CS195731B2 - Process for preparing n-/5-tetrazolyl/-1-oxo-1h-6-alkoxypyrimido/1,2-a/quinolin-2-carboxamides - Google Patents

Abstract

1500666 Pyrimido[1,2-a]quinoline - derived amides PFIZER Inc 14 July 1976 [1 Aug 1975] 29181/76 Heading C2C The invention comprises compounds of formula and their pharmaceutically acceptable cationic salts, wherein R 1 and R 2 are each H, Cl, F or C 1-5 alkyl or alkoxy, or R 1 -R 2 is methylenedioxy or ethylenedioxy, and R 3 is Cl, Br or C 1-5 alkoxy. In examples, the amide link is formed from 5-aminotetrazole and the analogous pyrimidoquinolinecarboxylic acid; the latter is made by hydrolysing the ethyl ester, which is in turn prepared by cyclizing a correspondingly substituted ethyl 2-quinolylaminomethylenemalonate. Additionally, the product in which R 3 is halogen may be converted to one in which R 3 is alkoxy, by reaction with an alkanol. Therapeutic compositions having antiallergy activity comprise compounds of the above formula, and may contain additional active agents such as theophylline or sympathomimetic amines.

Description

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of anallergically active N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimido (1,2-a) quinoline-2-carboxamides, their pharmaceutically acceptable cation addition salts, and the corresponding cations thereof. compounds wherein the benzene ring is substituted one or more times with substituents that may be said to be useful in the treatment of allergic reactions, particularly allergic bronchial-asthma. The invention also relates to the necessary intermediates.

The allergic reaction, which is a symptom of antigen-antibody interaction, is manifested in a number of ways and in various organs or tissues. Common allergic problems - for example, allergic rhinitis, characterized by occasional or perennial sneezing, nasal discharge, nasal congestion and irritation and lacrimation of eyes, hay fever, which refers to -allergic rhinitis, usually resulting from hypersensitivity to the pollen of various grasses, then bronchial asthma, which is one of the most difficult and most abusive forms of allergic reactions, characterized in that the body reacts excessively sensitively to the respiratory tract to various immunogenic or non-immunogenic stimuli, resulting in bronchospasm with wheezing, short-term paroxysm, and severely aggravated conditions air passages. The mechanical difficulty in passing air difficulty is usually eliminated by the use of bronchodilators providing symptomatic relief. In contrast, antiallergic agents prevent the release of mediators of anaphylaxis from tissue stores, and thus act prophylactically to prevent the induction of broncial contractions by mediators.

Much effort has already been made to find medications that can be relieved of these abnormal physiological conditions. Already in 1910 describes Matthews, Brit. - Med. J. - 1, 441 ('1910) bronchodilator effects of epinephrine, then - Chen and Schmidt, J. Pharmacol. Exper. Therap 24, 339- (1924) reported the possibility of using ephedrine alkaloid as an orally high-potency bronchodilator with the same spectrum of activity as epinephrine. - In 1940 Konzett, Arch. - Exp. Pathol. Pharmacol. 197, 27 (1940) describes the effects of the mighty-aerosol bronchodilator isoproterenol. Collum a - spol. - described in Brit. J. Pharmacol. Exp. 35, 141- (1969) - the pharmacology of salbutamol, i.e. it is also a 'potent' bronchodilator with protracted efficacy, and further administered either orally or in the form of an aerosol. - Many of the bronchodilators contain - theophylline. They are usually less effective than sympathomimetic amines such as isoproterenol and salbutamol, and are ineffective in aerosol administration.

Recently, Cox and Associates have described Advances in Drug Res. 5, 115 (1970) the pharmacology of one such agent, namely the disodium salt of chromoglycate, i.e. 1,3-bis- (2-carboxy chromon-5-yloxy) -2-hydroxypropane; the substance was called "Intai". It is not a bronchodilator, and the therapeutic effect is manifested by a unique mechanism of action to the extent that it inhibits the release of mediators of anaphylaxis and is therefore administered prophylactically. A disadvantage of this substance is ineffectiveness when administered orally, and is administered by inhalation of a solid preparation for best results. Furthermore, although it is effective against anaphylaxis caused by immunoglobulin E, it is only effective at anaphylaxis caused by immunoglobulin G at high doses (protection of 60-70% at doses of 100 and 300 mg / kg).

Although this substance represents a very extraordinary contribution to the treatment of asthma, and this also applies to previous substances, many of them suffer from undesirable side effects, namely the stimulation of heart activity.

The synthesis of 1H-pyrimido (-1,2-a) quinoline was first described by Antaki and colleagues in J. Chem. Soc. 1951, - 551; condensed 2-chloroquinoline with ethyl .beta.-aminocrototolate in the presence of anhydrous potassium carbonate and a trace of copper bronze. Thus, 1-oxo-1H-3-methylpyrimido (1,2-aquinoline) was prepared.

Antaki further describes in J. Am. Chem. Soc. 80, 3066 (1958) condensation of 2-aminoquinoline with ethyl ethoxyethylene cyanacetic acid ethyl ester to give ethyl 2-quinolylaminoethylene cyanacetic acid ethyl ester and distillation under reduced pressure further affords 1-oxo-1H-pyrimido (1,2-a) quinoline nitrile -2-carboxylic acid. The compound appears to have antischistosomal activity.

