CH636615A5 - Pharmaceutically effective, optionally substituted imidazo(1,5-d)-as-triazin-4-(3H)-ones and -thiones - Google Patents

Description

The invention also relates to therapeutic preparations in the form of a dosage unit for inhibiting the enzyme phosphodiesterase in humans and mammals, containing 5 to 500 mg of a compound of the formula:

30th

The invention relates to new pharmaceutically active, optionally substituted imidazo [1,5-d] -as-triazin-4 (3H) -ones and thiones of the following structural formula:

x n

R,

n-Hi and

(I)

1

r- \ ^ I

R2 X N

(Ia)

40

where X is oxygen or sulfur, Ri is hydrogen, chlorine, bromine or an alkyl group with up to 3 carbon atoms and R2 is hydrogen, an alkyl group with up to 4 carbon atoms or a phenyl, benzyl, methoxymethyl or o-propoxyphenyl group, and contain a pharmaceutical carrier.

The processes according to the invention for the preparation of the compounds of the formula Ia or Ic are defined in claims 50 5 to 7 and 9.

The invention further relates to new starting materials for carrying out the process according to claim 5. These starting materials are new substituted 3- (4-imidazolylmethylene) carbazate and dithiocar-55 bazate of the following structural formula:

R,

60

n

NH

Marg

(IIa)

-Rr

65

In this formula, R 1 and R 2 have the meanings given in claim 8, and Rs denotes a group of the formula:

636 615 4

O S

Il II

-CH = NH-C-O-R or -CH = N-NH-C-S-R

wherein R represents a methyl or ethyl group. The new 5 lie, which can be represented as follows, and starting materials can be pre-equivalent in two tautomeric forms for the purposes according to the invention:

R-

R,

n nh

"rr

R,

.X

hn n

R-,

-Rt

(IIa)

The novel compounds according to the invention and the starting materials are generally obtained as white to yellow crystalline materials with characteristic melting points and absorption spectra. They can be purified by recrystallization from conventional organic solvents, such as methanol, ethanol, dimethylformamide or chloroform. They are in non-polar organic

R.

Marg

R.

N

nh

(purple)

N

• ch2oh

R,

nh

-ch = n-nh

(iv)

(IIb)

Solvents such as diphenyl ether and carbon tetrachloride, readily soluble, but relatively insoluble in water.

The processes for the preparation of compounds of the formula Ia according to the invention, including the preparation of the new starting materials of the formulas IV and V, can be found in the following reaction scheme.

Ro n

Ri

R,

nh

(IÌIb)

-cho

V

* 2

N

0

S-0-.

V

m c-o-r

I.

• ch = n-nh (v)

(Ic)

(Id)

In these formulas, R is a methyl or ethyl I, which are not covered by the formula Ia, can be prepared in group, and Ri and r2 have the same manner as stated in claim 4. One can pre-meanings as follows. The corresponding compounds of the formula go: An appropriately substituted 4-imidazole methanol

(Illa) is oxidized with concentrated nitric acid to the corresponding 4-imidazole carboxaldehyde (Illb). This oxidation is best carried out by dissolving or suspending 1 g of starting material (purple) in about 1 to 7 ml of concentrated nitric acid and heating the reaction mixture to steam bath temperature for 2 to 3 hours. Instead, the reaction mixture can initially be left to stand at room temperature for 8 to 16 hours, after which it is heated on the steam bath for a short time (15 to 30 minutes). The I0 reaction solution formed is preferably first diluted with water and then with a customary base, such as sodium hydroxide solution.

Soda or concentrated aqueous ammonia, neutralized. The precipitated product (Illb) is separated off, washed with water and purified by recrystallization from a conventional organic solvent, such as ethyl acetate or ethanol. The 4-imidazole methanol (purple) can also be oxidized with activated manganese dioxide in chloroform or tetrahydrofuran at a temperature between room temperature and reflux for 4 to 6 hours to the 2o 4-imidazole carboxaldehyde (Illb).

The 4-imidazole carboxaldehyde (Illb) is readily treated in the 3- (4-imidazolylmethylene) dithiocarbazine ester (IV) or 2s 3- (4-imidazolylmethylene) by treatment with methyl or ethyl dithiocarbazate or with methyl or ethyl carbazate. carbazinates (V) transferred. This condensation is expediently carried out in a lower alkanol as solvent, which contains a few drops of glacial acetic acid, at a temperature of 25 to 75 ° C., the product (IV) or (V) 30 forming almost immediately and being able to be filtered off. The cyclization of the 3- (4-imidazolylmethylene) dithiocarbazinic acid ester (IV) and the 3- (4-imidazolylmethylene) carbazinic acid ester (V) is carried out by heating in a non-polar high-boiling organic solvent such as diphenyl ether 175 to 275 ° C, whereby the corresponding imidazo [l, 5-d] -as-triazine-4- (3H) -thione (Ic) and imi-dazo [l, 5-d] -as-triazine-4- (3H) -one (Id) can be obtained. The ring closure normally takes place within 15 to 30 minutes at the temperature mentioned. 40

636 615

The compounds (Ia), in the formula Ri of which is chlorine or bromine, are prepared by chlorination or bromination of the corresponding compounds of the formula Ib. This halogenation is achieved by treating the starting materials with chlorine or bromine in an inert solvent such as chloroform or carbon tetrachloride at 60 to 90 ° C. The oxo compounds (Id) are converted into the thio compounds (Ic) by treatment with phosphorus pentasulfide in an inert solvent such as pyridine at 100 to 150 ° C.

The compounds of the formula I, in which R i is iodine, can consequently be prepared:

An aldehyde (Illb), in the formula Ri of which is hydrogen, is converted into the dimethylacetal in methanol / HCl. The latter is iodinated and then hydrolyzed to the corresponding iodaldehyde (IIIc):

R,

N

-JH

(IIIc)

-CHO

The iodaldehyde (IIIc) thus obtained is then converted into the desired compound (I), in which Ri is iodine, in the manner described above.

The introduction of a substituent R4 into the imidazo-as-triazinone ring can be brought about by treating the aldehyde (Illb) with an alkylmagnesium bromide with 1 to 3 carbon atoms and subsequent Jones oxidation. The latter method is by Jones et al. in J.C.S. 1946, p. 39 and in J.C.S. 1953, pp. 457, 2548 and 3019. A ketone (VIII) is formed during the oxidation of the secondary alcohol. These reactions are illustrated below.

R.

N

R-

<JK

R,

+ Alkyl -.'- 'gBr

N

NH

• cho

R-

(Illb)

.CHOH I

alkyl

OXIDATION

R,

N

R.

NH

-C = 0

I.

Alkyl

(VI)

636 615

6

The remaining stages of the synthesis of compounds of the formula I, in which X is oxygen and R.4 is different from hydrogen, can be carried out by the process described above by cyclizing the carbazinate derivative of the ketone of the formula VI in diphenyl ether or, preferably, in 5-o-dichlorobenzene be performed.

The new compounds according to the invention act as broad-spectrum herbicides and inhibit the enzyme cyclic AM P phosphodiesterase, on which the metabolism depends on cyclic AMP. They are suitable for the 0

Treatment of psoriasis, a condition in which the cyclic AMP content in the epidermis has been reported to be reduced. They are also suitable for the treatment of asthma, since an increased content of cyclic AMP in most cells, as reported, inhibit the release of histamine 15 and other regulators and because increased contents of cyclic AMP in the smooth bronchial muscles are said to cause bronchodiolation ( Ann. Reports in Médicinal Chem., Vol. 10, pp. 197, 1975).

The inhibition of phosphodiesterase is determined using the mouse skin and monkey lung phosphodiesterase (PDE) inhibition tests described below.

(A) Mouse skin inhibition

Preparation of the mouse skin PDE 25

3-4 month old hairless mice (Jackson Laboratories) are killed by turning their necks and their skins are stripped. Epidermis strips with a thickness of 0.2 mm are weighed and homogenized in a ratio of 100 mg / ml in ice-cold tris-HCl buffer (0.04 m, pH 8, containing 0.005 m 30 MgCh). The homogenates are centrifuged at 17,000 g for 30 minutes. The supernatant liquid is divided and stored at -20 ° C. Dilutions of the PDE are made with tris-HCl buffer immediately before use. 35

Anion exchange resin

AG1-X2, R), 200-400 mesh, particle size about 37 to 74 microns (an 8% cross-linked polystyrene anion exchange resin from Bio-Rad Lab.) Is mixed with 0.5N HCl, 0.5N NaOH, 0.5n 40 HCl and washed several times with double distilled water to pH 5. The resin is allowed to settle and two volumes of water are added to one volume of settled resin.

45

Purification of 3H cyclic AMP

3H-cyclic AMP (21 c / m mol, Schwarz-Mann Inc.) is added to 5 ml of anion exchange resin and 0.4 ml of tris-HCl- by adding 0.1 to 0.2 ml of stock solution (in 50% ethanol). Buffer cleaned. The mixture is treated in a whisk and centrifuged at 1200 g for 5 minutes and the supernatant is discarded. The resin is washed another eight times in the same way with two volumes of tris-HCl buffer. The 3H-cyclic AMP bound to the resin is eluted by two successive 55 washes with 4 ml of 0.025 N HCl (pH of the resin = 2.0). After centrifugation, the combined acidic washing liquids containing 3H-cyclic AMP are divided and lyophilized. The material is stored dry at -20 ° C and immediately mixed with 60 tris-HCl buffer in a volume immediately before reuse, with which approximately 200,000 CPM / 0.1 ml are obtained.

PDE determination

PDE activity is measured using the WJ. 65 Thompson and N.N. Appleman, Biochemistry Vol. 10, p. 311 (1971). The determinations are carried out in 12x75 mm test vessels made of polypropylene. The reaction mixture consists of 3H-cyclic AMP (200,000 CPM),

Cyclic AMP not labeled with a radioactive isotope, PDE (10 ig protein) and test compound, which is prepared by dissolving the compound in methanol at a concentration of 10 mg / ml and diluting it in tris-HCl buffer of the incubation mixture is 10 μg / ml. The total volume of the incubation mixture is brought to 0.4 ml with tris-HCl buffer containing 3.75 mmol of 2-mercaptoethanol. The enzyme is stirred for 10 minutes at room temperature in the presence of the test compounds or of buffer before the mixture of 3H-cyclic AMP and unlabeled cyclic AMP is added The reactions are carried out for 15 minutes at 30 ° C. and then ended by immersion in acetone / dry ice until freezing and then heating to boiling for 3 minutes Vessels are cooled to room temperature and the 3H-5'-AMP formed during the reaction is added by adding 0.1 ml of a solution of 5'-nucleotidase (16 μl / ml in double distilled water, Crotalus Venom, Sigma Chemicals) to the vessels, which are left to stand for 20 minutes at room temperature, converted into 3H-adenosine. This reaction is stopped by adding 1 ml ice-cold stirred resin slurry that binds labeled nucleotides (including 3H-cyclic AMP) but not 3H-adenosine. The vessels are treated in a vortex device and immersed in an ice bath for 15 minutes. Then centrifuged at 1200 g for 5 minutes. 0.5 ml of each sample is taken, placed in liquid scintillation vials with 10 ml Ready-Solv VI (Beckman Ind.) And counted for radioactivity. Collection blind samples with buffer instead of PDE give less than 1% of the total 3H-cyclic AMP added when 3H-cyclic AmP is purified as indicated.

(B) Monkey lung inhibition

Preparation of monkey lung cyclic AMP-phosphodi-esterase

Lung parenchyma from African green monkeys is homogenized in a Waring mixer and centrifuged at 40,000 g for 20 minutes. The supernatant liquid is brought to 70 percent saturation in ammonium sulfate and centrifuged, and the residue is redissolved and dialyzed, followed by division and storage at -20 ° C.

Determination of monkey lung phosphodiesterase '. The phosphodiesterase is made according to the method of Thompson and Appleman, loc. cid., determined. A determination vessel contains 0.4 ml of a solution of the following components: 45 mM tris-HCl buffer, pH 7.4, 6.45 M MgCh, 0.1 mM dithioerythritol, IO "6 M cyclic AMP, 0.1 uCi [3H] cyclic AMP and test compound at the desired concentration (usually 1 mM or 0.1 mM). Compounds that are sparingly soluble in water are dissolved in methanol at a concentration 40 times the desired concentration and diluted 20 times with water If the compound is not yet dissolved at this point, it is sonicated before it is diluted 1: 2 and added to the determination tube, in which case the activity of the enzyme in the presence of the compound with a solvent blank (2.5% methanol), although the solvent alone has a negligible effect. The reaction is initiated by adding enzyme and continued for 20 minutes at 25 ° C. It is terminated by incubating for 2 minutes at 100 ° C. The Ge kegs are cooled to 25 ° C, each with 0.8 µg 5'-nucleotidase (Crotolus Ada-

7

636615

mantustoxin) and incubated at 25 ° C for 30 minutes. 1 ml suspension from Bio-Rad Labs. AGIXI (about 0.5 ml of settled resin) is added, the tubes are centrifuged at 900 g for 10 minutes, and portions of the supernatant are removed for scintillation counting. The inhibition by the test compound is calculated as follows:

Percent of control =

Connection - blank test control - blank test

Compound = cpm in the presence of compound Control = cpm in the absence of compound and blank = cpm in the absence of enzyme

Since this determination includes hydrolysis of cyclic AMP to AMP (by phosphodiesterase) and hydrolysis of AMP to adenosine (by 5'-nucleotidase), a compound that largely inhibits nucleotidase also appears to inhibit phosphodiesterase. For this reason, control vessels containing pH] -AMP instead of [3H] -cyclic APM are run in parallel. Correction of the apparent phosphodiesterase activity is made for the rare compounds that inhibit the hydrolysis of AMP.

Criterion for activity as an inhibitor of major phosphodiesterase

A compound is considered effective if it inhibits more than theophillin, i.e. 50% of the control at a concentration of the compound of 1 mM or 80% of the control at a concentration of 0.05 mM of the compound.

The results of the inhibition of phosphodiesterase obtained with exemplary representatives of the compounds according to the invention are summarized in Table I below.

Table l (continued)

d] -as-triazin-4 (3H) -thione effectively effective

8-Methyl-imidazo [1,5-d] -as-5 triazin-4 (3 H) -thione effective

6-o-Propoxyphenyl-imidazo [1,5-d] -as-triazin-4 (3H) -one effective

6-benzyl-imidazo [1,5-d] -as-

triazin-4 (3H) -one effective

10 6-tert-butyl-imidazo [1,5-d] -as-

triazin-4 (3H) -one effective

8-methyl-imidazo [1,5-d] -as-

triazin-4 (3H) -one effective

6,8-Dimethyl-imidazo [1,5-d] -as-! 5 triazin-4 (3 H) -thione

Some of the new compounds according to the invention show antihypertensive activity at non-toxic doses and are therefore suitable as hypotensive agents. Pharmacological testing of these compounds has shown that they have these properties at a desired wide distance between doses which lead to reduced blood pressure, and those who have toxic symptoms 25. To determine this effect on hypertension, approximately 300 g adult male 16-20 week old spontaneously hypertensive rats from Taconic Farms, Germantown, New York are used given dosage 30 administered by gavage, the active ingredients are suspended in 2 percent strength (2 ml / kg), a second equal dose of the test compound is administered in the 24th hour, the mean arterial blood pressure (MAP) of the conscious rats is in the 28th hour 35 directly through the femoral artery point measured. The results of this test are summarized in Table II.

