NL8006362A - ANTI-ALLERGIC AND ANTI-GESTIFYER 1-OXO-1 H- -THIAZOLO / 3,2-A / PYRIMIDINE-2-CARBONAMIDES AND INTERMEDIATES THEREFOR. - Google Patents

Description

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Anti-allergic and anti-gastric ulcer 1-oxo-1H-thiazolo-3,2-alpha / pyrimidine-2-carphonamides and intermediates therefor.

The invention relates to new derivatives of 1-oxo-1H-thiazolo / 3,2-a-pyrimidine-2-carboxamides and their acid precursors. These amides, and in many cases also their acid precursors, can be used to prevent the release of 5 allergic transmitters (histamine, serotonin, SRS-A, etc.) and thus can be used to treat bronchial asthma, hay fever, rhinitis , atopic dermatitis, etc., and further they are useful as anti-ulcer agents.

Allergic reactions, the symptoms of which result from an antigen-antibody interaction, are manifested in many different ways and different organs and tissues. General allergic conditions are, for example, allergic rhinitis, a condition characterized by sneezing in certain seasons or all year round, a runny nose, nasal congestion, as well as itching and blocking of the eyes? hay fever, a variant of allergic rhinitis that results from hypersensitivity to grass pollen; and bronchial asthma, one of the most debilitating and debilitating allergic reactions, a disease characterized by hyperresponsiveness of the 20 bronchi when exposed to various immunogenic and non-immunogenic stimuli, leading to bronchial spasms accompanied by wheezing, short-lived paroxvsmen and widespread narrowing of the airways. The mechanical obstruction of airflow in the airways is generally removed by the use of bronchodilators, which provide symptomatic relief. In contrast, antiallergic agents prevent delivery of anaphylaxis transducers from tissue stores, thereby prophylactically preventing the generation of narrowing of the bronchi by the transducers.

Cox et al., Adv. in Drug Res., 5, 115 (1970) described 8006362-442, the pharmacology of disodium chromoglycate / 1,3-di (2-carboxychromon-5-yloxy) -2-hydroxypropane, Intal_ /. It is not a bronchodilator, but transfers its therapeutic effect by preventing the release of anaphylaxis transmitters and is administered prophylactically. It has the drawback that it is not effective orally and for optimal results it is administered by inhalation as a solid inhaler.

More recently, several other antiallergic agents have been described, including 10 N- (tetrazol-5-yl) -1-oxo-1H-6-alkoxypyrimido / 1,2-α / quinoline-2-carbon amides (American U.S. Patent 4,017,625), 1-oxo-1H-6-substituted pyrimido / 1,2-α / quinoline-2-carboxylic acids (U.S. Patent 4,066,766), tetrazolo / α / quinazol-5-ones (U.S. Patent 4,085. 213), pyrimido / 2,1-a / isoquinolines (U.S. Patent 4,127,720) and NHtetrazol-5-yl) -4-oxo-4H-pyri-mido / 2,1-b-7-benzothiazole-3-carboxamides (U.S. Patent 4,041,163).

Chronic stomach and duodenal ulcers, collectively known as gastric ulcers, are a common condition for which various treatments have been developed. Treatment depends on the severity of the ulcer and can range from diet and drug treatment to surgery. Many different medicines have been used to treat stomach ulcers; the most recent of which has received widespread attention is carbenoxolone sodium, the disodium salt of the hemisuccinate of glycyrrhetinic acid. It is reported to prevent and accelerate the formation of gastric ulcers in animals including humans ("Carbenoxolone sodium: a synposium", JM Robson and FM Sullivan, Eds., 30 Butterworths, London, 1968) . However, their use is associated with unwanted aldosterone-like side effects, such as pronounced anti-diuretic and sodium retention, and often potassium loss, so that continued therapy with this drug often leads to increased blood pressure, muscle weakness and ultimately decompensation. More recently, a histamine receptor antagonist, 8006362 ί * κ 3% cimetidine, has been introduced in medical practice. The latter compound relieves stomach ulcers by reducing gastric acid secretion.

Several other compounds are said to have anti-gastric ulcer activity and include 1-oxo-1H-6-piperidinopyrimidino / 1,2-a / quinoline-2-carboxylic acid esters (U.S. Patent 4,014,881), 1-oxo 1H-6-substituted pyri-mido / -1,2-α-7quinoline-2-carbon2 hours and esters thereof (U.S. Patent 4,031,217) and tetrazolo / α / chinazo-1-5-ones (U.S. Patent 4,085,213) .

The amides and most of the intermediate acids of this invention are new compounds. The known acids are the compounds of formula II, wherein R 1 and R 2 are hydrogen or R 1 is a methyl group and R 2 is hydrogen / Dunwell et al., 15 J. Chem. Soc. (C), 1971, 2094-7. The corresponding ethyl esters are also known, as is the ethyl ester in which R1 is a methyl group and R2 is hydrogen. Dunwell et al., J. Chem. Soc. (C), 1971, 2094; Allen et al., J. Org. Chem., 24, 779 (1959)]. Neither of these publications describes an application of either the acids or the esters.

We have now found that compounds of formula 1 as well as their pharmaceutically acceptable cationic salts are orally active anti-allergic and anti-ulcer agents. In formula 1, R 1 and R 2 are both hydrogen or a short chain alkyl-25 group with 1 to 5 carbon atoms / such as a methyl, ethyl, propyl, isopropyl, 2-methyl-2-propyl (tert-butyl), 2-butyl, 2-methyl-1-propyl (isobutyl), pentyl group __ /, or R 1 and R 2, which together form a third 5 to 8 ring, are alkylene groups of 3-9 carbon atoms, such as groups of formula 4, formula 5, formula 6, formula 7, formula 8, formula 9, formula 10 or formula 11, or they are a phenylalkylene group having 9-11 carbon atoms such as, for example, groups of formula 12, formula 13, formula 14 or formula 15.

We have also found that acids of formula 2, wherein R 1 and R 2 have the above meaning, are not only valuable intermediates for the synthesis of the amides, but in many cases 8 0 06 36 2 4 together with their pharmaceutically acceptable cationic salts, also have useful biological activity. Acids of useful antiallergic action acids in which and r2 together form an alkylene group of 4-9 carbon atoms or a phenylalkylene group of 9-11 carbon atoms, provided that the ring system so formed is a 5-8 ring, or, taken Rj individually an alkyl group with 2-5 carbon atoms and R2 is hydrogen or an alkyl group with 1-5 carbon atoms. The preferred acids for antiallergic use are the acids wherein R 1 and R 2 together form an alkylene group of 4-6 carbon atoms, especially a butylene group. Acids of somewhat different structure have useful anti-gastric ulcer activity, such as the acids in which R 1 and R 2 together form an alkylene group of 3-9 carbon atoms or a phenylalkylene group of 9-11 carbon atoms, provided that the ring system thus formed has a 5- to 8- ring is whether R 1 and R 2 are each hydrogen or an alkyl group of 1 to 5 carbon atoms provided that when R 2 is hydrogen, R 1 is not hydrogen or methyl group. In this case, the preferred compounds are the compounds where R 1 and R 2 are each taken separately, especially when R 1 is an ethyl group and R 2 is hydrogen or an alkyl group of 1 or 2 carbon atoms.

The term "pharmaceutically acceptable cationic salts" is used for salts such as the alkali metal salts, for example sodium and potassium; the alkaline earth metal salts, such as calcium and magnesium; the aluminum salts; the ammonium salts and the salts with organic bases, for example amines, such as triethylamine, tributylamine, piperidine, triethanolamine, diethylaminoethylamine, Ν, Ν'-dibenzylethylenediamine and pyrrolidine.

As is known, the 5-substituted tetrazoles can exist in two isomeric forms, viz. Formula 16 or formula 17, which coexist in a dynamic tautomeric equilibrium mixture. Both forms of the tetrazolylamides are within the scope of the invention.

The compounds of the invention which are of particular interest of 8006362 ** are the compounds of formula 1 wherein R 1 is hydrogen or a methyl group and R 2 is a methyl group. Of these compounds, the compound in which R 1 is preferred is hydrogen because the corresponding acid which is considered to be its metabolite also exhibits activity Also of particular interest are the compounds in which R1 and R2 together form a propylene, butylene or pentylene group. R 2 and R 2 together form a butylene group, i.e., N- (tetrazol-5-yl) -1-oxo-1H-cyclohexenothiazolo / 3,2-a / pyrimidine-10 2-carboxamide of formula 3, because it has oral activity and is very stable in a pure solid state, as well as in the presence of standard pharmaceutical diluents and in solution In addition, its metabolite (the corresponding carboxylic acid) shows good activity The preferred form of the tetrazolylamide of formula 3 is the sodium salt (trihydrate), which is non-hygroscopic and has good water solubility thereby ensuring good bioavailability.

The anti-allergic properties of the compounds of the invention are determined by the passive cutaneous ana-20 phylaxisis (PCA) assay (Ovary, J. Immun., 31, 355, 1958). In the PCA assay, normal animals are injected intradermally (i.d.) with antibodies present 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 drains the dye from the site of the antibody injection. The test animals are then suffocated and the intensity of the reaction is determined by measuring the diameter and the intensity of the blue coloration on the inner surface of the skin of the animals.

The anti-gastric ulcer activity of the compounds according to the invention is assessed in the test on the so-called cold-held stressed rat. Alternatively, the anti-gastric ulcer activity can be determined in a newly developed test on an ethanol-induced rat gastric ulcer as described below 8006362 4 6.

The compounds of the invention are prepared according to scheme A.

In the first stage of the synthesis sequence, the suitably substituted 2-aminothiazole is condensed with a stoichiometric amount of a dialkylethoxymethylene malonate, usually with the readily available diethylethoxymethylene malonate, the choice of the ester not being critical to obtain the ultimately desired products according to the invention. The condensation is carried out at a temperature from about 80 ° C to about 125 ° C. Lower temperatures are not desirable because the reaction then proceeds at too slow a rate. Higher temperatures can be used but have no advantages. The reaction is therefore conveniently conducted as a melt. It can of course be performed in a solvent or mixture of solvents; for example in ethanol, N, N-dimethyl-formamide, acetonitrile. However, from a practical point of view, a solvent appears unnecessary. The products of this condensation are 4- and / or 5-substituted -2- (2,2-dicarbaroxyethenylamino) thiazoles. It should be noted that when and R2 together form a ring system, the nomenclature and numbering of the systems is changed as follows: cyclopentenothiazole of formula 18, cyclohexenothiazole of formula 19, cycloheptenothiazole of formula 20 and cyclooctenothiazole of formula 21.

Another nomenclature for the cyclohexenothiazoles is tetrahydrobenzothiazoles.

The second stage of the synthesis order is ring closure of the 4- and / or 5-substituted-2- (2,2-dicarbaroxyethenylamino) thiazoles while removing one equivalent of alkanol (ethanol in the case of the ethyl ester). In one method, this cyclization is accomplished by heating the intermediate to a temperature of 175-250 ° C until the reaction is nearly complete, usually in 1-2 hours. The cyclization is conveniently performed by heating the intermediate in a suitable inert diluent under the reaction conditions. that is, 8006362 7 in a compound which allows the reaction temperature to be controlled, is stable at the relatively high temperatures used and does not react with the starting material or the cyclization products. Examples of such diluents are high boiling hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, especially a mixture of 26.5% diphenyl and 73.5% diphenyl ether available under the trademark Dowtherm A.

The cyclization can also be accomplished under milder conditions (70-130 ° C), by heating the intermediate in the presence of an excess (1.1-3 equivalents) of trifluoroacetic anhydride in an inert solvent, such as toluene, until the reaction is complete (e.g., 15-20 hours at 15 reflux temperature of toluene). By both methods, the products of the cyclization step are alkyl esters of 1-oxo-1H-6 and / or 7-substituted-thiazolo / 3,2-a / pyrimidine-2-carboxylic acids.

It should be noted that when R 2 and R 2 together form a ring system, the nomenclature and numbering is changed as follows: 1-oxo-1 H-cyclopentenothiazolo / 3,2-a / pyrimidine of formula 22, 1-oxo -1 H-cyclohexenothiazo / o-3,2-a / pyrimidine of formula 23, 1-oxo-1H-cycloheptenothiazolo / 3,2-a / pyrimidine of formula 24 and 1-oxo-1 H-cyclooctenothiazolo, / 3,2-a / pyrimidine of formula 25.

The 1-oxo-1H-cyclohexenothiazolo / 3,2-a / pyrimidin-30s may alternatively also be designated as 6,7,8,9-tetrahydro-1-oxo-1H-pyriraidino / 2,1- b / benzthiazoles or using another numbering system 5,6,7,8-tetrahydro-4oxo-4H-pyrimido / 2,1-b / benzthiazoles.

It will be appreciated that the condensation and cyclization steps can be carried out in a single operation, without the need to isolate the intermediate, 2- {2,2-carbalkoxy-ethenylamino) thiazole, or by using make sufficiently high reaction temperature to effect both condensation and cyclization, or by condensing as described above, followed by addition of an inert solvent {if not already present) and excess trifluoroacetic anhydride (2.1 -4 equivalents) after which the ring closing step is performed.

The preferred method consists of separate ones. 10 stages for condensation and ring closure as described above. Isolation of the intermediate compound and its subsequent purification prior to cyclization generally provides a better quality cyclization product.

The esters obtained with the condensation / ring-15 closure described above are then hydrolyzed to the corresponding 1-oxo-1H-6 and / or -7-substituted-thiazoLV 3,2-α-pyrimidine-2-carboxylic acids. (Note the nomenclature and the modified numbering ring system described above, when and R £ together form a third ring). Preference is given to acid catalyzed hydrolysis. Heating the ester under reflux in 48% hydrobromic acid until hydrolysis is complete (0.5-3 hours is generally sufficient) is a particularly suitable method. When foaming presents a problem, the hydrolysis 2 can be performed at slightly elevated pressure, for example 1.49 kg / cm @ 25 at 85 ° C.

The N- (tetrazol-5-yl) amides of the invention are conveniently prepared by dehydrating coupling the acids with 5-aminotetrazole. The dehydrating coupling can be accomplished by any of a variety of means commonly used in the peptide syntheses. Examples of such agents are N, N'-carbonyldiimidazole, N, N'-carbonyldi-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphenylketene p-tolylimine, N-hydroxyphthalimide, N-hydroxysuccinimide, N- hydroxypiperidine, ethylene chlorophosphite, diethylethylene pyrophosphite, N-ethyl-5-phenyl-35-isoxazolium-3'-sulfonate, phenylphosphorodi- (1-imidazolate) and 8006362 9-carbodiimides such as dicyclohexylcarbodiimide, 1-cyclohexylmorphyl-carbomethyl-3-olimino-phenol - (3-dimethylaminopropyl) -N'-ethyl-carbodiimide hydrochloride, 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide hydrochloride and diethyl cyanamide.

The coupling agents described above are generally first reacted with acidic reagent and the resulting product is then reacted without isolation with 5-amino-tetrazole to yield the desired 1-oxo-1H-6 and / or -7-substituted thiazobg / 3,2-alpha / pyrimidine is obtained. (Note the nomenclature 10 and the modified numbering systems as described above, when and R2 together form a third ring).

The reaction is carried out in a solvent system inert under the reaction conditions, in which the acidic reagent need not be soluble. The only requirement for the solvent system is that it does not react to any appreciable extent with the reactants or the reaction products. The various coupling agents that can be used to effect the hydrating coupling allow for a wide choice of solvents. Examples of such solvents are Ν, Ν-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of the acidic reagent with the coupling agent is carried out at a temperature of 20-110 ° C. The reactive intermediate is then reacted with 5-aminotetrazole at a temperature of 20-110 ° C. Each of these steps is conveniently carried out at a temperature of 50-100 ° C, because it improves the speed and yield of the reaction.

The molar ratio of acid: coupling agent: 5-30 aminotetrazole is generally 1: 1: 1 to 1: 1.1: 1.1. Higher coupling agent and 5-aminotetrazole ratios can be used but do not provide any advantages. An excess of 10 mol% proves satisfactory.

As will be appreciated by those skilled in the art, all 35 reactants can be added at once instead of stepwise, as described above. However, pre-formation of the reactive intermediate (acid coupling agent product) usually yields better OD yields of the desired N-teetrazol-5-yl amides.

Instead, the desired amides can be synthesized by coupling the acids with 5-aminotetrazole using a mixed acid anhydride method. In that case, the acids are first converted in situ to tertiary amine salt in the presence of a 1-1.1 molar excess of the amine. Various tertiary amines (R'3N) are suitable for this purpose.

Examples are triethylamine, N-methylpiperidine, N-methylmorpholine, dimethylaniline or quinoline. Suitable inert solvents are methylene chloride, chloroform, dimethylformamide and dimethyl acetamide. It is preferred that the acid is completely dissolved by the excess tertiary amine, which may require stirring for some time, if necessary together with gentle heating.

The solution of the amine salt is then reacted with an equivalent of alkyl (eg ethyl), benzyl or phenyl chloroformate, at a temperature in the range from -40 ° C to + 25 ° C, preferably in the range from - 10 ° C to + 10 ° C to form a mixed acid anhydride in solution according to scheme B. Without isolation, the mixed acid anhydride is reacted directly with 5-aminotetrazole, preferably dissolved in an inert solvent, which is of the same type as used for the preparation of the mixed acid anhydride to give the desired N- (tetrazol-5-yl) amides. The reaction is usually started at a low temperature (such as -40 ° C to + 50 ° C), but the reaction mixture is allowed to warm to higher temperature (such as + 15-40 ° C) to complete the reaction. The characteristic mol, ratio of acid: amine: chloroformate: 5-aminotetrazole is 1: 2: 1: 1 to 1: 2.1: 1.1: 1.1.

Both the amides and the acids serve as intermediates for the pharmaceutically acceptable cationic salts of the invention. The salt formation occurs by reacting the amides or acids with the appropriate metal salt (such as an 8 0 0 6 36 2 * 11 carbonate, ethyl hexanoate, alkoxide or hydroxide), or the appropriate amine in a suitable medium such as water, methanol or ethanol, according to methods known per se. The salts are recovered by standard methods, such as by filtration, when they are insoluble in the medium, by evaporation of the solvent when they are soluble in the medium, or by precipitation by adding a non-solvent to the salt.

Many of the required 2-aminothiazole starting materials have been described in the literature. The starting materials not described in the literature can be prepared by condensation of the appropriate o-halo ketone with thiourea or by condensation of the appropriate aldehyde with thiourea and sulfuryl chloride, as illustrated in the related examples. α-Halo ketones, if not available in the literature, can be obtained by standard methods, eg halogenation of ketones, eg Catch et al., J. Chem. Soc., 272 (1948); Levine, Org. Synthesis Coll.

Full. II, 38 (1943); Buchman et al., J.A.C.S., 67, 400 (1945) /, by the action of hydrogen halides on diazoketones (eg, Catch et al., J. Chem. Soc. 278, (1948); Lutz et al., J. Org.

Chem. 12, 767 (1947); Wagner et al., J.A.C.S. 72, 2884 (1950) 7, decarboxylation of α-halogen-8-ketoacids / McPhee et al., JACS, 66, 1132 (1944) 7 and the spontaneous cleavage of the dibromo derivatives of alkenyl esters / e.g. Slanina et al., JACS, 58, 891 25 (1936) 7.

The reactions in the synthesis sequence leading from the 2-aminothiazoles to the acids and N- (5-tetrazolo) amides of the invention can be conveniently monitored by standard thin layer chromatography on silica gel plates containing an ultra-30 violet indicator which is commercially available through different channels. The eluent is varied to suit the reaction being performed and the nature of the substituents, to obtain Rf values between 0 and 1.0, and to distinguish between the intermediate participating in the reaction and the product formed at 800636212 the reaction. An eluent particularly suitable for thiazole formation, condensation ring closure and hydrolysis reactions of the invention is chloroform / 1% ethanol, while hydrolysis and conversion of acids to N- (tetrazol-5-yl) amides is best are followed by using chloroform / 5% acetic acid. As is known to those skilled in the art, if the materials tend to move too quickly (i.e., in the solvent front), the polarity of the eluent can be decreased. When materials tend to move too slowly, the polarity of the eluant can be increased. Such a chromatography is used to determine the completeness of the reaction and the purity, but it can also be used to further optimize the reaction conditions (concentration, time, temperature, solvent, etc.).

The products of the invention and the pharmaceutically acceptable salts thereof can be used as prophylactic agents for inhibiting or preventing the release of anaphylaxis transmitters (allergy, immediate hypersensitivity reactions) and the appearance of allergic manifestations in mammals and administered for such purposes alone or as mixtures with other agents! for example with theophylline or sympathomimetic amines. The products of the invention are also useful as anti-ulcer agents. These products not only accelerate the healing of such ulcers, but also prevent the formation of gastric ulcers and decrease gastric acid production in animals including humans. It can therefore be said that they are useful for controlling gastric ulcers.

The valuable compounds of the invention can be administered alone, but are generally administered in conjunction with a pharmaceutical carrier selected based on the route of administration chosen and standard pharmaceutical practice.

For example, they can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aerosol sprays, 8 0 06 36 2 A-p 13 canisters, aqueous suspensions or solutions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, the oral pharmaceutical compositions of the invention may be suitably sweetened and flavored by various means of the type commonly used for this purpose.

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

For parenteral administration and inhalation, solutions or suspensions of these compounds in sesame or groundnut oil or aqueous propylene glycol solutions can be used, as well as sterile aqueous solutions of the soluble pharmaceutically acceptable salts described herein. These specific solutions are particularly suitable for intramuscular or subcutaneous injection purposes, if such a mode of administration is desired. The aqueous solutions, including the solutions of the salts dissolved in pure distilled water, are also useful for intravenous injection purposes, provided their pH is correctly adjusted beforehand.

Such solutions should also be well buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient salt or glucose. When used as a prophylactic agent to prevent the delivery of anaphylaxis transfer agents, the compounds can be administered by inhalation. Compositions suitable for inhalation may consist of (1) a solution or suspension of the active ingredient in a liquid medium of the above type for administration via a nebulizer; (2) a suspension or solution of the active ingredient in a liquid propellant, such as dichloro-difluoromethane or chlorotrifluoroethane for administration from a pressure canister; or (3) a mixture of the active ingredient and a solid diluent (e.g., lactose) for administration from a powder inhaler. Preparations suitable for inhalation by means of a conventional nebulizer contain 0.1-1% active ingredient; and the preparations for use in pressure cans contain 0.5-2% active ingredient. Preparations for use as powder inhalants may contain an active ingredient to diluent ratio of 1: 0.5 to 1: 1.5.

Taking full account of the above 25 factors, it is believed that an effective daily dosage of the antiallergic or anti-ulcer compounds of the invention in humans is in the range of 10-1500mg per day, with a preferred range of 10-600mg per day in single or divided doses, or 0.2-12 mg / kg body weight. These values are exemplary only, and there may of course be individual cases where higher or lower dosage ranges are beneficial. With careful monitoring, the dosage level can rise to even 2 g / day.

When administered parenterally for both uses or by inhalation as an antiallergic agent, the effective daily dose is 0.05-400 mg per day and preferably 0.25-200 mg per day or is it at 0.005-4 mg / kg body weight in a single or divided dose.

It is necessary that the active ingredient 5 make up such an amount of the composition that a suitable dosage form is obtained. Of course, different dosage unit forms can be administered at about the same time. Although preparations with less than 0.005% by weight of active ingredient can be used in certain cases, it is preferable to use preparations containing not less than 0.005% of active ingredient; otherwise the amount of carrier becomes excessively large. The activity increases with the concentration of the active ingredient. The formulation may contain 10, 50, 75, 95 or even a higher weight percent active ingredient.

The PCA test is a measure of the anti-allergic (in particular anti-asthmatic) effect of a compound. Compounds that inhibit a positive PCA test elicited by the rat immunochemical equivalent of human immunoglobulin E (IgE), or reagin, are considered to have antiallergic activity (C. Mota, Ann. NY Acad. Sci., 103, 264, 1963). (Reagin is primarily immunoglobulin E f_ IgE_ / and is the primary immunoglobulin responsible for allergic asthma, anaphylaxis, hay fever, food sensitivities, and certain manifestations of drug sensitivities, although recent data have ascribed an important role in the IgG class of antibodies. transmitting allergic diseases). Such compounds, when administered to a sensitized individual, human or animal, prior to the time of contact of the individual with antigens or substances to which they are allergic, prevent the allergic reaction which would otherwise occur. They therefore provide a method for the prophylactic treatment of allergy or anaphylactic reactions of a reagent-mediated nature.

Stated differently, such compounds block the delivery of transporters induced by the antigen-anti-body (allergic) reaction, as shown in the PCA assay using rat homocytotropic antibody - a known correlation of human reagent antibody. Inhibition of reagent antigen-antibody responses in rats, the test animal of the 5 PCA assay, is considered representative of the inhibition of human reagent antigen-antibody responses, which occur during allergic periods.

The PCA reaction test method used to evaluate the compounds of the invention shows an excellent correlation between the activity for compounds in this test and their usefulness in the treatment of allergic asthma. The ability of agents to interfere with PCA reactions is measured in male Charles River Wistar rats, 170-210 g. Reagent antiserum, which is rich in IgE antibodies, is prepared according to Petillo et al., Int. Arch. Allergy, 44, 309 (1973). Hyperimmune antiserum rich in IgG antibodies for chicken egg albumin is prepared according to Orange et al., J. Exptl. Med., 127, 767 (1968).

48 hours before the antigen challenge, the reagent antiserum intradermal (i.d.) is injected into the shaved skin of a normal rat back. The hyperimmune antisera is injected correspondingly 5 hours before the challenge. In third place, 60 mcg histamine dihydrochloride and 0.5 mcg serotonin creatinine sulfate i.d. injected, just before the antigen challenge, as a control for antihistamine, anti-serotonin and nonspecific type 25 blocking; the compounds of the invention or physiological saline are then injected i.v. and immediately followed by the challenge of 5 mg egg protein and 2.5 mg Evans' blue dye in physiological saline. In the case of oral administration, the Evans' blue dye and egg albumin are administered 5 min after drug administration. 30 Min. later the animals are suffocated with the aid of chloroform and the skin of the back is removed and turned inside out for evaluation. Each injection site is assigned a number equal to the product of the diameter of the site in mm and a rating of 0.1; 0.5; 1; 2; 3 or 4 which is proportional to the intensity 8 0 06 36 2 17 of the coloring by the dye. The numbers for a given injection site are added for each group of five animals and compared to the control group treated with physiological saline. The difference is expressed as a percentage of blockage due to the compound used.

Compounds representative of the compounds of the invention are tested for antiallergic activity according to the procedure described above and the activities obtained are reported as degree of protection (%). Intal, dina-10 triumcromoglycai, a commercially available anti-allergic agent, has not been included for comparison because it is not effective by the oral route.

The compounds of formula 1 (amides) and formula 2 (acids, R 3 is hydrogen) which have been tested for antiallergic activity with the PCA test are detailed in Table A and Table B.

TABLE A

Oral action <% protection) of amides (formula 1), in the PCA test.

20 R. R- IgE mg / kg IgG mg / kg 1 2, 1 3 10 30 1 3 10 30 CH3 CH3 55 51 CH3 C2Hs 75 57 C2H5 CH3 29 28 25 C2H5 C2H5 62 49 (CH2) 3 46 43 (CH2) 4 47 45 (CH2) 5 25 38 (CH2) 6 94 57 30 H CH3 55 50 Η H 50 46 CH3 H 78 55 C2H5 H 85 58 HC (CH,) - 37 20 35 8006 362 18

TABLE A CONTINUED

R. R- IgE mg / kg IgG mg / kg 1 1 1 3 10 30 1 3 10 30 H C2H5 70 44 5 H CH (CH3) 2 72 53 CH-CH (C_Hc) CH-CH- 4 7 2 5 6 2 2 CH2CH (CH3) CH2CH2 44 33 CH2C (CH3) 2CH2CH2 38 27 H CHCH CH 6 6 10 ch3

TABLE B

15 Oral activity (% protection) of acids (formula 2; R3 is hydrogen) in the PCA test.

IgE mg / kg IgG mg / kg

Rj R 2 10 30 10 30 CH CH. 0 0 20 i 6 ch3 c2h5 0 0 C2H5 CH3 42 24 C2H5 C2H5 41 32 (CH2) 3 oo (CH2) 4 55 39 25 (CH2) 5 37 44 (CH _) _ 36 68 15 45 2, b H CH3 18 19 Η H 18 7 CH H 12 14 30 ^ C2H5 H 45 38 HC (CH3) 3 10 6 H C2H5 13 21 H CH (CH3) 2 0 0 CH-CH (C _H_) CH-CH- 15 5 35 2 5 6 2 2 8006362

X

19

TABLE B CONTINUED

* r R. R2 IgE mg / kg IgG mg / kg 10 30 10 30 5 CH2CH (CH3) CH2CH2 31 21 ch2c (ch3) 2ch2ch2 13 6 H CHCH2CH3 1 8 CH3 10

The effectiveness of the products according to the invention as anti-gastric ulcers is determined by the so-called cold-strained rat test. In this test, unfasted female rats (Charles River CD 15 strain) weighing 70-140 g are administered the drug or vehicle (control animals) intraperitoneally (in physiological saline 1% carboxymethyl cellulose and 0.1% Tween 80) or orally (in water) 3 hours before being lightly anesthetized with ether and taped back on separate plates of plexiglass. After recovering from the anesthesia, the strapped animals are placed horizontally in a refrigerator kept at 10-12 ° C and 3 hours later they are finished by decapitation. Each rat's abdomen is opened, the pylorus clamped, the stomach inflated with saturated saline via an oral tube, the esophagus clamped, and the stomach cut out. The stomachs are placed in a 0.4% formaldehyde solution for 30 seconds. to harden the outer layers and facilitate examination. Each stomach is then cut open over the large arch and the gland (back stomach) is examined for damage.

30 The number of stomach erosions, their severity and the color of the stomachs are recorded. The Mann-Whitney-Wilcoxan rank test is used to compare the mean number of skinny erosions in the comparison group with the mean number of skinny erosions in each drug-treated group to determine if these are statistically different. (Dixon et al., "Introduction of 8006362 20

Statistical Analysis, "3rd ed., McGraw-Hill Book Company, New York, biz. 344-347, 1969). In this test, N- (tetrazol-5-yl) thiazolo - {_ 3,2-a / pyrimidine -2-carboxamide (compound of formula 3) particularly effective as mentioned below.

Alternatively, the effectiveness of the products of the invention as anti-gastric ulcers can also be determined in an ethanol-induced rat gastric ulcer assay. In this test, fasted male rats overnight are administered drug (5 mg / kg) or water orally 15 min prior to an oral dose of absolute ethanol (1.0 ml). One hour after the ethanol challenge, the animals (8 per group) are sacrificed and the stomachs are examined for the presence of lesions. All drugs are dissolved in dilute NaOH. After finishing, the abdomen is opened and a occluded hemostat is placed on the pylorus. 6 ml of a 4% formaldehyde solution are injected into the stomach with a gastric feeding tube and a second occlusive hemostat is used to occlude the esophagus. The stomach was removed, opened along the largest arc and examined for ulcers.

The rating system used to quantify the 20 ethanol-induced lesions is listed below.

Assessment Peptic ulcer assessment table

Definition 1 Normal looking stomach 25 2 Lesions the size of a pin 3 Lesies, 2 or less

Pin button size lesions may also be present.

4 Lesions,> 2; pin button lesions may also be present.

5 Lesions with bleeding.

For each group of animals, an ulcer index is calculated in the following way: peptic ulcer index = (the sum of the numbers for the group) x (the sum of the number of peptic ulcers in the group) x (the portion of the group that has any occurrence of stomach - 8 0 06 36 2 21 ulcers).

The percentage of gastric ulcer obstruction is calculated as follows:% Inhibition = 100 x £ (gastric ulcer index of the 5 control animals) - (gastric ulcer index of the drug-treated animals) / r (gastric ulcer index of the control animals).

✓

Table C shows the activity in this test for different tetrazol-5-ylamides according to the invention, while Table D shows the activity of different acids.

10 TABLE C

Oral activity (% inhibition at 5 mg / kg dose) of amides (Formula 1) in the ethanol-induced rat gastric ulcer test v R R-% Inhibition 12 r 15 ---—------ CH3 CH3 96 H CH3 59 CH3 H 72 C2H5 C2H5 10 20 C2H5 H 86 (CH2) 6 45 (CH2) 4 97, 81

TABLE D

Oral activity (% inhibition at 5 mg / kg dose) of acids (Formula 2) in the ethanol-induced rat peptic ulcer assay.

Rj R2% Barrier 30 CH3 CH3 11 H CH3 27 ch3 H 0 C2H5 C2H5 48 C2H5 H 48 35 (CH2} 4 21 8 0 06 36 2 22

As noted previously, the most preferred compound of the invention is the compound of formula 3, i.e. the compound of formula 1 wherein R 1 and R 1 together form a butylene group / N- (tetrazol-5-5 yl) -1-oxo-1H-cyclohexenothiazolo / 3,2,3-pyrimidin-2-carbonaraide, which may alternatively also be named as 5,6,7,8-tetrahydro-N- (tetrazol-5-yl) - 4-oxo-4H-pyrimido / 2,1-b / benzothiazole-3-carbon-amide /.

In addition to its oral antiallergic activity as shown in Table A, Compound 3 also has intravenous activity in the range of 0.03-1.0 mg / kg in the PCA assay, and is approximately 26 times as effective as Intal by this route (as mentioned earlier, Intal is not effective by the oral route). The compound of formula 3 also blocks the changes in cutaneous permeability caused by IgE-transmitted passive cutaneous anaphylaxis (PCA), but does not interfere with the changes in permeability caused by intradermal injection of exogenous histamine and serotonin. The absence of antihistamine and antiserotonin actions shows that the antiallergic mechanism is a mechanism of inhibitor of transducer release and not antagonism on the transducer receptor.

The compound of formula 3 inhibits dextran-induced histamine release into the rat abdominal cavity.

The EDgg is 0.33 g / kg, i.p. and Intal's is 14.0 g / kg, demonstrating the much better efficacy of the former.

The increase in plasma histamine caused by antigen challenge in rats passively sensitized with IgE-rich antiserum (passive systemic anaphylaxis) is prevented by the compound of formula 3. Its ED is 28 µg / kg, 30 iv , 13 times stronger than Intal.

Guinea pigs receiving a dose of 30 mg / kg i.p. of a compound of formula 3 were not protected from the bronchial astringent actions of inhaled histamine.

-8 -4

In the concentration range of 10 to 10 moj. does not interfere with the formula 3 compound cramps of isolated guinea pig ileum caused by acetylcholine, histamine or slow-reacting anaphylaxisis (SRS-A) and the synthesis and release of SRS in isolated rat monocytes stimulated by ionophore, is not hindered by the compound of formula 3.

In addition to its strong action in the ethanol-induced rat gastric ulcer assay (see Table C above), the compound of formula 3 is very effective in the cold-strained tension gastric ulcer procedure (described in more detail above), in which it provides dose-related protection at oral doses in the range of 3-100 / xg / kg. The compound of formula 3 also protects against ulcerogenic effects of aspirin, 100 mg / kg po, showing dose related effects over the dose range of 10-1000 / µg / kg, po with an ED ^ of 100 µg / kg, The compound of formula 3 is also active in a phenylbutazone gastric ulcer model, with an oral ED of 200 µg / kg being observed. Although the compound of formula 3 is a very effective anti-gastric ulcer, it does not affect pentagastrin-stimulated acid production in Heidenhain dogs (5 mg / kg, iv) and is therefore different from the anti-secretion prostaglandins and from cimetidine. 20 and atropine. "Cytoprotective" a phrase recently developed to describe the anti-gastric ulcer activity of prostaglandins, which are independent of anti-secretory activity / "Robert, Advances in Prostaglandin and Thromboxane Research 2, 507, (1976); Miller et al., Gut 20, 75 (1979); Robert et al., Gastroenterolo-25 gy 72, 1121 (1977) _7 sufficiently characterizes the action of the compound of formula III.

In addition, the compound of formula 3 exhibits diuretic action. When administered orally, it causes a dose-related increase in the volume of urine excreted at doses in the range of 0.3-5 mg / kg. The maximum effect was a two-fold increase in volume secretion. The urine concentrations of sodium and potassium ions were unchanged, but due to the increase in volume secretion, an increase in sodium and potassium secretion was observed. These findings indicate that the dose response range for diuretic activity is considerably higher than for anti-gastric ulcer activities and just below that for anti-allergic actions (1-10 mg / kg).

Rats that had fasted for 24 hours and dosed orally with compound of formula 3 at doses of 10, 30, or 100 mg / kg do not show any change in blood glucose level.

The action of compound of formula 3 on glucose tolerance was investigated in rats given 10, 30 or 100 mg / kg po co-administered with glucose in an amount of 1 g / kg po. An apparent dose-dependent improvement in glucose tolerance was observed. This action may be due to a delayed absorption of glucose associated with a possible effect on stomach emptying.

The compound of formula 3 has no significant anticholinergic effects. Transient decreased blood pressure and various changes in heart rate were observed in anesthetized dogs with cumulative doses of 5 and 15 mg / kg IV. Pressor responses to epinephrine and carotid artery closure on either side were slightly reduced. The temporary changes in cardiovascular disease only occur at cumulative intravenous doses, which are 5-10 times higher than the maximum effective intravenous dose for anti-allergic actions and are very much higher than the oral doses required for anti-gastric ulcer actions.

In tolerance studies, the compound of formula 3 was administered orally by dosing to dogs over 7 days at doses of 50, 150 and 300 mg / kg / day. Vomiting, which is common in dogs, was observed at all doses, but subsequent studies showed that the vomiting effect could be avoided when the drug was administered with a capsule after rather than before meals. No major pathological changes were observed and microscopic examination of the liver, kidney, heart and lung did not reveal any changes. In other studies, the serum serum enzyme levels of dogs administered the compound of formula 8 0 06 36 2 25 3 for 5 days with successive daily doses of 1, 3, 10, 3 and 3 mg / kg became normal.

Rats received the compound of formula 3 orally by dosing at doses of 50, 150 and 300 mg / kg / day for 10 days. There were no resulting pathological changes in global and microscopic assessment of liver, kidney, heart and lung. Except for a slight increase in serum glutamine-hydrochloric acid transaminase observed at the highest dose, no changes in clinical chemistry were observed.

The compound of formula 3 was administered subcutaneously to mice at doses of 100, 300 or 1000 mg / kg. No symptoms of lethality were observed and it was concluded that the drug is well acutely tolerated with a subcutaneous LD <1000 mg / kg. At a dose of 32 mg / kg administered subcutaneously, no interactions were observed with a range of CNS active drugs.

Individual oral doses of the compound of formula 3, 40 mg / kg, were administered to groups of mice that were sacrificed 6, 12 or 24 hours later. Microscopic examination of the bone marrow did not reveal any damage to the chromosomes. Such findings were obtained after mice were treated with a dose of 20 mg / kg for 5 consecutive days. In vitro studies in which the compound of formula 3 was incubated with human lymphocytes at concentrations of 1000, 100, 10 or 0 fiq / ταΐ also showed no significant drug-induced chromosomes change. The compound of formula 3 in the Ames test in vitro did not cause point mutations. These findings show that the compound of formula 3 does not have a clear mutagenic potential.

In the rat PCA test, the ratio of comparable effective oral and intravenous doses of the compound of formula 3 is consistent with good oral absorption. This is supported by observations of plasma concentrations of 3-7 µg / ml one hour after oral administration of the compound of formula 35 3, 50-300 mg / kg. In dogs, the drug appears to be readily absorbed after oral administration of suspensions or capsules, giving plasma concentrations of 9-26 pjq / ml one hour after oral doses of 50-300 mg / kg. In both species, the plasma levels of the corresponding carboxylic acid 5 metabolite (the corresponding compound of formula 2) are similar to that of the compound of formula 3, identifying this compound as a major metabolite of the compound of formula 3. After the 8 daily doses, the levels of the parent drug and metabolite were 2-4 times greater than after 10 - the original dose, suggesting that it is possible to maintain a therapeutic drug level for a long time.

The compound of formula 3 in solid state alone or in admixture with standard inert ingredients used in oral formulations, or in solution, exhibits particularly good stability, making it easy to make stable preparations of this compound for clinical use.

The. the examples below serve to illustrate the invention.

Example I

2-Amino-4-ethyl-5-methylthiazole.

Thiourea (20.9 g, 0.275 mol) was dissolved in 250 ml of refluxed ethanol. 2-Bromopentan-3-one 25 (41.3 g, 0.25 mol), dissolved in 50 ml of ethanol, was added dropwise over 25 min to the refluxed urea solution. After heating under reflux for another 2 hours, the reaction mixture was boiled down to about 100 ml, cooled and the crude product was recovered as the hydrobromide salt by filtration. Purified 2-amino-4-ethyl-5-methyltetrazole (15.1 g, mp.

45-50 ° C; m / e calculated 142; found 142) was obtained by dissolving in water and reprecipitating with aqueous 3N potassium hydroxide.

According to the same method, 1-bromo-heptane-2-one, 3-bromo-heptane-4-one and 4-bromo-2,5-dimethylhexan-3-one are converted into 2-amino-4-pentylthiazole, 2-amino, respectively 4-ethyl-5- 80 06 36 2 27 propylthiazole and 2-amino-4,5-diisopropylthiazole.

Example II

2-Amino-4,5-diethylthiazole hydrochloride.

Thiourea (21.8 g, 0.286 mol), 4-chlorhexane-3-one (34.4 g, 0.26 mol) and 200 ml ethanol were combined and refluxed for 19 hours. The reaction mixture was cooled and de-solvent to yield the crude product as a white solid. White crystals of 4,5-diethylthiazole hydrochloride (31 g, mp 154-156 ° C) were obtained by recrystallization from a mixture of ethyl acetate and ethanol.

Example III

2-Amino cycloheptenothiazole.

Thiourea (41.9 g, 0.55 mol), 2-chlorocycloheptanone (72.3 g, 0.49 mol) and 500 ml ethanol were combined and refluxed for 7 hours. The solvent was removed to leave a semi-solid which was partitioned between ethyl acetate and water. Unreacted chloro ketone, which was recovered from the ethyl acetate phase by stripping, was combined with 20 g of thiourea and ethanol, refluxed for 24 hours, stripped and additional crude product partitioned between ethyl acetate and water as described above. In any case, the product was recovered by basifying the aqueous phase with ammonium hydroxide, extracting with ethyl acetate, drying over anhydrous sodium sulfate, stripping to an oil, triturating with hexane and filtering. Purified 2-amino-cycloheptenothiazole (49.5 g, mp 77-78.5 ° C) was obtained by recrystallization from cyclohexane.

Example IV

2-Amino-4-isopropylthiazole.

Thiourea (52.5 g, 0.69 mol) was slurried in 400 ml of ethanol. 1-Bromo-3-methylbutan-2-one (159.5 g, 35 0.66 mol) was added to the slurry. The resulting 80 06 36 2 28 exothermic reaction led to dissolution and reflux. The reflux was maintained by external heating for 1 hour. The solvent was removed by boiling and stripped to give an oil which crystallized on standing. Final purification of 2-amino-4-isopropylthiazole hydrobromide (104.4 g, mp 74-76 ° C) was accomplished by trituration with ether.

The hydrobromide salt was converted to free base (58.6 g) by dissolving the salt in water, basifying it with excess ammonium hydroxide, extracting the free base with ether, drying the ether over anhydrous sodium sulfate and then to a to strip oil.

Example V

2-Amino-6-phenylcyclohexenothiazole.

15

Thiourea (397.5 mg, 5.22 mmol) was slurried in 6 ml ethanol. 2-Bromo-4-phenylcyclohexanone (1.2 g, 4.74 mmol) was added to the slurry, resulting in an exothermic reaction and dissolution. The solution was refluxed for 30 min, cooled, and the solvent was stripped to yield crude product as the hydrobromide salt. This crude salt was dissolved in warm water, filtered and the free base precipitated by adding ammonium hydroxide. The crude base was recovered by filtration and purified 2-amino-6-phenyl-25 cyclohexenothiazole (802.4 mg, mp 181-183 ° C) was obtained by recrystallization from a mixture of water and ethanol.

Instead, on a larger scale using 8.2 g of thiourea, 24.6 g of 2-bromo-4-phenylcyclohexenone and 125 ml of ethanol, the reaction mixture, after refluxing for 30 min, was cooled in an ice bath and the hydrobromide salt immediately recovered by filtration. The hydrobromide salt was dissolved in water containing a trace of ethanol by heating and the free base (10.4 g, mp 180-182 ° C) precipitated by adding excess ammonium hydroxide. 2-Bromo-3 was added by the same methods - 8006362 ► t 29 phenylcyclopentanone, 2-bromo-3,5-dimethylcyclohexanone, 2-bromo-3,5,5-trimethylcyclopentanone and 2-bromo-5-methylcyclooctanone converted to the hydrobromide salt or the free base of 2-amino- 6-phenylcyclopentenothiazole, 2-amino-5,7-diraethylcyclohexenothiazole, 2-amino-4,4,6-trimethylcyclopentenothiazole and 2-amino-7-methylcyclooctenothiazole.

*

Example VI

2-Amino-6-methylcyclohexenothiazole.

Thiourea (22.3 g, 0.29 mol) was slurried in 275 ml of ethanol. 2-Bromo-4-methylcyclohexanone was added and the mixture was refluxed for 75 min, the reaction mixture was cooled to room temperature and the crude product was recovered as the hydrobromide salt by filtration.

The crude salt was dissolved in warm water, filtered and made basic with ammonium hydroxide to precipitate the free base as an oil which crystallized on cooling. Purified 2-amino-6-methylcyclohexenothiazole (25.2 g, mp 98-100 ° C) was obtained by recrystallization from cyclohexane.

Example VII

2-Amino-6,6-dimethylcyclohexenothiazole.

2-Amino-6,6-dimethylcyclohexenothiazole (9.8 g, mp. 109-111 ° C) was prepared from thiourea (9.2 g, 0.12 mol) and 2-bromo-4,4-dimethylcyclohexanone ( 22.6 g, 0.11 mol) in 100 ml of ethanol according to the method of example VI.

Example VIII

2-Amino-4- (but-2-yl) thiazole.

Thiourea (16.7 g, 0.22 mol), 1-bromo-3-methyl-pentan-2-one (36 g, 0.2 mol) and 100 ml of ethanol were combined and heated at reflux for 5 hours. Aqueous potassium hydroxide (3n, 100ml) was added and refluxing was continued for another half hour. The reaction mixture was cooled, acidified with hydrochloric acid and non-basic impurities, 8006362 extracted with ether. The aqueous phase was made basic with ammonium hydroxide and the product was extracted with ether. After backwashing with water and drying over anhydrous sodium sulfate, the ether was stripped to give 10 g of 2-amino-4- (but-2-yl) thiazole as a dark brown viscous oil.

Example E

2-Amino-5-methylthiazole.

Thiourea (45.7 g, 0.6 mol) and propionaldehyde (7.4 g, 0.3 mol) were combined with 150 ml of chloroform and cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mol) was added over 15 min. The exothermic reaction was maintained at 15-24 ° C. Gas evolution, which occurred during the addition, completely stopped about 1 hour after the addition. Most of the chloroform was boiled on a steam bath. Ethanol (150 ml) was added and the mixture was refluxed for 3 hours.

The reaction was stripped to an oil which was partitioned between water and ethyl acetate. The aqueous phase was made basic with ammonium hydroxide and the product was extracted into fresh ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate and stripped to give a crude product as a white solid. Purified 2-amino-5-methylthiazole (8.36 g, mp 94-95 ° C) was obtained by recrystallization from cyclohexane.

Example X.

2-Amino-5-ethylthiazole.

Thiourea (45.7 g, 0.6 mol) and butyraldehyde (21.6 g, 0.3 mol) were combined with 150 ml of chloroform and cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mol) was added over 15 min. The exothermic reaction was kept at 15-25 ° C. Gas evolution occurred during the addition and about 1 hour after. Ethanol (400 ml) was added, the chloroform was boiled off and the reaction mixture was heated at reflux overnight (about 16 hours). The reaction was stripped to an oil and recrystallized 2-amino-5-ethyl-thiazole (11.7 g, mp 54-55 ° C) was isolated by the method of Example IX.

According to the same method, pentanal, 3-methylbutanal and heptanal are converted into 2-amino-5-propylthiazole, 2-amino-5-isopropylthiazole and 2-amino-5-pentylthiazole, respectively.

Example XI

2- (2,2-Dicarbethoxyethenylamino) -4,5-dimethylthiazole.

2-Amino-4,5-dimethylthiazole (2.56g, 20mmol), diethyl ethoxymethylene malonate (4.8g, 22mmol) and ethanol (5ml) were refluxed for 1 hour. The reaction mixture was cooled and the pure product precipitated with hexane.

Purified 2- (2,2-dicarbethoxyethenylamino) -4,5-dimethylthiazole (4.21 g, mp 82-83.5 ° C) was obtained by recrystallization from hexane.

Example XII

2- (2,2-Dicarbethoxyethenylamino) -4-ethyl-5-methylthiazole.

