CS212346B2 - Method of making the condensated pyridimin derivatives the optically active isomeres thereof and physiologically tolerating salts - Google Patents

Description

The invention relates to a process for the preparation of novel condensed pyrimidine derivatives, their optically active isomers and physiologically tolerable salts. The compounds produced by the process according to the invention exhibit valuable pharmacological effects, for example analgesic, anti-inflammatory, PG-antagonistic and entidepressive. In addition, some of these compounds have other beneficial effects on the nervous system and are antilipemic active.

The compounds produced by the process of the invention can be represented by the general formula I,

CONH, (X), wherein each of R ¹ and R ¹ is C 1 -C 6 alkyl.

The present invention also provides a process for the preparation of optically active isomers as well as physiologically tolerable salts of the compounds of formula (I).

The compounds of formula (I) are prepared by the process of the invention by optionally adding racemic or optically active fused pyrimidine derivatives of formula (XI),

(IX) where

H and r 'are as defined above, reacted with ammonia and optionally the racemate (I) thus formed is distributed in a known manner in its component (b) or converted into a physiologically tolerable salt thereof.

The process according to the invention, i.e. the reaction of the fused pyrimidine derivatives of the formula II with ammonia, can be carried out in various ways. For example, the fused pyrimidine derivatives of formula (II) can be formed by reaction with halogenating reagents to form the corresponding acid halide and react with the ammonia. Suitable halogenating agents are thionyl chloride, phosgene, phosphorus oxychloride, phosphorus trichloride, phosphorus trichloride or mixtures thereof.

Alternatively, a mixed anbydride of the compound of formula (II) can be formed in the first step and reacted with ammonia. In this process, the compound of formula (II) is dissolved in an organic solvent, preferably in a chlorinated hydrocarbon, in particular chloroform, or in an ether, preferably dioxane or tetrahydrofuran, and added after the addition of a trialkylamine, preferably triethylamine. range from -30 to 50 ° C, acid chloride, preferably trimethylacetic acid chloride, or chloroformic acid ester, preferably methyl ester, ethyl ester or isopropyl ester thereof. The mixed acid anhydride thus obtained is treated with ammonia and optionally dissolved in the solvent used in the reaction to form the mixed anhydride.

According to another embodiment of the process according to the invention, the condensed pyrimidine derivative of the general formula II, preferably dissolved in an organic solvent, is reacted with ammonia in the presence of a water binding agent.

As a water binding agent, a carbodiimide is preferably used, particularly preferably dicyclohexylcarbodiimide. The reaction is preferably carried out in the presence of 1-hydroxybenztriazole, N-hydroxysuccinimide or pentachlorophenol, since side reactions are least likely in the presence of these compounds.

Suitable solvents are aromatic hydrocarbons, preferably benzene, toluene or chlorinated hydrocarbons, preferably chloroform or chlorobenzene, ketones, in particular acetone and methyl ethyl ketone, ethers, preferably dioxane or tetrahydrofuran, esters, preferably ethyl acetate, optionally using carbodiimides % soluble in aqueous alcohol, an alcohol / water mixture, or even a mixture of the above solvents.

The reaction is preferably carried out at temperatures ranging from -30 to 50 ° C. The resulting condensed pyrimidine derivatives of formula (I) are isolated from the reaction mixture in a conventional manner.

The preparation of the fused pyrimidine derivatives of the formula I can also be started from optically active fused pyrimidine derivatives of the formula II.

Fused pyrimidine derivatives of formula II which can be used as starting materials are known from several prior patents (Hungarian patents 156,119, 158,085, 162,384, 162,373 and 166,577, Dutch Patent Application Publication No. 72). 12286) as well as from the literature (Arz, Forsch. 22, p. 8.5 (1972)), or may be prepared by the processes described therein.

The fused pyrimidine derivatives of the formula I have valuable pharmacological effects and can therefore be used in the pharmaceutical industry. Individual representatives of this class of compounds exhibit analgesic, anti-inflammatory, RQ-antagonistic and antidepressant effects, while others of the compounds of the invention also exhibit longer-lasting beneficial effects on the nervous system as well as antilipemic activity.

