Tricyclic dicarbonyl derivatives and medicinal drugs based on them

 

(57) Abstract:

Usage: in medicine as a protective substances for the nervous system. Disclosed tricyclic dicarbonyl derivatives of the formulae Ia, Ib, II, where R1and R2each independently of one another denote hydrogen, (lower)alkyl, (lower)alkoxy, nitro, trifluoromethyl, amino, halogen and R2can optionally designate morpholino, 5 - or 6-membered heterocycle with 1 to 3 nitrogen atoms, optionally substituted (lower)alkyl, hydroxy-group, or the group-NR5R6where R5and R6may be identical or different and denote hydrogen, (lower)alkyl, and X in formula II represents-CH=CH-, -CH=N-, -NH-, -CO - or-O-, and pharmaceutically acceptable salts of the compounds of General formulas Ia, Ib and II, except 2,3,5,6-tetrahydro[1,2,4]triazole[1,5-C] hinzelin-2,5-dione, as well as drug based on them. 2 S. and 9 C.p. f-crystals, 3 PL.

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The present invention relates to tricyclic dicarbonyl derivative of General formula

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where R1and R2each independently of one another denote hydrogen, (lower)alkyl, (lower)alkoxy, nitro, trifluoromethyl, amino, halogen, cyano, or R3R4 is Lino or dimorpholino, 5 - or 6-membered heterocycle with 1 to 3 nitrogen atoms, optionally substituted (lower)alkyl, hydroxy-group, an amino group or a group-CH2NHCH3, the bicyclic heterocycle with 1-3 nitrogen atoms or the group-NR5R6or5where R5and R6may be identical or different and denote hydrogen, (lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, amino(lower)alkyl or (lower)alkylamino(lower)alkyl, and X in formula II represents-CH = CH-, -CH = N-, -NH-, -CO - or-O-, and pharmaceutically acceptable salts of the compounds of General formulas Ia, Ib and II.

These compounds and their salts are new, except 2,3,5,6-tetrahydro[1,2,4]triazole[1,5-c]hinzelin-2,5-dione, and it was found that they possess valuable pharmacodynamic properties as non-competitive antagonists of NMDA and/or AMPA/KA receptors, so they can be used as a protective substances for the nervous system, in particular for treating or preventing ischemic disease, hypoglycemia, hypoxia, cerebral vascular spasms, muscle spasticity, trauma, bleeding, infections (viral, bacterial, amoebic, prialnik), epileptic seizures, autoimmune diseases, symptoms is ntington, intoxication, olivopontocerebellar atrophy, spinal cord injury, schizophrenia, depression, anxiety, drug addiction, pain, autism and mental retardation.

Objects of the present invention are the above compounds and their pharmaceutically acceptable salts, both individually and as therapeutically active substances, the method of obtaining these new compounds and salts, pharmaceutical preparations containing such a compound or its salt, the receipt of such drugs, the use of the above compounds and salts as protective substances for the nervous system, in particular for treating or preventing ischemic disease, hypoglycemia, hypoxia, cerebral vascular spasms, muscle spasticity, trauma, bleeding, infections (viral, bacterial, amoebic, prialnik), epileptic seizures, autoimmune diseases, symptoms of the syndrome, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington disease, intoxication, olivopontocerebellar atrophy, spinal cord injury, schizophrenia, depression, anxiety, drug addiction, pain, autism, and C is aparatow.

The term "lower" includes compounds or groups containing a maximum of 7, preferably a maximum of 4 carbon atoms.

The term "alkyl" includes saturated hydrocarbon group with a straight or branched chain such as methyl, ethyl, propyl, etc.

The term "alkoxy" includes alkyl groups in the above definition, linked through the oxygen atom, such as methoxy, etc.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

The term "5 - or 6-membered heterocycle" includes a cyclic system consisting of saturated or unsaturated rings, such as, for example, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, pyrazolyl, pyrazolidine, triazole, pyrimidine, piperazinil, piperidinyl, etc. and cyclic system optionally may be substituted (lower)alkyl, hydroxy-, amino group or a group-CH2NHCH3.

The concept of "the bicyclic heterocycle" means a cyclic system consisting of two rings condensed with each other, and one of the rings is a heterocyclic ring and the second ring is usually a benzene ring, for example, khinoksalinona group.

Compounds of the formulae Ia, Ib and II in accordance with the invention can also be represented in the form of the tautomers, thus, the scope of the invention 5 includes all their isomers and mixture of isomers.

Preferred compounds of formula Ia are compounds in which R1and R2each represent hydrogen, halogen, nitro, methyl or methoxy, especially the following connections:

8,9-dichloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione;

9-chloro-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin - 3,5-dione;

9-bromo-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin - 3,5-dione;

8,10-dichloro-2,3,5,6-Tetra-8-methoxy-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione;

8-iodine-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione;

8-chloro-9-fluoro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione;

8,9-dinitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione; and

8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione.

In addition, preferred compounds of formula Ia, in which R1denotes nitro, R2denotes pyrrolidinyl or dimethylamino. They, in particular, are the following connections:

9-dimethylamino-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin - 3,5-dione; and

8-nitro-9-pyrrolidin-1-yl-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c]hinzelin-3,5-dione.

The following are the most preferred compounds of formula Ib:

9-chloro-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[1,5-c]hinzelin - 2,5-dione; and

9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro-1,2,4 - triazole[1,5-c] hinzelin-2,5-dione.

Preferred compounds of General formula II are those in which R1and R2each represent hydrogen, halogen or nitro, in particular the following compounds:

7-chloro-2,3,4,5-tetrahydrooxazolo[4,5-c]quinoline-3,4-dione;

7-nitro-2,3,4,5-tetrahydrooxazolo[4,5-c]quinoline-3,4-dione;

7,8-dichloro-4-hydroxy-2,3-dihydro-1H-pyrazole[4,3-c]hinali may be obtained in the following way:

a) the cyclization of compounds of General formula

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where R1and R2have the above significance, and R7represents (lower)alkyl, to obtain the compounds of General formula Ia, or

b) rearrangement of compounds of General formula Ia, under the action of the corresponding base in the proton solvent to obtain compounds of General formula Ib, or

the interaction of compounds of General formula III in which R1indicates NO2and R2denotes F, with the corresponding heterocycle with obtaining compounds of the formula Ia, in which R1indicates NO2and R2denotes a 5 - or 6-membered heterocycle with 1 to 3 nitrogen atoms, optionally substituted (lower) alkyl, hydroxy-, amino group or a group-CH2NHCH3or

g) the cyclization of compounds of General formula

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where R1, R2and R7have the above values, to obtain the compounds of General formula II in which X represents-CH = CH-, or

d) the interaction of compounds of General formula

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where R1and R2have the above values

with hydrazine hydrate to obtain compounds of General formula II in which X represents-CH = N-, or

e) hydrogenation of the compound of obiora, the cyclization and spontaneous oxidation with oxygen in obtaining the compounds of General formula II, in which X denotes-CO-, or

g) the cyclization of compounds of General formula

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where R1, R2and R7have the above values, to obtain the compounds of General formula II in which X represents-NH-, or

C) cyclization of compounds of General formula

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where R1and R2have the above values, to obtain the compounds of General formula II in which X represents-O-, and

and optionally converting the compounds of formula Ia, Ib or II in a pharmaceutically acceptable salt.

Compounds of General formula Ia can be obtained in accordance with variant a) of the above method by cyclization of compounds of General formula III in which R1and R2have the above values. This reaction is usually carried out by boiling at the temperature of reflux distilled in a suitable solvent, for example dimethylformamide.

Compounds of General formula Ib can be obtained in accordance with variant b) of the above method by regrouping Dimroth compounds of General formula Ia. This reaction is usually carried out in the presence of strong Osnovnoy Ia, in which the phenyl ring is substituted by a heterocycle and NO2usually receive in accordance with variant b) of the above method. Using as the starting material the compound of formula III in which R1indicates NO2and R2denotes F, the reaction is carried out with the appropriate heterocycle by boiling for several hours in a solvent, for example, in alcohol.

Compounds of General formula II in which X represents-CH = CH - and R1and R2have the above values, can be obtained in accordance with option g) of the above method by cyclization of compounds of formula IV. This reaction is usually carried out under conditions of boiling under reflux in an acid-water reaction mixture, and in this case, the most preferred mixture of sulfuric acid, acetic acid and water.

Compounds of General formula II in which X represents-CH = N - substituents R1and R2have the above values, can be obtained according to variant d) of the above method. To this end, compound of General formula V is dissolved in a solvent, for example dimethylsulfoxide, usually in a protective gas atmosphere, and then after adding hydrate hydropsy formula II, in which X represents-CO - and R1and R2have the above-mentioned values are in accordance with option e) of the above method. This reaction is usually carried out by hydrogenation of the azide of formula VI in the presence of a catalyst. Suitable for this purpose are catalysts based on platinum or palladium. The catalytic hydrogenation is carried out in a current of hydrogen at room temperature after dissolution of the compounds of General formula VI in a mixture consisting of an alcohol, e.g. methanol, and dimethylformamide. The desired compound of General formula II is obtained after the oxidation dimethylformamide solution in a stream of oxygen.

When X in formula II represents-NH-, such compounds can be obtained in accordance with option g) of the above method that can be carried out similarly as described for option a). Compound of formula VII is usually subjected to cyclization to obtain the compounds of formula II by boiling at the temperature of reflux distilled in an acceptable solvent, for example dimethylformamide.

In addition, compounds of General formula II in which X is-O - and R1and R2have the above values are obtained by cyclization of the compound of the suspension of the corresponding compounds of formula VIII in tetrahydrofuran and subsequent treatment with thionyl chloride. The compounds of formula II according to the invention are formed after the addition of base, such as triethylamine.

Compounds of General formulas Ia, Ib and II can be converted into pharmaceutically acceptable salts in accordance with the option and) of the above method. Under scope of the invention are subject not only salts of inorganic acids, but also salts of organic acids and salts with inorganic bases. Examples of such salts are hydrochloride, hydrobromide, nitrates, sulfates, phosphates, citrate, formate, fumarate, maleate, acetates, succinate, tartratami, methansulfonate, paratoluenesulfonyl, and sodium or potassium salts, etc., These salts can be obtained in accordance with known methods, which are obvious to a person skilled in the art.

The compounds used as starting substances can be obtained, for example, in accordance with the following reaction schemes and the following explanations of the various reactions.

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where R1, R2and R7have the above values.

The source of the substance to obtain the compounds of General formula Ia according to the invention can be obtained in accordance with chemoinvasion acid, containing as substituents R1and R2with urea by heating for several hours. Thus obtained hintlinin formula X next turn using a halogenation agent, preferably phosphorus oxychloride, in the compound of formula XI by stirring the reaction mixture at the temperature of reflux distilled in a few hours. The compound of formula IlIa is produced by interaction of the compounds of formula XI with ancillarisation in dimethyl sulfoxide. Depending on the nature of the substituents R1/R2this can be done by direct interaction (for example, when R1denotes alkyl or alkoxy), or with compounds of formula XII (for example, when R1denotes a halogen). The reaction temperature may vary between 70oC 95oC. Next, the thus obtained compound of formula III may be converted, following option a) of the above method, the compounds of formula Ia according to the invention.

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where R1, R2and R7have the above values.

The source of the substance to obtain the compounds of General formula II according to the invention, in which X represents-CH = CH-, can be obtained in accordance with scheme 2.

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where R1and R2have the above values.

The source of the substance to obtain the compounds of General formula II according to the invention, in which X represents-CH = N-, can be obtained in accordance with scheme 3.

The compounds of formula XVIII can be obtained using well-known methods by dissolving sodium in methanol, preferably in a protective gas atmosphere, and transformation after adding the IU connection is usually suspended in diethylmalonate and stirred at the boil under reflux for several hours. Thus obtained ether carboxylic acids of General formula XIX is then usually treated with hydrochloric acid, obtaining compounds of General formula V.

Another possible method of obtaining compounds of General formula V includes dissolving the compounds of formula XVIII in a solvent, preferably in dichloromethane, the processing solution of triethylamine and ethylmaleimide and stirring for a few minutes while cooling. Thus obtained compound of formula XX is then usually mixed in a mixture consisting of acetic acid, water and sulfuric acid, at a temperature of reflux distilled within a few hours of obtaining compounds of General formula V.

The compounds of formula V are used as starting compounds for preparing compounds of General formula II, the following variant d) of the above method.

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where R1, R2and R7have the above values.

The source of the substance to obtain the compounds of General formula II according to the invention, in which X denotes-CO-, can be obtained in accordance with scheme 4.

Nitrogen-containing compounds of the formula XXI, obtained in accordance with the "Helv. Chem. Acta, 1937, 20, 913", reduced to the amino compounds form a temperature of about 50oC. Then handle methanol solution of sodium azide using well-known methods. The resulting compound of formula XXIII is treated with triethylamine in a solvent, e.g. dichloromethane, in a protective gas atmosphere and treated with alkylmethacrylamide at 0oC. After stirring at room temperature and subsequent boiling under reflux obtain the compounds of formula VIa, which can be converted by following variant (e) of the above method, the compounds of the formula II according to the invention.

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where R1, R2and R7have the above values.

The source of the substance to obtain the compounds of General formula II according to the invention, in which X represents-NH-, can be obtained in accordance with scheme 5.

To obtain the compounds of formula XXV magnesium shavings are usually treated in a protective gas atmosphere a mixture of ethanol/carbon tetrachloride, and then add a solution of diallylmalonate, ethanol and simple ether until then, until the mixture just comes to a boil. After adding dropwise the corresponding substituted 2-nitrobenzotrifluoride in an acceptable solvent mixture, for example, in a simple ether/theta, obtaining the compounds of formula XXVI. Then carry out the hydrogenation of nitrogen-containing compounds to obtain the amino compounds of the formula VII. This reaction is usually carried out using a metal catalyst, for example, using a palladium catalyst in a stream of hydrogen at room temperature.

The compounds of formula VII are starting materials for preparing compounds of the formula II according to the invention, the following variant (e) of the above method.

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where R1and R2have the above values.

The source of the substance to obtain the compounds of formula II according to the invention, in which X represents-O-, can be obtained according to scheme 6.

A solution of the compounds of formula XXVIII, preferably in acetone, treated with triethylamine, and then methylmaleimide. After the reaction for several hours at room temperature concentrated solution is treated with sodium ethylate and thus obtained quinoline compound of the formula XXIX next turn with trimethylsilylmethylamine in the compounds of formula VIII.

The resulting compounds are starting materials for pole above, compounds of the formulae Ia, Ib and II according to the invention possess pharmacological activity as non-competitive antagonists of NMDA and/or AMPA/KA receptor. As a result of this activity of the compounds of the formulae Ia, Ib and II and their pharmaceutically acceptable salts can be used as protective substances for the nervous system, in particular for treating or preventing ischemic disease, hypoglycemia, hypoxia, cerebral vascular spasms, muscle spasticity, trauma, bleeding, infections (viral, bacterial, amoebic, prialnik), epileptic seizures, autoimmune diseases, symptoms of the syndrome, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington disease, intoxication, olivopontocerebellar atrophy, spinal cord injury, schizophrenia, depression, anxiety, drug addiction, pain, autism and mental retardation.

Described compounds inhibit competitive binding3H-DCKA (3H-5,7-dichloroquinoline acid) with the NMDA receptor (NMDA = N-methyl-D-aspartate) and3H-AMPA (DL-(3H)-amino-3-hydroxy - 5-methylisoxazole-4-propionic acid) with Kainat/AMPA-receptor.3H-DCKA and3H-AMPA are speci Kainat/AMPA-receptor. Experiments on binding was carried out similarly as described in the following activities: binding3H-DCKA: B. M. Baron and others, Eur. J. Pharmacol. 206 (1991) 149-154; binding3H-AMPA: D. E. Murphy and others, Neurochem. Res. 12 (1987) 775-782.

To study the binding used carefully washed membrane preparations of rat brain. Used the following concentrations radio:3H-DCKA - 20 nm and respectively3H-AMPA - 10 nm.

To determine nonspecific binding was added the appropriate ligands at concentrations of 1 mm glycine and 1 mm, respectively glutamate. Associated with the membrane radioligand was separated from unbound ligand by centrifugation (15 minutes at 40,000 kg;3H-DCKA) or filter (filter combination Whatmann GF/C and GF/B;3H-AMPA).

Described compounds were used in experiments on the binding of various concentrations. Concentration at which 50% inhibition of binding was determined on the basis of the curves dose-activity against inhibition of binding of relevant radio. These values (IC50) (in nm) are shown in tables 1-3.

Compounds of formulas la, lb and II and their pharmaceutically acceptable salts can primanatural can be entered enterline, for example, orally, including in the form of pills, tablets, shell, coated tablets, gelatin capsules, hard and soft shells, solutions, emulsions or suspensions; nasal, for example, in the form of nasal sprays; or rectally, for example in the form of suppositories. The introduction can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously, for example, in the form of solutions for injection. For the manufacture of tablets, coated tablets, coated tablets and gelatin capsules, hard shell compounds and their pharmaceutically acceptable salts can be combined with pharmaceutically inert inorganic or organic excipients. As such excipients, for example, tablets, coated tablets and gelatin capsules, hard shell, can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts etc., Suitable excipients for gelatin capsules, soft shell are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc., with Suitable excipients to obtain solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable excipients for reactivate for suppositories are, for example, natural or hydrogensource oils, waxes, fats, semi-liquid or liquid polyols etc., the Pharmaceutical preparations can also contain preservatives, soljubilizatory, substances that increase the viscosity, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, agents for the formation of coatings or antioxidants. In addition, they can also contain other therapeutically useful substances.

