NEW 3-(SUBSTITUTED TETRAZOLYL)-4-OXO-4H-PYRIDO-[1,2-a]PYRIMIDINES, SALTS THEREOF, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME

Abstract: The present invention relates to therapeutically useful 4-oxo-4H-pyrido[1,2-a]-pyrimidines of general formula (I) and/or formula (II), wherein R means C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-7cycloalkyl, C1-4alkoxycarbonyl group or C7-8aralkyl group, optionally substituted by one or more halogen atom(s), or by nitro-group, R<1> stands for hydrogen atom or a C1-4alkyl group, and salts thereof, further to a process for their preparation, and pharmaceutical compositions containing them. These new compounds may be therapeutically useful first of all as gastroprotectives in the treatment and prevention of ulcer.

Description: NEW 3 - (S UB S TITUTED TETRAZOLYL)-4-OXO-4H-PYRIDO- [ 1,2-a]PYRIMIDINES, SALTS THEREOF, PHARMACEUTICAL C OMP OS ITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME This invention relates to therapeutically useful novel 3-(l-substituted-lH-tetrazol-5-yl)-4-oxo-4H-pyrido[l,2-a]- pyrimidines and/or 3-(2-substituted-2H-tetrazol-5-yl)-4-oxo- 4H-pyrido[1,2-a]pyrimidines, salts thereof, process for their preparation, and pharmaceutical compositions contain¬ ing them. These new compounds may be therapeutically useful first of all as gastroprotectives in the treatment and pre- vention of ulcer. It is known that some representatives of the 4H-pyrido- [l,2-a]pyrimidine-4-ones exert significant antiallergic and ulcus preventing activity (EP-PS No. 217 673 and 218 423, BE-PS No. 873 197 and 873 194 and US-PS No. 4 122 274 and 4 457 932) . Cyctoprotective activity of the 9-methyl-3- tetrazolyl-4-oxo-4H-pyrido[l,2-a]pyrimidine potassium salt was shown more in detail (Gastroenterology 1985 88. / 1354). The invention is based upon the unexpected discovery that substitution of the acidic hydrogen atom of the tetra- zolyl group of the 3-tetrazolyl-4-oxo-4H-pyrido[l,2-a]pyri- midines results in derivatives with broader therapeutic spectrum. More particularly the invention relates to novel 4-oxo- 4H-pyrido[l,2-a]pyrimidines with general formula A 4779-77 KY and/or wherein R means C^-galkyl, C 3 _. 6 alkenyl, C 3 _6alkynyl, 03-7 cyclo- alkyl, Cι_4alkoxycarbonyl group or C-j__. s aralkyl group, optionally substituted by one or more halogen atom(s) , or by nitro-group, R 1 stands for hydrogen atom or a ^-_ \ alkyl group. As used herein: the term C^_4alkyl means straight or branched chain aliphatic saturated hydrocarbyl groups (such as the methyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, neopentyl group). Pharmaceutically acceptable salts of the compounds of general formulae (I) and (II) mean salts formed with alkali metals, alkaline-earth metals, or acid addition salts formed with organic or inorganic acids. According to another aspect of the invention there is provided a process for the preparation of the new compounds of the general formulae (I) and (II) , wherein R and R 1 are the same as defined above, and their pharmaceutically acceptable salts, which c o m p r i s e s reacting a 3-tetrazolyl-4-oxo-4H-pyrido[l,2-a]pyrimi- dine of general formula wherein R 1 is the same as defined above, with a halogenide of general formula R - X (IV) , wherein R means Ci-galkyl, C3_.galkenyl, C3_6alkynyl, 03-7- cycloalkyl, Cι_4 alkoxycarbonyl group or C7_3aral yl group optionally substituted by one ore more halogen atom(s) or by nitro-group and X stands for chlorine, bromine or iodine atom; or with a sulfate of general formula wherein R means Ci-galkyl, C3_galkenyl, C3-6 alkynyl, 3-7- cycloalkyl group or C7_g aralkyl group optionally substi¬ tuted by one or more halogen atom(s) or by nitro group or with a sulfonate of general formula 0 R-o-s-Fr 0 (VI) ' wherein R means Ci-galkyl, C3__galkenyl, C3-8 alkynyl, C2-I" cycloalkyl group or C7__garalkyl group, optionally substi¬ tuted by one or more halogen atom(s) or by nitro group and R 2 means phenyl, p-methylphenyl or methyl group; or with a phosphate of general formula wherein R means Ci-galkyl, C3_.galkenyl, C3-8 alkynyl, C3.7- cycloalkyl group or C7__ 8 aralkyl group optionally substituted by one or more halogen atom(s) or by nitro group; or with an ester of general formula wherein R 3 means Cι_4alkyl group, X stands for chlorine or bromine atom: and n is 0 or 1, preferably in the presence of solvent and acid-binding agent, and if desired separating the thus obtained mixture of the isomers of general formulae (I) and (II) from one- another by using one of the chromatographic methods or by crystallization, utilizing the differences in the solubility of the isomers, and if desired converting the isomers of general formulae (I) and (II) or the mixture thereof into their salts, and if desired liberating them from their salts and converting them to another salt thereof in a known way. In the preparation process according to the invention compounds of general formula (III) are treated with agents suitable to introduce the R moiety. Thus halogenides of gen¬ eral formula (IV) preferably chlorides, bromides or iodides, or sulfates of general formula (V) , sulfonates of general formula (VI) , phosphates of general formula (VII) and esters of general formula (VIII) may be applied. Introduction of the R moiety can be accomplished at temperatures ranging between 20-250 °C, preferably in the presence of solvent. The temperature may be chosen according to the solvent. The reaction may preferablyvearried out in the presence of an acid-binding agent, thus alkali hydroxides, preferably sodium hydroxide, potassium hydroxide, or alkaline-earth metal hydroxides, preferably calcium hydroxide, magnesium hydroxide, or alkali carbonates, preferably sodium car- bonate, potassium carbonate, potassium hydrogen carbonate may be used. If desired the reaction may be carried out by applying the alkali metal or alkaline-earth metal salts of compounds of general formula (III) . As solvent excess amount of the compounds of general formulae (IV) , (V) , (VI) or (VII) may be used, furthermore alcohols (e.g. ethanol, propanol) ketones (e.g. acetone, methyl ethyl ketone) , dipolar-aprotic solvents such as di- methylformamide, dimethylsulphoxide, hexamethylphosphor-tri- a ide, acetonitrile, nitromethane, aromatic hydrocarbons, (e.g. benzene) or halogenated