CH616679A5 - Process for the preparation of N-(5-tetrazolyl)-1-oxo-1H-pyrimido[1,2-a]quinoline-2-carboxamides - Google Patents

Abstract

Substituted N-(5-tetrazolyl)-1-oxo-1H-pyrimido[1,2-a]quinoline-2-carboxamides of formula I are obtained by acylation of 5-aminotetrazole with an acid of formula II, in the presence of a dehydrating agent. The symbols in these two formulae are defined in Claim 1. The reaction can be carried out using dehydrating agents commonly used in the synthesis of peptides. The compounds of formula I and their pharmaceutically usable salts are useful as antiallergic agents in that they prevent anaphylaxis mediators from causing bronchoconstriction. <IMAGE> <IMAGE>

Description

This invention relates to the preparation of N- (5-tetrazolyl) -pyrimido- [1,2-a] -quinoline-2-carboxamides. More specifically, it relates to the preparation of N-tetrazolyl-1-oxo-1H-6- (r3) -pyri-mido- [1,2-a] -quinoline-2-carboxamides in which the substituent in position 6 is the chlorine, bromine or a lower alkoxy group; their pharmaceutically acceptable cationic salts; and derivatives of compounds in which the benzene ring carries one or more substituents, which are useful as agents for treating allergic reactions, and in particular allergic bronchial asthma; and intermediaries to prepare them.

Allergic reactions, the symptoms of which result from an antigen / antibody interaction, manifest themselves in a wide variety of ways and in different organs and tissues. Common allergic disorders are, for example, allergic rhinitis, a seasonal or annual condition characterized by sneezing, a runny nose, nasal congestion, with tingling and eye congestion; hay fever, which is a variety of allergic rhinitis that results from hypersensitivity to herb pollens, and bronchial asthma, one of the most debilitating and disabling allergic allergic reactions, a condition characterized by hyper -

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responsiveness of the bronchial tubes to exposure to various immunogenic or non-immunogenic stimuli, resulting in bronchial spasms with noisy breathing, short-lived paroxysms and very extensive constriction of the airways. Mechanical obstruction to the flow of air through the airways is usually removed by the use of bronchodilators, which provide symptomatic relief. In contrast, antiallergic agents prevent the release of mediators of anaphylaxis from tissue stores, thus acting prophylactically to prevent mediators from causing the formation of bronchoconstriction.

There have been many efforts to discover medicinal agents that can relieve the symptoms of this abnormal physiological state. As early as 1910, Matthews, "Brit. Med. J ”, 1.441 (1910) indicated the bronchodilator effects of epinephrine. Since then, Chen and Schmidt, "J. Pharmacol. Exper. Therap. ”, 24, 339 (1924) reported the use of the alkaloid ephedrine as an effective oral bronchodilator, with the same spectrum of activity as epinephrine. In 1940 Konzett, “Arch. Exp. Path. Pharmak. ”, 197,27 (1940) highlighted the effects of isoproterenol as a potent aerosol bronchodilator. Cullum et al, "Brit. J. Pharmacol. Exp. ”, 35,141 (1969) indicated the pharmacology of salbutamol, a potent bronchodilator with a long duration of action, and active by oral and aerosol administration. Many bronchodilator preparations contain theophylline. They are generally less potent than sympathomimetic amines such as isoproterenol and salbutamol, and are ineffective when administered by aerosol.

Recently, Cox et al, “Adv. in Drug Res. ”, 5,115 (1970) described the pharmacology of a similar agent, sodium cromoglycate [1,3-bis- (2-carboxycromon-5-yloxy) -2-hydroxypropane, Intal]. It is not a bronchodilator, but it has therapeutic effects due to a unique mechanism of action involving the inhibition of the release of mediators of anaphylaxis, and it is administered prophylactically. It suffers from a lack of efficacy by the oral route and, for optimal results, it is administered by inhalation in the form of a solid inhalant. In addition, although it is effective against immunoglobulin E (IgE) anaphylaxis, it is only effective against immunoglobulin G (IgG) anaphylaxis high doses (60 to 70% protection at doses of 100 and 300 mg / kg).

Although the above agents represent remarkable contributions to the treatment of asthma, many of them have the undesirable side effect of pacing.

The synthesis of 1H-pyrimido- [1,2-a] -quinoline seems to have been indicated for the first time by Antaki et al, "J. Chem. Soc. ", Pp. 551-555 (1951), which condense 2-chloroquinoline with

ethyl ß-aminocrotonate in the presence of anhydrous potassium carbonate and a trace of copper bronze, to produce l-oxo-1H-3-methylpyrimido- [1,2-a] -quinoline. No utility for the compound has been indicated.

Antaki, "J. Am. Chem. Soc. ”, 80, 3066-9 (1958) indicates the condensation of ethyl 2-aminoquinoline and ethyl ethoxymethylene cyanoacetate to form ethyl 2-quinoleylaminomethylene-cyanoacetate which, when distilled under pressure reduced, provides l-oxo-1H-pyrimido- [1,2-a] -quinoline-2-carbo-nitrile. This compound has an antischistosomal action.

Richardson et al, "J. Med. Chem. ”, 15.1203-6 (1972) describe ethyl 1-oxo-1H-pyrimido- [1,2-a] -quinoline-2-carboxylate and indicate that it is inactive as an antimicrobial agent. When tested to determine its antiallergic activity by the PCA test, it is found to exhibit 100% inhibition, at a dose of 3 mg / kg intravenously (IV) administration, but it is without activity at a dose of 1 mg / kg (IV). It has an inhibition of approximately 90% at 30 mg / kg by the oral route of administration, but a dosage of 10 mg / kg by the oral route has no activity.

We have now found that compounds of formula:

r,

35

(I)

N— N

0 = C- NH ~ ^ Il

NOT

H

are useful antiallergic agents, i.e. agents which inhibit the release of mediators of anaphylaxis in mammals, including humans, and thereby prevent the mediators from causing bronchoconstriction. They are not bronchodilators. They are interesting, unlike disodium cromoglycate, vis-à-vis anaphylaxis caused by IgG and IgE by the routes of oral, intranasal and intraperitoneal administration, and by inhalation. In this formula, each of the benzene substituents and R 1 and R 2 are chosen from the group comprising hydrogen atoms, lower alkyl and lower alkoxy groups and fluorine and chlorine atoms; R 1 and R 2 when taken together form an alkylenedioxy group of 1 to 2 carbon atoms and are chosen from the group comprising the methylenedioxy and ethylenedioxy groups; R3 is chosen from the group comprising chlorine and bromine atoms and lower alkoxy groups, and their pharmaceutically acceptable cationic salts.

The terms lower alkyl and lower alkoxy as used rei denote alkyl and alkoxy groups having 1 to 5 carbon atoms, since the reagents required to prepare these compounds are more readily available than those having larger alkyl or alkoxy groups.

The expression “pharmaceutically acceptable cationic salts” denotes salts such as the alkali metal salts, for example sodium and potassium; alkaline earth metal salts such as calcium and potassium; aluminum salts; ammonium salts; salts with organic bases, for example amines such as triethylamine, tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, N, N'-dibenzylethylenediamine and Pyrrolidine.

The tetrazoles substituted in position 5 can exist, as is known, in two isomeric forms, namely:

N — N

<5 ii

N N

I

H

-G

NOT

.NOT

\

H

which coexist in a dynamic tautomeric equilibrium mixture. Both forms of tetrazolylamides fall within the scope of this invention.

The antiallergic activity of the corresponding acids, in particular the 1-oxo-1H-6-alkoxypyrimido- [1,2-a] -quinoline-2-carboxylic acids and their esters is known. The compounds described in the present patent have a spectrum of antiallergic activity 60 much wider than do the corresponding acids and esters. Their antiallergic activity is in fact surprising, since the corresponding simple amides (for example - conh2, - CON (C2Hs) 2) are inactive as antiallergic agents when tested by the methods described below.

“S The compounds of particular interest with respect to the invention are those in which R3 is a methoxy or ethoxy group and the benzene variables (Ri and R2) are hydrogen atoms and those in which R3 is a methoxy group and at least one

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benzene substituents is a lower alkoxy group or a fluorine atom, the other benzene substituent being hydrogen.

ri r2

rs h

h och3, oc2h5

h ch3

och3, oc2h5

h och3

och3

h oc2h5

och3

h f

och3

The antiallergic property of the above compounds 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. Then the animals are administered intravenously with an antigen mixed with a dye such as Evans blue. The increased capillary permeability caused by the antigen / antibody reaction causes the dye to escape from the site of the injection of the antibody. The test animals are then asphyxiated and the intensity of the reaction is determined by measuring the diameter and intensity of the blue color on the internal surface of the skin of the animals.

The compounds are conveniently prepared by acylation of 5-aminotetrazole with l-oxo-1H-6- (r3) -pyrimido- [1,2-a] -quinoline-2-carboxylic acid in the presence of an agent. dehydration, preferably those commonly used in the synthesis of peptides. Representative agents include N, N'-carbonyldiimidazole, N, N'-carbonyl-di-s-triazine, ethoxy-acetylene, 1,1-dichlorodiethyl ether, diphenyl ketene-p-tolyl-imine, N -hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, ethylene chlorophosphite, diethyl ethylene pyrophosphite, N-ethyl-5-phenyl-isoxazolium 3'-sulfonate, phosphorodi- (l-imidazolate) phenyl and carbo-diimides such as dicyclohexylcarbodiimide, l-cyclohexyl-3- (2-morpholinomethyl) carbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, l-ethyl-3- hydrochloride (3'-dimethylaminopropyl) carbodiimide and diethyl-cyanamide.

