FI67706B - FORM OF THERAPEUTIC PREPARATION OF THERAPEUTIC N-5-TETRAZOLYL) -1-OXO-1H-THIAZOLO (3,2-A) PYRIMIDINE-2-CARBOXYL ATR - Google Patents

Description

ν '1 67706

The present invention relates to novel 1-oxo-1H-thiazolyls, 3, 2-α7'-pyrimidine-2-carboxamides, and to a process for the preparation of therapeutically useful N- (5-tetrazolyl) -1-oxo-1H-thiazolyl. Derivatives of 2- [7-pyrimidine-2-carboxamides. These amides are useful as inhibitors of the release of allergic mediators (histamine, serotonin, SRS-A, etc.) and therefore can be used to treat asthma, hay fever, catarrh, hypersensitivity rashes, etc., and are also useful in the treatment of gastric ulcer. inhibitory substances.

Allergic reactions resulting from antigene-antibody interactions occur in very different ways and in different organs and tissues. Common allergic diseases include, for example, allergic nasal congestion, a condition characterized by seasonal or recurrent sneezing, runny nose, congestion in the nose with itching, and bleeding in the eyes; hay fever, a variant of an allergic 20 nasal catheter due to hypersensitivity to hay pollen; and asthma, one of the most allergic reactions to disability and weakness, a disease characterized by a bronchial hypersensitivity reaction to various immunogenic or non-immunogenic stimuli that cause bronchospasm, shortness of breath and shortness of breath. Mechanical obstruction of the airflow in the airways is usually counteracted by the use of bronchodilators to alleviate the symptoms. In contrast, antiallergic agents prevent the release of anaphylaxis mediators from tissue stores, thus having a prophylactic effect in preventing the development of bronchospasm caused by the mediators.

35 Cox et al., Adv. in Drug Res., 5, 115 (1970), have described the pharmacology of disodium cromoglycate ε-β, 3-bis (2-carboxy-chromon-5-yloxy) -2-hydroxypropane, Inta] j7.

2 67706

It is not a bronchodilator, but its therapeutic effect is based on the prevention of the release of mediators of anaphylaxis, and thus acts as a prophylactic agent. Its disadvantage is ineffectiveness when administered orally; to achieve optimal-5 results, it is administered as a solid inhalable drug.

Recently, various other antiallergic agents have been reported, including N- (5-tetrazolyl) -1-oxo-1H-6-alkoxypyrimido [1,2-a] quinoline-10 2-carboxamides (U.S. Patent 4,017,625). , 1-oxo-ΙΗ-6-substituted-pyrimido-1,2-quinoline-2-carboxylic acid (U.S. Patent 4,066,766), tetrazolo [e] quinazol-5-one (U.S. Patent 4,085,213), pyrimido-2-carboxylic acid , 1-α7isoquinolines (U.S. Patent 4,127,720), and N- (5-tetras-15-soyl) -4-oxo-4H-pyrimido [2,1-b] benzothiazole-3-carboxamides ( U.S. Patent 4,041,163).

Chronic gastric and duodenal ulcers, known collectively as peptic ulcers, are the general trial, which is developed to remove the 20 different treatment methods. Treatment depends on the severity of the wound and can range from diet and medication to surgery. A wide variety of drugs have been used to treat gastric ulcers; one of the most recent is carbenoxolone sodium, which is the disodium salt of glycyrrhetinic acid hemisuccinate. It is reported to prevent the formation of stomach ulcers and to heal them. ("Carbenoxolone Sodium; A Symposium", J. M. Robson and F. M. Sullivan, Eds., Butter-worths, London, 1968). However, its use is associated with unwanted aldosterone-like side effects, such as a marked anti-urinary and sodium-retaining effect and, often, potassium loss, so continued treatment with this substance often causes hypertension, muscle weakness and, ultimately, congestive heart failure. The drug is a recently introduced histamine receptor antagonist, cimetidine, which relieves gastric ulcers by reducing gastric acid secretion.

3 67706

Various other compounds have been reported to have antiulcer activity; these include, for example, 1-oxo-1H-6-piperino-pyrimidino [1,2-a] quinoline-2-carboxylic acid ester (U.S. Patent 4,014,881), 1-oxo-1H-6-substituted-pyrimido [1,2-a] quinoline-2-carboxylic acids and esters (U.S. Patent 4,031,217), tetrazolo-Za7 quinazol-5-ones (U.S. Patent 4,085,213).

The invention relates to a process for the preparation of therapeutically useful N- (5-tetrazolyl) -1-oxo-1H-thiazolo [3,2-b] pyrimidine-2-carboxylates of the formula

Rl -, - S

il l 15 o

r / N— N

20 | H X N -

B

wherein R 1 and together represent alkylene of 3 to 9 carbon atoms or phenylalkylene of 9 to 11 carbon atoms, provided that the ring system thus formed is 5 to 8 members; and R 1 and R 2 alone are each hydrogen or alkyl of 1 to 5 carbon atoms.

The process according to the invention is characterized in that (a) a compound of formula V__.

JT 1 D (II)

35 2 AA

0 J

Wherein R 1 and R 2 are as defined above, is reacted with at least one equivalent of 5-aminotetrazole under the action of at least one dehydrating coupling agent equivalent at 20-110 ° C in an inert organic solvent, or (b) a compound which is of formula (II) wherein and R 2 are as defined above are reacted with about one equivalent of a compound of formula

II

C1-C-R (III) wherein R is alkyl, benzyl or phenyl, in the presence of at least one tertiary amine equivalent at -40 to + 25 ° C in a reaction-inert organic solvent to form a compound of formula

Il l

z0 R NN

I! (IV)

^ C

25 ° C-OR

wherein R 1, R 9 and R 2 are as defined above, and then the compound obtained is reacted with about one equivalent of 5-aminotetrazole at -40 to + 40 ° C in the same or another similar reaction-inert organic solvent.

The mildly prepared amides of this invention and most of the intermediates are novel compounds. Known are acids of formula II wherein R 1 and R 2 are hydrogen or R 1 is methyl and R 2 is hydrogen / Dunwell et al., J. Chem. Soc. (C), 5 67706 19 71, 20947. Corresponding ethyl esters are also known, as is an ethyl ester having methyl and R 2 is hydrogen / Dunwell et al., J. Chem. Soc. , (C) 1971, 2094; Allen et al., J. Org. Chem. 24, 77 9 (19 5 9 17.

The compounds of formula I may also be in the form of pharmaceutically acceptable cationic salts, for example as alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts; aluminum salts; ammonium salts; And salts with organic bases, e.g. with amines such as triethylamine, tributylamine, piperidine, triethanolamine, diethylaminoethylamine, N, N'-dibenzylethylenediamine and pyrrolidine.

5-Substituted tetrazoles can exist in two isomeric forms, namely:

.N -— N N === N

// I

-C -C.

2 0 \ *

N ----- N N ----- N

k which occur as a dynamic tautomeric, equilibrium mixture. Both forms of tetrazolylamides are included within the scope of this invention.

Of particular interest are the compounds of this invention are those compounds of formula (I) wherein R 1 is hydrogen or methyl and R 2 is methyl. Of these, the most preferred is a compound wherein R 1 is hydrogen because the corresponding acid, which is believed to be its metabolite, is also active. Also preferred are compounds wherein R 1 and R 2 together correspond to propylene, butylene or pentylene. Particularly preferred is a compound wherein R 1 and R 2 together correspond to butylene, i. N- (5-tetrazolyl) -1-oxo-1H-cyclohexenithiazole-35 Solo [3,2-a] pyrimidine-2-carboxamide (Formula IA) 6 67706 Πγί

s ° * V

Ν-Ν

0 m <J

Η 10 (ΙΑ) because it has an excellent effect when administered orally and is very stable in the pure state, as well as in the presence and solution of normal pharmaceutical diluents. In addition, the activity of its metabolite (corresponding carboxylic acid) is good. The compound of formula IA is preferably in the form of a sodium salt (trihydrate) which is non-hygroscopic and has good solubility in water.

7 67706 The compounds of this invention are prepared by the following routes:

Rl \ _S y0C2Ei Δ 5 IS a ΐ | + (R3OOC) C = r ->

R2 NH

z 2 10 5 1S | R 1 | 6 5 ^ ___S 3 il 175-250 ° C ^ A, 1n R '\ \ - ^ R0, 4, 2T NH 11 2 d? R3 ciy

IS / CH

lb ^ \ ^ 0 ^ \ OR0 O 3 i 0 ^ 'Nttg d H, H20 20 \ /

Rn \ / N_N

nnf h2n- ^ i 25 r / N> n n n 1 "h, 6 5® U 2 A Η IL 7 i <hf

t N__N L 2 3 I

D ^ dehydrating \ M M / coupling 3o I ^:] c H or y \ via mixed anhydride ^ 8 67706

In the first step of the synthetic sequence, the appropriately substituted 2-aminothiazole is condensed with a stoichiometric amount of dialkyl ethoxymethylene malonate; readily available diethyl 5-ethoxymethylene malonate is usually used, in which case the choice of ester is not decisive for the yield of the final products according to the invention. The condensation is performed at a temperature of about 80 ° C to about 125 ° C. Lower temperatures are not desirable because the reaction then takes place too slowly. Higher temperatures can be used, but they do not appear to offer any advantages. Thus, the reaction is conveniently carried out in the molten state.

It can, of course, be carried out in a solvent or mixture of solvents; for example in ethanol, N, N-dimethyl-formamide, acetonitrile. However, for practical reasons, the solvent seems 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 2 together form a ring system, the 20 nomenclature and numbering system have been modified as follows: 25 cyclopentenothiazole Cyclohexenothiazole „CU Q>

3 0 N ^ —Zf ‘J

Cycloneptenothiazole Cyclooctenotes sol 9 67706

The second step in the series is the cyclization of 4- and / or 5-substituted-2- (2,2-dicarbalkoxyethenylamino) thiazoles to eliminate one equivalent of alkanol (ethanol in the case of ethyl ester). In one process, this cyclization is performed by heating the intermediate at about 17-250 ° C until the reaction is substantially complete, usually within about one to two hours. The cyclization is preferably carried out by heating the intermediate in a suitable reaction-inert diluent; i. in a medium which allows the reaction temperature to be controlled, is stable at relatively high temperatures and does not react with the starting material or cyclization products. Suitable diluents include high boiling hydrocarbons such as perhydronaphthalene, mineral oil, diethylbenzene, acetic anhydride containing sulfuric acid, diphenyl ether and diphenyl, especially a mixture containing 26.5% diphenyl and 73.5% diphenyl ether and sold commercially.

Alternatively, the cyclization is performed under milder conditions (70-130 ° C) by heating the intermediate in the presence of excess (1.1-3 equivalents) of trifluoroacetic anhydride in an inert solvent such as toluene until the reaction is complete (e.g., boiling toluene for 15-20 hours). -mislämpötilassa). In both methods, the products of the cyclization step are alkyl-1-oxo-1H-6- and / or -7-substituted-thiazolo [3,2-d] pyrimidine-2-carboxylates.

It should be noted that when R ^ and together form a ring system, the following designations and numbering systems are used: 10 67706 \ <VS 'TV3

\ β / 5 V / '5 V

N) N V 'k 2) N, N-oxo-1H-cyclopenteno-1-oxo-1H-cyclohexenothiazolo [2,3-a] pyrimidine thiazolo [2,3] -a / pyrimidine

Ox oAji 15 1-Oxo-1H-cyclohepteno-1-oxo-1H-cyclooctenothiazolazo [2,3-a] pyrimidine thiazolo [3,2-a] pyrimidine 1-oxo-1H-cyclohexenothiazole / , 2-α7-pyrimidines are alternatively designated as 6,7,8,9-tetrahydro-1-oxo-1H-pyrimidinoZ_2,11β benzotes, or using an alternative numbering system, 5,6,7,8, - to tetrahydro-4-oxo-4H-pyrimido [2,2-b] benzothiazoles.

It will be appreciated that the condensation and cyclization steps can be performed in a single operation without the need to isolate the intermediate 2- (2,2-carbalkoxyethenyl-25-amino) thiazole, either by using a sufficiently high reaction temperature to perform both condensation and cyclization, or by condensation. as described above, followed by the addition of an inert solvent (if not already present) and the addition of an excess of trifluoroacetic anhydride (2.1-4 equivalents) and continuing with the cyclization step.

The preferred method includes the separate condensation and cyclization steps described above.

11 67706

Isolation of the intermediate and purification prior to cyclization generally results in a better quality cyclized product.

The esters obtained by the condensation / cyclization procedures described above are then hydrolyzed to the corresponding 1-oxo-1H-6- and / or 7-substituted-thiazolo [3,2-a] pyrimidine-2-carboxylic acids. (Note the designations and modified numbering systems described above when and R2 together form a third ring). Acid catalyzed hydrolysis is the most suitable method. Particularly preferably, the ester is heated to reflux in 48% hydrobromic acid until the hydrolysis is complete (0.5-3 hours is generally a satisfactory time). If foaming causes problems, the hydrolysis can be performed at a slightly elevated pressure, e.g. 48 kPa at 85 ° C.

The N- (5-tetrazolyl) amides of this invention are conveniently prepared by coupling acids to the 5-aminotetrazole base by cleavage of water. The cleavage by water cleavage is performed with the aid of a wide variety of substances commonly used in peptide syntheses. Typical such substances are Ν, Ν'-carbonyldiimidazole, N, N 1-carbonyldi-s-triazine, ethoxyacetylene, 1,1-dichlorodiethyl ester, diphenylketene-p-tolylimine, N-hydroxyphthalimide. , N-hydroxysuccinimide, N-hydroxypiperidine, ethylene chlorophosphite, diethyl ethylene pyrophosphite, N-ethyl 5-phenylisoxazolium 3'-sulfonate, phenylphosphorodi- (1-imidazolate) and carbodi- imides such as dicyclohexylcarbodiimide, 1-cyclohexyl-3- (2-morpholinomethyl) carbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride and diethyl cyanamide.

