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    • 专利摘要:
    Compounds of the formula I <IMAGE> or pharmaceutically acceptable salts, hydrates, stereoisomers, optically active isomers, geometrical isomers or tautomeric forms thereof are disclosed wherein R is hydrogen or lower alkyl R1 is hydrogen, lower alkyl, styryl, or a carboxylic acid; or R and R1 together form a group of the formula -(CH=CH)2- and in this case the broken line represents a further C-C bond, while in all other cases there is a single bond between positions 6 and 7; R2 is hydrogen, lower alkyl or hydroxy; R3 is hydrogen, lower alkyl, aryl, lower alkanoyl, carboxyl or a carboxyl acid derivative or a group of the formula -(CH2)m-COOH or a derivative thereof formed in the carboxylic group; n=1-3; R4 is hydrogen, lower alkyl which can be substituted by hydroxy or carboxy; trifluoromethyl, substituted or unsubstituted aryl, phenyl-lower alkyl or substituted or an unsubstituted heterocyclic group; R5 is hydrogen, lower alkanoyl, substituted or unsubstituted benzoyl or heteroaryl; or R4 and R5 together with the adjacent nitrogen atom form a piperidino, pyrrolidino or morpholino ring; or R4 and R5 together with the adjacent nitrogen atom form a group of the formula <IMAGE> wherein R6 is hydrogen and R7 is substituted or unsubstituted phenyl; and Z is oxygen. The new compounds are useful for treating asthma.
    公开号:SU999972A3
    申请号:SU782704252
    申请日:1978-12-28
    公开日:1983-02-23
    发明作者:Хермец Иштван；Месарош Золтан；Брайнинг Тибор；Вираг Шандор；Вашвари Лелле；Хорват Агнеш；Надь Габор；Манди Аттила；Сюч Тамаш；Биттер Иштван；Шебештьен Дьюла
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    The method consists in that a compound of the formula or its optically active isomers, where K is a hydrogen atom or formyl, is reacted with a compound of the general formula where HZ has the indicated values, at, preferably at 0, followed by separation of the desired product: or by saponification of the resulting complex ether, or by converting it into an amide or hydrazide acid, and the desired products are isolated in free form or in the form of pharmaceutically acceptable salts, or optically active isomers. Lower alkyl or lower alkoxy is normal or branched aliphatic saturated hydrocarbon groups with 1-6, PREIMENTALLY with 1-4 carbon atoms, for example methyl, ethyl, -propyl, iso-propyl, n-butyl, secondary butyl, tert-butyl, H -pentyl, neopentyl, n-hexyl, etc. Compounds of general formula 1 containing carboxyl or sulfonic acid can form salts with physiologically tolerated bases, for example alkali metal salts, as well as sodium and potassium salts, as well as salts formed with organic amines, such as salts of three ethylamine, ethanolamine and etc. The invention also extends to optical and spatial isomers and toomers of compounds of general formula I. As a diazonium salt, for example, a compound of the general formula can be used. The process can be carried out by adding a compound of the general formula; M to acidic solution of the diazonium salt or vice versa. The components of the reaction are taken predominantly in an equimolar ratio, however, it is also possible to work with a slight excess of one or the other of the components. P is carried out in this case in the presence of an acid binding agent, such as sodium acetate. Preferably, the usual aqueous medium used in the reaction with diazonium salts is chosen as the reaction medium. Compounds of the general formula can be isolated from the reaction mixture in a known manner, or precipitated from the reaction mixture in the form of its salts or hydrates, which can be separated by filtration or centrifugation. If the reaction is carried out in an aqueous medium, the final product is extracted from the reaction mixture with a suitable organic solvent, for example, benzene, chloroform, ether, and isolated by evaporation of the organic extract. If the reaction is carried out in an organic solvent medium, then the compound of general formula I is isolated by removal of the solvent. The resulting compounds of general formula I can be purified by recrystallization or chromatography. in a way. The carboxyl group, standing as a substituent, can be esterified in a known manner to an alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl group. The carboxyl of the corresponding derivative can decarboxylate its heating, and in addition, the corresponding derivative containing hydrogen in place of the carboxyl group. It is advisable to carry out carboxylic acid in the presence of an acid, for example, phosphoric acid. The derivative containing the carboxyl group can be reacted with the corresponding amine, to the acid amide substituted in this case. Substituted acid amides are obtained in a known manner through an active ester, for example, an active ester formed with chloroformate ethyl ester. The ether group contained as a substituent can be reacted by heating with an excess of the corresponding alcohol. An ester of formula I with acid or alkaline treatment can be converted to the corresponding 1 arbonic acid of general formula I. Alkaline hydrolysis is carried out by heating with an alkali metal hydroxide in an aqueous or alcoholic medium, and the acid is liberated from the alkali metal salt due to acidification. By hydrolysis with mineral acids, the free carboxylic acid is obtained directly. .
    An ester of the general formula I, by reaction with ammonia in an aqueous-alcoholic medium, can be converted to the corresponding amide of Lormula I by treating with hydrazine in the necessary case mixed with (for example, hydrazine, methyl, or fvnilhydrazine) to the corresponding hydrazide of general formula I.
    Compounds of general formula I can be liberated in a known manner from salts formed by them with acids or alkalis,
    From the basic compounds of the general formula I, it is possible, by reaction with inorganic or organic acids, to form additive compounds. Salt formation is carried out by known methods, introducing the corresponding compound of the general formula I, together with the acid used in an equivalent amount or in excess, into an inert organic solvent.
    Compounds of general formula I containing acidic groups (carboxyl or sulfonic acid) can be reacted with a base (e.g., an alkali metal hydroxide, an earth metal hydroxide, organic amines) in a salt formed with a base.
    Those compounds of general formula I that contain substituents other than hydrogen as R have an asymmetry center and can exist as optically active compounds or a racemate. Optically active compounds of general formula I can be obtained by using noscaler optically active starting materials of general formula 1I or section racemic compound of the general formula {on its optically active antipodes. This can be done in a known manner. Compounds of the general formula (containing carboxyl groups can, for example, be divided into optical isomers, react the racemate with an optically active base, for example threo-1-P-nitrophenyl) -2-aminopropane-1,3-diol. The members of the obese salt pairs of diastereoisomeric salts are separated from each other on the basis of their differentiation. physical properties and separated from each other optical antipodes of general formula I are released from the salt by treatment with a strong base.
    The compounds of general formula 1 exhibit many pharmacological effects; they are anti-inflammatory, analgesic, anti-atherosclerotic, reduce aggregation
    thrombus, regulates the circulatory system and cardiac functions, affects the central nervous system, has a tranquilizing action, RU-antigonistic, anti-bacterial and antifungal actions, as well as anti-ulcer action. Therefore, the compounds of general Formula I are applicable in veterinary medicine and medicine. Of particular note is their activity against allergies and asthma.
    Allergic reactions resulting from the interaction of antigens and antibodies manifest themselves in various organs and tissues in a very different way. One of the most common forms of allergy is asthma. Diiatric chromoglycate (1,3-bis- (2-carboxychromon-b-yl-oxy-2-hydroxy-propane-intal R), which is not administered orally, is used as a remedy for asthma. It is used only in the form of inhalation when using complex adjuvants (SpInhaler). It has now been discovered that combining general formula I, either orally or intravenously, or in the form of inhalation, yields positive results in the treatment of allergic symptoms.
