DE1817861A1 - N-alkylated 3,4-methylenedioxymandelic acid amidines and their pharmacologically non-toxic acid addition salts and pharmaceutical compositions containing them - Google Patents
N-alkylated 3,4-methylenedioxymandelic acid amidines and their pharmacologically non-toxic acid addition salts and pharmaceutical compositions containing themInfo
- Publication number
- DE1817861A1 DE1817861A1 DE19681817861 DE1817861A DE1817861A1 DE 1817861 A1 DE1817861 A1 DE 1817861A1 DE 19681817861 DE19681817861 DE 19681817861 DE 1817861 A DE1817861 A DE 1817861A DE 1817861 A1 DE1817861 A1 DE 1817861A1
- Authority
- DE
- Germany
- Prior art keywords
- acid
- methylenedioxymandelic
- alkylated
- addition salts
- amidines
- 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.)
- Granted
Links
- -1 N-alkylated 3,4-methylenedioxymandelic acid amidines Chemical class 0.000 title claims description 18
- 239000002253 acid Substances 0.000 title claims description 9
- 231100000252 nontoxic Toxicity 0.000 title claims description 6
- 230000003000 nontoxic effect Effects 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 title claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000000144 pharmacologic effect Effects 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000008177 pharmaceutical 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 150000001875 compounds Chemical class 0.000 description 5
- 230000001077 hypotensive effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 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
- 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
- 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
- 230000000694 effects Effects 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
- 206010020772 Hypertension Diseases 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 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 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000002057 chronotropic effect Effects 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 229940081310 piperonal Drugs 0.000 description 2
- 239000000047 product Substances 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
- 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 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-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
- 208000037849 arterial hypertension Diseases 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
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 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
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005406 washing Methods 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
-y -i- >■- ■ ■■*" -y -i-> ■ - ■ ■■ * "
.' MÜηw.-..».-» Li,, ■U.i.i.Jürfatr. ij g6-l8.4O6P 1817861. ' MÜηw .- .. ».-» Li ,, ■ U.i.i.Jüratr. ij g6-l8.4O6P 1817861
P 18 11 804.2.-42 Tr.A.P 18 11 804.2.-42 Tr.A.
N-alkylierte 3,4-Methylendioxymandelsäureamidine und deren pharmakologisch nicht giftige Säureanlagerungssalze und diese enthaltende pharmazeutische MittelN-alkylated 3,4-methylenedioxymandelic acid amidines and their pharmacologically non-toxic acid addition salts and pharmaceuticals containing them middle
Die Erfindung betrifft N-alkylierte J5,4-Methylendioxymandelsäureamidine der FormelThe invention relates to N-alkylated J5,4-methylenedioxymandelic acid amidines the formula
in der zumindest einer der Reste R. und Rp eine Methyl-, Äthyl- oder Isopropylgruppe ist, während gegebenenfalls der andere ein Wasserstoffatom bedeutet und deren pharmakologisch nicht giftige Säureanlagerungssalze und diese enthaltende pharmazeutische Mittel.in which at least one of the radicals R. and Rp is a methyl, Ethyl or isopropyl group, while optionally the other is a hydrogen atom and their pharmacological non-toxic acid addition salts and pharmaceutical compositions containing them.
Diese neuen 3,4-Methylendioxymandelsäureamidine sind wegen ihrer Wirkung auf das Kardiovaskularsystem therapeu-These are new 3,4-methylenedioxymandelic acid amidines therapeutic due to their effect on the cardiovascular system
96- (3.4.107P)-Ausscheldung-NöE (1)96- (3.4.107P) - cut-out -NöE (1)
209840/115 5209840/115 5
tisch hochinteressant und sie sind insbesondere zur Behandlung von arterieller Hypertension geeignet.highly interesting and they are particularly suitable for the treatment of arterial hypertension.
Ihre Wirkung wurde in Vergleichsversuchen gegenüber dem bekannten Guanethidin £[i -(l-Azacyclooctyl)-äthylguani din J geprüft.Their effect was compared in comparison tests the well-known guanethidine £ [i - (l-azacyclooctyl) ethylguani din J 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 like them is found in guanethidine and compared to this known compound occur hypotensive when administered effective doses do not cause diarrhea.
