SE414175B - ANALOGY FLOW PROCEDURE FOR PREPARING ANTI-ALLERGIC N - (- TETRANZOLYL) -PYRIMIDO (1,2-A) QUINOLIN-2-CARBOXAMIDES - Google Patents

Description

- * 7607099-4 2 airflow in the airways is usually alleviated with the use of bronchodilators, which provide symptomatic relief. In contrast, anti-allergic agents prevent the release of mediators of anaphylaxis from tissue depots, thereby acting prophylactically to prevent the initiation of bronchoconstriction due to the mediators.

Efforts to detect medical agents to relieve the symptoms of the abnormal physiological condition have been extensive. As early as l9lO reported Matthews, Brit. With. J., L (1910), 441, The bronchodilator effects of epinephrine. Then Chen and Schmidt, J. Pharmacol. Exper. Therap., Gg (1924), 339, reported the use of the alkaloid ephedrine as an orally effective bronchodilator with the same spectrum of activity as epinephrine. 1940 demonstrated Konzett, Arch. “Exp. Path. Pnamak., _1_91 (1940), 27, the effects of the active aerosol bronchodilator isoproterenol. Cullum et al., Brit. J. Pharmacol. Exp., Ââ (1969), ll, reported the pharmacology of salbutamol, a potent bronchodilator with prolonged action and active via both oral and aerosol administration. Many bronchodilator preparations contain theophylline. These are usually less active than the sympathomimetic amines, such as isoproterenol and salbutamol, and are ineffective in aerosol administration.

Cox et al., Adv. in Drug Res., 2 (1970), 115, has more recently described the pharmacology of such an agent, disodium cromoglycate (1,3-bis (z-carboxychromone-s-yioxy) -2-hyaroxypropane, Iman. It is not a bronchodilator , but mediates its therapeutic effects by means of a unique mechanism of action, comprising inhibiting the release of mediators of anaphylaxis, and administered prophylactically.

It suffers from a lack of oral efficacy and for optimal results it is administered as a solid inhalant. Although it is further effective against anaphylaxis due to immunoglobulin E (IgE), it is further effective against anaphylaxis due to immunoglobulin G (IgG) only in large doses (60 ~ 70% protection at 10 0 and 300 mg / kg).

Although these agents represent excellent contributions to the treatment of asthma, many of them exhibit the undesirable effect of cardiac stimulation.

The synthesis of 1H-pyrimido [1,2-a] quinoline first appears to have been reported by Antaki et al., J. Chem. Soc., Pp. 551-555 (1951), which condensed 2-chloroquinoline with ethyl β-aminocrotonate in the presence of anhydrous potassium carbonate and traces of copper bronze to produce 1-oxo-1H--2-methylpyrimido [1,2- a] quinoline. No use of the association was reported. In Antaki, J. Am. Chem. Soc., §Q (1958), 3066-9, reports the condensation of 2-aminoquinoline and ethylethoxymethylene cyanoacetate to give ethyl 2-quinolylaminomethylene enicoanoacetate, which on distillation under reduced pressure gave 1-oxo-1H-pyrimido [1,2-a] quinoline-2-carbonitrile.

The compound exhibits antischistosomal activity.

Richardson et al., J. Med. Chem., Ia (1972), 1203-5, discloses ethyl 1-oxo-1H-pyrimido [1,2-a] quinoline-2-carboxylate and states that it is inactive as an antimicrobial agent. When tested for anti-allergic activity in the CPA test, this compound was found to give loyal inhibition at 3 mg / xg when administered intravenously, but it is inactive at 1 mg / kg i.v. Approximately 90% inhibition is shown at 30 mg / kg, but oral activity is absent at an oral dosage level of 10 mg / kg.

It has been found that compounds of the formula n Rl 3 \ N \ N R 2 CM N___N o = c- mæ- <I] _N I H are valuable anti-allergic agents, i.e. agents that inhibit the release of mediators of anaphylaxis in mammals and humans and thus prevent the initiation of bronchoconstriction by the mediators. They are not bronchodilators. In contrast to disodium chromoglycates, they are of practical value against both IgG- and IgE-mediated anaphylaxis during oral, intranasal and intraperitoneal administration as well as during inhalation. In said formula, the benzene substituents R 1 and H 2 each represent hydrogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, fluorine or chlorine. H 1 and R 2 may together represent alkylenedioxy having 1-2 carbon atoms and thus constitute methylenedioxy or ethylenedioxy and R 3 is chlorine, bromine or C 1-5 alkoxy. The invention also relates to the pharmaceutically acceptable cationic salts of these compounds.

The invention relates to an analogous process for the preparation of the abovementioned compounds, which is characterized in that dehydration coupling of an acid having the formula COOH with a 5-aminotetrazole is carried out; and optionally transferring a resulting compound to a pharmaceutically acceptable salt.

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

The 5-substituted tetrazoles may, as is well known, exist in two isomeric forms, namely, which coexist in a dynamic, tautomeric equilibrium mixture. Both forms of tetrazolylamides are included within the scope of the invention.

