CS222700B2 - Method of making the phenylchinolizidine - Google Patents

Description

The Fernicinoisidines produced according to the invention are compounds of formula I

(I) in which:

X is hydrogen, fluoro, chloro, (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl or C 1 -C 6 alkyl; trfUluLormrtySovsu group,

Y is hydrogen, fluoro, chloro, (C1-C6) alkoxy or (C1-C6) alkyl,

5, one of the radicals R and R ^x is hydrogen and the other is bromo, iodo, kyanostopinu alkoxy · 'carbonyl quick match with 1-6 carbon atoms in the alkoxy Casio or sulfonate methylpropylcarbamoyl group, in racemic form or ehantiomerů, and acid addition salts of such compounds with acids. As shown in formula I and in the various subsequent formulas, the hydrogen atoms at positions 7 and 9a and 7 and 2 respectively are in trans with respect to each other, and in the formulas, the hydrogen atoms at position 9a and at position 2 are intentionally indicated at β and atom. The quinolizidines of the invention, as well as the corresponding intermediates and starting materials are not limited to this absolute configuration, but also include the corresponding enantiomeric forms, i.e., the compounds having hydrogen at the 9aa, 2a and 7β position. as well as the racemates of both enantiomeric forms.

In the context of the present invention, alkyl groups having 1 to 6 carbon atoms or alkoxy groups are understood to be those groups having 1 to 6, in particular 1 to 4, carbon atoms, wherein the groups having 3 or more carbon atoms may be straight or branched.

Suitable acid addition salts of the phenylquinolizidines according to the invention are pharmacologically compatible salts with the inorganic and organic acids customarily used for salt formation. Examples of such acids include mineral acids such as sulfuric acid, nitric acid, phosphoric acid, hydrohalic acid, for example hydrochloric acid, hydrobromic acid; organic acids such as tartaric acid, citric acid, aliphatic or aromatic sulfonic acids, maleic acid, mandelic acid, etc. The salt formation can be carried out in a manner known per se.

The compounds of formula I are neuroleptically active substances.

Particularly preferred for their pharmacological activity are compounds of formula I wherein X is hydrogen and Y is o-chloro or o-fluoro.

Particularly preferred compounds for neuroleptic activity are:

γ-1 - [(9ββΗ) - β- (o-fluorophenyl) octahydro-2H-quinolizin-2α-yl] -5-bromo-2-benzimidazolinone; -fluorophenyl) octahydro-2H-quinolizin-2a-yl] -5-iodo-2-benzimidazolinone, [eta] < 1 > -1- [((9apH) -7 [beta] - (o-fluorophenyl) octahydro-2H-quinolin-2a-yl)] -5-Cyano-2-benzimidazolinone.

Phenylquinolizidines of the formula I according to the invention are produced by a process characterized in that the phenylenediamine of the formula VIII is condensed

(VIII) in which:

5

X, Y, R and R are as defined above, with the cyclizing agent of formula IX *

R ^b -CR ^c wherein (IX) and R ^c are halo, amino or 1-imidazolyl, whereupon. the racemates obtained are optionally resolved and the bases obtained are optionally converted into acid addition salts.

Said reaction can be carried out by known methods · As cylk-izační reagent IX can be used, for example phosgene, karbornldiimldazol or močooina · Method according ^- VYN & cut with special ^d navbox suited ^P ro výroto composites of formula I therein ^{R 4} and R have different meanings ·

The racemates obtained can be resolved into optical antipodes by methods known per se. The bases obtained, also according to conventional methods, are convertible to their corresponding acid addition salts.

The compounds referred to below as intermediates or as starting materials, if not known, are produced by methods known per se.

The phenylenedismin VII used above is obtained by reaction of the primary amine V

(V) in which

X and Y are as defined above

Q is a primary amino stopin, with an appropriately substituted o-halonitobeenzene, preferably a derivative of o-halo- or 1-fluoro-benzene, and reduction of the nitro group to an aminostopine, for example with hydrochloric acid and iron powder.

