DE1174311B - Process for the preparation of N-substituted 4'-aminoalkoxy-2 ', 4-dihydroxy-chalcones and their salts - Google Patents
Process for the preparation of N-substituted 4'-aminoalkoxy-2 ', 4-dihydroxy-chalcones and their saltsInfo
- Publication number
- DE1174311B DE1174311B DEW28781A DEW0028781A DE1174311B DE 1174311 B DE1174311 B DE 1174311B DE W28781 A DEW28781 A DE W28781A DE W0028781 A DEW0028781 A DE W0028781A DE 1174311 B DE1174311 B DE 1174311B
- Authority
- DE
- Germany
- Prior art keywords
- vol
- dihydroxy
- hydrochloride
- salts
- substituted
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 3
- SULYEHHGGXARJS-UHFFFAOYSA-N 2',4'-dihydroxyacetophenone Chemical group CC(=O)C1=CC=C(O)C=C1O SULYEHHGGXARJS-UHFFFAOYSA-N 0.000 claims description 14
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- UILPJVPSNHJFIK-UHFFFAOYSA-N p-methoxy-o-hydroxyacetophenone Natural products COC1=CC=C(C(C)=O)C(O)=C1 UILPJVPSNHJFIK-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 12
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 10
- 229960001789 papaverine Drugs 0.000 description 10
- -1 4'-Diethylaminoethoxy-2 ', 4-dihydroxy-chalcone hydrochloride Chemical compound 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 7
- 230000002048 spasmolytic effect Effects 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- UOTMYNBWXDUBNX-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinolin-2-ium;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 UOTMYNBWXDUBNX-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000000812 cholinergic antagonist Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 230000003170 musculotropic effect Effects 0.000 description 4
- 229960003207 papaverine hydrochloride Drugs 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 3
- FZQLEXXZAVVCCA-XCVCLJGOSA-N (e)-1,3-bis(4-hydroxyphenyl)prop-2-en-1-one Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1 FZQLEXXZAVVCCA-XCVCLJGOSA-N 0.000 description 2
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000005513 chalcones Nutrition 0.000 description 2
- 229930003949 flavanone Natural products 0.000 description 2
- 150000002207 flavanone derivatives Chemical class 0.000 description 2
- 235000011981 flavanones Nutrition 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- AETKQQBRKSELEL-UHFFFAOYSA-N (2E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one Natural products OC1=CC=CC=C1C(=O)C=CC1=CC=CC=C1 AETKQQBRKSELEL-UHFFFAOYSA-N 0.000 description 1
- RTCVAWRRHHSOCC-UHFFFAOYSA-N (2E)-1-(4-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one Natural products C1=CC(OC)=CC=C1C=CC(=O)C1=CC=C(O)C=C1 RTCVAWRRHHSOCC-UHFFFAOYSA-N 0.000 description 1
- FZQLEXXZAVVCCA-UHFFFAOYSA-N (E)-1,3-bis(4-hydroxyphenyl)prop-2-en-1-one Natural products C1=CC(O)=CC=C1C=CC(=O)C1=CC=C(O)C=C1 FZQLEXXZAVVCCA-UHFFFAOYSA-N 0.000 description 1
- KSHCTKZLHCSARH-MDZDMXLPSA-N (e)-1,3-bis(2-hydroxyphenyl)prop-2-en-1-one Chemical compound OC1=CC=CC=C1\C=C\C(=O)C1=CC=CC=C1O KSHCTKZLHCSARH-MDZDMXLPSA-N 0.000 description 1
- RTCVAWRRHHSOCC-NYYWCZLTSA-N (e)-1-(4-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1 RTCVAWRRHHSOCC-NYYWCZLTSA-N 0.000 description 1
- VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 0.000 description 1
- AETKQQBRKSELEL-ZHACJKMWSA-N 2'-hydroxychalcone Chemical compound OC1=CC=CC=C1C(=O)\C=C\C1=CC=CC=C1 AETKQQBRKSELEL-ZHACJKMWSA-N 0.000 description 1
- RAGSWDIQBBZLLL-UHFFFAOYSA-N 2-chloroethyl(diethyl)azanium;chloride Chemical compound Cl.CCN(CC)CCCl RAGSWDIQBBZLLL-UHFFFAOYSA-N 0.000 description 1