The anti-allergic activity of the corresponding acids, namely D1-oxo-1H-6-alkoxypyrimido [1,2-a] quinoline-2-carboxylic acids and esters thereof, is described in U.S. Patent Application 554,966 (which has expired and thus never been published). The compounds described herein exhibit a significantly broader spectrum of anti-allergic activity than the corresponding acids and esters. Their anti-allergy activity is really unexpected, since the corresponding simple amides [such as -coNH 2, -coN (c 2 H 5) 2] are inactive as anti-allergy flour when tested according to the methods described below.

Compounds of particular interest according to the invention are those in which R 3 is methoxy or ethoxy and the benzene variables R 1 and R 2 are hydrogen and those in which R 3 is methoxy and at least one of the benzene substituents is lower alkoxy or fluorine, the remaining benzene substituent being hydrogen. Kl R2 R3 HH ocus, ocz H s H CH3 OcH3, ocz H s H ocH3 OCH3 H OCZHS OCH3 HF OCH 3 7607099-4 The anti-allergic property of the compounds of the invention is evaluated by passive, cutaneous anaphylaxis, PCA test (Ovary, J. Immun., J. Immun. , 355, 1958). In the PGA test, intradermal (i.d.) injections are injected into normal animals with serum antibodies obtained from actively sensitized animals. The animals are then teased 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 leach from the site of the antibody injection. The experimental animals are 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 animal skin.

The compounds of the invention are conveniently prepared by dehydratively coupling the 1-oxo-1H-6- (R 3 -substituted) -pyrimido [1,2-a] quinoline-2-carboxylic acid with 5-aminotetrazole. The dehydrating coupling is performed by a large number of means used in peptide synthesis. Representative agents include N, N'-carbonyl diimidazole, N, N'-carbonyl-di-s-triazine, ethoxyacetylene, 1,1-dichloro-diethyl ether, diphenyl ketene-p-tolylimine, N-hydroxyphthalimide, N-hydroxy succinimide, N-hydroxypiperidine, ethylene chlorophosphite, diethylethylene pyrophosphite, N-ethyl 5-phenylisoxazolium-3 'sulfonate, phenylphosphorodi (1-imidazolate) and carbodiimides such as dicyclohexylcarbodiimide, 1-cyclohexyl-2-cyclohexyl -morpholine methyl) -carbodiimide, N- (3-dimethylaminopropyl) -N'- -ethylcarbodiimide hydrochloride, 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide hydrochloride and diethylcyanamide.

Said coupling agent is generally first reacted with the acid reactant and the product formed is then reacted without isolation with -aminotetrazole to give the desired N- (5-tetrazolyl) -1-oxo-1H- -6- (R 3 -substituted) -pyrimido [1,2-a] quinoline-2-carboxamides. The reaction is carried out in a reaction-inert solvent system, in which the acid reactant need not be soluble. The only requirement placed on the solvent system is that it does not react to any great extent with the reactants or products. The variety of coupling agents that can be used to perform the dehydrative coupling allows for a wide variety of solvents. Representative solvents are NJI-dimethylformamide, tetrahydrofuran, dioxane, methyl erichloride, nitromethane and acetonitrile. The reaction of the acid reactant with the coupling agent is carried out at a temperature of about 20-11000. The reactive intermediate is then reacted with 5-nminotetrazole at about 20-110 ° C.

Each of these trains is advantageously carried out at about 50-100 ° C, since the speed and the yield of the reaction are thereby improved. 76U7099 ~ h 6 The molar ratio of acid / coupling agent / 5-nminototrazole is usually about 1: 1: 1 - 1: 1, 1: 1, 1. Higher ratios of coupling agent and aminotetrazole can be used, but this does not bring any benefits. excess of 10 mole percent is satisfactory.

As will be appreciated by those skilled in the art, all reactants may be added at once instead of stepwise as above. Earlier formation of the reactive intermediate (acid coupling agent product) normally gives better yields of the desired N- (5-tetrazolyl) amides.

A particularly suitable coupling agent is N, N'-carbonyldiimidazole, as this gives an elegant reaction and reasonable yields of the desired product without optimizing reaction conditions. In connection with this coupling agent, the use of N, N-dimethylformamide and a temperature of 85-110 ° C constitute particularly suitable conditions for the above reasons.

The compounds wherein R 3 is alkoxy are also conveniently prepared according to the Williamson reaction between the N- (5-tetrazolyl) -1-oxo-1H-6-chloro (or bromo) -pyrimido [1,2-a] quinoline-2- carboxamide and the alkanol exemplified herein.

The required 1-oxo-1H-6- (R 3 -substituted) -pyrimido [1,2-a] -quinoline-2-carboxylic acids are prepared by condensation of the 2-amino-4- (R 3 -substituted) quinoline with the dialkyl ethoxymethylene malonate to give the corresponding intermediate dialkyl 4- (R 3 -substituted) -2-quinolyl-aminomethylene malonate, which is then cyclized to the desired alkyl-1-oxo-1H-6- (R 3 -substituted ) -pyrimido [1,2-a] quinoline-2-carboxylate.

