CS244698B2 - Method for producing 9-substituted 4-oxo-4H-pyrido [1,2-a] pyrimidine derivatives - Google Patents

Abstract

The method for producing 9-substituted 4-oxo-4H-pyridopyrimidine derivatives of the general formula I, in which the general symbols have the meanings given below, as well as their pharmaceutically acceptable salts and optically active antipodes, consists in reacting the compound of the general formula II (II) with an amine of the general formula III, in which the general symbols have the meanings given below, or with a salt thereof, or alternatively, the ester group or cyano group in the resulting compound of the formula I is saponified or converted into an amide or hydrazine acid group, or the resulting compound of the general formula I, where R4 = H, is benzoylated, or alternatively, the compound of the general formula I, where R4 and r5 denote hydrogen, is reacted with a compound of the general formula O-CR^R^, and/or the compound of the formula I is converted into a pharmaceutically acceptable salt and/or the resulting racemic mixture is resolved into its optical antipodes.

Description

-pyrido[1,2-a]-pyrimidine

Process for the production of 9-substituted 4-oxo-4H-pyrido pyrimidine derivatives of general formula I

in which the general symbols have the meanings given below, as well as their pharmaceutically acceptable salts and optically active antipodes, consists in that the compound of general formula II

(II) , reacts with an amine of general formula III

where the general symbols have the meanings given below, or with its salt, optionally the ester group or cyano group in the resulting compound of formula I is saponified or converted into an amide or hydrazine acid group, or the resulting compound of formula I, where R ⁴ = H, is benzoylated, optionally the compound of formula I, where R ⁴ and r5 denote hydrogen, is reacted with a compound of formula O-CR^R^, and/or the compound of formula I is converted into a pharmaceutically acceptable salt and/or the resulting racemic mixture is resolved into its optical antipodes.

The invention relates to a process for the production of new 9-substituted 4-oxo-4H-pyrido Cl,2-pyrimidine derivatives. These new compounds have primarily antiallergic and antiasthmatic effects and can therefore be used as active ingredients in the respective antiallergic and antiasthmatic preparations.

It is known that pyrido[_1,2-a]pyrimidine derivatives have valuable analgesic and other effects acting on the central nervous system (British Patent No. 1,209,946). One of the most preferred representatives of these compounds, used in clinical practice as an analgesic, is 1,6-dimethyl-3-ethoxycarbonyl-4-oxo-4.H-pyrido JjL, 2-aJ pyrimidinium methosulphate (PROBON, Rimazolium) , (Arzneimittelforschung, 22_, p. 815 (1972)). Pyridopyrimidine derivatives can be prepared by cyclisation of the corresponding dialkyl-(2-pyridylaminomethylene)malonate. Other substituted pyrido[_1,2-a]pyrimidine derivatives are described in British Patent No. 1,454,312

The compounds that can be prepared by the process of the invention can be represented by the general formula I (I),

R ¹ O in which

means hydrogen or alkyl group with 1 until 4 atoms carbon means hydrogen or alkyl group with 1 until 4 atoms carbon means hydrogen or alkyl group with 1 until 4 atoms carbon

means hydrogen, an alkyl group with 1 to 4 carbon atoms, a phenyl group, a carboxyl group, an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkoxy part, a carbomoyl group, a cyano group, a formyl group, an alkylcarbamoyl group with 1 to 4 carbon atoms in the alkyl part, a carboxylic acid hydrazide residue, a group of the formula -C-NHN=C(CH^) ₂ or a group of the formula

About β 8

-(CHj)-COOR, where m is 1 or 2 and R is hydrogen or an alkyl group with 1 to 4 carbon atoms, means hydrogen, an alkyl group with 1 to 4 carbon atoms, a benzoyl or tetrazolyl or pyridyl radical or a group of the formula