In accordance with the invention, compounds of General formulas I and II and their pharmaceutically acceptable salts can be used as protective substances for the nervous system, in particular for treating or preventing ischemic disease, hypoglycemia, hypoxia, cerebral vascular spasms, muscle spasticity, trauma, bleeding, infections (viral, bacterial, amoebic, prialnik), epileptic seizures, autoimmune diseases, symptoms of the syndrome, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington disease, intoxication, olivopontocerebellar atrophy, spinal cord injury, schizophrenia, depression, alarms, Lekarstva, and, of course, must be chosen according to the individual requirements in each particular case. During oral introduction of a daily dose of about 50-500 mg, although the upper limit may be exceeded if it is shown.

The following examples serve to further illustrate the present invention. However, they do not limit the scope of the invention. All temperatures are in degrees Celsius.

The formation of compounds of formulas Ia and Ib

Example 1

2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) 1.2 g (7.4 mmole) of 1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 10 ml (74 mmole) of phosphorus oxychloride and heated to 120oC for 24 h the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown precipitate was dried and was chromatographically on silica gel using methylene chloride as eluent. Output: 331 mg (22%) of 2,4-dichloroaniline in the form of white crystals; MS: me/e = 198,200 (M+).

b) To a solution containing 360 mg (1,80 mmole) of 2,4-dichloroaniline in 5 ml of dimethylsulfoxide, was added 281 mg (2.7 mmole) of ethylcarbonate. The reaction mixture was stirred at 80oC for 4 h and then magnesium n-butanol and the suspension is kept at 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Yield: 140 mg (31%) of ethyl-2-hydroxy-4-chinapoliticsanti in the form of white crystals; MS: me/e = 248 (M+).

in) 150 mg (0.6 mmole) of ethyl-2-hydroxy-4-chinapoliticsanti in 5 ml of dimethylformamide maintained at the temperature of reflux distilled for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. In this way received 66 mg (54%) of 2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione as white crystals; MS: me/e = 202 (M+).

Example 2

7-chloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 5.0 g (0,03 mole) 2-amino-3-chlorbenzoyl acid and 3.5 g (0,06 mol) of urea was heated to 140oC for 2 h and optionally kept at 180oC within 24 hours Received a brown mass was mixed with 50 ml water and 50 ml of ethyl acetate, thus obtaining a residue. It was filtered, dried under vacuum and got the beige crystals, which are recrystallized from methanol. Yield: 3.5 g (63%) of 8-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione as white crystals;6.8 ml (0,18 mol) of phosphorus oxychloride was heated under reflux for 17 hours The reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown residue was extracted with dichloromethane, was chromatographically on silica gel using dichloromethane as eluent and recrystallized from diisopropyl ether. Output: of 2.26 g (53%) 2,4,8-trichloroaniline in the form of yellow crystals; tPL155-156oC.

To the solution containing of 2.26 g (0,009 mole) 2,4,8-trichloroaniline in 95 ml of dimethylsulfoxide, was added 1.5 g (of 0.014 mole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The yellow precipitate was filtered, dried and recrystallized from methanol. Yield: 1.56 g (54%) of ethyl-2,8-dechlorination-4-ylcarbamate in the form of white crystals; tPL213-215oC.

g) a Solution containing 1.56 g (0,0052 mole) ethyl-2,8-dechlorination-4-ylcarbamate in 47 ml of dimethyl sulfoxide was heated to 95oC for 6 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The white precipitate was filtered and dried. Output: 0,86 g (59%) ethyl-8-chloro-2-hydroxyquinazoline-4-ylcarbamate in the form of white crystals; tPL348-350oC.

d) 1.27 g (0,0045 mole) ethyl-8-chloro-2-hydrox the mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, dried under vacuum and recrystallized from methanol/tetrahydrofuran. Yield: 0.66 g (62%) of 7-chloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione as yellowish crystals; tPL348-350oC.

Example 3

8-chloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 18 g (0,105 mole) 2-amino-4-chlorbenzoyl acid and 12 g (of 0.20 mol) of urea was heated to 160oC for 2 h and optionally kept at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and dried under vacuum. Yield: 12.2 g (59%) of 7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione in the form of light brown crystals; MS: me/e = 196 (M+).

b) of 10.5 g (0,053 mole) of 7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 35 ml of 0.48 mole) of phosphorus oxychloride and heated to 120oC for 24 h the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown precipitate was filtered under vacuum, dried and chromatographically on silica gel using methylene chloride as eluent. The way it was obtained 7.2 g (58%) of 2,4,7-trichloroaniline in the form of yellow crystals; MS: me/e = 232,234 (M+).

b) CB) ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The brown precipitate was filtered and dried. Brown crystals suspended in 20 ml of n-butanol and the suspension was heated to 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Yield: 0.45 g (39%) ethyl-7-chloro-2-hydroxy-4 - chinapoliticsanti in the form of white crystals; MS: me/e = 282 (M+).

g) 0.45 g (1.59 mmole) ethyl-7-chloro-2-hydroxy-4-chinapoliticsanti in 10 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. Yield: 0.18 g (48%) of 8-chloro-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c]hinzelin-3,5-dione as white crystals; MS: me/e = 236 (M+).

Example 4

9-chloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 2.0 g (of 11.6 mmole) of 2-amino-5-chlorbenzoyl acid and of 3.48 g (58 mmol) of urea was heated to 160oC for 2 h and was kept further at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and sushi is 1.4 g (7,13 mmole) of 6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 7 ml (96 mmol) of phosphorus oxychloride and heated to 120oC for 24 h the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown precipitate was filtered, dried and chromatographically on silica gel using methylene chloride as eluent. Yield: 1 g (60%) 2,4,6-trichloroaniline in the form of white crystals; MS: me/e = 232,234 (M+).

C) To a solution containing 500 mg (2.1 mmole) of 2,4,6-trichloroaniline in 20 ml of dimethylsulfoxide, was added 334 mg (3.2 mmole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The brown precipitate was filtered and dried. Brown crystals suspended in 20 ml of n-butanol and the suspension was heated to 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Output: 285 mg (47%) of ethyl-6-chloro-2-hydroxy-4-chinapoliticsanti in the form of yellow crystals; MS: me/e = 281 (M-H)+.

g) 0.16 g (0.68 mmole) of ethyl-6-chloro-2-hydroxy-4-chinapoliticsanti in 15 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuo is SUP>+
).

Example 5

10-chloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 2.0 g (11 mmol) 2-amino-6-chlorbenzoyl acid and 1.4 g (23 mmole) of urea was heated to 160oC for 2 h and was kept further at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and dried under vacuum. Yield: 1.2 g (53%) of 5-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione as white crystals; MS: me/e = 196 (M+);

b) 0.5 g (of 2.54 mmole) of 5-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 7 ml (96 mmol) of phosphorus oxychloride and heated to 120oC for 24 h the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown precipitate was filtered, dried and chromatographically on silica gel using methylene chloride as eluent. Yield: 260 mg (44%) 2,4,5-trichloroaniline in the form of white crystals; MS: me/e = 232,234 (M+).

C) To a solution containing 200 mg of 0.85 mmole) of 2,4,5-trichloroaniline in 5 ml of dimethylsulfoxide, was added 134 mg (1,28 mmole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The brown precipitate was filtered and dried. the awali to cool to room temperature, the crystals were filtered and dried under vacuum. Yield: 80 mg (37%) of ethyl-5-chloro-2-hydroxy-4-chinapoliticsanti in the form of white crystals; MS: me/e = 282 (M+).

g) 80 mg (0,28 mmole) ethyl-5-chloro-2-hydroxy-4-chinapoliticsanti in 5 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. Yield: 38 mg (57%) of 10-chloro-2,3,5,6-tetrahydro - 1,2,4-triazole[4,3-c]hinzelin-3,5-dione as white crystals; MS: me/e = 236 (M+).

Example 6

8-Fluoro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 0.2 g (1.3 mmole) of 2-amino-4-fermenting acid and of 1.16 g (20 mmol) of urea was heated to 160oC for 2 h and optionally kept at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and dried under vacuum. Yield: 167 mg (70%) of 7-fluoro-1,2,3,4-tetrahydroquinazoline-2,4-dione as yellow crystals; MS: me/e = 180 (M+).

b) 164 mg (0.9 mmole) of 7-fluoro-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 3.5 ml (48 mmol) of phosphorus oxychloride and heated to 120oC for 24 h the Reaction I under vacuum, dried and chromatographically on silica gel using methylene chloride as eluent. Yield: 130 mg (67%) of 2,4-dichloro-7-ftorhinolona in the form of orange crystals; MS: me/e = 216,218 (M+).

To the solution containing 780 mg (3.6 mmole) of 2,4-dichloro-7 - ftorhinolona in 10 ml of dimethylsulfoxide, was added 562 mg (5.4 mmole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The brown precipitate was filtered and dried. Brown crystals suspended in 20 ml of n-butanol and the suspension was heated to 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Output: 0,58 g (61%) of ethyl-7-fluoro-2-hydroxy-4 - chinapoliticsanti in the form of crystals of pale orange; MS: me/e = 266 (M+).

g) 30 g (0,11 mmole) ethyl-7-fluoro-2-hydroxy-4-chinapoliticsanti in 2 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. Yield: 10 mg (41%) of 8-fluoro-2,3,5,6-tetrahydro - 1,2,4-triazole[4,3-c]hinzelin-3,5-dione as white crystals; MS: me/e = 220 Rasul 7.2 g (0,046 mole) 2-amino-5-fermenting acid and 16.7 g (0,28 mol) of urea, was heated to 180oC for 3 hours Obtained brown mass was ground in a mortar, suspended in the night in the water, was filtered, washed with water and then with acetone and dried under vacuum. Output: 5,1 g (61%) of 6-fluoro-1,2,3,4-tetrahydroquinazoline-2,4-dione in the form of brownish crystals; tPL335-340oC (decomp.).

b) of 5.1 g (0,028 mole) of 6-fluoro-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 39 ml (0,425 mole) of phosphorus oxychloride and heated to 105oC for 18 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown residue was extracted with dichloromethane and was chromatographically on silica gel using dichloromethane as eluent. Yield: 5.0 g (81%) of 2,4-dichloro-6-ftorhinolona in the form of white crystals; tPL133-136oC.

To the solution containing 5.5 g (0,025 mol) of 2,4-dichloro-6-ftorhinolona in 220 ml of dimethylsulfoxide, was added 3,43 g (0,033 mole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The precipitate was filtered, dried and suspended in 200 ml of acetone. The crystals were filtered and dried under vacuum. Yield: 3.7 g (55%) of ethyl-6-fluoro-2-hydroxyquinazoline-4-ylcarbamate as white is, 0), 220(41), 180(90), 137(100), 109(83), 82(47).

g) 3.7 g (of 0.014 mol) of ethyl-6-fluoro-2-hydroxyquinazoline-4-ylcarbamate in 75 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with acetone and dried under vacuum. Yield: 1.7 g (56%) of 9-fluoro-2,3,5,6-tetrahydro - 1,2,4-triazole[4,3-c]hinzelin-3,5-dione as yellowish crystals; tPL> 350oC. MS: me/e = 220 (% basic peak) = 220 (C9H5FN4O2+, 100), 163(23), 136(26), 135(18), 121(23), 108(21), 43(23).

Example 8

8-bromo-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

to 63.8 mg (0,92 mmole) of sodium nitrite was added at 0oC to the suspension containing 210 mg (or 0.83 mmole) of the hydrochloride of 8-amino-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione in 5 ml of 48% Hydrobromic acid. The mixture was stirred at 0oC for 1 h and then was added dropwise 132 mg (0.99 mmole) of copper bromide (I) in 2 ml of water. After stirring at room temperature for 16 h, the precipitate was filtered, washed with methanol and dried under vacuum. Yield: 57 mg (24%) of 8-bromo-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione as yellowish crystals; MS: me/e = 280,282 () of sodium nitrite was added at 0oC to the suspension containing 210 mg (or 0.83 mmole) of the hydrochloride of 8-amino-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione in 10 ml of acetic acid and 10 ml of sulfuric acid. The reaction mixture was stirred at 0oC for 1 h Then was added dropwise 2,49 g (of 16.6 mmole) of sodium iodide in 10 ml of water and the mixture was stirred at room temperature for a further 1 h the Precipitate was filtered, brown crystals suspended in 10 ml of 5% aqueous sodium thiosulfate solution, was filtered and dried under vacuum. Yield: 145 mg (53%) 8-iodine-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione in the form of brownish crystals; MS: me/e = 328 (M+).

Example 10

8-chloro-9-fluoro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture of 8.9 g (0,047 mole) 2-amino-4-chloro-5-fermenting acid (R. Krishan, S. A. Lang Jr., M. M. Siegel, J. Het. Chem. 1986, 23, 1801) and 17 g (0,28 mol) of urea was heated to 180oC for 3 hours Obtained brown mass was ground in a mortar, suspended in the night in the water, was filtered, then washed with water and acetone and dried under vacuum. Yield: 7.9 g (78%) of 7-chloro-6-fluoro-1,2,3,4-tetrahydroquinazoline-2,4-dione in the form of brownish crystals; tPL320-345oC (decomp.). MS: me/e = (% basic peak) = 214 (CPR-1,2,3,4-tetrahydroquinazoline - 2,4-dione suspended in 9.6 ml of 0.10 mol) of phosphorus oxychloride and heated to 105oC for 84 h the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown residue was extracted with dichloromethane and was chromatographically on silica gel using dichloromethane as eluent. Yield: 1.45 g (82%) of 2,4,7-trichloro-6-ftorhinolona in the form of yellowish crystals; tPL90-92oC.

C) To a solution containing 4.0 g (to 0.016 mole) of 2,4,7-trichloro-6 - ftorhinolona in 160 ml of dimethylsulfoxide, was added 2.16 g (0,021 mole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The precipitate was filtered, washed with ethanol and dried under vacuum. Yield: 1.6 g (34%) ethyl-7-chloro-6-fluoro-2-hydroxyquinazoline-4-ylcarbamate in the form of yellow crystals; tPL> 350oC. MS: me/e (% basic peak) = 300 (C11H10ClFN4O3+, 18), 254(100), 227(14), 197(20), 170(27), 45(22), 31(50), 29(50).

g) 1.6 g (0,0053 mole) ethyl-7-chloro-6-fluoro-2-hydroxyquinazoline - 4-ylcarbamate in 30 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with acetone and dried under vacuum. Yield: 0.45 g (33%) of 8-chloro-9-fluoro-2 (% basic peak) = 254 (C9H4ClFN4O2+, 100), 197(12), 170(16), 155(11), 142(8), 58(6).

Example 11

8,9-dichloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 0.3 g (1.5 mmole) of 2-amino-4,5-dichlorobenzoyl acid 875 mg (15 mmol) of urea was heated to 160oC for 2 h and optionally kept at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and dried under vacuum. Yield: 230 mg (68%) of 5,6-dichloro-1,2,3,4-tetrahydroquinazoline - 2,4-dione as white crystals; MS: me/e = 230,232 (M+).

b) 200 mg (0.9 mmole) of 5,6-dichloro-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 3.5 ml (48 mmol) of phosphorus oxychloride and heated to 120oC for 24 h the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown precipitate was filtered under vacuum, dried and chromatographically on silica gel using methylene chloride as eluent. Yield: 110 mg (47%) 2,4,6,7-tetrachloroaniline in the form of yellow crystals; MS: me/e = 268 (M+).

To the solution containing 100 mg (0.4 mmole) 2,4,6,7-tetrachloroaniline in 2 ml of dimethylsulfoxide, was added 53 mg (0.6 mmole) of ethylcarbonate. The reaction mixture was stirred who Evie crystals suspended in 20 ml of n-butanol and the suspension was heated to 90oC for 2 hours the Mixture was allowed to cool to room temperature and the crystals were filtered and dried under vacuum. Yield: 55 mg (47%) of ethyl-6,7-dichloro-2-hydroxy-4-chinapoliticsanti in the form of white crystals; MS: me/e = 316 (M+).

g) 50 mg (0.11 mmole) of ethyl-6,7-dichloro-2-hydroxy-4-chinapoliticsanti in 2 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. Yield: 20 mg (46%) of 8,9-dichloro-2,3,5,6-tetrahydro - 1,2,4-triazole[4,3-c]hinzelin-3,5-dione as white crystals; MS: me/e = 270 (M+).

Example 12

8,10-dichloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 2 g (10 mmol) 2-amino-4,6-dichlorbenzene acid and 1.6 g (30 mmol) of urea was heated to 160oC for 2 h and optionally kept at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and dried under vacuum. Output: 880 mg (40%) of 5,7-dichloro-1,2,3,4-tetrahydroquinazoline - 2,4-dione in the form of beige crystals; MS: me/e = 230,232 (M+).

b) 0.5 g (2 mmole) of 5,7-dichloro-1,2,3,4-tetrahydroquinazoline-2,4-dione, suspender ladisa to room temperature and was poured into ice water. The brown precipitate was dried and was chromatographically on silica gel using methylene chloride as eluent. Output: 276 mg (43%) 2,4,5,7-tetrachloroaniline in the form of white crystals; MS: me/e = 268 (M+).

