CH495950A - 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
- CH495950A CH495950A CH876668A CH876668A CH495950A CH 495950 A CH495950 A CH 495950A CH 876668 A CH876668 A CH 876668A CH 876668 A CH876668 A CH 876668A CH 495950 A CH495950 A CH 495950A
- Authority
- CH
- Switzerland
- Prior art keywords
- tert
- hydroxy
- compounds
- formula
- 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 16
- 238000000034 method Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- WSABLXKFAPKFSO-UHFFFAOYSA-N 1,3-ditert-butylurea Chemical compound CC(C)(C)NC(=O)NC(C)(C)C WSABLXKFAPKFSO-UHFFFAOYSA-N 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
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000003944 halohydrins Chemical class 0.000 claims description 2
- 239000000155 melt Substances 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 2
- 150000002118 epoxides Chemical class 0.000 claims 1
- 238000001640 fractional crystallisation Methods 0.000 claims 1
- 239000012442 inert solvent Substances 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- 230000000059 bradycardiac effect Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000002585 base Substances 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
- 238000001816 cooling Methods 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
- 239000012074 organic phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- -1 toluyl tartaric acid Chemical compound 0.000 description 2
- 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
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- JDSHWUSBLSNDSV-UHFFFAOYSA-N C(C(=O)O)(=O)O.C(CCC)NCCC Chemical compound C(C(=O)O)(=O)O.C(CCC)NCCC JDSHWUSBLSNDSV-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
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 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
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 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
- 206010003119 arrhythmia Diseases 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical group C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 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
- 125000003700 epoxy group Chemical group 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
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 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
- 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
- 239000012452 mother liquor Substances 0.000 description 1
- CWYZDPHNAGSFQB-UHFFFAOYSA-N n-propylbutan-1-amine Chemical compound CCCCNCCC CWYZDPHNAGSFQB-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002924 oxiranes Chemical class 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
- 239000003208 petroleum Substances 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- 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
- A61K31/13—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
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (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)
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 Herstellung von neuen l-Phenoxy-2-hydroxy-3-tert.-butylaminopro- panen 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:
Umsetzung eines Epoxyds oder eines Halogenhydrins der Formeln IIa bzw.
IIb
EMI1.2
in denen Hal ein Halogen darstellt, mit N,N'-Di-tert.butylharnstoff bei Temperaturen zwischen 150 und 2200 C in der Schmelze oder in einem inerten hochsiedenden Lösungsmittel.
Die Ausgangsverbindungen sind zum Teil bereits bekannt, zum Teil können sie nach üblichen Verfahren gewonnen werden, wobei man dann meistens von Verbindungen der Formel III
EMI1.3
in der Kt Wasserstoff oder ein Kation (beispielsweise ein Alkalimetallion) bedeutet, ausgeht. Die Epoxyde der Formel IIa lassen sich aus den Verbindungen der
Formel III leicht durch Umsetzung mit Epichlorhydrin herstellen.
Die Verbindungen der Formel I besitzen an der -CHOH-Gruppierung ein asymmetrisches Kohlenstoff atom 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 Ausgangsverbindun gen ausgeht oder die erhaltenen Racemate auf übliche
Weise, beispielsweise mittels Dibenzoyl- oder -toluyl weinsäure 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, Methanol sulfonsäure, 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 Eigen schaften 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'-Nitrilophen- oxy)-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-isopropylaminoäthan] im Tierexperiment an Meerschweinchen als wesentlich wirksamer und auch weniger toxisch erwiesen als das bekannte
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 uner wünschten 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 (0,25-1,66 mg/kg) für die orale Anwendung und 0,1-25 mg (0,002 bis 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 pharmako- dynamisch 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. HCl
2,56 g (0,01 Mol) 1 -(2'-Nitrilophenoxy)-2-hydroxy3-brompropan werden in 20 ml Tetralin mit 3,44 g (0,02 Mol) N,N'-Di-tert.-butylharnstoff zwei Stunden auf 2000 C erhitzt. Nach Abkühlen werden 20 ml Äther zugegeben und die organische Phase wird mit verdünnter HCl ausgeschüttelt. Nach Abtrennung der wässrigen Phase wird diese mit NaOH alkalisch gestellt.