L(CH ₂ ) p N=C -, where £ represents 4 or 5, or a phenyl or naphthyl radical, which are optionally substituted by 1 to 5 substituents, the same or different, from the group consisting of halogen, alkyl group with 1 to 4 carbon atoms, nitro group, carboxyl group, hydroxyl group, trifluoromethyl group, amino group, monoalkyl- or -alkanoylamino group with 1 to 4 carbon atoms in the alkyl or alkanoyl part, dialkyl- or -alkanoylamino group with 1 to 4 carbon atoms in each alkyl or alkanoyl part, alkoxy group with 1 to 4 carbon atoms, sulfonic acid residue, sulfonamido group, alkanoyl group with 1 to 4 carbon atoms, phenyl residue, phenoxy group, cyano group and alkylenedioxy group with 1 to 4 carbon atoms, and

R ³ represents hydrogen, or

5

R and R together with the nitrogen atom to which they are attached represent a 5- or 6-membered heterocyclic ring which optionally contains nitrogen or oxygen as an additional heteroatom, or

5

R and R together with the nitrogen atom to which they are attached represent a group of the general formula -N=CR ⁶ R ⁷ , where each of the symbols R ⁶ and R ⁷ represents hydrogen, an alkyl group with 1 to 4 carbon atoms, a phenyl group or a dialkylaminophenyl group with 1 to 4 carbon atoms in each alkyl moiety, or together represent a group

5 ^-nh ·

The invention also includes a process for the preparation of pharmaceutically acceptable salts, solvates, optically active antipodes, geometric isomers and stereoisomers and tautomers of compounds of general formula I.

Examples of alkyl groups or alkoxy groups are saturated aliphatic hydrocarbon groups with 1 to 4 carbon atoms in a straight or branched chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl groups.

The term alkanoyl group means formyl, acetyl, propionyl, butyryl and isobutyryl groups.

Preferred representatives of the compounds prepared by the process of the invention are those compounds of general formula I, in which

R represents hydrogen,

R ⁴ represents hydrogen or a methyl group,

R represents hydrogen or an alkyl, for example methyl, group,

R represents a carboxyl group, an alkoxycarbonyl (preferably methoxycarbonyl or ethoxycarbonyl) group, a carbamoyl group, a cyano group, a formyl radical, an alkyl (preferably methyl) group or a phenyl radical and

R ⁴ represents an optionally substituted phenyl or naphthyl radical or a 2-, 34 5- or 4-pyridyl radical, or a group of the formula -NR R represents piperidinyl,

7 pyrrolidinyl or morpholine group or a group of the formula -N=CR R 6 , where R 6 represents hydrogen and R represents an optionally substituted phenyl radical.

from

Particularly preferably, the symbol R represents a phenyl radical which is optionally substituted with up to 3 of the following substituents in the ortho-, meta- and/or para-position: a hydroxyl group, a halogen atom, an alkyl group with 1 to 4 carbon atoms, a sulfonic acid residue, a carboxyl group or a derivative thereof, an alkoxy group with 1 to 4 carbon atoms, an amino group, a mono- or dialkyl (or alkanoyl)amino group with 1 to 4 carbon atoms in each alkyl moiety, a nitro group or a trifluoromethyl group.

Particularly advantageous properties are those compounds of general formula I, in which

2 wherein R represents hydrogen, R represents a methyl group attached at position 6, R represents hydrogen,

-4

R represents a carboxyl group, R represents an optionally substituted phenyl radical, c

R represents hydrogen and pharmaceutically acceptable salts thereof.

The compounds of general formula I form salts with pharmaceutically acceptable organic or inorganic acids, for example hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates or maleates, succinates, acetates, tartrates, lactates, fumarates, citrates, etc.

Compounds of general formula I containing a carboxyl group or a sulfonic acid residue can form salts with pharmaceutically acceptable bases (for example, salts with alkali metals such as sodium or potassium, salts with alkaline earth metals such as calcium or magnesium, ammonium salts, salts with organic amines such as triethylamine salts, ethanolamine salts, etc.).

The invention also includes the production of optical and geometric isomers and tautomers of compounds of general formula I. The structure of geometric isomers is shown by general formulas IA and IB

(IA) (IB)

The structure of the tautomers is illustrated by reaction scheme A

!

In the compounds shown in Reaction Scheme A, the general symbols have the meanings given above.

