CS212345B2 - Method of making the condensated pyrimidin derivatives - 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 are distinguished by valuable pharmacological effects, for example analgesic, anti-inflammatory, PG-antagonistic and antidepressant. In addition, some of these compounds have beneficial effects on the nervous system and are also antilipemically effective.

and

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

CONH, (I) each of R and r '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 condensed pyrimidine derivatives of formula (II),

H

AND

O

212345 2 where

R is as defined above, optionally in the form of a racemate or an optically active compound, reacted with the halides of the formula IIIa,

where R ¹ R-X (lila) is as defined above, and X means halogen, or with sulfates of the general formula Illb, (r ') ₂ Sat ₄ (Illb) where R ¹ my meaning as above, or with phosphates of formula IIIc, (S ¹ > ₃ P ° ₄₎ (IIIc) where r ' has the above meaning,

preferably in the presence of an acid scavenger, and optionally the racemate I thus formed is separated in a known manner by separation of the racemate into its component and / or the compound of formula I obtained is converted into its physiologically tolerable salts.

In the process of the invention, the fused pyrimidine derivatives of formula (II) are treated with a suitable reagent to introduce the R ¹ group into the molecule. The reagent may be, for example, a halide of formula IIIa. Preferably, chloride, bromide or iodide is used. The group R @ ¹ may, however, also be introduced by reacting with sulphates of general formula IIIb or phosphates of formula IIIe. The introduction of the group R ¹ is preferably carried out at temperatures ranging from 20 to 250 ° C and in the presence of a diluent.

The reaction is preferably carried out in the presence of an acid scavenger. Suitable acid scavengers are preferably an alkali metal hydroxide, for example sodium hydroxide or potassium hydroxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate.

Excess halides of formula IIIa or sulphate of formula IIIb or phosphate of formula IIIc may be used as solvents or may be used in the presence of water, alcohols, ketones, dimethylformamide, aromatic hydrocarbons, formamide, hexamethylphosphoric triamide, acetonitrile or mixtures thereof.

In order to isolate the obtained condensed pyrimidine derivatives of the general formula (I), the reaction mixture is worked up in a manner known per se.

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.

The condensed pyrimidine derivatives of formula (II) which can be used as starting materials are known from several earlier patents (Hungarian patents 156,119, 158,085, 162,384, 162,373 and 166,577), published Dutch patent application no. 72,12286. ) and from the literature (Arz. Forsch. 22, p. 815 (1972)), or may be prepared by the methods described therein. Compounds of formulas IIIb and IIIc are commercially available chemicals.

The fused pyrimidine derivatives of the general formula I have valuable pharmacological effects and can therefore be used in the pharmaceutical industry. Individual representatives of this class of compounds have analgesic, anti-inflammatory, PG-antagonistic and antidepressant effects, while others of the compounds of the invention are furthermore characterized by beneficial effects on the nervous system also by antilipemic effects.

The pharmacological activity of the compounds according to the invention is demonstrated by tests carried out using a typical representative of the compounds according to the invention, which is 1.6 _x dimethyl-4-oxo-1, 6,7,8,9,9a-hexahydro _AX-4H-pyrido [ 1,2-a] pyrimidine-3-carboxamide (CH-127). Table I shows the results of toxicity tests.

Tabulk. and I

Toxicity 1,6 _ax- dimethyl-4-oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide (CH-, 27)

experimental animals method of application ld ₅ o · · (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, and the molar values of intravenous toxicity are given due to the different molecular weights of both compounds. It can be seen from Table II that CH-127 is approximately 1.5 times less toxic than PROBON when administered intravenously.

Table II

Toxicity of PROBON and CH-127 by intravenous administration

compound '> ₅ o (mg / kg) molecular mass molar toxicity (mM / kg) PROBON 220 362.41 0.60 CH-, 27 210 223.27 0.94

Table III compares the analgesic activity of CH-127 with the analgesic activity of PROBON in a hot plate assay (J. Pharm. Exp. Ther. 80, 130, 1944). Table IV, then, in a convulsion-inducing test (Fed. Proc. 15: 494 (1956)) J. Pharm. Exp. Ther. 400, 133, 961) in mice.

