FI57949C - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANALYSIS OF 4-OXO-6,7,8,9-TETRAHYDROPYRIDO (1,2-A) PYRIMIDINDERIVAT - Google Patents

Description

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Patent · ta Registry Board .............

_ '(44) Date of issue | -

Patent * och registerstyrelsen Ameka utiijd oeh uti.skrHt «n pubUcwtd 21 07 80 (32) (33) (31) Privilege requested — Begird prlorltet 30.03.73

Hungary-Hungary (HU) CI-1361 (71) Chinoin Pharmaceuticals and Chemicals Gy. Rt., 1-5 To u.,

Budapest IV, Hungary-Hungary (HU) (72) Zoltän Meszäros, Budapest, Jozsef Knoll, Budapest, Istvan Hermecz, Budapest, Lelle Vasväri nee Debreczy, Budapest, Agnes Horvath,

Budapest, Hungary-Hungary (HU) (7¾) Oy Kolster Ab (5¾) Method for the preparation of therapeutically useful U-oxo-6,7,8,9-tetrahydro-pyrido / 1,2-a7 pyrimidine derivatives - Förfarande för framställning av therapeutiskt användbara The present invention relates to a process for the preparation of therapeutically useful U-oxo-6,7,8,9-tetrahydropyrido 0,2-α7-pyrimidine derivatives having the following characteristics: U-oxo-6,7,8,9-tetrahydro-pyrido [1,2-a] pyrimidine derivatives is of formula R1

N (D

-ύΛ (° ύΛ2) n "R3 R2 '> 0 and salts and quaternary salts thereof, wherein and R8 are independently hydrogen or C1-4alkyl R3 is carboxy, benzyloxycarbonyl, carbamoyl, ^ -alkyl- A carbamoyl, C 1-4 alkoxycarbonyl, hydrazinocarbonyl or phenyl-C 1-4 alkylcarbamoyl group optionally substituted with 1-2 C 1-4 alkoxy groups »and n = 1 or 2.

C 1-6 alkyl can mean straight-chain or branched alkyl groups containing 1-U carbon atoms (e.g. methyl, ethyl, etc.). The term "halogen atom" includes chlorine, bromine, fluorine and iodine. Alkoxy groups may be straight-chain or branched and may contain 1-U carbon atoms (e.g. methoxy, ethoxy, isopropoxy, n-butoxy).

Salts of the compounds of formula (I) may be formed with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, formic acid, acetic acid, citric acid, malic acid, glutamic acid, mandelic acid, salicylic acid, salicylic acid.

Quaternary salts of the compounds of formula (I) are formed with conventional quaternizing agents, e.g. in the form of toluenesulfonates with alkyl halides (e.g. methyl iodide, ethyl iodide, etc.), dialkyl sulphates (e.g. dimethyl sulphate) or alkyl or arylbenzenesulphonates.

The process according to the invention is characterized in that W Ί, of formula (II), is reduced, preferably by catalytic hydrogenation.

A compound of formula R (II) N (CVn-R520) wherein and is as defined above and R1 is carboxy or alkoxycarbonyl, and if desired, the resulting formula (Li)

V

In the compound of formula (M) 0 (m) 0, the alkoxycarbonyl group is hydrolyzed to the carboxy group, which is then either directly or first converted to a carbonyl halide group by esterification with benzyloxy or another alkoxycarbonyl group or by amination with carbamoyl, C to a β-alkylcarbamoyl group or, in the reaction with hydrazine, to a hydrazinocarbonyl group which can be further reduced to a carbamoyl group.

The reduction can preferably be carried out by catalytic hydrogenation. The hydrogenation can be carried out at a temperature between 0 ° C and 100 ° C and at normal atmospheric pressure or at a pressure of 1 to 50 atmospheres.

The reaction is carried out in a solvent. As the reaction medium, water, alkanols (e.g., methanol or ethanol), esters (e.g., ethyl acetate), ketones (e.g., acetone or methyl ethyl ketone), or organic acids (e.g., acetic acid) or mixtures thereof can be used.

Conventional hydrogenation catalysts can be used as catalysts. It is recommended to use palladium on carbon, Raney nickel, platinum or platinum oxide.

