DE1817861B2 - N-ALKYLATED 3,4-METHYLENOXYMANDEL ACID AMIDINES AND THEIR PHARMACOLOGICALLY NON-TOXIC ACID ADDITIONAL SALTS AND PHARMACEUTICAL AGENTS CONTAINING THESE - Google Patents
N-ALKYLATED 3,4-METHYLENOXYMANDEL ACID AMIDINES AND THEIR PHARMACOLOGICALLY NON-TOXIC ACID ADDITIONAL SALTS AND PHARMACEUTICAL AGENTS CONTAINING THESEInfo
- Publication number
- DE1817861B2 DE1817861B2 DE19681817861 DE1817861A DE1817861B2 DE 1817861 B2 DE1817861 B2 DE 1817861B2 DE 19681817861 DE19681817861 DE 19681817861 DE 1817861 A DE1817861 A DE 1817861A DE 1817861 B2 DE1817861 B2 DE 1817861B2
- Authority
- DE
- Germany
- Prior art keywords
- acid
- alkylated
- amidines
- methylenoxymandel
- pharmaceutical agents
- 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
- 239000002253 acid Substances 0.000 title description 10
- 150000001409 amidines Chemical class 0.000 title description 6
- 231100000252 nontoxic Toxicity 0.000 title description 5
- 230000003000 nontoxic effect Effects 0.000 title description 5
- 239000008177 pharmaceutical agent Substances 0.000 title description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- -1 3,4-methylenedioxymandelic acid amidines Chemical class 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 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
- 230000000694 effects Effects 0.000 description 5
- 230000001077 hypotensive effect Effects 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
- 239000000126 substance Substances 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
- 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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical group 0.000 description 3
- 230000009090 positive inotropic effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- 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 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000002057 chronotropic effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 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 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
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- KRIBGHFNGIBASL-UHFFFAOYSA-N C1OC2C=CC=CC2(O1)C(C(=O)O)O Chemical compound C1OC2C=CC=CC2(O1)C(C(=O)O)O KRIBGHFNGIBASL-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
- 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
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 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
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 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
- 229910052739 hydrogen Inorganic materials 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
- 229960001317 isoprenaline Drugs 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
- 235000010460 mustard Nutrition 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
- 239000000047 product Substances 0.000 description 1
- 239000001294 propane Substances 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
- 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
NHNH
H /H /
>- C — C> - C - C
OH NOH N
in der zumindest einer der Reste Rv und R2. eine Methyl-, Äthyl- oder Isopropylgruppe darstellt, während gegebenenfalls der andere Rest ein Wasserstoffatom bedeutet,und deren pharmakologisch nicht giftige Säureanlagerungssalze.in which at least one of the radicals R v 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.
2. Pharmazeutische Mittel, gekennzeichnet durch einen Gehalt an 3,4-Methylendioxymandelsäureamidinen gemäß Anspruch 1 neben üblichen inerten Trägerstoffen oder Verdünnungsmitteln.2. Pharmaceutical agents, characterized in that they contain 3,4-methylenedioxymandelic acid amidines according to claim 1 in addition to customary inert carriers or diluents.
2020th
Die Erfindung betrifft N-alkylierte 3,4-Methylendioxymandelsäureamidine der allgemeinen FormelThe invention relates to N-alkylated 3,4-methylenedioxymandelic acid amidines the general formula
H,CH, C
g gg g
- methylendioxymandel-- methylenedioxymandel-
siucmndiiydrochlorid wirkt auf ehe ,^-Rezeptoren jCs'iM.lii:ricn'Kaninchenherzens in einer Dosis von mi, .,., nil (Versuche an sechs Herzen): Es erhöht den K.-ronanlurchsal/ lim Mittel um + 30%) es führt /u eiivm positiven inotropen Effekt ( + 142 „) und verändert nicht den Rhythmus. 3-Isopropyhimino- ■> - maphihs lüxy - [ 1 ]) - propan -1 - öl verm.r -iyri in Dosen «<»n 1 und 2 ag die positive motrope W irkung des Produktes, aber weniger deutlich als die des lsoprenalins.siucmndiiydrochlorid acts on ehe, ^ - receptors j C s'iM.lii: ricn'Rabbit heart in a dose of mi,.,., nil (experiments on six hearts): it increases the K.-ronanlurchsal / lim mean by + 30 %) it leads to a positive inotropic effect (+ 142 ") and does not change the rhythm. 3-Isopropyhimino- ■> - maphihs lüxy - [1]) - propane -1 - oil verm.r -iyri in doses «<» n 1 and 2 ag the positive motropic effect of the product, but less clearly than that of isoprenaline .