The primary amines of formula (V) used can be obtained in a manner known per se by oximation of the ketone

(X) wherein

X and Y have the above-mentioned meanings by the action of the hydrolylamine-tyridone and the reduction of the yielding oxime to the amine by hydrogenation with a noble metal catalyst such as 860. The preferred diastereoisomeric mixture can be obtained from the mixture of diastereoisomers obtained. The amine of formula (V) may be separated by separation or may also be obtained by fractional crystallization of the appropriate addition salts (e.g., thioociools).

The ketone of formula (X) on the one hand can be obtained by decoding the β-to-este of formula (XI) by relative convergence to positions 1, 7 and 9a shown in this formula

(ГС) in which

X and Y have the same meaning as above and

^And R represents a lower alkyl group (see. E.g., Example 1a).

On the other hand, the O-ketoesters of formula XI can be obtained from the corresponding unsaturated β-ketoesters of formula I

(m) in which:

X and R ^{γ and} maai stej ^ n Jato ^{Y are as} defined above, in a known manner hydro ^g ENAC (see. E.g., Example FF).

Esters of formula XI can be obtained from the corresponding 5-phenyl-2-piperidones optionally substituted in the phenyl moiety by methods known per se (cf., for example, Example 1g).

The fernychinoisidines of the formula X according to the invention possess valuable pharmacological properties. They are newroleptic and can be used as antipsychotics in an anti-psychotic way to combat psychoses and nemroses.

The non-eoepeptic properties of the compounds were ascertained in numerical values by poNo! the tests described below:

Test. Pole Climbing (rat)

To perform the experiment, a group of 10 rats were used per dose, which were trained to jump on a vertical isolated rod in the experimental cage immediately after the acoustic signal (conditional reflex) to avoid the electric shock (unconditional reflex). ) from the grid bottom. The rotation of the conditioned reflex in 50% of the animals during the observation period of 6 hours is determined by the ED 50 BCR value, the suppression of the unconditional reflex by the value ED 10 BUR.

Spiroperidol Binding Assay (in vitro)

In in vitro experiments, the calf striatum (drug: Creese et al., Life Sci. £ 7, 993 (1975)) is used as the receptor and incubated in an analogous manner according to methods which have been used.

222700 Pisum Fields et al, Brain Research, 136. 5 ⁷⁸ (1 ⁹⁷⁷⁾ with a PLD-spiroperidol. Progrmem computer determined from 4 different konccetrací in triplicate embodiment, the IC 50 value, which indicates konceenraci test substance at which 50% of binding oddděení speeifické E ³ H] -S ^p iro ^p er ^ID ol receptor.

Table A summarizes some of the results of the experiments.

Table A

Compound Pole-Climbing Binding ipirlperidllž BCR BUR ED50 i.p. (IU / kg) ^{0 i} · ^p . (mg / kg) (Nano Aania $ ^m) rac-1- [phen ^y l) lktahydro-2H-ilhitl- bonds · - ^- ^ ^-) -5-Br <m-2 ^b enz- iuidazolinlt. HCl 0.08 0.1 3.8 rac-b - [(4-O) 0-7-O- (4-phenyl) -octahydro-2H-di-quinolin-2α-yl-5-yl] -benzimidazolyl. HCl 0.1 0,055 8.6 rac-1 - [(93 (110) -7--0- (R, R) -phenyl) -ctahydro-2H-ihlityl] -2-p-2-en-5-yn-2- be nz ^ 5 ^ 201 ^^. HCL 0.65 1.0 50

The compounds of the formula I according to the invention in the form of the racemate or enantiomers as well as in the form of the free bases and of the acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions or suspensions. Administration can also be effected rectally, for example in the form of suppositories, topically or percutaneously, for example in the form of maize, cream, jelly, solutions, or porenterally, for example in the form of injectable solutions.

