CA1097638A - Imidazo-as-triazine derivatives - Google Patents

Abstract

Abstract of the Disclosure The present invention relates to new organic compounds and pro-cesses for preparing the1n. In particular the present invention is concerned with novel substituted imidazo[1,5-d]-as-triazin-4(3H)-ones and thiones as represented by the structural formula:

Description

This invention relates to new organic compounds and, more par-ticularly, is concerned with novel substituted imidazo[l,S-d]-as-triazin-4 (311)-ones and -thiones which may be represented by the following structural formula:
~2 N / ~ N Nl-R3 (I) Rl~

wherein X is divalent oxygen or divalent sulfur; Rl is hydrogen, alkyl Cl-C3, bromo, chloro, iodo, or halo alkyl Cl-C3; R2 is hydrogen, alkyl Cl-C6, cyclo-alkyl C3-C6, methoxymethyl, benzyl, naphthyl, or phenyl optionally mono-substituted with halogen, alkyl Cl-C4, alkoxy Cl-C4, haloalkyl Cl-C3, amino, dialkylamino and nitro, R3 is hydrogen, alkyl Cl-C3, alkenyl C3-C4 or alkynyl C3-C4; and R4 is hydrogen or alkyl Cl-C3.
The present invention also relates to a process for the preparation of a compo~md of the formula: R X

N N ~ N-R3 ,~1 wherein X is divalent oxygen or divalent sulfur; Rl is hydrogen, alkyl (Cl-C3l, chloro, bromo, iodo or haloalkyl (Cl-C3); R2 is hydrogen, alkyl ~Cl-C6), cycloalkyl (C3-C6), methoxymethyl, benzyl, naphthyl, phenyl or monosubstituted phenyl which may be substituted with halogen, alkyl (Cl-C4), alkoxy (Cl-C4), haloalkyJ. (Cl-C3), amino, dialkylamino or nitro; R3 is 2Q hydrogen, alkyl (Cl-C3~, alkenyl (C3-C4) or alkynyl (C3-C4); R4 is hydrogen or alkyl (Cl-C3), which comprises:
(a) heating a compound of formula:

N ~ NH

Rl ,C-N-N~I-C-X-R

.. ~ I -1-7~

wherein R is methyl or ethyl and X, Rl, R2 and R~ are as hereinabove defined in a non-polar high boiling organic solvent at a temperature of 175-275C.
for a period of time sufficient for a substantial degree of ring closure to occur~
(b) treating a compound of formula:

X
L_ I I

wherein X and R2 are as hereinabove defined with chlorine or bromine in an inert solvent at a temperature of 60-~0C. for a period of time sufficient for a substantial degree of halogenation to occur, (c) treating a compound of formula:

N N N~l R - ~
wherein Rl and R2 are as hereinabove defined with phosphorus pentasulfide in an inert solvent at a temperature of 100~150C. for a period of time sufficient for a substantial degree of replacement to occur; and when R3 is hydrogen, if desired, alkylating the thus obtained compound with an alkylat-ing agent by known methods~
A preferred embodiment of the present invention may be represented by the abovc structural formula (I) wherein X is divalent oxygen; Rl is methyl, bromo or chloro; R2 is cycloalkyl C3-C6, phenyl or m-tolyl; and R3 20~ and R4 are both hydrogen.
rnis invention further relates to the new organic compo~mds which are intermediates for preparing the above compounds and more particularly, is concerned with novel substituted 3-(4-imidazolylmethylene)carbazic and dithio-carbazic acid esters which may be represented by the ~ollowing structural formula:

~ _la-?~7r~

N ~ NH
R~ R5 wherein Rl and R2 are as above, and R5 is a moiety of the formulae:

O S
" ~1 -CH=N-NH-C-O-R6 or -Cll=N-NH-C~S-R6 wherein R6 is alkyl having up to 3 carbon atoms. The novel intermediates may exist in two tautomeric forms which may be represented as follows and which are equivalent for purposes of this invention:

N ~ NH - ~ HN ~ N
Rl I I R5 Rl - I I R5 The novel compounds of the present invention and the intermediates are generally obtainable as white to yellow crystalline materials having characteristic melting points and absorp*ion spectra and which may be purified by recrystallization from common organic solvents such as methanol, ethanol, dimethylformamide, chloroform, and the like. They are appreciably soluble in non-polar organic solvents such as diphenyl ether and carbon tetrachloride but are relatively insoluble in water.

The compounds ~I) of the present invention wherein R~ and R~ are ; both hydrogen may be readily prepared in accordance with the following reaction scheme:

~1 -2-,, ~ .

7~3~
~2 R2 NH (II) N ~ N~
Rl l ~ C~2H R~L CHO

:~ /

R 2 S ~ ') O
N~NH C S-~ N~ Nll ~ -~
Rll==L CH3N-NH ~ LCH~N-NH

1 (IV) ¦ (V) ~ I

N N NH N ~ N N~
~ 1 1 Rl ~ N ~1 ~ N
I
~VI~ VII) wherein R is alkyl Cl-C3, and Rl and R2 is as hereinabove defined. In accordance with the above reaction scneme, an appropriately substituted 4-imidazolemethanol (II) is oxidized with concentrated nitric acid to provide the corresponding 4-imidazolecarboxaldehyde (III). This oxidation is best car-ried out by suspending or dissolving each gram of star~ing I material (II) in from about one ml. to about seven ml. of concentrated nitric acid and heating the reaction mixture at I ~ steam bath temperature for 2-3 hours. Alternatively, the re-action mixture may first be allowed to stand at room tempera-ture for 8-16 hours and then heated for a short time (1~-3U
minutes) on the steam bath. The resulting reaction solution 30 is preferably first dilute~ with water and then ne~tralized 1 with any convenient base such as caustic, soda ash, or con-centrated aqueous ammonia. The precipitated product (III) is removed, washed with water, and purified by recrystalliza-tion from common organie solvents s~eh as ethyl acetate, eth-anol, and the lilce. Alternatively, -the 4-imidazolemethanol (II) may be oxidized with activated manyanese dioxide in ehloro-form or tetrahydrofuran from room tempeature to reflux temp-eratures for a period of 4-6 hours to provide the 4-imidazo-lecarboxal~ehyde (III).
The 4-imidazoleearboxaldehyde (III) may be readily converted to the 3-(4-imidazolylmethylene)dithioearbazie aeid ester (IV) or the 3-(4-imidazolylmethylene)carbazic acid ester (V~ by treatment with methyl or ethyl dithioearbazinate or with methyl or ethyl carbazate, respeetively. This condensa-tion is eonveniently earried out in a lower alkanol solvent eontaining a few drops of glacial acetie acid at a temperature of 25-75C. whereupon the produet (IV) or (V) forms almost immediately and is removed by filtration. Cyelization of the 3-(4-imidazolylmethylene)dithioearbazie acid ester (IV) and ; 20 the 3-(4-imidazolylmethylene)earbazic aeid ester (V) is read-ily aeeomplished by heating in a non-polar high boiling organie solvent such as diphenyl e~ner at 175-~75C. for 15-30 min-utes whereby the corresponding imidazo[l,~-d]-as~triazine-4-(3H)-thiones (VI) and imidazo[l,5-d]-as-triâzin-4(3~)-ones (VI~) are obtained.
The eompounds (VII) wnerein Rl is ehloro or bromo may be prepared by the ehlorination or bromination, respeetive-ly, of the eorresponding eompounds (VII) wnerein Rl is hydro-gen. This halogenation is aceomplished by treating the start-ing materials with ehlorine or bromine in an inert solvent ~7~3~

l such as chloroform or carbon tetrachloride at steam bathtemperature. The oxo compounds (VII) can be converted to the thio compounds (VI) by treating witn phosphorus pentasulfide in an inert solvent such as pyridine at tne reflux temper-ature. This is a particularly convenien-t metnod when Rl is halogen.
The compounds (VII) wherein Rl is iodo may be pre-pared as follows:
~ le aldehyde (III) wherein Rl is hydrogen is con-verted to the dimethyl acetal in methanol/HCl. The dimetnyl acetal is iodinated, and then hydrolyzed to yield the corres-ponding iodoaldehyde (IIIa):
~2 ~\
~ NH (IIIa) I I I CHO
The thus-obtained iodoaldehyde (IIIa) is then con-verted by following the above-described route to the desired compound (VII) wherein Rl is iodo.
Introduction of a R4 substituent into the imidazo-as-triazinone ring may be accomplished by treatment of alde-hyde (III) with alkyl (Cl-C3) magnesium bromide followecl by a Jones oxidation. The latter method is described by Jones et al in J~C.So 1946, 3g and in J~C~So 1953~ 457r 2j48 and 3019. Durlng oxidation of the secondary alcohol, a ketone (VIII) is obtained. These reac~ions are illustrated herein-below as follows:

~3~ i3~

N i N~1 + alkyl(cl-c3)~lgBr Rl I C113 Rl C~10H
ALKYL(Cl-C3) ~III) /
/ O~IDATION

N ~ NH
Rl I I C=O
alkyl(Cl-C3) (VIII) The remaining synthetic steps to the formula (I) product, wherein X is oxygen and R3 is hydrogen, are accomplished by the above-described procedures via cyclization of the carbazic acid ester derivative of formula (VIII) ketone in either diphenyl ether or, preferably~ o-dichlorobenzene.
Alkylation of formula (I) imidazo-as-triazonone compounds (R3 is hydrogen) at the 3-N-position is accomplished using conventional alkylating agents.
Another superior procedure for the 3-N-methylation of a specific imidazo-as-triazinone, namely, 8-methyl-6-phenyl1midazo[1,5-~]-as-triazinin-4(3H)-one is the reaction of the latter triazinone with dimethyl formamide dimethyl acetal in an inert solvent, such as benzene or toluene, at a temperature of about 80-90C, The novel compounds of the present invention are active as broad spectrum herbicides and in inhibiting the enzyme cyclic -AMP phosphodie-sterase which is responsible for the metabolism of cyclic AM~. As such, they are useful in the treatment of psoriasis, a disease in which the epidermal ~ ~ 7~13~

1 cyclic AMP levels are reported to be decrease~. Also as such they are useful in the treatment of asthma, since elevated levels of cyclic AMP in most cells are reported to inhibit the release of histamine and other mediators and since ele-S vated levels of cyclic ~MP in bronchial smootn muscle arereported -to cause bronchodiolation. See Ann. Reports in Medicinal Chem., Vol. 10, 197 (1975).
The inhibition of phosphodiesterase is determined by the mouse skin and monkey lung phosphodiesterase (P~E) in-hibition tests as follows:(A) Mouse Skin Inhibition Preparation of Mouse Skin PDE
Hairless mice (Jackson Laboratories), 3-4 months old are killed by cervical dislocation and their skins re-moved. Epiderma] slices are taken at a tnickness of 0.2 mm.The slices are weighed and homogenized at 100 mg./ml. in ice--cold tris-HCl buffer (0.04M, pH 8, containing 0.005M MgC12).
Elomogenates are centrifuged at 17,000 ~ gravity for 30 min-- utes. The supernatants are divided into aliquots wnich are stored at -20C. Dilutions of the PDE are made with tris-HCl buffer just prior to use.
Anion Exchanae Resin AGl-X2~, 200-400 mesh (a polystyrene anionic ex-; ~ change resin 8% cross linked from Bio-Rad Lab.) is washed with 0.5N HCl, 0.5N NaOH, 0.5N HCl and repeatedly with double distilled water to pH 5. The resin is allowe~ to settle and

2 volumes of water are added to one volume of settled resin.
Purlfica~lon of 3H C~vclic AMP
3H-Cyclic AMP (21 c/m mole, Schwarz-Mann Inc.) is purified by addition of 0.1 to 0~2 ml. of stock (in S0% eth-; ~ 7 -,, "

~7~3~
1 anol) to 5 ml. of anion exchange resin and 0.4 ml. of tris--EICl buffer. The mlxture is vortexed, centrifuged at 1~00 x gravity for 5 minutes and the supernatant is discarded. The resin is washed in the same manner eight more times with two vo]umes of tris-HCl buffer. Resin bound H-cyclic AMP is eluted by two successive washings with 4 ml. of 0.025N HCL
(resin pH - 2.0). After centrifugation, the pooled acid washes containing H-cyclic AMP are aliquoted and lyophilized.
The material is stored dry at -20C. and reconstituted with tris-llCl buffer just prior to use with a volume sufficient to give approximately 200,000 CPM/~.l ml.
~DE ~s_ay PDE activity is measured by the method of W. J.
Thompson and N. N. Appleman, Blochemistry 10, 311 (19713.
Assays are conducted in 12 x 75 mm. polypropylene test tubes.
The reaction mixture consists of H-cyclic AMP (200,000 CPM) unlabeled cyclic AMP, PDE (100 ug. protein) and test compound which are prepared by dissolving the compounds in methanol at a concentration of 10 mg./ml and then dilution in tris-HCl buffer Final concentration of the test compounds in the incubation mixture is 10 ug~/ml. The total volume of tne in-cubation mixture is increased to 0.4 ml. with tris-HCL buffer containing 3.75 millimoles of 2-mercaptoethanol. The enzyme is incubated for 10 minutes at room temperature in the pres-ence o the test compounds or buffer prior to the addition ofthe mixture of H~CYClic AMP and unlabeled cyclic AMP. Reac-tions are run at ~0C. for 15 minutes and tilen termina-ted by immersing in acetone-dry ice until frozen, followed by boiling fox 3 minutes. Tubes are cooled to room -temperature. H-5' AMP, formed in the reaction is converted to 3H-adenosine by 7~
l the addition of O.l ml. of a solution of 51-nucleotidase Ll6 ug./ml in double distilled water Crotalus venom (Sigma Cllemi-cals)] to the tubes which are incubated for 2~ minu~es at room temperature. This reaction is ended by the addition of one ml. oE ice cold, stirred resin slurry which binds charged nucleotides (including 3H-cyclic AMP) but not 3H-adenosine.
Tubes are vortexed and immersed in an ice bath for l5 minutes and then centrifuged at 1200 x gravity for ~ minutes. A 0.5 ml. portion i5 taken from each, placed in li~uid scintillation vials with lO ml. of Ready-Solv VI (Beckman IndO) and counted for radio activity. Assay "blanks", determined with assay buffer substituted for PDE are less than l~ of total 3H-cyclic AMP added when 3H-cyclic AMP is purified as indicated.
(B) Monkey Lung Inhibition Preparation of Monke Lun C clic AMP Phos hodiesterase _ Y g Y P
Lung parenchyma oE African green monkeys is homo-genized in a Waring blender and centrifuged at 40,000 x grav-ity for 20 minutes. The supernatant is brought to 70~ satu-ration of ammonium sulfate, centrifuged and the pellet redis-so]ved and dialysed, before aliquoting and storage at -20C.
Assay of Monkey Lung Phosphodiesterase Phosphodiesterase is assayed by the method of Thomp-son and Appleman, ibid. An assay tube contains a 0.4 solu-tion of the following: 45 mM tris-HCl buffer, pH 7.4, 6.2 MgC12, O.l mM dithioerythritol, lO 6 M cyclic AMP, ~.l uCi [3H]-cyclic ~P, and test compound at the desired concentra-tion (usually l mM or O.l mM). Compounds not readily soluble in water are dissolved at 40 times the desired concentration in methanol, and diluted 20 times with water. If tne compound is not dissolved at this time, it is suspended by sonication _ 9 _ :, 1 before being diluted 1:2 into the assay tube. In tnis case the activlty of t~e enzyme in the presence of tne compound is compared to a solvent control (2.~% methanol), altnough tne ; solvent alone has negligible effect. The reaction is init-iated by addi-ton of enzyme and proceeds at 25C. for 20 rnin-utes. It is terminated by incubation at 100C. for 2 minutes.
The tubes are cooled to 25C., 0.~ u~ of 5'-nucleotidase (Cro-tolus adamantus toxin) is added to each and the tubes incubated at 25C. Eor 30 minutes. A one millili-ter suspension of Bio--Rad Labs. AGIXI (about 0.5 ml. of settled resin) is added, the tubes centrifuged at 900 x gravity for 10 minutes and an aliquot of supernatant removed for scintillation counting.
The inhibition by the test compound is calculated as:

% of control = 'compoundl - 'blank' 'control' - 'blank' where 'compound' is -the cpm in the presence of compound, 'con-trol' is the cpm in the absence of compound, and 'blankl is the cpm in the absence of enzyme. Since this assay requires sequential hydrolysis of cyclic AMP to AMP (by phosphodies-terase) followed by hydrolysis of AMP to adenosine (Dy j ~ -nuc-leotidase)~ a compound which profoundly inhibited nucleotidase would appear to inhibi~ phosphodiesterase. For tnis reason, control tubes which contained ~3H]-AMP instead of [3~]-cyclic AMP are run in parallel. A correction of the apparent phos-phodiesterase activity is made for the rare compound whichinhibited the hydrolysis of AMP?
Criterion for Activity as Inhibitor_of Skin Phosphodiesterase A compound is considered active if it inhibits more than theophylline, that is, to 50% of control at 1 mM con-~ .

