NO762170L - - Google Patents

Description

This invention relates to tetrazolo[a]quinazol-5-one

and derivatives thereof and their use in regulating peptic ulcers and allergic reactions.

Tetrazolo[a]quinazol-5-one, the parent compound for a

series of compounds described herein are described by Postovskii et al. , Zhur. Obshchei Khim., 33., 2334-2341 (1963)

[ABOUT. 5_9, 13987a]. Several 4-substituted tetrazolo[a]quinazole-

5-ones are described by Vereshchagina et al., Zhur. Obshchei Khim., 34, 1745-8 (1964) [CA. 61, 8307-8]. But these

the references do not indicate any use of the compounds.

The applicants have investigated the bronchodilator activity of tetrazolo[a]quinazol-5-one (described in the article of

Postovskii and so is the 7-methoxy-8-propoxy derivative

thereof in guinea pigs by the method of Van Arman et al., J.

Pharm. Exptl. Therap., 153, 90-7 (1961) and found that none of the compounds has any such activity.

A series of tetrazolo(1,5-c)quinazolin-5(6H)-ones

which are useful as bronchodialators are described in U.S. Pat. patent document no. 3,838,126, issued on 24 September 1974.

Allergic reactions, the symptoms that come from a mutual impact antigen-antibody, unfold in a number of ways and in different organs and tissues. Among the common allergic disorders are, for example, allergic rhinitis, which is a condition characterized by sneezing,

either certain times of the year or all year round, runny nose,

nasal congestion, with itching and congestion of the eyes ; high fever,

which is an allergic rhinitis resulting from hypersensitivity to pollen from grassy ground; and bronchial asthma,

one of the most debilitating and debilitating of allergic reactions, a disease characterized by hyper-reactivity of the bronchi upon exposure to various immunogens or

non-immunogenic stimuli, resulting in bronchospasm with wheezing, short-lived paroxysms and extensive constriction of the airways. The mechanical obstruction of airflow in the airways is usually reversed by the use of bronchodilators, which provide symptomatic relief. In contrast, antiallergic agents prevent the release of anaphylaxis mediators from tissue stores to preclude the production of bronchoconstriction by the mediators.

Recently, Cox et al., Adv. in Drug Res., 5_,

115 (1970), described the pharmacology of one agent, disodium cromoglycate [1,3-bis(2-carboxy-cromon-5-yloxy)-2-hydroxy-propane, Intal]. This is not a bronchodilator, but the therapeutic effect is mediated by a unique mechanism of action involving inhibition of the release of anaphylaxis mediators and the compound is administered prophylactically. It suffers from a lack of oral efficacy and to achieve optimal results it is administered by inhalation as a solid inhaler. Also, although it is effective against anaphylaxis caused by . immunoglobulin E (IgE), then it is effective against anaphylaxis caused by immunoglobulin G (IgG) only at high doses (60-70% protection at 100 and 300 mg/kg).

Although the aforementioned agents make an outstanding contribution to the treatment of asthma, many of them exert unwanted side effects on cardiac stimulation.

Chronic gastric and duodenal ulcers, collectively known as peptic ulcers, are a common affliction for which a number of treatments have been developed. The treatment depends on the severity of the ulcer and can vary from dietary and medical (drug) treatment to surgery. A number of different medications have been used to treat ulcers. The most recent of these to gain widespread attention is carbenoxolone sodium, the disodium salt of the hemisuccinate of glycyrrhetinic acid. It is indicated to prevent the formation of and accelerate the healing of gastric ulcers in animals, including humans ("Carbenoxolone Sodium: A Symposium", J.M. Robson and F.M. Sullivan, Ed. Buttersworths, London, 1968). But its use entails undesirable aldosterone-like side effects, such as a clear antidiuretic and sodium-conserving activity, and often loss of

potassium, so that continued therapy with this agent often leads to hypertension, muscle1 weakness and finally congestive heart

error.

Carbenoxolone sodium is almost completely absorbed in the stomach and is not effective against duodenal ulcers except when administered as a specially formulated capsule which allows it to be transported to the desired site.

A more effective treatment of peptic ulcers is therefore desirable. It is especially desirable to have one who

will affect ulcers in the duodenum, and also gastric ulcers, without the need for any special composition, and which reduces the aldosterol-like side effects of carbenoxolone to a minimum.

