DE2037661A1 - Aminohexa hydrobenzo substituted in 2 position square bracket on square bracket to chirföhzin derivatives and their pharmacologically acceptable salts - Google Patents

Description

DR. ING. F. WTTESTHOFF DIPIi. ING. G. PUIiS DR.E.V.PKCHMANN DR. ING. D. BEHRENS PATENT Attorney

8 MUNICH 9O SCHWEIOERSTRASSE 2

T «1.XOHAMMiDHESSBl PIIOTXCTPATCXT MÜNCUE.V

1A-38 107

Description of the patent application

MILES LABORATORIES, IUC. 1127 Myrtle Street, Elkbart, Indiana 465H, USA

concerning

Aminohexahydrobenzo Ta] cbinolizine derivatives substituted in the 2-position and their pharmacologically acceptable salts

Addition to patent 1 770 762 (P 17 70 762.9):

The main patent relates to aminohexahydrobenzo Qa] quinolizine derivatives of the general formula which are substituted in the 2-position
R.

109835 / 167S

in which R and R each represent a hydrogen atom, a hydroxyl group or an O-alkyl group, R a hydrogen atom, a

2 5

Alkyl or aryl group and R and R, inter alia, hydrogen atoms mean. In a further embodiment of this invention, it has now been shown that by further varying the Substituents on the amino nitrogen new compounds • can be obtained that are also pharmacological and therapeutic Have effects within the meaning of the invention of the main patent. The compounds of the present invention are therefore characterized by the general formula

in which R and R each represent a hydrogen atom, a hydroxyl or O-alkyl group, Ή? a hydrogen atom, an alkyl, cycloalkyl, substituted phenyl, diphenyl or a phenyl-alkyl group substituted by halogen, alkyl, O-alkyl, cyano, 0-alkylcarbonyl and / or nitro groups, R groups

0 0 (

one of the

-CH ₂ CH ₂ N C-

Alkyl

• nh.

■ Cycloalkyl - "C

or

Phenyl

NH,

and R is a hydrogen atom, an alkyl or phenyl group mean. · ·

109836/1676

The invention also relates to those pharmacologically acceptable Salts of these compounds. In all cases where alkyl groups are given in the above definitions, these are lower alkyl groups, preferably between 1 and 4 carbon atoms have and the cycloalkyl groups around those with preferably between 3 and 7 carbon atoms

The compounds of the invention can be prepared according to the following reaction scheme

R ⁵ bra,

PtO ₂ / E ₂

or

ITaBH ₁

R ⁴ X or (R ⁴ ) ₂ 0

R ⁵ R ⁴

109835/1675

wherein R, R, R, R and R have the meaning indicated above and X is a halogen atom.

In this sequence of reactions, 2-oxo-1,3 | 4,6,7,11b-hexahydro-2H-benzo £ a) quinolizine reacted with an amine in a suitable solvent, whereby a Schiff base is formed. The solvent used is not critical and can be dry toluene, benzene, xyxlol, etc. The reaction mixture is advantageously in the presence of a catalyst kept under reflux conditions. The reaction time is also not critical and preferably depends on the required amount of water separating, and can range from about 1 to 12 or more hours. The catalyst can be acidic and is preferably an organic acid such as p-toluenesulfonic acid.

The formed Schiff base is reduced, whereby a Amine is formed. Advantageously, this reaction is in a suitable solvent such as methanol, ethanol or 2-propanol carried out. To make the trans isomer, the Reduction advantageously with NaBH. carried out. For a catalytic hydrogenation, PtOp is preferably used as the catalyst used .. The amine is then alkylated or acylated with a halide or anhydride with the desired radical R. Although the operating conditions are not critical, this step is preferably carried out within 1 to 6 hours under reflux conditions carried out. The resulting compound can be purified according to known methods.

The 2-0xo-1,3,4,6,7,11b-hexahydro-2H-benzo [a] -quinolizine used as starting material in the above reaction sequence can be prepared according to the following reaction scheme:

- 5 -109835/1675

CH,

CH—

This synthesis is by DSnes, Beke and Csaba Szantay in Chem. Ber., 95, 2132-2136 (1962).

The compounds according to the invention can be prepared and used in the form of the free base. However, you will preferably in the form of pharmacologically acceptable, non-toxic, water-soluble addition salts of inorganic or organic acids such as halogen acids, sulfuric acid, maleic acid and the like.

The new compounds are available both in the form of the free base and in the form of the compatible addition salts antihypertensive agents suitable.

Medicines containing these compounds as an active ingredient are easily prepared by adding the Compounds in the appropriate dosage units with fillers, carriers, extenders and / or excipients, such as they are generally used for the manufacture of pharmaceutical

109835/1675 ~ ⁶ ~

■ - 6 -

rides are used, mixed. However, in such preparations, the compounds can be in the form of the free base vorliegenj it is preferable to use a _s pharmacologically acceptable acid addition salt. The medicaments can be either solid or liquid and can be in the form of tablets, powders, capsules, suspensions and similar dosage forms according to conventional manufacturing processes. These medicaments can be administered orally or subcutaneously, for example, in accordance with the usual pharmacological application forms.

