bis 170/0,25165 to 170 / 0.25 1,49051.4905 3737 N N-COOC2H5 N N-COOC 2 H 5 HClHCl C13H23N2O4ClC 13 H 23 N 2 O 4 Cl 306,79306.79 9898 3838 C15H19NO2 C 15 H 19 NO 2 245,31245.31 165/0,1165 / 0.1 1,56021.5602

(Fortsetzung)(Continuation)

CC. HH berechnetcalculated OO ClCl ElementaranalyseElemental analysis CC. HH gefundenfound OO ClCl JJ Verb.Verb. 65,5465.54 9,359.35 NN 65,5165.51 9,129.12 NN 54,6654.66 8,268.26 7,647.64 16,1416.14 JJ 54,6154.61 8,348.34 7,647.64 15,9615.96 2929 40,6340.63 6,206.20 6,376.37 9,849.84 40,6440.64 6,326.32 6,356.35 9,749.74 39,2039.20 3030th 66,9766.97 9,719.71 4,314.31 67,0567.05 9,749.74 4,294.29 3131 56,5256.52 8,628.62 7,107.10 13,6913.69 15,1715.17 39,0239.02 56,4556.45 8,618.61 6,606.60 13,8413.84 15,1315.13 3232 62,2362.23 9,509.50 5,995.99 62,3362.33 9,679.67 5,955.95 3333 46,3246.32 7,787.78 13,2013.20 24,8624.86 45,7645.76 7,807.80 13,0613.06 24,9324.93 3434 57,7657.76 8,208.20 57,6757.67 8,248.24 3535 50,8950.89 7,567.56 10,3610.36 11,5611.56 50,7050.70 7,487.48 10,3110.31 11,4111.41 3636 73,4473.44 7,817.81 9,199.19 73,2873.28 7,647.64 9,159.15 3737 3838

Die erwähnten Verbindungen werden an Versuchstieren untersucht, und sie zeigen interessante cardiovasculäre, analgetische und sedative Aktivitäten.The compounds mentioned are investigated in experimental animals and they show interesting cardiovascular, analgesic and sedative activities.

A. Cardio-vaskuläre AktivitätA. Cardio-vascular activity

Bei der Verabreichung an Katze oder Ratte auf intravenösem Weg zeigen die meisten der beschriebenen Verbindungen eine Hypotension. Diese Hypotension ist besonders dauerhaft im Falle des Hydrochloride des 1 - Propargyloxy - N - (N' - carbäthoxy)-3-piperazino-propanols-2. When administered to cats or rats by the intravenous route, most of those described show Connections a hypotension. This hypotension is particularly permanent in the case of the Hydrochloride des 1 - propargyloxy - N - (N '- carbethoxy) -3-piperazino-propanols-2.

In den anderen Fällen ergibt sich eine Hypertension, insbesondere beim Hydrochlorid des 1-Propargyloxy-3-pyrrolidino-propanols-2. In the other cases there is hypertension, especially with the hydrochloride of 1-propargyloxy-3-pyrrolidino-propanols-2.

Außerdem rufen bestimmte Substanzen eine Inhibierung der /3-adrenergischen Rezeptoren hervor, insbesondere das Hydrochlorid des 1-Propargyloxy-3-isopropylamino-propanols-2. In addition, certain substances cause an inhibition of the / 3-adrenergic receptors, in particular the hydrochloride of 1-propargyloxy-3-isopropylamino-propanols-2.

B. Analgetische WirkungB. Analgesic effect

Die meisten der beschriebenen Verbindungen besitzen eine analgetische Wirkung. So können sie bei Mäusen den Schmerzbekundungen auf Grund von intraperitonealer Injektion von algogenen Substanzen, wie Phenylbenzochinon oder Essigsäure, entgegenwirken. Most of the compounds described have an analgesic effect. So you can at Mice the symptoms of pain due to intraperitoneal injection of algogenic substances, such as phenylbenzoquinone or acetic acid, counteract.

C. Sedative WirkungC. Sedative effect

Bestimmte Derivate zeigen eine ausgeprägte sedative Wirkung, die sich durch eine Verminderung der Motilität bei Ratten und Mäusen äußert.Certain derivatives show a pronounced sedative effect, which is characterized by a reduction in the Expresses motility in rats and mice.

