DE1817861C3 - N-alkylated 3,4-methylenedioxymandelic acid amidines and their pharmacologically non-toxic acid addition salts and pharmaceutical compositions containing them. Eliminated from: 1811804 - Google Patents
N-alkylated 3,4-methylenedioxymandelic acid amidines and their pharmacologically non-toxic acid addition salts and pharmaceutical compositions containing them. Eliminated from: 1811804Info
- Publication number
- DE1817861C3 DE1817861C3 DE19681817861 DE1817861A DE1817861C3 DE 1817861 C3 DE1817861 C3 DE 1817861C3 DE 19681817861 DE19681817861 DE 19681817861 DE 1817861 A DE1817861 A DE 1817861A DE 1817861 C3 DE1817861 C3 DE 1817861C3
- Authority
- DE
- Germany
- Prior art keywords
- acid
- methylenedioxymandelic
- alkylated
- amidines
- addition salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 N-alkylated 3,4-methylenedioxymandelic acid amidines Chemical class 0.000 title claims description 21
- 239000002253 acid Substances 0.000 title claims description 9
- 231100000252 nontoxic Toxicity 0.000 title claims description 5
- 230000003000 nontoxic effect Effects 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 title claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000008177 pharmaceutical agent Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 6
- 229960003602 guanethidine Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000001077 hypotensive effect Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 4
- 230000009090 positive inotropic effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- JWZKLCWLXKKOLL-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetonitrile Chemical compound N#CC(O)C1=CC=C2OCOC2=C1 JWZKLCWLXKKOLL-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001409 amidines Chemical class 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical group 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- QGBGSPANMHQOAV-UHFFFAOYSA-N 2-hydroxy-2-(4-propan-2-ylphenyl)acetic acid Chemical compound CC(C)C1=CC=C(C(O)C(O)=O)C=C1 QGBGSPANMHQOAV-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- 229940081310 piperonal Drugs 0.000 description 2
- 230000033764 rhythmic process Effects 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- RGHMISIYKIHAJW-UHFFFAOYSA-N 3,4-dihydroxymandelic acid Chemical compound OC(=O)C(O)C1=CC=C(O)C(O)=C1 RGHMISIYKIHAJW-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 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
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000002057 chronotropic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000009290 primary effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/14—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
Description
Die Erfindung betrifft N-alkylierte 3,4-Methylendioxymandelsäureamidine der allgemeinen FormelThe invention relates to N-alkylated 3,4-methylenedioxymandelic acid amidines the general formula
NHNH
H7CH 7 C
Dosen von 50 mg/24 Stunden 20% Mißerfolg, 35% mäßige Ergebnisse und 45% gute Ergebnisse.Doses of 50 mg / 24 hours 20% failure, 35% moderate results, and 45% good results.
Das N - Isopropyl - 3,4 - methylendioxymandelsäureamidinhydrochlorid wirkt auf die /i-ReztptorenThe N - isopropyl - 3,4 - methylenedioxymandelic acid amidine hydrochloride acts on the / i-Reztptoren
des isolierten Kaninchenherzeus in einer Dosis von 100 μg/ml (Versuche an sechs Herzen): Es erhöht den Koronardurchsatz (im Mittel um + 30%), es führt zu einem positiven inotropen Effekt (+142%) und verändert nicht den Rhythmus. 3-Isopropylamino-2-(naphthyloxy-[l])-propan-l-ol vermindert inof the isolated rabbit heart in a dose of 100 μg / ml (tests on six hearts): It increases the Coronary throughput (on average by + 30%), it leads to a positive inotropic effect (+ 142%) and does not change the rhythm. 3-Isopropylamino-2- (naphthyloxy- [I]) - propan-1-ol decreased in
Dosen von 1 und 2 pg die positive inotrope WirkungDoses of 1 and 2 pg the positive inotropic effect
des Produktes, aber weniger deutlich als die des Isoprenalins.of the product, but less clearly than that of isoprenaline.