The invention is illustrated in more detail by the following examples which illustrate the preparation of the compounds according to the invention describe·

109838/1675

Examples - 7 -

example 1

¹ 13,4,6,7 f 11b-Hexahydro-2-metbylamino-2H-benzo [aT | quinolizine dihydrochloride monohydrate:

A solution of 40.2 g (0.2 mol) 1,3,4,6,7,11b-Hexahydro-SH-benzofVlchinolizin - ^ - one, 24.8 g or 62.1 g of a 40 # aqueous solution (0.8 mol, four-fold excess) methylamine and a catalytic amount of p-toluenesulfonic acid in 500 ml of methanol was refluxed for 3 1/2 hours and then cooled to room temperature. The solvent was removed in vacuo, resulting in a syrup. The IR spectrum of this syrup showed a strong absorption at 1717 cm "and a medium absorption at 1670 cm", indicating that only a small amount of the product had formed. The syrup was dissolved in 300 ml of anhydrous ethanol and a catalytic amount of p-toluenesulfonic acid was added. The solution was placed in a hydrogenation bottle (pair) and cooled in an ice bath. Gaseous anhydrous monomethylamine was bubbled through the solution until it was well saturated. The solution was then placed on a pair-hydrogenation apparatus and shaken for 8 hours at 65 ⁰ O and a pressure of 3.5 kg / cm (50 psi). The solution was then concentrated in vacuo to a syrup. The IR spectrum of this syrup showed that the desired product was formed in a larger amount. The syrup was dissolved in 300 ml of methanol and cooled in an ice bath. For this purpose, 16.0 g of NaEH. added in individual portions with stirring. After the surge had subsided, the solution was refluxed for 11/2 hours and then cooled. The solvent was removed in vacuo, resulting in a syrup. This syrup was shaken with 400 ml of a 5O: 5O mixture of water and ethyl ether. The resulting two phases were separated and the aqueous phase was extracted with ethyl ether. The combined ether extracts were _{dried over MgSO 4} and filtered. The piltrate was concentrated to a syrup in vacuo. The IR spectrum no longer showed any imine or ketone absorption. A sample of this syrup was dissolved in 100 ml anhydrous

109835/167 5

- 8th -

Dissolved ethyl ether and gaseous hydrogen chloride was passed through this solution with stirring. It made up a white precipitate is formed, which is filtered off and by successive recrystallization from anhydrous Äthaaal / Ethyl acetate was cleaned.

Yield 6.0 gj mp. 305-31O ⁰ C (varies with rate of heating).
Analysis calculated for C ₁₄ H ₂₄ N ₂ Cl ₂ O! N ( _Dumas ) 9.12;

C 54.72 H 7.87

fiefunden ^H (Dumas) ^{8 '99}

C 55.53 "H 8.12

Example 2

2- (3,4-dichloroanilino) -1,3,4,6,7,11b-hexabydro- ^ H-benzo- [VJ -quinolizine dihydrochloride monomethanolate:

A solution of 40.2 g (0.2 mol) 1,3,4,6,7,11b-Hexahydro-2H-benzo £ .a] ehinolizin-2-one, 32.4 g (0.2 mol) of 3,4-dichloroaniline and a catalytic amount of p-toluenesulfonic acid in 500 ml Benzene was refluxed on a Dean-Stark trap for 16 hours. The solution was cooled and that Removed solvent in vacuo to give a dark orange solid. The IR spectrum showed a strong one Imine absorption. The solid was added to 300 ml of methanol and the resulting mixture is cooled in an ice bath. For this purpose, 20 g of solid NaBH were added with stirring. in individual proportions' admitted. After the surge had subsided, the mixture was refluxed for 16 hours and then cooled. The filtrate was concentrated in vacuo to a syrup, which was shaken with 1000 ml of a 5O: 5O mixture of water / ethyl ether was * The resulting 2 phases were separated and the

109835/1675. _ 9 "

aqueous phase was extracted with ether. The combined ether extracts were over MgSO. dried and filtered. The piltrate was concentrated in vacuo to a dark orange syrup. The IR spectrum showed the presence of HgO. The syrup was divided into 2 equal portions and one of these portions was dissolved in 300 ml of benzene and dried over MgSO 4. dried. The MgSO. was filtered off and 300 ml of anhydrous ether was added to the benzene solution. The resulting solution was cooled in an ice bath and gaseous hydrogen chloride was passed in with stirring. The resulting white precipitate was filtered off, washed with anhydrous ether and recrystallized from methanol. Yield 12.7g; Pp. 209-212 ⁰ C. ■

Analysis: Calculated for C ₂₀ H ₂₆ N ₂ OCI ₄ ί N / j ^^) 6.19; C 53.11;

H 5.80

found · ^N (Dumas) ^{6 '26} * ^{C 53} » ⁶⁴

H 5.80

Example 3

1 »3 * 4,6,7,11b-hexahydro-2- (4-methylanilino) -2H-benzo Ja] quinoli zi ^ monohydrochloride monohydrate:

A solution of 20.1 g (0.1 mol) 1,3,4,6,7,11b-hexahydro-2H-benzo | V] quinolizin-2-one, 10.7 g (0.1 mol) p -Toluidine and a catalytic amount of p-toluenesulfonic acid in 500 ml of benzene were heated under reflux in a nitrogen atmosphere for 7 hours in a Dean-Stark water separator, 1.8 ml of H ₂ O separating out. The solvent was removed in vacuo and the IR spectrum of the solid residue showed a strong imine absorption at 1660 cm "and a weak ketone absorption at 1717 cm" ¹ .

