CS244699B2 - Production method in position 9 subsituted derivatives of 4-oxo-4h-pyrido(1,2)pyrimidine - Google Patents

Description

The invention relates to a process for the preparation of novel 9-position substituted 4-oxo-4H-pyrido [1,2-a] pyrimidine derivatives. In particular, these novel compounds have an antiallergic and antiasthmatic activity and can therefore be used as active substances in the respective antiallergic and antiasthmatic agents.

Pyrido [1,2-a] pyrimidine derivatives are known to 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, p. 815 (1972)).

Pyrido 1,2-α-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

AND

N _R ^{9 9} Ύΐ2 | < ^{Β Β} 1 o / 1 /,

in which

or alkyl group with 1 to 4 atoms carbon, or alkyl group with 1 to 4 atoms carbon, or alkyl group with 1 to 4 atoms carbon,

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

- a group of the formula - (CH3) -COOR in which m is 1 or 2 and R is hydrogen or C1-C4alkyl, is hydrogen, C1-C4alkyl, benzoyl or tetrazolyl or a pyridyl radical or a group of the formula

L (CH-) -N = C-, wherein? Represents 4 or 5, or a phenyl or naphthyl radical which is optionally substituted by 1 to 5 substituents, the same or different, from the group consisting of halogen, alkyl of 1 to 4 atoms carbon, 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 is hydrogen or together with the nitrogen atom on which are bound, represent a 5 or 6 membered heterocyclic ring optionally containing nitrogen or oxygen as another heteroatom, or together with the nitrogen atom to which they are attached represents a group of the formula

7 6 7

-N = CR R, wherein R and R are each hydrogen, C 1 -C 4 alkyl, phenyl or C 1 -C 4 dialkylaminophenyl in each alkyl moiety, or together represent

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

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

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

An example of a heterocyclic 5 or 6 membered ring optionally containing nitrogen or oxygen as another heteroatom is, for example, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, N-methylpiperazinyl, N-methylpiperazinyl.

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

R is hydrogen,

R ¹ represents hydrogen or methyl,

R is hydrogen or alkyl, for example methyl,

R 6 represents a carboxyl group, an alkoxycarbonyl (preferably methoxycarbonyl or ethoxycarbonyl) group, a carbamoyl group, a cyano group, a formyl radical, an alkyl (preferably methyl) radical or a phenyl radical, and

R represents an optionally substituted phenyl or naphthyl radical or a 2-, 3- or 4-pyridyl group, or

A group of the formula -NR R represents a pyridinyl, pyrrolidinyl or morpholinyl group or a group of the formula -N = CR ⁶ R ⁷ , wherein R ⁶ represents hydrogen and R ⁷ represents an optionally substituted phenyl radical.

R ^{@ 4} is particularly preferably a phenyl radical which is optionally substituted by 1 to 3 of the following substituents in the ortho-, meta- and / or para-position: hydroxyl, halogen, C1-C4alkyl, sulfonic acid radical , carboxyl 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.

Very advantageous properties are those compounds of formula I in which:

2 * 3

R is hydrogen, R is a methyl group bonded at the 6-position, R is hydrogen, R is a carboxyl group, R is an optionally substituted phenyl group, and r5 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 with organic amines such as are triethylamine salts, ethanolamine salts, etc.).

The invention encompasses the compounds of the formula also for the production of optical and geometric isomers and tautomers. The structure of the geometric isomers is represented by the general formulas

(IA)

The structure of tautomers is illustrated by Reaction Scheme A

R ⁴

In the compounds shown in Reaction Scheme A, the general symbols have the meanings given 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 1 stereoisomers and tautomers according to the invention is characterized in that the compound of the formula II

A ²

A ³ (II), in which

R, R ¹ , R ² , R ³ are as defined above, the dashed lines between positions 8 and 9 indicate an additional optional bond, and

L is a leaving group such as halogen, p-toluenesulfonyloxyamino, phenylamino and hydroxy, or a tautomer of a compound of formula II is reacted with a compound of formula III-4 (III) in which

R ⁴ and R ⁵ are as hereinbefore defined, and the optionally formed intermediate of formula IV

(IV),

R ¹ , R ² , R ³ ,

R ⁴ , r ⁵ and the dashed line are as defined above, subjected to oxidation, optionally the ester or cyano group in the resulting compound of formula I is saponified or converted into an amide or hydrazide group of the acid, or the resulting carboxylic acid of formula I is converted into an ester; the compound of formula (I) in which R ⁴ is hydrogen is benzoylated, or the resulting compound (5) of formula (1) in which R is hydrogen and R is hydrogen, optionally reacted with a compound of formula (O) and / or converting the obtained compound of formula (I) into a pharmaceutically acceptable salt or liberating it from the salt and / or resolving the racemic mixture formed into its optical antipodes.

