JPS62150B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel pyrimido[1,2a]heterocyclic compound represented by the general formula, optically active isomers thereof, and pharmaceutically acceptable salts thereof: General formula (wherein R ¹ represents alkyl having 1 to 6 carbon atoms). The present invention also provides pyrimido(1.2a) heterocyclic compounds of the general formula (wherein R ¹ is as defined above), optically active isomers thereof, diastereomers thereof and pharmaceutically acceptable salts thereof. It also relates to a manufacturing method. Compounds of the general formula are useful as analgesics, anti-inflammatory agents, PG-antagonists, antidepressants, and/or CNS- or antilyphemic agents.
Has activity. The invention therefore also encompasses pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the general formula (alone or together with another pharmaceutically active substance). The method of the present invention includes the following method. (a) General formula (wherein R ¹ is as defined above), the corresponding pyrimido(1.2a) heterocyclic compound or its optically active isomer or its pharmaceutically acceptable salt is reduced; or (b ) general formula (wherein R ¹ is as defined above), the corresponding pyrimido[1,2a] heterocyclic compound or its optically active isomer or its pharmaceutically acceptable salt can be combined with the general formula a R ¹ - A halide of ^the general formula b (R ¹ ) ₂ SO ₄ (b) (wherein R ¹ has the same meaning as defined above and X is a halogen) or a phosphate of the general formula c (R ¹ ) ₃ PO ₄ (c) in which R ¹ is as defined above, preferably in the presence of an acid binder. or (c) general formula (wherein R ¹ is as defined above) or an optically active isomer thereof or a pharmaceutically acceptable salt thereof is reacted with ammonia; or (d) General formula (In the formula, R ¹ is as defined above, and R ⁴ is 1 to
the corresponding pyrimido[1,2a]heterocyclic compound represented by (e ) If desired, the compound of the general formula thus obtained is suitably converted into a pharmaceutically acceptable salt thereof and/or, if desired, the racemic compound of the general formula thus obtained is converted by methods known per se. Divide by. The ring reaction of method (a) can be carried out using hydrogen in the presence of a suitable catalyst or using a metal complex hydride at 0°C.
It can be carried out at temperatures between 150°C and 150°C. Catalytic reduction can be carried out at atmospheric pressure or under slightly overpressure (preferably between 1 and 15 atm) in a suitable solvent. Palladium (preferably palladium on charcoal) or Raney nickel can be used as a catalyst. Examples of representative metal complex hydrides are sodium borohydride, sodium bis(2-methoxyethoxy)-aluminum hydride, potassium borohydride, and lithium aluminum hydride.
Depending on the reducing agent in the solvent. For example, reduction reactions with metal complex hydrides are carried out in water, alkanols (preferably methanol, ethanol), aromatic hydrocarbons (preferably benzene, toluene), ethers [preferably diethyl ether, tetrahydrofuran (THF), dioxane]. It is possible. The pyrimido(1.2a) heterocycle thus produced is separated from the reaction mixture by a method selected depending on the type of reduction. If catalytic reduction is used, the catalyst is separated and the reaction mixture is evaporated. If the reduction is carried out using a metal complex hydride, either the excess reducing agent is destroyed and the organic solvent is evaporated, or if water is used as the solvent, the aqueous reaction mixture is combined with an organic solvent (preferably chloroform or benzene). Shake and evaporate the organic phase. In method (a), the reaction starts from a pyrimido (1.2a) heterocyclic compound of the general formula or an optically active isomer thereof or a pharmaceutically acceptable salt thereof (preferably chloride, bromide, methyl sulfate, etc.) . In method (b), a pyrimide of the general formula (1.
