IE43466B1 - Tetrazolo /a/ quinzolone derivatives - Google Patents

Abstract

1499255 Tetrazolo[a]-quinazolone derivatives PFIZER Inc 1 July 1976 [10 July 1975 28 Jan 1976] 27543/76 Heading C2C Novel compounds of the Formula I wherein each of R 1 and R 2 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyloxy, benzyloxy, hydroxy, trifluoromethyl, or sulphonamide, or R 1 and R 2 when attached to adjacent carbon atoms in the ring and taken together form a methylenedioxy or ethylenedioxy group, provided R 1 and R 2 are not both hydrogen, and pharmaceutically acceptable cationic salts thereof, may be prepared by reacting the appropriate 2-chloro-4(3H)quinazolinone with a metal azide to form the tetrazole ring, optionally followed by debenzylating when R 1 and/or R 2 is benzyloxy to form the corresponding compound in which R 1 and/or R 2 is hydroxy and esterification of a free hydroxy group at R 1 and/or R 2 . The 2-chloro-4(3H)quinazolinones are prepared by reacting the appropriate anthranilic acid with urea or alkali metal isocyanate followed by heating to form a 2,4-(lH,3H)quinazolinedione, which with phosphorus oxychloride forms a 2,4-dichloroquinazoline which with base yields the required compound.

Description

This invention relates to pharmaceutical compositions containing tetrazolo[a]quinazol-5-one and derivatives thereof which are useful for the control of peptic ulcers and allergic reactions. The invention is also concerned with derivatives of tetrazolo[a] quinazol-5-one.

Tetrazolo[a]quinazol-5-one, the parent compound of the . derivatives described and claimed herein is described by Postovskii et a 1., Zhur. Obshchei Khim., 33, 2334-2341 (1963) [C.A. 59, 13987a] . Certain 4-substitUted tetrazolo[a]quinazol5-ones are described by Vereshchagina et al., Zhur. Obshchei. Khim., 34, 1745-8 (1964) [C.A. 61, 8307-8]. However, these references do not disclose any utility for the compounds.

Allergic reactions, the symptoms resulting from antigenantibody interaction, manifest themselves in a wide variety of ways and in different organs and tissues. Common allergic disorders, for example, are allergic rhinitis, a condition characterized by seasonal or perennial sneezing, running nose, nasal congestion, with itching and congestion of eyes; hay fever, a variety of allergic rhinitis that results from hypersensitivity to grass pollens? and bronchial asthma, one of the most disabling and debilitating of allergic reactions, a disease characterized by hyper-reactivity of the bronchi on exposure to various, immunogenic or nonimmunogenic stimuli, resulting in bronchospasms with wheezing, short-lived paroxysms and widespread constriction of airway passages. The mechanical obstruction to airflow in airways is generally reversed by the use of - 3 bronchodilators, which provide symptomatic relief. In contrast, antiallergy agents prevent the release of mediators of anaphylaxis from tissue stores to preclude elicitation of bronchoconstriction by the mediators.

Recently, Cox and co-workers, Adv- in Drug Res., 5., 115 (1970), described the pharmacology of one such agent, disodium cromoglycate [1,3-bis(2-carboxycromon-5-yloxy)-2-hydroxypropane, Intal (registered trade mark). It is not a bronchodilator, but mediates its therapeutic effects by a unique mechanism of action involving inhibition of release of mediators of anaphylaxis and is administered prophylactically. It suffers from lack of oral efficacy and, for optimum results, is administered by inhalation as a solid inhalant. Further, although it is effective against anaphylaxis due to immunoglobulin E (IgE), it is effective against anaphylaxis due to immunoglobulin G (IgG) only at high doses (60-70% protection at 100 and 300 mg./kg.).

Although the aforementioned agents represent outstanding contributions toward the treatment of asthma, many of them exert the undesired side effect of cardiac stimulation.

Chronic gastric and duodenal ulcers, collectively known as peptic ulcers, are a common afflication for which a variety of treatments have been developed. The treatment depends upon the severity of the ulcer and may range from dietary and medical (drug) treatment to surgery. A wide variety of drugs have been used to treat ulcers; the most recent of which to gain widespread attention is carbenoxolone sodium, the disodium salt of the hemisuccinate of glycyrrhetinic acid. It is reported to prevent formation of and to accelerate healing of gastric ulcers in animals, including humans (Carbenoxolone Sodium: a Symposium, J. M. Robson and F. M. Sullivan, Eds., Butterworths, London, 1968). However, its use is accompanied by undesirable - 4 aldosterone-like side effects, such as marked antidiuretic and sodium-retaining activity, and oftentimes, potassium loss, such that continued thereapy with this agent often leads to hypertension, muscle weakness and, ultimately, congestive heart failure.