3~

1 centration of compound, or to ~0% of control of 0.0~ mM con-centration of compound.
The results with typical compounds of the present invention on inhi~ition of phosphodiesterase are recorded in Table I below.

- -v~
~a a~
~ 0 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
r1 ~ U t) 1~ U U U U U U U
o ~o o .
:q a~ ~ ~ ~ ~ 1~
~ o o ~ u ~ u ~a æ
~:
__.

o o o o I r1 rl I O ~ o O r~ i I
~ ~ I X ~ X
O ~ ~ O ~ ~ ~ r~ r rl 1 ~ P N I I
I 0 -` ~ I I 111 ~ O
I rl O ~r~ O r~
N I N ~ -- rl ~ N ~) N N
N ~ 3 ~ .,~ ~
--' h 1 ~ .. ) ~ I ~ .
/V I I ~ I
t10 1 ~ 0 1 0 ~
~ I
~ ~ --. N~_ N ~ I r~
~ ,~ 7 8~ ~ 0 1 1 ~) Ir) U u~ u~
O 1 ~ i V V) ~ -- 01 rO ~ .
~ 2 , o ~ ~ o o~ o ~ o o ~ N 10 0 r~:l ~'O 'O ~ n~ ~ ~ I ~a I ~
, ~ In ,e ~ ~ ~ ON 'E~ E~ e ~ e e I I
~ ~ ~_,~ ~ , ~ ~ a) ~ ~
O ~ O ~ O ~ ~
o ,c ~.c ~ I ~ )h P. ~ e ' ' ~ ' O
Il ~ ~ r p, O C

3;~
, U) ,~ h a) ~ 0 U~.
.~
U ~ U U U U
~'aO ~ ~: '¢ '¢ '¢ '¢
O
P~
_ m C ~
a~
a~ 0 ~o P~
C
_ ~ ~
~ I .
. a~
o -- o ~ . ~-~ o ~ O _ . ~ N ~ ", ~r ~ ~ .,~ _ ,,~
I I ~ N

~10 C N
:~ a ~ 1~ I ~d I
~A I ~'1 0') .,.~
~ 113 h ia E~ ~ ~ ~ I J~ I
~ ~
O

_ 0 I ~
n e u~ O u~ O

I M ~
a N ~ N E3 N
~a .c ~ I ~a I
~ 4J
U ~ I ~
1~l N ~ .C ~ r1 ~ C4 ~: ~ ~ a :~ 01 ~ a~ ~' I
_ o~

r 3;~3 1 Some of the novel compounds of the present inven-tion possess anti-hypertensive activity at non-toxic doses and as such are useful as hypotesnive agents. These compounds have been tested pharmacologically and found to have sucn pro-perties wlth a desirable wide spread between doses producing lowered blood pressure and toxic symptoms. In determinging this eEfect of these compounds on hypertension, adult male, 16-20 week old, spontaneous hypertensive rats from Taconic Farms, Germantown, New York, weighing about 300 grams are used. The rats are dosed by gavage with the test compounds at the indicated dose. All doses of drug were suspended in 2% starch (2 ml./kg.). A second identical dose of tne test compound is given at the 24th hour. The mean arterial blood pressure (~AP) of the conscious rats is measured directly ~y femoral artery puncture at the 28th hour. The results of this test on these compounds appear in 'l'able II below.

;3~

TA~LE II

AP (mm ~19) Compound ¦Dose mg/kg l 28th hour ¦Imidazo[l,S-d]-a~-~ria- ¦100 1~3 ¦zin-4(3~l)-thione l ¦8-Methyl-imidazo[1,5-d]- ¦25 130 a~-triazine-4~H) -~hione l 6-Propyl-imidazo[1,5-d]- ¦100 136 ~a~-triazine-4(3H)-thione l 8-Methyl-6-phenyl-imida- ¦ 100 128 zo~l,5-d]-a~-tri~zine-

4(3~)-thione l 6-Phenyl imid~zoll,S-dl- ¦100 117 as-triazin-4(3~-one l 8-t~ethyl~6-phenyl~imida- I 100 133 zo~l,5-d]-as-triazin-~4t3H)-one l ¦6,8-Dimethyl-imidazo- ¦ S0 70 ¦11,5-dl-as~triazin-~(3H)-one l 6-tart-~utyl-imidazo- I100 135 ~1 ~ ]-as-triazin-~4(311)-one l .
6-Met~yl-imidazol1~5-dl- ¦ 100 120 ~a -triazin-4(3H~-one B-Methyl-imidazoll,5-d]~ 100 91 . l~a~triazin-4(3H)~one - 6-tert-Butyl-8-methyl- 100 133 -i~ zo[1,5-d~-a~--triazin-4(3H~-one .
6,8-Dim~thyl-imidazo- 100 93 ~1,5-d]-as-triazins- .
~5 -~(3H)-t~on~ .
8~Methyl-6-propyl-imi- S0 ~27 dazoll,5-dl -aB-tr~azin--4(3~)-one 6-Methoxymethyl~imida 20 ~ 10 0 1 1.5-dl a~-triaz~ne--4(3H1-t~lons .
Controls vehicl~ 166 ', ~

l The novel compounds o~ the present invention have inus ~en found to be highly useful for meliorating astnma and for in-hibiting the enzyme phosphodiesterase in mammals wnen a~min-istered in amounts ranging from about 1.0 migram to about lO0.0 mg. per kilogram of body weight per day. A preferred dosage regimen Eor optimum results would be from about ~.0 mg. to abou-t 50.0 mg. per kilogram of body weight per day, and such dosage units are employed tnat a total of from about 0.35 gram to about 3.5 gram of active compound for a subject of about 70 kg. of body weight are administered in a 24 hour period. The dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportion-ally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage of this invention is that the active compounds may be administered in any con-venient manner such as by the oral, intravenous, intramuscular, or subcutaneous routes, and also by inhalation therapy includ-ing aerosol sprays.
~ompositions according to the present invention having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.10% to 10.0%
by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereof. ~specially satis~actory are glycerin, propylene glycol, and polyethylene glycols. The polyethylene glycols consist of a mixture of ; non-volatile, normally liquid, polyethylene glycols whicn are soluble in both water and organic liquids and which nave mole-cular weights of from about 200 to 1500~ Although the amount of active compound dissolved in the above venicle may vary 1 from 0.10 to 10.0% by weight, it is preferred that the amount of active compound em~loyed be from about 3.0 to about ~.0~
by weight. Although various mixtures of tne aforementioned non-volatile polyethylene glycols may be employed, it is pre-ferred to use a mixture having an average molecular weigntof from about 200 to about 400.
In addition to tne active compound, tne parenteral solutions may also contain various preservatives which may be used -to prevent bacterial and fungal contamination. The pre-servatives which may be used for these purposes are, for ex-ample, myrlstyl-gamma-picolinium chloride, benzalkonium chlo-ride, phene-thyl alcohol, p-chlorophenyl-a glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matter, it is also convenient to employ antioxidants. Suit-able antioxidants include, for example, sodium bisulfite,sodium metabisulfite, and sodium formaldehyde sulfoxylate Generally, from about 0.05 to about 0.2~ concentrations of antioxidant are employed.
For intramuscular injection, the preferred concen-tration of active compound is 0.25 to 0.~0 mg./mlO of thefinished compositions. The novel compounds of the present invention are equally adapted to intravenous administration when diluted with water or diluents employed in intravenous therapy such as isotonic glucose in appropriate quantities.
For intravenous use, initial concentrations down to about 0.05 to 0.25 mg./ml. of active ingredient are satisfactory.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrierl or tney may be enclosed in hard or soft shell gelatin capsules, or tney may be com-1 pressed into tablets, or tney may b~ incorporated ~irectly with the food of the diet. ~or oral therapeutic a~ministra~
tion, the active compounds may be incorporated with excip-ients and used in the form of tablets, troches, capsules, elix-irs, suspensions, syrups, wa~ers, and the like. Such compo-sitions and prepara-tlons should contain at least 0.1~ of ac-tive compound. The percentage of -the compositions and pre-parations may, of couxse, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in sucn therapeutically useful com-positions is such that a suitable dosage wi~l be o~ained.
Preferred compositions or preparations according to the pre-sent invention are prepared so that an oral dosage unit form contains between about 250 and 500 milligrams of active com-pound.
The tablets, troches, pills, capsules and the likemay also contain the following: a binder such as gum traga-canth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry fla-voring. When the dosage unit form is a capsule, it may con-2~ tain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instanc~, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, 3~3 1 methyl and propylparabens as preservatives, a dye and flavor-ing such as cherry or orange flavor. of course, any material used in preparing any dosage unit form sno~ld be pharmac~ut-ically pure and substantially non-toxic in the amounts employ-ed.
As sta-ted above, -the compounds represented by form-ula (I) are useful herbicidal agents for the control of both monocotyledonous and dicotyledonous plants. They are highly effective for the preemergence control of said undesirable plants and when applied at a rate of from about 0.07 kg per hectare to 11.2 kg per hectare to soil containing seeds, seed-lings or propagating organs of said broadleaf weeds, or grass plants.
The compounds of formula (I) are also effective_for the postemergence control of said undesirable plant species when applied at the rate of from about 0.28 kg per hectare to 11.2 kg per hectare to the foliage of said plants.
Since the imidazo-as-triazinones and imidazo-as--triazinethiones exhibit limited solubility in water, they are generally formulated as wettable powders, emulsifiable con-centrates, or flowable ~thixotropic) concentrates which are usually dispersed in water or other inexpensive liquid diluent for application as a liquid spray. The above compounds may also be prepared as granular formulations con~aining, general-ly, about 10% to 15% by weight of toxicant.
Typically, a wettable powder can be prepared by grind-ing together about 25% to ~0% by weight of a formula (I) com-pound, about 2% to 5% by weight of a surfactant sucn as sodium N-methyl-N-oleoyl taurate, alkyl pheoxy polyoxyetnylene eth-anol, or sodium alkyl naphthalene sulfonate, ~% to 10~ by 3~
l weigh-t o~ a dispersing agent such as a highly purified sod-ium lignosulfonate and 25% to 63% by weight of a finely divided carrier such as kaolin, attapulgite, diatomaceous earth, or the like.
~ typical formulation prepared in accordance with the above description is as follows:
50~ by weigh-t of 8-methyl-6-phenyl-imidazo[l,~-d]-_-triazin-4(3~)-one, 3% by weight of sodium l~-metnyl-l~--oleoyl taurate, 10% by weight of sodium lignosulfonate, and 37~ by weight of kaolin.
Flowable (thixotropic) concentrates can be prepared by grinding together about 40% to 60% by weight of tne sodium salt of condensed naphthalene sulfonic acid, 2~ to 3% by weight of a gelling clay, 2% by weight of propylene glycol, and from 54% to 32% by weight of water.
A typical granular formulation can be prepared by dissolving or dispersing tne active compound in a solvent and applying the toxicant to a sorptive or nonsorptive carrier such as attapulgite, corn cob gritsj pumice, talc or the like.
The broad spectrum herbicidal activity of form-ula ; (I) compounds allows efficient control of undesired vegeta-tion along highways, railroad lines, right-of-ways under power transmission lines and along pipelines and under bridge approaches and/or wherever high degree o~ control of undesired vegetation is required.
The invention will be described in greater detail in conjunation with the following specific examples.
E ample 1

5-Methyl-2-~henyl-4-imidazolemethanol A 100 gm. portion of benzamidine hydrochloride is 7~

dissolved in a minimum of water (350 ml.) at room temperature.
A 67 gm. portion of freshly distilled 2,3-butanedione is added giving a yellow solution. Adjus-ting the pH to 6-7 with 2 NaOH gives a solid which is allowed to stand at ~C, for 2 hours, collected, pressed dry and then wasned with 100 ml. of acetone. This material is heated with stirring on a steam bath with 855 ml. of concentrated HCl and 2~37 ml. of water for 4 hours giving a solution. Cooling to room temperature overnight and then to 0C. produces a solid which is collected and air dried. This solid is dissolved in 3j~) ml. of ethanol, filtered and cooled producing a gel, which is taken up in 250 ml. of 50-60C. water, adjusted to pH 5.5 with c~ncen-trated NaOH and then to pH 7-~ with solid KHC03. The mix~ure is cooled to 0C. and the product is collected, wasned with water, and air dried. This product is recrystallized from one liter of methanol giving the final product, m.p. 197-199~C.
Alternatively, this product may be prepared by the method of Imbach et al., Bull. Soc. Chim. France, 1971, 1052.
Example 2 2-Phen 1-4-imidazolemethanol .
This product is prepared by the methods of Dziuron and Schunack, Arch. Pharm., 306, 347 (1973) and 307, 46 (1974).
Example 3 2-n-propyl-4-imida~olemethanol A mixture of 180 gm. of 1,3-dihydroxyacetone dimer, 245 gm. of butyramidine hydrochloride and one liter of liquid ammonia are warmed to 60C. for 5 hours in a bomb. The mix-ture is evaporated -to dryness and the residue is stirred with 30 600 ml. of 2-propanol. The mixture is filtered and the fil-~7~

