CS244131B2 - Method of substituted pyrido-(1,2-a) pyrimidines production - Google Patents

Description

244131 2

The present invention relates to methods for producing substituted pyrido [1,2-a] pyrimidines (I),

The present invention relates to compounds of formula I

Cu

O

RjOOC

CH-CH-Re α β 3 in which the hydrogen atom, methyl, ethyl or diethylaminoethyl group means a hydrogen atom or a C 1 -C 4 alkyl group means a thienyl group or a phenyl group which may optionally be substituted with chlorine, 1 or 2 methyl groups or 1-3 alkoxy groups having from 1 to 2 carbon atoms, and pharmaceutically acceptable salts thereof.

Compounds of the invention include such pharmaceutically acceptable salts of Formula I, all possible isomers < the cis- or trans-isomers) and their mixtures -CH = CH-Rj preferably have a trans-configuration.

The compounds are referred to herein as 6,7-methylene compounds in order to adopt a uniform nomenclature system which is based on a condensed pyridopyrimidine system. Alternatively, these compounds may be referred to as 1,5-diaza-4-oxo-tricyclo [5.4.0.0] undeca-2,9,11-triene derivatives. The numbering used to indicate the positions of the substituents in the Rj group is conventional, as shown in the following examples: a) when Rj is a phenyl group: 2 b) when Rj is a thienyl group:

The term "particularly" when used herein means convenience or convenience of the object in question. Renl intended as a delicacy of the subject in question in a way that is light.

The alkyl and alkoxy groups may have a long or branched chain.

R 1 is preferably a C 1 -C 4 alkyl group, preferably a methyl, propyl or butyl group.

When R1 is a straight-chain thienyl group, it is preferably a 2-thiyl group. Examples of pharmaceutically acceptable salts are salts of inorganic bases such as sodium, potassium, calcium and aluminum salts, or salts of organic bases such as lysine, triethyl-emine, dibenzylamine, methylbenzylamine, di- (2-ethylhexyl) amine, piperidine , K-ethylpiperidine, Ν, Ν-diethyleminoethylamine, N-ethylmorpholine, beta-phenethylamine, N-benzyl-beta-phenethylamine, N-benzyl-beta-phenethylamine, N-benzyl-N, N-dimethylamine and south acceptable organic amines, as well as salts with inorganic acids such as hydrochloric, hydrobromic and sulfuric acids, and organic acids such as citric acid, tartaric acid, maleic acid, amidic acid, fumaric acid, methanesulfonic acid, and ethanesulfonic acid. Preferred salts are the sodium or potassium salts and such basic ester hydrochlorides, e.g., diethylaminoethyl and dimethyleminoethyl esters.

Particularly preferred compounds of the invention are compounds of formula I wherein R 1 is hydrogen, b 1 is methyl, ethyl or diethylaminoethyl, K 2 is C 1 -C 4 alkyl and R 1 is phenyl. which is either unsaturated or substituted with a chlorine atom, a methyl group, or a C 1 -C 2 alkoxy group, or b '"2-thienyl, and the pharmaceutically acceptable salts thereof.

In preferred compounds of the invention, the group GOOR 1 is a carboxylic acid group. These compounds are then free, acids or salts of carboxylic acids. Examples of particular preferred compounds of the invention are: 2-trans- (2-phenylethylene) -3-propyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid; trans- (2-Phenylethyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (2-methylphenyl)] ethenyl / 3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (3-methylphenyl) ethenyl] - 3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid 2-trans- [2- (4-methylphenyl) ethenyl] -3-ethyl -6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (2-methoxyphenyl) ethenyl] -3-ethyl-6, 7-methylene-4-oxo-4H-pyrido [1,2-i] pyrimidine-7-carboxylic acid 2-trans- [2- (3-methoxyphenyl) ethenyl] -3-ethyl-6,7-methylene-4 -oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid; 2-trans- [2- (2,3-dimethoxyphenyl) ethenyl] -3-ethyl-6,7-methylene- 4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid 2-trans- [2- (2-methylphenyl) ethenyl] -3-propyl-6,7-methylene-4-ox o-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (2,3-dimethoxyphenyl) ethenyl] -3-propyl-6,7-methylene-4-oxo- 4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 244131 4 2-trans- [2- (2-Betoxy-3-ethoxyphenyl) ethenyl] -3-propyl-6,7-methylene- 4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, 2-trans- [2- (2) methoxy-3-ethoxyphenyl) ethenyl] -3-ethyl-6,7-methylene -4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carbonic acid as well as pharmaceutically acceptable salts thereof, especially sodium salts, basic esters (for example esters, 2-diethylaminoethanol) and their alkyl esters with the alkyl group β 1 to 2 carbon atoms.

The compounds of the invention may be prepared by a process characterized in that the compound of formula (IV) is cyclic

O (IV) CH = CH-R 3 wherein R 1, R 1 and B 3 are as defined above, or a salt thereof and, if desired, the compound of formula I obtained is converted to another compound of formula I and / or is If desired, the compound of formula (I) is converted into a pharmaceutically acceptable salt, and / or, if desired, the salt is converted to the free acid, and / or, if desired, the individual isomers are different.

