SI8211201A8 - Process for obtaining of 9-(2-hydroxy-ethoxymethyl) guanine derivatives of purine - Google Patents

Description

Technical field

The invention relates to a process for the preparation of 9- (2-hydroxyethoxymethyl) guanine and its pharmaceutically acceptable salts, which possess valuable pharmacological, especially antiviral properties.

Technical problem

The invention solves in a simple way the problem of obtaining a new guanine derivative of purine with the desired pharmacological properties, especially with excellent selectivity and without toxic effects, starting from the appropriately protected purine derivative from which it is removed in two stages, by sowolysis and ammonolysis, protecting groups.

The state of the art

In 1971, Schaeffer, et al. (J. Med. Chem., 14,367 (1971)) proposed the synthesis of several purine acyclic nucleosides in a study of adenosine deaminase enzyme-substrate interaction. Here, 9- (2-hydroxyethoxymethyl) adenyl 1 was specifically treated and its substrate activity with denosine deaminase measured.

Known antiviral agents include idoxuridine (Prusoff, Biochem Blophys Acta, 32 295 (1959) and trifluridyl, i.e. 5tifluoromethyl 2'-deoxyuridine (Kaufman and Heidelberger, Science, 145, 585 (1964)) and are used for the surface treatment of herpes infections ARA, 9-beta-Darabinofuranosyl-adenine, which is also used for systemic treatment of herpes encephalitis has also been proposed, but these antiviral agents are relatively nonselective in their antiviral activity, not only destroying the herpes virus, but also and the host cells containing the virus, which actually means that they are relatively toxic.

Description of a solution to a technical problem with the Executors

The process of the invention now provides purine derivatives that are highly selective in the therapeutic sense, destroying only undesirable viruses and not the Host Cells.

Thus, it is found that the substituted purinl of formula (I) 'λ ¹

wherein X is oxygen or sulfur and R ¹ , R ² , R ² , R ⁴ , R ⁵ and R ⁶ are different substituents, having antiviral activity against different classes of ONA 1 RNA viruses both in vitro and in other experiments. The compounds are particularly active against dtomegalovirus, adenovlrus, especially adenovlrus 5, rhino virus, Mengo virus 1 Sindbts virus. They are particularly active against vacdnia and herpes viruses, including the mammalian sumplex, zoster, and varlcella, which cause diseases such as rabbit herpetickeratitis and herpetic encephalitis in mice. In addition, they can be used in the treatment of Infectious Mononucleosis.

According to the invention, a compound of formula (I) is provided in which

X is sulfur or oxygen, R * is hydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, acylamino III diacylamino; R ² is hydrogen, halogen, amino or azide; R ³ is hydrogen, straight, branched or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or chenyl; R ⁴ is hydrogen, hydroxy or alkyl; R ⁵ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzolloxy, benzolloxyalkyl, sulfamoxy, phosphate, carboxypropionyloxy, acetoxy, or a substituted carbamoyl group of formula NH.CO-Z wherein Z is alkyl, aryl, or arylalkyl with optionally substituted aralkyl. Or more a suiphonyl, amino, carbamoyl or halogen group; R ^b is hydrogen or alkyl, provided that when X is oxygen and PT, R, RIR are hydrogen, R is not amino or methylamino, when R ^{5 is} hydrogen, hydroxy or benzyloxy; also provided that when R ^{2 is} hydrogen, R ¹ does not

Λ Λ A β be chlorine; and provided that when X is oxygen, Pr, R, R and R are hydrogen and R ^{6 is} methyl, R ^{1 is} not ethylamino lyl amino, or salts thereof, especially in the form of pharmaceutically acceptable salts.