2-Amino-4-ethyl-5-methylthiazole (2.84 g, 20 mmol) and diethylethoxymethylene malonate (4.76 g, 22 mmol) were combined and heated on a steam bath for 3 hours. The product obtained as an oil by cooling was used without further purification in the next step.

By the same method, 2-amino-4-penylthiazole, 2-amino-4-propyl-5-ethylthiazole, 2-amino-4,5-diisopropylthiazole, 2-amino-5-propylthiazole, 2-amino- 5-isopropylthiazole, 2-amino-5-pentylthiazole, 2-amino-6-phenylcyclopentenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,6,6-trimethylcyclopentenothiazole and 2 amino-7-methylcyclooctenothiazole converted to the corresponding 2- (2,2-dicarbethoxyethenylamino) thiazole derivatives.

35 According to the same method, the agreements 8006362 32

Corrosive dimethyl, dipropyl and diisopropyl esters prepared by using the appropriate dimethyl, dipropyl or diisopropylethoxymethylene malonate in place of the diethylethoxymethylene malonate. Example XIII

2- (2,2-Dicarbethoxyethenylamino) -4-ethyl-5-ethylthiazole.

4-Methyl-5-ethylthiazole (5.68 g, 40 mmol) and diethyl ethoxymethylene malonate (9.52 g, 44 mmol) were heated briefly at 86 ° C and then cooled to give the product as an oil, which was immediately was used in the next step.

Example XIV

2- (2,2-dicarbethoxyethenylamino) -4,5-diethylthiazole.

Diethylthiazole hydrochloride (15.4g, 80mmol), diethylethoxymethylene malonate (19.0g, 38mmol), triethylamine (8.1g, 80mmol) and ethanol (125ml) were combined and heated at reflux for 2½ hours. The reaction mixture was cooled and stripped of solvent. The semisolid product obtained was partitioned between ethyl acetate and water. The 2- (2,2-dicarbethoxyethenylamino) -4,5-diethylthiazole (28.6 g) was obtained as a gold oil from the ethyl acetate phase by drying over anhydrous sodium sulfate and stripping.

By the same method, the hydrobromide salts of 5,7-dimethylcyclohexenothiazole, 4,4,6-trimethylcyclopentenothiazole and 7-methylcyclooctenothiazole are converted to the corresponding 2- (2,2-dicarbethoxyethenylamino) thiazole derivatives.

According to the same method, the corresponding dimethyl, dipropyl and diisopropyl esters are prepared by using the appropriate dimethyl, dipropyl or diisopropylethoxymethylene malonate in place of the diethylethoxymethylene malonate. Example XV

2- (2,2-Dicarbethoxvethenylamino) cyclopentenothiazole.

35 2-Aminocyclopentenothiazole (3.6 g, 34.5 mmol) and diethyl ethoxymethylene malonate (8.2 g, 38.0 mmol) were combined and heated on a steam bath for 100 min. The reaction mixture was cooled with 2- (2,2-dicarbethoxyethenylamino) cyclopentenothiazole (7.0 g, Rf = 0.6 on silica gel thin layer chromatography using chloroform / 1% ethanol as eluent), crystallized by adding hexane.

*

Example XVI

2- (2,2-Dicarbethoxyethenylamino) cyclohexenothiazole.

10 2-Aminocyclohexenothiazole (7.7 g, 50 mmol) and diethyl ethoxymethylene malonate (11.9 g, 55 mmol) were combined with 10 ml of ethanol and heated at reflux for 50 min. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) cyclohexenothiazole (15 g, Rf - 0.5 on silica gel thin layer chromatography using chloroform / 1% ethanol as eluent) was added by adding 50 ml hexane.

Instead, 58.4 g of 2-amino-cyclohexenothiazole, 89.82 g of diethylethoxymethylene malonate and 584 ml of cyclohexane were combined and heated under reflux under nitrogen for 2½ hours, cooled to 15 ° C and the product (96 g, mp 113 ° C) was recovered by filtration.

Example XVII

2- (2,2-Dicarbethoxyethenylamino) cyclooctenothiazole.

25 2-Aminocyclooctenothiazole (2.0 g, 11 mmol) and diethyl ethoxymethylene malonate (2.52 g, 12.1 mmol) were combined and heated for 45 minutes on a steam bath for 2 hours.

The reaction mixture was cooled and 2- {2,2-dicarbethoxyethenylamino) cyclooctenothiazole (3.13 g, Rf = 0.6 on silica gel chromatography using chloroform / 1% ethanol as eluent) was precipitated by adding hexane.

Example XVIII

2- (2,2-Dicarbethoxyethenylamino) -4-methylthiazole.

35 2-Amino-4-methylthiazole (4.57 g, 40 mmol) and 80 06 36 2 34 diethylethoxymethylene malonate (9.51 g, 44 mmol) were combined and heated on a steam bath for 1 hour. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) -4-methylthiazole (9.8g, Rf = 0.5 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent) was precipitated by adding 60ml of hexane.

Example XIX

2- (2,2-Dicarbethoxyethenylamino) thiazole.

10 2-Aminothiazole (10.0 g, 0.10 mol) and diethyl ethoxymethylene malonate (23.8 g, 0.11 mol) were combined and heated on a steam bath for 1 hour and 15 minutes. The reaction mixture was cooled and the semisolid obtained recrystallized from hexane to give purified 2- (2,2-dicarbethoxyethenyl) thiazole (17.2 g in two harvests, Rf β 0.6 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent) was obtained.

Example XX

2- (2,2-Dicarbethoxyethenylamino) -5-methylthiazole.

2-Amino-5-methylthiazole (6.85 g, 60 mmol) and diethyl ethoxymethylene malonate (14.3 g, 66 mmol) were heated on a steam bath for 1 hour. The reaction mixture was cooled and the product precipitated by adding about 25 ml of hexane. Purified 2- (2,2-dicarbethoxyethenylamino) -5-methylthiazole (14.1 g in two harvests, Rf * 0.55-0.65 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent) was obtained by recrystallize from hexane.

Example XXI

2- (2,2-Dicarbethoxyethenylamino) -5-ethylthiazole.

2-Amino-5-ethylthiazole (11.7 g, 91.3 mmol) and diethyl ethoxymethylene malonate (21.7 g, 100.43 mmol) were combined and heated on a steam bath for 45 min. 2- (2,2-Di-35 carbethoxyethenylamino) -5-ethylthiazole (27.2 g, Rf = 0.6 and 0.7, respectively, 0 0 06 36 2 35, on silica gel thin layer chromatography, with chloroform / 1% ethanol and with 2: 1 hexane: ethyl acetate as eluent) was obtained as an oil by cooling and used immediately in the next step.

5 Example XXII

2- (2,2-Dicarbethoxyethenylamino) -4- {2-methylprop-2-yl) thiazole.

2-Amino-4- (2-methylprop-2-yl) thiazole (15.6 g, 0.1 mol) and diethyl ethoxymethylene malonate (23.8 g, 0.11 mol) were combined and on a steam bath for 2 hours heated.

2- (2,2-Dicarbethoxyethenylamino) -4- (2-methylprop-2-yl) thiazole was obtained as a wet solid on cooling and used immediately in the next step.

Example XXIII

2- (2,2-Dicarbethoxyethenylamino) -4-ethylthiazole.

2-Amino-4-ethylthiazole (20.5 g, 0.16 mol) and diethyl ethoxymethylene malonate (35 g, 0.17 mol) were combined and heated on a steam bath for 2 hours. 2- (2,2-Dicarbethoxy-20-ethenylamino) -4-ethylthiazole was obtained as an oil on cooling and immediately used in the next step (Rf = 0.75 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent) .

By the same method, 2-amino-4-iso-25-propylthiazole (58.6 g, 0.415 mol) and diethyl ethoxymethylene malonate (92 ml, 0.455 mol) were converted to 2- (2,2-dicarbethoxyethenylamino) -

4-isopropylthiazole. (Rf = 0.7 on silica gel thin layer chromatography using chloroform / 1% ethanol as the eluent.). Example XXIV

2- (2,2-Dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole.

2-Amino-6-phenylcyclohexenothiazole (10.4 g, 45.2 mmol) and diethylethoxymethylene malonate (10 ml, 49.5 mmol) were combined and heated on a steam bath. A solution was obtained after 15 minutes. After heating for a further 30 minutes, the entire mass solidified.

8006 362 36

The crude product was recrystallized from cyclohexane to give purified 2- (2,2-dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole (15.3 g, mp, 131-133 ° C).

Example XXV

2- (2,2-Dicarbethoxyethenylamino) -6-methylcyclohexenothiazole.

2-Amino-6-methylcyclohexenothiazole (23.3 g, 0.139 mol) was combined with diethyl ethoxymethylene malonate (31 ml, 0.153 mol) and heated on a steam bath. After heating for about 10 minutes, a clear orange-colored oil was obtained. After heating for 1 hour, crystallization was caused by scratching. Purified 2- (2,2-dicarbethoxyethenylamino) -6-methylcyclohexenothiazole (40.2 g, mp 106-109 ° C) was obtained by recrystallization from ethanol.

Example XXVI

2- (2,2-Dicarbethoxyethenylamino) -6,6-dimethylcyclohexenothiazole, 2-Amino-6,6-dimethylcyclohexenothiazole (9.8 g, 53.8 mmol), diethylethoxymethylene malonate (12 ml, 59.4 mmol) and 20 ethanol (about 5 ml) were combined and heated on a steam bath for 1½ hours. The ethanol was boiled down during the first part of the heating period. After cooling and scratching, the product crystallized out. Purified 2- (2,2-dicarbethoxyethenylamino) -6,6-dinethyl-yelohexenothiazole (14.3 g, mp 83-85 ° C) was obtained by recrystallization from hexane.

Analysis calculated: C17 H24 ° 4 N2 S: C 57.93; H 6.86; N 7.95;

Found: C 57.72, H 6.66; N 7.94.

Example XXVII

2- (2,2-Dicarbethoxyethenylamino) -4- (2-butyl) thiazole.

2-Amino-4- (2-butyl) thiazole (8.44 g, 54 mmol) and diethylethoxymethylene malonate (11.7 g, 54 mmol) were combined and heated on a steam bath for 1 hour and then cooled by 2 - (2,2-dicarbethoxyethenylamino) -4- (2-butyl) thiazole (17.6 g, 8 0 06 36 2 37

Rf = 0.75 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent) was obtained.

Example XXVIII

Ethyl ester of 1-oxo-1H-6,7-dimethylthiazolo / 3,2-a-pyrimidine-2-5 carboxylic acid.

2- (2-Dicarbethoxyethenylamino) -4,5-dimethylthiazole (4.17 g, 14 mmol) were combined with 30 ml Dowtherm A and heated at 220 ° C for 1½ hours. The reaction mixture was cooled and about 125 ml of petroleum ether were added. The solid that separated was filtered off, combined with the mother liquor and chromatographed on a 70 x 180 mm column of silica gel with chloroform as the eluent. After an original 125 ml fraction, 6 250 ml fractions were collected, stripped to dryness to yield crude product (2.42 g, mp 114-115 ° C). Recrystallization from cyclohexane gave purified ethyl ester of 1-oxo-1H-4,5-dimethylthiazolo / 3,2-a / pyrmidine-2-carboxylic acid (1.64 g, mp 119-120 ° C).

Analysis calculated: cnH12N2 ° 3S: 20 C 52.37; H 4.79; N 11.10; mass ion, 252;

Found: C 52.21; H 4.35; N 11.23; mass ion, 252.

Example XXIX

Ethyl ester of 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid.

2- (2-Dicarbethoxyethenylamino) -4-ethyl-5-methyl-thiazole (6.25 g) was combined with 30 ml Dowtherm A and heated at 215 ° C for 2½ hours. The reaction mixture was cooled, petroleum ether was added and the crude product (1.96 g) was recovered by filtration. Crude product (630 mg) was recrystallized from cyclohexane to give purified 1-oxo-1H-6-methyl-7-ethylthiazolo- / 3,2-a / pyrimidine-2-carboxylic acid ethyl ester (301 mg, mp 122-124 ° C).

Analysis calculated: c12H14N2 ° 3S: 35 c 54.12; H 5.30; N 10.52; 8 0 06 36 2 38

Found: C 54.09; H 5.26; N 10.63.

Example XXX

Ethyl ester of 1-oxo-1H-6-ethyl-7-methylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid 5 2- (2,2-Dicarbethoxyethenylamino) -4-methyl-5-ethyl-thiazole (12 g) was combined with 60 ml Dowtherm A and heated at 205 ° C for 3 hours. The reaction mixture was cooled and chromatographed on a 90 x 205 mm column of silica gel, eluting with chloroform containing 1% ethanol. Seven product-containing fractions of 250 ml each were collected, combined, stripped to an oil and re-chromatographed on silica gel (60 x 600 mm) with the same eluent. Fractions (165 x 8 ml) were combined, stripped to an oil and crystallized by trituration with diisopropyl ether. Recrystallization from cyclohexane gave purified ethyl ester of 1-oxo-1H-6-ethyl-7-methyl-thiazolo / 3,2-α / pyrimidine-2-carboxylic acid (2.45 g, mp 65-66 ° C) .

Anal calculated: c12H14N2 ° 3S: C 54.12; H 5.30; N 10.52; mass ion, 266; Found: C 54.26; H 5.23; N 10.57; mass ion, 266.

Example XXXI

Ethyl ester of 1-oxo-1H-6,7-diethylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) -4,5-diethylthiazole (26.1 g) and 300 ml Dowtherm A were combined and heated at 225 ° C for 3½ hours. The reaction mixture was cooled and chromatographed on a silica gel column (60 x 320 mm). Dowtherm A was eluted with hexane and the product eluted with 2: 1 hexane: chloroform. 33 fractions of 250 ml each were collected.

The eighth through 33rd fractions were combined and stripped to give ethyl ester of 1-oxo-1H-6,7-diethylthiazolo / 3,2-α / pyrimidine-2-carboxylic acid (22 g, Rf = 0.4-0.5 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent) was obtained as an oil.

| 80 06 36 2 • 4 39

By the same method, the following products of Examples XII and XIV were: 2- (2,2-dicar laelhoxyethenylamino) -4-ethyl-5-methylthiazole; 2- (2,2-dicarbopropoxyethenylamino) -4-ethyl-5-methylthiazole; 2- (2,2-dicarboisopropoxyethenylamino) -4-ethyl-5-methylthiazole; 2- (2,2-dicarbomethoxyethenylamino) -4,5-diethylthiazole; 2- (2,2-dicarbopropoxyethenylamino) -4,5-diethylthiazole; 2- (2,2-dicarboisopropoxyethenylamino) -4,5-diethylthiazole; 2- (2,2-dicarbethoxyethenylamino) -4-pentylthiazole; 2- (2,2-dicarbethoxyethenylamino) -4-propyl-5-ethylthiazole; 2- (2,2-dicarbethoxyethenylamino) -4,5-diisopropylthiazole; 2- (2,2-dicarbethoxyethenylamino) -5-propylthiazole; 2- (2,2-dicarbethoxyethenylamino) -5-isopropylthiazole; 2- (2,2-dicarbethoxyethenylamino) -5-phenylthiazole; 2- (2,2-dicarbethoxyethenylamino) -6-phenylcyclopentenothiazole; 2- (2,2-dicarbethoxyethenylamino) -5,7-dimethylcyclohexenothiazole; 2- (2,2-dicarbethoxyethenylamino-7-methylcyclooctenothiazole? 2- (2,2-dicarbethoxyethenylamino) -4,4,6-trimethylcyclopentomethylthiazole converted to: methyl ester of 1-oxo-1H-6-meth} 4 7-ethylthiazolo / 3,2-a-pyriraidin-2-carboxylic acid, propyl ester of 1-oxo-1H-6-methyl-7-ethylthiazolo / 3,2-a-pyrimidine-2-carboxylic acid; isopropyl ester of 1-oxo-1H-6-methyl-7-ethylthiazolo - / - 3,2-a / pyrimidine-2-carboxylic acid; methyl ester of 1-oxo-1H-6,7-diethylthiazolo / 3,2-a_ / pyrimidin-2-carboxylic acid; propyl ester of 1-oxo-1H-6,7-diethylthiazolo / 3,2-α / pyrimidine-2-carboxylic acid; isopropyl ester of 1-oxo-1H-6,7- diethylthiazolo / 3,2-a-pyrimidine-2-carboxylic acid; ethyl ester of 1-oxo-1H-7-pentylthiazolo / 3,2-a-pyrimidine-2-carboxylic acid; 8006362 40 ethyl ester of 1-oxo-1H- 6-ethyl-7-propylthiazolo-3,2-a-pyrimidine-2-carboxylic acid; ethyl ester of 1-oxo-1H-6,7-diisopropylthiazole-CV 3,2-a-pyrimidine-2-carboxylic acid; 5-ethyl ester of 1-oxo-1H-6-propylthiazolo / 3,2-a_ / pyrimidine-2-carbon acid; ethyl ester of 1-oxo-1H-6-isopropylthiazolo / 3,2-a-pyrimidine-2-carboxylic acid; ethyl ester of 1-oxo-1H-6-pentylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid; ethyl ester of 1-oxo-1H-6-phenylcyclopentenothiazole (V 3,2-a-pyrimidine-2-carboxylic acid; ethyl ester of 1-oxo-1H-6,8-dimethylcyclohexenothiazolo - / 3,2-a / pyrimidine- 2-carboxylic acid, ethyl ester of 1-oxo-1H-8-methylcyclooctenothiazolo- / 3,2-a / pyrimidine-2-carboxylic acid and ethyl ester of 1-oxo-1H-6,8,8-trimethylcyclopentenothiazo- [o 3,2-alpha / pyrimidin-2-carboxylic acid.

