CS203136B2 - Method of producing racemic optically active pyrimido/1,2a/heterocyclic compounds - Google Patents

Description

The present invention provides a process for the preparation of racemic or optically active pyrimido [1,2-a] heterocyclic compounds of formula (I)

R ¹

(I) where

R is C 1 -C 6 alkyl,

R ¹ represents an alkyl group having 1 to 6 carbon atoms,

R ³ is hydrogen, C 1 -C 6 alkyl, phenyl optionally substituted by halogen, C 1 -C 6 alkoxy, nitro or C 1 -C 6 alkyl, or C 1 -C 4 alkyl one or two phenyl groups,

R ⁴ is hydrogen, or

R ³ and R ⁴ together with the adjacent nitrogen atom form a 5- to 7-membered monocyclic saturated heterocyclic ring which optionally contains an additional oxygen or nitrogen atom, which method is characterized in that racemic or optically active pyrimido [1,2-a] a heterocyclic compound of formula II

R

COOH o

(II) where

R and b 'are as defined above, reacted at a temperature in the range of -30 to +100 ° C with a racemic or optically active amine of formula III

HN

(III) where

R ⁴ and R ⁴ are as defined above.

In one embodiment, novel compounds are prepared by reacting a compound of formula II with an amine of formula III by dissolving the compound of formula II in an organic solvent, preferably chlorinated hydrocarbons, especially chloroform, or ethers, such as dioxane or tetrahydrofuran, and a trialkylamine, preferably triethylamine or tributylamine, is added, followed by dropwise addition of an acid halide, preferably a trimethylacetic acid halide, such as trimethylacetic acid chloride or a haloformic acid ester, preferably a methyl ester, ethyl ester or isopropyl ester. acid, at a temperature in the range of -30 to +50 ° C, preferably at a temperature in the range of -20 to 0 ° C. The amine of formula III, optionally dissolved in the above solvent, or, if an acid addition salt thereof, is then added dropwise, is added together with a trialkylamine, for example triethylamine or tributylamine; the reaction mixture is stirred at a temperature in the above range, then shaken with an aqueous sodium bicarbonate solution and then with water. After shaking with water, the reaction mixture is allowed to reach room temperature.

After drying, the reaction mixture is evaporated and the residue is recrystallized from a suitable solvent.

In another embodiment of the process of the invention, the compound of formula II is treated with an amine of formula III, preferably in an organic solvent, in the presence of a water-binding agent. A preferred water binding agent is, for example, carbodiimides such as dicyclohexylcarbodiimide. In such a case, the reaction is preferably carried out in the presence of 1-hydroxybenztriazole, N-hydroxysuccinimide or pentachlorophenol, since in the presence of these substances the side reactions are limited to a minimum.

Solvents which may be used are aromatic hydrocarbons such as benzene, chlorinated hydrocarbons such as chloroform or chlorobenzene, ketones such as acetone or methyl ethyl ketone, ethers such as dioxane or tetrahydrofuran, esters such as ethyl acetate or, when carbodiimide is used. soluble in aqueous alcohol, a mixture of water and an alcohol, or a mixture of said solvents.

The reaction is carried out at temperatures ranging from -30 to +100 ° C. After completion of the reaction, the precipitated urea is filtered off, and the residue obtained after evaporation of the filtrate is recrystallized from a suitable solvent to give the pyrimido β, 2-a] heterocyclic compound of formula I.

The pyrimido [1,2-a] heterocyclic compounds of formula (II) can be prepared according to the procedures described in Hungarian patents 156 119, 158 085, 162 384, 162 373 and 166 577 and in Dutch patent 7 212 286, while the amines of general formula III are commercially available.

The invention also relates to the racemic and optically active forms of the pyrimido [1,2-a] heterocyclic compounds of the formula I. Optically active compounds of the formula I can be obtained by resolution of the racemic compounds of the formula I by methods known per se or optically used. of active starting materials of the formula II.

The compounds of formula I exhibit a marked degree of pharmacological activity. Some of the compounds of formula (I) are particularly effective anti-inflammatory agents, prostaglandin antagonists, prevent platelet aggregation, and have analgesic activity. Some derivatives have other beneficial effects on the central nervous system.

In pharmacological and toxicological tests, a significant degree of efficacy and low toxicity were found under various conditions.