Compounds of formula (I), wherein X is sulfur lyl oxygen; R ¹ is hydrogen, halogen, hydroxy, alkoxy, azide, H ¹ , alkylthio, amino, acylamino, and haloalkylamino; R ^{2 is} hydrogen, halogen, amino or azide; R ³ is hydrogen, straight, branched or cyclic alkyl, hydroxyacyl, benzyloxyalkyl or phenyl; R ⁴ is hydrogen, hydroxy or alkyl; R ⁵ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzolloxy, benzoyloxymethyl, benzyloxy, sulfamoyloxy, phosphate, carboxypropionyloxy, acetoxy or substituted carbamoyl group of formula NH.CO-Z where Z is alkyl, aryl or arlylalkyl optionally more sufonyl, amino, carbamoyl, halogen; R ³ is hydrogen or an alkyl group; as the conditions given above; or salts thereof, especially in the form of pharmaceutically acceptable salts, are preferred compounds.

In addition to the above moieties, compounds of the formula (I) above, wherein X is oxygen, are especially preferred; R ¹ is hydrogen, halogen, hydroxy, alkoxy, thio, alkylthio, amino, alkylamino, dialkylamino or azide; R ² is hydrogen, halogen, amino lyl azide; R ³ is hydrogen, straight or branched or cyclic alkyl, hydroxyalkyl or phenyl;

R ⁴ is hydrogen or hydroxy; R ⁵ is hydrogen. hydroxy, benzyloxy, hydroxyalkyl, amino, carboxypropionyloxy, acetoxy, benzyloxy, benzoyloxymethyl, phosphate, sulfamoyloxy, substituted carbamoyl group of formula NH.CO-Z wherein Z is alkyl, aryl or aralkyl optionally substituted with one or more carbamoyl, sulfonyl, amino , halogen; R ³ is hydrogen, or alkyl, provided that

R ^{5 is} hydroxy only when R ^{1 is} amino, hydroxy, alkylamino, alkylthio, or dialkylamino and R ² is amino and R ⁶ is hydrogen; R® is hydroxyalkyl 1 5 1 only when R is hydroxy; R is hydrogen only when R is hydroxy or halogen; when R ^{5 is} benzoyloxy R ² is not halogen; R®

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5 is acetoxy only when R and R are both amino or both halogen; R is a substituents carbamoyl of the formula NH.CO-Z wherein Z is a CH (NH ₂ ) CH ₂ CgHg group only when R ^{1 is} dialkylamino; or salts thereof, in particular in the form of pharmaceutically acceptable salts.

Particularly highly active compounds of formula (I), as defined above, are also found to be, in which X is oxygen, R ^{1 is} halogen, amino, hydroxy or alkylthio; R ² is amino; R ⁵ Is hydroxy, benzoioxy, carboxypropionyloxy, acetoxy or hydroxyalkyl and R ³ , 4 6 5

R and R are hydrogen, provided that R is hydroxyalkyl only 1 5 and when R is hydroxy and R is acetoxy only when R is amino. Compounds wherein X is sulfur, R ¹ halogen, amino or alkylamino IR ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen also have very high activity.

The porous halogen substituent is chlorine. The term alkyl used herein means this group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.

Salts that are particularly suitable for therapeutic use are salts of pharmaceutically acceptable organic acids such as lactic, acetic, maleic, or p-toylsulfonic acid, and salts of pharmaceutically acceptable mineral acids such as hydrochloric or sulfuric acid.

The present invention provides a process for the preparation of a substituents purine of formula (I) or their acid addition salts, characterized in that from the compound of formula (I) the blocking group is removed by hydrolysis or solvolysis when One or both of R ¹ IR ^{2 are} blocked; and when the product of said reaction is a base, it converts the Compound of Formula (i) to its acid addition salt as needed, or when the product of a salt of the compound of Formula (I), if necessary, converts said salt to its base or other salt thereof.

In the process, the substituents R ^ and R ² can be! blocked, for example, by trimstitsiiil groups. These blocking groups are very labile and can be removed by solvolysis with alcoholic or aqueous ammonia, or alcoholic.

Alternatively, the mercury chloride salt of purlene can be prepared in the presence of alkali and then condensed with the haloator in an aromatic organic type solvent. However, prior to the preparation of the salt, all reactive substituents on the purine must be blocked, and therefore the last step in this process is to unblock the blocking substituents.