The coupling agents described above are generally reacted first with the acid reagent, then the resulting product, without isolation, is reacted with 5-aminotetrazole to form the N- (5-tetrazolyl) -1 -oxo -1 H-6- (r3) -py rimido- [1,2-a] -quinoline-2-carboxamides desired. The reaction can be carried out in a solvent system inert to the reaction, in which the acid reagent need not be soluble. The only requirement with regard to the solvent system is that it does not react appreciably with the reagents or the products. The variety of dehydration agents, which at the same time promote acylation, which can be used allows a wide choice of solvents. Typical solvents are N, N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of the acid reagent with the coupling agent is usually carried out at a temperature of 20 to 110 ° C. The reactive intermediate is then reacted with 5-aminotetrazole at a temperature of 20 to 110 ° C. Each of these steps is advantageously carried out at a temperature between 50 and 100 ° C., since the speed and the yield of the reaction are improved.

The acid molar ratio: coupling agent: 5-aminotetrazole is generally from 1: 1: 1 to 1: 1.1: 1.1. Higher ratios of the coupling agent and 5-aminotetrazole can be used, but they do not offer advantages. Excesses of 10 mol% are satisfactory.

As those skilled in the art will see, all the reagents can be added at once rather than several times as described above. However, the prior formation of the reactive intermediate (acid product / coupling agent) normally gives better yields of the desired N- (5-tetrazolyl) amides.

A preferred dehydrating / acylating agent is N, N'-carbonyldiimidazole, since it provides a regular reaction and reasonable yields of the desired product, without optimizing the reaction conditions. When using this coupling agent, N, N-dimethylformamide and a temperature of 85 to 100 ° C are the preferred conditions for the reasons mentioned above.

Compounds in which R3 is an alkoxy group can also be conveniently prepared by the Williamson reaction between N- (5-tetrazolyI) -l-oxo-1H-6-chloro- (or bromo) pyrimido- [1,2- a] -quinoline-2-carboxamide suitable and the alkanol suitable as we give examples here.

The necessary l-oxo-1H-6- (R3) -pyrimido- [1,2-a] -quinoline-2-carboxylic acids can be prepared by condensation of the appropriate 2-amino-4- (R3) -quinoline with appropriate dialkyl ethoxymethylene malonate, to form the corresponding intermediate dialkyl 4- {R3) -2-quinoleyl-aminomethylenemalonate which is then cyclized to l-oxo-1H-6- (R3) -pyrimido- [1 , 2-a] -quinoline-2-alkyl carboxylate desired.

Condensation can be accomplished by heating a stoichiometric mixture of the 2-aminoquinoline reagent and dialkyl ethoxy-methylenemalonate to a temperature of about 80 to about 125 ° C. Lower temperatures are not given because the reaction takes place too slowly. Higher temperatures can be used, but it does not appear to offer any benefits. The reaction is thus conveniently carried out in the form of a molten product. The reaction can obviously be carried out in a solvent or a mixture of solvents, for example ethanol, N, N-dimethylformamide, acetonitrile. However, from a practical point of view, a solvent does not appear necessary.

Then cyclized the intermediate dialkyl 4- (R3) -2-quinoleylaminomethylenemalonate thus obtained, preferably thermally, by heating to a temperature of about 175 to about 250 ° C in a suitable diluent inert with respect to the reaction, that is to say in a compound which makes it possible to control the reaction temperature, is stable at the relatively high temperatures used and does not react with the starting substance or the products beyond cycli-sation. Examples of these diluents are high boiling point hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and biphenyl, in particular the solvent which contains 26.5% biphenyl and 73.5% diphenyl ether and is sold under the trademark Dowtherm A.

The alkyl l-oxo-1H-6- (R3) -pyrimido- [1,2-a] -quinoline-2-carboxylates are converted into corresponding acids by hydrolysis, preferably acid hydrolysis. Typical conditions include heating an aqueous mixture of the appropriate ester and a mineral acid such as hydrochloric, sulfuric, phosphoric or nitric acids to about 50-100 ° C for periods of up to 4 h or until the hydrolysis is almost complete. The preferred mineral acid is hydrochloric acid at a concentration of 3N to 12N. The less soluble the ester reagent in water, the more concentrated will be the acid used for hydrolysis. The free acids generally crystallize in the hydrolysis reaction mixture after cooling and are collected by filtration. When crystallization does not take place, the acids are collected by evaporation of the reaction mixture. The acids are purified by recrystallization from suitable solvents, such as N, N-dimethylformamide.

The formation of the salts can be carried out by reacting the appropriate acid with the appropriate metal salt, such as a carbonate, a bicarbonate, an acetate, a hexanoate, a hydroxide, in a suitable medium such as water, methanol or ethanol, according to well known procedures. The salts are collected by conventional methods, for example filtration if they are insoluble in

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the medium, evaporation of the solvent if they are soluble in the medium or precipitation by adding a non-solvent for the salt.

As indicated above, the above N- (5-tetrazolyl) amides have a much wider spectrum of antiallergic activity than do the acid precursors. Acids only inhibit the anaphylactic phenomena caused by immunoglobulin E (IgE). On the contrary, N- (5-tetrazolyl) -amides are not only effective against anaphylaxis induced by reactinic route (IgE, Immunoglobulin E), but also against anaphylaxis induced by immunoglobulin G ( IgG). This behavior is also different from the action of disodium cromo-glycate which does not inhibit reactions due to IgG,

except at high doses.

The products of this invention and their pharmaceutically acceptable cationic salts are useful as prophylactics to inhibit or prevent the release of mediators of anaphylaxis (allergy, immediate hypersensitivity reaction) and the onset of allergic symptoms in mammals, and may be administered for these purposes individually or as a mixture with other agents; for example with theophylline or sympathomimetic amines. They can be administered alone, but are generally administered with a pharmaceutical carrier chosen according to the route of administration provided and the pharmaceutical use accepted. For example, they can be combined with various inert pharmaceutically acceptable carriers, in the form of tablets, capsules, cachets, dragees, hard candies, powders, aerosol sprays, suspensions or aqueous solutions, injectable solutions, elixirs, syrups, etc. These supports include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, the oral pharmaceutical compositions of this invention can be appropriately flavored and sweetened using various agents of a type commonly used for this purpose.

The choice of the particular carrier and the proportion of the active ingredient to the carrier is influenced by the solubility and chemical nature of the therapeutic compounds, the route of administration chosen and the requirements of current pharmaceutical practice. For example, when the compounds of this invention are administered orally in tablet form, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate can be used. Various dilating agents such as starch, alginic acids and certain complex silicates, as well as lubricating agents such as magnesium stearate, sodium lauryl sulfate, can also be used to form tablets for the oral administration of these compounds. and talc. For oral administration in capsule form, lactose and high molecular weight polyethylene glycols are among the preferred materials for use as pharmaceutically acceptable carriers. When aqueous suspensions are to be used for oral administration, the compounds of this invention can be combined with emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerin and chloroform and their combinations and other substances can be used.

For the purposes of parenteral administration and inhalation, solutions or suspensions of these compounds may be used in sesame or peanut oil or in aqueous solutions of propylene glycol, as well as sterile aqueous solutions of pharmaceutically soluble salts described herein. These particular solutions are particularly suitable for intramuscular and subcutaneous injections if such an administration method is desired. Aqueous solutions, including those of salts dissolved in pure distilled water, are also useful for intravenous injections, provided their pH is adjusted appropriately previously. These solutions should also be appropriately buffered, if necessary, and the liquid diluent first made isotonic with sufficient saline or glucose.

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The compounds can be administered to asthmatic subjects suffering from bronchoconstriction, using inhalers or other devices which allow the active compounds to come into direct contact with the areas of the subject's tissues undergoing constriction. When administered by inhalation, the compositions may include: 1) a solution or suspension of the active ingredient in a liquid medium of the type mentioned above for administration using an atomizer; 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 using a conventional atomizer may contain from about 0.1 to about 1% of active ingredient, and those used in pressurized containers will have from about 0.5 to about 2% of active ingredient. The compositions used as powdered inhalants may have ratios of the active ingredient to the diluent of from about 1: 0.5 to about 1: 1.5.

It is necessary that the active ingredient constitutes a certain proportion of the composition so that an appropriate dosage form can be obtained. Obviously, several unit dosage forms can be used at about the same time. Although compositions with less than 0.005% by weight of active ingredient can be used in some cases, it is preferred to use compositions containing not less than 0.005% of active ingredient; otherwise, the amount of support becomes excessively large. The activity increases with the concentration of the active ingredient. The composition may contain 10, 50, 75.95% or even a higher percentage by weight of active ingredient.

With regard to the dosage of the compounds of this invention, the physician will ultimately determine the dosage which will best suit a particular patient, and this dosage varies with the age, weight and reaction of the patient as well as with the nature and degree of symptoms, pharma-codynamic characteristics of the particular agent to be administered and the chosen route of administration. Generally, small doses will be given first, gradually increasing the dose until the optimal level is determined. It will often be found that when the composition is administered orally, greater amounts of active ingredient will be required to obtain the same reaction as that obtained by a small amount administered parenterally.

With full consideration of the foregoing factors, it is considered that an effective daily oral dose of the compounds of the present invention in humans of about 10 to about 1500 mg, with a preferred range of about 10 to about 600 mg, in one single dose or in separate doses, or at a rate of about 0.2 to about 12 mg / kg of body weight, will effectively relieve bronchoconstriction in humans. These values are illustrative and there can obviously be special cases where lower or higher doses are necessary.

For intravenous or inhalation administration, the effective daily dose is from about 0.5 to about 400 mg / day, and preferably from about 0.5 to 200 mg / day, or about 0.005 to 4 mg / kg bodyweight, in a single dose or in separate doses.

The same two basic changes are present in the case of anaphylactic shock: 1) an increase in the permeability of the capillaries, and 2) the contraction of the smooth muscles. The increased capillary permeability is the result of the antigen / antibody interaction. It can be observed and easily measured as well as the contraction of the smooth muscles. This increase in capillary permeability forms the basis of the PCA test.

The PCA test is a measure of the antiallergic (in particular antiasthmatic) activity of a compound. Compounds that inhibit a positive PCA assay induced by the human immunoglobulin E (IgE), or reactin, rat immunochemical are

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6

considered to have antiallergic activity (C. Mota, "Ann. NY Acad. Sci.", 103,264 (1963). (Reain is essentially immunoglobulin E [IgE] and is the main immunoglobulin responsible for allergic asthma, anaphylaxis, hay fever, food sensitivities and certain manifestations of drug sensitivity.) These compounds, when administered to a sensitized subject, human or animal, before the subject comes into contact with antigens, or substances to which he is allergic, will prevent the allergic reaction which would have occurred otherwise, and therefore provide a method of prophylactic treatment of allergy or anaphylactic reactions of a nature caused by reactin.

In other words, these compounds block the release of mediators resulting from the antigen / antibody (allergic) reaction, as illustrated in the PCA assay, using the homopytotropic antibody in rats, a known related product of l 'human reaginic antibody.' Inhibition of antigen / antibody reactions. Reagin in rats, an animal used in the PCA assay, is believed to be representative of the inhibition of the antigen / reagin antibody reactions in humans which occur during allergic disorders.

The PCA reaction test procedure used to test the compounds of the present invention has an excellent correlation between the activity of the compounds in this test and their usefulness in the treatment of allergic asthma. The ability of the agents to prevent PCA reactions was measured in male Charles River Wistar rats, 170-210 g. A reactin antiserum, rich in IgE antibodies, is prepared, according to Petillo et al, “Int. Arch. Allergy ", 44.309 (1973). Hyperimmune antiserum rich in IgE antibodies against chicken egg albumin is prepared according to Orange et al, "J. Exptl. 30 Med. ”, 127,767 (1968). 48 h before the administration of the antigen, the reactinic antiserum is injected intradermally (I.D.) into the shaved skin of the back of a normal rat; 5 h before the administration of the antigen, the hyperimmune antisera are injected in the same way. At a third site, ID 60 jxg of histamine dihydrochloride 3s and 0.5 (ig of serotonin sulfate / creatinine, just before the administration of the antigen, are injected as a control for the antihistamine, antiserotonin and blocking unspecified, then the compounds of the present invention or the saline solution are administered IV, and immediately thereafter 5 mg of egg albumin and 2.5 mg of Evans blue dye in saline solution. in the case of oral administration, Evans blue dye and oval-bumine are given 5 minutes after the administration of the drug, 30 minutes afterwards, the animals are asphyxiated using chloroform and the back skin is removed and we turn it over to observe it. We assign a number to each injection site, a number equal to the product of the site diameter in millimeters and a value of 0.1,0,5,1,2,3 or 4 proportional to the intensity of the coloring of the dye. We add for each group of 5 animals the figures for an injection site ction given and compared with controls treated with saline. The difference is expressed in percent blocking due to the compound used.

Compounds representative of those of the present invention are tested to determine their antiallergic activity using the procedure described above and the resulting activities are given in degrees (%) of protection. Include for comparison Intal, disodium cromoglycate which is a commercial antiallergic agent.

The compounds tested have the formula

»1"

(I)

2 N —N

0 = C-NH- /

N _N I

H

Ri R2

R3

h h

och3

h h

oc2h5

h

8-

c1

oc2h5

h

8-

och3

och3

h

8-

och3

oc2h5

h

9-

och3

och3

h

9-

f och3

h

9-

ch3

och3

h

8-

c2h5

och3

IgE- (I.V.)

IgE -

- (Oral)

IgG- (I.V.)

IgG

- (Oral)

(mg / kg)

(%)

(mg / kg)

(%)

(mg / kg)

(%)

(mg / kg)

(%)

3

73

3

71

0.3

17

0.3

60

3

46

3

63

1

71

1

59

0.3

76

3

28

0.3

83

3

19

0.03

8

0.3

0

0.03

25

0.3

0

0.3

70

3

54

0.3

65

3

51

0.03

74

0.3

4

0.03

86

0.3

4

0.3

100

3

81

0.3

69

3

72

0.03

94

0.3

17

0.03

63

0.3

29

0.3

97

3

20

0.3

85

3

59

0.03

72

0.3

1

0.03

67

0.3

6

3

100

3

83

0.3

100

0.3

57

0.03

89

0.03

45

0.3

70

3

70

0.3

55

3

79

0.03

53

0.3

7

0.03

40

0.3

11

0.3

83

3

81

0.3

53

3

75

0.03

8

0.3

22

0.03

4

0.3

12

Example 1:

N- (5-Tetrazolyl) -1-oxo-1 H-6-methoxy pyrimido - \ _ l, 2-a '\ - quinoline-2-carboxamide

Stir and heat on a steam bath for 15 min a mixture of l-oxo-1H-6-methoxypyrimido- [1,2-a] -quinoline-2-carboxylic acid (540 mg, 2 mmol) and N, N'-carbonyl-

diimidazole (357 mg, 2.2 mmol) in 15 ml of N, N-dimethyl-formamide. A clear solution is formed after approximately 5 minutes of heating, then a precipitate is formed. The reaction mixture is stirred an additional 45 min 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

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it is cooled and filtered to recover the product (540 mg of yellow solid); m.p. 220 ° C with decomposition.