Table II

Table I

40 connection

MAP (mm Hg)

Dose mg / kg

28th hour

connection

Monkey lung phospho-

Mouse skin phos

Imidazo [1,5-d] -as-triazine-4 (3H) -

diesterase (B)

phodiesterase (A)

thion

100

123

45 8-methyl-imidazo [1,5-d] -as-triazine

6-propyl-imidazo [1,5-d] -as-

4 (3H) thione

25th

130

triazin-4 (3 H) -thione effectively effective

6-propyl-imidazo [1,5-d] -as-triazine

8-methyl-6-phenyl-imidazo [l, 5-

4 (3H) thione

100

136

d] -as-triazine-4 (3H) thione

effective

8-methyl-6-phenyl imidazo [1,5-d] -

6-phenyl-imidazo [1,5-d] -as-

50 as-triazine-4 (3H) thione

100

128

triazin-4 (3H) -one

effective

6-phenyl-imidazo [1,5-d] -as-triazine

8-methyl-6-phenyl-imidazo [l, 5-

4 (3H) -on

100

117

d] -as-triazin-4 (3 H) -one effectively effective

8-methyl-6-phenyl-imidazo [1,5-d] -

6-propyl-imidazo [1,5-d] -as-

as-triazin-4 (3 H) -one

100

133

triazin-4 (3H) -one

effective ss 6,8-dimethyl-imidazo [1,5-d] -as-

6,8-dimethyl-imidazo [1,5-d] -as-

triazin-4 (3H) -one

50

70

triazin-4 (3H) -one effectively effective

6-tert-butyl-imidazo [1,5-d] -as-

8-bromo-6-phenyl-imidazo [l, 5-

triazin-4 (3H) -one

100

135

d] -as-triazin-4 (3 H) -one effectively effective

6-methyl-imidazo [1,5-d] -as-triazine

8-chloro-6-phenyl-imidazo [l, 5-

60 4 (3H) -on

100

120

d] -as-triazin-4 (3 H) -one effectively effective

8-methyl-imidazo [1,5-d] -as-triazine

6-benzyl-8-methyl-imidazo [l, 5-

4 (3H) -on

100

91

d] -as-triazin-4 (3 H) -one

effective

6-tert-butyl-8-methyl-imidazo [1,5-

6-tert-butyl-8-methyl-imi-

d] -as-triazin-4 (3H) -one

100

133

dazo [l, 5-d] -as-triazin-4 (3H) -one effectively effective

65 6,8-dimethyl-imidazo [1,5-d] -as-

6-benzyl-8-methyl-imidazo [l, 5-

triazin-4 (3H) thione

100

93

d] -as-triazin-4 (3 H) -thione effectively effective

8-methyl-6-propyl-imidazo [1,5-d] -

8-methyl-6-propyl-imidazo [1,5-

as-triazin-4 (3 H) -one

50

127

636615

8th

Table // (continued)

MAP connection (mm Hg)

Dose mg / kg 28th hour

6-methoxymethyl-imidazo [1,5-d] -as-triazine-4 (3H) -thione 100 100

Controls carrier 166

The new compounds according to the invention have thus proven to be very suitable for improving asthma and inhibiting the phosphodiesterase enzyme in mammals when administered in amounts of approximately 1.0 to 100.0 mg / kg body weight and day. A preferred dosage for achieving optimal results is between about 5.0 and 50.0 mg / kg body weight and day, and such dosage units are used that a total of about 0.35 to 3.5 g of active ingredient to a living being of about 70 kg Body weight can be administered in 24 hours. The dosage can be adjusted for an optimal therapeutic effect. For example, several partial doses can be administered daily, or the dose can be reduced according to the requirements of the therapeutic situation. A decisive practical advantage of the invention is that the active compounds can be administered in any desired manner, for example orally, intravenously, intramuscularly or subcutaneously, and by inhalation with the aid of aerosol sprays.

Preparations according to the invention which are clear and stable and which can be adapted to parenteral use are obtained by dissolving 0.10 to 10.0% by weight of active ingredient in a carrier from a polyhydric aliphatic alcohol or mixtures of such alcohols. Glycerin, propylene glycol and polyethylene glycols are particularly suitable. The polyethylene glycols consist of a mixture of non-volatile, normally liquid, polyethylene glycols, which are soluble in both water and organic liquids and have molecular weights of about 200 to 1500. The amount of active ingredient dissolved in such a carrier can be between 0.10 and 10.0 percent by weight, but the active ingredient is preferably used in amounts of about 3.0 to 9.0 percent by weight. While various mixtures of the above non-volatile polyethylene glycols can be used, it is preferred to use a mixture with a molecular weight of about 200 to 400.

In addition to the active ingredient, the parenteral solutions can also contain a wide variety of preservatives that are used to prevent bacterial or fungal contamination. The preservatives which can be used for these purposes are, for example, myristyl-gamma-picolinium chloride, benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-alpha-glycerol ether, methyl and propylpa-rabenes and thimerosal. It is also expedient to use antioxidants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite and sodium formaldehyde sulfoxylate. Antioxidant concentrations of about 0.05 to 0.2% are generally used.

For intramuscular injection, the preferred concentration of the active ingredient is 0.25 to 0.50 mg / ml of the finished preparation. The new compounds according to the invention are also suitable for intravenous administration if they are diluted with water or with diluents, such as isotonic glucose, commonly used for intravenous therapy. Starting concentrations down to about 0.05 to 0.25 mg / ml of active ingredient are suitable for intravenous use.

The active compounds according to the invention can be administered orally, for example with an inert diluent or with an assimilable edible carrier or in hard or soft gelatin capsules or compressed into tablets or together with nutrients. For oral therapeutic administration, the active ingredients can be mixed with carriers and used in the form of tablets, dragées, capsules, elixirs, suspensions, syrups, waffles and the like. Such preparations should contain at least 0.1% active ingredient. The percentages can, of course, be changed and are expediently about 2 to 60% of the weight of the unit. The amount of active ingredient in such therapeutically applicable preparations is measured so that a suitable dosage is achieved. Preferred preparations contain about 250 to 500 mg of active ingredient in an oral dosage unit.

The tablets, dragees, pills, capsules and the like may also contain the following substances: binders such as tragacanth, acacia, corn starch or gelatin, carriers such as dicalcium phosphate, disintegrants such as corn starch, potato starch or alginic acid, lubricants such as magnesium stearate and sweeteners , such as sucrose, lactose or saccharin, and finally flavoring substances such as peppermint, wintergreen oil or cherry flavor. If the dosage unit is a capsule, it can contain, in addition to the materials mentioned above, a liquid carrier, for example a fatty oil. Various other substances can be present as coatings or for other modification of the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir can contain the active ingredient, sucrose as a sweetener, methyl and propyl parabens as a preservative, a colorant and a flavoring agent, such as cherry or orange aroma. Of course, all substances used to produce the dosage unit forms should be pharmaceutically pure and practically non-toxic in the amounts used.

The compounds of formula I are valuable herbicidal agents for controlling monocotyledons and docothyledons. They are highly effective for pre-emergence control of these unwanted plants when applied to the soil in a ratio of about 0.07 to 11.2 kg / ha, the seeds, seedlings or developing organs of these broad-leaved weeds or grass plants contains.

The compounds of the formula I are also suitable for combating the emergence of these undesirable plant species if they are applied to the foliage of these plants in a ratio of about 0.28 to 11.2 kg / ha.

Since the imidazo-as-triazinones and imidazo-as-criazin-thione are only sparingly soluble in water, they are generally processed into wettable powders, emulsifiable concentrates or thixotropic concentrates, which are usually used in water or another cheap liquid diluent for use as liquid spray can be dispersed. The compounds can also be administered to granules which generally contain about 10 to 15 percent by weight of active ingredient.

A wettable powder can be obtained, for example, by grinding together about 25 to 80 percent by weight of a compound of formula I, about 2 to 5 percent by weight of a surfactant such as sodium N-methyl-N-oleyl taurate, alkylphenoxypolyoxyethylene ethanol or sodium alkylnaphthalenesulfonate, 5 to 10% by weight of a Dis5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9

636615

Pergiermittel such as highly purified sodium lignosulfonate and 25 to 63 percent by weight of a finely divided carrier such as kaolin, attapulgite, diatomaceous earth or the like.

An example of a preparation prepared as described above is as follows:

50 weight percent 8-methyl-6-phenyl-imidazo [1,5-d] -as-triazin-4 (3H) -one, 3 weight percent sodium-N-methyl-N-oleyl taurate, 10 weight percent sodium lignosulfonate and 37 weight percent kaolin.

Thixotropic concentrates can be prepared by co-grinding about 40 to 60 percent by weight of the sodium salt of condensed naphthalenesulfonic acid, 2 to 3 percent by weight of a gelling clay, 2 percent by weight of propylene glycol and 54 to 32 percent by weight of water.

Granules can be prepared by dissolving or dispersing the active ingredient in a solvent and applying it to a sorbent or non-sorbent carrier such as attapulgite, corn cob, pumice, talc or the like.

The broad spectrum of the herbicidal activity of the compounds of the formula I enables effective control of undesired vegetation on and on motor roads, railway lines, rights of way under power transmission lines and along pipelines and under bridge feeders, and wherever a good control of undesired vegetation is required.

Manufacturing 1

5-methyl-2-phenyl-4-imidazomethanol

100 g benzamidine hydrochloride are at room temperature in the smallest possible amount of water (350 ml)

solved. 67 g of freshly distilled 2,3-butanedione are added to form a yellow solution. By adjusting the pH to 6 to 7 with 2N NaOH, a solid precipitates, which is left to stand at 0 ° C. for 2 hours, filtered off, pressed dry and washed with 100 ml of acetone. This material is heated with 855 ml of concentrated HCl and 2437 ml of water for 4 hours with stirring on a steam bath, and the solution thus formed is cooled to room temperature overnight and then to 0 ° C. The solid formed is filtered off and air-dried. It is dissolved in 350 ml of ethanol, filtered off and cooled, whereby a gel is formed, which is taken up in 250 ml of water at 50 to 60 ° C., adjusted to pH 5.5 with concentrated NaOH and then to pH 7 to 8 with solid KHCO3 brought. The mixture is cooled to 0 ° C and the product is filtered off, washed with water and air dried. It is recrystallized from one liter of methanol and provides a product with a melting point of 197 to 199 ° C.

This product can also be prepared by the method of Imbach et al., Bull. Soc. Chim. France, 1971,1052.

Manufacturing 2

2-phenyl-4-imidazole methanol

This product is manufactured according to the methods of Dziuron and Schunack, Arch. Pharm. Vol. 306, p. 347 (1973) and Vol. 307, p. 46 (1974).

Manufacturing 3

2-n-propyl-4-imidazole methanol

A mixture of 180 g dimeric 1,3-dihydroxyacetone, 245 g butyramide hydrochloride and 1 liter liquid ammonia is heated in a bomb at 60 ° C for 5 hours. The mixture is evaporated to dryness and the residue is stirred with 600 ml of 2-propanol. Then it is filtered off,

and the filtrate is concentrated in vacuo. After adding 600 m of 50 percent saturated aqueous sodium carbonate solution, the mixture is extracted three times with 450 ml of tetrahydrofuran. The combined organic extracts are washed with 330 ml of saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is recrystallized twice from acetone and gives the product of melting point = 95 to 101 ° C.

Manufacturing 4

2,5-dimethyl-4-imidazole methanol hydrochloride

This product is made according to the method of Imbach et al., Bull. Soc. Chim. France, 1971, p. 1052.

Manufacturing 5

2-methyl-4-imidazole methanol

189 g of acetamidine hydrochloride and 180 g of 1,3-dihydroxyacetone are treated with 1 liter of liquid ammonia as described in Preparation 3, and the desired product of mp = 115 to 117.5 ° C. is obtained.

Manufacturing 6

4,5-dimethyl-2-n-propyl-2-imidazoline-4,5-diol hydrochloride

112.7 g of butyramidine hydrochloride are dissolved in 200 ml of water. After adding 107 g of freshly distilled diacetyl, the mixture is stirred and the pH is adjusted to 6.5 to 7.0 with 2N NaOH. After cooling the solution, the desired product is obtained as a solid with a melting point of 104 ° to 107 ° C.

Manufacturing 7

5-methyl-2-n-propyl-4-imidazole methanol

The product obtained after preparation 6 is dissolved in 900 ml of water and 350 ml of concentrated hydrochloric acid, heated for 5 hours on a steam bath and then cooled. The solution is concentrated in vacuo and a mixture of 100 ml of acetone and 100 ml of ethanol is added. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in 50 ml of water and neutralized with concentrated K2C03 solution until no more bubbles form. The upper layer is separated and 5 ml of methanol are added. When standing, a precipitate forms, from which it is filtered off. The Fitlrat is diluted with acetone, which in turn forms a precipitate, which is also obtained. The solids are combined and recrystallized from warm acetone, whereby the desired product of mp = 134 to 136 ° C is obtained.

Manufacturing 8

5-methyl-4-imidazole methanol

This product is made according to the method of Ewins, J. Chem. Soc. Vol. 99, p. 2052 (1911).

Manufacturing 9

2- (o-propoxyphenyl) -4-imidazole methanol

130 g of salicylamide in 500 ml of ethanol are heated to boiling under reflux with 52.4 g of sodium methoxide and 164.9 g of 1-iodopropane. The mixture is cooled and poured into 1500 ml of water, and the solid substance formed is recrystallized from warm ethanol, whereby o-propoxybenzamide is obtained.

109 g of the compound thus obtained in 500 ml of chloroform are refluxed with 49.4 ml of methyl fluorosulfonate for 3 hours. After cooling, the mixture is concentrated to an oil. By adding

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

636 615

10th

Ether forms crystalline methyl prop-o-benzimidate fluorosulfate, which is obtained.

180 g of the latter compound and 55.0 g of 1,3-dihydroxyacetone in 1 liter of liquid ammonia are processed as described in Preparation 3, whereby the desired product of F. = 90 to 92 ° C is obtained.

Manufacturing 10

2-benzyl-4-imidazole methanol

352 g of benzyl cyanide, 750 ml of diethyl ether and 300 ml of dry ethanol are placed in a 2 liter three-necked flask equipped with a magnetic stirrer, a drying tube and a gas inlet that can be interrupted quickly. Hydrogen chloride gas is bubbled into the mixture with stirring and cooling in an ice bath for one hour. The mixture is then placed in a cold room overnight. After adding 1 liter of ether, the mixture is cooled again. The precipitate is filtered off and washed with ether to give ethyliminophenylacetate hydrochloride.

272 g of the compound thus obtained and 126 g of 1,3-dihydroxyacetone in 11 liquid ammonia are processed as described in Preparation 3, whereby the desired product of mp = 134-135 ° C. is obtained.

Manufacturing 11

2-methoxymethyl-4-imidazole methanol

307.2 g of ethyl 2-methoxyacetimidate hydrochloride (Rule, J. Chem. Soc. Vol. 113, p. 9.1918) and 180 g of 1,3-dihydroxyacetone in 11 liquid ammonia, as described in Preparation 3, processed, whereby the desired product is obtained as an oil. A crystalline picrate of mp = 175 to 178 ° C. is obtained by heating the oily product and picric acid in water.

