CS272784B2 - Method of pyrimido (5,4-8) (1,4) oxazin derivatives preparation - Google Patents

Abstract

The production method of pyrimido [5,4-b][1,4]-oxazine derivates of the general formula I, where R<1> stands for C1-4 alkyl group, R<2> stands for halogen atom or group -NR<5>R<6 >, where R<5> represents hydrogen or benzyl group or the C1-4 alkyl group, which is substituted for hydroxyl group, R<6> stands for the amino group, cycloalkyl group C3-6, alkyl group C, which can be substituted, or possibly substituted phenoxy group, while NR<5>R<6> can also stand for six-membered saturated heterocycle containing nitrogen atom, which can contain another nitrogen atom or oxygen atom and which can be substituted, R<3> and R<4> represent the same or different substituents, such as hydrogen atom or alkyl group C1-4, R<9> stand for the alkyl group C1-4 , which is substituted on the condition that if the substituent R<9> does not have benzyl group, then the substituent R<2> has a different meaning than chlorine atom and 4-morpholinyl group, and also tautomeric mixtures and addition salts with acids derived from these compounds, while the compound of the general formula II is brought into reaction with the compound of the general formula IIIR<9>X /III/,where R<9> has the above-mentioned meaning and X is chlorine or bromine atom or 4-toluene sulphonyl oxy group, in the presence of organic dissolvent and agent, which binds the acid at the boiling temperature of the used dissolvent. Afterwards, the acquired compound of the general formula I is converted into addition salt with acid and/or the free base acid is extricated from addition salt with acid.<IMAGE>

Description

The invention relates to a method for preparing pyríraído / ^_ _5} -4-B7 / 1.47-oxazine derivatives of formula I

wherein r 'is C 1 -C 4 alkyl,

R 6 represents a halogen atom or a group -MR ⁶ R ⁶ in which R ⁹ represents a hydrogen atom or a benzyl group or a C 1 -C 4 alkyl group which is substituted by a hydroxyl group,

R 6 represents an amine group, a C 3 -C 6 cycloalkyl group, a straight or branched chain alkyl group having 1 to 4 carbon atoms optionally substituted by a hydroxyl group, a mercapto group, an aminocarbonyl group, a furyl group, 2-benzo / l, (4) dioxanyl, C1-C4 dialkylamino or phenyl, or phenoxy optionally substituted by one or more of halogen, alkoxy or (C1-C4) groups, and a six-membered saturated heterocycle containing nitrogen and optionally containing an additional nitrogen or oxygen atom optionally substituted by a C1-C4 alkyl group or a benzyl group, wherein:

NR 6 R 6 may also be a six-membered saturated nitrogen-containing heterocycle optionally containing an additional nitrogen or oxygen atom and optionally substituted by a C 2 -C 4 alkoxycarbonyl or C 1 -C 4 hydroxyalkyl group and R ⁴ represent the same or different substituents which are hydrogen or C1-C4alkyl, o

R ^y is C 1 -C 4 alkyl substituted by oxo, cyano, aminocarbonyl, C 2 -C 5 alkoxycarbonyl, pyridyl, morpholinocarbonyl or phenyl, with the proviso that when the Z is benzyl, then R is other than chloro and 4-morpholinyl, as well as a process for preparing tautomeric mixtures from these compounds and acid addition salts thereof.

Said pyrimidc / ^- 5.4 ~ B7 / ^- 1,47oxazinové derivatives prepared according to the invention belongs structurally to the compounds with a cyclic system which hitherto

CS 272 784 B2 has been found little.

With respect to the prior art, it has been found that so far only a few types of these compounds have been found in the literature, as reported in several articles. For example, in I.V. Sazonova and T.S. Safonova (see Khim. Geterotsikl.

Soed., 1972, 1285) discloses derivatives which contain mainly an amino, acetamide or methyl group in the second position or a hydroxyl group, methyl group or chlorine atom in the fourth position; further known compounds (see ibidera, 1973, 1694) which contain a double bond and an ethoxycarbonyl group at the sixth position; derivatives with a lower alkyl group in the sixth position (see ibidem, 1976, 681), as well as compounds containing a morpholinyl group that is in the fourth position (see ibidem, 1978, 397) 397).