Ikvü^!ich der Wirkung auf den Koronardmehnuß des is-^ei-M-n Kaninchenherzens wurden mit N-Isopr;ipvl.U-methylendioxymandelsäuream.uin-hydrochlorid bei einer Versuchsreihe an drei von Bar.umchlorid enthaltender Van-Dyke-Hastings-Flüssigkeit durchströmten Herzen folgende Ergebnisse er/iclt:Ikvü ^! I of the effect on the coronary mustard of the is- ^ ei-Mn rabbit heart were treated with N-Iso pr ; ipv lU-methylenedioxymandelic acid am.uin hydrochloride in a series of tests on three Van Dyke Hastings fluid containing barium chloride, the following results were obtained:
Bei einer Dosis von 10 μ&ΊηΙ (fünf Versuche) wurde eine Erhöhung des Koronardurchtiusses um 18% em positiver inotroper Effekt von 64% und ein variabler chronotroper Effekt von + 100% bzw - 15% beobachtet.At a dose of 10 μ & ΊηΙ (five attempts) an increase of the coronary passage by 18% em positive inotropic effect of 64% and a variable chronotropic effect of + 100% and - 15% was observed.
Bei einer Dosis von 100 pg/ml (fünf Versuche) wurde eine Erhöhung des Koronardurchsatzes um 102"... ein positiver inotroper Effekt (+ 36%) mit nachfolgendem erheblichem negativem inotropem Effekt (- 70%) und ein negativer chronotroper Effekt t - 35%) beobachtet. Bei einer Dosis von 500 ^g/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. 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.At a dose of 100 pg / ml (five attempts) an increase of the coronary throughput by 102 "... a positive inotropic effect (+ 36%) with a significant negative inotropic effect (- 70%) and a negative chronotropic effect Effect t - 35%) observed. At a dose of 500 ^ g / ml (five attempts) the compound is a topical: it greatly increases coronary flow (+ 292%), leads to a negative inotropic effect (-67%) and does not change the rhythm. Also, the toxicity of the new compounds significantly lower than that of guanethidine and of other known mandelic acid amidines, such as from can be seen in the table below.
3535
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 pharmakologisch 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 ihrer Wirkung auf das Kardiovaskularsystem therapeutisch hochinteressant, und sie sind insbesondere zur Behandlung von arterieller Hypertension geeignet.These new 3,4-methylenedioxymandelic acid amidines are known for their effects 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 fjHl-Azacyclooctyl)-äthylguanidin] geprüft.Their effect was compared to the known guanethidine fjHl-Azacyclooctyl) -äthylguanidin] 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 mg N-Isopropyl-S^-methylendioxymandelsäureamidinhydrochlorid 24 Stunden 10C%ig eine Abnahme des systolischen Druckes um zumindest 40 mm gefunden. Guanethidin gibt beiIn clinical studies, 350 mg of N-isopropyl-S ^ -methylenedioxymandelic acid amidine hydrochloride were administered (per os) 24 hours a 10C% decrease in systolic pressure of at least 40 mm was found. Guanethidine is there
N,N -Diäthyl-S^-methylendioxymandelsäurer.midinhydro- N, N -diethyl-S ^ -methylenedioxymandelic acid.midine hydro-
chlorid (Beispiel) chloride (example)
N-Jsopropyl-S^methylendioxymandelsäureamidinhydrochlorid (Beispiel) N-Isopropyl-S 1-methylenedioxymandelic acid amidine hydrochloride (Example)
N-Isopropyl-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)
ß-{ 1 -Azacycloocty l)-äthylguanidin (bekannt) ß- { 1 -Azacycloocty l) -äthylguanidin (known)
DL50 bei der Maus intraDL 50 in the mouse intra
intravenös (mg kg)intravenous (mg kg)
88 9088 90
35 38 26 3635 38 26 36
muskulär (mg/kg)muscular (mg / kg)
400400
400400
Das aus Chemical Abstracts, Bd. 54 (1960),That from Chemical Abstracts, Vol. 54 (1960),
Spalte 10 134°, bekannte ρ - Isopropylmandelsäure-Column 10 134 °, known ρ - isopropylmandelic acid-
amidin weist keine hypotensive Wirksamkeit auf,amidine has no hypotensive activity,
und ebenso ergibt das aus dem Journal of Chemicaland so does the Journal of Chemical
Society 1957, S. 513 (Chemical Abstracts, Bd.Society 1957, p. 513 (Chemical Abstracts, Vol.