In order to produce tablets, coated tablets, dragees and hard gelatin capsules, the compounds of the invention may be admixed with pharmaceutically inert, inorganic or organic carriers. As such, for example, lactose, corn starch or derivatives thereof, talc, tartaric acid or its salt can be used for tablets, dragees, hard gelatin capsules, etc. For soft gelatin capsules, for example, oils, waxes, fats, and polyol etc., according to U.S. Pat. however, no carrier substances are required at all in soft gelatin capsules. Water, polyols, scchorose, invert cuar, glucose and the like are suitable as carriers for the preparation of solutions of syrups. For injectable solutions. suitable as carrier substances, for example, water, alcohols, polyols, glycerin, oil, etc. For suppositories c for topically or percutaneously applicable dosage forms, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols are suitable as carriers. .

The pharmaceutical compositions may additionally contain preservatives, co-solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, reinforcing agents, oscillating pressure agents, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable substances.

and

In the aforementioned pharmaceutical preparations, the dosage of active ingredient may be in the range of 0.5 to 100 mg. For oral administration, the amount of active ingredient may be from about 0.05 mp / kg to about 10 mg / kg per day and in the case of parenteral administration. application rates of active compound from about 0.01 mg / kg to 1 m 2 / kg per day are contemplated.

Example!

(a) To a solution of 4,80 g of rac- (9apH) -7β- (f-flusulfonyl) octEhydro-2α- (2-amine-4-iodo) -2H-quinoisoine in 80 ml of meaylene chloride is added 3.0 g of N, N * -carbonyldiimidazole (93%) and the reaction mixture was stirred overnight at room temperature. The precipitated reaction product is filtered off after 20 hours, washed three times with 100 ml of methylene chloride each time and then dried. Z ⁱ with the ^Ka ^ stallcký rac -1- ^[(9 řβH) -77- ^{(o f} e ^f1 usr ^nl l) ^to move Όs2 ^{LD with} a ^{2-quinolinyl from} no2α ^{yl-L-5-jo d} -2-beosimidazoline. Melting point 271-274 ° C. Hrddoolhoride melts at 265-267 ° C.

· If instead of rac- (9aaн) -7β- (o-fluorfeoll) oktaaldrf (2 (and ((2-aminco4 jodda0i of ^a) -2H-quinolizine nechaaí respond appropriately substituted phenyl n ^ © mines with N> ^N * carbon ^ l <^ i ^ imidazolsm, then the following products are obtained:

rac-1 - [(9ββΗ) - 7β- (()) sctahroso22-cCanolizine- (2? e-11) - (B) -2-ienzime ^from dazolioso: "and (B) Melting point (° C) s-flusrfeoll 5-bromo 296 to 299 (hldrschaorld) s- (flusrfeoll 5-ethoxycarbonyl 277 to 280 (Hydrochloride) s-flusrfeoyl 5-cyano > 300 (Hydroclhoride) s-fluorophenL 290 to 295 (base)

b) rac- (9apH) -7H- (s-trifluorophenyl) octehydrs-2 (e- (2-amino-4'-idanoyl) -2H-chanosizio as used in Example 1a) can be obtained as follows:

5.1 g of rac- (9apH) -7β- (o-fluorophenyl) octa- ^d 22s-22- (22nOtrs-4-jsdan01iro) -2H-caioolizine is inhaled in 100 ml of methanol, 2.0 ml of concentrated hydrochloric acid and 1.75 g of iron powder for 4 hours at reflux. The reaction mixture was then partitioned between 0.5 N sodium hydroxide solution and chloroform. The chloroform extracts were dried over anhydrous sodium carbonate and then evaporated. Rac- (9apH) -7β ^, ((s (fuofuoyl) octaaldrs-21e ((2-emonos-4-indole)) -2H-chancoisin) crystallizes from a mixture of ethanol and n-hexane ^, m.p. 106-110 ° C.

Similarly, rac- (9aβH) -7β- (s-fuusffer1LL) ocealvdrs-2- [2- (2-methyl-4-iromanilol)] (2H-chancoisin), m.p. 153-155 ° C, can also be produced.