2a) A heterocyclic compound is reacted with an appropriate substance to introduce an R ¹ group into the molecule. This substance is, for example, a halide of general formula a. chloride,
Preference is given to using bromide or iodide. The reaction can also be carried out using sulfates of general formula b or phosphates of general formula c. Reaction (b) is preferably carried out at a temperature of 20 to 250°C in the presence of a suitable solvent. It is also advisable to use an acid binder. Typical acid binders include alkali metal hydroxides (preferably sodium hydroxide, potassium hydroxide), alkali metal carbonates (preferably sodium carbonate, potassium carbonate), alkali metal bicarbonates (preferably sodium bicarbonate). ,
Contains potassium bicarbonate). an excess of a halide of general formula a as a solvent,
Sulfates of general formula b and phosphates of general formula c can be used. Other suitable solvents include water, alcohols, ketones, dimethylformamide, aromatic hydrocarbons, formamide, hexamethylphosphorostriamide, acetonitrile, or mixtures of these solvents. This reaction mixture is worked up using conventional techniques to give
A corresponding pyrimido(1.2a) heterocyclic compound of the general formula is obtained. Method (c) can also be carried out in other ways. A pyrimido(1.2a) heterocyclic compound of the general formula is reacted with a halogenating agent, and the acid halide thus obtained is reacted with ammonia. Typical halogenating agents are thionyl chloride, phosgene, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride, or appropriate mixtures thereof. Alternatively, it is also possible to prepare in a first step a mixed anhydride of a pyrimido(1.2a) heterocyclic compound of the general formula, which compound is then reacted with ammonia. Mixed anhydrides are prepared by dissolving a pyrimido(1.2a) heterocyclic compound of the general formula in an organic solvent (preferably a chlorinated hydrocarbon, more preferably chloroform; an ether, preferably dioxane or tetrahydrofuran) and treating it with a trialkylamine. (preferably triethylamine)
is added to this solution, and then acid chloride (preferably trimethylacetic acid chloride), chloroformate ester (preferably chloroformate methyl ester, chloroformate ethyl ester or chloroformate isopropyl ester) is added at -30°C to
Obtained by addition at a temperature of 50°C. The resulting mixed anhydride is then reacted with ammonia, which can optionally be dissolved in the solvent used in the mixed anhydride forming reaction described above. In a third embodiment of process (c), a pyrimido(1.2a) heterocyclic compound of general formula and ammonia are reacted in a suitable solvent (preferably an organic solvent) in the presence of a dehydrating agent. let As the dehydrating agent, galbodiimide is preferred, and dicyclohexylcarbodiimide is preferably used. Side reactions can be minimized if the reaction is carried out in the presence of 1-hydroxy-benzotriazole, N-hydroxysuccinimide or pentachlorophenol. Suitable solvents are, for example, benzene, toluene, chlorinated hydrocarbons (preferably chloroform, chlorobenzene), ketones (preferably acetone, methyl ethyl ketone), ethers (preferably dioxane, tetrahydrofuran), esters (preferably ethyl acetate). If a carbodiimide is used, it is miscible with aqueous alcohol, so that the reaction can be carried out in a mixture of water and alcohol or in a mixture of the abovementioned solvents. Process (c) can be carried out at temperatures from -30°C to +150°C, and the products are recovered using conventional separation techniques. In method (d), a pyrimide of the general formula (1.
2a) Heterocyclic compound under atmospheric pressure or
React with ammonia under 5 atm overpressure. A solvent can also be used, but is not required. The ammonia reactant also acts as a solvent. Other suitable solvents include, for example, water, alcohols, aromatic hydrocarbons, ketones, ethers, esters, and the like. The reaction is carried out at temperatures between 0°C and 250°C. The product can be recovered by conventional separation techniques. As starting materials for the production of the pyrimido(1.2a) heterocyclic compounds of the general formula, racemic pyrimido(1.2a) heterocyclic derivatives of the general formula and the optically active isomers thereof can likewise be used. R≠H in the starting materials. The starting materials for the general formulas, , and are based on our Hungarian patents no. 156119, no.
162384, 162373, 166577 or Dutch Patent No. 7212286 or known in the art (Arz. Forsch. Vol. 22, p. 815,
(1972) or can be produced by methods known in the art. Compounds of general formulas a, b, c and are commercially available products. Compounds of the general formula have valuable pharmaceutical activity and are useful, for example, as analgesics, anti-inflammatory agents, PG-antagonists, antidepressants, and/or
Exhibits CNS- or antilyphemic activity. The pharmaceutical activity of the compounds of the present invention is determined by the following: As a representative example of such compounds, 1,6-dimethyl-4-oxo-
1, 6, 7, 8, 9, 9a-hexahydro-4H-
This is shown by a test conducted using pyrido(1.2a)pyrimidine-3-carboxamide (CH-127). The toxicity test results, characterized by LD ₅₀ values, are shown in Table 1 and compared with the data obtained with the standard analgesic compound PROBON® intravenously given in Table 2. Since the molecular weights of probon and the test compound of the present invention are different, the molecular weights are also shown in Table 2.

