FI70015B - PROCEDURE FOR FRAMSTYELLING OF THERAPEUTIC THERAPEUTIC PHENYL QUINOLIZIDINE - Google Patents

Description

1 70015

A process for the preparation of new therapeutically useful phenylquinolizidines

Separated from patent application 811102 (Announcement-5 publication 6 77 00)

The invention relates to a process for the preparation of new therapeutically useful phenylquinolizinylbenzimidia-azolinone and thione derivatives of the general formula I ', R 2 H H i 1 Λ H. I 9a | 2 N-R3 15 (Pj / p) ir) / X r4 2 3 wherein X is hydrogen or fluorine, R is oxygen or sulfur, R is 4 5 hydrogen or lower alkyl and one of R and R is hydrogen and the other is bromine, iodine, cyano, lower alkoxycarbonyl or sulfamoyl, in the form of racemates or enantiomers or acid addition salts of such compounds.

As shown in formula 1 'and the various formulas below, it is shown that the hydrogen atoms in positions 7 and 9a or 7 and 2 are in the trans position relative to each other, wherein in formulas 9a and 2 the hydrogen atoms are arbitrarily represented at the fi position and the hydrogen atom 7 is respectively -position. However, the quinolizidines of the formula 1 'as well as the corresponding intermediates 30 and starting materials are not limited to this absolute configuration, but also the corresponding enantiomeric forms, i.e. the compounds with hydrogen in 9a-X, 2 «X and 7, - ^ and racemates of both enantiomeric forms.

By lower alkyl or lower alkoxy groups is meant groups containing 1 to 6, preferably 2, 700, 1 to 4, C atoms, wherein the groups having 3 or more C atoms may be straight-chain or branched.

Suitable acid addition salts of the phenylquinolizidines of the formula 1 'are pharmacologically tolerable salts with the organic and inorganic acids usually used for salt formation. Examples of such acids are: mineral acids such as sulfuric acid, nitric acid, phosphoric acid, hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid); organic acids such as tartaric acid, citric acid, aliphatic or aromatic sulfonic acids, maleic acid, mandelic acid, etc. Salt formation can take place in a manner known per se.

The compounds of formula 1 'have a variety of pharmacological effects. Thus, they have been found to have particularly neuroleptic (tension-triggering) effects.

Neuroleptically active benzimidiazolinone (and ion) derivatives are in particular those compounds of the formula I * in which R is bromine, iodine or cyano and R is hydrogen.

Particularly preferred neuroleptic active compounds are: ras-1 - [((o-fluorophenyl) octahydro-2H-quinolizin-2'-yl] -6-bromo-2-benzimidiazolinone, ras-1- [9a]? H) -7β- (o-fluorophenyl) octahydro-2H-quinolizin-2x, -yl-5-5-iodo-2-benzimidiazolinone, 25-ras-1-Z] [(H) -7/3 - (of chlorophenyl) octahydro-2H-quinolizin-2-C-yl-5-cyano-2-benzimidiazolinone.

The process according to the invention for the preparation of phenylquinolizinylbenzimidiazolinone and thione derivatives of the formula 1 'is characterized in that the phenyldiamine of the general formula VIII is condensed,

H H

ΓΤΊ '·· M I | NH NH,

W "" 'H

X 4

R3 R

3 70015 wherein X, R4 and R3 are as defined above, with a cyclizing agent of general formula IX, R2 Rb-C-RC (IX) bc wherein R and R are halogen or 1-imidazolyl 2 and R is the same as above, or with carbon disulphide, if desired, N-alkylating the obtained compound of general formula IV-8, HH r2, r-ι.

Hc | ij * N nh N y (IV-8) is / “· x r5 / Xr4 2 4 5 20 wherein X, R, R and R have the same meaning as above, and if desired a compound of general formula IV-6 is obtained, HH 0 25 'xL ^ sl HJI j'N' N-R3 (IV-6) x (Oj 0> \ _ / 30 R5 '' 'R4 where X and R3-R3 have the same meaning as above, to react with P2S5 , and the resulting racemate is optionally cleaved and the resulting bases are optionally converted to acid addition salts.

