DK151811B - ANALOGY PROCEDURE FOR THE PREPARATION OF N- (5-TETRAZOLYL) -1-OXO-1H-THIAZOLOOE3,2-AAA-PYRIMIDIN-2-CARBOXAMIDES OR PHARMACEUTICALLY ACCEPTABLE COATAL SALTS THEREOF AND 1-OXO-2XO-OXO-2-OXO2 FOR USE AS THE INITIAL MATERIALS IN THE PROCEDURE - Google Patents

Description

DK 151811 B

The invention relates to an analogous process for the preparation of novel N- (5-tetrazolyl) -1-oxo-1H-thiazolo (3,2-a] pyrimidine-2-carboxamide compounds of the general formula I or claim 1 pharmaceutically acceptable cation salts thereof and 1-oxo-1H-thiazolo Q 2,2-a] pyrimidine-2-carboxylic acids of the general formula set out in claim 4 for use as starting materials in the process. These amides are useful in preventing release of allergic agents such as histamine, serotonin, and SRS-A and can therefore be used to treat bronchial asthma, hay fever, rhinitis and atopic dermatitis, and are also useful as anti-ulcer agents.

Allergic reactions, which are symptoms resulting from an interaction between antigen and antibody, appear in many 15 different ways and in many different organs and tissues. Common allergic disease conditions are, for example, allergic rhinitis, a condition characterized by seasonal or persistent sneezing, nasal discharge, nasal congestion, itching and eye blockage? hay fever is a number of different allergic snow conditions that are the result of hypersensitivity to grass pollen; and bronchial asthma, which is one of the most deleterious and debilitating of the allergic reactions, is a condition characterized by hyper-reactivity of the bronchi when exposed to various stimuli that may be immunogenic or non-immunogenic, which leads to bronchial spasms with wheezing, short-term cramping conditions and widespread contraction of the air passages. The mechanical obstruction to the airflow in the respiratory tract can generally be overcome by the use of bronchodilators which provide symptomatic relief. In contrast, antiallergic agents prevent the release of tissue anaphylaxis mediators and thereby prophylactically impede bronchoconstriction release due to these mediators.

! DK 151811 B |

2 I

in

Cox et al. has in Adv. in Drug Res.f 5r 115 (1970) discloses the pharmacology of disodium cromoglycate [1,3-bis- (2-carboxy-1-cromon-5-yloxy) -2-hydroxypropane, Intal]. This is not a bronchodilator, but it transmits its therapeutic effect by inhibiting the release of the anaphylaxis agents and it is administered prophylactically. It suffers from a lack of efficacy in oral administration and to obtain the optimal results it is administered by inhalation as a solid inhalant.

A number of various other anti-allergic agents have been described later, including N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimidino [1,2-a] quinoline-2-carboxamides (Kadin, U.S. Patents No. 4,017,625), 1-oxo-1H-6-substituted pyrimidino [1,2-a] quinoline-2-carboxylic acids (Kadin, U.S. Patent No. 4,066,766), tetrazolo [a] quinazole -5-ions (Bindra, U.S. Patent No. 4,085,213), pyrimidino [2,1-a] isoquinoline (Jubi et al., U.S. Patent No. 4,127,720), and N- (5-tetrazolyl) -4 -oxo-4H-pyrimidino [2,1-b] benzothiazole-3-carboxamides (Bindra and Kadin, U.S. Patent No. 4,041,163).

Chronic ulcerations of the abdomen and duodenum, collectively referred to as peptic ulcerations, are a frequently occurring disorder for which a variety of treatment modalities have been developed. The treatment depends on the serious nature of the wound and it can range from dietary and medical treatment (with medication) to surgery. Many different drugs have been used to treat ulcers. The most recent of these that has gained general interest is sodium carbenoxolone, the disodium salt of the glycyrrhetic acid hemisuccinate. It is reported that this prevents the formation of and accelerates the healing of ulcers in animals, including humans ("Carbenoxolone Sodium: A Symposium," J.M.

Robson and F.M. Sullivan, editors, Butterworths, London, 35 1968). However, its use is accompanied by undesirable, aldosterone-like side effects, such as pronounced DK 151811 B, 3 antidiuretic and sodium-retarding effects, and frequent potassium loss, so long-term treatment with this agent often leads to hypertension, muscle weakness and eventually heart failure. because of congestion. A histamine receptor antagonist called cimetidine was later introduced into medical practice. The latter compound relieves stomach ulcers by reducing gastric acid secretion.

Many other other compounds are referred to as possessing antiulcus action, including: 1-oxo-1H-6-piperidinopyrimidino Q, 2-aJ quinoline-2-carboxylic acid esters (Kadin and Moore, U.S. Patent No. 4,014,881) , 1-oxo-1H-6-substituted pyrimidino [beta], 2-a] quinoline-2-carboxylic acids and esters (Kadin and Moore, U.S. Patent No. 4,031,217), tetrazolo [a] quinazol-5-ones (Bindra , U.S. Pat.

4 085 213).

US 4,041,163 (and DK application 1182/77) disclose compounds of the formula O / l

H

which at the 7- and 8-positions may have different alkyl or alkoxy substituents or a methylenedioxy or ethylene dioxide chain for which compounds are indicated antiallergic activity. The compounds of formula I prepared according to the present invention differ from the compounds of formula A in that they lack the condensed benzene ring, but in the 6- and 7-positions can be substituted with (C 1 -C 4) alkyl groups or with an optionally! phenyl-substituted alkylene chain. in

J

It is a principle in organic (and drug) chemistry that aromatic groups are not equivalent to alkyl groups, cyclic or others. The aromatic ring is strongly stabilized by conjugated double bonds. Alkyl or alkylene groups provide no such stabilization. Aromatic rings are planar, while alkyl and alkylene groups are generally not. Aromatic rings provide ring-shaped clouds of electrons for complex interaction, e.g. with a physiological substrate; alkyl or alkylene does not. The chemistry and physiological effect of functional groups linked to aromatic carbon atoms differs; dramatically from the same functional groups attached to 15 non-aromatic carbon atoms. Thus, it is clear that there is no equivalence between a condensed aromatic group and alkyl or alkylene substituents.

DE 2 810 863 discloses compounds of the formula <c> cox wherein X is hydroxy, alkoxy or N- (5-tetrazolyl) amino, which compounds are structurally even more different from the compounds of formula I according to the invention. shows the unpredictability of antiallergic action. Thus, this reference would indicate the equivalence of N- (5-tetrazolyl) carboxamide and carboxylic acid groups. In fact, the acids corresponding to the tetrazolyl amides prepared according to the present invention generally have lower activity or even lack activity. In view of the inactivity of certain of the acid precursors herein, one would not expect

DK 151811B

5 anticipate activity of the subject tetrazolylamides.

It has now been found that the compounds of formula I

'XL

I »—N

il

H B

H

and the pharmaceutically acceptable cation salts thereof are orally effective antiallergic and antiulcus agents. In Formula I, each of them is hydrogen or alkyl containing 1 to 5 carbon atoms {such as methyl, ethyl, propyl, isopropyl, 2-methyl-2-propyl (tert-butyl), 2-butyl, 2-methyl -1-propyl (isobutyl) or pentyl], or R 2 and R 2 together form a third ring system of 5-8 members, and may be the alkyl containing 3 to 9 carbon atoms, for example: CH-CE-ρττ · · 3 V, / 3 «3 CE ^. CH> - CH-. Γζ - Γζ / 2 / CE_ CH-

CEL CH, I I

VC- CS2 == »- '2 V" CH3 GE3 CE ^ "CEL ^ i

DK 151811 B

6 CE,, CE ^. CET "CE2" CE, - ~ CEf * / s' 1 / - CE- CE- CE-— CE.

I * 3 \ CF- CE CE2 ~ "~ CE ^ CE2 ^ CEr ^ 3 x - cHr! / Cs2 ~ cEr ~ CE- I" CH,

No.

CE- CH

ώ 2 I

in or phenylalkyl of 9-11 carbon atoms, for example:

C F

Ό J \ ** µ ± * 2 * + * CA-® * ° 3N / CH2-

CH2 6 I C E - C

CH "- E> 66 I

2 “prr— CE- - 7 - <~ τχ ^ -il, CE - CE— / —2 ^ 2

C-E- CH

0 = \ -il.

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7

The term "pharmaceutically acceptable cation salts" means salts such as alkali metal salts, e.g. sodium and potassium? alkaline earth metal salts such as calcium and magnesium; aluminum salts; ammonium salts; and salts with organic bases, e.g. amines such as triethylamine, tributylamine, piperidine, triethanolamine, diethylaminoethylamine, N, N'-dibenzylethylenediamine and pyrrolidine.

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

.N-N N = N

/ /

r * C t ~ C

\ ^

N-N XN-N

i \

Η H

10 which exists simultaneously in a dynamic, tautomeric, equilibrium mixture. In the present invention both forms of the tetrazolylamides are included.

The compounds of particular interest are those having formula I wherein R 1 is ethyl and R 2 is hydrogen. Of particular interest are also such compounds wherein and R 2 taken together are propylene, butylene or pentylene. Particularly desirable is the compound wherein R 1 and R 2 together are butylene, i.e. N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo (3,2-apyrimidine-2-carboxamide (formula III)):

DK 151811 B

8 Eye (XII) l i

° J X-N

· / * J

M-N

H

since it exhibits excellent oral administration activity and is extremely stable in its pure, solid state as well as in the presence of standard pharmaceutical diluents and in solution. Furthermore, its metabolite (the corresponding carboxylic acid) shows good activity. The preferred form of the tetrazolylamide (III) is the sodium salt (trihydrate), which is non-hygroscopic and exhibits good water solubility, ensuring good bioavailability.

The anti-allergic properties of the compounds of this invention are assessed by the so-called passive cutaneous anaphylaxis (PCA) test, J. Immun., 31, 355, 195δ].

The PCA test injected test animals into the skin (i.d.) with antibodies contained in serum derived from actively sensitized test animals. The test animals are then subjected to intravenous administration of antigen mixed with a dye, such as so-called "Evans Blue". The increased capillary permeability caused by reaction 20 between antigen and antibody causes the dye to leak from the site where the antibody is injected. The test animal is then suffocated and the intensity of the reaction is determined by measuring the diameter and intensity of the blue staining on the inner surface of the test animal skins.

DK 151811B

9

The antiulcus action of the compounds of this invention is assessed by the so-called rat test for stress induced by cold clamping. Alternatively, the antiulcus effect may be determined by the recently prepared test for ethanol-induced rat ulcer described later

The process according to the invention is characterized by the characterizing part of claim 1, cf. the reaction scheme below, which also indicates a synthetic route for the preparation of the starting compounds.

RI ----- 3, ^ OC-H- IC 3 Π. + (fij00CljC-C ^ e _ ^

_s Rl- -T - S

llu s il · Dowtierm. A I ",

Ari in '-►' L,

T 3 I

, 0 OR3 os5C ^ * or | ' H +, E20

'T

Ri 3 / * - V— * S

ri eH 11 l X

RS *. IT - N R-T

"YES *" YES

0 [Γ jj (j dehydrating * I

xr »in coupling (1)

0 mi 'Η <- $ OK

IT-II or via mixed ice. anhydride (2) (1) Process (a) of the invention.

DK 151811 B

10 where and is as previously defined and R 1 is alkyl of 1-4 carbon atoms.

In the first step of this synthesis sequence, the appropriately substituted 2-aminothiazole is condensed with a stoichiometric amount of a dialkylethoxymethylene malonate, usually with the readily available diethylethoxymethylene malonate, the choice of ester being not critical for the preparation of the final desired reaction product. The condensation is carried out at a temperature of approx. 80 ° C to 10 approx. 125 ° C. Lower temperatures are not desirable since the reaction takes place at too slow a rate. Higher temperatures can be used, but this does not appear to have any benefits. Thus, the reaction is conveniently carried out in the form of a melt. It can of course be carried out in a solvent or in a mixture of solvents, e.g. ethanol, Ν, Ν-dimethylformamide, acetonitrile.

From a practical point of view, however, a solvent appears to be unnecessary. The products of this condensation are 4- and / or 5-substituted 2- (2,2-dicarbalkoxyethenylamino) thiazoles. It should be noted that when and R £ together form a ring system, the nomenclature and numbering systems are modified as follows: CO co C7cicpenter.0rhi.a20i Cvcichexancrhiacci <TrT \ *

Zyciohaprenothiacoi lyciccctanc-chiarci

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11

An alternative nomenclature for cyclohexenothiazole is tetrahydrobenzothiazole.

The second step of the synthesis sequence consists in cyclization of the 4- and / or 5-substituted 2- (2,2-dicarbalkoxy-5-ethenylaminothiazoles) by elimination of an equivalent alpha-channel (ethanol in the case of ethyl ester). this cyclization by heating the synthesis intermediate to a temperature of from about 175 ° C to about 250 ° C until the reaction is substantially complete, usually within 1-2 hours. The cyclization is advantageously carried out by heating the intermediate in a suitable i.e., in a compound which allows control of the reaction temperature which is stable up to the relatively high temperatures used and which does not react with the starting material or cyclization products. As representatives of such diluents, high boiling hydrocarbons such as perhydronaphthalene may be mentioned. mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, especially one containing they contain 26.5% diphenyl and 73.5% diphenyl ether and are sold under the name "Dowtherm A".

Alternatively, the cyclization is performed under milder conditions (70-130 ° C) by heating the intermediate in the presence of an excess (1.1-3 equivalents) of trifluoroacetic anhydride in an inert solvent such as toluene until the reaction is complete (f. eg 15-20 hours at the reflux temperature of toluene). In any of the processes, the reaction products are prepared in the cyclization step of alkyl-1-oxo-1H-6-and / or -7-substituted-thiazolo [3,2-aJ pyrimidine-2-carboxylates.

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

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12

Q \ CK

N jT '1-cxc-1H-cyclopentano-1-oxc-iS-cyclohexenecthiazyclo3,2-ajpyrrmidine chiazoio ,23,2-ajpyrrniidin r ^ ^^ jj; S · 13 ~ \ ν O'sK> ^ é '' ^^ I-cxo-1H-cyclohepteno-1-cxo-1H-cycloctcnc-thiazoio [2,2-a] cyrimidine thiazole [3,2-a] The pyrimidine 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidines may alternatively be referred to as 6,7,8,9-tetrahydro-1-oxo-1H-pyrimidino- [2,1b] benzthiazoles or using an alternative 5,6,7,8, tetrahydro-4-oxo-4H-pyrimidino [2,1-b] benzthiazoles

It is to be understood that the condensation and cyclization steps can be carried out in a single treatment without the need for separation of the intermediate 2- (2,2-carbalkoxyethenylamino) -10 thiazole, either by using a sufficiently high reaction temperature, so that both the condensation and the cyclization. The lysis is carried out, or by condensing as above: described followed by the addition of an inert solvent (if not already present) and an excess of trifluoroacetic anhydride (2.1 to 4 equivalents) and further carrying out the cyclization treatment. treatment step.

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13

The preferred process comprises the above-described separate treatment steps for condensation and for cyclization. In general, isolation of the synthesis intermediate and subsequent purification thereof prior to cyclization leads to a better quality of the cyclized reaction product.

The esters prepared by the condensation / cyclization described above are then hydrolyzed to the corresponding 1-oxo-1H-6 (and / or 7) -substituted-thiazolo [3,2-a] -10 pyrimidine-2 carboxyisyrer. (Note the above described nomenclature and modified numbering system when and R2 R2 together form a third ring.) Acid-catalyzed hydrolysis is preferred. A particularly suitable process is refluxing the ester in 48% hydrobromic acid solution until the hydrolysis is complete (0.5 - 3 hours is generally sufficient). If the foaming is a problem, the hydrolysis may be carried out at slightly elevated pressure, e.g. 0.5 atmosphere at 35 ° C.

The present N- (5-tetrazolyl) amides are conveniently prepared according to process (a) of the invention by dehydrating coupling the acids with 5-aminotetrazole. The dehydrating coupling is carried out by a wide variety of agents, usually used in peptide synthesis. Representatives include N, N'-carbonyl-diimidazole, N, N'-carbonyl-di-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ether, diphenylketene-p-tolylimine, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, ethylene chlorophosphite, diethylethylene pyrophosphite, N-ethyl-5-phenylisoxazolium 3'-sulfonate, phenylphosphorus di (1-imidazolate) and carbodiimides such as dicyclohexylcarbodiimide, 1-cyclohexyl-3-cyclohexyl , N- (3-DimethylaminopropylD-N'-ethylcarbodiimide, hydrochloride, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, hydrochloride and diethylcyanamide.

The above-described coupling agents are generally reacted first with the acid reaction component and the reaction product thus obtained is reacted without isolation with 5-aminotetrazole to give the desired 1-oxo-1H-6-and / or -7 substituted-thiazolo [3,2-a] pyrimidine. (Note 5 above described nomenclature and modified numbering system when and R2 taken together form a third ring).

The reaction is carried out in a solvent-inert reaction system in which the acid reaction component does not necessarily have to be soluble. The only requirement of the solvent system is that it is not involved to any great extent in reaction with the reactants or with the reaction products. The very large number of coupling agents which can be used to carry out the dehydrating coupling leads to a wide choice of solvents. Representative solvents are Ν, Ν-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

i i

The reaction between the acid reaction component and the coupling agent is carried out at a temperature of from ca. 20 ° C to 20 approx. 110 ° C. The reactive synthesis intermediate is then reacted with 5-aminotetrazole at from ca. 20 ° C to 110 ° C.

Each of these processing steps is advantageously carried out at about 50 ° C to approx. 100 ° C as the rate and yield of the reaction are improved. ; The mutual molar ratio of acid: coupling agent: 5-aminotetrazole is generally about 1: 1: 1 to about 1: 1.1: in 1.1. Greater ratios of coupling agent to 5-aminotetrazole can be used, but it offers no benefits.

!

Profit of 10 mole percent is satisfactory. As will be appreciated by those skilled in the art, all reaction components may be added at once instead of stepwise as described above. However, prior formation of the reactive intermediate (acid coupling agent) leads

DK 151811 B

15 usually for better yields of the desired N- (5-tetrazolyl) amides.

The desired amides are prepared according to process (b) of the invention by coupling the acids with 5-amino-tetrazole using a mixed anhydride procedure. In this case, the acids are first converted in situ to tertiary amine salts in the presence of 1 - 1.1 molar excess of the amine. Many different tertiary α-mines can be used for this purpose. Examples include triethyl-10 amine, N-methylpiperidine, N-methylmorpholine, dimethylaniline or quinoline. Suitable inert solvents are methylene chloride, chloroform, dimethylformamide and dimethylacetamide. It is preferred that the acid dissolve completely with the excess tertiary amine, which may require a stirring period, if necessary together with gentle heating. The solution of the amine salt is then reacted with an equivalent alkyl (e.g. ethyl), benzyl or phenyl chloroformate at a temperature in the range of -40 to 25 ° C, preferably in the range of -10 to 10 ° C, to form a mixed anhydride in solution.

v 0

^ tert.-amide P

I \ H- Cl-C-OR * .1 J + tert. -amide HCl

0 ^ C'OH C "0-C-OR

IN! wherein R is alkyl, benzyl or phenyl.

Without isolation, the mixed anhydride is reacted directly with 5-aminotetrazole, preferably dissolved in an inert solvent of the same type used to prepare the mixed anhydride, to give the desired N- (5-tetrazolyl) amides. The reaction is usually started at a low temperature (such as from -40 to 15 ° C), but sheep

DK 151811B

16 is allowed to warm to higher temperatures (such as 15-40 ° C) to complete the reaction. The typical mutual molar ratio of acid: amine: chloroformate: 5-aminotetrazole is from 1: 2: 1: 1 to 1: 2.1: 1.1: 1.1.

in the 5 N- (5-tetrazolyl) amides can be converted to pharmaceutically acceptable cation salts. The salt formation is carried out by reacting the amides with the appropriate metal salt (such as a carbonate, ethyl hexanoate, alkoxide or hydroxide) or the appropriate amine in a suitable medium such as water, methanol or ethanol and in accordance with well known methods. The salts are recovered by standard methods such as by filtration if they are insoluble in the medium, by evaporation of the solvent, if they are soluble in the medium, or by precipitation by the addition of a substance which is not a solvent for the salt.

Many of the 2-aminothiazole compounds required as starting materials are discussed in the literature. Those which are not may be prepared by condensing the appropriate * halogen ketones with thiourea or by condensing the appropriate aldehyde with thiourea and sulfuryl chloride, as illustrated in specific examples. λ-Halogen ketones not mentioned in the literature are prepared by standard methods, e.g. by halogenation of ketones [e.g.

Catch et al., J. Chem. Soc., 272 (1948); Levine, Org. Synthesis 25 Coll. Vol. II, 38 (1943); Buchman et al., J. Am. Chem.

soc. 67, 400 (1945) ^, by the effect of hydrogen halides on diazoketones [e.g. Catch et al., J. Chem. Soc., 278 (1948); Lutz et al., J. Org. Chem. 12, 767 (1947); Wagner et al., J. Am. Chem. Soc. 72, 2884 (1950) ^, decarboxylation of γ Chem. Soc. 66, 1132 (1944) 3, and by spontaneous cleavage of dibromo derivatives of alkenyl esters [e.g. Slanina et al., J. Am. Chem. Soc. 58, 891 (1936) 3.

Most of the acid precursors to the novel amides

DK 151811 B

17 prepared by the process of the invention are also novel compounds. The known acids are those of the formula II as set forth in claim 1 wherein R 1 and R 2 are hydrogen or methyl and R 2 is hydrogen [Dunwell et al., J. Chem. Soc. (C) 1971, 2094J. The corresponding ethyl esters are also known together with the ethyl ester in which R 1 is hydrogen and R 2 is methyl [punwell et al., J. Chem. Soc. (C) 1971, 2094; Allen et al., J. Org. Chem. 2Λ, 779 (1959)]. In neither of these publications is the utility of either the acids or esters mentioned.

The reactions in the synthesis sequence leading from the 2-amino-thiazoles to the acids and thence to the N- (5-tetrazolyl) amides by the process of the invention are conveniently monitored by standard thin-layer chromatography on silica gel plates containing an ultraviolet indicator. which is commercially available from various sources. The eluent varies to suit the reaction being performed and to the nature of the substituents so as to obtain Rf values for the intermediate between 0 and 1.0 and so as to distinguish between the intermediate to participate. the reaction, and the reaction product produced by the reaction. An eluent particularly suitable for controlling thiazole formation, condensation cyclization and hydrolysis in the preparation of the acid intermediates is chloroform / 1% ethanol, while hydrolysis and and conversion of the acids to N- (5-tetrazolyl) amides are best controlled using chloroform / 5% acetic acid.

As is well known to those skilled in the art, the polar content of the eluent can be reduced if the materials have a tendency to move too fast (i.e., in the solvent front). If the materials have a tendency to move too slowly, the polar properties of the eluent can be increased. Such chromatography is used to assess the purity of the reaction, but it can also be used for further optimization.

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reaction conditions (concentration, time, temperature, solvent, etc.).

The present products and the pharmaceutically acceptable salts thereof are useful as prophylactic agents for inhibition

5 ring or to prevent the release of the agent

for anaphylaxis (allergy, immediate hypersensitivity reactions), and the occurrence of allergic symptoms in mammals, and may be administered for such purposes individually or in mixtures with other agents, e.g. with theophylline or with sympathomimetic amines. The products in question are also useful as anti-ulcer agents. Not only do these products promote the healing of such ulcers, but they also prevent the formation of gastric ulcers, and they reduce the excretion of gastric acid in animals, including 15 in humans. They can therefore be said to be useful for controlling ulcers.

The present valuable compounds may be administered alone, but they are generally administered with a pharmaceutical carrier selected on the basis of the method of administration chosen and standard pharmaceutical practice. For example, they may be admixed with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, lozenges, bolsters, powders, aerosol sprays, aqueous suspensions or solutions, solutions for injection, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Pharmaceutical compositions for oral use with the subject compounds can further be suitably made sweet or give flavor by various additives of the type commonly used for these purposes.

The carrier you choose and the proportion of active ingredient

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19 relative to the carrier is influenced by the solubility and chemical nature of the therapeutically active compound, by the method of administration chosen and by general pharmaceutical practice requirements. For example, when the compounds of the present invention are to be administered orally in tablet form, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate can be used. For the preparation of tablets for oral administration of the subject compounds, various disintegrants such as starch, alginic acid and certain complex silicates can also be used, along with glitter agents such as magnesium stearate, sodium lauryl sulfate and talc. High molecular weight lactose and polyethylene glycols are among the preferred materials for use as pharmaceutically acceptable carriers for oral administration in the form of capsules. When aqueous suspensions are to be used for oral administration, the subject compounds may be combined with emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerol and chloroform and combinations thereof can be used as well as other materials.

For parenteral administration and for inhalation, solutions or suspensions of the subject compounds in sesame oil or peanut oil or aqueous propylene glycol solutions, as well as sterile aqueous solutions of the soluble pharmaceutically acceptable salts described herein may be used. These particular solutions are particularly suitable for intramuscular and subcutaneous injection purposes if such a method of administration is desired. The aqueous solutions, including those consisting of the salts dissolved in pure distilled water, are also useful for intravenous injection purposes, provided that their pH is appropriately adjusted beforehand. Such solutions should also be appropriately buffered if necessary, and the liquid diluent should first be made isotonic with sufficient salt or glucose.

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When used as prophylactic agents to prevent the release of anaphylaxis agents, the compounds may be administered by inhalation. Compositions suitable for inhalation may comprise: (1) a solution or suspension of the active ingredient in a liquid medium of the type described above for administration by a nebulizer; (2) a suspension or solution of the active ingredient in a liquid propellant such as dichlorodifluoromethane 10 or chlorotrifluoroethane for administration from a pressure vessel; or (3) a mixture of the active ingredient and a solid diluent e.g. lactose, for administration from a powder inhalation device.

Compositions suitable for inhalation by means of a conventional nebulizer will comprise from ca. 0.1 to approx. 1% active ingredient; compositions for use in pressure vessels will comprise from ca. 0.5 to approx. 2% active ingredient. Compositions for use as inhalation powders may comprise proportional ratios of active ingredient to diluent of from ca. 1: 0.5 to approx. 1: 1.5.

Taking into account the factors just mentioned, it is believed that an effective daily oral dosage of the subject compounds as anti-allergic and anti-ulcer agents for humans is from about 25%. 10 to approx. 1500 mg per day. with a preferred range of from ca. 10 to approx. 600 mg per per day in a single dose or in multiple sub-doses, or from ca. 0.2 to approx. 12 mg / kg body weight. These values are indicative and, of course, individual cases may occur where 30 higher or lower dosage ranges may be of value. With careful monitoring, the dosage level can reach up to approx. 2 g per day.

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21 When the compounds are administered parenterally for both uses or by inhalation as an anti-allergic agent, the effective daily dose is from ca. 0.05 to approx. 400 mg per day per day, preferably from ca. 0.25 to approx. 200 mg per day 5 or from approx. 0.05 to approx. 4 mg / kg body weight in a single dose or in sub-doses.

It is necessary that the active ingredient constitute such a proportion of the composition that a suitable dosage form can be obtained. Of course, several dosage unit forms can be administered at about the same time. Although compositions with less than 0.05% by weight of active ingredient may be used in some cases, it is preferred to use compositions containing at least 0.05% of active ingredient; otherwise the amount of carrier will be excessive. The activity is increased by the concentration of the active ingredient. The composition may contain 10, 50, 75, 95 or an even higher weight percent of the active ingredient.

The aforementioned PCA test is a measure of a compound's anti-allergic (especially anti-asthmatic) activity.

Compounds which inhibit a positive PCA test induced by the rat's immunochemical counterpart to the human immunoglobulin E (IgE), or reagent, are considered to have anti-allergic activity £ c. Mota, Ann. NEW. Acad. Sci., 103, 264 (1963)]. (Reagin is primarily immunoglobulin E 25 [igE], and it is the major immunoglobulin responsible for allergic asthma, anaphylaxis, hay fever, food hypersensitivity, and certain manifestations of hypersensitivity to drugs, although recent evidence suggests the IgG class of antibodies a significant role in the transmission of allergic diseases). When such compounds are administered to a sensitized test subject, which may be a human or an animal, prior to the time when the individual comes into contact with antigen

DK 151811B

22 or with substances to which it is allergic, they will prevent the allergic reaction that would otherwise occur. They therefore provide a method for the prophylactic treatment of allergy or anaphylactic reactions of the type mediated by the reagent.

Put another way, such compounds block the release of mediators derived from antigen-antibody (allergic) reaction, as shown in the PCA test using the rat homocytotropic antibody, a known correlate to human reagent antibody. Inhibition of reagent antigen-antibody responses in rats, the test animal in the PCA assay, is considered representative of inhibition of human reagent antigen-antibody reactions occurring during allergic epidemics.

The PCA reaction assay procedure used to evaluate the compounds of the present invention exhibits an excellent correlation between the activity of the compounds in this assay and their utility in the treatment of allergic asthma. The ability of the agents to interfere with PCA reactions is measured on male Charles River Wistar rats, 170-210 g. Reagent antiserum having a high content of IgE antibodies as described by Petillo et al., Int.

25 Arch. Allergy; 44, 309 (1973). Hyperimmune antiserum, containing high IgG antibodies to chicken egg albumin, as described by Orange et al., J. Exptl. Med., 127, 767 (1968). Twenty-four hours before exposure to antigen, the reagent antiserum is injected intradermally (i.d.) 30 into the shaved skin on the back of a normal rat; Five hours before exposure, the hyperimmune antisera are similarly injected. In a third place, the i.d. immediately prior to the exposure with antigen 60 µg histamine dihydrochloride and 0.5 µg serotonin creatinine sulfate as a control for antihistaminic, antiserotonic and nonspecific antibodies; then administered i.v. the compounds or saline immediately followed by an influence of 5 mg of egg albumin and 2.5 mg of dye (Evans' Blue) in saline. In the case of 5 oral administration, the dye (Evans' Blue) and egg albumin are added 5 minutes after administration of the drug. Twenty minutes later, the animals are stifled using chloroform and the skin on the back is removed and turned over for observation. Each injection site is assigned a numerical value 10 corresponding to the product of the injection site diameter expressed in mm, and a scale rating of 0.1, 0.5, 1, 2, 3 or 4 proportional to the color staining of dyes. The values thus determined for a particular injection site are summarized for each group of five animals and compared with the control group treated with saline. The difference is expressed as the percent blockage caused by the compound used.

Representative compounds for the compounds of the invention are tested for antiallergic effect by the procedure described above and the activity values thus determined are given as the degree (%) of protection. The comparison does not include Intal, disodium cromoglycate, which is a commercially available antiallergic agent as it is not effective with oral administration.

Table I gives results for the compounds of formula I which have been tested for antiallergic effect in the PCA test.

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24

TABLE I

Oral_virkning __ (% _ bitter ^ PROTECTION ^ _with

IgE mg / kg IgG mg / kg 5 R R2 1 3 10 30 1 3 10 30 CH3 CH3 55 51 CH3 C2H5 75 57 C2H5 CH3 29 28 C2H5 C2H5 62 49 10 (Ch2) 3 46 43 (CH2) 4 47 45 (CH2 ) 5 25 38 (CH2) 6 94 57 H CH3 55 50 15 Η H 50 46 CH3 H 78 55 C2H5 H 85 58 HC (CH3) 3 37 20 H C2H5 70 44 20 H CH (CH3) 2 72 53 CH2CH (C5H6 ) CH2CH2 4 7 CH2CH (CH3) CH2CH2 44 33 CH2C (CH3) 2CH2CH2 38 27 H CHCH2CH3 6 ch3

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25

The effectiveness of the subject products as anti-ulcer agents is determined by testing on cold-stressed rats. In this test, the drug or vehicle (control animal) is administered intraperitoneally (in saline solution containing 1% carboxymethyl cellulose and 0.1% Tween 3% 0) or orally (in water) to non-fasted female rats (Charles River CD strain), weighing 70-140 g and this is done 3 hours before being lightly anesthetized with ether and glued in landscape position to individual plexiglass plates.

10 Upon awakening from the anesthesia, the strapped animals are placed in a vertical position in a refrigerator maintained at 10-12 ° C, where they are slaughtered 3 hours later by cracking of the spine. The abdomen of each rat is opened, the pylorus is closed with a clamp, the abdomen is flushed with saline via an oral tube, 15 esophagus is closed with a clamp, and the abdomen is removed. The stomachs are placed in 0.4 percent formaldehyde solution for approx. 30 seconds to cure the outer layers and to facilitate examination. Each abdomen is then cut up along the large curvature and the glandular area (abdomen) is examined for injury effects. The number of gastric ulcerations, their strength and the color of the stomachs are recorded. The Mann-Whitney-Wilcoxan rank-sum test is used to compare the mean number of gastric ulcerations in the control group and the mean number of gastric ulcerations in each of the drug-treated groups to determine whether they are statistically different. (Dixon et al., "Introduction to Statistical Analysis", 3rd Ed., McGraw-Hill Book Company, New York, pages 344-347, 1969). As can be seen in the following set-up, in this test, N- (5-tetrazolyl-1-oxo-30H-cyclohexeno-thiazolo (3,2-a ^ pyrimidine-2-carboxamide (Compound III)) is extremely effective.

Alternatively, the efficacy of the subject compounds as anti-ulcer agents is determined in the ethanol-induced ulcer test in rats. In this test,

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2 6 give fasted male rats the drug (5 mg / kg) or in water through the mouth 15 minutes before an oral administration of! absolute ethanol (1.0 ml). One hour after exposure to ethanol, the animals are killed (8 per group) and the stomachs 5 are examined for the presence of damage. All the drugs were dissolved in dilute NaOH. After slaughter, the abdomen is opened and a closing hemostat is placed at the pylorus. 6 ml of 4 percent formaldehyde solution is injected into the stomach by means of a gastric tube, and another sealing hemostat is used to seal the esophagus. The stomach was then removed and opened at the large curvature and examined for ulceration.

Hereinafter, the assessment table is used to set numerical values for the damage caused by ethanol.

Ulcus point table ·

Points Definition 1 Normal appearance of stomach 2 Button-sized lesions 20 3 Two or fewer lesions? pineal lesions may be present 4 More than two lesions; pineal sized lesions may be present. 5 Lesions with bleeding

For each group of animals, an ulcer index is calculated as follows:

Ulcer formation index = (sum of group points scores) x (sum of number of ulcerations in group) x (fraction of group showing any signs of ulcer formation).

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27

The percent inhibition of ulcer is calculated as follows:% Inhibition = 100 x [(ulcer index for control) - (ulcer index for drug treated) J: (ulcer index control).

5 Table II shows the activity of various of the 5-tetrazolylamides in question in this assay.

TABLE II

Oral action (% inhibition at 5 mg / kg dosage) for amides (Formula I) in ethanol-induced rat ulcer test R2% inhibition CH3 CH3 96 H CH3 59 CH3 H 72 15 C2H5 C2H5 10 C2H5 η 86 (ch2) 6 45 (CH 2) 4 97, 81 10 As previously noted, the most preferred of the compounds of the present invention have Formula III, viz. Formula I wherein and R 2 together are butylene, [n- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide, which may alternatively be designated as 5,6,7, 8-15 tetrahydro-N- (5-tetrazolyl) -4-oxo-4H-pyrimido- (2,1-b) -benzothiazole-3-carboxamide].

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28;

In addition to the oral anti-allergenic effect shown in Table I, Compound III exhibits intravenous activity in the range of 0.03 - 1.0 mg / kg in the PCA test, being approx. 26 times as potent as Intal administered in 5 this way (as previously noted, Intal misses by oral administration). Compound III also blocks alterations in skin permeability induced by an IgE mediated passive cutanaphylaxis (PCA), but it does not interfere with changes in permeability caused by intradermal injection of exogenous histamine and serotonin. The absence of antihistaminic and antiserotonin activity indicates that the anti-allergic mechanism consists in inhibiting the release of mediators rather than in antagonism with the receptor for the mediator.

Compound III inhibits dextran-induced release of histamine in the rat's peritoneal cavity. Its ED, -q is 0.33 µg / kg, i.p., and the corresponding value for Intal is 14.0 µg / kg, showing a much stronger effect of the former. The increase in plasma histamine caused by antigenic action in rats passively sensitized to IgE-rich antiserum (passive systemic anaphylaxis) is prevented by compound III. The ED, -q is 28 µg / kg, i.v., 13 times more powerful than Intal.

Guinea pigs dosed with compound III, 30 mg / kg 25 i.p., were not protected from the bronchoconstrictive effect of inhaled histamine. In the concentration range -8. -4 to 10 M, Compound III does not antagonize the spasms of isolated guinea pig ileum induced by acetylcholine, histamine or slow-reacting anaphylaxis (SRS-A), 30 and the synthesis and release of SRS in isolated rat monocytes, stimulated by an ionophore, is not inhibited by compound III.

Compound III is in addition to its powerful effect at

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The ethanol-induced rat ulcer test (see above Table II) is highly effective in the cold stress test for ulcer under stress as described above, leading to dose-related protection at oral doses in the range 3-100. ^ ug / kg. Compound III also protects against the ulcerogenic effects of aspirin, 100 mg / kg p.o., where dose-related effects are seen through a dosage range of 10-1000 yug / kg, p.o. with an ED ^ q of ^ ug / kg. The binder ice III is also active in conjunction with a phenylbutazone gastric ulcer model, observing an oral Ed 2 of 200 µg / kg. Although Compound III is a highly potent anticulcus agent, it does not affect pentagastrin-stimulated acid production in Hei-denhain pouch dogs (5 mg / kg, iv), and therefore differs from antisecretory prostaglandins, as well as cimetidine and atropine. . The effects of compound III may aptly be termed "cytoprotective", a term recently designed to describe the antiulcus effects of prostaglandins 20 independent of antisecretory activity [Robert, Advances in Prostaglandin and Thromboxane Research 2, 507 (1976); Miller et al., Gut 20, 75 (1979); Robert et al., Gastroenterology 72, 1121 (1977.}].

Furthermore, compound III exhibits diuretic action.

When administered orally, it produced a dose-related increase in volume urine production at doses in the range of 0.3-5 mg / kg. The maximum effect was a doubling of the separated volume. The concentration of sodium and potassium ions in the urine remained unchanged; but due to the increase in the secreted volume, an increase in the excretion of sodium and potassium was observed. These observations indicate that the dose-response range for diuretic activity is significantly higher than the range for antiulcus effects and just below the range 35 for anti-allergy effects (1-10 mg / kg).

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30

Rats that had been starved for 24 hours and orally dosed with compound III at doses of 10, 30 or 100 mg / kg showed no changes in blood sugar levels. The effect of compound III on glucose tolerance was studied in rats given orally, 10, 30 or 100 mg / kg at the same time as glucose, 1 g / kg, p.o. |

An apparent dose-dependent improvement in glucose tolerance was observed. This effect may be due to a delayed absorption of glucose related to a possible effect on the emptying of the stomach.

Compound III has no significant anticholinergic effect. On anesthetized dogs, cumulative doses of 5 and 15 mg / kg, i.v., caused transient hypotension and variable changes in heart rhythm. Pressor response over 15 for epinephrine as well as bilateral carotid occlusion was slightly diminished. The transient cartio-vascular changes occurred only at cumulative intravenous doses that are 5 to 15 times higher than the maximum effective intravenous dose for antiallergic effects and 20 much higher than the oral doses required for antiulcer effects. , i

For study of tolerance, compound III was administered orally by probe feeding to dogs for a period of 7 days at doses of 50, 150 and 300 mg / kg / day. Emesis, which is common in dogs, was observed at all doses, but subsequent studies revealed that this emetic effect could be eliminated if the drug was administered with a capsule after instead of before meals. j

No major pathological changes were observed, and; 30 microscopic examination of liver, kidney, heart and lungs revealed no change. In other studies, serum enzyme levels in dogs remained normal when administered intravenously for Compound III for 5 days in consecutive daily doses of 1, 3, 10, 3 and 3 mg / kg.

in

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31

Rats were administered Compound III by oral probe feeding at doses of 50, 150 and 300 mg / kg / day for 10 days.

No resulting pathological changes were observed in macroscopic and microscopic assessment of liver, kidney, heart and lungs. Except for a slight increase in serum glutamic acid pyruvic acid transaminase observed at the highest dosage, no changes in clinical chemistry were observed.

Compound III was administered subcutaneously to mice at doses 10 of 100, 300 and 1000 mg / kg. No symptoms or mortality were observed and it can be concluded that the drug has a good acute tolerance with a subcutaneous LDj.q> 1000 mg / kg. At a dose of 32 mg / kg administered subcutaneously, no concurrent effect was observed with a large number of CNS-15 active drugs.

Single oral doses of compound III of 40 mg / kg were administered to groups of mice sacrificed 6, 12 or 24 hours later. Microscopic examination of the bone marrow revealed no chromosomal lesions. Similar observations were made when mice were treated for five consecutive days at a dose of 20 mg / kg. In vitro studies in which compound III was incubated with human lymphocytes at concentrations of 1000, 100, 10 or 0 µg / ml also revealed no significant chromosomal degradation induced by the drug. In the Ames test in vitro, compound III did not induce point mutations. From these results, it is clear that compound III has no distinct mutagenic potential.

In the rat PCA assay, the ratio of comparatively effective oral and intravenous doses of compound III is consistent with good oral absorption. This was supported by observations of plasma concentrations of 3-7 yug / ml one hour after oral administration of compound III, 50-300 mg / kg.

In dogs, the drug appears to be rapidly absorbed after

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32 oral administration of suspensions or capsules to achieve plasma concentrations of 9 - 36 µg / ml one hour after oral doses of 50 - 300 mg / kg. In both species, the plasma levels of the corresponding carboxylic acid metabolite 5 (the corresponding compound of formula II) are comparable to the levels of compound III, which identifies the said compound as an important metabolite of compound III. After the eighth daily dose, the levels of the starting compound and metabolite were 10 to 4 times greater than after the initial first dose, suggesting that it is possible to maintain therapeutic drug levels over extended periods of time.

Compound III shows solid state alone or mixed with standard inert ingredients used in oral compositions, or in solution, extremely good stability, making it easy to prepare stable compositions of this compound for clinical use.

The following examples further illustrate the preparation of starting materials and the process of the invention.

EXAMPLE 1 2-Amino-4-ethyl-5-methylthiazole

Thiourea (20.9 g, 0.275 mol) was dissolved in 250 ml of ethanol under reflux. 2-Bromo-3-pentanone (41.3 g 0.25 mol) dissolved in 50 ml of ethanol is added dropwise over 25 minutes to the refluxed urine solution. After a further 2 hours of reflux, the reaction mixture was evaporated to ca. 100 ml, cooled and the crude product was recovered as the hydrogen bromide salt by filtration. Purified 2-amino-4-ethyl-5-methyltetrazole (15.1 g; m.p. 45-50 ° C; m / e calcd: 142; found: 142) was obtained by dissolving in water and re-precipitating with aqueous 3N potassium hydroxide solution.

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EXAMPLE 2 2ΐ5ϊϊΰ2ΐ 1β-diethyl thiazole hydrochloric

Thiourea (21.8 g, 0.286 mol) was mixed with 4-chloro-3-hexanone (34.4 g, 0.26 mol) and 200 ml of ethanol, and the mixture was heated under reflux for 19 hours. The reaction mixture was cooled and freed of solvent by evaporation to give the crude product as a white solid. White crystals of 2-amino-4,5-diethylthiazole hydrochloride (31 g, m.p. 154 - 156 ° C) were obtained by recrystallization 10 from a mixture of ethyl acetate and ethanol.

EXAMPLE 3 2z§2) ii22l2Y2l2 ^ 2Et§i} 2thiazole

Thiourea (41.9 g, 0.55 mol) was mixed with 2-chloro-cycloheptanone (72.3 g, 0.49 mol) and 500 ml of ethanol, and the mixture was heated under reflux for 7 hours.

The solvent was evaporated leaving a semi-solid which was partitioned between ethyl acetate and water. Unreacted chlorone ketone recovered from the ethyl acetate phase by evaporation was mixed with 20 g of thiourea and ethanol, refluxed for 24 hours, solvent free, and the additional crude product was partitioned between ethyl acetate and water as above. described. In both cases, the reaction product was recovered by basifying the aqueous phase with ammonium hydroxide and extracting with ethyl acetate, and the ethyl acetate phase was dried over anhydrous sodium sulfate and evaporated to an oil which was solidified by tearing off with hexane and filtering off. Purified 2-amino-cycloheptenothiazole (49.5 g, mp 77-78.5 ° C) was obtained by recrystallization from cyclohexane.

34

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EXAMPLE 4 3I§i & iS2Z4li§22 £ 2BZli ^ i§52l

Thiourea (52.3 g, 0.69 mol) was suspended in 400 ml of ethanol. To the slurry was added 1-bromo-3-methyl-2-butanone (109.5 g, 0.66 mol). The resulting exothermic reaction 5 led to dissolution and reflux. The reflux was maintained by external heating for 1 hour. The solvent was removed by boiling and by evaporation to give an oil which crystallized on standing. Final purification of 2-amino-4-isopropylthiazole, hydrobromide (104.4 g, m.p. 74-76 ° C) was obtained by tearing off with ether.

The hydrogen bromide salt was converted to the free base (58.6 g) by dissolving the salt in water, basifying with excess ammonium hydroxide, extracting the free base in ether, drying the ether over anhydrous sodium sulfate and evaporating to an oil.

EXAMPLE 5 3l2S} i22Z§lEi} §SYi2Y2l2hexengthiazole

Thiourea (397.5 g, 5.22 mmol) was slurried in 6 ml of ethanol. To the slurry was added 2-bromo-4-phenyl-cyclohexanone (1.2 g, 4.74 mmol) leading to an exothermic reaction and solution. The solution was refluxed for 30 minutes, cooled, and the solvent evaporated to give crude product in the form of the hydrogen bromide salt.

This crude salt was dissolved in hot water, the solution filtered, and the free base precipitated by the addition of ammonium hydroxide. The crude base was recovered by filtration and purified 2-amino-6-phenylcyclohexenothiazole (302.4 mg, mp 181 - 183 ° C) was obtained by recrystallization

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35 from a mixture of water and ethanol.

Alternatively, the reaction mixture was on a larger scale. using 8.2 g of thiourea, 24.6 g of 2-bromo-4-phenylcyclohexanone and 125 ml of ethanol after the 30 minute reflux cooled in an ice bath, and the hydrogen bromide salt recovered directly by filtration. The hydrogen bromide salt was dissolved in water containing a trace of ethanol on heating, and the free base (10.4 g, mp 180 - 182 ° C) was precipitated by the addition of excess ammonium hydroxide.

EXAMPLE 6

Thiourea (22.3 g, 0.29 mol) was slurried 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 product was recovered as the hydrobromide salt by filtration. The crude salt was dissolved in hot water and the solution was filtered and basified with ammonium hydroxide to precipitate the free base as an oil which crystallized on cooling. Purified 2-amino-6-methylcyclohexenothiazole (25.2 g, m.p. 98-100 ° C) was obtained by recrystallization from cyclohexane.

Example 7β-Amino-eβ-dimethylcyclohexengthiazole 2-amino-6,6-dimethylcyclohexenothiazole (9.8 g, m.p. 109-111 ° C) was prepared from thiourea (9.2 g, 0.12 mol) and 2-bromo-4,4-dimethylcyclohexanone (22.6 g, 0.11 mol) in 100 ml of ethanol by analogy to the method described in Example 6.

EXAMPLE 8 36 2-Amino24 - (β - butY3) Thiazole

Thiourea (16.7 g, 0.22 mol), 1-bromo-3-methyl-2-pentanone (36 g, 0.2 mol) and 100 ml of ethanol were mixed together and heated under reflux for 5 hours. Aqueous potassium hydroxide solution (3N, 100 ml) was added and the reflux was continued for an additional 0.5 hour. The reaction mixture was cooled, acidified with hydrochloric acid, and non-basic impurities were extracted with ether.

The aqueous phase was made basic with ammonium hydroxide, and the reaction product extracted into ether. After washing back with water and drying over anhydrous sodium sulfate, the ether was evaporated to give 10 g of 2-amino-4- (2-butyl) thiazole as a dark brown viscous oil.

EXAMPLE 9 Thiourea (45.7 g, 0.6 mole) and propionaldehyde (7.4 g, 0.3 mole) were 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. The exothermic reaction was maintained between 15 and 24 ° C. Gas development, which took place during the addition, ceased approx. 1 hour after the addition was complete. Most of the chloroform was boiled off in a steam bath. Ethanol (150 ml) was added and the mixture was refluxed for 3 hours.

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

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37 solid. Purified 2-amino-5-methylthiazole (8.36 g, m.p. 94 - 95 ° C) was obtained by recrystallization from cyclohexane.

EXAMPLE 10 Thiourea (45.7 g, 0.6 mole) and butyraldehyde (21.6 g, 0.3 mole) were mixed with 150 ml of chloroform and cooled in an ice bath. Sulfuryl chloride (44.5 g, 0.33 mole was added over 15 minutes. The exothermic reaction was maintained between 15 and 25 ° C. Gas evolution occurred during the addition and for about 1 hour thereafter. ethanol (400 ml), the chloroform was boiled off and the reaction mixture was refluxed overnight (about 16 hours). The reaction mixture was evaporated to give an oil and recrystallized 2-amino-5-15 ethylthiazole (11.7 g 54 - 55 ° C) was isolated by the procedure of Example 9.

EXAMPLE 11 ii-Dicarbethoxyethenyl amino H 2 S-dimethylthiazole 2-amino-4,5-dimethylthiazole (2.56 g, 20 mmol), diethylethoxymethylene malonate (4.8 g, 22 mmol) and ethanol (5 ml) were obtained. heated at reflux for 1 hour. The reaction mixture was cooled and the crude product precipitated with hexane. By recrystallization from hexane, purified 2- (2,2-dicarbethoxyethenylamino) -4,5-dimethylthiazole (4.21 g, mp 82 - 83.5 ° C) was prepared.

EXAMPLE 12 2i2l2I25S25T2-2SY6thenylamino] -4-ethyl-5-methyl thiazole 2-amino-4-ethyl-5-methylthiazole (2.84g, 20mmol) and diethylethoxymethylene malonate (4 (76 g, 22 mmol) was mixed in 38

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together and heated in a steam bath for 3 hours. The reaction product obtained as an oil on cooling was used in the subsequent step without further purification.

in

EXAMPLE 13 I

In 2,212-dicarbethoxyethenylamino2-4-methyl-5-ethylthiazole in 4-methyl-5-ethylthiazole (5.68 g, 40 mmol) and diethylethoxy, methylene malonate (9.52 g, -44 mmol) were heated briefly. to 86 ° C and then cooled to obtain the reaction product as an oil used directly in the subsequent step.

EXAMPLE 14 2- [2- [2-Dicarbethoxyethenylamino] 2,4-5-diethylthiazole

Diethylthiazole hydrochloride (15.4 g, 80 mmol), diethyl ethoxymethylene malonate (19.0 g, 88 mmol), triethylamine (8.1 g, 80 mmol) and ethanol (125 ml) were mixed together and heated under reflux for one hour. 2.5 hours. The reaction mixture was cooled and evaporated free of solvent. The semi-solid reaction product thus prepared was partitioned between ethyl acetate and water. 2- (2,2-dicarbethoxyethenylamino) -4,5-diethylthiazole (28.6 g) was obtained as golden oil from the ethyl acetate phase by drying over anhydrous sodium sulfate and evaporation of the solvent.

EXAMPLE 15 2zi2i2-dicarbethoxyethenylamino2-cyclopentenothiazole 20 2-Aminocyclopentenothiazole (3.6 g, 34.5 mmol) and diethyl ethoxymethylene malonate (8.2 g, 38.0 mmol) were mixed together and heated on a steam bath for 100 minutes. The reaction mixture was cooled and by the addition of ethanol, 2- (2,2-dicarbethoxyethenylamino) cyclopentene -othothiazole (7.0 g, Rf 0.6 on thin silica gel was crystallized out

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39 chloroform / 1% ethanol elution as eluent).

EXAMPLE 16 e 2 - dicarbethoxylethenylaminol CYClohexenothiazole 2-aminocyclohexenothiazole (7.7 g, 50 mmol) and diethyl ethoxymethylene malonate (11.9 g, 55 mmol) were mixed with 5 ml of methanol and heated under reflux for 50 minutes. The reaction mixture was cooled and, with the addition of 50 ml of hexane, 2- (2,2-dicarbethoxyethenylamino) cyclohexenothiazole (15 g, Rf 0.5 on silica gel by thin layer chromatography with chloroform / 1% ethanol as eluent) was precipitated).

Alternatively, 58.5 g of 2-aminocyclohexenothiazole, 89.82 g of diethylmethoxymethylene malonate and 584 ml of cyclohexane were mixed and heated under reflux under nitrogen for 2.5 hours, cooled to 15 ° C, and the reaction product (96 g, m.p. 113 ° C). ) recovered by filtration.

EXAMPLE 17 2li2, 2-dicarbethoxyethenylamino cyclooctenothiazole 2-aminocyclooctenothiazole (2.0 g, 11 mmol) and diethylethoxymethylene malonate (2.62 g, 12.1 mmol) were mixed together and heated on a steam bath for 2.75 hours. The reaction mixture 20 was cooled and 2- (2,2-dicarbethoxyethenylamino) cyclooctene thiazole (3.13 g, Rf 0.6 on silica gel by chromatography with chloroform / 1% ethanol as eluent) was precipitated by the addition of hexane.

EXAMPLE 18 2 µl of 2-carbethoxyethenylaming2-4-methylthiazole 2-amino-4-methylthiazole (4.57 g, 40 mmol) and diethyl ethoxymethylene malonate (9.51 g 44 mmol) were mixed together.

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and heated in a steam bath for 1 hour. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) -4-methyl-thiazole (9.8 g, Rf 0.5 on silica gel thin-layer chromatography with chloroform / 1% ethanol as eluent was precipitated by the addition of 60 g. ml of hexane.

EXAMPLE 19 dicarbethoxyethenylamino-thiazole 2-aminothiazole (10.0 g, 0.10 mol) and diethylethoxymethyl enmalonate (23.8 g, 0.11 mol) were mixed together and heated on a steam bath for 1.2 hours. The reaction mixture was cooled and the thus obtained semi-solid product was recrystallized from hexane to give purified 2- (2,2-dicarbethoxyethenyl) thiazole (17.2 g in two cycles, Rf 0.6 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluant).

EXAMPLE 20 2- µg of g-dicarbethoxyethenylaminol-5-methylthiazole 2-amino-5-methylthiazyl (6.85 g, 60 mmol) and diethylethoxymethylene malonate (14.3 g, 66 mmol) were heated on a steam bath. 1 hour. The reaction mixture was cooled and the reaction product precipitated by adding about 75 ml of hexane. Purified 2- (2,2-dicarbethoxyethenylamino) -5-methylthiazole (14.1 g in two cycles, Rf 0.55 - 0.65 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent was obtained by recrystallization from hexane.

EXAMPLE 21 2 L-Hydrocarbethoxyethenylamino] 5-ethyl thiazole 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. On cooling

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41, 2- (2,2-dicarbethoxyethylamino) -5-ethyl-thiazole (27.2 g, Rf 0.6 and 0.7, respectively, were obtained on silica gel thin-layer chromatography with chloroform / 1% ethanol and hexane: ethyl acetate ratio 2: 1 as eluent) 5 as an oil which was used directly in the next step.

EXAMPLE 22 2, 2-Dicarbethoxyethenylamino | -4- {2-methyl-2-propyl] -thiazole 2-amino-4- (2-methyl-2-propyl) thiazole (15.6 g, 0.1 mole) and diethyl ethoxymethylene malonate (23.8 g, 0.11 mol) was mixed together and heated on a steam bath for 2 hours. On cooling, 2- (2,2-dicarbethoxyethenylamino) - 4- (2-methyl-2-propyl) thiazole as a wet solid was obtained directly in the next step.

EXAMPLE 23 2 µl of 2-dicarbethoxyethenylamino2-4-ethylthiazole 2-amino-4-ethylthiazole (20.5 g, 0.16 mol) and diethylethoxy methylene malonate (35 g, 0.17 mol) were mixed together and heated on a steam bath. for 2 hours. On cooling, 2- (2,2-dicarbethoxyethenylamino) -4-ethylthiazole was obtained as oil which was used directly in the next step. (Rf 0.75 on silica gel by thin layer chromatography with chloroform / 1% ethanol as eluent).

By the same procedure, 2-amino-4-isopropylthiazole (58.6 g, 0.415 mol) and diethylethoxymethylene malonate (92 ml, 0.45 mol) were converted to 2- (2,2-dicarbethoxyethenyl-amino) -4 -isopropylthiazol. (Rf 0.7 on silica gel thin layer chromatograph with chloroform / 1% ethanol as eluent).

EXAMPLE 24 2- (2,2-DicarbethoxyethyleneaminoZ = 6-phenylcyclohexenothiazole

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42 2-Amino-6-phenylcyclohexenothiazole (10.4 g, 45.2 mmol) and diethylethoxymethylene malonate (10 mL, 49.5 mmol) were mixed together and heated on a steam bath. After 15 minutes, a solution occurred. After another 30 minutes of heating, the whole mass solidified. The crude product was recrystallized from cyclohexane to give purified 2- (2,2-dicar-bethoxyethenylamino) -6-phenylcyclohexenothiazole (15.3 g, mp 131 - 133 ° C).

EXAMPLE 25 2li2,2-dicarbethoxyethenylamino2,66methylcyclohexenothiazole X 2 2-amino-6-methylcyclohexenothiazole (23.3 g, 0.139 mol) was mixed with diethylethoxymethylene malonate (31 ml, 0.153 mol) and heated on a steam bath. After about 10 minutes of heating, a clear orange oil emerged. After 1 hour of heating, crystallization was induced by scraping. By recrystallization from ethanol, purified 2- (2,2-dicarbethoxyethenylamino) -6-methylcyclohexenothiazole (40.2 g, m.p. 106 - 109 ° C) was obtained.

EXAMPLE 26-Zi-1-Dicarbethoxyethenylaminol-e-dimethylcyclohexenothiazole 20-amino-6,6-dimethylcyclohexenothiazole (9.3 g, 53.8 mmol), diethylethoxymethylene malonate (12 ml, 59.4 mmol) and ethanol (about 5 ml) was mixed and heated on a steam bath for 1.5 hours. The ethanol boiled away during the first part of the heating time. After cooling and scraping, the reaction product crystallized. By recrystallization from hexane, purified 2- (2,2-dicarbethoxyethenylamino) - 6,6-dimethylcyclohexenothiazole (14.3 g, mp 83-85 ° C) was obtained.

4 3

DK 151811 B; 'V

"'A;

Elemental analysis for ci7H24 ° 4N2S:

Calculated: C 57.93 - H 6.36 - N 7.95

Found: C 57.72 - H 6.66 - N7.94 EXAMPLE 27 2 [212-Dicarbethoxyethenyl] mino] -4- [2-butyl] thiazole 2-amino-4- (2-butyl) thiazole (8, 44 g, 54 mmol) and diethyl ethoxymethylene malonate (11.7 g, 54 mmol) were mixed together and heated on a steam bath for 1 hour and then cooled to give 2- (2,2-dicarbethoxyethenylamino) -4- (2 -butyl) thiazole (17.6 g, Rf 0.75 on silica gel thin-layer chromatography with chloroform / 1% ethanol as eluant).

EXAMPLE 28

Ethyl 1-oxo-1H-6β-dimethylthiazolo CSig ^ ^ pyrimidine-2- (2-dicarbethoxyethenylamino) 4,5-dimethylthiazole (4.17 g 14 mmol) was mixed with 30 ml of Dowtherm A and heated to 220 ° C for 1.5 hours. The reaction mixture was cooled and ca. 125 ml of petroleum ether.

The solid that was separated was filtered off, returned to the mother liquor and chromatographed on a 70 x 180 mm silica gel column using chloroform as the eluent. After an initial fraction of 125 ml, six 250 ml fractions were collected which were evaporated to dryness to give crude product (2.42 g, mp 114 - 115 ° C).

Recrystallization from cyclohexane gave purified ethyl 1-oxo-1H-4,5-dimethylthiazolo (3,2-apyrimidine-2-carboxylate (1.64 g, mp 119-120 ° C)).

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44

Elemental Analysis for cnHi2N2 ° 3S:

Calculated: C 52.37 - H 4.79 - N 11.10; mass ion, 252

Found: C, 52.21; H, 4.35; N, 11.23; mass ion, 252.

EXAMPLE · 29

Ethyl 1-oxo-1H-76-methyl-7-ethylthiazolo [1,2-a] pyrimidine-5-2-carboxylate 2- (2-dicarbethoxyethenylamino) -4-ethyl-5-methylthiazole (6.25 g) was mixed with 30 ml of "Dowtherm A" and heated to 115 ° C for 0.5 hours. The reaction mixture was cooled, added with petroleum ether and the crude product (1.96) was recovered by filtration. Part of the crude product (630 mg) was recrystallized from cyclohexane to give purified 1-oxo-1H-6-methyl-7-ethylthiazolo (3,2-pyrimidine-2-carboxylate (301 mg, m.p. 122-24 ° C).

Elemental Analysis for 2 2 14 14 35 35: 15 Calculated: C 54.12 - H 5.30 - N 10.52

Found: C 54.09 - H 5.26 - N 10.63.

EXAMPLE 30 YlIIIlO ^ SlI ^ I ^ I ^ tlilYilZliQfthYlthiazolojga ^ eYrimidine 2- (2,2-dicarbethoxyethenylamino) -4-methyl-5-ethylthiazole (12 g) was mixed with 60 ml of Dowtherm A and heated to 205 ° C for 3 hours. The reaction mixture was cooled and chromatographed on a silica gel column 90 x 205 mm eluting with chloroform containing 1% ethanol. 7 product-containing fractions were collected on each 250 ml which were combined, evaporated to an oil and chromatographed again on silica gel (60 x 600 mm) with the same eluent. Fractions (165 x 8 ml) were combined, evaporated to an oil and crystallized by trituration with diisopropyl ether.

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45 ether. Recrystallization from cyclohexane gave purified ethyl 1-oxo-1H-6-ethyl-7-methyl-thiazolo (3,2-a] pyrimidine-2-carboxylate (2.45 g, mp 65-66 ° C).

Elemental Analysis for C12 H13 N2 O3: 5 Calculated: C, 54.12; H, 5.30; N, 10.52; mass ion, 266

Found: C, 54.26; H, 5.23; N, 10.57; mass ion, 266 EXAMPLE 31 Ιΐΐ3Υΐΐ2Χ2ΐ1ΐΐ3ΐ6 £ Ζΐ ^ ϊ§ £ ΐ ·} Υΐΐ:] 3ϊ§ £ 2ΐ2β2-pyrimidine-2-carb2xylate 2- (2,2-dicarbethoxyethenylamino) -4,5-diethylthiazole (26, (10 g) and 300 ml of "Dowtherm A" were mixed together and heated to 225 ° C for 3.5 hours. The reaction mixture was cooled and chromatographed on a silica gel column (60 x 320 mm). "Dowtherm A" was eluted with hexane and the product was eluted with 2: 1 hexane: chloroform. A total of 33 fractions of 250 ml were collected. The 8th to 33rd fractions were combined and solvent free to give 1-oxo-1H-6,7-dimethylthiazolo (3 (2-a) pyrimidine-2-carboxylate in the form of an oil (22g, Rf 0 , 4 - 0.5 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent).

EXAMPLE 32ethyl-1-oxo-1H-cyclopententhiazolojB 2-g] pyrimidin-2-carb2XYl§t 2- (2,2-dicarbethoxyethenylamino) cyclopentenothiazole (7.0 g) was mixed with 40 ml of Dowtherm A "and heated to 225 -25 230 ° C for approx. 1 hour. The reaction mixture was cooled and chromatographed on silica gel (70 x 190 ml). "Dowtherm A" was eluted with hexane. The reaction product was eluted with chloroform / 1% ethanol. Four fractions of 250 ml each were collected which were combined and freed from the solution.

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46 to form an oil. Part of this oil was crystallized by trituration with cyclohexane to give crude product (1.91 g). Recrystallization of 0.6 g of the crude product gave purified ethyl 1-oxo-1H-cyclopentenothiazolo [β, 2-apyrimidine-2-carboxylate (0.33 g, mp 102 - 103 ° C).

Elemental Analysis for ci2Hi2N2 ^ 3S:

Calculated: CC54.53 - H 4.58 - N 10.60 Found: C 54.54 - H 4.71 - N 10.71.

EXAMPLE 33 Ethyl 1-oxo-1H-cyclohexenothiazolo [g] -alpyrimidine - 2 - 2- (2,2-dicarbethoxyphenylamino) cyclohexenothiazole (12.6 g) was mixed with 125 ml of "Dowtherm A" and heated to 230 ° C. for 25 minutes. The reaction mixture was cooled and chromatographed on silica gel (60 x 320). "Dowtherm A" was eluted with hexane and the product was eluted with chloroform / 1% ethanol in 14 fractions of 125 ml each. Crude ethyl 1-οχο-ΙΗ-cyclohexenothiazoloC3,2-a] pyrimidine-2-carboxylate (10.7 g, m.p. 92 - 94 ° C) was obtained by combining the fractions and evaporating the solvent.

Alternatively, 2- (2,2-dicarbethoxyethenylamino) -cyclohexenothiazole (30 g, 0.25 mol), trifluoroacetic anhydride (101 g, 68 ml, 0.48 mol), toluene (0.8 liter) and ethanol (1 liters) mixed and heated under reflux for 21 hours. The reaction mixture was cooled and 300 ml of water added. The toluene layer (the top was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to 150 ml (one slurry), diluted with 1 liter ethanol (solution), concentrated to 280 ml, cooled to 5). ° C, granulated and filtered to give relatively pure ethyl-1-oxo-1

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47 hexenothiazolo [3,2-a] pyrimidine-2-carboxylate (47 g, mp 105 - 106 ° C).

EXAMPLE 34

Ethyl 11-oxo-1H-CYCloheptenothiazolo ^ Sig-α ^ pyrimidine-g-carboxylate 5-2-aminocyclophtenothiazole (25.2 g, 0.15 mol), diethyl ethoxymethylene malonate (35.7 g, 0.165 mol) and Dowtherm A "(400 ml) was mixed and heated to 220 - 230 ° C for 2 hours. The reaction mixture was cooled and chromatographed on silica gel (90 x 235 mm). "Dowtherm A" was eluted with 10 hexane. The reaction product was eluted with hexane: chloroform in a 1: 1 ratio in 30 fractions of 500 ml each. The 6th to 30th fractions were combined and liberated from the solvent to give crude product as a wet solid. On recrystallization from cyclohexane, purified ethyl 1-oxo-1H-cycloheptenothiazolo [2-a] pyrimidine-2-carboxylate (27.1 g, mp 78-79 ° C) was obtained.

The same product was prepared by heating 2- (2,2-dimcarbethoxyethenylamino) cycloheptenothiazole in "Dowtherm A" and subsequent isolation and purification in a similar manner.

EXAMPLE 35 Ethyl 1-oxo-1H-cyclooctength thiazoloCSig-α-pyrimidine-β-carboxylate 2- (2,2-dicarbethoxyethenylamino) cyclooctenothiazole (3.13 g) was mixed with 30 ml of Dowtherm A and heated to 220 °. C for 2.5 hours. The reaction mixture was cooled and chromatographed on silica gel (70 x 190 mm). "Downtherm A" was eluted with hexane. The reaction product was eluted with chloroform / 1% ethanol in 4 fractions of 125 ml. The fractions were combined and evaporated to an oil, and triturated with hexane to give solid ethyl 1-οχο-ΙΗ-30 cyclooxtenothiazolo [3,2-a] pyrimidine-2-carboxylate (1.95 g,

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48

Rf 0.5 on thin layer chromatography on silica gel and eluted with chloroform / 1% ethanol).

EXAMPLE 36 Ethyl-1-oxo-1H-7-methylthiazole C 1-6 pyrimidine-g-carb oxylate 5 2- (2,2-dicarbethoxyethenylamino) -4-methylthiazole (9.8 g) was mixed with 50 ml "Dowtherm A" and heated to 220 ° C for 2 hours. The reaction mixture was cooled, 50 ml of hexane was added and the crude product was collected by filtration. Recrystallization of the crude product from ethanol afforded purified ethyl 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylate (4.6 g, mp 187-189 ° C).

Alternatively, this ester is prepared by condensation of 2-amino-4-methylthiazole directly with ethyl ethoxymethylene malonate at reflux in trichlorobenzene [Alien et al., 15 J. Org. Chem., 24, 779 (1959)].

EXAMPLE 37

IthYliIioxoilHlthiazolo ™ - aLpyrinidine - ^ - carboxylate 2- (2,2-dicarbethoxyethenylamino) thiazole (17.2g) was mixed with 200 ml of Dowtherm A and heated to 215 ° C for 30 minutes. The reaction mixture was cooled to form a slurry. Hexane (100 ml) was added and the crude product collected by filtration. Recrystallization from ethanol gave purified ethyl 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylate (8.0 g, mp 184-185 ° C).

Alternatively, this ester is prepared by condensation of 2-aminothiazole directly with ethyl ethoxymethylene malonate at reflux in trichlorobenzene. Allen et al., J. Org. Chem., 24, 779 (1959)].

EXAMPLE 38 ^ lYlllllO ^ lIHl ^ l ^ thylthiazoloCBig-a ^ gyrimidine ^ carboxylate 2- (2,2-dicarbethoxyethenyl) -5-methylthiazole (14.1 g) was mixed with 150 ml. Dowtherm A "and heated to 220 ° C for 1.5 hours. The reaction mixture was cooled and added to ca. 300 ml of hexane. The reaction product was recovered by filtration and purified ethyl 1-oxo-1H-6-methylthiazole o [3,2-g pyrimidine-2-carboxylate (6.4 g, mp 149-151 ° C) was obtained by recrystallization from diisopropyl ether.

Alternatively, this ester is prepared by condensation of 2-amino-5-methylthiazole directly with ethyl ethoxymethylene malonate in boiling trichlorobenzene [punwell, et al., J. Chem.

Soc., (C) 1971, 2094].

EXAMPLE 39 15-Thyl-1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -5-ethylthiazole (25.7 g, 36 mmol), trifluoroacetic anhydride ( 36.2 g, 172 mmol) and toluene (150 ml) were mixed and heated at reflux for approx. 20 hours. The reaction mixture was evaporated to dryness and redissolved in 300 ml of chloroform. The chloroform solution was washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to dryness and triturated with diisopropyl ether to give ethyl 1-oxo-25-1H-6-ethylthiazolo [3,2-a] pyridine 2-carboxylate (17.8 g, m.p. 148-150 ° C). A portion of the product (5.2 g) was recrystallized from ca. 75 moles of ethyl acetate to give further purified product (4.1 g, m.p. 149-150 ° C).

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50

Elemental Analysis for C

Calculated: C 52.37 - H 4.79 - N 11.10

Found: C 52.30 - H 4.51 - N 11.14.

EXAMPLE · 40? £ ίϊΥΐΐ! Ϊ́ΐ222ΐΐ5ΐΖ "ί2ΐ5§ ^ γ1-2- £ Γθ £ γ1) ΐ] ιϊηζο1ο £ 3Λ2; §ί]; 5 £ Y £ iniidin; 2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -4- (2-methyl-2-propyl) -thiazole (32.6 g) was mixed with 400 ml of Dowtherm A and heated to 230 ° C for 1 hour. The reaction mixture was cooled and chromatographed on silica gel (60 x 600 "Dow-10 therm A" was eluted with hexane. The reaction product was eluted with chloroform. Nine fractions of 500 ml were collected each. The 6th to 9th fractions were combined and evaporated to dryness to give ethyl-1. -oxo-1H-7- (2-methyl-2-propyl) thiazolo [1,2-a] pyrimidine-2-carboxylate (11.4 g, m.p. 145 - 147 ° C). Additional product (2.04 g) was obtained from the 5th fraction by evaporation to a wet solid and subsequent trituration with cyclohexane. 1 g of the largest was recrystallized from cyclohexane to give further purified product 20 (0.62 g, m.p. 148) - 149 ° C).

Element analysis for

Calculated: C 55.70 - H 5.75 - N 9.99

Found: C, 55.14; H, 5.58; N, 9.95 EXAMPLE 41, 5, 5, 5, 5, 5, 5, 5, 5, 5, 7, 7, 7, 7, 7, 6, 6, 6, 6, 6, 6, 6, 6, 2, 2, 2, 2, 2, 2-trimidine-2-carboxylate. 7 g, 0.16 mol) was stirred in 500 ml of toluene and trifluoroacetic anhydride (45 ml, 0.32 mol) was added. A weak exothermic reaction was observed. The reaction mixture was heated to reflux for 26 hours, cooled and added

DK 151811B

51 250 ml of ethyl acetate. The mixture was gently extracted with 250 ml of aqueous sodium bicarbonate solution (carbon dioxide evolution) and then with 250 ml of saturated sodium chloride solution dried over anhydrous sodium sulfate and evaporated to dryness. The residue was slurried in diisopropyl ether and the crude product recovered by filtration. Recrystallization of the crude product from acetonitrile afforded purified ethyl 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate (10.33 g, mp 175-177 ° C).

Elemental Analysis for:

Calculated: C 52.37 - H 4.79 - N 11.10 Found: C 52.34 - H 4.85 - N 11.27.

From the acetonitrile mother liquor another amount was obtained (1.58 g, mp 176 - 178 ° C).

EXAMPLE 42 Ethyl 1-oxo-4H-7-isogrogylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxy) -4-isopropylthiazole (10 g) was mixed with 100 ml. Dowtherm A "heated to 220 ° C for 2 hours, cooled to room temperature overnight and reheated to 20 220 ° C for an additional 5 hours. The mixture was cooled to room temperature and ca. 200 ml of hexane and filtered to remove small amounts of insoluble constituents. The hexane was evaporated and the residue was chromatographed at ca. 500 g of silica gel. "Dowtherm A" was eluted with hexane and the reaction product eluted with chloroform. Fractions containing the reaction product were combined and evaporated to dryness, the residue was slurried in diisopropyl ether and the product (mp 143-144 ° C) recovered by filtration. The crude product was crystallized from ethanol to give purified ethyl 1-oxo-1H-7-isopropylthiazolo 2,2-aJ pyrimidine-2

DK 151811B

52 carboxylate (1.49 g, m.p. 145 - 147 ° C, NMR: sing-1 after at <£ 8.6 and <f7.3 corresponding to one portion each), and multiples centered on (f4.2 and £ 1, 2 corresponding to 3 protons and 9 protons respectively).

EXAMPLE 43 5β: 7 PPenoxy-cyclohexenothiazoloC3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole (15.3 g, 38 2 mmol) was suspended in 150 ml of toluene.

Trifluoroacetic anhydride (19.8 mL, 10 76.5 mmol) was added, resulting in a clear solution which was refluxed for 16 hours. The reaction mixture was cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 150 ml of 5% potassium carbonate solution and once with 150 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The solid evaporation residue was recrystallized from acetonitrile to give purified ethyl 1-oxo-1H-7-phenylcyclohexenothiazolo [β, 2-a] pyrimidine-2-carboxylate (9.89 g, mp 160 - 161.5 ° C).

EXAMPLE 44 Methyl-1-oxo-1H-7-methylcyclohexenothiazolo [3H-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -6-methylcyclohexenothiazole (40.2g, 0.119 mol) was dissolved in 400 ml of toluene. Trifluoroacetic anhydride (33.5 mL, 0.237 mole) was added, leading to a slight exothermic reaction. The reaction mixture was heated at reflux overnight (16 hours), cooled to room temperature, diluted with 400 ml of ethyl acetate, extracted twice with 400 ml of 1 N potassium carbonate solution and once with 400 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and

DK 151811 B

53 evaporated to dryness. Recrystallization from cyclohexane containing a small amount of ethyl acetate afforded purified ethyl 1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate (29.3 g, m.p. 127 - 129 ° C).

EXAMPLE 45 Ethyl 1-oxo-1H-7'-dimethylcyclohexenothiazolo [3L2-a ^ -BYEisyl] 6-carboxylate 2- (2,2-dicarbethoxyethenylamino) -6,6-dimethylthiazole (13g, 36.9mmol) was dissolved in 130 ml of toluene. Trifluoroacetic anhydride (10.4 ml, 73.6 mmol) was added and the mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with 150 ml of ethyl acetate, extracted twice with 130 ml of saturated sodium bicarbonate solution and once with 150 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization from hexane gave purified ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate (9.40 g, m.p. 92-94 ° C).

Elemental Analysis for C ^H ^ gKKO₂S: 20 Calculated: C 58.30 - H 5.92 - N 9.14

Found: C 58.93 - H 5.48 - N 9.01 EXAMPLE 46

Ethyl 1-oxo-1H-7- [2-butyl] thiazole [3,3-2-a] pyrimidine-2-9-toxylate 2- (2,2-dicarbethoxyethenylamino) -4- (2-butyl) Thiazole (17.6 g) was mixed with 170 ml of "Dowtherm A" and heated to 225 ° C for 2.5 hours. The reaction mixture was cooled and chromatographed on silica gel (60 x 600 mm). "Dowtherm A" was eluted with hexane. The reaction product was eluted with

DK 151811B

54 chloroformrhexane in a 2: 1 ratio. Fractions 4-8 (each of 500 ml) were combined and evaporated to an oil which was dissolved in ca. 400 ml carmt hexane. This solution was treated with charcoal and cooled to give crystalline ethyl 1-oxo-1H- (2-butyl) thiazolo [1,2-a] pyrimidine-2-carboxylate (2.12 g, m.p. 105.5 - 108 ° C).

Elemental Analysis for ci3Hig ° 3N2®:

Calculated: C 55.70 - H 5.75 - N 9.99

Found: C, 55.82; H, 5.40; N, 10.22.

EXAMPLE 47 11252ZISz§rZl ^ ii2§ £ hYl thiazolo [3,2-a] 2-yrimidine 22-carboxylic acid

Ethyl 1-oxo-1H-6,7-dimethylthiazolo [3,2-a) pyrimidine-2-carb oxylate (1.41 g) was heated on a steam bath together with 20 ml of 48% hydrogen bromic acid for 1 hour. Dissolution occurred within 15 minutes, and solids began to form at the end of the reaction period. The reaction mixture was cooled and the reaction product recovered by filtration. Recrystallization from ethanol gave purified 1-oxo-1H-6,7-dimethyl thiazolo (3,2-apyrimidine-2-carboxylic acid (508 mg, m.p. 189-190 ° C)).

Elemental Analysis for C

Calculated: C 48.21 - H 3.60 - N 12.49; mass ion, 224.

Found: C, 48.21; H, 8.68; N, 12.44; mass ion, 224.

EXAMPLE 48 1- 2X2ilH-6 ~ methyl-7yethylthiazglg CSi ^ y ^ pyrimidine-g-carb-2

Ethyl 1-oxo-1H-6-methyl-7-ethylthiazolo (3,2-a) pyrimidine-2-carboxylate (971 mg) was heated on a steam bath together with 15 ml of 48% hydrogen bromic acid. Resolution occurred approximately

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55 right away. The heating was continued for 2.5 hours, after which the reaction mixture was cooled to give the reaction product in the form of a filterable solid. Recrystallization of the crude product from isopropyl alcohol yielded purified 1-oxo-1H-6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (354 mg, mp 201-202 ° C).

Elemental Analysis for C10H10 ° 3N2S:

Calculated: C 50.41 - H 4.23 - N 11.76 Found: C 50.28 - H 4.26 - N 11.80 EXAMPLE 49 1- oxo-lt ^ e-ethyl ^ -methylthiazolo 2 -a] pyrimidine-2-

Ethyl 1-oxo-1H-6-ethyl-7-methylthiazolo [* 3,2-apyrimidine-2-carboxylate (1.33 g) was heated on a steam bath with 15 ml of 48% hydrogen bromic acid for 30 minutes, at which time time began to form a solid. The mixture was cooled and crude product recovered by filtration. Recrystallization from isopropyl alcohol gave purified 1-oxo-1H-6-ethyl-7-methylthiazolo (3,2-a] pyrimidine-2-carboxylic acid (596 mg, m.p. 174 - 176 ° C).

Elemental Analysis for C10H10 ° 3N2S:

Calculated: C 50.41 - H 4.23 - Nll, 76

Found: C, 50.44; H, 4.22; N, 11.32.

EXAMPLE 50 11/22/115 SrZl ^ i6thylthiazole O 3 -3-a3-pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-6,7-diethylthiazolo (1, 2-a] pyrimidine-2-carb oxylate (19 (2 g) was heated to 85 ° C together with 48% aqueous HBr for 1 hour, gas evolution (probably decarboxylation of the product) was observed.

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The mixture was cooled and basified with concentrated ammonium hydroxide solution, and unreacted starting material and impurities were extracted with ethyl acetate. The aqueous phase was acidified with acetic acid, and solid product 5 was obtained by filtration. The crude product was recrystallized from isopropyl alcohol to give partially purified reaction product (5.4 g) in two portions. Partially purified material (2.5 g) was recrystallized again from isopropyl alcohol to give purified 1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid 1,6 g, mp 104 - 196 ° C (unclear)].

Elemental Analysis for cnHi2 ^ 3N2 ^:

Calculated C 52.37 - H 4.79 - N 11.10

Found: C, 52.31; H, 4.79; N, 11.15.

EXAMPLE 51 Lygil H-Cyclopentenothiazolo [1,2-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-cyclopentenothiazolo 3,2-a pyrimidine-2-carb oxylate (1.3 g) was heated together with 15 ml of 48% hydrogen bromic acid on a steam bath for 30 minutes. Resolution occurred 20 after ca. 5 minutes walk; a solid began to form at the end of the heating period. The reaction mixture was cooled and crude product recovered by filtration. Recrystallization from isopropyl alcohol afforded purified 1-oxo-1H-cyclopentenothiazo-10 [β, 2-ό] pyrimidine (0.51 g, m.p. 202 - 203 ° C).

Elemental analysis for cigH8 ° 3N2S:

Calculated: C, 50.84; H, 3.41; N, 11.36

Found: C 50.42 - H 3.57 - N 11.65.

The sodium and potassium salts are prepared by dissolving the free acid in water with an equivalent of the appropriate hydrogen peroxide.

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57 droxide and either evaporate the water under vacuum or freeze dryer.

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

EXAMPLE 52 [2,2ZiZ2Z5Y212 HexenothiazoloC3L22a] -gyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-cyclohexenothiazolo (3,2-a] pyrimidine-2-carb oxylate (2.8 g) was heated on a steam bath together with 30 ml of 48% hydrobromic acid. Solution occurred within a few minutes after The reaction product was cooled in an ice bath and 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (1.66 g, m.p. 188). - 189 ° C) isolated by filtration Recrystallization from ethanol gave 1.38 g of the same melting point.

This reaction product was alternatively prepared by stirring 22.3 g of the ethyl ester with 223 ml of 48% hydrogen bromide acid in a low pressure vessel. Solution occurred at 65 - 70 ° C. The reaction mixture was heated over 40 minutes to a maximum temperature of 85 ° C and a maximum pressure of 0.5 atm. The reaction mixture was cooled to 45 ° C, the pressure was removed, the mixture was cooled to 5 ° C, stirred for 1 hour, and the relatively pure product recovered directly by filtration (12.4 g, mp 102 - 194 ° C). .

The sodium salt is prepared by dissolving the acid in ethanol together with an equivalent amount of sodium methoxide and evaporating to dryness or precipitating the salt by cooling and adding hexane.

3J

58 DK 151811B

EXAMPLE 53 1-Oxo-1H-Cycloheptenothiazolo [2,2-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-cycloheptenothiazolo [3,2-a) pyrimidine-2-carboxylate (5.8 g) was heated for 15 minutes on a steam bath with 50 ml of hydrogen bromic acid. The reaction mixture was poured into ice, stirred, and the crude product recovered by filtration. Recrystallization from ethanol afforded purified 1-oxo-1H-cycloheptenothiazolo [3,2-a) pyrimidine (2.63 g, mp 162 - 163 ° C).

Element Analysis for C₂L₂Hi₂ ° 3N₂S:

Calculated: C 54.53 - H 4.58 - N 10.60; mass ion, 264

Found: C, 54.72; H, 4.73; N, 10.88; mass ion, 264.

The amine salts are prepared by adding an equivalent amine to a hot ethanolic solution of the acid followed by cooling and concentrating or adding hexane.

EXAMPLE 54

Il252li§l2Y2l22St®S2thi§z2l2r3z.2-a2pYrimidin32-carboxylic acid

Ethyl 1-oxo-1H-cyclooctenothiazolo (~ 3/2-a] pyrimidine-2-carb oxylate (1.23 g), together with 30 ml of 48% hydrogen bromic acid, was heated in an oil bath to 90 ° C for 4 hours. The reaction mixture was cooled, the pH adjusted to 1.5, and the reaction product extracted into ethyl acetate. The ethyl acetate extract was washed with water and then with saturated sodium chloride solution, dried over sodium sulfate and evaporated to an oil. dissolved in ethyl acetate and the reaction product extracted into 1N potassium hydroxide solution. The basic solution was acidified again with 3N hydrochloric acid and the reaction product extracted back into methyl acetate. The ethyl acetate solution was extracted with water and then dried over saturated sodium chloride solution.

DK 151811B

59 free sodium sulfate and evaporated to dryness to give 1-oxo-1H-cycloheptenothiazolo 3,2-a pyrimidine-2-carboxylic acid (308 mg, Rf 0.6 on silica gel thin layer chromatography with chloroform / 1% ethanol as eluent) .

EXAMPLE 55 1 ~ pxo-1H-7-methylthiazoloj ~ 3,2-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylate (3.1 g) was heated on a steam bath together with 50 ml of 48% hydrobromic acid. The solution occurred within 5 minutes. After approx. At 15 minutes of heating, the reaction mixture was cooled and the reaction product which precipitated was recovered by filtration. Recrystallization from acetic acid gave pure 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid 1.4 g; mp 265 ° C (decomposition).

Elemental Analysis for C

Calculated: C 45.71 - H 2.88 - N 13.33

Found: C 45.57 - H 3.04 - N 13.40.

EXAMPLE 56 1-Oxo2H-Thiazolo [3] 2-cipyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-thiazoloC3,2-alpyrimidine-2-carboxylate 20 (7.5 g) was heated on a steam bath for 20 minutes together with 80 ml of 48% hydrogen bromic acid. Dissolution occurred within 5 minutes and precipitation of a solid began a few minutes later. The reaction mixture was cooled in an ice bath and the crude product recovered by filtration. Purified 25-oxo-1H-thiazolo, 2-a-pyrimidine-2-carboxylic acid C C, 66 g, m.p. 276 ° C (decomposition)].

Elemental Analysis for C ^ H ^ O ^ I ^ S: DK 151811B: ✓ 60

Calculated: C 42.86 - H 2.06 - N 14.28

Found: C 42.71 - H 2.21 - N 14.32.

This acid may alternatively be prepared from the same intermediate by reflux heating in excess of 2N hydrochloric acid. Cellen et al., J. Org. Chem., 24, 779 (1959)].

EXAMPLE 57 µl of SSllSl ^ I ^ t ^ Ylthiazolo ^ S ^ -a ^ pyrimidine-2-carboxylic acid

Ethyl 1-oco-1H-6-methylthiazoloj3,2-a) pyrimidine-2-carboxylate (5.96 g) was heated on a steam bath for 1 hour with 10 60 ml of 48% hydrogen bromic acid. The reaction mixture was cooled in an ice bath and the crude product recovered by filtration, followed by washing with isopropyl alcohol and ether. Recrystallization of the crude product from dimethylformamide gave purified 1-oxo-1H-6-methylthiazoplo (3,2-a] pyrimidine-2-carboxylic acid [3.73 g, mp 246 - 248 ° C (decomposition).

Elemental Analysis for C

Calculated: C 45.71 - H 2.88 - N 13.33

Found: C, 45.87; H, 2.94; N, 13.47;

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

EXAMPLE 58

Il252ll5l§I®t ^ Yli ^ i§52l2i- = ii.-I-3EY £ iiSi§iSl2; carbgxylic acid Ethyl 1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate (12 , 6 g) was heated on a steam bath together with 125 ml of 48% hydrogen bromic acid. Resolution occurred within a few minutes. After 10 minutes, solid formation began. Heating continued for a total of 40 minutes.

DK 151811B

61

The reaction mixture was cooled and the crude product (10.1 g) recovered by filtration. Recrystallization of 2.32 g of crude product (out of 6.8 g recovered from a previous attempt of recrystallization from acetic acid) from iso-propyl alcohol gave purified 1-oxo-1H-6-ethylthiazole 3,2-a-pyrimidine-2 -carboxylic acid (1.85 g, mp 162 - 163 ° C).

Elemental Analysis for C

Calculated: C 48.21 - H 3.60 - N 12.49

Found: C 48.17 - H 3.73 - N 12.42.

EXAMPLE 59 1-Oxo-1H-7 - (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2

Ethyl 1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxylate (5.6 g) was heated on a steam bath for 6 hours together with 60 ml of 48% hydrogen bromic acid. After approx.

For 10 minutes, and before complete dissolution of the ester, the reaction mixture became very thick. At the end of the heating period, the reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from acetic acid and drying over dimethylformamide afforded purified 20 l-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid [3.33 g, mp 241 - 242 ° C (decomposition) J.

EXAMPLE 60 1-Oxo-1H-7-Ethylthiazolo 3,3-g-apyrimidine-1-carboxylic acid

Ethyl 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate (1.5 g) was heated on a steam bath together with 15 ml of 48% hydrogen bromic acid for 20 minutes. Within 5 minutes, solution, and after 10 minutes, solid precipitation began. After completion of the reaction time, the mixture was cooled to room temperature, diluted with ca.

DK 151811 B

62 25 ml of water and the crude product obtained by filtration.

The crude product was partially purified by dissolving in 1N potassium carbonate solution and re-precipitating by acidification with 3N hydrochloric acid.

Recrystallization from acetic acid gave purified 1-oxo-1H-7-ethylthiazolo (3,2-a] pyrimidine (594 mg, m.p. 206-209 ° C).

Elemental Analysis for C

Calculated: C 48.21 - H 3.60 - N 12.49 Found: C 48.01 - H 3.69 - N 12.50 EXAMPLE 61 1-Oxo-1H-V-isopropylthiazolof ^ -carboxylic

Ethyl 1-oxo-1H-7-isopropylthiazolo (3,2-ε ^ pyrimidine-2-carb oxylate (909 mg) was heated on a steam bath together with 10 ml of 48% hydrogen bromic acid for 20 minutes. Within 5 minutes-15 within 10 minutes, the reaction product began to precipitate. After the heating period, the reaction mixture was cooled to room temperature and the crude product recovered by filtration. Recrystallization from ethanol gave purified l-oxo-1H-7-isopropyl-20-pylthiazolo [3 2-a] pyrimidine-2-carboxylic acid (538 mg, mp 216 - 217 ° C).

EXAMPLE 62

Il ^^ lllSlZZhenhenhenhenhenhenhenhenhenhenhenhenhenhenhenhenhenhen ahenhen a a a a

Ethyl 1-oxo-1H-7-phenylcyclohexenothiazolo Q}, 2-a] pyrimidine-2-carboxylate (9.8 g) was heated under reflux with 200 ml of 48% hydrogen bromic acid for 20 minutes, during which solution occurred after 10 minutes. The reaction mixture was cooled and the crude product recovered.

DK 151811B

63 it by filtration. Recrystallization from acetic acid gave purified 1-oxo-1H-7-phenylcyclohexenothiazoloC3,2-a) pyrimidine-2-carboxylic acid (2.25 g, mp 224 - 226 ° C).

Elemental Analysis for C ^H ^^ OO₂S: Calculated: C 62.56 - H 4.32 - N 8.58

Found: C, 62.26; H, 4.11; N, 8.52

Another amount was obtained from the mother liquor. (704 mg, mp 217 - 220 ° C).

EXAMPLE 63 1-Oxo-1H-β-Methylcyclohexenothiazolo-β-alpha-pyrimidine

Ethyl 1-oxo-1H-7-methylcyclohexenothiazolo [3,2-pyrimidine-2-carboxylate (27.5 g) was heated on a steam bath for 35 minutes together with 275 ml of 48% hydrogen bromic acid. After 10 minutes, a clear solution appeared; after 15 minutes the precipitation of the reaction product began. The reaction mixture was cooled to room temperature and the crude product (14.9 g, mp 181.5 - 183.5 ° C) was recovered by filtration with subsequent washing. with water. Recrystallization from dimethylformamide afforded purified 1-oxo-20 H-7-methylcyclohexenothiazolo 05,2-a] pyrimidine-2-carboxylic acid (10.1 g, mp 183.5 - 185.5 ° C).

Elemental Analysis for C₂ 2H₂2N₂O 3S:

Calculated: C 54.53 - H 4.58 - N 10.60

Found: C 54.41 - H 4.28 - N 10.58.

Another amount was obtained by adding water to the dime thyl formamide mother liquor (3.11 g, mp 182 - 184 ° C).

EXAMPLE 64

DK 151811 B

64 izO ^ oziHlZ ^ Zz ^ i ^ i ^ YlcYclohexenothiazolo ^ S

Ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo 3,2-a3 pyrimidine-2-carboxylate (7/9 g) was mixed with 80 ml of 48% hydrogen bromic acid and heated on a steam bath for 50 ml. . Before the dissolution of the ester was complete, the precipitation of acid began. The reaction mixture was cooled, diluted with ca. 100 ml of water and the crude product (6.7) recovered by filtration, followed by washing with a small volume of water. Recrystallization of the crude product from ethanol gave purified 1-oxo-1H-7,7-dimethylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (4.7 g, m.p. 197 - 198 ° C).

Calculated C 56.10 - H 5.07 - N 10.06

Found: C 55.85 - H 4.84 - N 10.14.

EXAMPLE 65: ZZZZZZZZZZZZZZ? B £ Yii tazazole ojj-ajpyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-7- (2-butyl) thiazolo (3,2-a] pyrimidine-2-carb oxylate (2.0 g) was mixed with 20 ml of 48% hydrogen-bromic acid and heated on steam bath for 25 minutes. Solution occurred within 5 minutes; precipitation of the reaction product began within 10 minutes. The reaction mixture was cooled to room temperature, diluted with about 40 ml of water, and the crude product (1.3 g, m.p. 191 - 194). 25 ° C) recovered by filtration followed by washing with a small volume of water. Recrystallization of the crude product from ethyl acetate containing a small amount of ethanol gave purified 1-oxo-1H-7- (2-butyl) thiazolo [3 2-aJ pyrimidine-2-carboxylic acid (606 mg, mp 194 - 197 ° C).

DK 151811 B

65

Elemental Analysis for C ^^ HH ^₂N₂®3S:

Calculated: C 52.37 - H 4.79 - N 11.10

Found: C, 52.20; H, 4.48; N, 11.11

The ethyl acetate mother liquor was concentrated to give a slightly different amount.

EXAMPLE 66 N- 5-Tetrazolyl-1-oxo-1H-6'-dimethyl thiazoloyl] -α- -EYIIIilyl-carboxamide 1-oxo-1H-6,7-dimethylthiazolo Q, 2-aJ pyrimidine-2 carboxylic acid (367 mg, 1.6 mmol) was dissolved in 3 ml of dimethylformamide by heating on a steam bath. 1,1-carbonyldiimidazole (292 mg, 1.8 mmol) was added. There was an instant evolution of gas. As soon as gas evolution ceased, 5-aminotetrazole (153 mg, 1.8 mmol) was added. Dissolution occurred and a new solid formed. The reaction mixture was cooled and the crude product recovered by filtration. Recrystallization of the crude product from dimethyl formamide gave purified N- (5-tetrazolyl) -1-oxo-1H-6,7-dimethylthiazolo 3,2-a) pyrimidine-2-carboxamide (336 mg, m.p.> 317 ° C ).

Elemental Analysis for C ]qHH ° °N7S:

Calculated: C 41.23 - H 3.11 - N 33.66 Found: C 41.52 - H 3.40 - N 33.47 Example 67

N1S-tetrazolyl-1-oxo-1H-3-methyl-V-ethylthiazolo [beta] PY 2 -in-1-beta-carboxamide 1-oxo-1H-6-methyl-7-ethylthiazolo [2-a] pyrimidine-2-carboxylic acid (238 mg, 1.0 mmol) was dissolved in 5 ml of dimethylformamide and heated on a steam bath. 1.1'-

DK 151811B

66 carbonyl diimidazole (178 mg, 1.1 mmol). When gas evolution ceased, 5-aminotetrazole (93.5 mg, 1.1 mmol) was added.

After approx. Within 15 minutes, a solid began to precipitate. The reaction mixture was cooled and filtered to give N- (5-tetrazolyl) -1-oxo-1H-6-methyl-7-ethyl-thiazolo [3,2-a] pyrimidine-2-carboxamide (227 mg, mp> 310 ° C).

Elemental Analysis for cnHn ° 2N7S:

Calculated: C 43.27 - H 3.63 - N 32.11 Found: C 43.20 - H 3.72 - N 31.88.

EXAMPLE 68 N - (53Tetrazolyl2) -1-oxo-1H-6-ethyl-73-methylthiazolo-E ^ i -α-pyrimidine-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 1,1'-dicarbonylimidazole (357 mg, 2.2 mmol); After gas evolution had ceased, 5-aminotetrazole (187 mg, 2.2 mmol) was added and a solid formed over a few minutes, the reaction mixture was cooled and the crude product recovered by filtration. dimethylformamide afforded purified N- (5-tetrazolyl) -1-oxo-1H-6-ethyl-7-methylthiazolo (3,2-α ^-pyrimidine-2-carboxamide 388 mg, mp 303 ° C (decomposition)).

Elemental Analysis for cnHn ° 2N7 +:

Calculated: C 43.3 - H 3.6 - N 32.1

Found: C 43.6 - H3.9 - N 32.3.

Example 15

N11β-tetrazolyl) -7ΟΧΟ-ΙΗ-6,7-diethylthiazolo, 2-a] -EYEiSiSli-carboxamide 1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxyl Acid (2.52 g, 10 mmol) and 1,1'-carbonyldiimidazole (1.78 g, 5 11 mmol) were combined with 15 ml of dimethylformamide and heated on a steam bath. Gas evolution and formation of a solution occurred. After gas evolution had ceased, 5-aminotetrazole (1.13 g, 11 mmol) was added and heating was continued for 30 minutes. The reaction mixture was cooled and the precipitated crude product recovered by filtration. Recrystallization of the crude product from acetic acid gave purified N- (5-tetrazolyl) -1-oxo-1H-6,7-diethyl-thiazolo (3/2-a] pyrimidine-2-carboxamide [1.1 g, m.p. 283 ° C (decomposition)].

Elemental Analysis for C₂ 2H ^ °₂NSS:

Calculated: C 45.13 - H 4.10 - N 30.70; mass ion, 319.

Found: C 45.18 - H 4.24 - N 30.52; Massion, 319 EXAMPLE 70 ΐ! ΐί§ΐί§ί £ §52ΐΥΐ1ΐΙΐ252ΐΐ5ΐ2Υ2ΐ2Ε§ί} ϊβηο ^ ϊιϊ§ζο1ο] _3 ^ 2-η] _- EYii ^ idin ^ -carboxamide 20 1-oxo-1H-cyclopentenothiazolo [3.2 -α] pyrimidine-2-carboxylic acid (378 mg, 16 mmol) and 1,1'-carbonyldiimidazole (285 mg, 17.6 mmol) were combined with 3 ml of dimethylformamide and heated in a steam bath; that occurred dissolution and gas evolution. After cessation of gas evolution, 5-aminotetrazole (150 mg, 17.6 mmol) was added. Within a few minutes, the reaction product began to precipitate. The reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from dimethylformamide gave purified N- (5-tetrazolyl) -1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-car ~ 68

DK 151811B

boxamide (313 mg, m.p.> 310 ° C).

Elemental Analysis for C ^H ^C CN ^S:

Calculated: C 43.6 - H3, o - N 32.3

Found: C 43.6 - H3.3 - N 32.0 EXAMPLE 71 5 "tetrazolyl] -1- oxo-1H-cyclohexenothiazole [10 oarboxamide 1-oxo-1H-cyclohexenothiazolo [3,2-aT] pyrimidine-2-carboxylic acid (0.5 g, 2 mmol) and 1,11-carbonyldiimidazole (0.36 g, 2.2 mmol) were dissolved in 3 ml of dimethylformamide at room temperature, dissolution and gas evolution occurred, and when the gas evolution ceased, the reaction mixture was heated on a steam bath, during which a further gas evolution occurred, to the hot solution was added 5-aminotetrazole (0.19 g Within a few minutes, the reaction product began to precipitate. The reaction mixture was cooled and the dry product recovered by filtration. Recrystallization of the crude product gave purified N- (5-tetrazolyl) - 1-oxo-1H-cyclohexenothiazolo [3,2-a) pyrimidine-2-carboxamide 0319 mg, mp 310 ° C (decomposition)

Elemental Analysis for C ^H-qC ^N ^S:

Calculated: C 45.42 - H 3.49 - N 30.90

Found: C 45.59 - H 3.62 - N 30.44.

Alternatively, the acid (2.27 g was dissolved in 40 ml of methylene chloride and 1.74 ml of triethylamine at 0 ° C. Over 20 25 minutes, ethyl chloroformate (0.85 ml) was added to 8.1 ml of methylene chloride while the temperature of the reaction mixture was After maintaining the reaction mixture at 0-5 ° C for 45 minutes, 5-amino-tetrazole (0.87 g) was added in 8.1 ml of dimethylacetamide and the reaction mixture heated. to 20 ° C over 25 minutes

DK 151811B

69 and maintained at this temperature for 90 minutes. The product was recovered by filtration (2.0 g, mp 308 -310 ° C). The product thus prepared (3.9 g) was recrystallized from dimethylacetamide to give 5 purified N- (5-tetrazolyl) 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide (3 , 1 g, m.p. 314 - 315 ° C).

The sodium salt of this amide was prepared by dissolving 5.5 g (17.3 mmol) of the amide in 44 ml of water and 17.3 ml (17.3 mmol) of standard 1N sodium hydroxide solution at 10 stirring for 30 minutes (pH 11.0 ). The solution was clarified and the sodium salt precipitated by the addition of 35 ml of acetone. The slurry was cooled to 5 ° C, granulated for 3 hours, and the sodium salt (4.9 g) was recovered by filtration followed by washing with cold acetone. This sodium salt (100 mg) slurried in 1 ml of water) had a pH of 10.22. The sodium salt was 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 over 1 hour and granulated at this temperature for 1 hour. The sodium salt (1.68 g) was recovered by filtration. The pH of 100 mg of recrystallized sodium salt in 1 ml of water was 8.80.

Analysis for c12 H10 ° 2N7SNa

Calculated: H00 13.7; weight loss on drying 13.7; Neutralization number 393

Found: H 2 O, 3.43; weight loss on drying 13.8; neutralization number 391.

In the mixed anhydride process described above, equivalent amounts of methyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, tert-butyl chloroformate, pentyl chloroformate, phenyl chloroformate or benzyl chloroformate can be used.

DK 151811 B

70 ethyl chloroformate to obtain substantially similar results. Similarly, equivalent amounts of the other acids mentioned in Examples 47 to 65 are reacted with chloroformates and then further with 5 5-aminotetrazole to form the corresponding N- (5-tetrazolyl) amides.

EXAMPLE · 72

N11S ^ tetrazolyl-1-oxo-1H-cycloheptenothiazoloQi ^ -a ^ -__ EYEiiDi ^ iS1 ^ -carboxamide 1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (2, 1 g, 8 mmol) and 1,1'-carbonyl diimidazole (1.4 g, 8.8 mmol were combined with 15 ml of dimethylformamide and heated in a steam bath. After gas evolution had ceased, 5-aminotetrazole monohydrate (0.86 g, 8.8 mmol). Within 5 minutes, a solid formed. After a further 15 minutes heating, the reaction mixture was cooled and reaction products recovered by filtration. Recrystallization of the crude product from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-cycloheptenothiazolo (3,2-a] pyrimidine-2-carboxamide Q, 61 g mp 295 - 296 ° C (decomposition) j].

Elemental Analysis for C ^H ^O₂N ^S:

Calculated: C 47.12 - H 3.95 - N 29.59

Found: C 47.10 - H 4.11 - N 29.72.

EXAMPLE · 73 N- [S-Tetrazolyl] -1-oxo-1H-cyclooctenothiazolofs-g-al · -25 EY-15 [11S] -2-carboxamide 1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxyl Acid (308 mg, 1.1 mmol) was dissolved in 10 ml of dimethylformamide and heated on a steam bath. 1,1'-Carbonyldiimidazole (196 mg, 1.21 mmol) was added. After the gas evolution was

DK 151811B

71 stopped, 5-aminotetrazole (103 mg, 1.21 mmol) was added. The reaction mixture was heated for 10 minutes during which a solid began to precipitate. The reaction mixture was cooled and the crude product was recovered by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-cyclooctenothiazolo (3,2-a] pyrimidine-2-carboxamide 183 mg, (m.p. 310 ° C (decomposition G)

Elemental analysis for c14 H; [502 N7 S: 10 Calculated: C, 48.69; H, 4.38; N, 28.39

Found: C 49.01 - H 4.63 - N 27.35 EXAMPLE 74 N- [5-Tetrazolyl2-130XO-1H-7-methylthiazolo C3-2-a] pyrimidin-1S1a-carboxamide 1-oxo-1H -7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid 15 (0.91 g 4.3 mmol) and 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol) were placed in 5 ml of dimethylformamide and heated. on the steam bath. After gas evolution had ceased, 5-aminotetrazole (0.47 g, 5.5 mmol) was added. Before complete dissolution was achieved, a new solid began to precipitate.

After a few minutes, the reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxamide (1.0 g, m.p.> 310 ° C).

Elemental Analysis for CgH₂O₂N₂S:

Calculated: C, 38.99; H, 2.54; N, 35.36

Found: C, 38.97; H, 2.73; N, 34.97. Example 75

Nzi5-tetrazolyll-l-oxo-lH-thia.zoloC3i2-aJ_pYrimidi.n-2-

DK 151811 B

72 1-Oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid (1.96 g, 10 mmol) was dissolved in 20 ml of dimethylformamide on a steam bath.

1,1'-Carbonyldiimidazole (1.78 g, 11.0 mmol) was added.

After gas evolution had ceased, 5-aminotetrazole monohydrate (1.13 g, 11 mmol) was added. In less than 1 minute 5 a solid formed. After heating for a further 15 minutes, the reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-thiazolo- (3,2-a] pyrimidine-2-carboxamide (1.8 g, m.p.> 315 ° C).

Elemental Analysis for C CHj-C ^N ^S: i

Calculated: C 36.50 - H 1.91 - N 37.25 1

Found: C 36.62 - H 2.26 - N 37.72.

EXAMPLE 76 µl-Tetrazolyl-1-oxo-1H-e-methylthiazolo [g] pyrimidinyl] arboxamide 1-oxo-1H-6-methylthiazolo (3,2-a] pyrimidine-2-carboxylic acid (2.10 20 g, 10 mmol) and 1,11-carbonyldiimidazole (1.78 g, 11 1 mmol) were combined with 15 ml of dimethylformamide and heated in a steam bath, followed by gas evolution, and then dissolution was added. -aminotetrazole monohydrate (1.13 g, 11 mmol). In less than 1 minute a solid formed. After 5 minutes of heating, the reaction mixture was cooled. Filtration gave N- (5-tetrazolyl) -1-oxo-1 6-methylthiazolo [3,2-a] pyrimidine-2-carboxamide (2.33 g, m.p.> 318 ° C).

Elemental Analysis for CgH2 O2N7S:

Calculated: C, 38.99; H, 2.54; N, 35.36

Found: C 39.35 - H 3.00 - N 35.06.

DK 151811 B

EXAMPLE 77

Nli5-Tetrazolyl | -1-Oxo2HH-6-Ethylthiazolo C1-6a ^ gyrimi-olyl ^ icarboxamide

1-oxo-1H-6-ethylthiazolo [3/2-aj pyrimidine-2-carboxylic acid (4.48 g 20 mmol) and 1,1'-carbonyldiimidazole (3.57 g, 22 5 mmol) were combined with 30 ml of dimethylformamide and heated on a steam bath. Gas evolution and dissolution occurred. After gas evolution had ceased, 5-aminotetrazole monohydrate (2.27 g, 22 mmol) was added. A solid formed within 1 minute. The reaction mixture was heated for a further 15 minutes, cooled, and the crude product recovered by filtration. Recrystallization from dimethyl formamide gave pure N- (5-tetrazolyl) -1-oxo-1H-6-ethylthiazolo (3,2-a] pyrimidine Γ 4.7 g, mp 274 ° C

(decomposition) J.

Elemental Analysis for c10H902N7S;

Calculated: C, 41.23; H, 3.11; N, 33.66

Found: C, 41.41; H, 3.30; N, 33.84.

EXAMPLE 78

Nis-tetrazolyll-1-oxo-1H 2 -g ^ 3-methyl-g-propyl-1-thiazolo ^ E [β, 2 ~ eel pyrimidine-2-carboxylic acid (2.52 g, 10 mmol) and 1,1'-carbonyldiimidazole (1.78 g, 11 mmol) were combined with 15 ml of dimethylformamide and heated in a steam bath. Gas evolution and dissolution occurred and within a few minutes a solid formed. The heating continued in total for approx. 10 minutes. The reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from dimethyl formamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7- (2-methyl-2-propyl) -thiazolo [3,2-a] pyrimidine-2-carboxamide [IF62, m.p. 280 ° C (decomposition)].

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74

Element analysis for

Calculated: C 45.13 - H 4.10 - N 30.70

Found: C 45.22 - H 4.40 - N 30.05.

EXAMPLE 79 2-Carboxamide 5 1-Oxo-1H-7-Ethylthiazolo (3,2-a3 pyrimidine-2-carboxylic acid (502 mg, 2.24 mmol) and 1,1'-carbonyl diimidazole (399.7 mg, 2 46 mmol) was combined with 3 ml of dimethylformamide and heated in a steam bath, dissolution and gas evolution occurred, and after the gas evolution ceased, 5-10 aminotetrazole monohydrate (253.0 mg, 2.45 mmol) was added to give a clear solution. After 2 minutes, a solid began to precipitate, the mixture was heated for an additional 20 minutes, cooled to room temperature, and the crude product recovered by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo -H-7-ethyl-thiazoloC3,2- J -pyrimidine-2-carboxamide (48 486.8 mg, mp 261 - 262 ° C (decomposition) 3)

Elemental Analysis for C ^H ^N NC ^S:

Calculated: C, 41.23; H, 3.11; N, 33.66; Found: C, 41.35; H, 3.31; N, 33.55; mass ion 291.

EXAMPLE 80 ϊ? Ϊ́ί5ζ £ §έ £ §52ΐγ11ΐΙΐ252ΐ1ίίζΖζΐ§22 £ 2ΕΥΐίίΐΐ§52ΐ2Γ2ζ.2; §] _ργΓΪ- nfi ^ i (537 mg, 2.25 mmol) and Ι, Ι'-carbonyldimidazole (401 mg, 2.47 25 mmol) were combined with 3 ml of dimethylformamide and heated in a steam bath. Dissolution and gas evolution occurred. After gas evolution had ceased, 5-aminotetrazole monohydrate (255 mg, 2.47 mmol) was added. Precipitation of reaction pro- 75

DK 15181TB

the product began immediately thereafter. The heating was continued for 20 minutes, after which the reaction mixture was cooled and the crude product recovered by filtration. Recrystallization from dimethylformamide gave pure N-5 (5-tetrazolyl) -1-oxo-1H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxamide (328 mg, m.p.> 300 ° C).

Element Analysis for:

Calculated: C, 43.27 - H, 3.63 - N, 32.11

Found: C, 43.34; H, 3.76; H, 31.82.

EXAMPLE 81 N- [5-Tetrazolyl) -1-oxo-1H-7-ghenylcyclohexenothiazolo- [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-7-phenylcyclohexenothiazolo (3,2-a] | pyrimidine-2-carboxylic acid (980 mg, 3.0 mmol) and 1,1'-carbonyldiimidazole (320 mg, 3.1 mmol) were combined with 12 ml of dimethylformamide and the mixture was heated in a steam bath. after gas evolution had ceased, 5-aminotetrazole monohydrate (496 mg, 3.1 mmol) was added. After 10 minutes, the reaction product began to precipitate. After a total heating time of 1 hour, the reaction mixture was cooled to room temperature and the crude product (312 mg) recovered by filtration Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7-phenylcyclohexenothiazolo (3,2-aj-pyrimidine-2-carboxamide (131.5 mg, m.p. > 300 ° C).

Elemental Analysis for 5 ^ 2 ^ 7 ^: 25 Calculated: C 54.95 - H 3.84 - N 24.92

Found: C, 54.38; H, 3.93; N, 24.61.

EXAMPLE 82 N- 5-Tetrazolyl2-1-oxo-1H-22methylcyclohexenothiazolo pyrimidine-2-carboxamide

DK 151811B

76 1-Oxo-1H-7-methylcyclohexenothiazolo [β, 2-a) pyrimidine-2-carboxylic acid (1.0 g, 3.78 mmol) and 1,1'-carbonyl diimidazole (675 mg, 4.16 mmol) ) was combined with 6 ml of dimethylformamide and heated on a steam bath. Gas evolution 5 occurred and dissolution occurred. After gas evolution had ceased, 5-aminotetrazole (429 mg, 4.16 mmol) was added and heating was continued. After a few minutes, a precipitate began to form. After 30 minutes, the reaction mixture was cooled and the crude product (m.p.> 300 ° C) recovered by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7-methylcyclohexenothiazolo (β, 2-a] pyrimidine-2-carboxamide (980 mg, m.p.> 300 ° C).

Elemental Analysis for C 13 H 33 ° 2 N 7 +: Calculated: C 47.12 - H 3.95 - N 29.59

Found: C 47.32 - H 4.18 - N 29.60.

EXAMPLE 83

Millisetetrazolyl2-1-oxo-1H-7,7-dimethylcyclohexenothiazolo- (3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-7,7-dimethylcyclohexenothiazolo (3,2-gJ pyrimidine-2-carboxylic acid ( 558 mg, 2.0 mmol) and 1,1'-carbonyldiimidazole (357 mg, 2.2 mmol) were combined with 3 ml of dimethylformamide and heated in a steam bath. Gas evolution occurred and a solution occurred. After quenching, 5-aminotetrazole monohydrate (227 mg, 2.2 mmol) was added and heating was continued for 20 minutes. The reaction mixture was cooled and the crude product (561 mg, m.p.> 300 ° C) recovered by filtration. -amide gave pure N- (tetrazolyl) -1-oxo-1H-7,7-dimethylthiazolo- (3,2-a] pyrimidine-2-carboxamide (469 mg, m.p.> 300 ° C).

30 Element Analysis for

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77

Calculated: C 48.69 - H 4.38 - N 28.39

Found: C, 48.80; H, 4.18; N, 28.42.

EXAMPLE 84 N- [5-Tetrazolyl] -1-oxo-1H-7 - [(2-butyl2thiazolo [3,3,2-a]) - -butyl) thiazoloic acid, 2-a) pyrimidine-2-carboxylic acid (379 mg, 1.5 mmol) and 1,1'-carbonyldiimidazole (270 mg, 1.66 mmol) were combined with 3 ml of dimethylformamide and heated on Steam. Gas evolution occurred and a solution occurred. After gas evolution was complete, 10 5-aminotetrazole monohydrate (170 mg, 1.65 mmol) was added and the mixture, which began to precipitate after a few minutes, was heated for 20 minutes. The reaction mixture was cooled to room temperature and the crude product recovered by filtration. Recrystallization gave pure N- (5-15 tetrazolyl) -1-oxo-1H-7- (2-butyl) -thiazolo [β, 2-aj pyrimidine (247 mg, m.p.> 300 ° C).

Elemental Analysis for C

Calculated: C 45.13 - H 4.10 - N 30.70

Found: C 45.12 - H 4.05 - N 30.68.

Claims (3)

An analogous process for the preparation of N- (5-tetrazolyl) -1-oxo-1H-thiazolo [[3,2-a] pyrimidine-2-carboxamides of the general formula: R 1 ) In wN if h \ r - n H 5 wherein and R 2 together represent the (C 1 -C 6) alkyl or (C 6 -C 9 phenylalkyl, where the ring system thus formed is 5- to 8-membered, or R 2 and R 2 each represents hydrogen or (C 1 -C 4) alkyl, or pharmaceutically acceptable cation salts thereof, characterized in that (a) a compound of the formula: R 1 -, - S ΓΊ I. R 2 and R 2 have the above meaning, reacted with at least one equivalent of 5-aminotetrazole under the influence of at least one equivalent of a dehydrating coupling agent at a temperature of 20-110 ° C in an inert organic solvent, or (b) a compound of formula II is reacted with about one equivalent of a compound of formula: 0 "(III) C 1 -C-R 5 wherein R is (C 1 -C 4) alkyl, benzyl or phenyl, in the presence of at least one equivalent of a tertiary a min at a temperature of from -40 to 25 ° C in a reaction inert organic solvent to form a solution of a compound of the formula: R 1'd X 2 O 2 C 2 Or-C-OR 10 wherein R 2, R 2 and R has the above meaning in which this solution is reacted with about an equivalent of 5-aminotetrazole at from -40 to 40 ° C in the same or a similar reaction-inert organic solvent, to which the compound of formula I, if desired, is transferred in a pharmaceutically acceptable cation salt thereof. Process according to claim 1, characterized in that R 1 and R 2 together are butylene. Process according to claim 1, characterized in that R 1 is ethyl and R 2 is hydrogen. DK-151811 B 4. 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acids for use as a starting material in the process according to claim 1, characterized in that they have the general formula: R-i_ c Π E, Wherein R and R are as defined in claim 1 except that R cannot be hydrogen or methyl when R is hydrogen.