To a cooled suspension of the solid residue in 500 ml of methanol were added in individual portions to 10 g of solid NaBH * with stirring. After the surge has subsided

109835/1675 " ¹⁰ ~

the resulting solution was refluxed for 2 hours, then cooled and the solvent removed in vacuo. The resulting pesticide was extracted with water against chloroform. The chloroform extracts were dried over magnesium sulfate and filtered. The piltrate was concentrated in vacuo and the ΙΕ spectrum of the resulting oil no longer showed any imine or ketone bands. It was not possible to obtain a crystalline product from the oil. Neither did it succeed in separating the mixture by column chromatography, with part of the oil being recovered. The oil was dissolved in hot benzene and cleaned with activated charcoal. Removal of the solvent in vacuo gave a light yellow oil. This oil was dissolved in 2-propanol and 30 ml of 2.7 η HCl in 2-propanol were added to this solution. When the resulting solution was cooled, no crystalline product was formed and anhydrous ether was added until no further precipitate formed. The precipitate was filtered off and dissolved in hot water. A pink plague formed as it cooled. . Yield: 6.0 gj Pp 150-200 ⁰ C (dec.).

The pink pest was dissolved in hot water and cleaned with activated charcoal. Upon cooling the aqueous solution, 2 g of a white pesticide were obtained. Pp. (Unsharp) 170 - 235 ⁰ C (decomp.). After recrystallization of the white plague, 1.9 g of a white plague were obtained, which slowly melted with decomposition above 273 ° C.

Analysis. · Calculated for C ₂₀ H ₂₇ NpOCIi N 8.07; C 69.25; HCl 10.51; H 7.84.

found N 8.14? C- 71.35?

HCl 10.61; H 7.90

Example 4 /

1 »3,4,6,7,11b-hexahydro-2- (3,4,5-trimethokyanillno) -2H-benzo- (a] quinolizine dihydrochloride monomethanolate ι

109835/1675 - ir -

A solution of 30.2 g (0.15 mol) 1,3,4,6,7,11b-hexahydro-2H-benzo [aJquinolizin-2-one, 27.5 g (0.15 mol) 4,5 , 5-trimethoxyaniline and a catalytic amount of p-toluenesulfonic acid in 500 ml of benzene was refluxed for 16 hours under a nitrogen atmosphere in a Dean-Stark trap The IR spectrum showed a strong imine band at 1660 cm ~. The syrup was dissolved in 400 ml of methanol and the resulting solution was cooled in an ice bath After the surge had subsided, the solution was refluxed for 4 hours and then cooled to room temperature, the solvent was removed in vacuo and the residue was shaken with 600 ml of a 50/50 mixture of HpO and ethyl ether. The 2 phases formed were separated and the aqueous phase with ether extr disregards. The ether extracts were over MgSO. dried and filtered. The filtrate was concentrated in vacuo to a dark syrup. This syrup was dissolved in 600 ml of benzene and divided into 2 equal portions. A 300 ml portion of this benzene solution was added to 300 ml of anhydrous ethyl ether and the resulting solution was cooled in an ice bath. Gaseous hydrogen chloride was bubbled through this solution with stirring until no further precipitate formed. The light tan solid was filtered off and washed with anhydrous ethyl ether. The product was recrystallized from methanol. Yield: 6.2 g; Mp 225 -. 228 ⁰ C (dec.).

Analysis: Calculated for C _0x H ^ N ₀ O ,, Cl i: L ,, _moo N 5.92; C 58.34

————— · - ^ pp q. £ q. £ yJUinaS /

H 7.24

found »(Dumas) ^{6 '03} ? ^{C 58} > 9 °

H 7.13

Example 5

2- (4-Ätboxycarbonyl) anilino-1,3,4,6,7,11b ~ hexabydro-2H-

benzo fa "} quinolizine hydrochlorideJ _
. ^J 109835/1675

- 12 -

A solution of 20.1 g (0.1 mol) 1,3,4,6,7,1 Ib-hexahydro-2H-benzo pal quinolizin-2-one, 16.6 g (0.1 mol) ethyl-p -aminobenzoate and a catalytic amount of p-toluenesulfonic acid in 500 ml of benzene was refluxed overnight on a Dean-Stark water separator The syrup was dissolved in anhydrous ethanol, the resulting solution was cooled in an ice bath and 10 g of solid NaBH were added in portions with stirring The excess solvent was removed in vacuo and the residue was shaken with a 1: 1 mixture of ethyl ether and water. The 2 phases formed were separated. The aqueous phase was extracted again with ether and the combined ether extracts were dried over MgSO. And filtered t. The filtrate was concentrated in vacuo to a yellow oil. The oil was dissolved in chloroform and 73.5 ml of 2.7 η HGl in 2-propanol were added with stirring. The resulting solution was cooled in an ice bath and anhydrous ethyl ether was added until no further precipitate formed. A brown precipitate formed, which was filtered off and dissolved in hot methanol. Water was added to the boiling methanol solution and a solid began to form as the methanol boiled off. 25 ml of concentrated hydrochloric acid were then added and the mixture was kept at the boil in order to remove the methanol from the aqueous mixture. This was cooled in an ice bath and the solid filtered off. This solid was recrystallized from methanol. Yield: 2.5 g; M.p. 271-275 ° C (dec.). Analysis: Calculated for 0 ₂₂ ^H 27 ^1T 2 ⁰ 2 ^{Cil! N 7} » ²⁴ ' ^{σ 68} > 3 °>

