NO803521L - PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE TIAZOLO-PYRIMIDINE-CARBOXAMIDE DERIVATIVES - Google Patents

Abstract

New, therapeutically active compounds, which have a particularly antiallergic and anti-ulcer effect, with the formula: where. The total is alkylene having 3 to 9 carbon atoms or phenylalkylene having 9 to 11 carbon atoms, with the proviso that the ring system thus formed is 5- to 8-membered; and Rog R 2 are each hydrogen or alkyl of 1 to 5 carbon atoms. Preparation of the compounds is described.

Description

The present invention relates to an analogous process for the preparation of derivatives of 1-oxo-1H-thiazolo[3,2-a]pyrimidine-2-carboxamides and their acid precursors. These amides, and in many cases their acid precursors, are useful for preventing the release of allergic mediators (histamine, serotonin, SRS-A, etc.) and can therefore be used in the treatment of bronchial asthma.

ma, hay fever, rhinitis, atopic dermatitis, etc. and can also be used as anti-ulcer agents.

Allergic reactions, symptoms arising from an antigen-antibody interaction, manifest themselves in many different ways and in different organs and tissues. Common allergic diseases are, for example, allergic rhinitis, a condition characterized by seasonal or constant sneezing, runny nose, stuffy nose, with itching and stuffy eyes; hay fever, a variety of allergic rhinitis caused by hypersensitivity to grass pollen; and bronchial asthma, one of the most crippling and debilitating of allergic reactions, a disease characterized by over-reactivity of the bronchi upon exposure to various immunogenic or non-immunogenic stimuli, resulting in bronchospasm with heavy breathing, short-lasting attacks and widespread contraction of the airway passages. The mechanical blockage of airflow in the airways is generally reversed by the use of bronchodilators, which provide symptomatic relief. In contrast to this, antiallergic agents prevent the release of mediators of anaphylaxis from tissue stores, thereby acting prophylactically to prevent the mediators from causing broncho-occlusion.

Cox et al., Adv., in Drug Res.,. 5, 115 (1970), described the pharmacology of disodium cromoglycate [1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane, Intal]. It is not a bronchodilator but mediates its therapeutic effects by inhibiting the release of mediators of anaphylaxis and is administered prophylactically. It suffers from a lack of oral efficacy and is administered for optimal results by inhalation as a solid inhalant.

Later, a number of other antiallergic agents have been described, including N-(5-tetrazolyl)-1-oxo-1H-6-alkoxypyrimido-[1,2-a]-quinoline-2-carboxamides (Kadin, U.S. patent 4,017,625), 1-oxo-1H-6-substituted-pyrimido[1,2-a]quinoline-2-carboxylic acids

(US Patent 4,066,766), tetrazolo[a]quinazol-5-ones (US Patent 4,085,213), pyrimido[2,1-a]isoquinolines (US Patent 4,127,720) and N-(5-tetrazolyl)-4- oxo-4H-pyrimido-(2,1-b)benzothiazole-3-carboxamides (US patent 4,041,163).

Chronic gastric and duodenal ulcer, collectively known as peptic ulcer, is a common disorder for which a number of treatments have been developed. The treatment depends on the severity of the ulcer and can vary from diet and medical treatment to surgical treatment. A wide range of medicines are used for wound treatment. The latest to gain widespread attention is carbenoxolone sodium, the disodium salt of the hemisuccinate of glycyrrhetinic acid. It has been reported to prevent the formation of and accelerate the healing of gastric ulcers in animals, including humans ("Carbenoxolone Sodium: A Symposium," 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 often potassium loss, so that continued therapy with this agent often leads to increased pressure, muscle weakness and finally congestive heart failure. Even later, a histamine receptor antagonist, cimetidine, has been introduced into medical practice. The latter compound relieves ulcers by reducing secretion of stomach acid.

A number of other compounds have been reported to have antiulcer activity, including 1-oxo-1H-6-piperidinopyrimidino[1,2-a]quinoline-2-carboxylic acid esters (US patent 4,014,881), 1-oxo-1H- 6-substituted-pyrimidino(1,2-a)quinoline-2-carboxylic acids and esters (US patent 4,031,217) and tetrazolopha)quinazol-5-ones (US patent 4,085,213).

The amides and most of the intermediate acids produced according to the invention are new compounds. The known acids are those of formula II where R-j_ and R2 are hydrogen or R-j_ is methyl and R2 is 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 1 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)). None of these publications describes an application for either the acids or the esters.

It has now been found that compounds of formula (I)

bg their pharmaceutically acceptable cationic salts are orally effective antiallergic and antiulcer agents. In formula (i) and R2 are each hydrogen or lower alkyl of 1 to 5 carbon atoms (such as methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl (isobutyl), pentyl, etc.) or R- ^ and R2 which together form a third,. The 5- to 8-membered, ring system is the alkylene with 3 to 9 carbon atoms, e.g.: or the phenylalkylene with 9-11 carbon atoms, e.g.: It has also been found that acids of the formula (II),

where R 1 and R 2 are as defined above, but not limited to. are valuable intermediates for the synthesis of the amides, but in many cases together with their pharmaceutically acceptable cationic salts have useful biological activity. Acids that have useful antiallergic activity are those where R^ and R2 together are alkylene with 4 to 9 carbon atoms, or phenylalkylene with 9 to 11 carbon atoms with the proviso that the ring system thus formed is 5- to 8-membered, or when each R R 2 is alkyl of 2 to 5 carbon atoms and R 2 is hydrogen or alkyl of 1 to 5 carbon atoms. The preferred acids for antiallergic use are those where R 1 and R 2 together are alkylene of 4 to 6 carbon atoms, especially butylene. Acids with a slightly different structure have antiulcer activity, namely those where R-^ and R2 together are alkylene with 3 to 9 carbon atoms or phenylalkylene with.9 to 11 carbon atoms, with the proviso that the ring system thus formed is 5- to 8-membered, or R-^

and R 2 is each hydrogen or alkyl of 1 to 5 carbon atoms, with the proviso that when R 2 is hydrogen, R 2 is different from hydrogen or methyl. In this case, the preferred compounds are those where R 1 and R 2 are each separately, especially when R 1 is ethyl and R 2 is hydrogen or alkyl of 1 to 2 carbons

atoms.

By the expression "pharmaceutically acceptable, cationic salts" is meant salts such as e.g. alkalime take Unsalts, e.g. the sodium and potassium salts; the alkaline earth metal salts such as the calcium and magnesium salts; the aluminum salts; the ammonium salts; and salts with organic bases, e.g. amines such as triethylamine, tributylamine, piperidine, triethanolamine, diethylaminoethylamine, N,N'-dibenzylethylenediamine and pyrrolidine.

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

which coexist in a dynamic, tautomeric equilibrium mixture. Both forms of the tetrazolamides lie within the scope of the invention. Compounds of particular interest in the present invention are those of formula (i) where is hydrogen or methyl and R-2 is methyl. Of these, the compound where R-^ is hydrogen is preferred, since the corresponding acid, believed to be its metabolite, also shows activity. The compounds where R 1 and R 2 together are propylene, butylene or pentylene are also of particular interest. Particularly desirable is the compound where R 1 and R 2 together are butylene, i.e. N-(5-tetrazolyl)-1-oxo-1H-cyclohexenothiazolo-[3,2-a]pyrimidine-2-carboxamide (formula III)

since it shows excellent oral activity and is very stable in

pure, solid state, as well as in the presence of standard pharmaceutical diluents and in solution. Furthermore, its metabolite (the corresponding carboxylic acid) shows good activity. The preferred form of the tetrazolylamide (III) is the sodium salt (trihydrate), which is non-hygroscopic and has good water solubility

which ensures good bioavailability.

The antiallergic properties of the compounds produced according to the invention are assessed by the passive, cutaneous anaphylaxis (PCA) test (Ovary. J. Immun., 31, 355, 1958). In the PCA test, normal animals are injected intradermally (i.d.) with antibodies contained in serum obtained from actively sensitized animals. The animals are then given intravenously antigen which is mixed with a dye, such as e.g. Evans Blue. The increased capillary permeability caused by the antigen-antibody reaction causes the dye to leak from the site of antibody injection. The test animals are then suffocated and the intensity of the reaction determined by measuring the diameter and intensity of the blue staining on the inside of the animals' skin.

The anti-ulcer activity of the compounds produced according to the invention is assessed with the so-called cold-barred experiment on stressed rats. Alternatively, the antiulcer activity is determined using a recently established ethanol-induced rat wound assay described below.

The following analogous methods for the production of the therapeutically active thiazolo-pyrimidine-carboxamide derivatives are used in the invention:

In the first step in the synthesis sequence, the suitably substituted 2-aminothiazole is condensed with a stoichiometric amount of a dialkylethoxymethylene malonate, usually with the readily available diethylethoxymethylene malonate, the choice of ester not being critical to the final desired product obtained by the invention- The Condensation carried out at a temperature of from approx. 80 to approx. 125°c. Lower temperatures are not desirable because the reaction then proceeds too slowly. Higher temperatures can be used but do not seem to offer advantages. The reaction is thus suitably carried out as a melt. It can of course be carried out in a solvent or a mixture of solvents; e.g. ethanol, N,N-dimethylformamide, acetonitrile. From a practical point of view, however, a solvent appears to be unnecessary. The products produced according to the invention are 4- and/or 5-substituted-2-(2,2-dicarbaloxyethenylamino)thiazoles. It should be noted that when R, and R2 together form a ring system, the nomenclature and numbering systems are modified as follows:

An alternative nomenclature for cyclohexenothiazoles is tetrahydrobenzothiazoles.

The second step in the synthesis sequence is the cyclization of the 4- and/or 5-substituted 2-(2,2-dicarbalkoxyethenylaminothiazoles) with the elimination of an equivalent alkanol (ethanol in the case of the ethyl ester). In one method, this cyclization is carried out by heating the intermediate to a temperature of from about 175 to about 250°C until the reaction is substantially complete, usually within one to two hours.The cyclization is advantageously accomplished by heating the intermediate in a suitable reaction-inert diluent; i.e. in a compound which enables regulation of the reaction temperature, is stable against the relatively high temperatures used and which does not react with the starting materials or the products of the cyclization. Representative of such diluents are high-boiling hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, especially that containing 26.5% diphenyl and 73.5% diphenyl ether and sold under the trademark "Dowtherm A".

The cyclization is alternatively carried out under milder conditions (70-130°C) by heating the intermediate product in the presence of an excess (1.1 to 3 equivalents) of trifluoroacetic acid in an inert solvent such as e.g. toluene, until the reaction is complete (e.g. 15-20 hours at the reflux temperature of toluene). In both methods, the products of the cyclization step are alkyl-1-oxo-1H-6-and/or-7-substituted-thiazolo[3,2-a]pyrimidine-2-carboxylates.

It should be noted that when andR^ together form a ring system, the nomenclature and numbering systems are modified as follows:

1-oxo-1H-cyclohexenothiazolo(3,2-a)pyrimidines are alternatively called 6,7,8,9-tetrahydro-1-oxo-1H-pyrimidino(2,1^b)benz-thiazoles or using another numbering system, 5,6,7,8-tetrahydro-4-oxo-4H-pyrimido(2,1-b)benzthiazoles.

It is clear that the condensation and cyclization steps can be carried out in a single operation without the need for separation of the intermediate product 2-(2,2-carbaloxyethenylamino)thiazole, either by using a sufficiently high reaction temperature so that both condensation and cyclisation are carried out , or by condensation as described above, followed by the addition of an inert solvent (if not already present) and an excess of trifluoroacetic anhydride (2.1 to 4 equivalents) and proceeding with the cyclization step.

The preferred method involves separate condensation and cyclization steps as described above. Isolation of the intermediate compound and subsequent purification of this before cyclization generally gives a cyclized product of better quality.

The esters obtained by the above condensation/cyclization are then hydrolyzed to the corresponding 1-oxo-1H-6- and/or 7-substituted-thiazolo(3,2-a)pyrimidine-2-carboxylic acids.

(Note the nomenclature and modified numbering systems described above when and R2 together form a third ring). Acid-catalyzed hydrolysis is preferred. Refluxing the ester in 48% hydrobromic acid until hydrolysis is complete (0.5 to 3 hours is generally satisfactory) is a particularly suitable method. If foaming is a problem, the hydrolysis can be carried out at slightly elevated pressure, e.g. 0.5 kg/cm 2 (overpressure)' at 85°C.

The N-(5-tetrazolyl)amides produced according to the invention are conveniently produced by dehydrating coupling of the acids with 5-aminotetrazole. The dehydrating coupling is carried out using a number of different agents which are commonly used in peptide syntheses. Representative agents include N,N'-carbonyldiimidazole, N,N'-carbonyldi-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphenylketene-p-tolylimine, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine , ethylene chlorophosphite, diethylethylene pyrophosphite, N-ethyl-5-phenyl-isoxazolium-3'-sulfonate, phenylphosphordi-(1-imidazolate) and carbodiimides such as e.g. dicyclohexylcarbodiimide, 1-cyclohexyl-3-(2-morpholinomethyl)carbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide- hydrochloride and diethylcyanamide.

The coupling agents described above are generally first reacted with the acid reactant and the resulting product is then reacted without isolation with 5-amino-tetrazole to give the desired 1-oxo-1H-6 and/or 7-substituted-thiazolo(3, 2-a) pyrimidine.

(Note the nomenclature and modified numbering systems described above when R 1 and R 2 together form a third ring).

The reaction is carried out in a reaction-inert solvent system where the acidic reactant does not need to be soluble. The only requirement for the solvent system is that it does not participate significantly in reaction with the reactants or products. The different coupling agents that can be used to carry out the dehydrating coupling enable a wide choice of solvents. Representative solvents are N,N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

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

The molar ratio of acid:coupling agent:5-aminotetrazole is generally approx. 1:1:1 to approx. 1:1,1:1,1. Higher ratios between coupling agent and 5-aminotetrazole can be used but offer no advantages. A surplus of ten mole percent is satisfactory.

As will be clear to the person skilled in the art, all reactants can be added simultaneously instead of stepwise as described above. However, pre-formation of the reactive intermediate (acid-coupling agent-product) gives a better yield of the desired N-(5-tetrazolyl)amides.

Alternatively, the desired amides can be synthesized by coupling the acids with 5-aminotetrazole using a mixed-anhydride method. in this case the acids are first converted in situ to the tertiary amine salt in the presence of a 1 to 1.1 molar excess of the amine. Various tertiary amines can be used (R'^N) for this purpose. Examples are triethylamine, N-methylpiperidine, N-methylmorpholine, dimethylaniline or quinoline. Suitable inert solvents are methylene chloride, chloroform, dimethylformamide and dimethylacetamide. It is preferred that the acid is completely dissolved by excess tertiary amine, which may require a stirring time,

along with gentle heating if necessary. The solution of

the amine salt is then reacted with an equivalent alkyl (e.g. ethyl), benzyl or phenyl chloroformate, at a temperature in the range of

-40 to 25, preferably in the range -10 to 10°C, to form a mixed anhydride: N N 0RNN N

A +Cl-i-OR l— P- A A + R -N.HCl

0=*C>0~ O^^O-C-OR;l ;in solution. Without isolation, the mixed anhydride is reacted directly with 5-aminotetrazole, preferably dissolved in an inert solvent of the same type used to prepare the mixed anhydride, to give the desired N-(5-tetrazolyl)amides. The reaction is usually started at a low temperature (such as -40 to 15°C), but may be heated to higher temperatures (such as 15 to 40 o C) to complete the reaction. The typical molar ratio of acid:amine:chloroformate:5-aminotetrazole is 1:2:1:1 to 1:2.1:1.1:1.1. Both the amides and the acids serve as intermediates for the pharmaceutically acceptable cationic salts prepared according to the invention. Salt formation is carried out by reacting the amides or acids with a suitable metal salt (such as carbonate, ethyl hexanoate, alkoxide or hydroxide) or a suitable amine in a suitable medium such as e.g. water, methanol or ethanol according to well-known methods. The salts are extracted by standard methods such as e.g. filtration if they are insoluble in the medium, by evaporation of the solvent if they are soluble in the medium or by precipitation by adding a non-solvent for sal- . tight. Many of the necessary 2-aminothiazole starting materials are described in the literature. Those not from it can be prepared by condensation of a suitable alpha-halo ketone with thiourea or by condensation of a suitable aldehyde with thiourea and sulphuryl chloride, as illustrated in special examples. Alpha haloketones, when not available in the literature, can be obtained by standard procedures, e.g. by halogenation of ketones (eg Catch et al., J. Chem. Soc, 272 (1948); Levine, Org. Synthesis Coll. Vol. II, 38 (1943); Buchman et al., J. Am. Chem. Soc. 67, 400 (1945)), by the action of hydrogen halides on diazo ketones (eg 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 alpha-halo-beta-keto acids (McPhee et al., j . Am. Chem. Soc. 66, 1132 (1944)) and the spontaneous cleavage of the dibromo derivatives of alkenyl esters (eg, Slanina et al., J. Am. chem. Soc. 58, 891 ; (1936)). ;The reactions in the synthesis sequence leading from 2-amino-thiazoles to the acids and N-(5-tetrazolo)amides of the present invention are conveniently controlled by standard thin-layer chromatography on silica gel plates containing an ultraviolet indicator, which is commercially available from many sources . The eluent is varied to suit the reaction carried out and the nature of the substituents, so that Rf values between 0 and 1.0 are obtained, and so that a distinction is made between the intermediate product that enters the reaction and the product that is produced by the reaction. An eluent that is particularly suitable for thiazole formation, condensation, cyclization and hydrolysis reactions in the present invention is chloroform'-1% ethanol, while hydrolysis and conversion of acids to N-(5-tetrazolyl)amides is best controlled by using chloroform</>5% acetic acid. As is well known to those skilled in the art, the polarity of the eluent can be reduced if materials tend to move too quickly (ie in the solvent trough). If the materials tend to move too slowly, the polarity can be raised. Such chromatography is used to determine whether the reaction is complete and to determine the purity, but can also be used to further optimize the reaction conditions (concentration, time, temperature, solvent, etc.). The products prepared according to the invention and the pharmaceutically acceptable salts thereof are useful as prophylactic agents to inhibit or prevent the release of mediators of anaphylaxis (allergy, immediate hypersensitivity reactions) and the appearance of allergic symptoms in mammals, and can be administered for such applications individually or as mixtures with other means,; e.g. with theophylline or symptomatic amines. The products produced according to the invention are also useful as anti-wound agents. These products not only accelerate the healing of such wounds but also prevent the formation of wounds and reduce gastric acid secretion in animals, including humans. They can therefore be said to be useful for the control of stomach ulcers.' The valuable compounds produced according to the invention can be administered alone, but in general they are administered with a pharmaceutical carrier selected on the basis of the desired mode of administration and standard pharmaceutical practice. For example, they can be combined with various pharmaceutically acceptable, inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aerosol sprays, 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. Furthermore, oral pharmaceutical preparations can be suitably sweetened and flavored by means of various agents of the type usually used for this purpose. The particular carrier selected and the amount of active ingredient relative to carrier are influenced by the solubility and chemical nature of the therapeutic compounds, the chosen mode of administration and the needs of standard pharmaceutical practice. When, for example, compounds prepared according to the invention are administered orally in the form of tablets, binders such as e.g. lactose, sodium citrate, calcium carbonate and dicalcium phosphate. Various disintegrants such as e.g. starch, alginic acid and certain complex silicates, together with lubricants such as magnesium stearate, sodium lauryl sulfate and talc, can also be used for the preparation of tablets for oral use. administration of these connections. For oral administration in capsule form, lactose and high molecular weight polyethylene glycols are among the preferred materials for use as pharmaceutically acceptable carriers. When aqueous suspensions are to be used for oral administration, compounds produced according to the invention can be combined with emulsifying or suspending agents. Diluents such as e.g. ethanol, propylene glycol, glycerol and chloroform and their combinations can be used as well as other materials. For parenteral administration and inhalation, solutions or suspensions of these compounds in sesame or peanut oil or propylene glycol solutions can be used, 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, should such administration methods be desirable. The aqueous solutions, including those in which the salts are dissolved in pure, distilled water, are also useful for intravenous injection provided their pH is properly adjusted in advance. Such solutions should also be suitably buffered if necessary, and the liquid diluent first made isotonic with sufficient saline or glucose. When used as prophylactic agents to prevent the release of mediators of anaphylaxis, the compounds may be administered by inhalation. Preparations suitable for inhalation may comprise 1) a solution or suspension of the active ingredient in a liquid medium of the type mentioned above for administration with an atomizing device; 2) a suspension or solution of the active ingredient in a liquid propellant such as e.g. dichlorodifluoromethane or chlorotrifluoroethane for administration from a pressurized container; or 3) a mixture of the active ingredient and a solid diluent (eg lactose) for administration from a powder inhalation device. Preparations that are suitable for inhalation using a conventional atomizing device will include approx. 0.1 to approx. 1% active ingredient; and those for use in pressurized containers will include from approx. 0.5 to approx. 2% active ingredient. Preparations for use as powder inhalants can comprise amounts of active ingredient in relation to diluent of from 1:0.5 to approx. 1:1.5. In consideration of the above factors, it is believed that an effective daily oral dosage of anti-allergy or anti-ulcer compounds produced according to the invention is for humans from approx. 10 to approx. 1500 mg per day, with a preferred range of from approx. 10 to approx. 600 mg per day in single or divided doses, or with approx. 0.2 to approx. 12 mg/kg body weight. These values are illustrative and they can naturally be higher or lower in some cases. With careful control, the dosage level can go up to as high as approx. 2 g per day. When the agent is administered parenterally for any application or by inhalation as an antiallergic agent, the effective daily dose is from approx. 0.05 to approx. 400 mg per day, and preferably from approx. 0.25 to 200 mg per day, or with approx. ;0.005 to 4 mg/kg body weight in a single or divided dose..; It is necessary that the active ingredient forms part of the preparation so that a suitable dosage form will be achieved. Ty-certainly can. f several dosage forms are administered at approximately the same time. Although preparations with less than 0.005% by weight of active ingredient can be used in certain cases, it is preferred that preparations are used which do not contain less than 0.005% of active ingredient, because otherwise the amount of carrier will be too large. The activity increases with increasing concentration of the active ingredient. The preparations can contain 10, 50, 75, 95 or even higher weight% of the active ingredient. ;The PCA test is a measure of the anti-allergic (especially anti-asthmatic) activity of a compound. Compounds that inhibit a positive PCA test induced by the rat immunochemical equivalent of human immunoglobulin E (igE), or reagin, are believed to have antiallergic activity (C. Mota, Ann.N.Y. Acad. Sci. 103, 264 (1963)) . (Reagin is the main immunoglobulin responsible for allergic asthma, anaphylaxis, high fever, food sensitivities, and certain manifestations of drug sensitivity, although recent work attributes a significant role to the IgG class of antibodies in the transmission of allergic diseases). Such compounds, when administered to a sensitive patient, human or animal, before the time the patient comes into contact with antigens or substances to which he is sensitive, will prevent the allergic reaction that would otherwise occur. They therefore provide a method for the prophylactic treatment of allergy or anaphylactic reactions of a reagin-induced nature. ;To put it another way, such compounds block the release of mediators resulting from antigen-antibody (allergic) reaction as illustrated in the PCA test using homocytotropic rat antibody — a known correlate of reactive human antibody .Inhibition of reagin antigen-antibody reactions in rats, the test animal of the PCA test, is considered representative of inhibition of human reagin antigen-antibody reactions occurring during allergic episodes. The PCA reaction test procedure used to evaluate the compounds prepared according to the invention demonstrates an excellent correlation between the activity of compounds in this test and their utility in the treatment of allergic asthma. The ability of agents to affect PCA reactions is measured on Charles River Wistar harrier rats of 170-210 g. Reagin antiserum rich in igE antibodies is prepared according to Petillo et al., Int. Arch. Allergy, 44, 309 (1973). Hyperimmunt antiserum rich in IgG antibodies against hen's egg albumin is prepared according to Orange et al., J. Exptl. With. 127, ;767 (1968). Forty-eight hours before antigen addition, the reagin antiserum is injected intradermally (i.d.) into shaved skin of a normal rat's back; 5 hours before the addition, hyperimmune antisera are injected in a similar way. In a third place, 60 meg of histamine dihydrochloride and 0.5 meg of serotonin-creatinine-sulphate are injected i.d. just before the antigen addition, as a check for antihistamine, antiserotonin and unspecified types of blockade. The compounds produced according to the invention or a salt solution are then administered i.v. and is immediately followed by the addition of 5 mg of egg albumin and 2.5 mg of Evans Blue dye in saline solution. In case of oral administration, Evans Blue dye and egg albumin are given 5 minutes after administration of the medicine. Thirty minutes later, the animals are suffocated with chloroform and the skin from the rat's back is removed and sniffed for observation. A score is given to each injection site which is equal to the product of the diameter of the site in mm and a grade of 0.1, 0.5, 1, 2, 3 or 4 proportional to the intensity of the color development. The score for a given injection site is summed for each group of five animals bg compared with the saline-treated controls. The difference is expressed as percent blocking due to the compound used. Compounds which are representative of the present invention are tested for antiallergic activity by means of the method described above and the resulting activities are given as degree (%) of protection. "Intal", disodium cromoglycate, a commercial anti-allergy agent is not included as a comparison, since it is not active when given orally. ;Compounds of formula I (amides) and II (acids, R3 is hydrogen) which have been tested for antiallergic activity by means of the PCA test are detailed in Tables I and II: ; The effectiveness of the products produced according to the invention as anti-ulcer agents is determined with the so-called cold-barred experiment with stressed rats. In this test, non-fasted female rats (Charles River C-D strain) weighing 70-140 g are administered intraperitoneally the drug or the vehicle (control animals) (in saline solution containing 1% carboxymethyl cellulose and 0.1% "Tween 80") or orally (in water) three hours before being lightly anesthetized with ether and taped lying on their backs to separate sheets of Plexiglas. After recovering from anesthesia, the restrained animals were placed horizontally in a refrigerator maintained at 10-12°c°g three hours later killed by snapping the neck. Each rat's abdomen is opened, the gastric port is clamped, the stomach is filled with saline via an oral tube, the esophagus is clamped, and the gullet is removed. The stomachs are placed in a 0.4% formaldehyde solution for approx. 30 seconds to harden the outer layers and facilitate examination. Each stomach is then cut open along the outer curvature and the glandular part (posterior stomach) examined for destruction. The number of stomach erosions, how severe they are and the color of the stomach are recorded. The Mann-Whitney-Wilcoxon rank-sum test is used to compare the median number of ulcers in the control group with the median number of ulcers in each drug-treated group to determine whether they are statistically different. (Dixon et al., "Introduction to Statistical Analysis", 3rd ed., McGraw-Hill Book Company, New York, pages 344-347, 1969). In this test, N-(5-tetrazo-lyl)thiazolo(3,2-a)pyrimidine-2-carboxamide (compound III) is very potent, as shown in detail below. ;Alternatively, the effectiveness of the products produced according to the invention as anti-ulcer agents is determined in an ethanol-induced rat wound experiment. In this test, overnight fasted male rats are given drug (5 mg/kg) or water orally fifteen minutes before an orally administered dose of absolute ethanol (1.0 ml). One hour after the addition of ethanol, the animals are killed (8/group) and the stomachs are examined for the presence of lesions. All drugs were dissolved in dilute NaOH. After being killed, the rats' stomachs were opened and a closing hemostat placed at the gastric port. ;6 ml of a 4% solution of formaldehyde was injected into the stomach with a gastric feeding tube and a second closing hemostat was used to seal the esophagus. The stomach was then removed and opened along the greater curvature and examined for ulcers. The scoring system used to quantify the ethanol-induced lesions is outlined below. ; For each group of animals, a wound index is calculated as follows: Wound formation index = (sum of scores for the group) x (sum of the number of wounds in the group) x (the part of the group with the appearance of wounds). ;Percentage inhibition of wounds is calculated as follows:;% inhibition;lOO x wound index controls - wound index medicine - treated wound index controls ;Table III shows the activity in this test for various 5-tetrazolylamides prepared according to the invention, while table IV shows the activity for different acids. ; As previously noted, the most preferred compound prepared according to the invention is that of formula III, i.e. formula i wherein R-^ and R2 together are butylene [N-(5-tetrazoly])-1-oxo-1H-cyclohexenothiazolo [3,2-a]pyrimidine-2-carboxamide, which may alternatively be called 5,6,7,8-tetrahydro-N-(5-tetrazolyl)-4-oxo-4H-pyrimido(2,1-b)berisothiazole -3-carboxamide]. In addition to its oral, antiallergic activity shown in Table i, compound 1 exhibits intravenous activity in the range of 0.03-1.0 mg/kg in the PCA test, and is 26 times more potent than "Intal" by this route of administration (as previously noted, "Intal" lacks effectiveness when given orally). Compound III also blocks changes in cutaneous permeability induced by an IgE-induced passive cutaneous anaphylaxis (PCA), but does not affect changes in permeability induced by intradermal injection of exogenous histamine and serotonin. Absence of antihistamine and antiserotonin effects shows that the antiallergic mechanism consists in inhibition of mediator