2.2345

Table III

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

compound way application ^ 50. (mg / kg) ED ^ q (molar) (mM / kg) PROBON intravenous 52 0.14 subcutaneous 66 0.18 CH-, 27 intravenous 13 0,058 subcutaneous 25 0.11

Table IV

Comparison of the analgesic efficacy of PROBON and CH-127 in a test that induces mouse convulsions

compound way application ^W 50 (mg / kg) ^ 50 (mg / kg) therapeutic index (ld ₅₀ / ed ₅₀ ) PROBON oral 380 1.05 2.9 intravenous , 40 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 edem tests on rat paw; the flights examined are applied orally.

Table V

carrageenan edema (Why. Soc. Exp. Btol. 111. p. 544 /, 962 /) CH-, 27: ED ₃₀ = 15 mg / kg phenylbutazone: ED ₃₀ = 60 mg / kg kaolin edem CH-127: ED ₃₀ = 33 mg / kg (arch. Int. Fharmacodyn. 132. pp. 16/196, /) phenylbutazone: _ED30 = 95 mg / kg dextran edem CH-127: ED ₃₀ = 51 mg / kg (Arch. Int. Pharmacodyn, 102, page 33 (1955) phenylbutazone: ED ₃ q = 220 mg / kg

As shown in Table VI below, the inhibitory effect of CH-127 in adrenal ectomized rats is unchanged, which means that the anti-inflammatory effect is independent of endogenous sterolds.

Table VI

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

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

The synergistic effect of CH-127 when co-administered with other anti-inflammatory agents is illustrated by the results shown in Table VII.

Table VII

compound dose inhibition of edema,% (carrageenan edema orally) CH-127 6.25 18 CH-127 25 30.4 Indomethaein 2.5 24 Suprophen 1,25 26.4 Suprophene + CH-127 1.25 + 25 65.7 Indomethaein + CH-127 2.5 + 5.25 41 Indomethaein + CH-127 2.5 + 25 83

As can be seen from the above test results, oral administration of CH-127 is more effective than the analgesic PROBON; its therapeutic index is more favorable.

The other compounds of formula I also exhibit similarly good analgesic and anti-inflammatory activity.

The fused pyrimidine derivatives of formula I are useful in combination with other analgesic, anti-inflammatory or other active compounds. Thus, the compounds produced by the process of the invention exhibit 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.

The 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.

The medicaments may optionally contain customary auxiliaries and additives, for example emulsifiers, disintegrants, etc.

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

Example 1

10.2 g of 6 _ax- methyl-4-oxo-1,6,7,8,9,9a _ax -hexahydro-4-pyrido-4-pyrido [1,2-a] pyrimidine-3-carboxamide is suspended in solution of 2 g of sodium hydroxide in 65 ml of water.

During the suspension, a solution of 4 g of sodium hydroxide in 20 ml of water and 9.5 g of dimethylsulphate was added dropwise. After stirring for 1 hour, the pH of the solution was adjusted to neutral by adding 10% hydrochloric acid and the aqueous solution was then shaken with chloroform. Fez organics were combined, dried over sodium sulfate and evaporated under reduced pressure to give 10.8 g of amide acid 1,6 -dioethyl _{AX-4-oxo-1,6,7,8,9,9a-hexahydro ax} -4H-pyrido (1,2-a) -

pyrimidine-3-carboxylic acid. The product, recrystallized twice from ethanol, has a melting point of 185-186 ° C. Analysis: calculated: 59.18% C, 7.67% H N, 18.82; found: 58.95% C, Example 2 7.69% H , 18.85% N.

10.2 g of amide acid, bis-methyl-4-oxo-6,7,8,9,9a-hexahydro _AX-4H-pyrido [1,2-a] pyrlmidinr3-carboxylic acid are suspended in a solution of 2 g NaOH sodium chloride in 65 ml of water. Simultaneously to the reaction mixture separately added dropwise 11.55 _t g of diethyl sulfate and a solution of 4 g sodnéhp hydroxide in 25 ml water. After stirring for one hour, the pH of the solution was adjusted to neutral by adding 0% hydrochloric acid, and the solution was shaken with chloroform. The organic phase is evaporated under reduced pressure. This afforded 9.9 g amide 1-ethyl-6-methyl-4-oxo-1,6,7,8,9,9a _AX hexahydro-4H-pyrldo [1,2-a] pyrimidine-3- carboxylic acid which melts in the range from 162 to 163 ° C after recrystallization from isopropanol.