The process for preparing compounds of the general formula I, their pharmaceutically acceptable salts, hydrates, optically active and geometric isomers, as well as stereoisomers and tautomers, according to the invention consists in allowing a compound of the general formula II to react with

in which e ®

3

R, R, R and R have the meanings given above and

L represents a leaving group, for example halogen, p-toluenesulfonyloxy or hydroxy.

react with an amine of general formula III

HN (III), in which _R 4 _r 5 have the above meaning, or with its salt, optionally the ester group or cyano group in the resulting compound of general formula I is saponified or converted into an amide or hydrazide group of an acid, or the resulting compound of general formula X, in which R represents hydrogen, is benzoylated, with

or the obtained compound of the general formula I, in which R and R are hydrogen, is reacted with a compound of the general formula O=CR^R^, in which R^ and R? have the above-mentioned meaning and/or the resulting compound of the general formula I is converted into a pharmaceutically acceptable salt or is released from the salt and/or the resulting racemic mixture is resolved into its optical antipodes

The reaction is preferably carried out in the presence of an acid-binding agent. For this purpose, alkali metal carbonates, alkali metal bicarbonates, for example sodium or potassium bicarbonates, salts of weak organic acids with alkali metals, for example sodium acetate, or an excess of the general formula III used as starting material are preferably used. The reaction can be carried out in an inert solvent. Aromatic hydrocarbons such as benzene, toluene or xylene, esters such as ethyl acetate, alcohols such as methanol or ethanol, or dimethylformamide are preferably used as reaction media. The reaction is carried out at a temperature of 0 to 200 ° C, preferably at room temperature or with heating or at the boiling point of the reaction mixture.

If compounds of the general formula II in which L represents a hydroxyl group are used as starting materials, the reaction is preferably carried out in the presence of a water-binding agent, for example in the presence of dicyclohexylcarbodiimide.

The starting amine of general formula III can also be used in the form of its salt, for example the carbonate.

The compounds of formula I, prepared as described above, can be isolated from the reaction mixture by methods known per se. The compounds of formula I often precipitate from the reaction mixture of their salts or hydrates and can be separated by filtration or centrifugation. If the reaction is carried out in an aqueous medium, the final product can be extracted from the reaction mixture with a suitable organic solvent, such as benzene, chloroform or ether, and isolated by evaporation of the organic solvent. If the reaction is carried out in an organic medium, the compound of formula I is isolated by removal of the organic solvent. The compounds of formula I can be purified by recrystallization, optionally by chromatography.

The compounds of general formula I thus obtained can be converted into another compound of general formula I by known transformations. Several transformations can be carried out in succession. The said transformation can be carried out on groups with the meanings of the symbols R ¹ , R ² , r\ R ⁴ and/or r\ These subsequent transformations can be carried out by reactions and under conditions conventionally used in reactions of this type.

The carboxyl group represented by R 1 or present in the group represented by R ⁴ can be converted into an alkoxycarbonyl group or an ester group by known esterification reactions. The esterification can be carried out, for example, by reacting the carboxylic acid with the corresponding alcohol or phenol in the presence of an acid catalyst, for example concentrated sulfuric acid, or by the action of a diazoalkane, for example diazomethane or diazoethane.

Compounds containing a carboxyl group may be subjected to decarboxylation by heating to obtain the corresponding compounds containing a hydrogen atom in place of the carboxyl group, the decarboxylation being preferably carried out in the presence of an acid, for example phosphoric acid.

The derivative containing a carboxyl group can be converted into an optionally substituted acid amide by reaction with the appropriate amine. Substituted acid amides can be prepared in a known manner via an active ester, for example ethyl chloroformate.

The ester group R can be transesterified by heating with an excess of the corresponding alcohol. The ester of formula I can be converted to the corresponding free carboxylic acid by the action of acid or alkali. Alkaline hydrolysis can be carried out by heating with an alkali metal hydroxide in aqueous or alkanol medium, and the carboxylic acid is liberated from the resulting alkali metal salt by acidification. Hydrolysis carried out with a mineral acid leads directly to the formation of the free carboxylic acid.

The ester of formula I can be converted into the corresponding acid amide of formula I by reacting it with ammonia in an aqueous alcoholic medium, or it can be converted into the corresponding hydrazide of formula I by reacting it with an optionally substituted hydrazine, such as hydrazine, methylhydrazine or phenylhydrazine.

