DE3434597A1 - Novel condensed as-triazinium derivatives, a process for the preparation thereof and pharmaceutical compositions containing these compounds - Google Patents

Abstract

The invention relates to novel condensed as-triazinium derivatives of the general formula (I) <IMAGE> in which R1 denotes C1-10-alkyl or phenyl or naphthyl which is optionally substituted by one or more halogen, nitro, amino, hydroxyl, C1-4-alkyl and/or C1-4-alkoxy group(s), R2 is hydrogen, C1-4-alkyl, hydroxyl, halogen or phenyl or naphthyl which is optionally substituted by one or more halogen, nitro, amino, hydroxyl, C1-4-alkyl and/or C1-4-alkoxy group(s), R3 represents hydrogen or C1-4-alkyl, Z denotes buta-1,3-dienyl or a group of the formula (a) <IMAGE> or (b) <IMAGE> and A<-> is an anion and isomers thereof. The novel compounds of the general formula (I) have useful pharmacological properties, in particular antidepressant properties.

Description

Claims and description of new condensed as-triazinium derivatives, a process for the preparation of the same and pharmaceutical compositions containing these compounds middle Description The invention relates to new condensed as-uriazinium derivatives, a process for the preparation of the same and pharmaceutical compositions containing these compounds Middle.

The invention relates to new condensed as-triazinium derivatives of the general formula (I) and isomers thereof, in which R1 is 0110-alkyl or phenyl or naphthyl optionally substituted by one or more halogen, nitro, amino, hydroxy, C14-alkyl and / or C1-4alkoxy group (s), R2 is hydrogen, C1 4-alkyl, hydroxy, halogen or phenyl or naphthyl optionally substituted by one or more halogen, nitro, amino, hydroxy, C1-4-alkyl and / or C1-4-alkoxy group (s), for hydrogen or C1-4-alkyl, Z buta-1,3-dienyl or a group of the formula (a) means and is an anion.

By the term "alkyl group" is meant straight or branched chain to understand aliphatic hydrocarbon groups with preferably 1 to 4 carbon atoms, e.g.

Methyl, ethyl, n-propyl, isopropyl, tert. Butyl etc.).

The term alkoxy group refers to straight or branched chain Alkyl ether groups, e.g. method, etho, Isopropoxy, etc.). The expression t'Halogenatom "includes the fluorine, chlorine, bromine and iodine atoms.

An advantageous subgroup of the compounds of the general formula (I) represent äene derivatives in which Z is a group of the general formula (b) means.

Another advantageous subgroup of the compounds of the general Formula (I) represent Äene derivatives in which R1 optionally represents one in the 4-position halogen-substituted phenyl group, in particular 4-chloro-phenyl.

R2 advantageously represents hydrogen and R3 likewise means advantageous Hydrogen.

Particularly advantageous representatives of the compounds of the general Formula (I) are the following derivatives: 1-24-chloro-phenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium ethanesulphonate and 1- (4-chloro-pheny1) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium chloride.

The invention furthermore relates to a process for the preparation of new condensed as-triazinium derivatives of the general formula (I) and isomers thereof, when carried out a1) for the preparation of compounds of the general formula (I) in which R3 is hydrogen, a Compound of general formula (II) in which R1, R2 and A- have the above meanings, reacts with water or a2) for the preparation of compounds of the general formula I in which R3 is hydrogen, a compound of the general formula (IV) in which R1, Z and A- have the above meanings, in the presence of a dehydrating agent, reacts NH2 - CO - R4 (V) with a compound of the general formula (V) in which R4 is hydrogen, C1 4 -alkyl or optionally substituted phenyl, and then treated the reaction mixture with water or b) a compound of the general formula (III) in which R1 s R2, R3 and Z have the above definitions, with an acid of the general formula (VIII), in which has the above meaning, or c) for the preparation of compounds of the general formula (I) in which R3 \ Is hydrogen and R2 is hydrogen, calcium alkyl or unsubstituted phenyl, a compound of the general formula (IV) is reacted with an orthoester of the general formula (VI) R6C (OR5)) (VI), in which R5 is C1-4-alkyl and R6 is hydrogen, C1 ~ 4-alkyl or unsubstituted phenyl, and then the formino ether of the general formula (VII) obtained in this way in which R1, R5, R6 1 Z and Ag have the above meanings, cyclized by reaction with ammonia, or d) for the preparation of compounds of the general formula (I), in which R3 is C1-alkyl, a compound of the general formula (II ) reacts with a metal alcoholate containing 1-4 carbon atoms, or e) for the preparation of compounds of the general formula (I) in which R3 is hydrogen and R2 is halogen, a compound of the general formula (IV) in the presence of organic solvents and a reacting halogen-containing dehydrating agent with urea, and optionally separating a compound of the general formula (I) obtained in this way into the isomers and / or optionally exchanging one A anion for another A anion.