Richardson and colleagues have described in J. Med. Chem. 15, 1203, (1972), 1-oxo-1H-pyrimido (1,2-a) quinoline-2-carboxylic acid ethyl ester, and reported to be inactive as an antimicrobial compound. Testing for antiallergic efficacy with a passive cutaneous anaphylactic test, it was found to be 100% efficacious at an intravenous dose of 3 mg / kg, but ineffective at a dose of 1 mg / kg. About 90% efficacy was found when administered at 30 mg / kg by the oral route, but no efficacy was demonstrated at 10 mg / kg.

It has now been found that N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimido (1,2-a) quinoline-2-carboxamides of the formula I have been found to be valuable antiallergic agents.

STEED

N - N I and their pharmaceutically acceptable salts with cations.

That is, they inhibit the release of mediators of anaphylaxis in mammals, including humans, and in this way prevent the induction of bronchoconstrictions by mediators. But they are not their own bronchodilators. In contrast to the disodium salt of chromoglycate, said Intal, they are of practical value against anaphylation induced by both immunoglobulin G and immunoglobulin E for administration by oral, intranasal and intraperitoneal as well as by inhalation.

In the above general formula (I), R 1 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, fluorine or chlorine. R represents a lower alkyl group.

As used herein, the terms "lower alkyl" and "lower alkoxy" refer to alkyl and alkoxy groups of 1 to 5 carbon atoms, since the starting compounds for the preparation of such substituents are more readily available than those of higher alkyl or alkoxy groups.

The term "pharmaceutically acceptable cation salts" refers to alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, ammonium salts, as well as salts of organic bases such as amines such as triethylamine , tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, N, N'-dibenzylethylenediamine and pyrrolidine.

5-substituted tetrazole derivatives may exist, as is known, in two isomeric forms:

Z-N / N-NH-N which exist in the form of dynamically tautomeric equilibrium mixtures. Both forms of tetra zolylamides are within the scope of this invention.

Antiallergic activity of the corresponding amides,. The 1-oxo-1H-6-alkoxypyrimido (1,2-a) quinoline-2-carboxylic acids and the corresponding esters are described in U.S. Pat. No. 4,066,766. The compounds disclosed in this document are characterized by a substantially broader spectrum of antiallergic activity in comparison with the corresponding acids. Their antiallergic efficacy is indeed surprising since the corresponding simple amides, i.e., the functional group -COONH2 or -CON (C2H5) 2, are non-allergic antiallergic agents when tested as antiallergic agents using the methods described below.

According to the present invention, they are particularly preferred. compounds of the above formula wherein OR is methoxy or ethoxy and R 1 is hydrogen, compounds where OR is methoxy-and R 1 is lower alkoxy or fluoro. These compounds can be summarized as follows:

RíOR

H, OCH-, OC2H5

CH 1 OCH 3, OC 2 H 5

OCh'3OCHs

OC2H5OCHs

FOCHs

The antiallergic activity of the compounds of the invention was evaluated by passive cutaneous anaphylactic assay [see Ovary, J. Immun. 81, 355 (19-8)]. In this test, normal animals are injected intradermally with serum antibodies from actively sensitized animals. The challenge is then by intravenous administration of the antigen in a mixture with a dye such as Evans Blue. Increased capillary permeability due to the reaction of the antigen with the antibody receives dye from the injection site of the antibody. The test animals are asphyxiated, and the intensity of the reaction is determined by measuring the diameter and intensity of the blue color on the inner surface of the animal skin.

The compounds of the formula I according to the invention are readily prepared by the corresponding RO-substituted 1-oxo-1H-6-pyrimido (1,2-a) quinoline-2-carboxylic acid derivative of the formula II

OR oV (1i) ^coc in which R and R 1 are as defined above, dehydrate condensates with 5-aminotetrazole and, optionally, convert the product to a pharmaceutically acceptable salt.

. Dehydration condensation can be carried out by a variety of commonly used reagents, as are known in peptide chemistry. Examples are:

N, N‘-carbonyldiimidazole, N, N-carbonyl-di-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphenylketene-p-tolylimine, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, ethylene chlorophosphite, diethylethylenepyrophosphite,

N-ethyl-5-phenylisoxazolium-3'-sulfonate, phenylphosphorodi (1-imidazolate) and carbodiimides such as dicyclohexylcarbodiimide, 1-cyclohexyl-3- (2-morpholinomethyl) carbodiimide,

N- (3-dimethylaminopropyl) -N‘-ethylcarbodiimide hydrochloride, 1-ethyl-3- (3‘-dimethylaminopropyl) carbodiimide hydrochloride, and diethyl cyanamide. .

