SE448732B - N- (5-TETRAZOLYL) -1-OXO-1H-TIAZOLO / 3,2-A / -PYRIMIDIN-2-CARBOXAMIDES WITH ANTI-ALLERGIC AND ANTIULCEROS EFFECTS AND THE SIMILAR 2-CARBOXYL ACID - Google Patents

Description

40 448 732 2 phylactic. The disadvantage is that it is not effective for oral administration and for optimal results it must be administered by inhalation in solid form.

Later, a number of other antiallergic agents have been described, e.g. N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimido- [1,2-a] quinoline-2-carboxamides (Kadin, U.S. Pat. No. 4,017,625), 1-oxo-1n-a - (substitute pyrimino-nz-αq-quinoline-2-carboxylic acids (Kadin, U.S. Pat. No. 4,066,766), tetrazolo [a] quinazol-5-ones (Bindra, U.S. Pat. No. 4,085,213), pyrimido [2 , 1-a] isoquinolines (Jubyoa, U.S. Pat. No. 4,127,720) and N- (5-tetrazoyl) -4-oxo-4H-pyrimido [2,1-b] benzothiazole-3-carboxamides (Bindra and Kadin , U.S. Pat. No. 4,041,163).

Chronic gastric ulcer and duodenal ulcer, commonly referred to as ulcer peptica, is a common disease for which a number of treatment methods have been developed. These depend on the severity of the disease and can range from diet and medication to surgery. A large number of medications have been used to treat ulcers. The most recent is carbene oxolone sodium, ie the disodium salt of hemisuccinate of glycyrretinic acid, and this has been widely noticed. It is reported to prevent the onset of gastric ulcers in animals including humans and to accelerate the healing of pre-existing wounds ("Carbenoxolone Sodium: A Sumposium", J. M. Robson and F. M. Sullivan, Eds., Butterworths, London, 1968). However, its use is accompanied by unwanted aldosterone-like side effects, such as marked antidiuretic and sodium-retaining activity and frequent potassium loss, which is why continuous therapy with this drug often leads to hypertension, muscle weakness and finally congestive heart failure. Even later, a histamine receptor antagonist, the drug cimetidine, has been introduced in medical practice. This relieves ulcers by reducing gastric acid secretion.

Several other compounds have been reported to have antiulcer activity, e.g. 1-oxo-1H-6-piperidinopyrimidino [1,2-a] quinoline-2-carboxylic acid esters (Kadin and Moore, U.S. Patent 4,014,881), 1-oxo-1H-6-substituted pyrimido [1,2 -a] quinoline-2-carboxylic acids and esters VV) 9/40 3 448 732 (Kadin and Moore, U.S. Pat. No. 4,031,217), tetrazolo [a] quinazol-5-ones (Bindra, U.S. Pat. No. 4,085 213).

The amides and most acid precursors of the present invention are novel compounds. The known acids are those having the form II, wherein R 1 and R 2 represent hydrogen or R 1 methyl and R 2 hydrogen (Dunwell et al., J.

Chem. Soc. (C) 1971, 2094. The corresponding ethyl esters are also known together with the ethyl ester in which R; is methyl and R 2 is hydrogen (Dunwell et al., J. Chem. Soc.

(C) 1971, 2094; Allen et al., J. Org. Chem. 24, 779/1959 /).

These publications do not describe the use of the acids or the esters.

It has now been found that compounds of the general formula R1 Rz N \ N (I) and pharmaceutically acceptable cationic salts thereof when administered orally are effective antiallergic and antiulcer agents. In formula I, each of R represents; and R; hydrogen or lower alkyl having 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, 2-methyl-2-propyl (t-butyl), 2-butyl, 2-methyl-1-propyl (isobutyl), pentyl, etc. or R 1 and R 2 together represent alkylene having 3-9 carbon atoms, for example: c 44 ha 1, cm 2; I / \ \ cH2 \ cH \ en, ac \ / I / GHz CH 2 CH \ 2 (lïHg \ C32 /> c <C212 / C112 CH; C113 C112 / f * cH \ CH fen? CHZ / ca 2 ~ Tag CH: cH g-cß fm; CH2 ~ CH f ° H2 \ cr1f CH; cH 2 / cH2-c1a, \ TP "c fi z CH gíc fl g? Or phenylalkylene with 9-11 carbon atoms, for example: CQH5 CH1 / CH2 \ cH \ cH2 \ c I, / 'I, / ”/// I cnz csns-clm csns CHZ 2 C32 cnz CHZ / cnz / cH2-cæ12 \ Cans-CH CH 2" "CHQ? wherein R1 and R; together form a third 5- to 8-joint ring system.

It has also been found that acids of the general formula (M) wherein R1 and R2 have the meanings given above are not only valuable intermediates for the synthesis of the amides, but in many cases together with their pharmaceutically acceptable cationic salts also has useful biological activity. Acids with useful antiallergic activity are those in which R; and R 2 together form the alkylene having 4-9 carbon atoms or the phenylalkylene having 9-11 carbon atoms, provided that the ring system thus formed is 5- to 8-membered, or those in which R 1 represents alkyl having 2-5 carbon atoms and R; hydrogen or alkyl of 1-5 carbon atoms. The preferred acids for use as antiallergics are those in which R; and R 2 together form alkylene having 4-6 carbon atoms, preferably butylene. Acids of any other structure have useful antiulcer activity, namely those in which R 1 and R 2; together the alkylene having 3-9 carbon atoms or the phenylalkylene having 9-11 carbon atoms, provided that the ring system thus formed is 5- to 8-membered, or those in which each of R 1 and R 2 represents hydrogen or alkyl having 1- 5 carbon atoms, provided that when R 2 is hydrogen, R 1 represents one of the other groups with the exception of hydrogen and methyl. In this case, the preferred compounds are those in which R 1 and R 2 represent separate substituents, especially when R; is ethyl and R 2 is hydrogen or alkyl of 1-2 carbon atoms.

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

The 5-substituted tetrazoles, as is well known, can exist in isomeric forms, namely '' ° \ H H which coexist in a dynamic tautomeric equilibrium mixture. Both forms of the tetrazolylamides fall within the scope of the present invention.

The compounds of the present invention of particular interest are those of formula I, wherein R 1 represents hydrogen or methyl and R 2 represents methyl. Of these compounds, those in which R; is hydrogen, since the corresponding acid, which is assumed to be its metabolite, also shows activity. Of particular interest are also those compounds in which R 1 and R 2; together represent propylene, butylene or pentylene. Particularly desirable is the compound in which R 1 and R 2; together represent butylene, i.e. N- (5-tetrazolyl) -1-oxo-1H--cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide of the formula NN o / Ng o / cÉH-š T / N (III) Since it exhibits excellent oral activity and is highly stable in the 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 tetrazolylamide III is the sodium salt (trihydrate), which is not hygroscopic and has good water solubility, which ensures good bioavailability.

The antiallergic properties of the compounds of the present invention have been evaluated by means of tests for passive skin anaphylaxis (PCA test, Ovary, J.

Immun., 31, 355, 1958). In PCA testing, intradermal (i.d.) injection on normal animal antibodies from serum obtained from actively sensitized animals is administered. The animals are then administered intravenously a dose of antigen sufficient for reaction mixed with a dye such as Evan's Blue. The increased capillary permeability caused by the antigen-antibody reaction causes the dye to leak from the site of the antibody injection. The experimental animals are then suffocated and the intensity of the reaction is determined by measuring the diameter and intensity of the blue staining on the inside of the animals' skins.

The antiulcerous activity of the compounds according to the invention is evaluated by the so-called "cold re- straint stressed rat assay". Alternatively, the antiulcerative activity is determined by means of a newly prepared test, described in more detail below, in which ethanol induces ulcers in rats (see page 10, lines 5, 6 and 7).

Detailed Description of the Invention The compounds of the invention are prepared according to the following reaction scheme: S OC2Hs 1 Å + (RgÛoc) 2C = C </ Nm H 40 448 732 s R1 R1 IG 5 Q 3 /} V 7 // J \\\ R2 N NH DOWTHERM A * R2 N \ * \ N ïR3 l eller // j 2 C / H (CF3co), o 0 O af ”\\\ C, / '| 0474L \\ OR C 3 / o / \ oR3 H *, H20 f »HN R1 2 Q R1 s 6 S '"' ss 1 Å 1 Å R2 \\\ R, N \\\ N 3 Dehydrative coupling 1 3 1 3 // I or via mixed% /// ° anhyaria 0 \ N ß ¿; íC \\\ o \\ NH IH o on N / NH * Regarding Dowtherm A, see page 10, line 5.

In the first synthesis step, appropriately substituted 2-aminothiazole is condensed with a stoichiometric amount of a dialkylethoxymethylene malcnate, usually with the readily available diethylethoxymethylene malonate.

The choice of ester is not critical to obtaining the desired salt product of the invention. The condensation is carried out at a temperature between about 80 ° C and about 12 ° C. Lower temperatures are undesirable, because at these the reaction proceeds at too low a speed.

Higher temperatures can be applied but do not seem to provide any benefits. Accordingly, the reaction is conveniently carried out in a melt. It can of course be carried out in a solvent or in a mixture of solvents, for example ethanol, N, N-dimethylformamide or acetonitrile, but for practical reasons solvents are unnecessary. The condensation products are 4- and / or 5-substituted 2-- (2,2-dicarboxyethylamino) thiazoles. It is to be noted that when R 1 and R 2; together form a ring system, the nomenclature and the numbering are modified as follows: S S 1 1 vi w / Cyclopentenothiazole Cyclohexenothiazole S 1 |. 3 / Cycloheptenothiazole Cyclootenothiazole An alternative nomenclature for cyclohexenothiazoles is tetrahydrobenzothiazoles.

In the second synthesis step, the 4- and / or 5-substituted 2- (2,2-dicarbalkoxyethenylaminothiazoles are cyclized to eliminate one equivalent of alkanol (ethanol is eliminated from the ethyl ester). In one process, this cyclization is accomplished by heating the intermediate to a temperature between about 175 and about 250 ° C, until the reaction is substantially complete, which usually takes place in 1-2 hours.The cyclization is conveniently accomplished by heating the intermediate in a suitable, reaction-inert diluent, namely in a compound which enables the control of the reaction temperature, is stable even up to the relatively high temperatures used and which does not react with the starting material or the cyclizing products. Among representative diluents of this kind may be mentioned high-boiling hydrocarbons, such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphen yl, in particular a mixture of 26.5% diphenyl and 73.5% diphenyl ether (a product marketed under the registered trademark "Dowtherm A").

The cyclization is alternatively carried out under mild 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, for example toluene, until the reaction is completed (for example after 15-20 hours at the reflux temperature of toluene). In any of these processes, the products of the cyclization step are alkyl 1-oxo-1H-6- and / or -v-substituted thiazolo [s, z-a] pyrimain-z-carboxylate.

It is to be noted that when R; and R 2 together form a ring system, the nomenclature and the numbering are modified as follows: / Ä 1 N g NN q N l 3 l 3 2 ”2 / OO 1-oxo-1H-cyclopenteno-1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine ewa '1-oxo-1H-cyclohepteno-1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine thiazolo [3,2-a] pyrimidine thiazolo [3,2- a] pyrimidine Û 2532 40 11 448 732 The compounds 1-oxo-1H-cyclohexenothiazolo- [3,2-a] pyrimidines are alternatively referred to as 6,7,8,9-tetrahydro-1-oxo-1H-pyrimidino [2, 1-b] benstiazoles, or (using an alternative numbering system) 5,6,7,8-tetrahydro-4-oxo-4H-pyrimido- [2,1-b] benstiazoles.

It is obvious that the condensation and cyclization steps can be carried out in a single operation without the need to separate the intermediate 2- (2,2-carbalkoxyethenylamino) thiazole either by using a sufficiently high reaction temperature, so that both condensation and cyclization are achieved, el. by condensation in the manner indicated above, followed by the addition of an inert solvent (if not already present) and an excess of trifluoroacetic anhydride (2.1-4 equivalents), whereupon the cyclization is carried out.

The preferred process comprises the separate condensation and cyclization steps described above. By isolating the intermediate product and subsequent purification thereof before cyclization, a better quality of the cyclized product is generally achieved.

The esters obtained by the above condensation / cyclization are then hydrolyzed to and / or -7-substituted thiazolo [3,2-a] pyrimidine-2-the corresponding 1-oxo-1H-6-carboxylic acids. (Note the nomenclature and the modified numbering systems described above, when R; and R2 together form a third ring). Acid-catalyzed hydrolysis is preferred. A particularly suitable method is refluxing the ester in 48% hydrobromic acid until the hydrolysis is complete (0.5-3 hours of refluxing generally gives satisfactory results). If foaming is a problem, the hydrolysis can be carried out at a slightly elevated pressure, for example at an overpressure of 48 kPa and a temperature of 85 ° C.

The N- (5-tetrazolyl) amides of the invention are conveniently prepared by dehydrating coupling of the acids with 5-aminotetrazole. Dehydrating coupling is accomplished by a large number of different means commonly used for peptide synthesis. Representative of such agents are N, N'-carbonyldiimidazole, N, N'-carbonyldi-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphenyl ketene-p-tolylimine, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine , ethylene chlorophosphite, diethylethylene pyrophosphite, N-ethyl-5-phenylisoxazolium-3'-sulfonate, phenylphosphorodi- (1-imidazolate), and carbodiimides such as dicyclohexylcarbodiimide, 1-cyclohexyl-3- (2-morpholine) (2-morpholine) 3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride, and diethylcyanamide.

The above coupling agents are generally reacted first with the acid and the product thus obtained is then reacted without isolation with 5-aminotetrazole to the desired 1-oxo-1H-6- and / or -7-substituted thiazolo [3,2-a] pyrimidine . (Note the above nomenclature systems and modified numbering systems, when R; and R2 together form a third ring).

The reaction is carried out in a solvent system inert to the reaction, in which the acid need not be soluble. The only requirement for the solvent system is that it does not react to any appreciable degree with the reactants or with the products. Due to the large number of coupling agents that can be used for the dehydrating coupling, a large selection of solvents is made possible. Representative solvents are N, N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction between the acid and the coupling agent is carried out at a temperature between about 20 and about 110 ° C. The reactive intermediate is then reacted with 5-aminotetrazole at a temperature between about 20 and about 110 ° C. Each of these steps is conveniently carried out at a temperature between about 50 and about 100 ° C, since within this temperature range the reaction yields are improved.

The molar ratio of acid coupling agent: 5-aminotetrazole is generally between about 1: 1: 1 and about 1: 1.1: 1.1. Higher coupling agent ratios: 5-aminotetrazole can be used, but provides no benefits. surplus of 10 mole percent is satisfactory.

It is obvious to the person skilled in the art that all the reactants can be added at once instead of, as stated above, stepwise. However, earlier formation of the reactive intermediate (the product of acid and coupling agent) normally gives better yields of the desired N- (5-tetrazolyl) amides.

Alternatively, the desired amides can be synthesized by coupling the acids with 5-aminotetrazole using the procedure using a mixed anhydride. In this case, the acids are first converted in situ to tertiary amine salt in the presence of an excess of 1 to L1 molar of the amine. A number of tertiary amines (R'3N) are suitable for this purpose. Examples which may be mentioned are triethylamine, N-methylpiperidine, N-methylmorpholine, dimethylaniline and quinoline. Suitable inert solvents are methylene chloride, chloroform, dimethylformamide and dimethylacetamide. It is preferred that the acid be completely dissolved in the excess tertiary amine, which may require a period of stirring, if necessary, with gentle heating. The solution of the amine salt is then reacted with an equivalent of alkyl (for example ethyl), benzyl or phenyl chloroformate at a temperature between -40 and + 25 ° C, preferably between -10 and + 10 ° C, to produce a mixed anhydride: 40 448 732 14 \ N) \ N (å ngn Nw / .šu + cl-c-on ___ »+ R-.Nmcl // // ooc / \ C 0 / \ o 'O O -% - OR in solution. Without insulation For example, the mixed anhydride is reacted directly with 5-aminotetrazole, preferably dissolved in an inert solvent of the same type as that used to prepare the mixed anhydride, to produce the desired N- (5-tetrazolyl) amides. The reaction is usually initiated at a low temperature (for example between -40 and + 15 ° C) but the temperature of the reaction mixture is then allowed to rise to higher values (for example 15-40 ° C) to complete the reaction.Typical molar ratios acid: amine: chloroformate -aminotetrazole is between 1: 2: 1: 1 and 1: 2.1: 1.1: 1.1.

Both the amides and the acids act as intermediates for the pharmaceutically acceptable cation salts according to the invention. The salt formation is effected by reacting the amides or acids with a suitable metal salt (for example a carbonate, an ethyl hexanoate, an alkoxide or a hydroxide) or with a suitable amine in a suitable reaction medium such as water, methanol or ethanol, all in accordance with with well-known practice. The salts are recovered by standard methods, such as filtration, if they are insoluble in the reaction medium, by evaporation of the solvent, if they are soluble in it or by precipitation by the addition of a non-solvent for the salt.

Many of the 2-aminothiazoles required as starting materials are described in the literature. The rest can be prepared by condensation of the appropriate α-haloketone with thiourea or by condensation of the appropriate aldehyde with thiourea and sulfuryl chloride, as illustrated in specific examples. u-halogen ketones, if not available in the literature, can be prepared according to standard procedures, for example by halogenation of ketones (for example according to Catch et al., J. Chem.

Soc., 272/1948 /; Levine, Org. Synthesis Coll. Vol. II, 88/1943 /; Buchman et al., J. Am. Chem. Soc. 67, 400/1945 /), by reacting hydrogen halide with diazocetones (see, for example, Catch et al., J. Chem. Soc., 278/1948 /; Lutz et al., J. Org. Chem. 12, 767/1947 /; Wagner et al., J. Am. Chem. Soc. 72, 2884/1950 /), decarboxylation of α-halo-B-keto acids (McPhee et al., J. Am. Chem.

Soc. 66, 1132/1944 /), and spontaneous cleavage of dibromo derivatives of alkenyl esters (see, for example, Slanina et al., J. Am. Chem. Soc. 58, 891/1936 /).

The reactions in the synthetic sequence leading from 2-aminothiazoles to the acids and N- (5-tetrazolo) amides of the present invention are conveniently monitored by standardized thin layer chromatography on silica gel plates containing a UV indicator, which can be commercially available from a variety of sources. . The eluent is adapted to the reaction and the nature of the substituents, so that Rf values are obtained between 0 and 1.0 and so that the intermediates which react and the product formed in the reaction are differentiated. Eluents particularly suitable for thiazole formation, condensation cyclization and hydrolysis reactions in the process of the present invention are chloroform / 1% ethanol, while hydrolysis and conversion of acids to N- (5-tetrazolyl) amides are best monitored using of chloroform / 5% acetic acid. It is well known to those skilled in the art in question that if materials tend to move too fast (ie in the solvent front), the polarity of the eluent can be reduced. If material tends to move too slowly, the polarity of the eluent may be increased.

Such chromatography is used to assess the completeness and purity of the reaction, but it can also be applied to further optimize the reaction conditions (concentration, time, temperature, solvent, etc.).

The products of the invention and pharmaceutically acceptable salts thereof are useful as prophylactics for inhibiting or preventing the release of mediators of anaphylaxis (allergy, immediate hypersensitivity reactions) and the occurrence of allergic symptoms in mammals. For this purpose they can be administered alone or in the form of mixtures with other agents, for example with theophylline or sympathomimetic amines. The products according to the invention are also useful as antiulcer agents. These products not only accelerate the healing of ulcers but also prevent the formation of ulcers and reduce the release of stomach acid in animals including humans. They can therefore be said to be useful for the treatment of gastric ulcers.

The valuable compounds of the invention may be administered alone, but will generally be administered together with a pharmaceutical carrier selected having regard to the mode of administration and standard pharmaceutical practice. By way of example, they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, caramels, powders, aerosol sprays, 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, pharmaceutical preparations according to the present invention intended for oral administration may conveniently be sweetened or flavored by various means of the type commonly used for this purpose.

Carrier and volume ratio active ingredient: carriers are selected having regard to the solubility and chemical nature of the therapeutic compounds, the mode of administration and standard pharmaceutical practice. For example, when the compounds of the present invention are administered orally in the form of tablets, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate may be used. Various disintegrants, such as starch, alginic acids and certain silicate complexes, together with lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, can also be used in the manufacture of tablets for oral administration of these compounds. As pharmaceutically acceptable carriers for oral administration in capsule form, preferred materials include lactose and high molecular weight polyethylene glycols. When water suspensions are used for oral administration, the compounds according to the invention can be combined with emulsifiers or suspending agents. Diluents such as ethanol, propylene glycol, glycerol and chloroform as well as combinations thereof and other materials may be used.

For parenteral administration and inhalation, solutions or suspensions of these compounds in sesame or peanut oil or aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the soluble, pharmaceutically acceptable salts described herein. These special solutions are particularly suitable for intramuscular and subcutaneous injection, when such a mode of administration is desired. Aqueous solutions, including those of salts dissolved in pure distilled water, are also useful for intravenous injection, provided that their pH has been adjusted in advance to a suitable value. Such solutions should suitably also be buffered, and, if necessary, the liquid diluent must first be made isotonic with a sufficient amount of saline or glucose.

When used as prophylactic agents or to prevent the release of anaphylaxis mediators, the compounds may be administered by inhalation.

Mixtures suitable for inhalation may contain (1) a solution or suspension of the active ingredient in a liquid medium of the above kind for administration by means of a nebulizer; (2) a suspension or solution of the active ingredient in a liquid propellant, such as dichlorodifluoromethane or chlorotrifluoroethane for administration from a pressure vessel; or (3) a mixture of the active ingredient and a solid diluent (for example lactose) for administration by means of a powder inhaler. Formulations suitable for inhalation using a conventional nebulizer contain between about 0.1 and 1% of active ingredient. The formulations used in pressure vessels contain between about 0.5 and about 2% of active ingredient. In powder inhalation formulations, the active ingredient: diluent ratio may be between about 1: 0.5 and about 1: 1.5.

Taking full account of the above factors, an effective daily oral dose of the anti-allergic or antiulcer compounds of the invention when administered to humans may be between about 10 and about 1500, preferably between about 10 and 600 mg per day administered in a single dose or in several sub-doses or you can administer between about 0.2 and about 12 mg / kg body weight. These values are given by way of example only and in individual cases larger or smaller doses may of course be required. With careful monitoring, you can dose up to about 2 degrees per day.

When administered parenterally for both purposes or when inhaled as an antiallergic, the effective daily dose is between about 0.05 and about 400, preferably between about 0.25 and about 200 mg per day or between about 0.005 and about 4 mg / kg body weight. , the administration being carried out in the form of a single dose or in the form of partial doses.

It is necessary that the active ingredient constitutes such a proportion of the mixture that a suitable dosage form is obtained. Of course, several dosing units can be administered approximately simultaneously. Although in some cases formulations containing less than 0.005% by weight of active ingredient may be used, it is preferred to use formulations containing at least 0.005% of active ingredient, otherwise the amount of carrier will be too large.

The activity increases with the concentration of the active ingredient. The mixture may contain 10, 50, 75, 95 or even a higher weight percent of active ingredient.

PCA testing is a measure of the antiallergic activity (particularly anti-asthmatic activity) of a compound. Compounds that inhibit a positive PCA test induced by the rat immunochemical counterpart to human immunoglobulin E (IgE) or reagin are considered to have antiallergic activity (C. Mota, Ann. N.Y. Acad.

Sci., 103, 264 1963). Reagin is mainly immunoglobulin E (IgE) and is the main immunoglobulin responsible for allergic asthma, anaphylaxis, hay fever, food sensitivity and some manifestations of drug sensitivity, although recently presented evidence attributes antibodies of the class IgG an essential role in the transmission of allergic diseases). When such compounds are administered to a sensitized individual (animal or human) before the individual comes into contact with antigens or substances to which it is allergic, they prevent the allergic reaction which would otherwise occur. Consequently, they provide a method for the prophylactic treatment of allergies or anaphylactic reactions of a reagin-mediated nature.

In other words, such compounds block the release of mediators resulting from the antigen-antibody reaction (the allergic reaction) as elucidated in the PCA test using rat homocytotropic antibody (a known correlate to human reagent antibody). Inhibition of Reaginic Antigen-Antibody Reactions in Rats (Experimental Animals in the PCA Test) is considered representative of the inhibition of human reaginic antigen-antibody reactions, which occur during allergic episodes.

The PCA reaction test performed to evaluate the compounds of the present invention shows excellent correlation between the activity of the compounds tested and their use in the treatment of allergic asthma. The ability of the agents to intervene in the PCA reactions is assessed in male rats (Charles River Wistar) with a body weight of 170-210 g. Reaginic antiserum rich in IgE antibodies is prepared according to Petillo et al., Int. Arch. Allergy, 44, 309 (1973). Hyperimmunantiserum rich in IgG antibodies to chicken egg albumin was prepared according to Orange et al., J. Exptl. Med., 127, 767 (1968). 40,448,752 2 ° Forty-eight hours before the antigen test, reagent serum was injected i.d. in the normal, shaved back skin of a rat. Five hours before the antigen test, hyperimmunantize was similarly injected. In a third place, i.d. 60 mcg of histamine dihydrochloride and 0.5 mcg of serotonin creatinine sulphate just before the antigen test as a check for antihistamine blocking, anti-serotonin blocking and blocking of unspecified types. The compounds of the present invention or saline were then administered i.v. and immediately thereafter, the antigen test was performed with 5 mg of egg albumin and 2.5 mg of Evan's Blue in saline. For oral administration, Evan's Blue and egg albumin were administered 5 minutes after drug administration. Thirty minutes later, the experimental animals were suffocated with chloroform and the dorsal skin was removed, after which its inside was subjected to examination. Each injection site was assigned a score equal to the product of the site diameter in mm and a number of 0.1; 0.5; 1; 2; 3 or 4 which was proportional to the color intensity. The score for a given injection site was summed for each group of 5 experimental animals and compared with the saline-treated control animals. The difference was expressed as percentage block due to the compound used.

Compounds representative of those according to the present invention were tested for antiallergic activity according to the above procedure and the activities thus obtained are stated as degree of protection (%). Intal, disodium cromoglycate, a commercially available antiallergic was not used as a comparison, as it is not active in oral administration.

The compounds of formula I (amides) and II (acids, R; = hydrogen) tested by the PCA test for antiallergic activity have been compiled in Tables 1 and 2. Table 1 448 732 Oral activity (degree of protection,%) determined at PCA test for amides of the formula I IQE mg / kq IJG Ing / kg R1 R2 1 3 10 30 1 3 10 30 c fl a cna ss 51 CH; C2H5 75 57 C2H5 CH3 29 28 C2H5 CZHS 62 49 (CH2) s 46 43 (CH2) k 47 45 (CH2) 5 25 38 (CH2) 6 94 57 H CH3 55 50 H H 50 46 CH; H 78 S5 C2H5 H 85 58 HC (cH3) 3 37 20 H CZHS 70 44 H CH (CH3) 2 72 53 cH2cH (C5H5) CH2cH, 4 _ 7 CH2CH (CH;) CH, CH2 44 33 CH2C (CH3) zCH2CH2 38 27 1-1 c fl cmc fl g 6 6 CH; Table 2 Oral activity (degree of protection,%) determined by PCA test for acids of formula II (Ra = hydrogen) IgE Ing / kg; Igc: ng / kg R1 R; 10 30 10 30 CH; CH3 CH; C2H5 C2H5 CH3 42 24 C2H5 CZHS 41 32 (CH2) 3 0 0 (CH2) u 55 39 (cm) s 37 44 (CH2) s 36 68 15 45 40 448 732 22 Table 2 (continued) IsE Ing / kg IQG ms / kg a, n, 10 30 1o 30 a ca, 18 19 HH '18 7 ca, H 12 14 czas H 45 38 H _ c (cH3) 3 10 6 1-1 can,' 13 21 _ H cfucaa) , oo cnzcæucsngcnzcn, 15 cazcruca fl cnzcnz '31 21 CHQC (C fl g) 2CH2CH2 13 H cacazcaa 1 CH; The effectiveness of the products according to the invention as antiulcer agents is determined by the so-called "cold-restraint stressed rat assay". In this V test is administered to non-fasting female rats (Charles River CD strain) with a body weight of 70-140 g of the medicine (or for the control animal vehicle). intraperitoneally (in saline containing 1% carboxymethylcellulose and 0.1% Tween 80; polysorbate 80 (Merck Index 7360)) or orally (in water) 3 hours before the experimental animals are lightly anesthetized with ether and taped in a dorsal position to plexiglass sheets. from the anesthetic, they are placed in a horizontal position in a refrigerator, the temperature of which is kept between 10 and 12 ° C. Three hours later the animals are killed by cervical dislocation.The abdomen is opened on each of the rats, the pylorus is clamped, the stomach is filled with saline via an oral tube , esophagus is clamped and the stomach is cut off. The stomachs are placed in a 0.4% formaldehyde solution, where they are allowed to remain for about 30 seconds. so that the outer layers harden, which facilitates the examination. Each stomach is then cut along the largest curvature and the glandular part (the back of the stomach) is examined for damage. The number of superficial wounds, their severity and the color of the stomachs are recorded. The Mann-Whitney 40 23 448 732 Wilcoxan rank sum test is used to compare the average number of wounds in the control group with the average number of wounds in each of the drug-treated groups to determine whether they are statistically different. (Dixon et al., "Introduction to Statistical Analysis" 3rd Ed., McGraw-Hill Book Company, New York, pp. 344-347, 1969). In this test, N- (5-tetrazolyl) thiazolo [3,2-a] pyrimidine-2-carboxamide (Compound III) is found to be extremely potent, as shown below.