- SIZZBPHMVBYWKZ-UHFFFAOYSA-N 2-phenylchromen-4-one;hydrochloride Chemical compound Cl.O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 SIZZBPHMVBYWKZ-UHFFFAOYSA-N 0.000 description 1
- LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 1
- PWWCDTYUYPOAIU-DHZHZOJOSA-N 4-hydroxychalcone Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=CC=C1 PWWCDTYUYPOAIU-DHZHZOJOSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus 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
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 150000001789 chalcones Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- DXDRHHKMWQZJHT-FPYGCLRLSA-N isoliquiritigenin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-FPYGCLRLSA-N 0.000 description 1
- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 description 1
- DXDRHHKMWQZJHT-UHFFFAOYSA-N isoliquiritigenin chalcone Natural products C1=CC(O)=CC=C1C=CC(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000002276 neurotropic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229940066768 systemic antihistamines aminoalkyl ethers Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Internat. KI.: C 07 cBoarding school KI .: C 07 c
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
AUSLEGESCHRIFTEDITORIAL
Deutsche KL: 12 ο-20German KL: 12 o-20
Nummer: 1174311Number: 1174311
Aktenzeichen: W 28781 IV b / 12 οFile number: W 28781 IV b / 12 ο
Anmeldetag: 25. Oktober 1960 Filing date: October 25, 1960
Auslegetag: 23. Juli 1964Opening day: July 23, 1964
Nach dem Verfahren der Erfindung werden N-substituierte 4' - Aminoalkoxy - 2',4 - dihydroxy - chalkone der allgemeinen Formel hergestelltAccording to the process of the invention, N-substituted 4 '- aminoalkoxy - 2', 4 - dihydroxy - chalcones made of the general formula
N—Ri-ON-Ri-O
in der R niedrigmolekulare Alkylreste bedeutet, beide R zusammen mit dem Stickstoffatom auch einen gesättigten 6gliedrigen Ring bilden können und in der Ri ein niedrigmolekularer unverzweigter Alkylenrest ist. Diese Verbindungen haben eine geringe Giftigkeit und eine hohe muskulotropspasmolytische Wirksamkeit bei nur geringer atropinartiger Wirkung.in which R denotes low molecular weight alkyl radicals, both R together with the nitrogen atom as well can form a saturated 6-membered ring and in the Ri a low molecular weight unbranched ring Is alkylene. These compounds have a low toxicity and a high musculotropic spasmolytic Effective with only a slight atropine-like effect.
In der nachstehenden Tabelle werden einige der nach der Erfindung herstellbaren Verbindungen hin-Verfahren
zur Herstellung von N-substituierten
4/-Aminoalkoxy-274-dihydroxy-chalkonen und
deren SalzenIn the table below, some of the compounds which can be prepared according to the invention are described by processes for the preparation of N-substituted compounds
4 / -Aminoalkoxy-274-dihydroxy-chalcones and
their salts
Anmelder:Applicant:
Fa. M. Woelm, Eschwege, Max-Woelm-Str. 6M. Woelm, Eschwege, Max-Woelm-Str. 6th
Als Erfinder benannt:Named as inventor:
Dr. Herbert Graßhof, EschwegeDr. Herbert Graßhof, Eschwege
sichtlich ihrer Giftigkeit und ihrer spasmolytischen Wirkung mit Papaverin verglichen. Die muskolotrope bzw. neurotrope Wirkung wurde am isolierten Kaninchendarm geprüft.visibly compared to papaverine in terms of their toxicity and spasmolytic effect. The muscolotropic and the neurotropic effect was tested on the isolated rabbit intestine.