    The efficacy of compounds I was proved using standard tests that serve to determine the antiallergic effect. In the PGA test, disodium chromoglycolate is used as a substance for comparison. Tests are performed on rats. The results are given in table. one.
    In the PGA test (050 / intravenously), the following medications show this; efficiency:
    9-p; 2-Carboxyphenyl) -hydrazino-2-6-methyl-4-oxo-6, 7, 8,9-tetrahydro-4H-pyrido) (1,2-a) -pyrimidine-3-carboxylic acid / 0.48
    9- | C (4-Ethoxyphenyl) -hydrazino-3-b-methyl-4-oxo-6,7, 8,9-tetrahydro-4H-pyrido (l, 2-a) -pyrimidine-2-carboxylic acid1 0
    9-C (4-Chlorfen.sh) -hydrazine 6-methyl-4-oxa-b, 7, 8,9-tet agidro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid 0.53
    9- (3-Pyridylhydrazino-) b-methyl-4-oxo-6, 7,8,9 tetrahydro-4H-pyrido (1,2-a) -pyridine-3-carboxylic acid,. 0.54
    From the above data, it can be seen that the compounds of the formula) also act in oral use. When administered intravenously, the compounds of the formula I are also more effective than the known control compounds. The toxicity of the compounds of formula I is insignificant, determined in rats and mice, and is in LDg. 500 mg / kg orally. From the general formula I, it can be used in pharmacy in the form of preparations containing the active substance, as well as solid or liquid, organic or organic substances - carriers. Preparations are made in the usual way for the manufacture of medicines. The preparations can be produced in forms suitable for oral and parenteral administration, or in the form of inhalations, for example, in the form of tablets, dragees, capsules, pellets, powder mixture, in the form of aerosols, aqueous suspension or solution, injection solution or syrup. The preparations may contain a suitable solid excipient, a carrier, a sterile aqueous solvent or a non-toxic organic solvent. Saccharin and the usual flavoring agents can be added to the preparations provided for oral administration. Orally administered tablets may contain as carrier, for example, lactose, sodium citrate, calcium carbonate, as well as binders, for example starch, alginic acid, glidants, such as talc, sodium lauryl sulfate, magnesium stearate. Capsule material can be lactose and polyethylene glycol. Aqueous suspensions may contain emulsifying and suspending agents. Suspensions prepared using organic solvents may contain ethanol, glycerol chloroform, etc. as solids. Formulations suitable for parenteral administration and for inhalation are solutions or suspensions of the active substance prepared in a suitable medium, for example, peanut oil, sesame oil, polypropylene glycol or water; Injectables can be administered intramuscularly, intravenously or subcutaneously. Injection solutions are prepared predominantly with an aqueous medium, setting the required pH value to the medium. Solutions, if necessary, can be prepared in the form of an isotonic saline solution or glucose solution. For asthma, medications can also be administered by inhalation with an inhaler or an aerosol device. The content of active quality in the preparation can vary widely and lies in the range of 0.005-90%. The daily dose in terms of the active substance can vary over a wide range and depends on the age, weight and condition of the patient, as well as on the dosage form of the preparation and the activity of the active active substance. For oral administration, the daily dose is generally 0.05-15 mg / kg, while for intravenous administration and inhalation, the daily dose, divided into several partial doses, is in the range of 0.001-5 mg / kg. This data is indicative, in individual cases and depending on the doctor's prescriptions, they may deviate towards increasing or decreasing the dose. Example. To a mixture of 18.6 (0.2 mol) of aniline and 100 ml of 1: 1 diluted aqueous hydrochloric acid at p-5 ° C and stirring, 13.8 g (0.2 mol) of sodium nitrite in 100 ml are slowly added dropwise. ml of water. Then to the mixture is slowly added dropwise with vigorous stirring, a solution of 47.2 (0.2 mol) ethyl 6-methyl-4-oxo-b, 7,8,9-tetrahydro-4H-pyrido- (l , 2-a) PIRSHI1-SHIN3-carboxylic acid in 100 ml of water. The reaction mixture is stirred for 2 to 3 hours and then left in the refrigerator overnight. The precipitated crystals are filtered and washed with 1 of it with a large amount of water. 500 f-w of water and 500 MP of chloroform are added to the substance and adjusted by adding a 5% aqueous solution of sodium carbonate to the pH of the aqueous phase of pH 7. The organic layer is separated and the aqueous layer is shaken twice with 500 ml of chloroform. The purified organic layer is dried over calcined sodium sulfate, then the solvent is distilled off under reduced pressure. As a precipitate, a red oil remains, which is crystallized from two, threefold amounts of ethanol. 48.7 g (63.0%) of product are obtained, which melts at 8687 ° C. -7 Compound is crystallized with 1 mole of ethanol; ethanol can be removed with a bag at 90-100s in vacuum over phosphoric anhydride. Dried 9- (phenylhydpasono) -b-methyl-4oxo-6, 7,8.9 ethyl ester tetro-4H-pyrcdo (1,2-a) pyrimidine-3-carboxylic acid ethyl ester melts at 138-139 C. Elemental analysis. Calculated,%: C, 63.51; n, 5.92; N 16.45. (; aHjc, N4.o Found,%: C 6.3.53; H 6.03, N 16.60. PRI me R 2. Work in the manner described in example 1, with the difference that instead of aniline use P -bromoaniline. The resulting ethyl ester of 9- (p-bromophenylhydrazono) -b-methi 4-oxo-b, 7,8,9-tetrahydro-4H-pyrido (1,) pyrimidine-3-carboxylic acid has a melting point of 188 -189 C. Elemental analysis. Calculated,% C 51.69, H 4.34, N 13.39, Br 19.10. Found,%; C 51.84, H 4.54, N 13.26, Br 19.13 Example 3. It was worked in the manner described in Example 1, with the difference that m-toluidine was used instead of aniline. - tetragilro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid has mp 159-160 C. Elemental analysis calculated as C 64.39, H 6.25, N 15, 80. Found: C, 64.30; H, 6.22; N, 15.85. Example 4. To a mixture (0.02 mol of P-chloroaniline and 10 ml of 1: 1 times a diluted aqueous solution of hydrochloric acid while stirring slowly, 1.4 g (0.01 mol) of sodium nitrite in 10 Mp of water are added slowly by means of lasers. Then, 12.0 g of solid sodium acetate was added to the mixture in several portions and then, with vigorous stirring, 4.7 (0.02 mol) of ethyl 6-methyl 4-OXO-6,7,8 was slowly added dropwise. 