CS241467B2 - Method of new fussed derivatives production - Google Patents

Description

The invention relates to a process for the preparation of novel fused pyrimidine derivatives of the general formula (I)

or ⁶

-R \ _R S

AC 'R ⁴⁰ , 11

X./R ⁹ R, © where they are

R, R ¹ and R ² hydrogen or C to C alkyl,

R ^{3 is} hydrogen, C 1 -C 1 -alkyl, phenyl, carboxy, alkali metal carboxylate, C 1 -C 9 alkoxycarbonyl, carbamoyl or cyano and n is 0 or 1; and R ⁷ is hydrogen, R ⁵ and R ⁶ together represent an additional bond and R ^{4 is} one of the groups in which X is halogen,

R ^{8 is} hydrogen or C 1 -C 1 -alkyl,

R ^{9 is} hydrogen, C 1 -C 1 -alkyl, optionally halogen substituted C 6 -C 10 -aryl,

R ^{10 is} C 1 -C 4 alkyl, optionally halogen, C 1 -C 1 alkyl, C 1 -C 4 alkoxy, C 1 -C 1 alkoxycarbonyl or nitro substituted phenyl or naphthyl, and

R ^u Ci to C alkyl, or BJ ^R6 and ^R7 together an additional bond and R ⁴ and R ⁵ together one of the groups

N

-C ^ ^X R <° \ ^N \ .R *

Ή = \ p *>

X

J = C

I _χ \ (CH ^ tJJ Ř Ř) in which

X, R ^8, R ⁹ and R ¹¹ are as defined above,

R ^12, independently of the currently valid R @ ⁸ is defined as R ⁸ and n is 1, 2, 3 or 4, and their optical antipodes and salts thereof.

Particularly preferred are those compounds of formula I wherein n is 1, R ^{1 is} hydrogen or C 1 -C 4 -alkyl, especially methyl, R ² hydrogen or C 1 -C 6 -alkyl and R ^{3 is} carboxy, methoxycarbonyl, ethoxycarbonyl or carbamoyl .

The term C1-C4-alkyl denotes linear or branched alkyl groups. The term optionally substituted C 6 -C 10 aryl refers to a single or multiply substituted phenyl or naphthyl group, wherein the substituents may be the same or different and are C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, amino, hydroxy, carboxy , carboxylic acid derivative, nitro or halogen.

The C 1 -C 6 -alkoxy group comprises linear or branched alkoxy groups. The term "carboxylic acid group derivative" refers to alkoxycarbonyl of 1 to 4 carbon atoms in the alkyl moiety, ntril, aminocarbonyl, which may also be substituted on the amino acid by C 1 -C 4 alkyl, C 1 -C 4 acyl, dialkylaminomethylamino C 1 -C 4 alkyl. or carbohydrazide.

Compounds of formula (I) which contain carboxylic acid groups may form alkali metal salts such as sodium or potassium salts, ammonium salts, alkaline earth metal salts such as calcium or magnesium salts or amine salts (e.g. triethylamine).

Some of the compounds of formula (I) also exhibit valuable biological activity, while the other may serve to produce valuable biologically active compounds.

In particular, the novel compounds of the formula I can be used as pharmaceutical intermediates. The compounds can be further reacted with aryldiazonium salts, for example, to pyrido [1,2-a] pyrimidine derivatives substituted in the 9-position with a hydrazone group, which are the end products exhibiting a variety of pharmaceutical effects, for example antiallergic effects.

Some representatives of the compounds of formula I are also prostaglandin (PG 1) antagonists and exhibit analgesic, antiarteriosclerotic, tranquilizing or other effects.

It is already known that 2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid derivatives can be prepared by catalytic hydrogenation of the corresponding unsaturated compounds (J. Het Chem., 13, 797 [1978]).

The invention is based on the surprising finding that the methylene group of the fused pyrimidine derivative of the general formula II

which, with respect to nitrogen atoms, occupies the β position, contains active hydrogens which may be involved in electrophilic substitution reactions.

The essence of the invention consists in · that are reacted in such condensed pyrimidine derivative of formula II wherein R, R, R ^2, R ^{3 and} n are as defined above, with dihalogenmethylenimmoniumhalogenidem formula III \ ® / ^R c = R

X R

(III) wherein

X, R ¹⁰ and R ¹¹ are as defined above, and the compound of formula Ia

wherein R ⁸ is C 1 -C 4 -alkyl, is reacted with a C 1 -C 4 -alcohol in the presence of a C 1 -C 4 -alkali metal alkanoate or for the preparation of a compound of formula (I) wherein R is R ¹ , R ² , R ³ and ⁿ are as defined above, R ⁷ is hydrogen, R ⁵ and R ⁶ together represent an additional bond and R ⁴ represents a group. Wherein X, R, R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ and n are as defined above, optionally for the preparation of a compound of formula I, wherein R, R ¹ , R ² , R ³ and ⁿ are as defined above, R ⁷ is hydrogen, R ⁵ and R ⁶ together represent a bond and R ⁴ represents a group

