CS244698B2 - Production method in position 9 substituted derivatives of 4-oxo-4-h-pyrido(1,2-)-pyrimidine - Google Patents

Abstract

Process for the production of the 9-substituted 4-oxo-4H-pyrido pyrimidine derivatives of formula (I) wherein the general symbols are as defined below, as well as their pharmaceutically acceptable salts and optically active antipodes, wherein the compound of formula (II) (II) is reacted with an amine of formula III wherein the general symbols are as defined below, or with a salt thereof, optionally an ester or cyano group in the resulting compound of formula I is saponified or converted into an amide or hydrazine group of the acid, or a compound of formula I is formed wherein R4 = H, benzoyl alternatively, a compound of formula (I) wherein R 4 and R 5 are hydrogen may be reacted with a compound of formula (O-CR 5 R 6) and / or the compound of formula (I) may be converted into a pharmaceutically acceptable salt and / or the racemic mixture formed will be cleaved in its optical antipodes.

Description

-pyrido [1,2-a] pyrimidine

A process for the preparation of the 9-position of substituted 4-oxo-4H-pyrido-pyrimidine derivatives of 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:

(II), is reacted with an amine of formula III

wherein the general symbols are as defined below, or with a salt thereof, optionally the ester or cyano group in the resulting compound of formula I is saponified or converted into an amide or hydrazine acid group, or a compound of formula I wherein R ⁴ = H is benzoylated, optionally, a compound of formula I wherein R ⁴ and r ⁵ is hydrogen is reacted with a compound of formula O-CR 2 R 4, and / or the compound of formula I is converted into a pharmaceutically acceptable salt and / or the resulting racemic mixture is resolved in its optical antipodes.

The invention relates to a process for the preparation of novel, 9-position substituted 4-oxo-4H-pyrido-C1,2-pyrimidine derivatives. In particular, these novel compounds have an antiallergic and anti-asthma effect and can therefore be used as active substances in the respective antiallergic and anti-asthma agents.

It is known that pyrido [1,2-a] pyrimidine derivatives have valuable analgesic and other central nervous system effects (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-4H-pyrido [1,2-a] pyrimidinium methosulfate (PROBON, Rimazolium), (Arzneimittelforschung, 22). 815 (1972)). Pyrido pyrimidine derivatives can be prepared by cyclization of the corresponding dialkyl (2-pyridylaminomethylene) malonate. Other substituted pyrido [1,2-a] pyrimidine derivatives are disclosed in British Patent No. 1,454,312

The compounds which can be prepared by the process according to the invention can be represented by the general formula I (I),

R ¹ O in which

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

is hydrogen, (C1-C4) -alkyl, phenyl, carboxyl, (C1-C4) alkoxycarbonyl, carbomoyl, cyano, formyl, (C1-C4) alkylcarbamoyl, a carboxylic acid hydrazide residue, a group of formula -C-NHN = C (CH 2) _2, or a group of formula

O β 8

- (CH3) -COOR, wherein m is 1 or 2 and R is hydrogen or (C1-C4) alkyl, is hydrogen, (C1-C4) alkyl, benzoyl or tetrazolyl or pyridyl or a group of the formula

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

R ³ is hydrogen, or

5

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

5

R 6 and R 7 together with the nitrogen atom to which they are attached represent a group of the formula -N = CR ⁶ R ⁷ , wherein each of R ⁶ and R ⁷ is hydrogen, C 1 -C 4 alkyl, phenyl or dialkylaminophenyl C1-C4 in each alkyl moiety, or together represent a moiety

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 the compounds of formula (I).

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

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

Preferred representatives of the compounds of the present invention are those compounds of formula (I) wherein:

R is hydrogen,

R ⁴ represents hydrogen or methyl,

R is hydrogen or alkyl, for example methyl,

R is carboxyl, alkoxycarbonyl (preferably methoxycarbonyl or ethoxycarbonyl), carbamoyl, cyano, formyl, alkyl (preferably methyl) or phenyl, and

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

7 is a pyrrolidyl or morpholino group or a group of the formula -N = CRR, wherein r6 is hydrogen and R is an optionally substituted phenyl radical.

of

Particularly preferably R represents a phenyl radical which is optionally substituted by up to 3 substituents in the ortho-, meta- and / or para-position: hydroxyl, halogen, C1-C4 alkyl, sulfonic acid, carboxylic acid or a derivative thereof, C 1 -C 4 alkoxy, amino, mono- or dialkyl (or alkanoyl) C 1 -C 4 amino in each alkyl moiety, nitro or trifluoromethyl.