The cyclopropanation of a compound of formula IV can be carried out, for example, by treatment with dimethylsulfoxonium methylide (which is produced, for example, by the method described in J. Chsm. Soc. 1967, 2,495). The treatment is carried out in an inert organic solvent selected from the group consisting of dimethylformamide, dimethylsulfoxide in the range of about 0 ° C to 50 ° C. The reaction time is usually less than 5 hours, and preferably less than 2 hours. Preferably, 1 to 3 moles of reagent is used per nole of the compound of the formula I, in particular 1 to 1.5 mol of the reagent.

As noted above, a compound of formula I can be converted to another compound of formula I by known methods. For example, a compound of formula (I) wherein -COOR is an esterified carboxyl group can be converted to a compound of formula (I) wherein -GOOR1 is a carboxyl group by hydrolysis, for example, by basic hydrolysis, e.g. potassium hydroxide in a solvent such as, for example, water or a lower aliphatic alcohol, the temperature is raised to about 150 ° C. The standing roakeo is cut with the knife, for example, by treatment with lithium bromide in dimethylformamide at a temperature of 50 ° C. *

The compound of general formula Z, in which -OOOR, represents a carboxyl group, can be converted to a compound of formula Z, in which -GOQa, is an erythiocarboxylic group, for example an alkoxy group, by conventional means. For example, and the alkali metal salt is treated and suitably substituted with an alkyl halide in an inert solvent such as acetone, dioxane, dimethylformanide or hexamethylfoafortrlamide, at a temperature ranging from aal to 0 ° to 100 ° C.

The compound of formula Z can also be purified by a) converting a compound of formula Z, in which -COOR, is a carboxyl group to the corresponding halocarbonyl, and preferably chlorocarbonyl derivative, by treatment with, for example, an oxalic acid halide, for example oxelic chloride, thionyl chloride, 5,241,131 chloride phosphorous, phosphorus pentachloride or phosphorus oxychloride. This treatment is carried out either without solvent or in an inert organic solvent such as benzene, toluene, xylene, dioxene, dichloroethene, dichloromethane or tetrahydrofuran, at a temperature in the range of preferably from 0 to about 120 ° C, and then b ') is processed. the resulting helogen carbonyl derivative with a suitable alcohol of the general formula R 1 -OH, in which R 1 is as defined above. This treatment is carried out in an inert solvent such as benzene, toluene, xylene, dioxene, dichloroethane, dichloromethane, or tetrahydrofuran at a temperature in the range of about 0 to about 120 ° C. The treatment is preferably carried out in the presence of a base such as triethylamine or diethylamine. Conventional methods can also be used to convert the compound of Formula 1 into its sd1, convert it into the free acid, and divide the isomer mixtures into individual isomers. The separation of the mixture of optical isomers into individual isomers can be accomplished by making a salt with an optically active base and fractionating the product.

The mixture of geometric isomers can be separated, for example, by fractional crystallization.

Compounds of formula IV may be prepared, for example, by the compound of formula II

O

where

R 1 and R 8 are as defined above, treated with an aldehyde of formula III OHC-R 1 (III) in which

R 1 is as defined above under the above experimental conditions.

The compounds of formula (II) can be prepared, for example, by the cyclization compounds of formula (VI) wherein:

(VI), R 1 and R 1 are as defined above, and f 10 is a hydrogen atom or a lower alkyl group, preferably a methyl or ethyl group. 244131 6

The cyclization of the compound of formula (VI) may be carried out, for example, in the presence of an acid catalyst, such as, for example, polyphosphoric acid (polyphosphoric acid means a mixture of equal parts by weight of 99% phosphoric acid and phosphorus pentoxide), hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and p-toluenesulfonic acid, at temperatures in the range of preferably 90 to 290 ° C. The cyclization may be carried out in an inert organic solvent selected, for example, from the group consisting of an aliphatic alcohol of 1 to 6 carbon atoms, dimethylformamide, dioxane, tetrahydrofuran, benzene, toluene, xylene, acetic acid, ethylene glycol and mixtures thereof. However, the cyclisecession is preferably carried out without solvents.

Compounds of formula (VI) may be prepared by forming a compound of formula (IX)

RtOOC

nh2 (ix) in which

means as above, treated with a compound of formula X COOR, Λ10 CHR „

CO (X) wherein a R 1 is as defined above.

The treatment of a compound of formula IX with a compound of formula X can be carried out, for example, under the same experimental conditions as the aforementioned procyclization of compounds of formula VI.

The compound of formula III is a known compound. It can be produced by conventional methods and is a commercially available product.