It has now been found that tetrazolo[a]quinazol-5-ones of the formula

where h<y>is of and is selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms, alkanoyloxy having from one to four carbon atoms, benzyloxy or hydroxy, trifluoromethyl, sulfonamido and halogen, and R 1 and R 2 are alkylenedioxy when taken together and are selected from the group consisting of methylenedioxy and ethylenedioxy;

are valuable antiallergenic agents, that is, they are agents which inhibit the release of anaphylaxis mediators in mammals, including humans, and which in this way preclude the production of bronchial contractions with the mediators. They are not bronchodilators. They are, unlike Intal, of practical value against anaphylaxis mediated by both IgG and IgE, via oral, intranasal and intraperitoneal administration, and by inhalation. Moreover, they are effective anti-ulcer agents that do not require any special composition for the treatment of peptic ulcers.

Compounds of the above formula, except those where each of R 1 and R 2 is hydrogen, are novel compounds.

According to one aspect of the invention, a method for the production of a pharmaceutically active compound with the formula where R is alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkanoyloxy with 1-4 carbon atoms has therefore been provided .

with an azide.

According to another aspect of the invention, there is provided a pharmaceutical mixture and methods for its preparation by mixing a compound of the formula

where each of R3 and R4 is independently hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkanoyloxy with 1-4 carbon atoms,, benzoyloxy, hydroxy, trifluoromethyl, sulfonamido or halogen, or R^ and R ^is together -OCH20-or -0-CH2CH2-0-, with pharmaceutically acceptable inert dilution forged 1 , carrier, filler or solvent.

Compounds of the above formula which are of particular interest due to their significant oral activity in PCA-

the test against both igG and IgE, are such where each of R^ and R2

is lower alkoxy with from one to four carbon atoms, and especially those where R 1 and R 2 are placed in the 7 and 8 positions on the molecule.

Compounds of formula I where R 1 and/or R 2 are benzyloxy are intermediates for the preparation of compounds where R 1 and/or R 2 are hydroxy or alkanoyloxy.

The effectiveness of these compounds as anti-ulcer agents is determined by the rat stress test described below. The antiallergenic properties of the compounds according to this invention are assessed by the passive cutaneous anaphylaxis (PCA) test (Ovary, J. Immun., ai, 355, 1958). In the PCA test, normal animals are injected intradermally (i.d)

with antibodies contained in serum obtained from actively sensitized animals. The animals are then challenged intravenously with antigen mixed with a dye such as Evans' blue. The increased capillary permeability caused by the antigen-antibody reaction causes the dye to leak away from the injection site of the antibody. The test animals are then asphyxiated and the intensity of the reaction is determined by measuring the diameter and intensity of the blue staining on the inner surface of the animals' skin.

The compounds of this invention are conveniently prepared by reacting a metal azide, preferably an alkali metal azide, with a suitable 2-chloro-4(3H)-quinazolinone in approximately equimolar amounts. However, in common practice it is preferred to use an excess, usually 5-20% excess, of the meta11-azide to achieve maximum conversion of 2-chloro-4(3H)quinazolinone to the azide.

The reaction is carried out in a suitable solvent, such as aqueous ethanol or aqueous N,N-dimethylformamide, at a temperature of from approx. 50 to approx. 100°C. Higher or lower temperatures do not seem to offer any benefits.

The required 2-chloro-4-(3H)quinazolinones are in turn prepared by a reaction sequence starting with an appropriately substituted o-aminobenzoic acid. The aminobenzoic acid reactant is converted to a ureido derivative by treatment with an alkali metal cyanate (eg, KOCN, NaOQN) followed by cyclization of the ureido derivative under aqueous acid or base conditions, as described in U.S. Pat. Patent Document No. 3,511,836, issued May 12, 1970.

Alternatively, the o-aminobenzoic acid can be reacted with urea

according to the method of Curd et al., J. Chem. Soc. ,

1947, page 777, to provide the same connection. The 2,4-(1H,3H)kinase<q>lindione is then reacted, as described in U.S. Pat. patent document No. 3,511,836, with a halogenation agent1, so

as phosphorus oxychloride or a mixture thereof, to give the 2,4-dichloroquinazoline. The 2,4-dichloro compound is then converted to a 2-chloro-4(3H)-quinazolinone by hydrolysis, in accordance with known methods, with an aqueous alkali metal or alkaline earth metal hydroxide, and preferably with sodium

or potassium hydroxide. The conversion is conveniently carried out by reacting the dichloro compound with sodium or potassium hydroxide in tetrahydrofuran or another reaction-inert solvent.

