DE1948144C3 - 1 - (I -Keto-tetrahydronaphthyl-5-oxy) ^ -hydroxy-S-alkylaminopropanes, process for their preparation and pharmaceutical composition based on them - Google Patents
1 - (I -Keto-tetrahydronaphthyl-5-oxy) ^ -hydroxy-S-alkylaminopropanes, process for their preparation and pharmaceutical composition based on themInfo
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- DE1948144C3 DE1948144C3 DE1948144A DE1948144A DE1948144C3 DE 1948144 C3 DE1948144 C3 DE 1948144C3 DE 1948144 A DE1948144 A DE 1948144A DE 1948144 A DE1948144 A DE 1948144A DE 1948144 C3 DE1948144 C3 DE 1948144C3
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- hydroxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
- C07C217/30—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 having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/38—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 having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
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- 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
- C07D263/10—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
- C07D303/26—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds having one or more free hydroxyl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- Animal Behavior & Ethology (AREA)
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- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
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- Neurology (AREA)
- Neurosurgery (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
in der R einen Alkylrest mit bis zu 6 Kohlenstoffatomen bedeutet, sowie ihre pharmazeutisch verträglichen Säureadditionssalze.in which R denotes an alkyl radical with up to 6 carbon atoms, as well as their pharmaceutically acceptable ones Acid addition salts.
2. 5-[3-(tert.-Butylamino)-2-hydroxypropyloxy]-tetralon. 2. 5- [3- (tert-Butylamino) -2-hydroxypropyloxy] -tetralone.
3. 5-[3-(Isopropylamino-2-hydroxy)-propyloxy]-tetralon. 3. 5- [3- (Isopropylamino-2-hydroxy) propyloxy] tetralone.
4. Verfahren zur Hersieiiung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man in jeweils an sich bekannter Weise das Tetralonol der Formel4. The method for Hersieiiung the compounds according to claim 1, characterized in that one in a manner known per se, the tetralonol of the formula
(H)(H)
mit einer Verbindung der allgemeinen Formelwith a compound of the general formula
2525th
JOJO
X-CH2-CHOH-CH2X (III)X-CH 2 -CHOH-CH 2 X (III)
X-CH2-CH — CH2 (IV)X-CH 2 -CH - CH 2 (IV)
4040
in der X ein Halogenatom bedeutet, zu Verbindungen der allgemeinen Formel Vin which X is a halogen atom, to compounds of the general formula V
oder VIor VI
OCH2-CH — CH2 (VI) \ /OCH 2 -CH - CH 2 (VI) \ /
5555
umsetzt und anschließend die erhaltenen Reaktionsprodukte mit einem Amin der allgemeinen Formelreacts and then the reaction products obtained with an amine of the general formula
R-NH2,R-NH 2 ,
in der R die vorstehend angebene Bedeutung be- mi sitzt, umsetzt.in which R has the meaning given above sits, implements.
5. Phi.rma/.eutische Zusammensetzung, enthaltend eine oder mehrere Verbindungen nach Anspruch I neben üblichen Träger- und Hilfsstoffen.5. Phi.rma / .eutic composition containing one or more compounds according to claim I in addition to customary carriers and auxiliaries.
Der Erfindung liegen die in den Patentansprüchen definierten Gegenstände zugrunde.The invention is based on the subject matter defined in the claims.
Die erfindungsgemäßen Verbindungen weisen eine j3-adrenerge Blockierungswirkung auf und sind deshalb wertvoll in Fällen von Angina pectoris, Herzarrhythmien und verwandten cardiovasculären Erkrankungen. The compounds of the invention have a j3 adrenergic blocking effect and are therefore valuable in cases of angina pectoris, cardiac arrhythmias and related cardiovascular diseases.
