CH509256A - 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives - Google Patents
1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensivesInfo
- Publication number
- CH509256A CH509256A CH1167870A CH1167870A CH509256A CH 509256 A CH509256 A CH 509256A CH 1167870 A CH1167870 A CH 1167870A CH 1167870 A CH1167870 A CH 1167870A CH 509256 A CH509256 A CH 509256A
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- hydroxy
- tert
- compounds
- optically active
- Prior art date
Links
- 208000001953 Hypotension Diseases 0.000 title abstract 2
- 208000021822 hypotensive Diseases 0.000 title abstract 2
- 230000001077 hypotensive effect Effects 0.000 title abstract 2
- 235000013849 propane Nutrition 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- NSFIAKFOCAEBER-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methylphenyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(O)(C(O)=O)C(O)(C(O)=O)C1=CC=C(C)C=C1 NSFIAKFOCAEBER-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 2
- 238000001640 fractional crystallisation Methods 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000000059 bradycardiac effect Effects 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HZBOQOXQPRQKTF-UHFFFAOYSA-N bis(4-methylphenyl) 2,3-dihydroxybutanedioate Chemical compound C1=CC(C)=CC=C1OC(=O)C(O)C(O)C(=O)OC1=CC=C(C)C=C1 HZBOQOXQPRQKTF-UHFFFAOYSA-N 0.000 description 2
- 229940039009 isoproterenol Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- WICGEDGLANNLND-UHFFFAOYSA-N 1-(tert-butylamino)-3-(2-prop-2-ynoxyphenoxy)propan-2-ol oxalic acid Chemical compound OC(=O)C(O)=O.CC(C)(C)NCC(O)COC1=CC=CC=C1OCC#C WICGEDGLANNLND-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- YIUIVFFUEVPRIU-UHFFFAOYSA-N 8-chlorotheophylline Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21 YIUIVFFUEVPRIU-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000001778 cardiodepressive effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000003944 halohydrins Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- UFNAECVCKNHAKN-UHFFFAOYSA-N pargolol Chemical compound CC(C)(C)NCC(O)COC1=CC=CC=C1OCC#C UFNAECVCKNHAKN-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- 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
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/275—Nitriles; Isonitriles
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
(A) Cmpds. (I) R = CN or (3-6C) alkinyloxy (B) Salts of (I). beta-Adrenolytics and hypotensives. Dose 1-300 mg. (p.o.), 0.1-25 mg. (parent). (a) + Me3CNHCONHCMe3 Z = or -CHOHCH2Hal. (b) + HalCMe (c) (III) + H2NCMe3 (d) By deprotection of an O- or N-protected deriv. of (I), e.g. an O- or N-acyl or benzyl deriv. (e) (f) (g) (I) (R=NH2) (I) (R=CN).
Description
Verfahren zur Herstellung von neuen racemischen oder optisch aktiven 1-Nitrilophenoxy oder 1-Alkinyloxyphenoxy-2-hydroxy-3-tert.-butylaminopropanen und deren Salzen
Die Erfindung betrifft ein Verfahren zur Herstel- lung von neuen 1 - Phenoxy - 2 - hydroxy - 3 - tert. - butyl- aminopropanen der Formel I
EMI1.1
in der R eine Nitrilgruppe (-C=-N) oder eine Alkinyloxygruppe mit 3 bis 6 Kohlenstoffatomen (vorzugsweise in 2-Stellung) bedeutet, sowie von deren physiologisch verträglichen Salzen, mit therapeutisch wertvollen Eigenschaften an Warmblütern.
Die neuen Verbindungen werden erfindungsgemäss in folgender Weise hergestellt:
Hydrolytische Abspaltung einer Schutzgruppe aus einem Amin der Formel II
EMI1.2
in der R die obengenannte Bedeutung hat und Sch eine übliche leicht abspaltbare Gruppe, z. B. die Acetylgruppe, bedeutet.