Verbindungenlinks
Verabreichte tödlichAdministered fatally
wirkende Menge ineffective amount in
Milligramm je KilogrammMilligrams per kilogram
Maus, LDiooMouse, LDioo
subkutan intravenössubcutaneously intravenously
Muskulotropspasmolytische Musculotropic spasmolytic
Wirkung,Effect,
bezogen aufbased on
Papaverin = 1Papaverine = 1
Neuralspasmolytische Neural spasmolytic
Wirkung,
bezogen auf
Atropin = 1Effect,
based on
Atropine = 1
Papaverin-hydrochlorid Papaverine hydrochloride
4'-Diäthylaminoäthoxy-2',4-dihydroxy-chalkonhydrochlorid 4'-Diethylaminoethoxy-2 ', 4-dihydroxy-chalcone hydrochloride
4'-Dimethylaminopropoxy-2',4-dihydroxychalkon-hydrochlorid ,4'-dimethylaminopropoxy-2 ', 4-dihydroxychalcone hydrochloride,
160160
750750
40004000
40
130
12040
130
120
1
1
0,41
1
0.4
1/25001/2500
1/5001/500
1/10001/1000
Aus den erhaltenen Werten ergibt sich, daß das 4'-Diäthylaminoäthoxy-2',4-dihydroxy-chalkon-hydrochlorid bei gleicher Wirksamkeit eine geringere Giftigkeit als Papaverin hat und daß das 4'-Dimethylaminopropoxy-2',4-dihydroxy-chalkon-hydrochlorid bei geringerer Wirksamkeit wesentlich ungiftiger als Papaverin ist. Somit besitzen die Chalkone eine größere therapeutische Wirkungsbreite. Die Unterschiede bei der sehr schwach neutral-spasmolytischen Wirkung fallen nicht ins Gewicht.The values obtained show that the 4'-diethylaminoethoxy-2 ', 4-dihydroxy-chalcone hydrochloride with the same effectiveness has a lower toxicity than papaverine and that 4'-dimethylaminopropoxy-2 ', 4-dihydroxy-chalcone hydrochloride is much less toxic than papaverine if it is less effective. Thus, the chalconies have a wider range of therapeutic effects. The differences in the very weakly neutral spasmolytic Effects are irrelevant.
Die Herstellung der Chalkone erfolgt durch Umsetzung der entsprechenden am Stickstoff substituierten 4-Aminoalkyläther des Resacetophenons in Gegenwart von starkem Alkali mit p-Hydroxybenzaldehyd. Die entstandenen Basen werden in üblicher Weise mit physiologisch verträglichen Säuren in die Salze übergeführt.The chalcones are produced by reacting the corresponding ones substituted on the nitrogen 4-aminoalkyl ethers of resacetophenone in the presence of strong alkali with p-hydroxybenzaldehyde. The bases formed are in the usual way with physiologically compatible acids in the Salts transferred.
Der chemische Aufbau der herstellbaren Verbindungen kann infolge der Übereinstimmung der gefundenen und berechneten Analysenwerte beim 4'-Diäthylaminoäthoxy-2',4-dihydroxy-chalkon-hydrochlorid als gesichert gelten.The chemical structure of the compounds that can be produced may be due to the correspondence of the found and calculated analytical values for 4'-diethylaminoethoxy-2 ', 4-dihydroxy-chalcone hydrochloride are considered secured.
GaHa8O4NCl:
GefundenGaHa 8 O 4 NCl:
Found
C 63,90, H 6,47, N 3,76, Cl 9,01, aktiver H 0,70%; berechnetC 63.90, H 6.47, N 3.76, Cl 9.01, active H 0.70%; calculated
C 64,36, H 6,69, N 3,58, Cl 9,05, aktiver H 0,77%.C 64.36, H 6.69, N 3.58, Cl 9.05, active H 0.77%.
Der Wert für den aktiven Wasserstoff beruht auf der Anwesenheit von drei aktiven Wasserstoffatomen, von denen zwei den beiden Hydroxylgruppen in der 2'- und in der 4-Stellung entsprechen. Die Hydroxylgruppe in der 2'-Stellung gibt sich außerdem durch eine schmutzig-braune Färbung mit Eisenchlorid zu erkennen.The active hydrogen value is based on the presence of three active hydrogen atoms, two of which correspond to the two hydroxyl groups in the 2'- and in the 4-position. The hydroxyl group in the 2'-position there is also a dirty brown color with ferric chloride recognize.
