DE1770762A1 - Aminohexahydrobenzo [a] -quinolizines substituted in the 2-position and their pharmaceutically acceptable salts - Google Patents

Description

MIIES LABORATORIES, IHO.
1127 Myrtle Street, Elkhart, Indiana / USA

concerning

Amino-hexahydrobenzo substituted in the 2-position / ~ & J- ehinolizine and their pharmaceutically acceptable salts

The present invention relates to amino-hexahydrobenzo / ~ "a / -quinolizines and substituted in the 2-position their pharmaceutically acceptable salts, which are used as antihypertensive Funds are useful. The new compounds are obtained by adding a 2-0xo-1,2,3,4,6,7-hexahydro-11bH-benzo / ~ a_7quinolizine reacted with a 1min to a Schiff's view base and this hydrogenated will. The amine obtained is then with a halide or aylated or alkylated to an anhydride

209832/1177

-Z-

The connections gained in the process are made through the general formula

reproduced, in which Ti is hydrogen, an OH-G group or ü-All: ylgriippe, Π hydrogen, an OH-G group or O-alkyl

group, R * '"denotes a hydrogen, an alkyl or aryl group, Jl ^J denotes hydrogen, an aryl or aryl group,

L.
R. one of the groups,

HH

/ -G-alkyl, -CH ₉ G = GH,

-CE ₀ GK ₀ KC-IiH ₀ -G-KIL

and -GH ₀ GH ₀ -G = KOH ■ ΪΪΗ2

is, R What f. he nt off, an alkyl or aryl group and Ii "also means hydrogen, an alkyl or aryl group. Pre? .ugnuine the alkyl, aryl and aralkyl groups are in the invented invention fertilize lower ir: \ ^r l- lk3, aryl and aralkyl, the invention unifrsr, b also those of the formula indicated enbsprechenden Nhar ^on1. ologi.scli acceptable salts.

BATH ORIGINAL

209832/1177

The compounds according to the invention x ^ earth according to prepared according to the following reaction scheme:

R ³ NH, PtO ₂ / H ₂

or (R ^) _p Q

209 8 3 2/1 177

IA-3 ^

wherein R, R, R, R and R are as defined above and X represents a halogen atom.

According to the equation, a 2-0xo-1, 2, 3, k, 6, 7-hexahydro-llbH-benzo / ä "J7quinolizine is reacted with an amine in a suitable solvent to form a Schiff base which has the primary structure The solvent used is not critical, it can be dry toluene, benzene, xylene, etc. The reaction mixture is advantageously refluxed in the presence of a catalyst. The reaction time is not critical; it preferably depends on the amount of water required from which is collected and may be 1 to 12 or more hours. the catalyst may be an acid catalyst, preferably an organic acid-catalyzed ψ is sator such as p-toluenesulfonic acid is used.

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

209832/1 1 77

-34

The amine obtained is then treated with a -

■■ "■ '■ k' anhydride that has the desired R group,

acylated or alkylated. It is true that the ■ procedural conditions not critical, but this stage is preferably carried out under reflux for about 1 to 6 hours » The compound obtained can then be purified in the usual way «

2-Oxo-1,2,3,4,6,7-hexahydro-IIbH-benzo _i ^ _7-quinolizine £, the starting material according to the above reaction scheme can be prepared according to the following reaction:

, LL:

209832/1177

This synthesis is detailed by Denes Szantay in Ghem. Described at ··, 95, 2132 - 2136 / (1 ^ 2).

The compounds according to the invention can be in the form the free base are produced and used. However, the compounds are preferably used in the form of their pharmacologically ' compatible, non-toxic, water-soluble addition salts of inorganic or organic acids such as halogen acid, sulfuric acid, maleic acid and others are used.

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

The drugs prepared with these compounds as the active ingredient are atif easy by Mixing the compounds in dosage units with fillers, carriers, extenders and / or excipients obtained as they are generally used in the manufacture of pharmaceuticals. The connection can do the

209832/1177

- 7 -. ^1A " ³

Approaches in the form of the free base are added, preferably it is pharmacologically acceptable Addition salt before. The medicine can be solid or liquid and is usually administered as tablets, Powders, capsules, suspensions, and similar dosage forms. The drugs can be, for example, oral or subcutaneously in accordance with recognized pharmacological en working methods are administered. The invention is explained in more detail by means of the following examples; in which the preparation of a compound according to the invention is described. These examples will show those skilled in the art how others fall within the scope of the invention Connections can be obtained easily.

Example 1:

N-ZJZ- (11 ² J 3 "^ f 617-Hexahydro-IIbH-benzoZaJ7Ohiholizinylj7 propionanilide.

Gis and trans isomers »

A mixture of 2 ~ oxo-1,2,3,4,6,7-hexahydro-IIbH-benzo Za_7quinolizine (5.6 g, 0.027 mol) ,. Aniline (2.5 g, 0.027 mole) and 50 cirr dry toluene was made using a Dean-Stark trap with p-toluenesulfonic acid as a catalyst Refluxed for 12 h. The solvent was Stripped off in vacuo and the residue extracted with η-hexane. The n-hexane solution was concentrated in vacuo and

- 8 209832/1177

· - tr · "

the residue recrystallized from ether. A light tan product crystallized out. Yield 2.14 g, ¹ MP 129 to 131 ^° C.