Die Ausgangsverbindungen sind zum Teil bereits bekannt, zum Teil können sie nach üblichen Verfahren gewonnen werden, indem man beispielsweise ein Epoxyd bzw. ein Halogenhydrin der Formeln
EMI1.3
bzw.
EMI1.4
in denen Hal ein Halogen darstellt, mit einem Amin der Formel
EMI1.5
reagieren lässt, oder dass man eine Verbindung der Formel
EMI1.6
in der Kt Wasserstoff oder ein Kation, beispielsweise ein Alkalimetallion, bedeutet, mit einer Verbindung der Formel
EMI1.7
in der Z die Gruppe
EMI1.8
oder-CHOH-CH.°Hal und Sch sowie Hal die obige Bedeutung haben, umsetzt.
Die Verbindungen der Formel I besitzen an der -CHOH-Gruppierung ein asymmetrisches Kohlenstoffatom und kommen daher in Form von Racematen wie auch von optisch aktiven Antipoden vor. Die optisch aktiven Verbindungen können erhalten werden, indem man entweder von optisch aktiven Ausgangsverbindungen ausgeht oder die erhaltenen Racemate auf übliche Weise, beispielsweise mittels Dibenzoyl- oder -toluylweinsäure oder 3-Bromcampher-8-sulfonsäure, in ihre optischen Antipoden spaltet.
Die erhaltenen Verbindungen der Formel I können gewünschtenfalls in üblicher Weise in ihre physiologisch verträglichen Säureadditionssalze überführt werden. Für die Salzbildung geeignete Säuren sind beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Methansulfonsäure, Maleinsäure, Essigsäure, Oxalsäure, Milchsäure, Weinsäure und 8-Chlortheophyllin.
Die Verbindungen der Formel I bzw. deren physiologisch verträglichen Säureadditionssalze haben wertvolle therapeutische, insbesondere ss-adrenolytische Eigenschaften und können daher beispielsweise zur Behandlung oder Prophylaxe von Erkrankungen der Herzkranzgefässe und zur Behandlung von Herzarrhythmien, insbesondere von Tachycardien, an Menschen eingesetzt werden. Auch die blutdrucksenkenden Eigenschaften der Verbindungen sind therapeutisch interessant.
Therapeutisch wertvoll sind dabei insbesondere die Substanzen, bei denen der Rest R in 2-Stellung steht.
Als besonders wirksam hat sich das 1-(2'-Nitrilophenoxy)-2-hydroxy-3-tert.-butylaminopropan der Formel
EMI2.1
herausgestellt. Diese Verbindung hat sich sowohl bezüglich der bradycardischen Eigenwirkung als auch bezüglich der isoproterenolantagonistischen Wirkung [Isoproterenol= 1-(3',4'-Dihydroxyphenyl)-
1 -hydroxy-2-isopropylamino äthan] im Tierexperiment an Meerschweinchen als wesentlich wirksamer und auch weniger toxisch erwiesen als das bekannte 1-(1 -(1'-Naphthoxy)-2-hydroxy-3-isopropyl- aminopropan.
Überdies tritt die bradycardische Wirkung schon bei sehr niedrigen Dosen ein und lässt sich durch höhere Dosierung nicht mehr über einen bestimmten Grenzwert hinaus steigern, was auf ein Fehlen der unerwünschten cardiodepressiven Komponente der bradycardischen Eigenwirkung hindeutet. Die Verbindung zeigt zudem eine starke antiarrhythmische Wirkung bei Strophantin-G-Intoxikationen und eine gute orale Resorption.
Eine bevorzugte Verbindung stellt auch das 1 -(2'-Propargyloxyphenoxy)-2-hydroxy-
3-tert.-butylaminopropan dar.
Als Einzeldosis der erfindungsgemäss erhältlichen Verbindungen der Formel I werden 1-300 mg (0,016 bis 5 mg/kg), vorzugsweise 15-100 mg (0,25 bis 1,66 mg/kg) für die orale Anwendung und 0,1-25 mg (0,002-0,4 mg/kg) für die parenterale Anwendung am Menschen vorgeschlagen.