Particularly advantageous properties are those compounds of formula (I)

Wherein R is hydrogen, R is methyl attached at the 6-position, R is hydrogen,

-4

R is a carboxyl group, R is an optionally substituted phenyl moiety, c

R is hydrogen and pharmaceutically acceptable salts thereof.

The compounds of 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 Formula I containing a carboxyl group or sulfonic acid moiety may form salts with pharmaceutically acceptable bases (e.g., alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, ammonium salts, salts with organic amines (such as triethylamine salts, ethanolamine salts, etc.).

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

(IA)

The structure of tautomers is illustrated by Reaction Scheme A

!

In the compounds shown in Reaction Scheme A, the general symbols are as defined above.

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

in which e ®

3

R, R, R and R are as defined above and

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

with an amine of formula III

HN (III) in which _R 4 _R 5 is as defined above, or with a salt thereof, optionally ester or cyano in the resulting compound of formula I is saponified or converted into an amide or hydrazide group of the acid, or the resulting compound of formula X wherein R is hydrogen, benzoyl, p

or the obtained compound of formula I, in which R and R are hydrogen, is reacted with a compound of formula O = CR ^R R in which R ^ and R? are R?; are as defined above and / or the resulting compound of formula I is converted into a pharmaceutically acceptable salt or 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 such as sodium or potassium bicarbonates, alkali metal salts of weak organic acids such as sodium acetate, or an excess of the general formula III used as starting material are preferably used. The reaction may 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 the reaction medium. 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.

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

The starting amine (III) may also be used in the form of a salt thereof, for example a 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 are often excreted from the reaction mixture of their salts or hydrates and can be separated by filtration or centrifugation. When the reaction is carried out in an aqueous medium, the end 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. When 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 the formula I can be purified by recrystallization, optionally by chromatography.

The compounds of the formula I thus obtained can be converted into another compound of the formula I by known conversions. There may be several transformations over time. Said conversion may be carried out on the groups R ¹ , R ² , R ¹ , R ⁴ and / or R ^1. These subsequent transformations may be carried out by reactions and under the conditions commonly used in reactions of this kind.

The carboxyl group R @ 1 or present in the group R @ ⁴ may 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 appropriate alcohol or phenol in the presence of an acid catalyst, for example concentrated sulfuric acid, or by treatment with a diazoalkane, for example diazomethane or diazoethane.

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

The carboxyl-containing derivative can be converted to 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 may be transesterified by heating with an excess of the corresponding alcohol. The ester of formula (I) may be converted to the corresponding free carboxylic acid by treatment with an acid or an alkali. The alkaline hydrolysis can be carried out by heating with an alkali metal hydroxide in an aqueous or alkanol environment, and the carboxylic acid is liberated from the formed alkali metal salt by acidification. Hydrolysis by mineral acid leads directly to the formation of the free carboxylic acid.

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

The cyano group or present in the group R @ 1 may be converted to a carboxyl group by heating with concentrated sulfuric acid, concentrated hydrochloric acid or concentrated alkali metal hydroxide, or it may be converted to an acid amide (carbamoyl group) by converting the compound subjected to 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 R @ 1 may be converted to a carboxyl group by heating in an alkaline or acidic medium. Hydrolysis of acid amides which are difficult to hydrolyse can be carried out in the presence of nitric acid.

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

The compounds of formula I may be acylated on hydrogen bonded to nitrogen (R ⁵ ) to give 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. Acylating agents are preferably acid halides, for example acid chlorides, anhydrides or reactive esters, for example pentachlorophenyl esters. 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 preferred to carry out this reaction in the presence of a water-binding agent such as dicyclohexylcarbodiimide. The acylation may be carried out using acylating agents and procedures known in the art of peptide chemistry.

5

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

5

The phenyl or naphthyl radicals R and / or R may undergo one or more known transformations. For example, a compound of formula (I) wherein:

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

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

The compound of formula (I) may be liberated from its acid or base salts by methods known per se.

A compound of 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 a compound of the formula I with an appropriate acid, used in equimolar amounts or in excess, in an inert organic solvent.