In the starting compound of formula II, L is a conventional leaving group such as halogen, for example chlorine or bromine, an alkylsulfonyloxy group such as methanesulfonyloxy group, further optionally substituted arylsulfonyloxy group, for example p-toluenesulfonyloxy or p-bromophenylsulfonyloxy or p-toluenesulfonyloxy or p-toluenesulfonyloxy.

The reaction of the compound of formula II with the compound of formula III is preferably carried out in the presence of an acid binding agent. For this purpose, alkali metal carbonates or bicarbonates such as sodium or potassium carbonate or bicarbonate, alkali metal salts of weak organic acids such as sodium acetate, or an excess of the amine used as starting material of the formula III can be advantageously used.

The reaction may be carried out in an inert solvent. Aromatic hydrocarbons such as benzene, toluene, xylene, or esters such as ethyl acetate or alcohols such as methanol or ethanol are preferably used as the reaction medium.

Dimeylformamide may also be used. The reaction is carried out at a temperature in the range of 0 to 200 ° C, preferably at room temperature or with heating or at the boiling point of the reaction mixture.

The intermediates of formula (IV) are preferably not isolated but the reaction mixture containing them is treated with atmospheric oxygen at room temperature or with heating to oxidize.

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

The compounds of formula I prepared as described above can be isolated from the reaction mixture by methods known per se. The compounds of the formula I are often excreted from the reaction mixture in the form 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 formula (I) may be purified by recrystallization or chromatography.

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

The carboxyl group or present in the group R ⁴ may be converted into an ester or alkoxycarbonyl 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 may be subjected to decarboxylation by heating to give 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 carboxyl-containing derivative can be converted to an optionally substituted acid amide by reaction with the appropriate amine. Substituted acid amides can be prepared by a known method via an active ester, for example ethyl chloroformate.

The ester group in the meaning of the symbol can 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 alkane medium, and the carboxylic acid is liberated from the formed 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 to the corresponding acid amide of formula I by reacting with ammonia in an aqueous alcoholic medium, or can be converted to the corresponding hydrazide of formula I by reacting with an optionally substituted hydrazine, such as hydrazine, methylhydrazine or phenylhydrazine.

4 • The cyano group R or present in the group R can be converted to 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), thereby by subjecting the compound to cold acidic 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.

Compounds of formula (I) may be acylated on hydrogen bonded to nitrogen 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 the acylation is carried out with a free carboxylic acid, it is preferred to carry out the 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 wherein R and R are hydrogen may be condensed with an aldehyde to give the corresponding compound of formula I wherein the -NR R group is -N-CR ^b R ^z . The condensation may be carried out in an inert solvent such as benzene or 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.

The phenyl or naphthyl radical R may be subjected to one or four more transformations. For example, a compound of formula I in which R is unsubstituted phenyl may be nitrated with a mixture of nitric acid and sulfuric acid, the resulting nitro derivative may optionally be reduced, for example by catalytic hydrogenation, and the resulting amino derivative 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 to an inorganic or organic acid addition salt. The salt formation can be carried out in a manner known per se by reacting a compound of formula I with the appropriate acid, used in equimolar or in excess, in an inert organic solvent.

Compounds of formula (I) which contain an acid residue (carboxylic or sulfonic acid residue) can be converted into their salts by reaction with an appropriate base, for example an alkali metal hydroxide, alkaline earth metal hydroxide, organic amine 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 exist as an optically active antipode 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) _Z or by resolution of a racemic compound of formula (I). Compounds of Formula I a carboxyl group can be resolved into an optically active antipode, for example by reaction of a racemate with a suitable optically active base, such as an optically active threo-1- (p-nitrophenyl) -2-aminopropane-1,3-diol, whereupon the diastomeric pair members thus formed the salts are separated by virtue of their different physical properties (e.g. crystallization), and then the optically active antipode of formula I is liberated from the salt by reaction with a strong base.

The nitrogen compounds used as starting materials of formula II can be prepared from analogous compounds containing hydrogen instead of leaving group L by halogenation. >

These starting materials are known in the art (Arzneimittelforschung, 22, p. 815 (1972)) or can be prepared by analogous procedures. The starting compounds of formula III are known from the literature and are generally commercially available or can be prepared from commercially available compounds by methods known per se.