O

-CR ⁹

X

R 'in which R ⁸ and R ⁹ have the above meanings, is reacted with an alcohol Cl to C4 containing water, or for producing compounds of formula I, wherein R, R ^1, R ^2, R ^{3 and} n are as defined above , ^R and R ⁷ together form an additional bond and R ⁴ and R ⁵ together represent a group

^X R ⁰ where X, R ⁸ , R ⁹ , R ⁴⁰ and R ¹¹ are as defined above, is reacted with a primary or secondary amine of the formula

R ⁹

HN

R ⁸ wherein R ⁸ and R ⁹ are as defined above, in the presence of an inert solvent, and the compound thus obtained for the preparation of a compound of formula I, wherein R, R ¹ , R ² , R ³ and ⁿ are as defined above, R ⁶ and R ⁷ taken together represent an additional bond and R ⁴ and R ^{5 taken} together are the group • W of ^R

N \ R ^{3 N} \

X o in which R ⁸ , R ¹² and n are as defined above, is reacted with a diamine of the formula

R ⁸ -NH (CH ₂ ) _n NH-R ¹² , wherein R ⁸ , R ¹² and _n are as defined above, preferably in the presence of an inert solvent, or for the preparation of a compound of formula I, wherein R, R ¹ , R ² , R ^{3 and} n are as defined above, R ⁷ is hydrogen, R ⁵ and R ⁶ together represent an additional bond and R ⁴ represents a group in which R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are as defined above, optionally treated with with a basic reagent, preferably an alkali metal carbonate or alkali metal bicarbonate, or for the preparation of a compound of formula I, wherein R, R ¹ , R ² , R ³ and ⁿ are defined as above, R ⁶ , R ⁷ together represent an additional bond with R ⁴ and R ⁵ together are / ^R / ^N '10, CR

X, in which X, R ¹⁰ and R ¹¹ are as defined above, is reacted with a C 1 -C 4 trialkylamine in the presence of a solvent which is inert with respect to the reaction, preferably an ether.

In the compound of formula I obtained, the group present as substituent R ^{3 is} converted into another group, within the meaning of R ^3, and / or the compound obtained is converted into a pharmaceutically acceptable salt or released from its salt and / or the optionally obtained racemate of formula I splits in their optical antipodes.

The compounds of formula I produced can exist in tautomeric forms, for example according to the following formulas:

It is dependent on the substituents present whether there is predominantly one of the tautomeric forms, or whether the 2 tautomeric forms, in certain circumstances, form an equilibrium mixture, where the amount of the individual components can be demonstrated by spectroscopic methods. Geometric isomerism is possible between the individual tautomeric forms (Z, Ej). The invention also encompasses the production of possible geometric isomers and the production of racemic mixtures or optically active forms of the compounds of formula (I).

Preferably, the reaction of a fused pyrimidine derivative of the general formula II, wherein R, R ¹ , R ² , R ³ and ⁿ are as defined above, with a dihalomethylenimmonium halide of the general formula III, wherein X, R ¹⁰ and R ¹¹ are as defined above solvents which are inert to the reaction.

In carrying out the process of the invention, the compound of formula II, optionally dissolved in an inert solvent, is added to a solution of the dihalomethylenimmonium halide in an inert solvent and the reaction mixture is heated to quench the reaction quantitatively. To isolate the compounds of formula (Ia), the reaction mixture is preferably concentrated under reduced pressure and the residue is crystallized.

Suitable inert solvents are hydrocarbons, preferably benzene, toluene, xylene, chlorinated hydrocarbons, preferably chloroform, dichloromethane, chlorobenzene, etc.

In particular, an optionally halogenated aromatic hydrocarbon is used as the preferred inert solvent.

The reaction is preferably carried out at a temperature in the range of 0 to 180 ° C, in particular at 10 to 120 ° C.

Aliphatic alcohols are preferably used in the reaction with the water-containing alcohol. The reaction is preferably carried out at 0 to 150 ^Q C, especially at the boiling point alcohol.

According to a preferred embodiment of the process according to the invention, a compound of the formula Ia, wherein X, R, R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ and n are as defined above, is treated with an alcohol in the presence of an alkali metal alkanoate at 0 to 150 ° C.

Suitable alcohols are aliphatic alcohols and aralkylalcohols. Alkali metal alkanoates with aliphatic carboxylic acids are particularly suitable. Sodium acetate and potassium acetate may also be used as the alkali metal alkanoate.

According to one preferred embodiment of the process of the invention, a compound of formula (Ia) wherein X, R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ and n are as defined above, is reacted with a primary or secondary amine at a temperature in the range 0 to 150 ^° C, preferably at the boiling point of the inert solvent used. As inert solvents, aromatic hydrocarbons such as benzene, toluene, etc., halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, etc. may be used.