Die nach dem Verfahren der Erfindung herstellbaren Verbindungen zeichnen sich1 nicht nur gegenüber Papaverin, sondern auch gegenüber anderen bekann-The obtainable by the process of the invention compounds are distinguished not only to 1 papaverine, but also over other well-known
409 637/428409 637/428
ten vergleichbaren Verbindungen durch bessere therapeutische Eigenschaften aus. Die bekannten Verbindungen haben im Vergleich zu Papaverin keine so günstige therapeutische Wirkungsbreite wie die Verbindungen des Verfahrens der Erfindung. Dies ergibt sich aus den nachstehenden Tabellen. Der dort angegebene Wert über die Giftigkeit des Papaverins ist der Zeitschrift Arzneimittel-Forschung, Bd. 9, 1959, S. 693, entnommen (vgl. die deutsche Auslegeschrift 1054 091; Arzneimittel-Forschung, Bd. 9, 1959, S. 693; Journal of Pharmacology and Experimental Therapeutics, Bd. 130, 1960, S. 356, und Pharmaceutica Acta Helvetiae, Bd. 33, 1958, S. 437, und Bd. 34, 1959, S. 241).ten comparable compounds through better therapeutic properties. The known Compounds do not have such a favorable therapeutic range of activity as compared to papaverine the compounds of the method of the invention. This can be seen from the tables below. That one given value about the toxicity of papaverine is the journal Arzneimittel-Forschung, Vol. 9, 1959, p. 693, taken (cf. the German Auslegeschrift 1054 091; Arzneimittel-Forschung, Vol. 9, 1959, p. 693; Journal of Pharmacology and Experimental Therapeutics, Vol. 130, 1960, p. 356, and Pharmaceutica Acta Helvetiae, Vol. 33, 1958, p. 437, and Vol. 34, 1959, p. 241).
Milligramm je Kilogramm Maus
bei intraperitonealer
Verabreichung, LDaiDeadly crowd in
Milligrams per kilogram of mouse
with intraperitoneal
Administration, LDai
Wirkung, bezogen auf
Papaverin = 1Musculotropic-spasmolytic
Effect, based on
Papaverine = 1
7-DimethyIaminopropoxyflavon-hydrochlorid ...
7-Piperidinoäthoxyflavon-hydrochlorid
7-Dimethylaminoäthoxyflavon-hydrochlorid
7-Diäthylaminoäthoxyflavon-hydrochlorid
7-Morpholinoäthoxyflavon-hydrochlorid Papaverine hydrochloride
7-Dimethylaminopropoxyflavone hydrochloride ...
7-piperidinoethoxyflavone hydrochloride
7-dimethylaminoethoxyflavone hydrochloride
7-diethylaminoethoxyflavone hydrochloride
7-morpholinoethoxyflavone hydrochloride
312
225
403
259
>1500240
312
225
403
259
> 1500
0,63
0,56
0,47
0,44
0,251
0.63
0.56
0.47
0.44
0.25
Verbindungen Tödlich wirkende Menge in
Milligramm je Kilogramm Maus, LD»)Compounds Lethal amount in
Milligrams per kilogram of mouse, LD »)
verabreicht
I oral intraperitoneal intravenösadministered
I orally intraperitoneally intravenously
Muskulotropspasmolytische Wirkung, bezogen auf Papaverin = 1Musculotropic spasmolytic effect, based on papaverine = 1
Papaverin-hydrochlorid Papaverine hydrochloride
3-Methyl-6-[N-diäthylaminomethyl]-flavonhydrochlorid 3-methyl-6- [N-diethylaminomethyl] flavone hydrochloride
PiperidinoäthyW-methylflavon-S-carboxylathydrochlorid PiperidinoethyW-methylflavone-S-carboxylate hydrochloride
Verbindungenlinks
Papaverin-hydrochlorid ...Papaverine hydrochloride ...
Flavon Flavone
Flavanon Flavanone
2'-Hydroxychalkon 2'-hydroxy chalcone
2,2'-Dihydroxychalkon 2,2'-dihydroxychalcone
2',4,4'-Trihydroxychalkon .2 ', 4,4'-trihydroxychalcone.