The above condensing agents are generally used such that:. they are first treated with an acidic reactant of formula (II) and the resulting product is treated with ammlnotetrazel without isolation to give, - expected RO - substituted N- (5-tetrazolyl) -1,4-oxo-1-amide derivatives. H-6-pyrimido (1,2-a) -quinoline-2-carboxylic acid. The reaction is carried out in an inert solvent under the reaction conditions and it is not necessary for the acid used as the reaction component to be soluble in the solvent used. The only requirement for the solvent is that it does not react substantially to any of the reactants, even to the reaction product. The large number of condensing agents that can be used allows the use of a large number of solvents. Examples of solvents include Ν, Ν-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of the acid used with the condensing agent is carried out at a temperature in the range of about 20 ° C to about 110 ° C, and the reactive intermediate is then treated with 5-aminotetrazole at a temperature of about 20 ° C to 110 ° C. Each of these steps is preferably carried out at a temperature of from about 50 to about 100 ° C; yields and reaction rates at this temperature are most preferred.

The molar ratio of acid to condensing agent and 5-aminotetrarol is generally from 1: 1: 1 to 1: 1.1: 1.1. Larger amounts of condensing agent and 5-aminotetrazole may be used, but without any advantage. An excess - - of 10 mol% is satisfactory.

As will be readily apparent to those skilled in the art, it is also possible to mix all 3 reactants at once instead of sequential addition. However, if the acid is premixed with the condensing agent to form a reactive intermediate, this usually results in better yields of the expected N- (5-tetrazolyl) amides.

The preferred condensing agent is označ, Ν-carbonyldimidazole, since the reaction proceeds smoothly with very good yields of the reaction product without seeking the best reaction conditions. Using this condensing agent, N, N-dimethylformamide and a temperature in the range of about 85 to 100 ° C are recommended as the solvent; these reaction conditions may be said to be preferred for the reasons set forth above.

Compounds of formula (I) may also conveniently be prepared by the Williamson reaction of the corresponding N- (5-tetrazolyl) -1-oxo-1H-6-chloro (or bromo) -pyrimido (1,2-a) quinolin-2-yl acid amide. with a suitable alkanol.

The required RO-substituted 1-oxo-1H-6-pyrimido (1,2-a) quinoline-2-carboxylic acid derivatives are prepared by condensation of the corresponding 2-aminoquinoline derivative with the substituent RO at the -4-position _{and the} corresponding dialkyl acid ester ethoxymethylene malonic acid to give the dialkyl ester of the RO-substituted 2-quinolylaminomethylenemic acid derivative with the RO substituent at the 4-position, and this is then cyclized to form the 6-RO-substituted alkyl ester of 1-oxo-1H-pyrimido (1,2-alkyl) ester -a) quinoline-2-carboxylic acid.

The condensation is carried out by heating the stoichiometric mixture of the reagent from the group of 2-aminoquinolinone derivatives and ethoxymethylenemalonic acid dialkyl ester to a temperature in the range of about 80 to about 125 ° C. Lower temperatures are not desirable because the reaction proceeds too slowly. Although higher temperatures can be used, but without any advantages. The reaction is usually carried out preferably in the melt, but - of course - can also be carried out in a solvent or in a mixture of solvents such as ethanol, N, N-dimethylformamide and acetonitrile. But from a practical point of view, the presence of a solvent is not necessary.

The alkyl 2-quinolylaminomethylenemalonic acid alkyl ester having the substituent RO- in the -4-position is then cyclized, preferably by heating to about -175-250 ° C in a suitable diluent inert under the reaction conditions; that is, using a reaction temperature control agent, it is stable at the high reaction temperature used, and does not react with either the starting compound or the cyclization product. Examples of suitable solvents and diluents include high boiling hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, sulfuric acid acetic anhydride, diphenyl ether and diphenyl, especially a mixture of 26.5% diphenyl and 73.5%. diphenylether, which is carried out under the name Dowtherm A.

Alkyl esters of 1-oxo-lHspygimido (1,2- and quinoline-2-carboxylic acids with the substituent RO- at the -6-position) can be converted to the corresponding free acids by hydrolysis, preferably under acidic conditions. an ester and an inorganic acid such as hydrochloric, sulfuric, phosphoric or nitric acid at a temperature of from about 50 to about 100 ° C for up to 4 hours until the hydrolysis is substantially complete. hydrochloric acid at a concentration of from about 3 N to about 1 N. The less soluble the ester as the reactant in water, the more concentrated the acid is used in the hydrolysis. The free acids usually crystallize from the reaction mixture by cooling, and If no crystallization occurs, then acids are obtained by concentration of the reaction mixture. is N, N-dimethylformamide.

The salts are prepared by treating the free acid with a suitable metal salt, such as carbonate, bicarbonate, acetate, hexanoic acid salt, and hydroxide, and in a suitable environment such as water, methanol or ethanol, in each case. using well known procedures. The salts are isolated by conventional techniques such as filtration if they are insoluble in the medium used; - evaporation of the solvent, if it is soluble in the medium used, or precipitation from solution by addition of a salt insoluble material.

As mentioned above, the N- (5-tetrazolyl) amides of the present invention exhibit a substantially broader spectrum of antiallergic activity compared to the corresponding acids. Acids are capable of inhibiting only anaphylactic events due to immunoglobulin E. In contrast to this finding, N - (.5-tetrazolyl) amides are effective not only against anaphylaxis induced by immunoglobulin E but also against anaphylaxis induced by immunoglobulin G. This is also a difference when compared to the efficacy of the disodium salt of chromoglycate, which inhibits immunoglobulin G responses only at high doses.