Manufacturing 14

2-Benzyl-5-methyl-4-imidazolemethanol 55.4 g of freshly distilled diacetyl. The mixture is stirred, the precipitate is filtered off, triturated in portions with 200 ml of acetone and air-dried, whereby 2-benzyl-4,5-dimethyl-4,5-dihydroxyimidazolidine is obtained.

I0 A mixture of 106 g of this product, 170 ml of concentrated hydrochloric acid and 170 ml of water is processed as described in preparation 7, whereby the desired product of mp = 134 to 138 ° C is obtained.

15 Manufacturing 15

2-phenyl-4-imidazolecarboxaldehyde 17.4 g of 2-phenyl-4-imidaimethanoI and 13.4 ml of concentrated HNO3 are heated for 2 hours on a steam bath. To start the reaction, three 20 drops of smoking HNO3 are added. The pH is adjusted to 8 with concentrated aqueous Na2CÜ3 and the mixture is kept at 0 ° C overnight. The solid is filtered off, washed with water and recrystallized from a mixture of 70 ml of ethyl acetate with 20 ml of petroleum ether to give a yellow solid. Adding petroleum ether to the mother liquor gives another sticky substance, which is triturated with isopropanol and gives a second solid. These two solids are taken up in warm isopropanol and crystallize out as a yellow solid which is recrystallized from ethanol / water (1: 1), giving yellow crystals of mp = 169 to 171.5 ° C.

35

Manufacturing 12

2-tert-Butyl-4-imidazole-methanol A mixture of 326 g of methyl pivalimidic acid hydrochloride and 193.5 g of 1,3-dihydroxyacetone in 21 liquid ammonia is processed as described in preparation 3, whereby the desired product from F. = 212 to 221 ° C is obtained.

Manufacturing 13

2-tert-butyl-5-methyl-4-imidazole methanol

In a mixture of 200 g of trimethylacetonitrile, 250 ml of methanol and 500 ml of diethyl ether in a 21 three-necked flask equipped with a magnetic stirrer, a drying tube and a gas inlet tube, gaseous hydrogen chloride is introduced with stirring for 2 hours. The mixture is placed in a beaker, mixed with ether and, after covering the beaker, left to stand in a cold room overnight. After adding 500 ml of ether, the solid is filtered off and washed with ether, whereby methyl pivalimidate hydrochloride is obtained in the form of white crystals.

75 g of the substance obtained in this way are prepared by the method of Brown and Evans, J. Chem. Soc. 1962, p. 4039, converted into the 2,2-dimethylpropionamidine hydrochloride.

61 g of the latter product are dissolved in 50 ml of water with heating and then cooled to room temperature. Then 38.3 g of freshly distilled diacetyl are added and the reaction is continued as described in Preparations 6 and 7, whereby the desired product in the form of white crystals of mp = 195.5 to 196.5 ° C. is obtained.

Manufacturing 16

2-n-propyl-4-imidazole carboxaldehyde A solution of 108.6 g of 2-n-propyl-4-imidazole methanol in 107 ml of concentrated HNO3 is processed as described in preparation 15. The desired product of F. = 103.5 to 105.5 ° C is obtained.

40

Manufacturing 17

2-n-butyl-4-imidazole carboxaldehyde

According to the procedure described in preparation 15, 2-n-butyl-4-imidazole-methanol is converted into 2-n-butyl-4-imidazole-45 carboaldehyde.

Manufacturing 18

5-methyl-2-phenyl-4-imidazole carboxaldehyde

102.1 g of 5-methyl-2-phenyl-4-imidazole methanol are dissolved in 765 ml of concentrated HNO3. The solution is cooled in an ice bath and left to stand for 16 hours. Then it is heated on a steam bath for 30 minutes, diluted with 2.31 water and then diluted with 50% NaOH while cooling in an ice bath. The solid is filtered off, dried and recrystallized from 20 ml of ethanol and then from 11 55 ethanol / water (1: 2), whereby the desired product of mp = 102 to 115 ° C. is obtained.

This product can also be prepared using the method of Diels and Schleich, Chem. Ber. 49, pp. 1711, 1916.

60

Manufacturing 19

5-ethyl-2-phenyl-4-imidazole carboxaldehyde

The procedure described in Preparation 18 is repeated using an equimolar amount of 5-ethyl-2-65 phenyl-4-imidazole methanol instead of the 5-methyl-2-phenyl-4-imidazole methanol used in that preparation. In this way, the compound mentioned in the heading is obtained in equally good yield.

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Manufacture 20

2,5-dimethyl-4-imidazole carboxaldehyde

42.2 g of 2,5-dimethyl-4-imidazole methanol and 44.8 ml of concentrated nitric acid are mixed together.

When the initial reaction subsides, the solution is heated on a steam bath for 1 hour. The reaction mixture is neutralized with concentrated aqueous sodium carbonate solution and then concentrated in vacuo. After leaching the residue several times with 150 ml of warm ethanol, the combined organic solutions are concentrated in vacuo. Chromatography of the remaining oil on silica gel gives a solid which is recrystallized from isopropanol / ethyl acetate, giving the desired product of mp = 164.5 to 166 ° C.

Manufacturing 21

5-methyl-4-imidazole carboxaldehyde

This product is made by the method of Hubball and Pyman, J. Chem. Soc. 1928, p. 21.

Manufacture 22

2-o-propoxyphenyl-4-imidazole carboxaldehyde

44 g of 2- (o-propoxyphenyl) -4-imidazole-methanol are heated together with 500 ml of chloroform and 100 g of manganese dioxide in a 21 round-bottomed flask for 5 hours under reflux without stirring. The reaction mixture is filtered while still warm. The manganese dioxide is triturated with 500 ml of warm chloroform and filtered. The two filtrates are combined and evaporated. The solid residue is recrystallized from 200 ml of warm ethyl acetate with the addition of animal charcoal and gives the desired product of F. = 104 to 105 ° C.

Manufacture 23

2-methyl-4-imidazole carboxaldehyde

143.0 ml of concentrated HNO3 are added in two portions to 119.2 g of 2-methyl-4-imidazole methanol, cooling after the addition of the first portion. The reaction is carried out as described in preparation 15 and gives the desired product of mp = 170 to 176 ° C.

This product can also be prepared using the method of Streit et al., Bull. Soc. Chim. France, 4159 (1971) and Abu-shanab et al., J. Org. Chem. Vol. 40, p. 3376 (1975).

Manufacturing 24

2-benzyl-4-imidazole carboxaldehyde

125 g of 2-benzyl-4-imidazole methanol and 500 g of manganese dioxide in 21 chloroform are processed as described in preparation 22, whereby the desired product of melting point = 130 to 136 ° C. is obtained.

Manufacturing 26

2-benzyl-5-methyl-4-imidazole carboxaldehyde

A mixture of 8.79 g of 2-benzyl-5-methyl-4-imidazole-methanol and 55.7 ml of concentrated HNO3 is left overnight at room temperature. The solution is heated on a steam bath for 45 minutes, cooled and made alkaline with aqueous sodium carbonate. After the mixture obtained has been heated on a steam bath, the mixture is cooled and the solid is separated off. The desired product of melting point = 171 to 173 ° C. is obtained by recrystallizing twice from 10 ml from ethanol.

Manufacturing 27

2-Benzyl-5-n-propyl-4-imidazole carboxaldehyde 15 The procedure described in Preparation 26 is carried out using 2-benzyl-5-n-propyl-4-imidazole methanol instead of 2-benzyl-5-methyl-4-imidazole methanol repeated.

20th

Manufacturing 28

5-methyl-2-n-propyl-4-imidazole carboxaldehyde 80 g of 5-methyl-2-n-propyl-4-imidazole methanol are oxidized with 67.3 ml of concentrated HNO3. A second portion of 101.4 g of the above compound is oxidized with 77 ml of the 25 acid. The reaction mixtures are combined, neutralized and worked up as described in preparation 25. As a result, the desired product is obtained from F. = 126 to 129 ° C.

30th

Manufacturing 29

2-tert-Butyl-4-imidazole carboxaldehyde 7.7 g of 2-tert-butyl-4-imidazole methanol are added to 100 ml of chloroform and 100 ml of tetrahydrofuran and gently warmed. After adding 25 g of manganese dioxide, the mixture is further processed as described in preparation 22, whereby the desired product is obtained as white crystals of mp = 194 to 195 ° C.

40

Manufacturing 30

2-tert-Butyl-5-methyl-4-imidazoIcarboxaldehyde 19.76 g of 2-tert-butyl-5-methyl-4-imidazole methanol and 16.5 ml of concentrated HNO3 are reacted as described in Preparation 25, whereby the desired product from F. = 196 to 198 ° C is obtained.

Manufacturing 25

2- (methoxymethyl) -4-imidazole carboxaldehyde 145.9 g of 2-methoxymethyl-4-imidazole methanol and 137 ml of concentrated HNO3 are reacted as described in preparation 15. After adjusting the pH to 7.0 with concentrated aqueous Na2CCb solution, the solution is concentrated in vacuo. By extracting the residue three times with warm ethanol, combining and concentrating the extracts, a yellow smear is obtained which is chromatographed on silica gel. Fractions 7 to 15 are combined and recrystallized from 120 ml of isopropanol with the use of animal charcoal, whereby the desired product of F. = 100 to 103 ° C is obtained.

Manufacture 31

2-isobutyl-5-isopropyl-4-imidazole carboxaldehyde The procedure described in preparation 30 is carried out using an equimolar amount of 2-isobutyl-5-iso-propyl-4-imidazole methanol instead of 2-tert-butyl-5-methyl-4 -imidazole methanol repeated. As a result, the compound mentioned in the heading is obtained in equally good yield.

55

example 1

Methyl 3- (4-imidazolylmethylene) -dithiocarbazate 60 17.78 g imidazole-4-carboxaldehyde (Pyman, J. Chem. Soc. 1916, p. 186) are dissolved in 200 ml warm ethanol. A warm solution of 24.4 g methyldithiocarbazinate (Audrieth et al., J. Org. Chem. Vol. 19, p. 733 (1954) in 50 ml ethanol is added, whereupon a precipitate forms immediately. 65 The mixture becomes approx The mixture is heated for 10 minutes with stirring, then it is cooled to 0 ° C. and the precipitate formed from yellow crystals of mp = 259 to 261 ° C. is obtained.

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12

Example 2

Methyl 3- (2-phenyl-4-imidazolylmethylene) dithiocarbazate

35 g2-phenyl-4-imidazolecarboxadehyde are taken up in 250 ml of warm ethanol and a solution of 22.8 g of methyldithiocarbazinate in 40 ml of warm ethanol is added, and the procedure is continued as described in Example 1. The desired product of F. = 166 to 170 ° C is obtained.

Example 3

3 - [(5-Methyl-2-phenyl-4-imidazolyl) methylene] dithiocarbazic acid methyl ester

60 g of 5-methyl-2-phenyl-4-imidazole carboxaldehyde and 36.8 g of methyl dithiocarbazinate are reacted as described in Example 1 and give the desired product of mp = 180 to 185 ° C.

Example 4

3 - [(5-Ethyl-2-phenyl-4-imidazolyl) methylene] dithiocarbazic acid methyl ester

According to the procedure described in Example 3, 5-ethyl-2-phenyl-4-imidazolecarboxaldehyde is converted to 3 - [(5-ethyl-2-phenyl-4-imidazolyl) methylene] dithiocarbazinic acid methyl ester.

Example 5

Methyl 3- (2-n-propyl-4-imidazolylmethylene) dithiocarbazate

60 g of 2-n-propyl-4-imidazole carboxaldehyde and 53.7 g of methyl dithiocarbazinate are reacted with one another, as described in Example 1, and give the desired product of melting point = 95 to 104 ° C.

Example 6

Methyl 3- (2-methyl-4-imidazolylmethylene) dithiocarbazate

33 g of 2-methyl-4-imidazole carboxaldehyde and 40.3 g of methyl dithiocarbazinate are, as described in Example 1, reacted with each other and give the desired product of mp = 274 to 279 ° C.

Example 7

Methyl 3- (5-methyl-4-imidazolylmethylene) dithiocarbazate

16 g of 5-methyl-4-imidazole carboxaldehyde and 19.5 g of methyl dithiocarbazinate are reacted with one another, as described in Example 1, and give the desired product of F. = 180 ° C. (decomp.), Which solidifies again, and then melts at 230 to 260 ° C.

Example 8

3 [(2,5-Dimethyl-4-imidazolyI) -methyl] -dithiocarbazinic acid methyl ester

20 g of 2,5-dimethyl-4-imidazole carboxaldehyde and 20.8 g of methyl dithiocarbazinate are reacted with one another, as described in Example 1, and give the desired product of mp = 279 to 281 ° C.

Example 9

3 - [[2- (Methoxymethyl) -4-imidazolyl] methylene | -dithiocarbazic acid methyl ester

40 g of 2- (methoxymethyl) -4-imidazolecarboxaldehyde and 38.4 g of methyldithiocarbazinate are reacted with one another as described in Example 1 and give the desired product of melting point = 150 to 154 ° C.

Example 10

3- [5-methyl-2-n-propyl-4-imidazolyl) methylene] dithio-carbazinic acid methyl ester

20 g of 5-methyl-2-n-propyl-4-imidazolecarboxaldehyde and 17.7 g of methyldithiocarbazinate are reacted with one another, as described in Example 1, and give the desired product of melting point = 175 to 179 ° C.

Example 11

io The procedure described in Example 10 is repeated using 2-benzyl-5-n-propyl-4-imidazolecarboxaldehyde

Example 12

's 3- [2,5-Dimethyl-4-imidazoIyI) -methyIen] -carbazinsäure-ethyl ester

6.2 g of 2,5-dimethyl-4-imidazole carboxaldehyde and 6.24 g of ethyl carbazate are reacted with one another as described in Example 1 and give the desired product of F.

20 = 207.5 to 210 ° C (solidifies again and then melts at 248 to 252 ° C).

Example 13

3- (2-n-Propyl-4-imidazolylmethylene) -carbazinsäureethyl-

25 esters

7.8 g of 2-n-propyl-4-imidazolecarboxaldehyde and 6.24 g of ethyl carbazate are reacted with one another, as described in Example 1, and give the desired product, mp = 180 to 182 ° C.

30th

Example 14

3- (2-Phenyl-4-imidazolylmethylene) carbazinate

A mixture of 8.16 g of 2-phenyl-4-imidazole carboxal

35 dehyde and 5.52 g of ethyl carbazate is reacted as described in Example 1 and gives the desired product of mp = 196 to 200 ° C.

Example 15

40 3 - [(5-Methyl-2-phenyl-4-imidazolyl) methylene] carbacid, ethyl ester

A mixture of 10.25 g of 5-methyl-2-phenyl-4-imidazole-carboxaldehyde and 5.72 g of ethyl carbazate in 30 ml of ethanol, which contains a drop of acetic acid, is used for 30 minutes

45 boiling warmed. The mixture is cooled to 0 ° C and concentrated on a steam bath under an air stream. After adding 50 ml of carbon tetrachloride, the mixture is cooled to 0 ° C. overnight. The solid formed, which is the desired product, melts at 209 to 211 ° C.