C) To a solution containing 200 mg (0.75 mmole) 2,4,5,7-tetrachloroaniline in 5 ml of dimethylsulfoxide, was added 116 mg (1.1 mmole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The brown precipitate was filtered and dried. Brown crystals suspended in 20 ml of n-butanol and the suspension was heated to 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Yield: 90 mg (38%) ethyl-5,7-dichloro-2-hydroxy-4-chinapoliticsanti in the form of white crystals; MS: me/e = 316 (M+).

g) 90 mg (0,28 mmole) ethyl-5,7-dichloro-2-hydroxy-4-chinapoliticsanti in 2 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. Yield: 15 mg (20%) 8,10-dichloro-2,3,5,6-tetrahydro - 1,2,4-triazole[4,3-c] hinzelin-3,5-dione as white crystals; MS: me/e = 270,272 (MoC for 2 h and optionally kept at 180oC for 2 h Obtained brown mass was mixed with 100 ml of water and 100 ml of ethyl acetate, thus obtaining a residue. The precipitate was filtered, dried under vacuum, obtaining

this light-brown crystals, which are recrystallized from dimethylformamide/methanol. Output: 4.26 deaths g (62%) of 7,8-dimethyl-1,2,3,4 - tetrahydroquinazoline-2,4-dione in the form of beige crystals; tPL305-307oC.

b) of 7.96 g (0,042 mole) of 7,8-dimethyl-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 40 ml of 0.43 mole) of phosphorus oxychloride and kept at the boiling point under reflux for 16 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown residue was extracted with ethyl acetate, was chromatographically on silica gel using dichloromethane as eluent and recrystallized from ethyl acetate/n-hexane. Yield: 5.9 g (62%) of 2,4-dichloro-7,8-dimethylindoline in the form of white crystals; tPL145-146oC.

To the solution containing of 5.83 g (0,025 mol) of 2,4-dichloro-7,8-dimethylindoline in 140 ml of dimethyl sulfoxide was added to 5.40 g (0,051 mole) of ethylcarbonate. The reaction mixture is re who has centriole and the residue was stirred in acetonitrile at room temperature over night, separating white crystals. The crystals were filtered under vacuum and dried under vacuum. Output: 3,21 g (45%) ethyl-2-hydroxy-7,8-dimethylpyrazole-4-ylcarbamate in the form of white crystals; tPL370-372oC.

g) 3.88 g (0,012 mol) ethyl-2-hydroxy-7,8-dimethylpyrazole-4 - ylcarbamate in 220 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered and dried under vacuum. If this had been white crystals, which are recrystallized from dimethylformamide. Output: 1,62 g (50%) of 7,8-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin - 3,5-dione as yellowish crystals; tPL380-382oC.

Example 14

8,9-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 7.0 g (0,042 mole) 2-amino-4,5-dimethylbenzoic acid and 5,07 g (0,084 mol) of urea was heated to 140oC for 2 h and optionally kept at 180oC for 2 h Obtained brown mass was mixed with 50 ml water and 50 ml of ethyl acetate, thus obtaining a residue. The precipitate was filtered, dried under vacuum, thus obtaining a light-brown crystals, which paracrystals the x crystals; tPL327-329oC.

b) 4.5 g (is 0.023 mole) of 6,7-dimethyl-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 25 ml of 0.27 mole) of phosphorus oxychloride and kept at the temperature of reflux distilled for 16 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown residue was extracted with dichloromethane, was chromatographically on silica gel using dichloromethane as eluent and recrystallized from ethyl acetate/n-hexane. Output: 2,48 g (46%) of 2,4-dichloro-6,7-dimethylindoline in the form of white crystals; tPL140-142oC.

To the solution containing 2,48 g (0,010 mol) of 2,4-dichloro-6,7-dimethylindoline in 60 ml of dimethylsulfoxide, was added 2,33 g (at 0.020 mole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 5 h and then was poured into ice water. The yellow precipitate was filtered, dried and recrystallized from dimethylformamide/methanol. Output: 1, 24 g (41%) of ethyl-2-hydroxy-6,7 - dimethylindoline-4-ylcarbamate in the form of white crystals; tPL> 350oC. MS: me/e (% basic peak) = 276 (C13H16N4O3+, 16), 230(100), 203(20), 174(34), 146(43), 131(22), 31(31).

g) 1.0 g (0,0030 mole) ethyl-2-hydroxy-6,7-dimethylindoline-4 - ylcarbamate 5 room temperature and was poured into ice water. The precipitate was filtered and dried under vacuum. If this had been white crystals, which are recrystallized from dimethylformamide/methanol. Output: 0,43 g (52%) of 8,9-dimethyl-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c]hinzelin-3,5-dione as yellowish crystals; tPL> 350oC. MS: me/e (% basic peak) = 230 (C11H10N4O2+, 100), 215(5), 186(3,5), 173(25), 146(32), 131(14), 116(13).

Example 15

9,10-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture of 11.8 g (0,070 mole) 2-amino-5,6-dimethylbenzoic acid and charged 8.52 g (of 0.14 mmole) of urea was heated to 140oC for 2 h and optionally kept at 180oC for 2 h Obtained brown mass was mixed with 50 ml water and 50 ml of ethyl acetate, thus obtaining a residue. The precipitate was filtered and dried under vacuum. Output: 3.11 g (23%) of 5,6-dimethyl-1,2,3,4-tetrahydroquinazoline - 2,4-dione in the form of brown crystals; tPL> 350oC. MS: me/e (% basic peak) = 190 (C10H10N2O2+, 73), 147(100), 120(20), 118(24), 104(16), 91(19).

6) of 3.69 g is 0.019 mole) 5,6-dimethyl-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in and 17.7 ml (0,194 mole) of phosphorus oxychloride and kept at the boiling point under reflux is the song data precipitate was extracted with dichloromethane, was chromatographically on silica gel using dichloromethane as eluent and recrystallized from ethyl acetate/n-hexane. Output: 2,37 g (54%) of 2,4-dichloro-5,6-dimethylindoline in the form of white crystals; tPL121-123oC.

To the solution containing 2.37 g (0,010 mol) of 2,4-dichloro-5,6 - dimethylindoline in 60 ml of dimethylsulfoxide, was added 2.2 g (at 0.020 mole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 5 h and then was poured into ice water. The yellow precipitate was filtered and dried. Yield: 0.71 g (29%) ethyl-5,6-dimethyl-2 - hydroxyquinazoline-4-ylcarbamate in the form of yellowish crystals; tPL358-360oC.

g) of 0.67 g (0,0020 mole) ethyl-5,6-dimethyl-2-hydroxyquinazoline-4 - ylcarbamate in 38 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered and dried under vacuum. If this had been white crystals, which are recrystallized from methanol/dimethylformamide. Output: 0,41 g (74%) of 9,10-dimethyl-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c]hinzelin-3,5-dione as yellowish crystals; tPL> 350oC. MS: me/e (% basic peak) = 230 (C11H10N4O2
a) a Mixture containing 4.7 g (0,028 mole) 2-amino-3-methoxybenzoic acid and 3,37 g (0,056 mol) of urea was heated to 140oC for 2 h and optionally kept at 180oC for 2 h Obtained brown mass was mixed with 100 ml of water and 100 ml of ethyl acetate, thus obtaining a residue. The precipitate was filtered and dried under vacuum. Output: 3.28 g (61%) of 8-methoxy-1,2,3,4-tetrahydroquinazoline - 2,4-dione in the form of beige crystals; tPL266-268oC.

b) 3.28 g (of 0.017 mole) of 8-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 15.6 ml of 0.17 mole) of phosphorus oxychloride and kept at the temperature of reflux distilled for 16 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown residue was extracted with dichloromethane, was chromatographically on silica gel using dichloromethane as eluent and recrystallized from diisopropyl ether. Yield: 2.38 g (61%) of 2,4-dichloro-8-methoxyquinazoline in the form of white crystals; tPL161-162oC.

To the solution containing 2.38 g (0,010 mol) of 2,4-dichloro-8-methoxyquinazoline in 60 ml of dimethylsulfoxide, was added to 1.59 g (0,015 mol) of ethylcarbonate. The reaction mixture was stirred at 70oC for 3 h and ZAT is shivali in a mixture of 1:4 acetonitrile/ethanol at room temperature over night, separating a white precipitate. The precipitate was filtered under vacuum, dried under vacuum and recrystallized from methanol/simple ether. Yield: 1.06 g (61%) of ethyl-2-hydroxy-8-methoxyquinazoline-4-ylcarbamate in the form of white crystals; tPL314-316oC.

g) of 1.02 g (0,0036 mole) ethyl-2-hydroxy-8-methoxyquinazoline-4 - ylcarbamate in 65 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered and dried under vacuum. If this had been white crystals, which are recrystallized from methanol. Yield: 0.52 g (61%) of 7-methoxy-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione as yellowish crystals; tPL308-310oC.

Example 17

8-methoxy-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Solution containing 1.0 g (0,015 mol) of sodium cyanate in 10 ml of water was added dropwise at 70oC for 10 minutes to a suspension containing 1.7 g (0,010 mol) 2-amino-4-methoxybenzoic acid in 17 ml of acetic acid. After stirring additionally for 10 minutes and the obtained white suspension was cooled to room temperature, diluted with water and then filtered under in the acid, was cooled, diluted with 75 ml of water, filtered under vacuum, washed with water and dried under vacuum. Yield: 0.73 g (37%) of 7-methoxy-1,2,3,4-tetrahydroquinazoline - 2,4-dione as white crystals; tPL320-323oC.

b) 10 g (0,052 mole) of 7-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 72 ml (0,78 mole) of phosphorus oxychloride and heated to 105oC for 4 h the Reaction mixture was allowed to cool to room temperature, treated with toluene, was carefully poured into ice water and filtered through dicalite (Dicalite). The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated and the residue was chromatographically on silica gel using dichloromethane as eluent. Yield: 10.8 g (91%) of 2,4-dichloro-7-methoxyquinazoline in the form of white crystals; tPL123-124oC.

C) To a solution containing 4.0 g (0,0175 mole) of 2,4-dichloro-7-methoxyquinazoline in 160 ml of dimethylsulfoxide, was added 2,72 g (0,026 mol) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The precipitate was filtered, the solution was concentrated and the residue suspended in methanol. The suspension was filtered under vacuum, washed with a small amount of methanol is in; tPL330-332oC.

g) of 1.65 g (0,0059 mole) ethyl-2-hydroxy-7-methoxyquinazoline-4 - ylcarbamate in 30 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. If this had been white crystals, which are recrystallized from methanol. Output: 0,58 g (42%) of 8-methoxy-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c]hinzelin-3,5-dione as white crystals; tPL344-346oC.

Example 18

9-methoxy-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) 12.5 g (0,075 mol) 2-amino-5-methoxybenzoic acid was dissolved in 60 ml of 2N hydrochloric acid, with over 10 formed mass, which could not stir; she was turned into a slurry after dilution 120 ml of water. Then for 10 minutes at room temperature was added dropwise a solution containing 6.8 g (0,105 mole) of sodium cyanate in 70 ml of water. After additional stirring for 16 h the resulting suspension was filtered under vacuum, then washed with water and simple with ether, and dried under vacuum. The obtained crystals were boiled under reflux in Tecali water and dried under vacuum. Yield: 8.6 g (60%) of 5-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione in the form of beige crystals; tPL330 to 340oC.

b) of 7.3 g (of 0.038 mole) of 5-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 52 ml (or 0.57 mole) of phosphorus oxychloride and heated to 105oC for 18 hours the Reaction mixture was allowed to cool to room temperature, treated with toluene, was carefully poured into ice water and filtered through dicalite. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, concentrated and the residue was chromatographically on silica gel using dichloromethane as eluent. Yield: 8.0 g (92%) of 2,4-dichloro-6-methoxyquinazoline in the form of yellowish crystals; tPL175-177oC.

To the solution containing 8.0 g (or 0.035 mole) of 2,4-dichloro-6-methoxyquinazoline in 320 ml of dimethylsulfoxide, was added 4.8 g (0,046 mole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The precipitate was filtered under vacuum, washed with water and suspended in 50 ml of methanol. The suspension was filtered under vacuum, washed with a small amount of methanol and dried under vacuum. Yield: 3.0 g (31%) of ethyl-2-hydroxy-6-methoxyquinazoline-4-ylcarbamate in the form of white to the, 32(100), 217(19), 205(7,5), 191 (9), 176(30), 148(22), 133(26), 45(25), 31(43), 29(38).

g) 3.0 g (to 0.011 mole) ethyl-2-hydroxy-6-methoxyquinazoline-4-ylcarbamate in 70 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. If this had been white crystals, which are recrystallized from methanol/acetone. Output: 1,16 g (46%) of 9-methoxy-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione in the form of beige crystals; tPL> 350oC. MS: me/e (% basic peak) = 232 (C10H8N4O3+, 100), 217(26), 190 (6,5), 176(36), 161(14), 148(42), 133(64).

Example 19

10-methoxy-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Solution containing 16.6 g (0,255 mole) of sodium cyanate in 170 ml of water was added dropwise at room temperature over 40 minutes to a solution containing 14.2 g (of 0.085 mole) of 2-amino-6-methoxybenzoic acid in 150 ml of 2N hydrochloric acid. After 2 h was added dropwise addition of 100 ml of 2N hydrochloric acid, and then to 8.3 g (of 0.13 mole) of sodium cyanate in 85 ml of water After an additional stirring for 67 h obtained white suspension was filtered under vakuumtechnik fridge for 30 minutes in 80 ml of 37% aqueous hydrochloric acid, was cooled, diluted with 500 ml of water, filtered under vacuum, washed with water and then with acetone, and dried under vacuum. Output: 8,35 g (51%) of 5-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione as white crystals; tPL> 350oC. MS: me/e (% basic peak) = 192 (C9H8N2O3+, 74), 174(11), 163 (100), 149(27), 146(36), 122(48), 119(57), 107(65).

b) 9.7 g (of 0.50 mole) of 5-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 70 ml (0,76 mole) of phosphorus oxychloride and heated to 105oC for 20 h the Reaction mixture was allowed to cool to room temperature, treated with toluene, was carefully poured into ice water and filtered through dicalite. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated and the residue was chromatographically on silica gel using dichloromethane as eluent. Output: 8,9 g (77%) of 2,4-dichloro-5-methoxyquinazoline in the form of white crystals; tPL169-170oC.

C) To a solution containing 5.0 g (0,22 mole) of 2,4-dichloro-5-methoxyquinazoline in 200 ml of dimethylsulfoxide, was added 3.0 g (to 0.29 mol) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The precipitate was filtered, the solution of kontsentrirovanie recrystallized from hot methanol. Yield: 2.0 g (33%) ethyl-2-hydroxy-5-methoxyquinazoline-4-ylcarbamate in the form of yellowish crystals; tPL> 350oC. MS: me/e (% basic peak) = 278 (C12H14N4O4+, 13), 232(100), 203(29), 190(45), 175(26), 161 (40), 145(19), 118(34), 45(40), 31(84).

g) 2.4 g (0,0086 mole) ethyl-2-hydroxy-5-methoxyquinazoline-4-ylcarbamate in 50 ml of dimethylformamide was heated under reflux for 3 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. If this had been white crystals, which are recrystallized from dimethylformamide. Yield: 0.32 g (16%) 10-methoxy-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione as white crystals; tPL> 350oC. MS: me/e (% basic peak) = 232 (C10H8N4O3+, 100), 203(34), 161 (43), 145(23), 118(29).

Example 20

7-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 10.7 g (0,059 mole) 2-amino-3-nitrobenzoic acid and 21.6 g (0,35 mol) of urea was heated to 180oC for 5 hours Received brown mass was ground in a mortar, suspended in water overnight, was filtered, then washed with water and ashallow; tPL272-276oC (decomp.).

b) of 7.70 g (0,037 mole) of 8-nitro-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 51 ml of 0.56 mole) of phosphorus oxychloride and heated to 105oC for 40 h, the Suspension was allowed to cool to room temperature, was treated with 250 ml of toluene was filtered under vacuum and carefully poured into 0.5 l of water. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated and the residue was chromatographically on silica gel using dichloromethane as eluent. Output: 4,50 g (50%) of 2,4-dichloro-8-nitroquinazoline in the form of yellow crystals; tPL155-157oC.

To the solution containing 4,40 g (0,018 mole) of 2,4-dichloro-8-nitroquinazoline in 160 ml of dimethylsulfoxide, was added 2,44 g (is 0.023 mole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The precipitate was filtered and dried. The solution was concentrated; the residue was dissolved in methanol, the precipitate was filtered under vacuum and combined with the first precipitate. Yield: 1.54 g (29%) ethyl-2-hydroxy-8-nitroquinazoline-4-ylcarbamate in the form of orange crystals; tPL> 350oC. MS: me/e (% basic peak) = 293 (C11H11N5O5+0 ml of dimethylformamide was heated under reflux for 2 hours The reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, suspended in the night in methanol, was filtered under vacuum and dried under vacuum. If this had been white crystals, which are recrystallized from methanol. Yield: 1.1 g (59%) of 7-nitro-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c]hinzelin-3,5-dione as yellow crystals; tPL> 350oC. MS: me/e (% basic peak) = 247 (C9H5N5O4+, 100), 207(9), 174 (9), 144(12), 130(14), 117(19), 90(14).

Example 21

8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 5 g (or 0.027 mole) of 2-amino-4-nitrobenzoic acid and 16.5 g (of 0.27 mole) of urea was heated to 160oC for 2 h and optionally kept at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and dried under vacuum. Yield: 4.8 g (80%) of 7-nitro-1,2,3,4-tetrahydroquinazoline-2,4-dione as a white solid; MS: me/e = 207 (M+).

b) of 18.6 ml (0,204 mole) of phosphorus oxychloride was added to a solution containing 3.5 g (of 0.017 mole) of 7-nitro-1,2,3,4 - tetrahydroquinazoline-2,4-dione and 6.5 ml (0,051 mole) collidine in 60 ml of acetonitrile, and the mixture is then boiled to reverse the water and 300 ml of ethyl acetate. The organic phase is washed with 200 ml of a saturated solution of NaHCO3and twice 200 ml of saturated sodium chloride solution and finally dried over sodium sulfate. After filtration and concentration the residue was chromatographically on Florisil, using methylene chloride as eluent. Output: 2,46 g (60%) of 2,4-dichloro-7-nitroquinazoline in the form of yellow crystals; MS: me/e = 243,245 (M+).

