JPS635392B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to substituted purine compounds and pharmaceutically acceptable salts thereof and methods for their preparation.
The invention particularly relates to esters of 9-(2-hydroxyethoxymethyl derivatives of guanine and 2,6-diaminopurine) and pharmaceutically acceptable salts of such compounds.

The substituted purine shown by the formula () (In the formula, R ¹ is a hydroxy or amino group,
R ² is hydrogen or a straight-chain or branched alkyl group having 5 to 16 carbon atoms) is in
It was found to have antiviral activity against various types of DNA and RNA viruses in vitro and against DNA viruses in vivo.
This compound is particularly active against herpes, vaccinia and rhinovirus. These herpesviruses include herpes simplex, zoster, and varicella viruses in mammals, which are responsible for diseases such as herpetic keratitis in rabbits and herpetic encephalitis in mice. Cause.

The present invention provides a compound of formula () or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in which R ¹ and R ² have the meanings defined above.

Among the compounds represented by formula (), R ¹ is hydroxy or a salt thereof, and R ² is hydrogen or a straight or branched alkyl group having 5 to 8 carbon atoms. Certain compounds are preferred.

In particular, the most preferred compound is 9-(2-
formyloxyethoxymethyl)guanine, and 2-amino-9-(2-formyloxyethoxymethyl)adenine.

Particularly suitable salts for therapeutic use are the salts of pharmaceutically acceptable organic acids such as lactic acid, acetic acid, malic acid or p-toluenesulfonic acid and the salts of pharmaceutically acceptable mineral acids such as hydrochloric acid or sulfuric acid. When R ¹ is hydroxy, pharmaceutically acceptable alkali metal salts can also be used, with the sodium salt being most preferred. Other salts can also be prepared and then converted into salts suitable directly for therapeutic purposes.

From its second aspect, the present invention provides a method for producing a substituted purine represented by the formula () as defined above, comprising: (a) the formula (); The compound shown by and the formula () (wherein A is a leaving atom or group and Q is a hydrogen atom or an alkali metal), or (b) formula () (In the formula, R ² is defined earlier, and M
and one or both of G are R ¹ and 2-amino group precursors, respectively) into a compound represented by formula (), or (c) formula () or (d) removing the protecting group from a compound of formula () in which the 2-amino group and the R ¹ substituent are protected, and then Depending on the case, a compound represented by the formula () formed by any of the methods (a) to (d) above,
by transesterification into another compound of formula () and, where the product of any of the above reactions is a base, optionally converting the product into its acid addition salt or alkali metal salt. , or when the product is a salt of the compound represented by formula (), the above method for producing substituted purines is characterized in that the salt is optionally converted to its base or another salt thereof. provide.

In method (a), the leaving atom or group A is preferably a reactive residue of an organic or inorganic acid, therefore a halogen atom or a sulfonate group, and Q is hydrogen or an alkali metal, preferably sodium. Purine and acyl-protected 2-halomethoxyethanol or acyl-protected acyloxymethoxyethanol with the desired 2- and 6-substitutions (e.g. 2-propionoyloxyethoxymethyl chloride or butyryloxyethoxymethyl acetate) ) in the presence of a base (eg sodium hydride) in a strongly polar solvent such as dimethylformamide (DMF) is a preferred method. This reaction is preferably carried out at room temperature over an extended period of time (ie, hours or days may be required to obtain reasonable yields).

The conversion of compounds of the formula ( (can be converted into a base).

This method, along with other known methods, is used in the "Heterocyclic Compound-Fused Pyrimidine
Brown (1971) Published by Wiley-Interscience”
It can be found inside.

Compounds containing precursor substituents Q and M and which can be converted into compounds of formula () can be regarded as intermediates in the synthesis of these compounds and can be produced similarly to method (a).