On. Preferably, 1 mole of the starting compound of the formula (Ia) is used, preferably 1 to 5 moles, preferably 1.9 to 2.9 moles of ammonia or an amine.

The compound of formula I obtained can be further reacted using an alkali metal carbonate, bicarbonate, alkali metal hydroxide or trialkylamine.

The reaction conditions below are used to react with the diamine.

The compound of formula (Ia) obtained can be reacted without isolation, for example with an amine, and thus converted into a compound of formula (I).

The condensed pyrimidine derivatives used as starting materials can be prepared by the methods described in Hungarian patents 156,119, 158,089, 162,384, 162,373, 166,577, and Dutch Patent Application Publication No. 72,126,287, as opposed to compounds of the general formula Formula III, as well as the reagents used to make it, are common commercial products.

When a compound of formula (I) is to be used as a pharmaceutically active agent, it is possible, depending on the area of use, to administer to the patient a dose of 1 to 1500 mg per die once daily or in divided doses throughout the day.

The compounds of formula (I) may be formulated as dragees, tablets, suspensions, injections, capsules, powders, suppositories or other forms, and disintegrants and other carriers may be added.

The invention will be further elucidated by means of the following examples, without being limited thereto. He did

To the mixture 16.3 g phosgene-N _; A solution of 23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine in N-dimethylimmonium chloride in 50 ml of dichloromethane is added dropwise with stirring. 30 ml of dichloromethane and the mixture was stirred for 3 hours. The solvent was distilled off and the residue was crystallized from ether; 35.2 g of strongly hygroscopic 3-ethoxycarbonyl-6-methyl-9 [(chloro-N, N-dimethylimmonio) methylene-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] The pyrimidine chloride is dried under vacuum.

Analysis for C15H20N3O3Cl2:

calc .: Cl ₁₀ nt. 19.6%, found: Cl. . 19.4%.

Example 1 a d 2

A solution of 1.8 g of 3-ethoxycarbonyl-6-methyl-9 - [(chloro-N, N-dimethylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- and pyrimidine chloride and 5 mmol of sodium acetate in 5 ml of anhydrous ethanol are allowed to stand at room temperature for 24 hours, the precipitated sodium chloride is filtered off and the filtrate is concentrated, the residue is dissolved in water and adjusted to pH 7 by addition of sodium bicarbonate. The solid was collected by filtration, washed with water and dried to give 0.92 g (60% of theory) of 3,9-diethoxycarbonyl-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido (1, 2, 3, 4, 6, 8, 8). 2-a] pyrimidine melting at 138-140 ° C.

Analysis for C15H20N2O5:

calculated:

% C, 58.43;% H, 6.54;% N / 9.09;

58.65 ° C, 6.53% H, 9.06 N. Example 3

A solution of 1.8 g of 3-ethoxycarbonyl-6-methyl-9 - [(chloro-N, N-dimethylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine chloride and 5 mmol of sodium acetate in 5 ml of anhydrous methanol are allowed to stand at room temperature for 24 hours, the precipitated sodium chloride is filtered off and the filtrate is concentrated. The residue is dissolved in water and adjusted to pH 7 with sodium carbonate. The mixture was filtered, washed with water and dried to give 0.96 g (65% of tert.) 3-ethoxycarbonyl-6-methyl-9-methoxycarbonyl-4-Oxo-1,6,7,8-tetrahydro-4H-pyrido [ 1,2-aj pyrimidine melting at 136-139 ° C.

Analysis for C14H18N2O5:

calculated:

H, 6.17; N, 9.52. Found:

57.00% C, 6.25% / H, 9.52% H.

Examples 4 to 9

To a solution of 3.65 g of 3-ethoxycarbonyl-6-methyl-9 - [(chloro-N, N-dimethylimmonoylmethylene) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] 0.02 mole of amine was added in 15 ml of anhydrous dichloromethane, and the reaction mixture was heated to boiling for one hour. The product was recrystallized from anhydrous ethanol to obtain the products and their characteristic data from Table 1:

TABLE 1

example C. amine product yield % melting point (° C) summary formula 4 aniline 3-ethoxycarbonyl-6-methyl-9- (N-phenyl-N, N'-dimethylformamidinium) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine chloride 74 236 to 239 (decomposition) C21H27N4O31Cl 5 4-chloro- aniline 3-Ethoxycarbonyl-6-methyl-9- [N- (4-chlorophenyl) -N-, N-dimethylformamidinium] -4-oxo-4H-pyrido [1,2-a] pyrimidine chloride 75 230 to 232 (decomposition) C21H28N4O3Cl2 6 4-methyl- aniline 3-ethoxycarbonyl-6-methyl-9- [N- (4-methylphenyl) -N ', N'-dimethylformamide] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1, 2-pyrimidine chloride 81 225 to 226 (decomposition) C22H29N4O3Cl 7 4-me- thoxy- aniline 3-ethoxycarbonyl-6-methyl-9- [N- (4-methoxyphenyl) -N ', N'-dimethylformamidinium] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2] -a] pyrimidine chloride 38 222 to 224 (decomposition) C22H29N4O4Cl 8 2-Naphthyl- amine 3-ethoxycarbonyl-6-methyl • 9- [N- (2-naphthyl-N ', N'-dimethylformamide)] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2] -a] pyrimidine chloride 68 234 to 235 C25H29N4O3Cl • 9 · - 2-ráe- thoxy- 3-ethoxycarbonyl-6-methyl- -9- [N- (2-methoxycarbonyl- 63 210 to 211 (decomposition) C23H2SN4O5Cl