To the solution containing of 2.45 g (0,01 mol) of 2,4-dichloro-7-nitroquinazoline in 100 ml of dimethylsulfoxide, was added 1,574 g (0,015 mol) of ethylcarbonate. The reaction mixture was stirred at room temperature for 2 h and then was poured into ice water. The brown precipitate was filtered and dried. Brown crystals suspended in 20 ml of n-butanol and the suspension was heated to 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Yield: 1.77 g (60%) ethyl-7-nitro-2-hydroxy-4 - chinapoliticsanti in the form of yellow crystals.

g) 1.7 g (5.4 mmole) ethyl-7-nitro-2-hydroxy-4-chinapoliticsanti in 20 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. Sediment Hotfile azolin-3,5-dione as yellow crystals: MS: me/e = 247 (M+).

Example 22

9-nitro - 2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 2.0 g (10 mmol) 2-amino-5-nitrobenzoic acid and 6.6 g (110 mmol) of urea was heated to 160oC for 2 h and optionally kept at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and dried under vacuum. Yield: 2 g (78%) of 5-nitro-1,2,3,4-tetrahydroquinazoline-2,4-dione in the form of light brown crystals; MS: me/e = 207 (M+).

b) 1 g (5 mmol) of 5-nitro-1,2,3,4-tetrahydroquinazoline-2,4-dione suspended in 7 ml (96 mmol) of phosphorus oxychloride and heated to 120oC for 24 h the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown precipitate was filtered, dried and chromatographically on silica gel using methylene chloride as eluent. Output: 754 mg (63%) of 2,4-dichloro-6-nitroquinazoline in the form of white crystals; MS: me/e = 243,245 (M+).

To the solution containing 750 mg (3.1 mmole) of 2,4-dichloro-6 - nitroquinazoline in 15 ml of dimethylsulfoxide, was added 480 mg (4.6 mmole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. Brown Odo 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Output: 640 mg (71%) of ethyl-2-hydroxy-7-nitro-4 - chinapoliticsanti in the form of yellow crystals; MS: me/e = 293 (M+).

g) 620 mg (2.1 mmole) of ethyl-2-hydroxy-7-nitro-4-chinapoliticsanti in 15 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. Yield: 460 mg (88%) of 9-nitro-2,3,5,6-tetrahydro - 1,2,4-triazole[4,3-c]hinzelin-3,5-dione as yellow crystals; MS: me/e = 247 (M+).

Example 23

8-trifluoromethyl-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 1.0 g (0,005 mol) 2-amino-4-triftorperasin acid and 2.64 g (0,044 mol) of urea was heated to 160oC for 2 h and optionally kept at 180oC for 2 h brown Received a lot triturated with 200 ml of methanol, was filtered and dried under vacuum. Yield: 0.7 g (62.5%) and 7-trifluoromethyl-1,2,3,4-tetrahydroquinazolin-1,4-dione in the form of light brown crystals; MS: me/e = 230 (M+).

b) 200 mg (of 0.87 mmole) 7-trifluoromethyl-1,2,3,4-then it is carbonated is 24 hours The reaction mixture was allowed to cool to room temperature and was poured into ice water. The brown precipitate was filtered under vacuum, dried and chromatographically on silica gel using methylene chloride as eluent. Yield: 142 mg (58%) of 2,4-dichloro-7-triftormetilfullerenov in the form of pink crystals; MS: me/e = 266,286 (M+).

To the solution containing 630 mg (2,37 mmole) of 2,4-dichloro-7 - triftormetilfullerenov in 20 ml of dimethylsulfoxide, was added 500 mg (4.8 mmole) of ethylcarbonate. The reaction mixture was stirred at 70oC for 2 h and then was poured into ice water. The brown precipitate was filtered and dried. Brown crystals suspended in 20 ml of n-butanol and the suspension was heated to 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Output: 0,46 g (61%) of ethyl-2-hydroxy-7-trifluoromethyl-4-chinapoliticsanti in the form of white crystals; MS: me/e = 316 (M+).

g) 0.35 g (1,11 mmole) ethyl-2-hydroxy-7-trifluoromethyl-4 - chinapoliticsanti in 10 ml of dimethylformamide was heated under reflux for 2 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. Sediment tfilter-c]hinzelin-3,5-dione as white crystals; MS: me/e = 270 (M+).

Example 24

8-chloro-9-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) 20 g (101,7 mmole) of 7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione was dissolved in 100 ml of concentrated sulfuric acid and was treated with 7 ml of concentrated nitric acid. The mixture was heated to 100oC for 10 minutes. After cooling, the reaction mixture was poured into ice water. The precipitate was filtered, dried in high vacuum and recrystallized from acetic acid. Output: 13.3 g (54%) of 7-chloro-6-nitro-1,2,3,4-tetrahydroquinazoline-2,4-dione in the form of beige crystals; MS: me/e = 241 (M+).

b) 2.2 g (9.1 mmole) of 7-chloro-6-nitro-1,2,3,4-tetrahydroquinazoline - 2,4-dione suspended in 15 ml of acetonitrile and boiled under reflux for 3 h with 10 ml (110 mmol) of phosphorus oxychloride and 3.6 ml (27.3 mmole) collidine. After removal of solvent the residue is suspended in methylene chloride, was filtered through Florisil and dried under vacuum. Yield: 1.4 g (55%) of 6-nitro-2,4,7-trichloroaniline in the form of white crystals; MS: me/e = 277,279 (M+).

C) To a solution containing 1.0 g (3.6 mmole) of 6-nitro-2,4,7-trichloroaniline in 25 ml of dimethylsulfoxide, was added 0.54 g (5.2 mmole) of ethylcarbonate. The reaction mixture peremeshali and dried. Brown crystals suspended in 20 ml of n-butanol and the suspension was heated to 90oC for 2 hours the Mixture was allowed to cool to room temperature, the crystals were filtered and dried under vacuum. Output: 660 mg (56%) ethyl-7-chloro-6-nitro-2-hydroxy-4 - chinapoliticsanti in the form of yellow crystals; MS: me/e = 327 (M+).

g) 550 mg (1.68 mmole) of ethyl-7-chloro-6-nitro-2-hydroxy-4 - chinapoliticsanti in 5 ml of dimethylformamide was heated under reflux for 2 hours, the Reaction mixture was cooled to room temperature and then was poured into ice water. The precipitate was filtered, washed with methanol and dried under vacuum. Output: 327 mg (69%) of 8-chloro-9-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione in the form of orange crystals; MS: me/e = 281 (M+).

Example 25

9-chloro-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 6.0 g (27,7 mole) 2-amino-5-chloro-4-nitrobenzoic acid and 10.0 g (0,166 mol) of urea was heated to 180oC for 2.5 hours Received brown mass was boiled with 200 ml of water. Then it was filtered, washed with water and acetone and dried under vacuum. Output: 4.35 g (65%) of 2,4-dioxo-6-chloro-7-nitro-1,2,3,4 - tetrahydroquinazoline in the form of a dark brown powder is suspended in 40 ml of phosphorus oxychloride and heated to 140oC for 48 hours the Reaction mixture was allowed to cool to room temperature and was poured into ice water. The mixture was extracted with methylene chloride and the organic phase was dried over magnesium sulfate, was filtered and was concentrated. The residue was dried and was chromatographically on silica gel, using methylene chloride as eluent. Output: 2,535 g (50%) of 2,4,6-trichloro-7-nitroquinazoline in the form of yellow crystals; MS: me/e = 277 (M+), 279 (M+), 281 (M+).

To the solution containing 2,535 g (9.1 mmole) of 2,4,6-trichloro-7 - nitroquinazoline in 40 ml of anhydrous dimethyl sulfoxide was added 1.23 g (11.8 mmole) of ethylcarbonate. After 1 h the mixture was poured into ice water. The yellow precipitate was filtered, dried and chromatographically on silica gel, using as eluent a mixture (1:1) ethyl acetate/hexane. Output: 2,61 g (83%) of ethyl-2,6-dichloro-7-nitro-4-chinapoliticsanti in the form of yellow crystals; MS: me/e = 345 (M+), 347 (M+).

g) a Solution containing 2.6 g (7.5 mmole) of ethyl-2,6-dichloro-7-nitro-4 - chinapoliticsanti and 50 ml of anhydrous dimethyl sulfoxide was heated to 100oC for 1.5 hours Then the mixture was poured on ice and the yellow precipitate was filtered and dried. Yield: 2.35 g (95%) ethyl-6-chloro-7-nitro-2-hydroxy-4-chinapoliticsanti in type-4 - chinapoliticsanti in 100 ml of dimethylformamide was heated under reflux for 1.5 hours The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue is triturated with 50 ml of acetone and light yellow precipitate was filtered, washed with a small amount of acetone and dried under vacuum. Output: 1,284 g (64%) of 9-chloro-8-nitro-2,3,5,6-tetrahydro - 1,2,4-triazole[4,3-c] hinzelin-3,5-dione in the form of beige crystals; MS: me/e = 281 (M+), 283 (M+).

Example 26

Sodium salt of 9-chloro-8-nitro-1-yl-2,3,5,6 - tetrahydro[1,2,4] triazole[1,5-c]hinzelin-2,5-dione

5,33 ml of 0.1 M NaOH was added to the solution containing 150 mg (of 0.533 mmole) of 9-chloro-8-nitro-1-yl-2,3,5,6-tetrahydro[1,2,4] triazole[4,3 - c]hinzelin-3,5-dione and 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Then the mixture was filtered, concentrated to dryness, was treated three times with deionized water and again concentrated. The residue was dried in high vacuum. Yield: 142 mg (74%) of sodium salt of 9-chloro-8-nitro-1-yl-2,3,5,6-tetrahydro[1,2,4] triazole[1,5-c] hinzelin - 2,5-dione as a red-brown powder. MS: me/e = 280 (M-Na)-.

Example 27

9-fluoro-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) 3.8 g (19 mmol) of 2-amino-5-fluoro-4-nitrobenzoic acid was dissolved in 190 ml of ethyl acetate and attil-2-amino-5-fluoro-4-nitrobenzoate as a yellow crystals; MS: me/e = 214 (M+).

b) 4.0 g (to 18.7 mmole) of methyl 2-amino-5-fluoro-4-nitrobenzoate was dissolved in 250 ml of methanol and saturated with ammonia at -40oC. the mixture was stirred at room temperature overnight. The solution was concentrated and the residue triturated with methylene chloride. The precipitate was filtered under vacuum and dried. Output: 3,17 g (85%) 2-amino-5-fluoro-4-nitrobenzamide in the form of yellow crystals; MS: me/e = 214 (M+).

b) 3.1 g (15.6 mmole) of 2-amino-5-fluoro-4-nitrobenzamide was dissolved in 130 ml of tetrahydrofuran and, at 0oC was treated with 3.1 g (of 10.4 mmole) of triphosgene. The mixture was allowed to warm to room temperature and was further stirred for 1.5 hours Then the solution was concentrated and triturated with water. The precipitate was filtered under vacuum and dried. Output: 2,09 g (60%) of 2,4-dioxo-6-fluoro-7-nitro - 1,2,3,4-tetrahydroquinazoline in the form of yellowish crystals; MS: me/e = 225 (M+).

g) 2.1 g (9.3 mmole) of 2,4-dioxo-6-fluoro-7-nitro-1,2,3,4 - tetrahydroquinazoline suspended in 12 ml of phosphorus oxychloride and heated to 140oC for 72 h the Reaction mixture was allowed to cool to room temperature and was poured into ice water. Then the mixture was extracted with methylene chloride and the organic phase was dried over sulfate moored as eluent. Output: 1,69 g (69%) of 2,4-dichloro-6-fluoro-7-nitroquinazoline in the form of yellow crystals; MS: me/e = 261 (M+), 263 (M+), 265 (M+).

d) To a solution containing 2.0 g (7.7 mmole) of 2,4-dichloro-6-fluoro-7 - nitroquinazoline in 44 ml of anhydrous dimethyl sulfoxide was added to 0.98 g (9.2 mmole) of ethylcarbonate. After 15 minutes the mixture was poured into ice water. The yellow precipitate was filtered and dried. Output: 2,13 g (84%) of ethyl-2-chloro-6-fluoro-7-nitro-4-chinapoliticsanti in the form of yellow crystals; MS: me/e = 329 (M+), 331 (M+).

e) a Solution containing 2,13 g (6.5 mmole) of ethyl-2-chloro-6-fluoro-7 - nitro-4-chinapoliticsanti and 50 ml of anhydrous dimethyl sulfoxide was heated to 100oC for 1 h Then the mixture was poured on ice and the yellow precipitate was filtered and dried. Yield: 1.90 g (94%) of ethyl-6-fluoro-7-nitro-2-hydroxy-4-chinapoliticsanti in the form of yellow crystals; MS: me/e = 311 (M+).

W) 404 mg (1.3 mmole) of ethyl-6-fluoro-7-nitro-2-hydroxy-4 - chinapoliticsanti in 20 ml of anhydrous dimethylformamide was heated under reflux for 2 hours, the Reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue is triturated with a small amount of acetone and the orange precipitate was filtered and dried under Zhevago color; MS: me/e = 265 (M+).

Example 28

Hydrochloride, 8-amino-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin - 3,5-dione

1.98 g (8.8 mmole) of tin dichloride was dissolved in 10 ml of concentrated hydrochloric acid at 80oC. To the solution portions were added 494 mg (2 mmole) of 8-nitro-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c] hinzelin-3,5-dione. After soaking for 2 hours at the temperature of reflux distilled precipitate was filtered, washed with water and dried under vacuum. Output: 315 mg (62%) of the hydrochloride of 8-amino-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione as white crystals; MS: me/e = 217 (M-HCl)+.

Example 29

9-amino-8-chloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

672 mg (2,98 mmole) of tin dichloride was dissolved in 3.4 ml of concentrated hydrochloric acid at 80oC. To the solution portions were added 200 mg (of 0.71 mmole) of 8-chloro-9-nitro-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c] hinzelin-3,5-dione. After exposure for 2 h at the temperature of reflux distilled precipitate was filtered, washed with water and dried under vacuum. Yield: 137 mg (67%) of the hydrochloride of 9-amino-8-chloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione as white crystals; MS: me/e = 251 (M-HCl)+.

Example 30

9-dimethylamino-8-nitro-2,3,5,6-tetrahydro-incarnata and 50 ml of 33% ethanolic solution of dimethylamine, was stirred at room temperature for 24 h Then the solvent was blown away and the residue was dissolved in 20 ml of methylene chloride. The precipitate was filtered and dried. Yield: 360 mg (67%) of ethyl-(6-dimethylamino-7-nitro-2-oxo-1,2-dihydroquinazolin-4-yl)carbazate in the form of a powder orange; MS: me/e = 337 (M+H)+.

b) 350 mg (1.04 million mmole) of ethyl-(6-dimethylamino-7-nitro-2-oxo - 1,2-dihydroquinazolin-4-yl)carbonate in 30 ml of anhydrous dimethylformamide was kept for 3 h at the temperature of reflux distilled. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue is triturated with a small amount of acetone, the precipitate was filtered red and dried under vacuum. Yield: 195 mg (65%) 9-dimethylamino-8-nitro - 2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione as a red powder; MS: me/e = 291 (M+H)+.

Example 31

Sodium salt of 9-dimethylamino-8-nitro-1-yl-2,3,5,6 - tetrahydro[1,2,4] triazole[1,5-c]hinzelin-2,5-dione

To a solution containing 150 mg (0,52 mmole) 9-dimethylamino-8 - nitro-1-yl-2,3,5,6-tetrahydro[1,2,4] triazole[4,3-c] hinzelin-3,5-dione and 20 ml of dimethylformamide, added with 8.05 ml of 0.1 M NaOH and the mixture was stirred at room temperature for 30 minutes. The mixture is then contentcom vacuum. Yield: 123 mg (76%) of sodium salt of 9-dimethylamino-8-nitro-1-yl - 2,3,5,6-tetrahydro[1,2,4]triazole[1,5-c]hinzelin-2,5-dione as a red-brown powder; MS: me/e = 289 (M-Na)-.

Example 32

8-nitro-9-pyrrolidin-1-yl-2,3,5,6-tetrahydro-1,2,4-triazole[4,3 - c]hinzelin-3,5-dione

a) a Mixture containing 500 mg (1.6 mmole) of ethyl-6-fluoro-7-nitro-2 - hydroxy-4-chinapoliticsanti and 50 ml of pyrrolidine, was stirred at room temperature for 4 h Then the solvent was blown away and the residue was chromatographically on silica gel using a mixture (95:5 methylene chloride/methanol as eluent. Output: 512 mg (88%) of ethyl-(7-nitro-2-oxo-6-pyrrolidin-1-yl-1,2-dihydroquinazolin-4-yl)carbazate in the form of a red powder; MS: me/e = 363 (M+H)+.

b) 500 mg (1,38 mmole) of ethyl-(7-nitro-2-oxo-6-pyrrolidin-1-yl - 1,2-dihydroquinazolin-4-yl)carbonate in 30 ml of anhydrous dimethylformamide was kept for 3 h at the temperature of reflux distilled. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue is triturated with a small amount of acetone, the precipitate was filtered red and dried under vacuum. Output: 342 mg (78%) of 8-nitro-9-pyrrolidin-1-yl - 2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione as a red p is 1,2,4] triazole[1,5-c]hinzelin-2,5-dione

To a solution containing 200 mg (to 0.63 mmole) of 8-nitro-9-pyrrolidin - 1-yl-2,3,5,6-tetrahydro[1,2,4] triazole[4,3-c]hinzelin-3,5-dione and 20 ml of dimethylformamide, was added 9,86 ml of 0.1 M NaOH and the mixture was stirred at room temperature for 30 minutes. The mixture is then concentrated to dryness, treated three times with deionized water and again concentrated. The residue was dried in high vacuum. Output: 193 mg (90%) of sodium salt of 8-nitro-9-pyrrolidin-1-yl-2,3,5,6 - tetrahydro[1,2,4] triazole[1,5-c]hinzelin-2,5-dione as a red-brown powder; MS: me/e = 315 (M-Na)-.

