Pyrimido[5,4-B][1,4]oxazine derivatives and pharmaceutical compositions containing them

The invention relates to novel pyrimido [5,4-b][1,4]oxazine derivatives of the formula (I), and the acid addition salts thereof, pharmaceutical compositions containing them and a process for their preparation. In the formula (I) ##STR1## wherein R.sup.1 stands for a C.sub.1-4 alkyl group; PA0 R.sup.2 stands for hydrogen or halogen or an azido group or an --NR.sup.5 R.sup.6 group, wherein PA1 R.sup.5 represents hydrogen or a benzyl group, or a C.sub.1-4 alkyl group unsubstituted or substituted by a hydroxyl group, PA1 R.sup.6 stands for hydrogen, an amino group, a C.sub.3-6 cycloalkyl group, a straight or branched-chain C.sub.1-4 alkyl group optionally substituted by a hydroxyl, mercapto, aminocarbonyl, furyl, 2-benzo[1,4]dioxanyl, di(C.sub.1-4 alkyl)amino group or by a phenyl or phenoxy group optionally mono- or polysubstituted by halogen or C.sub.1-4 alkoxy group (s) or by a 6-membered, saturated nitrogen-containing heterocycle optionally containing an additional nitrogen or oxygen atom and optionally substituted by a C.sub.1-4 alkyl or benzyl group; further PA0 NR.sup.5 R.sup.6 may also represents a 6-membered, saturated, nitrogen-containing heterocycle optionally containing an additional nitrogen or oxygen atom and optionally substituted by a C.sub.2-4 alkoxycarbonyl or C.sub.1-4 hydroxyalkyl group; PA0 R.sup.3 and R.sup.4 are the same or different and stand for hydrogen or a C.sub.1-4 alkyl group; PA0 R.sup.9 stands for hydrogen or a C.sub.1-4 alkyl group unsubstituted or monosubstituted by an oxo, cyano, aminocarbonyl, C.sub.2-5 alkoxycarbonyl, pyridiyl, morpholinocarbonyl, or phenyl group or mono- or polysubstituted by OH group(s), with the proviso that R.sup.2 is different from chlorine, 4-morpholinyl and piperidyl group when R.sup.9 stands for hydrogen; or PA1 R.sup.2 is different from chlorine and 4-morpholinyl group when R.sup.9 stands for a methyl or benzyl group. The compounds of the formula (I) are capable to increase the myocardial contractile force (the performance of the failing heart) and the coronary blood flow, thus they can therapeutically be used for the treatment of the chronic heart failure and coronary disturbances.

This invention relates to novel pyrimido[5,4-b][1,4]oxazine derivatives of 
the formula (I), 
##STR2## 
wherein R.sup.1 stands for a C.sub.1-4 alkyl group; 
R.sup.2 stands for hydrogen or halogen or an azido group or an --NR.sup.5 
R.sup.6 group, wherein 
R.sup.5 represents hydrogen or a benzyl group, or a C.sub.1-4 alkyl group 
unsubstituted or substituted by a hydroxyl group, 
R.sup.6 stands for hydrogen, an amino group, a C.sub.3-6 cycloalkyl group, 
a straight or branched-chain C.sub.1-4 alkyl group optionally substituted 
by a hydroxyl, mercapto, aminocarbonyl, furyl, 2-benzo[1,4]dioxanyl, 
di(C.sub.1-4) alkyl amino group or by a phenyl or phenoxy group optionally 
mono- or polysubstituted by halogen or C.sub.1-4 alkoxy group(s) or by a 
6-membered, saturated nitrogen-containing heterocycle optionally 
containing an additional nitrogen or oxygen atom and optionally 
substituted by a C.sub.1-4 alkyl or benzyl group; further 
NR.sup.5 R.sup.6 may also represent a 6-membered, saturated, 
nitrogen-containing heterocycle optionally containing an additional 
nitrogen or oxygen atom and optionally substituted by a C.sub.2-4 
alkoxycarbonyl or C.sub.1-4 hydroxyalkyl group; 
R.sup.3 and R.sup.4 are the same or different and stand for hydrogen or a 
C.sub.1-4 alkyl group; 
stands for hydrogen or a C.sub.1-4 alkyl group unsubstituted or 
monosubstituted by an oxo, cyano, aminocarbony, C.sub.2-5 alkoxycarbonyl, 
pyridyl, morpholinocarbonyl or phenyl group or mono- or polysubstituted by 
OH group(s), with the proviso that R.sup.2 is different from a chlorine, 
4-morpholinyl or piperidyl group when R.sup.9 stands for hydrogen; or 
R.sup.2 is different from a chloro or 4-morpholinyl group when R.sup.9 
stands for a methyl or benzyl group, 
as well as their tautomers and tautomeric mixtures and acid addition salts 
thereof and pharmaceutical preparations containing these compounds. 
According to another aspect of the invention, there is provided a process 
for the preparation of the new compounds of the formula (I) and acid 
addition salts thereof. 
The novel pyrimido[5,4-b][1,4]oxazine derivatives of the invention possess 
valuable pharmacodynamic, mainly cardiovascular effects, particularly a 
cardiotonic (positive inotropic) action increasing the performance of 
deficient failing heart musculature. Some of these compounds also exert a 
favorable effect on the coronary circulation. 
In a preferable group of the compounds of the formula (I): R.sup.1 means a 
C.sub.1-4 alkyl group; R.sup.2 stands for NR.sup.5 R.sup.6, wherein 
R.sup.5 and R.sup.6 are as defined above; R.sup.3 and R.sup.4 are 
independently hydrogen or a C.sub.1-2 alkyl group; and R.sup.9 stands for 
hydrogen or a C.sub.1-4 alkyl group optionally substituted by an oxo, 
cyano, aminocarbonyl C.sub.2-5 alkoxycarbonyl or one or more hydroxyl 
group(s). 
The new pyrimido[5,4-b][1,4]oxazine derivatives of the invention belong to 
a ring system structurally less investigated hitherto. 
Only a few articles referring to this type of compound are to be found in 
the literature. I. V. Sazonov and T. S. Safonov (Khim. Geterotsikl. Soed. 
1972, 1285) described derivatives containing mainly an amino, acetamido or 
methyl group in the 2-position or a hydroxyl, methyl group or chlorine in 
the 4-position; and later (ibidem, 1973, 1694) compounds containing a 
double bond and ethoxycarbonyl group in the 6-position; thereafter, 
derivatives with a lower alkyl group in the 6-position (ibidem, 1976, 
681); as well as compounds containing a morpholinyl group in the 
4-position (ibidem, 1978, 391). 
It is commonly known that the diseases affecting the cardiovascular system 
(e.g. chronic heart failure, myocardial infarction, hypertension) are the 
most frequent causes of death. Within this category the number of heart 
cases, mainly the number of patients suffering from chronic heart failure 
is continuously increasing. Today, most of these patients are treated with 
cardiac glycosides; however, it is well known that the use of these drugs 
is not safe because of the harmful side-effects (e.g. tachycardia and 
arrhythmia). Besides the setting-the dosage is difficult, as individual 
judgement and high care are required of from the physician since the 
therapeutic safety of these drugs is low. In addition, these drugs cannot 
be used for treating an acute or post-infarction heart failure. 
In the last decade, the therapeutic damand became higher for drugs capable 
of increasing the performance of the failing myocardium without harmful 
side-effects after oral administration. 
Several new cardiotonic compounds resulted from these investigations. The 
larger and more important groups may be characterized by some examples as 
follows. 
Prenalterol [1-(4-hydroxyphenyl)-3-tertiary-butylamino-2-propanol] is a 
representative of the adrenergic .beta..sub.1 -agonists thoroughly studied 
in clinics. When given intravenously in acute cardiac insufficiency, this 
drug was very effective but the cardiac performance was not improved by it 
when chronic oral treatment was used [J. Cardiovasc. Pharm. 6, 491 
(1984)]. 
Pirbuterol 
[1-(5-hydroxy-6-hydroxymethyl-2-pyridyl)-2-tertiary-butylaminoethanol], a 
drug stimulating both .beta..sub.1 and .beta..sub.2 adrenergic receptors, 
showed a favorable effect during oral treatment for some weeks but 
addiction was observed after a longer period [New Engl. J. Med. 305, 185 
(1981)]. 
The mode of action of the bipyridine-type cardiotonics is different from 
that of the adrenergic .beta.-agonists and not cleared up to the present. 