【table】

[Table] From the table above, it can be seen that the molar toxicity of CH-127 is 1.5 times greater than the corresponding value of probon (in intravenous administration, i.e., the toxicity of the compounds of the invention is lower. Test compound of the invention (CH-
127) and probon, which are based on the "hot plate" test (J.
Pharm.Exp.Ther. vol. 80, p. 130, 1944;
Kise´rleti Orvostudom´any, Volume 2, Page 295,
(1950). The test animal is a mouse.

[Table] Table 4 compares the analgesic activity obtained by the "writting" test of the above two compounds (Fed. Proc. Vol. 15, p. 494, 1956; J. Pharm.
Exp. Ther. Vol. 133, p. 400, 1961).

Table 5 compares the anti-inflammatory activities of CH-127 and phenylbutazone. Anti-inflammatory activity was determined using a method known in the art as the "rat paw oedema" method, and the drug was administered orally.

[Table] The following Table 6 shows that the inhibitory effect of CH-127 does not change even in adrenalectomized rats (ie, the anti-inflammatory effect is not dependent on endogenous Cevdogevous steroids).

[Table] When mixed with other anti-inflammatory agents in Table 7
This shows the synergistic effect of CH-127.

[Table] From the test results given in the above table, CH-127
was found to be more effective than probon in mice and had a better therapeutic rate when administered orally. The test compound (CH-127) is representative of the compounds according to the invention, and other pyrimido(1.2a) heterocyclic compounds of the general formula have similar favorable analgesic and antiinflammatory properties. A compound of the invention can be formulated into a composition comprising a compound of general formula or an optically active isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Carriers can be solid or liquid, and the compositions can take solid forms (eg, tablets, capsules, dragees, etc.) or liquid forms (eg, solutions, suspensions, emulsions, etc.). The carriers used in the preparation of the formulations according to the invention are the customary substances known for this purpose, such as talc, calcium carbonate, magnesium stearate, water, polyethylene glycol, and the like. The composition may also contain conventional excipients (eg, emulsifiers, disintegrants, etc.), if desired. The compounds can also be used in conjunction with other active ingredients (eg, other analgesic, anti-inflammatory compounds, etc.). The composition thus obtained has synergistic activity. For example, the compound of the present invention may be combined with morphine, 1.
It exhibits a synergistic effect when used with 4-hydroxy-azidomorphine, fentanil, indomethacin, azidomorphine, azidocodeine, etc. This very important property has made the compounds of the invention particularly useful in surgical anesthesiology. The invention is illustrated by the following non-limiting examples. Example 1 of 23.5 g of 1,6-dimethyl-3-(N-methyl-carbamoyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine in 300 ml of ethanol. The solution is hydrogenated at room temperature and under atmospheric pressure in the presence of 15 g of 10% by weight palladium on charcoal catalyst. Once 1 mole of hydrogen has been absorbed, the catalyst is separated and the liquid is evaporated under reduced pressure. Subsequently, the residue was recrystallized twice from ethanol.
1.6eq-dimethyl-3-(N-methyl-carbamoyl)-4-oxo-1.6.7.8.9.
9a _ax -hexahydro-4H-pyrido(1.2a)pyrimidine, melting point 203°C to 204°C is obtained. Analyzed value: Calculated value:
C 60.74% H 8.07% N 17.71% Measured values:
C 60.95% H 8.03% N 17.83%. Example 2 10.2g of 6 _ax -methyl-4-oxo-1.6.
7, 8, 9, 9a _ax -hexahydro-4H-pyrido (1, 2a) pyrimidine-3-carboxamide 65
Suspend in a solution of 2 g of sodium hydroxide in ml of water while adding 9.5 g of dimethyl sulfate and 25 ml of
of sodium hydroxide solution in water are added dropwise separately to the reaction mixture. The reaction mixture is stirred for 1 hour and then adjusted to pH 7 by adding 10% by weight hydrochloric acid. This aqueous solution is shaken with chloroform. The combined chloroform solutions are dried over sodium sulfate and concentrated under reduced pressure. 1.6 _ax of 10.8g
-dimethyl-4-oxo-1.6.7.8.9.
9a _ax -hexahydro-4H-pyrido(1.2a)pyrimidine-3-carboxamide is obtained. After recrystallization from ethanol (twice), the melting point is 185℃ or more.