Bei klinischen Untersuchungen wurden bei (per os) Verabreichung von 550 mg N-IsopropylOi^-methylendioxymandelsäureamidinhydrochlorid 24 Std. 100#ig gute Ergebnisse (d.h. eine Abnahme des systolischen Druckes um zumindest 40 mm gefunden. Guanethidin gibt bei Dosen von 50 mg/24 Std. 20# Mißerfolg, 35% mäßige Ergebnisse und 45# gute Ergebnisse.In clinical studies, with (per os) administration of 550 mg of N-isopropylOi ^ -methylenedioxymandelic acid amidine hydrochloride for 24 hours, 100% good results (ie a decrease in systolic pressure of at least 40 mm were found. Guanethidine gives at doses of 50 mg / 24 hours 20 # failure, 35% moderate results, and 45 # good results.
Das N-Isopropyl-3,4-methylendioxymandelsäureamidinhydrochlorid wirkt auf die ß-Rezeptoren des isolierten Kaninchenherzens in einer Dosis von 100 /Ug/ml (Versuche an 6 Herzen): Es erhöht den Koronardurchsatz (im Mittel um + 30$), es führt zu einem positiven inotropen Effekt (+ l42#) und verändert nicht den Rhythmus. Propanolol |f;5-Isopropylamino-2-(naphthyloxy-(l) J-propan-l-olJ vermindert in Dosen ^on 1 ,ug und 2 /Ug die positive inotrope Wirkung des Produktes, aber weniger deutlich als die des Isoprenalins.The N-isopropyl-3,4-methylenedioxymandelic acid amidine hydrochloride acts on the ß-receptors of the isolated rabbit heart in a dose of 100 / Ug / ml (tests on 6 hearts): It increases the coronary throughput (on average by + 30 $), it leads to a positive inotropic effect (+ 142 #) and does not change the rhythm. Propanolol | f; 5-isopropylamino-2- (naphthyloxy- (l) J-propan-l-ol] in doses of 1, µg and 2 / Ug reduces the positive inotropic effect of the product, but less clearly than that of isoprenaline.
Bezüglich der Wirkung auf den Koronardurchsatz desRegarding the effect on the coronary throughput of the
209840/1155209840/1155
isolierten Kaninchenherzens wurden mit N-Isopropyl-3i^- methylendioxymandelsäureamidin-hydrochlorid bei einer Versuchsreihe an 3 von Bariumchlorid enthaltender Van Dyke-Hast ings-Flüssi-gkeit durchströmten Herzen folgende Ergebnisse erzielt:isolated rabbit hearts were treated with N-isopropyl-3i ^ - methylenedioxymandelic acid amidine hydrochloride in a series of tests on 3 Van Dyke-Hast containing barium chloride ings fluid perfused hearts with the following results achieved:
- Bei einer Dosis von 10 /Ug/ml (5 Versuche) wurde eine Erhöhung des Koronardurchsatzes um l8#, ein positiver inotroper Effekt von 64$ und ein variabler chronotroper Effekt (+ lOOji, - 15Ji) beobachtet.- At a dose of 10 / Ug / ml (5 experiments) a Increase in coronary throughput by 18 #, a positive inotropic Effect of $ 64 and a variable chronotropic effect (+ 100ji, - 15Ji) observed.
- Bei einer Dosis von 100 /Ug/ml (5 Versuche) wurde eine Erhöhung des Koronardurchsatzes um 102$, ein positiver inotroper Effekt (+ 36^) mit nachfolgendem erheblichen negativen inotropen Effekt (- 70$) und ein negativer chronotroper Effekt (- 35 %) beobachtet.- At a dose of 100 / Ug / ml (5 attempts), an increase in the coronary throughput by $ 102, a positive inotropic effect (+ 36 ^) with a significant negative inotropic effect (- 70 $) and a negative chronotropic effect (- 35 %) observed.
- Bei, einer Dosis von 500 /Ug/ml (5 Versuche) ist das Produkt ein Topikuiu: Es erhöht stark den Durchsatz (+ 292$), führt zu einem negativen inotropen Effekt (- 6796) und verändert nicht den Rhythmus.- At a dose of 500 / Ug / ml (5 attempts) the product is a Topikuiu: It greatly increases throughput (+ $ 292), leads to a negative inotropic effect (- 6796) and changes not the rhythm.