According to method a1) of the process according to the invention, compounds of the general formula (I), in which Rf is hydrogen, by reacting one Compound of the general formula (II) and water produced. The implementation can in a suitable, water-miscible organic solvent or water or in a mixture of water and a water-miscible organic solvent be performed. Organic solvents miscible with water can be advantageous Alkanols, e.g. 3. Methanol or ethanol, aliphatic or cyclic ethers, e.g. diethyl ether, Dioxane or ethrahydrofuran, ester (Xthylace.at) or acetonitrile can be used. The reaction is preferably carried out in a mixture of water and acetonitrile. The reaction can be carried out at a temperature between 500 and 5000, preferably at room temperature, be performed.

According to method a2) of the process according to the invention, compounds of the general formula (I), in which R3 is hydrogen, prepared in such a way that a compound of the general formula (IV) with a twist of the general Formula (V) and then treated the reaction mixture with water. The implementation of the compounds of the general formulas (IV) and (V) is in the presence of a dehydrating agent carried out. Lewis acids, e.g. titanium tetrachloride, aluminum chloride, Boron trifluoride, etc., or phosphorus oxychloride can be used. The reaction can at a temperature between 500C and 1200C, advantageously at 8090C will. Inert organic solvent such as halogenated hydrocarbons, e.g. chloroform or chlorobenzene, aromatic Hydrocarbons, e.g. xylene, toluene or benzene, dialkylamides, e.g. dimethylformamide, Dialkylsulfox each, e.g. Dimethylsulfox d, cyclic ethers, e.g. tetrahydrofuran or Dioxane, aliphatic ethers, e.g. diethyl ether, or acetonitrile. An excess of the liquid acid amide used as starting material of the general formula (V), e.g. an excess of formamide can also play the role of the reaction medium.

According to method b) of the process according to the invention, a compound of the general formula (III) with an acid of the general formula (VIII) H - A (VIII) implemented. Such an acid of the general formula (VIII) is advantageous which contains the desired Qnion. The acid can be in an equimolar close or in a small excess. As a reaction medium can such inert organic solvents are advantageously used in which the acid of the general formula (VIII) is sufficiently soluble.

For this purpose, lower alkanols, e.g.

Methanol or ethanol can be used. The reaction is already running at room temperature, but the reaction mixture can also be warmed slightly.

According to method c) of the process according to the invention, compounds of the general formula (I), where R3 is hydrogen and R2 is hydrogen, C1 mean 4-alkyl or unsubstituted phenyl, prepared so that one compound of the general formula (IV) is reacted with an orthoester of the general formula (VI) and treating the formimino ether of the general formula (VII) thus obtained with ammonia.

The orthoester of the general formula (VI) used is a function chosen by the R2 group to be introduced. When making connections to the General formula (I), in which R2 is hydrogen, are alkyl orthoformates or general formula (VI) is used (R6 represents hydrogen). It can be beneficial the methyl or ethyl esters of the general formula (VI) can be used. The implementation of the compounds of the general formulas (IV) and (VI) can be in an inert organic Solvent such as a carboxylic acid nitrile such as acetonitrile or an aromatic one Hydrocarbon such as benzene or toluene. An excess of the The compound of the general formula (VI) used as starting material can also be used Play the role of the solvent. The reaction can be carried out with heating, advantageously at the boiling point of the reaction mixture.