4 · (ka? Bio0ttll t. t.: : 190 to 193 Noc: 2 ° C 4-SulfonEmad t. t .: : 226 to 228 Noc: 2 ° C 4-Ethyl carboxylic acid ester t. t .: : 149 to 156 Noc: 2 ° C

c) rac- (9ββ) -7β- (o -fluorenyl) octahydro-4α- (2-nitro-4-i (4-iodo) -2H-chanosines), which is used as starting material in Example 1b), can be obtained as follows:

Dissolve 7.5 g of rac- (9aaH) -7β- (s-fuusrfθ1 ^, yrl) (22 ¢ - (amino) octra-2H-chanoSiziou) in 75 ml of cyclohexanol (99%), add 6.40 g of sodium carbonate ( The mixture was heated to 160 [deg.] C. At this temperature, a solution of 9.2 g of 2-calsr-d-O-dithiode in 75 ml of cyclohexanol (more than 99%) was added dropwise over 3 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo, dissolved in 80 ml of hot ethyl acetate and 100 ml of methylene chloride, 2 g of active OHi were added and the mixture was stirred at room temperature for 16 hours. After refluxing for 5 minutes, the mixture is filtered while hot and the filtrate is concentrated to a volume of 100 ml. Rac- (9ββ) -7β- (o-fluorophenyl) octahydro-2α- (2-nitro-4-bromonnilino) - 175 DEG-177 DEG C. Chromatography of the mother liquor to 150 g of SiH2, eluting with n-hexane / diethyl ether 2: 1 gives the title compound as a white solid. another product.

When appropriately substituted o-chloro nitrobenzenes are used in place of 2-chloro-5-hydroxybenzene, the following products are obtained:

^B a (B) Melting point (° C) o-iluorfenyl 2-nitro-47bromahrlinc 175 to 177 o-fluorophenyl 2-nitro-4-thiocarbonyl 135 to 140 o-fluorophenyl 2-nitro-4-thyane 215 to 219 o-fluorophenyl 2-ni tro-suufamoyl 235 to 237

d) rac- (9apH) -7β- (o-fluorophenylYr 1) -2a- (nino) octalxydro-2H-quinolizine which is used as starting material in Example 1c) _K can be obtained as follows:

84.3 g of rac- (taaH) -77- (10-fluorophenyl) octahydroxy-2H-chlorizin-2-one are heated in 1700 mm mmole of potassium carbonate with 47.4 g of potassium hydrogen carbonate and 94.3 g of potassium carbonate. (anhydrous) for f 1/2 hour under a reflux condenser. The meeanol was then distilled off and the residue was partitioned between 750 ml of water, 600 ml of chloroform and 150 ml of propanol. The aqueous phase is extracted twice more with 250 ml of a mixture consisting of 200 ml of chloroform and 50 ml of propanol each time, all the organic phases are combined and dried over magnesium sulphate and then evaporated. 85.3 g of oxime are obtained, which is dissolved in 1.5 liters of tetrahydrofuran, 0.5 liters of ethanol, as well as IVf of a 5% [g / g] solution of ammonia in ethanol and added with 45 g of Raney nickel for 30 hours. The catalyst is hydrogenated (at room temperature and at atmospheric pressure). Then the catalyst is filtered off and the filtrate is drawn. From the residue, other portions (53.5 g) of crystalline oac- (9aF) -7β- (2HH7 (6O)) can be obtained by dissolving in 400 ml of Stand and adding 130 ml of 5N ethanolic HCl. Lnn in the form of dihydrochlorides, m.p.