It was 186℃. Analyzed value: Calculated value:
C 59.18% H 7.67% N 18.32% Measured values:
C 58.95% H 7.69% N 18.85%. Example 3 10.2g of 6 _ax -methyl-4-oxo-1.6.
7, 8, 9, 9a _ax -hexahydro-4H-pyrido (1, 2a) pyrimidine-3-carboxamide 65
While suspended in a solution of 2 g of sodium hydroxide in ml of water, 11.55 g of diethyl sulfate and 25
A solution of 4 g of sodium hydroxide in ml of water is added dropwise separately into the reaction mixture. The reaction mixture is stirred for 1 hour and then adjusted to pH 7 by adding 10% by weight hydrochloric acid. This aqueous solution is shaken with chloroform. The chloroform extract was concentrated under reduced pressure to yield 9.9 g of 1-ethyl-6 _{ax -methyl} -4-oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido(1,2a)pyrimidine-
3-carboxamide is obtained. After recrystallization from isopropanol, the melting point is 162°C to 163°C. Analyzed value: Calculated value:
C 60.74% H 8.07% N 17.71% Measured values:
C 60.58% H 8.08% N 17.85%. Example 4 10.2g of 6 _ax -methyl-4-oxo-1.6.
7.8.9.9a _ax -hexahydro-4H-pyrido (1.2a) Pyrimidine-3-carboxamide and 27.3 g of triethyl phosphate are stirred at 235° C. in the presence of 6.4 g of potassium carbonate. When no gas evolution is observed, the reaction mixture is poured into 150 ml of water and the aqueous solution is shaken with chloroform. The combined chloroform extracts are concentrated under reduced pressure. 8.5 g of 1-ethyl-6 _ax -methyl-4-oxo-1.6.7.8.
9.9a _ax -hexahydro-4H-pyrido (1.
2a) Obtain pyrimidine-3-carboxamide. The melting point after recrystallization from isopropanol is 163°C. When this product is mixed with the product of Example 3, no decrease in melting point is observed. Example 5 10.2 g of 6 _ax -methyl-4-oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido(1,2a)pyrimidine- in 125 ml of ethanol
3-carboxamide, 25 g n-butyl bromide and 7.5 g potassium carbonate are heated under reflux for 30 hours. The reaction mixture is filtered and concentrated under reduced pressure. 8.5 g of 1- n melting at 160°C to 162°C
-butyl-6 _ax -methyl-4-oxo-1,6,
7.8.9.9a _ax -hexahydro-4H-pyrido(1.2a)pyrimidine-3-carboxamide is obtained. Analyzed value: Calculated value:
C 63.37% H 8.74% N 15.84% Measured values:
C 63.08% H 8.83% N 15.78%. Example 6 12.6 g of ethyl-1.6 _ax -dimethyl-4-oxo-1. in 50 ml of concentrated ammonia hydroxide solution.
6.7.8.9.9a _ax -hexahydro-4H-pyrido (1.2a) pyrimidine-3-carboxylate is cooled to 0°C and saturated with ammonia gas.
After closing the apparatus, heat the mixture at 40°C to 50°C for 24 hours.
Shake for an hour. The solution is shaken with chloroform, the combined chloroform solutions are concentrated under reduced pressure and the residue is successively recrystallized twice from ethanol. 1.6 _ax -dimethyl-4-oxo-1.6.
7.8.9.9a _ax -hexahydro-4H-pyrido(1.2a)pyrimidine-3-carboxamide, melting point 183-184°C is obtained. When this product is mixed with the product of Example 2, no decrease in melting point is observed. Example 7 6.6 g of 1,6 _ax -dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido (1,2a) pyrimidine-3-carboxamide in 300 ml of methanol are mixed with 4,5 g of 10 Hydrogenation is carried out at atmospheric pressure and room temperature in the presence of a wt% palladium on charcoal catalyst. After absorbing 1 mole of hydrogen, the catalyst is separated and the liquid is concentrated under reduced pressure. The residue is recrystallized three times in succession from ethanol. 2.6 g of 1·6eq-dimethyl-4-oxo- melting at 205°C to 206°C
1, 6, 7, 8, 9, 9a _ax -hexahydro-4H
-Pyrido(1.2a)pyrimidine-3-carboxamide is obtained. Analyzed value: Calculated value:
C 59.18% H 7.67% N 18.82% Measured values:
C 59.07% H 7.68% N 18.85% Example 8 As starting material (-)-1.6 _ax -dimethyl-
4-oxo-1,6,7,8-tetrahydro-
Following the procedure described in Example 7 but using 4H-pyrido(1,2a)pyrimidine-3-carboxamide ([α] ²⁰ _D = -70°, C = 2, methanol).