The compound of the general formula (VII) thus obtained is with Ammonia, advantageously treated with ammonia gas. This reaction can be beneficial be carried out in an inert organic solvent. As a reaction medium may advantageously be aliphatic alkanols, e.g.

Ethanol, serve. The reaction takes place even at room temperature instead of, however, it is expedient to work at 15-35 ° C. The ammonia can be in an equimolar Amount or in an excess of a few percent can be used.

According to method d) of the process according to the invention, compounds are obtained of the general formula (I), in which R3 is C1-4alkyl, prepared in such a way that a compound of the general formula (II) having one containing 1-4 carbon atoms Metal alcoholate converts. Preferably alkali metal alcoholates, e.g. potassium or sodium alcoholates, can be used. The implementation can be in such a suitable organic solvents are carried out in which the alkali metal alcoholate is soluble. According to an advantageous embodiment of the process, the reaction medium is the alkanol, which corresponds to the alkali metal alcoholate, is used. The alkali metal alcoholate can be used in an equimolar amount or in an excess of 10-100%. It is advantageous to work at a temperature of 10-100 ° C.

According to method e) of the process according to the invention, compounds of the general formula (I), in which R3 is hydrogen and R2 is halogen, that a compound of the general formula (1V) in the presence of organic Reacts solvents and a halogen-containing dehydrating agent with urea. Phosphorus oxychloride can preferably be used as the halogen-containing dehydrating agent used will. The reaction is carried out in an inert organic Solvent carried out. It can advantageously use high-boiling solvents a boiling point above 10,000 can be used.

A compound of the general formula (I) thus obtained can in an can be separated into the isomers in a known manner.

In a compound of the general formula (I) thus obtained, can an A0 anion, optionally in a manner known per se, against another AC anion be replaced.

A compound of the general formula (I), wherein AQ is Chlaid, can e.g. by treatment with perchloric acid into the corresponding compound of the general Formula (I), in which stands for perchlorate, can be converted. Connections of general Formula cm), in which Ai is bromide, can be selected from the corresponding compounds of the general formula (I), in which À- is another anion, e.g. perchlorate Treatment with tetrabutylammonium bromide.

Compounds of the general formula (I), in which an ethanesulfonate anion means, can from the corresponding compounds of the general formula (I), in which Ae represents another anion, e.g. bromide, by reaction with ethanesulfonic acid getting produced.

The starting materials of the general formula (II) in which R2 is a has a meaning other than halogen are known (DE-OS 3 128 386). Raw materials of the general formula (II), in which R2. stands for halogen, are new and can prepared in a manner analogous to the process described in DE-OS 3,128,386 will. The new starting materials of the general formula (II) in which R2 means halogen, are in DE-OS;, 4 it ,,.) ,, (patent application, the same Tag like the present application under the internal processing reference P 2 036 has been submitted). The other starting materials of the formula (II) and the starting materials of the general formula (IV) are described in DE-OS ......

The starting materials of the general formula (III) are new compounds. These connections are in the DE-OS .......... (Patent application filed on the same Tag like the present application under the internal processing reference P 2 036 has been submitted).

The starting materials of the general formulas (V) and (VI) are known Commercial products.

The invention also relates to pharmaceutical agents which as active ingredient at least one compound of the general formula (I) and suitable contain inert solid or liquid pharmaceutical carriers and / or excipients.

The pharmaceutical agents can be prepared according to methods known per se in the pharmaceutical industry.

The means can be in solid form, e.g. as tablets, capsules or Dragees, semi-solid form, e.g. as ointments, or liquid form, e.g. as solutions, suspensions or emulsions. The funds are particularly intended for oral use or parenteral administration.

The pharmaceutical agents can be suitable in addition to the active ingredient Contain carriers and / or auxiliaries. As a carrier can e.g. solid carriers, fillers, sterile aqueous solutions or non-toxic organic ones Solvents are used. The orally administrable tablets can e.g. Sweeteners and / or other auxiliary substances, e.g.

