DK151885B - METHOD OF PREPARING PYRIDOOE1,2AAAPYRIMIDIN-3-CARBOXAMIDES OR OPTICALLY ACTIVE ISOMERS OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF - Google Patents

Description

The present invention relates to a peculiar process for the preparation of partially novel pyrido [1,2a] pyrimidine-3-carboxamides of the general formula

(I) wherein R 1 is alkyl of 1-6 carbon atoms or optically active isomers and pharmaceutically acceptable salts thereof.

The compounds of general formula (I) are useful as analgesics, antiphlogistics, PG antagonists and antidepressants and / or have CNS or similar antiliphemic effect.

A process for the preparation of compounds of formula (I) is known from J. Chem. Soc. Perkin I (1974), 1753, and DE Patent No. 1,795,762. In this process, a tetrahydropyridopyrimidine-3-acid amide is quaternized with methyl sulfate, and then a reduction with e.g. sodium borohydride for the hexahydro compound. This known process can be reproduced by the following reaction scheme:

It is a disadvantage of this known method that the intermediate (A) is not sufficiently stable as it can disintegrate during ring opening (Magyar Kémikusok Lapja 31, (1976), 281-292) or during ring conversion (Tetrahedron Letters 1979, 1337- 1338). These reactions are favored by the basic environment, including the use of NaHB ^, and it may be related that the yields of the known process are only moderate (55-60%) and that the quality of (A) is not the best (indications). of mp ranges from about 175 ° C to about 200 ° C).

The process of the present invention is characterized in that, preferably in the presence of an acid-binding agent, a corresponding pyrido [1,2a] pyrimidine-3-carboxamide of the general formula is reacted

(III) or an optically active isomer or a pharmaceutically acceptable salt thereof with a halide of the general formula R 1 - X (IVa) wherein R "*" has the meaning given above and X means halogen, or with a sulfate having the general formula Formula (R1) 2SO4 (IVb) wherein R4 has the meaning given above, or with a phosphate of the general formula (R1) 3po4 (IVc) where has the meaning given above and optionally converts the pyrido [1] thus obtained. 2a] pyrimidine-3-carboxamide of the general formula (I) into a pharmaceutically acceptable salt thereof and, if desired, a prepared racemate of the general formula (I) splits into the optically active isomers.

Thus, the process of the present invention, in contrast to the known process mentioned above, is a direct N-alkylation, without prior N-quaternization. Furthermore, it yields surprisingly better yields than the known ones.

In the process of the invention, a pyrido [1,2a] pyrimidine-3-carboxamide of the general formula (III) is treated with an agent suitable for introducing an R 2 group into the molecule. This agent may e.g. be a halide of the general formula (IVa). Chloride, bromide or iodide are preferably used. The reaction may also be carried out with a sulfate of the general formula (IVb) or with a phosphate of the general formula (IVc).

The reaction is preferably carried out at 20-250 ° C, preferably in the presence of a suitable solvent. Preferably, acid binding agents are also used. Representative acid-binding agents include alkali metal hydroxides, preferably sodium hydroxide and potassium hydroxide, alkali metal carbonates, preferably sodium carbonate and potassium carbonate, and alkali metal hydrogen carbonates, preferably sodium bicarbonate and potassium hydrogen carbonate.

As the solvent, the excess of the halide of the general formula (IVa), of the sulphate of the general formula (IVb) or of the phosphate of the general formula (IVc) may be used.

Other suitable solvents include water, alcohols, ketones, dimethylformamide, aromatic hydrocarbons, formamide, hexamethylphosphoric triamide, acetonitrile or the mixtures of the indicated solvents.

After treatment of the reaction mixture by conventional technique, the corresponding pyridotl, 2a] pyrimidine-3-carboxamide of the general formula (I) is obtained.

Surprisingly, the process of the invention results in a selective 1-N-alkylation without simultaneously attacking the carboxamide group. It is known that both of these groups are reactive, cf. Arz, Forsch. 22, 815 (1972), showing that both groups can be acylated.

Selective 1-N alkylation, according to this literature site, is only possible with compounds containing only one alkylatable N atom, e.g. 3-carboxylic acid esters.

The starting materials of the general formula (III) are described in HU-PS 156,119, 158,085, 162,384, 162,373 and 166,577 as well as in NL-PS 7,212,286, or they are known materials [Arz, Forsch. 22, 815 (1972)], or they can be prepared by known methods. The compounds of the general formula (IVa), (IVb) and (IVc) are commercially available products.

The compounds of general formula (I) have valuable pharmacological activity. Thus, they are e.g. useful as analgesics, antiphlogistics, PG antagonists and antidepressants and / or have CNS or antilyphemic activity.

The pharmacological activity of the compounds of this invention is illustrated by experiments carried out using 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2a] pyr - midin-3-carboxamide (CH-127) as a typical representative example of these compounds.

Toxicological results characterized by LDt-g values are given in Table I and can be compared with the data obtained intravenously with a standard analgesic compound "PROBON" ® listed in Table II. Due to the different molecular weights of "PROBON" and of the test compound herein, the molecular weights are also given in Table II.