The cyano group in or present in the group in R^ can be converted into a carboxyl group by heating with concentrated sulfuric acid, concentrated hydrochloric acid or concentrated alkali metal hydroxide, or it can be converted into an acid amide (carbamoyl group) by subjecting the compound to cold acid hydrolysis or alkaline hydrolysis at a temperature of about 50° C. The alkaline hydrolysis is preferably carried out in the presence of hydrogen peroxide.

The carbamoyl group represented by R1 can be converted into a carboxyl group by heating in an alkaline or acidic environment. The hydrolysis of acid amides which are not easily hydrolyzed can be carried out in the presence of nitric acid.

Carboxylic acid hydrazides of the general formula I can be hydrolyzed to the corresponding carboxylic acids of the general formula I by heating in the presence of acid or alkali.

Compounds of formula I can be acylated at the hydrogen bonded to the nitrogen (R ⁵ ) in the presence of the corresponding compounds of formula I containing a formyl, alkanoyl, aroyl or heteroaroyl group. The acylation is carried out by known methods using a suitable carboxylic acid or a reactive derivative thereof. As acylating agent, acid halides, for example acid chlorides, further anhydrides or reactive esters, for example pentachlorophenyl esters, are preferably used. The acylation is preferably carried out in the presence of an acid-binding agent, such as triethylamine. When acylation is carried out with a free carboxylic acid, it is advantageous to carry out this reaction in the presence of a water-binding agent, such as dicyclohexylcarbodiimide. The acylation can be carried out using acylating agents and methods known from peptide chemistry.

5

Compounds of the general formula I, in which R and R are hydrogen, can be condensed with an aldehyde to form the corresponding compound of the general formula I, in which the group -NR R is a group of the general formula -N=CR°R ^/ . The condensation can be carried out in an inert solvent, such as benzene, toluene, at room temperature or with heating. The water formed during the reaction can be removed in the form of an azeotropic mixture or with the help of a water-binding agent. As the aldehyde or ketone, for example, acetone, acetaldehyde or benzaldehyde can be used.

5

The phenyl or naphthyl group in the meaning of the symbol R and/or R can undergo one or more of the known transformations. For example, a compound of the general formula I, in which 4 5

R and/or R represent an unsubstituted phenyl group, can be nitrated with a mixture of nitric acid and sulfuric acid, the nitro derivative thus formed can optionally be reduced, for example by catalytic hydrogenation, and the amino derivative thus obtained can optionally be alkylated or acylated.

These additional transformations described above also fall within the scope of the invention.

The compound of general formula I can be liberated from its salts with an acid or base by methods known per se.

A compound of the general formula I of basic nature can be converted into an addition salt with an inorganic or organic acid. The salt formation can be carried out in a known manner by reacting the compound of the general formula I with the appropriate acid, used in equimolar amounts or in excess, in an inert organic solvent.

Compounds of the general formula I which contain an acid residue (carboxylic acid or sulfonic acid residue) can be converted into their salts by reaction with a corresponding base, for example by reaction with alkali metal hydroxides, alkaline earth metal hydroxides, organic amines, in a manner known per se.

Compounds of formula I in which R and/or R ¹ are other than hydrogen contain a chiral (asymmetric) carbon and may be present in the form of an optically active antipode or a racemate. Optically active antipodes of the above compounds of formula I may be prepared either by using optically active starting materials of formula II or by resolving a racemic compound of formula I. This resolution may be carried out by known methods. Compounds of formula I containing a carboxyl group may be resolved into optically active antipodes, for example, by reacting the racemate with a suitable optically active base, for example, an optically active base, for example, an optically active threo-1-(p-nitrophenyl)-2-aminopropane-1,3-diol, after which the members of the diastereomeric salt pair thus formed are separated from each other on the basis of their different properties (for example, by crystallization) and then the optically active antipode of formula I is released from the salt by reaction with a strong base.

The nitrogen compounds used as starting materials are in part known. The starting compounds of the general formula II are known from the prior art (Arzneimittelforschung, 22, p. 815, 1972) or can be prepared by analogous processes.

