CS203094B2 - Process for preparing substituted purines - Google Patents

Description

The present invention relates to substituted purines and pharmaceutically acceptable salts thereof, and to processes for their preparation. More specifically, the invention relates to 9- (2-hydroxyethoxymethyl) purine derivatives such as adenine, guanine, thioguanine and 2,6-diaminopurine, and pharmaceutically acceptable salts thereof. In 1971 Schaeffer et al. [J. Copper. Chem. 14, 367 (1971)] reported the synthesis of several purine acyclic nucleosides in the study of adenosine deaminase enzyme-substrate interactions. 9- (2-Hydroxyethoxymethyl) adenine was introduced and its activity measured as an adenosine deaminase substrate.

It has now been found that the substituted purines of formula I,

where

X is an oxygen or sulfur atom; and

R ^1, R ^2, R ^3, R ^4, R ⁵ and R ⁶ are different stibstituenty have antiviral activity against various classes of DNA and RNA viruses, and in experiments both in vitro and in vivo. In particular, the compounds are active against cytomegalovirus, adenovirus, in particular adenovirus 5, rhino virus, Mengo virus and Sindbis vorus. They are particularly effective against vaccinia and herpes viruses, including simplex noster and varicella in mammals that cause diseases, such as herpetic keratitis in rabbits and herpetic encephalitis in mice. In addition, they are useful for treating infectious mononucleosis.

The invention relates to a process for the preparation of compounds of formula I

where

X is a sulfur or oxygen atom,

R ¹ is halogen, hydroxyl, C 1 -C 4 alkoxy, hydrogen, mercapto, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl or an azido group,

R ² is hydrogen, halogen, amino or azido,

R ³ is hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms or cyclic of up to 8 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, benzyloxyalkyl of 1 to 4 carbon atoms or phenyl,

R ⁴ is hydrogen, hydroxyl or alkyl having 1 to 4 carbon atoms,

R ⁵ is hydrogen, amino, C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, benzoyloxy, benzoyloxymethyl, benzyloxy, sulfamoyloxy, phosphate, carboxypropionyloxy, acetoxy, or substituted carbamoyloxy-H, wherein —N-

Z is alkyl of 1 to 4 carbon atoms, aryl of up to 8 carbon atoms or arylalkyl of up to 8 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the alkyl, optionally substituted with one or more groups such as sulfonyl, amino, carbamoyl or halogen,

R ⁶ is hydrogen, alkyl of 1 to 12 carbon atoms, and when X is oxygen, and R ² , R ³ , R ⁴ and R ® are hydrogen, R ¹ is not amino or methylamino when R ⁵ is hydrogen or benzyloxy, wherein if R? is hydrogen, ^R1 is not a chlorine atom, or their salts, especially pharmaceutically acceptable salts, characterized in that a compound of formula IV

react with a compound of formula V,

A — CH — X — CH — CH — R ⁵ (V),

R ³ R ⁴ where

A is a leaving group such as a reactive radical of an organic or inorganic acid and a

Q is hydrogen or a leaving group, and if the product of the reaction is a base, optionally converting a compound of formula I to an acid salt or, if the product is a salt of a compound of formula I, converts the salt to a base or other salt.

Preferred compounds are those compounds of formula I as defined above, wherein

X is an oxygen atom,

R ¹ is hydrogen, halogen, hydroxyl, C 1 -C 4 alkoxy, mercapto, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl or an azido group,

R ² is hydrogen, halogen, amino or azido,

R ³ is hydrogen, straight or branched (C 1 -C 8) alkyl, or cyclic (C 1 -C 8) alkyl, (C 1 -C 4) hydroxyalkyl or phenyl,

R ⁴ is hydrogen or hydroxyl,

R ⁵ is hydrogen, benzoyloxy, hydroxyalkyl of 1 to 4 carbon atoms, amino,. carboxypropionyloxy, acetoxy, benzyloxy, benzoyloxymethyl, phosphate, sulfamoyloxy, substituted carbamoyl of formula

NH — CO — Z, where

Z is alkyl of 1 to 4 carbon atoms, aryl of up to 8 carbon atoms, or arylalkyl of up to 8 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the alkyl optionally substituted by one or more groups such as sulfonyl, amino, carbamoyl, halogen, R ^e is hydrogen, C 1 -C 12 alkyl, wherein R ⁵ is alkylhydroxyl only when R ¹ is hydroxyl, R ® is hydrogen only when R ¹ . is hydroxyl or halogen when R ⁵ is benzoyloxy, R ² is not halogen, R ® is acetoxy only when R ¹ is hydroxyl or amino and R ² is amino or R ¹ and R ² are both halogen, R ⁵ is substituted carbamoyl formulas

NHCOZ, where

Z is CH (NH 2) CH 2 C 6 H 5 only if R ¹ is a dialkylamino group, except that if R ⁵ is hydroxyl and R ¹ is an alkylamino group, R ² is not a hydrogen atom, and also when R ² is a hydrogen atom R ¹ is not a chlorine atom or a salt thereof, especially a pharmaceutically acceptable salt.

Compounds of formula I as defined above wherein

X is an oxygen atom,

0 3) 0 O 4

R 1 is halogen, amino, hydroxy, or C 1 -C 4 alkylthio,

R ² is amino,

R ⁵ is benzoyloxy, carboxypropionyl, acetoxy or C 1 -C 4 hydroxyalkyl; and

R ³ , R ⁴ and R ⁶ are hydrogen atoms, where R ⁵ is hydroxyalkyl only when R ¹ is hydroxyl, and R ⁵ is acetoxy only when R ¹ is amino, are most preferred and have been found to be highly active. Compounds wherein X is sulfur, R ¹ is halo, amino, or alkylamino of 1 to 4 carbon atoms and R ^2, R ^3, R ^4, R ⁵ and R ⁶ are hydrogen, they are also highly active.

A preferred atom is chlorine.

Salts which are particularly suitable for therapeutic use are salts with pharmaceutically acceptable organic acids, such as lactic, acetic, malonic or p-toluenesulfonic acid, as well as salts with pharmaceutically acceptable mineral acids, such as hydrochloric or sulfuric acid.

In the method of the invention, leaving group A is a reactive residue of an organic or inorganic acid and may thus be a halogen atom, a sulfonate or a carboxylate and Q is a hydrogen or acyl or a metal atom. A preferred method involves condensing a purine which is desirably substituted at positions 2 and 6 with an acyl or arylalkyl protected with 2-haloalkoxyethanol, for example 2-benzoyloxyethoxymethyl chloride in a strongly polar solvent such as DMF, and in the presence of a base such as triethylamine or potassium carbonate . The reaction is preferably carried out at room temperature and several days is needed for sufficient yield.

Alternatively, thermal condensation, such as melting, can be performed to directly obtain the product. For this reaction, the appropriately substituted purine is heated together with an acyloxyalkoxymethyl carboxylate, for example 2-oxa-1,4-butanediol diacetate, in the presence of a catalytic amount of a strong acid such as sulfuric acid. Generally, temperatures above 100 ° C are used, but temperatures above 200 degrees Celsius are preferred to avoid decomposition. The temperatures are selected so as not to melt the reaction of the mixture, e.g., melting, prior to decomposition.

The melting reaction can also be carried out under the same conditions as above, with a somewhat lower temperature, between 9-acylpurine and an alkoxymethyl carboxylate or halide. Alternatively, the melting is carried out using a diester, for example 2-acetoxyethoxymethyl acetate.

Alternatively, the mercuric chloride salt with the purine can be prepared in the presence of alkali and then condensed with a haloether in an aromatic organic type solvent. However, before reacting the salt, all reactive purine substituents must be protected and therefore the last step in this method is the removal of the protecting substituents.

In yet another aspect, the invention relates to pharmaceutical compositions or formulations containing compounds of formula I wherein X is sulfur or oxygen, R ¹ is halogen, hydroxy, thio, alkoxy, azido, alkylthio, amino, alkylamino, or dialkyraminoskupina,

R ² is hydrogen, halogen, amino or azido, R ³ is hydrogen, straight or branched chain alkyl or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl, R ⁴ is hydrogen, hydroxy, and alkyl, R ⁵ is hydrogen , hydroxy, amino, alkyl, hydroxyalkyl, benzoyloxy, benzoyloxymethyl, benzyloxy, sulfamoyloxy, phosphate, carboxypropionyloxy, acetoxy or substituted carbaffiylOxy, NH-CO-Z, wherein NH-CO-Z,

Z is alkyl, aryl or arylalkyl, optionally substituted with one or more sulfonyl, amino, carbamoyl or halogen, R ⁶ is hydrogen, alkyl wherein R ⁶ has from 1 to 8 carbon atoms and in all other cases the alkyl substituents have from 1 to 4 carbon atoms, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. According to a feature, the pharmaceutical composition comprises a compound of formula I in an active unit form.

The term "unit dosage form" means a predetermined antiviral amount that is sufficiently effective against viral organisms in vivo. Pharmaceutically acceptable carriers are materials useful for drug delivery, which may be solid, liquid or gaseous and which are otherwise inert, pharmaceutically acceptable, and compatible with the active ingredients.

These pharmaceutical compositions can be applied parenterally, orally, used in the form of suppositories or pessaries, applied topically in the form of ointments, creams or aerosols, powders or as drops to the eyes or nose of the nose, etc., depending on whether the internal treatment is to be treated. or external infection.

For internal infections, the composition is administered orally or parenterally at a dosage calculated as the free base, from 0.1 to 250 mg per kg body weight, preferably from 1.0 to 50 mg per kg mammal weight, and is used in humans in a unit dose. a dosage form to be administered several times a day in an amount of from 1 to 250 mg per unit dose.

For oral administration, the fine powders or granules may contain diluents, dispersing and / or surfactants and may be applied as infusions in water or syrup, in capsules or cachets in the dry state or as non-aqueous solutions or suspensions which may also contain suspending agents. , such as tablets, which may contain binders and lubricants or in the form of a suitable suspension in water or syrup. Where desired and necessary, the preparations may contain flavoring, preservative or suspending, thickening or emulsifying agents. Tablets and granules which may be coated are preferred.

For parenteral administration or for application by drops, for example in ocular infections, the compound may be administered in the form of an aqueous solution in an amount of about 0.1 to 10%, preferably 0.1 to 1%, preferably 0.2% wt. The solution may still contain antioxidants, buffers and the like.

Alternatively, for infection of the eyes or other external tissues such as the mouth and skin, it is applied topically in the form of an ointment or cream to the infected part of the patient. The compounds may be administered in the form of an ointment, for example, in an ointment which is soluble in water or in a cream, eg as an oil, in an ointment for a water-soluble cream, at a concentration of 0.1 to 10%, preferably from 0.3 to 3%, preferably 1% w / w; vol.,

Of the compounds of formula I, 9- (2-hydroxyethoxymethyl) guanine (R1 ⁼ OH, R2 = NH2) and 2-amino-9- [2-hydroxyethoxymethyl] aenine are particularly preferred, particularly because of their high antiviral activity against herpes viruses. Further compounds

2-amino-6-chloro-9 - [(2-benzoyloxyethoxy) methyl] -purine,

9- (2-benzoyloxyethoxymethyl) guanine,

9- (3-hydroxypropoxymethyl) guanine,

2-amino-6-methylthio-9- (2-hydroxyethoxymethyl) purine,

9- [2- (3-carboxypropionyloxy) ethoxymethyl] guanine,

9- (2-acetoxyethoxymethyl) -2,6-diaminopurine;

6-chloro-9-ethylthiomethylpurine,

9-ethylthiomethyladenine,

9-ethylthiomethyl-6-methylaminopurine show high activity against herpes and vaccinia viruses.

In yet another aspect, the invention relates to a method of treating viral infections in a mammal comprising administering to the mammal an effective antiviral amount as defined above, of a substituted purine of formula I or a pharmaceutically acceptable salt thereof. Administration is preferably carried out topically, orally or parenterally.

The invention is illustrated by the following examples.

He did

6-Chloro-9- (2-benzoyloxyethoxymethyl) purine

A solution of benzonitrile (103 g) in ethylene glycol (310 g) was heated to boiling under anhydrous conditions for three days. The reaction mixture was cooled and added to a mixture of ice and water (about 300 mL). The resulting mixture was extracted with ether (3X300 mL) and the combined ethereal extract was backwashed with water (2X300 mL) and then brine (300 mL). The ethereal solution was dried over anhydrous sodium sulfate. The ether was evaporated and the residual oil was distilled to give 108 g (65 percent) of ethylene glycol monobenzoate, m.p. 132-135 ° C / 1.5 Torr.

A cold (0 ° C) mixture of ethylene glycol monobenzoate (166 g) and paraformaldehyde (30 grams) in anhydrous dichloroethane was saturated with anhydrous HCl with stirring for three hours. The pink-red liquid was dried with anhydrous calcium chloride, the volatile components were removed on a rotary evaporator at 30 degrees Celsius to give 1-benzoyloxy-2-chloromethoxyethane (215 g). The infrared spectrum indicates the absence of a hydroxyl group.

Following the procedure described by Schaeffer et al., But with slight modifications, 1-benzoyloxy-2-chloromethoxyethane (4.4 g) was added with stirring to an anhydrous solution of 6-chloropurine (3.1 g) and triethylamine (6.5 ml) in dimethylformamide. The reaction is exothermic and triethylamine hydrochloride precipitates immediately. The reaction mixture was stirred at room temperature for 24 hours and then filtered. The filtrate was evaporated on a rotary evaporator at 70 ° C. The remaining thick amber oil was dissolved in a minimum amount of benzene and purified by silica gel column chromatography. Elution with benzene removes traces of unidentified material. Elution with ether first removed a small amount of ethylene glycol monobenzoate and then 6-chloro-9- (2-benzoyloxyethoxymethyl) purine. Crystallization from ether gave a white material, mp 108.5-111 ° C.

Example 1 a d 2

2-Chloro-9- (2-hydroxyethoxymethyl) adenine

Following the procedure of Example 1, 2,6-dichloropurine was condensed with 1-benzyloxy-2-chloromethoxyethane to give a 41% yield of 2,6-dichloro-9- (2-benzoyloxyethoxymethyl) purine, m.p. 121-125 ° C. This was treated as in Example 1 and simultaneously ammonolized with 6-chloro and benzoyloxy to give 2-chloro-9- (hydroxyethoxymethyl) adenine in 94% yield, mp 188-190 ° C after crystallization from isopropanol.

Example 3

9- (2-Hydroxy droxyethoxymethyl) guanine (I, R = OH, R ² = NH 2)

A mixture of guanine (2.0 g), ammonium sulfate (1.5 g) and hexamethyldisilazane (126 g) was heated to boiling overnight under a nitrogen atmosphere. The excess hexamethyldisilazane was distilled off under reduced pressure. Dry benzene (10 mL) was added to the remaining oil and the ammonium sulfate was filtered off. To this solution was added triethylamine (4 mL) and a solution of 2-benzoyloxyethoxymethyl chloride (2.8 g) in anhydrous benzene (15 mL), and the mixture was heated to reflux overnight under nitrogen. The solvent was removed on a rotary evaporator under reduced pressure and the residue was dissolved in 95% ethanol. The solution was heated on a steam bath for 30 minutes and the silyl groups were hydrolyzed. The ethanol was then evaporated and the residual solid was washed with water, filtered and dried. Crystallization from methanol and then water (residual guanine is insoluble in hot solvents and removed by filtration) afforded 9- (2-benzoyloxyethoxymethyl) guanine (0.58 g, 14% of theory) m.p. 222-226 ° C. The latter condensation of tris- (trimethylsilyl) guanine with a 60% excess of 2-benzoyloxymethyl chloride gave a 32% yield of 9- (2-benzoyloxyethoxymethyl) guanine.

9- (2-Benzoyloxy ethoxymethyl) guanine (0.58 g) and methanol (80 mL) saturated with ammonia were heated in a pressure vessel at 80 ° C for 16 hours. The reaction mixture was removed from the pressure vessel and the solvent was evaporated under reduced pressure. The residue was washed with ether and then crystallized from methanol. There was thus obtained 9- (2-hydroxyethoxymethyl) guanine (0.31 g, 75%), mp 256.5-257 ° C. Example 4

2-Amino-6-chloro-9- (2-benzoyloxyethoxymethyl) purine

A suspension of potassium carbonate (4.1 g) and 2-amino-6-chloropurine (5.0 g) in anhydrous dimethylformamide (120 ml was stirred for 20 minutes. 2-Benzoyloxyethoxymethyl chloride (6.3 g) was added and the pinkish suspension formed. The reaction mixture was then poured into ice / water (210 mL) with vigorous stirring, extracted with chloroform (3X200 mL), and the resulting chloroform solution was washed with 5% acetic acid solution and twice with water. The solution was dried over anhydrous sodium sulfate and evaporated in vacuo, redissolved in a minimum amount of chloroform, and the remaining solution was applied to a silica gel column (200 g) in chloroform, eluting with 2% methanol in 98% chloroform and collecting the eluate until 30 min. ml fractions The fractions containing 2-amino-6-chloro-9- (2-benzoyloxyethoxymethyl) purine (determined by thin layer chromatography) were combined, evaporated and the residue was recrystallized from benzene to give 2-amino-6-chloro -9- (2-benzoyloxyethoxymethyl) purine (2.0 g, mp 130-133.5 ° C).

Example 1 a d 5

Preparation of 2,6-dichloro-9- (2-acetoxyethoxymethyl) -purine

2,6-Dichlorpurine (5.5 g) and 2-oxa-1,4-butanediol diacetate (513 g) were placed in a flask and partially evacuated and then heated to 130 ° C. The reaction mixture is too thick, but gradually melts. The melt is stirred and after 20 minutes is completely molten and the reaction mixture is still heated for 10 minutes (total heating time is 30 minutes). The mixture was then cooled to room temperature and p-toluenesulfonic acid (150 mg) was added, evacuated again and heated with stirring. After heating for 20 minutes, vigorous bubbling occurred, the reaction mixture was cooled to room temperature, chloroform was added and the solution was extracted once with saturated aqueous sodium bicarbonate solution and once with water. It is dried over anhydrous sodium sulphate and evaporated. The residual oil was dissolved in benzene and loaded onto a 200 g silica gel column. Elution with benzene removes acetate co-products. Elution with ether gave the 9-isomer in 64% yield. Recrystallization from benzene gave shiny white flakes, m.p. 96-99 ° C.

Example 1 a d 6

2,6-Diamino-9- (2-benzoyloxyethoxymethyl) purine

A mixture of 2,6-diaminopurine monohydrate (2.0 g), ammonium sulfate (1.32 g) and hexamethyldisilazane (100 g) was heated to reflux under nitrogen for 18 hours. The solvent was evaporated under reduced pressure and the residual oil was dissolved in a minimum amount of benzene. To the benzene solution was added 2-benzoyloxymethyl chloride (2.56 g), triethylamine (2 mL) and benzene (55 mL). The reaction mixture was heated to reflux under nitrogen for 18 hours. Additional 2-benzoyloxyethoxymethyl chloride (2.56 g) and trimethylmin (2 mL) were added and refluxed for 6 hours. The solvent was evaporated under reduced pressure and the residue was digested for 30 minutes in a steam bath in 95% ethanol (40 ml). The solvent was evaporated and the gummy residue was recrystallized from ethanol, twice from methanol and finally from water to give 2,6-diamino-9- (2-benzoyloxyethoxymethyl) purine as a yellow solid, mp 205 ° C, yield 7.5 %.

Example 7

9-Ethylthiomethyladenine

The reaction mixture containing chloromethyl ethylsulfide (5.53 g), 6-chloropurine (7.73 g) and triethylamine (5.57 g) in dimethylformamide (50 ml was allowed to stand at room temperature for three days), then filtered and the filtrate was evaporated Dissolve the semisolid residue in chloroform (about 70 mL), place on a column of florisil (activated magnesium silicate) (360 grams) in chloroform and elute with chloroform, discarding the initial eluate (about 500 mL), collecting an additional 2.8 liters. Ligroin (about 50 mL) was added to the residual oil, the mixture was cooled and the resulting white 6-chloro-9-ethylthiomethylpurine crystals were collected by filtration and washed with ligroin to yield 3.3 g (mp 78-81 ° C). ether and ligroin gave white needles, mp 81-82.5 ° C.

6-Chloro-9-ethylthiomethylpurine (1.5 g) and liquid ammonia (20 mL) were placed in a pressure vessel and heated to 60 ° C overnight. The ammonia was evaporated and the residue was triturated with cold water, filtered and washed with cold water. The resulting 9-ethylthiomethyladenih (1.17 g) is a white solid, mp 140-142 ° C. Recrystallization from ethanol gave white plates, m.p. 142-143 ° C.

Example

9- (2-Hydroxyethylthiomethyl) adenine

According to the method of Miles and Owen,). Chem. Soc., 817 (1952), prepare 2-acetoxyethenethiol. Acetic anhydride (102.1 g) was added to a mixture of 3-mercaptoethanol (78.1 g) and a 10% solution of sulfuric acid in acetic acid (3 mL) over one and a quarter hours. During the addition, the reaction temperature is kept below 40 ° C by external cooling. After addition of the acetic anhydride, the reaction mixture was heated at 65 ° C for one hour and allowed to stand overnight at room temperature. Ether (500 mL) was added to the reaction mixture and the resulting solution was washed with water (3X100 mL) and brine (1X100 mL). The ethereal solution was dried with anhydrous sodium sulfate and sodium bicarbonate. Distillation gave 212 acetoxyethanthiol (77.5 g), b.p. 57-67 ^D C at 10 Torr.

Hydrogen chloride gas was slowly introduced into the mixture of 2-acetoxyethanethiol (24.0 g) and paraformaldehyde (6.0 g) under external cooling over three hours. Calcium chloride (25 g) was added and the reaction mixture was allowed to stand in a salt-ice bath for 4 hours. Methylene chloride (200 mL) was added, the reaction mixture was filtered, and the solvent was evaporated to remove moisture. The residual oil was distilled to give 2-acetoxyethylchloromethylsulfide (18.5 g), bp 82-87 ° C at 3 Torr.

According to the procedure (Schaeffer et al.). Copper. Chem. 14, 367 (1971)) was added 2-acetoxyethylchloromethylsulfide (3.37 g) to a mixture of 6-chloropurine (3.09 g), triethylamine (2.23 g) and dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 90 hours and the solvent was removed under reduced pressure. The residual oil was dissolved in chloroform (30 mL) and loaded onto a florisil column (200 grams) in chloroform. Elution with chloroform gave the desired product in 2.1 L of eluate (after initial 300 mL). The solvent was evaporated to give an oil, ether and petroleum ether were added and the mixture was cooled. There was thus obtained 9- (2-acetoxyethylthiomethyl) -6-chloropurine (1.4 g), m.p. 82-87 ° C. Recrystallization from ether gave white crystals, mp 89-91 ° C.

9- (2-Acetoxyethylthiomethyl) -6-chloropurine - (1.1 g) and ammonia (20 ml) were placed in a pressure vessel and heated at 60 degrees Celsius for 24 hours. The reaction mixture was removed from the pressure vessel and the ammonia was allowed to evaporate. The residue is triturated with cold water, filtered and washed with plenty of cold water. The resulting crude 9- (2-hydroxyethylthiomethyl) -adenine (0.73 g) has a melting point of 166-169.5 ° C. Recrystallization from ethanol gave white plates, m.p. 170-172 ° C.

Example 1 a d 9

9- (2-Aminoethoxymethyl) adenine

To the stirred, ice-cooled dispersion of sodium hydride (4.0 g, 60% dispersion in mineral oil) in dimethylformamide (500 mL) was added adenine (13.5 g). After one hour, the ice bath was removed and the mixture was stirred at room temperature for another three hours. A solution of N- (2-chloromethoxyethyl) phthalmide (23.9 g) in dimethylformamide (100 mL) was added dropwise over half an hour, and the reaction mixture was stirred at room temperature for 18 hours and then poured into ice water (2 L) with stirring. The resulting solid was recrystallized from 2-methoxyethanol and then dimethylformamide to give 9- (2-phthalimidoethoxymethyl) adenine (15.0 g), mp 256-258 ° C.

A mixture of 9- (2-phthalimidoethoxymethyl) adenine (3.38 g), hydrozine hydrate (1.0 mL, 85% aqueous solution) and ethanol (150 mL) was heated at reflux for two hours. 2-Me203094 thoxyethanol (50 mL) was added and boiling was continued for another two hours. The solvent was removed under reduced pressure and 1N hydrochloric acid (50 ml) was added. The mixture was stirred for 30 minutes at room temperature and allowed to stand at ^0? C overnight. The solution was filtered and the filtrate was diluted with water (100 mL) and stirred with an excess of basic ion exchanger (Rexyn 201 (OH)) until silver nitrate was no longer detectable. Then the solution was filtered and most of the water was removed under reduced pressure. The aqueous solution was cooled and the resulting solid was filtered off. Recrystallization from isopropanol gave 9- (2-aminoethoxymethyl) adenine (1.0 g), m.p. 170-171 ° C.

Example 10

9- (3-Hydroxypropoxymethyl) guanine

Sodium benzoate (96.32 g) in dimethylformamide (690 mL) was heated to 80 ° C, and 1-chloro-3-hydroxypropane (63.06 g) was added over 15 minutes. The temperature rose to 135 ° C and the reaction mixture was heated to 135-175 ° C for three hours. 38 g of sodium chloride (97% of theory) were removed by filtration. The filtrate was partially evaporated under reduced pressure at a temperature below 40 ° C. The concentrated filtrate was poured into ice water and extracted thoroughly with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The residual oil was distilled on a Vigreux column to give 3-benzoyl-1-propanol (85.2 g, bp 124-132 ° C at 0.055 Torr).

Anhydrous hydrogen chloride was bubbled through a solution of 3-benzoyloxypropanol (15.02 g) and paraformaldehyde (2.49 g) in dichloromethane (35 mL) at 0 ° C for 1 hour. The solvent was evaporated under reduced pressure at a temperature below 40 ° C to give crude benzoyloxypropoxymethyl chloride in 92% yield, which was used without further purification.

A solution of trimethylsilylated guanine in benzene (25 mL), prepared as in Example 6 (from 2.0 g guanine) containing triethylamine, was heated to boiling and 3-benzoyloxypropoxymethyl chloride (2.96 g) dissolved in benzene (15 mL) was added. within three hours. The reaction mixture was heated to reflux under nitrogen overnight. The solvent was removed under reduced pressure and 95% ethanol and methanol were added to the remaining oil. The mixture was heated on a steam bath for several minutes and the solvent was then evaporated under reduced pressure. Chloroform (200 mL) was added and the resulting solid was filtered off. The solid was dissolved in a minimum amount of dimethylformamide, filtered (to remove all guanine) and re-precipitated by the addition of water. Recrystallization by 14 from methanol (activated carbon) gave 9- (3-benzoyloxypropoxymethyl) guanine (0.94 g) as a pale yellow solid, m.p. 198 DEG-201 DEG.

A mixture of 9- (3-benzoyloxypropoxymethyl) guanine (0.5 g) and aqueous 45% methylamine (10 mL) was stirred at room temperature overnight. Excess methylamine and water are evaporated at a temperature below 30 ° C under reduced pressure and the residue is recrystallized from ethanol. There was thus obtained 9- (3-hydroxypropoxymethyl) guanine (0.24 g), m.p. 223 DEG C. (solidified) as a semihydrate.

They did

9- (3-Benzoylpropoxymethyl) guanine (R1 = OH, R2 = NH2)

9- (3-Benzoylpropoxymethyl) guanine was prepared according to the procedure of Example 4 (m.p. 198-201 ° C).

Example 12

9-Ethoxymethylguanine

9-Eethoxymethylguanine was prepared according to the procedure of Example 4 (m.p. 275-280 ° C, dec.).

Example 1 d

6-Diethylamino-9- [1- (2-benzoyloxyethoxy) ethyl] purine

6-Diethylamino-9- [1- (2-benzoyloxyethoxy) ethyl ]purine was prepared as in Example 1 (m.p. 83-86 ° C).

Example 14

2-Amino-6-chloro-9- [1- (2-benzoyloxyethoxyethyl) purine

2-Amino-6-chloro-9- [1- (2-benzoyloxyethoxy) ethyl ]purine was prepared as in Example 4 (mp 125-130 ° C). Example 15

2-Amino-6-chloro-9- (4-benzoyloxybutoxymethyl) purine

2-Amino-6-chloro-9- (4-benzoyloxybutoxymethyl) -purine was prepared as in Example 4 (m.p. 119-121 ° C).

He did

Preparation of 9- (2-benzoyloxyethoxymethyl) -2,6-diaminopurine

An anhydrous solution of 2,6-diaminopurine in dimethylformamide is prepared by heating 3.45 g of the monohydrate in a 250 ml steam bath until dissolved, cooled and allowed to stand for 18 hours over molecular sieves.

To this mixture was added 57% sodium hydride dispersion (0.95 g) in mineral oil. After stirring the suspension overnight, 2-benzoyloxyethoxymethyl chloride (4.66 g) was added dropwise and the reaction mixture was stirred overnight at room temperature. The supernatant has a greenish-yellow color.

After filtering off the sieves and a white gummy solid, the mother liquors were combined with chloroform washes and evaporated at 1 Torr (bath temperature 60 ° C).

The resulting greenish-yellow oil was extracted with boiling benzene to give an insoluble crude product. Crystallization from ethanol and water gave 9- (2-benzoyloxyethoxymethyl) -2,6-diaminopurine (0.9 g) mp 184-186 ° C. The yield of 15% NMR and UV spectra are in accordance with the desired values.

Example 1 7

Oil in an aqueous cream base

9- (2-Hydroxyethoxymethyl) -

guanine 5.0 g lanolin, anhydrous 20,0 g polysorbate 60 4.0 g sorbitan monopalmitate 2,0 g light liquid paraffin 4.0 g propylene glycol 5.0 g methylhydroxybenzoate 0.1 g cleaned water to 100.0 g Example 1 8

Water-soluble ointment base

2-Amino-9- (2-hydroxyethoxy-

methyl jadenin 0.5 g glycerine 15,0 g macrogol 300 20,0 g polyethylene glycol 1500 64,5 g Example 19 Tablet - (total weight 359 mg) 9- (2-hydroxyethoxymethyl) - guanine 100 mg lactose 200 mg starch 50 mg polyvinylpyrrolidone 5 mg magnesium stearate 4 mg

SUBJECT

Claims (5)

A process for the preparation of substituted purines of general formula I, wherein. X.is sulfur or oxygen, R ¹ is halogen, hydroxyl, C 1 -C 4 alkoxy, hydrogen, mercapto, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl or an azido group, R ² is hydrogen, halogen, amino or azido, R ³ is hydrogen, alkyl of straight or branched chain having 1-8 carbon atoms the invention, or cyclic alkyl having up to 8 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, benzyloxyalkyl with 1 to 4 carbon atoms or phenyl, R ⁴ is hydrogen, hydroxyl or alkyl having 1 to 4 carbon atoms, R ⁵ is hydrogen, amino, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, benzoyloxy, benzoyloxymethyl, benzyloxy, sulfamoyloxy, phosphate, carboxypropionyloxy, acetoxy or substituted carbamoyl of the formula —NH- is alkyl of 1 to 4 carbon atoms, aryl of up to 8 carbon atoms or arylalkyl of up to 8 carbon atoms in the aryl portion of 1 to 4 carbon atoms in the alkyl optionally substituted by one or more of sulfonyl, amino, carbamoyl or a halogen atom. R ⁶ is hydrogen, alkyl of 1 to 12 carbon atoms, and when X is oxygen and R ² , R ³ , R ⁴ and R ⁶ are hydrogen, R ¹ is not amino or methylamino, when R ⁵ is hydrogen or benzyloxy, wherein when R ² is a hydrogen atom, R ¹ is not a chlorine atom, or a salt thereof, especially a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (IV): Q is a hydrogen atom or a leaving group and R ¹ and R ² are as defined above, is reacted at a temperature of 20 ° C to 200 ° C with a compound of formula V A — CH — X — CH — CH — R ⁵ R ³ R ⁴ (V) where A is a leaving group such as a reactive radical of an organic or inorganic acid and R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, and if the product of the reaction is a base, optionally converting a compound of formula I to an acid salt, or if the product is a salt of a compound of formula I or another salt. 2. The process of item 1 for preparing substituted purines of general formula I as defined in item 1, wherein X is an oxygen atom, R ¹ is chlorine, hydroxyl, mercapto or amino, R ² is hydrogen, chloro, amino or azido, R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, R ⁵ is hydroxyl or benzyloxy; and R ⁶ is hydrogen, characterized in that the compound of formula IV, as defined in point 1, wherein Q is hydrogen or silyl, is reacted with a compound of formula V, as defined in point 1, wherein A is chlorine. 3. A process according to claim 1, wherein the starting compound of formula (V) is a compound wherein A is silyl or acyl. 4. A process as claimed in claim 1, wherein the starting compound of formula (V) is a compound wherein A is a halogen atom or a carboxylate. 5. A process according to claim 4 wherein the starting compounds of formulas IV and V are those wherein A is carboxylate and Q is hydrogen or A is carboxylate or halogen and Q is acyl.