1 trate is concentrated in vacuo . A 600 ml. portion of 5~
saturated aqueous sodium carbonate is added and tne mixture is extracted with three 1~0 ml. portions of tetrahydrofuran.
The combined organic layers are washed wi-th 330 ml. of sacu-rated aqueous sodium carbonate The organic layer is driedover anhydrous sodium sulfate and evaporated to dryness. The residue is twice recrystallized from acetone giving ihe pro-duct, m.p. 95-101C.
Example 4 2,5-Dimethyl-4-imidazolemethanol nydrochloride This produc~ is prepared by the method of Imbach et _., Bull. Soc. Chim. France, 1971, 1052.
Example 5 2-Methyl-4-im _azolemethanol A 189 gm. portion of acetamidine hydrochloride and 180 gm. of 1,3-dihydroxyacetone are combined with one liter of liquid ammonia as described in Example 3, giving tne de-sired product, m.p. 115-117.5C.
Example 6 4F5-Dirnethyl-2-n-propyl-2-imidazoline-4~j-diol hydrochloride A 112.7 gm. portion of butyramidine hydrochloride is dissolved in 200 ml. of water. A 107 gm. portion of freshly distilled diacetyl is added and the mixture is stirred.
The p~l is adjusted to 6.5-7.0 with 21~ NaOH and the solution is chilled. The desired product is collected as a solid, m.p.
: 104_l070C
Example 7 5-Methyl-2-n-propyl-4-imidazolemethanol The produc-t from Example 6 is dissolved in 900 ml.
of water and 350 ml. of concentra-ted hydrochloric acid, heated - 2~ -~?7~3~

1 on a steam bath for 5 hours and then chilled. The solu~ion is concentrated in vacuo and a mixture of 100 rnl. of acetone and 100 ml. of ethanol is added. The mixture is filtered.
The filtrate is evaporated and the residue is dissolved in 50 ml. of water and neutraliæed with a concentra-ted solution oE K2CO3, until bubb:ling ceases. 'rhe top layer is separated and combined with 5 ml. of methanol. On standing, a precipi-tate forms. The solid i5 collected and the filtrate is di-luted with acetone to give a second precipitate wnich is also collected. The solids are combined and recrystallized from hot acetone giving the desired product, m.p. 134-13bC.
Example ~
5-Methyl-4-imidazolemethanol _ This product is prepared by the me~hod of Ewins, J. Chem. Soc. 99, 205~ (1911).
Example 9 2-(o-Propoxyphenyl)-4-imidazolemethanol A 130 gm. portion of salicylamide in 500 ml. of ethanol is reacted with 52.4 gm. of sodium metnoxide and 164.9 gm. of l-iodopropane by heating at reflux. The mixture is cooledj precipitated in 1500 ml. of water and tne solid is recrystallized from hot ethanol glving _-propoxybenzamide.
A 109 gm~ portion of the above compound in j00 ml.
of chloroform is reacted with 49.4 ml. of methyl fluorosulfo-nate by refluxing for 3 hours. After cooling, the mix~ure isconcentrated to an oil. Ether is added forming crystals whicn are recovered, giving _-propoxy benzimidic acid methyl ester fluorosulfate.
A 180 gm. portion of this latter product and 55.0 gm. of 1,3~dihydroxyac~tone in one liter of liquid arnmonia -. -- 2 3 /

~ ~7 ~' 3~

1 are reacted as in Example 3, giviny the desired produ~t, m.p.
90-92C.
Example 10 2-Benzyl-4-imidazolemethanol -A 352 gm. portion of benzyl cyanide, 750 ml. of di-ethyl ether and 300 ml. of dry ethanol are placed in a two liter, three-nec]ced flask wi-th a magnetic stirrer, drying tube and quick-disconnect gas inlet. The mixture is stlrred in an ice bath while hydrochloride gas is bubbled in for one hour.
The mixture is placed in a chill room overnight. One liter of ether is added and the mixture is cooled. The precipitate is collected and washed with ether giving ethyliminophenylace-tate hydrochloride.
A 272 gm. portion of the above compound and 12~ gm.
of 1,3-dihydroxyacetone in one liter of liquid amrnonia are reacted as in Example 3 giving the desired product, m.p.
134-13SC.
Example 11 2-Methoxymethyl-4-imidazolemethanol A 307.2 gm. portion of ethyl 2-methoxyacetimidate hydrochlorlde [Rule~ J. Chem. Soc~ 113, 9 (1918)~ and 180 gm.
of 1,3-dihydroxyacetone in one liter of liquid ammonia are reacted as described in Example 3 giving the desired product as an oil. A crystalline picrate salt (m.~p. 175-178C.) is obtained by heating the oily product and picrlc acid in water.

2-tert-Butyl-4-imidazolemethanol ~ - . ,~ .
A mixture of 326 gm. of pivalimidic acid methyl ester hydrochloride and 193.5 gm. of 1,3-dihydroxyacetone in 2 liters of liquid ammonia are reacted as described in Exam-ple 3, giving the desired product, m.p. 212-221C.
Example 13 2-tert-Butyl-4-methyl-4-imidazolemethanol In a two liter, three-necked flask, equipped with a magnetic stirrer, drying tube and gas inlet tube, is put 200 gm. of trimethylacetonitrile, 250 ml. of methanol and 500 ml.
of diethyl ether. Ilydrochloride gas is bubbled in for 2 hours with stirring. The mixture is transferred to a beaker, ether is added and the beaker is covered and stored in a cold room overnight. A 500 ml. portion of ether is added and the solid is filtered and washed with ether, giving white crystals of pivalimidic acid methyl ester hydrochloride.
A 75 gm. portion of the above material is converted to 2,2-dimethylpropionamidine hydrochloride by the method of Brown and Evans, J. Chem. Soc. 1962, 4039. - - -A 61 gm. portion of this latter product is dissolved in 50 ml of water with warming and then cooled to room tem-perature. A 38.3 gm. portion of freshly distilled diacetyl is added and the reaction is continued as described in Examples

6 and 7 giving the desired product as white crystals, m.p.
.5-l96.5C-xample 14 2-Benzyl-S-methyl-4-imidazolemethanol To a solution of 109.6 gm. of a-phenylacetamidine hydrochloride [Luckenbach, Chem. Ber. 17, 1423 ~1884)~ in 50 ml. of water is added 55.4 gm. of freshly distilled di-acetyl. The mixture is stirred, the precipitate is collected, triturated in portions with 200 ml. of acetone and air dried, giving 2-benzYl-4,5-dimethyl-4,5~dihYdroxyimidazolidine.
3~ A mixture of 106 gm. of this latter produc~, 170 ml.

~r~7 E;,3~

1 of concentrated hydrocnloride and 170 ml. of water is reac~e~
as described in ~xample 7 givlng the desired product, m.~.
134-13~C.
Example 15 2-Phenyl-4-imidazolecarboxaldehyde A 17.4 gm. portion of 2~phenyl-4-imidazolemethanol and 13.4 ml. of concentrated HNO3 are heated on a steam bath for 2 1/2 nours. Three drops of fuming HN~3 are added to start the reaction. The pH ls adjusted to 8 witn concentrated aqueous Na2CO3 and the mixture is cooled to 0C. overnignt.
The solid is recovered, washed with water and recrystallized from a mixture of 70 ml. of ethyl acetate and 20 ml. of pet-roleum ether giving a yellow solid. Treatment of tne mother liquor with petroleum ether gives an additional tacky substance which is triturated with isopropanol giving a second solid.
These two solids are taken up in hot isopropanol and recrys-tallized as a yellow solid. This solid is recrystallized from ethanol:water (1:1) giving yellow crystals, m.p. 169-171.5C.
Example 16 2-n-Propyl-4-imidazolecarboxaldehyde A solution of 108.6 gm. of 2-_-propyl-4-1midazole-methanol in 107 ml. of concentrated ~NO3 ls reacted as in Example 15, giving the desired product, m.p. 103~5-105.5C.
Example 17 2-n-Butyl-4-imidazolecarboxaldehyde Following the general procedure of Example 15, ~--n-butyl-4-imidazolemethanol is converted to 2-n-butyl-4-imidazolecarboxaldehyde.
Example 1~
5-Methyl-?-phenyl-4-imidazolecarboxaldehyde 3~

1 A 102.1 gm. portion of 5-methyl-2-phenyl-4-imi~azole-methanol is dissolved in 765 ml. of concen-trated ~INO3. TlIe solution is cooled in an ice bath and allowed to stand for 1~
hours. The solution is heated on a steam batn for 3~ minutes, diluted wi-th 2.3 liters oE water and neutralized witn 506 ,~aOH
while cooling in an ice bach. Tne solid is collected, dried, recrystallized from 200 ml. of ethanol and then from one liter of 1:2 ethanol:water giving the desired pro~uci, m.p. 102-115C.
Alternatively, this product may be prepared by the method of Diels and Schleich, Chem. Ber. 49, 1711 (1916).
Example 19 ~ _t ~ ~A~ 4-imidazolecarboxaldehyde The procedure of Example 18 is repeated su~stituting an equimolecular amoun-t of 5-ethyl-2-phenyl-4-imidazolemein-anol for the 5-methyl-2-phenyl-4-imidazolemethanol em~loyed in that exampleO There is thus obtained the title compound in equally good yield.
Exa ple 20 2,5-Dimethyl-4-imidazoleCarboxaldehyde ~ 42.2 gm. portion of 2,5-dimethyl-4-imidazolemeth-anol and 44.8 ml. of concentrated nitric acid are mixed.
When the initial reaction subsidesj the solution is heated on a steam bath for one hour. The reaction mixture is neutral-ized with concentrated aqueous sodium carbonate, then concen-trated under vacuum. After leaching the residue with 150 ml.
of hot ethanol several times, the combined organic solutions are concentrated under vacuum. Chromatograpning the resid~al oil on silica gel gives a solid which is recrystallized from isopropanol-ethyl acetate to give the desired proauct, m.p.

~ ~,4 1 164.5-166C.
Example 21 5-Methyl-4-imidazolecarboxaldehyde This product is prepared by the method of Hubball and Pyman, J. Chem. Soc. 1928, 21.
Example 22 2-_-Propoxyphenyl-4-imidazolecarboxaldehyde A 44 gm. portion of 2-(o-propoxyphenyl)-4-imidazole-methanol is placed in a 2 liter round bottom flask togetner with 500 ml. of chloroform and 100 gm. of manganese dioxide.
The mixture is stirred and refluxed for 5 1/2 hours. rrne reaction mixture is filtered while hot. The manganese dioxide is triturated with 500 ml. of hot chloroform and filtered.
The two filtrates are combined and evaporated. Tne solid re-sidue is recrystallized from 200 ml. of hot ethyl acetate andcharcoal giving the desired product, m.p. 104-105C.
Example 23 2-Methyl-4-imidazolecarboxaldehyde ': :
A 143.0 ml. portion of concentrated HNO3 is added in two portions to 119.2 gm. of 2-methyl-4-imidazolemethanol, with cooling after the first portion, and reacted as described in Example 15, giving the desired product, m.p. 170-176C.
Alternatively, this product may~be made~by the meth-ods of Streith et al., Bull. Soc. Chim. France, 4159 (1971) and also Abushanab et al., J. Org. Chem. 40, 3376 (197~).
:
~ Example 24 .~
2-Benzyl-4-imidazolecarboxaldehyde A 125 gm. portion of 2-benzyl-4-imidazolemethanol and 500 g. of manganese dioxide in 2 liters of chloroform are reacted as described in Example 22 giving the desired product, :

2~ -.

1 mOp. 130-136C.

Example 25 2-(Methox meth 1)-4-imidazolecarboxaldenyde Y Y . .
A 1~5.9 gm~ portion of 2-methoxymethyl-4-imidazole-methanol and 137 ml. of concentrated ~ o3 are reacted as de-scribed in Example 15. After adjusting -the pH to 7.0 with concentrated aqueous Na2CO3, the solution is concencrated under vacuum. Extraction of the residue three times with hot ethanol gives, af-ter combining and concentrating the extracts, a yellow gum. This gum is chromatographed on silica gel.
Fractions 7-15 are combined and recrystallized from 120 ml.
of _sopropanol, treated with charcoal and the desired product is recovered, m.p. 100-103~C.
Example 26 2-Benzyl-5-methyl-4-imidazolecarboxaldenyde A mixture of 8.79 gm. of ~-benzyl-5-methyl-4-imida-zolemethanol and 55O7 ml. of concentrated H1~03 is left at room temperature overnight. The solution is heated for 45 minutes on a steam bath, cooled, the basified with aqueous sodium carbonate. After heating the resulting mixture on a steam bath, it is cooled and the solid collected. Two recrys-tallizations from ethanol give the desired product, m.p. 171-~173C.
Example 27 . .
2-Benzyl-5-n-propyl-4-imidazolecarboxaldehyde The general procedure of Example 26 is repeated but replacing the 2-benzyl-5-methyl-4-imidazolemethanol employed in that example with 2-benzyl-~-n-propyl-4-imida2Olemetllanol Exampl_ 28 5-Methyl-2-n-propyl-4-lmidazolecarboxaldehyde .

~$~ ,3~

1 An 80 gm. por-tion of 5-metnyl-2-n-propyl-4-imida-zolemethanol is oxidized with 67.3 ml. of concentrated lll~O3.
A second portion of 101.4 gm. oE the above compound is oxi-dized with 77 ml. of the acid. The reac-tion mixtures are combined, neutralized and worked up as in Example 25, giving the desired product, m.p. 126-129C.
Example 29 2-tert-Butyl-4-imidazolecarboxaldehyde A 7.7 gm. portion of 2-tert-butyl-4-imidazolemeth-anol is added to 100 ml. of chloroform and 100 ml. of tetra-hydrofuran and heated gently. A 25 gm. portion of manganese dioxide is added and the mixture is reacted as described in Example 22 giving the desired product as wnite crystals, m.p.
194-195C.
lS Example 30 2-tert-sutyl-5-methyl-4-imidazolecarboxaldehyde A 19.76 gm. portion of 2-tert-butyl-5-methyl-4-imi-dazolemethanol and 1 b . 5 ml. of concentrated HNO3 are reacted as described in Example 25 giving the desired product, m.p.
196-198C.
Example _l 2-Isobutyl-5-isopropyl-4-imidazolecarboxaldenyde The procedure of Example 30 is repeated substitut-ing an equimolecular amount of 2-1 butyl-5-isopropyl-4-imi-dazolemethanol for the 2-tert-butyl-5-methyl-4-imidazolemeth-anol employed in that example. There is thus obtained the title compound in equally good yieldO
Example 32 3-(4-Imid~zolvlmethylene)dithiocarbazic acid methyl ester A 17.78 gm. portion of imidazole-4-carboxaldehyde 1 (Pyman, J. Chem. Soc. 1916, 186) is dissolved in 200 ml. of hot ethanol. A hot solution of 24.4 gm. of methyl ditniocar-; bazinate [Audrie-th et al., J. Org. Chem~ 19, 733 (1954)] in 50 ml. of ethanol is added. A precipitate forms immediately ; 5 and the mixture is heated and stirred for about 10 minu-tes.
The mixture is cooled to 0C. The precipitate is collected giving yello~ crystals, m.p. 259-261Co Example 33 3-(2-Phenyl-4-imidazolylmethylene)dithiocarbazic acid methyl ester A 35 gm. portion of 2-phenyl-4-imidazolecarboxalde-hyde is taken up in 250 ml. of not ethanol. A solution of 22.8 gm. of methyl dithiocarbazinate in 40 ml. of hot ethanol is added and the procedure of Example 32 is followed giving the desired product, m.p. 166-170C.
Example 34 3-[(5-Meth 1-2-phenyl-4-imidazolyl)methylene]dithiocarbazic acid meth~ es-ter - - A 60 gm. portion of 5-methyl-2-phenyl-4-imidazole-; 20 carboxaldehyde and 36.8 gm. of methyl dithiocarbazinate are reacted as descrlbed in Example 32 giving the desired product, m.p. 180-185C.
Example 35 - 3-1(5-Ethyl-2- henyl-4-imidazolyl)methylene]dithiocarbazic P
acid methyl ester Following the general procedure of Example 34, 5--ethyl-2-phenyl-4-imidazolecarboxaldehyde is converted to 3--[(S-ethyl~2-phenyl-4-imidazolyl)me-thylene]dithiocarbazic acid methyl ester.