Die ausfallenden basischen Anteile werden in Äther aufgenommen, die Ätherlösung abgetrennt und über MgSO4 getrocknet. Der Äther wird abdestilliert, der verbleibende Rückstand (1,5 g) in wenig Äther gelöst und filtriert. Dem Filtrat wird ätherische HC1 zugesetzt, wobei das Hydrochlorid ausfällt. Es wird abgesaugt und zweimal aus wenig Äthanol umkristallisiert.
Ausbeute: 0,4 g, Fp. 159 bis 1630 C.
Beispiel 2 1 -(2'-Nitrilophenoxy)-2-hydroxy
3-tert.-butylaminopropan HC1
4,8 g (0,025 Mol) 1-(2'-Nitrilophenoxy)-2,3-epoxy- propan werden mit 8,6 g (0,05 Mol) N,N'-Di-tert.-butylharnstoff in 30 ml Tetralin eine Stunde lang auf 1900 C erhitzt. Nach dem Abkühlen wird mit verdünnter HCI ausgeschüttelt und die saure wässrige Phase abgetrennt.
Man wäscht mit Äther nach und stellt mit Natronlauge alkalisch. Dabei scheiden sich die basischen Anteile als Niederschlag ab, der in Äther aufgenommen wird.
Die Ätherlösung wird mit MgSO4 getrocknet; anschlie ssend wird der Äther abdestilliert. Der Rückstand wird aus Essigester/Petroläther umkristallisiert. Die Base wird in Äthanol gelöst, mit ätherischer Salzsäure versetzt und das ausfallende Hydrochlorid isoliert. Nach einer Umkristallisation aus Alkohol hat es einen Schmelzpunkt von 161 bis 1630 C.
Analog werden erhalten:
1 -(2'-Propargyloxyphenoxy)-2-hydroxy-3 -tert. butylaminopropan-oxalat, Fp. 132-1340 C
1 -(3'-Nitrilophenoxy)-2-hydroxy-3-tert.
butylarninopropan-oxalat, Fp. 154-1570 C 1-(4'-Nitrilophenoxy)-2-hydroxy-3 -tert. butylaminopropan HC1, Fp. 187-1890 C.
Beispiel 3 (-) - 1 -(2'-Nitrilophenoxy)-2-hydroxy-
3-tert.-butylaminopropan HCl (Darstellung durch Racematentrennung):
24,8 g (0,1 Mol) 1-(2'-Nitrilophenoxy)-2-hydroxy- 3-tert.-butylaminopropan (racemisch) werden in 100 ml absolutem Methanol gelöst und mit einer Lösung von 38,6 g (0,1 Mol) (-)-Di-p-toluyl-weinsäure 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]u20 90,50 (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 HC1 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 preparation of new 1-phenoxy-2-hydroxy-3-tert.-butylaminopropanes 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 acceptable salts, with therapeutically valuable properties in warm-blooded animals. According to the invention, the new compounds are prepared in the following manner:
Implementation of an epoxide or a halohydrin of the formula IIa or
IIb
EMI1.2
in which Hal represents a halogen, with N, N'-di-tert-butylurea at temperatures between 150 and 2200 C in the melt or in an inert high-boiling solvent.
Some of the starting compounds are already known, and some can be obtained by customary processes, in which case compounds of the formula III
EMI1.3
in which Kt is hydrogen or a cation (for example an alkali metal ion). The epoxies of the formula IIa can be derived from the compounds of
Easily produce formula III by reaction with epichlorohydrin.
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 customizing the racemates obtained
Way, for example by means of dibenzoyl or toluyl tartaric acid or 3-bromocamphor-8-sulfonic acid, splits into their optical antipodes.
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, methanol, sulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid and 8-chlorotheophylline.
The compounds of the formula I or their physiologically acceptable acid addition salts have valuable therapeutic, especially 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 to be significantly more effective and also less toxic in animal experiments with guinea pigs, both with regard to its own bradycardic effect and with regard to the isoproterenol antagonistic effect [isoproterenol = 1- (3 ', 4'-dihydroxyphenyl) -1-hydroxy-2-isopropylaminoethane] than the known
1- (1'-naphthoxy) -2-hydroxy-3-isopropyl aminopropane.