An outstanding member of this group, amrinone 
[3-amino-5-(4-pyridyl)-2(1H)-pyridinone] significantly increased the 
cardiac output of patients suffering from chronic heart failure and the 
resistance of the peripheral vessels was also diminished. However, the 
therapeutic suitability of amrinone is strongly limited by severe 
side-effects appearing in the blood picture [Am. J. Med. 72, 113 1983; 
Brit. J. Clin. Pharm. 17, 317 (1984)]. 
Sulmazole, a member of the imidazopyridines 
[2-(2-methoxy-4-methylsulfinylphenyl)-1H-imidazo[4,5-b]pyridine] also 
possesses a vasodilatory effect. In addition to the favorable target 
effect, relatively frequent side-effects of sulmazole were revealed by 
clinical tests [Annal. Cardiol. Anghiol. 33, 219 (1984)]. 
The biologic properties of the more important cardiotonics having an effect 
different from that of the cardiac glycosides indicate that an unaltered 
and continuous demand exists for newer drugs which can orally and 
chronically be used, which are free of side-effects and thus, can more 
safely be employed. 
Now it has been found that the new pyrimido[5,4-b][1,4]oxazines of the 
formula (I), wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.9 are as 
defined above, fairly satisfy the above-defined therapeutical demands. 
According to the invention, the compounds of the formula (I) are prepared 
by 
(a) reacting a compound of the formula (II), 
##STR3## 
wherein R.sup.1, R.sup.3 and R.sup.9 are as defined for the formula (I) 
and R.sup.10 stands for a leaving group with an amine of the formula 
HNR.sup.5 R.sup.6, optionally having a protecting group, wherein R.sup.5 
and R.sup.6 are as defined for formula (I), to obtain compounds of the 
formula (I), wherein R.sup.2 stands for an --NR.sup.5 R.sup.6 group 
(wherein R.sup.5 and R.sup.6 are as defined above ) and R.sup.1, R.sup.3, 
R.sup.4 and R.sup.9 are as defined above or 
(b) diazotizing a compound of the formula (I), wherein R.sup.1, R.sup.3, 
R.sup.4 and R.sup.9 are as defined for formula (I) and R.sup.2 stands for 
a hydrazino group, to obtain compounds of the formula (I), wherein R.sup.2 
stands for an azido group and R.sup.1, R.sup.3, R.sup.4 and R.sup.9 are as 
defined above, or 
(c) reacting a compound of the formula (I), wherein R.sup.1, R.sup.2, 
R.sup.3 and R.sup.4 are as defined for formula (I) and R.sup.9 stands for 
hydrogen, with 2,3-epoxypropanol to obtain compounds of formula (I), 
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above and 
R.sup.9 means a 2,3-dihydroxypropyl group, 
and, if desired, reacting a compound of the formula (I), optionally 
containing a protective group and obtained by processes (a) or (b), 
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined for formula 
(I) and R.sup.9 stands for hydrogen, with a compound of the formula 
R.sup.9 X optionally containing a protective group, wherein R.sup.9 is as 
defined for formula (I) except hydrogen and X means a leaving group; 
and/or, if desired, removing the protective group from a product obtained 
by any one of processes (a) to (c); and/or, if desired, transforming a 
compound of the formula (I) obtained in the above way to an other compound 
of the formula (I); and/or, if desired, transforming a base of the formula 
(I), obtained in the above way, by treating it with an acid, to an acid 
addition salt; and/or, if desired, transforming an acid addition salt into 
another acid addition salt; and/or, if desired, liberating a free base of 
the formula (I) from its acid addition salt. 
According to the literature definition [T. A. Geissman: Principles of 
Organic Chemistry, 3rd edition; Editor W. H. Freeman, London, 1968], 
R.sup.10 and X as "leaving groups" are moieties which are easy to cleave 
by nucleophilic agents. Such groups are e.g. halogens; sulfonyloxy groups 
such as lower alkanesulfonyloxy and optionally substituted 
benzenesulfonyloxy groups; as well as lower alkanesulfonyl and -sulfinyl 
groups, e.g. methanesulfonyl group. 
in the processes of the invention, chlorine or 4-toluenesulfonyloxy group 
as R.sup.10, whereas chlorine or bromide as X are particularly preferred. 
A preferred embodiment of process (a) of the invention comprises reacting a 
compound of the formula (II), wherein R.sup.10 is chlorine, with an 
HNR.sup.5 R.sup.6 amine. This reaction is carried out in an inert organic 
solvent or diluent, in the presence of an acid binding agent. Lower 
aliphatic alkanols, e.g. n-butanol or an aromatic hydrocarbon, e.g. 
benzene, are suitably used as solvents. An excess of the amine may 
conveniently be used as an acid binding agent though a tertiary organic 
amine, e.g. triethylamine, or an inorganic base such as potassium 
carbonate may also be employed. This reaction is carried out at 50.degree. 
to 150.degree. C., suitably at the boiling point of the solvent. 
According to another preferred embodiment of process a) of the invention, a 
compound of the formula (II), wherein R.sup.10 is an arylsulfonyloxy, e.g. 
the 4-toluenesulfonyloxy group, is reacted with a HNR.sup.5 R.sup.6 amine. 
The components are similarly reacted in an organic solvent or diluent, in 
the presence of an acid binding agent. It is suitable to use an ester-type 
solvent such as ethyl acetate and an excess of the amine or an organic 
tertiary amine, e.g. triethylamine, or an inorganic base such as potassium 
carbonate as acid binding agent. This reaction is established between 
10.degree. C. and the boiling point of the reaction mixture. 
When using process (b) of the invention, a compound of the formula (I), 
wherein R.sup.2 is a hydrazino group, is treated with sodium nitrite in an 
aqueous acetic acid medium under the known conditions of diazotization at 
0.degree. to 5.degree. C. 
A preferred embodiment of process (c) of the invention comprises reacting a 
compound of the formula (I), wherein R.sup.9 is hydrogen, with 
2,3-epoxypropanol in a solvent, in the presence of a quaternary ammonium 
salt as catalyst. It is preferable to use an aromatic hydrocarbon, e.g. 
benzene as solvent and tetrabutylammonium bromide as catalyst and to work 
at the boiling point of the solvent, e.g. benzene. 
The reaction mixture obtained from the above processes may be worked up in 
a known way, e.g. by evaporation under vacuo, optionally after filtering 
out the inorganic salts and/or catalyst, by mixing the residue with water, 
alkalizing and separating the thus-obtained product by filtration or 
extraction. If desired, the thus-obtained base of the formula (I) can be 
purified and/or transformed to an acid addition salt which can be 
purified, if desired, by recrystallization. 
A compound of formula (I), obtained in process (a) or (b), wherein R.sup.9 
is hydrogen, may be transformed, if desired, to a compound of the formula 
(I), wherein R.sup.9 is different from hydrogen. This transformation is 
preferably carried out in such a way that the compound of the formula (I) 
containing hydrogen as R.sup.9 is reacted with a compound of the formula 
R.sup.9 X, wherein X preferably means chlorine or bromine or 
4-toluenesulfonyloxy group, in the presence of a solvent and an acid 
binding agent. Ketones such as acetone, preferably methyl ethyl ketone, or 
lower alkanols, e.g. ethanol or isopropanol, are suitable solvents. As a 
base, an alkali metal alkoxide prepared from the alkanol solvent may be 
used; when employing a ketone as solvent, the use of potassium carbonate 
for acid-binding is particularly advantageous. This reaction is suitably 
carried out at the boiling point of the solvent. 
It is obvious for one skilled in the art that in some cases, the compounds 
used in processes (a) to (c) should be provided with protective groups for 
avoiding side reactions. Such protective groups are commonly known. Out of 
these, the benzyl group is particularly favorable in the preparation of 
the compounds of the invention as it can easily be removed by catalytic 
hydrogenolysis. 
The bases of the general formula (I) may be transformed in a known way to 
acid addition salts which are suitably pharmaceutically acceptable, e.g. 
by dissolving the base in a suitable organic solvent and adding the 
appropriate acid or a solution of this acid in a suitable organic solvent. 
The salt is isolated by filtering or by evaporating under vacuo then, if 
desired, it is purified in a known way, e.g. by recrystallization. 
Non-toxic inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric or 
phosphoric acid, or non-toxic organic acids such as acetic, tartaric, 
maleic or fumaric acid are preferable acid components. 
