DE1770762C3 - Substituted 2-amino-hexahydrobenzo [a] quinolizines - Google Patents

Description

NO

in which R is a hydrogen atom or a propionyl group means, as well as the pharmacologically acceptable salts of these compounds.

2. N- [2- (1,2,3,4,6,7-hexahydro-l 1 bH-benzo [a> quinolizinylß-propionanilide.

3. Process for the preparation of the compounds according to claim 1, characterized in that a compound of the general formula is used in a manner known per se

reacts with aniline to form a Schiff base, this to the amine of the formula

35

40

NH

hydrogenated and this amine optionally with propionic anhydride or a propionyl halide converts and optionally then the compound obtained with an acid in a pharmacological compatible salt transferred.

4. Medicament, consisting of one or more substances according to claim 1 and pharmaceutical customary carriers or diluents.

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The invention relates to substituted 2-aminohexahydrobenzo [a] quinolizines the general formula

60

reacts with aniline to form a Schiff base, this to the amine of the formula

hydrogenated and this amine optionally reacted with propionic anhydride or a propionyl halide and optionally then the compound obtained with an acid into a pharmacological compatible salt transferred.

The 2-oxo -1,2,3,4,6,7-hexahydro -HbH-benzo- [a] quinolizine is reacted with aniline in a suitable solvent to form a Schiff base. The solvent used is not critical, it can be dry toluene, benzene or xylene. Advantageously the reaction mixture is refluxed in the presence of a catalyst. the Response time is not critical; it depends preferably on the required amount of water to be collected and can be 1 to 12 or more hours. The catalyst can be an acid catalyst an organic acid catalyst such as p-toluenesulfonic acid is preferably used.

The Schiff base that is formed is then hydrogenated to the amine. This hydrogenation is advantageous made in an appropriate solvent such as methanol, ethanol or 2-propanol. Preferably platinum oxide is used as a catalyst.

The amine obtained is then optionally treated with propionic anhydride or a propionyl halide acylated. Although the process conditions are not critical, this stage is preferably below The reflux is carried out for about 1 to (i h. The compound obtained can then be used in a conventional manner Way to be cleaned.

The starting material 2-oxo-1,2,3,4,6,7-hexahydro-11 bH-benzo [a] quinolizine can be

Settlement are established

+ CH ₃ C-CH = CH ₂

This synthesis is described in more detail by Denes B e k e and Csaba S ζ ä η t a y in Chem. Ber., 95 (1962), 2132 bis 2136 described.

The compounds according to the invention can be prepared in the form of the free base and use Find. Preferably, however, the compounds are in the form of their pharmacologically acceptable, non-toxic water-soluble addition salts of inorganic or organic acids, such as halogen acid, Sulfuric acid or maleic acid, is used.

The new compounds are both in the form of the free bases or the compatible addition salts useful antihypertensive agents.

It is known that the direct peripheral vascular

table

enlargement is a desirable mechanism for lowering blood pressure in hypertensive patients Humans, as increased peripheral resistance due to arterial vasoconstriction, is the main one homodynamic abnormality in this disease. It is also known that the application of hydralazine, which lowers blood pressure by this mechanism, as an antihypenensive agent to lower blood pressure is limited because

ίο such a reduction is accompanied by a increase in heart rate caused by reflexes. Dogs Receiving Subacute Doses of Hydralazine show cardiac stimulation leading to focal necrosis in the papillary muscles of the left ventricle.

The benzoquinolizine derivatives and hydralazine of the present invention were used on hypertensive dogs examined for lowering of blood pressure and cardiac stimulation. In this investigation, the The blood pressure and heart rate of dogs hypertensive with mecamylamine are linked For a month without treatment, and then for a month after treatment with hydralazine or the specified compounds according to the invention determined in daily oral doses of 3.1 mg / kg were administered. The table below shows the mean blood pressure and mean heart rate of untreated and treated dogs and the respective differences between them are given.

The comparison refers to untreated dogs.

Mean blood pressure, mm Hg heart rate, beats / min

Comparison Treats Difference Comparison Treats Sub

divorced

j R. 13Γ. 110 -23 94 83 -11 H (free base) j H 128 105 -23 77 75 -2 (Dihydrochloride) ι O
Μ 1 Il
-CC ₂ H ₅ 118 91 -27 103 101 -2 i Hydralazine 111 85 -26 97 212 + 115

It was observed that the benzoquinolizines of the present invention reduced the blood pressure of the examined Degraded dogs to essentially the same extent as hydralazine. But it was observed that with the benzoquinolizines the cardiac stimulation occurring as an accompanying reaction is avoided.

The acute LD ₅₀ of hydralazine, as given by CD Barnes and LG Elterington (Drug Dosage in Laboratory Animals, University of California Press, Berkeley and Los Angeles, 1965, p. 113) is 83 mg / kg in mice with intraperitoneal ones Administration and 173 mg / kg in rats when administered orally. The acute LD _{50 of} the compound in which

R = —CC ₇ H,

is, became 300 mg / kg in mice when intraperitoneally Administration and determined to be 530 mg / kg in rats when administered orally.

As can be seen from the data given above, the benzoquinolizines of the invention have a antihypertensive effectiveness equal to or greater than that of hydralazine. You are against it however, they are much less toxic and have no harmful side effects; they lead particularly not for cardiac stimulation as seen with hydralazine.