Es wurde gefunden, daß die erfindungsgemäßen Verbindungen bei Säugetieren, z. B. Hunden, Katzen oder Affen, sowohl bei oraler Verabreichung als auch bei Injektion eine /?-adrenerge Blockierungswirkung besitzen. Im allgemeinen ist eine Dosis von etwa 0,1 bis etwa 1 mg/ kg Körpergewicht bei Verabreichung auf oralem Wege oder durch Injektion vorgeschrieben. Die /?-adrenerge Blockierungswirkung der erfindungsgemäßen Verbindungen wird durch Verabreichung verschiedener Dosen von Isoproterenol nach Behandlung des Versuchstiers mit den erfindungsgemäßen Verbindungen bestimmt. Es wurde gefunden, daß die Ansprechempfmdiiehkeit der Kerzkoritraktiönskrafl und der Herzschlaggeschwindigkeit gegenüber Isoproterenol durch die erfindungsgemäßen Verbindungen in verschiedenem Ausmaß, je nach der verabreichten Dosis, blockiert wird. Als Beispiel für die 0-Blockierwirkung der erfindungsgemäßen Verbindungen wurde das 5-[3-(tert.-Butylamino)-2-hydroxypropoxy]-tetraIon-hydro- chbrid anästhesierten Hunden in einer Dosis von 6,7 μg/kg intravenös verabreicht. Dann wurde den Hunden 03 μg/kg Isoproterenol gegeben. Die Verbindung konnte 50% der Isoproterenolwirkungen auf die Herzfrequenz des Hundes unterdrücken.It has been found that the compounds of the invention are effective in mammals, e.g. B. dogs, cats or Monkeys, both when administered orally and when injected, have a /? - adrenergic blocking effect. Generally, a dose of from about 0.1 to about 1 mg / kg of body weight when administered by the oral route will be or prescribed by injection. The /? - adrenergic The blocking action of the compounds of the present invention is achieved by administration of various Doses of isoproterenol after treatment of the test animal with the compounds according to the invention certainly. It was found that the responsiveness the Kerzkoritraktiönskrafl and the Heart rate compared to isoproterenol by the compounds according to the invention in various ways Extent, depending on the dose administered. As an example of the 0-blocking effect of the compounds according to the invention was the 5- [3- (tert-butylamino) -2-hydroxypropoxy] -tetraIon-hydro- chbrid administered intravenously to anesthetized dogs at a dose of 6.7 μg / kg. Then the dogs 03 μg / kg isoproterenol given. The connection was able to suppress 50% of the effects of isoproterenol on the dog's heart rate.
Die Dosierung kann entsprechend Alter, Geschlecht. Körpergewicht und Spezies des zu behandelnden Säugetieres variiert werden.The dosage can vary according to age, gender. Body weight and species of the mammal to be treated can be varied.
In den Rahmen der vorliegenden Erfindung gehören auch die pharmazeutisch verträglichen Säureadditionssalze der erfindungsgemäßen Verbindungen, beispielsweise die Hydrochloride, Hydrobromide, Phosphate, Sulfate oder die von organischen Säuren abgeleiteten Salze, wie z. B. die Lactaie oder Salicylate.The pharmaceutically acceptable acid addition salts also belong within the scope of the present invention of the compounds according to the invention, for example the hydrochlorides, hydrobromides, phosphates, Sulphates or the salts derived from organic acids, such as. B. the lactaie or salicylates.
Die vorliegende Erfindung umfaßt auch die d- oder 1-Enantiomeren oder die racemische Mischung sowie ihre oben beschriebenen Salze.The present invention also encompasses the d- or 1-enantiomers or the racemic mixture as well their salts described above.
Vergleichsdaten, aus denen sich die Überlegenheit der erfindungsgemäßen Verbindungen ergibt, sind in ]. Med. Chem. 1970, 684 und folgende veröffentlicht worden.Comparative data showing the superiority of the compounds according to the invention are given in ]. Med. Chem. 1970, 684 et seq.