All the reactions mentioned in the above process can be carried out by methods known per se. The obtained racemates * 70015 can be cleaved into optical anti-tips by methods known per se. The resulting bases can also, as with conventional methods, be converted into their corresponding acid addition salts.

5 Listed below as intermediates or starting materials

If they are not known, these compounds can be prepared by methods known per se. Thus, for example, a phenyldiamine of general formula VIII is obtained by reacting a primary amine of general formula V

10

H H

1 f H.,

Nv - 'o (V)

15 X

wherein X is as defined above and Q is a primary amino group, to react with an appropriately substituted o-halonitrobenzene, preferably an o-chloro or o-fluoronitro-20 benzene derivative, and reducing the nitro group to an amino, for example with hydrochloric acid or iron powder.

The phenylquinolizidines of the formula 1 'have an excellent neuroleptic effect and can thus be used as antipsychotic drugs in the treatment of psychosis and neuroses. The neuroleptic properties of the compounds were determined numerically by the following tests: "Column climbing" test (for rats)

For the experiment, a group of 10 rats per dose were used, which were trained to avoid an electric shock (absolute stimulus) conducted through the basal cage immediately after the acoustic signal (conditional stimulus) by jumping on a vertical insulated rod. The inhibition of the conditioned reaction in 50% of the animals during the six-hour observation is determined with the para-35 meter ED ^ -g BCR, the inhibition of the absolute reaction with the parameter ED1q BUR.

5 70015

Spiroperidol binding assay (in vitro)

In vitro experiments used calf brain streak as a β-receptor, literature: Creese et al., Life Sci. 17 (1975) 9937 and incubated with 1H-spiroperidol according to the methods described by Fields et al., Brain Research 3-536 (1977) 578. A computer program was used to determine, in triplicate, IC 50 g from four different concentrations, giving the concentration of test substance at which 50% cleavage of β-H7-spiro-peridol binding to the receptor occurs. 10 The following Table A summarizes some of the trials tested: 6 70015

Table A

Compound Climbing the column.Spiroperidol- BCR_BILE_ Binding ED50 α · Ρ · edio ϊ · Ρ · IC50 (nano-mo “5 ______ (mcf / kq) _Lmg / kg.) _ 1 aarine.n) _ ras-1 - /" (9a / (H) -7β- (fluorophenyl) octahydro-2H-quinolizin-20C-yl-7-5-bromo-2-benzimidiazolinone HCl 0.08 0.1 3.8 ras-1- "(9α / 2H) -7 / 3 * (of chlorophenyl) octahydro-2H-quinolizin-2-yl] -5-iodo-2-benzimidiazolinone · HCl 0.1 0.055 8.6 ras-1 - [(9α / 3H) -7β- (fluorophenyl) octahydro-2H-quinolizin-20i-yl] -5-cyano-2-benzimidiazolinone-HCl_0f 65_1_42_5J3_ ras-4-amino-5 -Chloro-N - [(9a) 1H-7β- (o-chlorophenyl) octahydro-2H-quinolizin-2H-yl] -o-anisamide 12.5 12.5 30 ras-N - [(9,3H) -7β- (o-chlorophenyl) octahydro-2H-quinolizin-2H-yl] -5- (ethylsulfonyl) -o-anisamide 10.0 10, 0 135 ras-N - [(9α) 1H-7- [3- (o-chlorophenyl) octahydro-2H-quinolizin-2 * -yl] -7-p-fluorobenzamide 12.0 5.5 67 35 7 70015