The assays were performed using 3-carbamoyl-1,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [beta], 2-a] pyrimidine (in a further CH = 105). Known anti-inflammatory agents such as phenylbutazone, aspirin, indomethacin, mebron and amidazofen were used in comparative experiments.

The anti-inflammatory activity of compound CH = 10 5 was investigated by the known method of rat paw edema (E. Domenju: Ann. Univ. Saraviensis 1, p. 317 1953).

The test results obtained by the various methods and the excellent activity of the compound CH = 10O are shown in Table 1.

Table!

substance dose inhibiting effect against edema mg / kg in% after application of the test substance 1 hour 2 hrs 24 hours CH-105 100 ALIGN! 25 34 300 45 52 8 mebron 100 ALIGN! 8 22nd 300 25 25 3 phenyl- butazone 100 ALIGN! 2 2 200 1 1 10 3

According to recent publications in the literature, prostaglandins play an important role in the formation of inflammation (J. R. Vane: Prostaglandins in inflammatory response, In .: Inflammation, 1972,

N.Y. Ycademic Press). Therefore, it appeared appropriate to test the efficacy of the compounds produced by the method of the invention in the inflammatory response induced by prostaglandin E 2 and E 2 in particular with respect to vascular wall permeability, which plays an important role in inflammation.

Table

substance dose mg / kg inhibition of edema («) prostaglandin inhibition of vascular wall permeability («) prostaglandin ^E 1 ^E 2 ^E 1 ^E 2 200 30 3, 40 35 CH = 10O 500 42 45 40 50 200 41 20 May 30 25 aspirin 500 45 54 42 50 , 00 5 10 10 5 phenylbutazone 200 15 Dec 28 20 May 20 May From the data as shown in Table 2 shows that: the compound CH = 10O is characterized by its activity at the same level as a known prostaglandin antagonist aspirin with respect to efficiency CH = .05, as an edema inhibitor or lowering agents vascular wall permeability (J.R. Vane: Hospi · tal Practice, 1, pp. 61 (1972)) . Favorably properties were found during tests,

by the Northover method (J. Path. Bact, 85, p. 365, (1963)) ·

Table substance 3 dose mg / kg anti-inflammatory activity (¾) after 1 hour after 2 hours after 24 hours CH = 0.55 , 00 40. 55 30 mebron 100 ALIGN! 23 23 0 phenylbutazone 100 ALIGN! 18 20 May 0

The significant anti-inflammatory activity of compound CH = 105 is preferably accompanied by analgesic activity. In a modified animal test that induced painful convulsions (Witkin et al .: J. Pharm. Exp. Ther. 113 p. 400 (1961)), the following results were obtained:

Table 4 substance

ED? Q therapeutic mg / kg index

CH = 105 70.4 mebron 380 4.3 phenylbutazone 63 5.5 indomethacin 2.4 12

The results show favorable toxicity of GH = .05 · *

Table 5

substance ^LD 50 mg / kg in rats per os in mice CH = 10O 750 975 aspirin 1 600 1 100 phenylbutazone .770 350

It was not found to induce gastric ulcers during long-term tests with compound CH = 10O5; this compound was administered to 50-month-old rats at 50 mg / kg. Based on the tests performed, the compound CH = 10 5 is an important anti-inflammatory agent, also having analgesic activity and a favorable therapeutical index.

The compounds of formula (I) may be used as active ingredients in pharmaceutical compositions in admixture with inert, non-toxic, solid or semi-solid diluents or carriers.

Preferred pharmaceutical forms of the compounds prepared by the process of the invention are solid forms such as tablets, capsules or dragees, or liquid forms such as solutions, suspensions or emulsions.

Substances such as talc, calcium carbonate, magnesium stearate, water or polyethylene glycol are generally used as carriers.

In addition, the pharmaceutical compositions optionally contain some other commonly used excipients, such as emulsifiers or disintegrants.

The following examples illustrate the invention.

