DE1178856B - Process for the preparation of new 3-phenyl-garnet (2) derivatives and their salts. - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school KL: C07d

German KI .: 12 ρ -13

Number: 1178856

File number: B 75930IV d / 12 ρ

Filing date: November 3, 1962

Opening day: October 1, 1964

The invention relates to a method of manufacture of new 3-phenyl-garnet- (2) -derivatives of the general formula I.

(D Process for the preparation of new 3-phenylgranate (2) derivatives and their salts

Applicant:

C. F. Boehringer & Soehne G. m. B. H., Mannheim-Waldhof

Named as inventor:

Dr. rer. nat Otto DoId, Lampertheim (Hess.), Dr.-Iag. Kurt Stach, Mannheim, Dr. med. Wolfgang Schaumann, Maonheim-Waldhof

in which R is lower alkyl radicals and R 'is lower alkyl or dialkylamino radicals, and their salts, which is characterized in that N-substituted norgranatanone- (3) of the general formula II

Granatanols (3a) of the general formula IV

(H)

OH (3 a)

(IV)

with organometallic compounds of the general formula III

(III)

in which Me is an alkali metal atom or the monovalent magnesium halide radical of a Grignard compound means, and the 3 / S-phenyl obtained are treated with dehydrating agents and optionally the bases obtained are reacted with acids.

The reaction of the compounds II and ΠΙ takes place under the usual organometallic conditions Syntheses; it is preferable to use organolithium compounds. The dehydration of the intermediates IV obtained in this way is also described in carried out in the usual way; In particular, inorganic acid halides are used as dehydrating agents, such as thionyl chloride, or mineral acids, e.g. B. hydrochloric acid in question.

The 3-phenyl garnet (2) derivatives prepared according to the process of the general formula I have an antihypertensive effect with a point of attack hn central nervous system. The cause of the rise in blood pressure is an excitation of the vasomotor center, because it does not occur when

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this is removed surgically. The hypertensive effect can therefore not be compared to that of the known Sympathicomimetica can be compared, the blood pressure as a result of peripheral vasoconstriction increase.

The grenades produced according to the method were compared with the known 1 - phenyl - 2 - pyrrolidino - pentane hydrochloride, which is known to increase blood pressure, with regard to their circulatory stimulating effect. The pharmacological tests were carried out on cats, with an extensive circulatory analysis (determination of blood pressure, cardiac output, heart rate, etc.). In this case, it was found that the compounds produced according to the method as well as the comparison substance S ¹ increase arterial blood pressure and lead to an increase in cardiac output. However, they differ from the known compound in terms of the regulatory processes and their effects. The emergency ^Μ manoeuvrable multiplication of the cardiac output is achieved stroke volume in the Granatenen by a primary magnification, while in the known compound has a very strong increase of the heart frequency is present; the simultaneous reduction in the ejection volume per heartbeat inevitably leads to an uneconomical burden on the heart with this connection, reducing the efficiency.

From the Journal of the American Chemical Society, Vol. 73 (1951), pp. 3419 to 3424, is already the 3-Phenyl-Granaten- (2) is known, but no information was given about its mode of action. This compound has also been studied for its circulatory stimulating effect; she is Considerably inferior to the new grenade derivatives with the same dosage ratio. In particular It should be emphasized that the new compounds primarily increase cardiac output and only exceptionally lead to an increase in the vascular resistance, while the known garnet derivative only increases the vascular resistance.

In comparison with centrally excitatory substances such as pentamethylenetetrazole and /?, /? - pentamethylene-5> -hydroxy-sodium butyrate, the process products have practically no analeptic effect, increase but still the blood pressure in rats, rabbits and cats under urethane anesthesia while the compounds mentioned in this experimental set-up are ineffective even in convulsive doses are.

The products of the process can be used in the treatment of hypotension.

The following examples illustrate the invention.

For the designation of the process products, that introduced by K. Aider into the literature modern nomenclature used (see reports of the German Chemical Society, vol. 86 (1953), pp. 1544 to 1554).

6o

Examples
1. 3- (p-Dimethylaminophenyl) garnets (2)

To a mixture prepared from 2.1 g (0.3 mol) of lithium shavings in 120 ml of absolute ether and 30 g (0.15 mol) of p-bromo- ^6s- dimethylaniline in 150 ml of absolute ether, which was refluxed for 1 hour , 15.3 g (0.1 mol) of garnetan-3-one in 100 ml of absolute ether are added dropwise. The reaction solution is refluxed for 4 hours and then slowly decomposed with 100 ml of ice water. The ether solution is separated off, dried and concentrated. Upon distillation of the residue is obtained 8.3 g of 3 / - (p-dimethylaminophenyl) -granatanol- (3a) of Kp.0,5 205-220 ⁰ C?; F. 106 to 108 ⁰ C (after recrystallization from petroleum ether). The yield is 30.3% of theory.

36.3 g of 3β - (p-dimethylaminophenyl) -granatanol- (3a) are heated in a mixture of 50 ml of concentrated hydrochloric acid and 50 ml of water with stirring in a boiling water bath for 7 hours. After cooling, the reaction solution is mixed with 200 ml of water, made alkaline with sodium hydroxide solution and extracted with methylene chloride. The extract is dried and concentrated, the residue is distilled. This gives 29.4 g (= 86.7%) of 3- (p-dimethylamino-phenyl> grenade (2) from Kp.0,4 193-200 ⁰ C; the base melts after recrystallization from petroleum ether at 79 to 8O ⁰ C. The hydrochloride produced in the usual way is recrystallized from isopropanol and melts with decomposition at 239 ⁰ C.

2. 3- (p-Tolyl> garnet- (2)

According to the procedure described in Example 1, p-tolyl-lithium prepared from p-bromotoluene and lithium in ether is reacted with garnetan-3-one. In 54.3% yield is obtained 3jS- (p-tolyl) -granatanol- (3a), bp _0, i 190 to 220 ⁰ C. F. 163 to 164 ⁰ C (after recrystallization from ligroin). The hydrochloride produced in the usual way melts at 228 ^° C. with decomposition (after recrystallization from ethanol).

24.7 g of 3 / Kp-tolyl) -granatanol- (3a) are dissolved in 60 ml of water and 60 ml of concentrated hydrochloric acid and refluxed for 7 hours; After cooling, the batch is made alkaline with sodium hydroxide solution and extracted with ether. The ether extract is dried and concentrated, and the residue is distilled. This gives 21.2 g (= 92.6%) of 3- (p-TolyI) -granaten- (2) from Kp.0,15 123-132 ⁰ C. From an ethereal solution of 3- (p-tolyl) -granaten- (2) the maleinate is precipitated with maleic acid dissolved in ether; the salt melts after recrystallization from methyl ethyl ketone at 149 to 151 ^° C.

Claims (1)

Claim: Process for the preparation of new 3-phenylgranate (2) derivatives the general formula in which R is a lower alkyl radical and R 'is a lower alkyl or dialkylamino radical, and their salts, thereby known ·; draws that in a known manner N-substituted Norgranatanone- (3) the general formula IO with organometallic compounds of the general formula '5 compound means, converts, and the resulting 3ß- phenyl-garnetanols (3 o) of the general formula OH (3 a) in which Me treats an alkali metal atom or the monovalent magnesium halide residue of a Grignard ² 5 and 717. with dehydrating agents and, if necessary, reacts the bases obtained with acids. Considered publications:
Journal of the American Chemical Society, 73, 3419-3424 (1951);
B. H e 1 wig, Modern Medicines, 1961, p. 716