CS241497B2 - Method of pyrimidine new fussed derivatives - Google Patents

Description

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

where they mean

R, R ¹ and R ² are independently hydrogen or C to C ₄ alkyl,

R ³ is hydrogen, C _r to C ₄ -alkyl, phenyl, carboxy; or a alkali metal carboxylate, alkoxycarbonyl of 2-5 carbon atoms, carbamoyl or cyano ·, n is 0 or 1 and

a) when R ⁹ is hydrogen and R ⁷ and R ^8, and R ⁵ and R ⁶ are just now an additional bond, X and Y denote a sulfur atom and R ⁴ is hydrogen or C _r · to C ₄ alkyl , or,

b) when R ⁴ and R ⁶ as well as R ⁹ and R ⁸ together represent another bond, and R ⁷ is hydrogen, X and Y are sulfur and R ^{5 is} hydrogen or C 1 -C ₄ -alkyl , or ·

(c) where R ⁹ and R ⁸ as well as R ⁷ and R ⁶ represent just another bond, Y and X are either a negatively charged sulfur atom, R ⁴ and R ^{5 being} an alkali metal cation, or Y and X represent a · sulfur atom or a group of formula> N-R ¹⁰ wherein R ¹⁰ represents hydrogen or · Cp C4-alkyl and R ⁵ and R ⁴ together represent a group of formula - (CH2 I _s in which s is 1, 2, 3 or 4 as well as their optically active antipodes or salts.

Some of the compounds of formula I exhibit valuable biological activity, while another may serve as a starting material for the production of valuable biologically active compounds. The compounds of formula I produced can exist in three tautomeric forms:

Depending on the substituents present, whether one of the tautomeric forms predominates or, alternatively, the two tautomeric forms form an equilibrium mixture under the conditions indicated by spectrophotometric methods. Geometric Z — E isomerism is also possible between the individual tautomeric forms.

The invention also includes a process for the preparation of possible geometric isomers and racemic or optical forms of the compounds of formula I.

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 (1976)].

The process according to the invention is characterized in that the compound of the general formula (II)

wherein, R, R ¹ , R ² , R ³ , n are as defined above, reacted with carbon disulfide, preferably in the presence of an alkali metal cation, in a C 1 -C 4 alcohol at 0 to 120 ° C, and obtained a compound of formula I or an alkylating agent suitable for introducing C _r to C ₄ -alkyl groups, or is reacted with the formula alkylendihalogenidem

Hlg- _{(CH2) S} where -Hlg

H 1g is halogen and is as defined above and optionally reacted with a diamine of formula (CH ₂ ) _with (NH ₂ ) ₃ wherein s is as defined above and optionally converting the compound of formula I obtained into another compound of formula I and or is converted into a pharmaceutically acceptable salt or released from its salt and / or the optionally obtained racemate of formula I is resolved into its optically active antipodes.

It has been found, surprisingly, that the methylene group of the compound of formula I, which occupies the β position with respect to the nitrogen atom, has active hydrogen atoms which may be involved in electrophilic substitution reactions.

The reaction according to the invention is preferably carried out by dropwise addition of an alkali metal hydroxide solution to the alkaline solution of the compound of formula II and carbon disulphide under gentle external cooling, and the reaction mixture is preferably stirred at room temperature.

During the reaction of the primary compound of formula Ia,

in which it means

The alkali metal mercury and other substituents as defined above may optionally be isolated by removing the solvent under reduced pressure. The compounds of formula Ia can be converted without isolation, for example, using alkylating agents, into other compounds of formula I.

As the alcohols, methanol, ethanol, n-propanol, or isopropyl alcohol or n-butanol can be used. Sodium hydroxide or potassium hydroxide are suitable as the hydroxides of the alkali metals. 1 to 5 moles of carbon disulfide may be used per mole of the compound of formula (II).

For the preparation of the compounds of the formula I in which R @ ¹ , R @ ² , R @ ³ and n are as defined above, X and Y are sulfur, R @ ⁵ and R @ ⁶ as well as R @ ⁷ and R @ ⁸ a bond, preferably a compound of formula I, wherein R, R ¹ , R ² , R ³ and ⁿ are as defined above and R ⁶ and R ⁷ as well as R ⁸ and R ⁹ now just represent together another bond, X and Y are a negatively charged sulfur atom and R ⁴ and R ⁵ are an alkali metal cation, alkylated. Conventional reagents may be used as alkylating agents.

Alkyl halides, such as methyl iodide, ethyl bromide, arylalkylbalides, such as benzyl chloride, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, trialkyl phosphates, e.g.

The reaction may be carried out preferably in the presence of a solvent at 0 to 160 ° C. Solvents used are those customary in alkylation and aralkylation reactions. Preferably, 0.3 to 2.0 moles of alkylating or aralkylating agent is used per mole of the compound of formula (I). The molar ratio of the reagents may optionally deviate from the indicated numerical values.