The compound climbs the column. Spiroperidol- BCR_BUR binding to ED, _0 i.p. ED5q ϊ · Ρ · (nano-mo- (mg / kg) (mg / kg) linear 5__ ras-N- [9a / 1H) -7 / N- (o-chlorophenyl) octahydro-2H-quinolizine-2> N-yl-cyclopropanecarboxamide 6.0 5.5 550 10 ras-N - [(9a /> H) -7H- (o-chlorophenyl) octahydro-2H-quinolizin-2 * L-yl ' 7-2-thiophenecarboxamide 18.0 25.0 123 ras-NZ "(9a / .H) -7Λ- (o-chloro-15-phenyl) octahydro-2H-quinolizin-2-yl] -2-oxo- 1-pyrrolidinecarboxamide 23.0> 30 ras-7 (9a / 1H) -1- (o-chloro-20-phenyl) octahydro-2H-quinolizin-2c * -yl] -p-fluorophenyl ketone 3, - 0 3.0 11

The compounds of formula 1 'can be used as medicaments in the form of racemate 25 or enantiomers as well as in the form of free bases or acid addition salts.

In said pharmaceutical preparations, the dosage may be between about 0.5 and 100 mg. When administered orally, the amounts of active ingredient are between n.

30 0.05 mg / kg to about 10 mg / kg per day and when administered parenterally at doses between approx.

0.01 mg / kg to 1 mg / kg per day in question.

S 70015

Example 1 a) To a solution of 4.80 g of ras- (9 (phenyl) -N- (o-fluorophenyl) octahydro-2- (2-amino-4-iodoaniline) -2H-quinolizine in 80 ml methylene chloride, 3.0 g of N, N1-carbonyldiimidazole (93%) was added and stirred at room temperature overnight. The precipitated reaction product was filtered off after 20 hours, washed with 3 x 100 ml of methylene chloride and then dried. Crystalline ras-1- (9a) (H) -7 / 1- (o-fluoro-10-phenyl) octahydro-2H-quinolizin-2H-yl] -5-iodo-2-benzimidiazolinone was obtained. Sp. 271-274 ° C. The hydrochloride melts 26 5-26 at 7 ° C.

When, instead of ras- (9a / 5H) -7 / 7- (o-fluorophenyl) octahydro-2α- (2-amino-4-iodoaniline) -2H-quinolizine, the correspondingly substituted phenyldiamines are reacted with N, N- carbonyldi-diimidiazole, the following products are obtained: ras-1 - [- (9a / 3H) -11- (Ra) octahydro-2H-quinolizin-2-yl] - (B) -2-benzimidiazolinone: 20

Sp. ° C

R = o-fluorophenyl B = 5-bromo 296-299 (HCl salt) 3.

o-fluorophenyl B = 5-ethoxycarbonyl 277-280 (HCl salt) 25 o-fluorophenyl B = 5-cyano> 300 (HCl salt) o-fluorophenyl B = 5-sulfamoyl 290-295 (base) b) The ras- (9α, H) -7β- (o-fluorophenyl) octahydro-2x- (2-amino-4-iodoaniline) -2H-quinolizine used as starting material in Example 1a can be obtained as follows: 5.1 g ras- PH 9a) -JS- (o-fluorophenyl) octahydro-2d- (2-nitro-4-iodoaniline) -2-H-quinolizine is heated in 100 ml of methanol, 2.0 ml of concentrated hydrochloric acid. With 5 acids and 1.75 g of iron powder for 4 hours under reflux. The reaction mixture is then partitioned between 0.5 N NaOH and chloroform. The chloroform extracts are dried over anhydrous sodium carbonate and then evaporated.

5 Ethanol / n-hexane crystallizes from ras- (9α, 1 H) -7β- (o-fluorophenyl) octahydro-2 - [(2-amino-4-iodoaniline) -2H- kinolit-toxin. Sp. 106-110 ° C.

