CS241476B2 - Method of substituted n-5-tetrazolyl-1-oxo-1h-thiazolo- (3,2-a )pyrimidine-2-carboxamides production - Google Patents

Abstract

Antiallergy and antiulcer agents having the formula (I), <IMAGE> and their pharmaceutically acceptable salts, wherein R1 and R2 taken separately are each hydrogen or C1-5 alkyl; and R1 and R2 taken together are alkylene of 3 - 9 carbon atoms or phenylalkylene of 9 - 11 carbon atoms, with the proviso that the ring so formed is between 5- and 8-membered; acids of the formula (II), <IMAGE> wherein R1 and R2 are as defined above and R3 is hydrogen, which are useful as intermediates for compounds of the formula (I), but in many instances also possess the same useful biological activity as do formula I compounds; and intermediates of the formula II wherein R1 and R2 are defined as above, and R3 is alkyl of 1 to 4 carbon atoms, carbalkoxy of 2 to 5 carbon atoms, carbophenoxy or carbobenzoxy, are described.

Description

The invention relates to a process for the preparation of novel 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxamides and their acid precursors. These amides and, in many cases, precursors can be used to prevent the release of substances that cause allergies such as histamine, serotonin, SRS-A and the like, and can be used to treat bronchial asthma, hay fever, inflammation nasal mucous membranes, atopic dermatitis and, moreover, for the treatment of gastric ulcers.

Allergic reactions are disorders whose symptoms are the result of a reaction between an antigen and an antibody and manifest in a variety of ways in different organs and tissues. A common allergic disorder is, for example, allergic rhinitis, which is manifested by seasonal rhinitis with nasal congestion and sneezing and sometimes conjunctivitis, often hay fever, which results from hypersensitivity to pollen of various grasses.

It may also be bronchial asthma, which is the most serious of allergic reactions, manifesting: bronchial hypersensitivity to various immunogenic and non-immunogenic stimuli, resulting in bronchial spasm, associated with difficulty of air passage due to the general constriction of honor through which air enters the lungs. The mechanical narrowing of these pathways can usually be alleviated by bronchodilators that cause the symptom to become stronger. As such, antiallergic agents prevent release of the mediators from the tissues. In this way, the prylacthocyte acts and prevents bronchial spasm which is caused by the release of these mediators.

Soh et al. In Adv. It Crushing> φί. · 5, 115 (1970) described the pharmacology of disodium salt), 1,3-chrombglýkátuf Ш ^(А квгЪохуойг®йэ0п 2-5-yloxy) -2-hydroxypropane, Inthal]. The compound has no bronchodilator effect, but its therapeutic effect consists in inhibiting the release of mediators of anaphylaxis and can therefore be administered pro-phylactically. It is not orally active and can be administered by solid inhalation for optimal results. '

A number of antiallergic agents have recently been described, including N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimido [1,2-y] choline-2-carboxamides (Kadin, U.S. Patent No. 4). 017 625), 1-oxo-1H-6-substituted pyrimido [1,2-a] quinoline-> 2-carboxylic acids (Kadin, U.S. Pat. No. 4,066,766), tetrazolo [a] quinazol-5-ones ( Bindra U.S. Patent No. 4,085,213), pyrimido [2,1-l] isoquinoline (Juby et al., U.S. Patent No. 4127,720) and N- (5-tetrazolyl) -4-oxo-4H-pyrimido [2,1b] ] benzothiazole-3-carboxamides (Bindra and Kadin, US Patent No. 4,041,163).

Chronic gastric and duodenal ulcers, collectively known as peptic ulcers, are a common disease for which a number of treatments have been proposed. The treatment depends on the severity of the ulcers and may range from dietary treatment to medication to surgical treatment. Currently, many drugs are used for the treatment of ulcers, of which the new drugs are mainly sodium carbenoxolone and 1 disodium salt of glycerretinic acid hemisuccinate. This substance is likely to prevent ulceration and accelerate the healing of gastric ulcers in animals, including humans. ("Carbenoxolone Sodium; A Symposium," J.M. Robson and F.M. Sullivan, Eds., Butterworths, London, 1968).

However, the use of this substance is associated with undesirable side effects similar to the effect of aldosterone, for example, a clear antidiuretic. efficacy associated with sodium retention and often potassium loss, so long-term treatment with this substance often results in increased blood pressure, muscle weakness, and heart weakness. More recently, cimetidine, a histamine receptor antagonist, has been used. This compound helps to treat ulcers by reducing gastric acid secretion.

Also, other substances have activity against the formation and in the treatment of ulcers, especially esters of 1-oxo-1H-6-piperidinopyrimidin [1,2-a] quihine-2-carboxylic acid (Kadin and Moor, UD). No. 4,014,881), 1-oxo-1H-6-substituted pyrimidoyl 1,2-a] quinoline-2-carboxylic acids and their esters (Kadin and Moor, U.S. Patent No. 4,031,217), tetrazolo. [ a.] ohinazQ1-5-ones. (Bindra, U.S. Patent Nos: 4.085 _t 2; i3V: _^..;,.?; И.

The amides and the many acids (which are intermediate) are carried out in the zipper process. According to the invention, known compounds are known in the art. R ₂ represents a hydrogen atom or knows níclíž _R? denotes methyl and R ₂ denotes a hydrogen allone, [Dunwell et al., J. Chem. Sqc. , [CJ, 1971]. 20a4] (The corresponding ethyl esters) are also known, as is the ester in which R f represents methyl and R ₂ represents hydrogen (Dúwell et al., J. Chem. Soc. (C) 1971, 2094, Allen et al., J. Org. Chem., 24, 779 (1959)] None of these publications disclose the possibility of using acids or esters.

. It has now been found that the compounds of formula I

and their pharmaceutically acceptable salts with cations are substances which are active orally against allergic reactions and against ulcers.

In the general formula

R 1 and R ₂ are hydrogen atoms or lower alkyl radicals 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, and the like or form

R 1 and R ₂ together are a third ring of 5 to 8 atoms, so that they are alkylene of 3 to 9 carbon atoms, e.g.

CH *

CH ₂ f

CH ₂

24147S i

сн ₃

_/ Сн -сн _2:, ^ ^{с б} &, ^ ^ си -сн ^

С Ha ^с ^ сн ₂ -сн ₂ /

It has also been found that acids of formula II

or phenylalkylene from 9 to 11 carbon atoms, for example:

where

R ₁ and R 2 are as defined above, they are not only valuable intermediates for the production of amides, but in many cases also have biological activity together with their pharmaceutically acceptable salts with cations. Acids having antiallergic activity are in particular those in which R _t and R _2nd together form alkylene of 4-9 carbon atoms or a phenylalkylene of 9-11 carbon atoms, provided that the ring so formed contains from 5 to 8 atoms or, taken separately, R _(an alkyl group of 2-5 carbons and R ₂ is hydrogen or Preferred acids are those in which R ₁ and R ₂ together form alkylene of 4 to 6 carbon atoms, especially butylene. , and R ₂ together form an alkylene of 3 to 9 carbon atoms or phenylalkylene of 9 to 11 carbon atoms, provided that the ring thus formed contains 5 to 8 atoms or R 1 and R ₂ are hydrogen or alkyl of 1 to 5 carbon atoms in provided that when R 1 is a hydrogen atom, R 1 is different from a hydrogen atom or a methyl radical.

In this case, 241476 are preferred

7 ~

ninaml those substances, v. . wherein R 1 and R 2 are separately from each other. 'Ethyl and R _2nd , hydrogen or alkyl having 1 to 2 carbon atoms.

"Pharmaceutically acceptable salts with cations" means alkali metal salts such as sodium and potassium salts. salts with alkali metals. soils such as calcium and magnesium, aluminum salts, ammonium salts and salts with organic bases such as amines such as triethylamine, tributylamine, piperidine, triethanolamine, diethylaminoethylamine. . N, N‘-dibenzylethylenediamine and pyrrolidine.

It is known that -b-substituted tetrazoles can exist in the following two isomeric forms:

_Z N = N —c

Vn \

H which exist simultaneously in. dynamic tautomeric equilibrium mixtures. Both of these forms fall into. field. invention.

Method of production . the compounds of formula I or pharmaceutically acceptable salts thereof, in which:

R x and R 2 are hydrogen or al. C 1 -C 5 alkyl;

R ₁ and R 2 together form an alkylene radical of 3 to 9 carbon atoms or a phenylalkylene radical of 9 to 11 carbon atoms and the ring thus formed is five-. to 8-membered, characterized in that the compound of general interest is activated. . of formula II

where,

Rt. and R2 have the above-mentioned meanings by condensation. reagents. dehydrative. or. . by molar action. equivalent of compound. of formula III

About 'II' · <'

Cl — c — OR (III) wherein

R is an alkyl, phenyl or benzyl radical; the presence of at least one equivalent of tertiary amine and the resulting solution is reacted with a molar equivalent of 5-aminotetrazole, the reaction temperature depending on the activation method used, using a dehydrating condensation agent in the range of 20 to 110 ° C and in the case where the activation is carried out by reaction with a compound of the formula III in the range of -40 to +40 ° C, the process is carried out in an organic solvent inert under the reaction conditions and the resulting product is optionally converted. to a pharmaceutically active salt of a compound of general formula. Formula I.

Especially valuable. the compounds which can be prepared by the process according to the invention are those compounds of the formula I in which R @ 1 is known as hydrogen or methyl and R @ 3 is methyl. Of these, the most valuable compound in which R 1 is a hydrogen atom, the corresponding acid is also active. Of great importance are also those in which R1 and R2 together form propylene, butylene or pentylene.

Of particular interest is a compound in which R1 and R2 together form butylene, i.e. N- (5-telrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide, a compound of formula III

N-N I

H (III) this substance has excellent oral activity, and is highly stable in pure solid state as well as in the presence of conventional pharmaceutical diluents and solutions. . Furthermore, it also has a metabolite, i.e. it has the corresponding carboxylic acid. good efficiency. A preferred form of the tetrazolylamide of formula III is the sodium salt in the form of the hydrate, which is not hygroscopic and is well soluble in water so that it is readily bioavailable. The antiallergic properties of the compounds of the invention can be demonstrated by the PCA passive cutaneous anaphylaxis assay described by Ovary, J. Immun., 31, 355, 1958. In the PCA test. is administered to normal animals indradermally (i. d.) serum antibody obtained from actively sensitized animals.

The animals are then injected intravenously with an antigen mixed with a dye such as evan blue. Due to the increased permeability of the capillaries caused by the reaction between. antigen and antibody - penetrates the dye from the injection site of the antibody. The test animals are then sacrificed by suffocation and the intensity of the reaction is determined by measuring the diameter and intensity of the blue color on the inside of the skin.

The anti-ulcer activity of the compounds of the invention is evaluated in stressed rats. It is also possible to use a new test in which the ulcer in rats is induced with ethanol. This test will be described in more detail below.

The compounds of the invention can be prepared by the following routes:

Dovtherm. - A zs * or '(Ct ^ CO ^ O

/

dehydration

---------------------------------------------->

or a mixed anbydride

In the first step, the appropriately substituted 2-aminothiazole is condensed with a stoichiometric amount of dialkylethoxymethylene malonate, usually with commercially available diethylethoxymethylene malonate, the choice of ester is not critical to obtain the final product of the invention. The condensation is carried out at a temperature of 80 to 125 ° C. Lower temperatures are not desirable because the reaction proceeds too slowly. It is possible. higher temperatures, but no more benefits can be obtained in this way. The reaction is preferably carried out in the melt, but can also be carried out in a solvent. or in a solvent mixture, for example in ethanol, N, N-dimethylformamide or. acetonitrile. In practice, however, the use of a solvent is not. necessarily. The products of this condensation are 4- and / or 5-substituted-2- (2,2-dicarbalkoxyethenylamino) thiazoles.

It should be noted that when R 1 and R 2 co-form a ring, the numbering of the compounds is as follows:

cyclohexenothiazole

cycloheptenothiazole

cyclooktenothiazole

Another possible name for cyclohexenothiazoles is tetrahydrobenzothiazoles.

The second step of the synthetic sequence is the cyclization of 4- and / or 5-substituted 2- (2,2-dicarbalkoxyethyleneamino) thiazoles excluding one equivalent. an alkanol such as ethanol in the case of an ethyl ester. This cyclization may be carried out by heating the intermediate to 175 DEG-25 DEG C. until the reaction is complete, i.e. usually for 1 to 2 hours. The cyclization is preferably carried out by heating the intermediate in a diluent which is inert under the reaction conditions, i.e.

241478 in a compound that allows 'control of the reaction temperature' is stable at relatively high temperatures and does not react with the starting material or the cyclization product.

Examples of such diluents are high-boiling hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, sulfuric acid, acetic anhydride, diphenylether and diphenyl, especially those which are preferred. contains 26.5% diphenyl and 73.5% diphenyl ether and is sold under the name Dowtherm A.

The cyclization can also be carried out at a lower temperature of 70-130 ° C by heating the intermediate in the presence of an excess of 1.1-3 equivalents of anhydride. trifluoroacetic acid in an inert solvent such as toluene until the reaction is complete, i.e. 15 to 20 hours, at the reflux temperature of toluene. In each of these methods, the product of the cyclization step is alkyl-1-oxo-1H-6- and / or -7-substituted thia-. [3,2-a] pyrimidine-2-carboxylate remained.

Obviously, if R ₁ and R ₂ . together to form a circle, the following occurs. modification of nomenclature and numbering:

1-oxo-1H-cyclopententhiazolo [3,2-a] pyrimidine

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

1-oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine 1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine 1-oxo-1H-cyclohexenothiazolo (3,2-a) pyrimidines may also be termed 6 , 7,8,9-tetrahydro-1-oxo-1H-pyrimidino [2,1-b] benzothiazole or by using other numbering 5,6,7,8-etrahydro-4-oxo-4H-pyrimidof2,1 -b] benzothiazoles.

It will be appreciated that condensation and cyclization can be performed. in a single step,. without the need to isolate the 2- (2,2-carbalkoxyethenylamino) thiazole intermediate, either by using a sufficiently high reaction temperature, such that both condensation and cyclization occur, or by condensation as described above. and then an inert solvent is added if the mixture is not yet present and an excess of 2.1 to 4 equivalents of trifluoroacetic anhydride is followed as in the cyclization step.

In a preferred embodiment of the process according to the invention, the condensation and cyclization are carried out. separately. Isolation of the intermediate product, followed by its purification prior to cyclization, usually provides for better quality of the cyclized product.

Estery,. The resulting condensation and cyclization are then hydrolyzed to the corresponding 1-oxo-1H-6- and / or 7-substituted thiszolo [3,2-a] pyrimidine-2-carboxylic acid. The nomenclature and numbering are changed for Ri and R ₂ together form the third ring. Acid catalyzed hydrolysis is preferred. A particularly preferred method is to heat the 48% ester in 48% hydrobromic acid to reflux until the hydrolysis is complete, i.e. 0.5 to 3 hours. . If the reaction mixture foams, the hydrolysis can be carried out at a higher pressure, i.e. 0.042. MPa at 85 ° C.

The N- (5-tetrazolyl) amides of the present invention can be obtained by a dehydration bond, starting with acids and 5-amino-tetrazole. The reaction is carried out using various reagents commonly used in peptide chemistry. . Examples of such reagents are N, N‘-carbonyldiimidazole, N, N‘-carbonyl-di-s-triazine. E-thoxyacetylene. 1,1-dichlorodiethyl ether, diphenylketene-p-tolylimide, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, ethylene chlorophosphite, diethylethylene pyrophosphite, N-ethyl-5-phenylisoxazolium-3'-sulfonate, phenylphosphorodi (1-imidazolate) and carbodiimides such as dicyclohexylcarbodiimide, 1-cyclohexyl-3- (2-morpholinomethyl) carbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride and diethylcyanamide.

The above reagents are first reacted with an acid and the resulting product. is then reacted without isolation with

5-aminotetrazole to give the desired

1-οχο-1Η-6-. and / or 7-substituted-thiazolo [3,2-a] pyrimidine. The nomenclature and numbering are changed when R and R2 together form a third ring.

The reaction is carried out in a solvent which is inert under the reaction conditions and in which the acids may not be soluble. The only requirement for solvent. is the fact that the solvent must not react with. the reactants or the final product; The various reagents mentioned above allow the use of the reagents. wide - choice - solvents. An example of · - applicable. the solvents may be N, N-diipethylformamide, tetrahydrofuran, and the like. - dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of the - acid with the reagent is carried out at a temperature of 20 - 110 ° C. The resulting intermediate is then reacted with 5-aminotetrazole at -20. to-110 ° C. Each of these steps is preferably carried out at a temperature of 50 to 100 ° C, because at this temperature the reaction is accelerated and a higher yield can be achieved.

The molar ratio of acid to reagent to 5-aminotetrazole is generally 1-. : 1: ί to - 1 -: -1.1 -:: - - 1.1. Higher amounts of reagent and 5-aminotetrazole may be used, but further advantages are no longer achieved. Excess 10 mol. - % is sufficient.

Obviously, all the reactants are preferable to be reacted at once - rather than sequentially. However, in some cases, by separately forming an intermediate, a better yield of the desired N- (5-tetrazolyl) amide can be achieved.

The resulting amide can also be obtained by coupling the acid to -5-aminotetrazole using a mixed anhydride. In this case, the acid is first converted into a direct reaction mixture into a salt with a tertiary amine in the presence of 1 to 1.1 moles of amine. For this purpose, a series of tertiary amines of the formula R ^ may be used. N. Examples include - triethylamine, N-methylpiperidine, N-methylmorpholine, dimethylaniline or quinoline. Suitable inert solvents are methylene chloride, chloroform, dimethylformamide and dimethyl acetamide. It is advantageous to completely dissolve the acid with an excess of the tertiary amine, which may - require -. a certain time of stirring and sometimes a slight warm-up. Solution. salts with an amine are then reacted with an equivalent. alkyl chloroformate, for example - ethyl chloroformate, benzyl chloroformate or phenyl chloroformate - at a temperature of -40 ° C to 25 ° C, preferably at a temperature of -10 ° C to 10 ° C to form a mixed anhydride:

O

Ct-1j-OR

RÍN ——►

4- r ^ n ·. HCl

The mixed anhydride is reacted without isolation directly with 5-aminotetrazole, preferably in a solution in an inert solvent of the same type as the solvent used for the reaction. anhydride to give the desired N- (5-tetrazolyl) amide. The reaction is usually carried out initially at. a temperature of -40 to 15 ° C; however, it is then allowed to proceed at a higher temperature, for example 15 to 40 ° C, in order to complete the reaction. A typical molar ratio of acid, amine, chloroformate and 5-aminoacetate is 1: -2: 1: 1 to 1: 2.1: 1: 1.1: 11.

Amides i. The acids of the invention are also pharmaceutically acceptable intermediates of the procationic salt of the invention. The salts are formed by reacting amides or acids with the appropriate metal salt, for example, carbonate, ethylhexanoate, alkoxide or hydroxide, or with the appropriate amine in a suitable environment. for example in water, methanol or ethanol in a known manner. The salts are isolated by conventional means. by a method, for example by filtration if it is insoluble in the environment, by evaporating the solvent if it is soluble in the environment, or by precipitation with a solvent in which the salt does not dissolve.

Many starting 2-aminothiazoles are described in the literature. Those starting materials not described can be obtained by condensation of the corresponding α-haloketone with urea. or by condensation of the corresponding aldehyde with thioquinone and sulfuryl chloride as described in the specific examples. If the production of α-haloketones is not described in the _T literature, the usual procedure is to proceed, i.e. by ketone halogenation, as described, for example, in Catch et al., J. Chem. Soc., 272 (1948), Levine, Org. Synthesls Coli, Vol. II, 38 (1943), Buchnian et al., J. Am. Chem. Soc. 67, 400 (1945), by treating the diazocetones with hydrogen halides as described by Cotch et al., J. Chem. Soc., 278 (1948), Lutz et al., J. Org. Chem. 12, 767 (1947), Wagner et al., J. Am. Chem. Soc. 72, 2884 (1950), by decarboxylation of α-halo- (3-keto acids) as described by McPhee et al., J Am. Chem. Soc., 66, 1132 (1944) and by spontaneous cleavage of alkenyl ester dibromo derivatives as described in Slanina et al., J. Am Chem Soc 58: 891 (1936).

The reaction to obtain the acids from the 2-aminothiazoles and thus to obtain the resulting N- (5-tetrazole) amides of the invention can be monitored by standard silica gel thin layer chromatography using ultraviolet light, a method commonly used. The solvent is varied so that the reaction is adapted to the nature of the substituents, the Rf of the intermediate being in the range of 0 to 1.0 and so as to distinguish between the intermediate and the resulting product. A solvent which is very useful in the formation of thiazole, condensation, cyclization and hydrolysis is a mixture of chloroform with 1% ethanol, when hydrolysis is used, and when converting acids to N- (5-tetrazolyl) amides, it is preferable to use a mixture of chloroform with 5% of acetic acid. As is well known, it is possible to reduce the polarity of the solvent if the materials to be examined are moving too fast, that is, at the same time as the solvent front. Conversely, the polarity of the solvent can be increased if the test substances move too slowly. This type of chromatography can be used to determine the completeness of the reaction and the purity of the product so that optimal reaction conditions in terms of concentration, time, temperature, solvent and the like can be achieved.

Products obtained by the process of the invention and; their pharmaceutically acceptable salts are valuable in the prophylaxis and treatment of allergic reactions and hypersensitivity reactions because they inhibit the release of the anaphylaxis mediator. They may be administered as such or in admixture with other agents of a similar type, for example, in admixture with theophylline or sympathomimetic arteries. The products according to the invention are also valuable for their anti-ulcer effect. They accelerate the healing of ulcers and, moreover, their creativity and reduce gastric acid secretion in animals, including humans.

They can therefore be used for the treatment of gastric ulcer.

The active ingredients obtained by the process of the invention may be administered per se, but usually together with a conventional pharmaceutical carrier in connection with the chosen route of administration and in accordance with conventional pharmaceutical practice. For example, they may be mixed with inert inert pharmaceutical carriers and formulated into tablets, capsules, powders, sweets, aerosol sprays, aqueous suspensions or solutions, injectable solutions, elixirs, syrups, and the like.

The carrier can be a solid diluent or filler, sterile aqueous media, or various non-toxic organic solvents. In addition, sweetening or flavoring agents conventionally used for this purpose may be added to the pharmaceutical compositions.

The choice of carrier and the proportion of active ingredient relative to the carrier depends on the solubility and chemical nature of the active ingredient, the chosen route of administration, and various other circumstances. For example, when the compounds obtained according to the invention to be _O-: given orally as tablets; lactose, sodium citrate, calcium carbonate, and dibasic calcium phosphate can be used as carriers. Other injectables such as starch, alginic acid and complex silicates as well as glidants such as magnesium stearate, sodium lauryl sulfate and talc may also be used. For oral administration in capsule form, the preferred substances are lactose and high molecular weight polyethylene glycols as carriers. When the active ingredient is to be administered orally in the form of an aqueous suspension, the compounds obtained by the process of the invention can be mixed with emulsifying agents or suspending agents. Diluents such as ethanol, propylene glycol, glycerin, chloroform and mixtures thereof, as well as other materials, may be used.

For parenteral administration and inhalation, solutions and suspensions of the active compounds in sesame or peanut oil or solutions and suspensions in a mixture of water and propylene glycol, as well as sterile aqueous suspensions in water-soluble pharmaceutically acceptable salts may be used. These solutions are also suitable for intramuscular and subcutaneous administration when such administration is preferred.

Aqueous solutions, including salt solutions in pure distilled water, are also suitable for intravenous administration provided the pH is first adjusted to a suitable value. These solutions should also contain a buffer and the solvent should be isotonic. Sufficient sodium chloride or glucose is added for this purpose.

In prpfylactic use for inhibition

releasing m-editors of anaphylaxis, the compounds of the invention may be administered by inhalation. Pharmaceutical compositions suitable for inhalation may include

1) - a solution or suspension of the active ingredient in a liquid medium from above. of this type - for use in a sprayer,

(2) a suspension - or solution of the active substance - in a liquid propellant, for example dichlorodifluoromethane - or chlorotrifluoroethane - for the - administration by pressure apparatus, or

3) a mixture of the active ingredient - in a solid diluent, for example lactose, administered by an inhalation device adapted for powder inhalation.

Compositions suitable for use in the nebulizer contain from 0.1 to 1% of active ingredient. Compositions intended for use in a pressure apparatus contain from 0.5 to 2% of active ingredient. Formulations for inhalation in solid form will contain the active ingredient and diluent in a ratio of 1: 0.5 to 1: 1.5.

The effective daily dose for oral administration of a compound of the invention with an antiallergic and anti-ulcer effect in humans is in the range of 10 to 1-500 mg, preferably 10 to 600 mg. This dose is administered singly or in divided doses, and can also be expressed as 0.2 to 12 mg / kg a day. These values are given by way of example only, and higher or lower doses may be used in individual cases. Up to -2 g of active ingredient per day can be used if necessary.

For parenteral administration or inhalation, the effective daily dose is in the range 0.05-400 mg, preferably 0.25 to 200 milligrams, or 0.005-4.4 mg / kg, and . day as a single dose or in several individual doses. .

It is necessary that the active ingredient consisted of such a treatment. appropriate dosage forms. Je vý. the proportion - of a device which guarantees the possible processing of an - appropriate - dosage form. It will be appreciated that several sub-doses may be administered at the same time as needed. Although in some cases a pharmaceutical composition containing less than 0.005% by weight of the active ingredient may be used, it is nevertheless preferred to use compositions containing - more than 0.005% by weight of the active ingredient - otherwise the amount of carrier is unnecessarily high . The efficacy of the composition increases with the concentration of the active ingredient. The pharmaceutical composition containing the active compound according to the invention may contain - 10, 50, - 75, 95 or even more by weight of the active compound.

The PCA assay is a measure of the antiallergic, particularly the antlastic, activity of a compound. Compounds which inhibit the -positive PCA test - induced in rats by the immunochemical equivalent of human immunoglobulin E (IgE), or the reagent - are considered to have antiallergic activity as described in C. Mota, Ann. . N. Ϋ. Acad. Sci.,

103, 264 (1963). Reagin is the primary immunoglobulin E (IgE) and is - a major, immunoglobulin responsible for allergic asthma, anaphylaxis, - cold fever, hypersensitivity to food and some - manifestations of hypersensitivity to drugs, although recent research suggests that also, IgG antibodies play an essential role in the development of allergic diseases. When - when these substances are administered to a sensitized object, - to a human or animal prior to the moment in which they come into contact with the antigen or the substance on which they are hypersensitive, an allergic reaction to which otherwise it would have occurred. It is therefore a prophylaxis of an allergy or anaphylactic reaction caused by reagin.

Substances of the above type block the release of mediators that are the result of re-action - between. an antigen and an antibody as evidenced by a PCA assay using a rat homocytotropic antibody that is a known equivalent of a human reagin-type antibody. Inhibition of the reaction between antigen and reagin-type antibody in a rat in the PCA test is considered to be equivalent to inhibiting a similar reaction in humans occurring during allergy.

The PCA assay used to evaluate the compounds obtained by the process of the invention has a very good performance. correlation with respect to the efficacy of the compounds in the test and their efficacy in the treatment of allergic asthma. The ability of the compounds to prevent PCA responses was investigated in male Charles Rivier Wistar rats weighing 170-210 g. Reagin '-antl serum, IgE-rich, was prepared according to PetiUo et al., Int. - Arch. Allergy, 44, 309 (1973). Hyperimmune-antiserum-rich IgG-antibodies to hen-egg albumin was prepared according to the method of Orange et al., J. Exptl. Med, 127,. 767 (1968). 48 hours before administration of the antigen, the intradermal reagin antiserum is administered to the shaved skin of the back of normal rats. Five hours prior to the experiment, hyperlmunhistamine dihydrochloride was administered subcutaneously, and 0.5 'microtubes of serotonincreatinine sulfate intradermally just prior to administration of the antigen to detect antihistamine, antiserotonin and not antifoam.

In the third place, 60 micrograms of a specific type of blockade is administered. The compounds obtained by the process according to the invention or sodium chloride solution are then administered intravenously and immediately thereafter 5 mg of egg albumin and 2.5 mg of Evans blue in sodium chloride solution are administered.

In the case of oral administration of Evans blue and egg albumin, these substances are delivered 5 minutes after administration of the active ingredient.

After 3030 minutes, the animals are sacrificed with chloroform and the back of the skin is monitored. Each injection site - is - evaluated by - determining - the diameter in mm - and - the numbers 0,1, 0,5, 1, 2, 3 or

241,

4 the color intensity is assessed. The injection site numbers are summed for each group of 5 animals and compared to control animals receiving only sodium chloride solution. The difference is expressed as why, blockade by the active substance.

The compounds obtained by the process according to the invention are examined for antiallergic activity as described above and the observed activity is reported as the degree of protection in%. Intal, which is a commercially available, antiallergic agent. - is not given for comparison because it is not effective when administered orally.

Compounds of formula I, i.e. amides and formula II, i.e. acids in which R3 represents a hydrogen atom were examined by the PCA test, the results are shown in Tables I and II below.

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Oral efficacy (° / o protection) of amides (Formula I) in the PC A test

СН ₂ СН (С ₅ С) СН, СН2

CH ₂ CH (CH ₃ ) CH ₂ CH ₂

CH ₂ C (CH ₂ J ₂ CH ₂ CH ₂

Table II

Oral efficiency (% protection) of acids (Formula II, R 3 is hydrogen) in the PCA assay

Ri R ₂ CH3 CH3 CHa C2H5 C2H5 CH-1 C2H5 (CH-2H3 (CH 2) 4 (CH 2) 5 (CH 2) 6 C2H5 H CH3 H H CH3 H C2H5 H H C (CH3h H C2H5 H CH (CH 3) 2 CH2CH (C5H6) CH2CH2 CH2CH (CH3) ₂ CH2 CH2 C _(CH3) 2CH2CH-i H CHCH2CH3

IgE mg / kg IgG mg / kg 10 30 10 30 0 0 0 0 42 24 41 32 0 0 55 39 37 44 36 68 15 Dec 45 18 19 Dec 18 7 12 14 45 38 10 * 6 13 21 0 0 15 Dec 5 31 21 13 • 6 1 8

CH3

The activity of the compounds produced by the method of the invention as antiulcer agents is determined in rats. In this test, 70-140 g of Charles River C-D 0 ' rat female rats were dosed intraperitoneally in sodium chloride solution containing &lt;1%; carboxymethylcellulose and 0.1% Tween 80 or orally. in water 3 hours before the animals. · Be introduced by · light therapists. narcosis and pinned upside down on a plexiglass plate. After waking, the animals are placed horizontally in a refrigerator at 10 to 12 ° C and sacrificed after 3 hours by breaking the ligament. . The abdomen of each rat is opened, the porter is closed with a clamp, the stomach is filled with sodium chloride solution by the esophagus, the esophagus is closed with a · clamp · and the stomach · is excised. The stomachs. deposited in a solution of formaldehyde at a concentration of · 0.4 ^; ° / o for approximately 30 seconds, thereby. hardens. outer layer and facilitate examination. Everybody. the stomach is then incised along a large 'curvature' and the gland portion is inspected to detect damage. . The number is noted. places where there is a mucous membrane. damaged the severity of the damage; and. color of stomach.

To compare the average number of damage. v. a control group with an average number of lesions in treated animals will use the Mann, Witney and Wilcoxan test and demonstrate. se. whether the results obtained differ significantly from each other - as was. described . in Dixon et al., “Introduction to? Statistical Analysis ”, 3rd edition

Mc Graw-Hill Book Company, New York, pp. 344-347 (1969). It was found that N- [5-tetrazolyl] thiazolo [3,2-a] pyrimidine-2-carboxamide, i.e. compound III, is exceptionally effective in the above test. led experiment.

The activity of the compounds obtained by the process of the invention as anti-ulcer agents is determined in the case of ethanol-induced ulcers in rats. In this experiment, male rats were fasted with 5 mg / kg of active ingredient or. water orally 15 minutes before oral administration of 1.0 ml of absolute ethanol. Per hour . with the animals to be used. 8 '. in one. the group is killed and the gastric mucosa is examined. All active substances were dissolved. in dilute solution. sodium hydroxide. . The abdomen opens and the porter closes with tweezers. Not into your stomach. 6 ml of a 4% formaldehyde solution and sealed with a second tweezer. esophagus. The stomach is removed, it opens. along the great curvature and exploring.

Damage caused by ethanol. are evaluated quantitatively as follows:

Evaluation of ulcers

Assessment Definition of normal gastric mucosa pinhead size damage greater damage less than 2 millimeters, pinhead size damage may be present greater than 2 mm, pinhead size damage may be present with bleeding damage.

24147B

Resulting index --- = (sum of scores for group), x (sum of number of ulcers per group) x (number of animals per group with any ulcer ·).

The inhibition of ulcer formation in% is calculated as follows:% - inhibition = 100 x ((index for controlTable III lu) - (index for treated animals)) - (index for control).

The following Table III shows the activity of the various 5-tetrazolylamines produced by the method of the invention in the above test, and the following Table IV shows the activity of the various acids in the same test.

Oral efficacy (% inhibition at 5 mg / kg) of amides (Formula I) in ethanol-induced gastric ulceration of rats

Ri Ra % Inhibition CH _a CHa 96 H CH3 59 - CH3 H 72 C2H5 C2H5 10 C2H5 H 86 (CH ₂ ) ₆ 45 _(CH2) 4 97, 81 Table IV Oral efficacy (% inhibition in 5 ethanol-induced rat ulcers) mg.Vkg) of acids (formula II) in the stomach Ri R2 % inhibition ' . CH3 CHa 11 · · H CHa 27 Mar: CH3 H 0 C2H5 C2H5 48 C2H5 H 48 _(CH2) 4 21

As mentioned, the most preferred compound produced by the process of the invention is a compound of formula III, i.e. a compound of formula I wherein R ₁ and R ₂ are butylene, i.e. [N- (5-tetrazolyl) 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide, also called 5,6,7,8-tetrahydro-N- (5-tetrazolyl) -4 -o * xo-4H-pyrimidine * [2,1-b-benzothiazole-4-carboxamide].

In addition to the oral antiallergic efficacy shown in Table I, Compound III is effective when administered intravenously at a dose of 0.03 to 1.0 mg / kg in a PCA test, i.e. it is approximately 2.6 times more potent than the intal when administered. As already mentioned, intal is ineffective when administered orally. Compound III also blocks changes in dermal permeability induced by passive dermal anaphylaxis by IgE in the PCA assay, but does not alter the permeability induced by the intra-skin injection of exogenous histamine and serotonin. The absence of an antihistamine and antiserotonin effect demonstrates that the antiallergic mechanism - consists in inhibiting mediator release rather than blocking the receptor of this mediator.

Compound III inhibits histamine release in the rat peritoneal cavity induced by dextran. The ED- _{0 of} this compound when administered intraperitoneally is 0.33 (Ug / kg, the same pro-intal value is 14.5 µg / kg, so it is apparent that the compound of the invention is histamine caused by antigen administration in rats, passively sensitized -IgE-rich antiserum - shows that the ED50 is 28 -ug / kg by intravenous administration, i.e. 13x higher than in the intal, in which case passive systemic -aphylaxis is prevented by the action of the compound III.

When guinea pigs were given * 10 mg / kg intraperitoneally of compound III, these guinea pigs were not protected against. bronchitis caused by inhalation. histamine. At a concentration of 10 -4 to 10 -4, compound III does not antagonize the convulsions of the isolated small intestine of the guinea pig induced. acetylcholine, histamine, or SRS-A, and synthesis and release of SRS in isolated rat ion-stimulated monocysts is not inhibited by compound III.

Compound III is effective in preventing ulceration by administering ethanol in rats as shown in Table III and, moreover, effectively preventing gastric ulceration in rats exposed to chlorine as described above. This effect is dose-dependent and can be achieved by an oral dose of 3 to 100 µg / kg. Compound (III) also protects against ulcers that can be induced by aspirin at a dose of 100 mg / kg pen241470 orally, the effect is also dose-dependent and can be achieved with an administration of 10 10 to 1000 · µg / kg orally, ED ₅₀ is 100 pg / kg.

Compound (III) is also effective in phenylbutazone-induced gastric ulcers, where the ED50 for oral administration is 200 µl. Although Compound III is a highly effective anti-ulcer, it does not affect · the secretion of gastric acid stimulated by penta / astrin in dogs in · Heidenhain's trial (5 mg / k / iv) · and is therefore from cimetidine and atropine. It is thus a so-called "cytoprotective" effect that is currently used to describe anti-ulcer effects of prostaglandins that are independent of antisecretory efficacy as described in Robert, Advances in Prosta / landln and Thromboxane Research 2, 507 (1976), Mlller et al., Gut 20, 75 (1979), Robert et al., Gastroenterolo / y 72, 1121 (1977). This effect is typical of compound III.

In addition, compound III has a diuretic effect. When administered orally, it causes a dose-dependent increase in urine volume, ranging from 0.3 to 5 mg / k. At maximum effect, the volume of urine is doubled. The sodium and potassium concentration in the urine is unchanged, but due to increased urine volume, sodium and potassium excretion are increased. These experiments show that the range for this potency is considerably wider than the range for the antiulcer effect and lower than the range for the antialleric effect, which is 1 to 10 m / k.

Rats treated with compound · III at 10, 30, or 100 m // k / after 24 hours of fasting had no changes in blood level / lucosis.

The effect of Compound III on tolerance / lucosis was investigated in rats given the compound at 10, 30, or 100 m // (k) orally at the same time as the lucosis administered at 1 // k / orally. Dose-dependent improvement in tolerance / lucosis was observed. This effect may be due to delayed absorption / lucosis, which in turn may be due to the effect of the substance on gastric emptying.

Compound III has no significant anticholinergic effects. In anesthetized dogs at a cumulative dose of 5 and 15 m // k / intravenously, there was a transient decrease in blood pressure and various transient changes in cardiac activity. The effect of epinephrine and double-sided carotid artery occlusion was somewhat reduced. Transient changes in the cardiovascular system only occur when a cumulative intravenous dose is given that is 5 to · 15 times higher than the maximum effective intravenous dose when given against alleric reactions and is much higher than when administered orally in anti-ulcer therapy. .

In the tolerance test, compound III was administered orally by gavage to dogs for 7 days at doses. 50, 150 '· and 300 m // k // day. Vomiting is common in dogs at all doses, but it has been shown that this effect can be reduced or eliminated when the compound is administered as capsules after a meal. No gross pathological changes were observed in microscopic examination of liver, kidney, heart and lung. In further investigations, blood serum enzyme levels in dogs were administered intravenously for 5 days at Compound III at doses of 1, 3, 10, 3, and 3 m / (k), and enzyme levels were normal.

Rats were administered compound III orally by gavage at doses of 50, 150, and 300 m // k / day for 10 days. No pathological changes were observed, even when microscopic observation of the liver, kidneys, heart and lungs. Increases in serum / lutamic acid / pyruvic acid transaminase were observed at the highest dose, otherwise no clinico-chemical changes were observed.

Compound III was administered subcutaneously to mice at doses of 100, 300, and 1000 m / k. No deaths were observed and it can therefore be concluded that acute toxicity is very low at LD5 ₀ - 1000 m // k /. No interactions with other central nervous system active substances were observed at a dose of 32 m // / k subcutaneously.

Microscopic examinations of bone marrow were performed at a single oral dose of compound 40 m / k administered to mice killed at 6, 12, or 24 hours following administration.

No chromosome damage was detected. Similar conclusions could be drawn when mice were given 5 consecutive days of 20 m / k of the substance. In vitro experiments were also carried out, in which compound III was incubated with human lymphocytes at a concentration of 1000, 100, 10 or · 0 · zg / ml, no chromosome damage caused by the compound was observed. · Compound III · in Ames test in vitro · does not induce mutations. From these findings, it is apparent that compound III has no mutant ability.

In the rat PCA test, the ratio of the oral effective dose to the intravenous dose of Compound III is stable, indicating good oral absorption. This observation may also be supported by a concentration of 3-7 µg / ml of the compound in the blood plasma one hour after oral administration of Compound III at a dose of 50-300 m / k. In dogs, this compound is absorbed immediately after oral administration as a suspension or in the form of a capsule and a plasma concentration of 9 to 26 µg / ml can be achieved after an oral dose of 50 to 300 m // to/. In both cases, the levels of the carboxylic acid metabolite can also be determined, thereby. it can also be shown that this acid is an important metabolite of compound III. After eight days of administration, the levels were self-contained. the compound and its metabolite. to. 4x higher than the first dose, so it would be possible. assume that it is possible to maintain the therapeutic dose over a longer period of time.

Compound III in the solid state as such or in admixture with commonly used inert ingredients when administered orally or also in solution is very stable, so that. very stable pharmaceutical compositions can be prepared. p. containing this substance for> clinical use.

The invention will be illustrated by the following examples.

Example 1

2-Amino-4- (4-ethoxy-4-methyl-thiazole)

20.9 g, 0.275. mole of thiourea are dissolved in 250 ml of ethanol at boiling point below. reflux condenser. Then, it is added dropwise at reflux. during 25 minutes 41.3 g, 0.25 mol. 2-bromo-3-pentanone, dissolved. in 50 ml of ethanol. The mixture is refluxed for 2 hours, the volume of the reaction mixture is reduced to approximately 100 ml, the mixture is cooled and the crude product is isolated in the form of the hydrobromide by filtration. Dissolving in water. and reprecipitation by addition of 3N aqueous potassium hydroxide solution gives 15.1 g of purified

2 ^of ammc---ethyl-5-mnthylletrazolu ^on; m.p. 45-50 ° C, m / e calcd 142, found 142.

A similar manner: l-bromo--heptanon, 3-bromo-4-heptanone and 4-bromo-2,5-dimethyl-3-hexanone converted to 2-amino-4-pentylthiazolo 2 - _<L-Amino-4 4-Isopropyl-5-propylthiazole and 2-amino-4,5-diisopropylthiazole.

Example 2

2-amino-4,5-diethylthiazole hydrochloride

21.8 g of 0.286 mol of thiourea, 34.4 g, 0.26 mol of 4-chloro-3-hexanone and 200 ml of ethanol are mixed and refluxed for 19 hours. Then the reaction mixture. Cool and evaporate the solvent. thereby. is obtained. crude product as a white solid. 31 g of 4,5-diethylthiazole hydrochloride white crystals, m.p. 154. up to 156 ° C is obtained by recrystallization from a mixture of ethyl acetate and ethanol.

Example 1 a d 3

2-aminocyclohepte.nothiazole

41.9. g, 0.55 mole of thiourea, 72.3 g, 0.49 mole of 2-chlorocycloheptanone and 500 ml of ethanol are decanted and heated to 200 ml. reflux for 7 hours. The solvent is evaporated to give a semi-solid. which was partitioned between ethyl acetate and water. . The unreacted chloroketone, which is isolated from the ethyl acetate phase by evaporation, is mixed. with 20 g of thiourea and ethanol and reheated to boiling point below. backward. 24 hours, re-evaporated the solvent and the other crude product was partitioned between ethyl acetate and water as above. In any case, the product is isolated by basifying the aqueous phase by adding ammonium hydroxide, extracting with ethyl acetate, and drying over anhydrous sulfate. sodium, evaporate. to oily. a liquid which solidifies by trituration with hexane and subsequent filtration. 49.5 g are obtained. of purified 2-aminocycloheptenothiazole, m.p. 77-78.5 ° C after recrystallization from cyclohexane.

Example 4

-. amino-4-isopropylthiazole

52.5 g (0.69 mol) of thiourea are suspended in 400 ml of ethanol. 1-Bromo-3-methyl-2-butanone (109.5 g, 0.66 mol) was added to the suspension. Resulting. the exothermic reaction causes first dissolution and then heating the reaction mixture to reflux. cooler. By external heating, the reaction mixture was refluxed for an additional hour, then the solvent was removed by evaporation to give an oily liquid which crystallized on standing.

After final purification by trituration with ether. of 2-amino-4-isopropylthiazole hydrobromide, m.p. 74-76 ° C.

58.6 g of hydrobromide is converted to the free compound by dissolution. in water, basified with excess ammonium hydroxide, then the free base is extracted with ether, a solution. Dried over anhydrous sodium sulfate, which was evaporated to an oil.

Example 5

2-Amino-6-phenylcyclohexenthiazole

397.5 mg, 5.22 mmol thiourea se. . is suspended in 6 ml of ethanol. 1.2 g (4.74 mmol) of 2-bromo-4-phenylcyclohexanone are added to the suspension, which exotherms and dissolves. Solution. The mixture is heated to reflux. 30 ^ minutes, then. Cool and evaporate the solvent to give the crude product as the hydrobromide.

This crude salt was dissolved in warm water, the solution was filtered, and the free base was precipitated by the addition of ammonium hydroxide. Then. is a crude base. isolate by filtration. and recrystallization from water-ethanol to afford 802.4 mg of the purified ^2-1-amínOf6 fenylcyklo24147В hexanothiazolu о mp 181-183 ^C C.

The process can also be carried out on a larger scale using 8.2 g of thiourea,

24.6 g of 2-bromo-4-phenylcyclohexenone and 125 ml of ethanol, the reaction mixture was refluxed for 30 minutes, then cooled in an ice bath and the hydrobromide was collected directly by filtration. The hydrobromide is then dissolved in water containing traces of ethanol, the solution is heated and, after the addition of an excess of ammonium hydroxide, 10.4 g of the free base are precipitated, m.p. 180 DEG-182 DEG.

Similarly, 2-bromo-3-phenylcyclopentanone, 2-bromo-3,5-dimethylcyclohexanone, 2-bromo-3,5,5-trimethylcyclopentanone and 2-bromo-5-methylcyclooctanone can be converted to 2-amino 6-phenylcyclopentenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,4,6-trimethylcyclopentenothiazole and 2-amino-7-methylcyclooctenothothiazole in free base or hydrobromide form.

Example 6

2-amino-6-methylcyclohexenothiazole

22.3 g (0.29 mol) of thiourea are suspended in 275 ml of ethanol. 2-Bromo-4-methylcyclohexanone was added and the mixture was heated to reflux for 75 minutes. The reaction mixture was cooled to room temperature and the crude hydrobromide product was isolated by filtration. The crude salt obtained is dissolved in warm water, filtered and basified with ammonium hydroxide to precipitate the free base as an oily liquid which crystallizes on cooling. Recrystallization from cyclohexane gave. in this way 25.2 g of purified 2-amino-6-methylcyclohexenothiazole, m.p. 98-100 ° C.

Example 7

2-amino-6,6-dimethylcyclohexenothiazole

9.8 g of 2-amino-6,6-dimethylcyclohexenothiazole, m.p. 09 DEG-111 DEG C., is obtained from 9.2 g, 0.12 mol of thiourea and 2.2.6 g, 0.11 mol of 2-bromo-4, Of 4-dimethylcyclohexanone in 100 ml of ethanol by the method of Example 6.

Example

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

16.7 g, 0.22 mol of thiourea, 36 g, 0.2 mol of 1-bromo-3-methyl-2-pentanone and 100 ml of ethanol are decanted and refluxed for 5 hours. Then 100 ml of an aqueous potassium hydroxide solution having a concentration of 3N and the mixture was further zahřívá.1 / 2 hours boiling under back ³² Nym condenser. The reaction mixture is then cooled, acidified with hydrochloric acid and the non-alkaline impurities are extracted with ether. The aqueous phase was basified with ammonium hydroxide and the product was extracted with ether. After backwashing with water and drying over anhydrous. the ether was evaporated to give 10 g of 2-amino-4- [2-butyl) thiazole as a dark brown viscous oil.

Example 9

2-amino-5-methylthiazole

45.7 g (0.6 mole) of thiourea and 7.4 g (0.3 mole) of propionic acid aldehyde are mixed with 150 ml of chloroform and cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mol) was added over 15 minutes. An exothermic reaction is formed, the temperature of which is maintained between 15 and 24 ° C. The initial gas evolution ceases approximately 1 hour after completion of the addition. Most of the chloroform is removed by evaporation on a steam bath. 150 ml of ethanol are added and the mixture is refluxed for 3 hours. IN

The reaction mixture was evaporated to an oil which was partitioned between water and ethyl acetate. The aqueous phase was basified with ammonium hydroxide and the product was extracted with fresh ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate and the solution was evaporated to give the crude product as a white solid. Recrystallization from cyclohexane yielded 8.36 g purified

94 DEG-95 DEG C. 2-amino-5-methylthiazole.

Example 10

2-Amino-5-ethylthiazole

45.7 g, 0.6 mol of thiourea and 21.6 g, 0.3 mol of butyric acid aldehyde are mixed with 150 ml of chloroform and cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mol) was added over 15 minutes. There is an exothermic reaction which is maintained at a temperature of 15-25 ° C. During the addition, a gas evolves which evolves 1 hour after the final addition. Ethanol (400 ml) was added, the chloroform was evaporated by boiling, and the reaction mixture was heated at reflux overnight, i.e. about 16 hours. Then, the reaction mixture is filtered off. It was recrystallized to give 11.7 g of 2-amino-5-ethylthiazole, m.p. 54-55 ° C, which was isolated as in Example 9.

A similar way is. maybe pentanal,

Convert 3-methylbutanal and heptanal to 2-amino-5-propylthiazole, 2-amino-5-isopropylthiazole and 2-amino-5-pentylthiazole.

34

P rílkldli.

2- (2,2-dicarbethoxyethenylamino) -4,5-dimethylthiazo-1

2.56 g, 20 mmol of 2-amino-4,5-dimethylthiazole, 4.8 g, 22 mmol of diethylethoxymethylene malonate and 5 ml of ethanol are heated at reflux for 1 hour. The reaction mixture was cooled and the crude product was precipitated with hexane. After recrystallization from hexane, this is obtained

4.21 g of purified 2- (2,2-dicarbethoxyethenylamino) -4,5-dimethylthiazole, m.p. 82-83.5 PC.

Example 12

2- (2,2-Dicarbethoxyethenylamino) -4-ethyl-5-methylthiazole

2.84 g, -20 mmol of 2-amino-4-ethyl-5-methylthlazole and 4.76 g, 22 mmol of diethylethoxymethylene malonate were mixed and heated on a steam bath for 3 hours. On cooling, an oily product is obtained which is used in the next step without prior purification.

Similarly, 2-amino-4-pentylthiazole, 2-amino-4-propyl-5-ethylthiazole, 2'-amino-4,5-diisopropylthiazole, 2-amino, 5-propylthlazole, 2-amino-5-isopropylthiazole, 2-amino-5-pentylthiazole, 2-amino-6-phenylcyclopententhiazole, 2-amino-5,7-dimethylcyclohexenthiazole, 2-amino-4,6,6-trimethylcyclopententhiazole, and - - 2-amino-7-methylcyklooktenthiazol - - - converted into the corresponding 2- (2,2-dÍkarbethoxyethenylammo] thiazole derivatives. _-,. ··:

Similarly - In a manner may also be appropriate dtmethylestery dipropyl diisoproipylestery gain and substituting the appropriate dimethyl, dipropyl or dlisopropyletiioxymet lenmatonátu ^di ^ e ^thyl ethox ^y methylenmalonátem-.

Example 1 - and d - 1 3

2- (2,2-dicarbethoxyethenylamino) -4-methyl-5-ethylthiazole

4.68 g (40 mmol) of 4-methyl-5-ethylthiazole and 9.52 g (44 mmol) of diethylethoxymethylene malonate were briefly heated to 86 DEG C. and then cooled to give an oily product which was used directly. in the next step.

Example 14

2- (2,2-dicarbethoxy ^y ethene ^ylamino) -4,5-diethylthiazol

15.4 g, 80 mmoles of diethylthiazole hydrochloride, 19.0 g, 88 mmoles of diethylethoxymethylene malonate, 8.1 g, 80 mmoles of triethylamine and - 125 ml of ethanol are mixed and heated to reflux 2, 5 ho diny. The reaction mixture was cooled and the solvent was evaporated. The resulting slurry. the product was partitioned between ethyl acetate and water. It is obtained

28.6 g of 2- (2,2-d-carbethoxyethenylamino-β-4,5-diethylthlazole) as an oil of gold color from ethyl acetate phase after drying over anhydrous sodium sulfate and evaporation.

In a similar manner, the hydrobromide of 5,7-dimethylcyclohexeneothiazole, 4,4,6-methyl-cyclopentenothiazole and

7-methylcyclooctenothiazole to the corresponding 2- [2,2-dicarbethoxyethenylene amino] thiazole derivatives.

Similarly, the corresponding dimethyl, dipropyl and diisopropyl esters can also be obtained by using the appropriate dimethyl, dipropyl or diisopropylethoxymethylene malonate instead of diethyl ethoxymethylene malonate.

Example 1 5

2- (2,2-Dichloro-ethoxy) -henyl-amino) cyclopententhiazole

3.6 g (34.5 mmol) of 2-aminocyclopentene thiazole and 8.2 g (38.0 mmol) of diethylethoxy oxymalonate are mixed and heated on a steam bath for 100 minutes. The mixture was cooled and 7.0 g of 2- (2,2-dicarbethoxyethenylamino) cyclopententhiazole of Rf 0.6 in silica gel thin layer chromatography using chloroform with 1% ethanol was obtained by crystallization after addition of hexane.

Example 1 a d - 1 6

2- (2,2-Dicarbethoxyethenylamino) cyclohexenthiazole

7.7 g (50 mmol) of 2-aminocyclo-xenthiazole and 11.9 g (55 mmol) of diethyl ethoxymethylene malonate are mixed with 10 ml of ethanol and the mixture is heated under reflux for 50 minutes. The reaction mixture was cooled and precipitated by the addition of 50 ml of hexane to give 15 g of 2- (2,2-dicarbethoxyethenylamino) cyclohexenothiazole of Rf 0.5 by thin layer chromatography on silica gel using chloroform with 1% ethanol.

Alternatively, 58.4 g of 2-amino-cyclohexenothiazole, 89.82 grams of diethylethoxymethylene malonate and 584 ml of cyclohexane can be mixed and refluxed under a nitrogen atmosphere for 2.5 hours. After cooling to 15 ° C, 96 g of product are obtained after filtration, m.p. 113 ° C.

Example 17

2- (2,2-Dicarbethoxyethenylamino) cyclooctenthiazole

2.0-g, 11 mmol of -2-aminocyclooctenthiazole and 2.62 g, 12.1 mmol of diethylethoxyme241476 thylene malonate were mixed and heated on a steam bath for 2.75 hours. The reaction mixture was cooled and 3.13 grams of 2- (2,2-dicarbethoxyethenylaimino) cyclooctenthiazole of Rf 0.6 precipitated by thin-layer chromatography on silica gel using chloroform with 1% ethanol by addition of hexane.

Example 18

2- (2,2-carbethoxyethenylamino) -4-methylthiazole

4.57 g, 40 mmol of 2-amino-4-methylthiazole and 9.51 g, 44 mmol of diethylethoxylmethylene malonate were mixed and heated on a steam bath for 1 hour. The reaction mixture was cooled and 9.8 g of 2- (2,2-dicarbethoxyethenylamino) -4-methylthiazole of Rf 0.5 precipitated by thin layer chromatography on silica gel using chloroform with 1% ethanol by addition of 60 ml of hexane.

Example 19

2- (2,2-dicarbethoxyethenylamino) thiazole

2-Aminothiazole (10.0 g, 0.10 mol) and diethylethoxymethylene malonate (23.8 g, 0.11 mol) were mixed and heated on a steam bath for 1.25 hours. The reaction mixture was cooled and the resulting semi-solid was recrystallized from hexane to give two portions.

17.2 g of 2- (2,2'-dicarbethoixyethenyl) thiazole in pure form of Rf 0.6 on a thin layer of silica gel, using chloroform with 1% ethanol.

Example 20

2- (2,2-dicarbethoxyethenylamino) -5-methylthiazole

2-Amino-5-methylthiazole (6.85 g, 60 mmol) and diethyl ethoxymethylene malonate (14.3 g, 66 mmol) were heated on a steam bath for one hour. The reaction mixture is cooled and the product is precipitated by the addition of approximately 75 ml of hexane. 14.1 g of purified 2- (2,2-dicarboxyethenylamino) -5-methylthiazole having an Rf of 0.55 to 0.65 are obtained in two portions by thin layer chromatography on silica gel using chloroform with 1% ethanol after recrystallization from hexane.

Example 21

2- (2,2-dicarbethoxyethenylamino) -5-ethylthiazole

2-Amino-5-ethylthiazole (11.7 g, 91.3 mmol) and diethyl ethoxymethylene malonate (21.7 g, 100.43 mmol) were mixed and heated on a steam bath for 45 minutes. In this way it is obtained

27.2 g of 2- (2 ₎ 2-dicarbethoxyethylamino) -5-ethylthiazole of Rf 0,6 to 0,7 by thin layer chromatography on silica gel, using chloroform with 1% ethanol and a 2: 1 mixture of hexane and ethyl acetate as an oily substance liquid which is used directly in the next step.

Example 22

2- (2,2-Dicarbethoxyethoxy) amino} -4 (2-methyl-2-propyl) thiazole

2-Amino-4- (2-methyl-2-propyl) thiazole (15.6 g, 0.1 mol) and diethylethoxymethylene malonate (23.8 g, 0.11 mol) were combined and heated on a steam bath for 2 hours to give 2- (2,2-dicarbethoxyxyenylamino) -4- (2-methyl-2-propyl) thiazole as a wet solid which was used directly in the next step.

Example 1 a d 2 3

2- (2,2-dicarbethoxyethenylamino) -4-ethylthiazole

2-Amino-4-ethylthiazole (20.5 g, 0.16 mol) and diethyl ethoxymethylene malonate (35 g, 0.17 mol) were mixed and heated on a steam bath for 2 hours. After cooling, 2- (2,2-dicarbethoxyethenylarainoyl-4-ethylthiazole) is obtained as an oily liquid which is used directly in the next step: Rf is 0.75 by thin layer chromatography on silica gel using chloroform with 1% ethanol.

Similarly, 58.6 g (0.415 mole) of 2-amino-4-isopropylthiazole and 92 ml (0.455 mole) of diethylethoxymethylene malonate can be converted to 2- (2,2-di-carbethoxyethenylamino) -4-isopropylthiazole. Rf 0.7 in thin layer chromatography on silica gel using chloroform with 1% ethanol.

Example 24

2- (2,2-Dicarbethoxyethenylamino) -6-phenylcyclohexenethiazole

10.4 g (45.2 mmol) of 2-amino-6-phenylcyclohexenthlazole and 10 ml (49.5 mmol) of diethyl ethoxymethylene malonate were mixed and heated on a steam bath. After 15 minutes a solution formed. After another 30 minutes of heating the mass solidified and the crude product is recrystallized from cyclohexane to afford 15.3 g of purified 2- (2,2-dikarbethoxyethenylamino fenylcyklohexenthiazolu} -6-O · m.p. 131-133 C. ^Q

Example 25

2- (2,2-dicarbethoxyethenylamino) -6-methylcyclohexenthiazole

23.3 g (0.139 mol) of 2-amino-6-methylcyclohexenthlazole are mixed with 31 ml, 0.153 mol of diethylethoxymethylene malonate and the mixture is heated on a steam bath. After 10 minutes of heating, a clear orange oil develops

241478 liquid. After heating, crystallization was induced. Recrystallization from ethanol gave 40.2 g of purified 2- (2,2-dicarbethoxyethenylamino) -6-methylcyclohexenethiazole, m.p. 106-109 ° C.

Example 26

2- (2,2-dicarbethoxyethenylamino) -6,6-dimethylcyclohexylthiazole

9.3 g, 53.8 mmol · ⁱ 2-amino-6,6 dimethylcyklohexenthiazolu, 12 mL, 59.4 mmol diethyl. and 5 ml of ethanol are mixed and heated. on a steam bath for 1.5 hours. The ethanol was evaporated at the beginning of the heating. Upon cooling, the resulting product crystallizes. In this way, after recrystallization from hexane, 14.3 g of purified 2- (2,2-dicarbethoxyethenylamino) -6,6-dimethylcyclohexenethiazole are obtained, m.p. 83-85 ° C.

Analysis for G ^ O ^ calculated:

57.93% S, 6.86 ·% H, 7.95% N, found:

. % H, 6.66;% N, 7.94.

Example 27

2- (2,2-dicarbethoxyethenylamino) -4- (2-butyl) thiazole

8.44 g (54 mmol) of 2-amino-4- (2-butyl) thlazole and 11.7 g (54 mmol) of diethylethoxylmethylene malonate are mixed and heated on a steam bath for one hour and then cooled to give 17. 6 g of 2- (2,2-dicarbethoxyethenylamino) -4- (2-butyl) thiazole of Rf 0.75 by thin layer chromatography on silica gel using chloroform with 1% ethanol.

Example 1 8 '

Eiliyl 1-oxo-1H-6,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxylate

2- (2-Dicarbethosyethenylamino) -4,5-dimethylthiazole (4.17 g, 14 mmol) was mixed with 30 ml of Dowtherm-A and heated at 220 ° C for 1.5 hours. The reaction mixture was then cooled and petroleum ether (125 ml) was added. The precipitated solid was collected by filtration, re-mixed with mother liquor and chromatographed on a 70 x 180 mm silica gel column using chloroform as eluent. After an initial fraction of 125 ml, 6 fractions of 250 ml each were collected and evaporated to dryness to give 2.42 g of crude product, m.p. 114-115 ° C. Recrystallization from cyclohexane gave 1.64 g purified. ethyl 1-oxo-1H-4,5-dimethylhiazole-O [3,2-a] pyrimidine-2-carboxylate, m.p. 119-120 ° C.

Analysis for C 11 H 15 KOS calculated:

% C, 52.37;% H, 4.79;% N, 10.10;

% C, 52.21;% H, 4.85;% N, 11.23.

Example 29

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

6.25 g of 2- (2-d ^| ikarbethoxyethenylamíno) -4-ethyl-5-methylthiazole was mixed with 30 ml of the composition · Dowtherm A and heated at · 215 degrees Celsius for 2.5 hours ·. The reaction mixture was cooled, petroleum ether was added and 1.96 grams of the crude product was collected by filtration. 630 mg of the crude product is. It was recrystallized from cyclohexane to give 301 mg of purified 1-oxo-1H-6-methyl-7H-ethyl-thiazol-3,2-a] pyrimidine-12-carboxylic acid, m.p. 122-124 ° C.

Analysis for C12HHN2O3S calculated:

% C, 54.12;% H, 5.30;% 10.52;

% H, 5.26;% N, 10.63.

EXAMPLE 30 Ethyl-10-oxo-11,6-ethyl-7-methylthiazolol [3,2-a] pyrimidine-4-carboxylate. . ' g of 2- (2,2-dicarbethoxyethenylamino) -4-methyl-5-ethylthiazole is mixed with 60 ml of Dowtherm A and heated to 205 degrees Celsius for 3 hours. The reaction mixture is cooled and chromatographed on a 90 x 205 mm silica gel column eluting with chloroform containing 1% ethanol. 7 fractions of 250 ml containing product are obtained, which are combined, evaporated, to an oily liquid and re-chromatographed on a 60 x 600 mm silica gel column using the same solvent.

The fractions (165 x 8 ml) were combined, evaporated to an oily liquid and crystallization was induced by trituration with diisopropyl ether. After recrystallization from cyclohexane, 2.45 g of purified ethyl-1-octyl-16-ethyl-7-methylthiazolo [3,2-a] pyrimidine-12-carboxylate, m.p. 65 DEG-66 DEG C., is obtained.

Analysis calculated for: C H HH ^ CCkS:

54.12 ° C, 5.30% H, 10.52 N, mass ion 266, found:

% H, 5.23;% N, 10.57. mass ion 266.

Example 1 a d 3 1

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

26.1 g of 2- (2,2-dicabbethoxeethenylainino) -4,5-diethylthiazole and 300 ml of Dowtherm A are mixed and heated to 225 ° C for 3.5 hours. The reaction mixture is cooled and chromatographed on A silica gel column of 60 by 320 mm size was eluted with Dowtherm A eluting with hexane and eluting with 2: 1 hexane: chloroform. Collecting 33 fractions of 250 ml each. Fractions 8 to 33 were pooled and evaporated to give 22 g of the desired product. g of ethyl 1-hoo-1H-6,7-diethylthio [3,2-a] pyrimidine-2-carboxylate of Rf 0.4 to 0.5 on a thin layer of silica gel using chloroform with 1% ethanol. it is in the form of an oily liquid.

Example 3 2

Ethyl 1-hoo-1H-cyclopeeteeothiazole [3,2-a] pyrimidine-2-carboxylate

7.0 g of 2- (2,2-dicarbethoxyethenyl-amino) -cyclophetheehiazole are mixed with 40 ml of Dowtherm® A and heated at 225-230 ° C for about 1 hour. The reaction mixture was cooled and chromatographed on a 70 x 190 mm silica gel column. Dowtherm A elutes with hexane. The product was then washed with chloroform with 1% ethanol. Four 250 ml fractions were collected, combined and the solvent was evaporated to give an oil. A portion of this liquid crystallized upon trituration with cyclohexane to give 1.91 g of crude product. After recrystallization of 0.6 g of crude product, 0.33 g of purified ethyl 1-oxh-1H-cyclopentenothiazole [3,2-a] pyrimidine-2-carboxylate, m.p. 103 ° C.

Analysis for C12H12N2O3S calculated:

% C, 54.53;% H, 4.58;% N, 10.60.

% C, 54.54;% H, 4.71;% 10.71.

Example 33

Ethyl 1-ox (h1-cyclohexylhthiazhl [3,2-a] pyrimidine-2-carboxylate

12.6 g of 2- (2,2-dicabethoxyethenylamino) cyclohexenothiazole are mixed with 125 ml of Dowtherm A and heated at 230 ° C for 25 minutes. The reaction mixture was cooled and chromatographed on a 60 x 320 mm silica gel column. The Dowtherm A was washed with hexane and the resulting product was eluted with chloroform with 1% ethanol in 14 125 ml fractions. 10.7 g of crude ethyl-lolo-1H-cyclohexyl-nothi-azoto 3,2-a] pyrimidin-2-carboxylate, m.p. 92 DEG-94 DEG C., are obtained by collecting the fractions and evaporating the solvent.

Alternatively, 80 g (0.25 mole) of 2- (2,2-dicarbethoxyethylethylamino) cyclohenothiazole, 101 g (68 ml), 0.48 mole of trifluoroacetic anhydride (0.8 L), and 0.8 l of toluene are mixed. The reaction mixture was cooled and added with 300 ml of water. The upper toluene layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous. MgSO4, filtered, concentrated to 150 mL to give a suspension which was diluted with 1 L of ethanol, concentrated to 280 mL, cooled to 5 ° C, and filtered to give 47 g of relatively pure product. ethyl 1-oxo-1H-cyclohexo-thiothiyzhlo [3,2-a] pyrimidine-2-kyrboxylate, m.p. 105-106 ° C.

Example 34

Ethyl 1-oxh-1H-cycloheptenothiazzo [3,2-a] β-yrimidine-4-carboxylate

2-Yminocyclohepteothothiazole (25.2 g, 0.15 mol), diethylethoxymethylenemylonate (35.7 g, 0.165 mol) and Dowtherm A (400 ml) were mixed and heated at 220-230 ° C for 2 hours. The reaction mixture was cooled and chromatographed on a 90 x 335 mm silica gel column. The Dowtherm A was washed with hexane and the product was eluted with 1: 1 hexane / chloroform, collecting a 30 'fraction of 500 ml each. Fractions 6 to 30 were combined and evaporated to give a wet crude product. 27.1 g of purified ethyl 1-pxh-1H-cyclheptenothiaoolo [3,2-a] pyrimidia-2-kyrbxylate, m.p. 78 DEG-79 DEG C., is obtained by recrystallization from cyclohexane.

The same product is obtained by heating 2- (2,2-dicarbethoxyethylamino) cycloheptenothiazolo in Dowtherm A followed by isolation and purification as described above.

Example 35

Ethyl·l-oxh-lH-cyclhoctenhthiazole [3,2-y] pyrimidine-2-cyclohexylate

3.13 g of 2- (2,2-dicarbethooyethenylymino-cyclooctenol-thiazole) are mixed with 30 ml of Dowtherm A and heated at 220 ^° C for 2.5 hours. The mixture was washed with hexane and the product eluted with chloroform with 1% ethanol in 4 fractions

125 ml. The fractions were combined, evaporated to an oil, triturated with hexane to give 1.956 g of solid ethyl 1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxylate of Rf 0.5 by chromatography on a thin layer of silica gel using chloroform with 1% ethanol.

Example 3 6

Ethyl 1-oxo-1H-7-methylthiazolo 3,2-apyrimidine-2-carboxylate

9.8 g of 2- (2,2-dicarbethoxyethenylamino) -amethylthiazole are mixed with 50 ml of Dowtherm A and heated at 220 ° C for 2 hours. The reaction mixture is cooled and 50 ml of hexane are added, after which Recrystallization of the crude product from ethanol gave 4.6 g of purified ethyl 1-oxo-1H-7-methylthiazolo 3,2-apyrimidine-2-carboxylate, m.p. 187-189 ° C. .

The same ester can be obtained by direct condensation of 2-amino-4-methylthlazole with ethylethoxymethylenemionate refluxing trichlorobenzene, as described by Allen et al., J. Org. Chem., 24, 779 (1959).

Example 3 7

Ethyl 1-oxo-1 H-4-oxyl-3,2-apyrimidine-2-carboxylate

17.2 g of β-2,2-di-thiazole were combined with the following: with 200 ml of Dowtherm A · and the mixture is heated at 215 ^DEG C. for 30 minutes. The reaction mixture is cooled to give a suspension, 100 ml of hexane are added and the crude product is collected by filtration. 184 DEG-185 DEG C., ethyl 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylate.

The same ester can be obtained by direct condensation of 2-aminothiazole with ethyl ethoxymethylene malonate by boiling with trichlorobenzene at reflux, as described in Allen et al., J. Org. Chem., 24, 779 (1959).

Example 1 a d 3 8 ‘

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

14.1. - (2,2-Dimethoxybenzoyl) -5-methylthliiazole was mixed with 150 ml of Dowtherm A and heated to 220 ° C for 1.5 hours. The reaction mixture was cooled and added. about 300 mL hexane. The product is collected by filtration and recrystallized from diisopropyl ether to give the title compound

6.4 g of purified 4-methyl-11-oxo-H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylate, m.p. 149-151 ° C.

The same ester can also be obtained by direct condensation of β-amithio-5-methylthiazole with ethyl ethoxymethylene malonate in. boiling trlchlorobenzene as described in U.S. Pat. Dunwell et al., J. Chem. Soc., (C) 1971, 2094.

Example 39

Pthyl-1-oro-11,16-ethylthiazoio [3,2-a] pyximidine-2-carboxylate

25.7 g (86 mmol) of N, N-dicarbethoxyethenylamino-5-ethylthiazole, 36.2 g (172 mmol) of trifluoroacetic anhydride and 150 ml of toluene are added and the mixture is heated under reflux for 20 hours. The reaction mixture was evaporated to dryness. 300 ml of chloroform are added. The chloroform solution was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated defective sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to dryness and triturated with diisopropyl ether to give 17.8 g of βΠιν1-οχο. 148-150 ° C, -1Η-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate. 5.2 g of this product are recrystallized from about 75 ml of ethyl acetate to give 4.1 g of purified product, m.p. 149-150 ° C.

Analysis calculated for C CHH ^NO · ^ ':

52.37 O / o C, 4.79, 79% H, 11.10% N, found ·:

% C, 52.30;% H, 3.51;% N, 11.14.

Example 40

Pthyl-1-oxo-7- (2-methyl-2-palopyl) thiazolo [3,2-a] pyrimidine-2-carboxylate

32.6 g of 2 - [, 2-dicarnethoxyethenylamino] -4- (2-methyl-2-propyl) thiazoles are mixed with 400 ml of Dowtherm · A and heated at 230 ° C for 1 hour. the mixture is cooled and chromatographed on a silica column. of likagel · 60 x 600 · mm. Dpwtherm A was washed with hexane and the product eluted with chloroform. 9 fractions of 500 ml are collected. Fractions 6-9 are combined and evaporated to dryness to give 11.4 g of ethyl 1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxylate. mp 145-147 ° C. An additional 2.04 g of product was obtained from the fifth fraction by evaporation to a wet solid followed by trituration with cyclohexane, m.p. 1 g of the first crop was recrystallized from cyclohexane to give 0.62 g of purified product, m.p. 148-149 ° C.

Analysis calculated for:

55.70% С, 5.75% Η, 9.99% Ν, found:

55.14% С, 5.58% Η, 9.95% Ν.

Example 41

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

47.7 g (0.16 mol) of 2- (2,2-dicarbethoxyethenylamino) -4-ethylthiazole are stirred with 500 ml of toluene and 45 ml, 0.32 mol of trifluoroacetic anhydride. There is a slight exothermic reaction. The reaction mixture was heated at reflux for 25 hours, then cooled and 250 ml of ethyl acetate were added. The mixture was then carefully extracted with 250 ml of aqueous sodium bicarbonate solution to release carbon dioxide and then with 250 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is suspended in diisopropyl ether and the crude product is collected by filtration. Recrystallization of the crude product from acetonitrile gave 10.33 g of purified ethyl 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate, m.p. 175-177 ° C.

Analysis calculated for C ₁₁ H ₁₂ N ₂ O ₃ S:

% C, 52.37;% H, 4.79;% N, 11.10%.

% C, 52.34;% H, 4.85;% N, 11.27.

1.58 g of additional product, m.p. 176 DEG-178 DEG C., is obtained from the acetonitrile mother liquor.

Example 42

Ethyl 1-oxo-4H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxy) -4-isopropylthiazole g was mixed with 100 ml of Dowtherm A and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature overnight and reheated to 220 ° C for 5 hours. The mixture was cooled to room temperature, approximately 200 mL of hexane was added and the mixture was filtered to remove traces of insoluble solids. The hexane is evaporated and the residue is chromatographed on approximately 500 g of silica gel. The Dowtherm A was washed with hexane and the product eluted with chloroform. The product fractions were combined and evaporated to dryness, the residue suspended in diisopropyl ether and the resulting product, m.p. 143-144 ° C, collected by filtration.

The crude product was recrystallized from ethanol to give 1.49 g of purified ethyl 1-oxo-1H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxylate, m.p. 145-147 ° C.

NMR Spectrum: singlets at δ 8.6 and 7.3 correspond to 1 proton each and multiplets at δ 4.2 and 1.2 correspond to three and nine protons.

Example 43

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

2- (2,2-Dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole (15.3 g, 38.2 mmol) is suspended in 150 ml of toluene. Trifluoroacetic anhydride (10.8 mL, 76.5 mmol) was added to give a clear solution which was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, diluted with 150 mL of ethyl acetate, extracted twice with 150 mL of 5% potassium carbonate and once with 150 mL of saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The solid residue was recrystallized from acetonitrile to give 9.89 g of purified ethyl 1-oxo-1H-7-phenylcyclohexenohiazolo [3,2-a] pyrimidine-2-carboxylate, m.p. 160-161.5 ° C.

Example 1 a d 4 4

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

2- (2,2-Dicarbethoxyethenylamino) -6-methylcyclohexenothiazole (40.2 g, 0.119 mol) was dissolved in toluene (400 ml). 33.5 ml (0.237 mol) of trifluoroacetic anhydride are added to give a slightly exothermic reaction. The reaction mixture was heated at reflux for 16 hours, cooled to room temperature, diluted with 400 ml of ethyl acetate, extracted twice with 400 ml of 1N potassium carbonate and once with 400 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporates to dryness. Recrystallization from cyclohexane with a small amount of ethyl acetate gave 29.3 grams of purified ethyl 1-oxo-1H-7 methyl carboxylate, m.p. 127-129 ^° C.

Example 45

Ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolof 3,2-a] pyrimidine-2-carboxylate g, 36.9 mmol of 2- (2,2-dicarbethoxyethenylamino) -6,6-dimethylthiazole are dissolved in 130 ml toluene. Trifluoroacetic anhydride (10.4 ml, 73.6 mmol) was added and the mixture was heated under reflux for 16 hours. The mixture is cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 130 ml of saturated sodium bicarbonate solution and once with 150 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. Re-installation from hexane yielded 9.40 g of purified ethyl 1-oxo-1H-7,7-dimethylcyclohexsothiothiazolo [3,2-a] pyrimidine-2-carboxylate, m.p. 92-94 ° C.

Analysis. calculated for Cm> Hi ₆ N ₂ O ₃ S:

% H, 5.92;% N, 9.14.

% C, 58.93;% H, 5.48;% N, 9.01.

Example 4 6

Ethyl 1-cis-1H-7- (2-butyl) thiazolo [3,2-a] pyrimidine-2-carboxylate.

17.6 g of 2- (2,2-dicarbethoxyethenylamino) -4- [2-butyl] thiazole are mixed with 175 ml of Dowtherm® A and heated at 225 ° C for 2.5 hours. The reaction mixture is then cooled and chromatographed on a 60 x 600 mm silica gel column. Dowtherm A is washed with hexane and the resulting product is eluted with a 2: 1 mixture of chloroform and hexane. Fractions 4 to 8 of 500 ml are combined and evaporated to an oily liquid which is mixed with approximately 400 ml of hot hexane. Activated carbon was added and the mixture was cooled to give 2.12 g of crystalline ethyl 1-οχο---7- (2-butyl) thiazolo [3,2-a] pyrimidine-2-carboxylate, m.p. 105 , 5 to 108 ^C C.

Analysis calculated for C C -H ^Oa · S S:

% C, 55.70;% H, 5.75;% N, 9.99.

% C, 55.82;% H, 5.40;

Example 1 4

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

1.41 g of ethyl-1-oxo-1H-6,7-dimethylthiazolo [3,2-a. The pyrimidine-2-carboxylate was heated on a steam bath with 20 ml of 48% hydrobromic acid for 1 hour. A solution is formed in a few minutes and a solid begins to precipitate at the end of the reaction time. The reaction mixture was cooled and the resulting product collected by filtration. Recrystallization from ethanol gave 508 mg of purified 1-oxo-1H-6,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid, m.p. 189-190 ° C.

Analysis for C9H8O3N2S calculated:

48.21% C, 3.60% H, 12.49% N, mass ion 224, found ·

48.21 _: % C, 3.68% H, 12.44% N, mass ion 224.

Example 1 a d 4 8 ..

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

971 mg of ethyl 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate was heated in a steam bath with 15 ml of 48% hydrobromic acid. The solution formed almost immediately and the mixture was further heated for 2.5 hours, then the reaction mixture was cooled, and the resulting product was collected as a solid by filtration. Recrystallization of this crude product from isopropyl alcohol gave 354 mg of purified 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid, mp 201-202 ° C.

Analysis for CjoHkONS calculated:

% C, 50.41;% H, 4.23;% N, 11.76.

% H, 4.26;% H, 11.80. % ₀ ; N.

Example 1 4 4 _

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

1.33 g of ethyl 1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid is heated on a steam bath with 10 ml of 48% hydrobromic acid for 30 minutes, after at this time a solid begins to form. The mixture was cooled and the crude product was collected by filtration. Recrystallization from isopropanol gave 596 mg of purified 1-cis-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine, m.p. 174-176 ° C. ·

Analysis for ^C 1.0 ^H 10 ° 3 ^N 2 ^S calculated:

H, 4.23%, 11.76%

% C, 50.44;% H, 4.22;% N, 11.82

Example 1 a d 5 0

1-cis-1H-6,7-diethylthiazocc [3,2-a] pyrimidine-2-carboxylic acid

19.2 g of ethyl 1-oxo-1H-6,7-diethylthiazole [3,2-a] pyrimidine-2-carboxylate was heated to 85 ° C with 48% hydrobromic acid for 1 hour. The formation of gas is likely to be caused by the decarboxylation of the product. The reaction mixture was cooled and basified with concentrated ammonium hydroxide and the unreacted starting material and impurities were extracted with ethyl acetate. The aqueous phase is acidified with acetic acid and the solid product collected by filtration. The crude product was recrystallized from isopropyl alcohol to give 5.4 g of partially purified product in two portions.

2.5 g of the partially purified product were recrystallized a second time from isopropyl alcohol to give 1.6 g of purified 1-oxo-1H-6,7-diethylthiazolo [3,2-a. 104 DEG-106 DEG C .; (Turbidity).

Analysis for · СцН ^ Оз ^ calculated:

% C, 52.37;% H, 4.79;% N, 11.10.

% C, 52.31;% H, 4.79;% N, 11.16.

ExampleSl

1-Oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylic acid

1.3 g of γ-O-oxo-1H-cycl (trans-phenothiazol-3,2-a) pyrimidine-2-carboxylate was heated with 15 ml of 48% hydrobromic acid on a steam bath for 30 minutes. The reaction mixture was cooled and the crude product was collected by filtration to give 0.51 g of purified 1-oxo-1H-chloropentene-2-thiazolo [3,2-a] after recrystallization from isopropyl alcohol. -a] pyrimidine, m.p. 202-203.5 ° C.

Analysis for C10H8O3N2S calculated:

% C, 50.84;% H, 3.41;% N, 11.86.

H, 3.57; N, 11.65.

The sodium and potassium salts are obtained by dissolving the free acid in water with 1 equivalent of the appropriate hydroxide followed by evaporation of the water in vacuo or subsequent freeze-drying.

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

Example 5 2

1-Oxo-1H-cyclohexenothiazolo [3,2-a] phrimidine-2-carboxylic acid

2.8 g of ethhl-1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidin-2-carboxylate was heated on a steam bath with 30 ml of 48% hydrobromic acid. A few minutes after the start of heating a solution is formed, the product begins to precipitate at the end of the reaction. The reaction mixture is cooled in an ice bath and 1.66 g of 1-oxo-1H-cyclohexenothiazole-3,2-a] pyrimidine-2-carboxylate are isolated by filtration at a temperature. mp 188-189 ° C. Recrystallization from ethanol gave 1.38 g of the same product with the same melting point.

Alternatively, 22.3 g of ethyl ester and 223 ml of 48% hydrobromic acid can be mixed. The solution is formed at a temperature of 65 to 70 ° C. The reaction mixture was heated to a maximum temperature of 85 ° C at a maximum pressure of 0.042 MPa for 40 minutes. The reaction mixture was then cooled to 45 ° C, further cooled to 5 ° C under atmospheric pressure, stirred for one hour, and then directly obtained by filtration, 12.4 g of the relatively pure product, m.p. 192-194 ° C. . The sodium salt is obtained by dissolving the acid in methanol with an equivalent amount of sodium methoxide and evaporating to dryness or precipitating and cooling by adding hexane to give the resulting salt.

Example 1 a d 5 3

1-Oxo-1H-cycloheptenothiazolo [3,2-y] phrimidine-2-carboxylic acid

5.8 g of thio-1-oxo-1H-cyclohexylthiazole of 3,2-a] pyrimidine-2-carboxylate was heated on a steam bath with 50 ml of hydrobromic acid for 15 minutes. The reaction mixture was poured onto ice, stirred and the crude product collected by filtration. Recrystallization from ethanol gave 2.63 g of purified 1-oxo-1H-chloro-heptothiothiazolo [3,2-a] pyrimidine, m.p. 162-163 ° C.

Calcd for C ₁ H ₁₂ O ₂ N ₃ N ₂ S calculated:

% C, 54.53;% H, 4.58;% N, 10.60%. Found:

% C, 54.72;% H, 4.73;% N, 10.88.

The amine is obtained by adding 1 equivalent of amine to a warm ethanolic acid solution followed by cooling, evaporation or addition of hexane.

Example 1 4

Acid I-1: ^ (^ - ^. H ^ (^^^ o ^ (^ (^ J ^{^;} Íenothiazolo [3,2-a] phrimidm-2-carboxylic acid

1.23 g of ethhi-1-oxool-4-cyclooctenothiazole [3,2-a] phrimidine-2-carboxylate was heated in an oil bath with 30 ml of 48% hydrobromic acid at 90 ° C for 4 hours. The reaction mixture was cooled, the pH was adjusted to 1.5 and the product was extracted with ethyl acetate. The ethyl acetate extract was washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to a residue.

241478 oil. This liquid was redissolved in ethyl acetate and the product was extracted with 1 N potassium hydroxide. The alkaline solution was acidified again with 3 N hydrochloric acid and the product was extracted again with ethyl acetate. The ethyl acetate solution was extracted with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give 308 mg of 1-oxo-1H-cycloheptenothiazolo] 3,2-a] pyrimidine-2-carboxyloye, Rf 0.6 thin layer chromatography on silica gel using chloroform with 1% ethanol.

Example 1 5

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

3.1 g of ethyl 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2'-carboxylate was heated on a steam bath with 50 ml of 48% hydrobromic acid. After 5 minutes a solution was formed. After heating for 15 minutes, the reaction mixture was cooled and the resulting product precipitated by filtration. _F After recrystallization from acetic acid obtained in this manner

1.4 g of purified Ι-οχο-ΙΗ-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid, m.p. 265 DEG C. with decomposition.

Analysis for C ₈ H _G N ₃ O ₂ S Calculated:

45.71% C, 2.88% H, 13.33% N, found *

H, 3.04; N, 13.40.

At 1 and d 5 6

1-O'xo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid

7.5 g of ethyl 1-oxo-1H-thiazolo [3,2- a] pyrimidine-2-carboxylate was heated on a steam bath for 20 minutes with 80 ml of 48% hydrobromic acid. The solution is formed within 5 minutes, and the solid begins to precipitate a few minutes later. The reaction mixture was then cooled in an ice bath and the crude product was then collected by filtration. 4.66 g of purified 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid, m.p. 276 DEG C. with decomposition, are thus obtained.

Analysis calculated for C ₇ H ₇ O ₃ N ₂ S:

42.86%; C, 2.06% H, 14.28% N, found:

% C, 42.71;% II, 2.21%. N. 14.32%

The same acid can be obtained from the same intermediate. refluxing with 2 N hydrochloric acid according to Allen et al., J. Org. Chem., 24, 779 (1959).

Example 57

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

5.96 g of ethyl 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylate were heated on a steam bath with 60 ml of 48% hydrobromic acid for 1 hour. The reaction mixture was cooled in an ice bath and the crude product was collected by filtration, and the filter cake was washed with isopropyl alcohol and ether. The crude product was recrystallized from dimethylformamide to give 3.73 g of purified 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid, m.p. 246 DEG-248 DEG C. with decomposition.

Analysis calculated for C8H10O5S:

% C, 45.71;% H, 2.38;% N, 13.33.

H, 2.94; N, 13.47.

The same acid can also be obtained from the same intermediate by refluxing in 2 N hydrochloric acid as described by Dunwell et al., J. Chem. Soc. (Cj 1971, 2094.

Example 58

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

12.6 g of ethyl 1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate were heated on a steam bath with 125 ml of 48% hydrobromic acid. A solution is formed in a few minutes. After 10 minutes a solid began to form. Heating is performed for a total of 40 minutes. The reaction mixture was cooled and 10.1 g of crude product collected by filtration. Recrystallization of 2.32 g of crude product from isopropyl alcohol (6.8 g obtained in an attempt to recrystallize from acetic acid) gave 1.85 g of purified 1-oxo-1H-6-ethylthiazolo [3,2- a] pyrimidine-2-carboxylic acid, m.p. 162-163 ° C.

· Analysis for C 9 H ₈ N ₂ O ₃ S Calculated:

% C, 48.21;% H, 3.60;% N, 12.49.

H, 3.73; N, 12.42.

Example 59

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

5.6 g of ethyl 1-oxo-1H-7- (2-methyl-2-propyl) thiazolido [3,2-a] pyrimidine-2-carbonyloxy is heated for 6 hours on a steam bath with 60 ml of 48% hydrobromic acid After 10 minutes before complete dissolution of the ester, the reaction mixture is cooled and the crude product is thickened and separated by filtration at the end of heating. of dimethylformamide, 3.33 g of purified 1-oxo-1H-7--2-methyl-2-propyl Jihlazolo [3,2-a] pyrimidine-2-carboxylic acid, m.p. 241 DEG-242 DEG C. dec. .

Analysis calculated for C ^ HiH -OaN -S ·

52.37% C - 4.7? 9 o / o H- 11.10% N. found:

% C, 52.45;% H, 4.82;% N, 11.26.

Example 60

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

1.5 g of ethyl-11-oxo-1H-7-ethylthiazolo {3,2-a] pyrimidine-2-carboxylate were heated on a steam bath with 15 ml of 48% hydrobromic acid for 20 minutes. After 5 minutes a solution was formed and after 10 minutes a solid began to form. At the end of the reaction time, the mixture was cooled to room temperature, diluted with approximately 25 ml of water and the crude product collected by filtration. The crude product is partially purified by dissolving 1N potassium carbonate and further precipitating by acidifying with 3N hydrochloric acid. Recrystallization from acetic acid yielded 594 mg of purified 1-oxo-1H-7-ethylthiazoio {3,2-a] pyrimidine, m.p. 206 DEG-209 DEG.

Analysis for C 9 H ₈ N2O3S Calculated:

% C, 48.21;% H, 3.60;% N, 12.49.

H, 3.69; N, 12.50.

Example 6 1

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

909. mg of ethyl 10-oxo-1H-7-isopropylthiazol [3,2-aipyrimidine-2-carboxylate was heated on a steam bath with 10 ml of 48% hydrobromic acid for 20 minutes. After 5 minutes complete dissolution occurred, after 10 minutes the resulting product began to precipitate. After heating, the reaction mixture was cooled to room temperature and the crude product was collected by filtration. Mon. recrystallization from ethanol takes place in this way. 438 mg of purified 1-OXO-1H-7-isopropyl-thiazolo [3,2-a] pyrimidine-2-carboxylic acid is obtained, m.p. 216-217 ° C.

Example 6 2

III-H-7-phenylcyclohexanothiazol [3,2-a] pyrimidine-6-carboxylic acid

9.8 g of ethyl 1-xyl-1H-1-phenyl-cyclohexylthiazolo [3,2-a] pyrimidine-2-carboxylate was added. was heated to reflux with 200 ml of 48% hydrobromic acid for 20 minutes. After 10 minutes a solution formed. The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from acetic acid gave 2.25 g of purified 1-oxo-1H-7-phenylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid, m.p. 224 DEG-226 DEG.

Analysis for C: CH ^^OSS calculated:

% C, 62.56;% H, 4.32;% N, 8.58.

% H, 4.11;% N, 8.52.

704 mg of the title product, m.p. 217 DEG-220 DEG C., were recovered from the mother liquor.

Example63

1-Oxo17-methylcyclohexene-4-thiazolo [3,2-a] pyrimidin- ^12- carboxylic acid

27.5 Ethyl 1-oxo-1H-1-methyl-chloro [3,2-a] pyrimidine-12-carboxylate was heated in a steam bath with 275 ml of 48% hydrobromic acid for 35 minutes. After 10 minutes a clear solution after 15 minutes, ¹ began precipitating the resultant product. The reaction mixture was cooled to room temperature and 14.9 grams of crude product, m.p.

181.5 to 183.5 ° ^C with fi ^ J ^ l ^ Pro- iracíí after washing of the filter cake with water. After recrystallization from dimethylformamide, 10.1 g of purified 1-oxo-1H-7-methylcyclohexyl-thiazolo [3,2-a] pyrimidine-2-carboxylic acid, melting at 183.5 to 185.5 DEG, is obtained. C.

Analysis calculated for C 12 ^H 12 ^N 2 ^O 3 ^S :

% C, 54.53;% H, 4.58;% N, 10.60.

% C, 54.41;% H, 4.28;

A second crop was obtained from the mother liquor in dimethylformamide solution by the addition of water. 3.11 g of product, m.p.

184 ° C.

Example 64

1'-oc-1 H -7,7-dimethylcyclohexyl] -enothiazolo [3,2-a] pyrimidine-6-carbaxyl

7.9 g of efbyl-L-oxo-1H-7,7-clinylcyclohexenothiazole [3,2-a] pyriniidine-2-carboxylate with a mixture of 38 ml of 48% hydrobromic acid and a mixture of is heated on a steam bath for 50 minutes. The acid is precipitated before the ester is completely dissolved. The reaction mixture is cooled, diluted with 100 ml of water and 6.7 g of crude product collected by filtration, washed with a small amount of water on the filter.

Recrystallization of the crude product from ethanol gave 4.7 g of purified 1-oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid, m.p. 197-198 ° C.

Analysis for calculated:

% C, 56.10;% H, 5.07; N, found:

H, 4.84; N, 10.14.

Example 65

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

2.0 g of ethyl 1-oxo-1H-7- (2-butylthiazolo [3,2-a] pyrimidine-2-carboxylate) was mixed with 20 ml of 43% hydrobromic acid and heated on a steam bath for 25 minutes. After 5 minutes a solution is formed, after 10 minutes the resulting product begins to precipitate, then the reaction mixture is cooled to room temperature, diluted with approximately 40 ml of water, and 1.3 g of the crude product, m.p. The product on the filter was washed with a small amount of water, and after recrystallization of the crude product from ethyl acetate containing a small amount of ethanol, 606 mg of purified 1-oxo-1H-7- (2-butyl) thiazolo [3,2-a] was obtained. 194 DEG -197 DEG C. pyrimidinyl-2-carboxylic acid.

Analysis for СиНп ^ ОзБ calculated:

% C, 52.37;% H, 4.79;% N, 11.10.

% C, 52.20;% H, 4.48;

Another small portion of the resulting product was obtained from the ethyl acetate mother liquor by concentration.

Example 66

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

367 mg, 1.6 mmol of 1-oxo-1H-6.7 acid

Dimethylthiazolof 3,2-a] pyrimidine-2-carboxylic acid is dissolved in 3 ml of dimethylformamide by heating on a steam bath. 292 mg (1.8 mmol) of 1,1‘-carbonyldlimidazole are then added. Immediately evolution of gas begins, as soon as the gas stops evolving, 153 mg of 1.8 mmol of 5-ammotetrazole are added.

A solution formed and after some time a solid formed again. The reaction mixture was cooled and the precipitated crude product was collected by filtration. After recrystallization of this crude product from dimethylformamide, 336 mg of purified N- (5-tetrazolyl) -1-oxo-1H-6,7-dimethylthiazolo [3,2a] pyrimidine-2-carboxamide, m.p. C.

Analysis for C 10 H 8 OQNyS calculated:

H, 3.11; N, 33.66. Found:

H, 3.40; N, 33.47.

Example 67

N- (5-tetrazolyl) -1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxamide

1-Oxo-1H-6-methyl-7-ethyl-thiazolo [3,2-a] pyrimidine-2-carboxylic acid (238 mg, 1.0 mmol) was dissolved in dimethylforminamide (5 ml) and heated on a steam bath. 178 mg, 1.1 mmol of Ι, Γ-carbonyldlimidazole are then added. When gas evolution ceased, 5-aminotetrazole (93.5 mg, 1.1 mmol) was added. After about 15 minutes a solid began to precipitate. The reaction mixture was cooled and filtered to give 227 mg of N- (5-tetrazolyl) -1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxamide, m.p. Deň: 32 ° C.

Analysis for СцНцОз ^ Б calculated:

% C, 43.27;% H, 3.63;% N, 32.11;

% C, 43.20;% H, 3.72;

Example 68

N- (5-tetrazolyl) -1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxamide

1-Oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (476 mg, 2.0 mmol) was dissolved in dimethylformamide on a steam bath. To the hot solution was added 357 mg (2.2 mmol) of 1,1 &apos; -decarbonylimidazole to evolve gas. As soon as the gas ceases to evolve, 187 mg (2.2 mmol) of 5-aminotetrazole are added. After a few minutes a solid began to form. The reaction mixture was cooled and the resulting crude product collected by filtration. Recrystallization from dimethylformamide gave 388 mg of purified N- (5-tetrazolyl.) -1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxamide, m.p. 303 DEG C. dec.

Analysis for CuHnCoN-S calculated:

43.3% C, 3.6% H, 32%, 1% N, found:

43.6 ° C, 3.9% H, 32.3% N.

Example 69

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

2.52 g, 10 mmol of 1-oxo-4 H-6,7-diethylhiazolo [3,2- a] pyrimidine-2-carboxylic acid and 1.78 g, 11 mmol of Ι, Γ-carbonyldimidazole are mixed with 15 ml of dimethylformamide and the mixture was heated on a steam bath. The mixture goes into solution with gas evolution. When the gas stops evolving, add

5-Ammotetrazole (1.13 g, 11 mmol) was added and the mixture was heated for a further 30 min. The reaction mixture was cooled and the precipitated crude product was collected by filtration. Recrystallization of the crude product from acetic acid afforded 1.11 g of purified N- (5-tetrazolyl) -1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxamide. mp 283 ° C dec.

Analysis calculated for: C12H113D2N7S:

45.13% C, 4.10% H, 30.70% N, mass ion 319, found:

C, 45.18; H, 4.24; N, 30.52.

Example · 7 0

N- (5-tetrazolyl) -1-oxo-1H-cyclopentenothiazolo [3,2-a] 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'-carbonyldiimidium azole were mixed with 3 ml of dimethylformamide and the mixture is heated on a steam bath. The components dissolve and gas evolves. As soon as the gas stops evolving, 150 mg of 17.6 mmol of 5-aminotetrazole are added. After a few minutes, the resulting product begins to precipitate. The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from dimethylformamide gave 313 mg of purified N- (5-tetrazolyl) -1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxamide, m.p. &gt; 310 ° C. . \

Analysis for C Ch ^ Ci ChN SS calculated:

43.6% C, 3.0% H, 32.3 o / o N, found:

% C, 43.6;% H, 3.3;% N, 32.0.

Example 1 and 7 1

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

0.5 g, 2 mmol · 1-oxo-lH-3,2-cyklohéxenothiazolj pyrimido-2-carboxylic acid and 0.36 g, 2.2 mmol · l l ⁶ · carbonyldiimidazole were dissolved in 3 ml DMF at at room temperature, a solution is formed and gas evolves as soon as the gas stops evolving, · the reaction mixture is heated on a steam bath, · further evolution of gas occurs. To the hot solution was added 0.19 grams. 2.2 mmol of 5-aminotetrazole. · Within a few minutes the DC will start to precipitate the resulting product. The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization of the crude product yielded 319 mg of purified N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidin-2-carboxamide, m.p. 310 DEG C. with decomposition.

Analysis calculated for: C H HHj ^N-S:

45.42% C, 3.99% H, 30.90% found:

% C, 45.59;% H, 3.62;% N, 30.44.

Alternatively, 2.07 g of acid can be dissolved in 40 ml of methylene chloride and 1.74 ml of triethylamine at a temperature of 0 ° C. 0.85 ml of ethyl chloroformate in. 8.1 ml of methylene chloride, maintaining the reaction temperature at 0-5 ° C. After a reaction time of 45 minutes at 0-5 ° C, 0.87 g of 5-aminoetetradiol in 8.1 ml of dimethylacetamide is added, and the reaction mixture is heated at 20 ° C for 25 minutes and then stirred at room temperature. at this temperature for a further 90 minutes. Filtration gave 2.0 g of product, m.p. 308-310 ° C. 3.9 g of the product obtained in this way are recrystallized from dimethylacetamide to give 3.1 g of purified N- (S-ethoxy) -olyl: o-1H-cyclohexenothiazolo 3,2- a] pyrimidine-4-carboxamide, m.p. 314 DEG-315 DEG.

The sodium salt of this amide is obtained by dissolving 5.5 g (17.3 mmol) of amide in 44 ml of void and adding 17.3 ml (17.3 mmol) of standardized solution over 30 minutes. sodium hydroxide at a concentration of 1 o at pH 11.0. The solution becomes clear and the sodium salt is precipitated by the addition of 35 ml of acetone. The suspension is cooled to 5 ^DEG C., allowed to stand for 3 hours and

4,9 · oddiékooi · S · detached, iltlaaoní

The 241478 cake was washed with cold acetone. 100 mg of sodium salt are suspended in 1 ml of water, the suspension having a pH of 10.22. The sodium salt is recrystallized by dissolving 2.3 g of the salt in 23 ml of water at 60 ^° C.

The clear solution was cooled to 5 ^° C for one hour and allowed to stand at this temperature for another hour. 1.68 g of the sodium salt are separated by filtration. 100 mg of recrystallized sodium salt in 1 ml of water has a pH of 8.80.

Analysis for C ₁₂ H ₁₀ O ₂ N ₇ SNa. 3 H ₂ O calculated:

H ₂ O: 13.7, weight loss on drying 13.7, neutralization equivalent 393.

found ¹ :

H ₂ O: 13.43, weight loss on drying

13.8, neutralization equivalent of 391.

When using mixed anhydride, equivalent amounts of different salts can be obtained by using an equivalent amount of methyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, tert-butyl chloroformate, pentyl chloroformate, benzyl chloroformate instead of ethyl chloroformate. Similar amounts of other acids described in Examples 47-65 may also be used to provide the corresponding N- (5-tetrazolyl) amides.

Example 72

N (5-tetrazolyl) -1-oxo-1H-cycloheptenothiazolo [3,2-a] 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 Ι, Γ-carbonyldiimidazole are mixed with 15 ml of dimethylformamide and the mixture heated on a steam bath. Once gas evolution ceased, S-aminotetrazole monohydrate (0.86 grams, 8.8 mmol) was added. A solid formed over 5 minutes. After an additional 30 minutes of heating, the reaction mixture was cooled and the product collected by filtration. Recrystallization of the crude product from dimethylformamide gave 1.61 g of purified N (5-tetrazolyl) -1-oxo-1H-cycloheptenothiazole-10 [3,2-a] pyrimidine-2 carboxamide, m.p. 295-296 ° C with decomposition. .

Analysis calculated for C ^ HH ^C ^NSS ¹ :

% C, 47.12;% H, 3.95;% N, 29.59.

H, 4.11; N, 29.72.

Example 1 a d 7 3

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

308 mg, 1.1 mmol of 1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxylic acid are dissolved in 10 ml of dimethylformamide and the solution is heated on a steam bath. 196 mg, 1.21 mmol of 1,1'-carbonyldiimidazole are then added. When gas evolution ceased, 5-aminotetrazole (103 mg, 1.21 mmol) was added. The reaction mixture was heated for 10 minutes, during which time the reaction mixture was stirred for 1 hour. a solid begins to precipitate. The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from dimethylformamide gave 183 mg of purified N- (5-tetrazolyl) -1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxamide, m.p. 310 DEG C. with decomposition.

Analysis for C14HJ5O2N7S calculated:

% C, 48.69;% H, 4.38;% N, 28.39.

% C, 49.01;% H, 4.63;% N, 27.35.

At 1 and d 7 4

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

0.91 g, 4.3 mmol of Ι-οχο-ol-7-methylthiazolof 3,2-a] pyrimidine-2-carboxylic acid and 0.89 g, 5.5 mmol of Ι, Γ-carbonyldiimidazole are mixed with 5 ml dimethylformamide and heated on a steam bath. When gas evolution ceased, 0.47 g of 5.5 mmol of 5-aminotetrazole was added. Before a clear solution is formed, another solid begins to precipitate. After a few minutes, the reaction mixture was cooled and the crude product was collected by filtration. Recrystallization; starting from dimethylformamide, 1.0 g of purified N- (5-tetrazolyl) -1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxamide was obtained, m.p. &gt; 310 ° C.

Analysis for C0H7O2N7S calculated:

38.99 O / o C, 2.54% H, 35.36% N, found:

% C, 38.97;% H, 2.73;% N, 34.97.

Example 75

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

1.96 g, 10 mmol of 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid are dissolved in 20 ml of dimethylformamide on a steam bath. 1.78 g, 11.0 mmol of 1,1‘-carbonyldilmidazole are added. When gas evolution ceased, 5-aminotetrazole monohydrate (1.13 g, 11 mmol) was added. Approximately 1 minute a solid began to form. The mixture was heated for a further 15 minutes, then cooled and the crude product collected by filtration.

After recrystallization from dimethylformamide, 1.8 g of purified N- (5-tetrazolyl) -1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxamide having a temperature of 315 ° C is obtained.

Analysis for C ₈ H ₅ N ₂ O ₇ S Calculated:

% C, 36.50;% H, 1.91;% N, 37.25.

H, 2.26; N, 37.72.

Example 76

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

2.10 g, 10 mmol of Ι-οχο-ΙΗ-6-methylthiazolo [3,2-a] pyrimidine-2-carboxyloic acid and 1.78 g, 11 mmol of Ι, Γ-carbonyldiimidazole are mixed with 15 ml of dimethylformamide and heated to steam bath. Gas evolution occurs and the components dissolve. As soon as gas evolution ceased, 1.13 g, 11 mimols of 5-aminotetrazole monohydrate were added. A solid formed within 1 minute. The mixture was heated for a further 5 minutes and then cooled. Filtration gave 2.33 g of N- (5-tetrazolyl) -1-bromo-ΙΗ-6-methylthiazolo [3,2-a] pyrimidine-2-carboxamide, m.p. &gt; 318 ° C.

Analysis for C ₉ H ₇ O ₂ N ₇ S calculated:

38.99% C, 2.54% H, 35.36 «/ o N, found:

39.35% C, 3.00 ° / o H, 35.06% N.

Example 77

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

4.48 g, 20 mmol of 1-oxo-1H-6-ethylthiazolo [3 _] 2-a] pyrimidine-2-carbonyl-xyloric acid and 3.57 g, 2: 2 mmol of Ι, Γ-carbonyldiimidazole are mixed with 20 ml of dimethylformamide and heated on a steam bath. Gas evolution began and a solution formed. When gas evolution ceased, 5-aminotetrazole monohydrate (2.27 g, 22 mmol) was added.

A solid formed over 1 minute and the reaction mixture was heated for a further 15 minutes, then cooled and the crude product collected by filtration. Recrystallization from dimethylformamide gave 4.7 g of purified N- (5-tetrazolyl) -1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine, m.p. 274 DEG C. with decomposition.

Analysis calculated for C ₁ H ₁₁ O ₂ N ₇ S:

H, 3.11; N, 33.66. Found:

41.41 ° C, 3.30% H, 33.84% N.

Example 78

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

2.52 g, 10 mmol of 1-oxo-1H-7- (2-methyl-2-propylthiazolo) 3,2-a] pyrimidine-2-carboxylic acid and 1.78 g, 11 mmol of Ι, Γ-carbonyldiimidazole are mixed with 15 ml of dimethylformamide and the mixture was heated on a steam bath, gas evolution began, a solution formed, and after a few minutes a solid precipitated, the mixture was heated for a total of 10 minutes, then cooled and the crude product collected by filtration. from dimethylforniamide there was obtained 1.62 g of purified N- (5-tetrazolyl) -1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxamide, m.p. decomposition.

Analysis for C ₁₂ H ₁₃ O ₂ N ₇ S calculated:

% C, 45.13;% H, 4.10;% N, 30.70.

H, 4.40; N, 30.05.

Example 79

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

505.5 mg, 2.24 mmol of 1-ο-χο-1Η-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid and 399.7 mg, 2.46 mmol of 1,1'-k The carbonyldiimidazole is mixed with 3 ml of dimethylformamide and heated on a steam bath. A solution is formed and gas evolution begins. When the gas stops evolving, 253.0 mg, 2.45 mmol of 5-aminotetrazole monohydrate is added.

A clear solution is formed. After 2 minutes a precipitate began to form. The mixture was heated for a further 20 minutes, then cooled to room temperature and the crude product collected by filtration. Recrystallization from dimethylforinamide yielded 486.8 mg of purified N- (5-tetrazolyl) -1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxamide, up to 262 ° C with decomposition.

melting 261

Analysis for C ₁₀ H ₉ NO ₂ S calculated:

41.23% C, 3.11% H, 33.66 mass ion 291, found:

% C, 41.35;% H, 3.31;% Ion 291, 33.55.

% N,

Example 80

......... 1

537 mg, 2.25 mmol of 1-oxo-1H-7N- [5-tetrazolyl] -1-oxo-1H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxamide

Isopropythiazolo [3,2-a] pyrimidine-2-carboxylic acid and 401 mg, 2.47 mmol of 1'-co-bonyldiimldazole are mixed with 3 ml of dimethylformamide and heated on a steam bath. The components dissolve and gas evolves. When the gas ceases to evolve, 255 mg (2.47 mmol) of 5-aminotetasol monohydrate are added. The product immediately precipitates. The mixture was heated for a further 20 minutes, after which time the reaction mixture was cooled and the crude product was collected by filtration. After recrystallization from dimethylformamide, 328 mg of purified N- (5H, 4H, 4'-azolyl) -1-oxo-1H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxamide o- is obtained. a melting point greater than 300 ° C.

Analysis _for C ^ Hj _n O ₂ Calculated NYS:

% C, 43.27;% H, 3.63;% N, 32.11. found-:

% C, 43.34;% H, 3.76;

Example 81

N- [5,11- (4'-oxazol-1-yl) -1-oxo-7-phenylcyclohexenothiazole 3,2-a] 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'-carboinyl Dimidazole was mixed with 12 ml of dimethylformamide and heated on a steam bath. When gas evolution ceased, 5-aminotetrazole monohydrate (496 mg, 3.1 mmol) was added. After 10 minutes the resulting product began to precipitate. The mixture was heated for an hour then cooled to room temperature and 312 mg of crude product collected by filtration. Recrystallization from dimethylformamide yielded 131.5 mg of purified N- (5-tetrazolyl) -Ι-οχο-ΙΗ-7-phenylcyclohexenothlazolo (3,2-a) pyrimidine-2-carboxylate, m.p. C.

I. :

Analysis for C18H15O2N7S i

calculated ·:

% C, 54.95;% H, 3.84;% N, 24.92.

% H, 3.93;% N, 24.61.

Example 82 '

N- (5-tetrazolyl) -Ι-οχο-ΙΗ-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide

1.0 g, 3.78 mmol of 1-oxo-1H-7-methylcycloilexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid and 675 mg, 4.16 mmol of 1,1'-carboxylic acid imidazole were 6 ml of dimethylformamide are added and the mixture is heated on a steam bath. Gas evolution began and a solution formed. As soon as the gas ceased to evolve, 5-amino tetrazole (425 mg, 4.16 mmol) was added and the mixture was further heated. After a few minutes a precipitate began to form. After 30 minutes, the reaction mixture was cooled and filtered to give the crude product, m.p. &gt; 300 ° C. After recrystallization from dimethylformamide, 980 mg of - purified - N- (5-tetrazolyl) - Ι-οχο-ΙΗ-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide is obtained, m.p. 300 degrees Celsius.

Analysis for C 13 H 13 O 2 N 7 S calculated:

C, 47.12; H, 3.95; 29.59% N, found:

% C, 47.32;% H, 4.18;

Example 83

N- (5-tetrazolyl) -1-oxo-1H-7,7-dimethylcyclohexenothiazole 3,2-a] pyrimidin-2-carboxamide

558 mg, 2.0 mmol of 1-, o-xo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid and 357 mg, 2.2 mmol, 1'-carbonyldiimidazole. with 3 ml of dimethylformamide and heated on a steam bath. Gas evolution and solution formed. Once gas evolution ceased, 5-aminotetrazole monohydrate (227 mg, 2.2 mmol) was added and the mixture was heated for a further 20 minutes. The reaction mixture was cooled and filtered to give 561 mg of crude product, m.p. &gt; 300 ° C. Recrystallization from -dimethylformamide yields 469 mg of purified N- (5-tetra-azyl) -1-oxo-1H-7,7-dimethylthiazolo [3,2-a] pyrimidin-2. A carboxylic acid having a melting point greater than 300 ° C.

Analysis for C14H15O2N7S calculated:

H, 4.38; N, 28.39%. found:

% H, 4.18;% H, 28.42;

EXAMPLE 8 4

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

1-Oxo-1H-7- (2-methyl-thiazolo [3,2-a-] pyrimidine-2-carboxylic acid, 379 mg, 1.5 mmol) and 1H-carbonyldiimldazole (270 mg, 1.66 mmol) were mixed with 3 ml of dimetityltanamide and the mixture is heated on a steam bath, gas evolves and a solution is formed, as soon as the gas stops evolving, 170 mg of 1.65 mmol of 5-amino-tetrazole monohydrate are added and the mixture begins The mixture is allowed to cool to room temperature and the crude product is stirred for a further 20 minutes.

64 duct se. separated by filtration. Recrystallization gave 247 mg of purified N- (5-tetrazolyl) -1-oxo-1H-7- (2-butyl) thiazolo [3,2-a] pyrimidine, m.p. &gt; 300 ° C.

Analysis for C C ^H ^ OOSS calculated:

% C, 45.13;% H, 4.10;% N, 30.70.

% C, 45.12;% H, 4.05;% N, 30.68.

EXAMPLE 8 5

The method of the example. 66-84, the following compounds can be obtained from the corresponding 1-oxole-1H-thiazolo [3,2-a-] pyrimidine-2-carboxylic acids:

N- (5-tetrazolyl) -1-oxo-1H-7-pentylthiazolo [3,2-a] pyrimidine-2-carboxamide, N- (5-tetrazolyl) -1-oxo-1H-6-ethyl -7-propylthiazolo (3 ', 2-a] piperazin-2-yl) -2-carboxylic acid,

N- (5-tetrazolyl) -1-oxo-1H-6,7-diisopropylthiazolo [3,2-a] pyrimidine-2-carbamide,

N- (5-triazolyl) -1-oxo-1H-6-propylthiazole [3,2-a] pyrimidine-2-carboxamide,

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

N- (5-tetrazolyl) -1-oxo-1H-6-pentylthiazolo (3,2-a) pyrimidine-2-carboxamide,

N- (5-tetrazolyl) -Ι-οχο-ΙΗ-6-phenylcyclopentenothiazolo (3,2-a) pyrimidine-2-carboxamide,

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

N- (5-tetrazolyl) -1-oxo-1H-8-methylcycloocttenothiazolo [3,2-a] pyrimidine-2-carboxamide; and

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

Example 86

Capsule

Capsules can be obtained by mixing the following ingredients in the proportions indicated by weight:

Ingredient Weight Calcium carbonate U. S. P.17,6 Calcium hydrogen phosphate18.8 Magnesium silicate U. S. P.5,2 Lactose U. S. P.5,2 Potato starch5,2 Stearate · Magnesium A0,8 Magnesium stearate B0,35

Sufficient amount of N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide trihydrate sodium salt is added so that the capsule contains 10, 25 and 50 milligrams of active ingredient [weight · equivalent] In unsolvated form of free substance) per capsule. The resulting mixture is filled into conventional hard gelatin capsules in an amount of 350 mg of mixture per capsule.

In a similar manner, capsules containing 2.0 mg and 6.0 mg of the active ingredient and containing 300 mg of the resulting mixture can be prepared from the following mixtures, the amount being given per capsule.

Component mg / capsule active substance 2.00 N-methylglucamine 18.00 anhydrous lactose 251.20 anhydrous maize starch 8.80 Component mg / capsule active substance 6.00 N-methylglucamine 18.00 lactose [anhydrous] 237.20 anhydrous maize starch 30,00 talc 3.80 Example 87 Tablets

The mixture for the manufacture of tablets is obtained by mixing the following components in the parts by weight indicated:

Component parts by weight sucrose U. S. P. 80,3 tapioca starch 13,2 magnesium stearate6,5

To this basic Mines ss added sufficient sodium NF E ^ - ^ 'tetta; ^. ^I of y / 1 - l-oxo-lH-€ yklohexenothiazolo- [3,2-a] pyrimidine-2-karboxamidtrihydrátu so to form tablets containing 20, 100 and 250 mg of active ingredient per tablet. The resulting mixture is then compressed into tablets in a conventional manner.

241470

12.36 g

376,00 g

103 ml

At. to produce tablets with a lower effect, for example containing 1 mg, 2 mg or 5 mg of active ingredient, a lower amount of active ingredient is added to the masterbatch.

Example 8 8

Solution

A solution of N- (5-tetrazolyl) -1-oxo-ΙΗ-cyclobenzenothiazolo [3,2-a] pyrimidine-2-carboxamide sodium salt can be obtained by mixing the following ingredients in the indicated amounts:

Ingredient Amount Active Ingredient 6.04 g (7.49 g sodium salt trihydrate) magnesium chloride hexahydrate propyleuglycol distilled water

The resulting solution has an active compound concentration of 10 mg / ml and is suitable for parenteral administration, especially intramuscular administration.

Example 89

Suspensions for aerosol production

For use against allergic reactions, micronize a mixture of N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo (3,2-ajpyriimine-2-carboxamide sodium salt and the other ingredients listed in a) of the following tables to a particle size of 1 to 5. 5 in a ball mill. The resulting slurry is then placed in a reservoir equipped with the valve and propellant referred to in paragraph (b) of the following tables with a pressure such that the resulting reservoir pressure at 20 ° C is approximately 0.24 to 0.28 MPa.

Suspension A

Folder%

(a) antiallergic agent (in unsolvated free form) 0,25 isopropyl myristate0,10 ethanol26,40

(b) a mixture of 1,2-dichlorotetrafluoroethian; and

1-chloropentafluoroethane in a ratio of 4073.25

Suspension В

Component% a) Antiallergic (in unsolvated free form) 0.25 ethanol26.50

(b) a 60: 4073,25 mixture of 1,2-dichlorotetrafluoroethane and 1-chloropentafluoroethian

Suspension C

Component%

(a) antiallergic agent (in unsolvated free form) 2,00 ethanol26,50

(b) a mixture of 1,2-dichlorotetrafluoroethane; and

1-Chloro-pentilluoroethane: 4071.50

Claims (1)

object of the invention A process for the preparation of substituted N- (5-tetrazolyl) -1-oxo-1H-thiazolo [3,2-a.] Pyrimidine-2-carboixamides of formula (I) or pharmaceutically acceptable salts thereof, wherein: R ₁ and R 2 are hydrogen or alkyl of 1 to 5 carbon atoms or R ₁ and R ₂ together form an alkylene radical of 3 to 9 carbon atoms or a phenylalkylene radical of 9 to 11 carbon atoms and the ring thus formed is 5- to 8-membered, characterized in that the compound of formula II is activated