/ H 7.03

found: N 7.18; C 67.87;

H 7.01

- 13 -

^: '. 109835/1675

Example 6

2- (m -nitroanilino) -1-3-4-6-7-11b-hexahydro-2H-benzo [a] quinoli zin-dihydr ο chloride:

A solution of 20.1 g (Ο, Ί mol) 1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizin-2-one, 13.8 g (0.1 mol) m Nitroaniline and a catalytic amount of p-toluenesulphonic acid in 500 ml of benzene were refluxed under a nitrogen atmosphere in a Dean-Stark trap for 20 hours, 1.6 ml of HpO separating out. The solvent was removed in vacuo and the ΙΕ spectrum of the resulting oil showed both imine and carbonyl bands. The oil was dissolved in 500 ml of methanol, a precipitate being formed. The mixture was cooled and the yellow solid filtered off. As the IR spectrum showed, this compound was the pure imine. The solid was suspended in 250 ml of methanol and cooled in an ice bath. 10 g of solid NaBH were added to the cooled solution with stirring. added in individual portions. The suspension was stirred for a further 3 hours with cooling and then the ice bath was removed. The temperature rose to 45 ⁰ O before it fell back to room temperature. The suspension was cooled again in an ice bath and the bright yellow solid was filtered off. This solid was dissolved in an ethyl ether / chloroform mixture and gaseous hydrogen chloride was passed through the resulting solution with cooling in an ice bath. The resulting precipitate was filtered off and recrystallized from 2-propanol. A pale yellow solid was obtained. Yield: 6.4 g; Mp 211 -. 216 ⁰ C (dec.).

10.60j C 57.58

Analysis: Calculated for 5 C ₁₀ H _{1 0} N ^ O ₀ Cl 8th, N 93 H .85 | HCl 1 40 found 6th 7, N H , 00? HCl 1 example 7th

10.63; 0 58.12

N- ^ phenyl-N- (1,3,4,6,7,11 b-hexahydro-2H-benzo [a] quinolizin-2-yl) cyclopropane ~ carboxamide-monohydrochloride-mono] nethanolate:

109835/1675

- 14 -

8 ml of cyclopropane-carboxylic acid were added to a solution of 13.9 g (0.05 mol) of 2-anilino-1,3,4,6,7,11b-bexahydro-2H-benzo [a] quinolizine in 100 with stirring ml of dry tetrahydrofuran and 25 ml of dry pyridine, which boiled under reflux, were added dropwise. The resulting white mixture was refluxed for 12 hours and. then poured over ice. The resulting mixture was made alkaline with 20 # UaOH and diluted to 2 liters with HpO. A white solid formed which was filtered off. This solid was dissolved in a hot mixture of 100 ml CH ₃ OH and 150 ml CHCl ₅ . The solution was cooled and 25 ml of 2.7 η HCl in 2-propanol were added to this. The resulting solution boiled as soon as methanol was added. Ethyl acetic ester was added to the concentrated methanol solution and the resulting solution was allowed to cool. A white solid formed which was filtered off. Yield 19.6 g. The product slowly melted above 194 ^° C.
Analysis: Calculated for C ₂₄ H ₂₁ N ₂ O ₂ Cli p. 6.75? C 69.465

H 7.53

found 1 6 _s 69i 0 69.96}

H 7.32

Example 8

N-phenyl-N- (1,3,4,6,7 * 11 b-hexahydro-2H-benzo jjaj quinolizine-

2-yl) benzoamide monohydrochloride monometiiaalate

7 ml of benzoyl chloride were added under tubes to a refluxing solution of 13 _S 9 δ (Q >> Q5 mol) 2-anilino-1®3 ₉ 4.6 ₉ 11b-hexahydro-2H-benzo [a] quinolizine in 100 ml dry Tetrahydrofuran and 25 ml of dry pyridine drained _o The resulting solution was "refluxed for 12 hours and then poured over ice". A white solid formed. Then 2Q $> IfaCM was added in order to remove the excess benzoyl chloride . The Q®n ± sch was

103835/1871. " ^{% 5} "

extracted with ethyl ether. The combined etherealists were over MgSO. dried and filtered. The solvent was removed in vacuo. The resulting oil was crystallized from a mixture of benzene and n-heptane and recrystallized. A white plague was obtained which was dissolved in warm methanol. 11 ml of 2.7 η HCl in 2-propanol were added to this. When the solution was heated, a solid formed which was filtered off and recrystallized from a mixture of methanol and ethyl acetate. Yield: 10.3 g · The product slowly melted above 175 0. Analysis: Calculated for C ₂₇ H ₃₁ N ₂ O ₂ Cl: N 6.21? C 71.91I

H 6.93

found N 6.25; C 71.67;

H 6.85

Example 9

N -cyclohexyl-N- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizin-2-yl) propionamide hydrochloride