In a similar manner, ras- (9a / 3H) -7β- (o-fluorophenyl) octahydro-2- (2-amino-4-bromoaniline-10-yl) -2H-quinolizine can be prepared, m.p. 153-155 ° C, and the like

4-carbonitrile m.p. 190-193 ° C

4-sulfonic acid amide m.p. 226-228 ° C

4-Carboxylic acid ethyl ester m.p. 149-156 ° C

c) The ras- (9a / 3H) -157/3 - (o-fluorophenyl) octahydro-2X- (2-nitro-4-iodoaniline) -2H-quinolizine used as starting material in Example Ib can be obtained as follows: 7.5 g of ras- (9α- (3H) -7/3 - (of fluorophenyl) -2α- (amino) -octahydro-2H-quinolizine are dissolved in 75 ml of cyclohexanol (99%), 6.40 g are added. sodium carbonate 20 (anhydrous) and heated to 160 ° C. At this temperature, a solution of 9.2 g of 2-chloro-5-iodo-nitrobenzene in 75 ml of cyclohexanol (> 99%) is added dropwise over three hours. The reaction solution is then kept at 160 ° C for a further 14 hours. After cooling to room temperature, the inorganic residue is separated off and the filtrate is evaporated in vacuo. The evaporation residue is dissolved in 80 ml of hot ethyl acetate and 100 ml of methylene chloride, 2 g of activated carbon are added and the mixture is refluxed for five minutes. It is then filtered hot and the filtrate is evaporated to 100 ml. In this case, ras- (9a <3H) -7/3 - (o-fluorophenyl) octahydro-20 ° C- (2-nitro-4-bran-aniline) -2H-quinolizine crystallizes. Sp. 175-177 ° C. Chromatography of the mother liquor on 150 g of silica gel using n-hexane / diethyl ether 2: 1 gives more product.

35 If, instead of 2-chloro-5-iodo-nitrobenzene, correspondingly substituted o-chloro-nitrobenzenes are used, 10 7001 5 the following products are obtained:

Sp. ° C

R = o-fluorophenyl B = 2-nitro-4-bromoaniline 175-177 a 2-nitro-4-ethoxycarbonyl 135-140 2-nitro-4-cyano 215-219 2-nitro-4-sulfamoyl 235-237 d) The ras- (9α) H) -7β- (o-fluorophenyl) -2α- (amino) octahydro-2H-quinolizine 10 used in Example 1e as a starting material can be obtained as follows: 84.3 g of ras- (9a (H) -7R- (o-fluorophenyl) octahydro-2H-quinolizin-2-one is heated under reflux in 1700 ml of methanol with 47.4 g of hydroxylamine hydrochloride and 94.3 g of potassium carbonate (anhydrous) for 1.5 hours. The methanol is then distilled off and the residue is partitioned between 750 ml of water, 600 ml of chloroform and 150 ml of isopropanol. The aqueous phase is extracted twice with 250 ml of a mixture of 200 ml of chloroform and 50 ml of isopropanol, the combined organic phases are dried over magnesium sulphate and then evaporated. 85.3 g of oxime are obtained, which is dissolved in 1.5 l of tetrahydrofuran, 0.5 l of ethanol and 1 l (5% g / g of ammonia in ethanol) and hydrogenated with 45 g of Raney nickel for 30 hours. time (at room temperature-25, atmospheric pressure). The catalyst is then filtered off and the filtrate is evaporated. 53.5 g of ras- (9a / 3H) -7 / 3- (of fluorophenyl) -2c- (amino) octahydro-2H-quinolizine can be crystallized from the residue by dissolving in 400 ml of ethanol and adding 130 ml of 5N hydrochloric acid in ethanol. the dihydrochloride salt. Sp. 299-302 ° C. The diastereomeric ras- (9H-H) -7β- (o-fluorophenyl) -2 (amino) octahydro-2H-quinolizine is dissolved in the mother liquor as the dihydrochloride.