It is well known that diseases affecting the cardiovascular system (such as cardiac weakness, myocardial infarction, hypertension) are among the most common causes of death. In this category of diseases, the number of heart attacks has been increasing recently, especially the number of patients suffering from chronic cardiac weakness. Until now, most of these patients have been treated with glycoside cardiacs. However, it should be noted in this context that it is generally well known that the use of these drugs is not safe since they experience side effects (such as tachycardia and arrhythmias). In addition, it should be noted that it is very difficult to determine the dosage of these substances, with individual assessment of each case and great care to be taken by each doctor, as the therapeutic safety of these drugs is poor. Besides, it is. it should be noted that these drugs cannot be used in the treatment of acute cardiac weakness and post-infarction.

It follows from the foregoing that, over the past decade, it has become increasingly important to find therapeutically effective drugs to stimulate cardiac activity in cases of flaccid myocardium, without causing side effects when administered orally.

Due to the above therapeutic requirement, several new cardiotonic drugs have recently appeared. Larger and more important groups can be characterized as follows:

Prenalterol, i.e. 1- (4-hydroxyphenyl) -3-tertiary butyl-amino-2-propanol, is a representative example of adrenergic β 5 agonists, which have been studied very carefully in clinical practice. When administered intravenously in cases of acute cardiac insufficiency, the drug is very effective, but there is no improvement in cardiac activity in cases of sustained oral therapy (see J. Cardiovasc. Pharm. 6, 491 (1984)).

Pirbuterol, which is 1- (5-hydroxy-6-hydroxymethyl-2-pyridinyl) -2-tertiary butylaminoethanol constitutes stimulating drug as 2) and _1/2 ^ aůrenergické receptors - which has a favorable effect during oral administration over several weeks , however, addiction to this substance has been observed over longer intervals / see New Engl. J. Med. 305, 185 (1981)].

The mode of action of bipyridine-type cardiotonics is different from the mode of action of adrenergic β-agonists, and this has not been fully elucidated to date. An important member of this group, amrinone (which is 3-amino-5- (4-pyridyl) -2- (1H) -pyridinone)), contributes significantly to increasing the cardiac performance of patients suffering from persistent cardiac impairment and peripheral vascular resistance, with in addition to stimulating cardiac activity, this substance also reduced the resistance of these peripheral blood vessels. However, it should be noted that the therapeutic suitability of this amrinone is greatly limited by the occurrence of intense side effects that occur in the blood count (see Am. J. Med. 72, 113, 1983; Brit. J. Clin. Pharm. 17, 317). (1984)

Sulinazole, an imidazopyridine / t. 2- (2-methoxy-4-methylCS 272 784 B2 sulfinylphenyl) -1H-imicazo [4,5-b] pyridine also exhibits a vasodilating effect.

However, in addition to the favorable target effect, this sulmazole has relatively frequent side effects, which have been found in clinical trials (see Annal). Cardiol. Anghiol. 33, 219 (1984).

The biological properties of these more important cardiotonics, which have an effect different from glycoside cardiacs, show that there is still a need in this field to find new drugs that can be orally administered permanently, free of side effects and thus safely used.

According to the present invention, it has been found that the novel pyriruido [5,4-b7] 1,4] oxazines of the formula I in which the substituents have -R ¹ ; R ^2, R, R ^4, and R? The above meaning, as prepared by the process of the present invention, suitably satisfies the above therapeutic requirements.

The method for the preparation of novel pyriruido / ^- 5,4-B7 / ^_ 1,47oxazinových derivatives of. of formula I

wherein R ^{1 is} C 1 -C 4 alkyl,

S 6 *

R represents a halogen atom or a group -NR ⁷ R, which is meant

R represents a hydrogen atom or a benzyl group or a C 1 -C 4 alkyl group which is substituted by a hydroxyl group,

