Substituted 1,2,4-triazolo[1,5-c]pyrimido[1,4]-azines have been found to have potent bronchodilator activity. Also, pharmacological methods for inducing bronchodilation using such compounds, pharmaceutical compositions containing such compounds, and synthetic intermediates, including 1,2,4-triazolo[4,3-c]-pyrimido[1,4]azines, for preparing such compounds.

TECHNICAL FIELD 
This invention relates to novel heterocyclic compounds exhibiting 
bronchodilator activity. Pharmacological methods of using such compounds, 
pharmaceutical formulations containing such compounds and synthetic 
intermediates for preparing such compounds are also described. 
BACKGROUND OF THE INVENTION 
A variety of aromatic heterocyclic compounds are known to exhibit 
bronchodilator activity. One of the most widely used compounds for 
treatment of mammals is theophylline, which has the structure shown below: 
##STR1## 
Numerous attempts to obtain a safer, more potent bronchodilator have not 
yet supplanted theophylline. 
Pyrimido[5,4-]oxazines are known compounds which are reported by Sazonov, 
et al., Khimiya Geterotsiklicheskikh Soedinenii, 1973, 171; ibid., 1972, 
1285, and ibid., 1976, 681. These compounds, which have not been described 
as bronchodilators, have the following structure: 
##STR2## 
wherein R is amino, acetamido, hydrogen or methyl; R' is hydrogen, methyl, 
hydrazino, piperidino, morpholino, methoxy, methylthio, mercapto, chloro 
or hydroxy; and R" is hydrogen, methyl, ethyl, propyl, or dimethyl. 
Pyrimido[4,5-b][1,4]oxazines are known compounds which are reported by 
Melik-Ogandzhanyan, et al., Khimiya Geterotsiklicheskikh Soedinenii, 1985, 
974. The corresponding 4-chloro, 4-hydroxy, 4-dialkylamino, 4-morpholino 
and 4-piperidino derivatives are reported. They have the following 
structure: 
##STR3## 
wherein R is methyl or hydrogen and R, is chloro, hydroxy, 
N,N-dimethylamino, N,N-diethylamino, morpholino or piperidino. None of the 
reported compounds were described as bronchodilators. 
Some pyrimido[5,4-b][1,4]thiazines are known, reported by E. F. Schroeder 
and R. M. Dodson, J. Amer. Chem. Soc., 84, 1904-1913 (1962) and by R. N. 
Henri, R. A. Lazarus and S. J. Benkovic, J. Med. Chem., 26, 559-563 
(1983). None of the reported compounds were described as bronchodilators. 
U.S. Pat. Nos. 4,477,450 and 4,572,910, respectively, disclose 
triazolo[4,3-c]pyrimidines and triazolo[1,5-c]pyrimidines which contain a 
heterocyclic amine moiety such as piperazino, piperidino, morpholino or 
thiomorpholino on the 5- and/or 7-position of the pyrimidine ring. These 
compounds are bronchodilators. 
Triazolo[1,5-c]pyrimido[4,5-b][1,4]oxazines, 
triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazines and 
triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazines have not previously been 
reported. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to substituted 
1,2,4-triazolo[1,5-c]pyrimido[1,4]azines which are bronchodilators. The 
invention also relates to a method for obtaining bronchodilation in a 
mammal using a 1,2,4-triazolo[1,5-c]pyrimido[1,4]azine of the invention, 
and to pharmaceutical compositions comprising an effective amount of a 
1,2,4-triazolo[1,5-c]pyrimido[1,4]azine of the invention and a 
pharmaceutically acceptable carrier. The invention also relates to 
synthetic intermediates useful for preparing pharmaceutical compounds of 
the invention. 
More specifically, the present invention relates to compounds of Formula I 
below 
##STR4## 
wherein A is methylene or carbonyl; B is methylene, carbonyl or -CHR.sub.9 
-; Q is N-R.sub.7 or O, with the proviso that when Q is O then A is 
methylene and B is methylene or carbonyl; Y is N-R.sub.10, O, S, SO or 
SO.sub.2, with the provisos that when Y is N-R :, Q is 0, when Q is 
N-R.sub.7, Y is not N-R.sub.10 and B is not carbonyl, and when Q is 0, Y 
is N-R.sub.10 ; R.sub.2 is hydrogen or lower alkyl; R.sub.5 is lower 
alkyl; R.sub.7 is hydrogen, lower alkyl, benzyl or acetyl, with the 
proviso that when R.sub.7 is hydrogen or acetyl and Y is S, SO or 
SO.sub.2, then A is methylene; R.sub.9 is lower alkyl; and R.sub.10 is 
lower alkyl or benzyl; and pharmaceutically acceptable acid addition salts 
of compounds wherein A is methylene and B is methylene or --CHR.sub.9 --. 
Three subsets of Formula I are described herein below: compounds of 
Formula VI wherein Y is O and Q is NR.sub.7, compounds of Formula VI 
wherein Y is N-R.sub.10 and Q is O and compounds of Formula XIX and 
Formula XXVI wherein Y is shown as S, but could also be oxidized to SO or 
SO.sub.2. 
The instant invention also provides novel compounds of Formula II below 
##STR5## 
wherein A is methylene or carbonyl; B is methylene, carbonyl or -CHR.sub.9 
--; Q is N-R.sub.7 or O with the proviso that when Q is O then A is 
methylene and B is methylene or carbonyl; Y is N-R.sub.10, O, S, SO or 
SO.sub.2, with the provisos that when Y is N-R.sub.10, Q is O when Q is 
N-R.sub.7, Y is not N-R.sub.10 and B is not carbonyl, and when Q is O, Y 
is N-R.sub.10 ; R.sub.5 is lower alkyl; R.sub.7 is hydrogen, lower alkyl 
or benzyl, with the proviso that when R.sub.7 is hydrogen and Y is S, SO 
or SO.sub.2, then A is methylene; R.sub.9 is lower alkyl; and R.sub.10 is 
lower alkyl or benzyl. The compounds of Formula II are useful 
intermediates for preparing compounds of Formula I. 
Also, the instant invention further provides compounds of Formula III below 
##STR6## 
wherein A is methylene or carbonyl; B is methylene, carbonyl or 
--CHR.sub.19 ; Q is N-R.sub.7 or O, with the proviso that when Q is O, 
then A is methylene and B is methylene or carbonyl; Y is N-R.sub.10,O, S, 
SO or SO.sub.2 with the provisos that when Y is N-R .sub.10, Q is O, when 
Q is N-R.sub.7, Y is not N-R.sub.10 and B is not carbonyl, and when Q is 
O, Y is N-R.sub.10 ; R.sub.2 is hydrogen or lower alkyl; R.sub.5 is lower 
alkyl; R.sub.7 is hydrogen, lower alkyl, benzyl or acetyl, with the 
proviso that when R.sub.7 is hydrogen or acetyl and Y is S, SO or 
SO.sub.2, then A is methylene; R.sub.9 is lower alkyl; and R.sub.10 is 
lower alkyl or benzyl. The compounds of Formula III are also useful 
intermediates for preparing compounds of Formula I. 
"Lower alkyl" as used in the instant specification and claims designates 
straight and branched-chain alkyl groups containing one to about 4 carbon 
atoms. Preferred lower alkyl groups are methyl and ethyl. 
The presently preferred compounds of the invention are listed below. These 
compounds are preferred because of their generally higher potency in 
protecting against histamine-induced contraction of isolated guinea pig 
tracheal tissue. This assay is discussed in greater detail below. 
Specific examples of preferred compounds which are active in the 
aforementioned assay at concentrations of 5 micrograms per milliliter or 
lower are: 
8,9-dihydro-2-ethyl-5-methyl-7H-1,2,4-triazolo[1,5-c]-pyrimido[5,4-b]1,4]ox 
azin -8-one, 
8,9-dihydro-2,5,7-triethyl-1,2,4-triazolo[1,5-c]pyrimido-[5,4][1,4]oxazin-8 
-one hydrate, 
2,5-diethyl-8,9-dihydro-7-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]t 
hiazin-8-one, 
7-(n-butyl)-2,5-diethyl-8,9-dihydro-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1, 
4]thiazin-8-one 
5 
7-benzyl-8,9-dihydro-2,5,9-triethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1 
,4]thiazin-8-one, 
8,9-dihydro-5-ethyl-2-methyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]th 
iazine, 
7-benzyl-8,9-dihydro-5-ethyl-2-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][ 
1,4]thiazine, 
5,7-diethyl-8,9-dihydro-2-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4] 
thiazine, -benzyl-2,5-diethyl-8,9-dihydro-1,2,4-triazolo[1,5-c]pyrimido[ 
5,4-b][1,4]thiazine, 
8,9-dihydro-2-ethyl-5-methyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]ox 
azine, 
2,5-diethyl-8,9-dihydro-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazin- 
8-one, 
2,9-diethyl-8,9-dihydro-7H-5-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1, 
4]oxazin-8-one, 
8,9-dihydro-5,9-dimethyl-2-ethyl-7H-1,2,4-triazolo[1,5-c] 
]oxazin-8-one, 
8,9-dihydro-2,5,9-trimethyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxa 
zin-8-one, 
8,9-dihydro-2,5,9-triethyl-7H-1,2,4-triazolo[1,5-c]pyrimido[ 
5,4-b][1,4]oxazin-8-one, C, 
5,9-diethyl-8,9-dihydro-2-methyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1 
,4]oxazin-8-one, 
2,5-diethyl-8,9-dihydro-9-methyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1, 
4]oxazin-8-one, (n-butyl)-8,9-dihydro-5-ethyl-2-methyl-1,2,4-triazolo[ 
1,5-c]pyrimido[5,4-b][1,4]thiazin-8-one, 
2,7-diethyl-8,9-dihydro-5-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]t 
hiazine, 
2,5-diethyl-8,9-dihydro-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazin 
e, 
2,5-diethyl-8,9-dihydro-7-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]t 
hiazine, 
2,5-diethyl-8,9-dihydro-10-methyl-1,2,4-triazolo[1,5-c]pyrimido[4,5-b][1,4] 
oxazine, and 
8,9-dihydro-2,5,10-triethyl-1,2,4-triazolo[1,5-c]pyrimido[4,5-b][1,4]oxazin 
e. 
Particularly preferred compounds of Formula I are the last fourteen 
mentioned above. 
Compounds of Formula I are bronchodilators. The bronchodilator activity of 
the compounds of Formula I may be shown by the measurement of effects on 
isolated tracheal spirals. This is a well-known and long established in 
vitro test method. The bronchodilator activity is determined according to 
the following procedure: Female guinea pigs were sacrificed and each 
trachea removed and cut into a spiral strip. This strip was mounted in a 
constant temperature (37.degree. C.) muscle bath having a volume of 
approximately 15 ml. The bathing medium was Krebs-Henseleit solution. 