When the acid component is an inorganic mineral acid, then a lower alkanol, 
e.g. ethanol or isopropanol, or acetone is suitable used as solvent. When 
the acid is organic, then the above solvents or an ether such as ethyl or 
isopropyl ether may also be used. 
In the starting substances of the formula (II), required for process (a) of 
the invention, R.sup.10 preferably means chlorine or a 
4-toluenesulfonyloxy group. A part of the compounds, wherein R.sup.10 
means chlorine, are known [see, e.g. Khim. Geterotsikl. Soed. 1972, 1985]. 
The compounds of the formula (II) hitherto not described may be prepared 
by methods known from the literature or analogously to known methods. 
The compounds of the formula (II) containing an alkane- or arylsulfonyloxy 
group as R.sup.10 are new and may be prepared e.g. by reacting a compound 
of the formula (I), wherein R.sup.2 is a hydroxyl group, in a known manner 
with the appropriate alkane- or arylsulfonyl chloride in a basic medium. 
This method will be illustrated in Example 23. 
The compounds of the formula (II) containing a methylsulfonyl group as 
R.sup.10 are also new and may be prepared e.g. by oxidizing a compound of 
the formula (II), wherein R.sup.10 is a methylthio group, in a known 
manner. This method will be illustrated in Example 26. A part of the 
appropriate methylthio compounds are known (Khim. Geterotsikl. Soed 1973, 
171). The new methylthio compounds may be prepared by known methods or 
analogously to known methods. 
The majority of the compounds of the formula R.sup.9 X, required for the 
subsequent (additional) transformation of compounds of the formula (I) 
containing hydrogen as R.sup.9, are known (see e.g. E. H. Rodd: Chemistry 
of Carbon Compounds, Elsevier Publishing Co., London, 1951, 615). The new 
R.sup.9 X compounds may be prepared by known methods or analogously to 
known methods. 
As mentioned above, the compounds of the invention possess valuable 
biological, particularly cardiotonic action. 
The myocardial contractile force (with an international abbreviation: MCF) 
increasing effect of the compounds of the invention was proved by using in 
vivo tests and methods as follows. 
METHODS 
(A) Investigation on anaesthetized cats 
The animals were intravenously (i.v.) anaesthetized by 30 mg/kg of 
pentobarbital-sodium. After arranging the artificial respiration, the 
chest and pericardium were opened. A strain gauge arch was sutured onto 
the epicardial surface of the left ventricle [J. Pharm. Exp. Ther. 90, 26 
(1947)]. The blood pressure was measured by a catheter inserted to the 
femoral artery and joined to a P 23 Db pressure transducer and 
electromanometer. The test compounds were administered either i.v. through 
a femoral vein cannule, or intraduodenally (i.d.) through the duodenum 
cannule. At the beginning of the experiment, 0.2 .mu.g/kg of isoproterenol 
(IS) was i.v. given as an internal standard for checking the myocardial 
reactivity. Namely, the value of the peak MCF response can also be altered 
according to the individual animals in the case of each positive inotropic 
agent. Thus, IS was not used as a real reference drug. 
The MCF responses were expressed in the percentage changes of the initial 
value: the effect on MCF of 5 mg/kg i.v. of the test compound was compared 
to that of 0.2 .mu.g/kg i.v. of IS. The results are summarized in Table 1. 
TABLE 1 
______________________________________ 
MCF-increasing effect of compounds of formula (I) 
in open-chest, anaesthetized cats after i.v. 
administration of 5 mg/kg of the compound 
Effectivity as 
Compound Increase in MCF 
compared to 
Example as % of the 0.2 .mu.g/kg 
No. initial value 
i.v. of IS 
______________________________________ 
22 (23, 26) 70 1.2 
11 83 1.2 
60 51 1.2 
56 100 1.5 
57 45 1.3 
27 130 3.0 
37 55.5 1.2 
29 40 0.9 
66 58.3 0.82 
67 37 1.8 
69 66 0.87 
73 50 0.86 
______________________________________ 
Thus, the compounds of the invention possess an MCF-increasing effect 
similar to or higher than that of IS. Being a strong adrenergic 
.beta.-stimulant, IS caused a measurable MCF increase in an i.v. dose of 
as low as 0.2 .mu.g/kg. Further on, IS elicited a short-lasting and 
completely reversible MCF response and did not influence the blood 
circulation parameters. Remarkably, the heart rate was hardly or not at 
all increased by the compounds of the invention of Table 1. 
The effect of several compounds was also studied after i.d. administration. 
Compounds 27 and 37 showed a strong positive inotropic action in a dose of 
both 20 mg/kg and 5 mg/kg. A strong and long-lasting MCF increase was 
observed after even a 1 mg/kg dose of compound 22. 
(B) Investigation on anaesthetized dogs 
The animals were i.v. anaesthetized by 35 mg/kg of pentobarbital-sodium. 
After opening the chest and pericardium, the lower ascending part of the 
left circumflex coronary artery was prepared and fitted with an 
electromagnetic flow probe for measuring the blood flow in the coronary 
artery. A strain gauge arch was placed onto the area supplied by this 
coronary artery for measuring the MCF. For determining the systemic blood 
pressure a femoral arterial cannule, for i.v. drug administration a 
femoral venous cannule was used. The dp/dt value was calculated from the 
pressure measured by a Millar type pressure transducer introduced to the 
left ventricle. All parameters were registered on a Beckman R 12 8-channel 
dynograph. 
(C) Investigation on conscious cats 
These animals were used according to either the method of Rabloczky and 
Mader ("Measurement of Systemic and Pulmonary Arterial Pressure in 
Conscious Animals", lecture on Congress of the International Union of 
Pharmacologists, Budapest, 1980) or to some modification thereof. The 
aorta and pulmonary artery were chronically catheterized for measuring 
both blood pressures. In the modification, the right ventricle was also 
catheterized for determining the dp/dt.sub.max value. 
The positive inotropic and coronary-dilating activity of the compounds of 
the invention are shown by the results obtained on the detailed study of 
compounds 22, 27 and 37 by using the above methods. 
STUDY ON COMPOUND 22 
The positive inotropic effect of this compound could be observed in 
open-chest anaesthetized dogs after an i.v. administration of doses as low 
as 0.025 to 1.6 mg/kg. The strength and duration of the MCF increase were 
dose-dependent. The positive inotropic and coronary-dilating effect of 
0.2, 0.4 and 0.8 mg/kg i.v. doses of this compound were compared to those 
of 0.5, 1.0 and 2.0 mg/kg of amrinone 
[5-amino-(3,4'-bipyridin)-6(1H)-one]. In this dose interval, compound 22 
only elicited a dose-dependent MCF-increasing effect. The action of 2 
mg/kg of amrinone was not more effective than that of 0.4 mg/kg of 
compound 22. Obviously, the positive inotropic effect of both compounds 
was promoted by the increase in the coronary blood flow; however, the 
MCF-increasing effect was more lasting than the coronary one. 
The favorable action of copound 22 on the heart muscle was also proved 
after i.d. administration. MCF was increased by 35 to 40% after an 1 mg/kg 
dose without any change in the coronary flow. The MCF effect of compound 
22 was at least 5 times higher than that of amrinone. 
In anaesthetized open-chest dogs, after an acute myocardial ischaemia, the 
positive inotropic action of amrinone significantly decreased, whereas 
that of compound 22 remained statistically unchanged. An 0.8 mg/kg i.v. 
dose of compound 22 significantly diminished the negative inotropic effect 
of 0.2 IU/kg of vasopressin, and even reversed the coronary-constricting 
effect of the latter. Thus, compound 22 could prevent the development of a 
chemically induced ischaemia. 
On administering 0.5, 2.0, 4.0 and 8.0 mg/kg oral doses of compound 22 to 
chronically catheterized conscious cats, the systemic arterial pressure 
and heart rate remained practically unchanged but MCF was significantly 
increased after each dose. The higher was the dose, the longer lasted the 
positive inotropic effect. The peak increase in dp/dt.sub.max was about 
60%. 
The positive inotropic effect of compound 22 remained unchanged after a 
pre-treatment with an adrenergic .beta.-blocking agent, a histamine H-2 
antagonist or reserpine. 
STUDY ON COMPOUND 27 
This substance was given in 1 mg/kg i.v. or 5 mg/kg i.d. doses to 
anaesthetized open-chest dogs. 