Die galenische Verarbeitung der Verbindungen der Formel I zu den üblichen Anwendungsformen wie Lösungen, Emulsionen, Tabletten, Dragees oder Depotformen kann in bekannter Weise unter Heranziehung der dafür gebräuchlichen galenischen Hilfsstoffe erfolgen. Die erfindungsgemäss erhältlichen Verbindungen können auch in Kombination mit anderen pharmakodynamisch wirksamen Stoffen wie beispielsweise herzoder kreislaufwirksamen Sympathicomimetica oder Coronardilatatoren, angewendet werden.
Die folgenden Beispiele erläutern die Erfindung, ohne sie zu beschränken:
Beispiel 1
1 (2'-Nitrilophenoxy)-2-hydroxy
3-tert.-butylaminopropan HC1 2 g 1 -(2'-Nitrilophenoxy)-2-hydroxy-3 -(N-acetyl-N- tert.-butylamino)-propan werden in 20 ml Äthanol mit 4 g KOH - in 6 ml HG gelöst - versetzt und unter Rühren am Rückfluss zwei Stunden zum Sieden erhitzt.
Der Alkohol wird dann im Vakuum abdestilliert. Der Rückstand wird mit verdünnter HC1 angesäuert, zweimal ausgeäthert, die wässrige Phase mit NaOH alkalisch gestellt und die ausfallende Base in Äther aufgenommen. Die ätherische Lösung wird über MgSO4 getrocknet und der Äther abdestilliert. Als Rückstand verbleiben 650 mg Rohbase, die in wenig Äthanol gelöst wird.
Nach Zugabe von ätherischer HC1 fallen farblose Kristalle aus, die nochmals aus Äthanol/Äther umkristallisiert werden.
Fp. 160 bis 1630 C.
Analog werden erhalten:
1 -(3'-Nitrilophenoxy)-2-hydroxy-3-tert.-butyl aminopropanoxalat,
Fp. 154 bis 1570 C
1 -(4'-Nitrilophenoxy)-2-hydroxy-3 -tert.-butyl aminopropan HCl,
Fp. 187 bis 1890 C 1 -(2'-Propargyloxyphenoxy)-2-hydroxy-
3-tert.-butylaminopropanoxalat,
Fp. 132 bis 1340 C.
Beispiel 2 (-)-1 -(2'-Nitrilophenoxy)-2-hydroxy-
3-tert.-butylaminopropan HCI (Darstellung durch Racematentrennung)
24,8 g (0,1 Mol) 1 -(2'-Nitrilophenoxy)-2-hydroxy3-tert.-butylaminopropan (racemisch) werden in 100 ml absolutem Methanol gelöst und mit einer Lösung von 38,6 g (0,1 Mol) (-)-Di-p-toluylweinsäure in 150 ml absolutem Methanol vereinigt. Nach mehrstündigem Stehen bei Raumtemperatur wird die Lösung filtriert und drei Tage bei 200 C stehengelassen. Das langsam auskristallisierende Di-p-toluyltartrat wird sodann abgesaugt und nochmals in gleicher Weise umkristallisiert.
Es werden 18,2 g (-)-1-(2'-Nitrilophenoxy)-2-hydroxy- 3-tert.-butylaminopropan-di-p-toluyltartrat vom Fp. 135 bis 1370 C (Zersetzung) erhalten.
[a]2D = ¯90,so (in Methanol).
6 g dieses Tartrates werden in 100 ml Äther und 50 ml NaOH geschüttelt. Die organische Phase wird abgetrennt und über MgSO4 getrocknet. Nach Filtration wird ätherische HC1 zugegeben, wobei Kristallisation eintritt. Es werden 2,4 g Hydrochlorid vom Fp. 161 bis 1640 C gewonnen.
[a]D = + 14,70 (in Methanol).