Upon hydrogenation of the starting material of formula (II), the pyridine ring becomes saturated by binding 2 moles of hydrogen. After absorption of the calculated amount of hydrogen, the catalyst is removed (preferably by filtration, centrifugation, sedimentation or decantation) and the solvent is distilled off. The compound of formula (III) thus obtained, or an acid addition salt thereof, can be recrystallized, if necessary, from a suitable solvent.

The R 1 group of the compound of formula (III) may, if desired, be converted into an R 2 group of the compound of formula (I), or the R 2 group may be converted into another R 2 group by methods known per se. Thus, the alkoxycarbonyl group can be converted into a carboxyl group by hydrolysis. The reaction can preferably be carried out under time conditions using alkali hydroxide, preferably aqueous sodium or potassium hydroxide solution. The alkoxycarbonyl group can be converted to an acid hydrazide group by treatment with hydrazine * the latter can be preferably used as an alcoholic hydrazine solution; salts of hydrazine and hydrate can both be used. The carboxyl group can be converted to an alkoxycarbonyl group (e.g., ethoxycarbonyl) by treatment with an alcohol (e.g., ethanol) in the presence of a solvent (e.g., benzene). The carboxyl group can be converted to the acid amide by reaction with the corresponding amine in a solvent (e.g., xylene) or without it. The free carboxylic acid can be converted to the acid chloride by treatment with a halogenating agent (e.g., thionyl chloride, phosphorus oxychloride, etc.). Acid halides can be converted to the free acids by treatment with water or to alkoxycarbonyl esters by treatment with the corresponding alcohol or by treatment with acid amides with the corresponding amines.

The aforementioned conversions of the R 1 group into other R 2 groups can be performed by conventional methods well known in the art.

The starting material of formula (II) may be prepared by cyclization of formula (IV)

V

* JL R6 (iv)

R 'N 2 NH-CH = C

“K I

A compound according to R 5, wherein R 1, R 2, R 2 and n have the same meaning as above and R 8 represents an alkoxycarbonyl group. The ring closure can be carried out in the presence of an inert solvent or in the presence of an acidic condensing agent, e.g. phosphorus oxychloride, phosphorus trihalide, phosphoric acid, etc., at a temperature between 25 ° C and 1 + 00 ° C. (The preparation of the starting material is described in DE-A-2 315 1 + 22).

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The compounds of formula I have low toxicity and are particularly effective as analgesics, anesthetics and anti-inflammatory agents. The LD50 value of 3- [ethoxycarbonylmethyl] -1,6-dimethyl-4-oxo-6,7,9,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulphate in rats is 1,300 mg / kg administered subcutaneously. According to the hot plate test, the subcutaneous EDc value in the rat is 160 mg / kg. At a dose of 120 mg / kg intravenously, the compound is active in an algolytic experiment and also potentiates the effect of morphine.

The toxicity of 5- [carboxymethyl] -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine to rats is greater than 2,000 mg / kg orally. In the narcosis-enhancing test, the ED50 is 1000 mg / kg given orally.

The experiments were performed using the following known methods.

Hot plate test: Voolfe and McDonald, A.P., J. Pharm. 80, (1944) 300; modified by Porszasz and F. Kiserl. Orvostud. 2, (1930) 292.

Algolytic Experiment: Knoll J., in: Animal and Clinical Pharmacologic Techniques in Drug Evaluation. Eds. Siegler, P.E. and Moyer, J. II. Year Book Medical Pub. Chicago, 1967 »PP · 305-321.

Toxicity: Litchfield, J.T. and Wilcoxon, F ·, J. Pharmacol. Sci. 54, (1965) 888.

The following are experimental results from experiments performed with a known compound A and a compound B according to the invention.

Koevhdisteet:

Compound A - 1,6-dimethyl-3-ethoxycarbonyl-4-oxo-6,7,8,9-tetrahydropyrido [1,2-a] pyrimidinium methosulfate (GB Pat.

1,209,946 most active compound).

Compound B - 3- (ethoxycarbonylmethyl) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine · 5 79 4 9

Compound i.v. * ^ 50 * s »°» _p.o.