A 1 mg/kg i.v. dose increased the MCF by 40%, the coronary flow by 20% and 
elicited only a slight tachycardia (of 10%) and a slight decrease (of 10%) 
in the systemic systolic arterial blood pressure (the diastolic pressure 
was decreased by 20%). The half-life of the MCF effect proved to be 10 
minutes. The coronary response remained unchanged for 20 minutes. 
After a 5 mg/kg i.d. dose, the MCF increase was 30% and remained unchanged 
for 30 minutes. 
STUDY ON COMPOUND 37 
This substance was given in 0.5 and 1.0 mg/kg i.v. or 5 mg/kg i.d. doses to 
anaesthetized open-chest dogs. A 0.5 mg/kg i.v. dose increased the MCF by 
56%, the coronary flow by 34%, elicited only a very slight tachycardia (of 
6 to 7%) and a slight decrease (of 10 to 15%) in the systemic arterial 
blood pressure. 
A 1.0 mg/kg i.v. dose increased the MCF by 46% for 10 minutes, the coronary 
flow by 20% for 10 minutes, increased the heart rate by only 13% (for 5 
minutes) and decreased the systemic arterial blood pressure by 20%. 
After a 5 mg/kg i.d. dose, the MCF increase was about 30% persisting for 60 
minutes. 
BIOCHEMICAL-PHARMACOLOGICAL INVESTIGATIONS 
The following study was performed for exploring the action of compound 22 
on various enzymes, particularly on the membrane-bound enzymes of the 
heart muscle cells. 
EFFECT OF COMPOUND 22 ON THE NA-K-ATP-ASE AND NADH OXYDASE ENZYMES 
Sarcolemma preparations were made according to D. M. Bers [Biochem. 
Biophys. Acta 555, 131 (1979)]. NADH-dichlorophenol-reductase was 
determined by using a Centrifi-CHEM.RTM. enzyme-analyzer. The activity of 
Na-K-ATP-ase was measured in 50 mM Tris-HCl (at pH 7.5). Ouabain, used as 
reference substance, strongly inhibited Na-K-ATP-ase and slightly the 
indophenol-reductase at 10.sup.-7 M concentration. The activity of these 
enzymes was not altered by even a 10.sup.-4 M concentration of compound 
22. 
EFFECT OF COMPOUND 22 ON THE Ca-ATP-ASE MAINLY REGULATING THE OUTWARD FLOW 
OF Ca.sup.2+ THROUGH THE SARCOLEMMA 
The activity of this enzyme was measured according to Mc Namara [J. 
Biochem. 75, 795 (1974)]. 
The enzyme activity was changed from a control value of K.sub.a =0.83 mM to 
K.sub.a =1.8 mM by a 10.sup.-4 M concentration of compound 22. Thus, the 
effect was slight. 
In another experiment, compound 22 was given in a 2 mg/kg i.p. daily dose 
for 5 days. After taking an ex vivo sample, the enzyme activity was found 
as decreased by 30% (as corrected to 1 g of heart tissue). 
EFFECT OF COMPOUND 22 ON THE .sup.45 Ca.sup.2+ UPTAKE INTO THE SARCOPLASMA 
RETICULUM IN THE PRESENCE OF ATP 
The method of S. Harigaya [Circ. Res. 25, 761 (1969)] was used. 
The Ca-uptake was inhibited by 25% by 5.times.10.sup.-3 M concentration of 
compound 22, similarly to the inhibition by 10.sup.-2 M concentration of 
caffeine. 
EFFECT OF COMPOUND 22 ON THE CYCLIC ADENOSINE MONOPHOSPHATE cAMP CONTENT OF 
THE HEART MUSCLE CELLS 
[For the method, see: Amer. J. Sci. 179, 807 (1973); and Clin. Chim. Acta 
66, 221 (1974)]. 
Rats were given i.p. 5 mg/kg of compound 22, then sacrified at 0, 2, 5, 15 
and 30 minutes, respectively, after treatment. The hearts were homogenized 
with trichloroacetic acid and the cAMP content was measured by a 
radioactive method, by using a specific binding protein. The cAMP content 
of the heart was not significantly altered by compound 22. 
EFFECT OF COMPOUND 22 ON THE PHOSPHODIESTERASE (PDE) ACTIVITY OF THE HEART 
MUSCLE 
PDE.sub.1 was prepared according to Sharma [Adv. Cycl. Nucl. Res. 10, 187 
(1979)]. 
PDE.sub.2 [Adv. Cycl. Nucl. Res. 5, 159 (1975)] and PDE.sub.3 [Adv. Cycl. 
Nucl. Res. 10, 69 (1979)] were isolated according to Thompson et al. The 
enzyme activity was determined by using the same authors' method [Adv. 
Cycl. Nucl. Res. 5, 161 (1975)]. 
None of the PDE subtypes was influenced by a 100 .mu.M concentration of 
compound 22. 
According to the above experiments, compound 22 did not produce either the 
typical enzyme effects of the cardiac glycosides (on Na-K-ATP-ase or 
NADH-oxydase) or the characteristic effect of vegetative receptor 
stimulants (increase in the cAMP content, i.e. effect on the 
adenylate-cyclase enzyme activity). 
Unlikely to some xanthine derivatives of the new bipyridine-type compounds 
(e.g. amrinone), compound 22 did not alter the activity of any of the PDE 
enzymes. 
The acute toxicity data of compound 22 are given as LD.sub.50 values in 
Table 2. 
TABLE 2 
______________________________________ 
LD.sub.50 values in mg/kg 
Male Female 
______________________________________ 
Mice i.v. 323.9 339.89 
(312.08-336.29) 
(331.7-348.2) 
i.p. 572.23 573.08 
(524.17-624.7) (520.09-631.47) 
p.o. 1355.9 1419.6 
(1192.7-1541.4) 
(1313.3-1534.4) 
Rats i.v. 253.45 232.3 
(235.18-273.14) 
(209.4-257.7) 
i.p. 315.0 260.0 
(277.28-357.8) (201.55-335.4) 
p.o. 829.6 809.9 
(722.5-952.6) (724.7-901.4) 
______________________________________ 
Note: The values in parentheses are the confidence limits. Thus, the acut 
toxicity of compound 22 is low. 
On the basis of the pharmacological results, the compounds of the invention 
can be used for treating cardiovascular diseases, mainly for increasing 
the performance of the failing heart musculature and improving the 
coronary circulation (flow). Their toxicity is in general low. When taken 
together these properties, a broad spectrum of effects and therapeutic 
safety are provided. 
For therapeutical use, an indicated daily dose is in the range from about 
0.2 mg/kg to 250 mg/kg, preferably from 0.2 mg/kg to 50 mg/kg optionally 
administered in divided daily doses with consideration of the absorption 
conditions. 
For therapeutical use, the active compounds of the invention are suitably 
formulated to pharmaceutical compositions by mixing them non-toxic, inert, 
solid or liquid carriers and/or additives which are appropriate for 
enteral or parenteral administration and are commonly used in the 
pharmaceutical industry. E.g. water, gelatin, lactose, starch, pectin, 
magnesium stearate. stearic acid, talc and vegetable oils are suitable 
carriers. As additives preserving wetting (surface active), emulsifying or 
dispersing, buffering and aromatizing agents may be used. 
By using the above carriers and additives, the active substances of the 
invention may be formulated to the usual pharmaceutical compositions, e.g. 
solid forms (such as tablets, capsules, pills and suppositories) or liquid 
forms (such as aqueous or oily solutions, suspensions, emulsions, syrups) 
as well as to injectable solutions, suspensions and emulsions. 
The invention also relates to the pharmaceutical compositions containing a 
compound of the general formula (I) or a pharmaceutically acceptable acid 
addition salt thereof as active ingredient; as well as to a process for 
preparing these compositions.

The invention is illustrated in detail by the following non-limiting 
Examples. 
EXAMPLE 1 
4-(4-Ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][ 
1,4]oxazin-7-one 
A mixture containing 1 g of 
4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Khim. 
Geterotsikl. Soed. 1976, 681), 10 ml of n-butanol and 1.58 g of 
1-ethoxycarbonylpiperazine is refluxed under protection against moisture 
and carbon dioxide, then evaporated. The residue is triturated with water 
and the product precipitated at 0.degree. to 4.degree. C. is filtered, 
washed with water and ether and dried to give 1.4 g (87%) of product, 
m.p.: 197.degree.-198.degree. C. 