carbophenyl} -N ‘, N‘-dimethylformnylaniline amidinium] -4-oxo-1,6,7,8, tetrahydro-4 H -pyrido [1,2- a] pyrimidine chloride (continued Table 1)

- ‘example - - C. elementary analysis' % C ' calculated% H % N 4 60.30 6.45 13.40 60.08 6.54 13.42 5 55.60 5.74 12.35 54.95 5.73 12.26 6 61.10 6.70 12.92 60.83 6.81 12.79 7 58.95 6.47 12.50 58.58 6.65 12.58 8 64.10 6.19 11.95 63.69 6.17 11.82 9 57.91 6.09 11.75 57.33 6.09 11.76

241487

Example 10

To an aqueous solution of 4.2 g of 3-ethoxycarbonyl-6-methyl-9- ^{(N-phenyl-N!,} N dimethylforrnamidium) -4-oxo-l, 6,7,8-tetrahydro-4H-pyrido [1 2-a] pyrimidine chloride was added 20 M potassium carbonate solution. The precipitated crystals are filtered off, washed with water and dried. 3.4 g (89% of theory) of 3-ethoxycarbonyl-6-methyl 9- (N-phenyl-N ', N'-dimethylformainidino) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido are obtained. [1,2-a (pyrimidine, which melts at 193-195 ° C after recrystallization from ethanol. Analysis for C 21 H 26 N 4 O 3:

calculated:

% H, 6.81;% N, 14.65.

H, 6.79; N, 14.69. Example 11

To a mixture of 22.1 g of phosgene-N-methyl-N-phenylimmonium chloride in 50 ml of dichloromethane is added dropwise a solution of 23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- pyrido [1,2-a (pyrimidine in 30 ml of dichloromethane) and the reaction mixture was heated to boiling for 3 hours. (chloro-N-methyl-N-phenylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine chloride, which is dried under vacuum.

Analysis for CmHHísNNjOíCIž:

calculated:

8.36% (Jli ,,, found:

8.45% Cl _it , -, ..

Example 12

To a solution of 3-ethoxycarbonyl-6-methyl-9 - [(chloro-N-methyl-N-phenylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] of pyrimidine chloride in 20 ml of anhydrous dichloromethane was added 0.2 ml of aniline and the reaction mixture was heated to reflux for 1 hour. After cooling, the precipitated aniline hydrochloride is filtered off. The mother liquor containing dichloromethane is concentrated. The residue was crystallized from ether. The precipitated crystals are filtered off, washed with ether and dried. 25.9 g (54% of theory) of 3-ethoxycarbonyl-6-methyl-9- (N ', N'-diphenyl-N-methylforminamidinium) -4-oxo-1,6,7,8- was obtained. tetrahydro-4H-pyrido [1,2-a] pyrimidine chloride, which, upon recrystallization from ethanol, melts with decomposition at 186-188 ° C.

Analysis for C18H29N4O3CI:

calculated:

64.95% c, 6.04% H, 11.66% N, found:

% H, 6.09;% N, 11.26.

Example 13

To an aqueous solution of 24 g of 3-ethoxycarbonyl-6-methyl-9- (N, N'-diphenyl-N-methylformamidinium) -4-oxo-1,6,7,8-tetrahydro-4H-pyridO '[1,2] A 20 M potassium carbonate solution was added to pyridine chloride. The precipitated crystals are filtered off, washed with water and dried. 16.7 g (75% of theory) of 3-ethoxycarbonyl-6-methyl-9- (N, N'-diphenyl-N-methyl-fluoramidino) -4-oxo-6,7,8,9-tetrahydro-4H- are obtained. pyrido (1,2-a jpyrimidinu after recrystallization from ethanol melts at 199-202 C. ^c.

Analysis for C26H23N4O3:

calculated:

% C, 70.25;% H, 6.31;% N, 12.61.