The compounds of formula I have anti-inflammatory, analgesic, antiatherogenic, calming effects, inhibit blood clotting in the blood vessels, regulate cardiac activity and circulation, affect the central nervous system and have PG-antagonistic, anti-ulcer, antibacterial and fungicidal effects and can therefore 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 r-R τ [1,3-bis- (2-carboxychromon-6-yloxy) -2-hydroxypropane, Intal J, is generally used but is ineffective when administered orally and produces the desired effect only when applied using a complicated therapy device (spinhaler). The novel compounds of formula I have been found to treat allergic syndromes when administered orally or intravenously, or by inhalation.

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

81, p. 355 [1958], and the Church test described in British J. Pharm., 46, pp. 56-66 (1989) and Immunology, 29, pp. 527-534 (1975)]. These tests are performed in rats. The test results are summarized in Table 1.

Table I

The test compound of Example no.

disodium chromoglycolate test compound of example no.

Test PCA

EDgo /imol.kg ⁴

i.v. after.

0.60 1.2

1.00 Ineffective PCA Test Percentage Effectiveness For Single Dose 320yUmoles.kg ⁴

Church test ed 5Q _from umolu.kg ⁴ i .v.

0.31

0.84 released histamine in vltro

EC ⁴ g / µmol ⁴

Pharmacologic data

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

Compound

ED? Is _from umoles. kg 9 - [(2-carboxyphenyl) hydrazono] -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 0,48 kg 9 - [(4-ethoxyphenyl) hydrazono] -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 9- [ (4-chlorophenyl) hydrazono] -6-methyl-4-oxo-6,7,8,9 ^{<-etrahydro-4H-pyrido} [l, 2-aJ pyrimijlin-3-carboxylic acid, 9- 0.53 ( 3-pyridylhydrazono) -6-methyl-4-ΟΧΟ-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 0.54

From the results shown in the table, it is evident that representatives of the compounds prepared by the process of the invention are also effective when administered orally, as opposed to disodium chromoglycolate, which has proved to be effective only when administered intravenously. Compounds of formula I are more potent than said reference compound, even when administered intravenously.

Toxicity of compounds of formula I is low, the value LD_ _n is typically greater than

-1 ^υ 500 mg.kg po in rat and mouse.

The compounds of formula (I) may be used in the form of pharmaceutical compositions containing the 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 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 sprays, aqueous suspensions or solutions or injectable solutions or syrups. These compositions may contain suitable solid diluents or carriers, a sterile aqueous solvent or a 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, for example lactose, sodium citrate, calcium carbonate, disintegrants such as starch, alginic acid, glidants, for example 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 containing the compounds produced by the method of the invention may also be administered to an organism for treating asthma also by inhalation using conventional inhalation and fog 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 formulation and the efficacy of the active ingredient. In the case of oral administration, the daily dose of active ingredient is generally 0.05 to 15 mg.kg ^A , while when administered by inhalation or intravenously it is 0.001 to 5 mg.kg

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.

He did

6.3 g (0.02 mol) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine ethyl ester are dissolved in 30 ml of anhydrous ethanol. -3-carboxylic acid and 4.3 ml (0.044 mol) of phenylhydrazine are added. The reaction mixture was heated at reflux for 4 hours, after which time the solvent was distilled off under reduced pressure. 30 ml of water and 15 ml of chloroform were added to the residue, and the pH of the aqueous layer was adjusted to 2-3 by addition of an aqueous solution of 10% w / v hydrochloric acid with stirring. The organic layer was separated and the aqueous layer was extracted twice with 15 ml of chloroform each. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The remaining red oil crystallized from two to three times the amount of ethanol.

Yield: 5.3 g (68.6%), m.p .: 86-87 ° C.

The product obtained crystallizes with 1 mole of ethanol, which can be removed by drying under reduced pressure over phosphorus pentoxide at a temperature of 90 to 100 ° C. The melting point of the dried 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester is in the range 138-139 ° C. .

Example 2

2.5 g (0.01 mol) of 9-hydroxy-6-methyl-4-oxo-6,7-dihydro-4H-pyrido [1,2-a] pyrimidine ethyl ester are dissolved in 7.5 ml of anhydrous ethanol. -3-carboxylic acid and 1.2 ml (0.012 mol) of phenylhydrazine are added. The reaction mixture is heated to boiling for half an hour and then allowed to cool. Orange crystals are separated.

Yield: 3.5 g (90.6%) Melting point: 86-87 ° C.