Compounds of general formula I have anti-inflammatory, analgesic, antiatherogenic, sedative effects, inhibit blood clotting in blood vessels, regulate cardiac activity and blood circulation, affect the central nervous system and have PG-antagonistic, antiulcer, antibacterial and fungicidal effects and can be used in human and veterinary medicine. Their antiallergic and antiasthmatic effects are particularly pronounced.

Allergic reactions, caused by the interaction of antigens and protective bodies, can occur in various tissues and organs. The most common form of allergy is asthma. Disodium chromium glycolate φ,3-bis-(2-carboxychromon-6-yloxy)-2-hydroxypropane, Intal^J, is generally used as an anti-asthma agent, but it is ineffective when administered orally and produces the desired effect only when administered using a complicated therapeutic device (spinhalator). It has been found that the new compounds of general formula I treat allergic symptoms both when administered orally or intravenously and when administered by inhalation.

The efficacy of the compounds of general formula I was demonstrated by standard tests for determining antiallergic efficacy. The PCA test described by Ovary in the journal J. Immun was used.

81, p. 355 (1958)), and the Church test, described in the journals Britisch J. Pharm. 46, p. 56-66 (1972) and Immunology 29, p. 527-534 (1975). These tests are carried out on rats. The results of the tests are summarized in Table I.

Table 1

Tested Test PCA Church's test

compound from example no. ^ED 50 IV ^umol.kg p.o. ^ED 50 iV 1 0.60 1.2 0.31 disodium chromo- glycolate 1.00 ineffective 0.84

Pharmacological data

The Εϋ^θ values of other compounds of general formula I, examined by PCA test, are summarized in the following table:

Table 2

Compound 9-[(2-carboxyphenyl)hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[Ϊ,2-3 pyrimidine-3-carboxylic acid 9-[(4-ethoxyphenyl)hydrazono]-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-S-carboxylic acid 9-Q4-ochlorophenyl)hydrazono]-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid

Eϋ,-θ yumol.kg * i.v.

0.48

1.0

0.53

0.54

From the results shown in the table it is evident that the representatives of the compounds prepared by the method according to the invention are effective even when administered orally, unlike disodium cromoglycate, which has been shown to be effective only when administered intravenously, the compounds of general formula I are more effective than the reference compound, even when administered intravenously:

The toxicity of compounds of general formula I is low, the LD_ _n value is usually higher than -1

500 mg.kg p.o. in rats and mice.

The compounds of formula I can be used in therapy in the form of pharmaceutical compositions containing these active ingredients in admixture with solid or liquid, organic or inorganic carriers. These compositions are prepared by methods known in the pharmaceutical industry.

Compositions containing as active ingredient a compound of general formula I can be formulated into a form suitable for oral or parenteral administration and can be in the form of tablets, dragees, capsules, pills, powder mixtures, aerosol sprays, aqueous suspensions or solutions or injectable solutions or syrups.

These compositions may contain suitable solid diluents or carriers, sterile aqueous solvents or non-toxic organic solvents. Sweetening or flavoring agents useful for such purposes may be added to the composition for oral administration.

Tablets for oral administration may contain carriers, for example lactose, sodium citrate, calcium carbonate, disintegrating agents such as starch, alginic acid, lubricants, for example talc, sodium lauryl sulfate, magnesium stearate. The carrier in the case of capsules is usually lactose or polyethylene glycol. Aqueous suspensions may contain emulsifying or suspending agents. The diluent for suspensions formed with organic solvents may be ethanol, glycerol, chloroform, etc.

Formulations suitable for parenteral administration or for inhalation include solutions or suspensions of the active ingredient in a suitable medium, such as coconut oil, sesame oil, polypropylene glycol or water. Injectable formulations may be administered intramuscularly, intravenously or subcutaneously. Injection solutions are preferably prepared in an aqueous medium and the pH adjusted to a suitable value. Solutions may be prepared, if desired, in isotonic saline or glucose solution.

Compositions containing compounds produced by the method of the invention can be administered to the body for the treatment of asthma also by inhalation using conventional inhalation and mist-generating devices.

The content of the active ingredient in the pharmaceutical compositions according to the invention can vary within wide limits from 0.005 to 90%.