A 245.0 660.0 1,200.0 (224.7-267.0) (589.2-759.2) (960.0-1452.0) B 500 850 2,000 (406.5-615) (0) (602.8-1 198.5) (1 562.5-2 560.0)

Compound i.v. BD ^ / hot plate test) P · 0 * B.C.

A 65 58 85 (61.3-68.4) (53.7-62.6) (77.9-92.6) B 58 68 75 (52.2-58.58) (54.4-85 .0) (58.8-99.0)

The compound ED ^ Q / (algolytic, so-called writhing test) p.o.

A 380 (299.0-482.6) B 420 (333.3-529.2)

Evaluation of experiments

It can be seen from the experimental results that the toxicity of Compound B of the invention, both orally and parenterally, is substantially lower than that of Compound A of the prior art. In the hot plate test as well as in the twist test, the activity of both compounds is approximately the same. The therapeutic index (LD, .q / ED ^ q) of compound B is thus clearly more advantageous than that of compound A.

Similar results were obtained with other compounds prepared by the process of the invention.

From the experimental results presented above, it appears that the compounds of formula I having a methylene or ethylene bridge between the 3-position of the pyrido [1,2-a] pyrimidine ring and the R 1 support are clearly superior in therapeutic properties to the known compounds in which the subethyl support is directly connected to the 3-position of the ring system.

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The following examples illustrate the invention:

Example 1: 3- (Carboxymethyl) -6-methyl-U-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine U, U g (0.02 moles) 3- (carboxymethyl) -6- methyl U-oxo-UH-pyrido [1,2-b] pyrimidine is suspended in 60 ml of glacial acetic acid and hydrogenated under normal pressure using palladium / carbon as catalyst.

The calculated amount of hydrogen is absorbed over 30 minutes, after which the catalyst is filtered off and the solution is evaporated to dryness in vacuo. The residual oil (8.2 g) is recrystallized from 9 ml of 96% alcohol. 3.3 g (75%) of white 3- (carboxymethyl) -6-methyl-.alpha.-oxo-6,7,8,9-tetrahydro-1H-pyrido β, 2-a7-pyrimidine are obtained, m.p. 193 ~ ^ 19 ° C. The melting point does not change in recrystallization.

Analysis:

Calculated: C 59, U5%> H 6.35 52, N 12.9%

Found: C 59.81%, H 6.22%, N 12.59%

Example 2: 3- (Carboxymethyl) -6-methyl-U-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine 6.0 g (0.15 mol) of sodium hydroxide are dissolved in 60 ml. of water. To the resulting solution, 1 g (0.05 mol) of 3- (ethoxycarbonylmethyl) -6-methyl-U-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine hydrochloride is added, and the solution is stirred. at room temperature for 3 hours, after which the pH is adjusted to 7 with 1: 1 hydrochloric acid (about 8 ml) and the solution is decolorized with activated carbon. The pH of the colorless solution is adjusted to 1 * (at lower pH the acid dissolves). The solution is allowed to stand in the refrigerator for a few hours, and the precipitated crystals are filtered off. 3.6 g (32%) of 3- (carboxymethyl) -6-methyl-.alpha.-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine are obtained, melting at 191 ° C. . The aqueous mother liquor is evaporated to dryness and the residue (10 g) is dissolved in 20 ml of water by heating. After cooling the solution, 3.5 g (30%) of acid are obtained, melting at 192 ° C. The total yield is 7.1 g (62%). Upon recrystallization from 96 # alcohol, the melting point rises to 193 ~ 19 ° C. When mixed with the product obtained in Example 1, the melting point remained the same.

When 3- (ethoxycarbonylmethyl) -1 * -oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine is used as the starting material in the above process, 3- (carboxymethyl) -4-oxo- 6,7,8,9-tetrahydro-UH-pyrido [1,2-a] pyrimidine, m.p. 17-175 ° C, yield 80%.

