NO122068B - - Google Patents
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- Publication number
- NO122068B NO122068B NO16661667A NO16661667A NO122068B NO 122068 B NO122068 B NO 122068B NO 16661667 A NO16661667 A NO 16661667A NO 16661667 A NO16661667 A NO 16661667A NO 122068 B NO122068 B NO 122068B
- Authority
- NO
- Norway
- Prior art keywords
- piperidylcarbinol
- trimethyl
- hydrogen
- compound
- diphenylacetate
- Prior art date
Links
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003589 local anesthetic agent Substances 0.000 claims description 3
- MSYLETHDEIJMAF-UHFFFAOYSA-N 2,2-diphenylacetyl chloride Chemical compound C=1C=CC=CC=1C(C(=O)Cl)C1=CC=CC=C1 MSYLETHDEIJMAF-UHFFFAOYSA-N 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- RJUAEBLXGFKZMS-UHFFFAOYSA-N piperidin-1-ylmethanol Chemical compound OCN1CCCCC1 RJUAEBLXGFKZMS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 2
- 150000007513 acids Chemical class 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 description 9
- 206010002091 Anaesthesia Diseases 0.000 description 8
- 230000037005 anaesthesia Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229960004194 lidocaine Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 238000001949 anaesthesia Methods 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 description 1
- XNMYNYSCEJBRPZ-UHFFFAOYSA-N 2-[(3-butyl-1-isoquinolinyl)oxy]-N,N-dimethylethanamine Chemical compound C1=CC=C2C(OCCN(C)C)=NC(CCCC)=CC2=C1 XNMYNYSCEJBRPZ-UHFFFAOYSA-N 0.000 description 1
- 241000269350 Anura Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000005371 pilomotor reflex Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229960005038 quinisocaine Drugs 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/04—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent
- C08J9/06—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent by a chemical blowing agent
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2327/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers
- C08J2327/02—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment
- C08J2327/04—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment containing chlorine atoms
- C08J2327/06—Homopolymers or copolymers of vinyl chloride
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
Fremgangsmåte ved fremstilling av en ny lokalanestisk forbindelse.
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av den nye forbindelse 1,a,a-trimethyl-2-piperidylcarbinol-difenylacetat, som kan finne anvendelse som et utmerket lokalanestetikum. Fremgangsmåten ved fremstillingen, som vil bli beskrevet i detalj i det fdlgende, består hovedsakelig i at a,a-dimethyl-2-pyri-dylcarbinol forst hydreres til den tilsvarende piperidylcarbinol, så omsettes med formaldehyd og hydrogen i nærvær av en egnet katalysator og tilslutt forestrer.
Denne fremgangsmåte ifolge oppfinnelsen kan fremstilles skje-matisk som folger:
1,a,a-trimethyl-2-piperidylcarbinol-difenylacetat oppviser en interessant lokalanestetisk virkning: det er undersokt i sammen-ligning med Lidocain (2-diethylamino-2',6<1>-aceto-xylidid), som er det hittil mest virksomme og mest anvendte lokalanestetikum, og viser ved samme toksisitet en vesentlig hoyere anestetisk virkning.
Med hensyn til sin farmakologiske aktivitet kan den ifolge oppfinnelsen fremstillede forbindelse klassifiseres blant de stoffer som blokkerer de sentripetale nerveimpulser i nervetrådene.
Denne virkning ble undersokt ved hjelp av folgende metoder: a) overflateanestesien: denne ble undersokt ved anestesi av dyebindehud på kaniner, hvilket forte
til forsvinning av dyelokklukningsrefleksen. (Sollmann X.:
J. Pharmacol. exp. Ther., 11, 1, 1918).
b) infiltrasjonsanestesien: denne ble undersokt ved intradermal
anestesi på marsvin, som forer til forsvinning av pilomotorrefleksen. (Bulbring und Wajda:
J. Pharmacol. exp. Ther., 85, 78, 1945).
c) ledning sanestesi: denne ble undersokt ved hjelp av anestesi av Lumbalplexus hos frosk, som
forte til forsvinning av forsvarsrefleksen av de nedre lemmer.