The daily dose of the active ingredient may also vary within a wide range and its amount depends on the condition, age and weight of the patient, the method of formulation of the preparation and the effectiveness of the active ingredient. In the case of oral administration, the daily dose of the active ingredient is usually 0.05 to 15 mg.kg ^-1 , while in the case of inhalation or intravenous administration it is 0.001 to 5 mg.kg ¹ .

This dose may be administered all at once or in several divided doses. The above ranges are for information only and the actual dose used may be lower or higher, depending on the doctor's prescription and the circumstances of the case.

Further details of the method according to the invention will be apparent from the examples given below, which illustrate the invention in more detail without limiting its scope.

Example 1

To a solution of 0.6 g (0.015 mol) of sodium hydroxide in 25 ml of water is added 3.4 g (0.01 mol) of ethyl 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [i,2-a| pyrimidine-3-carboxylic acid. The resulting suspension is stirred for 4 to 5 hours at a temperature in the range of 50 to 60 °C, whereby a solution is formed. By adding a dilute (1:1) aqueous solution of hydrochloric acid, the pH of the solution is adjusted to 2. The precipitated crystals are filtered off and washed with a small amount of water.

2.7 g (86.4%) of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[jL,2-^a]pyrimidine-3-carboxylic acid with a melting point in the range of 267-268°C are obtained.

Example 2

Dry hydrogen chloride gas is introduced into a suspension of 34.0 g (0.14 mol) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[i,2-a| pyrimidine-3-carboxylic acid in 700 ml of anhydrous ethanol with stirring at a temperature in the range of 10 to 15 ° C. After saturation, the solution is left to stand overnight in a refrigerator.

The next day, the solvent is distilled off under reduced pressure. The residue is dissolved in 50 ml of water, the resulting solution is neutralized by adding an aqueous solution of sodium carbonate with a weight/volume concentration of 5%, and extracted four times with 100 ml of chloroform each time. The combined organic phases are dried over anhydrous sodium sulfate and evaporated under reduced pressure.

After crystallization of the residue from methanol, 18.0 g (48.6%) of ethyl 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[j,2-a]pyrimidine-3-carboxylic acid ester with a melting point in the range of 199-200 °C is obtained.

Analysis for ^C 12 ^H 16 ^N 4^3 calculated: C 54.54 found: C 53.88

Example 3

H 6.10 N 21.20% H 6.20 N 21.10%.

To a solution of 2.0 g (7.57 mmol) of ethyl 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[Q,2-a]pyrimidine-3-carboxylic acid ester in 20 ml of anhydrous chloroform were added 1.6 ml (11.35 mmol) of triethylamine and 1.3 ml (11.35 mmol) of benzoyl chloride. The mixture was heated to boiling for two hours, then cooled to room temperature and thoroughly mixed with 20 ml of water. The organic phase was separated and the aqueous phase was extracted with 10 ml of chloroform.

The combined organic phases are dried over anhydrous sodium sulfate and evaporated under reduced pressure.

The residue was recrystallized from methanol to give 1.5 g (53.8%) of ethyl 9-(benzoylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[Ί,2-a| pyrimidine-3-carboxylic acid ester, melting point 209-210 °C.

Analysis for C ₁₉ ^H 20 ^N 4°4 calculated: c 61.96 found: c 62.02

H 5.47 N 15.20% H 5.58 N 15.61%

Example 4

A suspension of 2.0 g (7.57 mmol) of ethyl 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[Ϊ,2-á]pyrimidine-3-carboxylic acid ester in 20 ml of ethanol is heated to boiling, after which 4.0 ml of an aqueous solution of hydrazine hydrate with a weight/volume concentration of 50% are added dropwise. The reaction mixture is then heated to boiling for 15 minutes, whereby a solution is formed. On cooling

Γ will exclude crystals.

Recrystallization of the crude product from methanol yielded 1.0 g (52.8%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid hydrazide with a melting point in the range of 219 to 220 °C.

Analysis for ^c io ^h x4 ^N 6°2 calculated: C 47.99 found: C 48.43

H 5.64 H 5.67

N 33.58% N 23.59%.

