DE1149002B - Process for the preparation of hypertensive salts of N, N-dialkyl-2-ethyl-3, 3-diphenyl-propen- (2) -yl-amines - Google Patents

Description

GERMAN

PATENT OFFICE

G33376TVb / 12o

REGISTRATION DATE: OCTOBER 19, 1961

NOTICE THE REGISTRATION ANDOUTPUTE EDITORIAL: MAY 22, 1963

It is known that by Grignardation of / 9-aminopropionic acid esters with phenylmagnesium bromide to S-hydroxy-S ^ -diphenyl-propylamines can get. It is also known that these amino alcohols can be obtained by splitting off water the corresponding 3,3-diphenyl-propen- (2) -yl-amine is obtained. (D. W. Adamson, J. Chem. Soc. Supplement, 1949, pp. 144 ff.).

C ₆ H ₅ OH

\ l

C-CH-CH ₂ NR ₂ R ₃ C ₆ H ₅ Ri

C ₅ H ₅

C ₆ H ₅

= C-CH ₂ NR ₂ R ₃

Ri

A number of such substances of the above formulas, in which Ri = hydrogen or methyl, R ₂ and R ₃ = alkyl, were prepared and examined in particular for their spasmolytic effect.

Surprisingly, it has now been shown that in those cases in which the carbon chain is branched and Ri represents an ethyl group, one obtains new substances, the other interesting ones possess pharmacological properties. Namely, you get substances that are strong and strong all cause long-lasting increase in blood pressure.

The production of hypertensive salts of N, N-dialkyl-2-ethyl-3,3-diphenyl-propen- (2) -ylamines takes place according to the invention that either in a known manner the 2-ethyl-3,3-diphenyl-propen (2) -yl-amine is reacted with carbonyl compounds and formic acid or in a manner known per se from the N, N-dialkyl-2-ethyl-3,3-diphenyl-3-hydroxypropyl-amines 1 mol of water is split off, whereupon the N, N-dialkyl-2-ethyl-3,3-diphenyl-propen (2) -yl-amines obtained isolated in the usual way as salts.

It results z. B. The following increase in blood pressure in cats under urethane-chloralose anesthesia:

a) N, N-dimethyl-2-ethyl-3,3-diphenyl-propen- (2) -yl-amine as Hydrochloric !, gluconate, nicotinate or methanesulfonate

1 mg / kg i.v. v. Blood pressure increase of 15 to 20 mm Hg, lasting about 30 minutes;

Process for the production of

hypertensive salts of

N, N-dialkyl-2-ethyl-3,3-diphenyl-

propen- (2) -yl-amines

Applicant:

Giulini brothers G. mb H.,
Ludwigshafen / Rhine, Giulinistr. 2

Dipl.-Chem. Dr. Werner Heinrich,
Dipl.-Chem. Dr. Walter Heigel,

Ludwigshafen / Rhine,

and Dipl.-Chem. Dr. Horst Eißler,

Ludwigshafen / Rhein-Mundenheim,

have been named as inventors

2 mg / kg i.v. v. Blood pressure increase of 25 to 40 mm Hg, about 1 to 2 hours persistent.

b) N, N-Dipropyl-2-ethyl-3,3-diphenyl-propen (2) -yl-amine as hydrochloride, gluconate, nicotinate or methanesulfonate

1 mg / kg i.v. v. Blood pressure increase from 20 to

30 mm Hg, lasting about 1 hour;

2 mg / kg i.v. v. Blood pressure increase from 30 to

60 mm Hg, ^{lasting about 1 1} ^ to 4 hours.

If the initial blood pressure is reduced, the blood pressure-increasing effect is stronger and longer lasting than if the initial blood pressure is normal or too high.
Under the same test conditions z. B.

the l- (3-hydroxyphenyl) -l-hydroxy-2-N-ethyl-

amino ethane hydrochloride at a dosage of 1 to 4 mg / kg an increase in blood pressure of 20 to 60 mm Hg, but only lasts 4 to 8 minutes.