hydrocarbons (e.g. chloro-ben- zene; chloroform) and a mixture of the above solvents may be applied. The solvents may contain optional amount of water. The starting nitrogen-bridgehead compounds are known materials (US Patent No. 4,122,274). Toxicity of the compounds of the general formulae (I) and (II) is low, in general their oral LD5 0 values are higher than 250 mg/kg in rats and mice. The compounds of general formulae (I) and (II) and their pharmaceutically acceptable salts possess significant gastroprotective effect and exert their protective- and healing (therapeutic) action both in the stomach and in the small intestine. Activity of the compounds of. general for¬ mulae (I) and (II) was demonstrated in standard tests gen¬ erally accepted for determining antiulcerogenic effect. Com¬ pounds of general formulae (I) and (II) may be used separ- ately or in the form of their isomeric mixture as the active component of pharmaceutical preparations. As an example, the protective action of the compounds according to the invention against gastric ulcer induced by 0.5 ml of a 1:0.02 volume ratio mixture of 96% ethanol and hydrochloric acid is illustrated in Table 1. [for the method, see: Gastroenterology 11_, 433 (1979)] Table 1 Protective action in rats of the compounds according to the invention against the gastric mucosa laesion induced by 96% ethanol containing hydrochloric acid Compound ID5 0 ID50 mg/kg p.o. M/kg p.o. 3-(l-isopropyl-lH-tetrazol-5-yl)- -9-methyl-4-oxo-4H-pyrido[l,2-a]- 0.34 1.25 pyrimidine 3-(2-isopropyl-2H-tetrazol-5-yl)- -9-methyl-4-oxo-4H-pyrido[l,2-a]- 0.23 0.85 pyrimidine 3-(2-isopropyl-2H-tetrazol-5-yl)- -4-oxo-4H-pyrido[l,2-a]pyrimidine 2.2 8.5 3-(2-butyl-2H-tetrazol-5-yl)-9- methyl-4-oxo-4H-pyrido[l,2-a]- 2.0 7.0 pyrimidine 3-(allyl-2H-tetrazol-5-yl)-9-methyl- -4-oxo-4H-pyrido[1,2-a] yrimidine 2.9 11.0 3-(2-propyl-2H-tetrazol-5-yl)-9- __ethyl-4-oxo-4H-pyrido[l,2-a]- 0.05 0.18 pyrimidine The effect of the compounds to the invention, given as examples, against the indomethacin-induced ulcer [Arch. Int. Pharmacodyn 117. 113 (1964)] is shown in Table 2. Table 2 Inhibition of the indomethacin-induced gastric mucosa laesion in rats Compound I°50 DSO p.o. mg/kg p.o. M/kg 3-(2-isopropyl-2H-tetrazol-5-yl)- -9-methyl-4-oxo-4H-pyrido[l,2-a]- 2.6 9.6 pyrimidine 3-(2-allyl-2H-tetrazol-5-yl)- -9-methyl-4-oxo-4H-pyrido[l,2-a]- 2.5 9.3 pyrimidine 3- (2-isopropyl-2H-tetrazol-5-yl) - -4-oxo-4H-pyrido [ l , 2-a]pyrimidine 4 . 0 15. 6 3-(2-propyl-2H-tetrazol-5-yl)-9- methyl-4-oxo-4H-pyrido[l,2-a]- 5.5 20.3 pyrimidine To demonstrate the inhibiting effect of the compounds on the formation of indomethacin-induced duodenal ulcer in rat, the effect of 3-(2-propyl-2H-tetrazol-5-yl)-9-methyl-4- oxo-4H-pyrido[l,2-a]pyrimidine is given as an example. According to the method of Tsuromi (J. Pharm. Dyn. 1980, 2. 1 659) the compound was administered to the rats in a dose of 50 mg/kg on 4 consecutive days. On the 2nd day a 15 mg/kg oral dose of indomethacin was given to the rats. The ulcer formation was determined in the small intestine on the 3rd day following the administration of the indomethacin. In comparison to the control, the compound according to the invention exerted an inhibition of 20% on the ulcer form¬ ation and also an inhibition of 100% on the lethality caused by indomethacin. The known compound 9-methyl-3-(5-tetrazolyl)-4-oxo-4H- pyrido[l,2-a]pyrimidine potassium salt did not prevent the gastrointestinal ulceration induced by indomethacin. The compounds of general formulae (I) and (II) or their salts may therapeutically be used in the form of composi¬ tions containing the active ingredient in an admixture with inert solid or liquid organic or inorganic carriers. These compositions may be prepared by using methods well known in the pharmaceutical industry. The compositions may be formulated for oral or parente- ral use in the form of e.g. tablets, dragees,: capsules or in the sustained-release variants thereof. The compositions may contain suitable solid diluents or carriers, sterile aqueous solvents or non-toxic organic solvents. The composi¬ tions for oral use may be supplemented with sweeting or flavouring (aromatizing) agents which are suitable for this purpose. - 8 - Tablets for oral use may contain: carriers such as lactose, sodium citrate, or calcium carbonate; disintegrat¬ ing agents such as starch or alginic acid; and sliding agents such as talc, sodium lauryl sulfate or magnesium stearate. The carrier in capsules may be e.g. lactose or polyethylene glycol. Aqueous suspensions may contain emul¬ sifying or suspending agents. The diluent of a suspension in an organic solvent may be glycerol, ethanol, chloroform and the like. The compositions for parenteral use are solutions or suspensions of the active ingredient in a suitable medium such as peanut oil, sesam oil, polypropylene glycol or water. The active ingredient content of the pharmaceutical com- positions according to the invention may be varied within wide limits: it may amount to 0.005 to 99%. The daily dose of the active ingredient may also be varied within wide limits and depends on the severity of the disease as well as on the age and body weight of the pati- ent, on the formulation of the composition and efficiency of the active ingredient used. For oral use, the daily dose of the active ingredient is commonly between 0.05 and 15 mg/kg daily once or in divided doses. However, the above data are only informative in character, which may be increased or lowered, dependently on the demands of the situation and prescriptions of the physician. When justified, compositions (formulations) differing from the above application forms may also be used. The invention is illustrated in detail by the following non-limiting Examples. Example 1 Preparation of 3-(l-ethyl-lH-tetrazol-5-yl)-4-oxo-4H-pyrido- [(1,2-a] yrimidine and 3-(2-ethyl-2H-tetrazol-5-yl)-4-oxo- 4H-pyrido[1,2-a]pyrimidine A mixture of 0.9 g (0.0042 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 25 ml of dimethyl- formamide, 0.58 g (0.0042 moles) of anhydrous potassium car¬ bonate and 0.7 ml (0.0084 moles) of ethyl iodide was heated at 80-90 °C under stirring for 3 hours. From the orange- coloured solution the inorganic material was filtered off, and the filtrate was evaporated. To the residue 30 ml of water were added, and the crystals were separated. 