(−)-1・6eq-dimethyl-4-oxo-1・
6.7.8.9.9a _ax -hexahydro-4H-pyrido(1.2a)pyrimidine-3-carboxamide is obtained. Melting point: 221°C to 222°C, yield: 40%. Analyzed value: Calculated value:
C 58.18% H 7.67% N 18.80% Measured values:
C 59.31% H 7.71% N 18.80%. Example 9 (+)-1・6 _ax -dimethyl-4-oxo-
Procedure as described in Example 7, but starting from 1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine-3-carboxamide ([α] ²⁰ _D = +70°, C=2, methanol) According to 220℃
(+)-1.6eq-dimethyl-4-oxo-1.6.7.8.9.9a _ax −
Hexahydro-4H-pyrido(1.2a)pyrimidine-3-carboxamide is obtained. Yield: 41%,
[α] ²⁰ _D = +228°, C = 1, ethanol. Analyzed value: Calculated value:
C 59.18% H 7.67% N 18.82% Measured values:
C 59.19% H 7.80% N 18.75% Example 10 14.5 g of (+)-1,6 _ax -dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido(1,2a)pyrimidine-3 -Carboxamide sulfate monomethyl ester ([α] ²⁰ _D = +37.5°, C
= 2, methanol) was dissolved in 150 ml of water, 20
Cool to below ℃. A solution of 1.82 g of sodium borohydride in 13 ml of water is added dropwise to this solution, and the reaction mixture is then stirred for 2 hours at room temperature.
The mixture is adjusted to pH 7 and shaken twice with 50 ml of chloroform. Combine with chloroform solution, dry over sodium sulfate and concentrate under reduced pressure. The residue is recrystallized from ethanol. 209℃
7.5 g of (+)-1.6 _a melting at ~210℃
_x -dimethyl-4-oxo-1.6.7.8.
9.9a _ax -hexahydro-4H-pyrido (1.
2a) Pyrimidine-3-carboxamide ([α] ³⁰ _D =
+268°, C=1, methanol). Analyzed value: Calculated value:
C 59.18% H 7.67% N 18.82% Measured values:
C 59.02% H 7.65% N 18.84%. Example 11 (-)-1・6 _ax -dimethyl-4-oxo-
1,6,7,8-tetrahydro-4H-pyrido (1,2a) pyrimidine-3-carboxamide sulfate monomethyl ester ([α] ²⁰ _D = -37.5°, C =
(-)-1.6 _ax -dimethyl-4 following the procedure described in Example 10 but starting from (2, methanol)
-oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido(1,2a)pyrimidine-3-
Carboxamide ([α] ³⁰ _D =-261°, C=1, methanol) is obtained. Melting point: 209°C to 210°C, yield: 79%. Analyzed value: Calculated value:
C 59.18% H 7.67% N 18.82% Measured values:
C 59.25% H 7.71% N 18.78%. Example 12 9.0 g of 1,6-dimethyl-3-(N-methyl-
carbamoyl)-4-oxo-1,6,7,8-
Tetrahydro-4H-pyrido(1・2a)pyrimidine monomethyl sulfate was dissolved in 100ml of water, and 1.8g of sodium borohydride was added little by little to this solution.
Add within 15 minutes while stirring at below 10℃. The reaction mixture was stirred for 2 hours and a hydrochloric acid solution was added.
Adjust to PH3 or 4. The solution is extracted with chloroform, and the chloroform extract is dried over sodium sulfate, filtered, and concentrated under reduced pressure. 5.5 g of 1.6 _ax -dimethyl-3-(N-methyl-carbamoyl)-4-oxo-1.6.7.8.9.9a
-hexahydro-4H-pyrido(1.2a)pyrimidine is obtained. Melting point after recrystallization from ethanol:
177℃ to 179℃. Analyzed value: Calculated value:
C 60.74% H 8.07% N 17.71% Measured values:
C 60.53% H 8.11% N 17.72%. Example 13 Injectable drug preparation 2000g of 1.6 _ax -dimethyl-4-oxo-
1, 6, 7, 8, 9, 9a _ax -hexahydro-4H
- Pyrido(1,2a)pyrimidine-3-carboxamide (pharmaceutical grade) was weighed to an accuracy of 1 g in a 40000-ml graduated glass flask, and the flask was then filled with injection grade distilled water. When will it be filled to capacity? Dissolve all solids. The solution was filtered by conventional techniques to remove fibers, and 2-ml.