The product crystallizes with 1 mole of ethanol, which can be removed by drying under reduced pressure over phosphorus pentoxide at a temperature of 90 to 100 ° C. The melting point of dried 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester is in the range of 138-139 °. C. Addition of the product to the compound of Example 1 does not reduce the melting point.

Example 3

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 at 50-60 ° C for 4-5 hours 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-3-carboxylic acid are obtained. mp 267-268 ° C.

Example 4

To 780 mL of methanol was added 80.0 g (0.28 mol) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine- 3-carboxylic acid, then 155 ml of a 50% w / v aqueous solution of hydrazine hydrate are rapidly poured into the resulting suspension while stirring. This warms the reaction mixture and forms a solution. The reaction mixture is then stirred at room temperature for 2 to 3 hours and the crystals formed are filtered off.

The filtered hydrazinium salt is dissolved in 400 ml of water and acid is added by adding an equivalent amount of solid potassium bisulfate. The precipitated crystals are filtered off, washed with a little water and dried. Recrystallization from 50% aqueous ethanol gave 40.2 g (60.8%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] -2- 202- 203 ° C.

Analysis for ^{C 10 H} 12 ^N 4 ° 3

Calculated: C 50.84 H 5.12 N 23.72%

Found: C 50.46 H 5.30 N 23.68%.

Example 5

To a suspension of 34.0 g (0.14 mol) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridof1,2-a] pyrimidine-3-carboxylic acid in 700 ml of anhydrous ethanol was treated with dry hydrogen chloride gas with stirring at 10-15 ° C. After saturation, the solution was left in the refrigerator overnight.

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.

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

Calculated: C 54.54

Found: C, 53.88

H 6.20 N 21.20% H 6.20 N 21.10%.

Example

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 2 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 1.5 g (53.8%) of 9- (benzoylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] ethyl ester. M.p. 209-210 ° C, 2-a] pyrimidine-3-carboxylic acid.

Calculated: C 61.96

Found: C, 62.02

Example 7

H 5.47 N 15.20%

H 5.58 N 15.61%

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 a suspension Heat 20 ml of ethanol to boiling, then add 4.0 ml of a 50% w / v aqueous hydrazine hydrate solution dropwise. The reaction mixture was then heated to boiling for 15 minutes to form a solution. By cooling, crystals precipitate.

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

Analysis for ^C 10 ^H 14 ^N 6 ° 2

H, 5.64; N, 33.58.

Found: C 48.43 H 5.67 N 23.59%.

Example 8

To a solution of 4.0 g (12.73 mmol) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester in 20 ml of ethanol, 8.0 ml of an aqueous solution of 50% w / v hydrazine hydrate was added dropwise with stirring. The reaction mixture was stirred at room temperature for 2 hours. The precipitated crystals are filtered off, washed with a small amount of ethanol and dried. Recrystallization from ethanol gave 1.6 g (50.2%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine acid hydrazide M.p. 219-220 ° C. Adding the resulting product to the compound of Example 7 does not reduce the melting point.

Example 9

To 12 ml of dimethyl sulfoxide 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 4-6 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. The isomers were separated on a plate of silica gel 60 F254 + 1 366 ^{rec-h dimensions} 20 x 20 cm x 1.5 mm) by thin layer chromatography. Detection reagent: mixture of (7: 1) benzene with methanol; eluent: a mixture (1:10) of methanol with dichloromethane. The product having a higher R ^ value is 9- (benzylidenehydrazino) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid ethyl ester o m.p. 142-144 ° C.

Analysis for ^C 19 ^H 20 ^N 4 ° 3

Calculated: C 64.77 H 5.72 N 15.89%

Found: C 64.70 H 5.85 N 15.73%

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

Yield 0.75 g

Analysis for ^C 19 ^H 20 ^N 4 ° 3

H, 5.72; N, 15.89

Found: C 64.43 H 5.53 N 15.82 i.

Example 10

7.8 g (0.02 mol) of 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] -2- (4-oxo-4-oxo-4-oxo) -acetate are dissolved in 100 ml of ethanol. and 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. There was thus obtained 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine acid hydrazide (5.4 g, 82.7%). M.p. 205-207 ° C.

Analysis for ^{C H} ig jg 6 ^N ° 2

Calculated: C 58.89 H 5.56 N 25.75%

Found: C 59.06 H 5.47 N 25.52%.