Alternatively, the efficacy of the products of the invention as antiulcer agents is determined. ulcer in rats induced by ethanol. In this test, in male rats fasted overnight, the drug (5 mg / kg) or water is administered orally 15 minutes before oral administration of absolute ethanol (1.0 ml). One hour after alcohol administration, the experimental animals are killed (8 per group) and the stomachs are examined for pathological change. All medicines are dissolved in dilute sodium hydroxide solution. After the experimental animals are killed, the abdomen is opened and a lockable hemostat is placed at the pylorus. 6 ml of a 4% solution of formaldehyde is injected into the stomach using a gastric feeding tube and a second lockable hemostat is used to close the esophagus. The stomach is then removed, opened along the largest curvature and examined for ulceration.

The scoring system used for the quantitative determination of ethanol-induced pathological changes is as follows: Elkëšßåëai _ _ gang Definition 1 Normal appearance of the stomach 2 Morbid changes in needle tip size 3 Morbid changes, 2 or less: pathological changes in needle tip size may occur 4 Disease changes 2; pathological changes of needle tip 40 448 732 24 Ulcer points (continued) ggëng Definition size may exist.

Morbid changes with bleeding.

For each experimental animal group, an ulcer index is calculated as follows: Ulcer index = (sum of points for the group) x (sum of the number of ulcers in the group) x (fraction of the group with some occurrence of ulceration).

The percentage inhibition of ulcers is calculated as follows: æ inhibition = 100 x [mlkus index for the control animals) - (ulcer index for drug-treated animals)] + (ulcer index for the control animals).

Table 3 shows the activity of this sample for various 5-tetrazolylamides according to the invention.

Table 4 shows the activity for different acids.

Table 3 Oral activity (% inhibition at a dose of 5 mg / kg) for amides of formula I against ethanol-induced ulcers in rats.

R1 R2% inhibition CH; CH; 96 H CH; 59 CH; H-72 C2H5 CZHS 10 CZHS H 86 (CH2) s 45 (CH2) ~ 97, 81 40 448 732 Table 4 Oral activity (% inhibition at a dose of 5 mg / kg) for acids of formula II against ethanol induced ulcers in rats.

R1 R2% inhibition CH3 CH3 11 H CH3 27 CH3 H Û C1H5 C¿H5 48 C2H5 H 48 (CH2) u 21 As pointed out above, the most preferred compound of the invention is that of formula III (ie the compound of formula I, wherein R; and R 2 together represent butylene) namely N- (5-tetrazolyl) -1-oxo-1H-cyclohexanothiazolo [3,2-a] pyrimidine-2-carboxamide, which may alternatively be referred to as 5,6,7,8-tetrahydro -N- - (5-tetrazolyl) -4-oxo-4-H-pyrimido [2,1-b] benzothiazole-3-carboxamide.

In addition to the antiallergic activity indicated in Table 1 for oral administration, the compound III in the PCA test exhibits activity during intravenous administration in the range of 0¿03-1.0 mg / kg, which activity is about 26 times as strong as those who are presented by Intal in this method of administration (as pointed out above, Intal lacks effectiveness in oral administration). Compound III also blocks the changes in cutaneous permeability induced by IgE-mediated passive cutaneous anaphylaxis (PCA) but does not affect the changes in the permeability caused by intradermal injection of exogenous histamine and serotonin. The absence of antihistamine and antiserotonin effect shows that the allergic mechanism is an inhibition of mediator release rather than antagonism of the mediator receptor. In Compound III, dextran-induced release of histamine in the abdominal cavity of rats inhibits. Its EDSO is 0.33 ng / kg i.p. and the EDSO for Intal is 14.0 ug / kg, which shows the superior strength of the former association. The increase in plasma histamine caused by antigen injection in rats passively sensitized with IgE-rich antiserum (passive systemic anaphylaxis) is prevented by compound III. Its EDSO is 28 ug / kg i.v., which means that it is 13 times as powerful as Intal.

Guinea pigs on which 30 mg / kg i.p. of compound III were found to be unprotected against bronchoconstrictive effects when inhaled histamine. At concentrations between 10 "and 10" M, compound III does not antagonize acetylcholine, histamine or slow-reacting substance from anaphylaxis (SRS-A) in isolated ileum from guinea pig-induced spasm and synthesis and release of SRS in isolated mo rat nocytes stimulated by an ionophore are not inhibited by compound III.

In addition to the potent activity against ethanol-induced ulcers in rats (see Table 3 above), compound III is highly active in the so-called "cold-restraint stress gastric ulcer procedure" (as described in more detail above), where the compound provides protection during oral administration, which depends on the dose size in the range of 3-100 pg / kg. Compound III also protects against the ulcerogenic action of acetylsalicylic acid. Upon oral administration of 100 mg of acetylsalicylic acid per kg, a dose-dependent effect in the range of 10-1000 pg / kg p.o. of the compound III per kg body weight with an ED50 of 100 ng / kg. Compound III is also active against gastric ulcer caused by phenylbutazone, where an ED50 of 200 μg / kg has been determined by oral administration.

Although compound III is a highly effective antiulcer agent, it affects non-pentagastrin-stimulated acid secretion in Heidenhain's small stomach in dogs (5 mg / kg, i.v.) and is therefore different from the antisecretory prostaglandins as well as cimethidine and atropine. There is a newly formed term, namely "Cytoprotective" which denotes the antiulcerative effects of prostaglandins independent of antisecretory activity (Robert, Advances in Prostaglandin 40 27 448 732 and Thromboxane Research 2, 507/1976 /; Miller et al., Gut 20, 75 / 1979 /; Robert et al., Gastroenterology 72, 1121/1977 /). This expression aptly characterizes the effects achievable with compound III.

In addition, the compound III exhibits diuretic activity. When administered orally, it causes a dose-dependent increase in urinary excretion at doses between 0.3 and 5 mg / kg. The maximum effect was an increase in urine excretion to double volume. The sodium and potassium ion levels in the urine remained unchanged, but due to the increase in volume, an increase in sodium and potassium excretion was observed. This observation indicates that the dose-response range for diuretic activity is significantly greater than the range for antiulcer effect and just below the range for antiallergic effects (1-10 mg / kg).

Rats fasted for 24 hours and orally administered 10, 30 and 100 mg / kg, respectively, of compound III showed no changes in blood glucose levels. The effect of the compound III on glucose tolerance was examined in rats administered 10, 30 and 100 mg / kg, respectively, orally, while the rats received 1 g of glucose per kg p.o. A clear dose-dependent improvement in glucose tolerance was observed.

This effect may be due to a delayed absorption of glucose, which is associated with a possible effect on gastric emptying.

Compound III has no significant anticholinergic effects. In anesthetized dogs, cumulative doses of 5 and 15 mg / kg i.v. transient hypotension and variable changes in heart rhythm.

Pressure changes caused by avepinephrine and bilateral carotid occlusion are slightly reduced. The transient cardiovascular changes occur only at cumulative intravenous doses that are 5-15 times as large as the maximum effective intravenous dose for antiallergic effects and much greater than the oral dose required for antiulcer effects. Tolerance studies were administered via an è- J! 40 448 732 28 gastric tube compound III orally in dogs for 7 days in doses of 50, 150 and 300 mg / kg and day. Emes that are common in dogs were observed at all doses, but later research showed that the emetic effect could be eliminated if the compound was administered in capsules after instead of before food. No macroscopic pathological changes were observed and microscopic examination of the liver, kidneys, heart and lungs showed no changes. In other studies, serum enzyme levels in dogs remained normal during a 5-day test with intravenous administration of compound III on the first day with 1, the second with 3, the third with 10, the fourth with 3 and the fifth with 3 mg / kg "In rats, the gastric III compound III was administered orally at doses of 50, 150 and 300 mg / kg and daily for 10 days. No pathological changes were observed during macroscopic and microscopic examination of the liver, kidneys, heart and lungs.

Apart from a slight increase in serum glutamic acid-pyruvic acid transaminase, which was observed at the highest dose, no changes in clinical chemistry could be observed.

Compound III was administered subcutaneously to mice at doses of 100, 300 and 1000 mg / kg, respectively. No lethality symptoms were observed and it could be concluded that the compound is well tolerated acutely with an LDSU when subcutaneously administered less than 1000 mg / kg.

At a subcutaneous dose of 32 mg / kg, no interaction with a battery of CNS-active compounds was observed.

Single oral doses of 40 mg of compound III per kg were administered to groups of mice, which were killed 6, 12 and 24 hours later, respectively. During microscopic examination of the bone marrow, no chromosomal damage was observed. Similar observations were made when mice were treated for five consecutive days at doses of 20 mg / kg. In vitro studies in which compound III was incubated with human lymphocytes at concentrations of 1000, 100, 10 and 0 ug / ml, respectively, no significant chromosome-induced degradation of the compound occurred. Compound III did not induce point mutations in the Ames test in vitro. From these observations it is clear that compound III has no obvious mutagenic potential.

In PCA tests on rats, the ratio of comparable effective oral and intravenous doses of compound III is consistent with good oral absorption. This is supported by the observation that plasma concentrations were 3-7 ug / ml one hour after oral administration of Compound III at doses of 50-300 mg / kg. In dogs, the compound appeared to be readily absorbed after oral administration of suspensions or capsules, and plasma concentrations of 9-26 μg / ml were reached one hour after oral doses of 50-300 mg / kg. In both cases, the plasma concentrations of the corresponding carboxylic acid metabolite (the compound corresponding to formula II) are comparable to those of compound III, which identifies this compound as an important metabolite of compound III. After eight doses daily, the levels of the starting compound and metabolites were 2-4 times as high as after the first dose, indicating that it is possible to maintain therapeutic concentrations for a long time. Compound III alone in solid state or in admixture with inert constituents of the type normally used in preparations for oral administration, or in solution, exhibits exceptionally good stability, which facilitates the preparation of stable preparations of this compound for clinical use.

The following examples are given merely to illustrate the invention and this is of course not bound to the details and measures given in the examples.

Many variations are possible without departing from the inventive idea or exceeding the scope of the invention.

Example 1 2-Amino-4-ethyl-5-methylthiazole Thiourea (20.9 g, 0.275 mol) was dissolved in 250 ml of refluxing ethanol, 2-bromo-3-pentanone (41.3 g, 0.25 mol) was dissolved in 50 ml of ethanol and the solution was added dropwise over 25 minutes to the urea boiling under reflux. After an additional 2 hours at reflux, the reaction mixture was distilled off to about 100 ml, then cooled. The crude product was filtered off as the hydrobromide. Purified 2-amino-4-ethyl-5-methyltetrazole (15.1 g; melting point 4s-50 ° C; m / e calculated; 142; found = 142) was dissolved by dissolving the crude product in water and reprecipitating with a 3-normal aqueous solution of potassium hydroxide.

The procedure described above was repeated to convert 1-bromo-2-heptanone, 3-bromo-4-heptanone, and 4-bromo-2,5-dimethyl-3-hexanone, to 2-amino-4-pentylthiazole, 2- amino-4-ethyl-5-propylthiazole, and 2-amino-4,5-diisopropylthiazole, respectively.

Example 2 2-Amino-4,5-diethylthiazole hydrochloride Thiourea (21.8 g, 0.286 mol), 4-chloro-3-hexanone (34.4 g, 0.26 mol) and 200 ml of ethanol were mixed together. and the mixture was refluxed for 19 hours. The reaction mixture was cooled and the solvent was evaporated to give 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 Gel 3 2-Amino-cyclopetenothiazole Thiourea (41.9 g, 0.55 mol), 2-chlorocycloheptanone (72.3 g, 0.49 mol) and 500 ml of ethanol were mixed and the mixture was refluxed for 7 hours. hours. The solvent was evaporated, leaving a semi-solid. This was partitioned between ethyl acetate and water. Unreacted chloroketone was recovered from the ethyl acetate phase by evaporation, combined with 20 g of thiourea and ethanol, then the mixture was refluxed for 24 hours. After evaporation of the solvent, additional crude product was obtained. This was partitioned between ethyl acetate and water as above. In both cases, the product was recovered by basifying the aqueous phase with ammonium hydroxide and extracting with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, the solvent was evaporated and a residual oil was obtained. This solidified on trituration with hexane and was filtered off. Purified 2-amino-cycloheptenothiazole (49.5 g; mp 77-78.5 ° C) was obtained by recrystallization from cyclohexane.

Example 4 2-Amino-4-isopropylthiazole Thiourea (52.5 g, 0.69 mol) was slurried in 400 ml of ethanol. 1-Bromo-3-methyl-2-butanone (109.5 g, 0.66 mol) was added to the slurry. As a result, an exothermic reaction took place, whereby the solid material dissolved and the solution boiled under reflux. The reflux was maintained by heating from the outside for one hour; The solvent was evaporated and an oil was obtained. This crystallized when allowed to stand. Finally, purification was performed by trituration with ether to give 2-amino-4-isopropylthiazole hydrobromide (104.4 g; mp 74-7 ° C).

The hydrobromide was converted to the free base (58.6 g) by dissolving it in water, basifying the solution with excess ammonium hydroxide, extracting the free base into ether, drying the ether solution over anhydrous sodium sulfate and evaporating the ether. whereby the remaining oil was obtained.

Example 5 2-Amino-6-phenylcyclohexenothiazole Thiourea (397.5 mg, 5.22 mmol) was slurried in 6 mL of ethanol. 2-Bromo-4-phenylcyclohexanone (1.2 g, 4.74 mmol) was added to the slurry, whereby an exothermic reaction occurred and the solid dissolved. The solution was refluxed for 30 minutes, then cooled. The solvent was evaporated to give the crude product as the hydrobromide.

