HU211903A9 - New 3-(subst. tetrazolyl)-4-oxo-4h-pirido/1,2-a/ pyrimidines, salts thereof, pharmaceutical composition containing them and process for preparing them - Google Patents

Description

The present invention relates to pharmaceutically active novel 3- (1-substituted-1H-tetrazol-5-yl) -4-oxo-4H- and / or 3- (2-substituted-2H-tetrazol-5-yl) -4-oxo-4H -pyrido [1,2-a] pyrimidines and its salts. These novel compounds are primarily used in medicine as a gastroprotective agent for curing and preventing ulcers.

Some representatives of 4H-pyrido [1,2-a] primidin-4-ones are known to have significant antiallergic and anti-ulcer properties (European Nos. 217,673 and 218,423, Belgian Nos. 873,192 and 873,194, and 4,122,274 and 4,457). 932, U.S. Pat. The cytoprotective effect of the potassium salt of 9-methyl-3-tetrazolyl-4-oxo-4H-pyrido [1,2-a] pyrimidine has been described in more detail (Gastroenterology 1985, 88,1354).

The present invention is based on the unexpected discovery that by substituting the acidic hydrogen atom of the tetrazolyl group of 3-tetrazolyl-4-oxo-4H-pyrido [1,2-a] pyrimidines, a broader spectrum of derivatives can be obtained.

The present invention relates to novel 4-oxo-4H-pyrido [1,2-a] pyrimidines of formula (I) and / or (II) and pharmaceutically acceptable salts thereof wherein R is C 1-6 alkyl, C 3-6 alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C1-C4) alkoxycarbonyl, or (C7-C8) aralkyl optionally substituted with one or more halogen or nitro groups,

R ¹ is hydrogen or C 1-4 alkyl.

The term C 1-6 alkyl as used herein refers to straight or branched chain aliphatic saturated hydrocarbon groups (such as methyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl).

Pharmaceutically acceptable salts of the compounds of formula (I) and (II) may be the corresponding alkali metal or alkaline earth metal salts or acid addition salts with suitable organic or inorganic acids.

The present invention also provides a process for the preparation of a novel compound of formula (I) and (Π), wherein R and R ¹ are as defined above, and pharmaceutically acceptable salts thereof, by reacting a 3-tetrazolyl-4 compound of formula (ΠΙ) -oxo-4H-pyrido [1,2-a] pyrimidine wherein R ¹ is as defined above, with a halide of formula IV, wherein R is C 1-6 alkyl, C 3-6 alkenyl C 3 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or C 7 -C 8 aralkyl optionally substituted with one or more halogen or nitro groups, X is chlorine, bromine or iodine, or a compound of formula V sulfate - wherein R is C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-7 cycloalkyl, or optionally one or more halo; C 7 -C 8 aralkyl substituted with N or N, or with a sulfonate of Formula VI wherein R is C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl; group, C3-7 cycloalkyl group or an optionally by one or more halogens or nitro-substituted aralkyl group of 7-8 carbon atoms, R ² is phenyl csopQrt, p-methylphenyl group -, or a group Meulen, or (VII) phosphate of the general formula wherein R is

C 1-6 -alkyl, C 3-6 -alkenyl, C 3-6 -alkynyl, C 3-7 -cycloalkyl, or C 7-8-aralkyl optionally substituted with one or more halo or nitro, or one of (VII) with an ester of the formula wherein R ³ is C 1 -C 4 alkyl, X is chlorine or bromine, and n is 0 or 1, preferably in the presence of a solvent and an acid acceptor, and thus of formula (I) and (Π). yielding a mixture of isomeric compounds which may be separated, if desired, for example by chromatographic techniques or by recrystallization using different solubilities of the isomers, and optionally forming or liberating the salts of the compounds of formula (I) or <H) or their salts; to other salts.

The compound of formula (III) is treated with a compound capable of introducing R, such as a halide of formula (IV), preferably chloride, bromide, or iodide, or a sulfate of formula (V), a sulfonate of formula (VI). a phosphate of formula (II) or an ester of formula (VII). The introduction of the R group can be carried out at a temperature of 20-250 ° C, preferably in the presence of a solvent. The reaction temperature chosen will also depend on the solvent used. Acid-binding agents are preferably used in the reaction. Thus, alkali metal hydroxide, preferably sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxide, preferably calcium hydroxide, magnesium hydroxide, alkali metal carbonate, preferably sodium carbonate, hydrogen carbonate, preferably alkali metal, can be used. potassium bicarbonate. If desired, it is also possible to employ an alkali metal or alkaline earth metal salt of the compounds of formula (ΙΠ).

An excess of a compound of formula (IV), (V), (VI) or (VH) may also be used as a solvent. The solvent may also be an alcohol (e.g. ethanol, propanes), a ketone (e.g. acetone, methyl ethyl ketone), a dipolar aprotic solvent such as dimethylformamide, dimethylsulfoxide, formamide, 1,3-dimethyl-2-oxo. imidazolidine, hexamethylphosphoric triamide, acetonitrile, nitromethane, or an aromatic hydrocarbon (e.g., benzene) or a halogenated hydrocarbon (e.g., chlorobenzene, chloroform), or mixtures thereof. Alternatively, the solvent may contain a certain amount of water.

The nitrogenous compounds used as starting materials are known (U.S. Pat. No. 4,122,274).

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The toxicity of the compounds of formulas I and II is low, generally LD ₅₀ > 250 mg / kg po in rats and mice.

The compounds of formulas I and II and their pharmaceutically acceptable salts have significant gastroprotective effects. They protect and cure both the stomach and the small intestine. The efficacy of the compounds of formula (I) and (II) was demonstrated in standard assays for the determination of antiulcerogenic activity. The compounds of formula (I) and (II) may be used as pharmaceutical compositions individually or in combination.

By way of example, Table 1 illustrates the anti-gastric ulcer activity of rats in gastroenterology (Gastroenterology 1979, 77, 433) induced by a mixture of 0.5 ml of 96% alcohol and hydrochloric acid (1: 0.02).