50

Example 16

Ethyl 3 - [(2-o-propoxyphenyl-4-imidazolyl) methylene] carbazate

55 4.3 g2-o-propoxyphenyl-4-imidazolecarboxaldehyde and 1.98 g of ethyl carbazate are reacted with one another, as described in Example 1, and give the desired product, mp = 129 to 132 ° C.

60

Example 17

3 [(2-Benzyl-4-imidazolyl) methylene] carbazinate

37.2 g of 2-benzyl-4-imidazole carboxaldehyde in 200 ml

20.8 g of ethyl carbazate and a few drops of concentrated acetic acid are added to 65 ethanol. The mixture is treated further, as described in Example 1, and gives the desired product of mp = 184 to 185 ° C.

13

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Example 18

Ethyl 3- (2-tert-butyl-4-imidazolylmethylene) carbazate

7.6 g of 2-tert-butyl-4-imidazole carboxaldehyde and 5.2 g of ethyl carbazate in 100 ml of ethanol are reacted with one another, as described in Example 1, and give the desired product of melting point = 194 to 197 ° C.

Example 19

3- (2-n-Butyl-4-imidazolylmethylene) carbazinate

The procedure described in Example 18 is repeated using an equimolar amount of 2-n-butyl-4-imidazolecarboxaldehyde instead of 2-tert-butyl-4-imidazolecarboxaldehyde. In this way, the compound mentioned in the heading is obtained in equally good yield.

Example 20

3- (2-Methyl-4-imidazolylmethylene) carbazinate

A solution of 16.68 g of ethyl carbazate in 50 ml of warm ethanol is added to a solution of 16.50 g of 2-methyl-4-imidazolecarboxaldehyde in 100 ml of warm ethanol, which contains 2 drops of acetic acid. The process is then continued as described in Example 1, whereby the desired product of F. = 210.5 to 211.5 ° C. is obtained.

Example 21

3- (5-Methyl-4-imidazoylmethylene) carbazinate

7.0 g of 5-methyl-4-imidazolecarboxaldehyde and 7.3 g of ethyl carbazate are reacted with one another, as described in Example 1, and give the desired product of mp = 195 to 203 ° C.

Example 22

Ethyl 3- [2- (methoxymethyl) -4-imidazolyl] methylene carbazate

19.60 g of 2- (methoxymethyl) -4-imidazolecarboxaldehyde and 16.02 g of ethyl carbazate are reacted with one another, as described in Example 1, and give the desired product of mp = 186 to 190 ° C.

Example 23

3 [(2-Benzyl-5-methyl-4-imidazolyl) methylene] carbacidic acid ethyl ester

4.08 g of 2-benzyl-5-methyl-4-imidazole carboxaldehyde and 2.29 g of ethyl carbazate are reacted with one another, as described in Example 1, and give the desired product of melting point = 190 to 191.5 ° C.

Example 24

3 - [(2-tert-Butyl-5-methyl-4-imidazolyl) methylene] ethyl carbazate

6.17 g of 2-tert-butyl-5-methyl-4-imidazole carboxaldehyde and 4.20 g of ethyl carbazate are reacted with one another, as described in Example 1, and give the desired product of mp = 226 to 228.5 ° C.

Example 25

3 - [(2-Isobutyl-5-iso-propyl-4-imidazolyl) methylene] ethyl carbazate

According to the procedure described in Example 24, 2-isobutyl-5-isopropyl-4-imidazole carboxaldehyde is converted into the compound mentioned in the title in the same yield.

Example 26

3 - [(5-Methyl-2-n-propyl-4-imidazolyl) methylene] carbazinic acid ethyl ester

12 g of 5-methyl-2-n-propyl-4-imidazoicarboxaldehyde and 9.06 g of ethyl carbazate are reacted with one another, as described in Example 1, and give the desired product of mp = 184 to 188 ° C.

Example 27 Imidazo [1,5-d] -as-triazine-4 (3 H) -thione A suspension of 164.5 g of methyl 3- (4-imidazolylmethylene) dithiocarbazate in 1.21 diphenyl ether is stirred at 175 ° C. warmed until the methyl mercaptan development subsides (20 minutes). The precipitate formed on cooling to room temperature is filtered off and washed with petroleum ether and then with acetone. Then it is slurried in 1.21 boiling methanol and filtered off under heat, whereby the desired product of F. = 271 to 273 ° C is obtained.

Example 28

8-Methyl-imidazo [1,5-d] -as-triazin-4 (3 H) -thione A suspension of 14.39 g of methyl 3- (5-methyl-4-imidazolylmethylene) -dithiocarbazate in 100 ml of diphenyl ether treated as described in Example 27 and gives the product as yellow crystals of mp = 262 to 268 ° C.

Example 29

6-phenyl-imidazo [1,5-d] -as-triazin-4 (3H) -thione A suspension of 7.05 g of methyl 3- (2-phenyl-4-imidazolylmethylene) -dithiocarbazinate in 100 ml of diphenyl ether is made as treated as described in Example 27 and gives the desired product of F. = 210 ° C.

Example 30

6-n-Propyl-imidazo [l, 5-d] -as-triazin-4 (3H) -thione 102.2 g of 3- (2-n-propyl-4-imidazolylmethylene) -dithiocarbazic acid methyl ester in 500 ml of diphenyl ether , as described in Example 27, reacted with one another and give the desired product as a white solid of mp = 201.5 to 203.5 ° C.

Example 31

8-Methyl-6-phenyl-imidazo [1,5-d] -as-triazine-4 (3 H) -thione 73.4 g of 3 - [(5-methyl-2-phenyl-4-imidazolyl) methylene ] -di-Thiocarbazinsäuremethylester in 500 ml of diphenyl ether are further processed as described in Example 27 and give the desired product as purple crystals of mp = 237.5 to 239 ° C.

Example 32

8-Ethyl-6-phenyl-imidazo [1,5-d] -as-triazine-4 (3H) -thione The procedure described in Example 31 is carried out using 3 - [(5-ethyl-2-phenyl-4 -imidazolyl) -methylene] -dithiocarbazic acid methyl ester repeated.

Example 33

6,8-Dimethyl-imidazo [1,5-d] -as-triazine-4 (3H) -thione 30.26 g of 3 - [(2,5-dimethyl-4-imidazolyl) -methylene] -dithio-carbazinate of methyl ester in 125 ml of diphenyl ether are treated as described in Example 27, whereby the desired product is obtained as a solid of mp = 287.5 to 290 ° C.

Example 34

6-benzyl-8-methyl-imidazo [1,5-d] -as-triazin-4 (3H) -thione 2.04 g of 2-benzyl-5-methyl-4-imidazole carboxaldehyde see

10th

15

20th

25th

30th

35

40

45

50

55

60

65

636 615

14

are dissolved in 20 ml of ethanol containing 2 drops of acetic acid. After adding 1.34 g of methyldithiocarbazinate, the mixture is heated to boiling for 30 minutes and then cooled to 0 ° C. overnight. The mixture is evaporated to give methyl 3- (2-benzyl-5-methylimidazoyl) -methylene] -dithiocarbazate as an oil.

3.40 g of this ester are dissolved in 30 ml of diphenyl ether and heated to 194 to 207 ° C. for 9 minutes. After cooling to room temperature, it is diluted with hexane. The solid formed is recrystallized from 150 m) of methanol using animal charcoal and gives the desired product of mp = 207 to 209.5 ° C.

Example 35

6-Benzyl-8-n-propyl-imidazo [1,5-d] -as-triazine-4 (3H) -thione

The procedure described in Example 34 is repeated using an equimolar amount of 3 - [(2-benzyl-5-n-propylimidazolyl) methylene] dithiocarbazate. In this way, the compound mentioned in the heading is obtained in equally good yield.

Example 36

8-methyl-6-n-propyl-imidazo [1,5-d] -as-triazine-4 (3H) -thione

32.12 g of 3 - [(5-methyl-2-n-propyl-4-imidazolyl) -methylene] -dithiocarbazic acid methyl ester in 200 ml of diphenyl ether are treated as described in Example 27 and give the desired product of mp = 183 up to 186 ° C.

Example 37

6-methyl-imidazo [1,5-d] -as-triazine-4 (3H) -thione

53.9 g of methyl 3- (2-methyl-4-imidazolylmethyl) dithiocarbacinate in 200 ml of diphenyl ether are treated as described in Example 27 and give the desired product, mp = 280.5 to 284 ° C .

Example 38

6-methoxymethyl-imidazo [1,5-d] -as-triazine-4 (3 H) -thione

62.4 g of methyl 3- [2- (methoxymethyl) -4-imidazolyl] -methylendit-hiocarbazate in 250 ml of diphenyl ether are treated as described in Example 27 and give the desired product of melting point = 219.5 to 223 ° C.

Example 39

6-o-Propoxyphenyl-imidazo [1,5-d] -as-triazin-4 (3H) -one

10.5 g of 3 - [(2-o-propoxyphenyl-4-imidazolyl) -methylene] -car-bazinsäureethylester in 100 ml of diphenyl ether are heated on an oil bath with stirring to 255-265 ° C until the foaming subsides. The mixture is cooled to room temperature and petroleum ether is added to form a precipitate which is recrystallized from methanol using animal charcoal. This gives the desired compound as a light yellow solid with a melting point of 197 to 200 ° C.

Example 40

6-benzyl-imidazo [1,5-d] -as-triazin-4 (3 H) -one

7.0 g of ethyl 3 - [(2-benzyl-4-imidazolyl) -methylene] -carbazate in 50 ml of diphenyl ether is treated as in Example 39, giving the desired product in the form of white crystals of melting point = 215 to 217 ° C. is obtained.

Example 41

6-phenyl-imidazo [1,5-d] -as-triazin-4 (3H) -one

7.76 g of ethyl 3- (2-phenyl-4-imidazolylmethylene) carbazate in 50 ml of diphenyl ether are treated as described in Example 39, whereby the desired product of mp = 245 to 248 ° C. is obtained.

Example 42

8-methyl-6-phenyl-imidazole [1,5-d] -as-triazin-4 (3H) -one 8.33 g of 3 - [(5-methyl-2-phenyl-4-imidazolyl) -methylene] -car-bazinsäureethylester in 60 ml of diphenyl ether are heated in an oil bath at 215 to 230 ° C for 20 minutes. The reaction mixture is diluted to 400 ml with petroleum ether, and the precipitate formed is filtered off and recrystallized from 350 ml of benzene. The desired product of F. = 182 to 184.5 ° C is obtained.

10th

Example 43

6-n-Propyl-imidazo [l, 5-d] -as-triazin-4 (3 H) -one 8.75 g of 3- (2-n-propyl-4-imidazolylmethylene) carbazinate in 50 ml Diphenyl ethers are treated as described in Example 39 ls and give the desired product with a melting point of 159 to 162.5 ° C.

Example 44

6,8-dimethyl-imidazo [1,5-d] -as-triazin-4 (3H) -on 20 7.37 g of 3 - [(2,5-dimethyl-4-imidazolyl) -methylene] -carbazine- Acid ethyl ester in 50 ml of diphenyl ether are treated as described in Example 39 and give the desired product of mp = 263 to 263.5 ° C.

25 Example 45.

6-tert-Butyl-imidazo [1,5-d] -as-triazin-4 (3H) -one 6.15 g of 3- (2-tert-butyl-4-imidazolylmethylene) carbazinate in 40 ml of diphenyl ether are treated as described in Example 39 and give the desired product of F. = 186 to 188 ° C.

Example 46

6-n-Butyl-imidazo [1,5-d] -as-triazin-4 (3 H) -one Following the procedure described in Example 45, 35 is ethyl 3- (2-n-butyl-4-imidazolylmethylene) carbazate transferred into the connection mentioned in the heading.

Example 47

6-methyl-imidazo [1,5-d] -as-triazin-4 (3H) -one 40 27.2 g of 3- (2-methyl-4-imidazolylmethylene) carbazinate in 200 ml of diphenyl ether, as in Example 39 described, treated and give the desired product of F. = 303 to 305.5 ° C.

45 Example 48

8-Methyl-imidazo [l, 5-d] -as-triazin-4 (3H) -one 10.26 g of 3- (5-methyl-4-imidazolylmethylene) carbazinate in 100 ml of diphenyl ether, as in Example 39 described, treated and give the desired proso product of F. = 276 to 282 ° C.

Example 49

6-benzyl-8-methyl-imidazo [1,5-d] -as-triazin-4 (3H) -one 4.89 g of 3 - [(2-benzyl-5-methyl-4-imidazolyl) methylene] -car-55 ethyl bazate in 50 ml of diphenyl ether are treated as described in Example 39 and give the desired product of mp = 244 to 247 ° C.

Example 50

60 6-tert-butyl-8-methyl-imidazo [1,5-d] -as-triazin-4 (3H) -one 5.11 g 3 - [(2-tert-butyl-5-methyl-4- imidazolyl) -methylene] -carbazinsäureethylester in 50 ml of diphenyl ether are treated as described in Example 39, and give the desired product of mp = 198 to 20 ° C.

65

Example 51

6-isobutyl-8-isopropyl-imidazo [1,5-d] -as-triazin-4 (3H) -one The procedure described in Example 50 is described in

15

636615

Repeated use of 3 - [(2-isobutyl-5-isopropyl-4-imidazolyI) -methylene] -carbazinate.

Example 52

8-Methyl-6-n-propyl-imidazo [1,5-d] -as-triazin-4 (3H) -one 14.50 g of 3 - [(5-methyl-2-n-propyl-4-imidazolyl ) -Methylene] -carbazinsäureethylester in 100 ml of diphenyl ether are treated as described in Example 39, and give the desired product of mp = 129.5 to 131.5 ° C.

Example 53

6-Methoxymethyl-imidazo [1,5-d] -as-triazin-4 (3H) -one 25.9 g of ethyl 3- [2- (methoxymethyl) -4-imidazolyl] -methylene-car-bazinate in 125 ml of diphenyl ether are treated as described in Example 39 and give the desired product of F. = 200 to 205 ° C.

Example 54

8-bromo-6-phenyl-imidazo [l, 5-d] -as-triazin-4 (3H) -one 3.0 g 6-phenyl-imidazo [l, 5-d] -as-triazine-4 ( 3H) -on are stirred with 100 ml of chloroform. The mixture is warmed slightly and then a solution of 1 ml of bromine in 10 ml of chloroform is slowly added dropwise. After heating at reflux for 1 hour and cooling to room temperature, the mixture is filtered. The solid is mixed with aqueous NazCCb and chloroform and shaken in a separating funnel. The remaining solid and the organic phase are combined and evaporated on a steam bath. The residue is taken up in methanol and 2-propanol and the mixture is treated twice with animal charcoal. After cooling, the desired product is obtained as a solid of mp = 192 to 194 ° C.

Example 55

8-bromo-6-n-butyl-imidazo [1,5-d] -as-triazin-4 (3 H) -one The procedure described in Example 54 is carried out using an equimolar amount of 6-n-butyl-imi -dazo [l, 5-d] -as-triazin-4 (3H) -one repeated. In this way, the compound mentioned in the heading is obtained in equally good yield.

