FR2470132A1 - 1-OXO-1H-THIAZOLO- (3,2-A) -PYRIMIDINE-2-CARBOXAMIDES, ANTI-ALLERGIC AND ANTI-ULCEREUX, MEDICAMENT CONTAINING THEM AND INTERMEDIARY COMPOUNDS FOR OBTAINING THEM - Google Patents

Abstract

THE INVENTION RELATES TO THE FIELD OF THE CHEMISTRY OF DRUGS. IT CONCERNS IN PARTICULAR 1-OXO-1H-THIAZOLO- (3,2-A) -PYRIMIDINE-2-CARBOXAMIDES OF FORMULA: (CF DRAWING IN BOPI) IN WHICH R AND R REPRESENT H OR A LOWER OR FORM TOGETHER ALKYL GROUP, UNDER CERTAIN CONDITIONS, AN ALKYLENE GROUP IN CAC OR PHENYLALKYLENE IN CAC; INTERMEDIATE COMPOUNDS TO OBTAIN THEM; AS WELL AS THEIR PRODUCTION PROCESS. THE COMPOUNDS OF THE INVENTION HAVE ANTI-ALLERGIC AND ANTI-ULCEROUS ACTIVITY.

Description

1. The present invention relates to derivatives

  of 1-oxo-1H-thiazolo-13,2-a-pyrimidine-2-carboxyl

  amides and the acids constituting their precursors. These amides and, in many cases, the acids that make up their precursors, are useful for preventing the release of allergic mediators (histamine, serotonin, anaphylaxis slow reacting substance (SRS-A), etc.) and they can be used to treat bronchial asthma, hay fever, rhinitis, atopic dermatitis, etc., and they are

  also useful as anti-ulcer agents.

  Allergic reactions, symptoms resulting from an antigen-antibody interaction, occur in many different 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 asthma

  bronchial, one of the most common allergic reactions

  the most debilitating diseases, which is a characteristic disease

  risk of bronchial hyperreactivity by exposure to various immunogenic or non-immunogenic stimuli,

  manifesting with bronchospasm accompanied by a whistle

  short paroxysms and extensive constriction of the airways. Mechanical obstruction of the passage of air through the airways is usually suppressed by means of bronchodilators

  symptomatic relief. On the contrary, anti-

  allergies prevent the release of mediators from the anaphylaxis.

  laxity of the tissue stores, thereby acting in a prophylactic manner to inhibit the onset of

  bronchoconstriction by the mediators.

  Cox et al., Adv. in Drug Res., 5, 115 (1970) describe the pharmacology of disodium cromoglycate

  (1,3-bis- (2-carboxycromon-5-yloxy) -2-hydroxypropane IntalJ.

  It's not a bronchodilator, but a substance that

  manifest its therapeutic effects by inhibition of

  2. ration of mediators of anaphylaxis and is administered prophylactically. He suffers from a lack of efficiency

  and, for the best results, it should be administered

  inhaled in the form of a solid substance.

  Various other antiallergic agents have been

  described more recently; it is N- (5-tetrazolyl) -1-oxo

  1H-6-alkoxypyrimido- (1,2-a-quinoline-2-carboxamides (patent

  United States of America No. 4,017,625), 1-oxy-1H-6- acids

  (substituted pyrimido) - [1,2-a] quinolinec-2-carboxylic

  (U.S. Patent No. 4,066,766), tetra-

  zolo-LaJ-quinazol-5-ones (US Pat. No. 4,085,213), pyrimido- (2,1-alpha-isoquinolines (US Pat.

  United States of America No. 4,127,720) and N- (5-tetrazoyl) -4-

  oxo-4H-pyrimido-L2,1-bj-benzothiazole-3-carboxamides Ibrevet

  United States of America No. 4,041,163).

  Chronic ulcers of the stomach and duodenum, referred to as the collective expression of 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 dietary and medical (drug) treatment to surgery. A wide variety of drugs have been used to treat ulcers; the newest of these drugs that deserves a

  special attention is the sodium salt of carbony

  xolone, which is the disodium salt of glycyrrhetinic acid hemisuccinate. It has a reputation for preventing the formation and accelerating healing of gastric ulcers in animals as well as humans ("Carbenoxolone Sodium: A Symposium", JM Robson and FM Sullivan, Eds., Butterworths, London, 1968 ). However, its use is accompanied by undesirable side effects resembling those of aldosterone, for example a clear antidiuretic and sodium retention activity and often a loss of potassium, so that further treatment with this agent often leads to high blood pressure, muscle weakness and, ultimately, congestive heart failure. More recently, a histamine receptor antagonist, cimetidine, has been introduced in medical practice. This last compound attenuates the ulcers by

  reducing the secretion of acid from the stomach.

  It has been reported the anti-ulcer activity of various

  other compounds comprising 1-oxo-1H-6-piperidino-1-esters

  pyrimidino- (1,2-a-quinolinec-2-carboxylic

  United States of America No. 4,014,881), 1-oxo-1H-6- acids

  (substituted pyrimido) - (1,2-a) -quinoline-2-carboxylic acids and their esters (US Pat. No. 4,031,217) and tetrazolo- (a] quinazol-5-ones (US Pat. United

of America 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 R 1 and R 2 are hydrogen or R 1 is a methyl group and R 2 is hydrogen LDunwell et al., J.

  Chem. Soc. (C), 1971, 2094J. The corresponding ethyl esters

  Also, as are the ethyl ester wherein R 1 is methyl and R 2 is hydrogen LDunwell et al., J. Chem. Soc. (C) 1971, 2094; Allen et al., J. Org. Chem. 24, 779

  (1959) J. None of these publications makes known any

  cation of both acids and esters.

  We have just discovered that compounds that respond to

tooth in formula (I):

- 2 N-

J- NH1

N- CI.

2470132 I

4.

  and their cationic salts acceptable from the pharmaceutical point of view

  are anti-allergic and anti-ulcer agents

  effective oral. In formula (I), R1 and R2 represent

  each have 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 R1 and R2, together forming a third ring of 5 to B chain members, are alkylene groups of 3 to 9 carbon atoms, for example: Ca 1 CH 2 t -3 A 1 -CII C C 2 CE 2 cil C 2 eE 2 CH 3 / CiH 3 / - C EC, 2 \ 2 CHE

/ 2 -

_I2

CÀ C

CI; "CEi rxC

Cz-T -

2% C

CH'2- = "

-2 the 2

C'r- CH.

  ## STR2 ## or phenylalkylene groups of 9 to 11 carbon atoms, per

example:

5. C RI- CE C., CE _2 CH ', C-2

C __...- CE

o D

CE, 5- CE2

  It has also been found that

(II): 8? l l 2 5

0 / O O.

  in which R 1 and R 2 are as defined above, are not only interesting intermediate compounds for amide synthesis, but also in many cases, as well as their acceptable cationic salts.

  from a pharmaceutical point of view, a biological activity

  ressante. Acids with anti-allergic activity CS-5

CE -.

THIS

2470132 I

  6. are those in which R 1 and R 2 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 considered separately, R 1 is an alkyl group having 2 to 5 carbon atoms and R 2 is hydrogen or an alkyl group having 1 to carbon atoms. Preferred acids for anti-allergic application are those wherein R 1 and R 2 together form an alkylene group having 4 to 6 carbon atoms, particularly a butylene group. Acids of

  slightly different structure possess anti-activity

  useful ulcer, namely 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 is a system of 5 to

  8 links, or R1 and R2 considered separately

  each is hydrogen or an alkyl group having 1 to 4 carbon atoms, provided that when R2 is hydrogen, R1 is other than hydrogen or a methyl group. In this case, the preferred compounds are those in which R1 and R2 are considered separately, in particular

  when R1 is an ethyl group and R2 is hydrogen

  gene or an alkyl group having 1 or 2 carbon atoms.

  The term "cationic salts" is intended to mean

  pharmaceutically acceptable salts such as alkali metal salts, for example, sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, salts, and the like; ammonium and organic base salts, for example amines such as triethylamine, tributylamine, piperidine, triethanolamine, diethylaminoethylamine,

  N, N'-dibenzylethylenediamine and pyrrolidine.

  The tetrazoles substituted at the 5-position can exist, as is known, in two isomeric forms, namely:

2471 3

7.

N-N N-N

-Col It C

CN. N-N

H H

  which coexist in a dynamic tautomeric mixture

  free. Both forms of tetrazolylamides enter the

of the present invention.

  Compounds of particular interest in the present invention are the compounds of formula (I) wherein R 1 is hydrogen or a methyl group and R 2 is a methyl group. Among these compounds, preference is given to the compound in which R 1 is hydrogen, because the corresponding acid, which is believed to be its metabolite, shows

  also an activity. There is also a particular interest

  compounds where R1 and R2 together form a

  propylene, butylene or pentylene group. We particularly appreciate

  the compound in which R1 and R2 together form a

  butylene group, ie N- (5-tetrazolyl) -1-oxo-1H-

  cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide of formula (III):

NOT

XN I CIIi 1 2470132 i 8.

  because it has excellent oral activity and-

  because it is very stable in the pure solid state, as well as

  the presence of conventional pharmaceutical diluents and in

  tion. In addition, its metabolite (the carboxylic acid corre-

  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 antiallergic property of the compounds of the present invention was evaluated by the Passive Cutaneous Anaphylaxis (PCA) test (Ovary, J. Immun., 31, 355, 1958). In the PCA test, animals are intradermally injected

  antibodies contained in a serum from animals

  ailments that have acquired active sensitivity. The animals are then challenged by intravenous administration of a

  antigen mixed with a dye such as Evans blue.

  The increase in capillary permeability due to the antigen antibody reaction causes the dye to spread from the injection site of the antibody. The test animals are then sacrificed not asphyxiation and the intensity of the reaction is determined by measuring the diameter and intensity of the blue color on the inner surface of the

skin of the animal.

  The anti-ulcer activity of the compounds of the present invention is evaluated by the so-called cold stress test in the rat. Alternatively, the anti-ulcer activity is determined by a recent development test involving an ulcer induced by

  ethanol in the rat, as described later.

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

KE. 1.

  e. ai, E c; - L, ax- spxPFkru, I Xd aoussnd Iz - F eL 8S-IG110 i-N j, -0i KR-N 0E

ID o; -

c L to i i

E 1: E 1

  o EDd D = Dc- (DOOO) c IDO f ED - F1: 1 -1 u sIL 0I. + S jE i

-r-E) I; .4.nocl.

z z

HN '', E

úin.11 - L E 4 - IL,

2470132 1

  10. In the first step of the synthesis sequence, the appropriately substituted 2-aminothiazole is condensed with a stoichiometric amount of an ethoxymethylenemalonate

  dialkyl, usually ethoxymethylenemalonate diethyl

  It is easy to obtain, since the choice of ester is not critical for obtaining the desired end products of the invention. Condensation is brought to a temperature

  ranging from about 80 to about 125 C. More temperatures - -

  are not desirable because the reaction takes place

  a speed too slow. Higher temperatures can be used but obviously do not offer any benefit. The reaction is therefore advantageously carried out in the melt state. Naturally, it can be conducted in a solvent or

  in a mixture of solvents, for example ethanol, N, N-di-

  methylformamide, acetonitrile. However, from a point of view

  In practice, 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 position 5. It should be noted that when R1 and R2 together form a ring, the nomenclature and numbering are modified as follows:

X) X 9

  Cyclopentenothiazole Cyclohexenothiazole v -Cycloheptenothiazole Cyclooctenothiazole

  Cyclohexenothiazoles may also be called

tetrahydrobenzothiazoles.

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

2470132 1

  1. substituted in position 4 and / or in position 5 with elimination of one equivalent of alkanol (ethanol in the case of the ethyl ester). According to one operating mode, this cyclization is

  accomplished by heating the intermediate compound to a temperature of

  from about 175 to about 250 C until the reaction is essentially accomplished, usually

  a period of about 1 to 2 hours. Cyclization is advantageous

  performed by heating the intermediate compound in a suitable diluent which is inert to the reaction,

  that is, in a compound that can influence the temperature

  reaction, which is stable at relatively

  used and which does not react with the starting material or the cyclisation products. Representative examples of these diluents are high boiling hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, especially which contains 26.5% diphenyl and 73.5% diphenyl ether and is sold under the trade name

"Dowtherm A".

  Cyclization is carried out alternatively under milder conditions (70-130 C) by heating the

  intermediate compound in the presence of an excess (1.1 to 3 equiva-

  of trifluoroacetic anhydride in an inert solvent such as toluene until the reaction is complete (by

  Example 15 to 20 hours at the reflux temperature of toluene).

  Whatever the mode of operation, the products of the stage of

  cyclization are 1-oxo-1H-thiazolo [3,2-aj-pyrimidine-2-

  6-substituted alkyl carboxylates and / or

position 7.

  He. It should be noted that when R1 and R2 together form a kernel, the nomenclature and numbering systems are modified as follows:

2470132 I

12. PU o

1-oxo-1H-cyclopenteno

thiazolo- 3,2-a-pyrimidine

7 6 '

2 9 0- S

off

* 1-oxo-1H-cyclohexéno-

thiazolo- (3,2-a) pyrimidine I c i

N.! + X

  1-oxo-1H-cyclohepteno-1-oxo-1H-cycloocteno

  thiazolo-13,2-a-pyrimidine thiazolo-13,2-a-pyrimidine

  1-Oxo-1H-cyclohexenothiazolo-13,2-a-pyrimidine

  dines are also known as 6,7,8,9-tetrahydro-1-oxo-1H-

  pyrimidino- (2,1-b) -benzthiazoles or, when using a.

  other numbering system, .5,6,7,8-tetrahydro-4-oxo-4H-

  pyrimido (2,1-b) -benzthiazoles. It is obvious that the condensation and cyclization steps can be conducted in one and the same

  operation, without the need to separate the 2- (2,2-

  carbalkoxy-ethenylamino) -thiazole intermediate, either

  reading a reaction temperature high enough to carry out both condensation and cyclization, or by condensing as described above, then adding an inert solvent

  (if not already present) and an excess of tri-

  fluoracetic (2.1 to 4 equivalents) and driving the stage

cyclisation.

S

24701 32

  13. The preferred procedure comprises the separate condensation and cyclization steps as described

  above. Isolation of the intermediate compound and its purification

  subsequent cation before cyclization generally provide a higher quality cyclized product. The esters obtained by condensation / cyclization as indicated above are then hydrolyzed to 1-oxo-1H-thiazolo-13,2-a-pyrimidine-2-carboxylic acids

  substituted in position 6 and / or in the corresponding position 7.

  (Note the nomenclature system and modified numbering system described above when R1 and R2 together form a third core). Acid catalyzed hydrolysis is preferred. The refluxing of the ester in 48% hydrobromic acid until the hydrolysis is complete (a period of 0.5 to 3 hours is

  generally satisfactory) constitutes a particular process

  just right. If foaming is a problem, the hydrolysis can be conducted at a gauge pressure

  slightly high, for example from 49 kPa to 85 C.

  N- (5-Tetrazolyl) amides of the present invention

  are advantageously prepared by dehydration coupling.

  acid with 5-aminotetrazole. The coupling deshy-

  Dratant is performed using a wide variety of agents commonly used in peptide synthesis operations. Representative examples of agents include N, N'-carbonyldiimidazole, N, N'carbonyldi-s-triazine, ethoxy-acetylene, 1,1-dichlorodiethyl ether,

  diphenylketene-p-tolylimine, N-hydroxyphthalimide, N-

  hydroxysuccinimide, N-hydroxypiperidine, chlorophosphate,

  ethylene phite, diethylethylene pyrophosphite, N-

  ethyl-5-phenylisoxazolium-3'-sulfonate, phenylphosphorodine

  (1-imidazolate) and carbodiimides such as dicyclohexyl-

  carbodiimide, 1-cyclohexyl-3- (2-morpholinomethyl) carbodiimide

  imide, N- (3-dimethylaminopropyl) -N'-ethylhydrochloride

  carbodiimide, 1-ethyl-3- (3'-dimethylamino) hydrochloride

  propyl) carbodiimide and diethylcyanamide.

  The coupling agents listed above are generally reacted first with the reactant

2470132 1

  14. acid and the resulting product is then reacted without

  isolation with 5-aminotetrazole to give 1-oxo-1H-

  thiazolo-13,2-a-pyrimidine substituted in the 6-position and / or in the 7-position desired. (Note the nomenclature system and modified numbering system shown above when

  R1 and R2 together form a third nucleus).

  The reaction is carried out in an inert solvent for

  with respect to the reaction in which the acidic reactant is not necessarily soluble. The only requirement that the solvent must satisfy is that it does not react appreciably with the reactants or with the products. The diversity of coupling agents that can be used to conduct dehydration coupling offers a wide choice of solvents. Representative examples of solvents are N, N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile. The reaction of the acidic reactant with the coupling agent is conducted at a temperature of about 20 to about 1100C. The reactive intermediate compound is

  then reacted with 5-aminotetrazole at a temperature of

  about 20 to 1100C. Each of these operations is

  tainted at a temperature of about 50 to about 1 ° C, since the rate and the yield of the reaction are

improved.

  The molar ratio of acid, coupling agent and aminotetrazole is generally from about 1: 1: 1 to about 1: 1, 1: 1.1. We can use more

  high proportions of the coupling agent and 5-amino

  Tetrazole, but it does not offer any benefit. Excesses of

moles% are satisfactory.

  As will be appreciated by those skilled in the art, all reactants may be added at once to

  instead of being added discontinuously as indicated below.

  above. However, prior training of the intermediate

  reactive diary (product formed between the acid and the

  coupling) normally gives better N- (5-

tetrazolyl) -amides desired.

2470132 1

  15. Alternatively, one can synthesize

  desired amides by coupling the acids with 5-amino

  Tetrazole by the mixed anhydride method. In this case, the acids are first converted in situ to the tertiary amine salt in the presence of an excess of 1 to 1.1 moles of the amine. Various tertiary amines (R'3N) are suitable for this purpose. We

* mentions as examples triethylamine, N-methyl-

  piperidine, N-methylmorpholine, dimethylaniline or quinoline. Suitable inert solvents are methylene chloride, chloroform, dimethylformamide and the like.

  dimethylacetamide. It is preferable that the acid be

  dissolved by excess tertiary amine, which may require a period of agitation at the same time as possible moderate heating. The solution of the amine salt is then reacted with one equivalent of alkyl chloroformate (for example ethyl), benzyl or phenyl, at a temperature of

  temperature within a range of -40 to 25WC, preferably

  in the range of -10 to 10 C, to form a mixed anhydride in solution, according to the scheme: NR N 9 + Cl-C-OR '3 - + / N

0 CR -

  Without isolating the mixed anhydride, it is reacted directly with 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 N-

  (5-Tetrazolyl) amides desired. The reaction is usually initiated 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 (eg 15 ° C.) to complete the reaction. The normal molar proportion of acid, amine, chloroformate and aminotetrazole has

  a value of 1: 2: 1: 1 to 1: 2.1: 1.1: 1.1.

2470132 1

  Amides as well as acids serve as intermediates for the pharmaceutically acceptable cationic salts of the invention. The formation of a salt is carried out by reaction of the amides or acids with the suitable metal salt (such as a carbonate, ethylhexanoate, alcoholate or hydroxide) or the amine suitably chosen in a suitable medium such as water, methanol or

  ethanol according to well-known procedures.

  The salts are collected by conventional procedures such as filtration if they are insoluble in the medium, by evaporation of the solvent if they are soluble in the medium or

  by precipitation by adding a non-solvent of the salt.

  Many of the 2-aminothiazoles that need to be

  used as starting materials are described in the literature.

  temperature. Those which are not, can be prepared by condensation of the appropriately chosen α-haloketone with thiourea or by condensation of the appropriate aldehyde with thiourea and sulfuryl chloride, as illustrated in particular examples. When halogenoketones 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.

  (1945)) by the action of hydrogen halides on diazo-

  ketones Lvoir, for example, Catch et al., J. Chem. Soc., 278 (1948); Lutz et al., J. Org. Chem. 12, 767 (1947); Wagner et al., J. Am. Chem. Soc. 72, 2884 (1950) J, by decarboxylation of α-halo-e-ketoacidic acid LMcPhee et al., J. Am. Chem. Soc. 66, 1132 (1944) J

  and by spontaneous cleavage of dibromed derivatives of alkenyl esters

  (see, for example, Sianina et al., J. Am.

Chem. Soc. 58, 891 (1936) J.

  The reactions in the synthesis sequence lead

  of 2-aminothiazoles with acids and N- (5-tetrazolo) -

  The amides of the present invention are advantageously followed by normal thin layer chromatography on silica gel plates containing an ultraviolet indicator, of which there are various commercially available sources. The choice of the eluent is varied according to the reaction which is carried out and the nature of the substituents, so as to obtain

  intermediate Rf values between 0 and 1.0, and in order to

  identify the intermediate compound that is reacting and the product that is formed in the reaction. An eluent which is particularly well suited for thiazole formation, condensation ringing and hydrolysis reactions in the process of the invention is a mixture of chloroform and 1% ethanol, while hydrolysis and the conversion of acids to N- (5-tetrazolyl) amides are most suitably 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 fast, 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 can 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, time, temperature, solvent, etc.).

  The products of the invention and their salts

  pharmaceuticals are useful as prophylactic agents to inhibit or prevent the release of

  mediators of anaphylaxis (allergy, hypersensitivity

  immediate sensibility) and the onset of

  in mammals, and they can be administered for such purposes individually or as mixtures 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

  to fight gastric ulcers.

2470132 I

  18. The compounds of interest of the invention can be administered alone, but are generally administered with a carrier or pharmaceutical carrier which is selected according to the adopted route of administration and normal pharmaceutical practice. For example, they may be combined with a variety of pharmaceutically acceptable inert carriers or carriers in the form of tablets, capsules, troches, lozenges, hard pellets, powders, aerosol sprays, suspensions or aqueous solutions, injectable solutions, elixirs and the like. , syrups, etc. Such carriers or carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. In addition, the oral pharmaceutical compositions of

  the invention may be suitably sweetened and perfumed

  by means of various agents of the type commonly used in

this end.

  The particular support chosen and the ratio of the active ingredient to this support are influenced by

  the solubility and chemical nature of the therapeutic compounds

  the adopted route of administration and the necessities of classical 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 may be used. Various disintegrating agents 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 the 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 for oral administration are to be used, the compounds of the invention may be combined with emulsifiers or suspending agents. Diluents such as ethanol, propylene glycol, glycerol

2470132 1

  19 .. and chloroform and their mixtures can be used

same as other matters.

  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.

  sterile aqueous solutions of the acceptable soluble salts

  tables from the pharmaceutical point of view described in this

  memory. These particular solutions are specially adapted

  intramuscular and subcutaneous injection, when these modes of administration are desired. Aqueous solutions, including salt solutions in pure distilled water, are also useful for intravenous injection provided that their pH has been suitably adjusted beforehand. These solutions must also be suitably buffered, if necessary, and the liquid diluent must first be rendered isotonic with a sufficient amount of chloride.

sodium or glucose.

  When used as prophylactic agents

  to prevent the release of mediators of anaphy-

  laxie, 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 the administration of

  using a nebulizer; (2) a suspension or solution of the active ingredient in a liquid propellant such as dichlorodifluoromethane or chlorotrifluoroethane for administration by means of a pressure vessel; or (3) a mixture of the active ingredient and a solid diluent (eg, lactose) for administration by means of a powder inhalation device. Compositions suitable for inhalation by means of a conventional nebulizer contain about 0.1 to about 1% of active ingredient; and compositions for use in pressure vessels contain from about 0.5 to about 2% of active ingredient. Compositions for inhalation in powder form may contain the ingredient

  active and diluent in ratios of about 1: 0.5 to 1: 1.5.

  In view of the factors set forth above, it is considered that an effective daily oral dose of the anti-allergic or anti-ulcer compounds of the present invention in human medicine is from about 10 to about 1500 mg per day. a preferred range of from about 10 to about 600 mg per day in a single dose or divided doses, or about 0.2 to about 12 mg per kg of body weight. These values are only examples and there can of course be individual cases that require higher or lower doses. With proper supervision, we can raise the

  dose rate up to about 2 g per day.

  In case of parenteral administration for one or

  the other uses or by inhalation for anti-inflammatory use

  allergic, the effective daily dose is from about 0.05 to about 400 mg per day and preferably from about 0.25 to mg per day, or about 0.005 to 4 mg per kg of weight

  in a single dose or in divided doses.

  It is necessary that the active ingredient

  a proportion of the composition as to obtain a suitable dosage form. Of course, several unit dosage forms can be administered at about the same time. Although compositions containing less than 0.005% by weight of active ingredient can be used

  in some cases it is better to use

  containing not less than 0.005% of the ingredient

  active; otherwise, the amount of media 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 cutaneous anaphylaxis test is a measure of the antiallergic activity (including anti-asthmatic activity) of a compound. Compounds which inhibit a positive test of passive cutaneous anaphylaxis induced by the immunochemical counterpart in the rat of human immunoglobulin E (IgE), or reagin, are considered to be endowed with anti-allergic activity (C. Mota, Ann. NY Acad Sci.,

  103, 264 (1963)). (Reagin is mainly an immune

  globulin E (IgE) and is the main immunoglobulin

  21. buline responsible for allergic asthma, anaphylaxis, hay fever, food sensitivities and some manifestations of drug sensitivities, although recent evidence attributes IgG class antibodies to an important role in mediated allergic disorders).

  When such compounds are administered to a sensitive 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

  would manifest otherwise. These compounds therefore offer a possibility

  prophylactic treatment of allergic or anaphylactic reactions of a nature generated by the mediation of a reagin.

  In other words, these compounds inhibit the release of

  mediators resulting from the antigen-antibody reaction (allergic) as shown in the passive cutaneous anaphylaxis test using the rat homocytotropic antibody, known

  for its correlation with a human reaginic antibody.

  Inhibition of rat antigen-antibody reactions, selected as a test animal in the passive cutaneous anaphylaxis test, is considered representative of the inhibition of antigenic reactin reactin antibody reactions.

  occurring during allergic episodes.

  The test method of the passive cutaneous anaphylaxis reaction used to evaluate the compounds of the present invention reveals the excellent correlation which exists between the activity of compounds in this test and their utility in the treatment of allergic asthma. . The ability of agents to interfere with passive cutaneous anaphylaxis reactions is measured in male Wistar Charles River rats weighing 170-210 g. A reaginic antiserum rich in

  IgE antibody is prepared as described by Petillo et al.

  borators in Int. Arch. Allergy, 44, 309 (1973). An anti-

  hyperimmune serum rich in chicken anti-ovalbumin IgG antibody is prepared as described by Orange et al. in J. Exptl. Med. 127, 767 (1968). Forty-eight hours before the antigen challenge, the antiserum reaginic is injected intradermally into the shaved skin of the back of a 22.

  normal rat; 5 hours before the test, the antisera

  immune are injected in the same way. In a third site, 60 μg of histamine dihydrochloride and 0.5 μg of serotoninecretatinine sulfate are injected intradermally just before the antigenic challenge, as an anti-tumor control.

  histamine, anti-serotonin and non-specific types

  blocking; the compounds of the present invention or

  physiological saline are then injected intra-

  venous and the injection is immediately followed by the

  5 mg of ovalbumin and 2.5 mg of blue dye

  Evans in saline. In the case of the

  oral treatment, the Evans blue dye and ovalbumin are

  administered 5 minutes after drug absorption.

  minutes later, the animals are sacrificed by asphyxiation with chloroform and the skin of the back is removed and returned 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 of 0.1, 0.5, 1, 2, 3 or 4

  the intensity of the coloring. The scores obtained for a given injection site are tabulated for each group of five animals and the total is compared with the value obtained for saline-treated controls. The difference is expressed by the blocking percentage due to

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 as the degree (%) of protection. The product "Intal", or disodium cromoglycate, which is a commercial antiallergic agent, is not included for comparison, expected

  that he is not active orally.

  The compounds of formula (I) (amides) and

  formula (II) (acids, R3 = hydrogen) whose anti-

  Allergic was determined by the cutaneous anaphylaxis test

  passive are given in detail in Tables I and II.

2470132 1

23.

TABLE I

  Oral activity (percent protection) of amides (formula I) in the passive cutaneous anaphylaxis test R, mg / kg mg

1 3 10 30

_Ci3 CI3 5 '53

3 CH2

C25 Cl3i

C255 C2: {5

(': L_3 46

2 _, CIi

C 3 CE3

C25 E

! 2! ! ci 53

CCC3);

E CaX,

* C HZ1 (C: 3) 2

  C2CCE CCEa). CIF2C2: ## STR2 ##

1 3 10 30

  I ', 38 i: i t 50 2 O - r,: A, r, I 1 53 - - 1,

2470132 1

24.

TABLE II

  Oral activity (percentage of protection) of acids (formula II, R3 = hydrogen) in the passive cutaneous anaphylaxis test TgE mg./kg IgG mg / kg

-R .-- R .. 1 - 30 1l. 30.

CHEC3 CQ. 0.

Cu'3 2i Q O

C2H5 CH 42 24

2 5 3

C2t5 C2H5 41 32

(CH213 Q 0

(_ H2) -4 55 39.

(.CH215 3744

* (H26 36 68 15 45

2 6

H CH3 18 19

H H 18 7

CH3

CH 3 H 12 14

C25 H 45 38

H C (CH 3) 310 6

H C2H5 13 21

H CH (CH3) 2 0 0

CH 2 CH (C 5 H 6) C 2 CH 2. 15 5

CH2Cf (CH3) CH2CH2 31 21

C2C H32C2CH2 13 6

H CHCHCH 2H3 1 8

CX32

...... DTD: -I. -J l 25.

  The effectiveness of the products of this invention

  antiulcer agents is determined by the so-called cold stress test in the rat. In this test, females of fasting rats (Charles River strain C-D) weighing 70-140 g receive the drug or its carrier (animals

  controls) intraperitoneally (in saline solution containing

  1% carboxymethylcellulose and 0.1% "Tween 80") or

  orally (in water) three hours before

  are anesthetized with ether and immobilized in the

  supination on individual "Plexiglass" plates.

  When the anesthetic effect has ceased, the animals

  are placed horizontally in a refrigerator

  maintained at 10-121C and, three hours later, they are sacri-

  by cervical dislocation. The abdomen of each rat is open, 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 largest curvature and the alteration of the glandular portion (posterior stomach) is examined. We note the number of gastric erosions, their severity and the color of the stomachs. 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 treated group

  with the drug to determine if there are differences

  statistics. (Dixon et al., "Introduction to Statistical Analysis", 3rd Edition, McGraw-Hill Book

  Company, New York, pages 344-347, 1969). In this test, the N-

  (5-Tetrazolyl) -thiazolo- (3,2-a) pyrimidine-2-carboxamide (Compound III) is extremely potent, as indicated below, Alternatively, the efficacy of the products of the invention as antiulcer agents is determined in an ethanol-induced ulcerative test in the rat In this test, rat males fasting for approximately 18 hours receive 5 mg / kg of drug or water orally

2470132 1

  26. minutes before oral administration of a 1.0 ml dose of absolute ethanol. One hour after the ethanol challenge, the animals (eight per group) are sacrificed and the stomachs are examined for lesions. All drugs are dissolved in dilute sodium hydroxide. When the animals were sacrificed, their abdomen is opened

  and a hemostat is disposed at the pylorus.

  6 ml of a 4% solution of formaldehyde is injected into the stomach through a gastric feeding tube and

  second hemostat is used to seal the esophagus

  phage. The stomach is removed, opened along the largest

  curvature and examined for ulceration.

  The notation system used for the expression

  Quantitative ethanol-induced lesions are given below.

below.

TABLE OF NOTATION OF ULCERATION

  Rating Definition 1 Normal-looking stomach 2 Pin-point-sized lesions 3 lesions, two or fewer; pinpoint lesions may be present 4 lesions, in number greater than 2; pinpoint lesions may be present Lesions with haemorrhage.

  For each group of animals, an ulcer index

  was calculated as follows: Ulcer index = (sum of grades obtained by the group) x (sum of the number of ulcers in the group) x

  (fraction of the group showing signs of ulceration).

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

  x L (ulceration index of the controls) -

  (ulcer index of animals treated with the drug) J

  t (ulceration index of the controls).

  Table III shows the activity in this test of various tetrazolylamides of the invention, while the

  Table IV shows the activity of various acids.

2470132 1

27.

TABLE III

  Oral activity (inhibition,% at 5 mq / kg dose) of amides (formula I) in the ethanol-induced ulcerative challenge in rats R, Rn R% inhibition

CH3 CH3 96

* CH3 59_

CE 72

C2 C2.EE!

C2 5 - 86

cc) 45 Cc2 L 97, 31

TABLE IV

  Oral Activity (Inhibition,% at the 5 mg / kg dose) of Acids (Formula II) in the Ethanol-induced Ulcerative Test in the Rat R., CH3 CH3 CH2E 27 C3 aE0 C3.O. c2; a; C2H5 48

C235 24

2470132 I

  28. As may be noted in the foregoing, the most preferred compound of the invention is the compound of formula (III), i.e. the compound of formula (I) in wherein R 1 and R 2 together form a butylene group, namely LN- (5-tetrazoyl) -1-oxo-1H-cyclohexenothiazolo-L3,2-a-pyrimidine-2-carboxamide, which can be

  also called 5,6,7,8-tetrahydro-N- (5-tetrazolyl) -4-oxo-4H-

  pyrimido (2,1-b) benzothiazole-3-carboxamide). In addition to its oral anti-allergenic activity shown in Table I, Compound III is endowed with an intravenous activity in the range of 0.03 to 1.0 mg / kg in the passive cutaneous anaphylaxis test. being about twenty times more potent than the "Intal" product by this route of administration (as noted above, the "Intal" product lacks oral efficacy). Compound III also inhibits IgE-mediated changes in skin permeability induced by passive cutaneous anaphylaxis (PCA) but does not interfere with permeability changes caused by intradermal injection.

  exogenous histamine and serotonin. The absence of anti-

  histamine and anti-serotonin demonstrate that the antiallergic mechanism is a mechanism of mediator release inhibition rather than antagonism at the level of the receptor

mediators.

  Compound III inhibits the release of histamine

  Dextran-induced mine in the peritoneal cavity of the rat. Its DE50 dose is 0.33 μg / kg intraperitoneally and that of the "Intal" product is 14.0 μg / kg, which demonstrates the superiority of the power of the former. The elevation of plasma histamine level by administration of antigen to passively sensitized rats with IgE-rich antiserum (passive systemic anaphylaxis) is prevented by

  compound III. Its DE50 dose is 28 gg / kg intra-

  venous, that is to say, it is thirteen times more powerful than

the product "Intal".

  Guinea pigs to which compound III is administered

  administered at 30 mg / kg intraperitoneally are not protected against the bronchoconstrictor effects of inhaled histamine. In the concentration range of 108 to -4 M, compound III does not antagonize guinea pig isolated ileum spasm induced by acetylcholine, histamine and the slow-reacting substance of anaphylaxis (SRS). A), and the synthesis and release of SRS in ionophore stimulated monocytes isolated from the rat are not inhibited by the

compound III.

  In addition to its potent activity in the ethanol-induced ulcerative test in rats (see Table III above), compound III is very potent in the gastric ulcerative method under the stressful effect of restraint and cold (see detail above) where it provides dose proportional protection at oral doses in the range of 3 to 100 pg / kg. Compound III also protects against the ulcerogenic effects of aspirin at a dose of 100 mg / kg orally, and dose-proportional effects in the dose range of 10 to

  1000 μg / kg orally with a DE50 value of 100 μg / kg.

  Compound III is also active in a model of gastric ulceration under the effect of phenylbutazone, where an oral DE50 dose of 100 μg / kg is observed. Although compound III is a

  very powerful anti-ulcer agent, it does not affect the produc-

  of pentagastrin-stimulated acid in dogs

  with Heidenhain fistula (5 mg / kg, intravenous

  venous) and is therefore distinguished from prostaglanders

  anti-secretory drugs as well as cimetidine and

  atropine. The term "cytoprotective" is a term recently coined

  to describe the anti-ulcer effects of prostaglandin

  dines, which are independent of anti-secretory activity (see Robert, Advances in Prostaglandin and Thromboxane Research 2, 507 (1976), Miller et al., Gut 20, 75 (1979), Robert et al., Gastroenterology 72, 1121 ( 1977) and this term characterizes the effects of

compound III.

  In addition, compound III exhibits diuretic activity. When administered orally, it causes

  a dose-related increase in urine volume

  released at doses in the range of 0.3 to

2470132 1

  30. 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 range of

  response to the dose of diuretic activity is consid-

* higher than the anti-ulcer effects and just below the anti-allergic effect

(1 to 10 mg / kg).

  Rats, fasting for 24 hours and having received orally compound III at doses of 10, 30 or mg / kg, show no change in blood glucose levels. The effect of compound III on glucose tolerance was examined in rats receiving 10, 30 or mg / kg orally together with glucose in an amount of 1 g / kg orally. There is an improvement

  demonstrated tolerance for glucose, under the

  dose. This effect may be due to delayed glucose uptake in relation to a possible effect on

gastric evacuation.

  Compound III has no anticholinergic effects

  noticeable differences. 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 occur only at cumulative intravenous doses that are 5 to 15 times higher than the maximum efficacy intravenous dose for achieving anti-allergic effects and are much stronger than

  oral doses necessary to obtain anti-

  ulcer. In tolerance studies, compound III was administered orally by gavage to dogs during a

  7-day period at doses of 50, 150 and 300 mg / kg / day.

  Emesis, which is common in dogs, has been observed at all 31 doses, but subsequent studies have shown that the emetic effect can be suppressed by administering the capsule drug after meals rather than 'before. No macroscopic pathological changes were observed and microscopic examination of liver, kidney, heart and lung revealed no changes. In other studies, the levels of serum enzymes in dogs, receiving compound III intravenously for five days at consecutive daily doses of 1, .3, 10, 3 and

3 mg / kg, remained normal.

  Compound III was administered to rats by gavage at doses of 50, 150 and 300 mg / kg / day for days. No pathological changes appeared on macroscopic and microscopic examination of the liver, kidney, heart and lung. Except for a slight elevation of serum glutamic-pyruvic transaminase at the highest dose, no changes occurred in the

clinical chemistry.

  Compound III was administered subcutaneously

  cutaneous to mice at doses of 100, 300 or 1000 mg / kg.

  No symptoms or no cases of mortality are observed and it is concluded that the drug is well tolerated in the test.

  Acute toxicity with an LD50 subcutaneous dose lower than

  less than 1000 mg / kg. At the dose of 32 mg / kg administered subcutaneously, there is no interaction with a set of drugs acting on the central nervous system. Single oral doses of 40 mg / kg of compound III are administered to groups of mice that are sacrificed 6, 12 or 24 hours later. Microscopic examination of the marrow

  bone shows no chromosomal alteration. Observations

  Similar dosages are performed when the mice are treated for five consecutive days with a dose of mg / kg. In vitro studies in which incubation is performed

  compound III with human lymphocytes at concentrations

  Also, 1000, 100, 10, or 0 μg / ml do not reveal significant drug-induced chromosomal disruption. Compound III, in the In vitro Ames test, does not cause

2470132 1

32.

  point mutations. Based on these findings, it is obvious

  that compound III has no mutagenic potential

  feast. In the passive rat cutaneous anaphylaxis test, the ratio of oral and intravenous doses of comparable efficacy of compound III is consistent with good oral absorption. This finding is confirmed by the observation of plasma concentrations of 3 to 7 μg / ml one hour after oral administration of compound III at a dose of 50 to 300 mg / kg. In dogs, the drug is readily absorbed after oral administration of suspensions or capsules, and reaches plasma concentrations of 9 to 26 μg / ml one hour after 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, which makes it possible to identify 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 the initial dose, suggesting the possibility of maintaining

  therapeutic drug levels for prolonged periods of time

  elderly. Compound III in the solid state, alone or as a mixture

  with classic inert ingredients used in -

  oral formulations, or in solution, presents stability

  extremely good, which facilitates the preparation of

  stable formulations of this compound for clinical use.

  The invention. is illustrated by the examples

  following, given in a non-limitative manner.

EXAMPLE 1

  2-amino-4-ethyl-5-methylthiazole 20.9 g (0.275 mol) of thiourea are dissolved in 250 ml of refluxing ethanol. 41.3 g (0.25 moles) of 2-bromo-3-pentanone dissolved in 50 ml of ethanol are added dropwise over 25 minutes to the refluxing urea solution. After an additional reflux period of 2 hours, the reaction solution is concentrated by boiling to a volume of about 1 ml, cooled and the crude product is collected.

  the form of the hydrobromide by filtration. We obtain 2-amino

  Purified 4-ethyl-5-methyltetrazole (15.1 g, mp 45-500 ° C, m / e calc .: 142, found: 142) by dissolving in water and reprecipitating with an aqueous solution

of 3N potassium hydroxide.

  By the same procedure, we convert the 1-

  bromo-2-heptanone, 3-bromo-4-heptanone and 4-bromo-2,5-

  dimethyl-3-hexanone, respectively to 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 mol) of thiourea, 34.4 g (0.26 mol) of 4-chloro-3-hexanone and 200 ml of ethanol are mixed together and the mixture is refluxed for 19 hours. The reaction mixture was cooled and stripped of solvent to obtain the crude product as a white solid. White crystals of 4,5-diethylthiazole hydrochloride (31 g, mp 154 ° -156 ° C.) are obtained by recrystallization from an acetate mixture.

of ethyl and ethanol.

EXAMPLE 3

  2-aminocycloheptenothiazole 41.9 g (0.55 mol) of thiourea, 72.3 g (0.49 mol) of 2-chlorocycloheptanone and 500 ml of ethanol are mixed and the mixture is refluxed for 7 hours. The solvent is removed, and there remains a semi-solid substance that is

  distributes between ethyl acetate and water. Chlorine

  unreacted 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, free of solvent and the raw product addi-

  is distributed between ethyl acetate and water as above. In each case, the product is collected by

2470132!

34.

  alkalinization of the aqueous phase with ammonium hydroxide

  Extraction in ethyl acetate, drying over anhydrous sodium sulfate, evaporation to an oil, trituration with hexane and filtration. Purified 2 aminocycloheptenothiazole

  (49.5 g, mp 77-78.5 ° C.) is obtained by recrystallization.

in cyclohexane.

EXAMPLE 4

  2-Amino-4-isopropylthiazole 52.5 g (0.69 mol) of thiourea are stirred into 400 ml of ethanol. 109.5 g are added to the suspension

  (0.66 moles) 1-bromo-3-methyl-2-butanone. The exotic reaction

  resultant thermal causes dissolution and reflux. The reflux is maintained by external heating for 1 hour. The solvent is evaporated off by boiling to give an oil which crystallizes on standing. The final purification of 2-amino-4-isopropylthiazole hydrobromide (104.4 g,

  melting, 74-76WC) is obtained by trituration with ether.

  The hydrobromide is converted to the free base (58.6 g) by dissolving the salt in water, alkalinizing with excess ammonium hydroxide, extracting the free base in ether, dehydrating the ether on anhydrous sodium sulphate and evaporation of the solvent to obtain a

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, and the result is an exothermic reaction and dissolution. The solution is refluxed for 30 minutes, cooled and the solvent removed by evaporation to obtain the crude product.

as the hydrobromide.

  This crude salt is dissolved in lukewarm water,

  filter the solution and precipitate the free base by the addi-

  ammonium hydroxide. The gross base is collected by

240132 1

35.

  filtration and 802.4 mg of 2-amino-6-phenylcyclohexane are obtained.

  hexenothiazole (mp 181-183 C) by recrystalline

  in 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 direc-

  filtration. The hydrobromide is dissolved in water containing traces of ethanol by heating and precipitated

  the free base (10.4 g, m.p. 180-182 C) by the addi-

  excess ammonium hydroxide.

  By the same procedures, we convert the

  2-bromo-3-phenylcyclopentanone, 2-bromo-3,5-dimethylcyclopentanone

  hexanone, 2-bromo-3,5,5-trimethylcyclopentanone and 2-

  bromo-5-methylcyclooctanone respectively in 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

octénothiazole.

EXAMPLE 6

  2-amino-6-methylcyclohexenothiazole 22.3 g (0.29 mol) of

  thiourea in 275 ml of ethanol. 2-bromo-4- is added

  methylcyclohexanone and the mixture is refluxed for minutes. The reaction mixture was allowed to cool to room temperature and the crude product as the hydrobromide was collected by filtration. The crude salt is dissolved in lukewarm water, the solution is filtered and alkalized by the addition of ammonium hydroxide to precipitate the free base as an oil which crystallizes on heating.

  cooling. 2-Amino-6-methylcyclohexene is obtained

  purified thiazole (25.2 g, mp 98-100 ° C)

  recrystallization from cyclohexane.

2470132 i 36.

EXAMPLE 7

  2-amino-6,6-diméthylcyclohexénothiazole

  2-Amino-6,6-dimethylcyclohexene is prepared

  thiazole (9.8 g, m.p. 109-111 C) from 9.2 g (0.12 mole) of thiourea and 22.6 g (0.11 mole) of 2-bromo-4,4-dimethylcyclohexanone in 100 ml ethanol according to

in the procedure of Example 6.

EXAMPLE 8

  2-amino-4- (2-butyl) -thiazole 16.7 g (0.22 moles) of thiourea, 36 g (0.2 moles) of 1-bromo-3-methyl-2-pentanone and 100 ml

  of ethanol and the mixture is refluxed for 5 hours.

  An aqueous solution of potassium hydroxide (3N, 100 ml) is added and refluxing is continued for a further 0.5 hours. 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 the addition of ammonium hydroxide and the product is extracted into ether. After rinsing with water and drying over anhydrous sodium sulfate, the ether is removed to give 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. We add in 15 minutes

  44.5 g (0.33 moles) of sulfuryl chloride. The exotic reaction

  The gas evolution that takes place during the addition ceases about 1 hour after the end of the addition. Most of the chloroform is boiled off in a boiling water bath. 150 ml of ethanol are added and the mixture is refluxed

3 hours.

  The reaction mixture was evaporated to give an oil which was partitioned between water and ethyl acetate. The aqueous phase is made basic by the addition of ammonium hydroxide and the product is extracted into fresh ethyl acetate. The ethyl acetate is dried over anhydrous sodium sulfate and chased to give the crude product as a white solid. Purified 2-amino-5-methylthiazole (8.36 g, m.p.

   C) is obtained by recrystallization from cyclohexane.

EXAMPLE 10

  2-amino-5-ethylthiazole 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 an ice-bath. We add in 15 minutes

  44.5 g (0.33 moles) of sulfuryl chloride. The exotic reaction

  temperature is maintained between 15 and 25 ° C. Gas evolution takes place during the addition and for about 1 hour after

  the bill. 400 ml of ethanol are added, the chloro

  boiling and refluxing the reaction mixture for about 16 hours. The reaction mixture is evaporated

  to obtain an oil and isolates 11.7 g of 2-amino-5-ethyl-

  recrystallized thiazole (mp 54-55uC) by

  method shown in Example 9.

  By the same process, the pentanal, the

  3-methylbutanal and heptanal respectively at 2-amino-5-

  propylthiazole, to 2-amino-5-isopropylthiazole and 2-amino-

5-pentylthiazole.

EXAMPLE 11

  2- (2,2-dicarbethoxy-éthénylamino) -4,5-dimethylthiazole

  2.56 g (20 mmol) of 2-amino

  4,5-dimethylthiazole, 4.8 g (22 mmol) of ethoxymethylene

  diethyl malonate and 5 ml of ethanol for 1 hour. The reaction mixture is cooled and the product is precipitated

  crude by addition of hexane. 2- (2,2-dicarboxylic acid) is obtained

  purified ethenylamino) -4,5-dimethylthiazole (4.21 g,

  melting 82-83.5 ° C) by recrystallization from hexane.

2470132 1

38.

EXAMPLE 12

  2- (2,2-dicarbethoxy-éthénylamino) -4-ethyl-5-methylthiazole

  2.84 g (20 mmol) of 2-amino-4-ethyl-

  -ethylthiazole and 4.76 g (22 mmol) of diethyl ethoxymethylene malonate and the mixture is heated on a steam 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, we convert the 2-

  4-amino-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, the

  2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,6,6-

  trimethylcyclopentenothiazole and 2-amino-7-methylcyclo

  octenothiazole to the 2- (2,2-dicarbethoxyethenyl)

amino) -thiazolic corresponding.

  By the same procedure, the corresponding dimethyl, dipropyl and diisopropyl esters are prepared by

  replacing diethyl ethoxymethylenemalonate with ethoxy

  dimethyl, dipropyl or diisocyanate methylenemalonate

corresponding propyl.

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 and then cooled to obtain the product as an oil

  that we use 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) triethylamine and 125 ml ethanol and. the mixture is refluxed for 2 hours and a half. The reaction mixture is cooled and the

2470132 1

  39. solvent. The resulting semi-solid product is distributed among

  ethyl acetate and water. 2- (2,2-dicarbethoxy)

  ethenylamino) -4,5-diethylthiazole (28.6 g) is obtained as a golden-colored oil from the ethyl acetate phase by dehydration over anhydrous sulphate

  of sodium and removal of the solvent by evaporation.

  By the same process, the hydrobromides are converted

  5,7-dimethylcyclohexenothiazole, 4,4,6-trimethylcyclohexyl

  pentenothiazole and 7-methylcyclooctenothiazole in the

  2- (2,2-dicarbethoxy-ethenylamino) thiazole derivative

  laying. Following the same procedure, we prepare the

  dimethyl, dipropyl and diisopropyl esters

  by replacing the diethyl ethoxymethylenemalonate

  with dimethyl or dipropyl ethoxymethylenemalonate or

diisopropyl corresponding.

EXAMPLE 15

  2- (2,2-dicarbethoxy-éthénylamino) -cyclopenténothiazole

  3.6 g (34.5 mmol) of 2-aminocyclic acid are mixed together.

  pentenothiazole and 8.2 g (38.0 mmol) of ethoxymethylene

  diethyl malonate and the mixture is heated in a bain-marie

  boiling for 100 minutes. The reaction mixture is cooled

  and 2- (2,2-dicarbethoxy-ethenylamino) -cyclo-

  pentenothiazole (7.0 g, Rf 0.6 in thin layer chromatography on silica gel eluted with a mixture of chloroform and 1% ethanol) crystallized by addition of hexane.

EXAMPLE 16

  2- (2,2-dicarbethoxy-éthénylamino) -cyclohexénothiazole

  7.7 g (50 mmol) of 2-aminocyclic

  hexenothiazole and 11.9 g (55 mmol) of ethoxymethylene

  diethyl malonate with 10 ml of ethanol and the mixture is refluxed for 50 minutes. We cool

  reaction mixture and 15 g of 2- (2,2-dicarbethoxyethenyl)

  amino) -cyclohexenothiazole (Rf 0.5 by thin layer chromatography on silica gel with a mixture of

2470132 1

  40% chloroform and 1% ethanol) precipitate by addition

50 ml of hexane.

  Alternatively, 58.4 g of 2-amino

  cyclohexenothiazole, 89.82 g of diethyl ethoxymethylenemalonate and 584 ml of cyclohexane and the mixture is heated under reflux under nitrogen for 2.5 hours, cooled to 15 ° C and the product is collected.

  (96 g, mp 113 ° C) by filtration.

EXAMPLE 17

  2- (2,2-dicarbethoxy-éthénylamino) -cycloocténothiazole

  2.0 g (11 mmol) of 2-aminocyclic acid are mixed

  octenothiazole and 2.62 g (12.1 mmol) of ethoxymethylene

  diethyl malonate and the mixture is heated on a steam bath for 2.75 hours. We cool the mixture

  The reaction mixture is precipitated by addition of hexane to 3.13 g of

  (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-éthénylamino) -4-methylthiazole

  4.57 g (40 mmol) of 2-amino-4-

  methylthiazole and 9.51 g (44 mmol) of ethoxymethylene

  diethyl malonate and the mixture is heated in the bath.

  marie boiling for 1 hour. The reaction mixture is cooled and precipitated by the addition of 60 ml

  of hexane, 9.8 g of 2- (2,2-dicarbethoxyethenylamino) -4-

  methylthiazole (Rf 0.5 by silica gel thin layer chromatography with a mixture of chloroform and

1% ethanol).

EXAMPLE 19

  2- (2,2-dicarbethoxy-ethenylamino) -thiazole 10.0 g (0.10 mol) of 2-aminothiazole and 23.8 g (0.11 mol) of diethyl ethoxymethylenemalonate are mixed and the mixture is heated. boiling water bath for 1.25 hours. The reaction mixture is cooled and the resulting semisolid substance is recrystallized.

  hexane to give 2- (2,2-dicarbethoxyethenyl) -

  purified thiazole (17.2 g in two crops, Rf 0.6 in thin layer chromatography of silica gel with chloroform and 1% ethanol as eluent).

EXAMPLE 20

  2- (2,2-dicarbethoxy-ethenylamino) -5-methylthiazole 6.85 g (60 mmol) of 2-amino-5-methylthiazole and 14.3 g (66 mmol) of ethoxymethylenemalonate were heated in a boiling bath for 1 hour. diethyl. The reaction mixture is cooled and the product is precipitated

  by adding about 75 ml of hexane. 2- (2,2-

  purified dicarbethoxy-ethenylamino) -5-methylthiazole (14.1 g in two crops, Rf 0.55-0.65 in silica gel thin layer chromatography with a mixture of

  chloroform and 1% ethanol) is obtained by recrystallization.

in hexane.

EXAMPLE 21

  2- (2,2-dicarbethoxy-éthénylamino) -5-éthylthiazole

  11.7 g (91.3 mmol) of 2-amino-5-

  ethylthiazole and 21.7 g (100.43 mmol) of ethoxymethylene

  diethyl malonate and the mixture is heated in a bain-marie

  boiling for 45 minutes. 2- (2,2-dicarbethoxyethyl)

  amino) -5-ethylthiazole (27.2 g, respective Rf values of 0.6 and 0.7 in silica gel thin-layer chromatography with a mixture of chloroform and 1% ethanol as eluents and a 2: 1 mixture of hexane and acetate

  of ethyl) is obtained in the form of an oil by cooling.

  and is used directly in the next step.

EXAMPLE 22

  2- (2,2-dicarbethoxy-éthénylamino) -4-

(2-methyl-2-propyl) -thiazol

  15.6 g (0.1 mol) of 2-amino-4- (2-

  methyl-2-propyl) -thiazole and 23.8 g (0.11 mol) of ethoxylated

  diethylmethylenemalonate and the mixture is heated to

2470132 1

42.

  boiling water bath for 2 hours. 2- (2,2-dicarboxylic acid)

* ethoxy-ethenylamino) -4- (2-methyl-2-propyl) -thiazole is obtained as a wet solid upon cooling and is used directly in the next step.

EXAMPLE 23

  2- (2,2-dicarbethoxy-éthénylamino) -4-éthylthiazole

  20.5 g (0.16 mol) of 2-amino-4-ethyl-

  thiazole and 35 g (0.17 mole) of diethyl ethoxymethylenemalonate and the mixture is heated in a boiling water bath

  during 2 hours. On cooling, the 2- (2,2-

  dicarbethoxy-ethenylamino) -4-ethylthiazole as an oil and used directly in the next step (Rf = 0.75 by thin layer chromatography of silica gel, eluting with a mixture of chloroform and 1% ethanol).

  By the same procedure, 2-amino-4-iso-

  propylthiazole (58.6 g, 0.415 mole) and ethoxymethylene

  diethyl malonate (92 ml, 0.455 mole) are converted to 2-

  (2,2-dicarbethoxyethenylamino) -4-isopropylthiazole (Rf = 0.7 by thin layer chromatography of silica gel, with a

  mixture of chloroform and 1% ethanol as eluent).

EXAMPLE 24

  2- (2,2-dicarbethoxy-éthénylamino) -6-phénylcyclohexénothiazole

  10.4 g (45.2 mmol) of 2-amino-6-

  phenylcyclohexenothiazole and 10 ml (49.5 mmol) of ethoxylated

  diethyl methylenemalonate and the mixture is heated on a steam bath. A solution is obtained after minutes. After an additional heating period of minutes, the entire mass solidifies. The gross product is

  recrystallized from cyclohexane to give 15.3 g of 2- (2,2-

  dicarbethoxy-éthénylamino) -6-phénylcyclohexénothiazole

purified melting at 131-133 C.

43.

EXAMPLE 25

  2- (2,2-dicarbethoxy-éthénylamino) -6-méthylcyclohexénothiazole

  23.3 g (0.139 mol) of 2-amino-6-

  methylcyclohexenothiazole with 31 ml (0.153 mol) of ethoxylated

  diethyl methylenemalonate and the mixture is heated on a steam bath. After a heating period of about

  minutes, a light orange oil is obtained.

  After heating for 1 hour, the crystal is triggered.

  scratching. 40.2 g of 2- (2,2-dicarboxylic acid) are obtained.

  purified ethoxy-ethenylamino) -6-methylcyclohexenothiazole (mp 106-109 ° C) by recrystallization from ethanol.

EXAMPLE 26

  2- (2,2-dicarbethoxy-éthénylamino) -

6,6-diméthylcyclohexénothiazole

  9.8 g (53.8 mmol) of 2-amino-6,6-

  dimethylcyclohexenothiazole, 12 ml (59.4 mmol) of ethoxylated

  diethyl methylenemalonate and about 5 ml of ethanol and the mixture is heated on a steam bath for 1.5 hours. The ethanol is boiled off during the first part of the heating period. The product is crystallized

  by cooling and scraping. 2- (2,2-dicarbethoxy)

  purified ethenylamino) -6,6-dimethylcyclohexenothiazole

  (14.3 g, mp 83-85 ° C) - is obtained by recrystallization

in 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-éthénylamino) -4-

(2-butyl) -thiazol

  8.44 g (54 mmol) of 2-amino-4- (2-

  butyl) -thiazole and 11.7 g (54 mmol) of ethoxymethylene

  diethyl malonate and the mixture is heated on a steam bath for 1 hour, then cooled to obtain

  17.6 g of 2- (2,2-dicarbethoxyethenylamino) -4- (2-butyl) -

  44. Thiazole (Rf = 0.75 by thin layer chromatography of silica gel with a mixture of chloroform and 1%

ethanol as eluent).

EXAMPLE 28

  1-oxo-1H-6,7-diméthylthiazolo-L3,2-aJ-pyrimidine

2-ethyl carboxylate

  4.17 g (14 mmol) of 2- (2-dicarboxylic acid) are mixed together.

  ethoxy-ethenylamino) -4,5-dimethylthiazole with 30 ml of "Dowtherm A" and the mixture is heated at 220 ° C.

  1.5 hours. The reaction mixture is cooled and

  ml of petroleum ether. The precipitated solid is separated by filtration, re-admixed with the mother liquor and chromatographed on a gel column.

  silica of 70 x 180 mm, the eluent used being chloroform.

  After an initial fraction of 125 ml, six 250 ml fractions are collected and evaporated to dryness to give 2.42 g of crude product (mp 114-115 ° C). By

  recrystallization from cyclohexane, 1-oxo-1H-

  4,5-diméthylthiazolo-13.2-aJ-pyrimidine-2-carboxylate

  purified ethyl (1.64 g, mp 119-120 ° C).

  Analysis: CH% H% N,% calculated for C11H12N2O3S 52.37 4.79 11.10 mass ion: 252 found 52.21 4.85 11.23

mass ion: 252.

EXAMPLE 29

  1-oxo-1H-6-methyl-7-ethylthiazolo-L3,2-aJ-pyrimidine

2-ethyl carboxylate

  6.25 g of 2- (2-dicarbethoxy-ethenyl)

  amino) -4-ethyl-5-methylthiazole with 30 ml of "Dowtherm A" and the mixture is heated at 215 ° C. for 2.5 hours. The reaction mixture is cooled, the ether is added

  oil and the crude product (1.96 g) is collected by filtration.

  tion. 630 mg of the crude product is recrystallized from

  cyclohexane to obtain 301 mg of 1-oxo-1H-6-methyl-7-ethyl-

  thiazolo-L3,2-a) purified ethyl-pyrimidine-2-carboxylate

melting at 122-124 C.

  45. Analysis: C,% H,% N,% calculated for C12H14N2O3S 54.12 5.30 10.52

found 54.09 5.26 10.63.

EXAMPLE 30

  1-oxo-1H-6-ethyl-7-methylthiazolo-t3,2-aJ-pyrimidine

2-ethyl carboxylate

  12 g of 2- (2,2-dicarbethoxyethenyl)

  amino) -4-methyl-5-ethylthiazole with 60 ml of "Dowtherm A" and the mixture is heated at 205WC for 3 hours. The reaction mixture is cooled and chromatographed on a

  column of 90 x 205 mm of silica gel when carrying out the elu-

  with chloroform containing 1% ethanol. Seven 250 ml fractions each containing the product are collected, combined, the solvent is removed to obtain an oil and this oil is rechromatographed on silica gel (60 x 600 mm) with the same eluent. 165 fractions of 8 ml are collected, freed from the solvent and an oil is obtained which is recrystallized by trituration with diisopropyl ether. By recrystallization from cyclohexane,

  obtains 1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a]

  purified ethyl pyrimidine-2-carboxylate (2.45 g,

melting 65-66 C).

  Analysis: C,% H,% N,% calculated for C12H14N2O3S 54.12 5.30 10.52 mass ion: 266 found 54.26 5.23 10.57

mass ion: 266.

EXAMPLE 31

  1-oxo-1H-6,7-diéthylthiazolo-13.2-aJ-pyrimidine

2-ethyl carboxylate

  26.1 g of 2- (2,2-dicarbethoxyethenyl)

  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 was cooled and chromatographed on a column of silica gel (60 x 320 mm). "Dowtherm A" 2470132.146 is eluted with hexane and the product is eluted with a mixture of hexane and chloroform 2: 1. 33 fractions of

  250 ml each. Fractions of the eighth to the thirty-

  third are combined and stripped of the solvent to give 22 g of ethyl 1-oxo-1H-6,7-diethylthiazolo-3 (2-a) pyrimidine-2-carboxylate (Rf -0.4-0.5 in thin-layer chromatography of silica gel with, as eluent, a mixture of chloroform and 1% ethanol), under

the shape 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, -2- (2,2-dicarbomethoxy-ethenylamino) -4,5-diethylthiazole, -2- (2,2-dicarbopropoxy-ethenylamino) -4,5-diethylthiazole, 2- (2,2dicarbisopropoxy-ethenylamino) -4,5-diethylthiazole, -2- (2,2-dicarbethoxyethenylamino) -4-pentylthiazole, -2- (2,2-dicarbethoxyethenylamino) 4-propyl-5-ethylthiazole, 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-dicarbethoxyethenylamino) -6-phenylcyclopentenothiazole, -2- (2,2-dicarbethoxyethenylamino) ) -5,7-dimethylcyclohexenothiazole, 2- (2,2-dicarbethoxyethenylamino) -7-methylcyclooctenothiazole, and

  2- (2,2-dicarbethoxy-ethenylamino) -4,4,6-trimethylcyclopenteno

  methylthiazole are converted into the following compounds, respectively: methyl 1oxo-1H-6-methyl-7-ethylthiazolo- [3,2-a] pyrimidine-2-carboxylate, 1-oxo-1H-6-methyl-7-ethylthiazolo propyl 2-tert-2-yl-pyrimidine-2-carboxylate, 1-oxo-1H-6-methyl-7-ethylthiazol-3-yl-2-yl-pyrimidine-2-carboxylic acid, 1-oxo-1H-6, Methyl 7-diethylthiazolo- (3,2-a) pyrimidine-2-carboxylate, propyl-47.-1-oxo-1H-6,7-diethylthiazolo- [3,2-a] pyrimidine-2-carboxylate; ethyloxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidin-2-carboxylic acid, ethyl 1-oxolH-7-pentylthiazolo [3,2-a] pyrimidine-2-carboxylate 1-Oxo-1H6-ethyl-7-propylthiazolo [3,2-a] pyrimidine-2-carbox] ethyl, -1-oxo-6,7-diisopropylthiazolo [3,2-a] pyrimidine; 2-carboxy] ethyl, 1oxo-1H-6-propylthiazolo [3,2-a] pyrimidine-2-carboxylic acid ethylamine, 1-oxo-1H-6-isopropylthiazolo [3,2-a]; ethyl pyrimidine-2-carboxylate, ethyl 1oxo-1H-6-pentylthiazolo [3,2-a] pyrimidine-2-carboxylate,

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

ethyl carboxylate,

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

ethyl carboxylate,

  1-oxo-1H-8-methylcyclooctenothiazolo [3,2-a] pyrimidine-2-

  ethyl carboxylate, and - 1-oxo-1H-6,8,8-trimethylcyclopentenothiazolo [3,2-a] pyrimidine

2-ethyl carboxylate.

EXAMPLE 32

  1-oxo-l1H-cyclopenténothiazolo- [3,2-aJ-pyrimidine

2-ethyl carboxylate

  7.0 g of 2- (2,2-dicarbethoxyethenyl)

  amino) -cyclopentenothiazole with 40 ml of "Dowtherm A" and the mixture is heated at 225-230 C for about 1 hour. The reaction mixture was cooled and chromatographed on silica gel (70 x 190 mm). The "Dowtherm A" is eluted with hexane. The product is eluted with a mixture of chloroform and 1% ethanol. Four 250 ml fractions are collected, collected and the solvent removed to obtain an oil. A portion of the oil is crystallized by trituration with cyclohexane, to obtain 1.91 g of

2470132 1

  48. gross product. By recrystallization of 0.6 g of the crude product,

  there is obtained 1-oxo-1H-cyclopentenothiazolo-L3,2-aJ-

  purified ethyl pyrimidine-2-carboxylate (0.33 g,

melting 102-103 C).

  Analysis: C,% H1% N,% calculated for C12H12N2O3S 54.53 4.58 10.60

found 54.54 4.71 10.71.

EXAMPLE 33

  1-oxo-1H-cyclohexénothiazolo- [3,2-aJ-pyrimidine

2-ethyl carboxylate

  12.6 g of 2- (2,2-dicarbethoxyethenyl)

  amino) -cyclohexenothiazole with 125 ml of "Dowtherm A" and the mixture is heated at 230 ° C. for 25 minutes. The reaction mixture was cooled and chromatographed on silica gel (60 x 320 mm). The "Dowtherm A" is eluted with hexane and the product is eluted with a mixture of chloroform and 1% ethanol in fourteen fractions of 125 ml each. We obtain

  1-oxo-1H-cyclohexenothiazolo-L3,2-a-pyrimidine-2-

  crude ethyl carboxylate (10.7 g, mp 92-94 ° C) with

  combining the fractions and removing the solvent.

  Alternatively, 80 g (0.25 moles) of 2- (2,2-dicarbethoxyethenylamino) -cyclohexenothiazole, 101 g (68 ml, 0.48 moles) of trifluoroacetic anhydride, 0.8 liters of toluene are mixed. and 1 liter of ethanol and reflux the mixture for 21 hours. The reaction mixture is cooled and 300 ml of water are added. The toluene (upper) phase is separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated to 150 ml (suspension), diluted with 1 liter of ethanol (solution) concentrated to 280 ml, cooled to 5 ° C,

  granulated and filtered to give 1-oxo-1H-cyclohexeno-

  thiazolo- (3,2-a) pyrimidine-2-carboxylic acid relative to

  pure (47 g, mp 105 ° -106 ° C.).

24701:

49.

EXAMPLE 34

  1-oxo-1H-cyclohepténothiazolo- (3,2-aj-pyrimidin-2-

ethyl carboxylate

  25.2 g (0.15 mole) of 2-aminocyclo

  heptenothiazole, 35.7 g (0.165 mole) of diethyl ethoxymethylene malonate and 400 ml of "Dowtherm A" and the mixture is heated at 220-230uC for 2 hours. The reaction mixture was cooled and chromatographed on silica gel (90 x 235 mm). The "Dowtherm A" is eluted with hexane. We

  eluted the product with a 1: 1 mixture of hexane and

  form in thirty fractions of 500 ml each. The fractions from the sixth to the thirtieth are pooled and stripped of the solvent to give the crude product as a

  moist solid substance. 1-oxo-1H-cycloheptenothiazolo-

  Purified ethyl 3,2-aj-pyrimidine-2-carboxylate (27.1 g, m.p. 78-79 ° C) was obtained by recrystallization from

cyclohexane.

  The same product is obtained by heating 2- (2,2-

  dicarbethoxy-ethenylamino) -cycloheptenothiazole in "Dowtherm A '" by carrying out the isolation and purification of

the same way.

EXAMPLE 35

  1-oxo-1H-cycloocténothiazolo- [3,2-a) -pyrimidine-2-

ethyl carboxylate

  3.13 g of 2- (2,2-dicarbethoxyethenyl)

  amino) -cyclooctenothiazole 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). The "Dowtherm A" is eluted with hexane. The product is eluted with a mixture of chloroform

  and 1% ethanol in four 125 ml fractions. We are gathering

  fractions, evaporate to obtain an oil and

  obtained, by trituration with hexane, 1-oxo-1H-cyclohexane

  solid ethyl octenothiazolo-3,2-a-pyrimidine-2-carboxylate (1.956 g, Rf = 0.5 by silica gel thin layer chromatography, the elution being carried out with a mixture of

chloroform and 1% ethanol).

50.

EXAMPLE 36

  1-oxo-1H-7-methylthiazolo-t3,2-aJ-pyrimidin-2-

ethyl carboxylate

  9.8 g of 2- (2,2-dicarbethoxy-ethephenyl)

  amino) -4-methylthiazole 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 and

  Collects the crude product by filtration. By recrystalli-

  of the crude product in ethanol, 4.6 g of

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

  of purified ethyl, melting at 187-189 ° C.

  Alternatively, this ester is prepared by direct condensation of 2-amino-4-methylthiazole with ethyl ethoxymethylenemalonate by refluxing in trichlorobenzene LAllen et al., J. Org. Chem., 24, 779 (1959) J.

EXAMPLE 37

  Ethyl 1-oxo-1H-thiazolo-13,2-a-pyrimidine-2-carboxylate

  17.2 g of 2- (2,2-dicarbethoxyethenyl)

  amino) -thiazole with 200 ml "Dowtherm A" and the mixture is heated at 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, 1-oxo-1H-

  purified ethyl thiazolo-13,2-a-pyrimidine-2-carboxylate

(8.0 g, mp 184-185 ° C).

  As a variant, this ester is prepared by

  direct condensation of 2-aminothiazole with ethoxy-

  Ethyl methylenemalonate by refluxing in trichlorobenzene LAllen et al., J. Org. Chem., 24,

779 (1959) J.

EXAMPLE 38

  1-oxo-1H-6-methylthiazolo-t3,2-aj-pyrimidin-2-

ethyl carboxylate

  14.1 g of 2- (2,2-dicarbethoxy)

  ethenyl) -5-methylthiazole 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 approximately 300 ml is added thereto.

2470132 '

  51. hexane. The product is collected by filtration and

  6.4 g of 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-

  pyrific ethyl carboxylate (m.p. 149-151 C) by

  recrystallization from diisopropyl ether. -

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

2094).

EXAMPLE 39

  1-oxo-6-l1H-éthylthiazolo- [3,2-aj-pyrimidin-2-

ethyl carboxylate

  25.7 g (36 mmol) of 2- (2,2-dicarboxylic acid) are mixed together.

  ethoxy-ethenylamino) -5-ethylthiazole, 36.2 g (172 mmol) of trifluoroacetic anhydride and 150 ml of toluene and the mixture is refluxed for about 20 hours. The reaction mixture is evaporated to dryness and the residue is taken up in 300 ml of chloroform. The chloroform solution is washed with saturated sodium bicarbonate solution, followed by a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and the residue is triturated with diisopropyl ether to give 17.8 g. ethyl 1-oxo-1H-6-ethylthiazolo- (3,2-a) -pyrimidine-2-carboxylate, m.p. 148-150uC. A portion of the product (5.2 g) is recrystallized from about 75 ml of ethyl acetate to give an additional amount of purified product (4.1 g;

melting point 149-150 ° C).

  Analysis: C,% H,% Calculated for C11H12N2O3S 52.37 4.79 11.10

found 52.30 4.51 11.14.

EXAMPLE 40

  1-oxo-1H-7- (2-methyl-2-propyl) -thiazolo-L3,2-aJ-pyrimidin-2-

ethyl carboxylate

  32.6 g of 2- (2,2-dicarbethoxyethenyl)

  amino) -4- (2-methyl-2-propyl) -thiazole with 400 ml of "Dowtherm A" and the mixture is heated at 230 ° C for 52 hours.

  hour. The reaction mixture is cooled and chromatographed.

  on silica gel (60 x 600 mm). The "Dowtherm A" is eluted with hexane. The product is eluted with chloroform. Nine 500 ml fractions are collected. The fractions of the sixth to the ninth are collected and

  evaporated to dryness to give 1-oxo-1H-7- (2-methyl-2-propyl) -

  ethyl thiazolo- (3,2-a) pyrimidine-2-carboxylate (11.4 g,

  m.p. 145-147 ° C). An additional amount is obtained

  product (2.04 g) from the fifth fraction by evaporation to a solid

  wet that is triturated with cyclohexane. We are recreating

  make 1 g of the largest crop in cyclohexane to obtain an additional amount of purified product

  (0.62 g, m.p. 148-149 ° C).

  Analysis: C,% H% N% calculated for C13H16N2O3S 55.70 5.75 9.99

found 55.14 5.58 9.95.

EXAMPLE 41

  1-oxo-l1H-7-éthylthiazolo- (3,2-aj-pyrimidin-2-

ethyl carboxylate

  47.7 g (0.16 mol) of 2- (2,2-dicarboxylic acid) are

  ethoxy-ethenylamino) -4-ethylthiazole in 500 ml of toluene

  and 45 ml (0.32 moles) of trifluoroacetic anhydride are added.

  A moderate exothermic reaction is observed. The reaction mixture is refluxed for 26 hours, cooled and 250 ml of ethyl acetate are added. 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 dehydrated

  Drate on anhydrous sodium sulfate and evaporate to dryness.

  The residue is suspended in diisopropyl ether

  and the crude product is collected by filtration. By recrystall

  of the crude product in acetonitrile, 1-

  oxo-1H-7-éthylthiazolo- [3,2-aj-pyrimidine-2-carboxylate

  purified ethyl (10.33 g, mp 175-177 ° C).

  Analysis: C,% H,% N,% calculated for C11H12N2O3S 52.37 4.79 11.10 found 52.34 4.85 11.27 53. A second crop (1.58 g, m.p. C) from the acetonitrile constituting the mother liquor.

EXAMPLE 42

  1-oxo-4H-7-isopropylthiazolo- (3,2-aJ-pyrimidin-2-

ethyl carboxylate

  10 g of 2- (2,2-dicarbethoxy) -4-iso-

  propylthiazole 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 2200C for a further 5 hours. The mixture was allowed to cool to room temperature, about 200 ml of hexane was added and filtered to remove traces of insoluble material. We hexane and we

  chromatography the residue on about 500 g of silica gel.

  The "Dowtherm A" is eluted with hexane and the product is eluted with chloroform. Fractions containing the product are

  collected and evaporated to dryness, the residue is suspended

  in diisopropyl ether and the product (mp 143144 ° C) is collected by filtration. The product

  crude is recrystallized from ethanol to give 1-oxo-1H-

  Ethyl 7-isopropylthiazolo-3-yl-pyrimidine-2-carboxylate

  purified (1.49 g, m.p. 145-147 C, magnesium resonance).

  nuclear tick: singlets at 6 8,6 and 6,7,3 corresponding to a proton each and multiplets centered at 6 4,2 and 6 1,2 respectively corresponding to three protons and nine protons)

EXAMPLE 43

* 1-oxo-1H-7-phenylcyclohexenothiazolo [3,2-a] pyrimidine-2-

ethyl carboxylate

  15.3 g (38.2 mmol) of

  (2,2-dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole 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 was allowed to cool to room temperature, diluted to 150 ml with ethyl acetate, extracted twice with 150 ml of 5% potassium carbonate and once with 1 ml of ethyl acetate. saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The solid residue is recrystallized from acetonitrile to give 1-oxo-1H-7-phenylcyclohexenothiazolo-13,2aj-pyrimidine-2-carboxylate

  purified ethyl (9.89 g, mp 160-161.50 ° C).

EXAMPLE 44

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

ethyl carboxylate

  40.2 g (0.119 mol) of 2- (2,2-dicarboxylic acid) are dissolved in

  ethoxy-ethenylamino) -6-methylcyclohexenothiazole in 400 ml of toluene. 33.5 ml (0.237 mol) of trifluoroacetic anhydride are added, causing 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, and then extracted twice with 400 ml of 1N potassium carbonate and with 400 ml of saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. By recrystallization from cyclohexane containing a small

  amount of ethyl acetate, 29.3 g of 1-oxo-1H-7 are obtained.

  methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate

  of purified ethyl melting at 127-129 C.

EXAMPLE 45

  1-oxo-7,7-l1H-diméthylcyclohexénothiazolo-t3,2-N-

ethyl pyrimidine-2-carboxylate

  13 g (36.9 mmol) of 2- (2,2-dicarboxylic acid) are dissolved in

  ethoxy-ethenylamino) -6,6-dimethylthiazole in 130 ml of

  toluene. 10.4 ml (73.6 mmol) of trihydric anhydride are added.

  fluoracetic and the mixture is refluxed for 16 hours. The reaction mixture was 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 dehydrated on anhydrous sodium sulfate and 5.5. it is evaporated to dryness. By recrystallization from hexane,

  9.40 g of 1-oxo-1H-7,7-dimethylcyclohexenothiazolo-

  Purified ethyl 3,2-a-pyrimidine-2-carboxylate melting at

92-940C.

  Analysis: C,% H,% N,% calculated for C15H16N2O3S 58.80 5.92 9.14

found 58.93 5.48 9.01.

EXAMPLE 46

  1-oxo-IH-7- (2-butyl) -thiazolo- (3,2-aJ-pyrimidin-2-

ethyl carboxylate

  17.6 g of 2- (2,2-dicarbethoxy-ethenyl)

  amino) -4- (2-butyl) -thiazole with 175 ml of "Dowtherm A" and the mixture is heated at 225 ° C. for 2.5 hours. The reaction mixture was 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 about 400 ml of hot hexane, the solution is treated with charcoal and cooled to give

  2.12 g of 1-oxo-1H-7- (2-butyl) -thiazolo [3,2-a] pyrimidine-2-

  crystalline ethyl carboxylate melting at 105.5-108 C.

  Analysis: C,% H,% N,% calculated for C13H1603N2S 55.70 5.75 9.99

found 55.82 5.40 10.22.

EXAMPLE 47

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

carboxylic

  1.41 g of 1-oxo-1H-6,7-dimethyl-

  ethyl thiazolo- (3,2-a) pyrimidine-2-carboxylate in the bath

  boiling with 20 ml of 48% hydrobromic acid for 1 hour. The 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 in

  ethanol, 1-oxo-1H-6,7-dimethylthiazole acid is obtained

2470132!

  56. (3,2-a-pyrimidine-2-carboxylic acid purified (508 mg,

melting 189-190 C).

  Analysis: CI% H% N,% calculated for C9H803N2S 48.21 3.60 12.49 mass ion: 224 found 48.21 3.68 12.44

mass ion: 224.

EXAMPLE 48

  1-Oxo-1H-6-methyl-7-ethylthiazolo [3,2-a]

pyrimidine-2-carboxylic acid

  Boiling in a boiling water bath 971 mg of

  oxo-1H-6-methyl-7-éthylthiazolo- (3,2-aJ-pyrimidine-2-carboxylate

  of ethyl with 15 ml of 48% hydrobromic acid. Dissolution

  tion takes place almost immediately. Heating is continued for 2.5 hours, and at this stage the reaction mixture is cooled to yield a product in the form of

  a solid substance capable of being filtered. By recrystall

  of the crude product in isopropyl alcohol,

  obtains 1-oxo-1H-6-methyl-7-ethylthiazolo-13,2-a-

  purified pyrimidine-2-carboxylic acid (354 mg, mp 201-202 ° C). Analysis: C% H,% N,% calculated for C10H1003N2S 50.41 4.23 11.76

found 50.28 4.26 11.80.

EXAMPLE 49

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

  In a boiling water bath, 1.33 g of

  Ethyl oxo-1H-6-ethyl-7-methylthiazolo-13,2-a-pyrimidine-2-carboxylate with 10 ml of 48% hydrobromic acid for minutes and at this stage a solid begins to form. form. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization in

  isopropyl alcohol, 1-oxo-1H-6-ethyl-

  Purified 7-methylthiazolo- (3,2-a) pyrimidine-2-carboxylic acid

(596 mg, m.p. 174-176 ° C.

  57. Analysis: C,% H,% N,% calculated for C10H1003N2S 50.41 4.23 11.76

found 50.44 4.22 11.82.

EXAMPLE 50

  1-oxo-1H-6,7-diethylthiazolo-3-yl

pyrimidine-2-carboxylic acid

  19.2 g of 1-oxo-1H-6,7-diethyl-

  ethyl thiazolo- [3,2-a] pyrimidine-2-carboxylate at 85 ° C

  for one hour with 48% aqueous hydrobromic acid.

  Gas evolution (presumably due to decarboxylation of the product) is observed. The reaction mixture is cooled and made alkaline by the addition of concentrated ammonium hydroxide and the unreacted starting

  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 to give 4 g of partially purified product in two crops. 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] pyrimidine-2- acid. carboxyliqui

  purified (1.6 g, mp 104-106 ° C (cloud)).

  Analysis: C,% H,% NF% calculated for C11H1203N2S 52.37 4.79 11.10

found 52.31 4.79 11.16.

EXAMPLE 51

  1-Oxo-1H-cyclopentenothiazolo-t3,2-aj-acid

pyrimidine-2-carboxylic acid

  1.3 g of 1-oxo-1H-cyclopenteno

  ethyl thiazolo- (3,2-a) pyrimidine-2-carboxylate with 15 ml of 48% hydrobromic acid in a boiling water bath for 5 minutes, the dissolution takes place after about 5 minutes; The reaction mixture is cooled and the crude product is collected by filtration, recrystallization from isopropyl alcohol gives 58 g.

  0.51 g of 1-oxo-1H-cyclopentenothiazolo [3,2-a]

  purified pyrimidine-2-carboxylic acid (m.p.

203.5 ° C).

  Analysis: C,% H,% N,% calculated for C10H803N2S 50.84 3.41 11.86

found 50.42 3.57 11.65. -

  Sodium and potassium salts are obtained

  by dissolving the free acid in water with an equivalent

  suitably selected hydroxide and evaporation of the water.

under vacuum or lyophilization.

  The N-methylmorpholine salt is prepared by dissolving the acid in methylene chloride with a slight excess of N-methylmorpholine and evaporation at -sec or

  precipitation of the salt by cooling and addition of hexane.

EXAMPLE 52

  1-oxo-1H-cyclohexenothiazolo [3,2-a]

pyrimidine-2-carboxylic acid

  2.8 g of 1-oxo-1H-cyclohexenothiazolone are heated

  Ethyl 13,2-a-pyrimidine-2-carboxylate in a water bath

  boiling with 30 ml of 48% hydrobromic acid. Dissolution

  lution 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 a bath of

  ice and 1.66 g of 1-oxo-1H-

  cyclohexenothiazolo-13,2-aJ-pyrimidine-2-carboxylic acid melting at 188-189 C. By recrystallization from ethanol, we obtain

  1.38 g of product having the same melting point.

  Alternatively, this product is prepared by stirring 22.3 g of the ethyl ester with 223 ml of 48% hydrobromic acid in a low pressure vessel. The dissolution takes place at 65-70 C. The reaction mixture is

  heated in a period of 40 minutes to a maximum temperature of

  male at 85 C and at a maximum gauge pressure of 49 kPa. The reaction mixture is cooled to 45 ° C., the pressure is relaxed, the mixture is cooled to 5 ° C., stirred for one hour and the relatively pure product is collected.

  directly by filtration (12.4 g, m.p.

194WC)

  59. The sodium salt is prepared by dissolving the acid in methanol with one equivalent of sodium methoxide and evaporating to dryness or precipitating the salt by

  cooling and addition of hexane.

EXAMPLE 53

  1-oxo-1H-cycloheptenothiazolo-3,2-a-

pyrimidine-2-carboxylic acid

  5.8 g of 1-oxo-1H-cyclohepteno are heated

  ethyl thiazolo- (3,2-a) pyrimidine-2-carboxylate

  minutes in a boiling water bath with 50 ml bromhynic acid

  drique. The reaction mixture is poured into ice, stirred and the crude product is collected by filtration. By

  recrystallization from ethanol, 1-oxoacid is obtained

  1H-cyclohepténothiazolo- [3,2-aJ-pyrimidine-2-carboxylic acid

  purified (2.63 g, mp 162-163 ° C).

  Analysis: C,% H,% calculated for C12H12N3O2S 54.53 4.58 10.60 mass ion: 264 found 54.72 4.73 10.88

mass ion: 264.

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

hexane.

EXAMPLE 54

  1-Oxo-1H-cyclooctenothiazolo [3,2-a]

pyrimidine-2-carboxylic acid

  1.23 g of 1-oxo-1H-cycloocteno are heated

  ethyl thiazolo- (3,2-a) 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 and its pH adjusted at 1.5 and the product is extracted into ethyl acetate The extraction phase with ethyl acetate is washed with water and then with saturated sodium chloride, dehydrated

  on sodium sulphate and evaporated to give an oil.

  The oil is redissolved in ethyl acetate and the product is extracted into 1N potassium hydroxide. The basic solution is reacidified with 3N hydrochloric acid and the product is reextracted in ethyl acetate. The ethyl acetate solution is extracted with water and then with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness to give 308 mg of 1-oxo-1H-cycloheptenothiazolo- 13.2-α-pyrimidine-2-carboxylic acid (Rf = 0.6 by thin-layer chromatography on silica gel with chloroform added with 1% as eluent)

ethanol).

  The methodology of Examples 47 to 53 is used

  to convert 1-oxo-1H-thiazolo-L3,2-a-pyrimidine-2-

  corresponding alkyl carboxylates of Example 31 to the following acids:

  1-oxo-1H-6-methyl-7-ethylthiazolo-13,2-a-pyrimidine-1-acid

2-carboxylic acid,

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

carboxylic acid,

  1-oxo-1H-7-pentylthiazolo- (3,2-a) -pyrimidine-2-acid

carboxylic acid,

  1-Oxo-1H-6-ethyl-7-propylthiazolo [3,2-a] pyrimidine-2- acid

carboxylic acid,

  1-oxo-1H-6,7-diisopropylthiazolo-3,2-a-pyrimidine-1-acid

2-carboxylic acid,

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

carboxylic acid,

  1-oxo-1H-6-isopropylthiazolo-43,2-aj-pyrimidine-2-acid

carboxylic acid,

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

carboxylic acid,

  - 1-oxo-1H-6-phenylcyclopentenothiazolo-13,2-aJ-

pyrimidine-2-carboxylic acid,

  1-oxo-1H-6,8-dimethylcyclohexenothiazolo [3,2-a];

pyrimidine-2-carboxylic acid,

  1-oxo-1H-8-methylcyclooctenothiazolo [3,2-a]

pyrimidine-2-carboxylic acid, and

  - 1-oxo-1H-6,8,8-trimethylcyclopentenothiazolo-3,2-aj-

pyrimidine-2-carboxylic acid. 24; 61.

EXAMPLE 55

  1-Oxo-1H-7-methylthiazolo [3,2-a] pyrimidine acid

2-carboxylic acid

  3.1 g of 1-oxo-1H-7-methylthiazolone are heated

  Ethyl L3,2-a-pyrimidine-2-carboxylate in a water bath

  boiling with 50 ml of 48% hydrobromic acid. Dissolution

  lution takes place in 5 minutes. After a heating period of about 15 minutes, the reaction mixture is cooled and the product which precipitates is collected by filtration. Recrystallization from acetic acid gives 1.4 g

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

  purified carboxylic acid melting at 265vC decompose.

  Analysis: C,% H,% N,% calculated for C8H603N2S 45.71 2.88 13.33

found 45.57 3.04 13.40.

EXAMPLE 56

  1-Oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid The mixture is heated for 20 minutes in a water bath

  boiling 7.5 g of 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-

  ethyl carboxylate with 80 ml of 48% hydrobromic acid.

  The dissolution takes place in 5 minutes and the precipitation of a solid substance begins a few minutes later. The reaction mixture is cooled in an ice bath and the crude product is collected by filtration. 4.66 g of 1-oxo-1H-thiazolo- [3,2-a] pyrimidine-2-carboxylic acid are obtained.

  purified melting at 276 ° C decomposing.

  Analysis: C,% H,% N,% calculated for C7H403N2S 42.86 2.06 14.28

found 42.71 2.21 14.32.

  Alternatively, this acid can be prepared from the same intermediate compound by refluxing

  in an excess of hydrochloric acid 2N LAllen and collabora-

  J. Org. Chem., 24, 779 (1959) J.

2470132 1

62.

EXAMPLE 57

  1-Oxo-1H-6-methylthiazolo [3,2-a

pyrimidine-2-carboxylic acid

  5.96 g of 1-oxo-1H-6-methylthiazolone are heated

  Ethyl 1,3,2-di-pyrimidine-2-carboxylate in a water bath boiling 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 recrystall

  of the crude product in dimethylformamide, we obtain

  3.73 g of 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine acid

  Purified 2-carboxylic acid melting at 246-248 ° C as it decomposes.

  Analysis: C,% H1% N,% calculated for C8H603N2S 45.71 2.88 13.33

found 45.87 2.94 13.47.

  Alternatively, the acid is prepared from the same intermediate compound by heating under reflux in 2N hydrochloric acid (Dunwell et al., J. Chem.

Soc. (C) 1971, 2094).

EXAMPLE 58

  1-Oxo-1H-6-ethylthiazolo [3,2-a]

pyrimidine-2-carboxylic acid

  12.6 g of 1-oxo-1H-6-ethylthiazolone are heated

  Ethyl 13,2-a-pyrimidine-2-carboxylate in a water bath

  boiling with 125 ml of 48% hydrobromic acid. Dissolution

  lution takes place in a few minutes. After 10 minutes, a solid begins to form. Heating continues for a total of 40 minutes. The reaction mixture is cooled and 10.1 g of crude product is collected by filtration. By recrystallization of 2.32 g of crude product

  (taken from the 6.8 g of product collected in a

  recrystallization in acetic acid) in alcohol

  isopropyl, 1.85 g of 1-oxo-1H-6-ethyl-

  purified thiazolo- (3,2-a] pyrimidine-2-carboxylic acid

162-163 C.

  Analysis: C,% H,% N,% calculated for C9H 0 N S 48.21 3.60 12.49 9v 48.1 3, 12.42

found 48.17 3.73 12.42.

63.

EXAMPLE 59

  1-Oxo-1H-7- (2-methyl-2-propyl) -thiazolo [3,2-a] pyrimidine-2-carboxylic acid 5 g of 1-oxo-1H are heated in a boiling water bath for 6 hours Ethyl 7- (2-methyl-2-propyl) -thiazolo- (3,2-a) pyrimidine-2-carboxylate with 60 ml of 48% hydrobromic acid After a period of about 10 minutes, before the total dissolution of the ester, the reaction mixture becomes very thick At the end of the heating period, the reaction mixture is cooled and the product is collected.

  crude by filtration. By recrystallization from acetic acid

  tick and dehydration on dimethylformamide,

  1-Oxo-1H-7- (2-methyl-2-propyl) -thiazolo-L3,2-a

  purified pyrimidine-2-carboxylic acid (3.33 g, melting point,

241-242 C (decomposition) ".

  Analysis: C,% H1% N,% Calculated for C11H1203N2S 52.37 4.79 1110

found 52.45 4.82 11.26.

EXAMPLE 60 -

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

2-carboxylic acid

  1.5 g of 1-oxo-1H-7-ethylthiazolone are heated

  13.2-α-pyrimidine-2-carboxylate ethyl boiling on a water bath with 15 ml of 48% hydrobromic acid for minutes. The dissolution takes place in 5 minutes and, after 10 minutes, a solid begins to precipitate. At the end of the reaction period, the mixture is allowed to cool to room temperature, diluted with about 25 ml of water and the crude product is collected by filtration. The crude product is partially purified by dissolution in 1N potassium carbonate and reprecipitation by acidification

with 3N hydrochloric acid.

  By recrystallization from acetic acid,

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

  Purified 2-carboxylic acid (594 mg, mp 206-209 ° C).

  Analysis: C,% H,% N,% calculated for C9H8N2O3S 48.21 3.60 12.49

found 48.01 3.69 12.50.

64.

EXAMPLE 61

  1-Oxo-1H-7-isopropylthiazolo- (3,2-a)

pyrimidine-2-carboxylic acid

  909 mg of 1-oxo-1H-7-isopropyl

  thiazolo- (3,2-a) -pyrimidine-2-carboxylic acid on boiling water bath with 10 ml of 48% hydrobromic acid for minutes.In 5 minutes, the dissolution is complete, the product begins to precipitate at After 10 minutes, after

  heating period, the reaction mixture is allowed to cool

  at room temperature and the crude product is collected by filtration. By recrystallization in ethanol,

  obtains 1-oxo-1H-7-isopropylthiazolo [3,2-a]

  purified pyrimidine-2-carboxylic acid (538 mg, m.p.

216-217 C)

EXAMPLE 62

  1-Oxo-1H-7-phenylcyclohexenothiazolo- (3,2-al-

* Pyrimidine-2-carboxylic acid

  9.8 g of 1-oxo-1H-7-phenylcyclohexene are heated

  ethyl thiazolo-13,2-a-pyrimidine-2-carboxylate at reflux with 200 ml of 48% hydrobromic acid for 20 minutes; the dissolution takes place after about 10 minutes. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization in acid

  acetic acid, 2.25 g of 1-oxo-1H-7-phenylcycloacetic acid are obtained.

  purified hexenothiazolo- [3,2-a] pyrimidine-2-carboxylic acid

melting at 224-226 C.

  Analysis: C,% H,% NI% calculated for C17H14N2O3S 62.56 4.32 8.58

found 62.26 4.11 8.52.

  A second crop is obtained from the

  mother liquor (704 mg, mp 217-220 ° C).

EXAMPLE 63

  1-Oxo-1H-7-methylcyclohexenothiazolo-t3,2-a) -

  pyrimidine-2-carboxylic acid is heated in a boiling water bath

  minutes 27.5 g of 1-oxo-1H-7-methylcyclohexenothiazolo-

247013:

  65. (Ethyl 3,2-a) pyrimidine-2-carboxylate with 275 ml of 48% hydrobromic acid After 10 minutes, a clear solution is obtained, the precipitation of the product begins after 15 minutes. The reaction mixture was allowed to cool to room temperature and the crude product (14.9 g, mp 181.5-183.5 ° C) was collected by filtration, washed with water and recrystallized from dimethylformamide. , we

  obtains 1-oxo-1H-7-methylcyclohexenothiazolo-L3,2-aJ-

  purified pyrimidine-2-carboxylic acid (10.1 g, m.p.

183.5-185.5 ° C).

  Analysis: C,% H,% N,% calculated for C12H12N2O3S 54.53 4.58 10.60

found 54.41 4.28 10.58.

  A second crop is obtained by adding water to the mother liquor formed from dimethylformamide (3.11 g, point

melting point 182-184 C).

EXAMPLE 64

  1-Oxo-1H-7,7-dimethylcyclohexenothiazolo-13,2-a

pyrimidine-2-carboxylic acid

  7.9 g of 1-oxo-1H-7,7-dimethylcyclohexane are mixed together.

  ethyl hexenothiazolo- (3,2-a) pyrimidine-2-carboxylate with 48% hydrobromic acid and the mixture is heated on a steam bath for 50 minutes before the end of the dissolution of the ester. the acid begins to precipitate, the reaction mixture is cooled, diluted with about 1 ml of water and 6.7 g of product is collected by filtration.

  raw that washed with a small volume of water. By recrystall

  of the crude product in ethanol, 1- acid is obtained.

  oxo-1H-7,7-diméthylcyclohexénothiazolo- (3,2-aJ-pyrimidin-2 is

  purified boxylic acid (4.7 g, mp 197-198 ° C).

  Analysis: C,% H,% N,% calculated for C13H14N2O3S 56.10 5.07 10.06

found 55.85 4.84 10.14.

2470132 1

66.

EXAMPLE 65

  1-Oxo-1H-7- (2-butyl) -thiazolo-t3,2-a_-

pyrimidine-2-carboxylic acid

  2.0 g of 1-oxo-1H-7- (2-butyl) -

  ethyl thiazolo- (3,2-a) pyrimidine-2-carboxylate with 20 ml

  of 48% hydrobromic acid and the mixture is heated in the bath.

  boiling for 25 minutes. The dissolution takes place in 5 minutes; precipitation of the product begins after minutes. The reaction mixture was allowed to cool to room temperature, diluted with about 40 ml of water and 1.3 g of crude product (m.p.

  191-194 C) by washing with a small volume of water.

  Recrystallization of the crude product from ethyl acetate containing a small amount of ethanol yields

  1-Oxo-1H-7- (2-butyl) -thiazolo [3,2-a] pyrimidine-2-acid

  purified carboxylic acid (606 mg, m.p. 194-197 ° C).

  Analysis: C,% H,% N,% calculated for C11H12N2O3S 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-diméthylthiazolo-

L3,2-a] pyrimidine-2-carboxamide

  367 mg (1.6 mmol) of 1-oxo-1H-

  6,7-dimethylthiazolo-1,3,2-a-pyrimidine-2-carboxylic acid in 3 ml of dimethylformamide by heating in a water bath

  boiling. 292 mg (1.8 mmol) of 1,1-carbonyldi

  imidazole. There is an immediate release of gas. As soon as the evolution of gas has ceased, 143 mg (1.8 mmol) of aminotetrazole are added. The dissolution takes place and the solid substance is formed again. The reaction mixture is cooled and the crude product is collected by filtration. By recrystallization of the crude product in dimethylformamide,

  336 mg of N- (5-tetrazolyl) -1-oxo-11H-6,7-dimethyl-

  purified thiazolo-1,3,2-a-pyrimidine-2-carboxamide, m.p.

above 317 C.

  67. Analysis: C,% RH% N% calculated for C10H902N7S 41.23 3.11 33.66

found 41.52 3.40 33.47.

EXAMPLE 67

  N- (5-tetrazolyl) -1-oxo-1H-6-methyl-7-éthylthiazolo-

[3,2-a) -pyrimidine-2-carboxamide

  238 mg (1.0 mmol) of 1-oxo-1H-6-acid are dissolved

  methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid in

  5 ml of dimethylformamide and the solution is heated in the bath.

  boiling Marie. 178 mg (1.1 mmol) of 1,1

  carbonyldiimidazole. When the evolution of gas has ceased, 93.5 mg (1.1 mmol) of 5-aminotetrazole are added. A solid substance begins to precipitate after about 15 minutes. The reaction mixture is cooled and filtered to give 227 mg

  N- (5-Tetrazolyl) -1-oxo-1H-6-methyl-7-ethylthiazolo-L3,2-

  α-pyrimidine-2-carboxamide melting above 310 ° C.

  Analysis: C,% H1% N,% calculated for C11H11O2N7S 43.27 3.63 32.11

found 43.20 3.72 31.88.

EXAMPLE 68

  N- (5-tetrazolyl) -1-oxo-1H-6-ethyl-7-méthylthiazolo-

13.2-aJ-pyrimidine-2-carboxamide

  476 mg (2.0 mmol) of 1-oxo-1H-

  6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid in boiling-bath dimethylformamide 357 mg (2.2 mmol) of 1,1-dicarbonylimidazole are added to the hot solution; a release of gas occurs when the release of

  gas has ceased, 187 mg (2.2 mmol) of 5-amino

  tetrazole. Within minutes, a solid substance begins to form. The reaction mixture is cooled and

  Collects the crude product by filtration. By recrystalli-

  Dysation in dimethylformamide gives 388 mg of N- (5-

  tetrazolyl) -1-oxo-1H-6-ethyl-7-méthylthiazolo- [3,2-aJ-pyrimidine

  Purified 2-carboxamide melting at 303 ° C decomposing.

  Analysis: C,% H% N% calculated for C11H10O2N7S 43.3 3.6 32.1

found 43.6 3.9 3213.

2470132 1

68.

EXAMPLE 69

  N- (5-tetrazolyl) -1-oxo-1H-6,7-diéthylthiazolo-

[3,2-aJ-pyrimidine-2-carboxamide

  2.52 g (10 mmol) of 1-oxo-1H-

  6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid and 1,78 g (11 mmol) of 1,1'-carbonyldiimidazole with 15 ml of dimethylformamide and heated on a steam bath. There is a release of gas and a dissolution. When the evolution of gas has ceased, 1.13 g (11 mmol) of 5-aminotetrazole is added and heating is continued for minutes. The reaction mixture is cooled and the precipitated crude product is collected by filtration. By recrystallization of the crude product in acetic acid,

  gives 1.11 g of N- (5-tetrazolyl) -1-oxo-1H-6,7-diethyl-

  purified thiazolo- (3,2-a] pyrimidine-2-carboxamide melting at

283 C decomposing.

  Analysis: C,% H% N,% calculated for C12H1302N7S 45.13 4.10 30.70 mass ion: 319 found 45.18 4.24 30.52 mass ion: 319

EXAMPLE 70

  N- (5-Tetrazolyl) -1-oxo-1H-cyclopentenothiazolo

[3,2-aJ-pyrimidine-2-carboxamide

  378 mg (16 mmol) of 1-oxo-1H-

  cyclopentenothiazolo- (3,2-a) pyrimidine-2-carboxylic acid and 285 mg (17.6 mmol) of 1,1'-carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated in a boiling water bath; When the evolution of gas has ceased, 150 mg (17.6 mmol) of 5-aminotetrazole are added, and in a few minutes the product begins to precipitate.

  The crude product is collected by filtration.

  By recrystallization from dimethylformamide, we obtain

  313 mg of N- (5-tetrazolyl) -1-oxo-1H-cyclopentenothiazolo-

  Purified 3,2-aJ-pyrimidine-2-carboxamide melting above

310 C.

24701 3

  69. Analysis: C,% H,% N,% calculated for C11H902N7S 43.6 3.0 32.3

found 43.6 3.3 32.0.

EXAMPLE 71

  N- (5-tetrazolyl) -1-oxo-cyclohexénothiazolo-

(3,2-aJ-pyrimidine-2-carboxamide

  0.5 g (2 mmol) of 1-oxo-1H-

  cyclohexenothiazolo-13,2-a-pyrimidine-2-carboxylic acid and 0.36 g (2.2 mmol) of 1,1'-carbonyldiimidazole in 3 ml of dimethylformamide at room temperature; we are witnessing dissolution and a release of gas. When the release

  of gas has ceased, the reaction mixture is heated in the bath.

  marie boiling, period during which there is a new release of gas. To the hot solution was added 0.19 g (2.2 mmol) of 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, the N- (5-tetra-

  purified zolyl) -1-oxo-1H-cyclohexenothiazolo- (3,2-a) -pyrimidine-2-carbo amide (319 mg, m.p. 310 C (dec) J. Analysis: C,% H1% N,% Calcd for C12H11O2N7S 45.42 3.49 - 30.90

found 45.59 3.62 30.44.

  Alternatively, the acid is dissolved (2.07 g)

  in 40 ml of methylene chloride and 1.74 ml of triethyl

  amine at 0 ° C. 0.85 ml of ethyl chloroformate in 8.1 ml of methylene chloride are 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. C for 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 and then maintained at this temperature for 90 minutes. The product is collected by filtration (2.0 g, mp 308-3107 ° C). The product prepared in this manner (3.9 g) is recrystallized from

  dimethylacetamide to give 3.1 g of N- (5-tetrazolyl) -1-

  oxo-1H-cyclohexénothiazolo-13.2-aJ-pyrimidine-2-carboxamide

purified melting at 314-315uC.

  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 hydroxide. standardized sodium hydroxide 1H stirring for 30 minutes (pH 11.0). The solution is clarified and the sodium salt is precipitated by the addition of 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 at 5 C and granulated at this temperature during -

  1 hour. The sodium salt (1.68 g) is collected by filtration.

  tion. The pH of 100 mg of sodium salt recrystallized in 1 ml

of water is equal to 8.80.

  HO analysis Loss of boids Water equivalent of drying neutralization Calculated for C12Ho10O2N7SNa.3H20 13.7 13.7 393 Found 13.43 13.8 391

  In the mixed anhydride process described above

  above, equivalent amounts of methyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, chloroformate

  tert-butyl, pentyl chloroformate, chloroform

  Phenylmelate or benzyl chloroformate are used in place of ethyl chloroformate giving substantially similar results. Similarly, equivalent amounts of the other acids described in Examples 47 to 65 are reacted with chloroformates and then with 5-aminotetrazole to give the corresponding N- (5-tetrazolyl) amides.

EXAMPLE 72

  N- (5-tetrazolyl) -1-oxo-l1H-cyclohepténothiazolo-

[3,2-aJ-pyrimidine-2-carboxamide

  2.1 g (8 mmol) of 1-oxo-1H-

  cyclopentenothiazolo- [3,2-a] pyrimidine-2-carboxylic acid and 1.4 g (8.8 mmol) of 1,1-carbonyldiimidazole with 15 ml of 71. dimethylformamide and the mixture is heated on a steam bath. When the evolution of gas ceased, 0.86 g (8.8 mmol) of aminotetrazole monohydrate was added. A solid substance is formed in 5 minutes. After an additional heating period of 30 minutes, the

  reaction mixture and the product is collected by filtration.

  By recrystallization of the crude product in dimethyl

  formamide, 1.61 g of N- (5-tetrazolyl) -1-oxo-1H-

  purified cycloheptenothiazolo- (3,2-a) pyrimidine-2-carboxamide

  melting at 295-296 C decompose.

  Analysis: C,% H,% N,% calculated for C13H1302N7S 47.12 3.95 29.59

found 47.10 4.11 29.72.

EXAMPLE 73

  N- (5-tetrazolyl) -1-oxo-1H-cycloocténothiazolo-

(3,2-a] pyrimidine-2-carboxamide

  308 mg (1.1 mmol) of 1-oxo-1H-

  cyclooctenothiazolo-13,2-a-pyrimidine-2-carboxylic acid in

  10 ml of dimethylformamide and the solution is heated in the bath.

  boiling Marie. 196 mg (1.21 mmol) of 1,1'-

  carbonyldiimidazole. When the evolution of gas has ceased, 103 mg (1.21 mmol) of 5-aminotetrazole are added. The reaction mixture is heated for 10 minutes, during which time a solid begins to precipitate. The reaction mixture is cooled and the product is collected.

  crude by filtration. By recrystallization from dimethyl

  formamide gives 183 mg of N- (5-tetrazolyl) -1-oxo-1H-

  purified cyclooctenothiazolo- (3,2-a) pyrimidine-2-carboxamide

  melting at 310 ° C while decomposing.

  Analysis: C,% H,% N,% calculated for C14H1502N7S

48.69 4.38 28.39

found 49.01 4.63 27.35

2470132 1

72.

EXAMPLE 74

  N- (5-fétrazolYl) -l1-oxo-l1H-7-méthylthiazolo-

[3,2-aJ-pyrimidine-2-carboxamide

  0.91 g (4.3 mmol) of 1-oxo-1H-7-

  methylthiazolo- [3,2-a] pyrimidine-2-carboxylic acid and 0.89 g

  (5.5 mmol) of 1,1'-carbonyldiimidazole to 5 ml of dimethyl

  formamide and the mixture is heated in a boiling water bath.

  When the evolution of gas has ceased, 0.47 g (5.5 mmol) of aminotetrazole is added. Before the total dissolution has been obtained, a new solid substance begins to precipitate. After a few minutes, the reaction mixture is cooled and the product is collected.

  crude by filtration. By recrystallization from dimethyl

  formamide, 1.0 g of N- (5-tetrazolyl) -1-oxo-1H-7 are obtained.

  purified methylthiazolo-13,2-a-pyrimidine-2-carboxamide

melting above 310 C.

  Analysis: C% H1% N% calculated for C9H702N7S 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) -pyrimidine-2-carboxamide

  1.96 g (10 mmol) of 1-oxo-1H-

  thiazolo- [3,2-a] pyrimidine-2-carboxylic acid in 20 ml of

  dimethylformamide in a boiling water bath. 1.78 g is added

  (11.0 mmol) 1,1'-carbonyldiimidazole. When the

  After the addition of gas, 1.13 g (11 mmol) of mono-

  5-aminotetrazole hydrate. A solid substance is formed in less than 1 minute. After heating for another 15 minutes, the reaction mixture is cooled and the product is collected.

  crude by filtration. By recrystallization from dimethyl

  formamide, 1.8 g of N- (5-tetrazolyl) -1-oxo-1H-

  purified thiazolo [(3,2-a] pyrimidine-2-carboxamide, m.p.

above 315 C.

  Analysis: C,% H1% N% calculated for C8H502N7S 36.50 1.91 37.25

found - 36.62 2.26 37.72.

24701,

73.

EXAMPLE 76

  N- (5-tetrazolyl) -1-oxo-1H-6-méthylthiazolo-

(3,2-aJ-pyrimidine-2-carboxamide

  2.10 g (10 mmol) of 1-oxo-1H-6- acid are mixed

  methylthiazolo- (3,2-a) pyrimidine-2-carboxylic acid and 1.78 g

  (11 mmol) of 1,1'-carbonyldiimidazole with 15 ml of

  thylformamide and the mixture is heated in a boiling water bath. This results in a release of gas and the dissolution takes place. When the release of gas is complete,

  1.13 g (11 mmol) of 5-aminotetrazole monohydrate is added.

  A solid substance is formed in less than 1 minute. After

  heating for 5 minutes, the reaction mixture is cooled

  nel. 2.33 g of N- (5-tetrazolyl) -1 are obtained by filtration.

  oxo-1H-6-methylthiazolo-13.2-aJ-pyrimidine-2-carboxamide

melting above 318 C.

  Analysis: C,% H,% N,% calculated for C9H702N7S 38.99 2.54 35.36

found 39.35 3.00 35.06.

EXAMPLE 77

  N- (5-tetrazolyl) -1-oxo-1H-6-éthylthiazolo-

L3,2-aJ-pyrimidine-2-carboxamide

  4.48 g (20 mmol) of 1-oxo-1H-6- acid are mixed

  ethylthiazolo- (3,2-a) pyrimidine-2-carboxylic acid and 3.57 g

  (22 mmol) of 1,1'-carbonyldiimidazole with 20 ml of

  thylformamide and the mixture is heated in a boiling water bath. There is a release of gas and the dissolution takes place. When the evolution of gas has ceased, 2.27 g (22 mmol) of 5-aminotetrazole monohydrate are added. A solid substance is formed in 1 minute. The reaction mixture is heated for a further 15 minutes, cooled and the crude product is collected by filtration. By recrystallization in

  dimethylformamide, 4.7 g of N- (5-tetrazolyl) -1 are obtained.

  * Oxo-1H-6-éthylthiazolo- (3,2-aJ-pyrimidine-2-carboxamide

  melting at 274 C decompose.

  Analysis: C,% H% N,% calculated for C10H902N7S 41.23 3.11 33.66

found 41.41 3.30 33.84.

2470132 i1 74.

EXAMPLE 78

  N- (5-Tetrazolyl) -1-oxo-1H-7- (2-methyl-2-propyl) thiazolo-

t 3,2-a-pyrimidine-2-carboxamide

  2.52 g (10 mmol) of 1-oxo-1H-7-

  (2-methyl-2-propyl) -thiazolo-1,3,2-a] -3-pyrimidine-2-carboxylic acid and 1.78 g (11 mmol) of 1,1'-carbonyldiimidazole with 15 ml of dimethylformamide and heated with water. boiling Marie. There is a release of gas and the dissolution takes place; a solid material is formed in a few minutes. Heating is continued for a total period of about 10 minutes. The reaction mixture is cooled and the product is collected.

  crude by filtration. By recrystallization from dimethyl

  formamide, 1.62 g of N- (5-tetrazolyl) -1-oxo-1H-7 are obtained.

  (2-methyl-2-propyl) -thiazolo- (3,2-a) -pyrimidine-2-carboxamide

  purified melting at 280 ° C decomposing.

  Analysis: C,% H,% N,% calculated for C12H1302N7S 45.13 4.10 30.70

found 45.22 4.40 30.05.

EXAMPLE 79

  N- (5-tetrazolyl) -1l-oxo-1H-7-éthylthiazolo-

[3,2-aJ-pyrimidine-2-carboxamide

  502.5 mg (2.24 mmol) of 1-oxoacid

  1H-7-ethylthiazolo-L3,2-aj-pyrimidine-2-carboxylic acid and 399.7 mg (2.46 mmol) of 1,1'-carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated on a steam bath. . The dissolution takes place and a gas emerges. When the evolution of gas has ceased, 253.0 mg (2.45 mmol) of 5-aminotetrazole monohydrate is added. This gives a clear solution; after 2 minutes, a solid begins to precipitate. The mixture is heated for a further 20 minutes, allowed to cool to room temperature and

  Collects the crude product by filtration. By recrystalli-

  in dimethylformamide, 486.8 mg of N- (5-

  tetrazolyl) -1-oxo-1H-7-ethylthiazolo-L3,2-aJ-pyrimidin-2-carbox-

  purified amide melting at 261-262 C in decomposition.

  75. Analysis: C,% H,% NI% calculated for C10H9N7O2S 41.23 3.11 33.66 mass ion: 291 found 41.35 3.31 33.55 ion mass: 291.

* EXAMPLE 80

  N- (5-tetrazolyl) -1-oxo-1H-7-isopropylthiazolo-

[3,2-aJ-pyrimidine-2-carboxamide

  537 mg (2.25 mmol) of 1-oxo-1H-

  7-isopropylthiazolo-13,2-a-pyrimidine-2-carboxylic acid and 401 mg (2.47 mmol) of 1,1'-carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated on a steam bath. The dissolution takes place and a gas emerges. 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. We continue to heat for minutes, then cool the reaction mixture and

  Collects the crude product by filtration. By recrystalli-

  in dimethylformamide, 328 mg of N- (5-

  tetrazolyl) -1-oxo-1H-7-isopropylthiazolo- [3,2-aJ-pyrimidin-2-

  purified carboxamide melting above 300 C.

  Analysis: C,% H,% N% calculated for C11H11O2N7S 43.27 3.63 32.11

found 43.34 3.76 31.82.

EXAMPLE 81

  N- (5-tetrazolyl) -1-oxo-1H-7-phénylcyclohexénothiazolo-

(3,2-aJ-pyrimidine-2-carboxamide

  980 mg (3.0 mmol) of 1-oxo-1H-

  7-phenylcyclohexenothiazolo-3,2-a-pyrimidine-2-carboxylic acid and 320 mg (3.1 mmol) of 1,1'-carbonyldiimidazole with 12 ml of dimethylformamide and the mixture is heated on a steam bath. When the evolution of gas has ceased, 496 mg (3.1 mmol) of 5-aminotetrazole monohydrate is added. 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 collected.

2470132 1

  76. by filtration 312 mg of crude product. By recrystallization

  in dimethylformamide, 131.5 mg of N- (5-

  tetrazolyl) -1-oxo-1H-7-phénylcyclohexénothiazolo- (3,2-aJ-pyridinium

  purified midine-2-darboxamide melting above 300 C.

  Analysis: C,% H% N,% Calculated for C18H14O2N7S 54.95 3.84 24.92

found 54.38 3.93 24.61.

EXAMPLE 82

  N- (5-tetrazolyl) -1-oxo-7-méthylcyclohexénothiazolo-

[3,2-a) -pyrimidine-2-carboxamide

  1.0 g (3.78 mmol) of 1-oxo-1H-

  7-methylcyclohexenothiazolo-1,3,2-a-pyrimidine-2-carboxylic acid and 675 mg (4.16 mmol) of 1,1'-carbonyldiimidazole in 6 ml of dimethylformamide and the mixture is heated on a steam bath. A gas is evolved and the dissolution takes place. When the evolution of gas has ceased, 429 mg (4.16 mmol) of 5-aminotetrazole is added and heating is continued. After a few minutes, a precipitate begins to form. After 30 minutes, the reaction mixture is cooled and the crude product (melting above 300 ° C.) is collected by filtration. By recrystallization from dimethylformamide,

  980 mg of N- (5-tetrazolyl) -1-oxo-1H-7-methylcyclohexane are obtained.

  purified hexenothiazolo- (3,2-a) pyrimidine-2-carboxamide

melting above 300 C.

  Analysis: C% H,% N,% calculated for C13H1302N7S 47.12 3.95 29.59

found 47.32 4.19 29.60.

EXAMPLE 83

  N- (5-tetrazolyl) -1-oxo-7,7-diméthylcyclohexénothiazolo-

13.2-al-pyrimidine-2-carboxamide

  558 mg (2.0 mmol) of 1-oxo-1H-

  7,7-dimethylcyclohexenothiazolo-1,3,2-a-pyrimidine-2-carboxylic acid and 357 mg (2.2 mmol) of 1,1'-carbonyldiimidazole with 3 ml of dimethylformamide and the mixture is heated on a steam bath; a gas is evolved and the dissolution takes place. When the evolution of gas has ceased, 227 mg (2.2 mmol) of 77.-aminotetrazole monohydrate are added. and continue heating for 20 minutes. The reaction mixture was cooled and the crude product was collected by filtration (561 mg, mp> 300 C). Recrystallization from dimethylformamide gives 469 mg of N- (5-tetrazolyl) -1-oxo-1H-7,7-dimethylthiazolo-L3,2-aj-pyrimidine-2-carboxamide.

  purified (469 mg, melting point above 300WC).

  Analysis: C,% H,% N,% calculated for C14H14O2N7S 48.69 4.38 28.39

found 48.80 4.18 28.42.

EXAMPLE 84

  N- (5-tetrazolyl) -1-oxo-1H-7- (2-butyl) -thiazolo-

[3,2-aj-pyrimidine-2-carboxamide

  379 mg (1.5 mmol) of 1-oxo-1H-

  7- (2-butyl) -thiazolo- (3,2-a) pyrimidine-2-carboxylic acid and 270 mg (1.66 mmol) of 1,1'-carbonyldiimidazole in 3 ml of dimethylformamide and heated in a water-bath A gas is evolved and the dissolution occurs.

  gas evolution ceased, 170 mg (1.65 mmol) of

  aminotetrazole monohydrate 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 room temperature and the crude product is collected by

  filtration. By recrystallization 247 mg of N- (5-

  tetrazolyl) -1-oxo-1H-7- (2-butyl) -thiazolo-t3,2-aJ-pyrimidine

  purified carboxamide melting above 300 C.

  Analysis: C,% H,% N,% calculated for C12H1302N7S 45.13 4.10 30.70

found 45.12 4.05 30.68.

EXAMPLE 85

  Following the procedure of Examples 66 to

  84, the following compounds are prepared from the 1-

  corresponding oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid: N- (5-tetrazolyl) -1-oxo-1H-7-pentylthiazolo [3,2-a] pyrimidin-2-carboxamide,

2470132 1

78.

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

pyrimidine-2-carboxamide,

  N- (5-Tetrazolyl) -1-oxo-1H-6,7-diisopropylthiazolo [3,2-a];

pyrimidine-2-carboxamide,

  N- (5-Tetrazolyl) -1-oxo-1H-6-propylthiazolo-3-yl

pyrimidine-2-carboxamide,

  N- (5-Tetrazolyl) -1-oxo-1H-6-isopropylthiazolo-13,2-a-

pyrimidine-2-carboxamide,

  N- (5-Tetrazolyl) -1-oxo-1H-6-pentylthiazolo [(3,2-a);

pyrimidine-2-carboxamide,

  N- (5-Tetrazolyl) -1-oxo-1H-6-phenylcyclopentenothiazolo-

13.2-aJ-pyrimidine-2-carboxamide,

  N- (5-Tetrazolyl) -1-oxo-1H-6,8-dimethylcyclohexenothiazolo

  13,2-a-pyrimidine-2-carboxamide, N- (5-tetrazolyl) -1-oxo-1H-8-methylcyclooctenothiazolo-13,2-a-pyrimidine-2-carboxamide, and

  N- (5-Tetrazolyl) -1-oxo-1H-6,8,8-trimethylcyclopentomethyl-

  13.2-thiazolo-aj-pyrimidine-2-carboxamide.

EXAMPLE 86

capsules

  Capsules are prepared by mixing the ingredients

  following ingredients in the proportions indicated by weight: - Calcium carbonate, U.S.P. 17.6 - Dicalcium phosphate 18.8 - Magnesium trisilicate, U.S.P. 5.2 - Lactose, U.S.P. 5.2 - Potato starch 5, 2 - Magnesium stearate A 0.8 - Magnesium stearate B 0.35

  and adding a sufficient amount of N- (5-

  tetrazolyl) -1l-oxo-1H-cyclohexénothiazolo- [3,2-aJ-pyrimidin-2-

  sodium carboxamide to form capsules containing 10, 25

  and 50 mg of active ingredient (weight equivalent to the non-

  unsolvated salt) per capsule. The compositions can be loaded into conventional hard gelatin capsules in

amount of 350 mg per capsule.

  In the same way, capsules containing

  containing 2.0 mg and 6.0 mg of the active ingredient and containing 300 μg of the following mixtures per capsule: 79. Ingredients Weight in mg per capsule - Drug 2.00 - N-methylglucamine 18.00 - Anhydrous lactose 251.20 - Anhydrous corn starch 8.80 Ingredients Weight in mg per capsule - Medicinal product 6.00 N-methylglucamine 18.00 - Anhydrous lactose 237.20 - Anhydrous corn starch 30.00 - Talc 8.80

EXAMPLE 87

  Tablets A tablet base is prepared by mixing the following ingredients in the indicated proportions by weight: - Sucrose, U.S.P. 80.3 - Cassava starch 13.2 - Magnesium stearate 6, 5

  This tablet base is incorporated into a quantity

  sufficient quantity of N- (5-Tetrazolyl) -1-oxo-1H- trihydrate

  sodium cyclohexenothiazolo-L3,2-aj-pyrimidine-2-carboxamide to obtain tablets each containing 20, 100 and 250 mg of active ingredient. Each of the compositions is tableted by known means. To obtain lower potency tablets (eg, 1 mg, 2 mg, 5 mg), a lower ratio of the active ingredient to

  inert ingredients in the base mix for tablets.

EXAMPLE 88

Solution

  A solution of N- (5-tetrazolyl) -1-

  1-oxo-1H-cyclohexenothiazolo-13,2-a-pyrimidine-2-carboxamide sodium containing the following ingredients: - Active ingredient 6.04 g (7.49 g sodium salt trihydrate) - Magnesium chloride hexahydrate 12.36 g Propylene glycol 376.00 g - Distilled water 103 nl 80. The resulting solution has an effective ingredient concentration of 10 mg / ml and is suitable for administration.

  parenteral and in particular to intramuscular administration

lar.

EXAMPLE 89

  Aerosol suspension For a particular application as an agent

  antiallergic, a mixture of N- (5-tetrazolyl) -1-oxo-1H-

  Sodium cyclohexenothiazolo-13,2-a-pyrimidine-2-carboxamide and the other ingredients indicated in (a) in the following tables is micronized into particles of 1 to 5 μm in a ball mill. The resulting suspension is then loaded into a container equipped with a valve and the propellant (b) is pressurized through the nozzle of the valve to a pressure of approximately 245 to 280 kPa at C. Suspension A Percent (a) Antiallergic agent (equivalent to unsolvated non-salt) 0.25 Isopropyl myristate 0.10 Ethanol 26.40

  (b) 60% mixture of 1,2-dichlorotetrafluoride

  ethane and 40% 1-chloropentafluoroethane 73.25

Suspension B -

  (a) Antiallergic agent (equivalent to unsolvated non-salt) 0.25 Ethanol 26.50

  (b) Mixture of 60% 1,2-dichlorotetrafluorine

  ethane and 40% 1-chloropentafluoroethane 73.25 Suspension C (a) Antiallergic agent (equivalent to unsolvated non-salt) 2.00 Ethanol 26, 50

  (b) 60% mixture of 1,2-dichlorotetrafluoride

  ethane and 40% 1-chloropentafluoroethane 77.50

24701 3

81.

Claims (11)

  1. A compound of formula: ## STR1 ## 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 that the ring thus formed comprises 5 to 8 members; R1 and R2 taken separately each represents hydrogen or an alkyl group having 1 to 5 carbon atoms; and is a group of formula z N-N I1 N-N -N- H 'N   or of formula OR3 wherein R3 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 carbobenzoxy group; provided that when R 3 is hydrogen or lower alkyl and R 2 is hydrogen, R 1 is other than hydrogen or methyl and R 3 is lower alkyl and R 2 a methyl group, R1 represents something other than hydrogen; or a pharmaceutically acceptable cationic salt thereof when Q is a group of formula N-N -N- 4 - | H. N-N   or of formula OR3 in which R3 is hydrogen.   2. - A compound according to claim 1, characterized   rised in that Q responds to the formula -N - NOT   3. - A compound according to claim 2, characterized   in that R1 and R2 are considered together and represent a butylene group.   4. - A compound according to claim 2, characterized   in that R1 and R2 are considered separately, R1 is a   hydrogen atom and R2 is a methyl group.   5. A compound according to claim 2, characterized   in that R1 and R2 are considered separately, R1 is a   ethyl group and R2 is a hydrogen atom.   6. - A compound according to claim 2, characterized   in that R1 and R2 are considered separately, R1 is a   methyl group and R2 is hydrogen.   7. - A compound according to claim 1, characterized   in that Q is a group OR3 in which R3 is hydrogen. 83.   8. - A compound according to claim 7, characterized   in that R1 and R2 are considered separately, R1 is a   ethyl group and R2 is hydrogen.   9. - A compound according to claim 1, characterized   in that Q is a group OR3 in which R3 is a   lower alkyl radical having 1 to 3 carbon atoms.   10. - Compound, characterized in that it-meets the formula S-N I - R2 0 1 he CE 3   Wherein R'3 is a lower alkyl group having 1 to 3 carbon atoms; R1 and R2 taken together represent an alkylene group   having 3 to 9 carbon atoms or a phenyl group   alkylene having 9 to 11 carbon atoms; and R 1 and R 2 taken separately each represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms, provided that when R 1 is hydrogen, R 2 is other than hydrogen or a methyl group and that when R 1 is a methyl group, R2 is other than hydrogen. 11. - Drug, characterized in that it is constituted by or in that it contains a compound according to one of   any of claims 1 to 9.