The compounds of the invention have antiallergic activity. They are therefore useful in the treatment and treatment of all diseases of allergic origin, such as bronchial asthma, allergic rhinitis (inflammation of the nasal mucosa), hay fever, urticarle (urticaria) and dermetitis (inflammation). /

The anti-allergic activity of the compounds of the present invention is demonstrated by the fact that these compounds are effective in the passive skin anaphylaxis (PCA test) test in rats according to J. Goose A. U. J. N. Blair (Immunology 16,749 (1969)). An important feature of these compounds according to the invention is that they also exhibit high antiallergic activity in oral administration. The following table shows the efficacy in the PCA test in rats following the oral administration of several compounds of the invention, which are identified by codes: K 13 608, PCE 20 909, X 13 830, FCE 20 099, PCE 20 183, PCX 20 461 , respectively. FCE 20 188, as compared to the well-known antiallergic compound DSCG (disodium necromoglycate). 7 24 * 131 The potency is expressed as Kg, which is defined as the dose of the active ingredient that is capable of reducing the effectiveness of the sera used for sensitization by half:

B DH-1 where B is the antagonist compound dose in mg / kg and DB is the dose ratio: antilogarithm of the difference in the function of the log dose of the serum and the bas antagonist compound (JH Gaddum et al., Fixp. Physlol. 40: 9/1955). .

The Kg value is used here because this value is independent of the drug dose and the concentration of reagent used for sensitization. The lower the Κβ value, the higher the anti-allergic activity. The following table identifies the compounds identified by the following codes: K 13 808: 2-trans- (2-phenylethenyl) -3-propyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, K 13 830 : 2-trans- (2-phenylethenyl-3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, FCE 2099: 2-trans- [2- (2-Methylphenyl) ethenyl] -3-propyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, PCE20 183: 2-trans- / 2- (3 -methoxyphenyl) ethenyl) -3-propyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-tarboxylic acid, PCE 20 188: 2-trans- (2-phenylethenyl) -3-propyl- 6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, PCE 20 509: 2-tris- [2- (3-methoxyphenyl) ethenyl] -3-ethyl -6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, PCE 20 461: 2-trans- [2- (2,3-dimethoxyphenyl) ethenyl] -3-Propyl-6,7-methylene-4-oxo- H -pyrido [1,2-a] pyrimidine-7-carboxylic acid

Table

Compound Time before antigen administration Antiallergic activity KB (mg / kg) - p.o. FCE 15 '2.34 K 13 830 15' 1.15 FCE 20 183 15 '1.48 FCE 20 009 15' 2.02 K 13 808 15 '2.16 FCE 20 509 15' 0.61 FCE 20 461 15 '1.22 DSCG 15' over 200

244131

The anti-allergic efficacy has been refined, e.g., by inhibiting IgE-mediated PCA. Qoose and A.M. J. N, Blair (Immunology 16,749 (1969)) using homocytotropic rat antibodies caused by I. Mot ?: Immunology, 681 (1964).

Test compounds were administered per os (p.o.) 18 minutes before entlgen administration. At least 6 rats were used for each dose.

The compounds of the present invention exhibit the same anti-ulcer activity as demonstrated, for example, by demonstrating efficacy in the inhibition of stress-induced ulcers in rats that are kept in a 25 ° C water bath according to the modification of the described Taka-gim K for 40 minutes. and Okabem S. / Jep. J. of Pharmacology 12, 9 (1968).

In addition to antiallergic activity, the compounds of the present invention, in particular the compound of formula I wherein R8 is hydrogen or methyl, are useful as antidiabetic agents. This has been shown, for example, by such compounds being effective in reducing the hyperglycemic effect of glucosamine in mice.

Because of their high therapeutic index, the compounds of the invention can be safely used in medicine. For example, the approximate acute toxicity (LD50) of 2-trana- (2-phenylethenyl) -3-propyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid is higher than 800 mg / kg ( determined by single administration of increasing doses, measured on day 7 after oral administration. Analogous toxicity was found with other compounds of the invention.

The compounds of the invention may be administered in conventional manner. For example, in the treatment of allergies, for example bronchial asthma, orally and parenterally at daily doses of preferably 0.5 to 1) 5 mg / kg, by inhalation at daily doses of 0.5 to 100 mg, more preferably 0.5 to 25 mg, or topical application (e.g., in the treatment of nasal or skin inflammation), for example, as a cream containing 0.5 to 5 mg, preferably 1 to 2 mg, of the active ingredient in 100 mg of cream. In the treatment of diabetes, the compounds of the invention may be administered orally, preferably in daily doses of from 500 to 10000 mg.

The nature of the pharmaceutical compositions which contain the compounds of the invention together with pharmaceutically acceptable carriers or diluents is dependent on the therapeutic use and mode of administration. The compositions may be formulated in conventional manner using conventional additives.

The compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, aerosols as well as powders, tablets, pills, gelatin capsules, syrups, drops, suppositories or lotions (lotions) for topical use.