The condensation is carried out by heating a stoichiometric mixture of the 2-aminoquinoline reactant and the diolycoytoxymothionium ion at a temperature of about 80-125 ° C. Lower temperatures are not desirable because the reaction proceeds at too low a rate. Higher temperatures can be used, but they do not seem to provide any benefits. The reaction is thus conveniently carried out in a melt. It can of course be carried out in a solution or mixture of solvents, for example ethanol, N, N-dimethylformamide or acetonitrile. From a practical point of view, however, a solvent seems unnecessary.

The dialkyl 4- (R 3 -substituted) -2-quinolylaminomethylene malonate thus prepared is then cyclized, preferably thermally, by heating to a temperature of about 175-250 ° C in a suitable reaction-inert diluent, i.e. in a compound which enables control of the reaction temperature, is resistant to the relatively high temperatures used and which does not react with the starting material or cyclization products. Representative of such diluents are high boiling point hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, especially those containing 26.5% diphenyl and 73.5% diphenyl ether and provided under the name Dowtherm A.

The alkyl 1-oxo-1H-6- (R 3 -substituted) -pyrimido [1,2-a] quinoline-2-carboxylates are converted to the corresponding acids by hydrolysis, preferably acidic hydrolysis. The usual conditions comprise heating an aqueous mixture of the ster in question and a mineral acid, such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid, at about 50-10000 for a period of up to four hours or until the hydrolysis is substantially complete. The most suitable mineral acid is hydrochloric acid with a concentration of 3-12N. The less soluble the ester reactant is in water, the more concentrated acid is used for the hydrolysis. The free acids crystallize from the hydrolysis reaction mixture on cooling and are collected by filtration. When crystallization does not occur, the acids are recovered by evaporation of the reaction mixture. The acids are purified by recrystallization from suitable solvents, such as N, N-dimethylformamide.

Salt preparation is carried out by reacting the acid in question with the metal salt in question, such as a carbonate, bicarbonate, acetate, hexanoate, resp. hydroxide in a suitable medium, such as water, methanol or ethanol according to well known procedures. The salts are prepared by standard methods, such as by filtration, if they are insoluble in the medium, by evaporation of the solvent, if they are soluble in the medium, or by precipitation by the addition of a non-solvent for the salt.

The N- (5-tetrazolyl) -amides according to the invention thus show a significantly wider spectrum of anti-allergic activity than is the case with the precursor acids. The acids are effective in inhibiting only anaphylactic phenomena mediated by immunoglobulin E (IgE). In contrast, the N- (5-tetrazolyl) amides are effective not only against reagin-induced anaphylaxis (IgE, immunoglobulin E), but also against anaphylaxis induced by immunoglobulin G (IgG). This behavior also contrasts with the action of disodium cromoglycate, which does not inhibit IgG-mediated responses except at high doses.

The products of the invention and the pharmaceutically acceptable cationic salts thereof are useful as prophylactic agents for inhibiting or preventing the release of mediators of anaphylaxis (allergy, immediate hypersensitivity reactions) and the occurrence of allergic symptoms in mammals and may be administered for such purposes individually or as mixtures with other agents, such as theophylline or sympathomimetic amines. They may be administered separately, but are usually administered together with a pharmaceutical carrier, selected on the basis of the chosen route of administration and standard pharmaceutical practice. Thus, they can be combined with various, pharmaceutically acceptable, inert carriers in the form of tablets, capsules, lozenges, trocets, hard candies, powders, aerosol sprays, aqueous suspensions or solutions, injectable solutions, tinctures and mixtures, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Furthermore, the oral compositions may conveniently be sweetened and flavored by various means of the type commonly used for this purpose.

The particular carrier and the ratio of active ingredient to carrier are affected by the solubility and chemical nature of the therapeutic compounds, the chosen route of administration and the requirements of standard pharmaceutical practice. For example, when present compounds are administered orally in tablet form, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate may be used. Various disintegrants, such as starch, alginic acids and certain complex silicates, together with lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, can also be used for the manufacture of tablets for oral administration of these compounds. For oral administration in capsule form, high molecular weight lactose and polyethylene glycols are among the most suitable materials for use as pharmaceutically acceptable carriers. When aqueous pus is to be used for oral administration, the present compounds may be combined with emulsifiers or suspending agents. Diluents such as ethanol, propylene glycol, glycerol and chloroform and combinations thereof can be used as well as other materials.