5 7 9 4 9 a

Example 3: 3- (Ethoxycarbonylmethyl) -N-oxo-6,7,8,9-tetrahydro-UH-pyrido [1,2-a] pyrimidine 53.7 g (0.2 moles) of 3 '(ethoxycarbonylmethyl) -1 + oxo -UH-pyrido / .7,2-a (7 pyrimidine hydrochloride is dissolved in 250 ml of water. 10 ml of hydrochloric acid and 20 g of palladium / carbon catalyst are added and hydrogenation is carried out at a pressure of 5 to 10 atmospheres. After the calculated amount of hydrogen has been absorbed, the catalyst is filtered off and The pH is adjusted to 7 by adding 20 sodium carbonate solution, decolorized with activated carbon and filtered, the clear solution is extracted 3 times with 300 ml of benzene, the combined extracts are dried over sodium sulphate, the solution is filtered and the filtrate is evaporated to dryness to give 32.0 g (68%). ) crystalline product, melting at 63-66 [deg.] C. Extraction of the aqueous mother liquor with chloroform and further work-up yields an additional 2.8 g (5.5%) of product, total yield 73.5 Recrystallization from the alcohol-petroleum ether mixture gives a white 3- ( ethoxycarbonylmethyl) -1 + -oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-b] pyrimidine, m.p. 65-66 ° C.

Analysis:

Calculated: C 61.0%, H 6.75%, N 11.86%

Found: C 60.01% t H 6.82% t N 12.02%.

When starting from 3 '(ethoxycarbonylmethyl) -7-methyl-U-oxo-1 H -pyrido 2 -1,2% pyrimidine without crystallization, 3- (ethoxycarbonylmethyl) -7-methyl-N-oxo-6,7,8, 9-tetrahydro-UH-pyrido [1,2-a] pyrimidine as an oil The melting point of the hydrochloride is 1U6-1U7 ° C.

Using 3- [ethoxycarbonylmethyl] -methyl-N-oxo-1H-pyrido [1,2-a] pyrimidine hydrochloride as starting material gives 3- (ethoxycarbonylmethyl) -8-methyl-U-oxo-1H-pyrido [1,2-a] pyrimidine having a melting point of + U1 -U5 ° C.

Example U: 6-Methyl-U-oxo-6,7,8,9-tetrahydro-UH-pyrido [1,2-a] pyrimidine-3- (methylcarbohydrazide 0.25 g (1 mmol) 3- (ethoxycarbonylmethyl) Dissolve -6-methyl-U-oxo-6,7,8,9-tetrahydro-UH-pyrido [2,2-a] pyrimidine in 1 ml of absolute alcohol and add 0.1 ml (2 mmol) of 100 Ji from hydrazine hydrate.

The solution is allowed to stand for 2 hours at room temperature, then evaporated to dryness and the product obtained, which slowly crystallises, is recrystallized from an alcohol-ether mixture. 0.17 g (72%) of white 6-methyl-U-oxo-6,7,8,9-tetrahydro-UH-pyrido [1,2-a] pyrimidine-3- (methylcarbohydrazide) are obtained, melting at 132-133 ° C. :in. The melting point does not change during recrystallization.

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Analysis:

Calculated: C 55.91%, H 6.83%, N 23.72%

Found: C 55.20%, H 7.15%, N 23.69%

Example 5: 3- (Ethoxycarbonylmethyl) -1,6-dimethyl-1 + -oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidinium methosulfate 25.0 g (0.1 mol) 3- (Ethoxycarbonylmethyl) -6-methyl-1-oxo-6,7,8,9-t tetrahydro-1 + H-pyrido, / 1, is dissolved in 50 ml of absolute acetone, and 13.2 g ( 0.105 moles) of freshly distilled dimethyl sulfate. The solution is heated for 10 minutes at 1 * 0 ° C, then allowed to stand at room temperature. The next day the precipitated crystals are filtered off and washed with a small amount of absolute acetone. The product obtained is recrystallized from twice the amount of absolute alcohol to give 21 g (56%) of white 3- (ethoxycarbonylmethyl) -1,6-dimethyl-1 + oxo. -6,7,8,9-tetrahydro-1 + H-pyrido [1,2-a] pyrimidinium methosulfate, melting at 150 [deg.] C. The melting point does not change during recrystallization.

Analysis:

Calculated: C 1 * 7.86%, H 3.75%, H 7.1 + 1 *%, S 8.52%

Found: C 1 * 7.98%, H 3.70%, N 7.1 * 2%, S 8.1 + 1%.

