DD221179A5 - COMBINED ELECTROMAGNETIC AND ACOUSTIC TRANSFORMER FOR REMOTE CONTROL UNITS - Google Patents

Abstract

The invention relates to a process for the preparation of novel purine derivatives which have an acyclic chain in the 9-position. For example, 2-amino-6-chloro-purine is reacted with 2- (chloromethylthio) ethyl benzoate in dimethylformamide and in the presence of potassium carbonate to give 2-amino-9- (2-benzoyloxyethylthiomethyl) -6-chloro-9H-purine. This product is then in a hydrogenation with Pd (OH) 2 catalyst, triethylamine and methanol in the 2-amino-9- (2-hydroxyethylthiomethyl) -9H-purine over. Another new compound is, for example, 2-amino-9- ((2-benzoyloxy-1-benzoyloxymethylethoxy) methyl) -6-chloro-9H-purine. The new compounds also have a strong antiviral activity against various classes of viruses, especially against herpes viruses, even when administered orally.

Description

(VI)

CH-XCH-CHR ^

I ₅ II ₃

R CHO R

(wherein X, R ¹ , R ³ , R ⁴ and R ⁵ are as defined above) or a salt or ester thereof is reduced to form a compound of formula I (wherein Y represents a hydroxymethyl group) or a physiologically acceptable salt or Esters to form a compound of formula VII

(VII)

CH-X-CH-CH-NH

(in which X, R ¹ , R ² , R ³ and R ^{5 have} the abovementioned meaning) are converted into a corresponding compound of the formula I in which R ^{4 is} a hydroxyl group,

to form a compound of formula I or a physiologically acceptable salt or ester thereof and

optionally one or more of the following transformations is carried out in any desired sequence: i) when the product obtained is a base. Conversion of the base into a physiologically acceptable acid addition salt thereof,

U) if the product obtained is an acid addition salt, conversion of the salt into the parent base,

Ui) when the product obtained is a compound of formula I or a salt thereof, converting the compound or salt thereof into a physiologically acceptable ester of the compound or salt, and / or.

iv) when the product obtained is an ester of a compound of formula I. Conversion of the ester into the parent compound of the formula I, a physiologically acceptable salt thereof or a different physiologically acceptable ester thereof.

2. Method according to item 1a), characterized in that the deblocking of an acyl blocking group is effected by hydrolysis.

3. The method according to item 1a), characterized in that the deblocking of arylmethyl blocking groups is effected by hydrogenolysis.

4. The method according to item 1a), characterized in that the deblocking of trialkylsilyl blocking groups is effected by solvolysis or alcoholysis.

5. The method according to item 1 b), characterized in that M represents a halogen atom and the transfer is effected by hydrogenation in the presence of a palladium catalyst.

6. Process according to item 1c), characterized in that A represents a halogen atom or an acyloxy radical.

7. The method according to item 1c) or item 6, characterized in that Q represents a hydrogen atom or a Tn-C ₁ ^ - alkylsilyl group.

Field of application of the invention

The invention relates to a process for the preparation of novel purine derivatives which have an acyclic chain in the 9-position. The new compounds show antiviral activity against various classes of DNA viruses, especially against herpes viruses. ',.

Characteristic of the known technical solutions

From GB-PS 1523865 a broad class of purine derivatives having an acyclic side chain at the 9-position is known. It has been found that these purine derivatives have antiviral activity against various classes of DNA viruses, especially against herpes viruses such as herpes simplex.

It has also been found that among these derivatives 9- (2-hydroxyethoxymethyl) guanine (also known as acyclovir) has a particularly good activity against herpes viruses, such as herpes simplex. However, while acyclovir has been found to be particularly effective on external application or parenteral administration, it is only moderately absorbed in oral administration with the; corresponding drug concentrations in the plasma. In the treatment of internal disease by oral administration of a drug, it is desirable that the drug be well absorbed by the gastrointestinal tract with the resulting high plasma levels. This task is fulfilled only insufficiently by the preparations used so far.

Object of the invention

It was therefore the object and the object of the present invention to provide a process for the preparation of purine derivatives which show a better antiviral effect in oral administration.

Explanation of the essence of the invention

The invention relates to the preparation of medically valuable new purine derivatives and their precursors, as well as of ipharmaceutical preparations containing these compounds.

It has been observed that purine derivatives, which are characterized by the presence of a hydrogen atom in the 6-position of the vPrin core, are readily metabolized in vivo by the action of enzymes of the molybdenum flavo protein type (especially xanthine oxidase / dehydrogenase or aldehyde). Oxidase) can be converted into the corresponding 6-hydroxypurine derivatives with antiviral activity i . Furthermore, in experiments on rats, it has been shown that oral administration of such 6-hydrogen derivatives results in effective absorption from the gastrointestinal tract and high plasma levels of the corresponding 6-hydroxy compound formed by enzymatic conversion of the 6-hydrogen compound.