A 1,3,4,6,7,11b-Hexahydro-2-cyclohexylamino-2H-benzo £ aJ-cbinolizine:

A solution of 20.1 g (0.1 mol) 1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizin-2-one, 9.9 g (0.1 mol) cyelohexylainin and a catalytic amount of p-toluenesulfonic acid in 200 ml of benzene was refluxed on a Dean-Stark water separator for 3 hours, the theoretical amount of water taking leave. The solution was cooled and the solvent removed in vacuo to give a dark orange oil. The IR spectrum of this oil showed strong imine absorption at 1660 cnT. The oil was dissolved in 200 ml of methanol. 0.8 g of UaBH were added to this ice-cooled solution. added in individual portions. After the effervescence had subsided, the solution was refluxed for 11/2 hours and then cooled down. The solvent was removed in vacuo

109 835/1675 - 16 -

removed and the remaining oil with 400 ml of a 50150 mixture shaken from water and ethyl ether. The resulting 2 phases were separated and the aqueous phase with ether moved out. The combined ether extracts were dried over MgSO 4 and filtered. The filtrate became one in vacuo Concentrated oil, which crystallized out on cooling. An IR spectrum of the solid showed no imine or carbonyl band more. The oil was distilled giving a yellow oil. The nitrogen analysis of this oil showed that the free Base was present. The yellow oil solidified to a waxy solid on standing, and darkened on prolonged standing became*

B. N-Cyclohexyl-N- (1,3 »4,6,7 | 11b-hexahydro-2H-benzo [a] -quinolizin-2-yl) propionamide hydrochloride :

8.0 g (0.028 mol) 1,3,4,6,7,11b-hexahydro-2-cyclohexylamino-2H-benzo £ aJquinolizine, which had been prepared as described under A. were dissolved in 200 ml of benzene. To this solution 3.6 g (0.028 mol) of propionic anhydride were added. the

. The resulting solution was refluxed for 3 hours and then cooled to room temperature. The benzene solution was _{extracted with aqueous Na 2} CO 2 solution, dried over MgSO 4 and filtered. The filtrate was filtered through activated charcoal and kieselguhr while still hot and the solvent was removed in vacuo, a dark orange-colored oil being formed. The IR spectrum showed a strong amide absorption at 1630 cm ". The oil was dissolved in 100 ml of 2-propanol and 14 ml of 2.06 η HCl in 2-propanol were added to this solution with stirring. 2-propanol was added to this -Solution was so much anhydrous diethyl ether

given until no further precipitate formed. The white precipitate was filtered off and recrystallized from methanol. Yield: 3.3 g; Mp 216 -. 225 ⁰ C (dec.). Analysis: Calculated for C ₂₂ H, JJ ₂ OCIs ^N (D _{around s} ) 7.43?

^/ C 70.09; H 8.82;

. Found: C, 69.67; H 8.99; N ( _Duma ' _s ) 7.22

109835/1675 ₁₇

Example 10

N- (3-methylphenyl) -N- (1,3,4,6,7,11b-hexahydro-2H-benzo fa] quinolizin-2-yl) propionamide:

A. 2- (m-Methylanilino) -1,3,4,6,7,11b-hexabydro-2H-benzo- • [ajquinolizine:

A solution of 20.1 g (0.1 mol) 1,3,4,6,7,11b-hexahydro-2H-benzo | V] quinolizine-2-o: n, 10.7 g (0.1 mol) m -Toluidine and a catalytic amount of p-toluenesulfonic acid in 300 ml of benzene were refluxed under a nitrogen atmosphere for 17 h. 1.8 ml of HpO separated out in a Dean-Stark water separator. The solvent was removed from the reaction mixture in vacuo, giving a dark orange oil. The IR spectrum showed strong imine absorption. The oil was dissolved in 250 ml of methanol and cooled in an ice bath. 8 g of solid NaBH were added in individual portions to the cooled methanol solution with stirring. After the surge had subsided, the solution was refluxed for 3 hours and then cooled. The solvent was removed in vacuo and the semi-solid residue was extracted with chloroform against water. The chloroform extracts were over MgSO. dried and filtered. The filtrate. was concentrated in vacuo to an oil. The IR spectrum no longer showed any imine or ketone bands. The oil was dissolved in hot aqueous ethanol and then cooled and white crystals formed. The solid was filtered off, washed with cold aqueous ethanol and ^{dried overnight in vacuo at 78 0} C,

B. N- (3-methylphenyl) -N- (1,3,4,6,7,11b-hexahydro-2H-benzo £ a] quinolizin-2-yl) propionamide hydrochloride:

A solution of 5.1 g (0.0174 mol) 1,3,4,6,7,11b-hexahydro-2- (m- «ethylanilino) -2H-benzo (V | quinolizine and 2.6 g (0.02 mol) of propionic anhydride in 100 ml of benzene was taken for 24 hours Heated to reflux. The solvent was removed in vacuo and 100 ml of HpO were added to the residue. The mixture was heated on the steam bath and it became "concentrated