In the method (c), the alcohol represented by formula () is a suitable acylating agent such as carboxylic acid, aliphatic or aromatic acid anhydride, aliphatic or aromatic acyl halide, carbonic acid-carboxylic acid mixed acid anhydride. , or react with a carboxylic acid ester. The compound represented by the formula () is disclosed in German Published Patent Application No. 2539963.
It can be produced by the method described in No.

In the method (d), one or both of the amino groups substituted at the 2- and 6-positions may contain a protecting group such as a trialkylsilyl group, an activated acyl group or a benzyloxycarbonyl group (with the exception of the latter two types of groups). is reversibly protected by (protecting only R ¹ when R ¹ is amino). 2-position and 6
When the -substituted amino groups are both protected by trialkylsilyl groups, such compounds are products of the condensation of trialkylsilylated purines with esters or diesters in the same manner as in method (a). . Depending on the reaction activity, such protecting groups can be removed by solvolysis or alcoholysis using alcoholic or aqueous ammonia.

If one or both of the 2- and 6-positions of the purine ring are protected by an activated acyl group, such as a trihaloacyl group (eg trichloroacetyl), this together with the amino group becomes a protected form of the trichloroacetamide group. The 6-position of the purine ring is protected only when substituted with an amino group. Such groups can be reductively decomposed. When the protecting group is a benzyloxycarbonyl group, it can also be removed by reductive decomposition.

All methods (a) to (d) are based on intermediates that can be easily prepared from substituted purines. Such purines can of course be found in literature and textbooks (for example, "Heterocyclic Compounds - Fused Pyrimidines, Part Purin, edited by DJ Brown (1971), Wiley-
It can be produced by a technique known per se as disclosed in "Published by Interscience").

A compound represented by formula () produced by any of the methods (a) to (d) can be converted into another compound represented by formula () by transesterification, as the case may be. Such interconversion can be achieved by reacting a compound of formula () with a suitable carboxylic acid (e.g. reaction with propionic acid is required to produce 9-(2-propionoyloxyethoxymethyl)guanine). This can be achieved by In some cases, the acid also acts as an acid catalyst, while in other cases an additional acid catalyst, such as para-toluenesulfonic acid, is required.

A compound of formula () or a pharmaceutically acceptable salt thereof according to the present invention can form a pharmaceutical composition together with a pharmaceutically acceptable carrier thereof. In particular, the pharmaceutical composition contains an effective unit dose of a compound of formula ().

As used herein, the term "effective unit dose" means
It represents a predetermined antiviral amount that is sufficiently effective against viral pathogens in vivo. A pharmaceutically acceptable carrier is a substance useful for the purpose of administering a medical drug, which is solid, liquid or gaseous, and which is inert, medically acceptable and compatible with the active ingredient.

The pharmaceutical composition can be administered parenterally or orally;
Depending on whether it is used to treat internal or external viral infections, it can be administered as a suppository or pettuary, administered topically as an ointment, cream, aerosol, or powder, or as an eye or nasal drop. can.

For internal infections, the medicament is administered orally or parenterally in doses of about 0.1 to 250 mg/Kg of mammalian body weight, preferably 1 to 50 mg/Kg, calculated as free base. For humans, it is administered in unit dosage form, with unit doses of 1 to 250 mg administered two to three times a day.

For oral administration, fine powders or granules may contain diluents,
It may contain a dispersing agent and/or a surfactant, and may be administered as a drop-in solution, solution, or syrup. In the form of dry capsules or sachets or non-aqueous solutions or suspensions containing suspending agents, as tablets containing binders and lubricants, and in suspension in water or syrup. You can also take Flavoring agents, preservatives, suspending agents, thickening agents, or emulsifying agents may also be included, if desired or necessary.
Tablets and granules are preferred; these can also be coated.

When administered parenterally or as an infusion for eye infections, the compound is added to an aqueous solution at a concentration of approximately 0.1
It is present at a concentration of from 10% to 10%, more preferably from 0.1 to 1%, and most preferably from 0.2% W/V.
The solution may also contain antioxidants, buffers, and the like.

Alternatively, for infections of the eye or other external tissues (eg, mouth or skin), the compound is preferably applied topically as an ointment or cream to the infected area of the patient's body. The compound may be present in an ointment (e.g. using a water-soluble ointment base) or cream (e.g. using a water-in-oil cream base) at about 0.1 to 10%, preferably 0.3 to 3%, most preferably 1% W/V. It is present at a concentration of

A further aspect of the present invention provides a method of treating a viral infection in a mammal comprising administering an effective unit dose of a compound of formula () or a pharmaceutically acceptable salt thereof as defined above. Preferably, the method of administration is local application or oral or parenteral administration.

The acute toxicity (LD ₅₀ ) data of 9-(2-formyloxyethoxymethyl)guanine is greater than 100 mg/Kg by oral administration in mice.

The following examples illustrate the invention.

Example 1 9-(2-hydroxyethoxymethyl)guanine (4.73 g) in 97% formic acid (24 ml) prepared according to the method described in DE 2539963
The solution was stirred at room temperature overnight. The amber solution was diluted with approximately 200 ml of dry ether and cooled.
The resulting white precipitate was filtered, dried, and recrystallized from dimethylformamide to yield 9-(2-formyloxyethoxymethyl)guanine (3.6 g,
melting point 225-275°C).

Example 2 97% of 2-amino-9-(2-hydroxyethoxymethyl)adenine (0.5 g) prepared according to the method described in DE 2539963
A solution of formic acid (2.5ml) was stirred in an ice bath for 3 hours and then at room temperature overnight. Dry ether (80ml)
was added and the mixture was cooled. The solid was filtered off and dissolved in hot acetonitrile (125 ml).
The remaining solids were removed by filtration. The solution was treated with a column containing silica gel (14 g) in acetotrile. The column was eluted with dry acetone.
The eluate was evaporated and the remaining solid was recrystallized from acetonitrile to give 2-amino-9-(2-formyloxyethoxymethyl)adenine (93 mg, melting point
238-240℃).

Example 3 9-(2-hexanoyloxyethoxymethyl)
Production of guanine 9-(2-hydroxyethoxymethyl)guanine (1.0 g) produced according to the method described in DE 2539963 was dissolved in dry dimethylformamide (70 ml) by heating on a steam bath. This solution was cooled to room temperature and dried pyridine (10
ml) and hexane anhydride (9.4 g) were added.
After stirring for 4 days at room temperature, TLC (10% silica gel in methanol chloroform) showed the reaction to be complete.

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

Example 4 Production of 9-(2-tridecanoyloxyethoxymethyl)guanine 9-(2-hydroxyethoxymethyl)guanine (300 mg) produced according to the method described in German Published Patent Application No. 2539963 was dissolved in dry dimethylformamide. (20ml) and dry pyridine (30ml) and heated on a steam bath until dissolved. The solution was cooled to room temperature and tridecanoyl chloride (0.93 g) was added. This solution at ambient temperature
Stirring was continued until completion of the reaction as indicated by disappearance of starting material on thin layer chromatography (18 hours).

The solution was flash evaporated and the remaining yellow oil was crystallized from acetonitrile to give a creamy yellow solid (375mg). to the crude product
NMR analysis revealed the presence of several compounds. The resulting mixture was purified by column chromatography.

Example 5 9-(2-dodecanoyloxyethoxymethyl)
Production of -2,6-diaminopurine Ethylene glycol monodecanate (14.66
g) and paraformaldehyde (1.8 g) in dichloromethane (50 ml) (0°C
Dry hydrogen chloride gas is passed through the mixture until the solids are dissolved and the mixture is saturated with hydrogen chloride.

After drying the solution over molecular sieves and calcium chloride, the mixture was filtered to remove the solvent.
Remove by flash evaporation at 30°C.

The remaining oil, 2-dodecanoyloxyethoxymethyl chloride, is used directly. Yield 75%.