The above-mentioned class of 6-hydrogen purine derivatives can be represented by the general formula

(I)

CH-X-CH.CH-IT

I ₅ I ₂ I ₃

ir r r

in which X represents a sulfur or oxygen atom or a chemical bond, R ^{1 represents} a halogen atom, an amino or azide radical, R ^{2 represents} a hydrogen atom, a hydroxyl, alkyl or hydroxyalkyl radical, R ^{3 represents} a hydrogen atom or an alkyl radical R ^{4 represents} a hydroxyl, hydroxyalkyl, benzyloxy, phosphate or carboxypropionyloxy radical, R ^{5 represents} a hydrogen atom, an alkyl or hydroxyalkyl radical, and esters of these compounds in which R ^{2 represents} a hydroxyl or hydroxyalkyl radical, R ^{4 represents} a hydroxyl, hydroxyalkyl or Carboxypropionyloxyrest or R ⁵ is hydroxyalkyl, and physiologically acceptable salts of such compounds according to formula I and esters thereof, according to formula with the exception of the compound (I) wherein X is oxygen, R ¹ is an amino group, R ² , R ³ and R ⁵ each represent a hydrogen atom and R ^{4 represents} a hydroxyl group. In the above formula, the alkyl groups, which may be straight-chain or branched-chain, generally contain 1 to 8, preferably 1 to 4, carbon atoms, such as the methyl group. A preferred class of compounds according to formula I are those of formula IA

(IA)

CH ₀ XCH ₀ CH ₀ OH

(wherein X represents an oxygen or sulfur atom and Y represents a hydrogen atom or a hydroxymethyl radical) and physiologically acceptable esters and salts thereof, with the exception of the compound of formula (IA) wherein X represents an oxygen atom and Y represents a hydrogen atom, its benzoate ester and Physiologically acceptable salts.

Salts of the compounds of formula I that can be conveniently used in therapy include physiological

compatible salts of organic acids such as lactic acid, acetic acid, malic acid or p-toluenesulfonic acid, as well as physiologically acceptable salts of mineral acids such as hydrochloric acid or sulfuric acid.

Esters of the compound of formula I which can be conveniently used in therapy include those esters which have a formyloxy group or C ₁ -I ₆ (e.g., C ₁ -C 4) alkanoyloxy (e.g., acetoxy or propionyloxy), optionally

substituted Aralkanoyloxyreste (eg., phenyl-C ₁ _ ₄ alkanoyloxy such as phenylacetoxy) or optionally substituted aroyloxy

(eg, benzpyloxy or naphthoyloxy) ester moieties at one or both end positions of the 9-position chain

- α - 4.ΌΌ UOO O

Contain compound according to formula I. The aforementioned aralkanoyloxy and aroyloxy ester groups may be substituted, for example, by one or more halogen atoms (eg, chlorine or bromine) or amino, nitrile or sulfamido groups, the aryl moiety of the moiety advantageously containing from 6 to 10 carbon atoms.

The invention also relates to biological precursors of the compounds of formula I and their physiologically acceptable salts and esters, d. H. Compounds which are converted in vivo into compounds of formula I and their aforementioned derivatives.

2-Amino-9- (2-benzoyloxyethoxymethyl) purine (ie, the benzoate ester of the compound of Formula IA wherein X represents an oxygen atom and Y represents a hydrogen atom) is mentioned in U.S. Patent No. 4,195,547 and is not claimed herein as being the compound even raised. However, there is no indication or suggestion in the referenced U.S. Patent that the compound can be converted in vivo to the corresponding 6-hydroxy analog.

The finding that the above-mentioned 6-hydrogenpurines can be readily converted to the corresponding 6-hydroxy analogues is surprising, as in previous studies with xanthine oxidase from bovine milk (HJ Lettre et al (1967), Biochem. Pharmacol., 16, Pages 1747-1755; TA Krenitsky et al (1972) Arch. Biophys., 150, pages 585-599), it has been shown that the 9-substitution reduces or completely inhibits the rate at which a variety of purines are oxidized. Taking these observations into account, it was surprising that this enzyme, for example, proved to oxidize 6-deoxyacyclovir, a 9-substituted derivative of 2-aminopurine, at a rate greater than the 9-unsubstituted purine, as demonstrated in enzyme studies.

The high absorption level of the compounds of formula I from the gastrointestinal tract makes the compounds particularly valuable when oral administration of the compounds is desired, e.g. in the treatment of diseases caused by various DNA viruses, such as herpes infections such as herpes simplex, varicella or zoster, cytomegalovirus, as well as diseases caused by the hepatitis B virus or Epstein-Barr virus become. The compounds of formula I can also be used for the treatment or prophylaxis of papilloma or wart virus infections. In addition to use in human medicine therapy, the compounds of formula I can be administered to other animals for the treatment or prophylaxis of yiral disorders, e.g. B. other mammals. Those compounds of formula I in which Y represents a hydroxymethyl group are particularly valuable in the treatment of equinoxin pneumonitis. By administering a compound of the formula I or a physiologically acceptable salt or ester thereof, in particular orally, it is possible to produce a beneficial effect against such diseases.

Furthermore, the invention provides compounds of formula I and physiologically acceptable salts and esters thereof for use in the treatment or prophylaxis of a viral disease in animals, e.g. B. in mammals, such as humans available. The present invention also provides a method for the treatment or prophylaxis of a virus disease in an animal, e.g. In a mammal, such as a human, wherein the animal is administered an effective antiviral amount of a compound of Formula I or a physiologically acceptable ester or salt thereof.

The compounds of formula I and the physiologically acceptable salts and esters thereof (hereinafter generally referred to as the active ingredients) may be administered by any route suitable for the condition being treated, suitable routes of administration being oral, rectal, nasal, external ( including the buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) forms. For example, the preferred method of administration may depend on the condition of the recipient. For each of the uses and indications indicated above, the amount of active ingredient needed (as defined above) depends on a number of factors including the severity of the condition being treated and the personality of the recipient. Ultimately, this depends on the assessment by the responsible physician or veterinarian. In general, however, a suitable effective dose for each of these uses and indications is in the range of 0.1 to 250 mg per kilogram of body weight of the recipient per day, preferably in the range of 1 to 100 mg per kilogram of body weight per day, and most preferably in the range of 5 to 20mg per kilogram of body weight per day; an optimal dose is about 10mg per kilogram of body weight per day. (Unless otherwise specified, the weights of the active ingredient are calculated as the parent of Formula I: for salts and esters thereof, the numbers would be proportionally increased.) The desired dose is preferably transferred in two, three, four or more subdoses at appropriate intervals administered the day. These subdoses may be administered in unit dosage forms, and include, for example, 10 to 1000 mg, preferably 20 to 500 mg and most preferably 100 to 400 mg of the active ingredient per unit dosage form.

While it is also possible to administer the active ingredients alone, it is preferred to present them as pharmaceutical formulations. The veterinary and human formulations of the present invention comprise at least one active ingredient as defined above together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carriers must be "compatible" in the sense that they are compatible with the other ingredients of the formulation and are not harmful to the recipient.The formulations include those intended for oral, rectal, nasal, external (including buccal and sublingual) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration The formulations are conveniently presented in unit dosage form and can be prepared by any of the methods known in the pharmaceutical arts comprise the step of contacting the active ingredient with the carrier forming one or more additional ingredients In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and the like and subsequent molding of the product, if necessary.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each comprising a predetermined amount of the active ingredient; they may be presented as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or molding, optionally with one or more additional ingredients. Pressed tablets can be prepared by placing the active ingredient in a suitable machine in a suitable machine

free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Shaped tablets can be prepared by forming in a suitable device a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient therein.

For infections of the eye or other external tissues, eg. As the mouth or the skin, the formulations are preferably applied as an external ointment or cream, the active ingredient in an amount of, for example, 0.075 to 20% w / w, preferably 0.2 to 15% w / w and most preferably 0.5 to 10% w / w. When formulating in an ointment, the active ingredients may be used with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base can be, for example, at least 30% w / w of a polyhydric alcohol, i. H. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol, and mixtures thereof. Optionally, the external formulations may comprise a compound which accelerates the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration promoters include dimethylsulfoxide and related analogs.

The oily phase of the emulsions of the present invention may be prepared from known ingredients in a known manner. While the phase simply comprises an emulsifier (also known as emulsifier), it preferably contains a mixture of at least one emulsifier with a fat or an oil or with a fat and an oil. Preferably, a hydrophilic emulsifier is introduced together with a lipophilic emulsifier serving as a stabilizer. It is also preferable to input both an oil and a fat. Together, the emulsifiers with or without stabilizers form the so-called emulsifying wax and the wax together with the oil and / fat forms the so-called emulsifying ointment base, which forms the oil-like dispersed phase of cream formulations.

Emulsifiers and emulsion stabilizers suitable for use in formulations according to the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The selection of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties since the solubility of the active compound is very low in most of the oils that are commonly used in pharmaceutical emulsion formulations. Thus, the cream should preferably be a non-greasy, non-staining and washable product of suitable consistency to avoid leaks on tubes or other containers. Straight-chain or branched chain mono- or dibasic alkyl esters such as diisoadipate, isocetylstearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched chain esters known as crodamol CAP can be used the last three esters being preferred. These may be used alone or in combination depending on the required properties. Alternatively, high melting lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

Formulations suitable for external application to the eye also include eye drops wherein the active ingredient is dispersed or suspended in a suitable carrier, especially in an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w.

Formulations suitable for external administration in the mouth include lozenges containing the active ingredient in a taste-corrected base, usually sucrose and gum arabic or tragacanth; Pastilles comprise the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and gum arabic; Mouthwashes comprise the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base containing, for example, cocoa butter or a sucrose.

Formulations suitable for nasal administration in which the carrier is a solid include a coarse powder having a particle size of, for example, in the range of 20 to 500 microns, which is administered in the manner in which snuffing, i. by rapid inhalation through the nasal passage from a container of powder, which is held close to the nose. Suitable formulations in which the carrier is a liquid for administration as, for example, a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. i

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be suitable.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile Suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit dose or multi-dose containers, for example in sealed vials and vials, and stored in freeze-dried (lyophilized) condition, with only the addition of the sterile liquid carrier, for example water for injections, just prior to use is required. Injection solutions and suspensions suitable for immediate use can be prepared from sterile powders, granules and tablets of the type previously described. Preferred unit dose formulations are those containing a daily dose or a daily subdose as described above, or a suitable fraction thereof, of an active ingredient. In addition to the ingredients previously mentioned, the formulations of the invention may comprise other agents conventional in the art, taking into account the nature of the formulation in question, for example, the formulations suitable for oral administration may contain flavoring agents. The present invention further provides veterinary compositions containing at least one active ingredient as defined above with a veterinary carrier therefor.

- Ö - £ D9 UOO D

Veterinary carriers are materials which are suitable for the purpose of administering the composition and may be solid, liquid or gaseous materials otherwise inert or compatible in veterinary medicine and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired administration.

For oral administration, the compositions may be in the form of a tablet, granules, potion, paste, chachet, capsule or dietary supplement. Granules can be prepared by known techniques, such as wet granulation, pre-pressing or slugging. You can put the animals in an inert liquid vehicle to get a potion

or administered in the form of a suspension with water or oil base. Preferably, further minor ingredients, such as a dispersant, are included. These formulations preferably contain 15 to 85% of the active ingredient.

A paste can be formulated by suspending the active ingredient in a liquid diluent. A stiffening or thickening agent may be added together with a wetting agent or humectant if the liquid diluent is water. When an emulsion paste is required, one or more surfactants should desirably be included. From 25% to 80% by weight of these paste formulations may comprise the active ingredient.