Ein weiterer Gegenstand der vorliegenden Erfindung sind Dosierungsformen der erfindungsgemäßen Verbindungen, die zur oralen oder parenteralen Verabreichung geeignet sind. Die zur oralen Verabreichung geeigneten pharmazeutischen Präparate können in Form von Tabletten, Kapseln, wäßrigen oder öligen Lösungen und Suspensionen vorliegen, die nach dem Fachmann bekannlen Methoden leicht hergestellt werden können. Beispielsweise können Tabletten erzeugt werden, indem man den aktiven Bestandteil mit bekannten Hilfsstoffen, wie z. B. Calciumphosphat, Lactose, Mannit vermischt, mit z. B. Akazin oder einer Gelatinelösung granuliert und dann zu Tabletten verpreßt. Die Verbindungen können auch so formuliert werden, daß sie eine Depotwirkung im Organismus ergeben. Die zur parenteralen Verabreichung geeigneten Präparate können hergestellt werden, indem man den aktiven Bestandteil in einem parenteral verträglichen Hilfsstoff, wie z. IJ. sterilem Wasser, einer sterilen Salzlösung oder Öl. löst oder suspendiert.The present invention also relates to dosage forms of the compounds according to the invention, which are suitable for oral or parenteral administration. Those for oral administration Suitable pharmaceutical preparations can be in the form of tablets, capsules, aqueous or oily Solutions and suspensions are present which are easily prepared by methods known to the person skilled in the art can. For example, tablets can be made by mixing the active ingredient with known ones Auxiliaries, such as B. calcium phosphate, lactose, mannitol mixed with z. B. Akazin or one Gelatin solution granulated and then compressed into tablets. The compounds can also be formulated that way that they result in a depot effect in the organism. Those suitable for parenteral administration Preparations can be made by putting the active ingredient in a parenterally acceptable Auxiliary material, such as IJ. sterile water, a sterile saline solution or oil. dissolves or suspends.
Kin weiterer Gegenstand der Erfinduni» ist ein Ver-Another subject of the invention is a
fahren zur Herstellung dieser Verbindungen.drive to make these connections.
In den Verbindungen der Formeln III und IV ist X z, B. Cl. Die Ausgangsmaterialien Il und III oder II undIn the compounds of the formulas III and IV, X is, for example, Cl. The starting materials II and III or II and
IV werden entweder ohne Lösungsmittel miteinander unter Rückfluß gekocht oder bei Raumtemperatur in einer alkoholischen Lösung, die einen geringen Überschuß (1,1 Mol) einer Base, wie z. B. Natriumhydroxid, Kaliumhydroxid oder Natriummethylat, enthält, zu den entsprechenden Zwischenprodukten der Formeln V und Vl umgesetzt Die so erhaltenen ZwischenprodukteIV are either refluxed together without solvent or at room temperature in an alcoholic solution containing a slight excess (1.1 mol) of a base, such as. B. Sodium Hydroxide, Potassium hydroxide or sodium methylate, to the corresponding intermediates of the formulas V and VI reacted The intermediates thus obtained
V und Vl werden dann beispielsweise durch Kochen unter Rückfluß mit dem entsprechenden Amin der all-V and Vl are then, for example, by refluxing with the corresponding amine of the all-
10 gemeinen Formel RNH2 behandelt. Zu geeigneten Lösungsmitteln für diese Umsetzungen gehören beispielsweise niedere aliphatische Alkohole, wie z. B. Methanol oder Äthanol. Die gewünschten Endprodukte werden nach bekannten Methoden gewonnen. 10 common formula RNH 2 treated. Suitable solvents for these reactions include, for example, lower aliphatic alcohols, such as. B. methanol or ethanol. The desired end products are obtained by known methods.
Das Tetralonol Il wird erhalten, indem man den entsprechenden Äther, der im Handel erhältlich ist, mit Bromwasserstoff in Essigsäure behandelt.The tetralonol II is obtained by adding the corresponding Ether, which is commercially available, treated with hydrogen bromide in acetic acid.
Die folgenden Beispiele sollen die Erfindung erläutern. Die Beispiele 1 und 2 betreffen die Herstellung von Vorstufen.The following examples are intended to illustrate the invention. Examples 1 and 2 relate to the preparation of Preliminary stages.