Thus, for oral administration, the pharmaceutical compositions containing the compounds of the invention are preferably in the form of tablets, pills or gelatin capsules. The active ingredient comprises diluents such as lactose, dextrose, sacherose, mannitol, sorbitol and cellulose, lubricants, for example silica, talc, esters, magnesium or calcium stearate and / or polyethylene glycols. They also contain binders, such as, for example, starches, gelatin, methylcellulose, carboxymethylcellulose, acacia, tragacanth and polyvinylpyrrolidone, disintegrating agents such as microbes, alginic acid, alginates and sodium starch glycolate, effervescent mixtures, dyes, sweeteners, amaccharides. agents such as leclthin, polysorbates and lauryl sulfates and, in general, non-toxic and pharmacologically inactive compounds to be used (See Pharmaceutical Compositions.

Said pharmaceutical compositions may be prepared in a manner known per se, for example by mixing, granulating, tabletting, sugar-coating or film-coating. In the treatment of allergic asthma, the compounds of the invention are also administered as inhalations. Suitable formulations for this use may be suspensions or solutions of the active ingredient, preferably in the form of a salt, such as a sodium salt, in water, when administered by conventional spray. The compositions may also be suspensions or solutions of the active ingredient in a conventional liquid propellant such as dichlorodifluoromethane or dichlorotetrafluoroethane, which are then administered from a pressurized container, for example, an aerosol dispenser. If the drug is soluble in the propellant, it may be necessary to add a solvent, such as ethanol, dipropylene glycol, isopropyl myristate, and / or a surfactant to the composition to suspend the semedicament in the propellant. These surfactants may be any of the surfactants conventionally used for such purposes, such as nonionic surfactants, e.g., lecithin.

The compounds of the invention may also be administered in the form of powders by suitable devices. In this case, the fine powder of the active ingredient may be mixed with a diluent such as lactose.

The compounds of the invention may also be administered by the usual route of intradermal (subcutaneous) or intravenous injection.

In addition to internal administration, the compounds of this invention may be used in topical applications, e.g., creams, lotions or pastes, for the treatment of dermatitis. In the preparation of these compositions, the active ingredient may be mixed with conventional oily or emulsifying agents. The following examples illustrate, but do not limit, the invention. Example 1

Trimethylsulfoxonium iodide (0.7 g) was treated with 50% sodium hydride (0.15 g) in dimethylformamide (30 ml) for 1 hour with stirring at room temperature. Then a solution of 2-trans- (2-phenylethenyl) -3-ethyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid methyl ester (0.5 g, tt) is added. 214-216 ° C) in dimethylformamide (20 mL).

The mixture is reacted for 3 hours at room temperature with stirring. Then the mixture is diluted with ice water and filtered. Crystallization from acetone yields 2-trans- (2-phenylethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid methyl ester (0, 53 g, mp 194-195 ° C). This ester was treated with 1% potassium hydroxide in 95% ethanol (11 mL) for 15 minutes at the boiling point of the reaction mixture. After cooling, the reaction mixture was acidified with acetic acid, evaporated in vacuo and diluted with ice water. The precipitate is filtered off and washed with water until neutral. Crystallization from acetone yields 0.34 g of 2-trans- (2-phenylethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid , tt Mp 215-216 ° C. NMB spectrum (CF 3 COOD): δ: 1.22 (m) and 2.93 (m) (6,7-CH 2 protons), 1.36 (t, CH 2 CH 3). 2.93 (m, CH-GH3). 5.51 (dd, C ^ 6 proton), 7.01 (d, C-9 proton), 7.31 (d, H vinylprotone), 7.63 (br and, phenyl protons), 7.76 (d , vinyl proton).

The following compounds were prepared analogously: 2-trans- (2-Phenylethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 222-224 ° C, MIH spectrum (CP 2 COOD): 6: 1.18 (t) and 2.84 (dd) (6,7-methyleneprotones), 5.44 (dd, C-6 proton), 6 , 95 (d, C-9 proton), 8.18 (d, C-8 proton), 244131 10 2-tris (2-phenylethenyl) -3-propyl-6,7-methylene-4-oxo-4Hipyridone 1,2-e / pyrimidine-7- * arboxylic acid, m.p. 160 ° C (decomposition), NMR spectrum (CF 3 CO 2 D): 6: 1.13 (t, 6,7-methylene proton -CHgClUgBj). 1.60 to 2.00 (m,). 2.76 to 3.02 (m, -CH-C 6 H 4 H), 5.47 (dd, C-6 proton), 6.97 (d, C-9 proton), 7.26 (d, Hp) vinyl proton), 7.38 to 7.80 (m, Ha vinyl proton and phenyl protons), 8.20 (d, C-8 proton), 2-trans- (2-phenylethenyl) -6,7- methylene-4-oxo-4H-pyrrolo [1,2-e] pyrimidine-7-carboxylic acid, m.p. 205 DEG-210 DEG C. (decomposition); and 2-trans- (2-phenylethenyl) -3-butyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 135 ° C (decomposition), NUR spectrum (CF 3 COOB) δ: 1.00 (m, 6,7-methylene proton), 2.90 (m, 6,7-methylene proton and -CH 2 -GtU-GHo -GHj). 5.66 (dd, C-6 proton), 6.95 (d, C-9protone), 8.19 (d, (d, C-8 proton).