The necessary o-aminobenzoic acid reactants can, if

those not known compounds are obtained by methods known to those skilled in the industry.

The products according to this invention and the pharmaceutically acceptable cationic salts thereof are useful for regulating (prophylactic and therapeutic treatment) peptic ulcers, and as prophylactic agents inhibiting or preventing the release of anaphylaxis mediators (allergy, immediate hypersensitivity reactions) and the occurrence of allergic symptoms in mammals, and for such applications they can be administered singly or as mixtures with other agents, for example with theophylline or sympathomimetic amines. They may be administered alone, but usually they are administered together with a pharmaceutical carrier selected on the basis of the chosen route of administration and common pharmaceutical practice. They can, for example, be combined with different pharmaceutical accept-

able inert carriers in the form of tablets, capsules, cubes, troches, hard candy, powders, aerosol sprays, aqueous suspensions or solutions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Moreover, the oral pharmaceutical compositions according to this invention can be suitably sweetened and flavored by means of various agents of the type commonly used for this purpose.

The particular carrier selected and the ratio of active ingredient to carrier are determined by consideration of the solubility and chemical nature of the therapeutic compounds, the chosen route of administration, and the need for standard pharmaceutical practice. When, for example, the compounds according to the invention are administered orally in tablet form, inert shaping agents such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate can be used. Various disintegrants, such as starch, alginic acid and certain complex silicates, together with lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, can also be used in the preparation of tablets for oral administration of these compounds. For oral administration in capsule form, lactose and high molecular weight polyethylene glycols are among the preferred materials for use as pharmaceutically acceptable carriers. When aqueous suspensions are to be used for oral administration, the compounds according to the invention can be combined with emulsifying or suspending agents. Diluents, such as ethanol, propylene glycol, glycerol and chloroform and mixtures thereof, can be used, and likewise other materials.

When it comes to parenteral administration and inhalation, solutions or suspensions of these compounds in sesame or peanut oil or aqueous propylene glycol solutions can be used, and also sterile aqueous solutions of the soluble pharmaceutically acceptable salts described herein. These special solutions are particularly suitable for intramuscular and subcutaneous injection, if such administration methods are desired. The aqueous solutions,

including those where the salts are dissolved in pure distilled water, are also useful for intravenous injection provided their pH is properly adjusted beforehand. Such solutions should also, if necessary, be suitably buffered, and the liquid diluent should first be made isotonic with sufficient saline or glucose.

Taking full account of the foregoing factors, it is believed that an effective daily oral or intraperitoneal dose of the compounds according to the present invention to humans of from approx. 10 to approx. 1500 mg per day, with a preferred range of from approx. 10 to approx. 600 mg per day, in single or divided doses, or in approx. 0.2 to approx. 12 mgA<g>body weight, will effectively inhibit or prevent the release of anaphylaxis mediators in humans. These values are illustrative, and there may of course be some cases where it is advantageous to have higher or lower dose ranges. Under careful monitoring, the dose range can be as high as approx. two grams per day.

For intravenous administration or inhalation, the effective daily dose is from approx. 0.05 to approx. 400 mg per day, and preferably from approx. 0.25 to 200 mg per day, or from approx. 0.005 to 4 mg/kg body weight, in single or divided doses.

The compounds can be administered by inhalation when used as prophylactic agents to prevent the release of anaphylaxis mediators. Compositions suitable for inhalation may comprise (1) a solution or suspension of the active ingredient in a liquid medium of the type mentioned above for administration via a nebulizer, (2) a suspension or solution of the active ingredient in a liquid propellant, such as dichlorodifluoromethane or chlorotrifluoroethane, for administration from a pressurized container, or (3) a mixture of the active ingredient and a solid diluent1 (for example, lactose) for administration from a powder inhalation device. Mixtures suitable for inhalation using a conventional nebulizer will include from approx. 0.1 to approx. 1% with active ingredient, and mixtures for use in pressurized containers will include from approx. 0.5 to approx. 2% with active ingredient. Mixtures for use as powder inhalants can include ratios between active ingredient and diluent of from approx. 1:0.5 to approx. 1:1.5.