Using 3- (ethoxycarbonylmethyl) -1 + -oxo-6,7,8,9-tetrahydro-1 + H-pyrido [1,2-a] pyrimidine as the starting material in the above process, 3- (ethoxycarbonylmethyl) -1-methyl-1 * -oxo is obtained. -6,7,8,9-tetrahydro-1 * H-pyridoyl, 2-alpyrimidinium methosulfate, melting at 11 * l-11 * 2 ° C.

✓ 10 57949

Example 6: 3- (N-2-phenylethyl) carboxamidomethyl-6-methyl-U-oxo-6.7.8,9-tetrahydro-UH-pyrido [1,2-a] pyrimidine perchlorate

In a device equipped with a water separator, 22.2 g (0.1 mol) of 3- (carboxymethyl) -6-methyl-U-oxo-6,7,8,9-tetrahydro-UH-pyrido [1,2-s] [7-s] are heated to reflux. pyrimidine, 12.1 g (0.1 mol) of 2-phenylethylamine and 100 ml of xylene for 3 hours, during which time 1.8 ml of water condenses in the condenser. The solution is then evaporated to dryness. 32.3 g (99%) of 3- (N-2-phenylethyl) carboxamidomethyl-6-methyl-H-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine are obtained as a non-crystallized oil. Dissolving 3.35 g (0.01 mol) of the oil in 3 ml of alcohol and adding 1.5 ml of JO perchloric acid to the resulting solution gives 3.0 g (71%) of a pale yellow 3- (N-2- phenylethyl) carboxamidomethyl 6-methyl-k-oxo-6,7,8,9-tetrahydro-HH-pyrido [1,2-pyrimidine perchlorate, melting at 17-176 ° C. The melting point rises when recrystallized from 8 times the amount of ethanol to 176-177 ° C.

Analysis:

Calculated: C 53.59%, E 6.68%, N 9.87%, Cl 8.32%

Found: C 53.61% t H 5.65 g, N 9.91 *%, Cl 8.95%.

When 2- (3, 4-dimethoxyphenylethylamine) is used as the amine component in the above process, 3 - [- 2- (3,3-dimethoxyphenyl) ethyl] 7'-carboxamidomethyl-6-methyl-1 * oxo-6,7,8,9-tetrahydro -ltH-pyrido [3,2-b] pyrimidine in $ 99 yield as a non-crystallized oil.

Example 7: 3- (Carboxymethyl) -6,8-dimethyl-U-oxo-6,7,8,9-tetrahydro-1H-pyrido [3,2-a] pyrimidine 2.6 g (0.01 mol) of 3- (ethoxycarbonylmethyl) -6,8-Dimethyl-U-oxo-1 + H-pyrido [1,2-a] pyrimidine is dissolved in 30 ml of ethanol and hydrogenated under normal pressure in the presence of a neutral 10 to 10 palladium-on-carbon catalyst (1.0 g). After uptake of the calculated amount of hydrogen, the reaction is complete and the catalyst is filtered off and the alcoholic solution is evaporated to dryness. 2.2 g (8.5%) of 3- (ethoxycarbonylmethyl) -6,8-dimethyl-U-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine are obtained in the form of a colorless oil. .

Analysis:

Calculated: C 63.62% t H 7.63%, N 10.60 J5 Found: C 63.85 %% H 7.51 *%, N 10.65%.

0.5 g (0.0019 mol) of the ester obtained above is heated at reflux with 5% hydrochloric acid (5 ml) for 0.5 hour, then the solution is evaporated in vacuo.

Π 57949

The crystalline residue is dried in a desiccator over phosphorus pentoxide to constant weight. 4.3 g (95.5%) of white crystalline 3- (carboxymethyl) -6,8-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine are obtained. 120 ° C (decarboxylation at 144 ° C).

