FR2487355A1 - 5-Oxo 2,3,6,7-tetra:hydro 5H-thiazolo(3,2-a)pyrimidine derives. - antirheumatics, antiallergics and analgesics with low toxicity - Google Patents

Abstract

3-R3 6-R2 7-R1 7-R 2,3,6,7-tetrahydro- thiazolo(3,2-a)- pyrimidin-5-one derivs. of formula (I) are new. In (I) R is phenyl, 1-4C alkyl (opt. substd. by 1-3 halo atoms), 2-4C alkenyl or 3-6C cycloalkyl and R1 is H or R, R1 independently are phenyl or opt. substd. 1-4C alkyl or together form a 4-5C alkylene gp. and R2, R3 independently are H or 1-4C alkyl, (b) R, R1 are H and one of R2, R3 is H or 1-4C alkyl and the other is 1-4C alkyl. Treatment of rheumatic troubles and allergic states by oral (adult doses of 50-1000 mg. per day), parenteral or rectal admin. The cpds. also have analgesic activity and low toxicity, (LD50 in mice is 300-900 mg/kg. or above 900 mg/kg. by oral administration).

Description

dans laquelle R représente un radical phényle ou alcoyle contenant 1 à 4 atomes de carbone en chaine droite ou ramifiée, leur préparation et les médicaments qui les contiennent.The present invention relates to new thiazolo [3,2-a] pyrimidine derivatives of general formula

in which R represents a phenyl or alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, their preparation and the medicaments which contain them.

According to the invention, the products of general formula (I) can be prepared according to one of the following processes a) by the action of an acid halide of general formula
R - CH = CH - CCX (il) in which R is defined as above and X represents a halogen atom such as chlorine or bromine on 2-amino thiazoline-2 (in equilibrium with its imine form) of formula

 It is generally carried out in an aromatic organic solvent (for example benzene, toluene, xylenes), in a chlorinated solvent (for example chloroform, carbon tetrachloride, 1,2-dichloroethane) or in an ether (for example dioxane, tetrahydrofuran), at a temperature between about 200C and the reflux temperature of the reaction mixture in the presence of an acid acceptor such as a mineral base (alkaline bicarbonate) or organic (triethylamine).

 The halides of general formula (II) can be prepared from the corresponding acids by any method known per se which does not affect the rest of the molecule.

 The 2-amino thiazoline-2 of formula (III) can be prepared according to the method described by S. GABRIEL, Ber. 22, 1141 (1889).

b) by action of an ester of general formula
R - CH = CH - COOR '(Iv) in which R is defined as above and R' represents an alkyl radical containing 1 to 4 carbon atoms on the 2-amino-2-thiazoline-2 of formula (III).

It is generally carried out without solvent or else in an aromatic organic solvent such as benzene, toluene or xylenes
at a temperature between about 500C and the reflux temperature of the reaction mixture, in the presence of an antioxidant such as hydroquinone.

 The esters of general formula (IV) can be obtained from the corresponding acids by any method known per se to obtain an ester from an acid without affecting the rest of the molecule.

dans laquelle R est défini comme précédemment, dans un solvant organique anhydre tel que le diméthylformamide à une température comprise entre environ -10 et 250C maximum en présence d'un hydrure alcalin tel que l'hydrure de sodium.c) by action of 1,2-dibromo ethane on a 4,5-dihydro-2-thio uracil of general formula

wherein R is defined as above, in an anhydrous organic solvent such as dimethylformamide at a temperature between about -10 and 250C maximum in the presence of an alkaline hydride such as sodium hydride.

 The 4,5-dihydro-2-thio-uracils of general formula (V) can be prepared according to the method described by L.S. SBNDBKHCHEIEV and V.P. MAMAEV, Izvest. Sibir. Otdel. Akad. Nawk. S.S.S.R. (1961) NO 7 pages 72-76; C.A. 56 24482.

 The new products of general formula (I) can be purified by conventional methods such as crystallization and chromatography.

 We already know from Belgian patent 778 911 thiazolo [3,2-a] pyrimidinones-5; these products have analgesic activity.

 The new products of general formula (I) have interesting pharmacological properties making them useful for the basic treatment of rheumatic disease and also as anti-allergic.

They are in particular active at doses of between 10 and 100 mg / kg orally in the rat in the edema of the paw caused by a reaction of reverse ARTHUS edema caused by subplantar injection of 50 μg of serum of anti-albumin rabbit immediately followed by intravenous injection of ovalbumin according to the technique of DK GEMMELL et al., Agents and
Actions, 9, 107 (1979)].

 They are also active in rats at doses of between 5 and 50 mg / kg per day for 7 days orally in pleurisy caused by intrapleural injection of Hemophilus pertussis in rats sensitized to this antigen according to the PA DIEPPE technique. et al., Agents et Actions, 6, 618 (1976).

Some of them have been shown to be active at doses of between 20 and 80 mg / kg per day for 18 days orally in the technique of experimental polyarthritis of the rat caused by sub-plantar injection in a hind paw of complete FREUND adjuvant according to F. DELEARRE et al.,
CR Soc. Biol. 162, 58 (1968).

 In addition, the products according to the invention have low toxicity. In mice, the sour toxicity (expressed by its LD50) is generally between 300 and 900 mg / kg or greater than 900 mg / kg orally.

 The following examples, given without limitation, show how the invention can be put into practice.

EXAMPLE 1
A solution of 3.33 g of cinnamoyl chloride in 1.7 cm3 of chloroform is added dropwise over 3 minutes at a temperature close to 200C to a solution of 2.04 g of 2-amino-2-thiazoline-2 and 2.8 cm3 of triethylamine in 7.2 cm3 of chloroform. The reaction mixture, the temperature of which is then 700C, is then heated at reflux for 1 hour 40 minutes, then cooled to 40C using an ice bath. The crystals which appear are separated by filtration, washed twice with 5 cm 3 in total of chloroform and eliminated. The organic filtrates are combined and washed twice with 5 cm3 in total of distilled water, dried over anhydrous sodium sulfate, added with 0.2 g of bleaching black, filtered and concentrated to a volume of 9 cm3. concentrate is chromatographed on a column 1.5 cm in diameter containing 28 g of neutral alumina (0.12-0.15 mm). Eluted with a chloroform / cyclohexane mixture (40-60 by volume), collecting 50 cm 3 fractions. The first 4 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 40 C. This gives 1.1 g of crude product which is dissolved in 1.35 cm3 of boiling ethanol. After cooling to 40C for 1 hour, the crystals which appear are separated by filtration, washed twice with 0.4 em3 in total of ethanol cooled to about 5 C and dried under reduced pressure (20 mm. Of mercury; 2.7 kPa ) i a temperature close to 200C in the presence of potassium hydroxide pellets. 0.6 g of 5-oxo-phenyl-tetrahydro-2,3,6,7 5H-thiasolo [3,2-a] pyrimidine is thus obtained in the form of a white solid melting at 1150C.

EXAMPLE 2
A mixture of 299.5 g of ethyl cinnamate, 173.4 g of 2-anino-thiazoline-2 and 2 g of hydroquinone is heated at 1100C for 24 hours. After cooling to a temperature in the region of 20 ° C., 800 cm 3 of methylene chloride are added and extracted 5 times with 2500 μm in total of a 2N aqueous hydrochloric acid solution. The combined aqueous solutions are brought to fold 8 by addition of a 10N aqueous sodium hydroxide solution, then extracted 4 times with 2000 em3 in total of methylene chloride The organic extracts are combined and dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm mercury; 2.7 kPa) at 400 C. The residue obtained (113 g) is chromatographed on a column 7.5 cm in diameter containing 1100 g of silica (0.06-0.2 mm). methylene chloride, collecting fractions of 1000 cm 3. The first 2 fractions are eliminated and the following 14 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 400 C. This gives 26 g of crude product which is dissolved in 75 cm3 of boiling ethanol added with 1 g of bleaching black.

After hot filtration, the filtrate is cooled to 40C for 12 hours. The crystals which appear are separated by filtration, washed twice with 20 em 3 in total of ethanol cooled to about 50C and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 2O0C in the presence of potassium hydroxide pellets . 21.6 g of 5-oxo-phenyl-tetrahydro-2,3,6,7 5H-thiazolo [3,2-a] pyrimidine are thus obtained in the form of white crystals melting at 1130C.

EXAMPLE 3
51.7 g of sodium hydride in dispersion at 54.5% in oil are added in 25 minutes to a solution cooled to 80C of 110 g of 4-phenyl-4,5-dihydro-2-thio-uracil in 1200 cm3 of anhydrous dimethylformamide, ensuring that the temperature of the reaction mixture remains below 150 C. Twenty-five minutes after the end of the addition, 91.7 cm3 of 1,2-dibromo ethane are poured in dropwise in 30 minutes. the reaction mixture while always maintaining the temperature below 150C. Stirring is continued for a further 2 hours, then the temperature of the mixture is allowed to return to about 200 C. The reaction mixture is then brought to pH 5 by addition of a 1N aqueous hydrochloric acid solution and then concentrated to dryness under pressure reduced (1 mm of mercury; 0.13 kPa) at a temperature below 500C. The residue is taken up in 500 cm3 of distilled water, brought to pH 9 at
Using a 10N aqueous sodium hydroxide solution, and extracted 3 times with 1400 cm3 in total of methylene chloride. The organic phase thus obtained is washed with 300 cm3 of distilled water, dried over anhydrous sodium sulfate, filtered. and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 400C. The residue obtained (111 g) is dissolved in 1100 em 3 of methylene chloride, and chromatographed on a column of 6.8 cm in diameter containing 1100 g of basic alumina (0.05-0.16 mm). Eluted with methylene chloride, collecting fractions of 250 cm3. The first 3 fractions are eliminated; the following 3 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 4000. The residue obtained (32.5 g) is dissolved in a boiling mixture of 70 cm3 of ethanol and 70 cm3 of isopropyl ether. After cooling, the crystals which appear are separated by filtration and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 200C. 13.6 g of crude product are thus obtained, melting at 11000, which are combined with 1.4 g of product prepared in the same way in another operation and dissolved in 60 cm3 of boiling ethanol. The solution is filtered hot and the filtrate is cooled to 40C for 1 hour. The crystals which appear are separated by filtration, washed with 5 cm3 of ethanol then with 5 cm3 of isopropyl ether and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 200C in the presence of potash tablets. 13 g of 5-oxo-phenyl-tetrahydro-2,3,6,7 5H-thiazolo [3,2-a] pyrimidine are thus obtained in the form of white crystals melting at 1120C.

EXAMPLE 4
A solution of 440 g of crotonoyl chloride in 1200 cm 3 of chloroform is added dropwise over 47 minutes to a solution of 504 g of 2-amino-thiazoline-2 and 590 em 3 of triethylamine in 1200 cm 3 of chloroform. The reaction mixture, the temperature of which is then 630C, is maintained at reflux for 16 hours. After cooling to approximately 200C, the crystals which appear are separated by filtration, washed twice with 100 cm 3 in total of chloroform and eliminated. The organic filtrates are combined, concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 4000 and taken up in 700 cm3 of ethyl acetate. The crystals which appear are separated by filtration, washed with 200 em3 d '' a mixture of ethyl acetate and methanol (90-10 by volume) and eliminated.

The organic filtrates are combined and chromatographed on a column 9 cm in diameter containing 3.5 kg of silica (0.06-0.2 mm), eluting with ethyl acetate and collecting fractions of 1000 cm3 . The first 5 fractions are eliminated; the following 6 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 4000. This gives 124 g of crude product melting at 91 C which are divided into 3 equal batches to be chromatographed separately , each on a column 6 cm in diameter containing 480 g of silica (0.040-0.063 mm).

Eluted with ethyl acetate under a pressure of 0.5 bar (51 kPa), collecting fractions of 200 cm3. The first 8 fractions are eliminated; the following 10 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury 2.7 kPa) at 4000. This gives 109 g of product, in the form of white crystals melting at 930C, which are dissolved in 160 cm3 of boiling ethyl acetate added with 1 g of bleaching black.

After hot filtration, the filtrate is cooled to 40C for 2 hours; the crystals which have appeared are separated by filtration, washed 3 times with 100 cm 3 in total of isopropyl ether cooled to approximately 5 ° C., and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 C in the presence of potash tablets. 96.8 g of methyl-7 oxo-5 tetrahydro2,3,6,7 5H-thiazolo [3,2-a] pyrimidine are thus obtained in the form of white crystals melting at 960C.

EXAMPLE 5
A solution of 50 g of pentene-2 oyl chloride in 300 cm3 of chloroform is added dropwise over 30 minutes to a solution of 50.6 g of 2-amino thiazoline-2 and 59 cm3 of triethylamine in 350 cm3 chloroform. The reaction mixture, the temperature of which is then 490 ° C., is heated under reflux for 16 hours. After cooling to approximately 200C, the crystals which appear are separated by filtration and eliminated. The organic filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 400C and then taken up in 250 cm3 of acetone. The crystals which appear are separated by filtration, washed twice with a total of 60 cm3 of acetone and eliminated. The organic filtrates are concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 400C and chromatographed on a column. 7 cm in diameter containing 820 g of silica (0.06-0.2 mm), eluting with ethyl acetate and collecting 1000 cm 3 fractions. The first fraction is eliminated; the following 4 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury 2.7 kPa) at 400C. 31 g of crude product are thus obtained in the form of an oil, which are added to 6 g of product prepared in the same way in another operation to be chromatographed on a column 6 cm in diameter containing 480 g of silica (0, 0400.063 mm). Eluted with an ethyl acetate / cyclohexane mixture (70/30 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 200 cm3. The first 6 fractions are eliminated; the following 6 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 4000.

21.7 g of product are thus obtained which is dissolved in 50 cm3 of boiling isopropyl ether added with 0.2 g of bleaching black. After hot filtration, the filtrate is cooled to 40C for 1 hour and a half; the crystals which have appeared are separated by filtration, washed twice with 20 cm 3 in total of isopropyl ether cooled to approximately 50 ° C., and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 200 ° C. presence of potash tablets. 18.6 g of ethyl-7 oxo-5 tetrahydro-2,3,6,7 5H-thiazolo [3,2-a] pyrimidine are thus obtained in the form of white crystals melting at 600C.

EXAMPLE 6
A solution of 35.5 g of methyl 4-pentene-2 oyl chloride in 200 cm3 of chloroform is added dropwise over 20 minutes to a solution of 32.2 g of 2-amino-2-thiazoline-2 and 37, 7 cm3 of triethylamine in 200 cm3 of chloroform. The reaction mixture, the temperature of which is then 530 ° C., is heated to
reflux for 16 hours. After cooling to around 200C,
the crystals which have appeared are separated by filtration and eliminated. The
organic filtrate is concentrated to dryness under reduced pressure (20 mm
mercury; 2.7 kPa) at 400C and the residue is taken up by 200 cm3
acetone. The crystals which appear are separated by filtration, washed
2 times per 60 em3 in total of acetone and eliminated.
organics are concentrated to dryness under reduced pressure (20 mm
mercury; 2.7 kPa) at 400C and chromatographed on a column of
4 cm in diameter containing 550 g of neutral alumina (0.12-0.15 mm).

Eluted with ethyl acetate, collecting fractions of
500 cm3. The first fraction is eliminated; the 2 following fractions
They are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 4000. This gives 25 g of crude product in the form of an oil which is again chromatographed on a column 6 cm in diameter. containing 480 g of silica (0.040-0.063 mm). Eluted with an ethyl acetate / cyclohexane mixture (60/40 by volume) under a pressure of 0.5 bar (51 kPa), collecting fractions of 250 cm3. The first 7 fractions are eliminated; the following 9 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 4000. This gives 15 g of product which is dissolved in 50 cm3 of boiling isopropyl ether added 0.2 g of bleaching black. After hot filtration, the filtrate is cooled to 40C for 1 hour; the crystals which have appeared are separated by filtration, washed twice with 20 cm 3 in total of isopropyl ether cooled to about 50C and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 200C in the presence of potash in pellets. 11.8 g of isopropyl-7-oxo-5-tetrahydro-2,3,6,7 5H-thiazolo [3,2-a] pyrimidine are thus obtained in the form of white crystals melting at 50.60C.

EXAMPLE 7
A solution of 79.5 g of 2-hexene chloride oyl in 750 cm3 of chloroform is added dropwise over 75 minutes to a solution of 61.2 g of 2-amino-2-thiazoline-2 and 84.2 cm3 of triethylamine in 600 cm3 of chloroform. The reaction mixture, the temperature of which is then 400 ° C., is heated under reflux for 45 minutes, then after cooling to approximately 200 ° C., washed 4 times with 1200 cm 3 in total of distilled water; the organic phase is dried over anhydrous magnesium sulfate, supplemented with 10 g of bleaching black, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 400 C. An oily residue is thus obtained ( 110 g) which is chromatographed on a 5.1 cm diameter column containing 1.1 kg of alumina (0.12-0.15 mm). Eluted with methylene chloride, collecting 1000 cm3 of eluate.

This eluate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) to 4000. This gives 25 g of product which is again chromatographed on a column 3.2 cm in diameter containing 250 g alumina (0.12-0.15 mm) in the presence of cyclohexane. Elution is carried out with chloroform / cyclohexane mixtures, collecting 200 cm 3 fractions. The first 3 fractions (elution solvent: chloroform / cyclohexane 20/80 by volume) are eliminated; the following 4 fractions (elution solvent: chloroform / cyclohexane 30/70 by volume) and the last 3 fractions (chloroform / cyclohexane elution solvent 40/60 by volume) are combined and concentrated to dryness under reduced pressure (20 mm mercury; 2.7 kPa) at 4000.

This gives a residue (14.7 g) which is taken up in 50 cm3 of ethyl ether and filtered. After filtration, the solution is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 40 "C and chromatographed on a 2.4 cm diameter column containing 100 g of alumina (0.12- 0.15 mm) Eluted in fractions of 100 cm3 under the following conditions: - Fraction 1: (pure cyclohexane) - Fraction 2: (pure cyclohexane) - Fractions 3 and 4: (cyclohexane / chloroform: 90/10 by volume ) - Fractions 5 and 6: (cyclohexane / chloroform: 80/20 by volume) - Fractions 7 and 8: (cyclohexane / chloroform: 70/30 by volume)
Fraction 1 is eliminated; fractions 2 to 8 are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 4000. This gives 4.3 g of product which is dissolved in 20 cm3 of petroleum ether (P E. 40-650C) boiling. After cooling to 40C for 16 hours, the crystals which appear are separated by filtration, washed with 5 cm3 of petroleum ether (PE 40-650C) cooled to about 50C and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature close to 200C in the presence of potash in pellets. 2.5 g of 5-oxo-propyl-2,3,6,7 5H-thiazolo [3,2-a] pyrimidine are thus obtained in the form of white crystals melting at 470cl
The present invention relates to medicaments consisting of the products of general formula (I) in the pure state or in the form of compositions in combination with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention may be used orally, parenterally or rectally.

 As solid compositions for oral administration, tablets, pills, powders (especially in gelatin capsules) or granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents, such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.

 As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.

 The compositions according to the invention for parenteral administration can preferably be sterile non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, and injectable organic esters, for example ethyl oleate, can be used.

These compositions can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.

 The compositions for rectal administration are suppositories, which contain, in addition to the active product, excipients such as cocoa butter or synthetic mixtures of glycerides melting between 33 and 360C.

 In human therapy, the products according to the invention are particularly useful in the background treatment of rheumatic disease and allergic conditions. The doses depend on the desired effect and on the duration of the treatment; they are generally between 50 and 1000 mg per day orally for an adult in one or more doses.

 In general, the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.

 The following example, given without limitation, illustrates a composition according to the invention.

EXAMPLE
Tablets containing 50 mg of active product having the following composition - Oxo-5-methyl-7,2-tetrahydro-2,3,6,7 5H-thiazolo are prepared according to the usual technique
[3, 2-a] pyrimidine ... 50 mg - starch ... 15 mg - colloidal silica ... 9.5 mg - magnesium stearate ... 0.5 mg

Claims (5)

 in which R represents a phenyl or alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain.

 REVNLlCATlONS 1 - A rscuveau derived from thiazolo [3,2-a] pyrimidine characterized in that it corresponds to the general formula 2 - A process for the preparation of a product according to claim 1 characterized in that an acid halide of general formula is reacted  R - CH = CH - COX in which R is defined as in claim 1 and X represents a halogen atom on 2-amino-2-thiazoline-2 (in equilibrium with its imine form) of formula

 then isolates the product obtained. 3 - A process for the preparation of a product according to claim 1 characterized in that an ester of general formula is reacted:  R - CH = CH - COOR 'in which R is defined as in claim 1 and R' represents an alkyl radical containing 1 to 4 carbon atoms on 2-amino-2-thiazoline-2 (in equilibrium with its imine form) of formula

 then isolates the product obtained. 4 - A process for the preparation of a product according to claim 1 characterized in that the 1,2-dibromo ethane is reacted with a 4,5-dihydro-2-thio-uracil of general formula

 wherein R is defined as in claim 1, then isolates the product obtained. 5 - A medicament characterized in that it contains a product according to claim 1 in combination with one or more diluents or compatible and pharmaceutically acceptable adjuvants.