HU197913B - Process for producing thiazolo-, thiazino- and thiazepinopyrimidine derivatives - Google Patents

Abstract

The invention relates to processes for the preparation of novel fused pyrimidine derivatives of the general formula (I) in which A represents a group CH 2 CH 2, CH 2 CH 2 CH 2, CH 2 CH 2 CH 2 CH 2 or CHCH; R4 is hydrogen, C1-4alkyl or optionally substituted phenyl; r is 0, 1, 2, 3 or 4; R 1 is hydrogen or C 1-5 alkanoyl; R 2 represents hydrogen or C 1-5 alkanoyl or a group of general formula (a) wherein R is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, phenyl or phenyl-C 1-3 alkyl; and R3 is hydrogen, which can be obtained, for example, by reacting a 2-mercapto-4,6-diamino-pyrimidine with a dihalogen derivative. The novel fused pyrimidine derivatives are used as pharmaceutical preparations for stimulating immune system function. Formula (I)

Description

The present invention relates to novel condensed pyrimidine derivatives.

No. 1,072,414. United Kingdom Patent No. 4,198,125 to Thiazolo [3,2-d] -pyrimidines describes circulating, sedative, diuretic, cytostatic, bacteriostatic, anti-inflammatory and antipyretic effects.

The Japn. J. Tokyo Koho80 64 591 discloses dioxa derivatives of thiazolo [3,2-a] pyrimidines having immunomodulatory activity.

It is known that one of the basic functions of the control of infectious diseases is to increase the efficacy of immunoprophylaxis and to create a homogeneous immune state in large populations. Immune stimulating compounds are of great help in this endeavor.

It is an object of the present invention to provide novel condensed pyrimidine derivatives having improved immunostimulatory properties.

The present invention relates to a process for the preparation of condensed pyrimidine derivatives of formula (I): wherein:

A is -CH ₂ -, CH ₂ -, vinyl, -CH ₂ -CH ₂ -CH ₂ or -CH ₂ -CH ₂ -CH ₂ -CH ₂ -;

R ₄ is hydrogen, C 1-4 alkyl, or phenyl;

r is 1;

R 1 is hydrogen or C 1-5 alkanoyl;

R ₂ is hydrogen, C 1 -C 5 alkanoyl, or a group of formula (a) wherein:

R is C 1-4 alkyl, C 2-4 alkenyl, phenyl or phenyl (C 1-3 alkyl), and

R ₃ is hydrogen) and their pharmaceutically acceptable acid addition salts and hydrates of the compounds of formula I and their acid addition salts by

a) reacting a 2-mercapto-4,6-diaminopyrimidine of formula II (wherein R 1, R ₂ and R _{3 are} as defined above) with a dihalo derivative of formula III (wherein Y is a halogen atom, Z is halogen, preferably chlorine or bromine and A, R ₄ and R are as defined above); obsession

b) reacting a 2-mercapto-4,6-diaminopyrimidine of formula II with a compound of formula III to form a compound of formula IV wherein A, R 1, R ₂ , R ₃ and R ₄ is as defined above) cyclized after isolation; obsession

c) In the preparation of compounds of formula I wherein A is -CH ₂ -CH ₂ -, a compound of formula VII wherein A is -CH ₂ -CH ₁ - and R ₄ and R ₅ are as above) is reacted with malonic acid dinitrile of formula VIII;

optionally (i) reacting a compound of formula (I) wherein R ₁ and / or R _{2 are} hydrogen, with a carboxylic acid of formula (V) wherein R ₅ is hydrogen or C 1-4 alkyl or a reactive functional derivative thereof; or (ii) reacting a compound of formula (I) wherein R ₂ is hydrogen with an isothiocyanate of formula (VI) (wherein R is as defined above);

and optionally converting or releasing the compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt or converting the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof into a hydrate.

The compounds of formula (I) wherein R _{1 (} R ₂ and R _{3 are} hydrogen) may exist in two atoms as depicted in Scheme A. In the formulas A, R ₄ and r are as defined above.

It has now been found that the novel compounds of formula (I) possess an immunostimulatory activity which significantly enhances the cellular immune response and show no incompatibility with the vaccines used.

As used herein, the term "C 1-4 alkyl" is intended to mean straight or branched saturated aliphatic hydrocarbon groups (e.g., methyl, ethyl, η-propyl, isopropyl, n-util, etc.).

The term "C 1-5 alkanoyl" refers to acidic radicals of aliphatic carboxylic acids having the appropriate number of carbon atoms (e.g., formyl, acetyl, propionyl, butyryl, etc.). The term "C 2-4 alkenyl" refers to straight or branched, unsaturated aliphatic hydrocarbons e.g. vinyl, allyl, metal, etc.). Among the "phenyl (C1-C3) alkyl" groups are e.g. the benzyl or beta-phenylethyl group is mentioned.

It represents 1,2-ethylene, 1,3-propylene, 1,4-butylene or vinyl.

Preferred compounds of formula I are those wherein A is -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ * -CH ₂ -; R ₄ is hydrogen or methyl; r is 1; R 1 and R ₃ are hydrogen and R ₂ is hydrogen or a group of formula (a) wherein R is ethyl.

The compounds of formula I form salts with pharmaceutically acceptable inorganic or organic acids. Preferred salts include hydrogen halides (e.g., hydrochlorides or hydrobromides), carbonates, bicarbonates and sulfates, as well as acetates, fumarates, maleates, cifrates, ascorbates, and the like. we mention it.

According to process (a) of the present invention, a 2-mercapto-4,6-2197913 of formula II

-diaminopyrimidine is reacted with a dihalo derivative of formula (III). The reaction may be carried out in an inert organic solvent. As the reaction medium, e.g. dialkyl amides (preferably dimethylformamide), dialkyl sulfoxides (preferably dimethyl sulfoxide), aliphatic alcohols (e.g. ethanol or isopropanol), chlorinated aliphatic hydrocarbons (e.g. chloroform, carbon tetrachloride, dichloromethane), aromatic (aromatic), benzene, toluene, xylene), aliphatic ethers (e.g. diethyl ether, tetrahydrofuran or dioxane), aliphatic hydrocarbons (e.g. hexane or benzine), aliphatic ketones (e.g. acetone or methyl ethyl ketone) or mixtures thereof. The reaction may be carried out in the presence of an acid scavenger, preferably alkali metal carbonates (e.g., sodium carbonate or potassium carbonate), alkali metal bicarbonate (preferably sodium bicarbonate) or carbonate. , alkali metal hydroxides (e.g. sodium hydroxide craving potassium hydroxide), alkaline earth metal hydroxides (e.g. calcium) hydroxide) or tertiary amines (e.g., pyridine, triethylamine or other trialkylamines) may be used. Preferably, sodium carbonate or potassium carbonate may act as an acid scavenger.

The starting materials (II) and (III) may be used in equimolar amounts or may be added in an amount of 0.1 to 0.5 molar excess of the dihalo derivative (III).

Depending on the reactivity of the starting materials, the reaction may be carried out at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably at about 70 ° C.

However, the compound of formula (I) may also be isolated in the form of its acid addition salt, preferably its hydrobromide, and other pharmaceutically acceptable acid addition salts as mentioned above.

In process (b) of the present invention, a 2-mercapto-4,6-diaminopyrimidine of formula (II) is reacted with a compound of formula (III) and the resulting compound of formula (IV) is cyclized after isolation. The reaction may be carried out in the presence of inert organic solvents as described in process a) or in the presence of acid scavengers. The preparation of the compounds of formula (IV) can be carried out at a temperature lower than that used in process (a), preferably at 30-50 ° C, more preferably at 40 ° C, while the process (b) (including ring closure) we continue. The reaction time is 10-20 hours, depending on the reactivity of the starting materials and the temperature used. The ring closure of the compounds of formula (IV) may be advantageously carried out at elevated temperatures, in particular between 50 ° C and the boiling point of the reaction mixture.

The reaction mixture is worked up in a manner known per se.

In step i of the process of the present invention, the compound of formula (I) wherein R ₁ and / or R ₂ is hydrogen is reacted with a carboxylic acid (V) or a reactive functional derivative thereof. The reactive derivatives of the carboxylic acids of general formula (V) are preferably carboxylic anhydrides, carboxylic acid halides or carboxylic acid esters. The acylation can be carried out in a manner known per se. When acylated with acid chloride, it is preferable to work in the presence of an acid scavenger. For this purpose, e.g. Alkali metal carbonates, alkali metal bicarbonates or alkali metal hydroxides or triethylamine may be used. In the case of acid anhydride acylation, excess acid anhydride may serve as the reaction medium, otherwise it may be employed in an inert organic solvent medium. When the acylating agent is carboxylic acid (V), the reaction may be carried out in the presence of a dehydrating agent (e.g., dicyclohexylcarbodiimide). Depending on the reactivity of the reaction partners, the acylating agent may generally be carried out at a temperature between 10 ° C and the boiling point of the reaction mixture.

Depending on the amount of compound of formula (V) above, the compound of formula (I) containing one or two alkanoyl groups is obtained, i.e., the amino group and / or the imino group on the pyrimidine ring are acylated.

According ii step process provided by the present invention (1) compound is hydrogen, R ₂ is reacted with (VI) an isothiocyanate of formula and thus R to produce a compound of formula (I) containing a group of formula ₂ is (a). The reaction may be carried out in an inert organic solvent medium at a temperature between room temperature and the boiling point of the reaction mixture. Preferred reaction media are alkanols (e.g. ethanol). The isothiocyanate of formula (VI) may be used in an amount of from 1 to 1.5 molar equivalents per inch of amino compound of formula (I).

In process c) of the present invention, R _1; R ₂ and R ₃ is hydrogen and A is -CH ₂ -CH ₂ - compounds of formula (I) or -CH = CH- are prepared. The process involves reacting a compound of formula (VII) with malonic acid dinitrile (VIII). Suitable reaction media are inert organic solvents, preferably process solvents a), except aliphatic ketones. It is particularly preferred to work in an aliphatic alcoholic medium. The reaction may, if desired, be carried out in the presence of a basic catalyst. For this purpose, it is preferably an alkali metal alcoholate; (e.g., sodium methylate or sodium3)

-3197913

ethyl acetate), but other bases listed in process a) may also be used.

The starting materials (VII) and (VIII) may be used in equimolar amounts, or may be added in an amount of 0.1-0.5 mol of the malonic acid dinitrile (VIII).

The reaction may be carried out at room temperature to the reflux temperature of the reaction mixture, depending on the reactivity of the starting materials.

The reaction mixture may be worked up in a manner known per se.

The resulting compound of formula (I) can be converted to the acid addition salt by reaction with an appropriate acid in an inert organic solvent.

The compounds of formula I can be liberated from their acid addition salts by reaction with an appropriate base in a manner known per se.

The compounds of the formula I and their acid addition salts form hydrates. Hydrates may be prepared from the compound of formula I or an acid addition salt thereof by the addition of water or the hydrates may be formed spontaneously by the hygroscopic properties of the anhydrous compounds.

2-Mercapto-4,6-diaminopyrimidine (II) is a known compound which can be prepared by modified Traube synthesis [W. Traube, Ann. 331, 64 (1904)].

The compounds of formulas (III), (V) and (VI) are starting materials known in the art.

The compounds of formula I have, as already mentioned, a valuable immunostimulatory effect.

Exogenous regulation of the immune system, correction of its increased or defective function, has become the focus of research in the last decade, following a more detailed understanding of immunological processes.

Immunity, in the microbiological sense, is the defense of the body against pathogens (bacteria, viruses, fungi, parasites) or their toxic substances. The current immune status and its development can be influenced not only by genetic features but also by environmental physiological effects.

Cells in the immune system operate according to a strict division of labor, where some appear to recognize foreign matter (antigens), others produce antibodies, or differentiate into reactive immunocytes, and find cells that coordinate or regulate relationships between specific groups of cells. Based on this, immunity can also be characterized by the body recognizing foreign substances and being able to respond to them through complex, strictly defined cellular interactions.

The use of artificially induced vaccinations to prevent infectious diseases is extremely important. active immunity when the 'attenuated' version of the pathogen or the killed pathogen or its toxins are introduced into the body.

Vaccines used in immunoprophylaxis have different immunogenic effects. While some vaccines can induce life-threatening immunity, others give protection for 1 to 2 years, but most vaccines produce immunity of only a few months.

In the last decade, the so-called. Recognition or practical application of immunomodulatory and immunostimulatory agents has produced promising results and progress in correcting the immune deficiency of the body (immunodeficiency) and in enhancing the efficacy of weakly immunogenic vaccines.

The latter is of particular importance in the veterinary field, where the establishment of immunological homogeneity of large animal populations is a prerequisite for the production of flavored livestock according to their genetic characteristics.

In our attempts to study the immunostimulatory activity of certain compounds, it has been discovered that the compounds of formula (I) have a beneficial effect on the cellular defense of the body and, when used, may enhance the immunogenic activity of certain weakly immunogenic herpesvirus vaccines.

Tables 1 and 2 show the results of the immunostimulatory activity of the compound of formula (I) in mouse and porcine model experiments.

-4197913. Mouse model experiment

Tesztvegyü- being 0.1 mg / mouse Animals CT Vaccine Szana RCF 1. example Ay.att. 8) 6-20 / 4-12 18-8 / 8-6 Ay.inakt. 80 3-17 / 3-9 7-16 / 6-8 Example 4 Ay.att. 51 5-15 / 5-10 8-5 / 7-4 Example 7 Ay.att. 50 7-21 / 5-11 18-10 / 7-4 Example 2 Bi 9 160 12-23 / 6-12 21-6 / 9-6 Example 12 Ay.att. 50 4-20 / 3-10 14-6 / 6-4

Comment:

In the numerator, animals treated with the vaccine combined with the compound, and in the denominator, animals treated with the vaccine alone, respectively. the values measured in the 3rd or 4th week samples are expressed as a percentage.

Legend:

RCF = immunostaining formation CT = cytotoxic reactions

Table 2 Pig model experiment

test Compound Vaccine The number of the Α11ε case RCF CT 1. example attenuated 1C 14-24 / 6-14 18-13 / 5-11 5 mg / pig Inactive IC 5-26 / 4-15 5-21 / 4-11

Legend: Table 1

The following assay was used for in vitro reactions of peripheral lymphocytes:

Separation of lymphocytes:

Protein blood cells were separated with Ficoll Paque from blood samples inhibited by coagulation with heparin. Cell density was adjusted to 10 ⁶ / ml in Hanks's solution containing 10% fetal serum. 1.5-1.5 ml of cell suspensions were weighed into Leighton tubes and supplemented with assay antigens.

Immunoset formation (RCF): 3% solution of sheep red blood cells was adsorbed with Böiven antigen after appropriate pretreatment. From the red blood cells so treated

0.1 ml was added to Leighton tubes and after 16 hours of incubation, the proportion of rosette-forming cells in the stained preparations was evaluated microscopically.

Cytotoxic reactions (CT):

studies were performed in an allogeneic system. As an example, 0.1 ml of a 10 ⁶ / ml cell lymphocyte suspension was added to the antigen-sensitized suspension of sheep red blood cells. Cytotoxic capacity values were determined from haemolysis after 16 hours incubation, measured at 540 nm on a Spekol instrument. The magnitude of the reaction is expressed as a percentage of the control.

-5197913

As shown in the tables, the test compounds do not substantially affect the blastogenesis of lymphocytes, but they increase the efficiency of cellular immune responses, which, when used in the immuno-inducing phase, have RCF values of 8-

It is measured by 11% and 10-12% increase in CT values.

Comparing the activity of the compounds of formula (I) is described in Drugs of the Future. 9, 591 (1984), the difference is that while it activates only suppressor T cells, the compounds of formula (I) increase the activity of T-killer lymphocytes and so on. lymphocid-K cells, which is expressed as an increase in the cytotoxic capacity of the cellular immune system.

The compounds of formula (I) may be used in the art by methods well known in the art.

It is a further object of the present invention to provide a pharmaceutical composition, in particular an immunostimulant composition, by preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof or a hydrate of a compound of formula (I) or an acid addition salt thereof.

The pharmaceutical compositions are prepared by methods known in the art for the preparation of the immune system, so that the vaccine and the immunostimulatory compound of formula (1) can be delivered at various sites throughout the body. However, it is also possible to use the active ingredient of the formula I in the form incorporated in the vaccine.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

Preparation of 7-amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine hydrobromide

14.2 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine and 21.6 g (0.115 mol) of ethylene bromide in 200 cm ^{3 of} dimethylformamide, 13.8 g (0.1 mol) After stirring for 5 hours at 70 ° C in the presence of potassium carbonate, the product is cooled, filtered, washed with water and dried. 23.6 g (95%) of the title compound are obtained. Mp> 300 ° C.

C ₆ H ₉ BrN ₄ S = 249.136

Anal:

H, 3.64; N, 22.49; S, 12.87; Br, 32.07; Found: C, 28.88; H, 3.68; N, 22.66. %

S, 12.70%, Br32.08%.

Example 2

Preparation of 8- amino-6-imino-3,4-dihydro-2H, 6H-pyrimido [2,1-b] [1,3] thiazine hydrobromide

The method

14.2 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine and 23.2 g (0.115 mol) of 1,3-dibromopropane are reacted as described in Example 1. After working up the reaction mixture

23.7 g (90%) of the title compound are obtained. 01vadáspont> 300 ° C.

C ₇ H _n BrN ₄ S = 263.163

ANALYSIS:

Found: C, 31.95; H, 4.21; N, 21.29; S, 12.18; Br, 30.36; Found: C, 32.38; H, 4.24; N, 21.10 %

S, 12.04%, Br, 30.76%.

Method B.

14.2 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine and 15.8 g (0.1 mol) of 1,3-chlorobromopropane were reacted as described in Example 1. Workup of the reaction mixture gave 17.1 g (65%) of the title compound. Mp> 300 ° C.

C ₇ H ,, BrN ₄ S = 263.163

ANALYSIS:

Found: C, 31.95; H, 4.21; N, 21.29; S, 12.18; Br, 30.36%. Found: C, 33.18; H, 4.52; N, 21.28. %

S 12.10%, Br 30.85%.

Example 3

Preparation of 7-amino-2-phenyl-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine hydrobromide

14.2 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine and 30.4 g (0.115 mol) of (1,2-dibromoethyl) benzene in 200 cm ^{3 of} dimethylformamide, g (0.1 mol) in potassium carbonate for 6 hours at 45 ° C. After cooling, the reaction mixture is filtered, the precipitate is washed with water and dried. 26.0 g (80%) of the title compound are obtained. 01vadáspont> 300 ° C. C _1; H ₁₃ BrN ₄ S = 325.235

Anal:

H, 4.03; N, 17.23; S, 9.85; Br, 24.57. Found: C, 44.52; H, 4.04; N, 17.10.

S, 9.81%, Br, 25.05%.

Example 4

Preparation of 8- amino-6-imino-3-methyl-2H, 6H-pyrimido [2,1-b] [1,3] thiazine hydrobromide

14.2 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine and 19.7 g (0.115 mol) of 2-methyl-1,3-chlorobromopropane were prepared as described in Example 1. with. Work-up of the reaction mixture gave 18 g (65%) of the title compound. Mp> 300 ° C.

Calculated for C ₈ H ₁₃ BrN ₄ S 277.19: C 34.67, H 4.73, N 20.21, S 11.57, Br * 28.83% m: C 34, 68%, H 4.80%, N 19.96%,

S 11.40%, Br 29.39%.

Example 5

Preparation of 7-Amino-5-imino-3 (or 2) -methyl-2H, 5H-thiazolo [3,2-a] pyrimidine hydrobromide

-6197913

14.2 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine and 23.2 g (0.115 mol) of 1,2-dibromopropane were reacted as described in Example 1. After working up the reaction mixture

15.8 g (60%) of the title compound are obtained. Melting point> 300 ° C.

C ₇ H _H BrN ₄ S = 263.163

Calculated for C11H12N6O7: 0 31.95%, H 4.21%, N 21.29%, S 12.18%, Br 30.36%, Found: C 32.50%, H 4 , 47%, N, 21.24%,

S 11.97%, Br 30.79%

Example 6

Preparation of E-2 - [(2-bromo-vinyl) -thio] -4,6-diaminopyrimidine

14.2 g (0.1 mol) of 2-mercapto-4,6-diaminopyrimidine and 20.4 g (0.11 mol) of 1,2-dibromoethylene (cis - (- trans) in 200 cm ^{3 of} dimethyl) formamide, 13.8 g (0.1 mol) of potassium carbonate was reacted for 17 hours at 45 ° C, and the reaction mixture was poured into 1000 cm ^{3 of} water, and the precipitated crystals were filtered off, washed with water and dried. 0 g (44.5%) of the title compound are obtained, m.p. 184-186 ° C C ₆ H ₇ BrN ₄ S = 247.12

ANALYSIS:

H, 2.85; N, 22.67; S, 12.97; Br, 32.34. Found: C, 29.99; H, 3.00; N, 21.91. %

S, 12.83%, Br, 32.32%.

Example 7

Preparation of N-Ethyl-N'- (5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-7-yl) -thiourea hydrochloride

11.3 g of a suspension of 26.5 g (0.1 mol) of 7-amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine bicarbonate dihydrate in 140 cm ^{3 of} ethyl alcohol Ethyl isothiocyanate (0.13 mol) was added and the reaction mixture was stirred at reflux for 90 minutes. It is then cooled, filtered, washed with ethyl alcohol and dried. 23 g (90%) of the title base are obtained.

Salt formation:

To a base (12.8 g, 0.05 mol) was added ethyl alcohol containing equimolar hydrochloric acid in 80 cm ^{3 of} acetone. After stirring for 1 hour at room temperature, it is filtered, washed with acetone and dried. 14.6 g (100%) of the title compound are obtained. Mp> 360 ° C. C ₉ H _I4 C1NsS ₂ = 291.826

ANALYSIS:

H, 4.83; N, 24.00; S, 21.97; Cl, 12.15; Found: C, 37.88; H, 4.93; N, 23.70. %

S, 21.95%, Cl, 12.10%.

Example 8

Preparation of 7-amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine bicarbonate dihydrate

To a solution of 224 g of sodium bicarbonate in 2500 cm ^{3 of} water, 24.9 g (0.1 mol) of 7-amino-5-imino-2,3-dihydro'-5H-thiazolo [3,2-a] pyrimidine hydrobromide and the reaction mixture was stirred at room temperature for 1 hour. It is then filtered, washed with water and dried.

17.2 g (75%) of the title compound are obtained. 146-148 ° C.

C ₇ H ₅ N ₄ O ₅ S _I3 = 265.266

ANALYSIS:

Calculated: C, 31.70; H, 4.94; N, 21.12; S, 12.09; Found: C, 32.68; H, 4.70; N, 20.69.

S 12.18%.

Example 9

8-amino-6-imino-3,4-dihydro-2H, 6H-pyrimido [2, lb] [1,3] thiazine hydrochloride carbonate Dihydrate ¹⁵ 26.3 g (0.1 mol) of 8-amino- 6-Imino-3,4-dihydro-2H, 6H-pyrimido [2,1b] [1,3] thiazine hydrobromide gave 17 g (70%) of the title compound under the conditions described in Example 8. Melting point: 196-198 ° C.

C ₈ H ₁₅ N ₄ O ₅ S = 279.293 Life analysis:

Calculated: C 34.40%, H 5.41%, N 20.06%, δ 11.48%, Found: C 35.65%, H 5.52%, N 19.57%.

S, 11.32%.

Example 10

Preparation of 7-Amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine diacetate

(0.02 mole) of 7-amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-hydrocarbonate-dihydrate 5.3g stirred in 30 cm ³ of acetic acid for 6 hours, then the The solution was evaporated and the residual crystals were taken up in ethyl alcohol, filtered and dried. 3.6 g (59.5%) of the title compound are obtained. Melting point: 158-160 ° C.

C ,, H _I8 N ₄ O ₄ S = 320,351

Analysis

Found: C, 43.70; H, 6.00; N, 18.53; S, 10.60; Found: C, 43.68; H, 5.97; N, 18.17.

S, 10.56%.

4® Example 11

Preparation of 7-Amino-5-imino-5H-thiazolo [3,2-a] pyrimidine hydrobromide hydrate

12,35 'g (0.05 mol) of E-2- [(2-bromo-vinyl) ₅ 0 thio] -4,6-diaminopyrimidine in 50 ml of dimethylformamide was stirred at 150 ° C for 20 minutes . The solution is then cooled to 0 ° C, the precipitated product is filtered off, washed with isopropyl alcohol and dried. 9.5 g (72%) of the title compound are obtained. Melting point:> 300 ° C.

C ₆ H ₉ BrN ₄ OS = 265.1355.

Calculated: C 27.18%, H 3.42%, N 21.18%, S 12.09%, Br 30.14%,

C 27.27%, H 3.31%, N 20.32%, S 11.75%, Br 30.84%. example

Preparation of 7- (Acetylamino) -5- (acetylimino) -2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine hydrochloride

12th

-7197913

7-Amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine bicarbonate dihydrate (26.5 g, 0.1 mol) in acetic anhydride (260 cc) was reacted for 1 hour at reflux temperature. It is then cooled and filtered. 17.7 g (70%) of the title base are obtained.

salt formation

To a base of 12.6 g (0.05 mol) was added isopropyl alcohol containing equimolar hydrochloric acid in 210 cm ^{3 of} ethyl acetate. The reaction mixture was stirred at room temperature for 1 hour, then filtered, washed with ethyl acetate and dried. 13.0 g of compound (90%) of the title kapunk.Olvadáspont> 300 ^ö C C _io H ₁₃ C1N ₂ 0 ₄ S = 288.752

ANALYSIS:

Calculated: C 41.59%, H 4.54%, N 19.40%, S 11.10%, Cl 12.28%, Found: C 42.22%, H 4.60%, N 19.25. %

S, 10.96%, Cl, 12.42%.

Example 13

Method C

2-amino-thiazoline, 10.21 g (0.1 mole) and 6.61 g (0.1 mole) of malononitrile in 125 cm ³ of ethanol, 10.12 g of triethyl amine (0.1 mole) was reacted at room temperature for two days . The reaction mixture was clarified and then adjusted to pH 6 with 48% hydrogen bromide under ice-water cooling. 18 g (72%) of the title compound are obtained. Melting point:> 300 ° C

C ₆ H ₉ BrN ₄ S = 249.136

ANALYSIS:

H, 3.64; N, 22.49; S, 12.87; Br, 32.07.

Found: C 29.23%, H 3.70%, N 22.46%,

S, 12.85%, Br, 32.30%.

Example 14

Preparation of 7-Amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine

10.21 g (0.1 mol) of 2-aminothiazoline and 6.61 g of malonic acid dinitrile are reacted in 200 cm ^{3 of} dimethylformamide for 20 minutes at 155 ° C. The mixture was cooled to room temperature and evaporated. The resulting oily product was crystallized with acetonitrile and filtered. 5.1 g (30%) of the title compound are obtained. Mp> 300 ° C

C ₆ H ₈ N ₄ S = 168.218

ANALYSIS:

H, 4.79; N, 33.31; S, 19.06; Found: C, 42.81; H, 4.69; N, 33.29.

S, 19.03%.

Example 15

Preparation of -Amino -7-imino -2,3,4,5-tetrahydro-7H-thiazepino [1,3] [3,2-a] pyrimidine hydrobromide

14.2 g (0.1 mole) of 2-mercapto-4,6-diaminopyrimidine and 24.8 g (0.15 mole) of 1,4-dibromobutane in 200 cm @ ^{3 of} dimethylformamide, (1 mol) in the presence of potassium carbonate for 11 hours at 80 ° C. The precipitated inorganic salt 8 is filtered off, the reaction mixture is clarified after purification and cooled to 10 ° C. The precipitated product is filtered off, washed with isopropanol and dried. 23.3 g (84%) of the title compound are obtained. If necessary, recrystallize from ten times 50% aqueous ethanol. Melting point: 283-284 ° C.

C ₈ H ₃ BrN ₄ S = 277.19

ANALYSIS:

Calculated: C, 34.66; H, 4.73; N, 20.21; S, 11.57; Br, 28.83; Found: C, 34.65; H, 4.76; N, 19.58. %

S 11.35%, Bf 28.19%.

Example 16

Preparation of N-allyl-N'- (5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-7-yl) -thiourea

26.5 g (0.1 mol) of 7-amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine hydrochloride dihydrate (8 µL) and 14.87 ali-1-isothiocyanate (0.15 mol) in 200 cm ^{3 of} ethanol was reacted at reflux for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to 10 ° C, the product was filtered, washed with chilled ethanol and dried. 25.75 g (96.32%) of the title compound are obtained. Recrystallization from 420 cm ^{3 of a} 4: 1 mixture of dimethylformamide: water gave 21.4 g of product, mp 225-226 ° C.

C _io H ₁₃ N ₅ S ₂ = 267.38

ANALYSIS:

Found: C, 44.92; H, 4.90; N, 26.19; S, 23.98; Found: C, 45.70; H, 5.10; N, 26.25;

S, 23.30%.

salt formation

To a suspension of 13.37 g (0.05 mol) of base in 100 ml of isopropanol was added dropwise isopropanol containing equimolar amount of hydrogen chloride with stirring at 10 ° C. Stir at this temperature for a further 2 hours, filter, wash with a little chilled isopropanol, and dry. 15.19 g (100%) of the hydrochloride salt (14) are obtained. Melting point: 186-187 ° C.

C ₁₀ H, ₄ ClN ₅ S ₂ = 303.84

ANALYSIS:

Calculated: C, 39.53; H, 4.64; N, 23.05; S, 21.11; Cm, 67%; Found: C, 39.47; H, 4.58; N, 22.95. .

S, 21.15%, CH1, 70%.

Example 17

Preparation of N-phenyl-N'- (5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-7-yl) -thiourea

7-Amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine bicarbonate dihydrate (26.5 g, 0.1 mol) and 20.3 g (0.15 mol) phenyl isocyanate was reacted as in Example 14 for 35 minutes. Work up of the reaction mixture gave 30 g (98.88%) of compound. If necessary, it can be recrystallized from e'anol. Melting point: 299-210 ° C.

13 H _{1 3} N ₅ S ₂ = 303.413

-8197913

ANALYSIS:

H, 4.32; N, 23.08; S, 21.14; Found: C, 51.37; H, 4.41; N, 22.29.

S, 21.04%.

salt formation

15.17 g (0.05 mole) of the base were prepared as in Example 16 using the hydrochloride salt. 16.99 g (100%) of the hydrochloride are obtained. Melting point: 178-179 ° C. C ₃ H ₁₄ CIN ₅ S ₂ = 339.913

ANALYSIS:

Found: C, 45.94; H, 4.15; N, 20.60; S, 18.87; Cl, 10.43; Found: C, 45.89; H, 4.10; N, 20.57. %

S, 18.85%, Cri0.39%.

Example 18

Preparation of N-benzyl-N '- (5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-7-yl) -thiourea

7-Amino-5-imino-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine bicarbonate dihydrate (26.5 g, 0.1 mol) and 22.4 g (0.15 mol) benzyl isocyanate was reacted as described in Example 15. After working up the reaction mixture

31.2 g (98.8%) of product are obtained. It can be recrystallized from ethanol if necessary. Melting point: 210-211 ° C

C ₁₄ H ₁₅ N ₅ S ₂ - 317,440

ANALYSIS:

Found: C, 52.97; H, 4.77; N, 22.06; S, 20.20; Found: C, 52.63; H, 4.65; N, 21.27.

S, 20.17%.

salt formation

15.87 g (0.05 mole) of the base were prepared as in Example 16 using the hydrochloride salt. 17.69 g (1θθ%) of the hydrochloride is obtained. Mp: 201-202 ° CC, ₄ H, ₆ C1N ₅ S ₂ = 353.898

ANALYSIS:

Found: C, 47.52%, H, 4.56%, N, 19.79%, S, 18.12%, cr, 10.02%, Found: C, 47.48%, H, 4.53%, N, 19.74%. %

S 17.94%, ΟΓ9.97%.

Example 19

Preparation of N- [alpha] 11-yl- (6-imino-3,4-dihydro-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-8-yl) -thiourea

27.9 g (0.1 mol) of 8-amino-6-imino-3,4-dihydro-2H, 6H-pyrimido [2,1-b] [1,3] thiazine bicarbonate dihydrate (9 µl) and 14.87 g (0.15 mol) of allyl isothiocyanate was reacted as described in Example 14. After working up the reaction mixture, 28.0 g (99.5%) of product are obtained, which can be recrystallized from ethanol if necessary. Melting point: 196-197 ° C ₁ H ₁₅ N ₅ S ₂ = 281.407

H, 5.37; N, 24.89; S, 22.79. Found: C, 47.39; H, 5.41; 24.70%

S, 22.69%.

salt formation

From 14.0 g (0.05 mol) of the base to form hydrochloride salt according to Example 16, 15.8 g (100%) of hydrochloride 16 are obtained. Melting point: 175-176 ° C

C ,, Hi6CIN ₅ S ₂ = 317.907

ANALYSIS:

Found: C, 41.56%, H, 5.07%, N, 22.03%, S, 20.17%, Cm, 15%, Found: C, 41.52%, H, 4.95%, N, 21.97%. .

S, 19.98%, Cl, 11.21%.

Example 20

Preparation of N-phenyl-N '- (6-imino-3,4-dihydro-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-8-yl) thiourea

27.9 g (0.1 mol) of 8-amino-6-imino-3,4-dihydro-2H, 6H-pyrimido] 2,1b] [1,3] thiazine bicarbonate dihydrate and 20.3 g of Phenyl isothiocyanate (0.15 mol) was reacted for 2 hours as described in Example 16. The reaction mixture was worked up to give 31.68 g (99.81%) of product which could be recrystallized from methanol if necessary. Melting point: 215-216 ° C CuH ₁₅ N ₅ S ₂ = 317.44

ANALYSIS:

Calculated: C, 52.97; H, 4.76; N, 22.06;

S, 20.20%. Found: C, 5 ', 68%, H, 4.67%, N, 21.57%,

S, 20.23%.

Salt formation:

15.87 g (0.05 mole) of the base were prepared as in Example 16 using the hydrochloride salt. 17.60 g (100%) of hydrochloric acid are obtained. Melting point: 157-158 ° C ₁₄ H ₁₆ ClN ₅ S ₂ = 353.898

ANALYSIS:

Calculated: C 47.52%, H 4.56%, N 19.79%,

S, 18.12%, Cl, 10.02%, Found: C, 47.85%, H, 4.59%, N, 19.63%,

S, 17.98%, Cl, 9.89%.

Example 21

Preparation of N-benzyl-β- (6-imino-3,4-dihydro-2H, 6H-pyrimido [2,1-b] [1,3] thiazin-8-yl) thiourea

27.9 g (0.1 mol) of 8-amino-6-imido-3,4-dihydro-2H, 6H-pyrimido [2,1b] [1,3] thiazine bicarbonate dihydrate and 22.4 g of Benzyl isothiocyanate (0.15 mol) was reacted for 45 minutes as described in Example 16. Work up of the reaction mixture gave 32.98 g (99.5%) of product which was recrystallized from ethanol if necessary. Melting point: 210-211 ° C, ₅ H, ₇ N ₅ S ₂ = 331.466

ANALYSIS:

Calculated: C, 54.35; H, 5.17; N, 21.13.

S, 19.35%. Found: C, 54.28; H, 5.07; N, 20.98%.

S, 19.22%.

salt formation

16.57 g (0.05 mole) of the base was prepared as in Example 16 using the hydrochloride salt. 18.35 g (100%) of the hydrochloride are obtained. Mp: 189-190 ° CC _1s H ₁₅ C1N ₅ S ₂ = 367.924

ANALYSIS:

Calculated: C, 48.97; H, 4.93; N, 19.03.

S 17.43%, Cl ^_ 9.64% Found: C 48.67%, H 5.03%, N 18.97%;

S, 16.93%, Ci, 9.43%.

Claims (17)

PATENT CLAIMS 1. Process of Formula I! fused pyrimidine derivatives (wherein A is -CH ₂ -, CH ₂ -, vinyl, -CH ₂ -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ -CH ₂ -; R ₄ is hydrogen R 1 is C 1 -C 4 alkyl or phenyl; R 1 is hydrogen or C 1-5 alkanoyl; R ₂ is hydrogen, C 1 -C 5 alkanoyl, or a group of formula (a) wherein R is (1-4C) alkyl, (2-4C) alkenyl, phenyl or phenyl (1-3C) alkyl, and R ₃ is hydrogen) and their pharmaceutically acceptable acid addition salts and hydrates of the compounds of formula I and their acid addition salts, characterized in that a) reacting a 2-mercapto-4,6-diaminopyrimidine of formula II (wherein R 1, R ₂ and R _{3 are} as defined above), preferably at about 70 ° C, with a dihalo derivative of formula III (which wherein Y is halogen, preferably bromine; Z is halogen, preferably chlorine or bromine; and A, R ₄ and R are as defined above); obsession b) reacting a 2-mercapto-4,6-diaminopyrimidine of formula (II), preferably at 30-50 ° C, with a compound of formula (III) and then forming a compound of formula (IV): A, R 1, R ₂ , R ₃ and R ₄ are as defined above) cyclized; obsession c) For the preparation of compounds of formula I wherein A is -CH ₂ -CH ₂ - and R 1, R ₂ and R _{3 are} hydrogen, a compound of formula VII wherein A is -CH ₂ -CH alkyl and R ₂ and R ₄ are as defined as defined above) of malonic acid dinitrile of formula (VIII); and optionally (i) reacting a compound of formula (I) wherein R ₁ and / or R _{2 are} hydrogen, with a carboxylic acid of formula (V) wherein R ₅ is hydrogen or C 1-4 alkyl or a reactive functional derivative thereof; or (ii) reacting a compound of formula (I) wherein R ₂ is hydrogen with an isothiocyanate of formula (VI) (wherein R is as defined above); and optionally converting or releasing the compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt or converting the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof into a hydrate. Process (a) according to claim 1, characterized in that the reaction of the compounds of the general formulas (II) and (III) is carried out in the presence of an acid acceptor. 3. The process according to claim 2, wherein the word binder is selected from the group consisting of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkaline earth metal hydroxide, and tertiary amine. 4. A process according to claim 3 wherein the acid scavenger is potassium carbonate or sodium carbonate. Method a) according to claim 1 or steps 2-4. Process according to any one of claims 1 to 4, characterized in that the reaction is carried out in an inert organic solvent. 6. The process of claim 5 wherein the inert solvent is a dialkyl amide, a dialkyl sulfoxide, an aliphatic alcohol, a chlorinated aliphatic hydrocarbon, an aromatic hydrocarbon, an aliphatic ether, an aliphatic hydrocarbon, an aliphatic ketone or mixtures thereof. 7. The process of claim 6 wherein the inert organic solvent is dimethylformamide. Method a) according to claim 1 or steps 2-7. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature between 70 ° C and the boiling point of the reaction mixture. Process b) according to claim 1, characterized in that the compounds of the formula IV are cyclized by gentle heating. Process according to claim 9, characterized in that the reaction is carried out at 30-50 ° C, preferably 40-45 ° C. 11. Step i) of the process according to claim 1, characterized in that the compound of formula (V) the carboxylic acid reactive derivative is a carboxylic anhydride, a carboxylic acid halide or a carboxylic acid ester. The process according to claim 11, wherein the acylation with acid chloride is carried out in the presence of an acid acceptor. 13. The process according to claim 11, wherein the reaction is carried out with an acid anhydride and an excess of the acylating acid anhydride. Process according to any one of claims 11 to 13, characterized in that the reaction is carried out under heating at a temperature between 10 ° C and the boiling point of the reaction mixture. 15. Step ii) of the process of claim 1, wherein the reaction is carried out in an inert organic solvent medium at a temperature between room temperature and the reflux temperature of the reaction mixture. 16. A process for the preparation of compounds of formula I according to any one of claims 1 to 3, wherein A is -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ -; R ₄ is hydrogen or methyl; r is 1; R 1 and R ₃ are hydrogen and R ₂ is hydrogen or (a) -10197913 wherein R is ethyl; characterized in that the appropriate starting materials are used. 17. A process for the preparation of a pharmaceutical composition, in particular an immunostimulant, comprising the preparation of a compound of formula I (A, R ₄ , R, R ₁ , R ₂ and R ₃ ) according to claim 1. or a pharmaceutically acceptable acid addition salt thereof; or a pharmaceutically acceptable acid addition salt thereof The hydrate of a compound of formula (I) or an acid addition salt thereof is converted into a pharmaceutically acceptable form.