If, instead of rhC7 (thβH) -7βo10-flscrferdl, octahdd.rc7-H-ceinoCin-i-ors, amine is appropriately tubed, chiroCidir.cry is obtained, then the products are obtained:

rac-t (βH) -7βf (Rh) 7 -h- (hiinr) (ω 6 -derin72-quinrl) .zir:

Ra = O) c. mp: ° C (2 HCl): 293-296 ° C

e) ^ (- (9 (()) - 7 ((- (0-11 ^^ (0171)) (: ^ 31317010 (724-71100111,10-2-one used in example hd)) as starting material , can be obtained as follows:

76.2 g ^ y Mee-raccC 1f H, 9tβH) -7β- (ocfluscfen _I rl) · CK thhyero - 2-7oo-C7-cH.inilrzinr1Lckarbo 4У "is rczauutí acrylate in 1.2 liters of 4N hydrochloric acid and the reaction solution was refluxed for 7 hours. The cooled reaction solution was then poured onto ice and the mixture basified with concentrated sodium hydroxide solution. Extraction three times with 500 ml of methylene chloride and evaporation of the organic phase dried previously with magnesium sulphate yielded 68 g of sulfur product. From a mixture of swab and hexane, m.p. 74 DEG-76 DEG C. may be crystallized.

222700 8

When, instead of methyl rac- (1 _and H, 9apH) -7β- (o-chlorophenyl) octahydro-2-oxo-2H-quinolizine-1-carboxylate, an equimolar amount of the appropriately substituted β-ketoester is used and decarboxylated, the following products:

rac- (9a |] H) -7p- _(Ra) ~ octahydro-2H-quinolizine-2-one:

^B a Melting point (° C) phenyl 71 to 72 p-chlorophenyl 60 to 82 p-trifluoromethylphenyl 103 to 104 o-methylphenyl IC (film) 1,726 cm ’ m-methoxyphenyl ID (film) 1,726 cm ’ 2,4-dichlorophenyl 116 to 117 2,6-dichlorophenyl 116 to 118 o-chlorophenyl 80 to 82

f) The octahydrocarboxylate used as starting material in Example 1e) can be obtained from the corresponding hexahydrocarboxylate as follows:

180 g of methyl rac-7- (o-fluorophenyl) -3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate was suspended in 3.6 liters of monoglyme (dimethoxyethane) The suspension was cooled to -30 ° C and 1.33 L of DIBAH (diisobutylaluminum hydride, 20% solution in toluene) was added with stirring. The reaction mixture was stirred at -20 to -30 ° C for 1 hour and then hydrolyzed with 1.72 L of 2N sodium hydroxide solution at this temperature. For working-up, the reaction mixture was partitioned between 25 liters of water and 20 liters of chloroform. The organic phase is washed twice with 5 liters of water, dried over magnesium sulphate and evaporated. The crude product crystallized from a mixture of ether and hexane. Chromatography of the mother liquor on 1 kg of silica gel using ethyl acetate yielded an additional crop of product. There was obtained methyl rac- (1 H, 9 p H) -7β- (o-fluorophenyl) octahydro-2-oxo-2H-quinolizine-1-carboxylate, mp Ю9-110 ° C.

If, instead of methyl rac-7- (o-fluorophenyl) -3,5,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate, an equimolar amount of appropriately substituted starting materials is used and a reduction is performed diisobutylaluminum hydride, then the following compounds are obtained:

methyl rac- (1aH, 9apH) -7β- (R _a ) octahydro-2-oxo-2H-quinolizine-1-kerboxylate:

^R a Melting point (° C) phenyl 114 to 116 p-chlorophenyl 102 to 105 p-trifluoromethylphenyl 108 to 111 o-methylphenyl 94 to 98 m-methoxyphenyl IR spectrum (film): 1,752, 1,723, 1,660 cm '’ 2,4-dichlorophenyl 116 to 118 2,6-dichlorophenyl 130 to 131 o-chlorophenyl 122 to 124

g) Hexahydrocarbooylate, which is used as starting material in Example 1f), can be produced as follows:

and

150 g of 5- (o-fluoro-phenyl) -2-piperoidine were dissolved in 2 lb of speech methylene chloride and this solution was added dropwise at room temperature over 60 minutes to 410 g of triethyoonimethylfluoroborone (Meerwein's salt) in 1 liter of methylene chloride. The reaction mixture was then refluxed for 4 hours and left at room temperature for a further 15 hours. To this cooled solution ^h oto ^ O at 0 ° C was added dropwise ^{372 g} potassium uhll eni ^ ^ o ³⁷⁰ ml of water přieemž the mixture stirred vigorously. The reaction mixture is allowed to stir for a further 2 hours at room temperature, the meeven chloride phase is separated off by decantation and the residue is extracted twice with 500 ml of mseylennchoride. The potassium-dried methylene chloride phase is concentrated to an oily, partially crystallized residue which is then taken up in 1 liter of hexane and filtered while hot. An oily lactimeter is obtained from the filtrate after evaporation of hexane:

3- (o-fuoffenl-6 - .beta.-4 -, 3,4,5-etrahydropyridine).

The lactimeter was dissolved in 1.4 liters of methanol, 1.3 g of anhydrous p-toluene-toluone acid was added, and then 85 g of 3-ooo-5-pintecloic acid methyl ester (Naza reagent) was added over 60 minutes. After 20 hours at room temperature, the easily volatile solids are removed in vacuo, the residue is then taken up in methylene chloride and treated with 500 ml of saturated sodium bicarbonate solution. The methylene chloride phase is dried over magnesium sulphate and then rotten again, and the residue is allowed to stir in a 4: 1 ether (800 ml). Give meiyt ^rtc--7 - (of'iuofieryrl) -3,4,6, ^7, 8, ^H-2 IOTH} ydro- -oos-2H - 1-ChncOizic kabOoэQt.át · m.p. 165 DEG Mp 167 ° C.

If, instead of 5- (o-fluoroethyl) -piperidine, an equivalent tubing of piperidines is used, then the following compounds are obtained:

2- (1-) 8,7- (R) -3,4,6,7,8,9-hexa-htdOs 2 -oxos 2 H-chlorosin-1-carboolate:

^R a Temperature melting point (° C) bitches! 148 to 149 1-chlorophenyl 185 to 187 p-trff lotrme tylphenyl 144 to 145 s-mθittfentl 183 to 184 m-mmetophenyl 133 to 134 2,4-Dichlorophenyl 153 to 155 2,6-dichlorophenyl 159 to 162 .o-c] h 145 to 147

and

222700 10

Example 2

TaUety for 1 tablet rac-l - ^[(9apH) -7e- ^(o fluorfenrl) oktιaf rdro ^H 2 ^{C 2} -Cl Lnol ^of zilo22-yl] -5-bromo-2-beozimirazoliooo. HCl 10.0 mg lactose 129.0 mg cornstarch 50.0 mg gelatin maize starch 8.0 mg calcium stearic acid 3.0 mg total weight 2010,0 mg

The active ingredient, lactose, maize starch and gelatin maize starch are intimately mixed together. The mixture is forced through a comminution machine and then wetted with water to form a thick paste. The wet mass is passed through a sieve. The wet granulate is dried at 45 ° C. The dried granulate is thoroughly mixed with the calcium salt of stearic acid. The gnuanuate is now compressed to tablets of 200 nm and having a diameter as! 8 mm.

Example 3

Tablets for 1 tablet ^rac-1 - ^[(9 ββΗ) -7β - ^(o-fluoro ° ^f e ^y.) octa ^ ^-2 ^ dro- W.nolizino22-yl] -5-iodo-2-beozimldazolinoo. HCl 10.0 mg laktoia 1219.0 mg cornstarch 50.0 mg gelatin maize starch 8.0 mg calcium stearic acid 3.0 mg total weight 200.0 mg

The active substance, lactose, maize starch and gelatin maize starch are mixed well together. The mixture is ground on a comminution machine and then wetted with water to form a thick paste. The wet paste is passed through a sieve. The wet granulate is dried at 45 ° C. The dried granulate is thoroughly mixed with the calcium salt of stearic acid. The granulate is now compressed into tablets having a moisture content of 200 mg and a diameter of about 8 mm.