Carbenoxolone sodium is almost wholly absorbed in the stomach and is not effective against duodenal ulcers except when administered as a specially formulated capsule which enables its transport to the desired site.

A more effective treatment of peptic ulcers is, therefore, desirable. One which will effectively act upon ulcers in the duodenum, as well as upon gastric ulcers, without the need of special formulation and minimizes the aldosterone-like side effects of carbenoxolone is especially desirable.

It has now been found that tetrazolo[a]quinazol-5-ones of the formula wherein each of and R2 is a hydrogen or halogen atoms, an alkyl group having from one to four carbon atoms, an alkoxy group having from one to four carbon atoms, an alkanoyloxy group having from one to four carbon atoms, or a benzyloxy, hydroxy, trifluoromethyl or sulphonamido group, or R^ and R2 when attached to adjacent carbon atoms in the ring and taken together form a methylenedioxy or ethylenedioxy group, and 3 4 G 6 - 5 pharmaceutically acceptable cationic salts thereof, are valuable antiallergy agents; that is, agents which inhibit the release of mediators of anaphylaxis, in mammals, including man, and in this way preclude elicitation of bronchoconstrietion by the mediators. They are not bronchodilators. They are, in contrast to Intal, of practical value against both IgG and IgE mediated anaphylaxis via the oral, intranasal and intraperitoneal routes of administration, and by inhalation. Additionally, they are effective antiulcer agents for the treatment of peptic ulcers.

Accordingly the present invention provides a pharmaceutical composition active as an antiallergy agent which comprises, as the active ingredient, a compound of formula (I) as defined above in admixture with a pharmaceutically-acceptable carrier.

Compounds of the above formula (I), except for that wherein each of and R2 is a hydrogen atom, are new compounds.

Accordingly the present invention also provides a compound of formula (I) above, wherein R^ and R^ are as defined above, with the proviso that one of R^ or is other than hydrogen.

In a preferred case, is a methoxy group.

Compounds of formula (I) of special interest because of their significant oral activity in the PCA test against both IgG and IgE are those wherein each of R^ and R^ is an alkoxy group having from one to four carbon atoms and particularly those wherein R^ and R2 are located at the 7- and 8-positions of the molecule. Compounds of formula (I) in which is a 7-methoxy group and/or R2 is an n-propoxy group are preferred.

The pharmaceutically active compounds of formula (I) wherein R^ and/or R2 are benzyloxy may be used to prepare the pharmaceutically active compounds wherein R^ and/or R2 is hydroxy or alkanoyloxy. 2486 - 6 The effectiveness of those compounds as antiulcer agents is determined by the stressed rat assay described below. The antiallergy property of the compounds of this invention is evaluated by the passive cutaneous anaphylaxis (PCA) test (Ovary J. Immun. 81, 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 from the site of the antibody injection. The test animals are then asphyxiated and the intensity of the reaction determined by measuring the diameter and intensity of the blue colouration on the inner surface of the animals' skin.

The compounds of this invention are conveniently prepared by the reaction of a metal azide, preferably an alkali metal azide, with the appropriate 2-chloro-4(3H)quinazolinone in equimolar quantities. In ordinary practice, however, it is preferred to use an excess, generally 5 to 20% excess, of the metal azide to achieve maximum conversion of the 2-chloro-4(3H)quinazolinone to the azide.

The reaction may be carried out in a suitable solvent medium such as aqueous ethanol or aqueous N,N-dimethylformamide at a temperature of from 50°C. to 1OO°C. Higher or lower temperatures appear to offer no advantages.

The required 2-chloro-4(3H)quinazolinones may be prepared by a reaction sequence beginning with the appropriately substituted o-aminobenzoic acid. The aminobenzoic acid reactant is converted to a ureido derivative by treatment with an alkali metal cyanate (e.g., KOCN or NaOCN) followed by cyclization of the ureido derivative under aqueous acid or base conditions as is described in British Patent Specification No. 1,156,973 .

Alternatively, the o-aminobenzoic acid may be reacted with urea according to the procedure of Curd et al., J. Chem.

Soc., 1947, page 777, to provide the same compound. The 2,4(lH,3H)-quinazolinedione may then be reacted, as is described in British Patent Specification No. 1,156,973 with a halogenating agent, such as phosphorus oxychloride, to give the 2,4-dichloroquinazoline. The 2,4-dichloro compound is then converted to the 2-chloro-4(3H) quinazolinone by hydrolysis according to known procedures 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 a reaction-inert solvent, such as tetrahydrofuran.

The necessary o-aminobenzoic acid reactants, if not known compounds, are obtainable by methods known to those skilled in the art.