An anhydrous solution of 2,6-diaminopurine in dimethylformamide was heated until 3.54 g of the monohydrate was dissolved in 250 ml of solvent on a steam bath, cooled and purified over fresh molecular sieves at 18
Manufactured by leaving it for a period of time.

Add 0.95g of sodium hydride to this mixture.
% mineral oil dispersion. After stirring the slurry overnight, 2-dodecanoyloxyethoxymethyl chloride (6.35 g) is added dropwise and the reaction mixture is stirred at ambient temperature overnight.

The solid is filtered and washed with chloroform, and the washing liquid and mother liquor are combined and flash-evaporated at 60°C.

The residual oil is recrystallized from ethanol. Yield 20%.

Example 6 9-(2-palmitoyloxyethoxymethyl)
Production of guanine 9-(2-hydroxyethoxymethyl)guanine (0.3 g) produced according to the method described in DE 2539963 was heated on a steam bath for 1/2 hour to produce dry dimethylformamide ( 15 ml) and partially dissolved in dry pyridine (30 ml). The mixture was cooled in an ice bath (4.00 g) and palmitoyl chloride (1.1 g) was added with stirring. The mixture was allowed to reach room temperature and stirred for 20 hours during which time all solid material dissolved.
Quantitative changes in starting materials were determined by thin layer chromatography.

This solution was diluted with ethyl acetate to a volume of 300 ml and cooled overnight. 0.49 g of white solid was obtained by filtration.

Recrystallization of the crude material once from ethyl acetate and once from acetone yields analytically pure 9-(2-
palmitoyloxyethoxymethyl)guanine
Obtained 190 mg (31%). Melting point 190-210℃.

NMR, UV and mass spectra were consistent with the desired product.

Example 7 A tablet formulation containing a mixture of 9-(2-formyloxyethoxymethyl)guanine (100 mg), lactose (200 mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was wet granulated. It was formulated by chemical reaction.

Example 8 2-amino-9-(2-formyloxyethoxymethyl)adenine (100mg), lactose (200mg)
mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg)
A tablet formulation containing a mixture of was prepared by wet granulation.

Example 9 Contains 9-2-(2,2-dimethyl-propionoyloxy)ethoxymethylguanine (100 mg), lactose (200 mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) Tablet formulations were formulated by wet granulation.

Additional Relationship The present invention is disclosed in Japanese Patent No. 1379644 (Japanese Patent Publication No. 61-47839).
This invention is in addition to the invention described in No. The invention described in the original patent No. 1379644 (Special Publication No. 61-47839) is (1) Formula () ^[ In the formula ^, or azide; R ³ is hydrogen;
straight chain or branched chain or cyclic alkyl, hydroxyalkyl, benzoylalkyl or phenyl; R ⁴ is hydrogen, hydroxy or lower alkyl; R ⁵ is hydrogen, hydroxy, amino, alkyl, hydroxy Alkyl, benzoyloxy,
Benzyloxyalkyl, benzyloxy, sulfamoyloxy, phosphate, carboxypropionyloxy, acetoxy or with the formula NH.
a substituted carbamoyl group of CO-Z, where Z is alkyl, aryl or aralkyl optionally substituted with one or more of sulfonyl, amino, carbamoyl or halogen; R ⁶ is hydrogen; is alkyl or hydroxyalkyl;
provided that when X is oxygen and R ² , R ³ , R ⁴ and R ⁶ are hydrogen, R ¹ is not amino or methylamino (if R ⁵ is hydroxy);
or a salt thereof, particularly a pharmaceutically acceptable salt thereof] In the method for producing a substituted purine of the formula () or an acid addition salt thereof, the method comprises: (a) a substituted purine of the formula (); The protecting group Y of the compound represented by is substituted with a hydroxy group to obtain a compound of the formula () in which R ⁵ is hydroxy; (b) the formula () in which M and G are precursors of R ¹ and R ² , respectively; converting the compound of formula () into a compound of formula () in which R ¹ and R ² have the meanings as defined above; (c) formula () The compound of formula () (d) a precursor having either an incompletely formed pyrimidine or imidazole ring; Closing the ring of the compound; (e) removing the blocking group from a compound of formula () in which one or both of R ¹ and R ² is blocked; carrying out a reaction and then optionally producing the above reaction; When the product is a base, the compound of formula () is converted into its acid addition salt, or when the product is a salt of the compound of formula (), this salt is optionally converted to its base or its acid addition salt. A method characterized by converting it into another salt.