Movement of the tracheal strip was measured by means of an isometric 
transducer connected to an electric recorder. The bath was aerated with a 
mixture of 95% carbon dioxide and 5% oxygen. Contractions were induced in 
the strips by the addition of a suitable amount of histamine, leukotriene 
C.sub.4, acetylcholine or barium chloride. The amount of a given compound 
of Formula I (measured in mcg/ml) required to provide greater than 75% 
relaxation of drug-induced contraction is considered an effective 
concentration. For comparison, a well known standard bronchodilator, 
aminophylline (the ethylenediamine salt of theophylline), requires 
concentrations of 50 mcg/ml versus histamine, 100 mcg/ml versus 
acetylcholine and 10 mcg/ml versus barium chloride to provide greater than 
75% relaxation. 
The compounds of Formula I which were most active in the above described in 
vitro test, including most of those listed above as preferred compounds, 
were tested in vivo in the guinea pig for bronchodilator activity using 
the so-called Konzett-Rossler in vivo test method. The activity was 
determined according to the procedure which follows. The Konzett-Rossler 
technique [H. Konzett and R. Rossler, Naunyn-Schmiedebergs Arch. 
Pharmakol., 195, 71-74 (1940)]was used to assess the effect of test drugs 
on antigen challenge of male Hartley strain guinea pigs (350-500 g). 
Sensitized (50 mg/kg ovalbumin, i.p., 14-21 days previously) or naive 
animals were anesthetized with pentobarbital (70 mg/kg, i.p.) and 
spontaneous respiration eliminated with succinylcholine (2 mg/kg i.p.). 
The trachea was cannulated and respiration maintained under positive 
pressure with a miniature ventilator (5 ml/breath, 87/minute, 10 cm 
water). Bronchoconstrictor responses were represented as increased 
excursions of the tracing on a physiological recorder of air overflow to 
the lungs measured by a pneumotachograph in series with a differential 
pressure transducer. Sensitized animals were challenged with ovalbumin 
(100 mcg/kg, i.v.) after the i.p. or p.o. administration of test drugs. 
Active compounds are those which demonstrate an intraperitoneal or oral 
IC.sub.50 of 10 mg per 25 mg per kg or less, and preferably an IC.sub.50 
of 10 mg per kg or less. Most preferred compounds are active at 10 mg per 
kg. 
The compounds of Formula I may be administered to mammals in order to 
obtain bronchodilation. The compounds may be administered orally, 
parenterally or by inhalation. Preferably they are administered orally in 
tablets or capsules. The usual effective human dose will be in the range 
of 0.1 to 50 mg/kg of body weight. 
Salts of compounds of Formula I wherein A is methylene and B is methylene 
or --CHR.sub.9 -- are generally prepared by reaction with an equimolar 
amount of a relatively strong acid, preferably an inorganic acid such as 
hydrochloric, sulfuric or phosphoric acid, in a polar solvent. Isolation 
of the salt is facilitated by the addition of a solvent in which the salt 
is insoluble, an example of such a solvent being diethyl ether. 
The compounds of Formula I, either as the free base or in the form of a 
pharmaceutically acceptable acid addition salt, can be combined with 
conventional pharmaceutical diluents and carriers to form such dosage 
forms as tablets, capsules, suspensions, solutions, suppositories and the 
like. 
The pharmaceutical carrier employed may be, for example, either a solid or 
liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, 
gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the 
like. Liquid carriers include syrup, peanut oil, olive oil, water and the 
like. Similarly, the carrier or diluent can include a time delay material 
well known to the art, such as glyceryl monostearate or glyceryl 
distearate, these being employed alone or, for example, in combination 
with a wax. 
When Y is N-R.sub.1 or O, the compounds of Formula VI, which are subsets of 
compounds of Formula I, may be prepared according to Reaction Scheme I 
below, wherein the various substituents are as defined in the context of 
Formula I above with the exception that R.sub.7 may only be hydrogen, 
alkyl or benzyl. 
##STR7## 
In step (1), a 4-hydrazinopyrimido[5,4-b][1,4]-oxazine, or 
-[4,5-b][1,4]oxazine or -oxazinone of Formula IV, which can be prepared as 
described in Reaction Scheme II below, is reacted with an orthoester of 
the formula R.sub.2 C(OAlk).sub.3 to provide a novel compound of Formula 
V. Orthoesters of the formula R.sub.2 C(OAlk).sub.3 are well known and 
readily available. Examples of suitable orthoesters include trimethyl 
orthoformate, triethyl orthoformate, triethyl orthoacetate, triethyl 
orthopropionate and the like. Since the orthoesters are liquids, it is 
convenient to mix the compound of Formula IV with an excess of orthoester 
and to heat the mixture at reflux until reaction is complete. 
In step (2), the compound of Formula V is heated with a suitable reagent to 
provide a product of Formula VI, a subset of the compounds of Formula I. 
This reaction is preferably carried out by heating the reaction mixture at 
its reflux temperature in a solvent inert to these conditions such as a 
lower alkanol. In general, the preferred reagents to effect the reaction 
of step (2) are alkali metal alkoxides such as sodium methoxide or sodium 
ethoxide, in catalytic amounts. It is also possible to use aqueous lower 
alkanoic acids such as formic acid, acetic acid and propionic acid to 
effect the reaction of step (2). The products of Formula VI, a subset of 
the compounds of Formula I, are isolated by conventional methods such as 
filtration, extraction or chromatography. 
Compounds of either Formula V or VI, wherein R.sub.7 is hydrogen, may be 
readily acetylated by conventional methods. 
Compounds of Formula IV, appearing in Reaction Scheme I above, may be 
prepared according to Reaction Scheme II below wherein the various 
substituents are as defined in the context of Formula I above when Y is O 
or N-R.sub.10 with the exception that R.sub.7 may only be hydrogen, alkyl 
or benzyl. In this scheme, Q.sub.1 and Q.sub.2 are either N-H and O or O 
and N-H, respectively. In structures of the scheme of Formula VII or VIII 
either A or B, but not both simultaneously, must be carbonyl, while in 
structures IX and X, A and B can only be methylene or --CHR.sub.9 --. 
##STR8## 
The compounds of Formula VII wherein Q.sub.1 is NH, Q.sub.2 is O, A is 
carbonyl and B is methylene or --CHR.sub.9 -- are known and can be 
synthesized using the general procedure described by Sazonov, et al., 
Khimiya Geterotsiklicheskikh Soedinenii, 1973, 171; ibid., 1972, 1285, and 
ibid., 1976, 681, each of these three publications being incorporated 
herein by reference. Variations of the procedure described in these 
publications are conventional and involve primarily variations either in 
the starting amidine or in the added 2-haloalkanoic ester or acid. 
The compounds of Formula VII wherein Q.sub.1 is O, Q.sub.2 is NH, A is 
methylene, and B is carbonyl, are also known, and can be synthesized using 
the general procedures described by Melik-Ogandzhanyan, et al., Khimiya 
Geterotsiklicheskikh Soedinenii, 1985, 974, incorporated herein by 
reference. Variations of the procedures described in this publication are 
conventional and involve primarily variations in the starting amidine 
In step (3) of Reaction Scheme Il, a compound of Formula VII is reacted 
with a benzyl halide or an alkyl halide such as an alkyl iodide or alkyl 
bromide to provide a compound of Formula VIII. The reaction is conducted 
in a lower alkanol solvent in the presence of an alkali metal alkoxide 
such as sodium methoxide or in the solvent N,N-dimethylformamide in the 
presence of sodium hydride. The reaction mixture is generally heated at or 
near its reflux temperature in an alkanol solvent or from 20 to 50.degree. 
C. in N,N-dimethylformamide. 
When Q.sub.1 is Q.sub.2 is N-H the reaction preferably uses sodium hydride 
in N,N-dimethylformamide rather than an alkali metal alkoxide in an 
alkanol. 
Step (4) involves the reaction of a compound of Formula VIII with hydrazine 
hydrate optionally in a lower alkanol solvent such as n-butyl alcohol to 
provide a novel intermediate of Formula IV. 
The compounds of Formula IV wherein A is methylene and B is methylene or 
--CHR.sub.9 -- can be made by sequential application of steps (5) and (6). 
In step (5), the amide compounds of Formula VIII are reduced to the amines 
of Formula X by reaction with a borane reagent. Generally, 4 moles of 
borane per mole of the compound of Formula VIII are employed, and the 
reaction is accompanied by heating at a temperature up to the reflux 
temperature of the mixture. The reaction is carried out in an inert 
solvent such as tetrahydrofuran and the borane reagent employed may be, 
for example, a methyl sulfide complex of borane in tetrahydrofuran. 
In step (6), the amines of Formula X are reacted with hydrazine hydrate in 
the same fashion as in step (4) to provide the compounds of Formula IV. 
The compounds of Formula X can also be provided by sequential application 
of steps (7) and (8). Thus in step (7), the amide VII is first reduced 
with a borane reagent, in a fashion similar to that of step (5), to obtain 
the compound of Formula IX. Alkylation of compound IX in step (8) then 
provides a compound of Formula X. 
Compounds of Formula IV wherein R.sub.7 is hydrogen are obtained by 
omitting the alkylation steps (3) or (8), and instead reacting either a 
compound of Formula VII or a compound of Formula IX with hydrazine 
hydrate, using the method of step (4). 
When Y is S and A is carbonyl and B is methylene or --CHR.sub.9 --, the 
compounds of Formula XIX, which are a subset of compounds of Formula I, 
can be prepared according to Reaction Scheme III below, wherein the 
various substituents are as defined in the context of Formula I above with 
the exception that R.sub.7 may only be alkyl or benzyl. 
##STR9## 
Compounds of structure XI, where R.sub.7 is lower alkyl or benzyl, are 
known and can be prepared as described by Gewald in J. Prakt. Chem., 32, 
26-30 (1966), the disclosure of which is incorporated herein by reference. 
Compounds of Formula XIII are prepared in step (9) using Gewald's general 
procedure, but using an orthester of the formula R.sub.5 C(OAlk).sub.3 
rather than triethyl orthoformate. 
An alternate route to the preparation of the compounds of Formula XIII can 
be employed and is shown in step (9'). It involves the synthetic process 
described by Gewald with the exception that the compound of Formula XII is 
reacted with acetamidine hydrochloride in a refluxing solvent, preferably 
a lower chain alcohol, containing 1.5 to 2.0 equivalents of sodium 
methoxide, to form the compounds of Formula XIII. 
The reaction of step (10) to form the compounds of Formula XIV can be 
carried out according to the procedure of Gewald, J. Prakt. Chem., 32, 
26-30 (1966), although only 5-mercapto-6-phenylamino-3H-pyrimidin-4-one 
was specifically described by him. 
Step (11) to form the novel compounds of Formula XV is carried out by 
reacting a compound of Formula XIV with a 2-haloalkanoic acid in refluxing 
sodium hydroxide solution, followed by refluxing the resultant isolated 
intermediate in acetic anhydride to provide the compounds of Formula XV. 
Step (12) involves reaction of the compounds of Formula XV with phosphorus 
oxychloride to provide the 4-chloro compounds of Formula XVI. 
