FI60710B - ANALOGIFICATION OF THE FRAMSTAELLNING AV 9- (2-ACYLOXIETOXIMETYL) PURINFOERENINGAR ANVAENDBARA SAOSOM ANTIVIRALA MEDEL - Google Patents

Description

G35r71 ΓβΊ m ^ ANNOUNCEMENT * n9irx ^ HSTa l * J (11) UTLÄGCN I NCSSKRIFT Oli f 1 0 • g® C (45) Fi Lev. i.r.i ryinr; tty 10 03 1932 ^ ^ (51) Kv.ik.3 / incci.3 C 07 D 473/16, 473/18 FINLAND — FINLAND (21) P * t «flttlh» k * mus - Pattfltanseknlnf 770655 (22) HtkwnltpDvl —AmBkningidag 01.03.77 '' (23) Alkuptlvi — GUtlghutsdsg Ol.O3.77 (41) Tullut | ulklMkil - Bllvlt offmtllf 02.09.77

National Board of Patents and Registration .... .... „,,, ,, ,,„, _ ^ ^, (44) Date of publication of the Public Procurement Act and the Publications Act. -

Patent- och registerstyrelsen 'Ansdktn utlagd och utl.skrifttn publteitrad 30.11.8l (32) (33) (31) Pyydetty etuoikeus - Befird prioriwt 01.03.76

England-England (GB) 7988/76, 27.08.76 usa (us) 718105 (71) The Wellcome Foundation Limited, l83_193 Euston Road, London N.W.l,

England-England (GB) (72) Howard John Schaeffer, Richmond, Virginia, USA (US) (7 * 0 Oy Kolster Ab (5I +) Analogue method for the preparation of 9- (2-acyloxyethoxymethyl) purine compounds for use as antiviral agents - Analogiför- for the preparation of 9- (2-acyloxiethoxymethyl) purifiers of the anthers and antivirals

The invention relates to an analogous process for the preparation of 9- (2-acyloxyethoxymethyl) purine compounds of the formula I for use as antiviral agents,

R

rV> CH9.0.CHo.CHo0C, R2 2 2 2 n o. 1 2 wherein R is a hydroxy or amino group, R is hydrogen or a straight-chain or branched alkyl group having 2 to 6 carbon atoms, or salts thereof.

2 60710

In particular, this invention relates to esters of 9- (2-hydroxyethoxymethyl) derivatives of guanine and 2,6-diaminopurine, and pharmaceutically acceptable salts of these compounds.

It has now been found that the compounds of the invention have antiviral activity, targeting various DNA * and RNA-related viruses in vitro and DNA viruses in vivo. The compounds have particularly potent activity against herpes, vaccinia and rhino viruses; herpes viruses include mammalian simplex, Zoster, and varicella viruses, which cause diseases such as herpetic keratitis in rabbits and herpetic encephalitis in mice.

Preferred compounds of formula (I) are those wherein R

2 is · hydroxy, or a salt thereof, with R being an alkyl group, those compounds having 2 to 4 carbon atoms in the alkyl group are most preferred.

The most preferred compounds are 9- (2-formyloxyethoxymethyl) guanine, 9- (2-propionoyloxyethoxymethyl) guanine, 9- [2- (2,2-dimethylpropionoyloxy) ethoxymethyl] guanine and 2-amino-9- (2-formyloxyethoxymethyl) adenine , especially because they have a very effective herpes-killing effect.

Particularly suitable salts for therapeutic use are the salts of pharmaceutically acceptable organic acids such as lactic acid, acetic acid, maleic acid or p-toluenesulfonic acid, as well as the salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid or sulfuric acid. When R is hydroxy, pharmaceutically acceptable alkali metal salts, most preferably the sodium salt, may be used. Other salts may also be prepared and then converted directly to salts suitable for therapeutic purposes.