When ras- (9a H) -7/3 - (of fluorophenyl) octahydro-35 is substituted instead of 2H-quinolizin-2-one as correspondingly substituted quinolizides, the following products are obtained: 11 7001 5 ras- (9aβ H) -7 A - ( R_) -2 ° C - (amino) octahydro <-2H-- • a quinolizine: R = o-chlorophenyl M.p. ° C (.2HCl): 293-296 ae) The ras- (9a / ^ H) - 5,7- (o-Fluorophenyl) octahydro-2H-quinolizin-2-one can be obtained as follows: 76.2 g of methyl ras- (LocH, 9a / 3h) -7H- (o-fluorophenyl) ) octahydro-2-oxo-2H-quinolizine-1-carboxylate is dissolved in 1,2 Isaac of 4N hydrochloric acid and refluxed for seven to 10 hours. The cooled reaction solution is then poured onto ice and basified with concentrated NaOH. Extraction with 3 x 500 ml of methylene chloride and evaporation of the magnesium phase-dried organic phase gives 68 g of crude product. Ras- (9a / 3H) -7/3 - (o-fluorophenyl) octahydro-2H-quinolizin-2-one can be crystallized from ether-hexane. Sp. 74-76 ° C.

When decarboxylation of equimolar amounts of correspondingly substituted β-ketoesters is carried out instead of methyl ras (10H, 9a / AH) -β, - (o-chlorophenyl) -octahydro-2-oxo-2H-quinolizine-1-carboxylate, the following products are obtained: ras- (9a / 3 H) -Ίβ - (R &) octahydro-2H-quinolizin-2-one:

Sp. ° C

Ra = phenyl 71-72 p-chlorophenyl 80-82 25 p-trifluoromethylphenyl 103-104 o-methylphenyl IR (film 1726 cm-1 m-methoxyphenyl IR (film) 1726 cm-1 2,4-dichlorophenyl 116-117 2,6- dichlorophenyl 116-118 o-chlorophenyl f) The octahydrocarboxylate used as starting material in Example 1e can in turn be obtained from the corresponding hexahydrocarboxylate as follows: 180 g of methyl ras-7- (o-fluorophenyl) -3,4,5,6, 7.8-35 hexahydro-2-oxo-2H-quinolizine-1-carboxylate is suspended in 3.6 l of monoglyme (dimethoxyethane), cooled to -30 ° C and added with stirring 1.33 1 DIBAH (diisobutylaluminum hydride, 20%, solution in toluene). It is then stirred for one hour at -20 to -30 [deg.] C. and then hydrolysed at this temperature to 1.72 l of 2N5N5 NaOH. For pre-treatment, partition between 25 l of water and 20 l of chloroform; the organic phase is washed with a further 2x5 l of water, dried over magnesium sulphate and evaporated. The crude product is crystallized from ether / hexane. Chromatography of the mother liquor on 1 kg of silica gel with vinegar-10 ester gives even more product. Methyl ras- (1α, 9α and 3 H) -7/3 - (o-fluorophenyl) octahydro-2-oxo-2H-quinolizine-1-carboxylate is obtained, m.p. 109-110 ° C.

When methyl ras-7- (o-fluorophenyl) -3,4,5,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate is reduced to equimolar amounts, respectively, imported dyts DIBAH, the following compounds are obtained:

Methyl ras- (laqC H, 9apH) -7β- (Ra) octahydro-2-oxo-2H-quinolizine-1-carboxylate:

20 mp ° C

Ra = phenyl 114-116 p-chlorophenyl 102-105 p-trifluoromethylphenyl 108-111 o-methylphenyl 94-98 25 m-methoxyphenyl IR (film): 1752.1723.1660 cm -1 2,4-dichlorophenyl 116-118 2, 6-Dichlorophenyl 130-131 o-Chlorophenyl 122-124 g) The hexahydro-30-carboxylate used as starting material in Example 1f can in turn be obtained as follows: 150 g of 5- (o-fluorophenyl) -2-piperidone are dissolved in 2 l of methylene chloride and 410 g are added dropwise. to triethyl oxonium tetrafluoroborate (Meerweinsalz, sea wine salt) in 1 L of methylene chloride at room temperature with stirring for 35 minutes. It is then refluxed for four hours and allowed to stand for a further 15 hours at room temperature. 372 g of potassium carbonate in 370 ml of water are then added dropwise to the solution cooled to 0 [deg.] C., with vigorous stirring. After stirring for a further two hours at room temperature, the methylene chloride phase is then decanted off and the residue is extracted with 2 x 500 ml of methylene chloride. The methylene chloride phase, dried over potassium carbonate, is evaporated to an oily, partially crystalline residue, then boiled in 1 l of hexane and filtered hot. After evaporation of the hexane, the oily lactim ether is obtained: 3- (o-fluorophenyl) -6-ethoxy-2,3,4,5-tetrahydropyridine.