9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid. The reaction mixture is stirred for 2-3 hours and then left to stand overnight in a refrigerated cabinet. The precipitated crystals were washed off and washed with a small amount of water, Recrystallization and ethanol; g (56.0%) of ethyl ether 9- (d-chlorophenylhydrazono) 6-methyl-4-oxo-6,7,8,9-tetrahydro4H -pyrido (1,2-a) pyrimidine-3-carboxylic acid, so pl. 177-178s. Elemental analysis. Calculated,%: C 57.67; H 4.30, N 14.90; C1 9.45. (; CH, 9M40% C1 Found;% C 57.35 / H 4.40 / N 15.04, C1 9.57. Example3. To a mixture of 2.9 g (0.02 mol) of monohydrochloride t-toluene and 6 ml of a 1: 1 diluted aqueous solution of hydrochloric acid with stirring and slowly add a solution of 1.4 g (0.02 mol) of sodium nitrite in 10 ml of water. Next, work in the manner described in Example 3. 4.0 g are obtained (56.4%) 6-methyl-9- (p-methylphenylhydrazono) -4-oxo-5,7,8,9-tetrahydro-4H-pyrido4 (1,2-a) pyrimidine-3-carboxylic acid ethyl ester , mp 147-149 ° C. Elemental analysis: Calculated,%: C 64.39, H 6.25, N 15.80. Found,%: C 64.05, H 6.34, N 15, 71. In examples 6-11, spos work According to Example 6, however, other amines are chosen as the initial vet. Example 6 Based on 2,6-dichloroaniline, 9- (2,6-dichlorophenylhydrazono) -6-methyl4-oxo ethyl ester is obtained. -b, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pipimidine-3-carboxylic acid, mp 153-154 C. Elemental analysis. Calculated,% C 52.82j H 4.43 N 13.68, C1 17.32 fieH, 8N404 i Found: C 52.52, H 4.47; N 13.75 j C1 17.26. Example 7. Starting from o-toluidine, plychayut. 6-methyl-9- (-methylphenylhydrazono) -4-oxo-b, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid ethyl ester, m.p. 185 ° C. Elemental analysis. . Calculated,%: C 64.39 / H 6.25, N 15.80. Nadeir,% C 64.45, H 6.01, N 15.75. Example. Starting from 3,4-methylenedioxyaniline, 6-methyl-9, 3,4-methylenedioxyphenylhydrazono) -4-oxo-b, 7,8,9-tetra- .. hydro-4H-pyrido- (1 , 2-a) pyrimidine 3-carboxylic acid, m. Pl. 172173С .. Elemental, analysis. Calculated,%: C 58.02, H 5, 38, N 14.23. 5 Found: C 58.22; H 5.39, N 14.35. EXAMPLE 9: Exodus, from 6-nitroaniline, 6-methyl-9- (o-nitrophenylhydrazono) -4oxo-6, 7,8,9-tetrahydro-4H-pyrido- 3-methyl ester is obtained. (1,2-a) pyrimidine-3-carboxylic acid, etc. 190-192 0. Elemental analysis. Calculated% J C 56.10, H 4.96 / N 18.17. (Found, -%: C 56.12; H 5, -04, N 18.12. Example 10. Starting from N-nitroaniline, b-methyl-9 ethyl ester is obtained - (- nitrophenylhydrazono) 4-OXO-6, 7, 8,9-tetrahydro-4H-pyridine (1,2-a) pyrimidine-3-car6oic acid tn, mp 218-219c. Elemental analysis Calculated: C 56.10, H 4, 96, N 18.17, Found: C 55.98, H 4.80, N 18.03 Example 11. Starting from Naimide sulfate, 9f ethyl ester is obtained - (amino sulfonyl) phenylhydrazone 6-methyl-4- oxo-6,7,8,9-tetrahydropyrido- (1,2-a) pyrimidine-3-carboxylic acid, which in the form of its monohydrate has a melting point of 210-213 ° C. Elemental analysis. Calculated,% g C 49.42, H 5.30; N 16.01. Cie M -WaO., Found %: C 49.01; H 5.11; N 15.14. Example 12. To a mixture of 93.1 g (1.0 mol) of aniline and 480 ml (1: 1) of a dilute aqueous solution of hydrochloric acid with stirring and 0 slowly a solution of 68.9 (1.0 mol) of sodium nitrate in 500 ml; water is added dropwise. Then the reaction mixture is slowly mixed with 65.0 g of solid sodium acetate. To 208.2 g (1.0 mol) of 6-methyl4-OKCC- 6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carbonic acid was added 500 ml of water, and the pH of the solution was adjusted to 7 with 10% sodium carbonate aqueous solution. This with vigorous stirring, the solution is slowly added Applicants races thief diazonium salt. The reaction mixture is stirred for 2 to 3 hours and left to stand overnight in a refrigerator. The precipitated crystals are filtered and washed with a small amount of water. The crude product is dissolved in aqueous sodium hydroxide and the solution is clarified with activated charcoal. Then it is acidified and the precipitated crystals are filtered off. 293.0 g (93.8%) of 9- (phenylhydrazono) -6-methyl 4-OXO-6,7,8,9-tetragylro-4H-pyridine (1,2-a) pyrimidine-3-carboxylic acid are obtained. you, t. pl. 255-256 ° C. (After recrystallization from dimethylformamide, mp 237-268 C). Elemental analysis. Calculated,%: C 61.53 / H 5.16, N 17.94. Found,%: C 61.62; H 5.26, N 18.10 Example 13. To a solution of 0.6 (0.015 mol) of sodium hydroxide in 25 ml of water was added 3.4 g (0.01 of ethyl 9- (phenylhydrazono) 6-methyl-4- oxo-6, 7,8,9-tetrahydro4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid. The suspension is stirred at 50-60 s for 4-5 h, and everything goes into solution. Diluted 1: 1 The pH of the solution is adjusted to 1 with aqueous hydrochloric acid. The precipitated crystals are removed from the filter and washed with a small amount of water to obtain 2.7 g (86.4%) of 9- (phenylhydrazono) -6-methyl-4-oxo-6.7.8 , 9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid, t. mp 267-268C, which does not have a difference in the melting point temperature with the product obtained in Example 12. In Examples 14-21, the process was carried out as described in Example 12, however, it comes from other amines. Starting from p-bromoaniline, 9- (p-bromofbnylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3carboxylic acid is obtained, t . Pl. 250-252 C. Elemental analysis. Calculated,%: C 49.12, H 3.86; N 14.32, W 20.43; Found: C 48.90; H 3.86, N 14.36-, Br 20.66., Example 15. Starting from anthranilic acid, 9- (c -carboxyphenylhydrazono) 6-methyl-4-ocoo6, 7,8,9-tetrahydro-4H are obtained -pyrido (1,2-a) pyrimidine-3-carboxylic acid, so pl. 266-268 sec. Elemental analysis. Calculated,%: C, H 5.53, N15.72. N BM405. Found,%: C 57.87; H 4.40; N 15.6. PRI me R 16. Starting from R: -chloroaniline, 9- (p-chlorophenylhydroxy razono) -6-methyl-4-oxo-6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) pyrimidine-8carboxylic acid is obtained, m.p. 262-264 Elemental analysis. Calculated itano,%: C 55.42, H 4.36; N 16.16; C1 10.22. Found ,,%: C 55.40; H 4.2, N 16.02 / C) 10.21. . PRI me R 17. Starting from O-toluidine, 6-methyl-9- (o-methylphenylhydrazio) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido- (1,2- a) pyrimidine 3-carboxylic acid, so pl. 221223 C. Elemental analysis. Calculated,%: C, 62.57; H 5.56, N 17.17. C.4 C, 