0.4 g (40%) of the 1:1 isomeric mixture of the title compounds was obtained, m.p.: 160 °C. Analysis: Calculated for CnHio βO C = 54.54%; H = 4.16%; N = 34.70%; Found: C = 54.76%; H = 4.40%; N = 34.67%. Example 2 Preparation of 3-(l-methyl-lH-tetrazol-5-yl)-9-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidine and 3-(2-methyl-2H-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido-[l,2-a]pyrimidine A mixture of 0.4 g (0.0018 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine, 15 ml of dimethyl- formamide, 0.25 g (0.0018 moles) of anhydrous potassium car- bonate and 0.51 ml (0.0036 moles) of methyl iodide was stirred at 80 °C for 30 minutes. The yellow suspension gradually dissolved. From the warm yellow-coloured solution the inorganic material was filtered off, and the filtrate was allowed to stay overnight in refrigerator. The precipi- tated crystals were separated. 0.35 g (80.3%) isomeric mix¬ ture of the title compounds was obtained. The mixture was crystallized from dimethyl-formamide. 0.2 g (57%) of 3-(l- methyl-lH-tetrazol-5-y1)-9-methy1-4-oxo-4H-pyrido[1,2-a]- pyrimidine was obtained in the form of white crystals, m.p.. 294 °C under decomposition. Analysis: Calculated for CHHIQNSO C = 54.54%; H = 4.16%; N = 34.70%; Found: C = 54.27%; H = 4.05%; N = 34.36%. Example 3 Preparation of 3-(l-ethyl-lH-tetrazol-5-yl)-9-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidine and 3-(2-ethyl-2H- tetrazol-5-yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimi- dine A mixture of 0.55 g (0.0024 moles) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 20 ml of di- methylformamide, 0.3 g (0.0024 moles) of anhydrous potassium carbonate and 0.4 ml (0.0048 moles) of ethyl iodide was stirred at 80 °C for 1 hour. The lemon-coloured clear solu¬ tion was filtered, the filtrate evaporated. To the yellow oily residue, which upon staying started to crystallize, 50 ml of ethanol were added, and the crystals were collected. 0.25 g (61.5%) of the 3:7 isomeric mixture of the title com¬ pounds was obtained, in the form of pale-yellow crystals. M.p.: 168-170 °C (the ratio of the isomers was determined by ^-Hnmr spectroscopy) Analysis: Calculated for Ci2 H i2 N 6° C = 54.54%; H = 4.72%; N = 32.80%; Found: C = 56.14%; H = 4.80%; N = 32.38%. Example 4 Preparation of 3-(l-propyl-lH-tetrazol-5-yl)-4-oxo-4H-py- rido[1,2-a]pyrimidine and 3-(2-propyl-2H-tetrazol-5-yl)-4- oxo-4H-pyrido[1,2-a]pyrimidine A mixture of 0.4 g (0.00187 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 15 ml of dimethyl- formamide, 0.25 g (0.00187 moles) of anhydrous potassium carbonate and 0.34 ml (0.00374 moles) of propyl bromide was stirred at 90 °C for 1 hour. The hot dark brown solution was filtered, the filtrate evaporated. The dark brown oily resi- due, which is the mixture of the title compounds, started to crystallize. To the oily crystals 10 ml of ethanol were added, and the crystals were collected. 0.15 g (31.3%) of 3- (2-propyl-2H-tetrazol-5-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine was obtained, in the form of pale-yellow crystals, m.p.: 115-116 β C Analysis: Calculated for C12H12 6 O C = 54.54%; H = 4.72%; N = 32.80%; Found: C » 56.21%; H = 4.67%; N = 32.75%. Example 5 Preparation of 3-(l-propyl-lH-tetrazol-5-yl)-9-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidine and 3-(2-propyl-2H-tetrazol-5- y1)-9-methy1-4-oxo-4H-pyrido-[1,2-a]pyrimidine A mixture of 0.4 g (0.0018 moles) 3-(lH-tetrazol-5-yl)- 9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 25 ml of di- methylformamide, 0.25 g (0.0018 moles) of anhydrous potass¬ ium carbonate and 0.33 ml (0.0036 moles) of propyl bromide was stirred at 90 °C for 1 hour. The yellow suspension gra¬ dually turned into a brown, clear solution which was fil¬ tered, and the filtrate was evaporated. To the brown, oily residue, 50 ml of cold ethanol were added, and the crystals were collected. 0.2 g (48.7%) 2:3 isomeric mixture of the title compounds was obtained, m.p.: 127-128 °C. Analysis: Calculated for C^H^NgO C = 57.77%; H - 5.22%; N = 31.09%; Found: C - 57.87%; H = 5.32%; N = 31.14%. Example 6 Preparation of 3-(l-methyl-lH-tetrazol-5-yl)-4-oxo-4H-py- rido[1,2-a]pyrimidine A mixture of 4.28 g (0.02 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine; 100 ml of dimethyl- formamide, 2.76 g (0.02 moles) of anhydrous potassium car¬ bonate and 25 ml (0.04 moles) of methyl iodide was stirred at 75-80 °C for 1 hour. The yellow suspension gradually dis- solved and at the end of the reaction an orange-coloured solution was obtained. The warm reaction mixture was fil¬ tered, cooled down and the precipitating crystals were col¬ lected. 2.3 g (50.4%) of the title compound were obtained, and crystallized from dimethylformamide to obtain white cry- stals, m.p. : 280-282 °C (under decomposition) . Analysis: Calculated for Cιo H 3 N 6 ° C = 52.63%; H = 3.53%; N = 36.83%; Found: C = 52.56%; H = 3.48%; N = 36.89%. Example 7 Preparation of 3-(l-_nethyl-lH-tetrazol-5-yl)-4-oxo-4H- pyrido[1,2-a]pyrimidine and 3-(2-methyl-2H-tetrazol-5-yl)-4- oxo-4H-pyrido[1,2-a]pyrimidine The dimethylforma ide mother liquor obtained in Example 6 was diluted with 50 ml of water, then extracted with 2 x 50 ml of chloroform. The combined chloroformic phases were washed with 50 ml of water. The organic phase was dried on anhydrous sodium sulphate, filtered, and evaporated. To the crystalline residue cold ethanol was added, and the crystals were collected. 0.7 g (15.4%) of the 1:9 ratio mixture of the title compounds was obtained, m.p.: 208-210 °C (the ratio of the isomers was determined by 1 Hnmr spectroscopy) Analysis: Calculated for Cιo H 8 N 6 ° C = 52.63%; H = 3.53%; N = 36.83%; Found: C = 52.75%; H = 3.58%; N = 36.69%. Example 8 Preparation- of 3-(2-isopropyl-2H-tetrazol-5-yl)-4-oxo-4H-py- rido[1,2-a]pyrimidine A mixture of 0.9 g (0.0042 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 25 ml of dimethyl¬ formamide, 1.15 g (0.O084 moles) of anhydrous potassium car¬ bonate and 1.1 ml (0.0126 moles) of isopropyl bromide was stirred at 90 °C for 1 hour. The hot yellow solution was filtered, the filtrate evaporated. To the crystalline resi- due 25 ml of water was added, and the crystals were col¬ lected. 