For parenteral administration and inhalation, solutions or suspensions of these compounds in sesame or peanut or propylene glycol aqueous solutions as well as sterile aqueous solutions of the soluble, pharmaceutically acceptable salts described herein may be used. These particular solutions are particularly suitable for intramuscular and subcutaneous injection purposes, if such a method of administration is desired. The water solutions, incl. those of salts dissolved in pure, distilled water are also useful for intravenous injection purposes, provided that their pH is properly adjusted in advance. Such solutions should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with a sufficient amount of sodium chloride solution or glucose. The compounds can be administered to asthmatic individuals suffering from bronchoconstriction by means of inhalers or other devices which bring the active compounds into direct contact with the constricted areas of the individual's tissues. When administered by inhalation, the compositions may comprise (1) a solution or suspension of the active component in a liquid medium of the above-mentioned type for administration via an atomizer, (2) a suspension or solution of the active component in a liquid propellant, such as dichlorodifluoromethane or chlorotrifluoroethane for administration from a pressurized container or (3) a mixture of the active component and a solid diluent (such as lactose) for administration from a powder inhaler. Compositions suitable for inhalation using a conventional atomizing device contain about 0.1-1% of the active component and those for use in pressurized containers contain about 0.5 ~ 2% of active component. Compositions for use as a powder inhalant may comprise ratios of the active ingredient to the diluent of about 1: 0.5-1: 1.5. It is necessary that the active component constitutes such a proportion of the composition that a suitable dosage form is obtained. Clay dosage forms can obviously be administered at about the same time. Although compositions with less than 0.005% by weight of the active component may be used in some cases, it is advisable to use compositions containing at least 0.005% of the active component, otherwise the amount of carrier will be too great. The activity increases with the concentration of the active component. The composition may contain 10, 50, 75, 95% by weight or a higher content of the active component.

With regard to the dosage regimen of the compound of the invention, the physician ultimately determines the dosage most suitable for a particular individual and it varies with the age, weight and response of the particular patient as well as with the nature and extent of the symptoms, the pharmacodynamic characteristics of the particular subject. administration intended means and the chosen mode of administration. Small doses are usually administered from the beginning with a gradual increase in dosage, until the optimal level is determined. It is often found that when the composition is administered orally, larger amounts of the active component are required to provide the same level as with a small, parenterally administered amount. 7607099-4 '7607099-4 Taking full account of said factors, it is believed that an oral, daily dosage of the compounds of the invention to humans of about 10-1500 mg per day, especially about 10-600 mg per day in single or multiple doses , or about 0.2-12 mg / kg body weight, effectively relieves bronchoconstriction in humans. These values are illustrative only and there may, of course, be individual cases in which higher or lower doses are justified.

When administered intravenously or by inhalation, the effective daily dose is about 0.5-400 mg per day, preferably at about 0.25-2000 mg per day, or at about 0.5-4 mg / kg body weight. single or multiple doses.

The same two fundamental changes occur in cases of anal- Jylactic shock: (1) an increase in the permeability of the capillaries and (2) contraction of the smooth muscle. The increased capillary permeability is a result of antigen-antibody reaction. It and smooth muscle contraction can be observed and measured with ease. This increase in capillary permeability forms the basis of the PGA test.

The PGA test is a measure of the anti-allergic (especially anti-asthmatic) activity of a compound. Compounds that give a "positive PGA test, induced by the immunochemical equivalent of rat to human immunoglobulin E (IgE) or reagin are considered to have anti-allergic activity [C. Mota, Ann. NY Acad. Soi., Lgå (1963), 264 ].

LReagin consists primarily of immunoglobulin E (IgE) and is the major immunoglobulin responsible for allergic asthma, anaphylaxis, hay fever, food sensitivity and certain manifestations of drug sensitivity.] When such compounds are administered to a sensitized individual, human or animal, before the time at which the individual comes into contact with antigens or substances to which it is allergic, the allergic reaction that would otherwise occur is prevented. They therefore enable a method for the prophylactic treatment of allergies or anaphylactic reactions of a reagent-mediated nature.

In other words, such compounds block the release of the antigen-antibody reaction (the allergic reaction), as evidenced by the PGA test using rat homocytotropic antibody, a known correlate to human reagent antibody. Inhibition of reagin-antigen-antibody reactions in rats, the experimental animal in the PGA test, is considered representative of inhibition of human reagin-antigen-antibody reactions which occur during allergic episodes.

PCA-tested; used to evaluate the compounds of the invention shows an excellent correlation between the activity of the compounds in the test and their use in the treatment of allergic asthma. The ability of the compounds to interfere with PCA reactions is measured on male Charles River Wistar rats, 170-210 g. Reagent antiserum, rich in IgE antibodies, is prepared according to Petillo et al., Int. Arch. Allergy, ii (1973), 309. Hyperimmune antiserum, rich in IgG antibodies to egg albumin, is prepared according to Orange et al., J. Exptl. Med., Ig] (1968), 767. 48 hours before antigen stimulation, the reagent antiserum is injected intradermally (i.d.) into the shaved dorsal skin of a normal rat; five hours before the irritation, the hyperimmune antisera are injected in the same way. In a third place, 60 micrograms of histamine dihydrochloride and 0.5 micrograms of serotonin creatinine sulfate are injected i.d. immediately before antigen stimulation as a control of antihistamine, antiserotonin and nonspecific types of blockade; the compounds of the invention or sodium chloride solution are then administered intravenously and immediately thereafter the irritation is carried out with 5 mg of egg albumin and 2.5 g of Evans' Blue in sodium chloride solution. For oral administration, Evans' Blue and egg albumin are added five minutes after administration of the active substance. Thirty minutes later, the animals are asphyxiated using chloroform and the dorsal skin is removed and turned for observation. A score is given for each injection site corresponding to the product of the diameter in mm and a degree 0.1, 0.5, 1, 2, 3 or 4 proportional to the intensity of the staining. Scores for a given injection site summary For each group of five animals and compared with the sodium chloride-treated controls. The difference is expressed as a percentage block due to the compound used.