3~

1 Example 3~
3-(2-n-Propyl-4-imidazolylmethylene)dithiocarbazic acid methyl ester A 60 gm. portion of ~-n-propyl-4-imidazolecarboxal-dehyde and 53.7 gm. of methy:L dithiocarbazinate are reaceed as described in Example 32 giving the desired product, m.p.
95-104C~
Example 37 3-(2-Methyl-4-imidaæolyl-methylene)dithiocarbazic acid methyl -ester A 33 gm. portion of 2-methyl-4-imidazolecarboxalde-hyde and 40.3 gmO of methyl dithiocarbazinate are reacted as described in Example 32 giving the desired product, m.p. 274-_279C .
Example 33 3-(5-Methyl-4-im _ azo~y_methylene)ditniocarbazic acid methy ester A 16 gm. portion oE 5-methyl-4-imidazolecarboxalde-hyde and 19.5 gm. of methyl dithiocarbazinate are reacted as 20 described in Example 32 giving the desired product, m.p. 180C
(Dec.), reso1idi~ie~ 230-260C.
Example~39 - 3-[(2,5-Dimethyl-4-imidazolyl)methylenelditniocarbazic acid _ m ~ er A 20 gm. portion of 2,5-dlmethyl-4-imidazolecarbox-aldehyde and 20.8 gm. of methyl ~dithiocarbazillate are reac~ed as described in Example 32 giving the desired product, m.p.
279-281C.

3-~[2-(Methoxymethyl)-4-imidazolyl~methylene~ditniocarbazic acid methYl ester - 3~ -~C~7t~i3~

1 A 40 gm. portion of 2-(methoxyrnethyl)-~-imidazole-carboxaldehy~e and 38.~ gm. of methyl dithiocarba~inate are reacted as described in Example 32 giving the desired product, m.p, 150-1~4C.
Example 41 3-[(5-Methyl-2-n-propyl-4-imidazolyl~me-thylene]dithiocarbazic acid methyl ester A 20 gm. portion of ~-mecnyl-2-n-propyl-4-imidazole-carboxaldehyde and 17.7 gm. of metllyl dithiocar~azinate are reacted as described in Example 32 giving the desired product, m.p. 175-179C.
Example 42 The general procedure of Example 41 is repeated but replacing the 5-methyl-2-n-propyl-4-imidazolecarboxaldehyde lS employed in that example with 2-benzyl-5-n-~ropyl-4-imid-azolecarboxaldehyde.
~._ 3-[(2,~-~irnethyl-4-imidazolyl)rn thylene]car~azic acid etnyl ester A 6.2 gm. portion of 2,5-dimetnyl-4-imidazolecarDox-aldehyde and 6.24 gm. of ethyl carbazate are reacted as des-cribed in Example 32 giving the desired produc-t, m.p. 207.j-210C. (resolidifies 248-252C.).
Example 44 3-(2-n-Propyl-4-imidazolylmethylene?carbazic acid etnyl ester A 7.8 gm. portion of 2-n-propyl-4-imidazolecarbox-aldehyde and 6.24 gm. of ethyl carbaza-te is reacted as des-cribed in Example 32 giving the desired product, m.p. 180-30 182C.

3~

3-(2-Phenyl-4-imidazolylmethylene)ca_bazic acid etnyl ester A mixture of 8.]6 gm. or ~-pnenyl-4-imidazolecarbox-aldehyde and 5.52 gm. of ethyl carbazate are reac~ed as des-cribed in Example 3Z giving the desired product, m.p. 196-200C.
Example 46 3-[(5-Methyl-Z-phenyl ethyl es-ter A mixture of 10.25 gm. of S-metnyl-Z-phenyl-4-imi-dazolecarboxaldehyde and 5.72 gm. of etnyl car~azate in 30 ml, of ethanol containing one drop of acelic acid is boiled for 30 minutes. The mixture is cooled to 0~. and concen-trated under an air stream on a Steala bach. A 50 rll. portion of carbon tetracnloride is added and the mixture is cooled to 0C. overnight. The solid is collected giving the desired product, m.p. 209-211C.
Example 47 3-[(2-o-Propoxyphenyl-4-imidazolyl~methylene]carbazic acid ethyl ester A 4.3 gm. portion of 2~o-propoxypnenyl-4~imidazole-carboxaldehyde and 1.98 gm, of ethyl carbazate are reacted as described in Example 3~ giving tne desired producl, m.p.
129- 132C.
Z5 Example ~
3 [(2-Benzyl-4-imidazolyl~m_t~lylene]carbazic acid ethyl ester To a 37.~ gm. portion of ~-benzyl-4-imidazolecarbox-aldehyde ln 200 ml, of ethanol is added ~0~8 gm. of ethyl car-bazate and a few drops of concentrated acetic acid. The mix-ture is reac-ted as described in ~xam~le 32 giving tne desired - 3~ -, .

3~

1 product m.p. 184-1~5C.
Exarnple 49 3-(2-tert Butyl-4-imidazolylme-thylene)carDazic acid etnyl .,_ .
ester A 7.6 gm. portion of 2-ter~-~utyl-4-imidazolecar~ox-aldehyde and 5,2 grn. of etnyl carbazate in 100 ml. of etnanol are reacted as described in Example 32 giving tne desired pro-duet, m.pO 194-197C.
Example 50 3-(2-n-Butyl-4 imidazolylmethylene)carbazic aeid etnyl ester = , _ .
The procedure of Example 49 is repeated substituiing an equimolecular amount of 2-n-bu-tyl-4-imidazoleearboxaldehyde for the 2-tert-butyl-4-imidazolecarboxaldehyde employed in ; that example. There is thus obtained the title eompound in - equally good yield, Exam~le 51 3-(2-Methyl-4-imidazolylmetnylene)earDazic aeid ethyl es~er A solution oE 16.68 gm. or etnyl earbazate in 50 ml.
of hot ethanol is added to a solution of 16.50 grn. of 2-metn-yl-4-imidazoleearboxaldenyde in 100 ml. of hot ethanol con-taining 2 drops of acetie acid. The reaetion is earried ou-t as deseribed in Exarnple 3~ giving the desired producl, m.p.
210~ 5-211.5C.
Example 52 3~ (5-Methyl-4-imidazolylmetnylene)carD ie acid eth~l ester A mixture of 7.0 ym. of 5-metnyl-4-imidazoleearbox-aldehyde and 7.3 ym. of ethyl car~aza-te are reaeted as des-eri~ed in ~xample 32 giving the desired prod-uct, m.p. 195-2 0 3 C o 30 3~ [2- (Methoxyrnethyl)-4-imidazol~Ll]methylene car~azlc acid etnyl ester - 35 ~

'~7~3~
1 A 19.60 gm. portion of 2-(methoxy~.let.lyl)-4-imida-zolecarboxaldehyde and 16.02 gm. of etnyl carbazate are re-acted as described in Example 32 giving tne desired prod~ct, m p 18~-190C
Example 54 _-[(2-Benzyl-5-methyl-4-imidazolyl)methylene]carbazic acid ethyl ester A 4.08 gm. portion of 2-benzyl-5-rne-thyl-~-imidazole-carboxaldehyde and 2.29 gm. of ethyl carbazate are reacted as desc~ibed in Example 32 giving tne desired product, m.~. 190--191,5C.
Example 55 3{(2-tert-Butyl-S-methyl-4-imidazolyl)methylene]carbazic . .
acid ethyl ester A 6.17 gm. portion of 2-tert-butyl-5-methyl-4-imi-- dazolecarboxaldehyde and 4.20 gm. of ethyl carbazate are re-acted as described in Example 32 giving the desired product, m.p. 226-228.5C.
Example 56 3-[(2-Isobut 1-5-iso- ro 1-4-imidazolyl)meth~lene]carbazic Y, _ ., P PY~

Following the general procedure of Example 5~
-1 butyl-5-1sopropyl-4-imidazolecarboxaldehyde is converted to the title compound in equally good yield.
Example 57 3-[(5-Methyl-2-n-propyl-4-imidazolyl)methylene]carbazic acid ,, _ ~ . ._ . .
ethyl ester A 12 gm. portion of 5-metnyl-2-n-propyl-~-imidazole-carboxaldehyde and 9.06 gm. of ethyl carbazate are reacted as described in Example 32 giving ~he desired product, m.p.

~, . . .

,3~
1 184-188C.
Example 58 Imidazo[1,5-d]~as-triazine-4(3H)-tnione ~ suspension oE 164.5 gm. of 3-(4-imidazolyïme-thyl-ene)dithiocarbazic acid methyl ester in 1.2 liters of diphenyl ether is heated and s-tirred at 175C. until tne methylmercap-tan evolution subsides (20 minutes). The precipitate obtained on cooling to room temperature is collected and ~ashed with petroleum ether, then acetone. The precipitate is then slur-ried with 1.2 liters of boiling methanol and filtered whilehot to give the desired product, m.p. 271-273C.
Example 59 8-Methyl-imidazo[llS-d]-as-triazine-4(3~)-tnione __ _ A suspension of 14.39 gm. of 3-(5-metnyl-4-imida-zolylmethylene)ditniocarbazic acid methyl ester in 100 ml.
of diphenyl ether is reacted as described in Example 58 giving the desired product as yellow crystals, m.p. 26~-268C.
Example 60 6-Phenyl-imidazo[1,5-d]-as-triazine-4(3H)-thione . ~ . _ . - - -- A suspension of 7.05 gm. of 3-(2-phenyl-4-imidazol-ylmethylene)dithiocarbazic acid methyl ester in 100 ml. of diphenyl ether is reacted as described in Example 5~ giving the desired prod~ct, m.p. 210C.
E ~

6-n-Propyl-imidazo[1,5-d]-as-triazine-4(3H)-thione A 102.2 gm. portion of 3~(2-_-propyl-4-imidazolyl-methylene)dithiocarbazic acid methyl es-ter in 500 ml. of di-phenyl ether is reacted as described in Example 58 giving tne desired product as a white solid, m.p. 201.5-203.5C.

~$~7~

1 Example 62 8-Metnyl-6-pnenyl-imidazo[l,i-d]-as-triazine-4(3H)-tnione A mixture of 73.4 gm. of 3-[(5-methyl-2-pnenyl-4--imidazolyl)methylene]dithiocar~azic acid metnyl ester and 500 ml. of diphenyl ether is reacted as lescribed in ~xam-ple 5~ giving the desired product as purple crystals, m.p.
237.5-239C.
Exam~le ~3 8-Ethyl-6-phenyl-imidazo[l,~-d]-as-triazine-4(3H)-tllione .~
The general procedure of Example 62 is repeated but replacing the 3-[(5-methyl-2-phenyl-4-imidazolyl)methylene]-dithiocarbazic acid methyl ester employed in that example with 3-[(5-ethyl-2-phenyl-4-imidazolyl)methylene]ditlliocar-bazic acid methyl ester.

Example 64~
6,8-Dimethyl-imidazo[l,S-d]-as-triazine-4(3H)-thione _ A mix-ture of 30.26 grn. of 3-[~2,5-dimetnyl-4-imida-zolyl)methylene]dithiocarbaæic acid methyl ester and 1~5 ml.
of diphenyl ether is reacted as described in ~xample 5~ giving a solid which is the desired product, m.p. 2~7.5-2~0C.
Example 65 6-Benzyl-8-methyl-imidazo[1,5-d]-as~triazine-4(3H)-tllione A 2~04 gm. portion of 2-benzyl-5-methyl-4-imidazole- -carboxaldehyde is dissolved in 2U mlO of ethanol containing 2 drops of acetic acid. A 1.34 gm. portion of methyldithio-carbazinate is added, the mixture is boiled for 30 minutes and then cooled to 0C. overnight. The mixture is evaporated giving`3-[(2-benzyl-5-methylimidazoyl)methylene]dithiocarbazic acid methyl ester as an oil~

A 3.40 gm. portion of the above product is dissolved - 3~ -$3~

1 in 30 ml. of diphenyl ether and hea~ed for 9 minutes at 194~--207C. The mixtur~ is cooled to room temperature and diluted with hexane. The solid is recrystallized from 150 ml. of methanol ancl treated ~ith charcoal gi~ing tne desired product, m.p. 207-209.5C.
Example 66 6-Benzyl-8-n-propyl-imidazo[1,5-d]-as-triazine-4(3H)-thione _ The procedure of Example ~5 is repeated substitutiny an equimolecular amount of 3-[(2-benzyl-S-_-propylimidazolyl)-1~ methylene]dithiocarbazic acid metnyl ester for the 3-[(2-ben-zyl-5-methylimidazolyl)methylene]dithiocarbazic acid m~tnyl ester employed in that exampleO There is thus obtained the title compound in equally good yield.
Example 67 8-Methyl-6-n-propyl-imi~azo[l~5-d]-as-triazine-4(3H)-thiolle .
A mixture of 32.12 gm. of 3-[(S-methyl-2-_-propyl--4-imidazolyl)methylene]di~hiocarbazic acid me~hyl ester and 200 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product, m.p~ 183-186C.

EXample 68 .
6-Methyl-imidazo[1,5-d~-as- triazine-4(3H)-tnione A mixture of 53.9 gm. of 3-(2-methyl-4 imidazolyl-methylene)dithiocarbazic acid methyl ester and 200 ml. or di-phenyl ether is reacted as described in Example 58 giving the desired product, m.p. 280.5-2~4C.