The process according to the present invention is characterized in that a) the compound of formula II is R 1

Q

is reacted with a compound of formula III 60710

A.CH, .O.CH, .CH, .OC.R2 III

2 2 2 || 0 12 - · wherein R and R are as defined above, A is a reactive residue of an organic or inorganic acid and Q is a hydrogen atom or an alkali metal; or b) reacting hydrogen with a compound of formula IV in the presence of a catalyst

rJ

Il / IV

Ns N I

CHo.0.CHo.CHo.0C.R 2 2 2 || 0 1 1. .... 2

wherein R0 is either R as defined above or an azide and R

is as defined above; or (c) an alcohol of formula V R1 I / v h2n CH2 .o.ch2.ch2.oh where R is as defined above, is esterified by reacting it with an acylating agent, d) deprotecting the compound of formula I, 1.

wherein the 2-amino group or the R substituent or both are protected; and when the product of any of the above reactions is a base, the product is optionally converted into an acid addition salt or an alkali metal salt, or when the product is a salt of a compound of formula I, said salt is optionally converted into a base form or other salt.

In process variant a) the group A may be a halogen atom * 60710 or a sulfonate group, and Q is preferably sodium. chloride or butyryloxyethoxymethyl acetate in a strongly polar solvent such as dimethylformamide (DMF) in the presence of a base, e.g. sodium hydride. The reaction is preferably carried out at room temperature for a long time, i.e. achieving reasonable yields may require reaction times of several hours or even days.

The conversion of a compound of formula IV according to method b) can be carried out in a number of ways, e.g. when RQ is an azide group it can be converted into an amino group by reduction with a suitable catalyst such as palladium.

These can be found in "Heterocyclic compounds -Fused Pyrimidines Part II Purines, letter, D.J., Brown (1971), published by Wiley-Interscience".

In process c) the alcohol of formula V is reacted with a suitable acylating agent such as, for example, a carboxylic acid, an aliphatic or aromatic anhydride, an aliphatic or aromatic acyl halide, a carboxylic acid carboxylic acid mixed anhydride or a carboxylic acid ester. Compounds of formula V can be prepared by the methods described in German Application 2,539,963.

In process d) the amino group in the 2-position or the substituent in the 6-position or both may be reversibly protected by a protecting group, e.g. a trialkylsilyl group, an activated acyl group, or a benzyloxycarbonyl group, but the two vii-. . . . . Of the 1 types of groups mentioned, R can be protected only if it is an amino group. When both the amino groups in the 2-position and the substituents in the 6-position are protected by a trialkylsilyl group, such a compound may be a product obtained by condensing a trialkylsilylated purine and an ester or diester in the same manner as in process a). Such protecting groups are very labile and can be solvated by solvation of ammonia in alcoholic or aqueous solution or by alcoholysis,

One or both of the 2- and 6-positions of the purine ring may be i ..

5,60710 to protect with an activated acyl group such as a trihaloacyl group, e.g. trichloroacetyl, which together with the amino group it protects forms a trichloroacetamido group. The 6-position of the purine ring is protected only when it has an amino group as a substituent. Such groups can be cleaved off by reduction; if the protecting group is a benzyloxycarbonyl group, this too can be removed using reduction cleavage.

Methods a) to d) are all based on intermediates that can be prepared from simply substituted purines. Such purines are prepared by methods known in the art and described in the literature and manuals, such as "Heterocyclic compounds - Fused Pyrimidines Part II Purines, D.J. Brown (1971), Wiley-Interscience".

A compound of formula I prepared by any of methods a) to d) may be converted by transesterification to another compound of formula I. Such interconversion can be accomplished by reacting a compound of formula I with a suitable carboxylic acid, e.g. to prepare 9- (2-propionyloxyethoxymethyl) guanine, the compound must be reacted with propionic acid. In some cases, the acid may also act as an acid catalyst, but in other cases an additional acid catalyst, e.g. paratoluenesulfonic acid, is required.

As used herein, the term "effective dosage unit" means a predetermined amount of antiviral agent sufficient to be effective against viral organisms in vivo. Pharmaceutically acceptable carriers are substances that can be used for drug delivery purposes and can be solid, liquid, or gaseous substances that are otherwise neutral and medically acceptable and miscible with the active substances.

These pharmaceutical compositions can be administered parenterally, orally, applied in the form of a suppository or pessary, applied topically in the form of a fat, cream, aerosol, powder, or administered as eye or nasal drops, etc., depending on whether the preparation is used for intrinsic or external viruses. to treat infections.

In internal infections, the compositions are administered orally or parenterally in dosage amounts, calculated as the free base, of about 0.1 to 250 mg, preferably 1 to 50 mg per kilogram of mammalian body weight, and are administered to humans in unit dosage form, a few times a day. in an amount of 1-250 mg per dosage unit.