H, 6.27; N, 12.42. Example 14

To a solution of 21 g of 3-ethoxycarbonyl-6-methyl-9 - [(chloro-N-methyl-N-phenylimmonio) methylene) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2] 0.2 mole of pyrimidine chloride in 20 ml of anhydrous dichloromethane is added

Of 4-chloroaniline and the reaction mixture is heated at reflux for one hour. After cooling, the precipitated 4-chloroaniline hydrochloride is filtered off. The mother liquor containing dichloromethane is concentrated. The obtained 3-ethoxycarbonyl-6-methyl-9- [N- (4-chlorophenyl) -N'-phenyl-N'-methylformamidinium) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1] 2-a] pyrimidine chloride was dissolved in water and 20 M potassium carbonate solution was added. The precipitated crystals are filtered off, washed with water and dried. 13.3 g (55.5% of theory) of 3-ethoxycarbonyl-6-methyl-9- [N- (4-chlorophenyl) -N'-phenyl-N-methylmoramidino] -4-oxo-6 are obtained. 7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine, which melts at 194-196 ° C after recrystallization from ethanol.

Analysis for C2GH27N1O3CI:

calculated:

65.15 "/ o C, 5.65% H, 11.71 _0/0 N Found:

% C, 64.85;% H, 5.83;% N, 11.66.

Example 1 a d 15

To a solution of 3-ethoxycarbonyl-6-methyl-9-1 (chloro-N-methyl-N-phenylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-g] 4-Methylaniline (0.2 mol) was added to the pyrimidine chloride in anhydrous dichloromethane and the reaction mixture was heated at reflux for one hour. After cooling, the precipitated 4-methylaniline hydrochloride is filtered off. The dichloromethane filtrate was concentrated. The obtained 3-ethoxycarbonyl-6-methyl-9- [N- (4-methylphenyl) -N'-phenyl-N'-methylformamidinium] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [ 1,2-a) pyridine chloride is dissolved in water. To the aqueous solution was added 20 M potassium carbonate solution. The precipitated crystals are filtered off, washed with water and dried. 14.7 g (64% of theory) of 3-ethoxycarbonyl-6-methyl-9- (N '- (4-ethylphenyl) -N'-phenyl-N'-methylformamidino] -4-oxo-6 are obtained, m.p. 7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine, the product melts after recrystallization from ethanol at 161-163 ° C.

Analysis for C27H30N4O3:

calculated:

% C, 70.75;% H, 6.56;% N, 12.21.

H, 6.62; N, 11.91. Example 16

A solution of 1.8 g of 3-ethoxycarbonyl-6-methyl-9 - [(chloro-N-dimethylmethyl) -monio) methylene] -4-oxo-1,6,7,8-trahydro-4H-pyrido [1,2-a] of pyrimidine chloride in 5 ml of ethanol is heated to boiling for 30 minutes. After cooling, the precipitated crystals are filtered off, washed with alcohol and dried. 1.08 g (63% of theory) of 3-ethoxycarbonyl-6-methyl-9- (N, N-dimethylaminocarbonyl) -4-oxo-1,6,7,8-tetrahydr o-4H-pyrido [1] is obtained. , 2-a] pyr imidinhydr ochloridu after recrystallization from ethanol melts at 168-168 C with decomposition ^Ol.

Analysis for C15H22N3O4Cl:

calculated:

% C, 52.40;% H, 6.45;% N / 12.22;

H, 6.58; N, 12.30; Cl, 10.45. Example 17

Dissolve 1.0 g of 3-ethoxycarbonyl-6-methyl-9- (2-imidazolidene) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine in 10 ml of ethanol. The solution was saturated with hydrogen chloride gas and concentrated. The residue was crystallized from a mixture of ether and ethanol. 0.9 g of 3-ethoxycarbonyl-6-methyl-9- (2-imidazole-16-day) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-bis is obtained. -hydrochloride melting at 190 ° C with decomposition.

Analysis for C15H20N4O3Cl2:

calculated:

% C, 59.15;% H, 5.90;% N, 18.40.

% H, 5.85;% N, 18.35.

Example 18

3.6 g of 3-ethoxycarbonyl-6-methyl-9 - [(chloro-N, N-dimethylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] The pyrimidine chloride was stirred with 1.2 g of ethylenedlamine in 40 ml of dimethylformamide at 40 ^° C. After cooling, the precipitated crystals are filtered off, washed with water and dried. 1.0 g of 3-ethoxycarbonyl-6-methyl-9- (2-imidazolidene) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine is obtained, m.p. to 254 ° C.

Example 19

1.6 g of potassium hydroxide are dissolved in 20 ml of ethanol. To the ethanolic potassium hydroxide solution is added an ethanolic solution of 3.6 g of 3-ethoxycarbonyl-9- (phenylarmnocarbonyl) -5-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a]. ] pyrimidine. The reaction mixture is heated to boiling for 30 hours and, after cooling, the precipitated crystals are filtered off, washed with chloroform and dried. 3.1 g of potassium 9- (phenylaminocarbonyl) -6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylate are obtained, which is melts at 276-280 ° C with decomposition.