Compounds representative of them according to the invention are tested for antiallergic activity by said procedure and the resulting activities are reported as degree of protection in%.

"Intal", disodium cromoglycate, a commercially available anti-allergy drug, is included for comparison.

The tested compounds have the formula RR 1 Jg 'I \ i ./ N \ 2 Ûl-jïä N x: -N o = c-1 ~ m H q _14 IH 76070994: 12 00 0.0 0 00.0 00 0.0 0 00.0 00 0 00 0.0 00 0 00 0.0 i 0.0 00. 00.0 0 0.0 ... 00 00,0 .. 00 0 00 0.0 00 0 00 0.0 00 00.0 00 00.0 00 0.0 000 0.0 00 0 000. 0 0 0.0 _00 00.0. 0 0.0 00 00.0 00 0 00 0.0 00 0 00 0.0 00 0.0 00 00.0 Z 0.0 00 00.0 00 0 00 0.0 S 0 000 0.0 0 0.0 00 00.0 0 0.0 i 00.0 00 0 00 0.0 00 0 00 0.0 0 0.0 00 00.0 0 0.0 0 00.0 00 .. 0 00 0.0 00 0 00 0.0 00 0 2 0 00. 0 00 0 00 0.0 5 0.0. . ä. 0 00 0 .08 .. 0.00 05.3 1,000 S300 .. 0.00 05.5 .. mwH .ZOO m0 O m Ulm ore 7607099-4 13 The invention is further illustrated by the following examples, in which the temperatures given refer to degrees Celsius.

Exemgel l.

N- (5-tetrazolyl) -1-oxo-1H-6-methoxypryimido [1,2-a] quinoline-2-carboxamide A mixture of 540 mg (2.0 mmol) of 1-oxo-1H-6-methoxypyrimido [1,2-Ea] quinoline-2-carboxylic acid and 357 mg (2.2 mmol) of N, N'-carbonyldiimidazole in 15 ml of N, N-dimethylformamide are stirred and heated for 15 minutes on a steam bath. A clear solution is formed after about five minutes of heating, after which a precipitate forms. The reaction mixture is stirred for a further 45 minutes at room temperature and then treated with 187 mg (2.2 mmol) of 5-aminotetrazole. The mixture is heated for 40 minutes in a steam bath and cooled and then filtered to recover the product (540 mg yellow, solid) with melting point 2200 (decomposition).

It is purified by dissolving in hot N, N-dimethylformamide in an amount of 200 mg of crude product per 20 ml of solvent, after which the hot solution is filtered and then the filtrate is cooled. The yellow crystals are filtered off and dried. Melting point 2550 (decomposition). cläullofv? Calculated: C 53.41 H 3.29 N 29.07% Found: c 53.12 H 3.67 N 28.75 ve The following compounds are prepared in the same manner from the reactants in question: 2 R 1 'R 3 \ II \ RZ / '7607099-4 14 hwmhaß fl m hmmh fl mnm N hm pp flfl m fi o fl mm Aßv m bm Pw flfl mëo fi mw ^ mv eu ~ «.- ~ @ .m« @ .Hn m @. @ ~ Ssm.m n. ~ M ñuv «| nmN fl = Uo uo »m ñß mm. @ ~ H ~. fi ~ m.om ow.-« w. ~ ß.om ñvv @ | nm ~ mmuo w «m H« .m ~ @mm ~ wm «~« .m ~ m ~ .n ~ w. @ «A fi v @ | mß ~ mmwuo H0 | w ~ q. @ ~ H ~.« «H.mm« w. @ N «H. <mw.mm ñvv @ |« m ~ mmuo mm ~ u | w ^@vmo.-¶ mH. «nH.« m Hm.- nß.m 0>. «n Äwv ß | mm ~ n = Uo mwQ | m mm.m ~ Ho.« m @. ~ m H ~ .mN @mn «m.nm ^ vv m« @@ ~ mmwuo mmuo | w nm.m ~ mÛ.m -. ~ mm @. @ ~ ~ mm Nm. ~ m Awv w | mn ~ m = Uo mmuolw ^ mvom.m ~ HH. <Mm. «M Hm.- m> .m oß.« M ^ ¶vw | w @ ~. .mm ~ Uo m z 1 z Q z m 0 ^ .u ° vmsm mm Nm »mass wmnxmnwm S G I I N m N NH HHH> HH> ¶ ~>> H HHH HH mwmamxm veóïöêsén .. mmä mmuoàm mmul. _ mmnoLïo m m mmNUO Uzw mm mmm fi uußö mmöoà m m. 8 mmmulw m mmmukffo m Så m mmmuo må Im m mmquëlo Üà m Puma m fl mmuïuno fl mmmuà fl »mmuo SJ» Go mmNUO 'ol fl u Nmnïb. ï ïw. mm uu -nlßnuwmmulmïm fi w å nmuà mmulw mmuo må mA å m _ mmNQ mmmuLvmvlm mmmuëloà ... m mmm orm muoè mmä »må ßmnun fl ï fi ïm å mmuà m mmåëlo ókmu öà _ w 8 Ulm mUmMQ M Ü mm Mum NQm 8 Mm mmm MQ : oxmmu 1012. m .B mmm UIH mmuà »m3 lokmuloim. w S. m m oàm mmuè m 3 ßmmuhTw m S m .Bß fl. m WU mmua fi mmufm S mmuokw mm 8 “fw m mmuo mmwwnlw m mmä mmmmoà mmuoè mmä Sá m m. .B mmuà m mmä Tum m mm _ Nm Hm mm Nm Hm * älïtí fifi äx QUALITY '7607099-4 The product from example 8 is purified by resolution in 6N ammonium hydroxide, from which the product precipitates upon storage. The solid is filtered off, dissolved in water and precipitated from solution by acidification with 3N hydrochloric acid. It is filtered off, dried and recrystallized from N, N-dimethylformamide.