Aus der Mutterlauge (methanolisch) des oben genannten Di-p-toluyltartrates kann nach Verdampfen des Methanols im Vakuum der rechtsdrehende Antipode erhalten und durch Behandlung mit NaOH die Base gewonnen werden. Sie lässt sich mit Hilfe von ätherischer HCI aus ätherischer Lösung als Hydrochlorid fällen.
Process for the preparation of new racemic or optically active 1-nitrilophenoxy or 1-alkynyloxyphenoxy-2-hydroxy-3-tert.-butylaminopropanes and their salts
The invention relates to a process for the production of new 1-phenoxy-2-hydroxy-3-tert. - butyl aminopropanes of the formula I.
EMI1.1
in which R denotes a nitrile group (-C = -N) or an alkynyloxy group with 3 to 6 carbon atoms (preferably in the 2-position), as well as their physiologically tolerable salts, with therapeutically valuable properties in warm-blooded animals.
According to the invention, the new compounds are prepared in the following manner:
Hydrolytic cleavage of a protective group from an amine of the formula II
EMI1.2
in which R has the meaning given above and Sch is a customary easily cleavable group, e.g. B. the acetyl group means.
Some of the starting compounds are already known, and some can be obtained by customary processes, for example by adding an epoxide or a halohydrin of the formulas
EMI1.3
or.
EMI1.4
in which Hal represents a halogen, with an amine of the formula
EMI1.5
reacts, or that you can create a compound of the formula
EMI1.6
in which Kt is hydrogen or a cation, for example an alkali metal ion, with a compound of the formula
EMI1.7
in the Z the group
EMI1.8
or-CHOH-CH. ° Hal and Sch as well as Hal have the above meaning.
The compounds of the formula I have an asymmetric carbon atom on the -CHOH group and therefore occur in the form of racemates as well as optically active antipodes. The optically active compounds can be obtained either by starting from optically active starting compounds or by splitting the racemates obtained into their optical antipodes in a customary manner, for example using dibenzoyl- or -toluyltartaric acid or 3-bromocamphor-8-sulfonic acid.
The compounds of the formula I obtained can, if desired, be converted into their physiologically tolerated acid addition salts in the customary manner. Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid and 8-chlorotheophylline.
The compounds of the formula I or their physiologically tolerable acid addition salts have valuable therapeutic, in particular β-adrenolytic properties and can therefore be used, for example, for the treatment or prophylaxis of diseases of the coronary arteries and for the treatment of cardiac arrhythmias, in particular tachycardias, in humans. The antihypertensive properties of the compounds are also of therapeutic interest.
Substances in which the radical R is in the 2-position are particularly valuable therapeutically.
1- (2'-Nitrilophenoxy) -2-hydroxy-3-tert-butylaminopropane of the formula has proven to be particularly effective
EMI2.1
exposed. This compound has proven itself both in terms of its own bradycardic effect and in terms of the isoproterenol antagonistic effect [isoproterenol = 1- (3 ', 4'-dihydroxyphenyl)
1-hydroxy-2-isopropylamino ethane] has been shown in animal experiments on guinea pigs to be significantly more effective and also less toxic than the well-known 1- (1 - (1'-naphthoxy) -2-hydroxy-3-isopropyl aminopropane.
In addition, the bradycardic effect occurs even at very low doses and cannot be increased beyond a certain limit value with higher doses, which indicates a lack of the undesired cardiodepressive component of the bradycardic intrinsic effect. The compound also shows a strong antiarrhythmic effect in strophantine-G intoxications and good oral absorption.
A preferred compound is also 1 - (2'-propargyloxyphenoxy) -2-hydroxy-
3-tert-butylaminopropane.
The single dose of the compounds of the formula I obtainable according to the invention is 1-300 mg (0.016 to 5 mg / kg), preferably 15-100 mg (0.25 to 1.66 mg / kg) for oral use and 0.1-25 mg (0.002-0.4 mg / kg) are suggested for parenteral use in humans.