4-Hydroxychalkon 4-hydroxy chalcone
4,4'-Dihydroxychalkon 4,4'-dihydroxychalcone
4'-Hydroxy-4-methoxychalkon 4'-hydroxy-4-methoxy-chalcone
1 -(2-Hydroxy)-phenyl-3-(2-hydroxy)-phenyl-
propan-1-on = Dihydro-2,2'-dihydroxy-chalkon ..1 - (2-hydroxy) -phenyl-3- (2-hydroxy) -phenyl-
propan-1- ..
Muskulotropspasmolytische Wirkung, bezogen auf Papaverin = 1Musculotropic spasmolytic effect, based on papaverine = 1
0,400.40
0,750.75
0,400.40
0,500.50
0,500.50
0,500.50
0,670.67
0,420.42
0,500.50
Das am stärksten wirksame Flavanon ist nach den Angaben in der Literatur außerordentlich giftig. Angaben über die Giftigkeit der anderen Verbindungen sind wegen ihrer äußerst geringen Löslichkeit nicht zu machen. Die geringe Löslichkeit dieser Verbindungen ist ein großer Nachteil. Dagegen sind die nach der Erfindung herstellbaren Verbindungen Basen, die mit den entsprechenden Säuren leicht lösliche Salze bilden.According to the information in the literature, the most potent flavanone is extremely toxic. Information on the toxicity of the other compounds is because of their extremely low solubility not to make. The low solubility of these compounds is a major disadvantage. Against it the compounds which can be prepared according to the invention are bases, which are easily converted with the corresponding acids Form soluble salts.
60 g Resacetophenon werden in 200 ecm Alkohol gelöst. Zu dieser Lösung werden 50 g Diäthylaminoäthylchlorid-hydrochlorid sowie unter Schütteln eine60 g resacetophenone are in 200 ecm alcohol solved. To this solution, 50 g of diethylaminoethyl chloride hydrochloride and, with shaking, are added
240
109
350240
109
350
30,2
26,5
37,530.2
26.5
37.5
2,972.97
1,81.8
Lösung von 40 g Ätzkali in 200 ecm Alkohol gegeben. Die ausgeschiedenes Kaliumchlorid enthaltende Lösung wird noch einige Stunden unter Rückfluß gekocht. Dann wird sie mit Wasser verdünnt und der Alkohol im Vakuum bei 12 mm Quecksilbersäule entfernt. Dann werden einige wenige Kubikzentimeter Salzsäure so lange zugesetzt, bis sich zusätzlich kein öl mehr ausscheidet. Das ausgeschiedene öl wird in 41 Äther aufgenommen, die ätherische Lösung mit einem Gemisch aus 25 ecm konzentrierter Salzsäure und 250 ecm Wasser ausgezogen und zu der salzsauren Lösung dann so lange Kalilauge gegeben, bis kein öl mehr ausfällt. Dieses wird dann wieder in 1 1 Äther aufgenommen, die ätherische Lösung mit Natriumsulfat getrocknet und der Äther abgedampft. Man erhält 39 g ölige Base des 4-Diäthylaminoäthyläthers des Resacetophenons; das Hydrochlorid kristallisiert aus n-Butanol; der Schmelzpunkt beträgt 147 bis 149°C.A solution of 40 g of caustic potash in 200 ecm of alcohol is added. The excreted potassium chloride containing The solution is refluxed for a few more hours. Then it is diluted with water and the alcohol in a vacuum at 12 mm of mercury removed. Then a few cubic centimeters of hydrochloric acid are added until it settles in addition, no more oil separates. The excreted oil is absorbed in 41 ether, the ethereal solution extracted with a mixture of 25 ecm concentrated hydrochloric acid and 250 ecm water and then added potassium hydroxide solution to the hydrochloric acid solution until no more oil precipitates. This is then taken up again in 1 liter of ether, the ethereal solution is dried with sodium sulfate and the ether evaporated. 39 g of oily base of 4-diethylaminoethyl ether of resacetophenone are obtained; the hydrochloride crystallizes from n-butanol; the melting point is 147 to 149 ° C.