The product from Example 9 is purified by recrystallization from N, N # dimethylformamide, after which the purification procedure of Example 8 is carried out. Example 10.

The following compounds are prepared from the reactants according to Example 1: Example 11.

N- (5-tetrazolyl) -1-oxo-1H-6-ethoxypyrimido [1,2-alkinoline-2-carboxamide A mixture of 20 mg of p-toluenesulfonic acid monohydrate and 1.79 h of N- (5-tetrazolyl) - 1-Oxo-1H-6-chloropyrimido [1,2-a] quinoline-2-carboxamide and 75 ml of ethanol are refluxed for 24 hours. The solvent is removed under reduced pressure and the residue is partitioned between 25 ml of 3N hydrochloric acid and 100 ml of ethyl acetate. the strains are separated and the ethyl acetate phase is extracted with 2 x 20 ml of 3N hydrochloric acid. The acid extracts are combined, neutralized (pH 7-8) with 20% ammonium hydroxide and the precipitate formed is collected by filtration (235 m).

Said procedure is repeated, but using B-chloro (or bromine) products from Example 10 and the alkanol in question, to give the following compounds: .X6 / x [1 I, \, X yes / v N (1 h , _ ~ l oec ~ fi u ~ (ë / Ål H Rl __ï2 ____ ___ ï3 ___ H 8-OCH3 0m13 H 8 ~ oCu3 * 0 ~ nc¿n9 8 ~ CH3 10-CU3 OCH3 7 ~ cu3 10-undan OCZHS N l0 ~ Cl OQH3 H 8-CL a- OCH 3 U 9-Cl On-C 3 H 7 8-OCHS 9 -Cu 3 OCZHS H 1; OQHB Example 12.

Salt Formation The products of Examples 1 to 11 are transferred to the salts of sodium. potassium, ammonium, calcium, magnesium, aluminum, triethylamine, tri-n-butylamine, pipcridine, triethanolamine, diethylaminoethylamine, pyrrolidine and N, N-dibenzylethylenediumine by reaction with one equivalent of metal hydroxide, ammonium hydroxide or ethanol and subsequent filtration of the salt, if insoluble, or by evaporation of the solvent, if the salt is soluble therein.

Example 13

Injectable preparation 100 g of N- (5-tetrazolyl) -1-oxo-1H-6-methoxypyrimido [1,2-a] quinoline-2-carboxamide are intimately mixed and ground with 250 g of sodium ascorbate.

The ground, dry mixture is immersed in vials and sterilized with ethylene oxide, after which the vials are sealed sterile. For intravenous administration, a sufficient amount of water is added to the materials in the vials to form a solution containing 5.0 mg of active ingredient per ml of injectable solution.

Example 14.

Tablets 0 A tablet base is prepared by mixing the following components in the weight ratios given: sucrose, U.s.P. 80.3 Tapioca starch 13.2 Magnesium stearate 6.5 A sufficient amount of N- (5-tetrazolyl) -1-oxo-1H-6-methoxypyrimido [1,2-a] quinoline »2-carboxamide is mixed into this tablet base for formation of tablets, containing 20, 100 and 250 mg of active ingredient per tablet. The compositions are compressed into tablets, each weighing 360 mg, by conventional means.