The compounds of the formula I which contain an acid residue (carboxylic acid or sulphonic acid residue) can be converted into their salts by reaction with an appropriate 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 is other than hydrogen, contain a chiral (asymmetric) carbon and can exist as optically active antipodes or racemate. The optically active antipodes of the aforementioned compounds of formula (I) may be prepared either by using optically active starting materials of formula (II) or by resolution of the racemic compound of formula (I). Compounds of formula I containing a carboxyl group can be resolved into an optically active antipode, 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, whereupon the resulting diastereomeric salt pair members are separated from each other by virtue of their different properties (e.g., crystallization), and then the optically active antipode of formula I is liberated from the salt with a strong base.

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

The compounds of formula I have anti-inflammatory, analgesic, antiatherogenic, soothing properties. effects * inhibit blood clotting in blood vessels, regulate cardiac function and blood circulation, affect central nervous system and have PG-antagonistic, anti-ulcer, 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. As an asthma remedy, disodium chromate glycolate β, 3-bis- (2-carboxychromon-6-yloxy) -2-hydroxypropane, Intal®, is generally used, but is ineffective in oral administration and produces the desired effect only when administered with a complicated therapeutic device. (spinhaler). The novel compounds of formula (I) have been found to treat allergic symptoms both by oral or intravenous administration and by inhalation.

The efficacy of the compounds of formula I has been demonstrated by standard tests to determine antiallergic activity. The PCA assay described by Ovary in J. Immun.

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

Table 1

Tested PCA Church Test

Example compound C. ^ED 50 iv ^ umol.kg after. ^ED 50 iV 1 0.60 1,2 0.31 dinatriumchromo- glycolate 1.00 ineffective 0.84

Pharmacological data

The values of ϋϋϋ for the other compounds of formula (I) examined by the PCA assay are summarized in the following table:

Table 2

Compound 9 - [(2-Carboxyphenyl) hydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 9 - [( 4-ethoxyphenyl) hydrazono] -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-5-carboxylic acid 9-Q4-chlorophenyl) hydrazono] - 6-Methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 9- (3-pyridylhydrazono) -6-methyl-4-oxo 6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid

Εϋ, -θ yumol.kg * i.v.

0.48

1.0

0.53

0.54

The results of the table show that the compounds of the present invention are effective when administered orally, as opposed to disodium chromoglycate, which has been shown to be effective only by intravenous administration, the compounds of Formula I are more potent than the reference compound, even if intravenous:

Toxicity of compounds of formula I is low, the value LD_ _n is generally greater than -1

500 mg.kg p.o. in rat and mouse.

The compounds of formula (I) may be used in therapy in the form of pharmaceutical compositions comprising 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 comprising as an active ingredient a compound of formula I may be formulated in a form suitable for oral or parenteral administration and may be in the form of tablets, dragees, capsules, pills, powder mixes, aerosol formulations, aqueous suspensions or solutions or injectable solutions. or syrups.

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

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

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

Compositions comprising the compounds produced by the method of the invention can also be administered to an organism for treating asthma also by inhalation using conventional inhalation and mist generating devices.

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

Also, the daily dose of the active ingredient may vary within wide limits, and the amount will depend on the condition, age and weight of the patient, the formulation of the composition and the efficacy of the active ingredient. In the case of oral administration, the daily dose of the active ingredient is generally 0.05 to 15 mg.kg ^-1 , while inhaled or intravenously, it is 0.001 to 5 mg.kg ^-1 .

This dose may be administered at once or in several divided doses. The above ranges are for information only and the actual dose used may be lower or higher, as prescribed by the physician and the circumstances of the case.

Further details of the process according to the invention will become apparent from the following examples which illustrate the invention in greater 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 [1,2-a] pyrimidine-3-carboxylic acid. The resulting suspension was stirred for 4 to 5 hours at a temperature in the range of 50 to 60 ° C to form a solution. The pH of the solution was adjusted to 2 by adding dilute (1: 1) aqueous hydrochloric acid solution. The precipitated crystals were 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 [1,2- a] pyrimidine- are obtained. 3-carboxylic acid, m.p. 267-268 ° C.

Example 2

To a suspension of 34.0 g (0.14 mol) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] | Pyrimidine-3-carboxylic acid in dry ethanol (700 ml) was treated with dry hydrogen chloride gas with stirring at 10-15 ° C. After saturation, the solution was allowed to stand overnight in the refrigerator.