The pharmaceutical processing of the compounds of the formula I into the customary use forms such as solutions, emulsions, tablets, coated tablets or depot forms can be carried out in a known manner using the pharmaceutical auxiliaries customary for this purpose. The compounds obtainable according to the invention can also be used in combination with other pharmacodynamically active substances such as, for example, cardiac or circulatory sympathomimetics or coronary dilators.
The following examples illustrate the invention without restricting it:
example 1
1 (2'-nitrilophenoxy) -2-hydroxy
3-tert-butylaminopropane HC1 2 g of 1 - (2'-nitrilophenoxy) -2-hydroxy-3 - (N-acetyl-N-tert-butylamino) propane are in 20 ml of ethanol with 4 g of KOH - in 6 ml of HG dissolved - added and heated to boiling for two hours at reflux while stirring.
The alcohol is then distilled off in vacuo. The residue is acidified with dilute HCl and extracted twice with ether, the aqueous phase is made alkaline with NaOH and the base which precipitates is taken up in ether. The ethereal solution is dried over MgSO4 and the ether is distilled off. 650 mg of crude base remain as residue, which is dissolved in a little ethanol.
After the addition of ethereal HC1, colorless crystals precipitate, which are recrystallized again from ethanol / ether.
Mp. 160 to 1630 C.
Analogously the following are obtained:
1 - (3'-nitrilophenoxy) -2-hydroxy-3-tert.-butyl aminopropane oxalate,
M.p. 154 to 1570 ° C
1 - (4'-Nitrilophenoxy) -2-hydroxy-3 -tert.-butyl aminopropane HCl,
Mp. 187 to 1890 C 1 - (2'-propargyloxyphenoxy) -2-hydroxy-
3-tert-butylaminopropane oxalate,
Mp. 132 to 1340 C.
Example 2 (-) - 1 - (2'-Nitrilophenoxy) -2-hydroxy-
3-tert-butylaminopropane HCI (representation by racemate separation)
24.8 g (0.1 mol) of 1 - (2'-nitrilophenoxy) -2-hydroxy3-tert-butylaminopropane (racemic) are dissolved in 100 ml of absolute methanol and treated with a solution of 38.6 g (0.1 Mol) (-) - Di-p-toluyltartaric acid combined in 150 ml of absolute methanol. After standing for several hours at room temperature, the solution is filtered and left to stand at 200 ° C. for three days. The di-p-toluyl tartrate, which slowly crystallizes out, is then filtered off with suction and recrystallized again in the same way.
18.2 g of (-) - 1- (2'-nitrilophenoxy) -2-hydroxy-3-tert-butylaminopropane-di-p-toluyl tartrate with a melting point of 135 ° to 1370 ° C. (decomposition) are obtained.
[a] 2D = ¯90, see above (in methanol).
6 g of this tartrate are shaken in 100 ml of ether and 50 ml of NaOH. The organic phase is separated off and dried over MgSO4. After filtration, ethereal HCl is added, whereupon crystallization occurs. 2.4 g of hydrochloride with a melting point of 161 to 1640 ° C. are obtained.
[a] D = + 14.70 (in methanol).