Example 69_ 6-Methoxymethyl-imidazo[1,5-d~-as-triazine-4(3H)-thione A mixture of 62~4 gm. of 3- [2-(methoxymethyl~-4--imidazolyl]methylene dithiocarbazic acid methyl ester and 2jO ml. of diphenyl ether is reacted as described in ~xample :,

7~3~

1 58 giving the ~esire~ product, m.p. 219.5-2~3C.
Exarnple 70 6-o-Propoxyphenyl-imidazo[1,5-d]-as-Lriazin-4(3H)-one A 10.5 gm. portion of 3-[(2-o-propoxyphenyl-4-imida-zolyl)methylene]carbazic acid ethyl ester in 100 ml. of di-phenyl ether is heated on an oil bath with stirring at 255-265C. until effervesence subsides. The mixture is cooled to room temperature. The addition of petroleum etner produces a solid which is recrystallized from methanol wi-tn the aid of charcoal giving the desired product as a brighi yellow sol-id, m.p. 197-200C.
Exar~e~e 71 6-Benzyl-imidazo[1,5-d]-as-triazin-4(3H)~one A 7.0 gm. portion of 3-[(2-benzyl-4-imidazolyl)metn-ylene]carbazic acid ethyl ester in 30 ml. of dipnenyl etner is reacted as described in Example 70 giving tne desired pro-duct as white crystals, m.p. 215-217C.
Example 72 6-Phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one _ A 7.76 gm. portion of 3-(2-phenyl-4-imidazolylmethyl-ene)carbazic acid ethyl ester in 50 ml. of dipnenyl ether is reacted as described in Example 70 giving the desired product, m.p. 245-248C.
E ~
2j 8-Methyl-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one ~ ..
An 8.33 gm. portion of 3- L (5-methyl-2-phenyl-4-imi-dazolyl)methylene]carbazic acid ethyl ester in 60 ml. of di-phenyl ether is heated in an oil bath at ~15-230C. for 20 minutes. The reaction mixture is diluted to 400 ml. witn petroleum ether. The precipitate is collected and recrystal-.

;$~3 1 lized from 350 ml. of benzene giving the desired pro~uct, m.p. 1~2-184.5C.
Example 74 6-n-Propyl-imidazo[1,5-d]-as-triazin-4(311)-one An 8.75 gm. portion of 3-(2-n-propyl-4-imidazolyl-methylene)carbazic acid ethyl ester in 50 ml. of dipnenyl e-ther is reacted as described in Example 70 giving the de-sired product, m.p. 159-162.5C.
Example 75 6,8-Dimethyl-imidazo[1,5-d]~as-triazin-4(3H)-one A mixture of 7.37 gm. of 3-[(2,5-dimethyl-4-imida-zolyl)methylene]carbazic acid ethyl ester and 50 ml. of di-phenyl ether is reacted as described in Example 70 giving the desired product, m.p. 263-263.5C.-xample 76 6-tert-Butyl-imidazo[l,~-d]-as-triazin-4(3H)-orle .
A 6O15 gm. portion of 3-(2-tert-butyl-4-imidazolyl-methylene)carbazic acid ethyl ester in 40 ml. of dipnenyl ether is reacted as described in Example 70 giving the d~sired 20 product, m.p. 186-188C.
Example 77 6-n-Butyl-imidazo[1,5-d]-as triazin-4(3H)-one _ _ _ _ Following the general procedure of Ex.ample 76, 3~
-(2-n-butyl-4~imidazolylmethylene)carbazic aci~ ethyl ester is converted to the title compound.

6-Methyl-imidazo[1,5-d]-as -triazin-4(3H)~one A 27.2 gm. portion of 3-(2-methyl-4-imidazolylmethyl-ene)carbazic acid ethyl esler in 200 ml. of diphenyl ether 3~ is reacted as described in Example 70 giving the desired prod-~.7~

1 uct, m.p. 303-305.5C.

Example 79

8 ~ ~ [1,5-d]-as-triazin-4(3H)-one A mixture of 10.26 gm. of 3-(5-methyl-4-imidazolyl-methylene)carbazic acid ethyl ester and 100 ml. of diphenyl ether is reacted as described in Example 70 giving tne de-sired product, m.p. 276-~82C.
Exarnple 80 6-Benzyl-8~methyl-imidazo[1,5-d]-as-triazin-4(3~l)-one -A mixture of 4.89 gm. of 3-[(2-benzyl-5-m~thyl 4--imidazolyl)methylene]carbazic acid ethyl ester and 50 ml.
of diphenyl ether is reacted as described in Example 7~ giv-ing the desired product, m.p. 244-247C.
Example 81 6-tert-Butyl-8-methyl-imidazo[l~5~d]-as-triazin-4(3H)-one A mixture of 5.11 gm. of 3-[(2-tert-butyl-5-methyl--4 imidazolyl)methylene]carbazic acid ethyl ester and 50 ml.
of diphenyl ether is reacted as described in Example 70 giv-ing the desired product, m.p. 19~-~00C.
Example 82 ~ -6-Isobutyl-8-lsopropyl-imidazo[1,5-d]-as-triazin-4(3H)-one The general procedure of ~xample 81 is repeated but replacing the 3-[(2-tert-butyl-5-methyl-4-imidazolyl)-methylene]carbazic acid ethyl ester employed in that example 2~ with 3-[(2-1 butyl-5-isopropyl-4-imidazolyl)methylene]car-bazic acid ethyl ester.

i Example 83 8-Methyl-6-n-propyl-imidazo[1,5-d]-as-triazin-4(3H)-one A 14~50 gm. portion of 3-[(5-methyl-~-_-propyl-4-imidazolyl)methylene]carbazic acid etnyl ester and 10~ ml.

' ~7~

1 of diphenyl ether are reacted as described in Example 7~ giv-ing the desired product, m.p. 129.5-131.5C.
Example 84 6-Methoxymethyl-imidazo[1,5-d]-as-triazin-4(3H)-one A mixture of 25.9 grn. of 3-[2-(methoxymethyl)-4--imidazolyllmethylene carbazic acid ethyl ester and 125 ml.
oE diphenyl ether is reacted as described in Example 70 giv-ing -the desired product, m.p. 200-205C.
Example 85 8-Bromo-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one A 3.0 gm. por-tion of 6-phenyl-imidazo[1,5-d]-as--triazin-4(3H)-one is stirred with 100 ml. of cnloroform.
The mixture is heated slightly and a solution of one ml. of bromine in 10 ml. of chloroform is slowly dripped in-to the reaction mixture. The mixture is refluxe~ for one hour, cool-ed to room temperature, and filtered. To the solid is added aqueous Na~CO3 and chloroform and the mixture is shaken in a separatory funnel. The remaining solid and -the organic phase are combined and evaporated on a steam bath~ Methanol ; 20 and 2-propanol are added and the mixture is treated twice with charcoal. Cooling gives the desired product as a solid, m.p. 192-194C.
~ Example 86 - 8-Bromo-6-n-butyl-imidazo[1,5-d]-as-triazin-4(3H)-one r~he procedure of Example 85 is repeated substituting an equimolecular amount of 6-n-butyl-imidazo[1,5-d]-as--tria-zin-4(3H)-one for the 6-phenyl-imidazo[1,5-d]~as-triazin--4(3H)-one employed in that example. rrhere is -thus obtained the title compound in equally good yield.

- ~3 -1 Example 87 8~Chloro-6-phenyl-imidazo[1,5-d3-as-triazin-4(3H)-one A 5.0 gm. portion of 6-pnenyl-imidazo[1,5-d]-as--triazin-4(3H)-one is mixed with 100 ml. of chloroform on a s-team bath while chlorine gas is bubbled through the mixture.
A 25 ml. portion of methanol is added. Chlorine is again bubbled through for 10-15 minutes. Tne mixture is cooled to room temperature, transferred to a separatory funnel, washed with aqueous Na2CO3, aqueous NaHSO3 and finally witn waler.
The mixture is evaporated to 75 ml. on a steam bath, cooled and filtered. The filtrate is evaporated overnight giving a solid. This solid is dissolved in 30 ml. of hot chloroform and filtered. The filtrate is treated with charcoal and 2--propanol is added giving the desired product as a solid, m.p.
201-203C.
Example 88 8-Chloro-6-benzyl-imidazo~1,5-d~-as-triazin-4(3H)-one .
Following the general procedure of Example 87, 6--benzyl-imidazo[1,5-d~-as-triazin-4(3H)-one is cnlorinated to give the title compound.

Example ~9 8-Methyl-6-phenyl-imidazo[1,5-d~-as-triazine-4t3H)-thione To a solution of 4.5 gm. of 8-methyl-6-pnenyl-- -imidazo-[1,5-d]- _-triazin 4(3H)~one in 100 ml. of pyridine 2~ is added 5 gm. of phosphorus pentasulfide. The reaction mix-ture is heated at 100C. for 8 hours, filtered, and poured ` ~ ~ into dilute hydrochloric acid. The precipitated product is isolated by filtration, washed with water, and dried.

Example 30 8-Bromo-6-phenyl-imidazo[1,5-d]-as-triazine-4(3H)-thione 1 The ~jro~edure of ~xam~,le 89 is repeated but SUD-stituting an equimolar amount of ~-bromo-6-phenyl-imidazo [1,-5-d]-as-triazin-4~3H)-one for the 8-methyl-6-pnenyl-imidazo-[1,5-d]-as-triazin-4(3H)-one employed in that example.
~xample 91 8-Chloro-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one __ The use of 5-chloro-2-phenyl-4-imidazolecarboxalde-hyde and ethyl carbazate in the procedure of Example 46 af-fords 3-[(5-chloro-2-phenyl-4-imidazolyl)methylene]-carbazic acid ethyl ester, wnich is converted to the ti~le compound by heating in diphenyl ether as in ~xample 70.
Example 92 5-Methyl-2-m-tolyl-4-imidazolemethanol A mixture of cls and trans-4,5-dimethyl-2-m-tolyl--2-imidazoline~4,5-diol hydrochloride (9.0 g, 0.035 mole) and 3N hydrochloric acid (135 ml) is stirred and heated on a steam bath for 2.5 hours and then stirred at 0-5 for 0.75 hours. The reaction mixture is filtered to yield 7.4 g.
l0.031 mole) of a white solid. The solid istreated with base to afford the title compound, m.p. 190-192C ~d).
Analysis calculated for C12H14N2O, C 71.2b; H b.98; N 13.85;
Found: C 70.94; H 7.07; N 13.92.
Additional imidazolemethanol compounds prepared by the above procedure are llsted in Table III below.

' - ~5 -~4 $~

Tabl~ III
CH~OH
~N ~ CH3 _ ~ , .
m p.(C) Calculated Found O2N ~ 215-216(d) C 56.65 C 56.64 H 4.75 ~1 4.73 N 18.02 N 17.74 . . . _~ _ CH3 ~ C 71.26 C 70.86 >150~d) H 6.98 H 6.97 N 13.85 N 13.60 .. ,.~ . -- . .
C~3 ~ ~Cl 111-114 ~ . . . ......... , , CH O ~ C 66.04 C 65.75 3 \= ~ 235-207 H 6.47 H 6.88 ~; N 12.83 N 12.9Q
. . . . _ CH3 ~ .oHCl 132-134(d) _ . _ __ : -~
Cl ~ - H2Q C 59.33 C 59.73 205-207(d) H 4.98 H 5.22 _ _ N 12.58 N 12.44 Cl- ~ -HCl C 59.33 C 59.73 \==/ ~170(d) H 5~09 H 5.18 . N 10.11 N 9.86 . .

CH3 ~ 175-177 : ~ ~ . _ _ .
~ 1a8~190(d) ~ _~ __ HCl ~120(d) , _ ~ ~ . .
C~Hg_ ~yrup _ ___, ........ ,, ~ _ _ 6H13 ~yrup _ __. . _ _ _ _~ ____ _ 104-106(d1 l _ - 4~ -.. ,.I,f;, 3~

T~BLE III (cont.) _ _ Analysis R2 m.p.(C) CaLculate~-- Found 115-120(d) _ C 68.00~ C 67.73 182-183(d) H 9.34H 9.55 \__J ~ _ N 14.42N 13.87 ;

.

1 Example 93 Preparation of 2-substituted 5-methyl-4-imidazolecarbox-.
hydes Method A
5-Methyl-2-mtolyl-4-imidazolecarboxaldehyde A mixture of S-methyl-2-mtolyl-4-imidazolemethanol (13 0 g, o.064 mole), ac-tivated manganese dioxide (65g) and methylene chloride (200 ml) is stirred at room temperature for 20 hours. The reaction mixture is then filtered, tne solvent removed in vacuo to afford 9.1 g(~.04S mole) of peach-colored solid.
M thod B
5-methyl-2-(p-nitrophenyl)-4-imidazolecarboxaldehyde A mixture of 5-methyl-2-(p-nitrophenyl)-4-imidazole-methanol (2.9 g, 0.012 mole) and 70% nitric acid (20 ml) is stirred at 50C for 3 hours, followed by dilution with water and neutralization with base. The precipitated yellow solid is collected by filtration to yield 2.4 g (0.011 mole) of title product, dec ~270C.
Analysis calculated for CllH9N3O3: C 57.14; H 3~92; N 1~.17;
Found: C 56.69; H 3.96; N 18.08.
- Method C
Preparatlon of 2-alkyl(cycloalkyl)-5 methylimidazole-4-car-b aldehydes._ A mixture of 2-alky1(cycloalkyl)-5-methyl-4-imida-zolemetnanol (0.1 mole), activated manganese dioxide (0.5 mole) and chloroform (500 ml) is stirred and refluxed for two hours, then stirred overnignt ~appx. 15-16 hours) at room temperature. The mixture is filtered througn a bed of fil-ter-aid, the solution evapora-ted to dryness and the residue - 4~ -~7~B

1 recrystallized from the appropriate solvent.
By one or the other methods of preparation, a number of 2-substituted 5 methyl-4-imidazolecarboxalclehydes are made. The compounds, their me-thod of preparatlon, melt-ing points and analystical data are given in Table IV below.

' 3a ~7~3~

Table IV
H
~ ll CHO
2~N ll CH3 R~ Analysis _ M thod~ m.p.(C) Calculated Found CH3 ~ A142-194(d)N 13.99 N 14.28 - C 66.65 C-66.52 CH30 4/ ~ A161-163(d)H 5.89 H 5.86 ~=/ N 1'.95 N 13.08 C 5g.~8 C 59.30 C1 ~ ~ A237-239(d)H 4.11 H 4.17 \==/ N 12.70 N 12.61 , ~ 140-143(d) H 6 04CH 76.637 H3 N 13.99 N 13.87 ~ C 76.25 -C~76.15 I 1l l A 197-l99(d) H 5.12 H 5.25 ~"~,, N 11.86 N 11.81 C 65-.03 C 64.85 CqHg A 83- 84 H 8.49H 7.96 ~ N 16.85 N 17.04 i C 65.00 C 65.72 C6H15 A syrup H 9.42H 9.15 N 13.79 N 13.64 _ .

' C ~8.72 C 69.06 ~ A159-162 H 8.39H 8.44 _ ~-~ ! _ N 14 57 _ j N 14.43 * Preferred solvent in chloroform.
- ~dioxane and tert-butanol are also used.