Example 4

Rac-1 - [(9ββΗ) -7β- (o -fluorophenyl) octahrdo-22-cl ^, C.NOOOzino2α-yl] -5-bromo-2-benzimidazolinone capsule. HCl lactose corn starch talc total weight per capsule

10.0 mg

175.0 mg

30.0 mg

5.0 mg

220.0 mg

The active ingredient, lactose and corn starch are thoroughly mixed together and the mixture is comminuted in a comminuting machine. Maatek is then added to the mixture, mixed thoroughly and filled into hard gelatin capsules.

Example 5

Each 1 m capsule contains:

r ac-1 - [(9apH) - 7β - (o-fluorophenyl ein) ^and oct dihydro-2H-c ^{of C} Inn i zin-2-yl] -5-bromo-2-benzimidazolinone. HCl glucose for injection purposes water for injection purposes as needed into

0.204 mg (2% excess)

40.0 mg · 0 ml

2.04 g of active substance were mixed with 400 g of glucose was rozpussí in water for injection purposes ^ya solution čloplní water apos ^ is ^ ni ^{in law} enforcement to W volume ⁰⁰⁰ ml. . The solution ^B UN filtuuje sterile, filled into colorless amuU, nitrogen, and air was removed arnpule are closed or filled into -bezbarvých SIPH, nitrogen is removed by air ammule are closed and then 30 minutes steeriují a flowing steam or autoclave steeílují at temperatures! 120 [deg.] C.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of phenoquinoisidines of the general formula I (I) wherein: X is hydrogen, fluoro, chloro, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or Irfluoromethyl, Y represents hydrogen, fluorine, eel al ^ xy group having 1 to 6 carbon atoms or alkyl having 1 to 6 carbon Uh.íku, one of the radicals R @ ⁴ and R @ ⁵ represents hydrogen and the other is bromo, - iodo, cyano, a alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety or a sulfol moiety, in the form of the racemate or as addition salts of such compounds with acids, characterized in that the phenylenediamine of the formula VII is condensed Němž Η in which X, Y, R 6 and R 6 are as defined above, with the cyclizing agent of formula IX0 -CR ^b R ^c (IX) in which R @ ^b and R @ ^c are halo, amino or 1-imidazolyl, whereupon the racemates obtained are optionally resolved and the bases obtained are optionally converted into acid addition salts. 2. uso ^{p bb} by ^d u 1, ^the annual ^{It runs} rac- ^{1- (p} 9aβ) - ^-7 p (l ^f Olflulr ^ny l) of l ^kt Hydr-211-0 ^ 3 ^ 1- ^ ft oxazino- -yl-4-bromo-4-benzimidazolinone in the form of the racemate or enaithiomers, as well as the acid addition salts of these compounds, characterized in that the starting material is an otacrone compound of the formula TOI wherein X is -fluo Y is hydrogen R ⁴ stands for ^b rom and ^R ? means ^and leads ^to . . 3. uso ^{p bp b} ccording ODU ^{1 to} výrotté rac-s-t ^(p 9aβ) -7β- (olfluor ^{f i} l -yl) ^t LK ^ztydro-2H-l CCIN IIIn-2Z-yl] -5-boat -2-lin2imi ^d eillinonu racemate or ernaitiomerů or addition SOH of such compounds with acids vyinaZující the TM, as starting material is used a composite otocnáho ΉΙ formula ^ wherein ^χ represents the ^γ-fluo ^ ^á represents hydrogen, R ⁴ represents iodine and R 6 represents hydrogen. ^B caused by the fourth K3u ^{b 1} к productions ^{It runs} rac- ^{1- (p} 9zβ) - ^- βp (olfluor ^f l ^ny l) lktzh dro- ^{2p y l} --hini iiin- ^- α- ^yl] -5k ^to yi1- ^- - ^l enzim daillinonu ^also as racemates or enantiomers and salts adtontoh ftakových compounds with acids vyinaZující in that as starting material is used a composite of the ^{b s} ECN it ΠΙ formula ^ wherein ^χ represents l- ^f lulr ^{, γ} stands for guides R ⁴ stands for tyanosyl and ^R ? means in ^] f ^k . Severography, n. P., MOST Price 2,40 Kčs