United States Patent: 4544634

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United States Patent	4,544,634
Krenitsky	October 1, 1985 =

Method of producing acyclovir

Abstract

The novel compound 6-deoxyacyclovir is enzymatically converted to = acyclovir=20 by xanthine oxidase/dehydrogenase or aldehyde oxidase in vivo, i.e. = within the=20 body of the animal being treated. The enzymatic conversion may also be = effected=20 ex vivo (i.e. in vitro) as a method of synthesizing acyclovir.

Inventors:	Krenitsky; Thomas A. (Chapel = Hill, NC)=20
Assignee:	Burroughs Wellcome Co. = (Research=20 Triangle Park, NC)
Appl. No.:	06/434,384
Filed:	October 14, = 1982

Current U.S. = Class: 435/119 ; = 514/263.38;=20 514/934

Current International = Class:=20 C07D = 473/00 (20060101); C12P=20 017/18 (); A01N 043/90 (); A61K 031/52 ()

Field of Search: = 435/119,88 =

References Cited [Referenced=20 By]

Foreign Patent Documents


0074306	Mar., 1983	EP
0085424	Aug., 1983	EP

Other References

Krenitsky et al., Archive of Biochemistry and=20 Biophysics, vol. 185, No. 2, pp. 370-375, Jan. 30, 1978; vol. 150, = No. 2,=20 pp. 585-599, Jun. 1972..

Primary = Examiner:=20 Tanenholtz; Alvin E.
Attorney, Agent or Firm: Brown; = Donald=20

Claims

I claim:

1. A method of producing acyclovir which = comprises=20 converting 6-deoxyacyclovir or a physiologically acceptable salt thereof = in an=20 aqueous liquid in the presence of oxygen and xanthine oxidase to produce = said=20 acyclovir.

2. The method of claim 1 in which the salt is an acid = addition salt.

3. The method of claim 1 in which the salt is the = salt of=20 lactic, acetic, malic, p-toluenesulphonic, hydrochloric or sulphuric = acid.=20

4. A method of producing acyclovir which comprises converting=20 6-deoxyacyclovir or a physiologically acceptable salt thereof in an = aqueous=20 liquid in the presence of oxygen and aldehyde oxidase to produce said = acyclovir.=20

5. The method of claim 4 in which the salt is an acid addition = salt.=20

6. The method of claim 5 in which the salt is the salt of = lactic,=20 acetic, malic, p-toluenesulphonic, hydrochloric or sulphuric acid. =

7. A=20 method of producing acyclovir which comprises converting = 6-deoxyacyclovir or a=20 physiologically acceptable salt thereof in an aqueous liquid in the = presence of=20 oxygen and xanthine dehydrogenase to produce said acyclovir.

8. = The=20 method of claim 7 in which the salt is an acid addition salt.

9. = The=20 method of claim 8 in which the salt is the salt of lactic, acetic, = malic,=20 p-toluenesulphonic, hydrochloric or sulphuric acid.

=20 Description

The present invention relates to antiviral purine derivatives = containing=20 an acyclic chain in the 9-position.

U.K. Patent Specification = No.=20 1523865 and U.S. Pat. No. 4,199,574 describe a broad class of purine = derivatives=20 containing an acyclic side chain in the 9-position. These purine = derivatives=20 have been found to have antiviral activity against various classes of = DNA=20 viruses particularly against herpes viruses such as herpes simplex.=20

Among these derivatives, 9-(2-hydroxyethoxymethyl)guanine = (otherwise=20 known as acyclovir) has been found to have particularly good activity = against=20 herpes viruses such as herpes simplex. However, while acyclovir has been = found=20 to be especially effective upon topical or parenteral administration, it = is only=20 moderately well absorbed upon oral administration with corresponding = levels of=20 drug in the plasma. It will be appreciated that when one is treating an = internal=20 disorder by oral administration of a drug, it is clearly desirable that = the drug=20 should be well absorbed from the gastro-intestinal tract with resulting = high=20 plasma levels.

The surprising discovery has now been made that=20 6-deoxyacyclovir, a purine derivative, falling within the scope of the = compounds=20 broadly described in U.K. Patent Specification No. 1523865 and = characterized by=20 the presence of a hydrogen atom in the 6-position of the purine nucleus, = can be=20 readily converted in vivo by the action of the molybdo-flavo-protein = enzymes=20 xanthine oxidase/dehydrogenase or aldehyde oxidase into the = corresponding=20 6-hydroxy purine derivative acyclovir. Furthermore, from experiments in = rats, it=20 has been found that oral administration of 6-deoxyacyclovir results in = efficient=20 absorption from the gastro-intestinal tract and high plasma levels of = the=20 corresponding acyclovir, formed by enzymatic conversion of the = 6-hydrogen=20 compound. Indeed, it has been found that with oral administration higher = blood=20 levels of acyclovir are obtainable with 6-deoxyacyclovir than with = acyclovir=20 itself.

Also, for example, 6-deoxyacyclovir, i.e.=20 2-amino-9-(2-hydroxyethoxymethyl)purine, the 6-hydrogen analogue of = acyclovir,=20 is considerably more soluble in water than acyclovir, the former = compound having=20 a solubility of 50 mg/ml and the latter having a solubility of 1.25 = mg/ml at=20 25.degree. C. This improved water-solubility enables 6-deoxyacyclovir to = be used=20 in a greater variety of aqueous pharmaceutical formulations which = require some=20 solubilisation of the drug. The above-mentioned 6-hydrogen purine = analogue=20 6-deoxyacyclovir may be represented by the formula (I) ##STR1## and=20 physiologically acceptable salts thereof.

Salts of the compounds = of=20 formula (I) which may be conveniently used in therapy include = physiologically=20 acceptable salts of organic acids such as lactic, acetic, malic or=20 p-toluenesulphonic acid as well as physiologically acceptable salts of = mineral=20 acids such as hydrochloric or sulphuric acid.

It is thus = possible to=20 synthesize acyclovir in the body (i.e. in vivo) by administering=20 6-deoxyacyclovir to mammals including humans wherein the = 6-deoxyacyclovir is=20 acted upon by xanthine oxidase/dehydrogenase or aldehyde oxidase in the = body and=20 is thereby converted into acyclovir. It has also been demonstrated that=20 acyclovir may be synthesized, i.e. manufactured, by the ex vivo (i.e. in = vitro)=20 enzymatic oxidation of 6-deoxyacyclovir by the actions of the=20 molybdo-flavo-protein enzymes xanthine oxidase/dehydrogenase or aldehyde = oxidase. Oxygen or other appropriate electron acceptors such as = ferricyanide ion=20 or methylene blue may serve as the oxidizing agent. Microorganisms which = contain=20 or produce xanthine oxidase/dehydrogenase may be used to effect the = conversion=20 of 6-deoxyacyclovir to acyclovir.

The discovery that the = 6-hydrogen=20 purine of formula (I) above can be readily converted into its = corresponding=20 6-hydroxy analogue is surprising since in previous studies with xanthine = oxidase=20 from bovine milk (H. Lettre et al. (1967) Biochem. Pharmacol., 16, = 1747-1755; T.=20 A. Krenitsky et al. (1972) Arch. Biophys., 150, 585-599) it was shown = that=20 9-substitution obliterates or greatly diminishes the rate at which a = variety of=20 purines are oxidized. In view of these observations, it was surprising = to find=20 that this enzyme oxidized for example 6-deoxyacyclovir, a 9-substituted=20 derivative of 2-aminopurine, at a faster rate than the 9-unsubstituted = purine,=20 as established from enzyme studies.

The high level of absorption = of the=20 compound of formula (I) from the gastrointestinal tract renders the = compound=20 especially useful when oral administration of the compound is desired, = e.g. in=20 the treatment of diseases caused by various DNA viruses, such as herpes=20 infections for example herpes simplex, varicella or zoster or = Epstein-Barr=20 virus. In addition to its use in human medical therapy the compound of = formula=20 (I) can be administered to other animals for the treatment or = prophylaxis of=20 viral diseases, e.g. in other mammals.

According to a further = feature of=20 the present invention there is provided the compound of formula (I) and=20 physiologically acceptable salts thereof for use in the treatment or = prophylaxis=20 of a viral disease in an animal, e.g. a mammal such as man.

The = present=20 invention also provides a method for the treatment or prophylaxis of a = viral=20 disease in an animal, e.g. a mammal such as man which comprises = administering to=20 the animal an effective antiviral amount of a compound of formula (I) or = a=20 physiologically acceptable salt thereof.

The compound of formula = (I) and=20 the physiologically acceptable salts thereof (hereafter collectively = referred to=20 as the active ingredients) may be administered by any route appropriate = to the=20 condition to be treated, suitable routes including oral, rectal, nasal, = topical=20 (including buccal and sublingual), vaginal and parenteral (including=20 subcutaneous, intramuscular, intravenous, intradermal, intrathecal and=20 epidural). It will be appreciated that the preferred route may vary with = for=20 example the condition of the recipient.

For each of the = above-indicated=20 utilities and indications the amount required of an active ingredient = (as above=20 defined) will depend upon a number of factors including the severity of = the=20 condition to be treated and the identity of the recipient and will = ultimately be=20 at the discretion of the attendant physician or veterinarian. In general = however, for each of these utilities and indications, a suitable, = effective dose=20 will be in the range 0.1 to 250 mg per kilogram body weight of recipient = per=20 day, preferably in the range 1 to 100 mg per kilogram body weight per = day and=20 most preferably in the range 5 to 20 mg per kilogram body weight per = day; an=20 optimum dose is about 10 mg per kilogram body weight per day. (Unless = otherwise=20 indicated all weights of active ingredient are calculated as the parent = compound=20 of formula (I): for salts thereof the figures would be increased=20 proportionately.) The desired dose is preferably presented as two, = three, four=20 or more sub-doses administered at appropriate intervals throughout the = day.=20 These sub-doses may be administered in unit dosage forms, for example,=20 containing 10 to 1000 mg, preferably 20 to 500 mg and most preferably = 100 to 400=20 mg of active ingredient per unit dosage form.

While it is = possible for=20 the active ingredients to be administered alone it is preferable to = present them=20 as pharmaceutical formulations. The formulations, both for veterinary = and for=20 human use, of the present invention comprise at least one active = ingredient, as=20 above defined, together with one or more acceptable carriers therefor = and=20 optionally other therapeutic ingredients. The carrier(s) must be = "acceptable" in=20 the sense of being compatible with the other ingredients of the = formulation and=20 not deleterious to the recipient thereof.

The formulations = include those=20 suitable for oral, rectal, nasal, topical (including buccal and = sublingual),=20 vaginal or parenteral (including subcutaneous, intramuscular, = intravenous,=20 intradermal, intrathecal and epidural) administration. The formulations = may=20 conveniently be presented in unit dosage form and may be prepared by any = of the=20 methods well known in the art of pharmacy. Such methods include the step = of=20 bringing into association the active ingredient with the carrier which=20 constitutes one or more accessory ingredients. In general the = formulations are=20 prepared by uniformly and intimately bringing into association the = active=20 ingredient with liquid carriers or finely divided solid carriers or = both, and=20 then, if necessary, shaping the product.

Formulations of the = present=20 invention suitable for oral administration may be presented as discrete = units=20 such as capsules, cachets or tablets each containing a predetermined = amount of=20 the active ingredient; as a powder or granules; as a solution or a = suspension in=20 an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid = emulsion=20 or a water-in-oil liquid emulsion. The active ingredient may also be = presented=20 as a bolus, electuary or paste.

A tablet may be made by = compression or=20 moulding, optionally with one or more accessory ingredients. Compressed = tablets=20 may be prepared by compressing in a suitable machine the active = ingredient in a=20 free-flowing form such as a powder or granules, optionally mixed with a = binder,=20 lubricant, inert diluent, preservative, surface active or dispersing = agent.=20 Moulded tablets may be made by moulding in a suitable machine a mixture = of the=20 powdered compound moistened with an inert liquid diluent. The tablets = may=20 optionally be coated or scored and may be formulated so as to provide = slow or=20 controlled release of the active ingredient therein.

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

If desired, the aqueous = phase of=20 the cream base may include, for example, at least 30% w/w of a = polyhydric=20 alcohol, i.e. an alcohol having two or more hydroxyl groups such as = propylene=20 glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene = glycol=20 and mixtures thereof. The topical formulations may desirably include a = compound=20 which enhances absorption or penetration of the active ingredient = through the=20 skin or other affected areas. Examples of such dermal penetration = enhancers=20 include dimethylsulphoxide and related analogues.

The oily phase = of the=20 emulsions of this invention may be constituted from known ingredients in = a known=20 manner. While the phase may comprise merely an emulsifier (otherwise = known as an=20 emulgent), it desirably comprises a mixture of at least one emulsifier = with a=20 fat or an oil or with both a fat and an oil. Preferably, a hydrophilic=20 emulsifier is included together with a lipophilic emulsifier which acts = as a=20 stabilizer. It is also preferred to include both an oil and a fat. = Together, the=20 emulsifier(s) with or without stabilizer(s) make up the so-called = emulsifying=20 wax, and the wax together with the oil and/or fat make up the so-called=20 emulsifying ointment base which forms the oily dispersed phase of the = cream=20 formulations.

Emulgents and emulsion stabilizers suitable for = use in the=20 formulation of the present invention include Tween 60, Span 80, = cetostearyl=20 alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl = sulphate.=20

The choice of suitable oils or fats for the formulation is based = on=20 achieving the desired cosmetic properties, since the solubility of the = active=20 compound in most oils likely to be used in pharmaceutical emulsion = formulations=20 is very low. Thus the cream should preferably be a non-greasy, = non-staining and=20 washable product with suitable consistency to avoid leakage from tubes = or other=20 containers. Straight or branched chain, mono- or dibasic alkyl esters = such as=20 di-isoadipate, isocetyl stearate, propylene glycol diester of coconut = fatty=20 acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl = stearate,=20 2-ethylhexyl palmitate or a blend of branched chain esters known as = Crodamol CAP=20 may be used, the last three being preferred esters. These may be used = alone or=20 in combination depending on the properties required. Alternatively, high = melting=20 point lipids such as white soft paraffin and/or liquid paraffin or other = mineral=20 oils can be used.

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

Formulations suitable for topical administration in the = mouth=20 include lozenges comprising the active ingredient in a flavoured basis, = usually=20 sucrose and acacia or tragacanth; pastilles comprising the active = ingredient in=20 an inert basis such as gelatin and glycerin, or sucrose and acacia; and=20 mouthwashes comprising the active ingredient in a suitable liquid = carrier.=20

Formulations for rectal administration may be presented as a = suppository=20 with a suitable base comprising for example cocoa butter or a = salicylate.=20

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

Formulations=20 suitable for vaginal administration may be presented as pessaries, = tampons,=20 creams, gels, pastes, foams or sray formulations containing in addition = to the=20 active ingredient such carriers as are known in the art to be = appropriate.=20

Formulations suitable for parenteral administration include = aqueous and=20 non-aqueous sterile injection solution which may contain anti-oxidants, = buffers,=20 bacteriostats and solutes which render the formulation isotonic with the = blood=20 of the intended recipient; and aqueous and non-aqueous sterile = suspensions which=20 may include suspending agents and thickening agents. The formulations = may be=20 presented in unit-dose or multi-dose containers, for example sealed = ampoules and=20 vials, and may be stored in a freeze-dried (lyophilized) condition = requiring=20 only the addition of the sterile liquid carrier, for example water for=20 injections, immediately prior to use. Extemporaneous injection solutions = and=20 suspensions may be prepared from sterile powders, granules and tablets = of the=20 kind previously described.

Preferred unit dosage formulations = are those=20 containing a daily dose or unit daily sub-dose, as herein above recited, = or an=20 appropriate fraction thereof, of an active ingredient.

It should = be=20 understood that in addition to the ingredients particularly mentioned = above the=20 formulations of this invention may include other agents conventional in = the art=20 having regard to the type of formulation in question, for example those = suitable=20 for oral administration may include flavouring agents.

The = present=20 invention further provides veterinary compositions comprising at least = one=20 active ingredient as above defined together with a veterinary carrier = therefor.=20

Veterinary carriers are materials useful for the purpose of=20 administering the composition and may be solid, liquid or gaseous = materials=20 which are otherwise inert or acceptable in the veterinary art and are = compatible=20 with the active ingredient. These veterinary compositions may be = administered=20 orally, parenterally or by any other desired route.

For oral=20 administration the compositions can be in the form of a tablet, granule, = drench,=20 paste, cachet, capsule or feed supplement. Granules may be made by the = well=20 known techniques of wet granulation, precompression or slugging. They = can be=20 administered to animals in an inert liquid vehicle so as to form a = drench, or in=20 a suspension with water or oil base. Preferably further accessory = ingredients=20 such as a dispensing agent are included. These formulations preferably = contain=20 from 15 to 85% of the active ingredient.

A paste may be = formulated by=20 suspending the active ingredient in a liquid diluent. A stiffening or = thickening=20 agent may be included together with a wetting agent or a humectant if = the liquid=20 is water. If an emulsion paste is needed then one or more surface active = agents=20 should desirably be included. From 25 to 80% weight of these paste = formulations=20 may comprise the active ingredient.

In feed supplements the = active=20 ingredient is generally present in large amounts relative to the = accessory=20 ingredients, and the supplements may be added directly or after = intermediate=20 blending or dilution. Examples of accessory ingredients for such = formulations=20 include solid, orally ingestible carriers such as corn meal, soya flour, = wheat=20 shorts, soya grits, edible vegetable materials and fermentation = residues. The=20 active ingredient is usually incorporated in one or more of the = accessory=20 ingredients and intimately and uniformly dispersed by grinding, tumbling = or=20 stirring with conventional apparatus. Formulations containing 1 to 90% = by weight=20 of the active ingredient are suitable for adding to feeds.

For = the=20 treatment of herpes infections in horses, an oral or parenteral dose of = from 0.1=20 to 250 mg per kg body weight per day, preferably from 2 to 100 mg per kg = per day=20 may be required. The dose may be split up into discrete units = administered at=20 regular intervals during the day, and repeated daily for up to 14 days = or until=20 the infection is cleared. For viral infections in other animals the dose = may=20 vary depending on the size and metabolism of the animal. The = compositions may be=20 administered in unit dosage form, such as a tablet a few times daily in = the=20 amount of 10 to 1000 mg per unit dose.

The compound of formula = (I) and=20 physiologically acceptable salts thereof may be prepared in conventional = manner=20 by analogous processes for preparing compounds of similar structure, = such as=20 those methods described in U.K. Patent Sepcification No. 1523865. =

The=20 following Examples illustrate the present invention.

EXAMPLE 1=20

2-Amino-9-(2-hydroxyethoxymethyl)purine

A mixture of = 2.48 g=20 (7.13 mM) of 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine, 250 ml = of=20 absolute ethanol, 1.9 ml of triethylamine and 0.6 g of 5 palladium on = charcoal=20 was shaken under hydrogen at an initial pressure of 50 p.s.i. at room=20 temperature for twenty hours. The mixture was filtered, 0.265 g of fresh = palladium catalyst and 1.9 ml of triethylamine were added and the = mixture shaken=20 under hydrogen for an additional 16 hours.

The ethanolic = solution, after=20 filtration through a pad of Celite was evaporated in vacuo, and the = resulting=20 white solid extracted with boiling benzene several times. The benzene = extracts=20 were concentrated, combined with 20 ml of 40% aqueous methylamine and 20 = ml of=20 methanol and allowed to evaporate in an open flask on a steam bath to = dryness.=20 The resulting mixture was triturated with ether to remove the = N-methylbenzamide=20 and then recrystallized from 100% ethanol to yield=20 2-amino-9-(2-hydroxyethoxymethyl)purine as analytically pure white = granules,=20 m.p.=3D186.degree.-187.5.degree. C.

EXAMPLE 2

Enzymatic = Synthesis=20 of Acyclovir

A solution (20 .mu.L) of a purified bovine milk = xanthine=20 oxidase containing 1.06 units (nmoles of xanthine oxidized per minute) = of=20 activity was added to 500 .mu.L of a solution 43.6 .mu.M with respect to = 6-deoxyacyclovir, 0.05M with respect to potassium phosphate and 0.13 mM = with=20 respect to ethylenediaminetetraacetic acid at pH 6.8 and 25.degree. C. = The=20 reaction mixture was equilibrated with atmospheric oxygen, and the = oxygen served=20 as the electron acceptor. UV monitoring indicated nearly complete = conversion to=20 acyclovir after 24 hours. The identity of acyclovir as the product of = the=20 reaction was confirmed by its NMR spectrum.

The following = Examples 3 to=20 7 illustrate pharmaceutical formulations according to the invention = where the=20 active compound is a compound of formula (I) or a physiologically = acceptable=20 salt thereof.

______________________________________ Tablet = Example 3=20 ______________________________________ Active compound 100 mg Lactose = 200 mg=20 Starch 50 mg Polyvinylpyrrolidone 5 mg Magnesium stearate 4 mg 359 mg=20 ______________________________________

Tablets were prepated = from the=20 foregoing ingredients by wet granulation followed by compression.=20

______________________________________ Injectable Solution = Example 4=20 ______________________________________ Active compound 0.775 g Sterile,=20 pyrogen-free, pH 7 phosphate buffer to 25 ml=20 ______________________________________=20

______________________________________ Ophthalmic Solution = Example 5=20 ______________________________________ Active compound 1.0 g Sodium = chloride,=20 analytical grade 0.9 g Thiomersal 0.001 g Purified water to 100 ml pH = adjusted=20 to 5.5-7.5 ______________________________________=20

______________________________________ Oil based Paste Example 6 = ______________________________________ China Clay (solid diluent) 20.0% = w/w=20 Mineral Oil* (liquid diluent) 60.0% w/w Active compound 20.0% w/w=20 ______________________________________

The components were mixed = to=20 provide a paste of uniform consistency.=20

______________________________________ Feed Supplement - Pellets = Example=20 7 ______________________________________ Active compound 1% Cereal Base = 99%=20 ______________________________________

The two ingredients were = mixed=20 then fed to any conventional feed stuff pelleting plant. =

Biological=20 Activity

The following experiments were carried out to determine = the=20 urinary excretion and plasma levels of acyclovir after oral dosing of = rats with=20 acyclovir, 6-deoxyacyclovir and the 6-amino analogue thereof i.e.=20 2,6-diamino-9-(2-hydroxyethoxymethyl)purine, hereinafter referred to as=20 aminoacyclovir. The latter compound is a prodrug of acyclovir (Good S. = S. and de=20 Miranda P., Fed. Proc. (1982), 41, 1733) which depends on adenosine = deaminase=20 for conversion to acyclovir in vivo.

Procedure

Long = Evans male=20 rats were dosed by intragastric needle with the drug and placed in = metabolic=20 cages which separated urine from feces. The collected urine and plasma = samples=20 were analyzed for acyclovir content by a radioimmunoassay (Quinn, R. P., = et al.,=20 Anal. Biochem., 98, 319 (1979)). It was demonstrated that neither = aminoacyclovir=20 nor 6-deoxyacyclovir cross reacted with the antisera used in the assay.=20

Results

The results are given below in Tables I and II=20

TABLE I ______________________________________ The urinary = excretion of=20 acyclovir after oral dosing of rats with acyclovir, aminoacyclovir and=20 6-deoxyacyclovir % Dose Excreted as Acyclovir Dose Urine Acyclo- (No. of = Animals) mg/kg Samples vir Aminoacyclovir 6-Deoxyacyclovir=20 ______________________________________ 5 0-24 hr -- 24.7 (2) 67.0 (1) = 24-48 hr=20 -- 0.4 (2) 0.2 (1) 20 0-24 hr -- 24.8 (2) 69.1 (1) 24-48 hr -- 0.3 (2) = 0.3 (1)=20 25 0-48 hr 19.2 (4) -- -- ______________________________________ =

TABLE=20 II ______________________________________ A comparison of the plasma = levels of=20 acyclovir achieved after oral dosing of rats with deoxyacyclovir and = with=20 aminoacyclovir .mu.M Acyclovir Concentrations in Plasma Hr after a=20 Aminoacyclovir 6-Deoxyacyclovir 20 mg/kg dose Rat 1 Rat 2 Rat 3=20 ______________________________________ 0.5 2.75 30 1 3.03 16.6 18.6 2 = 2.48 4.96=20 17.5 4 0.93 1.00 6.7 6 0.34 0.41 4.06 20 <0.1 <0.1 0.25=20 ______________________________________

Toxicity Study =

Two male=20 and 2 female Beagle dogs were given 6-deoxyacyclovir per os (once daily = for 5=20 consecutive days) at a dose level of 40 mg/kg/day. There were no effects = in 1=20 male and 1 female sacrificed at the end of the treatment period or in 1 = male and=20 1 female sacrificed after a 2 week post-dose period.

* * * * *

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Current U.S. = Class:	435/119 ; = 514/263.38;=20 514/934
Current International = Class:=20	C07D = 473/00 (20060101); C12P=20 017/18 (); A01N 043/90 (); A61K 031/52 ()
Field of Search: =	435/119,88 =