Example 1

6.88 g (4 mmol) of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine are dissolved in 10 ml of chloroform and the solution is treated with 0.62 ml (4.4 mmol) of ethyl chloroformate were added dropwise with stirring. The resulting mixture was stirred for 10 minutes, then a solution of 0.70 g (4.2 mmol) of tert-butyl glycine ester hydrochloride and 0.58 ml (4.2 mmol) of triethylamine in 10 ml of chloroform was added while the temperature was added and one hour after the addition, it was maintained at -5 to -10 ° C. The reaction mixture was allowed to stand overnight in a refrigerator, then washed three times with 5% sodium bicarbonate solution and three times with water, dried over sodium sulfate. The resulting dark yellow resin product was dissolved in 5 ml of a mixture of ethyl acetate, pyridine, glacial acetic acid and water in a ratio of 240: 20: 6: 11 and the resulting solution was chromatographed on a silica gel 60 column 50 cm long and 1.8 cm diameter at particle size. between 0.063 and 0.125.

The eluent used was a mixture of ethyl acetate, pyridine, glacial acetic acid and water in a ratio of 240: 20: 6: 11 at 30 ml / h. The solvent, which was passed through the column, was evaporated under reduced pressure and, after evaporation of the solvent, the residue was left under reduced pressure of 1.33 Pa for a while to remove the solvent. 1.00 g of a colored amorphous resin is obtained, which is dissolved in 10 ml of ethyl acetate and 15 ml of cyclohexane are added while warm.

The precipitated crystals are filtered off and air-dried. 1.8 g (60% of theory) of 1,6-dimethyl-3 - [(N-tert-butoxycarbonylmethyl) carbamoyl] 4-oxo-1,6,7,8-tetrahydroxy-4H-pyrido [1] are obtained. 180 DEG-182 DEG.

Analysis calculated: found:

60.88% C, 61.12% C,

7.51% H, 7.70 # H,

N, 12.53; 11.94% N.

Example 2

4.4 g (0.02 mol) 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine and 3.1 ml (0.022) mol) of triethylamine is dissolved in 50 ml of chloroform and the solution obtained is cooled to -10 ° C. 2.1 ml (0.022 mol) of ethyl chloroformate were added dropwise to the solution. After stirring for an additional 10 minutes, a solution of 1.95 g (0.022 mol) of aniline in 25 ml of chloroform was added to the mixture; the temperature is maintained between -5 and -10 ° C during the addition and one hour after the addition. The reaction mixture was left in the refrigerator overnight and then shaken first with 5% sodium bicarbonate solution three times, then three times with water.

The chloroform solution was dried over sodium sulfate and concentrated in vacuo to give 5.7 g (96% yield) of yellow crystals, m.p. 180 ° C. Recrystallization twice from ethanol gave 1,6-dimethyl-3- (N-phenylcarbamoyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine, m.p. 189 to 190 ° C.

Analysis calculated: 68.67% C, 6.44% H, 14.13% N;

Found: C, 68.60; H, 6.50; N, 14.21.

Example 3

4.4 g (0.02 mol) of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine and 3, 3 are dissolved in 50 ml of chloroform. 1 ml (0.022 mol) of triethylamine.

The resulting solution was cooled to -10 ° C and 2.1 ml (0.022 mol) of ethyl chloroformate was added, followed by a suspension of 1.5 g (0.022 mol) of methylamine hydrochloride in 25 ml of chloroform and 1.3 ml of triethylamine. .

The solution was stirred for 1 hour at -5 to -10 ° C, then allowed to stand in the refrigerator overnight. The reaction mixture was then shaken first with 50 ml of 5% aqueous sodium carbonate solution three times, then with 50 ml of water.

The chloroform solution was dried over sodium sulfate and evaporated to give 3.9 g (83% yield) of yellow crystals. Recrystallization from ethanol gave 1,6-dimethyl-3- (N-methylcarbamoyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [b, 2-a] pyrimidine, m.p. 172-174 ° C. .

Analysis calculated: C 61.26, H 7.28, Found: C 61.08, H 7.40,

N, 17.86; 17.75% K.

Example 4

4.4 g (0.02 mol) of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine and 3.1 ml of triethylamine were Dissolve in 50 ml of chloroform and add, at -10 ° C, 2.1 ml (0.022 mol) of ethyl chloroformate and a solution of 1.9 g (0.022 mol) of piperidine in 25 ml of chloroform dropwise. The reaction mixture was stirred for an additional hour at -5 to -10 ° C, then allowed to stand in the refrigerator overnight.

The next day, the chloroform solution was shaken three times with 50 ml of 5% sodium bicarbonate solution each, then dried over sodium sulfate and evaporated.