Analysis:

H, 8.07; N, 17.71.

found: 60.58 «C, 8.88 55 H, 17.85% N.

Example 3

10.2 g of amide acid _{AX 6-methyl-4-oxo-1,6-AX} 7,8,9,9a- hexahydro-4H-pyrido [I, 2-a] pyrimidine-3-carboxylic acid and e at 235 ° C is mixed in the presence of 6.4 g of potassium carbonate with

27.3 g of triethyl phosphate. Once the evolution of gas has ceased, the reaction mixture is poured into 150 ml of water and shaken several times with chloroform. The combined organic phases were evaporated under reduced pressure. This afforded 8.5 g amide 1-sthyl _{AX-6-methyl-4-oxo-1,6,7,8,9,9a} -hexehydro _AX-4H-pyrido [1,2-a] pyrimidine-3 The carboxylic acid which melts at 163 DEG C. after recrystallization from isopropanol and does not produce any lowering of the melting point when mixed with the product obtained in Example 2.

Example 4

10.2 g of amide acid _AX 6-methyl-4-oxo-1,6,7,8,9,9a -hsxahydro _AX-4H-pyrido [l, 2-aJ pyrimidine-3-carboxylic acid, 2 g of N- $ of butyl bromide and 7.5 g of potassium carbonate were refluxed in 125 ml of ethyleneol for 30 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. This afforded 8.5 g amide 1-n-butyl-6-methyl-4 _{ax-oxo-1,6,7,8,9,9a AX} hexahydro-4H-pyrido [I, 2-a] pyrimidine M.p. 160-162 ° C.

Analysis:

H, 8.74; N, 15.84. Found: C, 63.08; H, 8.83; N, 15.78.

Example 5

Solution for injection

Weigh, to an accuracy of 1 g, 2 000 g of 1, N-dimethyl-et-oxo-1,6,7,8,9,9a _and hex-hexahydro-4H- acid amide into a calibrated 40,00 ml glass flask. pyrido [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 solution is filtered in a known manner and then filled into 2 ml ampoules. The filled ampoules are sterilized at 120 ° C for 30 minutes.

Example6

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 and} hexahydro-4H-pyrido 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 a second beaker. About 9 liters of distilled water for injection solutions are poured into the first flask, and 8 g of sodium pyrosulphite are then added after the weighed substance has dissolved. After dissolution of the pyrosulfite, a solution of azidomorphine is added. The flask is then filled up to the mark with stirring. The resulting solution is filled into 1 ml ampoules which are sterilized at 100 ° C for 1.5 hours.

Example 7

Cípky

500 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 amide is ground to a particle size under 10 µm 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 molten suppository. The mixture is homogenized and suppositories of 2.5 g each are produced in a casting machine in a manner known per se from the resulting homogeneous mass heated to 45 ° C.

Example 8

Dragee

000 g amide 1, b-dimethyl-s-oxo-6,7,8,9,9a-hexahydro _AX-4H-pyrido (l, 2-a] pyrimidine-3-carboxylic acid of pharmaceutical purity are homogenized with 300 g of crystalline cellulose and 150 g of potato starch, after which the homogenized mixture was granulated by adding a solution of 10 g of gelatin in 300 ml of water. The resulting blends are then compressed on both sides of a 200 mg convex tablet, and the tablets are coated in a drag drum.

Example 9

Anti-inflammatory ointment for skin treatment

At 45 ° C, 1200 g of cetyl alcohol and 400 g of sorboxethenstearate are dissolved in 400 g of liquid paraffin. 2000 g of white petrolatum are then added to the solution and the molten and liquid mass is optionally filtered. Separately, at 65 ° C Dissolve 500 g amide 1, O-dimethyl-s-oxo-6,7,8,9,9a-hexahydro _aX-4H-pyrido [1,2-a] pyrimidine 3-carboxylic acid in 5400 g of distilled water. The resulting solution was mixed with a solution of 3 g propyl p-oxybenzoate and 7 g methyl 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 a known manner with tubes or cups.