The crude salt was dissolved in hot water, the solution was filtered and the free base precipitated by the addition of ammonium hydroxide. The crude base was filtered off and purified to give 2-amino-6-phenylcyclohexenothiazole (802.4 mg, m.p. 181-183 ° C) by recrystallization from a mixture of water and ethanol. The procedure described above was repeated 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 was refluxed for 30 minutes, then cooled in an ice bath. The hydrobromide was filtered off immediately. The salt was dissolved under heating in water containing a trace amount of ethanol and the free base (10.4 g, m.p. 150 DEG-120 DEG C.) was precipitated by adding excess ammonium hydroxide.

Similarly, 2-bromo-3-phenylcyclopentanone, 2-bromo-3,5-dimethylcyclohexanone, 2-bromo--3,5,5-trimethylcyclopentanone and 2-bromo-5-methylcyclooctanone were converted to either the hydrobromide or to the free base of 2-amino-6-phenylcyclopentenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,4,6-trimethylcyclopentenothiazole and 2-amino-7-methylcyclooctenothiazole, respectively.

Example 6 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 minutes.

The reaction mixture was then cooled to room temperature and the crude product was filtered off as the hydrobromide. The crude salt was dissolved in hot water, the solution was filtered and basified with ammonium hydroxide to precipitate the free base as an oil.

This crystallized on cooling. Purified 2-amino-6-methylcyclohexenothiazole (25.2 g, m.p. 98-100 ° C) was obtained by recrystallization from cyclohexane.

Example 7 2-Amino-6,6-dimethylcyclohexenothiazole 2-Amino-6,6-dimethylcyclohexenothiazole (9.8 g, m.p. 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 procedure described in Example 6. Example 33 8 2-Amino-4- (2-butyl) thiazole Thiourea (16.7 g, 0.22 mol), 1-bromo-3-methyl-2-pentanone (36 g, 0.2 mol) and 100 ml of ethanol were mixed and the mixture was refluxed for hours. A 3-strength aqueous solution of potassium hydroxide (100 ml) was added and refluxing was continued for a further 0.5 hours. The reaction mixture was cooled, acidified with hydrochloric acid and non-basic impurities were removed by extraction with ether. The aqueous phase was made basic ammonium hydroxide and the product was extracted into ether. After washing with water and drying over anhydrous sodium sulfate, the ether was evaporated to give 10 g of 2-amino-4- (2-butyl) thiazole as a dark brown viscous oil.

Example 9 9-Amino-5-methylthiazole Thiourea (45.7 g, 0.6 mol) and propionaldehyde (7.4 g, 0.3 mol) were mixed together in 150 ml of chloroform and the mixture was cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mol) was added over minutes. The exothermic reaction was maintained between 15 and 24 ° C. The gas formation occurring during the addition subsided approximately one hour after the addition was completed. Most of the chloroform was evaporated on a water vapor bath. Ethanol (150 ml) was added to the mixture and the whole was refluxed for 3 hours.

The solvent was evaporated from the reaction mixture to give an oil as an evaporation residue.

This was partitioned between water and ethyl acetate. The aqueous phase was basified with ammonium hydroxide and the product was extracted into new ethyl acetate. The extract was dried over anhydrous sodium sulfate and the ethyl acetate was evaporated to give the crude product as a white solid. Purified 2-amino-5-methylthiazole (8.36 g, m.p. 94-95 ° C) was obtained by recrystallization from cyclohexane.

Example 10 2-Amino-5-ethylthiazole P3 40 448 732 Thiourea (45.7 g, 0.6 mol) and butyraldehyde (21.6 g, 0.3 mol) were mixed with 150 ml of chloroform and the mixture was cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mol) was added over 15 minutes. The exothermic reaction is maintained between 15 ° C and 2 ° C. during the tilieateen one and .hour thereafter gas evolution occurred. Ethanol (400 ml) was added and the chloroform was evaporated, after which the reaction mixture was refluxed overnight (about 16 hours). The reaction mixture was evaporated to give the remaining oil. Recrystallized 2-amino--5-ethylthiezel (11.7 g, enamel point-54-ss ° c) was eluted in the manner of Example 9.

Similarly, pentanal, 3-methylbutanal and heptanal were converted to 2-amino-5-propylthiazole, 2-amino-5-isopropylthiazole and 2-amino-5-pentylthiazole, respectively.

Example 11 2- (2,2-Dicarbethoxyethenylamino) -4,5-dimethylthiazole 2-amino-4,5-dimethylthiazole (2.56 g, 20 mmol), diethyl ethoxymethylene malonate (4.8 g, 22 mmol) and ethanol ( 5 ml) was refluxed for one hour. The reaction mixture was cooled and the crude product precipitated with hexane.

Purified 2- (2,2-dikarbethoxyethenylamino) -4,5-dimethylthiazole (4.21 g, m.p. 82-83 ° C) was obtained by recrystallization from hexane.

Example 12 2- (2,2-Dicarbethoxyethenylamino) -4-ethyl--5-methylthiazole 2-amino-4-ethyl-5-methylthiazole (2.84 g, 20 mmol) and diethyl ethoxymethylene malonate (4.76 g, 22 mmol ) were combined and heated on a steam bath for 3 hours. The product obtained on cooling in the form of an oil was used without further purification in the subsequent step. 4 Similarly, 2-amino-4-pentylthiazole, 2-amino-4-propyl-5-ethylthiazole, 2-amino-4,5-diisopropylthiazole, 207 40 n 448 732 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, to the corresponding 2- (2,2-dikarbethoxyethenylamino) thiazole derivatives.

In the same manner, the corresponding dimethyl, dipropyl and diisopropyl esters were prepared using the required dimethyl, dipropyl and diisopropyl ethoxymethylene malonate instead of diethyl ethoxymethylene malonate.

Example 13 2- (2,2-Dicarbethoxyethenylamino) -4-methyl--5-ethylthiazole 4-methyl-5-ethylthiazole (5.68 g, 40 mmol) and diethyl ethoxymethylene malonate (9.52 g, 44 mmol) were briefly heated at 86 ° C and then cooled to give the product as an oil. This was used directly in the subsequent step.

Example Gel 14 2- (2,2-Dicarbethoxyethenylamino) -4,5-diethylthiazole Diethylthiazole hydrochloride (1S, 4 g, 80 mmol), diethylethoxymethylene malonate (19.0 g, 88 mmol), triethylamine (8.1 g, 80 mmol) and ethanol (125 ml) were mixed and the mixture was refluxed for 2.5 hours. The reaction mixture was cooled and the solvent was evaporated. The semi-solid product thus obtained was partitioned between ethyl acetate and water. Drying of the ethyl acetate phase over anhydrous sodium sulfate and evaporation of the solvent gave 2- (2,2-dikarbethoxyethenylamino) -4,5-diethylthiazole (28.6 g) as a golden yellow oil.

Similarly, the hydrobromide of 7-dimethylcyclohexenothiazole, 4,4,6-trimethylcyclopentenothiazole and 7-methylcyclooctenothiazole was converted to the corresponding 2- (2,2-dicarboxetoxyethylamino) thiazole derivatives.

In the same manner, the corresponding dimethyl, dipropyl and diisopropyl esters were prepared using the required dimethyl, dipropyl and diisopropylethoxymethylene malonate instead of diethyl ethoxymethylene malonate.

Exemgel 15-2- (2,2-dikarbethoxyethenylamino) cyclo-. pentenothiazole 2-Aminocyclepentenothiazole (3.6 g, 34.5 mmol) and diethylethoxymethylene malonate (8.2 g, 38.0 mmol) were mixed and the mixture was heated on a water vapor bath for 100 minutes. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) cyclopentenothiazole (7.0 g, Rf 0.6 on thin layer chromatography on silica gel and using chloroform / 1% ethanol as eluent) crystallized out on addition of hexane.

Example Gel 16 2- (2,2-Dicarbethoxyethenylamino) cyclohexenothiazole 2-Aminocyclohexenothiazole (7.7 g, 50 mmol) and diethylethoxymethylene malonate (11.9 g, 55 mmol) were mixed with 10 mL of ethanol and the mixture was refluxed. flow for 50 minutes. The reaction mixture was cooled and 2- (2,2-dicarboxetoxyethenylamino) cyclohexenothiazole (15 g, Rf 0.5 on thin layer chromatography on silica gel and using chloroform / 1% ethanol as eluent) was precipitated by adding 50 ml of hexane.

As an alternative, 58.4 g of 2-aminocyclohexenothiazole, 89.82 g of diethylethoxymethylene malonate and 584 ml of cyclohexane were mixed and the mixture was refluxed under a nitrogen atmosphere for 2.5 hours. The mixture was then cooled to 15 ° C and the product (96 g, melting point 113 ° C) was filtered off.

Example Gel 17 2- (2,2-Dicarboxetoxyethenylamino) cyclooctenothiazole 2-Aminocyclooctenothiazole (2.0 g, 11 mmol) and diethylethoxymethylene malonate (2.62 g, 12.1 mmol) were mixed. The mixture was heated on a steam bath for 2.75 hours. The reaction mixture was cooled and 2- (2,2-dicharboxetoxyethenylamino) cyclooethenothiazole (3.13 g, Rf 40 37 448 732 0.6 by thin layer chromatography on silica gel using chloroform / 1% ethanol as eluent) precipitated by adding hexane .

Example 18 2- (2,2-Carbethoxyethenylamino) -4-methylthiazole 2-amino-4-methylthiazole (4.57 g, 40 mmol) and diethylethoxymethylene malonate (9.51 g, 44 mmol) were mixed and the mixture was heated on a water steam bath for one hour. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) -4-methylthiazole (9.8 g, Rf 0.5 on thin layer chromatography on silica gel using chloroform / 1% ethanol as eluent) precipitated by addition of 60 ml of hexane. Example Gel 19 2- (2,2-Dicarbethoxyethenylamino) thiazole 2-Aminothiazole (10.0 g, 0.10 mol) and diethylethoxymethylene malonate (23.8 g, 0.11 mol) were mixed and the mixture was heated on a water vapor bath in 1.25 hours. The reaction mixture was cooled and the semi-solid thus obtained was recrystallized from hexane to give purified 2- (2,2-dikarbethoxyethenyl) thiazole (17.2 g in two yields, Rf 0.6 by thin layer chromatography on silica gel using chloroform / 1% ethanol as eluent).

Example gel 20 g of 2- (2,2-dicarboxetoxyethenylamino) -5-methylthiazole 2-amino-5-methylthiazole (6.85 g, 60 mmol) and diethylethoxymethylene malonate (14.3 g, 66 mmol) were heated on a water vapor bath in a hour. The reaction mixture was cooled and the product precipitated by adding about 75 ml of hexane. Purified 2- (2,2-dikarbethoxyethenylamino) -5-methylthiazole (14.1 g in two yields, Rf 0.55-0.65 by thin layer chromatography on silica gel using chloroform / 1% ethanol as eluent) was obtained by recrystallization from hexane. Example 21 21 2- (2,2-Dicarbethoxyethenylamino) -5-ethylthiazole 2-amino-5-ethylthiazole (11.7 g, 91.3 mmol) and diethylethoxymethylene malonate (21.7 g, 100, 43 mmol) was mixed and the mixture was heated on a steam bath for 45 minutes. 2- (2,2-dikarbethoxyethylamino) -5-ethylthiazole (27.2 g, Rf 0.6 and 0.7, respectively, by thin layer chromatography on silica gel using chloroform / 1% ethanol and hexane / ethyl acetate, respectively 2: 1 as eluent) was obtained by cooling in the form of an oil. This was used directly in the subsequent step.

Example Gel 22 2- (2,2-Dicarboxetoxyethenylamino) -4- (2-methyl-2-propyl) thiazole 2-amino-4- (2-methyl-2-propyl) thiazole (15.6 g, 0.1 mol) and diethylethoxymethylene malonate (23.8 g, 0.11 mol) were mixed and the mixture was heated on a water vapor bath for 2 hours. 2- (2,2-Dicarboxetoxyethenylamino) -4- - (2-methyl-2-propyl) thiazole was obtained on cooling as a wet solid. This was used directly in the subsequent step.

Example Gel 23 2- (2,2-Dicarbethoxyethenylamino) -4-ethylthiazole 1,2-amino-4-ethylthiazole (20.5 g, 0.16 mol) and diethylethoxymethylene malonate (35 g, 0.17 mol) were mixed and the mixture was heated on a water steam bath for 2 hours. 2- (2,2-dikarbethoxyethenylamino) -4-ethylthiazole was obtained on cooling in the form of an oil. This was used directly in the subsequent step. (Rf 0.75 by thin layer chromatography on silica gel using chloroform / 1% ethanol as eluent).

Similarly, 2-amino-4-isopropylethylthiazole (58.6 g, 0.415 mol) and diethylethoxymethylene malonate (92 ml, 0.455 mol) were converted to 2- (2,2-dicarboxetoxyethylamino) -4-isopropylthiazole. (Rf 0.7 for thin layer chromatography on silica gel and use of chloroform / 1% ethanol as eluent).

Example 24 2- (2,2-Dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole 'I. H' W 40 39 448 732 2-Amino-6-phenylcyclohexenothiazole (10.4 g, 45.2 mmol) and diethylethoxymethylene malonate (10 mL, 49 .5 mmol) was mixed and the mixture was heated on a water vapor bath. After 15 minutes, the solid went into solution. After heating for an additional 30 minutes, the entire reaction mixture was converted to a solid mass. The crude product was recrystallized from cyclohexane to give purified 2- (2,2-dicarboxetoxyethenylamino) -6-phenylcyclohexenothiazole (15.3 g, m.p. 131-133 ° C).

Example Gel 2- (2,2-Dicarbethoxyethenylamino) -6-methylcyclohexenothiazole 2-Amino-6-methylcyclohexenothiazole (23.3 g, 0.139 mol) was mixed with diethylethoxymethylene malonate (31 ml, 0.153 mol) and the mixture was heated on a tenångbad. After about 10 minutes of heating, a clear, orange oil was obtained. After one hour of heating, the crystallization was induced by scraping. Purified 2- (2,2-dikarbethoxyethenylamino) -6-methylcyclohexenothiazole (40.2 g, m.p. 106-109 ° C) was obtained by recrystallization from ethanol.

Example gel 26 2- (2,2-dicarboxetoxyethenylamino) -6,6-dimethylcyclohexenothiazole 2-amino-6,6-dimethylcyclohexenothiazole (9.8 g, 53.8 mmol), diethylethoxymethylene malonate (12 mL, 59.4 mmol) and ethanol (about 5 ml) was mixed and the mixture was heated on a water vapor bath for 1.5 hours. The ethanol was evaporated during the first part of the heating period. Upon cooling and scraping, the product crystallized out. Purified 2- (2,2-dikarbethoxyethenylamino) -6,6-dimethylcyclohexenothiazole (14.3 g, m.p. 83-85 ° C) was obtained by recrystallization from hexane.

Analysis -% C% H% N calculated for C11H2 @ OrN2S: 57.93 6.86 7.95 Found: 57.72 6.66 7.94 Example Gel 27 2- (2,2-dikarbethoxyethenylamino) -4- - (2-butyl) thiazole 2-amino-4- (2-butyl) thiazole (8.44 g, 54 mmol) and diethylethoxymethylene malonate (11.7 g, 54 mmol) were mixed and the mixture was heated on a water vapor bath for one hour, after which it was cooled. 2- (2,2-Dicarbethoxyethenylamino) -4- (2-butyl) thiazole (17.6 g, Rf 0.75 was obtained by thin layer chromatography on silica gel using chloroform / 1% ethanol as eluent).

Example 28 Ethyl 1-oxo-1H-6,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxylate 1 2- (2-dicarboxetoxyethylamino) -4,5-dimethylthiazole (4.17 g, 14 mmol) was mixed with 30 ml of Dowtherm A (see page 10, lines 6 and 7) and the mixture was heated at 220 ° C for 1.5 hours. The reaction mixture was cooled and about 125 ml of petroleum ether was added. The solid which separated was filtered off, mixed again with the mother liquor and chromatographed on a 70 x 180 mm silica gel column using chloroform as eluent. After a first 125 ml fraction, six 250 ml fractions were collected. The solvent was evaporated to dryness to give the crude product (2.42 g, m.p. 114-115 ° C). By recrystallization from cyclohexane, purified ethyl 1-oxo-1H-4,5-dimethylthiazolo [3,2-a] pyrimidine-2-carboxylate (1.64 g, m.p. 119 DEG-120 DEG C.) was obtained.

Analysis -% C% H% N calculated for C 1 H 12 N 2 O 3 S: 52.37 4.79 11.10; ion mass 252 found: 52.21 4.85 11.23; ionic mass 252 Example gel 29 Ethyl 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimine-2-carboxylate 2- (2-dicarboxetoxyethyl) amino) -4-ethyl-5-methylthiazole ( 6.25 g) was mixed with 30 ml of Dowtherm A (see pages 6 and 7) and the mixture was heated at 215 ° C for 2.5 hours. The reaction mixture was cooled, petroleum ether was added and the crude product (1.96 g) was filtered off. 630 mg of the crude product were recrystallized from cyclohexane to give purified 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimine-2-carboxyate (301 mg, m.p. 122-124 ° C). ). 41 - 448 732 Analysis -% C% H% N calculated for C12H1 @ N2O3S: 54.12 5.30 10.52 found 54.09 5.26 10.63 Example gel 30 Ethyl 1-oxo-1H-6-ethyl -7-methylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethyl] amino) -4-methyl-5-ethylthiazole (12 g) was mixed with 60 ml of Dowtherm A (see page 10, rows 6 and 7) and the mixture was heated at 205 ° C for 3 hours. The reaction mixture was cooled and chromatographed on a 90 x 205 mm silica gel column.

Chloroform containing 1% ethanol was used as eluent. Seven product fractions, each 250 ml, were collected, combined and the solvent was evaporated, yielding an oil. This was re-chromatographed on a 60 x 600 mm silica gel column using the same eluent. Fractions (165 x 8 ml) were combined, the solvent was evaporated and an residual oil was obtained. This crystallized on trituration with diisopropyl ether. Recrystallization from cyclohexane gave purified ethyl 1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylate (2.45 g, m.p. ss-ss ° c).

Analysis -% C% H% N calculated for C 12 H 18 N 2 O 3 S: 54.12 5.30 10.52; ion mass 266 found: 54.26 5.23 10.57; ionic mass 266 Example gel 31 Ethyl oxo-1-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethenylamino) -4,5-diethylthiazole (26 , 1 g) and 300 ml of Dowtherm A (see page 10, lines 6 and 7) were mixed and the mixture was heated at 225 ° C for 3.5 hours. The reaction mixture was cooled and chromatographed on a 60 x 320 mm silica gel column. Dowtherm A was eluted with hexane and the product was eluted with hexane / chloroform 2: 1. Thirty-three fractions of 250 ml each were collected. Fractions 8-33 were combined and the solvent was evaporated, yielding ethyl 1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxylate (22 g, Rf 0.4-0 , By thin layer chromatography on silica gel (44 44 752 42 using chloroform / 1% ethanol as eluent) as an oil.

Similarly, the following products of Examples 12 and 14 were converted: 2- (2,2-dicarbomethoxyethenylamino) -4-ethyl-5-methylthiazole; 2- (2,2-dicarbopropoxyethenylamino) -4-ethyl--5-methylthiazole; 1- 2- (2,2-dicarboisopropoxyethenylamino) -4-ethyl--5-methylthiazole: 2- (2,2-dicarbomethoxyethenylamino) -4,5-diethylthiazole; 2- (2,2-Eicarbopropoxyethenylamino) -4,5-diethylthiazole; 2- (2,2-dicarboisopropoxyethenylamino) -4,5-diethylthiazole; 2- (2,2-dikarbethoxyethenylamino) -4-pentylthiazole; 2- (2,2-dikarbethoxyethenylamino) -4-propyl-5-ethylthiazole; 2- (2,2-dikarbethoxyethenylamino) -4,5-diisopropylthiazole; 2- (2,2-dikarbethoxyethenylamino) -5-propylthiazole; 2- (2,2-dikarbethoxyethenylamino) -5-isopropylthiazole; 2- (2,2-dikarbethoxyethenylamino) -5-pentylthiazole; 2- (2,2-dikarbethoxyethenylamino) -6-phenylcyclopentenothiazole; 2- (2,2-dikarbethoxyethenylamino) -5,7-dimethylcyclohexenothiazole; 2- (2,2-dicarboxetoxyethenylamino) -7-methylcyclooctenothiazole, and 2- (2,2-dicarboxetoxyethenylamino) -4,4,6-trimethylcyclopentenomethylthiazole, to methyl-1-oxo-1H-6-methyl- 7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate; propyl 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate; isopropyl 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate; methyl 1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxylate; propyl 1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxylate; isopropyl 1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxylate; ethyl 1-oxo-1H; 7-pentylthiazolo {3,2-a] pyrimidine-2-carboxylate; ethyl 1-oxo-1H-6-ethyl-7-propylthiazolo [3,2-a] pyrimidine-2-carboxylate; ethyl 1-oxo-1H-6,7-diisopropylthiazolo [3,2-a] pyrimidine-2-carboxylate; ethyl 1-oxo-1H-6-propylthiazolo [3,2-a] pyrimidine-2-carboxylate; ethyl 1-oxo-1H-6-isopropylthiazolo [3,2-a] pyrimidine-2-carboxylate; ethyl 1-oxo-1H-6-pentylthiazolo [3,2-a] pyrimidine-2-carboxylate; ethyl 1-oxo-1H-6-phenylcyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylate; ethyl 1-oxo-1H-6,8-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate: ethyl 1-oxo-1H-8-methylcycloothenothiazolo [3,2-a] pyrimidine-2- carboxylate, respectively, ethyl 1-oxo-1H-6,8,8-trimethylcyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylate.

Example gel 32 Ethyl 1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethylamino) cyclopentenothiazole (7.0 g) was mixed with 40 ml of Dowtherm A and the mixture was heated at 225-230 ° C for about one hour. The reaction mixture was cooled and chromatographed on silica gel (70 x 190 ml). "Dowtherm A" was eluted with hexane. The product was eluted with chloroform / 1% ethanol. Four 250 ml fractions each were collected, combined and evaporated to give an oil. A portion of the oil crystallized on trituration with cyclohexane to give the crude product (1.91 g). By recrystallization from 0.6 g of this crude product, purified ethyl 1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylate (0.33 g, m.p. 102 DEG-130 DEG C.) was obtained.

Analysis -% C% H% N calculated for C 12 H 12 N 2 O 3 S: 54.33 4.58 10.60 Found: 54.54 4.71 10.71 Exemgel 33 ethyl-1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate I 2- (2,2-dikarbethoxyethenylamino) cyclohexenothiazole (12.6 g) was mixed with 125 ml of Dowtherm A and the mixture was heated at 230 ° C for 25 minutes. The reaction mixture was cooled and chromatographed on silica gel (60 x 320 mm). Dowtherm A was eluted with hexane and the product was eluted with chloroform / 1% ethanol in 14 125 ml fractions each. The appropriate ethyl 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate (10.7 g, m.p. 92-94 ° C) was obtained by combining the fractions and evaporating the solvent.

As an alternative, 2- (2,2-dicarboxetoxyethenylamino) cyclohexenothiazole (80 g, 0.25 mol), trifluoroacetic anhydride (101 g, 68 ml, 0.48 mol), toluene (0.8 L) and ethanol (1 1) and the mixture was refluxed for 21 hours. The reaction mixture was cooled and 300 ml of water were added. The toluene phase (upper phase) was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, evaporated to 150 ml (slurry), diluted with 1 l of ethanol (solution), concentrated to 280 ml , cooled to s ° C, granulated and filtered to give relatively pure ethyl 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate (47 g, m.p. 105-1os ° C). ).

Example 34 Ethyl 1-oxo-1H-cycloheptenothiazolo [3,2-a] gyrimidine-2-carboxylate 2-aminocycloheptenothiazole (25.2 g, 0.15 mol), diethyl ethoxymethylene malonate (35.7 g, 0.165 mol) and Dow-40 45 448 732 therm A "(400 ml) was mixed together and the mixture was heated at 20 DEG-230 DEG C. for 2 hours. 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 hexane / chloroform 1: 1 in 30 fractions of 500 ml each. Fractions 6-30 were combined and the solvent was evaporated, yielding a crude product as a wet solid. Purified ethyl 1-oxo-1H--cycloheptenothiazolo [3,2-a] pyrimidine-2-carboxylate (27.1 g, m.p. 78-79 ° C) was obtained by recrystallization from cyclohexane. The same product was obtained by heating 2- (2,2-dikarbethoxyethenylamino) cycloheptenothiazole in "Dowtherm A". The product was isolated and purified as above.

Example 35 Ethyl 1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethylamino) cyclooctenothiazole (3.13 g) was mixed with 30 ml of Dowtherm A and the mixture was heated at 220 ° C for 2.5 hours.

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 in four 125 ml fractions each. The fractions were combined, the solvent evaporated to give an oily and solid ethyl 1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxylate (1.956 g, Rf 0.5 at the thin layer). matography on silica gel using chloroform / 1% ethanol as eluent) was obtained by trituration with hexane.

Example 36 Ethyl 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxyethoxyethylamino) -4-methylthiazole (9.8 g) was mixed with 50 ml of Dowtherm A and the mixture are kept at 22 DEG C. for 2 hours. The reaction mixture was cooled and 50 ml of hexane was added. The crude product was filtered off and recrystallized from ethanol to give purified ethyl 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylate (4.6 g, mp 187-119 ° C).

This ester was also prepared by directly condensing 2-amino-4-methylthiazole with ethylethoxymethylene malonate by refluxing the trichlorobenzene (Allen et al., J. Org. Chem., 24, 779/1959 /).

Example 37 Ethyl 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxyethoxyethylamino) thiazole (17.2 g) was mixed with 200 ml of Dowtherm A and the mixture was heated at 215 ° C for 30 minutes. The reaction mixture was cooled and a slurry was obtained. Hexane (100 ml) was added and the crude product was filtered off. By crystallization from ethanol, purified ethyl 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylate (8.0 g, m.p. 184 DEG-18 DEG C.) was obtained.

This ester was also prepared by directly condensing 2-aminothiazole with ethyl ethoxymethylene malonate by refluxing in trichlorobenzene (Allen et al., J. Org. Chem., 24, 779/1959 /).

Example 38 Ethyl 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethyl) -5-methylthiazole (14.1 g) was mixed with 150 ml Dowtherm A and the mixture was heated at 220 ° C for 1.5 hours. The reaction mixture was cooled and added with about 300 ml of hexane. The product was filtered off and purified ethyl 1-1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylate (6.4 g, m.p. 149-151 ° C) was obtained by recrystallization from diisopropyl ether.

This ester was also prepared by directly condensing 2-amino-5-methylthiazole with ethyl ethoxymethylene malonate by boiling in trichlorobenzene (Dunwel1 et al., J. Chem. Soc., (C) 1971, 2094).

Example 39 Ethyl 1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethylamino) -5-ethylthiazole 40 'funnetz 47 448 732 (25, 7 g, 86 mmol), trifluoroacetic anhydride (36.2 g, 172 mmol) and toluene (150 ml) were mixed together and the mixture was refluxed for about 20 hours. The reaction mixture was evaporated to dryness, the residue was taken up in 300 ml of chloroform and the chloroform solution was washed with a saturated sodium bicarbonate solution and then with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to dryness and the residue triturated with diisopropyl. ethyl 1-oxo-1H-6-ethylthiazole [3,2-a] pyrimidine-2-carboxylate (17.8 g, mp 148-150 ° C). A portion of the proauct (5.2 g) was recrystallized from about 75 ml of ethyl acetate to give further purified product (4.1 g, m.p. 149-150 ° C).

Analysis - g% C% H% N Calcd for C 11 H 12 N 2 O 3 SO 2 52.37 4.79 11.10 Found: 52.30 4.51 11.14 Example 40 ethyl-1-oxo-1H-7- (2-methyl-2 -propyl) thiazolo [3,2-alpyrimine-2-carboxylate 2- (2,2-dicarboxetoxyethylamino) -4- (2-methyl-2-propyl) thiazole (32.6 g) was mixed with 400 ml of Dowtherm The mixture was heated at 230 ° C for one hour.

The reaction mixture was cooled and chromatographed on silica gel (60 x 600 mm). Dowtherm A was eluted with hexane and the product was eluted with chloroform. Nine fractions of 500 ml each were collected. Fractions 6-9 were combined and the solvent was evaporated to dryness to give ethyl 1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxylate ( 11.4 g, m.p. 145-147 ° C).

Additional product (2.04 g) was obtained from the fifth fraction by evaporation to a wet solid and trituration of the residue with cyclohexane. 1 g of the larger yield was recrystallized from cyclohexane to give additional purified product (0.62 g, m.p. 148-19 ° C).

Analysis -% C% H% N calculated for C 13 H 15 N 2 O 3 S 2 § 5.7Û 5.75 9.99 55.14 5.58 9.95-40 4.48 732 48 Example 41 ethyl-1-oxo-1H-7-ethylthiazolo [3,2-a] Pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethenylamino) -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 mild exotherm followed and the reaction mixture was refluxed for 26 hours, then cooled and added with 250 ml of ethyl acetate. The mixture was carefully extracted with 250 ml of aqueous sodium bicarbonate solution (carbon dioxide evolution), then with 250 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was slurried in diisopropyl ether and the crude product was filtered off. By recrystallization of the crude product from acetonitrile, purified ethyl 1-oxo-1H-7-ethylthiazole [3,2-a] pyrimidine-2-carboxylate (10.33 g, m.p. 17s-177 ° C) was obtained.

Analysis -% C% H% N calculated for C 11 H 12 N 2 O 3 S 2 52.37 4.79 V 11.10 Found: 52.34 4.85 11.27 A second yield (1.58 g, mp 176-178 ° C) was obtained from acetonitrile mother liquor.

Example 42 Ethyl-1-oxo-4H-7-isopropylthiazolo [2,3-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxoxy) -4-isopropylthiazole (10 g) was mixed with 100 ml of Dowtherm A and the mixture was heated at 220 ° C for 2 hours, cooled to room temperature overnight and then reheated at 220 ° C for another 5 hours. The mixture was cooled to room temperature, about 200 ml of hexane and batches of insoluble constituents were filtered off. The hexane was evaporated and the residue was chromatographed on approximately 500 g of silica gel. Dowtherm A was eluted with hexane and the product was eluted with chloroform. Fractions containing product were combined and evaporated to dryness and the residue was slurried in diisopropyl ether. The product (m.p. 143-144 ° C) was filtered off. The crude product was recrystallized from ethanol. to give purified ethyl 1-oxo-1H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxylate (1.49 g, m.p. 145-147 ° C, NMR: singlets at 68 , 6 and 67.3 each corresponding to one proton, and multiplets centered at 64.2 and 61.2 corresponding to three protons and nine protons, respectively.

Example 43 Ethyl 1-oxo-1H-7-phenylcyclohexenothiazole [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethylamino) 6-phenylcyclohexenothiazole (15.3 g, 38.2 mmol ) was suspended in 150 ml of toluene. Trifluoroacetic anhydride (10.8 mL, 76.5 mmol) was added and a clear solution was obtained. This was boiled under reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 150 ml of 5% potassium carbonate solution and once with 150 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The solid residue was recrystallized from acetonitrile to give purified ethyl 1-oxo-1H-7-phenylcyclohexenothiazole: B, 2-a] pyrimidine-2-carboxylate (9, a9 g, m.p. 160-1a1.5 ° C ).

Example 44 Ethyl 1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethylamino) -6-methylcyclohexenothiazole (40.2 g, 0.119 mol) dissolved in 400 ml of toluene.

Trifluoroacetic anhydride (33.5 ml, 0.237 mol) was added, followed by a mild exotherm. The reaction mixture was refluxed overnight (16 hours), cooled to room temperature, diluted with 400 ml of ethyl acetate, extracted twice with 400 ml of 1N-K 2 CO; and once with 400 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. By recrystallization of the evaporation residue from cyclohexane containing a small amount of ethyl acetate, purified ethyl 1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate (29.3 g, m.p. 127) was obtained. -129 ° C). 448 732 W Exemgel 45 ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethylamino) -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 solution and once with 150 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The evaporation residue was recrystallized from hexane to give purified ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate (9.4 g, m.p. 92-94 ° C).

Analysis -% C% H% N calculated for C 15 H 15 N 2 O 3 S: 58.80 5.92 9.14 Found: 58.93 5.48 9.01 Exemgel 46 ethyl 1-oxo-1H-7- (2-butyl) thiazole [3,2-a] -pyrimidine-2-carboxylate 2- (2,2-dicarboxetoxyethyl) amino) -4- (2-butyl) -thiazole (17.6 g) was mixed with 175 ml of Dowtherm A and the mixture was heated at 225 ° C for 2.5 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 chloroform / hexane 2: 1.

Fractions 4-8 (500 ml each) were combined and evaporated to an oil. This was taken up in about 400 ml of hot hexane, the whole was mixed with charcoal and cooled to give crystalline ethyl-1-oxo-1H-7- (2-butyl) -thiazolo [3,2-a] pyrimidine-2 carboxylate (2.12 g, m.p. 105.5-1os ° C).

Analysis -% C% H% N calculated for C 13 H 12 GO 3 N 2 S: 55.70 5.75 9.99 Found: 55.82 5.40 10.22 Example gel 47 1-oxo-1h-6,7-dimethylthiazolo [3,2- a] pyrimidine-2-carboxylic acid 40 51 448 732 Ethyl 1-oxo-1H-6,7-methylethiazolo [3,2-a] pyrimidine-2-carboxylate (1.41 g) was heated on a water vapor bath together with 20 ml of 48% hydrobromic acid for one hour. Dissolution occurred within a few minutes and solid material began to form at the end of the reaction time. The reaction mixture was cooled and the product was filtered off. By recrystallization from ethanol, purified 1-oxo-1H-6,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (508 mg, m.p. 189-190 ° C) was obtained.

Analysis -% C% H% N calculated for C 9 H 3 O; N 2 S: 48.21 3.60 12.49; ion mass 224 found: 48.21 3.68 12.44; ionic mass 224 Example gel 48 1-oxo-1H-s-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl-1-oxo-1H-6-methyl-7-ethylthiazolo [3.2 Pyrimidine-2-carboxylate (971 mg) was heated on a water vapor bath with 15 ml of 48% hydrobromic acid. Dissolution occurred almost immediately. Heating was continued for 2.5 hours, after which the reaction mixture was cooled, whereby the product formed as a filterable solid. By recrystallization of the crude product from isopropyl alcohol, purified 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (354 mg, m.p. 201-202 ° C) was obtained.

Analysis -% C% H% N calculated for C 10 H 10 O 3 N 2 S: 50.41 4.23 11.76 Found: 50.28 4.26 11.80 Example gel 49 1-oxo-1H-6-ethyl-7-methylthiazolo [ 3,2-a] Pyrimidine-2-carboxylic acid Ethyl-1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (1.33 g) was heated on a water vapor bath together with 10 ml of 48% hydrobromic acid for minutes, after which a solid began to form.

The mixture was cooled and the crude product was filtered off. Recrystallization from isopropyl alcohol gave purified 1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine (596 mg, m.p. 174-176 ° C).

Analysis -% C% H% N calculated for C 10 H 10 O 2 N 2 S: 50.41 4.23 11.76 46 448 732 52% C% H% N found: 50.44 4.22 11.82 Example gel 50 1-oxo-1H- 6,7-Diethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-6,7-methylthiazalo [3,2-a] pyrimidine-2-carboxylate (19.2 g) was heated for one hour at 85 ° C together with 48% aqueous HBr solution. Gas evolution (probably decarboxylation product) was observed.

The reaction mixture was cooled, basified with concentrated ammonium hydroxide and unreacted starting material and impurities were removed by extraction with ethyl acetate.

The aqueous phase was acidified with acetic acid and the solid product was filtered off. The crude product was recrystallized from isopropyl alcohol to give a partially purified product (5.4 g) in two yields. Partially purified material (2.5 g) was recrystallized a second time in isopropyl alcohol to give purified 1-oxo-1H-6,7-diethylthiazolo [3,2-alpyrimidine-2-carboxylic acid (1.6 g, melting point 104-106 ° C, cloudy).

Analysis -% C% H% N calculated for C 11 H 12 O 3 N 2 S: 52.37 4.79 11.10 Found: 52.31 4.79 11.16 Exemgel 51 1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine Midin 2-carboxylic acid Ethyl 1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylate (1.3 g) was heated together with ml of 48% hydrobromic acid on a water vapor bath for 30 minutes.

Dissolution occurred after about 5 minutes. A solid began to form at the end of the heating period.

The reaction mixture was cooled and the crude product was filtered off. Recrystallization from isopropyl alcohol gave purified 1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine (0.51 g, m.p. 202 DEG-3 DEG C., s ° C).

Analysis -% C% H% N calculated as C10H3Û3N2S3 5Û .84 3.41 11.86 50.42 3.57 11.65 The sodium and potassium salts were obtained by dissolving the free acid in water together with the finding: 40 ü 448 732 an equivalent required hydroxide and evaporation of the water in vacuo or freeze-drying.

The N-methylmorpholine salt was prepared by dissolving the acid in methylene chloride together with N-methylmorpholine in a slight excess and evaporating to dryness or precipitating the salt by cooling and adding hexane.

Example 52 1-Oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate (2,8 9) was heated on a steam bath together with 30 ml of 48% hydrobromic acid. Dissolution occurred within a few minutes after the start of the heating. Product began to precipitate at the end of the reaction period. The reaction mixture was cooled in an ice bath and 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (1.66 g, m.p. 188-189 ° C) was filtered off. Recrystallization from ethanol gave 1.38 g of the same melting point.

The same product was prepared by stirring 22.3 g of the ethyl ester with 223 ml of 48% hydrobromic acid in a pressure vessel. Dissolution occurs at ss-70 ° C.

The reaction mixture was heated for 40 minutes to a maximum temperature of 85 ° C and a maximum overpressure of 48.3 kPa. The reaction mixture was cooled to 45 ° C, the overpressure was vented, the mixture was cooled to ° C, stirred for one hour and relatively pure product was filtered off immediately (12.4 g, m.p. 192-194 ° C).

The sodium salt was prepared by dissolving the acid in methanol together with one equivalent of sodium methoxide and evaporating to dryness or precipitating the salt by cooling and adding hexane.

Example 53 53 1-Oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine-2-carboxylate (5,8 g) was heated for 15 minutes on a water vapor bath together with 50 ml of hydrobromic acid.

The reaction mixture was poured onto ice, the whole was stirred and the crude product was filtered off. By recrystallization from ethanol, purified 1-oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine (2.6 g, m.p. 162 DEG-163 DEG C.) was obtained.

Analysis -% C% H% N calculated for C 12 H 12 O 3 N 2 S: 54.53 4.58 10.60; ion mass 264 found: 54.72 4.73 10.88; ionic mass 264 The amine salts were prepared by adding one equivalent of amine to a hot ethanol solution of the acid, then cooling the whole, concentrating or adding hexane. Example 54 1-Oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-cyclootenothiazolo [3,2-a] pyrimidine-2-carboxylate (1, 23 μl were heated in an oil bath together with 30 ml of 48% hydrobromic acid at 90 ° C for 4 hours. The reaction mixture was cooled, the pH was adjusted to 1.5 and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with water and then with a sodium chloride solution, dried over sodium sulfate and evaporated to an oil, the oil was dissolved in ethyl acetate and the product was extracted into 1N-KOH, the basic solution was acidified with 3N-HCl and the product was extracted into ethyl acetate, the ethyl acetate solution was extracted with then with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give 1-oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (308 mg, Rf 0.6 by thin layer chromatography on silica gel using chloroform / 1% ethanol as eluent el).

The procedures described in Examples 47-53 were applied to convert the corresponding alkyl 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylates of Example 31 to: 1-oxo-1H-6-methyl -7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid; 1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-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; 1-oxo-1H-6-isopropylthiazolo [3,2-a] pyrimidine-2-carboxylic acid; 1-oxo-18-6-pentylthiazolo [3,2-a] pyrimidine-2-carboxylic acid; 1-oxo-1H-6-phenylcyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylic acid: 1-oxo-1H-6-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid; 1-oxo-1H-8-methyloyclooktenothiazolo [3,2-a] pyrimidine-2-carboxylic acid, and 1-oxo-1H-6,8,8-trimethylcyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylic acid .

Example Gel S5 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-13-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylate (3 , 1 g) was heated on a water vapor bath together with 50 ml of 48% hydrobromic acid. Dissolution occurred within 5 minutes. After about 15 minutes of heating, the reaction mixture was cooled and the product which then precipitated was filtered off. Recrystallization from acetic acid gave purified 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (1.4 g, m.p. 265 ° C, dec.).

Analysis -% C% H% N calculated for C 9 H 11 O 3 N 2 S: 45.71 2.88 13.33 Found: 45.57 3.04 13.40 Example gel 56 1-oxo-1H-thiazolo [3,2-a] pyrinidine-2-carboxylic acid Ethyl 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylate (7.5 g) was heated on a water vapor bath for minutes together with 80 ml of 48% hydrobromic acid. Dissolution occurred within 5 minutes and a solid began to precipitate a few minutes thereafter.

The reaction mixture was cooled in an ice bath, the crude product was filtered off, recrystallized to give purified 1-oxo-1H- -thiazolo [3,2-a] pyrimidine-2-carboxylic acid (4.66 g, m.p. 276 ° C, dec. ).

Analysis -% C% H% N calculated for C7HQO3H2S2 42.86 2, Û6 14.28 Found: 42.71 2.21 14.32 This acid was also prepared from the above intermediate by refluxing in 2N- -HCl in excess ( Allen, et al., J. Org. Chem., 24, 779/1959 /).

Example Gel 57 1-Oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylate ( 5.96 g) was heated on a water vapor bath for one hour together with 60 ml of 48% hydrobromic acid.

The reaction mixture was cooled in an ice bath and the crude product was filtered off, 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, m.p. 246-248 ° C, dec.) .

Analysis -% c% H% N calculated for C; H6O3N2S: 45.71 2.88 13.33 Found: 45.87 2.94 13.47 This acid was also prepared from the above intermediate by refluxing in 2N-HCl ( Dunwell, et al., J. Chem. Soc. (C) 1971, 2094).

Example 58 1-Oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate (12 , 6 g) was heated on a water vapor bath together with 125 ml of 48% hydrobromic acid. Dissolution occurred within a few minutes. After 10 minutes, a solid began to form. Heating was continued for a total of 40 minutes, after which the reaction mixture was cooled. The crude product (10.1 g) was filtered off. By recrystallization of 2.32 g of crude product (of the 6.8 g obtained by experimental crystallization in acetic acid) in isopropyl alcohol, pure 1-oxo-1H was obtained. -6-ethylthiazolo {3,2-a] pyrimine-2-carboxylic acid (1, ss g, m.p. 162-163 ° C).

Analysis -% C% H% N calculated for C 9 H 10 O 2 N 2 S: 48.21 3.60 12.49 Found: 48.17 3.73 12.42 Example 59 1-oxo-1H-7- (2-methyl -2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2 -carboxylate (5.6 g) was heated on a water vapor bath for 6 hours together with 60 ml of 48% hydrobromic acid. After about 10 minutes (before complete dissolution of the ester occurred), the reaction mixture became very thick. At the end of the heating period, the reaction mixture was cooled and the crude product was filtered off.

By 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 (3.33 g, m.p. 242 ° C, decomposition).

Analysis -% C% H% N calculated for C 11 H 12 O; N 2 S: 52.37 4.79 11.10 Found: 52.45 4.82 11.26 Example 60 1-oxo-1H-7-ethylthiazolo [3,2- a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate (1.5 g) was heated on a water vapor bath together with 15 ml of 48% hydrobromic acid in 20 minutes. Within minutes, dissolution occurred and after 10 minutes, a solid began to precipitate. At the end of the reaction time, the reaction mixture was cooled to room temperature, diluted with about 25 ml of water and the crude product was filtered off. The crude product was partially purified by dissolving in 1N-K2COS and precipitating by acidification with 3N-HCl.

By recrystallization from acetic acid, purified 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine (594 mg, m.p. 206 DEG-209 DEG C.) was obtained. Analysis -% C% H% N calculated for C 9 H 9 N 2 O 3 S: 48.21 3.60 12.49 Found: 48.01 3.69 12.50 Example 61 1-oxo-1H-7-isopropylthiazolo [ 3,2-a] Pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxylate (909 mg) was heated on a water vapor bath together with 10 ml of 48% hydrobromic acid for 20 minutes. Within 5 minutes, complete dissolution occurred. Within 10 minutes, the product began to precipitate.

After completion of heating, the reaction mixture was cooled to room temperature and the crude product was filtered off.

Recrystallization from ethanol gave purified 1-oxo-1H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (538 mg, m.p. 216-217 ° C).

Example 62 1-Oxo-1H-7-phenylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-7-phenylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate ( 9.8 g) was refluxed with 200 ml of 48% hydrobromic acid for 20 minutes. Dissolution was achieved after about 10 minutes. The reaction mixture was cooled and the crude product was filtered off.

Recrystallization from acetic acid gave purified 1-oxo-1H-7-phenylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (2.2s g, m.p. 224-226 ° C).

Analysis -% C% H% N calculated for C11H1 @ N2O; S: 62.56 4.32 8.58 Found: 62.26 4.11 8.52 A second yield was obtained from the mother liquor (704 mg, m.p. 220 ° C).

Example 63 1-Oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate (27 .5 g) was heated on a water vapor bath for 35 minutes together with 275 ml of 48% hydrobromic acid. After 10 minutes, a clear solution was obtained. After 15 minutes, a product began to precipitate. : gu 4. The reaction mixture was cooled to room temperature and the rapper (14.99, m.p. 181.5-1s3, s ° c) was filtered off and washed with water. Recrystallization from dimethylformamide gave purified 1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (10.1 g, m.p. 183.5-1s, s ° c).

Analysis -% C% H% N calculated for C 12 H 12 N 2 O 4 S: 54.53 4.58 10.60 Found: 54.41 4.28 10.58 A second yield was obtained when water was added to the dimethylformamide mother liquor (3.11 g, m.p. 4 1s4 ° c).

Example Gel 1 1-Oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethl-1-oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine carboxylate (7.9 g) was mixed with 48 ml of hydrobromic acid and the mixture was heated on a water vapor bath for 50 minutes. Before the ester was completely dissolved, the acid began to precipitate. The reaction mixture was cooled, diluted with about 100 ml of water, the crude product (6.7 g) was filtered off and washed with a small volume of water.

By recrystallization of the crude product from ethanol, purified 1-oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (4.7 g, m.p. 197-198 ° C) was obtained.

Analysis -% C% H% N 1g calculated for C 1 H 11 N 2 O 2; S: 56.10 5.07 10.06 Found: 55.85 4.84 10.14 Example gel 65 1-oxo-1H-7- (2- butyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-7- (2-butyl) thiazolo [3,2-a] pyrimidine-2-xaryboxylac ( 2.0 9) b1anaaaes_mea zo m1 48% hydrobromic acid and the mixture was heated on a water vapor bath for 25 minutes. Within 5 minutes, dissolution occurred and within 10 minutes, product began to precipitate. The reaction mixture was cooled to room temperature, diluted with about 40 ml of water, the crude product (1.3 g, m.p. 191-149 ° C) was filtered off and washed with a small volume of water. By recrystallization of the crude product in ethyl acetate containing a small amount of ethanol, purified 1-oxo-1H-7- (2-butyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid (eos mg , melting point 194-197 ° C).

Analysis -% C% H% N calculated for C 11 H 12 N 2 O 3 S: 52.37 4.79 11.10 52.20 4.48 11.11 The ethyl acetate mother liquor was evaporated and it was found: kept a small amount of a second yield.

Example 66 N- (5-tetrazolyl) -1-oxo-1H-6,7-dimethylthiazolol; 2-a] pyrimidine-2-carboxamide 1-oxo-1H-6,7-dimethylthiazolo [3,2- alipyrimidine-2-carboxylic acid (367 mg, 1.6 mmol) was dissolved in 3 ml of dimethylformamide by heating on a water vapor bath. 1,1'-Carbonyldiimidazole (292 mg, 1.8 mmol) was added. Gas development occurred immediately. As soon as this ceased, 5-aminotetrazole (153 mg, 1.8 mmol) was added. Dissolution occurred and a new solid formed.

The reaction mixture was cooled, the crude product was filtered off, recrystallized from dimethylformamide to give N- (5-tetrazolyl) -1-oxo-1H-6,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxamide (336 mg). , melting point> 317 ° C).

Analysis -% C% H% N calculated for C 10 H 9 O 2 N 1 S: 41.23 3.11 33.66 Found: 41.52 3.40 33.47 Example gel 67 N- (5-tetrazolyl) -1-oxo-1H-6- Methyl 7-ethylthiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (238 mg, 1 .0 mmol) was dissolved in 5 ml of dimethylformamide and the solution was heated on a water vapor bath. 1,1'-Carbonyldiimidazole (178 mg, 1.1 mmol) was added. When gas evolution subsided, -aminotetrazole (93.5 mg, 1.1 mmol) was added. A solid began to precipitate after about 15 minutes. The reaction mixture was cooled and filtered to give N- (5-tetrazolyl) -1-oxo-1H-6-methyl-7-ethylthiazole [3,2-a] pyrimidine-2-carboxamide (227 mg, m.p. > 310 ° C).

Analysis - _% c 1% H% N calculated for C11H1102N7S: 43.27 3.63 32.11 40 61 448 732% C% H% N found 43.20 3.72 31.88 Exemggl 68 N- (5- tetrazolyl) -1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (476 mg, 2.0 mmol) was dissolved in dimethylformamide on a water vapor bath. 1,1'-Carbonyldiimidazole (357 mg, 2.2 mmol) was added to the hot solution.

After the onset of gas evolution, 5-aminotetrazole (187 mg, 2.2 mmol) was added. Within a few minutes, a solid began to form.

The reaction mixture was cooled, the crude product was filtered off, recrystallized from dimethylformamide to give N- (5-tetrazolyl) -1-oxo-1H-6-ethyl-7-methylthiazole- [3,2-a] pyrimidine-2-carboxamide ( 388 mg, mp 303 ° C, dec.

Analysis -% C% H% N calculated for C 11 H 110 O 2 N 7 S: 43.3 3.6 32.1 Found: 43.6 3.9 32.3 Example gel 69 N- (5-tetrazolyl) -1-oxo-1H-6, 7-Diethylthiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (2.52 g, 10 mmol) and 1,1'-carbonyldiimidazole (1.78 g, 11 mmol) were mixed with 15 ml of dimethylformamide and the mixture was heated on a water vapor bath, whereupon gas evolution and dissolution occurred. When gas evolution subsided, 5-aminotetrazole (1.13 g, 11 mmol) was added and heating was continued for 30 minutes. The reaction mixture was cooled, the precipitated crude product was filtered off, recrystallized from acetic acid to give purified N- (5-tetrazolyl) -1-oxo-1H-6,7-diethylthiazolo [3,2-alpyrimidine-2-carboxamide], 11 g, melting point 283 ° C, decomposition.

Analysis -% C% H% N calculated for C 12 H 13 O 2 N 1 S: 45.13 4.10 30.70; ion mass 319 found: 45.18 4.24 30.52; ionic mass 319 40 448 732 62 Example 70 N- (5-tetrazolyl) -1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-cyclopentenothiazolo [3,2-a ] pyrimidine-2-carboxylic acid (378 mg, 16 mmol) and 1,1'-carbonyldiimidazole (285 mg, 17.6 mmol) were mixed together with 3 ml of dimethylformamide and the mixture was heated on a water vapor bath. Gas evolution and dissolution occurred.

When gas evolution subsided, 5-aminotetrazole (150 gm, 17.6 mmol) was added. After a few minutes, the product began to precipitate. The reaction mixture was cooled, the crude product was filtered off, recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxamide (313 mg, m.p. c).

Analysis -% c% H% N calculated for C 11 H 9 O 2 N 7 S: 43.6 3.0 32.3 Found: 43.6 3.3 32.0 Example 71 N- (5-tetrazolyl) -1-oxo-1H-cyclohexeno- thiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (0.5 g, 2 mmol) and 1,1'-carbonyldiimide dazol (0.36 g, 2.2 mmol) was dissolved in 3 ml of dimethylformamide at room temperature. Gas development and dissolution occurred. When the gas evolution subsided, the reaction mixture was heated on a water vapor bath, during which further gas evolution occurred. To the hot solution was added 5-aminotetrazole (0.19 g, 2.2 mmol). Within a few minutes, the product began to precipitate. The reaction mixture was cooled, the crude product was filtered off, recrystallized to give purified N- (5-tetrazolyl) -1-oxo-1H--cyclohexenothiazole [3,2-a] pyrimidine-2-carboxamide (319 mg, m.p. 310 ° C, decomposition).

Analysis -% C% H% N calculated for C1 H1102 N, S: 45.42 3.49 30.90 Found: 45.59 3.62 30.44 According to an alternative procedure, the acid (2.07 g) was dissolved in 40 ml of methylene chloride and 1.74 ml of triethylamine at 0 ° C. Ethyl chloropharmate (o.ss ml) 1 8.1 ml of EEE 40 63 448 732 methylene chloride was added over the course of 20 minutes, keeping the temperature of the reaction mixture between 0 and 5 ° C; After maintaining that temperature for 45 minutes, 5-aminotetrazole (0.87 g) in 8.1 ml of dimethylacetamide was added, the reaction mixture was heated to 20 ° C for 25 minutes and kept at this temperature for 90 minutes, then the product was filtered off ( 2.0 g, m.p. 308-31000). Product prepared in this way (3.9 g) was recrystallized from dimethylacetamide to give purified N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide (3 , 1 g, melting point 314-31s ° c).

The sodium salt of this amide was prepared by dissolving 5.5 g (17.3 mmol) of the amide in 44 ml of water and 17.3 ml (17.3 mmol) of standardized 1N- -NaOH by stirring for 30 minutes (pH 11, 0). The solution was clarified and the sodium salt precipitated by adding 35 ml of acetone. The slurry was cooled to ° C, granulated for 3 hours, the sodium salt (4.9 g) was filtered off and washed with cold acetone. This sodium salt (100 mg suspended in 1 ml of water) showed a pH of 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 to S ° C over one hour and granulated at this temperature for one hour.

Sodium salt (1.68 g) was filtered off. The pH of 100 mg of recrystallized sodium salt in 1 ml of water was 8.80.

Analysis - beaded for C12H10O2N7SN8..3H2O2 H2O 13.7 weight loss on drying: 13.7 neutralization equivalent: 393 Found:: H2O 13.43 weight loss on drying: 13.8 neutralization equivalent: 391 The procedure described above (mixed anhydride) was repeated with the the change that instead of ethyl chloroformate equivalent amounts of methyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, t-butyl chloroformate, pentyl chloroformate, phenyl chloroformate and benzyl chloroformate were used. Substantially the same result was obtained. In the same manner, equivalent amounts of the other acids described in Examples 47-65 are reacted with chloroformates and then with 5-aminotetrazole to the corresponding N- (5-tetrazolyl) amides.

Example 72 N- (5-Tetrazolyl) -1-oxo-1H-cycloheptenothiazolo [s, za] pyrimain-z-carboxamia 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 mixed together with 15 ml of dimethylformamide and the mixture was heated on a water vapor bath. When gas evolution subsided, 5-aminotetrazole monohydrate (0.86 g, 8.8 mmol) was added.

A solid formed within 5 minutes. After heating for another 30 minutes, the reaction mixture was cooled and the product was filtered off. By recrystallization of the crude product from dimethylformamide, purified N- (5-tetrazolyl) -1-oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine-2-carboxamide (1.61 g, m.p. 296 ° C, dec.).

Analysis -% C% H% N calculated for C 13 H 11 N 2 O 5 N: 47.12 3.95 29.59 Found: 47.10 4.11 29.72 Example 73 N- (5-tetrazolyl) -1-oxo 1H-Cyclooctenothiazolo [3,2-1-pyrimidine-z-carboxamia] 1-oxo-1H-cyclotenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (308 mg, 1.1 mmol) was dissolved in 10 ml of di- methylformamide and the solution was heated on a water vapor bath. 1,1'-Carbonyldiimidazole (196 mg, 1.21 mmol) was added. When gas evolution subsided, -aminotetrazole (103 mg, 1.21 mmol) was added. The reaction mixture was heated for 10 minutes, during which time a solid began to precipitate. The reaction mixture was cooled, the crude product was filtered off, recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxamide (183 mg, m.p. 310 ° C, decomposition). 40 65 448 732 Analysis -% C a H% N calculated for C 11 H 15 O 2 N 7 S 2 48.69 4.38 28.39 Found: 49.01 4.63 27.35 Example gel 74 N- (5-tetrazolyl) -1-oxp-1H -7-methyl-thiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (0.91 g, 4.3 mmol ) and 1,1'-carbonyl-diimidazole (0.89 g, 5.5 mmol) were added to 5 ml of dimethylformamide and the whole was heated on a water vapor bath. When gas evolution subsided, 5-aminotetrazole (0.47 g, 5.5 mmol) was added. Before complete dissolution was achieved, a new solid began to precipitate. After a few minutes, the reaction mixture was cooled, the crude product was filtered off, recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-oxo--1n-7-methyl-thiazolo [z, za] pyrimine -z-carbaxamia (1, and, melting point> 310 ° C).

Analysis -% C% H% N calculated for C 9 H 7 O 2 N 7 S: 38.99 2.54 35.36 Found: 38.97 2.73 34.97 Example gel 75 N- (5-tetrazolyl) -1-oxo-1H-thiazolo [3,2-a] Pyrimidine-2-carboxamide 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid (1.96 g, 10 mmol) was dissolved in 20 ml of dimethylforamide on a water vapor bath . 1,1'-Carbonyldiimidazole (1.78 g, 11.0 mmol) of the saline solution. When gas evolution subsided, 5-amino-tetrazole monohydrate (1.13 g, 11 mmol) was added and a solid formed in less than one minute. After heating for an additional 15 minutes, the reaction mixture was cooled, the crude product was filtered off, recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-oxo-1H-thiazolo [3,2-a] pyrimidine. z-carboxamide (1.8 g, melting point> 31 ° C).

Analysis -% C% H% N calculated for C 25 H 50 2 N 7 S: 36.50 1.91 37.25 Found: 36.62 2.26 37.72 E91 »44 448 732 66 Example 76 N- (S-tetrazolyl) -1- oxo-1H-6-methylthiazolo [3,2-a] pyrimine-2-carboxamia 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 mixed together with 15 ml of dimethylformamide and the mixture was heated on a steam bath. Gas development and dissolution occurred. When gas evolution subsided, 5-aminotetrazole monohydrate (1.13 g, 11 mmol) was added. A solid formed in less than a minute. After heating for 5 minutes, the reaction mixture was cooled and N- (5-tetrazolyl) -1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxamide (2.33) was obtained by filtration. g, melting point> 318 ° C).

Analysis -% C% H% N calculated for C 9 H 10 O 2 N 1 S: 38.99 2.54 35.36 Found: 39.35 3.00 35.06 Example 77 N- (5-tetrazolyl) -1-oxo-1H-6- ethylthiaalo- [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-6-ethyl: aiazolo [3,2-a] pyrimidine-2-carboxylic acid (4.48 g, 20 mmol) and 1, 1'-Carbonyldiimidazole (3.57 g, 22 mmol) was mixed together with 20 ml of dimethylformamide and the mixture was heated on a water vapor bath. Gas development and dissolution occurred. When gas evolution subsided, 5-aminotetrazole monohydrate (2.27 g, 22 mmol) was added. Solid formed within a minute. The reaction mixture was heated for a further 15 minutes, cooled, the crude product was filtered off, recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-oxo-1H-6-ethylethiozo [3,2-a] pyrimidine ( 4.7 g, melting point 274 ° C, decomposition).

Analysis -% C% H% N calculated for C 11 H 9 O 7 N 7 S: 41.23 3.11 33.66 Found: 41.41 3.30 33.84 Example 78 N- (5-tetrazolyl) -1-oxo- 1H-7- (2-methyl-2-propyl) -thiazolo [3,2-a] pyrimidine-1-carboxamide 40 67 448 732 1-oxo-1H-7- (2-methyl-2-propyl) thiaz61o [ 3,2-α] -Pyrimidine-2-carboxylic acid (2.52 g, 10 mmol) and 1,1'-carbonyl diimidazole (1.78 g, 11 mmol) were mixed together with 15 ml of dimethylformamide and the mixture was dissolved. - heated on a water vapor bath. Gas evolution and dissolution occurred and a solid formed within a few minutes. Heating was continued for a total of about 10 minutes, after which the reaction mixture was cooled, the crude product was filtered off, recrystallized from dimethylformamide to give N- (5-tetrazolyl) -1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxamide (1.62 g, m.p. 280 ° C, dec.).

Analysis -% C% H% N calculated for C 12 H 13 O 2 N 7 S: 45.13 4.10 30.70 Found: 45.22 4.40 30.05 Example 79 N- (5-tetrazolyl) -1-oxo-1H- 7-Ethylthiazlo- [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimine-2-carboxylic acid (502.5 mg, 2.24 mmol) and 1,1'-Carbonyldiimidazole (399.7 mg, 2.46 mmol) was mixed together with 3 ml of dimethylformamide and the mixture was heated on a water vapor bath. Gas evolution and dissolution occurred. After gas evolution subsided, -aminotetrazole monohydrate (2S3.0 mg, 2.45 mmol) was added and a clear solution was obtained. After 2 minutes a solid began to precipitate. The mixture was heated for a further 20 minutes, cooled to room temperature, the crude product was filtered off, recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-oxo-1H-7-ethylthiazolo [3,2- a] pyrimidine-2-carboxamide (486.8 mg, m.p. 261-262 ° C, dec.).

Analysis -% C% H% N calculated for C 10 H 9 N 7 O 2 S: 41.23 3.11 33.66; ion mass 291 found: 41.35 3.31 33.55; ionic mass 291 Exemgel 80 N- (5-tetrazolyl) -1-oxo-1H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxamia 1-oxo-1H-7-isopropylthiazolo [3,2-a ] pyrimidine-2-carboxylic acid (537 mg, 2.25 mmol) and 1,1'-carbonyl diimidazole (401 mg, 2.47 mmol) were mixed together with 3 ml of dimethylformamide and the mixture was heated. was taken on a water vapor bath. Gas evolution and dissolution occurred. After gas evolution subsided, 5-aminotetrazole monohydrate (255 mg, 2.47 mmol) was added. The product immediately began to precipitate. Heating was continued for minutes, then the reaction mixture was cooled, the crude product was filtered off, recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-ox-1H-7-isopropylthiazolo [3,2-a] pyrimidine. 2-carboxamide (328 mg, mp> 300 ° C).

Analysis -% C% H% N calculated for C 11 H 11 O 2 N 7 S: 43.27 3.63 32.11 Found: 43.34 3.76 31.82 Example 81 N- (5-tetrazolyl) -1-oxo-1H-7- phenylcyclohexenothiazolo [3,2-a] pyrimidine-3-carboxamide 1-oxo-1H-7-phenylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (980 mg, 3.0 mmol) and 1.1 Carbonyldiimidazole (320 mg, 3.1 mmol) was mixed together with 12 ml of dimethylformamide and the mixture was heated on a water vapor bath. When gas evolution subsided, 5-aminotetrazole monohydrate (496 mg, 3.1 mmol) was added. After 10 minutes, the product began to precipitate. After heating for a total of one hour, the reaction mixture was cooled to room temperature, the crude product (312 mg) was filtered off, recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-oxo-1H-7-phenylcyclohexenothiazolo [3,2- a] pyrimidine-2-carboxylate (131.5 mg, m.p.> 300 ° C).

Analysis -% C% H% N calculated for C1 H1502N7S: 54.95 3.84 24.92 Found: 54.38 3.93 24.61 Example 82 N- (5-tetrazolyl) -1-oxo-1H-7- methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (1.0 g, 3.78 mmol) and 1,1'-Carbonyldiimidazole (675 mg, 4.16 mmol) was mixed in 6 ml of dimethylformamide and the mixture was heated on a water vapor bath. Gas evolution and dissolution occurred.

After gas evolution subsided, 5-aminotetrazole (429 mg, 4.16 mmol) was added and heating was continued. After a few minutes, a precipitate began to form. After 30 minutes, the reaction mixture was cooled and the crude product (melting point> 300 ° C) was filtered off. It was recrystallized from dimethylformamide to give purified N- (5-tetrazolyl) -1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide (980 mg, mp> 300 ° C).

Analysis -% C% H% N calculated for C 13 H 13 O 2 N 1 S: 47.12 3.95 29.59 Found: 47.32 4.18 29.60 Example 83 N- (5-tetrazolyl) -1-oxo-1H-7, 7-Dimethylcyclohexenothiazolo [3,2-a] pyrimine-2-carboxamide 1-oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (558 mg, 2, 0 mmol) and 1,1'-carbonyldiimidazole (357 mg, 2.2 mol) were mixed in 3 ml of dimethylformamide and the mixture was heated on a water vapor bath. Gas evolution and dissolution occurred. After gas evolution subsided, -aminotetrazole monohydrate (227 mg, 2.2 mmol) was added and heating was continued for 20 minutes. The reaction mixture was cooled and the crude product (561 mg, melting point> 300 ° C) was filtered off. Recrystallization from dimethylformamide gave purified N- (5-tetrazolyl) -1-oxo-1H-7,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxamide (469 mg, mp> 300 ° C). ).

Analysis -% C% H% N calcd for C1I4H1 50201732 48.69 4.38 28.39 Found: 48.80 4.18 28.42 Example gel 84 N- (5-tetrazolyl) -1-oxo-1H-7- (2-Butyl) -thiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-7- (2-butyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid (379 mg , 1.5 mmol) and 1,1'-carbonyldiimidazole (270 mg, 1.66 mmol) were mixed in 3 ml of dimethylformamide and the mixture was heated to a water vapor bath. Gas development and dissolution occurred. After gas evolution subsided, 5-aminotetrazole monohydrate (170 mg, 1.65 mmol) was added and the mixture, in which a precipitate formed after a few minutes, was heated for 20 minutes. The reaction mixture was then cooled to room temperature, the crude product was filtered off, recrystallized to give purified N- (5-tetrazolyl) -lifoxo-1H-7- (2-butyl) -thiazolo [3,2-a] pyrimidine-2 * carboxamide (247 mg, mp> 300 ° C).

Analysis -% C% H% N calculated for C 12 H 13 O 2 N 7 S: 45.13 4.10 30.70 Found: 45.12 4.05 30.68 Example gel 85 The procedures described in Examples 66-84 were repeated with compounds listed below for Position of the corresponding 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acids: N- (5-tetrazolyl) -1-oxo-1H-7-pentylthiazolo [3,2- a] pyrimidine-2-carboxamide; N- (5-tetrazolyl) -1-oxo-1H-6-ethyl-7-propylthiazolo [3,2-a] pyrimidine-2-carboxamide; N- (5-tetrazolyl) -1-oxo-1H-6,7-diisopropylthiazolo [3,2-a] pyrimidine-2-carboxamide; N- (5-tetrazolyl) -1-oxo-1H-6-propylthiazolo-L3,2-a] pyrimidine-2-carboxamide; N- (5-tetrazolyl) -1-oxo-1H-6-isopropylthiazolo [3,2-a] pyrimidine-2-carboxamide; N- (5-tetrazolyl) -1-oxo-1H-6-pentylthiazolo- [3,2-a] pyrimidine-2-carboxamide; N- (5-tetrazolyl) -1-oxo-1H-6-phenylcyclopentenothiazolo [3,2-a] pyrimidine-2-carboxamide; N- (5-tetrazolyl) -1-oxo-1H-6,8-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide; N- (5-tetrazolyl) -1-oxo-1H-8-methylcyclooctenothiazolo [3,2-alpyrimidine-2-carboxamide; and N- (5-tetrazolyl) -1-oxo-1H-6,8,8-trimethylcyclopentenomethylthiazolo [3,2-a] pyrimidine-2-carboxamide.

Exemgel 86 Kagsla fi Capsules were prepared by mixing 40 "448 752 of the following ingredients in the stated amounts by weight: Calcium carbonate, USP 17.6 Dicalcium phosphate 18.8 Magnesium trisilicate, USP 5.2 Lactose, USP 5.2 Potato starch _ 5.2 Magnesium stearate Magnesium stearate B 0.35 and addition of a sufficient amount of sodium N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide trihydrate to obtain capsules containing 10, 25 and 50 mg respectively of active ingredient (weight equivalent to unsolvated, non-salt form) per capsule The mixtures were filled into conventional hard gelatin capsules in an amount of 350 mg per capsule.

In the same way, capsules containing 2.0 and 6.0 mg of active ingredient and 300 mg of the following mixture per capsule were prepared: Ingredients Weight, mg / capsule Medicine 2.00 N-methylglucamine 18.00 Lactose, anhydrous 251.20 Maize starch , anhydrous 8.80 Ingredients weight, mg / capsule Medicine 6.00 g N-methylglucamine 18.00 Lactose, anhydrous 237.20 Maize starch, anhydrous 30.00 Talc 8.80 Exemgel 87 Tablets A tablet base was prepared by mixing the following Ingredients in specified amounts by weight: Sucrose, USP 80.3 Tapioca starch 13.2 'Magnesium stearate 6.5 A sufficient amount of sodium N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2 was mixed into this tablet base -carboxamide trihydrate for obtaining tablets containing 20, 100 and 250 mg of active ingredient per tablet, respectively. The mixtures were compressed into tablets in a conventional manner. For tablets with a lower strength (eg 1 mg, 2 mg, 5 mg) a lower ratio of the active ingredient to the inert ingredients of the tablet base was used.

Example 88 Solution A solution of sodium N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide was prepared as follows: Active ingredient: 6.04 g (7.49 g sodium salt trihydrate) Magnesium chloride hexahydrate: 12.36 g Propylene glycol = 376.00 g Water, distilled: 103 ml A solution with an effective ingredient concentration of 10 mg / ml was obtained in this way and suitable for parenteral, especially intramuscular administration.

Example 89 Aerosol suspension For use specifically as an antiallergic, a mixture of sodium N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide and the other ingredients listed under (a ) in the table below to a particle size of 1-5 μm in a ball mill. The slurry thus obtained was introduced into containers equipped with a valve. Fuel (b) was then introduced through the valve nozzle to an overpressure of approximately 240-275 kpa at 20 ° C.

Suepension A 'Percent (a) antiallergic agent (equivalent to unsolvated, non-salt) 0.25 Isopropyl myristate 0.10 ethanol 26.40 (b) 60-40% mixture of 1,2-dichlorotetrafluoroethane-1-chloropentafluoroethane 73 , 40 40 44 448 Susgension B (a) antiallergic agent (equivalent to unsolvated, non-salt) ethanol (b) 60-40% mixture of 1,2-dichlorotetrafluoroethane-1-chloropentafluoroethane Susgension C (a) antiallergic agent ( equivalent to unsolvated, non-salt) ethanol (b) 60-40% mixture of 1,2-dichlorotetrafluoroethane-1-chloropentafluoroethane 732 Percent 0.25 26.50 73.25 2.00 26.50 71.50

Claims (3)

í-'ä 10 l5 20 25 30 35 448 '132 74 Patentkrav A compound of the general formula R 1 is n, N and 8-membered; or each of R 1 and R 2 represents hydrogen or alkyl of 1-5 carbon atoms; and Q is N N * K / || H T H or OH, H provided that when Q is OH and R 2 is hydrogen, R 1 is not hydrogen or methyl, and when Q is OH and R 2 is methyl, R 1 is not hydrogen; or a pharmaceutically acceptable cationic salt thereof. A compound according to claim 1, characterized in that Q is A compound according to claim 2, characterized in that m 5 wherein R 5 and R 6 together represent R but and R 2 together represent butylene. A compound according to claim 2, wherein R 1 represents hydrogen and R 2 represents methyl. A compound according to claim 2, wherein R 1 represents ethyl and R 2 represents hydrogen. A compound according to claim 2, wherein R 1 represents methyl and R represents hydrogen. A compound according to claim 1, wherein Q represents OH. A compound according to claim 7, wherein R 1 represents ethyl and R 2 represents hydrogen. aV aV aV äV aV