39 g ölige Base werden zusammen mit 40 g (2 Mol) p-Hydroxybenzaldehyd in 165 ecm Alkohol gelöst und 625 ecm 40%ige wäßrige Kalilauge zugefügt. Nachdem das Gemisch 5 Tage bei Zimmertemperatur gestanden hat, wird Eis zugesetzt und so lange Salzsäure zugegeben, bis sich kein öl mehr ausscheidet.39 g of oily base are dissolved together with 40 g (2 mol) of p-hydroxybenzaldehyde in 165 ecm of alcohol and 625 ecm of 40% strength aqueous potassium hydroxide solution was added. After the mixture 5 days at room temperature ice is added and hydrochloric acid is added until no more oil separates out.
Dieses wird in 1 1 Äther aufgenommen und die ätherische Lösung mit einem Gemisch aus 40 ecm konzentrierter Salzsäure und 200 ecm Wasser ausgeschüttelt. Nach der Abtrennung der salzsauren Lösung kristallisiert bald aus dieser das 4'-Diäthylaminoäthoxy -2',4 - dihydroxy - chalkon - hydrochlorid aus. Dieses wird abgesaugt und mit Wasser gewaschen; die Ausbeute beträgt 18,7 g; der Schmelzpunkt 229 bis 2300C.This is taken up in 1 liter of ether and the ethereal solution shaken out with a mixture of 40 ecm of concentrated hydrochloric acid and 200 ecm of water. After the hydrochloric acid solution has been separated off, the 4'-diethylaminoethoxy -2 ', 4-dihydroxy-chalcone hydrochloride soon crystallizes out of it. This is suctioned off and washed with water; the yield is 18.7 g; the melting point 229 to 230 0 C.
Die Reaktion fuhrt zu einem Gleichgewicht. Aus der salzsauren Mutterlauge läßt sich nach der Zugabe von Alkali der nicht umgesetzte Resacetophenonäther, 18 g, gewinnen, der dann wieder zu einem neuen Ansatz verwendet wird.The reaction leads to equilibrium. From the hydrochloric acid mother liquor can after the addition of alkali the unreacted Resacetophenonether, 18 g, win, which then again to a new approach is used.
Nach derselben Methode wie im Beispiel 1 wird Resacetophenon mit Piperidinoäthylchlorid-hydrochlorid umgesetzt. 44 g der öligen Base des erhaltenen 4-Piperidinoäthyläthers des Resacetophenons werden zusammen mit 45 g p-Hydroxybenzaldehyd in 320 ecm Alkohol gelöst und zu dieser Lösung 750 ecm 40prozentige wäßrige Kalilauge gefügt. Nachdem das Gemisch 5 Tage bei Zimmertemperatur gestanden hat, wird Eis zugesetzt und so lange Salzsäure zugegeben, bis keine Ausscheidung mehr stattfindet. Nach ltägigem Stehen wird das Chalkon abgesaugt, mit Wasser gewaschen und in 200 ecm heißem wasserfreiem Alkohol gelöst. Nach dem Filtrieren wird die Lösung dann mit alkoholischer Salzsäure schwach angesäuert. Nach der Abkühlung der Lösung kristallisiert das 4'-Piperidinoäthoxy-2',4-dihydroxy-chalkon-hydrochlorid aus. Dieses wird abgesaugt und mit Alkohol gewaschen; die Ausbeute beträgt 11g; der Schmelzpunkt 230 bis 232°C. Nach dem Einengen der Mutterlauge werden noch weitere Kristalle erhalten.Using the same method as in Example 1, resacetophenone is made with piperidinoethyl chloride hydrochloride implemented. 44 g of the oily base of the 4-piperidinoethyl ether obtained from resacetophenone will be dissolved together with 45 g of p-hydroxybenzaldehyde in 320 ecm alcohol and added 750 ecm 40 percent to this solution aqueous potassium hydroxide solution added. After the mixture has stood at room temperature for 5 days ice is added and hydrochloric acid is added until no more excretion takes place. After standing for a day, the chalcone is suctioned off, washed with water and immersed in 200 ecm hot anhydrous Alcohol dissolved. After filtering, the solution then becomes weak with alcoholic hydrochloric acid acidified. After the solution has cooled, the 4'-piperidinoethoxy-2 ', 4-dihydroxy-chalcone hydrochloride crystallizes the end. This is suctioned off and washed with alcohol; the yield is 11 g; the melting point 230 to 232 ° C. After the mother liquor has been concentrated, further crystals are formed obtain.