Bestimmte Verbindungen wurden spezieller untersucht, es handelt sich dabei insbesondere um die folgenden:Certain compounds have been studied more specifically, in particular the following:

1. l-Propargyloxy-3-N-morpholinopropanol-2-hydrochlorid 1. 1-Propargyloxy-3-N-morpholinopropanol-2-hydrochloride

Diese Verbindung, deren DL50 bei Mäusen bei intravenöser Verabreichung 110 mg/kg und bei oraler Verabreichung über 1 g/kg beträgt, ist per os bei Schmerzäußerungen wirksam, die beim gleichen Tier durch intraperitoneale Injektion von Essigsäure mit der Dosis von 100 mg/kg und durch intraperitoneale Injektion von Phenylbenzochmon mit der Dosis von 200 mg/kg hervorgerufen worden sind. Diese Dosen rufen keine Änderungen des normalen Bewegungsverhaltens des Tieres hervor. This compound, the DL 50 of which in mice when administered intravenously is 110 mg / kg and when administered orally is more than 1 g / kg, is effective per os for pain manifestations, which in the same animal by intraperitoneal injection of acetic acid at a dose of 100 mg / kg and caused by intraperitoneal injection of phenylbenzochmone at the dose of 200 mg / kg. These doses do not produce any changes in the normal movement behavior of the animal.

2. l-Propargyloxy-3-N-(N'-carbäthoxy)-piperazinopropanol-2-hydrochlorid 2. 1-Propargyloxy-3-N- (N'-carbethoxy) -piperazinopropanol-2-hydrochloride

Diese Verbindung, deren DL50 bei intravenöser Verabreichung bei Mäusen 380 mg/kg beträgt, ruftThis compound, the DL 50 of which when administered intravenously to mice is 380 mg / kg, calls

bei der Katze bei 1Z10 dieser Dosis eine Hypotension von 30% hervor, wobei die Rückkehr des Arteriendruckes auf den ursprünglichen Wert nach 20 Minuten vollzogen ist.a hypotension of 30% in the cat at 1 Z 10 of this dose, with the return of the arterial pressure to the original value after 20 minutes.

Die Verbindung zeigt außerdem sedative Wirkungen: bei 200 mg/kg auf oralem Weg vermindert sie bei Mäusen die Zahl der Entweichungen auf einer geneigten Fläche um 50%.The compound also shows sedative effects: at 200 mg / kg by the oral route it decreases in mice the number of escapes on a sloping surface by 50%.

3. 1 -Propargyloxy-3-isopropylaminopropanol-2-hydrochlorid 3. 1-Propargyloxy-3-isopropylaminopropanol-2-hydrochloride

Diese Verbindung besitzt, injiziert auf intravenösem Weg mit der Dosis von 10 mgZkg, inhibierende Wirkungen gegenüber /S-adrenergischen Rezeptoren, die sich durch eine merkliche Verminderung der eine hohe Pulsfrequenz erzeugenden Wirkung eines Stimulans von /3-Rezeptoren, wie Isoprenalin, zeigt.This compound, when injected by intravenous route at the dose of 10 mgZkg, has inhibitory effects compared to / S-adrenergic receptors, which are characterized by a noticeable decrease in one shows the high pulse rate generating effect of a stimulant of / 3 receptors such as isoprenaline.

Die DL50 bei Mäusen beträgt bei intravenöser Verabreichung 156 mg/kg.The DL 50 in mice when administered intravenously is 156 mg / kg.

Die interessanten cardiovaskulären, analgetischen und sedativen Wirkungen der erfindungsgemäßen Verbindungen machen diese zu nützlichen Medikamenten für die Behandlung von verschiedenen Krankheiten, wie von Hypertension und Kreislaufstörungen, sowie für die Behandlung und die Schmerzlinderung von verschiedenen Schmerzen.The interesting cardiovascular, analgesic and sedative effects of the invention Compounds make these useful drugs for the treatment of various diseases, as of hypertension and circulatory disorders, as well as for treatment and pain relief of various pains.

Die therapeutisch aktiven Dosen hängen ab von Art und Schwere des Falles. Im allgemeinen liegt die tägliche Dosis für perorale Verabreichung beim Menschen zwischen 0,1 und 3 g.The therapeutically active doses depend on the type and severity of the case. In general, the daily dose for oral administration in humans between 0.1 and 3 g.

VergleichsversucheComparative experiments

Die drei vorstehend erwähnten erfindungsgemäßen Verbindungen wurden im Vergleich mit bekannten Arzneimittelwirkstoffen klinisch getestet, wobei folgende Ergebnisse erzielt wurden:The three above-mentioned compounds of the present invention were compared with known ones Active pharmaceutical ingredients have been clinically tested, with the following results:

1. l-Propargyloxy-3-N-morpholinopropanol-2-hydrochlorid 1. 1-Propargyloxy-3-N-morpholinopropanol-2-hydrochloride

Behandelte Krankheit: Arthrose.
Bisherige Behandlung mit: Acetylsalicylsäure, 2 - (3 - Trifluormethylphenylamino) - nikotinsäure oder Metiazinsäure.Treated disease: osteoarthritis.
Previous treatment with: acetylsalicylic acid, 2 - (3 - trifluoromethylphenylamino) - nicotinic acid or metiazinic acid.

W Bei der Behandlung mit den vorstehenden Wirkstoffen traten jeweils Erkrankungen des Verdauungstrakts auf, worauf die Behandlung abgebrochen werden mußte. W During the treatment with the above active ingredients, diseases of the digestive tract occurred in each case, whereupon the treatment had to be discontinued.