Powders or granules for oral administration may contain diluents, dispersants and / or surfactants and may be administered in the form of a medicament, water or syrup; in capsules, or sachets, as a dry or anhydrous solution or suspension, which may contain suspending agents; in tablets which may contain binders and glidants; or in aqueous suspension or among syrup. If desired or necessary, they may contain flavoring agents, preservatives, suspending agents, thickening agents, or emulsifying agents. Tablets or granules are recommended and may be coated.

For parenteral administration or for instillation, e.g. in connection with ocular infections, the compounds may be administered in aqueous solution at a concentration of about 0.1-10%, preferably 0.1-1%, most preferably 0.2% (w / v). The solution may contain antioxidants, buffers, etc.

Alternatively, in the case of ocular infections, or other external tissues, e.g., mouth and skin infections, the compositions are applied primarily to the infected part of the patient's body as a topical ointment or foam. The compounds may be administered as an ointment, e.g. as a water-soluble ointment base, or as a foam, e.g. with oil, as a water-foam base, at a concentration of about 0.1-10%, preferably 0.3-3%, most preferably 1% (w / v). .

The antiviral activity of the compounds prepared by the method of the invention was determined by a "plaque inhibition" test. This experiment is performed by infecting a uniform layer of VERO cells with a suitable virus to form a uniform viral plaque.

A solid coating is placed over the plaque, and a filter paper plate impregnated with a solution of the test compound (usually about 50 μg of test compound per filter paper plate) is placed in the center of this. The cultures are incubated at 37 ° C for 96-120 hours in an atmosphere of 5% carbon dioxide. The cells are then fixed with 10% formalin and stained with 0.05% methyl violet.

The gastrointestinal adsorption of the compounds of the invention prepared by the method of the invention was studied by orally administering to the rats the test compound as an aqueous suspension corresponding to 25 mg / kg of 9- (2-hydroxyethoxymethyl) guanine. Urine samples were collected over a period of 24 hours, and the concentration of test compound in urine was determined by high pressure liquid chromatography. The amount of test compound in urine was expressed as a percentage of the initial dose, which corresponded to the amount adsorbed in 24 hours,

The advantage of the compounds prepared by the process of the invention was demonstrated by using structurally similar compounds known from Finnish patent application 752,465 as reference compounds. The results of the above experiments are shown in the following table.

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The results show that when the test compounds are administered orally to experimental animals, compounds 4, 5, 6 and 7 (compounds according to the present application) are adsorbed more efficiently from the gastrointestinal tract than compounds 1, 2 and 3 (compounds according to Finnish patent application 752465). In this regard, the compounds of the present invention have surprising and valuable properties.

The invention is further illustrated by reference to the following examples.

Example 1

A solution of 9- (2-hydroxyethoxymethyl) guanine (4.73 g) prepared according to the methods described in German Patent Application 2,539,963 in 97% formic acid (24 ml) was stirred overnight at room temperature. The tan solution was diluted with about 200 mL of dried ether and cooled. The resulting white precipitate was filtered off, dried and recrystallized from dry dimethylformamide to give 9- (2-formyloxyethoxymethyl) guanine (3.6 g, mp 225-227 ° C).

Example 2

A solution of 2-amino-9- (2-hydroxyethoxymethyl) adenine (0.5 g) prepared according to the methods described in German Application 2,539,963 in 97% formic acid (2.5 ml) , was stirred in an ice bath for 3 hours, and then overnight at room temperature. Dry ether (80 mL) was added and the mixture was cooled. The solid was removed by filtration and dissolved in hot acetonitrile (125 mL); the remaining solid was removed by filtration. The filtrate was applied to a column of silica gel (14 g) in acetonitrile. The column was eluted with dry acetone. The eluate was evaporated to dryness and the solid residue was recrystallized from acetonitrile to give 2-amino-9- (2-formyloxyethoxymethyl) -adenine (93 mg, m.p. 38-240 ° C).

Example 3 Preparation of 9- (2-hexanoyloxyethoxymethyl) guanine 9- (2-hydroxyethoxymethyl) guanine (1.0 g) prepared according to the methods described in German Application 2,539,963 was dissolved in dry dimethylformamide (70 ml) by heating in a water bath. The solution was cooled to room temperature and dry pyridine (10 ml) and hexanoic anhydride (9.4 g) were added. After stirring at room temperature for four days, plate chromatographic analysis (silica gel in 10% methanol-chloroform) indicated that the reaction was complete.

The yellow reaction solution was diluted with ethyl acetate to 800 ml and cooled for several days. The precipitated fine powder was filtered off, dried and recrystallized from dry acetonitrile to give 400 mg (28%) of white granules, m.p. 221-223 ° C.

Example 4 Preparation of 9- (2-propionoyloxyethoxymethyl) guanine (A) A mixture of ethylene glycol (31 g), propionic acid (18.5 g) and 7.5 g of strong hydrogen ion resin, Bio Rod AG 50 WX-4 , In 100 mL of toluene, is boiled with stirring using a Dean Stark trap for eighteen hours.

The toluene is removed using expansion evaporation and the remaining liquid is distilled. Pre-distillation of ethylene glycol is followed by distillation of the desired product, ethylene glycol monopropionate. NMR determination is used to determine purity. Yield 70%.

(B) Dry hydrogen chloride gas is introduced into a cooled suspension (0 ° C) of the ethylene glycol monopropionate prepared above (7.1 g) and paraformaldehyde (1.8 g) in dichloromethane (50 ml) until the solid is dissolved. and the mixture is saturated with hydrogen chloride. After drying through a molecular sieve and calcium chloride, the mixture is filtered and the solvent is removed using expansion evaporation at 30 ° C.

The residual oil, 2-propionyloxyethoxymethyl chloride, is used directly as such. Yield 60%.

(C) A 57% suspension of sodium hydride (2.53 g) in mineral oil is washed with dry hexane and added to a solution of guanine (4.53 g) in 100 ml of dry dimethyl sulfoxide and the mixture is stirred at 30 ° C for 23 hours.

2-Propionoyloxyethoxymethyl chloride (5.5 g) is added and the reaction mixture is stirred at 20 ° C for 18 hours. The solution is filtered and the solvent is removed using expansion evaporation in vacuo. The residue is cooled in an ice bath, dissolved in water and neutralized with acetic acid.

After one hour, the product is filtered off, washed with water and dried. Recrystallization (3 times) from boiling acetonitrile gives 9- (2-propionyloxyethoxymethyl) guanine. Yield 35%, mp, 223-226 ° C.

n 60710

Example 5 9- (2-Propionyloxyethoxymethyl) guanine

A mixture of 9- (2-hydroxyethoxymethyl) guanine (1.0 g) and dry dimethylformamide (50 ml) was heated on a water bath until most of the solid had dissolved. The mixture was then cooled to room temperature. Dry pyridine (19 ml) and propionic anhydride (2.9 ml) were added and the mixture was stirred at room temperature overnight. Additional propionic anhydride (1.0 mL) was added and the mixture was further stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, cooled and the solid formed was filtered off. This was recrystallized from dimethylformamide to give 9- (2-propionyloxyethoxymethyl) guan (0.9 g), m.p. 223-226 ° C.

Example 6 9- [2- (2,2-Dimethylpropionyloxy) ethoxymethyl] guanine

A mixture of 9- (2-hydroxyethoxymethyl) guanine (2.46 g), dry pyridine (400 ml) and pivalic anhydride (6.5 ml) was heated on a water bath for a total of 33 days. On day 11 additional pyridine (150 ml) was added and on day 27 dimethylformamide (50 ml) was added. The volatiles were removed in vacuo and the residue triturated with ethyl acetate, the insoluble solid was removed by filtration and dissolved in methanol-acetone, silica gel (3 g) was added and the solvent was evaporated. The residue was applied to a column of silica gel (180 g) in acetone. Elution with acetone gave N, O-diacylated material as an initial fraction, followed by a fraction containing the desired monoacylated product. The acetone was evaporated from the latter fraction, and the residue was recrystallized from dimethylformamide / acetonitrile / ether acetate to give 9-A2- (2,2-dimethylpropionyloxy) ethoxymethyl] guanine (0.5 g), m.p. 245-246 ° C,

Example 7 Preparation of 9- (2-butyryloxyethoxymethyl) guanine

A solution of sodium methylate in dry methanol (10 ml) was added at room temperature to a methanol solution of 9- (2-hydroxyethoxymethyl) guanine. Removal of the solvent in vacuo gave the sodium salt of the purine as a white powder.