(Bulbring und Wajda: J. Pharmacol. exp. Ther., 85, 78, 1945).
I alle tilfelle ble der anvendt egnede avtrappede konsentrasjoner av 1,a,a-trimethyl-2-piperidylcarbinoldifenylacetat opplost i fysiologisk koksaltopplosning (NaCl 9°/oo eller 7°/oo for amfibi-er) . Bestemmelsene ble gjentatt på minst 6 - IO dyr for å få statis-tisk gyldige og bedombare data. Den statistiske bedommelse av akti-vitetsforholdene er utfort med 6-punkt-bestemmelsesmetoden svarende til 1.bilag til "Farmacopea Ufficiale Italiana", 7.utgave 1965.
I tabell 1 er angitt de virksomme konsentrasjoner (A) av 1,a,a-trimethyl-2-piperidylcarbinoldifenylacetatet og aktivitetsfor-holdet (B) i forhold til den konvensjonelle, lik 1 fastsatt sammen-ligningsforbindelse Lidocain.
Som virksom konsentrasjon forstår man den konsentrasjon av en forbindelse som forer til en total anestesi av varighet på minst 30 minutter hos de provede forsoksdyr.
Studium av ovenstående data viser hvorledes forbindelsen fremstillet ifblge oppfinnelsen er virksom allerede ved meget lave konsentrasjoner; ved den intradermale anestesi er den minst tre gan-ger mere virksan enn Lidocain, mens forholdet ved overflateanestesi stiger til ca. forti.
Den akutte giftighet som ble bestemt, på hvite albinomus efter engangs behandling ved forskjellige administrasjonsformer, er
praktisk lik den for Lidocain ved subcutan injeksjon. Proven ble utfort på grupper på minst 10 dyr pr. dose, og den tilsvarende statistiske beregning av LD5Qog pålitelighetsgrensen er utfort efter pro-bitmetoden (Burn J.H.: Biological Standardication Oxford 1950).
I tabell 2 er angitt data for LD (akutt giftighet) ved subcutan og intravenos administrasjon av 1,a,a-trimethyl-2-piperidyl-carbinoldifenylacetat i forhold til Lidocain.
Den ifdlge oppfinnelsen fremstillede forbindelse, 1, a, ei-tr imethyl-2-piperidylcarbinoldif eny lacetat , innsprbytet intravenost i en hund, er fullstendig tålbar ved en dose på 5 mg/kg, ved en dose på IO mg/kg opptrer tegn på sentral opphisselse som imidlertid henddr i lbpet av kort tid (10 - 15 minutter) uten å efterlate udnskede bi-virkninger.
Virkningen av forbindelsen på det systemiske blodtrykk og på åndingen av dyrene i narkose (rotte, katt) er middels og gjor sig ved hurtig injiserte, intravenose doser fra 1 mg/kg gjeldende ved en hurtig og forbigående histaminlignende blodtrykkssenkning.
De toksiske egenskaper for 1,a,a-trimethyl-2-piperidylcarbinol-difenylacetat er f.eks. vesentlig mindre enn for dimethiso-quin, hvilket fremgår av tabell 3.
Eksempel
1,g,a-trimethyl- 2- pipe cid ylcarbinol- dife nylacetat 39,75 g g,g-dimethyl-2-pyridylcarbinol (Ber. 41, 1908,
s. 4103) opploses i 60 ml ethanol, nøytraliseres med en ekvivalent hydrogenklorid i ethanol, tilsettes 1 g platinakatalysator (Adams)
og hydreres i autoklav under et trykk på 60 atmosfærer ved 90°C. Efter 4 timer er hydrogenopptagelsen avsluttet, der avkjoles, filtreres, opplosningsmidle t inndampes i vakuum, gjores alkalisk med konsen-trert natronlut og ekstraheres med ethylether. Efter fordampning av etheren destilleres ved 78 - 80°C under et redusert trykk på 5 mmHg.
Utbytte: 25 g<g>,<g->dimethyl-2-piperidylcarbinol.
9,7 g av den således erholdte forbindelse opploses i lOO ml ethanol og tilsettes 11 ml 30 %-ig formaldehyd og 0,7 g 10 %-ig palladium på kull. Der hydreres ved 110°C under et trykk på 60 atmosfærer. Efter 20 timer filtreres, alkoholen fjerner og der destilleres i vakuum. Man fanger opp den fraksjon som destillerer av mellom 70 og 75° ved 2 mm Hg-trykk. Man får således 6,5 g 1,<g>,<g->trimethyl-2-piperidylcarbinol. 2 g av sistnevnte forbindelse opploses i 10 ml pyridin, tilsettes 3 g difenylacetylklorid og får stå i 2 dager. Derefter av-dampes pyridinet i vakuum, residuet opptaes i benzen og opplosningen vaskes med IO %-ig natriumhydroxydopplosning. Benzenopplosrd ngen tor-res over natriumsulfat og helles på en kromatografisk kolonne av rø g silicagel. Ved eluering får man 2,5 g 1,a, a-trimethyl-2-piperidylcarbinol-difenylacetat. Omsetning med saltsyre gir hydrokloridet i form av et hvitt krystallpulver med smeltepunkt 177°C.
Claims (1)
- Fremgangsmåte ved fremstilling av en ny lokalanestetisk ak-tiv forbindelse 1,a,a-trimethyl-2-piperidylcarbinol-difenylacetat og dettes salt med farmasøytisk godtagbare syrer, karakterisert ved at a,a-dimethyl-2-pyridylcarbinol hydreres med hydrogen i nærvær av Adams-platina, den tilsvarende piperidylcarbinol omsettes med formaldehyd og hydrogen i nærvær av palladium på kull, det såledas erholdte produkt forestres på kjent måte med difenylacetylklorid, og omsettes eventuelt med syrer for fremstilling av farmasøy-tisk godtagbare salter.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1408166 | 1966-02-03 | ||
| IT228666 | 1966-02-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO122068B true NO122068B (no) | 1971-05-18 |
Family
ID=26325232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO16661667A NO122068B (no) | 1966-02-03 | 1967-01-30 |
Country Status (11)
| Country | Link |
|---|---|
| BE (1) | BE693587A (no) |
| CH (1) | CH484905A (no) |
| DK (1) | DK118186B (no) |
| ES (1) | ES336375A1 (no) |
| FR (1) | FR6135M (no) |
| GB (1) | GB1110637A (no) |
| IL (1) | IL27360A (no) |
| NL (1) | NL6701022A (no) |
| NO (1) | NO122068B (no) |
| SE (1) | SE321474B (no) |
| YU (1) | YU32140B (no) |
-
1967
- 1967-01-23 NL NL6701022A patent/NL6701022A/xx unknown
- 1967-01-30 IL IL2736067A patent/IL27360A/en unknown
- 1967-01-30 NO NO16661667A patent/NO122068B/no unknown
- 1967-01-30 GB GB4503/67A patent/GB1110637A/en not_active Expired
- 1967-01-31 DK DK54467A patent/DK118186B/da unknown
- 1967-01-31 FR FR93178A patent/FR6135M/fr not_active Expired
- 1967-01-31 YU YU18367A patent/YU32140B/xx unknown
- 1967-02-01 SE SE139967A patent/SE321474B/xx unknown
- 1967-02-02 ES ES336375A patent/ES336375A1/es not_active Expired
- 1967-02-02 CH CH151767A patent/CH484905A/de not_active IP Right Cessation
- 1967-02-02 BE BE693587D patent/BE693587A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| YU18367A (en) | 1973-08-31 |
| DK118186B (da) | 1970-07-20 |
| FR6135M (no) | 1968-06-24 |
| ES336375A1 (es) | 1968-04-01 |
| YU32140B (en) | 1974-04-30 |
| NL6701022A (no) | 1967-08-04 |
| CH484905A (de) | 1970-01-31 |
| GB1110637A (en) | 1968-04-24 |
| SE321474B (no) | 1970-03-09 |
| BE693587A (no) | 1967-08-02 |
| IL27360A (en) | 1971-01-28 |
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