NO131983B - - Google Patents
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- Publication number
- NO131983B NO131983B NO679/71A NO67971A NO131983B NO 131983 B NO131983 B NO 131983B NO 679/71 A NO679/71 A NO 679/71A NO 67971 A NO67971 A NO 67971A NO 131983 B NO131983 B NO 131983B
- Authority
- NO
- Norway
- Prior art keywords
- hydroxy
- compound
- phenyl
- general formula
- aminoethane
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical group NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- -1 ( 3- phenyl- 3- hydroxy) - propyl Chemical group 0.000 description 1
- KOJXGMJOTRYLBD-UHFFFAOYSA-N 1-[3,5-bis(phenylmethoxy)phenyl]ethanone Chemical compound C=1C(OCC=2C=CC=CC=2)=CC(C(=O)C)=CC=1OCC1=CC=CC=C1 KOJXGMJOTRYLBD-UHFFFAOYSA-N 0.000 description 1
- GYAWABSRCYDGGW-UHFFFAOYSA-N 2-(benzylamino)-1-phenylpropan-1-one Chemical compound C=1C=CC=CC=1C(=O)C(C)NCC1=CC=CC=C1 GYAWABSRCYDGGW-UHFFFAOYSA-N 0.000 description 1
- BMUKKTUHUDJSNZ-UHFFFAOYSA-N 4-[1-hydroxy-2-(1-phenoxypropan-2-ylamino)propyl]phenol Chemical compound C=1C=C(O)C=CC=1C(O)C(C)NC(C)COC1=CC=CC=C1 BMUKKTUHUDJSNZ-UHFFFAOYSA-N 0.000 description 1
- SYQQUIKADZCIGL-UHFFFAOYSA-N 4-amino-1-phenylpentan-1-ol Chemical compound CC(N)CCC(O)c1ccccc1 SYQQUIKADZCIGL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- OJYGBLRPYBAHRT-IPQSZEQASA-N chloralose Chemical compound O1[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]21 OJYGBLRPYBAHRT-IPQSZEQASA-N 0.000 description 1
- 229950009941 chloralose Drugs 0.000 description 1
- 239000003245 coal Substances 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
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- LSLYOANBFKQKPT-UHFFFAOYSA-N fenoterol Chemical compound C=1C(O)=CC(O)=CC=1C(O)CNC(C)CC1=CC=C(O)C=C1 LSLYOANBFKQKPT-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229960004819 isoxsuprine Drugs 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
- C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C215/62—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/48—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 unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av terapeutisk aktive aminoetanolderivater med den generelle formel:
hvor R er hydrogen eller hydroksyl, og OH-gruppen er i m- eller p-stilling til etanolamindelen, idet R er hydrogen når OH-gruppen er i p-stilling,
i form av racematene, eventuelt de diastereomere antipodepar, og syreaddisjonssaltene derav.
I henhold til oppfinnelsen fremstilles de nye forbindelser ved en av de følgende fremgangsmåter:
1. Fra en forbindelse med den generelle formel:
hvor R^ og R2 betyr hydrogenolytisk avspaltbare rester eller hvor også en av restene R^ og R2 kan bety et hydrogenatom, avspaltes den (de) gruppe(r) som skal fjernes.Avspaltningen foretas ved
hydrogenering i nærvær av en katalysator, særlig av nikkel, platina eller palladium.
2. En forbindelse med den generelle formel:
reduseres.
Reduksjonen foretas hensiktsmessig ved katalytisk hydrogenering over nikkel-, platina- eller palladiumkatalysatorer eller ved reduksjon med komplekse hydrider, særlig natriumboranat.
3. En forbindelse-med den generelle formel:.
ii
hvor B betyr =0 eller
reduseres.
Hvis B betyr et oksygenatom, reduseres begge karbonylgrupper samtidig, Som reduksjonsmiddel kan anvendes hydrogen og vanlige katalysatorer, f. eks. av nikkel, platina eller palladium, eller komplekse hydrider, særlig natriumboranat.
Om ønsket kan de erholdte produkter ved vanlige metoder separeres i de diastereomere antipodepar og / eller overføres til ønskede syreaddisjonssalter.
Utgangsstoffene fremstilles ved metoder som er kjente for fremstilling av slike forbindelser.
De nye forbindelser fremstilt i henhold til oppfinnelsen er terapeutisk aktive. De er særlig egnet som aktive bestand-
deler i hjerte- og kretsløpmidler. De anvendes i form av vanlige galeniske preparater sammen med vanlige hjelpe- og bæremidler f. eks. i form av tabletter, drageer, kapsler, aerosoler, dråpe-og injeksjonsoppløsninger. Enkeltdosen er ca 0,1 til ca 20 mg.