0 Found,%: C 62.83; H 5.55, N 16.83. ri p and m p 18. Starting from 2, methylaniline, 6-methyl-9 (2,6-dimethylphonylhydrazono) g 4-oxo 6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a pyrimidine- 3-carboxylic acid, mp 192-193 pp. Elemental analysis Calculated: C 63.14, H 5.88; N 16.36, B ioNxO Found: C 63.14, H 5.93 , N 16.15. EXAMPLE 19: Starting from 2,4,5-trimethylaniline, 6-methyl 9- (2,4,5-tri-methylphenylhydra-eono) -4oxo-6, 7,8,9-tetrahydro-4H is obtained. -pyrido (1,2-a) pyrimidine-3-carboxylic acid, which melts at 224-226 C. Elemental analysis: Calculated,% s C 62.78, H 6.28, N 15.81. Found,% : C, 62.43, H, 6.07, N, 15.32. EXAMPLE 20: Starting from 2,4,6-trimethylaniline, to obtain 6-methyl9- (2,4,6-trimethylphenylhydrazono) -4oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid, mp 195 -197 C. Elemental analysis. Calculated,%: C 62.78; - H 6.26, N 15.811 C N405 Found,%: C 63.29, H 6.17, N 15.68. Example21. -amine pyridine, get 6-methyl-9g (3-pyridine-hydrazono) -4-oxo-6, 9-tetra-agidro-4H-pyrido- (1,2-a) pyryutdin-3-carboxylic acid, mp. . 236237 ° C. Elemental analysis. Calculated,%: C 57.50, H 4.82; N 22.35. Found:%: 57.81; H 4.85 N 22.27. Example 22. In a mixture of 15 ml of glacial acetic acid and 1.1 MP of concentrated sulfuric acid, 1.8 g (0.01 mol) of aniline 2,4-dinitre is dissolved. The solution is cooled to 10-15 and, with stirring, mixed in parts with 0.7 g (0.01 mol) of sodium nitrite. The diazonium salt is isolated with ether, decanted and dissolved in 1015 ml of ice-cold water. Next, work according to the method of Example 12, but sodium acetate is added to the walls. The crude product is recrystallized from acetonitrile. 0.8 g (20.0%) of 6-methyl 9- (2,4-dinitrophenylhydrazono) -4-ox 6.7,8,9-tetrahydro-4H-pyrido- (1,2-a pyrimidine-3- carboxylic acid, etc., 257-258s. Elemental analysis. Calculated,%: C 47.88; H 3.26, N 20.94. Found,%: C 47.74; H 3.39 / N 20.66 Example 23 A solution of 1.9 g (0.01 mol) sulfanilic acid, 0.8 g (0.01 mol) sodium bicarbonate, and 0.7 g (0/01 mol) sodium nitrite in 10 ml of water with stirring 5 ml of a 1: 1 diluted aqueous solution of hydrochloric acid are then added dropwise. The process is carried out as described in Example 12. The crude product is recrystallized from 75% aqueous methanol. 0.3 g (7.6%) of 6-methyl-4-oxo-9 (P-sulfophenylhydrazono) -6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) pyrimyl. 3-carboxylic acid, mp above 290 "C. Elemental analysis. Calculated,%: C 48.98, H 4.11, N 14.28, S 8.17. C, 6H 6N406S Found,%: C 49.11; H 4.10, N 14.21, S 8.25. Example 24. In suspension 34.0 g (0.14 mol) of 9-hydrazoyl-6-methyl-4-oxo-6, 7.8, 9-tetrahydro-4α-pyrido- (1,2-a) pyrimidine-3-carboxylic acid in 700 MP of anhydrous ethanol, with 10–15 ° C and stirring, dry hydrogen chloride is introduced. After sat- The solution of the solution is left to stand overnight in a refrigerator. The next day, the solvent is distilled off under reduced pressure. The residue is dissolved in 50 ml of water, the solution is neutralized with a 5% aqueous soda solution and extracted with 4x100 ml of chloroform. The combined organic phases are dried over calcined sodium sulphate and then evaporated in vacuo. The residue is recrystallized from methanol. 18.0 g (48.6 g) of ethyl are obtained. 9-hydrazono-6-methyl.-4-oxo6, 7,8,9-tetrahydro-4H-pyridino (1,2-a pyrimidine-3-carboxylic acid ester, mp 199-200 ° C. Elemental analysis. Calculated,%: C 54.54; H 6.1 B; N 21.20. Hj.NjO Naydeyo, -% C 53.88; H 6.20 N. 21.10. Example 25. Suspension 2, 0 g (7.57 mol) of ethyl ether 9-gDrazono-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid and 20 ml of ethanol are brought to a boil and mixed dropwise with 4 ml of a 50% aqueous solution of hydrazinrirate. After 15 minutes of boiling, a solution is obtained from which crystals begin to precipitate upon cooling. Crystallized from methanol. 1.0 kg (52.8%) of 9-gilrazono-6-methyl-4-oxo-b, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carbogilrazine is obtained, mp 219-220 0.
    Elemental analysis.
    Calculated,%: C 47.99 / H 5.64, N 33.58.
     , Found,%: C 48.43, H 5.67;
    N 23.59.
    Example 26. 10.0 g (0.03 mol of 9- (phenylhydrazono) ethyl ester) 6-methyl-4-oxo-b, 7,8,9-tetrahydro4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid is dissolved in 30 ml of ethanol with heating. 40 ml of concentrated aqueous ammonia solution is added dropwise to the solution with stirring. The reaction mixture is left to stand for one day, then the precipitated crystals are filtered off. The crude product is recrystallized from nitromethane. 53.5%) 9- (phenylhydrazono) -b-methyl4-OXO-6, 7,8,9-tetrahydro-4H-oxo6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a pyrimidine -3- arboxylic acid T. pl. 246-247 0.
    Elemental analysis. Calculated,%: O 61.73 / H 5.50, M 22.49.
    Found,%: O 61.51 / H 5.58
    N 23.17.
    Example 27. To a mixture of 0.9 (0.01 mol) aniline and 5 ml of a 1: 1 dilute aqueous solution of hydrochloric acid, while stirring, a solution of 0; 7 g (0.01 mol) of sodium nitrite is slowly added dropwise in 5 ml of water. Then, 6.0 g of solid sodium acetate is added to the reaction mixture, then a solution of 2.5 g (9.01, mol) of ethyl 9-Lormyl-6-methyl-4- is slowly added dropwise with vigorous stirring. oxo1, 6,7,8-tetrahydro-4H-pyrido- (1,2-a pyrimidine 3-carboxylic acid in 20 ml of acetone. The reaction mixture at 0-50 is stirred for 3-4 h and then under reduced pressure is distilled off acetone .. The remaining aqueous solution is shaken with 3x10 ml of chloroform. The combined organic phases are thoroughly shaken with 30 ml of water. After separation, the organic phase is dried over Roasted sulphate of sodium and evaporated in vacuo. The residue is recrystallized from ethanol and dried in a vacuum oven at EO-CQ over phosphoric anhydride to give 0.7 g (20.6%) of ethyl 9- (phenylhydrazono) -6-methyl- 4-oxo6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a pyrimidine-3-carboxylic acid, which melts at 138-139 0 and does not
    differs in the melting point temperature of the products obtained in noi of Example 1
    Example 28. They work according to the method described in npHMeipe 12, but instead of aniline, p-phenyletadine is used. 7.6 g (53.3%) of 9- (ethoxyphenylhydrazono) -6-methyl4-oxo6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid are obtained, which melts at 213-219 0.