For feed supplements, the active ingredient will generally be present in large amounts relative to the additional ingredients and the supplements may be added directly or after intervening mixing or dilution. Examples of additional ingredients for such formulations include solid, oral food carriers such as cereal flour, soybean powder, wheat bran, soybean meal, edible plant materials and fermentation residues. The active ingredient is usually incorporated in one or more of the additional ingredients and intimately and uniformly dispersed by milling, tumbling, or stirring with conventional equipment. Formulations containing from 1% to 90% by weight of the active ingredient are suitable as an additive to feed.

For the treatment of herpes infections in horses, an oral or parenteral dose of 0.1 to 250 mg per kilogram of body weight per day, preferably from 2 to 100 mg per kilogram per day may be required. The dose may be split into separate units and administered at regular intervals during the day and may be repeated daily for up to 14 days or until the infection is cleared. For viral infections in other animals, the dose may vary depending on the size and metabolism of the animal. The compositions can be administered in unit dosage form, such as a tablet, several times a day in the amount of 10 to 1000 mg per unit dose.

The compounds of formula I and their physiologically acceptable salts and esters can be prepared in a conventional manner by analogous methods for the preparation of compounds of similar structure as by the methods described in British Pat. No. 1,523,865.

The present invention provides a process for the preparation of compounds of formula I and their physiologically acceptable salts and esters thereof, with the exception of the compound of formula I, wherein X is oxygen, R ^{1 is} an amino group, R ² , R ³ and R ⁵ each represents a hydrogen atom and R ^{4 represents} a hydroxyl group, the process comprising the steps of:

a) deblocking a compound of formula II

(ID

CHXCHCHR.

(wherein X and R ³ are as defined above and R _{a represents} an amino group or a blocked amino group, R _a and R _a , which are the same or different, each represents a hydroxyl or hydroxyalkyl group or a blocked hydroxyl or hydroxyalkyl group, R | Hydroxyalkyl or blocked hydroxyalkyl, provided that at least one of Ra, R |, R ⁴ and Ra is a blocked radical); b) conversion of a compound of formula III

(III)

CKXCHCHR

-7-269 083 6

(in which X, R ² , R ³ , R ⁴ and R ⁶ are as defined above, M represents a hydrogen atom or a group or an atom which can be converted into a hydrogen atom, and G denotes a group or an atom which may be converted to an amino group, or (when M is other than a hydrogen atom), G may alternatively represent an amino group) or a salt or ester thereof, to a compound of the formula I (wherein R ^{1 represents} an amino group) or a physiologically acceptable Salt or an ester thereof; ~

c) reaction of a compound of the formula IV

(IV)

(wherein Q represents a leaving atom or a leaving group) with a compound of the formula V ACHXCHCH B

I5> 2'3 IT FR

(V)

(wherein X, R ² , R ³ and R ⁵ are as defined above and A is a leaving group or a leaving atom and B is an optionally protected hydroxyl group);

d) closing a ring in a precursor compound containing either the pyrimidine or imidazole ring incompletely formed;

e) reduction of a compound of formula VI

(VI)

CH-XCH-CHR

R ^ CHO R

(wherein X, R ² , R ³ , R ⁴ and R ⁶ are as defined above) or a salt or ester thereof to form a compound of formula I (wherein Y represents a hydroxymethyl group) or a physiologically acceptable salt or ester thereof Widen; , ^; · ';'..''; :: '.' ^: ''. - ^; , '·. '.-V'. ''

f) conversion of a compound of the formula VII

(VII)

CH-X-CH-CH-NH.

I ₂ I

(wherein X, R ¹ , R ² , R ³ and R ^{B have} the abovementioned meaning) into a corresponding compound of formula I, wherein R ^{4 is} a hydroxyl group,

to form a compound of formula I or a physiologically acceptable salt or ester thereof and optionally wherein one or more of the following transformations is carried out in any order:

i) when the product obtained is a base, converting the base to a physiologically acceptable acid addition salt thereof;

N) when the product obtained is an acid addition salt. Transfer of the salt into the parent base; iii) when the product obtained is a compound of the formula I or a salt thereof, conversion of the compound or

the salt thereof into a physiologically acceptable ester of the compound or salt; and / or iy) if the product obtained is an ester of a compound of formula I, conversion of the ester into the parent compound. of the formula I, a physiologically acceptable salt thereof or a different physiologically contracted ester thereof.

In process a), the blocking groups may be selected according to the purpose of use, for example, acyl groups such as C 1-4 alkanoyl groups, ζ. Acetyl or pivaloyl, or aroyl groups, e.g. Benzoyl, arylmethyl groups, e.g. Benzyl, or tri-C, 4-alkylsilyl groups, e.g. B. trimethylsilyl. Arylmethyl blocking groups can be removed by, for example, hydrogenolysis, e.g. B. by hydrogenation in the presence of Raney nickel or a palladium catalyst. or by using sodium in liquid ammonia. For example, acyl blocking groups can be removed by hydrolysis using, for example, an amine such as methylamine or triethylamine, preferably in an aqueous medium. Trialkylsilyl blocking groups can be removed, for example, by solvolysis, e.g. with alcoholic or aqueous ammonia, or by alcoholysis.

The conversion of a compound of formula III into a compound of formula I according to process b) can be accomplished by numerous conventional means. For example, G may represent an azide group which may be reduced to an amino group by catalytic hydrogenation using a suitable catalyst such as palladium. Alternatively, G may represent a halogen atom or an alkylthio or alkylsulfonyl radical which may be converted to an amino group by aminolysis using, for example, ammonia. M may represent a halogen atom, for. B. a chlorine atom, or a mercapto or thio group (S <), which can be converted in a conventional manner into a hydrogen atom. In the case where M is a thio group, this conversion may be carried out using a compound of formula III wherein any amino or hydroxyl groups may optionally be blocked by acyl groups, the conversion being effected using Raney nickel, e.g. in a basic medium which additionally removes the amino and / or hydroxyl blocking groups according to method a).