Table 1

Protective effect of hydrochloric acid on gastric mucosa in rats

Name of compound id ₅₀ mg / kg after id ₅₀ μΜ / kg after 3- (1-Isopropyl-1H-tetrazol-5-yl) 9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine 0.34 1.25 3- (2-Isopropyl-2H-tetrazol-5-yl) 9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine 0.23 0.85 3-2- (2-isopropyl-2H-tetrazol-5- yl) -4-oxo-4H-pyrido [l, 2-a] pyrimidinyl, dyne 2.2 8.5 3- (2-Butyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine 2 7 3- (2-Allyl-2H-tetrazol-5-yl) -9-methyl- 4-oxo-4H-pyrido [1,2-a] pyrimidine 2.9 11.0 3- (2-Propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine 0.05 0.18

Table 2 illustrates the effect of indomethacin-induced gastric ulcer in rats (Arch. Int. Pharmacodyn. 1964, 117, 113) in the exemplified compounds.

Table 2

Inhibition of gastric mucosal damage by indomethacin in rats

Name of compound ID ₅₀ mg / kg after IU50 μΜ / kg p.o. 3- (2-isopropyl-2H-tetrazol-5- yl) -9-methyl-4-oxo-4H-piri- pyrido [l, 2-a] pyrimidine 2.6 9.6 3- (2-Allyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2a] pyrimidine 2.5 9.3 3- (2-Isopropyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine 4 15.6 3- (2-Propyl-2H-tetrazol-5-yl) 9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine 5.5 20.3

An example of the inhibition of indomethacin-induced intestinal ulceration in rats is the activity of 3- (2-propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido-1,2-a pyrimidine.

The intestinal ulcer formation assay utilized the Tsuromi method (J. Pharm. Dyn.1980, 3,659) to treat rats with an oral dose of 50 mg / kg body weight of the above compound for four consecutive days while indomethacin 15 mg / kg body weight was orally initiated on the second day. for animals. Ulceration in the small intestine was determined on the third day after indomethacin administration.

3- (2-Propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine exhibited 70% protection and 100% protection over the control. inhibited the death caused by indomethacin. The known 9-methyl-3- (5-tetrazolyl) -4-oxo-4H-pyrido [1,2-a] pyrimidine sodium salt did not prevent indomethacin-induced gastrointestinal damage.

The compounds of formula (I) and / or (Π), or salts thereof, may be used in medicine in the form of formulations containing the active compounds and inert solid or liquid organic or inorganic carriers. The formulations are prepared by methods well known in the art of pharmaceutical manufacture.

The compositions may be formulated for oral or parenteral administration, for example, in the form of tablets, dragees, capsules, or prolonged release forms thereof. The compositions may contain suitable solid diluents or carriers, sterile aqueous diluents or non-toxic organic solvents. Sweetening or flavoring agents may be added to the compositions for oral administration.

Tablets for oral administration may contain, for example, lactose, sodium citrate, calcium carbonate, and disintegrants (e.g., starch, alginic acid) lubricants (e.g., talc, sodium lauryl sulfate, magnesium stearate). The carrier for the capsules may be lactose and polyethylene glycol. Aqueous suspensions may contain emulsifying or suspending agents. The organic solvent slurry diluent is ethanol, glycerol, chloroform, and the like. may.

Formulations for parenteral administration may be in the form of solutions or suspensions of the active ingredient in a suitable medium (for example, peanut oil, sesame oil, polypropylene glycol) or water.

The active ingredient content of the pharmaceutical compositions may vary within wide limits and may range from 0.005% to 99%.

The daily dose of active ingredient may vary within wide limits and will depend on the severity, age, weight, form of preparation, and activity of the particular patient. In the case of oral administration, the daily dose is usually 0.01-15 mg / kg in single or multiple doses. The above information is for guidance purposes only and may vary depending on the requirements of the individual case and the prescription of the physician. Where appropriate, the above application forms may be departed from.

Further details of our procedure are given in the examples below

Without limiting the invention to the examples.

Examples

1.) Example

0.9 g (0.0042 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 25 ml of dimethylformamide, 0.58 g (0.0042) (mole) of anhydrous potassium carbonate and 0.7 ml (0.0084 mole) of ethyl iodide was stirred at 80-90 ° C for 3 hours. During heating, an orange solution, from which the inorganic material is filtered hot, and the solution is evaporated. The residue is suspended in 30 ml of water and the crystals are filtered off. Thus 0.4 g (40%) of 3- (letyl-1H-tetrazol-5-yl) and 3- (2-ethyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-b] A 1: 1 mixture of [alpha] -pyrimidine is melted at 160 [deg.] C.

Analysis based on C _n H ₁₀ N ₆ O.

Calculated: C, 54.54; H = 4.16%; N, 34.7%; Found: C, 54.76; H, 4.40; N = 34.67%;

2.) Example

0.4 g (0.0018 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 15 ml of dimethylformamide, 0.51 g A mixture of methyl iodide (0.0036 mol) and anhydrous potassium carbonate (0.25 g, 0.0018 mol) was stirred at 80 ° C for 30 minutes. The yellow suspension dissolves upon heating. The yellow solution was filtered hot and the filtrate was left in the refrigerator overnight. The precipitated crystals are filtered off. 0.35 g (80.3%)

3- (1-methyl-1H-tetrazol-5-yl) and 3- (2-methyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine A mixture of isomers is obtained which is crystallized from dimethylformamide, 0.2 g (57%) of 3- (1-methyl-1H-tetrazol-5-yl) 9-methyl-4-oxo-4H-prido [1,2-a] Pyrimidine is obtained in the form of a white, adherent crystal which decomposes at 294 ° C.

Analysis based on the formula ChH ₁₀ N ₆ O.