Lignende forbindelser er kjent fra US-patent 3 341 593 som
blant annet angår handelsproduktet "Berotec" (R i formel I i patentet betyr H). Sammenlignet med denne kjente forbindelse utmerker forbindelsen fremstilt ifølge eksempel 1 seg ved
a) bedre peroral virkning, og
b) lengre virkningsvarighet.
Den bedre perorale virkning ble demonstrert på hunder ved be-stemmelse av takykardi efter oral og intramuskulær administrering. Ved sammenligning av de doser som medfører samme hjertevirkning, får man resorpsjonskvotienten oral/intramuskulær. Den utgjør for forbindelsen fremstilt ifølge oppfinnelsen 4,1, og for den kjente forbindelse 20. Således er den orale virkning av den nye forbindelse nesten fem ganger bedre enn virkningen for den kjente forbindelse. Det er lett å innse at den bedre orale virkning representerer en vesentlig fordel for terapeutiske formål. For halveringstiden av virkningsvarigheten (hjertevirkning) får man for forbindelsen fremstilt ifølge oppfinnelsen: 152 min. forbindelsen ifølge US-patentet: 33 min.
Også med hensyn til virkningsvarighet er således den nye forbindelse fremstilt ifølge oppfinnelsen omtrentlig fem ganger bedre enn den kjente.
Lignende forbindelser er også kjent fra US-patent 3 225 095. For å foreta en sammenligning mellom forbindelser kjent fra nevnte patent og foreliggende oppfinnelse, ble en forbindelse fremstilt ifølge foreliggende oppfinnelse, nemlig forbindelsen ifølge eksempel 1(A), sammenlignet med to forbindelser ifølge US-oatent 3 225 095, nemlig forbindelsene ifølge eksempel 14 (B)og eksempel 10 (c).
Den anvendte metodikk var som følger:
Til narkotiserte hunder (kloralose-uretan-narkose) ble det arterielle blodtrykk målt med en Statham-trykkomformer, og koro-nargjennomblødningen med en elektromagnetisk strømningsmåler i den nedgående gren.av den venstre koronararterie. Forbindelsen ble administrert arterielt (i en koronararterie) eller intra-venøst.
I. Arteriell administrering
II. Intravenøs administrering
( II Intravenøs administrering forts.)
For økningen av koronargjennomfcrlødningen er for B middelverdien for 2 resp. 3 hunder angitt. Ved forsøkene med A ble begge doser undersøkt på forskjellige dyr, likeledes for C (1. til 3. dose på den ene side, 4. dose på den annen).
Videre ble forbindelsene ifølge eksempel 3 og. eksempel 5 sammenlignet med handelsproduktet "Duvadilan", formel
Virkningen på kretsløpet (perifer virkning) på hunder ble bestemt.
foreliggende oppfinnelse utmerker seg sammenlignet med de kjente forbindelser. Eksempel 1 l-( 4- hvdroksyfenyl)- l- hydroksy- 2- N- f( 3- fenyl- 3- hydroksy)- propyl]-aminoetan ( form Y) 15,25 g p-benzyloksy- oo-bromacetofenon kokes under tilbakeløps-kjøling med 12 g N-benzyl-N-(3-fenyl-3-hydroksy)-propylamin (fremstilt fra ai-benzylaminopropiofenon ved reduksjon med natriumborhydrid) i 100 ml acetonitril i nærvær av 11 g soda i 90 minutter. 9,3 g av det dannede 4-benzyloksy-w-N-benzyl-N-(3-fenyl-3-hydroksy)-propylamino-acetofenon (sm. p. 101°C, utbytte 93% av det teoretiske) settes til 45 ml etanol først med 0,8 g og etter 1 time med ytterligere 0,8 g natriumborhydrid. Etter ytterligere 2 timer avdestilleres etanolen, residuet opptas i etylacetat, utristes med vann, tørres med natriumsulfat, og oppløsningen inndampes. Deretter opptas residuet i etylacetat, tilsettes den beregnede mengde eterisk saltsyre, og etter poding med krystallkim får man 4,5 g av den som Y betegnede diastereomere form av det dannede l-(4-benzyl-oksyfenyl)-l-hydroksy-2-N-[(3-fenyl-3-hydroksy)-propyl]-N-benzyl-aminoetan som hydroklorid (sm.p. 142°C fra acetonitril); (moderluten inneholder X-diastereomeren). For debenzylering hydrogeneres 25,2 g av denne forbindelse i 250 ml metanol med Raney-nikkel som katalysator ved 60°C og 5 ato, inntil den hydrogenmengde som er nødvendig for avspaltning av de to bensylgrupper, er opptatt. Etter fjernelse av katalysatoren avdestilleres metanolen, og i litt vann frigjøres basen med pottaske og isoleres med etylacetat. Det med 75% utbytte dannede l-(4-hydroksyfenyl)-l-hydroksy-2-[(3-fenyl-3-hydroksy)-propyl]-aminoetan (form Y) har sm. p. 112°C (fra acetonitril) og gir et sulfat (sm.p. 150°C, begynner å smelte ved ca 140°C). Eksempel 2 l-( 4- hvdroksvfenyl)- l- hydroksy- 2- N- f( 3- fenyl- 3- hvdroksy)- propyl1-aminoetan ( form X).