The compositions of this invention containing compounds of formula (I) and the pharmaceutically-acceptable cationic salts thereof are useful for the control (prophylactic and therapeutic treatment) of peptic ulcers and as prophylactic agents to inhibit or prevent the release of mediators of anaphylaxis (allergy, immediate hypersensitivity reactions) and the occurrence of allergic symptoms in mammals, and may be administered for such uses alone or as mixtures with other agents; for example with theophylline or sympathomimetic amines. The compositions contain a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, the compounds of formula (I) may be admixed with pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies. 434SS - 8 powders, aerosol sprays, aqueous suspensions or solutions, injectable solutions, elixirs or syrups. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents. Moreover, the oral pharmaceutical compositions of this invention may be suitably sweetened and flavoured by means of various agents of the type commonly used for this purpose.

The particular carrier selected and the proportion of active ingredient to carrier are influenced by the solubility and chemical nature of the therapeutic compounds, the chosen route of administration and the needs of standard pharmaceutical practice. For example, when the compositions of this invention are administered orally in tablet form, excipients, such as lactose, sodium citrate, calcium carbonate or dicalcium phosphate, may be used. Various disintegrants such as starch, alginic acids and certain complex silicates, together with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, also may be used in producing tablets for the oral administration of these compounds. For oral administra tion in capsule form, lactose and high molecular weight polyethylene glycols are among the preferred materials for use as pharmaceutically-acceptable carriers. Where aqueous suspensions are to be used for oral administration, the active compounds may be admixed with emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerine and chloroform or mixtures thereof may be employed.

For the purpose of parenteral administration and inhalation, solutions or suspensions of the active compounds in sesame or peanut oil or aqueous propylene glycol solutions may be employed, as well as sterile aqueous solutions of the soluble pharmaceutically-acceptable salts described herein. These 3 4 8 6 - 9 particular solutions are especially suited for intramuscular and subcutaneous injection purposes should such method of administration be desired. The aqueous solutions, including those of the salts dissolved in pure distilled water, are also useful for intravenous injection purposes provided that their pH is properly adjusted beforehand. Such solutions also should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.

An effective daily oral or intraperitoneal dosage of the compounds of formula (I) in humans of from 10 to 1500 mg. per day, with a preferred range of 10 to 600 mg. per day in single or divided doses, or at 0.2 to 12 mg./kg. of body weight will effectively inhibit or prevent release of mediators of anaphylaxis in human subjects. These values are illustrative and there may be individual cases where higher or lower dose ranges are merited. With careful supervision, the dosage level may range up to as high as two grains per day.

When administered intravenously or by inhalation, the effective daily dose of the active compound is from 0.05 to 400 mg. per day, and preferably from 0.25 to 200mg. per day, or at 0.005 to 4 mg./kg. of body weight in single or divided doses.

When used as a prophylactic agent to prevent the release of mediators of anaphylaxis, the compositions may be administered by inhalation. 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 of the active ingredient in a liquified propellant such as dichlorodifluoromethane or chlorotrifluoroethane for administration from a pressurized container; or (3) a mixture of the active ingredient and a solid diluent - 10 13466 (e.g. lactose) for administration from a powder inhalation device. Compositions suitable for inhalation by means of a conventional nebulizer preferably comprise 0.1 to 1% of active ingredient; and those for use in pressurized containers preferably comprise from 0.5 to 2% of active ingredient. Compositions for use as powder inhalants may comprise ratios of active ingredient to diluent of from 1:0.5 to 1:1.5.

It is necessary that the active ingredient form a proportion of the composition such that a suitable dosage form will be obtained. Several dosage unit forms may be administered at about the same time. Although compositions with less than 0.005% by weight of active ingredient might be used in certain instances, it is preferred to use compositions containing not less than 0.005% of the active ingredient; otherwise, the amount of carrier becomes excessively large. Activity increases with the concentration of the active ingredient. The composition may contain 10, 50, 75, 95 or an even higher percentage by weight of the active ingredient.

The effectiveness of the compounds of formula (I) as antiulcer agents is determined by the stressed rat assay as follows : Cold-Restraint Stressed Rat Non-fasted female rats (Charles River C-D strain) weighing 70 to 140 gms. are administered the; drug or carrier (control animals) intraperitoneally (in saline solution containing 1% carboxymethylcellulose and 0.1% ’'Tween 80) or orally (in water) three hours before being lightly anesthetized with ether and taped in the supine position to individual sheets of Plexiglass. The words Tween and Plexiglass are registered Trade Marks. After recovery from the anesthesia, the restrained animals are positioned horizontally in a - 11 refrigerator maintained at 10° to 12°C. a nd three hours later sacrificed by cervical dislocation. The abdomen of each rat is opened, the pylorus clamped, the stomach inflated with saline via an oral tube, the oesophagus clamped and the stomach excised. The stomachs are placed in a 0.4% formaldehyde solution for 30 seconds to harden the outer layers and facilitate examination. Each stomach is then cut open along the greater curvature and the glandular portion (hind stomach) examined for damage. The nuiriber of gastric erosions, their severity and the colour of the stomachs is recorded. The Mann-WhitneyWilcoxon rank sum test is used to compare the median nuiriber of gastric erosions in the control group with the median number of gastric erosions in each drug-treated group to determine if they are statistically different.(Dixon etal., Introduction to Statistical Analysis, 3rd Ed., McGraw-Hill Book Company, New York, pp 344-347, 1969).