    Elemental analysis.
    Calculated,% i C 60.67, H 5.66; N 15.72.
    Crt} .4a, N404
    Found,% tC 60.52, H 5.73; N 15.74. .
    Example 29 Work according to the method described in Example 1, however, it comes from (-) - 6-methyl-4-oxo-6.7,
    8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid1; 113.7, (c 2, methanol). Output (-) -9-phenylhydrazono-6-methyl-4-oxo6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a)
    pyrimidine-3-carboxylic acid is 91%. The acid melts at 258-259 0. q (J -407.5 (c 2, dimethylformamium G ,.
    Elemental analysis.
    Calculated% O 61.53; H 5.16; N 18.94.
    C-, H..N, j03
    Found,%: O 61.48; H 5.04; N 17.82.
    Example 30. The method was worked up according to Example 1, however, it originated from (+) - 6-methyl-4-oxo-6,7,8, 9-tetrahydro-4H-pyrid- (1,2-th) pyrimidine 3-carboxylic acid, C «fj (C 2, methanol). The yield of (+) - 9-phenyl-hydrazono-6-methyl-4-oxo-6, 7.8, 9-tet gagidrog-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid is 92.5%. The acid melts at 255-256 0. +407.5 (c 2, dimethylformamide G.
    Elemental analysis. Calculated% i O 61.53, H 5.16; N 17.94.
     Ojl
    Found,% | O 61.72, H 5.22, N 18.01.
    Example 31. Work according to the method of Example 1, however, 7-methyl-4-oxo-6, 7,8,9-tetrahydro-4N-pyrido- (1,2-a) pyrimidine 3-carboxylic acid. 9-phenylhydrazono7-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido- (l, 2-a) p-idin-3-carboxylic acid are obtained, m, pl. 255-256 0. Elemental analysis. Calculated,%: O 61.53) H 5.16; N 17.9.
    Found,% s C 61.27, H 5.17; N 17.78. PRI me R s 32-55 (general description). 0.03 mole given in table. 2 aniline derivatives are dissolved in 14.4 MP of a 18% hydrochloric acid solution. The solution is cooled to i-dropwise moistened with a solution of 2.1 g of sodium nitrite in 15 ml of water. 18 g of sodium acetate is added to the reaction mixture. A mixture of 0.03 mol of 6-methyl-4. Oxo-b, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3 is added dropwise to the solution of the diazonium obtained in this way at a temperature below. -carboxylic acid, 30 MP of water and 7 ml of 10% aqueous solution of caustic soda. The reaction mixture is stirred at -O-SP C for 3 hours. Then the precipitated crystals are filtered, punched with water and recrystallized from the above table. 2 solvent. Example 56. 7.8 g (0.02 mol, E; 9-Lenilhydrazono-methyl-4-oxo-6, 7,8,9-tetrahydro-4N-pyrido- (1j2-a) pyrimidine-3-carbonic acid acid ester; dissolved in 100 ml of ethanol, the solution was poured from 6.0 ml of 98% hydrazine hydrate and then refluxed for two hours and refluxed when cooled, crystals began to precipitate, which were filtered and washed with ethanol to give 5.4 g (82 g , 7%) 9-phenylhydrazono-b-methyl-4-oxo-b, 7,8,9-tetrahydro-ro-4H-pyrido- (1,2-a) pecramidine-3-carbohydrazide, mp 205- 207 C. Elemental analysis. Calculated,%: C 58.89; H 5.5b; N 25.75. Found,%: C C 58.06; H 5.47; N 25.52. Example 57. But Example 12 gives 9-phenylhydrazono-6-methyl-4-oxo-b, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid, and sodium acetate is added to the reaction mixture. em 75%. The product melts at 256-251 ° C and has no difference in melting point from the product obtained in Example 12. Elemental analysis Calculated,% C 61.53, H 5.1b; N 17.94, Found: C, 61.48; H, 5.01; N, 17.80. Example 58. From aniline and 7-methyl-4-oxo-b, 7, 9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid ethyl ester, the procedure of Example 4 is obtained from 60 % yield ethyl ester of 7-methyl-E-phenyl hydrazone-4-oxo-b, 7,8, E-tetraidro 4H-pyrido- (1,2-a) pyrmidine-3-carboxylic acid, so pl. 165-167 C. Elemental analysis. Calculated,% C 63.51; H 5.92, N 16.45. Found%: C 63.24: H 5.80; N 16.35. . Example 59, From aniline and ethyl ester of 8-methyl-4-oxo-6,7,8, 9-tetrahydro-4H-pyrido- (1,2-a) pyridine-3-carboxylic acid by the method of Example 4 is obtained with 61 , B% yield 8-mv.til-9-phenylhydrazono-4-oxo-b ethyl ester, 7,8,9-tetraido-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid, m.p. 108-110 C. Elemental analysis. . Calculated,%; C 63.51) H 5, N 16.45. Qfe4iuN40i Found,%: C 63.63; H 6.01, N 16,5.2. Example 60. From aniline and npii prepared with dimethyl sulfoxide solution of 2,6-dimvtil-4-oxo-6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carbonoamide as described in example 4 -the method is obtained with 49.2% yield of 9-phenylhydrazine-2,6-; dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-car6cH f xamide, so pl. 235-237 C. Elemental analysis. . . Calculated,%: G 62.76, H 5.89, N 21.52. . H - NffOa. Found,%: C 62.84; H 5.77; N 21.51 .... PRE EXAMPLE 61. To a mixture of 0.45 ml (0.005 mol) of aniline and 2.5 ml of a 1: 1 mixture of aqueous hydrochloric acid are slowly added at a solution of 0.3 g ( 0,005 mol), sodium nitrite in 2.5 MP. water. First, 3.0 g of solid sodium acetate is added to the reaction mixture, and then 1.2 g (0.005 mol) of ethyl 1b-; methyl 4-c x 6, 7,8,9-tetrahydr6-4H-pyrido- () pyrimidin-3-yl-acetate in mp water with slow introduction in vigorous stirring. The reaction mixture is stirred for 2-3 hours at-0-5.6, after which it is left overnight in a holo-V dilator. The aqueous phase is decanted, and the yellow viscous residue is recrystallized from methanol, thereby obtaining 0.5 g (25.9%) ethyl f 9- (phenylhydrazone) -6-metsh-4-oiso .6jJj8,9-TeTparHflpQ-. 4H-nHpHj io- (lj, 2-a pyrimidin-3-yl} -ee1ax. The resulting product contains the mol equivalent of cr of stalled methanol. Mp, 100-102 ° C. Elemental analysis; Calculated,% C 62.16 ; H 56.78, N 14.50. (“JHj N OsCHiOH Found,% 1 C 62.34, H 6.69, N 14.73.