These methods, along with other conventional methods, are described in Fused Pyrimidines, Part II, Purine, by D. J. Brown (1971), Wiley-Interscience.

In the process (c), the group Q in the formula IV may be, for example, a hydrogen atom, an acyl group such as a C _1-4 alkanoyl group such as an acetyl group or an aroyl group such as a benzoyl group, or a tri-C _1-4 alkylsilyl group such as a trimethylsilyl group. The group A in formula VI can be, for example, a halogen atom (for example chlorine) or an acyloxy group, in which the acyl unit is, for example, a C 1-4 alkanoyl group, such as acetyl, or an aroyl group, such as benzoyl. The reaction may conveniently be effected in a strong polar solvent such as dimethylformamide or hexamethylphosphoramide, advantageously in the presence of a base such as triethylamine or potassium carbonate. Alternatively, thermal condensation may be achieved by heating the compounds of formulas IV and V in the presence of a catalytic amount of a strong acid, e.g. For example, sulfuric acid, are effected.

The process d) involves the ring closure of the imidazole or pyrimidine ring to the final product. In the case of the imidazole ring, this ring closure can be achieved by a reaction of a suitable precursor with a C 1-10 reagent such as triethyl orthoformate under, for example, mild acidic conditions at a temperature of about 25 ^° C. and a reaction time of a few hours. A suitable precursor is substituted pyrimidine of the formula IX

CH ₇ XCHCH ₀ OH

  I

γ ._. ,

An alternative reagent is diethoxymethyl acetate when neutral conditions at about 100 ^° C. and a reaction time of about 10 to 15 minutes are preferred.

The reduction of a compound of formula VI in process (e) can be accomplished, for example, by reaction with a suitable aldehyde reducing agent such as sodium bromide, sodium cyanoborohydride, tetraethylammonium borohydride or pyridine / diborane / tetrahydrofuran / trifluoroacetic acid.

In process f), the conversion is advantageously carried out by treating the amino compound of formula VII with a nitrite, for. B. causes sodium nitrite in an acidic medium.

The starting materials used in the above-described processes can be prepared in a conventional manner, e.g. Example, according to the methods which have been described in the aforementioned G8-PS 1 523865.

The following examples illustrate the present invention.

example 1

2-amino-9- (2-hYdroxyetbylthiomethyl) -9H-purine

A 1 liter round bottom flask equipped with a magnetic stir bar and a CaCl ₂ drying tube was charged with 5.0 g (29.5 oM) 2-amino-6-chloro-purine, 6.8 g (29.5 oM) 2- {chloromethylthio) ethyl benzoate , 4.07 g (29.5 oM) of potassium carbonate and 750 ml of anhydrous dimethylformamide. The reaction mixture was stirred at room temperature for 16 hours after which an additional 2.0 g (8.7 mM) of 2- {chloromethylthio) ethyl benzoate was added with 1.2 g (8.7 mM) of potassium carbonate and stirring continued for a further 24 hours at room temperature. The reaction mixture was filtered through a pad of celite in a sintered glass funnel and reduced to a viscous under reduced pressure in a rotary evaporator

evaporated yellow oil. ^,

The oil was adsorbed onto 20.0 g of Merck Süicagel 60 (70-230 mesh) and this preadsorbed phase was added to the top of a column of Merck silica gel 60 (230-400 mesh). Elution of the column using 6: 4 ethyl acetate / benzoi afforded 2-amino-9- (2-benzoyloxyethylthiomethyl) -6-chloro-9H-purir. as a discolored white solid as the sole material by thin layer chromatography (TLC) over silica gel with ethyl acetate / hexane in the ratio 8: 2. ¹ H NMR, CDCl ₃ 8.0-7j15, 6H, Multiplet; 5.1, 4H, broad singlet; 4.5, 2H, triplet, 2.985, 2H triplet.

The last-mentioned product (0.98 g, 2.7 mmol) was added to a 500 ml Parr hydrogenation bottle along with 2.5 g of Pd (OH) ₂ catalyst, 50 ml of triethylamine and 200 ml of methanol. This mixture was shaken in a Parr hydrogenator under a pressure of 3.44 χ 10 ⁵ Pa (50 psi) of hydrogen for 16 hours at room temperature. The TLC of the hydrogenolysis product over silica! with 8% methanol-ethyl acetate showed only a partial reaction. The catalyst was removed by filtering through a pad of celite in a sintered glass funnel, 2.0 g of fresh Pd (OH) ₂ catalyst and 7.0 ml of triethylamine were added, and the reaction mixture was re-sampled under 3.44 x 10 ⁵ Pa (50 psi) Hydrogen pressure shaken for 20 hours. At this point, TLC showed that the reaction was complete, the catalyst was removed as before, and the methanol was removed by rotary evaporation under reduced pressure to give a clear glass which was dissolved in 100 ml of 1: 1 methanol-water, 20 % Methylamine was taken. The resulting solution was stirred at room temperature for 4 hours and removed by rotary evaporation under reduced pressure to give an amorphous solid. The solid was adsorbed on 10.0 g Merck silica gel 60 (70-230 mesh) and this preadsorbed phase was applied to the top of a column of Merck silica gel 60 (230-400 mesh). The elution of the column using 10% methanol-ethyl acetate afforded a solid which crystallized from ethyl acetate-hexane to give the title compound as needles, melting point 122 to 124 ⁰ C, TLC: 1 dots on silica gel with 15% MethanoliEthylacetat , ¹ H NMR DMSOd ₆ 8.59.1H singlet; 8.15.1H singlet; 6,56,2H wide singlet; 5.24.2H singlet; 4.83.1H triplet, 3.49.2H multiplet; 2,69,2H, multiplet; Analysis:

CHN ^y

calculated: 42.65 4.92 31.09

Filled: 42.70 4.94 31.04

Example 2

a) 2-Amino-9 - [(2-benzoyloxy-1-benzoyloxymethylethoxy) -methyl] -6-chloro-9H-purine

A mixture of 7.0 g (41.2 mmol) of 2-amino-6-chloro-9H-purine, 4.55 g (34.4 mmol) of ammonium sulfate and 200 ml of hexamethyldisilazane was combined under nitrogen and refluxed with stirring for 5 hours. The mixture was flashed off, followed by the addition of 8.8 g (23.6 mM) of 2-0- (acetylmethyl) -1,3-bis (0-benzoyl) glycerol in about 10 ml of benzene. The mixture was heated in an oil bath for 1.5 hours and distilled under aspirator pressure with a distillation head hookup. The mixture was cooled to room temperature. Methanol was added to the mixture, which was placed on a steam bath for 30 minutes. The mixture was then washed with water and extracted three times with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate for about 30 minutes. The mixture was then filtered, the salt was washed with ethyl acetate and then flash evaporated. Flash column chromatography (flash column chromatography) with 6: 1 CH ₂ Cl ₂ / acetone as the eluent gave the title compound as an analytically-white solid having a melting point of 130 to 131 ^° C.

b) 2-Amino-9 - [(2-benzoyloxy-1-benzoyloxymethylethoxy) -methyl] -9H-purine

A mixture of 3,393g (7,04mM) 2-amino-9 - [(2-benoyloxy-1-benzoyloxymethylethoxy) methyl] -6-chloro-9H-purine, 100ml ethanol, 100ml tetrahydrofuran, 1.9ml triethylamine became 0.600 Put Pd-C catalyst in a Parr bottle. The mixture was shaken under hydrogen for 24 hours. The Pd-C was filtered through a celite pad and 0.650 g of fresh Pd-C was added to the reaction mixture and hydrogenation was continued for 4 days. Column chromatography using 100% CH ₂ Cl ₂ , 4: 1 CH ₂ Cl ₂ / acetone and 100% acetone gave the compound having a melting point of 132 to 133 ° C.

Example 3 2-Amino-9 - [(2-hydroxy-1-hydroxymethylethoxy) methyl] -9H-purine

A mixture of 0.844 g (1.88 mmol) of 2-amino-9 - [(2-benzoyloxy-benzoyloxymethylethoxy) methyl] -9H-purine and 100 ml of a 40% aqueous methylamine solution was stirred for 30 minutes at room temperature. The mixture was flash evaporated to give a yellow oil, which was then washed with water. The aqueous layer was then extracted twice with methylene chloride. The aqueous layer containing the product was then flash evaporated to give a light yellow oil. Recrystallization of the oil in hot acetonitrile yielded the title compound in the form of an analytically pure off-white solid having a melting point of 148-151 ⁰ C.

Example 4 9- (2-Acetoxyethoxymethyl) -2-amino-9H-purine

A mixture of 0.82 g (3.92 mM) of 9- (2-hydroxyethoxymethyl) -2-amino-9H-purine, 48 mg (0.392 mM) of 4-dimethylaminopyridine and 0.75 ml (7.84 mM) of acetic anhydride in 18 ml of anhydrous dimethylformamide was added Stirred for 2 days at room temperature.

The reaction mixture was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and absorbed on silica gel. The solvent was removed by flash evaporation, and the remaining powder was put on a column, which was removed for flash chromatography, and the remaining powder was placed on a column prepared for flash chromatography. Elution with 5% methanol in dichloromethane gave 1.0g of a semicrystalline oil which after recrystallization from benzene-hexane gave the analytically pure 9- (2-acetoxyethoxy methyl) -2-amino-9H-purine having a melting point 115-118 ⁰ C resulted.

Example 5 2-Amino-9 [(2-acetoxy-1-acetoxymethylethoxy) methyl] -9H-purine

A mixture of 0.45 g (1.88 mM) 2-amino-9 - [(2-hydroxy-1-hydroxymethylethoxy) methyl] -9H-purine, 1.15 g (11.3 mM) acetic anhydride and 23 mg (0.188 mM) 4 Dimethylaminopyridine in 10 ml of dry dimethylformamide was stirred at room temperature for 18 hours. The solution was evaporated under reduced pressure and the residue was dissolved in methanol and preabsorbed on silica gel. The solvent was evaporated under reduced pressure and the powder was placed on a column prepared for flash chromatography. Elution with 10% methanol in dichloromethane gave, after evaporation, the title compound. Recrystallization from ethyl acetate-hexane gave analytically pure 2-amino-9 [(2-acetoxy-1-acetoxymethylethoxy) methyl] -9H-purine.

Example 6 9- {2-Acetoxyethylthiomethyl) -2-amino-9H-purine

A 100 ml flask equipped with a magnetic stir bar and a CaCl ₂ dry tube was charged with 1.0g (4.4mM) 2-amino-9- (2-hydroxyethylthiomethyl) -9H-purine, 0.054g (0.44mM) 4-dimethylaminopyridine , 0.9ml (8.8mM) acetic anhydride and 20ml dry DMF. The solution was stirred at room temperature for 24 hours and then cooled with 5 mL of MeOH. The solution was evaporated under reduced pressure (bath temperature 4O ⁰ C) and the brown oil thus obtained was determined using the "Flash" method chromatography. Elution of the column with 1.5% methanol in ethyl acetate gave a yellow oil, which upon standing The pale yellow crystals were dissolved in a solution of 2% MeOH in toluene and treated with 0.05 g of Darco G-60 The methanol was evaporated from the toluene solution, resulting in the precipitation of pale yellow crystals.

The product was dried at 78 ° C for 16 hours to give the title compound; Melting point 119 to 120.5 ° C. Analysis for Ci ₀ H ₁₃ N ₆ O ₂ S: ·.

CHN: 44.93 4.9 26.20

F .: 44.97 4.96 26.17

¹ H NMR in DMSO ₆ 8.59 (1HS), 8.15 (1Hs), 6.52 (2H wide s) 5.26 (2Hs), 4.15 (2HtJ = 6.36Hz), 2.89 ( 2HtJ = 6.36Hz), 1.99 (3Hs).

Example? 2-amino-9- (2-benzoyloxyethylthiomethyl) -9H-purine

A 5-liter 3-necked flask was equipped with an air stirrer motor, a glass stir bar with a teflon attachment, and a device for evacuation and introduction of N ₂ or H ₂ gas into the flask. The flask was then treated with 7.0g (0.019M) 2-amino-9- (2-benzoyloxyethylthiomethyl) -6-chloro-9H-purine, 14.0g palladium hydroxide on carbon, 12.0ml (0.163M) triethylamine, 75, 0 ml of water and 3.0 liters of methanol. The flask was then sealed and evacuated using a water aspirator, filled with N ₂ -GaS, and evacuated until three complete cycles were completed. The flask was evacuated, charged with H ₂ -GaS, evacuated and refilled with H ₂ -GaS. The stirring motor was started and the reaction mixture was stirred under H ₂ at room temperature for 4 days.

The solution was filtered through a sintered glass funnel and the catalyst was washed with 800 ml of methanol. The methanol solution was evaporated under reduced pressure to give 6.0 g of a light yellow solid. The solid was absorbed on silica gel 60 (70-230 mesh) and this preabsorbed phase was placed on the top of a silica gel 60 (230-400 mesh) column. Elution of the column by the "flash" method using 5% methanol in ethyl acetate afforded a white solid which was recrystallized from ethyl acetate-hexane, dried at 78 ^° C. under 1.0 mm Hg vacuum, and white plates with a Melting point from 120 to 121 ° C; ¹ H NMR in DMSO d ₆ 8.60 (1H, s), 8.19 (1H, s), 8.07.5 (5H, m), 6.55 (2H , s), 5.32 (2H, s), 4.52 (2H, t), 3.06 (2H, t).

Analysis:

CHN calculated: 54.69 4.59 21.26

F .: 54.68 4.64 21.24.

2-Amino-9- (2-hydroxyethylthiomethyl) -9H-purine was obtained by continued elution of the column described above. packaging forms

tablet Active connection 200 mg lactose 235 mg Strength 50 mg polyvinylpyrrolidone 50 mg magnesium stearate 5mg

500 mg

The active compound is mixed with the lactose and the starch and the granules are moistened with a solution of the polyvinylpyrrolidones. The granules are dried, sieved and mixed with magnesium stearate and pressed.

capsule Active connection 200 mg lactose 184mg Sodium starch 8 mg polyvinylpyrrolidone 6 mg magnesium stearate 2 mg

The active compound is mixed with the starch and sodium starch glycolate and the granules are moistened with a solution of the polyvinylpyrrolidone. The granules are dried, sieved and mixed with the magnesium stearate and filled into hard gelatin capsules.

cream Active connection 5.00 g glycerin 2,00 g cetostearyl 6.75 g Sodium Iaurylsulfat 0.75 g white soft paraff in 12.50 g liquid paraffin 5.00 g chlorocresol 0.10 g purified water 100.00 g

The active compound is dissolved in a mixture of purified water and glycerol and heated to 70 ° C. The remaining ingredients are heated together to 7O ⁰ C. The two parts are joined together and emulsified. The product is cooled and placed in containers.

Intravenous infections

A) Active compound 200 mg sodium hydroxide solution q. s. to pH 7.0 to 7.5

Water for injections to 5.0 ml

The active compound is dissolved in a portion of the water for injections. The pH is adjusted with the sodium hydroxide solution and the volume required is achieved by adding water for injections. Under aseptic conditions, the solution is sterilized by filtration, filled into sterile ampoules and the vials are sealed.

B) Active compound 100mg sodium hydroxide solution q. s. to pH 7.0 to 7.5

Mannitol 125 mg

Water for injections to 2.5 ml

The active compound and part of mannitol are dissolved in water for injections. The pH is adjusted with sodium hydroxide solution and the required volume is achieved by adding water for injections. Under aseptic conditions, the solution is sterilized by filtration, filled into sterile vials, and the water is removed by freeze-drying. The vials are sealed under a nitrogen atmosphere and sealed with a sterile stopper and aluminum sleeve.

Comparison of plasma levels of acyclovir obtained after oral administration of deoxyacyclovir and aminoacyclovir to rats:

Acyclovir concentrations in plasma, μΜ

6-Deoxyacyclovir

Rat 3

30 18.6 17.5 6.7 4.06 0.25

Toxicity study

Two male and two female Beagle dogs received 6-deoxyacyclovir per os (once daily for five consecutive days) at a dose level of 40 mg / kg / day. There were no effects in one male and one female animal killed at the end of the treatment period, and in one male and one female animals sacrificed two weeks after the dosing period.

Antiviral activity

a) 70 CDI mice were infected with 300 μl _{60 of} the ICI strain of herpes simplex virus type 1, the administration being intracerebral at a dose of 0.025 ml. The mice were categorized into groups of 10 animals each, one group being untreated for virus control and the other groups receiving the following compounds: (A) acyclovir at a dose of 100 mg / kg / dose (i) subcutaneously (sc); (ii) orally, (Hi) intraperitoneally (ip). (B) Compound according to Example 1 (6-deoxyacyclovir) in 100 mg / kg / dose i) subcutaneously (sc), ii) orally, iii) intraperitoneally (ip). The treatment groups received doses of the drug two to three hours after infection and twice daily for 4 days. The observations were made over a period of 14 days and survival times were recorded. The results are shown below:

Acyclovir concentrations in plasma, μΜ Rat J Hours after a dose Aminoacyclovir of 20 mg / kg 16.6 Rat 1 4.96 0.5 2.75 1.00 1 3.03 0.41 2 2.48 0.01 4 0.93 6 0.34 20 0.1

Results

Treatment survival times middle

Group (days) reciprocal over

lifetimes i

Virus controls 4 + 2 1 + 2t5 + 3 0.407

Acyclovir (s.c.) 3 + 3 4 + 4 2+ 4t 1 + 6 0,261

6-deoxyacyc | ovir (s.c.) 1 + 23 + 31 + 42 + 4t 2 + 5 0.289

Acyclovir (oral) 2 + 2 3 + 3 5 + 4 0.325

6-deoxyacyclovir (pral) 1 + 2t 1 + 4 2 + 5 3 + 6 1 + 8 0.186

1 survivor acyclovir (i.p.) 2 + 2 2 + 4 2 + 5 2 + 7 0.242

1 survivor

6-deoxyacyclovir (i.p.) 1 + 2t2 + 3 1 + 4 1 + 4t 4 + 6 1 + 8 0.233

The above results show that 6-deoxyacyclovir has greater effect than acyclovir when administered orally. B) 40 CDI mice were infected with 300 LD _{50 of} the ICI strain of herpes simplex virus type 1, with administration at a dose of 0.025 ml intracerebrally. Mice were subdivided into four groups of 10 animals each, with one group not treated to serve as a virus control. Treatment group 1 received 100 mg / kg / dose of the compound of Example 3, treatment group 2 received 100 mg / kg / dose of the compound of Example 2b, and treatment group 3 received 100 mg / kg / dose of acyclovir to serve as a positive control. The treated groups received the dosages of the drugs 2-3 hours after infection, and twice a day for a period of four days, the administration being subcutaneous. Survival times were recorded for a period of 14 days and compared as shown in the table below.

Results

Treatment survival times middle

Group (days) reciprocal over

live times

Virus Control 1 + 2 4 + 2t4 + 3 1 +4 0.37

Group 1 1 + 9 1+ 10 8Belarus 0.02

Group 2 1 +4 2+ 4t 3 + 5 1 +7 1 +8 1 +9

Survivor 0.17 Group3. 1 + 2t 1 + 31 + 3t 1 + 42 + 52 + 6

1 + 13! Survivor 0.21

Claims (1)

Invention claim: R ⁴ wherein X represents a sulfur or oxygen atom or a chemical bond, R ^{1 represents} a halogen atom, an amino or azide radical, R ^{2 represents} a hydrogen atom, a hydroxyl, alkyl or hydroxyalkyl radical, R ^{3 represents} a hydrogen atom or an alkyl radical, R ^{4 represents} a hydroxyl, hydroxyalkyl, benzyloxy, phosphate or carboxypropiononyloxy radical, R ^{5 represents} a hydrogen atom, an alkyl or hydroxyalkyl radical, and physiologically acceptable esters of these compounds, wherein R ^{2 represents} a hydroxyl or hydroxyalkyl radical, R ^{4 represents} a hydroxyl, hydroxyalkyl or carboxypropionyloxy radical or R ^{5 represents} hydroxyalkyl, and physiologically acceptable salts of such compounds of formula I and their esters, to the exclusion the compound according to formula I in which X is oxygen, R ^{1 is} an amino group, R ² , R ³ and R ^{5 are} each a hydrogen atom and R ^{4 is} a hydroxyl group and the benzoate ester and the physiologically tolerable salts of this compound, characterized that a) a compound of formula II N. (II) CHXCHCHR R " '(wherein X and R ^{3 have} the abovementioned meaning and R 1 represents an amino group or blocked amino group, Ro and R ⁴ , which are identical or different, each represent a hydroxyl or hydroxyalkyl radical or a blocked hydroxyl or hydroxyalkyl radical,
Ra represents a hydroxyalkyl or blocked hydroxyalkyl radical, with the proviso that at least one of the substituents Rj, R ² , Ri and Rj is a blocked radical) is deblocked,
b) a compound of the formula " -- "H "'" (III) CHXCHCHR (in which X, R ² , R ³ , R ⁴ and R ^{5 have} the abovementioned meaning, M represents a hydrogen atom or a group or an atom which can be converted into a hydrogen atom, and G represents a group or atom which can be converted to an amino group, or (when M is about .nidorc., H-, a hydrogen atom) G may alternatively represent an amino group) or a salt or ester thereof in "in «Compound of the formula I (wherein R ^{1 represents} an amino group) or a physiologically acceptable salt or an ester thereof,
c) a compound of formula IV (IV) in f an Ahsnaltatnm orier means a Absnaltnriinnfi) with a Verbinduna of formula V ACHXCHCH B I ₂ I ₃ irir (V) (in which X, R ² , R ³ and R ^{6 have} the abovementioned meaning and A represents a leaving group or a cleavage atom and B represents an optionally protected hydroxyl group), d) in a precursor compound which contains either the pyrimidine or the imidazole ring is incomplete, a ring closure is performed, e) a compound of the formula VI