Example 5

To 12 ml of dimethyl sulfoxide are added 2.0 g (7.57 mmol) of ethyl 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [ϊ, 2-á] pyrimidine-3-carboxylic acid ester. To the resulting suspension is added 1.2 ml (11.88 mmol) of benzaldehyde. The reaction mixture is left to stand at room temperature for 4 to 6 days, whereby a solution is formed. This solution is diluted with 20 ml of water and extracted three times with 30 ml of benzene each time. The combined organic phases are dried over anhydrous sodium sulfate and evaporated under reduced pressure. To the remaining dark oil is added 25 ml of diethyl ether, whereby crystals are precipitated, which are filtered off and washed with a small amount of ether. The yield is 2.0 g (75.0%). The final product is a mixture of isomers. The isomers are separated from each other on a silica gel plate 60 ^PF 254+366 ^{( dimensions} 20 x 20 cm x 1.5 mm) by thin layer chromatography. Detection agent: mixture (7:1) of benzene with methanol: eluent: mixture (1:10) of methanol with dichloromethane. The product having a higher R^ value is ethyl ester of 9-(benzylidenehydrazino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid with a melting point in the range of 142 to 144 °C.

Analysis for ^C19H20N403 calculated: C64.77H5.72N15.89% found: ^{C64.70H5.85N15.73 %} .

The product having a lower R^ value is ethyl ester of 9-(benzylidenehydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with a melting point in the range of 133-134°C. The yield is 0.75 g.

Analysis calculated: C 64.77 H 5.72 N 15.89%, found: C 64.43 H 5.53 N 15.82%.

Example 6

7.8 g (0.02 mol) of ethyl ester of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ϊ.,2-a]pyrimidine-3-carboxylic acid are dissolved in 100 ml of ethanol. 6.0 ml of 98% hydrazine hydrate are added to the resulting solution, after which the reaction mixture is heated under reflux for 2 hours. Upon cooling, crystals begin to precipitate, which are filtered off and washed with ethanol. This gives 5.4 g (82.7%) of hydrazide of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [ϊ.,2-a]pyrimidine-3-carboxylic acid with a melting point in the range of 205 to 207 °C.

Analysis for ^c ig ^H |g ^N 6°2 calculated: C 58.89 H 5.56 N 25.57% found: C 59.06 H 5.47 N 25.52%

Example 7

To a solution of 2.15 g (0.036 mol) of potassium hydroxide in 50 ml of water is added 4.3 g (0.012 mol) of ethyl 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido|1,2-a-pyrimidin-3-yl acetic acid and the resulting mixture is stirred for 4 hours at room temperature. Then, by adding an aqueous solution of hydrochloric acid with a mass concentration of 10%, the pH of the solution is adjusted to 3. The precipitated crystals are filtered off and washed with water, thereby obtaining 2.95 g (yield 75.6% of theory) of 6-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido|1,2-a-pyrimidin-3-yl acetic acid with a melting point in the range of 161 to 162 °C.

Example 8

In 15 ml of anhydrous ethanol, 2.2 g (0.01 mol) of 9-hydroxy-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved. To the resulting solution, 0.012 mol of N-aminopiperidine is added. The reaction mixture is heated under reflux for half an hour with stirring, after which the reaction mixture is evaporated under reduced pressure. By dissolving the residue in methanol and adding 0.15 ml of an aqueous solution of perchloric acid with a mass concentration of 70%, filtering off the precipitated crystals and washing them with methanol, 6-methyl-9-(1-piperidinylimino)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid perchlorate is obtained.

-carboxylic about temperature melting in range 177 up to 178°C. The yield corresponds to 53.7% of theory Analysis for / ' ^{x C} 15 ^H 20 ^N 4°3 .hcio ₄ calculated: C 44.51 H 5.23 N 13.84 Cl 8.78 % found: C 44.20 H 5.21 N 13.81 Cl 8.91 %

Example 9

A solution of 1.05 g of ethyl 9-(4-methylphenylsulfonyl)oxyimino-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ester and 0.47 g of aniline in 20 ml of xylene is heated to boiling for 75 minutes, after which the reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated under reduced pressure. 0.8 g of the residue is dissolved in methanol and chromatographed on silica gel (Merck 60 F - 254) in plate form, using a mixture of benzene and methanol (4:1) as the solvent system. The spot corresponding to R^ = 0.65 is dissolved in methanol. The methanol solution was evaporated to give 100 mg of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine-3-carboxylic acid ethyl ester with a melting point between 138 and 139 °C after recrystallization from ethyl acetate.