    Example 62 Conducts the same operations and in the same sequence as in Example 61, except -. It is indicated that | 1) b-methyl-4-oxo6, 7,8,9-tetrahydr6-4H-pyrido- (1,2-a) pyrimidin-3-ylJ-ycyccyclic acid is used as the starting material. The resulting crude product is broken down with a tenfold amount of water and the pH is maintained at about 8 with sodium hydroxide solution, after which the resulting solution is acidified to pH 3 with hydrochloric acid. In this way, / 9- (phenylhydrazone) -b-methyl-4-oxo-b, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidH-3 and ij acetic acid is obtained with a yield of 59, 5%, so pl. 1br-162 p.
    Elemental analysis.
    Calculated,%: C, 62.57; H 5.56;
    N.
    (0h
    Found,% J C 63.11; H 5.49j N 16.98.
    Example 63. The same operations are carried out in the same sequence as in Example 61, with the exception that 6 methyl-6,7,8,9. T6 tragidro-4H-pnido- (1 j2 -a) pyrimidin-4-one. In this way, 9- (phenylhydrazone) -6-methyl-6,7,8,9, tetrahydro-4, I-pyrido (1,2-a) pyrimIDIN-4-OH is obtained with a yield of 52.2%, tons. square 163165С.
    Elemental analysis.
    Calculated,% j C 67.15, H 6.01, N 20, .88.
    Q, rlVgN403
    Found,%: C, 66.92; H, 5.98; N 21.00.
    Examples 64-71. The compounds of general formula I listed in Table. 3, is prepared according to the method described in examples 32-55.
    Examples 72-84. The compounds shown in Table. 4 $ 5, receive as in examples 32-35.
    Example 85. To 20 ml of acetone is added 0.5 g of 9- (phenylhydrazino) 6-methyl-4-oxo-6, 7,8,9-tetrahydro4H-pyrido- (1,2-a) -pyrimidine-3- carbo hydrazide. The reaction mixture is boiled for 3 hours with vigorous 1 remagnetization. After that, the mixture is cooled, the precipitated crystals are filtered, and washed with acetone. 0.35 g of N-isopropyliden-9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8, 9-tetrahydro-4H-pyrido- {1,2-a) -pyrimilin-8- is obtained carbohydrazide melting at 293-295С after recrystallization from a mixture of chloroform and ethanol.
    Elemental analysis ..
    Rasgitano,%: C 62.29 / H 6.05; N 22.93.
     62.29, H 6.14, N 23.10. 65
    Found
    Example86. To a mixture consisting of 0.9 g (0.01 mol) of aniline and 5 ml of a 1: 1 solution of hydrochloric acid in water, is added dropwise a solution of 0.7 g (0.01 mol) of sodium nitrite in 5 MWINS with mixing. Thereafter, 6.0 g of solid sodium acetate is added to the reaction mixture in small portions, AFTER then a solution of 2.5 g (0.01 mol) of 9-formyl-6-methyl-4-oxo-methyl ester is added dropwise. 1, 6,7,8-tetrahydro-4H-pyrido- (1,2-a) -pyrimilin-3carboxylic acid. In 20 ml of methanol with vigorous titration. The reaction mixture is stirred for 3-4 hours at which time 20 ml of water is added. The crystals are filtered, washed with water and dried. 2.5 g (76.7%) of 9- (phenylhydraeno) -6-methyl-4-OXO-6 methyl ester, 7,8,9-tetrahydrb-4H-pyrido- (1,2-a) are obtained. -pyrimidine-3-carboxylic acid, so pl. 122-123 C after recrystallization from a mixture of ethyl acetate and diethyl ether.
    Elemental analysis.
    Calculated,%: C 62.57j H 5.56 / N 17.17.
    Found: C, 62.75; H, 5.47; N, 17.26.
    ..V
    Example 87. When performing the experiment according to example 86, but with the replacement of the methanol solution of 9-formyl-6-methyl-4-oxo-1,6,7,3 methyl ester methyl tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid solution of 9-formyl-6-methyl-4-oxr-1,6,7; 8 tetrahydro-4H-pyrido- (1,2-a) -pyridine 3-carbonitrile in dimethylsulfoxide gives 3.0 g (96.0%) of 9- (phenylhydrazono-6-methyl-4-oxo. -6, 7, 8, 9-tetrahydro-4H-pyrido- (1,2-a) -pyrimidine 3 -carbonitrile, mp 223-224 0 (after recrystallization from acetonitrile). The product does not lower its melting point when offset with the product of example 32.
    Example 88. By repeating the experiment described in Example 86, but replacing the methanol solution of 9-formyl-6-methyl-4-oxo1, 6,7,8-tetrahydro-4H-pyrido- {1,2-a pyrimidine methyl ester -3-carboxylic acid with a solution of ethyl 1-9-formyl-6-methyl-4-OKCO-1, 6,7,8-tetrahydro-4H-pyrido- (1,2-a) -pyrimidine-3-yl. 3-acetic. acids in acetone receive 3.5 g (90.5%) of ethyl 9- (Lenilgilrazono) 6-methyl-4-o {co-6, 7,8,9-tetrahydro-4H-pyrido- (1,2- a) -pyrimylin-yl-acetic acid, so pl. (after recrystallization from methanol). The product does not reduce its melting point when mixed with the product from Example 61. Example 89. When conducting the experiment described in Example 86, but replacing the methanol solution of 9-formyl-6-methyl-4oxo-1, 6.7 methyl ester, 8-tetragilro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid with a methanol solution of 9-formyl3, 6-dimethyl-1,6,7,8-tetrahydro-4Npyrido- (1,2-a) pyrimilin-4-one, 2.54 g (90%) of 9 -. (enylhydrazo) -3,6-dimethyl-6,7,8,9-tetrahydro4H-pyrido- {1, 2-a) - pyrimidine 4a, melted after recrystallization from methanol. Elemental analysis. Calculated: C 68.06, H 6.43; N 19.84. Found,%: C 67.64; H 6, N 19.67. EXAMPLE 90 In the experiment described in Example 86, but with the replacement of the methanolic solution of 9-formyl-6-methyl-4oxo-1, 6,7,8-tetrahydro-4H-pyrido methyl ester (lj , 2-a) -pyrimidine-3-carboxylic acid with a solution of ethyl ether (9-foryl-7-methyl-4-6 x-1,6,7,8-tetra-ro-4H-pyrido- (1,2- a) -pyrimidine-3-and acetic acid in a mixture of 1: 1 aceto and methanol, get 2.26 g (67.3% of ethyl ester 9- (phenylhydrazono 7-methyl-4-oxo-6,7,8,9 -tetrahydro4H-pyrido- (1,2-a) -pyrimidin-3-yl-acetic acid, melting upon recrystallization from methanol. Elemental analysis. Calculated,%: C 64.39f Nb, 26; N 15.81. C, 9 2g "40e. Found,%: C 63.99; H 6.37, N 15.62. Example 91. While repeating the experiment described in the example 86, but with the replacement of the methanol plant of methyl 9-formyl-6-methyl-4oxo-1, 6,7,8-tetrahydro-4H-pyrido (1,2 - a) -pyrimidine-3-carboxylic acid methyl ester with a solution 3-phenyl-9-formyl-6methyl-1, 6,7,8-tetrahydro-4H-pyrido (1,2-a) -pyrimidin-4-one in dimethyl sulfoxide get 1.65 (96.0%) W- phenyl-9- (phenylhydrazono) -6-methyl6, 7,8,9-tetrahydro-4H-pyrido- (1 2 pyrimidin-4-one, t. pl. 146-148 ° C (after recrystallization from ethyl acetate). Elemental analysis. Calculated: C, 73.23; H 5.85, N 16.27. , Found,%: C 72.97 / H 5.70; N 16.03. Example92. By repeating the one described in the example. 