Example 56

8-chloro-6-phenyl-imidazo [1,5-d] -as-triazin-4 (3H) -one 5.0 g 6-phenyl-imidazo [1,5-d] -as-triazine-4 ( 3H) -one in 100 ml chloroform are heated on a steam bath while chlorine is passed through the mixture. After adding 25 ml of methanol, chlorine is passed through again for 10 to 15 minutes. The mixture is cooled to room temperature and washed in a separating funnel with aqueous Na2CC> 3, aqueous NaHSCb and finally with water. The mixture is evaporated to 75 ml on a steam bath, cooled and filtered. The filtrate is evaporated overnight to give a solid which is dissolved in 30 ml of warm chloroform and filtered off. The filtrate is treated with activated carbon and mixed with 2-propanol, whereby the desired product is obtained as a solid of F. = 201 to 203 ° C.

5

Example 57

8-chloro-6-benzyl-imidazo [1,5-d] -as-triazin-4 (3H) -one

According to the procedure described in Example 56, 6-benzyl-imidazo [1,5-d] -as-triazin-4 (3H) -one is chlorinated to the compound mentioned in the heading above.

Example 58

8-methyl-6-phenyl-imidazo [1,5-d] -as-triazine-4 (3H) -thione

5 g of phosphorus pentasulfide are added to a solution of 4.5 g of 8-methyl-6-phenylimidazo [l, 5-15 d] -as-triazin-4 (3H) -one in 100 ml of pyridine. The reaction mixture is heated to 100 ° C. for 8 hours, filtered off and poured into dilute hydrochloric acid. The precipitate is filtered off, washed with water and dried.

20th

Example 59

8-bromo-6-phenyl-imidazo [1,5-d] -as-triazine-4 (3 H) -thione

The procedure described in Example 58 is repeated using an equimolar amount of 8-bromo-6-phenyl-25 imidazo [1,5-d] -as-triazin-4 (3H) -one.

Example 60

8-chloro-6-phenyl-imidazo [1,5-d] -as-triazin-4 (3 H) -one

By using 5-chloro-2-phenyl-4-imidazolcar-30 boxaldehyde and ethyl carbazate in the procedure described in Example 15, 3 - [(5-chloro-2-phenyl-4-imidazolyl) methylene] - carbazinate, which, as described in Example 70, is converted 35 by heating in diphenyl ether into the compound mentioned in the title.

Manufacture 32

5-methyl-2-m-tolyl-4-imidazole methanol

A mixture of 9.0 g (0.035 M) of ice and trans-4,5-40 dimethyl-2-m-tolyl-2-imidazoline-4,5-diol hydrochloride and 135 ml of 3N hydrochloric acid is placed on a steam bath Stirring heated for 2.5 hours and then stirred at 0 to 5 ° C for 0.75 hours. By filtering off the reaction mixture, 7.4 g (0.031 M) of a white solid are obtained which, when treated with base, give the compound mentioned in the heading of F. = 190 to 192 ° C. (dec.).

Analysis, CiìHmHiO:

see above: C 71.26; H 6.98; N 13.85;

Found: C 70.94; H 7.07; N 13.92.

Further imidazole methanols prepared by the procedure described above are listed in Table 55 III below.

Table III N-ir-CH2OH

ch3

R; F. (° C) Analysis calculated found

C 56.65 C 56.64

° 2N \ / 215-216 (dec.) H 4.75 H 4.73

N-Y N 18.02 N 17.74

636 615

16

Table III (continued)

R:

F.rc)

Analysis calculated found ch3 ch3

-O

CH30 - // v

> 150 (dec.)

• HCl 111-114

205-207

ch3

Cl

"HC1

132-134 (dec.) -H2 0 205-207 (dec.)

HCl

C4H9-CsH.3-

D-

> 170 (dec.)

175-177

188-190 (dec.)

HCl> 120 (decomp.)

Syrup syrup

104-106 (dec.)

115-120 (dec.)

C 71.26 N 6.98 N 13.85

C 66.04 H 6.47 N 12.83

C 59.33 H 4.98 N 12.58

C 59.33 H 5.09 N 10.11

C 70.86 H 6.97 N 13.60

C 65.75 H 6.88 N 12.90

C 59.73 H 5.22 N 12.44

C 59.73 H 5.18 N 9.86

182-183 (dec.)

C 68.00 H 9.34 N 14.42

C 67.73 H 9.55 N 13.87

Manufacturing 33

Preparation of 5-methyl-4-imidazole carboxaldehydes substituted in the 2-position

60

Method A

5-methyl-2-m-tolyl-4-imidazole carboxaldehyde A mixture of 13.0 g (0.064 M) of 5-methyl-2-m-tolyl-4-imidazole methanol, 65 g of activated manganese dioxide and 200 ml of methylene chloride is added for 20 hours Room temperature stirred. The reaction mixture is then filtered off, 65 analysis, C11H9N3O3: and by removing the solvent in vacuo, 9.1 g (0.045 M) of a peach-colored solid substance are obtained.

Method B

5-methyl-2- (p-nitrophenyl) -4-imidazole carboxaldehyde A mixture of 2.9 g (0.012 M) 5-methyl-2- (p-nitro-phenyl) -4-imidazole methanol and 20 ml of 70 percent nitric acid is stirred for 3 hours at 50 ° C and then diluted with water and neutralized with a base. The precipitated yellow solid is filtered off, whereby 2.4 g (0.011 M) of the title compound with a decomposition point of over 270 ° C. are obtained.

Calc .: Found .:

C 57.14; C 56.69;

H 3.92; H 3.96;

18.17; 18.08.

17th

636 615

Method C

Preparation of 2-alkyl (cycloalkyl) -5-methylimidazole-4-carboxaldehydes

A mixture of 0.1 M 2-alkyl (cycloalkyl) -5-methyl-4-imidazole methanol, 0.5 M activated magnesium dioxide and 500 ml chloroform is heated to boiling under reflux for two hours and then overnight (about 15 to 16 hours) at room temperature. The mixture is filtered through a bed of filter aid, the filter

Manufacturing 34

Alpha-methyl-2-phenyl-4-imidazole methanol 15.3 ml of methyl magnesium bromide (2.5 molar in ether) are added dropwise to a solution of 3.0 g (0.017 M) of 2-phenyl-4-imidazole carboxaldehyde in 45 ml of dry tetrahydrofuran (dried over a molecular sieve), the temperature of the reaction mixture being accompanied by evaporation to dryness, and the residue being recrystallized from the appropriate solvent.

A series of 5-methyl-4-imidazole-carboxaldehydes substituted in the 2-position is prepared by one of the abovementioned methods. The compounds, the method of their preparation, their melting points and analysis results are summarized in Table IV below.

found

N 14.28

C 66.52 H 5.86 N 13.08

C 59.30 H 4.17 N 12.61

C 71.61 H 6.37 N 13.87

C 76.15 H 5.25 N 11.81

C 64.85 H 7.96 N 17.04

C 65.72 H 9.15 N 13.64

C 69.06 H 8.44 N 14.43

external cooling is kept at 25 ° C. The mixture is stirred for 2 hours and then a large volume of water is added by dropwise addition. The mixture is extracted three times with 75 ml of ether, and partial evaporation of the ethereal extract gives a white precipitate, the crystalline alcohol of mp = 197 to 198 ° C.

Table IV

H

l2 \

N-

-CHO

CH-

Method * F. (° C)

Analysis calculated

C-iHo

G.H.5

D> O O

A

A

142-194 (dec.) 161-163 (dec.) 237-239 (dec.) 140-143 (dec.) 197-199 (dec.) 83-84 syrup 104-109

114-130

159-162

N 13.99

C 66.65 H 5.89 N 12.95

C 59.88 H 4.11 N 12.70

C 71.98 H 6.04 N 13.99

C 76.25 H 5.12 N 11.86

C 65.03 H 8.49 N 16.85

C 65.00 H 9.42 N 13.79

C 68.72 H 8.39 N 14.57

The preferred solvent is chloroform, but p-dioxane and tert-butanol are also used.

636 615

18th

Analysis, C11H12N2O:

Calc .: C 70.19; H 6.43; N 14.88;

Found: C 70.10; H 6.68; N 14.90.

Manufacture 35

alpha, 5-Dimethyl-2-phenyl-4-imidazole-methanol Alpha, 5-dimethyl-2-phenyl-4-imidazole-methanol is made from 37.0 g (0.199 M) of 5-methyl-2-phenyl-4-imidazole carboxaldehyde obtained by the method described in Preparation 34. The product is obtained as a white crystalline solid of mp = 189 to 190 ° C in an amount of 38.4 g (95.5%).

Manufacturing 36

Production of methyl-2-phenyl-4-imidazolyl-ketone 5 ml Jones reagent (a solution of 10.3 g chromium trioxide in a mixture of 8.7 ml sulfuric acid and 30 ml water) are at 0 to 5 ° C within a Hour to a solution of 3.0 g (0.016 M) of methyl 2-phenyl-4-imidazole-methanol in 25 ml of acetone. The temperature is allowed to rise to 20 ° C in 30 minutes, after which 150 ml of water are added. The mixture is stirred for 1 hour and the precipitated solid is filtered off. It is stirred with 15 ml of 2N hydrochloric acid for 5 minutes and then neutralized with 10% sodium hydroxide. The aqueous mixture is extracted three times with 75 ml of methylene chloride. By removing the methylene chloride, the ketone is obtained as a white crystalline solid of mp = 158 to 158.5 ° C. in an amount of 1.73 g.

Analysis, C11H12N2O:

Calc .: C 70.95; H 5.41; N 15.04;

Found: C 70.34; H 5.52; N 15.08.

Manufacture 37

Preparation of methyl-5-methyl-2-phenyI-4-imidazolyI-ketone

Following the method of Preparation 36, methyl 5-methyl-2-phenyl-4-imidazolyl ketone is prepared from 12.0 g (0.059 M) of alpha, 5-dimethyl-2-phenyl-4-imidazole methanol. The product is obtained as a pale yellow crystalline solid of mp = 188 to 190 ° C in an amount of 6.88 g (58.3%).

Analysis, C12H12N2O:

Calc .: C 71.98; H 6.04; N 13.99;

Found: C 71.30; H 6.29; N 13.40.

Manufacturing 38

Preparation of 2-phenyl-5-imidazole carboxaldehyde dimethylacetal

A solution of 6.10 g (0.035 M) of 2-phenyl-5-imidazolcar-boxaldehyde in 200 ml of methanol is cooled in an ice bath and then saturated with hydrogen chloride. The reaction mixture is stirred overnight (about 15 to 16 hours) and slowly added to 200 ml of cold 6N sodium hydroxide. The solution is neutralized with concentrated hydrochloric acid and the precipitated substance is filtered off. 7.56 g (0.035 M) are obtained. By recrystallization from chloroform, white needles of F. = 158 to 160 ° C are obtained.

Analysis, C12H14N2O2:

Calculated: C 66.03; H 6.48; N 12.83; Found: C 65.38; H 7.01; N 12.63.

Manufacturing 39

Preparation of 4-iodo-2-phenyl-5-imidazolecarboxalodehyd-dimethylacetal and 4-iodo-2-phenyl-5-imidazolecarbox-5xaldehyde

A solution of 10.25 g (0.0404 M) iodine in 200 ml of methanol is stirred with a solution of 7.56 g (0.035 M) of 2-phenyl-5-imidazolecarboxaldehyde dimethyl acetal in 200 ml of methanol, 20 ml of water and 13 ml of 6N sodium 10 umhydroxid added. The reaction mixture is stirred for 5 hours and then concentrated in vacuo to a volume of about 75 ml. After adding 200 ml of water, the precipitated 4-iodo-2-phenyl-5-imidazolcarboxaldehyde-dimethylacetal is filtered off. 2.82 g (0.0082 M) of substance with a melting point of 144 to 148.5 ° C. (dec.) Are obtained.

The aqueous filtrate is acidified with concentrated hydrochloric acid and the precipitated 4-iodo-2-phenyl-5-imidazole-carboxaldehyde is filtered off. 5.51 g (0.018 M) of substance with a melting point of 208 to 210 ° C. (dec.) Are obtained. 20 The dimethyl acetal is recrystallized from methylcyclohexane, whereby white crystals of mp = 152 to 153.5 ° C are obtained.

25 Analysis, C12H13N2OI:

Calculated: C 41.88; H 3.82; N 8.14 Found: C 41.82; H 4.19; N 8.34.

30th

The aldehyde is recrystallized from ethyl acetate, whereby a white solid of mp = 211.5 to 212.5 ° C. is obtained.

35

Analysis, CioH7N: OI:

Calculated: C 40.29; H 2.37; N 9.39;

Found: C 40.19; H 2.37; N 9.34.

Example 61

Method for the preparation of 3 - [(2-substituted-5-methyl-4-imidazolyl) -methylene] carbazinate 45 A. 3 - [(5-methyl-2-m-tolyl-4-imidazolyl) -methylene] -car -bonic acid methyl ester

A mixture of 6.9 g (0.034 M) of 5-methyl-2-m-tolyl-4-imidazole carboxaldehyde, 3.1 g (0.034 M) of methyl carbazate, 70 ml of methylene chloride and 1 drop of acetic acid is boiled under reflux for 15 hours warmed up. By filtering off the precipitated white solid, 7.1 g (0.026 mol) of substance with a melting point of 162 to 164 ° C. are obtained.

Several 2-aryl analogs of the above compound are prepared by the method described above. These compounds, their melting points and analytical values are compiled in Table V.

B. Preparation of 3 - [(2-alkyl- or -cycloalkyl-5-methyl-4-imidazolyl) -methylene] -carbazinate 60 A mixture of 0.1 M 2-alkyl (cycloalkyl) -5-methyl-imidazole- 4-carboxaldehyde, 0.1 M methyl carbazate, 60 ml of toluene and 0.5 ml of acetic acid are heated to boiling under reflux for 2 hours. The reaction mixture is cooled and the solids are filtered off and recrystallized from the corresponding solvent.

The 2-alkyl and cycloalkyl compounds prepared by the procedure described above are summarized in Table V.

19th

Table V

636615

R2C

/

; N-

-CH = N-NH-C02CH3

F. (° C)

Analysis calculated found

° 2N_ <0 "

CHg - l ^ -

CII30-O-

C1 -f \ ~

Or ch3

CiHi

CsHi o

o o

I-Q

CH3- 264-265 (dec.)

CHa- 226-227 (dec.)

CH3- 176-178 (dec.)

CH3-234-235 (dec.)

CH3- 160-162 (dec.)

CH3-> 170 (dec.)

CH3- 189.5-190.5 (dec.)

CHj- 164-165 (dec.)

CH3- 184-186 (dec.)

CHj- 196-197 (dec.)

CH3- 193-194 (dec.)

C 51.49 H 4.32 N 23.09

C 58.32 H 5.59 N 19.43

C 53.34 H 4.48 N 19.14

H20

Cl

147-148

C 55.44 H 7.61 N 23.52

C 58.62 H 8.33 N 21.04

C 54.04 H 6.35 N 25.21

C 59.07 H 7.63 N 21.20

C 43.5 H 3.63 N 16.9

C 50.96 H 4.33 N 23.21

C 58.01 H 5.60 N 19.23

C 52.95 H 4.42 N 18.99

C 55.09 H 7.71 N 23.54

C 58.34 H 7.78 N 20.83

C 54.25 H 6.49 N 25.33

C 58.62 H 7.61 N 20.80

C 45.04 H 3.05 N 16.09

Example 62

Preparation of methyl 3- [1- (5-iodo-2-phenyl-4-imidazolyl) ethyl] -carbazate

A solution of 5.21 g (0.017 M) of 4-iodo-2-phenyl-5-imidazole carboxaldehyde in a mixture of 50 ml of methanol, 250 ml of toluene, 1 ml of acetic acid and 1.73 g (0.019 M) of methyl carbazate Heated to reflux for 24.5 hours. The solution is then heated for a further hour, with 100 ml of solvent distilling off. The

60 remaining solvents are removed in vacuo. The solids are extracted with 300 ml of methylene chloride and the extract is washed three times with 200 ml of water. At this point the product crystallizes and is obtained by refining (2.16 g 0.0056 M). Evaporation of the filtrate 65 gives a further 3.44 g (0.0093 mol) of product. Recrystallization from methanol / methylene chloride gives white crystals of mp = 145 to 147 ° C (dec.).