OHOH
Beispiel '
5-(2,3-Epoxypropyloxy)-l-tetralonExample '
5- (2,3-epoxypropyloxy) -l-tetralone
Q-CH2-CHQ-CH 2 -CH
-CH,-CH,
+ Cl-CHj—CH CH2 + Cl-CHj-CH CH 2
Eine Lösung von 83 g NaOH in 36,5 ml Wasser wird mit 292 ml Äthanol verdünnt, und dann werden 28,5 g 5-Hydroxy-«:tetralon und 98 g Epichlorhydrin zugegeben. Die Mischung wird 16 Stunden bei Raumtemperatur gerührt und dann 2 bis 3 Tage stehengelassen. Die Lösung wird dann eingedampft und der Rückstand zwischen 18OmI W .sser und 250 ml Chloroform verteilt. Die abgetrennte wäßrige Schieb» wird mit weite-A solution of 83 g NaOH in 36.5 ml water is diluted with 292 ml of ethanol, and then 28.5 g of 5-hydroxy ": tetralone, and 98 g of epichlorohydrin were added. The mixture is stirred for 16 hours at room temperature and then left to stand for 2 to 3 days. The solution is then evaporated and the residue is partitioned between 180 ml of water and 250 ml of chloroform. The separated aqueous sliding »is with wide-
ren 100 ml Chloroform extrahiert. Die vereinigten organischen Phasen werden zweimal mit 100 ml Wasser gewaschen, getrocknet unii eingeengt und ergeben 41 g Rückstand. Dieser wird in 280 ml Äther gelöst, abgekühlt, und es werden 4,5 g Kristalle abfiltriert. Das Filtrat wird abgedampft unter Bildung von 34 g Rück-JO stand; dieser wird bei 136 bis 144°C/0,106 mbar destilliert und ergibt 26,1 g Produkt.Ren 100 ml of chloroform extracted. The combined organic phases are washed twice with 100 ml of water, dried unii concentrated and give 41 g of residue. This is dissolved in 280 ml of ether, cooled, and 4.5 g of crystals are filtered off. The filtrate is evaporated to give 34 g of re-JO was standing; this is distilled at 136 to 144 ° C / 0.106 mbar and gives 26.1 g of product.
3-(Tetralon-5-oxy)-1,2-epoxy-propan
3-(Tetralon-5-oxy)-l-chlor-2-hydroxy-propan3- (tetralone-5-oxy) -1,2-epoxy-propane
3- (Tetralone-5-oxy) -l-chloro-2-hydroxy-propane
+ CI-CH2-CH CH,+ CI-CH 2 -CH CH,
13,8 g 5-HydroxytetraIon werden in 75 ml Epichlorhydrin gelöst, und die Lösung wird 44 Stunden unter Rückfluß gekocht. Das überschüssige Epichlorhydrin wird im Vakuum durch Erhitzen auf einem Wasserbad entfernt und der Rückstand in einer Kurzweg-Mikrodestillationsapparatur destilliert. Man erhält 5 Fraktionen, Kp. 160 bis 210°C/03 mbar. Alle haben eine starke Keton-Absorption, und die beiden letzten weisen13.8 g of 5-hydroxytetraIon are in 75 ml of epichlorohydrin dissolved, and the solution is refluxed for 44 hours. The excess epichlorohydrin is removed in vacuo by heating on a water bath and the residue in a short path microdistillation apparatus distilled. 5 fractions are obtained, boiling point 160 to 210 ° C./0.3 mbar. All have one strong ketone absorption, and the last two wise
CHCH
oder-/-OCH2CH-CH2CI I OH or - / - OCH 2 CH-CH 2 Cl I OH
auch eine starke Hydroxyl-Absorption auf. In früheren Versuchen wurde ermittelt, daß die niedrige Hydroxyl-also has a strong hydroxyl absorption. In earlier Experiments have shown that the low hydroxyl
absorption parallel zum niedriger, Wert der Chloranalyse und die hohe Hydroxylabsorpilion parallel zu hohen Chlorwerten läuft; daraus wird abgeleitet, daß eine Mischung aus der Epoxy-Verbindung und Chlorhydrin erhalten worden ist. Diese Fraktionen werden vereinigtabsorption parallel to the low, value of the chlorine analysis and the high hydroxyl absorption parallel to high Chlorine values running; it is deduced from this that a mixture of the epoxy compound and chlorohydrin is obtained has been. These factions will be united
ω und zur Umsetzung mit Aminen verwendet.ω and used for reaction with amines.