The products of the methods of the invention and the pharmaceutically acceptable salts of the cations are useful as prophylactic agents in inhibiting or preventing the release of anaphylactic mediators (allergy, immediate hypersensitivity reactions) as well as allergic sympton in animals, and can be administered as such, or in mixtures with other substances, for example theophylline or sympathomimetic amines. They may be administered as such, but are usually combined with a pharmaceutical carrier, which is chosen taking into account the chosen route of administration and taking into account standardized pharmaceutical practice. For example, they may be combined with various pharmaceutically acceptable and harmless carriers in the form of tablets, capsules, pills, candy, hard candies, powders, aerosol sprays, aqueous suspensions or suspensions. solutions, injectable solutions, elixirs, syrups, and the like. Useful carriers include solid diluents. fillers, sterile aqueous media, and various non-toxic organic solvents. . Further, the oral pharmaceutical compositions of this invention may be suitably sweetened or flavored by addition of agents of the type commonly known in the art.

The nature of the carrier selected and the proportion of active ingredient to carrier are influenced by solubility and chemical. the nature of the therapeutically active agent, the route of administration chosen and the needs of conventional pharmaceutical practice. For example, when the compounds of this invention are administered orally in the form of tablets, fillers such as lactose, sodium citric acid, calcium carbonate, calcium hydrogen phosphate, etc. may be used. Various disintegrating agents such as starch may be added. , alginic acids and certain complex silicates, along with glidants such as magnesium stearate, sodium lauryl sulfuric acid and talc. For oral administration in capsule form, lactose and high molecular weight polyethylene glycols are the most preferred excipients. . When aqueous suspensions are orally administered, the compounds of the invention may be combined with emulsifiers or suspending agents. Diluents such as ethanol, propylene glycol, glycerol and chloroform or mixtures thereof may be used.

For the purpose of parenteral administration and inhalation, solutions or suspensions of these compounds in sesame or peanut oil, or in aqueous propylene glycol solutions, as well as sterile aqueous solutions of soluble and pharmaceutically acceptable salts, as described herein, may be used. These solutions are particularly suitable for intramuscular and subcutaneous injection purposes, if such a mode of administration is desired. Aqueous solutions of substances, including solutions of salts in pure distilled water, can also be used for intravenous injection purposes, provided that the pH is adjusted appropriately prior to administration. Solutions of this type should also be suitably buffered, if necessary, and the liquid diluent treated with sodium chloride or glucose solution to make the solution isotonic.

The compounds may be administered to asthmatic individuals affected by bronchoconstriction using inhalers or other devices allowing the active ingredient to directly contact the affected area of the tissue. When administered by inhalation. For example, the composition may comprise (1) a solution or effervescent active ingredient in a liquid medium of the type mentioned hereinbefore, when administered in the form of a mist, [2] a suspension, or a solution. active ingredients in a liquid · under pressure, such as dichlorodifluoromethane · or · chlorotrifluoroethane for delivery under pressure from a reservoir, or (3) a mixture of the active ingredient and a solid diluent such as lactose for delivery from a powder inhalation device. ,

Compositions suitable for inhalation using a conventional nebulizer may contain from about 0.1 to about 1% of the active ingredient, and compositions for delivery from pressurized containers may contain from about 0.5 to about 2% of the active ingredient. Compositions for use of inhaled powders may contain the active ingredient and diluent in a ratio of about 1: 0.5 to about 1: 1.5.

It is necessary that the active ingredient be such a proportion of the composition that a suitable dosage is obtained. Of course, several dosage units may be administered at about the same time. Although compositions with a content of less than 0.005% by weight of the active ingredient can also be used in some cases, it is preferred to use formulations above 0.005% by weight of the active ingredient, otherwise the amount of carrier is unnecessarily excessively high. . Of course, the efficiency increases with the concentration of the active ingredient. The composition may contain by weight 10, 50, 75, 95% or more of the active ingredient.

Regarding the dosage regimen of the present invention, the physician will ultimately decide the dose that is most appropriate for one or the individual, and this dosage will, of course, vary with the age, weight and response of the patient being treated, as well as depending on the nature and extent of the symptoms, the pharmacodynamic properties of the drug used and the route of administration. Generally speaking, small doses are administered initially with gradual increase in dosage until an optimal level is found. It is often found that when the composition is administered orally, higher doses are required to achieve the same level as that achieved with parenteral administration of lower doses.

Taking into account all of the foregoing factors, an effective daily oral dose of the compounds of this invention is believed to vary from about 10 to about 1500 mg per day in humans, with a range of about 10 to about 10 being preferred. up to about Ό00 mg per day in a single dose or in divided doses, or about a range of 0.2 to about 12 mg / kg body weight; · This will provide effective relief for the bronchoconstriction of affected people. The values are given only as a possible example and in individual cases the possible doses will be higher or lower.

When administered the compounds of this invention intravenously · ^ or by inhalation, the daily effective dose ranges from about 0.5 to about 400 mg per day, and preferably is from about 0.25 to about 200 mg per day · ^or: may · Act - in other words - between 0.005 and 4. mg / kg body weight in a single dose or in divided doses.