Analysis for C17H16N3O4K:

calculated:

% H, 4.41;% N, 11.50. Found: ~ 7

% C, 56.02;% H, 4.50;

Example 20

Dissolve 3.1 g of potassium 9- (phenylaminocarbonyl) -6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylate in heating in 250 ml of water. The pH of the solution was adjusted at 40 to 50 ^c C, 38 M HCl to 1. The crystals precipitated from the cooled mixture was filtered, washed with water and dried. 9- (Phenylaminocarbonyl) -3-carboxy-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine is obtained in a yield of 25% of theory.

Analysis for C17H17N3O4:

Example 24 calculated:

% C, 62.37;% H, 5.24;% N, 12.84.

62.18% C, 5.18% H, 12.45% N. Example 21 g of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-1,2-apyrimidine was allowed to proceed. reacted with phosgene-N, N-dimethylimmonium chloride as described in Example 1. Strongly hygroscopic 6-methyl-9 - [(chloro-N, N-dimethylimmonio) methylene] -4-oxo-1, 6,7,8 is obtained. -tetrahydro-4H-pyrido [1,2-a] pyrimidine chloride, which is dried under vacuum. Analysis for C12H17N3OCl2:

calculated:

12.22 «/ o Cl, · ,, _t , found:

12.10% Cl _id , _t ,

Example 22

6-Methyl-9- [J-chloro-N, N-dimethylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine chloride was heated in ethanol for 30 minutes . The reaction mixture is concentrated and the obtained 6-methyl-9- (N, N-dimethylaminocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine hydrochloride is converted in a manner known per se in free base. The base was recrystallized from petroleum ether. There was thus obtained 6-methyl-9- (N, N-dimethylaminocarbonyl) -. Alpha.-oxo-1, 2.beta., 5S-tetrahydro-1 H -pyridol-4-a] pyrimidine.

Analysis for C12H17N3O2:

calculated:

% C, 61.26;% H, 7.28;% N, 17.86;

% C, 61.40;% H, 7.11;

3-Cyano-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine is reacted analogously to Example 1 with phosgene-N, N-dimethylimmonium chloride, This yields a strongly hygroscopic 3-cyano-6-methyl-9 - [(chloro-N, N-dimethylimmonio] methylene] 1-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine chloride.

Analysis for C13H16N4OCl2:

calculated:

10,70 «/ o Cl _ion , found:

10.52% Cl _{io "t}

3-Cyano-6-methyl-9 - [(chloro-N, N-dimethylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidide dichloride The ethanolic solution was concentrated and the residue was crystallized from ethyl acetate. 3-Cyano-6-methyl-9- (-, Ν-dimethylaminocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine is obtained, yield 60% of theory. .

Analysis for D13H16N4O2:

calculated ·:

% C, 59.98;% H, 6.20;% N, 21.51.

% H, 6.11;% N, 21.22

3.4 g of 3-ethoxycarbonyl-6-methyl-9- (N, N-dimethylaminocarbonyl] -4-oxo-1,6,7,8-tetrahydr o-4H-pyrido [1,2- a] pyrimidine hydrochloride is dissolved in The solution was neutralized with 5M sodium bicarbonate solution, the reaction mixture was shaken with chloroform, the chloroform solution was dried over sodium sulfate, filtered and concentrated, and the residue was recrystallized from ethanol-water to give 2.1 g of 3-ethoxycarbonyl-6. -methyl-9- (,8, Ν-dimethylaminocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine.

Analysis for C 18 H 25 N 5 Cu:

calculated:

% C, 58.60;% H, 6.90;% N, 13.66.

H, 6.94; N, 13.56. Example 26

3-Ethoxycarbonyl-6-methyl-9- (N, N-dimethylaminocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine is dissolved in ethanol, to the obtained solution 20 M ammonia solution was added and the reaction mixture was allowed to stand in a closed vessel for three days. The precipitated crystals are filtered off and washed with ethanol. 1.18 g of 3-aminocarbonyl-6-methyl-9- (N, N-dimethylaminocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine is obtained, m.p. mp 220 ° C.

Analysis for C 13 H 18 N 4 O:

calculated:

H, 6.53; N, 20.12. Found:

H, 6.52; N, 20.33.

Example 27

3,9-Diethoxycarbonyl-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine was treated as in Example 26 with ammonia in ethanol. 1.51 g of 3-aminocarbonyl-9-ethoxycarbonyl-6-methyl-4-Oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine are obtained, which melts. at 251 ° C.

Analysis for C 13 H 17 N 3 O 4: calculated:

57.12% C, 6.28 0/0 H, 15.30%, N found:

56.98% C, 6.12% H, 15.50% N

1.8 g of 3-ethoxycarbonyl-6-methyl-9 - [(chloro-Ν, Ν-dimethylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido | 1,2-a] pyrimidine dichloride (prepared according to Example 1j) is suspended in 20 ml of ether. 0.55 g of triethylamine is added dropwise to the suspension with vigorous stirring. 3-ethoxycarbonyl-6-methyl-9-1 (chloro-N, N-dimethylaminomethylene) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine, m.p. 74 DEG-77 DEG C. Analysis for C15 H20 N3 O3 Cl:

calculated:

% C, 55.30;% H, 6.19;% N, 12.90.