It is purified by dissolving it in hot N, N-dimethylformamide at the rate of 200 mg of crude product for 20 ml of solvent, filtering the hot solution, then cooling the filtrate. Filter and dry the yellow crystals; m.p. 255 ° C with decomposition.

Analysis for c15h11o3n7:

Calculated: C 53.41 H 3.29 N 29.07%

Found: C 53.12 H 3.67 N 28.75%. m

The following compounds are prepared in the same way from the appropriate reagents:

I

0 = C-NK— "N

H

Example Ri R2 R3 P-f- (° C) Analysis

VS

Calculated H

NOT

VS

Found H

NOT

2

H

H

oc2h5

266-8

(d)

54.70

3.73

27.91

54.59

4.11

26.50 '

3

H

8-och3

och3

255-8

(d)

52.32

3.57

26.69

52.27

3.69

25.93

4

H

8-och3

oc2h5

266-8

(d)

53.54

3.96

25.71

53.63

4.01

25.55

5

H

9-ch3

OCH3

235-7

(d)

54.70

3.73

27.91

54.15

4.15

27.05 '

6

H

8-c2h5

och3

254-6

(d)

55.88

4.14

26.84

55.14

4.21

26.42

7

H

8 —Cl oc2h5

273-6

(d)

49.82

3.13

25.42

49.53

3.38

25.41

8

H

9 — F

och3

235-6

(d)

50.70

2.84

27.60

50.32

3.21

26.98

9

H

9-och3

och3

253-4

(d)

52.32

3.57

26.69

51.64

3.62

27.43 '

a Average of 3 analyzes.

b Average of 2 analyzes.

The product of Example 8 is purified by dissolving it in 6N ammonium hydroxide, from which the product precipitates by standing. The solid is filtered, dissolved in water and precipitated from the solution by acidification with 3N hydrochloric acid. It is filtered, dried and recrystallized from N, N-dimethyl-formamide.

40

The product of Example 9 is purified by recrystallization from N, N-dimethylformamide, then following the purification process used for the product of Example 8.

Example 10

The compounds given in the table are prepared from the appropriate reagents by the procedure of Example 1.

1

H

laughed

r2

rs

rI

r2

rs h

8-Cl och3

h

8-ch3

och3

h

9 — Cl.

och3

8-

och3

9-ochs och3

h

8-oc2h5

och3

h

8 — f och3

h

8-och3

Cl

8-

ch3

10-chs och3

h

io-och3

Cl

h

8-Ì-c3h7

och3

8-

ch3

io-ch3

Cl

1

0

1

00 "

-ch2-o-

och3

7-

ch3

io-och3

Cl

SO

H- *

0

1

o

-ch2-o-

och3

h

10-c1

Cl

7-

oc2h5

io-oc2h5

o — n — c3h7

h

8 —Cl

Cl

8-

i — c3h7

9-Ì-c3h7

oc2h5

h

9 —Cl

Cl

OO

1

0

1

ch2-o-

o — n — c4h9

h

9-ch3

Br

8-

o — n — c3h7

9 — Br och3

8-

och3

9-och3

Br

8-

■ o - n — c4h9

9 — o — n — c4h9

oc2h5

h

h

Br

7-

f

9 — f och3

8-

■ chs

9-ch3

Br

8.9-0-

-ch2ch2-o-

och3

h

8-Cl o — sec

-c4h9

8.9 — o-

-ch2ch2-o-

oc2h5

8-

Cl

9 — Cl och3

7-

■ t — c4h9

10 — t — c4h9

och3

h

9 — Cl

We-

c4h9

h

8-och3

oc2h5

h

8-och3

We-

c4h9

h

8-C2H5

och3

h

9-och3

We-

c4h9

h

8 —Cl oc2h5

h

h

We-

c3h7

7-

• ch3

io-och3

och3

616,679

8

Example 11:

N- {5-Tetrazolyî) -l-oxo-1H-6-ethoxypyrimido- [1,2-a] -

quinoline-2-carboxamide

A mixture of p-toluenesulfonic acid monohydrate (20 mg) and N- (5-tetrazolyl) -l-oxo-1H-6-chloropyrimido- [1,2-a] - is refluxed for 24 hours. quinoline-2-carboxamide (1.79 g) in 75 ml of ethanol. 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 phases are separated and the ethyl acetate phase is extracted with 3N hydrochloric acid (twice 20 ml). The acid extracts are combined, neutralized to pH 7-8 with 20% ammonium hydroxide and the resulting precipitate (235 mg) is collected by filtration.

