DE952715C - Process for the production of new antihistamine effective basic AE ethers - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

ISSUED NOVEMBER 22, 1956

GERMAN PATENT OFFICE

PATENT LETTERING

CLASS 12q GROUP 3201 INTERNAT. CLASS C07c; d

A 16741 IVb / 12 q

Dr. phil. nat. habil. Herbert Arnold, Bielefeld,

Dr. med. habil. Norbert Brock, Wadersloh (district of Beckum),

and Dr. phil. Engelbert Kühas, Gadderbaum

have been named as inventors

Asta-Werke Aktiengesellschaft Chemical Factory, Brackwede (Westphalia)

Process for the production of new antihistamine effective basic ethers

Patented in the territory of the Federal Republic of Germany from October 26, 1952 Patent application known since April 28, 1965 Patent granted since October 31, 1956

They are already basic ethers of diphenylalkyl carbinols known by the following general formula:

CO-CH ₂ -CH ₂ -R "

Here, R 'denotes a methyl group, R "denotes a morpholino group and R"' denotes an alkyl group (cf. Chem. Abstr., Vol. 45, pp. 577 and 9521).

It is also known that such basic ethers of diphenyl-alkyl-carbinols have antihistamine effects own.

The basic substance of this whole class of compounds with antihistamine action is the / S-Di-

methylaminoethylbenzhydryl ether of the following formula:

-CHp-CH ₉ -N-

CH,

CH,

Try to make changes to the not-too-great antihistamine potency of these compounds Increasing the concentration resulted - as is apparent from U.S. Patent 2,527,963 - also to compounds whose one phenyl group in the p-S division by halogen-chlorine is substituted. These compounds also have antihistamine activity. It was found that the antihistamine effectiveness can be increased to a surprisingly large extent

can, if one does not only move into the p-position as suggested by the USA patent specification 2,527,963 one of the two phenyl groups of the diphenhydramine is a Cl-Atoni, but also introduces a methyl group at the tertiary carbon atom and thus more generally to compounds of the following Formula comes:

CO-CH ₂ -CH ₂ -R ₁ (I) CH ₃

Here, R ₁ denotes a dimethylamino, diethylamino or a piperidyl radical.

Such compounds can be made in a two-step process. In the first stage (a) in the case of [i (p-chloro-phenyl) -1-phenyl] -ethyl - (/ 3-dimethylarninoethyl) -äthei-s either p-chloroacetophenone with phenyl-Mg-halide or p -Chlor-benzophenone reacted with methyl-Mg-halide to (p-chloro-phenyl) -phenyl-methyl-carbinol. In the second stage (b) this carbinol is in the presence of NaNH ₂ in toluene solution with / 3-dimethylaminoethyl chloride in [1 - (p-chlorophenyl) -1-phenyl] -ethyl - (/? - dimethylamino-ethyl) - ether transferred.

p_Cl — C ₆ H ₄ —COH — C ₆ H ₅ —Mg —Hal _N

> -Cl-C ₆ H ₄

p —Cl- C ₆ H ₄ -COH-CH ₃ - Mg - Hai 'X-OH-I-Cl-CH ₂ -CH ₂ -N:

C ₆ H ₆

CH ₃ (II)

P-Cl-C ₆ H ₄ NaNH ₂ ^ ^) C-0-CH ₂ -CH ₂ -N (CH ₃ ) ₂ (III)

However, it has been shown that this two-step process gives unsatisfactory results, in particular poor yields.

The Grignard reactions are in the usual manner with an excess of up to about 20% of the Grignard reagent carried out. In experiments in which the Grignard reagent in excesses of about 16 to 20% was used, the ether (III), for example, could only be obtained in one yield of 40% if obtained from p-chlorobenzophenone, and in a yield of even only 30%, if p-chloroacetophenone was assumed.

The cause of these poor yields was recognized in the fact that the carbinol formed with the aid of the Grignard reaction still contained varying amounts of unchanged starting ketone and this reacted _{further with the NaNH 2} with the formation of undesired by-products. This fact had a particularly unpleasant effect because the carbinol (II) formed as an intermediate is very unstable and easily converts into the corresponding p-chlorodiphenylethylene with the escape of water. As a result, purification of the carbinol is practically out of the question.