Moderliten fra eksempel 1 med x-diastereomeren av l-(4-benzyl-oksyfenyl) -l-hydroksy-2-N-[(3-fenyl-3-hydroksy) -propyl ]-N-benzyl-aminoetan inndampes, og aminet bringes til krystallisasjon med
litt etylacetat (sm.p.< 116 - 118°C fra etylacetat). og hydrogeneres som i eksempel 1. Det oppnådde l-(4-hydroksyfenyl)-l-hydroksy-2-[(3-feny1-3-hydroksy)-propyl]-aminoetan (form X) har som base sm.p.
i
158°C (fra acetonitril).
Eksempel 3
l-( 3- hydroksyfenyl) - l- hydroksy- 2- N- r ( 3- fenyl- 3- hydroksy) - propyl " 1-aminoetan
3-benzyloksy-oi-bromacetofenon omsettes som beskrevet i eksempel 1 med N-benzyl-N-(3-fenyl-3-hydroksy)-propylamin til det til-
svarende aminoketon (90% utbytte, smeltepunkt for bioksalatet 173°C), og reduseres deretter i etanol med natriumborhydrid. Reduksjonsproduktet fraskilles som base med etylacetat, etyl-
acetaten avdestilleres, og residuet hydrogeneres i metanol etter tilsetning av en palladiumkloridoppløsning og aktivt kull ved
60°C og 5 ato til l-(3-hydroksyfenyl)-l-hydroksy-2-[(3-fenyl-3-hydroksy)-propyl]-aminoetan.
Forbindelsen krystalliserer som benzoat (sm. p. 128°C, fra acetonitril) .
Eksempel 4
1- ( 4- hydroksyfenyl)- l- hydroksy- 2- N- r( 3- fenyl- 3- hydroksy)- propyl1-aminoetan
7,2 g p-benzyloksy-OHbromacetofenon omsettes med 12 g t^-benzylaminopropiofenon i acetonitril, oj-benzylaminopropiofenon-hydro-bromidet fjernes, og det dannede 1-(4-benzyloksyfenyl)-1-okso-2- N-[(3-fenyl-3-okso)-propyl]N-benzyl-aminoetan hydrogeneres i metanol med Raney-nikkel inntil begge benzylrestene er avspaltet og deretter begge karbonylgrupper er redusert og l-(4-hydroksyfenyl)-l-hydroksy-2-N-[(3-fenyl-3-hydroksy)-propyl]-aminoetan er dannet.
Eksempel 5
l-( 3, 5- dihydroksyfenyl)- l- hydroksy- 2- N- T ( 3- fenyl- 3- hydroksy)- propyl1-aminoetan
3,5-dibenzyloksyacetofenon (sm. p. 63°C) omsettes med kobber(II)
bromid til 3,5-dibenzyloksy-ttf-bromacetofenon (sm.p. 85°C), og over-føres deretter ved kokning med N-benzyl-N-(3-fenyl-3-hydroksy-propylamin i acetonitril til (3 , 5-dibenzyl oksy)-<^-N-benzyl-N-(3-fenyl-3-hydroksy)-propylaminoacetofenon (sm. p. for bioksalatet: 179°C) <.> Aminoketonet reduseres med natriumborhydrid til amino-alkoholen og debenzyleres.hydrogenolytisk med palladium/kull som
katalysator. Ved omkrystallisering av l-(3,5-dihydroksyfenyl)-l-hydroksy-2-[(3-fenyl-3-hydroksy)-propyl]-aminoetan-benzoatet fra acetonitril får man først den diastereomere forbindelse med sm. p. 170°C (ren: sm. p. 187°C), og fra moderluten den andre diastereomere forbindelse med smeltepunkt 162°C.