The main points are as follows. Therefore, the present invention is an invention that has all or the essential parts of the essential elements of the original invention as its main constituent features, and does not include improvements or extensions of the original invention that achieve the same purpose as the original invention. For such inventions, Patent Law No. 31
This falls under Article 1.

Claims (1)

[Claims] 1 Formula () (In the formula, R ¹ is a hydroxy or amino group,
and R ² is hydrogen or a straight-chain or branched alkyl group having 5 to 16 carbon atoms) or a salt thereof, especially in its pharmaceutically acceptable form. 2 Substituted purines of formula () according to claim 1, wherein R ¹ is hydroxy, or a salt thereof, especially in its pharmaceutically acceptable form. 3. Formula () according to any one of claims 1 or 2, wherein R ² is hydrogen or a linear or branched alkyl group having 5 to 8 carbon atoms. Replacement purine indicated by. 4 9-(2-formyloxyethoxymethyl)
A substituted purine represented by the formula () according to claim 1, which is guanine. 5. A substituted purine represented by the formula () according to claim 1, which is 2-amino-9-(2-formyloxyethoxymethyl)adenine. 6 formula () (In the formula, R ¹ is a hydroxy or amino group,
and R ² is hydrogen or a linear or branched alkyl group having 5 to 16 carbon atoms) A method for producing a substituted purine or a salt thereof represented by the formula () The compound represented by and the formula () (wherein A is a halogen atom or a sulfonate group and Q is a hydrogen atom or an alkali metal), and when the product is a base, optionally the product is Convert to acid addition salt or alkali metal salt,
Alternatively, when the product is a salt of the compound represented by the formula (), the method for producing a substituted purine as described above, characterized in that the salt is optionally converted to its base or another salt thereof. 7. The method according to claim 6, for producing a compound of formula () in which R ¹ is hydroxy. 8. The method according to claim 6 or 7, which produces a compound of formula () in which R ² is hydrogen or a straight-chain or branched alkyl group having 5 to 8 carbon atoms. Any one of the methods described. 9 9-(2-formyloxyethoxymethyl)
A method according to claim 6 for producing guanine. 10. The method according to claim 6, for producing 2-amino-9-(2-formyloxyethoxymethyl)adenine. 11. Process according to claim 6, wherein A is halogen, Q is hydrogen and the reaction is carried out in the presence of a base. 12 formula () (In the formula, R ¹ is a hydroxy or amino group,
^R2 is hydrogen or a straight or branched alkyl group having 5 to 16 carbon atoms) A method for producing a substituted purine or a salt thereof, the method comprising:
formula() The alcohol of formula In the case of a salt of a compound represented by the above, the method for producing the substituted purine is characterized in that the salt is optionally converted into its base or another type of salt thereof. 13. The method according to claim 12, for producing a compound of formula () in which 13 R ¹ is hydroxy. 14. The method according to claim 12 or 13, which produces a compound of formula () in which R ² is hydrogen or a straight-chain or branched alkyl group having 5 to 8 carbon atoms. Any one of the methods described. 15 9-(2-formyloxyethoxymethyl)
13. A method according to claim 12 for producing guanine. 16. The method according to claim 12, for producing 2-amino-9-(2-formyloxyethoxymethyl)adenine. 17. Claims 12 to 17, wherein the acylating agent is a carboxylic acid, an aliphatic or aromatic acid anhydride, an aliphatic or aromatic acyl halide, a carbonic acid-carboxylic acid mixed acid anhydride, or a carboxylic acid ester.
A method according to any one of paragraph 16.