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)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Pulmonology (AREA)
- Otolaryngology (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: This invention relates to a process for the production of therapeutically active aminoethanol derivatives with the general formula:
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, where R is hydrogen or hydroxyl, and the OH group is in the m- or p-position to the ethanolamine part, with R being hydrogen when the OH group is in the p-position,
i form av racematene, eventuelt de diastereomere antipodepar, og syreaddisjonssaltene derav. in the form of the racemates, possibly the diastereomeric antipode pairs, and the acid addition salts thereof.
I henhold til oppfinnelsen fremstilles de nye forbindelser ved en av de følgende fremgangsmåter: According to the invention, the new compounds are produced by one of the following methods:
1. Fra en forbindelse med den generelle formel: 1. From a compound with the general formula:
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 where R^ and R2 mean hydrogenolytically cleavable residues or where one of the residues R^ and R2 can also mean a hydrogen atom, the group(s) to be removed are cleaved off. Cleavage is carried out by
hydrogenering i nærvær av en katalysator, særlig av nikkel, platina eller palladium. hydrogenation in the presence of a catalyst, in particular of nickel, platinum or palladium.
2. En forbindelse med den generelle formel: 2. A compound with the general formula:
reduseres. is reduced.
Reduksjonen foretas hensiktsmessig ved katalytisk hydrogenering over nikkel-, platina- eller palladiumkatalysatorer eller ved reduksjon med komplekse hydrider, særlig natriumboranat. The reduction is suitably carried out by catalytic hydrogenation over nickel, platinum or palladium catalysts or by reduction with complex hydrides, particularly sodium borate.
3. En forbindelse-med den generelle formel:. 3. A compound-with the general formula:.
ii ii
hvor B betyr =0 eller where B means =0 or
reduseres. is reduced.
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. If B means an oxygen atom, both carbonyl groups are reduced simultaneously. Hydrogen and common catalysts, e.g. of nickel, platinum or palladium, or complex hydrides, especially sodium borate.
Om ønsket kan de erholdte produkter ved vanlige metoder separeres i de diastereomere antipodepar og / eller overføres til ønskede syreaddisjonssalter. If desired, the products obtained can be separated by usual methods into the diastereomeric antipodal pairs and/or transferred to the desired acid addition salts.
Utgangsstoffene fremstilles ved metoder som er kjente for fremstilling av slike forbindelser. The starting materials are prepared by methods which are known for the preparation of such compounds.
De nye forbindelser fremstilt i henhold til oppfinnelsen er terapeutisk aktive. De er særlig egnet som aktive bestand- The new compounds produced according to the invention are therapeutically active. They are particularly suitable as active ingredients
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. parts in cardiac and circulatory agents. They are used in the form of ordinary galenic preparations together with ordinary aids and carriers, e.g. in the form of tablets, dragees, capsules, aerosols, drop and injection solutions. The single dose is about 0.1 to about 20 mg.
Lignende forbindelser er kjent fra US-patent 3 341 593 som Similar compounds are known from US patent 3,341,593 as
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 among other things concerns the commercial product "Berotec" (R in formula I in the patent means H). Compared to this known compound, the compound prepared according to example 1 excels by
a) bedre peroral virkning, og a) better oral effect, and
b) lengre virkningsvarighet. b) longer duration of action.
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. The better oral effect was demonstrated in dogs by determining tachycardia after oral and intramuscular administration. When comparing the doses that lead to the same cardiac effect, the resorption quotient oral/intramuscular is obtained. It amounts to 4.1 for the compound produced according to the invention, and 20 for the known compound. Thus, the oral effect of the new compound is almost five times better than the effect of the known compound. It is easy to realize that the better oral effect represents a significant advantage for therapeutic purposes. For the half-life of the duration of action (cardiac action), one obtains for the compound produced according to the invention: 152 min. the compound according to the US patent: 33 min.
Også med hensyn til virkningsvarighet er således den nye forbindelse fremstilt ifølge oppfinnelsen omtrentlig fem ganger bedre enn den kjente. Also with regard to duration of action, the new compound produced according to the invention is thus approximately five times better than the known one.
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). Similar compounds are also known from US patent 3,225,095. In order to make a comparison between compounds known from said patent and the present invention, a compound prepared according to the present invention, namely the compound according to example 1(A), was compared with two compounds according to US patent 3,225,095, namely the compounds according to example 14 (B) and example 10 (c).
Den anvendte metodikk var som følger: The methodology used was as follows:
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. In anesthetized dogs (chloralose urethane anesthesia) the arterial blood pressure was measured with a Statham pressure transducer, and the coronary perfusion with an electromagnetic flow meter in the descending branch of the left coronary artery. The compound was administered arterially (into a coronary artery) or intravenously.
I. Arteriell administrering I. Arterial administration
II. Intravenøs administrering II. Intravenous administration
( II Intravenøs administrering forts.) (II Intravenous administration continued)
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). For the increase in coronary blood flow, B is the mean value for 2 resp. 3 dogs specified. In the experiments with A, both doses were investigated on different animals, likewise for C (1st to 3rd dose on the one hand, 4th dose on the other).