R ^ is amino, C 3 -C 6 cycloalkyl, C 1 -C 4 straight or branched chain alkyl optionally substituted by hydroxyl, mercapto, aminocarbonyl, furyl, 2-benzo / 1,4 a dioxanyl group, a dialkylamino group having 1 to 4 carbon atoms or a phenyl group, or a phenoxy group optionally substituted by one or more groups selected from halogen, an alkoxy group or groups having 1 to 4 carbon atoms, and a six-membered saturated heterocycle containing nitrogen and optionally containing a further nitrogen or oxygen atom, which is optionally substituted by a C1-C4 alkyl group or a benzyl group, wherein g. NR R may also be a six-membered saturated nitrogen-containing heterocycle, optionally containing an additional nitrogen or oxygen atom, and optionally substituted by a C 2 -C 4 alkoxycarbonyl or C 1 -C 4 hydroxyalkyl group 4 carbon atoms,

CS and R4 are the same or different substituents, which are hydrogen or C 1 -C 4 alkyl,

R is C 1 -C 4 alkyl substituted by oxo, cyano, aminolecarbonyl, alkoxycarbonyl. From 2 to 5 carbon atoms, pyridyl, morpholinocarbonyl or phenyl, and with the proviso that when R p is benzyl, R is other than chloro and 4-morpholinyl, and as well as tautomeric mixtures derived from these compounds and acid addition salts thereof according to the invention consists in reacting a compound of formula II

in which the substituents R ^1, R ^2, R and R have the same meaning as above, with a compound of formula III

R ⁹ X / 111 /

Q in which R is as defined above and X is chlorine, bromine or 4-toluenesulfonyloxy, in the presence of an organic solvent and an acid-binding agent, at the boiling point of the solvent used, the basic compound of formula I obtained; is converted to an acid addition salt, and / or the base compound is released from its acid addition salt.

Preferably, the organic solvent used is a ketone such as methyl ethyl ketone or a lower alkanol such as ethanol or isopropanol.

Regarding the literature / see T.A. Geissman: Principles of Organic Chemistry, 3rd edition, edited by H. Freeman, London, 1968], the substituent X, which represents a leaving group, can be defined as part of a molecule that is readily cleaved by nucleophilic agents. Such groups are, for example, halogens, sulfonyloxy groups such as lower alkanesulfonyloxy, and optionally substituted benzenesulfonyloxy groups, and may also be alkanesulfonyl and alkanesulfinyl groups such as methanesulfonyl.

According to the present invention, a compound of formula II is reacted with a compound of formula III, wherein, as already mentioned, X is preferably a leaving group, a chlorine atom, a bromine atom or a 4-toluenesulfonyloxy group. The reaction is carried out in the presence of a solvent and an acid binding agent. Suitable solvents for this treatment are ketones such as acetone and preferably methyl ethyl ketone, or lower alkanols such as ethanol or isopropanol. As bases, representing an acid-binding substance

It is possible to use an alkali metal alkoxide which is prepared from an alkanol as a solvent, and in the case where the ketone is used as a solvent, it is particularly preferred to use potassium carbonate as an acid binding agent. This reaction is preferably carried out at the boiling point of the solvent used.

The basic compounds of formula (I) may be converted in known manner into acid addition salts which are particularly suitable for pharmaceutical purposes, for example by dissolving the base in a suitable organic solvent, and then adding the appropriate acid or a solution of the acid in a suitable organic solvent. . The salt thus obtained is isolated by filtration or evaporation in vacuo and then, if necessary, purified in a manner known per se, such as recrystallization. Particularly suitable acid components are non-toxic inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or non-toxic organic acids such as acetic acid, tartaric acid, maleic acid may also be used or fumaric acid.

When an inorganic mineral acid is used as the acid component, it is particularly suitable to use a lower alkanol such as ethanol or isopropanol or acetone as solvent. When organic acids are used as the acid components, it is particularly advantageous to use the solvents mentioned above or to use an ether such as ethyl ether or isopropyl ether.

Most of the compounds of formula III

R ⁹ Z (111) which are used as starting compounds for the reaction with a compound of formula (II) above and in which K is a hydrogen atom are known compounds (see, for example, EH Rodd: Chemistry of Carbon Compounds, Elsevier Publishing Co. , London, 1951, 615) The novel compounds of formula (III) may be prepared by known methods or by analogous procedures.

As mentioned above, the compounds of the present invention have a very significant biolobic effect, and in particular a cardiotonic effect.