Example 11

10.0 g (34.95 mmol) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] -2-oxo-6-amide was dissolved in 150 ml of methanol. a] pyrimidine-3-carboxylic acid. A solution of 20 ml of hydrazine hydrate was carefully added dropwise over 10 minutes with stirring. The reaction mixture was heated at reflux for 40 minutes, after which methanol was distilled off under reduced pressure. The precipitated crystals are filtered off, washed with water and recrystallized from water. This afforded 3.8 g (46.5%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine- 248 DEG-250 DEG.

Analysis for ^C iq i3 ^H 2 ^N ° 5

Calculated: C 51.06 H 5.57 N 29.77%

Found: C 50.59 H 5.46 N 29.85%.

Examples 12 to 14

2.9 g (0.01 mol) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid amide was Dissolve in 20 ml of methanol and add 0,025 mol of the hydrazine derivative listed in Table II. The reaction mixture is stirred at the boiling point for 1 to 3 hours, after which time the product is filtered off or isolated by evaporation. The product can be recrystallized from water.

Examples 15 and 16

2.9 g (0.01 mol) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid is dissolved in 20 ml of methanol and 0.025 mol of the hydrazine derivative listed in Table III is added to the solution. The reaction mixture is then heated to boiling for 1 to 3 hours. The resulting product is either filtered off or isolated by evaporation and can be recrystallized from water.

Example 17

5.7 g (0.02 mol) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] is dissolved in 30 ml of anhydrous ethanol. pyrimidine-3-carboxylic acid, then 4.3 ml (0.44 mol) of phenylhydrazine are added. The reaction mixture was heated to reflux for 4 hours with stirring, the precipitated crystals were then filtered off and washed with ethanol. This afforded 4.7 g (75.2%) of 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine- M.p. 258 DEG-260 DEG. Recrystallization from dimethylformamide raises the melting point to 267-268 ° C.

Example 18

2.2 g (0.01 mole) 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. Phenylhydrazine (1.2 mL, 0.012 mol) was added to the resulting solution. The reaction mixture was then heated under reflux for half an hour. The precipitated crystals are filtered off and washed with ethanol. This afforded 2.4 g (76%) of 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3- m.p. 267-268 ° C (from dimethylformamide).

Example 19

The procedure is as in Example 17 except that (-) - 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3 is used. -45 ° (c = 1, methanol).

There was thus obtained (+) - 9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid. Yield 76.0 g, mp 256-257 ° C.

[(c = 2, dimethylformamide)

Example 20

To 20 ml of acetone was added 0.5 g of 9- (phenylhydrazino) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3- acid hydrazide. carboxyl. The reaction mixture was heated to boiling for 3 hours with vigorous stirring. It is then cooled, the precipitated crystals are filtered off 2 and washed with acetone. 0.35 g of N-isopropylidene-9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3- acid hydrazide is obtained. m.p. 293-295 ° C after recrystallization from chloroform-ethanol.

Analysis for ^C 22 ^H x9 6 ^N ° 2

Calculated: C 62.29 Found: C 62.29

H, 6.05; H, 6.14

N 22.93% N 23.10%.

Example 21

To a solution of potassium hydroxide (2.15 g, 0.036 mol) in water (50 ml) was added [9- (phenylhydrazono) -6-methyl-4-oxo-6,7,8,9-ethyl ester, 4.3 g (0.012 mol). Tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl] acetic acid was added and the 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. The precipitated crystals are filtered off and washed with water to give 2.95 g (yield 75.6% of theory) of [9- (phenylhydrazono) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl] acetic acid, m.p. 161-162 ° C.

Example 22

Using the procedure of Example 18, but using N-aminopiperidine instead of phenylhydrazine, evaporation of the reaction mixture under reduced pressure, dissolution of the residue in methanol and addition of 0.15 ml of 70% perchloric acid solution, filtration of the separated crystals and washing with methanol gave acid perchlorate. 6-methyl-9- (1-piperidinylimino) -4-ΟΧΟ-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 177-178 ° C. Yield: 53.7%.

Analysis for ^C 15 ^H 20 ^N 4 ° 3 ^{> HClO} 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 23

Following the procedure of Example 18 but substituting 2-hydrazinopyridine for phenylhydrazine and recrystallizing the crude product from acetonitrile, 6-methyl-9- (2-pyridylhydrazono) -4-oxo-6,7,8,9-tetrahydro-4H was obtained. -pyrido [1,2-a] pyrimidine-3-carboxylic acid

mp 233-234 ° C. Yield: 66.2% Analysis for ^C 15 ^H 15 ^N 5 ° 3 ° C Calculated: C 57.50 H, 4.83 N, 22.35 % Found: C, 57.83 H, 4.86 N, 22.05 %.