Fill into an ampoule. Sterilize the ampoule at 120°C for 30 minutes. Example 14 Injectable preparation also containing other pharmaceutically active ingredients 500 g of 1.6 _ax -dimethyl-4-oxo-
1, 6, 7, 8, 9, 9a _ax -hexahydro-4H
- Pyrido(1.2a) pyrimidine-3-carboxamide (pharmaceutical grade) is measured with an accuracy of 1 g in a 10000-ml graduated glass flask. Add 1 g of azidomorphine to another flask.
Dissolve in 100 ml of 2% sodium bicarbonate solution. Fill the first flask with approximately 9 injection grade distilled water and add 8 g of sodium pyrosulfite once solid dissolution is complete. Once all the solids have dissolved, add 100 ml of the azidomorphine solution obtained above with stirring, filling the solution to the mark. The solution is then filtered to remove fibers by conventional techniques and filled into 1-ml ampoules. Sterilize the ampoule at 100°C for 1.5 hours. Example 15 Suppository 500g of 1.6 _ax -dimethyl-4-oxo-1.6.7.8.9.9a _ax crushed to a particle size of 10μ or less
-Hexahydro-4H-pyrido(1.2a)pyrimidine-3-carboxamide is placed in a heatable container equipped with a stirrer and the solid is then homogenized with 25 g of colloidal silicic acid. After this, 25 g of molten carrier is added in portions and the whole is mixed well until a homogeneous mixture is obtained. The temperature is adjusted to 45° C. and 2.5 g suppositories are prepared in a manner known per se. Example 16 Sugar coating 1000 g of pharmaceutical grade 1.6 _ax -dimethyl-4-
Oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido(1,2a)pyrimidine-3-carboxamide with 300g of crystalline cellulose and 150g
of potato starch and then dissolved in 300 ml of water containing 10 g of gelatin. This aqueous mixture is granulated. The resulting granules are dried, regranulated, mixed well with a mixture of 40 g talc and 5 g stearic acid, and compressed into tablets of appropriate size. The tablets are coated by techniques known per se. Example 17 Anti-inflammatory ointment for the skin 1200 g of cetyl alcohol and 400 g of sorboxyethane stearate are dissolved in 400 g of liquid paraffin at 45°C. Then add 2000 g of white petrolatum and strain the molten liquid mass as necessary. 500g of 1,6 _ax -dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H
-Pyrido(1.2a)pyrimidine-3-carboxamide is separately dissolved in 5400 g of distilled water at 65°C. To this solution are added 3 g of propyl- n -oxy-benzoate and 7 g of methyl- n -oxybenzoate in 90 g of ethanol, and the above mass is mixed with this solution to form a homogeneous ointment. After cooling, the ointment is packed into tubes or bottles in a manner known per se. Example 18 Anti-inflammatory skin ointment also containing other pharmaceutically active ingredients 200 g cholesterin, 300 g cetyl alcohol, 275 g white beeswax, 525 g lanolin and
Melt and homogenize 6500 g of white petrolatum at 55°C. The melt is filtered as necessary. 500g
1.6 _ax -dimethyl-4-oxo-1.6.
7.8.9.9a _ax -hexahydro-4H-pyrido(1.2a)pyrimidine-3-carboxamide
Screen through a No. 100 mesh screen and homogenize 20 g of colloidal pyrimidine in 2200 g of distilled water at 55°C. This mixture is then added to the melt prepared above and processed in an emulgator-homogenisator to give a homogeneous ointment. After cooling, the ointment is packed under sterile conditions into tubes or bottles or applied to the surface of a sterile dressing. Example 19 Eye medicine 11g borax, 22g sodium chloride, 115g
of boric acid and 1 g of pyrosulfite in approx.
dissolves in water. Add 100g of 1.6 _ax − to this solution.