Analysis:

Calculated: C 6 1.00%, H 6.83%, N 11.86%

Found: C 60.95%> H 6.90%, N 11.85%

Example f1: 3- (Ethoxycarbonylmethyl) -4-oxo-6,7,8,9-tetrahydro-4-pyrido [1,2-a] pyrimidine 3.03 g (0.01 mol) of 3- (ethoxycarbonylmethyl) -7-chloro- 4-Oxo-4H-pyrido-5S, 2,7-pyrimidine hydrochloride is dissolved in 75 ml of 5N hydrochloric acid and hydrogenated under normal pressure in the presence of 10% palladium on carbon (1.5 g). Kim hydrogen is bound to 0.03 moles, the reaction is complete. The catalyst is filtered off, and the filtrate is neutralized with 20% sodium hydroxide solution while cooling, then extracted with chloroform. The chloroform phase is dried and evaporated in vacuo. 1.7 g (72%) of white 3- (ethoxycarbonylmethyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine are obtained, m.p. 65-66 ° C.

An intelligence:

Calculated: C 61.00%, H 6.75% * N 11.86%

Found: C 61.15%, H 6.80%, N 11.92%.

Example 9: 3- (2-Ethoxycarbonylethyl) -4-oxo-6,7-8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine 2.46 g (0.01 mol) of 3- (2- ethoxycarbonylethyl) -4-oxo-4H-pyrido [1,2-a] pyrimidine is dissolved in 100 ml of ethanol and hydrogenated in the presence of 10.5 palladium-on-carbon catalyst (1.0 g). When the calculated amount of hydrogen is bound, the catalyst is filtered off and the alcoholic solution is evaporated. 2.0 g (80%) of white crystalline 3 '(2-ethoxycarbonylethyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine are obtained, m.p. 48-50 ° C.

Analysis:

Calculated: C 62.38%, H 7.25%> N 11.19%

Found: C 62.45%, H 7.30% t N 11.24%.

When 3- (2-ethoxycarbonylethyl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyridine is used as starting material, 3- (2-ethoxycarbonylethyl) -6-methyl-4-oxo- 6,7,8,9-Tetrahydro-4H-pyrido [1,2-a] pyrimidine as a colorless crystallized oil. Yield: 35%. Hydrochloridine m.p. 130-132 ° C.

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Analysis:

Calculated: C 55.91%, H 7.0%, M 9.31%, Cl 11.79%

Found: C 56.02, i, H 7.01% t 39, U 0 #, Cl 11.08%.

Example 10: o-net-3- (methoxycarbonylmethyl) -U-oxo-6,3,3,9-tetrahydro-Un-pyrido [1,2-a] pyridine, thidine U, U5 g ( 0.02 mol) of 3- (carboxymethyl) -6-methyl-U-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyridinidine is suspended in 60 ml of methanol and the suspension is saturated with hydrogen chloride gas at 5 ~ 10 ° C. The reaction mixture is allowed to stand overnight, then the pale yellow solution is evaporated and the residue is dissolved in 30 ml of water, the pH of the solution is adjusted to 7 by adding saturated sodium carbonate solution. The solution is treated with carbon to remove color, the carbon is filtered.

The clear solution is extracted 3 times with benzene. The combined benzene extracts are dried over sodium sulfate, the solution is filtered and evaporated. 3.0 g (63.5%) of a pale yellow oil are obtained, which is dissolved in 2 ml of ethanol, and 2 ml of ethanol containing 25% hydrochloric acid are added to the solution. The precipitated white 6-methyl-3- (methoxycarbonylmethyl) -N-oxo-6,7,8,9-tetrahydro-1H-pyrido [5,2-b] pyrimidine is filtered off. Sp. 222 ° C.

Analysis:

Calculated: C 52.85%, H 6.82%, N 10.27%, Cl 13.00%

Found: C 53.02%, H 6.85%, N 10.12%, Cl 12.95%

Example 11: 3- (Ethoxycarbonylmethyl) -1-methyl-U-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-f] pyrimidine iodide 3 g (0.015 mol) of 3- (ethoxycarbonylmethyl) - 1 + -oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine is dissolved in 5 ml of acetone, and 3.0 ml of methyl iodide is added to the solution. The solution is stirred and then allowed to stand for 5 days in the dark. The precipitated crystalline product is filtered and washed with acetone. U, 9 g (86.5 f) of pale yellow crystals are obtained, m.p. 150-153 ° C. Recrystallization from ethanol of 3- (ethoxycarbonylmethyl) -1-methyl-U-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine iodide gives a melting point of 15 U-155 ° C.

