ALLOPURINOL PRODRUGS

Abstract: Compounds of the general formulas (Ia and Ib), wherein R1 is a group of the formula (II): R3 - CO - A - wherein R3 is alkyl; mono- or polyhalogenated lower alkyl; phenyl; or substituted phenyl or R3 is an aromatic 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and A is a single bond or a group of the formula (IIa): - O - CR6R7 - wherein the carbon atom is attached to the nitrogen atom of the parent ring system, and wherein R6 and R7 are the same or different and each represent hydrogen or have the same meaning as R3 or R1 is a group of the formula (III): R8R9N - Y - CO - A - wherein R8 and R9 are ther same or different and each represent hydrogen or have the same meaning as R3; or R8 and R9 together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Y is a single bond or a group of the formula (IIIa): (- CR6R7 -)n wherein n is an integer from 1 to 5 and A, R6 and R7 are as defined above; or R1 is a group of the formula (IV): R'3 - O - CO - A - wherein A is as defined above and R'3 has the same meaning as R3 defined above, with the proviso that R'3 is not ethyl when A is a bond; or R1 is a group of the formula (VII): R13 - CO - (CH2)n - CO - A - wherein n and A are as defined above, and R13 is hydroxy or a group of the formula -NR8R9 are as defined above; or R1 is a group of the formula (IX): (HO)2PO2 - CR6R7 - wherein R6 and R7 are as defined above; R2 is any of the groups II, III, IV and VII as defined above with the proviso that A solely is the group (IIa) as defined above; and R5 is hydrogen or has the same meaning as R2 as defined above, and salts thereof. The compounds of the formula (Ia and Ib) are prodrugs of allopurinol and have i.a. a much higher solubility in water and/or a higher lipophilicity than allopurinol.

Description: ALLOPURI NOL PRODRUGS BACKG ROUND OF THE I NVENTION Field of the Invention The present invention relates to novel transient prodrug forms of al¬ lopu rinol useful in the prevention and treatment of hyperurice ia, to methods for preparing the prodrug forms, to pharmaceutical composi¬ tions containing such prodrug forms, and to methods for using the prodrug forms. As employed in this application , the term "prodrug" denotes a deriva¬ tive of allopurinol which derivative, when administered to warm-bloo¬ ded animals, e. g . humans, is converted into the proven drug, i . e. allopu rinol . The term "transient" indicates that the conversion of the prodrug forms proceeds in such a manner that the proven drug form (parent allopurinol) is released, and the remaining moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced. These novel prodrug forms of allopurinol are certain derivatives of allopurinol which possess a desirable high Iipophilicity and/or im¬ proved aqueous solubility in comparison to the parent compound, al¬ lopurinol . Description of the Prior Art Allopurinol is a widely used agent for the treatment and prevention of hyperuricemic states such as gout. Allopu rinol and its main metabolite oxipurinol lower the level of uric acid in plasma and u rine by inhibit¬ ing xanthine oxidase, the enzyme catalyzing the oxidation of hypoxan- thine to xanthine and xanthine to u ric acid (cf . e. g . Spector, 1977; OMPI Elion, 1978) . I n addition to its use as prophylaxis against and treat¬ ment of gout and other chronic hyperuricemic states allopurinol is commonly used to prevent the development of hyperuricosuria that often results from the rapid lysis of cells in patients with malignan- cies who are undergoing treatment with cytqtoxic drugs or radiation (cf. e. g. Elion, 1978) . Allopurinol is conventionally administered orally in the form of tablets. However, the development of nausea and vomiting among patients undergoing cancer chemotherapy frequently precludes the use of oral preparations in these patients. Consequently, a pharmaceutical and medical need exists for allopurinol preparations useful for the control of hyperurecemia in patients with neoplastic disease as well as in other individuals who are unable to take or retain oral medications . Alternative means of administering allopurinol may be provided by the use of injectable and rectal preparations . However, since allopurinol is only slightly soluble in water (about 0.5 mg/ml at 25°C) acceptable injection preparations such as for intramus¬ cular injection, are not available. Presently, it is only possible to deliver sufficient amounts of allopurinol parenterally by infusion . The infusion fluids used contain the sodium salt of allopurinol at a con¬ centration of 0.5-1% and are strongly alkaline (pH about 10.5-11 .5) ; consequently, their administration may cause th rombophlebitis or perivascular inflammation . With respect to the rectal route of administering allopurinol recent studies Rave demonstrated that this approach using allopurinol per se is not a suitable and reliable mode of therapy (Chang et al . , 1981 ; Appelbaum et al . , 1980, 1982) . It was shown in these studies that virtually no allopurinol or only very minute amounts (<5%) is absorbed