Example 34

9-morpholine-4-yl-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione

a) a Mixture containing 500 mg (1.6 mmole) of ethyl-6-fluoro-7-nitro-2 - hydroxy-4-chinapoliticsanti and 10 ml of the research, was stirred at room temperature for 4 h Then the solvent was blown away and the residue was dissolved in 20 ml of methylene chloride. The precipitate was filtered and dried. Yield: 360 mg (59%) of ethyl-(6-morpholine-4-yl-7-nitro-2-oxo - 1,2-dihydroquinazolin-4-yl)carbazate in the form of a powder orange; MS: me/e = 378 (M+).

b) 145 mg (range 0.38 mmole) of ethyl-(6-morpholine-4-yl-7-nitro-2-oxo - 1,2-dihydroquinazolin-4-yl)carbonate in 20 ml of anhydrous dimethylformamide was kept for 2 h at the temperature of the body. The residue is triturated with a small amount of acetone, the precipitate was filtered red and dried under vacuum. Yield: 76 mg (60%) 9-morpholine-4-yl-8-nitro - 2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione as a red-brown powder; MS: me/e = 333 (M+H)+.

Example 35

9-(4-methylpiperazin-1-yl)-8-nitro-2,3,5,6-tetrahydro - 1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) a Mixture containing 150 mg (0.48 mmole) of ethyl-6-fluoro-7-nitro-2 - hydroxy-4-chinapoliticsanti and 5 ml of N-methylpiperazine, was stirred at room temperature for 3 hours Then the solvent was blown away and the residue was transferred into 20 ml of methylene chloride. The precipitate was filtered and dried. Yield: 90 mg (48%) of ethyl-[6-(4-methylpiperazin-1-yl)-7-nitro-2 - oxo-1,2-dihydroquinazolin-4-yl)carbazate in the form of a powder orange; MS: me/e = 392 (M+H)+.

b) 73 mg (0,19 mmole) of ethyl-[6-(4-methylpiperazin-1-yl)-7-nitro-2 - oxo-1,2-dihydroquinazolin-4-yl)carbonate in 3 ml of anhydrous dimethyl sulfoxide was heated to 15oC for 2 h Then the solvent was blown away and the residue triturated with a small amount of acetone. The precipitate was filtered and dried under vacuum. Yield: 49 mg (73%) of 9-(4-methylpiperazin-1-yl)-8-nitro-2,3,5,6-tetrahydro-1,2,4 - triazole[4,3-c]hinzelin-3,5-dione in the form of orange powder tetrahydro[1,2,4] triazole[1,5-c]hinzelin-2,5-dione and antifungals

A mixture containing 500 mg (1.6 mmole) of ethyl-6-fluoro-7-nitro-2 - hydroxy-4-chinapoliticsanti and 7.5 g (110 mmol) of imidazole was heated to 100oC for 3 hours Then added 80 ml of methanol, the precipitate was filtered yellow and dried. Output: 547 mg (89%) of a mixture of salts of 9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro[1,2,4]triazole[1,5 - c]hinzelin-2,5-dione and imidazole; MS: me/e = 314 (M+H)+.

b) Sodium salt of 9-imidazol-1-yl-8-nitro-2,3,5,6 - tetrahydro[1,2,4]triazole[1,5-c]hinzelin-2,5-dione (1:1)

with 5.3 ml of 0.1 M NaOH was added to a solution containing a mixture (1:1) salt 9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro[1,2,4] triazole[1,5 - c] hinzelin-2,5-dione with imidazole and 40 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. The mixture is then concentrated to dryness, treated three times with deionized water and concentrated. The residue was dried in high vacuum. Yield: 134 mg (76%) of sodium salt of 9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro[1,2,4] triazole[1,5-c] hinzelin - 2,5-dione as an orange powder; MS: me/e = 314 (M-Na+H)+.

in) 9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro[1,2,4] triazole[1,5 - c]hinzelin-2,5-dione

To a solution containing 300 mg (from 0.84 mmole) 9-imidazol-1-yl-8 - nitro-2,3,5,6-tetrahydro[1,2,4] triazole[1,5-c] hinzelin-2,5-dione and 20 ml of water the IOM and dried. Output: 242 mg (91%) 9-imidazol-1-yl-8-nitro-2,3,5,6 - tetrahydro[1,2,4]triazole[1,5-c]hinzelin-2,5-dione as an orange powder; MS: me/e = 314 (M+H)+.

g) 9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro[1,2,4]triazole[4,3 - c]hinzelin-3,5-dione

A solution containing 100 mg (0,32 mmole) 9-imidazol-1-yl-8-nitro - 2,3,5,6-tetrahydro[1,2,4] triazole[1,5-c] hinzelin-2,5-dione and 10 ml DMF was heated to 80oC for 30 minutes and then concentrated to dryness. After trituration with acetone, the residue was filtered under vacuum. Yield: 84 mg (84%) 9-imidazol-1-yl-8-nitro-2,3,5,6 - tetrahydro[1,2,4] triazole[4,3-c]hinzelin-3,5-dione; MS: me/e = 314 (M+H)+.

Example 37

8,9-dinitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) 10 g (48.3 mmole) of 7-nitro-1,2,3,4-tetrahydroquinazoline-2,4-dione was added by portions at 0oC to 32 ml of fuming nitric acid. Then the mixture was additionally stirred at room temperature for 5 hours, the Reaction mixture was poured on ice, the precipitate was filtered under vacuum and washed with 65% nitric acid, diluted nitric acid, and then water. Output: 7,15 g (59%) of 6,7-dinitro-1,2,3,4 - tetrahydroquinazoline-2,4-dione as a yellow powder; MS: me/e = 252 (M+).

b) 2 g to (7.9 mmole) of 6,7-dinitro-1,2,3,4-tetrahydroquinazoline-2,4-di is atoi temperature the reaction mixture was concentrated to dryness. The residue was chromatographically on silica gel, using methylene chloride as eluent. Output: 1,11 g (48%) of 2,4-dichloro-6,7-dinitrobenzene in the form of yellow crystals; MS: me/e = 288 (M+), 290(M+), 292 (M+).

C) To a solution containing 1.1 g (3.8 mmole) of 2,4-dichloro-6,7 - dinitrobenzene in 25 ml of anhydrous dimethyl sulfoxide was added value (0.475) g (4,57 mmole) of ethylcarbonate. After 15 minutes the mixture was poured into ice water. The precipitate was filtered orange and dried. Yield: 1.12 g (83%) of ethyl-2-chloro-6,7-dinitro-4-chinapoliticsanti in the form of orange crystals; MS: me/e = 356 (M+).

g) a Solution containing 1.1 g (3.1 mmole) of ethyl-2-chloro-6,7-dinitro - 4-chinapoliticsanti and 25 ml of anhydrous dimethyl sulfoxide was heated to 100oC for 1 hour. The mixture is then poured on ice, the precipitate was filtered yellow and dried. Output: 0,82 g (79%) of ethyl-6,7-dinitro-2-hydroxy-4-chinapoliticsanti in the form of yellow crystals; MS: me/e = 338 (M+).

d) 810 mg (2,39 mmole) ethyl-6,7-dinitro-2-hydroxy-4-chinapoliticsanti in 30 ml of anhydrous dimethylformamide was kept at the temperature of reflux distilled for 3 hours the Reaction mixture was allowed to cool to room temperature and the solvent was removed on a rotary spritevector. Yield: 560 mg (80%) of 8,9-dinitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione in the form of orange crystals; MS: me/e = 292 (M+).

Example 38

9-bromo-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c]hinzelin-3,5-dione

a) of 25.8 g (93,8 mmole) of methyl 2-amino-5-bromo-4-nitrobenzoate was dissolved in 800 ml of methanol and saturated with ammonia at -40oC. Then the mixture was stirred at room temperature overnight. The solution was concentrated and the residue triturated with methylene chloride. The precipitate was filtered under vacuum and dried. Yield: 18.3 g (75%) of 2-amino-5-bromo-4-nitrobenzamide in the form of orange crystals; MS: me/e = 259 (M+), 261 (M+).

b) 17.3 g (66,5 mmole) of 2-amino-5-bromo-4-nitrobenzamide was dissolved in 500 ml of tetrahydrofuran and treated at 0oC 13 g (of 10.4 mmole) of triphosgene. The mixture was allowed to warm to room temperature and was further stirred for 1.5 hours Then the solution was concentrated and triturated with water. The precipitate was filtered under vacuum and dried. Yield: 8.6 g (45%) of 2,4-dioxo-6-bromo-7-nitro - 1,2,3,4-tetrahydroquinazoline in the form of yellowish crystals; MS: me/e = 285 (M+), 287 (M+).

in) 8.6 g (to 30.1 mmole) 2,4-dioxo-6-bromo-7-nitro-1,2,3,4 - tetrahydroquinazoline suspended in 42 ml of phosphorus oxychloride and is ovali dry. The residue was chromatographically on Florisil, using methylene chloride as eluent. Yield: 2.8 g (29%) of 2,4-dichloro-6-bromo-7-nitroquinazoline in the form of light yellow crystals; MS: me/e = 321 (M+), 323 (M+), 325 (M+), 327 (M+).

g) 1.0 g (9.6 mmole) of ethylcarbazole was added to the solution containing 2.6 g (8.1 mmole) of 2,4-dichloro-6-bromo-7-nitroquinazoline in 45 ml of anhydrous dimethyl sulfoxide. After 15 minutes the mixture was poured into ice water. The precipitate was filtered yellow and dried. Output: 2,88 g (91%) of ethyl-2-chloro-6-bromo-7-nitro-4-chinapoliticsanti in the form of yellow crystals; MS: me/e = 389 (M+), 391 (M+), 393 (M+).

d) a Solution containing 2,88 g (7,37 mmole) of ethyl-6-bromo-7-nitro-2-hydroxy-4-chinapoliticsanti and 55 ml of anhydrous dimethyl sulfoxide was heated to 100oC for 1 h Then the mixture was poured on ice, the yellow precipitate was filtered and dried. Output: 2,47 g (90%) ethyl-6-bromo-7-nitro-2-hydroxy-4-chinapoliticsanti in the form of yellow crystals; MS: me/e = 372 (M+H))+, 374 (M+H)+.

e) of 2.45 g (6.6 mmole) of ethyl-6-bromo-7-nitro-2-hydroxy-4 - chinapoliticsanti in 150 ml of anhydrous dimethylformamide was kept at the temperature of reflux distilled for 2 hours the Reaction mixture was allowed to cool to room temperature revival orange precipitate was dried under vacuum. Yield: 1.3 g (61%) of 9-bromo-8-nitro - 2,3,5,6-tetrahydro-1,2,4-triazole[4,3-c] hinzelin-3,5-dione in the form of a powder orange; MS: me/e = 325 (M+), 327 (M+).

Obtaining compounds of formula II

Example 39

5-hydroxy-3,4-dihydropyrido[3,4-c]quinoline-4-one

a) a Mixture containing 4,34 g (0,022 mol) of 2-methoxy-4-methylinosine - 3-carbonitrile and 7.8 g (of 0.066 mol) of dimethylacetal N,N-dimethylformamide, was kept in an argon atmosphere at a low boiling under reflux for 65 hours the Mixture was cooled and was chromatographically on silica gel using dichloromethane as eluent. The product was recrystallized from methanol. By re-chromatography of the mother liquor and subsequent recrystallization received an additional portion of the product. Output: 4,22 g (76%) of (E)-4-(2-dimethylaminovinyl)-2-methoxyquinoline-3-carbonitrile in the form of yellow crystals; tPL101-103oC.

b) 3.33 g (0,013 mol) of (E)-4-(2-dimethylaminovinyl)-2 - methoxyquinoline-3-carbonitrile kept at the temperature of reflux distilled for 2 h in a mixture of solvents consisting of 4,6 ml of sulfuric acid, 29 ml of acetic acid and 9.6 ml of water. The reaction mixture was cooled to room temperature and poured in 115 ml of ice water. The precipitate was filtered, proxy-3,4-dihydropyrido[3,4-c] quinoline-4-it is in the form of light yellow crystals; tPL312-327oC (subl.).

Example 40

8-chloro-5-hydroxy-3,4-dihydropyrido[3,4-c]quinoline-4-one

a) a Mixture containing 6.5 g (of 0.038 mol) of 1-(2-amino-4-chlorophenyl)ethanone and 5.2 g (0,046 mole) of ethylcinnamate, was heated to 200oC for 4 hours, fending off the resultant mixture of water/ethanol. The mixture was additionally stirred at 210oC for 2 h, allowed to cool to room temperature, the resulting brown mass was ground in a mortar, suspended in ethanol overnight, was filtered, washed with ethanol and dried under vacuum. Output: 7,28 g (87%) of 7-chloro-2-hydroxy-4-methylinosine-3-carbonitrile in the form of light brown crystals; tPL> 350oC; MS: me/e (% basic peak) = 218 (C11H7ClN2O2+, 100), 190(53), 189 (35), 163(7,5), 155(13), 140(4), 128(11), 101(6), 77(20).

b) 7,58 g (or 0.035 mole) of 7-chloro-2-hydroxy-4-methylinosine-3-carbonitrile suspended in 32 ml (0,347 mole) of phosphorus oxychloride and stirred at 105oC for 4 h, the Excess phosphorus oxychloride drove away. The residue was distributed between 1 l of ethyl acetate and 0.5 l of water and was filtered through dicalite. Then was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. Product precrystallization/SUB>153-154oC.

in) of 7.4 g (or 0.035 mole) of 2,7-dichloro-4-methylinosine-3-carbonitrile suspended in 600 ml of methanol. To the suspension was added to portions of 6.3 g (0,275 mole) of sodium in 40oC and the mixture is boiled under reflux for 16 hours the Mixture was cooled to 40oC, and to it was slowly added to 300 ml of water and stirred in an ice bath for 1/2 h, the resulting suspension was filtered, washed with water and dried under vacuum. Yield: 6.0 g (83%) of 7-chloro-2-methoxy-4-methylinosine - 3-carbonitrile in the form of white crystals; tPL183-185oC.

g) a Mixture containing 6.0 g (0,026 mol) of 7-chloro-2-methoxy-4 - methylinosine-3-carbonitrile and 30.7 g (0,258 mole) of dimethylacetal N,N-dimethylformamide, was kept at a low boiling under reflux for 23 h (after 19 h, to the mixture was added an additional portion of 15.4 g (0,129 mole) of dimethylacetal N, N-dimethylformamide). The mixture was cooled and was chromatographically on silica gel using a mixture (4:1) dichloromethane/n-hexane as eluent. The product was recrystallized from ethyl acetate. A single recrystallization of the mother liquor gave additional portion of product. Yield: 4.0 g (54%) of (E)-7-chloro-4-(2-dimethylaminovinyl)-2-methoxyquinoline-3-carbonitrile as chinolin-3-carbonitrile boiled under reflux for 2 h in a mixture of solvents, consisting of 3 ml of sulfuric acid, 19 ml of acetic acid and 6.3 ml of water. The reaction mixture was cooled to 0oC and then was poured into 80 ml of ice water. The precipitate was filtered, washed with water, dried under vacuum and recrystallized from dimethylformamide/ethyl acetate. Yield: 1.26 g (59%) of 8-chloro-5-hydroxy-3,4-dihydropyrido[3,4-c]quinoline-4-it is in the form of beige crystals; tPL340-342oC.

Example 41

8,9-dichloro-5-hydroxy-3,4-dihydropyrido[3,4-c]quinoline-4-one

a) a Mixture of 29.6 g (0,145 mole) of 1-(2-amino-4,5 - dichlorophenyl)ethanone and 19.7 g (0,174 mole) of ethylcinnamate, was heated to 210oC for 6 hours, fending off the resultant mixture of water/ethanol. The mixture was allowed to cool to room temperature, the resulting brown mass was ground in a mortar, suspended in ethanol overnight, was filtered, washed with ethanol and dried under vacuum. Output: 30,2 g (82%) of 6,7-dichloro-2-hydroxy-4-methylinosine - 3-carbonitrile in the form of light brown crystals. An analytical sample can be recrystallized from ethanol phase; tPL310-315oC (decomp.).

b) 15 g (0,059 mole) of 6,7-dichloro-2-hydroxy-4-methylinosine-3-carbonitrile suspended in 54 ml of 0.59 mol) of phosphorus oxychloride and stirred and 0.5 l of water and filtered through dicalite. Then was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The product was recrystallized from hot methanol. Output: 10.7 g (66%) 2,6,7-trichloro-4-methylinosine-3-carbonitrile in the form of white crystals; tPL195-197oC.

in) 10.7 g (0,039 mole) 2,6,7-trichloro-4-methylinosine-3-carbonitrile suspended in 1 l of methanol. To the suspension was added to portions of 8.0 g (0,35 mol) of sodium in 40oC and the mixture was stirred at the boiling point under reflux for 16 hours the Mixture was cooled to 40oC and to it was slowly added to 0.5 l of water. The resulting suspension was filtered, washed with water and dried under vacuum. Product with impurities recrystallized from ethyl acetate. Output: 7,42 g (71%) of 6,7-dichloro-2-methoxy-4-methylinosine-3-carbonitrile in the form of white crystals; tPL179-181oC.

g) a Mixture containing 7,42 g (0,028 mole) of 6,7-dichloro-2-methoxy-4 - methylinosine-3-carbonitrile and 33.1 g (0,278 mole) of dimethylacetal N,N-dimethylformamide, was kept at a low boiling under reflux for 17 hours the Mixture is completely concentrated and the residue was recrystallized from hot ethyl acetate. Using recrystallization of the mother liquor gave additional HRP greenish crystals; tPL230-232oC.

d) 2.2 g (0,0069 mol) of (E)-6,7-dichloro-4-(2-dimethylaminovinyl)-2 - methoxyquinoline-3-carbonitrile boiled under reflux for 2 h in a mixture of solvents consisting of 2.4 ml of sulfuric acid, 15 ml of acetic acid and 5.0 ml of water. The reaction mixture was cooled to room temperature and then was poured into 150 ml of ice water. The precipitate was filtered, washed with water, dried under vacuum and recrystallized from dimethylformamide. Output: 1,36 g (70%) of 8,9-dichloro-5-hydroxy-3,4-dihydropyrido[3,4-c]quinoline-4-it is in the form of crystals of pale yellow; tPL> 350oC; MS: me/e (% basic peak) = 280 (C12H6Cl2N2O2+, 90), 252(100), 223 (14), 189(31), 162(18), 127(15), 111(16), 97(22), 81(29), 69(43), 55 (44), 41 (52).