0.6 g (55.8%) of the title compound was obtained, in the form of white crystals, m.p.: 146-148 °C Analysis: Calculated for C^H^^O C = 56.24%; H = 4.72%; N = 32.80%; Found: C = 56.32%; H = 4.81%; N = 32.71%. Example 9 Preparation of 3-(l-isopropyl-lH-tetrazol-5-yl)-4-oxo-4H-py- rido[1,2-a]pyrimidine and 3-(2-isopropyl-2H-tetrazol-5-yl)- 4-oxo-4H-pyrido[l,2-a]pyrimidine The aqueous mother liquor obtained in Example 8. was extracted with 2 x 20 ml of benzene. The combined organic phases were dried, filtered and evaporated. To the yellow crystalline residue 5 ml of cold ethanol were added, and the crystals were collected. 0.1 g (9.3%) of the 1:9 ratio mix- ture of the title compounds was obtained, m.p.: 135-137 β C (the ratio of the isomers was determined by ^Hnmr spectro- scopy) . Analysis: Calculated for C12H12N6O C = 56.24%; H = 4.72%; N = 32.80%; Found: C = 56.39%; H = 4.87%; N = 32.67%. Example 10 Preparation of 3-(l-isopropyl-lH-tetrazol-5-yl)-9-methyl-4- oxo-4H-pyrido[l,2-a]pyrimidine and 3-(2-isopropyl-2H-tetra- zol-5-yl)-4-oxo-4H-pyrido[1,2-a]-pyrimidine A mixture of 0.4 g (0.00175 moles) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 15 ml of di- methylformamide, 0.25 g (0.0018 moles) of anhydrous potass¬ ium carbonate and 0.3 ml (0.0035 moles) of isopropyl bromide was stirred at 80 °C for 3 hours. The hot reaction mixture was filtered, the clear, yellow filtrate was cooled down and diluted with 10 ml of water, then extracted with 3 x 15 ml of benzene. The combined benzene phases were washed with 20 ml of water, dried on anhydrous sodium sulphate, filtered and evaporated. 0,2 g (42.0%) yellow crystals, of the 2:3 ratio mixture of the title compounds was obtained, m.p.: 143-144 °C Analysis: Calculated for C1 3 H14N6O C = 57.77%; H = 5.22%; N = 31.09%; Found: C = 57.85%; H = 5.32%; N = 31.13%. Example 11 Preparation of 3-(l-allyl-lH-tetrazol-5-yl)-4-oxo-4H-pyrido- [1,2-a]pyrimidine and 3-(2-allyl-2H-tetrazol-5-yl)-4-oxo-4H- pyrido[1,2-a]-pyrimidine A mixture of 0.4 g (0.00187 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 15 ml of dimethyl- formamide, 0.25 g (0.0018 moles) of anhydrous potassium car¬ bonate and 0,3 ml (0.0036 moles) of allyl bromide was stirred at 70 °C for 1 hour. The hot reaction mixture was filtered, the clear, orange-coloured filtrate was evapor¬ ated, to the crystalline residue 5 ml of ethanol were added. 0.1 g white crystals were obtained which were the 1:1 ratio mixture of the title compounds, m.p.: 149-151 °C Analysis: Calculated for C = 56.68%; H = 3.96%; N = 33.05%; Found: C = 56.73%; H = 4.04%; N = 34.12%. Example 12 Preparation of 3-(l-allyl-lH-tetrazol-5-yl)-9-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidine and 3-(2-allyl-2H-tetrazol-5-yl)- 9-__ethyl-4-oxo-4H-pyrido [1,2-a]pyrimidine A mixture of 0.4 g (0.00175 moles) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 15 ml of di¬ methylformamide, 0.25 g (0.0018 moles) of anhydrous potass- ium carbonate and 0.31 ml (0.0036 moles) of allyl bromide was stirred at 70 °C for 1 hour. The hot reaction mixture was filtered, the filtrate was cooled down and diluted with 20 ml of water, then extracted with 3 x 15 ml of benzene. The combined benzene phases were dried on anhydrous sodium sulfate, filtered and evaporated. The yellow oily crystals were crystallized from ethanol to give 0.2 g (52.0%) of the 1:1 mixture of the title compounds, m.p.. 145-150 °C Analysis: Calculated for C 13 __i2 N 6 0 C = 58.20%; H = 4.51%; N = 31.33%; Found: C = 58.31%; H = 4.59%; N = 31.29%. Example 13 Preparation of 3-(l-methoxycarbonyl-lH-tetrazol-5-yl)-4-oxo- 4H-pyrido[1,2-a]pyrimidine and 3-(2-methoxycarbo-nyl-2H-tet- razol-5-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine A mixture of 1.07 g (0.005 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine; 45 ml of dimethyl- formamide, 0.75 g (0.0055 moles) of anhydrous potassium car¬ bonate and 0.76 ml (0.01 moles) of methyl chloroformate was stirred at 80-90 β C for 6 hours. The hot reaction mixture was filtered, the crystals precipitating from the filtrate were collected to obtain 0.32 g (23.5%) of the 1:1 ratio mixture of the title compounds, which on crystallization from ethanol gave the 3-(l-methoxycarbonyl-lH-tetrazol-5- yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine, m.p.: 182-183 °C Analysis: Calculated for CnHβNgO C = 48.53%; H = 2.96%; N - 30.87%; Found: C = 48.61%; H » 2.91%; N = 30.92%. Example 14 Preparation of 3-(2-methoxycarbonyl-lH-tetrazol-5-yl)-9- methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine and 3-(2-methoxycar- bonyl-2H-tetrazol-5-yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyri¬ midine A mixture of 0.25 g (0.0011 moles) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 10 ml of di- ethylformamide, 0.15 g (0.0011 moles) of anhydrous potass¬ ium carbonate and 0.17 ml (0.0022 moles) of methyl chloro¬ formate was stirred at 80-85 °C for 2 hours. The reaction mixture was diluted with 15 ml of water and extracted with 3 x 15 ml of benzene. The combined benzene phases were dried on anhydrous sodium sulf te, filtered and evaporated. 0.1 g (37.0%) crystals were obtained which were the mixture of the title compounds. The crystals were crystallized from ethanol to obtain yellow crystals of the 3-(lH-tetrazol-5-yl)-9- methyl-4-oxo-4H-pyrido[l,2-a]a]pyrimidine isomer, m.p.: 240 β C (under decomposition) . Analysis: Calculated for C12H1 0 N6O3 C = 52.17%; H = 3.65%; N = 30.42%; Found: C = 52.21%; H = 3.75%; N = 30.28%. Example 15 Preparation of 3-[l-(3-methylbutyl)-lH-tetrazol-5-yl]-4-oxo- 4H-pyrido[l,2-a]pyrimidine and 3-[2-(3-methyl-butyl)-2H- tetrazol-5-yl]-4-oxo-4H-pyrido[l,2-a]pyrimidine A mixture of 1.07 g (0.005 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 15 ml of dimethyl- formamide, 0.70 g (0.005 moles) of anhydrous potassium car¬ bonate and 1,51 (0.O1 moles) of 3-methylbutyl bromide was stirred at 100 °C for 3 hours. The hot reaction mixture was cooled down and diluted with 50 ml of water, then extracted with 3 x 25 ml of benzene. The combined benzene phases were dried on anhydrous sodium sulfate, filtered, and evaporated. 