IE43028B1 - Substituted pyrimido-quinoline derivatives and pharmaceutical compositions containing them - 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

This invention relates to substituted pyrimidoquinoline derivatives, particularly N-(5-tetrazolyl)pyrimido/l,2-a7qulnoline-2-carboxamides and derivatives thereof, which are useful as antiallergy agents. More particularly, the invention relates to N-tetrazolyl-1oxo-lH-6-substituted-pyrimido/T,2-_a7quinoline-2carboxamides wherein the 6-substituent is chlorine, bromine or alkoxy; pharmaceutically-acceptable cationic salts thereof; and derivatives of such compounds wherein the benzenoid ring bears one or more substituents, which are useful as agents for the treatment of allergic reactions, and especially of allergic bronchial asthma, and pharmaceutical compositions containing such compounds.

Allergic reactions, the symptoms resulting from an > antigen antibody interaction, manifest themselves in a wide variety of ways and in diffusely different organs and tissues. One of the most disabling and debilitating of the allergic reactions is asthma, a functional condition of the bronchi characterized, by periodic and ) spasmodic attacks of breathlessness, wheezing, coughing, and expectoration of mucous.

It has now been found that compounds of the formula (I) herein are effective antiallergy agents.

In accordance with the present invention there is i provided a compound having the formula:- 3 - wherein each of and R2 is a hydrogen, chlorine or fluorine atom, or a lower alkyl or lower alkoxy group or Rj and I<2 when taken together form a methylenedioxy or ethylenedioxy group., and Rg is a chlorine or bromine atom or a lower alkoxy group and the pharmaceuticallyacceptable cationic salts thereof.

The terms lower alkyl and lower alkoxy as used herein refer to alkyl and alkoxy groups having from one to five carbon atoms.

By the term pharmaceutically-acceptable cationic salts is intended salts of the alkali metals, e.g., sodium and potassium, and alkaline earth metals, such as calcium, magnesium salts, aluminium salts, ammonium salts, and salts with organic bases, e.g., amines such as triethylamine, tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, Ν,Ν'-dibenzylethylenediamine and pyrrolidine.

The 5-substituted tetrazoles, as is known, may exist in two isomeric forms, viz: - 4 3 0 28 /- N //n I which co-exist in a dynamic tautomeric, equilibrium mixture. Both forms of the tetrazolyl amides are included within the scope of this invention.

The compounds of formula I herein exhibit a significantly broader spectrum of antiallergy activity than do the corresponding l-oxo-lH-6-alkoxypyrimido2T’,2qa7quinoline-2-carboxylic acids and esters thereof. The antiallergy activity of the compounds of formula (I) is indeed surprising since the corresponding simple amides /e.g., -C0NH2, -CON (CgHg are inactive as antiallergy agents when tested by the methods described below.

Compounds of particular interest to this invention 5 are those wherein Rg is lower alkoxy, particularly methoxy or ethoxy, ahd R^ and R2 are hydrogen; and those ) wherein Rg is methoxy and at least one of R^ and Rg is lower alkoxy or fluorine. Examples of preferred compounds are the following:-R1R2R3 H H OCHg, OCgHg H CHg OCHg, OCgHg H OCHg OCHg H oc2h5 OCHg H F OCHg OCHg OCHg OCHg 43038 - 5 Particularly preferred compounds are :N-(5-Tetrazolyl)-l-oxo-lH-6-methoxypyrimido/I~, 2-a7~ quinoline-2-carboxamide.

N-(5-Tetrazolyl)-l-oxo-lH-6-ethoxypyrimido/L, 2-a/quinoline-2-carboxamide.

N-(5-Tetrazolyl)-l-oxo-lH-6-ethoxy-8-methoxypyrimido/T, 2 -_a7quinoline-2 -carboxamide.

N-(5-Tetrazolyl)-l-oxo-lH-6,8,9-trimethoxypyrimido/T, 2-_a7~ quinoline-2-carboxamide.

N-(5-Tetrazolyl)-l-oxo-lH-6-methoxy-9-fluoropyrimidoyl ,2-afquinoline-2-carboxamide.

The antiallergy property of the compounds of formula (I) 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 coloration on the inner surface of the animals' skin.

The compounds of this invention are conveniently prepared by dehydrative coupling of the appropriate l-oxo-lll-6-(R^-substituted)pyrimido/T, 2-a7quinoline-2carboxylic acid with 5-aminotetrazole. The dehydrative coupling may be accomplished by means of a wide variety of agents commonly used in peptide syntheses. Representative agents include Ν,Ν'-carbonyldiimidazole, N,N'carbonyl-di-s-triazine, ethoxyacetylene, 1,1-dichlorodiethylether, diphenylketene p-tolylimine, N-hydroxy28 - 6 phthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, ethylene chlorophosphite, diethyl ethylene pyrophosphite, N-ethyl-5-phenylisoxazolium-3'-sulfonate, phenylphosphorodi (1-imidazolate) and carbodiimides such as dicyclohexylcarbodiimide, l-cyclohexyl-3-(2-morpholinomethyl)carbodiimide/ N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride and diethyl cyanamide.

The above-described coupling agents are generally reacted first with the acid reactant and the resulting product then reacted, without isolation, with 5-aminotetrazole to afford the desired N-(5-tetrazolyl)-1-oxo1H-6 - (Rg - substituted) pyr imido/ΐ, 2 -a7quinoline-2carboxamides. The reaction may be carried out in a reaction-inert solvent system in which the acid reactant need not be soluble. The only requirement for the solvent system is that it does not enter into any appreciable reaction with the reactants or products. The variety of coupling agents which may be used to hring about the dehydrative coupling allow a wide choice of solvents. Representative solvents are Ν,Ν-dimethyIformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of the acid reactant with the coupling agent is preferably conducted at a temperature of from 20°G to 110°C. The reactive intermediate is then reacted with 5-aminotetrazole at from 20°C to 110°C. Each of these steps is advantageously carried out at from 50°C to 100°C since the rate and yield of the reaction are improved.

The molar ratio of acid:coupling agent:5-aminotetrazole is generally 1:1:1 to 1:1.1:1.1. Higher ratios of coupling agent 5-aminotetrazole may be used but offer no advantages. Excesses of ten mole percent are satisfactory. 3 0 2 8 - 7 If desired, all the reactants may be added at once rather than in stepwise fashion as described above. However, prior formation of the reactive intermediate (acid-coupling agent product) normally produces better yields of desired N-(5-tetrazolyl) amides.

A favoured coupling agent is Ν,Ν'-carbonyldiimidazole since it affords a smooth reaction and reasonable yields of desired product without optimization of reaction conditions. When using this coupling agent, Ν,Ν-dimethylformamide and a temperature of from 85°C to 100°C are preferred conditions for the reasons mentioned above.

The compounds wherein R^ is alkoxy also may be conveniently prepared by the Williamson reaction between the appropriate N-(5-tetrazolyl)-l-oxo-lH-6-chloro (or bromo) pyrimido/T,2-_a7quinoline-2-carboxamide and the appropriate alkanol as exemplified herein.

The required l-oxo-lH-6-(Rg-substituted)pyrimidoZr,2-a7quinoline-2-carboxylic acids may be prepared by condensation of the appropriate 2-amino-4-(R^-substituted)quinoline with the appropriate dialkyl ethoxymethylenemalonate to produce the corresponding intermediate dialkyl 4-(R^-substituted)-2-quinolylaminomethylenemalonate which Is then cyclized to the desired alkyl 1-oxo-lH6-(R-j-substituted)pyrimido/I,2-£7quinoline-2-carboxylate.

The condensation is preferably carried out by heating a stoichiometric mixture of the 2-aminoquinoline reactant and the dialkyl ethoxymethylenemalonate at a temperature of from 80°C to 125°C. Lower temperatures are not desirable because the reaction proceeds at too slow a rate. Higher temperatures may be used but appear to offer no advantages. The reaction is thus conveniently carried out as a melt. It may be conducted in a solvent or mixture of solvents; for example, ethanol, Ν,Ν-dimethylformamide, acetonitrile. However, from a practical stand2 8 - 8 point a solvent appears unnecessary.

The intermediate dialkyl 4-(Rg-substituted)-2quinolylaminomethylenemalonate thus produced is then cyclized, preferably thermally, by heating to a temperature of from 175°C to 250° C in a suitable reaction-inert diluent; that is, in a compound which permits control of the reaction temperature, is stable to the relatively high temperatures employed and which does not react with the starting materials or the products of cyclization.

Representative of such diluents are high boiling hydrocarbon such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulphuric acid, diphenyl ether and diphenyl, especially that which contains 26.5% diphenyl and 73.5% diphenyl ether and is sold under i the Trade Mark Dowtherm A.

The alkyl l-oxo-lH-6-(Rg-substituted)pyrimido/1,2-a/quinoline-2-carboxylates may be converted to the corresponding acids by hydrolysis, preferably acid hydrolysis.

The usual conditions comprise heating an aqueous mixture ) of the appropriate ester and a mineral acid such as hydrochloric, sulphuric, phosphoric or nitric acids, from 50°C to 100°C for periods of up to four hours or until hydrolysis is essentially complete. The favoured mineral acid is hydrochloric acid of from 3N to 12N concentration. ί The less soluble the ester reactant in water, the more concentrated the acid used for hydrolysis. The free acids generally crystallize from the hydrolysis reaction mixture upon cooling and are recovered by filtration. When crystallization does not occur the acids may be ι recovered by evaporation of the reaction mixture. The acids are purified by recrystallization from solvents, such as Ν,Ν-dimethyIformamide.