Trimethylsulfoxonium iodide (1 g) was treated with stirring at room temperature for 30 minutes, with 509 sodium hydride (0.22 g) in dimethylformamide (30 ml). A solution of the methyl ester of 2-tris (2- (3-methoxyphenyl) ethenyl) -3-ethyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid (tt 177) is then added. to 179 ° C, 1.27 g) in dimethylformamide (20 mL). The mixture was reacted with stirring at room temperature for 2 hours, then diluted with ice water and the precipitate was filtered off. 1.19 g of 2-trans- (2- (3-methoxyphenyl) -ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine methyl ester is obtained. -7-carboxylic acid (mp 184-188 ° C).

This was treated with 0.59 potassium hydroxide for 15 minutes in 959 ethanolic solution (40 ml). After cooling, the reaction mixture was diluted with water, acidified with acetic acid, and the precipitate was filtered off. Crystallization from a mixture of dichloromethane-methanol produces 2-trens (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyrimidine. 7-carboxylic acid (0.65 g), m.p. Mp 184-188 ° C. NMR Spectrum (CF 3 COOD): 6: 1.22 (dd, one of the 6,7-methylene protons), 1.36 (t, -OH 2 -CH 3). 3.96 (m, -CH-CH3 and 6,7-methylene proton), 4.12 (s, OCH3), 5.50 (dd, C-6-ton), 7.03 (d, C -9 proton), 7.36 (d, Hp vinyl proton), 7.68 (d, Ha vinyl proton), 7.18 to 7.70 (m, 4 phenyl protons), 8.26 (d, C- 8 proton), JHo, Hp “H ··

The following compounds were prepared in a similar manner: 2-trans- (2- (2-methylphenyl) ethenyl) -1-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrlmidine-7- carboxylic acid, m.p. 225-227 ° C, 2-trans- (2- (3-methylphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7 carboxylic acid, m.p. 165 ° C (decomposition), 2-trans (2- (3-methylphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7 carboxylic acid, m.p. 140 ° C (decomposition), 2-trans- (2- (4-methylphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyridine-7- carboxylic acid, m.p. 225-239 ° C (decomposition), 2-trans (2- (4-methylphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine-7 carboxylic acid, m.p. 140-150 ° C (decomposition), 2-trans- (2- (2-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine- 7-carboxylic acid, m.p. 208-210 ° C, 11 244131 2-Trens- (2- (2-methoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine-- 7-carboxylic acid, m.p. 130 ° C (decomposed), 2-trens- (2- (2-methylphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7 carboxylic acid, m.p. 140 ° C (decomposition), NMK spectrum (GF 2 COOD): 1.12 (m, 6.7-methylene proton and -CH 2 CH 2 CH 3), 1.73 (m, -CH 2 CH 2 CH 3) . 2.47 (s, -CH2), 2.87 (m, 6,7-methyl-new proton and -CH2CH2CHO). 5.46 (dd, C-6 proton), 6.94 (d, C-9 proton), 7.16 (d, d, Ηβ vinyl proton), 7.96 (d, Ha vinyl proton), 8.19 Cd, C-8 proton), 1H H 16 Hz, 2-trans- (2- (3-methoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1 , 2-a) pyrimidine-7-carboxylic acid, m.p. 130 ° C (decomposition), NMR spectrum (GF 4 COOD) δ: 1.13 (m, 6,7-methylene proton and -CH 2 CH 2 CH 3). 2.88 (m, 6,7-methylene proton and -GH 2 CH 2 CH 3). 