The novel and superior effect of the compounds of the present invention can be confirmed by myocardial contraction force (MCE), and the effect of the compounds of the present invention to increase myocardial contraction force was confirmed by tests and in vivo methods to be described. below.

Methods

A) Tests performed on cats under anesthesia:

In these animals, anesthesia was induced intravenously (i.v.) at a dose of 30 mg / kg body weight of sodium pentobarbital. Artificial respiration was then performed and the chest and pericardium opened. A tensioned arc was then sewn onto the epicardial surface of the left ventricular (see J. Pharm. Exp. Ther. 90, 26 (1947)). P 23Db and electromanometer. Test compounds were administered either intravenously (i. V.) Via a femoral artery cannula, or intraduodenally (i.d.) via a duodenal cannula. At the beginning of the experiment, isoproterenol (IS) was administered intravenously at a rate of 0.2 µg / kg, which served as an internal standard for determining myocardial reactivity. Indeed, the peak value of the MCF response can also vary individually for each animal for each of the 272724 B2 or positive inotropic agents. Thus, isoproterenol was not used as a true reference drug.

Tytop MCF responses were expressed as percent changes from baseline, with the effect of the test compound at 5 milligrams / kilograin administered intravenously on MCF compared to the effect of isoproterenol administered intravenously at 0.2 µg / kilogratn. The results obtained are shown in Table 1 below.

Table 1

Effect of an increased MCF value of compounds of formula I in open-chest anesthetized cats after intravenous administration of 5 mg / kg of this compound

Example compound C. MCF increase in% relative to original value Efficacy compared to 0.2 µg / kg i.v. filed IS 1 40 0.9 i-i & v = - 55,5 1,2 28 58.3 0.82 29 37 1,8 31 66 0.87 > 32 50 0.86

The above results show that the compounds of the present invention exhibit an effect in which an MCF value is increased, similar to or greater than that of isoproterenol. Because isoproterenol is a potent adrenergic stimulant, it causes a measurable increase in MCF when administered intravenously at a dose as low as 0.2 µg / kg, for example. Furthermore, isoproterenol induces a short-term and completely reversible MCF response and does not affect blood circulation parameters in any way. Surprisingly, it was found that the heart rate was increased very little or not at all when the compounds of the present invention were administered, as shown in Table 1.

The effect of some of the compounds of the invention was also tested by intraduodenal administration. Compound 9 showed a strong positive inotropic effect at both 20 mg / kg and 5 mg / kg.

B) Tests performed on dogs under anesthesia.

In these animals, anesthesia was induced intravenously with a dose of 35 mg / kg of sodium pentobarbital. The chest and pericardium were then opened, and an electromagnetic flow probe was attached to the left circumflex coronary artery, its lower ascending part, which was prepared, to measure blood flow in the coronary artery.

A calibration arc was then tensioned to the point where the coronary artery was altered as described above to measure the MCF value. A femoral arterial cannula was used to determine systolic blood pressure and a femoral venous cannula was used for intravenous drug administration. The dp / dt value was determined from the pressure measured using a Millar pressure sensor placed in the left ventricular.

CS 272 784 B2

All parameters were registered on a Beckman R 12 8-channel dynograph.

C) Tests on conscious cats.

These animals were used for testing by the Eabloczky and Mader method (see Measurement of Systemic and Pulmonary Arterial Pressure in Conscious Animals, lecture at the Congress of the International Union of Pharmaeologists, Budapest, 1980) or certain modifications of this method were used. In these tests, the aorta and pulmonary arteries were permanently catheterized to measure both blood pressures. In this modification, the right ventricle was also catheterized to determine the dp / dt value. » ^H max

Based on the results obtained from the detailed testing of compound 9 using the above methods, it can be concluded that the compound of the present invention exhibited positive inotropic and coronary-dilatory activity.

Analysis of the effects of compound 9.

It was administered intravenously at doses of 0.5 and 1.0 mg / kg, or intraduodeally at a dose of 5 mg / kg in open-chest anesthesia dogs. At an intravenous dose of 0.5 mg / kg, an increase in MCF of 56% and an increase in coronary flow of about 34% was observed, with only very slight tachycardia (about 6-7%) and a slight decrease (about 10 to 15). %) systemic arterial blood pressure.