109835/1675 '- \ ¹⁸ , -

Hydrochloric acid added to dissolve the solid. The hot solution was made alkaline with KpCO, and cooled. The mixture was extracted with ether and the combined ether extracts were dried over magnesium sulfate and filtered. Removal of the solvent in vacuo gave a yellow oil which crystallized on standing. The yellow plague was recrystallized from n-heptane. Yield 4.0 g; Pp. 126-127 ⁰ C.
Analysis Calculated for C ₂₃ H ₂₈ N ₂ O: N 8.04J C 79.27;

H 8.10
found H 8.21; N 7 _{9 9} Oj C 79.87 s

The solid was dissolved in 2-propanol and 10 ml of 2.7 η HCl in 2-propanol were added to this solution. Anhydrous diethyl ether was then added until the solution became cloudy. An oil formed that did not crystallize. The solvent was removed in vacuo, giving a light yellow oil. This oil was dissolved in ethanol and the solution was concentrated by boiling on a hot plate. Ethyl acetic ester was then added to the solution and a clear oil formed which crystallized on standing for one week. The white solid was filtered off. Yield? 3.5 gj m.p. 192-198 ⁰ C.
Analysis: Calculated for C ₂₅ H ₂ QF ₂ OCIs I 7 | 28; C 71.755.

H 7.59

found H 7.67s H 7 * 21? G 71.17;

Example 11

H- (1,31416,7111b-hexahydro-2H-benzo [a] quinolizin-2-yl) -2 *, 4 * -dimethoxypropionanilide hydrochloride s

A. 2- (2,4-Dimethoxyanilino) -1,3,4,6,7,1 i'b-hexahydro-2H-benzo [ajquinolizine: ,

10983B / 1S75 - 19 -

A solution of 40.2 g (0.2 mol) of 1 »3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizin-2-one, 33.7 g (0.22 mol) 2 , 4-Dimethoxyaniline and a catalytic amount of p-toluenesulfonic acid in 500 ml of benzene were refluxed for 20 hours under a nitrogen atmosphere in a Dean-Stark trap. The reaction solution was cooled and the solvent was removed in vacuo, resulting in a dark syrup. The IR spectrum showed an imine band at 1660 cm "*. The syrup was dissolved in 500 ml of methanol and cooled in an ice bath. To this cooled solution, 16.0 g of solid MaBH were added in individual portions with stirring effervescence, the mixture was heated for 1 hour at reflux and then cooled the Peststoff formed was filtered, washed with cold methanol and dried in air at room temperature exploits 36.8 gj mp 116-118 ⁰ C. analysis:... Calculated for ^C 2i ^H 26 ^K 2 ° 2 ^{i N} (Dumas) ⁸ » ²⁸ » ^c * 74 _f 53;

H 7.74

found; H 7.8Sj ^ (Dumas) ⁸ » ¹¹ '» ° 74.21.

B. N- (1,3 »4,6,7,11b-Hexahydro-2H-benzo £ a} quinolizin-2-yl) -2 *, 4 ^l 7-dimethoxypropionanilide hydrochloride:

A solution of 16.9 g (0.05 mol) 2- (2,4-dimethoxyanilino) -1,3,4,6,7,11b-hexahydro-2H-benzopa] quinolizine and 13 »O g (0, 1 mol) propionic anhydride in 200 ml benzene became 1%. Heated under reflux for hours, cooled and extracted with an aqueous Na ^ CO ^ solution. The benzene solution was then dried over MgSO, and filtered. The filtrate was concentrated in vacuo to an oil. The IR spectrum showed strong anhydride absorptions in addition to the strong amide band at 1640 cm. The oil was dissolved in 500 ml of anhydrous ether and gaseous hydrogen chloride was passed through the cooled solution with stirring. A white solid formed which was filtered off and washed well with anhydrous ether. The solid was first extracted from 2-propanol and then extracted

109835/1675 ._ ₂ o -

Recrystallized methanol / diethyl ether. Yield 16.6 g mp 265} -. 267 ⁰ C.

Analysis: Calculated - for C ₂₄ H ₅₁ H ₂ Q ₅ Cl: N / _Dumas ) 6.50; C 66.88;

H 7.25

found: H 7.45; ^N (Dumas) ^6f40; ° ⁶⁶ » ⁶⁸ ?

Example 12

K-C1 >> 3f4,6,7,11b-hexahydro-2H-benzo [aj quinolizin-2-yl] -3 * t 4 * i 5'f-trimethoxypropionanilide hydrochloride:

A. 1,3,4,6,7,11b-Hexahydro-2- (3,4,5-rtrime tboxyanilino) -2H-benzo [ajcbinolizine:

A solution of 30.2 g (0.15 mol) l, 3.4.6 _t 7.1 lb-Hexahydro-2H-benzo | V | quinolizin-2-one _f 27.5 g (0.15 mol) 3 , 4,5-trimethoxyaniline and a catalytic amount of p-toluenesulfonic acid in 500 ml of benzene was refluxed for 16 hours under a nitrogen atmosphere in a Dean-Stark water separator. The solution was then cooled and the solvent was removed in vacuo, a dark reddish-orange-colored syrup being formed. The ΙΕ spectrum showed a strong imine band at 1660 cm. The syrup was dissolved in 400 ml of methanol and the resulting solution was cooled in an ice bath. To this cooled solution, 12 g of solid NaBHx were added in individual portions with stirring. After the surge had subsided, the solution was refluxed for 4 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was shaken with 600 ml of a 5O: 5O mixture of water and diethyl ether. The resulting 2 phases were separated and the aqueous phase was extracted with ether. The ether extracts were made over MgSO. dried and filtered. The piltrate was concentrated in vacuo to a dark syrup. This dark syrup was dissolved in 600 ml of benzene and divided into 2 equal portions of 300 ml each.