Table I

Toxicological data for 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexa-hydro-4H-pyrido [1,2a] pyrimidine-3-carboxamide (CH-127)

Species Route of administration LD50 orally 370 rats intravenously 210 subcutaneously 280 mice orally 360

Table II

Toxicological data for "PROBON" ® and CH-127 Compound LD 50 Molar weight Molecular toxicity mM / kg “PROBON” ® 220 362.41 0.60 CH-127 210 223.27 0.94

It can be seen from the tables that the molar toxicity of CH-127 is approx. 1.5 times greater than the corresponding data for "PROBON" ® by intravenous administration, ie. the compound of this invention has a lower toxicity.

Table III shows data for the -algesic activity of the subject compound (CH-127) and of "PROBON" which data were obtained using a "hot plate" experiment [J. Pharm. Exp. Ther. J30, 130 (1944), Kisérleti Orvostudomåny 2, 295 (1950)]. The experimental animals are mice.

Table III

Results of analgesic activity obtained using a hot plate experiment in mice ED50 Molar ed50

Compound Route of administration (mg / kg) (mM / kg) "PROBON" ® intravenous 52 0/14 subcutaneously 66 0.18 CH-127 intravenously 13 0.058 subcutaneously 25 0.11 Table IV compares the analgesic activity achieved by a " twist "experiment with the two compounds listed above [Fed. Proc. 15, 494 (1956), J. Pharm. Exp. Ther. 133, 400 (1961)].

Table IV

Results of analgesic activity obtained using a twist test on mice.

EDc-q Molar ED, -q Therapeutic Index Compound Route of administration (mg / kg) (mM / kg) (LD ^ q / ED ^ q) "PROBON" ® oral 380 1.05 2.9 intravenously 140 0.38 subcutaneously 215 0.59 - CH-127 orally 58 0.26 6.2 intravenously 34 0.15 - subcutaneously 43 0.19 Table V compares the antiphlogistic activity of CH-127 and Phenylbutazone. The antiphlogistic activity is tested by a method known in the art as the "rat paw edema" method and the compositions are administered orally.

Table V

Carrageenin Edema ED30 = m9 / k9 CH-127 [Proc.Soc.exp.Biol., ED3n = 60 m9 / k9 Phenylbutazone 111, 544 (1962)]

Kaolin Edema ED30 = 33 CH-127 [Arch.Int.Pharmacodyn., ED, n = 95 mg / kg Phenylbutazone

132, 16 (1961)] U

Dextran Edema ED30 = CH-127 [Arch.Xnt.Pharmacodyn., ED-.n = 220 mg / kg Phenylbutazone

102, 33 (1955)] U

Table VI below illustrates that the inhibitory effect of CH-127 is unchanged on adrenalectomized rats, ie. the antiphlogistic effect is independent of endogenous steroids.

Table VI

Effect of CH-127 on normal and adrenalectomized rats (Carrageenin edema, oral administration) Edema inhibition (%)

Dose of normal adrenalectomized (mg / kg) rats in rats 25 29 25 75 50 44

The synergistic effect of CH-127 in admixture with other antiphlogistic drugs is illustrated in Table VII.

Table VII

Dose edema inhibition (%)

Compound (mg / kg) (Carrageenin edema, oral) CH-127 6/25 18 CH-127 25 30/4

Indomethacin 2.5 24

Suprophene 1.25 26/4 CH-127 + 1 6/25)

Indomethacin / 2.5) CH-127 + 1 25 1 83

Indomethacin / 2.5 J

CH-127 + 25 '1

Suprophene j 1.25 / 65.7

With the test results listed in the above tables, it has been shown that CH-127 is more effective on mice than "PROBON" and has a better therapeutic index at oral administration.

The compound tested (CH-127) is a typical representative example of the compounds of this invention, and the other pyrimido [1,2a] heterocyclic compounds of the general formula (I) have similar beneficial, analgesic and antiphlogistic properties.

The compounds of this invention may be formulated into compositions containing a compound of general formula (I) or an optically active isomer or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The carrier may be either a solid or a liquid and the compositions may be in solid form, e.g. in the form of tablets, capsules and dragees, or in liquid form, e.g. in the form of solutions, suspensions or emulsions.

The carriers which can be used in the manufacture of the products herein are the conventional materials known for this purpose, e.g. talc, calcium carbonate, magnesium stearate, water and polyethylene glycol.

If desired, the compositions may contain the conventional excipients such as emulsifiers and disintegrants.

The compounds can also be combined with other active ingredients, e.g. with other analgesic or antiphlogistic compounds. The preparations prepared in this way have a synergistic effect. The compounds of this invention have e.g. synergistic action when combined with morphine, 1,4-hydroxy-azidomorphine, phentanile, indomethacin, azidomorphine and azido-codeine. This very important feature of the compounds of this invention has been found to be particularly useful in anesthesiology of surgery.

The present invention is illustrated by the following examples.