Step (13) involves reaction of hydrazine or hydrazine hydrate with the 
compounds of Formula XVI to provide the novel compounds of Formula XVII. 
Step (14) involves reaction of a hydrazino compound of Formula XVII with an 
orthoester of the formula R.sub.2 C(OAlk).sub.3 to provide a novel 
compound of Formula XVIII. Orthoesters of the formula R.sub.2 
C(OAlk).sub.3 are well known and readily available compounds or may be 
prepared by known methods. Specific examples of suitable orthoesters 
include trimethyl orthoformate, triethyl orthoformate, triethyl 
orthoacetate, triethyl orthopropionate and the like. Since the orthoesters 
are liquids, it is convenient to mix an excess of orthoester with the 
compound of Formula XVII and reflux until the desired compound of Formula 
XVIII is formed. 
In step (15) the compound of Formula XVIII is rearranged by refluxing in a 
solution of a catalytic amount of methanolic sodium methoxide to form the 
compounds of Formula XIX, a subset of the compounds of Formula I, wherein 
A is carbonyl. 
Compounds of Formula XIX are solids which may be readily isolated by 
conventional methods such as filtration, extraction or chromatography. 
Structural assignments may be confirmed by infrared and nuclear magnetic 
resonance spectral analyses. 
When Y is S, A is methylene and B is methylene or --CHR.sub.9 --, the 
compounds of Formula XXVI, which are a subset of compounds of Formula I, 
can be prepared according to Reaction Scheme IV below, wherein the various 
substituents are as defined in the context of Formula I above. 
##STR10## 
The 5,6-dihydro-3-ethoxy-2-ethoxycarbonyl-2H-[1,4]thiazines of Formula XX 
can be prepared according to the procedure of Great Britain patent 
application 2,143,234A and Henrie II, Robert N., Lazarus, Robert A., and 
Benkovic, Stephen J., J. Med. Chem., 26, No. 4, 559-563 (1983), the 
disclosures of both of which are incorporated herein by reference. The 
compound of Formula XX is reacted in step (16) with an amidine salt in a 
refluxing alcohol to which has been added 2.0 to 2.5 equivalents of sodium 
methoxide; thus forming the oxopyrimido[5,4-b][1,4]thiazines of Formula 
XXI. 
Step (17) involves reaction of the compounds of Formula XXI with phosphorus 
oxychloride to provide the 4-chloro compounds of Formula XXII. 
Step (18) involves reaction of hydrazine or hydrazine hydrate with the 
compounds of Formula XXII to provide the novel hydrazino compounds of 
Formula XXIII. 
Step (19) involves reaction of a hydrazino compound of Formula XXIII with 
an orthoester of the formula R.sub.2 C(OAlk) to provide a novel compound 
of Formula XXIV. 
Orthoesters of the formula R.sub.2 C(OAlk).sub.3 are well known and readily 
available compounds or may be prepared by known methods. Specific examples 
of suitable orthoesters include trimethyl orthoformate, triethyl 
orthoformate, triethyl orthoacetate, triethyl orthopropionate and the 
like. Since the orthoesters are liquids, it is convenient to mix an excess 
of orthoester with the compound of Formula XXIII and reflux until the 
desired compound of Formula XXIV is formed. 
In step (20) the compound of Formula XXIV is rearranged by refluxing in a 
solution of a catalytic amount of methanolic sodium methoxide to form the 
compounds of Formula XXV. 
Step (21) involves the further reaction of the 
8,9-dihydro-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazines of Formula 
XXV with an alkyl, acyl or benzyl halide to form the compounds of Formula 
XXVI, which are a subset of compounds of Formula I. Although in the 
specific examples described herein alkylation was carried out using a 
compound of Formula XXV, alkylation could have also been carried out using 
a compound of either Formula XXII or Formula XXIV. 
Compounds of Formula XXII, Formula XXIV, Formula XXV or Formula XXVI can be 
oxidized to their respective sulfoxides by reaction with sodium 
metaperiodate, or a peracid such as meta-chloroperbenzoic acid. Similarly, 
any of the compounds previously mentioned which are capable of oxidation 
to the sulfoxide may be independently oxidized to the sulfone by the 
action of a peracid such as metachloroperbenzoic acid. Alternatively, any 
sulfoxide may be further oxidized to form the corresponding sulfone. 
All compounds of Formula XXVI, a subset of compounds of Formula I, are 
solids which may be readily isolated by conventional methods such as 
filtration, extraction or chromatography. Structural assignments may be 
confirmed by infrared and nuclear magnetic resonance spectral analyses.

The following examples are provided to illustrate the methods used in the 
invention. They are not intended to limit the invention. 
EXAMPLE 1 
Step 1 
Preparation of 
8,9-Dihydro-5,7-dimethyl-3-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4,-b]-[1, 
4]oxazin-8-one 
A mixture of 4.0g (0.019 mole) of 
6,7-dihydro-2,8-dimethyl-4-hydrazinopyrimido[5,4-b][1,4]oxazin-7-one and 
25 ml of triethyl propionate was heated first at 110.degree. C for about 
16 hours and then at 130.degree. C for an additional 25.5 hours. The 
mixture was evaporated by passing a stream of nitrogen gas over it, and 
1.0g of the solid residue was separated for reaction in Step 2. The 
remainder of the residue was dissolved in dichloromethane and passed 
through a silica flash chromatography column, eluting sequentialy with 
ethyl acetate and acetone. The fractions were checked by thin layer 
chromatography, and were evaporated to provide solid fractions. A later 
fraction which showed only one component was determined to be 
8,9-dihydro-5,7-dimethyl-3-ethyl-1,2,4 -triazolo[4,3-c]pyrimido[5,4 
-b][1,4]-oxazin-8-one, m.p. 200.degree. C. Analysis: Calculated for 
C.sub.11 H.sub.13 N.sub.5 O.sub.2 : %C, 53.4; %H, 5.3; %N, 28.3: Found: 
%C, 53.4; %H, 5.3; %N, 28.4. 
EXAMPLES 2-22 
Using the method of Step 1, Example 1, the indicated intermediates of 
Formula IV wherein Y is O, Q is N-R.sub.7 and B is methylene or 
--CHR.sub.9 - were reacted with the indicated trialkyl orthoesters to 
provide novel intermediates of Formula V (Table IA). 
TABLE IA 
__________________________________________________________________________ 
Intermediate of Formula V 
Example 
Orthoester 
R.sub.2 
R.sub.5 
R.sub.7 
B A 
__________________________________________________________________________ 
2 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.3 
H CH.sub.2 
C.dbd.O 
orthopropionate 
3 triethyl 
H CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
C.dbd.O 
orthoformate 
4 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
C.dbd.O 
orthopropionate 
5 triethyl 
H CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 
orthoformate 
6 triethyl 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
C.dbd.O 
orthoacetate 
7 triethyl 
CH.sub.3 
CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 
orthoacetate 
8 triethyl 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 
orthoacetate 
9 triethyl 
H CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 
orthoformate 
10 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
H CH.sub.2 
C.dbd.O 
orthopropionate 
11 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.3 
H CHCH.sub.2 CH.sub. 3 
C.dbd.O 
orthopropionate 
12 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.3 
H CHCH.sub.3 
C.dbd.O 
orthopropionate 
13 triethyl 
CH.sub.3 
CH.sub.3 
H CHCH.sub.3 
C.dbd.O 
orthoacetate 
14 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
H CHCH.sub.2 CH.sub.3 
C.dbd.O 
orthopropionate 
15 triethyl 
CH.sub.3 
CH.sub.2 CH.sub.3 
H CHCH.sub.2 CH.sub.3 
C.dbd.O 
orthoacetate 
16 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
H CHCH.sub.3 
C.dbd.O 
orthopropionate 
17 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 
orthopropionate 
18 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.3 
H CH.sub.2 
CH.sub.2 
orthopropionate 
19 triethyl 
H CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
CH.sub.2 
orthoformate 
20 triethyl 
CH.sub.3 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
CH.sub.2 
orthoacetate 
21 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
CH.sub.2 
orthopropionate 
22 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.3 
CH.sub.2 
CH.sub.2 
orthopropionate 
__________________________________________________________________________ 
EXAMPLES 23-40 
Using the method of Step 1, Example 1, the indicated intermediates of 
Formula IV wherein Y is N--R.sub.10, Q is O, and A is methylene were 
reacted with the indicated trialkyl orthoesters to provide novel 
intermediates of Formula V (Table IB). Example 39 has not actually been 
carried out. 
TABLE IB 
______________________________________ 
Exam- Intermediate of Formula V 
ple Orthoester R.sub.2 R.sub.5 
R.sub.10 
B 
______________________________________ 
23 triethyl CH.sub.3 CH.sub.3 
CH.sub.3 
C.dbd.O 
orthoacetate 
24 triethyl CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.3 
CH.sub.2 
orthopropionate 
25 triethyl CH.sub.3 CH.sub.3 
CH.sub.3 
CH.sub.2 
orthoacetate 
26 triethyl CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.3 
C.dbd.O 
orthopropionate 
27 triethyl CH.sub.3 CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
orthoacetate 
28 triethyl CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
orthopropionate 
29 triethyl CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
C.dbd.O 
orthopropionate 
30 triethyl CH.sub.3 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
orthoacetate 
31 triethyl CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
orthopropionate 
32 triethyl CH.sub.3 CH.sub.2 CH.sub.3 
CH.sub.3 
C.dbd.O 
orthoacetate 
33 triethyl CH.sub.3 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
C.dbd.O 
orthoacetate 
34 triethyl CH.sub. 3 
CH.sub.3 
CH.sub.2 Ph 
CH.sub.2 
orthoacetate 
35 triethyl CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 Ph 
CH.sub.2 
orthopropionate 
36 triethyl CH.sub.3 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
orthoacetate 
37 triethyl CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
orthopropionate 
38 triethyl CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
C.dbd.O 
orthopropionate 
39 triethyl H CH.sub.3 
CH.sub.3 
C.dbd.O 
orthoformate 
40 triethyl H CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
orthoformate 
______________________________________ 
EXAMPLE 41 
Step 2 
Preparation of 
8,9-Dihydro-5,7-dimethyl-2-ethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b]-[[1, 
4]oxazin-8-one 
One gram (4.05 mmole) of crude 
8,9-dihydro-5,7-dimethyl-3-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4-b][1,4] 
-oxazin-8-one obtained in Step 1, Example 1 was dissolved in 20 ml of 
methanol. Two drops of 25% sodium methoxide solution were added and the 
solution was heated at its reflux temperature for one hour. The solution 
was evaporated under vacuum and the residue was dissolved in 
dichloromethane and eluted through a flash chromatography column with 1:1 
(by volume) dichloromethane:ethyl acetate to obtain a white solid which 
was recrystallized from a benzene-hexane mixture to provide 
8,9-dihydro-5,7-dimethyl-2-ethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4] 
oxazin-8-one, m.p. 169-170.degree. C. Analysis: Calculated for C.sub.11 
H.sub.13 N.sub.5 O.sub.2 : %C, 54.4; %H, 5.3; %N, 28.3; Found: %C, 53.4; 
%H, 5.2; %N, 28.5. 