The previous procedure is repeated, but using the β-chlo ^ (or brominated) products of Example X and the appropriate alkanol to obtain the tables given in the table below:

li ri r2

rs h

8-och3

och3

h

8-och3

o — n — c4h9

8-ch3

io-ch3

och3

7-chj io-och3

oc2h5

h

10-Cl och3

h

8 — Cl och3

h

9 — Cl o — n — c3h7

8-och3

9-och3

oc2h5

h h

och3

Example 12:

Salt formation

The products of Examples 1-11 are transformed into sodium, potassium, ammonium, calcium, magnesium, aluminum, triethylamine, tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine salts, of Pyrrolidine and N, N-dibenzylethylenediamine, by reaction with an equivalent of the appropriate metal hydroxide, ammonium hydroxide or amine in water or ethanol, then filtering the salt s' it is insoluble or by evaporating the solvent if the salt is soluble in it.

Preparation A:

1-Oxo-1 H-6-methoxypyrimido- [1,2-a] -quinoline-2-ethyl carboxylate

1) A mixture of 2-amino-4-methoxyquinoline (34 g, 0.196 mole) and diethyl ethoxymethylene malonate (46.8 g, 0.216 mole) is heated on a steam bath. A clear molten product is formed in about 10 minutes, which begins to solidify in about 20 minutes. The mixture is heated for a total of 45 min, then cooled. The product, diethyl 4-methoxy-2-quinoleylamino-methylenemalonate, is recrystallized from ethanol (350 ml) in the form of a flake solid, mp: 136.5-137.5 ° C.

Analysis for C18H20N2O5:

Calculated: C 62.78 H 5.85 N 8.14%

Found: C 62.72 H 6.10 N 8.37%.

2) To 350 ml of Dowtherm A at 100 ° C., the product of 1) is added (55 g, 0.16 mole) and the resulting clear yellow solution is heated at 230-233 ° C for 1.75 h. The reaction mixture is cooled, diluted with 500 ml of ethyl acetate and then extracted with 3 x 120 ml of IN hydrochloric acid. The extracts are combined, basified with 20% ammonium hydroxide and cooled to precipitate the product. It is filtered and recrystallized successively from ethanol, a 1: 1 mixture of benzene and cyclohexane and ethanol and 15.5 g of yellow crystals are obtained; m.p. : 130-130.5 ° C.

3) Or the procedure of preparation A 2 is repeated, but starting with 3.5 g of diethyl 4-methoxy-2-quinoleylaminomethylene-malonate. The product is collected by cooling the reaction mixture, diluting it with 150 ml of cyclohexane to precipitate the crude product in the form of a brown gummy material. A crystalline form is obtained by heating the reaction mixture diluted to the boil and by filtering the hot mixture. Upon cooling, the product precipitates in the form of yellow crystals and is collected by filtration. 1.1 g are obtained. Further purification is carried out by recrystallization from ethanol.

Preparation B

Following the procedures for preparations A1) and A3), the compounds indicated below are prepared from the appropriate reagents. In most cases, the product separates as crystals by diluting the reaction mixture with cyclohexane and hot filtration of the mixture is not necessary.

The following compounds are thus prepared:

r3

ri rz 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

och3

oc2h5

h

163.5-164.5

oc2h5

h h

143-145

och3

h f

141-143

och3

F H

175.5-177

Preparation C:

Acid 1-oxo-l H-6-methoxypyrimido- [l, 2-d] -quinoline-2-

carboxylic

A mixture of ethyl l-oxo-1H-6-methoxypyrimido- [1,2-a] -quinoline-2-carboxylate (3 g) and concentrated hydrochloric acid (3 g) is heated on a steam bath for 1 h. 60 ml). Then cooled and filtered to obtain 0.87 g of the title product. It is recrystallized from N, N-dimethylformamide; mp: 219 ° C with decomposition.

In the same way, the products of preparation B are hydrolyzed to corresponding acids.

5

10

15

20

25

30

35

40

45

50

55

60

65

9

616,679

io r3

ri r2

mp (° C)

och3

Cl h

239 (dec.)

och3

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.)

25

Preparation D:

1-Oxo-1 H-6-chloropyrimido- \ 1,2,2-a \ -quinoline-2-ethyl carboxylate

1) A mixture is heated on a steam bath for 45 minutes 30

of 2-amino-4-chloroquinoline (15.5 g, 0.087 mole) and diethyl ethoxy-methylenemalonate (20.8 g, 0.096 mole). 75 ml of isopropanol are added to the hot clear product which is then cooled. The product separates and is filtered, washed with isopropanol and dried. 26 g of a white solid are obtained; m.p. : 108.5-109.5 ° C. It is used directly in step 2) without further purification.