It is necessary that the active ingredient constitutes such a proportion of the mixture that a suitable dosage form is obtained. It is obvious that several dosage unit forms can be administered approximately simultaneously. Although mixtures with less than 0.005% by weight of active ingredient can be used in certain cases, it is preferred to use mixtures that do not contain less than 0.005% of active ingredient, because otherwise the amount of carrier will be excessively large. The activity increases with the concentration of the active ingredient. The mixture may contain 10, 50, 75, 95 or even higher percentages by weight of active ingredient.

The effectiveness of the products according to this invention as anti-ulcer agents is determined by the rat stress test, as indicated in the following Rat stress when staying in the cold

To female rats (Charles River C-D breed) that do not

have fasted and weighing 70-140 g, the drug or vehicle (control animal) is administered intraperitoneally (in saline solution containing 1% carboxymethylcellulose and 0.1% "Tween 80") or orally (in water) three hours before they are

lightly anesthetized with ether and tied lying on their backs to individual plates of Plexiglas. After recovering from anesthesia, the tied animals are placed horizontally in a refrigerator kept at 10-12°C, and three hours later they are euthanized by cervical dislocation. The abdomen of each rat is opened, the pylorus are clamped, the stomach is filled with saline solution using an oral tube, the esophagus is clamped and the stomach is cut open The stomachs are placed in a 0.4% formaldehyde solution to harden the outer layers for approximately 30 seconds to facilitate the examination. Each stomach is then cut open along the greatest curvature and the glandular part (posterior stomach) is examined for damage. The number of stomach erosions, their severity and the color of the stomachs are then noted down. Male -Whitney-Wilcoxon rank sum test is used to compare the mean number of gastric erosions in the comparison group with the mean number of gastric erosions in each drug-treated group, to determine if there is a statistical difference.

(Dixon et al., "Introduction to Statistical Analysis", 3rd ed. McGraw-Hill Book Company, New York, pp. 344-347, 1969).

Their effect on gastric acid secretion in pylorus-under-ligated (dys. Shay rats) is determined by the following procedure.

Shay rat

48 hours before surgery, female rats (Charles River C-D breed, 100-140 grams) are placed individually in cages and are deprived of regular food. Each animal is given two sugar cubes and water as desired to effect emptying of the stomach. Drug or carrier is administered intraperitoneally and three hours later, under ether anesthesia, the abdomen is shaved and

opened along the linea alba. After exposure and ligation of the pylorus, the incision is closed and the animal is returned to its cage and allowed to regain consciousness.

Three hours later, the animal is euthanized by cervical dislocation, the abdomen is reopened, the distal esophagus is clamped and the stomach is cut open. The stomach is cut open and the contents are washed in a beaker with one ml of deionized water. The volume of gastric juice is noted down after centrifugation. Excessively dirty (more than 0.5 ml of solids) or bloody samples are discarded. The acidity of one ml of gastric juice is determined by titration with a standardized NaOH (0.1 N) solution using phenolphthalein as an indicator, and total acid excretion (^ueqH+/100 g's body weight/3 hours) is calculated. An unpaired test is used to compare the average for the comparison groups and the tested groups. (Dixon et al., Technometrics, X, 83-98, 1969). Carbenoxolone at 40 mg/kg body weight consistently reduced gastric acid secretion in the three-hour Shay rats. With 80

mg/kg significantly reduced carbenoxolone acid excretion in Shay rats.

The same two basic changes are present in anaphylactic shock: (1) an increase in capillary permeability and (2) contraction of smooth muscle. The increased capillary permeability is a result of mutual influence between antigen and antibody. It, and the contraction of smooth muscles, can be observed and easily measured. This increase in capillary permeability forms the basis for the PCA test.

The PCA test is a measure of the anti-allergenic (especially anti-asthmatic) activity of a compound. Compounds that inhibit a positive PCA test caused by the rat immunochemical counterpart of human immunoglobulin E (IgE), or reagin, are believed to have anti-allergenic activity (Co Mota, Ann. N.Y. Acad. Sei., 103, 264, 1963). (Reagin is primarily immunoglobulin E [IgE] and is the principal immunoglobulin responsible for allergic asthma, anaphylaxis, high fever, food sensitivities and certain manifestations of drug sensitivities). When such compounds are administered to a sensitized test subject, human or animal, before the time when the test subject comes into contact with antigens or substances to which it is allergic, they will prevent the allergic reaction that would otherwise occur. They therefore provide a method for the prophylactic treatment of allergy or anaphylactic reactions of a reagin-mediated nature.