EXAMPLES 42-62 
Using the method of Step 2, Example 41, the indicated intermediate of 
Formula V wherein Y is O, Q is N-R.sub.7 and B is methylene or -CHR.sub.9 
- was reacted with methanolic sodium methoxide to provide the indicated 
product of Formula VI (TABLE IIA). 
TABLE IIA 
__________________________________________________________________________ 
Intermediate Calculated: 
% C; 
% H; 
% N 
from Product of Formula VI Found: 
% C; 
% H; 
% N 
Example 
Example 
R.sub.2 
R.sub.5 
R.sub.7 
B A (m.p. in .degree.C.) 
__________________________________________________________________________ 
42 2 CH.sub.2 CH.sub.3 
CH.sub.3 
H CH.sub.2 
C.dbd.O 51.5; 
4.75; 
30.0 
51.5; 
4.7; 
30.0 
(284-285) 
43 3 H CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
C.dbd.O 53.4; 
5.3; 
28.3 
53.8; 
5.5; 
28.3 
(113-114) 
44 4 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
C.dbd.O 54.9; 
6.4; 
24.6 
[.multidot. 1/2 H.sub.2 O]; 
55.4; 
6.1; 
24.5 
(78-80) 
45 5 H CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 49.3; 
4.1; 
31.95 
49.3; 
4.2; 
31.8 
(210-211) 
46 6 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
C.dbd.O 55.2; 
5.8; 
26.8 
55.3; 
5.8; 
26.9 
(153-154) 
47 7 CH.sub.3 
CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 51.5; 
4.75; 
30.0 
51.5; 
4.7; 
30.1 
(195-196) 
48 8 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 53.4; 
5.3; 
28.3 
53.3; 
5.3; 
28.4 
(201-202) 
49 9 H CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 51.5; 
4.75; 
30.0 
51.7; 
4.8; 
29.9 
(174-175) 
50 10 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
H CH.sub.2 
C.dbd.O 53.4; 
5.3; 
28.3 
53.2; 
5.4; 
28.0 
(231-233) 
51 11 CH.sub.2 CH.sub.3 
CH.sub.3 
H CHCH.sub.2 CH.sub.3 
C.dbd.O 55.2; 
5.8; 
26.8 
54.9; 
5.6; 
26.7 
(185-186) 
52 12 CH.sub.2 CH.sub.3 
CH.sub.3 
H CHCH.sub.3 
C.dbd.O 53.4; 
5.3; 
28.3 
53.4; 
5.4; 
28.7 
(145-146) 
53 13 CH.sub.3 
CH.sub.3 
H CHCH.sub.3 
C.dbd.O 51.5; 
4.75; 
30.0 
51.0; 
4.8; 
30.2 
(149-151) 
54 14 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
H CHCH.sub.2 CH.sub.3 
C.dbd.O 56.7; 
6.2; 
25.4 
56.4; 
6.3; 
25.7 
(217-218) 
55 15 CH.sub.3 
CH.sub.2 CH.sub. 3 
H CHCH.sub.2 CH.sub.3 
C.dbd.O 55.2; 
5.8; 
26.8 
54.7; 
5.8; 
26.4 
(208-209) 
56 16 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
H CHCH.sub.3 
C.dbd.O 55.2; 
5.8; 
26.8 
54.6; 
5.8; 
26.8 
(229-230) 
57 17 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
C.dbd.O 55.2; 
5.8; 
26.8 
55.3; 
5.8; 
26.9 
(138-139) 
58 18 CH.sub.2 CH.sub.3 
CH.sub.3 
H CH.sub.2 
CH.sub.2 54.8; 
6.0; 
31.9 
54.9; 
6.0; 
31.7 
(173-175) 
59 19 H CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
CH.sub.2 54.8; 
6.0; 
31.9 
54.8; 
6.1; 
31.9 
(133-134) 
60 20 CH.sub.3 
CH.sub. 3 
CH.sub.2 CH.sub.3 
CH.sub.2 
CH.sub.2 56.6; 
6.5; 
30.0 
57.0; 
6.6; 
30.3 
(137-138) 
61 21 CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
CH.sub.2 58.3; 
6.9; 
28.3 
58.3; 
6.9; 
28.6 
(119-120) 
62 22 CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.3 
CH.sub.2 
CH.sub.2 56.6; 
6.5; 
30.0 
56.4; 
6.5; 
30.0 
(135-136) 
__________________________________________________________________________ 
EXAMPLES 63-14 78 
Using the method of Step 2, Example 41, the indicated intermediate of 
Formula V wherein Y is N-R.sub.10, Q is O and A is methylene was reacted 
with methanoloc sodium methoxide to provide the indicated product of 
Formula VI (TABLE IIB). 
TABLE IIB 
__________________________________________________________________________ 
Intermediate Calculated: 
% C; 
% H; 
% N 
from Product of Formula VI 
Found: 
% C; 
% H; 
% N 
Example 
Example 
R.sub.2 
R.sub.5 
R.sub.10 
B (m.p. in .degree.C.) 
__________________________________________________________________________ 
63 23 CH.sub.3 
CH.sub.3 
CH.sub.3 
C.dbd.O 51.5; 
4.75; 
30.0 
51.7; 
4.8; 
29.8 
(193-194) 
64 24 CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.3 
CH.sub.2 56.6; 
6.5; 
30.0 
56.7; 
6.5; 
30.2 
(97-98) 
65 25 CH.sub.3 
CH.sub.3 
CH.sub.3 
CH.sub.2 54.8; 
6.0; 
31.9 
54.5; 
6.0; 
31.8 
(140-141) 
66 27 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 56.6; 
6.5; 
30.0 
56.5; 
6.4; 
30.0 
(123-124.5) 
67 28 CH.sub.2 CH.sub.3 
CH.sub. 2 CH.sub.3 
CH.sub.3 
CH.sub.2 58.3; 
6.9; 
28.3 
58.0; 
6.9; 
28.5 
(67-70) 
68 29 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
C.dbd.O 55.2; 
5.8; 
26.8 
55.3; 
5.8; 
27.0 
(99-100.5) 
69 30 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 58.3; 
6.9; 
28.3 
58.6; 
7.0; 
28.6 
(81-82) 
70 31 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 59.7; 
7.3; 
26.8 
59.2; 
7.3; 
26.7 
(60-62.5) 
71 32 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
C.dbd.O 53.4; 
5.3; 
28.3 
53.5; 
5.3; 
28.2 
(133-134) 
72 35 CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 Ph 
CH.sub.2 66.0; 
6.2; 
22.6 
65.8; 
6.2; 
22.1 
(89-90) 
73 36 CH.sub.3 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 56.6; 
6.5; 
30.0 
56.6; 
6.6; 
30.3 
(111-113) 
74 34 CH.sub.3 
CH.sub.3 
CH.sub.2 Ph 
CH.sub.2 65.1; 
5.8; 
23.7 
64.7; 
5.8; 
23.6 
(92-95) 
75 37 CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 58.3; 
6.9; 
28.3 
58.5; 
7.0; 
28.6 
(83-84) 
76 33 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
C.dbd.O 55.2; 
5.8; 
26.8 
55.2; 
5.8; 
26.9 
(120-121) 
77 38 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
C.dbd.O 56.7; 
6.2; 
25.4 
56.8; 
6.2; 
25.5 
(73.5-76) 
78 40 H CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 54.8; 
6.0; 
31.9 
55.0; 
6.0; 
32.3 
(85-88) 
__________________________________________________________________________ 
EXAMPLE 79 
Preparation of 
8,9-Dihydro-2,5-dimethyl-7-ethyl-1,2,4triazolo[1,5-c]pyrimido [5,4-b][1,4] 
oxazine dihydrogen sulfate 
One gram (4.3 mmole) of 8,9-dihydro-2,5-dimethyl-7-ethyl-1,2,4-triazolo 
1,5-c]pyrimido[5,4-b][1,4]oxazine, obtained in Example 42, was dissolved 
in 5 ml of ethanol. Concentrated sulfuric acid (0.42g, 4.3 mmole) was 
added, followed by the addition of diethyl ether to precipitate a white 
solid which was filtered, washed with diethyl ether and then dried to 
provide 8,9-dihydro-2,5-dimethyl-7-ethyl1,2,4-triazolo[1,5-c]pyrimido 
5,4-b][1,4]oxazine dihydrogen sulfate, m.p. 245-246.degree. C. Analysis: 
Calculated for C.sub.11 H.sub.15 N.sub.5 O.multidot.H.sub.2 SO.sub.4 : %C, 
39.9; %H, 5.2; %N, 21.1; Found: %C, 40.3; %H, 5.4; %N, 20.7. 
EXAMPLE 80 
STEP 3 
Preparation of 4-chloro-6,7-dihydro-2,8-dimethyl-pyrimido-8 
5,4-b]1,4]oxazin-7-one 
Using the method of Sazonov, et al., Khimiya Geterotsiklicheskikh 
Soedinenii, 9, 1285-1288 (1972), 
4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4b][1,4]oxazin-7-one one was 
prepared. To a mixture of 8.0g (0.0402 mole) of 
4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one and 17.9 
ml of methyl iodide was added 8.75g of 25% sodium methoxide in 250 ml of 
methanol, and the solution was heated at its reflux temperature for three 
hours. The solvent was removed by evaporation under vacuum, and the solid 
was separated by filtration, washed with water, and dried. The yellow 
solid was 
4-chloro-6,7-dihydro-2,8-dimethylpyrimido[5,4b][1,4]oxazin-7-one, m.p. 
142-143.degree. C. 
EXAMPLE 81 
To a stirred suspension of 5g (0.023 mole) of 
4-chloro-6,7-dihydro-2-ethyl-5H-pyrimido[4,5-b][1,4]oxazin-6-one (prepared 
using the method of Melik-Ogandzhanyan, et al., Khimiya 
Geterotsiklicheskikh Soedinenii, 1985, 974) in 100 ml of 
N,N-dimethylformamide was added 0.75g (0.025 mole) of 80% sodium hydride 
in oil. After ten minutes 3.5g (0.025 mole) of methyl iodide was added. 
After two hours the solution was diluted with about 400ml of water, and 
extracted thrice with 250ml portions of chloroform. The extracts were 
washed with water, dried over magnesium sulfate, treated with decolorizing 
charcoal, and evaporated in vacuo. The resulting oil was triturated with a 
mixture of diethyl ether and hexanes to provide light green solid 
4-chloro-6,7-dihydro-2-ethyl-5-methylpyrimido[4,5-b][1,4]oxazin-6-one. 
EXAMPLES 82-84 
Using the method described in Example 81 the following compounds of Formula 
VIII wherein Q is O, A is methylene and B is carbonyl were prepared. 