Bezüglich der Wirkung auf den KoronardurchflußRegarding the effect on coronary flow
des isolierten Kaninchenherzens wurden mit N-Isopropyl - 3,4- methylendioxymandelsäureamidin -hydrochlorid bei einer Versuchsreihe an drei von Bariumchlorid enthaltender Van-Dyke-Hastings-Flüssigkeii durchströmten Herzen folgende Ergebnisse erzielt:of the isolated rabbit heart were washed with N-isopropyl - 3,4-methylenedioxymandelic acid amidine hydrochloride in a series of tests on three Van Dyke Hastings liquids containing barium chloride perfused heart achieved the following results:
Bei einer Dosis von 10 μΕ/ηιΙ (fünf Versuche) wurde eine Erhöhung des Koronardurchflusses um 18%, ein positiver inotroper Effekt von 64% und ein variabler chronotroper Effekt von +100% bzw. -15% beobachtet.At a dose of 10 μΕ / ηιΙ (five attempts) an increase of the coronary flow by 18%, a positive inotropic effect of 64% and a variable chronotropic effect of + 100% and -15% was observed.
Bei einer Dosis von 100 μ§/πι1 (fünf Versuche) wurde eine Erhöhung des Koronardurchsatzes um 102%, ein positiver inotroper Effekt ( + 36%) mit nachfolgendem erheblichem negativem inotropem Effekt (-70%) und ein negativer chrono-At a dose of 100 μ§ / πι1 (five attempts) an increase of the coronary throughput by 102%, a positive inotropic effect (+ 36%) with subsequent significant negative inotropic effect (-70%) and a negative chrono-
troper Effekt (- 35%) beobachtet.tropical effect (- 35%) observed.
Bei einer Dosis von 500 (ig/ml (fünf Versuche) ist die Verbindung ein Topikum: Es erhöht stark den Koronardurchfluß (+ 292%), führt zu einem negativen inotropen Effekt (-67%) und verändert nicht den Rhythmus.At a dose of 500 (ig / ml (five attempts) the compound is a topical: it greatly increases the coronary flow (+ 292%), leads to a negative inotropic effect (-67%) and changes not the rhythm.
Außerdem ist die Toxizität der neuen Verbindungen bedeutend geringer als die von Guanethidin und von anderen bekannten Mandelsäureamidinen. wie aus der nachfolgenden Tabelle ersichtlich ist.In addition, the toxicity of the new compounds is significantly lower than that of guanethidine and of other known mandelic acid amidines. as can be seen from the table below.
in der zumindest einer der Reste R1 und R2 eine Methyl-, Äthyl- oder Isopropylgruppe darstellt, während gegebenenfalls der andere Rest ein Wasserstoffatom bedeutet, und deren pharmakclogisch nicht giftige Säureanlagerungssalze und diese enthaltende pharmazeutische Mittel.in which at least one of the radicals R 1 and R 2 represents a methyl, ethyl or isopropyl group, while optionally the other radical represents a hydrogen atom, and their pharmacologically non-toxic acid addition salts and pharmaceutical agents containing them.
Diese neuen 3,4 - Methylendioxymandelsäureamidine sind wegen ihr;r Wirkung auf das Kardiovaskularsystem therapeutisch hochinteressant, und sie sind insbesondere zur Behandlung von arterieller Hypertension geeignet.These new 3,4-methylenedioxymandelic acid amidines are because of their effect on the cardiovascular system therapeutically of great interest, and they are particularly useful for treating arterial Suitable for hypertension.
Ihre Wirkung wurde in Vergleichsversuchen gegenüber dem bekannten Guanethidin [/J-O-Azacyclooctyl)-äthylguanidin] geprüft.Their effect was compared to the known guanethidine [/ J-O-Azacyclooctyl) ethylguanidine] in comparative tests checked.
Dabei wurde bei den neuen Verbindungen insbesondere keine hypertensive Primärwirkung festgestellt, wie sie beim Guanethidin gefunden wird, und im Vergleich zu dieser bekannten Verbindung treten bei Verabreichung hypotensiv wirkender Dosen keine Diarrhöen auf.In particular, no hypertensive primary effect was found with the new compounds, as found in guanethidine, and in comparison to this known compound diarrhea does not occur when hypotensive doses are administered.