5-[3-(tert.-Butylamino)-2-hydroxypropyloxy]-tetralon (oder auch 5-f.(3-tert.-Butylamino)-2-hydroxypropyloxy]-5- [3- (tert-Butylamino) -2-hydroxypropyloxy] -tetralone (or also 5-f. (3-tert-Butylamino) -2-hydroxypropyloxy] -
3,4-dihydro-l(2H)-naphthalinon)3,4-dihydro-l (2H) -naphthalenone)
OHOH
-CH-CH2CI/ oder -/1O-CH2CH CH2\ + H2NC(CH,).,-CH-CH 2 CI / or - / 1 O-CH 2 CH CH 2 \ + H 2 NC (CH,).,
O < O <
O —CH2CH-CH,- NH UCH1), · HCI OHO —CH 2 CH — CH, —NH UCH 1 ), · HCl OH
6 ml der Mischung der Epoxy- und Chlorhydrin-Verbindungen gemäß Beispiel 2 werden in 100 ml 95%igcm Alkohol gclösl, 24 ml t-Biitylamin zugegeben und die Mischung 2 Stunden auf einem Dampfbad unier Rückfluß gekocht. Dann wird das Lösungsmittel abgestreift, der Rückstand mit einer gesättigten Natriumbicarbo-6 ml of the mixture of epoxy and chlorohydrin compounds According to Example 2, 24 ml of t-biitylamine are added in 100 ml of 95% alcohol and the Mix on a steam bath under reflux for 2 hours cooked. Then the solvent is stripped off, the residue with a saturated sodium bicarbonate
5 65 6
natlösung und Äther verrieben, und es werden 9,2 g der nitril umkristallisiert; F. 170 bis 171'3C.sodium solution and ether triturated, and 9.2 g of nitrile are recrystallized; F. 170 to 171 ' 3 C.
Base abfiltriert. Diese wird mit alkoholischer HCI be- Nach zwei Umkristallisationen aus Acetonitril: F. 226Base filtered off. After two recrystallizations from acetonitrile: F. 226
handelt, und das ausgefallene NaCI wird abfiltriert. Die bis 228°C.acts, and the precipitated NaCl is filtered off. The up to 228 ° C.
Lösung wird abgestreift und der Rückstand aus Aceto-Solution is stripped off and the residue from aceto-
5-[2-Hydrov.y-3-(isopropylamino)-propyIoxy]-tetralon O5- [2-Hydroxy-3- (isopropylamino) propyoxy] tetralone O
OCH,—CH CHJ oder -/-OCH1CH-CH^Cl \+ IsopropylaminOCH, -CH CHJ or - / - OCH 1 CH-CH ^ Cl \ + isopropylamine
" T "iH )"T" i H )
OHOH
-OCH2CH-CH2NH-CH(CHj): · HCl-OCH 2 CH-CH 2 NH-CH (CHj): · HCl
7 ml der Mischung aus der Epoxy- ui.J der Chlorhydrinverbindung werden in 10OmI 95%igem Alkohol gelöst. 28 ml Isopropylamin zugegeben und die Lösung 2 Stunden unter Rückfluß gekocht. Das Lösungsmittel wird abgestreift und der Rückstand mit einer gesättigten Natriumbicarbonatlösung verrieben, mit Äther, der mit Wasser gewaschen wurde, extrahiert und die Lösung getrocknet. Es wird die errechnete Menge an alkoholischer HCI zugegeben, um das Hydrochlorid zu bilden, das abfiltriert wird (4 g). Nach zwei Umkristallisationen aus Alkohol erhält man die analysenreine Probe: F. 198.5 bis 199,5"C.7 ml of the mixture of the epoxy and the chlorohydrin compound are dissolved in 10OmI 95% alcohol. 28 ml of isopropylamine are added and the solution Boiled under reflux for 2 hours. The solvent is stripped off and the residue with a saturated Triturated sodium bicarbonate solution, extracted with ether, which was washed with water, and the Solution dried. The calculated amount of alcoholic HCl is added in order to add the hydrochloride form, which is filtered off (4 g). The analytically pure one is obtained after two recrystallizations from alcohol Sample: F. 198.5 to 199.5 "C.