Example XXXII

Ethyl ester of 1-oxo-1H-cyclopentenothiazolo 3,2-a / pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamine) cyclopentenothiazole (7.0 g) was combined with 40 ml Dowtherm A and heated at 225-230 ° C for 1 hour. The reaction mixture was cooled and chromatographed on silica gel (70 x 190 mm). Dowtherm A was eluted with hexane. The product was eluted with chloroform-1% ethanol. 4 fractions of 250 ml each were collected, combined and the solvent stripped to give an oil. Part of the oil was crystallized by trituration with cyclohexane to obtain a crude product (1.91 g). Recrystallization of 0.6 g of crude product gave purified ethyl ester of 1-oxo-1H-cyclopentenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid (0.33 g, mp 102-103 ° C).

35 8 0 06 36 2 41

Analysis calculated: C 54.53, H 4.58; N 10.60;

Found: C 54.54; H 4.71; N 10.71.

Example XXXIII

5 Ethyl ester of 1-oxo-1H-cyclohexenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) cyclohexenothia sole (12.6 g) was combined with 125 ml Dowtherm A and heated at 230 ° C for 25 min. The reaction mixture was cooled and chromatographed on silica gel (60 x 320 mm). Dowtherm A was eluted with hexane and the product eluted with chloroform-1% ethanol in 14 fractions of 125 ml each. Crude ethyl ester of 1-oxo-1H-cyclohexenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid (10.7 g, mp 92-15 94 ° C) was obtained by combining the fractions and dissolving stripping agent.

Instead, 2- (2,2-dicarbethoxy-ethenylamino) cyclohexenothiazole (80 g, 0.25 mol), trifluoroacetic anhydride (101 g, 68 ml, 0.48 mol), toluene (0.8 L) and ethanol were added 20 (11) combined and heated at reflux for 21 hours. The reaction mixture was cooled and 300 ml of water were added. The toluene (top) layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated to 150 ml (slurry), diluted with 1 L ethanol (solution), concentrated to 280 ml, cooled to 5 ° C , granulated! filtered off to give relatively pure ethyl ester of 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (47 g, mp 105-106 ° C).

Example XXXIV

Ethyl ester of 1-oxo-1H-cycloheptenothiazolo / 3,2-α / pyrimidine-2-carboxylic acid.

2-Aminocycloheptenothiazole (25.2 g, 0.15 mol), diethyl ester of ethoxymethylene malonic acid (35.7 g, 0.165 mol) and 35 Dowtherm A (400 ml) were combined and 2 h at 220-230 ° C

8 0 06 36 2 42 heated. The reaction mixture was cooled and chromatographed on silica gel (90 x 235 mm). Dowtherm A was eluted with hexane. The product was eluted with 1: 1 hexane: chloroform in 30 fractions of 500 ml each. The 6th to 13th fractions were combined and stripped to yield crude product as a wet solid. Purified ethyl ester of 1-oxo-1H-cyclohep-

..... ✓ Q

tenothiazolo / 3,2-α / pyrimidine-2-carboxylic acid (27.1 g, mp 78-79 C) was obtained by recrystallization from cyclohexane.

The same product is obtained by heating 2- (2,2-10 dicarbethoxyethenylamino) cycloheptenothiazole in

Dowtherm A and to be isolated and purified in a corresponding manner. Example XXXV

Ethyl ester of 1-oxo-1H-cyclooctenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

2- {2,2-Dicarbethoxyethenylamino) cyclooctenothiazole (3.13 g) was combined with 30 ml Dowtherm A and heated at 220 ° C for 2 h. The reaction mixture was cooled and chromatographed on silica gel (70 x 190 mm). Dowtherm A was eluted not hexane. The product was eluted with chloroform-1% ethanol in 4 fractions of 125 ml each. The fractions were combined, stripped to an oil and solid ethyl ester of 1-oxo-1H-cycloocteno-thiazolo 3,2 3,2-α / pyrimidine-2-carboxylic acid (1.956 g, Rf * 0.5 on silica gel thin layer, eluted with chloro-25 form-1% ethanol) was obtained by trituration with hexane.

Example XXXVI

Ethyl ester of 1-oxo-1H-7-methylthiazolo / 3,2-a / pyrimidin-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) -4-methylthiazole (9.8 g), was combined with 50 ml Dowtherm A and heated at 220 ° C for 2 hours. The reaction mixture was cooled and 50 ml of hexane was added and the crude product was recovered by filtration. Recrystallization of the crude product from ethanol gave purified ethyl ester of 1-oxo-1H-7-methylthiazolo / 3,2-a / pyrimidine-2-carbon- | 8 0 06 36 2 J * 43 acid (4.6 g, mp 187-189 ° C).

Alternatively, this ester can be prepared by condensing 4-amino-4-methylthiazole directly with the ethyl ester of ethoxymethylene malonic acid by refluxing in trichlorobenzene Allen et al., J. Org. Chem., 24, 779 (1959) -

Example XXXVII

Ethyl ester of 1-οχο-1H-thiazolo / 3,2-a-pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) thiazole (17.2 g) was combined with 200 ml Dowtherra A and heated at 215 ° C for 30 min.

The reaction mixture was cooled to yield a slurry. Hexane (100 ml) was added and the crude product was recovered by filtration. Recrystallization from ethanol gave purified ethyl ester of 1-o-1H-thiazolo / 3,2-a / pyrimidine-2-carboxylic acid (8.0 g, mp 184-185 ° C).

Alternatively, this ester can be prepared by condensing 2-aminothiazole directly with the ethyl ester of ethoxymethylene malonic acid by refluxing in trichlorobenzene / Allen et al., J. Org. Chem., 24, 779 (1959)]. Example! 1 «XXVIII

Ethyl ester of 1-oxo-1H-6-methylthiazolo / 3,2-alpha / pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenyl) -5-methylthiazole (14.1 g) was combined with 150 ml Dowtherm A and heated at 220 ° C for 1 hour. The reaction mixture was cooled and about 300 ml of hexane was added. The product was recovered by filtration and purified ethyl ester of 1-oxo-1H-methylthiazolo / 3,2-a / pyrimidine-30 2-carboxylic acid (6.4 g, mp 149-151 ° C) was obtained by recrystallization from diisopropyl ether.

Alternatively, this ester can be prepared by condensing 2-amino-5-methylthiazole directly with the ethyl ester of ethoxymethylene malonic acid in boiling trichlorobenzene 35 (Dunwell, et al., J. Chem. Soc., (C), 1971, 2094).

80 06 36 2

Example XXXIX

Ethyl ester of 1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid.

44 5 2- (2,2-Dicarbethoxyethenylamine) -5-ethylthiazole (25.7g, 86mmol), trifluoroacetic anhydride (36.2g, 172mmol) and toluene (150ml) were combined and refluxed for about 20 hours. The reaction mixture was stripped to dryness, taken up in 300 ml of chloroform. The chloroform solution was washed with saturated sodium bicarbonate and then saturated sodium chloride, dried over anhydrous sodium sulfate, stripped to dryness and triturated with diisopropyl ether to give the ethyl ester of 1-oxo-1H-6-ethylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid (17.8 g, mp 148-150 ° C) was obtained. A portion of the product (5.2 g) was recrystallized from about 75 ml of ethyl acetate to give further purified product (4.1 g, mp 149-150 ° C).

Analysis calculated: cnHi2N2 ° 3S: C 52.37? H 4.79; N 11.10; 20 Found: C 52.30? H 4.51; N 11.14.

Example XL

Ethyl ester of 1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) -4- (2-methyl-2-propyl) thiazole (32.6 g) was combined with 400 ml Dowtherm A and heated at 230 ° C for 1 hour. The reaction mixture was cooled and chromatographed on silica gel (60 x 600 mm). The Dowtherm A was eluted with hexane. The product was eluted with chloroform. 9 fractions of 500 ml each were collected. The 6th through 9th fractions were combined and stripped to dryness to give the ethyl ester of 1-oxo-1H-7- (2-methyl-2-propyl) thiazoLV 3,2-α-pyrimidine-2-carboxylic acid (11, 4 g, mp 145-147 ° C) was obtained. Further product (2.04 g) was obtained from the 5th fraction by stripping to a wet solid and triturating with cyclohexane.

8 0 06 36 2 45

One gram of the largest crop was recrystallized from cvlo-hexane to obtain further purified product (0.62 g, mp 148-149 ° C).

Analysis calculated: C ^ H ^ 6N2 ° 3S: 5 C 55.70? H 5.75; N 9.99?

Found: C 55.14; H 5.58; N 9.95.

Example XLI

Ethyl ester of 1-oxo-1H-7-ethylthiazobV 3,2-a / pyrimidin-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) -4-ethylthiazole (47.7 g, 0.16 mol) was stirred in 500 ml of toluene and trifluoroacetic anhydride (45 ml, 0.32 mol) was added. A weak exotherm was observed. The reaction mixture was heated under reflux for 26 hours, cooled and 250 ml of ethyl acetate were added. The mixture was carefully extracted with 250 ml of aqueous sodium bicarbonate (carbon dioxide evolution) and then with 250 ml of saturated sodium chloride, dried over anhydrous sodium sulfate and stripped to dryness. The residue was slurried in diisopropyl ether and the crude product was recovered by filtration. Oral crystallization of the crude product from acetonitrile gave purified ethyl ester of 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (10.33 g, mp 175-177 ° C). Analysis calculated: cnHi2N203S: 25 C 52.37? H 4.79; N 11.10;

Found: C 52.34; H 4.85; N 11.27.

A second crop (1.58 g, mp. 176-178 ° C) was obtained from the acetonitrile mother liquor.

Example XLII

Ethyl ester of 1-oxo-4H-7-isopropylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxy) -4-isopropylthiazole (10g) was combined with 100ml Dowtherm A and heated at 220 ° C for 2 hours, cooled to room temperature overnight and again 8006362 46

220 ° C heated for an additional 5 hours. The mixture was cooled to room temperature, about 200 mls were added thereto and filtered to remove a trace of insolubles. The hexane was stripped and the residue was chromatographed on about 500 g of silica gel. The Dowtherm A

was eluted with hexane and the product was eluted with chloroform. Fractions containing product were combined and stripped to dryness, the residue slurried in diisopropyl ether and the product (mp 143-144 ° C) recovered by filtering. The crude product was recrystallized from ethanol

whereby purified ethyl ester of 1-oxo-1H-7-isopropylthiazolo - / - 3,2-a / pyrimidine-2-carboxylic acid (1.49 g, mp. 145-147 ° C, kmt of singlets at 68.6 and 67, 3 corresponding to one proton each and multiplets centered at 64.2 and 61.2 corresponding to 15 three protons and nine protons, respectively, was obtained.

Ethyl ester of 1-oxo-1H-7-phenylcyclohexenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) -6-phenylcyclohexethothiazole (15.3g, 38.2mmol) was slurried in 250ml toluene. Trifluoroacetic anhydride (10.3ml, 76.5mmol) was added to give a clear solution which was heated at reflux for 16 hours. The reaction was cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 150 ml of 5% potassium carbonate and once with 150 ml of saturated sodium chloride, dried over anhydrous sodium sulfate and stripped to dryness. The solid residue was recrystallized from acetonitrile to give purified ethyl ester of 30 1-oxo-1H-7-phenylcyclohexenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid (9.89 g, mp 160-161.5 ° C) was obtained.

Example XLIV

Ethyl ester of 1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid.

35 i 8 0 06 36 2 47 2- (2,2-Dicarbethoxyethenylamino) -6-methylcyclohexenothiazole (40.2 g, 0.119 mol) was dissolved in 400 ml of toluene. Trifluoroacetic anhydride (33.5 ml, 0.237 mol) was added, causing a weak exotherm. The reaction mixture was heated to reflux overnight (16 hours), cooled to room temperature, diluted with 400 ml ethyl acetate, extracted twice with 400 ml ln potassium carbonate and once with 400 ml saturated sodium chloride, dried over anhydrous sodium sulfate and stripped to dryness . Recrystallization from cyclohexane containing a small amount of ethyl acetate gave purified ethyl ester ve 1-oxo-1H-7-methylcyclohexenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid (29.3 g, mp 127-129 ° C ).

Example XLV

Ethyl ester of 1-oxo-1H-7,7-dimethylcyclohexenothiazolo / 3,2-a-pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) -6,6-dimethylthiazole (13 g, 36.9 mmol) was dissolved in 130 ml of toluene. Trifluoroacetic anhydride (10.4 ml, 73.6 mmol) was added and the mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 130 ml of saturated sodium bicarbonate and once with 150 ml of saturated sodium chloride, dried over anhydrous sodium sulfate and stripped to dryness. Recrystallization from hexane gave purified ethyl ester of 1-oxo-1H-7,7-dimethylcyclohexenothiazolo / 3,2-α / pyrimidine-2-carboxylic acid (9.40 g, mp, 92-94 ° C).

Analysis calculated: h16N2 ° 3S: C 58.80; H 5.92; N 9.14; Found: C, 58.93; H 5.48; N 9.01.

Example XLVI

Ethyl ester of 1-oxo-1H-7- (2-butyl) thiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

2- (2,2-Dicarbethoxyethenylamino) -4- (2-butyl) - 8 0 06 36 2 48 thiazole (17.6 g) was combined with 175 ml Dowtherm A and heated at 225 ° C for 2½ hours. The reaction mixture was cooled and chromatographed on silica gel (60 x 600 mm). Dowtherm A was eluted with hexane. The product was eluted with 2: 1 chloroform: hexane.

Fractions 4-8 (500 ml each) were combined and stripped to an oil, which was taken up in about 400 ml of hot hexane, treated with charcoal and cooled to give crystalline ethyl ester of 1-oxo-1H-7- (2-butyl ) thiazolo / 3,2-α / pyrimidine-2-carboxylic acid (2.12 g, mp 105.5-108 ° O) was obtained.

IQ Analvse Calculated: C-H, O, N-S: 13 16 3 2 C 55.70; H 5.75; N 9.99;

Found: C 55.82; H 5.40; N 10.22.

Example XLVII

1-Oxo-1H-6,7-dimethylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

15

Ethyl ester of 1-oxo-1H-6,7-dimethylthiazolo- / 3,2-a / pyrimidine-2-carboxylic acid (1.41 g) was heated on a steam bath with 20 ml of 8% hydrobromic acid for 1 hour. A solution was formed within minutes and solids started to form at the end of the reaction period. The reaction mixture was cooled and the product was recovered by filtration. Recrystallization from ethanol gave purified 1-oxo-1H-6,7-dimethylthiazolo / 3,2-α / pyrimidine-2-carboxylic acid (508 mg, mp 189-190 ° C).

Analysis calculated: C 8 Hg O 2 S: C 48.21; H 3.60; N 12.49; mass ion, 224;

Found: C 48.21; H 3.68; N 12.44; mass ion, 224.

Example XLVIII

1-Oxo-1H-6-methyl-7-ethylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

30

Ethyl ester of 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (971 mg) was heated on a steam bath with 15 ml of 48% hydrobromic acid. The substance dissolved almost immediately. Heating was continued for 2½ and the reaction mixture was cooled to form a product as a filterable solid. Recrystallization of the crude 8006362 49 product from isopropyl alcohol gave purified 1-oxo-1H-6-methyl-7-ethylthiazolo 3,2-α / pyrimidine-2-carboxylic acid (354 mg, mp 201-202 ° C).

Analysis calculated: C 10 H 10 O 3 N 2 S: 5 C 50.41; H 4.23; N 11.76;

Found: C 50.28; H 4.26; N 11.80.

Example XLIX

1-Oxo-1H-6-ethyl-7-methylthiazolo / 3,2-α / pyrimidine-2-carboxylic acid.

10 Ethyl ester of 1-oxo-1H-6-ethvl-7-methylthiazolo- / 3,2-a / pyrimidine-2-carboxylic acid (1.33 g) was heated on a steam bath with 10 ml of 48% hydrobromic acid for 30 min heated at which time a solid started to form. The mixture was cooled and the crude product was recovered by filtration.

Recrystallization from isopropyl alcohol gave purified 1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine (596 mg, mp 174-176 ° C).

Analysis calculated C._H, nO_N 3 S: 10 10 3 2 C 50.41; H 4.23; N 11.76;

Found: C 50.44; H 4.22; N 11.32.

20 Example L

1-Oxo-1H-6,7-diethylthiazolo / 3,2-a-pyrimidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-6,7-diethylthiazolo - (- 3,2-a-7-pyrimidine-2-carboxylic acid (19.2 g) was heated at 85 ° C for 1 hour with 48% aqueous hydrobromic acid. gas evolution (probably decarboxylation of the product) was observed.

The reaction mixture was cooled and made basic with concentrated aramium hydroxide and unreacted starting material, and impurities were extracted with ethyl acetate. The aqueous phase was acidified with acetic acid and the solid product was recovered by filtration. The crude product was recrystallized from isopropyl alcohol to yield a partially purified product (5.4 g) in two harvests. Partially purified material (2.5 g) was recrystallized a second time from isopropyl alcohol-35 to give purified 1-oxo-1H-6,7-diethylthiazolo / _ 3,2-a _ / - 8 0 06 36 2 50 pyrimidine- 2-carbon2hr / 1.6g, mp. 104-106 ° C (cloudy) / was obtained.

Analysis calculated: C 12 H 21 N 3 N 2 S: C 52.37; H 4.79; N 11.10; 5 Found: C 52.31; H 4.79; N 11.16.

Example LI

1-Oxo-1H-cyclopentenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-cyclopentenothiazolo-10 / 3,2-α / pyrimidine-2-carboxylic acid (1.3 g) was heated on a steam bath with 15 ml of 48% hydrobromic acid for 30 min. Dissolution occurred after about 5 minutes; a solid started to form at the end of the heating period. The reaction mixture was cooled and crude product was recovered by filtration. Recrystallization from isopropyl alcohol gave purified 1-oxo-1H-cyclopentenothiazol / 3,2-a / pyriraidine (0.51 g, mp 202-203.5 ° C).

Analysis calculated: C 1 HgO NjS: C 50.84; H 3.41; N 11.86;

Found: C 50.42; H 3.57; N 11.65.

The sodium and potassium salts are obtained by dissolving the free acid in water with 1 equivalent of the appropriate hydroxide and either stripping the water under vacuum or by freeze drying.

The N-methylmorpholine salt is prepared by dissolving the acid in methylene chloride with a slight excess of N-methylmorpholine and then stripping to dryness, or by precipitating the salt by cooling and adding hexane.

Example Lil 1-Oxo-1H-cyclohexenothiazolo / 3,2-a / pyriraidine-2-carboxylic acid.

30

Ethyl ester of 1-oxo-1H-cyclohexenothiazolo- / 3,2-a / pyrimidine-2-carboxylic acid (2.8 g) was heated on a steam bath with 30 ml of 48% hydrobromic acid. Within a few minutes of the start of heating, the fabric began to loosen; product began to precipitate at the end of the reaction time. The reaction mixture was cooled in an ice bath and 1-oxo-1H-cyclohexenothiazo-1a-3,2-α / pyrimidine-2-carboxylic acid (1.66 g, mp. 188-189 ° C) was isolated by filtration. Recrystallization from ethanol gave 1.38 g with the same melting point.

Instead, this product was prepared by stirring 22.3 g of the ethyl ester with 223 ml of 48% hydrobromic acid in a low pressure vessel. Dissolution occurred at 65-70 ° C.

The reaction mixture was heated at a maximum temperature of 85 ° C and a maximum pressure of 1.49 kg / cm for 40 min. The reaction mixture was cooled to 45 ° C, deaerated, cooled to 5 ° C, stirred for 1 hour and the relatively pure product was recovered directly by filtration (12.4 g, mp 192-194 ° C).

The sodium salt is prepared by dissolving the acid in methanol with 1 equivalent of sodium methanolate and stripping or precipitating the salt to dryness by cooling and adding hexane.

Example XLIH

1-Oxo-1H-cycloheptenothiazolo 3,2-a / pyrimidin-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-cycloheptenothiazolo- / 3,2-a / pyrimidine-2-carboxylic acid (5.8 g) was heated on a steam bath with 50 ml of hydrobromic acid for 15 min. The reaction mixture was poured into ice, stirred and the crude product recovered by filtration. Recrystallization from ethanol gave purified 1-oxo-25 H cycloheptenothiazolo [3,2-a] pyrimidine (2.63 g, mp 162-163 ° C).

Analysis calculated: ^ j2H12 ^ 3 ^ 2 ^! C 54.53; H 4.58; N 10.60; Mass ion, 264;

Found: C 54.72; H 4.73; N 10.88; Mass ion, 264.

Amine salts are prepared by adding 30 L equivalent of amine to a warm ethanolic solution of the acid followed by cooling, concentrating or adding hexane.

Example LIV

1-Oxo-1H-cyclooctenothiazolo / 3,2-a-pyrimidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-cyclooctenothiazolo-8006362 52 {3,2-a / pyrimidin-2-carboxylic acid (1.23 g) was heated with 30 ml of 48% on an oil bath for 4 hours at 90 ° C. ig hydrobromic acid. The reaction mixture was cooled, the pH adjusted to 1.5 and the product extracted with ethyl acetate. The ethyl acetate extra was washed with water and then with saturated sodium chloride, dried over sodium sulfate and stripped to an oil.

The oil was redissolved in ethyl acetate and the product was extracted with potassium hydroxide. The basic solution was acidified again with 3N hydrochloric acid and the product was back-extracted with ethyl acetate. The ethyl acetate solution was extracted with water and then saturated sodium chloride, dried over anhydrous sodium sulfate and stripped to dryness to give 1-oxo-1H-cyclo-heptenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid (308 mg, Rf = 0.6 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent) was obtained.

The methodology of Examples XLVII-LIII is used to convert the corresponding alkyl esters of 1-oxo-1H-thiazolo / ~ 3,2-alpha / pyrimidine-2-carboxylic acid from Example XXXI to: 20 l-oxo-1H- 6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid; 1-oxo-1H-6,7-diethylthiazolo / 3,2-a / pyrimidin-2-carboxylic acid; 1-oxo-1H-7-pentylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid; 1-oxo-1H-6-ethyl-7-propylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid; 1-oxo-1H-6,7-diisopropylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid, 1-oxo-1H-6-propylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid; 30 1-oxo-1H-6-isopropylthiazolo / 3,2-a / pyriraidine-2-carboxylic acid; 1-oxo-1H-6-pentylthiazolo / 3,2-a-pyrimidine-2-carboxylic acid; 1-oxo-1H-6-phenylcyclopentenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid; 35 1-oxo-1H-6,8-dimethylcyclohexenothiazolo / 3,2-a / pyrimidine-8 0 06 36 2 53 2-carboxylic acid; 1-oxo-1H-8-methylcyclooctenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid and 1-oxo-1H-6,8,8-trimethylcyclopentenothiazolo / 3,2-a / pyri-5 midine-2-carboxylic acid .

Example LV

1-Oxo-1H-7-methylthiazolo / 3,2-a / pyriraidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-7-raethylthiazolo / 3,2-α / 10 pyrimidine-2-carboxylic acid (3.1 g) was heated on a steam bath with 50 ml of 48% hydrobromic acid. The solid dissolved within 5 minutes. After about 15 minutes of heating, the reaction mixture was cooled and the product which precipitated was recovered by filtration. Recrystallization from acetic acid gave purified 1-oxo-1H-7-methylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid, m.p. 265 ° C (dec.) /.

Analysis calculated: C 1 H-N 5 S o b 3 ^ C 45.71; H 2.88; N 13.33;

Found: C 45.57; H 3.04; N 13.40.

20 Example LVI

1-Oxo-1H-thiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-thiazolo / 3,2-a / pyrimidine-2-carboxylic acid (7.5 g) was heated with steam-bath 80 ml of 48% hydrobromic acid for 20 min. The substance dissolved within 5 minutes and a solid started to precipitate a few minutes later. The reaction mixture was cooled in an ice bath and the crude product was recovered by filtration. Purified 1-oxo-1H-thiazolo / 3,2-alpha-pyrimididine-2-carboxylic acid (4.66 g, mp 276 ° C (dec.)) Was obtained.

Analysis calculated: C 1 H H O N N S: C 42.86; H 2.06; N 14.28;

Found: C 42.71; H 2.21; N 14.32.

Alternatively, this acid can be prepared from the same intermediate by refluxing in 80 06 36 2 54

excess 2N hydrochloric acid / Allen et al., J. Org. Chem., 24, 779 (1959)]. Example LVII

1-Oxo-1H-6-methylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidin-2-carboxylic acid (5.96 g) was heated on a steam bath with 60 ml of 48% hydrobromic acid for 1 hour. The reaction mixture was cooled in an ice bath and the crude product was recovered by filtration and washed with isopropyl alcohol and ether.

Recrystallization of the crude product from dimethylformamide gave purified 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (3.73 g, mp 246-248 ° C (dec)). ^ /.

Analysis calculated: C 8 Hg O 2 N 5 S: C 45.71; H 2.88? N 13.33? Found: C 45.87; H 2.94? N 13.47.

Instead, this acid is prepared from the same intermediate by refluxing in 2N hydrochloric acid (Dunwell et al., J. Chem. Soc., (C) 1971, 2094).

Example LVIII

1-Oxo-1H-6-ethylthiazolo / 3,2-a / pyrimidin-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-6-ethylthiazolo / 3,2-a-pyrimidine-2-carboxylic acid (12.6 g) was heated on a steam bath with 125 ml of 48% hydrobromic acid. The substance dissolved within a few minutes. After 10 minutes, a solid started to form.

Heating was continued for a total of 40 minutes. The reaction mixture was cooled and the crude product (10.1 g) was recovered by filtration. Recrystallization of 2.32 g of crude product (recovered from 6.8 g in an attempt to recrystallize from acetic acid) from isopropyl alcohol gave purified 1-oxo-1H-6-ethyl-thiazolo / 3,2-a-pyrimidine-2 -carboxylic acid (1.85 g, mp 162463 ° C). Analysis calculated: C 25 O 25: C 48.21; H 3.60; N 12.49;

Found: C 48.17? H 3.73; N 12.42.

35 | 8006362 55

Example LIX

1-Oxo-1H-7- (2-methyl-2-propyl) thiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

5-Ethyl ester of 1-oxo-1H-7- (2-methyl-2-propylthiazole] / 3,2-alpha / pyrimidine-2-carboxylic acid (5.6 g) was heated on a steam bath with 60 ml for 6 hours 48% hydrobromic acid After about 10 minutes before complete dissolution of the ester was obtained, the reaction mixture became very thick At the end of the heating period, the reaction mixture was cooled and crude product was recovered by filtration. Recrystallization from acetic acid and drying over dimethylformamide, purified 1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid gave 3.33 g, mp 242-242 ° C (dec.) _ /.

Analysis calculated: C 11 H 12 O 3 N 2 S: C 52.37; H 4.79; N 11.10;

Found: C 52.45; H 4.82; N 11.26.

Example LX

1-Oxo-1H-7-ethylthiazolo / -3,2-a / pyrimidine-2-carboxylic acid.

20

Ethyl ester of 1-oxo-1H-7-ethylthiazolo / 3,2-a-pyrimidine-2-carboxylic acid (1.5 g) was heated on a steam bath with 15 ml of 48% hydrobromic acid for 20 min. Dissolution occurred within 5 min and after 10 min a solid started to precipitate. At the end of the reaction time, the mixture was cooled to room temperature, diluted with about 25 ml of water and the crude product was recovered by filtration. The crude product was partially purified by dissolving in potassium carbonate and reprecipitating with 3N hydrochloric acid.

Recrystallization from acetic acid gave purified 1-oxo-1H-7-ethylthiazolo / 3,2-a / pyrimidine (594 mg, mp 206-209 ° C). Analysis calculated C 8 H N 2 O O S: C 48.21; H 3.60; N 12.49;

Found: C 48.01; H 3.69; N 12.50.

35 8006362 56

Example LXI

1-10x-1H-7-isopropylthiazolo / 3,2-alpha / pyrimidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-7-isopropylthiazolo-5 / 3,2-a / pyrimidine-2-carboxylic acid (909 mg) was heated on a steam bath with 10 ml of 48% hydrobromic acid for 20 min. Complete dissolution occurred within 5 minutes; within 10 minutes a product started to precipitate. After the heating period, the reaction mixture was cooled to room temperature and crude product was recovered by filtration. Recrystallization from ethanol gave purified 1-oxo-1H-7-isopropylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid (538 mg, mp 216-217 ° C).

Example LXII

1-Oxo-1H-7-phenylcyclohexenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid. 15

Ethyl ester of 1-oxo-1H-7-phenylcyclohexenothiazo-10 / 3,2-a / pyrimidine-2-carboxylic acid (9.8 g) was heated under reflux with 200 ml of 48% hydrobromic acid for 20 minutes, after which a solution was formed for about 10 min. The reaction mixture was cooled and the crude product was recovered by filtration. Recrystallization from acetic acid gave purified Ι-οχο-ΙΗ-7-phenyl-cyclohexenothiazolo / 3,2-3,2-α / pyrimidine-2-carboxylic acid (2.52 g, mp 224-226 ° C).

Analysis calculated: ^ 7H ^ 4N2 ° 3: 25 C 62.56; H 4.32; N 3.58;

Found: C 62.26; H 4.11; N 3.52.

A second crop was obtained from mother liquor (704 mg, mp 217-220 ° C).

Example LXIII

30 1-Oxo-1H-7-methylcyclohexenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-7-methylcyclohexenothiazole / 3,2-a / pyrimidine-2-carboxylic acid (27.5 g) was heated on a steam bath with 275 ml of 48% hydrobromic acid for 35 min. After 10 min.

A clear solution was obtained; after 15 minutes a product started to precipitate 80 06 36 2 57. The reaction mixture was cooled to room temperature and crude product (14.9 g, mp 181.5-183.5 ° C) was recovered by filtration and washing with water. Recrystallization from dimethylformamide gave purified 1-oxo-1H-7-methylcyclohexeno-5 thiazolo / 3,2-α-7pY1'imidine-2-carboxylic acid (10.1 g, mp 183.5-185.5 ° C).

Analysis calculated: c12H12N2 ° 3S: C 54.53; H 4.58; N 10.60;

Found: C 54.41; H 4.28; N 10.58.

A second crop was obtained by adding water to the dimethylformamide mother liquor (3.11 g, mp 182-184 ° C).

Example LXIV

1-Oxo-1H-7,7-dimethylcyclohexenothiazolo / 3,2-a / pyrimidin-2-car-15 carboxylic acid.

Ethyl ester of 1-oxo-1H-7,7-dimethylcyclohexeno-thiazolo / 3,2-a / pyrimidine-2-carboxylic acid (7.9 g) was combined with 80 ml of 48% hydrobromic acid and 50 min. steam bath 20 heated. The acid began to precipitate before dissolution of the ester was complete. The reaction mixture was cooled, diluted with about 100 ml of water and crude product (6.7 g) was recovered by filtration and washed with a small volume of water. Recrystallization of the crude product from ethanol gave purified 1-oxo-1H-25 7,7-dimethylcyclohexenothiazolo / 3,2-α / pyrimidine-2-carbon2HUr (4.7 g, mp 197-198 ° C).

Analysis calculated: c13 H14 N2 ° 3Ss C 56.10; H 5.07; N 10.06;

Found: C 55.85; H 4.84; N 10.14.

30 Example LXV

1-Oxo-1H-7- (2-butyl) thiazolo / 3,2-a / pyrimidine-2-carboxylic acid.

Ethyl ester of 1-oxo-1H-7- (2-butyl) thiazolo- / 3,2-a / pyrimidine-2-carboxylic acid (2.0 g) was combined with 35 20 ml of 48% hydrobromic acid and on a steam bath Heated for 25 minutes.

t i 8 0 06 36 2 58

Dissolving took place within 5 minutes; the precipitation of a product began within 10 minutes. The reaction mixture was cooled to room temperature, diluted with about 40 ml of water and crude product (1.3 g, mp 191-194 ° C) was recovered by filtration with a small volume of water for washing. Recrystallization of the crude product from ethyl acetate containing a small amount of ethanol gave purified 1-oxo-1H-7- (2-butyl) thiazolo / 3,2-alpha / pyrimidine-2-carboxylic acid (606 mg, mp 194). -197 ° C).

Analysis calculated cnH12N2 ° 3S: 10 C 52.37; H 4.79; N 11.10;

Found it; C 52.20; H 4.48; N 11.11.

The ethyl acetate mother liquor was concentrated to give a small second crop.

Example LXVI

N- (Tetrazol-5-yl) -1-oxo-1H-6,7-dimethylthiazolo / 3,2-a / pyrimidine-2-carboxamide.

1-Oxo-1H-6,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (367 mg, 1.6 mmol) was dissolved in 3 ml dimethylformamide-20 by heating on a steam bath. 1,1-Carbonyldiimidazole (292 mg, 1.8 mmol) was added. Gas development immediately occurred. Once gas evolution ceased, 5-aminotetrazole (1.53mg, 1.8mmol) was added. Dissolution occurred and a new solid was formed. The reaction mixture was cooled and crude product was recovered by filtration. Recrystallization of the crude product from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-6,7-dimethylthiazolo / 3,2-a / pyrimidine-2-carboxamide (336 mg, m.p. 317 ° C).

Analysis calculated C H 2 O N 2 S: C 41.23; H 3.11; N 33.66;

Found: C 41.52; H 3.40; N 33.47.

Example LXVII

N- (Tetrazol-5-yl) -1-oxo-1H-6-methyl-7-ethyl thiazolo / 3,2-a-pyrimidin-2-carboxamide.

8006362 59 1-Oxo-1H-6-methyl-7-ethylthiazole CV 3,2-α / pyrimidine-2-carboxylic acid (238 rag, 1.0 ramol) was dissolved in 5 ml dimethylformamide and heated on a steam bath. 1,11-Carbonyldiimidazole (178 mg, 1.1 mmol) was added. After gas evolution had ceased, 5-aminotetrazole (93.5 mg, 1.1 mmol) was added. A solid started to precipitate after about 15 min. The reaction mixture was cooled and filtered to give N- (tetrazol-5-yl) -1-oxo-1H-6-methyl-7-ethylthiazolo / 3.2 -a / pyrimidine-2-carboxamide (227 mg, mp> 310 ° C) was obtained.

Analysis calculated cjjhjiO2N7S: C 43.27; H 3.63; N 32.11;

Found it; C, 43.20; H 3.72; N 31.88.

Example LXVIII

N- (Tetrazol-5-yl) -1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidin-2-carboxamide.

1-Qxo-1H-6-ethyl-7-methylthiazolo / 3,2-a / pvri-midine-2-carboxylic acid (467 mg, 2.0 mmol) was dissolved in dimethylformamide on a steam bath, 1.1- Dicarbonylimidazole (357mg, 2.2 20mmol) was added to the warm solution; gas development occurred. After gas evolution ceased, 5-aminotetrazole (187mg, 2.2mmol) was added. A solid started to form within minutes. The reaction mixture was cooled and crude product was recovered by filtration. Recrystallization from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-6-ethyl-7-raethylthiazolo / 3,2-a-pyrimidine-2-carboxamide (388 mg, mp. 303 ° C). C (dec.)).

Analysis calculated: C 43.3; H 3.6; N 32.1; Found: c 43.6; H 3.9; N 32.3.

Example LXIX

N- (Tetrazol-5-yl) -1-oxo-1H-6,7-diethylthiazolo / 3,2-a-pyrimidine-2-carboxamide.

35 1-Oxo-1H-6,7-diethylthiazolo / 3,2-a / pyrimidine-8006362 60 2-carboxylic acid (2.52 g, 10 mmol) and 1,1'-carbonyldiimidazole (1.78 g, 11 mol) were combined with 15 ml of dimethylformamide and heated on a steam bath. Gas evolution and dissolution occurred. After gas evolution had ceased, 5-aminotetrazole (1.13 g, 11.5 mmol) was added and heating was continued for 30 min. The reaction mixture was cooled and the precipitated solid product was recovered by filtration. Recrystallization of the crude product from acetic acid gave purified N- (tetrazol-5-yl) -1-oxo-1H-6,7-diethylthiazolo / 3,2-a / pyrimidine-2-carbonamide (1.11 g, mp.

283 ° C (dec.)).

Analysis calculated: ^ 12 ^ 13 ^ 2 ^^: C 45.13; H 4.10; N 30.70; mass ion, 319; Found: C 45.18; H 4.24; N 30.52; Mass ion, 319.

Example LXX

N- (Tetrazol-5-yl) -1-oxo-1H-cyclopentenothiazolo / 3,2-a / pyrimldine-2-carboxamide.

1-Oxo-1 H -cyclopentenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid (378 mg, 16 mmol) and 1,1'-carbonyldiimidazole (285 mg, 17.6 mmol) were combined with 3 ml dimethylformamide and heated on a steam bath; dissolving and gas development occurred. After gas evolution had ceased, 5-aminotetrazole (150 mg, 17.6 mmol) was added. Product started to precipitate within minutes. The reaction mixture was cooled and crude product was recovered by filtration. Recrystallization from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-cyclopentenothiazolo - [_ 3,2-a / pyrimidine-2-carboxamide (313 mg, mp> 310 ° C).

Analysis calculated: C 19 H 9 ° 2 N 7 S: C 43.6; H 3.0; N 32.3; Found: C 43.6; H 3.3; N 32.0.

Example LXXI

N- (Tetrazol-5-yl) -1-oxo-1H-cyclohexenothiazolo / 3,2-a-pyrimidine-2-carboxamide.

35 1 - Oxo - 1 H -cyclohexenothiazolo / 3,2-a / pyrimidine- 8 0 06 36 2 61 2 carboxylic acid (0.5 g, 2 mmol) and 1,1 * -carbonyldiimidazole (0.36 g, 2 , 2 mmol) were dissolved in 3 ml of dimethylformamide at room temperature; dissolution and gassing occurred. After gas formation had ceased, the reaction mixture was heated on a steam bath, during which time additional gas evolution occurred. 5-Aminotetrazole (0.19 g, 2.2 mmol) was added to the hot solution. The product started to precipitate within a few minutes. The reaction mixture was cooled and crude product was recovered by filtration. Recrystallization of the crude product gave purified N- (tetrazol-10 5-yl) -1-oxo-1 H -cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide (319 mg, mp 310 ° C (dec. )).

Analysis calculated: C 21 H 11 ° 2 N 7 S: C 45.42; H 3.49; N 30.90;

Found: C 45.59; H 3.62; N 30.44.

Instead, the acid (2.07 g) was dissolved in 40 ml of methylene chloride and 1.74 ml of triethylamine at 0 ° C. Ethyl chloroformate (0.85 ml) in 8.1 ml of methylene chloride was added over 20 min. while maintaining the temperature of the reaction mixture at 0-5 ° C. After 45 min at 0-5 ° C, 5-aminotetra-20 sole (0.87 g) in 8.1 ml dimethylacetamide was added, and the reaction mixture was warmed to 20 ° C over 25 min, and for 90 min. kept at this temperature. The product was recovered by filtration (2.0 g, mp 308-310 ° C). The product prepared in this way (3.9 g) was recrystallized from dimethylacet-25 amide to give purified N- (tetra2ol-5-yl) -1-oxo-1 H -cyclohexenothiazolo / 3,2-a / pyrimidine- 2-carboxamide (3.1 g, mp 314-315 ° C) was obtained.

The sodium salt of this amide was prepared by dissolving 5.5 g (17.3 mmol) of the amide in 14 ml of water and 17.3 ml (17.3 mmole) of standardized sodium hydroxide by stirring for 30 min ( pH 11.0). The solution was purified and the sodium salt was precipitated by adding 35 ml of acetone. The slurry was cooled to 5 ° C, granulated for 3 hours and the sodium salt (4.9 g) was recovered by filtration and washed with cold acetone. This sodium salt (100 mg), stored in 1 ml of water, had a pH of 8006362 62 10.22. The sodium salt was recrystallized by dissolving 2.3 g in 23 ml of water at 60 ° C. The clear solution was cooled at 5 ° C for 1 hour and granulated at this temperature for 1 hour.

The sodium salt (1.68 g) was recovered by filtration. The pH 5 of 100 mg of recrystallized sodium salt in 1 ml of water was 8.80.

Analysis calculated: C ^ 2 ^ g ^ N ^ SNa.3 ^ 0: ^ 0 13.7; weight loss on drying 13.7; neutralization equivalent 393.

Found: H 2 O 13.43; weight loss on drying 13.8; neutralization equivalent 391.

In the above-described mixed anhydride process, equivalent amounts of methyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, t-15 butyl chloroformate, pentyl chloroformate, phenyl chloroformate or benzyl chloroformate are used in place of ethyl chloroformate with the same results. Similarly, equivalent amounts of other acids as described in Examples XLVII-LXV can be reacted with chloroformates and then with 5-aminotetrazole to give the corresponding N- (tetrazol-5-yl) amides.

Example LXXII

N- (Tetrazol-5-yl) -1-oxo-1H-cycloheptenothiazolo / 3,2-a / pyrimidine-2-carboxamide.

25 1-Oxo-1H-cyclopentenothiazolo / 3,2-a / pyrimidine-2-carboxylic acid (2.1 g, 8 mmol) and 1,1'-carbonyldiimidazole (1.4 g, 8.8 mmol) were combined with 15 ml of dimethylformamide and heated on a steam bath. After gas evolution had ceased, 5-aminotetrazole monohydrate (0.86 g, 8.8 mmol) was added. A solid formed within 5 min. After heating for an additional 30 minutes, the reaction mixture was cooled and the product was recovered by filtration. Recrystallization of the crude product from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-cycloheptenothiazolo-35 / 3,2-a / pyrimidine-2-carboxamide (1.61 g, mp 295). -296 ° C (dec.)).

80 06 36 2 63

Analysis calculated: cjjh ^ 3 ^ 2N7S: C 47.12; H 3.95; N 29.59;

Found: C 47.10; H 4.11; N 29.72.

Example LXXIII

5 N- (Tetrazol-5-yl) -1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxamide.

1-Oxo-1H-cyclooctenothiazolo / 3,2-α / pyrimidine-2-carboxylic acid (308 mg, 1.1 mmol) was dissolved in 10 ml of dimethylforma-10 mide and heated on a steam bath. 1,1'-Carbonyldiimidazole (196 mg, 1.21 mmol) was added. After gas evolution had ceased, 5-aminotetrazole (103 mg, 1.21 mmol) was added. The reaction mixture was heated for 10 min, during which time a solid started to precipitate. The reaction mixture was cooled and the crude product was recovered by filtration. Recrystallization from dimethylformaraide gave purified N- (tetrazol-5-yl) -1-oxo-1H-cyclooctenothiazolo / 3,2-a / pyrimidine-2-carboxamide (183 mg, mp 310 ° C (dec. .)).

Analysis calculated: C14 H15 ° 2 N7 S: 20 C, 48.69; H 4.38; N 28.39;

Found: C 49.01; H 4.63; N 27.35.

Example LXXIV

N- (Tetrazol-5-yl) -1-οχο-1H-7-methylthiazolo / 3,2-a / pyrimidine-2-carboxamide.

25 l-Oxo-1H-7-methylthiazolo / 3,2-a / pyrimidin-2-carboxylic acid (0.91 g, 4.3 mmol) and 1,11-carbonyldiimidazole (0.89 g, 5.5 mmol ) were placed in 5 ml of dimethylformamide and heated on a steam bath. After gas evolution had stopped, 5-amino-30 tetrazole (0.47 g, 5.5 mmol) was added. Before completion of the dissolution, a new solid began to precipitate. After a few minutes, the reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-7-methylthiazolo / 3,2-a-pyrimidine-2-carboxamide (1.0 g, mp> 310 ° C).

80 06 36 2 64

Analysis calculated: C 1 H H O N N S: C 38.99; H 2.54; N 35.36;

Found: C 38.97; H 2.73; N 34.97.

Example LXXV

N- (Tetrazol-5-yl) -1-oxo-1H-thiazolo / 3,2-a / pyrimidin-2-carboxamide.

1-Oxo-1H-thiazolo / 3,2-α / pyrimidine-2-carboxylic acid (1.96 g, 10 mmol) was dissolved in 20 ml of dimethylformamide on a steam bath, 1,1'-Carbonyldiimidazole (1.78 g, 11.0 mmol.) was added. After gas evolution had ceased, 5-aminotetrazole monohydrate (1.13 g, 11 rranol) was added. A solid formed in less than 1 min. After heating for an additional 15 minutes, the reaction mixture was cooled and the crude product was recovered by filtration. Recrystallization from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-thiazolo / ~ 3,2-a / pyriraidine-2-carbonamide (1.8 g, mp> 315 ° C ).

Analysis calculated: C8 Hg Cl2 N2 S: C 36.50; H 1.91; N 37.25; Found: C, 36.62; H 2.26; N 37.72

Example LXXVI

N- (Tetrazol-5-yl) -1-oxo-1H-6-methyl-thiazolo / 3,2-a / pyrimidine-2-carboxamide.

25 1-Oxo-1H-6-methylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid (2.10 g, 10 mmol) and 1,1'-carbonyldiimidazole (1.78 g, 11 mmol) were combined with 15 ml of dimethylformamide and heated on a steam bath. Gas evolved and dissolution occurred. After gas evolution was complete, 5-aminotetrazole monohydrate (1.13 g, 11 mmol) was added. A solid formed in less than 1 minute. After heating for 5 min, the reaction mixture was cooled. Filtration gave N- (tetrazol-5-yl) -1-oxo-1H-6-methylthiazolo / 3,2-alpha pyrimidine-2-carboxamide (2.33 g, mp> 318 ° C).

Analysis calculated: C 8 H 4 O N 2 S: 8006362 65 C 38.99; 4 2.54; N 35.36;

Found: C 39.35; Η 3.00; N 35.06.

Example LXXVII

N- (Tetrazol-5-yl) -1-oxo-1H-6-ethylthiazolo / 3,2-a / pyrimidin-2-5 carbonamide.

1-Oxo-1H-6-ethylthiazolo / 3,2-a / pyrimidin-2-carboxylic acid (4.48 g, 20 mmol) and 1,1'-carbonyldiimidazole (3.57 g, 22 mmol) were added combined with 20 ml of dimethylformamide and heated on a steam bath. Gas evolution and dissolution occurred. After gas evolution had stopped, 5-aminotetrazole monohydrate (2.27 g, 22 mmol) was added. A solid formed within 1 minute. The reaction mixture was heated for an additional 15 min, then cooled and the crude product was recovered by filtration.

Recrystallization from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-6-ethylthiazolo / 3,2-a / pyrimidine-2-carboxamide (4.7 g, mp, 274 ° C) c (dec.)).

Analysis calculated: C 4 Hg O N N S: C 41.23; H 3.11; N 33.66; Found: C 41.41; H 3.30; N 33.84.

Example LXXVIII

N- (Tetrazol-5-yl) -1-oxo-1H-7- (2-methyl-2-propyl) thiazolo £ 3,2-a-pyrimidine-2-carboxamide, 25 1-Oxo-1H-7 - (2-methyl-2-propyl) thiazolo / 3,2-a-pyrimidine-2-carboxylic acid (2.52 g, 10 mmol) and 1,11-carbonyldiimida sole (1.78 g, 11 mmol) were combined with 15 ml of dimethylformamide and heated on a steam bath. Gas evolution and solution occurred and a solid formed within minutes. Heating was continued for a total of about 10 minutes.

The reaction mixture was cooled and crude product was recovered by filtration. Recrystallization from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-7- (2-methyl-2-propyl) thiazolo - [_ 3,2-a / pyrimidine-2-carboxamide (1, 62 g, mp 280 ° C (dec.)).

Analysis calculated: C 12 H 13 O 2 N 7 S: 8 0 0 6 3 6 2 66 C 45.13; Η 4.10; N 30.70;

Found: C 45.22; Η 4.40; N 30.05.

Example LXXIX

N- (Tetrazol-5-yl) -1-oxo-1H-7-ethylthiazolo / 3,2-a / pyrimidin-2-5 carbonamide.

1-Oxo-1H-7-ethylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid (502.5 mg, 2.24 mmol) and 1,1'-carbonyldiimidazole (399.7 mg, 2.46 mmol) were combined with 3 ml of dimethylformamide 10 and heated on a steam bath. Dissolution and gas development occurred. After gas evolution had ceased, 5-aminotetrazole monohydrate (253.0 mg, 2.45 mmol) was added. A clear solution was obtained; after 2 min. a solid started to precipitate. The mixture was heated for an additional 20 minutes, cooled to room temperature, and crude product was recovered by filtration. Recrystallization from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-7-ethylthiazolo / ~ 3,2-a / pyrimidine-2-carboxamide (486.8 mg, mp. 261-262 ° C (dec.)).

Analysis calculated: cigHgN7 ° 2S5 20 C 41.23; H 3.11; N 33.66; mass ion, 291.

Found: C 41.35; H 3.31; N 33.55; mass ion, 291.

Example LXXX

N- (Tetrazol-5-yl) -1-oxo-1H-7-isopropylthiazolo / 3,2-a / pyrimidin-2-carboxamide.

25 1-Oxo-1H-7-isopropylthiazolo / 3,2-a / pyrimidine-2-carboxylic acid (537 mg, 2.25 mmol) and 1,1'-carbonyldiimidazole (401 mg, 2.47 mmol) were combined with 3 ml of dimethylformamide and heated on a steam bath. Dissolution and gas development occurred. After gas evolution ceased, 5-aminotetrazole monohydrate (255mg, 2.47mmol) was added. Precipitation of product started immediately. Heating was continued for 20 minutes, then the reaction mixture was cooled and crude product was recovered by filtration. Recrystallization from dimethylformamide gave purified 35 N- (tetrazol-5-yl) -1-oxo-1H-7-sopropythiazolo / 3,2-a / pyrimidine-8006362 67 2-carboxamide (328 mg, mp,> 300 ° C ).

Analysis calculated: C 1 H H 2 N 7 S: C 43.27; H 3.63; N 32.11;

Found: C 43.34; H 3.76; N 31.82.

5 Example LXXXI

N- (Tetrazol-5-yl) -1-oxo-1H-7-phenylcyclohexenothiazolo / 3,2-a-pyrimidine-2-carboxamide.

1-Oxo-1H-7-phenylcyclohexenothiazolo / 3,2-a / pyri-10 midine-2-carboxylic acid (980 mg, 3.0 mmol) and 1,1'-carbonyldiimidazole (320 mg, 31 mmol) were combined with 12 ml of dimethylformamide and the mixture was heated on a steam bath. After gas evolution had stopped, 5-aminotetrazole monohydrate (496 mg, 3.1 mmol) was added. Product started to precipitate after 10 min. After heating for a total of 1 hour, the reaction mixture was cooled to room temperature and the crude product (312 mg) was collected by filtration. Recrystallization from dimethylformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-7-phenylclohexenothiazolo / 3,2-a / pyrimidine-2-carbon amide (131.5 mg, mp> 300 °) C).

Analysis calculated: C18 H19 gO2 N2 S: C 54.95; B 3.84; N 24.92;

Found: C 54.38; H 3.93; N 24.61.

Example LXXXII

N- (Tetrazol-5-yl) -1-oxo-1H-7-methylcyclohexenothiazolo / 3,2-a / pyri-2 midine-2-carboxamide.

1-0xo-1H-7-methylcyclohexenothiazolo / 3,2-α / pyrimidine-2-carboxylic acid (1.0 g, 3.78 mmol) and 1,1'-carbonyldiimidazole (675 mg, 4.16 mmol) were combined in 6 ml of dimethylformamide 30 and heated on a steam bath. Gas evolution occurred and the substance dissolved. After gas evolution had stopped, 5-aminotetrazole (429 mg, 4.16 mmol) was added and heating was continued. A precipitate started to form after a few minutes. After 30 min, the reaction mixture was cooled and crude product (mp.

35> 300 ° C) was recovered by filtration. Recrystallization from 8006362 68 dimethyiformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-7-methylcyclohexenothiazolo, / 3,2-a / pyrimidine-2-carboxamide (980 mg, mp> 300 ° C) .

Analysis calculated: Ο ^ Η ^ 02Ν73: 5 C 47.12? H 3.95? N 29.59?

Found: C 47.32? H 4.18? N 29, .60.

Example LXXXIII

N- (Tetrazol-5-yl) -1-oxo-1H-7,7-dimethylcyclohexenothiazolo / 3,2-a-pyrimidine-2-carboxamide.

10 1-Oxo-1H-7,7-dimethylcyclohexenothiazolo / 3,2-a / pyrimidin-2-carboxylic acid (558 mg, 2.0 mmol) and 1,1'-carbonyldiimida sole (357 mg, 2.2 mmol) were combined with 3 ml of dimethylforramide and heated on a steam bath; gas evolution occurred and the substance dissolved. After gas evolution had ceased, 5-aminotetrazole monohydrate (227 mg, 2.2 mmol) was added and heating was continued for 20 min. The reaction mixture was cooled and the crude product (561 mg, mp> 300 ° C) was recovered by filtration. Recrystallization from dimethyiformamide gave purified N- (tetrazol-5-yl) -1-oxo-1H-7,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxamide (469 mg, m.p. 300 ° C).

Analysis calculated: C 48.69? H 4.38? N 28.39?

Found: C 48.80? H 4.18? N 28.42.

25 Example LXXXIV

N- (Tetrazol-5-yl) -1-oxo-1H-7- (2-butyl) thiazolo / 3,2-a / pyriraidine-2-carboxamide.

1-Oxo-1H-7- (2-butyl) thiazolo / 3,2-a / pyrimidine-30 2-carboxylic acid (379 mg, 1.5 mmol) and 1,11-carbonyldiimidazole (270 mg, 1.66 mmol ) were combined in 3 ral dimethyiformamide and heated on a steam bath. Gas evolution occurred and the substance dissolved. After gas evolution had ceased, 5-aminotetrazole monohydrate (170 mg, 1.65 mmol) was added and the mixture, which started to precipitate after a few minutes, was stirred for 20 min.

8 0 06 36 2 69 heated. The reaction mixture was cooled to room temperature and crude product was recovered by filtration. Recrystallization afforded purified N- (tetrazol-5-yl) -1-oxo-1H-7- (2-butyl) thiazolo / 3,2-a / pyrimidine-2-carboxamide (247 mg, mp> 300 ° C).

Analysis calculated: C12H13 ° 2N7S: C 45.13; H 4.10; N 30.70;

Found: C 45.12; H 4.05; N 30.68.

Example LXXXV

According to the method of Examples 10 LXVI-LXXXIV, the following compounds are prepared from the corresponding 1-oxo-1H-thiazolo / 3,2-a / pyrimidin-2-carboxylic acids: N- (tetrazol-5-yl) -1 oxo-1H-7-pentyl thiazolo / 3,2-a / pyrimidine-2-carboxamide; N- (tetrazol-5-yl) -1-oxo-1H-6-ethyl-7-propylthiazoloi / 3,2-a-pyrimidine-2-carboxamide; N-ftetrazol-S-yD-1-oxo-1H-e-diisopropylthiazolo / 3,2-a-pyrimidine-2-carboxamide; N- (tetrazol-5-yl) -1-oxo-1H-6-propylthiazolo / 3,2-a / pyrimidine-2-carboxamide; N- (tetrazol-5-yl) -1-oxo-1H-6-isopropylthiazolo [3,2-a] pyrimidine-2-carbonamide; N- {tetrazol-5-yl) -1-oxo-1H-6-pentylthiazolo [3,2-a] pyrimidine-2-carboxamide; N- (tetrazol-5-yl) -1-oxo-1H-6-phenylcyclopentenothiazolo-25 / -3,2-a / pyrimidine-2-carboxamide; N- (tetrazol-5-yl) -1-oxo-1H-6,8-dimethylcyclohexenothiazolo - {_ 3,2-a / pyrimidin-2-carbonamide] N- (tetrazol-5-yl) -1-oxo— 1H-8-methylcyclooctenothiazolo [3,2-a] pyrimidine-2-carboxamide; and 30 N- (tetrazol-S-yl) -1-oxo-1H-6,8,8-trimethylcyclppentenomethylthiazolo / 3,2-a / pyrimidine-2-carboxamide.

Example LXXXVI

capsules

Capsules are manufactured by mixing the following ingredients in the weight ratios as indicated: 8006362 70

Calcium Carbonate U.S.P. 17.6

Dicalcium phosphate 18.8

Magnesium trisilicate, U.S.P. 5.2

Lactose, U.S.P. 5.2 5 Potato starch 5.2

Magnesin stearate a 0.8

Magnesium stearate b 0.35 and add enough sodium N- (tetrazol-5-yl) -1-oxo-1H-cyclohexenothiazolo - [_ 3,2-a / pyrimidine-2-carboxamide trihydrate to provide capsules. containing 10.25 or 50 mg of active ingredient (weight equivalent with the unsolvated, non-salt form) per capsule.

The compositions can be filled in conventional hard gelatin capsules in an amount of 350 mg per capsule.

Likewise, capsules containing 2.0 mg and 6.0 mg of active ingredient and containing 300 mg of the following mixtures per capsule are prepared:

Ingredients Wt. In mg / capsule

Medicine 2.00 N-methylglucamine 18.00 20 Lactose, anhydrous 251.20

Corn starch, anhydrous 8.80

Ingredients Weight in tog / capsule

Medicine 6.00 N-methylglucamine 18.00 25 Lactose, anhydrous 237.20

Corn starch, anhydrous 30.00

Talk 8.80

Example -LXXXVII

Tablets.

A tablet base is prepared by mixing the following ingredients in the weight ratio as indicated. Sucrose U.S.P. 80.3

Tapioca starch 13.2

Magnesium stearate 6.5 35 In this tablet base, sufficient sodium 8006362 71 N- (tetrazol-5-yl) -1-oxo-1H-cyclohexenothiazolo / -3,2-a / pyrimidine-2-carbonamide trihydrate is admixed with tablets containing 20, 100 and 250 mg of active ingredient per tablet. The compositions are each compressed into tablets by conventional means. For low strength tablets (eg 1mg, 2mg or 5mg), a lower ratio of active ingredient to inert ingredients is used in the tablet base.

Example LXXXVIII

Solution.

A solution of sodium N- (tetrazol-5-yl) -1-oxo-1H-cyclohexenothiazolo / 3,2-a / pyrimidine-2-carboxamide is prepared as follows:

Active ingredient: 6.04 g (7.49 sodium salt, trihydrate)

Magnesium chloride hexahydrate: 12.36 g

Propylene glycol: 376.00 g

Distilled water 103 ml

The resulting solution has an active ingredient concentration of 10 mg / ml and is suitable for parenteral and in particular for intramuscular administration.

Example LXXXIX

Aerosol suspension.

For use particularly as an anti-allergy agent, a mixture of sodium N- (tetrazol-5-yl) -1-oxo-1H-cyclohexenothiazolo / 3,2-α / pyrimidine-2-carboxamide with the other components under (a) in the tables immediately below are marinated to a particle size of 1-5 µm in a ball mill. The resulting slurry is then placed in a container fitted with a valve and a propellant (b) is added by pressure filling through the valve nozzle to an O Λ gauge pressure of 2.45-2.8 kg / απ at 20 C.

35 8006362 72

Suspension 1% _ (a) Anti-allergy agent (equivalent to non-solvated, non-salt) 0.25

Isopropyl myristate 0.10 5 Ethanol 26.40 (b) 60-40% mixture of 1,2-dichloro-tetrafluoroethane-1-chloropentafluoroethane 73.25 10 Suspension 2jfe (a) Anti-allergy agent (equivalent to no - solvated, non-salt) 0.25

Ethanol 26.50 15 (b) 60-40% mixture of 1,2-dichlorotetrafluore thane-1-chloropentafluoroethane 73.25

Suspension 3 (a) Anti-allergy agent (equiv. To 20 unsolvated, non-salt) 2.00

Ethanol 26.50 (b) 60-40% mixture of 1,2-dichlorotransfluoroethane-1-chloropentafluoroethane 71.50 8 0 06 36 2

Claims (12)

1. Novel 1-oxo-1H-thiazolo / 3,2-a / pyrimidine-2-carboxamides and derivatives thereof, of formula 26, wherein R 1 and R 1 together are an alkylene group of 3-9 carbon atoms or a phenyl-alkylene group of 9-11 carbon atoms provided the ring system so formed is a 5- to 8-ring; R 1 and R 1 are each hydrogen or an alkyl group of 1 to 5 carbon atoms; and Q is a tetrazol-5-ylamide group or a -OR group, wherein R 1 is hydrogen, a short chain alkyl group of 1-3 carbon atoms, a carbaloxy group of 2-5 carbon atoms, a carbophenoxy, or a carbobenzoxy group, that when R 1 is hydrogen or a short chain alkyl group and R 1 is hydrogen, R 1 is not hydrogen or methyl group, and when a short chain is alkyl group and is a methyl group, R 1 is not hydrogen; or a pharmaceutically acceptable cationic salt thereof, when Q is a tetrazol-5-yl-amide group or an -OR ^ group and R1 is hydrogen, A compound according to claim 1, characterized in that Q is a tetrazol-5-ylamide group. 3. A compound according to claim 2, characterized in that R 1 and R 2 together form a butylene group. Compound according to claim 2, characterized in that R 1 is hydrogen and R 2 is a methyl group. Compound according to claim 2, metffite characterized in that R1 is an ethyl group and R2 is hydrogen. A compound according to claim 2, characterized in that R 1 is a methyl group and R 2 is hydrogen. 7. A compound according to claim 1, characterized in that Q is a group -OR ^ and R ^ is hydrogen. 8. A compound according to claim 7, characterized in that R 1 is an ethyl group and R 2 is hydrogen. 9. A compound according to claim 1, characterized in that Q is an OR ^ group and R3 is a short chain alkyl group with 1-3 carbon atoms. 10. A compound of formula 27, characterized in that R 'is a short chain alkyl group with 1-3 carbon atoms, R' and 8006362 Rj together an alkylene group with 3-9 carbon atoms or a phenyl-alkylene group with 9- 11 carbon atoms form whether R 1 and R 2 are each hydrogen or a short chain alkyl group of 1 to 5 carbon atoms, provided that when R 1 is hydrogen, R 2 is not hydrogen or methyl group and when R 1 is methyl group, R 2 is not hydrogen. 11. Novel 1-oxo-1H-thiazolo / 3,2-a-pyrimidine-2-carboxamides and derivatives thereof, as described herein. 10 _ 8 0 06 36 2 R, Ri xv. v_-c '' 'γ "S \ γ-S Γ 1 Π LII R. ^ An 0AJ oV« V "✓%" _ ƒ I </ ° χ ° η i' N— N 2, - <'h 3 * CHt—- ^ Hj CHj CHi CH, / CH ^ CH,) 0χ CH,. CHt CHj XV CHj Iu 4 chj ch3 5 6 ch * 7 XHj.— CHj ^ xCH \ CHj. - CH * - -. CH, CH - CHj— / I 1 x '' CHj —CH CHS-CH CH * \ XcH.— ^ CH * -CH * '' CHt- CHj 8 9! 0, ", _ c" ^ ίΛ / "V £ C ' KC, HI CH * CH * u CH * X / \ 1J ^ CHi— CHj ^ "CH *., CH, * 11 12 NN _ / I CHi ^ / CHl \ ^ CHt— CH * .. VN n C CjHj-CH I CtHi ^ XCHa- CH * "'H} g XchX" u 15 8 0 0 6 36 2 PFIZER INC., Te New York, New York, United States of America ^ n = - N 1 ^ 1 \ if ^ N '^> N— N \ A 3 / OkJvM XH N XNX 17 18 19 CO CO% ”” AJ / T ^ \ --- i χχ__ 22 \ 1 ^ ylP // ^ S n ^ n \ r * \ ii mi 23 ° ^^ 24 n <n \ -S «Τ ο CO Μ XI 25» V .8> .Cx 0. I, 27 26 f * o -B- 'V' n o \ nA-m II ll r 'κι N N II + Cl-C-OR RNN. I oM 0AX * RjN.HCl ^ O-C-OR II 8 0 06 36 2 o PFIZER INC., New York, New York, United States of America “A. / R>> - ^ / 4 -0CiHr JTX + -5- ^ Re "" ^ NH2 h Rn Ri ^. n 1 _e 1 "TS 14 rj L% ύ Dowthcrm A JU I NH Δ RaT ™, N OR. I or" Χίβ '0 ^ 0¾ O **' 'OR ^ H + j Ha0' 'R1 - ^, _- .N- N Rl ς jp | ** - <ii 1Γ1 Rl Ν "ΛΝ N_ N N- ^ N n <kJ H 0AJ 0. N-N dehydrating A / II N-N or I via mixed acid anhydride 8006362 PFIZER INC., New York / New York / United States America