DE1948144B2 - 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 them

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DE1948144B2
DE1948144B2 DE1948144A DE1948144A DE1948144B2 DE 1948144 B2 DE1948144 B2 DE 1948144B2 DE 1948144 A DE1948144 A DE 1948144A DE 1948144 A DE1948144 A DE 1948144A DE 1948144 B2 DE1948144 B2 DE 1948144B2
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hydroxy
oxy
tetrahydronaphthyl
keto
solution
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DE1948144C3 (en
DE1948144A1 (en
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Sheldon Livingston Farber
John Mendham Shavel Jun.
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Warner Lambert Co LLC
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Warner Lambert Pharmaceutical Co
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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
    • 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
    • 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
    • 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
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • 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
    • 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
    • C07D263/10—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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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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  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Urology & Nephrology (AREA)
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  • Biomedical Technology (AREA)
  • 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)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Epoxy Compounds (AREA)

Description

in der R einen Alkylrest mit bis zu 6 Kohlenstoffatomen bedeutet, sowie ihre pharmazeutisch verträglichen Säureadditionssalze. isin which R denotes an alkyl radical with up to 6 carbon atoms, as well as their pharmaceutically acceptable acid addition salts. is

Z 5-[3-{tert.-ButyIamino)-2-hydroxypropyloxy]-tetralon.Z 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 Herstellung der Verbindungen 20 nach Anspruch 1, dadurch gekennzeichnet, daß man4. Process for the preparation of the compounds 20 according to claim 1, characterized in that one in jeweils an sich bekannter Weise das Tetralonol der Formelin a manner known per se, the tetralonol of the formula

OHOH

(H)(H)

2525th

JOJO

.rait einer Verbindung der allgemeinen Formel.rait of a compound of the general formula

X-CH2-CHOH-CH2X (III) J5X-CH 2 -CHOH-CH 2 X (III) J5

X-CH2-CH — CH2 OX-CH 2 -CH - CH 2 O

(IV)(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

0-CH1-CHOH-CH2Cl (V)0-CH 1 -CHOH-CH 2 Cl (V)

/~V-OCH2-CH—CH2 (VI)/ ~ V-OCH 2 -CH — CH 2 (VI)

»-ο»-Ο

4545

5050

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- bo sitzt, umsetzt.in the R the meaning given above be bo sits, implements.

5. Pharmazeutische Zusammensetzung, enthaltend eine oder mehrere Verbindungen nach Anspruch I neben üblichen Träger- und Hilfsstoffen.5. A pharmaceutical composition containing one or more compounds according to claim I in addition to customary carriers and auxiliaries.

6565 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 jj-adrenerge Blockierungswirkung auf und sind deshalb wertvoll in Fällen von Angina pectoris, Herzarrhythmien und verwandten cardiovasculären Erkrankungen.The compounds of the invention have a jj-adrenergic blocking effect and are therefore valuable in cases of angina, cardiac arrhythmias and related cardiovascular diseases.

Es wurde gefunden, daß die erfindungsgemäßen Verbindungen bei Säuretieren, z. B. Hunden, Katzen oder Affen, sowohl bei oraler Verabreichung als auch bei Injektion eine /f-adrenerge Blockiemngswirkung 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 Blockiemngswirkung der erfindungsgemäßen Verbindungen wird durch Verabreichung verschiedener Dosen von Isoproterenol nach Behandlung des Versuchstiers mit den erfindungsgemäßen Verbindungen bestimmt Es wurde gefunden, daß die Ansprechempfindlichkeit der Herzkontraktionskraft 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]-tetralon-hydrochlorid anästhesierten Hunden in einer Dosis von 6,7 ug/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 according to the invention are effective in acid animals, e.g. B. dogs, cats or Monkeys, both when administered orally and when injected, have an / f-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 effect of the compounds according to the invention is achieved by administration of various types Doses of isoproterenol after treatment of the test animal with the compounds according to the invention It has been found that the responsiveness of the force of contraction of the heart and the Heart rate compared to isoproterenol by the compounds according to the invention to different extents, depending on the dose administered, blocked. As an example of the 0-blocking effect of the compounds according to the invention was the 5- [3- (tert-butylamino) -2-hydroxypropoxy] -tetralone hydrochloride anesthetized dogs in a dose of 6.7 µg / kg administered intravenously. The dogs were then given 03 μg / kg of isoproterenol. 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 Lactate oder Salicylate.The pharmaceutically acceptable acid addition salts 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 lactates or salicylates.

Die vorliegende Erfindung umfaßt auch die d- oder I-Enantiomeren oder die racemische Mischung sowie ihre oben beschriebenen Salze.The present invention also encompasses the d- or I-enantiomers or the racemic mixture and their salts described above.