In the case of anaphylactic shock, there are two always the same major changes:

(1) increase capillary perfusion and (2) smooth muscle contraction. Increased capillary permeability is the result of antigen-antibody interactions. This phenomenon, as well as smooth muscle contraction, can be observed and easily measured. And an increase in capillary permeability underlies the passive cutaneous anaphylactic test.

The passive cutaneous anaphylactic test is a measure of the antiallergic, particularly anti-asthmatic, activity of the compound. Compounds inhibiting a positive passive cutaneous anaphylactic test elicited. the rat immunochemical partner of human immunoglobulin E, or reagin, is considered to be with. antiallergic activity, see C. Nota, Ann. N. Y. Ac-ad. Sci. 103, 264 (1963). Reagin is mainly immunoglobulin E and it is the major immunoglobulin that is responsible for allergic asthma, anaxylaxis, hay fever, food sensitivity and some drug hypersensitivity phenomena. If these compounds are administered to a sensitized individual, whether human or animal, before contact with the antigens or substances to which they are allergic, it will prevent an allergic reaction that would otherwise occur. Thus, they represent the possibility of prophylactic treatment of allergy or anaphylactic reactions of a nature induced by reagin.

In other words, these compounds block the release of mediators resulting from the antigen-antibody reaction as evidenced by a passive cutaneous-anaphylactic test using a rat homocyte-β-petroleum antibody, which is known to be correlated with human reaginic antibodies . Inhibition of the reaginic antigen-antibody responses in rats by testing an animal with a passive cutaneous anaphylactic assay is believed to correlate inhibition of human reactive antigen-antibody responses that occur during allergic conditions.

The passive cutaneous anaphylactic reaction as a procedure for evaluating the compounds of this invention is an excellent possibility of correlating the efficacy of the compounds in the test and the utility in the treatment of allergic asthma.

The ability to interfere with passive - cutaneous anaphylactic reactions is measured in male rats, Charles River Wi-star strain, weight 170-210 g. Reaginic -antiserum, rich in immunoglobulin E antibodies, is prepared according to the procedure described by Petillo et al. Arch. Allergy 44: 309 (1973). Hyperimmune antiserum - rich in immunoglobulin G antibodies to albumin - from hen eggs is prepared as described by Orange et al., J. Exptl. Copper. 127, 767 (1968). 48 hours prior to challenge, the reaginic antiserum is injected itradermally into the skin of the shaved back of a normal rat, and 5 hours prior to challenge, the hyperimmune antiserum is injected in a similar manner. And - at the third site - 60 histamine dihydrochloride and 0.5 μξ - serotonin creatinine sulphate are injected intradermally - just prior to antigen challenge as evidence of antihistamine, antiserotonin and unspecified types of blocking. Thereafter, the compounds of the present invention or sodium chloride solution are intravenously administered and immediately provoked by administration of 5 mg of egg albumin and 2.5 mg of Evans blue and egg albumin administered in cases of oral administration of Evans blue and egg dye. albumin is administered 5 minutes after drug administration. 30 minutes later, the animals were suffocated with chloroform, the back skin removed and evaluated on the reverse side. The diameter of each injection site of the product in mm, and the degree of 0.1, 0.5, 1, 2, 3, or 4, is evaluated as proportional to the color intensity of the dye. The data for each injection site is mathematically evaluated for each group of 5 animals, and the results are compared with control animals receiving sodium chloride solution. The difference is expressed as the blocking affected by the compound administered.

Some exemplary compounds of this invention were tested for anti-allergic activity by the above-described procedure and the resulting efficiencies are reported as a percentage of protection. For comparison, intal, a disodium salt of chromoglycates, a commercially available antiallergic agent, is also included in the results.

The general formula of the test compounds is

NH-N

Ri STEED . Immunoglobulin E Immunoglobulin G intravenously orally intravenously orally mg / kg% mg / kg% mg / kg% mg / kg%

H ОСНз H ' OC2H5 8-C1 OCžHs 0.3 76 0.03 8 8-OCH3 ОСНз 0.3 70 0.03 74 8-OCH5 OCáHs 0.3 100 ALIGN! 0.03 94 9-ОСНз ОСНз 0.3 97 0.03 72 9-F ОСНз 3 100 ALIGN! 0.3 100 ALIGN! 0.03 89 9-СНз ОСНз 0.3 70 0.03 53 8-C2H5 ОСНз 0.3 0.03 83 8 Example I

N-1 (5-Tetrazolyl) -1-oxo-ΙΗ-6-methoxypyrimido (1,2-aquinoline-2-carboxylic acid amide)

A mixture of 540 mg (2.0 mmol) of 1-oxo-ΙΗ-6-methoxypyrimidoyl (1,2-a) quinoline-2-carboxylic acid and 357 mg (2.2 mmol) of N, N'-carbonyldiimldazole was added to 15 ml of Ν, Ν-dimethylformamide was heated on a steam bath for 15 minutes with stirring. After about five minutes of heating, a clear solution was formed, whereupon a precipitate formed. The reaction mixture was stirred After heating for a further 45 minutes at _a room temperature, and then added 187 mg (2.2 mmol) of 5-aminotetrazole ,. The reaction mixture is heated on a steam bath for 40 minutes, then cooled, and the precipitated product is filtered off; yield 540 mg