1.12 g (80.0%) oil, the isomeric mixture of the title com¬ pounds was obtained which crystallized upon staying at room temperature, m.p. : 90-95 °C. Analysis: Calculated for C^HigNgO C = 59.14%; H = 5.67%; N = 29.56%; Found: C = 59.30%; H = 5.61%; N = 29.67%. Example 16 Preparation of 3-(l-propargyl-lH-tetrazol-5-yl)-9-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidine and 3-(2-propargyl-2H-tetra- zol-5-yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]-pyrimidine A mixture of 3.42 g (0.O15 moles) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 35 ml of di- methyIformamide, 2.07 g (0.015 moles) of anhydrous potassium carbonate and 3.57 ml (0.03 moles) of propargyl bromide was stirred at 100 °C for 10 hour. The reaction mixture was cooled down and diluted with 100 ml of water. The resulting crystals were collected, washed with water. 2.46 g (61.65%) of an isomeric mixture of the title compounds were obtained, m.p.: 182-184 °C. Analysis: Calculated for C1 3 H1 0 6 O C = 58.64%; H = 3.79%; N = 31.56%; Found: C = 58.52%; H = 3.64%; N = 31.82%. Example 17 Preparation of 3-(l-p-chlorobenzyl-lH-tetrazol-5-yl)-4-oxo- 4H-pyrido[l,2-a]pyrimidine and 3-(2-p-chloro-benzyl-2H-tet- razol-5-yl)-4-oxo-4H-pyrido[1,2-a]-pyrimidine A mixture of 4.28 g (0.02 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 50 ml of dimethyl-for¬ mamide, 2.76 g (0.02 moles) of anhydrous potassium carbonate and 6.0 g (0.04 moles) of p-chlorobenzyl chloride was stirred at 100 °C for 3 hours. The reaction mixture was cooled down and diluted with 100 ml of water. The precipi- tating yellow crystals were collected, washed with water to obtain 4.27 g (63.73%) of the 1:1 mixture of the title com¬ pounds; m.p.: 166-167 °C. Analysis: Calculated for CigHnNgOCl 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 Preparation of 3-(l-isoamyl-lH-tetrazol-5-yl)-9-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidine and 3-(2-isoamyl-2H-tetrazol- 5-yl)-9-methyl-4-oxo-4H-pyrido-[1,2-a]pyrimidine A mixture of 3.42 g (0.015 moles) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine, 30 ml of di- methyIformamide, 2.07 g (0.015 moles) of anhydrous potassium carbonate and 4.53 ml (0.03 moles) of isoamyl bromide was stirred at 100 °C for 3 hours. The reaction mixture was diluted with 100 ml of water. The precipitating brown oil crystallized upon staying. The crystals were collected, washed with water. 2.65 g (59.20%) of a mixture of the title compounds were obtained, m.p.: 124-126 °C. Analysis: Calculated for C sHisNgO - 18 - C = 60 . 39% ; H = 6 . 08% ; N = 28 . 17% ; Found : C = 60 . 08% ; H = 6 . 26% ; N = 28 . 35% . Example 19 Preparation of 3-(l-phenylethyl-lH-tetrazol-5-yl)-9-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidine and 3-(2-phenylethyl-2H- tetrazol-5-y2)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine A mixture of 4.56 g (0.02 moles) of 3-(lH-tetrazol-5- yl)-9-methy1-4-oxo-4H-pyrido[1,2-5]pyrimidine, 60 ml of di¬ methylformamide, 2.8 g (0.02 moles) of anhydrous potassium carbonate and 7.4 ml (0.04 moles) of 2-phenylethyl bromide was stirred at 100 °C for 3 hour. The yellow suspension was poured onto 180 ml of water. The precipitating crystals were collected, washed with water, to obtain 5.84 g (87.82%) of the 3:7 mixture of the title compounds, m.p.. 153-155 °C. Analysis: Calculated for CigHiβNβO C = 65.05%; H = 4.85%; N = 25.29%; Found: C = 65.38%; H = 4.89%; N = 25.44%. Example 20 Preparation of 3-(l-isobutyl-lH-tetrazol-5-yl)-9-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidine and 3-(2-isobutyl-2H-tetra- zol-5-yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine A mixture of 9.13 g (0.04 moles) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 100 ml of di- methylformamide; 5.53 g (0.04 moles) of anhydrous potassium carbonate and 11.0 g (0.08 moles) of isobutyl bromide was stirred at 100 °C for 5 hours. The reaction mixture was diluted with 300 ml of water. The precipitating oil crystal¬ lized upon longer staying and cooling. The crystals were collected, washed with water. 8.28 g (73.34%) of the 3:7 isomeric mixture of the title compounds were obtained, m.p.: 108-109 °C. Analysis: Calculated for C^HigNgO C = 59.57%; H = 5.71%; N = 29.77%; Found: C = 59.87%; H = 5.63%; N - 29.52%. - 19 - Example 21 Preparation of 3-(2-propyl-2H-tetrazol-5-yl)-9-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidine hydrochloride salt 1.5 g (0.0055 moles) of 3-(2-propyl-2H-tetrazol-5-yl)- 9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine was dissolved in 20 ml of abs. ethanol under heating and stirring. To the solution 10 ml of 10% aqueous hydrochloric acid solution was added dropwise. After a few minutes of stirring the mixture was filtered and the filtrate was cooled down. The precipi- tating crystals were collected, 1.50 g (89.29%) of the title compound were obtained in the form of white crystals, m.p.: 198-199 β C. Analysis: Calculated for Cι 3 Hι 5 ClN 6 0 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 Preparation of 3-(2-propyl-2H-tetrazol-5-yl)-9-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidine ethane-sulfonic acid salt 1.5 g (0.0055 moles) of 3-(2-propyl-2H-tetrazol-5-yl)- 9-methyl-4-oxo-4H-pirido[l,2-a]pyrimidine was dissolved in 20 ml of abs. ethanol under heating and stirring at reflux temperature. To the solution 0.6 ml (0.009 moles) of methanesulfonic acid was added dropwise. After a few minutes of stirring the reaction mixture was filtered and the fil¬ trate was cooled down. The precipitating crystals were col¬ lected. 1.77 g (87.84%) of the title compound were obtained in the form of white crystals, m.p.: 154-155 C C. Analysis: Calculated for C14H16N6O4S 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 Hydrochloric acid addition salt of the 3-(2-isopropyl- 2H-tetrazol-5-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine prepared similarly as described in Example 22, is a white crystalline - 20 - material, m.p.: 222°C (under decomposition). Analysis: Calculated for C12H1 3 CIN6O 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 Hydrochloric acid addition salt of the 3-(2-isopropyl- 2H-tetrazol-5-yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine prepared similarly aa described in Example 22, is a white crystalline material, m.p.: 219 °C (under decomposition). Analysis: Calculated for C1 3 H15CIN5O 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. Exam p le 25 Methanesulfonic acid addition salt of the 3-(2-iso- propyl-2H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine prepared similarly as described in Example 23, is