Beispiel 5
5-[2-Hydroxy-3-(iscpropylamino)-propyloxy]-tetralonExample 5
5- [2-Hydroxy-3- (iscpropylamino) propyloxy] tetralone
O OHO OH
OCH2-CHOCH 2 -CH
CH2 + Isopropylamin + HClCH 2 + isopropylamine + HCl
26,1 j (0,12 Mol) Epoxid (vgl. Beispiel 1) und 34,8 g (0,59 Mol) Isopropylamin in 121 ml 95%igem Äthanol werden 40 Minuten unter Rückfluß gekocht. Die gesamte Lösung wird abgedampft und ergibt einen Rückstand, der aus 240 m! Cyclohexan umkristallisiert wird unter Bildung von 29.5 g Produkt: F. 77 bis 800C. Dieses wird in 135 ml Chloroform gelöst, ur;d es wird HCI-Gas ein-26.1 j (0.12 mol) of epoxide (see. Example 1) and 34.8 g (0.59 mol) of isopropylamine in 121 ml of 95% ethanol are refluxed for 40 minutes. The entire solution is evaporated and gives a residue that consists of 240 m! Cyclohexane is recrystallized with the formation of 29.5 g of product: F. 77 to 80 0 C. This is dissolved in 135 ml of chloroform, ur; the HCl gas is
O =O =
OCH2CH-CH2NH-CH(Ch3I2 ■ HCIOCH 2 CH-CH 2 NH-CH (Ch 3 I 2 ■ HCI
geleitet, bis die Lösung sauer ist. Dann werden 25 ml j Äther zugegeben und so lange gerührt, bis Feststoffe ausfallen. Es werden weitere 240 ml Äther zugegeben.until the solution is acidic. Then 25 ml j ether added and stirred until solids precipitate. Another 240 ml of ether are added.
und das Rühren wird eine Zeit lung fortgesetzt, filtriert.and stirring is continued for a time, filtered.
mit Äther gewaschen und getrocknet. Man erhält 33 gwashed with ether and dried. 33 g are obtained
Produkt: F. 195 bis I97,5°C. Nach lier Umkristallisation 4i aus 320 ml absolutem Äthanol: F. 196,5 bis 1980C.Product: m.p. 195 to 197.5 ° C. After recrystallization lier 4i from 320 ml of absolute ethanol: mp 196.5 to 198 0 C.
Beispiel 6
5-[(3-tert.-Butylamino)-2-hydroxypropyloxy]-tetralonExample 6
5 - [(3-tert-butylamino) -2-hydroxypropyloxy] tetralone
OCH2-CH CH2 +HNC(CH,).,OCH 2 -CH CH 2 + HNC (CH,).,
O + HCIO + HCI
20,1 g (0,918 Mol) Epoxid und 33 g tert.-Butylamin in 90 ml 95%igem Äthanol werden 40 Minuten unter Rückfluß gekocht. Die Gesamtlösung wird abgedampfi und ergibt einen Rückstand, der aus 90 ml Cyclohexan unter Bildung von 25,8 g Produkt: F. 84 bis 86°C. kristallisiert. Dieses wird in 115 ml Chloroform gelöst und HCI-Gas eingeleitet, bis die Lösung sauer ist, dann ab-20.1 g (0.918 mol) of epoxide and 33 g of tert-butylamine in 90 ml of 95% ethanol are refluxed for 40 minutes. The entire solution is evaporated and gives a residue which, from 90 ml of cyclohexane, gives 25.8 g of product: mp 84 to 86 ° C. crystallized. This is dissolved in 115 ml of chloroform and HCI gas is passed in until the solution is acidic, then
OH
O-CH;-CH-CH2NH-C(CH,). · HCIOH
O-CH; -CH-CH 2 NH-C (CH,). · HCI
gekühlt und mit 17 ml Äther verdünnt. Nach dem Abtrennen der Kristalle werden weitere 2,5 ml Äther zugegeben und das Rühren eine Zeit lang fortgesetzt. Die Kristalle werden abfiltriert. mit Äther gewaschen und getroLKiiet. und man erhält 28 g Produkt: F. 223 bis 225"C. Nach Umkristallisation aus absolutem Äthanol erhält man ein Prodiik' vom F. 223,5 bis 225.5°C.cooled and diluted with 17 ml of ether. After detaching a further 2.5 ml of ether are added to the crystals and stirring is continued for a while. the Crystals are filtered off. washed with ether and dried. and 28 g of product are obtained: F. 223 bis 225 "C. After recrystallization from absolute ethanol, a product with a melting point of 223.5 to 225.5 ° C. is obtained.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76185768A | 1968-09-23 | 1968-09-23 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1948144A1 DE1948144A1 (en) | 1970-03-26 |
| DE1948144B2 DE1948144B2 (en) | 1979-05-03 |
| DE1948144C3 true DE1948144C3 (en) | 1980-01-17 |
Family
ID=25063434
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1948144A Expired DE1948144C3 (en) | 1968-09-23 | 1969-09-23 | 1 - (I -Keto-tetrahydronaphthyl-5-oxy) ^ -hydroxy-S-alkylaminopropanes, process for their preparation and pharmaceutical composition based on them |
| DE1967162A Expired DE1967162C3 (en) | 1968-09-23 | 1969-09-23 | 5-methoxytetralone (1) derivatives, process for their preparation and their use |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1967162A Expired DE1967162C3 (en) | 1968-09-23 | 1969-09-23 | 5-methoxytetralone (1) derivatives, process for their preparation and their use |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US3641152A (en) |
| JP (1) | JPS4843734B1 (en) |
| BE (1) | BE739195A (en) |
| CH (1) | CH525183A (en) |
| DE (2) | DE1948144C3 (en) |
| DK (2) | DK125588B (en) |
| ES (1) | ES371737A1 (en) |
| FI (1) | FI51936C (en) |
| FR (1) | FR2018626B1 (en) |
| GB (1) | GB1223527A (en) |
| IT (1) | IT1033032B (en) |
| NL (1) | NL139166B (en) |
| NO (1) | NO128869B (en) |
| SE (1) | SE362414B (en) |
| ZA (1) | ZA695648B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE755071A (en) * | 1969-09-17 | 1971-02-22 | Warner Lambert Pharmaceutical | METHOD FOR RESOLVING DL-5- / 3- (TERBUTYLAMINO) -2- HYDROXY-PROPOXY / -3,4-DIHYDRO-1 (2H) NAPHTHALENONE |
| US3959486A (en) * | 1970-05-27 | 1976-05-25 | Imperial Chemical Industries Limited | Method for producing β-adrenergic blockage with alkanolamine derivatives |
| DE2130393C3 (en) * | 1970-06-22 | 1981-02-26 | E.R. Squibb & Sons Inc., New York, N.Y. (V.St.A.) | 6,7-dihydroxy -5,6,7,8-tetrahydronaphthyloxyaminopropanols and their salts with acids and their use in combating heart disease |
| FR2119843B1 (en) * | 1970-12-28 | 1974-03-22 | Laroche Navarro Labo | |
| JPS5122737Y2 (en) * | 1972-12-30 | 1976-06-11 | ||
| US3966749A (en) * | 1975-02-10 | 1976-06-29 | Interx Research Corporation | Novel synthesis of optically active m-acyloxy-α-[(methylamino)methyl]benzyl alcohols, the pharmaceutically acceptable acid addition salts thereof and intermediate useful in the preparation thereof |
| GB1493848A (en) * | 1975-07-24 | 1977-11-30 | Beecham Group Ltd | Aryltetralins |
| CH621330A5 (en) * | 1976-05-14 | 1981-01-30 | Sandoz Ag | |
| DE2810869A1 (en) * | 1977-03-24 | 1978-09-28 | Sandoz Ag | 3-AMINO-2-HYDROXYPROPOXY DERIVATIVES, THEIR PRODUCTION AND USE |
| US4176183A (en) * | 1977-05-02 | 1979-11-27 | Merck & Co., Inc. | Novel naphthyridines |
| US4270005A (en) * | 1977-11-14 | 1981-05-26 | Pfizer Inc. | 1,9-Dihydroxyoctahydrophenanthrenes and intermediates therefor |
| CH641147A5 (en) * | 1979-01-17 | 1984-02-15 | Sandoz Ag | 3-AMINO-2-HYDROXYPROPOXYARYL DERIVATIVE, ITS PREPARATION AND REMEDIES CONTAINING THEREOF. |