-?7~`3~

1 ~xample 94 ~-Methyl-2-phenyl-4-imidazolemethanol Methyl magnesium to ~romide tl5.3 ml, ~.5 molar in ether) is added dropwise -to a solution of 2-phenyl-4-imidazolecarboxaldehyde (3.0 g, 0.017 mole) in dry -~etrahy-drofuran (45 ml; dried over a molecular sieve) while the tem-perature of the reaction mixture is main-tained with cooling a-t 25C~ The mixture is stirred for 2 hours and th~n decom-posed by adding a large volume of water dropwise. The mixture is extracted with ether (3 x 75 ml), the ethereal extract is partially evaporated to yield a white precipitate, the crys-talline alcohol, m.p. 197-198C.
Analysis calculated for CllH12N2O: C 70.19; H 6.43; l~ 14.~8;
Found: C 70.10; H 6.68; N 14.90.
~xample 95 a, 5~dimethyl-2-pnenyl-4-imidazolemetnanol a, 5-Dimethyl-2-phenyl-4-imidazolemethanol is pre-pared from 5-methyl-2-phenyl-4-imidazolecarboxaldehyde (37.U
g, 0.199 mole) by the method of Example 94. Tne product (38.4 g, 95.5~) is obtained as a white crystalline solid, m.p. 189-190C.
Exarnple 96 Preparation of methyl 2-phenyl-4-1midazolyl Ketone Jones reagent [5 ml; a solution of chromium tri-oxide (10~3 g) is a mixture of sulfunic acid (8.7 ml) and water (30 ml)] is added at 0-SC over 1 hour to a solution of methyl-2-phenyl-4-imidazolemethanol (3.0 g, 0.016 mole) in acetone (25 ml). Tne temperature is allowed to rise to -20C for 30 minutes then water (150 ml) is added. Tne mix-ture is stixred for 1 hour and the precipitated solid col-~$~3~

1 lected by filtration. The solid is treated with 2N hydr~-chloric aci~ (15 ml), stirred 5 minutes, and is tnen neutra-lized with 10~ sodium hydroxide. The aqueous mixture is extracted with methylene chloride (3 x 75 ml). Removal of the methyléne chloride yields the ketone as a white crystal-line solid (1.73 g), m.p. 158-158.5C.
Analysis calculated for CllE112N20: C 70.9j; H j.41; N 1~.04;
Found: C 70.34; 1l 5.52; N 15.08.
Example 97 Pre aration of methyl-5-meth 1-2-phen 1-4-imidazolyl ketone .~ P Y Y
sy the method of Example 96, methyl-j-methyl 2-phenyl-4-imidazolyl ketone is prepared from a,5-dimetnyl-2~
phenyl-4-imidazolemethanol (12.0g, O.OS9 mole). Tne pro~uct i5 obtained as a pale yellow crystalline solid (6.88 g, 58.3~), m,p. 188-190C.
Analysis calculated for Cl~II12N2O: C 71.98; H 6.04; N 13.99;
Found: C 71.30; H 6.29; N 13.40.
Example 98 Preparation of 2-phenyl-5-imidazolecarboxaldehyde dimethyl acetal .
A solution of 2-phenyl-5-imidazolecarboxald~hyde (6.10 g, 0.035 mole) in methanol (200 ml) is cooled in an ice bath and then saturated with hydrogen chloride. The re-action mixture is stirred overnignt (appx. 15-16 hrs.) and added slowly to cold 6N sodium hydroxide (200 ml)~ rrhe solution is neutralized with concentrated hydrochloric acid and the precipitated solid collected by filtration (7.j6 g;
0.035 mole). Recrystallization from chloroform yields w~ite needles, m.p. 158-160C.

Analysis calculated for C12H14N2O2: C 66.03; H 6.48; N 12.83;

~?~ ~

1 Found: C 65.38; H 7.01; N 12.63.
Example 99 Preparation of 4-iodo-2-phenyl-5-imidazolecarboxaldehyde di-methyl acetal, and 4-iodo-2-phenyl-5-imidazolecarboxaldehyde A solution of iodine (10.2~ ~, 0.0404 mole) in meth-anol (20~ ml) is added with stirring to a solution of 2-phenyl-5-imidazolecarboxaldehyde dime-thyl acetal (7.56 g, 0.035 mole) is methanol (200 ml), water (20 ml) and 6N sodium hydroxide ~13 ml). The reaction mixture is stirred for 5 nours, and then coneentrated ln vaeuo to about 75 ml volume. Water (200 ml) is added and the preeipitated 4-iodo-2-phenyl-5--imidazoleearboxaldehyde dimethyl acetal (2.82 g, 0.00~2 mole) is collected by filtration, m.p. 144-148.5C(d).
The aqueous filtrate i5 aeidified with eoneentrated hydroehloric acid and the precipitat~d 4-iodo-~-phenyl-5-imidazoleearboxaldehyde (5.51 g, 0.018 mole) is eolleeted by filtration, m.p. 20~-210C(d).
Reerystallization of 4-iodo-2-phenyl-j-imidazole-carboxaldehyde dimethyl aeetal from methyl eyelohexane. The yields wnite erystals, m.p. 152-153.5C.
Analysis caleulated for C12H13N2OT: C 41.88; H 3.~2; N 8.14;
Found: C 41.82; H 4.19; N 8.34.
Recrystalllzation of 4-iodo-2-phenyl~5 imidazole-earboxaldehyde from ethyl aeetate yields a white solid, m.p.
211.5-212.5C.
Analysis ealeulated for CloH7N~OI: C 40.29; II 2.37; l~ ~.39;
Found: C 40019; H 2.37; N 9.34.
Example 100 - Method for the ~reparation of 3-[(2-substituted-5-mechyl-4-imidazolyl)methylene]earbazie aeid methyl_escer ~7~3~

1 A. 3-[(5-methyl-2-m-tolyl-4-imidazolyl)methylene]-carhazic acid, methyl ester.
A mixture of 5-methyl-2-m-tolyl-4-imidazolecarbox-aldehyde (6.9 g, 0.034 mole), methyl carbazate (3.1 g, ~.034 mole). methylene chloride (70 ml) and acetic acid (1 drop) is refluxed for 1 hour. The precipitated white solid is col-lected by filtra-tion to yield 7.1 g (0.026 mole), mp. 162-By the above procedure, several 2-aryl analogs of the above compound are prepared. These compounds, their melt-ing points and analyses are listed in Table V below.
B. Preparation of 3-[(2-alkyl or cycloalkyl-5-methyl-4-imidazolyl)methylene]carbazic acid, methyl esters.
A mixture of 2-alkyl(cycloalkyl)-5-methylimidazole-15 4-carboxaldehyde (0.1 mole), methyl carbazate (0.1 mole), toluene (60 ml) and acetic acid (O.j ml) is refluxed for 2 hours. The reaction mixture is then cooled down, tne solids are collected by filtration, and are recrystallized from the appropriate solvent.
The 2-alkyl and cycloalkyl compounds prepared by the above procedure are listed in Table V below.

.
..

3~
Table V
y N -lrCH=N-NH-CO2CH 3 ~ 11 Rl _ Anal ~ ~is R2_ LRl m.p. SC) ¦ Calculated Found . I c 5l.4g c sa 96 O2N~ CH3- 264-265 (d)H 4.32 H 4 33 _ _ N 23.09 N 23.21 CH6 - ~3 - CH 3 - 226-227 ( d ) , ~ C 5-8.32 C 58.01 CH30-~3 _ CH3- 176-178 (d)H 5.59 H 5.60 N 19.43 N 19.23 ~C 53.34 C 52.95 Cl ~3 ~ CH3- 234-235 (d) H 4.48 H4.42 N 19.14 N18.99 CE~ CH3 - 160 - 162 ( d ) _ ~_ _ __ ~3- >170 (d) _ C ~5.44 - C- 5~; . Og C4Hg - ~H3~ 189.5- H 7.61 H 7.71 _ _ ~ 190.5 (d)N 23.52 N 23_.54 ___~_ C 5~.~2 C 58.34 C6H13- CH3-- 164- L65 Sd)H 8.33 H 7.78 N 21.04 N 20.83 _ _ _ ~-54.04 C 54.25 CH3- 184-186 (d)H 6.35 H 6.49 N 2S.21 N 25.33 _ _. , _ .
} CH3- 196-197 (d~
_C 59~07 C 58.62 CH3- 193-194 (d)H 7.63 H 7.61 \ N 21.20 N 20.80 ~__ _ ~ -~ C 43.5 ~.04 Cl~-H20 C:l 147-148 H 3. ~3 H 3.05 ~/ N 16.9 N16.09 ;

~ A
,. .,:

~37~3~3 1 Example_101 Preparation of 3- Ll- (5-iodo-2-phenyl-4-imi~azolyl)ethyli-A solution of 4-iodo-2-phenyl-5-imidazolecarbox-aldehyde (5.21 g, 0.017 mole) in a mixture of methanol (50 ml), toluene (250 ml), acetic acid (1 ml) and methyl car-baza~e (1.73 g, 0.019 mole) is refluxed for 24.5 hours. Tne solution is then heated for an additional hour, allowing sol-vent (100 ml) to distill off. The remaining solvent is then received in vacuo. The solids are extracted with methylene chloride (300 ml), and the extract washed with wa~er (3 x 200 ml). At this point the product crystallizes and is collected by filtration (2.16 g, 0.0056 mole). Evaporation of the fil-trate yields additional product (3.44 g, 0.0093 mole). Re-crystallization from methanol-methylene chloride yields white crystals, m.p. 145-147C(d).
Example 102 Preparation of 3-~5-methyl-2-phen-yl-4-imidazolyl)et-hylidene]
carazic acid methyl ester.
.
~ethyl 5-methyl-2-phenyl-4-imidazolyl ketone (4.5 g, 0.023 mole) i~ refluxed with methyl carbazatc (i.4 g, 0.023 mole) in toluene (112 ml) for 5 hours. The toluene is re-moved, and the solid washed with water (3 x 50 ml). ~he solid is recrystallized from methanol to yield the product ?5 (1028 g, 20~9%), m,p. 201-201C.
Analysis calculatPd for C14H16N4O2: C 61.75; H 5.92; N 20.57;
Found: C 60.05; H 6.257 N 19.96.
Example 103_ Preparation of 3- ~ bazic ~

..
_ ~t, --.. ., .i . . ~

~L~a7 ~ 3~3 1 By the method of Exami~le 102, tile title pro~uct is prepared fr~m methyl 2-phenyl-4-imida~olyl ketone and methyl carbazaic. The product is obtained in 91% yiel~, m.~. ~J6.5-227C.
Analysis calculated for C13H14N4O~: C 60.46; H 5.46; ~ J1.69;
Found: C 60.59; H 5.60; N 21.89.
Example 104 Pre aration of 6-(aryl)-~-methyl-imidazo[1,5-d]-as-triazin-p . .
4(3H)-ones.
Method A
8 Meth 1-6-m-tol 1-imidazo[1,5-d]-as-trazine-4~3H)-one.
Y Y _ _ __ A mixture of 3 [(5-methyl-2-m-tolyl-4-imidazolyl)-methylene]carbazic acid, methyl ester (S.l g, 0.019 mole) and o-dichlorobenzene (75 ml) is heated slowly (4~ minutes) to reflux, refluxed for 1.5 hours, then stirred at room tempera-ture over night (appr. 15-16 hours). The reaction mixture is filtered to afford 3.9 g (0.016 mole) title product. Re-crystallization from o-dichlorobenzene yields partially solvated product/ m.p. 188-198~C~
By substituting 3~[5-methyl-2-(a,a,a-trifluoro-m-- tolyl)-4-imidazolyl]methylene}carbazic acid, methyl ester for 3-[(5-methyl-2-m-tolyl-4-imidazo1yl)methylene~carbazic acid, methyl ester in the above reaction. 8-methyl-6 (~a,a-tri-fluror-m-tolyl)-imidazo[1,5-d]~as- triazine-4(3H) one can be obtained.
Method B
8-Methvl-6-(p-nitro~henyl)-imidazo[l,S-a]-as-triazine-4(3H)-one, monohydrate.
3-{[2-(p-nitrophenyl)-j-methyl-4-imidazolyl]m~thy-lene~carbazic acid, methyl ester (2.5 g, 0.00~2 mole) is _ 57 -1 immersed in diphenyl ether (25 ml) at 240C for ~0 minutes, then stirred in an ice bath for 1 hour. The reaction mix-ture is diluted with ether and filtered to afford 2.~ g (0.008 mole) title product. The product is purified via an acetone soxhlet extraction to give a yellow solid, m.p.
295-297C, Analysis calculated for C12HllN5O4: C 49.83; H 3.83; N ~4.21;
Found: C 49.69; H 3.71; N 23.88, Method C
Preparation of 6-alkyl(cycloal~ 8-methylimidazo-[1!5-a]-as -triazin-4(3H)-ones.
__ The above compounds are prepared by Method A
excepting that the mixture of 2-alkyl(cycloalkyl)-5-methylim idazole-4-carboxalolehyde methyl carbazone and _dichloroben-zene is heated until a boiling point of 180C is obtained.
The solvent is removed by evaporation and the residue recrys-tallized from the appropriate solvents.
The compounds prepared by Method A, B and C, their melting points and analyses are listed in Table VI below.
2~

~.~
, . . . . .

7~

TABLE VI

N z~\ N N-H
R ~ ' ~ N

~ _ , . _ __ . . ..
Rl R2 R4 Metho ¦ m.p. (C) Calcu~t ~8 Found . ... , . . . . ._ CH3- CH3~ H A 169-171.5(a _ _ _ _ . . . _ _ _ ~ , r-~ c 60.93 C 60.52 CH3- CH30 ~ H A216-217(a) Hb~.72 H 4.80 N21. 86 N 21.70 ~ , . _~, _ __ , CH3- Cl ~ ~ A>240(a) _ , . _ . ` _ _. ~ ..... __ _ _ .
CH~- ~ ~ H A247-251(o~ _ ~ C 47.00 C 47.72 Cl- Cl~/ \~ H B245~246(a) H 2.1S H 2.41 _ . N 19.93 N 19.57 H ~ CH A281-281.8 __ _ _ __A ____A . _ ____ ¦ -- - - - - _ .
CH ~ CH A 207-212 3 _ . I C 58.23 C 58016 CH3 C4Hg- H C 118-120 H 6.84 H 6.84 N 27.17 N 27.14 _ _ . C 61.51 C 61.28 ~H3 C5H13 - H C 118-119 H 7.74 H 7.61 _ _ _ N 23.91_ N 23.68 C 56.83 C 56.65 ~- H C 210.5-211.5 H 5.30 H 5.64 CH3 _~ ~ ~ N 29.46 N 2g.43 (:~H3 __ H (: 179-18l . .
f~~~ C 64.94 C 63.~8 ~ ~- H C 145-147 H 7.78 H 8.10 CH3 ~__f _ _ _ N 21.15 N 20.41 ,.. .. .

9~ 3 Example 105 Preparation of 6-Phenyl-8-iodo-imidazo[1,5-d]-as-triazin-4(3H)-one.

3-[1-~5-Iodo-2-phenyl-4-imidazolyl)alkylidene]car-bazic acid methyl ester (1.01 g, 0.0027 mole) is dissolved in a mixture of o-dichlorobenzene (150 ml) and methanol (15 ml). The solution is heated to the boiling point and boiled for 20 minutes allowing solvent to distill off partially.
The reaction mixture is chromatographed over a silica gel column and eluted with a hexane-ethyl acetate (2:1) mixture to yield the title product ~0.63 g, 0.0019 mole). Recrystal lization from ethyl acetate-hexane yields the product as yellow needles, m.p. 170-189C.
Exam~ 106 Preparation of 6-~p-aminophenyl)-8-methyl-imidazo[1,5-~-as--triazin-4~3H)-one.