a white crystalline material, m.p.: 213-214 °C. Analysis: Calculated for C1 3 H1 5 N 6 O4S C = 44.31%; H = 4.58%; N = 23.85%; Cl = 9.10 Found: C = 44.22%; H = 4.33%; N = 23.52%; Cl = 9.28. Example 26 Methanesulfonic acid addition salt of the 3-(2-isopro- pyl-2H-tetrazol-5-yl)-9-methyl-4-oxo-4H-pyrido-[l,2-a]pyri¬ midine prepared similarly as described in Example 23, is a white crystalline material, m.p.: 155-156 °C. Analysis: Calculated for Ci4HιgNgθ4S 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. Example 27 Hydrochloric acid addition salt of the 3-(2-allyl-2H- tetrazol-5-yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine prepared similarly as described in Example 22, is a white crystalline material, m.p.: 203 °C (under decomposition). Analysis: Calculated for C13H13CIN6O 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 Methanesulfonic acid addition salt of the 3-(2-allyl- 2H-tetrazol-5-yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine prepared similarly as described in Example 23, is a white crystalline material, m.p.: 156-157 β C. Analysis: Calculated for C14H1 6 N6O4S 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. Example 29 Preparation of 3-(l-methyl-lH-tetrazol-5-yl)-6-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidine A mixture of 2.3 g of 3-(lH-tetrazol-5-yl)-6-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidine, 50 ml of dimethylformamide, 1.38 g (0.O01 mole) of anhydrous potassium carbonate and 2.85 g (0.02 moles) of methyl iodide was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room tempera¬ ture and diluted with 150 ml of water. The precipitating crystals were collected. 1.61 g (66.53%) of the title com- pound was obtained, which was crystallized from dimethyl- formamide, m.p.: 232-234 °C. Analysis: Calculated for CnHioNβO C = 54.54%; H = 4.16%; N = 34.69%; Found: C ■ 54.83%; H = 3.76%; N = 34.92%. Example 30 Preparation of 3-(l-butyl-lH-tetrazol-5-yl)-4-oxo-4H-pyrido- [1,2-a]pyrimidine and 3-(2-butyl-2H-tetrazol-5-yl)-4-oxo-4H- pyrido[1,2-a]pyrimidine A mixture of 4,8 g (0.0224 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine, 100 ml of dimethyl- - 22 - formamide, 3.2 g (0.0232 moles) of anhydrous potassium car¬ bonate and 6,13 g (0.0448 moles) of butyl bromide was stirred at 80-85 °C for 3 hours. The reaction mixture was cooled down to room temperature, diluted with 300 ml of water, and extracted with 3 x 25 ml of benzene. The combined benzene phases were dried on anhydrous sodium sulfate, fil¬ tered and evaporated. 4.77 g (78.84%) oil, the isomeric mix¬ ture of the title compounds was obtained which crystallized upon staying at room temperature, m.p.: 98-100 °C. Analysis: Calculated for Cj^H^NgO C = 57.77%; H = 5.22%; N = 31.09%; Found: C = 58.11%; H = 5.22%; N = 31.33%. Example 31 Preparation of 3-(l-isobutyl-lH-tetrazol-5-yl)-4-oxo-4H- pyrido[1,2-a]pyrimidine and 3-(2-iso-butyl-2H-tetrazol-5- y1)-4-oxo-4H-pyrido[1,2-a]-pyrimidine A mixture of 1.07 g (0.005 moles) of 3-(lH-tetrazol-5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 15 ml of dimethyl- formamide, 0.70 g (0.005 moles) of anhydrous potassium car¬ bonate and 1.32 g (0,01 mole) of isobutyl bromide was stirred at 100 °C for 5 hours. The reaction mixture was cooled down to room temperature and diluted with 50 ml of water, then extracted with 3 x 25 ml of benzene. The com- bined benzene phases were dried on anhydrous sodium sulfate, filtered and evaporated. 1.03 g (76.3%) oil, the isomeric mixture of the title compounds was obtained which cry¬ stallized upon staying at room temperature, m.p.. 85-89 °C. Analysis: Calculated for C13H14N6O C = 57.77%; H = 5.22%; N «= 31.09%; Found: C = 57.52%; H = 5.08%; N = 31.25%. Example 32 Preparation of 3-(l-ethyl-lH-tetrazol-5-yl)-6-methyl-4-oxo- 4H-pyrido([l,2-a]pyrimidine and 3-(2-ethyl-2H-tetrazol-5- yl)-6-methyl-4-oxo-4H-pyrido-[1,2-a]pyrimidine A mixture of 2.3 g (0.O1 mole) of 3-(lH-tetrazol-5-yl)- 6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 50 ml of di- methylformamide, 1.38 g (0.01 mole) of anhydrous potassium carbonate and 3.12 g (0.02 moles) of ethyl iodide was stirred at 80 β C for 1 hour. The hot reaction mixture was diluted with 150 ml of water. After longer staying and cool¬ ing a crystalline material precipitated, the crystals were collected, washed with water. 0.63 g (24.6%) of the isomeric mixture of the title compounds was obtained: m.p.: 182-184 °C Analysis: Calculated for C1 H12N6O C = 56.24%; H = 4.72%; N = 32.79%; Found: C = 56.52%; H = 4.81%; N = 32.72%. Example 33 Preparation of 3-(l-ethyl-lH-tetrazol-5-yl)-6-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidine and 3-(2-ethyl-2H-tetrazol-5-yl)- 6-methyl-4-oxo-4H-pyrido[1,2-a]-pyrimidine A mixture of 2.3 g (0.01 mole) of 3-(lH-tetrazol-5-yl)- 6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 8.5 ml (0.05 moles) of triethyl phosphate and 1.38 g (0.01 mole) of anhydrous potassium carbonate was stirred at 280 °C for 30 minutes. The hot reaction mixture was diluted with 150 ml of water, cooled down and extracted with 3 x 30 ml of benzene. The combined benzene phases were decolorized on charchoal, dried on anhydrous sodium sulfate, filtered, and evaporated. To the oily residue 20 ml of diethyl ether was added, the crystalline product was collected. 1.12 g (80.0%) crystals were obtained, which were the 1:4 isomeric mixture of the title compounds, m.p.: 122-130 °C. Analysis: Calculated for C^H^NgO C = 56.24%; H = 4.72%; N = 32.79%; Found: C = 56.11%; H = 4.58%; N = 32.87%. Example 34 Preparation of 3-(l-cyclopentyl-lH-tetrazol-5-yl)-9-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidine and 3-(2-cyclopentyl-2H- tetrazol-5-yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine A mixture of 6.85 g (0.03 moles) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine, 35 ml of dimethyIformamide, 4.17 g (0.03 moles) of anhydrous potass¬ ium carbonate and 8.94 g o£ cyclopentyl bromide was stirred at 100 β C for 5 hours. The reaction mixture was cooled down to room temperature and it was poured onto 450 ml of cold water. The resulting crystals were collected, washed with water. 