Analysis:

Calculated: C Ui, 29 / &, H 5.06%, N 7, U1%, J 33.55%

Found: C U1.10%, H 5.11%, N 7, U8%, J 33, ^ 5% 57949 13

Example 12: 3- (Benzyloxycarbonylmethyl) -6-methyl-U-oxo-6.7.8,9-tetrahydro-1H-pyrido [1,2-b] pyrimidine hydrochloride 2.22 g (0.01 mol) 1.6 -dimethyl-3 - (carboxymethyl) -. until the benzyl alcohol is saturated. The reaction mixture is stirred until a clear solution is obtained. The benzyl alcohol is evaporated in vacuo and the crystalline residue is recrystallized from ethanol. White crystalline 3- (benzyloxycarbonylmethyl) -6-methyl-U-oxo-6,7,8,9'-tetrahydro-UH-pyrido [1,2-a] pyrimidine hydrochloride is obtained. Sp. + 202-20l ° C. Yield 60%.

Analysis:

Calculated: C 61.9%, H 6.07%, N 8.03%, Cl 10.16%

Found: C 61.91%, H 6.02%, N 8.10%, Cl 10.11%

Example!! : 3- (carbamoylmethyl) -1 + -oxo-6,7,8,9-tetrahydro- [4H-pyrido] [2,2-b] pyrimidine 2.18 g (0.01 mol) U-oxo-1H-pyrido [1,2- 17β-pyrimidine-3- (methylcarbohydrazide) (m.p. 228-229 ° C) is dissolved by heating in 700 ml of ethanol, then 10 g of Raney nickel catalyst are added and the reaction mixture is refluxed until the evolution of ammonia gas ceases (3 ~ 3.5 h). The catalyst is filtered off and the filtrate is evaporated. White crystalline 3 "(carbamoylmethyl) -U-oxo-6,7,8,9-tetrahydro-UH-pyrido [1,2-a] pyrimidine is obtained. Mp 182-110 ° C (recrystallized from ethanol). Yield 95% .

Analysis:

Calculated: C 57.96%, H 6.32%, N 20.28%

Found: C 57.68%, H 6.02%, N 20.3 * +%.

Example 14: 3- (Carbamoylmethyl) -6-methyl-U-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine hydrochloride 1.6 g (6.5 mmol) of 6-methyl-U -oxo-6,7,8,9-tetrahydro-UH-pyrido [1,2-a] pyrimidine-3- (methylcarbohydrazide is dissolved in 50 ml of ethanol in the presence of a Raney nickel catalyst (10 g). The reaction mixture is refluxed for 2 hours. after which the catalyst is filtered off and the alcoholic filtrate is evaporated to give 1. * ♦ g of a pale yellow oil which is treated with 10 ml of ethanol containing 20% of hydrochloric acid, the precipitated crystals are filtered off and dried to give 1.15 g (68%) of 3- ( carbamoylmethyl) -6-methyl-4-oxo-6,7,8,9-tetrahydro-1H-pyrido [1,2-a] pyrimidine hydrochloride, mp 235-236 DEG C. The melting point remains unchanged after recrystallization from ethanolic hydrochloric acid 11-57949. .

Analysis:

Calculated: C 51.2? %, H 6.26%, N 16.30%, Cl 13.76%

Found: C 51.10%, H 6.30%, N 16.18%% Cl 13.52%.

The following examples illustrate the preparation of starting materials: A) 3- (ethoxycarbonylmethyl) -1 + -oxo-7-methyl-α-pyrido [1,2-a] pyrimidine 1U, 6 g (0.05 moles) of 2- [5-methyl-2 -Pyridyl) -aminomethylene-7-succinic acid diethyl ester is dissolved in 100 ml of diphyl at 130 ° C. The solution is heated to 250 ° C and stirred at this temperature. The ethanol formed is continuously evaporated from the reaction mixture. The calculated amount of alcohol can be evaporated at 30-UO per minute. The reaction mixture is worked up by diluting with 10 ml of petroleum ether and extracting 3 times with 100 ml of 20% hydrochloric acid. After neutralization of the hydrochloric acid phase and extraction with benzene, 3- (ethoxycarbonylmethyl) -1 + -oxo-7-methyl-1 + H-pyrido [1,2-a] pyrimidine is obtained. Yield 50-55% · The melting point of the base after recrystallization from twice the amount of anhydrous alcohol is 12-130 ° C.