At an intravenous dose of 1.0 mg / kg, an increase in MCF of 46% for 10 minutes, an increase in coronary flow of 20% for 10 minutes, an increase in heart rate of only 13% (for 5 minutes) and a decrease in systemic arterial blood pressure by 20%.

At an intraduodenal dose of 5 mg / kg, an increase in MCF of about 30% was observed, which lasted for 60 minutes.

Based on the results of the pharmacological tests, the compounds according to the invention can be used for the treatment of cardiovascular diseases, in particular for improving cardiac muscle failure activity and for improving coronary circulation (i.e., flow). The toxicity of these compounds is generally low. Taking these properties comprehensively together, a wide variety of effects can be achieved with the compounds of the present invention, and the compounds are therapeutically safe.

For therapeutic administration, the daily dose is in the range of about 0.2 mg / kg to 250 mg / kg, preferably in the range of 0.2 mg / kg to 50 mg / kg, optionally administered in one day divided, taking into account the absorption conditions.

For therapeutic application, the active compounds prepared by the process of the present invention are mixed with other pharmaceutical formulations, mixed with non-toxic, inert, solid or liquid carriers and / or additives suitable for enteral or parenteral administration, these being The substances are well known and widely used in the pharmaceutical industry. For example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc and vegetable oil can be used as carriers. Preservatives, wetting agents (surfactants), emulsifying or dispersing agents, buffering agents and flavoring agents may be used as additives.

By using such carriers and additives, the active ingredients prepared by the process of the present invention can be formulated in the form of conventional pharmaceutical compositions such as a solid form (such as tablets, capsules, pills and suppositories) or a liquid form (such as an aqueous or oleCS 272 784 B2 (solutions, suspensions, emulsions, syrups) as well as the compounds prepared by the process of the invention may be mixed into injectable solutions to form suspensions and emulsions.

Pharmaceutical compositions containing the compounds of Formula I or pharmaceutically acceptable acid addition salts thereof as active ingredients can be prepared from the compounds of the present invention.

The process of the present invention will be illustrated by the following non-limiting examples.

Example 1

Preparation of 4- (2-hydroxyethyl) amino-2-methyl-8- (2-oxopropyl) -6,7-dihydro-8H-pyrimido [5,4-b7] 1,47-oxazin-7-one.

0.31 g of chloroacetone was dissolved in 5 ml of methyl ethyl ketone, and the solution was added dropwise over 15 minutes to a suspension containing 0.68 g of 4- (2-hydroxyethyl) amino-2-methyl-6, 7-dihydro-8H-pyrimido / 5,4-B7 / ^- 1,47oxazin-7-one ,. 0.5 g of anhydrous potassium carbonate and 15 ml of methyl ethyl ketone were added and the mixture was heated to boiling and stirred at this temperature for 8 hours, then filtered while hot. The filtrate was evaporated to a volume of 10 mL and then allowed to stand at 0-4 ° C overnight. The crystals were collected by filtration, washed with ether and dried to give 0.70 g of the desired product (83% yield), mp 150-152 ° C. The hydrochloride salt had a melting point of 185-187 ° C.

Example 2

Preparation of 8-cyanomethyl-2-methyl-4- / 2- (4-morpholinyl) ethyl-7-amino-6,7-dihydro-8H-pyrimičo / ^- 5,4-B7 / ^- 1.47 ° benzoxazine-7-one .

0.25 g of chloroacetonitrile was dissolved in 50 ml of methyl ethyl ketone, and this solution was then added dropwise over a period of 15 minutes to a suspension containing 0.88 g of 2-methyl-4- / 2- (4-morpholinyl) ethyl-7-amino-6. , 7-dihydro-8H-pyrimido / ^- 5,4-B7 / ^- 1,47oxazin-7-one as a base, .and 0.5 g of anhydrous potassium carbonate in 15 ml of methyl ethyl ketone, which was carried out under boiling and stirring for 8 hours. The precipitate thus obtained was filtered off and washed hot with methyl ethyl ketone. The filtrate was evaporated and the residue triturated with diisopropyl ether. After filtering off the solid, it was washed with diisopropyl ether and dried. 0.91 g of the desired product is obtained (corresponding to a yield of 91%). Melting point: 126 - 128 ° C.