Calculated: C, 54.54; Η = 4.16%; N = 34.7%; Found: C, 54.27%; Η = 4.05%; N = 34.36%;

Example 3)

0.55 g (0.0024 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 20 ml of dimethylformamide, 0.4 ml A mixture of ethyl iodide (0.0048 mol) and anhydrous potassium carbonate (0.3 g, 0.0024 mol) was stirred at 80 ° C for 1 hour. The citric yellow crude solution was filtered hot and concentrated. The yellow oily residue, which crystallizes on standing, is suspended in 50 ml of alcohol and filtered. 0.25 g (61.5%) of 3- (1-ethyl-1H-tetrazol-5-yl) and 3- (2-ethyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido There is obtained a 3: 7 isomer mixture of [1,2-a] pyrimidine (based on 1 HNMR) which is a pale yellow crystalline solid, m.p. 168-170 ° C.

Analysis for C ₁₂ H ₁₂ N ₆ O.

Calculated: C, 56.24; H = 4.72%; N = 32.80%; Found: C, 56.14%; H = 4.80%; N = 32.38%;

4.) Example

0.4 g (0.00187 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 15 ml of dimethylformamide, 0.34 ml (0.00374) mole) of propyl bromide and 0.25 g (0.00187 mole) of anhydrous potassium carbonate was stirred at 90 ° C for 1 hour. The dark brown solution was filtered hot and concentrated. A dark brown crystalline oil mixture of 3- (1-propyl-1H and 3- (2-propyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine) isomer was triturated with 10 mL of ethanol. crystals were collected by filtration to give 0.15 g (31.3%) of 3- (2-propyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, m.p. on melting pale yellow crystal.

Analysis for C ₁₂ H ₁₂ N ₆ O.

Calculated: C, 56.24; H = 4.72%; N = 32.8%; Found: C, 56.21%; H = 4.67%; N = 32.75%;

5.) Example

0.4 g (0.0018 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 15 ml of dimethylformamide, 0.25 g A mixture of anhydrous potassium carbonate (0.0018 mol) and propyl bromide (0.33 ml, 0.0036 mol) was stirred at 90 ° C for 1 hour. On reconstitution, the yellow suspension dissolves during heating and darkens in color. The brown solution was filtered hot and concentrated. The brown oily residue is taken up in 10 ml of cold alcohol and the crystals are filtered off. 0.2 g (48.7%) of 3- (1-propyl-1H-tetrazol-5-yl) and 3- (1-propyl-1H-tetrazol-5-yl) and 3- (2-propyl- 2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine isomer mixture (2: 3), m.p. 127-128 ° C.

Calcd for C] ₃ H ₁₄ N ₆ O O.

Calculated: C, 57.77; H = 5.22%; N = 31.09%; Found: C, 57.87%; H = 5.32%; N = 31.15%;

Example 6)

4.28 g (0.02 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 100 ml of dimethylformamide, 25 ml (0.04 mol) mole) of methyl iodide and 2.76 g (0.02 mole) of anhydrous potassium carbonate was stirred at 75-80 ° C for 1 hour. When reconstituted, the yellow suspension dissolves upon heating and the solution becomes orange at the end. The reaction mixture was filtered hot and the crystals precipitated from the filtrate were cooled after cooling. 2.3 g (50.4%) of 3- (1-methyl-1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine are obtained, which is crystallized from dimethylformamide 280-282. 'C' decomposes white, cotton-like substance.

Analysis for C ₁₀ H ₈ N ₆ O.

Calculated: C, 52.63; H = 3.53%; N = 36.83%; Found: C, 52.56%; H = 3.48%; N = 36.89%;

7.) Example

The dimethylformamide mother liquor obtained in the above example was diluted with 50 ml of water and extracted with 2 x 50 ml of chloroform. The combined chloroform layers were back-shaken with water (50 mL). The chloroform layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crystalline residue is suspended in a little cold ethanol and filtered. 0.7 g (15.4%) of 3- (1-methyltetrazol-5-yl) and 3- (2-methyltetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine isomeric mixture, 1: 9 (based on 1 HNMR), mp 208-210 ° C.

Analysis for C ₁₀ H _g N ₆ O.

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Calculated: C, 52.63; H = 3.53%; N = 36.83%; Found: C, 52.75%; H = 3.58%; N = 36.69%;

8.) Example

0.9 g (0.0042 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 25 ml of dimethylformamide, 1.15 g (0.0084) mole) of anhydrous potassium carbonate and 1.1 ml (0.0126 mole) of isopropyl bromide was stirred at 90 ° C for 3 hours. The yellow solution was filtered hot and concentrated. The solid residue was suspended in water (25 mL) and the crystals were filtered. 0.6 g (55.8%) of 3- (2-isopropyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine is obtained, m.p. 146-148 ° C. white crystal.

Analysis for C ₁₂ H ₂ N ₆ O.

Calculated: C, 56.24; H = 4.72%; N = 32.79%; Found: C, 56.32%; H = 4.81%; N = 32.71%;

Example 9)

In the above example, the aqueous mother liquor was extracted with benzene (3 x 20 mL), the benzene layer was dried over anhydrous sodium sulfate, filtered and evaporated. The yellow crystalline residue is suspended in 5 ml of cold ethanol and the crystals are filtered off. 0.1 g (9.3%) of 3- (1-isopropyl-1H-tetrazol-5-yl) and 3- (2-isopropyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1 2-a] 1: 1 isomeric pyrimidine (m.p. 135-137 ° C based on 1 HNMR).

Analysis calculated for C ₁₂ H ₁₂ N ₆ O.

Calculated: C, 56.24; H = 4.72%; N = 32.79%; Found: C, 56.39%; H = 4.87%; N = 32.67%;

10.) Example

0.4 g (0.00175 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 15 ml of dimethylformamide, 0.3 ml A mixture of isopropyl bromide (0.0035 mol) and anhydrous potassium carbonate (0.25 g, 0.0018 mol) was stirred at 80 ° C for 3 hours. The reaction mixture was filtered hot, and after cooling the crude yellow solution was diluted with water (10 mL) and extracted with benzene (3 x 15 mL). The combined benzene portion was shaken with water (1 x 20 mL). The benzene layer was dried over anhydrous sodium sulfate, filtered and evaporated. 0.2 g (47.0%) of 3- (1-isopropylH-tetrazol-5-yl) and 3- (2-isopropyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido A 2: 3 mixture of [1,2-a] pyrimidine isomers is obtained which is a yellow solid, m.p. 143-144 ° C.