The next day, the solvent was distilled off under reduced pressure. The residue is dissolved in 50 ml of water, neutralized by the addition of 5% w / v aqueous sodium carbonate solution and extracted four times with 100 ml of chloroform each. The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure.

After crystallization of the residue from methanol, 18.0 g (48.6%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] ethyl ester is obtained. Pyrimidine-3-carboxylic acid, m.p. 199-200 ° C.

Analysis for ^C 12 ^H 16 ^N 4 ^O 3 Calculated: C 54.54 Found: C 53.88

Example 3

H 6.20 N 21.20% H 6.20 N 21.10%.

To a solution of 2.0 g (7.57 mmol) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester in 20 ml of anhydrous chloroform, 1.6 ml (11.35 mmol) of triethylamine and 1.3 ml (11.35 mmol) of benzoyl chloride are added. The mixture was heated to boiling for two hours, cooled to room temperature and stirred vigorously with 20 ml of water. The organic phase is separated and the aqueous phase is extracted with 10 ml of chloroform.

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

The residue was recrystallized from methanol to give 5 g (53.8%) of 9- (benzoylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [Ί, 2-a | pyrimidine-3-carboxylic acid, m.p. 209-210 ° C.

Analysis for _C19 ^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

Suspension of 2.0 g (7.57 mmol) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester The mixture is heated to boiling in 20 ml of ethanol and 4.0 ml of a 50% w / v aqueous hydrazine hydrate solution are added dropwise. The reaction mixture was then heated to boiling for 15 minutes to form a solution. Cooling down

Čí eliminates crystals.

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

Analysis Calculated for ^C io ^H X4 ^N ° 2 6 Calcd: 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 dimethylsulfoxide was added 2.0 g (7.57 mmol) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] ethyl ester pyrimidine-3-carboxylic acid. 1.2 ml (11.88 mmol) of benzaldehyde was added to the resulting suspension. The reaction mixture was allowed to stand at room temperature for 4 to 6 days to form a solution. This solution is diluted with 20 ml of water and extracted three times with 30 ml of benzene each. The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure. To the remaining dark oil was added 25 mL of diethyl ether to precipitate crystals which were filtered off and washed with a small amount of ether. Yield 2.0 g (75.0%). The final product is a mixture of isomers. Se'od isomers were separated on a plate of silica gel 60 ^PF 254 + 366 ® ^{Rech dimensions} 20 x 20 cm x 1.5 mm), thin layer chromatography Detection reagent: mixture (7: 1) of benzene and methanol: eluent: ( 1:10) of methanol with dichloromethane. The product having a higher R R value is 9- (benzylidenehydrazino) -6-methyl-4-oxo-6,7-dihydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester, m.p. range 142-144 ° C.

Analysis for ^C 20 ^H i9 4 ^N ° 3: Calculated: C 64.77 H 5.72 N 15.89% found C 64.70 H 5.85 N 15.73 d.

The product having a lower R R value is 9- (benzylidenehydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester mp 133-134 ° C. Yield 0.75 g

H, 5.72; N, 15.89. Found: C, 64.43; H, 5.53; N, 15.82%.

Example 6

Dissolve 7.8 g (0.02 mol) of 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-b] ethyl ester in 100 ml of ethanol. a] pyrimidine-3-carboxylic acid. 6.0 ml of 98% hydrazine hydrate was added and the reaction mixture was heated under reflux for 2 hours. On cooling, crystals begin to precipitate, which are filtered off and washed with ethanol. This gave 5.4 g (82.7%) of 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine acid hydrazide. -3-carboxylic acid, m.p. 205-207 ° C.

Analysis for ^{C H} ig | 6 g of ^N ° 2 requires 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 was 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 was stirred at room temperature for 4 hours. The pH of the solution is adjusted to 3 by the addition of an aqueous solution of hydrochloric acid of 10% by weight. 4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl acetic acid, m.p. 161-162 ° C.