Videre ble forbindelsene ifølge eksempel 3 og. eksempel 5 sammenlignet med handelsproduktet "Duvadilan", formel Furthermore, the compounds according to example 3 and. example 5 compared to the commercial product "Duvadilan", formula
Virkningen på kretsløpet (perifer virkning) på hunder ble bestemt. The effect on the circuit (peripheral effect) in dogs was determined.
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). present invention excels compared to the known compounds. Example 1 1-(4-hydroxyphenyl)-1-hydroxy-2-N-f(3-phenyl-3-hydroxy)-propyl]-aminoethane (form Y) 15.25 g of p-benzyloxy-oo-bromoacetophenone are boiled under reflux with 12 g of N-benzyl-N-(3-phenyl-3-hydroxy)-propylamine (prepared from α-benzylaminopropiophenone by reduction with sodium borohydride) in 100 ml of acetonitrile in the presence of 11 g of soda ash for 90 minutes. 9.3 g of the formed 4-benzyloxy-w-N-benzyl-N-(3-phenyl-3-hydroxy)-propylamino-acetophenone (m.p. 101°C, yield 93% of the theoretical) is added to 45 ml ethanol first with 0.8 g and after 1 hour with a further 0.8 g of sodium borohydride. After a further 2 hours, the ethanol is distilled off, the residue is taken up in ethyl acetate, shaken out with water, dried with sodium sulphate and the solution is evaporated. The residue is then taken up in ethyl acetate, the calculated amount of ethereal hydrochloric acid is added, and after seeding with crystal seeds, 4.5 g of the diastereomeric form designated as Y of the formed l-(4-benzyl-oxyphenyl)-l-hydroxy-2- N-[(3-phenyl-3-hydroxy)-propyl]-N-benzylaminoethane as hydrochloride (m.p. 142°C from acetonitrile); (the mother liquor contains the X diastereomer). For debenzylation, 25.2 g of this compound are hydrogenated in 250 ml of methanol with Raney nickel as catalyst at 60°C and 5 at, until the amount of hydrogen required for splitting off the two benzyl groups is taken up. After removing the catalyst, the methanol is distilled off, and in a little water the base is liberated with pot ash and isolated with ethyl acetate. The 1-(4-hydroxyphenyl)-1-hydroxy-2-[(3-phenyl-3-hydroxy)-propyl]-aminoethane (form Y) formed with a 75% yield has sm. p. 112°C (from acetonitrile) and gives a sulfate (m.p. 150°C, starts to melt at about 140°C). Example 2 1-(4-hydroxyphenyl)-1-hydroxy-2-N-f(3-phenyl-3-hydroxy)-propyl-aminoethane (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 The parent from Example 1 with the x-diastereomer of 1-(4-benzyl-oxyphenyl)-1-hydroxy-2-N-[(3-phenyl-3-hydroxy)-propyl]-N-benzylaminoethane is evaporated, and the amine brought to crystallization with
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. a little ethyl acetate (m.p. < 116 - 118°C from ethyl acetate). and hydrogenated as in example 1. The obtained 1-(4-hydroxyphenyl)-1-hydroxy-2-[(3-phenyl-3-hydroxy)-propyl]-aminoethane (form X) has as a base m.p.
i in
158°C (fra acetonitril). 158°C (from acetonitrile).
Eksempel 3 Example 3
l-( 3- hydroksyfenyl) - l- hydroksy- 2- N- r ( 3- fenyl- 3- hydroksy) - propyl " 1-aminoetan l-( 3- hydroxyphenyl) - l- hydroxy- 2- N- r ( 3- phenyl- 3- hydroxy) - propyl " 1-aminoethane
3-benzyloksy-oi-bromacetofenon omsettes som beskrevet i eksempel 1 med N-benzyl-N-(3-fenyl-3-hydroksy)-propylamin til det til- 3-benzyloxy-o-bromoacetophenone is reacted as described in example 1 with N-benzyl-N-(3-phenyl-3-hydroxy)-propylamine to the
svarende aminoketon (90% utbytte, smeltepunkt for bioksalatet 173°C), og reduseres deretter i etanol med natriumborhydrid. Reduksjonsproduktet fraskilles som base med etylacetat, etyl- corresponding amino ketone (90% yield, melting point for the bioxalate 173°C), and then reduced in ethanol with sodium borohydride. The reduction product is separated as a base with ethyl acetate, ethyl
acetaten avdestilleres, og residuet hydrogeneres i metanol etter tilsetning av en palladiumkloridoppløsning og aktivt kull ved the acetate is distilled off, and the residue is hydrogenated in methanol after adding a palladium chloride solution and activated carbon at
60°C og 5 ato til l-(3-hydroksyfenyl)-l-hydroksy-2-[(3-fenyl-3-hydroksy)-propyl]-aminoetan. 60°C and 5 ato to 1-(3-hydroxyphenyl)-1-hydroxy-2-[(3-phenyl-3-hydroxy)propyl]-aminoethane.