EXAMPLE 2 
2,6-Dimethyl-4-[4-(2-hydroxyethyl)-1-piperazinyl]-6,7-dihydro-8H-pyrimido[5 
,4-b][1,4]oxazin-7-one 
A mixture containing 0.86 g of 
4-chloro-2,6-dimethyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
(Khim. Geterotsikl. Soed. 1972, 1285), 20 ml of n-butanol and 1.04 g of 
1-hydroxyethylpiperazine is refluxed for 7 hours, then evaporated. After 
adding 20 ml of water, the residue is extracted with ethyl acetate. The 
organic solution is dried and evaporated. After recrystallizing the 
residue from ethyl acetate, 0.90 g of product is obtained, m.p.: 
160.degree.-161.degree. C. 
The compounds of the formula (I), wherein R.sup.1 is a methyl group and 
R.sup.9 is hydrogen, shown in Table 3, were prepared analogously to the 
process described in Example 1 or 2. 
TABLE 3 
__________________________________________________________________________ 
Method 
(No. of M.p. 
Example type Yeild 
(base) 
No. R.sup.2 R.sup.3 
R.sup.4 
example 
% .degree.C. 
__________________________________________________________________________ 
3 Cyclopropylamino H H 1 60 .sup. 224-226.sup.x 
4 2-Hydroxyethylamino CH.sub.3 
H 1 49 195-197 
5 bis(2-Hydroxyethyl)-amino 
CH.sub.3 
H 2 57 155-157 
6 N--Methyl-N--(2-hydroxyethyl)-amino 
H H 1 92 156-158 
7 2-Mercaptoethylamino CH.sub.3 
H 2 52 185-187 
8 N--Methyl-N--(aminocarbonylmethyl)-amino 
H H 1 82 255-257 
9 [2-(4-Fluorophenoxy)-ethyl]-amino 
CH.sub.3 
H 1 64 140-141 
10 [2-(3,4-Dimethoxyphenyl)-ethyl]-amino 
CH.sub.3 
H 1 74 148-150 
11 N--Benzyl-N--(2-hydroxyethyl)-amino 
H H 1 77 136-138 
12 [2-(4-Morpholinyl)-ethyl]-amino 
CH.sub.3 
H 2 53 152-154 
13 [2-(4-Morpholinyl)-ethyl]-amino 
CH.sub.3 
CH.sub.3 
2 71 148-149 
14 4-(2-Hydroxyethyl)-1-piperazinyl 
H H 1 68 187-188 
15 (2-Furlymethyl)-amino CH.sub.3 
H 1 54 142-144 
16 (2-Benzo[1,4]dioxanyl)-methylamino 
H H 2 37 .sup. 165-167.sup.x 
17 4-Chlorobenzylamino CH.sub.3 
H 1 83 171-173 
18 2-Phenoxyethylamino CH.sub.3 
H 1 57 162-164 
__________________________________________________________________________ 
Note: 
.sup.x Hydrochloride 
EXAMPLE 19 
4-(2-Hydroxyethyl)amino-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin- 
7-one 
A solution containing 2 g of the product of Example 11 in 60 ml of methanol 
is hydrogenated on 1.2 g of 10% of palladium-on-charcoal catalyst at 
atmospheric pressure and room temperature, then the mixture is boiled for 
15 minutes and filtered as hot. The filtrate is evaporated to 35 ml, 
cooled at 0.degree. to 4.degree. C., the precipitate is filtered and 
washed with methanol to give 1.26 g (90%) of the product, m.p.: 
192.degree.-194.degree. C. 
EXAMPLE 20 
4-(2-Diethylaminoethyl)amino-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]ox 
azin-7-one dihydrochloride 
A mixture containing 2 g of 
4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 1.52 g 
of triethylamine 1.16 g of 2-diethylaminoethylamine and 50 ml of abs. 
benzene is refluxed while stirring for 20 hours, then evaporated. After 
adding water to the residue, the pH is adjusted to 3 and the mixture is 
extracted with chloroform. The aqueous phase is alkalized to pH 9, 
extracted with chloroform, the latter organic phase is washed with water, 
dried and evaporated. The oily residue is taken up in ethanol and 
ethanolic hydrogen chloride solution is added. The precipitate is filtered 
to give 0.56 g (16%) of the product, m.p.: 252.degree.-255.degree. C. 
EXAMPLE 21 
2-Methyl-4-[2-(1-piperidyl)-ethyl]-amino-6,7-dihydro-8H-pyrimido[5,4-b][1,4 
]oxazin-7-one dihydrochloride 
According to Example 20, starting from 1.23 g of 
2-(1-piperidyl)-ethylamine, 0.91 g (25%) of the product is obtained, m.p.: 
135.degree.-140.degree. C. 
EXAMPLE 22 
2-Methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihydro-8H-pyrimido[5,4-b][1 
,4]oxazin-7-one dihydrochloride 
According to Example 20, a mixture containing 1 g of 
4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 1.01 g 
of triethylamine and 0.65 g of 2-(4-morpholinyl)-ethylamine is refluxed 
for 40 hours to give 0.46 g (25%) of the product, m.p.: 
233.degree.-237.degree. C. (with decomposition). 
EXAMPLE 23 
2-Methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihydro-8H-pyrimido[5,4-b][1 
,4]oxazin-7-one dihydrochloride 
Method (A) 
A mixture containing 50 g of 
2-methyl-4-(4-toluenesulfonyloxy)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazi 
n-7-one, 20.73 g of anhydrous potassium carbonate, 19.5 g of 
2-(4-morpholinyl)-ethylamine and 1250 ml of abs. ethyl acetate is stirred 
at 20.degree. C. for 72 hours, then the insoluble fraction is filtered. 
The filtrate is extracted with 1N aqueous hydrochloric acid, the pH of the 
aqueous phase is adjusted to 4 to 5 and the solution is extracted with 
dichloromethane. Then the pH of the aqueous phase is adjusted to 9 to 10 
and it is extracted with dichloromethane. The combined organic solution 
obtained from the latter extraction is dried and evaporated. The remained 
crude base is dissolved in acetone, then abs. ethanolic hydrogen chloride 
solution is added under cooling. The precipitate is filtered and washed 
with acetone to give 27.31 g (50%) of product, m.p.: 
233.degree.-237.degree. C. (with decomposition). 
Method (B) 
A mixture containing 5 g of 
2-methyl-4-(4-toluenesulfonyloxy)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazi 
n-7-one, 2.99 g of 2-(4-morpholinyl)-ethylamine, 9.11 g of triethylamine 
and 130 ml of abs. ethyl acetate is boiled for 5 hours, then filtered and 
the filtrate is evaporated. The residue is mixed with water, the pH is 
adjusted to 2, the solution is extracted with ethyl acetate and the 
aqueous phase is adjusted to pH 5. Further on, the working-up is carried 
out as described in method (A) to give 3.28 g (60%) of product, m.p.: 
233.degree.-237.degree. C. (with decomposition). 
The fumarate of the desired base is prepared as follows: 
To a solution containing 1 g of crude base [prepared according to method 
(A) or (B)] in 9 ml of ethanol, 0.2 g of fumaric acid dissolved in 5 ml of 
hot ethanol is portionwise added at 70.degree. C., then the mixture is 
cooled and kept at 0.degree. to 4.degree. C. overnight. The fumarate of 
the desired base, containing the base in a 2:1 mole ratio as related to 
fumaric acid, is obtained in a nearly quantitative yield, m.p.: 
215.degree.-216.degree. C. 
Analysis: Calculated for C.sub.30 H.sub.42 N.sub.10 O.sub.10 (molecular 
weight: 702.72): C 51.27; H 6.03; N 19.93%; found C 51.63; H 5.96; N 
19.66%. 
The fumaric acid content was found to be 16.50% (calculated 16.52%). 
2-Methyl-4-(4-toluenesulfonyloxy)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin 
-7-one, the common starting material of both method A) and B) may be 
prepared e.g. as follows: 
To a solution containing 135.8 g of 
4-hydroxy-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Khim. 