Vergleichsdaten, aus denen sich die Überlegenheit der erfindungsgemäßen Verbindungen ergibt, sind in J. Med. Chem. 1970, 684 und folgende veröffentlicht worden.Comparative data showing the superiority of the compounds according to the invention are given in J. Med. Chem. 1970, 684 et seq.

Ein weiterer Gegenstand der vorliegenden Erfindung sind Dosierungsformen der erfindungjgemäßen Verbindungen, die zur oralen oder parenteralen Verabr^hhung 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 bekannten 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. B. sterilem Wasser, einer sterilen Salzlösung oder Öl, löst oder suspendiert.Another object of the present invention are 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 can easily be prepared by methods known to the person skilled in the art. For example, tablets can be produced by adding the active ingredient with known excipients, such as. B. Calcium phosphate. Lactose, mannitol mixed with e.g. B. granulated acacia or a gelatin solution 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 B. sterile water, a sterile saline solution or oil, dissolves or suspends.

Ein weiterer Gegenstand der Erfindung ist ein Ver-Another object of the invention is a ver

fahren zur Herstellung dieser Verbindungen,drive to make these connections,

In den Verbindungen der Formeln IH und IV ist X ■£, B. Cl. Die Ausgangsmaterialien II und IH oder II undIn the compounds of the formulas IH and IV, X ■ £, B. Cl. The starting materials II and IH 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 MoI) einer Base, wie z.B. Natriumhydroxid, Kaliumhydroxid oder Natriummethylat, enthält, zu den entsprechenden Zwischenprodukten der Formeln V und VI umgesetzt. Die so erhaltenen ZwischenprodukteIV are either refluxed together without solvent or at room temperature in an alcoholic solution containing a small excess (1.1 mol) of a base such as sodium hydroxide, Potassium hydroxide or sodium methylate, to the corresponding intermediates of formulas V and VI implemented. 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-

IOIO

gemeinen Formel RN H2 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.common formula RN H2 treated. Suitable solvents for these reactions include, for example lower aliphatic alcohols, such as. B, methanol or ethanol. The desired end products will be 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 using the corresponding ether, which is commercially available Treated 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.

Beispiel 1 5-(23-Epoxypropyloxy)-1 -tetralonExample 1 5- (23-epoxypropyloxy) -1-tetralone

Q-CH2-CH CH2 Q-CH 2 -CH CH 2

+ Cl-CH,-CH + Cl-CH, -CH

CH2 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 Epichiorhydrin 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 180 ml Wpsser und 250 ml Chloroform ver- jo teilt. Die abgetrennte wäßrige Schicht wird mit weiteren 100 ml Chloroform extrahiert. Die vereinigten organischen Phasen werden zweimal mit 100 ml Wasser gewaschen, getrocknet umj eingeengt und ergeben 41 g Rückstand. Dieser wird in 280 ml Ärher gelöst, abgekühlt, und es werden 4,5 g Kristalle abfiltriert. Das Filtrat wird abgedampft unter Bildung von 34 g Rückstand; dieser wird bei 136 bis I44°C/0,106 mbar destilliert und ergibt 26,1 g Produkt.A solution of 83 g of NaOH in 36.5 ml of water becomes diluted with 292 ml of ethanol, and then 28.5 g of 5-hydroxy - «- tetralone and 98 g of epichiorhydrin are added. The mixture is stirred for 16 hours at room temperature and then left to stand for 2 to 3 days. the The solution is then evaporated and the residue is mixed between 180 ml of water and 250 ml of chloroform Splits. The separated aqueous layer is extracted with another 100 ml of chloroform. The united organic Phases are washed twice with 100 ml of water, dried and concentrated and give 41 g Residue. This is dissolved in 280 ml of ether, cooled and 4.5 g of crystals are filtered off. That The filtrate is evaporated to give 34 g of residue; this is distilled at 136 to 144 ° C./0.106 mbar and yields 26.1 g of product.

+ CI-CH2-CH+ CI-CH 2 -CH

13,8 g 5-Hydroxytetralon werden in 75 ml Epichiorhydrin gelöst, und die Lösung wird 44 Stunden unter Rückfluß gekocht. Das überschüssige Epichiorhydrin wird im Vakuum durch Erhitzen auf einem Wasserbad entfernt und der Rückstand in einer Kurzweg-Mikrodestillationsapparatur destilliert. Man erhält 5 Fraktionen, Kp. 160 bis 2IO°C/O,3 mbar. Alle haben eine starke Keton-Absorption, und die beiden letzten weisen13.8 g of 5-hydroxytetralone are dissolved in 75 ml of epichiorhydrin dissolved, and the solution is refluxed for 44 hours. The excess epichiorhydrin 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