______________________________________ 
Product of Formula VIII 
Example R.sub.5 R.sub.10 
______________________________________ 
82 CH.sub.3 CH.sub.2 CH.sub.3 
83 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
84 CH.sub.3 CH.sub.3 
______________________________________ 
EXAMPLE 85 
Using the procedure of Example 80, 
4-chloro-6,7-dihydro-2-ethyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one was 
alkylated providing 4-chloro-6,7-dihydro-2-ethyl-8-methylpyrianido 
5,4-b][1,4]oxazin-7-one. 
EXAMPLE 86 
Using the procedure of Example 80, except that 1-bromoethane was used 
instead of methyl iodide, 
4-chloro-6,7-dihydro-2-ethyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one was 
alkylated providing 4-chloro-2,8-diethyl-6,7dihydropyrimido[5,4-b 
][1,4]oxazin-7-one. 
EXAMPLE 87 
Step 4 
Preparation of 6, 
7-Dihydro-2,8-dimethyl-4-hydrazinopyrimido[5,4-b][1,4]oxazin-7-one 
To a solution of 5.78g (0.0271 mole) of 
4-chloro-6,7-dihydro-2,8-dimethylpyrimido[5,4-b][1,4]- oxazin-7-one, 
obtained from Example 80, in 100 ml of n-butyl alcohol was added 1.74g 
(0.0543 mole) of hydrazine hydrate, and the mixture was heated at its 
reflux temperature for three hours. On cooling a solid precipitated and 
was separated by filtration, washed with water and dried. The structure of 
the light yellow product was 
6,7-dihydro-2,8-dimethyl-4-hydrazinopyrimido[5,4b][1,4]oxazin-7-one 
according to infrared spectral analysis. 
EXAMPLES 88-89 
Using the procedure of Example 87, the intermediates of Example 85 and 
Example 86 were independently reacted with hydrazine hydrate to provide 
the novel compounds 
6,7-dihydro-2-ethyl-4-hydrazino-8methylpyrimido[5,4-b][1,4]oxazin-7-one 
and 2,8-diethyl-6,7- dihydro-4-hydrazinopyrimido[5,4-b][1,4]oxazin-7-one 
respectively. 
EXAMPLE 90-98 
The method of Sazonov, et al., Khimiya Geterotsiklicheskikh Soedinenii, 9, 
1285-1288 (1972), was used to prepare the 
4-chloropyrimido[5,4-b][1,4]oxazin-7-ones which were independently reacted 
with hydrazine hydrate, according to the procedure of Example 87, to 
provide the novel compounds of Formula IV (TABLE IIIA). 
TABLE IIIA 
______________________________________ 
Compound of Formula IV 
Example R.sub.5 R.sub.7 B 
______________________________________ 
90 CH.sub.3 CH.sub.3 CH.sub.2 
91 CH.sub.3 H CH.sub.2 
92 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 
93 CH.sub.2 CH.sub.3 
CH.sub.3 CH.sub.2 
94 CH.sub.2 CH.sub.3 
H CH.sub.2 
95 CH.sub.3 H CHCH.sub.2 CH.sub.3 
96 CH.sub.3 H CHCH.sub.3 
97 CH.sub.2 CH.sub.3 
H CHCH.sub.2 CH.sub.3 
98 CH.sub.2 CH.sub.3 
H CHCH.sub.3 
______________________________________ 
EXAMPLES 99-101 
The method of step 4, Example 87 was used to prepare the novel compounds of 
Formula IV wherein Q is O, Y is N-R.sub.10 and A is methylene as shown in 
Table IIIB. 
TABLE IIIB 
______________________________________ 
Intermediate 
Compound of Formula IV 
Example from Example R.sub.5 R.sub.7 
______________________________________ 
99 84 CH.sub.3 CH.sub.3 
100 83 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
101 81 CH.sub.2 CH.sub.3 
CH.sub.3 
______________________________________ 
EXAMPLE 102 
Step 5 
Preparation of 4-Chloro-6,7-dihydro-8-ethyl-2-methylpyrimido 
[5,4-b][1,4]oxazine 
A solution of 2.0g (8.81 mmole) of 
4-chloro-6,7-hydro8-ethyl-2-methylprimido[5,4-b][1,4oxazin -7-one in 25 ml 
of tetrahydrofuran was added dropwise to 3.5 ml of cold (0.degree. C.) 
borane-methyl sulfide complex in tetrahydrofuran. After the completion of 
the addition, the mixture was heated at its reflux temperature for three 
hours. The mixture was cooled and 14 ml of 6N hydrochloric acid was slowly 
added. This mixture was heated for one hour at 115.degree. C., and was 
then cooled and neutralized with ammonium hydroxide. The mixture was 
extracted with chloroform, and the organic layer was then dried and 
evaporated to provide an oil residue which crystallized on cooling. 
Nuclear magnetic resonance spectral analysis showed the product to be 
4-chloro-6,7-dihydro-8-ethyl-2methylpyrimido[5,4-b][1,4]oxazine. 
EXAMPLES 103-104 
Using the method of Example 102, 4-chloro-6,7-dihydro-2,8-dimethylpyrimido 
5,4-b][1,4]oxazin-7-one and 
4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4b][1,4]oxazin-7-one were 
reduced to white solids 
4-chloro-6,7-dihydro-2,8-dimethylpyrimido[5,4-b][5,4-b][1,4]oxazine and 
4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4b][1,4]oxazine, respectively. 
EXAMPLE 105 
2-methylpyrimido[5,4-b][1,4]oxazine 
Using the method of Example 87, 
4-chloro-6,7-dihydro-8-ethyl-2-methylpyrimido [5,4-b][1,4]oxazine, from 
Example 102, was reacted with hydrazine hydrate to provide 
6,7-dihydro-8-ethyl-4-hydrazino-2-methylpyrimido[5,4-b][1,4]oxazine. 
EXAMPLES 106-107 
Using the procedure of Example 105, the indicated intermediates of Formula 
X were reacted with hydrazine hydrate to provide the compounds of Formula 
IV wherein Y is O, Q is N-R.sub.7, and A and B are methylene (TABLE IV). 
TABLE IV 
______________________________________ 
Intermediate 
Intermediate of Formula X 
from and Compound of Formula IV 
Example Example R.sub.5 R.sub.7 
______________________________________ 
106 103 CH.sub.3 CH.sub.3 
107 104 CH.sub.3 H 
______________________________________ 
EXAMPLE 108 
Step 9 
Preparation of 5-Ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione 
The general procedure of Gewald, J. Prakt, Chem., 32,26-30 (1966) was used 
to prepare 4-amino-3-methylthiazoline-2-thione-5-carboxamide, of which 
27.3g (0.14 mole) was suspended in a mixture of approximately 144ml of 
acetic anhydride and about 144ml of triethyl orthopropionate. The 
resultant mixture was refluxed for approximately one half hour, then 
cooled in an ice bath. The solid which precipitated was separated by 
filtration, washed with diethyl ether and dried in a vacuum oven at 
approximately 100.degree. C. to provide 21.4g (65%) of 
5-ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. Infrared 
spectral analysis confirmed the structural assignment. 
EXAMPLES 109 AND 110 
Utilizing the procedure of Example 108, the designated intermediates of 
Formula XI were reacted with triethyl orthopropionate to provide the 
corresponding compounds of Formula XIII listed in TABLE V, the structures 
of which were confirmed by the indicated spectral analysis. 
TABLE V 
______________________________________ 
Intermediate 
of Formula XI 
and Compounds 
of Formula XIII 
Reflux Time 
Yield Spectral 
Example 
R.sub.7 (in min.) (%) Analysis 
______________________________________ 
109 (CH.sub.2).sub.3 CH.sub.3 
30 59 IR, NMR 
110 CH.sub.2 Ph 30-60 53 IR, NMR 
______________________________________ 
EXAMPLE 111 
Step 9 
Preparation of 3,5-Dimethyl-6H-thiazolo[4,5d]pyrimidin-7-one-2-thione 
Ethyl 4-amino-3-methylthiazoline-2-thione-5-carboxylate (1.4g, 6.4 mmoles), 
prepared according to the procedure of Gewald, J. Prakt. Chem., 32, 26-30 
(1966), was suspended in approximately 40ml of ethanol. Acetamidine 
hydrochloride (0.6g, 6.4 mmole) and 2.77g (12.8 mmole) of a 25% solution 
of sodium methoxide in methanol were added to the suspension and the 
resultant mixture refluxed for approximately 20 hours. The ethanol was 
removed in vacuo and the residue was suspended in water and neutralized 
with concentrated hydrochloric acid. The resultant precipitate was 
filtered and dried to provide 1g of 
3,5-dimethyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. The structural 
assignment was confirmed by nuclear magnetic resonance spectral analysis. 
EXAMPLE 112 
Step 10 
Preparation of 2-Ethyl-5-mercapto-6-methylamino-3H-pyrimidin-4-one 
5-Ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione (9.5g, 41.8 
mmole) from Example 108 was suspended in approximately 500ml of 4N sodium 
hydroxide solution. The resultant mixture was refluxed for 2 to 4 hours, 
followed by cooling at approximately 4.degree. C. for about hours. The 
mixture was slowly acidified with concentrated hydrochloric acid; the 
solid was separated by filtration and dried, providing 6.6g (85%) of 
2-ethyl-5-mercapto-6-methylamino-3H-pyrimidin-4-one. Infrared and nuclear 
magnetic resonance spectral analyses confirmed the structural assignment. 
EXAMPLES 113 AND 114 
Using the procedure of Example 112, the intermediates of Formula XIII were 
refluxed in sodium hydroxide solution, then acidified to provide the 
compounds of Formula XIV listed in TABLE VI, the structures of which were 
confirmed by the indicated spectral analysis. 
TABLE VI 
______________________________________ 
Intermediate 
Inter- of Formula XIII 
mediate and Compound 
from of Formula XIV 
Yield Spectral 
Example Example R.sub.7 (%) Analysis 
______________________________________ 
113 109 (CH.sub.2).sub.3 CH.sub.3 
98 IR, NMR 
114 110 CH.sub.2 Ph 96 IR, NMR 
______________________________________ 
EXAMPLE 115 
Step 11 
Preparation of 
6,7-Dihydro-2-ethyl-8-methyl-3H-pyrimido[5,4-b][1,4]thiazine-4,7-dione 
2-Ethyl-5-mercapto-6-methylamino-3H-pyrimidin-4-one (6.6g, 0.036 mole) from 
Example 112 and 3.37g (0.036 mole) of chloroacetic acid were added to 
approximately 120ml of water containing 4.27g (0.107 mole) of sodium 
hydroxide. The resultant solution was refluxed for approximately 4 hours, 
allowed to cool and acidified to about pH 2 with concentrated hydrochloric 
acid. The white solid was separated by filtration and dried (7.4g), then 
refluxed in approximately 100ml of acetic anhydride for about 2 hours and 
allowed to cool. The precipitate was removed by suction filtration, washed 
with diethyl ether and dried, providing 6.26g (78%) of 
6,7-dihydro-2-ethyl-8-methyl-3H-pyrimido[5,4-b][1,4]thiazane-4,7-dione. 