Außerdem ist die Toxizität der geprüften 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 tested is significantly lower than that of guanethidine and from other known mandelic acid amidines, such as from the can be seen in the table below.
209840/1 155209840/1 155
N,N-Diäthyl-3,4-methylen-
dioxymandelsäureamidin-
hydrochlorid
N-Isopropyl-3,4-methylen-
dioxymandelsäureamidin-
hydfochlorid- according to the invention -
N, N-diethyl-3,4-methylene
dioxymandelic acid amidine
hydrochloride
N-isopropyl-3,4-methylene
dioxymandelic acid amidine
hydrofluoride
400 mg/kg400 mg / kg
400 mg / kg
N-Isopropyl-m-hydroxy-
mandelsäureamidinhydro-
;chlorid
,3>4-Dihydroxy-mandelsäure-
amidinhydrochlorid
p-Isopropyl-mandelsäure-
amidinhydrochlorid
ß-(l-Azacyclooctyl)-äthyl-
guanidin! - known -
N-isopropyl-m-hydroxy-
mandelic acid amidine hydro
;chloride
, 3> 4-dihydroxy mandelic acid
amidine hydrochloride
p-isopropyl mandelic acid
amidine hydrochloride
ß- (l-azacyclooctyl) ethyl
guanidine
90 mg/kg88 mg / kg
90 mg / kg
38 mg/kg
26 mg/kg
36 mg/kg35 mg / kg
38 mg / kg
26 mg / kg
36 mg / kg
Das aus Chemical Abstracts, Band 54, Spalte 10.1j54a bekannte p-Isopropylmandelsäureamidin weist keine hypotensive Wirksamkeit auf und ebenso ergibt das aus dem Journal of Chemical Society I957, S. 513 (Chemical Abstracts, Bd. %\_, Spalte 9592b) bekannte 3j4~Dihydroxymandelsäureamidin keiner lei hypotensive Wirkung, wohl aber eine vorübergehende Hypertension bei Verabreichung an Ratten und Kaninchen in Dosen von I60 mg/kg (i.m.) Das N-Isopropyl-m-hydroxy-mandelsäureamidin-hydrochlorid besitzt zwar mit eine gewisseThe Chemical Abstracts, Volume 54, column 10.1j54 a known p-Isopropylmandelsäureamidin has no hypotensive activity and as resulting from the Journal of Chemical Society I957, p 513 (Chemical Abstracts, Vol.% \ _, Column 9592b) known 3j4 ~ Dihydroxymandelic acid amidine no slight hypotensive effect, but a temporary hypertension when administered to rats and rabbits in doses of 160 mg / kg (im)
209840/1155209840/1155
hypotensive Wirksamkeit, diese ist jedoch geringer als die des bekannten Guanethidins.hypotensive potency, but this is less than that of the well-known guanethidine.
Die neuen geprüften Verbindungen sind weniger toxisch als die bekannten Substanzen und sie besitzen gegenüber dem Guanethidin eine überlegene hypotensive Wirkung bei etwas abweichendem Wirkungsmechanismus.The new compounds tested are less toxic than the known substances and they have opposite a superior hypotensive effect to guanethidine with a slightly different mechanism of action.
Die 2,4-Methylendioxymandelsäureamidine der oben angegebenen allgemeinen Formel und deren pharmakologisch nicht giftige Säureanlagerungssalze werden dadurch hergestellt, · daß man in an sich bekannter Weise J>, 4-Methylendioxymandelsäurenitril der Formel:The 2,4-methylenedioxymandelic acid amidines of the general formula given above and their pharmacologically non-toxic acid addition salts are prepared by adding, in a manner known per se, J>, 4-methylenedioxymandelic acid nitrile of the formula:
CHOH-C=NCHOH-C = N
mit einem niederen aliphatischen Alkohol umsetzt, den gebildeten Iminoester mit einem Amin der allgemeinen Formel NHR,Rg, in der R. und Rp die oben angegebene Bedeutung besitzen, behandelt und das erhaltene Amidin gegebenenfalls in ein pharmakologisch nicht giftiges Säureanlagerungssalz überführt.reacts with a lower aliphatic alcohol, the imino ester formed with an amine of the general formula NHR, Rg, in which R. and Rp have the meaning given above, treated and the amidine obtained optionally in a pharmacologically non-toxic acid addition salt convicted.