Example 3

Preparation of 8-aminocarbonylmethyl-4- (4-ethoxycarbonyl-1-piperazinyl) -2-methyl-6,7-dihydro-8H-pyrimido / ^- 5,4-B7 / ^- 1,47oxazin-7-one.

In this example, a suspension containing 0.96 grams of 4- (4-ethoxycarbonyl-1-piperazinyl) -2-methyl-6,7-dihydro-8H-pyrimido [5,4-b7] -1, 47 ° xazin-7-one, followed by milliliters of methyl ethyl ketone, 0.5 g of anhydrous potassium carbonate and 0.31 gra9

CS 272 784 B2 mu. chloroacetanide, heated under boiling and stirring for 8 hours, then hot filtered, washed with methyl ethyl ketone, and the filtrate was allowed to stand aside. A precipitate was formed, which was washed with water, then with ether and dried. 0.65 g of the expected product is obtained, m.p. 225-227 ° C.

The above filtrate was evaporated to a volume of 10 ml and held at 0-4 ° C overnight. The crystals thus obtained were filtered, washed and dried to give an additional 0.2 g of the desired product. The melting point of the product was 225-227 ° C (total yield 75%).

Example 4

Preparation of 4-chloro-8-ethoxycarbonylmethyl-2-methyl-6,7-dihydro-8H-pyrimido [5,4-b] 1.47 oxazin-7-one.

A solution containing 0.41 grams of ethyl chloroacetate in 5 ml of methyl ethyl ketone was added dropwise to a mixture containing 0.6 grams of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido [-5] 4-b7 / 1,47-oxazin-7-one, followed by 0.5 g of anhydrous potassium carbonate and 15 ml of methyl ethyl ketone over a period of 15 minutes while heating the reaction mixture under reflux and stirring. The mixture was heated to reflux while stirring for 8 hours. The mixture was then hot filtered and washed with methyl ethyl ketone. The filtrate was evaporated to a volume of 10 ml, cooled and the unreacted starting material was filtered off. Mother liquor. It was evaporated and the residue was triturated with n-hexane, the solid precipitate was filtered off, washed with n-hexane and finally dried. 0.59 g of the desired product is obtained (corresponding to a yield of 68%). The melting point of this product was in the range of 69 to 70 ° C.

Table 2 below shows compounds that were prepared essentially by the same procedures as the products of Examples 1-4.

Table 2

Compounds of formula I in which R ¹ represents a methyl group

Example

E.

4. Q

R ^5- R Preparation Yield according to Example (%) of Comp.

Melting point (° C)

5 Cl H H CH CN G 2 79 147-149 6 Cl H H CH ₂ CO ₃ 1 76 105-107 7 Cl ch ₃ ch ₃ CH ₂ CN 4 80 110-111 8 2-hydroxyethylamino H H CH ₂ CN 2 99 138-140 9 2-hydroxyethylamino H H ch ₂ c ° ₂ c ₂ h ₅ 4 73 185-187 * 10 2-hydroxyethylamino H H ch ₂ con ₂ 3 48 222-224

CS 272 784 B2

Example 2 (continued) Example ZR ⁴ R ⁴ R ⁸ Preparation Yield Temperature by melting (%)

Lay No (° C)

N-methyl-N- (2-hydroxyethyl) amine

group H H CH ₂ CN 2 96 90-92 12 H-methyl-N- (2-hydroxyethyl) amino group H II CH ₂ CO ₂ C ₂ H 4 63 134-137 ⁺ 13 K-methyl-N- (2-hydroxyethyl) amino group H II CH ₂ COCl ₃ 1 39 190-192 14 N-methyl-N- (arainocarbonylmethyl) amino group H H CH ₂ CO ₂ C ₂ H ₅ 4 25 142-145 1 5 Cl if H CH ₂ COKH ₂ 3 66 55-2 55 16 4-morpholinyl H H ch ₂ ch 2 69 158-161 17 4-morpholinyl H II c: i ₂ co ₂ c ₂ h ₅ 4 75 117-119 18 2- (4-morpholinyl) ethylamino H H CH ₂ CO ₃ 1 85 148-1 50 19 Dec 2- (4-morpholinyl) ethylamine group H II ch ₂ co ₂ c ₂ h ₅ 4 77 176-180 + 20 May 4- (2-hydroxyethyl) -1-piperazinyl H if CH 'COC_li. d 2 p 4 69 125-128 21 4-ethoxycarbonyl-1- piperazinyl group H II CH ₂ CN 2 80 194-196 22nd 4-ethoxycarbonyl-1- piperazinyl group H H CH ₂ COCH ₃ 1 76 143-145 23 4-ethoxycarbonyl-1-piperazinyl H H CH ₂ CO ₂ C ₂ H ₅ 4 79 105-106 24 N-benzyl-N- (2-hydroxyethyl) amino group II II -ch ₂ cn 30 40 100-103