212346 The pharmacological activity of the compounds of the invention is exemplified by tests carried out with a representative representative of the compounds of the invention which is an acid amide of 1.6 _ea; -dimethyl-4-oxo-1,6,7,8,9,9a _and -hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid (CH-127). Table 1 shows the results of the toxicity test.

Table I

Toxicity 1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-e] pyrimidine-3-carboxamide

8X «X amide (CH-127)

experimental animals way application ' ₅ 0 (mg / kg) rats oral 370 intravenous 210 subcutaneous 280 mice oral 360

The toxicities observed by intravenous administration are compared in Table II with the toxicities of the known analgesic PROBON, with the molar values of intravenous toxicity given in the table due to the different molecular weights of both compounds. Table II shows that CH-127 is approximately 1.5 times less toxic than PROBON when administered intravenously.

T and b u 1 k and II

Toxicity of PROBON and CH-127 by intravenous administration

compound “50 (mg / kg) molecular mass molar toxicity (mM / kg) PROBON 220 362.41 0.60 CH-127 210 223.27 0.94

Table III compares the anelgesic activity of CH-127 with the analgesic activity of PROBON in the hot plate assay (J. Pharm. Exp. Ther. 80, p. 130, 1944; Kysarletes Orvostudomones 2, p. 295, 1950). IV in a convulsion-induced test (Fed. Proo. 15, p. 494, 1956; J. Pharm. Exp. Ther. 1 * 33, p. 400 (1961)) in mice.

III

Table

Comparison of analgesic efficacy of PROBON and CH-127 in a hot plate test in mice

compound way application ^ 50 (mg / kg) ED10 (molar) (mM / kg) PROBON intravenous 52 0.14 subcutaneous 66 0.18 CH-127 intravenous 13 0,058 subcutaneous 25 0.11

Table IV

Comparison of analgesic efficacy of PROBON and CH-127 in a mouse cramp test

compound way application ^ 50 (mg / kg) ^ 50 (mM / kg) ---- r therapeutic index (^ 0 ^^ 50) PROBON oral 380 1.05 2.9 intravenous 140 0.38 - subcutaneous 215 0.59 - CH-127 oral 58 0.26 6.2 intravenous 34 ' 0.15 - subcutaneous 43 0.19 -

Table V compares the anti-inflammatory activity of CH-127 and phenylbutazone in various edema tests on the rat paw; the test substances are applied orally.

Table V

carrageenan edema (Proc. Soc. Exp. Biol. £££, page 544 (1962) CH-127: ED ₃₀ = 15 mg / kg of phenylbutazone: q = ₃ ED 60 mg / kg kaolin edem (Arch. Int. Pharmacodyn. CH-127: ED ₃₀ = 33 mg / kg 132. p. 16/1961 /) phenylbutazone: ED ₃ q = 95 mg / kg

dextran edeia (Arch. Int. Pharmacodyn. £ 02, p. 33 (1955))

CH-127: ED ₃₀ = 51 mg / kg phenylbutazone: ^ed 3q = 220 mg / kg

As shown in Table VI below, the inhibitory effect of CH-127 in adrenalectomized rats does not change, which means that the anti-inflammatory effect is independent of endogenous eteroids.

T a b u 1 k and VI

Anti-inflammatory effect of CH-127 on normal and adranalectomized rats (carrageenan edema, oral administration)

dose (mg / kg) inhibition of edema (%) to normal to adrenalectomized rats 25 29 25 75 50 44

The synergistic effect of CH-127 when co-administered with other anti-inflammatory agents is exemplified in Table VII.

Table VII

compound dose inhibition of edema (%) (carrageenan edema, oral application) CH-127 6.25 18 ' CH-127 25 30.4 Indomethacin 2.5 24 Suprofen 1,25 26.4 Suprofen + CH-127 1,25 + 25 65.7 Indomethacin + CH-127 2.5 + 6.25 41 Indomethacin + CH-127 2.5 + 25 83

As shown by the test results, CH-127 is more potent than the analgesic PSOBON when administered orally; its therapeutic index is more favorable.

The other compounds of formula I also exhibit a similarly good analgesic anti-inflammatory effect.

The fused pyrimidine derivatives of formula I are useful in combination with other analgesics, anti-inflammatory or other active compounds. Thus, the compounds produced by the process of the invention have a synergistic effect with, for example, morphine, 14-hydroxyazidomorphine, Fentanil, Indomethacin, azidomorphine, azidocodeine, etc. This property of the compounds produced by the process of the invention is important for example for anesthesia in surgery.