The above sodium salt was suspended in a solution of ethyl butyrate and dry DMF (20 mL) and heated to reflux with stirring. After 3 1/2 days, most of the solid had dissolved, whereupon the reaction mixture was evaporated to dryness in vacuo i2 6071 0 and the residue was dissolved in 2N acetic acid (15 ml). Removal of the solvent in vacuo gave a semi-solid mass which solidified after treatment with water (15 mL) and SD3A (15 mL) and removal of the solvents in vacuo. This product was slurried in SD3A (25 mL), filtered and air dried to give 135.2 mg of a tan solid, m.p. 225-227.5 ° C.

Example 8 9 - [(2-Formyloxyethoxy) methyl] 2,6-diaminopurine

A solution of 9 - [(2-formyloxyethoxy) methyl] -7-2-azidoadenine (610 mg) in dry dimethylformamide (125 ml) with an additional 5% palladium / carbon (palladium 120 mg) was hydrogenated to initial pressure. being 50 psi For 24 hours at room temperature. Examination of the hydrogenation product by TLC (silica gel + acetone) revealed only one spot corresponding to 9-LX2-formyloxyethoxy) methyl / -2,6-diaminopurine and no starting material at all.

The solution was filtered through a pad of celite, the celite pad was washed with ethyl acetate, the washings and filtrate were combined, and the solvent was evaporated in vacuo at 60 ° C. The resulting yellow solid was purified by column chromatography (silica gel) and the desired product was eluted with acetone.

The eluates were evaporated and the residue was triturated with acetone to give 119 mg (22%) of 9- (2-formyloxyethoxy) methyl] -2,6-diaminopurine, the UV and NMR spectra of which corresponded to the authentic structure (m.p. 238-240 ° C). ,

Example 9 9- (2-Formyloxyethoxymethyl) guanine

Hydrogen chloride gas was bubbled into a cooled (0 ° C) suspension of ethylene glycol monoformate (3.6 g; Annalen der Chemie 641 (1961) 1) and paraformaldehyde (1.2 g) in dry dichloromethane (100 ml) until the mixture became saturated. the oily suspension was dried through molecular sieves using ethanol and anhydrous calcium chloride, filtered and the solvent removed by evaporation under reduced pressure (30 ° C). The resulting crude 2- (formyloxyethoxymethyl) chloride (2.5 g) was added to a solution of tris- (trimethylsilyl) guanine (4.8 g) in dry toluene (50 ml), and the mixture was refluxed under nitrogen for 24 hours. The solvent was removed under reduced pressure to give oily 9- (2-formyloxyethoxymethyl) -bis-N, O-trimethylsilyl) -60710 13 * guanine, which was worked up without further purification, an excess of methanol was added to the oily product, and the mixture was stirred for one hour. The methanol was removed by evaporation and the residue was recrystallized from dimethylformamide and acetonitrile to give 9- (2-formyloxyethoxymethyl) guanine, m.p. 225-227 ° C.

Example 10 9- (2-Propionyloxyethoxymethyl) guanine hydrochloride

A solution of 9- (2-propionyloxyethoxymethyl) -guanine (300 mg) in ethanol (400 ml) was adjusted to pH 1.0 (determined on a wide range of pH paper) with ether / hydrochloric acid at room temperature. The solution was diluted to 1.9 L with dry ether and cooled overnight. The precipitated granules were filtered off, washed with ether and dried in a desiccator under reduced pressure for three days. The product was further dried at 3.5 mmHg for 2.5 hours to give 9-2-propionyloxyethoxymethyl) guanine hydrochloride (260 mg), m.p.

125-131 ° C. Elemental analysis and NMR spectrum (DMSO-d 6) were consistent with the authentic structure. The silver nitrate test gave a positive result for halogen.

Example 11 Sodium salt of 9- (2-propionyloxyethoxymethyl) guanine 9- (2-propionyloxyethoxymethyl) guanine (125 mg) was added with stirring to cooled 0.01 N sodium hydroxide (44.5 ml).

The mixture was frozen and lyophilized to give the sodium salt of 9- (2-propionyloxyethoxymethyl) guanine. Elemental analysis and NMR and IR spectra were consistent with the authentic structure.

Example 12 9- (2-Formyloxyethoxymethyl) guanine

To a mixture of acetic acid-formic anhydride (1.0 ml) and p-toluenesulfonic acid (0.1 g) was added dioxolane (1.0 g) with stirring (reaction exothermic). The solution was allowed to cool for several minutes. Dry toluene (10 ml) and guanine (1.0 g) were added, and the reaction mixture was heated at 50 ° C for 24 hours. The toluene was decanted off and the residue was washed thoroughly with dry toluene (25 ml) and recrystallized twice from dry dimethylformamide to give 9- (2-formyloxyethoxymethyl) guanine, m.p. 225-227 ° C.

lu 6071 0

Example 13 9- (2-Propionyloxymethoxymethyl) guanine

A mixture of guanine (4.9 g, 0.03 mol), ammonium sulfate (3.6 g) and hexamethyldisilazane (225 mL) was refluxed under nitrogen for 20 hours. Excess hexamethyldisilazane was removed by distillation under reduced pressure, dry toluene (40 mL), dry triethylamine (11.6 mL, 0.083 mol) and 2-propionyloxyethoxymethyl chloride (6.6 g, 0.04 mol) dissolved in toluene were added to the oily residue. 40 ml). The mixture was refluxed under nitrogen for 6 hours, triethylamine (5 ml) was added, and the mixture was further refluxed for 18 hours.

The reaction solution was cooled to room temperature, ethanol (100 ml) was added, and the mixture was refluxed with stirring for 15 minutes. The solvents were removed by the evaporative evaporation method in vacuo. The resulting semi-solid residue was triturated with acetone (300 mL) followed by ethanol (150 mL). The acetone and ethanol washings were combined, evaporated to dryness in vacuo and triturated with water. The product was recrystallized from water to give 9- (2-propionyloxyethoxymethyl) guanine (3.1 g), the NMR and UV spectra of which corresponded to the authentic product. The product yield was 37%. Sp. 22 3-226 ° C.

Claims (2)

An analogous method for the preparation of 9- (2-acyloxyethoxymethyl) purine compounds of the formula I for use as antiviral agents, R1 H2N / ^ N * \ CH0.O.CH0.CH0OC.R 2 2 2 II 0 1. 2 wherein R is a hydroxy or amino group, R is hydrogen or a straight-chain or branched alkyl group having 2 to 6 carbon atoms, or salts thereof, characterized in that a) a compound of formula II is R 1; Q is reacted with a compound of formula III is A.CHo.0.CHo.CHo.0C.R2 III 2 2 2 II o 2 wherein R and R are as defined above, A is a reactive residue of an organic or inorganic acid and Q is a hydrogen atom or an alkali metal; or 2 b) hydrogen is reacted with a compound of formula IV in the presence of a catalyst: 16 6071 0 ί ° Ν <| Γ ^ \ ιν Ν3 ^ CH0.0.CH0.CH „.OC.R2 2 2 2 II o wherein R0 is either R is as defined above, tax azide and R is as defined above; or c) an alcohol of formula V is R1 »V \\ Λ JL / h2n ^ CH2.O.CH2.CH2.OH wherein R is as defined above is esterified by reacting it with an acylating agent, d) protecting groups are removed from a compound of formula I, .1 wherein the 2-amino group tax R substituent or both are protected; and when the product of any of the above reactions is a base of formula I, the product is optionally converted into an acid addition salt or an alkali metal salt, or when the product is a salt of a compound of formula I, said salt is optionally converted to a base form or another salt. i7 60710 Analog-free form for the preparation of 9- (2-ayloxLetoxymethyl) purifiers with the formulation I of the same antiviral formulation, RMI H2N CH0.0.CH0.CHo0C.R2 2 2 2 II o 1. color R is en hydroxy- or amino group , R is the same or higher than the alkyl group having 2-6 cholatomers, or the same or more than the alkyl group having 2 to 6 carbon atoms in the compound, R a r | .0, CH0.CH0.OC.R2 III 2 2 2 || ) provides for the use of catalysts in the form of catalysts in Form IV