CS 272 784 B2

Example 25

Preparation of 4-chloro-2-methyl-8- (3-pyridylmethyl) -6,7-dihydro-8H-pyrimido [5,4-b] 1,4-oxazin-7-one.

According to this embodiment, the base is liberated from the T-ehlormethylpyridinu hydrochloridu.3 g and dissolved in 5 mL of methyl ethyl ketone added dropwise to a mixture containing 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido / 5,4 ^_ 1,47-oxazin-7-one, 15 ml of methyl ethyl ketone and 0.83 g of anhydrous potassium carbonate, with stirring.

The suspension was heated to reflux and stirred for 8 hours, then filtered and evaporated hot. The residue thus obtained was triturated with diisopropyl ether and finally the solid was filtered off. 0.97 g of the desired product was obtained (corresponding to a yield of 66%). The melting point of the product thus obtained was between 116 and 118 ° C.

The melting point of the hydrochloride salt ranged from 220 to 224 ° C.

Example 26

Preparation of 8-ethoxycarbonylmethyl-4- (2-hydroxyethyl) amino-2,6-dimethy1-6,7-dihydro-8K-pyrimido / ^- 5,4-B7 / ~ 1,47 oxazin-7-one.

This compound was prepared in a similar manner to Example 4, with a yield of 41, mp 105-108 ° C.

Example 27

Preparation of 2,6-dimethy1-S- (1-ethoxycarbonyl-l-ethyl) -4- (4-raorfolinyl) -6,7-dihydro-8H-pyrimido / ^- 5,4-B7 / "l, 47oxazin-7 -onu.

In the process of this example, starting from 4-chloro-2,6-dimethyl-6,7-dihydro-8H-pyrimido / ^- 5,4-B7 / ^- 1,47oxazin-7-one (see Khim. Geterotsikl. Soed, 1972, 1285) and 2-bromopropionate ethyl ester in the same manner as in Example 4. After refluxing for 12 hours and evaporation, the residue (most of which was formed 4-chloro-2,6-dimethy1- (1-ethoxycarbonyl-1-ethyl) -6,7-dihydro-SH-pyriraido / ^- 5,4-B7 / ~ 1,47oxazin-7-one) was reacted with π-α-folinera, the further treatment was carried out in the same manner as in Example 1, except that the evaporated residue was triturated with ether, then filtered off and the filtrate thus obtained was evaporated, and the residue was crystallized from n-hexane . According to this embodiment HYL obtain a product with a yield of 42 ^E I. The melting point of this product was in the range of 80 to 82 ° C.

Example 28

Preparation of 4- (2-hydroxyethyl) -araino-2-methyl-8- (4-morpholinylcarbonyl) methyl-6,7-dihydro-8H-pyrimido / "5,4-B7 / ^- 1,47oxazin-7-one.

This compound was prepared in a similar manner to Example Example

4, the yield in this embodiment being 89%. The melting point of this product was in the range of 162 to 165 ° C.

CS 272 784 B2

Example 29

Preparation of 8- (n-butoxycarbonyl) methy1-4- (2-hydroxyethyl) amino-2-methyl-6,7-dihydro-8 H-pyrimido / 5,4-H7 ~ / ^- 1.47 oxazin-7-one .

This compound was prepared in a similar manner to Example 4, with a yield of 62%. The melting point of the prepared compound ranged from 142 to 145 ° C.