Contain starch, such as potato starch. These funds can also Binders, e.g. polyvinylpyrrolidone or gelatin, lubricants, e.g. Magnesium stearate, Sodium lauryl sulfate or talc, and other additives such as sodium citrate, calcium carbonate, Dicalcium phosphate, etc. included.

The orally administrable aqueous suspensions or elixirs can flavor-enhancing additives, dyes, emulsifiers, diluents, e.g. water, ethanol, propylene glycol or glycerine etc.

The pharmaceutical suitable for parenteral administration Agents can be pharmaceutically acceptable solvents, e.g., sesame oil, peanut oil, aqueous Propylene glycol, dimethylformamide, etc., or in the case of water-soluble active ingredients, Water. The aqueous solutions can be treated with a buffer solution or isotonicized with a liquid diluent such as sodium chloride or glucose. The aqueous solutions are particularly intravenous and intramuscular or intraperitoneal administration. The sterile aqueous solutions can be completed by methods known per se.

The daily dose of the new active ingredients of the general formula (I) depends on several factors, e.g. on the effectiveness of the active ingredient used, the route of administration, the condition of the patient, etc., and can be within wide boundaries fluctuate.

1. Acute toxicity in mice The experiment is carried out on male and female white mice (18-22 g; CFLP strain). After oral administration of the active ingredient, the animals are observed for 7 days. Every group consists of 50:50 from male and female mice. The animals are in plastic boxes (39 x 12 x 12 cm) kept at room temperature. The animals receive a standardized Mouse chow and tap water ad libitum. The toxicity information is given with the help calculated using the Litchfield-Wilcoxon method.

The test compounds are administered in aqueous solution, the obtained Results are summarized in Table I.

Table I Toxicity in mice 50 Connection A 410 Connection B 560 ' Compound C 590 I. Reference connection D 600 Amitriptyl in 225 2. Acute toxicity in rats The procedure is as under item 1, with the difference that the observation period is 14 days and the rats are kept in plastic boxes measuring 30 x 39 x 12 cm. 5 rats are kept in each box.

The results are shown in Table II.

Table II Toxicity in rats Test compound LD mg / kg po Compound A 1 300 Compound B about 1 100 Compound C. about 1 030 Reference compound D 'about 1 000 Amitriptyline - | 530 3. Tetrabenazine ptosis antagonism in mice and rats, po

The test compound is administered orally to groups consisting of 10 mice each administered, after which, after 30 minutes, 50 mg / kg tetrabenazine i.p. be applied. The animals exhibiting ptosis (with closed eyelid gap) are in each group paid.

The evaluation of the results is carried out as follows: an average The ptosis value is calculated on the basis of all measurements and the deviation from the mean value of the control (inhibition) is expressed in Yo. the ED50 values are calculated from the above results and reported in Table III.

Table III Tetrabenazine ptosis antagonism in mice and rats Test compound mice rats ED50 | Ther. ED50 j Rather. .mg / k; Index mg / kg t index Connection A j 0.3 1 367 0.3 4 333 Compound B 0.3 1 867 1.0 1 1 100 Compound C 2.9 203 5.4 191 Reference compound D 3.2 188 5.6 1? 9 Amitriptyline j12.0 19 11.5 46 4. Reserpine ptosis antagonism in rats, po

2.5 mg / kg of reserpine are added to groups consisting of 10 rats each administered subcutaneously. The test compound is administered after 60 minutes and the animals exhibiting ptosis are counted every hour until effect diminishes.

The evaluation is carried out as in the previous ptosis test. The results obtained are shown in Table IV.

Table IV Reserpine ptosis agonism in rats Test compound ED50 mg / kg Ther. index Compound A 14 92.8 Connection 3 t 28 39.3 Compound C 21 49.0 Reference connection D ewa 60 16.7 Amitriptyline about 140 3.6 5. Antiarrhythmic effects on rats The experiments are carried out according to the modified method of Marmo et al. The animals are anesthetized with ethyl urethane (1.2 g / kg, ip). The acotinin is administered intravenously at a dose of 75 mg / kg in the form of a bolus injection. The ECG changes are observed in a standardized II lead for 5 minutes after the aconitine administration. The changes obtained are expressed on a scale from 0 to 5. The test compound is added either intravenously 2 minutes or orally one hour prior to aconitine administration. The results are shown in Table V.

