CH629806A5 - Process for the preparation of substituted purines - Google Patents

Description

The invention relates to a process for the preparation of substituted purines and their salts. The esters of the 9- (2-hydroxyethoxymethyl) derivatives of guanine and 2,6-diaminopurine and the pharmaceutically acceptable salts of these compounds are preferably prepared.

It has now been found that substituted purines of the formula

30th

(I),

CHL. 0. CH0 "CHo0C .R

2 2 2 n

0

(v)

H,

, nÄnJL /

ch2.o.ch2.ch2.oh esterified by reaction with an acylating agent, and if the process product is the free base, this is converted into an acid addition salt or an alkali metal salt or, if the process product is a salt, this into the free base or into a transferred other salt.

2. The method according to claim 1, characterized in that one produces a compound of formula I, wherein R1 is hydroxy.

3. The method according to claim 1 or 2, characterized in that one produces a compound of formula I, wherein R2 is hydrogen or an alkyl group with a straight or branched chain and 2 to 8 carbon atoms.

4. The method according to claim 1 or 2, characterized in that a compound of formula I, wherein R2 is an aryl group substituted by a halogen atom, an amino, nitrite or sulfonamido group or an acyl or alkyl group having 1 to 4 carbon atoms means manufactures.

5. The method according to any one of claims 1, 2, or 4, characterized in that a compound of the formula I in which R 2 is a substituted aryl group having fewer than 10 carbon atoms is prepared.

6. The method according to claim 1, characterized in that 60 one produces 9- (2-formyloxyethoxymethyl) guanine.

7. The method according to claim 1, characterized in that 9- (2-propionyloxyethoxymethyl) guanine is prepared.

8. The method according to claim 1, characterized in that 9- [2- (2,2-dimethyl-propionyloxy) ethoxymethyl] guanine 65 is prepared.

9. The method according to claim 1, characterized in that 2-amino-9- (2-formyloxyethoxymethyl) adenine is prepared.

wherein

R1 R2

35

40

45

50

55

a hydroxyl or amino group, and hydrogen, a straight-chain or branched alkyl group having 2 to 16 carbon atoms, an unsubstituted aryl group having 10 carbon atoms or a substituted aryl group having 6 to 18 carbon atoms, preferably having less than 10 carbon atoms,

mean, are effective against viruses, namely against different types of DNA and RNA viruses in vitro and against DNA viruses in vivo. In particular, these compounds are particularly effective against herpes, cowpox and rhinoviruses, including herpes simplex, herpes zoster and Windpok ken viruses in mammals, which cause diseases such as keratitis herpetica in rabbits and encephalitis herpetica in mice.

The invention accordingly relates to a process for the preparation of compounds of the formula I in which R1 and R2 have the meanings given above, or a salt thereof, in particular a pharmaceutically acceptable salt.

The compounds of the formula I in which R 1 is hydroxy or their salts are preferred, as are compounds in which R 2 is hydrogen or a straight-chain or branched alkyl group having 2 to 8 carbon atoms, 2 to 4 carbon atoms being particularly preferred. When R2 represents a substituted aryl group having 6 to 18 carbon atoms, preferably less than 10, the preferred substituents on the aryl group are halogen atoms, amino, nitrilo- or sulfonamido groups, and acyl or alkyl groups having 1 to 4 carbon atoms.

The most preferred compounds are: 9- (2-formyloxyethoxy methyl) guanine; 9- (2-propionyloxyethoxymethyl) guanine; 9- [2- (2,2-dimethylpropionyloxy) ethoxymethyl] guanine, and 2-amino-9- (2-formyloxyethoxymethyl) adenine.

These compounds are distinguished by their extraordinarily strong activity against herpes viruses.

Salts which are particularly suitable for therapeutic purposes are those of pharmaceutically acceptable acids such as lactic acid,

3,629,806

Acetic acid, malic acid or p-toluenesulfonic acid and the same amount of salts, which is sufficient to combat the virus organism in vivo of pharmaceutically acceptable mineral acids, such as. Pharmaceutically acceptable carriers are wise hydrochloric acid or sulfuric acid. R1 means a hydroxy substance which is suitable for the administration of the medicament. group. This is how pharmaceutically acceptable products come in. They can be solid, liquid or gaseous, and they should also

Alkali metal salts into consideration, the sodium salt being particularly inert and medically acceptable and preferred with the active ingredients. Other salts can also be made and tolerated.

then in these pharmaceutical preparations suitable for the respective treatment purpose can be converted parenterally, salts. administered orally, as suppositories or as a pessary; further

The process according to the invention for the production of sub- they can be administered locally as an ointment, cream, aerosol, powder or in the form of substituted purines of the formula I, characterized in that eye drops or nose drops are administered. The particular form of preparation depends on whether an internal or external virus infection is to be treated.

In the case of internal infections, the preparations are usually administered orally or parenterally in doses of 0.1 to 250, preferably 1 to 50 mg / kg of body weight of the mammal, the amount of the active ingredient being calculated in relation to the free base. In humans, these compounds are administered in the form of single doses, several times a day in an amount of 1 to 250 mg per single dose. 20 For oral administration, fine powders or granules are suitable which contain diluents, dispersants and / or surface-active agents and in a mixture, either in water or in a syrup, in capsules or sachets in the dry state or in a non-aqueous solution or 25 suspension, which may contain suspending agents. The preparations for oral administration can also be in the form of tablets into which binders are converted; or if the product can be incorporated in one of the foregoing or lubricants, or the reactions described in the form of the free base, these are present in a suspension in water or syrup. In addition, if converted into an acid addition salt or an alkali metal salt, if desired or necessary, taste or, if the product obtained is a salt of a compound of substances, preservatives, suspending agents, thickening agents formula I, if appropriate, this is converted into another salt or emulsifiers be added. Releases from the aforementioned accessories or the base. Formats are preferred tablets and granules, which

According to the invention, an alcohol of formula V can also be provided with a coating.

suitable acylating agents, e.g. For example, for parenteral administration or for the administration aliphatic or aromatic acid anhydride, an aliphatic in drop form, for example in the case of eye infections, or aromatic acyl halide, a mixed carbon, the compounds can be dissolved in aqueous solution in a concentration. Lentic acid / carboxylic acid anhydride or a carboxylic acid ester, tration of 0.1 to 10%, preferably 0.1 to 1% and especially implemented. The compounds of the formula V can then be 0.2% (w / v). These solutions can be prepared using the process described in DE-OS2 539 963, containing 40 antioxidants, buffers and / or other additives. In case of infections of the eye or other external

The method according to the invention is based on intermediate tissue, e.g. B. in the mouth or on the skin, the preparations that are obtained from monosubstituted purines are preferred directly on the infected part of the body than can. Such purines are readily available and can be applied after topical ointment or cream. The compounds known per se, which are known in the literature and in text books, can be published in an ointment, for example with a water-soluble solvent such as “Heterocyclic Compounds - Fused Pyrimidines Part II Ointment Base, or in a cream, for example with a Purines” DJ Brown (1971), published 01-in-water cream base, in a concentration of 0.1 at Wiley-Interscience. up to 10%, preferably 0.3 to 3% and in particular 1% (w / w

A compound of formula I vol.) Obtained according to the invention can be administered.

can optionally be converted into another compound by transesterification. The examples below serve to explain the formula I formula. Such a conversion invention.

for example, by implementing the connection of the

Formula I can be carried out with a suitable carboxylic acid. Example 1

the; For example, 9- (2-propionylo- a solution of 4.73 g of 9- (2-hydroxyethoxymethyl) guanine,

xyäthoxymethyl) guanine propionic acid required. In certain 55 prepared according to the cases described in DE-OS No. 2 539 963, the acid can simultaneously act as an acid catalyst, process, in 24 ml of 97% formic acid was overnight, however, in other cases, an additional acid catalyst at room temperature touched. The amber-colored solution required, for which p-toluenesulfonic acid, for example, was diluted with about 200 ml of dried ether and comes. cooled down. The white precipitate obtained was filtered.

The compounds of the formula 60 obtainable according to the invention dried and, after recrystallization from dry I and their pharmaceutically acceptable salts, can together give dimethylformamide 3.6 g9- (2-formyloxyethoxymethyl) guanine, with pharmaceutically acceptable excipients to give pharmaceutical m.p. 225 to 227 ° C.

preparations and preparations are processed. Example 2

In a special embodiment of a pharmaceutical- A solution of 0.5 g of 2-amino-9- (2-hydroxyethoxymethyl

The preparation is a compound of the formula I in the form 65 adenine, prepared in accordance with an “effective single dose” preparation in DE-OS No. 2,539,963. described method, in 2.5 ml 97% formic acid

The expression "effective was used for 3 hours on an ice bath and then overnight at a single room dose" means a predetermined temperature that is effective against viruses. 80 ml of dry ether were added and an alcohol of the formula V

R1

H2N '

(v)

n-

.N '

ch2.o.ch2.ch2.oh esterified by reaction with an acylating agent and optionally subsequently a compound of the formula I by transesterification into another compound of the formula I.

629 806

the mixture cooled. The solid was removed by filtration and dissolved in 125 ml of hot acetonitrile. The remaining solids were removed by filtration. The filtrate was placed on a column containing 14 g of silica gel in acetonitrile. The column was eluted with dry acetone. The eluent was evaporated and the remaining solid was recrystallized from acetonitrile. 93 mg of 2-amino-9- (2-formyloxyethoxymethyl) adenine were obtained, mp. 238 to 240 ° C.

10th

Example 3

Preparation of 2- (2-hexanoyloxyethoxymethyl) guanine

1.0 g of 9- (2-hydroxyethoxymethyl) guanine, prepared by the processes described in DE-OS No. 2,539,963,

was dissolved in 70 ml of dry 15 dimethylformamide by heating on a steam bath, the solution was then cooled to room temperature and 10 ml of dry pyridine and 9.4 g of hexanoic anhydride were added. After stirring at room temperature for 4 days, thin layer chromatography (silica gel in 10% methanochloroform) showed that the reaction was complete.

The yellow reaction solution was diluted to a volume of 800 ml with ethyl acetate and cooled for a few days. The precipitated fine white powder was filtered off, dried and, after recrystallization from dry acetonitrile 400, gave 25 mg of white grains (28% of theory), mp. 221 to 223 ° C.

Example 4

Preparation of 9- (2-tridecanoyloxyethoxymethyl) guanine

300 mg of 9- (2-hydroxyethoxymethyl) guanine, prepared 30 according to the processes described in DE-OS No. 2,539,963, were heated in 20 ml of dry dimethylformamide and 30 ml of dry pyridine on the steam bath until completely dissolved. The solution was cooled to room temperature and 0.93 g of tridecanoyl chloride was added. Solution 35 was stirred at room temperature until thin layer chromatography showed that the reaction was complete with the disappearance of the starting material (18 h).

The solution was concentrated by flash evaporation and the remaining yellow oil crystallized from acetonitrile. 375 mg of a creamy, yellow solid were obtained. NMR analysis of the crude product showed the presence of various compounds. The clarified mixture was

Chromatography cleaned. Mp 217 to 219 ° C.

45

Example 5 9- (2-Propionyloxyethoxymethyl) guanine A mixture of 1.0 g of 9- (2-hydroxyethoxymethyl) guanine and 50 ml of dry dimethylformamide was heated on a steam bath until most of the solid was dissolved. So it was then cooled to room temperature. 10 ml of dry pyridine and 2.9 ml of propionic anhydride were added and the mixture was stirred at room temperature overnight. Another 1.0 ml of propionic anhydride was introduced and the mixture was stirred for a further 18 h. The reaction mixture was diluted with 55 ethyl acetate, cooled, and the solid obtained was removed by filtration. This was recrystallized from dimethylformamide and gave 0.9 g of 9- (2-propionyloxyethoxymethyl) guanine, mp. 223 to 226 ° C.

60

Example 6

9- [2- (2,2-Dimethylpropionyloxy) ethoxymethyl] guanine A mixture of 2.46 g of 9- (2-hydroxyethoxymethyl) guanine, 400 ml of dry pyridine and 6.5 ml of pivalic anhydride was heated on a steam bath for a total of 33 days. A further 150 ml of pyridine was added on the eleventh 65 days and 50 ml of dimethylformamide on the 27th day. The volatiles were removed under reduced pressure and the residue was triturated with ethyl acetate. The insoluble solid was removed by filtration and dissolved in methanol-acetone. 3 g of silica gel was added and the solvent evaporated. The residue was placed on a column of 180 g silica gel in acetone. Elution in acetone gave a first fraction of N, 0-diacyclized material and then a fraction containing the desired monoacylated product. The acetone was evaporated from the latter fraction and the residue was recrystallized from dimethylformamide acetonitrile / ethyl acetate and gave 0.5 g of 9- [2- (2,2-dimethylpropionyloxy) ethoxymethyl] guanine, mp. 245 to 246 ° C.

Example 7

Preparation of 9- (2-palmitoyloxyethoxymethyl) guanine 0.3 g9- (2-hydroxyethoxymethyl) guanine, prepared according to the processes described in DE-OS No. 2,539,963, were carried out in 15 ml of dry dimethylformamide and 30 ml of dry pyridine Half an hour heating on a steam bath partially solved. The mixture was cooled in an ice bath and 4.00 palmitoyl chloride (1.1 g) was added with stirring. The mixture was allowed to come to room temperature and stirred for 20 hours. During this time, all of the solid dissolved. Thin layer chromatography showed the quantitative conversion of the starting material. The solution was diluted to a volume of 300 ml with ethyl acetate and cooled overnight. After filtering, 0.49 g of a white solid was obtained.

The raw material was recrystallized once from ethyl acetate and once from acetone and gave 190 mg of analytically pure 9- (2-palmitoyloxyethoxymethyl) guanine, yield 31% of theory. Th., Mp. 190 to 210 ° C.

The NMR, UV and mass spectra matched the desired product.

Example 8

Preparation of 9- (2-butyryloxyethoxymethyl) guanine A solution of sodium methoxide in dry methanol (10 ml) was added to a methanolic solution of 9- (2-hydroxyoxyethoxymethyl) guanine at room temperature.

After removal of the solvent in vacuo, the sodium salt of the purine was obtained as a white powder.

The above sodium salt was suspended in a mixture of ethyl butyrate and dry dimethylformamide (20 ml) and brought to reflux with stirring. After 3/2 days most of the solid had dissolved. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in 15 ml of 2N acetic acid. After removal of the solvent in vacuo, a semi-solid mass was obtained, which solidified after treatment with 15 ml of water and 15 ml of SD3A with removal of the solvents in vacuo. This product was slurried with 25 ml SD3A, filtered and air dried. It gave 195.2 mg of a tan solid.

Example 9

Preparation of 9- (2-p-toluoyloxyethoxymethyl) guanine Following the procedure according to Example 7, a mixture of 9- (2-hydroxyethoxymethyl) guanine (0.3 g) in dry dimethylformamide (15 ml) and dry pyridine (30 ml) heated on a steam bath for 0.5 h. The mixture is then cooled in an ice bath and p-toluoyl chloride (0.6 g) is added with stirring. The mixture is warmed to room temperature and stirred at this temperature for 20 h. The reaction mixture is diluted to a volume of 300 ml with ethyl acetate and cooled overnight. The resulting solid is separated off by filtration and recrystallized from ethyl acetate. Elemental analysis, NMR and UV spectra confirm the structure of 9- (2-p-toluoyloxyethoxymethyl) guanine. Mp 220-221 ° C.

629 806

Example 10

Preparation of 9- (2-β-naphthoyloxyethoxymethyl) guanine The procedure of Example 9 is repeated, but 0.8 g of β-naphthoyl chloride is used instead of p-toluoyl chloride. The product 9- (2- (3-naphthoyloxyethoxymethyl) guanine is recrystallized from ethyl acetate. The elemental analysis, NMR and UV spectra agree with the assumed structure. Mp. 219 to 220 ° C.

Example 11

Preparation of 9- (2-m-chlorobenzoyloxyethoxymethyl) guanine The procedure of Example 9 is repeated, except that 0.7 g of m-chlorobenzoyl chloride is used instead of p-toluoyl chloride. The product 9- (2-m-chlorobenzoyloxyethoxymethyl) guanine is recrystallized from ethyl acetate. Elemental analysis, NMR and UV spectra agree with the assumed structure. Mp 218 to 220 ° C.

Example 12 Preparation of 9- (2-propionyloxy-ethoxymethyl) guanine hydrochloride The pH of a solution of 300 mg of 9- (2-propionyloxy-ethoxymethyl) guanine in 400 ml of ethanol was adjusted to 1.0 with ethereal hydrochloric acid at room temperature. measured with a broadband pH paper. The solution was diluted to a volume of 1.91 with dry ether and cooled overnight. The precipitated granules were filtered, washed with ether and dried in a desiccator under reduced pressure for 3 days. They were further dried at 3.5 mm Hg for 2.5 hours. 260 mg of 9- (2-propionylo-

xyäthoxymethyl) guanine hydrochloride obtained with a melting point of 125 to 131 ° C. Elemental analysis and NMR spectrum (DMSO-d6) corresponded to the above compound. The silver nitrate test was positive for halogen.

Example 13

Sodium salt of 9- (2-propionyloxyethoxymethyl) guanine 125 mg of 9- (2-propionyloxyethoxymethyl) guanine were added to 44.5 ml of a cooled 0.01N sodium hydroxide solution with stirring. The mixture was frozen and lyophilized. The sodium salt of 9- (2-propionyloxyethoxymethyl) guanine was obtained. Elemental analysis, NMR and IR spectra corresponded to the above compound.

15

Preparations

1) A tablet preparation containing a mixture of 100 mg of 9- (2-formyloxyethoxymethyl) guanine, 200 mg of lactose, 50 mg of starch, 5 mg of polyvinylpyrrolidone and 4 mg of magnesium stearate was prepared by wet granulation.

2) A tablet preparation containing a mixture of 100 mg of 2-amino-9- (formyloxyethoxymethyl) adenine, 200 mg of lactose, 50 mg of starch, 5 mg of polyvinylpyrrolidone and 4 mg of magnesium stearate was prepared by wet granulation.

3) A tablet preparation that contains a mixture of 100 mg 9-

25 (2-propion-yloxyethoxymethyl) guanine, 200 mg lactose, 50 mg

Starch containing 5 mg polyvinylpyrrolidone and 4 mg magnesium stearate was prepared by wet granulation.

4) A tablet preparation containing a mixture of 100 mg of 9- [2- (2,2-dimethylpropion-yloxy) ethoxymethyl] guanine, 200 mg

Lactose, 50 mg starch, 5 mg polyvinylpyrrolidone and 4 mg magnesium stearate was prepared by wet granulation.

M

Claims (2)

629 806 2nd PATENT CLAIMS 1. Process for the preparation of substituted purines of the formula .1 10. The method according to any one of claims 1 to 9, characterized in that a carboxylic acid, an aliphatic or aromatic anhydride, an aliphatic or aromatic acyl halide, a mixed carbonic acid / carboxylic acid anhydride or a carboxylic acid ester is used as the acylating agent. (I), 10th ch2.o.ch2.ch2oc.r 15 0 wherein R1 is a hydroxyl or amino group, and R2 is hydrogen, an alkyl group with a straight or branched 20 chain and 2 to 16 carbon atoms, an unsubstituted aryl group with 10 carbon atoms or a substituted aryl group with 6 to 18 carbon atoms, characterized in that an alcohol of Formula V 25