Calcd for _{C] 3} H ₁₄ N ₆ O O.

Calculated: C, 57.77; H = 5.22%; N = 31.09%; Found: C, 57.85; H = 5.32%; N = 31.13%;

Example 11)

0.4 g (0.00187 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 15 ml of dimethylformamide, 0.3 ml (0.0036) mole) of allyl bromide and 0.25 g (0.0018 mole) of anhydrous potassium carbonate was stirred at 70 ° C for 1 hour. The reaction mixture is filtered hot, the crude orange solution is evaporated and the solid residue is suspended in 5 ml of ethanol and filtered. 0.1 g of 3- (1-allylH-tetrazol-5-yl) and 3- (2-allyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine 1: A mixture of 1 is obtained which is a white crystalline solid, m.p. 149-151 ° C.

Analysis for C _{12 H) 6} N ₀ O O.

Calculated: C, 56.68; H = 3.96%; N = 33.05%; Found: C, 56.73%; H = 4.04%; N = 34.12%;

72.) Example

0.4 g (0.00175 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 15 ml of dimethylformamide, 0.31 ml A mixture of allyl bromide (0.0036 mol) and anhydrous potassium carbonate (0.25 g, 0.0018 mol) was stirred at 70 ° C for 1 hour. The yellow solution was filtered hot, cooled, diluted with water (20 mL) and extracted with benzene (3 x 15 mL). The benzene portion was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. Yellow crystallizing oil, crystallized from ethanol, 0.25 g (52.0%) of 3- (1-allyl-1H-tetrazol-5-yl) and 3- (2-allyl-2H-tetrazol-5-yl) -9 1: 1 mixture of methyl 4-oxo-4H-pyrido [1,2-a] pyrimidine isomers melting at 145-150 ° C.

Analysis for C ₁₃ H | ₂ N ₆ O.

Calculated: C, 58.20; H = 4.51%; N = 31.33%; Found: C, 58.31%; H = 4.59%; N = 31.29%;

Example 13)

1.07 g (0.005 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 45 ml of dimethylformamide, 0.75 g (0.0055 mol) a mixture of anhydrous potassium carbonate and methyl chloroformate (0.76 ml, 0.01 mol) was stirred at 8090 ° C for 6 hours. The solid was filtered off while warm. During cooling, the crystals precipitated from the dimethylformamide solution are filtered. 0.32 g (23.5%) of 3- (1-methoxycarbonyl-1H-tetrazol-5-yl) and 3- (2-methoxycarbonyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido A 9: 1 mixture of [1,2-a] pyrimidine isomers crystallized from ethanol, mp 182-183 ° C; 3- (1-Methoxycarbonyl-1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine.

Analysis using the formula C _U H ₈ N ₆ O ₃ .

Calculated: C, 48.53; H = 2.96%; N, 30.87%; Found: C, 48.61%; H = 2.91%; N = 30.92%;

14.) Example

0.25 g (0.0011 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 10 ml of dimethylformamide, 0.15 g Anhydrous potassium carbonate (0.0011 mol) and methyl chloroformate (0.17 ml, 0.0022 mol) were stirred at 80-85 ° C for 2 hours. The reaction mixture was diluted with water (15 mL), extracted with benzene (3 x 15 mL), dried over anhydrous sodium sulfate, filtered and evaporated. 0.1 g (37.0%) of 3- (1-methoxycarbonyl-1H-tetrazol-5-yl) and 3- (2-methoxycarbonyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H of pyrido [1,2-a] pyrimidine isomers are obtained which, when crystallized from ethanol, is a yellow crystalline solid, m.p.

3- (l-methoxycarbonyl-lH-tetrazol-5-yl) isomer.

Calc'd for _C] H _{2] 0} O ₆ N ₃ O:

Calculated: C, 52.17; H = 3.65%; N = 30.42%; Found: C, 52.21%; H = 3.75%; N = 30.28%;

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Example 15)

1.07 g (0.005 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 15 ml of dimethylformamide, 0.70 g (0.005 mol) a mixture of anhydrous potassium carbonate and 1.51 g (0.01 mol) of 3-methylbutyl bromide was stirred at 100 ° C for 3 hours, cooled to room temperature, diluted with 50 ml of water and extracted with 3 x 25 ml of benzene. The combined benzene layer was dried over anhydrous sodium sulfate, filtered, and concentrated. 1.12 g (80%) of 3- (1-3-methylbutyl-1H-tetrazol-5-yl) and 3- (2-3-methylbutyl-2H-tetrazol-5-yl) -4-oxo crystallize at room temperature. Isomeric mixture of -4H-pyrido [1,2-a] pyrimidine, m.p. 90-95 ° C.

Calcd for _C] N ₆ O ₄ H ₁₆ O:

Calculated: C, 59.14; H = 5.67%; N = 29.56%; Found: C, 59.30; H = 5.61%; N = 29.67%;

Example 16)

3.42 g (0.015 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 35 ml of dimethylformamide, 2.07 g ( 0.015 mol) of anhydrous potassium carbonate and

A mixture of propargyl bromide (3.57 g, 0.03 mol) was stirred at 100 ° C for 10 hours. The reaction mixture was cooled to room temperature, diluted with 100 mL of water, and the precipitated crystalline material was filtered off with suction and washed with water.

2.46 g (61.65%) of 3- (1-propargyl-1H-tetrazol-5-yl) - and

Isomeric mixture of 3- (2-propargyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, m.p. 182-184C.

Calcd for _C] O ₃ H ₁₀ N ₆ O:

Calculated: C, 58.64; H = 3.79%; N = 31.56%; Found: C, 58.52%; H = 3.64%; N = 31.82%;

Example 17)

4.28 g (0.02 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 50 ml of dimethylformamide, 50 ml of dimethylformamide, A mixture of anhydrous potassium carbonate (76 g, 0.02 mol) and p-chlorobenzyl chloride (6.0 g, 0.04 mol) was stirred at 100 ° C for 3 hours, cooled to room temperature and diluted with water (100 ml). , the precipitated crystalline material is filtered off with suction and washed with water.