5.46 (dd, C-6 proton), 6.97 (d, C-9 proton), 7.18 (d, lovýβ wave proton), 7.64 (d, Ha vinylproton), 8.21 (d , C-8 proton, g = 1.6 Hz, 2-trans- (2- (3-ethoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2 -a) pyrimidine-7-carboxylic acid, m.p. 188-190 ° C, 2-trans- (2- (3-ethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7- carboxylic acid, m.p. 97-102 ° C (decomposition), 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl): 3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine, 7-carboxylic acid, m.p. 188-190 ° C, 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-- 7-carboxylic acid, t. 100-110 ° C (decomposition), 2-trans- (2- (2,5-dimethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 170-173 ° C, NMK spectrum (CF 3 COODbs: 1.20 (m, 6,7-methylene proton), 2.89 (m, 6,7-methylene proton and -CH 2 CH 2 CH 2 CH 2) 5.48 (dd, C-6 proton), 7.00 (d, C-9 proton), 7.45 (d, Ηβ vinyl proton), 7.98 (d, H "vinyl proton), 8, 22 (d, C-8 proton), JH = 16 Hz, 2-trans- (2- / 2,5-dimethoxyphenyl / ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido ( 1,2-a) pyrimidine-7-carboxylic acid, mp 92-195 ° C 2-trans- (2- (2-methoxy-3-ethoxyphenyl) ethenyl) -3-ethyl-6,7-methylene -4-oxo-3H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 180-185 ° C (decomposition), 2-trans- (2- / 2-methoxy-3-ethoxyphenyl / ethenyl) ) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 141-143 ° C, 2-trans- (2- 2-methoxy-3-methoxyphenyl / ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyridine-7-carboxylic acid, mp 181-183 ° C 2-trans- (2- (2,4,5-trimethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7- carboxylic acid, mp 224-226 ° C, 2-trens- (2- (2,4-dimethylphenyl / ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 84-86 ° C 2-trans- (2- (3,4-dimethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo- H -pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 208-209 ° C, 2-trans- (2- (4-methoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7- carboxylic acid, m.p. 180-190 ° C, 244131 12 2-traaa- (2- (4-ethoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-- 7-carboxylic acid, m.p. 235-237 ° C, 2-Traas- (2- (2-ethoxyphenyl) ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7- carboxylic acid, m.p. 178-180 ° C, 2-trans- (2- (3,5-dimethoxyphenyl) ethenyl) -3-propyl-6,7-methylan-4-oxo-4H-pyrido (1,2-a) pyrimidine-- 7-carboxylic acid, m.p. 170-180 ° C, (decomposition), 2-trans- (2- / 2,5-dl-ethylphenyl / ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine-7-carboxylic acid, m.p. 150 ° C (decomposition), 2-trans- (2- (2,5-dimethylphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine- -7-carboxylic acid, m.p. 205-207 ° C, 2-trans- (2- (2-ethylphenyl) ethenyl) -3-butyl-6,7-ethylene-4-oxo-4H-pyrido (1,2-a) pyrinidine-7- carboxylic acid, m.p. 240 ° C (decomposition), 2-tert- (2- (3-methoxyphenyl) ethenyl) -3-butyl-6,7-methylene-4-oxo-4H-pyridO (1,2-a) pyrimidine-7- -carboxylic acid, m.p. 156-158 [deg.] C., 8 [alpha] - (2- (2,3-Diaethoxyphenyl) ethenyl) -3-butyl-6,7-methylene-4-oxo-4H-pyrido [1,2-a] pyridine; 7-carboxylic acid, m.p. 197 DEG-198 DEG C. 2-trans- (2- (2-ethoxy-3-ethoxyphenyl) ethoxy) -3-butyl-6,7-aethylene-4-oxo-4H-pyrido [1,2-a] pyrimidine; -7-carboxylic acid, 1555-157 ° C, 2-trans- (2- (2,3-diethoxyphenyl) ethenyl) -3-propyl-6,7-ethylene-4-oxo-4H- pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 177-179 ° C, Example 3