Their effect on gastric acid output in pylorus-ligated (i.e., Shay) rats is determined by the following procedure.

Shay Rat Forty-eight hours before surgery female rats (Charles River C-D strain; 100 to 140 gms.) are individually caged and taken off normal food. Each animal is given two sugar cubes and water ad libitum 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 exposing and ligating 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 sacrificed by cervical dislocation, the abdomen reopened, the distaloesophagus clamped, and the stomach excised. The stomach is cut open and the contents washed into a beaker 3 4 3 6 - 12 with one ml. of deionized water. The volume of gastric juice is recorded following centrifugation. Excessively dirty (greater 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.IN) solution using phenolphthale in as an indicator and total acid output (geqH+/100 gms. body weight/3 hours) is. calculated. A non-paired t test is used to compare the means of the control and tested groups. (Dixon et al., Technometrics, X, 83-98, 1968). Carbenoxolone at 40 mg./kg. body weight consistently reduced gastric acid output in the three-hour Shay rat. At 80 mg./kg., carbenoxolone significantly decreased acid output in the Shay rat.

The same two basic changes are present in cases of anaphylactic shock: (1) an increase in permeability of capillaries, and (2) contraction of smooth muscle. The increased capillary permeability is the result of antigen-antibody interaction. If, and smooth muscle contraction, can be observed and readily measured. This increase in capillary permeability forms the basis of the PCA test.

The PCA test is a measure of the anti-allergic (especially anti-asthmatic) activity of a compound. Compounds which inhibit a positive PCA test induced by the rat immunochemical counterpart of human immunoglobulin E (IgE), or reagin, are considered to have anti-allergic activity (C. Mota, Ann. N.Y. Acid. Sci., 103, 264, 1963). (Reagin is primarily immunoglobulin E [IgE] and is the principal immunoglobulin responsible for allergic asthma, anaphylaxis, hay fever, food sensitivities and certain manifestations of drug sensitivities). Such compounds when administered to a sensitized subject, human or animal, prior to the time when the subject comes into contact with antigens or substances to which it is allergic, will prevent the allergic reaction which would otherwise occur. They, therefore, provide - 13 43466 a method for the prophylactic treatment of allergy or anaphylactic reactions of a reagin mediated nature.

To put it another way, such compounds block the release of mediators resulting from the antigen-antibody (allergic) reaction as illustrated in the PCA test using rat homocytotropic antibody - a known correlate of human reaginic antibody. Inhibition of reaginic antigen-antibody reactions in rats, the test animal of the PCA test, is regarded as representative of inhibition of human reaginic antigen-antibody reactions which occur during allergic episodes.

The PCA reaction test procedure employed to evaluate the compounds of formula (I) demonstrates an excellent correlation between activity for compounds in this test and their utility in the treatment of allergic asthma. The ability of agents to interfere with PCA reactions is measured in male Charles River Wistar rats, 170 to 210 g. Reaginic antiserum, rich in IgE antibodies is prepared according to Petillo et al., Int. Arch. Allergy, 44, 309 (1973). Hyperimmune antiserum rich in IgG antibodies to hen egg albumin is prepared according to Orange, et al., J. Exptl. Med., 127, 767, (1968). Forty-eight hours prior to antigen challenge, the reaginic antiserum is injected intradermally (i.d.) into the shaved skin of a normal rat's back; five hours before challenge the hyperimmune antisera is similarly injected. At a third site 60 meg. histamine dihydrochloride and 0.5 meg. serotonin creatinine sulphate are injected i.e. just prior to antigen challenge as a check for antihistaminic, antiserotonin and unspecific types of blockage; the compounds of formula (I) or saline are then administered i.v. and immediately followed by the challenge of 5 mg. egg albumen and 2.5 mg. Evans' Blue dye in saline. In the case of 3 4 3 6 - 14 oral administration Evans 1 Blue dye and egg albumen are given five minutes after administration of the drug. Thirty minutes later the animals are asphyxiated using chloroform and the skin of the back removed and reversed for observation. A score is assigned each injection site equal to the product of the diameter of the site in mm. and a grade of 0.1, 0.5, 1, 2, 3 or 4 proportional to intensity of dye colouration. The scores for a given injection site are summed for each group of 5 animals and compared to the saline treated controls. The difference is expressed as percent blockade due to the compound employed .