Example 10

Combined anti-inflammatory ointment for skin treatment

200 g of cholesterol, 300 g of ethyl alcohol, 275 g of white beeswax and 525 g of lanolin are treated at 55 ° C with 6 500 g of white petrolatum to form a homogeneous melt. The liquid mass is then optionally filtered. 500 g of 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexa-8-hydroxy-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid amide, ground to particle size 1:00 mesh, and 20 g of colloidal pyrimidine are homogenized in 2200 g of distilled water at 55 ° C and then added to the above mass. The mixture is then homogenized in a suitable homogenizer to a homogeneous ointment. The cooled ointment is then filled in a known manner with tubes or cups or applied to the surface of a sterile dressing which is then rolled up.

They did

OF

Eye drops of g borax, 22 g of sodium chloride, 115 g of boric acid and 1 g of pyrosulphite are dissolved in 10 liters of water, and 00 g of 1,6'-dimethyl amide are added to the resulting solution.

SX

-4-oxo-6,7,8,9,9a -hexshydro _AX-4H-pyrido [1,2-a pyrimičin-3-carboxylic acid. The solution was made up to 10,000 ml with distilled water and then filled with 5 ml eye drop vials under sterile conditions with a machine filler.

Example 12

Combined eye drops

To a solution of 11 g of borax, 21.2 g of sodium chloride, 1.4 g of boric acid and 1 g of pyrosulphite in almost 10 liters of water was added 200 mg of primycin and the solution was heated to boiling. Then, 1.00 g of N, N-dimethyl-6-oxo-1, N, N, N-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid amide is dissolved in the resulting solution, and the resulting solution make up to 10 000 ml with distilled water. This solution is then filled into a 5 ml eye drop vial in a machine filler under sterile conditions.

Example 13

Combined backfill

A mixture of 35 g of oxytetracycline hydrochloride, 65 g of 1,1'-dimethyl-α-oxo-1,6,6,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid amide _and 250 g of urea and 9650 g of anhydrous lactose are homogenized to a fine powder. The particle size of this powder is adjusted by passing it through a 100 mesh screen and then filling the resulting mixture into suitable backfill packages.

Claims (5)

A process for the production of fused pyrimidine derivatives of the general formula I, R ¹ I (X) o wherein each of R ¹ and R ¹ represents an alkyl group having 1 to 6 carbon atoms, as well as 1 optically active isomers and physiologically tolerable salts thereof, characterized in that the fused pyrimidine derivatives of the general formula II, About where R is as hereinbefore defined, optionally in the form of a racemate or an optically active compound, reacted with the halides of the general formula IIIa, where η’-χ (lila) R ¹ has the above meaning; and X means halogen, or sulphates of the formula IIIb, ^(R1 > 2 ^SO 4 (Illb) where R ¹ has the above meaning, or β phosphates of formula IIIc, where R ¹ (R ¹ ) ₃ to ₄ (IIIc) my meaning as above, and optionally the thus obtained racemate of the formula I is separated into its constituents and / or the compound of the formula I obtained is converted into its physiologically tolerable salts. ' 2. A process according to claim 1, wherein the reaction of the fused pyrimidine derivatives of formula II with the halides of formula IIIa or the sulfates of formula IIIb or phosphates of formula IIIe is carried out in the presence of an acid scavenger. 3. A process according to claim 2, wherein the acid binding agent is an alkali metal hydroxide, preferably sodium or potassium hydroxide, an alkali metal bicarbonate, preferably sodium or potassium bicarbonate, or an alkali metal carbonate, preferably sodium carbonate. or potassium carbonate. 4. A process according to any one of claims 1 to 3, wherein the reaction is carried out at temperatures ranging from 20 to 250 ° C. 5. Process according to claims 1-4 for the manufacture of compounds of formula I wherein each of R and ^R1 represents a methyl group, characterized in that as starting Letek uses compounds of formulas II and IIIa or IIIb or IIIc wherein R and R ¹ is as defined in this point, and X is halogen.