4.27 g (63.73%) of 3- (1-chlorobenzyl-1H-tetrazol-5-yl) and 3- (2-p-chlorobenzyl-2H-tetrazol-5-yl) -4-oxo A 1: 1 mixture of -4H-pyrido [1,2-a] -pyrimidine which is a yellow crystalline solid melting at 166-167 ° C.

Analysis at the bottom of the formula C ₁₆ HhN ₆ OC 1:

Calculated: C, 56.73; H, 3.27%;

N = 24.81%; Cl = 10.47%;

Found: C, 56.89; H = 3.45%;

N = 24.79%: Cl = 10.28%;

Example 18)

3.42 g (0.015 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 30 ml of dimethylformamide, 2.07 g (0.015 mol) moles) of anhydrous potassium carbonate and

A mixture of 4.53 g (0.03 mol) of isoamyl bromide was stirred for 3 hours at 100 ° C, diluted with 100 ml of water. Abama, the oily peel turns crystalline when standing. The precipitated crystals are filtered off with suction and washed with water.

2.65 g (59.20%) of 3- (1-isoamyl-1H-tetrazol-5-yl) and 3- (2-isoamyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H- a mixture of pyrido [1,2a] pyrimidine isomer which is a crystalline solid melting at 124-126 ° C.

Analysis using the formula C ₁₅ H _lg N ₆ O:

Calculated: C, 60.39; H = 6.08%; N = 28.17%; Found: C, 60.08%; H = 6.26%; N = 28.35%;

19.) Example

4.56 g (0.02 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 60 ml of dimethylformamide, 2.8 g a mixture of anhydrous potassium carbonate and 7.4 g (0.04 mol) of 2-phenylethyl bromide was stirred at 100 ° C for 3 hours. The dilute yellow suspension is poured warm into 180 ml of water. After cooling, the precipitated crystalline material is suctioned off under vacuum and washed with water.

5.84 g (87.82%) of 3- (1-phenylethyl-1H-tetrazol-5-yl) - and

3: 7 isomer mixture of 3- (2-phenylethyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 153-155 ' A crystalline material melting at C.

Calcd for _Ig H ₁₆ N ₆ O O:

Calculated: C, 65.05; H, 4.85; N = 25.29%; Found: C, 65.38%; H, 4.89; N = 25.44%;

20.) Example

9.13 g (0.04 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 100 ml of dimethylformamide, 5.53 g A mixture of anhydrous potassium carbonate (0.04 mol) and isobutyl bromide (11.0 g, 0.08 mol) was stirred at 100 ° C for 5 hours. The reaction mixture was diluted with water (300 mL) and the oily precipitate, upon standing and cooling, crystallized, which was filtered off with suction and washed with water.

8.28 g (73.34%) of 3- (1-isobutyl-1H-tetrazol-5-yl) - and

3: 7 mixture of 3- (2-isobutyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, m.p. 108-109 ° C melting crystalline material.

Calcd for C _i4 H ₁₆ N ₆ O O:

Calculated: C, 59.57; H = 5.71%; N, 29.77%; Found: C, 59.87; H = 5.63%: N = 29.52%;

21) Example

1.5 g (0.0055 mol) of 3- (2-propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine in 20 ml of abs. dissolved in ethanol while stirring and 10 ml of 10% hydrochloric acid abs. ethanol is added dropwise. After stirring for a few minutes, the solution is filtered and the crystalline solid which precipitates is filtered off with suction under vacuum.

1.50 g (89.29%) of hydrochloric acid salt of 3- (2-propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, m.p. 'C melting snow-white crystalline material.

Analysis using the formula C ₁₃ Hi ₅ C ₁ N ₆ O:

Calculated: C, 50.90; H = 4.93%;

N, 27.40%; Cl = 11.56%;

Found: C, 50.87; H = 4.87%;

N = 27.18%; Cl = 11.50%;

Example 22)

1.5 g (0.0055 mol) of 3- (2-propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine in 20 ml of abs. ? 6

Dissolve in methanol while stirring and add 0.6 ml (0.009 mol) of methanesulfonic acid dropwise. After stirring for a few minutes, the solution is filtered and the crystalline solid which precipitates is filtered off with suction under vacuum. 1.77 g (87.84%) of the methanesulfonic acid salt of 3- (2-propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, m.p. Mp 155 ° C, a white crystalline solid.

Calcd Ci4H _Ig N ₆ O ₄ S O:

Calculated: C, 45.89; H = 4.95%;

N = 22.94%; S = 8.75 ^% ;

Found: C, 45.73; H = 4.91%;

N = 22.72%; S = 8.96%;

Example 23)

The hydrochloride salt of 3- (2-isopropyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine prepared according to Example 22 is a white crystalline solid. .

Analysis using the formula C ₁₂ H ₁₃ ClN ₆ O:

Calculated: C, 49.24; H = 4.48%;

N = 28.71%; Cl = 12.11%;

Found: C, 49.42; H = 4.18%;

N = 28.48%; Cl = 12.23%;

Example 24)

The hydrochloride salt of 3- (2-isopropyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine prepared according to Example 22 is white. crystalline material.

Analysis using the formula C ₁₃ H ₁₅ ClN ₆ O:

Calculated: C, 50.90; H = 4.93%;

N, 27.40%; Cl = 11.56%;

Found: C, 50.99%; H = 4.90%;

N, 26.97%; Cl = 11.49%;

Example 25)

The methanesulfonic acid salt of 3- (2-isopropyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, prepared according to Example 23, is a white crystalline solid. .

Calcd for C ₁₃ H _I6 N ₆ O ₄ S O:

Calculated: C, 44.31; H = 4.58%;

N = 23.85%; S = 9.10%;

Found: C, 44.22%; H = 4.33%;

N = 23.52%; S, 9.28%;

Example 26)

The methanesulfonic acid salt of 3- (2-isopropyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, prepared according to Example 23, is 155-156 ° C. on white crystalline solid.