Catalytic reduction of 8-methyl-6-~-nitrophenyl)-imidazo[l,5-d]-as-triazin-4(3H)-one, monohydrate (1.3 g, 0.0048 mole) in dimethylformamide ~50 ml) with hydrogen in the presence of 10% P~/C catalyst and at atmospheric pressure, followed by solvent removal n vacuo, affords the product ~1.0 g, 0.0043 mole). Crystallization from dimethylformamide water yields a mustard yellow solid, m.p. 252-254C ~Dec.) Example 107 Preparation of 8-Bromo-~-~m-aminophenyl) imidazo-[1,5-~d)]-as-triazin-4~3H)-one.

~ A mixture of 8 bromo-6-~m-nitrophenyl)imidazo-; [1,5-~-as-triazin-4~3H~-one ~2.0 gJ 0.00595 mole) and catalyst ~Ru/C, 5%, 700 mg) are blanketed with nitrogen at atmospheric pressure and dimethylformamide (45 ml) is added.

~ ~r~

The flask containing the above mixture is vigorously shaken while hydrogen is introduced and absorbed ~399 ml, 0.01785 mole). The catalyst is then filtered and washed with di-methylformamide. The filtrate is evaporated in vacuo. The product is recrystallized from dietllyl ether, m.p. 205C (Dec.) Example_108 Preparation of 8-Bromo-6-(m-dimethylaminophenyl)-imidazo-[1,5-d~-as-triazin-~(3H)-one.

Sodium cyanoborohydride (1.2 g, 0.019 mole) is added to a stirred solution of 8-bromo 6-(m-aminophenyl)-imidazo-[1,5-d]-as-triazine-4(3ll)-one, aqueous formaldehyde (5 ml. 37%) in acetonitrile (110 ml). The reaction mixture is stirred for 15 minutes then acetic acid is added to ad-just the pH of the reaction mixture to 7. The reaction mix-ture is stirred for ~5 minutes while the pH of the mixture is maintained at 7 with acetic acid being added as needed.
The solvent is then evaporated in vacuo, the residual oil is added to 2N potassium hydroxide (150 ml), and crystal-lized. The product is washed with waterl and recrystallized from acetone-water~ m.p. 206C (Dec.) Example 109 Preparation of 6-(m-Nitrophenyl)-imidazo[1,5-d~-as-triazin-~(3H)-one.

A mix~ure of 90% fuming nitric acid (0.4 ml; ~=1.5, 0.0086 mole) and sulfuric acid (10 ml) is added slowly at 5C to a solution of 6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one (2.12 g, 0.01 mole) in sulfuric acid (50 ml~. The mixture is stirred overnight (appr. 15-16 hours) at room tem-perature, and then poured over ice. The mixture is made slightly alkaline, stirred with ethyl acetate and is filtered.

, 1~37~3~

1 The isolated solid is recrystallized from aqueo~s dimethyl-formamide to yield 0.83 g of a buff-colored, fluffy solid (32%), m.p. 294-296C(with violent decomposition).
Analysis calculated for Cl1~I7N5O3: C 51.36; ~I 2.74; N 27.23;
Found: C 51.28; H 2.85; N 27.17.
Example 110 Preparation of 8-Bromo-6-(m-nitrophenyl)imidazo[l,~-d]-as triazin-4(3H)-one, compound with dimethylformamide.
A mixture of 90~ fuming nitric acid (1.87 ml, ~=
1.5, ~.04 mole) and sulfuric acid (10 ml) is added slowly at 5~C to a solution of 8-bromo-6-phenyl imidazo[l,j-d]-as-triazine-4(3H)-one (5.82 g, 0.02 mole) in sulfuric acid.
The reaction mixture is stirred for 1 hour, poured over ice, the precipitated solid is isolated by filtration and dried.
A dark brown solid (6.58 g, 98~) is obtained, m.p. 244-246C
~Dec.). Recrystallization from aqueous dimethyl formamide yields the title compound, a buff colored solid, m.p. 246-248C(Dec.).
Analysis calculated for Cl1H6BrN5O3, C3H7NO: C 41-09;
H 3.20; N 20.54; Br 19.53; Found C 40.99; II 3.15; N 2~.34, Br 20.50.
Example 111 Preparation of 8-Bromo-imidazo[1,5-d]-as-triazin-4(3H)-one.
A solution of bromine (8.0g, 0.05 mole) in acetic acid (10 ml) is added to a mlxture of imidazo[l,5-d]-as-triazine-4(3H) one (6.8 g, 0.05 mole) and acetic acid (500 ml). The reaction mixture is stirred for 1 hour, poured into water and extracted with chloroform. The aqueous layer is separated, made slightly alkaline an~ extracted Witil ether.
Evaporation of the chloroform and the ether layers yields 5.0 g of a solid (46.3~). This solid is recrystallized to - ~2 -63~

1 afford the title product, a cream colored solid, m.p. ~44-245C~Dec.).
Analysis calculated for C5E~3Bri~40: C 27.80; ll 1.40; N ~5.94;
Br 37.00; Found: C 28.99; H 1.36; i~ 26.46; Br 33.91.
Example 112 6,8-Dibromo-imidazo[1,5-d]-as-triazin-4(3H)-one.

_ Bromine (1.5 ml, 0.03 mole) is added dropwise to a well stirred mixture of imidazo [1.5-d]-as-trizin-4(3H)-one (1.36 g, 0.01 mole), sodium bicarbonate (2 52 g, 0.03 mole) and water (25 ml). The mix-ture is stirred for 4 hours and is then filtered. The isolated product is washed well with water and air-dried. The product (2.78 g, 95%) is recrystal-lized from toluene-hexane(l l) to yield a cream colored solid, m.p. 210-212QC.
15 Analysis calculated for C5H2Br2N4O: C 20.44; H 0.~9; N 19.10;
Br 54.39; Found: C l9.1b; H 0.88; i~ 18.80; Br ~4.12.
Example 113 ?reparation of 8-bromomethyl-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one.
A mixture of 8-methyl-~-phenylimidazo[1,1-~]-as-triazine-4(3H)-one (4.52 g, 0.02 mole), N-bromosuccinimide (3.92 g, 0.044 mole), benzoyl peroxide (0.24 g, 0~00~ mole) and carbon tetrachloride (2~00 ml) is refluxed for 8 hours.
The reaction mixture ls cooled and filtered. The isolated product is washed with water and with methylene chloride.
The product (2.1 g, 34.4%~ is recrystallized from nitrometnane to yielcl pale yellow crystals, m.p. 254-256C(d).
Analysis calculated for C12HgBrl~4O: C 47.24; El 2.97; 1~ 18.~;
Br 26.20; Found: C 47.50; H 3.21; N 18.48; Br 25.7~.
Evaporation of the filtrates and washings followed - ~3 -3~

1 by recrystallization o~ the residue from nitrometnane yields a second crop (14.8%) of the product.
Example 114 Prepara-tion of 3-alkyl-8-methyl-6-phenylimidazo-as-[1,~-d]-triazin-4(3H)-ones.
Method ~
Sodium methoxlde (0.~1 g, 0.01~ mole) is added to a solution of 8-methyl-6-phenylimidazo-as-[l,j-dJ-triazin-4(3H)-one (3.39 g, 0.015 mole), followed by the addition of the approprivte alkylating agent (i.e. methyl iodide, allyl bromide, propargyl bromide, benzyl chloride, dipropyl sulfate, and the like). The reaction mixture is then stirred at 2~C
for 16 hours, heated at 40C for 45 minutes, cooled and poured on a mixture of ice and dilute hydrochloric acid. The product is extracted from the above aqueous mixture with chloroform and isolated by evaporation of the chloroform layer.
Purification is affected by crystallization (cyclo-hexane or cyclohane-benzene), or by silica gel dry column chromatography in chloroform.
Method B
~. _ 3,8-Dimethyl-6-phenylimidazo[l r 5-d]-as-triazin-4(3~ one.
Dimethylformamide dimethyl acetal (~.73 ml; ~=
0.897, 0.005 mole) is added slowly to a slurry of ~-methyl-6-phenylimidazo[1,5-_]-as--triazin-4(3~)-one (1,13 g, 0.005 mole in benzene (25 ml). The reaction mixture is stirred, refluxed for 24 hours, cooled and filtered. The filtrate is evaporated to yield 1.4 g (100%) product. Recrystallization from methyl cyclohexane yields yellow crystals, found to be identical (ir: nmr) to the product obtained by Metno~ A.

Compounds prepared by the above procedures are listed in Table VII below.

7~

Table VII
¢~

N ~ ~ ~ - R3 CH3 ~ ~ ~

----R Analv~i~ .
_ __ Method ~ C) Calculated Found ~- C 64.98 -- C~-~.09 .
CH3- A or B 144-146}~ 5.03 H S.ll . _ __~C 67 65 C-67 70 .
CH2=CH~CH2- A 134-134.5H 5.30 H 5~25 . ~ _ N 21 04 N 21 21 .
CH--C-CH2- A 192.5- H 4.58 H 4.56 193.5N 21~20 N 21.17 .
. C 67 X4-- C ~7.15 C3H7- A 144.5-145 H 6.01 H 6.19 . N 20 88 N 20 96 __~ . ~ C 72 13 C-71 71 .
-CH2- A 143-144 H 5.10 H 5.24 ~ _ ~ . _ _ _ .

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1 Example 115 Preparation of 3,~-Dimeth~l-6-phe~l-imidazo[l,i-d]-as-triazin-=
4(3H)-thione.
.
8-Methyl-6-phenyl-imidazo[1,5-~]-as-triazin-~(3EI)--thione (3.76 g, 0.014 mole) is dissolved in aqueous sodium bicarbonate (125 ml, 6.7%). ~imethyl sulfate (1.~5 g, 0.0147 mole) is added at room temperature and the reaction mixture stirred overnight (appr. 15-16 hours). The precipitated solid is collected by filtration and washed thoroughly wi~h water.
The dried solid (3.84 g) is extracted with benzene. The ben-zene solution is evaporated to dryness, and the residual red solid obtained is extracted with hexane. Evaporation of the hexane solution yields a tan solid (0.25 g). Recrystalliza-tion of this tan solid from methanol yields pale yellow crys-tals, m.p. 194-195C.
Analysis calculated for C13H12N4S: C 60.92; H 4.72; N ~1.8~;
Found: C 60.31; H 4.90; N 21.34.
Example 116 Preparation of 50 mg. Tablets 20Per Tablet Per 10,000 Tablets 0.050 gm. 6-phenyl-8-isopro-pyl-imidazo[1,5-d]--as triazine-4(3H)--~hione 500 gm.
0.080 gm. Lactose 800 gm.
0.010 gm. Corn Starch (for mix) 100 gm.
0.008 gm. Corn Starch (for paste) 75 gmn 0.148 gm. 1475 gm~
25 0.002 gm. Magnesium Stearate (1%) 15 gm.
gm. -1~90 gm.

The 6-phenyl-8-1sopropyl-imidazo[1,5-d~-as-triazine--4(3H)-thione, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in ~ ml.
of water and heated with stirring to form a paste. This paste 3~

1 is then used to granulate the mixed powders. Additional water is used if necessary. The wet granules are passed through a No. ~ hand screen and dried at 120F. Tne dry gran-ules are then passed through a No. 16 screen. The mixture is lubricated with 1~ magnesium stearate and compressed into ta~lets in a suitable table-ting machine.
Example 117 Preparation of Oral Suspens on .
Ingredient Amount

10 6-benzyl-8-ethyl-imidaæo[1,5-d]--as triazin-4(3H)-one 500 mg.
S-~bitol solution (70% N.F.) 40 ml Sodium benzoate 150 mg Saccharin 10 mg.
Red dye 10 mg.
Cherry flavor 50 mg.
Distilled water qs to 100 ml.

The sorbitol solution is added to 4~ ml. of distil-led water and the 6-benzyl-8-ethyl-imidazoLl,~d]-as-triazin--4(3H) one is suspended therein. The saccharin, sodium ben-zoate, flavor and dye are added and dissolved. The volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 5 mg. o~ 6-benzyl-8~ethyl-imidazo[1,5-d]-as-triazin-4(3H)-one.
; Example 118 Preparation of Parenteral solution ~ , In a solution of 700 ml. of propylene glycol and 200 ml. of water ~or injection is suspended 20.0 grams of 6- _ butyl-8-n-propyl-imidazo[1,5-d~-as-triazin-4(3H)-one with stirring. After suspension is complete, the pH is adjusted to 5.5 with hydrochloric acid and the volume is made up to 1000 ml. with water for injection. The formulation is steri-lized, filled into 5.0 ml. ampoules each containing 2.0 ml.

3~

1 (representing 40 mg. of drug) and sealed under nitrogen.
Example 119 Preparation of ~erosol Spray A suspension ls prepared of:

5 8-chloro-6-isopropyl-imidazo[1,5-d]--as-triazlne-4t3H)-thione; micro-nlzed (0.~-i.0 microns) 400 mg.
Dichlorodifluoromethane 100 ml.
Sorbitan trioleate 6.9 mg.
The active ingredient and sorbitan trioleate are placed in a beaker and the dichlorodifluoromethane is added at -40C. whereupon a suspension is formed. The mixture is sonified, that is, treated with a Sonifier, manufactured by the Branson Sonic Power CoO of ~anbury, Connecticui, as model LS-75 at a current input of 9 amperes for 2 minutes. Addi-tional cold dichlorodifluoromethane is added as necessary tokeep the volume at 100 ml. The mixture is uniformly dis-persed, and has increased stability resulting from the soni-fication. Each of six l9 ml. stainless steel containers are filled with 15 ml. of the cold mixture, then valves are in-serted and sealed in place. On warming, after storage, the3-chloro-6-isoprop~l-imidazo[1,5-d]-as-triazine-4(3~l)-thione remains dlspersed and, after merely casual snaking gives uni-form doses of finely divided drug.
~xample 120 ~r-u~=~ti~ .idi~
The amidines prepared by known procedures and used as starting~materials for the preparation of imidazo-as-tria-zinones are listed in Table VIII below, characterized as hy-drochlorides unless otherwise noted. Known literature ref-erences are also given.

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Cis and trans-4,5-Dimethyl-2-m-tolyl-2-imidazoline-4,j-diol hydrochloride 2~3-Butanedione ~7.3 ml., 0.084 mole) is added dropwise to a cold slurry of m-toluamidine hydrochloride (13.6 gm., 0.0797 mole) in water (35 ml.) and stirred at room temperature for lS minutes. The precipitated product is collected by Eiltration and washed with ace-tone to give 12.2 gm., m.p. 135-137C.
Analysis calculated for C12H17N2O2Cl: C ~6.1 ;
N 10.91; Cl 13.81. Found: C 5j.32; H 6.66; N 10.94;
Cl 1409.
Additional 2-substituted c~s and trans -4,5-dimethyl-imidazoline 4,5-diol hydrochlorides prepared by the above procedure, their melting points, and deviations from -the above procedure, are listed in Table IX below.

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1 L:xamplc 1~2 Preemergencc l~erbicidal Activit Y
The preemergence nerbicidal activity of the compounds of -the present invention is exemplified by the following tests in which the seeds or propagating organs of a variety of monocotyledonous and dicotyledonous plants are separately mixed wlth potting soil and planted on top of approximately 2.5 crn. of soil in separate cups. After planting, the cups are sprayed with the selected aqueous acetone solution contain-ing test compound is sufficient quantity to provide theequivalent of about 0.07 kg to 11.2 kg per hectare of test compound per cup. The treated cups are then placed on green-house benches, watered and cared for in accordance with con-ventional greenhouse procedures. Three to five weeks af~er treatment, the tests are terminated and each cup is examined and rated according to the rating system provided below. The data obtained are reported in Table X below.
.