H, 6.10; N, 12.98.

Example 29

2.15 g of 3-cyano-6-methyl - [(9-chloro-N, N-dimethylmethyl-mono) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] of pyrimidine chloride (prepared according to Example 23) is suspended in 20 ml of dioxane. 1.01 g of triethylamine are added dropwise to the suspension with vigorous stirring. The precipitated triethylamine hydrochloride is filtered off. The precipitated crystals are filtered from the residual dioxane solution after cooling. 1.41 g of 79 percent of theory are obtained. 3-Cyano-6-methyl-9 - [(chloro-Ν, Ν-dimethylamino) methylene] -4-oxo-6,7,8,9 tetrahydro, -4H- pyrido [1,2-a] pyrimidine melting at 128-130 ° C.

Analysis for C 13 H 15 N 4 OCl:

% C, 56.02;% H, 5.42;% N, 20.10.

H, 5.51; N, 20.14.

Example 30

3-ethoxycarbonyl-6-methyl-9 - [(chloro-N-methyl-N-phenylimmonio) methylene] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] The pyrimidine chloride (prepared according to Example 11) was suspended in 20 ml of ether, and 0.55 g of triethylamine was added dropwise to the reaction mixture with vigorous stirring. g (42% of theory) 3-ethoxycarbonyl-6-methyl-9 - [(chloro-N-methyl-N-phenylamino) -methylene] -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine, m.p. 56-62 T. Anal. Calcd for C 20 H 22 N 3 O 3 Cl:

% C, 61.93;% H, 5.71;% N, 10.83.

% C, 62.02;% H, 5.80;% N, 10.75.

Example 31 to 33

The oil obtained after evaporation of the dichloromethane mixture was dissolved in water and neutralized with sodium carbonate. The separated crystals are filtered off and recrystallized from ethanol.

Example 31: methyl amine is used as the amine. To give 3-ethoxycarbonyl-6-methyl-9- (N-methyl-N ⁱ N ^{<-dimethylforinamidino)} -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine (yield: 76% of theory, m.p. 243 DEG C.).

Analysis for C1 & H24N4O3:

calculated:

% C, 59.98;% H, 7.55;% N, 17.48.

59.99% C 7.68% H 17.37 _0/0 N.

Example 32: ethylamine is used as amine. 3-Ethoxycarbonyl-6-methyl-9- (N-ethyl-N, N'-dimethylformamidino) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] was obtained. pyrimidine (yield 81% of theory, m.p. 249 DEG C.).

Analysis for C17H16N1O3:

calculated:

% C, 61.05;% H, 7.83;% N, 16.75.

% H, 7.83;% N, 16.74.

Example 33: The amine used is isopropylamine. There was obtained 3-ethoxycarbonyl-6-methoxy-1,414B7-ethyl 1-9- (N-isopropyl-N &apos;, N &apos; -dimethylformamidino) -4-oxo-6,7,8,9-tetrahydr o-4H-pyrido [1,1-a]. 2-a] pyrimidine, m.p. 244-247 ^° C. Analysis for C18H28N4O3:

calculated:

62.04% c, 8.10% H, 16.08% N, found:

% C, 62.15;% H, 8.00;% N, 16.14

The procedure was as in Examples 19 and 20, but starting from 3-ethoxycarbonyl-9- [N- (4-methoxyphenyl) aminocarbonyl] -6-methyl-4-oxo-1,6,7,8-tetrahydro -4H-pyrido [1,2-a] pyrimidine gave the compound having the free carboxylic acid group at the 3-position of the ring system in a yield of 44% of theory, m.p. 101-202 ° C. Analysis for C18H19N3O5:

calculated:

% C, 60.50;% H, 5.36;% N, 11.67.

% H, 5.19;% N, 11.85.

Claims (6)