Analysis for _{C] 4H] g} N ₆ O ₄ S based on the formula:

Calculated: C, 45.89; H = 4.95%;

N = 22.94%; S = 8.75%;

Found: C, 45.70; H = 4.75%;

N = 22.40%; S = 8.74%;

27.) Example

The hydrochloride salt of 3- (2-allyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine prepared according to Example 22 is a white solid. crystalline material.

Analysis using the formula C ₁₃ H ₁₃ N ₆ OC 1:

Calculated: C, 51.24; H = 4.30%;

N = 27.58%; Cl = 11.63%;

Found: C, 51.06; H = 3.99%;

N = 27.28%; Cl = 11.97%;

Example 28)

The methanesulfonic acid salt of 3- (2-allyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine prepared according to Example 23, m.p. on white crystalline solid.

Analysis using the formula C _{) 4} H ₁₆ N ₆ O ₄ S:

Calculated: C, 46.15; H = 4.43%;

N = 23.06%; S = 8.80%;

Found: C, 45.91%; H = 4.47%;

N = 23.48%; S = 8.54%;

29.) Example

2.3 g of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 50 ml of dimethylformamide, 1.38 g (0, A mixture of anhydrous potassium carbonate (01 mol) and methyl iodide (2.85 g, 0.02 mol) was stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The precipitated crystalline material is suctioned off under vacuum.

1.61 g (66.53%) of 3- (1-methyl-1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, which was obtained from dimethylformamide. crystallized, m.p. 232-234 ° C.

Analysis for CnH ₁₀ N ₆ O:

Calculated: C, 54.54; H = 4.16%; N = 34.69%; Found: C, 54.83; H = 3.76%; N = 34.92%;

30.) Example

4.8 g (0.0224 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 100 ml of dimethylformamide, 3.2 g (0, A mixture of anhydrous potassium carbonate (0232 mol) and butyl bromide (6.13 g, 0.0448 mol) was stirred at 80-85 ° C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (300 mL) and extracted with benzene (3 x 25 mL). The combined benzene layer was dried over anhydrous sodium sulfate, filtered and evaporated. Crystallization at room temperature gave 4-77 g (78.84%) of 3- (1-butyl-1H-tetrazol-5-yl) and 3- (2-butyl-2H-tetrazol-5-yl) -4-oxo-4H- isomeric mixture of pyrido [1,2-a] pyrimidine which is a crystalline material melting at 98-100 ° C.

Analysis calculated for C ₁₃ H ₁₄ N ₆ O: C, 57.77; H, 5.22; N, 31.09;

Found: C, 58.11; H, 5.22; N, 31.33;

Example 31)

1.07 g (0.005 mol) of 3- (1H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine, 15 ml of dimethylformamide, 0.70 g (0.005 mol) of anhydrous A mixture of potassium carbonate and 1.32 g (0.01 mol) of isobutyl bromide was stirred at 100 ° C for 5 hours, cooled to room temperature, diluted with 50 ml of water and extracted with 3 x 25 ml of benzene. The combined benzene layer was dried over anhydrous sodium sulfate, filtered and evaporated. Szo7

The crystals which crystallize upon standing at b.t. 90 ° C are 1.03 g (76.3%) of 3- (1-isobutyl-1H-tetrazol-5-yl) and 3- (2-isobutyl-2H-tetrazol-5-yl). Isomeric mixture of -4-oxo-4H-pyrido [1,2-a] pyrimidine, m.p. 85-89 ° C.

Analysis for C ₁₃ H ₁₄ N ₆ O:

Calculated: C, 57.77; H = 5.22%; N = 31.09%; Found: C, 57.52%; H = 5.08%; N = 31.25%;

Example 32)

2.3 g (0.01 mol) of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 50 ml of dimethylformamide,

A mixture of 1.38 g (0.01 mol) of anhydrous potassium carbonate and 3.12 g (0.02 mol) of ethyl iodide is stirred at 80 ° C for 1 hour. The reaction mixture was diluted with water (150 mL) while still warm. After standing for a longer period, the crystalline material which had separated off under cooling was suctioned off under vacuum.

0.63 g (24.6%) of 3- (1-ethyl-1H-tetrazol-5-yl) and 3- (2-ethyl-2H-tetrazol-5-yl) -6-methyl-4-oxo-4H a mixture of pyrido [1,2-a] pyrimidine isomers.

Analysis for C ₁₂ H ₁₂ N ₆ O:

Calculated: C, 56.24; H = 4.72%; N = 32.79%; Found: C, 56.52%; H = 4.81%; N = 32.72%;

Example 33)

2.3 g (0.01 mol) of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 1.38 g (0.01 mol) a mixture of anhydrous potassium carbonate and 8.5 mL (0.05 mol) of triethyl phosphate was heated for 30 minutes in a 280 ° C oil bath with stirring. The hot reaction mixture was diluted with water (150 mL), cooled, and extracted with benzene (3 x 30 mL). The combined benzene phase, after charcoal clarification, was dried over anhydrous sodium sulfate, filtered and evaporated. The oily residue was suspended in diethyl ether (20 mL) and the crystals were suctioned off in vacuo. 1.12 g (80.0%) of 3- (1-ethyl-1H-tetrazol-5-yl) and 3- (2-ethyl-2H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido 1: 4 mixture of [1,2-a] pyrimidine isomers, m.p. 122-130 ° C.

Analysis for C, ₂ H ₁₂ N ₆ O:

Calculated: C, 56.24; H = 4.72%; N = 32.79%; Found: C, 56.11; H = 4.58%; N = 32.87%;

Example 34)

6.85 g (0.03 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 35 ml of dimethylformamide,

A mixture of 4.17 g (0.03 mol) of anhydrous potassium carbonate and 8.94 g of cyclopentyl bromide was stirred at 100 ° C for 5 hours. The reaction mixture was cooled to room temperature and poured into 450 ml of cold water. The precipitated crystalline material is filtered off with suction and washed with water. 7.08 g (79.64%) of 3- (1-cyclopentyl-1H-tetrazol-5-yl) and 3- (2-cyclopentyl-2H-tetrazol-5-yl) -9-methyl-4-oxo A mixture of 4H-pyrido [1,2-a] pyrimidine isomer 1: 4 (Ή NMR) is obtained as a crystalline solid, m.p. 130-131 ° C.