Beispiel 2Example 2

-(Tetralon-5-oxy)-l,2-epoxy-propan 3-(Tetralon-5-oxy)-l-chlor-2-hydroxy-propan- (Tetralone-5-oxy) -l, 2-epoxy-propane 3- (Tetralone-5-oxy) -l-chloro-2-hydroxy-propane

CH2 -> < J— \OCH2—CH CH2 CH 2 -><J \ OCH 2 CH 2 CH

oder 4-OCH2CH-CH2CIor 4- OCH 2 CH-CH 2 CI

OHOH

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

4Ί absorption parallel zum niedrigen Wert der Chloranalyse und die hohe Hydroxylabsorption parallel zu hohen Chlorwerten läuft; daraus wird abgeleitet, daß eine Mischung aus der Epoxy-Verbindung und Chlorhydrin erhalten worden ist. Diese Fraktionen werden vereinigt und zur Umsetzung mit Aminen verwendet.4Ί absorption parallel to the low value of the chlorine analysis and the high hydroxyl absorption runs parallel to high chlorine levels; from this it is deduced that a mixture from the epoxy compound and chlorohydrin. These factions will be united and used for reaction with amines.

Beispiel 3Example 3

5-[3-(tert.-Butylamino)-2-hydroxypropyloxy]-tetralon (oder auch 5-r(3-tert.-Butylamino)-2-hydroxypropyloxy]-5- [3- (tert-Butylamino) -2-hydroxypropyloxy] -tetralone (or also 5-r (3-tert-butylamino) -2-hydroxypropyloxy] -

3,4-dihydro-l(2H)-naphthalinon)3,4-dihydro-l (2H) -naphthalenone)

OHOH

/ V/ V

PCH2-CH-CH2Cl/ oder -fO—CH2CH CH2\ + H2NC(CH,).,PCH 2 -CH-CH 2 Cl / or -fO — CH 2 CH CH 2 \ + H 2 NC (CH,).,

6 ml der Mischung der Epoxy- und Chlorhydrin-Verbindungen gemäß Beispiel 2 werden in 100 ml 95%igcm Alkohol gelöst, 24 ml t-Butylamin zugegeben und die /~^O—CH2CH-CH2-NH-C(CH,)., · HCI6 ml of the mixture of the epoxy and chlorohydrin compounds according to Example 2 are dissolved in 100 ml of 95% alcohol, 24 ml of t-butylamine are added and the / ~ ^ O-CH 2 CH-CH 2 -NH-C (CH, )., · HCI

Mischung 2 Stunden auf einem Dampfbad unter Rückfluß gekocht. Dann wird das Lösungsmittel abgestreift, der Rückstand mit einer gesättigten Natriumbicarbo-Mixture refluxed on a steam bath for 2 hours. Then the solvent is stripped off, the residue with a saturated sodium bicarbonate

natlösung und Äther verrieben, und es werden 9,2 g der Base abfiltriert. Diese wird mit alkoholischer HCI behandelt, und das ausgefallene NaCI wird abfiltriert. Die Lösung wird abgestreift und der Rückstand aus Acetonitril umkristallisiert; F, 170 bis 17!°GNatural solution and ether triturated, and 9.2 g of the base are filtered off. This is treated with alcoholic HCI, and the precipitated NaCl is filtered off. The solution is stripped off and the residue from acetonitrile recrystallized; F, 170 to 17! ° G

Nach zwei Umkristallisationen aus Acetonitril; F. 226 bis 228° C.After two recrystallizations from acetonitrile; F. 226 up to 228 ° C.

Beispiel 4 5-[2-Hydroxy-3-(isopropyIamino)-propyloxy]-tetralonExample 4 5- [2-Hydroxy-3- (isopropylamino) propyloxy] tetralone

I2-CH-I 2 -CH-

-CH2; oder -/-OCH2CH-CH2Cn+ Isopropylamin-CH 2 ; or - / - OCH 2 CH-CH 2 Cn + isopropylamine

I OH JI OH J

OHOH

V-OCH,CH—CH2NH—CH(CHj)2 · HClV-OCH, CH-CH 2 NH-CH (CHj) 2 • HCl

7 ml der Mischung aus der Epoxy- i;nd der Chlorhydrinverbindung werden in 100 ml 95°/oigem 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, der7 ml of the mixture of the epoxy and chlorohydrin compounds are dissolved in 100 ml of 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 Sodium bicarbonate solution triturated with ether, the

mit Wasser gewaschen wurde, extrahiert und die Lösung getrocknet Es wird die errechnete Menge an alkoholischer HCI zugegeben, um das Hydiochlorid zu bilden, das abfiltriert wird (4 g). Nach zwei Umkristalli-'iationen aus Alkohol erhält man die analysenreine Probe: F. 198,5 bis 199,5° C.Was washed with water, extracted and the solution dried. The calculated amount of alcoholic HCl added to form the hydrochloride, which is filtered off (4 g). After two recrystallizations the analytically pure sample is obtained from alcohol: F. 198.5 to 199.5 ° C.