(1957], Spalte 9592b), bekannte 3,4-Dihydro*ymantlelsiiureamidin keinerlei hypotensive Wirkung, wohl stber eine vorübergehende Hypertension bei Verabreichung an Ratten und Kaninchen in Dosen von I6ümj!,kg (Lm.). Das N-Isopropyl-m-hydroxy-mandelsaureamidin-hydrochlorid besitzt zwar eine gewisse hypotensive Wirksamkeit, diese ist jedoch i>eringer als die des bekannten Guanethidins.(1957], column 9592b), known 3,4-dihydro * ymantle iureamidine no hypotensive effect whatsoever, but a temporary hypertension on administration on rats and rabbits in doses of 16ümj !, kg (Lm.). The N-isopropyl-m-hydroxy-almond 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 bei etwas abweichendem Wirkungsmechanismus.The new compounds have a superior hypotensive effect compared to guanethidine with a slightly different mechanism of action.
Die 3,4 - Methylendioxymandelsäureamidine der i)!-oii angegebenen allgemeinen Formel und deren pharnuikologisch nicht giftige Säureanlaperungssalze werden dadurch hergestellt, daß man in an sich betinnier Weise 3,4-Methylendioxymandelsäurenitril der Formel The 3,4-methylenedioxymandelic acid amidines of the general formula given i)! - oii and their pharmaceutically non-toxic acidic acidic salts are prepared by adding 3,4-methylenedioxymandelic acid nitrile of the formula in a conventional manner
H2CH 2 C
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 obe 1 angegei ene Bedeutung besitzen, behandelt und das erhaltene Amidin gegebenenfalls in ein pharmakoiiigisch nicht giftiges Säureanlagerungssalz über- führt. 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 the amidine obtained is optionally converted into a pharmaceutically non-toxic acid addition salt. leads.
Vorzugsweise wird als aliphatischer Alkohol Methanol verwendet.Methanol is preferably used as the aliphatic alcohol.
RN-Diäthyl-S^-methylendioxymandelsäureamidinhydrochloridRN-diethyl-S ^ -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 00C stehengelassen und dann das ausgefallene 3,4-Met'iiylendioxymandelsäureiminoäthylesterhydrochlorid abfiltriert 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 saturated with dry gaseous hydrogen chloride in the cold. The mixture is then allowed to stand for about 10 hours at 0 0 C and then the precipitated 3,4-Met'iiylendioxymandelsäureiminoäthylesterhydrochlorid filtered off 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 2o-Natronlauge alkalisiert (End-pH > 14 bzw. etwa 14,5), und das freigesetzte N,N - Diäthyl - 3,4 - methylendioxymandelsäureamidin wird mit 3 · 50 ml Äthyläther extrahiert. Die vereinigten 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-3,4-methylendioxymandelsäureamidinhydrochlorid wird aus einer 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 refluxed for 2 hours in a water bath. The reaction solution is then evaporated in vacuo, the residue is taken up again 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 20 sodium hydroxide solution (final pH> 14 or about 14.5), and the released N, N - diethyl - 3,4 - methylenedioxymandelic acid amidine is extracted with 3 × 50 ml of ethyl ether. The combined 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-3,4-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. 1600C. Das Hydrochlorid ist in Wasser, Methanol und Äthanol löslich und in Äthylacetat, Äthyläther, Petrolälher und Benzol unlöslich. Die Ausbeute beträgt 32%.The compound is obtained in the form of a white powder of F. 160 0 C. The hydrochloride is, methanol and ethanol and soluble in ethyl acetate, ethyl ether, Petrolälher and benzene insoluble in water. 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-methylendioxymandelsäureamidinhydrochlorid (F. 212'C) und das N - Isopropyl - 3,4 - methj lendioxymandelsäureamidinhydrochlorid (F. 145 C) erhalten. According to the method described above, when the corresponding amine is used instead of diethylamine, N, N-dimethyl-3,4-methylenedioxymandelic acid amidine hydrochloride (temperature 212 ° C.) and N - isopropyl - 3,4 - methj lendioxymandelic acid amidine hydrochloride (temperature 145 ° C.) are used C) received.