In addition, the bradycardic effect occurs even at very low doses and can no longer 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 (0.25-1.66 mg / kg) for oral use and 0.1-25 mg (0.002 to 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. HCl
2.56 g (0.01 mol) of 1 - (2'-nitrilophenoxy) -2-hydroxy3-bromopropane are dissolved in 20 ml of tetralin with 3.44 g (0.02 mol) of N, N'-di-tert.- butylurea heated to 2000 C for two hours. After cooling, 20 ml of ether are added and the organic phase is extracted with dilute HCl. After the aqueous phase has been separated off, it is made alkaline with NaOH.
The precipitating basic components are taken up in ether, the ether solution separated and dried over MgSO4. The ether is distilled off, the remaining residue (1.5 g) is dissolved in a little ether and filtered. Ethereal HC1 is added to the filtrate, and the hydrochloride precipitates. It is filtered off with suction and recrystallized twice from a little ethanol.
Yield: 0.4 g, m.p. 159 to 1630 C.
Example 2 1 - (2'-Nitrilophenoxy) -2-hydroxy
3-tert-butylaminopropane HC1
4.8 g (0.025 mol) of 1- (2'-nitrilophenoxy) -2,3-epoxypropane are mixed with 8.6 g (0.05 mol) of N, N'-di-tert-butylurea in 30 ml Tetralin heated to 1900 C for one hour. After cooling, it is extracted by shaking with dilute HCl and the acidic aqueous phase is separated off.
It is rewashed with ether and made alkaline with sodium hydroxide solution. The basic components separate out as a precipitate, which is absorbed in the ether.
The ether solution is dried with MgSO4; the ether is then distilled off. The residue is recrystallized from ethyl acetate / petroleum ether. The base is dissolved in ethanol, ethereal hydrochloric acid is added and the precipitating hydrochloride is isolated. After recrystallization from alcohol, it has a melting point of 161 to 1630 C.
Analogously the following are obtained:
1 - (2'-propargyloxyphenoxy) -2-hydroxy-3-tert. butylaminopropane oxalate, m.p. 132-1340 C
1 - (3'-nitrilophenoxy) -2-hydroxy-3-tert.
butyl aminopropane oxalate, m.p. 154-1570 C 1- (4'-nitrilophenoxy) -2-hydroxy-3-tert. butylaminopropane HC1, m.p. 187-1890 C.
Example 3 (-) - 1 - (2'-Nitrilophenoxy) -2-hydroxy-
3-tert-butylaminopropane HCl (representation by racemate separation):
24.8 g (0.1 mol) of 1- (2'-nitrilophenoxy) -2-hydroxy-3-tert-butylaminopropane (racemic) are dissolved in 100 ml of absolute methanol and mixed with a solution of 38.6 g (0 , 1 mol) (-) - Di-p-toluyl-tartaric 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 slowly crystallizing di-p-toluyl tartrate 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] u20 90.50 (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 an ethereal solution with the help of ethereal HC1.