Analysis:

Calculated: C 63.0%, H 5.73%, N 11.38 JC Found: C 63.92%, H 5.58%, N 11.1 + 2%.

B) 3- (Ethoxycarboylmethyl) -1 + -oxo-9-methyl-1 + H-pyrido [2,2-a] pyrimidine

When 2 - [(3-methyl-2-pyridyl) -aminomethylene] -succinic acid diethyl ester is used as the starting material in the above process, the title compound is obtained, m.p.

88-90 ° C.

C) 3- (ethoxycarbonylmethyl-U-oxo-1H-pyrido) -2-pyrimidine

Using 2- (2-quinolylaminomethylene) -succinic acid diethyl ester as starting material, the title compound (m.p. 121-122 ° C) is obtained in 60% yield.

D) 3- (Ethoxycarbonylmethyl) -1 + -oxo-6-methyl-1 + H-pyrido [1,2-b] pyrimidine 10.8 g (0.1 mol) of 2-amino-6-methylpyridine and 20.2 g (0.1 mol) of 2-formylsuccinic acid are dissolved in 150 ml of diphyl. The solution is stirred and heated at 250 ° C for one hour. First, water and then ethanol evaporate from the reaction mixture. After the calculated amount of water and ethanol has evaporated, the solution is cooled and treated as described in Example A). The product is purified by column chromatography (Merck silica gel, grain size: 0.063-0.125 mm). The title compound is obtained in 25% yield. Sp. 89-90 ° C (eluted with benzene).

Claims (2)

15 5 7 9 4 9 Patent: A process for the preparation of therapeutically useful U-oxo-6,7,8,9-tetrahydropyrido J 2, 2-α / pyrimidine derivatives of formula (I) and their for the preparation of salts and quaternary salts, wherein R 1 and R 4 are independently hydrogen or C 1-4 alkyl, are conical, benzyloxycarbonyl, carbamoyl, alkylcarbamoyl, C 1-4 alkoxycarbonyl, hydrazinocarbonyl or phenyl-C 1-4 alkyl; an alkylcarbamoyl group optionally substituted by a 1-2 C alkoxy group, and n = 1 or 2, characterized by reducing, preferably by catalytic hydrogenation, a compound of formula (II) wherein H 1 and R 8 have the same meaning as above and is carboxy or alkoxycarbonyl, and if desired, the alkoxycarbonyl group in the resulting compound of formula (IIi) Vy> RN (CH2} n'R5 2 0 16 57949 is converted by hydrolysis to a carboxy group which is then either directly or first converted to carbonyl. the skin halide group is converted with the corresponding alcohol by esterification to benzyloxy or another C 1-4 alkoxycarbonyl group or by amination with a corresponding amine by carbamoyl, C 1-4 alkylcarbamoyl or phenyl-C 1-4 alkylcarbamoyl group to the carbamoyl group, and, if desired, converting the compound of formula (I) thus obtained into its acid addition salt or quaternary salt, or liberating the compound of formula (I) from its acid addition salt or quaternary salt. 57949 17 For the preparation of therapeutically active compounds U-oxo-6,7,8,9-tetrahydropyrido E, 2-g7pyrimidines with the formula (i) R, „ 1. N 1 -N 2 A (CH 2) n -R 3 - R 2 O and a different salt and a quaternary salt, in which the formula is different and Rg is optionally substituted with C 1-4 alkyl-C 1-4 carboxy-, benzyloxycarbonyl-, carbamoyl C 1-4 alkylcarbamoyl, C 1-4 alkoxycarbonyl, hydrazinocarbonyl or phenyl C 1-4 alkylcarbamoyl, optionally substituted with 1-2 C 1-4 alkoxycarbonyl groups, and n = 1 or 2, to give a reduction, to reduce the genomic catalytic hydrogenation, and to give the formula (yl) r (II) ^ N ^ A (CH2) n-R5 R2 0 color R. | and Rg is substituted with carboxy or alkoxycarbonyl, and is optionally substituted with alkoxycarbonyl groups and further formed with the formulation (lii) V By ^ * 2) ® ^ (III)