Example 1 10.2 g of 6-methyl-4-oxo-1,6,7,8,9,9a = -hexahydro-4H-pyrido [1,2a] pyrimidine-3-carboxamide are suspended in a solution of 2 g of sodium hydroxide in 65 ml of water, while 9.5 g of dimethyl sulfate and a solution of 4 g of sodium hydroxide in 25 ml of water are added dropwise to the reaction mixture. The reaction mixture is stirred for 1 hour, then adjusted to a pH of 7 by the addition of 10% by weight hydrochloric acid. The aqueous solution is shaken with chloroform. The combined chloroform solution is dried over sodium sulfate and concentrated under reduced pressure. 10.8 g of 1,6ax-dimethyl-4-oxo-1,6,7,8,9,9aax-hexahydro-4H-pyrido [1,2a] pyrimidine-3-carboxamide are obtained. Melting point after (two times) recrystallization from ethanol: 185-186 ° C.

Analysis;

Calculated: C = 59.18%, H = 7.67%, N = 18.32%.

found; C = 58.95%, H = 7.69%, N = 18.85%.

Example 2 10.2 g of 6-methyl-4-oxo-1,6,7,8,9,9ariv'-hexahydro-4H-pyridoxide [1,2a] pyrimidine-3-carboxamide are suspended in a solution of 2 g. sodium hydroxide in 65 ml of water, while 11.55 g of diethyl sulfate and a solution of 4 g of sodium hydroxide in 25 ml of water are added dropwise to the reaction mixture. The reaction mixture is stirred for 1 hour and then adjusted to a pH of 7 by the addition of 10% by weight hydrochloric acid. The aqueous solution is shaken with chloroform.

The chloroform extract is concentrated under reduced pressure to give 9.9 g of 1-ethyl 1-6, -methyl-4-oxo-1,6,7,8,9,9a-hexahydro-hydroxide.

αΛ aX

-4H-pyrido [1,2-a] pyrimidine-3-carboxamide. Melting point after recrystallization from isopropanol: 162-163 ° C.

Analysis;

calculated; C = 60.74%, H = 8.07%, N = 17.71%.

found; C = 60.58%, H = 8.08%, N = 17.85%.

Example 3 10.2 g of 6-methyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-

dX dX

Pyrido [1,2a] pyrimidine-3-carboxamide and 27.3 g of triethyl phosphate are stirred at 235 ° C in the presence of 6.4 g of potassium carbonate. When no further gas evolution is visible, the reaction mixture is poured into 150 ml of water and the aqueous solution is shaken with chloroform. The combined dhloroform extract is concentrated under reduced pressure. 8.5 g of 1-ethyl-6β-methyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2a] pyrimidine-3-carboxamide are obtained.

»X

Melting point after recrystallization from isopropanol; 163 ° C. The product gives no decrease in the melting point when mixed with the product of Example 2.

Example 4 -4 10.2 g of 6-methyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-

dX dX

Pyrido [1,2a] pyrimidine-3-carboxamide in 125 ml of ethanol, 25 g of n-butyl bromide and 7.5 g of potassium carbonate are heated at reflux for 30 hours. The reaction mixture is filtered and concentrated under reduced pressure. 8.5 g of 1-n-butyl-6-methyl-4-oxo-oxide are obtained.

Q.X

-1,6,7,8,9,9a = -hexahydro-4H-pyrido [1,2a] pyrimidine-3-carboxamide,

dX

melting at 160-162 ° C.

Analysis;

calculated; C = 63.37%, H = 8.74%, N = 15.84%.

found; C = 63.08%, H = 8.83%, N = 15.78%.

Claims (4)

A process for the preparation of pyrido [1,2-a] pyrimidine-3-carboxamides of the general formula (I) wherein R 1 is alkyl of 1-6 carbon atoms, or optically active isomers and pharmaceutically acceptable salts thereof, characterized in that a corresponding pyrido [1,2a] pyrimidine-3 is reacted with a corresponding pyrido [1,2a] -carboxamide of the general formula (III) or an optically active isomer or a pharmaceutically acceptable salt thereof having a halide of general formula R 1 -X (IVa) wherein R 1 is as defined above and X is halogen, or with a sulfate of the general formula ( r1) 2so4 (IVb) wherein R4 has the meaning given above, or with a phosphate of the general formula (R1) 3 PO4 (IVc) where R5 * - has the meaning given above and optionally converts it thus obtained pyrido [1,2a] -pyrimidine-3-carboxamide of the general formula (I) to a pharmaceutically acceptable salt thereof, and, if desired, a prepared racemate of the general formula (I) splits into the optically active isomers. Process according to claim 1, characterized in that the reaction of the compound of the general formula (III) with a compound of the general formula (IVa), (IVb) or IVc) is carried out in the presence of an acid-binding agent. Process according to claim 2, characterized in that the acid binding agent is alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide, alkali metal carbonate, preferably sodium carbonate or potassium carbonate, or alkali metal hydrogen carbonate, preferably sodium bicarbonate or potassium hydrogen bicarbonate. Process according to any one of claims 1-3, characterized in that the reaction is carried out at a temperature of 20-250 ° C.