Eksempel 6
l-( 4- hydroksyfenyl) - l- hydroksy- 2- N- f ( 3- fenyl- 3- hydroksy) - propyl]-aminoetan
23,3 g (0,05 mol) 4-benzyloksy-uH5T-benzyl-N-(3-fenyl-3-hydroksy) - propylamino-acetofenon (jfr. eksempel 1) settes til en blanding av 125 ml metanol og 125 ml vann med 10 ml 17,6%ig eterisk saltsyre og hydrogeneres ved 60°C ved 5 ato i nærvær av palladium/
kull som katalysator inntil 0,1 mol hydrogen er opptatt. Det dannede 4-hydroksyfenyl-o;-N-(3-fenyl-3-hydroksy) -propylamino-acetofenon-hydroklorid (sm. p. 188°C; fra vann) hydrogeneres med platina som katalysator til l-(4-hydroksyfenyl)-l-hydroksy-2-[(3-fenyl-3-hydroksy)-propyl]-aminoetan. Spaltningen i diastereo-merene utføres over basen. De diastereomere forbindelser har smelte-o
punktene 112- resp. 158 C.
Eksempel 7
1-( 4- hydroksyfenyl)- l- hydroksy- 2- N-[( 3- fenyl- 3- hydroksy)- propyl1-aminoetan
10,2 g 4-benzyloksy-w-bromacetofenon omsettes med.10, 2 g B-benzylaminopropiofenon-hydroklorid i acetonitril i nærvær av 16 g soda til 4-benzyl6ksy-w-N-benzyl-N-(3-fenyl-3-okso)-propylamino-aceto-fenon, og begge ketogrupper reduseres med natriumborhydrid. Basen fraskilles og debenzyleres med palladium/kull, hvorved man får 1-(4-hydroksyfenyl)-1-hydroksy-2-[(3-fenyl-3-hydroks^-propy1]-aminoetan.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser med den generelle formel hvor R er hydrogen eller hydroksyl, og OH-gruppen er i m- eller p-stil- ling til etanolamindelen, idet R er hydrogen når OH-gruppen er i p-stilling, i form av racematene, eventuelt de diastereomere antipodepar, og syreaddisjonssaltene derav,karakterisert ved at a) fra en forbindelse med den generelle formel hvor R1 og R2 betyr hydrogenolytisk avspaltbare rester eller hvor også en av restene R^ og R^ kan bety et hydrogenatom, avspaltes den (de) gruppe (r) som skal fjernes, eller b) en forbindelse med den generelle formel reduseres, eller c) en forbindelse med den generelle formel IIhvor B betyr =0 ellerreduseresog de erholdte forbindelser spaltes eventuelt i de diasteromere antipodepar, og eventuelt fremstilles syreaddisjonssaltene av basene med formel I.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19702008654 DE2008654A1 (de) | 1970-02-25 | 1970-02-25 | Ammoathanoldenvate |
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| Publication Number | Publication Date |
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| NO131983B true NO131983B (no) | 1975-05-26 |
| NO131983C NO131983C (no) | 1975-09-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO679/71A NO131983C (no) | 1970-02-25 | 1971-02-24 |
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| BE (1) | BE763408A (no) |
| BG (3) | BG18855A3 (no) |
| CH (4) | CH568269A5 (no) |
| CS (3) | CS166749B2 (no) |
| DE (1) | DE2008654A1 (no) |
| ES (3) | ES388561A1 (no) |
| FR (1) | FR2081541B1 (no) |
| GB (1) | GB1340407A (no) |
| IE (1) | IE34970B1 (no) |
| IL (1) | IL36269A (no) |
| NL (1) | NL7102432A (no) |
| NO (1) | NO131983C (no) |
| PL (3) | PL82843B1 (no) |
| RO (3) | RO62244A (no) |
| SE (1) | SE377561B (no) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ZA791403B (en) * | 1978-04-10 | 1980-05-28 | Draco Ab | Composition of matter |
| FI70205C (fi) * | 1978-05-17 | 1986-09-15 | Degussa | Foerfarande foer framstaellning av nya terapeutiskt anvaendbara l-/3-hydroxi-3-fenylpropyl-(2)/-/3-oxo-propyl/aminer |
| US4853381A (en) * | 1984-04-17 | 1989-08-01 | Glaxo Group Limited | Ethanolamine compounds |
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- 1971-01-22 AT AT54671A patent/AT305250B/de not_active IP Right Cessation
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- 1971-01-22 AT AT204572A patent/AT306706B/de not_active IP Right Cessation
- 1971-02-10 RO RO68599A patent/RO62244A/ro unknown
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- 1971-02-10 CS CS982A patent/CS166748B2/cs unknown
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- 1971-02-10 RO RO65888A patent/RO60182A/ro unknown
- 1971-02-10 RO RO68598A patent/RO58559A/ro unknown
- 1971-02-17 SU SU1752084A patent/SU421181A3/ru active
- 1971-02-17 SU SU1752085A patent/SU424349A3/ru active
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