Table V Antiarrhythmic effects in rats Test compound ED50 mg / kg animal. I i, v, po index Compound A 0.9 40 32.5 Compound B 1.6 1 30 27.5 can not Lidocaine 4.0 120 calculated (23.4%) (3.5%) will; 1 (3.5%) inactive 6. Effect on Blood Pressure The test compounds exert a uniform long-term antihypertensive effect of 20-30 mmHg on anesthetized cats when administered intravenously.

7. Have other effects in addition to the activities listed above the compounds of general formula (I) spasmolytic, local anesthetic, analgesic, anti-inflammatory and tranquil-sedative properties. Some Compounds of the general formula (I) also exert an antitremorine effect.

Anti-inflammatory effect on rats. In the plantar surface the posterior sole of rats (150-180 g) is injected with 0.1 ml of 1% carrageenin. The volume of the sole is measured before and after three hours of administration of the irritating Determined by means of a plethysmometer. The animals are with the test substance or the vehicle (control) pretreated for one hour. Because of the different Solubility ratios, Tween 80 is used as an adjuvant.

The results obtained are shown in Table VI.

Table VI Anti-inflammatory effects in rats Test compound Cdem inhibiting therapy Ther. index ED50 mg / kg Compound A 24.5 53.1 Reference compound D no effect - Phenylbutazone about 90.0 5.3 Antitremorine effect in mice The characteristic tremor formed is recorded in mice 45 minutes after the ip administration of tremorin (20 mg / k). The test compound is added orally one hour before tremorin administration. The results obtained are shown in Table VII.

Table VII Antitremorin effects in mice Test compound ED50 mg / kg | Ther. index Compound B 6 '93.3 Reference connection ineffective The following test compounds are used: Compound A = 1- (4-chloro-phenyl) -1-hydroxy-1,2-dihydro-as-triazino [(3,1-a] isoquinolinium ethanesulfonate (Example 2) Compound B = 1- (4-chloro-phenyl) -1-hydroxy-1,2-dihydro-as-triazino [t;,? -A] isoquinolinium chloride (Example 4) Compound C = 1- (4-chloro -phenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium bromide (Example 1) Reference compound D = 1- (4-chloro-phenyl) -as-triazino [6 , 1-a] isoquinolinium bromide (Example 5 of DE-OS 3 128 386) amitriptyline = N, N-dimethyl-3- (dibenzo [a, d] -cycloheptadien-5-ylidene) propylamine lidocaine = -diethylamino -2,6-dimethyl-acetanilide Phenylbutazon = 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione It can be stated in summary that the compounds according to the invention show an excellent effect in the antidepressive and antiarrhythmic test experiments of the new compounds according to the invention is more effective than that described in DE-OS 3,128,386 The compound was superior to the tetrabenazine antagonism test in mice and rats by orders of magnitude, both in terms of the absolute dose and in terms of the therapeutic index.

The compounds of the invention are in the reserpine ptosis test 2-6 times more effective than the reference compound D.

In addition to this unexpected and surprising increase in effectiveness The spectrum of activity of the compounds according to the invention differs from those in the DE-OS 3 128 386 described compounds also (qualitatively different. This is shown in an occurrence of therapeutically very favorable tranquillant, analgesic, spasmolytic, anti-inflammatory and antitremoric effects.

The daily dose of the compounds of general formula (I) depends depends on various factors and can be varied within wide limits. The average oral dose can generally be between 5 and 150 mg. In severe cases, the dose can be increased up to 300 mg. The daily parenteral dose is generally between 5 and 50 mg.

Further details of the present invention are as follows See examples that do not limit the scope of protection.

Example 1 Preparation of 1- (4-chloro-phenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium bromide A mixture of 2.0 g (0.0054 vol.) 1- (4-chloro-phenyl) -as-triazino [6,1-a] isoquinolinium bromide 10 ml of acetonitrile and 5 ml of water are stirred at room temperature. The starting material temporarily goes into solution, after which colorless crystals separate out. It will 1.5 g of the compound mentioned in the title were obtained. Yield 71, m.p .: 270-271 ° C.

