FI59409B - FORM OF ANTIALLERGIC ACTIVATION OF N- (5-TETRAZOLYL) -1-OXO-1H-6- (R3-SUBSTITUTE) -PYRIMIDO (1,2-A) QUINOLIN-2-CARBOXAMIDER - Google Patents

Description

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WlHwWKlipeweF JB nRB | V ** BNM P »Bi ® * ^ λ λ I q · fMant * och rtglatantyraliai» 'AmMimoch «Ukrtft · * pub ** · ™» äu.ou.öi (32) (33) (31) PyHtty Hiolfc — t »n» prtorKt 01.08.75 USA (US) 601039 (71) Pfizer Inc., 235 East l »2nd Street, New York, NY, USA (US) (72) Saul Bernard Kadin, New London, Connecticut, USA (US) (7 * 0 Oy Kolster Ab (5U) Method for the treatment of antiallergically active N- (5-tetrazolyl) -1-oxo-1H-6- (R-substituted) pyrimido [1,2-%] quinoline-2- The present invention relates to a process for the preparation of carboxyamides. The present invention relates to a process for the preparation of carboxyamides. The present invention relates to a process for the preparation of carboxyamides. The present invention relates to a process for the preparation of carboxyamides. N-2-α-quinoline-2-carboxamide For the preparation of (5-tetrazolyl) -pyrimido [1,2-a] quinoline-2-carboxamides and their derivatives. In particular, N-tetrazolyl-1-oxo-1H-6- (R 1 -substituted) -pyrimido [1,2-a] quinoline-2-carboxamides having a 6-substituent of chlorine, bromine or lower alkoxy are prepared, their pharmaceutically acceptable cationic salts and derivatives of such compounds having 1 or more substituents on the benzenoid ring, which compounds are useful in the treatment of allergic reactions, in particular in the treatment of allergic asthma.

Allergic reactions, symptoms caused by an antigen-antibody interaction, manifest in many different ways and in different organs and tissues. Common allergic disorders include, for example, allergic rhinitis, characterized by intermittent or prolonged sneezing, 2 59409 nasal discharge, nasal congestion, and at the same time itchy and swollen eyes; hay fever, a type of allergic rhinitis caused by hypersensitivity to hay pollen; asthma, one of the most debilitating and debilitating allergic reactions characterized by bronchial hypersensitivity when exposed to various immunogenic or non-immunogenic effects that cause transient bronchospasm, transient wheezing. Mechanical airway obstruction in the airways is usually eliminated by the use of bronchodilators, which cause the symptoms to disappear. Antiallergic agents, on the other hand, prevent the release of anaphylaxis mediators from tissue stores and thus prevent the bronchi-induced bronchoconstriction.

Efforts to find drugs to alleviate the symptoms of the physiological condition of this abnormality have been extensive. As early as 1910 Matthews, Brit. Med. J., 1, 441 (1910) reported bronchodilatory properties of epinephrine. Subsequently, Chen and Schmidt, J. Pharmacol. Exper. Therap., 24, 339 (1924), reported the use of the alkaloid ephedrine as an orally effective bronchodilator with the same spectrum of action as epinephrine. In 1940, Konzett, Arch. Exp. Path. Pharmak., 197, 27 (1940) published a study on the efficacy of isoproterenol, an effective aerosol-bronchodilator. Cullum et al., Brit. J. Pharmacol. Exp., 35, 141 (1969) disclosed salbutamol, an effective bronchodilator with a long duration of action and active both orally and by aerosol administration. Many bronchodilators contain theophylline. These are generally less effective than sympathomimetic amines such as isoproterenol and salbutamol, and are also ineffective in aerosol drug delivery.

Recently, Cox. at ai., Adv. in Drug Res., 5, 115 (1970) have described the pharmacology of one substance, disodium cromoglycate, 3-bis (2-carboxy-chromon-5-yloxy) -2-hydroxypropane, Int. It is not a bronchodilator, but its therapeutic effect is mediated by a completely different mechanism that prevents the release of anaphylaxis mediators and is administered as a prophylactic drug. Its disadvantage is the lack of oral action, and, for best results, it is administered as a medicament as an inhaled solid inhalant. In addition, although effective against immunoglobulin E (IgE) -induced anaphylaxis, it is effective against immunoglobulin G (IgG) -induced anaphylaxis only at high doses (60-70% protection at doses of 100-300 mg / kg).

Although the above agents represent a significant improvement in the treatment of asthma, many of them have an undesirable side effect of a heart-stimulating effect.

The synthesis of 1H-pyrimodo-1,2-α-quinoline appears to have been first reported by Antaki et al., J. Chem. Soc, pages 551-555 (1951), which condensed 2-chloroquinoline with ethyl-4-aminocrotonate in the presence of anhydrous potassium carbonate and copper bronze (slow) to give 1-oxo-1H-3-methylpyrimodo (1,2-a? Quinoline). No use was reported for the compound.

Antaki, J. Am. Chem. Soc., 80, 3066-9 (1958) condensed 2-aminoquinoline and ethyl ethoxymethylene cyanoacetate, and distilled the reaction product, ethyl 2-quinolylaminomethylene cyanoacetate under reduced pressure, to give 1-oxo-1H-pyrimodo- [1,2- } quinoline-2-carbonitrile. The compound has antiscistomoma activity.

Richardson et al., J. Med. Chem., 15, 1203-6 (1972) describe ethyl 1-oxo-1H-pyrimido [1,2-a] quinoline-2-carboxylate and state that it is ineffective as an antimicrobial agent. When tested for antiallergic activity in the PCA assay, this compound was found to be 100% inhibited at 3 mg / kg intravenously (i.v.) but without activity at 1 mg / kg i.v. When administered orally, the compound had a 90% inhibitory effect at 30 mg / kg, but no oral activity occurred at the 10 mg / kg dose level.

It has now been invented that the formula 59409 rwa

R2 N— N

0 = C- NH - // l |

N— N

II

and their pharmaceutically acceptable cationic salts are valuable antiallergic agents, i. substances that prevent the release of anaphylaxis mediators in mammals, including humans, and thus prevent mediator-induced bronchoconstriction. They are not bronchodilators. In contrast to disodium cromoglycate, they have practical value against both IgG and IgE-mediated anaphylaxis in both oral, intranasal and intraperitoneal administration as well as by inhalation. In this formula, each of the substituents and R 2 separately represents hydrogen, lower alkyl, lower alkoxy, fluorine or chlorine, and together R 1 and R 2 represent alkylenedioxy having 1 to 2 carbon atoms, such as methylenedioxy and ethylenedioxy, R 1 is chlorine, bromine or lower alkoxy.

The terms "lower alkyl" and "lower alkoxy" as used herein refer to alkyl and alkoxy groups having 1 to 5 carbon atoms, as the starting materials required for the preparation of such compounds are more readily available than compounds containing higher alkyl or alkoxy groups.

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

As is known, 5-substituted tetrazoles can exist in two different isomeric forms, namely: 5 59409

N-N, N-N

-c (5 II I

N-N N-N

A

which occur simultaneously as a dynamic, equilibrium mixture of tautomers. Both forms of tetrazolylamide are included within the scope of this invention.

U.S. Patent 4,066,766 discloses that the corresponding acids, namely 1-oxo-1H-6-alkoxypyrimido [1,2-a] quinoline-2-carboxylic acids and their esters, are antiallergically active. The compounds of the present invention exhibit substantially broader antiallergic activity than these corresponding acids and esters. The antiallergic activity of the compounds according to the invention is quite surprising, since the corresponding simple amides [e.g. -CONH2, -CON (C2Hg) 2J are ineffective as antiallergic agents tested by the methods described below.

Of particular interest from the compounds of this invention are those wherein R 8 is methoxy or ethoxy and the substituents R 1, R 2 are hydrogen, and those wherein R 8 is methoxy and at least one of the benzenoid substituents is lower alkoxy or fluoro with the other substituent being hydrogen.

H ^ 2 R3 H H OCHg, OC2H5 H CH3 OCHg, OC2H5 H 0CH3 0CH3 H OC2H5 0CH3 H F 0CH3

The antiallergic properties of the compounds according to the invention are evaluated by a passive skin anaphylaxis test (PCA) (Ovary, J. Immun. 81, 355, 1958). In the PCA test, normal animals are injected subcutaneously (i.d.) with serum containing antibody from actively sensitized animals. The animals are then injected intravenously with an antigen mixed with a dye, such as Evans' blue. The increased capillary permeability caused by the antigen-antibody reaction causes dye to migrate from the antibody injection site. The animals are then killed by suffocation, and the intensity of reaction 6 59409 is determined by measuring the diameter of the blue stained area and the intensity of the color from the inner surface of the animal's skin.

The compounds of the invention are conveniently prepared by dehydrating the addition of the appropriate 1-oxo-1H-6- (R 1 -substituted) pyrimido [1,2-a] quinoline-2-carboxylic acid to 5-aminotetrazole. Dehydrating coupling can be performed using a variety of agents commonly used in peptide syntheses. These include N, N'-carbonyldiimidazole, N, N'-carbonyl-di-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphenyl ketene-p-tolylimine, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, ethylene chlorophosphite, diethylethylene pyrophosphite, N-ethyl-5-phenylisoxazolium 3'-sulfonate, phenylphosphorodi- (1-imidazolate) and carbodiimides such as dicyclohexylcarbodiimide, (2-morpholinomethyl) carbodiimide, N- (3-dimethylaminopropyl) -N * -ethylcarbodiimide hydrochloride, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride and diethyl cyanamide.

The coupling agents described above are generally first reacted with an acid reactant and the resulting product is then reacted without isolation with 5-aminotetrazole to give the desired N- (5-tetrazolyl) -1-oxo-1H-6 - (- substituted) pyrimido-1 H 2. - ^ - quinoline-2-carboxamide. The reaction is carried out in a reaction-inert solvent system in which the acid need not be dissolved. The only requirement for the solvent system is that it does not substantially react with the reactants or products. Due to the variety of substances used in the coupling, the solvent in the dehydrating coupling reaction can be selected from a variety of solvents. Suitable solvents include N, N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of the acid reactant with the coupling agent is performed at temperatures of about 20 to about 110 ° C. The reactive intermediate is then reacted with 5-aminotetrazole at about 20 to about 110 ° C. Each of these reaction steps is preferably carried out at about 50 to about 100 ° C, since the reaction rate and the yield are then advantageous.

The molar ratio of acid to excipient to 5-aminotetrazole is generally from about 1: 1: 1 to about 1: 1.1: 1.1. Higher relative amounts of coupling agent and 5-aminotetrazole can be used, but do not provide any benefit. 10 mol% excesses are suitable.

7 59409

As will be apparent to one skilled in the art, all reactants may be added at once instead of the stepwise addition described above. However, first forming a reactive intermediate (acid-coupling agent reaction product) gives better yields of the desired N- (5-tetrazolyl) amides.

The preferred coupling agent is N, N'-carbonyldiimidazole because the reaction using it proceeds easily and in good yield of the desired product without optimizing the reaction conditions. Using this coupling agent, N, N-dimethylformamide and a temperature of 85-100 ° C, the reaction conditions are highly preferable for the reasons mentioned above.

Compounds of alkoxy are conveniently prepared by the Williamson reaction of the appropriate N- (5-tetrazolyl) -1-oxo-1H-6-chloro (or bromo) pyrimido [1,2-a] quinoline-2-carboxamide and the appropriate alkanol. as shown in the examples.

The required 1-oxo-1H-6- (R 1 -substituted) pyrimido [1,2-b] quinoline-2-carboxylic acids are prepared by condensing the appropriate 2-amino- (4- (R 1 -Substituted) quinoline with the appropriate dialkyl ethoxymethylene malonate, to give the corresponding intermediate, dialkyl 4- (R 9 -substituted) -2-quinolylaminomethylene malonate, which is then cyclized to the desired alkyl-1-oxo-1H-6- (R 1 -substituted) pyrimido-1,2-α7-quinoline-2- carboxylate.

The condensation is performed by heating a stoichiometric mixture of 2-aminoquinoline reactant and dialkyl ethoxymethylene malonate at about 80 to about 125 ° C. The use of lower temperatures is not recommended because the reaction rate is then too low. Higher temperatures can be used, but they do not achieve any advantages. The reaction is thus conveniently carried out as a melt. It can, of course, also be carried out in solution or in a solvent mixture, e.g. ethanol, Ν, Ν-dimethylformamide, or acetonitrile. From a practical point of view, however, the solvent is useless.

The intermediate thus obtained, 4- (R 1 -substituted) -2-quinolylaminomethylene malonate, is then preferably cyclized by heating at a temperature of about 175 to about 250 ° C in a suitable reaction-inert diluent, i. in a compound in which the reaction temperature control can take place, which is stable at the relatively high temperature used and which does not react with the starting material or the cyclization product. Examples of diluents are high-boiling hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, β 59409 acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, especially 26.5% of diphenyl and 73.5% of diphenyl ether, .

Alkyl 1-oxo-1H-6- (R 9 -substituted) pyrimido [1,2-a] quinoline-2-carboxylates are converted to the corresponding acids by hydrolysis, preferably by acid hydrolysis. The reaction is usually carried out by heating an aqueous mixture of a suitable ester and a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid at about 50 to about 100 ° C for up to 4 hours, i.e. until the hydrolysis is substantially complete. The most preferred mineral acid is hydrochloric acid as 3- or 12-normal. The less the ester reactant is soluble in water, the more concentrated acid is 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 are recovered by evaporation of the reaction mixture. The acids are purified by recrystallization from a suitable solvent such as N, N-dimethylformamide.

The salt formation is carried out by well known methods by reacting the appropriate acid with a suitable metal salt such as carbonate, bicarbonate, acetate, hexanoate, or hydroxide in a suitable medium such as water, methanol or ethanol. The salts are recovered by known methods, such as by filtration if they are insoluble in the reaction medium, or by evaporation of the solvent if they are soluble in the reaction medium, or by precipitation by adding a solvent in which the salt is insoluble.

As indicated above, the N- (5-tetrazolyl) amides prepared in accordance with this invention have a significantly broader antiallergic spectrum than the parent compounds. Acids remain only to prevent anaphylactic phenomena mediated by immunoglobulin E (IgE). Instead, N- (5-tetrazolyl) amides are effective not only for reagent-induced anaphylaxis (IgE, immunoglobulin E) but also for anaphylaxis caused by immunoglobulin G (IgG). In this respect, it also differs from the mode of action of disodium cromoglycate, which compound does not inhibit the IgG-mediated response at the highest doses.

The products of this invention and their pharmaceutically acceptable cationic salts are useful as prophylactic agents in inhibiting the release of anaphylaxis mediators (allergy, immediate hypersensitivity) and the occurrence of allergic symptoms in mammals, and may be administered alone or in admixture with such agents, e.g. with theophylline or sympathomimetic amines. They may be administered alone, but will usually be administered in conjunction with pharmaceutical carriers selected with regard to the mode of administration and in accordance with standard pharmaceutical practice. They may be combined, for example, with various pharmaceutically acceptable, inert carriers in the form of tablets, capsules, lozenges, medicated buttons, medicated candies, powders, aerosol sprays, aqueous suspensions or solutions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents and excipients, sterile aqueous media and various non-toxic organic solvents. In addition, the oral pharmaceutical compositions of this invention may be suitably sweetened and flavored with various agents commonly used for this purpose.

An effective daily dose of the compounds of the invention in humans may be considered to be a dose of about 10 to about 1500 mg / day, preferably about 10 to about 600 mg / day given in one or more sub-doses, i.e. about 0.2 to about 12 mg / kg body weight. which doses are effective in relieving bronchoconstriction in human patients. These values are guide values, and lower or higher doses may be used individually.

When administered intravenously or by inhalation, the effective daily dose is about 0.5 to about 100 mg per day, preferably about 0.25 to 200 mg per day, i.e. about 0.005 mg / kg body weight in one or more sub-doses.

There are two basic changes in anaphylactic shock: (1) capillary permeability increases and (2) smooth muscles contract. The increased capillary permeability is due to the antigen-antibody interaction. It, like smooth muscle contraction, can be detected and easily measured. The PCA test is based on this capillary permeability.

The PCA test measures the anti-allergic (especially asthma) activity of a compound. Compounds that give a positive PCA test result in a rat with an immunochemical equivalent to human immunoglobulin E (IgE) or a reagent are considered antiallergically active (C. Mota, Ann. NY Acad. Sci., 103 »26U, 1963) · The reagent is primarily immunoglobulin E and is an immunoglobulin primarily causing allergic asthma, anaphylaxis, hay fever, food sensitivity and certain drug sensitivities.) When antiallergic compounds are administered to a sensitized subject, human or animal, prior to contact with antigens or substances to which it is allergic, they prevent an allergic reaction that would otherwise occur. They thus constitute a prophylactic treatment for allergic or anaphylactic reactions of a reagent nature.

10 59409

To put it another way, such compounds inhibit the release of mediators that cause an antigen-antibody reaction (allergic reaction), as can be demonstrated in a PCA assay using a rat homocytotropic antibody, a known equivalent of a human reagent antibody. The inhibition of the reactive antigen-antibody reaction obtained in the PCA test of the rat used in the experimental animal is considered to indicate that the reactive antigen-antibody reactions occurring in the allergic stages of humans are inhibited.

There is an excellent correlation between the activity of the compounds obtained in the PCA reaction experiment used in the evaluation of the mock-prepared compounds of the present invention and their utility in the treatment of allergic asthma. The ability of the substances to affect PCA reactions is measured in male Charles River Wistar rats, weight 170-210 g. Reagent antiserum high in IgE antibody is prepared according to Petillon et al. Int. Arch. Allergy, 4¼, 309 (1973). Hyperimmune antiserum high in chicken egg IgE antibody is prepared by Organon et al., J. Exptl. Med., 127, 767 (1968). 48 hours before antigen administration, the reagent antiserum is injected intradermally (i.d.) into the shaved back of a normal rat; 5 hours before antigen administration, hyperimmune antiserum is injected in the same manner. In third place, 60 mcg of histamine dihydrochloride and 0.5 mcg of serotonin creatine sulfate are injected i.d. just prior to antigen administration to control antihistamine, antiserotonin, and unspecified type blockade; the compounds or saline of the present invention are then administered i.v. and immediately thereafter 5 mg of egg albumin and 2.5 mg of Evans blue in saline. For oral administration, Evans blue and egg albumin are given 5 minutes after dosing. Thirty minutes later, the animals are killed with chloroform, the dorsal skin is removed, and inverted for examination. Each injection site is given a score equal to the diameter of the stained area in mm multiplied by the color intensity using a scale of 0.1, 0.5, 1, 2, 3 and 4. The injection site scores for each group of 5 animals are added together and the sum is compared with saline. controls obtained. The difference is expressed as% inhibition by the compound used.

59409

Representative compounds of the present invention were tested for antiallergic activity by the method described above, and the resulting activities are expressed as degrees of protection (#). For comparison, the experiment was also performed with the commercial antiallergic drug Intal, disodium chromoglycate.

The compounds tested have the formula 2 R2

I .N — N

o = c-nh- <2 I

N-N

B

i2 5 94 0 9

•B

4-> tn

, ri I rHOmONCTiOr-t <r (NO> ONNO ON rH m CM

m sm] r- vo vo m r- <m r- * cm m rH rH

5- * J

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He oooooooof ^ oooooo

•B

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mx cm cm X cm X X XX

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o o X m pj o o o o X υ u -1 i i t - * - «i

X X CO 00 CO On On On CO

ρΓΊ XXXXXÄ «WÄ 13 59409

Example I

N- (5-tetrazolyl) -1-oxo-1H-6-methoxypyrimido [1. 2-a7kino-

Line-2-carboxamide 1-oxo-1H-6-methoxypyrimido [1,2-a] quinoline-2-carboxylic acid (540 mg, 2.0 mmol) and N, N'-carbonyldiimidazole (357 mg, 2 2 mmol) in N, N-dimethylformamide (15 ml) is stirred and heated on a steam bath for 15 minutes. After heating for about 5 minutes, a clear solution is obtained and a precipitate forms. The reaction mixture is stirred for an additional 45 minutes at room temperature, then treated with 5-aminotetrazole (187 mg, 2.2 mmol). The mixture is heated on a steam bath for 40 minutes, then cooled and the product collected by filtration (540 mg of a yellow solid), m.p. 220 ° C (dec.).

s

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

Analysis calculated for C 15 H 11 O 3 N 7: C 53.41 H 3.29 N 29.07% Found: C 53.12 H 3.67 N 28.75%.

The following compounds are prepared in a similar manner from suitable starting materials: R1 h ίί '^ ιι h 0 T. / »Hi 0 = C-IIU- <'J 1 2 2 u 59409 Λ ^ Λ

rt, α JO

OrOtO'OtN. — IOOO "2 incniriOO '- ^ cr» · ^' vO to to to Γ "~

^. CMtNOMfMCMtNtMCM

£ -μ rrj T— (t— (lO H OO> i rt

• ί r-tvOOrH <M <OCMO

jg1 ^ ........

J <frOv3- ~ i - 3-fO <OiO

crir -roio ^ JO-OM ^ ^ T

LOOMtOiH' — ΙΌ <0 -3 u · <· · · · · · • jTCStO'J'iOO'O'-f ιΛιΛίΛΗ'ΙιΟ'ΐΙΛΌ ^ HO> rHrH <r <NOCh cnvDt ^ aicOvrOO K ..... ·· · Ι '^ νΟιΟΟ'ΌΌΓ ^ νΟ

CMrsJtNCM0 ^ O. »CMO> J

£ '

Tj for ^ voo <r <^ <J ·

Qj r ^ ino ^ r ^ r- ^ rHcoto S X *. ♦ * ···· yj ηπίη, ίΟ'ίΠΝ ^ 3

O r \ l -J O oo cM O fM

Γ'.γοιλΓ'-οοοογ'-γο υ .......

No-cMtovi'uoG'OfM

ιΟιΟιΟΐΟΌ'β'ΐΛΐΛ

· 'J I I Ίίί II

A- · 'w w w ww S ~~ \ \ ^ _ y ^ v ^ OOtOCOr ^ vOvO'D'O'

O | | I I I I I I

"- tototoio ^ tooro

-JtOiOOfOmOstOuO

^ CMOMCMCMCMCSCMfM

tO lO Ό k ro k ro <o s: ro n CO CMS fM 5J Ä, CM S3 3 <ϋ ουυυυυυο oooooooo oo ro tO to <0 · Η · ι-) ffi rt to tn K -X 44

fM UU-KCMrS U W W

*? ? v v v *? * i ft; ooco «r> oooocr \ CTt _ • 5.5 a> co pfl

00 (N

S r-s 3 M H H λ m MM> MMMX JJ ö

£ j> -imM >>>> H

15 59409

The product of Example VIII is purified by dissolving it in ammonium hydroxide (6-n), from which the product precipitates on standing. The precipitated product is filtered, dissolved in water and mixed from the solution with 3N hydrochloric acid. It is filtered, dried and recrystallized from N, N-dimethylformamide.

The product of Example IX is purified by recrystallization from N, N-dimethylformamide followed by purification as in the product of Example VIII.

Example X

N- (5-tetrazolyl) -1-oxo-1H-6-ethoxypyrimido [1,2-a] quinoline-2-carboxamide p-toluenesulfonic acid monohydrate (20 mg) and N- (5-tetrazolyl) -1-oxo- A mixture of 1H-6-chloropyrimido (rT, 2-α7-quinoline-2-carboxamide (1.79 g) in ethanol (75 ml) is heated at reflux for 2b. The solvent is removed under reduced pressure and the residue is partitioned between 3N hydrochloric acid (25 ml) and ethyl acetate ( The phases are separated and the ethyl acetate phase is extracted with 3N hydrochloric acid (2 x 20 ml), the acid extracts are combined, neutralized (pH 7 ~ 8) with 20% ammonium hydroxide and the precipitate obtained is collected by filtration (235 mg).

Example XI

The salt formation

The products of Examples IX are converted to sodium, potassium, ammonium, calcium, magnesium, aluminum, triethylamine, tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, pyrrolidine and N, N-dibenzyl. ethylenediamine salts by reaction with an equivalent amount of a suitable metal hydroxide, ammonium hydroxide or amine in water or ethanol, filtering off the salt if it is insoluble, or evaporating the solvent if the salt is soluble therein.

16 5 9 4 0 9 Examples of starting materials

Example A

Ethyl 1-oxo-1H-6-methoxypyrimido [1,2-a] quinoline-2-carboxylate (1) 2-amino-4-methoxyquinoline (34 g, 0.196 mol) and diethyl ethoxymethylene malonate (46.8 g, 0.216 moles) the mixture is heated on a steam bath. A clear melt is obtained in about 10 minutes, and after about 20 minutes it begins to solidify again. The mixture is heated for a total of 45 minutes, then cooled. The product, diethyl 4-methoxy-2-quinolylaminomethylene malonate is crystallized from ethanol (350 ml) to give a fluffy solid, m.p. 136.5 to 137.5 ° C.

Analysis calculated for C 18-8 ^ 20 ^ 2 ^ 5: ^ 62 s7® H 5.85 N 8.14% found: C 62.72 H 6.10 N 8.37% (2) to Dowtherm A (350 ml) is added at 100 ° C the product obtained in (1) (55 g, 0.16 mol), and the resulting bright yellow solution is heated at 230-233 ° C for 1.75 hours. The reaction mixture is cooled, diluted with ethyl acetate (500 ml) and then extracted with 1N hydrochloric acid (3 x 120 ml). The extracts are combined, basified with 20% ammonium hydroxide and cooled to precipitate the product. It is filtered and crystallized successively from ethanol, benzene cyclohexane (1: 1) and ethanol to give 15.5 g of yellow crystals, m.p. 130 to 130.5 ° C.

(3) However, the procedure of Preparation A (2) is repeated using diethyl 4-methoxy-2-quinolylaminomethylene malonate (3.5 g) as a starting material. The product is recovered by cooling the reaction mixture, and diluting with cyclohexane (150 mL) to precipitate the crude product as a brown gum. It is obtained as crystals by heating the diluted reaction mixture to boiling and filtering the hot mixture. Upon cooling, the product precipitates as yellow crystals which are filtered. Yield = 1.1 g. Further purification is performed by recrystallization from ethanol.

Example B

Following the procedures of Preparations A (1) and A (3), the following compounds are prepared from suitable reactants. In most cases, the product separates as crystals upon dilution of the reaction mixture with cyclohexane and hot filtration of the mixture is unnecessary.

it 59409 The following compounds are thus prepared: .3 R1

«V

C00C21I5 R3 Y R2 Sp. (° C) 0CH3 Cl H '213-214 0C113 CH3 H 191.5-192.5 0CII3 0Cl13 H 200-201.5 0CII3 H 0CH3 184-185 0C1I3 H Cl 178-179 0C1I3 H CH3 139-141 0C113 0C113 0CH3' 215-216 0C1I3 OC2H5 H 163.5-164.5 OC2H5 HH 143-145 0CH3 HF 141-143 0CH3 FH 175.5-177 M 5 & 4 O 9

Example C

1-Oxo-1H-6-methoxypyrimido [1,2-a] quinoline-2-carboxylic acid Ethyl 1-oxo-1H-6-methoxypyrimido [1,2-a] quinoline-2-carboxylate (3.0 g) and a mixture of concentrated hydrochloric acid (60 ml) is heated on a steam bath for 0.5 hours. The mixture is then cooled and filtered to give 0.87 g of the title product. It is recrystallized from N, N-dimethylformamide, m.p. 219 ° C (dec.).

In a similar manner, the products of Preparation B are hydrolyzed to the corresponding acids.

B

Ap

COOH

R3 R1 R2 Sp. (° C) OCH 3 Cl H 239 (dec.) OCH 3 CH 3 H 2 Λ7 (dec.)

och3 och3 H

0CH3 h 0C113 230 (dec.) 0C1I3 H Cl 234 (dec.) Och3 h ch3 0CH3 0CH3 0CH3 245 (ha3 ·) 0C1I3 OC2K5 H 237 (ha3 *) OC2H5 HH 205 (ha3 ·) 0C113 HF ^ 196-198 (dec.) .) OCH FH 265-268 (ha3 ·) »59409

Example D

Ethyl 1-oxo-1H-6-chloropyrimido [1,2-b] quinoline-2-carboxylate (1) 2-amino-4-chloroquinoline (15.5 g, 0.087 mol) and diethyl ethoxymethylene malonate ( 20.8 g, 0.096 mol) the mixture is heated on a steam bath for 45 minutes. Isopropanol (75 ml) is added to the hot clear melt and the mixture is cooled. The product separates, is filtered off, washed with isopropanol and dried. Yield = 26.0 g of a white solid, m.p. 108.5 to 109.5 ° C. It is used without further purification directly in the next step (2).

Recrystallization from ethanol gives an analytical sample, m.p. 109-110 ° C.

(2) The intermediate from step (1), diethyl 4-chloro-2-quinolylaminomethylene malonate (26 g) is added to Dowtherm A (75 ml) at 100 ° C. The resulting clear solution is heated at 235-237 ° C for 80 minutes, then cooled. Hexane (100 mL) is added to the reaction mixture, and the precipitated product is collected by filtration, washed with hexane and dried. The product is recrystallized from acetonitrile, m.p. 178-179 ° C.

Claims (2)

20 59409 Patents: Method for the preparation of antiallergically active 1- (5-tetrazolyl N1-oxo-1H-β-1H-substituted) pyrimido [1,2-a] quinoline-2-carboxamides and their pharmaceutically acceptable cationic salts of formula R 2 - N / r 1 n / NN oXC 1 H 2 N, wherein N 1 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluorine or chlorine, or R 1 and R 2 may together form a -O-CH 2 -CH 2 -O- or -O-CH 8 -O- group, and is chlorine, bromine, or C 1-4 alkoxy, characterized in that the formula R 3 is dehydratingly joined together. COOH acid and 5-aminotetrazole by first contacting the acid with a dehydrating coupling agent followed by contacting it with 5-amino-tetrazole, and if desired converting the product to a pharmaceutically acceptable cationic salt.