Vorzugsweise wird als aliphatischer Alkohol Methanol verwendet.Methanol is preferably used as the aliphatic alcohol.
N,N-Diäthyl-3,4-methylendioxymandelsäureamldinhydrochlorid N, N-Diethyl-3,4-methylenedioxymandelic acid amldine hydrochloride
20 98 40/115520 98 40/1155
Eine Lösung von 0,4 Mol ^^-Methylendioxymandelsäurenitril in 250 ml wasserfreiem Äthyläther und 40 ml absolutem Äthanol wird in der Kälte mit trockenem gasförmigen Chlorwasserstoff . gesättigt. Anschließend wird das Gemisch über etwa 10 Stunden bei 0 C stehen gelassen und dann das ausgefallene Hydrochlorid des 3*4-Methylendioxymandelsäureiminoäthylesters abfiltriert und die Substanz zweimal mit je 100 ml wasserfreiem Äthyläther gewaschen.A solution of 0.4 mol ^^ - methylenedioxymandelonitrile in 250 ml of anhydrous ethyl ether and 40 ml of absolute ethanol is in the cold with dry gaseous hydrogen chloride. saturated. Then the mixture is left for about 10 hours Left to stand at 0 C and then the precipitated hydrochloride of the 3 * 4-methylenedioxymandelic acid iminoethyl ester was filtered off and washed the substance twice with 100 ml of anhydrous ethyl ether each time.
0,1 Mol des so hergestellten 3*4-Methylendioxymandelsäureiminoäthylesterhydrochlorids werden zu einer Lösung von 0,3 Mol Diäthylamin in 150 ml absolutem Äthanol hinzugegeben und das ganze wird zwei Stunden im Wasserbad zum Rückfluß erhitzt. Dann wird das Gemisch 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 alkalisch gemacht (End-pH > 14 bzw. etwa 14,5) und das freigesetzte basische N,N-Diäthyl-3,4-methylendioxymandelsäureamidin wird mit 3 x 50 ml Äthyläther extrahiert. Die gereinigten 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-Diäthyl-3,^- methylendioxymandelsäureamidinhydrochlorid wird aus einer 1:1 Mischung von Äthanol und Äthyläther umkristallisiert. Man erhält die Verbindung in der Form eines weißen Pulvers von Fp 1600C. Das Hydrochlorid ist in Wasser, Methanol und Äthanol löslich und in Äthylacetat, Äthyläther, Petroläther und Benzol unlöslich. Die Ausbeute beträgt0.1 mol of the 3 * 4-methylenedioxymandelic acid iminoethyl ester hydrochloride prepared in this way are added to a solution of 0.3 mol of diethylamine in 150 ml of absolute ethanol and the whole is refluxed for two hours in a water bath. The mixture is then evaporated in vacuo, the residue is taken up in 100 ml of water and extracted with ethyl ether in order to remove excess diethylamine. The aqueous solution is made alkaline by adding about 2N sodium hydroxide solution (final pH> 14 or about 14.5) and the released basic N, N-diethyl-3,4-methylenedioxymandelic acid amidine is extracted with 3 × 50 ml of ethyl ether. The purified ether extracts are washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. An ethereal hydrogen chloride solution is then added to the residue and the resulting precipitate is filtered off. The separated crude N, N-diethyl-3, ^ - methylenedioxymandelic acid amidine hydrochloride is recrystallized from a 1: 1 mixture of ethanol and ethyl ether. The compound is obtained in the form of a white powder of mp 160 0 C. The hydrochloride is insoluble soluble in water, methanol and ethanol and ethyl acetate, ethyl ether, petroleum ether and benzene. The yield is
Das oben als Ausgangsmaterial verwendete 3*4-Methylendioxymandelsäurenitril ist wie folgt hergestellt worden:The 3 * 4-methylenedioxymandelonitrile used as the starting material above has been manufactured as follows:
209840/1 155209840/1 155