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Claims (8)

A process for the preparation of the 9-substituted 4-oxo-4H-pyrido [1,2-a] pyrimidine derivatives of the general formula I wherein: 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 4 5 R and R ^J R ⁴ and R ⁵ represent hydrogen, C 1 -C 4 alkyl, phenyl, carboxyl, C 1 -C 4 alkoxycarbonyl, carbamoyl, cyano, formyl, C 1 -C 4 alkylcarbamoyl carbon in the alkyl moiety, carboxylic acid hydrazide residue, -C-NHN = C (CH 2) 2, or - a group of the formula - (C1-6-COOR) in which m represents 1 or 2 and R represents hydrogen or a C1-C4 alkyl group, represents hydrogen, a C1-C4 alkyl group, a benzoyl radical, a tetrazolyl radical or a pyridyl radical or a radical of formula * _ (CH ₀₎ -N = C-, zp wherein p is 4 or 5, or a phenyl or naphthyl radical, which are optionally substituted by one to five identical or different substituents from the group consisting of halogen, C C 1 -C 4, nitro, carboxyl, hydroxyl, trifluoromethyl, amino, C 1 -C 4 monoalkyl or alkanoylamino, C 1 -C 4 -alkyl or C 1 -C 4 -alkanoylamino; alkyl or alkanoyl moieties, C 1 -C 4 alkoxy, sulfonic acid moiety, sulfonamido, C 1 -C 4 alkanoyl, phenoxy, phenyl moiety, k yano and C 1 -C 4 alkylenedioxy, and are hydrogen, or 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 together with the nitrogen atom to which they are attached are attached represent a group of formula -N = CR ° R ^/ wherein each R c and R ^a is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or dialkylaminophenyl having from 1 to 4 carbon atoms in each alkyl moieties or together represent a group of the formula - (CHp ₅ -NH-) and pharmaceutically acceptable salts, solvates, stereoisomers, optically active antipodes, geometric isomers and tautomers thereof, characterized in that the compound of formula II (II), in which R, R ¹ , 2 3 R, R are as defined above, the dashed line between positions 8 and 9 denotes an additional optional bond and L is a leaving group such as halogen napříkald p-toluensulfonyloxyaminoskupina, phenylamino or hydroxy, or a tautomer of a compound of formula II by reacting III CE _{'n is} 4 with a compound of formula a (III) in which. 4 5 R and R are as hereinbefore defined, and optionally the resulting intermediate of formula (IV) wherein (IV), R, R ¹ , R ² , 3 4 5 R, R, R and the dotted line are as defined above, are oxidized, optionally ester or cyano in the resulting compound of formula I is saponified or converted to an amide or hydrazide acid, or the resulting carboxylic acid of formula I is converted to an ester or obtained a compound of formula (I) wherein R is hydrogen, benzoylated, or a resulting compound of formula (I) wherein each of R and R is hydrogen, optionally reacted with a compound Wherein R and R are as defined above, and / or the compound of formula I obtained is converted into a pharmaceutically acceptable salt or released from a salt, and / or the racemic mixture formed is resolved. in their optical antipodes. 2. The process of claim 1, wherein the starting compound is used Wherein R, R, R and R are as defined in I and L is halogen. 3. Process according to claim 1 or 2, characterized in that the resulting intermediate of formula IV wherein R, R ^1, R ^2, R ^3, R ⁴ and R ⁵ are as defined in claim 1, is oxidized by atmospheric oxygen without previous insulation. 4. A process according to claim 1, wherein R, R, R, R are as defined in point 1, the dashed line between positions 8 and 9 denotes a further bond and L represents p-toluenesulfonyloxyamino or hydroxyl. 5. A process according to any one of claims 1 to 4, wherein the corresponding compound (s) of formula (I) and (II) and (III) are used to form 9-phenylhydrazono-6-methyl-4-oxo-6,7,8 9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid or (+) antipodes thereof. 6. The process of claims 1, 2, 4 and 5 wherein the reaction of a compound of formula II with a compound of formula III is carried out in the presence of an acid binding agent. 7. A process according to claim 6, wherein the acid binding agent is an alkali metal carbonate or bicarbonate or an alkaline salt of a weak organic acid or an excess of a compound of formula III. 8. Process according to claim 1, characterized in that the reaction is carried out at a temperature of 0 to 200 ° C, preferably at room temperature or at the boiling point of the reaction mixture.