It was possible to prevent the formation of troublesome by-products and to reduce the yield basic ether can be increased to about twice as much by adding the starting compound in the first stage, z. B. p-chlorobenzophenone with an excess of about 5o% Grignard reagent or let react more. A complete conversion took place, so that in that as an intermediate product formed carbinol was no longer contained undesired starting ketone in the second stage the desired reaction between carbinol and the basic alkyl chloride in the above could interfere with the specified meaning and deliver undesirable by-products.

The synthesis could be further improved by using the Grignard reagent which can use methyl-Mg-chloride, which is easily obtained from methyl chloride and Mg powder, so did not rely on the expensive methyl-Mg-bromide or methyl-Mg-iodide, which reagents had heretofore been generally preferred because of their responsiveness. The good usability of methyl Mg chloride in the present process was particularly instrumental dar implementation of the process in technical

Extent advantageous.

For the medical use of the ethers produced according to the invention, it is advisable to use them to be converted into suitable salts. As has been found, hydrochloric acid salts have proven to be special proved suitable. The conversion of the ether into hydrochloric acid salts (hydrochloride) is however with

associated considerable difficulties, since the ethers z. B. by excess hydrochloric acid can be split very easily according to the following equation:

P-Cl-C ₆ H ₄

C-Ο - CH ₂ - CH ₂ - N (CHg) ₂ + HCl

CH ₃

_n π r

-CH ₂ -CH ₂ -N (CH ₃ ) ₂ -HC1

This difficulty has been overcome according to the invention in such a way that the basic Ether in ethereal solution the theoretical amount of an ether saturated with HCl drop by drop added with stirring. The hydrochloride which precipitates out is very hygroscopic in its raw state can be converted to moisture-proof form by processing it after Drying in vacuo from an acetone solution with dry ether precipitates and then one subjected to further drying over phosphorus pentoxide in vacuo.

example 1

[ι - (p-chloro-pheny 1) -1-phenyl] ethyl- (/? - dimethylamino-ethyl) -ether

To prepare the 'Grignard's solution, methyl chloride is dissolved in a boiling suspension of 36 g magnesium in 1000 ecm absolute ether up to initiated for the complete implementation of the magnesium. Be in the Grignard solution obtained in this way 216 g of p-chlorobenzophenone with ice cooling and Stirring slowly entered and the product thus obtained after 15 hours in a mixture of 200 g Ammonium chloride and ice entered, whereupon it is extracted with ether. The ether extract is dried with sodium sulfate and then the

4-5 ether distilled off. The remaining carbinol is added to a suspension of 45 g of sodium amide in 500 ecm of toluene. The mixture thus obtained, after adding 125 g of dimethylaminoethyl chloride, is then heated to boiling for 3 hours with stirring. The mixture is taken up in water and the base is extracted from the toluene with dilute hydrochloric acid. The hydrochloric acid solution is made alkaline with sodium hydroxide solution, the base is shaken out with ether, dried and, after the ether has been distilled off, fractionated in vacuo. Kp. _0i05 150 to 155 ⁰ . The basic ether is now dissolved in dry ether and ether saturated with dry hydrogen chloride is added dropwise with stirring. An excess of hydrogen chloride should be avoided, as this could cause it to break down into the corresponding diphenylethylene. The ether-moist hydrochloride is expediently dried immediately in vacuo and then subjected to further drying over phosphorus pentoxide in vacuo. Hydrochloride F. 128 ⁰ .

Example 2

[1- (p-chlorophenyl) -i-phenyl] -ethyl- (ß-dimethyl-

amino-ethyl) -ether

32 g of magnesium and 130 g of chlorobenzene are heated to the boil in an oil bath until phenyl-Mg-chloride is formed. The Grignard compound is then dissolved in 1000 ecm of absolute ether, and 155 g of p-chloroacetophenone are added while stirring and cooling with ice. After 15 hours, it is added to a mixture of 200 g of ammonium chloride and ice and then extracted with ether. The ether extract is dried with sodium sulfate, the ether is distilled off and the remaining carbinol is condensed as in Example 1 with dimethylaminoethyl chloride. Kp. _{0> 05} 150 to 155 ⁰ .