636615

20th

Manufacturing 40

Preparation of 3- [5-methyl-2-phenyl-4-imidazolyl) ethyl-lidenj-carbazinate

4.5 g (0.023 M) of methyl 5-methyl-2-phenyl-4-imidazolyl ketone are heated to reflux with 2.4 g (0.023 M) of methyl carbazate in 112 ml of toluene for 5 hours. After removing the toluene, the solid substance is washed three times with 50 ml of water. Then it is recrystallized from methanol, whereby 128 g (20.9%) product of mp = 199-201 ° C are obtained.

Analysis, C14H16N4O2:

Calc .: C 61.75; H 5.92; N 20.57;

Found: C 60.05; H 6.25; N 19.96.

Manufacturing 41

Preparation of methyl 3- [1- (2-phenyl-4-imidazolyl) ethylidene] carbazate

According to the procedure described in preparation 40, the compound mentioned in the heading is prepared from methyl 2-phenyl-4-imidazolyl ketone and methyl carbazate. The product is obtained in a yield of 91% with a melting point of 226.5 to 227 ° C.

Analysis, C13H14N4O2:

Calc .: Found .:

C 60.46; C 60.59;

H 5.46; H 5.60;

N 21.69; N, 21.89.

Mix is obtained 3.9 g (0.016 M) of the compound mentioned in the heading. Recrystallization from o-dichlorobenzene provides partially solvated product with a melting point of 188 to 198 ° C.

By using 3 | [5-methyl-2- (alpha, alpha, alpha-trifluoro-m-toyl) -4-imidazolyl] -methylene) carbazinate in the above-described reaction, 8-methyl-6- (alpha , alpha, alpha-trifluoro-m-tolyI) -imidazo [1,5-d] -as-10 triazin-4 (3H) -one obtained.

Method B

8-methyl-6- (p-nitrophenyl) imidazo [1,5-d] -as-triazine-4 (3H) -one monohydrate 15 2.5 g (0.0082 M) 3 - ([2- (p-Nitrophenyl) -5-methyl-4-imidazolyl] -methylene | -carbazinic acid methyl ester are introduced into 25 ml diphenyl ether at 240 ° C. and left in it for 20 minutes, then stirred in an ice bath for 1 hour Ether diluted and filtered to give 2.2 g (0.008 M) of the title compound The product is purified by Soxhlet extraction with acetone to give a yellow solid of mp = 295 to 297 ° C.

25 Analysis, C12H11N5O4:

Calc .: C 49.83, Found: C 49.69;

H 3.83; H 3.71;

N 24.21; N 23.88.

Example 63

Preparation of 6- (aryl) -8-methyl-imidazo [1,5-d] -as-triazin-4 (3 H) -ones

Method A

8-methyl-6-m-tolyl-imidazo [1,5-d] -as-triazin-4 (3H) -one

A mixture of 5.1 g (0.019 M) of 3 - [(5-methyl-2-m-tolyl-4-imidazolyl) -methylene] -carbazinate and 75 ml of o-dichlorobenzene is slowly heated to boiling under reflux in 45 minutes , Held at reflux for 1.5 hours and then stirred at room temperature overnight (about 15 to 16 hours). By filtering the reaction

30 Method C

Preparation of 6-alkyl (cycloalkyl) -8-methylimidazo [1,5-d] -as-triazin-4 (3 H) -ones

These compounds are prepared by Method A with the exception that the mixture of 35 6-alkyl (cycloalkyl) -5-methyl-imidazole-4-carboxaldehyde-methylcarbazone and o-dichlorobenzene is heated until a boiling point of about 180 ° C. is reached. The solvent is evaporated and the residue is recrystallized from the appropriate solvent.

40 The compounds prepared by methods A, B and C, their melting points and analytical values are summarized in Table VI.

Table VI

Ri R <R4 Method F (° C) Analysis calculated found

CHj- h A 169-171.5 (dec.)

C 60.93 C 60.52

CH3-HA 216-217 (dec.) H 4.72 H 4.80

N 21.86 N 21.70

CHj- H A> 240 (dec.)

21st

Table Vi (continued)

636615

Ri R; R «Method F (° C) Analysis calculated found f \ -

chj- w h a 185-191

ch3

ch3

CQr H A 247-251 (dec.)

CI O H B 245-246 (dec.) H 2.15 H 2.41

H \ ~ y ~ H C 179-181

/ \ C 64.94 C 63.38

H (r-HC 145-147 H 7.78 H 8.10

X 'N 21.15 N 20.41

C 47.00 C 47.72

H 2.15 H 2.41

N 19.93 N 19.57

"O CHj- A 281-281.8

CHa- o- CHa- A 207-212

C 58.23 C 58.16

CHa-C4H9 H C 118-120 H 6.84 H 6.84

N 27.17 N 27.14

C 61.51 C 61.28

H CôHu H C 118-119 H 7.74 H 7.61

N 23.91 N 23.68

pN. C 56.83 C 56.65

H H C 210.5-211.5 H 5.30 H 5.64

^ N 29.46 N 29.43

Example 64

Preparation of 6-phenyl-8-iodo-imidazo [1,5-d] -as-triazin-4 (3H) -one

1.01 g (0.0027 M) of methyl 3- [1- (5-iodo-2-phenyl-4-imidazolyl) alkylidene] carbazate are dissolved in a mixture of 150 ml of o-dichlorobenzene and 15 ml of methanol . The solution is heated to the boiling point and held here for 20 minutes, some of the solvent being distilled off. The reaction mixture is chromatographed on silica gel and eluted with a mixture of hexane and ethyl acetate in a ratio of 2: 1, whereby 0.63 g (0.0019 M) of the title compound are obtained. By recrystallization from ethyl acetate / hexane, the product is obtained as yellow needles with a melting point of 170 to 189 ° C.

Example 65

Preparation of 6- (p-aminophenyl) -8-methyl-imi-dazo [1,5-d] -as-triazin-4 (3 H) -one

This product is obtained by catalytic reduction of 1.3 g (0.0048 M) of 8-methyl-6- (p-nitrophenyl) imidazo [1,5-d] -as-triazine-4 (3H) -one monohydrate 50 ml of dimethylform amide with hydrogen in the presence of 10% palladium-on-carbon as a catalyst and at atmospheric pressure and subsequent removal of the solvent in vacuo

4s obtained (1.0 g, 0.0043 M). Crystallization from dime

thylformamide / water gives a mustard yellow solid with a melting point of 252 to 254 ° C (dec.).

Example 66

50 Preparation of 8-bromo-6- (m-aminophenyl) imidazo [1,5-d] -as-triazin-4 (3 H) -one

A mixture of 2.0 g (0.00595 M) 8-bromo-6- (m-nitro-phenyl) -imidazo [l, 5-d] -as-triazin-4- (3H) -one and 700 mg Catalyst (Ru / C, 5%) is covered with a protective nitrogen layer at 55 and 45 ml of dimethyl-ylformamide are added. Hydrogen is introduced into the flask containing this mixture with vigorous shaking and is absorbed in an amount of 399 ml (0.01785 M). The catalyst is filtered off and washed with dimethylformamide 60. The filtrate is evaporated in vacuo. The product is recrystallized from diethyl ether; F. = 205 ° C (dec.).

Example 67

65 Preparation of 8-bromo-6- (m-dimethylaminophenyl) -imi-dazo [1,5-d] -as-triazin-4 (3 H) -one

1.2 g (0.019 M) sodium cyanoborohydride is stirred with a solution of 8-bromo-6- (m-aminophenyl) -

636615

22

imidazo [l, 5-d] -as-triazin-4 (3H) -one, 5 ml of aqueous formaldehyde (37 percent) in 110 ml of acetonitrile. The reaction mixture is stirred for 15 minutes, after which the pH is adjusted to 7 with acetic acid. The reaction mixture is then stirred for 45 minutes, the pH of the mixture being kept at 7 by adding acetic acid if necessary. The solvent is removed in vacuo and the remaining oil is added to 150 ml of 2N potassium hydroxide. The crystalline product is washed with water and recrystallized from acetone / water; F. = 206 ° C (dec.).

Example 68

Preparation of 6- (m-nitrophenyl) imidazo [1,5-d] -as-triazin-4 (3H) -one

A mixture of 0.4 ml of 90 percent fuming nitric acid (d = 1.5.0.0086 M) and 10 ml of sulfuric acid is slowly at 5 ° C to a solution of 2.12 g (0.01 M) 6-phenyl- imidazo [l, 5-d] -as-triazin-4 (3H) -one added in 50 ml of sulfuric acid. The mixture is stirred overnight (about 15 to 16 hours) at room temperature and then poured onto ice. It is made weakly alkaline, stirred with ethyl acetate and filtered. The isolated solid is recrystallized from aqueous dimethylformamide and gives 0.83 g of a brownish fluffy solid (32%) of mp = 294 to 296 ° C (violent decomposition).

Analysis, CsH3BrN40:

Calc .: Found .:

C 27.80; C 28.99;

H H

1.40; 1.36;

N 25.94; N 26.46;

Br 37.00; Br 35.91.

Example 71

6,8-dibromo-imidazo [l, 5-d] -as-triazin-4- (3H) -one 1.5 ml (0.03 mol) of bromine are added dropwise to a mixture of 1.36 g with thorough stirring (0.01 M) Imidazo [l, 5-10 d] -as-triazin-4 (3H) -one, 2.52 g (0.03 M) sodium bicarbonate and 25 ml water. The mixture is stirred for 4 hours and then filtered. The isolated product is washed thoroughly with water and air dried. The product, (2.78 g, 95%) is recrystallized from toluene / hexane (1: 1) ls, whereby a cream-colored solid of mp = 210 to 212 ° C. is obtained.

Analysis, CsftBnNiO:

20 reports: found:

C 20.44; C 19.16;

H 0.69; H 0.88;

N 19.10; Br 54.39; N 18.80; Br 54.12.

Analysis, C11H7N5O3:

Calc .: Found .:

C C

51.36; 51.28;

2.74; 2.85;

N 27.23; N 27.17.

Example 69

Preparation of 8-bromo-6- (m-nitrophenyl) imidazo [l, 5-d] -as-triazin-4 (3H) -one, compound with dimethylformamide A mixture of 1.87 ml (0.04 mol) 90 percent fuming nitric acid (d = 1.5) and 10 ml sulfuric acid slowly become a solution of 5.82 g (0.02 mol) 8-bromo-6-phenyl-imidazo [5, d] at 5 ° C -as-triazin-4 (3H) -one given in sulfuric acid. The reaction mixture is stirred for 1 hour and poured onto ice, and the precipitated solid is filtered off and dried. 6.58 g (98%) of a dark brown solid of mp = 244 to 246 ° C. (dec.) Are obtained. Recrystallization from aqueous dimethylformamide gives the compound mentioned in the heading, a brownish-colored solid of mp = 246 to 248 ° C (dec.).

Example 72

Preparation of 8-bromomethyl-6-phenyl-imidazo [1,5-d] -25 as-triazin-4 (3H) -one

A mixture of 4.52 g (0.02 M) 8-methyl-6-phenylimi-dazo [l, 5-d] -as-triazin-4 (3H) -one, 3.92 g (0.044 M) N -Bromosuccinimide, 0.24 g (0.002 M) benzoyl peroxide and 200 ml carbon tetrachloride is heated to boiling under reflux for 8 hours. The reaction mixture is cooled and filtered. The isolated product is washed with water and methylene chloride. The product (2.1 g, 34.4%) is recrystallized from nitromethane, whereby pale yellow crystals of mp = 254 to 256 ° C. (dec.) Are obtained.

35

Analysis, CnHsBrNtO:

Calculated: C 47.24; H 2.97; N 18.48; Br 26.20;

Found: C 47.50; H 3.21; N 18.48; Br 25.78.

40

Evaporation of the filtrates and washing liquids and recrystallization of the residue from nitromethane gives a second crop (14.8%) of the product.

45 Example 73

Production of 50 mg tablets

Analysis, CnHóBrNsCb, C3H7NO:

per tablet

50

Calc .: Found .:

C 41.09; C 40.99;

H 3.20; H 3.15;

N 20.54; N 20.34;

Br 19.53; Br 19.50.

Example 70

Preparation of 8-bromo-imidazo [1,5-d] -as-triazin-4 (3H) -one

A solution of 8.0 g (0.05 M) bromine in 10 ml acetic acid is added to a mixture of 6.8 g (0.05 M) imidazo [l, 5-d] -as-triazine-4 (3H) -on and 500 ml of acetic acid. The reaction mixture is stirred for 1 hour, poured into water and extracted with chloroform. The aqueous layer is separated off, made slightly alkaline and extracted with ether. Evaporation of the combined chloroform and ether layers gives 5.0 g (46.3%) of a solid which is recrystallized and the title compound as an off-white solid of mp = 244 to 245 ° C (dec. ) delivers.

0.050 g

0.080 g ss 0.010 g 0.008 g

0.148 g 0.002 g

6-phenyl-8-isopropyl-imi-dazo [1,5-d] -as-triazine-4 (3H) -thione lactose

Corn starch (for mixing) Corn starch (for paste)

10,000 tablets each

500 g

800 g 100 g 75 g

Magnesium stearate (1%)

1475g 15g

60

0.150 g

14.90 g

65

6-phenyl-8-isopropyl-imidazo [1,5-d] -as-triazin-4 (3H) -thione, lactose and corn starch (for mixing) are mixed together. The corn starch for the paste is suspended in 600 ml of water and heated with stirring, whereby a paste forms. This paste is then used to granulate the powder mixture. If necessary, additional water is used. The moist granules are sieved through a No. 8 hand sieve and dried at about 50 ° C. The dry granules

23

636615

is sieved through a No. 16 sieve. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a tablet machine.

Example 74

Preparation of a suspension for oral administration

Component quantity

6-benzyl-8-ethyl-imidazo [1,5-d] -as-triazine

4 (3H) -on 500 mg

Sorbitol solution (70% N.F.) 40 ml

Sodium benzoate 150 mg

Saccharin 10 mg red dye 10 mg

Cherry flavor 50 mg distilled water q.s. ad 100 ml

The sorbitol solution is added to 40 ml of distilled water and the 6-benzyl-8-ethyl-imidazo [1,5-d] -as-triazin-4 (3H) -one is suspended therein. Saccharin, sodium benzoate, flavor and color are added and dissolved. The volume is adjusted to 100 ml with distilled water. Each milliliter of the syrup contains 5 mg 6-benzyl-8-ethyl-imidazo [1,5-d] -as-triazin-4 (3H) -one.

Example 75 Preparation of a parenteral solution In a solution of 700 ml of propylene glycol in 20 ml of water for injections, 20.0 g of 6-isobutyl-8-n-propyl-imidazo [1,5-d] -as-triazine-4 (3H ) -on suspended with stirring. The pH of the suspension is adjusted to 5.5 with hydrochloric acid and the volume is brought to 1000 ml with water for injections. The preparation is sterilized and placed in 5.0 ml ampoules, each containing 2.0 ml of active ingredient (corresponding to 40 mg), and sealed under nitrogen.

light, whereby the seeds or developing organs of several mono- and dicotyledons are each individually mixed with flower potting soil and placed in individual cups on about 2.5 cm of soil. After planting, the beakers are sprayed with the respective aqueous acetone solution which contains the test compound in an amount which is equivalent to approximately 0.07 to 11.2 kg / h of test compound per beaker. The treated cups are then placed on greenhouse benches and, as is customary in greenhouses, are watered and supplied. Tests are terminated three to five weeks after treatment and each cup is examined and evaluated according to the rating system below. The results obtained are shown in Table X.

Rating System

20th

0 - no effect

1 - possible effect

2 - little effect

3 - moderate effect

25 5 - clear damage

6 - herbicidal activity

7 - good herbicidal activity

8 - almost complete killing

9 - total mortality

Difference in growth compared to control * in percent

0

1-10 11-25 26-40 41-60 61-75 76-90 91-99 100

30 4 - abnormal growth; i.e. a clear physiological malformation, but overall an effect that is less than 5 on the evaluation scale

* is based on visual determination of the position, size, strength, chlorosis, growth abnormality and overall appearance of the plant

Example 76 Preparation of Aerosol Sprayers

Out

8-chloro-6-isopropyl-imidazo [1,5-d] -as-triazine-4 (3H) -thione (0.5-5.0 micron) 400 mg

Dichloride fluoromethane 100 ml 45

Sorbitan trioleate 6.9 mg, a suspension is prepared.

The active ingredient and sorbitan trioleate are placed in a beaker and the dichlorodifluoromethane is added at -40 ° C. The mixture is sonicated, i.e. treated with a 50 sonicator manufactured by Branson Sonic Power Co., Danbury, Connecticut, model LS-75.2 minutes with 9 amps power. In order to keep the volume at 100 ml, additional dichloride fluoromethane is optionally added. The mixture is evenly dispersed and has increased stability due to the sonication. Six containers made of corrosion-resistant steel and with a capacity of 19 ml are filled with 15 ml of the cold mixture, after which valves are inserted and fastened. After storage, the 8-chloro-6-isopropyl-imidazo [1,5-d] -as-triazin-4 (3H) -thione remains dispersed when heated, and after occasional shaking, uniform dosages of finely divided active ingredient are obtained.

Herbicidal pre-emergence effect

The herbicidal pre-emergence effect of the compounds according to the invention is illustrated by the following tests

Abbreviations for plants

40 SE - Sesbania (Sesbania exaltata)

LA - White Goosefoot (Chenopodium album)

MU mustard (Brassica kaber)

PI - Foxtail (Amaranthus retroflexus) RW- Ambrosia plant (Ambrosia artemisiifolia) MG- Purple winch (Ipomoea purpurea)

BA - Millet (Echinochloa crusgalli)

Cr - finger grass (Digitarla sanguinalis)

FO - green foxtail (Setaria viridis)

WHERE- wild oats (Avena fatua)

TW - Tea herb (Sida spinosa)

VL - Velvet leaf (Abutilon theophrasti)

JW - common thorn apple (Datura strammonium L.)

Herbicidal post-emergence action The herbicidal post-emergence action of the compounds according to the invention is determined by the following tests, various monocotyledons and dicotyledons being treated with dispersions of the test compounds in aqueous acetone mixtures. In the tests, seed plants are grown in separate cups for about 2 weeks. The test compounds are dispersed in 50/50 acetone / water containing 0.5% of a polyoxyethylene sorbitan monolaurate (Tween (R) 20, surfactant from Atlas Chemical Industries), the test compound being present in an amount approximately 0.07 to 11.2 kg / ha of active ingredient is equivalent if the application to the plant is carried out through a spray nozzle at a pressure of 2.81 kg / cm 2 for a predetermined period of time. After spraying

60

636 615 24

the plants are placed on greenhouse benches and and according to the evaluation system given in Example 122

there, as usual in greenhouses. Rated for two weeks. The results obtained are summarized in Table XI after the treatment, the seed plants are examined.

'Table X

Evaluation of the herbicidal pre-emergence effects of imidazo-as-triazinones and triazinthions on mono- and dicotyledonous weeds

Connection kg / ha SE LA MU PI RW MG TW VL BA CR FO WO JW

8-methyl-6-phenyl-imida-zo [1,2-d] as-triazine-4 (3 H) -thione

8-methyl-imidazo [l, 5-d] -as-11.2 triazin-4 (3H) -thione 4.48

1.12

6-phenyl-imidazo- [1,5-d] -as-11.2 triazin-4 (3H) -thione 4.48

1.12

6-n-Propyl-imidazo [l, 5-d] -as-11.2 triazin-4 (3H) -thione 4.48

1.12 11.2 4.48 1.12 0.56 0.28

3,8-dimethyl-6-phenyl-imida-11.2 zo [l, 5-d] -as-triazin-4 (3H) -one 2.24

1.12 0.56 0.28

8-methyl-6-phenyl-3-n-propyl-11.2 imidazo [1,5-d] -as-triazine 2,24 4 (3H) -one 1.12

8-methyl-3-propynyl-6-phe-11.2 nyl-imidazo [1,5-d] -as-triazin-4 (3H) -one

2.24 1.12 0.56 11.2 2.24 1.12

3-alkyl-8-methyl-6-phenylimidazo [1,5-d] -as-triazin-4 (3H) -one 8-bromomethyl-6-phenyl-imi-11,2 dazo [1,5-d ] -as-triazin-4 (3 H) -one 2.24

1.12

8-bromo-6- (m-nitrophenyl)

-imidazo [1,5-d] -as-triazin-4 (3H) -one

6-phenyl-imidazo (l, 5-d] -as triazine (3H) -one

8-methyl-6-phenyl-imida-zo [1,5-d] -as-triazin-4 (3H) -one

11.2 2.24 1.12 11.2 4.48 1.12 0.56 0.28 11.2 4.48 2.24 1.12 0.56 0.28 0.14 0.07 0.035

6-n-Propyl-imidazo- [1,5-d] -as-11,2 triazin-4 (3H) -one 4.48

1.12 0.56

6,8-Dimethy l-imidazo- [1,5-d] - 11.2 as-triazin-4 (3H) -one 11.2

6-t-Butyl-imidazo- [1,5-d] -as-4,48 triazin-4 (3H) -one 1.12

9 9

8th

6 1

9

9

9 *

9 * 9 *

9 *

3.5; 0

7

6 3 0

7

8 5 3

9 * 9 * 9 *

9 *

9

9

7

2nd

9

9

7

6

7

0

8th

8th

0

3rd

9

9

5

7

3rd

0

0

0

0

0

0

0

0

0 "

9

9

8th

0

9

9

5

7

7

0

9

1

7

0

3rd

0

3rd

6

1

0

0

0

0

0

0

0

0

0

8th

9

0

4th

3rd

0

2nd

6

8th

1

l

2nd

0

0

0

3rd

2nd

3rd

0

0

0

0

0

0

0

0

0

9

9

9

9

9

9

9

9

9

9

9

9

9

8th

5

9

9

9

9

6

9

8th

8th

0

0

2nd

7

6

7

6

8th

3rd

0

0

0

0

6

5

3rd

l

5

0

0

0

0

3rd

0

0

0

9

9

9

9

9

9

8th

9

9

8th

9

5

9

9

9

3rd

7

7

8th

8th

9

0

9

8th

5

0

2nd

0

0

3rd

7

0

8th

7

0

0

0

0

0

3rd

8th

0

5

0

0

0

0

0

0

0

8th

9

0

0

9

2nd

8th

9

9

8th

9

0

0

9

0

3rd

5

3rd

1

9

2nd

0

0

2nd

0

0

1

0

0

3rd

9

9

0

9

9

8th

7

9

9

7

9

3rd

9

9

3rd

3rd

8th

5

0

7

9

0

0

9

0

2nd

7

2nd

0

7

9

0

0

9

0

0

0

0

0

0

7

8th

6

7

9

8th

6

9

9

3rd

9

2nd

0

0

0

2nd

9

5

2nd

3rd

0

0

0

0

0

0

0

0

9

8th

8th

9

9

9

8th

9

9

7

2nd

1

9

0

0

5

5

3rd

8th

9

0

0

0

0

0

0

2nd

0

0

0

9

9

7

9

9

9

7

9

9

6

9

2nd

9

0

0

6

8th

5

7

2nd

8th

0

0

0

0

0

6

0

0

0

9

9

9

9

9

9

9

9

9

7

9

9

9

9

9

9

7

9

9

9

9

8th

9

8th

9

9

6

7

6

7

9

0

6

1

5

2nd

2nd

3rd

1

3rd

1

0

1

1

0

0

1

0

0

1

9

9

9

9

9

9

9

9

9

8th

9

9

9

9

9

9

9

9

9

9

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

8.9 *

8.7 *

8.8 *

9 *

8.9 *

8.6 *

8th*

8.4 *

8.5 *

8.7 *

8.7 *

8.1 *

8.6 *

8.6 *

9 *

7.6 *

6.8 *

3.1 *

4.7 *

5.8 *

7.7 *

7.6 *

6.7 *

7.3 *

8.4 *

4 *

2.8 *

4.5 *

1.3 *

0 *

1.7 *

5 *

4.5 *

2.8 *

3.8 *

4.4 *

0

0 *

0 *

0 *

0 *

0 *

1*

1*

0 *

0 *

0

8th

8th

7

7

7

8th

7

7

8th

6

9

8th

3rd

6

7

6

5

6

5

7

0

0

0

0

0

2nd

2nd

0

0

0

0

0

0

0

0

0

0

7

8th

1

7

5

5

7

6

7

6

9

8th

6

7

8th

6

7

7

8th

6

3rd

3rd

2nd

5

2nd

2nd

2nd

0

3rd

1

2nd

0

2nd

0

0

1

0

0

25th

Table X (continued)

636615

Connection kg / ha

SE

LA

MU

PI

RW

MG

TW

VL

BA

CR

FO

WHERE

JW

8-bromo-6-phenyl imidazo

5.6

8th

9

9

9

9

9

9

9

9

9

9

9

[1,5-d] -as-triazin-4 (3 H) -one

1.12

9

9

9

9

9

9

9

9

9

9

9

9

0.56

9

9

9

9

9

9

9

9

9

9

9

9

0.28

9

9

9

9

5

9

9

9

9

9

9

9

0.14

9

9

9

9

0

8th

8th

9

9

9

9

6

8-chloro-6-phenyl-imidazo-

11.2

9

9

9

9

9

9

9

9

9

9

9

[1,5-d] -as-triazin-4 (3 H) -one

1.12

9

9

9

9

9

9

9

9

9

9

9

0.56

9

9

9

9

9

9

9

9

9

9

9

0.28

9

9

9

9

8th

9

9

9

9

9

9

0.14

9

9

9

8th

0

8th

9

9

9

9

7

8-methyl-imidazo- [1,5-d] -as-

11.2

7

6

7

6

9

2nd

2nd

7

2nd

6

4th

triazin-4 (3H) -one

4.48

2nd

3rd

8th

0

0

0

0

2nd

2nd

2nd

1.12

0

0

0

0

0

0

0

0

0

0

6-t-butyl-8-methyl-imida-

11.2

8th

8th

9

8th

9

9

9

9

9

9

9

zo [1,5-d] -as-triazin-4 (3H) -one

4.48

9

9

9

9

9

9

5

9

9

9

8th

1.12

8th

7

5

6

2nd

2nd

0

6

5

3rd

7

0.56

2nd

2nd

2nd

1

0

0

0

5

3rd

0

5

8-methyl-6-n-propyl-imida-

11.2

9

9

9

9

9

9

9

9

9

9

8th

zo [1,5-d] -as-triazin-4- (3 H) -one

4.48

9

9

9

9

9

9

9

9

9

9

9

1.12

8th

9

9

9

3rd

0

1

8th

9

9

6

0.56

1

5

7

9

0

0

0

7

7

7

5

0.28

0

0

0

0

0

0

0

0

2nd

0

0

8-methyl-6-n-propyl-imida-

11.2

8th

9

9

9

5

2nd

9

7

8th

9

6

zo [1,5-d] -as-triazin-4 (3H) -one

4.46

5

9

9

9

1

8th

9

9

9

9

1.12

0

0

0

2nd

0

0

2nd

6

8th

2nd

0.56

0

0

0

0

0

0

0

0

0

0

8-chloro-6- (p-chlorophenyl) -

11.2

9

9

9

9

9

9

9

9

9

9

9

imidazo [1,5-d] -as-triazine

1.12

9

9

6

0

6

8th

5

8th

6

3rd

8th

4 (3H) -on

0.56

8th

9

5

0

2nd

0

3rd

5

0

0

7

0.28

0

8th

0

0

0

0

0

0

0

0

0

8-bromo-imidazo [1,5-d] -as-tria-

11.2

6

9

9

0

6

8th

8th

4th

7

7

5

zin-4 (3H) ~ on

2.24

0

8th

0

0

0

2nd

0

2nd

0

0

0

6- (p-methoxyphenyl) -8-

11.2

9

9

9

9

9

9

9

9

9

9

9

methylimidazo-t 1,5-d] -as-

2.24

9

8th

9

6

8th

9

8th

9

8th

6

9

triazine-4 (3H) -one

1.12

5

3rd

7

2nd

0

2nd

7

8th

8th

1

8th

0.56

2nd

0

2nd

0

0

0

7

6

5

0

0

3,8-dimethyl-6-phenyl-imida-

11.2

0 *

8th*

9 *

0 *

9 *

5 *

5 *

0 *

7 *

2 *

0 *

zo [1,5-d] -as-triazine-4 (3 H) -

1.12

2nd

6

0

0

3rd

6

0

2nd

2nd

0

5

thion

0.56

0

0

0

0

0

0

0

0

0

0

8-methyl-6- (p-tolyI) -imida-

11.2

9 *

9 *

9 *

9 #

9 *

9 *

9 *

9 *

9 *

9 *

9 *

zo [1,5-d] -as-triazin-4 (3 H) -one

2.24

9

9

9

9

8th

9

9

9

9

9

9

1.12

7

2nd

2nd

0

0

2nd

7

7

7

5

5

0.56

0

0

0

0

0

0

3rd

3rd

3rd

5

0

6-cyclohexyl-8-methyl-imida-

11.2

9

9

9

9

9

9

9

9

9

9

9

zo [1,5-d] -as-triazin-4 (3 H) -one

2.24

9

9

9

9

9

9

9

9

9

9

9

©

1.12

9

7

9

9

8th

9

9

9

9

9

9

0.56

9

3rd

8th

6

2nd

9

9

9

9

9

9

0.28

7

0

5

0

0

0

8th

6

5

8th

9

0.14

3rd

0

0

0

0

0

2nd

2nd

0

3rd

5

6-n-hexy 1-8-methyl-imida-

11.2

9

9

9

9

9

9

9

9

9

8th

7

zo [1,5-d] -as-triazin-4 (3 H) -one

2.24

9

9

9

9

9

9

9

5

5

9

9

1.12

5

5

3rd

9

0

5

5

0

0

3rd

2nd

0.56

3rd

2nd

1

3rd

0

0

2nd

0

0

2nd

0

0.28

0

0

0

0

0

0

0

0

0

2nd

0

8-methyl-6- (m-tolyI) -imida-

11.2

9

9

9

9

9

9

9

9

9

9

9

zo [1,5-d] -as-triazin-4 (3 H) -one

2.24

9

9

9

9

9

9

9

9

9

9

9

1.12

9

9

9

9

9

9

9

9

9

9

9

0.56

9

9

9

9

9

9

9

9

9

9

9

0.28

9

0

9

9

2nd

2nd

9

9

9

9

9

0.14

7

0

5

0

0

0

2nd

3rd

0

3rd

0

8-methyl-6- (o-tolyl) imida

11.2

9

9

7

9

9

8th

8th

7

7

6

8th

zo [1,5-d] -as-triazin-4 (3 H) -one

2.24

0

0

0

0

0

0

0

0

0

3rd

0

1-methyl-6-phenyl-imida-

11.2

1

2nd

0

0

2nd

7

8th

0

8th

0

0

zo [1,5-d] -as-triazin-4 (3H) -one

1.12

2nd

0

2nd

0

0

2nd

0

0

0

2nd

1

636615

26

Table ^ (continued)

Connection kg / ha

SE LA

MU PI

RW

MG

TW

VL

BA

CR

FO

Where

JW

8-iodo-6-phenylimide azo [1,5-d] -1,12

9

9

9

9

9

9

9

9

9 •

9

9

as-triazin-4 (3H) -one

0.56

9

9

9

3rd

9

8th

9

9

8th

9

9

0.28

9

9

9

0

3rd

5

5

5

7

7

7

0.14

3rd

9

7

0

1

0

3rd

3rd

0

8th

8th

: Average of 2 or more repetitions

Table XI

Evaluation of the herbicidal post-emergence effect of imidazo-as-triazinones and -triazinthions in the control of mono- and dicotyledonous weeds

Connection kg / ha

SE

LA

MU

PI

RW

MG

TW

VL

BA

CR

FO

WHERE

JW

8-methyl-6-phenyl-imida-

11.2

9

9

9

9

9

9

9

9

9

9

9

zo [1,5-d] -as-triazine-4 (3 H) -

4.48

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

9 *

8.5 *

thion

2.24

9

9

6

7

6

3rd

3rd

3rd

9

1.12

9 *

9 *

7 *

6 *

9 *

3rd

3rd

3 *

2 *

5 *

1

9

0.56

9 *

8.5 *

5.5 *

6

7 *

1

1

1

1.5 *

4.5 *

0

9

0.28

7.5 *

7.5 *

4 *

4.5 *

4.5 *

1

1

1*

0.5 *

1.5 *

0 *

6

8-methyl-6-phenyl-imida-

11.2

9

9

9

9

9

9

9

9

9

9

9

zo [1,5-d] -as-triazin-4 (3H) -one

4.48

9

9

9

9

9

9

9

9

9

9

9

9 *

2.24

9 *

9 *

8.7 *

9 *

5.7 *

9 *

7.3 *

4.4 *

7 *

5.7 *

9 *

1.12

9

8.7 *

9

9 *

8.7 *

9 *

3.7 *

8th*

3.5 *

3 *

3.2 *

4.2 *

8.3 *

0.56

3rd

6.3 *

9

8.2 *

5.7 *

7.2 *

2.5

7 *

0.5 *

0.5 *

0.5 *

1.7 *

7 *

0.28

2nd

3.3 *

9

7.5 *

1.7 *

4 *

0.5 *

4.5 *

0 *

0 *

0.2 *

1*

2.3 *

0.14

2 *

9 *

0 *

2 *

0 *

3.3 *

0 *

0 *

0 *

0 *

0 *

8-bromo-6-phenyl-imidazo [l, 5-

5.6

9

9

9

9

9

9

9

9

9

9

9

d] -as-triazin-4 (3 H) -one

8-chloro-6-phenyl-imidazo [l, 5-

11.2

9

9

9

9

9

9

9

9

9

9

9

d] -as-triazin-4 (3 H) -one

6-t-butyl-8-methyl-imida-

11.2

8th

9

9

9

5

6

7

5

7

7

7

zol [1,5-d] -as-triazin-4 (3H) -one

4.48

9

9

9

3rd

9

3rd

1

5

5

6

8th

1.12

2nd

8th

8th

2nd

9

5

0

3rd

3rd

3rd

2nd

0.56

1

0

0

0

8th

1

0

2nd

1

2nd

1

8-methyl-6-n-propyl-imida-

11.2

9

9

9

9

9

8th

9

7

5

6

9

zo [1,5-d] -as-triazin-4- (3 H) -one

4.48

9

9

9

9

9

9

9

7

9

9

9

1.12

9

9

9

9

9

5

6

6

7

8th

6

0.56

9

9

9

3rd

9

5

2nd

0

0

3rd

2nd

0.28

0

0

9

0

3rd

0

0

0

2nd

0

8-methyl-6-n-propyl-imida-

11.2

9

9

9

9

8th

9

9

8th

9

9

9

zo [1,5-d] -as-triazine-4 (3H) -

4.48

9

9

9

9

9

5

1

9

9

9

8th

thion

1.12

9

9

9

9

9

5

2nd

6

9

9

6

0.56

9

9

9

0

9

2nd

1

1

1

9

2nd

0.28

5

9

8th

0

1

0

0

0

0

9

1

8-chloro-6- (p-chlorophenyl) -

11.2

9

9

1

9

9

9

9

9

9

9

8th

imidazo [l, 5-d] -as-triazine

2.24

3rd

9

0

7

0

2nd

0

0

2nd

2nd

8th

4 (3H) -on

1.12

3rd

7

0

9

0

0

0

0

0

0

8th

0.56

0

3rd

0

0

0

0

0

0

0

0

7

6- (p-methoxyphenyl) -8-me-

11.2

9

8th

0

5

8th

8th

5

7

5

3rd

7

thyl-imidazo [l, 5-d] -as-triazine

2.24

9

5

8th

2nd

0

0

0

0

0

2nd

0

4 (3H) -on

1.12

0

0

0

0

0

0

8-methyl-6- (p-tolyl) imida

11.2

9

9

9

9

8th

9

6

9

6

9

8th

zo [1,5-d] -as-triazin-4 (3 H) -one

6-cyclohexyl-8-methyl-imida-

11.2

9

9

8th

9

9

7

9

6

8th

7

9

zo [1,5-d] -as-triazin-4 (3 H) -one

2.24

9

0

9

9

3rd

9

7

0

5

6

9

1.12

2nd

0

0

9

0

5

6

0

0

3rd

3rd

0.56

2nd

0

0

9

0

5

0

0

0

2nd

3rd

6-n-hexyl-8-methyl-imida-

11.2

9

9

9

9

9

9

9

9

9

9

zo [1,5-d] -as-triazin-4 (3 H) -one

2.24

9

9

9

9

9

9

9

5

9

9

1.12

5

5

3rd

9

0

5

5

0

3rd

2nd

0.56

3rd

2nd

1

3rd

0

0

2nd

0

2nd

0

27th

Table XI (continued)

636 615

Connection kg / ha

SE

LA

MU

PI

RW

MG

TW

VL

BA

CR

FO

WHERE

JW

8-methyl-6- (m-tolyl) imida

11.2

9

9

9

9

9

9

9

9

9

9

9

zo [1,5-d] -as-triazin-4 (3H) -one

2.24

9

9

9

9

0

3rd

7

5

3rd

6

9

1.12

9

9

9

9

0

3rd

2nd

2nd

0

5

0

0.56

9

9

9

9

0

0

0

0

0

3rd

0

0.28

7

9

3rd

9

0

0

0

0

0

2nd

0

8-methyl-6- (o-tolyl) imida

11.2

3rd

5

9

2nd

2nd

3rd

8th

7

5

5

5

zo [1,5-d] -as-triazin-4 (3H) -one

2.24

2nd

3rd

0

0

0

3rd

0

0

0

5

0

8-iodo-6-phenyl-imidazo [1,5-d] -

• 1.12

9 *

9 *

9 *

9 *

9 *

9 *

7 *

1*

6 *

7 *

9 *

as-triazin-4 (3H) -one

0.56

9 *

9 *

9 *

6 *

9 *

8th*

6 *

4.5 *

5.5 *

5 *

8th*

0.28

9 *

9 *

7 *

3 *

5 *

5.5 *

2.5 *

2.5 *

2.5 *

3.5 *

7 *

0.14

6 *

8th*

4.5 *

1*

3 *

1*

1.5 *

1.5 *

1.5 *

1.5 *

7.5 *

8-bromo-6- (m-aminophenyl) -

2.24

0

9

7

2nd

0

0

0

0

0

0

imidazo [1,5-d] -as-triazine

1.12

0

9

0

0

0

0

0

0

0

0

4 (3H) -on

0.56

0

9

0

0

0

0

0

0

0

0

0.28

0

2nd

0

0

0

0

0

0

0

0

* = Average of 2 or more repetitions

B

Claims (2)

636 615 2 PATENT CLAIMS 1. Pharmaceutically active compounds of the formula: R. R, N R r. (I) 1 "TN (Ia) wherein X is oxygen or sulfur, Ri is hydrogen or an alkyl group having up to 3 carbon atoms and R2 is hydrogen, an alkyl group having up to 4 carbon atoms or a phenyl, benzyl, methoxymethyl or o-propoxyphenyl group, characterized in that a compound of the formula: 15 R. wherein: X is oxygen or sulfur, R 1 is hydrogen, an alkyl radical having 1 to 3 carbon atoms, chlorine, bromine, iodine or a haloalkyl radical having 1 to 3 carbon atoms, r2 is hydrogen, an alkyl radical with 1 to 6 carbon atoms, a cycloalkyl radical with 3 to 6 carbon atoms, a methoxymethyl, benzyl, naphthyl, phenyl or monosubstituted phenyl radical, this substituent being halogen, an alkyl radical with 1 to 4 carbon atoms , an alkoxy group with 1 to 4 carbon atoms, a haloalkyl group with 1 to 3 carbon atoms, an amino, dialkylamino or nitro group, and R4 is hydrogen or an alkyl group with 1 to 3 Carbon atoms. 2. Compounds according to claim 1, characterized in that X is oxygen, Ri is a methyl group, bromine or chlorine, r2 is a cycloalkyl group having 3 to 6 carbon atoms, a phenyl or m-tolyl group and Rt is hydrogen. 3. As compounds according to claim 1 8-methyl-6-phenyl-imidazo- [1,5-d] -as-triazin-4 (3 H) -one, 8-bromo-6-phenyl-imi-dazo- [ 1,5-d] -as-triazin-4 (3H) -one, 8-chloro-6-phenyl-imidazo- [1,5-d] -as-triazin-4 (3H) -one, 6-cyclohexyl -8-methyl-imidazo- [1,5-d] -as-triazine-4 (3H) -one, 8-methyl-6-m-tolyl-imidazo- [l, 5-d] -as-triazine 4 (3H) -one, 6-phenyl-imidazo- [1,5-d] -as-triazine-4 (3H) -one, 8-iodo-6-phenyl-imidazo- [1,5-d] - as-triazin-4 (3H) -one, 8-methyl-6-n-propyl-imidazo- [l, 5-d] -as-triazin-4 (3H) -one and 8-methyl-6-n- propyl-imidazo- [1,5-d] -as-triazine-4 (3 H) -thione. 4. Therapeutic preparation in the form of a dosage unit for inhibiting the enzyme phosphodiesterase in humans and mammals, characterized in that it contains 5 to 500 mg of a compound of the formula: 20 R., NH X CH = N-NH- (Ü-XR (II ) or their tautomers, in which R is a methyl or ethyl group, heated in a non-polar, high-boiling organic solvent until ring closure to a temperature of 175 to 275 ° C. 6. Process for the preparation of compounds of the formula: 30 35 (Ia) in which X is oxygen or sulfur, Ri chlorine or bromine and 40 r2 hydrogen, an alkyl group having up to 4 carbon atoms or a phenyl, benzyl, methoxymethyl or o-propoxyphenyl group, characterized in that a compound of Formula: 45 50 (Ib) r2 x Ni and NH (Ia) Rh treated with chlorine or bromine in an inert solvent at a temperature of 60 to 90 ° C. 55 7. Process for the preparation of compounds of the formula: N wherein X Oxygen or Sch wefel, Ri is hydrogen, chlorine, bromine or an alkyl group with up to 3 carbon atoms and r2 is hydrogen, an alkyl group with up to 4 carbon atoms or a phenyl, benzyl, methoxymethyl or o-propoxyphenyl group, and contains a pharmaceutical carrier. 5. A process for the preparation of compounds of the formula: R, (Ic) 65 wherein R 1 is hydrogen, chlorine, bromine or an alkyl group having up to 3 carbon atoms and r 2 is hydrogen, an alkyl group having up to 4 carbon atoms or a 3 636 615 phenyl, Benzyl, methoxymethyl or o-propoxyphenyl group, characterized in that a compound of the formula: R, (X "N 0 r 1 NH! N (IcÜ in an inert solvent at a temperature of 100 to 150 ° C treated with phosphorus pentasulfide 8. Starting materials for carrying out the process according to claim 5, which have the formula: III, X NH 1 or CH = N-NH-C-0-R (V) X _L (XV) -CII = H-N1I-CSH, in which: R denotes methyl or ethyl, R 1 is hydrogen or an alkyl group having up to 3 carbon atoms and R: hydrogen, an alkyl group having up to 4 carbon atoms or a methoxymethyl, phenyl, benzyl or o- Propoxyphenyl group and its tautomers 9. A process for the preparation of compounds of claim 5 defined formula Ia, characterized in that a 4-imidazole carboxaldehyde of the formula: r,; h r (Illb) 1 -chc where Ri and R? have the meanings given in claim 8, with an alkyl carbazate of the formula H: N-NH-CChR or an alkyl dithiocarbazate of the formula H2N-NH-CS2R, in which R has the meaning given in claim 8, in a lower alkanol as solvent at one temperature condensed from 25 to 75 ° C and the resulting compound of formula II or its tautomers, wherein both X are either oxygen or sulfur, is reacted according to the process of claim 5 to the compound of formula Ia. in which mean: X oxygen or sulfur, Ri is hydrogen, an alkyl group with 1 to 3 carbon atoms, bromine, chlorine, iodine or a haloalkyl group with 5 1 to 3 carbon atoms, R2 is hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a methoxymethyl, benzyl, naphthyl, phenyl or monosubstituted, phenyl group, the substituent being halogen, an alkyl or alkoxy group 1 to 4 carbon atoms, a haloalkyl group with 1 to 3 carbon atoms, an amino, dialkylamino or nitro group, and R4 is hydrogen or an alkyl group with 1 to 3 carbon-15 atoms. Preferred embodiments of the invention are compounds in the formula IX of which is oxygen, R 1 is a methyl group, bromine or chlorine, R 2 is a cycloalkyl group having 3 to 6 carbon atoms, a phenyl or m-tolyl group and 20 R 4 are hydrogen. The next state of the art (technical background) are US-PS No. 2 837 520.3 840 537.4126 444 and 4168964.