86, but with the change of etanologo. a solution of 9-formyl-6-methyl-4-oxo-1,6, 7-8-tetrahydro-4H-pyrido- (1,2-a) -pyrimidine-3-carboxylic acid methyl ester with solution 3, 9-di-Formyl-2, 6-dimethyl-1, -6, 7,. 8-tetrahydro-4H-pyrido- (1,2-a) -pyrimidin-4-one in dimethyl sulfoxide gives 2.67 g (86.2%) of 9- (phenylhydrazono) -3-formyl-2, 6-dimethyl- 6,7,8,9 tetragilro-4H-pyrido- (1,2-a) -pyrimidin-4-one, t. Pl. 197С (after re-crystallization from acetonitrile). Elemental analysis. Calculated,% C 65.79, H 5.85, N 18.05 (, H "N40, Found,%" C 65.70; H 5.90; N 18.02. Example 93. With repetition; experiment, described in example 86, but replacing the methanol solution of 9-formyl-6-methyl-4-oxo-1, 6,7,8-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carbonyl methyl ester acids with a solution of 3,9-diLormyl-6-methyl1,6,7,8-tetrahydro-4H-pyrido- (1,2-a) pyrimidin-4-one in dimethyl sulfoxide get 3.05 g (97.0%) 9 - (phenylhydrazono) -3-formyl-6-methyl-6, 7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyrimidin-4-one, so pl. 166-1b7 with (after recrystallization from acetonitride). Elemental analysis -. Calculated,%: C 61.15, N. , N 17.82. (.HF Found,%: C 61.22, H 5.53, N 17.80. Example 94. By repeating the experiment described in Example 86, but replacing the methanol solution of methyl ether 9- formyl-6-methyl-4-oxo-1, 6,7,8-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid with a solution of 9-formyl-6-methyl-1,6, 7, 8-tetrahydro-4H-pyrido- (1,2-a) -pyrimidin-4-one in methanol gives 2.26 g (84.3%) of 9- (phenylhydrazono) -b-methyl-1, 6, 7,8-tetrahydro-4H-pyrido- (1,2-a) -pyrimidin-4-one, so pl. 163-165 C after recrystallization from mvtanol). The product does not lower the melting point when mixed with the product of example 63. Example 95. By repeating the experiment described in example .86, but replacing the methanol solution of 9-formyl-6-methyl methyl ether 4oxo-1, 6,7,8-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid with a methanol solution of ethyl 9-formyl-6-methyl-4-oxo-1,6, 7,8-tetrahydro-4H-pyrido- (1,2-a) -pyrimidin-3-yl3-propionic acid yield 2.2 g (59.8%) of the ethyl ester - (phenylhydrazono) -6-methyl-4- oxo6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine- 3-yl-propionic acid melting at 102 s after recrystallization From methanol.
    Elemental analysis.
    Calculated,%: C, 65.27; H 6.5; N 15.21.
    Found,%: C 65.25, H 6.70, N 14.98%.
    Example 96, by repeating the experiment described in example 86, but replacing the methanol solution of 9-formyl-6-methyl-4oxo-1, 6,7,8-tetragilro-4H-pyrido (1,2-a) - methyl ester methyl ester pyrimidine-3-carboxylic acid solution of 9-formyl-6-methyl-4-oxo1, 6,7,8-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid in dimethyl sulfoxide get 2.86 g (91.6%) of 9- (phenylhydrazono) -b-methyl4-oxo-6, .7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid, t. square 267-268 C (after recrystallization from dimethylformamide). The npo product does not lower the melting point when mixed with the product of Example 12.
    Example 97. To a solution of 2.15 (0.036 mol) of potassium oxide hydrate in 50 ml of water was added 4, E g (0.012 mol) of ethyl (9-phenylhydrazono) -6-methyl-4-oxo-6,7,8 , 9-tetrahydro-4H-pyrido- (1,2-a) -pyrimidin-3-yl3-acetic acid. The resultant mixture was stirred at room temperature for 4 hours. The pH of the solution was adjusted to 3 using a 10% w / w hydrochloric acid solution. The precipitated crystals are filtered and washed with water. 2.95 g (75.6%) of f9 (phenylhydrazono) -6-methyl-4-oxo6, 7,8,9-tetrahydide) o-4H-pyrido- (1,2-a) pyrimidin-3-ylJ are obtained - acetic acid, so pl. 161-162 #C. The product does not lower its melting point when mixed with the product of Example 62,
    Example 98. When repeating the experiment described in Example 62, but with the 6-methyl-4-oxo-6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyrim.din-carboxylic acid salt 8-methyl-4oxo-6 .7.8 9-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid gives 9- (phenylhydrazono) -8methyl-4-oxo-b, 7, 8,9-tetrahydro-4Npyrido- (1,2-a) -pyrimidine-3-carboxylic acid, t, pl. 23f4-236C (after recrystallization from acetonitrile). The yield is 52.1%.
    Elemental analysis.
    Calculated,%: C 61.53, H 5.16, N 17.94.
    C kChgvM40 Found,%: C 61.48; H 5.1;
    N 18.03%.
    Example 99 When repeating the experiment described in Example 12, but replacing aniline with para-nitroaniline, 6-metsh-9- (4-nitrophenylhydrazono) -4-oxo-6,7,8,9-tetrahydro4-H-pyrido (1,2-a) -pyrimidine-3-carbO new acid, so pl. 242-244 ° C. The yield is 55.5%.
    Elemental analysis.
    Calculated,% C 53.78, H 4.23. N 19.60.
    C AgN OsNaidenb,% j C 53-, 25; H 3.94} N, 19.40.
    , Example 100. By repeating the experiment described in example 12, but replacing aniline with 2-amino-4-chlorobenzoic acid, 9-2-carboxy-5 chlorobenzylhydrazono) 6-methyl-4-oxo-6 monohydrate; 7, 8.9 -tetrahydro4H-pyrido- (1,) - pyrimidine-3-carboxylic acid. The yield is 61.2 mp. 275-276 C.
    Elemental analysis ...
    Calculated,%: C 49.85; H 4.191 N 13.71 / C1 8.76.
    S-H, HQ.O
    Found,% 1 C 50.65; H 4.22, N 13.64; C1 9.03.