In other words, such compounds block the release of mediators originating from the antigen-antibody reaction (allergic) as illustrated by the PCA test using rat homocytotropic antibody -

a known correlate of human reaginic antibody. Inhibition of reaginic antigen-antibody reactions in rats, which is the test animal of the PCA test, is considered representative of inhibition of human reaginic antigen-antibody reactions that occur during allergic episodes.

The PCA reaction test method used to evaluate the compounds of the present invention shows an excellent correlation between the activity

to the compounds of this test and their applicability in the treatment of allergic asthma. The ability of the agents to affect PCA reactions is measured in 170-210 g male Charles River Wistar rats. Reaginic antiserum rich in IgE antibodies is prepared according to Petillo et al., Int. Arch. Allergy, 44, 30? (1973). Hyper-immune antiserum which* is rich in IgG antibodies to hen's egg albumin is prepared according to Orange et al., J. Exptl. Med., 127, 767 (1968). 48 hours before the antigen challenge, the reaginic antiserum is injected intradermally (i.d.) into the shaved skin of a normal rat back, and 5 hours before the challenge, the hyperimmune antisera are injected in the same way. At a third site, 60 meg histamine dihydrochloride and 0.5 meg serotonin-creatinine sulfate are injected i.d. just before the antigen provocation as a control of antihistaminic, antiserotoninic and unspecified types of

, blocking, and the compounds according to the present invention or saline solutions are then administered i.v. and this is immediately followed by the provocation of 5 mg of egg albumin and 2.5 mg of Evans blue dye in saline. In the case of oral administration, Eyans' blue dye and egg albumin are given 5 minutes after the administration of the drug. 30 minutes later the animals are asphyxiated using chloroform and the skin on the back is removed and turned over for observation. Points are awarded for each

injection site which is equal to the product of the diameter of the site in mm and a gradation of 0.1, 0.5, 1, 2, 3 and 4 which is proportional to the intensity of the staining with the dye. The scores for a given injection site are summed for each group of 5 animals and compared to the saline-treated control animals. The difference is expressed as percent blocking due to the compound used.

Compounds that are representative of the compounds

according to the invention, are tested for anti-allergenic activity by the method described above, and the resulting activities are indicated as degree of protection. Initial, disodium oromoglycate, a commercial anti-allergenic agent, is included for comparison.

The tested compounds have the formula

Intravenous and oral activity of the compounds according to this invention are indicated in Table I and Table II, respectively.

8,9-Dimethoxytetrazolo[1,5-c]quinazol-5(6H)-one, a compound disclosed in U.S. Pat. patent document no..3,838,126, when tested by the PCA test by intravenous administration, shows 18, 83 and 70% protection against anaphylaxis due to immunoglobulin G (IgG) at doses of 0.3, 3 and 30 mg/ kg, and 21, 84 and 85% protection against anaphylaxis due to immunoglobulin E (IgE) at doses of

0.3, 3 and 30 mg/kg. Oral administration of this compound provides 35 and 57% protection against IgG-mediated anaphylaxis at doses of 30 and 100 mg/kg, respectively, and 52 and 59% protection against IgE-mediated anaphylaxis at doses of 30 and 100 mg/kg, respectively.

Example 1

6- methoxy- 7- propoxy- 2, 4(1H, 3H) quinazolinedione

3-Propoxy-4-methoxy-2-aminobenzoic acid (6.2 g, 27 mmol) was suspended in water (180 mL) containing acetic acid (3.5 mL) and potassium isocyanate solution (6.2 g in 20 mL water) was added dropwise. ._ The reaction mixture was stirred at 30-40°C for 2 hours. Sodium hydroxide pellets (55 g) were then slowly added keeping the temperature below 40°C. After the addition was complete, the temperature of reaction mixture one was raised to 90°C for 1/2 hour. It was then cooled and concentrated and hydrochloric acid was added dropwise, keeping the temperature below 40°C. The resulting solid was filtered and washed with water. Yield = 5.0 g (73%), m.p. 259-261°C.

Example 2

8-methyl-2,4-(1H,3H)quinazolinedione

3-Methylanthranilic acid (15 g, 0.1 mol), urea (36 g, 0.6 mol), and phenol (86 g) were mixed together and heated to reflux for three hours. The reaction mixture was then allowed to cool to 100°C and ethanol (75 mL) was added dropwise. The resulting solid was filtered and washed twice with cold ethanol to give 13.2 g (75% yield), m.p. 170°C.