The dextrorotatory antipode can be obtained from the mother liquor (methanolic) of the abovementioned di-p-toluyl tartrate after evaporation of the methanol in vacuo and the base can be obtained by treatment with NaOH. It can be precipitated as hydrochloride from ethereal solution with the help of ethereal HCI.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1167870A CH509256A (en) | 1967-06-15 | 1968-06-13 | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1967B0093025 DE1593782B2 (en) | 1967-06-15 | 1967-06-15 | 1-NITRILOPHENOXY- 2- HYDROXY -3- TERT.BUTYLAMINOPROPANE, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THESE |
| CH1167870A CH509256A (en) | 1967-06-15 | 1968-06-13 | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH509256A true CH509256A (en) | 1971-06-30 |
Family
ID=25708734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1167870A CH509256A (en) | 1967-06-15 | 1968-06-13 | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH509256A (en) |
-
1968
- 1968-06-13 CH CH1167870A patent/CH509256A/en not_active IP Right Cessation
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2404113C2 (en) | 3-Substituted 4-phenylpiperidines and their salts with pharmaceutically acceptable acids, processes for their preparation and medicaments containing these compounds | |
| DE1948144B2 (en) | 1 - (I -Keto-tetrahydronaphthyl-5-oxy) ^ -hydroxy-S-alkylaminopropanes, process for their preparation and pharmaceutical composition based on them | |
| DE1793779A1 (en) | PROCESS FOR THE PREPARATION OF (+) - 2 AMINO-1-BUTANOL - (+) - HYDROGENT ARTRATE | |
| CH495950A (en) | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives | |
| CH510631A (en) | Substd. 1-phenoxy 2-hydroxy-3-alkyl aminopropanes - beta-adrenolytics, antiarrhythmics and hypotensives substd. 1-phenoxy 2-hydroxy-3-alkyl aminopropanes - beta-adrenolytics, anti-arrhythmics and hypotensives substitute phenoxy hydroxy alkyl aminopropan | |
| DE953256C (en) | Process for the preparation of therapeutically active bis-[ª‰-(o-oxyphenyl)-isopropyl]-amines | |
| CH509255A (en) | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives | |
| DE1620222B2 (en) | 3-pyrrolidinyloxy-substituted diphenylacetic acid derivatives and process for their preparation | |
| AT282595B (en) | PROCESS FOR THE PREPARATION OF NEW RACEMIC OR OPTICALLY ACTIVE (1-2'-NITRILOPHENOXY) -2-HYDROXY-3-ISOPROPYLAMINOPROPANE AND ITS SALTS | |
| CH509253A (en) | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives | |
| CH509257A (en) | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives | |
| AT282592B (en) | PROCESS FOR THE PREPARATION OF NEW RACEMIC OR OPTICALLY ACTIVE (1-2'-NITRILOPHENOXY) -2-HYDROXY-3-ISOPROPYLAMINOPROPANE AND ITS SALTS | |
| CH509254A (en) | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives | |
| CH510629A (en) | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives | |
| DE2539941C2 (en) | Basic benzyloxyalkyl derivatives, their preparation and pharmaceuticals containing these compounds | |
| AT283315B (en) | PROCESS FOR THE PRODUCTION OF NEW MIXED SUBSTITUTE 1-PHENOXY-3-ALKYLAMINOPROPANOL (2) AND THEIR ACID ADDITION SALTS | |
| DE825416C (en) | Process for the preparation of tertiary amines | |
| AT282593B (en) | PROCESS FOR THE PREPARATION OF NEW RACEMIC OR OPTICALLY ACTIVE (1-2'-NITRILOPHENOXY) -2-HYDROXY-3-ISOPROPYLAMINOPROPANE AND ITS SALTS | |
| CH509973A (en) | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives | |
| DE1643266C3 (en) | 1 phenoxy 2 hydroxy 3 sec alkylamino propane, a process for their production and preparations containing them | |
| DE2822473A1 (en) | ALKANOLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME | |
| AT282586B (en) | PROCESS FOR THE PREPARATION OF NEW RACEMIC OR OPTICALLY ACTIVE (1-2'-NITRILOPHENOXY) -2-HYDROXY-3-ISOPROPYLAMINOPROPANE AND ITS SALTS | |
| AT282597B (en) | PROCESS FOR THE PRODUCTION OF NEW MIXED SUBSTITUTE 1-PHENOXY-3-ALKYLAMINOPROPANOL (2) AND THEIR ACID ADDITION SALTS | |
| AT282601B (en) | Process for the preparation of new, mixed substituted 1-phenoxy-3-alkylaminopropanolen- (2) and their acid addition salts | |
| DE2309023C3 (en) | Acyl xylidides and local anesthetic agents containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |