CH649299A5 - 1-OXO-1H-THIAZOLO (3,2-A) PYRIMIDINE-2-CARBOXYLIC ACIDS AND DERIVATIVES THEREOF. - Google Patents

Description

The present invention relates to novel derivatives of 1-oxo-1H-thiazolo- [3,2-a] -pyrimidine-2-carboxamides and the acids constituting their precursors. These amides and, in many cases, the acids, which are their precursors, are useful in preventing the release of allergic mediators (histamine, serotonin, slow-reacting anaphylaxis substance (SRS-A), etc.), and they can therefore be used to treat bronchial asthma, hay fever, rhinitis, atopic dermatitis, etc., and they are also useful as antiulcer agents.

Allergic reactions, symptoms resulting from an antigen-antibody interaction, manifest themselves in a variety of ways and in different organs and tissues. Examples of common allergic disorders are allergic rhinitis, a condition characterized by seasonal or persistent sneezing, runny nose, nasal congestion with itching and ophthalmic congestion; hay fever, a variety of allergic rhinitis that results from hypersensitivity to grass pollen; and bronchial asthma, one of the most overwhelming and debilitating allergic reactions, which is a disease characterized by hyperreactivity of the bronchi by exposure to various immunogenic or non-immunogenic stimuli, manifested by bronchospasm accompanied by wheezing , short-term paroxysms and extensive constriction of the airways. The mechanical obstruction of the passage of air in the respiratory tract is generally removed by means of bronchodilators which provide symptomatic relief. Rather, antiallergic agents prevent the release of mediators from anaphylaxis from tissue stores, thereby acting prophylactically to inhibit the initiation of bronchoconstriction by mediators.

Cox et al., "Adv. in Drug Res. ”, 5, 115 (1970), describe the pharmacology of disodium cromoglycate [1,3-bis- (2-carboxy-cromon-5-yloxy) -2-hydroxypropane, Intal], It is not a bronchodilator, but a substance that manifests its therapeutic effects by inhibiting the release of mediators of anaphylaxis and is administered prophylactically. It suffers from a lack of oral efficacy and, for the best results, it is administered by inhalation in the form of a solid substance.

Various other antiallergic agents have been described more recently; it is N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimido- [1,2-a] -quinoline-2-carboxamides (United States patent No. 4017625), 1-oxy-1H-6- (substituted pyrimido) - [1,2-a] -quinoline-2-carboxylic acids (United States Patent No. 4066766), tetrazolo- [a] - quinazol-5-ones (United States patent No. 4085213), pyrimido- [2, la] -isoquinolines (United States patent No. 4127720) and N- (5-tetrazoyl ) -4-oxo-4H-pyrimido- [2, lb] -benzothiazole-3-carboxamides (United States Patent No. 4041163).

British Patent No. 1331059 describes compounds, useful as intermediates for the synthesis of compounds having fungicidal activity, comprising the 1-oxo-1H-thiazolopyrimidine system of formula I.

Chronic stomach and duodenal ulcers, commonly referred to as peptic ulcers, are a common disease for which various treatments have been developed. Treatment depends on the severity of the ulcer and can range from diet and medical treatment (medication) to surgery. A wide variety of drugs have been used to treat ulcers; the most recent of these drugs that deserves special attention is the sodium salt of carbenoxolone, which is the disodium salt of glycyrrhetinic acid hemisuccinate. It has a reputation for preventing the formation and accelerating the healing of gastric ulcers in animals as well as in humans ("Carbenoxo-lone Sodium: A Symposium" JM Robson and FM Sullivan, Ed., Butterworths, London, 1968). However, its use is accompanied by undesirable side effects resembling those of aldostone, for example a marked antidiuretic activity and sodium retention and, often, a loss of potassium, so that the continuation of the treatment with this agent often leads to hypertension, muscle weakness and, ultimately, congestive heart failure. More recently, a receptor antagonist

5

10

15

20

25

30

35

40

45

50

55

60

65

3

649299

histamine, namely cimetidine, has been introduced into practice CgH_

medical. The latter compound alleviates ulcers by reducing the se ^ ^ £ g '' ^ 3 ^

stomach acid creation. / S 5 d ~ ^ q

Various other compounds ^^ 2 CH "" 5 5 i including anti-ulcer activity including l-oxo-1H-6-piperidinopyrimidino- [1,2-a] - s C3 £ "" <~ '" 2

quinoline-2-carboxylic acid (United States patent ^ 2 N CH * ""

No. 4014881), l-oxo-1H-6- acids (pyrimidosubstituted) - [l, 2-a] - ^ ^

quinoline-2-carboxylic acids and their esters (United States patent / "2 ^

America No. 4031217) and tetrazolo- [a] -quinazol-5-ones (patent ~

No. 4085213). io cv— CH £ "

The amides and most of the intermediate acids of this. invention are novel compounds. The acids known are: It has also been found that acids of formula II:

acids of formula II in which Rj and R2 represent hydrogen g or else R, is a methyl group and R2 is hydrogen (Dunwell et al. "J. Chem. Soc. (C)", 1971, 2094). The corresponding ethyl esters are also known, as is the ethyl ester in ^ 2 * "" *

which R, is a methyl group and R2 is a hydrogen atom

[Dunwell et al. “J. Chem. Soc. (C) ", 1971, 2094; Allen and ^

coll. "J. Org. Chem. ”, 24, 779 (1959)]. None of these publications ® I

makes known both acids and esters. It has just been discovered that compounds which respond to the

■ 1 ^

(II)

formula I; in which R] and R2 have the definition given above, are not

"—JS only intermediate compounds of interest for synthesis

| 7 of the amides, but also in many cases have

3 as well as their pharmaceutically acceptable cationic salts

2 I 1 maceutics, an interesting biological activity. Acids possessed

(I) dant a useful antiallergic activity are those in which R: and

O Ti ^ R2 together form an alkylene group having 4 to 9 atoms

, C N .. carbon or a phenylalkylene group having 9 to 11 atoms

■ O NBC- \ I 30 carbon, provided that the ring thus formed has 5 to 8 links, or

2d fj well, considered separately, R! is an alkyl group having 2 to

I 5 carbon atoms and R2 is hydrogen or an alkyl group

^ having 1 to 5 carbon atoms. The most appreciated acids in view and their pharmaceutically acceptable cationic salts for an antiallergic application are those in which Rj and R2

that, are effective antiallergic and antiulcer agents together form an alkylene group having 4 to 6 oral atoms. In formula I, R! and R2 each represents hydro-carbon, in particular a butylene group. Acids of gene structure or an alkyl group having 1 to 5 carbon atoms (as slightly different have useful antiulcer activity, except

methyl, ethyl, propyl, isopropyl, 2-methyl-2-propyl- (tertiobu- know those in which R! and R2 together form an al-

tyle), 2-butyl, 2-methyl-1-propyl- (isobutyl), pentyl, etc.), or else kylene having 3 to 9 carbon atoms or a phenylalkylene group

R [and R2 together forming a third ring of 5 to 8 members, 40 having 9 to 11 carbon atoms, provided that the ring thus formed

are alkylene groups of 3 to 9 carbon atoms, for example: either a 5 to 8-membered system, or Rj and R2 considered separately each represent hydrogen or an alkyl group

C & 2 C1 * "^ 3 \ having 1 to 5 carbon atoms, provided that when R2 is hy-

cH .- ^ ~ drogenic, Rj is something other than hydrogen or a group

/ 2 / i * ~ 2 45 methyl. In this case, the preferred compounds are those in which

\ 2 çLjj I Ri is an ethyl group and R2 represents hydrogen or a

CH ^ "^ C ^" ~ ^ 2 çg. alkyl group having 1 or 2 carbon atoms.

CH ^ CU '"' * \ We mean by the expression acceptable cationic salts

2 çw - ■ from the pharmaceutical point of view salts such as the alkali metal salts, for example sodium and potassium; metal salts

Ct £ alkaline earth such as calcium and magnesium salts; the salts

^ ^ aluminum; ammonium salts; and organic base salts,

/ CH2 ^ for example amines such as triethylamine, tributylamine,

CH_ qtt Qp- ~ piperidine, triethanolamine, diethylaminoethylamine,

I \ 2 3 ^ 55 N; N'-dibenzylethylenediamine and Pyrrolidine,

c :: - rj "2" ~ "CH ^ * ^ 2 CH ^" "The tetrazoles substituted in position 5 may exist, as

CHf this is known, in two isomeric forms, namely:

ftr - fjr

/ 2 \

CH.

N .N:

/ I /

60 -C -C

N N N N

. 2 I

t H H

CH

which coexist in a dynamic tautomeric mixture in equilibrium. CH, - CH ^ 65 The two forms of tetrazolylamides are part of the pre

invention.

or phenylalkylene groups of 9 to 11 carbon atoms, by The compounds of particular interest in the present example: vention are the compounds of formula I in which R] is hydro-

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gene or a methyl group and R2 is a methyl group. Among these compounds, preference is given to the compound in which Rj is hydrogen, because the corresponding acid, which is believed to be its metabolite, also shows activity. Particular interest is also attached to the compounds in which R 1 and R 2 together form a propylene, butylene or pentylene group. Particularly preferred is the compound in which R 1 and R 2 together form a butylene group, that is to say N- (5-tetrazolyl) -1-oxo-1H-cyclo-hexenothiazolo- [3,2-a] - pyrimidine-2-carboxamide of formula III:

(III)

j? not.

•NOT

"- <? i |

N S

I

a because it displays excellent oral activity and because it is very stable in the pure solid state, as well as in the presence of conventional pharmaceutical diluents and in solution. In addition, its metabolite

H,

(the corresponding carboxylic acid) shows good activity. The preferred form of tetrazolylamide (III) is the sodium salt (trihydrate) which is not hygroscopic and whose good solubility in water ensures correct biological availability.

The antiallergic property of the compounds of the present invention was evaluated by the passive cutaneous anaphylaxis (PCA) test (Ovary, "J. Immun.", 31, 355, 1958). In the PCA test, normal animals are injected intradermally with antibodies contained in a serum from animals having acquired active sensitivity. The animals are then tested by intravenous administration of an antigen in admixture with a dye such as Evans blue. The increase in capillary permeability due to the antigen-antibody reaction results in the dye spreading from the injection site of the antibody. The test animals are then sacrificed by asphyxiation and the intensity of the reaction is determined by measuring the diameter and the intensity of the blue coloration on the internal surface of the animal's skin.

The antiulcer activity of the compounds of the present invention is evaluated by the so-called cold stress test in rats. As a variant, the antiulcer activity is determined by a test, of recent development, involving an ethanol-induced ulcer in the rat, as described below.

The compounds of the present invention are prepared according to the following reaction processes:

(B3QOCI., C = C

-ÛC2H5

"NH_

H,

- i "S

H-

• NH

OR3

,.VS . CH

'GOLD,

"Dowtherm A" £

or

(CF3C0) 20

ï2n- <f

N_ÎI

i

M N

Coupling by dehydration or passage through mixed anhydride

In the first step of the synthesis sequence, the suitably substituted 2-amino-thiazole is condensed with a stoichiometric amount of a dialkyl ethoxymethylenemalonate, usually the readily available diethyl ethoxymethylenemalonate, the choice of ester being not critical to obtain the ultimately desired products of the invention. Condensation is carried out at a temperature ranging from about 80 to about 125 ° C. Lower temperatures are not desirable because the reaction takes place at too slow a rate. Higher temperatures can be used but clearly do not offer any advantages. The reaction is therefore advantageously carried out in the molten state. Naturally, it can be carried out in a solvent or in a mixture of solvents, for example ethanol, N, N-dimethylformamide, aceto-nitrile. However, from a practical point of view, the presence of a solvent does not seem necessary. The products of this condensation are 2- (2,2-dicarbalkoxyethenylamino) thiazoles substituted in 55 position 4 and / or in position 5. It should be noted that when Rj and R2 together form a nucleus, the nomenclature and the numbering are modified as follows:

60

Cyclohexenothiazole

Cycloheptenothiazole

Cyclooctenothiazole

5

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Cyclohexenothiazoles can also be called tetrahydro-benzothiazoles.

The second step of the synthesis sequence is the cyclization of the 2- (2,2-dicarbalkoxyethenylamino) thiazoles substituted in position 4 and / or in position 5 with elimination of an equivalent of alkanol (ethanol in the case of the ester ethyl). According to one procedure, this cyclization is accomplished by heating the intermediate compound at a temperature of about 175 to about 250 ° C until the reaction is essentially accomplished, usually in a period of about 1 to 2 hours. The cyclization is advantageously carried out by heating the intermediate compound in a suitable diluent inert to the reaction, that is to say in a compound which makes it possible to influence the reaction temperature, which is stable at relatively temperatures high used and which does not react with the starting material or with cyclization products. Representative examples of these diluents are high boiling point hydrocarbons such as perhydronaphthalene, mineral oil, di-ethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether, diphenyl, in particular that which contains 26.5% of diphenyl and 73.5% of diphenyl ether and which is sold under the trade name Dowtherm A.

The cyclization is carried out as a variant under milder conditions (70-130 ° C) by heating the intermediate compound in the presence of an excess (1.1 to 3 equivalents) of trifluoroacetic anhydride in an inert solvent such as toluene until the reaction is complete (for example 15 to 20 h at the reflux temperature of toluene). Whatever the procedure, the products of the cyclization step are l-oxo-1H-thiazolo- [3,2-a] -pyrimidine-2-carboxy-alkyl substituted in position 6 and / or in position 7.

It should be noted that when Ri and R2 together form a nucleus, the nomenclature and numbering systems are modified as follows:

1-oxo-1 H-cyclopenteno-thiazolo- [3,2-a] -pyrimidine

1-oxo-1 H-cyclohexeno-thiazolo- [3,2-a] -pyrimidine

1 -oxo-1H-cyclohepteno-thiazolo- [3,2-a] -pyrimidine

1-oxo-l H-cycloocteno-thiazolo- [3,2-a] -pyrimidine

The l-oxo-1H-cyclohexenothiazolo- [3,2-a] -pyrimidines are also called 6,7,8,9-tetrahydro-l-oxo-1H-pyrimidino- [2, lb] -benzothiazoles or, when another numbering system is used, 5,6,7,8-tetrahydro-4-oxo-4H-pyrimido- [2, lb] -benzothiazoles.

It is obvious that the condensation and cyclization steps can be carried out in a single operation, without it being necessary to separate the intermediate 2- (2,2-carbalkoxyethenylamino) thiazole, either by using a reaction temperature high to carry out both the condensation and the cyclization, either by condensing as described above, then by adding an inert solvent (if it is not already present) and an excess of trifluoroacetic anhydride (2.1 to 4 equivalents ) and by conducting the cyclization step.

The preferred procedure includes the separate stages of condensation and cyclization as described above. The isolation of the intermediate compound and its subsequent purification before cyclization generally provides a better quality cyclized product.

The esters obtained by condensation / cyclization as indicated above are then hydrolyzed to 1-oxo-1 H-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acids substituted in position 6 and / or in position 7 correspondents. (Note the nomenclature system and the modified numbering system described above when R, and R2 together form a third nucleus.) Preference is given to acid catalyzed hydrolysis. Heating the reflux of the ester in 48% hydrobromic acid until the hydrolysis is complete (a period of 0.5 to 3 hours is generally satisfactory) is a particularly suitable process. If foaming is a problem, hydrolysis can be carried out at a slightly high gauge pressure, for example 49 kPa at 85 ° C.

The N- (5-tetrazolyl) amides of the present invention are advantageously prepared by coupling by dehydration of the acids with 5-aminotetrazole. The desiccant coupling is carried out using a wide variety of agents commonly used in peptide synthesis operations. Representative examples of agents include N, N'-carbonyldiimidazole, N, N'-carbonyldi-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphe-nylketene-p-tolylimine, N-hydroxyphthalimide, N-hydroxysucci-25 nimide, N-hydroxypiperidine, ethylene chlorophosphite, diethylene pyrophosphite, N-ethyl-5-phenylisoxazolium-3'-sulfonate, phenylphosphorodi- (l-imidazolate ) and carbodiimides such as dicyclohexylcarbodiimide, l-cyclohexyl-3- (2-morpholinomethyl) carbodiimide, N- (3-dimethyl-aminopropyl) hydrochloride -N'-ethylcarbodiimide, l-ethyl hydrochloride -3- (3'-dimethylaminopropyl) carbodiimide and diethylcyanamide.

The coupling agents listed above are generally reacted first with the acidic reactant and the resulting product is then reacted without isolation with 5-35 aminotetrazole to give l-oxo-1H-thiazolo - [3,2-a] -pyrimidine substituted in position 6 and / or in position 7 desired. (Note the nomenclature system and the modified numbering system indicated above when Rj and R2 together form a third nucleus.)

The reaction is carried out in a solvent inert to the reaction, in which the acidic reactant is not necessarily soluble. The only requirement which the solvent must satisfy is that it does not react appreciably with the reactants or with the products. The variety of coupling agents which can be used for the conduct of coupling by dehydration offers a wide choice of solvents. Representative examples of solvents are N, N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of the acidic reactant with the coupling agent 50 is carried out at a temperature of about 20 to about 110 ° C. The reactive intermediate compound is then reacted with 5-aminotetrazole at a temperature of about 20 to 110 ° C. Each of these operations is advantageously carried out at a temperature of about 50 to about 100 ° C, since the speed and the yield of the reaction are improved.

The molar ratio between the acid, the coupling agent and 5-aminotetrazole is generally from about 1: 1: 1 to about 1: 1.1: 1.1. Higher proportions of the coupling agent and 5-aminotetrazole can be used, but this has no advantages. 60 Excesses of 10 mól% are satisfactory.

As will be appreciated by those skilled in the art, all reactants can be added all at once instead of being added discontinuously as indicated above. However, the prior formation of the reactive intermediate body (product formed between acid 65 and the coupling agent) normally gives better yields of the desired N- (5-tetrazolyi) amides.

Alternatively, the desired amides can be synthesized by coupling the acids with 5-aminotetrazole by the process of

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mixed anhydride. In this case, the acids are first of all converted in situ to the tertiary amine salt in the presence of a 1 to 1.1 mol excess of the amine. Various tertiary amines (R'3N) are suitable for this purpose. Examples of triethylamine, N-methylpiperidine, N-methylmorpholine, dimethylaniline or quinoline are mentioned. Suitable inert solvents are methylene chloride, chloroform, dimethylformamide and dimethylacetamide. It is preferable that the acid is completely dissolved by the excess tertiary amine, which may require a period of stirring at the same time as possible moderate heating. The solution of the amine salt is then reacted with an equivalent of alkyl chloroformate (for example ethyl), benzyl or phenyl, at a temperature ranging from -40 to 25 ° C, preferably in the range of -10 to 10 ° C, to form a mixed anhydride in solution, according to the scheme:

O

+ CI — C — OR

R'3N

+ R'3N-HC1

o ^ cf

OrC-C-R it

Without isolating the mixed anhydride, it is reacted directly with 5-aminotetrazole, preferably in solution in an inert solvent which is of the same type as that which is used to prepare the mixed anhydride, so as to obtain the N- (5-tetrazolyl) amides desired. The reaction is usually started at a low temperature (for example at a temperature of -40 to 15 ° C), but the reaction mixture is allowed to warm to a higher temperature (for example 15 to 40 ° C) to complete the reaction . The normal molar proportion of acid, amine, chloroformate and 5-aminotetrazole is 1: 2: 1: 1 to 1: 2.1: 1.1: 1.1.

Both the amides and the acids serve as intermediates for the pharmaceutically acceptable cationic salts of the invention. The formation of a salt is carried out by reaction of the amides or acids with the suitable metal salt (such as a carbonate, ethylhexanoate, alcoholate or hydroxide) or the amine suitably chosen in a correct medium such as water, methanol or ethanol according to well known procedures. The salts are collected by conventional operations such as filtration if they are insoluble in the medium, by evaporation of the solvent if they are soluble in the medium or by precipitation by addition of a non-solvent for the salt.

Many of the 2-aminothiazoles which are to be used as starting materials are described in the literature. Those which are not can be prepared by condensing the suitably chosen α-halogen tone with thiourea or by condensing the suitable aldehyde with thiourea and sulfuryl chloride, as illustrated in examples particular. When α-halo-nocetones are not available in the literature, they are obtained by conventional methods, for example by halogenation of ketones [see, for example, 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 diazoketones [see, for example, Catch et al.,“ J. Chem. Soc. ”, 278 (1948); Lutz et al., "J. Org. Chem. ”, 12,767 (1947); Wagner et al., "J. Am. Chem. Soc. ”, 72, 2884 (1950)], by decarboxylation of α-halo-p-keto acids [McPhee et al.,“ J. Am. Chem. Soc. ”, 66,1132 (1944)] and by spontaneous cleavage of the dibromo derivatives of alkenyl esters [see, for example,

Slanina et al., "J. Am. Chem. Soc. ”, 58, 891 (1936)].

The reactions in the synthetic sequence leading from 2-aminothiazoles to the acids and to the N- (5-tetrazolo) amides of the present invention are advantageously followed by normal thin layer chromatography, on silica gel plates containing an ultraviolet indicator, of which there are various sources in the trade. The choice of the eluent is varied according to the reaction which is carried out and the nature of the substituents, so as to obtain intermediate Rf values between 0 and 1.0, and in order to differentiate the intermediate compound which enters reaction and the product 5 which is formed in the reaction. An eluent which is particularly well suited to thiazole formation, condensation cyclization and hydrolysis reactions in the process of the invention is a mixture of chloroform and 1% ethanol, while hydrolysis and the transformation of acids into N- (5-tetrazolyl) amides is best followed by the use of a mixture of chloroform and 5% acetic acid. As is well known to those skilled in the art, if substances tend to move too quickly, i.e. in the solvent front, the polarity of the eluent can be reduced. If materials tend to move too slowly, the polarity of the eluent may be high. Such a chromatographic method is used to assess the completion of the reaction and the purity, but it can also be used to further optimize the reaction conditions (concentration, duration, temperature, solvent, etc.).

The products of the invention and their pharmaceutically acceptable salts are useful as prophylactics to inhibit or prevent the release of mediators of anaphylaxis (allergy, immediate hypersensitivity reactions) and the onset of allergic symptoms in mammals, and can be administered for such purposes individually or as mixtures with other agents, for example theophylline or sympathomometic amines. The products of the present invention are also useful as antiulcer agents. These products not only accelerate the healing of these ulcers, but also prevent the formation of ulcers and reduce the production of stomach acid in mammals, including humans. We can therefore consider that they are useful in combating gastric ulcers.

The compounds of interest of the invention can be administered very alone, but they are generally administered with a pharmaceutical carrier or vehicle which is chosen according to the adopted route of administration and normal pharmaceutical practice. For example, they can be combined with various inert carriers or vehicles which are acceptable from a pharmaceutical point of view in the form of 40 tablets, capsules, tablets, lozenges, hard lozenges, powders, sprayable aerosol compositions, aqueous suspensions or solutions, injectable solutions, elixirs, syrups, etc. These supports or vehicles include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents. In addition, the oral pharmaceutical compositions of the invention can be suitably sweetened and perfumed using various agents of the type commonly used for this purpose.

The particular support that is chosen and the ratio of the active ingredient to this support are influenced by the solubility and the chemical nature of the therapeutic compounds, the route of administration adopted and the requirements of conventional pharmaceutical practice. For example, when the compounds of the invention are administered orally in tablet form, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate can be used. Various disintegrants such as starch, alginic acids and certain complex silicates, combined with lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc, can also be used in the production of tablets for oral administration of these compounds. For oral administration in the form of capsules, lactose and high molecular weight polyethylene glycols are among the materials which are appreciated for use as pharmaceutically acceptable carriers. When aqueous suspensions are to be used for oral administration, the compounds 65 of the invention can be combined with emulsifying agents or suspending agents. Diluents such as ethanol, propylene glycol, glycerol and chloroform and mixtures thereof can be used, as can other materials.

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For parenteral administration and inhalation, solutions or suspensions of these products in sesame oil or peanut oil or aqueous propylene glycol solutions may be used, as well as sterile aqueous solutions pharmaceutically acceptable soluble salts described herein. These particular solutions are specially adapted for intramuscular and subcutaneous injection, when these modes of administration are desired. Aqueous solutions, including solutions of salts in pure distilled water, are also useful for the purposes of intravenous injection provided that their pH has been properly adjusted beforehand. These solutions should also be suitably buffered, if necessary, and the liquid diluent should first be made isotonic with a sufficient amount of sodium chloride or glucose.

When used as prophylactics to prevent the release of mediators from anaphylaxis, the compounds can be administered by inhalation. Compositions suitable for inhalation may be 1) a solution or suspension of the active ingredient in a liquid medium of the type mentioned above for administration by means of a nebulizer; 2) a suspension or solution of the active ingredient in a liquid propellant such as dichlorodifluoromethane or chlorotrifluoroethane for administration by means of a pressure vessel, or 3) a mixture of the active ingredient and a solid diluent (e.g. lactose) for administration by means of a powder inhalation device. Compositions suitable for inhalation using a conventional nebulizer contain from about 0.1 to about 1% of the active ingredient; and compositions for use in pressure vessels contain from about 0.5 to about 2% of the active ingredient. Compositions for inhalation in powder form may contain the active ingredient and the diluent in ratios of from about 1: 0.5 to 1: 1.5.

Taking into account the factors set out above, it is considered that an effective daily oral dose of the antiallergic or antiulcer compounds of the present invention, in human medicine, ranges from about 10 to about 1500 mg / d, a preferred range being about 10 to about 600 mg / d in a single dose or in divided doses, or about 0.2 to about 12 mg / kg of body weight. These values are only examples and there may naturally be individual cases which require higher or lower doses. With proper monitoring, the dose rate can be increased to around 2g / d.

When administered parenterally for either use or by inhalation for antiallergic use, the effective daily dose is from about 0.05 to about 400 mg / d and, preferably, from about 0.25-200 mg / d, or approximately 0.005-4 mg / kg bodyweight in a single dose or in divided doses.

It is necessary that the active ingredient represents a proportion of the composition such that a suitable dosage form is obtained. Obviously, several unit dosage forms can be administered at about the same time. Although compositions containing less than 0.005% by weight of active ingredient may be used in some cases, it is preferable to use compositions which contain not less than 0.005% of active ingredient; otherwise, the amount of support becomes too large. The activity increases with the concentration of the active ingredient. The composition can contain 10, 50, 75 or 95% by weight of active ingredient or even a higher percentage.

The passive skin anaphylaxis test is a measure of the antiallergic activity (especially the anti-asthma activity) of a compound. Compounds which inhibit a positive passive anaphylaxis cutaneous test induced by the immunochemical counterpart in the rat of human immunoglobulin E (IgE), or reactin, are considered to be endowed with antiallergic activity [C. Mota, "Ann. N.Y. Acad. Sci. ”, 103,264 (1963)]. (Reagin is primarily an immunoglobulin E (IgE) and is the primary immunoglobulin responsible for allergic asthma, anaphylaxis, hay fever, food sensitivities and certain manifestations of drug sensitivities , although recent evidence attributes antibodies to the IgG class to an important role in mediating allergic disorders.) When such compounds are administered to a sensitized subject, human or animal, before the subject comes into contact with antigens or substances to which he is allergic, they prevent the allergic reaction that would manifest itself otherwise. These compounds therefore offer a possibility of prophylactic treatment of allergic or anaphylactic reactions of a nature generated with the mediation of a reactin.

In other words, these compounds inhibit the release of mediators resulting from the antigen-antibody (allergic) reaction as illustrated in the passive skin anaphylaxis test using the rat homocytotropic antibody, known for its correlation with a human reactin antibody. The inhibition of reaginic antigen-antibody reactions in rats, chosen as a test animal in the passive cutaneous anaphylaxis test, is considered to be representative of the inhibition of human reactive antigen-antibody reactions which occur during allergic episodes.

The method for testing the passive skin anaphylaxis reaction used to evaluate the compounds of the present invention shows the excellent correlation which exists between the activity of compounds in this test and their usefulness in the treatment of allergic asthma. . The ability of agents to interfere with passive skin anaphylaxis reactions is measured in male Wistar Charles River rats weighing 170-210 g. A reactin antiserum, rich in IgE antibodies, is prepared as described by Petillo et al. in "Int. Arch. Allergy ", 44, 309 (1973). A hyperimmune antiserum rich in chicken anti-albumin IgG antibodies is prepared as described by Orange et al. in "J. Exptl. Med. ”, 127, 767 (1968). 48 h before the antigen test, the reactin antiserum is injected intradermally into the shaved skin of the back of a normal rat; 5 h before the test, the hyperimmune antisera are injected in the same way. At a third site, 60 μg of histamine dihydrochloride and 0.5 μg of serotonin-creatinine sulfate are injected intradermally just before the antigen test, as a control of the antihistamine type, of the antiserotonin type and of non-specific types of blockage; the compounds of the present invention or physiological saline are then injected intravenously and the injection is immediately followed by the administration of 5 mg of ovalbumin and 2.5 mg of Evans blue dye in physiological serum. In the case of oral administration, Evans blue dye and ovalbumin are administered 5 min after absorption of the drug. 30 min later, the animals are sacrificed by asphyxiation using chloroform and the back skin is removed and turned over for observation. A score is assigned to each injection site equal to the product of the site diameter in millimeters by a factor 0.1, 0.5.1, 2, 3 or 4 proportional to the intensity of the coloring. The scores obtained for a given injection site are totaled for each group of five animals and the total is compared with the value obtained for controls treated with physiological saline. The difference is expressed by the percentage of blockage due to the compound used.

Compounds representative of those of the present invention are subjected to an antiallergic activity test by the method described above, and the resulting activities are expressed by the degree (%) of protection. The product Intal, or disodium chromoglycate, which is a commercial antiallergic agent, is not included for comparison, since it is not active orally.

The compounds of formula (I) (amides) and of formula (II) (acids, R3 = hydrogen) whose antiallergic activity was determined by the passive cutaneous anaphylaxis test are indicated in detail in Tables I and II. . _.,,. , (Tables at the top of the next page)

The efficacy of the products of the present invention as antiulcer agents is determined by the so-called cold stress test in rats. In this test, female rats without fasting (Charles River C-D strain) weighing 70 to 140 g receive the drug.

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Table I

Oral activity (percentage of protection) of amides (formula I) in the passive skin anaphylaxis test ri

r2

IgE (mg / kg)

IgG (mg / kg)

1

3

10

30

1

3

10

30

ch3

ch3

55

51

ch3

c2h5

75

57

c2h5

ch3

29

28

c2hs

c2h5

62

49

(ch2) 3

46

43

(ch2) 4

47

45

(CH2) s

25

38

(ch2) 6

94

57

h

ch3

55

50

h

h

50

46

ch3

h

78

55

c2h5

h

85

58

h

c (ch3) 3

37

20

h

c2h5

70

44

h

ch (ch3) 2

72

53

ch2ch (c5h6) ch2ch2

4

7

ch2ch (ch3) ch2ch2

44

33

ch2c (ch3) 2ch2ch2

38

27

h

chch2ch3

1

6

6

ch3

Table II

Oral activity (percentage of protection) of amides (formula II, R3 = hydrogen) in the passive skin anaphylaxis test ri

r2

IgE (mg / kg)

IgG (mg / kg)

10

30

10

30

ch3

ch3

0

0

ch3

C2hs

0

0

C2hs

ch3

42

24

c2h5

c2hs

41

32

(ch2) 3

0

0

(ch2) 4

55

39

(CH2) s

37

44

(ch2) 6

36

68

15

45

h

ch3

18

19

h

h

18

7

ch3

•

h

12

14

c2h5

h

45

38

h

c (ch3) 3

10

6

h

c2h5

13

21

h

ch (ch3) 2

0

0

CH2ch (csh6) ch2ch2

15

5

ch2ch (ch3) ch2ch2

31

21

ch2c (ch3) 2ch2ch2

13

6

h

chch2ch3

1

1

8

ch3

ment or its support (control animals) intraperitoneally (in saline solution containing 1% carboxymethylcellulose and 0.1% Twenn 80) or orally (in water) 3 h before being slightly anesthetized with ether and immobilized in the supine position on individual Plexiglas plates. When the anesthetic effect has ceased, the animals in restraint are placed horizontally in a refrigerator maintained at 10-12 ° C and, 3 h later, they are sacrificed by cervical dislocation. The abdomen of each rat is opened, the pylorus is closed, the stomach is swollen with physiological saline by means of an oral tube, the esophagus is closed and the stomach is excised. The stomachs are kept in a 0.4% formaldehyde solution for about 30 s to harden the outer layers and to facilitate examination. Each stomach is then excised along the greater curvature and alteration of the glandular portion

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(posterior stomach) is examined. The number of gastric erosions, their severity and the color of the stomachs are noted. The Man-Whitney-Wilcoxon test is used to compare the average number of gastric erosions in the control group with the average number of gastric erosions in each group treated with the drug to determine if there are any statistical differences. (Dixon et al., "Introduction to Statistical Analysis", 3rd ed., McGraw-Hill Book Company, New York, pages 344-347, 1969). In this test, N- (5-tetrazolyl) thiazolo- [3,2-a] -pyrimidine-2-carboxamide (compound III) is found to be extremely potent, as indicated below.

Alternatively, the efficacy of the products of the invention as antiulcer agents is determined in an ethanol-induced ulceration test in rats. In this test, male rats fasted for approximately 18 h receive 5 mg / kg of drug or water orally 15 min before the oral administration of a dose of 1.0 ml of absolute ethanol. 1 h after the ethanol test, the animals (eight per group) are sacrificed and the stomachs are examined for the presence of lesions. All drugs are dissolved in dilute sodium hydroxide. When the animals have been sacrificed, their abdomen is open and a hemostatic forceps is placed at the level of the pylorus. 6 ml of a 4% formaldehyde solution is injected into the stomach using a gastric tube and a second hemostatic forceps is used to close the esophagus. The stomach is removed, opened along the greatest curvature, and examined for ulceration.

The scoring system used for the quantitative expression of lesions induced by ethanol is given below.

Ulceration scoring table

Note Definition

1 Stomach appears normal.

2 Pin point size lesions

3 Lesions, two or less; pin point lesions may be present.

4 Lesions, in number greater than 2; pin point lesions may be present.

5 Lesions with hemorrhage.

For each group of animals, an ulceration index was calculated as follows:

Ulceration index = (sum of the scores obtained by the group) x (sum of the numbers of ulcers in the group) x (fraction of the group showing signs of ulceration).

The percentage of inhibition of ulcers is expressed as follows: Inhibition (%) =

100 x [(control ulceration index) - (drug-treated animal ulceration index)] (control ulceration index).

Table III shows the activity in this test of various 5-tetrazolylamides of the invention, while Table IV shows the activity of various acids.

Table III

Oral activity (inhibition,% at a dose of 5 mg / kg) of amides (formula I) in the ethanol-induced ulceration test in rats r,

r2

Inhibition (%)

ch3

ch3

96

h

ch3

59

ch3

h

72

c2h5

c2h5

10

c2h5

h

86

(ch2) 6

45

(ch2) 4

97.81

Table IV

Oral activity (inhibition,% at a dose of 5 mg / kg) of acids (formula II) in the ethanol-induced ulceration test in rat ri

r2

Inhibition (%)

ch3

ch3

11

h

ch3

27

ch3

h

0

c2hs

c2h5

48

C2hs

h

48

(ch2) 4

21

As has been noted in the foregoing, the compound of the invention which is most appreciated is the compound of formula (III), that is to say the compound of formula (I) in which R , and R2 together form a butylene group, namely N- (5-tetrazoyl) -l-oxo-1H-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxamide, which can also be called 5 , 6,7,8-tetrahydro-N- (5-tetrazolyl) -4-oxo-4H-pyrimido- [2,1 -b] -benzothiazole-3-carboxamide.

In addition to its oral antiallergenic activity illustrated in Table I, compound III is endowed with intravenous activity in the range of 0.03 to 1.0 mg / kg in the passive cutaneous anaphylaxis test, this compound being approximately 26 times more potent than the Intal product via this route of administration (as noted above, the Intal product lacks oral efficacy). Compound III also inhibits the variations in skin permeability induced by passive cutaneous anaphylaxis (PCA) mediated by IgE, but does not interfere with the variations in permeability caused by the intradermal injection of exogenous histamine and sero-tonin. The absence of antihistamine and antiserotonin effects demonstrates that the antiallergic mechanism is a mechanism for inhibiting the release of mediators rather than an antagonism at the mediator receptor.

Compound III inhibits the release of histamine induced by dextran in the rat's peritoneal cavity. Its DES0 dose is 0.33 ng / kg intraperitoneally and that of the Intal product is 14.0 | tg / kg, which demonstrates the superior potency of the former. The elevation of the histamine level in the plasma by the administration of an angitene to rats sensitized passively with an antiserum rich in IgE (passive systemic anaphylaxis) is prevented by compound III. Its ED50 dose is 28 ng / kg intravenously, that is to say it is 13 times more powerful than the Intal product.

Guinea pigs to which compound III is administered at a dose of 30 mg / kg intraperitoneally are not protected against the bronchoconstrictor effects of inhaled histamine. In the concentration range of 10 ~ 8 to 10 "4 M, compound III does not antagonize the spasms of the isolated ileum of the guinea pig induced by acetylcholine, histamine and the slow-reacting substance of anaphylaxis (SRS-A), and the synthesis and release of SRS in monocytes isolated from the rat, stimulated by an ionophore, are not inhibited by compound III.

In addition to its powerful activity in the ethanol-induced ulceration test in rats (see Table III), compound III is very powerful in the method of gastric ulceration under the stressful effect of compression and cold ( see detail above), where it provides dose proportional protection, at oral doses in the range of 3 to 100 (ig / kg. Compound III also protects against the ulcerogenic effects of aspirin at dose -100 mg / kg orally, and dose proportional effects are observed in the dose range of 10 to 1000 ng / kg orally with an ED50 value of 100 ng / kg. Compound III is also active in a model of gastric ulceration under the effect of phenylbutazone, where an oral ED50 dose of 100 μg / kg is observed. Although compound III is a very potent antiulcer agent, it does not affect the production of pentagastrin-stimulated acid in dogs with

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Heidenhain fistula (5 mg / kg, intravenous), and it is therefore distinguished from antisecretory prostaglandins as well as ci-metidine and atropine. The term cytoprotective is a term recently created to describe the antiulcer effects of prostaglandins, which are independent of antisecretory activity [see Robert, "Advances in Prostaglandin and Thromboxane Research", 2, 507 (1976); Miller et al., "Gut", 20, 75 (1979); Robert et al., "Gas-troenterology", 72.1121 (1977)] and this term characterizes well the effects of compound III.

In addition, compound III displays a diuretic activity. When administered orally, it causes a dose-proportional increase in the volume of urine emitted, at doses in the range of 0.3 to 5 mg / kg. The maximum effect is a 2-fold increase in the volume emitted. The urinary concentrations of sodium and potassium ions are unchanged but, due to the increase in the volume emitted, an increase in the excretion of sodium and potassium is observed. These findings indicate that the dose response range of diuretic activity is considerably higher than for antiulcer effects and just below that corresponding to antiallergic effects (1-10 mg / kg).

Rats, fasting for 24 hours and having received compound III orally at doses of 10, 30 or 100 mg / kg, show no change in blood sugar levels.

The effect of compound III on tolerance to glucose was examined in rats receiving 10.30 or 100 mg / kg orally together with glucose in an amount of 1 g / kg orally. There is a clear improvement in tolerance to glucose, depending on the dose. This effect may be due to delayed absorption of glucose in connection with a possible effect on gastric emptying.

Compound III has no significant anticholinergic effects. In anesthetized dogs, at cumulative doses of 5 and 15 mg / kg intravenously, it causes transient hypotension and variable changes in heart rate. Vasomotor responses to epinephrine and bilateral carotid occlusion are slightly reduced. Transient cardiovascular changes only appear at cumulative intravenous doses that are 5 to 15 times stronger than the intravenous dose of maximum efficacy for achieving antiallergic effects and that are much stronger than the oral doses required for obtaining antiulcer effects.

In tolerance studies, Compound III was administered orally by gavage to dogs for a period of 7 d at doses of 50, 150 and 300 mg / kg / d. Emesis, which is common in dogs, has been observed at all doses, but subsequent studies have shown that the emetic effect can be suppressed by administering the drug in capsule form after meals rather than before . No gross pathological changes were observed and microscopic examination of the liver, kidney, heart and lung revealed no changes. In other studies, the levels of enzymes in the serum of dogs, having received compound III intravenously for 5 d at consecutive daily doses of 1, 3, 10, 3 and 3 mg / kg, remained normal .

Compound III was administered to rats by gavage at doses of 50, 150 and 300 mg / kg / d for 10 d. No pathological changes appeared on gross and microscopic examination of the liver, kidney, heart and lung. Except for a slight increase in the level of glutamic-pyruvic transaminase in the serum observed at the maximum dose, no modification appeared in clinical chemistry.

Compound III was administered subcutaneously to mice at doses of 100, 300 or 1000 mg / kg. No symptom or no case of mortality is observed and it is concluded that the drug is well tolerated in the acute toxicity test with an LD50 dose subcutaneously less than 1000 mg / kg. At the dose of 32 mg / kg administered subcutaneously, no interaction with a combination of drugs acting on the central nervous system is observed.

Single oral doses of 40 mg / kg of compound III are administered to groups of mice which are sacrificed 6,12 or 24 h later. Microscopic examination of the bone marrow reveals no chromosomal alteration. Similar observations are made when the mice are treated for 5 consecutive d with a dose of 20 mg / kg. In vitro studies in which compound III is incubated with human lymphocytes at concentrations of 1000,100.10 or 0 Hg / ml also do not reveal any significant drug-induced chromosomal breakdown. Compound III, io in the Ames test in vitro, does not cause point mutations. From these findings, it is evident that compound III has no overt mutagenic potential.

In the passive cutaneous anaphylaxis test in rats, the ratio of oral and intravenous doses of comparable efficacy of compound III is compatible with good oral absorption. This observation is confirmed by the observation of plasma concentrations of 3 to 7 μg / ml 1 h after the oral administration of compound III at a dose of 50 to 300 mg / kg. In dogs, the drug is readily absorbed after oral administration of suspensions or capsules, and reaches plasma concentrations of 9 to 26 Hg / ml 1 h after administration of oral doses of 50 to 300 mg / kg . In both species, the plasma levels of the corresponding carboxylic acid metabolite (corresponding compound of formula II) are comparable to those of compound III, thereby identifying this compound as an important metabolite of compound III. After the eighth daily dose, the initial drug and metabolite levels are two to four times higher than after the initial dose, suggesting the possibility of maintaining therapeutic drug levels for extended periods.

30

Compound III in the solid state, alone or in admixture with conventional inert ingredients used in oral formulations, or in solution, has extremely good stability, which facilitates the preparation of stable formulations of this compound for conventional use. -35 picnic.

The invention is illustrated by the following examples, given without limitation.

These examples first include Preparations 1 to 46, illustrating the preferred methods of obtaining the starting compounds, and then Examples 47 to 89 relating to the claimed compounds.

Preparation 1:

2-Amino-4-ethyl-5-methylthiazole

20.9 g (0.275 mol) of thiourea are dissolved in 250 ml of ethanol at reflux. 41.3 g (0.25 mol) of 2-bromo-3-pentanone dissolved in 50 ml of ethanol are added dropwise over 25 min to the urea solution at reflux. After an additional reflux period of 2 h, the reaction solution is concentrated by boiling to a volume of about 100 ml, cooled and the crude product is collected in the form of hydrobromide by filtration. Purified 2-amino-4-ethyl-5-methyltetrazole is obtained (15.1 g; melting point 45-50 ° C; calculated m / e: 142; found: 142) by dissolution in water and reprecipita- tion with an aqueous solution of potassium hydroxide 3N. 55 By the same procedure, 1-bromo-2-hepta-none, 3-bromo-4-heptanone and 4-bromo-2,5-dimethyl-3-hexa-none are respectively converted into 2-amino -4-pentylthiazole, 2-amino-4-ethyl-5-propylthiazole and 2-amino-4,5-diisopropylthiazole.

Preparation 2:

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2-amino-4,5-diethylthiazole hydrochloride

21.8 g (0.286 mol) of thiourea, 34.4 g (0.26 mol) of 4-chloro-3-hexanone and 200 ml of ethanol are mixed and the mixture is heated at reflux for 19 h. The reaction mixture is cooled and challenged with solvent barrel to obtain the crude product as a white solid. White crystals of 4,5-diethylthiazole hydrochloride (31 g, m.p. 154-156 "C) are obtained by recrystallization from a mixture of ethyl acetate and ethanol.

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Preparation 3:

2-Aminocycloheptenothiazole

41.9 g (0.55 mol) of thiourea, 72.3 g (0.49 mol) of 2-chlorocycloheptanone and 500 ml of ethanol are mixed and the mixture is refluxed for 7 h. The solvent is removed, and a semi-solid substance remains which is divided between ethyl acetate and water. The unreacted chloroketone, recovered from the ethyl acetate phase by evaporation, is mixed with 20 g of thiourea and ethanol, the mixture is heated at reflux for 24 h, freed from the solvent and the additional crude product is partitioned between ethyl acetate and water as above. In each case, the product is collected by alkalinization of the aqueous phase with ammonium hydroxide, extraction in ethyl acetate, dehydration over anhydrous sodium sulfate, evaporation until a oil, solidification by trituration with hexane and filtration. The purified 2-aminocycloheptenothiazole (49.5 g, mp 77-78.5 ° C) is obtained by recrystallization from cyclohexane.

Preparation 4:

2-Amino-4-isopropylthiazole

52.5 g (0.69 mol) of thiourea are diluted in 400 ml of ethanol. 109.5 g (0.66 mol) of 1-bromo-3-methyl-2-butanone are added to the suspension. The resulting exothermic reaction causes dissolution and reflux. The reflux is maintained by external heating for 1 h. The solvent is removed by boiling evaporation to obtain an oil which crystallizes on standing. The final purification of 2-amino-4-isopropylthiazole hydrobromide (104.4 g, mp 74-76 ° C) is obtained by trituration with ether.

The hydrobromide is converted into the free base (58.6 g) by dissolving the salt in water, alkalinization with excess ammonium hydroxide, extraction of the free base in ether, dehydration of the ether on anhydrous sodium sulfate and evaporation of the solvent to obtain an oil.

Preparation 5:

2-Amino-6-phenylcyc! Ohexenothiazole

397.5 mg (5.22 mmol) of thiourea are suspended in 6 ml of ethanol. 1.2 g (4.74 mmol) of 2-bromo-4-phenylcyclohexanone is added to the suspension, resulting in an exothermic reaction and dissolution. The solution is refluxed for 30 min, cooled and the solvent is removed by evaporation to obtain the crude product in the form of hydrobromide.

This crude salt is dissolved in lukewarm water, the solution is filtered and the free base is precipitated by the addition of ammonium hydroxide. The crude base is collected by filtration and 802.4 mg of 2-amino-6-phenylcyclohexenothiazole (mp 181-183 ° C) is obtained by recrystallization from a mixture of water and ethanol.

Alternatively, operating on a larger scale with 8.2 g of thiourea, 24.6 g of 2-bromo-4-phenylcyclohexenone and 125 ml of ethanol, the reaction mixture is cooled after the period of reflux for 30 min, in an ice bath and the hydrobromide is collected directly by filtration. The hydrobromide is dissolved in water containing traces of ethanol by heating and the free base is precipitated (10.4 g, mp 180-182 ° C) by the addition of excess ammonium hydroxide.

By the same procedures, 2-bromo-3-phenylcyclopentanone, 2-bromo-3,5-dimethylcyclohexanone, 2-bromo-3,5,5-trimethylcyclopentanone and 2-bromo-5-methylcyclo- are converted. octanone respectively as hydrobromide or free base of 2-amino-6-phenylcyclopentenothiazole, 2-amino-5,7-dimethylcyclo-hexenothiazole, 2-amino-4,4,6-trimethylcyclopentenothiazole and 2-amino-7- methylcyclooctenothiazole.

Preparation 6:

2-Amino-6-methylcyclohexenothiazole

22.3 g (0.29 mol) of thiourea are suspended in 275 ml of ethanol. 2-Bromo-4-methylcyclohexanone is added and the mixture is heated at reflux for 75 min. The reaction mixture is allowed to cool to room temperature and the crude product is collected in the form of hydrobromide, by filtration. The crude salt is dissolved in lukewarm water, the solution is filtered and alkalinized by adding ammonium hydroxide to precipitate the free base in the form of an oil which crystallizes on cooling. Purified 2-amino-6-methylcyclohexenothiazole is obtained (25.2 g, m.p. 98-100 ° C) by recrystallization from cyclohexane.

Preparation 1:

2-Amino-6,6-dimethylcyclohexenothiazole

2-amino-6,6-dimethylcyclohexenothiazole (9.8 g, mp 109-11 l ° C) is prepared from 9.2 g (0.12 mol) of thiourea and 22.6 g ( 0.11 mol) of 2-bromo-4,4-dimethylcyclohexanone in 100 ml of ethanol according to the procedure of Preparation 6.

Preparation 8:

2-Amino-4- (2-butyl) thiazole

16.7 g (0.22 mol) of thiourea, 36 g (0.2 mol) of 1-bromo-3-methyl-2-pentanone and 100 ml of ethanol are mixed and the mixture is heated to reflux. for 5 h. An aqueous solution of potassium hydroxide (3N, 100 ml) is added and the heating is continued at reflux for a further 1 h. The reaction mixture is cooled, acidified with hydrochloric acid and the non-basic impurities are removed by extraction with ether. The aqueous phase is made basic by addition of ammonium hydroxide and the product is extracted into ether. After rinsing with water and dehydration over anhydrous sodium sulfate, the ether is removed to obtain 10 g of 2-amino-4- (2-butyl) thiazole in the form of a viscous oil of dark brown color.

Preparation 9:

2-Amino-5-methylthiazole

45.7 g (0.6 mol) of thiourea and 7.4 g (0.3 mol) of propionaldehyde are mixed with 150 ml of chloroform and the mixture is cooled in an ice bath. 44.5 g (0.33 mol) of sulfuryl chloride are added over 15 min. The exothermic reaction is maintained between 15 and 24 ° C. The evolution of gas which takes place during the addition ceases approximately 1 hour after the end of the addition. Most of the chloroform is removed by boiling in a boiling water bath. 150 ml of ethanol are added and the mixture is refluxed for 3 h.

The reaction mixture is evaporated to obtain an oil which is distributed between water and ethyl acetate. The aqueous phase is made basic by addition of ammonium hydroxide and the product is extracted into fresh ethyl acetate. The ethyl acetate is dried over anhydrous sodium sulfate and removed to give the crude product as a white solid. The purified 2-amino-5-methylthiazole (8.36 g, mp 94-95 ° C) is obtained by recrystallization from cyclohexane.

Preparation 10:

2-Amino-5-ethylthiazole

45.7 g (0.6 mol) of thiourea and 21.6 g (0.3 mol) of butyraldehyde are mixed with 150 ml of chloroform and the mixture is cooled in an ice bath. 44.5 g (0.33 mol) of sulfuryl chloride are added over 15 min. The exothermic reaction is maintained between 15 and 25 ° C. A gas evolution takes place during the addition and for approximately 1 h after the addition. 400 ml of ethanol are added, the chloroform is removed by boiling and the reaction mixture is refluxed for approximately 16 h. The reaction mixture is evaporated to obtain an oil and 11.7 g of recrystallized 2-amino-5-ethylthiazole (m.p. 54-55 ° C) are isolated by the method indicated in preparation 9.

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

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Preparation 11:

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

2.56 g (20 mmol) of 2-amino-4,5-dimethyl-thiazole, 4.8 g (22 mmol) of diethyl ethoxymethylenemalonate and 5 ml of ethanol are refluxed for 1 h. The reaction mixture is cooled and the crude product is precipitated by the addition of hexane. Purified 2- (2,2-dicarbethoxyethenylamino) -4,5-dimethylthiazole (4.21 g, mp 82-83.5 ° C) is obtained by recrystallization from hexane.

Preparation 12:

2- (2,2-Dicarbethoxyethény lamino) -4-ethyl-5-methylthiazole

2.84 g (20 mmol) of 2-amino-4-ethyl-5-methyl-thiazole and 4.76 g (22 mmol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 3 h. The product, obtained in the form of an oil by cooling, is used without further purification in the subsequent step.

By the same procedure, convert 2-amino-4-pentyl-thiazole, 2-amino-4-propyl-5-ethylthiazole, 2-amino-4,5-diiso-propylthiazole, 2-amino- 5-propylthiazo.le, 2-amino-5-isopropyl-thiazole, 2-amino-5-pentylthiazole, 2-amino-6-phenylcyclo-pentenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2 -amino-4,6,6-trimethylcyclopentenothiazole and the 2 ~ amino-7-methyl-cyclooctenothiazole in the 2- (2,2-dicarbethoxyethenylamino) -thiazole derivative thereof.

By the same procedure, the corresponding dimethyl, dipropyl and diisopropyl esters are prepared by replacing the diethyl ethoxymethylenemalonate with the corresponding dimethyl, dipropyl or diisopropyl ethoxymethylene malonate.

Preparation 13:

2- (2,2-Dicarbethoxyethény lamino) -4-methyl-5-ethylthiazole

A mixture of 5.68 g (40 mmol) of 4-methyl-5-ethylthiazole and 9.52 g (44 mmol) of diethyl ethoxymethylenemalonate is briefly heated to 86 ° C., then cooled to obtain the product. in the form of an oil which is used directly in the next step.

Preparation 14:

2- (2,2-Dicarbethoxyethenylamino) -4,5-diethylthiazole

15.4 g (80 mmol) of diethylthiazole hydrochloride, 19.0 g (88 mmol) of diethyl ethoxymethylenemalonate, 8.1 g (80 mmol) of triethylamine and 125 ml of ethanol are mixed and the mixture is refluxed. mixing for 2 '/> h. The reaction mixture is cooled and the solvent is removed. The resulting semi-solid product is partitioned between ethyl acetate and water. 2- (2,2-dicarbethoxyethenyl-amino) -4,5-diethylthiazole (28.6 g) is obtained in the form of a golden-colored oil from the ethyl acetate phase by dehydration on anhydrous sodium sulfate and removal of the solvent by evaporation.

By the same process, the hydrobromides of 5,7-di-methylcyclohexenothiazole, 4,4,6-trimethylcyclopentenothiazole and 7-methylcyclooctenothiazole are converted to the corresponding 2- (2,2-dicarbethoxy-ethenylamino) thiazole derivative.

Following the same procedure, the corresponding dimethyl, dipropyl and diisopropyl esters are prepared by replacing the diethyl ethoxymethylenemalonate with the corresponding dimethyl, dipropyl or diisopropyl ethoxymethylene malonate.

Preparation 15:

2- (2,2-Dicarbethoxyethenylamino) cyclopentenothiazole

3.6 g (34.5 mmol) of 2-aminocyclopentenothiazole and 8.2 g (38.0 mmol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 100 min. The reaction mixture and the 2- (2,2-dicarbethoxyethenyl-) are cooled.

amino) cyclopentenothiazole (7.0 g, Rf 0.6 in thin layer chromatography on silica gel using a mixture of chloroform and 1% ethanol as eluent) crystallized by adding hexane.

Preparation 16:

2- (2,2-Dicarbethoxyethény lamino) cyclohexenothiazole

7.7 g (50 mmol) of 2-aminocyclohexenothiazole and 11.9 g (55 mmol) of diethyl ethoxymethylenemalonate are mixed with 10 ml of ethanol and the mixture is heated at reflux for 50 min. The reaction mixture is cooled and 15 g of 2- (2,2-dicarbethoxy-ethenylamino) cyclohexenothiazole (Rf 0.5 by thin layer chromatography on silica gel with, as eluent, a mixture of chloroform and 1% of ethanol) precipitate by adding 50 ml of hexane.

Alternatively, 58.4 g of 2-aminocyclohexenothiazole, 89.82 g of diethyl ethoxymethylenemalonate and 584 ml of cyclohexane are mixed and the mixture is heated to reflux under a nitrogen atmosphere for 2 h, cools to 15 ° C and the product is collected (96 g, mp 113 ° C) by filtration.

Preparation 17:

2- (2,2-Dicarbethoxyethény lamino) cyclooctenothiazole

2.0 g (11 mmol) of 2-aminocyclooctenothiazole and 2.62 g (12.1 mmol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 23 h. The reaction mixture is cooled and precipitated by the addition of hexane 3.13 g of 2- (2,2-dicarbethoxyethenylamino) cyclooctenothiazole (Rf 0.6 by chromatography on silica gel with, as eluent, a mixture of chloroform and 1% ethanol).

Preparation 18:

2- (2,2-Carbethoxyethény lamino) -4-methylthiazoIe

4.57 g (40 mmol) of 2-amino-4-methylthiazole and 9.51 g (44 mmol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 1 h. The reaction mixture is cooled and 9.8 g of 2- (2,2-dicarbethoxyethenylamino) -4-methyl-thiazole (Rf 0.5 by thin layer chromatography) are precipitated by the addition of 60 ml of hexane. silica gel with, as eluent, a mixture of chloroform and 1% ethanol).

Preparation 19:

2- (2,2-Dicarbethoxyethény lamino) thiazole

10.0 g (0.10 mol) of 2-aminothiazole and 23.8 g (0.11 mol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 1 lA h. The reaction mixture is cooled and the resulting semi-solid substance is recrystallized from hexane to obtain the purified 2- (2,2-dicarbethoxy-ethenyl) thiazole (17.2 g in two crops, Rf 0.6 in the Chromatography on a thin layer of silica gel with a mixture of chloroform and 1% ethanol as eluent).

Preparation 20:

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

Heated in a boiling water bath for 1 h 6.85 g (60 mmol) of 2-amino-5-methylthiazole and 14.3 g (66 mmol) of diethyl ethoxymethylenemalonate. The reaction mixture is cooled and the product is precipitated by the addition of approximately 75 ml of hexane. Purified 2- (2,2-dicarbethoxyethenylamino) -5-methylthiazole (14.1 g in two crops, Rf 0.55-0.65 in thin layer chromatography on silica gel with a mixture of chloroform and 1% ethanol) is obtained by recrystallization from hexane.

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Preparation 21:

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

11.7 g (91.3 mmol) of 2-amino-5-ethylthiazole and 21.7 g (100.43 mmol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 45 min. 2- (2,2-dicarbethoxyethylamino) -5-ethylthiazole (27.2 g, respective Rf values of 0.6 and 0.7 in thin layer chromatography on silica gel with a mixture of chloroform and 1% ethanol and a 2: 1 mixture of hexane and ethyl acetate) is obtained in the form of an oil by cooling and is used directly in the following step.

Preparation 22:

2- (2,2-Dicarbethoxyethény lamino) -4- (2-methyl-2-propyl) thiazole

15.6 g (0.1 mol) of 2-amino-4- (2-methyl-2-propyl) -thiazole and 23.8 g (0.11 mol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated. mix in a boiling water bath for 2 h. 2- (2,2-dicarbethoxyethenylamino) -4- (2-methyl-2-propyl) thiazole is obtained in the form of a wet solid substance on cooling and is used directly in the next step.

Preparation 23:

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

20.5 g (0.16 mol) of 2-amino-4-ethylthiazole and 35 g (0.17 mol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 2 h. 2- (2,2-Dicarbethoxyethenylamino) -4-ethylthiazole is obtained, by cooling, in the form of an oil and is used directly in the following step (Rf = 0.75 by thin layer chromatography of silica gel, with a mixture of chloroform and 1% ethanol as eluent).

By the same procedure, 2-amino-4-isopropylthiazole (58.6 g, 0.415 mol) and diethyl ethoxymethylenemalonate (92 ml, 0.455 mol) are converted into 2- (2,2-dicarbethoxyethenyl-amino) -4-isopropylthiazole (Rf = 0.7 by thin layer chromatography on silica gel, with a mixture of chloroform and 1% ethanol as eluent).

Preparation 24:

2- (2,2-Dicarbethoxyêthénylamino) -6-phenylcyclohexênothiazole

10.4 g (45.2 mmol) of 2-amino-6-phenylcyclohexe-nothiazole and 10 ml (49.5 mmol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath. A solution is obtained after 15 min. After an additional heating period of 30 min, the entire mass solidifies. The crude product is recrystallized from cyclohexane, giving 15.3 g of purified 2- (2,2-dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole, melting at 131-133 ° C.

Preparation 25:

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

23.3 g (0.139 mol) of 2-amino-6-methylcyclohexeno-thiazole are mixed with 31 ml (0.153 mol) of diethyl ethoxymethylenemalonate and the mixture is heated in a boiling water bath. After a heating period of approximately 10 min, a light orange-colored oil is obtained. After heating for 1 h, crystallization is started by scraping. 40.2 g of 2- (2,2-dicarbethoxy-ethenylamino) -6-methylcyclohexenothiazole are obtained (mp 106-109 ° C) by recrystallization from ethanol.

Preparation 26:

2- (2,2-Dicarbethoxyethenylamino) -6,6-dimethylcyclohexenothiazole

9.8 g (53.8 mmol) of 2-amino-6,6-dimethylcyclo-hexenothiazole, 12 ml (59.4 mmol) of diethyl ethoxymethylenemalonate and about 5 ml of ethanol are mixed and the mixture is heated. in a boiling water bath for 1 h. The ethanol is removed by boiling during the first part of the heating period. The product is crystallized by cooling and scraping. The purified 2- (2,2-dicarbethoxy-ethenylamino) -6,6-dimethylcyclohexenothiazole (14.3 g, mp 83-85 ° C) is obtained by recrystallization from hexane.

Analysis for Ci7H2404N2S:

Calculated: C 57.93 H 8.86 N 7.95%

Found: C 57.72 H 6.66 N7.94%

Preparation 27:

2- (2,2-Dicarbethoxyethény lamino) -4- (2-butyl) thiazole

8.44 g (54 mmol) of 2-amino-4- (2-butyl) thiazole and 11.7 g (54 mmol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 1 h , then cooled to obtain 17.6 g of 2- (2,2-dicarbethoxyethenylamino) -4- (2-butyl) thiazole (Rf = 0.75 by thin layer chromatography on silica gel with a mixture of chloroform and 1% ethanol as eluent).

Preparation 28:

Ethyl 1-oxo-1 H-6,7-Dimethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate

4.17 g (14 mmol) of 2- (2-dicarbethoxyethenyl-amino) -4,5-dimethylthiazole are mixed with 30 ml of Dowtherm A and the mixture is heated to 220 ° C. for 1 h. The reaction mixture is cooled and 125 ml of petroleum ether are added. The solid substance which precipitates is separated by filtration, mixed again with the mother liquor and chromatographed on a silica gel column of 70 x 180 mm, the eluent used being chloroform. After an initial fraction of 125 ml, six 250 ml fractions are collected and evaporated to dryness to obtain 2.42 g of crude product (mp 114-115 ° C). By recrystallization from cyclohexane, 1-oxo-1H-4,5-dimethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate is purified (1.64 g; mp 119-120 ° C ).

Analysis for C11H12N203S:

Calculated: C 52.37 H 4.79 N 11.10% mass ion: 252 Found: C 52.21 H 4.85 N 11.23% mass ion: 252

Preparation 29:

Ethyl 1-oxo-1 H-6-methyl-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate

6.25 g of 2- (2-dicarbethoxyethenylamino) -4-ethyl-5-methylthiazole are mixed with 30 ml of Dowtherm A and the mixture is heated to 215 "C for 2Vi h. The reaction mixture is cooled, petroleum ether and the crude product is collected (1.96 g) by filtration. 630 mg of the crude product is recrystallized from cyclohexane to give 301 mg of 1-oxo-1 H-6-methyl-7-ethylthiazolo - [3,2-a] -pyrimidine-2-purified ethyl carboxylate melting at 122-124 ° C.

Analysis for C12H14N203S:

Calculated: C 54.12 H 5.30 N 10.52%

Found: C 54.09 H 5.26 'N 10.63%

Preparation 30:

Ethyl 1-oxo-1 H-6-Ethyl-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylate

12 g of 2- (2,2-dicarbethoxyethenylamino) -4-methyl-5-ethylthiazole are mixed with 60 ml of Dowtherm A and the mixture is heated at 205 ° C. for 3 h. The reaction mixture is cooled and chromatographed on a 90 x 205 mm column of silica gel, eluting with chloroform containing 1% ethanol. Seven fractions of 250 ml each containing the product are collected, they are combined, the solvent is removed to obtain an oil and this oil is rechromatographed on silica gel (60 x 600 mm) with the same eluent. 165 fractions of 8 ml are collected, the solvent is freed and an oil is obtained which is made

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recrystallize by trituration with diisopropyl ether. By recrystallization from cyclohexane, ethyl l-oxo-1H-6-ethyl-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylate (2.45 g, mp 65-66) is obtained. ° C).

Analysis for C12H14N203S:

Calculated: 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

Preparation 31:

Ethyl 1-oxo-1H-6,7-Diethylthiazolo- [3,2-aJ-pyrimidine-2-carboxyIate

26.1 g of 2- (2,2-dicarbethoxyethylenylamino) -4,5-di-ethylthiazole and 300 ml of Dowtherm A are mixed and the mixture is heated to 225 ° C. for 3! 4 h. The reaction mixture is cooled and chromatographed on a column of silica gel (60 x 320 mm). Dowtherm A is eluted with hexane and the product is eluted with a mixture of hexane and chloroform at 2: 1. 33 fractions of 250 ml each are collected. The fractions from the eighth to the thirty-third are combined and freed from the solvent, giving 22 g of ethyl 1-oxo-1H-6,7-diethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate ( Rf = 0.4-0.5 in thin layer chromatography on silica gel with, as eluent, a mixture of chloroform and 1% ethanol), as an oil.

By the same procedure, the following products of preparations 12 and 14:

2- (2,2-dicarbomethoxyethenylamino) -4-ethyl-5-methylthiazole, 2- (2,2-dicarbopropoxyethenylamino) -4-ethyl-5-methylthiazole, 2- (2,2-dicarbisopropoxyethylenylamino) -4-ethyl- 5-methylthiazole, 2- (2,2-dicarbomethoxyethenylamino) -4,5-diethylthiazole, 2- (2,2-dicarbopropoxyethenylamino) -4,5-diethylthiazole, 2- (2,2-dicarbisopropoxyethenylamino) -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) , 6-trimethylcyclopentenomen-

thylthiazole are respectively converted into the following compounds: methyl l-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate,

1-oxo-1 H-6-methyl-7-ethylthiazolo- [3,2-a] -pyrimidine-2-propyl carboxylate,

1-oxo-1 H-6-methyl-7-ethylthiazolo- [3,2-a] -pyrimidine-2-isopropyl 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,

1-oxo-1 H-6-phenylcyclopentenothiazolo- [3,2-a] -pyrimidine-2-

ethyl carboxylate, 1-oxo-1H-6,8-dimethylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-ethyl carboxylate, 5 l-oxo-1H-8-methylcyclooctenothiazolo- [3,2- ethyl a] -pyrimidine-2-carboxylate, and ethyl 1-oxo-1H-6,8,8-trimethylcyclopentenothiazolo- [3,2-a] -pyrimidine-2-carboxylate.

10 Preparation 32:

Ethyl I-oxo-1H-Cyclopentenothiazolo- [3,2-a] -pyrimidine-2-carboxylate

7.0 g of 2- (2,2-dicarbethoxyethenylamino) -cyclopentenothiazole are mixed with 40 ml of Dowtherm A and the mixture is heated to 225-230 ° C for about 1 h. The reaction mixture is cooled and chromatographed on silica gel (70 x 190 mm). The Dowtherm A is eluted with hexane. The product is eluted with a mixture of chloroform and 1% ethanol. Four fractions of 250 ml each are collected, pooled and the solvent is removed to obtain an oil. A portion of the oil is crystallized by trituration with cyclohexane, to obtain 1.91 g of crude product. By recrystallization of 0.6 g of the crude product, the purified ethyl l-oxo-1H-cyclopentenothiazolo- [3,2-a] -pyrimidine-2-car-boxylate (0.33 g, mp 102- 103 ° C).

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Analysis for C12H12N203S:

Calculated: C 54.53 H 4.58 N 10.60%

Found: C 54.54 H 4.71 N 10.71%

30 Preparation 33:

ethyl l-oxo-1H-Cyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxylate

12.6 g of 2- (2,2-dicarbethoxyethenylamino) -cyclohexenothiazole are mixed with 125 ml of Dowtherm A and the mixture is heated at 230 ° C for 25 min. The reaction mixture is cooled and chromatographed on silica gel (60 x 320 mm). The Dowtherm A is eluted with hexane and the product is eluted with a mixture of chloroform and 1% ethanol in fourteen fractions of 125 ml each. Crude ethyl 1-oxo-1H-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylate (10.7 g, mp 92-94 ° C) is obtained by combining the fractions and removing the solvent .

Alternatively, 80 g (0.25 mol) of 2- (2,2-dicarbethoxyethenylamino) cyclohexenothiazole, 101 g (68 ml, 45 0.48 mol of trifluoroacetic anhydride, 0.8 1 of toluene and 11 ethanol and the mixture is refluxed for 21 h, the reaction mixture is cooled and 300 ml of water are added The toluene phase (upper) is separated, washed with a saturated aqueous solution of sodium chloride, dehydrated on anhydrous sulfate of magnesium-50 sium, filtered, concentrated to 150 ml (suspension), diluted with 11 of ethanol (solution), concentrated to 280 ml, cooled to 5 ° C, granulated and filtered giving the 1 -oxo -1 relatively pure ethyl H-cyclohexenothiazolo- [3,2-a] -pyri-midine-2-carboxylate (47 g, mp 105-106 ° C).

55 Preparation 34:

Ethyl 1-oxo-1 H-Cycloheptenothiazolo- [3,2-a] -pyrimidine-2-carboxylate

25.2 g (0.15 mol) of 2-aminocycloheptenothiazole, so 35.7 g (0.165 mol) of diethyl ethoxymethylenemalonate and 400 ml of Dowtherm A are mixed and the mixture is heated to 220-230 ° C for 2 h. The reaction mixture is cooled and chromatographed on silica gel (90 x 235 mm). The Dowtherm A is eluted with hexane. The product is eluted with a 1: 1 mixture of hexane and chloroform in 65 thirty fractions of 500 ml each. The fractions from the sixth to the thirtieth are combined and freed from the solvent, giving the crude product as a wet solid. Ethyl 1-oxo-1H-cycloheptenothiazolo- [3,2-a] -pyrimidine-2-carboxylate

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purified (27.1 g, mp 78-79 ° C) is obtained by recrystallization from cyclohexane.

The same product is obtained by heating 2- (2,2-dicarbethoxy-ethenylamino) cycloheptenothiazole in Dowtherm A by carrying out the isolation and purification in the same way.

Preparation 35:

Ethyl 1-oxo-1 H-Cyclooctenothiazolo- [3,2-a] -pyrimidine-2-carboxylate

3.13 g of 2- (2,2-dicarbethoxyethenylamino) -cyclooctenothiazole are mixed with 30 ml of Dowtherm A and the mixture is heated to 220 ° C. for 2 h. The reaction mixture is cooled and chromatographed on silica gel (70 x 190 mm). The Dowtherm A is eluted with hexane. The product is eluted with a mixture of chloroform and 1% ethanol in four 125 ml fractions. The fractions are combined, evaporated to obtain an oil and, by trituration with hexane, 1-oxo-1H-cyclooctenothiazolo- [3,2-a] -pyrimidine-2-carboxylate is obtained (1.956 g, Rf = 0.5 by thin layer chromatography on silica gel, elution being carried out with a mixture of chloroform and 1% ethanol).

Preparation 36:

Ethyl 1-oxo-1 H-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylate

9.8 g of 2- (2,2-dicarbethoxyethenylamino) -4-methylthiazole are mixed with 50 ml of Dowtherm A and the mixture is heated at 220 ° C for 2 h. The reaction mixture is cooled, 50 ml of hexane are added thereto and the crude product is collected by filtration. By recrystallization of the crude product from ethanol, 4.6 g of 1-oxo-1 H-7-methyl-thiazolo- [3,2-a] -py rimidine-2-carboxy late ethyl purified to melt are obtained. 187-189 ° C.

Alternatively, this ester is prepared by direct condensation of 2-amino-4-methylthiazole with ethyl ethoxymethylenemalonate by heating at reflux in trichlorobenzene [Allen et al., "J. Org. Chem. ”, 24, 779 (1959)].

Preparation 37:

Ethyl 1-oxo-IH- Thiazolo- [3,2-aJ-pyrimidine-2-carboxylate

17.2 g of 2- (2,2-dicarbethoxyethenylamino) thiazole are mixed with 200 ml of Dowtherm A and the mixture is heated at 215 ° C for 30 min. The reaction mixture is cooled to obtain a suspension. 100 ml of hexane are added and the crude product is collected by filtration. By recrystallization from ethanol, 1-oxo-1 H-thiazolo- [3,2-a] -pyrimidine-2-carboxylate of purified ethyl is obtained (8.0 g, mp 184-185 ° C).

As a variant, this ester is prepared by direct condensation of 2-aminothiazole with ethyl ethoxymethylenemalonate by heating at reflux in trichlorobenzene [Allen et al., "J. Org. Chem. ”, 24, 779 (1959)].

Preparation 38:

Ethyl 1-oxo-1H-6-Methylthiazolo- [3,2-a] -pyrimidine-2-carboxylate

14.1 g of 2- (2,2-dicarbethoxyethylenyl -) - 5-methyl-thiazole are mixed with 150 ml of Dowtherm A and the mixture is heated to 220 ° C. for A h. The reaction mixture is cooled and about 300 ml of hexane are added thereto, the product is collected by filtration and 6.4 g of 1-oxo-1 H-6-methylthiazolo- [3,2-a] -pyrimidine- are obtained.

Purified ethyl 2-carboxylate (m.p. 149-151 "C) by recrystallization from diisopropyl ether.

Alternatively, this ester is prepared by direct condensation of 2-amino-5-methylthiazole with ethyl ethoxymethylenemalonate in boiling trichlorobenzene (Dunwell et al., "J. Chem. Soc.", (C) 1971 , 2094).

Preparation 39:

ethyl l-oxo-1H-6-Ethylthiazolo- [3,2-aJ-pyrimidine-2-carboxylate

25 J g (36 mmol) of 2- (2,2-dicarbethoxyethenyl-amino) -5-ethylthiazole, 36.2 g (172 mmol) of trifluoroacetic anhydride and 150 ml of toluene are mixed and the mixture is heated at reflux for about 20 h. The reaction mixture is evaporated to dryness, the residue is taken up in 300 ml of chloroform. The chloroform solution is washed with a saturated sodium bicarbonate solution, then a saturated sodium chloride solution, dehydrated over anhydrous sodium sulfate, evaporated to dryness and the residue is triturated with diisopropyl ether, giving 17.8 g of ethyl 1-oxo-1H-6-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate melting at 148-150 ° C. A portion of the product (5.2 g) is recrystallized from approximately 75 ml of ethyl acetate, giving an additional quantity of purified product (4.1 g; mp, 149-150 ° C).

Analysis for CnH12N203S:

Calculated: C 52.37 H 4.79 N 11.10%

Found: C 52.30 H 4.51 N 11.14%

Preparation 40:

Ethyl 1-oxo-1 H-7- (2-methyl-2-propyl) thiazolo- [3,2-a] -pyrimidine-2-carboxylate

32.6 g of 2- (2,2-dicarbethoxyethylenylamino) -4- (2-methyl-2-propyl) thiazole are mixed with 400 ml of Dowtherm A and the mixture is heated at 230 ° C for 1 h. The reaction mixture is cooled and chromatographed on silica gel (60 x 600 mm). The Dowtherm A is eluted with hexane. The product is eluted with chloroform. Nine 500 ml fractions are collected. The fractions from the sixth to the ninth are combined and evaporated to dryness, giving 1-oxo-1 H-7- (2-methyl-2-propyl) thiazolo- [3,2-a] -pyrimidine-2-carboxylate ethyl (11.4 g, mp 145-147 ° C). An additional quantity of product (2.04 g) is obtained from the fifth fraction by evaporation until a wet solid substance is obtained which is triturated with cyclohexane. 1 g of the largest crop is recrystallized from cyclohexane to obtain an additional quantity of purified product (0.62 g, mp 148-149 ° C).

Analysis for C13H16N203S:

Calculated: C 55.70 H 5.75 N9.99%

Found: C 55.14 H 5.58 N9.95%

Preparation 41:

ethyl l-oxo-1H-7-Ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate

47.7 g (0.16 mol) of 2- (2,2-dicarbethoxyethenyl-amino) -4-ethylthiazole are stirred in 500 ml of toluene and 45 ml (0.32 mol) of trifluoroacetic anhydride are added. A moderate exothermic reaction is observed. The reaction mixture is heated at reflux for 26 h, cooled and 250 ml of ethyl acetate are added thereto. The mixture is carefully extracted with 250 ml of aqueous sodium bicarbonate solution (release of carbon dioxide), then with 250 ml of saturated sodium chloride, it is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is suspended in diisopropyl ether and the crude product is collected by filtration. By recrystallization of the crude product from acetonitrile, purified ethyl l-oxo-1H-7-ethyl-thiazolo- [3,2-a] -pyrimidine-2-carboxylate (10.33 g, mp 175 -177 ° C).

Analysis for CuH12N203S:

Calculated: C 52.37 H 4.79 N 11.10%

Found: C 52.34 H 4.85 NI 1.27%

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

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Preparation 42:

ethyl l-oxo-4H-7-Isopropylthiazolo- [3,2-a] -pyrimidine-2-carboxylate

10 g of 2- (2,2-dicarbethoxy) -4-isopropylthiazole are mixed with 100 ml of Dowtherm A and the mixture is heated at 220 ° C for 2 h, allowed to cool to room temperature for about 16 h and it is again heated to 220 ° C for another 5 h. The mixture is allowed to cool to room temperature, about 200 ml of hexane is added to it and filtered to remove traces of insoluble matter. The hexane is removed and the residue is chromatographed on approximately 500 g of silica gel. The Dowtherm A is eluted with hexane and the product is eluted with chloroform. The fractions containing the product are combined and evaporated to dryness, the residue is suspended in diisopropyl ether and the product (mp 143-144 ° C) is collected by filtration. The crude product is recrystallized from ethanol to give purified ethyl l-oxo-1H-7-isopropyl-thiazolo- [3,2-a] -pyrimidine-2-carboxylate (1.49 g, mp 145- 147 ° C, nuclear magnetic resonance: singlets at S 8.6 and S 7.3 corresponding to one proton each, and multiplets centered at 8 4.2 and 8 1.2 corresponding respectively to three protons and nine protons).

Preparation 43:

Ethyl 1-oxo-1 H-7-Phenylcyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxylate

15.3 g (38.2 mmol) of 2- (2,2-dicarbethoxy-ethenylamino) -6-phenylcyclohexenothiazole are suspended in 150 ml of toluene. 10.8 ml (76.5 mmol) of trifluoroacetic anhydride are added, which gives a clear solution which is refluxed for 16 h. The reaction mixture is allowed to cool to room temperature, diluted to 150 ml with ethyl acetate, extracted twice with 150 ml of 5% potassium carbonate and once with 150 ml of chloride of saturated sodium, it is dried over anhydrous sodium sulfate and evaporated to dryness. The solid residue is recrystallized from acetonitrile, giving purified ethyl 1-oxo-1 H-7-phenylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylate (9.89 g, mp 160-161 , 5 ° C).

Preparation 44:

Ethyl 1-oxo-1 H-7-methylcyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxylate

40.2 g (0.119 mol) of 2- (2,2-dicarbethoxyethenyl-amino) -6-methylcyclohexenothiazole are dissolved in 400 ml of toluene. 33.5 ml (0.237 mol) of trifluoroacetic anhydride is added, which causes a slightly exothermic reaction. The reaction mixture is refluxed for about 16 h, allowed to cool to room temperature, diluted with 400 ml of ethyl acetate, then extracted twice with 400 ml of IN potassium carbonate and with 400 ml of saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. By recrystallization from cyclohexane containing a small amount of ethyl acetate, 29.3 g of 1-oxo-1 H-7-methylcyclohexeno-thiazolo- [3,2-a] -pyrimidine-2-carboxylate d are obtained. purified ethyl melting at 127-129 ° C.

Preparation 45:

ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo- [3,2-a J-pyrimidine-2-earboxylate

13 g (36.9 mmol) of 2- (2,2-dicarbethoxyethenyl-amino) -6,6-dimethylthiazole are dissolved in 130 ml of toluene. 10.4 ml (73.6 mmol) of trifluoroacetic anhydride is added and the mixture is heated at reflux for 16 h. The reaction mixture is allowed to cool to ambient temperature, it is diluted with 150 ml of ethyl acetate, it is extracted twice with 130 ml of saturated sodium bicarbonate and once with 150 ml of saturated sodium chloride, it is dried over anhydrous sodium sulfate and evaporated to dryness.

By recrystallization from hexane, 9.40 g of ethyl 1-oxo-1 H-7,7-dimethylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylate, melting at 92 ° -94 °, are obtained. vs.

Analysis for C, 5H16N203S:

Calculated: C 58.80 H 5.92 N9.14%

Found: C 58.93 H 5.48 N9.01%

Preparation 46:

Ethyl 1-oxo-1 H- 7- (2-Butyl) thiazolo- [3,2-aJ-pyrimidine-2-carboxylate

17.6 g of 2- (2,2-dicarbethoxyethenylamino) -4- (2-butyl) thiazole are mixed with 175 ml of Dowtherm A and the mixture is heated to 225 ° C for 2 h. The reaction mixture is cooled and chromatographed on silica gel (60 x 600 mm). The Dowtherm A is eluted with hexane. The product is eluted with a 2: 1 mixture of chloroform and hexane. Fractions 4 to 8 (500 ml each) are combined and evaporated to give an oil which is taken up in approximately 400 ml of hot hexane, the solution is treated with charcoal and it is cooled to give 2.12 g of 1-oxo-1 H-7- (2-butyl) thiazolo- [3,2-a] -pyrimidine-2-crystalline ethyl carboxylate melting at 105.5-108 ° C.

Analysis for C13H1603N2S:

Calculated: C 55.70 H 5.75 N9.99%

Found: C 55.82 H 5.40 N 10.22%

Example 47:

1-Oxo-1 H-6,7-dimethylthiazolo- [3,2-a] -pyrimidine-2-carbo-xylic acid

1.41 g of ethyl l-oxo-1H-6,7-dimethylthiazolo- [3,2-a] -pyri-midine-2-carboxylate are heated in a boiling water bath with 20 ml of hydrobromic acid. 48% for 1 hour. Dissolution takes place in a few minutes and solids begin to form at the end of the reaction period. The reaction mixture is cooled and the product is collected by filtration. By recrystallization from ethanol, the purified l-oxo-1H-6,7-dimethylthiazolo- [3,2-a] -pyrimi-dine-2-carboxylic acid (508 mg, mp 189-190 ° C) is obtained. ).

Analysis for C9H803N2S:

Calculated: 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-l H-6-methyl-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

971 mg of ethyl l-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate are heated in a boiling water bath with 15 ml of 48% hydrobromic acid . Dissolution takes place almost immediately. Heating is continued for 2% h, and at this stage the reaction mixture is cooled, which gives a product in the form of a solid substance capable of being filtered. By recrystallization of the crude product from isopropyl alcohol, the l-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid is obtained (354 mg, mp 201 -202 ° C).

Analysis for CioH1003N2S:

Calculated: C 50.41 H 4.23 N 11.76%

Found: C 50.28 H 4.26 N 11.80%

Example 49:

1-oxo-1 H-6-ethyl-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

Heated in a boiling water bath 1.33 g of 1-oxo-1 H-6-ethyl-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylate with 10 ml of hydrobromic acid at 48% for 30 min and, at this point, a solid substance begins to form. The mixture is cooled

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reaction and the crude product is collected by filtration. By recrystallization from isopropyl alcohol, 1-oxo-1 H-6-ethyl-7-methylthiazolo- [3,2-al-pyrimidine-2-carboxylic acid (596 mg, mp 174-176 C) is obtained. ).

Analysis for C10HI0O3N2S:

Calculated: C 50.41 H 4.23 N 11.76%

Found: C 50.44 H 4.22 NI 1.82%

Example 50:

1-oxo-l H-6,7-diethylthia: olo- [3,2-a] -pyrimidine-2-carbo-xylic acid

19.2 g of ethyl l-oxo-1H-6,7-diethylthiazolo- [3,2-a] -pyri-midine-2-carboxylate are heated at 85 ° C. for 1 h with hydrobromic acid 48% aqueous. A gas evolution is observed (probably due to the decarboxylation of the product). The reaction mixture is cooled and made alkaline by addition of concentrated ammonium hydroxide and the unreacted starting compound and the impurities are removed by extraction with ethyl acetate. The aqueous phase is acidified with acetic acid and the solid product is collected by filtration. The crude product is recrystallized from isopropyl alcohol, which gives 5.4 g of partially purified product, in two harvests. The partially purified material (2.5 g) is recrystallized a second time from isopropyl alcohol, which gives 1-oxo-1H-6,7-diethylthiazolo- [3,2-a] -pyrimidine-2 acid. - purified carboxylic [1.6 g, mp 104-106 ° C (cloudy)].

Analysis for CnH1203N2S:

Calculated: C 52.37 H 4.79 N 11.10%

Found: C 52.31 H 4.79 N 11.16%

Example 51:

1-oxo-1 H-cyclopentenothiazolo-f3,2-aJ-pyrimidine-2-carb-oxylic acid

1.3 g of ethyl 1-oxo-1 H-cyclopentenothiazolo- [3,2-a] -pyri-midine-2-carboxylate are heated with 15 ml of 48% hydrobromic acid in a boiling water bath for 30 min. The dissolution takes place after approximately 5 min; a solid substance begins to form towards the end of the heating period. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from isopropyl alcohol, 0.51 g of 1-oxo-1 H-cyclopentenothiazolo- [3,2-a] -pyrimidine-2-carboxy lique acid is obtained (mp 202-203.5 ° C ).

Analysis for C10H8O3N2S:

Calculated: C 50.84 H 3.41 NI 1.86%

Found: C 50.42 H 3.57 NI 1.65%

The sodium and potassium salts are obtained by dissolving the free acid in water with an equivalent of the suitably chosen hydroxide and evaporating the water under vacuum or lyophilization.

The N-methylmorpholine salt is prepared by dissolving the acid in methylene chloride with a slight excess of N-methylmorpholine and evaporation to dryness or precipitation of the salt by cooling and addition of hexane.

Example 52:

L-oxo-IH-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carbo-xylic acid

2.8 g of ethyl 1-oxo-1 H-cyclohexenothiazolo- [3,2-a] -pyri-midine-2-carboxylate are heated in a boiling water bath with 30 ml of 48% hydrobromic acid. Dissolution takes place a few minutes after the start of heating; precipitation of the product begins towards the end of the reaction period. Cool the reaction mixture in an ice bath and isolate by filtration 1.66 g of 1-oxo-1H-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid, melting at 188-189 ° C. By recrystallization from ethanol, 1.38 g of product is obtained, having the same melting point.

Alternatively, this product is prepared by shaking 22.3 g of the ethyl ester with 223 ml of 48% hydrobromic acid in a container at low pressure. Dissolution takes place at 65-70 ° C. The reaction mixture is heated over a period of 40 min to a maximum temperature of 85 ° C and to a maximum gauge pressure of 49 kPa. The reaction mixture is cooled to 45 ° C, the pressure is relaxed, the mixture is cooled to 5 ° C, stirred for 1 h and the relatively pure product is collected directly by filtration (12.4 g, mp 192-194 C) .

The sodium salt is prepared by dissolving the acid in methanol with an equivalent of sodium methylate and evaporation to dryness or precipitation of the salt by cooling and addition of hexane.

Example 53:

1-oxo-l H-cycloheptenothiazolo- [3,2-a] -pyrimidine-2-carbo-xylic acid

5.8 g of ethyl 1-oxo-1 H-cycloheptenothiazolo- [3,2-a] -pyrimidine-2-carboxylate are heated for 15 min in a boiling water bath with 50 ml of hydrobromic acid. The reaction mixture is poured into ice, stirred and the crude product is collected by filtration. By recrystallization from ethanol, the purified l-oxo-1H-cycloheptenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid (2.63 g, m.p. 162-163 ° C) is obtained.

Analysis for C12H12N302S:

Calculated: 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

The amine salts are prepared by adding an equivalent of an amine to a warm ethanolic solution of the acid, then cooling, concentration or addition of hexane.

Example 54:

1-oxo-l H-cyclooctenothiazolo- [3,2-a] -pyrimidine-2-carbo-xylic acid

1.23 g of ethyl 1-oxo-1 H-cyclooctenothiazolo- [3,2-a] -pyri-midine-2-carboxylate is heated in an oil bath with 30 ml of 48% hydrobromic acid , at 90 ° C for 4 h. The reaction mixture is cooled, its pH is adjusted to 1.5 and the product is extracted into ethyl acetate. The ethyl acetate extraction phase is washed with water, then with saturated sodium chloride, dried over sodium sulfate and evaporated to give an oil. The oil is redissolved in ethyl acetate and the product is extracted into IN potassium hydroxide. The basic solution is re-acidified with 3N hydrochloric acid and the product is reextracted in ethyl acetate. The ethyl acetate solution is extracted with water, then with saturated sodium chloride, dehydrated over anhydrous sodium sulfate and evaporated to dryness giving 308 mg of 1-oxo-1 H-cycloheptenothiazolo acid - [3,2-a] -pyrimidine-2-carboxylic (Rf = 0.6 by thin layer chromatography on silica gel with chloroform added with 1% ethanol as eluent).

The methodology of Examples 47 to 53 is used to convert the corresponding 1-oxo-1 H-thiazolo- [3,2-a] -pyrimidine-2-carboxylates of preparation 31 into the following acids:

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

1-oxo-1 H-6,7-diethylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid,

1-oxo-1 H-7-pentylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid, l-oxo-1H-6-ethyl-7-propylthiazolo- [3,2-a] -pyrimidine acid -2-carboxylic,

1-oxo-1 H-6,7-diisopropylthiazolo- [3,2-a] -pyrimidine-2-carb-oxylic acid,

l-oxo-1H-6-propylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid, 1 -oxo-1 H-6-isopropylthiazolo- [3,2-a] -pyrimidine-2-carboxyli acid -than,

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l-oxo-1H-6-pentylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid, l-oxo-1H-6-phenylcyclopentenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid,

1-oxo-1 H-6,8-dimethylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid,

1-oxo-1 H-8-methylcyclooctenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid, and 1 -oxo-1 H-6,8,8-trimethylcyclopentenothiazoIo- [3,2-a] acid -pyrimi-dine-2-carboxylic.

Example 55:

1-oxo-l H-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

3.1 g of ethyl 1-oxo-1 H-7-methylthiazolo- [3,2-a] -pyrimidi-ne-2-carboxylate are heated in a boiling water bath with 50 ml of hydrobromic acid at 48 %. Dissolution takes place in 5 min. After a heating period of approximately 15 min, the reaction mixture is cooled and the precipitated product is collected by filtration. By recrystallization from acetic acid, 1.4 g of 1-oxo-1 H-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid melting at 265 ° C. is decomposed.

Analysis for C8H603N2S:

Calculated: 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

Heated for 20 min in a boiling water bath 7.5 g of ethyl 1-oxo-1H-thiazolo- [3,2-a] -pyrimidine-2-carboxylate with 80 ml of 48% hydrobromic acid. Dissolution takes place in 5 min and the precipitation of a solid substance begins a few minutes later. The reaction mixture is cooled in an ice bath and the crude product is collected by filtration. 4.66 g of 1-oxo-1H-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid, purified at 276 ° C., decomposing, are obtained.

Analysis for C7H403N2S:

Calculated: 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 compound by heating to reflux in an excess of 2N hydrochloric acid [Allen et al., "J. Org. Chem. ”, 24, 779 (1959)].

Example 57:

I-oxo-1H-6-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

5.96 g of ethyl l-oxo-1H-6-methylthiazolo- [3,2-a] -pyrimi-dine-2-carboxylate is heated in a boiling water bath for 1 h with 60 ml of hydrobromic acid at 48%. The reaction mixture is cooled in an ice bath and the crude product is collected by filtration, and washed with isopropyl alcohol and ether. By recrystallization of the crude product from dimethylformamide, 3.73 g of purified l-oxo-1H-6-methylthiazolo- [3,2-a] -pyrimidi-ne-2-carboxylic acid, melting at 246-248 °, are obtained. C by decomposing.

Analysis for C8H603N2S:

Calculated: C 45.71 H 2.88 N 13.33%

Found: C 45.87 H 2.94 N 13.47%

Alternatively, the acid is prepared from the same intermediate compound by heating at reflux in 2N hydrochloric acid (Dunwell et al., "J. Chem. Soc." (C), 1971, 2094).

Example 58:

1-oxo-l H-6-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

12.6 g of ethyl 1-oxo-1H-6-ethylthiazolo- [3,2-a] -pyrimidi-ne-2-carboxylate are heated in a boiling water bath with 125 ml of 48% hydrobromic acid . Dissolution takes place in a few minutes. After 10 min, a solid substance begins to form. Heating is continued for a total period of 40 min. The reaction mixture is cooled and 10.1 g of crude product is collected by filtration. By recrystallization of 2.32 g of crude product (taken from the 6.8 g of product collected in an attempt to recrystallize from acetic acid) in isopropyl alcohol, 1.85 g of acid is obtained 1- oxo-1 H-6-ethylthiazolo- [3,2-a] -pyrimidi-ne-2-carboxylic purified melting at 162-163 'C.

Analysis for C9H803N2S:

Calculated: C 48.21 H 3.60 N 12.49%

Found: C 48.17 H 3.73 N 12.42%

Example 59:

15 1-Oxo-1 H-7- (2-methyl-2-propyl) -thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

5.6 g of 1-oxo-1H-7- (2-methyl-2-propyl) -thiazolo- [3,2-a] -pyrimidine-2-carboxylate d are heated in a boiling water bath for 6 h with 60 ml of 48% hydrobromic acid. After a period of about 10 min, before the ester is completely dissolved, the reaction mixture becomes very thick. At the end of the heating period, the reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from acetic acid and dehydration from dimethylformamide, 1-oxo-1 H-7- (2-methyl-2-propyl) -thiazolo- [3,2-a] -pyrimidine- acid is obtained. Purified 2-carboxylic [3.33 g, mp 241-242 ° C (decomposition)].

Analysis for CnH1203N2S:

Calculated: C 52.37 H 4.79 N 11.10%

30 Found: C 52.45 H 4.82 N 11.26%

Example 60:

1-oxo-1 H-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

1.5 g of ethyl 1-oxo-1H-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylate are heated in a boiling water bath with 15 ml of 48% hydrobromic acid for 20 min. The dissolution takes place in 5 min and, after 10 min, a solid substance begins to precipitate. At the end of the reaction period, the mixture is allowed to cool to room temperature, diluted with about 25 ml of water and the crude product is collected by filtration. The crude product is partially purified by dissolution in IN potassium carbonate and reprecipitation by acidification with 3N hydrochloric acid.

By recrystallization from acetic acid, 1-oxo-1H-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid 45 (594 mg, m.p. 206-209 ° C) is obtained.

Analysis for C9HsN203S:

Calculated: C 48.21 H 3.60 N 12.49%

Found: C 48.01 H 3.69 N 12.50%

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Example 61:

1-oxo-1H-7-isopropylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

55 909 mg of ethyl 1-oxo-1H-7-isopropylthiazolo- [3,2-a] -pyrimidine-2-carboxylate is heated in a boiling water bath with 10 ml of 48% hydrobromic acid for 20 min . In 5 min, the dissolution is complete; the product begins to precipitate after 10 min. After the heating period, the reaction mixture is allowed to cool to room temperature and the crude product is collected by filtration. By recrystallization from ethanol, 1-oxo-1 H-7-isopropylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid (538 mg, m.p. 216-217 ° C) is obtained.

65 Example 62:

1-oxo-l H-7-phenylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

9.8 g of l-oxo-1H-7-phenylcyclohexenothiazolo- [3,2-

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a] -pyrimidine-2-ethyl carboxylate at reflux with 200 ml of 48% hydrobromic acid for 20 min; dissolution takes place after approximately 10 min. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from acetic acid, 2.25 g of 1-oxo-1 H-7-phenylcyclohexenothia-zolo- [3,2-a] -pyrimidine-2-carboxylic acid melting at 224-226 'are obtained. vs.

Analysis for CI7H14N203S:

Calculated: C 62.56 H 4.32 N 8.58%

Found: C 62.26 H 4.11 N 8.52%

A second harvest is obtained from the mother liquor (704 mg, mp 217-220 ° C).

Example 63:

1-oxo-1 H-7-methylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid

Heated in a boiling water bath for 35 min 27.5 g of 1-oxo-1 H-7-methylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxy-late with 275 ml of acid hydrobromic at 48%. After 10 min, a clear solution is obtained; precipitation of the product begins after 15 min. The reaction mixture is allowed to cool to room temperature and the crude product is collected (14.9 g, mp 181.5-183.5 ° C) by filtration, with washing with water. By recrystallization from dimethylformamide, 1-oxo-1 H-7-methylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid is obtained (10.1 g, mp 183.5-185.5 ° C).

Analysis for C12H12N203S:

Calculated: C 54.53 H 4.58 N 10.60%

Found: C 54.41 H 4.28 N 10.58%

A second harvest is obtained by adding water to the mother liquor formed from dimethylformamide (3.11 g, mp 182-184 ° C).

Example 64:

1-oxo-l H-7,7-dimethylcyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid

7.9 g of ethyl 1-oxo-1 H-7,7-dimethylcyclohexeno-thiazolo- [3,2-a] -pyrimidine-2-carboxylate are mixed with 80 ml of 48% hydrobromic acid and heat the mixture in a boiling water bath for 50 min. Before the dissolution of the ester ends, the acid begins to precipitate. The reaction mixture is cooled, diluted with about 100 ml of water and collected by filtration 6.7 g of crude product which is washed with a small volume of water. By recrystallization of the crude product from ethanol, 1-oxo-1 H-7,7-dimethylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid is obtained (4.7 g, mp 197 -198 ° C).

Analysis for CI3H14N203S:

Calculated: C 56.10 H 5.07 N 10.06%

Found: C 55.85 H 4.84 N 10.14%

Example 65:

1-oxo-IH-7- (2-butyl) -thiazolo- [3,2-a] -pyrimidine-2-carbo-xylic acid

2.0 g of ethyl 1-oxo-1H-7- (2-butyl) -thiazolo- [3,2-a] -pyri-midin-2-carboxylate are mixed with 20 ml of 48 hydrobromic acid % and the mixture is heated in a boiling water bath for 25 min. The dissolution takes place in 5 min; the precipitation of the product begins after 10 min. The reaction mixture is allowed to cool to ambient temperature, it is diluted with approximately 40 ml of water and 1.3 g of crude product are collected by filtration (melting at 191-194 ° C.) by washing with a small volume of water. By recrystallization of the crude product from ethyl acetate containing a small amount of ethanol, 1-oxo-1H-7- (2-butyl) -thiazolo- [3,2-a] - is obtained. purified pyrimidine-2-carboxylic acid (606 mg, mp 194-197 ° C).

Analysis for C,! H12N203S:

Calculated: C 52.37 H 4.79 N 11.10%

Found: C 52.20 H 4.48 N 11.11%

The ethyl acetate making up the mother liquor is concentrated giving a small amount of a second crop.

Example 66:

N- (5- Tetrazolyl) -1-oxo-l H-6,7-dimethylthiazolo- [3,2-a] -pyrimidine-2-carboxamide

367 mg (1.6 mmol) of l-oxo-1H-6,7-dimethyl-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid are dissolved in 3 ml of dimethylformamide while heating with a bath. marie boiling. 292 mg (1.8 mmol) of 1,1-carbonyldiimidazole are added. An immediate release of gas is observed. As soon as the evolution of gas has ceased, 153 mg (1.8 mmol) of 5-aminotetrazole is added. Dissolution takes place and the solid substance forms again. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization of the crude product from dimethylformamide, 336 mg of N- (5-tetrazolyl) -1-oxo-1 H-6,7-dimethylthiazolo- [3,2-a] -pyrimidine-2-carboxamide fondant are obtained. above 317 ° C.

Analysis for C10H9O2N7S:

Calculated: 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-ethylthiazolo- [3,2-a] -pyrimi-dine-2-carboxamide

238 mg (1.0 mmol) of 1-oxo-1 H-6-methyl-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid are dissolved in 5 ml of dimethylformamide and the mixture is heated. solution in a boiling water bath. 178 mg (1.1 mmol) of l.l'-carbonyldiimidazole are added. When the evolution of gas has ceased, 93.5 mg (1.1 mmol) of 5-aminotetrazole is added. A solid begins to precipitate after about 15 min. The reaction mixture is cooled and filtered, giving 227 mg of N- (5-tetrazolyl) -1-oxo-1H-6-methyl-7-ethyl-thiazolo- [3,2-a] -pyrimidine-2-carboxamide fondant above 310 ° C.

Analysis for C11H1102N7S:

Calculated: 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] -pyrimi-dine-2-carboxamide

476 mg (2.0 mmol) of 1-oxo-1H-6-ethyl-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid is dissolved in dimethylformamide in a boiling water bath. 357 mg (2.2 mmol) of 1,1-dicarbonylimidazole is added to the hot solution; a gas evolution takes place. When the evolution of gas has ceased, 187 mg (2.2 mmol) of 5-aminotetrazole is added. In a few minutes, a solid substance begins to form. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from dimethylformamide, 388 mg of purified N- (5-tetrazolyl) -1-oxo-1H-6-ethyl-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxamide is obtained, melting at 303 ° C when decomposing.

Analysis for CnHu02N7S:

Calculated: C 43.3 H 3.6 N32, l%

Found: C43.6 H 3.9 N 32.3%

Example 69:

N- (5-Tetrazolyl) -1-oxo-1H-6,7-diethylthiazolo- [3,2-a] -pyrimidine-2-carboxamide

2.52 g (10 mmol) of 1-oxo-1 H-6,7-diethyl- acid are mixed

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thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 1.78 g (11 mmol) of l, r-carbonyldiimidazole with 15 ml of dimethylformamide and the mixture is heated in a boiling water bath. There is a release of gas and a dissolution. When the evolution of gas has ceased, 1.13 g (11 mmol) of 5-aminotetrazole are added and the heating is continued for 30 min. The reaction mixture is cooled and the precipitated crude product is collected by filtration. By recrystallization of the crude product from acetic acid, 1.11 g of N- (5-tetrazo-lyl) -l-oxo-1H-6,7-diethylthiazolo- [3,2-a] -pyrimidine- are obtained. Purified 2-carboxamide melting at 283 ° C while decomposing.

Analysis for C12H1302N7S:

Calculated: C 45.13 H 4.10 N 30.70% mass ion: 319

Found: C 45.18 H 4.24 N 30.52% by mass: 319

Example 70:

N- (5-Tetrazolyl) -1-oxo-1H-cyclopentenothiazolo- [3,2-a] -pyrimidine-2-carboxamide

378 mg (16 mmol) of 1-oxo-1 H-cyclopenteno-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 285 mg (17.6 mmol) of l. carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated in a boiling water bath; there is a dissolution and an evolution of gas. When the evolution of gas has ceased, 150 mg (17.6 mmol) of 5-aminotetrazole is added; in a few minutes, the product begins to precipitate. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from dimethylformamide, 313 mg of N- (5-tetrazolyl) -1-oxo-1H-cyclopentenothiazolo- [3,2-a] -pyrimidine-2-carboxamide purified melting above 310 ° C. are obtained.

Analysis for C,! H902N7S:

Calculated: C43.6 H 3.0 N32.3%

Found: C43.6 H 3.3 N 32.0%

Example 71:

N- (5-Tetrazolyl) -1-oxo-1H-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxamide

0.5 g (2 mmol) of 1-oxo-1 H-cyclohexenothiazo-lo- [3,2-a] -pyrimidine-2-carboxylic acid and 0.36 g (2.2 mmol) of 1 are dissolved. , 1'-carbonyldiimidazole in 3 ml of dimethylformamide at room temperature; there is dissolution and a release of gas. When the evolution of gas has ceased, the reaction mixture is heated in a boiling water bath, a period during which a new evolution of gas is noted. 0.19 g (2.2 mmol) of 5-aminotetrazole is added to the hot solution. In a few minutes, the precipitation of the product begins. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization of the crude product, the N- (5-tetrazolyl) -1-oxo-1H-cyclohexeno-thiazolo- [3,2-a] -pyrimidine-2-carboxamide purified is obtained [319 mg, m.p. '310 ° C (decomposition)].

Analysis for C ^ HjjOjNyS:

Calculated: C 45.42 H 3.49 N 30.90%

Found: C 45.59 H 3.62 N 30.44%

Alternatively, the acid (2.07 g) is dissolved in 40 ml of methylene chloride and 1.74 ml of triethylamine at 0 ° C. 0.85 ml of ethyl chloroformate in 8.1 ml of methylene chloride is added over 20 min while maintaining the temperature of the reaction mixture between 0 and 5 ° C. After maintaining the temperature at 0-5 ° C for 45 min, 0.87 g of 5-aminotetrazole in 8.1 ml of dimethylacetamide is added and the reaction mixture is allowed to warm to 20 ° C in 25 min, then maintains it at this temperature for 90 min. The product is collected by filtration (2.0 g, mp 308-310 ° C). The product prepared in this way (3.9 g) is recrystallized from dimethylacetamide, which gives 3.1 g of N- (5-tetrazolyl) -l-oxo-1H-cyclohexenothiazolo- [3,2-a] - purified pyrimidine-2-carboxamide melting at 314-315 ° C.

The sodium salt of this amide is prepared by dissolving 5.5 g (17.3 mmol) of the amide in 44 ml of water and 17.3 ml (17.3 mmol) of standard 1H sodium hydroxide by stirring for 30 min (pH 11.0). The solution is clarified and the sodium salt is precipitated by the addition of 35 ml of acetone. The suspension is cooled to 5 ° C, granulated for 3 h and the sodium salt (4.9 g) is collected by filtration and washed with cold acetone. This sodium salt (100 mg suspended in 1 ml of water) has a pH of 10.22. The sodium salt is recrystallized by dissolving 2.3 g of this salt in 23 ml of water at 60 ° C. The clear solution is cooled in 1 h to 5 ° C and granulated at this temperature for 1 h. The sodium salt (1.68 g) is collected by filtration. The pH of 100 mg of sodium salt recrystallized from 1 ml of water is equal to 8.80.

Analysis for Ci2H10O2N7SNa-3H2O:

q Weight loss Equivalent to

2 during neutralization drying

Calculated: 13.7 13.7 393

Found: 13.43 13.8 391

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

Example 72:

. N- (5-Tetrazolyl) -1-oxo-l H-cycloheptenothiazolo- [3,2-a] -pyrimidine-2-carboxamide

2.1 g (8 mmol) of 1-oxo-1H-cyclopenteno-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 1.4 g (8.8 mmol) of 1 are mixed. 1-carbonyldiimidazole with 15 ml of dimethylformamide and the mixture is heated in a boiling water bath. When the evolution of gas has ceased, 0.86 g (8.8 mmol) of 5-aminotetrazole monohydrate is added. A solid substance is formed in 5 min. After an additional 30 min heating period, the reaction mixture is cooled and the product is collected by filtration. By recrystallization of the crude product from dimethylformamide, 1.61 g of N- (5-tetrazolyl) -l-oxo-1H-cycloheptenothiazolo- [3,2-a] -pyrimidi-ne-2-carboxamide melting at 295 are obtained. -296 ° C when decomposing.

Analysis for C13H1302N7S:

Calculated: 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-aJ-pyrimidine-2-carboxamide

308 mg (1.1 mmol) of 1-oxo-1H-cycloocteno-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid are dissolved in 10 ml of dimethylformamide and the solution is heated in a water bath boiling. 196 mg (1.21 mmol) of 1,1'-carbonyldiimidazole are added. When the evolution of gas has ceased, 103 mg (1.21 mmol) of 5-aminotetrazole is added. The reaction mixture is heated for 10 min, during which time a solid substance begins to precipitate. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from dimethylformamide, 183 mg of N- (5-tetrazolyl) -1-oxo-1H-cycooctenothiazolo- [3,2-a] -pyrimidine-2-carboxamide, melting at 310 ° C., decomposing, are obtained.

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Analysis for C14H, s02N7S:

Calculated: 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

0.91 g (4.3 mmol) of 1-oxo-1 H-7-methylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 0.89 g (5.5 mmol) are added 1,1'-carbonyldiimidazole to 5 ml of dimethylformamide and the mixture is heated in a boiling water bath. When the evolution of gas has ceased, 0.47 g (5.5 mmol) of 5-aminotetrazole is added. Before complete dissolution has been achieved, a new solid substance begins to precipitate. After a few minutes, the reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from dimethylformamide, 1.0 g of purified N- (5-tetrazolyl) - 1-oxo-1 H-7-methylthiazolo- [3,2-a] -pyrimidine-2-carb-oxamide is obtained. - above 310 ° C.

Analysis for C9H702N7S:

Calculated: 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 J-pyrimidine-2-carboxa-mide

1.96 g (10 mmol) of l-oxo-1H-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid are dissolved in 20 ml of dimethylformamide in a boiling water bath. 1.78 g (11.0 mmol) of 1,1'-carbonyl-diimidazole are added. When the evolution of gas has ceased, 1.13 g (11 mmol) of 5-aminotetrazole monohydrate are added. A solid substance forms in less than 1 min. After heating for a further 15 min, the reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from dimethylformamide, 1.8 g of purified N- (5-tetrazolyl) -l-oxo-1H-thiazolo- [3,2-a] -pyri-midine-2-carboxamide melting above are obtained. 315 ° C.

Analysis for C8Hs02N7S:

Calculated: C 36.50 H 1.91 N 37.25%

Found: C 36.62 H 2.26 N 37.72%

Example 76:

N- (5-Tëtrazolyl) -1-oxo-1H-6-methylthiazolo- [3,2-a] -pyrimldine-2-carboxamide

2.10 g (10 mmol) of l-oxo-1H-6-methylthiazo-lo- [3,2-a] -pyrimidine-2-carboxylic acid and 1.78 g (11 mmol) of 1 are mixed, 1'-carbonyldiimidazole with 15 ml of dimethylformamide and the mixture is heated in a boiling water bath. There follows a release of gas and the dissolution takes place. When the evolution of gas is complete, 1.13 g (11 mmol) of 5-aminotetrazole monohydrate is added. A solid substance forms in less than 1 min. After heating for 5 min, the reaction mixture is cooled. 2.33 g of N- (5-tetrazolyl) -1-oxo-1H-6-methylthiazolo- [3,2-a] -pyrimidine-2-carboxamide, melting above 4th 318 ° C., are obtained by filtration.

Analysis for C9H702N7S:

Calculated: 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

4.48 g (20 mmol) of l-oxo-1H-6-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 3.57 g (22 mmol) of l, l are mixed -car-bonyldiimidazole with 20 ml of dimethylformamide and the mixture is heated in a boiling water bath. A gas evolution is noted and the dissolution takes place. When the evolution of gas has ceased, 2.27 g (22 mmol) of 5-aminotetrazole monohydrate are added. A solid substance is formed in 1 min. The reaction mixture is heated for a further 15 min, cooled and the crude product is collected by filtration. By recrystallization from dimethylformamide, 4.7 g of N- (5-tetrazolyl) -1-oxo-1 H-6-ethylthiazolo- [3,2-a] -pyrimidi-ne-2-carboxamide obtained at 274 are obtained. ° C when decomposing.

Analysis for C10H9O2N7S:

Calculated: 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

2.52 g (10 mmol) of 1-oxo-1 H-7- (2-methyl 1-2-propyl) -thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 1 are mixed , 78 g (11 mmol) of 1,1'-carbonyldiimidazole with 15 ml of dimethylformamide and the mixture is heated in a boiling water bath. A gas evolution is noted and the dissolution takes place; solid matter is formed in a few minutes. Heating is continued for a total period of approximately 10 min. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from dimethylformamide, 1.62 g of N- (5-tetrazolyl) -1-oxo-1 H-7- (2-methyl-2-propyl) thiazolo- [3,2-a] -pyrimidine are obtained. -2-purified carboxamide melting at 280 ° C while decomposing.

Analysis for C12H1302N7S:

Calculated: 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

502.5 mg (2.24 mmol) of l-oxo-1H-7-ethylthia-zolo- [3,2-a] -pyrimidine-2-carboxylic acid and 399.7 mg (2.46 mmol) are mixed ) l, l'-carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated in a boiling water bath. Dissolution takes place and a gas is released. When the evolution of gas has ceased, 253.0 mg (2.45 mmol) of 5-aminotetrazole monohydrate is added. This gives a clear solution; after 2 min, a solid substance begins to precipitate. The mixture is heated for a further 20 min, allowed to cool to room temperature and the crude product is collected by filtration. By recrystallization from dimethylformamide, 486.8 mg of N- (5-tetrazolyl) -1-oxo-1H-7-ethylthiazolo- [3,2-a] -pyrimidine-2-carboxamide, melting at 261-262, are obtained. ° C when decomposing.

Analysis for C10H9N7O2S:

Calculated: C 41.23 H 3.11 N 33.66% mass ion: 291

Found: C 41.35 H 3.31 N 33.55% by mass: 291

Example 80:

N- (5-Tëtrazolyl) - 1-oxo-1H-7-isopropylthiazolo- [3,2-aJ-pyrimidine-2-carboxamide

537 mg (2.25 mmol) of 1-oxo-1 H-7-isopropyl-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 401 mg (2.47 mmol) of 1 are mixed , l'-carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated in a boiling water bath. Dissolution takes place and a gas is released. When the evolution of gas has ceased, 255 mg (2.47 mmol) of 5-aminotetrazole monohydrate is added. The precipitation of the product begins immediately. Heating is continued for 20 min, then the reaction mixture is cooled and the crude product is collected by filtration. By recrystallization from dimethylformamide, 328 mg of purified N- (5-tetrazolyl) -l-oxo-1H-7-isopropylthiazolo- [3,2-a] -pyrimidine-2-carboxamide, melting above 300 ° C., are obtained. .

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Analysis for ChHuOjN-jS:

Calculated: 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

980 mg (3.0 mmol) of 1-oxo-1H-7-phenyl-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 320 mg (3.1 mmol) of 1 are mixed. l'-carbonyldiimidazole with 12 ml of dimethylformamide and the mixture is heated in a boiling water bath.

When the evolution of gas has ceased, 496 mg (3.1 mmol) of 5-aminotetrazole monohydrate is added. After 10 min, the product begins to precipitate. After a total heating period of 1 h, the reaction mixture is allowed to cool to room temperature and 312 mg of crude product are collected by filtration. By recrystallization from dimethylformamide, 131.5 mg of N- (5-tetrazolyl) -l-oxo-1H-7-phenylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxamide are obtained, melting above. 300 ° C.

Analysis for C18H1502N7S:

Calculated: 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

1.0 g (3.78 mmol) of 1-oxo-1 H-7-methylcyclo-hexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 675 mg (4.16 mmol) are mixed of U'-carbonyldiimidazole in 6 ml of dimethylformamide and the mixture is heated in a boiling water bath. A gas is released and dissolution takes place. When the evolution of gas has ceased, 429 mg (4.16 mmol) of 5-aminotetrazole is added and heating is continued. After a few minutes, a precipitate begins to form. After 30 min, the reaction mixture is cooled and the crude product is collected (melting above 300 ° C) by filtration. By recrystallization from dimethylformamide, 980 mg of N- (5-tetrazolyl) -1 -oxo-1 H-7-methylcyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxamide are obtained, melting above 300. ° C.

Analysis for C13Ht302N7S:

Calculated: 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-dimethylcyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxamide

558 mg (2.0 mmol) of l-oxo-1H-7,7-dimethyl-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 357 mg (2.2 mmol) are mixed. 1, l'-carboriyldiimidazole with 3 ml of dimethylformamide and the mixture is heated in a boiling water bath; a gas is released and dissolution takes place. When the evolution of gas has ceased, 227 mg (2.2 mmol) of 5-aminotetrazole monohydrate is added and the heating is continued for 20 min. The reaction mixture is cooled and the crude product is collected by filtration (561 mg, melting point above 300 ° C). By recrystallization from dimethylformamide, 469 mg of N- (5-tetrazolyl) -l-oxo-1H-7,7-dimethylthiazolo- [3,2-a] -pyrimidine-2-carboxamide (469 mg, mp are obtained). higher than 300 ° C).

Analysis for C14H1502N7S:

Calculated: C 48.69 H 4.38 N 28.39%

Found: C 48.80 H 4.18 N 28.42%

Example 84:

N- (5- Tetrazolyl) -I-oxo-1H-7- (2-butyl) thiazolo- [3,2-aJ-pyrimidine-2-carboxamide

379 mg (1.5 mmol) of l-oxo-1H-7- (2-butyl) -thiazolo- [3,2-a] -pyrimidine-2-carboxylic acid and 270 mg (1.66 mmol) are mixed ) of 1,1'-carbonyldiimidazole in 3 ml of dimethylformamide and the mixture is heated in a boiling water bath. A gas is released and dissolution occurs. When the evolution of gas has ceased, 170 mg (1.65 mmol) of 5-aminotetrazole monohydrate are added and the mixture, which begins to form a precipitate after a few minutes, is heated for 20 min. The reaction mixture is allowed to cool to room temperature and the crude product is collected by filtration. 247 mg of N- (5-tetrazolyl) -1-oxo-1 H-7- (2-butyl) thiazolo- [3,2-a] -pyrimidine-2-carboxamide purified above 300 ° C.

Analysis for C12H1302N7S:

Calculated: C 45.13 H 4.10 N 30.70%

Found: C 45.12 H 4.05 N 30.68%

Example 85:

Following the procedure of Examples 66 to 84, the following compounds are prepared from the corresponding l-oxo-1H-thiazolo- [3,2-a] -pyrimidine-2-carboxylic acids:

N- (5-tetrazolyl) - 1-oxo-1 H-7-pentylthiazolo- [3,2-a] -pyrimidine-2-carboxamide,

N- (5 (tetrazolyl) -1-oxo-1H-6-ethyl-7-propylthiazolo- [3,2-a] -pyrimidi-

ne-2-carboxamide, N- (5-tetrazolyl) -I-oxo-1H-6,7-diisopropylthiazolo- [3,2-a] -pyrimidi-

ne-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-1 H-6,8,8-trimethylcyclopentenomethyl-thiazolo- [3,2-a] -pyrimidine-2-carboxamide.

Example 86:

Capsules

Capsules are prepared by mixing the following ingredients in the proportions indicated by weight:

- Calcium carbonate, U.S.P. 17.6

- Dicalcium phosphate 18.8

- Magnesium trisilicate, U.S.P. 5.2

- Lactose, U.S.P. 5.2

- Potato starch 5.2

- Magnesium stearate A 0.8

- Magnesium stearate B 0.35

and adding a sufficient amount of N- (5-tetra-zolyl) -l-oxo-1H-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxamide sodium trihydrate to form capsules containing 10, 25 and 50 mg of active ingredient (weight equivalent to the non-salted, unsolvated form) per capsule. The compositions can be loaded into conventional hard gelatin capsules in an amount of 350 mg per capsule.

Capsules containing 2.0 mg and 6.0 mg of active ingredient and containing 300 mg of the following mixtures per capsule are prepared in the same manner:

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Ingredients Weight (mg) per capsule

- Drug 2.00,

- N-Methylglucamine 18.00

- Anhydrous lactose 251.20

- Anhydrous corn starch 8.80 5

Ingredients Weight (mg) per

- Drug

- N-Methylglucamine

- Lactose anhydrous

- Anhydrous corn starch

- Talc

Example 87:

Tablets

A base for tablets is prepared by mixing the following ingredients in the proportions indicated by weight:

- Sucrose, U.S.P. 80.3

- Cassava starch 13.2

- Magnesium stearate 6.5 20 A sufficient amount of N- (5-tetrazolyl) -l-oxo-1H-cyclohexeno-thiazolo- [3,2-a] -pyrimidine-2 trihydrate is incorporated into this base for tablets. -carboxamide sodium to obtain tablets each containing 20, 100 and 250 mg of active ingredient. Each of the compositions is made into tablets by known means. To obtain lower potency tablets (e.g. 1 mg, 2 mg, 5 mg), a lower ratio of the active ingredient to the inert ingredients is used in the base tablet mixture.

Example 88: 30

Solution

A solution of N- (5-tetrazolyl) -1-oxo-1 H-cyclohexenothiazolo- [3,2-a] -pyrimidine-2-carboxamide sodium containing the following ingredients is prepared:

- Active ingredient (7.49 g of sodium salt trihydrate) 6.04 g

- Magnesium chloride hexahydrate 12.36 g

- Propylene glycol 376.00 g

- Distilled water 103 ml

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

Example 89:

Aerosol suspension

For a particular application as an antiallergic agent, a mixture of N- (5-tetrazolyl) -l-oxo-1H-cyclohexeno-thiazolo- [3,2-a] -pyrimidine-2-carboxamide sodium and other ingredients indicated in a in the following tables is micronized into particles of 1 to 5 µm in a ball mill. The resulting suspension is then loaded into a container fitted with a valve and the propellant b is introduced under pressure through the nozzle of the valve to a gauge pressure of approximately 245 to 280 kPa at 20 ° C.

Suspension A%

a) Antiallergic agent (equivalent of the unsolvated non-salt) 0.25

Isopropyl myristate 0.10

Ethanol 26.40

b) 60% mixture of 1,2-dichlorotetrafluo-

rethane and 40% 1-chloropentafluoroethane 73.25

Suspension B

a) Antiallergic agent (equivalent of the unsolvated non-salt) 0.25

Ethanol. 26.50

b) 60% mixture of 1,2-dichlorotetrafluor-

ethane and 40% 1-chloropentafluoroethane 73.25

Suspension C

a) Antiallergic agent (equivalent to non-solvated non-salt) 2.00

Ethanol 26.50

b) 60% mixture of 1,2-dichlorotetrafluor-

ethane and 40% 1-chloropentafluoroethane 77.50

capsule 6.00 18.00 237.20 30.00 10 8.80

R

Claims (9)

649,299 2 1. Compound of formula: ^ ri o-K in which R1 and R2 together form an alkylene group having 3 to 9 carbon atoms or a phenylalkylene group having 9 to 11 carbon atoms, provided that the ring thus formed comprises 5 to 8 members; Rt and R2 considered separately each represents hydrogen or an alkyl group having 1 to 5 carbon atoms; and Q is a group of formula: , N N -r ('I H XN N I H or of formula OR3 in which R3 is hydrogen, provided that when R2 is hydrogen, R1 represents something other than hydrogen or a methyl group; or a pharmaceutically acceptable cationic salt of this compound when Q is a group of formula: .N N - "- ('i H N N I H or of formula OR3 in which R3 is hydrogen. 2. Compound according to claim 1, characterized in that Q corresponds to the formula: N — N 'i H N I H 3. Compound according to claim 2, characterized in that R „and R2 are considered together and represent a butylene group. 4. Compound according to claim 2, characterized in that Rt and R2 are considered separately, R, is a hydrogen atom and R2 is a methyl group. 5. Compound according to claim 2, characterized in that Rj and R2 are considered separately, R1 is an ethyl group and R2 is a hydrogen atom. 6. Compound according to claim 2, characterized in that Rj and R2 are considered separately, R, is a methyl group and R2 is hydrogen. 7. Compound according to claim 1, characterized in that Q is an OR3 group in which R3 is hydrogen. 8. A compound according to claim 7, characterized in that Rj and R2 are considered separately, Rj is an ethyl group and R2 is hydrogen. 9. Medicament, characterized in that it consists of, or in that it contains, a compound according to one of claims 1 to 6.