Example 2 Preparation of 1- (4-chloro-phenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium ethanesulphonate 3.55 g (0.0091 mole) 1- (4-chloro-phenyl) -1-hydroxy -1,2-dihydro-as-triazino [6,1-a] isoquinolinium bromide are reacted in 50 ml of acetonitrile with 2.22 g (0.0022 mol) of ethanesulfonic acid, whereupon the reaction mixture is evaporated. The residue is dissolved in ethyl acetate dissolved, the solution is cooled. It will be in the form of prisms 3.3 g of the one in the title obtained connection. Yield 86%, mp: 187-188 ° C.

Example 3 Preparation of 1- (4-chloro-phenyl) -1-hisrdrox; y-1,2-dihydro-as-triazino [6,1 ~ a] isoquinolinium perchlorate 3.5 g (0.008 mol) of 1- (4-chloro-benzoyl) -2- [N- (ethoxyiminoformyl)] isoquinolinium perchlorate are treated with gaseous ammonia in 30 ml of ethanol. The solvent will distilled off, the crystalline residue dissolved in ethanol containing 5% water and mixed with 5 ml of 70% perchloric acid. The product is made with nitromethane extracted and the solvent removed.

1.64 g of the compound mentioned in the title are obtained, yield 50%, m.p .: 239-240 ° C.

The starting material is prepared as follows: A mixture of 4.55 g (0.010 mol) 2-amino-1- (4-chloro-benzoyl) -isoquinolinium tosylate, 4.45 g (0.030 Mol) ethyl orthoformate and acetonitrile is boiled for one hour heated. The reaction mixture is cooled and the product is precipitated with ether. There are 4.4 g of 1- (4-chloro-benzoyl) -2- [N- (etho «; yiminoform; yl) g-isoquinolinium tosylate obtained, yield 86%, m.p .: 183184OC.

2.6 g (0.05 mol) of the product prepared according to the previous paragraph are heated to boiling for a short time in 30 ml of thionyl chloride, whereupon the excess thionyl chloride is distilled off. The residue is triturated with ether. There are 1.7 g (90%) of the yellow 1- (4-chloro-benzoyl) -2- [N- (ethoxyiminoformyl)] -isoquinolinium - chloride obtain. F. 158-160 ° C. After recrystallization from acetonitrile 1.4 g of needle crystals melting at 167-169 ° C. are obtained. Yield 74%.

3 g (0.006 mol) of the above product are dissolved in ethanol, whereupon 5 ml of 70% perchloric acid are added.

The precipitated crystals are filtered. There are 2.3 g of the crystalline 1- (4-chloro-benzoyl) -2- [N- (ethox; yiminoformyl)] isoquinolinium perchlorate obtained, yield 90%, F .: 224-2250C (from a mixture of acetonitrile and ether).

Example 4 Preparation of 1- (4-chloro-phenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium chloride 3.1 g (0.01 mole) 1- (4-chloro-phenyl) -1-hydroxy-as-triazino [6,1-a] isoquinolin-5-ium-2- (1H) -ide are dissolved in 15 ml of ethanol and at room temperature with 11 ml of hydrochloric acid (1 mol / l) treated, whereupon the desired product after half an hour by adding Water is excreted. 3 g of the compound mentioned in the title are obtained, Yield 87%, mp .: 227-228 ° C.

Example 5 Preparation of 1-phenyl-1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium perchlorate A mixture of 10 g (0.024 mol) of 2-amino-1-benzoylisoquinolinium tosylate, 30 ml Formamide and 15 5 ml Phosphorus oxychloride is heated to 80-900C. The reaction mixture is peeled off, diluted with water, whereupon 10 ml of 70% strength Perchloric acid can be added. There are 4.8 g of the compound mentioned in the title obtain. Yield 55%, mp .: 245-246 ° C (after crystallization from a mixture of Acetonitrile and water).