Example 30

Preparation of 4- (4-chlorobenzyl) amino-2,6-dimethyl-8-ethoxycarbonylmethyl-6,7-dihydro-8H-pyrimido [5,4-b] 1,47-oxazin-7-one.

This compound was prepared in a similar manner to Example 4, with a yield of 62%. The melting point of the compound thus prepared was in the range of 101 to 104 ° C.

Example 31

Preparation of 8-benzyl-2-methyl-4- (2-hydroxyethyl) amino-2-methyl-6,7-dihydro-8H-pyrimido [5,4-b] 1,47-oxazin-7-one.

The compound was prepared in a similar manner to Example 1, yield 84%. Melting point: 124-126 ° C. The melting point of the hydrochloride of this compound ranged from 153 to 157 ° C.

Example 32

Preparation of 4-amino-8-ethoxycarbonylmethyl-2-methyl-6,7-dihydro-8H-pyrimido [5,4-b7] 1.47 oxazin-7-one.

In this embodiment, the suspension containing 0.90 grams of 4-amino-2-methyl-6,7-dihydro-8H-pyrimido [5,4-b7] 1,47-oxazin-7-one, followed by 0.69 grams of anhydrous potassium carbonate and 65 ml of ethyl chloroacetate in 20 ml of methyl ethyl ketone was refluxed for 20 hours. The inorganic salt thus obtained was filtered off and the filtrate was evaporated to give a residue which was recrystallized from isopropanol. 0.43 g of the desired product is obtained (corresponding to a yield of 32.3%). The melting point of the product is 149 to 150 ° C. An additional 0.22 g of the desired product was obtained from the mother liquor (corresponding to a yield of 16.2%).

Claims (3)

SUBJECT OF THE INVENTION 1. A process for preparing pyrimido / ^- 5,4-B7 / ^- 1,47oxazinových derivatives of formula I CS 272 784 B2 wherein R is a C 1 -C 4 alkyl group, 2 5 6 R represents a halogen atom or a group -NR R where R represents a hydrogen atom or a benzyl group or an alkyl group containing from 1 to 4 carbon atoms which is substituted by a hydroxyl group, R ⁵ is amino, C 3 -C 6 cycloalkyl, C 1 -C 4 straight or branched chain alkyl optionally substituted by hydroxyl, raarkaptro, aminocarbonyl, furyl, 2-benzo (C 1 -C 4) -alkyl; 1,4-dioxanyl, C 1 -C 4 dialkylamino or phenyl, or phenoxy optionally substituted with one or more groups selected from halogen, alkoxy or C 1 -C 4 groups, and a six-membered saturated heterocycle containing nitrogen and optionally containing an additional nitrogen atom or an oxygen atom optionally substituted by a C1-C4 alkyl group or a benzyl group, wherein NRRR may also be a six-membered saturated nitrogen-containing heterocycle optionally contains an additional nitrogen atom or an oxygen atom and which is optionally substituted by a C 2 -C 4 alkoxy or C 1 -C 4 hydroxyalkyl group, R ⁴ and R ⁴ represent the same or different substituents which are hydrogen or an alkyl group C 1 -C 4 alkyl, R is C 1 -C 4 alkyl substituted by oxo, cyano, aminocarbonyl, C 2 -C 5 alkoxycarbonyl, pyridyl, morpholinocarbonyl or phenyl, with the proviso that when R 'is benzyl, R is other than chlorine and 4-morpholinyl, as well as tautomeric mixtures and tautomeric compounds and acid addition salts thereof, characterized in that: that they do re the compound of formula II H In which the substituents R ¹ , R ² , R ⁴ and R ^{3 have the} same meaning as above, with a compound of formula III R ⁹ X / 111 / g wherein R is as defined above, and X represents a chlorine, bromine or 4-toluenesulfonyloxy group, in the presence of an organic solvent and an acid-binding agent, at the boiling point of the solvent used, converting the basic compound of the formula I obtained into the acid addition salt and / or releasing the free base compound from its addition salt. 2. The process according to claim T, wherein the organic solvent is a ketone, such as methyl ethyl ketone, or a lower alkanol, such as ethanol or isopropyl alcohol. 3. The method of claim 1, wherein the acid binding agent is an alkali metal alkoxide or potassium carbonate.