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1168170A CH509973A (en) | 1967-06-15 | 1968-06-13 | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives |
| CH1168070A CH510629A (en) | 1967-06-15 | 1968-06-13 | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives |
Applications Claiming Priority (1)
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH495950A true CH495950A (en) | 1970-09-15 |
Family
ID=6986720
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH876668A CH495950A (en) | 1967-06-15 | 1968-06-13 | 1-Phenoxy-2-hydroxy-3-tert.-butylamino propanes - beta-adrenolytics, hypotensives |
Country Status (17)
| Country | Link |
|---|---|
| JP (2) | JPS51100B1 (en) |
| AT (8) | AT289067B (en) |
| BE (1) | BE716647A (en) |
| BG (6) | BG15041A3 (en) |
| CH (1) | CH495950A (en) |
| DE (1) | DE1593782B2 (en) |
| DK (1) | DK127059B (en) |
| ES (6) | ES354823A1 (en) |
| FI (1) | FI48922C (en) |
| FR (2) | FR1583559A (en) |
| GB (1) | GB1187546A (en) |
| IE (1) | IE32373B1 (en) |
| IL (1) | IL30181A (en) |
| MY (1) | MY7300288A (en) |
| NL (2) | NL6808196A (en) |
| SE (1) | SE355571B (en) |
| YU (7) | YU33777B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3937834A (en) | 1970-10-02 | 1976-02-10 | Ciba-Geigy Corporation | Pharmaceutical preparations |
| JPS57125772U (en) * | 1981-01-30 | 1982-08-05 | ||
| DE3744371A1 (en) * | 1987-12-29 | 1989-07-13 | Jacobs Suchard Ag | PACKAGING FOR CONFECTIONERY |
| DE4014252A1 (en) * | 1990-05-04 | 1991-11-07 | Boehringer Ingelheim Vetmed | ENANTIOMER DETECTION OF CIMATEROL, (-) - CIMATEROL AND ITS USE AS A MEDICAMENT OR AS A PERFORMANCE SUPPLIER |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL301580A (en) * | 1962-12-11 |
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1967
- 1967-06-15 DE DE1967B0093025 patent/DE1593782B2/en active Granted
- 1967-06-17 FR FR1583559D patent/FR1583559A/fr not_active Expired
-
1968
- 1968-06-05 JP JP43038048A patent/JPS51100B1/ja active Pending
- 1968-06-08 ES ES354823A patent/ES354823A1/en not_active Expired
- 1968-06-11 NL NL6808196A patent/NL6808196A/xx unknown
- 1968-06-13 SE SE07980/68A patent/SE355571B/xx unknown
- 1968-06-13 CH CH876668A patent/CH495950A/en not_active IP Right Cessation
- 1968-06-14 AT AT572568A patent/AT289067B/en not_active IP Right Cessation
- 1968-06-14 AT AT248170A patent/AT289080B/en active
- 1968-06-14 AT AT248370A patent/AT289082B/en not_active IP Right Cessation
- 1968-06-14 IL IL6830181A patent/IL30181A/en unknown
- 1968-06-14 DK DK281968AA patent/DK127059B/en not_active IP Right Cessation
- 1968-06-14 AT AT247870A patent/AT289077B/en active
- 1968-06-14 AT AT248070A patent/AT289079B/en active
- 1968-06-14 AT AT247970A patent/AT289078B/en not_active IP Right Cessation
- 1968-06-14 BE BE716647D patent/BE716647A/xx not_active IP Right Cessation
- 1968-06-14 GB GB28529/68A patent/GB1187546A/en not_active Expired
- 1968-06-14 FI FI681664A patent/FI48922C/en active
- 1968-06-14 AT AT247770A patent/AT289076B/en not_active IP Right Cessation
- 1968-06-14 IE IE710/68A patent/IE32373B1/en unknown
- 1968-06-14 AT AT248270A patent/AT289081B/en active
- 1968-06-15 BG BG011631A patent/BG15041A3/en unknown
- 1968-06-15 BG BG011632A patent/BG15042A3/en unknown
- 1968-06-15 BG BG011629A patent/BG15039A3/en unknown
- 1968-06-15 BG BG011630A patent/BG15040A3/en unknown
- 1968-06-15 BG BG011627A patent/BG15037A3/en unknown
- 1968-06-15 BG BG011628A patent/BG15038A3/en unknown
- 1968-09-17 FR FR166464A patent/FR8162M/fr not_active Expired
-
1969
- 1969-06-16 ES ES368398A patent/ES368398A1/en not_active Expired
- 1969-06-16 ES ES368401A patent/ES368401A1/en not_active Expired
- 1969-06-16 ES ES368399A patent/ES368399A1/en not_active Expired
- 1969-06-16 ES ES69368396A patent/ES368396A1/en not_active Expired
- 1969-06-16 ES ES368395A patent/ES368395A1/en not_active Expired
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1973
- 1973-12-31 MY MY1973288A patent/MY7300288A/en unknown
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1974
- 1974-08-21 YU YU2290/74A patent/YU33777B/en unknown
- 1974-08-21 YU YU2294/74A patent/YU33780B/en unknown
- 1974-08-21 YU YU2293/74A patent/YU35578B/en unknown
- 1974-08-21 YU YU2288/74A patent/YU33775B/en unknown
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- 1974-10-17 JP JP49119881A patent/JPS5112613B1/ja active Pending
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