DE1939109A1 - 2-methyl-3- [2- (2-diaethylaminoaethoxy) phenyl] quinazolinone- (4) and process for its preparation - Google Patents

Description

Patent attorneys. · - ". · -

ν * - ** "'Br.-fng. von Kreisler Dr.-tag .. SchSnwbld ... Dr.-fng.Th.M3yer.Dr.ru s Dipl.-Chern.Äteii before * Kreisler - Dipl.-Chem Carola Kelier Dr.-lng. Klöpsch -. - Cologne, Deichrnannhvu »

2Ί _α July 1969 Fu / from,.

i. Cologne-Mülheim, Berli ner Road £ 20-232.

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.From clen many made in recent years about 8O quinazolinones) derivatives have only a few eini ge - and found them only in the last 5 years ■ * as hypnotics, sedatives and when Diuretifca input in human therapy * Some other was in the patent - and scientific literature ascribed an anticonvulsive, muscle-relaxing and bronchodilatoric efficacy; according to literature references, others are said to have anti-malarial and antihistamine effects, but in human medicine these products have not yet been found ... * '- ■.

Use, -"·.',.

In the pharmacological test there are more than one number of quinazolinone derivatives were surprisingly present

extremely "s'tarke öäemhenanendf properties gefundeiij while the other above-stuffed Wirkurigsquaij ^ Ht-en largely failed | s _o Ödemhenimende effectiveness of the above compound was & n different edema _r the Rattenpfete .modellen" proven - On 7üX'q _r.. Käoün he

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■ produced paw edema, the compound after oral administration in a dose ranging from 10 to IGO mg / kg proved to be just as strongly ■ edema-causing as the 1,2-diphenyl-4-n-butyl used ^{because of its strong ■ edema-suppressing effect 1 as a comparison substance} -3 _i 5-dioxopyra2olidine _i On the protein and formal inedema, 2 ^ methyl-J- ^ f§ - (. 2-diethylaminoUthoxyr phenylpquinazoline-CV, with oral administration even a clearly stronger effect than S 1,2-diphenyl- ^ n-butyl-3>, 5-dioxopy- ■ razölidln * These pharinacological findings could also be confirmed in clinical trials on humans, whereby the compound in animal experiments and in the clinic was not very "toxic and extremely well tolerated"

The invention therefore provides a process for the "production of 2-methyl-3 ~ / 2 ~; 2-diethylaminoethcxy ', -phenyl / -quinazolinone- ( ^; r ^ with the structural formula

and its salts with physiologically compatible inorganic and organic acids ^ which is characterized in that the 2-Kethyl-3- / 2-hydroxychenyl7-quinazolinone ~ (4) known from the literature first with an alkali alkali in the presence of a solvent in the phenolate ^ is libergeführt and this is reacted ralsäuren in a known manner with a ß-Diathylaminoäthylhalogenid or the equivalent ß-Diäthylaminoäthyltosylat bzvi _o their salts with mineral _o The best yields are obtained in this reaction in a homogeneous phase in the presence of alcohols or other polar solvents , the reaction takes place less favorably in the heterogeneous phase., for example: by boiling in toluene or other inert solution

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agents * or in the absence of solvents *

The new compound according to the invention can also be obtained in a manner known per se by reacting 2-methyl-I - / ^ 2-hydro :: yphenyJ.7-ehinazolinon- (4} with excess ethylene oxide or ethylene chlorohydrin First of all, 2-Methy1-5- / 2- (2-hydroxy- or _c -2-chloroethoxy) -phenyl7-quinasolinone - (^}, which is then reacted with diethylamine in the case of the * hydroxy compound via its halide «.

The invention also relates to the new-mentioned Compound, optionally in the form of their salts with physiological compatible acids,

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0.2 mol of sodium are dissolved in 150 ml of absolute alcohol, 0.1 mol of 2-kethyl-3- / 2-hydroxyphenyl7-quinazolinone ( ^; t) and 0.1 mol of ß-diethylaminoethyl chloride hydrochloride are added and the mixture is refluxed for 4 hours After the alcohol has been distilled off, the residue is first extracted with dilute sodium hydroxide solution and then with ether. The ethereal solution is dried and ethereal hydrochloric acid is added. The precipitated 2-methyl-5-y2-f2-diäthylaminoäthcxy] -phenylZ-ehinazolinon- zsrsetzt (4) -dihydrcchlorid with gassing bä 224 ° to ⁰ C ₀ 2.26 The yield is 88.4% of theory., Based on the Chinazolinone- (4) used ο - ""

Analysis values: ■ ₍ - ■ -

0098 107 1761

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calculated: C 59, ^ '; H 6.41: Ol I6.72r Ii 9, SO. found: \ - C 59.00; H 6, ^ 5; : Ί l6.72; N 10.01c

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92 g pieces of sodium are dissolved in 2/5 l of absolute alcohol with cooling. The solution is mixed with 510 g of 2-kethyl-3- / 2-hydrqxyphenyl7- ^c hlnazolinon- {4) and then partially with ~ y \ K g of diethylaminoethyl chloride hydrochloride, while stirring. After 6 hours of cooking. If the excess alcohol is distilled off, the residue is extracted several times with dilute sodium hydroxide solution and then with water, then taken up in ether and dried over sodium sulphate to naph the filtering off and evaporation of the ether; If the residue is dissolved in isopropariol in the vial and introduced into the solution with a little bit of cooling to end the precipitation, hydrogen chloride is then filtered out and then the yield of 2-methyl- ^ r- ^ 2 is -i / 2-di ^
ehinarolinQn - (^> dihy ^ rcc; hlQrid f | lg, what one see Äusgiewte ¥ @ n BM $ ent ^ praises _c

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PP9810 / 17i1

Claims (3)

Claims 1) 2-methyl - ^ - / 2- (2-diethylaminoathoxy) -phenylz-quinazoline n- _v 'V, and its salts with physiologically acceptable acidsc " 2 "", experienced, for the preparation of 2-methyl -> - ^ 2-v _% '2-diethyl- £ ininoethoxy -phenyir-quinazölinon- ( ⁱ i) of the formula. '- C ₂ H ₅ O 0 - CH ₂ - CH ₂ - N -C ₂ ^ S bzvi, its salts with physiologically compatible inorganic or organic acids, characterized in that 2-methyl-.3- _{> i} _2 ^ hydroxypheiiy27-quina2olinon- ( ⁱ 0 either -.-...., -. a; with alkali alcohol rum Fhenolät and this with one ß-diethylaminoethyl halide or with ß-diethylaniino- • ethyl tosylate or its salts with mineral acids. set or b) with excess ethylene oxide to form 2-methyl-3- / 2 ~ (2-hydroxyethoxy) -phenyl7-quinazolinone - {^) and its halide reacts with diethylamine or c) with excess ethylenechlorohydrin sum 2-methyl-3- / 2- (2-chloroethoxy) -phenyl7-quinazolinone- (4) and converts this directly with diethyiamine and d) optionally then in a manner known per se from your frody of a, b or c the inorganic or extracts organic salts, 009810/1761 ^: BAD QRfGINiAL. ■ '■.' ■ '■■■ V · - ■; ■. ■ - ■ 6 - ..: ■ "■. - ■; ·;;.' - ■■ - ■. ' 3) Process according to claim 2, characterized in that the reaction of the phenolate in a homogeneous body is carried out in the counterv / kind of alcohols or other polar substances 4} The method according to claim 2, characterized. That one in the implementation of the-Phenolate- in heterogeneous-Phasein Presence of toluene or other inert solvents or in the absence of solvents works. BATH ORIGINAL 009810/1761