The structural assignment was confirmed by infrared spectral analysis. 
EXAMPLES 116 AND 117 
Utilizing the method of Example 115, the intermediates of Formula XIV were 
converted to the compounds of Formula XV listed in TABLE VII, the 
structures of which were confirmed by the indicated spectral analysis. 
TABLE VII 
______________________________________ 
Intermediate 
of Formula XIV 
Intermediate 
and Compound 
from of Formula XV 
Yield Spectral 
Example 
Example R.sub.7 (%) Analysis 
______________________________________ 
116 113 (CH.sub.2).sub.3 CH.sub.3 
36 IR, NMR 
117 114 CH.sub.2 Ph 41 IR, NMR 
______________________________________ 
EXAMPLE 118 
2Ethyl-5-mercapto-6-benzylamino-3H-pyrimidin-4-one (10.0g, 0.038 mole) from 
Example 114 was suspended in approximately 100ml of water containing 4.6g 
(0.115 mole) of sodium hydroxide and the suspension was stirred for about 
10 minutes. 2-Bromobutyric acid (6.39g, 0.038 mole) was added and the 
resultant mixture refluxed for about 2 hours, allowed to cool and 
acidified to approximately pH 4-5 with concentrated hydrochloric acid. The 
precipitate was separated by filtration and dried providing 8.8g which was 
suspended in approximately 100ml of acetic anhydride, refluxed for about 
one hour and then allowed to cool. Since no solid precipitated on cooling, 
a stream of nitrogen was blown over the solution to evaporate the acetic 
anhydride. The residue was then dissolved in methylene chloride and flash 
chromatographed, eluting with 1:10 (by volume) ethyl acetate:methylene 
chloride. Evaporation provided 3.0g (24%) of yellow solid, 
2,6-diethyl-6,7-dihydro-8-benzyl-3H-pyrimido[5,4-b][1,4]thiazine-4,7-dione 
. Infrared spectral analysis confirmed the structural assignment. 
EXAMPLE 119 
Step 12 
Preparation of 
4-Chloro-6,7-dihydro-2-ethyl-8-methylpyrimido[5,4-b][1,4]thiazin-7-one 
The 6,7-dihydro-2-ethyl-8-methyl-3H-pyrimido-[5,4-b][1,4]thiazine-4,7-dione 
of Example 115 (2.7g, 12.04 mmole) was suspended in approximately 150ml of 
phosphorus oxychloride and refluxed for about 20 hours. The solution was 
concentrated in vacuo and the excess phosphorus oxychloride was decomposed 
with the careful addition of ice and water. The aqueous solution was 
neutralized with the cautious addition of concentrated ammonium hydroxide, 
followed by the addition of sodium bicarbonate. The aqueous solution was 
extracted numerous times with chloroform; the extracts were combined, 
washed well with water, then brine, dried over magnesium sulfate, filtered 
and evaporated in vacuo to provide 2.4g (83%) of an off-white solid. The 
structural assignment was confirmed by infrared and nuclear magnetic 
resonance spectral analyses. 
EXAMPLES 120-122 
Utilizing the method of Example 119, the intermediates of Formula XV were 
chlorinated, providing the compounds of Formula XVI listed in TABLE VIII. 
These compounds were isolated as oils and required further purification 
utilizing flash chromatography, eluting with methylene chloride. The 
structural assignment of the compounds was confirmed by nuclear magnetic 
resonance spectral analysis. 
TABLE VIII 
__________________________________________________________________________ 
Inter- 
mediate Intermediate of Formula XV 
from and Compound of Formula XVI 
Yield 
Spectral 
Example 
Example 
R.sub.5 
R.sub.7 
B (%) Analysis 
__________________________________________________________________________ 
120 116 CH.sub.2 CH.sub.3 
(CH.sub.2).sub.3 CH.sub.3 
CH.sub.2 
74 NMR 
121 117 CH.sub.2 CH.sub.3 
CH.sub.2 Ph 
CH.sub.2 
43 NMR 
122 118 CH.sub.2 CH.sub.3 
CH.sub.2 Ph 
CHCH.sub.2 CH.sub.3 
60 NMR 
__________________________________________________________________________ 
EXAMPLE 123 
Step 13 
Preparation of 6,7-Dihydro-2-ethyl-4-hydrazino-8methylpyrimido 
[5,4-b][1,4]thiazin-7-one 
4-Chloro-6,7-dihydro-2-ethyl-8-methylpyrimido[5,4-b][1,4]thiazin-7-one from 
Example 119 (2.4g, 9.93 mmole) was suspended in approximately 100ml of 
n-butanol. Hydrazine monohydrate (0.99g, 19.9 mmole) was added and the 
resultant mixture was refluxed for about 20 hours. The reaction mixture 
was allowed to cool and the precipitate was separated by filtration, 
washed with water and dried, providing 1.93g (81%) of 
6,7-dihydro-2-ethyl-4-hydrazino-8-methylpyrimido 
[5,4-b][1,4]thiazin-7-one. Infrared and nuclear magnetic resonance 
spectral analyses confirmed the structural assignment. 
EXAMPLES 124-125 
Using the procedure of Example 123, the intermediates of Formula XVI were 
reacted with hydrazine monohydrate to provide the respective intermediates 
of Formula XVII listed in TABLE IX. For Example 125, the reaction mixture 
was refluxed for about 3 hours instead of approximately 20 hours. The 
structures were confirmed by the indicated spectral analysis. 
TABLE IX 
__________________________________________________________________________ 
Inter- 
mediate Intermediate of Formula XVI 
from and Compound of Formula XVII 
Yield 
Spectral 
Example 
Example 
R.sub.5 
R.sub.7 
B (%) Analysis 
__________________________________________________________________________ 
124 120 CH.sub.2 CH.sub.3 
(CH.sub.2).sub.3 CH.sub.3 
CH.sub.2 
93 IR, NMR 
125 122 CH.sub.2 CH.sub.3 
CH.sub.2 Ph 
CHCH.sub.2 CH.sub.3 
85 NMR 
__________________________________________________________________________ 
EXAMPLE 126 
Step 14 
Preparation of 
8,9-Dihydro-3,7-dimethyl-5-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4-b][1,4t 
hiazin-8-one 
Approximately 20ml of triethyl orthoacetate was added to 1.lg (4.6 mmole) 
of 6,7-dihydro-2-ethyl-4-hydrazino-8-methylpryimido[5,4-b][1,4thiazin-7-on 
e from Example 123) and the mixture heated at approximately 115.degree. C. 
for about 20 hours. The reaction mixture was cooled in an ice bath; the 
precipitate was separated by filtration, washed with diethyl ether and 
dried, providing 0.65g (54%) of 
8,9-dihydro-3,7-dimethyl-5-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4-b][1,4] 
thiazin-8-one. Nuclear magnetic resonance spectral analysis confirmed the 
structural assignment. 
EXAMPLES 127-130 
Using the procedure of Example 126, the intermediates of Formula XVII were 
reacted with the indicated orthoester to provide the intermediates of 
Formula XVIII listed in TABLE X. The solid residues of Examples 128, 129 
and 130 were triturated with hexanes, then separated by filtration, washed 
with diethyl ether and dried. The structural assignment of the compounds 
was confirmed by nuclear magnetic resonance spectral analysis. 
TABLE X 
__________________________________________________________________________ 
Intermediate 
from Compound of Formula XVIII 
Yield 
Example 
Example 
Orthoester 
R.sub.2 
R.sub.5 
R.sub.7 
B (%) 
__________________________________________________________________________ 
127 123 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 
63 
orthopropionate 
128 124 triethyl 
CH.sub.3 
CH.sub.2 CH.sub.3 
(CH.sub.2).sub.3 CH.sub.3 
CH.sub.2 
89 
orthoacetate 
129 124 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
(CH.sub.2).sub.3 CH.sub.3 
CH.sub.2 
67 
orthopropionate 
130 125 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 Ph 
CHCH.sub.2 CH.sub.3 
56 
orthopropionate 
__________________________________________________________________________ 
EXAMPLE 131 
Step 15 
Preparation of 8,9-Dihydro-2,7-dimethyl-5-ethyl-1,2,4-triazolo 
[1,5-c]pyrimido[5,4-b][1,4]thiazin-8-one 
To approximately 20ml of methanol to which had been added 3-5 drops of a 
25% solution of sodium methoxide in methanol was added 0.65g (2.5 mmole) 
of 8,9-dihydro- 3,7 -dimethyl-5-ethyl-1,2,4-triazolo 
[4,3-c]pyrimido[5,4-b][1,4]thiazin-8-one (from Example 126). The reaction 
mixture was refluxed for about 20 hours and allowed to cool. The 
precipitate was separated by filtration, washed with water and dried, 
providing 0.48g (74%) of 8,9-dihydro-2,7-dimethyl-5-ethyl-1,2,4-triazolo 
1,5-c]pyrimido[5,4-b]-[1,4]thiazin-8-one, m.p. 187-188.degree. C. 
Analysis: Calculated for C.sub.11 H.sub.13 N.sub.5 OS: %C, 50.2; %H, 5.0; 
%N, 26.6; Found: %C, 50.1; %H, 4.9; %N, 26.7. The structural assignment 
was confirmed by infrared and nuclear magnetic resonance spectral 
analyses. 
EXAMPLES 132-135 
Using the procedure of Example 131, the intermediates of Formula XVIII were 
rearranged to provide the compounds of Formula XIX, a subset of compounds 
of Formula I, listed in TABLE XI. For Examples 133 and 134, the reaction 
solution was concentrated in vacuo, and the resulting solid was purified 
by flash chromatography, eluting with 1:9 (by volume) ethyl 
acetate:methylene chloride. For Example 135, after reflux for about 2 
hours, the reaction solution was concentrated in vacuo and then purified 
by flash chromatography, eluting with methylene chloride. The structural 
assignment of the compounds was confirmed by infrared and nuclear magnetic 
resonance spectral analyses. 
TABLE XI 
__________________________________________________________________________ 
Intermediate Calculated: 
% C; 
% H; % N 
from Product of Formula XIX Found: 
% C; 
% H; % N 
Example 
Example 
R.sub.2 
R.sub.5 
R.sub.7 
B (m.p. in .degree.C.) 