Bei klinischen Untersuchungen wurden bei (per os) Verabreichung von 350 mgN-IsopropyW^-melhylendioxymandelsäureamidinhydrochlorid 24 Stunden 100%ig eine Abnahme des systolischen Druckes um zumindest 40 mm gefunden. Guanethidin gibt beiIn clinical investigations, 350 mg N-isopropyW ^ -melhylenedioxymandelic acid amidine hydrochloride were administered (per os) A 100% decrease in systolic pressure of at least 40 mm was found for 24 hours. Guanethidine is there
Geprüfte VerbindungTested connection
N,N-Diäthyl-3,4-methylendioxymandelsäureamidinhydro-
chlorid (Beispiel) N, N-diethyl-3,4-methylenedioxymandelic acid amidine hydro-
chloride (example)
N-IsopropylO^-methylcndioxymandelsäureamidinhydrochlorid (Beispiel) N-IsopropylO ^ -methyldioxymandelic acid amidine hydrochloride (Example)
N-lsopropyl-m-hydroxymandelsäureamidinhydrochlorid
(bekannt) N-Isopropyl-m-hydroxymandelic acid amidine hydrochloride
(known)
3,4-Dihydroxy-mandelsäureamidinhydrochlorid (bekannt)3,4-dihydroxy-mandelic acid amidine hydrochloride (known)
p-Isopropyl-mandelsäureamidinhydrochlorid (bekannt)p-Isopropyl-mandelic acid amidine hydrochloride (known)
ji-( 1 -AzacyclooctylHthyl- ji- ( 1-azacyclooctylHthyl-
guanidin (bekannt) guanidine (known)
DL5n bei der Maus intraDL 5n in the mouse intra
intravenösintravenous
jmg/kg) (mg_kg)_jmg / kg) (mg_kg) _
88
9088
90
35
38
26
3635
38
26th
36
muskulärmuscular
400400
400400
180180
Das aus Chemical Abstracts, Bd. 54 (1960), Spalte 10 134", bekannte p-Isopropylmandelsäurcamidin weist keine hypotensive Wirksamkeit auf. und ebenso ergibt das aus dem Journal of Chemical Society 1957, S. 513 (Chemical Abstracts, Bd. 51That from Chemical Abstracts, Vol. 54 (1960), Column 10 134 ", known p-isopropylmandelic acid camidine has no hypotensive activity. and so does the Journal of Chemical Society 1957, p. 513 (Chemical Abstracts, Vol. 51
ϊ 817ϊ 817
[1957], Spalte 9592 b), bekannte 3,4-Dihydroxymandelsäureamidin keinerlei hypotensive Wirkung, wohl aber eine vorübergehende Hypertension bei Verabreichung an Ratten und Kaninchen in Dosen von 160 mg/kg (im·)· Das N-Isopropyl-m-hydroxy-mandelsäureamidin-hydrochlorid besitzt zwar eine gewisse hypotensive Wirksamkeit, diese ist jedoch geringer als die des bekannten Guanethidins.[1957], column 9592 b), known 3,4-dihydroxymandelic acid amidine no hypotensive effect, but temporary hypertension when administered on rats and rabbits in doses of 160 mg / kg (im ·) · N-isopropyl-m-hydroxy-mandelic acid amidine hydrochloride Although it has a certain hypotensive effectiveness, it is less than that of the well-known guanethidine.
Die neuen Verbindungen besitzen gegenüber dem Guanethidin eine überlegene hypotensive Wirkung ι ο bei etwas abweichendem Wirkungsmechanismus.Compared to guanethidine, the new compounds have a superior hypotensive effect ι ο with a slightly different mechanism of action.
Die 3,4 - Methylendioxymandelsäureamidine der oben angegebenen allgemeinen Formel und deren pharmakologisch nicht giftige Säureanlagerungssalze werden dadurch hergestellt, daß man in an sich bekannter Weise 3,4-Methylendioxymandelsäurenitril der FormelThe 3,4-methylenedioxymandelic acid amidines of the general formula given above and their Acid addition salts which are pharmacologically non-toxic are produced in that one is known per se Way 3,4-methylenedioxymandelonitrile the formula
RCRc
CHOH-C =CHOH-C =
mit einem niederen aliphatischen Alkohol umsetzt, den gebildeten Iminoester mit einem Amin der allgemeinen Formel NHR1R2, in der R1 und R2 die oben angegebene Bedeutung besitzen, behandelt und das erhaltene Amidin gegebenenfalls in ein pharmakologisch nicht giftiges Säureanlagerungssalz überführt. reacts with a lower aliphatic alcohol, treats the imino ester formed with an amine of the general formula NHR 1 R 2 , in which R 1 and R 2 have the meaning given above, and optionally converts the amidine obtained into a pharmacologically non-toxic acid addition salt.