For the preparation of compounds of the formula I, wherein R, R ¹ , R ² , R ³ and ⁿ are defined as above, R ⁶ and R ⁷ as well as R ⁸ and R ⁹ represent just another bond, X and Y are now atom sulfur and R ⁴ and R ⁵ together represent a group of formula - (0Η _{2) 8} in which s is as defined above, is reacted with preferably a compound of formula I, wherein R, R ^1, R ^2, R ^{3 and} n are defined as From the above, R ⁶ and R ⁷ as well as R ⁸ and R ⁹ are now a further bond, X and Y are now a negatively charged sulfur atom, and R ⁴ as well as R ⁵ are an alkali metal cation with an alkylene dihalide.

The reaction is preferably carried out under the conditions indicated for alkylation.

The compound of formula (I) wherein R, R ¹ , R ² , R ³ , and n are as defined above, R ⁵ and R ⁶ as well as R ⁷ and R ⁸ are just another bond, R ⁹ is hydrogen, X as well as Y represents sulfur and R ⁴ is C _r to C ₄ -alkyl, can also be reacted with an alkylating agent, preferably in the presence of an acid to give those compounds of formula I wherein R, R ^1, R ^2, R ^{3 and} n are as defined above, R ⁶ and R ^7, and ^R and R ⁹ form now together an additional bond, X and Y represent a sulfur atom, and R ⁴ and R ⁵ are identical or different and denote C _r to C _4- alkyl.

The above-mentioned reagents can be used as alkylating agents. Preferred acid binding agents are, for example, alkali metal carbonate, alkali metal bicarbonate, trialkylamine, alkaline earth metal carbonate. The reactions may preferably be carried out in the presence of a solvent. The reaction conditions are selected as described above;

b) is heated with an acid anhydride to form a 1,3-dithiethane ring from two alkyl-S-C = S and result in a compound of formula 1b

where

F R ^1, R ^2, R n are defined as above.

The acid anhydrides used are preferably aliphatic acid anhydrides, for example acetic anhydride, propionic anhydride. The reaction is preferably conducted at the boiling point of the acid anhydride.

For the preparation of compounds of formula I wherein R, R ¹ , R ² , R ³ and ⁿ are defined as above, R ⁶ and R ⁷ as well as R ⁸ and R ⁹ together represent another bond, X and Y represent a group of the formula > N-R ¹⁰ 'in which R ¹⁰ is hydrogen or C 1 -C 4 -alkyl and R ⁴ and R ⁵ together form an optionally substituted - (CH 2) _{S group} , in which s is as defined above, is preferably the above compound of formula I can be reacted

c) a diamine of the above formula.

In this specification, the term C _t - to C ₄ -alkyl means an alkyl group with straight or branched chain.

The heterocyclic compounds of formula II 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 in Patent No. 7,212,286.

Compounds of formula I may form alkali metal salts such as sodium or potassium salts, ammonium salts, alkaline earth metal salts such as calcium or magnesium salts or may form salts with organic amines (such as triethylamine) when the carboxyl group contains the carboxyl group.

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

Several representatives of the compounds of formula I are themselves PG antagonists, exhibit an additional analgesic, antiarteriosclerotic, transquilizing or other effect.

When the compounds of formula (I) are used as pharmaceutical active ingredients, depending on the area of use, patients may be administered a dose of 1 to 1500 mg per die once daily or in divided doses.

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

The invention will be further elucidated by means of the following examples, without being limited thereto. Example 1

5.9 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine and 2.3 ml of carbon disulfide are dissolved in 35 ml of ethanol and a solution of 2.8 g of potassium hydroxide in 25 ml of ethanol is added dropwise at 25-30 ° C. The reaction mixture was stirred at room temperature for one hour and evaporated under reduced pressure. 9.8 g of the dipotassium salt of 3-ethoxycarbonyl-6-methyl-9 - [(bis-thiolate) methylene] -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] is obtained. ] pyrimidine.

Example 2

To a solution of 9.7 g of the dipotassium salt of 3-ethoxycarbonyl-6-methyl-9 - [(bis-thiolate) methylene] -4-oxo-6,7,8,9-tetrahydr o-4H-pyrido [1,2- and the pyrimidine, which was prepared according to Example 1, in 60 ml of ethanol, 4.7 ml of dimethyl sulfate was added dropwise under external cooling, and the reaction mixture was stirred for one hour at 40 ° C. The yellow crystals formed are filtered off, washed with water and dried. 7.1 g (86%) of 3-ethoxycarbonyl-6-methyl-9- (methylthiocarhonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine are obtained. The product melts after recrystallization from benzene at 198-199 degrees Celsius.

Analysis for · C _! / ₁ H _J8 N ₂ O ₂ S ₂ :

calculated:

% C, 51.51;% H, 5.56;% N, 8.58.