Beispiel 5 5-[2-Hydroxy-3-(isopropyIamino)-propyloxy]-tetralonExample 5 5- [2-Hydroxy-3- (isopropylamino) propyloxy] tetralone

/
OCH2-CH/
OCH 2 -CH

-CH2 + Isopropylamin + HCl-CH 2 + isopropylamine + HCl

26,1 g (0,12 Mol) Epoxid (vgl. Beispiel 1) und 34,8 g (0,59 Mol) Isopropyiamin in 121 ml 95%igem Äthanol werden 40 Minuten unter Rückfluß gekocht. Die gesamte Lösung wird abgedampft und ergibt einen Rückstand, der aus 240 ml Cyclohexan umkristallisiert wird unter Bildung von 29,5 g Produkt: F. 77 bis 80°C. Dieses wird in 135 ml Chloroform gelöst, 'ind es wird HCI-Gas ein-26.1 g (0.12 mol) of epoxide (see Example 1) and 34.8 g (0.59 mol) isopropylamine in 121 ml of 95% ethanol are refluxed for 40 minutes. The whole Solution is evaporated to give a residue which is recrystallized from 240 ml of cyclohexane under Formation of 29.5 g of product: mp 77 to 80 ° C. This is dissolved in 135 ml of chloroform, 'ind it is HCI gas

OHOH

OCH2CH-CH2NH-CH(CHj)2 · HClOCH 2 CH-CH 2 NH-CH (CHj) 2 • HCl

geleitet, bis die Lösung sauer ist. Dann werden 25 mluntil the solution is acidic. Then 25 ml

in Äther zugegeben und so lange gerührt, bis Feststoffe ausfallen. Es werden weitere 240 ml Äther zugegeben, und das Rühren wird eine Zeit lang fortgesetzt, filtriert, mit Äther gewaschen und getrocknet Man erhält 33 g Produkt: F. 195 bis 197,5°C. Nach der Umkristallisation aus 320 ml absolutem Äthanol: F. 196,5 bis I98°C. added in ether and stirred until solids precipitate. A further 240 ml of ether are added and the stirring is continued for a while, filtered, washed with ether and dried. 33 g of product are obtained: mp 195 to 197.5 ° C. After recrystallization from 320 ml of absolute ethanol: mp 196.5 to 198 ° C.

Beispiel 6 5-[(3-tert.-Butylamino)-2-hydroxypropyloxy]-tetralonExample 6 5 - [(3-tert-butylamino) -2-hydroxypropyloxy] tetralone

OCH2-CH CH2 +HNC(CHj)3 OCH 2 -CH CH 2 + HNC (CHj) 3

+ HCI+ 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 abgedampft 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 crystallizes from 90 ml of cyclohexane with formation of 25.8 g of product: mp 84 to 86.degree This is dissolved in 115 ml of chloroform and HCI gas is passed in until the solution is acidic, then

OHOH

)-CH2-CH CH2NH-C(CHj), · HCl) -CH 2 -CH CH 2 NH-C (CHj), · HCl

gekühlt und mil 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 getrocknet, und man erhält 28 g Produkt: F. 223 bis 225°C. Nach Umkristallisation aus absolutem Äthanol erhält man ein Produkt vom F. 223,5 bis 225,5°C.refrigerated and diluted with 17 ml of ether. After separation 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)

Patentansprüche:Patent claims: 1. 1 -{1 -Keto-tetrahydronaphthyl-5-oxy)-2-hydroxy-3-aIkylamino-propane der allgemeinen For- 5 nie!1. 1 - {1-keto-tetrahydronaphthyl-5-oxy) -2-hydroxy-3-alkylamino-propane of the general formula 5 never! 0-CH2-CHOH-CH2-NH-R (I)0-CH 2 -CHOH-CH 2 -NH-R (I) IOIO
DE1948144A 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 Expired DE1948144C3 (en)

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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
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US5225565A (en) * 1988-09-15 1993-07-06 The Upjohn Company Antibacterial 3-(fused-ring substituted)phenyl-5β-amidomethyloxazolidin-2-ones
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AU7905001A (en) * 2000-07-27 2002-02-13 Pharmacia Corp Epoxy-steroidal aldosterone antagonist and beta-adrenergic antagonist combination therapy for treatment of congestive heart failure

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CH525183A (en) 1972-07-15

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