Correspondingly, at a dose of 1 to 3 mg / kg, ephedrine increases blood pressure from 20 to 50 mm Hg, which lasts a maximum of about 40 minutes.

309 597/345

example 1

N-methyl-N-cyclohexyl-2-ethyl-3,3-diphenylpropene- (2) -ylamine hydrochloride

6.4 g of N-cyclohexyl-2-ethyl-3,3-diphenyl-propen (2) -yl-amine are mixed with 2.3 g of formic acid and 0.25 ml of water while cooling. 1.9 ml of aqueous formaldehyde solution (35%) are also added and the batch is ^{heated to 110 °} C. for 15 hours. After cooling, it is acidified with 9 ml of concentrated hydrochloric acid and distilled to dryness in vacuo. The residue is mixed with dilute sodium hydroxide solution, extracted with ether and the ether part, dried with sodium sulfate, is distilled off. The residue is dissolved in ¹ S methanolic hydrochloric acid and, by adding ether, the N-methyl-N-cyclohexyl-2-ethyl-3,3-diphenyl-propen-(2) -ylamine hydrochloride is obtained in crystalline form.

Mp. 170 to 173 ^° C. Yield: 80% of theory.

Example 2

N, N-Dipropyl-2-ethyl-3,3-diphenyl-propen- (2) -yl-

amine hydrochloride

4.7 g of 2-ethyl-3,3-diphenyl-propen- (2) -yl-amine are cooled to give a mixture of 4.6 g Formic acid and 0.5 ml of water were added. 3.2 ml of propionaldehyde are added and the batch is heated 15 hours at 110 ° C. After cooling, 18 ml of concentrated hydrochloric acid are added and the Excess formic acid and the excess propionaldehyde are distilled off in vacuo. The residue is made alkaline, etherified and the ether part, dried with sodium sulphate, is separated distilled off. The residue is dissolved in methane hydrochloric acid and added obtained from ether the N, N-dipropyl-2-äthylpropen- (2) -yl-amine hydrochloride.

Mp. 221 to 222 ° C.

Example 3

N, N-dimethyl-2-ethyl-3,3-diphenyl-propen (2) -ylamine hydrochloride

14.1 g of 2-ethyl-3,3-diphenyl-propen- (2) -yl-amine are added with cooling to a mixture of 13.8 g of formic acid and 1.5 ml of water. To the reaction mixture are added 11.4 ml of 35 ° / o aqueous formaldehyde solution and the whole was then heated for 15 hours 110 ⁰ C. After cooling, it is acidified with 54 ml of concentrated hydrochloric acid and the excess formic acid-formalin solution is distilled off in vacuo on a water bath. The residue is made alkaline with sodium hydroxide solution, extracted with ether, the separated ether part is dried with sodium sulfate and then distilled off. An oil remains which is dissolved in methanolic hydrochloric acid. By adding ether to the solution, the hydrochloride of N, N-dimethyl-2-ethyl-3,3-diphenyl-propen (2) -ylamine crystallizes out.

Mp. 198 to 200 ^° C. Yield: 84% of theory.

Claims (1)

PATENT CLAIM: Process for the preparation of hypotensive salts of N, N-dialkyl-2-ethyl-3,3-diphenyl-propen (2) -yl-amines, characterized in that either the 2-ethyl-3 , 3-diphenyl-propen- (2) -yl-amine is reacted with carbonyl compounds and formic acid or in a manner known per se from the N, N-dialkyl-2-ethyl-3,3-diphenyl-3-hydroxypropyl -amines split off 1 mol of water, whereupon the N, N-dialkyl-2-ethyl-3,3-diphenyl-propen (2) -ylamines obtained are isolated as salts in the customary manner. Considered publications:
German Auslegeschriften No. 1051281, 1104499; Swiss Patent No. 294 173. © 309 597/345 5.65