    PRI and eper 101. When repeating the experiment, o / embossed in example 1, but with the replacement of ethyl ester 6-methyl 4-OXO-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid | Lot 6-metsh4-4-oxo-6,7,8,9-tetra 21DRO-4H-pyrido- (1,2-a) -pyrimidine 3- (N-methylcarboxamide) with recrystallization of the crude of aceto nitrile, 9- (phenylhydrazono 6-methyl-4-oxo-6,7,8,9-tetrahydro4H-pyrido- (1,2-a) -pyrimidin-3- (Nmethylcarboxamide), m.p. 153-154 pp. The product is a mixture of optical isomers-E. The yield is 53.1%.
    Elemental analysis.
    Calculated,%: C 62.76 H 5.89, N 21.62.
    Found: C, 62.43; H, 5.81; N, 21.23.
    Example 102. By repeating the experiment described in Example 6, but replacing aniline with anthranilic acid and purifying the crude product with alkaline (acidic) precipitation, 2 b-methyl-4-oxo-6,7,8,9-tetrahydro-4H- is obtained. pyrido (1,2-a) -pyrimidine-9idenehydrogen-benzoic acid, t. pl. 170-172 C. The yield is 64.8%.
    Elemental analysis.
    Calculated,%: C 61.53, H 5.16, N 17.94.
    Found,%: C 64.40 / H 5.00;
    N 17.91.
    Example 103. When repeating the experiment described in example 63, but with the replacement of aniline 3-aminobenzoic acid and the purification of the crude product by alkaline (acidic) precipitation,
    3- 6-methyp-4-oxo-b, 7, 8.9) are obtained with tetrahydro-4H-pyrido- (1,2-a) -firi "din-3-ylidenehydraiono-benoic acid, t, pl. 260-2b2s. The input leaves 57.6%
    Elemental analysis.
    Calculated:% C 61.53, H 5.16; N 17.94.
    Cji VN- 0l
    Find% | WITH
    61, 37} H 5.11; M 17, 77.
    Example 104. 0.93 g of aniline is dissolved in 10 ml of a 15% (w / v) solution; hydrochloric acid. The reaction mixture is cooled to a temperature C. After that, a solution of 0.7 g of sodium nitrite in 5 ml of water is introduced into the reaction mixture, after which a solution of 3-ethyl 2, 6-dimethyl-4-oxo-b, 7, is added dropwise 8,9-tetrahydro-4H-pyrido- {1, 2-a) -pyrimidine in a mixture of 20 ml of water and 10 mp of ethanol at a temperature below. The reaction mixture is decanted to separate from oily-droplets and the oil phase is crystallized from aqueous methanol to obtain 0.8-g (25.8%) of a yellow product. The precipitated crystals are filtered and rinsed with water. The combined product is recrystallized from ethyladetate to obtain 3-ethyl-9-phenyl-2,6-dimethyl 1; l-47 oxo-6, 7,8,9-tetrahydro-4H-pyrido (1 2 -a) -pyrimidine, m.p. . 135-137 ° C. The product is a mixture of geometric isomers.
    elemental analysis.
    Calculated,% C 69.65; H 7.14; N 18.05.
    e% vo
    Found,% C 69.34; H 7.06 And 17.93.
    Example 105. Work according to the method described in example 6, but instead of an aqueous ethyl solution
    6-methyl-4-oxo-6,7,8,9-tetragyl-4H-pyrido- (1,2-a) -primidine 3-carboxylic acid ester prepared using acetone solution of b-methyl-4-oxo-6,7 , 8,9-tetrag.hydro4H-pyrido- (1,2-a) pyrimidine-3-carbonitride. The 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyrimidine-3-carbonitride hydrate is obtained, m.p. 2230.
    Elemental analysis.
    Calculated,% C 61.73 / H 5.50, N 22.49.
    g i N-gO-Hid
    5 Found,%: C 61.40; H 5.32, N 22.76.
    Example 106. To a solution of 2.0 g (7.57 mmol) of 9-hydrazono-6-methyl-4 "oxo-6,7,8,90 ethyl ester of tetrahydro-4H-pyrido- (1,2-a) pyrimidine -3-carboxylic acid in 20 ml of anhydrous chloroform was added 1.6 ml (11.35 mmol) of triethylamine and 1.3 ml (11.35 mmol) of benzochloride.
    5 Mixture K1; pt t for 2 hours, then cooled to room temperature and thoroughly shaken with 20 ml of water. The organic phase is separated, the aqueous phase is extracted with 10 ml of chloroform. The combined cytuaT organic phases are over calcined sodium sulfate and then evaporated in vacuo. The residue is recrystallized from methanol. 1.5 g (53.8%) of these 9- (benabylhydrazono) -6lolu-pkso-6., 7,8,9-tetrahydro-4Htcrcpb- (i,) pyrimidine-3-carboyl 11 acid are obtained, t pl. 209-210 0. Elemental analysis. Calculated,% t С 61.96 Н 5.47 /
    0 N 15.20.
    Find about G C 62.02, H 5.58 N 15.61.
    about
    ;
    about
    cm

    G4
    I
    about es
    N 00
    r m
    rl l
    U o
    tn r-l r 1Л
    tn M
    oh oh
    fS fM
    rH T-)
    oo "aVO r
    "T Tt (N
    r o
    n VO
     CO rO kO
    tn r
    about oo
    oh oh
    GM TN 1L Yu
    权利要求:
    Claims (1)
    [1]
    VC VO VO VO O VD Claim of the invention The method of obtaining pyr-to- (1,2-a) pyrimidine derivatives of the general formula N-NH-R where L is a hydrogen atom, or C.-C.-alkyl; R. is a hydrogen atom, or C. i kil; . R is a hydrogen atom, C —C-alkyl, phenyl, carboxyl, lower alkoxycarbonyl, carbamoyl, lower alkyl alkylcarbamoyl, hydrazo COORg, where Rg is a hydrogen atom or lower alkyl, and m 1 or 2, RA is phenyl, which may be substituted with 1-5 identical or different substituents selected from the group: halo atoms, lower alkyls, nitro groups, carboxyl groups, hydroxyl groups, trifluoromethyl, alkoxysulfonyl, sulfonamido, acetyl, phenyl, phenoxy, cyano or methylenedioxy, or R naphtha l, possibly substituted by a carboxy group, or benzoyl, or pyridyl, or their pharmaceutically acceptable salts, or their optically active isomers, characterized in that the compound of the formula Ms f R, o or its optically active isomers where K is -toM hydrogen, or formyl, is reacted with a compound of the general formula III: where R has the indicated meanings, with, preferably, O-2 O with a subsequent selection of the desired product or saponification with semi-. ester, or by converting it to an amide or hydrazide acid, and the target products are isolated in free form or in the form of pharmaceutically acceptable salts, or in the form of optically active isomers. Sources of information taken into account during the examination 1. Experiment in Organic Chemistry, Kimi, 1969, p. 400-402,
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU77CI1794A|HU178496B|1977-12-29|1977-12-29|Process for preparing 6,7,8,9-tetrahydro-4h-pyrido/1,2-a/pyrimidine derivatives with antiallergic activity|
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