Example 6 Preparation of 1- (4-chloro-pheny1) -1-bydrox; y-1,2-dihydro-as-triazino [6,1-a] isoquinolinium-pe rchl orat s A mixture of 5 g (0.013 mol) 2-amino-1- (p-chloro-benzoyl) -isoquinolinium perchlorate, 8 ml of titanium tetrachloride and 40 ml of formamide are left to stand at 90-100 ° C., whereupon 10 ml of water are added. After the beginning of the precipitation of crystals will a solution of 5 g of sodium perchlorate and 10 ml of water was added. It will be 30 g of the compound mentioned in the title, yield 56%, melting point: 238-239 ° C (from a Mixture of acetonitrile and water).

Example 7 Preparation of 1 - (4-chloro-phenyl) -1-methoxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium chloride The procedure is as in Example 4, with the difference that the starting material is 3.23 g (0.01 mol) 1- (4-chloro-phenyl) -1-methox; sr-as-triazino [6,1-a] isoquinolin-5-ium-2 - (1H) -ide used. Yield 85%, mp .: 158-160 ° C.

Example 8 Preparation of 4- (4-chloro-phenyl) -4-hydro-3, 4-dihydro-as-triazino [1 , 6-schinolinium - perchlorate A mixture of 5 g (0.011 mol) 1-aanino-2- (4 - chloro-benacyl) -quinolinium-tosylate, 30 ml of formamide and 20 ml of phosphorus oxychloride are heated at 90 ° C. for one hour. The reaction mixture is poured into the water and the mixture becomes after one hour 70% perchloric acid added. There are 3.3 g of the compound mentioned in the title obtained, yield 73%, F .: 293-2940C - (from a mixture of nitromethane and ether).

Example 9 Preparation of 1- (4-chloro-phenyl) -1-hydroxy-1,2-dihydro-pyrido [2,1-f] as-triazinium perchlorate.

The procedure is as in Example 6, with the difference that as Starting material 11 g (0.027 mol) of 1-amino-2- (4 - chlorobenzoyl) pyridinium tosylate used, Yield 79.5%, m.p .: 254-2550C (acetonitrile).

Example 10 Preparation of 1-phenyl-1, 3-dihydroxy-1 2-dihydro-pyrido [2, 1-f] asriazinium bromides A mixture of 2.6 g (0.0087 mol) of 1-amino-2-benzoyl-pyridinium perchlorate and 5.2 grams (0.0087 moles) of urea in polyphosphoric acid is used in 160 0C heated. The reaction mixture is poured into water and the mixture with Saturated sodium perchlorate. 1.8 g of the compound mentioned in the title are obtained. Yield 64%, e.g .: 263-2640C.

Example 11 Preparation of 1- (4-chloro-pheny1) -1-hydroxy-3, 4-dihydro-pyrido [2,1 -f] as -. Triazinium bromids The procedure is as in Example 1, with the difference that 1- (4-chloro-phenyl) -pyrido [2,1-f] as-triazinium bromide) is used as the starting material. Yield 87%, m.p .: 280-281 ° C.

Example 12 Preparation of 1- (4-chloro-phenyl) -1-methoxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium perchlorate To 3.91 g (0.01 mol) of 1- (4-chloro-phenyl) -as-triazino [6,1-a] isoquinolinium perchlorate methanol containing 0.02 mol of sodium methylate is added, whereupon the product is added is excreted by adding 8 ml of a 7% aqueous perchloric acid solution. Yield 83%, mp .: 158-159 ° C.

summary

Claims (15)