Geterotsikl. Soed. 1976, 681) in 1205 ml of 1N aqueous sodium hydroxide, a 
solution of 157.2 g of 4-toluenesulfonyl chloride in 450 ml of acetone is 
dropped at room temperature under stirring for 3 hours and then the 
mixture is stirred at room temperature for 5 hours. The crystals are 
filtered, washed with water and taken up in 1800 ml of acetone. The 
precipitate (i.e. the unchanged starting material) is filtered out and 
washed with acetone. The filtrate is evaporated, the crystals are 
filtered, washed with a little acetone and dried to give 123.2 g (49%) of 
the product, m.p.: 185.degree.-186.degree. C. 
The compounds of Table 4 were essentially prepared according to method (A) 
of Example 23. 
______________________________________ 
M.p. 
Example Yield .degree.C. 
No. R.sup.2 % salt form 
______________________________________ 
24 2-(2-Methyl-4-morpholinyl)- 
18 186-190 
ethylamino (dihydro- 
chloride) 
25 2-(4-Methyl-1-piperazinyl)- 
69 193-195 
ethylamino (diemaleate) 
______________________________________ 
EXAMPLE 26 
2-Methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihydro-pyrimido[5,4-b][1,4] 
oxazin-7-one dihydrochloride 
A mixture of 0.34 g of 
4-methanesulfonyl-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
and 0.40 g of 2-(4-morpholinyl)-ethylamine is heated at 75.degree. to 
80.degree. C. for 10 minutes and after cooling taken up in 8 ml of 1N 
sodium hydroxide solution and exhaustively extracted with dichloromethane. 
The organic solution is extracted with water, dried, filtered and 
evaporated to give 0.21 g (52.5%) of the crude base which can be 
transformed to the dihydrochloride as described in Example 22 or 23. The 
crude base can be crystallized by mixing thoroughly with ethanol or 
acetone, m.p.: 143.degree.-145.degree. C. 
4-Methanesulfonyl-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]-oxazin-7-one 
, i.e. the starting material can be prepared e.g. as follows: 
2 ml of 30% hydrogen peroxide are added to a solution containing 0.83 g of 
2-methyl-4-methylthio-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
(Khim. Geterotsikl. Soed. 1973, 171) in 8 ml of acetic acid and heated at 
60.degree. C. under stirring for 3 hours. The solution is evaporated to 
dryness. The traces of acetic acid are removed and the remaining white 
crystalline material is triturated with 5 ml of water. The pH of the 
mixture is adjusted to 6.5, the precipitate is filtered and dried to give 
0.36 g (38%) of product, i.e. the starting material of Example 26, m.p.: 
211.degree. C. 
EXAMPLE 27 
4-[(4-Benzyl-2-morpholinyl)-methyl]-amino-2-methyl-6,7-dihydro-8H-pyrimido[ 
5,4-b][1,4]oxazin-7-one dihydrochloride dihydrate 
Method (A) 
A suspension containing 16 g of 
2-methyl-4-(4-toluenesulfonyloxy)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazi 
n-7-one (Example 23), 8.93 g of 2-aminomethyl-4-benzylmorpholine and 6.6 g 
of anhydrous potassium carbonate in 400 ml of abs. ethyl acetate is 
stirred at room temperature for 80 hours, then the insoluble part is 
filtered and the filtrate is extracted with 1N hydrochloric acid. The pH 
of the aqueous phase is adjusted to 7 by 1N sodium hydroxide solution and 
extracted with ether. The ethereal solution is dried and evaporated. The 
crude residue is dissolved in abs. ethanol and a calculated amount of abs. 
ethanolic hydrogen chloride solution is portionwise added. After cooling 
at 0.degree. to 4.degree. C., the precipitate is filtered, washed with 
cold abs. ethanol and dried to give 2.33 g (15%) of the product, m.p.: 
196.degree.-199.degree. C. 
Method (B) 
A suspension containing 3 g of 
2-methyl-4-(4-toluenesulfonyloxy)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazi 
n-7-one (Example 23), 1,85 g of 2-aminomethyl-4-benzylmorpholine, 5.43 g of 
triethylamine and 80 ml of abs. ethyl acetate is boiled for 8 hours while 
stirring, then evaporated. The residue is mixed with 50 ml of water and 
the pH is adjusted to 1 to 2 by adding 1N hydrochloric acid. After 
extracting with ethyl acetate, the pH of the aqueous phase is adjusted to 
7 by 1N sodium hydroxide solution and extracted with ether. Further on, 
method (A) is followed to give 1.0 g (13%) of the product, m.p.: 
195.degree.-198.degree. C. 
2-Aminomethyl-4-benzylmorpholine, the common starting material of both 
method (A) and (B) can be prepared e.g. as follows: 
Step (a): 4-Benzyl-2-phthalimidomethylmorpholine 
50.2 g of potassium phthalimide are added to 61.2 g of 
4-benzyl-2-chloromethylmorpholine [Synth. Com. 10, 59 (1980)] dissolved in 
150 ml of abs. dimethylformamide and the mixture is boiled under stirring 
for 6 hours. After cooling, the crystals are filtered, washed with 
dimethylformamide and then with cold water and dried to give 68.95 g (76%) 
of the product, m.p.: 130.degree.-132.degree. C. 
Step (b): 2-Aminomethyl-4-benzylmorpholine dihydrochloride 
A mixture containing 19.3 g of the product of Step (a) and 38 ml of 
concentrated hydrochlorid acid is boiled under stirring for 10 to 14 
hours. After cooling, the phthalic acid precipitate is filtered and the 
solution is extracted with ethyl acetate. The aqueous phase is evaporated 
to dryness and the residue is triturated with abs. ethanol. The crystals 
are filtered, washed with abs. ethanol and dried to give 10.3 g (65%) of 
the product, m.p.: 244.degree.-246.degree. C. 
The base is liberated from an aqueous solution of the dihydrochloride by 
alkalizing with sodium hydroxide and extracting with chloroform. After 
drying the organic phase and evaporating, the crude base is obtained in a 
nearly quantitative yield and can be used as starting material in 
processes according to this Example. 
EXAMPLE 28 
8-(2,3-Dihydroxypropyl)-4-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dih 
ydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
A suspension containing 0.96 g of 
4-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b] 
[1,4]oxazin-7-one (Example 1), 0.44 g of 2,3-epoxy-1-propanol, 0.0966 g of 
tetra(n-butyl)-ammonium bromide and 20 ml of abs. benzene is boiled under 
stirring for 5 hours and left to stand at room temperature overnight. The 
crystals are filtered, washed with diisopropyl ethyl and dried to give 
0.98 g (83%) of the product, m.p.: 146.degree.-148.degree. C. 
EXAMPLE 29 
4-(2-Hydroxyethyl)-amino-2-methyl-8-(2-oxopropyl)-6,7-dihydro-8H-pyrimido[5 
,4-b][1,4]oxazine-7-one 
0.31 g of chloroacetone dissolved in 5 ml of methyl ethyl ketone is dropped 
to a suspension containing 0.68 g of 
4-(2-hydroxyethyl)-amino-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazi 
n-7-one (Example 19), 0.5 g of anhydrous potassium carbonate and 15 ml of 
methyl ethyl ketone, then the mixture is boiled while stirring for 8 hours 
and filtered as hot. The filtrate is evaporated to 10 ml and left to stand 
at 0.degree. to 4.degree. C. overnight. The crystals are filtered, washed 
with ether and dried to give 0.70 g (83%) of the product, m.p.: 
150.degree.-152.degree. C. The hydrochloride melts at 
185.degree.-187.degree. C. 
EXAMPLE 30 
8-Cyanomethyl-2-methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihydro-8H-pyr 
imido[5,4-b][1,4]oxazin-7-one 
0.25 g of chloroacetonitrile dissolved in 50 ml of methyl ethyl ketone is 
dropped within 15 minutes to a suspension containing 0.88 g of 
2-methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihydro-8H-pyrimido[5,4-b][ 
1,4]oxazin-7-one base (e.g. prepared as described in Example 23) and 0.5 g 
of anhydrous potassium carbonate in 15 ml of methyl ethyl ketone under 
boiling and stirring. The mixture is further boiled under stirring for 8 
hours, the precipitate is filtered as hot and washed with methyl ethyl 
ketone. The filtrate is evaporated and the residue is triturated with 
diisopropyl ether. After filtering, the solid is washed with diisopropyl 
ether and dried to give 0.91 g (91%) of the product, m.p.: 
126.degree.-128.degree. C. 