The lactim ether is dissolved in 1.4 l of methanol, 1.3 g of anhydrous p-toluenesulfonic acid are added and then 85 g of 3-oxo-5-pentenoic acid methyl ester (Nazarov's reagent) are added over 60 minutes. After 20 hours at room temperature, the volatiles are removed in vacuo, the residue is then taken up in methylene chloride and washed with a total of 500 ml of sodium carbonate solution. The methylene chloride phase dried over magnesium sulphate is evaporated again and the residue is crystallized from ethyl acetate / ether = 4: 1 (800 ml). Methyl ras-7- (o-fluorophenyl) -3,4,5,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate is obtained. Sp. 165-167 ° C.

When equimolar amounts of correspondingly substituted piperidones are used instead of 5- (o-fluorophenyl) -2-piperidone, the following compounds are obtained:

Methyl ras-7- (R) -3,4,5,6,7,8-hexahydro-2-oxo-α 2H-quinolizine-1-carboxylate:

Mp. ° C

30 R = phenyl 148-149 cl p-chlorophenyl 185-187 p-trifluoromethylphenyl 144-145 o-methylphenyl 183-184 m-methoxyphenyl 133-134 35 2,4-dichlorophenyl 153-155 2,6-dichlorophenyl 159-162 o -chlorophenyl 145-147 14 7 0015

Example 2 0.3 90 g of ras-1- [4- (1H) -7R- ((fluorophenyl) octahydro-2H-quinolizidin-2H-yl] -5-cyano-2-benzimidazolinone dispersed in 10 ml of dry monoglyme, 0.058 g of sodium hydride (50-60% in mineral oil) is added to dispersion 5 and the mixture is stirred for one hour at room temperature, then the mixture is cooled to 0 [deg.] C. and 0.142 g of methyl iodide in 10 ml of dry monoglyme are added. The mixture is allowed to stand for 90 minutes at room temperature, then poured into 25 ml of water and extracted with chloroform, the organic phase is dried over magnesium sulphate and concentrated, and the crude product obtained is chromatographed on a silica gel column using ethyl acetate as eluent to give ras-1. -7/3 - (o-fluorophenyl) octahydro-2H-quinolizin-2-yl-3-yl] -3-methyl-5-cyano-2-benzimidazolinone, yield 47%, mp 212-213 ° C (base).

Example 3

A mixture of 0.300 g of ras-1 - [. (9a / 3h) -7R] - (of fluorophenyl) octahydro-2H-quinolizin-2 (PC-yl) -5-cyano-2-20 benzimidazolinone and 1, 0 g of phosphorus pentasulfide in 5 ml of dry pyridine, heated for 3 hours at 150 [deg.] C. The reaction mixture is then evaporated to dryness and the residue is partitioned between 2N aqueous sodium hydroxide solution and chloroform-soluble portions. The crude product obtained is chromatographed on a silica gel column using a 1: 1 mixture of ethyl acetate and n-hexane as eluent to give ras-1- [9a, OH) -7A- (o-fluorophenyl) octahydro-2H-quinolizin-30 ° C]. 7-5-cyano-2-benzimidazoline thione, yield 32%, m.p. 310-315 ° C (base).