Example 42

5-hydroxy-3,4-dihydropyridin[4,5-c]quinoline-4-one

a) of 6.1 g (0,021 mole) ethyl-4-dimethoxymethyl-2-hydroxyquinolin-3 - carboxylate (E. Ziegler, T. Kappe, G. H. Foraita, Monatsh. Chem. 1966, 97, 409) suspended in 60 ml of 6N aqueous hydrochloric acid and boiled under reflux for 3 minutes. The mixture was cooled to 0oC, was treated with 150 ml of water, filtered under vacuum and washed with water, methanol and ethyl acetate. Yield: 3.5 g (77%) of (RS)-1,4-dihydroxy-1,3-dihydrofuro[3,4-c]quinoline-3-it is in the form hidrofor[3,4 - c]quinoline-3-one was dissolved in 5 ml of dimethyl sulfoxide while bubbling with argon. To the solution was added 0.125 g (0,0025 mole) of hydrazine hydrate and the mixture was stirred at room temperature for 4 days. The resulting suspension was filtered under vacuum and washed with ethyl acetate. Yield: 0.28 g (53%) of 5-hydroxy-3,4 - dihydropyridin[4,5-c] quinoline-4-it is in the form of yellow crystals; tPL> 350oC; MS: me/e (% basic peak) = 213 (C11H7N3O2+, 100), 185(46), 157(18), 129(32), 102(17), 75(10).

Example 43

8-chloro-5-hydroxy-3,4-dihydropyridin[4,5-c]quinoline-4-one

a) 16.0 g (0,083 mole) of a mixture (1:2) 7-chlorhydrin-2,4-diol, 5-chlorhydrin-2,4-diola (T. Kappe, A. S. Karem, W. Stadlbauer, J. Heterocycl. Chem. 1988, 28, 857) suspended in 80 ml of dioxane. To the suspension was added dropwise 9.4 g (to 0.17 mole) of sulfurylchloride at 50oC for 10 minutes and the mixture is boiled under reflux for 20 minutes. The mixture was cooled, poured onto 300 ml ice water, extracted with ethyl acetate and was chromatographically on silica gel using a mixture (19:1) toluene/ethyl acetate as eluent. Both product was recrystallized from simple ether/n-hexane. Yield: 8.8 g (40%) 3,3,7-trichloro-1,2,3,4-tetrahydroquinoline-2,4-dione as yellow-orange crystals; tPL235-236oC and 10.7 g (49%) 3,3,5-trichloro-1,2,3,4-tetrahydroquinoline-2,4-dione in the form of geotrupinae argon. To the mixture dropwise at 65oC for 20 minutes was added a warm solution containing a 13.4 g (0,051 mole) 3,3,7-trichloro-1,2,3,4-tetrahydroquinoline-2,4-dione in 140 ml of methanol. The mixture was boiled under reflux for 15 minutes, and treated with 150 ml of 2N aqueous sodium hydroxide solution and distilled until then, until the internal temperature of the reaction mixture did not reach the 100oC. the Mixture was cooled, extracted with ethyl acetate, and recrystallized from simple ether/n-hexane and the mother liquor was chromatographically on silica gel using a mixture (1:2) n-hexane/ethyl acetate as eluent. Output: 8,9 g (77%) of 1-(2-amino-4-chlorophenyl)-2,2-dimethoxyethane in the form of yellowish crystals; tPL81-82oC.

in) of 8.9 g (0,039 mole) of 1-(2-amino-4-chlorophenyl)-2,2-dimethoxyethane suspended in 31 g (0,19 mole) of diethylmalonate and stirred at 170oC for 18 hours the Mixture was cooled, diluted with 50 ml of a mixture (1:1) ethyl acetate/n-hexane, filtered, concentrated and chromatographically on silica gel using a mixture (1:1) n-hexane/ethyl acetate as eluent. The product was recrystallized from ethyl acetate/n-hexane. Output: 6,63 g (53%) ethyl-7-chloro-4-dimethoxymethyl-2-hydroxyquinolin-3-carboxylate as white crystals; tPLo
C, was treated with 200 ml of water, filtered under vacuum, washed with water and ethyl acetate and dried under vacuum. The product was recrystallized from dimethylformamide/ethyl acetate. Output: 3,85 g (75%) of (RS)-7-chloro-l,4-dihydroxy-1,3-dihydrofuro[3,4 - c] quinoline-3-it is in the form of light beige crystals; tPL270-310oC (decomp. ); MS: me/e (% basic peak) = 251 (C11H6ClNO4+, 31), 223(45), 205(100), 179(80), 177(64), 151(43), 149(43), 114(44).

d) 2.0 g (0,0079 mol) of (RS)-7-chloro-1,4-dihydroxy-1,3 - dihydrofuro[3,4-c] quinoline-3-one was dissolved in 20 ml of dimethyl sulfoxide while bubbling with argon. To the solution was added 0.40 g (0,0062 mole) of hydrazine hydrate and the mixture was stirred at room temperature for 90 hours. The resulting suspension was filtered under vacuum and washed with ethyl acetate. Output: 1,21 g (61%) of 8-chloro-5-hydroxy-3,4 - dihydropyridin[4,5-c] quinoline-4-it is in the form of yellow crystals; tPL> 350oC; MS: me/e (% basic peak) = 247 (C11H6N3O2+, 100), 219(57), 191(15), 163(23), 128(22), 99(13).

Example 44

8,9-dichloro-5-hydroxy-3,4-dihydropyridin[4,5-c]quinoline-4-one

a) 169,8 g (0,738 mole) of a mixture (1:9) 6,7-dichlorohydrin-2,4-diol with 5,6-dichlorohydrin-2,4-diola (T. Kappe, A. S. Karem, W. Stadlbauer, J. Heterocycl.

oC for 3/4 hours and the mixture was stirred at 90oC for 15 minutes. The mixture was cooled, poured into 4 l of ice water and was extracted with ethyl acetate. Output: 204 g (93%) of a mixture with impurities (1:9) 3,3,6,7-tetrachloro-1,2,3,4-tetrahydroquinoline-2,4-dione with 3,3,5,6-tetrachloro-1,2,3,4-tetrahydroquinoline-2,4-dione as yellow crystals.

b) of 47.1 g (2.05 mol) of sodium was dissolved in 1 l of methanol while bubbling with argon. To the mixture dropwise at 65oC for 20 minutes was added a warm solution containing 204 g (of 0.68 mole) of a mixture with impurities (1:9) 3,3,6,7-tetrachloro-1,2,3,4-tetrahydroquinoline - 2,4-dione with 3,3,5,6-tetrachloro-1,2,3,4-tetrahydroquinoline-2,4-dione in 1.2 l of methanol. The mixture was boiled under reflux for 10 minutes, and treated with 2 l 2 N. aqueous sodium hydroxide solution and distilled until then, until the internal temperature of the reaction mixture did not reach the 100oC. the Mixture was cooled, extracted with ethyl acetate and was chromatographically on silica gel using a mixture (4:1) n-hexane/ethyl acetate as eluent. Both product was recrystallized from simple ether/n-hexane. Output: 22,7 g (13%) 1-(2-amino-4,5-dichlorophenyl)-2,2-dimethoxyethane in the form of yellowish crystals; tPL91-92oC and 45.3 g (25%) of 1-(2-amino-5,6-dichlorophenyl)-2,2-dimethoxyethoxy suspended in 69 g (of 0.43 mole) of diethylmalonate and stirred at 170oC for 15 h the Mixture was cooled, diluted with 50 ml ethyl acetate and several times was chromatographically on silica gel using a mixture (3:1) n-hexane/ethyl acetate as eluent. The product was dissolved in hot ethyl acetate and recrystallized by adding n-hexane. In this way they obtained 7.6 g (33%) of the educt in the form of an orange oil. Yield: 3.1 g (15%) ethyl-6,7-dichloro-4 - dimethoxymethyl-2-hydroxyquinolin-3-carboxylate as white crystals; tPL198-200oC.

g) 4.7 g (0,013 mol) ethyl-6,7-dichloro-4-dimethoxymethyl-2 - hydroxyquinolin-3-carboxylate suspended in 50 ml of 25% aqueous hydrochloric acid and stirred at 100oC for 30 minutes. The mixture was cooled to 0oC, was treated with 150 ml of water, filtered under vacuum and dried under vacuum. The product was recrystallized from dimethylformamide/ethyl acetate. Output: 2,90 g (78%) of (RS)-7,8-dichloro-1,4-dihydroxy-1,3-dihydrofuro[3,4 - c] quinoline-3-it is in the form of a beige-brownish crystals; tPL275oC (decomp.).

d) of 1.76 g (0,0062 mol) of (RS)-7,8-dichloro-1,4-dihydroxy-1,3 - dihydrofuro[3,4-c] quinoline-3-one was dissolved in 18 ml of dimethyl sulfoxide while bubbling with argon. To the solution was added 0.31 g (0,0062 mole) of hydrazine hydrate and the mixture was stirred at room is 0.32 g (18%) of 8,9-dichloro-5-hydroxy - 3,4-dihydropyridin[4,5-c]quinoline-4-it is in the form of yellow crystals; tPL> 350oC; MS: me/e (% basic peak) = 281 (C11H5Cl2N3O2+, 100), 253(62), 225(16), 197(37), 162(29), 124(13), 99(19).

Example 45

9,10-dichloro-5-hydroxy-3,4-dihydropyridin[4,5-c]quinoline-4-one

a) of 13.1 g (0,050 mole) of 1-(2-amino-5,6-dichlorophenyl)-2,2-dimethoxyethane was dissolved in 250 ml dichloromethane and treated with 5.5 g (by 0.055 mole) of triethylamine. Within 15 minutes at 0oC was added dropwise to 8.2 g (by 0.055 mole) of ethylmaleimide. The mixture was additionally stirred at 0oC for 15 minutes, and treated with 150 ml of water, was extracted with dichloromethane and was chromatographically on silica gel using first a mixture (4:1) dichloromethane/n-hexane and then methanol as eluent. The methanol fractions were concentrated, dissolved in hot ethyl acetate, filtered and concentrated. The residue was recrystallized from a simple ether/n-hexane. Yield: 10.2 g (54%) of racemic mixtures of ethyl(CIS and/or TRANS)-5,6-dichloro - 4-dimethoxymethyl-2,4-dihydroxy-3,4-dihydroquinoline-3-carboxylate as white crystals; tPL265-270oC (decomp.).

b) 5.0 g (0,013 mol) of racemic mixtures of ethyl(CIS and/or TRANS)-5,6-dichloro-4-dimethoxymethyl-2,4-dihydroxy-3,4-dihydroquinoline - 3-carboxylate suspended in the UP>C. the Mixture was cooled, and treated with 400 ml of water, filtered under vacuum and dried under vacuum. The product was dissolved in hot dimethylformamide, filtered, and partially concentrated and recrystallized by adding ethyl acetate. Output: 2,95 g (78%) of (RS)-8,9-dichloro-1,4 - dihydroxy-1,3-dihydrofuro[3,4-c]quinoline-3-one as yellowish crystals; tPL285-290oC (decomp.).

in) 2.9 g (0,010 mol) of (RS)-8,9-dichloro-1,4-dihydroxy-1,3 - dihydrofuro[3,4-c] quinoline-3-one was dissolved in 60 ml of dimethyl sulfoxide while bubbling with argon. To the solution was added 0.51 g (0,010 mol) of hydrazine hydrate and the mixture was stirred at room temperature for 50 hours Received an orange solution, which was treated with 300 ml of ethyl acetate. The precipitated product was filtered under vacuum, washed with ethyl acetate and recrystallized from dimethylformamide/ethyl acetate. Output: 0,70 g (25%) of 9,10-dichloro-5-hydroxy - 3,4-dihydropyridin[4,5-c] quinoline-4-it is in the form of yellow-orange crystals; tPL270oC; MS: me/e (% basic peak) = 281 (C11H5Cl2N3O2+, 100), 253(60), 239(19), 213(40), 185(15), 162(23). 148(16), 123(16), 45(58).

Example 46

8,10-dichloro-5-hydroxy-3,4-dihydropyridin[4,5-c]quinoline-4-one

a) and 9.1 g (0,040 mole) of 5,7-Dahl who was spencervale in 60 ml of dioxane. To the suspension was added dropwise to 14.7 g (of 0.11 mol) of sulfurylchloride at 50oC for 10 minutes and the mixture is boiled under reflux for 10 minutes. The mixture was cooled, poured onto 150 ml of ice water and was extracted with ethyl acetate. An analytical sample was recrystallized from methanol. Yield: 12.3 g (100%) 3,3,5,7-tetrachloro-1,2,3,4-tetrahydroquinoline-2,4-dione as yellowish crystals; tPL248-254oC (decomp.).

b) 2.83 g (0,123 mole) of sodium was dissolved in 60 ml of methanol while bubbling with argon. To this solution was added dropwise a solution containing 12.3 g (0,040 mole) 3,3,5,7-tetrachloro-1,2,3,4 - tetrahydroquinoline-2,4-dione in 300 ml of methanol at the boiling point under reflux for 10 minutes. The mixture was boiled under reflux for 10 minutes, and treated with 120 ml of 2 N. aqueous sodium hydroxide solution and distilled until then, until the internal temperature of the reaction mixture did not reach the 100oC. the Mixture was cooled, extracted with ethyl acetate and was chromatographically on silica gel using a mixture (19:1) toluene/ethyl acetate as eluent. Output: value of 4.76 g (43%) of 1-(2-amino-4,6-dichlorophenyl)-2,2-dimethoxyethane in the form of red-orange viscous oil; MS: me/e (% basic peak) = 232(1,0), 200(6,4), 188(6,0), 160(2,0)�Tana and was treated with 2.2 g (0,022 mol) of triethylamine. At 0oC for 10 minutes was added dropwise 3.3 g (0,022 mol) of ethylmaleimide. The mixture was stirred at room temperature for 16 h, and treated with 50 ml of water and was extracted with dichloromethane. Product with impurities was dissolved in 50 ml of ethanol for 15 minutes at the temperature of reflux distilled was added dropwise to a solution containing 1.24 g (0,054 mole) of sodium in 60 ml of ethanol. The mixture was boiled under reflux for 1 h, concentrated, treated with water, extracted with ethyl acetate and was chromatographically on silica gel using a mixture (9:1) dichloromethane/n-hexane as eluent. The product was recrystallized from simple ether/n-hexane. Output: 3.58 g (55%) of ethyl-5,7-dichloro-4-dimethoxymethyl-2-hydroxyquinolin-3-carboxylate as white crystals; tPL167-170oC.

d) 5.0 g (of 0.014 mole) ethyl-5,7-dichloro-4-dimethoxymethyl-2 - hydroxyquinolin-3-carboxylate suspended in a mixture of 84 ml of acetic acid, 28 ml of water and 14 ml of sulfuric acid, and stirred at 100oC for 16 hours the Mixture was cooled, and treated with 50 ml of water, filtered under vacuum and dried under vacuum. Output: 3.88 g (98%) of (RS)-7,9-dichloro-1,4-dihydroxy-1,3-dihydrofuro[3,4-c]quinoline-3-one as white crystals; tPLPL> 350oC; MS: me/e (% basic peak) = 281 (C11H5Cl2N3O2+, 100), 253(92), 213(14), 197(17), 162(29), 57(42).