Subject VYNALEZU A process for the preparation of novel fused pyrimidine derivatives of the general formula I Λ, N “R N R ⁸ , Θ where they mean R, R ¹ and R ² hydrogen or C to C4 alkyl, R ³ is hydrogen, Ci-C4-alkyl, phenyl, carboxyl, alkali metal carboxylate, alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part, carbamoyl, or cyano and n is 0 or 1, a) R ⁷ represents hydrogen, R ⁵ and R ⁶ together represent an additional bond and R ^{4 represents} one of the groups in which X represents halogen, R ^{8 is} hydrogen or C 1 -C 1 -alkyl, R ^{9 is} hydrogen, C 1 -C 4 -alkyl, optionally halogen-substituted C 5 -C 10 -aryl, R ^{10 is} C 1 -C 4 -alkyl, optionally halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl or nitro substituted phenyl or naphthyl; and R ^{11 is} C 1 -C 1 -alkyl, or b) R ⁶ and R ⁷ taken together ^are an additional bond, R ⁴ and R ⁵ together represent one of the groups Ν '~ \ a V 'R < ¹ C, R = ¹ ° X N241467 in which X, R ^8, R ^9, R ¹⁰ and R ¹⁴ have the above meanings, λ R ¹² independently of the current meaning of Z 2 R ⁸ is defined as R ⁸ and "(y R 8) - n represents 1, 2, 3 or 4, as well as their optical antipodes and salts, characterized in that the fused pyrimidine derivative of the general formula II in which R ⁸ and R ⁹ are as defined above is reacted with an alcohol with 1 up to 4 carbon atoms containing water, or optionally for the preparation of a compound of formula I, wherein R, R ¹ , R ² , R ³ and ⁿ are as defined above, R ⁶ and R ⁷ together form an additional bond and R ⁴ and R ⁵ together they represent a group J2. wherein R, R ¹ , R ² , R ³ and n are as hereinbefore defined, are reacted with a dihalomethylenimmonium halide of formula III R i N (CH Jn NR® X r ' ¹¹ ' ^1C '(III) wherein X, R ¹⁰ and R ¹¹ are as defined above and the compound of formula I obtained and in which R ⁸ , R ^{12 and} n are defined as above, is reacted with a diamine of formula ' R 8 -NH (CH ₂ ) _n NH-R ⁴² , wherein R ⁸ , R ¹² and _n are as defined above, preferably in the presence of an inert solvent, or optionally for the preparation of a compound of formula I wherein R, R ¹ , R ² , R ^{3 and} n are as defined above, R ⁷ is hydrogen, R ⁵ and R ⁶ together represent an additional bond and R ⁴ represents a group wherein X, R, R ¹ , R ² , R ³ , R ¹⁰ , R ¹¹ and ⁿ are from above wherein R, R ¹ , R ² , R ³ and ⁿ are as defined above, R ⁷ is hydrogen, R ⁵ and R ⁶ together represent a bond and R ⁴ represents a group in which R1 is C1-C4 alkyl, reacted with a C1-C4 alcohol in the presence of a C1-C4 alkali metal alkanoate or optionally for the preparation of a compound of formula I wherein R, R, ⁴ , R ² , R ³ and ⁿ are as defined above, R ⁷ is hydrogen, R ⁵ and R ⁶ together represent an additional bond and R ⁴ representations n ® group Nc ^ R <° \ ^and in which X, R ^8, R ^9, R ¹⁰ and R ¹¹ have the above meanings, is reacted with a primary or secondary amine · formula R ⁹ HN R ⁸ wherein R ⁸ and R ⁹ are as defined above in the presence of an inert solvent and the compound thus obtained is optionally for the preparation of a compound of formula I wherein R, R ¹ , R ² , R ³ and ⁿ are as defined above, R ⁶ and R ⁷ together represent an additional bond and R ⁴ and R ⁵ together are a group N F \ f? ³ RFL in which R ^8, R ^9, R ^10, R ¹¹ are as defined above, is treated with a basic agent, preferably an alkali metal or optionally for producing compounds of formula I, wherein R, R ^1, R ^2, R ³ and n are defined as above, R ⁶ and R ⁷ together represent an additional bond and R ⁴ and R ⁵ together form a group in which X, R ¹⁹ and R ¹¹ are as defined above, reacted with a C 1 -C 4 trialkylamine, in the presence of a reaction inert solvent, preferably an ether, in the compound of formula I obtained, optionally the group present as substituent R ^{3 is} converted into another group within the meaning of substituent R ³ and / or into a pharmaceutically acceptable salt or released from its salt and / or the optionally obtained racemate of the formula I is separated into its optical antipodes. 2. Method according to claim 1, characterized in that the reaction is condensed · pyrimidine derivative of the formula II wherein R, R ^1, R ^2, R ^{3 and} n are defined as above, with dihalogenmethylimmoniumhalogenidem of formula III wherein X, R ¹⁹ and R ¹¹ are defined as above, carried out in the presence of a reaction inert solvent. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature ranging from 0 to 180 ^q C 4. Process according to claims 1-3, characterized in that a compound of formula I wherein X, R, R ^4, R ^2, R ^3, R ^10, R ¹¹ and n are as hereinbefore defined, with an alcohol with 1 up to 4 carbon atoms in the presence of an alkali metal alkanoate having 1 to 4 carbon atoms, carried out at a temperature of 0 to 150 ^and G. 5. Process according to claims 1-3, characterized in that a compound of formula Ia wherein X, R, R ^1, R ^2, R ^3, R ^LFL, R ¹¹ and n are as hereinbefore defined, is reacted with a primary or a secondary amine of the formula NHR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are as defined above, at a temperature in the range of 0 to 150 ° C, preferably at the boiling point of the inert solvent used. 6. A process according to any one of claims 1 to 3, wherein an optionally halogenated aromatic hydrocarbon is used as the inert solvent. Z ^R N -θ ' ^X R ¹⁰ X