When proceeding according to Example 2, starting from the appropriate 2-heteroarylethenyl derivatives, 2-trens- (2- (2-thienyl / ethenyl) -3-propyl-6,7-methylene-4-oxo was prepared. -4H-pyrido (1,2-a) pyrinidine-7-carboxylic acid, m.p. Mp 157-162 ° C. Attaches

Following Examples 2 and 3, starting from the appropriate 2-arylethenyl and 2-heteroarylethenyl derivatives, the following compounds are prepared: 2-trans- (2- (2-ethylphenyl) ethenyl) -6,7-methylan- 4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 179 DEG-182 DEG C. 2-trans- (2- (3-ethylphenyl) ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 272-274 ° C, 2-trans-12- (4-ethylphenyl) ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 190-194 ° C, 2-trene- (2- (2-ethoxyphenyl) ethenyl) -6,7-methylene-4-oxo-4K-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 150 ° C (decomposition), 2-trans- (2- (3-astoxyphenyl) ethenyl) -6,7-ethylan-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxy-lvaic acid , t. 204 ° C (decomposition)

Severografia, n. P., MOST

Price 2,40 Kčs> 3,244) 31 2-Trene- (2- / 4-methoxyphenyl / ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7- carboxylic acid, tt 95 DEG-110 DEG C. (decomposition), 2-tren8- (2- (3-chlorophenyl) ethenyl) -6,7-methylene-4-oxo-4H-pyrido [1,2-e] pyrimidine-7-carboxylic acid 209-210 ° C (dec.), 2-trans- (2- / 2,4-dimethylphenyl / ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1,2-e pyrimidine-7-carboxylic acid, mp 199-202 ° C, 2-Trens- (2- (2,5-dimethylphenyl) ethenyl) -6,7-methylene-4-oxo-4H-pyrido (1, 2-a) pyrimidine-7-carboxylic acid, mp 195-200 ° C, 2-trans- (2- (2,3,4-trimethoxyphenyl) ethenyl) -6,7-methylene-4-oxo-4H -pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 180-182 ° C, 2-trans- (2- (2-methylphenyl) ethenyl) -3-methyl-6,7-methylene-4 -oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid, mp 240 ° C (decomposition), 2-trans- (2- (3-methylphenyl) ethynyl) -3-methyl-6, 7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid, m.p. 190-209 ° C (dec.), 2-tran- (2- (4-methylphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid, mp 260-269 ° C (dec.), 2-trans- (2- / 2- methoxyphenylphenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, m.p. 200-209 ° C (decomposition), 2-trens- (2- (3-methoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine- 7-carboxylic acid, m.p. 200 to 209 ° C, 2-trans- (2- (4-methoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7 - carboxylic acid, m.p. M.p. 338 DEG C., 2-trans- (2- (2,4-dimethylphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine; 7-carboxylic acid, m.p. 220-223 ° C (dec.), 2-trans- (2- (2,5-dimethylphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2a) pyrimidine- -7-carboxylic acid, m.p. 235-240 ° C (decomposition), 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-e) pyrimidine-7-carboxylic acid, m.p. 207-209 ° C (decomposition), 2-trans (2- [2,4-dimethoxyphenyl] ethenyl) -3-methyl-6,7-methylene-4-oxo-4U-pyrido [1,2-a] pyrimidine-7-carboxylic acid 2-tris- (2- (2,5-dimethoxyphenyl) ethenyl) -3-methyl-6,7-ethylene-1-oxo-4H-pyrido (1,2-a) pyrimidine Carboxylic acid, m.p. 171 DEG -174 DEG C. (decomposition); 2- (2- (2,4-dimethoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido [1,2 &apos; e) pyrimidine-7-carboxylic acid, m.p. 207-210 ° C (decomposition), 2-trans- (2- (3,4,5-trimethoxyphenyl) ethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido [1,2- e) pyrimidine-7-carboxylic acid, m.p. 175 DEG-280 DEG C. (decomposed) and 2-trans- (2- (2-thienyl) phenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine -7-carboxylic acid, m.p. 208 DEG-211 DEG C. (decomposition). 244131 Example 5 14 2-trans- (2-phenylethenyl) -3-methyl-6,7-methylene-4-oxo-4K-pyrido (1,2-a) pyrimidine-7-carboatylic acid (0.8 g) was treated with methyl iodide (0.55 g) and anhydrous potassium carbonate (0.65 g) in dimethylformamide (7 ml) for 4 hours with stirring at room temperature. The reaction mixture was diluted with ice water and the precipitate was filtered off. Crystallization from acetone yields 0.5 g of methyl 2-trans- (2-phenylethenyl) -3-methyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid. acid, tt Mp 164-165 ° C.

The following compounds were prepared analogously: 2-trans- (2-phenylethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid methyl ester, tt 194-195 ° C, 2-trans- (2-phenylethenyl) -3-butyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid methyl ester, m.p. 112-113 ° C, 2-trans- (2- / 2,5-dimethoxyphenyl / ethenyl) -3-propyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine methyl ester -7-carboxylic acid, m.p. 117-120 ° C and 2-trens- (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyridine (1,2-a) pyrimidine-methyl ester 7-carboxylic acid, m.p. 143-146 ° C. Example 6

If Example 5 is followed and ethanol or ethyl iodide is used, the compound is prepared: ethyl 2-trens- (2- (3-methoxyphenyl) ethenyl-3-ethyl-6,7-methylene-4-oxo-4H) -pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 123-125 ° C Example 7 2-trans- (2- / 2-methylphenyl) ethenyl-3-propyl-4-oxo-4H -pyrido (1,2-a) pyrimidine-7-carboxylic acid (3.6 g) was treated with 1-chloro-2- (diethylamino) ethane (2.7 g) for 8 hours and anhydrous potassium carbonate ( 2.8 g) in dimethylformamide (40 ml) with stirring at 50 [deg.] C. After dilution with water, the precipitated material is filtered off and washed with water until neutral. Crystallization from isopropyl ether produces 2.1 g of 2-diefcylaminoethyl ester 2-trans- (2 - [2-Methyl-phenyl] -ethyl) -3-propyl-4-oxo-4H-pyrido (2-a) pyrimidine-7-carboxylic acid Example 2-trans- (2- / 2,3-dimethoxyphenyl) (ethenyl) -3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carbonic acid (1.2 g) was treated with thionyl chloride (0.6 silos) for 3 hours, dioxane (20 mL) The mixture is then evaporated to dryness in vacuo. The residue was dissolved in dioxane (60 mL) and treated with 2- (diethyl amine) ethanol (1.2 g) at room temperature for 20 hours. After dilution with water, the precipitate is filtered off, dissolved in acetone (100 ml) and treated with a stoichiometric amount of hydrochloric acid in ether. The precipitate is filtered, washed with ethyl ether and dissolved in water.