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_ 75 -.
I' ~7~38 Rating System: % Difference in Growth from the Check*
O - No efEect O
1 - Possible ef.Eect 1-10 2 - Slight e~fect 11-25 3 ~ Modera-te e~fect 26-40 5 - Definite injury 41-60 6 - Herbicidal effect 61-75 7 - Good hérbicidal effect 76-90 8 - Approaching complete kill 91-99 10 9 - Complete kill 100 4 - ~bnormal growth; that is, a definite physiological malformation but with an over-all effect less than a 5 on the rating scaleO
*Based on visual determinati.on of stand, size, vigor, chlorosis, growth malformation and over-all plant appearance.
Plant Abbreviations SE - Sesbania (Sesbania exaltata) LA - I.ambsquarters (Chenopodium album) MU - Mustard (Bra sica kaber) PI - Pigweed (Amaranthus retroflexu ) RW - Ragweed (Pmbrosia rtemisiifolia) MG - Morningglory (Ipomoea ~urpurea) - BA - Barnyardgrass (Echinochloa crus~alli) Ck - Crabyrass ~ ~ sanguinalis) FO - Green Foxtail (Setaria viridis) WO - Wild Oats (Avena fatua) TW - Teaweed (Sida s~__osa) VL - ~elvetleaf (Abuti~on theophrasti) JW - Jim60nweed (Datura stramonlum L.) 7~3~
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1 Example 123 Postemergence Herbicidal Activity The postemergence herbicidal activity of the com-pounds of the present invention is demonstrated by the fol-lowing tests, wherein a variety of monocotyledonous, anddicotyledonous plants are treated with test compounds dis-persed in aqueous acetone mixtures. In the tests, seedling plants ar~ grown in separate cups for about 2 weeks. The test compounds are dispersed in 50/50 acetone/water mixtures containing 0 r 5% TW~EN~ 20, a polyoxyethylene sorbitan mono-laurate surfactant of Atlas Chemical Industries, in suffic-ient quantity to provide tne equivalent of about 0.~7 kg to

11.2 kg per hectare of ac~ive compound when applied to tne plants through a spray nozzle operating at ~o81 kg/cm pres-sure for a predetermined time. A~ter spraying, the plantsare placed on greenhouse benches and are cared for in the usual manner, commensurate with conventional greenhouse prac-tices. Two weeks after treatment, the seedling plants are examined and rated according to the rating syst~m set forth in Example 122. The data obtained are reported in - Table XI below.

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Claims (60)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula:

wherein X is divalent oxygen or divalent sulfur; R1 is hydrogen, alkyl (C1-C3), chloro, bromo, iodo or haloalkyl (C1-C3); R2 is hydrogen, alkyl (C1-C6), cycloalkyl (C3-C6), methoxymethyl, benzyl, naphthyl, phenyl or monosubstituted phenyl which may be substituted with halogen, alkyl (C1-C4), alkoxy (C1-C4), haloalkyl (C1-C3), amino, dialkylamino or nitro; R3 is hydrogen, alkyl (C1-C3), alkenyl (C3-C4) or alkynyl (C3-C4); R4 is hydrogen or alkyl (C1-C3), which comprises:
(a) heating a compound of formula:

wherein R is methyl or ethyl and X, R1, R2 and R4 are as hereinabove defined in a non-polar high boiling organic solvent at a temperature of 175°-275°C.
for a period of time sufficient for a substantial degree of ring closure to occur, (b) treating a compound of formula:

?9 wherein X and R2 are as hereinabove defined with chlorine or bromine in an inert solvent at a temperature of 60°-90°C. for a period of time sufficient for a substantial degree of halogenation to occur, (c) treating a compound of formula:

wherein R1 and R2 are as hereinabove defined with phosphorus pentasulfide in an inert solvent at a temperature of 100°-150°C. for a period of time sufficient for a substantial degree of replacement to occur; and when R3 is hydrogen, if desired, alkylating the thus obtained compound with an alkylat-ing agent by known methods.

2. A compound of formula:

wherein X, R1, R2, R3 and R4 are as defined ahove, whenever prepared accord-ing to the process of Claim 1 or by an obvious chemical equivalent thereof.

3. A process for the preparation of 8-Methyl-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-[(5-methyl-2-phenyl-4-imidazolyl)methylene]carbazic acid ethyl ester in an inert organic solvent at a temperature of from 215°-230°C.

?0

4. The compound 8-Methyl-6-phenyl-imidazo [1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 3 or by an obvious chemical equivalent thereof.

5. A process for the preparation of 8-Bromo-6-phenyl-imidazo[1,5-d]-as-triazin-4-(3H)-one which com-prises reacting 6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one with bromine in an inert solvent at reflux temperature.

6. The compound 8-Bromo-6-phenyl-imidazo [1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 5 or by an obvious chemical equivalent thereof.

7. A process for the preparation of 8-Chloro-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one which com-prises reacting chlorene gas with 6-phenyl-imidazo [1,5-d]-as-triazin-4(3H)-one in an inert organic solvent.

8. The compound 8-Chloro-6-phenyl-imidazo [1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 7 or by an obvious chemical equivalent thereof.

9. A process for the preparation of 6-Phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-(2-phenyl-4-imidazolylmethylene)carbazic acid ethyl ester in an inert organic solvent at a temperature range of from 255°-265°C.

10. The compound 6-Phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 9 or by an obvious chemical equivalent thereof.

11. A process for the preparation of 6-Phenyl-8-iodo-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-[1-(5-Iodo-2-phenyl-4-imidazolyl) alkylidene]
carbazic acid methyl ester in an inert solvent and ?1 heated to the boiling point of the solvent and kept at that temperature for 20 minutes.

12. A compound 6-Phenyl-8-iodo-imidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 11 or by an obvious chemical equivalent thereof.

13. A process for the preparation of 6-n-Propyl-imidazo[1,5-d]-as-triazine-4(3H)-thione which comprises cyclizing 3-(2-n-propyl-4-imidazolylmethylene)dithiocarbazic acid methyl ester in an inert organic solvent at a tempera-ture of 175°C.

14. The compound 6-n-Propyl-imidazo[1,5-d]-as-triazine-4(3H)-thione whenever prepared by the process of Claim 13 or by an obvious chemical equivalent thereof.

15. A process for the preparation of 8-Methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione which comprises cyclizing 3-(5-methyl-4-imidazolylmethylene)dithiocarbazic acid methyl ester in an inert organic solvent at a tempera-ture of 175°C.

16. The compound 6-n-Propyl-imidazo[1,5-d]-as-triazine-4(3H)-thione whenever prepared by the process of Claim 15 or by an obvious chemical equivalent thereof.

17. A process for the preparation of 6-n-Propyl-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises cycliz-ing 3-(2-n-propyl-4-imidazolylmethylene)carbazic acid ethyl ester in the inert organic solvent at a temperature range of 255°-265°C.

18. The compound 6-n-Propyl-imidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 17 or by an obvious chemical equivalent thereof.

19. A process for the preparation of 6,8-Di-methyl-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises ?2 cyclizing 3-[(2,5-dimethyl-4-imidazolyl)methylene] car-bazic acid ethyl ester in an inert organic solvent at a temperature of 255°-265°C.

20. The compound 6,8-Dimethyl-imidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 19 or by an obvious chemical equivalent thereof.

21. A proeess for the preparation of 8-Methyl-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-(5-methyl-4-imidazolylmethylene)carbazic acid ethyl ester in an inert organic solvent at a temperature of 255°-265°C.

22. The compound 8-Methyl-imidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 21 or by an obvious chemical equivalent thereof.

23. A process for the preparation of 6-tert-Butyl-8-methyl-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-[(2-tert-butyl-5-methyl-4-imidazolyl) methylene]carbazic acid ethyl ester.

24. The compound 6-tert-Butyl-8-methyl-imidazo [1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 23 or by an obvious chemical equivalent thereof.

25. A process for the preparation of 8-Methyl-6-n-propyl-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-[(5-methyl-2-n-propyl-4-imidazolyl)methylene]
carbazic acid ethyl ester in an inert organic solvent at a temperature of 255°-265°C.

26. The compound 8-Methyl-6-n-propyl-imidazo [1,5-d]-as-triazin-4(3H)-one whenever prepared by the pro-cess of Claim 25 or by an obvious chemical equivalent thereof.

?3

27. A process for the preparation of 6-p-chloro-phenyl-8-methylimidazo[1,5-d]-as-triazin -4(3H)-one which comprises cyclizing 3[(5-methyl-2-(p-chlorophenyl)-4-imi-dazolyl)methylene]carbazic acid methyl ester in an inert organic solvent at reflux temperature.

28. The compound 6-p-chlorophenyl-8-methylimidazo [1,5-d]-as-triazone-4(3H)-one whenever prepared according to Claim 27 or by an obvious chemical equivalent thereof.

29. A process for the preparation of 6-n-butyl-8-methylimidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3[(5-methyl-2-n-butyl-4-imidazolyl)-methylene]
carbazic methyl ester in an inert organic solvent at reflux temperature.

30. The compound 6-n-butyl-8-methylimidazo[1,5-d]-as-trizin-4(3H)-one whenever prepared by the process of Claim 29 or by an obvious chemical equivalent thereof.

31. A process for the preparation of 6-cyclo-propylimidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3[(2-cyclopropyl-4-imidazolyl)methylene]carbazic methyl ester in an inert organic solvent at reflux tempera-ture.

32. The compound 6-cyclopropylimidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 31 or by an obvious chemical equivalent thereof.

33. A process for the preparation of 6,8-dibromo-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises cycliz-ing 3-[(2,5-dibromo-2-phenyl-4-imidazolyl)methylene]car-bazic methyl ester in an inert organic solvent at reflux temperature.

34. The compound 6,8-dibromoimidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 33 or by an obvious chemical equivalent thereof.

35. A process for the preparation of 8-bromo-6-m-aminophenylimidazo[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3[(5-bromo-2-(m-amino-phenyl)-4-imidazolyl)methylene]carbazic acid methyl ester in an inert organic solvent at reflux temperature.

36. The compound 8-bromo-6-m-aminophenylimidazo [1,5-d]-as-triazin-4(3H)-one whenever prepared by the pro-cess of Claim 35 or by an obvious chemical equivalent there-of.

37. A process for the preparation of 6-m-nitro-phenylimidazo-[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3[2-(m-nitrophenyl)-4-imidazolyl)methylene]-carbazic acid methyl ester in an inert organic solvent at reflux temperature.

38. The compound 6-m-nitrophenylimidazo-[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 37 or by an obvious chemical equivalent thereof.

39. A process for the preparation of 3,8-dimethyl-6-phenyl[1,5-d]-as-triazin-4(3H)-one which comprises alkylating 8-methyl-6-phenyl-imidazo-[1,5-d]-as-triazin-4(3H)-one with methyl iodide in an organic solvent at a temperature of 40°C.

40. The compound 3,8-dimethyl-6-phenyl[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 39 or by an obvious chemical equivalent thereof.

41. A process for the preparation of 8-methyl-6-phenyl-3(2-propynyl)-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises alkylating 8-methyl-6-phenylimidazo-[1,5-d]-as-triazin-4(3H)-one with 2-propynyl iodide in an organic solvent at 40°C.

42. The compound 8-methyl-6-phenyl-3(2-propynyl)-imidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 41 or by an obvious chemical equivalent thereof.

43. A process for the preparation of 8-methyl-6-phenyl-3-n-propyl-imidazo[1,5-d]-as-triazin-4(3H)-one which comprises alkylating 8-methyl-6-phenylimidazo-[1,5-d]-as-triazin-4(3H)-one with n-propyl iodide in an organic solvent at 40°C.

44. The compound 8-methyl-6-phenyl-3-n-propylimidazo[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 43 or by an obvious chemical equivalent thereof.

45. A process for the preparation of compounds of the formula wherein R4 is methyl, ethyl, or n-propyl, which comprises heating a compound of formula wherein R is methyl or ethyl, and R4 is as hereinabove defined, in a non-polar high boiling organic solvent at a temperature of 175°-275°C for a period of time sufficient for a substantial degree of ring closure to occur.

46. Compounds of the formula wherein R4 is methyl, ethyl, or n-propyl, whenever prepared by the process of claim 45, or by an obvious chemical equivalent thereof.

47. The process according to claim 1(a), wherein X is divalent oxygen, R1 is methyl, R2 is n-propyl, R3 is hydrogen and R4 is hydrogen or alkyl (C1-C3).

48. The process according to claim 1(a), wherein X is divalent oxygen, R1 is methyl, R2 is n-propyl, R3 is hydrogen, and R4 is methyl.

49. The process according to claim 1(a), wherein X is divalent oxygen, R1 is methyl, R2 is n-propyl, R3 is hydrogen, and R4 is ethyl.

50. The process according to claim 1(a), wherein X is divalent oxygen, R1 is methyl, R2 is n-propyl, R3 is hydrogen, and R4 is n-propyl.

51. A process for the preparation of 1,8-dimethyl-6-n-propyl-imidazo-[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-[(2-n-propyl-5-methyl-4-imidazolyl)-ethylidene]carbazic acid C1-C2alkyl ester.

52. 1,8-Dimethyl-6-n-propyl-imidazo-[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 51 or by an obvious chemical equivalent thereof.

53. A process for the preparation of 1-ethyl-8-methyl-6-n-propyl-imidazo-[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-[(2-n-propyl-5-methyl-4-imidazolyl)-n-propylidene]carbazic acid C1-C2 alkyl ester.

54. 1-Ethyl-8-methyl-6-n-propyl-imidazo-[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 53 or by an obvious chemical equivalent thereof.

55. A process for the preparation of 1,6-di-n-propyl-8-methyl-imidazo-[1,5-d]-as-triazin-4(3H)-one which comprises cyclizing 3-[(2-n-propyl-5-methyl-4-imidazolyl)-n-butylidene]carbazic acid C1-C2 alkyl ester.

56. 1,6-Di-n-propyl-8-methyl-imidazo-[1,5-d]-as-triazin-4(3H)-one whenever prepared by the process of Claim 55 or by an obvious chemical equivalent thereof.

57. The process according to Claim 1, wherein X is divalent oxygen, R1 is hydrogen or methyl, R2 is hydrogen or alkyl C1-C6, R3 is hydrogen, and R4 is hydrogen or alkyl C1-C3.

58. The process according to Claim 1, wherein X is divalent oxygen or divalent sulfur, R1 is methyl, R2 is n-propyl, R3 is hydrogen, and R4 is hydrogen or alkyl C1-C3.

59. The process according to Claim 1, wherein X is divalent oxygen, R1 is methyl, R2 is hydrogen, methyl, n-propyl, or t-butyl, R3 is hydrogen, and R4 is hydrogen, methyl, ethyl, or n-propyl.

60. The process according to Claim 1, wherein X is divalent oxygen, R1 is hydrogen or methyl, R2 isn-propyl, R3 is hydrogen, and R4 is hydrogen, methyl, ethyl, or n-propyl.