Das Methansulfonat kristallisiert aus Alkohol und schmilzt bei 194 bis 196°C.The methanesulfonate crystallizes from alcohol and melts at 194 to 196 ° C.
Nach derselben Methode wie im Beispiel 1 wird Resacetophenon mit Dimethylaminopropylchloridhydrochlorid umgesetzt.Using the same method as in Example 1, resacetophenone is made with dimethylaminopropyl chloride hydrochloride implemented.
Der ölige Äther wird mit p-Hydroxybenzaldehyd zu 4'-Dimethylaminopropoxy-2',4-dihydroxy-chalkon umgesetzt. Wie im Beispiel 1 wird der Lösung der entstandenen rohen öligen Base in Äther das Hydrochlorid mit einem Gemisch aus 1 Volumen konzentrierter Salzsäure und 2 Volumen Wasser entzogen, aus dem es dann auskristallisiert. Nach dem Umkristallisieren des Hydrochloride aus n-Butanol liegt der Schmelzpunkt bei 2020C.The oily ether is reacted with p-hydroxybenzaldehyde to form 4'-dimethylaminopropoxy-2 ', 4-dihydroxy-chalcone. As in Example 1, the solution of the resulting crude oily base in ether is removed from the hydrochloride with a mixture of 1 volume of concentrated hydrochloric acid and 2 volumes of water, from which it then crystallizes out. After the hydrochloride has been recrystallized from n-butanol, the melting point is 202 ° C.
Claims (1)
Deutsche Auslegeschrift Nr. 1 054 091;
Chemische Berichte, Bd. 92, 1959, S. 1672 bis 1674; Bd. 93, 1960, S. 1913 bis 1924;Considered publications:
German Auslegeschrift No. 1 054 091;
Chemical Reports, Vol. 92, 1959, pp. 1672 to 1674; Vol. 93, 1960, pp. 1913 to 1924;
Arzneimittel-Forschung, Bd. 9, 1959, S. 693.Pharmaceutica Acta Helvetiae, Vol. 33, 1958, pp. 437 to 444; Vol. 34, 1959, p. 241; reported in Chemical Abstracts, Vol. 53, 1959, column 15 380 g, and Vol. 54, 1960, column 11 009 i to 11010b;
Drug Research, Vol. 9, 1959, p. 693.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEW28781A DE1174311B (en) | 1960-10-25 | 1960-10-25 | Process for the preparation of N-substituted 4'-aminoalkoxy-2 ', 4-dihydroxy-chalcones and their salts |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEW28781A DE1174311B (en) | 1960-10-25 | 1960-10-25 | Process for the preparation of N-substituted 4'-aminoalkoxy-2 ', 4-dihydroxy-chalcones and their salts |
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| Publication Number | Publication Date |
|---|---|
| DE1174311B true DE1174311B (en) | 1964-07-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEW28781A Pending DE1174311B (en) | 1960-10-25 | 1960-10-25 | Process for the preparation of N-substituted 4'-aminoalkoxy-2 ', 4-dihydroxy-chalcones and their salts |
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| DE (1) | DE1174311B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5118682A (en) * | 1988-07-28 | 1992-06-02 | Basf Aktiengesellschaft | P-hydroxy phenone derivatives and the use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1054091B (en) * | 1958-05-30 | 1959-04-02 | Chemiewerk Homburg Ag | Process for the preparation of N-substituted 2-phenyl-7-aminoalkoxy-chromones |
-
1960
- 1960-10-25 DE DEW28781A patent/DE1174311B/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1054091B (en) * | 1958-05-30 | 1959-04-02 | Chemiewerk Homburg Ag | Process for the preparation of N-substituted 2-phenyl-7-aminoalkoxy-chromones |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5118682A (en) * | 1988-07-28 | 1992-06-02 | Basf Aktiengesellschaft | P-hydroxy phenone derivatives and the use thereof |
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