Alkalization with potassium carbonate, filtration and crystallization from acetone to produce 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl) -3-ethyl-4-oxo-4H-pyrido [eta] < 2 &gt; - (1,2-a) pyrimidine-7-carboxylic acid, m.p. 148-150 ° C. 15 244131 Ex. 1 ad 9

Trimethylsulfoxonium iodide (2.3 g) was treated with 50% aqueous (0.5 g) in dimethylformamide (30 ml) for 1 hour with stirring at room temperature. A solution of 2- (diethylamino) ethyl ester 2- was added thereto. trans- (2- / 2,3-Dimethoxyphenyl) ethenyl) -3-ethyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid (3.5 g) in dimethylformamide (20 mL). The mixture was allowed to react for 90 minutes at room temperature from stirring. Then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and evaporated to dryness in a vacuum. The residue (2.9 g) was purified on a silica gel column eluting with acetone.

1.9 g of 2- (diethylamino) ethyl 2-trans- (2- (2,3-dimethoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido is produced (1 g). 2-a) pyrimidine-7-carboxylic acid oil. N2-sh3 NUK spectrum (SUSO-dg): S: 0.97 (t, -N, 0.95-1.30 (m, 6,7-ethylene ^ ch2-sh3 ^ CH2-fH3

2.54 (q, -ΝΐΓ). 2.70 (t, -OCH 2 -CH 3 -Sg 3 -N 2 CH 2 -H 3), 2.4 ei 2.8 (m, 6,7-methylene> proton and -Stk-CH 3), 3.88 (s , 3.81 (s, -OC 1), 4.22 (t, -O-H 2 -CH 2 -NC), 4.78 (dd, C-6 proton), 6.38 ( d, C-9 proton), 7.18 (d, C-8 proton), 7.39 (d, Hp-vinyl proton), 8.07 (Ho-vinyl proton, 7.18 to 7.46 (m phenyl protons Example 10 2-trans- (2- (2-methylphenyl) ethenyl) -3-propyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid ( 5 g) is treated with sodium bicarbonate (1.25 g) in water (15 ml) at 80 ° C until the work-up is complete, and a precipitate is formed by cooling to not more than 5 ° C, which is filtered off and washed with ice water. sodium αAl 2-trans- (2- / 2-methyl-phenyl / ethenyl) -3-propyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 300 ° C ( 3.9 g).

The following compounds were prepared in an analogous manner: 2-trans- (2-phenylethenyl) -3-methyl-4-oxo-4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid sodium salt, m.p. over 300 ° C and 2-trens- (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine sodium salt -7-carboxylic acid, m.p. than 300 ° C (decomposition). Example 1 2-trans- (2- / 3-methoxyphenyl / ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido- (1,2-arypyrimidine-7-carboxylic acid (1.2%) g) is reacted with thionyl chloride (0.6 ml) in dioxane (12 ml) under reflux for 1 hour, and then the mixture is evaporated to dryness under vacuum and reacted with excess methanol at 50 ° C for 30 minutes, the solution was then evaporated in vacuo and the residue diluted with ice water to give 1.2 g of methyl ester of 2-trifluoro- (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo. -4H-pyrido (1,2-a) pyrimidine-7-carboxylic acid, mp 143-146 ° C Example 12 Tablets, each weighing 150 mg and containing 50 mg active, are prepared as follows. folders:.

Claims (2)

244131 16 Composition (for 10,000 tablets): 2-trana- (2- / 3-methoxyphenyl / ethenyl-3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) pyrimidine) -7-carboxylic acid 500 gcactose 710 gcuric starch 237.5 gmastek powder 37.5 gstearate magnesium 15 g 2-trans- (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene- 4-Oxo-4H-pyrido (1,2-8) pyrimidine-7-carboxylic acid, the lecturer and half of the corn starch are mixed together and passed through a 0.5 mm sieve in warm water (180 ml). the starch is suspended (18 g), the paste obtained is used to grind powder, the granules are dried, spread on a sieve of 1.4 mm mesh size, then the remaining amount of starch, magnesium stearate is added and mixed thoroughly. 8 mm tablets Example 13 2-trans- (2- (3-methoxyphenyl) ethenyl) -3-ethyl-6,7-methylene-4-oxo-4H-pyrido (1,2-a) aerosol composition. pyrimidine-7-carboxylic acid 2% ethanol 10% licithine 0.2% m / m with dichlorofluoromethane and dichlorotetrafluoromethane (70:30 blend) to 100% redefined in a process for the preparation of substituted pyrido (1,2-a) pyrimidine of formula (I) ™ CH-CH-83 P (i) wherein K 1 represents a hydrogen atom, a methyl, ethyl or diethylaminoethyl group, R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, R 1 represents a thienyl group or a phenyl group which may optionally be substituted with chlorine, one or two methyl groups C 1 -C 2 alkoxy groups or pharmaceutically acceptable salts thereof, characterized in that the cyclopropane compound of formula IV is 8,000 "2 CH-CH-RJ17 244131 in which Hp. Hg e Jij is as defined above, or a salt thereof, to form a compound of general formula I, and optionally yielding a compound of formula 1 wherein f 1i is hydrogen is converted to the other compound of formula 1 within other meanings of R 1, the above-mentioned and / or compound of formula X is converted into a pharmaceutically acceptable salt and / or the salt is converted to the free compound and / or isomeric mixture into individual isomers.