The medicaments produced with the compounds according to the invention as an active ingredient are used in a simple way by mixing the compounds in dosage units with fillers. Carriers, Extenders and / or excipients obtained, as are generally used in the manufacture of pharmaceuticals Find application. The connection can

admixed with the batches in the form of the free base will; it is preferably in the form of a pharmacologically acceptable addition salt. The Medicine can be solid or liquid and is usually supplied as tablets, powders, capsules, suspensions and the like Dosage forms manufactured. The drugs can e.g. B. oral or subcutaneous in accordance administered using recognized pharmacological procedures.

The invention is illustrated in more detail by means of the following examples.

example 1

N- [2- (l, 2,3,4,6,7-hexahydro-l 1 b H-benzo [a] -quinolizinyl)] - propionanilide, Trans isomer

A mixture of 2-oxo-1,2,3,4,5,6,7-hexahydrollbH-benzo [a] quinolizine (5.6 g, 0.027 mol), aniline (2.5 g, 0.027 mol) and 50 cm ³ dry toluene was refluxed for 12 hours using a Dean-Stark trap with p-toluenesulfonic acid as a catalyst. The solvent was removed in vacuo and the residue was extracted with n-hexane. The n-hexane solution was concentrated in vacuo and the residue was recrystallized from ether. A light tan product crystallized out; Yield 2.14g; F. 129 to 13TC.

A solution of the resulting 2-phenylimino-1,2,3,4-6,7-hexahydro -HbH-benzo [a] quinolizine (2.14 g, 0.007 mol) in dry ethanol was hydrogenated using platinum oxide as a catalyst. After the reaction had ended, ie after about 1 hour, the catalyst was filtered off and the filtrate was concentrated in vacuo. 2.2 g of 2-anilino-1,2,3,4-6,7-hexahydro-IIbH-benzo [a] quinolizine were obtained as an oil. This procedure was repeated with sufficient quantities of the reactants to obtain 20.6 grams of the product. A solution of the aniline compound (20.6 g) in 100 cm ^{3 of} propionic anhydride was refluxed for about 1 hour. The excess propionic anhydride was removed in vacuo. The residue was dissolved in water and made alkaline with potassium carbonate. The organic compound was extracted with chloroform and the chloroform extract was dried, filtered and concentrated in vacuo. The residue was taken up in hot ether, filtered and the filtrate was cooled. White lumpy crystals were obtained and filtered off; Yield 10.05g; M.p. 125 to 126 ° C.

Analysis for C ₂₂ H ₂₆ N ₂ O:

Example 2
Trans isomer

The procedure was as in Example 1 with the following modification:

Larger amounts of reactants were used, ie 69.5 g (368 mol) of 2-oxo-1,2,3,4,6,7-hexahydro-IIbH-benzo [a] quinolizine, 34.2 g (0.368 mol) of aniline and 200 cm ³ propionic anhydride and that

ίο mixture for acylation under reflux for 6 hours held.

After acylation, the reaction mixture was evaporated to dryness on a steam bath in vacuo. The semi-solid residue was treated with water and heated on a steam bath. The insoluble one Part was filtered off. The filtrate was set aside. The insoluble portion was diluted in Dissolved hydrochloric acid and precipitated with potassium carbonate. The precipitate was dissolved in chloroform, dried over magnesium sulfate and the solvent removed in vacuo. The residue was with Slurried ether, filtered and washed with cold ether. 29 g of solid substance were obtained, which was recrystallized twice from benzene / n-hexane; Yield 20 g; M.p. 125 to 126 ° C. The connection (15g) was chromatographed on an alumina column (350g) and the column using in benzene Benzene and benzene / ether (4: 1) eluted. 7.5 g of the trans isomer were obtained, which was recrystallized from ether would. Yield 7g; M.p. 125 to 126 ° C.

Analysis for C ₂₂ H ₂₆ N ₂ O:

Calculated ... C 79.01, H 7.84, N 8.38;
found .... C 78.91, H 7.96, N 8.44.
IR spectrum ι ·! ,,!, ¹ , ¹ 'Ί645, 2755 and 2815 cm " ¹ .

Example 3
Cis isomer

The filtrate obtained according to Example 2 and set aside was worked up further to obtain the cis isomer to separate. The filtrate was made alkaline with potassium carbonate. The semi-solid precipitate solidified soon and was filtered off and washed with water. The precipitate was dissolved in chloroform dissolved, dried over magnesium sulfate and the solvent removed in vacuo. The residue was stirred with ether, filtered and washed with cold ether. 14 g of solid product were obtained, which was recrystallized from benzene-n-hexane. Yield 8.5 g; 158-159 ° C.

Analysis for C ₂₂ H ₂₆ N ₂ O:

Calculated ... C 79.01, H 7.84, N (basic) 4.19,

N (total) 8.38%;
found .... C 79.35, H 7.98, N (basic) 4.20,

N (total) 8.38%.

Calculated ... N (basic) 4.19, C 79.01, H 7.84%; found .... N (basic) 4.21, C 79.12, H 7.90%. IR spectrum v ^l _m T 1645 cm " ¹
2755 or 2815 cm " ¹ ) ·

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Claims (1)

Patent claims: 1. Substituted 2-amino-hexahydrobenzo [a] | - quinolizine of the general formula in which R denotes a hydrogen atom or a propionyl group, and their pharmaceutically acceptable ones Salts. The compounds are useful as antihypertensive agents. The compounds according to the invention can be prepared by being known per se Way 2 - Oxo -1,2,3,4,6,7 - hexahydro -HbH- benzo- [a] quinolizine the formula