5.2 g (yield 90% of theory) of 1,6-dimethyl-4-oxo- (1-piperidyl) carbonyl-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine are obtained in this way. in the form of a yellow, non-crystalline oil.

H, 8.01; N, 11.52.

Found:% C, 66.58;% H, 8.20;% N, 14.47.

Example 5

4.44 g (0.02 mol) of 1,6-dimethyl-3-carboxy-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine and 3.1 ml of triethylamine were treated with Dissolve in 50 ml of chloroform and add, at -10 ° C, 2.1 ml (0.022 mol) of ethyl chloroformate and 5.26 g (0.022 mol) of diphenylpropylamine dissolved in 25 ml of chloroform dropwise. The reaction mixture was then stirred at -5 to -10 ° C for 1 hour, then allowed to stand in the refrigerator overnight.

The next day, the chloroform solution was shaken first with 5% sodium bicarbonate solution, then with water, then dried over sodium sulfate and evaporated to give 6.8. g (yield 82% of theory) of yellow crystals.

Recrystallization from ethanol gave 1,6-dimethyl-3- (β- (3,3-diphenylpropyl) -carbamoyl] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [d], 2- m.p. 173-175 ° C.

Analysis calculated: 75.15% C, 7.04% H, 10.11% N;

Found:% C, 74.92;% H, 6.96;% N, 9.84.

Example 6

4,44 g of 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine and

3.1 ml of triethylamine are dissolved in chloroform at -10 ° C and added to the solution

2.1 ml of ethyl chloroformate and 1.6 g of tert-butylamine in chloroform.

The reaction mixture is stirred at a temperature in the range of -5 to -10 ° C, then allowed to stand in the refrigerator overnight. The next day, the chloroform solution was shaken first with 5% sodium bicarbonate solution, then water, then dried over sodium sulfate, filtered and evaporated to give 5.3 g (95% yield) of yellow crystals.

Recrystallization from ethanol gave 1,6-dimethyl-3- (N-tert-butylcarbamoyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine, m.p. 181 ° C.

Analysis calculated: 64.96% C, 8.36% H, 15.15% N;

Found:% C, 64.68;% H, 8.32;% N, 15.12.

Example 7

4,44 g 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine and

3.1 ml of triethylamine are dissolved in chloroform and 2.1 ml of ethyl chloroformate and 2.7 g of beta-phenylethylamine are added thereto at -10 ° C.

The reaction mixture was stirred at -5 to -10 ° C for 1 hour, then allowed to stand overnight in the refrigerator. The next day, the chloroform solution was shaken first with 5% sodium bicarbonate solution, then with water, then dried over sodium sulfate, filtered and evaporated to give 2.1 g of yellow crystals. Recrystallization from ethanol gave 1,6-dimethyl-3- [n- (2-phenylethyl) carbamoyl] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine mp 141-143 ° C.

% H, 7.12;% H, 69.83;% H, 6.96.

12.91% N; 12.74% N.

Example

Following the procedure described in Example 6, but using p-chloroaniline instead of aniline, 1,6-diethyl-3- [N-4-chlorophenyl) carbamoyl] -4-oxo-1,6,7 was obtained in 83% yield. 8-tetrahydro-4H-pyrido [1,2-a] pyrimidine, m.p. 234-235 ° C (after recrystallization from dimethylformamide).

Analysis calculated: 6.11% C, found: 61.52% C,

H, 5.47; N, 66%; Cl, 10.68;

H, 5.80; N, 12.55; Cl, 10.79.

Example

Following the procedure of Example 6, but using p-ethoxyaniline in 3% yield, 1,6-dimethyl-3- [4- (4-ethoxyphenyl) carbamoyl] -4-oxo-1,6,7,8-tetrahydro- 4H-pyrido [1,2-a] pyrimidine, m.p. 192-194 ° C (recrystallized from dimethylformamide).

H, 6.79; N, 12.31.

Found:% C, 66.65;% H, 6.84;% N, 12.25.

Example 10

Following the procedure of Example 6 but substituting m-toluidine for aniline in a yield of 94%, 1,6-dimethyl-3- [N- (3-methylphenyl) carbamoyl] -4-oxo-1,6,7,8 was obtained. -tetrahydro-4H-pyrido [1,2-a] pyrimidine, m.p. 16-163 ° C (after recrystallization twice from ethanol).