Das oben als Ausgangsmaterial verwendete 3,4-Methylendioxymandelsäurenitril ist wie folgt hergestellt worden:The 3,4-methylenedioxymandelonitrile used as the starting material above is prepared as follows been:
In einen 20-1-Ballon mit drei 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 20-1 balloon with three nozzles and the one with a stirrer, a precision thermometer and an inlet funnel and which, moreover, only communicates with the external environment via one Is connected to a bubble counter, the output of which is connected to a hydrocyanic acid trap, will
1600 g 95%iges Kaliumcyanid (23.5 Mol), 3000 g Piperonal (20 Mol) und 10 1 Wasser1600 g 95% potassium cyanide (23.5 mol), 3000 g 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 cm3 einer Natriumbisulfitlösung der Dichte 1,32 hinzugegeben, und hierauf wird sehr langsam halbkonzentrierte (etwa 6-n) Chlorwasserstoffsäurelösung 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 24 Stunden getrocknet. Dann wird das Chloroform im Vakuum abgedampft, wobei man ungefähr 3200 g rohes 3,4-MethylendioxymandelSKiurenitril von braunoranger Farbe, das einen Brechungsindex bei 200C 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 of density 1.32 are slowly added to the mixture with stirring, and then half-concentrated (about 6N) hydrochloric acid solution is added very slowly in such a way and in the amount that the temperature does not exceed 15 ° C and stopping the addition of the hydrochloric acid when the pH of the reaction mixture has reached 4.0-5.0. 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. Then the chloroform is evaporated in vacuo to give about 3200 g of crude 3,4-MethylendioxymandelSKiurenitril of brown orange color, having a refractive index at 20 0 C. of about 1,546 obtained
Das erhaltene Nitril läßt sich selbst unter vermindertem Druck nicht destillieren, da es zu Aldehyd und Cyanwasserstoffsäure dissoziiertThe nitrile obtained cannot be distilled even under reduced pressure, since it becomes aldehyde and hydrocyanic acid dissociated
Claims (1)
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 DE1817861A1 (en) | 1972-09-28 |
| DE1817861B2 true 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) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2926828A1 (en) * | 1978-07-03 | 1980-01-17 | Dow Chemical Co | METHOD FOR PRODUCING N, N'-DISUBSTITUTED 2-NAPHTHALINAETHANIMIDAMIDES AND THEIR SALTS AND 2-NPHTHYLIMIDOACETIC ACID ESTER SALTS |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2926828A1 (en) * | 1978-07-03 | 1980-01-17 | Dow Chemical Co | METHOD FOR PRODUCING N, N'-DISUBSTITUTED 2-NAPHTHALINAETHANIMIDAMIDES AND THEIR SALTS AND 2-NPHTHYLIMIDOACETIC ACID ESTER SALTS |
Also Published As
| Publication number | Publication date |
|---|---|
| NL162909C (en) | 1980-07-15 |
| GB1243186A (en) | 1971-08-18 |
| ES360636A1 (en) | 1970-10-16 |
| CH488651A (en) | 1970-04-15 |
| DE1817861A1 (en) | 1972-09-28 |
| 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 |