7.08 g (79.64%) of the 1:4 isomeric mixture of the title compounds were obtained, m.p.: 130-131 °C. (The isomeric ratio was determined on the basis of the ^-Hnmr spectrum) Analysis: Calculated for Ci5Hig N 6 0 C = 60.80%; H = 5.44%; N = 28.36%; Found: C = 60.21%; H = 5.36%; N = 28.36%. Example 35 Preparation of 3-(l-p-nitrobenzyl-lH-tetrazol-5-yl)-6- methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine and 3-(2-p-nitroben- zyl-2H-tetrazol-5-yl)-6-methyl-4-oxo-4H-pyrido[l,2-a]py- rimidine A mixture of 2.28 g (0.O1 mole) of 3-(lH-tetrazol-5- yl)-6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 50 ml of di- methyIformamide, 1.38 g (0.01 mole) of anhydrous potassium carbonate and 3.43 g (0.02 moles) of p-nitrobenzyl chloride was stirred at 100 °C for 3 hours. The reaction mixture was cooled down to room temperature and diluted with 150 ml of water. The crystals, precipitating after longer stay, were collected. 2.26 g (62.26%) of the 3:2 isomeric mixture of the title compounds were obtained; m.p.: 182-184 °C (under decomposition) . Analysis: Calculated for ^7^ 3 ^0 3 C = 56.20%; H = 3.61%; N = 26.98%; Found: C = 56.43%; H = 3.94%; N = 26.46%. Example 36 Formulation Composition of tablets containing 100 mg active ingredient: 3-(2-propyl-2H-tetrazol-5-yl)-9-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidine CMC-Na Lactose Plaster Stearinic acid Magnesium stearate Talc Example 37 Preparation of 3-(2-propyl-2H-tetrazol-5-yl)-6-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidine A mixture of 3.62 g (0.0159 moles) of 3-(lH-tetrazol-5- yl)-6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 30 ml of di¬ methyl formamide, 2.21 g (0.016 moles) of anhydrous potassium carbonate and 3.70 g (0.03 moles) of propyl bromide is stirred at a temperature of 100°C for one hour. The reaction mixture is diluted with 60 ml of water while hot, cooled and shaken three times with 35 ml of benzene each The combined benzene phase is dried over anhydrous sodium sulfate, filtered and evaporated. The oily residue is separated by column chromatography (column: Kieselgel 60, eluent: chloroform and methanol). 2.12 g (57.30%) of the title compound are obtained by recrystal- lizing from diisopropyl ether in the form of a bright yellow crystalline substance which melts at 88-90°C. Analysis: Calculated for C^H^NeO C = 57.77%; H = 5.22%; N = 31.09%; Found: C = 57.83%; H = 5.10%; N = 30.78%. Example 38 Preparation of 3-(l-propyl-lH-tetrazol-5-yl)-6-methyl-4- oxo-pyrido[1,2-a]pyrimidine During the column chromatography separation process described in Example 37 1.20 g (32.43%) of 3-(l-propyl-lH- tetrazol-5-yl)-6-methyl-4-oxo-pyrido[l,2-a]pyrimidine are obtained in the form of a crystalline product which melts at 137-137°C. Analysis: Calculated for C1 3 H14N6O C = 57.77%; H = 5.22%; N = 31.09%; Found: C = 57.53%; H = 4.81%; N = 30.65%. Example 39 Preparation of 3-(2-isopropyl-2H-tetrazol-5-yl)-6-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidine A mixture of 4.60 g (0.0200 moles) of 3-(lH-tetrazol-5- yl)-6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 100 ml of di¬ methyl formamide, 2.76 g (0.020 moles) of anhydrous potassium carbonate and 4.92 g (0.04 moles) of isopropyl bromide is stirred at a temperature of 100 β C for 2 hours. The reaction mixture is diluted with 200 ml of water while hot, cooled and shaken three times with 60 ml of benzene each. The combined benzene phase is dried over anhydrous sodium sulfate, filtered and evaporated. The oily residue is separated by column chromatography (column: Kieselgel 60, eluent: chloroform and methanol). 3.34 g (71.83%) of the title compound are obtained by recrystal- lizing from abs. ethanol in the form of a yellow crystalline substance which melts at 117-118-90°C. Analysis: Calculated for C13H14N6O C = 57.77%; H = 5.22%; N ■ 31.09%; Found: C - 57.66%; H = 5.28%; N = 30.85%. Example 40 Preparation 3-(l-isopropyl-lH-tetrazol-5-yl)-6-methyl-4- oxo-pyrido[1,2-a]pyrimidine During the column chromatography separation process described in Example 38 1.19 g (25.60%) of the title compound are obtained in the form of a crystalline product which melts at 166-167°C. Analysis: Calculated for C^H^NgO C = 57.77%; H = 5.22%; N = 31.09%; Found: C » 57.84%; H = 5.27%; N = 31.51%. Example 41 Preparation of 3-(2-pentyl-2H-t.etrazol-5-yl)-6-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidine A mixture of 2.28 g (0.0100 mole) of 3-(lH-tetrazol-5- yl)-6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 25 ml of di- methyl formamide, 1.38 g (0.010 mole) of anhydrous potassium carbonate and 3.02 g (0.02 moles) of pentyl bromide is stirred at a temperature of 100-110°C for 1 hour. The reaction mixture is diluted with 75 ml of water while hot, cooled under stirring and shaken three times with 60 ml of benzene each. The combined benzene phases are dried over anhydrous sodium sulfate, filtered and evaporated. The oily residue is separated by column chromatography (column: Kieselgel 60, eluent: chloroform and methanol). 1.20 g (44.28%) of the title compound are obtained which is a yel- lowish brown oil at room temperature. Analysis: Calculated for CisHigNgO C = 60.39%; H = 6.08%; N = 28.17%; Found: C = 60.74%; H = 6.12%; N = 28.37%. Example 42 Preparation of 3-(l-pentyl-lH-tetrazol-5-yl)-6-methyl-4- oxo-pyrido[1,2-a]pyrimidine During the column chromatography separation process described in Example 41 0.71 g (26.20%) of the title compound are obtained in the form of a crystalline product which melts at 113-115°C. Analysis: Calculated for CisH gN O C - 60.39%; H = 6.08%; N = 28.17%; Found: C = 61.12%; H ■ 6.17%; N = 28.08%. Example 43 Preparation of 3-(l-ethoxycarbonyl-methyl-lH-tetrazol-5- yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine and 3-(2-ethoxycarbonyl- methyl-2H-tetrazol-5-yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine A mixture of 2.28 g (0.0100 mole) of 3-(lH-tetrazol-5- yl)-6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 25 ml of di¬ methyl formamide, 1.38 g (0.010 mole) of anhydrous potassium carbonate and 5.01 g (0.03 moles) of bromoacetic ethyl ester is stirred at a temperature of 100°C for 1 hour. The reaction mixture is diluted with 75 ml of water while hot. The crystalline substance precipitated during cooling is separated by suction in vacuo. 