Vorzugsweise wird als aliphatischer Alkohol Methanol verwendet.Methanol is preferably used as the aliphatic alcohol.
N,N-Diäthyl-3,4-methylendioxymandelsäureamidinhydrochlorid N, N-diethyl-3,4-methylenedioxymandelic acid amidine hydrochloride
Eine Lösung von 0,4 Mol 3,4-Methylendioxymandelsäurenitril in 250 ml wasserfreiem Äthyläther und 40 ml absolutem Äthanol wird in der Kälte mit trockenem gasförmigem Chlorwasserstoff gesättigt. Anschließend wird das Gemisch etwa 10 Stunden bei OC stehengelassen und dann das ausgefallene 3.4-Methylendioxymandelsäureiminoäthylesterhydrochlorid abliltrien und die Substanz zweimal mit je 100 ml wasserfreiem Äthyläther gewaschen.A solution of 0.4 mol of 3,4-methylenedioxymandelonitrile in 250 ml of anhydrous ethyl ether and 40 ml of absolute ethanol is in the cold with saturated dry gaseous hydrogen chloride. Then the mixture is about 10 hours at Left to stand OC and then the precipitated 3,4-methylenedioxymandelic acid iminoethyl ester hydrochloride abliltrien and washed the substance twice with 100 ml of anhydrous ethyl ether.
0,1 Mol des obigen 3,4-Methylendioxymandelsäureiminoäthylesterhydrochlorids wird zu einer Lösung von 0,3 Mol Diäthylamin in 150 ml absolutem Äthanol hinzugegeben, und das Gemisch wird 2 Stunden im Wasserbad zum Rückfluß erhitzt. Dann wird die Reaktionslösung im Vakuum eingedampft, der Rückstand mit 100 ml Wasser wieder aufgenommen und mit Äthyläther extrahiert, um überschüssiges Diäthylamin zu entfernen. Die wäßrige Lösung wird durch Zugabe von etwa 2n-Natronlauge alkalisiert (End-pH > 14 bzw. etwa 14,5), und das freigesetzte N,N - Diäthyl - 3.4 - methylendioxymandelsäurcamidin wird mil 3 · 50 ml Äthyläther extrahiert. Die ver- f>o einigten Ätherextrakte werden mit Wasser gewaschen, über wasserfreiem Natriumsulfat getrocknet, filtriert und im Vakuum eingedampft. Der Rückstand wird dann mit einer ätherischen Chlorwasserstofflösung versetzt und der erhaltene Niederschlag abfiltriert. Das abgetrennte rohe N,N-Diäihyl-3,4-methylendioxymandelsäureamidinhydrochlorid wird aus einer 1:1-Mischung von Äthanol und Äthyläther umkristallisiert. 0.1 mol of the above 3,4-methylenedioxymandelic acid iminoethyl ester hydrochloride is added to a solution of 0.3 mol of diethylamine in 150 ml of absolute ethanol, and the mixture is 2 hours heated to reflux in a water bath. Then the reaction solution is evaporated in vacuo, the The residue was taken up with 100 ml of water and extracted with ethyl ether to remove excess Remove diethylamine. The aqueous solution is made alkaline by adding about 2N sodium hydroxide solution (Final pH> 14 or about 14.5), and the released N, N-diethyl-3,4-methylenedioxymandelic acid camidine is extracted with 3 x 50 ml ethyl ether. The ver f> o The combined ether extracts are washed with water, dried over anhydrous sodium sulfate and filtered and evaporated in vacuo. The residue is then washed with an ethereal hydrogen chloride solution added and the resulting precipitate filtered off. The separated crude N, N-diethyl-3,4-methylenedioxymandelic acid amidine hydrochloride is recrystallized from a 1: 1 mixture of ethanol and ethyl ether.