3 73 ‘3 71 0.3 17 0.3 60 3 46 3 63 1 71 1 59 3 28 0.3 83 3 19 Dec 0.3 0 0.03 25 0.3 0 3 54 0.3 65 3 51 0.3 4 0.03 86 0.3 4 3 81 0.3 69 3 72 0.3 17 0.03 63 0.3 29 3 20 May 0.3 85 3 59 0.3 Ϊ 0.03 67 0.3 6 3 83 0.3 57 / 0.03 45 3 70 0.3 55 3 79 0.3 7 0.03 40 0.3 11 3 81 0.3 53 3 75 0.3 22nd 0.03 4 0.3 12

220 DEG C. (dec.).

The material was purified by dissolving it in hot N, N-dimethylformamide at a ratio of 200 mg of crude product per 20 ml of solvent, filtering the hot solution, and cooling the filtrate. The precipitated yellow crystals are filtered off, m.p. 255 DEG C. (dec.).

Analysis calculated for C15H11O3N7:

% C, 53.41;% H, 3.29;% N, 2-9.07%.

% C, 53.12;% H, 3.67;

The following compounds are prepared in a similar manner from the appropriate starting reagents:

STEED

N II

NH-N found%

Analysis calculated%

Example Ri STEED Melting point ° C C H N C H N II H OC2H5 266–268 (r) 54.70 3.73 27.91 54.59 4,11 26.50 ”' III 8-ОСНз ОСНз 255—258 (r) 52.32 3.57 26.69 52.27 3.69 25.93 IV 8-ОСНз OC2H5 266—268 (r) 53.54 3.96 25.71 53.63 4.01 25.55 in 9-СНз ОСНз 235—237 (rj 54.70 3.73 27.91 54.15 4.15 27.05 ^<b) VI 8-C2H5 ОСНз 254—256 (rj 55.88 4.14 26.84 55.14 4.21 26.42 VII 8-C1 OC2H5 273—276 (rj 49.82 3.13 25.42 49.53 3.38 25.41 VIII 9-F ОСНз 235-236 (r) 50.70 2.84 27.60 50.32 3.21 26.98 ^(b > IX 9-ОСНз ОСНз 253–254 (r) 52.32 3.57 26.69 51,54 3.62 27.43 ^b Product from the example VIII se cleans solvent- nolamine, diethylamino-ethylaftine, pyrroli- in 6 N ammonia solution; by standing this . dinu and N, N-dibenzylethylenediamine reactions with solution the product precipitates. The fixed portion is equivalent corresponding hydroxide ко-

It is filtered, dissolved in water and precipitated from the solution by acidification with a 3 N hydrochloric acid solution. After filtration, the product is dried and recrystallized from N, N-dimethylformamide.

The product of Example IX is purified by crystallization from Ν, Ν-dimethylformamide and further purified according to the procedure described for the product of Example VIII.

vu, ammonium hydroxide or amine in water or ethanol followed by aspiration of the salt if insoluble in the solvent used; or the solvent needs to be distilled off if the salt dissolves in the solvent.

Example XII

Example X

Injectable preparations

N- (5-Tetrazolyl) -1-oxo-1H-6-ethoxypyrimido (1,2-a) quinoline-2-carboxylic acid amide; boxylové

A mixture of 20 mg of p-toluenesulfonic acid monohydrate and 1.79 g of N- (5-tetrazolyl) -1-oxo-1H-6-chloropyrimido (1,2-a) quinoline-2-carboxylic acid amide in 75 ml of ethanol is added. is heated to reflux for 24 hours. The solvent was distilled off under reduced pressure and the residue was partitioned between 3 N hydrochloric acid solution (25 ml and 100 ml ethyl acetate). The phases were separated, and the solution in ethyl acetate was extracted twice with 20 ml 3 N hydrochloric acid each. The pH was adjusted to 7-8 by addition of 20% ammonia solution and the precipitated portion (235 mg) was filtered off.

Example XI

Preparation of salts

The products of Examples I to X are converted to the corresponding sodium, potassium, ammonium, calcium, magnesium, aluminum, triethylamine, tri-n-butylamine, piperldine, trieth100 g salts of N- (5-tetrazolyl) -1-oxo-1H. The 6-methoxypyrimido (1,2- and quinoline-2-carboxylic acid is mixed gently and ground with 250 g of sodium ascorbic acid. intravenous administration adds sufficient water to the substance in the vial to give a solution containing 5.0 mg of active ingredient per ml of solution for injection.

Example XIII

Tablets

A tablet base is prepared by mixing the following ingredients in weight proportions as indicated:

sucrose80,3 tapioca starch13,2 magnesium stearic acid6,5

Sufficient N- (5-tetrazolyl) -1-oxo-1H-6-methoxypyrimido (1,2-a) quinoline-2-carboxylic acid amide is mixed into the blended tablet bed to give 20, 100 tablets and

250 mg of active ingredient per tablet. Tablets of 360 mg each are conventionally compressed from the composition using conventional techniques.