A solution of this compound 2-phenylimino-1,2,3,4,6,7-hexahydro-IIbH-benzo / 7-quinolizine (2.14 g, 0.007 mol) in dry ethanol was _{hydrogenated using PtO 2} 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 / 7-quinolizine were obtained. This procedure was repeated with sufficient reactants to obtain 20.6 grams of product. A solution of the aniline compound (20.6 g) in 100 cnr propionic anhydride was refluxed for about 1 hour. The excess propionic anhydride was stripped off in vacuo. The residue was dissolved in H ₉ O and washed with KoCOo

C. C J)

made alkaline. The organic compound was with

o extracted and the CHCl ^ extract dried, filtered and concentrated in vacuo. The residue was taken up in dissolved ether, filtered and the filtrate was cooled. White lumpy crystals were obtained and collected on the filter. Yield 10.05 Γ, ', FP 125 to 126 ⁰ C.

20 9832/1177

Ber. for C ₂ 2 ^H 26 ^N 2 ^{O : N} (basecn) ^ fl9; G 79.01 H 7.84. Found N (basic) 4.21 C 79.12 H 7.90.

Example 2;

trans isomer.

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

Larger numbers of participants were taken in. ~ sets, i.e. 69.5 g (0.368 mol) of 2-oxo-1,2,3,4,6,7-hexahydro-IIbH-benzo / ÄJTchinolizln, 34.2 g (0.368 mol) of aniline and 200 cnr propionic anhydride and the mixture for Acylation refluxed for 6 h.

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 part was ab- %

filtered. The Federal Council was put aside. The insoluble fraction was dissolved in dilute HGl and _{precipitated with K 9} COo. The precipitate was dissolved in CHGIo, dried over MgSi1 and the solvent stripped off in vacuo. The residue was slurried with ether, filtered and washed with cold ether. 29 g of solid substance were obtained, which were recrystallized twice from benzene / n-hexane, yield 20 g, PP 125 to 126 ^° C.

209 832/1177

BATH
- 10 -

lA-34

- 10 -

The compound (15 g) was _{chromatographed on an Al 2} 0o column (350 g) and the column was eluted with benzene and Belol / ether (4: 1). 7.5 g of the trans isomer were obtained, which was recrystallized from ether. Yield 7 g, FP 125 to 126 ⁰ C.

Ber. for C ₂₂ H ₂₆ N ₂ O: G 79.01; H 7.84 N 8.38. m found. C, 78.91-; H 7.96; N 8.44

IR spectrum _v CHGIO 1645, 2755 and 2815 cm ¹ " ¹ , max ^J.

Example 3:

cis isomer.

The filtrate prepared according to Example 2 and set aside was worked up further in order to separate off the cis isomer. The filtrate was made alkaline _{with K 2 COo.} The semi-solid precipitate soon solidified and was collected on the filter and washed with water. The precipitate was dissolved in CHCIo over

^ dried and the solvent stripped off in vacuo. The residue was stirred with ether, filtered and washed with cold ether. There were 14 g of solid product obtained, which was recrystallized from benzene-η-hexane. Yield 8.5g, F.P. 158 to 159 ° C

Ber. for G ₂₂ H ₂₆ N ₂ O: G 79.01 H 7.84 N (basic) 4.19; N (total) 8.38.

Found C 79.35 H 7.98 N (basic), 4.2O, N (total), 8.38.

IR spectrum x, CHGl ₃ 1645 cm * " ¹ (no bands at 2755 or

^max 2815 cm- ¹ ).

20983-2 / 1 177

Claims (1)

8MtJNOHEN SCHWEIGERSTRASSE TXLSTOH 22 06 Sl ΓΗΟΤΕΟΙΡΛΙΚΒΙ MUNICH A - ^ - I-? a t eY) t s. η s ρ r ü c h e 1. Amino-liexahyaro-benzo / a substituted in the 2-position quinolizine 6, he general formula ι
wherein H and R are each hydrogen, an OH group or C-alkyl group, Ϊ1 "hydrogen, an alkyl or aryl group, R- ^ denote hydrogen, an aryl or aralkyl group, 11 one of the groups HI ITH -C-HH and -CH ₉ GIi ₀ -C = KOH
² HH ₂ is and ϊί ~ ^/ and R are each hydrogen, one Mean aryl group, as well as the pharmacologically acceptable Salts of these compounds. BATH ORIGINAL 209 832/1177 - Jfr-. 2. N- / 2- (1 * 2,3, ^, 6,7-hexahydro-llbH-benzo / a_7chino- 1 i zinylj [7propi onanil id. 3 · Method of making a connection according to Claim 1, characterized in that one compound of the formula with a compound of the formula R- ⁵ NH ₂ to form a Schiff's base, the Schiff's base to the amine of the formula 209832/1177 / 3 hydrogenated and the AmIn with a compound (RJ ₂ O or HX where X is a halogen atom, reacts to the desired compound. k. Use of the compounds according to claim Ί for the production of a blood pressure lowering medicament. ■■ '■■■■■■''.^; , : ■ ' i 209832/1177