Man erhält die Verbindung in der Form eines weißen Pulvers von F. 160° C. Das Hydrochlorid ist in Wasser, Methanol und Äthanol löslich und in Äthylacetat, Äthyläther, Petroläther und Benzol unlöslich. Die Ausbeute beträgt 32%.The compound is obtained in the form of a white powder with a temperature of 160 ° C. The hydrochloride is in water, Methanol and ethanol soluble and insoluble in ethyl acetate, ethyl ether, petroleum ether and benzene. the Yield is 32%.
Nach der oben beschriebenen Methode wird bei Verwendung des entsprechenden Amins an Stelle von Diäthylamin das N,N-Dimethyl-3,4-methylendioxymandelsäureamidmhydrochlorid (F. 212CC) und das N - Isopropyl - 3,4 - methylendioxymandelsäureamidiuhydrochlorid (F. 145° C) erhalten.After the above-described method using the appropriate amine in place of diethylamine, the N, N-dimethyl-3,4-methylendioxymandelsäureamidmhydrochlorid (F. 212 C C) and the N - isopropyl - 3,4 - methylendioxymandelsäureamidiuhydrochlorid (145 ° F. C) received.
Das oben als Ausgangsmaterial verwendete 3,4-Methylendioxymandelsäurenitril ist wie folgt hergesteJlt worden:The 3,4-methylenedioxymandelonitrile used as the starting material above has been produced as follows:
In einen 20-1-Ballon mit drei Stutzen und der mit
einem Rührer, einem Präzisionsthermometer und einem Einlauftrichter ausgestattet ist und der · "
dem mit der äußeren Umgebung nw
Blasenzähler in Verbindung steht
mit einer Cyanwasserstoffsäuref
werdenIn a 20-1 balloon with three nozzles and which is equipped with a stirrer, a precision thermometer and an inlet funnel and the · "
the one with the external environment nw
Bubble counter communicating
with a hydrocyanic acid f
will
1600 g 95%iges Kaliunu.
3000 e Piperonal (20 Mol) unu
10 1 Wasser1600 g of 95% Kaliunu.
3000 e piperonal (20 mol) unu
10 1 water
eingebracht.brought in.
Man prüft die Dichtigkeit der Apparatur mit dem Blasenzähler, kühlt den Ballon von außen mit Eiswasser, rührt zur Auflösung des Cyanids, bringt das Piperonal in Suspension und sorgt für einen Temperaturausgleich innerhalb der Apparatur. Dann werden zu dem Gemisch unter Rühren langsam 400 cm3 einer Natriumbisulfitlösung der Dichte 1,32 hinzugegeben, und hierauf wird sehr langsam halbkon/entrierte (etwa 6-n) Chlorwasserstoffs«!υrelösung in dem Maße und in der Menge zugegeben, daß die Temperatur 15 C nicht übersehreitet und die Zugabe der Chlorwasserstoffsäure beendet wird. w?nn derpH-Wert des Reaktionsgemisches den Wert 4,0 bis 5.0 erreicht hat. Das Nitril bildet sich ziemlich rasch in Form von öligen hellbraunen Tröpfchen, die sich spontan absetzen, wenn der Rührer abgestellt wird. Die ölige Schicht wird dann durch Abheben bzw. mit Hilfe eines Siphons abgetrennt und diese in einem Ballon mit einem unteren, mit Hahn versehenen Stutzen dreimal mit Wasser gewaschen. Das erhaltene Nitril wird in Chloroform gelöst und über wasserfreiem Calciumchlorid 24 Stunden getrocknet. Dann wird das Chloroform im Vakuum abgedampft, wobei man ungefähr 3200 grohes3.4-Methylendioxymandelsüurenitril von braunoranger Farbe, das einen Brechungsindex bei 20 C von etwa 1.546 aufweist, erhält.The tightness of the apparatus is checked with the bubble counter, the balloon is cooled from the outside with ice water, stirred to dissolve the cyanide, the piperonal is brought into suspension and the temperature within the apparatus is equalized. Then 400 cm 3 of a sodium bisulfite solution with a density of 1.32 are slowly added to the mixture with stirring, and half-concentrated (about 6N) hydrogen chloride solution is then added very slowly to the extent and in the amount that the temperature 15 C is not exceeded and the addition of the hydrochloric acid is ended. when the pH of the reaction mixture has reached 4.0 to 5.0. The nitrile forms rather quickly in the form of oily, light brown droplets which spontaneously settle when the stirrer is switched off. The oily layer is then separated off by lifting it off or with the aid of a siphon and this is washed three times with water in a balloon with a lower nozzle provided with a tap. The nitrile obtained is dissolved in chloroform and dried over anhydrous calcium chloride for 24 hours. The chloroform is then evaporated off in vacuo to give approximately 3200 coarse 3,4-methylenedioxymandelic acid nitrile, brown-orange in color and having a refractive index at 20 C of approximately 1,546.