Example XI V

Capsule

A mixture is prepared from the following components:

calcium carbonate17,6 dibasic calcium phosphate18,8 magnesium silicate5,2 lactose5,2 potato starch5,2 magnesium stearic acid A 0,8 magnesium stearic acid В0,35

Sufficient N- (5-tetrazolyl) -1-oxo-1H-6,9-dimethoxypyrimido (1,2- and quinoline-2-carboxylic acid amide amide) is added to this mixture to give capsules containing 10,25. and 50 mg of the active ingredient out of a total of 350 mg of the mixture in a hard gelatin capsule.

Similarly, capsules containing 2.0 mg and 6.0 mg of active ingredient and containing 300 mg of the following mixture per capsule are obtained:

weight in mg ingredient per drug capsule2.00

N-methylglucamine18.00 anhydrous lactose 241.20 talc) 8.80 or weight in mg ingredient per capsule drug6.00

N-methylglucamine18.00 anhydrous lactose 237.20 maize starch30.00 talc *) 8.80

’) The talc is added before the capsule is closed

Example XV

Solution

A solution of N- (5-tetrazolyl) -1-oxo-1H-6-methoxy-9-fluoro-

pyrimido- (1,2-a) quinoline-2-carboxylic acid The following composition: active ingredient 6.04 g chloride hexahydrate magnesium 12.36 g monoethanolamine 8,95 ml propylene glycol 376,00 g Distilled water 94,00 ml

In solution, the concentration of the active ingredient is 10 mg / ml, and the solution is suitable for parenteral and especially intramuscular administration.

Example XVI

An aqueous solution of sodium N- (5-tetrazolyl) -1-oxo-1H-6-methoxypyrimidino (1,2-a) quinoline-2-carboxylic acid amide salt (containing 3 mg of drug per ml of solution) is placed in a conventional mist production apparatus (e.g., from Vaponephrine Co., Edison, NJ). The solution is sprayed at an air pressure of 42 kPa into a 20-by-30-cm plastic container for 6 minutes. The container has 4 holes for attaching the heads of 4 rats. And 4 rats are exposed simultaneously to the drug so that only the rat heads come into contact with the aerosol. The results are evaluated as in the case of a passive cutaneous anaphylactic reaction as described hereinabove.

Example XVII

Aerosol suspension

A mixture of N- (5-tetrazolyl) -1-oxo-1H-6-methoxypyrimido- (1,2-a) quinoline-2-carboxylic acid amide as an antiallergic agent and the other ingredient shown in (a) in the following examples Crushed to a particle size of 1 to 5 microns in a ball mill. The mixture is then placed in a reservoir equipped with a valve and a pressure reagent as described in (b), which is pressurized by said valve to a pressure of about 20 to 20 psi at 20 ° C.

Suspense A%

a) antiallergic agent 0.25 myristic acid isopropyl ester0.10 ethanol26.40

b) 60-40% mixture of 1,2-dichlorotetrafluoroethane and 1-chloropentafluoroethane73,25

Suspense В%

a) antiallergic agent 0.25 ethanol26.50

b) 60-40% mixture of 1,2-dichlorotetrafluoroethane and 1-chloropentafluoroethane73,25

Preparation

1-Oxo-1H-6-methoxypyrimido (1,2-a) quinoline-2-carboxylic acid ethyl ester

1. A mixture of 34 g (0.196 mol) of 2-amino-4-methoxyquinoline and 46.8 g (0.216 mol) of ethoxymethylenemalonic acid diethyl ester is heated on a steam bath. After about 10 minutes a clear melt is formed, which begins to set in about 20 minutes. The mixture was heated at room temperature for 45 minutes and then cooled. The product, 4-methoxy-2-quinolylaminomethylenemalonic acid diethyl ester, is recrystallized from 350 ml of ethanol to give a fluffy solid, m.p. 136.5-137.5 ° C.

Analysis:

РГО С1вН20smeО5 calculated:

% C, 62.78;% H, 5.85;% N, 8.14; П A 1070ΙΊ A *

62.72 o / o C, 6.10 o / o H, 8.37 o / o N.

2. 55 g (0.16 mol) of the product of Step 1 are introduced into 350 ml of Dowtherm A at 100 DEG C. and the clear yellow solution thus prepared is heated at 230 DEG to 233 DEG C. for 1.75 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 mL) and extracted with three portions of 1 N hydrochloric acid (120 mL). The acidic extracts were combined, basified by addition of 20% ammonia solution, and the product precipitated upon cooling. It is filtered, and it is gradually crystallized from ethanol, a 1: 1 mixture of benzene and cyclohexane and ethanol to give 15.5 g of yellow crystals, m.p. 130-130.5 ° C.

3. Otherwise repeat the procedure described as "Preparation A (2)" but use 3.5 g of 4-methoxy-2-quinolylaminomethylene malonic acid diethyl ester as starting material. The product was isolated by cooling the reaction mixture, diluting with 150 mL of cyclohexane to precipitate the crude product as a brown gummy precipitate. In crystalline form it is obtained by heating the diluted reaction mixture to boiling and filtering the hot mixture. Upon cooling, the product precipitated as yellow crystals, and was collected by filtration. Yield 1.1 g. Further purification was performed by crystallization from ethanol.