Example 15.

Capsules A mixture containing the following components is prepared: Calcium carbonate, U.S.P, - 17.6 Dicalcium phosphate Sat, 8 Magnesium trisilicate, U.S.P. 5.2 Lactose, U.s.P.e 5 5.2 Potato starch 5.2 Magnesium stearate A 0.8 Magnesium stearate B. 0.35 350 g of this mixture are added with a sufficient amount of N- (5-tetrazolyl) -1-oxo-1H-6,9-amethoxypyrimyl] 1,2-a] quinoline-2-carboxamide to form hard gelatin capsules, containing , 25 and 50 mg of active ingredient. 760709944 19 in the same way capsules are prepared, containing 2.0 mg and 6.0 mg of active ingredient and 300 mg of the following mixtures per capsule: Components Weight mg¿ capsule Active substance 2.00 N-methylglucamine 18.00 Lactose, anhydrous 241, Maize starch, anhydrous 30.00 * Talc 8.80 Components Weight m ka sel Active substance 6.00 N-methylglucamine 18.00 Lactose, anhydrous 237.20 Maize starch, anhydrous 30.00 * Talc 8.80 * Talc is added before encapsulation Example 16.

A solution of N- (5-tetrazolyl) -1-oxo-1H-6-methoxy-9-fluoropyrimido- + [1,2-a] quinoline-2-carboxamide is prepared with the following composition: Effective component 6.04 g Magnesium chloride -hexahydrate 12.36 g Monoethanolamine 8.85 ml Propylene glycol 376.00 g Water, distilled 94.00 ml The resulting solution has an effective component concentration of 10 mg / ml and is suitable for parenteral and especially for intramuscular administration.

Example 17.

An aqueous solution of N- (5-tetrazolyl) -1-oxo-1H-6-methoxypyrimido- [1,2-a] quinoline-2-carboxamide sodium salt (containing 3 mg of active ingredient per ml of solution) is immersed in a standard atomizer. such as one available from Vaponephrine Co., Edison, NJ The solution is sprayed under an air pressure of 0.4 kp / cm2 into a closed plastic container (20 x 20 x 30 cm) for six minutes. The container has four openings for the heads of four rats. These are exposed to the agent at the same time as their heads come in contact with the aerosol.

The results are evaluated for the PGA reaction test procedure described above.

Example 18.

Aerosol suspension A mixture of N- (5-tetrazolyl) -1-oxo-LH-6-methoxypyrimido [1,2-a] -7607099'4-quinoline-2-carboxamide (antiallergic agent) and the other components under (a) is finely divided as follows: example to a particle size of 1-5 microns in a ball mill. The resulting slurry is then lowered into a container, equipped with a valve, and propellant (b) is introduced under pressure through the arch nozzle to a total pressure of about 3.5-3.8 Kp / cm 2 via 20 °. - m 'Suspension A _ F (a) Antinerging agent 0.25 Isopropyl myristone 1 0.10 Ethanol 26.40 (b) 60-40% mixture of 1,2-chlorotetra- 73.25 fluoroethane-1-chloropentafluoroethane Suspension B f (a) Antiallergic agent 0.25 Ethanol 1 26.50 (b) 60-40% mixture of 1,2-dichlorotetra-73.25 fluoroethane-L-chloropentafluoroethane Preparation A. - Ethyl-1-oxo-1H- O-methoxypyrimido [1,2-a] quinoline-2-carboxylate (1) A mixture of 34 g (0.66 mol) of 2-amino-4-methoxyquinoline and 46.6 g (0.2 lb) of dictylethoxymethylene malonate is heated on a steam bath. A clear melt is formed within about 10 minutes and within about 20 minutes it begins to solidify again. The mixture is heated for a total of 45 minutes and then cooled. The product, diethyl 4-methoxy-2-quinolylaminomethylene malonate, is crystallized from 350 ml of ethanol as a bulky solid, m.p. 136.5-137.5 °.

C18H20N2 ° 5 ~ Calculated: C 62.78 H 5.85 N 8.14% Found 62.72 H 6.10 N 8.37% (2) 350 ml Dowtherm A was added at 100 ° with the product from (1) (55 g, 0.16 mol) and the resulting clear yellow solution is heated to 230 ~ 233 ° for 1.75 hours. The reaction mixture is cooled, diluted with 300 ml of ethyl acetate and then extracted with 3 x 120 ml of 1N hydrochloric acid. The extracts are combined, basified with 20% ammonium hydroxide and cooled to precipitate the product. This is filtered off and successively recrystallized from ethanol, benzene / cyclohexane (IIz) and ethanol to give 15.5 g of yellow crystals, m.p. 130-130 °, 5 °. n ... .........-..- ~~ i 'å fl šošose-u _ .. V ..- n. -e-a- .Q-a -... a-i. - .., ..... _ ....... ........... 21 (3) Alternatively repeat from preparation A (2), but starting from 3.5 g diethyl 4-methoxy-2-quinolylaminomethylene malonate. The product is recovered by cooling the reaction mixture, diluting it with 150 ml of cyclohexane to precipitate the crude product in the form of a brown, sticky material. This is obtained in crystalline form by heating the dilute reaction mixture to boiling and filtering the hot mixture. Upon cooling, the product precipitates as yellow crystals, which are separated by filtration. Yield 1.1 g. Further purification is obtained by recrystallization from ethanol.