Example 47

4-hydroxy-2,3-dihydro-1H-pyridinol[4,3-c]quinoline-3-one

a) 5.35 g (0,22 mol) of magnesium shavings were treated with a mixture consisting of 5 ml of methanol and 0.5 ml of carbon tetrachloride, while bubbling with argon. After start of the reaction to a mixture of caution was added dropwise 75 ml of diethyl ether. Then was added dropwise a mixture of 35.2 g (0,22 mole) of diethylmalonate, 20 ml ethanol and 20 ml simple ether, thereby to maintain a low boil the reaction mixture. After stirring at the boiling point under reflux for an additional 2.5 h was added dropwise a solution containing 37,1 g (of 0.20 mole) of 2-nitrobenzotrifluoride in 130 ml of diethyl ether. The mixture was boiled under reflux for 1 h, techenie 20 minutes was extracted with diethyl ether, concentrated and dried at 120oC in high vacuum. Output: 53,7 g (86%) of diethyl-2-(2-nitrobenzoyl)malonate liquid orange. MS: me/e (% basic peak) = 309 (C14H15NO7+, 0,3), 264(2,5), 263(2,3), 217(3,7), 205(5,3), 189(8), 159(13), 150(100), 135(21), 104(19), 76(19), 51(22), 44(19), 29(46).

b) a Freshly prepared solution of diazomethane (0,038 mol in 150 ml diethyl ether) was added dropwise in 5oC for 2 minutes to a solution containing 9,90 g (to 0.032 mole) diethyl-2-(2-nitrobenzoyl)malonate in 150 ml of diethyl ether. The yellow solution was kept at room temperature for 2 h, excess diazomethane was dissolved with 2 g of benzoic acid, the mixture was concentrated and was chromatographically on silica gel using a mixture (9: 1) toluene/ethyl acetate as eluent. The product was distilled in a tube with ball extension (tKip210-220oC/if of 0.005 Torr) and recrystallized from diethyl ether/n-hexane at -40oC. Yield: 9.0 g (87%) of diethyl(2-[methoxy-(2-nitrophenyl)methylene] malonate in the form of white crystals; tPL73-74oC.

in) of 3.23 g (0,010 mol) diethyl(2-[methoxy-(2-nitrophenyl)methylene]malonate was dissolved in 70 ml of hot ethanol. To ohlazhdeniya 2 h, then thereto was added 1.1 g (0,022 mol) of hydrazine hydrate, and the mixture was boiled under reflux for 2 h and concentrated completely. The oil obtained was transferred into a 100 ml acetic acid ethyl ester are boiled under reflux and cooled. The resulting suspension was filtered under vacuum. The precipitate on the filter was transferred into 100 ml of water, brought to pH 2 using 10 ml of 1 N. aqueous hydrochloric acid and the precipitated product was filtered under vacuum. The product was recrystallized from ethanol/water. Output: 1,93 g (70%) ethyl-5-(2-nitrophenyl)-3-oxo - 2,3-dihydro-1H-pyrazole-4-carboxylate as white crystals; tPL183-185oC.

g) a Solution containing 0.55 g (0,002 mol) ethyl-5-(2-nitrophenyl)- 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate in 40 ml of ethanol was treated with 50 mg 10% Pd/C and was first made for 1.5 h at room temperature under atmospheric pressure. The catalyst was filtered, the filtrate was concentrated and the residue was recrystallized from ethyl acetate/hexane. Yield: 0.34 g (69%) of ethyl-5-(2-AMINOPHENYL)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate as white crystals; tPL> 350oC. MS: me/e (% basic peak) = 247 (C12H13N3O3+, 18), 201(100), 145(36), 144(33), 117(56), 89(30).

d) 0.25 g (0,00 who recorded under reflux for 2 hours The mixture was cooled, and treated with 20 ml of ethyl acetate, filtered under vacuum and dried under vacuum. Yield: 0.14 g (70%) 4-hydroxy-2,3-dihydro-1H - pyridinol[4,3-c] quinoline-3-it is in the form of beige crystals; tPL> 350oC. MS: me/e (% basic peak) = 201 (C10H7N3O2+, 100), 145(27), 144(32), 127(7), 117(33), 116(24), 89(21), 69(17), 57(21), 43(22).

Example 48

7-chloro-4-hydroxy-2,3-dihydro-1H-pyridinol[4,3-c]quinoline-3-one

a) to 3.52 g (0,145 mol) magnesium turnings while bubbling with argon was treated with a mixture consisting of 3.5 ml of ethanol and 0.35 ml of carbon tetrachloride. After start of the reaction to a mixture of caution was added dropwise 50 ml of diethyl ether. Then was added dropwise a mixture of 23.3 g (0,145 mole) of diethylmalonate, 15 ml of ethanol and 15 ml of diethyl ether, thereby to maintain a low boil the reaction mixture. After stirring at the boiling point under reflux for 3 h was added dropwise a solution containing of 25.8 g (0.12 moles) of 4-chloro-2-nitrobenzotrifluoride in 60 ml of a simple ester. The mixture was boiled under reflux for 1 h, cooled to 0oC, slowly was added dropwise 150 ml of 2 N. aqueous hydrochloric acid, the mixture was stirred for 10 minutes, extras the Ira/n-hexane at -78oC. Output: 36,6 g (91%) of diethyl-2-(4-chloro-2-nitrobenzoyl)malonate in the form of white crystals; tPL43-45oC.

b) a Freshly prepared solution of diazomethane (0,034 mol in 150 ml diethyl ether) was added dropwise in 5oC for 2 minutes to a solution of 10.3 g (0,030 mole) diethyl-2-(4-chloro-2-nitrobenzoyl)malonate in 150 ml of diethyl ether. The yellow solution was stirred at 5oC for 1 h, boiled under reflux for 10 minutes and fully concentrated. Yield: 10.8 g (100%) of diethyl-2-[(4-chloro-2-nitrophenyl)methoxymethyl]malonate in the form of a yellowish viscous oil; MS: me/e (% basic peak) = 312(17), 297(5), 239(5), 237(13), 225(2), 186(10), 180(11), 154(13), 138(11), 125(19), 112(9), 99(5), 87(6), 75(9), 59(10), 29(100).

in) 10.7 g (0,030 mole) diethyl-2-[(4-chloro-2-nitrophenyl) methoxymethyl] malonate was dissolved in 200 ml of ethanol and was treated with 6.0 g (0.12 moles) of hydrazine hydrate. The mixture was boiled under reflux for 1 h and fully concentrated. The resulting oil was dissolved in 400 ml of water, the pH was brought to 1 with 30 ml of 25% aqueous hydrochloric acid, and treated with 1.5 l of ethyl acetate, filtered, extracted with ethyl acetate and concentrated. The product was recrystallized from hot ethyl acetate. Output: 5.2 g (56%) of ethyl-5-(4-chloro-2-no="ptx2">

g) a Solution containing 5.2 g (of 0.017 mole) ethyl-5-(4-chloro-2 - nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate in 300 ml of tetrahydrofuran, was treated with 520 mg of 10% Pd/C and was first made for 21 h at room temperature and at atmospheric pressure. The catalyst was filtered, the filtrate was concentrated and the residue was recrystallized from ethyl acetate/n-hexane. Yield: 3.1 g (66%) of ethyl-5-(2-amino-4-chlorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate as white crystals; tPL> 350oC; MS: me/e (% basic peak) = 281 (C12H12ClN3O3+, 11), 235(100), 206(2), 178(24), 151(35), 123(12), 114(9), 89(12), 45(14), 31(27).

d) 3.1 g (to 0.011 mole) ethyl-5-(2-amino-4-chlorophenyl)-3-oxo-2,3 - dihydro-1H-pyrazole-4-carboxylate was dissolved in 30 ml of dimethylformamide was heated under reflux for 2 hours the Mixture was concentrated, the residue is suspended in 150 ml of methanol at the temperature of reflux distilled, cooled, filtered under vacuum and dried under vacuum. Yield: 1.1 g (42%) of 7-chloro-4-hydroxy-2,3-dihydro-1H - pyridinol[4,3-c]quinoline-3-it is in the form of brownish crystals; tPL> 350oC; MS: me/e (% basic peak) = 235 (C10H6ClN3O2+, 100), 201(2), 179(26), 178(34), 151(42), 123(17), 114(14), 89(15).

Example 49

7,8-desu, consisting of of 1.95 ml of ethanol and of € 0.195 ml of carbon tetrachloride. After start of the reaction to a mixture of caution was added dropwise 30 ml of diethyl ether. Then was added dropwise a mixture of 1.28 g (0,080 mole) of diethylmalonate, 8 ml of ethanol and 9 ml of diethyl ether, thereby to maintain a low boil the reaction mixture. After stirring at the boiling point under reflux for 2 h was added dropwise a solution containing 19.5 g (0,072 mole) of 4,5-dichloro-2-nitrobenzotrifluoride in 30 ml of diethyl ether. The mixture was boiled under reflux for 1 h, cooled to 0oC, slowly was added dropwise 75 ml of 2 N. aqueous hydrochloric acid, the mixture was stirred for 15 minutes, was extracted with diethyl ether and concentrated. The crystalline residue was recrystallized from hot ethanol. Yield: 17.9 g (65%) of diethyl-2-(4,5-dichloro-2-nitrobenzoyl)malonate in the form of whitish crystals; tPL93-94oC.

b) a Freshly prepared solution of diazomethane (0,052 mole in diethyl ether) was added dropwise in 5oC for 2 minutes to a solution containing 17.9 g (0,047 mole) diethyl-2-(4,5-dichloro-2 - nitrobenzoyl)malonate in 350 ml of diethyl ether. The solution yellow premesis the Lee. Yield: 18.6 g (100%) of diethyl-2-[(4,5-dichloro-2-nitrophenyl)methoxymethyl] malonate in the form of a yellow viscous oil; MS: me/e (ISP) = 392,2 (C15H15Cl2NO7+).

in) of 18.6 g (0,047 mole) diethyl-2-[(4,5-dichloro-2-nitrophenyl) methoxymethyl] malonate was dissolved in 400 ml of ethanol and was treated with 9.5 g (to 0.19 mol) of hydrazine hydrate. The mixture was boiled under reflux for 1 h and fully concentrated. The residue is suspended in 200 ml of ethyl acetate was filtered under vacuum and dissolved in 2 l of water. Then the pH was brought to 1 with 2 N. aqueous hydrochloric acid and the precipitated product was filtered under vacuum, was dissolved in hot ethyl acetate and recrystallized by adding n-hexane at 0oC. Yield: 11.8 g (72%) of ethyl-5-(4,5-dichloro-2-nitrophenyl)-3-oxo-2,3-dihydro-1H - pyrazole-4-carboxylate in the form of light beige crystals; tPL156-158oC.

g) a Solution containing 5.0 g (of 0.014 mole) ethyl-5-(4,5-dichloro-2 - nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate in 200 ml of ethyl acetate, and treated with 0.5 g 10% Pd/C and was first made for 6 h at room temperature under atmospheric pressure. The catalyst was filtered, the filtrate was concentrated and the residue was recrystallized from ETDE white crystals; tPL170-175oC (decomp.).

d) to 0.63 g (0,002 mol) ethyl-5-(2-amino-4,5-dichlorophenyl)-3-oxo - 2,3-dihydro-1H-pyrazole-4-carboxylate was dissolved in 10 ml of dimethylformamide was heated under reflux for 0.5 hours the Mixture was cooled, the suspension was treated with 50 ml of ethanol, filtered under vacuum and dried under vacuum. Yield: 0.18 g (33%) of 7,8-dichloro-4-hydroxy-2,3-dihydro-1H-pyridinol[4,3-c] quinoline-3-it is in the form of brownish crystals; tPL> 350oC; MS: me/e (% basic peak) = 269 (C10H5Cl2N3O2+, 100), 213(31), 185(36), 157(12), 150(15), 125(11), 73(48), 44(68).

Example 50

4-hydroxy-7,8-dimethyl-2,3-dihydro-1H-pyridinol[4,3-c]quinoline-3-one

a) 2,96 g (0,122 mol) magnesium turnings while bubbling with argon was treated with a mixture consisting of 3 ml of ethanol and 0.3 ml of carbon tetrachloride. After start of the reaction to a mixture of caution was added dropwise 90 ml of diethyl ether. Then was added dropwise a mixture of 19.5 g (0,122 mole) of diethylmalonate, 11 ml of ethanol and 14 ml of diethyl ether, thereby to maintain a low boil the reaction mixture. After stirring while boiling under reflux for 2.5 h was added dropwise a solution containing 24.5 g (0,106 mole) of 4,5-him. Acta 1980, 63, 385) with thionyl chloride in 300 ml of a mixture (2:1) diethyl ether/tetrahydrofuran. The mixture was boiled under reflux for 1 h, cooled to 0oC slowly dropwise added 160 ml of 2 N. aqueous hydrochloric acid, the mixture was stirred for 10 minutes, was extracted with diethyl ether and concentrated. The oily residue was recrystallized from diethyl ether/n-hexane at -20oC. Yield: 32.7 g (88%) of diethyl-2-(4,5-dimethyl-2-nitrobenzoyl)malonate in the form of a whitish-beige crystals; tPL78-80oC.

b) a Freshly prepared solution of diazomethane (0,070 mole in diethyl ether) was added dropwise in 5oC for 2 minutes to a solution containing a 20.3 g (to 0.060 mole) diethyl-2-(4,5-dimethyl-2 - nitrobenzoyl)malonate in 250 ml of diethyl ether. The yellow solution was stirred at 5oC for 0.5 h, kept at room temperature for 16 hours and fully concentrated. Output: 21,5 g (100%) of diethyl-2-[(4,5-dimethyl-2-nitrophenyl)methoxymethyl] malonate in the form of an orange oil; MS: me/e (% basic peak) = 306 (C17H21NO7, 13), 231(38), 189(7), 188(7), 174(14), 158(8), 148(27), 119(47), 106(25), 91(21), 77(20), 29(100).

in) of 21.5 g (0,06 mole) diethyl-2-[(4,5-dimethyl-2-nitrophenyl) methoxymethyl] mA what Hladilnika for 2 h, was cooled to 0oC and the suspension was filtered under vacuum. The crystals were dissolved in 1 l of water. After that, the pH of the mixture was brought to 1 with 1 N. aqueous hydrochloric acid and the precipitated product was filtered under vacuum. Output: 15,8 g (86%) of ethyl-5-(4,5-dimethyl-2-nitrophenyl)-3-oxo-2,3-dihydro - 1H-pyrazole-4-carboxylate in the form of light beige crystals; tPL166-167oC.

g) a Solution containing 15,8 g (0,051 mole) ethyl-5-(4,5-dimethyl-2 - nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate in 450 ml of ethanol was treated with 1.6 g of 10% Pd/C and was first made for 17 h at room temperature and at atmospheric pressure. The mixture was boiled under reflux, the catalyst was filtered from the hot mixture, the filtrate was concentrated and the residue was recrystallized from ethyl acetate/n-hexane. Output: 9,40 g (66%) of ethyl-5-(2-amino-4,5-dimetilfenil)-3-oxo-2,3-dihydro-1H-pyrazole-4 - carboxylate as white crystals; tPL> 350oC; MS: me/e (% basic peak) = 275 (C14H17N3O3+, 12), 229(100), 214(14), 172(24), 158(16), 144(12), 130(9), 115(11), 69(13), 45(17), 31(32).

d) of 4.2 g (0,015 mol) ethyl-5-(2-amino-4,5-dimetilfenil)-3-oxo - 2,3-dihydro-1H-pyrazole-4-carboxylate was dissolved in 50 ml of dimethylformamide and heated with reverse is dried under vacuum. Yield: 3.0 g (86%) of 4-hydroxy-7,8-dimethyl-2,3 - dihydro-1H-pyridinol[4,3-c] quinoline-3-one as white crystals; tPL> 350oC; MS: me/e (% basic peak) = 229 (C12H11N3O2+, 100), 214(14), 172(27), 158(20), 144(14), 130(9), 115(12).

Example 51

4-hydroxy-7-methoxy-2,3-dihydro-1H-pyrazole[4,3-c]quinoline-3-one

a) of 3.07 g (to 0.127 mol) magnesium turnings while bubbling with argon was treated with a mixture consisting of 3 ml of ethanol and 0.3 ml of carbon tetrachloride. After start of the reaction to a mixture of caution was added dropwise 100 ml of diethyl ether. Then was added dropwise a mixture of 20.3 g (to 0.127 mole) of diethylmalonate, 11.5 ml of ethanol and 14.5 ml of diethyl ether, thereby to maintain a low boil the reaction mixture. After stirring at the temperature of reflux distilled for 2.5 h was added dropwise a solution containing of 26.1 g (0.12 moles) of 4-methoxy-2-nitrobenzaldehyde in 100 ml of tetrahydrofuran. The mixture was boiled under reflux for 1/4 h, cooled to 0oC slowly dropwise added 160 ml of 2 N. aqueous hydrochloric acid, the mixture was stirred for 15 minutes, was extracted with diethyl ether, concentrated and chromatographically on silica gel using dichloromethane as the main peak) = 293(2), 247(8), 219(12), 180(65), 134(23), 106(43), 63(54), 29(100).

b) a Freshly prepared solution of diazomethane (0,10 mol in diethyl ether) was added dropwise in 5oC for 2 minutes to a solution containing 33 g (0,097 mole) diethyl-2-(4-methoxy-2 - nitrobenzoyl)malonate in 200 ml of diethyl ether. The solution was stirred at room temperature for 2 hours and fully concentrated. Yield: 34 g (100%) of diethyl-2-[(4-methoxy-2 - nitrophenyl)methoxymethyl]malonate in the form of an orange oil; MS: me/e (% basic peak) = 353 (C16H19NO8+, 2), 308(21), 233(29), 189(14), 176(16), 150(24), 121(29), 106(22), 77(12), 63(14), 29(100).

in) 34 g (0,097 mole) diethyl-2-[(4-methoxy-2-nitrophenyl) methoxymethyl] malonate was dissolved in 400 ml of ethanol and treated with 19.4 g (0,387 mole) of hydrazine hydrate. The mixture was boiled under reflux for 1.5 h, cooled to 0oC and then concentrated to a volume of 200 ml of the Obtained crystals was then cooled, filtered under vacuum and dissolved in 3/4 liter of water. After that, the pH of the mixture was brought to 2 with 1 N. aqueous hydrochloric acid and the precipitated product was filtered under vacuum. Output: 22.9 grams (77%) of ethyl-5-(4-methoxy-2-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole - 4-carboxylate in the form of light yellow crystals; toC at atmospheric pressure. The catalyst was filtered and the filtrate is completely concentrated. Yield: 19 g (91%) of ethyl-5-(2-amino-4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate in the form of light yellow crystals; tPL> 350oC; MS: me/e (% basic peak) = 277 (C13H15N3O4+, 13), 231(100), 188(18), 174(17), 147(10), 132(14).

d) 5.8 g (0,021 mole) ethyl-5-(2-amino-4-methoxyphenyl)-3-oxo - 2,3-dihydro-1H-pyrazole-4-carboxylate was dissolved in 60 ml of dimethylformamide was heated under reflux for 0.5 hours the Mixture was cooled, the suspension was treated with 120 ml of ethanol, filtered under vacuum and dried under vacuum. Yield: 4.5 g (93%) of 4-hydroxy-7-methoxy-2,3-dihydro-1H-pyrazole[4,3-c]quinoline-3-one as light yellow crystals; tPL> 350oC; MS: me/e (% basic peak) = 231 (C11H9N3O3+, 100), 188(27), 174(20), 146(14), 132(18), 104(8), 77(11), 69(14), 43(16).