release rather than antagonism at the mediator receptor. ;Compound ill inhibits dextran-induced release of histamine into the rat peritoneal cavity. Its ED^q is 0.33^ug/kg, i.p. and for "Intal" it is 14.0 µg/kg, showing the superior potency of the former. The increase in plasma histamine caused by antigen addition to rats passively sensitized with IgE-rich antiserum (passive systemic anaphylaxis is prevented by compound III). Its ED50 is 28/ug/kg, i.v., 13 times stronger than "Intal". Guinea pigs given compound III at doses of 30 mg/kg i.p. were not protected against the bronchoconstrictor effect of inhaled histamine. In the concentration range 10 to 10 m, III does not antagonize convulsions in isolated guinea pig midgut induced with acetylcholine, histamine or slow-reacting anaphylaxis substance (SRS-A) and the synthesis and release of SRS in isolated rat monocytes stimulated by an ionophore , is not inhibited by III. ;In addition to its potent activity in the ethanol-induced rat ulcer test (see Table III above), compound III is very potent in the cold-inhibited stress-induced gastric ulcer test (described in detail above), where it provides dose- dependent protection at oral doses in the range of 3 to 100 µg/kg. Compound III also protects against aspirin's ulcerative effects at doses of 100mg/kg p.o. where dose-dependent effects can be observed in the dosage range 10 to 1000 /ug/kg, p.o. with an ED^0 of 100/ug/kg. Compound III is also active in a phenylbutazone gastric ulcer mode11 where an oral ED^Q of 100/ug</>kg is observed. Although ill is a very potent anti-ulcer agent, it does not affect pentagastrin-stimulated acid release in Heidenhain's possum dogs (5 mg/kg i.v.) and is therefore different from the anti-secretory prostaglandins, and from cimetidine and atropine . "Cytoprotective", a term recently coined to describe the antiulcer effects of prostaglandins that are independent of antisecretory activity, (Robert, Advances in Prostaglandin and Thromoxane Research 2, 507. (1976); Miller et al. , Gut 20, 75 (1979); Robert et al., Gastroenterology 72, 1121 (1977)) aptly characterize the effects of compound II. Furthermore, compound III exhibits diuretic activity. When given orally, it caused a dose-related increase in urine volume at doses ranging from 0.3 to 5 mg/kg. The maximum effect was a doubling of urine volume. The concentration of sodium and potassium ions in the urine was unchanged, but due to the increase in volume, an increase in sodium and potassium excretion was observed. These findings indicate that the dose-response range for diuretic activity is significantly higher than for the antiulcer effect and just below the range for antiallergic effects (1 to 10mg/kg). Rats fasted for 24 hours were given oral doses of III of 10, 30 or 100 mg/kg. They showed no change in blood sugar levels. ;The effect of III on glucose tolerance was investigated in rats given 10, 30 or 100 mg/kg p.o. simultaneously with glucose, 1 g/kg p.p. An apparent dose-dependent improvement in glucose tolerance was observed. This effect may be caused by a delayed absorption of glucose associated with a possible effect on gastric emptying. ;Compound ill has no significant anticholinergic effects. In anesthetized dogs in cumulative doses of 5 and 15 mg/kg i.v. it caused transient depression and various variations in the heart rate. Pressure responses to epinephrine and bilateral neck occlusion were slightly reduced. The transient cardiovascular changes only occur at cumulative intravenous doses that are 5 to 10 times higher than the maximum effective intravenous dose for antiallergic action and very much higher than the oral doses needed for antiulcer action. In tolerance studies, m was given orally to dogs for a period of seven days at doses of 50, 100 and 300 mg/kg/day. Vomiting, which is common in dogs, was observed at all doses but subsequent studies revealed that emetic activity ning could be eliminated if the medicine was administered with capsules after instead of before meals. No major pathological changes were observed and microscopic examination of the liver, kidneys, heart and lungs revealed no changes. In other studies, serum enzyme levels remained stable in dogs given III intravenously for five days with consecutive daily doses of 1, 3, . 10, 3 and 3 mg/kg, normal. ;Rats were given III orally in doses of 50, 100 and 300 mg/kg/- day for 10 days. There were no resulting pathological changes in gross and microscopic assessments of the liver, kidneys, heart and lungs. Apart from a slight increase in serum glutamine pyrrole transaminase observed at the highest dose, no clinical-chemical changes were observed. ;Compound III was administered subcutaneously to mice at doses of 100, 300 or 1000 mg/kg. No symptoms or mortality were observed and it is concluded that the medicine is well tolerated acutely with a subcutaneous LD^q of 1000 mg/kg. At doses of 32 mg/kg given subcutaneously, no reactions were observed with a battery of CNS active drugs. ;Single oral doses of III, 40 mg/kg, were administered to groups of mice that were killed 6, 12, or 24 hours later. Microscopic examination of the bone marrow revealed no chromosome destruction. Similar findings were made when mice were treated for five consecutive days with a dose of 20mg/kg. In vitro studies in which III was incubated with human lymphocytes at concentrations of 1000, 100, 10 or 0 µg/ml also failed to reveal any significant drug-induced chromosome destruction. Compound II did not induce any induction point mutations 1 Ames test in vitro. From these findings it is clear that III has no clear mutagenic potential. ;In the rat PCA test, the ratio of comparable effective oral and intravenous doses of III is consistent with good oral absorption. This is supported by observations of plasma concentrations of 3 to 7 ./ug/ml one hour after oral administration of III, 50 to 300 mg/kg. In dogs, the medicine appears to be readily absorbed after oral administration of suspensions or capsules, whereby plasma concentrations of 9 to 26 yug/ml are achieved one hour after oral doses of 50 to 300 mg/kg. In both species, plasma levels of the corresponding carboxylic acid metabolite (the corresponding compound of formula II) are comparable to those of II, identifying this compound as an important metabolite of III. After the eighth daily dose, parent drug and metabolite levels were 2- to 4-fold greater than after the initial dose, suggesting that it is possible to maintain therapeutic drug levels for extended periods. ;Compound III in the solid state" alone or mixed with inert standard ingredients used in oral preparations, or in solutions, exhibits particularly good stability, which makes it easy to prepare stable preparations of this compound for clinical use. ;The following examples shall serve as illustration and not limiting the invention, and many variations are possible without deviating from the spirit or scope of the invention.; Example 1; 2- Amino-4-ethyl-5-methylthiazole; Thiourea (20.9 g, 0.275 mol) was dissolved in 250 mL ethanol under reflux. 2-Bromo-3-pentanone (41.3 g, 0.25 mol) dissolved in 50 mL ethanol was added dropwise over 25 minutes to the refluxing urea solution. After an additional 2 hours reflux treatment, the reaction mixture was boiled down to approx. 100 ml, cooled and the crude product recovered as the hydrobromide salt by filtration. : 142, found: 142) was obtained by dissolving in water and re-extracting lning with aqueous, 3n potassium hydroxide. ;Using the same method, 1-bromo-2-heptanone, 3-bromo-4-heptanone, and 4-bromo-2,5-dimethyl-3-hexanone were converted 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 combined and heated to reflux for 19 hours. The reaction mixture was cooled and desolvated 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 3 ;2-Aminocycloheptenothiazole;Thiourea (41.9 g, 0.55 mol), 2-chlorocycloheptanone (72.3 g, 0.49 mol) and 500 ethanol were combined and refluxed for 7 hours. The solvent was evaporated, leaving a semi-solid substance which was partitioned between ethyl acetate and water. Unreacted chloroketone, recovered from the ethyl acetate phase by evaporation, was combined with 20 g of thiourea and ethanol, refluxed for 24 hours, evaporated and additional crude product partitioned between ethyl acetate and water as above. in each case, product was recovered by basifying the aqueous phase with sodium sulfate, drying over anhydrous sodium sulfate, evaporating to an oil, solidifying by trituration with hexane, and filtering Purified 2-aminocycloheptenothiazole (49.5 g, mp 77-78.5°c) was obtained by recrystallization from cyclohexane. ;Example 4 ;2-Amino6-4-isopropyl lt i a z o1 ;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. The resulting exothermic reaction caused dissolution and reflux. Reflux was continued with external heating for one hour. Solvent was removed by boiling and evaporation to give an oil which crystallized on standing. Final purification of 2-amino-4-isopropylthiazole hydrobromide was achieved by trituration with ether. ;The hydrobromide salt was converted to the free base (58.6 g) by dissolving the salt in water, basifying with excess ammonium hydroxide, extracting the free base with ether, drying the ether over anhydrous sodium sulfate and evaporating to an oil. ;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, resulting in an exothermic reaction and dissolution. The solution was refluxed for 30 minutes, cooled and the solvent evaporated to give crude product as the hydrobromide salt. ;This crude salt was dissolved in hot water, filtered and the free base precipitated by addition of ammonium hydroxide. Crude base was recovered by filtration and purified 2-amino-6-phenylcyclohexenothiazole (802.4 mg, m.p. 181-183°C) obtained by recrystallization from a mixture of water and ethanol. ;Alternatively, using, on a larger scale, 3 .2 g of thiourea, 24.6 g of 2-bromo-4-phenylcy chlorhexenone and 125 ml of ethanol, the solution after a 30 minute reflux treatment, cooled in an ice bath and the hydrobromide salt recovered directly by filtration. The hydrobromide salt was dissolved in water containing traces of ethanol by heating and the free base (10.4 g, m.p. 180-182°C) precipitated by the addition of excess ammonium hydroxide. By the same method, 2-bromo-3-phenylcyclopentanone, 2-bromo-3,5-dimethylcyclohexanone, 2-bromo-3,5,5-trimethylcyclopentanone and 2-bromo-5-methylcyclooctanone were converted into either the hydrobromide salt or 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 heated to reflux for 75 minutes. The reaction mixture was cooled to room temperature and the crude product recovered as the hydrobromide salt by filtration. The crude salt was dissolved in hot water, filtered and basified with ammonium hydroxide to precipitate the free base as an oil, which crystallized on cooling. Purified 2-amino-6-methylcyclohexenothiazole (25.2 g, mp 98-100°C) was obtained by recrystallization from cyclohexane. ;Example 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 from example 5. ;Example 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 combined and heated to reflux for 5 h. Aqueous potassium hydroxide (3n, 100ml) was added and refluxing continued for a further 0.5 hour. The reaction mixture was cooled, acidified with hydrochloric acid and non-basic impurities were extracted with ether. The aqueous phase was made basic with ammonium hydroxide and the product extracted with 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 2-Amino-5-methylthiazole Thiourea (45.7 g, 0.6 mol) and propionaldehyde (7.4 g, 0.3 mol) were combined with 150 ml of chloroform and cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mol) was added over 15 minutes. The exothermic reaction was kept between 15 and 24°C. Gas evolution that occurred during the addition ceased approx. 1 hour after the addition was finished. Most of the chloroform was boiled off on a steam bath. Ethanol (150 mL) was added and the mixture refluxed for 3 hours. The reaction mixture was evaporated to an oil, which was partitioned between water and ethyl acetate. The aqueous phase was made basic with ammonium hydroxide and the product extracted into fresh ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate and evaporated to give the crude product as a white solid. Purified 2-amino-5-methylthiazole (8.36 g, mp 94-95°C) was obtained by recrystallization from cyclohexane. ;Example 10;2-Amino-5-ethylthiazole;Thiourea (45.7 g, 0.6 mol) and butyraldehyde (21.6 g, 0.3 mol) were combined with 150 ml of chloroform and cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mol) was added over 15 minutes. The exothermic reaction was maintained between 15 and 25°C. Gas evolution occurred during the addition and for approx. 1 hour after. Ethanol (400 mL) was added, the chloroform was boiled off and the reaction mixture was refluxed overnight (about 16 hours). The reaction mixture was evaporated to an oil and recrystallized 2-amino-5-ethylthiazole (11.7 g, m.p. 54-55°C) isolated according to the method from Example 9. Using the same method, 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 1 hour. The reaction mixture was cooled and the crude product precipitated with hexane. Purified 2-(2,2-dicarbethoxyethyleneamino)-4,5-dimethylthiazole (4.21 g, mp 82-83.5°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 diethylethoxymethylene malonate (4.76 g, 2 2 raiol) were combined and heated on a steam bath for 3 hours. The product, obtained as an oil on cooling, was used without further purification in the following step. ;Using the same method, 2-amino-4-pentylthiazole, 2-amino-4-propyl-5-ethylthiazole, 2-amino-4,5-diisopropylthiazole, 2-amino-5-propylthiazole, 2-amino-5 -isopropylthiazole, 2-amino-5-pentylthiazole, 2-amino-6-phenylcyclopentenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,6,6-trimethylcyclopentenothiazole and 2-amino- 7-Methylcyclooctenothiazole converted to the corresponding 2-(2,2-dicarbethoxyethyleneamino)thiazole derivatives. By the same method, the corresponding dimethyl, dipropyl and diisopropyl esters are prepared by replacing diethyl oxymethylene malonate with dimethyl, dipropyl or diisopropyl ethoxymethylene malonate. Example 13 2-(2,2-Dicarbethoxyethenylamino)-4-methyl-5-ethylthiazole 4-Methyl-5-ethylthiazole (5.68 g, 40 mmol) and diethylethoxymethylene malonate (9.52 g, 44 mmol) were heated briefly to 86°C and then cooled to give the product as an oil, which was used directly in the next step. ;Example 14 ;2-( 2, 2- Dicarbethoxyethenylamino)- 4, 5- diethylthiazole Diethylthiazole hydrochloride (15.4 g, 80 mmol), diethylethoxy- ;methylene malonate (19.0 g, 88 mmol), triethylamine (8, 1 g, 80 mmol) and ethanol (125 mL) were combined and refluxed for 2.5 h. The reaction mixture was cooled and the solvent evaporated. The resulting semi-solid product was partitioned between ethyl acetate and water. 2-(2,2-Dicarbethoxyethenylamino)-4,5-diethylthiazole (28.6 g) was obtained as a golden oil from the ethyl acetate phase by drying over anhydrous sodium sulfate and evaporation. ;Using the same method, the hydrobromide salts of 5,7-dimethylcyclohexenothiazole, 4,4,6-trimethylcyclopentenothiazole and 7-methyl-cyclooctenothiazole were converted into the corresponding 2-(2,2-dicarbethoxyethyleneamino)thiazole derivatives. By the same method, corresponding dimethyl, dipropyl and diisopropyl esters are prepared by using suitable dimethyl, dipropyl or diisopropyl ethoxymethylene malonate instead of diethyl ethoxyethylene malonate. ;Example 15 ;2-(2,2-Dicarbethoxyethenylamino)cyclopentenothiazole 2-Aminocyclopentenothiazole (3.6 g, 34.5 mmol) and diethylethoxymethylene malonate (8.2 g, 38.0 mmol) were combined and heated on a steam bath for 100 minutes. The reaction mixture was cooled and 2-(2,2-diberethoxyethyleneamino)cyclopentenothiazole (7.0 g, Rf 0.6 on silica gel thin layer chromatography with chloroform/1% ethanol as eluent) crystallized by addition of hexane. ;Example 16 ;2-(2,2-Dicarbethoxyethenylamino)cyclohexenothiazole 2-Aminocyclohexenothiazole (7.7 g, 50 mmol) and diethylethoxymethylene malonate (11.9 g, 55 mmol) were combined with 10 ml of ethanol and refluxed for 50 minutes. The reaction mixture was cooled and 2-(2,2-diberethoxyethyleneamino)cyclohexenothiazole; (15 g, Rf 0.5 on silica gel thin-layer chromatography with chloroform/-1% ethanol as eluent) precipitated by adding 50 ml of hexane. Alternatively, 58.4 g of 2-aminocyclohexenothiazole, 89.82 g of diethylethoxymethylene malonate and 584 ml of cyclohexane were combined and refluxed under nitrogen for 2.5 hours, cooled to 15°C and product (96 g, mp 113°C) obtained by filtering. Example 17 2-{2,2-Dicarbethoxyethenylamino)cyclooctenothiazole 2-Aminocyclooctenothiazole (2.0 g, 11 mmol) and diethylethoxymethylene malonate (2.62 g, 12.1 mmol) were combined and heated on a steam bath for 2.75 h .The reaction mixture was cooled and 2-(2,2-dicarbethoxyethyleneamino)cyclooctenothiazole (3.13 g, Rf 0.6 on silica gel chromatography with chloroform/1% ethanol as eluent) was precipitated by the addition of 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 combined and heated on a steam bath for 1 hour. The reaction mixture was cooled and 2-(2,2-dicarbethoxyethyleneamino)-4-methylthiazole (9.8 g, Rf 0.5 on silica gel thin layer chromatography with chloroform/1% ethanol as eluent) was precipitated by the addition of 60 ml of hexane. ;Example 19 ;2-(2,2-Dicarbethoxyethenylamino)thiazole 2-Aminothiazole (10.0g, 0.10 mol) and diethylethoxymethylene malonate (23.8g, 0.11 mol) were combined and heated on a steam bath for 1 ,25 hours. The reaction mixture was cooled and the resulting semi-solid recrystallized from hexane to give purified 2-(2,2-dicarboxytenylamino)thiazole (17.2 g in two yields, Rf on silica gel thin layer chromatography with chloroform</>1% ethanol; as eluent). ;Example 20 ;2-(2,2-Dicarbethoxyethenylamino)5-methylthiazole 2-Amino-5-methylthiazole (6.85 g, 60 mmol) and diethylethoxymethylene malonate (14.3 g, 66 mmol) were heated on a steam bath for 1 hour. The reaction mixture was cooled and the product precipitated by adding approx. 75 ml of hexane. Purified 2-(2,2-dicarbethoxyethyleneamino)-5-methylthiazole (14.1 g in two yields, Rf 0.55-0.65 on silica gel thin layer chromatography with chloroform/1% ethanol as eluent) was obtained by recrystallization from hexane. Example 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) were combined and heated on a steam bath for 45 minutes. 2-(2,2-Dicarbethoxyethenylamino)-5-ethylthiazole (27.2 g, Rf 0.6 and 0.7 respectively, by silica gel thin-layer chromatography with chloroform/1% ethanol and with 2:1 hexane:ethyl acetate as eluents) was obtained as an oil on cooling and used directly in the next step. ;Example 22 ;2-(2,2-Dicarbethoxyethenylamino)-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 combined and heated on a steam bath for 2 hours. 2-(2,2-Dicarbethoxyethenylamino)-4-(2-methyl-2-propyl)thiazole was obtained as a moist solid on cooling and used directly in the next step. Example 23 2-(2,2-Dicarbethoxyethenylamino)- 4-Ethylthiazole 2-Amino-4-ethylthiazole (20.5 g, 0.16 mol) and diethylethoxymethylene malonate (35 g, 0.17 mol) were combined and heated on a steam bath for 2 hours. 2-(2,2-Dicarbethoxyethenylamino)-4-ethylthiazole was obtained as an oil on cooling, and was used directly in the next step (Rf by silica gel thin layer chromatography with chloroform/1% ethanol as eluent). ;Using the same method, 2-amino-4-isopropylthiazole (58.6 g, 0.415 mol) and diethylethoxymethylene malonate (92 mL, 0.455 mol) were converted to 2-(2,2-dicarbethoxyethyleneamino)-4-isopropylthiazole. (Rf 0.7 on silica gel thin-layer chromatography with chloroform/1% ethanol as eluent) . ;Example 24 ;2-(2,2-Dicarbethoxyethenylamino)-6-phenylcyclohexenothiazole 2-Amino-6-phenylcyclohexenothiazole (10.4 g, 45.2 mmol) and diethylethoxymethylene malonate (10 mL, 49.5 mmol) were combined and heated in a steam bath. After 15 minutes a solution emerged. After a further 10 minutes of heating, the whole mass solidified. The crude product was recrystallized from cyclohexane to give purified 2-(2,2-dicarbethoxyethyleneamino)-6-phenylcyclohexenothiazole (15.8 g, mp 131-133°C). Example 25 2-(2,2-Dicarbethoxyethenylamino)-6-methylcyclohexenothiazole 2-Amino-6-methylcyclohexenothiazole (23.3 g, 0.139 mol) was combined with diethyl ectoxymethylene malonate (31 ml, 0.153 mol) and heated on a steam bath. After approx. After 10 minutes of heating, a clear, orange colored oil appeared. After one hour of heating, crystallization was induced by scraping. Purified 2-(2,2-dicarbethoxyethenylamino)-6-methylcyclohexenothiazole (40.2 g, m.p. 106-109°C) was obtained by recrystallization from ethanol.. ;Example 26 2-(2,2-Dicarbethoxyethenylamino)- 6 . for 1.5 hours. The ethanol was evaporated during the first part of the heating period. On cooling and scraping, the product crystallized. Purified 2-(2,2-dicarbethoxyethyleneamino)-6,6-dimethylcyclohexenothiazole (14.3 g, mp 83-85°C) was obtained by recrystallization from hexane. ;Analysis calcd:<C>17H24O4N2S: C, 57.93; H,' 6.86; N, 7.95. ;Found : C, 57.72; H, 6.66; ;N, 7.94. ;Example 2 7 ;2-(2,2-Dicarbethoxyethenylamino)-4-(2-butyl)thiazole 2-Amino-4-(2-butyl)thiazole (8.44 g, 54 mmol) and diethylethoxymethylene malonate (11.7 g, 54 mmol) were combined and heated on a steam bath for 1 h and cooled to give 2-(2,2-dicarbethoxyethyleneamino)-4-(2-butyl)thiazole (17.6 g, Rf 0.75 on silica gel thin-layer chromatography with chloroform/1% ethanol as eluent). ;Example 28 ;Ethyl 1-oxo-1H-6,7-dimethylthiazolo-(3,2-a)pyrimidine-2-carboxylate; 2-(2,2-Dicarbethoxyethenylamino)-4,5-dimethylthiazole (4.17 g, 14 mmol) was combined with 30 ml "Dowtherm A" and heated at 220°C for 1.5 hours. The reaction mixture was cooled and approx. 125 ml petroleum ether added. The solid which separated was filtered off, recombined with the mother liquor and chromatographed on a 70 x 180 mm column of silica gel with chloroform as eluent. After a first fraction of 125 ml, six fractions of 250 ml were collected, evaporated to dryness to give the crude product (2.42 g, m.p. 114-115°C). Recrystallization from cyclohexane gave purified ethyl 1-oxo-1H-4,5-dimethylthiazolo(3,2-a)pyrimidine-2-carboxylate (1.64 g, mp 119-120°C). ;Analysis calculated: C11H12N2°3S: C'52'37? H'4.79; N, 11.10; ;mass ion, 252; ;Found: : C, 52.21; H, 4.35;-N, 11.23; ;mass ion, 252. ;Example 29 ;Ethyl 1-oxo-1H-6-methyl-7-ethylthiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-4-ethyl -5-Methylthiazole (6.25 g) was combined with 30 mL of "Dowtherm A" and heated to 215°C for 2.5 hours. The reaction mixture was cooled, petroleum ether added and the crude product (1.96 g) recovered by filtration. The crude product (630 mg) was recrystallized from cyclohexane and purified ethyl 1-oxo-1H-6-methyl-7-ethylthiazolo-(3,2-a)pyrimidine-2-carboxylate (301 mg, mp 122- 124°c). Analysis calculated: C12H14N2°3S:C'54'12; H'5'30'N'10.52. ;Found : C, 54.09; H, 5.26; N, 10.63. ;Example 30 ;Ethyl-1-oxo-1H-6-ethyl-7-methylthiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-4-methyl- 5-Ethylthiazole (12g) was combined with 60ml "Dowtherm A" and heated to 205°C for 3 hours. The reaction mixture was cooled and chromatographed on a 90 x 205 mm column of silica gel, eluted with chloroform containing 1% ethanol. Seven product-containing fractions of 250 ml each were collected, combined, evaporated to an oil and rechromatographed on silica gel (60 x 600 mm) with the same eluent. Fractions (165 x 8 mL) were combined, evaporated to an oil and crystallized by 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, mp 65-66°C). ;Analysis calcd: C12H14N2O3S: C, 54.12; H, 5.30; N, 10.52; ;mass ion, 266. ;Found : C, 54.26; H, 5.23; N, 10.57; ;mass ion, 266. ;Example 31 ;Ethyl 1-oxo-1H-6,7-diethylthiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-4,5-diethylthiazole (26.1 g) and 300 ml "Dowtherm A" were combined and heated to 225°C for 3.5 hours. The reaction mixture was cooled and chromatographed on a silica gel column (60 x 320 mm). "Dowtherm A" was eluted with hexane and the product was eluted with 2:1 hexane:chloroform. Thirty-three fractions of 250 ml each were collected. The eighth to thirty-third were combined and evaporated to give ethyl 1-oxo-1H-6,7-diethylthiazolo(3,2-a)pyrimidine-2-carboxylate (22g, Rf 0.4-0.5 on silica gel thin layer chromatography with chloroform/1% ethanol as eluent), as an oil. By means of the same procedure, the following products were obtained from examples 12 and 14: 2-(2,2-Dicarbomethoxyethyleneamino)-4-ethyl-5-methylthiazole; 2-(2,2-Dicarbopropoxyethenylamino)-4-ethyl-5-methylthiazole; 2-(2,2-Dicarboisopropoxyethenylamino)-4-ethyl-5-methylthiazole; 2-(2,2-Dicarbomethoxyethyleneamino)-4,5-diethylthiazole; 2-(2,2-Dicarbopropoxyethenylamino)-4,5-diethylthiazole; 2-(2,2-Dicarboisopropoxyethenylamino)-4,5-diethylthiazole; 2-(2,2-Dicarbethoxyethenylamino)-4-pentylthiazole; 2-(2,2-Dicarbethoxyethenylamino)-4-propyl-5-ethylthiazole; 2-(2,2-Dicarbethoxyethenylamino)-4,5-diisopropylthiazole; 2-(2,2-Dicarbethoxyethenylamino)-5-propylthiazole; 2-(2,2-Dicarbethoxyethenylamino)-5-isopropylthiazole; 2-(2,2-Dicarbethoxyethenylamino)-5-pentylthiazole; 2-(2,2-Dicarbethoxyethenylamino)-6-phenylcyclopentenothiazole; 2-(2,2-Dicarbethoxyethenylamino)-5,7-dimethylcyclohexenothiazole; 2-(2,2-Dicarbethoxyethenylamino)-7-methylcyclooctenothiazole and 2-(2,2-Dicarbethoxyethenylamino)-4,4,6-trimethylcyclopenteno-methylthiazole are converted, respectively, into: 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-phenylcyclopentene thiazolo[3,2-a]pyrimidine-2-carboxylate; Ethyl 1-oxo-1H-6,8-dimethylcyclohexenothiazolo[3,2-a]pyrimidine-2-carboxylate; ;Ethyl-1-oxo-1H-8-methylcyclooctenothiazolo[3,2-a]pyrimidine-2-carboxylate and ;Ethyl-1-oxo-1H-6,8,8-trimethylcyclopentenothiazolo[3,2-a jpyrimidine -2-carboxyl t. ;Example 32 ;Ethyl 1-oxo-1H-cyclopentenothiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)cyclopentenothiazole (7.0 g) was combined with 40 ml "Dowtherm A" and heated to 225-230°C for approx. 1 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 fractions of 250 ml each were collected, combined and desolvated to give an oil. A portion of the oil was crystallized by trituration with cyclohexane to give the crude product (1.91 g). Recrystallization of 0.6 g of crude product gave purified ethyl 1-oxo-1H-cyclopentenothiazolo(3,2-a)pyrimidine-2-carboxylate (0.33 g, mp 102-103°C). ;Analysis calculated: C12H]_2<N>203S: C'54.53; H»4.58;. ;N, 10.60. ;Found : C, 54.54; H, 4.71; ;N, 10.71. ;Example 33 ;Ethyl-1-oxo-1H-cyclohexenothiazolo(3,2-a)pyrimidine-2-carboxyl ;2-(2,.2-Dicarbethoxyethenylamino)cyclohexenothiazole (12.6 g) was combined with 125 ml " Dowtherm A" and heated to 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 eluted with chloroform-1% ethanol in 14 fractions of 125 ml each. Crude ethyl 1-oxo-1H-cyclohexenothiazolo(3,2-a)-pyrimidine-2-carboxylate (10.7 g, mp 92-94°C) was obtained by combining the fractions and evaporating the solvent. ;Alternatively, 2-(2,2-diberoxyethyleneamino)cyclohexenothiazole (30 g, 0.25 mol), trifluoroacetic anhydride (101 g, 68 mL, 0.48 mol), toluene (0.3 L) and ethanol (1 L) combined and backwashed for 21 hours. The reaction mixture was cooled and 300 ml of water was added. The toluene (upper layer) was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated to 150 mL (slurry), diluted with 1 L ethanol (solution), concentrated to 280 ml, cooled to 5°c, granulated and filtered to give relatively pure ethyl 1-oxo-1H-cyclohexenothiazolo(3,2-a)pyrimidine-2-carboxylate (47 g , mp 105-106°C). ;Example 34 ;Ethyl 1-oxo-1H-cycloheptenothiazolo(3,2-a)pyrimidine-2-carboxylate ;2-Aminocycloheptenotiazole (25.2 g, 0.15 mol), diethylethoxymethylene malonate (35.7 g, 0.165 mol ) and "Dowtherm A" (400ml) were combined and heated to 220-230°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 1:1 hexane:chloroform in thirty fractions of 500 ml each. The sixth through thirty-first fractions were combined and evaporated to give the crude product as a moist solid. Purified ethyl 1-oxo-1H-cycloheptenotiazolo(3,2-a)pyrimidine-2-carboxylate (27.1 g, mp 78-79°C) was obtained by recrystallization from cyclohexane. ;The same product is obtained by heating 2-(2,2-dicarbethoxyethyleneamino)cycloheptenothiazole in "Dowtherm A" and isolation and purification in a similar manner. ;Example 3 5 ;Ethyl 1-oxo-1H-cyclooctenothiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)cyclooctenothiazole (3.13 g) was combined with 30 ml of "Dowtherm A " and heated to 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. The fractions were combined, the solvent evaporated to give an oil and solid ethyl 1-oxo-1H-cyclooctenothiazolo(3,2-a)pyrimidine-2-carboxylate (1.956 g, Rf 0.5 by thin layer chromatography on silica gel eluted with chloroform-1% ethanol) obtained by trituration with hexane. ;Example 36 ;Ethyl 1-oxo-1H-7-methylthiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-4-methylthiazole (9.8 g) was combined with 50 ml "Dowtherm A" and heated to 220°C for 2 hours. The reaction mixture was cooled and 50 ml of hexane added and the crude product recovered by filtration. Recrystallization of the crude product from ethanol gave purified ethyl 1-oxo-1H-7-methylthiazolo-(3,2-a)pyrimidine-2-carboxylate (4.6 g, mp 187-189°C). Alternatively, this ester can be prepared by condensation of 2-amino-4-methylthiazole directly with ethyl ethoxymethylene malonate by reflux treatment in 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-Dicarbethoxyethenylamino)thiazole (17.2 g) was combined with 200 ml of "Dowtherm A" and heated to 215°C for 30 minutes. The reaction mixture was cooled to give a slurry. Hexane (100 mL) was added and the crude product recovered by filtration. Recrystallization from ethanol gave purified ethyl 1-oxo-1H-thiazolo(3,2-a)pyrimidine-2-carboxylate (8.0 g, mp 184-185°C). Alternatively, this ester can be prepared by condensation of 2-aminothiazole directly with ethylethoxymethylene 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-Dicarbethoxyethenylamino)-5-methylthiazole (14.1 g) was combined with 150 ml "Dowtherm A" and heated to 220°c for 1.5 hours. The reaction mixture was cooled and approx. 300 ml of hexane added. The product was recovered by filtration and purified ethyl 1-oxo-1H-6-methylthiazolo(3,2-a)pyrimidine-2-carboxylate (6.4 g, mp 149-151°C) obtained by recrystallization from diisopropyl ether. Alternatively, this ester can be prepared by condensation of 2-amino-5-methylthiazole directly with ethylethoxymethylene malonate in boiling trichlorobenzene (Dunwell 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-Dicarbethoxyethenylamino)-5-ethylthiazole (25.7 g, 86 mmol), Trifluoroacetic anhydride (36.2 g, 172 mmol) and toluene (150 mL) were combined and heated to reflux for ca. 20 hours. The reaction mixture was evaporated to dryness and taken up in 300 ml of chloroform. The chloroform solution was washed with saturated sodium bicarbonate and then saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to dryness and triturated with diisopropyl ether to give ethyl-1-oxo-1H-6-ethylthiazolo(3,2-a)pyrimidine-2 -carboxylate (17.8 g, m.p. 148-150°C). A portion of the product (5.2 g) was recrystallized from approx. 75 ml of ethyl acetate to give further purified product (4.1 g, mp 149-150°C). Analysis calculated: C-L1H12N2°3S : C' 52<37;H'4.79; ;N, 11.10. ;Found : C, 52.30; H, 4.51; ;N, 11,14. ;Example 40 ;Ethyl 1-oxo-1H-7-(2-methyl-2-propyl)thiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-4-( 2-Methyl-2-propyl)thiazole (32.6 g) was combined with 400 ml "Dowtherm A" and heated to 230°C. for 1 hour. 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. Nine 500 ml fractions were collected. The sixth to ninth fractions were combined and evaporated to dryness to give ethyl 1-oxo-1H-7-(2-methyl-2-propyl)thiazolo(3,2-a)pyrimidine-2-carboxylate (11.4 g, mp 145-147°c). Additional product (2.04 g) was obtained from the fifth fraction by evaporating it to a moist solid and trituration with cyclohexane. One gram of the largest yield was recrystallized from cyclohexane to give further purified product (0.62 g, mp 148-149°C). ;Analysis calculated:<c>13<H>16<N>2<0>3<S:>C, 55.70; H, 5.75; ;N, 9.99. ;Found : C, 55.14; H, 5.58; ;N, 9.95. ;Example 41 ;Ethyl-1-oxo-1H-7-ethylthiazolo(3,2-a)pyrimidine-2-carboxylate 2-(2,2-Dicarbethoxyethenylamino)-4-ethylthiazole (47.7 g, 0.16 mol ) was stirred in 500 ml of toluene and trifluoroacetic anhydride (45 ml, 0.32 mol) was added. A mild exothermic reaction was noted. The reaction mixture was heated to reflux for 26 hours, cooled and 250 ml of ethyl acetate added. The mixture was carefully extracted with 250 ml of aqueous sodium bicarbonate (evolution of carbon dioxide) and 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 recovered by filtration. Recrystallization of the crude product from acetonitrile gave purified ethyl-1-oxo-1H-7-ethylthiazolo(3,2-a)pyrimidine-2-carboxylate (10.33 g, mp 175-177°C). ;Analysis calculated: c 11H]_2N2O3S: C/52'37'H'4'79? ;N, 11.10. ;Found : C, 52.34; H, 4.85; ;N, 11.27 ;A second crop (1.58 g, mp 176-178°C) was obtained from the acetonitrile mother liquor. ;Example 42 ;Ethyl 1-oxo-4H-7-isopropylthiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-4-isopropylthiazole (10 g) was combined with 100 ml "Dowtherm A" and. heated at 220°C for 2 hours, cooled to room temperature overnight and reheated to 220°C for a further 5 hours. The mixture was cooled to room temperature, approx. 200 ml of hexane was added and filtered to remove traces of insoluble substances. The hexane was evaporated and the residue chromatographed at approx. 500 g silica gel. "Dowtherm A" was eluted with hexane and the product eluted with chloroform. Fractions containing product were combined and evaporated to dryness, the residue slurried in diisopropyl ether and the product (m.p. 143-144°C) recovered by filtration. 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, mp 145-147°C, n.m.p.: singlets at £8.6 and £7.3 corresponding to one proton each, and multiplets centered at £4.2 and Sl.2 corresponding to three protons and nine protons respectively. ;Example 43 ;Ethyl-l-oxo-lH-7- phenylcyclohexenothiazolo(3,2-a)pyrimidine-2-carboxylate;2-(2,2-Dicarbethoxyethenylamino)-6-phenylcyclohexenothiazole (15.3 g, 38.2 mmol) was slurried in 150 ml of toluene.Trifluoroacetic anhydride (10.3 ml , 76.5 mmol) was added to give a clear solution which was refluxed for 16 hours. The reaction was cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 5% sodium carbonate solution and once with 150 mL 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-phenylcyclohexenothiazolo(3, 2-a)-pyrimidine-2-carboxylate (9.89 g, m.p. 160-161.6°C). ;Example 44 ;Ethyl-1-oxo-1H-7-methylcyclohexenothiazolo(3,2-a)-pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-6-methylcyclohexenothiazole (40.2 g, 0.119 mol ) was dissolved in 400 ml of toluene. Trifluoroacetic anhydride (33.5 mL, 0.237 mol) was added which led to a mild exothermic reaction. 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 ln potassium carbonate solution and once with 400 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization from cyclohexane containing a small amount of ethyl acetate gave purified ethyl 1-oxo-1H-7-methylcyclohexenothiazolo(3,2-a)pyrimidine-2-carboxylate (29.3 g, mp 127-129°C). ;Example 45 ;Ethyl-1-oxo-1H-7,7-dimethylcyclohexenothiazolo(3,2-a)-pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-6,6-dimethylthiazole (13 g, 36.9 mmol) was dissolved in 130 mL of toluene. Trifluoroacetic anhydride (10.4 mL, 73.6 mmol) was added and the mixture heated to reflux for 16 h. 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. Recrystallization from hexane gave purified ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo-(3,2-a)pyrimidine-2-carboxylate (9.40 g, mp 92-94°C). ;Analysis calcd: c15<H>16<N>2°3S: C, 58.80; H, 5.92; ;N, 9.14. ;Found : C, 58.93; H, 5.48; ;N, 9.01. ;Example 46 ;Ethyl 1-oxo-1H-7-(2-butyl)thiazolo(3,2-a)pyrimidine-2-carboxylate ;2-(2,2-Dicarbethoxyethenylamino)-4-(2-butyl) thiazole (17.6 g) was combined with 175 ml "Dowtherm A" and heated to 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 2:1 chloroform:hexane. Fractions 4-8 (500 ml each) were combined and evaporated to an oil, which was taken up in approx. 400 ml of hot hexane, treated with charcoal and cooled to give crystalline ethyl 1-oxo-1H-7-(2-butyl)thiazolo(3,2-a)pyrimidine-2-carboxylate (2,12 g, mp 105.5-108°C). Analysis calcd:<C>13<H>16°3<N>2<S:>C'55'70'H, 5.75; ;N, 9.99. ;Found : C, 55.82; H, 5.40; ;N, 10.22. ;Example 47 1-Oxo-1H-6,7-dimethylthiazolo(3,2-a)pyrimidine-2-carboxylic acid Ethyl-1-oxo-1H-6,7-dimethylthiazolo(3,2-a)pyrimidine-2- carboxylate (1.41 g) was heated on a steam bath with 20 ml of 48% hydrobromic acid for 1 hour. Dissolution occurred within minutes and solids began to form at the end of the reaction period. The reaction mixture was cooled and the product recovered by filtration. Recrystallization from ethanol gave purified 1-oxo-1H-6,7-dimethylthiazolo(3,2-a)pyrimidine-2-carboxylic acid (508 mg, mp 189-190°C). ;Analysis calcd: CgH 3 O 3 N 2 S: C, 48.21; H, 3.60,;N,. 12.49; mass ion, 224. ;Found : C, 48.21; H, 3.68; ;N, 12.44; mass ion, 224. ;Example. 48 ;1-oxo-1H-6-methyl-7-ethylthiazolo(3,2-a)pyrimidine-2-carboxylic acid;Ethyl-1-oxo-1H-6-methyl-7-ethylthiazolo(3,2- a) pyrimidine-2-carboxylate (971 mg) was heated on a steam bath with 15 ml of 48% hydrobromic acid. Resolution occurred almost immediately. Heating was continued for 2.5 hours at which time the reaction mixture cooled and formed a filterable solid. Recrystallization of the crude product from isopropyl alcohol gave purified 1-oxo-1H-6-methyl-7-ethylthiazolo(3,2-a)pyrimidine-2-carboxylic acid (354 mg, mp 201-202°C). ;Analysis calculated:<c>i0<H>io°3<N>2<S:>C'50'41'H'4'23; ;N, 11.76. ;Found : C, 50.28; H, 4.26; ;N, 11.80. ;Example 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-carboxylate (1.33 g) was heated on a steam bath with 10 ml of 48% hydrobromic acid for 30 minutes, at which time a solid began to form. The mixture was cooled and crude product recovered by filtration. Recrystallization from isopropyl alcohol gave purified 1-oxo-1H-6-ethyl-7-methylthiazolo(3,2-a)pyrimidine-2-carboxylic acid (596 mg, mp 174-176°C). ;Analysis calcd:<c>i0<H>io°3<N>2<S:>C'50'41'H, 4.23; ;N, 11.76. ;Found : C, 50.44; H, 4.22; ;N, 11/32. Example 50 1-oxo-1H-6,7-diethylthiazolo(3,2-a)pyrimidine-2-carboxylic acid Ethyl-1-oxo-1H-6,7-diethylthiazolo(3,2-a)pyrimidine-2 -carboxylate (19.2 g) was heated to 85°C with 48% aqueous HBr for 1 hour. Gas evolution (probable decarboxylation of the product) was noted. The reaction mixture was cooled and basified with conc. ammonium hydroxide, and unreacted starting material and impurities extracted away with ethyl acetate. The aqueous phase was acidified with acetic acid and solid product recovered by filtration. The crude product was recrystallized from isopropyl alcohol, which gave purified product in two yields (5.4 g). Partially purified material (2.5 g) was recrystallized a second time from isopropyl alcohol, whereby purified 1-oxo-1H-6,7-diethylthiazolo(3,2-a)pyrimidine-2-carboxylic acid (1,6 g, mp 104-106°C, hazy). ;Analysis calculated: C-^H-^O^^: C , 52 , 37; H, 4, 79; ;N, 11.10. ;Found : C , 52 , 31; H, 4, 79; ;N, 11,16. ;Example 51 ;1-Oxo-1H-cyclopentenothiazolo(3,2-a)pyriroidine-2-carboxylic acid;Ethyl 1-oxo-1H-cyclopentenothiazolo(3,2-a)pyrimidine-2-carboxylate (1.3 g ) was heated with 15 ml of 48% hydrobromic acid on a steam bath for 30 minutes. Resolution occurred after approx. 5 minute course; a solid began to form at the end of the heating period. The reaction mixture was cooled and a crude product recovered by filtration. Recrystallization from isopropyl alcohol gave purified 1-oxo-1H-cyclopentenothiazolo(3,2-a)-pyrimidine-2-carboxylic acid (0.51 g, mp 202-203.5°C). ;Analysis calcd: Cl0H303N2S: C, 50.84; H, 3.41; N, 11.36. ;Found : C, 50.42; H, 3.57; N, 11.65. ;The sodium and potassium salts are obtained by dissolving the free acid in water with an equivalent of the appropriate hydroxide and either evaporating the water in a vacuum or freeze-drying. The N-methylmorpholine salt is prepared by dissolving the acid in methylene chloride with a small excess of N-methylniorfolin 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 g ) was heated on a steam bath with 30 ml of 48% hydrobromic acid. Dissolution occurred within minutes of starting the heating; precipitation of product had begun 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, mp 188-189°C) isolated by filtration. Recrystallization from ethanol gave 1.38 g with the same melting point. Alternatively, this product was prepared by stirring 22.3 g of the ethyl ester with 223 ml of 48% hydrobromic acid in a low-pressure vessel. Dissolution occurred at 65-70°C. The reaction mixture was heated over a 40-minute period to a maximum temperature of 85°C and a maximum pressure of 0.5 kg/cm<2>gauge. The reaction mixture was cooled to 45°c, vented, cooled to 5°c, stirred for 1 hour and the relatively pure product recovered directly by filtration (12.4 g, mp 192-194°c). The sodium salt is prepared by dissolving the acid in methanol with an equivalent amount of sodium methoxide and evaporating to dryness or precipitating the salt by cooling and adding hexane. ;Example 53 ;1-Oxo-1H-cycloheptenothiazolo(3,2-a)pyrimidine-2-carboxylic acid;Ethy1-1-oxo-1H-cycloheptenothiazolo(3,2-a)pyrimidine-2-carboxylate (5.8 g ) was heated for 15 minutes on a steam bath with 50 ml of hydrobromic acid. The reaction mixture was poured into ice, stirred and the crude product recovered by filtration. Recrystallization from ethanol gave purified 1-oxo-1H-cycloheptenotiazolo(3,2-a)pyrimidine-2-carboxylic acid (2.63 g, mp 162-163°C). ;Analysis calculated: C12Hi2O3<N>2<S:>C'54'53; H- 4.58:,;N, 10.60; mass ion, 264. Found : C , 54.72; H, 4.73; ;N, 10.88; mass ion, 264. ;Amine salts are prepared by adding one equivalent of amine to a hot ethanol solution of the acid followed by cooling, concentration or addition of hexane. ;Example 54 ;1- Oxo-1H-cyclooctenothiazolo(3,2-a)pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-cyclooctenothiazolo(3,2-a)pyrimidine-2-carboxylate (1.23 g) was heated in an oil bath with 30 ml of 48% hydrobromic acid at 90°C for 4 hours. The reaction mixture was cooled, the pH adjusted to 1.5 and the product extracted with ethyl acetate. The ethyl acetate extract was washed with water and then saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to an oil. The oil was redissolved in ethyl acetate and the product extracted with 1N potassium hydroxide. The basic solution was acidified again with 3N hydrochloric acid and the product was extracted back with ethyl acetate. The ethyl acetate solution was extracted with water and then saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give 1-oxo-1H-cyclooctenothiazolo(3,2-a)pyrimidine-2-carboxylic acid (308 mg, Rf 0.6 on silica gel thin-layer chromatography with chloroform/1% ethanol as eluent). ;The method from examples 47 to 53 is used to convert the corresponding alkyl-1-oxo-1H-thiazolo(3,2-a)pyrimidine-2-carboxylates from 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-1H-6-pentylthiazolo[3,2-a]pyrimidine-2-carboxylic acid; 1-Oxo-1H-6-phenylcyclopentenothiazolo[3,2-a]pyrimidine-2-carboxylic acid; 1-Oxo-1H-6,8-dimethylcyclohexenothiazolo[3,2-a]pyrimidine-2-carboxylic acid; 1-Oxo-1H-8-methylcyclooctenothiazolo[3,2-a]pyrimidine-2-carboxylic acid and 1-Oxo-1H-6,8,8-trimethylcyclopentenothiazolo[3,2-a]pyrimidine-2-carboxylic acid. Example 55 1-Oxo-1H-7-methylbiazolo(3,2-a)pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-7-methylthiazolo(3,2-a)pyrimidine-2-carboxylate (3,1 g) was heated on a steam bath with 50 ml of 48% hydrobromic acid. Resolution occurred within 5 minutes. After approx. After 15 minutes of heating, the reaction mixture was cooled and the product, which precipitated, was recovered by filtration. Recrystallization from acetic acid gave purified 1-oxo-1H-7-methyl-thiazolo(3,2-a)pyrimidine-2-carboxylic acid (1.4 g, m.p. 265°c, (dec.)). Analysis calcd: CqH6<0>3<N>2S: C, 45.71; H, 2.88; N, 13.33. ;Found: C, 45.57; H , 3.04; N, 13.40. ;Example 56 ;1-Oxo-1H-thiazolo(3,2-a)pyrimidine-2-carboxylic acid Ethy1-1-oxo-1H-thiazolo(3,2-a)pyrimidine-2-carboxylate (7.5 ;g ) was heated on a steam bath for 20 minutes with 80 ml of 48% hydrobromic acid. Dissolution occurred within 5 minutes and precipitation of a solid began a few minutes later. The reaction mixture was cooled in an ice bath and the crude product recovered by filtration. Purified 1-oxo-1H-thiazolo(3,2-a)pyrimidine-2-carboxylic acid (4.66 g, m.p. 276°C (dec.)). ;Analysis calcd: C-^O^S: C, 42.86; H, 2.06; N, 14,28. Found: C, 42.71; H, 2.21; N, 14.32. Alternatively, this acid can be prepared from the same intermediate by refluxing it in excess 2n hydrochloric acid (Allen et al., J. Org. Chem., 24, 779 (1959)). ;Example 57 ;l-Oxo-lH-6-methylthiazolo(3,2-a)pyrimidine-2-carboxylic acid Ethyl l-oxo-lH-6-methylthiazolo(3,2-a)pyrimidine-2-carboxylate (5 .96 g) was heated on a steam bath for 1 hour with 60 ml of 48% hydrobromic acid. The reaction mixture was cooled in an ice bath and the crude product recovered by filtration and washed with isopropyl alcohol and ether. Recrystallization of the crude product from dimethylformamide gave purified 1-oxo-1H-6-methylthiazolo(3,2-a)pyrimidine-2-carboxylic acid (3.73 g, mp 246-248°C (dec.)). ;Analysis calculated: CQH,0oN_S: C, 45.71; H, 2.88; N, 13,33.; b b J2. ;Found : C, 45.87; H, 2.94; N, 13.47. Alternatively, this acid can be prepared from the same intermediate by reflux treatment in 2n hydrochloric acid (Dunwell et al., J. Chem. Soc. (C) 1971, 2094). ;Example 58 ;1-Oxo-1H-6-ethylthiazolo(3,2-a)pyrimidine-2-carboxylic acid Ethy1-1-oxo-1H-6-ethylthiazolo(3,2-a)pyrimidine-2-carboxy-; lat (12.6 g) was heated on a steam bath with 125 ml of 48% hydrobromic acid. Resolution occurred within minutes. After 10 minutes, a precipitate began to form. Heating was continued for a total heating time of 40 minutes. The reaction mixture was cooled and the crude product (10.1 g) recovered by filtration. Recrystallization of 2.32 g of crude product; (of 6.3 recovered from attempted recrystallization from acetic acid); from isopropyl alcohol gave purified 1-oxo-1H-6-ethylthiazolo(3,2-a)-pyrimidine-2-carboxylic acid (1, 85 g, mp 162-163°c). Analysis calcd: CgHgO^S: C, 48.21; H, 3.60; N, 12.49. ;Found : C, 48.17; H, 3.73; N, 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 steam bath for 6 hours with 60 ml of 48% hydrobromic acid. After approx. 10 minutes, before complete dissolution of the ester, the reaction mixture became very thick. At the end of the heating period, the reaction mixture was cooled and crude product recovered by filtration. Recrystallization from acetic acid and drying over dimethylformamide gave purified 1-oxo-1H-7-(2-methyl-2-propyl)thiazolo(3,2-a)pyrimidine-2-carboxylic acid (333 g, m.p. 241-242° C (dec.)). ;Analysis calculated:<c>11<H>i2°3<N>2<S:>C'52, 37; H'4'79; N' 11'10- ;Found : : C, 52.45. ; H, 4.82; N, 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-carboxyl (1) .5 g) was heated on a steam bath with 15 ml of 48% hydrobromic acid for 20 minutes. Within 5 minutes dissolution occurred and after 10 minutes precipitation of a solid began. By. end of the reaction period, the mixture was cooled to room temperature, diluted with approx. 25 ml of water and the crude product recovered by filtration. The crude product was partially purified by dissolution in 1N potassium carbonate solution and reprecipitation by acidification with 3N hydrochloric acid. Recrystallization from acetic acid gave purified 1-oxo-1H-7-ethylthiazolo(3,2-a)pyrimidine-2-carboxylic acid (594 mg, m.p. 206-209°C). ;Analysis calcd: CoHoN_0_S: C, 48.21; H, 3.60; N, 12.49.;y oz 6;Found : C, 48.01; H, 3.69; N, 12.50. Example 61 1-Qxo-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 steam bath with 10 ml of 48% hydrobromic acid for 20 minutes. Within 5 minutes, resolution occurred; within 10 minutes the product started falling out. After the heating period, the reaction mixture was cooled to room temperature and crude product recovered by filtration. Recrystallization from ethanol gave purified 1-oxo-1H-7-isopropylthiazolo-(3,2-a)pyrimidine-2-carboxylic acid (538 mg, mp 216-217°C). ;Example 62 ;l-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 heated to reflux with 200 ml of 48% hydrobromic acid for 20 minutes, dissolution occurring after approx. 10 minute course. The reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from acetic acid gave purified 1-oxo-1H-7-phenylcyclohexenothiazolo-(3,2-a)pyrimidine-2-carboxylic acid (2.25 g, mp 224-226°C). ;Analysis calculated: C.-H. N O S: C, 62.56; H, 4.32; N, 8.58. ;J- / J. 4-2. j; Found : C, 62.26; H, 4.11; N, 8.52. A second yield was obtained from the mother liquor (704 mg, mp 217-220°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 steam bath with 275 ml of 48% hydrobromic acid for 35 minutes. After 10 minutes a clear solution emerged; after 15 minutes precipitation of the product began. The reaction mixture was cooled to room temperature and crude product (14.9 g, m.p. 181.5-183.5°C) recovered by filtration with water washing. Recrystallization from dimethylformamide gave purified 1-oxo-1H-7-methylcyclohexenothiazolo(3,2- a) pyrimidine-2-carboxylic acid (10.1 g, m.p. 183.5-185.5°C). ;Analysis calcd: C12H12<N>2<0>3S: C, 54.53; H, 4.58; N, 10.60. Found: C, 54.41; PI, 4.28; N, 10.58. A second yield was obtained by adding water to the dimethylformamide mother liquor (3.11 g, mp 182-184°C). ;Example 64 ;1-Oxo-1H-7,7-dimethylcyclohexenothiazolo(3,2-a)-pyrimidine-2-carboxylic acid ;Ethy1-1-oxo-1H-7,7-dimethylcyclohexenothiazolo(3,2-a)- Pyrimidine-2-carboxylate (7.9 g) was combined with 80 ml of 48% hydrobromic acid and heated on a steam bath for 50 minutes. Before dissolution of the ester was complete, precipitation of the acid began. The reaction mixture was cooled, diluted with approx. 100 ml of water and crude product (6.7 g) recovered by filtration and washed with a small amount of water. Recrystallization of the crude product from ethanol gave purified 1-oxo-1H-7,7-dimethylcyclohexenothiazolo(3,2-a)pyrimidine-2-carboxylic acid. (4.7 g, mp 197-198C). ;Analysis calculated: c ]_3Hi4N2°3S : C'56'10:H- 5.07; N, 10.06. Found: C, 55.85; H, 4.84; N, 10,14. Example 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-carboxylate (2.0 g) was combined with 20 ml of 48% hydrobromic acid and heated on a steam bath for 25 minutes. Within 5 minutes, resolution occurred; within 10 minutes precipitation of the product began. The reaction mixture was cooled to room temperature, diluted with approx. 40 ml of water and crude product (1.3 g, m.p. 191-194°c) recovered by filtration with washing with a little water. Recrystallization of the crude product from ethyl acetate containing a small amount of ethanol gave purified 1-oxo-1H-7-(2-butyl)-thiazolo(3,2-a)pyrimidine-2-carboxylic acid (606 mg,, mp 194-197° C). Analysis calculated: cnHi2N2°3S : C'.52'37>H'4-79; N*H/10. Found: C, 52.20; H, 4.48; N, 11,11.

The ethyl acetate mother liquor was concentrated to obtain a small second yield.

Example 66

N-(5-Tetrazolyl)-1-oxo-1H-6,7-dimethylthiazolo(3,2-a)-pyrimidine-2-carboxamide l-Oxo-1H-6,7-dimethylthiazolo(3,2-a )pyrimidine-2-carboxylic acid (367 mg, 1.6 mmol) was dissolved in 3 mL of dimethylformamide by heating on a steam bath. 1,1<1->Carbonyldiimidazole (292 mg, 1.8 mmol) was added. A gas immediately developed. As soon as gas evolution ceased, 5-aminotetrazole was added.

(153 mg, 1.8 mmol). A solution occurred and a new solid formed. The reaction mixture was cooled and crude product obtained by filtration. Recrystallization of the crude product from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-6,7-dimethylthiazolo(3,2-a)pyrimidine-2-carboxamide (336 mg, 317°C). • Analysis calculated: Cl0Hg02N7S: C, 41.23; H, 3.11; N, 33.66.

Found: C, 41.52; H, 3.40; N, 33.47.

Example 67

N-(5-Tetrazolyl)-1-oxo-1H-6-methyl-7-ethyl-thiazolo-(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 heated on a steam bath. 1,1'-Carbonyldiimidazole (178 mg, 1.1 mmol) was added. When gas evolution ceased, 5-aminotetrazole (93.5 mg, 1.1 mmol) was added. A solid began to fall out after approx. 15 minute course. The reaction mixture was cooled and filtered to give N-(5-tetrazolyl)-1-oxo-1H-6-methyl-7-ethylthiazolo-(3,2-a)pyrimidine-2-carboxamide (227 mg, mp 310° C).

Analysis calcd: C^H^C^N-^: C, 43.27; H, 3.63; N, 32,11. Found: C, 43.20; H, 3.72; N, 31.88.

Example 68

N-(5-Tetrazolyl)-1-oxo-1H-6-ethyl-7-methylthiazolo-(3,2-a)pyrimidine-2-carboxamide l-Oxo-1H-6-ethyl-7-methylthiazolo(3, 2-a)pyrimidine-2-carboxylic acid (476 mg, 2.0 mmol) was dissolved in dimethylformamide on a

steam bath. 1,1'-Dicarbonylimidazole (357 mg, 2.2 mmol) was added to the hot solution; gas development occurred. As soon as gas evolution stopped, 5-aminotetrazole (187 mg, 2.2 mmol) was added. Within a few minutes a solid began to form. The reaction mixture was cooled and the crude product obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-6-ethyl-7-methylthiazolo (3,2-a).-pyrimidine-2-carboxamide ( 388 mg, mp 303°C (dec )).

Analysis calculated: ciiHn°2N7S:C'43.3; 11' 3'5;N'32 >lm Found : C, 43.6; H, 3.9; N, 32 , 3 .

Example 69

N-(5-Tetrazolyl)-1-oxo-1H-6,7-diethylthiazolo-(3,2-a)pyrimidine-2-carboxamide l-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 combined with 15 mL of dimethylformamide and heated on a steam bath. Gas evolution and dissolution occurred. When gas evolution ceased, 5-aminotetrazole (1.13 g, 11 mmol) was added and heating continued for 30 minutes. The reaction mixture was cooled and the precipitated product recovered by filtration. Recrystallization of the crude product from acetic acid gave purified N-(5-tetrazolyl)-1-oxo-1H-6,7-diethylthiazolo(3,2-a)pyrimidine-2-carboxamide (1.11 g, mp 283°C ( Dec.)).

Analysis calcd: C12H13O2<N>7<S:>C, 45.13; H, 4.10;

N, 30.70; mass ion, 319. Found : C, 45.18; H, 4.24;

N, 30.52; mass ion, 319.

Example 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 combined with 3 mL of dimethylformamide and heated in a steam bath. Dissolution and gas evolution were observed. When gas evolution ceased, 5-aminotetrazole (150 mg, 17.6 mmol) was added. Within minutes the product started to fall out. The reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-cyclopentenothiazolo(3,2-a)pyrimidine-2-carboxamide (313 mg, mp >310°C).

Analysis calcd: C 2 H 2 O 2 - 2 S: C, 43.6; H, 3.0; N, 32.3. Found: C, 43.6; H, 3.3; N, 32.0.

Example 71

N-(5-Tetrazolyl)-1-oxo-1H-cyclohexenothiazolo-(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'-carbonyldiimidazole (0.36 g, 2.2 mmol) were dissolved in 3 ml of dimethylformamide at room temperature. Dissolution and gas evolution were observed. When gas evolution ceased, the reaction mixture was heated on a steam bath and more gas evolved during this treatment. 5-Aminotetrazole (0.19 g, 2.2 mmol) was added to the hot solution. Within a few minutes, the elimination of product began. The reaction mixture was cooled and crude product recovered by filtration. Recrystallization of the crude product gave purified N-(5-tetrazolyl)-1-oxo-1H-cyclohexenothiazolo(3,2-a)pyrimidine-2-carboxamide (319 mg, m.p. 310°C (dec.)).

Analysis calculated:<c>i2Hn°2<N>7S:C'45 ' 42; H'3 '49 ; N'30 '90 • Found: C, 45, 59; I-1, 3 , 62 ; N , 30 , 44 .

Alternatively, the acid (2.07 g) was dissolved in 40 ml of methylene chloride

rid and 1.74 ml of triethylamine at 0°c. Ethyl chloroformate (0.85 ml)

in 8.1 ml of methylene chloride was added over 20 minutes, while the temperature of the mixture was kept between 0 and 5°c. After holding at 0-5°C for 45 minutes, 5-aminotetrazole (0.87 g) in 8.1 ml of dimethylacetamide was added, and the reaction mixture was warmed to 20°C over 25 minutes and held at this temperature for 90 minutes. The product was obtained by filtration (2.0 g, mp 308-310°C). Product produced in this way (3.9

g) was recrystallized from dimethylacetamide and purified N-(5-tetrazolyl)-1-oxo-1H-cyclohexenothiazolo(3,2-a)-

pyrimidine-2-carboxamide (3.1 g, mp 314-315°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) standardized in sodium hydroxide by stirring for 30 minutes (pH 11). The solution was clarified and the sodium salt precipitated by adding 35 ml of acetone. The slurry was cooled to 5°C, granulated for 3 hours and the sodium salt (4.9 g) obtained by filtration and washing 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 for one hour to 5°C and granulated at this temperature for 1 hour. Sodium salt (1.68 g) was obtained by filtration. Recrystallized sodium salt (100 mg) in 1 ml of water had a pH of 8.80.

Analysis calcd.: C12H1002N7SNa.3H2O: H2O, 13.7; loss of weight on drying, 13.7;

neutralization

equivalent, 393..

Found ho, 13.43; loss of weight on drying, 13.8; .neutral li sa tion equivalent, 391.

In the mixed anhydride process described above, equivalent amounts of methyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, tert-butyl chloroformate, pentyl chloroformate, phenyl chloroformate or benzyl chloroformate are used instead of ethyl chloroformate with essentially equivalent results. Similarly, equivalent amounts of the other acids described in Examples 47 to 65 are reacted with chloroformates, and then with 5-aminotetrazole to give the corresponding N-(5-tetrazolyl)amides.

Example 72

N-(5-Tetrazolyl)-1-oxo-1H-cycloheptenotiazolo-(3,2-a)pyrimidine-2-carboxamide

1-Oxo-1H-cycloheptenotiazolo(3,2-a)pyrimidine-2-carboxylic acid (2(1 g, 9 mmol)) and 1,1'-carbonyldiimidazole (1.4 g, 8.8 mmol) were combined with 15 ml of dimethylformamide and heated on a steam bath. When gas evolution ceased, 5-aminotetrazole monohydrate (0.86 g, 8.8 mmol) was added. A solid formed over 5 min. After an additional 30 min of heating, the reaction mixture was cooled and the product obtained by filtration. Recrystallization of the crude product from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-cycloheptenotiazolo(3,2-a)pyrimidine-2-carboxamide (1.61 g, m.p. 295- 296°C

(dec.) ) .

Analysis calcd:<C>13<H>13<0>2<N>7<S:>C, 47.12; H, 3.95; N, 29.59. Found: C, 47.10; H, 4.11; N, 29.72.

Example 73

N-(5-Tetrazolyl)-1-oxo-1H-cyclooctenothiazolo(3,2-a)-pyrimidine-2-carboxamide

1-Oxo-1H-cyclooctenothiazolo(3,2-a)pyrimidine-2-carboxylic acid (308 mg, 1.1 mmol) was dissolved in 10 mL of dimethylformamide and heated on a steam bath. 1,1'-Carbonyldiimidazole (196 mg, 1.21 mmol) was added. When gas evolution ceased, 5-amino-tetrazole (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 and the crude product obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-cyclooctenothiazolo(3,2-a)pyrimidine-2-carboxamide (183 mg, m.p. -310°C (dec.)).

Analysis calcd: C 2 H 0 2 N 7 S: C, 48.69; H, 4.38; N, 28,39. Found: C, 49.01; H, 4.63; N, 27,35..

Example 74

N-(5-Tetrazolyl)-1-oxo-1H-7-methylthiazolo(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'-carbonyldiimidazole (0.89 g, 5.5 mmol) were placed in 5 mL of dimethylformamide and heated on a steam bath.When gas evolution ceased, 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 and the crude product obtained by filtration. Crystallization from dimethylformamide gave purified N-(5 -tetrazolyl)-1-oxo-1H-7-methylthiazolo(3,2-a)pyrimidine-2-carboxamide (1.0 g, m.p. 310°C).

Analysis calcd: CgH 7 O 2 N 7 S: C, 38.99; H, 2.54; N, 35,36. Found: C, 38.97; H, 2.73; N, 34.97.

Example 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 dimethylformamide on a steam bath. 1,1'-Carbonyldiimidazole (1.78 g, 11.0 mmol) was added. When gas evolution ceased, 5-aminotetrazole monohydrate (1.13 g, 11 mmol) was added. A solid formed in less than 1 minute. After heating for an additional 15 minutes, the reaction mixture was cooled and the crude product obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazo-lyl)-1-oxo-1H-thiazolo(3,2-a)pyrimidine-2-carboxamide (1.8 g, m.p.; >315°C).

Analysis calcd: C 2 H 2 H 2 S 2 S: c, 36.50; H, 1.91; N, 37.25. Found: C, 36.62; H, 2.26; N, 37.72.

Example 76

N-(5-Tetrazolyl)-1-oxo-1H-6-methylthiazolo(3,2-a)-pyrimidine-2-carboxamide

1-Oxo-1H-6-methylthiazolo(3,2-a)pyrimidine-2-carboxylic acid (2.1 g, 10 mmol) and 1,1'-carbonyldiimidazole (1.78 g, 11 mmol) were combined with 15 ml of dimethylformamide and heated on a steam bath. Gas evolution started and dissolution occurred. When gas evolution ceased, 5-aminotetrazole monohydrate (1.13 g, 11 mmol) was added. A solid formed in less than a minute. After 5 minutes of heating, the reaction mixture was cooled. Filtration gave N-(5-tetrazolyl)-1-oxo-1H-6-methylthiazolo(3,2-a)pyrimidine-2-carboxamide (2.33 g, mp >318 °C). Analysis calcd: C 2 H 2 O 2 N 7 S: C, 38.99; H, 2.54; N, 35,36. Found: C, 39.35; H, 3.00; N, 35.06.

Example 77

N-(5-Tetrazolyl)-1-oxo-1H-6-ethylthiazolo(3,2-a)-pyrimidine-2-carboxamide 1-oxo-1H-6-ethylthiazolo(3,2-a)pyrimidine-2- carboxylic acid (4.48 g, 20 mmol) and 1,1'-carbonyldiimidazole (3.57 g, 22 mmol) were combined with 20 mL of dimethylformamide and heated on a steam bath. Gas evolution and dissolution were observed. When gas evolution ceased, 5-aminotetrazole monohydrate (2.27 g, 22 mmol) was added. A solid formed within 1 minute. The reaction mixture was heated for a further 15 minutes, cooled and the crude product obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-6-ethylthiazolo(3,2-a)pyrimidine-2- carboxamide (4.7 g, m.p. 2 74°c (dec.)).

Analysis calcd: ClHgO 2 N 7 S: C, 41.23; H, 3.11; N, 33.66. Found: C, 41.41; H, 3.30; N, 33.84.

Example 78

N-(5-Tetrazolyl)-1-oxo-1H-7-(2-methyl-2-propyl)-thiazolo(3,2-a)pyrimidine-2-carboxamide 1-oxo-1H-7-(2- Methyl-2-propyl)thiazolo(3,2-a)pyrimidine-2-carboxylic acid (2.52 g, 10 mmol) and 1,1'-carbonyldiimidazole (1.78 g, 11 mmol) were combined with 15 mL of dimethylformamide and heated.on a steam bath. Gas evolution and dissolution occurred, and a solid formed within a few minutes. Heating was continued for a total of approx. 10 minutes. The reaction mixture was cooled and crude product obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazo-lyl)-1-oxo-11-1-7-(2-methyl-2-propyl)-thiazolo(3,2-a)pyrimidine-2-carboxamide (1 .62 g, mp 280°c (dec.)).

Analysis calcd: C12<H>13<0>2N7S: C, 45.13; H, 4.10; N, 30.70.

Found: C, 45.22; H, 4.40; N-, 30.05.

Example 79

N-(5-Tetrazolyl)-1-oxo-1H-7-ethylthiazolo(3,2-a)-pyrimidine-2-carboxamide 1-oxo-1H-7-ethylthiazolo(3,2-a)pyrimidine-2- carboxylic acid (502.5 mg, 2.24 mmol) and 1,1<1->carbonyldiimidazole (399.7 mg, 2.46 mmol). was combined with 3 ml of dimethylformamide and heated on a steam bath. This resulted in gas evolution and dissolution. After gas evolution had ceased, 5-amino-tetrazole monohydrate (253.0 mg, 2.45 mmol) was added. This resulted in a clear solution. After 2 minutes, a solid began to fall out. The mixture was heated for an additional 20 minutes, cooled to room temperature and crude product obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-7-ethylthiazolo(3,2-a)pyrimidine-2-carboxamide (486.8 mg, mp 261-262°C (dec. )).

Analysis calcd:<C>10HgN7O2S: C, 41.23; H, 3.11;

N, 33.66; mass ion, 291. Found : C, 41.35; H, 3.31;

N, 33.55; mass ion, 291.

Example 80

N-(5-Tetrazolyl)-1-oxo-1H-7-isopropylthiazolo(3,2-a)-pyrimidine-2-carboxamide

1-Oxo-1H-7-isopropylthiazolo(3,2-a)pyrimidine-2-carboxylic acid (537 mg, 2.25 mmol) and 1,1'-carbonyldiimidazole (401 mg, 2.47 mmol) were combined with 3 ml of dimethylformamide and heated on a steam bath. Dissolution and gas evolution occurred. After gas evolution had ceased, 5-aminotetrazol monohydrate (255 mg, 2.47 mmol) was added. Precipitation of product began immediately. Heating was continued for 20 minutes, after which the reaction mixture was cooled and crude product obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-oxo-1H-7-isopropylthiazolo (3,2-a)pyrimidine-2-carboxamide (328 mg, m.p. >300°C)-

Analysis calculated: C^H^O^S : C, 43.27; H, 3.63; N, 32,11. Found : C, 43.34; H, 3.76; N, 31.82.

Example 81

N-(5-Tetrazolyl)-1-oxo-1H-7-phenylcyclohexenothiazolo(3,2-a)pyrimidine-2-carboxamide 1-oxo-1H-7-phenylcyclohexenothiazolo(3,2-a)pyrimidine-2 -carboxylic acid (980mg, 3.0mmol) and 1,1'-carbonyldiimidazole (320mg, 3.1mmol) were combined with 12ml of dimethylformamide and. the mixture heated on a steam bath. When gas evolution ceased, 5-aminotetrazole monohydrate (496 mg, 3.1 mmol) was added. After 10 minutes, the product started to fall out. After a total time of 1 hour of heating, the reaction mixture was cooled to room temperature and the crude product (312 mg) was obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-7-phenylcyclohexenothia zolo(3,2-a)-pyrimidine-2-carboxamide (131.5 mg, m.p. >300°C).

Analysis calcd: C1QH15<0>2<N>7<S:>C, 54.95; H, 3.84; N, 24.92. Found: C, 54.38; H, 3.93; N, 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) were combined in 6 ml of dimethylformamide and heated on a steam bath. Gas was evolved and a solution was obtained. After gas evolution had ceased, 5-amino-tetrazole (429 mg, 4.16 mmol) was added and heating continued. After a few minutes a precipitate began to form. After 30 minutes, the reaction mixture was cooled and crude product (m.p.

> 300°C) obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-7-methylcyclohexenothiazolo(3,2-a)pyrimidine-2-carboxamide (980 mg , m.p.

> 300°C).

Analysis calculated:<C>13<H>13<0>2<N>7<S:>C, 47.12; H, 3.95; N, 29.59. Found: C, 47.32; H, 4.18; N, 29.60.

Example 83

N-(5-Tetrazolyl)-1-oxo-1H-7,7-dimethylcyclohexeno-thiazolo(3,2-a)pyrimidine-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 mmol) were combined with 3 mL of dimethylformamide and heated on a steam bath. Gas evolution started and dissolution occurred. As soon as gas evolution ceased, 5-aminotetrazole monohydrate (227 mg, 2.2 mmol) was added and heating continued for 20 minutes. The reaction mixture was cooled and the crude product (561 mg, m.p. 300°C) obtained by filtration. Recrystallization from dimethylformamide gave purified N-(5-tetrazolyl)-1-oxo-1H-7,7-dimethylcyclohexenothiazolo(3,2-a)pyrimidine-2-carboxamide (469 mg, mp >300°C).

Analysis calculated: C14H15<0>2<N>7S: C'48'69; H, 4.38; N, 28,39. Found: C, 48.80; H, 4.18; N, 28.42.

Example 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 combined in 3 ml of dimethylformamide and heated on a steam bath. Gas was evolved and dissolution was the result. After gas evolution was complete, 5-aminotetrazole monohydrate (170 mg, 1.65 mmol) was added and heating continued for 20 minutes, as the mixture began to separate a precipitate

after a few minutes. The reaction mixture was cooled to room temperature and crude product was obtained by filtration. Recrystallization gave purified N-(5-tetrazolyl)-1-oxo-1H-7-(2-butyl)thiazolo(3,2-a)pyrimidine-2-carboxamide (247 mg, m.p.

> 300°C).

Analysis calculated: C12<H>13<0>2<N>7<S:.>C, 45.13; H, 4.10; N, 30.70. Found: C, 45.12; H, 4.05; N, 30.68.

Example 85

By following the methods of Examples 66 to 84, the following compounds were prepared from 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[3,2-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-a]-pyrimidine-2-carboxamide and

N-(5-tetrazolyl)-1-oxo-1H-6,8,8-trimethylcyclopentenomethylthiazolo[3,2-a]pyrimidine-2-carboxamide.

Claims (3)

1. Analogy method for the preparation of a therapeutically active compound with the formula: (^ where and R 2 together are alkylene with 3 to 9 carbon atoms or phenylalkylene with 9 to 11 carbon atoms, with the proviso that the ring system thus formed is 5- to 8-membered; and R 1 and R 2 are each hydrogen or alkyl of 1 to 5 carbon atoms, characterized by (a) a compound with the formula: where and R 2 is as indicated above, is reacted with at least one equivalent of 5-aminotetrazole by the action of at least one equivalent of a dehydrating coupling agent at a temperature of 20-110°C in an inert organic solvent, or (b) a compound with formula (II) where R 1 and R 2 are as indicated above, is reacted with approx. one equivalent of a compound of the formula wherein R is alkyl, benzyl or phenyl, in the presence of at least one equivalent of a tertiary amine at -40 to 25°C in a reaction-inert organic solvent to form a solution of a compound with the formula where R1, R2 and R are as indicated above, and then this solution is reacted with approx. one equivalent of 5-aminotetrazole at -40 to 40°C in the same or another similar reaction-inert organic solvent. 2. Method as stated in claim 1, characterized in that a starting material of formula II is used where R 1 and R 2 together are butylene. 3. Method as stated in claim 1, characterized in that a starting material of formula II is used where R 1 is ethyl and R 2 is hydrogen.