Preparation B.

The experiments according to Preparation A (1) and A (3) are repeated, the following compounds being obtained from the reactants in question. In most cases, the product separates out in the form of crystals upon dilution of the reaction mixture with cyclohexane and hot filtration of the mixture is unnecessary.

The following compounds are obtained: cooczu a “a“ i “z m.p. (° c.) Ocus cl n 213-214 ocu3 ens n 191.5-192.5 ocus ocna u znu-201.5 ocn3 n ocn3 184-185 ocn3 n cl 173-179 \ _ Af oLn3 n cn3 139 141 onna ocna ocng 215-216 v r_ -¿ ocn3 oc2n5 u 163. » 1o..s oczn, u u 143-145 J ocn3 u F g 141-143 OCIIB l * H 1.75. 5-17? 760709944 »22 PreEaration.C. 1-Oxo-1H-6-methoxypyrimido [1,2-a] quinoline-2-carboxylic acid A mixture of 3.0 g of ethyl-1-oxo-1H-6-methoxypyrimido [1,2-a] quinoline-2- carboxylate and 60 ml of concentrated hydrochloric acid are heated on a steam bath for 30 minutes. It is then cooled and filtered to give 0.87 g of the title product. It is recrystallized from N, N-dimethylformamide; melting point 2190 (decomposition).

In the same way, the products from preparation B are hydrolyzed to the corresponding acids. “3 RIÜ \\ Rz n '\. \' / O coon R3 R1 R2 5mP- (° c.) OCH3 Cl H 239 (decomposition) ocn3 C113 11 _24? ('") ocn3 ocn3 f! i I ocn3 n ocn3 230 = (")' ocn3 n c1 234 ("- ocu3 n 0113 (n.) ocn3 ocu3 ocua 245 - ocn3 oc2n5 u 237 (-) 002115 un 205 ( -). ocn3 n F / 196-198 (- ~) ocn3 F u 265-268 LH) Pregaration D.

Ethyl 1-oxo-1fl-6-chloropyrimido [1,2-a] quinoline-2-carboxylate (1) A mixture of 15.5 g (0.087 mol) of 2-amino-2-chloroquinoline and 20.8 g ( 0.096 mol) of diethylethoxymethylene malonate is heated on a steam bath for 45 minutes. 75 ml of isopropanol are added to the hot, clear melt, which is then cooled. The product is separated and filtered, washed with isopropanol and dried. Yield 26.0 g of white, 23 e 7607099-4 solid with a melting point of 108.5-109.50. It was used directly in step (2) without further purification.

Recrystallization from ethanol gives an analytical sample with melting point 1o9-11o °. (2) The intermediate diethyl 4-chloro-2-quinolylaminomethylene malonate from step (1) (26 g) is combined to 75 ml of Dow fi herm A at 100 °. The clear solution formed is heated for 80 minutes at 235-237 ° and then cooled. 100 ml of hexane are added to the reaction mixture and the precipitated product is collected by filtration, washed with hexane and dried. It is recrystallized from acetonitrile, m.p. 178-1790. The following compounds are prepared from the corresponding reactants according to Preparation D (H3 = Cl, Br) and A (1) and A (1) (H3 = alkoxy) and C: 7663595-4 _ d. 4 -... 24 .LUO moø mo 0 E00 CW (fiflfifl ulw. M mmwuuw m mm0o | ww @m «u | u1U fl mm -o» ~ mu ~ mU | o «mw 1o | ~ mu ~: u | o« @ .w .Ham on mmeulünolm owqululolw F) Hmlm Pm U | fl lo | w ßmmu | «| m. mmun fi aw mmmoolo fl mm ~ U @ 1 ~ | o- ~ mU | o «oH. @ | 0 | ~ mU | o | @ .m ~ zmu« «| w _ m mmuxø fl A mmulw mulß PÛÛR QUALITY

Claims (1)

BACKGROUND OF THE INVENTION Analogous process for the preparation of pharmaceutically active compounds of the formula below and optionally salts thereof R 1 R 1, R 2 and R 2 are each of R 1 and R 2 is hydrogen, C 1-5 alkyl, C 1-5 alkoxy, fluorine or chlorine or wherein R 1 and R 2 together form the group -O-CH 2 -CH 2 -O- or -O-CH 2 -O- and R 3 is chlorine, bromine or C 1-5 alkoxy, characterized in that dehydration coupling of an acid, having the formula COOH with a 5-aminotetrazole is performed; and optionally transferring a resulting compound to a pharmaceutically acceptable salt. BEFORE PUBLICATIONS: