NO131106B - - Google Patents

Description

Process for the production of purine derivatives.

The invention relates to a process for the production of new derivatives of 6-mercaptopurine different from bis-(6-purinyl) sulphide.

It has been found that the heterocyclic 6-purinyl sulfides of formula (I) have a high chemotherapeutic index against experimental tumors in laboratory animals. 1-Methyl-4-nitro-5-(2-amino-6-purinylthio)imidazole has been shown to induce remission in chronic granulocytic leukemia in humans. The compounds also inhibit the growth of certain pathogenic bacteria, especially in the presence of a folinic acid antagonist such as sulfonyldianiline. (Dap zone).

The new 6-purinyl sulphides have the general formula:

in which X is a hydrogen atom or an amino group and Z is a chain of 3 or 4 atoms, one of which may be nitrogen or sulfur and the others carbon to complete an unreduced heterocyclic ring where the nitrogen atoms may have alkyl or aralkyl substituents , the carbon atoms may have methyl, carboxy, amino, nitro, hydroxy or halogen substituents, or a benzene or imidazole ring may be fused to two neighboring carbon atoms in the ring, or a carbon atom adjacent to a nitrogen atom in the ring may be substituted with 6-purinylthio or 2-amino-6-purinylthio group. The compounds according to formula (I) are produced by reacting a compound of formula (II) with a compound of formula (III) while splitting off hydrogen halide

in which formulas X and Z have the same meaning as stated above and one of W and Y is a mercapto group and the other is a chlorine, bromine or iodine atom. The reaction is preferably carried out in a solvent with a high dielectric constant in the presence of a proton acceptor at a temperature not exceeding 130° C. The course of the reaction can be followed by removing aliquots periodically and examining their ultraviolet absorption spectra, as the spectra of the products are completely different from the starting material's spectra.

The following examples illustrate the invention.

Example 1:

A solution of 6-iodopurine (2.5 g) and 4-mercaptopyrimidine (1.12 g) in 2-N sodium hydroxide (10 ml) was heated on a steam bath for 24 hours. The reaction mixture was cooled and neutralized with acetic acid. The precipitate was collected, washed with water and dried in a vacuum desiccator to give 4-(6-purinylthio)pyrimidine, m.p.

184—185° C during decomposition. Its ultraviolet absorption spectrum showed maxima at 273 and 300 mu at pH 1 and at 280 and 305 mu at pH 11.

Example 2:

A solution of 6-iodopurine (10 g) and 2-amino-6-mercaptopurine (7.3 g) in 2-N sodium hydroxide (60 ml) was treated according to the procedure in Example 1 to give 2-amino- 6-(6-purinylthio)purine, which did not melt at 325° C. Its ultraviolet absorption spectrum showed maxima at 270, 302 and 330 mu at pH 1 and at 287 and 328 mu at pH 11.

Example 3:

A solution of 6-iodopurine (10 g) and 2-hydroxy-4-mercaptopyrimidine (5.12 g) in 2-N sodium hydroxide (60 ml) was treated according to the procedure of Example 1 to give 2-hydroxy-4- (6-purinylthio)-pyrimidine. Its ultraviolet absorption spectrum showed a maximum at 320 mu at pH 1, and at 310 mu at pH 11.

Example 4:

A mixture of 3,6-dichloropyridazine (3

g) 6-mercaptopurine (3 g) and anhydrous sodium acetate (1.64 g) in dry dimethyl sulfoxide

(75 mL) was heated at 125° C. for 4 hours with a drying tube on top of the condenser. After standing overnight at room temperature, the mixture was poured into water (300 ml) and cooled. 3-Chloro-6-(6-purinylthio)-pyridazine was collected, washed with water and dried at room temperature. Its ultraviolet absorption spectrum showed a maximum at 290 mu at pH 1 and at 295 mu at pH 11.

Example 5:

A mixture of 5-chloro-1-methyl-4-nitroimidazole (5 g), anhydrous 6-mercaptopurine (4.6 g) and anhydrous sodium acetate (2.5 g) in dry dimethylsulfoxide (100 ml) was heated met at 100° C for 7 hours. After standing overnight at room temperature, the mixture was poured into cold water (200 mL) and the yellow precipitate (7.0 g) of 1-methyl-4-nitro-5-(6-purinylthio)imidazole was collected. After recrystallization from 50% aqueous acetone, the substance melted at 243-244° C during decomposition. Its ultraviolet absorption spectrum showed a maximum at 280 mu at pH 1 and at 285 ltiu at pH 11.

Example 6:

A mixture of 4,6-dichloro-5-nitropyrimidine (3.84 g) anhydrous 6-mercaptopurine

(6 g) and anhydrous sodium acetate (3.3 g) in dry dimethyl sulfoxide (150 ml) were heated at 100° C. for 5 hours. The reaction mixture was poured into cold water (400 mL) and the yellow precipitate (5.0 g) of 5-nitro-4,6-bis-(6-purinylthio)pyrimidine was collected. Its ultraviolet absorption spectrum showed maxima at 260 and 360 mu at pH 1 and at 275 and 390 mu at pH 11.

Example 7:

A mixture of 5-chloro-1-methyl-4-nitroimidazole (5 g), 2-amino-6-mercaptopurine (5 g) and anhydrous sodium acetate (2.5 g) in dry dimethyl sulfoxide (200 ml) was heated at 110° C for 5 hours, cooled and poured into water (300 ml). 1-Methyl-4-nitro-5-(2-amino-6-purinylthio)imidazole (5.8 g) was collected, washed with water and dried at room temperature. It decomposed just above 200° C. Its ultraviolet absorption spectrum showed a maximum at 320 mu at pH 1 and at 315 mu at pH 11.

Example 8:

A solution of 6-iodopurine (6.6 g) and 2-mercaptoquinoline (5.3 g) in 2-N sodium hydroxide (35 ml) was heated on a steam bath for 24 hours, cooled and neutralized with acetic acid. 2-(6-purinylthio)quinoline was collected. Its ultraviolet absorption spectrum showed maxima at 240, 280 and 348 mu at pH 1 and at 295 and 325 mu at pH 11.

Example 9:

A solution of 6-iodopurine (5g) and 2-mercaptopyridine (2.2g) in 2N sodium hydroxide (20ml) was treated by the method of Example 1 to give 2-(6-purinylthio)pyridine. Its ultraviolet absorption spectrum showed maxima at 277 and 312 mu. at pH 1 and a maximum at 298 mu at pH 11.

Example 10:

A solution of 6-iodopurine (770 mg)

and the ammonium salt of 4-mercapto-5-nitroimidazole (500 mg) in NaOH (6 ml) was heated on a steam bath for 24 hours. On cooling, 4-nitro-5-(6-purinylthio)imidazole precipitated as yellow crystals which decomposed at 220° C. Its ultraviolet absorption spectrum showed maxima at 282 and 345 mu at pH 1 and at 290 and 388 mu at pH 11.

An identical substance was prepared in the same manner from a solution of 4-bromo-5-nitroimidazole (580 mg) and 6-mercaptopurine (500 mg) in NaOH (6 ml).

An identical substance was prepared in the same manner from a solution of 6-chloropurine (310 mg) and 4-mercapto-5-nitroimidazole (320 mg) in N-sodium hydroxide (4 ml).

Example 11:

A solution of 4-bromo-5-nitroimidazole (1.75 g) and 2-amino-6-mercaptopurine (1.5 g) in 2 Af sodium hydroxide (13.5 ml) was heated on a steam bath for 48 hours. On cooling, 4-nitro-5-(2-amino-6-purinylthio)imidazolyl is precipitated. Its ultraviolet absorption spectrum showed a maximum at 325 mu at pH 1 and a maximum at 312 and 390 imu at pH 11.

Example 12:

A solution of 2-mercapto-4-methyl-thiazole (1 g) and 6-iodopurine (1.87 g) in N-sodium hydroxide (20 ml) was heated on a steam bath for 46 hours, then cooled and acidified to pH 7, 5. The precipitate formed by rapid cooling was collected and dissolved in 200 parts of boiling 5% aqueous acetone, filtered and the acetone was removed under reduced pressure. The precipitate formed by removing acetone was collected, dried and leached with 60 parts of ether. The pure crystalline 4-methyl-2-(6-purinylthio)thiazole then melted at 170-171° C.

Example 13:

A solution containing 2-amino-6-mercaptopurine (780 mg) and 5-bromo-4-nitro-1-p-nitrobenzylimidazole (1.6 g) in NaOH (10 ml) and ethanol (1 ml) was heated at steam bath for 4 hours. The mixture was cooled, adjusted to pH J with hydrochloric acid and the precipitate was collected. 1-p-nitrobenzyl-4-nitro-5-(2-amino-6-purinylthio)imidazole after re-dissolution in alkali and new precipitation with acetic acid fell out as a dihydrate which decomposed slowly above: 210° C.

Example 14:

A mixture of 2-amino-6-mercaptopurine (1.8 g), 2-carboxy-5-chloro-1-methyl-4-nitroimidazole (2 g) and anhydrous sodium acetate (1.8 g) in dry dimethylsulfoxide (40 ml ) was heated at 60° C. for 18 hours. The mixture was cooled and poured into cold water

(150 ml). The yellow precipitate (2.85 g) was collected and purified by dissolution in dimethylsulfoxide (50 ml), filtration and reprecipitation by dilution with 4 times the volume of water.

1-Methyl-2-carboxy-4-nitro-5(2-amino-6-purinylthio)imidazole does not melt below 300°C, and its ultraviolet absorption spectrum has a maximum at 322 mu at pH 1.

Example 15:

A solution of 2-amino-6-mercaptopurine (2 g) and 2-amino-6-iodopurine (3.1 g)

in 1V sodium hydroxide (24 ml) was heated overnight on a steam bath. The reaction mixture was cooled and adjusted with acetic acid to a pH of 7. The precipitate was collected and purified by dissolution in AT sodium hydroxide and reprecipitation with acetic acid. 2-amino-6-(2-amino-6-purinylthio)purine shows an ultraviolet absorption maximum at 335 mu at pH 1. It does not melt below 320°C.

Example 16:

A mixture of 2-amino-6-mercaptopurine (6.7 g), trichloropyrimidine (3.64 g) and anhydrous sodium acetate (3.3 g) in dry dimethyl sulfoxide (150 ml) was heated overnight on a steam bath. The reaction mixture was cooled, poured into cold water (200 mL) and filtered. The precipitate was purified by dissolving in dilute sodium hydroxide and reprecipitated by acidifying to pH 5. 2,4-bis-(2-amino-6-purinylthio)-6-chloropyrimidine

forms a dihydrate which decomposes above 260°C.

Example 17:

A solution containing 2-amino-6-mercaptopurine (840 mg) and 1-benzyl- L 5-bromo-4-nitroimidazole (1.4 g) in NaOH (7.5 mL) and ethanol , (7.5 ml) . was heated for 20 hours on a steam bath, the heated solution was quenched and filtered. The precipitate (800 mg) was purified by dissolution in N-sodium hydroxide (10 ml) and reprecipitation by acidification with acetic acid. 1-t Benzyl-4-nitro-5-(2-amino-6-purinylthio)r imidazole melts at 249° C with decomposition.

Claims (2)

1. Process for the preparation of therapeutically active heterocyclic 6-purinyl sulfides, except bis-(6-purinyl) sulfide, with formula in which X is a hydrogen atom or an amino group and Z is a chain of 3 or 4 atoms, one of which may be nitrogen or sulfur and the others are carbon to complete an unreduced heterocyclic ring, in which the nitrogen atoms may have alkyl or aralkyl substituents, the carbon atoms may have methyl, carboxy, amino, nitro, hydroxy or halogen substituents, or a benzene or imidazole ring may be fused to two adjacent carbon atoms in the ring, or a carbon atom adjacent to a nitrogen atom in the ring may be substituted with a 6-purinylthio or 2-amino-6-purinylthio group, characterized in that a compound with the formula is reacted with a compound with the formula in which formulas X and Z have the above-mentioned meanings, and one of W and Y is a mercapto group and the other is a chlorine, bromine or iodine atom, and the reaction is carried out in a solvent of high dielectric constant in the presence of a proton acceptor at a temperature that does not exceed 130°C. 2. Process according to claim 1, characterized in that in the starting material the radical of formula is a 1-methyl-4-nitro-5-imidazolyl radical.