Compounds representative of those of formula (I) are tested for antiallergy activity by the above-described procedure and the resulting activity are reported as the degree (%) of protection. Intal, disodium cromoglycate, a commercial antiallergy agent, is included for comparison.

The compounds tested are of the formula wherein the values for R„, R,, R. and R. and the intravenous 3 4 5 o and oral activity of the compounds are presented in Tables I and II, respectively. 434S6 O O ID r-l in ro Ed Ed A cn cn tn < tn E o O co 8 8 8 in O co CO O' rd OJ OI O' CO Sf kp co co in cn cn rd ro rd rd Lf) Ο ω co co CO O' O' rd cn OJ O kO O cn o rd in co tn co Λ! CO CO \ m tn rd co £ CO • O • o I.V rd o 6 cn H tn c O ό E cn oj co in I 111 w (J ra g cn OJ O rd CO rd O' rd cm oj cn co in in oo· co co CN CO CO CD CO O' CO CO CN tn CO CO CO r-· m in vo r-mnO ω v in in vo V o CN rd rd rd o 8 tc EC ffi 8 M 8 K o· σι o· 8 EC 8 tc n co V CO in 1 in a U u □ m K o W 1 . I , 1 . J , 8 CN 1 OI cl •rl| cl al 8 8 OJ X 8 o O o o U I in OJ m ffi ffl co m CO m 8 CN ϋ W 8 tc 8 u y 1 y y y y o O O 1 O 0 o o ii 8 w W M 8 M 8 M o ffi * Ed Ed Ed CO O co co co co co co rd Ή K S S ϋ ffl ffl ϋ □ U O co co ns u w m □ a co ro ffi Q « W ffi W ϋ Intal 34G6 - 16 O| Ol ω t-dl Γ'»· κο a I CM co in tn r- 7—t KO r» co co KD CO KO cc tn tn tn r-Ί CM tf CO CO CO cn rn CM CM o CM tn 00 t- o at Q KO tn co O r-1 rn KD cn o in r—I cn O σι co cn kO 1—1 r* r4 O KO £> tn KO j—} KO r- KO co O CQ σι r-1 KO in in KO tf r* CM r—l CO o tf· tf tn in in tf cn tn r- i-4 O cn tf CM σ r4 O r—1 CM ffi a a a a a a a a a r-» Ch a a a a 1 tn cn tn o I J* u U o □ tn I CM pH w CM ?’ 41 cl cl ffi a PH o 8 o O o o a CM a cn □ cn π cn tn a 1 a B a a tn y o □ y υ y a ffi σ a 1 o O o o a u a a a a a a a a a a H H H d CQ - 17 43436 The following Examples illustrate the invention and the manner in which it may be performed. Examples 1 to 7 illustrate the preparation of intermediate compounds used in the preparation of the compounds of the invention. Examples 8 to 12 illustrate the preparation of novel compounds according to the invention and Examples 13 to 18 illustrate the preparation of pharmaceutical compositions according to the invention.

EXAMPLE 1 6-Methoxy-7-n-propoxy-2,4-(1H,3H)quinazolinedione 4-n-Propoxy-5~methoxy-2-aminobenzoic acid (6.2 g., 27 mmole) was suspended in water (180 ml.) containing acetic acid (3.5 ml.) and potassium cyanate solution (6.2 g. in 20 ml. water) added dropwise. The reaction mixture was stirred at 30° to 40°C. for two hours. Then, sodium hydroxide (55 g.) pellets were added slowly, keeping the temperature below 40°C. After addition was completed, the temperature of the reaction mixture was raised to 90°C. for 0.5 hours. It was then cooled, concentrated and hydrochloric acid was added dropwise keeping the temperature below 40°C. The resulting solid was filtered and washed with water. Yield of title compound was 5.0 g. (73%)? m.p. 259° to 261°C.

EXAMPLE 2 8-Methyl-2,4-(IH,3H)quinazolinedione 3-Methylanthranilic acid (15 g., 0.1 mole), urea (36 g., 0.6 mole) 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.) added dropwise. The resulting solid was filtered and washed twice with cold ethanol to afford 13.2 g. of the title compound (75% yield); m.p. 170°C. - 18 EXAMPLE 3 The following compounds were prepared according to the procedures of Examples 1 and 2 from appropriate reactants.

H H H H H H H H H H CH3 H H H H H -och2~ch2o°ch3 H H CH3 och3 H H CH3 H H ocn3 H OCH, H Method Yield (%) Μ. P., C.