2.00 g (63.70%) of a 96:4 isomeric mixture of the title compounds are obtained in the form of a crystalline substance which melts at 164-165°C. Analysis: Calculated for Ci4Hi4Ngθ 3 C = 53.50%; H = 4.49%; N = 26.74%; Found: C = 53.39%; H = 4.54%; N = 26.31%. Example 44 Preparation of 3-[l-(4-bromobenzyl)-lH-tetrazol-5-yl]-4- oxo-4H-pyrido[1,2-a]pyrimidine and 3-[2-(4-bromobenzyl)-2H- tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine A mixture of 2.28 g (0.0100 mole) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 50 ml of di¬ methyl formamide, 1.38 g (0.010 mole) of anhydrous potassium carbonate and 2.49 g (0.01 mole) of 4-bromobenzyl bromide is stirred at a temperature of 100°C for 3 hours. The reaction mixture is diluted with 100 ml of water while hot. The crystalline substance precipitated during cooling is separated by suction in vacuo. 3.06 g (77.08%) of a 59:41 mixture of 3-[l-(4- bromobenzyl)-lH-tetrazol-5-yl] and 3-[2-(4-bromobenzyl)-2H- tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine isomers are obtained in the form of a crystalline substance which melts at 166-170°C. Analysis : Calculated for C^H^BrNgO C = 51.40%; H = 3.30%; N = 26.16%; Br = 20.12%; Found: C = 51.81%; H = 3.35%; N = 21.60%. Br = 19.50%. Example 45 Preparation of 3-[l-(3,4-dichlorobenzyl)-lH-tetrazol-5- yl)-4-oxo-4H-pyrido[l,2-a]pyrimidine and 3-[2-(3,4-dichloro- benzy1)-2H-tetrazol-5-y1)-4-oxo-4H-pyrido[1,2-a]pyrimidine A mixture of 2.28 g (0.0100 mole) of 3-(lH-tetrazol-5- yl)-9-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine, 30 ml of di¬ methyl formamide, 1.38 g (0.010 mole) of anhydrous potassium carbonate and 1.95 g (0.02 moles) of 3,4-dichlorobenzyl chloride is stirred at a temperature of 100°C for 3 hours. The reaction mixture is diluted with 100 ml of water while hot. The crystalline substance precipitated is sepa¬ rated by suction in vacuo after cooling. 3.35 g (86.56%) of a 2:1 isomeric mixture of the title compounds are obtained in the form of a crystalline substance which melts at 168-170 β C. Analysis: Calculated for C^H^NgO 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: Claims wherein R means C^.galkyl, C3_galkenyl, C3_galkynyl, 03-7 cyclo¬ alkyl, Cι_4alkoxycarbonyl group or C7_8 aralkyl group, optionally substituted by one or more halogen atom(s) , or by nitro-group and R 1 stands for hydrogen atom or a C^-4 alkyl group and pharmaceutically acceptable salts thereof. 2. Compounds of general formula wherein R means Ci-galkyl, C 3 _galkenyl, C3_galkynyl, C3-7 cyclo¬ alkyl, Cι_4alkoxycarbonyl group or C7__g aralkyl group, optionally substituted by one or more halogen atom(s) , or by nitro-group and R! stands for hydrogen atom or a Cι_4 alkyl group and pharmaceutically acceptable salt thereof. 3. 3-(2-propyl-2H-tetrazol-5-yl)-9-methyl-4-oxo-4H-pyri- do[1,2-a]pyrimidine. 4. 3-(2-isopropyl-2H-tetrazol-5-yl)-9-methyl-4-oxo-4H- pyrido[l,2-a]pyrimidine 5. 3-(2-allyl-2H-tetrazol-5-yl)-9-methyl-4-oxo-4H-pyri- do[1,2-a]pyrimidine 6. 3-(2-isopropyl-2H-tetrazol-5-yl)-4-oxo-4H-pyrido[l,2- a]pyrimidine 7. 3-(l-isopropyl-lH-tetrazol-5-yl)-9-methyl-4-oxo-4H- pyridof1,2-a]pyrimidine 8. A process for the preparation of novel 4-oxo-4H-pyri- do[1,2-a] yrimidines of general formulae (I) and/or (II), wherein R means C^-galkyl, C3_galkenyl, C3_galkynyl, C3-7 cyclo- alkyl, Cι_4alkoxycarbonyl group or C7-8 aralkyl group, optionally substituted by one or more halogen atom(s) , or by nitro-group and R 1 stands for hydrogen atom or a C1-4 alkyl group, and pharmaceutically acceptable salts thereof, which coa¬ prises reacting a 3-tetrazolyl-4-oxo-4H-pyrido[1,2-a]-pyrimi¬ dine of general formula H wherein R 1 is the same as defined above, with a halogenide of general formula R - X (IV) , wherein R means Cι_galkyl, C3_galkenyl, C3_galkynyl, C3_7cyc- loalkyl group or C7-9 aralkyl group optionally substituted by one or more halogen atom(s) or by nitro-group and X stands for a chlorine, bromine or iodine atom; or with a sulphate of general formula wherein R means C^-galkyl, C3_galkenyl, C3_galkynyl, C3.7 cycloalkyl, group or C7-8 aralkyl group, optionally substituted by one or more halogen atom(s) , or by nitro- group; or with a sulfonate of general formula 0 R-0-S-R (VI), 0 wherein R means Cι_galkyl, C3_galkenyl, C3„g alkynyl, C3-7- cycloalkyl group or C7_βaralkyl group, optionally substituted by one or more halogen atom(s) or by nitro group: and R 2 stands for a phenyl, p-methylphenyl or methyl group; or with a phosphate of general formula R - C R-0 - P = 0 (I D . R- CΓ wherein R means C^-galkyl, C3_galkenyl, C3-8 alkynyl, C 3 .7- cycloalkyl group or C7_saralkyl group optionally substituted by one or more halogen atom(s) or by nitro group; or with an ester of general formula wherein R 3 means Ci-^alkyl group, X stands for chlorine or bromine atom, and n is 0 or 1, and, if desired, separating the thus obtained mixture of the isomers of general formulae (I) and (II) , wherein R and R 1 are the same as defined in claim 1, and if desired conver¬ ting the compounds of general formula (I) and (II) or the mixture thereof to their salts, or liberating them from their salts and converting them to another salt. 9. A process claimed in claim 8, which comprises react- ing compounds of general formula (III) , wherein R 1 is the same as defined in claim 8, with compounds of general formulae (IV) or (V) or (VI) or (VII) or (VIII) , wherein R, R 1 , R 2 , R 3 and X are the same as defined in claim 8, in the presence of solvent and acid binding agent. 10. A process claimed in claim 8, which comprises separating the compounds of general formulae (I) and (II) , wherein R and R 1 are the same as defined in claim 1, by a chro atographic method or by crystallization. 11. A pharmaceutical composition which comprises as active ingredient compounds of general formulae (I) and/or (II), wherein R and R 1 are the same as defined in claim 1, or pharmaceutically acceptable salts thereof in admixture with carriers and/or additives commonly used in the pharmaceutical industry.

Inventors: BALOGH MARIA, GYIRES KLARA, HERMECZ ISTVAN, HORVATH AGNES, KAPUI ZOLTAN, KNOLL JOZSEF, PAPP ILONA, SIPOS JUDIT, TARDOS LASZLO, VASVARI LELLE, BALOGH, MARIA, GYIRES, KLARA, HERMECZ, ISTVAN, HORVATH, AGNES, KAPUI, ZOLTAN, KNOLL, JOZSEF, PAPP, ILONA, SIPOS, JUDIT, TARDOS, LASZLO, VASVARI, LELLE
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER- ES VEGYESZETI TERMEKEK GYARA RT
Application year: 1992
Main classification: C07D257
IPC codes: A61K31, A61P1, C07D239, C07D403, C07D471