Example 3

[i- (p-chloro-phenyl) - i-phenyl] -ethyl- (/? - diethylamino-ethyl) -ether

By reacting p-chlorobenzophenone with methyl-Mg-bromide in the manner described in Example 1 or by reacting p-chloroacetophenone with phenyl-Mg-chloride under the reaction conditions given in Example 2, (p-chloro-phenyl) -phenyl- methyl-carbinol obtained, which in ToluoUösung and in the presence of NaNH ₂ with diethylaminoethyl chloride, as indicated in Example 1, is condensed. Kp. _0i02 142 to 147 ⁰ . Hydrochloride: m.p. 138 ⁰ .

Example 4 [i- (p-chloro-phenyl) -i-phenyl] -ethyl-

(/ 3-piperidino-ethyl) -ether

By reacting p-chlorobenzophenone with methyl Mg chloride in the manner described in Example 1 or by reacting p-chloroacetophenone with phenyl Mg chloride under the reaction conditions given in Example 2, (p-chloro-phenyl) - phenyl-methyl-carbinol obtained, which is condensed analogously to the manner indicated in Example 1 with piperidinoethyl chloride. Kp. _0i05 i ^ & 168 to 171 ⁰ . Hydrochloride: m.p. 175 ^% .

In pharmacological studies with / 5-Dimethylaminoäthylbenzhydryläther, [ι - (p-chlorophenyl) -1 - phenyl] - methyl - (JS- dimethyl - aminoethyl) ether and the compounds prepared according to the invention on the isolated organ (guinea pig intestine) were carried out , it was found that the antihistamine effectiveness, e.g. B. of [i - (p - chloro-phenyl) -i-phenyl] -ethyl - (/? - dimetbylamino-ethyl) -ether is more than twice as large as that of / S-dimethylaminoethylbenzhydrylether. Since the spasmolytic anticholinergic (atropine-like) effect of [i- (p-chloro-phenyl) -i-phenyl] -ethyl - (/ J-dimethyl-amino-ethyl) -ether is fully retained in comparison to / S-dimethylarninoethylbenzhydryl ether to address this connection as the most effective in the experiments on the isolated organ.

Subsequent tests carried out on the whole animal (histamine spray) with the same compounds gen resulted in a completely surprising increase in the therapeutic range of the invention produced [i- (p-chloro-phenyl) -i-phenyl] -ethyl - (/? - dimethyl-amino-ethyl) -ether compared to // - Dimethylaminoäthylbenzhydryläther. So owns [i- (p-chloro-phenyl) -i-phenyl] - ethyl- (/? - dimethylamino-ethyl) -ether in whole animal experiments compared to / 3-dimethylaminoäthylbenzhydiryläther antihistamine activity almost four times stronger, on the other hand the compound shows a reduction the toxicity by more than half, so that the therapeutic index of the new compound of 15 (^ -Dirnethylaminoäthylbenzhydryläther) to 156 increases by more than ten times. Completely analogous conditions can be found in comparison of [i- (p-chloro-phenyl) -i-phenyl] -methyl - (/ ^ dimethyl-amino-ethyl) -ether determine with the compound produced according to the invention.

Claims (3)

Patent claims: i. Process for the preparation of new antihistamine effective basic ether, characterized in that ρ-chloroacetophenone with a phenyl magnesium halide or p-chlorobenzophenone with a methyl magnesium halide converts in a manner known per se under Grignard conditions, the resultant [a-Oxy-ot- (p-chlorophenyl) -a-phenyl] ethane in an known manner with a compound of the general formula Hai · CH ₂ - CH ₂ - R, where R is a dimethylamino, diethylamino or a piperidyl radical, condensed and the basic ether obtained, if appropriate by known methods, physiologically in salts harmless acids transferred. 2. Modification of the method according to claim i, characterized in that the Phenyl or methyl magnesium halide in an excess of more than 50%, based on to the theoretically required amount. 3. The method according to claim 1, characterized in that that the basic ether for the conversion into the hydrochloric acid salt in ethereal Solution with the theoretical amount of an ether saturated with hydrochloric acid dropwise and is added with stirring, the precipitated hydrochloride is dried in vacuo, then reprecipitated from a solution in dry acetone with dried ether and after isolation, subjected to further drying in vacuo over phosphorus pentoxide will. Considered publications:
German Patent Nos. 851 066, 853 164; U.S. Patent No. 2,527,963;
French patent specification No. 898 245,
948, ι 007 975. <609 689 11.56