Dimethyl-4-oxo-1, 6, 7, 8, 9,
9a Add _ax -hexahydro-4H-pyrido(1.2a)pyrimidine-3-carboxamide. The resulting solution is made up to 10,000 ml with distilled water, filtered, and packed under aseptic conditions into small eye drops bottles. Example 20 Eye drops also containing other pharmaceutically active ingredients 11 g borax, 21.2 g sodium chloride, 114
about 10 g of boric acid and 1 g of pyrosulfite
Add 200 mg of Primicin to the solution in water and bring the resulting solution to a boil. Next 100g
1.6 _ax -dimethyl-4-oxo-1.6.
7.8.9.9a _ax -hexahydro-(1.2a)pyrimidine-3-carboxamide is added, the solution is made up to 10,000 ml with distilled water, filtered and packed under sterile conditions into 5 ml eye drop bottles. Example 21 Powder powder also containing other pharmaceutically active ingredients: 35 g of oxytetracycline chlorohydrate, 65 g of 1.6 _ax -dimethyl-4-oxo-
1, 6, 7, 8, 9, 9a _ax -hexahydro-4H
-Pyrido-(1.2a)pyrimidine-3-carboxamide, 250 g of carbamide and 9650 g of dry lactose are homogenized in the form of a fine powder. The particle size is adjusted to No. 100 mesh by methods known per se and packed into a suitable dispersant carrier.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents alkyl having 1 to 6 carbon atoms) pyrimido[1,2a]heterocyclic compounds thereof, optically active isomers thereof, diastereomers thereof, and pharmaceutically acceptable thereof A method for producing salt that can be prepared using the general formula The corresponding pyrimido[1,2a] heterocyclic compound represented by the general formula a R ¹ -X (a) (wherein R ¹ is as defined above) or an optically active isomer thereof or a pharmaceutically acceptable salt thereof or sulfates of the general formula b (R ¹ ) ₂ SO ₄ (b), in which R ¹ is as defined above; or react with a phosphate of the general formula c (R ¹ ) ₃ PO ₄ (c), in which R ¹ is as defined above, and then, optionally, a compound of the general formula thus obtained. Converting the compound to its pharmaceutically acceptable salt as appropriate and/or optionally
A method comprising resolving the racemic compound of the general formula obtained by methods known per se. 2. The method according to claim 1, wherein the reaction of the compound of the general formula with the halide of the general formula a or the sulfate of the general formula b or the phosphate of the general formula c is carried out in the presence of an acid binder. 3 The acid binder is an alkali metal hydroxide (preferably sodium hydroxide, potassium hydroxide), an alkali metal carbonate (preferably sodium carbonate, potassium carbonate), an alkali metal hydrogen carbonate (preferably sodium hydrogen carbonate, hydrogen carbonate) 3. The method according to claim 2, wherein the potassium chloride is potassium. 4. The method according to any one of claims 1 to 3, wherein the reaction is carried out at a temperature of 20 to 250°C. 5. Any one of claims 1 to 4, in which the obtained pyrimide [1.2a] heterocyclic compound of the general formula is converted into an acid addition salt thereof using a pharmaceutically acceptable acid. The method described in. 6 General formula (In the formula, R ¹ represents alkyl having 1 to 6 carbon atoms) pyrimido[1,2a]heterocyclic compounds thereof, optically active isomers thereof, diastereomers thereof, and pharmaceutically acceptable thereof A method for producing salt that can be prepared using the general formula A corresponding pyrimido[1,2a]heterocyclic compound represented by the formula (wherein R ¹ is as defined above) or an optically active isomer thereof or a pharmaceutically acceptable salt thereof is reacted with ammonia, and then If desired, the compound of the general formula thus obtained is suitably converted into a pharmaceutically acceptable salt thereof and/or, if desired, the racemic compound of the general formula thus obtained is converted by methods known per se. A method that involves dividing. 7 General formula (In the formula, R ¹ represents alkyl having 1 to 6 carbon atoms) pyrimido[1,2a]heterocyclic compounds thereof, optically active isomers thereof, diastereomers thereof, and pharmaceutically acceptable thereof A method for producing salt that can be prepared using the general formula A corresponding pyrimido[1,2a]heterocyclic compound represented by the formula (wherein R ¹ is as defined above) or an optically active isomer thereof or a pharmaceutically acceptable salt thereof is reacted with a halogenating agent. , reacting the acid chloride thus obtained with ammonia, optionally converting the compound of general formula thus obtained into its pharmaceutically acceptable salt, and/or optionally converting the compound of general formula thus obtained A method comprising resolving a racemic compound of the general formula by methods known per se. 8. The method according to claim 7, wherein thionyl chloride, phosgene, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or a mixture of the listed compounds is used as the halogenating agent. 9 A pyrimido[1,2a] heterocyclic compound of the general formula (wherein R ¹ is as defined above) or an optically active isomer thereof or a pharmaceutically acceptable salt thereof is treated with a trialkylamine (preferably triethylamine). ) in the presence of an acid chloride (preferably trimethylacetyl chloride or chloroformate) and the resulting mixed anhydride is reacted with ammonia. 10. The method of claim 7, wherein the reaction is carried out at a temperature of -30 to +50<0>C. 11 Pyrimide [1.2a] heterocyclic compound of the general formula (wherein R ¹ is as defined above)
8. The method according to claim 7, wherein the optically active isomer thereof or a pharmaceutically acceptable salt thereof is reacted with ammonia in the presence of a water binding agent. 12. Process according to claim 7, wherein the water binding agent is a carbodiimide, preferably dicyclohexylcarbodiimide. 13. The method according to any one of claims 7, 11 and 12, wherein the reaction is carried out in the presence of a solvent. 14 Claims 7 to 1 in which the obtained pyrimido[1.2a] heterocyclic compound of the general formula is converted into an acid addition salt thereof using a pharmaceutically acceptable acid.