Example 10

A solution of 2.1 g of ethyl 9-[(4-methylphenylsulfonyl)oxyimino]-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ester and 1.08 g of phenylhydrazine in 40 ml of toluene is heated to boiling for 1 hour. The reaction mixture is then cooled to room temperature and the precipitated crystals are filtered off. The filtrate is evaporated under reduced pressure and the residue is dissolved in 7 ml of 30% w/v ethanolic hydrogen chloride solution. The hydrochloride precipitate is filtered off, suspended in 100 ml of water and the pH of the suspension is adjusted to 8 by adding 20% w/v aqueous sodium carbonate solution. The separated oily phase is brought to crystallization by scraping against the wall, whereby 1.4 g of ethyl ester of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are obtained, crystallising with 1 mol of ethanol. The aqueous phase is shaken with chloroform, the solution is dried and evaporated to dryness, whereby a further 3.3 g of the above product are obtained. Recrystallization of 1.7 g of the product from 20 ml of ethyl acetate gives ethyl ester of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid, melting point between 137 and 139 °C.

Subject matter of the invention

Claims (1)

1. Process for the production of 9-substituted 4-oxo-4H-pyrido[ϊ,2-α] pyrimidine derivatives of general formula 1 About which means hydrogen or an alkyl group with 1 until 4 carbon atoms, means hydrogen or an alkyl group with 1 until 4 carbon atoms, means hydrogen or an alkyl group with 1 until 4 carbon atoms, represents hydrogen, an alkyl group with 1 to 4 carbon atoms, phenyl group a carboxyl group, an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkoxy part, a carbamoyl group, a cyano group, a formyl group, an alkylcarbamoyl group with 1 to 4 carbon atoms in the alkyl part, a carboxylic acid hydrazide residue, a group of the formula -C-NHN-C(CH _Q ) _o or a group of the formula il ^{J 1} 8 8 -(CE^) _m ”COOR , where m represents 1 or 2 and R represents hydrogen or an alkyl group with 1 to 4 carbon atoms, R ⁴ represents hydrogen, an alkyl group with 1 to 4 carbon atoms, a benzoyl or tetrazolyl or pyridyl radical or a group of the formula 1— (CH?) -N=C -, where p represents 4 or 5, or a phenyl or naphthyl radical, of which p is optionally substituted by 1 to 5 identical or different substituents from the group consisting of halogen, alkyl group with 1 to 4 carbon atoms, nitro group, carboxyl group, hydroxyl group, trifluoromethyl group, amino group, monoalkyl- or -alkanoylamino group with 1 to 4 carbon atoms in the alkyl or alkanoyl part, dialkyl- or -alkanoylamino group with 1 to 4 carbon atoms in each alkyl or alkanoyl part, alkoxy group with 1 to 4 carbon atoms, sulfonic acid radical, sulfonamido group, alkanyl group with 1 to 4 carbon atoms, phenyl radical, phenoxy group, cyano group and alkylenedioxy group with 1 to 4 carbon atoms, and R ⁵ represents hydrogen, or R ⁴ and R° together with the nitrogen atom to which they are attached represent a 5- or 6-membered heterocyclic ring which optionally contains nitrogen or oxygen as an additional heteroatom, or R^ and together with the nitrogen atom to which they are attached represent a group of the general formula -N=CR ^O R ^Z , in which each of the symbols R° and R ^z represents hydrogen, an alkyl group with 1 to 4 carbon atoms, a phenyl group or a dialkylaminophenyl group with 1 to 4 carbon atoms in each alkyl moiety, or together represent the group -(CH ₂ ) ^ -NH-, as well as their pharmaceutically acceptable salts, solvates, stereoisomers, optically active antipodes, geometric isomers and tautomers, characterized in that the compound of the general formula II R, R ¹ , R ² 2 3 R and R have the meanings given above and L represents a leaving group, for example halogen, p-toluenesulfonyloxy or hydroxyl, is reacted with an amine of the general formula III