Example 3

The following compounds were prepared according to the procedures of Examples 1 and 2 from appropriate reactants.

Example 4

6- methoxy- 7- propoxy- 2, 4- dichloroquinazoline

6-Methoxy-7-propoxy-2,4(1H,3H)quinazolinedione (4.95 g, 19.7 mmol) was suspended in phosphorus oxychloride (60 mL). The reaction mixture was heated to reflux for 5 hours, then cooled and slowly poured onto 800 ml of ice. The resulting orange-brown precipitate was filtered and washed twice with water and dried. Yield = 4.8 g (86%), m.p. 118-120°C.

Example 5

By following the procedure in Example 4, the appropriate quinazoline diones are converted into the 2,4-dichloroquinazolines indicated in the table below.

Example 6

6- methoxy- 7- propoxy- 2- chloro- 4( 3H) quinazolinone

6-Methoxy-7-propoxy-2,4-dichloroquinazoline (4.5 g, 15.6 mmol) was suspended in sodium hydroxide and tetrahydrofuran (30 mL) and the reaction mixture was stirred at room temperature for 36 h until a clear solution was obtained . Water (20 mL) was added to the mixture and this was then acidified with acetic acid to a pH of 5. The resulting solid was filtered and washed with water to give 3.8 g (90%

yield) of the title monochloro compound, m.p. 246-248°C.

Example 7

The appropriate 2,4-dichloroquinazolines are converted into the corresponding 2-chloro-4(3H)quinazolinones by the method in example 6. The following compounds are thus prepared:

Example 8

7- methoxy- 8- propoxy- tetrazolo[ a] quinazol- 5- one

6-Methoxy-7-propoxy-2-chloro-4(3H)quinazolinone (30 g, 11 mmol) was suspended in a mixture of N,N-dimethylformamide (60 mL), water (40 mL) and sodium azide (0, 8 g, 12 mmol) and the mixture was refluxed for 2 hours. After cooling, water (20 ml) was added and the product which crystallized out was filtered, washed with water and dried. Recrystallization from N,N-dimethylformamide/water gave 1.0 g (33%) of tetrazole, m.p. 244-245°C.

Analysis:

Calculated for ci2H13N5°3! C'52»36» H» 4'76» N» 25.44

Funaeti C, 52.66, H, 4.96, N, 25.60

Example 9 Using the method in example 8, the tetrazolo[a]quinazol-5-ones listed in the table below are prepared from the appropriate 2-chloro-4(3H)quinazolinones.

Example 10

The following compounds are prepared from suitably substituted benzoic acids by the procedures of Examples 1, 4, 6 and 8.

Example 11

7- hydroxyz- 8- methoxytetrazolo[ a] quinazol- 5- one

v7-Benzyloxy-8-methoxytetrazolo[aJkinaz61-5-one (0.05 g) is dissolved in trifluoroacetic acid (2 ml) and the solution becomes

refluxed for 1 1/2 hours. The reaction mixture is cooled to room temperature and ether (4 ml) is added.

The resulting solid is filtered off, washed with

ether (2 x 4 ml) and air-dried. The product is recrystallized from N,N-dimethylformamide-water (1-1). Yield = 0.025 g (48 Sm.p. >400°C.

In a similar manner, 7-methoxy-8-benzyloxytetrazolo[a]-quinazol-5-one is debenzylated to the corresponding 8-hydroxy compound as the trifluoroacetate salt.

Neutralization of the above-mentioned salts with sodium or potassium hydroxide in water gives the base form.

/

Example 12

7- acetoxy- 8- metokaitetrazolo[ a] quinazol- 5- one tosvlate

A mixture of 7-hydroxy-8-methoxytetrazolo[a]quinazol-5-one trifluoroacetate (0.01 g), acetic anhydride (3 ml) and p-toluenesulfonic acid (0.005 g) is heated at 100°C for 4 hours. The reaction mixture is cooled and evaporated to dryness under reduced pressure. The residue is dissolved in chloroform, de-coloured and filtered and the filtrate is evaporated to dryness under reduced pressure. The residue crystallizes after the addition of ether.

Neutralization in aqueous NaOH gives the base.

In a similar manner, the following compounds are prepared from the appropriate alkanoic anhydrides and the products of Example 11.