Zum Vergleich wurde das vorstehende, erfindungsgemäße Propanol-2-derivat in Form von Tabletten mit einem Wirkstoffgehalt von 250 mg 6mal täglich verabreicht, wobei eine befriedigende Wirksamkeit und eine völlige Verträglichkeit festgestellt wurde.For comparison, the above propanol-2-derivative according to the invention was used in the form of tablets with an active ingredient content of 250 mg administered 6 times a day, with a satisfactory effectiveness and complete compatibility was found.

2. l-Propargyloxy-3-N-(N'-carbäthoxy)-piperazinopropanol-2-hydrochlorid 2. 1-Propargyloxy-3-N- (N'-carbethoxy) -piperazinopropanol-2-hydrochloride

Behandelte Krankheit: Großenteils auf Neurotonie zurückzuführende mittelstarke Hypertension. Disease Treated: Moderate hypertension, largely due to neurotension.

Bekannte Behandlung mit: Trimetazidin oder Reserpinderivaten.Known treatment with: trimetazidine or reserpine derivatives.

Mit diesen Arzneimittelwirkstoffen war nur eine geringfügige und völlig unbefriedigende Besserung des Zustande der behandelten Patienten zu erzielen.With these active pharmaceutical ingredients there was only a slight and completely unsatisfactory improvement in the To achieve the condition of the treated patient.

Behandlung mit dem vorstehenden erfindungsgemäßen Propanol-2-derivat: Die Verabreichung der genannten erfindungsgemäßen Verbindung führte auf Grund der sedierenden und hypotensiven Wirkung dieser Verbindung sofort zu einer unbestreitbaren wesentlichen Besserung des Zustands der Patienten.Treatment with the above propanol-2 derivative according to the invention: The administration of the mentioned compound according to the invention led due to the sedative and hypotensive effect This connection immediately led to an undeniable, substantial improvement in the condition of the patient.

3. l-Propargyloxy-3-isopropylaminopropanol-2-hydrochlorid 3. 1-propargyloxy-3-isopropylaminopropanol-2-hydrochloride

Behandelte Krankheit: Paraxystische supraventrikulare Tachykardie vom Typ BOUVERET in Verbindung mit Asthma oder Herzschwäche.Disease treated: Paraxystic supraventricular tachycardia of the BOUVERET type associated with asthma or heart failure.

Die Paraxystische supraventrikulare Tachykardie wird üblicherweise mit Propanolol (1 - (Isopropylamino) - 3 - (1 - naphthyloxy) - propanol - 2) behandelt. Wenn jedoch gleichzeitig ein asthmatisches Leiden oder eine Herzschwäche auftrat, so konnte dieser Wirkstoff nicht angewandt werden.Paraxystic supraventricular tachycardia is usually treated with propanolol (1 - (isopropylamino) - 3 - (1 - naphthyloxy) - propanol - 2) treated. However, if at the same time an asthmatic condition or heart failure occurred, this agent could not be used.

Behandlung mit dem vorstehend genannten erfindungsgemäßen Propanol-2-derivat: Das erfindungsgemäße Propanol-2-derivat zeigte eine ausgezeichnete Wirksamkeit und eine sehr gute Verträglichkeit. Zusammenfassend ist festzustellen, daß die drei vorstehenden erfindungsgemäßen Verbindungen bei der klinischen Erprobung sich den zum Vergleich geprüften bekannten Arzneimittelwirkstoffen durch eine höhere Wirksamkeit und/oder dadurch als überlegen erwiesen, daß sie auch dann anwendbar sind, wenn die zu behandelnden Patienten an anderen Erkrankungen leiden, die die Anwendung der genannten bekannten Verbindungen ausschließen.Treatment with the above-mentioned propanol-2 derivative according to the invention: The inventive Propanol-2-derivative showed an excellent activity and a very good tolerance. In summary, it can be stated that the three above compounds according to the invention the clinical trials with the known active pharmaceutical ingredients tested for comparison a higher effectiveness and / or proven to be superior because they can also be used, if the patients to be treated suffer from other diseases that require the use of the above exclude known compounds.

Claims (1)

I 643I 643 Patentanspruch:Claim: Verbindungen der allgemeinen FormelCompounds of the general formula CH2- 0-CH2-C=CH
CH-OH R1 CH 2 - 0 CH 2 -C = CH
CH-OH R 1 (I)(I)
DE19671643913 1966-12-30 1967-12-22 Derivatives of 3-amino-1,2-propanediol Pending DE1643913B1 (en)

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FR2479813A1 (en) * 1980-04-04 1981-10-09 Fabre Sa Pierre ALCOXY PROPANOLAMINES USEFUL AS MEDICAMENTS AND PROCESS FOR THEIR PREPARATION
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