OCHfCH,) H CH3 H och2ch3 och2ch3CH3 H H H 3'2 och2ch2ch2ch3 OCH,CH CH 2 2 3 OCH2C6H5 OCH C H 2 6 5 OCH, H H och3 H H H H ch3 CH CH3 Cl Η H H H 317 348° 269° 255° 320° 316° (d) 287° 290 328° 290° 300° 321° 228°-23θ' 261°-263' 279°-281° EXAMPLE 4 6-Methoxy-7-n-propoxv-2,4-dichloroquinazoline 6-Methoxy-7-n-propoxy-2,4(1H,3H)quinazolinedione (4.95 g. 19.7 mM) was suspended in phosphorus oxychloride (60 ml.). The reaction mixture was heated to reflux for 5 hours, then cooled 3 4 8 6 and poured slowly onto 800 ml. of ice. The resulting orangebrown precipitate was filtered and washed twice with water and dried. Yield of title product was 4.8 g. (86%),· m.p. 118° to 120°C.

EXAMPLE 5 Following the procedure of Example 4, the appropriate guinazoline diones are converted to the 2,4-dichloroquinazolines Cl ch3 H H H H H H H H H H H H H H H H CH3 H H H H CH3 OCH, H och3 Η H οαϊ3 OCH, H H CH3 H CH3 H H OCH(CH ) -och2-ch2oOCH, och2ch3 och2c6h5 OCH2cH2CH3OCH2CH2CH2CH3 0CH„C,H 2 6 5 OCH, CH3 ch3CH3 Cl H CH3 H H H Η H och3 H Η H H Yield (%) 45 m.p., C. 125° 153° 142° 125° 107° 137° 144° 190° 225° 118° 161° 156° 55° 118°-12O° 16O°-162° 188°-191° 34SG - 20 EXAMPLE 6 6-Methoxy-7-n-propoxy-2-chloro-4(3H)quinazolinone 6-Methoxy-7-n-propoxy-2,4-dichloroquinazoline (4.5 g., .6 mmoles) was suspended in sodium hydroxide and tetrahydro furan (30 ml.) and the reaction mixture stirred at room temperature for 36 hours until a clear solution resulted. Water (20 ml.) was added to the mixture which was then acidified with acetic acid to pH 5. The resulting solid was filtered and washed with water to yield 3.8 g. (90% yield) of the title monochloro compound? m.p. 246°-248°C.

EXAMPLE 7 The appropriate 2,4-dichloroquinazolines are converted to the corresponding 2-chloro-4(3H)quinazolinones by the procedure of Example 6. The following compounds are thus prepared: R3 *4 r5R6 Yield (%) M.P., °C. ch3 H HCH3 75 HCH3 H CH 85 235° H H CH3C„3 90 225° H H H Cl 77 141° H H HCH3 71 221° H HCH3 H 88 235° HCH3 H H 95 225° H OCH OCH2CH2CH2CH3 H 47 233-235° H -3 OCH(CH3)2 H 88 247° H -°¾ -ch2°- H 88 282° H 0CK3 och2ch3 H 83 269° H H 0CH,CH9CHq H 95 180° H H -3 H 85 240° H 0CH5CHq och2ch3 H 89 221° HOCH2C6H5 och3 H 88 254°-256° H H H och3 87 195°-197° EXAMPLE 8 7-Methoxy-8-n-propoxy-tetrazolo|α| quinazol-5-one 6-Methoxy-7-n-propoxy-2-chloro-4(3H)quinazolinone (30 g., mmoles) was suspended in a mixture of N,N-dimethylformamide (60 ml.), water (40 ml.) with sodium azide (0.8 g., 12 mmoles) and the mixture 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 yielded 1.0 g. (33%) of the tetrazole, m.p., 244°-245°C.

Analysis: Calcd. for ^-^2^13^5^3: C' 52.36; H, 4.76; N, 25.44; Pound : C, 52.66; H, 4.96: N, 25.60 EXAMPLE 9 By means of the procedure of Example 8, the tetrazolo[a]quinazol-5-ones listed below are prepared from the appropriate 43486 - 22 2-chloro-4(3H)quinazolinones.

R. «3R4R6 R5 N- R6 -N Yield (%) M.P.(°C. ) H H H Η 98 243° HCH3 H H 50 284-285° H Ξ CH H 45 283-284° 3 H H HCH3 44 229-230°CH3 H H ch3 30 214-215° HCH3 H “3 17 251-252° H HCH3 ch3 10 252-253° H H H Cl 40 264-265° H OCH3 0CH(CH3)2 H 33 264-265° (d) H -°¾ -ch2o- H 80 291-292° (d) H H och2ch2ch3 H 42 231-232° H H och3 H 67 271-272° H OCH CH 2 3 och2ch3 H 76 245-246° H och3 OCH CH H 25 264-265° H och3 cch3 H 57 249-250° H och3 OCH^C^CHg H 57 233-234° H och3 H H 60 264-265° H Cl H H 75 268-369° (d) H H Cl H 80 340° H °CH2C6h5 och3 H 13 260°-26l' \d) - 23 EXAMPLE 10 The following compounds are prepared from appropriately substituted benzoic acids by the procedures of Examples 1, 4, 6 and 8.