Analysis using the formula C ₁₅ H ₁₆ N ₆ O:

Calculated: C, 60.80; H = 5.44%; N = 28.36%; Found: C, 60.21%; H = 5.36%; N = 28.36%;

Example 35)

2.28 g (0.01 mol) of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 50 ml of dimethylformamide, 1.38 g (0.01 mol) anhydrous potassium carbonate and

A mixture of 3.43 g (0.02 mol) of p-nitrobenzyl chloride was stirred for 3 hours at 100 ° C.

The reaction mixture was cooled to room temperature and diluted with 150 mL of water. After prolonged standing, the sticky material will fall apart on crystals.

2.26 g (62.26%) of 3- (1-p-nitrobenzyl-1H-tetrazol-5-yl) and 3- (2-p-nitrobenzyl-2H-tetrazol-5-yl) -6-methyl-4-oxo-4H Pyrido [1,2-a] pyrimidine is a 3: 2 (by 1 H NMR) isomeric mixture which is a crystalline material decomposed at 188-190 ° C.

Analysis using the formula C ₁₇ H ₁₃ N ₇ O ₃ :

Calculated: C, 56.20; H = 3.61%; N = 26.98%; Found: C, 56.43; H, 3.94; N = 26.46%;

Packaging example

36.) Example

Composition of 100 mg tablet:

3- (2-Propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2a] pyrimidine 10.0 g

CMC-Na 2.0 g

Lactose 1.5 g

Gypsum 12.0 g

Stearic acid 1.5 g

Magnesium stearate 0.25 g

Talcum 0.5 g

Example 37)

3.62 g (0.0159 mol) of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 30 ml of dimethylformamide, 2.21 g (0.016 mol) of anhydrous potassium carbonate and

A mixture of propyl bromide (3.70 g, 0.03 mol) was stirred at 100 ° C for 1 hour. The reaction mixture was diluted with warm water (60 mL), cooled, and extracted with benzene (3 x 35 mL). The combined benzene layer was dried over anhydrous sodium sulfate, filtered and evaporated.

The oily residue was separated by column chromatography (column: Kieselgel 60, eluent: chloroform-methanol).

2.12 g (57.30%) of 3- (2-propyl-2H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, crystallized from diisopropyl ether M.p. 88-90 ° C.

Calcd for _[3 H ₆ O N _I4 O:

Calculated: C, 57.77; H = 5.22%; N = 31.09%; Found: C, 57.83; H = 5.10%; N = 30.78%;

38.) Example

Column chromatography in Example 37 gave 1.20 g (32.43%) of 3- (1-propyl-1H-tetrazol-5-yl) -6-methyl-4-oxopyrido [1,2-a]. pyrimidine, a crystalline solid, m.p. 137-138 ° C.

Analysis for C ₁₃ H ₁₄ N ₆ O:

Calculated: C, 57.77; H = 5.22%; N = 31.09%; Found: C, 57.53%; H = 4.81%; N = 30.65%;

39.) Example

4.60 g (0.0200 mol) of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 100 ml of dimethylformamide, 2.76 g (0.020 mol) of anhydrous potassium carbonate and

HU 211 903 A9

A mixture of 4.92 g (0.04 mol) of isopropyl bromide was stirred at 100 ° C for 2 hours.

The reaction mixture was diluted with hot water (200 mL), cooled, and extracted with benzene (3 x 60 mL). The combined benzene layer was dried over anhydrous sodium sulfate, filtered and evaporated.

The oily residue was separated by column chromatography (column: Kieselgel 60, eluent: chloroform-methanol).

3.34 g (71.83%) of 3- (2-isopropyl-2H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, m.p. crystallized from ethanol, yellow crystalline melting at 117-118 ° C.

Calcd for C _{13 H]} N ₆ O ₄ wherein:

Calculated: C, 57.77; H = 5.22%; N = 31.09%; Found: C, 57.66%; H, 5.28%; N = 30.85%

40.) Example

Column chromatography in Example 38 gave 1.19 g (25.60%) of 3- (1-isopropyl-1H-tetrazol-5-yl) -6-methyl-4-oxopyrido [1,2-a]. pyrimidine, a crystalline solid, m.p. 166-167 ° C.

Analysis for C _] 3H H | According to the formula ₄ N ₆ O:

Calculated: C, 57.77; H = 5.22%; N = 31.09%; Found: C, 57.84%; H, 5.27%; N = 31.51%;

41.) Example

2.28 g (0.0100 mol) of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 25 ml of dimethylformamide, 1.38 g (0.010 mol) of anhydrous potassium carbonate and 3.02 g (0.02 mol) of pentyl bromide was stirred at 100-110 ° C for 1 hour. The reaction mixture was diluted with water (75 mL) while warm, further stirred with cooling and extracted with benzene (3 x 30 mL). The combined benzene layer was dried over anhydrous sodium sulfate, filtered and evaporated. The oily residue was separated by column chromatography (column: Kieselgel 60, eluent: chloroform-methanol).

1.20 g (44.28%) of 3- (2-pentyl-2H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine is yellowish at room temperature. brown oil.

Analysis for C | Based 5 H ₁₈ N ₆ O O:

Calculated: C, 60.39; H = 6.08%; N, 28.17. Found: C, 60.74; H = 6.12%; N = 28.37%;

Example 42)

Column chromatography in Example 41 provided 0.71 g (26.20%) of 3- (1-pentyl-1H-tetrazol-5-yl) -6-methyl-4-oxopyrido [1,2-a]. pyrimidine, which is a crystalline material.

Calcd for C ₁₅ H ₁₈ N ₆ O O:

Calculated: C, 60.39; H = 6.08%; N = 28.17%; Found: C, 60.12%; H = 6.17%; N = 28.08%;

Example 43)

2.28 g (0.0100 mol) of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 25 ml of dimethylformamide, 1.38 g (0.010 mol) of anhydrous potassium carbonate and 5.01 g (0.03 mol) of ethyl bromoacetate were stirred at 100 ° C for 1 hour.