Example 8

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 in 15 ml of anhydrous ethanol. To the resulting solution was added 0.012 mol of N-aminopiperidine. The reaction mixture was heated under reflux for half an hour, then the reaction mixture was evaporated under reduced pressure. Dissolution of the residue in methanol and addition of 0.15 ml of 70% strength aqueous perchloric acid solution, filtration of the separated crystals and washing with methanol gave 6-methyl-9- (1-piperidinylimino) -4-oxo-6,7-acid perchlorate. , 8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-

-carboxylic temperature melting v range 177 mp 178 ° C. Yield: 53.7% Analysis for ^m / ^{z 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 9- [4- (4-methylphenylsulfonyl) oxyimino] -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester and 0.47 g of aniline in 20 ml of xylene is heated to boiling for 75 minutes, then the reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated under reduced pressure. 0.8 g of residue is dissolved in methanol and chromatographed on silica gel (Merck 60 F-254) in the form of a plate, using a mixture of benzene and methanol (4: 1) as the solvent system. The spot corresponding to Rf = 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 of o mp 138-139 ° C after recrystallization from ethyl acetate.

Example 10

A solution of 2.1 g of 9- [1,4-methylphenylsulfonyl) oxyimino] -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester and 1.08 g of phenylhydrazine in 40 ml of toluene is heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and the precipitated crystals were 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 addition of an aqueous solution of 20% w / v sodium carbonate. The precipitated oil phase was crystallized by scraping on the wall, yielding 1.4 g of 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-yprido [ethyl] ester, 2-a] pyrimidine-3-carboxylic acid, crystallizing with 1 mole of ethanol. The aqueous phase was shaken with chloroform, the solution was dried and evaporated to dryness to give an additional 3.3 g of the above product. Recrystallization of 1.7 g of the product from 20 ml of ethyl acetate gave ethyl 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine- 3-carboxylic acid, m.p. 137-139 ° C.

object of the invention

Claims (1)

A process for the preparation of the 9-position of substituted 4-oxo-4H-pyrido [1,2-a] derivatives of a pyrimidine of formula 1 O in which is hydrogen or alkyl group with 1 to 4 carbon atoms, is hydrogen or alkyl group with 1 to 4 carbon atoms, is hydrogen or alkyl group with 1 to 4 carbon atoms, is hydrogen, an alkyl group of 1 to 5 carbon atoms 4 carbon atoms, phenyl group carboxyl, C 1 -C 4 alkoxycarbonyl, carbamoyl, cyano, formyl, C 1 -C 4 alkylcarbamoyl, carboxylic acid hydrazide residue, -C-NHN-C (CH) _Q ) _o or a group of formula II ^{J 1} 8 8 - (CE 1) _m "COOR, wherein m is 1 or 2 and R is hydrogen or C 1 -C 4 alkyl, R ⁴ is hydrogen, C 1 -C 4 alkyl, benzoyl or tetrazolyl or pyridyl or a group of the formula 1- (CH 2) -N = C -, wherein p is 4 or 5, or a phenyl or naphthyl radical, z, optionally substituted with 1 to 5 same or different substituents from the group consisting of halogen, C 1 -C 4 alkyl , nitro, carboxyl, hydroxyl, trifluoromethyl, amino, monoalkyl of 1 to 4 carbon atoms in the alkyl or alkanoyl moiety, dialkyl or -alkanoylamino of 1 to 4 carbon atoms in each alkyl or alkanoyl moiety, alkoxy C 1 -C 4, sulfonic acid, sulfonamido, C 1 -C 4 alkanyl, phenyl, phenoxy, cyano and C 1 -C 4 alkylenedioxy, and R ⁵ is hydrogen, or R ⁴ and R 0 together with the nitrogen atom to which they are attached represent a 5- or 6-membered heterocyclic ring optionally containing nitrogen or oxygen as another heteroatom, or R1 and, together with the nitrogen atom to which they are attached, represent a group of the formula -N = CR ^O R ^Z , in which each of R ° and R ^z is hydrogen, C 1 -C 4 alkyl, phenyl or phenyl; a (C 1 -C 4) dialkylaminophenyl group or together represent - (CH ₂ ) 4 -NH-, as well as the pharmaceutically acceptable salts, solvates, stereoisomers, optically active antipodes, geometric isomers and tautomers thereof, The method of claim 1 wherein the compound of formula (II) R, R ¹ , R ² 2 3 R and R are as defined above and L is a leaving group, for example halogen, p-toluenesulfonyloxy or hydroxyl, reacted with an amine of formula III