EXAMPLE 31 
8-aminocarbonylmethyl-4-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dihyd 
ro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
A suspension containing 0.96 g of 
4-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b] 
[1,4]oxazin-7-one (Example 1), 25 ml of methyl ethyl ketone, 0.5 g of 
anhydrous potassium carbonate and 0.31 g of chloroacetamide is boiled 
under stirring for 8 hours, filtered as hot, washed with methyl ethyl 
ketone and this filtrate is set aside. The precipitate is washed with 
water, then with ether and dried to give 0.65 g of the product, m.p.: 
225.degree.-227.degree. C. 
The above filtrate is evaporated to 10 ml and kept at 0.degree. to 
4.degree. C. overnight. The crystals are filtered, washed and dried to 
give additional 0.20 g of the product, m.p.: 225.degree.-227.degree. C. 
(the total yield is 75%). 
EXAMPLE 32 
4-Chloro-8-ethoxycarbonylmethyl-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4 
]oxazin-7-one 
A solution of 0.41 g of ethyl chloroacetate in 5 ml of methyl ethyl ketone 
is dropped to a mixture containing 0.6 g of 
4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 0.5 g 
of anhydrous potassium carbonate and 15 ml of methyl ethyl ketone within 
15 minutes under refluxing and stirring. Then the mixture is refluxed 
under stirring for 8 hours, filtered as hot and washed with methyl ethyl 
ketone. The filtrate is evaporated to 10 ml, cooled and the unchanged 
starting material is filtered out. The mother liquor is evaporated, the 
residue is triturated with n-hexane, the solid precipitate is filtered, 
washed with n-hexane and dried to give 0.59 g (68%) of product, m.p.: 
69.degree.-70.degree. C. 
The compounds of Table 5 were essentially prepared by the methods described 
in Examples 28 to 32. 
TABLE 5 
__________________________________________________________________________ 
Compounds of the formula (I), wherein R.sup.1 means methyl group 
Method 
Example type ex. 
Yeild 
M.p. 
No. R.sup.2 R.sup.3 
R.sup.4 
R.sup.9 No. % .degree.C. 
__________________________________________________________________________ 
33 Cl H H CH.sub.2 CN 
30 79 147-149 
34 Cl H H CH.sub.2 COCH.sub.3 
29 76 105-107 
35 Cl CH.sub.3 
CH.sub.3 
CH.sub.2 CN 
32 80 110-111 
36 2-Hydroxyethylamino 
H H CH.sub.2 CN 
30 99 138-140 
37 2-Hydroxyethylamino 
H H CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
32 73 185-187* 
38 2-Hydroxyethylamino 
H H CH.sub.2 CH(OH)CH.sub.2 OH 
28 99 128-131 
39 2-Hydroxyethylamino 
H H CH.sub.2 CONH.sub.2 
31 48 222-224 
40 N--Methyl-N--(2-hydroxyethyl)-amino 
H H CH.sub.2 CN 
30 96 90-92 
41 N--Methyl-N--(2-hydroxyethyl)-amino 
H H CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
32 63 134-137* 
42 N--Methyl-N--(2-hydroxyethyl)-amino 
H H CH.sub.2 COCH.sub.3 
29 39 190-192 
43 N--Methyl-N--(aminocarbonylmethyl)- 
H H CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
32 25 142-145 
amino 
44 Cl H H CH.sub.2 CONH.sub.2 
31 66 253-255 
45 4-Morpholinyl H H CH.sub.2 CH 
30 69 158-161 
46 4-Morpholinyl H H CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
32 75 117-119 
47 2-(4-Morpholinyl)-ethylamino 
H H CH.sub.2 COCH.sub.3 
29 85 148-150 
48 2-(4-Morpholinyl)-ethylamino 
H H CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
32 77 .sup. 176-180* 
49 4-(2-Hydroxyethyl)-1-piperazinyl 
H H CH.sub.2 COC.sub.2 H.sub.5 
32 69 125-128 
50 4-Ethoxycarbonyl-1-piperazinyl 
H H CH.sub.2 CN 
30 80 194-196 
51 4-Ethoxycarbonyl-1-piperazinyl 
H H CH.sub.2 COCH.sub.3 
29 76 143-145 
52 4-Ethoxycarbonyl-1-piperazinyl 
H H CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 
32 79 105-106 
53 (2-Benzo[1,4]dioxanyl)-methylamino 
H H CH.sub.2 CH(OH)CH.sub.2 OH 
28 28 200-201 
54 N--Benzyl-N--(2-hydroxyethyl)-amino 
H H --CH.sub.2 CN 
30 40 100-103 
55 N--Benzyl-N--(2-hydroxyethyl)-amino 
H H CH.sub.2 CH(OH)CH.sub.2 OH 
28 57 .sup. 99-103* 
__________________________________________________________________________ 
Note: 
*Hydrochlodride 
EXAMPLE 56 
4-Chloro-8-(2,3-dihydroxypropyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1, 
4oxazin-7-one 
A mixture containing 10 g of 
4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 0.7 g 
of triethylamine hydrochloride, 7.4 of 2,3-epoxypropanol and 300 ml of 
abs. benzene is refluxed for 4 hours under stirring. Then the solution is 
washed with water and the organic phase is extracted with chloroform. 
After drying the chloroformic phase, the solvent is evaporated, the oily 
residue is taken up in chloroform and mixed with a 1:1 mixture of ether 
and petroleum ether. The precipitated oil soon crystallizes. After 
filtering, it is washed with petroleum ether and dried to give 5.21 g 
(38%) of the product, m.p.: 117.degree.-118.degree. C. 
EXAMPLE 57 
8-(2,3-Dihydroxypropyl)-2-methyl-4-(4-morpholinyl)-6,7-dihydro-8H-pyrimido[ 
5,4-b][1,4]oxazin-7-one 
A mixture containing 1 g of 
2-methyl-4-(4-morpholinyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
, 0.59 g of 2,3-epoxypropanol, 0.128 g of tetra(n-butyl)ammonium bromide 
and 60 ml of abs. benzene is refluxed under stirring for 7 hours. After 
filtering, the precipitate is washed with benzene and ether and dried to 
give 1.04 g (77%) of the product, m.p.: 153.degree.-155.degree. C. 
EXAMPLE 58 
8-(2,3-Dihydroxypropyl)-2-methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihy 
dro-8H-pyrimido[5,4-b][1,4]oxazin-7-one dihydrochloride 
A mixture containing 1 g of 
2-methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihydro-8H-pyrimido[5,4-b][ 
1,4]oxazin-7-one base (e.g. of Example 23), 0.57 of 2,3-epoxypropanol, 0.11 
g of tetra(n-butyl)ammonium bromide and 40 ml of abs. benzene is refluxed 
under stirring for 8 hours. Then the benzene solution is washed with 
water, the aqueous phase is extracted with chloroform or with ethyl 
acetate, and the combined organic phase is dried and evaporated. The 
residue is dissolved in abs. ethanol and a calculated amount of ethanolic 
hydrogen chloride solution is added. After cooling, the precipitate is 
filtered, washed and dried to give 0.45 g (30%) of the product, m.p.: 
158.degree.-160.degree. C. 
EXAMPLE 59 
8-(2,3-Dihydroxypropyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin- 
7-one 
The solution of 2 g of 
.gamma.chloro-8-(2,3-dihydroxypropyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4 
-b][1,4]oxazin-7-one and 0.739 g of triethylamine in 50 ml of abs. ethanol 
is hydrogenated in the presence of 0.20 g of 5% palladium-on-charcoal 
catalyst at room temperature and atmospheric pressure. Then the catalyst 
is filtered out, the filtrate is evaporated, the residue is taken up in 
water and extracted with chloroform. The organic phase is dried and 
evaporated. The residue is triturated with petroleum ether and dried to 
give 0.33 g (19%) of the product, m.p.: 70.degree.-72.degree. C. 
EXAMPLE 60 
2-Methyl-4-[3-(4-morpholinyl)-1-propyl]-amino-6,7-dihydro-8H-pyrimido[5,4-b 
][1,4]oxazin-7-one 
A mixture of 0.7 ml of triethylamine and 1.44 g of 
3-(4-morpholinyl)-1-propylamine is added in the course of 8 hours to a 
mixture containing 2 g of 
4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one and 1.4 
ml of triethylamine in 5 ml of abs. benzene while stirring and refluxing. 
Then the mixture is refluxed under stirring for 8 hours, evaporated, the 
residue is taken up with 16 ml of water, triturated, filtered and washed 
with water and ether to give 1.1 g (36%) of the aimed product, m.p.: 
165.degree.-168.degree. C. 