Salt formation is accomplished by reacting the appropriate acid with the appropriate metal salt, such as a carbonate, bicarbonate, acetate, hexanoate, hydroxide, ‘13 0 2 8 - 9 in a suitable liquid medium such as water, methanol or ethanol, according to well-known procedures. The salt may be recovered by standard methods such as by filtration if it is insoluble in the medium, by evaporation of the solvent if it is soluble in the medium or by precipitation by addition of a non-solvent for the salt.

As noted above, the N-(5-tetrazolyl)amides of this invention exhibit a significantly broader spectrum of antiallergy activity than do the precursor acids. The acids are effective in inhibiting only anaphylactic phenomena mediated by immunoglobin E (IgE). In contrast, the N-(5tetrazolyl)amides are not only effective against reaginic induced anaphylaxis (IgE immunoglobin E) but also against immunoglobin G (igG) induced anaphylaxis.

The compounds of this invention, particularly those wherein R^ is lower alkoxy, and the pharmaceuticallyacceptable cationic salts thereof, are useful for the control (prophylactic and therapeutic treatment) of allergic symptoms and reactions in mammals and may be administered either as individual therapeutic agents or as mixtures of therapeutic agents; for example, with theophylline or sympathomimetic amines. They may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be admixed with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aerosol sprays, aqueous suspension or solutions, injectable solutions, elixirs or syrups.

Accordingly the present invention also provides a pharmaceutical composition active as an antiallergy agent comprising as the active ingredient, a compound of the formula (I) herein, or a pharmaceutically-acceptable cationic salt thereof, in admixture with a pharmaceuticallyacceptable carrier. 0 28 - 10 Suitable carriers include solid diluents or fillers, sterile aqueous media and various non-toxic 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, the active compounds of this invention may be administered orally in tablet form in admixture with excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate. 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 administration in capsule form, lactose; and high molecular weight polyethylene glycols are among the preferred materials for use as pharmaceutiaally-acceptable carriers. Where aqueous suspensions are to be used for oral administration the compounds of this > invention may be admixed with emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerine and chloroform and mixtures thereof may be employed as well as other materials.

A. preferred composition for administration uses a i solution or suspension of the active compound in water.

For the purpose of parenteral administration and inhalation, solutions or suspensions of the active compounds in sesame or peanut oil or in aqueous propylene glycol solutions may be employed, as well as sterile aqueous solutions of the soluble pharmaceutically43028 - 11 acceptable salts described herein. These 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 should also be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.

The compounds may be administered to asthmatic subjects suffering from bronchoconstriction by means of inhalators or other devices which permit the active compounds to come into direct contact with the constricted areas of the tissues of the subject.

When administered by inhalation, the compositions may comprise (1) a solution or suspension of the active ingredient in a liquid medium of the type mentioned above for administration via a nebulizer; (2) a suspension or solution of the active ingredient in a liquid propellant such as dichlorodifluoromethane or chlorotrifluoroethane for administration from a pressurized container; or (3) a mixture of the active ingredient and a solid diluent (e.g., lactose) for administration from a powder inhalation device. Compositions suitable for inhalation by means of a conventional nebulizer will preferably comprise 0.1 to 1% of active ingredient; and those for use in pressurized containers will 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 forms a sufficient proportion of the composition such that a suitable dosage form will be obtained. Several dosage unit forms may be administered at the same time. Although 3028 - 12 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% by weight 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 PCA reaction test procedure employed to evaluate LO the compounds of the present invention 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, .5 170-210 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 sulfate are injected i.d. just prior to antigen challenge as a check for antihistaminic, antiserotonin and unspecific types of blockage; the compound of the present invention or saline is then administered i.v. and immediately followed by the challenge of 5 mg egg albumin and 2.5 mg Evans' Blue dye in saline. In the case of oral administrat ion Evans' Blue dye and egg albumin 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 to each injection site equal to the product of the diameter of the site in mm and a grade of 0.1, 0,5, - 13 1, 2, 3 or 4 proportional to intensity of dye coloration. 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 of the present invention are tested for antiallergy activity by the above-described procedure and the resulting activities are reported as the degree (%) of protection. Intal,(registered Trade Mark) disodium cromoglycate, a commercial antiallergy agent, is included for comparison.

The compounds tested are of the formula:- - 14 13028 I-1 nJ M O o ro o\ o· 10 io in σ\ o r-l rd tn Ol Ch O' Ol <3\ IO in I ϋ tn H tn \ tn e dp > H 1 tn λ; o \ tn tn H 6 dP tn cn η co ro co in co m m io io co σ> co io io co in o* co io co r* co in co co co CO co O σ» o ro o ro o co O O O o O o O o co O co o· O* —I r-t •sp O* co O oi in H oCO - H O fH Ol ro ro m co m ro O ro r-J ro O ro o co o’ CO o > H dP tn 1 \ w • tn tn H £ \O 00 O O o· oi O o o· O' O' O σι O' O o H H H co n co tn m O co O CO O co O co O O O O O O O O CO O in m in ro W a CO a co co a Ol Ol a Ol a a U u a o O o u O o o o Q o o co co co a K r—1 Q I 00 a o o 1 co a u o 1 00 a u o 1 σ\ Cm CTl a a a a a a a - 15 tn ΓΟ Ο σ\ ΓΟ 43038 in ΓΓΟ Ο ΓΟ ό ΓΟ Ο ΓΟ ο ΓΟ Ο ί—I 00 tn Λ! X άΡ | Ο Γtn Λί Γ0| β I «Ί ΓΟ Ο ΓΟ ο ΓΟ ο γο m ΓΟ Ο ΓΟ Β υ ο ΓΟ Β υ ο ΓΟ Β U I σ\ ιη Β (Ν Ο I J028 As regards the dosage regimen of the compounds of this Invention, the physician will ultimately determine the dosage which will be most suitable for a particular individual, and it will vary with 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 agent to be administered and the route of administration chosen. Generally, small doses will be administered initially, with a gradual increase in the dosage until optimum level is determined. It will often be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a small quantity administered parenterally.

Having full regard for the foregoing factors, it is considered that an effective daily oral dosage of the compounds of the present invention 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 alleviate bronchoconstriction in human subjects. These values are illustrative and there may, of course be individual cases where higher or lower dose ranges are merited.

When administered intravenously or by inhalation, !5 the effective daily dose is from 0.5 to 400 mg per day, and preferably from 0.25 to 200 mg per day, or at 0.005 to 4 mq/kg of body weight in single or divided doses.

The following Examples illustrate the invention and the manner in which it may be performed.

Example I N-(5-Tetrazolyl)-l-oxo-lH-6-methoxypyrimido/T, 2-aJquinoline-2-carboxamide A mixture of l-oxo-lH-6-methoxvpvr imido/ΐ~,2 - a7quinoline-2-carboxylic acid (540 mg., 2.0 mmole) and N,Ν'-carbonyldiimidazole (357 mg., 2.2 mmole) in N,N17 dimethylformamide (15 ml.) is stirred and heated on a steam bath for fifteen minutes. A clear solution forms after approximately five minutes' heating, followed by formation of a precipitate. The reaction mixture is stirred an additional 45 minutes at ambient temperature and is then treated with 5-aminotetrazole (187 mg., 2.2 mmole). The mixture is heated on a steam bath for forty minutes and is then cooled and filtered to recover the product (540 mg. of yellow solid); m.p. 22O°C. (dec.).

It is purified by dissolving in hot Ν,Ν-dimethylformamide at the rate of 200 mg. crude product per 20 ml. of solvent, filtering the hot solution and then chilling the filtrate. The yellow crystals are filtered and dried; m.p. 255°C. (dec.).

Analysis; Calc'd for εχ5Ηχχ°3Ν7: C, 53.41; H, 3.29; N, 29.07% Found: C, 53.12; H, 3.67; N, 28.75% The following compounds are similarly prepared from appropriate reactants: R.

R. '3 R.

N II 3038 - 18 3 I X I U 1 U O CM I «Ί (β Λ 3 Λ o cn tn m CM rH co cn in cn If) o TP Tl* cn Tt* KO tn in r- KD m KO Γ cm CM CM CM CM CM CM CM rH σ» rH in H 00 rH CM rH KO υ 1—1 CM co CM KO cn Ti* TJ* *3* cn cn σ» r* co in Tp m CM Ti* in CM KO «—1 rH in co KO • « ^r CM cn τρ in cn o rH in in in in in ti* in in rH σι t—j rH Tp CM O cn σι KO l> σι CO Tp KO KO Γ KO tn Γ“ KO in P- KO CM CM CM CM CM CM CM CM co r- KO cn Tt* cn TP Γ*· Γ in cn Ρ* rH rH co in • • • « * • β » ro cn rn co TP cn CM cn O CM Tp a 00 CM n CM r- rn in r* CO 00 Γ* co Tt* CM co τρ in σι O CM in in in in in TJK in tn .. ^_L ___ ___ _ Ό τ) τ, *-* *-* 00 co 00 r* KO KO KO Tp KO in Ko in τρ cn in CO KO tn KO cn in r- rn in CM CM CM CM CM CM CM CM in in in X cn X cn rn X co co CM X CM X X CM X X U (J I) u u n u u o o O υ o o o o co cn in co X X X X u o X CM rH o o o u U u o X co co σι co 00 σι cn X X X X X X X X in Φ ω nJ rtf § § m o Φ tn nJ Φ mh o φ tn nJ M Φ H rd nr H W H ,-S H H > H H H X nl Λ H H H > > > > H 3 0 38 The product of Example VIII is purified by dissolution in ammonium hydroxide (6N) from which the product precipitates on standing. The solid is filtered, dissolved in water and precipitated from solution by acidification with 3N hydrochloric acid. It is filtered, dried and recrystallized from N,N- dimethylformamide.

The product of Example IX is purified by recrystallization from Ν,Ν-dimethylformamide, followed by the purification method of Example VIII.

EXAMPLE X The compounds tabulated below are prepared from appropriate reactants by the procedure of Example I.

R.

R, R. '3 0=C-NH· - 20 co Ε (Μ r-l co Ε Ο η co C0 co co co co I 35 Ε Ε Ε Ε Ε Ε β υ α Q υ U U Ο 1 ο ο Ο ο Ο Ο Ο ο ΓΠ co Γ- Ε co ιη Ε CM co Ε Ε υ U Ε Ο υ ι I Ο U I Ο I Ε I ι ο Ή 1 1 ο Ο 1 1 ο 00 σι 00 γ4 00 1 CM ι—Ι CM Ε Ε U Ο 1 ί Ο Ο 1 ο * σι rH ιη C0 κ Ε Ε CO 00 σι CM α Ε Ο ο Ο Ο I Ε 00 Ε co Ε 1 Ο ιη ο ιη ιη Ε 1 co « C0 CO Ε CO CM β Ε CM Ε Ε CM Ε U 1 υ Ο υ U υ U Ο ο ο Ο ο Ο ο Ο σι Ε σι Γ* Ε Ε υ co ι I 1 Ο ο β Ο Ο I Η ι 1 1 4J ♦Η | Ε ο Ε CM CM I | Ο 1 I Ε Ε ο σι 1 σι σι σι Ο Ο ι—J CM CM CM Ε Ε Ε U U U | Γ* σι I I Ο Ε Ε Ο Ο r* 1 co tr 1 1 σι Ε σι U U σι Οι Ε co I 1 *. *· □ | co β β 00 00 Ο 1 •Η I ο I ο | Ε ι 4J 1 00 1 00 00 r* 1 Γ- co η co Ε Ε Ε □ υ Ο Η γ4 r4 Η Η Γ—1 e—1 Ο ο ο Ο Ο α υ ο υ □ μ u μ ΕΕ Ε σι Ε ^ί* υ ϋ ο η ι Ο co in co co r-T 1—1 Ε CM Ο co Ε U Ε Ο ο C0 Ε ' U Ε Ο Ο r—{ ο Η γΗ co Ε co Ε Ο co Ε Η υ U Ο ο 1 1 1 1 Ο ο υ Ο U υ I 1 1 1 ο Ο ο ο 1 I | 1 σ» Ε 1 I C0 σι co 00 ρ4 Η Η r-l CO σι σι σι 00 co Ε Ο co Ε U Ε U Ο co Ε □ | rH Ο 33 Μ 35 Ε Β co t-~ 35 35 35 Ε co Ε ω 33 1 CO ΓΌ m m « » CN 33 f L) u u O o o 43038 8-OCH S3 O U I I co co S3 33 ® σ» cn cn W 33 33 33 a U O υ 1 1 | 1 CO c β β β S3 1 1 1 υ o o o ο ο co ro CO S3 33 S3 Ο U Ο Ο Ο Ο 1 1 ί ο CO σ» 33 Η rH PS ; ffi a w n ffl u I r028 - 22 EXAMPLE XI Ν-(5-Tetrazolyl)-l-oxo-lH-6-ethoxypyrimido/l,2-5/quinoline-2-carboxamide A mixture of p-toluenesulfonic acid monohydrate (20 mg.) and N-(5-tetrazolyl)-l-oxo-lH-6-chloropyrimido/l,2-a/qulnoline-2-carboxamlde (1.79 g.) in ethanol (75 ml.) is heated at reflux for 24 hours. The solvent is removed under reduced pressure and the residue partitioned between 3N hydrochloride acid (25 ml.)-ethyl acetate (100 ml.). The phases are separated and the ethyl acetate phase extracted with 3N hydrochloric acid (2 x 20 ml.).

The acid extracts are combined, made neutral (pH 7-8)with 20% ammonium hydroxide and the resulting precipitate recovered by filtration (235 mg.).

The above procedure is repeated but using the 8chloro(or bromo) products of Example X and the appropriate alkanol to give the compounds tabulated below: '13 0 38 R1R2R3 H 8-OCHg0CH3 H 8-och3 O-n-C4Hg 8-CHg 10-CHg och37CH3 10-OCHgOC2H5 H 10-C1 °ch3 H 8-C1 och3 H 9-C1 O-n-C3H7 8-OCHg 9-°ch3OC2H5 H H och3 EXAMPLE XII Salt Formation The products of Examples I-XI are converted sodium, potassium, ammonium, calcium, magnesium, aluminum, triethylamine, tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, pyrrolidine and N,N-di-benzylethylenediamine salts by reaction with an equivalent of the appropriate metal hydroxide, ammonium hydroxide or amine in water or ethanol followed by filtration of the salt if it is insoluble or by evaporation of the solvent if the salt is soluble therein.

EXAMPLE XIII Injectable Preparation One hundred grams of N-(5-tetrazolyl)-l-oxo-lH-6methoxypyrimido/I”,2qa7quinoline-2-carboxamide are intimately mixed and ground with 250 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, 28 - 24 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 XIV Tablets A tablet base is prepared by blending the following ingredients in the proportion by weight indicated: Sucrose, U.S.P. 80.3 Tapioca Starch 13.2 Magnesium Stearate 6.5 into this tablet base there is blended sufficient N-(5-tetrazolyl)-l-oxo-lH-6-methoxypyrimido/l,2-a/quinoline-2-carboxamide 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 XV Capsules A blend is prepared containing the following 20 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 N-(5-tetrazolyl)oxo-lH-6,9-dimethoxypyrimido/T, 2qa7quinoline-243028 carboxamide to provide capsules containing 10, 25 and 50 mg. 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: Ingredients Weight mg,/capsule effective ingredient 2.00 N-Methylglucamine 18.00 Lactose, anhydrous 241.20 Corn starch, anhydrous 30.00 *'falc 8.80 Ingredients Weight mg./capsule effective ingredient 6.00 N-Methylglucamine 18.00 Lactose, anhydrous 237.20 Corn starch, anhydrous 30.00 *Talc 8.80 *Talc added before encapsulation EXAMPLE XVI Solution A solution of N-(5-tetrazolyl)-l-oxo-lH-6-methoxy9-fluoropyrimido/r72-a7quinoline-2-carboxaniide is prepared with the following composition: Effective ingredient 6.04 grams Magnesium chloride hexahydrate 12,36 grams Monoethanolamine 8.85 ml. Propylene glycol 376.00 grams Water, distilled 94.00 ml. - 26 The resultant solution has a concentration of effective ingredient of 10 mg./ml. and is suitable for parenteral and, especially for intramuscular administration.

EXAMPLE XVII An aqueous solution of N-(5-tetrazolyl)-1-oxo-lH6-methoxypyrimido/T’, 2-a7quinoline-2-carboxamide sodium salt (containing 3 mg. of effective ingredient 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 under an air pressure of 6 lbs. per square inch into a closed 8'' x 8’' x 12'1 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 XVIII Aerosol Suspension A mixture of N-(5-tetrazolyl)-l-oxo-lH-6-methoxypyrimido/T, 2~a/quinoline-2-carboxamide (antiallergy agent) and the' other ingredients under (a) in the examples below are ground 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. - 27 Suspension A Percent (a) Antiallergy agent 0.25 Isopropyl myristate 0.10 Ethanol 26.40 (b) 60-40% mixture of 1,2-dichlorotetrafluoroethane: chloropentafluoroethane 73.25 Suspension B Percent (a) Antiallergy agent 0.25 Ethanol 26.50 (b) 60-40% mixture of 1,2-dichlorotetrafluoroethane:chloropentafluoroethane 73.25 PREPARATION A Ethyl l-0xo-lH-6-methoxypyrimido(/T', 2qa7quinoline-2carboxylate (1) A mixture of 2-amino-4-methoxyquinoline (34 g., 0.196 mole) and diethyl ethoxymethylenemalonate (46.8 g., 0.216 mole) is heated on a steam bath. A clear melt forms within about ten minutes and within about twenty minutes begins to resolidify. The mixture is heated a total of 45 minutes and is then cooled. The product, diethyl 4-methoxy-2-quinolylaminomethylenemalonate, is crystallized from ethanol (350 ml.) as a fluffy solid; m.p. 136.5-137.5°C.

Analysis: Calc'd for cxgH2ON2°5: C, 62.78; H, 5.85; N, 8.14 % Found: C, 62.72; H, 6.10; N, 8.37 % (2) To Dowtherm A (350 ml.) at 100°C. is added the product from (1) (55 g., 0.16 mole) and the resulting clear yellow solution heated to 23O-233°C. for 1.75 3028 - 28 hours. The reaction mixture is cooled, diluted with ethyl acetate (500 ml.) and then extracted with IN hydrochloric acid (3 x 120 ml.). The extracts are combined, made basic with 20% ammonium hydroxide and chilled to precipitate the product. It is filtered and recrystallized successively from ethanol, benzene-cyclohexane (lil) and ethanol to give 15.5 g. of yellow crystals; m.p. 130-l30.5°C. (2) Alternatively, the procedure of Preparation A(2) is repeated but starting with 3.5 g. of diethyl .0 4-methoxy-2-quinolylaminomethylenemalonate. The product is recovered by cooling the reaction mixture, diluting it with cyclohexane (150 ml.) to precipitate the crude product as a brown gummy material. It is obtained in crystalline form by heating the diluted reaction mixture to boiling and filtering the hot mixture. Upon cooling the product precipitates as yellow crystals and is separated by filtration. Yield = 1.1 g. Further purification is achieved by recrystallizing it from ethanol.

PREPARATION B Following the procedures of Preparation A(l) and A(3), the compounds listed below are prepared from appropriate reactants. In most instances, the product separates in the form, of crystals upon dilution of the reaction mixture with cyclohexane and hot filtration of the mixture is unnecessary.

The following are thus prepared: 28 - 29 10 R3R1R2 m.p. (°C.) och3 Cl H 213-214 och3 CH3 H 191.5-192.5 och3 och3 H 200-201.5 och3 H och3 184-185 och3 H Cl 178-179 OCH3 H ch3 139-141 och3 och3 och3 215-216 0CH3oc2H5 H 163.5-164.5OC2H5 H H 143-145 och3 H F 141-143 och3 F H 175.5-177 PREPARATION C l-Oxo-lli-6-methoxypyrimido/l~,2-_a7quinoline-2-carboxylic Acid A mixture of ethyl l-oxo-lH-6-methoxypyrimido/T,2-^7quinoline-2-carboxylate (3.0 g.) and concentrated hydrochloric acid (60 ml.) is heated on a steam bath for a half hour. It is then cooled and filtered to give 0.87 g. of the title product. It is recrystallized from N,Ndimethylformamide; m.p. 219°C. (dec.). 8 - 30 In like manner, the products of Preparation B are hydrolyzed to the corresponding acids.

R3R1R2 m.p. (° C.) 0CH3 Cl H 239 (dec.) 0CH3 CH3 H 247 (dec.) och3 och3 H och3 H och3 230 (dec.) och3 H Cl 234 (dec.) och3 H CH3 och3 OCH3 och3 245 (dec.) och3 oc2h5 H 237 (dec.)OC2H5 H H 205 (dec.) och3 H F 196-198 (dec.) och3 F H 265-268 (dec.) PREPARATION D Ethyl l-0xo-lH-6-chloropyrimido/l,2qa/quinoline-2carboxylate (1) A mixture of 2-amino-4-chloroquinoline (15.5 g., .0 0.087 mole) and diethyl ethoxymethylenemalonate (20.8 g., - 31 0.096 mole) is heated on a steam bath for 45 minutes. Isopropanol (75 ml.) is added to the hot clear melt which is then cooled. The product separates and is filtered, washed with Isopropanol and dried. Yield = 26.0 g. of white solid; m.p. 108.5-109.5°C. It is used directly in step (2) without further purification.

Recrystallization from ethanol affords an analytical sample, m.p. 109-110°C. (2) The intermediate diethyl 4-chloro-2-quinolyl10 aminomethylenemalonate from step (1) (26 g.) is added to Dowtherm A (75 ml.) at 100°C. The resulting clear solution is heated to 235-237°C. for 80 minutes and then cooled. Hexane (100 ml.) is added to the reaction mixture and the product which precipitates recovered by filtration, washed with hexane and dried. It is recrystallized from acetonitrile, m.p. 178-179°C.