Das erhaltene Nitril läßt sich selbst unter vermindertem Druck nicht destillieren, da es zu Aldehyd und Cvanwasserstoffsäure dissoziiert.The nitrile obtained can be reduced even under Do not distill pressure as it will dissociate to aldehyde and hydrocarbon acid.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB34947/68A GB1243186A (en) | 1967-11-29 | 1967-11-29 | Improvements in or relating to mandelamidine derivatives |
| GB5443067 | 1967-11-29 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1817861A1 DE1817861A1 (en) | 1972-09-28 |
| DE1817861B2 DE1817861B2 (en) | 1973-09-06 |
| DE1817861C3 true DE1817861C3 (en) | 1974-04-04 |
Family
ID=26262509
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19681817861 Expired DE1817861C3 (en) | 1967-11-29 | 1968-11-29 | N-alkylated 3,4-methylenedioxymandelic acid amidines and their pharmacologically non-toxic acid addition salts and pharmaceutical compositions containing them. Eliminated from: 1811804 |
Country Status (7)
| Country | Link |
|---|---|
| BE (1) | BE723974A (en) |
| CH (1) | CH488651A (en) |
| DE (1) | DE1817861C3 (en) |
| ES (1) | ES360636A1 (en) |
| FR (2) | FR1591540A (en) |
| GB (1) | GB1243186A (en) |
| NL (1) | NL162909C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1121792B (en) * | 1978-07-03 | 1986-04-23 | Dow Chemical Co | A PROCESS TO PREPARE 2-NAPHTHALENETHANIMIDAMIDS N, N'-OF-SUBSTITUTES AND INTERMEDIATES USED IN THIS PROCESS |
| US4623659A (en) * | 1983-05-23 | 1986-11-18 | Riet Bartholomeus Van T | Polyhydroxybenzoic acid derivatives |
-
1967
- 1967-11-29 GB GB34947/68A patent/GB1243186A/en not_active Expired
-
1968
- 1968-11-14 FR FR1591540D patent/FR1591540A/fr not_active Expired
- 1968-11-14 FR FR173695A patent/FR7744M/fr not_active Expired
- 1968-11-15 CH CH1708868A patent/CH488651A/en not_active IP Right Cessation
- 1968-11-18 BE BE723974D patent/BE723974A/xx not_active IP Right Cessation
- 1968-11-23 ES ES360636A patent/ES360636A1/en not_active Expired
- 1968-11-27 NL NL6816939A patent/NL162909C/en active
- 1968-11-29 DE DE19681817861 patent/DE1817861C3/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB1243186A (en) | 1971-08-18 |
| ES360636A1 (en) | 1970-10-16 |
| NL6816939A (en) | 1969-06-02 |
| NL162909C (en) | 1980-07-15 |
| BE723974A (en) | 1969-05-19 |
| FR7744M (en) | 1970-03-09 |
| DE1817861A1 (en) | 1972-09-28 |
| CH488651A (en) | 1970-04-15 |
| DE1817861B2 (en) | 1973-09-06 |
| DE1811804A1 (en) | 1969-11-27 |
| FR1591540A (en) | 1970-04-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C3 | Grant after two publication steps (3rd publication) | ||
| E77 | Valid patent as to the heymanns-index 1977 |