The hydrochloride, m.p.: 250.degree.-251.degree. C., is obtained by adding 
ethanolic hydrogen chloride solution to the base dissolved in ethyl 
acetate. 
EXAMPLE 61 
4-Chloro-2-methyl-8-(3-pyridylmethyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]ox 
azin-7-one 
The base liberated from 1 g of 3-chloromethylpyridine hydrochloride and 
dissolved in 5 ml of methyl ethyl ketone is dropped to the mixture 
containing 
4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 15 ml 
of methyl ethyl ketone and 0.83 g of anhydrous potassium carbonate while 
stirring. 
The suspension is refluxed while stirring for 8 hours, filtered as hot and 
evaporated. The residue is triturated with diisopropyl ether and filtered 
to give 0.97 g (66%) of the product, m.p.: 116.degree.-118.degree. C. The 
hydrochloride melts at 220.degree.-224.degree. C. 
EXAMPLE 62 
4-(2-Hydroxyethyl)-amino-2,6,6-trimethyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4 
]oxazin-7-one 
This compound is prepared similarly to Example 2 in a yield of 83%, m.p.: 
168.degree.-170.degree. C. The hydrochloride melts at 
190.degree.-191.degree. C. 
EXAMPLE 63 
8-Ethoxycarbonylmethyl-4-(2-hydroxyethyl)amino-2,6-dimethyl-6,7-dihydro-8H- 
pyrmido[5,4-b][1,4]oxazin-7-one hydrochloride 
This compound is prepared similarly to Example 32 in a yield of 41%, m.p.: 
105.degree.-108.degree. C. 
EXAMPLE 64 
2,6-Dimethyl-4-(1-methyl-2-phenylethyl)-amino-6,7-dihydro-8H-pyrimido[5,4-b 
][1,4]oxazin-7-one 
This compound is prepared similarly to Example 2 in a yield of 31%, m.p.: 
126.degree.-130.degree. C. The hydrochloride melts at 
181.degree.-184.degree. C. 
EXAMPLE 65 
2,6-Dimethyl-8-(1-ethoxycarbonyl-1-ethyl)-4-(4-morpholinyl)-6,7-dihydro-8H- 
pyrimido[5,4-b][1,4]oxazin-7-one 
Starting from 
4-chloro-2,6-dimethyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
(Khim. Geterotsikl. Soed. 1972, 1285) and ethyl 2-bromopropionate, Example 
32 is followed. After refluxing for 12 hours and evaporating, the residue 
[the most part of which is 
4-chloro-2,6-dimethyl-(1-ethoxycarbonyl-1-ethyl)-6,7-dihydro-8H-pyrimido[5 
,4-b][1,4]oxazin-7-one] is reacted with morpholine and worked up as 
described in Example 1, except that the evaporation residue is triturated 
with ether, filtered, the filtrate is evaporated and the residue is 
recrystallized from n-hexane to give the product in a yield of 42%, m.p.: 
80.degree.-82.degree. C. 
EXAMPLE 66 
4-(2-Hydroxyethyl)-amino-2-methyl-8-(4-morpholinylcarbonyl)-methyl-6,7-dihy 
dro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
This compound is prepared similarly to Example 32 in a yield of 89%, m.p.: 
162.degree.-165.degree. C. 
EXAMPLE 67 
8-(n-Butoxycarbonyl)methyl-4-(2-hydrocyethyl)amino-2-methyl-6,7-dihydro-8H- 
pyrimido[5,4-b][1,4]oxazin-7-one hydrochloride 
This compound is prepared similarly to Example 32 in a yield of 62%, m.p.: 
142.degree.-145.degree. C. 
EXAMPLE 68 
4-(4-Chlorobenzyl)-amino-2,6-dimethyl-8-ethoxycarbonylmethyl-6,7-dihydro-8H 
-pyrimido[5,4-b][1,4]oxazin-7-one 
This compound is prepared similarly to Example 32 in a yield of 62%, m.p.: 
101.degree.-104.degree. C. 
EXAMPLE 69 
8-Benzyl-2-methyl-4-(2-hydroxyethyl)-amino-2-methyl-6,7-dihydro-8H-pyrimidi 
no[5,4-b][1,4]oxazin-7-one 
This compound is prepared similarly to Example 1 in a yield of 84%, m.p.: 
124.degree.-126.degree. C. The hydrochloride nelts at 
153.degree.-157.degree. C. 
EXAMPLE 70 
4-Hydrazino-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
12.8 ml of 98% hydrazine hydrate dissolved in 40 ml of n-butanol are 
dropped to a solution of 20 g of 
4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one in 320 
ml of n-butanol at 117.degree. C. within 30 minutes while stirring. The 
mixture is stirred for an additional 45 minutes at 117.degree. C., then 
cooled to room temperature. The precipitate is filtered and washed with 
water to give 11.66 g (56.3%) of the product, m.p.: 
262.degree.-264.degree. C. 
EXAMPLE 71 
4-Azido-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxzazin-7-one 
4.90 g of the product of Example 70 is suspended in 55 ml of water and 90 
ml of glacial acetic acid and 1.75 g of sodium nitrite dissolved in 14 ml 
of water is dropwise added at 0.degree. to 5.degree. C. while stirring. 
The mixture is stirred at 5.degree. C. for 20 minutes and at room 
temperature for 30 minutes. The precipitate is filtered, successively 
washed with water, ethanol and ether and dried to give 4.80 g (93.2%) of 
the product, m.p.: 214.degree.-217.degree. C. 
EXAMPLE 72 
4-Amino-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
hydrochloride 
25 ml of 20% hydrochloric acid kept at 10.degree. C. are dropped to a 
suspension of 4.0 g of 
2-methyl-4-(triphenylphosphoranylidene)-imino-6,7-dihydro-8H-pyrimido[5,4- 
b][1,4]oxazin-7-one in 25 ml of ethanol within 15 minutes under stirring. 
The mixture is stirred at room temperature for 5 hours, the precipitate is 
filtered, washed with ethanol and dried to give 1.80 g (91%) of the 
hydrochloride melting above 260.degree. C. 
The base can be liberated from the hydrochloride by adding aqueous sodium 
hydrogen carbonate solution. 
2-Methyl-4-(triphenylphosphoranylidene)-imino-6,7-dihydro-8H-pyrimido[5,4-b 
][1,4]oxazin-7-one, used as starting material, can be prepared as follows. 
3.50 g of 4-azido-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one 
(Example 71) are portioned within 20 minutes to a solution of 4.48 g of 
triphenylphosphine in 140 ml of dry dichloromethane at room temperature 
under stirring. The mixture is stirred overnight, filtered and the 
solution is evaporated. The residue is suspended in 70 ml of ether, the 
precipitate is filtered and dried to give 6.75 g (95%) of product, m.p.: 
245.degree. C. 
EXAMPLE 73 
4-Amino-8-ethoxycarbonylmethyl-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4o 
xazin-7-one 
A suspension containing 0.90 g of 
4-amino-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4-oxazin-7-one, 0.69 g 
of anhydrous potassium carbonate and 0.65 ml of ethyl chloroacetate in 20 
ml of methyl ethyl ketone is refluxed for 20 hours. The inorganic salts 
are filtered out, the filtrate is evaporated and the residue is 
recrystallized from isopropanol to give 0.43 g 32.3% of the product, m.p.: 
149.degree.-150.degree. C. From the mother liquor, additional 0.22 g 
(16.2%) of the product can be isolated. 
EXAMPLE 74 
Preparation of tablets 
______________________________________ 
Composition (for 1000 tablets) 
g 
______________________________________ 
Fumarate of the base described in 
10 
Example 22 
Lactose 185 
Microcrystalline cellulose 
25 
Talc 5 
Corn starch 73 
Magnesium stearate 2 
Total: 300 
______________________________________ 
The above ingredients are mixed, homogenized and compressed to tablets 
containing 10 mg of the active ingredient each. 
EXAMPLE 75 
Preparation of an injectable solution 
______________________________________ 
Composition (for 2 liters of solution) 
______________________________________ 
Fumarate of the base described in Example 22 
2 g 
Sodium chloride 20 g 
water for injection purposes q.s. ad 
2000 ml 
______________________________________ 
The mixture is filled as divided into ampoules containing 2 ml of the 
solution each.