Example 52

4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c]quinoline-3-one

a) a Solution containing of 1.03 g (0,0058 mole) of 1-(2-AMINOPHENYL)-2-azidoethoxy (J. H. Boyer, D. Straw, J. Am. Chem. Soc. 1953, 75, 1642, 2683) in 25 ml dichloromethane, treated of 0.53 g (0,0053 mol) of triethylamine while bubbling Argo at 0oC for 1/2 h at room temperature and for 2.5 hours at a temperature of reflux distilled. The mixture was cooled to room temperature, was poured into dilute aqueous hydrochloric acid, was extracted with dichloromethane and fully concentrated. The residue was dissolved in 30 ml of hot toluene was added 3 drops of piperidine and the mixture is boiled under reflux for 2 hours the Mixture was cooled to 0oC and the resulting suspension was filtered under vacuum. The product was recrystallized from hot ethyl acetate. Yield: 0.88 g (56%) of ethyl-4-azidomethyl-2-hydroxyquinolin-3-carboxylate as white crystals; tPL195-197oC (decomp.).

b) 0.27 g (0,0010 mole) ethyl-4-azidomethyl-2-hydroxyquinolin-3 - carboxylate was dissolved in 20 ml of hot dimethylformamide and treated with 14 mg of 10% Pd/C. for 1.5 hours slowly passed a stream of hydrogen. The suspension was filtered in an atmosphere of argon and the filtrate was partially concentrated in high vacuum. The residue was treated with 25 ml of degassed ethanol was filtered, dried under vacuum and received 60 mg (30%) 4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c] quinoline-3-it is as sensitive to the action of air solid product. The mother solution is completely concentrated. Was antirouille, was chromatographically on silica gel using a mixture (9:1) ethyl acetate/methanol as eluent, and the product was recrystallized from hot ethyl acetate. Output: 0,033 g (15%) 4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c]quinoline-3-dione as yellow crystals; tPL340-350oC (decomp. , subl.); MS: me/e (% basic peak) = 214 (C11H6N2O3+, 100), 186(9), 171(18), 158(7), 143(33), 115(34), 88(14), 58(16).

Example 53

7-chloro-4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c]quinoline-1,3-dione

a) of 8.9 g (to 0.032 mole) of 2-bromo-1-(4-chloro-2-nitrophenyl)ethanone (obtained analogously to 2-bromo-1-(2-nitrophenyl)ethanone, as described in P. Ruggy, H. Reichwein, Helv. Chem. Acta 1937, 20, 913), was dissolved in 66 ml of sulfuric acid at 50oC. To the solution was added in portions 7.78 g (0.12 gram-atom) of copper powder thus, in order to maintain the temperature at approximately the 50oC. the Mixture was stirred at 50oC for 15 minutes, poured on ice, was added water to obtain a volume of 510 ml, was extracted with diethyl ether and concentrated. The residue was recrystallized from isopropyl ether. Output: of 6.26 g (79%) of 1-(2-amino-4-chlorophenyl)-2-brometea in the form of beige crystals; tPL112-114oC.

b) a Solution containing 0.54 g (0,0084 mole) of azide nattonal. The mixture was stirred at 0oC for 1/2 h at room temperature for 1/2 h at the boiling point under reflux for 1 h, cooled, poured into water and was extracted with diethyl ether. The product was recrystallized from diethyl ether/n-hexane. Yield: 1.47 g (87%) of 1-(2-amino-4-chlorophenyl)-2-azidoethoxy in the form of beige crystals; tPL107-108oC.

C) a Solution containing to 3.92 g (0,0018 mole) of 1-(2-amino-4-chlorophenyl)- 2-azidoethoxy in 150 ml of dichloromethane, was treated 3,76 g (0,0037 mol) of triethylamine while bubbling with argon. At 0oC was added dropwise to 4.2 g (0,028 mole) of ethylmaleimide and the mixture was stirred at 0oC for 5 minutes, at room temperature for 1/2 h at the boiling point under reflux for 24 hours the Mixture is completely concentrated and chromatographically on silica gel using a mixture (2: 1) cyclohexane/ethyl acetate as eluent. The product was recrystallized from diethyl ether. Output: of 2.26 g (83%) of ethyl-4-azidomethyl-7-chloro-2-hydroxyquinoline-3-carboxylate as white crystals; tPL188-190oC.

g) 1.0 g (0,0032 mole) ethyl-4-azidomethyl-7-chloro-2-hydroxyquinoline - 3-carboxylate was dissolved in the mixture, sauce and a stream of hydrogen. The suspension was filtered under vacuum and the residue on the filter is suspended in dimethylformamide. The suspension was filtered, concentrated, the residue is suspended in methanol and filtered under vacuum. Substance (0.31 g) suspended in dimethylformamide and slowly let in a stream of oxygen for 4 h the Mixture was concentrated and the product recrystallized from dimethylformamide/methanol. Output: 0,13 g (18%) of 7-chloro-4-hydroxy-2,3 - dihydro-1H-pyrrole[3,4-c] quinoline-3-dione as yellow crystals; tPL> 350oC; MS: me/e (% basic peak) = 248 (C11H5ClN2O3+, 100), 205(23), 177(27), 149(18), 114(20).

Example 54

7,8-dichloro-4-hydroxy-2,3-dihydro-1H-pyrrole[3,4-c]quinoline-1,3-dione

a) 9,17 g (ě 0.030 mole) of 2-bromo-1-(4,5-dichloro-2-nitrophenyl)ethanone (obtained analogously to 2-bromo-1-(2-nitrophenyl)ethanone, as described in P. Ruggy, H. Reichwein, Helv. Chem. Acta 1937, 20, 913), was dissolved in 100 ml of sulfuric acid at 50oC. To the solution was added in portions 7,13 g (0,112 gram-atom) of copper powder thus, in order to maintain the temperature at approximately the 50oC. the Mixture was stirred at 50oC for 15 minutes, poured on ice, was added water to obtain a volume of 470 ml, the mixture was extracted with diethyl ether, concentrated is from isopropyl ether. Output: 6,82 g (54%) of 1-(2-amino-4,5-dichlorophenyl)-2-brometea in the form of yellow crystals; tPL122-123oC.

b) a Solution containing 1,38 g (0,021 mole) of sodium azide in 60 ml of methanol, was added at 0oC to a solution containing 5.75 g (at 0.020 mole) of 1-(2-amino-4,5-dichlorophenyl)-2-brometea in 110 ml of methanol. The mixture was stirred at 0oC for 1/2 h at room temperature for 1/2 h at the boiling point under reflux for 1.5 h, cooled, poured into water and was extracted with diethyl ether. The product was recrystallized from isopropyl ether. Output: 4.94 g (100%) 1-(2-amino-4,5-dichlorophenyl)- 2-azidoethoxy as greenish crystals; tPL136-137oC.

C) a Solution containing of 3.78 g (0,015 mol) of 1-(2-amino-4,5 - dichlorophenyl)-2-azidoethoxy in 150 ml of dichloromethane, was treated with 3.12 g (0,030 mol) of triethylamine while bubbling with argon. At 0oC was added dropwise 3,48 g (is 0.023 mole) of ethylmaleimide and the mixture was stirred at 0oC for 5 minutes, at room temperature for 1/2 h at the boiling point under reflux for 48 hours the Mixture was cooled to room temperature, fully concentrated and chromatographically on silica gel using a mixture of (a) ethyl-4-azidomethyl-6,7-dichloro-2-hydroxyquinolin-3-carboxylate in the form of beige crystals; tPL197-198oC.

g) 1.0 g (of 0.003 mole) ethyl-4-azidomethyl-6,7-dichloro-2-hydroxyquinolin - 3-carboxylate was dissolved in a mixture consisting of 80 ml of methanol and 20 ml of dimethylformamide, and treated with 50 mg 10% Pd/C. for 1.25 hours slowly passed a stream of hydrogen. The suspension was filtered under vacuum and the residue on the filter is suspended in dimethylformamide. The mixture was filtered, concentrated, the residue is suspended in methanol and filtered under vacuum. Substance (0.31 g) suspended in dimethylformamide and slowly let in a stream of oxygen for 2 hours the Mixture was concentrated and the product recrystallized from dimethylformamide/methanol. Yield: 0.27 g (20%) of 7,8-dichloro-4-hydroxy - 2,3-dihydro-1H-pyrrole[3,4-c] quinoline-3-dione as yellow crystals; tPL> 350oC; MS: me/e (% basic peak) = 282 (C11H4Cl2N2O3+, 100), 239(18), 211(29), 183(15), 148(24), 92(10).

Example 55

7-nitro-2,3,4,5-tetrahydrooxazolo[4,5-c]quinoline-3,4-dione

a) and 7.7 ml (55 mmol) of triethylamine was added dropwise to a suspension containing 10.0 g (4.3 mmole) of the hydrochloride of the ethyl-2-amino-4-nitrobenzoate in 100 ml of acetone. Then added 6,55 ml (52 mmole) of methylmaleimide. The reaction mixture was left for paramashiva the 83 mmole) of sodium in 110 ml of ethanol. The reaction mixture is boiled under reflux for 2.5 hours After removal of the solvent the residue was dissolved in 200 ml of water and heated to 60oC for 1 h Then the mixture was filtered through dicalite and then the pH was brought to pH 3.5 with 3 N. HCl. Emitted when this precipitate was filtered, washed with water and dried in high vacuum. Yield: 7.2 g (60%) of ethyl-4-hydroxy-7-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate in the form of beige crystals; MS: me/e = 278 (M+).

b) 4 ml (30 mmol) of trimethylsilylmethylamine at room temperature was added by spraying with a suspension consisting of 1,38 g (5 mmol) of ethyl-4-hydroxy-7-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate in 40 ml of dioxane. After heating to 100oC all substances slowly passed into the solution. The reaction mixture was left for stirring at 90oC for 20 h, then cooled to room temperature and was filtered released a voluminous precipitate. This precipitate was washed with water and dried in high vacuum. Output: 740 mg (65%) 4,N-dihydroxy-7-nitro-2-oxo-1,2-dihydroquinoline-3-carboxamide in the form of light beige crystals; MS: me/e = 254 (M+).

in) 200 mg (0.75 mmole) 4,N-dihydroxy-7-narm spray was added to 0.11 ml (1.6 mmole) of thionyl chloride and then the mixture was heated to room temperature. After stirring for 16 h tetrahydrofuran was removed and the residue was treated with 3 ml of dioxane. After cooling to 0oC by spraying added of 0.32 ml (2.25 mmole) of triethylamine. Then the mixture was heated to room temperature and left stirring for 2 hours the Resulting brown precipitate was filtered under vacuum and recrystallized from methanol. Yield: 30 mg (16%) 7-nitro-2,3,4,5-tetrahydrooxazolo[4,5 - c] quinoline-3,4-dione in the form of light brown crystals; MS: me/e = 247 (M+).

Example 56

7-chloro-2,3,4,5-tetrahydrooxazolo[4,5-c]quinoline-3,4-dione

a) and 7.7 ml (55 mmol) of triethylamine was added dropwise to a suspension containing 10.0 g (45 mmol) of the hydrochloride of the ethyl-2-amino-4-chlorobenzoate in 100 ml of acetone. Then was added 6.8 ml (54 mmole) of methylmaleimide. The reaction mixture was left for stirring at room temperature for 48 h, concentrated and then treated with a solution containing of 4.2 g (183 mmole) of sodium in 110 ml of ethanol. The reaction mixture is boiled under reflux for 2.5 hours After removal of the solvent the residue was dissolved in 200 ml of water and kept at 60oC for 1 h Then the mixture was filtered through dicalite, after which the pH value of the split is deep vacuum. Output: 6,94 g (58%) of 7-chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in the form of beige crystals; MS: me/e = 267 (M+).

b) 2 ml (15 mmol) of trimethylsilylmethylamine at room temperature by sputtering was added to a suspension consisting of 2.64 g (10 mmol) ethyl-7-chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 20 ml of dimethylformamide. After heating to 100oC all substances slowly passed into the solution. The reaction mixture was left for stirring at 80oC for 2 h, then cooled to room temperature and was stirred overnight. After adding 6 ml of water was separated and was filtered voluminous precipitate, washed with water and dried in high vacuum. Yield: 1.48 g (58%) of 7-chloro-4,N-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide in the form of light beige crystals; MS: me/e = 254 (M+).

in) 1.48 g (5.8 mmole) of 7-chloro-4,N-dihydroxy-2-oxo-1,2 - dihydroquinoline-3-carboxamide suspended in 10 ml of tetrahydrofuran and cooled to 0oC. By spraying was added to 0.85 ml of 11.6 mmole) of thionyl chloride and then the mixture was heated to room temperature. After stirring for 1 h tetrahydrofuran was removed and the residue was treated with 20 ml of dioxane. After the OHL the first temperature and left to stir for 2 hours The resulting brown precipitate was filtered under vacuum, and the product was separated from the mother liquor by acidification. After recrystallization from methanol were obtained 200 mg (15%) of 7-chloro-2,3,4,5-tetrahydrooxazolo[4,5 - c]quinoline-3,4-dione in the form of light brown crystals; MS: me/e = 236 (M+).

An example of a

Tablets containing the following composition are produced in the usual way: mg/tablet

Active ingredient: 100

Powdered lactose - 95

White corn starch - 35

Polyvinylpyrrolidone - 8

Na-carboximetilkrahmal - 10

Magnesium stearate - 2

Weight tablets - 250

Example B

Tablets containing the following composition are produced in the usual way: mg/tablet

Active substance - 200

Powdered lactose - 100

White corn starch - 64

Polyvinylpyrrolidone - 12

Na-carboximetilkrahmal - 20

Magnesium stearate - 4

Weight tablets - 400

The example IN

Receive capsules containing the following composition: mg/capsule

Active substance - 50

Crystalline lactose - 60

Microcrystalline cellulose - 34

Talc - 5

Magnesium stearate - 1

The weight of the contents of the capsule - 150
mini cellulose mixed together until homogeneous, sift, and then mix the talc and magnesium stearate. The final mixture fill gelatin capsules with a hard shell that has the appropriate dimensions.

1. Tricyclic dicarbonyl derivatives of General formula

< / BR>
< / BR>
< / BR>
where R1and R2each independently of one another denote hydrogen, (lower)alkyl, (lower)alkoxy, nitro, trifluoromethyl, amino, halogen;

R2can optionally designate morpholino, 5 - or 6-membered heterocycle with 1 to 3 nitrogen atoms, optionally substituted (lower)alkyl, hydroxy-group, or the group-NR5R6where R5and R6may be identical or different and denote hydrogen, (lower)alkyl;

X in formula II represents-CH=CH-, -CH=N-, -NH-, -CO - or-O-,

as well as pharmaceutically acceptable salts of the compounds of General formulas Ia, Ib and II, except 2,3,5,6-tetrahydro[1,2,4]triazole[1,5-C]hinzelin-2,5-dione.

2. Compounds of General formula Ia and II under item 1, where R1and R2have the values listed in paragraph 1.

3. Compounds of General formula Ia under item 1, where R1and R2each represent hydrogen, halogen, methyl or methoxy.

4. 8,9-dichloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione;

9-chloro-what Natolin-3,5-dione;

8,10-dichloro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione;

8,9-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione;

8-methoxy-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione;

8-iodine-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione;

8-chloro-9-fluoro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione;

8,9-dinitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione;

8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione.

5. The compound of General formula Ia under item 1, where R1denotes nitro and R2denotes pyrrolidinyl or dimethylamino.

6. 9-dimethylamino-8-nitro-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione;

8-nitro-9-pyrrolidin-1-yl-2,3,5,6-tetrahydro-1,2,4-triazole[4,3-C]hinzelin-3,5-dione.

7. The compound of General formula Ib under item 1, where R1denotes chlorine or nitro and R2indicates imidazolyl.

8. 9-chloro-8-nitro-2,3,5,6-tetrahydro[1,2,4] triazole[1,5-C] chinadoll-2,5-dione;

9-imidazolyl-1-yl-8-nitro-2,3,5,6-tetrahydro[1,2,4]triazole[1,5-C]chinadoll-2,5-dione.

9. Compounds of General formula II under item 1, where R1and R2each represent hydrogen, halogen or nitro.

10. 7-chloro-2,3,4,5-tetrahydrooxazolo[4,5-C]quinoline-3,4-dione;

7-chloro-4-hydroxy-2,3-dihydro-1H-pyrazole[4,3-C]quinoline-3-one.

11. Drug exhibiting pharmacological activity as nekonkurentno antagonist of NMDA and/or AMPA/KA receptors containing the active substance and a therapeutically inert carrier, wherein the active substances it includes the connection PP.1 - 10, and 2,3,5,6-tetrahydro[1,2,4]triazole[1,5-C]hinzelin-2,5-dione, or its pharmaceutically acceptable salt.

Priority points and features:

24.05.94 - PP.1 - 11;

17.02.95 - PP.1 - 11 (varieties radicals)

 

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