Forbindelsen krystalliserer som benzoat (sm. p. 128°C, fra acetonitril) . The compound crystallizes as benzoate (m.p. 128°C, from acetonitrile).
Eksempel 4 Example 4
1- ( 4- hydroksyfenyl)- l- hydroksy- 2- N- r( 3- fenyl- 3- hydroksy)- propyl1-aminoetan 1-( 4- hydroxyphenyl)- l- hydroxy- 2- N- r( 3- phenyl- 3- hydroxy)- propyl1-aminoethane
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. 7.2 g of p-benzyloxy-OHbromoacetophenone is reacted with 12 g of t^-benzylaminopropiophenone in acetonitrile, the oj-benzylaminopropiophenone hydrobromide is removed, and the formed 1-(4-benzyloxyphenyl)-1-oxo-2-N-[(3 -phenyl-3-oxo)-propyl]N-benzyl-aminoethane is hydrogenated in methanol with Raney nickel until both benzyl residues are split off and then both carbonyl groups are reduced and l-(4-hydroxyphenyl)-l-hydroxy-2-N- [(3-phenyl-3-hydroxy)-propyl]-aminoethane is formed.
Eksempel 5 Example 5
l-( 3, 5- dihydroksyfenyl)- l- hydroksy- 2- N- T ( 3- fenyl- 3- hydroksy)- propyl1-aminoetan l-(3,5-dihydroxyphenyl)-l-hydroxy-2-N- T (3-phenyl-3-hydroxy)-propyl1-aminoethane
3,5-dibenzyloksyacetofenon (sm. p. 63°C) omsettes med kobber(II) 3,5-dibenzyloxyacetophenone (m.p. 63°C) reacts with copper(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 bromide to 3,5-dibenzyloxy-ttf-bromoacetophenone (m.p. 85°C), and then transferred by boiling with N-benzyl-N-(3-phenyl-3-hydroxy-propylamine in acetonitrile to (3 , 5-dibenzyloxy)-<^-N-benzyl-N-(3-phenyl-3-hydroxy)-propylaminoacetophenone (m.p. for the bioxalate: 179°C) <.> The amino ketone is reduced with sodium borohydride to the amino alcohol and debenzylated.hydrogenolytically with palladium/charcoal which
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. catalyst. By recrystallization of the 1-(3,5-dihydroxyphenyl)-1-hydroxy-2-[(3-phenyl-3-hydroxy)-propyl]-aminoethane benzoate from acetonitrile, the diastereomeric compound with sm. p. 170°C (pure: sm. p. 187°C), and from the mother liquor the other diastereomeric compound with melting point 162°C.
Eksempel 6 Example 6
l-( 4- hydroksyfenyl) - l- hydroksy- 2- N- f ( 3- fenyl- 3- hydroksy) - propyl]-aminoetan l-(4-hydroxyphenyl)-l-hydroxy-2-N-f(3-phenyl-3-hydroxy)-propyl]-aminoethane
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/ 23.3 g (0.05 mol) of 4-benzyloxy-uH5T-benzyl-N-(3-phenyl-3-hydroxy)-propylamino-acetophenone (cf. example 1) is added to a mixture of 125 ml of methanol and 125 ml water with 10 ml of 17.6% ethereal hydrochloric acid and hydrogenated at 60°C at 5 ato in the presence of 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 coal as catalyst until 0.1 mol of hydrogen is occupied. The formed 4-hydroxyphenyl-o;-N-(3-phenyl-3-hydroxy)-propylamino-acetophenone hydrochloride (m.p. 188°C; from water) is hydrogenated with platinum as a catalyst to 1-(4-hydroxyphenyl )-1-hydroxy-2-[(3-phenyl-3-hydroxy)-propyl]-aminoethane. The cleavage into the diastereomers is carried out over the base. The diastereomeric compounds have melting-o
punktene 112- resp. 158 C. items 112- or 158 C.
Eksempel 7 Example 7
1-( 4- hydroksyfenyl)- l- hydroksy- 2- N-[( 3- fenyl- 3- hydroksy)- propyl1-aminoetan 1-(4-hydroxyphenyl)-1-hydroxy-2-N-[(3-phenyl-3-hydroxy)-propyl1-aminoethane
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. 10.2 g of 4-benzyloxy-w-bromoacetophenone is reacted with 10.2 g of B-benzylaminopropiophenone hydrochloride in acetonitrile in the presence of 16 g of soda to give 4-benzyl6oxy-w-N-benzyl-N-(3-phenyl-3-oxo )-propylamino-aceto-phenone, and both keto groups are reduced with sodium borohydride. The base is separated and debenzylated with palladium/charcoal, whereby 1-(4-hydroxyphenyl)-1-hydroxy-2-[(3-phenyl-3-hydroxy^-propyl]-aminoethane is obtained).
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