[% Yield] 
__________________________________________________________________________ 
132 127 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 52.0; 
5.5; 25.3 
51.8; 
5.5; 25.5 
(160-161) 
[86] 
133 128 CH.sub.3 
CH.sub.2 CH.sub.3 
(CH.sub.2).sub.3 CH.sub.3 
CH.sub.2 55.1; 
6.3; 22.9 
54.9; 
6.3; 22.9 
(144-145) 
[52] 
134 129 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
(CH.sub.2).sub.3 CH.sub.3 
CH.sub.2 56.4; 
6.6; 21.9 
56.1; 
6.7; 22.1 
(116-117.5) 
[61] 
135 130 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 Ph 
CHCH.sub.2 CH.sub.3 
63.0; 
6.1; 18.4 
62.5; 
6.1; 18.1 
(94-95) [38] 
__________________________________________________________________________ 
EXAMPLE 136 
Step 16 
Preparation of 6,7-Dihydro-2-methyl-4(3H)-oxopyrimido[5,4-b][1,4]thiazine 
5,6-Dihydro-3-ethoxy-2-ethoxycarbonyl-2-H [1,4]thiazine was prepared 
according to the procedure described in Great Britain Patent 2,143,234A 
and in Robert N. Henrie II et al, J. Med. Chem., 26, 559-563 (1983). 
Acetamidine hydrochloride (4.4g, 46.8 mmole) was suspended in 
approximately 80ml of ethanol to which was added 20.7g (95.8 mmole) of a 
25% solution of sodium methoxide in methanol, followed by the addition of 
9.4g (43.2 mmole) of 
5,6-dihydro-3-ethoxy-2-ethoxycarbonyl-2H-[1,4]thiazine. The resultant 
mixture was refluxed for about 29 hours, allowed to cool and concentrated 
in vacuo to provide a brown solid residue. About 40ml of water were added 
to the residue; the suspension was cooled in an ice bath and carefully 
acidified (pH 5-6) with approximately 5ml of concentrated hydrochloric 
acid. The precipitate was separated by filtration, washed with water and 
dried in a vacuum oven at about 80.degree. C. for approximately 20 hours, 
providing 6.7g (85%) of a light tan solid, 
6,7-dihydro-2-methyl-4(3H)-oxopyrimido[5,4-b][1,4]thiazine. The structural 
assignment was confirmed by nuclear magnetic resonance spectral analysis. 
EXAMPLE 137 
Following the procedure of Example 136, with the exception that 
propionamidine acetate was used instead of acetamidine hydrochloride, 
6,7-dihydro-2-ethyl-4(3H)-oxopyrimido[5,4-b][1,4]thiazine was isolated in 
86% yield. The structural assignment was confirmed by nuclear magnetic 
resonance spectral analysis. 
EXAMPLES 138-139 
Step 17 
Using the procedure of Step 12, Example 119, the intermediates of Formula 
XXI were chlorinated to provide the compounds of Formula XXII as listed in 
TABLE XII. For Example 138, filtration following the neutralization of the 
aqueous solution was necessary to remove a small amount of particulate 
matter; the product was isolated as a reasonably pure solid. The 
structural assignment of the compounds was confirmed by the indicated 
spectral analysis. 
TABLE XII 
__________________________________________________________________________ 
Inter- 
mediate Intermediate of Formula XXI 
from and Compound of Formula XXII 
Yield 
Spectral 
Example 
Example 
R.sub.5 
R.sub.7 
B (%) Analysis 
__________________________________________________________________________ 
138 136 CH.sub.3 
H CH.sub.2 
72 IR, NMR 
139 137 CH.sub.2 CH.sub.3 
H CH.sub.2 
92 NMR 
__________________________________________________________________________ 
EXAMPLES 140-141 
Step 18 
Following the procedure of Step 13, Example 123, with the exception that 
hydrazine hydrate was used neat (about 3 ml/g) instead of hydrazine 
hydrate in n-butanol, the intermediates of Examples 138 and 139 were 
reacted to provide the intermediates of Formula XXIII as listed in TABLE 
XIII. The structures were confirmed by the indicated spectral analysis. 
TABLE XIII 
__________________________________________________________________________ 
Inter- 
mediate Intermediate of Formula XXII 
from and Compound of Formula XXIII 
Yield 
Spectral 
Example 
Example 
R.sub.5 
R.sub.7 
B (%) Analysis 
__________________________________________________________________________ 
140 138 CH.sub.3 
H CH.sub.2 
87 IR, NMR 
141 139 CH.sub.2 CH.sub.3 
H CH.sub.2 
98 NMR 
__________________________________________________________________________ 
EXAMPLES 142-144 
Step 19 
Using the procedure of Step 14, Example 126, the intermediates of Formula 
XXIII were reacted with the designated orthoester to provide the compounds 
of Formula XXIV as listed in TABLE XIV. For Example 142, the reaction 
mixture was refluxed for about 3 days instead of approximately 20 hours. 
The structural assignment of the compounds was confirmed by nuclear 
magnetic resonance spectral analysis. 
TABLE XIV 
__________________________________________________________________________ 
Intermediate 
from Compound of Formula XXIV 
Yield 
Example 
Example 
Orthoester 
R.sub.2 
R.sub.5 
R.sub.7 
B (%) 
__________________________________________________________________________ 
142 140 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.3 
H CH.sub.2 
96 
orthopropionate 
143 141 triethyl 
CH.sub.3 
CH.sub.2 CH.sub.3 
H CH.sub.2 
88 
orthoacetate 
144 141 triethyl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
H CH.sub.2 
90 
orthopropionate 
__________________________________________________________________________ 
EXAMPLES 145-147 
Step 20 
Following the procedure of Step 15, Example 131, the intermediates of 
Formula XXIV were rearranged to provide the compounds of Formula XXV as 
listed in TABLE XV. For each of the compounds, the reaction mixture was 
for about 5-6 hours, about 4 hours and about 20 hours respectively, then 
concentrated in vacuo. The residue was suspended in water (approximately 
10ml/g of starting material) and extracted five times with 60ml portions 
of chloroform. The combined extracts were washed with about 50ml of water, 
then approximately 75ml of brine, dried over magnesium sulfate, filtered, 
and concentrated in vacuo to provide a solid which was triturated with 
hexanes, filtered and dried, yielding a solid which was recrystallized 
from benzene:hexanes. The structural assignment of the compounds of 
Formula XXV, a subset of the compounds of Formula I, was confirmed by 
infrared and nuclear magnetic resonance spectral analyses. 
TABLE XV 
__________________________________________________________________________ 
Intermediate Calculated: 
% C; 
% H; 
% N 
from Product of Formula XXV 
Found: 
% C; 
% H; 
% N 
Example 
Example 
R.sub.2 
R.sub.5 
R.sub.7 
B (m.p. in .degree.C.) 
[% yield] 
__________________________________________________________________________ 
145 142 CH.sub.2 CH.sub.3 
CH.sub.3 
H CH.sub.2 49.2; 
5.8; 
28.7 
48.8; 
5.8; 
29.0 
(139-143) 
[92] 
146 143 CH.sub.3 
CH.sub.2 CH.sub.3 
H CH.sub.2 51.0; 
5.6; 
29.8 
50.8; 
5.6; 
29.8 
(139-141) 
[93] 
147 144 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
H CH.sub.2 53.0; 
6.1; 
28.1 
53.0; 
6.0; 
28.2 
(104-107) 
[62] 
__________________________________________________________________________ 
EXAMPLE 148 
Preparation of 
2,5-diethyl-10-oxo-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4-9 thiazine 
The sulfoxide of the compound of Example 147 was prepared by dissolving 
0.5g (2 mmole) of 
2,5-diethyl-1,2,4triazolo[1,5-c]pyrimido[5,4-]1,4thiazine in a mixture of 
approximately 25ml of ethyl alcohol and about 5ml of water. To this 
solution was added 1.0g (4.7 mmole) of sodium metaperiodate and the 
resultant solution was stirred at about 20.degree. C for approximately 2 
hours, at which time thin layer chromotographic analysis, eluting with 
ethyl acetate indicated the absence of starting material. The reaction 
solution was then diluted with about 150ml of water and extracted thrice 
with approximately 75ml of chloroform. The chloroform extracts were 
combined, dried over magnesium sulfate, filtered and concentrated in vacuo 
to provide a solid in about 87% yield, m.p. 217-219.degree. C. The crude 
solid was recrystallized from ethyl acetate to provide 0.25g of 
2,5-diethyl-10-oxo-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine, m.p. 
217-219.degree. C. Analysis: Calculated for C.sub.11 H.sub.15 N.sub.5 SO: 
%C, 49.8; %H, 5,7; %N, 26.4; Found: %C, 49.8; %H, 5.8; %N, 46.9. The 
structural assignment was confirmed by infrared and nuclear magnetic 
resonance spectral analyses. 
EXAMPLE 149 
Step 21 
Preparation of 
8,9-dihydro-5,7-dimethyl-2-ethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4- 
b]1,4]thiazine 
The 
8,9-dihydro-2-ethyl-5-methyl-1,2,4-triazolo-[1,5-c]pyrimido[5,4-b][1,4]thi 
azine of E 4.3 mmole) was dissolved in approximately 25ml of dry 
N,N-dimethylformamide and the mixture was stirred under a nitrogen 
atmosphere at about 20.degree. C. during the addition of 0.2g (5.0 mmole) 
of a 60% oil dispersion of sodium hydride; a yellow solid formed and gas 
evolution was observed. After addition was complete, the mixture was 
allowed to stir for about 20 minutes at which time the solid had 
dissolved. Methyl iodide (1.2g, 8.5 mmole) was then added with continued 
stirring under a nitrogen atmosphere at about 20.degree. C. When addition 
was complete, the solution was allowed to stir at approximately 20.degree. 
C. for about 5 hours. The reaction solution was then poured into about 
40ml of water and extracted five times with 40ml portions of chloroform; 
the combined extracts were washed six times with 200ml portions of water, 
dried over magnesium sulfate, filtered and concentrated in vacuo to 
provide a tan oil. The oil was purified by flash chromatography, eluting 
with 1:4 (by volume) ethyl acetate:methylene chloride, yielding 0.8g (76%) 
of a pale yellow solid which on recrystallization from cyclohexane 
provided 0.6g of 8,9-dihydro-5,7-dimethyl-2-ethyl-1,2,4-triazolo 
1,5-c]pyrimido[5,4-b][1,4]thiazine, m.p. 103-104.degree. C. Analysis 
Calculated for C H &gt;N&gt;S: %C, 53.0; 103-104.degree. H, 6.1; %N, 28.1; 
Found: %C, 52.6; %H, 6.0; %N, 28.4. The structural assignment was 
confirmed by infrared and nuclear magnetic resonance spectral analyses. 
EXAMPLES 150-156 
Following the procedure of Example 149, the designated compounds of Formula 
XXV were reacted with an alkyl halide to form the compounds of Formula 
XXVI, a subset of the compounds of Formula I, as listed in TABLE XVI. For 
Example 150, after the addition of the alkyl halide, the reaction mixture 
was refluxed about 2 hours instead of stirring for approximately 5 hours 
at about 20.degree. C. For all other examples, the reaction mixture was 
stirred at approximately 20.degree. C. for about 20 hours before work-up. 
The structural assignment of the compounds of Formula XXVI was confirmed 
by infrared and nuclear magnetic resonance spectral analyses. 