Example 13

Injectable preparation

1000 grams of 7-methoxy-8-n-propoxy-tetrazolo[aJquinazol-5-one are thoroughly mixed and ground together with 2500 grams of sodium ascorbate. The ground, dry mixture is placed in jars and sterilized with ethylene oxide, after which the jars are sterilized and stoppered. For intravenous administration, sufficient water is added so that the materials in the bottles form a solution containing 5.0 mg of active ingredient per milliliters of injectable solution.

Example 14

Pills

A tablet base is produced by mixing them

the following ingredients in the indicated weight ratio:

Sufficient 7-methoxy-8-n-propoxytetrazolo[a]quinazol-5-one is mixed into this tablet base to provide tablets containing 20, 100 and 250 mg of active ingredient per tablet. tablet. The mixtures are then compressed into tablets, each weighing 360 mg, in a conventional manner.

Example 15

Capsules

A mixture containing the following is produced

ingredients:

Sufficient 7-methoxy-8-isopropoxytetrazolo[a]quinazol-5-one is added to this mixture to provide capsules containing 10, 25 and 50 mg of active ingredient per capsule. capsule. The mixtures are filled into conventional hard-gelatin capsules in an amount of 350 mg per capsule.

In a similar way, capsules containing 2.0 and 6.0 mg of active ingredient and consisting of 300 mg of the following mixture per cap ice cream

Example 16

Resolution

A solution of 8-n-propoxytetrazolo-[alquinazol-5-one with the following composition is prepared:

The resulting solution has a concentration of effective ingredient of 10 mg/ml and is suitable for parenteral use

and especially for intramuscular administration.

Example 17

An aqueous solution of 7-methoxy-8-n-propoxytetrazol-[a]quinazol-5-one (containing 3 mg of drug per ml of solution) is placed in a conventional nebulizer available from Vaponephrine Co., Edison, N.J. The solution remains under an air pressure on

0.42 kg/cm 2 injected into a closed plastic container with the size

20.32 cm x 20.32 cm x 30.48 cm for six minutes. The container has four openings, which are adapted to the heads of four rats. Four rats are simultaneously exposed to the drug, with only their heads coming into contact with the aerosol. The results are assessed

as with the PCA reaction test process described above.

Example 18

Aerosol suspension

A mixture of 7-methoxy-8-n-propoxytetrazolo[a]quinazol-5-one (antiallergenic agent) and the other ingredients under (a) in the example below is micronized to a particle size of 1 to 5 microns in a ball mill. The resulting slurry is then placed in a container equipped with a valve and propellant (b) is introduced by pressure filling through the valve nozzle to a manometer pressure of approximately 2.45-2.80 kg/cm at 20°C.

Claims (14)

1. Process for preparing a compound of the formula where R1 is alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, alkanoyloxy of 1-4 atoms, benzyloxy, hydroxy, trifluoromethyl, sulfonamido or halogen and R2 is selected from the same group as or is hydrogen, or R^ and R2 is together -0-CH20- or -0-CH2 -CH2 -0-, characterized by reacting with an azide. 2. Method according to claim 1, characterized in that an alkali metal azide is used as azide. 3. Method according to any of the preceding claims, characterized in that the azide is used in a molar excess of 5-20%. 4. Method according to any one of the preceding claims. characterized in that the reaction is carried out at a temperature of 50 to 100°C. 5. Method according to any one of the preceding claims, characterized in that the reaction is carried out in an aqueous ethanol or aqueous N,W-dimethylformamide solvent1. 6. Process according to any of the preceding claims, characterized in that each of R 1 and R 2 is alkoxy. 7. Method according to claim 6, characterized in that R 1 is 7-alkoxy and R 2 is 8-alkoxy. 8. Method according to claim 7, characterized in that R 1 is 7-methoxy and R 2 is 8-alkoxy. 9. Method according to claim 8, characterized in that R2 is 8-n-propoxy. 10. Method according to any one of claims 1 to 5, characterized in that R 1 is hydrogen and R 2 is 8-alkyloxy. 11. Method according to claim 10, characterized in that R2 is 8-isopropoxy. 12. Process according to claim 10, characterized in that R2 is 8-methoxy. 13. Method according to any of the preceding claims, characterized in that a compound of the formula: is produced by converting with an alkali metal cyanate followed by cyclization of the product under aqueous acidic or alkaline conditions. 14. Method according to any one of claims 1 to 12, characterized in that a compound with the formula: is produced by converting with urea followed by halogenation and subsequent hydrolysis with an alkali or alkaline earth metal hydroxide.