The method described in any one of Section 3. 15 General formula (In the formula, R ¹ represents alkyl having 1 to 6 carbon atoms) pyrimido[1,2a]heterocyclic compounds thereof, optically active isomers thereof, diastereomers thereof, and pharmaceutically acceptable thereof A method for producing salt that can be prepared using the general formula (In the formula, R ¹ is as defined above, and R ⁴ is 1 to 6
The corresponding pyrimido[1,2a]heterocyclic compound represented by (representing an alkyl having 5 carbon atoms) or an optically active isomer thereof or a pharmaceutically acceptable salt thereof is reacted with ammonia, and then, if desired, The compound of the general formula thus obtained is suitably converted into its pharmaceutically acceptable salt and/or, if desired, the racemic compound of the general formula obtained is resolved by methods known per se. method including. 16 A pyrimido[1,2a] heterocyclic compound of general formula (wherein R ¹ and R ⁴ are as defined above) or an optically active isomer thereof or a pharmaceutically acceptable salt thereof is treated with excess ammonia. and under atmospheric pressure or slightly overpressure, (preferably 0.1~10atm)
16. The method according to claim 15, wherein the reaction is performed with: 17. Any one of claims 15 or 16, wherein the reaction is carried out at a temperature of 0°C to 250°C.
The method described in. 18 Claims 15 to 18, wherein the obtained pyrimido[1.2a] heterocyclic compound of the general formula is converted into an acid addition salt thereof using a pharmaceutically acceptable acid.
18. The method according to any one of clause 17. 19 General formula (wherein R ¹ represents alkyl having 1 to 6 carbon atoms) and its optically active isomers and diastereomers, and their pharmaceutically acceptable An anti-inflammatory agent containing at least one salt together with a pharmaceutically acceptable carrier. 20 (±)1.6 _ax -dimethyl-4-oxo-
1, 6, 7, 8, 9, 9a _ax -hexahydro-4H
- The anti-inflammatory agent according to claim 19, which contains pyrido[1.2a]pyrimidine-3-carboxamide. 21 (+)1.6 _ax -dimethyl-4-oxo-
1, 6, 7, 8, 9, 9a _ax -hexahydro-4H
- The anti-inflammatory agent according to claim 19, which contains pyrido[1.2a]pyrimidine-3-carboxamide. 22 (-)1.6 _ax -dimethyl-4-oxo-
1, 6, 7, 8, 9, 9a _ax -hexahydro-4H
- The anti-inflammatory agent according to claim 19, which contains pyrido[1.2a]pyrimidine-3-carboxamide. 23 Patent containing (±)1-ethyl-6 _ax -methyl-4-oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido[1,2a]pyrimidine-3-carboxamide The antiinflammatory agent according to claim 19. 24 (±)1-n-butyl-6 _ax -methyl-4
-oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido[1,2a]pyrimidine-3-
Claim 1 containing a carboxamide
The anti-inflammatory agent according to item 9. 25 Claims 19 to 25 for therapeutic purposes in the form of oral tablets, dragees, parenteral injections, suppositories, skin ointments, eye drops or wound powders
The anti-inflammatory agent according to any one of Item 24.