H, 5.78; N, 8.48. Example 3

To a solution of 9.7 g of 3-ethoxycarbonyl-6-methyl-9 - [(bis-thiolate) methylene] -4-oxo-6,7,8,9-tetrahydr o-4H-pyrldo [1,2- and the pyrimidine prepared according to Example 1 in 60 ml of ethanol was added 4.7 g of ethylene bromide. The reaction mixture was stirred for one hour at 40 ° C and the precipitated sodium bromide was filtered off. The mother liquor was evaporated in half and the crystals precipitated upon cooling were filtered off and dried. 3 g of 3-ethoxycarbonyl-6-methyl-9- (1,3-dithiolan-2-ylidene) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] are obtained. pyrimidine. The product melts after recrystallization from ethanol at 205-207 ° C.

Analysis for calculated:

% C, 53.23;% H, 5.36;% N, 8.27.

53.17% C, 5.41 o / ₀ h, 8.2% N. Example 4

3.26 g of 3-ethoxycarbomyl-6-methyl-9- (methylthiothioicarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine and 0.6 g of ethylenediamine are treated with The resulting yellow crystals were collected by filtration, overlaid with benzene and dried to give 1.9 g (62%) of 3-ethoxy-414: 9 carboinyl-6-inethyl-; imidazoliden-2) _{-4-oxo-6,7,8,9-tetrahydro-4H-1} pyrj DOI [1,2- jpyrimidinu after recrystallization from dimethylformamide, melts at 252-254 ° C. Analysis for 0 · ₁₅ Η ₁₈ Ν ₄ 0 _;

calculated:

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

5.8.91% C, 5.85% H, 18.35% N, Example 5

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

Analysis for ϋ ₁₅ Η ₂ οΝ ₄ 0 ₃ (3ΐ2 calculated:

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

H, 5.85; N, 18.35.

Claims (1)

Subject A process for the preparation of the novel fused pyrimidine derivatives of the general formula I wherein they are R, R ¹ and R ² independently hydrogen or _Ci-4 to E -allkyl, R ^{3 is} hydrogen, C ₁ -C ₄ -alkyl, phenyl, carboxy, or an alkali metal carboxylate, C 2 -C 5 alkoxycarbinyl, carbamoyl or cyano group, n 0 or 1; and (a) in the case where R ⁹ is hydrogen and R ⁷ and R ⁸ as well as R ⁵ and R ⁶ together represent another bond, Y and X are both sulfur and R ^{4 is} hydrogen or C ₄ -C ₄ -alkyl, or Example: bad 6 To a solution of 0.8 g of 3-cyano-4-OXO-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine and 0.6 ml of carbon disulfide in 10 ml of ethanol is added dropwise a solution of 0. 6 g of potassium hydroxide and 10 ml of ethanol. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. 3-Cyano-8 - [(bis-thiolate) methylene] -4Oso-4,6,7,8-tetrahydropyrrolo) 1,2-a] pyrimidine disodium salt is obtained. Example 1 a d 7 The cyano-8 - [(bis-thiolate) methylene] -4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine disodium salt prepared according to Example 6 is dissolved in 20 ml of ethanol, to a solution of 1.25 g of dimethyl sulfate was added and the reaction mixture was stirred for 1 hour at 40 DEG C. The precipitated crystals were filtered and washed with ethanol to give 0.46 g (36.5%) of 3-cyano-8- (methylthiothiocarbonyl). -4-oxo-1,4,6,7-tetrahydropyrrolof 1,2-a] pyrimidine melting at 202-203 ° C. Analysis for C ₁₀ HGN ₃ OS2: calculated: % C, 47.79;% H, 3.61;% N, 16.72% H, 3.53; N, 16.81. YNÁLEZU b) when R ⁴ and R ⁶ as well as R ⁹ and R ⁸ together represent another bond and R ⁷ is hydrogen, X and Y are sulfur and R ^{5 is} hydrogen or C ₄ -C ₄ -alkyl, or· c) when R ⁹ and R ⁸ and R ⁷ and R ^s is just an additional bond, Y and X is either a sulfur atom with a negative charge, and R ⁴ and R ⁵ represent a cation of an alkali or Y and X are a sulfur atom or • a group of formula> N-R ¹⁰ in which R ¹⁰ represents hydrogen or · C4-alkyl and R ⁵ and R ⁴ together represent a group of formula - (CH2) _s in which s is 1, 2, 3 or 4 and optically active antipodes or salts thereof, characterized in that the compound of formula (II) wherein: R, R ¹ , R ² , R ³ and n have the aforementioned 244949, react with carbon disulfide, preferably in the presence of an alkali metal cation in a C 1 -C 4 alcohol at 0 to 120 ° C, and optionally obtain the alkylated compound a reagent suitable for introducing C _r to C ₄ -alkyl groups, optionally reacted with alkvlendihalogenidem · general formula Hlg- (CH _a) -Hlg wherein Hlg represents halogen and has the abovementioned meaning and this is optionally reacted with a diamine of the formula (CH _{2) s} (NH _{2) 2,} wherein s has the above meaning, and if appropriate the resulting compound of formula I is converted into another compound of formula I and / or converted into a pharmaceutically acceptable salt or released from its salt and / or the optionally obtained racemate of formula I is resolved into its optically active antipodes.