In einen 20 1 Ballon mit 3 Stutzen und der mit einem Rührer, einem Präzisionsthermometer und einem Einlauftrichter ausgestattet ist und der außerdem mit der äußeren Umgebung nur über einen Blasenzähler in Verbindung steht, dessen Ausgang mit einer Cyanwasserstoffsäurefalle verbunden ist, werdenIn a 20 l balloon with 3 nozzles and the one with a stirrer, a precision thermometer and an inlet funnel and which is only connected to the external environment via a bubble counter, the outlet of which is connected to a hydrocyanic acid trap
l600 g 95#iges Kaliumcyanid (23,5 Mole), 3000 g Piperonal (20 Mole) und 10 1 Wasser1,600 g of 95% potassium cyanide (23.5 moles), 3000 g of piperonal (20 moles) and 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 cnr einer Natriumbisulfitlösung der Dichte 1,32 hinzugegeben und hierauf wird sehr langsam halbkonzentrierte (etwa 6 n) Chlorwasserst offsäurelösung in dem Maße und in der Menge zugegeben, daß die Temperatur 15°C nicht überschreitet und die Zugabe der Chlorwasserstoffsäure beendet wird, wenn der pH-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 2h Stunden getrocknet. Dann wird das Chloroform imThe 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 suspended and the temperature within the apparatus is equalized. Then 400 cnr of a sodium bisulphite solution of density 1.32 are slowly added to the mixture with stirring and then half-concentrated (approx Addition of the hydrochloric acid is ended when the pH of the reaction mixture has reached the value 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 by lifting it off or with the aid of a siphon and washing it 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 2 hours. Then the chloroform is im
2098*0/11552098 * 0/1155
Vakuum abgedampft, wobei man ungefähr 3200 g rohes ^>Λ-Methylendioxymandelsäurenitril von braunoranger Farbe, das einen Brechungsindex bei 200C von etwa 1,5^6 aufweist, erhält .Evaporated in vacuo, about 3200 g of crude ^> Λ- methylenedioxymandelonitrile of brown-orange color, which has a refractive index at 20 0 C of about 1.5 ^ 6 obtained.
Das erhaltene Nitril läßt sich selbst unter vermindertem Druck nicht destillieren, da es zu Aldehyd und Cyanwasserstoff säure dissoziiert.The nitrile obtained cannot be distilled even under reduced pressure, since it gives aldehyde and hydrogen cyanide acid dissociates.
Nach der oben beschriebenen Methode wird bei Verwendung des entsprechenden Amins anstelle von Diäthylamin das N,N-Dimethyl-3,4-methylendioxymandelsäureamidinhydrochlorid (Pp 2120C) und das N-Isopropyl-J^-methylendioxymandelsäureamidinhydrochlorid (Fp l45°C) erhalten.According to the method described above of the corresponding amine using diethylamine instead of the N, N-dimethyl-3,4-methylendioxymandelsäureamidinhydrochlorid (Pp 212 0 C) and obtain the N-Isopropyl-J ^ -methylendioxymandelsäureamidinhydrochlorid (mp l45 ° C).
2 U 9 8 4 ü / 1 1 5 52 U 9 8 4 o / 1 1 5 5
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB5443067 | 1967-11-29 | ||
| GB34947/68A GB1243186A (en) | 1967-11-29 | 1967-11-29 | Improvements in or relating to mandelamidine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1817861A1 true DE1817861A1 (en) | 1972-09-28 |
| DE1817861B2 DE1817861B2 (en) | 1973-09-06 |
| DE1817861C3 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) | FR7744M (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 FR173695A patent/FR7744M/fr not_active Expired
- 1968-11-14 FR FR1591540D patent/FR1591540A/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 |
|---|---|
| NL162909C (en) | 1980-07-15 |
| GB1243186A (en) | 1971-08-18 |
| ES360636A1 (en) | 1970-10-16 |
| DE1817861B2 (en) | 1973-09-06 |
| CH488651A (en) | 1970-04-15 |
| FR7744M (en) | 1970-03-09 |
| BE723974A (en) | 1969-05-19 |
| NL6816939A (en) | 1969-06-02 |
| DE1817861C3 (en) | 1974-04-04 |
| 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 |