H Hn“C4H9 H H H H X H Hsec-C4H9 H H H -O-CH 2° H Ht_C4H9 H H F F H H HC2*5 H H S02NH2 H H ^4Η9 H t-C.H„ 4 9 H H H so2m2 H H 0-i-C3H? °-i-C3H7 H H H HSo2nh2 οοη3 H OCH3 H H Cl so2nh2 Η H och3 H och3 H so2nh2 Cl H Br H H H H OH OCH3 H H Br H H H H oh H H H Br H H H H OH H H H Br H 0-n- C3H7 och3 H Cl H H H H H 0-n- C3H7 H Br Br H H H H H 0-n-C.H, 3 Br H Br H H OCH3 OH H H H Br Cl 0-n- C3H7 H o-n- C3H7 H I H H H H H cf3 H - 24 3-466 ?3 ?5 V H I H H I H I H OCOCH3 H 0C0CH3 H H CP3 H H H οοη3 OCHCH 2 6 5 H H o-n-c3H7 OCHCH 2 6 5 H EXAMPLE 11 7-Hydroxy-8-methoxytetrazoloraI quinazol-5-one 7-Benzyloxy-8-methoxytetrazolo[a]quinazol-5-one (0.05 g.) is dissolved in trifluoroacetic acid (2 ml.) and the solution refluxed for 1.5 hours. The reaction mixture is cooled to room temperature and ether (4 ml.) is added. The resulting solid is filtered off, washed With ether (2x4 ml.) and air dried. The product is recrystallized from N,N-dimethylformamide-water (1-1) Yield = Ο.Ό25 g. (48%). M.P. 400°C. in like manner, 7-methoxy-8-benzyloxytetrazolo[a] quinazol5-one is debenzylated to the corresponding 8-hydroxy compound.

Neutralization of the above salts with sodium or potassium hydroxide in water affords the base form.

EXAMPLE 12 7-Acetoxy-8-methoxytetrazolorά| quinazol-5-one A mixture of 7-hydroxy-8-methoxytetrazolo[a]quinazol-5one trifluoroacetate (0.01 g.), acetic anhydride (3 ml.) and p-toluenesulfonic acid (0.005 g.) is heated at 100° C. for four hours. The reaction mixture is cooled and evaporated to dryness under reduced pressure. The residue is dissolved in chloroform, decolorized, filtered and the filtrate evaporated to dryness under reduced pressure. The residue crystallizes upon addition of ether. - 25 Neutralization in aqueous NaOH affords the base.

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

OCOH OCH3 OCOC H OCH OCO-n~C,H OCH, J 7 3 R4Rs och3 OCOH οοη3 ococh3 och3 OCO-n-C3H, EXAMPLE 13 Injectable Preparation One thousand grams of 7-methoxy-8-n-propoxy tetrazolo [ a] quinazol-5-one are intimately mixed and ground with 2500 grams of sodium ascorbate. The ground, dry mixture is placed in vials and sterilized with ethylene oxide after which the vials are sterilely stoppered. For intravenous administration, sufficient water is added to the materials in the vials to form a solution containing 5.0 mg. of active ingredient per milliliter of injectable solution.

EXAMPLE 14 Tablets A tablet base is prepared by blending the following ingredients in the proportion by weight indicated: 13466 - 26 - Sucrose, U.S.P. 80.3 Tapioca Starch 13.2 Magnesium Stearate 6.5 Into this tablet base there is blended sufficient 7 methoxy-8-n-propoxytetrazolo[a]quinazol-5-one to provide tablets containing 20, 100, and 250 mg. of active ingredient per tablet. The compositions are each compressed into tablets each weighing 360 mg., by conventional means.

EXAMPLE 15 Capsules A blend is prepared containing the following ingredients Calcium carbonate, U.S.P. 17.6 Dicalcium phosphate 18.8 Magnesium trisilicate, U.S.P. 5.2 Lactose, U.S.P. 5.2 Potato starch 5.2 Magnesium stearate A 0.8 Magnesium stearate B 0.35 To this blend is added sufficient 7-methoxy-8-isopropoxy tetrazolo[a] quinazol-5-one to provide capsules containing 10, 25 and 50 mg. of active ingredient per capsule. The compositions are filled into conventional hard gelatin capsules in the amount of 350 mg. per capsule.