Preparation В

According to the procedures of Preparations A1) and A3), the substances listed below can be prepared from the appropriate starting compounds. In many cases, the product is isolated in the form of crystals by diluting the reaction mixture with cyclohexane, and hot filtration of the reaction mixture is unnecessary.

Thus, the following compounds of the general formula:

STEED

COOC ^ g

STEED R1 Melting point (° ι ОСНз 8-С1 213—214 ОСНз 8-СНз 191.5—192.5 ОСНз 8-ОСНз 200-201,5 ОСНз 9-ОСНз 184—185 ОСНз 9-С1 178—179 ОСНз 9-СНз 139—141 ОСНз 8-ОСНз 215 ^ 216 ОСНз 8-ОС2Н5 163.5—164.5 ОСгН5 Н 143—145 ОСНз 9-F 141—143 ОСНз 8-F 175,5—177

Preparation C

1-Oxo-1H-6-methoxypyrimido (1,2-a) quinoline-2-carboxylic acid

A mixture of 3.0 g of 1-oxo-1H-6-methoxypyrimido (1,2-a) quinoline-2-carboxylic acid ethyl ester and 60 ml of concentrated hydrochloric acid was heated on a steam bath for 30 minutes. After cooling, 0.87 g of the title product is obtained by filtration. Recrystallized from N, N-dimethylformamide, mp 219 ° C (dec.).

In a similar manner, the products of Preparation V can be hydrolyzed to the corresponding acids of formula

STEED

СООН

STEED

Ri Melting point (° C)

ОСНз 8-С1 239 (decomposition) ОСНз 8-СНз 247 (decomposition) ОСНз 8-ОСНз ОСНз 9-ОСНз 230 (decomposition) ОСНз 9-С1 234 (decomposition) ОСНз 9-СНз ОСНз 8-ОСНз 245 - (decomposition) ОСНз 8-ОС2Н5 237 (decomposition) ОС2Н5 Н 205 (decomposition) ОСНз 9-F 196—198 (decomposition) ОСНз 8-F 265—268 (decomposition)

Preparation D

1-Oxo-1H-6-chloro-pyrimido (1,2-a) quinoline-2-carboxylic acid ethyl ester

1. A mixture of 15.5 g (0.087 mol) of 2-amino-4-chloroquinoline and 20.8 g (0.096 mol) of ethoxymethylenemalonic acid diethyl ester was heated on a steam bath for 45 minutes. 75 ml of isopropyl alcohol are added to the clear hot melt, the mixture is cooled, the precipitated product is filtered off, washed with isopropyl alcohol and dried. Yield: 26.0 g of white solid, m.p. 108.5-109.5 ° C. The product was used directly in step 2, without any purification.

Recrystallization in ethanol gave an analytically pure sample, m.p. 109-110 ° C.

2. The intermediate of step 1, 4-chloro-2-chloro-2-quinolylaminomethylenemalonic acid diethyl ester, was added at 100 ° C to 75 ml of Dowtherm A at 26 ° C and the clear solution thus prepared was heated at 235-237 ° C for 80 minutes. C and then cooled. Hexane (100 ml) was added to the reaction mixture, the product thus precipitated was filtered off, washed with hexane and dried. After recrystallization from acetonitrile, the product melts at 178-179 ° C.

"Dowtherm" A, used in Preparations A and D, is the trade name of a eutectic mixture of phenyl ether and 26.5% diphenyl.

Claims (7)

A process for the preparation of N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimido (1,2-a) quinoline-2-carboxamides of the formula I having 1 to 5 carbon atoms, a fluorine or chlorine atom and R represents a C 1 -C 5 alkyl group, and pharmaceutically acceptable salts thereof, characterized in that the acid of formula (II): R 1 is hydrogen, C 1 -C 5 alkyl, alkoxy wherein R and R 1 are as defined above, dehydrates with 5-aminotetrazole, and optionally converts the product to a pharmaceutically acceptable salt. 2. A process according to claim 1, wherein the acid of formula II is first contacted with a dehydrating condensing agent and then with 5-aminotetrazole. 3. Process according to claim 1 or 2, characterized in that N, N‘-carbonyldlimidazole is used as condensing agent. 4. A process according to any one of claims 1 to 3, wherein the acid of formula II, a condensing agent with 5-aminotetrazole, is used in a molar ratio of from 1: 1: 1 to 1: 1.1: 1.1. 5. Process according to any one of claims 1 to 4, characterized in that N, N‘-carbonyldiimidazole is used as the condensing agent and the reaction is carried out at a temperature of from 85 to 100 ° C in the presence of Ν, Ν-dimethylformamide as solvent. 6. The process of item 1 for producing a compound of formula N-N II Wherein the starting material is a compound of formula 8. The process of item 1, for producing a compound of the formula Ο = Ο-ΝΗ-ζ ^Ν ~% characterized in that the compound of the formula is used as the starting material, 7. The process of item 1, for producing a compound of formula