109835/1675 - 21 -

B. N- (1 ^^, o ^ jiib
2-yl) -3 ', 4', S'-trimethoxypropionanilide hydrochloride:

300 ml 1,3,4,6,7,11b-hexahydro-2- (3,4,5-trimethoxyanilino) -2H-benzo [a] cbinolizi ^/ n ^i: wur1ien ^O to 19.5 g (0.15 mol) propionic anhydride was added. The resulting solution was refluxed for 24 hours and then cooled to room temperature. The solvent was removed in vacuo, giving a dark syrup. This syrup was dissolved in 100 ml of anhydrous diethyl ether and 37.5 ml of 2.06 η HCl in 2-propanol were added to this solution with stirring. Afterward ·

,. , / anhydrous ._, .. ..._

more ether was added until a product precipitated. The solid was filtered off, washed with anhydrous ether and recrystallized 3 times from 2-propanol / diethyl ether. Yield 8.1 g; PP 197.5 -. 198 ⁰ O.
Analysis: Calculated for C ₂₅ H ₅₅ N ₂ O ₄ Cl! Nz-Jj _11111218 V 6.08} C 65.14}

H 7.22
. found: H 7.36} ^N (Dumas) ^{5 '89; C 64} » ⁷² ?

Example 13 .

N- (4-Cyanophenyl) -N- (1,3,4,6,7,11b-hexahydro-2H-benzo [aj quinolizin-2-yl) propionamide:

A. 2- (p-Cyanoanilino) -1,3,4,6,7,11b-hexahydro-2H-benzo [a] -quinolizine:

A solution of 20.1 g (0.1 mol) 1,3,4,6,7,11b-hexahydro-2H-benzo | ja} quinolizin-2-one, 11 _f 8 g (0.1 mol) p Aminobenzonitrile and a catalytic amount of p-toluenesulfonic acid in 250 ml of benzene was refluxed under a nitrogen atmosphere for 96 hours. 1.2 ml of water separated out on a Dean-Stark water separator (theoretical amount = 1.8 ml of H ₂ O). The volume of the solution was reduced to 75 ml by distillation. The orange-colored one that separates out on cooling

- 22 109835/167 5

Pest was filtered off. The IR spectrum showed a strong one Nitrile absorption at 2225 cm "and a strong imine absorption at 1670 cm. It had no carbonyl band · The orange-colored one Solid was suspended in 300 ml of methanol and cooled in an ice bath. 20 g of solid NaBH were added to this suspension. added in individual portions. After the effervescence had subsided, the resulting solution was refluxed for 2 hours. then cooled and the solvent removed in vacuo. The resulting semi-solid residue was treated with chloroform extracted against water. The chloroform extracts were over MgSO. dried and filtered off. The Piltrat was im The vacuum was concentrated and the IR spectrum of the resulting yellow oil showed no imine absorption, but still the desired one Nitrile absorption. The yellow oil turned into a light yellow oil by dissolving it in hot aqueous ethanol and then cooling it Obtain plague.

B, N- (4-cyanophenyl) -N- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] -quinolizin-2-yl) propionamide hydrochloride:

A solution of 5.3 g (0.0175 mol) of 2- (p-cyanoanilino-1,3, -4,6,7,11b-hexahydro-2H-benzoJaJquinolizine and 2.6 g (0.02 mol) of propionic anhydride in 100 ml of benzene was refluxed for 24 hours, the solvent was removed in vacuo and the resulting residue was stirred in 100 ml of hot water to which 10 ml of concentrated hydrochloric acid was added to cause a solution to come in. The resulting solution was made basic with KpCO3 The mixture was extracted with chloroform and the combined chloroform extracts were dried over MgSO. and filtered. Removal of the solvent in vacuo gave an oil whose IR spectrum corresponded to that of the starting amine. 50 ml of propionic anhydride were then added was added to the oil and the resulting mixture was heated on the steam bath for 48 hours. The solution was cooled and 100 ml of H ₂ O was added, followed by 25 ml of concentrated hydrochloric acid. The solution was made alkaline with 20% NaOH and extracted with chloroform t. The combined chloroform extracts

109835/1675 - 23 -

were dried over MgSO 4, filtered and the solvent was removed from the filtrate in vacuo. The resulting solid residue was recrystallized from benzene and n-heptane. Yield 3.5 g; Fp. 105 - 185 ⁰ C.
Analysis: Calculated for: C ₂₃ H ₂₅ N ₃ O: N 11.68; C 76.85} H 7 »01

found H 11.77} 0 76.20; H 7.00

The solid was dissolved in hot 2-propanol and 10 ml of 2.7 η HCl in 2-propanol were added twice in succession to the solution. The solution was concentrated by boiling on a hot plate and ethyl acetate was added until crystals began to form. A white solid formed on cooling and was filtered off. Yield 1.4 g; Mp. 248-258 ° C (dec.).
Analysis: Calculated for C ₂₃ H ₂₆ N ₃ OCl: N, 10.61; C 69.78} H 6.62

found N, 10.10} C, 69.62; H 6.73

Example 14

N- (4-Biphenyl) -N- (1,3,4,6,7,11b-hexahydro-2H-benzo [a] quinolizin-2-yl) propionamide hydrochloride:

A. 2- (4-Biphenylamino) -1,3,4,6,7,1Ib-Hexahydro-2H ^ benzo- (a [] quinolizine:

A solution of 20.1 g (0.1 mol) 1,3,4,6,7,11b-hexahydro-2H-benzo [Vjchinolizin-2-one, 16.9 g (0.1 mol) of 4-aminobiphenyl and a catalytic amount of p-toluenesulfonic acid in 250 ml Benzene was refluxed under a nitrogen atmosphere for 18 hours heated. 1.8 ml of HgO collected in a Dean-Stark trap. The solvent was removed in vacuo and the IR spectrum of the resulting reddish-orange-colored Oils showed strong imine absorption at 1670 cm. The oil was dissolved in 500 ml of methanol and the resulting solution was cooled in an ice bath. 8 g of solid NaBH were added to this solution. under

109835/1675 -24-

Rübren added in individual portions. After the surge has subsided the solution was refluxed for 2 hours. A solid began to separate out of the solution and approximately 350 ml of the solvent were distilled off. After this Cooling, the mixture was filtered. A light-colored plague was obtained, which was recrystallized from 95% ethanol.

B. N- (4-biphenyl) -N- (1,3,4,6,7,11 b-hexahydro-2H-benzo [atf quinolizin-2-yl) propionamide hydrochloride:

A solution of 8.9 g (0.0251 mol) 2- (4-biphenylamino) -1 * 3 »4» 6 _f 7.11 b-hexahydro-2H-benzo [ajquinolizine and 3.9 g (0.03 mol) propionic anhydride in 100 ml of benzene was refluxed overnight. The solvent was removed in vacuo and the resulting residue was stirred in 100 ml of hot HgO. 10 ml of concentrated hydrochloric acid were added to dissolve the pesticide, and the resulting hot solution was made alkaline with Kp00 ^. An oil formed which immediately solidified in the hot solution. The resulting mixture was cooled, the pesticide filtered off and washed with H _{2 O.} 1 g of a brown pesticide was obtained which slowly melted above 115 °. The IR spectrum showed no NH absorption, but both a strong amide absorption at 1645 cm "and a salt-like absorption in the region of 2500 cm". The brown plague was dissolved in hot chloroform and filtered through activated charcoal. The piltrate was absorbed heated to boiling on a hot plate and gradually added individual portions of ethyl acetate, and the chloroform evaporated until a pesticide began to crystallize in the hot solution. The mixture was cooled and the resulting pesticide filtered off. Yield 4.0 gi pp. 265 - 275 ° C (dec.) This pest was dissolved in boiling water to which 10 ml of concentrated hydrochloric acid had been added. The hot solution was filtered through activated charcoal to give a colorless solution. On cooling, a white pest formed which was filtered off . ' To afford 2.2 g of a white Peststoffes, the above 165 ⁰ C and softened with decomposition at

109 835/1675 - 25 -

265 - 27.5 O melted.

white solid was dissolved in methanol and the resulting solution was heated to boiling to azeotropically remove the water. The solution was then further concentrated and ethyl acetate was added. On cooling, a white pest formed which was filtered off. "Yield 2.0 gj bp 274-279 ° C (dec.).

Analysis: Calculated for O ₂₈ H ₃₁ Ii ₂ OGIs U 6.27j C 75.24; H 6.99

found

N 6.17} C 75.74i H 7.28

Claims

109835/1675

- 26 -

Claims (2)

Claims y. AminohexahydrobenzoJV substituted in the 2-position] quino- licin derivatives of the general formula in which R and R each represent a hydrogen atom, a hydroxyl group or an O-alkyl group, R a hydrogen atom, an alkyl or aryl group and R and R represent hydrogen atoms, according to Patent 1,770,762 (Pat. Ann. 17 70 762.9) _f characterized in that of the substituents present on the amino nitrogen the 'substituent Br is a hydrogen atom, an alkyl, cycloalkyl, substituted phenyl, diphenyl or a halogen, alkyl, O-alkyl, cyano, O-alkylcarbonyl and / or nitro groups substituted phenyl A. * alkyl group, and the substituent R is one of the groups J-. Alkyl - C cycloalkyl • phenyl -CH ₂ CH ₂ N- C — NH, You , -0 NH ₂ 109835/1675 or -CH ₂ CH ₂ C = - HH, NOH - 27- means, where among alkyl groups in each case lower alkyl groups with preferably 1 to 4 carbon atoms and below Cycloalkyl groups those having preferably 3 to 7 carbon atoms are to be understood, as well as their pharmacologically acceptable salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that a compound the general formula with a compound of the formula Β * Ί3Ηρ converts the resulting Schiff base to an amine of the general formula reduced, and this amine with a compound of the general formula (R ⁴ ) -O or E ⁴ X brings to reaction, where E, E, B, E and E are those given above Have meaning "and X is a halogen atom, and optionally the product obtained is converted into the acid addition salt with a suitable acid. 109835/1675