The compounds of formula (I) may be used as active ingredients in medicaments, the medicaments containing conventional non-toxic, inert, solid or liquid fillers and carriers. .-r ..

These medicaments may be in solid (e.g. tablets, capsules, dragees, etc.) or liquid (e.g. solutions, suspensions, emulsions) forms. Suitable carriers for this purpose are, for example, talc, calcium carbonate, magnesium stearate, water, polyethylene glycol, and the like.

These medicaments may optionally contain conventional excipients and additives, for example emulsifiers, disintegrants, etc.

The invention is illustrated in more detail by the following non-limiting examples.

Example 1

12.6 g of 1,6 _ax- dimethyl-4-oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid in 50 ml concentrated ammonia was cooled to 0 ° C and the solution was saturated with ammonia gas. The reaction vessel is sealed and shaken at 40-50 ° C for 24 hours. The reaction mixture was then shaken with chloroform. The combined chloroform phases were evaporated under reduced pressure and the residue was recrystallized twice from ethanol. Yield amide _AX 1,6-dimethyl-4-oxo-1, 6,7,8,9,9a-hexahydro _AX-4H-pyrido [1, 2-a] pyrimidine-3-carboxylic acid of melting point in the range from 183 to 184 ° C.

Example 2

Solution for injection

Weigh, to the nearest 1 g, 2 000 g of 1,6- _ax- dimethyl-4-oxo-1,6,7,8,9,9a- _ax -hexahydro-4H-pyrido acid into a 40 000 ml graduated glass flask. [1,2-a] pyrimidine-3-carboxylic acid (pharmaceutical grade). The flask is then made up to the mark with distilled water of the purity required for injection, completely dissolving the active substance. The resulting solution is filtered in a known manner and then filled into ampoules of 2 ml each. Full vials are sterilized for 30 minutes at 20 ° C.

Example 3

Combined solution for injection

Weigh, to the nearest ± 1 g, 500 g of 1,6 _ax- dimethyl-4-oxo-1,6,7,8,9> 9a _ax -hexahydro-4H-pyrido acid into a 10 000 ml graduated glass flask [ 1,2-a} pyrimidine-3-carboxylic acid of pharmaceutical purity. Weigh 1 g of azidomorphine and 100 ml of a 2% sodium bicarbonate solution into another beaker. Approximately 9 liters of distilled water of the purity required for the injectable solutions are poured into the first flask, and 8 g of sodium pyrosulphite are then added after the weighed substance has dissolved. After dissolving the pyrosulfite, a solution of azidomorphine is added. The flask is then made up to the mark with stirring. The resultant solution was filled in ampoules of 1 ml each and sterilized at 100 ° C for 1.5 hours.

Example 4

Cípky

500 g amide _{1,6-dimethyl-AX} 4-oxo-1, 6,7,8,9,9a-hexahydro _AX-4H-pyrido [l, 2-a] Pyrimidin-3-carboxylic acid is comminuted to a particle size below 10 µl and weigh into a vessel equipped with a stirrer that can be heated. 25 g of colloidal silicic acid are then added, followed by 25 kg of suppository mass in the molten state. The mixture is homogenized and suppositories of 2.5 g each are prepared in a casting machine in a manner known per se from the obtained homogeneous mass heated to 45 ° C.

Example 5

Dragee

1,000 g of 1,1'-dimethyl-α-oxo-1,1'-dimethyl-4'-hexamido-1,2-a] pyrimidine-3-carboxylic acid amide of pharmaceutical purity is homogenized with 300 g of crystalline cellulose and 150 g of potato starch, after which the homogenized mixture is granulated by adding a solution of 10 g of gelatin in 300 ml of water. The resulting granulate is dried and re-granulated, then mixed homogeneously with a mixture of 40 g talc and 5 g stearic acid. The resulting blend is then compressed into a tablet, convex on both sides, each weighing 200 mg. The tablets thus obtained are then coated in a coating drum.