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

2) 26 g of intermediate 4-chloro-2-quinoleylaminomethylene-ethyl malonate from step 1) are added to 75 ml of Dowtherm A at 100 ° C. The clear solution is heated to 235-237 ° C for 80 min. resulting, then it is 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 .: 178-179 ° C.

The following compounds are prepared from the appropriate reagents, by the procedures of preparation D (R3 = C1, Br) and A1) and A3) (R3 = alkoxy) and C:

cooh laughed

r2

r3

Ri rz r3

h

8-och3

Cl

8-

ch3 io-ch3

och3

h

10-och3

Cl

h

8-ì-c3h7

och3

8-

ch3

10-ch3

Cl

8.9-0-ch2-0-

och3

7-

ch3

10-och3

Cl

9.10 — o — ch2 —o -

och3

h

10-Cl

Cl

7-

oc2h5 io-oc2h5

o — n —c3h7

h

8 —Cl

Cl

8-

ì-c3h7 9 — i —c3h7

oc2h5

h

9 — Cl

Cl

8.9 — o — ch2 —o -

o — n — c4h9

h

9-ch3

Br

8-

o — n — c3h7 9 — Br och3

8-

och3

9-och3

Br

8-

o — n — c4h9 9 —o — n — c4h9

oc2h5

h

h

Br

7-

f 9 — f och3

8-

ch3

9-ch3

Br

8.9 — o — ch2ch2 - o—

och3

h

8 — Cl o — sec

-c4h9

8.9 — O — ch2ch2 — O—

oc2h5

8-

Cl

9 — Cl och3

7-

t — c4h9 10 — t — c4h9

och3

h

9 — Cl

We-

c4h9

h

8-och3

oc2h5

h

8-och3

We-

c4h9

h

8 —C2H5

och3

h

9-och3

We-

c4h9

h

8 — Cl oc2h5

h

h

We-

c3h7

7-

ch3

io-och3

ocha

R

Claims (13)

616,679 CLAIMS 1. Process for the production of pharmaceutically active compounds of formula: in which each of Ri and R2 is independently chosen from hydrogen, C1-c5 alkyl, C1-c5 alkoxy, fluorine and chlorine atoms, or else Ri and R2 taken together form a group - O— CH2 —CH2 - O— or - O — CH2 — O—, and R3 is chosen from chlorine, bromine and C1-c5 alkoxy groups, characterized in that the acylation of a 5-aminotetrazole is carried out with an acid of formula: cooh in the presence of a dehydrating agent. 2. Method according to claim 1, wherein the product is transformed into a pharmaceutically acceptable salt. 3. Method according to one of claims 1 or 2, characterized in that said acid is first contacted with a dehydrating agent and that it is then brought into contact with 5-amino-tetrazole. 4. Method according to one of claims 1 to 3, characterized in that a compound chosen from N, N'-carbonyldiimidazole, N, N'-carbonyl-di-s-triazine, is used as dehydrating agent, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphenyl ketene p-tolylimine, N-hydroxyphthalimide, N-hydroxypiperidine, ethylene chlorophosphite, ethylene pyrophosphite, N-ethyl-5-phenylisoxazolium 3'-sulfonate, phenyl phosphorodi- (1-imidazolate), and carbodiimides such as dicyclo-hexylcarbodiimide, l-cyclohexyl-3- (2-morpholinomethyl) -carbodiimide N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, l-ethyl-3- (3'-dimethylamino-propyl) carbodiimide hydrochloride and diethylcyanamide. 5. Method according to any one of claims 1 to 4, characterized in that an acid molar ratio: dehydrating agent: 5-aminotetrazole of 1: 1: 1 to 1: 1.1: 1.1 is used. 6. Method according to one of claims 1 to 5, characterized in that N, N'-carbonyl-diimidazole is used as dehydrating agent and that the process is carried out at a temperature of 85 at 100 ° C, in the presence of N, N-dimethylformamide as solvent. 7. Method according to one of claims 1 to 6, characterized in that a compound of formula is prepared: in which R3 is Cl or Br, and then this product is reacted with a C1-c5 alkanol to obtain the corresponding compound with R3 C1-c5 alkoxy. 8. Method according to one of claims 1 to 7, characterized in that each of Ri and R2 is a hydrogen atom and r3 is a lower alkoxy group. 9. Method according to one of claims 1 to 7, characterized in that Ri is a hydrogen atom, R2 is a lower alkoxy group in position 8 and R3 is an ethoxy group. 10. Method according to one of claims 1 to 7, characterized in that Ri is a hydrogen atom, R2 is a fluorine atom and R3 is a methoxy group. 11. Method according to claim 8, characterized in that R3 is a methoxy group. 12. Method according to claim 9, characterized in that R2 is a methoxy group in position 8. 13. Application of the method according to claim 1 to the acid of formula II prepared by hydrolysis of the corresponding ester of the acid with a C1 to C5 alkanol.