The reaction mixture was diluted with water (75 mL) while still warm. The crystalline material which precipitated out during cooling was suctioned off under vacuum.

2.00 g (63.70%) of 3- (1-ethoxycarbonylmethyl-1H-tetrazol-5-yl) and 3- (2-ethoxycarbonylmethyl-2H-tetrazol-5-yl) 4-oxo-4H- a 96: 4 mixture of pyrido [1,2-a] pyrimidine isomers, m.p. 164-165 ° C.

Analysis using the formula C ₁₄ H ₁₄ N ₆ O ₃ :

Calculated: C, 53.50; H = 4.49%; N = 26.74%; Found: C, 53.39; H = 4.54%; N = 26.31%;

Example 44)

2.28 g (0.010 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 50 ml of dimethylformamide, 1.38 g (0.010) moles) of anhydrous potassium carbonate and

A mixture of 2.49 g (0.01 mol) of 4-bromobenzyl bromide was stirred at 100 ° C for 3 hours.

The reaction mixture was diluted with 100 mL of water while still warm, and the precipitated crystalline material was filtered off with suction after cooling.

3.06 g (77.08%) of 3- [1- (4-bromobenzyl) -1H-tetrazol-5-yl] and 3- [2- (4-bromobenzyl) -2H-tetrazol-5-yl] and 3- 59:41 [2- (4-bromobenzyl) -2H-tetrazol-5-yl] -4-oxo-4H-pyrido [1,2-a] pyrimidine isomer, m.p. 166-170 ° C.

Analysis for C _I7 H ₁₃ BrN ₆ O based formula:

Calculated: C, 51.40; H = 3.30%;

N = 21.16%; Br = 20.12%;

Found: C, 51.81; H = 3.35%;

N, 21.60%; Br = 19.50%;

45.) Example

2.28 g (0.0100 mol) of 3- (1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine, 30 ml of dimethylformamide, 1.38 g (0.010 mol) of anhydrous potassium carbonate and

A mixture of 3,4-dichlorobenzyl chloride (1.95 g, 0.02 mol) was stirred at 100 ° C for 3 hours.

The reaction mixture was diluted with 100 ml of water while still warm, and the precipitated crystalline material was suctioned off in vacuo after cooling.

3.35 g (86.56%) of 3- [1- (3,4-dichlorobenzyl) -1H-tetrazol-5-yl] and 3- [2- (3,4-dichlorobenzyl) -2H-tetrazol-5] -yl] -4-oxo-4H-pyrido [1,2-a] pyrimidine isomer 2: 1, m.p. 168-170 ° C.

Analysis for the Formula C] ₇ H, 2C1 ₂ N ₆ O:

Calculated: C, 52.73; H = 3.12%;

N, 21.70%; Cl = 18.31%;

Found: C, 52.20; H = 2.94%;

N, 20.99%; Cl = 18.56%;

Claims (11)

1.) The present invention relates to compounds of the formula I and their pharmaceutically acceptable salts. R is C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxycarbonyl, or In the case of A9, C7-C8-aralkyl substituted with one or more halogen or nitro groups, and R ¹ is hydrogen or C 1-4 alkyl. 2.) The compounds of the formula (Π) and their pharmaceutically acceptable salts R is C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxycarbonyl, or optionally one or more thereof. C 7 -C 8 aralkyl substituted with halogen or nitro; and R ¹ is hydrogen or C 1-4 alkyl. 3.) 3- (2-Propyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine. 4.) 3- (2-Isopropyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine. 5.) 3- (2-Allyl-2H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine. 6.) 3- (2-Isopropyl-2H-tetrazol-5-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine. 7.) 3- (1-Isopropyl-1H-tetrazol-5-yl) -9-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine. 8. A process for the preparation of new 4oxo-4H-pyrimidines of the formula I and / or II and their pharmaceutically acceptable salts R is C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C3-C7 cycloalkyl, C1-C4 alkoxycarbonyl, or C7-C8 aralkyl optionally substituted with one or more halogen or nitro groups, and R ¹ is hydrogen or C 1 -C 4 alkyl, characterized in that a 3-Tetrazolyl-4-oxo-4 H -pyrido [1,2-a] pyrimidine of formula (III) wherein R ¹ is as defined herein - a halide of formula IV wherein R is C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-7 cycloalkyl, or optionally one or more halogen atoms substituted C 7 -C 8 aralkyl, X is chloro, bromo or iodo, or a sulfate of formula (V) wherein R is C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or C 7 -C 8 aralkyl optionally substituted with one or more halo, or nitro, or a sulfonate of formula VI wherein R C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl C 3 -C 7 cycloalkyl, or C 7 -C 8 aralkyl optionally substituted with one or more halogen or nitro groups, R ² is phenyl, p-methylphenyl or methyl, or with a phosphate of formula VII wherein R is C 1-6 alkyl, C 3-6 alkenyl C 3-6 alkynyl, group, C3-7 cycloalkyl, or optionally substituted with one or more halogens or nitro-substituted aralkyl of 7-8 carbon atoms, - or a (VHI) ester of the formula - wherein R ³ is C 1-4 alkyl, X is chlorine or bromine and n is 0 or 1, the resulting mixture of isomers (I) and (II) is optionally separated and optionally The salts of the compounds of formula (I) or (II), or mixtures thereof, are formed, liberated or converted into their other salts. 9. A process according to claim 8 wherein the compound of formula (ΠΙ), wherein R ¹ is as defined in claim 8, and (IV), (V), (VI), (VII), or reacting a compound of formula (VIII) wherein R, R ¹ , R ² , R ³ and X are as defined in claim 8 in the presence of a solvent and an acid acceptor. 10. A process according to claim 8, wherein the separation of the compounds of formula I and II, wherein R and R ¹ are as defined in claim ^1, is carried out by chromatography or recrystallization. 11.) A pharmaceutical composition comprising as active ingredient a compound of formula (I) and / or (II), wherein R and R ¹ are as defined in claim 1, or a pharmaceutically acceptable salt thereof, in a carrier and a pharmaceutically acceptable carrier. mixed with excipients.