The invention particularly relates to a process for the preparation of 1 2 compounds of formula (I) defined above wherein R is hydroxy, R is amino, R ³ , R ⁴ 1 R ³ are hydrogen and R ³ is hydroxy, and X is Idseonic by hydrolysis removal or by solvolysis of trimethylsilyl blocking groups in the corresponding compound wherein the radicals R ¹ and R ¹¹ carry these groups.

The reaction is preferably carried out in the presence of a solvent such as ethanol, preferably at a cotton bath temperature.

According to a further aspect of the invention, a depleted I pharmaceutical composition comprising a compound of formula (I) wherein X, R, R ² , R ³ , R ⁴ , R ³ and R have the meanings given above, when R ^{3 is an} alkyl group, it has from 1 to 8 carbon atoms and in all other cases where the substituents have an alkyl nucleus, they have from 1 to 4 C atoms; Or its pharmaceutically acceptable salt; together with a pharmaceutically acceptable carrier. In a particular aspect of the invention, the pharmaceutical composition comprises a compound of formula 0) in the form of an effective unit dose.

The term effective unit dosage or effective unit dose used herein means a predetermined antiviral amount sufficient to effectively act against viral organisms in vivo. Pharmaceutically acceptable carriers are medicaments which are used for the administration of medicaments, and may be solid, liquid or gaseous materials, which are inert and medically acceptable and agree with the active ingredients.

These pharmaceutical preparations may be administered parenterally, orally, as suppositories of or nut inserts, superficially in the form of ointments, creams, aerosols, powders, or in the form of nose drops III eyes, etc., depending on the use of the II preparation for treatment internal or external viral infections.

For internal infections, the compositions are administered orally III parenterally at a dose calculated from the free base of from about 0.1 to 250 mg per kg, preferably 1.0 to 50 mg per kg, of body weight of the mammal, and in humans used in the form of a standard dose. given several times daily in an amount of 1 to 250 mg per unit dose.

For oral administration, fine powder! ill granules may contain diluents, perfumers and / or surfactants, and may be in the form of a beverage, in water or in syrup; in capsules or bags in the dry form or in the form of a non-aqueous solution or suspension, the suspension of which may be included; in the form of tablets, where binders may be included; 1 lubricant; III in suspension in water tli syrup. When desirable or necessary, fortunes for taste, protection, suspension, coagulation or emulsification may be included.

Preferred forms are pills and granules, and these can be overcome.

For parenteral administration, lil administration in the form of drops, such as for ocular infections, the compounds may be presented in a cloud of aqueous solutions at a concentration of about 0.1 to 10%, preferably 0.1 to 7%, preferably 0.2% w / v. The solution may contain antioxidants, buffers, etc.

Alternatively ee for Eye infection, Or for other external tissues e.g. mouth and skin, the preparations are preferably applied to the infected body of the pad as a surface cream or ointment. The composition may be in the form of an ointment, for example with a water-soluble oily base, III cream, e.g. with water-cream base oil, at a concentration of about 0.1 to 10%, preferably 0.1 to 7%, most preferably 1% w / v.

Of the compounds of formula (I), 9- (2-hydroxymethyl) guanine (R ¹ 'OH, R ² NH ^ I 2-amino-9- (2-hydroxyethoxymethyl) -adenyl are the most preferred, especially because of their very high activity against herpes virus In addition, 2-amino-64ylor-9 ((2-benzolloxyethoxymethylpurine, 9 (2-benzoxyethoxymethyl) guanine, 9- (3-hydroxypropoxymethyl) guanine, 2-amino-6-methylthio-9- (2-hydroxyethoxymethylpurine, 9- (2- (3carboxypropionyloxyethoxymethylguanine, 9- (2acetoxytoxoxymethyl) -2,6-dlamino purine, 6-chloro-9-ethylthiomethyl purine, 9-ethyltomethylladenyl, 9-ethylthiomethyl-6-methylamino-purine also show high activity against vaccinia herpes virus.

According to another aspect of the invention, there is provided a method for dispensing viral infections in a mammal comprising administering an effective antiviral amount, such as the previously defined, substituted purine of formula (I), or a pharmaceutically acceptable salt thereof. The administration is preferably by surface application or by oral or parenteral route.

The invention will now be illustrated by the following example.