H, 6.80; N, 13.49.

Found:% C, 69.40;% H, 6.55;% N, 13.60.

They did

Following the procedure of Example 6, but using p-nitroaniline instead of aniline, 1,6-dimethyl-3-β- (nitrophenyl) carbamoyl] -4-oxo-1,6,7,8-tetrahydro- 4H-pyrido-2,2-a] pyrimidine, m.p. 305 DEG-308 DEG C. (after recrystallization from dimethylformamide).

H, 5.30; N, 16.36.

Found:% C, 60.03;% H, 5.32;% N, 16.48.

Example 12

The procedure was as described in Example 6 except that (-) - 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [-] was used as the starting material. 1,2-a] pyrimidine 20 '(α = -103 °, c = 2%, methanol). In 89% yield was obtained (-) - l, 6-dimethyl-3-carbamoyl-4D of ²⁰

-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine ( _D = -70 DEG, c = 2%, methanol). The yellow crystalline material obtained has a melting point in the range from 170 to 172 ° C.

Analysis calculated: C 59.71, H 6.83, N 18.99;

Found:% C, 59.53;% H, 7.01;% N, 18.72.

Example13

The procedure was as described in Example 6 except that (+) -1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1] was used as the starting material. , 2-a pyrimidine 20 (α = (-) 03 °, 0 = 2%, methanol). The yield of (+) -, 1,6-dimethyl-3-carbamoyl-4D20 oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine is obtained in 93% yield. 70 °, c = 2%, methanol). The yellow crystalline solid obtained has a melting point of 170-172 °.

Analysis calculated: C 59.71, H 6.83, N 18.99;

Found:% C, 59.60;% H, 6.72;% N, 18.81.

(+) - optionally (-) - 1,6-dimethyl-3-carboxy-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine, used as starting material in Examples 12 and 13, is obtained according to the process described in Belgian patent specification 856 612.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of racemic or optically active pyrimidine, 2-aheterocyclic compounds of the general formula I (I) wherein: R is C 1 -C 6 alkyl, R ¹ represents an alkyl group having 1 to 6 carbon atoms, R1 is hydrogen, C1-C6alkyl, phenyl optionally substituted by halogen, C1-C6alkoxy, nitro or C1-C4alkyl substituted by one or two phenyl groups, R 1 represents hydrogen or r 3 and R 3 together with the adjacent nitrogen atom form a 5-7 membered monoeylic saturated heterocyclic ring optionally containing an additional oxygen or nitrogen atom, characterized in that the racemic or optically active pyrimido [1,2-e] a heterocyclic compound of formula II COOH O (II) where R, H are as defined above, reacted at a temperature ranging from -30 to +100 ° C with a racemic or optically active amine of formula III (III) wherein: R ⁴ and R ⁴ are as defined above 2. Method according to claim 1 for the preparation of racemic or optically active pyrimido 0, 2-a] heterocyclic compounds of formula I wherein R, R \ R ^, and R ⁴ have the meanings given výěe, characterized in that a racemic or optically The active pyrimido 0,2-a] heterocyclic compound of formula II, wherein R and R ¹ are as defined above, is dissolved in a chlorinated hydrocarbon, preferably chloroform, or an ether, preferably dioxane or tetrahydrofuran, and then to the resulting solution. preferably adds triethylamine followed by addition of an acid halide, preferably trimethylacetic acid halides, or a chloroformic ester at a temperature in the range of -30 to +50 ° C, followed by the addition of a racemic or optically active amine of formula III wherein R 1 and R 2 ⁴ as defined above, to the resulting solution in a chlorinated hydrocarbon, preferably chloroform, or in an ether, preferably dioxane or tetrahydrofuran at. 3. A process according to claim 1, for the preparation of a racemic or optically active pyrimido [1,2-a] heterocyclic compound of the general formula I, wherein R, R, ^RJ and R * are as defined above, characterized in that they are racemic or optically the active pyrimido [1,2-a] heterocyclic compound of formula II wherein R and f 'are as defined above is reacted with a racemic or active amine of formula III wherein R ⁴ and R ⁴ are as defined above in the presence of an agent binding water. 4. Process according to claim 1, characterized in that carbodiimides, preferably dicyclohexylcarbodimide, are used as water-absorbing agents.