TABLE XVI 
__________________________________________________________________________ 
Inter- 
medi- Flash Chromato- 
ate Product of graphy Solvent 
Calculated: 
% C; 
% H; 
% N 
from Alkyl Formula XXVI System [Recrystal- 
Found: 
% C; 
% H; 
% N 
Example 
Example 
Halide 
R.sub.2 
R.sub.5 
R.sub.7 
lization Solvent] 
(m.p. in .degree.C.) 
[% 
__________________________________________________________________________ 
yield] 
150 145 CH.sub.3 CH.sub.2 I 
CH.sub.2 CH.sub.3 
CH.sub.3 
CH.sub.2 CH.sub.3 
1:4 EtOAc:CH.sub.2 Cl.sub.2 
54.7; 
6.5; 
26.6 
[Cyclohexane] 54.6; 
6.6; 
26.8 
(91-92) [55] 
151 146 CH.sub.3 I 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
1:9 EtOAc:CH.sub.2 Cl.sub.2 
53.0; 
6.1; 
28.1 
then 1:4 EtOAc:CH.sub.2 Cl.sub.2 
52.6; 
6.1; 
28.1 
(159-160) 
[43] 
152 147 CH.sub.3 I 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.3 
(not chromatographed) 
54.7; 
6.5; 
26.6 
[Petroleum Ether] 55.0; 
6.5; 
26.6 
(75-77) [6] 
153 146 CH.sub.3 CH.sub.2 I 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
1:9 EtOAc:CH.sub.2 Cl.sub.2 
54.7; 
6.5; 
26.6 
[not recrystallized] 
54.7; 
6.5; 
26.6 
(92-93) [21] 
154 147 CH.sub.3 CH.sub.2 I 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
1:9 EtOAc:CH.sub.2 Cl.sub.2 
56.3; 
6.9; 
25.2 
[Petroleum Ether] 56.0; 
6.8; 
25.2 
(75-76) [30] 
155 146 PhCH.sub.2 Cl 
CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 Ph 
1:9 EtOAc:CH.sub.2 Cl.sub.2 
62.7; 
5.9; 
21.5 
[Petroleum Ether] 62.5; 
5.9; 
21.6 
(83-85) [38] 
156 147 PhCH.sub.2 Cl 
CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
CH.sub.2 Ph 
(not chromatographed) 
63.7; 
6.2; 
20.6 
[Petroleum Ether] 63.7; 
6.2; 
20.9 
(68-70) [38] 
__________________________________________________________________________ 
EXAMPLE 157 
Preparation of 
5,7-diethyl-10,10-dioxo-2-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4t 
hiazine 
The sulfone of the compound of Example 153 was prepared by dissolving 2.0g 
(7.6 mmole) of 
5,7-diethyl-2methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine in 
about 36ml of chloroform and cooling the resultant solution to 
approximately 0.degree. C in an ice bath. To this solution was added, in 
small portions, a suspension of 4.0g (18.5 mmole) of meta-chloroperbenzoic 
acid (80-85% pure) in about 35ml of chloroform. When addition was 
complete, the solution was stirred at about 0.degree. C for approximately 
2 hours, at which time thin layer chromatographic analysis, eluting with 
ethyl acetate indicated the absence of starting material. The reaction 
solution was diluted with about 1 liter of chloroform and washed 
sequentially with 5% sodium hydroxide solution (thrice with about 500ml) 
and then with water (thrice with 500ml). The chloroform solution was dried 
over magnesium sulfate, filtered and concentrated in vacuo to provide 
2.48g of the light pink solid. The crude solid was purified by flash 
chromatography, eluting with ethyl acetate. The fractions containing the 
pure compound were combined and concentrated in vacuo. The solid obtained 
was triturated with hexanes, filtered and dried to provide 0.5g of 
5,7-diethyl-10,10-dioxo-2-methyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][1,4]t 
hiazine as a white crystalline solid, m.p. 218-221.degree. C. Analysis: 
Calculated for C.sub.12 H.sub.17 N.sub.5 SO.sub.2 ; %C, 48.8; %H, 5.8; %N, 
23.7; Found: %C, 48 8; %H, 5.8; %N, 23.8. The structural assignment was 
confirmed by infrared spectral analysis. 
EXAMPLE 158 
Preparation of 
8,9-dihydro-2,5,7-triethyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazin 
e dihydrogen sulfate 
The dihydrogen sulfate salt of the compound of Example 154 was prepared by 
dissolving 0.5g (1.8 mmole) of 
8,9-dihydro-2,5,7-triethyl-1,2,4-triazolo[1,5- C]-dihydro-2,5,7-triethyl 
[1,5-c]pyrimido[5,4-b][1,4]thiazine in approximately 5ml of ethyl alcohol. 
To this solution, was added dropwise 0.18g (1.8mmole) of concentrated 
sulfuric acid and the resultant solution was diluted with diethyl ether to 
produce a slightly cloudy solution. Upon standing at about 20.degree. C., 
a solid precipitated. The solid was separated by suction filtration and 
dried in a vacuum oven (without heat) to provide 0.6g (89%) of 
8,9-dihydro-2,5,7-triethyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazin 
e dihydrogen C.sub.13 H.sub.19 N.sub.5 S.multidot.H.sub.2 SO.sub.4 : %C, 
41.6%H, 5.6; %N, 18.7; Found: %C, 41.8; %H, 5.7; %N, 18.4. 
EXAMPLE 159 
Preparation of 7-acetyl-8,9-dihydro-2-ethyl-5-methyl-1,2,4-triazolo 
[1,5-c]pyrimido[5,4-b][1,4]thiazine 
To a solution of 0.9g (3.62 mmole) of 
8,9-dihydro-2-ethyl-5-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thia 
zine (from Example 145) in approximately 50ml of chloroform was added 0.4g 
(4.05 mmole) of triethylamine, followed by the addition of 0.58g (7.4 
mmole) of acetyl chloride. The reaction mixture was refluxed under a 
nitrogen atmosphere for about 2 hours at which time thin layer 
chromatographic analysis, eluting with ethyl acetate, indicated that the 
reaction was complete. After cooling and dilution with about 100ml of 
chloroform, the reaction solution was washed twice with 50ml portions of 
water, twice with 40ml portions of a 5% solution of hydrochloric acid, 
twice with 50ml portions of aqueous sodium bicarbonate solution, twice 
with 50ml portions of water, dried over magnesium sulfate, filtered and 
concentrated in vacuo to provide a yellow solid. The solid was flash 
chromatographed, eluting with ethyl acetate, to provide 0.5g (23%) of 
product which after recrystallization from benzene:hexanes yielded 0.32g 
of a white solid, 
7-acetyl-8,9-dihydro-2-ethyl-5-methyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][ 
1,4]thiazine, m.p. 164-165.degree. C. Analysis: Calculated for C.sub.12 
:H.sub.15 N.sub.5, SO: %C, 52.0; %H, 5.5; %N, 25.3; Found: %C, 52.1; %H, 
5.5; %N, 25.4. The structural assignment was confirmed by infrared and 
nuclear magnetic resonance spectral analyses. 
EXAMPLES 160 and 161 
Using the procedure of Example 159, the designated compounds of Formula XXV 
were reacted with acetyl chloride to provide the compounds of Formula 
XXVI, a subset of the compounds of Formula I, as listed in TABLE XVII. For 
Example 160, after refluxing for about 2 hours, the reaction mixture was 
stirred at approximately 20.degree. C. for about 20 hours before work-up. 
TABLE XVII 
__________________________________________________________________________ 
Intermediate 
Product of Calculated: 
% C; % H; % N 
Ex- from Formula XXVI Flash Chromatography 
Found: 
% C; % H; % N 
ample 
Example 
R.sub.2 
R.sub.5 
R.sub.7 
Elution Solvent System 
(m.p. in .degree.C.) 
[% yield] 
__________________________________________________________________________ 
160 146 CH.sub.3 
CH.sub.2 CH.sub.3 
##STR11## 
1:9 EtOAc:CH.sub.2 Cl.sub.2 then 1:4 
EtOAc:CH.sub.2 Cl.sub.2 then 1:1 EtOAc:CH.sub.2 
Cl.sub.2 52.0; 5.4; 25.2 52.8; 5.6; 
25.2 (189-191) [60] 
161 147 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
##STR12## 
1:9 EtOAc:CH.sub.2 Cl.sub.2 
53.06; 5.9; 24.0 53.6 5.8; 
24.3 (148-150) 
__________________________________________________________________________ 
[76] 
EXAMPLES 162-163 
Using the method of Example 102 the indicated intermediates were reduced to 
provide intermediates of Formula X as shown in the following Table. 
TABLE XVIII 
______________________________________ 
Compound 
of Formula X 
Example Intermediate R.sub.5 R.sub.10 
______________________________________ 
162 Example 81 CH.sub.2 CH.sub.3 
CH.sub.3 
163 Example 84 CH.sub.3 CH.sub.3 
______________________________________ 
EXAMPLES 164-168 
Using the method of Example 87 except no solvent was used, the indicated 
intermediates were reacted to provide intermediates of Formula IV as shown 
in the following Table. 
TABLE XIX 
______________________________________ 
Compound 
of Formula IV 
Example Intermediate R.sub.5 R.sub.10 
______________________________________ 
164 Example 163 CH.sub.3 CH.sub.3 
165 Example 162 CH.sub.2 CH.sub.3 
CH.sub.3 
166 Example 174 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
167 Example 173 CH.sub.3 CH.sub.2 Ph 
168 Example 172 CH.sub.3 CH.sub.2 CH.sub.3 
______________________________________ 
EXAMPLES 169-170 
Step 7 
The method of Melik-Ogandzhanyan, et al., Khimiya Geterotsiklicheskikh 
Soedinenii, 1985, 974 was used to prepare 
4-chloro-6,7-dihydro-2-methyl-5H-pyrimido-[4,5-][1,4]oxazin-6-one and 
4-chloro-6,7-dihydro-2-ethyl-5-H-pyrimido[4,5-][1,4]oxazin-6-one which 
were reacted separately with borane-methyl sulfide complex using the 
method of Example 102 to provide intermediates of Formula IX wherein 
Q.sub.1 is O, Q.sub.2 is NH and B is methylene as shown in the following 
Table. 
TABLE XX 
______________________________________ 
Compound 
of Formula IX 
Example R.sub.5 
______________________________________ 
169 CH.sub.3 
170 CH.sub.2 CH.sub.3 
______________________________________ 
EXAMPLE 171-174 
Step 8 
Using the method of Example 81, the indicated intermediates were reacted to 
provide intermediates of Formula X as shown in the following Table. 
TABLE XXI 
______________________________________ 
Compound 
of Formula X 
Example Intermediate R.sub.5 R.sub.10 
______________________________________ 
171 Example 169 CH.sub.3 CH.sub.3 
172 Example 169 CH.sub.3 CH.sub.2 CH.sub.3 
173 Example 169 CH.sub.3 CH.sub.2 Ph 
174 Example 170 CH.sub.2 CH.sub.3 
CH.sub.2 CH.sub.3 
______________________________________