In like manner, capsules containing 2.0 mg. and 6.0 mg. of active ingredient, and having 300 mg. of the following blends per capsule are prepared: 43486 Ingredients Drug N-methylglucamine Lactose, anhydrous Corn starch, anhydrous *Talc Ingredients Drug N-methylglucamine Lactose, anhydrous Corn starch, anhydrous *Talc Weight mg./capsule 2.00 18.00 241.00 .00 8.80 Weight mg./capsule 6.00 18.00 237.20 .00 8.80 *Talc added before encapsulation EXAMPLE 16 Solution A solution of 8-n-propoxytetrazolo[a]quinazol-5-one is prepared with the following composition: Effective ingredient 6.04 grams Magnesium chloride hexahydrate 12.36 grams MonoethanoIamine 8.85 ml. Propylene glycol 376.00 grams Water, distilled 94.00 ml.

The resultant solution has a concentration of effective ingredient of 10 mg./ml. and is suitable for parenteral and, especially, for intramuscular administration.

EXAMPLE 17 An aqueous solution of 7-methoxy-8-n-propoxytetrazolo[a] quinazol-5-one (containing 3 mg. of drug per ml. of solution) is placed in a standard nebulizer such as is available from the Vaponephrine Co., Edison, N. J. The solution is sprayed I486 - 28 under an air pressure of 6 lbs. per square inch into a closed 8 x 8 x 12” plastic container for six minutes. The container has four openings to accommodate the heads of four rats. Four rats are exposed to the drug simultaneously with only their heads coming in contact with aerosol. The results are evaluated as per the PCA reaction test procedure described above.

EXAMPLE 18 Aerosol Suspension A mixture of 7-methoxy-8-n-propoxytetrazolo[a] quinazol-5one (antiallergy agent) and the other ingredients under (a) in the examples below are 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) introduced by pressure filling through the valve nozzle to a gauge pressure of approximately 35-40 pounds per square inch at 20°C.

Suspension A (a) Antiallergy agent 0.25 Isopropyl myristate 0.10 Ethanol 26.40 (b) 60-40% mixture of 73.25 1,2-dichlorotetrafluoroethane-l-chloropentafluoroethane Suspension B (a) Antiallergy agent 0.25 Ethanol 26.50 (b) A 60-40% mixture of 1,2- 73.25 dichlorotetrafluoroethane-Ichloropentafluoroethane

Claims (16)

1. A pharmaceutical composition act ive as an ant in IIency agent which comprises, as the active ingredient, a compound having the general formula: wherein each of R^ and R 2 is a hydrogen or halogen atom, an alkyl group having from one to four carbon atoms, an alkoxy group having from one to four carbon atoms, an alkanoyloxy group having from one to four carbon atoms, or a benzyloxy, 10 hydroxy, trifluoromethyi or sulphonamide group, or R^ and R 2 , when attached to adjacent carbon atoms in the ring and taken together form a methylenedioxy or ethylenedioxy group, or a pharmaceutically acceptable cationic salt thereof, in admixture with a pharmaceutically-acceptable carrier. 15

2. A composition according to claim 1, wherein each of R^ and R 2 is an alkoxy group having from one to four carbon atoms.

3. A composition according to claim 2, wherein R^ is 7-alkoxy and R 2 is 8-alkoxy, wherein the alkoxy groups each 20 have from one to four carbon atoms.

4. A composition according to any one of claims 1 to 3, wherein Rj is 7-methoxy. 3466 - 30

5. A composition according to any one of claims 1 to 4 wherein R^ is n-propoxy.

6. A pharmaceutical composition according to any one of the preceding claims, in a form suitable for administration by inhalation.

7. A pharmaceutical composition according to any one of claims I to 6, comprising a suspension of the active compound in a liquified propellant.

8. A pharmaceutical composition according to any one of claims 1 to 5, comprising the active compound as a solid and a solid diluent.

9. A compound of the formula wherein R 1 and R'have the same meaning as R^ and R^ as defined in claim 1 with the proviso that one of R'^ or R/ is other than hydrogen, or a pharmaceutically acceptable cationic salt thereof.

10. A compound according to claim 9, wherein each of R'^ and R/ an alkoxy group having from one to four carbon atoms

11. A compound according to claim 10, wherein R 1 ^ is 7alkoxy and R' 2 is 8-alkoxy, wherein the alkoxy groups each have from one to four carbon atoms.

12. A compound according to any one of claims 9 to 11, wherein R' is methoxy.

13. 7-Methoxy-8-n-propoxy tetrazolo[a] quinazol-5-one.

14. A compound according to claim 9, wherein R'^ and R' 2 taken together are 7,8-ethylenedioxy.

15. A compound of formula (IA) as claimed in claim 9 substantially as hereinbefore described with reference to Examples 8 to 12.

16. Pharmaceutical compositions according to claim 1 10 substantially as hereinbefore described with reference to Examples 13 to 18.