Example 4

A solution of 0.365 g of ras- (9α, 3H) -7β- (o-fluorophenyl) octahydro-2. - (2-amino-4-cyanoanilino) -2H-quino-35 lysine in 10 ml of dry methylene chloride and 0.25 g of N, N-thiocarbonyldiimidazole are stirred overnight at room temperature. The next day, the reaction mixture is cooled for one hour in an ice bath. The precipitated reaction product is collected by filtration, washed twice with 5 ml of cold methylene chloride and dried. 5 ras-1 - [(9α / bH) -7β- (o-fluorophenyl) octahydro-2H-quinolizin-2H-yl] -5-cyano-2-benzimidazoline ion is obtained, yield 74%, mp 310-315 ° C (base) ..

The same product is obtained if thiophosgene or carbon disulphide is used instead of N, N'-thiocarbonyldiimidazole.

Example 5 70 g of ras-1-ZT (9apH) -7 / 3- (o-fluorophenyl) octahydro-2H-quinolizin-2 ° C-yl] -2-oxo-5-benzimidiazoline carboxylic acid ethyl ester hydrochloride are boiled in 500 ml: 11a 5N hydrochloric acid at reflux for 96 hours. It is then cooled to 0 [deg.] C., the reaction product is filtered off with suction, the residue is washed with 3 * 100 ml of water and dried under high vacuum. Ras-1-ZiOapHO- (trans-fluorophenyl) -octahydro-2H-quinolizin-20 (1-yl) -2-oxo-5-benzimidiazoline-carboxylic acid hydrochloride is obtained, mp 285-295 ° C.

Claims (4)

7,001 5 16 A process for the preparation of novel therapeutically useful phenylquinolizinylbenzimidiazolinone and thione derivatives of the general formula 1 ', "R" (0 <X £> X / \ „5 4 RR 2 3 15 wherein X is hydrogen or fluorine, R is oxygen or sulfur, R is hydrogen or lower alkyl and one of R and R is hydrogen and the other is bromine, iodine, cyano, lower alkoxycarbonyl or sulfamoyl, racemate or enantiomers or in the form of acid addition salts of such compounds, characterized in that the phenylenediamine of the general formula VIII is condensed, wherein X, R 1 and R 2 have the same meaning as above, with a cyclizing agent of general formula IX, R 2 Rb-C-RC (IX) K n 35 wherein R and R represent halogen or 1-imidazolyl and R is as defined above, or with carbon disulfide, 17 7001 5 if desired N- alkylating the resulting compound of general formula IV-8, HH 2 5 H ^ 1 1 A. .J! IN NH (IV - 8) tsf ........ '@ 10. R5 / R4 2 4 5 wherein X, R, R and R have the same meaning as above and and if desired a compound of general formula IV-6 is obtained, 15 H H | H ^ '' N XN-R3 (IV-6) 'Ί N / \ 20 r / "- /" -> - <0 Ώ X RS / V 3 5 where X and R -R have the same meaning as above, react 25 P 2 SO 2, and then the racemate obtained is optionally cleaved and the bases obtained are optionally converted into acid addition salts. A process according to claim 1 for the preparation of ras-1- (19a (H) -1β- (fluorophenyl) octahydro-2H-quinolizin-2H-γ-η 5 -5-bromo-2-benzimidazolinone acid of the racemate or enantiomers or of such compounds. in the form of addition salts, characterized in that correspondingly substituted starting compounds are used. A process according to claim 1 for the preparation of ras-1- 35 ['(9a) 1H-β- (fluorophenyl) octahydro-2H-quinolizin-2-yl] -5-iodo-2-benzimidazolinone racemate or in the form of acid addition salts of enantiomers or of such compounds, characterized in that correspondingly substituted starting compounds are used. A process according to claim 1 for the preparation of ras-1 -, ([9a / bH) -7β- (fluorophenyl) octahydro-2H-quinolizin-2H-5-cyano-2-benzimidazolinone racemate or in the form of acid addition salts of enantiomers or of such compounds, characterized in that correspondingly substituted starting compounds are used. 19 7001 5