The following compounds are prepared from appropriate reactants by the procedures of Preparation D (R^ = Cl, Br) and A(l) and A(3) (R3 = alkoxy) and C: COOH Ο 2 8 - 32 r* Ch Ό ιη υ ιη ιη ιη ιη 8 <*> 8 8 I 8 ι 8 8 8 8 8 η 8 8 8 8 8 8 8 β οί β 8 οι 8 8 04 8 OJ 8 οι υ Ο υ Ο 1 Ο I U ϋ Ο υ U υ Ο Ο ϋ ο Ο Ο Ο Ο Ο ο Ο ο Ο ο Ο ο Ο Ο Ο σ> Β •Cp <35 CJ « Η Η 8 8 8 a 1 1 η η Ol 8 I o o a 8 8 8 Ο 1 U U β 1 1 1 8 8 U 1 1 o O 1 β I 04 03 •U u 04 Η I •Η Ο I 1 •rt o 8 o 8 8 1 o O Ο ο 1 I 04 O 1 1 1 I 1 O U o 1 1 1 Η CO οι 8 rH 05 Ol 05 05 05 04 OJ rH 8 8 8 8 U 8 8 8 α 1 Q a ϋ ι o 1 I 1 ο 1 O Γ* 05 o o 1 o 1 8 8 1 ί σι rH 0~ <35 8 cP 05 05 05 •w - in 8 K. a *. 8 co <35 8 8 CO 1 I co 00 M* 8 04 U β β o 8 U | 1 1 1 U O H • o o Ph 1 4J | 1 co 8 I Ο- 1 co co co 1 O' O' 8 8 8 05 8 •cP 05 05 05 Γ o 8 8 8 8 I Cp τρ ρ u O υ ϋ a a) ro 1 | I ι in 8 β β β β Η Η Η rH Η H H β β β M ί O 1 1 1 I ϋ Ο u o O U U ro 8 8 8 o O o Ο Ο ο m 8 8 8 8 8 co 8 8 8 υ 8 O H ro 8 ro 8 8 υ ο U O O H H 8 O 8 H H H Ο U ο ι 1 I U a O o U U ϋ υ Ο Ο ο O o o 1 _ 1 1 | 1 1 1 I 1 ί CO γ-4 H rH H co 05 05 05 8 05 8 05 05 8 05 8 CO 8 m 8 ro 8 8 U 8 H U O I o Q a I 8 8 1 CO I r> w 8 8 8 co 8 co 8 1 8 8 8 8 8 -CH, 1O-OCH, OCH

Claims (19)

1. CLAIM S:1. A compound of the formula:- H wherein each of R^ and R 2 is a hydrogen, chlorine or 5 fluorine atom, or a lower alkyl or lower alkoxy group, or R^ and R 2 when taken together form a methylenedioxy or ethylenedioxy group, R^ is a chlorine or bromine atom or a lower alkoxy group and the pharmaceuticallyacceptable cationic salts thereof. 10

2. A compound according to claim 1 wherein each of R^ and R 2 is hydrogen and R 3 is lower alkoxy.

3. A compound according to claim 1 wherein R^ is hydrogen, R 2 is 8-lower alkoxy and R 3 is ethoxy.

4. A compound according to claim 1 wherein R^ is 15 8-lower alkoxy, R 2 is 9-lower alkoxy, and R 3 is methoxy.

5. A compound according to claim 1 wherein R^ is hydrogen, R 2 is fluorine and R 3 is methoxy.

6. N-(5-Tetrazolyl)-l-oxo-lH-6-methoxypyrimido/Γ, 2 -^

7. <3Uinoline-2-carboxamide. 028 - 34 7. N-(5-Tetrazolyl)-l-oxo-lH-6-ethoxypyrimido/Γ, 2 -_a7quinoline-2-carboxamide.

8. N-(5-Tetrazolyl)-l-oxo-lH-6-ethoxy-8-methoxypyrimido/T,2-afquinoline-2-carboxamide. 5

9. N-(5-Tetrazolyl)-l-oxo-lH-6,8,9—trimethoxypyrimldo/1,2-a7quinoline-2-carboxamide.

10. N-(5-Tetrazolyl)-l-oxo-lH-6-methoxy-9-fluoropyrimido/1,2-a7quinoline-2-carboxamide.

11. A pharmaceutical composition active as an LO antiallergy agent comprising as the active ingredient, a compound of the formula (I) as claimed in claim 1, or a pharmaceutically-acceptable cationic salt thereof, in admixture with a pharmaceutically-acceptable carrier.

12. A composition according to claim 11, wherein L5 the active ingredient is a compound according to any one of claims 2 to 10.

13. A composition according to either one of claims 11 or 12, in a form suitable for administration by inhalation. !0

14. A composition according to either one of claims 11 or 12, comprising a solution or suspension of the active compound in water.

15. A composition according to any one of claims 11 to 13, comprising a suspension of the active compound 5 in a liquefied propellant.

16. A composition according to either one of claims 11 or 12 comprising the active compound and carrier in solid form.

17. Compounds of formula (I) as claimed in claim 0 1 and the pharmaceutically-acceptable cationic salts 43038 - 35 thereof substantially as hereinbefore described with reference to Examples I to XI.

18. A process for preparing a compound of formula (I) as claimed in claim 1 substantially as hereinbefore 5 described with reference to Examples I to XI.

19. A pharmaceutical composition according to claim 11 and substantially as hereinbefore described with reference to Examples XIII to XVIII.