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Example: 9- (2-HydroxyIetoxymethyl) guanyl (I; R ¹ = OH, R ² = NHg)

A mixture of guanine (2.0 g), ammonium sulfate (1.5 g), and hexamethyldisilazane (126 g) was refluxed under a nitrogen atmosphere overnight. Excess hexamethyldisilazane was removed by distillation under reduced pressure. Dry benzene (10 ml) was added to the residual oil and any remaining ammonium sulfate was removed by filtration. To this solution was added triethylamine (4 ml) and a solution of 2-benzolloxyethoxymethyl chloride (2.8 g) in dry benzene (15 ml) and the mixture was refluxed under nitrogen overnight. The solvent was evaporated on a rotary evaporator under reduced pressure and the residue was dissolved in 95% ethanol. The solution was heated in a steam bath for 1/2 h to induce hydrolysis of the silyl group. The ethanol was then evaporated to a solid residue, washed well with water, filtered and dried. Recrystallization from methanol and then from water (residual guanine is insoluble in hot solvent and removed by filtration) 9- (2benzyloxyethoxymethylguanine (0.58 g, 14% of theory) is obtained, mp 222 r 226 ° C. trimethylsilyl) guanine with 6% excess 2-benzoyloxyethoxymethyl chloride gave 32% yield of 9 (2-benzolloxyethoxymethyl) guanine.

9- (Benzoyloxyethoxymethyl) guanine (0.58 g) and methanol (80 ml) saturated with ammonia were heated in a bomb at 80 ° C for 16 h. The reaction mixture was removed from the bomb and the solvent was evaporated under reduced pressure. The residue was carefully evaporated with ether and then crystallized from methanol to give 9- (2-hydroxylethoxymethyl) guanine (0.31 g, 75% of theory), mp 256.5 - 257 ° C.

then 9 ({2benzoyloxyethoxymethyl) guanine (0.58 g, 14% of theory) was obtained from water (residual guanine insoluble in hot solvents 1 was removed by filtration), m.p. 222 - 226 ° C. Subsequent condensation of trls- (trimethylsilyl) guanine with 6% excess 2-benzoyloxyethoxymethyl chloride gave 32% yield of 9 (2-benzoyloxyethoxymethyl) guanine.

9- (Benzoyloxylethoxylmethyl guanine (0.58 g) and methanol (80 ml) saturated with ammonia were heated in a bomb at 80 ° C for 16 h. The reaction mixture was removed from the bomb and the solvent was evaporated under reduced pressure The residue was carefully evaporated with ether and then recrystallized from methanol to give 9- (2-hydroxyethoxymethyl) guanine (0.31 g, 75% of theory), mp 256.5 - 257 ° C.

Claims (1)

PATENT APPLICATION Process for the Preparation of 9- {2-Hydroxyethoxymethyl) guanine Purine Derivatives of Formula (I): A mixture of guanine (2.0 g), ammonium sulfate (1.5 g), 1 hexamethyldisilazane (126 g) was refluxed under a nitrogen atmosphere overnight. Excess hexamethyldisilazane was removed by distillation under reduced pressure. Dry benzene (10 ml) was added to the residual oil and any remaining ammonium sulfate was removed by filtration. To this solution was added triethylamine (4 ml) and a solution of 2-benzoyloxyethoxymethyl chloride (2.8 g) in dry benzene (15 ml) and the mixture was refluxed under nitrogen overnight. The solvent was evaporated on a rotary evaporator under reduced pressure and the residue was dissolved in 95% ethanol. The solution was heated in a steam bath for 1/2 h to cause hydrolysis of the silyl group. Then the ethanol was evaporated and the solid residue was washed thoroughly with water, filtered and dried. Recrystallization from methanol, wherein the 9- (benzoyloxyethoxy) methyl-2- (bistrimethylsilylamino) -6- (trmethylsilyloxy) purine is heated in ethanol at the temperature of the steam bath, and then the 2benzoyloxylethoxymethyl substituent is removed by heating with a warm heating 80 ° C in methanol saturated with ammonia. Published and printed by the Federal Patent Office, Belgrade, Uzun Mirkova 1