| DE2943406A1 (en) * | 1979-10-26 | 1981-05-07 | Basf Ag, 6700 Ludwigshafen | AMINO DERIVATIVES OF 2-METHYL-5- (2-HYDROXYSTYRYL) -1,3,4-THIADIAZOL |
| FR2507181A1 (en) * | 1981-06-05 | 1982-12-10 | Sanofi Sa | NOVEL ETHERS OF PHENOL ACTIVE ON THE CARDIOVASCULAR SYSTEM, PROCESS FOR PREPARING THEM AND USE THEREOF IN MEDICAMENTS |
| SE8801518D0 (en) * | 1988-04-22 | 1988-04-22 | Astra Pharma Prod | A NOVEL PROCESS |
| US5225565A (en) * | 1988-09-15 | 1993-07-06 | The Upjohn Company | Antibacterial 3-(fused-ring substituted)phenyl-5β-amidomethyloxazolidin-2-ones |
| ES2065278B1 (en) * | 1993-06-24 | 1995-09-01 | Medichem Sa | LEVOBUNOLOL ENANTIOSELECTIVE PROCEDURE FOR OBTAINING. |
| JP2004511435A (en) * | 2000-07-27 | 2004-04-15 | ファルマシア・コーポレーション | Combination therapy of an epoxy-steroidal aldosterone antagonist and a β-adrenergic antagonist for the treatment of congestive heart failure |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH454839A (en) | 1962-12-17 | 1968-04-30 | Ici Ltd | Process for the preparation of homocyclic compounds |
-
1968
- 1968-09-23 US US761857A patent/US3641152A/en not_active Expired - Lifetime
-
1969
- 1969-08-06 ZA ZA695648A patent/ZA695648B/en unknown
- 1969-08-22 GB GB41987/69A patent/GB1223527A/en not_active Expired
- 1969-09-11 FR FR696930899A patent/FR2018626B1/fr not_active Expired
- 1969-09-17 NL NL696914077A patent/NL139166B/en not_active IP Right Cessation
- 1969-09-18 JP JP44073683A patent/JPS4843734B1/ja active Pending
- 1969-09-22 IT IT22348/69A patent/IT1033032B/en active
- 1969-09-22 NO NO693770A patent/NO128869B/no unknown
- 1969-09-22 CH CH1430069A patent/CH525183A/en not_active IP Right Cessation
- 1969-09-22 DK DK503669AA patent/DK125588B/en unknown
- 1969-09-22 SE SE13017/69A patent/SE362414B/xx unknown
- 1969-09-22 BE BE739195D patent/BE739195A/xx not_active IP Right Cessation
- 1969-09-22 ES ES371737A patent/ES371737A1/en not_active Expired
- 1969-09-23 FI FI692717A patent/FI51936C/en active
- 1969-09-23 DE DE1948144A patent/DE1948144C3/en not_active Expired
- 1969-09-23 DE DE1967162A patent/DE1967162C3/en not_active Expired
-
1971
- 1971-11-12 DK DK556771AA patent/DK128536B/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH454839A (en) | 1962-12-17 | 1968-04-30 | Ici Ltd | Process for the preparation of homocyclic compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| CH525183A (en) | 1972-07-15 |
| SE362414B (en) | 1973-12-10 |
| IT1033032B (en) | 1979-07-10 |
| GB1223527A (en) | 1971-02-24 |
| DK125588B (en) | 1973-03-12 |
| FI51936C (en) | 1977-05-10 |
| FI51936B (en) | 1977-01-31 |
| US3641152A (en) | 1972-02-08 |
| DK128536B (en) | 1974-05-20 |
| NO128869B (en) | 1974-01-21 |
| DE1967162B1 (en) | 1980-07-31 |
| DE1948144A1 (en) | 1970-03-26 |
| ZA695648B (en) | 1971-03-31 |
| DE1967162C3 (en) | 1981-03-19 |
| NL139166B (en) | 1973-06-15 |
| ES371737A1 (en) | 1972-03-16 |
| NL6914077A (en) | 1970-03-25 |
| FR2018626B1 (en) | 1973-06-08 |
| DE1948144B2 (en) | 1979-05-03 |
| BE739195A (en) | 1970-03-23 |
| JPS4843734B1 (en) | 1973-12-20 |
| FR2018626A1 (en) | 1970-06-26 |
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