LU82950A1 - 1-OXO-1H-THIAZOLO- (3,2-A) -PYRIMIDINE-2-CARBOXAMIDES, ANTI-ALLERGIC AND ANTI-ULCER, DRUGS CONTAINING THEM AND INTERMEDIATE COMPOUNDS FOR OBTAINING THEM - Google Patents

Description

1.

The present invention relates to novel derivatives of 1-oxo-1H-thiazolo- [3,2-aJ-pyrimidine-2-carboxamide and the acids constituting their precursors. These amides and, in many cases, the acids which form their precursors, are useful in preventing the release of allergic mediators (histamine, serotonin, slow-reacting anaphylaxis substance (SRS-A), etc.) and can therefore be used to treat bronchial asthma, hay fever, rhinitis, atopic dermatitis, etc., and they are further 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 accompanied by 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 whistling, short-lived 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. In contrast, anti-allergic agents inhibit 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 35 (1970) describe the pharmacology of disodium cromoglycate [1,3-bis- (2-carboxycromon-5-yloxy) -2-hydroxypropane, Intal J. Ce is not a bronchodilator, but a substance which manifests its therapeutic effects by inhibiting freedom 2.

ration of mediators of anaphylaxis and it 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 anti-allergic agents have been described more recently; it is N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimido - (. 1,2-a J-quinoline-2-carboxamides (US Patent No. 4 017 625), 1-oxy-1H-6- (substituted pyrimido) acids - (. 1,2-a J-quinoline-2-carboxylic 10 (United States Patent No. 4,066,766) , tetra-zolo- [a J-quinazol-5-ones (U.S. Patent No. 4,085,213), pyrimido - (. 2,1-aJ-isoquinolines (U.S. Patent d America No. 4,127,720) and N- (5-tetrazoyl) -4-oxo-4H-pyrimido- [2,1-b J-benzothiazole-3-carboxamides (United States patent 15 ° 4,041,163).

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 dietetic and medical treatment (medication) to surgical intervention. A wide variety of drugs have been used to treat ulcers; the most recent of these drugs which deserves special attention is the sodium salt of carbeno-25 xolone, 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 ("Carbenoxolone Sodium: A Symposium", JM Robson and FM Sullivan, Eds., Butterworths, 30 London, 1968). However, its use is accompanied by undesirable side effects resembling those of 'aldosterone, 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 histamine receptor antagonist, namely cimetidine, has been introduced into »3.

medical practice. The latter compound reduces ulcers by reducing the secretion of acid from the stomach.

Anti-ulcer activity of various other compounds including 1-oxo-1H-6-piperidino-5 pyrimidino- [1,2-aJ-quinoline-2-carboxylic esters has been reported (United States patent No. 4,014,881), 1-oxo-1H-6- (substituted pyrimido) - (1,2-a) -quinoline-2-carboxylic acids and their esters (United States Patent No. 4 031 217) and tetrazolo- [aJ-quinazol-5-ones (U.S. Patent No. 4,085,213).

The amides and most of the intermediate acids of the present invention are novel compounds. The known acids are the acids of formula II in which and 1 * 2 represent hydrogen or else R <| is a methyl group and is hydrogen (Dunwell et al., J. Chem. Soc. (C), 1971, 2094 J. The corresponding ethyl esters are also known, as is the ethyl ester in which R <| is a methyl group and R2 is a hydrogen atom [Dunwell et al., J. Chem. Soc. (C) 20 1971, 2094; Allen et al., J. Org. Chem. 24, 779 (1959) J. None of these publications makes known application of both acids and esters.

We have just discovered that compounds which correspond to formula (I): 25

i —5S

Gpl

LJ

0 * v sh: - ^! |

N-N

σι.

35 to 4.

and their pharmaceutically acceptable cationic salts, are effective oral anti-allergic and anti-ulcer agents. In formula (I), and R2 each represents hydrogen or a lower alkyl group having 1 to 5 carbon atoms [such as methyl, ethyl, propyl, isopropyl, 2-methyl-2-propyl- (tert-butyl) , 2- butyl, 2-methyl-1-propyl- (isobutyl), pentyl, etc.J, or else * r. and R2, together forming a third ring of 5 to 8 members, are alkylene groups of 3 to 9 carbon atoms, for example: ÇS3 CE ^ CS - »·. CH "v, QTJ CH- / C /, ** 2 i 2 15 Ctt CH- * '\ 2 \ 2 CH9 CH2 i X CH— \ 2 \.

2 ^ CS3 Csf 20 rrz I J rrrx - / ^ ** 2 - jL “

/ 'r4' CH- CS

CH- C ‘<2 3 NCS -! CH--, - - “2 CS 2 2 25. CHT ^ ^ es-; 30 Λ ““ * · CS, i CS9 ^ / -> tr CH ^ or phenylalkylene groups of 9 to 11 carbon atoms, for example î 35 ♦ 5.

ς

CeH— I 5 ο. wXJ, 7 ^ · C, -H -— CH J \ / 2 5 4 6 5 'C.H. "= CH- ° 52 ° 3' 2 X ιΛη ^ <C ^ 2 ^ 2 X% ^ wï2

W

1 °

CH -, - CH ^ -C ~ E, - ~ CH

0 3 CH9— CE ^ 15

It has also been found that acids of formula (II): 20

R1 "V-S

not

-, “„ V

0 ^ CSs, 0E

(111 in which R 1 and R 2 have the definition given above, are not only intermediate compounds of interest for the synthesis of amides, but also have in many cases, as well as their cationic salts acceptable from the point of view pharmaceutical, an interesting biological activity. Acids with anti-allergic activity 6.

"* R useful are those in which and R2 together form an - alkylene group having 4 to 9 carbon atoms or a phenylalkylene group having 9 to 11 carbon atoms, provided that the ring thus formed has 5 to 8 members, or else , considered separately, R ^ is an alkyl group having 2 to 5 carbon atoms and R2 is hydrogen or an alkyl group having 1 to 5 carbon atoms. Preferred acids for anti-allergic application are those in which R 1 and R 2 together form an alkylene group having 4 to 6 carbon atoms, in particular a butylene group. Acids of slightly different structure have useful antiulcer activity, i.e. those in which R 1 and R 2 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 either a 5 to 8 membered system, or Rj and R2 considered separately each represents hydrogen or an alkyl group having 1 to 5 carbon atoms, provided that when R2 is hydrogen, RJ is something else than hydrogen or a methyl group. In this case, the preferred compounds are those in which R 1 and R 2 are considered separately, in particular when R 1, j is an ethyl group and R 2 represents hydrogen or an alkyl group having 1 or 2 carbon atoms.

The expression "catagonally acceptable pharmaceutically acceptable salts" is intended to denote salts such as the alkali metal salts, for example sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; aluminum salts? ammonium salts; and organic base salts, for example amines such as triethylamine, tributylamine, piperidine, triethanolamine, diethylaminoethylamine, Ν, Ν'-dibenzylethylenediamine and pyrrolidine.

The tetrazoles substituted in position 5 can exist, as is known, in two isomeric forms, viz: 7.

N-N

j y 5 N— k '10 which coexist in a dynamic tautomeric mixture in equilibrium. Both forms of tetrazolylamides fall within the scope of the present invention.

The compounds of particular interest in the present invention are the compounds of formula (I) in which is hydrogen or a methyl group and R2 is a methyl group. Among these compounds, preference is given to the compound in which R-j 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-j and R2 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, i.e. N- (5-tetrazolyl) -1-oxo-1H-25 cyclohexenothiazolo- [3,2-aJ-pyrimidine -2-carboxamide of formula (III):

Oo 30

XJ

0 χ

r N — N

| j 35 fs

E

cm J.

* 8.

because it has 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 (corres-5 carboxylic acid laying) 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 anti-allergic property of the compounds of the present invention was evaluated by the Passive Skin 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 mixed 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 intensity of the blue coloration on the internal surface of the animal's skin.

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

The compounds of the present invention are prepared according to the following reaction procedures: 9.

5 ΗΙ-Π- ·, 3 ^ GQ'dr. * L 3 2 I + (B3QOCJ.2C = C ^ 3.

r2 ^ s ^ nh2 *> ► 10

V-r-rS Rl-p-, S

} ^ i iî h ° ~ i [L 3 d "Dowthemi A (dd | SE ± •? r3 I" * ", kj 15 0" \ rc? 3coi, o 0 'cr * ^ ° * 3 20 h ", a70

T

V — ÎS / -, N VpHs liT l a2s- <il | i-

Ry 'S ~ N R ^ XSX ^ ÎI

; 'J <2ß * Jk} ß ° n ^ -N 0 c _ _ /.Cv A i Coupling by <î> ^ \

30 q J dehydration O OH

S - S ^ ôïï ‘l passage by î £ 11 mixed anhydride 35 10.

In the first step of the synthesis sequence, the suitably substituted 2-aminothiazole is condensed with a stoichiometric amount of a dialkyl ethoxymethylenemalonate, usually 5-ethoxy methylenemalonate readily available, the choice of ester not being determining for obtaining 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 advantage. 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, 1-di-methylformamide, acetonitrile. 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-di-carbalkoxy-ethenylamino) -thiazoles substituted in position 4 and / or in position 5. It should be noted that when and R 2 together form a nucleus, the nomenclature and numbering are modified as follows: CO HT / "

Cyclopentenothiazole Cyclohexenothiazole 30, γ-τ ^ λ X-. ! 3 // \ S 4 / ^ $ '

Cycloheptenothiazole Cyclooctenothiazole 35 Cyclohexenothiazoles can also be called tetrahydrobenzothiazoles.

The second step of the synthesis sequence is the cyclization of 2- (2,2-dicarbalkoxy-ethenylamino) -thiazoles 11.

% substituted in position 4 and / or in position 5 with elimination ”of an equivalent of alkanol (ethanol in the case of ethyl ester). According to one procedure, this cyclization is accomplished by heating the intermediate compound to 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, in other words in a compound which makes it possible to influence the reaction temperature, which is stable at the relatively high temperatures used and which does not react with the starting material or with the cyclization products. Representative examples of these diluents are high boiling point hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, in particular that which contains 26.5% diphenyl and 73.5% 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 hours at the reflux temperature of toluene).

= Whatever the procedure, the products of the cyclization step are 1-oxo-1H-thiazolo- [3,2-aJ-pyrimidine-2-alkyl carboxylates substituted in position 6 and / or in position 7 .

It should be noted that when and R2 form a nucleus together, the nomenclature and numbering systems are modified as follows: 35 c 12.

5 Ολ χλ Μ Μ- N »„ Jw * - 10 1-οχο-lH-cyclopenténo- '1-oxo-1H-cyclohexeno-thiazolo-13,2-aJ-pyrimidine thiazolo- (3,2-a J-pyrimidine 15 \ V ,, / A3,. (9 U, χ ys,. Ma ij - f \ s

“/ 'M

1-oxo-iH-cyclohepteno-1-oxo-1H-cycloocteno-thiazolo- [3,2-a J-pyrimidine thiazolo- [3,2-a J-pyrimidine

The 1-oxo-1H-cyclohexenothiazolo - (. 3,2-a J-pyrimi-25 dines are also called 6,7,8,9-tetrahydro-1-oxo-1H-; pyrimidino- [2,1-bJ -benzthiazoles or, when another numbering system is used, 5,6,7,8-tetrahydro-4-oxo-4H-pyrimido- (2,1-b) -benzthiazoles.

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-carbalkoxy-ethenylamino) -thiazole, either by using a reaction temperature high enough to effect both condensation and cyclization, either by condensing as described above, then adding an inert solvent (if not already present) and an excess of trihydride acetic fluorine (2.1 to 4 equivalents) and conducting the cyclization step.

'13.

. 'i /

The operating mode which we appreciate comprises the separate stages of condensation and of 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-1H-thiazolo - (, 3,2-a J-pyrimidine-2-carboxylic acids substituted in position 6 and / or in position 7 correspondents.

; 10 (Note the nomenclature system and the modified numbering system described above when R "j 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 method. 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 dehydration coupling 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 Ν, Ν'-carbonyldiimidazole, N, N'-carbonyldi-s-triazine, - ethoxy-acetylene, 1,1-dichlorodiethyl ether, diphenylketene-p-tolylimine , N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, ethylene chlorophos-phite, diethylene pyrophosphite, N-ethyl-5-phenylisoxazolium-3'-sulfonate, phenylphosphorodi- (1- imidazolate) and carbodiimides such as dicyclohexyl-carbodiimide, 1-cyclohexyl-3- (2-morpholinomethyl) -carbodi-imide, N- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide hydrochloride, hydrochloride of 1-ethyl-3- (3'-dimethylamino-propyl) -carbodiimide and diethylcyanamide.

The coupling agents listed above are generally caused to react first with the reactant "14.

acid and the resulting product is then reacted without isolation with 5-aminotetrazole to give the desired 6-position and / or 7-position substituted 1-oxo-1H-thiazolo- [3,2-aJ-pyrimidine. (Note the nomenclature system 5 and the modified numbering system indicated above when R.j 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 ~ 10 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 conducting coupling by dehydration offers a wide choice of solvents. Representative examples of solvents are Ν, Ν-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of the acidic reactant with the coupling agent is carried out at a temperature of from 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 approximately 50 to approximately

H

100 ° C, since the speed and 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 does not offer any advantage. Excesses of 10 mole% are satisfactory.

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

Ç 15.

* r Alternatively, the desired i amides can be synthesized by coupling the acids with 5-aminotetrazole by the mixed anhydride process. In this case, the acids are first converted in situ to the tertiary amine salt in the presence of a 1 to 1.1 mole excess of the amine.

Various tertiary amines (R'3N) are suitable for this purpose. Examples of triethylamine, N-methyl-i piperidine, 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 (e.g. ethyl), benzyl or phenyl, at a temperature in the range of -40 to 25 ° C, preferably in the range of -10 to 10 ° C, to form a mixed anhydride in solution, according to the scheme: 20 + * “V · ®3 · *

25 0 ^ o ^ C'O-G.-QR

; u

O

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 used to prepare the mixed anhydride, so as to obtain the desired N- (5-tetrazolyl) -amides. 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. 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.

e 16.

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, ethyl hexanoate, alcoholate or hydroxide) or the suitably chosen amine in a correct medium such as water, methanol or ethanol according to well known procedures. The salts are collected by conventional operations such; 10 only 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 of the salt.

Many of the 2-aminothiazoles to be used as starting materials are described in the literature. Those which are not suitable can be prepared by condensation of choisie'α-haloketone suitably chosen with thiourea or by condensation of suitable aldehyde with thiourea and sulfuryl chloride, as illustrated in particular examples. When α-halogen ketones 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., Volume II, 38 (1943); Buchman et al., J. Am. Chem. Soc. 67, 400 25 (1945)) by the action of halides. hydrogen on diazo-; ketones (see, for example, Catch et al., J. Chem.

Soc., 278 (1948); Lutz et al., J. Org. Chem. 12, 767 (1947); Wagner et al., J. Âm. Chem. Soc. 72, 2884 (1950) J, by decarboxylation of α-halo-B-keto acids (McPhee et al., J. Am. Chem. Soc. 66, 1132 (1944) J and by spontaneous cleavage of the dibromo derivatives alkenyl esters (see, for example, Slanina et al., J. Am. Chem. Soc. 58, 891 (1936) J.

The reactions in the synthetic sequence leading to 2-aminothiazoles with acids and 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 it is 17.

AT

ç- there are various sources in the trade. The 4 choice of 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 compound intermediate which enters into reaction and the product which is formed in the reaction. An eluent which is particularly well suited to reactions of formation of a thiazole, of cyclization by condensation and of hydrolysis in the process of the invention is a mixture of chloroform and; 10% ethanol, while the hydrolysis and transformation of acids into N- (5-tetrazolyl) -amides are 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 may be administered for such purposes individually or as a mixture with other agents, for example theophylline or sympathomimetic amines. The products of the present invention are also useful as anti-ulcer agents. These products not only accelerate the healing of these ulcers, but also prevent the formation of ulcers and reduce the production of gastric acid in mammals, including humans. We can therefore consider that they are useful in combating gastric ulcers.

e 18.

The compounds of interest of the invention can be administered 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 acceptable from the pharmaceutical point of view in the form of tablets, capsules, tablets, lozenges, hard lozenges, powders, compositions; sprayable in aerosols, suspensions or aqueous solutions, 10 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 carrier chosen and the ratio of the active ingredient to this carrier are influenced by the solubility and 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 of the invention can be combined with emulsifying agents or suspending agents. Diluents such as ethanol, propylene glycol, glycerol e 19.

and chloroform and mixtures thereof can be used as well as other materials.

For parenteral administration and inhalation, solutions or suspensions of these products in sesame oil or peanut oil or aqueous solutions of propylene glycol may be used as well as aqueous solutions sterile pharmaceutically acceptable soluble salts described herein. These particular solutions are specially suitable 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 must also be suitably buffered, if necessary, and the liquid diluent must first be made isotonic with a sufficient amount of sodium chloride or glucose.

When used as prophylactics to prevent the release of mediators of 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 container; or ; (3) a mixture of the active ingredient and a solid diluent (eg 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.

e 20.

In view of the factors set out above, it is believed that an effective daily oral dose of the antiallergic or antiulcerous compounds of the present invention in human medicine is from about 10 to about 1500 mg per day, 5 preferred range from about 10 to about 600 mg per day in a single dose or in divided doses, or from about 0.2 to about 12 mg per kg of body weight. These values are only examples and of course there may be individual cases which require higher or lower doses. With proper monitoring, the dose rate can be increased to about 2 g per day.

In the case of parenteral administration for one or other of the uses or by inhalation for the antiallergic use, the effective daily dose ranges from approximately 0.05 to approximately 400 mg per day and, preferably, from approximately 0.25 to 200 mg per day, or approximately 0.005 to 4 mg per kg of body weight 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 anti-allergic activity (in particular of the anti-asthmatic activity) of a compound. Compounds which inhibit a positive immunochemical counterpart induced passive skin anaphylaxis test in rats of human immunoglobulin E (IgE), or reactin, are considered to have anti-allergic activity (C. Mota, Ann NY Acad. Sci. 103, 264 (1963)). (Reagin is primarily an immunoglobulin E (.IgEj and is the primary immunoglobulin 21.

buline responsible for allergic asthma, anaphylaxis, hay fever, food sensitivities and certain manifestations of drug sensitivities, although recent evidence attributes IgG 5 antibodies to an important role in mediation allergic disorders). When such compounds are administered to a sensitized subject, human or animal, before the subject comes into contact with the antigens or substances to which he is allergic, they prevent the allergic reaction which would otherwise manifest itself. 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 reactin antibody human. The inhibition of reactive antigen-antibody reactions in rats, selected as the test animal in the passive skin 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). An anti-hyperimmune serum rich in IgG antibodies against hen ovalbumin is prepared as described by Orange et al in J. Exptl. Med. 127, 767 (1968). Forty-eight hours before the antigen test, the reactin antiserum is injected intradermally into the shaved skin of the back of a 22.

r normal rat; 5 hours before the test, the hyper-1 immune antisera are injected in the same way. At a third site, 60 μg of histamine dihydrochloride and 0.5 μg of serotonin-creatinine sulphate are injected intradermally just before the antigen test, as a control of the antihistamine type, of the anti-serotonin type and of types non-specific blocking? the compounds of the present invention or physiological saline are then injected intravenously and the injection is immediately followed by the administration of 10 mg of ovalbumin and 2.5 mg of blue dye

Evans in physiological saline. In the case of oral administration, Evans blue dye and ovalbumin are administered 5 minutes after absorption of the drug. 30 minutes 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 diameter of the site 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 tested for anti-allergic activity by the method described above and the resulting activities are expressed by the degree (%) of protection. The product "Intal", or disodium cromoglycate, which is a commercial anti-allergic agent, is not included for comparison, since it is not active orally.

The compounds of formula (I) (amides) and of formula (II) (acids, = hydrogen) whose anti-allergic activity was determined by the passive cutaneous anaphylaxis test are shown in detail in Tables I and II.

23.

*

TABLE I

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

IgE mg Ag IgG me /! <Q \ ^ 1 3 '10; 30'_1 3 10 30 CH- CH-! 551 1! i 51 î! J J) | | 1; CH3 C7H-! ! 75; > ’57; d ** ** d d. 'l I CH-! 22.; i 23:! * · D -3. ; 1 1. : j c22s c2h5 i i j! 621. :; ; ! 42d

! Cch2 13 Us; j! ! : 43; ; I

I CCH214; ; 47! ; I j45; j I

j (-CH2} 5;; j! 25; j il38!

j ®a2 * S i I ^ 94; :; ; 57 I

! ! I i! ; ! :; 1 i s CH- i 55 1 i i: 50; i i 3 i: S! ; :: i! i I H H::! \ 5Q; | ! d45! ! ; '! ! . ! i i! I ch3 h i ·! I 178! ; ; i! 55 d! i \ ί! ; ; :! c235 h; ! I j 85; ; ; : 53! 1 H C (CH -) -; j: -37 1:! i! 20! j:; NOT A WORD : : : . :: j; i i! H C-H- ’'! : 70; ; ! ^ 44 j • Δ Ώ j: 'j ί; · Ί H CH (CH3) -; I j -72; I; s53! i! i i! i; i:; Î ί CH-CHCC-H-) CH-CH-> i i! 4 i: | ; 7 i! 2- o a '2 2 j j I j j:! ; ; 1 I CH2CHÇCH3) CH7CH2 I j I; 44 j! | ; ! 33 | ! j] I i! ί i ':; CH ^ CCCIL ^ Cï ^ CI ^ i j; 38 j I j 37 j I i i; 1: H CHCH-CH- Μ j U! '! S! ; 1 2 3 i i! : i ί j; 3; 1-: 1 -: -! ; ! =: 1: 1 · 1; ! 24.

TABLE II

Oral activity (percentage of protection) of acids (formula II, R ^ = hydrogen) in the passive skin anaphylaxis test

IgE mg / Kg * IgG mg, / kg —1- K2 1Q: 30 1CL 30 ch3 ch3 a a Cïï3 c2 * 5 0 C2H5 CH3 42 24 C2H5 C2H5 41 32 (ÇH2J_3 0. 0 CCh2) -4 55 39. | (-CK2} -5 37 44! ^ • CH2 ^ 6 36 68 15 45 H CH3 18 19 HH 18 7 CH3 H 12 14; C2H5 H 45 38 HC (-CH3) 3 1Q 6 H C2H5 13 21 H CH (- CH3 ^ 2 0 o CH2CH (C5H6) CH2CH2 15 5 CH2CE (CH3ICH2CH2 31 21 CH2C (CH3) 12CH2CH2 13 ç H CHCH'2CH3 1 8 0¾ 25.

The efficacy of the products of the present invention as anti-ulcer agents is determined by the so-called cold stress test in rats. In this test, female rats without fasting (Charles River CD strain) weighing 5 70 to 140 g receive the drug or its support (control animals) intraperitoneally (in saline solution containing 1% of carboxymethylcellulose and 0.1% "Tween 80") or orally (in water) three hours before being lightly anesthetized with ether and immobilized in the supine position on individual "Plexiglass" plates.

When the anesthetic effect has ceased, the animals in restraint are placed horizontally in a refrigerator kept at 10-12 ° C and, three hours later, they are sacrificed by cervical dislocation. The abdomen of each rat is opened, the pylorus is closed, the stomach is swollen with 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 seconds to harden the outer layers and to facilitate examination. Each stomach is then excised along the greater curvature and the alteration of the glandular portion (posterior stomach) is examined. The number of gastric erosions, their severity and the color of the stomachs are noted. The Mann-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 differences. statistics. (Dixon et al., "Introduction to Statistical Analysis", 3rd edition, McGraw-Hill Book 30 Company, New York, pages 344-347, 1969). In this test, N- (5-tetrazolyl) -thiazolo - (. 3,2-a J-pyrimidine-2-carboxamide (compound III) was found to be extremely potent, as shown below.

Alternatively, the efficacy of the products of the invention as anti-ulcer agents is determined in an ethanol-induced ulceration test in rats. In this test, fasted rat males for approximately 18 hours receive 5 mg / kg of drug or water orally 26.

15 minutes before oral administration of a 1.0 ml dose - absolute ethanol. One hour after the ethanol test, the animals (eight per group) are sacrificed and the stomachs are examined for the presence of lesions. All 5 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 are injected into the stomach by means of a gastric tube and a => 10 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 RATING TABLE

Note Definition 1 Stomach appearing normal 2 Pin point lesions 20 3 Lesions, two or less; pin point lesions may be present 4 Lesions, more than 2; pin point lesions may be present 5 Lesions with hemorrhage.

25 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) - (ulceration index of animals treated with the drug) J 35 f (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.

27.

TABLE III

Oral activity (inhibition,% at a dose of 5 mg / kg) of amides (formula I) in the ethanol-induced ulceration test in rats 5 _ R -_% Inhibition CH3 CH3 96 H CH3 53 .

10 Cü 3 h 72

iQ

C ^ Hr- H 3 6. CCH2, L. ~ 45 15 ^ ° - CC32L4 97, 31

20 TABLE IV

Oral activity (inhibition,% at a dose of 5 mg / kg) of acids (formula II) in the ethanol-induced ulceration test in rats 25 3 _ _% Inftlcition CS3 CX3 11 ET. CE- 27

30 J

CE3 E 0.

C'i_ C, E ~ 48

2 d 2 Q

C '1- E 48 2 □ Ί> 35 © H2I4 21 “28.

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

In addition to its oral anti-allergenic 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 skin anaphylaxis test, this compound being approximately twenty-six times more potent than the "Intal" product by this route of administration (as noted above, the "Intal" product lacks efficacy by the oral route). Compound III also inhibits variations in permeability induced by passive cutaneous anaphylaxis (PCA) mediated by IgE but does not interfere with variations in permeability caused by the intradermal injection of exogenous histamine and serotonin. The absence of antihistamine and anti-serotonin effects demonstrates that the anti-allergic mechanism is a mechanism for inhibiting the release of mediators rather than an antagonism at the mediator receptor.

Compound III inhibits dextran-induced release of hista mine from the rat's peritoneal cavity. Its dose DE ^ q is 0.33 yg / kg intraperitoneally and that of the product "Intal" is 14.0 ug / kg, which demonstrates the superiority of the power of the first. The elevation of the histamine level in the plasma by the administration of an antigen to rats sensitized passively with an anti-serum rich in IgE (passive systemic anaphylaxis) is prevented by compound III. Its dose DE ^ q is 28 ug / kg intravenously, that is to say that it is thirteen times more powerful than the product "Intal".

Guinea pigs to which compound III is administered at a dose of 30 mg / kg intraperitoneally are not protected against the bronchoconstrictor effects of 29.

inhaled histamine. In the concentration range of 10 to -4 10 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 s »- 10 Table III above), compound III is very powerful in the method of gastric ulceration under the stressful effect. compression and cold (see detail above), where it provides dose-proportional protection, at oral doses in the range of 3 to 100 ug / kg. Compound III also protects from the ulcerogenic effects of aspirin at a dose of 100 mg / kg orally, and dose-proportional effects are seen in the dose range of 10 to 1000 µg / kg orally with a DE5Q value of 100 ug / kg. Compound III is also active in a model of gastric ulceration under the effect of phenylbutazone, where an oral DE5q dose of 100 ug / kg is observed. Although Compound III is a very potent anti-ulcer agent, it does not affect the production of pentagastrin-stimulated acid in dogs with Heidenhain fistula (5 mg / kg, intravenously) and it is therefore distinguished from anti-secretory prostaglan dines as well as cimetidine and atropine. The term "cytoprotective" is a term recently created to describe the anti-ulcer effects of prostaglan-; dinners, which are independent of anti-secretory activity 30 (see Robert, Advances in Prostaglandin and Thromboxane Research 2, 507 (1976); Miller and collaborators, Gut 20, 75 (1979)? Robert and collaborators, Gastroenterology 72, 1121 (1977) J and this term characterizes well the effects of 'compound III.

In addition, compound III displays 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 30.

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 anti-ulcer effects and just below that corresponding to anti-allergic effects (1 to 10 mg / kg).

^ 10 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 which are 5 to 15 times greater than the intravenous dose of maximum efficacy for achieving anti-allergic effects and which are much stronger than the doses needed to obtain anti-ulcer effects.

In tolerance studies, Compound III was administered orally by gavage to dogs for a period of 7 days at doses of 50, 150 and 300 mg / kg / day. Emesis, which is common in dogs, was observed at 31.

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 five days at consecutive daily doses of 1, 3, 10, 3 and 10 3 mg / kg, are remained normal.

Compound III was administered to rats by gavage at doses of 50, 150 and 300 mg / kg / day for 10 days. 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 case of mortality is observed and it is concluded that the drug is well tolerated in the acute toxicity test with a DL5Q 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 nervous system is observed. central.

Single oral doses of 40 mg / kg of compound III are administered to groups of mice which are sacrificed 6, 12 or 30 24 hours later. Microscopic examination of the bone marrow reveals no chromosomal alteration. Similar findings are made when the mice are treated for five consecutive days 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 µg / ml also do not reveal any significant drug-induced chromosomal breakdown. Compound III, in the Ames test in vitro, does not cause 32.

ad hoc transfers. 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 finding is confirmed by the observation of plasma concentrations of 3 to 7 μg / ml one hour after the oral administration of compound III at the 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 ug / ml one hour 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 greater than after the initial dose, suggesting the possibility of maintaining therapeutic drug levels for prolonged periods.

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

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

EXAMPLE 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 to the urea solution at reflux in 25 minutes. After an additional reflux period of 2 hours, 33 is concentrated.

β the reaction solution by boiling to a volume of approximately 9,100 ml, it is cooled and the crude product is collected in the form of hydrobromide by filtration. Purified 2-amino-4-ethyl-5-methyltetrazole (15.1 g; melting point 45-50 ° C; m / e calculated: 142; found: 142) is obtained by dissolving in water and reprecipitation with an aqueous solution of potassium hydroxide 3N.

By the same procedure, 1-bromo-2-heptanone, 3-bromo-4-heptanone and 4-bromo-2,5-10 dimethyl-3-hexanone, respectively, are converted into 2-amino-4- pentyl-thiazole, 2-amino-4-ethyl-5-propylthiazole and 2-amino-4,5-diisopropylthiazole.

EXAMPLE 2 2-Amino-4,5-diethylthiazole hydrochloride

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

EXAMPLE 3 2-aminocycloheptenothiazole 41.9 g (0.55 mole) of thiourea, 72.3 g (0.49 mole) of 2-chlorocycloheptanone and 500 ml of ethanol are mixed and the mixture is refluxed for 7 hours. The solvent is removed, and a semi-solid substance remains which is divided between ethyl acetate and water. The unreacted chloro-ketone, 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 hours, 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 34.

alkalinization of the aqueous phase with ammonium hydroxide, extraction in ethyl acetate, dehydration on anhydrous sodium sulfate, evaporation until an oil is obtained, solidification by trituration with hexane 5 and filtration. The purified 2-aminocycloheptenothiazole (49.5 g, melting point 77-78.5 ° C) is obtained by recrystallization from cyclohexane.

-, EXAMPLE 4 10 2-amino-4-isopropylthiazole

52.5 g (0.69 mole) of thiourea are diluted in 400 ml of ethanol. 109.5 g (0.66 mole) 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 hour. 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, melting point, 74-76 ° C) is obtained by trituration with ether. The hydrobromide is converted to the free base (58.6 g) by dissolving the salt in water, basifying with excess ammonium hydroxide, extracting the base. free in ether, dehydrating the ether over anhydrous sodium sulfate and evaporating the solvent to obtain an oil.

EXAMPLE 5 2-amino-6-phenylcyclohexenothiazole 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 are added to the suspension, resulting in an exothermic reaction and dissolution. The solution is refluxed for 30 minutes, cooled and the solvent is removed by evaporation to obtain the crude product as the 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. We collect the gross base by 35.

filtration and 802.4 mg of 2-amino-6-phenylcyclo-hexenothiazole (melting point 181-183 ° C) is obtained by recrystallization from a mixture of water and ethanol.

Alternatively, by 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 reflux period. 30 minutes 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, melting point 180-182 ° C) by the addition of ammonium hydroxide in excess.

By the same procedures, 2-bromo-3-phenylcyclopentanone, 2-bromo-3,5-dimethylcyclo-15 hexanone, 2-bromo-3,5,5-trimethylcyclopentanone and 2-bromo-5 are converted. -methylcyclooctanone respectively as hydrobromide or free base of 2-amino-6-phenylcyclopentenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,4,6-trimethylcyclopentenothiazole and 2-amino-7-methylcyclo -20 octenothiazole.

EXAMPLE 6 2-amino-6-methylcyclohexenothiazole 22.3 g (0.29 mole) of thiourea are suspended in 275 ml of ethanol. 2-bromo-4-methylcyclohexanone is added and the mixture is heated at reflux for 75 minutes. 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 made basic by the addition of ammonium hydroxide to precipitate the free base in the form of an oil which crystallizes on cooling. Purified 2-amino-6-methylcyclohexeno-thiazole (25.2 g, melting point 98-100 ° C) is obtained by recrystallization from cyclohexane.

36.

EXAMPLE 7 2-amino-6,6-dimethylcyclohexenothiazole 2-amino-6,6-dimethylcyclohexenothiazole (9.8 g, melting point 109-111 ° C) is prepared from 9.2 g 5 (0.12 mole) of thiourea and 22.6 g (0.11 mole) of 2-bromo-4,4-dimethylcyclohexanone in 100 ml of ethanol according to the procedure of Example 6.

EXAMPLE 8 2-amino-4- (2-butyl) -thiazole

16.7 g (0.22 mole) of thiourea, 36 g (0.2 mole) of 1-bromo-3-methyl-2-pentanone and 100 ml of ethanol are mixed and the mixture is heated under reflux for 5 hours. An aqueous potassium hydroxide solution (3N, 100 ml) is added and heating is continued at reflux for a further 0.5 hour. 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 .

EXAMPLE 9 2-amino-5-methylthiazole

45.7 g (0.6 mole) of thiourea and 7.4 g (0.3 mole) of propionaldehyde are mixed with 150 ml of chloroform and the mixture is cooled in an ice bath. 44.5 g (0.33 mole) of sulfuryl chloride are added over 15 minutes. 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 hours.

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 37.

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, melting point 94-95 ° C) is obtained by recrystallization from cyclohexane.

v EXAMPLE 10 2-amino-5-ethylthiazole 10 45.7 g (0.6 mole) of thiourea and 21.6 g (0.3 mole) of butyraldehyde are mixed with 150 ml of chloroform and the mixture is cooled in the bath of ice. 44.5 g (0.33 mole) of sulfuryl chloride are added over 15 minutes. The exothermic reaction is maintained between 15 and 25 ° C. Gas evolution takes place during the addition and for about 1 hour after the addition. 400 ml of ethanol are added, the chloroform is removed by boiling and the reaction mixture is refluxed for approximately 16 hours. The reaction mixture is evaporated to obtain an oil and 11.7 g of recrystallized 2-amino-5-ethyl-20-thiazole (melting point 54-55 ° C.) are isolated by the method indicated in Example 9.

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

EXAMPLE 11 2- (2,2-dicarbethoxy-ethenylamino) -4,5-dimethylthiazole 3 "2.56 g (20 mmol) of 2-amino-4,5-dimethylthiazole, 4.8 g (22 g) are refluxed mmol) of diethyl ethoxymethylene malonate and 5 ml of ethanol for 1 hour, the reaction mixture is cooled and the crude product is precipitated by addition of hexane. 2- (2,2-dicarbethoxy-ethenylamino) is obtained -4.5-dimethylthiazole purified (4.21 g, melting point 82-83.5 ° C) by recrystallization from hexane.

38.

EXAMPLE 12 2- (2,2-dicarbethoxy-ethenylamino) -4-ethyl-5-methylthiazoIt is mixed 2.84 g (20 mmol) of 2-amino-4-ethyl-5-methylthiazole and 4.76 g (22 mmoles} of 5-ethoxymethylene diethyl malonate and the mixture is heated in a boiling water bath for 3 hours 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 2-10 amino-4-pentylthiazole, 2-amino-4-propyl-5-ethylthiazole, 2-amino-4,5-diisopropylthiazole, 2-amino-5-propyl -thiazole, 2-amino-5-isopropylthiazole, 2-amino-5-pentylthiazole, 2-amino-6-phenylcyclopentenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,6, 6-15 trimethylcyclopentenothiazole and the 2-amino-7-methylcyclo-octenothiazole to the corresponding 2- (2,2-dicarbethoxy-ethenylamino) -thiazole derivative.

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 ethoxymethylenemalonate.

EXAMPLE 13 2- (2,2-dicarbethoxy-ethenylamino) -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.

EXAMPLE 14 2- (2,2-dicarbethoxy-ethenylamino) -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 refluxed. the mixture for 2.5 hours. The reaction mixture is cooled and the 39 is removed.

ο solvent. The resulting semi-solid product is partitioned between ethyl acetate and water. 2- (2,2-dicarbethoxy-ethenylamino) -4,5-diethylthiazole (28.6 g) is obtained in the form of a golden-colored oil from phase 5 of ethyl acetate by dehydration over anhydrous sodium sulfate and removal of the solvent by evaporation.

By the same method, the hydrobromides of 5,7-dimethylcyclohexenothiazole, 4,4,6-trimethylcyclo-pentenothiazole and 7-methylcyclooctenothiazole are converted to the corresponding 2- (2,2-dicarbethoxy-ethenylamino) -thiazolic 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 ethoxymethylenemalonate.

EXAMPLE 15 2- (2,2-dicarbethoxy-ethenylamino) -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 minutes. The reaction mixture and the 2- (2,2-dicarbethoxy-ethenylamino) -cyclo-pentenothiazole (7.0 g, Rf 0.6 in thin layer chromatography on silica gel are cooled with a mixture of - chloroform and 1% ethanol) crystallized by adding hexane.

EXAMPLE 16 2- (2,2-dicarbethoxy-ethenylamino) -cyclohexenothiazole

7.7 g (50 mmol) of 2-aminocyclohexenothiazole and 11.9 g (55 mmol) of diethyl ethoxymethylene malonate are mixed with 10 ml of ethanol and the mixture is heated at reflux for 50 minutes. 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 a mixture 40).

? chloroform and 1% ethanol) precipitate by adding 50 ml of hexane.

Alternatively, 58.4 g of 2-amino-cyclohexenothiazole, 89.82 g of diethyl ethoxymethylenemalonate and 584 ml of cyclohexane are mixed and the mixture is heated under reflux under a nitrogen atmosphere for 2 hours and half, it is cooled to 15 ° C and the product is collected (96 g, melting point 113 ° C) by filtration.

EXAMPLE 17 2- (2,2-dicarbethoxy-ethenylamino) -cyclooctenothiazole

2.0 g (11 mmol) of 2-aminocyclo-octenothiazole and 2.62 g (12.1 mmol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated. in a boiling water bath 15 for 2.75 hours. The reaction mixture is cooled and precipitated by addition of hexane 3.13 g of 2- (2,2-dicarbethoxy-ethenylamino) -cyclooctenothiazole (Rf 0.6 by chromatography on silica gel with, as eluent, a mixture of chloroform and 1% ethanol).

EXAMPLE 18 2- (2,2-carbethoxy-ethenylamino) -4-methylthiazole

4.57 g (40 mmol) of 2-amino-4-methylthiazole and 9.51 g (44 mmol) of ethoxymethylene, diethyl malonate are mixed and the mixture is heated in a boiling water bath for 1 hour . The reaction mixture is cooled and 9.8 g of 2- (2,2-dicarbethoxy-ethenylamino) -4-methylthiazole (Rf 0.5 by thin layer chromatography) are precipitated by the addition of 60 ml of hexane. 30 silica gel with a mixture of chloroform and 1% ethanol as eluent).

EXAMPLE 19 2- (2,2-dicarbethoxy-ethenylamino) -thiazole 10.0 g (0.10 mole) of 2-aminothiazole and 23.8 g (0.11 mole) of diethyl ethoxymethylenemalonate are mixed and heat the mixture in a boiling water bath for 1.25 hours. The reaction mixture is cooled and "41.

recrystallize the resulting semi-solid substance in hexane to obtain the purified 2- (2,2-dicarbethoxy-ethenyl) -thiazole (17.2 g in two crops, Rf 0.6 in thin layer gel gel chromatography silica with, as eluent, a mixture of chloroform and 1% ethanol).

EXAMPLE 20 2- (2,2-dicarbethoxy-ethenylamino) -5-methylthiazole

Heated in a boiling water bath for 10 hours 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-dicarbethoxy-ethenylamino) -5-methylthiazole (14.1 g in two harvests, Rf 0.55-0.65 in silica gel thin layer chromatography with, as eluent, a mixture of chloroform and 1% ethanol) is obtained by recrystallization from hexane.

EXAMPLE 21 2- (2,2-dicarbethoxy-ethenylamino) -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 minutes . 2- (2,2-dicarbethoxy-ethylamino) -5-ethylthiazole (27.2 g, respective Rf values of 0.6 and 0.7 in silica gel thin layer chromatography with, as eluents , 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 next step.

EXAMPLE 22 2- (2,2-dicarbethoxy-ethenylamino) -4-35 (2-methyl-2-propyl) -thiazole

15.6 g (0.1 mole) of 2-amino-4- (2-methyl-2-propyl) -thiazole and 23.8 g (0.11 mole) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated. mix with 42.

boiling water bath for 2 hours. 2- (2,2-dicarbethoxy-ethenylamino) -4- (2-methyl-2-propyl) -thiazole is obtained in the form of a wet solid substance on cooling and is used directly in the following step 5 .

EXAMPLE 23 2- (2,2-dicarbethoxy-ethenylamino) -4-ethylthiazole

20.5 g (0.16 mole) of 2-amino-4-ethyl-10 thiazole and 35 g (0.17 mole) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated in a boiling water bath for 2 hours . 2- (2,2-Dicarbethoxy-ethenylamino) -4-ethylthiazole is obtained, by cooling, in the form of an oil and is used directly in the following step 15 (Rf = 0.75 by chromatography on thin layer of silica gel, with a mixture of chloroform and 1% ethanol as eluent).

By the same procedure, 2-amino-4-iso-propylthiazole (58.6 g, 0.415 mole) and diethyl ethoxymethylene-malonate (92 ml, 0.455 mole) are converted to 2- (2.2 -dicarbethoxy-ethenylamino) -4-isopropylthiazole (Rf = 0.7 by thin layer chromatography on silica gel, with a mixture of chloroform and 1% ethanol as eluent).

EXAMPLE 24 2- (2,2-dicarbethoxy-ethenylamino) -6-phenylcyclohexenothiazole 10.4 g (45.2 mmol) of 2-amino-6-phenylcyclohexenothiazole and 10 ml (49.5 mmol) are mixed diethyl ethoxy-methylenemalonate and the mixture is heated in a boiling water bath. A solution is obtained after 15 minutes. After an additional heating period of 30 minutes, the entire mass solidifies. The crude product is recrystallized from cyclohexane to give 15.3 g of purified 2- (2,2- • dicarbethoxy-ethenylamino) -6-phenylcyclohexenothiazole melting at 131-133 ° C.

43.

* EXAMPLE 25 * 2- (2,2-dicarbethoxy-ethenylamino) -6-methvlcvclohexenothiazole 23.3 g (0.139 mole) of 2-amino-6-methylcyclohexenothiazole are mixed with 31 ml (0.153 mole) of 5-ethoxy methylenemalonate of diethyl and the mixture is heated in a boiling water bath. After a heating period of approximately 10 minutes, a light orange-colored oil is obtained. After heating for 1 hour, crystallization is started by scraping. 40.2 g of 2- (2,2-dicarb-10 ethoxy-ethenylamino) -6-methylcyclohexenothiazole are obtained (mp 106-109 ° C) by recrystallization from ethanol.

EXAMPLE 26 2- (2,2-dicarbethoxy-ethenylamino) - 6,6-dimethylcyclohexenothiazole 9.8 g (53.8 mmol) of 2-amino-6,6-dimethylcyclohexenothiazole, 12 ml (59.4 mmol) are mixed ) of diethyl ethoxy-methylenemalonate and about 5 ml of ethanol and the mixture is heated in a boiling water bath for 1 hour and a half. 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, melting point 83-85 ° C) is obtained by recrystallization from hexane.

Analysis: C,% H,% N,% calculated for C17H2404N2S 57.93 6.86 7.95 found 57.72 6.66 7.94.

EXAMPLE 27 2- (2,2-dicarbethoxy-ethenylamino) -4- (2-butyl) -thiazole * 8.44 g (54 mmol) of 2-amino-4- (2- butyl) -thiazole are mixed and 11.7 g (54 mmol) of diethyl ethoxymethylene malonate and the mixture is heated in a boiling water bath for 1 hour, then cooled to obtain 17.6 g of 2- (2,2-dicarbethoxy- ethenylamino) -4- (2-butyl) - 44.

thiazole (Rf = 0.75 by thin layer chromatography of 4 silica gel with a mixture of chloroform and 1% ethanol as eluent).

EXAMPLE 28 Ethyl 1-oxo-1H-6,7-dimethylthiazolo-j3,2-a J-pyrimidine-2-carboxylate

4.17 g (14 mmol) of 2- (2-dicarb-ethoxy-ethenylamino) -4,5-dimethylthiazole are mixed with 30 ml of 10 "Dowtherm A" and the mixture is heated at 220 ° C. for 1.5 hour. The reaction mixture is cooled and 125 ml of petroleum ether are added. The precipitating solid is filtered off, mixed again with the mother liquor and chromatographed on a 70 x 180 mm column of silica gel, the eluent used being chloroform. After an initial 125 ml fraction, six 250 ml fractions are collected and evaporated to dryness to obtain 2.42 g of crude product (melting point 114-115 ° C). By recrystallization from cyclohexane, 1-oxo-1H-20 4,5-dimethylthiazolo - (. 3,2-aJ-pyrimidine-2-carboxylate of purified ethyl is obtained (1.64 g; melting point 119- 120 ° C).

Analysis: C,% H,% N,% calculated for C ^ H ^ N ^ S _ 52.37 4.79 11.10 mass ion: 252 25 found 52.21 4.85 11.23 mass ion: 252.

EXAMPLE 29 Ethyl 1-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-a J-pyrimidine-30-2-carboxylate

6.25 g of 2- (2-dicarbethoxy-ethenyl-amino) -4-ethyl-5-methylthiazole are mixed with 30 ml of "Dowtherm A" and the mixture is heated at 215 ° C for 2 and a half hours. The reaction mixture is cooled, petroleum ether is added and the crude product (1.96 g) is collected by filtration. 630 mg of the crude product is recrystallized from cyclohexane to obtain 301 mg of ethyl purified 1-oxo-1H-6-methyl-7-ethyl-thiazolo- [3,2-aJ-pyrimidine-2-carboxylate 122-124 ° C.

45.

Analysis: C,% H,% N,% calculated for C12H14N203S 54.12 5.30 10.52 found 54.09 5.26 10.63.

EXAMPLE 30 Ethyl 1-oxo-1H-6-ethyl-7-methylthiazolo- [3,2-a) -pyr imidine- 2-carboxylate

12 g of 2- (2,2-dicarbethoxy-ethenyl-amino) -4-methyl-5-ethylthiazole are mixed with 60 ml of "Dowtherm A" and the mixture is heated at 205WC for 3 hours. The reaction mixture is cooled and the chromatography is carried out on a column of 90 x 205 mm 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 8 ml fractions are combined, freed from the solvent and an oil is obtained which is recrystallized by trituration with diisopropyl ether. By recrystallization from cyclohexane, 1-oxo-1H-6-ethyl-7-methylthiazolo - (. 3,2-a J-pyrimidine-2-carboxylate, purified ethyl (2.45 g, melting point) 65-66 ° C).

Analysis: C,% H,% N,% 25 calculated for ^ 12 ^ 14 ^ 2 ^ 33 54.12 5.30 10.52 mass ion: 266 'found 54.26 5.23 10.57 mass ion : 266.

EXAMPLE 31 Ethyl 1-oxo-1H-6,7-diethylthiazolo- [3,2-aJ-pyrimidine-2-carboxylate ·> 26.1 g of 2- (2,2-dicarbethoxy-ethenyl-) are mixed 35 amino) -4,5-diethylthiazole and 300 ml of "Dowtherm A" and the mixture is heated at 225 ° C. for 3.5 hours. The reaction mixture is cooled and chromatographed on a column of silica gel ( 60 x 320 mm). The "Dowtherm A" "ψ 46.

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, yielding 22 g of ethyl 1-oxo-1H-6,7-diethylthiazolo- [3,2-aJ- 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), in the form of an oil.

By the same procedure, the following products of Examples 12 and 14: - 2- (2,2-dicarbomethoxy-ethenylamino) -4-ethyl-5-methylthiazole, - 2- (2,2-dicarbopropoxy-ethenylamino) - 4-ethyl-5-methylthiazole, - 2- (2,2-dicarbisopropoxy-ethenylamino) -4-ethyl-5-methylthiazole, 15 - 2- (2,2-dicarbomethoxy-ethenylamino) -4,5-diethylthiazole, - 2- (2,2-dicarbopropoxy-ethenylamino) -4,5-diethylthiazole, - 2- (2,2-dicarbisopropoxy-ethenylamino) -4,5-diethylthiazole, - 2- (2,2-dicarbethoxy-ethenylamino) - 4-pentylthiazole, - 2- (2,2-dicarbethoxy-ethenylamino) -4-propyl-5-ethylthiazole, 20 - 2- (2,2-dicarbethoxy-ethenylamino) -4,5-diisopropylthiazole, - 2- (2 , 2-dicarbethoxy-ethenylamino) -5-propylthiazole, - 2- (2,2-dicarbethoxy-ethenylamino) -5-isopropylthiazole, - 2- (2,2-dicarbethoxy-ethenylamino) -5-pentylthiazole, - 2- ( 2,2-dicarbethoxy-ethenylamino) -6-phenylcyclopentenothiazole, 25 - 2- (2,2-dicarbethoxy-ethenylamino) -5,7-dimethylcyclohexenothiazole - 2- (2,2-dicarbethoxy-ethenylamino) -7-methylcyclooc tenothiazole, and - 2- (2,2-dicarbethoxy-ethenylamino) -4,4,6-trimethylcyclopenteno-methylthiazole are respectively converted into the following compounds: - 1-oxo-1H-6-methyl-7-ethylthiazolo- (. Methyl 3,2-a J-pyrimidine-2-carboxylate, - propyl 1-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxylate *, 35 - 1-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-a J-pyrimidine-2-isopropyl carboxylate, - 1-oxo-1H-6,7-d iethylth iazolo- [3,2 -a methyl J-pyrimidine-2-carboxylate, 47.

- 1-oxo-1H-6,7-diethylthiazolo - (. 3,2-a propyl J-pyrimidine-2-carboxylate, - 1-oxo-1H-6,7-diethylthiazolo - (. 3,2-a Isopropyl J-pyrimidine-2-carboxylate, 5 - 1-oxo-1H-7-pentylthiazolo- (3,2-aJ-ethyl pyrimidine-2-carboxylate, - 1-oxo-1H-6-ethyl- 7-propylthiazolo- (3,2-a ethyl J-pyrimidine-2-carboxylal, - 1-oxo-1H-6,7-diisopropylthiazolo- [3,2-a J-pyrimidine-2-carboxylate 10 ' ethyl, - 1-oxo-1H-6-propylthiazolo- (3,2-aJ-pyrimidine-2-ethyl carboxylate, - 1-oxo-1H-6-isopropylthiazolo- [3,2-a J-pyrimidine- Ethyl 2-carboxylate, 15 - 1-oxo-1H-6-pentylthiazolo- [3,2-a Ethyl J-pyrimidine-2-carboxylate, ^ - 1-oxo-1H-6-phenylcyclopentenothiazolo- [3 , 2 ~ a ethyl J-pyrimidine-2-carboxylate, - 1-oxo- 1H-6,8-d imethylcyclohexenothiazolo- (, 3,2-a ethyl J-pyrimidine-2-20 carboxylate, - 1-oxo-1H-8-methylcyclooctenothiazolo- (3,2-a ethyl J-pyrimidine-2-carboxylate, and - 1-OXO-1H-6,8,8-trimethylcyclopentenothiazolo- [3,2-a J -pyrimidine-ethyl 2-carboxylate.

EXAMPLE 32 Ethyl 1-oxo-1H-cyclopentenothiazolo- [3,2-a J-pyrimidine-2-carboxylate

7.0 g of 2- (2,2-dicarbethoxy-ethenyl-30 amino) -cyclopentenothiazole are mixed with 40 ml of "Dowtherm A" and the mixture is heated to 225-230 ° C for about 1 hour. The reaction mixture is cooled and chromatographed on silica gel (70 x 190 mm). We elect "Dowtherm A" with hexane. The product is eluted with a mixture of chloroform and 1% ethanol. Four fractions of 250 ml each are collected, combined 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 48.

gross product. By recrystallization of 0.6 g of the crude product, 1-oxo-1H-cyclopentenothiazolo- (3,2-aJ- pyrimidine-2-carboxylate of purified ethyl (0.33 g, melting point 102-103) is obtained ° C).

5 Analysis: C,% H,% N,% calculated for C- | 2H12N2 ° 3S 54.53 4.58 10.60 found 54.54 4.71 10.71.

EXAMPLE 33 Ethyl 1-oxo-1H-cyclohexenothiazolo- [3,2-a J-pyrimidine-2-carboxylate

12.6 g of 2- (2,2-dicarbethoxy-ethenyl-amino) -cyclohexenothiazole are mixed with 125 ml of "Dowtherm A" and the mixture is heated at 230 ° C for 25 minutes. The reaction mixture is cooled and chromatographed on silica gel (60 x 320 mm). "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. Obtained ethyl 1-oxo-1H-cyclohexenothiazolo- [3,2-a J-pyrimidine-2-carboxylate (10.7 g, melting point 92-94 ° C) by combining the fractions and expelling the solvent.

Alternatively, 80 g (0.25 mole) of 2- (2,2-dicarbethoxy-ethenylamino) -cyclohexenothiazole, 101 g (68 ml, 0.48 mole) of trifluoroacetic anhydride, 0.8 1 are mixed. 25 of toluene and 1 L of ethanol and the mixture is refluxed for 21 hours. The reaction mixture is cooled and 300 ml of water are added. The toluene phase (upper) is separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to 150 ml (suspension), diluted with 1 l of ethanol (solution) , concentrated to 280 ml, cooled to 5 ° C., granulated and filtered to give relatively pure ethyl 1-oxo-1H-cyclohexeno-thiazolo- [3,2-a J-pyrimidine-2-carboxylate (47 g, melting point 105-106 ° C).

49.

EXAMPLE 34 Ethyl 1-oxo-1H-cycioheptenothiazolo- [3,2-a j-pyrimidine-2-carboxylate

25.2 g (0.15 mole) of 2-aminocyclo-5 heptenothiazole, 35.7 g (0.165 mole) of ethoxymethylene diethyl malonate and 400 ml of "Dowtherm A" are mixed and the mixture is heated to 220 -230üC for 2 hours. 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 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 moist solid. Purified ethyl 1-oxo-1H-cycloheptenothiazolo-15 [3,2-aJ-pyrimidine-2-carboxylate (27.1 g, melting point 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 performing the isolation and purification in the same manner.

EXAMPLE 35 1-oxo-1H-cyclooctenothiazolo- (3,2-a J-pyrimidine-2-25 ethyl carboxylate

3.13 g of 2- (2,2-dicarbethoxy-ethenyl-amino) -cyclooctenothiazole are mixed with 30 ml of "Dowtherm A" and the mixture is heated at 220 ° C. for 2.5 hours. The reaction mixture is cooled and chromatographed on silica gel (70 x 190 mm). "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, they are evaporated to obtain an oil and • 1-oxo-1H-cyclo-35 octenothiazolo-j3,2-aJ-pyrimidine-2-carboxylate is obtained by trituration with hexane solid ethyl (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).

50.

EXAMPLE 36 Ethyl 1-oxo-1H-7-methylthiazolo- (3,2-a) -pyrimidine-2-carboxylate

9.8 g of 2- (2,2-dicarbethoxy-ethenyl-5 amino) -4-methylthiazole are mixed with 50 ml of "Dowtherm A" and the mixture is heated at 220 ° C for 2 hours. 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 Ι-ΙΟ oxo-1H-7-methylthiazolo- [3,2-a J-pyrimidine-2-carboxylic acid purified at 187-189 are obtained. ° 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) J.

EXAMPLE 37 Ethyl 1-oxo-1H-thiazolo- [3,2-a j-pyrimidine-2-carboxylate 17.2 g of 2- (2,2-dicarbethoxy-ethenylamino) -thiazole are mixed with 200 ml "Dowtherm A" and the mixture is heated to 215 ° C for 30 minutes. 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, ethyl 1-oxo-1H-thiazolo- (3,2-aJ-pyrimidine-2-carboxylate (8.0 g, melting point 184-185 ° C) is obtained. .

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) J.

EXAMPLE 38 Ethyl 1-oxo-1H-6-methylthiazolo- (3,2-a) -pyrimidine-2-carboxylate

14.1 g of 2- (2,2-dicarbethoxy-ethenyl) -5-methylthiazole are mixed with 150 ml of "Dowtherm A" and the mixture is heated at 220 ° C for one and a half hours. The reaction mixture is cooled and about 300 ml are added to it 51.

of hexane. The product is collected by filtration and 6.4 g of pyrified ethyl 1-oxo-1H-6-methylthiazolo- [3,2-aJ-pyrimidine-2-carboxylate are obtained (melting point 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 ).

EXAMPLE 39 Ethyl 1-oxo-1H-6-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxylate

25.7 g (36 mmol) of 2- (2,2-dicarb-15 ethoxy-ethenylamino) -5-ethylthiazole, 36.2 g (172 mmol) of trifluoroacetic anhydride and 150 ml of toluene are mixed and heated mix at reflux for about 20 hours. 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 solution of sodium bicarbonate, then a saturated solution of sodium chloride, 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 J-pyrimidine-2-carboxylate melting at 148-150UC. A portion of the product (5.2 g) is recrystallized in approximately 75 ml of ethyl acetate giving an additional quantity of purified product (4.1 g; melting point, 149-150 ° C).

- Analysis: C,% H,% N,% 30 calculated for C ^ H ^ N ^ S 52.37 4.79 11.10 found 52.30 4.51 11.14.

EXAMPLE 40 Ethyl 1-OXO-1H-7- (2-methyl-2-propyl) -thiazolo- [3,2-a) -pyrimidine-2-35 carboxylate

32.6 g of 2- (2,2-dicarbethoxy-ethenyl-amino) -4- (2-methyl-2-propyl) -thiazole are mixed with 400 ml of "Dowtherm A" and the mixture is heated to 230 ° C during a 52.

hour. The reaction mixture is cooled and chromatographed on silica gel (60 x 600 mm). "Dowtherm A" is eluted with hexane. The product is eluted with chloroform. Nine 500 ml fractions are collected. The 5 fractions from the sixth to the ninth are combined and evaporated to dryness, giving 1-oxo-1H-7- (2-methyl-2-propyl) -thiazolo- [3,2-aJ-pyrimidine-2-carboxylate ethyl (11.4 g, tl melting point 145-147 ° C). An additional quantity of product (2.04 g) is obtained from the fifth fraction 10 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, melting point 148-149 ° C).

Analysis: C,% H,% N,% calculated for 0 ^ 311 ^ 5N2O3S 55.70 5.75 9.99 found 55.14 5.58 9.95.

EXAMPLE 41 Ethyl 1-oxo-1H-7-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxylate

47.7 g (0.16 mole) of 2- (2,2-dicarb-ethoxy-ethenylamino) -4-ethylthiazole are stirred in 500 ml of toluene and 45 ml (0.32 mole) of trifluoroacetic anhydride are added . A moderate exothermic reaction is observed. The reaction mixture is heated to reflux for 26 hours, cooled and 250 ml of ethyl acetate are added thereto. The mixture is carefully extracted with 250 ml of aqueous sodium bicarbonate solution (evolution 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 in acetonitrile, 1-35 oxo-1H-7-ethylthiazolo - (. 3,2-a J-pyrimidine-2-carboxylic acid, purified (10.33 g , melting point 175-177 ° C).

Analysis: C,% H,% N,% calculated for C, | 52.37 4.79 11.10 found 52.34 4.85 11.27 53.

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

EXAMPLE 42 Ethyl 1-oxo-4H-7-isopropylthiazolo- [3,2-aJ-pyrimidine-2-carboxylate

10 g of 2- (2,2-dicarbethoxy) -4-iso-propylthiazole are mixed with 100 ml of "Dowtherm A" and the mixture is heated at 220 ° C for 2 hours, allowed to cool to room temperature for about 16 hours and reheated to 220 ° C for another 5 hours. The mixture is allowed to cool to room temperature, about 200 ml of hexane is added thereto and filtered to remove traces of insoluble matter. The hexane is removed and the residue is chromatographed on approximately 500 g of silica gel. "Dowtherm A" is eluted with hexane and the product is eluted with chloroform. The product-containing fractions are combined and evaporated to dryness, the residue is suspended in diisopropyl ether and the product (melting point 143-144 ° C) is collected by filtration. The crude product is recrystallized from ethanol to give purified ethyl 1-oxo-1H-7-isopropylthiazolo- (3,2-aJ-pyrimidine-2-carboxylate (1.49 g, melting point 145-147 ° C, nuclear magnetic-25 resonance: singlets at δ 8.6 and δ 7.3 corresponding to one proton each and multiplets centered at δ 4.2 and δ 1.2 corresponding to three protons and nine protons respectively).

EXAMPLE 43 Ethyl 1-oxo-1H-7-phenylcyclohexenothiazolo- [3,2-a) -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 to give a clear solution which is refluxed for 16 hours. The reaction mixture is allowed to cool to room temperature and diluted 54.

t to 150 ml with ethyl acetate, it is extracted twice with 150 ml of 5% potassium carbonate and once with 150 ml of saturated sodium chloride, it is dried over anhydrous sodium sulfate and we evaporate it dry. The solid residue is recrystallized from acetonitrile to give purified ethyl 1-oxo-1H-7-phenylcyclohexenothiazolo- [3,2-a J-pyrimidine-2-carboxylate (9.89 g, melting point 160 -161.5 ° C).

EXAMPLE 44 Ethyl 1-oxo-1H-7-methylcyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxylate

40.2 g (0.119 mole) of 2- (2,2-dicarb-ethoxy-ethenylamino) -6-methylcyclohexenothiazole are dissolved in 400 ml of toluene. 33.5 ml (0.237 mole) of trifluoroacetic anhydride is added, which causes a slightly exothermic reaction. The reaction mixture is refluxed for about 16 hours, allowed to cool to room temperature, diluted with 400 ml of ethyl acetate, then extracted twice with 400 ml of 1N potassium carbonate 20 and with 400 ml of saturated sodium chloride, it is 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-1h-7-methyl-cyclohexenothiazolo - (. 3,2-a J-pyrimidine-2-carboxylate) are obtained. of purified ethyl melting at 127-129 ° C.

= EXAMPLE 45 ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo- [3f2-a) -pyrimidine-2-carboxylate 13 g (36.9 mmol) of 2- (2,2-dicarb-) are dissolved ethoxy-ethenylamino) -6,6-dimethylthiazole in 130 ml of toluene. 10.4 ml (73.6 mmol) of trifluoroacetic anhydride are added and the mixture is heated at reflux for Ί6 hours. The reaction mixture is allowed to cool to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 130 ml of saturated sodium bicarbonate and once with 150 ml of saturated sodium chloride , it is dried over anhydrous sodium sulfate and 55.

it is evaporated to dryness. By recrystallization from hexane, 9.40 g of ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo- [3,2-αJ-pyrimidine-2-carboxylate, melting at 92-94 ° C, are obtained.

5 Analysis: C,% H,% N,% calculated for C15H-J6N203S 58.80 5.92 9.14 found 58.93 5.48 9.01.

EXAMPLE 46 Ethyl 1-oxo-1H-7- (2-butyl) -thiazolo- (3,2-aJ-pyrimidine-2-carboxylate)

17.6 g of 2- (2,2-dicarbethoxy-ethenyl-amino) -4- (2-butyl) -thiazole are mixed with 175 ml of "Dowtherm A" and the mixture is heated at 225 ° C for 2 hours and a half. The reaction mixture is cooled and chromatographed on silica gel (60x600 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 ethyl 1-oxo-1H-7- (2-butyl) -thiazolo- [3,2-aJ-pyrimidine-2-carboxylate melting at 105.5-108 ° C.

Analysis: C,% H,% N,% 25 calculated for C13H-jg03N2S 55.70 5.75 9.99 found 55.82 5.40 10.22.

EXAMPLE 47

1-oxo-1H-6,7-dimethylthiazolo- [3,2-a J-pyrimidine-2-30 carboxylic acid

1.41 g of ethyl 1-oxo-1H-6,7-dimethyl-thiazolo- [3,2-aJ-pyrimidine-2-carboxylate is heated in a boiling water bath with 20 ml of 48 hydrobromic acid % for Ί hour. Dissolution takes place in a few minutes and the 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, 1-oxo-1H-6,7-dimethylthiazolo-56 acid is obtained.

[3,2-aJ-pyrimidine-2-carboxylic purified (508 mg, melting point 189-190 ° C).

Analysis: C,% H,% N,% calculated for CgHgO ^ S 48.21 3.60 12.49 5 mass ion: 224 found 48.21 3.68 12.44 mass ion: 224.

EXAMPLE 48 10-1-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid 971 mg of 1-oxo-1H-6-methyl- are heated in a boiling water bath Ethyl 7-ethylthiazolo- [3,2-aJ-pyrimidine-2-carboxylate with 15 ml of 48% hydrobromic acid. Dissolution takes place almost immediately. Heating is continued for 2.5 hours, and at this point the reaction mixture is cooled, giving a product in the form of a solid substance capable of being filtered. By recrystallization of the crude product from isopropyl alcohol, 1-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxylic acid is obtained (354 mg, point 201-202 ° C).

Analysis: C,% H,% N,% calculated for cioH10 ° 3N2S 50.41 4.23 11.76 „25 found 50.28 4.26 11.80.

'' EXAMPLE 49

1-oxo-1H-6-ethyl-7-methylthiazolo- [3,2-a J-pyrimidine acid; 2-carboxylic 30 The mixture is heated in a boiling water bath 1.33 g of ethyl 1-oxo-1H-6-ethyl-7-methylthiazolo - (. 3,2-a J-pyrimidine-2-carboxylate with 10 ml 48% hydrobromic acid for 30 minutes and at this point a solid substance begins to form, the reaction mixture is cooled and the crude product is collected by filtration and recrystallization from isopropyl alcohol is carried out. obtains purified 1-oxo-1H-6-ethyl-7-methylthiazolo- [3,2-a J-pyrimidine-2-carboxylic acid (596 mg, melting point 174-176 ° C.

57.

Analysis: C,% H,% N,% calculated for 50.41 4.23 11.76 found 50.44 4.22 11.82.

5 EXAMPLE 50

1-oxo-1H-6,7-diethylthiazolo- [3,2-a j-pyrimidine-2-carboxylic acid 19.2 g of 1-oxo-1H-6,7-diethyl-thiazolo- [3, Ethyl 2-a-J-pyrimidine-2-carboxylate at 85 ° C for one hour with 48% aqueous hydrobromic acid. 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 to give 1-oxo-1H-6,7 - diethylthiazolo- [3,2-a J-pyr purified imidine-2-carboxylic [1.6 g, melting point 104-106 ° C (cloudy) J.

Analysis: C,% H,% N,% 25 calculated for C ^ H ^ 2 ° 3N2 ^ 52.37 4.79 11.10 found 52.31 4.79 11.16.

EXAMPLE 51 1-oxo-1H-cyclopentenothiazolo- (3,2-aj-pyr imid ine-2-carboxylic acid)

1.3 g of ethyl 1-oxo-1H-cyclopenteno-thiazolo- [3,2-aJ-pyrimidine-2-carboxylate are heated with 15 ml of 48% hydrobromic acid in a boiling water bath for 30 min. minutes. Dissolution takes place after about 35 5 minutes; 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, 58 is obtained.

0.51 g of 1-oxo-1H-cyclopentenothiazolo acid - (. 3,2-a J-pyrimidine-2-carboxylic purified (melting point 202-203.5 ° C).

Analysis: C,% H,% N,% 5 calculated for C ^ HgOg ^ S 50.84 3.41 11.86 found 50.42 3.57 11.65.

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-methyl morpholine salt is prepared by dissolving the acid in methylene chloride with a slight excess of N-methyl morpholine and evaporating to dryness or precipitating the salt by cooling and adding hexane. 15 EXAMPLE 52

1-oxo-1H-cyclohexenothiazolo- (3,2-a] -pyrimidine-2-carboxylic acid 2.8 g of 1-oxo-1H-cyclohexenothiazolo-20 [3,2-aJ-pyrimidine-2-carboxylate) are heated ethyl 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. The reaction mixture is cooled in an ice bath and isolated by filtration 1.66 g of 1-oxo-1H-cyclohexenothiazolo- ^ S ^ -aJ-pyrimidine-2-carboxylic acid, melting at 188-189 ° C. By recrystallization from ethanol , 1.38 g of product having the same melting point are obtained.

Alternatively, this product is prepared by shaking 22.3 g of the ethyl ester with 223 ml of 48% hydrobromic acid in a low pressure container. Dissolution takes place at 65-70 ° C. The reaction mixture is heated over a period of 40 minutes to a maximum temperature of 85 ”C and to a maximum gauge pressure of 35 49 kPa. The reaction mixture is cooled to 45 ° C, the pressure is relaxed, the mixture is cooled to 5 ° C, stirred for one hour and the relatively pure product is collected directly by filtration (12.4 g, melting point 192-194 ° C).

59.

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.

5 EXAMPLE 53

1-oxo-1H-cycloheptenothiazolo-3,2-aJ-pyrimidine-2-carboxylic acid

5.8 g of 1-oxo-1H-cyclohepteno-10 thiazolo - (. 3,2-a ethyl J-pyrimidine-2-carboxylate) are heated for 15 minutes in a boiling water bath with 50 ml of bromhy acid The reaction mixture is poured into ice, stirred and the crude product is collected by filtration and recrystallization from ethanol gives 1-oxo-1H-cycloheptenothiazolo- [3,2- a purified J-pyrimidine-2-carboxylic acid (2.63 g, melting point 162-163 ° C).

Analysis: C,% H,% N,% calculated for C- | 2H12N3 ° 2S 54.53 4.58 10.60 mass ion: 264 20 found 54.72 4.73 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, followed by cooling, concentration or addition of hexane.

"EXAMPLE 54

1-Oxo-1H-cyclooctenothiazolo- [3,2-a J-pyrimidine-2-carboxylicfue 30 1.23 g of 1-oxo-1H-cyclooctenothiazol - (. 3,2-a J-) are heated ethyl pyrimidine-2-carboxylate in an oil bath with 30 ml of 48% hydrobromic acid at 90 ° C. for 4 hours The reaction mixture is cooled, its pH is adjusted to 1.5 and extract the product in ethyl acetate The extraction phase with ethyl acetate is washed with water, then with saturated sodium chloride, dried over sodium sulfate and evaporated to give a The oil is redissolved in ethyl acetate and 60.

product is extracted into 1N 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, dried over anhydrous sodium sulfate and evaporated to dryness giving 308 mg of 1-oxo-1H-cycloheptenothiazolo acid - (. 3,2-a J-pyrimidine-2-carboxylic (Rf = 0.6 by chromatography on a thin layer of silica gel with, as eluent, chloroform supplemented with 1% ethanol).

The methodology of Examples 47 to 53 is used to convert the corresponding 1-oxo-1H-thiazolo - (. 3,2 ~ a J-pyrimidine-2-carboxylates of Example 31 into the following acids: 15 - acid 1 -oxo-1H-6-methyl-7-ethylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic, - acid 1-oxo-1H-6,7-diethylthiazolo- (3,2-aJ-pyrimidine-2 - carboxylic, - 1-oxo-1H-7-pentylthiazolo- [3,2-aJ-pyrimidine-2- 20 carboxylic acid, - 1-oxo-1H-6-ethyl-7-propylthiazolo- (3,2- aJ-pyrimidine-2-carboxylic acid, - l-oxo-IH-e ^ -diisopropylthiazolo - ^^ - aJ-pyrimidine-2-carboxylic acid,, 25 - acid 1-oxo-1H-6-propylthiazolo- [3,2 -aJ-pyrimidine-2-carboxylic, - 1-oxo-1H-6-isopropylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid, - 1-oxo-1H-6-pentylthiazolo- [3,2 -aJ-pyrimidine-2-carboxylic acid, - 1-oxo-1H-6-phenylcyclopentenothiazolo acid - (. 3,2-aJ- pyrimidine-2-carboxylic acid, - 1-oxo-1H-6,8-dimethylcyclohexenothiazolo- acid Î3,2-aJ- * pyrimidine-2-carboxylic, 35 - 1-oxo-1H-8-methylcyclooctenoth acid iazolo- [3,2-aJ-pyrimidine-2-carboxylic acid, and - 1-oxo-1H-6,8,8-trimethylcyclopentenothiazolo acid - (. 3,2-aJ-pyrimidine-2-carboxylic acid.

✓ 61.

t EXAMPLE 55

1-oxo-1H-7-methylthiazolo-t3,2-aJ-pyriroidine- 2-carboxylic acid

3.1 g of ethyl 1-oxo-1H-7-methylthiazolo-5 [3,2-aJ-pyrimidine-2-carboxylate is heated in a boiling water bath with 50 ml of 48% hydrobromic acid. Dissolution takes place in 5 minutes. After a heating period of about 15 minutes, the reaction mixture is cooled and the precipitated product is collected by filtration. By recrystallization from acetic acid, 1.4 g of purified 1-oxo-1H-7-methylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid, melting at 265 ° C. as it decomposes, are obtained. Analysis: C,% H,% N,% calculated for CgHgOg ^ S 45.71 2.88 13.33 15 found 45.57 3.04 13.40.

EXAMPLE 56

1-oxo-1H-thiazolo- [3,2-a J-pyrimidine-2-carboxylic acid

Heated for 20 minutes in a boiling water bath 7.5 g of ethyl 1-oxo-1H-thiazolo- [3,2-aJ-pyrimidine-2-carboxylate with 80 ml of 48% hydrobromic acid. Dissolution takes place in 5 minutes and 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 J-pyrimidine-2-carboxylic acid = purified are obtained, melting at 276 ° C. as they decompose.

Analysis: C,% H,% N,% calculated for C7H403N2S 42.86 2.06 14.28 30 found 42.71 2.21 14.32.

Alternatively, this acid can be prepared from the same intermediate compound by heating under reflux in an excess of 2N hydrochloric acid [Allen et al., J. Org. Chem., 24, 779 (1959) J.

62.

EXAMPLE 57

1-oxo-1H-6-methylthiazolo- (, 3,2-a) -pyrimidine-2-carboxylic acid 5.96 g of 1-oxo-1H-6-methylthiazolo-5 [3,2-aJ- ethyl pyrimidine-2-carboxylate in a boiling water bath for 1 hour with 60 ml of 48% hydrobromic acid. 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 in dimethylformamide, 3.73 g of 1-oxo-1H-6-methylthiazolo acid - (. 3,2-aJ-pyrimidine-2-carboxylic acid melting at 246-248 are obtained. ° C when decomposed Analysis: C,% H,% N,% calculated for CgHgO ^^ S 45.71 2.88 13.33 15 found 45.87 2.94 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).

20 EXAMPLE 58

1-oxo-1H-6-ethylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid 12.6 g of 1-oxo-1H-6-ethylthiazolo-25 (, 3,2-a J-) are heated ethyl pyrimidine-2-carboxylate in a boiling water bath with 125 ml of 48% hydrobromic acid Dissolution takes place in a few minutes After 10 minutes a solid substance begins to form. "for a total period of 40 minutes. The reaction mixture is cooled and 10.1 g of crude product are collected by filtration. By recrystallization of 2.32 g of crude product (taken from 6.8 g of product collected in an attempt to recrystallize from acetic acid) in isopropyl alcohol, 1.85 g of 1-oxo-1H-6-ethyl-35 thiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid are obtained purified melting at 162-163 ° C.

Analysis: C,% H,% N,% calculated for CgHgO ^ S 48.21 3.60 12.49 found 48.17 3.73 12.42.

63.

EXAMPLE 59

1-OXO-1H-7- (2-methyl-2-propyl) -thiazolo-13,2-aJ-pyrimidine-2-carboxylic acid

Heated in a boiling water bath for 5 6 hours 5.6 g of 1-oxo-1H-7- (2-methyl-2-propyl) -thiazolo- [3,2-aJ-pyrimidine-2-carboxylate ethyl with 60 ml of 48% hydrobromic acid. After a period of about 10 minutes, before the ester has 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-1H-7- (2-methyl-2-propyl) -thiazolo- [3,2-a J- pyrimidine-2- acid is obtained. purified carboxylic [3.33 g, melting point, 15 241-242 ° C (decomposition) J.

Analysis: C,% H,% N,% calculated for C, | 52.37 4.79 11.10 found 52.45 4.82 11.26.

20 EXAMPLE 60

1-oxo-1H-7-ethylthiazolo- [3,2-a l-pyr imidine- 2-carboxylic acid

1.5 g of ethyl 1-oxo-1H-7-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxylate are heated in a water bath

25 boiling with 15 ml of 48% hydrobromic acid for 20 minutes. Dissolution takes place in 5 minutes and, after 10 minutes *, a solid substance begins to precipitate. AT

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 1N potassium carbonate and reprecipitation by acidification with 3N hydrochloric acid.

By recrystallization from acetic acid, purified 1-oxo-1H-7-ethylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid (594 mg, melting point 206-209 ° C) is obtained. . Analysis: C »% H,% N,% calculated for CgHgN ^ S 48.21 3.60 12.49 found 48.01 3.69 12.50.

64.

EXAMPLE 61

1-oxo-1H-7-isopropylthiazolo- (3,2-aJ-pyrimidine-2-carboxylic acid 909 mg of 1-oxo-1H-7-isopropyl-5 thiazolo- [3,2-aJ-pyrimidine-) are heated Ethyl 2-carboxylate in a boiling water bath with 10 ml of 48% hydrobromic acid for 20 minutes, the solution is completely dissolved in 5 minutes, the product begins to precipitate after 10 minutes. , the reaction mixture is allowed to cool to room temperature and the crude product is collected> by filtration. By recrystallization from ethanol, 1-oxo-1H-7-isopropylthiazolo- [3,2 -aJ-pyrimidine-2-carboxylic purified (538 mg, melting point 216-217 ° C).

15 EXAMPLE 62

1-oxo-1H-7-phenylcyclohexenothiazolo- (3,2-a I-pyrimidine-2-carboxylic) 9.8 g of 1-oxo-1H-7-phenylcyclohexeno-20 thiazolo- (3,2-aJ) are heated -pyrimidine-2-ethyl carboxylate at reflux with 200 ml of 48% hydrobromic acid for 20 minutes, dissolution takes place after approximately 10 minutes, the reaction mixture is cooled and the crude product is collected by filtration By recrystallization from acetic acid, 2.25 g of purified 1-oxo-1H-7-phenylcyclo-hexenothiazolo- [3,2-a J-pyrimidine-2-carboxylic acid * melting at 224- are obtained. 226uC.

Analysis: C,% H, _% N,% calculated for 62.56 4.32 8.58 30 found 62.26 4.11 8.52.

A second harvest is obtained from the mother liquor (704 mg, melting point 217-220UC).

EXAMPLE 63 35 1-oxo-1H-7-methylcyclohexenothiazolo- [3,2-a J-pyrimidine-2-carboxylic acid 27.5 g of 1-oxo-1H-7- are heated in a boiling water bath for 35 minutes methylcyclohexenothiazolo- 65.

(3,2-αJ-pyrimidine-2-ethyl carboxylate with 275 ml of 48% hydrobromic acid. After 10 minutes, a clear solution is obtained; precipitation of the product begins after 15 minutes. the reaction mixture is allowed to cool to room temperature and the crude product is collected (14.9 g, melting point 181.5-183.5 ° C) by filtration, with washing with water. By recrystallization from dimethylformamide , 1-oxo-1H-7-methylcyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid, purified (10.1 g, melting point 10 183.5-185.5 ° C), is obtained.

Analysis: C,% H,% N,% calculated for C12H12N2 ° 3S 54.53 4.58 10.60 found 54.41 4.28 10.58.

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

EXAMPLE 64

1-oxo-1H-7,7-dimethylcyclohexenothiazolo- (3,2-a J-20 pyrimidine-2-carboxylicrue) acid

7.9 g of ethyl 1-oxo-1H-7,7-dimethylcyclo-hexenothiazolo- [3,2-aJ-pyrimidine-2-carboxylate are mixed with 80 ml of 48% hydrobromic acid and the mixture is heated. mix in a boiling water bath for 50 minutes. Before the dissolution of the ester is complete, the acid begins to precipitate. The reaction mixture is cooled, diluted with about 100 ml of water and 6.7 g of crude product are collected by filtration and washed with a small volume of water. By recrystallization of the crude product from ethanol, purified 1-30 oxo-1H-7,7-dimethylcyclohexenothiazolo - (. 3,2-a J-pyr imidine-2-carboxylic acid (4,7) is obtained. g, melting point 197-198 ° C).

Analysis: C,% H,% N,% calculated for C13H14N203S 56.10 5.07 10.06 found 55.85 4.84 10.14.

66.

EXAMPLE 65

Acid 1-OXO-1H-7- (2-butyl) -thiazolo- [3,2-aJ-pyrimidine-2-carboxylicrue 2.0 g of 1-oxo-1H-7- (2-butyl) are mixed - 5 ethyl thiazolo- (3,2-aJ-pyrimidine-2-carboxylate with 20 ml of 48% hydrobromic acid and the mixture is heated in a boiling water bath for 25 minutes. Dissolution takes place 1 "· after 5 minutes precipitation of the product begins after 10 minutes, the reaction mixture is allowed to cool to room temperature, diluted with about 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, the acid 1- is obtained. oxo-1H-7- (2-butyl) -thiazolo - (. 3,2-a J-pyr imidine-2-carboxylic purified (606 mg, melting point 194-197 ° C). Analysis: C,% H ,% N,% calculated for 52.37 4.79 11.10 found 52.20 4.48 11.11.

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

EXAMPLE 66 N- (5-tetrazolyl) -1-oxo-1H-6,7-dimethylthiazolo- [3,2-a J-pyrimidine-2-carboxamide 367 mg (1.6 mmol) of acid are dissolved -oxo-1H- 6,7-dimethylthiazolo- (3,2-a J-pyrimidine-2-carboxylic in 3 ml of dimethylformamide while heating in a boiling water bath. 292 mg (1.8 mmol) of 1 , 1-carbonyldi-imidazole. Immediate gas evolution is observed. As soon as gas evolution ceases, 153 mg (1.8 mmol) of 5-aminotetrazole is added. Dissolution takes place and the solid forms. The reaction mixture is cooled and the crude product is collected by filtration and recrystallization of the crude product from dimethylformamide gives 336 mg of N- (5-tetrazolyl) -1-oxo-1H-6,7-dimethyl. - thiazolo - (. 3,2-aJ-pyrimidine-2-carboxamide purified melting above 317 ° C.

67.

Analysis: C,% H,% N,% calculated for cioH9 ° 2N7S 41.23 3.11 33.66 found 41.52 3.40 33.47.

EXAMPLE 67 N- (5-tetrazolyl) -1-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-aJ-pyrimidine-2-carboxamide 238 mg (1.0 mmol) of acid are dissolved 1-oxo-1H-6-methyl-7-ethylthiazolo - (. 3,2-aJ-pyrimidine-2-carboxylic in 10 5 ml of dimethylformamide and the solution is heated in a boiling water bath. 178 mg is added (1 , 1 mmol) of 1,1'-carbonyldiimidazole. When the gas evolution has ceased, add 93.5 mg (1.1 mmol) of 5-aminotetrazole. A solid substance begins to precipitate after about 15 minutes The reaction mixture is cooled and filtered to give 227 mg of N- (5-tetrazolyl) -1-oxo-1H-6-methyl-7-ethylthiazolo- [3,2-aJ-pyrimidine-2-carboxamide fondant - above 310 ° C.

Analysis: C,% H,% N,% calculated for C ^ H ^ 02NyS 43.27 3.63 32.11 20 found 43.20 3.72 31.88.

EXAMPLE 68 N- (5-tetrazolyl) -1-oxo- 1H: -6-ethyl-7-methylthiazolo- (3,2-a J-pyrimidine-2-carboxamide) 476 mg (2.0 mmol) is dissolved 1-oxo-1h- 6-ethyl-7-methylthiazolo- (3,2-a J-pyrimidine-2-carboxylic acid ~ in dimethylformamide in a boiling water bath. 357 mg (2.2 mmol) of 1,1-dicarbonylimidazole to the hot solution; evolution of gas takes place. When the evolution of gas has ceased, 187 mg (2.2 mmol) of 5-aminotetrazole is added. Within 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 N- (5-35 tetrazolyl) -1-oxo-1H-6-ethyl-7-methylthiazolo are obtained. - (. 3,2-a J-pyrimidine-2-carboxamide purified melting at 303 ° C while decomposing.

Analysis: C,% H,% N,% calculated for C, j, jH.j43.3 3.6 32.1 found 43.6 3.9 32.3.

68.

EXAMPLE 69 N- (5-tetrazolyl) -1-oxo-1H-6,7-diethylthiazolo- (3,2-a) -pyrimidine-2-carboxamide 2.52 g (10 immoles) of acid 1- oxo-1H-5 6,7-diethylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid and 1.78 g (11 mmol) of 1,1'-carbonyldiimidazole with 15 ml of dimethylformamide and heated in a bath- marie boiling. There is a release of gas and a dissolution. When the evolution of gas has ceased, 1.13 g (11 mmol) of 10 5-aminotetrazole are added and the heating is continued for 30 minutes. 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-tetrazolyl) -1-oxo-1H-6,7-diethyl-15 thiazolo- [3,2-aJ-pyrimidine- are obtained. Purified 2-carboxamide melting at 283 ° C while decomposing.

Analysis: C,% H,% N,% calculated for C12H1302N7S 45.13 4.10 30.70 mass ion: 319 20 found 45.18 4.24 30.52 mass ion: 319 EXAMPLE 70 N- (5 -tetrazolyl) -1-oxo-1H-cyclopentenothiazolo-25 [3,2-a J-pyrimidine-2-carboxamide

378 mg (16 mmol) of 1-oxo-1H- "cyclopentenothiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid and 285 mg (17.6 mmol) of 1,1'-carbonyldiimidazole are mixed with 3 ml of dimethylformamide and the mixture is heated in a boiling water bath, dissolution and evolution of gas is observed, when the evolution of gas is stopped, 150 mg (17.6 mmol) of 5-aminotetrazole are added; in a few minutes the product begins to precipitate, the reaction mixture is cooled and the crude product is collected by filtration 35. By recrystallization from dimethylformamide, 313 mg of N- (5-tetrazolyl) -1-oxo-1H are obtained. -cyclopentenothiazolo- [3,2-aJ-pyrimidine-2-carboxamide purified melting above 310 ° C.

69.

Analysis: C,% Hf% N,% calculated for C ^ HgO ^ S 43.6 3.0 32.3 found 43.6 3.3 32.0.

EXAMPLE 71 N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo- (3,2-aJ-pyr imidine-2-carboxamide 0.5 g (2 mmol) of 1-oxo-1H acid is dissolved -cyclohexenothiazolo- [3,2 ~ aJ-pyrimidine-2-carboxylic acid and 0.36 g (2.2 mmol) of 1,1'-carbonyldiimidazole in 3 ml of dimethylformamide at room temperature; dissolution is observed and gas evolution. When the gas evolution has ceased, the reaction mixture is heated in a boiling water bath, during which time a new gas evolution is noted. 0.19 g (2, 2 mmol) of 5-aminotetrazole. 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, N- (5-tetra-20 zolyl is obtained ) -1-oxo-1H-cyclohexenothiazolo - (. 3,2-aJ-pyrimidine-2-carbox- purified amide (.319 mg, melting point 310 ° C (decomposition) J. Analysis: C,% H,% N,% calculated for 45.42 3.49 30.90 found 45 , 59 3.62 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 minutes while maintaining the temperature of the reaction mixture between 0 and 5 ° C. After maintaining the temperature at 0-5 ° C for 45 minutes, 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 minutes, then keep it at this temperature for 90 minutes. The product is collected by filtration (2.0 g, melting point 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) -1-oxo- iH-cyclohexenothiazolo- (.3,2-a J -pyr purified imidine-2-carboxamide melting at 314-315ÜC.

70.

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 minutes (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 hours 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 hour to 5 ° C and granulated at this temperature for 1 hour. The sodium salt (1.68 g) is collected by filtration. The pH of 100 mg of recrystallized sodium salt in 1 ml of water is equal to 8.80.

Analysis: H ^ O Weight loss Equivalent to „„ „, after drying neutralization

Calculates for - C12H10 ° 2N7SNa * 3H2 ° 13.7 13i7 393 20 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, 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 Examples 47 to 65 are reacted with chloroformates, then with 5-aminotetrazole to give the corresponding N- (5-tetrazolyl) -amides.

EXAMPLE 72 35 N- (5-tetrazolyl) -1-oxo-1H-cycloheptenothiazolo- (3,2-a 1-pyrimidine-2-carboxamide) 2.1 g (8 mmol) of 1-oxo-1H acid are mixed -cyclopentenothiazolo - (. 3,2-a J-pyrimidine-2-carboxylic and 1.4 g (8.8 mmol) of 1,1-carbonyldiimidazole with 15 ml of 71.

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 minutes. After an additional 30 minutes of heating, 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) -1-oxo-1H-cycloheptenothiazolo- [3,2-aJ-pyrimidine-2-carboxamide 10) are obtained, melting at 295-296 ° C when decomposing.

Analysis: C,% H,% N,% calculated for C ^ H ^ C ^ NyS 47.12 3.95 29.59 found 47.10 4.11 29.72.

EXAMPLE 73 N- (5-tetrazolyl) -1-oxo-1H-cyclooctenothiazolo-33,2-a J-pyrimidine-2-carboxamide 308 mg (1.1 mmol) of 1-oxo-1H- acid is dissolved cyclooctenothiazolo- [3,2-a J-pyrimidine-2-carboxylic acid in 10 ml of dimethylformamide and the solution is heated in a boiling water bath. 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 minutes, during which time a solid substance begins to precipitate. The reaction mixture is cooled and the crude product is collected by filtration. Recrystallization from dimethyl formamide gives 183 mg of purified N- (5-tetrazolyl) -1-oxo-1H-cyclooctenothiazolo- [3,2-aJ-pyrimidine-2-carboxamide melting at 310 ° C. while decomposing .

Analysis: C,% H,% N,%

calculated for C 14H15 ° 2N7S

48.69 4.38 28.39 found 49.01 4.63 27.35 35 * 72.

EXAMPLE 74 N- (5-tetrazolyl) -1-oxo-1H-7-methylthiazolo- [3,2-aj-pyrimidine-2-carboxamide 0.91 g (4.3 immoles) of 1-oxo acid is added -1H-7-5 methylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid and 0.89 g (5.5 mmol) of 1,1'-carbonyldiimidazole to 5 ml of dimethyl-v formamide and the mixture is heated mix 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 N- (5-tetrazolyl) -1-oxo-1H-7-15 methylthiazolo - (, 3,2-a J-pyrimidine-2-carboxamide fondant is obtained. above 310 ° C.

Analysis: C,% H,% N,% calculated for CgH ^ C ^ NyS 38.99 2.54 35.36 found 38.97 2.73 34.97.

EXAMPLE 75 N- (5-tetrazolyl) -1-oxo-1H-thiazolo- [3,2-a J-pyrimidine-2-carboxamide 1.96 g (10 mmol) of 1-oxo-1H acid are dissolved -25 thiazolo- (3,2-aJ-pyrimidine-2-carboxylic acid in 20 ml of dimethylformamide in a boiling water bath. 1.78 g (11.0 mmol) of 1,1'-carbonyldiimidazole are added. When the release takes place gas stopped, 1.13 g (11 mmol) of 5-aminotetrazole monohydrate was added, a solid formed in less than 1 minute, after heating for a further 15 minutes, the reaction mixture was cooled and the crude product by filtration. By recrystallization from dimethylformamide, 1.8 g of purified N- (5-tetrazolyl) -1-oxo-1H-thiazolo- [3,2-aJ-pyrimidine-2-carboxamide melting at- 35 above 315 ° C.

Analysis: C>% H,% N,% calculated for CgHt-C ^ N ^ S 36.50 1.91 37.25 found 36.62 2.26 37.72.

73.

EXAMPLE 76 N- (5-tetrazolyl) -1-oxo-1H-6-methylthiazolo- [3,2-a J-pyrimidine-2-carboxamide 2.10 g (10 mmol) of 1-oxo- acid are mixed 1H-6-5 methylthiazolo- [3,2-aJ-pyrimidine-2-carboxylic and 1.78 g (11 mmol) of 1,1 '-carbonyldiimidazole with 15 ml of dime-thylformamide and the mixture is heated in the bath- marie boiling. 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 minute. After heating for 5 minutes, the reaction mixture is cooled. 2.33 g of N- (5-tetrazolyl) -1-oxo-1H-6-methylthiazolo - (, 3,2-a J-pyr imidine-2-carboxamide 15, melting above 318 °, are obtained by filtration. vs.

Analysis: C,% H,% N,% calculated for C ^ H ^ 02N ^ S 38.99 2.54 35.36 found 39.35 3.00 35.06.

EXAMPLE 77 N- (5-tetrazolyl) -1-oxo-1H-6-ethylthiazolo- [3,2-a) -pyr imidine-2-carboxamide 4.48 g (20 mmol) of acid 1- oxo-1H-6-ethylthiazolo - (. 3,2-a J-pyr imidine-2-carboxylic and 3.57 g 25 (22 mmol) of 1,1'-carbonyldiimidazole with 20 ml of dimethylformamide and heated mixing in a boiling water bath w Gas evolution is noted and dissolution takes place When the gas evolution has ceased, 2.27 g (22 mmol) of 5-aminotetrazole monohydrate is added. The reaction mixture is heated for a further 15 minutes, cooled and the crude product is collected by filtration, and by recrystallization from dimethylformamide, 4.7 g of N- (5-tetrazolyl) -1- are obtained. oxo-1H-6-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxamide 35 melting at 274 ° C as it decomposes.

Analysis: C,% H,% N,% calculated for 0 ^ 11 ^ 02 ^ 3 41.23 3.11 33.66 found 41.41 3.30 33.84.

74.

EXAMPLE 78 N- (5-tetrazolyl) -1-oxo-1H-7- (2-methyl-2-propyl) -thiazolo- [3,2-aJ-pyrimidine-2-carboxamide 2.52 g (10 mmol) of 1-oxo-1H-7-5 (2-methyl-2 “propyl) -thiazolo-1,3,2-aJ-pyrimidine-2-carboxylic acid and 1.78 g (11 mmol) of 1 , 1'-carbonyldiimidazole with 15 ml of dimethylformamide and heating in a boiling water bath. Is there a release of gas and dissolution takes place? solid matter is formed in a few minutes. Heating is continued for a total period of about 10 minutes. 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-1H-7- (2-methyl-2-propyl) -thiazolo- (3,2-a J-pyrimidine) are obtained. -2-purified carboxamide 15 melting at 280 ° C while decomposing.

Analysis i C,% H,% N,% calculated for C- | 2H13 ° 2N7S 45.13 4.10 30.70 found - 45.22 4.40 30.05.

EXAMPLE 79 N- (5-tetrazolyl) -1-oxo-1H-7-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxamide, 502.5 mg (2.24 mmol) of acid are mixed 1-oxo-1H-7-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxylic and 399.7 mg (2.46 mmol) of 1,1 '-carbonyldiimidazole with 3 ml of dimethylformamide and heated the mixture 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. A clear solution is thus obtained; after 2 minutes, a solid substance begins to precipitate. The mixture is heated for a further 20 minutes, allowed to cool to room temperature and the crude product is collected by filtration. By recrystallization from dimethylformamide, 486.8 mg of N- (5-35 tetrazolyl) -1-oxo-1H-7-ethylthiazolo- [3,2-a J-pyrimidine-2-carboxamide) are obtained. purified melting at 261-262 ° C while decomposing.

75.

Analysis: C,% H,% N,% calculated for C ^ HgN ^ S 41.23 3.11 33.66 mass ion: 291 found 41.35 3.31 33.55 5 mass ion: 291.

EXAMPLE 80 N- (5-tetrazolyl) -1-oxo-1H-7-isopropylthiazolo-1 3,2-a J-pyrimidine-2-carboxamide 10 537 mg (2.25 mmol) of 1-oxo acid are mixed -lH- 7-isopropylthiazolo- [3,2-a J-pyr imidine-2-carboxylic acid and 401 mg (2.47 mmol) of 1,1'-carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated in the bath- marie boiling. 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 minutes, then the reaction mixture is cooled and. collects the crude product by filtration. By recrystallization from dimethylformamide, 328 mg of N- (5-tetrazolyl) -1-oxo-1H-7-isopropylthiazolo- [3,2-a J-pyr imidine-2-carboxamide melting agent are obtained. above 300 ° C.

Analysis: C,% H,% N,% calculated for C.j, jH.j-jC ^ N ^ S 43.27 3.63 32.11 25 found 43.34 3.76 31.82.

EXAMPLE 81 N- (5-tetrazolyl) -1-oxo-1H-7-phenylcyclohexenothiazolo- (3,2-a J-pyrimidine-2-carboxamide) 980 mg (3.0 mmol) of 1-oxo acid are mixed -1H- 7-phenylcyclohexenothiazolo - (. 3,2-a J-pyr imidine-2-carboxylic and 320 mg (3.1 mmol) of 1,1'-carbonyldiimidazole with 12 ml of dimethylformamide and the mixture is heated in the bath When the gas evolution has ceased, 35,496 mg (3.1 mmol) of 5-aminotetrazole monohydrate is added and after 10 minutes the product begins to precipitate, after a total heating period of 1 hour, the reaction mixture is allowed to cool to room temperature and 76 is collected.

by filtration 312 mg of crude product. By recrystallization from dimethylformamidef, 131.5 mg of N- (5-tetrazolyl) -1-oxo-1H-7-phenylcyclohexenothiazolo- (3,2-a J-pyr i-midine-2-carboxamide) are obtained, melting with- above 300 ° C.

5 Analysis: C,% H,% N,% calculated for C ^ gH-dd ^ NyS 54.95 3.84 24.92 found 54.38 3.93 24.61.

EXAMPLE 82 10 N- (5-tetrazolyl) -1-oxo-1H-7-methylcyclohexenothiazolo- [3,2-a J-pyrimidine-2-carboxamide 1.0 g (3.78 mmol) of acid is mixed -oxo-1H- 7-methylcyclohexenothiazolo- (3,2-a J-pyrimidine-2-carboxylic acid and 675 mg (4.16 mmol) of 1,1'-carbonyldiimidazole in 6 ml of dimethylformamide and the mixture heated Boiling water bath. A gas is given off and dissolution takes place. When the gas evolution has ceased, 429 mg (4.16 mmol) of 5-aminotetrazole is added and the heating is continued. After a few minutes, a The precipitate begins to form. After 30 minutes, 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- are obtained. (5-tetrazolyl) -1-oxo-1H-7-methylcyclo-hexenothiazolo- (3,2-a J-purified pyrimidine-2-carboxamide-2 melting above 300 ° C.

Analysis: C,% H,% N,% calculated for C ^ H ^ C ^ NyS 47.12 3.95 29.59 found 47.32 4.18 29.60.

EXAMPLE 83 N- (5-tetrazolyl) -1-ΟΧΟ-1Η-7,7-dimethylcyclohexenothiazolo- 13,2-a) -pyrimidine-2-carboxamide 558 mg (2.0 mmol) of acid are mixed 1- oxo-1H-'7,7-dimethylcyclohexenothiazolo- (.3,2-a J-pyr imidine-2-carboxy 1 ique 35 and 357 mg (2.2 mmol) of 1,1'-carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated in a boiling water bath, a gas is evolved and dissolution takes place. When the gas evolution has ceased, 227 mg (2.2 mmol) of 77 are added.

5-aminotetrazole monohydrate and the heating is continued for 20 minutes. 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) -1-oxo-1H-7,7-dimethylthiazolo- (.3.2-a J-pyr imidine-2-carboxamide (469 mg) are obtained. mg, melting point above 300 ° C).

Analysis: C,% H,% N,% calculated for C ^ H-ji ^ N ^ S 48.69 4.38 28.39 10 found 48.80 4.18 28.42.

EXAMPLE 84 N- (5-tetrazolyl) -1-OXO-1H-7- (2-butyl) -thiazolo- [3,2-a J-pyrimidine-2-carboxamide 15 379 mg (1.5 mmol) is mixed 1-oxo-1H- 7- (2-butyl) -thiazolo - (. 3,2-a J-pyrimidine-2-carboxylic acid and 270 mg (1.66 mmol) 1,1'-carbonyldiimidazole in 3 ml of dimethylformamide and heated in a boiling water bath. A gas is evolved and dissolution occurs. When the gas evolution 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 minutes, the reaction mixture is allowed to cool to ambient temperature and the crude product is collected by filtration. 247 mg of N- (5) are obtained by recrystallization - tetrazolyl) -1-OXO-1H-7- (2-butyl) -thiazolo- [3,2-a J-pyrimidine-2 - *> purified carboxamide melting above 300 ° C.

Analysis: C,% H,% N,% calculated for C12H1302N7S 45.13 4.10 30.70 30 found 45.12 4.05 30.68.

EXAMPLE 85

Following the procedure of examples 66 to 84, the following compounds are prepared from the corresponding 1-35 oxo-1H-thiazolo- (3,2-a J-pyrimidine-2-carboxylic acids): - N- (5- tetrazolyl) -1-oxo-1H-7-pentylthiazolo- [3,2-aJ-pyrimidine-2-carboxamide, 78.

* - N- (5-tetrazolyl) -1-oxo-1H-6-ethyl-7-propylthiazolo - (. 3,2-aJ-pyrimidine-2-carboxamide, - N- (5-tetrazolyl) -1-oxo -lH-6,7-diisopropylthiazolo- (3,2-aJ-pyr imid ine-2-carboxamide, - N- (5-tetrazolyl) -1-oxo-1H-6-propylthiazolo- [3,2-a J -5 pyrimidine-2-carboxamide, - N- (5-tetrazolyl) -1-oxo-1H-6-isopropylthiazolo- [3,2-aJ-pyrimidine-2-carboxamide, - N- (5-tetrazolyl) -1 -oxo-1H-6-pentylthiazolo - (. 3,2-aJ-pyrimidine-2-carboxamide, 10 - N- (5-tetrazolyl) -1-oxo-1H-6-pherylcyclopentenothiazolo- [3,2-a J -pyr imidine-2-carboxamide, - N- (5-tetrazolyl) -1-oxo-1H-6,8-dimethylcyclohexenothiazolo- (3,2-a J-pyrimidine-2-carboxamide, - N- (5-tetrazolyl ) -1-oxo-1H-8-methylcyclooctenothiazolo- (3,2-aJ-pyrimidine-2-carboxamide, and - N- (5-tetrazolyl) -1-oxo-1H-6,8,8-trimethylcyclopentenomethyl- thiazolo- [3,2-a J-pyrimidine-2-carboxamide.

EXAMPLE 86 20 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 25 - Magnesium trisilicate, U.S.P. 5.2k - Lactose, U.S.P. 5.2 - Potato starch 5.2 - Magnesium stearate A 0.8 - Magnesium stearate B 0.35 30 and by adding a sufficient amount of N- (5-tetrazolyl) -1-oxo- trihydrate iH-cyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxamide sodium to form capsules containing 10, 25 and 50 mg of active ingredient (weights equivalent to the unsolvated unsolvated form) per capsule. The compositions can be loaded into conventional hard gelatin capsules in the amount of 350 mg per capsule.

Capsules containing 2.0 mg and 6.0 mg of active ingredient and containing 300 mg are prepared in the same manner. These following mixtures per capsule: 79.

‘Ingredients Weight in mq per capsule - Drug 2.00 - N-methylglucamine 18.00 - Lactose anhydrous 251.20 5 - Starch corn anhydrous 8.80

Ingredients Weight in mq per capsule - Medicine 6.00 - N-methylglucamine 18.00 - Lactose anhydrous 237.20 10 - Corn starch anhydrous 30.00 - Talc 8.80 EXAMPLE 87

Tablets A tablet base is prepared by mixing the following ingredients in the proportions indicated by weight: - - Sucrose, U.S.P. 80.3 - Cassava starch 13.2 20 - Magnesium stearate 6.5

A sufficient quantity of N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo trihydrate - (> 3,2-a J-pyrimidine-2-sodium carboxamide L · is incorporated into this base for tablets. tablets each containing 20, 100 and 250 mg of active ingredient Each of the compositions is transformed into tablets by known means. To obtain tablets of lower potency (for example 1 mg, 2 mg, 5 mg), a lower ratio of the active ingredient to the inert ingredients in the base tablet mix.

EXAMPLE 88

Solution

A solution of N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo - (> 3,2-a J-pyrimidine-2-carboxamide 35 containing the following ingredients is prepared containing the following ingredients; - Active ingredient 6.04 g ( 7.49 g of sodium salt trihydrate) - Magnesium chloride hexahydrate 12.36 g - Propylene glycol 376.00 g - Distilled water 103 ml 80.

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

5 EXAMPLE 89

Aerosol suspension *

For a particular application as an anti-allergic agent, a mixture of N- (5-tetrazolyl) -1-oxo-1H-10 cyclohexenothiazolo- [3,2-aJ-pyrimidine-2-carboxamide sodium and the other ingredients indicated in (a) on the following tables is micronized into particles of 1 to 5 μι 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 Percent (a) Anti-allergic agent (equivalent to 20 unsolated non-salt) 0.25

Isopropyl myristate 0.10

Ethanol 26.40 (b) Mixture of 60% 1,2-dichlorotetrafluoroethane and 40% 1-chloropentafluoroethane 73.25

25 Suspension B

(a) Anti-allergic agent (equivalent to ** · non-solvated non-salt) 0.25

Ethanol 26.50 (b) Mixture of 60% 1,2-dichlorotetrafluoroethane and 40% 1-chloropentafluoroethane 73.25

Suspension C

(a) Anti-allergic agent (equivalent to non-solvated non-salt) 2.00

Ethanol 26.50 35 (b) Mixture of 60% 1,2-dichlorotetrafluoroethane and 40% 1-chloropentafluoroethane 77.50

Claims (14)

81. te I CLAIMS 1. A compound of formula; 5 R -, .__ c r ~! \ R, '': ..U 'f l 10 0 Q in which R-, 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; R. | and R2 taken separately represent each hydrogen or an alkyl group having 1 to 5 carbon atoms; and Q is a group of formula: oc, N N \ - "- <i | Ί H NN N i H 30 or of formula ORg in which Rg is hydrogen, a lower alkyl group having 1 to 3 carbon atoms, a carbalkoxy group having 2 to 5 carbon atoms, a carbophenoxy group or a group carbobenzoxy; provided that when Rg is hydrogen or a lower alkyl group and R2 is hydrogen, Rj represents i "82. something other than hydrogen or a methyl group and that when R3 is a lower alkyl group and R2 a methyl group, R> | represents something other than hydrogen; or a pharmaceutically acceptable cationic salt of this compound when Q is a group of the formula:, N-N! Ί- ('1 K? —N, K or of the formula OR3 in which R3 is hydrogen. 2. Compound according to claim 1, character-ized in that Q corresponds to the formula: N - N ~ r {Ί j 20 H -N j H. 1 2 3 4 5 - Compound according to Claim 2, character-25 rised in that R- | and R2 are considered together and represent a butylene group. 2 - Compound according to Claim 2, characterized in that R- | and R2 are considered separately, R ^ is a hydrogen atom and R2 is a methyl group. 5. - Compound according to claim 2, character 3 rised in that R-j and R2 are considered separately, R ^ is an ethyl group and R2 is a hydrogen atom. 4 - Compound according to claim 2, characterized in that R <and R2 are considered separately, R1 is a methyl group and R2 is hydrogen. 5 - Compound according to claim 1, characterized in that Q is an OR3 group in which R3 is hydrogen. 83. " 8. A compound according to claim 7, characterized in that R-j and R2 are considered separately, R ^ is an ethyl group and R2 is hydrogen. 9. Compound according to claim 1, character-ized in that Q is a group OR ^ in which R3 is a lower alkyl radical having 1 to 3 carbon atoms. 10. Compound, characterized in that it corresponds to the formula; 10 * 1 -— s 0 I! DD ^ CH! R30C-C / CORi II 30 wherein r'3 is a lower alkyl group having 1 to 3 carbon atoms; R <1 and R2 taken together represent an alkylene group having 3 to 9 carbon atoms or a phenyl- * alkylene group having 9 to 11 carbon atoms; and r ^ and R2 taken separately each represents a hydrogen atom or a lower alkyl group having 1; with 5 carbon atoms, provided that when R ^ is hydrogen, R2 is something other than hydrogen or a methyl group and that when R ^ is methyl, R2 is something other than hydrogen. 11. Medicament, characterized in that it is constituted by or in that it contains a compound according to any one of claims 1 to 9.