The coupling agents described above are usually reacted first with a compound of formula II and the product obtained is then reacted without isolation with 5-aminotetrazole to give the desired 1-oxo-1H-6- and / or 7-substituted-thiazoloZ.3, 2- AJ-pyrimidine. (Note the modified naming and numbering systems described above when and R2 together form a third ring).

The reaction is carried out in a reaction-inert solvent system in which the compound of formula II need not be dissolved. The only requirement for a solvent system is that it does not react significantly with reagents or products. The various coupling agents that can be used to cause the water cleavage coupling allow for the selection of many solvents. Typical solvents include N, N-dimethylformamide tetrahydrofuran, dioxane, methylene chloride, nitromethane and acetonitrile.

The reaction of a compound of formula II with a coupling air is carried out at a temperature in the range of about 20 ° C to about 110 ° C. The reactive intermediate is then reacted with 5-aminotetrazole at about 20-110 ° C.

Each of these steps is preferably carried out at about 50 ° C to about 100 ° C because the reaction rate and yield are improved.

The molar ratio of compound (II): coupling agent: 5-amino-25 tetrazole is generally between about 1: 1: 1 to 1: 1.1: 1.1.

The coupling agent and 5-aminotetrazole can be used in larger amounts, but there is no benefit. Ten percent surpluses are satisfactory.

As will be appreciated by those skilled in the art, all of the reactants may be added at the same time as in steps, as described above. However, the formation of a reactive intermediate (with a coupling agent) first produces normally the desired N- (5-tetrazolyl) amides in better yield.

Il 13 67706

Alternatively, compounds of formula I may be synthesized by coupling acids with 5-aminotetrazole using the mixed anhydride method. In this case, the acid (of formula II) is first converted in situ to the tertiary amine salt; 1-1.1 5 moles of amine are used in excess. Various tertiary amines (R '^ N) are suitable for this purpose. Examples are triethylamine, N-methylpiperidine, N-methylmorpholine, dimethylaniline or quinoline. Suitable inert solvents include methylene chloride, chloroform, dimethylformamide and dimethylacetamide. It is recommended that the acid be completely soluble in the excess tertiary amine used, which may require a longer mixing time, with slight heating if necessary. The amine salt solution is then reacted with an equivalent amount of alkyl, (e.g. ethyl), benzyl or phenyl chloroformate at a temperature in the range of -40 to + 25 ° C, mainly in the range of -10 to + 10 ° C, to form a mixed anhydride. : 20 X ° R3NH © I + C1-C-OR - ^ II + R 'N.HCl

S 0 ^ ^ O-C-OR

0 0 H

25 which is in solution. The mixed anhydride is reacted without isolation directly with 5-aminotetrazole, which is preferably dissolved in the same type of inert solvent 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 -40 ° to + 15 ° C), but the mixture is allowed to warm to a higher temperature such as between 15 ° and 40 ° C to complete the reaction). A typical molar ratio of acid: amine: chloroformate: 5-aminotetrazole is between 1: 2: 1: 1 and 1: 2.1: 1.1: 1.1.

14 67706

Many of the required 2-aminothiazole starting materials are known. Those not described in the literature can be prepared by condensing the appropriate oC-haloketone with thiourea or by condensing the appropriate aldehyde with thiourea and sulfuryl chloride, as illustrated in the examples. oC haloketones, the preparation of which has not been reported in the literature, are obtained by standard methods, e.g. by halogenating ketones Zjesim. Catch et al., J. Chem. Soc. , 272 (1948); Levine, Org. Synthesis Coll., Vol. II, 88 (1943); 10 Buchman et al., J. Am. Chem. Soc. 67, 400 (1945, 1745, by allowing hydrogen halides to act on diazoketones Aesim. 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 (19501./, by decarboxylation of α-halo-15/3-keto acids / flcPhee et al., J. Am. Chem. Soc., 66, 1132 (19 4 41./, and by cleavage). spontaneously dibromo derivatives of alkenyl esters / J = sim. Slanina et al., J. Am. Chem. Soc. 58, 891 (193617.

A series of synthetic reactions to prepare acids of formula II and N- (5-tetrazolo) amides of formula I from 2-aminothiazoles can be performed by standard thin layer chromatography on silica gel plates with ultraviolet indicators obtained as commercial products from various sources.

The eluent is selected according to the reaction to be carried out and, depending on the nature of the substituents, so as to obtain Rf values between 0 and 1.0 and such that the intermediate involved in the reaction and the product formed in the reaction are separated. A suitable eluent to follow the process of the invention is a 95: 5 chloroform / acetic acid mixture.

Pharmacological Assays The PCA assay is a method of measuring the anti-allergic (particularly anti-asthmatic) activity of a compound. Compounds that inhibit a positive PCA assay induced by a rat immunochemical counterpart of human immunoglobulin E li 67706 (IgE), or a reagent, are considered to have antiallergic activity (C, Mota, Ann.NY Acad. Sci., 103 , 264 1963). (The reagent is primarily immunoglobulin E (IgE) and the major immunoglobulin, which is a cause of allergic asthma, anaphylaxis, hay fever, food sensitivities and some forms of drug sensitivities, although recent evidence suggests a significant role in allergies to IgG class antibodies. the transmission). Such compounds, when administered to a sensitized subject, human or animal, prior to the time the subject comes into contact with the antigens, i.e. allergenic agents, prevent an allergic reaction that would otherwise occur. Therefore, they provide a method for preventing allergic or anaphylactic reactions of a reagent nature in advance.

In other words, such compounds inhibit the release of mediators resulting from an antigen-antibody (allergic) reaction that is illuminated by a PCA assay using a rat homocytropic antibody - a known human reactive antibody correlate. Inhibition of reactive antigen-antibody reactions in rats, an experimental animal used in the PCA experiment, is considered equivalent to inhibition of reactive antigen-antibody reactions in humans during allergic events.

The PCA reaction test method used to evaluate the compounds of this invention illustrates the excellent equivalence between the activity of the compounds used in this test and their utility in the treatment of allergic asthma. The ability of substances to interfer with PCA reactions is measured in male Charles River Wistar rats, 35 170-210 g. IgE antibodies are prepared from the reagent antiserum rich in IgE antibodies, 16 67706 are prepared according to Petillo et al., Int. Arch. Allergy, 44, 309 (1973). Hyperimmune IgG antibody-rich antiserum to egg albumin is prepared according to Orange et al., J. Exptl. Med., 127, 5,767 (1968). Forty-two hours before antigen challenge, the reagent antiserum is injected intradermally (i.d.) into the hairlessly shaved dorsal skin of normal rats; 5 hours before challenge, hyperimmune anti-10 serum is injected in the same manner. The third site is injected intradermally just prior to antigen challenge with 60 micrograms of histamine dihydrochloride and 0.5 micrograms of serotonin-creatinine sulfate to control antihistamine, antiserotonin, and unspecified block types; then the compounds of this invention or saline are administered by intravenous injection, followed immediately by exposure to 5 mg of egg albumin and 2.5 mg of Evans' Blue dye in saline. For oral administration, Evans' Blue dye and egg albumin-20 ni are administered 5 minutes after drug administration. Thirty minutes later, the animals are asphyxiated using chloroform and the dorsal skin is removed and inverted for inspection. Each injection site is scored with points corresponding to the product of the millimeter of the site diameter and a scale of 0.1, 0.5, 1, 2, 3 or 4 using the relative intensity of the color determined. For each of the five animals in the group, the score for the given injection site is added together and compared to the saline-treated control groups. The difference is expressed as the percentage of block due to the 30 compounds used.

The antiallergic activity of the typical compounds of this invention has been studied by the method described above, and the activities obtained are expressed as degree of protection (%). Intal, disodium cromogly-35, a commercial anti-allergic agent, is not included for comparison because it is not active when administered orally.

Compounds of formula I (amides) and formula II (acids, is hydrogen) whose antiallergic activity has been tested by the PCA test are detailed in Tables I and II.

Table I

Activity of amides (formula I) orally in the PCA assay (% protection)

IqE mq / kq IqG nq / kg -¾_R: I 3 10 30 1 3 10 30 CH3 CH3 55 j 51 15 C!) 3 C2H5. 75 | 57 C2H5 c :: 3 29 j 28 C2H5 C2H5 62 | 49 (CH2; 3 46; 43 20! (CH2) 4 47 45 (CH2) 5 25 38 ^ H2 ^ 6 94 j 57 H CH3 55 j 50 H H 50! 46 25 CH3 h 78 1 55

i I

C 21 H 85 and 58 H C (CH 3) 37 and 20 H C 2 H 5 70; 44 30 »CH (CH3) 2 72 53 CH2CU fC5Hg) Cl2CH2 I 4 7 I CH, Ci (Cl1,) Cl, CH-, 44 I33

I 2 3 2 2 iJJ

J CII2C (CH3) 2CH2C »2 38, 27 I H CUCH-CH, 6 I 6 o c] '1 J 1

I CU, I

! 3 I

I .__! 5 18 67706

Table II

Activity of acids (formula II; is hydrogen) orally in the PCA test (% protection)

IgE mg./kg. IgG mg./kg.

—1 - R2 10 30_ 10 30 CII3 CH3 Q 0 10 CH3 C2I «5 Q 0 | C2U5 ch3 42 24 i C2! 15 C2H5 41 32 j (α, 2} 3 0 0 15 | (CH2) 4 55 39 | (CH2> 5 37 44 6 36 68 15 45 H CH3 18 19 11 H ia 7 20 CH3 HI 12 14 C2H5 H! 45 j 38 jH C (CH3 »3 10 6 H C2H5 13 I 21 25 H CU CCH3) 2 o 0 CU2CU (C5! I6) CH2CH2 15 5

Cli2CH (CH3) CH2Cir2 31 21 CII2C (CH3) 2CH2CH2 13 6

H CI1Cl! 2C113 1 S

30 ch3

_ I

Il 19 67706 The effectiveness of the products of this invention as antiulcer agents is determined by the so-called "cold, restraint stressed rat" test. In this experiment, fasted female rats (Charles River CD strain) weighing 70-140 grams are administered drug or vehicle (control animals) intraperitoneally in saline with 1% carboxymethylcellulose and 0.1% Tween 80. ) or orally (in water) for three hours before being lightly anesthetized with 10 ethers and taped to separate plexiglass plates. After recovery from anesthesia, the animals kept immobile are placed in a horizontal position in a refrigerator kept at 10-12 ° C and, after three hours, killed by twisting 15 necks. The abdomen of each rat is opened, the gastric port is squeezed, the stomach is cleansed with saline delivered through an oral tube, the esophagus is squeezed, and the stomach is excised. The stomachs are placed in a 0.4-20% formalin solution for about 30 seconds to cure the outer layers and facilitate the study. Each stomach is then cut open along the great curve and examined for damage to the gland (post-stomach). The number of gastric corrosions, their severity 25, and the color of the stomachs are recorded. To compare the mean number of gastric cancers in the control group to the average number of gastric cancers in each drug-treated group, the Mann-Whitney-Wilcoxan rank sum test is used to determine whether they are statistically different. (Dixon et al., "Introduction to Statistical Analysis," 3rd Ed., McGraw-Hill Book Company, New York, pp. 344-347, 1969). As detailed below, N- (5-tetrazolyl) thiazolo [3,2-a] pyramidine-2-carboxy-35 amide (Compound IA) is extremely effective in this experiment.

2 0 67706

Alternatively, the efficacy of the compounds of the invention as antiulcer agents is determined in rats by an ethanol-induced ulcer test. In this experiment, overnight fasted male rats 5 are orally administered drug (5 mg / kg) or water for fifteen minutes before being given an oral dose of absolute ethanol (1.0 ml). One hour after the ethanol dose, the animals (8 / group) are sacrificed and the stomachs are examined for possible damage. All 10 drugs were dissolved in dilute NaOH. After killing, the abdomen is opened and a device to stop the bleeding is placed in the gastric port. 6 ml of a .mu.l of a formaldehyde solution was administered to the stomach with gastric gavage, and a second hemostatic device was placed to close the esophagus. The stomach was removed, opened along the great curve, and the ulcer examined.

The evaluation system used to quantify ethanol-induced damage is set forth below.

Ulcer Assessment Table Estimate Number Definition 1 Stomach that looks normal 2 Needle-sized lesions 25 3 Damage 2 or less; needle tip size damage may occur.

M- Damage> 2; needle tip size damage may occur.

5 Damage with bleeding.

30 For each group of animals, the ulcer index was calculated as follows:

Ulcer index = (sum of group estimate numbers) x (sum of group ulcer numbers) x (part of group without ulcer incidence).

35 The percentage ulcer prevention is calculated according to 67706

Prophylaxis% = 100 x / '(ulcer index of controls) - (ulcer index of drug-treated ulcers // + (ulcer index of controls).

Table III shows the activity of the various 5-tetrazolylamides of this invention in this experiment.

Table III

Activity of amides (formula I) when administered orally 10 (% prevention at a dose of 5 mg / kg) in an ethanol-induced rat gastric ulcer test_pp Prevention% n .__ ^ 2__ CH3 CH3 96 H CH3 59 15 CH3 H 72 C2H5 C2H5 10 C2H5 H 86 (ΟΗ2) 6 45 (CH2 ^ 97, 81

20 H

22 67706

As previously mentioned, the most preferred compound of formula I is that wherein R 1 and together represent butylene, i.e., (N- (5-tetrazoyl) -1-oxo-1H-cyclohexeno-thiazolo [3,2-a] pyrimidine-2 -carboxamide, (formula IA) which may alternatively be referred to as 5,6,7,8-tetrahydro-N- (5-tetrazolyl) -4-oxo-4-H-pyrimido-7 ", > 7-benzothiazole-3-carboxamide.

In addition to its antiallergic effect shown orally in Table I, the compound of formula 10 III proves to be active in the PCA test at an intravenous dose of 0.03-1.0 mg / kg, and is 26 times more potent than Intal (as previously mentioned, Intal is not efficacy when administered orally). Compound IA also blocks changes in skin permeability caused by IgE-mediated passive skin anaphylaxis (PCA), but does not affect changes in permeability caused by external; subcutaneous injection of histamine and serotonin. The absence of anti-histamine and anti-serotonin effects indicates that the anti-allergy mechanism is inhibition of neurotransmitter release rather than anti-mediator receptor activity.

Compound I A inhibits dextran-induced histamine release into the rat peritoneal cavity.

Its ED 50 q is 0.33 μg / kg i.p. and the corresponding value of Intal is 14.0 μg / kg, indicating the superior efficiency of the former. Compound I A inhibits the elevation of plasma histamine caused by administration of the antigen to rats passively sensitized with anti-IgE-ricin serum (passive systemic anaphylaxis). Its ED 1 -q is 28 μg / kg i.v., with an efficiency 13 times that of Intal.

2a 67706

Guinea pigs given Compound I A 30 mg / kg i.p. could not be protected from the bronchospasm effects of inhaled histamine

. . -8 -H

against. Konsentraatxon in the range of 10-10 M, 5 Compound IA is not of the isolated guinea-pig ileum against the effect of anticonvulsant which convulsion is induced by acetylcholine, histamine or slow-responding anaphylaxis antibody (SRS-A) and Compound IA prevent the ionophore-stimulated SRS 10 synthesis of and release in isolated rat monocytes.

In addition to being effective in the ethanol-induced rat gastric ulcer assay (see Table III above), Compound IA is very effective in the "cold-restraint stress" gastric ulcer method (detailed description above) in which it provides a dose of dependent protection at oral doses ranging from 3 to 100 ug / kg. Compound IA also protects against the ulcerative effects of aspirin at a dose of 100 mg / kg p.o., with dose-dependent effects being observed in the dose range of 10-100 μg / kg p.o., with an ED 2 g value of 100 μg / kg. Compound IA is also active against the phenylbutazone-induced type of gastric ulcer, with an ED50 of 200 ug / kg when administered orally. Although Compound IA is a very potent antiulcer agent, it does not affect pentagastrin-stimulated acid production in Heidenhain poach dogs (5 mg / kg, iv) and is therefore clearly distinguishable from anti-secretory prostaglandins, and cimetidine and atropine. . "Cyto-protective", a term recently invented to describe the antiulcer effects of prostaglandins that are independent of the secretory inhibitory effect / Robert, Advances in Prostaglandin and Thromboxane Research 2, 507 (1976); Miller et al., Gut 20, 75 (1979); Robert et al., Gastroenterology 72, 1121 (1977) ./, randomly describe the effects of compound 5 IA.

In addition, Compound IA has an effect on increasing urinary excretion. When administered orally, it causes dose-dependent urinary excretion at doses ranging from 0.3 to 5 mg / kg. The maximum effect was a doubling of the amount of excretion.

Urinary sodium and potassium ion concentrations did not change, but due to the increase in excretion, an increase in sodium and potassium excretion was observed. These findings indicate that the dose-dependent range for urinary excretion activity is significantly higher than the range for anti-ulcer activity and just below the range for anti-allergic effects (1-10 mg / kg).

There were no changes in blood glucose levels in fasted rats for 24 hours and 20 orally administered Compound IA at doses of 10, 30 or 100 mg / kg.

The effect of Compound IA on glucose tolerance was studied in rats given orally at doses of 10, 30 or 100 mg / kg concomitantly with oral glucose, 1 g / kg. A clear dose-dependent improvement in glucose tolerance was observed. This effect may be due to the delayed absorption of glucose associated with the potential gastric emptying effect.

Compound IA does not have significant peristalsis inhibitory effects. In anesthetized dogs, increasing doses of 5 and 15 mg / kg i.v. when administered, it caused transient vacuum and variable changes in 35 heart rate. Pressure responses to epinephrine and 25 6 7 7 0 6 bilateral common main artery occlusion decreased to some extent. Transient cardiovascular changes occur only when administered at increasing intravenous doses 5-15 times more than the maximum effective intravenous dose to prevent allergic effects and very much more than the oral doses required to prevent gastric ulcer effects.

In tolerability studies, Compound IA was administered orally by gavage to dogs for one day at doses of 50, 150, and 300 mg / kg / day. Vomiting, which is common in dogs, was observed at all doses, but subsequent studies revealed that the vomiting effect could be eliminated if the drug was administered as a capsule, preferably after feeding rather than before. No major pathological changes were observed and microscopic examination of the liver, kidneys, heart, and lungs did not reveal any changes. In other studies, blood enzyme levels remained normal in dogs given Compound IA intravenously for five days at successive daily doses of 1, 3, 10.3 and 3 mg / kg.

Rats were orally administered Compound IA using 25 tubular feeds for 10 days at doses of 50, 150 and 300 mg / kg / day. In general and microscopic examinations of the liver, kidneys, heart and lungs, no pathological changes were observed as a result. With the exception of a slight increase in blood glutamine-pyruvine-30 transaminase, which was observed at the highest dose, no clinical chemical changes were observed.

Compound I A was administered subcutaneously to mice at doses of 100, 300 or 1000 mg / kg. No symptoms or 35 deaths were observed and it was concluded, 26 67706 that the drug is acutely well tolerated when administered subcutaneously; LD50 q <1000 mg / kg. At a subcutaneous dose of 32 mg / kg, no interactions were observed with the CNS-active classes of drugs.

Groups of mice were given the only oral doses of 40 mg / kg of Compound IA, which were killed 6, 12, or 24 hours later. Microscopic examination of the bone marrow did not reveal any-10 types of chromosomal damage. Similar observations were made after treatment of mice for five consecutive days at doses of 20 mg / kg. In vitro studies in which Compound IA was incubated with human lymphocytes at concentrations of 1000, 100, 10 or 0 ug / ml also did not reveal any significant drug-induced chromosomal degradation. In an in vitro Ames experiment, compound I A did not cause point mutations. From these findings, it is apparent that compound I A has no clear effect on altering genetic factors.

In the rat PCA test, the ratio of the corresponding effective oral and intravenous doses of Compound IA is steady, with good oral absorption. This is supported by observations of plasma concentrations of 3-7 μg / ml one hour after administration of Compound IA, 50-300 mg / kg. In dogs, the drug appears to be easily absorbed after oral administration as suspensions or capsules; plasma concentrations are 9-26 ug / ml one hour after oral doses of 50-300 mg / kg. For both species, the plasma levels of the corresponding carboxylic acid metabolite (corresponding compound of formula II) are comparable to the corresponding values of compound 35 IA, indicating that this compound is a metabolite of compound IA. After the eighth 2 n 6,7706 daily dose, the amounts of parent drug and metabolite were 2-4 times higher than after the initial dose, suggesting that it is possible to maintain the therapeutic amount of drug for long periods of time.

The solid state stability of Compound I A alone, or in admixture with the usual neutral ingredients commonly used in oral formulations or solutions, proves to be exceptionally good, making it possible to prepare stable formulations of this compound for clinical use.

the following examples are presented to illustrate the invention.

15 Preparation of starting materials Preparation 1 2-Amino-4-ethyl-5-methylthiazole 20 Thiourea (20.9 g, 0.275 mol) was dissolved in 250 ml of boiling ethanol. To the boiling urea solution was added 2-bromo-3-pentanone (41.3 g, 0.25 mol) dissolved in 50 ml of ethanol dropwise over 25 minutes. After boiling for 2 hours, the reaction mixture was concentrated by boiling to about 100 mL, cooled and the crude product was collected as the hydrobromide salt by filtration. Pure 2-amino-4-ethyl-5-methyl-thiazole (15.1 g; m.p. 45-50 ° C; m / e calcd; 142; obtained: 142) was obtained by redissolving the product in water and reprecipitating from 30 ml. -norm. With an aqueous solution of KOH.

1-Bromo-2-heptanone, 3-bromo-4-heptanone and 4-bromo-2,5-dimethyl-3-hexanone are converted to 2-amino-4-pentylthiazole, 2-amino-4-ethyl-5 -propylthiazole and 2-amino-4,5-di-35-isopropylthiazole.

67706 28

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

Thiourea (21.3 g, 0.286 mol), 4-chloro-3-hexanone (34.4 g, 0.26 mol) and 200 ml of ethanol were combined and heated at reflux for 19 hours. The reaction mixture was cooled and the solvent removed to give the crude product as a white solid. White crystals of 4,5-diethylthiazole hydrochloride (31 g, m.p. 154-156 ° C) were obtained by recrystallization from a mixture of ethyl acetate and ethanol.

Preparation 3 2-Amino-cycloheptenothiazole

Thiourea (41.9 g, 0.55 mol), 2-chlorocycloheptanone (72.3 g, 0.49 mol) and 500 ml of ethanol were combined and boiled for 7 hours. The solvent was removed to leave a semi-solid which was partitioned between ethyl acetate and water. The unreacted chloroketone obtained from the ethyl acetate phase by removing the solvent was combined with 20 grams of thiourea and ethanol, boiled for 24 hours, the solvent removed and the additional product obtained partitioned between ethyl acetate and water-soluble portions as above. In either case, the product was recovered by basifying the aqueous phase with ammonium hydroxide, extracting into ethyl acetate, drying over anhydrous sodium sulfate, evaporating to an oil, converting to a solid by trituration with hexane and filtering. Pure 2-aminocycloheptenothiazole (49.5 g, mp 77-78.5 ° C) was obtained by recrystallization from cyclohexane.

Preparation 4 2-Amino-4-isopropylthiazole

Thiourea (52.5 g, 0.69 mol) was slurried in 400 mL of ethanol. To the slurry was added 1-bromo-3-methyl-35 2-butanone (109.5 g, 0.66 mol). Resultant

II

The exothermic reaction of JS 67706 caused dissolution and boiling. Boiling was maintained by heating from the outside for one hour. The solvent was removed by boiling and distillation to give an oil which crystallized on standing. Final purification of 2-amino-4-isopropylthiazole hydrobromide (104.4 g, mp 74-76 ° C) was performed by trituration with ether.

The hydrobromide 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 into ether, drying the ether phase over dry sodium sulfate and distilling off the oil.

Preparation 5 2-Amino-6-phenylcyclohexreotriazole

Thiourea (397.5 mg, 5.22 mmol) was slurried in 6 mL of ethanol. 2-Bromo-4-phenylcyclohexanone (1.2 g, 4.74 mmol) was added to the slurry, resulting in an exothermic reaction and dissolution. The solution was boiled for 30 minutes, cooled and the solvent was distilled off to give the crude product as a hydrobromide salt.

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

Alternatively, on a larger scale, using 8.2 g of thiourea, 24.6 g of 2-bromo-4-phenyl-cyclohexenone and 125 ml of ethanol, after a boiling period of 30 minutes, the reaction mixture was cooled in an ice bath and the hydrobromide salt was collected directly by filtration. The hydrobromide salt was dissolved by heating in water with some ethanol, and the free base (10.4 g, 307706 m.p. 180-182 ° C) was precipitated by the addition of excess ammonium hydroxide.

2-Bromo-3-phenylcyclopentanone, 2-bromo-3,5-dimethylcyclohexanone, 2-bromo-3,5,5-trimethylcyclo-5 pentanone and 2-bromo-5-methylcyclooctanone are converted by the same methods to 2-amino-6 -phenylcyclopentenothiazole to the hydrochloride salt of 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,4,6-trimethylcyclopentenothiazole and 2-amino-7-methylcycloocteno-10-thiazole, respectively.

Preparation 6 2-Amino-6-methylcyclohexenothiazole

Thiourea (22.3 g, 0.29 mol) was slurried in 15,275 mL of ethanol. 2-Bromo-4-methylcyclohexanone was added and the mixture was heated at reflux for 75 minutes. The reaction mixture was cooled to room temperature and the crude product was collected as the hydrobromide salt by filtration. The crude salt was dissolved in warm water, filtered and basified with ammonium hydroxide to precipitate the free base as an oil which crystallized on cooling. Pure 2-amino-6-methylcyclohexenothiazole (25.2 g, mp 98-100 ° C) was obtained by recrystallization from cyclohexane.

Preparation 7 2-Amino-6,6-dimethylcyclohexenothiazole 2-Amino-6,6-dimethylcyclohexothiazole (9.8 g, mp 109-111 ° C) was prepared according to the procedure of Example 6 from thiourea (9.2 g, 0, 12 moles) of 30 and 2-bromo-4,4-dimethylcyclohexanone (22.6 g, 0.11 moles) in 100 mL of ethanol.

Preparation 8 2-Amino-4- (2-butyl) thiazole

Thiourea (16.7 g, 0.22 mol), 1-bromo-3-methyl-2-pentanone (36 g, 0.2 mol) and ethanol (100 ml)

II

3 6 7 706 were combined and heated at reflux for 5 hours. Aqueous potassium hydroxide solution (3N, 100 ml) was added and boiling was continued for a further 0.5 hours. The reaction mixture was cooled, acidified with hydrochloric acid and the non-basic impurities extracted with ether. The aqueous phase was basified with ammonium hydroxide and the product was extracted into ether. After backwashing with water and drying over anhydrous sodium sulfate, the ether was distilled off to give 10 g of 2-amino-4- (2-butylhiazole as a dark brown viscous oil.

Preparation 9 2-Amino-5-methylthiazole

Thiourea (45.7 g, 0.6 mol) and propionial dehyde (7.4 g, 0.3 mol) were combined 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 quenched by maintaining the temperature between 15-24 ° C. The formation of gas, which occurred during the reaction, ceased about an hour after the end of the addition. Most of the chloroform was boiled off in a water bath. Ethanol (150 ml) was added and the mixture was boiled for 3 hours.

The reaction mixture was evaporated to an oil which was partitioned between water and ethyl acetate.

The aqueous phase was basified with ammonium hydroxide and the product was extracted into fresh ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and distilled to give the crude product as a white solid. Pure 2-amino-5-methylthiazole (8.36 g, mp 94-95 ° C) was obtained by recrystallization from cyclohexane.

Preparation 10 2-Amino-5-ethylthiazole 35 Thiourea (45.7 g, 0.6 mol) and butyraldehyde (21.6 g, 0.3 mol) were combined 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 quenched by maintaining the temperature between 15-2 ° C.

Gas was formed during the addition and for about an hour thereafter. Ethanol (400 ml) was added, chloroform was boiled off and the reaction mixture was boiled overnight (about 16 hours). The reaction mixture was evaporated to an oil and the recrystallized 2-amino-5-ethylthiazole (11.7 g, mp 54-55 ° C) was isolated as described in Preparation 9.

Pentanal, 3-methylbutanal and heptanal are converted to 2-amino-5-15 propylthiazole, 2-amino-5-isopropylthiazole and 2-amino-5-pentylthiazole, respectively, by the same method.

Preparation li 2- (2,2-Dicarbethoxyethenylamino) -4,5-dimethylthiazole 2-Amino-4,5-dimethylthiazole (2.56 g, 20 mmol), diethyl ethoxymethylene malonate (4.8 g, 22 mmol) and ethanol (5 mL) were boiled for 1 h. The reaction mixture was cooled and the crude product was precipitated with hexane to give pure 2- (2,2-dicarbethoxyethylamino) -4,5-dimethylthiazole (4.21 g, mp 82-83.5 ° C) by recrystallization from hexane.

Preparation 12 2- (2,2-Dicarbethoxyethenylamino) -4-ethyl-5-methylthiazole 2-Amino-4-ethyl-5-methylthiazole (2.84 g, 20 mmol) and diethyl ethoxymethylene malonate (4.76 g, 22 mmol) ) was combined and heated on a water bath for 3 hours. The product obtained on cooling as an oil was used in the next step without further head purification.

33 67706 2-Amino-4-pentylthiazole, 2-amino-4-propyl-5-ethylthiazole, 2-amino-4,5-diisopropylthiazole, 2-amino-5-propylthiazole, 2-amino-5- isopropylthiazole, 2-amino-5-pentylthiazole, 2-amino-6-phenylcyclopene-5-teenothiazole, 2-amino-5,7-dimethylcyclohexenothiazole, 2-amino-4,6,6-trimethylcyclopentenothiazole and 2-amino-7 -methylcyclooctenothiazole is converted to the corresponding 2- (2,2-dicarbethoxyethenylamino) thiazole derivatives by the same method.

By the same procedure, the corresponding dimethyl, dipropyl and diisopropyl esters are prepared by substituting the appropriate dimethyl, dipropyl or diisopropylethoxymethylene malonate for diethyl ethoxymethylene malonate.

Preparation 13 2- (2,2-Dicarbethoxyethenylamino) -4-methyl-5-ethylthiazole 4-methyl-5-ethylthiazole (5.68 g, 40 mmol) and diethyl ethoxymethylene malonate (9.52 g, 44 mmol). lia) was briefly heated at 86 ° C and then cooled to give the product as an oil which was used directly in the next step.

Preparation 14 2- (2,2-Dicarbethoxyethenylamino) -4,5-diethyl-thiazole

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 combined and boiled for 2.5 h. 30 tia. The reaction mixture was cooled and the solvent was distilled off. The resulting semi-solid product was partitioned between ethyl acetate and water. The ethyl acetate phase was dried over sodium sulfate and, after distilling off the solvent, 2- (2,2-dicarbethoxyethenylamino) -4,5-diethylthiazole (28.6 g) as a golden oil.

The hydrobromide salts of 5,7-dimethylcyclohexenothiazole, 4,4,6-trimethylcyclopentenothiazole and 7-methylcyclooctenothiazole are converted to the corresponding 2- (2,2-dicarbethoxyethenylamino) -5-thiazole derivatives by the same method.

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

.Valfliis.tus.lj.

2- (2,2-Dicarbhetoxyethenylamino) cyclopentenothiazole 2-Aminocyclopentenothiazole (3.6 g, 34.5 mmol-15) and diethylethoxymethylene malonate (8.2 g, 38.0 mmol) were combined and heated on a water bath for 100 h. minutes. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) cyclopentenothiazole (7.0 g,

Rf 0.6 on silica gel as determined by thin layer chromatography eluting with chloroform / 1% ethanol) was crystallized by the addition of hexane.

Preparation 16 2- (2,2-Dicarbethoxyethenylamino) cyclohexenothiazole 2 2-Aminocyclohexenothiazole (7.7 g, 50 mmol) and diethyl ethoxymethylene malonate (11.9 g, 55 mmol) were combined with 10 mL of ethanol. and boiled for 50 minutes. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) cyclohexenothiazole (15 g, 30 Rf 0.5 as determined by thin layer chromatography on silica gel using chloroform / 1% ethanol as eluent) was precipitated by the addition of 50 ml of hexane.

Alternatively, 58.4 g of 2-aminocyclohexenothiazole, 89.82 g of diethylethoxymethylene malonate 35 and 584 ml of cyclohexane were combined and boiled under nitrogen for 2.5 hours, cooled to 15 ° C and the product (96 g, m.p. 113 ° C) taken recovered by filtration.

Preparation 17 2- (2,2-Dicarbethoxyethenylamino) cyclooctenothiazole 2-Aminocyclooctenothiazole (2.0 g, 11 mmol) and diethyl ethoxymethylene malonate (2.62 g, 12.1 mmol) were combined and heated in a water bath-10 la for 2.75 hours. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) cyclooctenothiazole (3.13 g, Rf 0.6 by chromatography on silica gel using chloroform / 1% ethanol as eluent) precipitated upon addition of hexane.

Preparation 18 2- (2,2-Carbethoxyethenylamino) -4-methylthiazole 2-Amino-4-methylthiazole (4.57 g, 40 mmol) and diethyl ethoxymethylene malonate (9.51 g, 44 mmol) were combined and heated in a water bath for one hour. The reaction mixture was cooled and 2- (2,2-dicarbethoxyethenylamino) -4-methylthiazole (9.8 g, Rf 0.5 as determined by thin layer chromatography on silica gel using chloroform / 1% ethanol-25) as eluent precipitated on addition of 60 ml of hexane.

Preparation 19 2- (2,2-Dicarbethoxyethenylamino) thiazole 2-Aminothiazole (10.0 g, 0.10 mol) and diethyl ethoxymethylene malonate (23.8 g, 0.11 mol) were combined and heated on a water bath for 1.25 hours. . The reaction mixture was cooled and the resulting semi-solid was recrystallized from hexane to give pure 2- (2,2-dicarbethoxyethenyl) thiazole (17.2 g in two portions, Rf 0.6 on silica gel as determined by thin layer chromatography eluting with chloroform / 1% ethanol). ).

Preparation 20 2- (2,2-Dicarbhetoxyethenylamino) -5-methyl-5-thiazole.

2-Amino-5-methylthiazole (6.85 g, 60 mmol) and diethylethoxymethylene malonate (14.3 g, 66 mmol) were heated on a water bath for 1 h. The reaction mixture was cooled and the product precipitated on addition of about 75 mL of hexane. Pure 2- (2,2-dicarbethoxyethenylamino) -5-methylthiazole (14.1 g in two portions, Rf 0.5-0.65 as determined by thin layer chromatography on silica gel using eluting with chloroform / 1% ethanol) was obtained by recrystallization from hexane.

Preparation 21 2- (2,2-Dicarbethoxyethenylamino) -5-ethylthiazole 2-amino-5-ethylthiazole (11.7 g, 91.3 mmol-20) and diethyl ethoxymethylene malonate (21.7 g, 100.43 mmol) ) was combined and heated on a water bath for 45 minutes. 2- (2,2-Dicarbethoxyethylamino) -5-ethylthiazole (27.2 g, Rf 0.6 and 0.7, respectively, as determined by thin layer chromatography on silica gel, eluting with chloroform / 1% ethanol and hexane / ethyl acetate 2: 1). ) was obtained by cooling as an oil and used directly in the next step.

Preparation 22 30 2- (2,2-Dicarbethoxyethenylamino) -4- (2-methyl-2-propyl) thiazole 2-Amino-4- (2-methyl-2-propyl) thiazole (15.6 g, 0.1 moles) and diethyl ethoxymethylene malonate (23.8 g, 0.11 moles) were combined and heated on a water bath for 2 hours. On cooling, 2- (2,2-dicarbethoxyethylamino) -4- (2-methyl-2-propylthiazole) was obtained as a wet solid and used directly in the next step.

Preparation 23 5 - (2,2-Dicarbethoxyethenylamino) -4-ethylthiazole 2-Amino-4-ethylthiazole (20.5 g, 0.16 mol) and diethylethoxymethylene malonate (35 g, 0.17 mol) were combined and heated. in a water bath for 2 hours.

On cooling, 2- (2,2-dicarbethoxyethenylamino) -4-ethylthiazole was obtained as an oil and used directly in the next step. (Rf 0.75 on silica gel as determined by thin layer chromatography using chloroform / 1% ethanol for elution).

2-Amino-4-isopropylthiazole (58.6 g, 0.415 mol) and diethylethoxymethylene malonate (92 ml, 0.455 mol) were converted to 2- (2,2-dicarbethoxyethenylamino) -4-isopropylthiazole by the same method.

(Rf 0.7 on silica gel as determined by thin layer chromatography eluting with chloroform / 1% ethanol).

Preparation 24 2- (2,2-Dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole 2-Amino-6-phenylcyclohexenothiazole (10.4 g, 45.2 mmol) and diethylethoxymethylene malonate (10 mL, 49.5 mmol) were combined. and heated with a water bath. After 15 minutes a solution formed. After the solution was heated for another 30 minutes, the entire mass 30 became solid. The crude product was recrystallized from cyclohexane to give pure 2- (2,2-dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole (15.3 g, mp 131-133 ° C).

38 67706

Preparation 25 2- (2,2-Dicarbethoxyethenylamino) -6-methylcyclohexenothiazole 2-Amino-6-methylcyclohexenothiazole (23.3 g, 0.139 mol) was combined with diethyl ethoxymethylene malonate (31 mL, 0.153 mol) and heated with water. After heating for about 10 minutes, a clear orange oil formed. After heating for one hour, crystallization was initiated by scraping. Pure 2- (2,2-dicarbethoxyethenylamino) -6-methylcyclohexenothiazole (40.2 g, mp 106-109 ° C) was obtained by recrystallization from ethanol.

Preparation 2 6 2- (2,2-Dicarbethoxyethenylamino) -6,6-dimethyl-15-cyclohexenothiazole-2-amino-6,6-dimethylcyclohexenothiazole (9.8 g, 53.8 mmol), diethyl ethoxymethylene malonate (12 mL) , 59.4 mmol) and ethanol (about 5 mL) were combined and heated on a water bath for 1.5 h.

20 Ethanol boiled off at the beginning of the heating season. The product crystallized on cooling and scraping. Pure 2- (2,2-dicarbethoxyethenylamino) -6,6-dimethylcyclohexenothiazole (14.3 g, mp 83-85 ° C) was obtained by recrystallization from hexane.

Analysis calculated for O 2 S 2 S: C, 57.93; H, 6.86; N, 7.95; Found: C, 57.72; H, 6.66; N, 7.94.

Preparation 27 2- (2,2-Dicarbethoxyethenylamino) -4- (2-butyl) -30 thiazole 2-Amino-4- (2-butyl) thiazole (8.44 g, 54 mmol) and diethyl ethoxymethylene malonate (11.7 g , 54 mmol) was combined and heated on a water bath for 1 hour and cooled to give 2- (2,2-3,5 dicarbethoxyethenylamino) -4- (2-butyl) thiazole 39,67070 (17.6 g, Rf 0.75 on silica gel). as determined by thin layer chromatography using chloroform / 1% ethanol for elution).

Preparation 28 S Ethyl 1-oxo-1H-6,7-dimethylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2-dicarbhetoxyethenylamino) -4,5-dimethylthiazole (4.17 g, 14 mmol) was combined with 30 ml of Dowtherm A and heated at 220 ° C for 1.5 hours. The reaction mixture was cooled and about 125 ml of petroleum ether was added. The separated solid was filtered off, recombined with mother liquor and chromatographed on a 70 x 180 mm silica gel column using chloroform as eluent. After an initial fraction of 125 ml, six 250 ml fractions were collected and evaporated to dryness to give the crude product (2.42 g, mp 114-115 ° C). Recrystallization from cyclohexane gave pure ethyl 1-oxo-1H-4,5-dimethylthiazolo [3,2-a] pyrimidine-2-carboxylate-20 (1.64 g, mp 119-120 ° C).

Analysis calculated for O 3 S: C, 52.37; H, 4.79; N, 11.10; mass ions, 252; Found: C, 52.21; H, 4.85; N, 11.23; mass ion, 25 252.

Preparation 29

Ethyl 1-oxo-1H-6-methyl-7-ethyl Ethyl Solo-L3,2-α7-pyrimidine-2-carboxylate 2- (2-dicarbethoxyethenylamino) -4-ethyl-5-methyl-thiazole (6.25 g ) was combined with 30 ml of Dowtherm A and heated at 215 ° C for 2.5 hours. The reaction mixture was cooled, petroleum ether was added and the crude product (1.96 g) was collected by filtration. The crude product (630 mg) was recrystallized from cyclohexane-35 to give pure 1-oxo-1H-6-methyl-7-ethylthio Solo [3,2-a] pyrimidine-2-carboxylate (301 mg, m.p. 122- 124 ° C).

_____ - Γ7 _____ 40 67706

Analysis calculated for C, 54.12; H, 5.30; N, 10.52. Found: C, 54.09; H, 5.26; N, 10.63.

Preparation 30 Ethyl 1-oxo-1H-6-ethyl-7-methylthiazolo [S, 2-4,7-pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -4-methyl-5-ethylthiazole (12 g ) was combined with 60 ml of Dowtherm A and heated at 205 ° C for 3 hours.

The reaction mixture was cooled and chromatographed on a 90 x 205 mm silica gel column eluting with chloroform with 1% ethanol. Seven fractions containing 250 ml of product were collected, combined, evaporated to an oil and rechromatographed on silica gel (60 x 600 mm) with the same eluent.

The fractions (165 x 8 ml) were combined, evaporated to an oil and crystallized by trituration with diisopropyl ether. Recrystallization from cyclohexane gave pure ethyl 1-oxo-1H-6-ethyl-7-methyl-thiazolo [3,2-a] pyrimidine-2-carboxylate (2.45 g, mp 65-66 ° C).

Analysis calculated for C 12 H 11 + N 2 O 3 S: C, 54.12; H, 5.30; N, 10.52; mass ion, 266; Found: C, 54.26; H, 5.23; N, 10.57; massaioni, 266.

25 Preparation 31

Ethyl oxo-1-1H-6,7-diethyls. 3,2-α, Pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -4,5-diethylthiazole (26.1 g) and 300 ml of Dowtherm A were combined for 30 hours and heated for 3.5 hours 225 ° C. 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 hexane-chloroform 2: 1. Thirty-three 250 ml fractions were collected. Fractions 35 to thirty-three were combined and the solvent was removed to give ethyl 1-oxo-1H-6,7-diethylsiazolo [3,2-a] pyrimidine-2-carboxylate-1,1,670,707 (22 g, Rf 0, 4-0.5 on silica gel as determined by thin layer chromatography eluting with chloroform / 1% ethanol) as an oil.

Preparation 32 Ethyl 1-oxo-1H-cyclopentenothiazolo 0,2 -] - pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) cyclopentenothiazole (7.0 g) was combined with 40 ml of Dowtherm A: and heated for about one hour at 225-230 ° C.

The reaction mixture was cooled and chromatographed on silica gel (70 x 190 mL). Dowtherm A was eluted with hexane. The product was eluted with chloroform / 1% ethanol. Four 250 ml fractions were collected, combined and the solvent removed to give an oil.

A portion of the oil was crystallized by trituration with cyclohexane to give the crude product (1.91 g). Recrystallization of 0.6 g of crude product gave pure ethyl 1-oxo-1H-cyclopentenothiazolo 1,2-ethypyrimidine-2-carboxylate (0.33 g, mp 102-103 ° C).

Analysis calculated for C, 54.53; H, 4.58; N, 10.60; Found: C, 54.54; H, 4.71; N, 10.71.

Preparation 33

Ethyl 1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -cyclohexenothiazole (12.6 g) was combined with 125 ml of Dowtherm A: and heated at 230 ° C for 25 minutes. The reaction mixture was cooled and chromatographed on silica gel (60 x 320 mm). Dowtherm A was eluted with hexane and the product was eluted with mixtures of chloroform - 1% ethanol by collecting 14,125 ml fractions. The fractions were combined and the solvent was evaporated, yielding crude ethyl 1-oxo-1H-cyclohexenothiazolo-1,2-a-pyrimidine-35-n-2-carboxylate (10.7 g, mp 92-94 ° C).

Alternatively, 2- (2,2-dicarbethoxyethylamino) cyclohexenothiazole (80 g, 0.25 mol, 42,6706 L), trifluoroacetic anhydride (101 g, 68 mL, 0.48 mol), toluene (0.8 L) and ethanol (1 L) and boiled for 21 hours. The reaction mixture was cooled and 300 ml of water were added. The toluene layer (upper) was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to 150 ml (slurry), diluted with one liter of ethanol (solution), concentrated to 280 ml, cooled to 5 ° C, cooled to 5 ° C: 10 and filtered to give relatively pure ethyl 1-oxo-1H-cyclohexenothiazolo 13.2-pyrimidine-2-carboxylate (47 g, mp 105-106 ° C).

Preparation 34

Ethyl 1-oxo-1H-cycloheptenothiazolo, E-3,2-dj-15 pyrimidine-2-carboxylate 2-aminocycloheptenothiazole (25.2 g, 0.15 mol), diethyl ethoxymethylene malonate (35.7 g, 0.165 mol) ) and Dowtherm A (400 ml) were combined and heated at 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 hexane. The product was eluted with hexane-chloroform 1: 1 by collecting thirty 500 ml fractions. Fractions six to thirty were combined and the solvent was evaporated to give the crude product as a wet solid. Pure ethyl 1-oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine-2-carboxylate (27.1 g, m.p. 78-79 ° C) was obtained by recrystallization from cyclohexane.

The same product is obtained by heating 2- (2,2-di-30-carbethoxyethenylamino) -cycloheptenothiazole

In Dowtherm A and by isolation and purification in the same way.

Preparation 35

Ethyl 1-oxo-1H-cyclooctenathiazolo [3,2-a] -35-pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) cycloocteno- 43 6 7 7 0 6 thiazole (3.13 g) was combined with 30 ml of Dowtherm A and heated at 220 ° C for 2.5 hours. The reaction mixture was cooled and chromatographed on silica gel (70 x 190 mm). Dowtherm A was eluted with hexane. The product was eluted with chloroform / 1% ethanol by taking four 125 ml fractions. The fractions were combined, evaporated to an oil and the solid ethyl 1-oxo-1H-cyclooctene Solo Z'3,2-α / pyrimidine-2-carboxylate (1.956 g, Rf 0.5 as determined by thin layer chromatography on silica gel eluting with the mixture). chloroform / 1% ethanol) was obtained by trituration with hexane.

Preparation 36

Ethyl 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -4-methylthiazole (9.8 g) was combined with 50 ml of Dowtherm A and heated at 220 ° C for 2 hours. The reaction mixture was cooled and 50 ml of hexane was added and the crude product 20 was collected by filtration. Recrystallization of the crude product from ethanol gave pure ethyl 1-oxo-1H-7-methylsolo [3,2-α] pyrimidine-2-carboxylate (4.6 g, mp 187-189 ° C).

Alternatively, this ester is prepared by condensing 2-amino-4-methylthiazole directly with ethyl ethoxymethylene malonate by boiling in trichlorobenzene / Allen et al., J. Org. Chem., 24, 779 (195,917.

Preparation 37 3 0 Ethyl 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) thiazole (17.2 g) was combined with 200 ml of Dowtherm A and heated for 30 minutes at 215 ° C. The reaction mixture was cooled to give a slurry, hexane 44 67706 (100 mL) was added and the crude product was collected by filtration and recrystallized from ethanol to give pure ethyl 1-oxo-1H-thiazoloZ. 33,2-a] pyrimidine-2-carboxylate (8.0 g, mp 184-185 ° C).

Alternatively, this ester is prepared by condensing 2-aminothiazole directly with ethyl ethoxymethylene malonate by boiling in trichlorobenzene / Allen et al., J. Org. Chem. , 24, 77 9 (1959) 7.

Preparation 38 10 Ethyl 1-oxo-1H-β-methylthiazolo [TS, 1,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenyl) -5-methylthiazole (14.1 g) was combined with 150 ml: with Dowtherm A and heated at 220 ° C for 1.5 hours. The reaction mixture was cooled and about 300 mL of hexane was added. The product was collected by filtration and purified ethyl 1-oxo-1H-6-methylthiazolo [3,2-a] pyramidine-2-carboxylate (6.4 g, mp 149-151 ° C) was obtained by recrystallization. di-isopropyl ether. Alternatively, these esters are prepared by condensing 2-amino-5-methylthiazole directly with ethyl ethoxymethylene malonate in boiling trichlorobenzene (Dunwell, et al., J. Chem. Soc., (C) 1971, 2094).

Preparation 39 Ethyl 1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -5-ethylthiazole (25.7 g, 86 mmol), trifluoroacetic anhydride (36.2 g, 172 mmol) and toluene (150 mL), were combined and heated at reflux for about 20 hours.

The reaction mixture was evaporated to dryness; was dissolved in 300 ml of chloroform. The chloroform solution was washed with saturated sodium hydrogen carbonate and then saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and triturated with diisopropyl ether to give ethyl 1-oxo-1H-6-ethyl-3-ethyl-3-ethyl α7-pyramidine-2-carboxylate (17.8 g, mp 148-150 ° C). A portion of the product (5.2 g) was recrystallized from about 75 mL of ethyl acetate to give additional pure product (4.1 g, mp 149-150 ° C).

Analysis calculated for C 11 H 12 N 2 O 3 S: C, 52.37; H, 4.79; N, 11.10; Found: C, 52.30; H, 4.51; N, 11.14.

10 Preparation 40

Ethyl 1-oxo-1H-7- (2-methyl-2-propyl) -thiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -4- (2-methyl- 2-Propyl) thiazole (32.6 g) was combined with 400 ml of Dowtherm A and heated for 1 hour at 230 C. The reaction mixture was cooled and chromatographed on silica gel (60 x 600 mm) Dowtherm A was eluted with hexane. The product was eluted with chloroform and nine 500 ml fractions were collected, fractions six to nine were combined and evaporated to dryness to give ethyl 1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2- N-pyrimidine-2-carboxylate (11.4 g, mp 145-147 ° C).

Additional product (2.04 g) was obtained from the fifth fraction by evaporation to a wet solid and trituration with cyclohexane. A gram of a larger batch was recrystallized from cyclohexane to give additional pure product (0.62 g, mp 148-149 ° C).

Analysis calculated for C 13 H 16 N 2 O 3 S: 30 C, 55.70; H, 5.75; N, 9.99; Found: C, 55.14; H, 5.58; N, 9.95.

46 67706

Preparation 41

Ethyl 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbhetoxyethenylamino) -4-ethylthiazo-5'L (47.7 g, 0.16 mol) was stirred In 500 ml of toluene and trifluoroacetic anhydride (45 ml, 0.32 mol) was added, a slight exotherm was observed, the reaction mixture was heated at reflux for 26 hours, cooled and 250 ml of ethyl acetate were added. Mixture 10 was carefully extracted with 250 ml of sodium hydrogen carbonate. aqueous solution (evolution of carbon dioxide) and then 250 ml of saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness, the residue was taken up in diisopropyl ether and the crude product was collected by filtration. [2,3-a] pyrimidine-2-carboxylate (10.33 g, mp 175-177 ° C) Analysis calculated for O 3 S: 20 C, 52.37; H, 4.79; N, 11.10 Found: C, 52.34; H, 4.85; N, 11.27.

A second crop of product (1.58 g, mp 176-178 ° C) was obtained from the acetonitrile mother liquor.

Preparation 42 2 5 Ethyl 1-oxo-4H-7-isopropylthiazolo [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarhetoxy) -4-isopropylthiazole (10 g) was combined with 100 ml. Dowtherm A and heated at 220 ° C for 2 hours, cooled to room temperature overnight and reheated for an additional 5 hours at 220 ° C. The mixture was cooled to room temperature, about 200 mL of hexane was added and filtered to remove a small amount of insoluble material. evaporated off and the residue chromatographed on about 500 g of silica gel Dowtherm A eluted with hexane and the product eluted with chloroform The fractions containing product were combined and evaporated to dryness, the residue was slurried in diisopropyl ether and the product (m.p. 143). The crude product was recrystallized from ethanol to give pure ethyl 1-oxo-1H-7-isopropylthiazolo [-3,2-a] pyrimidine-2-carboxylate (1.49 g, m.p. 145-147 ° C, nmt: singlet cf. at £ 8.6 and £ 10 7.3 each corresponding to one proton, and multiples concentrated at S 4.2 and ^ 1.2 corresponding to three protons and nine protons, respectively).

Preparation 43

Ethyl 1-oxo-1H-7-phenylcyclohexrothiazolo-15Z-3,2-α-pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -6-phenylcyclohexenothiazole (15.3 g, 38.2 mmol) was slurried in 150 mL of toluene. Trifluoroacetic anhydride (10.8 mL, 76.5 mmol) was added to give a clear solution which was boiled 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 and once with 150 ml of saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The solid residue was recrystallized from acetonitrile to give pure ethyl 1-oxo-1H-7-phenylcyclohexenothiazole / 3,2- [7-pyramidine-2-carboxylate (9.89 g, mp 160-161.5 ° C). .

30 Preparation 44

Ethyl 1-oxo-1H-7-methylcyclohexenothiazolo [Z * 3,2-3] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -6-methylcyclohexene (40.2 g, 0.119 mol) was dissolved in 400 ml of toluene. Trifluoroacetic anhydride (33.5 mL, 0.237 mol) was added, causing a slight 1.8 67706 exothermic reaction. The reaction mixture was boiled overnight (16 hours), cooled to room temperature, diluted with 400 ml of ethyl acetate, extracted twice with 400 ml of 1-norm. potassium carbonate and 400 ml each of saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization from cyclohexane with a small amount of ethyl acetate gave pure ethyl 1-oxo-1H-7-methylcyclohexenates Solo, 3.2-7 pyrimidine-10 2-carboxylate (29.3 g, m.p. 127-129 ° C).

Preparation 45

Ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazole [3,2-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -6,6-dimethyl-15 thiazole (13 g , 36.9 mmol) was dissolved in 130 mL of toluene, trifluoroacetic anhydride (10.4 mL, 73.6 mmol) was added and the mixture was warmed to reflux for 16 h.The reaction mixture was cooled to room temperature, diluted with 150 mL of ethyl acetate, extracted twice. 130 ml of saturated sodium hydrogen carbonate and once 150 ml of saturated sodium chloride, dried over anhydrous sodium sulphate and evaporated to dryness, recrystallization from hexane gave pure ethyl 1-oxo-1H-7,7-dimethyl-25-cyclohexenothiazole. 2,2-pyrimidine-2-carboxylate (9.40 g, mp 92-94 ° C).

Analysis calculated for C 18 H 18 N 2 O 2 S 2 O 2 S: C, 58.80; H, 5.92; N, 9.14; Found: C, 58.93; H, 5.48; N, 9.01.

30 Preparation 46

Ethyl 1-oxo-1H-7- (2-butyl) thiazolo [2,3-a] pyrimidine-2-carboxylate 2- (2,2-dicarbethoxyethenylamino) -4- (2-butyl) thiazole (17, 6 g) was combined with 175 ml of Dowtherm 35 A and heated at 225 ° C for 2.5 hours. The reaction mixture> 49 67706 was cooled and chromatographed on silica gel (60 x 600 mm). Dowtherm A was eluted with hexane.

The product was eluted with chloroform / hexane 2: 1.

Fractions 4-8 (500 ml each) were combined and evaporated to an oil which was dissolved in about 400 ml of hot hexane, treated with charcoal and cooled to give crystalline ethyl 1-oxo-1H-7- (2-butyl). -li) thiazolo [3.2-3] pyrimidine-2-carboxylate (2.12 g, m.p. 105.5-108 ° C).

Analysis calculated for C, 55.70; H, 5.75; N, 9.99; Found: C, 55.82; H, 5.40; N, 10.22.

Preparation 47 1-Oxo-1H-6,7-dimethylthiazolo [2,3-b] pyrimidine-15-carboxylic acid

Ethyl 1-oxo-1H-6,7-dimethylthiazolo [3,2-a]? -pyrimidine-2-carboxylate (1.41 g) was heated in a water bath with 20 ml of 48% hydrobromic acid for 1 hour. Dissolution occurred within a few minutes and at the end of the reaction time a solid began to form. The reaction mixture was cooled and the product was collected by filtration. Recrystallization from ethanol gave pure 1-oxo-1H-6,7-dimethylthiazolo-[3,2-a] pyrimidine-2-carboxylic acid (50 mg, m.p. 189-2 59 ° C).

Analysis calculated for C 9 H 9 O 3 S 2: C, 48.21; H, 3.60; N, 12.49; mass ions, 224; Found: C, 48.21; H, 3.68; N, 12.44; 30 mass ions, 224.

Preparation 48 1-Oxo-1H-6-methyl-7-ethylthiazolo [2,3-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-6-methyl-7-ethylthiazolo [-3,2-a] pyrimidine-2-carboxylate (971 mg) was heated at 50 ° C.

IL

67706 in a water bath with 15 ml of 48% hydrobromic acid. Dissolution occurred almost immediately. Heating was continued for 2.5 hours, after which time the reaction mixture was cooled to give the product as a solid on the filtrate. Recrystallization of the crude product from isopropyl alcohol gave pure 1-oxo-1H-6-methyl-7-ethyl acids Solo [3,2-a] pyrimidine-2-carboxylic acid (354 mg, m.p. 201-202 ° C). . Analysis calculated for C 18 H 18 N 2 O 2 S 2 S: 10 C, 50.41; H, 4.23; N, 11.76; Found: C, 50.28; H, 4.26; N, 11.80.

Preparation 49 1-Oxo-1H-6-ethyl-7-methyls 1'-3,2-α7-pyrimidine-2-carboxylic acid 15 Ethyl-1-oxo-1H-6-ethyl-7-methyls Solo Β-3,2-α] -Pyrimidine-2-carboxylic acid (1.33 g) was heated on a water bath with 10 mL of 48% hydrobromic acid for 30 minutes during which time a solid began to form. The mixture was cooled and the crude product was collected by filtration. Recrystallization from isopropyl alcohol gave pure 1-oxo-1H-6-ethyl-7-methylthiazolo [2,3-a? pyrimidine (5 96 mg, m.p. 17 4-17 6 ° C).

Analysis calculated for C 18 H 19 N 2 O 2 N 2 S: 25 C, 50.41; H, 4.23; N, 11.76; Found: C, 50.44; H, 4.22; N, 11.82.

Preparation 50 1-Oxo-1H-6,7-diethylthiazolo [2,3-b] pyrimidine-2-carboxylic acid 30 Ethyl-1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrrole mididine-2-carboxylate (19.2 g) was heated for 1 hour at 85 ° C with 48% aqueous HBr. Gas formation was observed (probably due to decarboxylation). The reaction mixture was cooled and basified with concentrated ammonium hydroxide and the unreacted starting material and impurities were extracted off with ethyl acetate. The aqueous phase was acidified with acetic acid and the solid product was collected by filtration. The crude product was recrystallized from isopropyl alcohol to give partially purified product (5.4 g) in two portions. The partially purified material (2.5 g) was recrystallized a second time from isopropyl alcohol to give pure 1-oxo-10H-6,7-diethylthiazolo [3,2-a] pyramidine-2-carboxylic acid Z ", 6 g, mp 104-106 ° C (cloudy) ./.

Analysis calculated for C, 52.37; H, 4.79; N, 11.10; Found: C, 52.31; H, 4.79; N, 11.16.

15 Preparation 51 1-Oxo-1H-cyclopentenothes Solo Z- "3,2-α7-pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-cyclopentenothiazolo Z -3,2-a] pyrimidine-2-carboxylate (1.3 g) was heated with 15 ml of 48% hydrobromic acid in a water bath for 30 minutes. Dissolution occurred after about 5 minutes; at the end of the heating period, a solid began to form. The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from isopropyl alcohol gave pure 1-oxo-1H-cyclopentenothiazolo [3.2-3] pyrimidine (0.51 g, m.p. 022-230 ° C).

Analysis calculated for C 11 H 9 O 2 • S.

C, 50.84; H, 3.41; N, 11.86; Found: C, 50.42; H, 3.57; N, 11.65.

The sodium and potassium salts are obtained by dissolving the free acid in water with one equivalent of the appropriate hydroxide and either evaporating the water off in vacuo or by freeze-drying.

The N-methylmorpholine salt is prepared by dissolving the acid in methylene chloride with a small excess of N-methylmorpholine and evaporating to dryness, or precipitating the salt by cooling and adding hexane.

5 Preparation 52 1-Oxo-1H-cyclohexenothiazolo Z * 3,2-a-pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-cyclohexenothiazolo Z3,2-α-7-pyrimidine-2-carboxylate (2.8 g) was heated in a 10 water bath with 30 ml of 48% hydrobromic acid. Dissolution occurred within a few minutes of starting heating; precipitation of the product had begun at the end of the reaction time. The reaction mixture was cooled in an ice bath and 1-oxo-1H-cyclohexenothiazolo Z 3,2-α-15-pyrimidine-2-carboxylic acid (1.66 g, mp 188-189 ° C) was isolated by filtration. Recrystallization from ethanol gave 1.38 g of product with the same melting point.

Alternatively, this product was prepared by mixing 22.2 g of ethyl ester with 223 ml of 48% hydrobromic acid in a low pressure vessel. Dissolution occurred at 65-70 ° C. The reaction mixture was heated for 40 minutes at a maximum temperature of 85 ° C and a maximum pressure of 48.3 kPa. The reaction mixture was cooled to 45 ° C, the gases were vented, cooled to 5 ° C, stirred for 1 hour and the relatively pure product was recovered directly. by filtration (12.4 g, mp 192-194 ° C).

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

Preparation 53 1-Oxo-1H-cycloheptenothiazolo Z "3,2-α7-pyrimidine-35-n-2-carboxylic acid

Ethyl 1-oxo-1H-cycloheptenothiazolo [3,2-b] pyrimidine-2-carboxylate (5.8 g) was heated at 15 ml.

II

53 67706 minutes in a water bath with 50 ml of hydrobromic acid. The reaction product was poured onto ice, stirred and the crude product was collected by filtration. Recrystallization from ethanol gave pure 1-oxo-1H-cyclo-5-heptenothiazolo, 2-α / pyrimidine (2.63 g, mp 162-163 ° C).

Analysis calculated for C 12 H 22 N 2 O 2 S: C, 54.53; H, 4.58; N, 10.60; mass ion, 264; Found: C, 54.72; H, 4.73; N, 10.88; 10 mass ions, 264.

Amine salts are prepared by adding one equivalent of amine to a warm ethanolic solution of the acid, followed by cooling, concentrating or adding hexane.

Preparation 54 1-Oxo-1H-cyclooctene-thiazolo Z "3,2-a7-pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-cyclooctenothiazolo 2-α-pyrimidine-2-carboxylate (1.23 g) was heated in an oil-20 bath with 30 ml of 48% hydrobromic acid at 90 ° C for 4 hours. The reaction mixture was cooled, the pH was adjusted to 1.5 and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with water and then saturated sodium chloride, dried over sodium sulfate and evaporated to an oil, the oil was redissolved in ethyl acetate and the product was extracted with 1N norm. potassium hydroxide. The basic solution was re-acidified to 3-norm. hydrochloric acid and the product was back-extracted into ethyl acetate. The ethyl acetate solution was extracted with water and then saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness to give 1-oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine-2-carboxylic acid (308 mg, Rf 0.6 using chloroform / 1% ethanol for elution).

51+ 67706

Preparation 55 1-Oxo-1H-7-methylthiazolo [2,3-b] pyramidine-2-carboxylic acid

Ethyl 1-oxo-1H-7-methylthiazolo [1,2-a] pyrim-5-mididine-2-carboxylate (3.1 g) was heated in a water bath with 50 ml of 48% hydrobromic acid. Dissolution occurred within 5 minutes. After heating for about 15 minutes, the reaction mixture was cooled and the precipitated product was collected on a filter pad. Recrystallization from acetic acid gave pure 1-oxo-1H-7-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid (1.4 g), m.p. 2 65 ° C (decomp.) 7. Analysis calculated for C 9 H 9 O 9 N 2 S: C, 45.71; H, 2.88; N, 13.33; Found: C, 45.57; H, 3.04; N, 13.40.

Preparation 56 1-Oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-20 carboxylate (7.5 g) was heated on a water bath for 20 minutes with 80 ml of 48% hydrobromic acid. Dissolution occurred within 5 minutes and precipitation of the solid began a few minutes later. The reaction mixture was cooled in an ice bath and the crude product was collected by filtration. Pure 1-oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid / 4.68 g, m.p. 276 ° C (dec.) ./.

Analysis calculated for CyH1 + O3N2S: C, 42.86; H, 2.06; N, 14.28; Found: C, 42.71; H, 2.21; N, 14.32.

Alternatively, this acid can be prepared from the same intermediate by boiling the excess 2-norm used. with hydrochloric acid /.Allen et al., J. Org.

Chem. , 24, 779 (1959 V.

55 6 7 7 0 6

Preparation 57 1-Oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-6-methylthiazolo [2,3-b] pyridine-5-mididine-2-carboxylate (5.96 g) was heated on a water bath for 1 hour with 60 ml of 48% hydrobromic acid. The reaction mixture was cooled in an ice bath and the crude product was collected by filtration, washing with isopropyl alcohol and ether. Recrystallization of the crude product from dimethylformamide gave pure 1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxylic acid -f3.7 3 g, m.p. 2 46-2 48 ° C (dec.) ./. Analysis calculated for C 9 H 9 O 2 • S: 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 by boiling 2-norm. in hydrochloric acid (Dunwell et al., J. Chem. Soc. (C) 1971, 2094).

Preparation 58 2 0 1-Oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate (12.6 g) was heated in a water bath with 125 mL of 48% hydrobromic acid.

25 Dissolution occurred within minutes. After 10 minutes, a solid began to form. Heating was continued for a total of 40 minutes. The reaction mixture was cooled and the crude product (10.1 g) was collected by filtration. Recrystallization of the crude product 2.32 g (6.8 g from the recrystallization of acetic acid) from isopropyl alcohol gave pure 1-oxo-ΙΗ-6-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid ( 1.85 g, mp 162-163 ° C). Analysis calculated for C 9 H 9 O 9 N 9 S: 35 C, 48.21; H, 3.60; N, 12.49; Found: C, 48.17; H, 3.73; N, 12.42.

56 6 7 7 0 6

Preparation 59 1-Oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-b] pyramidine-2-carboxylic acid Ethyl 1-oxo-1H-7- (2-methyl-2 -propyl) -5-thiazolo [3,2-a] pyrimidine-2-carboxylate (5.6 g) was heated on a water bath for 6 hours with 60 ml of 48% hydrobromic acid. After about 10 minutes, before complete dissolution of the ester, the reaction mixture became very thick. At the end of the heating time, the reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from acetic acid and drying over dimethylformamide gave pure 1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid Z "3.33 g, m.p. 241- 242 ° C (decomposed).

Analysis calculated for C 18 H 23 N 2 O 3 • 2 · 2 * C, 52.37; H, 4.79; N, 11.10; Found: C, 52.45; H, 4.82; N, 11.26.

Preparation 60 2 0 1-Oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxylate (1.5 g) was heated on a water bath with 15 ml of 48% hydrobromic acid for 20 minutes. . Dissolution occurred within 5 minutes and after 10 minutes precipitation of the solid began. At the end of the reaction time, the mixture was cooled to room temperature, diluted with about 25 ml of water and the crude product was collected by filtration. The crude product was partially purified by dissolving 1-norm. potassium carbonate and reprecipitation by acidification to 3-norm. hydrochloric acid. Recrystallization from acetic acid gave pure 1-oxo-1H-7-ethylthiazolo-Z-3,2-α7-pyrimidine (594 mg, mp 206-209 ° C).

57 6 7 7 0 6

Analysis calculated for C 9 H 9 N 2 O 2 S: C, 48.21; H, 3.60; N, 12.49; Found: C, 48.01; H, 3.69; N, 12.50.

Preparation 61 5 1-Oxo-1H-7-isopropyl-thiazolo [3,2-a] pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-7-isopropylthiazolo [3,2-d] pyrimidine-2-carboxylate (909 mg) was heated in a water bath with 10 mL of 48% hydrobromic acid for 10 minutes. Dissolution was complete. After 10 minutes, the reaction mixture was cooled to room temperature and the crude product was collected by filtration and recrystallized from ethanol-15 to give pure 1-oxo-1H-7-isopropylthiazolo [,23,2- α) Pyrimidine-2-carboxylic acid (δ 38 mg, m.p. 216-217 ° C).

Preparation 62 1-Oxo-1H-7-phenylcyclohexenothiazolo L 3,2-α-20-pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-7-phenylcyclohexenothiazolo [1,2-a] pyrimidine-2-carboxylate (9.8 g) was heated to boiling with 200 ml of 48% hydrobromic acid for 20 minutes; dissolution occurred after about 10 to 25 minutes. The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from acetic acid gave pure 1-oxo-1H-7-phenylcyclohexeneazolo L3,2-α / pyrimidine-2-carboxylic acid (2.25 g, mp 224-226 ° C).

Analysis calculated for O 3 S: C, 62.56; H, 4.32; N, 8.58; Found: C, 62.26; H, 4.11; N, 8.52.

A second crop of the mother liquor was obtained (704 mg, mp 217-220 ° C).

58 67706

Preparation 63 1-Oxo-1H-7-methylcyclohexenothiazolo L2,2-αJ-pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-7-methylcyclohexeneazolo-5H-3,2-a] pyridine-2-carboxylate (27.5 g) was heated on a water bath for 35 minutes with 275 ml of 48% hydrobromic acid. After 10 minutes a clear solution formed; After 15 minutes, the product began to precipitate. The reaction mixture was cooled to room temperature and the crude product (14.9 g, mp 181.5-183.5 ° C) was collected by filtration, rinsing with water. Recrystallization from dimethylformamide gave pure 1-oxo-1H-7-methylcyclohexenothiazolo L3,2-α7-pyrimidine-2-carboxylic acid (10.1 g, mp 183.5-185.5 ° C).

Analysis calculated for ^ 2% 2Ν2 ^ 3 ^: C, 54.53; H, 4.58; N, 10.60; Found: C, 54.41; H, 4.28; N, 10.58.

Addition of water to the dimethylformamide mother liquor gave a second crop of product (3.11 g, mp 182-184 ° C).

20 Preparation 6 4 1-Oxo-1H-7,7-dimethylcyclohexenothiazolo-Γ3,2-a-pyrimidine-2-carboxylic acid Ethyl 1-oxo-1H-7,7-dimethylcyclohexenothiazolo-TS, 2-a7pyrimidine-2 carboxylate (7.9 g) was combined with 80 ml of 48% hydrobromic acid and heated on a water bath for 50 minutes. Before the dissolution of the ester was complete, acid began to precipitate. The reaction mixture was cooled, diluted with about 100 mL of water, and the crude product (6.7 g) was collected by filter-35 rins, rinsing with a small amount of water. Recrystallization of the crude product from ethanol gave pure 1-oxo-1H-7,7-dimethylcyclohexenothiazolo, 13,2-α] pyrimidine-2-carboxylic acid (4.7 g, mp 197-198 ° C).

59 67706

Analysis calculated for C, 56.10; H, 5.07; N, 10.06; Found: C, 55.85; H, 4.84; N, 10.14.

Preparation 65 5 1-Oxo-1H-7- (2-butyl) thiol Solo [3,2-a7 pyrimidine-2-carboxylic acid

Ethyl 1-oxo-1H-7- (2-butyl) thiazolo [3,2-e] pyrimidine-2-carboxylate (2.0 g) was combined with 20 ml of 48% hydrobromic acid and heated with water. in the bath for 25 minutes. Dissolution occurred within 5 minutes; Within 10 minutes, the product began to precipitate. The reaction mixture was cooled to room temperature, diluted with about 40 mL of water, and the crude product (1.3 g, mp 191-194 ° C) was collected by filtration by rinsing with a small volume of water. Recrystallization of the crude product from ethyl acetate with a small amount of ethanol gave pure 1-oxo-1H-7- (2-butyl) thiazolo [3,2-a] pyrimidine-2-carboxylic acid (606 mg, mp 194-197 °). C).

Analysis calculated for O 3 S: 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 another small batch of product.

Example 1 N- (5-Tetrazolyl) -1-oxo-1H-6,7-dimethyl-thiazolo [3,2-b] pyrimidine-2-carboxamide 1-oxo-1H-6,7-dimethylthiazolo] [3,2-e] pyrimidine-2-carboxylic acid (367 mg, 1.6 mmol) was dissolved in 3 mL of dimethylformamide by heating in a water bath, and 1,1'-carbonyldiimidazole (292 mg, 1.8 mmol) was added. Immediately upon evolution of gas, 5-aminotetrazole (153 mg, 1.8 mmol) was added, dissolution occurred, 35 new solid formed, and the reaction mixture was cooled and the crude product was collected by filtration. obtained pure N- (5-tetrazolyl) -1-oxo-1H-6,7-dimethylthiazolo [2S, 2H-pyrimidine-2-carboxamide-5 dia (336 mg, m.p.> 317 ° C).

Analysis calculated for C 18 H 9 Cl 2 N 2 O 2: C, 41.23; H, 3.11; N, 33.66; Found: C, 41.52; H, 3.40; N, 33.47.

Example 2 N- (5-Tetrazolyl) -1-oxo-1H-e-methyl-4-ethylthiazolo [1,2-a] pyramidine-2-carboxamide 1-oxo-1H-6-methyl-7-ethylethyls Solo / " 3,2-α7 Pyrimidine-2-carboxylic acid (238 mg, 1.0 mmol) was dissolved in 5 mL of dimethylformamide and heated on a water bath, 1,1,1-carbonyldiimidazole (178 mg, 1.1 mmol) was added. After gas evolution ceased, 5-aminotetrazole (93.5 mg, 1.1 mmol) was added, after about 15 minutes a solid began to precipitate, and the reaction mixture was cooled and filtered to give N- (5-tetrazolyl) -1-oxo-1H- 6-methyl-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxamide (227 mg, m.p.> 310 ° C).

Analysis calculated for C 18 H 18 N 2 N 7 S: C, 43.27; H, 3.63; N, 32.11; Found: C, 43.20; H, 3.72; N, 31.88.

Example 3 N- (5-Tetrazolyl) -1-oxo-1H-6-ethyl-7-methylthiazolo [3,2-e] pyrimidine-2-carboxamide 1-oxo-1H-6-ethyl-7-methylthiazolo "3,2-Dipyr-30-mididine-2-carboxylic acid (476 mg, 2.0 mmol) was dissolved in dimethylformide in a water bath. To the hot solution was added 1,1'-dicarbonylimidazole (357 mg, 2.2 mmol); gas was formed. After gas evolution ceased, 5-aminotetrazole (187 mg, 2.2 mmol) was added.

61 67706

Within five minutes, a solid began to form. The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -5'-oxo-1H-6-ethyl-7-methylthiazolo [3,2-a] pyrimidine-2-carboxamide / 388 mg, m.p. 303 ° C (dec.) Analysis calculated for C 12 H 12 Cl 2 N 2 S: C, 43.3; H, 3.6; N, 32.1; Found: C, 43.6; H, 3.9, N, 32.3.

Example 4 N- (5-Tetrazolyl) -1-oxo-1H-6,7-diethylthiazolo Z "3,2-α-pyrimidine-2-carboxamide 1-oxo-1H-6,7-diethyls Solo / 3.2-3 / 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. 5-aminotetrazole (1.13 g, 11 mmol) was added and heating was continued for 30 minutes after the evolution of gas ceased, and the reaction mixture was cooled, and the precipitated crude product was collected by filtration. pure N- (5-tetrazolyl) -1-oxo-1H-6,7-diethylthiazolo [3,2-a] pyrimidine-2-carboxamide-25 dia / 1.11 g, mp 283 ° C (dec.) was obtained. .

Analysis calculated for C 18 H 18 N 2 O 2 S 2 S: C, 45.13; H, 4.10; N, 30.70; mass ion, 319; Found: C, 45.18; H, 4.24; N, 30.52; 30 mass ions, 319.

Example 5 N- (5-Tetrazolyl) -1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-35-n-2-carboxylic acid (378 mg, 16 mmol) and 1,1'-carbamyl diimidazole (285 mg, 17.6 mmol) were combined with 3 mL of dimethylformamide and heated on a water bath; dissolution occurred and gas evolved. After gas evolution ceased, 5-aminotetrazol-5 (150 mg, 17.6 mmol) was added. The product started to precipitate within a few minutes. The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-cyclopentenothiazolo [Z3,2-a] -10 pyrimidine-2-carboxamide (313 mg, m.p.> 310 ° C).

Analysis calculated for C 18 H 18 O 2 N 7 S: C, 43.6; H, 3.0; N, 32.3; Found: C, 43.6; H, 3.3; N, 32.0.

Example 6 N- (5-Tetrazolyl) -1-oxo-1H-cyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide 1-Oxo-1H-cyclohexenothiazolo-L3,2-a-pyrimidine-2-carboxylic acid ( 0.5 g, 2 mmol) and 1,1'-carbonyldiimidazole (0.36 g, 2.2 mmol) were dissolved in 3 mL of dimethylformamide at room temperature; dissolution occurred and gas formed. After gas evolution ceased, the reaction mixture was heated with a water bath, during which time more gas evolved. To the hot solution was added 5-aminotetrazole (0.19 g, 2.2 mmol / 25). The product started to precipitate after a few minutes.

The reaction mixture was cooled and the crude product was collected by filtration. Recrystallization of the crude product gave pure N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo CZ, 2-α7-pyrimidine-2-carboxamide Z319 mg, 30 m.p. 310 ° C (decomp.) ./.

Analysis calculated for C, 45.42; H, 3.49; N, 30.90; Found: C, 45.59; H, 3.62; N, 30.44.

Alternatively, the acid (2.07 g) was dissolved in 40 ml of methylene chloride and 1.74 ml of triethylamine at 0 ° C. Ethyl 63 67706 chloroformate (0.85 mL) in 8 mL of methylene chloride was added over 20 minutes, keeping the temperature of the reaction mixture between 0-5 ° C.

After maintaining the mixture at 0-5 ° C for 45 minutes, 5-aminotetrazole (0.87 g) in 8.1 ml of dimethyl-5-acetamide was added, and the reaction mixture was warmed to 20 ° C over 25 minutes and kept at this temperature. 90 minutes. The product was collected by filtration (2.0 g, mp 308-310 ° C). The product thus prepared (3.9 g) was recrystallized from dimethylacetamide to give pure N- (5-tetrazolyl) -1-oxo-1H-cyclohexenothiazolo Z'3,2-α7pyrimidine-2-carboxamide (3 , 1 g, mp 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 15 and 17.3 mL (17.3 mmol) of standardized 1-norm.

sodium hydroxide with stirring for 30 minutes (pH 11.0). The solution was clarified and the sodium salt precipitated on 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 collected by filtration by rinsing with cold acetone. The pH of this sodium salt (100 mg slurried in 1 any water) was 10.22. The sodium salt was recrystallized by dissolving 2.3 g of it in 23 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 collected by filtration. The pH of the recrystallized sodium salt (100 mg in 1 ml of water) was 8.80.

Analysis calculated for C 11 H 18 N 2 O 3 YSNa. 3H 2 O: 30 H 2 O, 13.7; weight loss on drying, 13.7; neutralization equivalent, 393; Found: H 2 O, 13.43; weight loss on drying, 13.8; neutralization equivalent, 391.

__ - I

64 67706

Example 7 N- (5-Tetrazolyl) -1-oxo-1H-cycloheptenathiazolo [3,2-a] pyrimidine-2-carboxamide 1-Oxo-1H-cyclopentenothiazolo [3,2-a] pyrimidine-5-di-2-carboxylic acid ( 2.1 g, 8 mmol) and 1,1'-carbonyldiimidazole (1.4 g, 8.8 mmol) were combined with 15 mL of dimethylformamide and heated on a water bath. After gas evolution ceased, 5-aminotetrazole monohydrate (0.86 g, 8.8 mmol / 10) was added. Within 5 minutes a solid formed. After heating for a further 30 minutes, the reaction mixture was cooled and the product was collected by filtration. Recrystallization of the crude product from dimethylformamide gave pure N- (5-tetrazolyl-15-yl) -1-oxo-1H-cycloheptenothiazolo [3,2-a] pyrimidine-2-carboxamide Z'1.61 g, m.p. 2 95-296 ° C (dec.) _7. Analysis calculated for C, 47.12; H, 3.95; N, 29.59; Found: C, 47.10; H, 4.11; N, 29.72.

20 Example 8 N- (5-tetrazolyl) -1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-cyclooctene Solo. /* 3,2-α7 Pyrimidine-2-carboxylic acid (308 mg, 1.1 mmol) was dissolved in 10 mL of dimethylformamide and heated on a water bath. 1,1'-Carbonyldiimidazole (196 mg, After gas evolution had ceased, 5-aminotetrazole (103 mg, 1.21 mmol) was added and the reaction mixture was heated for 10 minutes at which time a solid began to precipitate 30. The reaction mixture was cooled and the crude product was collected by filtration. Dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-cyclooctenothiazolo [3,2-a] pyrimidine-2-carboxamide / "183 mg, m.p. 310 ° C (decomp.). .

Analysis calculated for O 2 N 7 S: C, 48.69; H, 4.38; N, 28.39; Found: C, 49.01; H, 4.63; N, 27.35.

Example 9: N- (5-Tetrazolyl) -1-oxo-1H-7-methylthiazo-10β, 3,2-3-pyrimidine-2-carboxamide 1-oxo-1H-7-methylthiazolo [3,2- α7-Pyrimidine-2-carboxylic acid (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 a water bath. After 15 days, 5-aminotetrazole (0.47 g, 5.5 mmol) was added, and before dissolution was complete, new solid began to precipitate.After a few minutes, the reaction mixture was cooled and the crude product was collected by filtration.Recrystallized again from dimethylformamide. pure N- (5-tetrazolyl) -1-oxo-1H-7-methylthiazolo [3,2-a] -pyrimidine-2-carboxamide (1.0 g, m.p.> 310 ° C) was obtained.

Analysis calculated for C 18 H 18 N 2 N 2 O 2: C, 38.99; H, 2.54; N, 35.36; Found: C, 38.97; H, 2.73; N, 34.97.

Example 10 N- (5-Tetrazolyl) -1-oxo-1H-thiazolo [3,7-a] pyrimidine-2-carboxamide 1-Oxo-1H-thiazolo [3,2-a] pyrimidine-2-carboxylic acid ( 1.96 g, 10 mmol) was dissolved in 20 mL of _____ 66 67706 dimethylformamide in a water bath. 1,1'-Carbonyldiimidazole (1.78 g, 11.0 mmol) was added. After gas evolution ceased, 5-aminotetrazole monohydrate (1.13 g, 11 mmol) was added. In less than 5 minutes, a solid formed. After heating for an additional 15 minutes, the reaction mixture was cooled and the crude product was collected by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-thiazolo [3,2-a] pyrimidine-10-2-carboxamide (1.8 g, m.p.> 315 ° C).

Analysis calculated for C 9 H 12 N 2 N 5 S: C, 36.50; H, 1.91; N, 37.25; Found: C, 36.62; H, 2.26; N, 37.72.

Example 11 N- (5-Tetrazolyl) -1-oxo-1H-6-methylthiazolo-Z '3,2-epyramidine-2-carboxamide 1-oxo-1H-6-methylthiazolo [3,2-a] pyramidine 2-Carboxylic acid (2.10 g, 10 mmol) and 1,1'-carbonyldiimidazole (1.78 g, 11 mmol) were combined with 15 mL of dimethylformamide and heated on a water bath. Gas was formed and dissolution occurred. When gas evolution ceased, 5-aminotetrazole monohydrate (1.13 g, 11 mmol) was added. In less than a minute, solid 25 formed. After heating for 5 minutes, the reaction mixture was cooled. Filtration gave N- (5-tetrazolyl) -1-oxo-1H-6-methylthiazolo [3,2-a] pyrimidine-2-carboxamide (2.33 g, mp> 318 ° C).

Analysis calculated for C 9 H 18 N 2 O 2 S: 30 C, 38.99; H, 2.54; N, 35.36; Found: C, 39.35; H, 3.00; N, 35.06.

67 · 67706

Example X2 N- (5-Tetrazolyl) -1-oxo-1H-6-ethylthiazolo-Z * 3,2-a? pyrimidine-2-carboxamide 1-oxo-1H-e-ethylthiazolo [2S, 7-pyrimidine-2 -5 carboxylic acid (4.48 g, 20 mmol) and 1,1'-carbonyldiimidazole (3.57 g, 22 mmol) was combined with 20 mL of dimethylformamide and heated on a water bath. Gas was formed and dissolution occurred. After gas evolution ceased, 5-amino-10 tetrazole monohydrate (2.27 g, 22 mmol) was added. Within a minute a solid formed. The reaction mixture was heated for an additional 15 minutes, cooled and the crude product was collected by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-6-ethyls Solo Z "3,2 -a] -pyrimidine Z'4.7 g, mp 27 4 ° C ( dec),?.

Analysis calculated for C 18 H 18 O 2 N 2 S: C, 41.23; H, 3.11; N, 33.66; Found: C, 41.41; H, 3.30; N, 33.84.

Example 13 N- (5-Tetrazolyl) -1-oxo-1H-7- (2-methyl-2-propyl) -thiazolo [3,2-a] pyrimidine-1-carboxamide 1-oxo-1H-7 - (2-methyl-2-propyl) thiazolo-Z-3,2-α7-pyrimidine-2-carboxylic acid (2.52 g, 10 mmol-25) and 1,11-carbonyldiimidazole (1.78 g, 11 mmol) was combined with 15 ml of dimethylformamide and heated with a water bath to give a gas and dissolve and a solid formed in a few minutes, heating was continued for a total of about 10 minutes, the reaction mixture was cooled and the crude product was collected by filtration. (5-Tetrazolyl) -1-oxo-1H-7- (2-methyl-2-propyl) thiazolo [3,2-e] pyrimidine-2-carboxamide / 1.62 g, 35 mp 2 80 ° C (decomposition! /.

, »« ».

.1 _ ·% [. i r ’68 67706

Analysis calculated for · C, 45.13; H, 4.10; N, 30.70; Found: C, 45.22; H, 4.40; N, 30.05.

Example 14 N- (5-Tetrazolyl) -1-oxo-1H-7-ethylthiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-7-ethylthiazolo [3,2-b] 7 Pyrimidine-2-carboxylic acid (502.5 mg, 2.24 mmol) and 1,1'-carbonyldiimidazole (399.7 mg, 2.46 mmol) were combined with 3 mL of dimethylformamide and heated on a water bath. Dissolution and gas formation occurred, and 5-aminotetrazole monohydrate (253.0 mg, 2.45 mmol) was added after gas evolution ceased to form a clear solution, after 2 minutes a solid began to precipitate, the mixture was warmed for an additional 20 minutes, cooled to room temperature. and the crude product was collected by filtration, and recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7-ethylthiazolo [2,3-a] 20-20 pyrimidine-2-carboxamide (486.8 mg; m.p. 261-262 ° C, (decomp.).

Analysis calculated for C, 41.23; H, 3.11; N, 33.66; mass ion, 291; Found: C, 41.35; H, 3.31; N, 33.55; massaioni, 291.

Example 15 N- (5-Tetrazolyl) -1-oxo-1H-7-isopropyl-thiazolo [3,2-a] pyrimidine-2-carboxamide 1-oxo-1H-7-isopropylthiazolo [3,2-a] pyramidine- 2-Carboxylic acid (537 mg, 2.25 mmol) and 1,1'-carbonyldiimidazole (401 mg, 2.47 mmol) were combined with 3 mL of dimethylformamide and heated on a water bath. Dissolution occurred and gas evolved. After gas evolution ceased, 5-amine 67706 notetrazole monohydrate (255 mg, 2.47 mmol) was added. Precipitation of the product began immediately. Heating was continued for 20 minutes, after which the reaction mixture was cooled and the crude product was collected by filtration.

Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7-isopropyl-thiazolo [2,3-a] pyrimidine-2-carboxamide (32.8 mg, m.p.> 300 ° C).

Analysis calculated for C 11 H 18 N 2 O 3 S: 10 C, 43.27; H, 3.63; N, 32.11; Found: C, 43.34; H, 3.76; N, 31.82.

Example 16 N- (5-Tetrazolyl) -1-oxo-1H-7-phenylcyclohexenathiazolo Z3,2-α7-pyrimidine-2-carboxamide 15-oxo-1H-7-phenylcyclohexenothiazolo Z.3,2-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 on a water bath. After gas evolution ceased, 5-aminotetrazole monohydrate (495 mg, 3.1 mmol) was added. After 10 minutes, the product began to precipitate. After a total of one hour of heating, the reaction mixture was cooled to room temperature and the crude product (312 mg) was collected by filtration. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7-phenylcyclohexenothiazolo [2S] -2-pyrimidine-2-carboxylate (131.5 mg, m.p.> 300 ° C).

Analysis calculated for C 18 H 15 N 2 N 2 N 2 O 2: 30 C, 54.95; H, 3.84; N, 24.92; Found: C, 54.38; H, 3.93; N, 24.61.

70 6 7 7 0 6

Example 17 N- (5-Tetrazolyl) -1-oxo-1H-7-methylcyclohexenothiazolo Z'3,2-pyrimidine-2-carboxamide 5'-oxo-1H-7-methylcyclohexenothiazolo 'C3,2- N-pyrimidine-2-carboxylic acid (1.0 g, 3.78 mmol) and 1,1'-carbonyldiimidazole (675 mg, 4.16 mmol) were combined in 6 mL of dimethylformamide and heated on a water bath. Gas evolved and a solution formed.

After gas evolution 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) was collected by filtration.

Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7-methylcyclohexenothiazolo [3,2-a] pyrimidine-2-carboxamide (980 mg, m.p.> 300 ° C).

Analysis calculated for 20 C, 47.12; H, 3.95; N, 29.59; Found: C, 47.32; H, 4.18; N, 29.60.

Example 18 N- (5-Tetrazolyl) -1-oxo-1H-7,7-dimethylcyclohexenols Solo. Z, 3,2-α7-pyrimidine-2-25 carboxamide 1-oxo-1H-7,7-dimethylcyclohexenothiazole -Z "3,2-α7-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 on a water bath. After gas evolution had ceased, 5-amino-tetrazole 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, mp> 300 ° C) was taken up to 71 ° C. Recrystallization from dimethylformamide gave pure N- (5-tetrazolyl) -1-oxo-1H-7,7-dimethylcyclohexenates Solo Z, 3,2-α-pyrimidine-2-carboxamide (469 mg, m.p. 67706). > 300 ° C).

Analysis calculated for C 18 H 18 N 2 O 2 S: C, 48.69; H, 4.38; N, 28.39; Found: C, 48.80; H, 4.18; N, 28.42.

Example 19 N- (5-Tetrazolyl) -1-oxy-1H-7- (2-butyl) -10-thiazolo [2,3-a] pyrimidine-2-carboxamide 1-oxo-1H-7- (2-butyl) - Thiazolo [2,3-b] pyrimidine-2-carboxylic acid (379 mg, 1.5 mmol) and 1,1'-carbonyldiimidazole (270 mg, 1.66 mmol) were combined in 3 mL of dimethylformamide and heated on a water bath. 15 A gas evolved and a solution formed. After gas evolution ceased, 5-aminotetrazole monohydrate (170 mg, 1.65 mmol) was added and the mixture, which began to form a precipitate after a few minutes, was heated for 20 minutes. The reaction mixture was cooled to room temperature, the crude product was collected by filtration. Recrystallization gave pure N- (5-tetrazolyl) -1-oxo-1H-7- (2-butyl) thiazolo-β3,2-7,7-pyrimidine (247 mg, m.p.> 300 ° C).

Analysis calculated for C, 45.13; H, 4.10; N, 30.70; Found: C, 45.12; H, 4.05; N, 30.58.

Claims (8)

67706 T1 Claim A process for the preparation of therapeutically useful N- (5-tetrazolyl) -1-oxo-1H-thiazolo [2,2-a] pyramidine-2-carboxylates of the formula R 1 "n N 10 0" V (I> f - <f 1 H XN_N 15 H wherein and R 2 together represent alkylene of 3 to 9 carbon atoms or phenylalkylene of 9 to 11 carbon atoms, provided that the ring system thus formed is 5 to 8 members; and and R 2 separately are each hydrogen or alkyl of 1 to 5 carbon atoms; characterized in that (a) a compound of formula V, 25 ΓL R N 2 1 (II) 0 1 C \ 30. OH wherein R 1 and R 2 are as defined above, is reacted with at least one equivalent of 5-aminotetrazole by reacting at least one equivalent of a dehydrating coupling agent at a temperature of 20-110 ° C in an inert organic solvent, or (b) the compound, of formula (II), wherein R 1 and are as defined above, is reacted with about one equivalent of a compound of formula 0 C1-C-R (III) wherein R is alkyl, benzyl or phenyl in the presence of at least one tertiary amine equivalent at -40 to 25 ° C in a reaction-inert organic solvent to form a compound of formula 10 n xn 15. UV) ^ c \ OC-OR rt o 20 wherein R 1, R 2 and R are as defined above, and then the resulting compound is reacted with about one equivalent of 5-aminotetrazole at -40 to + 40 ° C in the same or another similar reaction inert. in an organic solvent. Patent number 67706 for the preparation of a therapeutically active N- (5-tetrazolyl) -1-oxo-1H-thiazolo [2,3-a] pyridine-5-mididine-2-carboxylate with the formula R1'> R0 "" 10. J (I) .0 / N-N 0 'V N ~ (/ j I I \ H XN_N 15 H color R 1 and R 2 are further selected from the group consisting of 3-9 colaters or phenylalkyls of 9-11 colaters, under the reaction of which the ring system is 5- to 8-ledat; 20 and R 2 and R 2 are selected from the group consisting of alkyl and 1-5 cholatom; kännetecknat därav, att man (a) omsätter en förening med formuleln R-, Γ- 'R ^ 30 0 ^ "X0H color R ^ och R ^ är som ovan definierats, med ätminstone en equival av av equivalent to a dehydrate coupling medium at a temperature of 35 to 110 ° C and an inert organic feed medium, or (b) a mixture of compounds of formula (II), II