Example 6

Anti-inflammatory ointment for skin treatment

At 45 ° C, 1,200 g of ethyl ethyl alcohol and 400 g of sorboxethenstearate are dissolved in 400 g of liquid paraffin. 2000 grams of white petrolatum are then added to the solution and the molten and liquid mass is filtered if necessary. Separately, at 65 ° C Dissolve 500 g amide 1, O-dimethyl-4-oxo-6,7,8,9,9a-hexahydro _AX-4H-pyrido [l, 2-a] pyrimidine 3-carboxylic acid in 5400 g of distilled water. The resulting solution was mixed with a solution of 7 g methyl p-oxybenzoate and 3 g propyl p-oxybenzoate in 90 g ethanol. The resulting solution is then immediately processed in a suitable homogenizer with the above mass to form a homogeneous ointment. The cooled ointment is then filled in known manner into tubes or cups.

Example 7

Combined anti-inflammatory ointment for skin treatment

200 g of cholesterol, 300 g of cetyl alcohol, 275 g of white beeswax and 525 g of canoline at 55 DEG C. are treated with 6 500 g of white petrolatum to form a homogeneous melt, which is then optionally filtered. 500 g of N, N-dimethyl-6-oxo-N, N, N-hexahydro-4 H -pyrido [1,2- a] pyrimidine-3-carboxylic acid amide, ground to a particle size of 100 and 20 g of colloidal Pyrimyoin are homogenized in 2200 g of distilled water at 55 ° C and then the homogenized suspension is added to the above mass. The resulting mixture is then homogenized in a suitable homogenizer to form a homogeneous mixture. The cooled ointment is then filled in a known manner into tubes or cups or applied to the surface of a sterile dressing mule, which is then rolled up.

Example 8

Eye drops

II g of borax, 22 g of sodium chloride, 115 g of boric acid and 1 g of pyrosulphite are dissolved in 10 l of water and 100 g of 1, 6-dimethyl-α-oxo-1,6 are added. 7, 8,9,9a-hexahydro _AX-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid. The solution was made up to 10,000 ml with distilled water, and then filled with 5 ml eye drops vials under sterile conditions.

Example 9

Combined eye drops

To a solution of 11 g of borax, 21.2 g of sodium chloride, 14 g of boric acid and 1 g of pyrosulphite in almost 10 l of water was added 200 mg of Primycin and the solution was heated to boiling. 100 g of N, N-dimethyl-6-methyl-6-oxo-6-oxo-1,2-ahexhydro-1H-pyrido [1,2-a] pyrimidine-3-carboxylic acid amide are dissolved in this solution and made up to distilled water. to a volume of 10,000 ml. This solution is then filled into a machine filler under sterile conditions with an eye drop bottle of 5 ml each.

Example 10

Combined préSkový backfill hydroohloridu g of oxytetracycline, 65 g of amide BE-Dimethyl-b-oxo-ljó,?, 8,9,9a-hexahydro-4H _ax-pyridofl, 2-a] pyrimidine-3-carboxylic-250'g of urea and 9- 650 g of anhydrous lactose are homogenized to a fine particle size. The particle size of the powder is adjusted by passing it through a 100 mesh screen, after which the appropriate backfill packages are filled with the resulting mixture.

Claims (6)

SUBJECT OF THE INVENTION A process for the production of fused pyrimidine derivatives of formula X, (I) II CONH, wherein each of R ¹ and R ¹ represents a C 1 -C 6 alkyl group, as well as their optically active isomers and physiologically tolerable salts, characterized in that the fused pyrimidine derivatives of the general formula II (II) COOH where R and R * are as defined above, optionally in the form of a racemate or in an optically active form, reacted with ammonia and the racemate of the formula I thus formed is optionally separated in its constituents and / or the compound of the formula I obtained is converted into its physiologically tolerable salts . 2) 2346 2. The method of item 1, up to +50 ° C. characterized in that the reaction is carried out in the range of -30 ° C 3. The process of claim 1 wherein the condensed pyrimidine derivatives of formula II, optionally in the form of a racemate or optically active, are reacted with ammonia in the presence of a water binding agent. 4. Process according to claim 1, characterized in that carbodiimide, preferably dicyclohexylcarhodiimide, is used as the water-binding agent. 5. A process according to claim 1, wherein the reaction is carried out in the presence of a solvent. 6. A process as claimed in any one of claims 1 to 5, wherein the starting materials are compounds of the formula II, optionally in the form of a racemate or in the form of optically active substances, in which each of R and r '