Claims 1.) Condensed as-triazinium derivatives of the general formula (I) and isomers thereof in which R1 is C1-10-alkyl or phenyl or naphthyl optionally substituted by one or more halogen, nitro, amino, hydroxy, C1-4-alkyl and / or C1-4-alkoxy group (s), R2 is hydrogen , C1-4-alkyl, hydroxy, halogen or phenyl or naphth optionally substituted by one or more halogen, nitro, amino, hydroxy, C1-4-alkyl and / or C1-4-alkoxy group (s), R3 represents hydrogen or C1-4-alkyl, Z buta-1,3-dienyl or a group of the formula (a) means and is an anion. 2.) Compounds according to claim 1, characterized in that Z is a Group of formula (b). 3.) Compounds according to claim 1 or 2, characterized in that R1 for phenyl which is optionally halogen-substituted in the 4-position, in particular 4-chloro-phenyl. 4.) 1- (4-Chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium ethanesulfonate. 5.) 1- (4-Chloro-phenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinoline chloride. 6.) Process for the preparation of compounds of the general formula (I), and isomers thereof according to claim 1, characterized in that a1) for the preparation of compounds of the general formula (I) in which R3 is hydrogen, a compound of the general formula (II) in which R1, R2,, Z and Ae have the meanings given in claim 1, reacts with water or a2) for the preparation of compounds of the general formula (I), in which R3 is hydrogen, a compound of the general formula (IV) in which R1, Z and At 'have the meanings given in claim 1, in the presence of a dehydrating agent with a compound of the general formula (V) NH2 - CO - R4 (V) in which R4 is hydrogen, C1 4 -alkyl or optionally substituted phenyl means, and then the reaction mixture is treated with water or b) a compound of the general formula (III) in which R1, R2, R3 and Z have the meanings given in claim 1, with an acid of the general formula (VIII) H - A (VIII) in which A- has the meaning given in claim 1, or c) for the preparation of compounds of the general formula (1), in which R3 is hydrogen and R2 is hydrogen, C1-4-alkyl or unsubstituted phenyl, converts a compound of the general formula (IV) with an orthoester of the general formula (VI) R6CCOR5) 3 (VI) , in which R5 is C1-4-alkyl and R6 is hydrogen, O14-alkyl or unsubstituted phenyl and then the formino ether of the general formula (VII) thus obtained in which R1, R5, R6, Z and A- have the meanings given in claim 1, cyclized by reaction with ammonia, or d) for the preparation of compounds of the general formula (I) in which R3 is C1-4-alkyl, a compound of the general formula (II) with a metal alcoholate containing 1-4 carbon atoms, or e) for the preparation of compounds of the general formula (I) in which R3 is hydrogen and R2 is halogen, a compound of the general formula (IV) is present of organic solvents and a halogen-containing dehydrating agent is reacted with urea, and optionally a compound of the general formula (I) obtained in this way is separated into the isomers and / or optionally an A-anion is exchanged for another A'-anion. 7.) The method according to claim 6, characterized in that at the implementation of method a1) the implementation in a water-miscible organic solvent or water or a mixture thereof. 8.) The method according to claim 7, characterized in that the Reaction in a mixture of acetonitrile and water at a temperature between 500 and 500C performs. 9.) The method according to claim 6, characterized in that at the implementation of method a2) as a dehydrating agent a Bewis acid, preferably Titanium tetrachloride, aluminum chloride or boron trifluoride or phosphorus oxychloride are used. 10.) The method according to claim 6, characterized in that at the implementation of the method c) the implementation of the formiminoether of the general Formula (VII) is carried out with ammonia in an inert organic solvent. 11.) The method according to claim 6, characterized in that at the implementation of method d) the alkanol used as the solvent, which corresponds to the alkali metal alcoholate. 12.) Method according to claim 6, characterized in that one is at the implementation of method e) as a halogen-containing dehydrating agent Phosphorus oxyhalide used. 13.) Pharmaceutical agents, characterized in that -es as an active ingredient at least one compound of the general formula (I) or an isomer thereof, wherein R1, R2, R3, Z and Ag have the meanings given in claim 1, and suitable ones contains inert solid or liquid pharmaceutical carriers and / or excipients. 14.) Pharmaceutical agent according to claim 13, characterized in, that it is 1- (4-chloro-phenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium-ät as active ingredient hansulfonate or 1- (4-chloro-phenyl) -1-hydroxy-1, 2-dihydro-as-triazino [6,1-a] Contains isoquinolinium chloride. 15.) Process for the preparation of a pharmaceutical agent according to Claim 13, characterized in that at least one compound of the general Formula (I) or an isomer thereof as active ingredient with suitable inert solid or mixed liquid pharmaceutical carriers and / or auxiliary substances. description