from various suppository preparations administered rectaily to man . This very poor ability of allopurinol to be absorbed rectaily can be attributed to the low Iipophilicity of the drug combined with its poor water solubility. Although oral administration of allopu rinol provides the attainment of effective serum concentrations the absorption of the compound is not complete. Thus, it has been reported that the absolute systemic bio¬ availability of oral allopurinol tablets in man are about 70% (Appelbaum et al . , 1982) while another study (Elion et al . , 1966) reported that about 20-25% of an oral dose is excreted in the stool unchanged . The incomplete and variable absorption behaviour of allopurinol can , like noted above for the rectal absorption, be attributed to the low water and lipid solubility of the drug. Thus, it is quite obvious that a serious need exists for improved forms of allopurinol, which would be devoid of those disadvantages and drawbacks that to date have characterized the parent drug, allopurinol . From the foregoing, it also appears that successful allo¬ purinol prodrugs for the preparation of pharmaceutically acceptable injection preparations should exhibit a high water-solubility at a physiologically acceptable pH . Fu rthermore, to provide an efficient, reliable and rapid absorption upon rectal administration it also appears that successful allopurinol prodrugs should possess both a desirable high water-solubility and Iipophilicity. I n addition to these properties, successful prodrug derivatives should be capable of reverting to the active allopurinol when absorbed into the bloodstream of a warm-blooded animal or when reaching the site of therapeutic activity of the parent drug . The only previously described prodrug types for allopu rinol are some ether derivatives (Hussain & Rytting, 1974) , N-Mannich bases (Bund- gaard & Johansen, 1981 ) and N-hydroxymethyl derivatives ( Bansal et al . , 1981 ) . These compounds differ considerably from the compounds of the present invention . They are extremely unstable in aqueous solutions, are relatively insoluble in water and lipid and apparently offer no advantage over allopurinol with respect to bioavailability following rectal or parenterai administration . OMPI SUMMARY OF THE INVENTION One object of the present invention is to provide novel prodrug forms of allopurinol, useful for the prevention and treatment of hyper¬ uricemic states such as gout. Another object of this invention is to provide novel prodrug forms of allopurinol which prodrugs, or transient derivatives, owing to their improved lipid and/or water solubility, exhibit superior bioavailability over allopurinol per se, when administered rectaily or orally. A further object of the present invention is to provide novel transient prodrug forms of allopurinol which are characterized as being highly soluble in water and hence are extremely useful as parenteral delivery forms of allopurinol. All foregoing objects are obtained with selected transient prodrug forms of allopurinol. The ring structure named "allopurinol" exists in different tautomeric forms: 1 ,5-dihydro-4H-pyrazolo- 2,5-dihydro-4H-pyrazolo- [3,4-d]pyrimidin-4-one [3,4-d]pyrimidin-4-one Two of the tautomeric forms are drawn above and their systematic names are given, but in the present context, the term "allopurinol" encompasses all tautomeric forms of the ring system. The invention relates to compounds of the formulas la or l b wherein R. is a group of the formula I I R 3 - β C - A - I I wherein R 3 is alkyl ; phenyl; phenyl substituted with halogen , lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; phenyl-lower alkyl in which the phenyl group may be substituted . with halogen , lower alkyl, hydroxy, lower alkoxy, acetoxy or phenoxy; or phenyl- lower alkenyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; or R~ is an aromatic 5- og 6-membered heterocyclic ring containing one or, two heteroatoms selected from the group consisting of nitro¬ gen, oxygen, and sulfur; and A is a single bond or a group of the formula I la O - C I R- wherein the carbon atom is attached to the nitrogen atom of the parent ring system, and wherein Rg and Ry are the same or different and each represent hydrogen or have the same meaning as R- as defined above; or R-J is a group of the formula I I I wherein g and Rg are the same or different and each represent hydrogen or have the same meaning as R- as defined above; or R« and Rg together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Y is a single bond or a group of the formula I l ia wherein n is an integer from 1 to 5; and A, R g , and R-, are as defined above; or R- is a group of the formula IV „ A - IV wherein A is as defined above and R-,' has the same meaning as R- defined above, with the proviso that R« is not ethyl when A is a bond; or R- is a group of the formula VI ϊ k 10 - C - A VI wherein R, 0 is a mono- or polyhalogenated lower alkyl group and A is as defined above; ' " - " 7 - £ T / " " or R, is a group of the formula VII _ R-, - C - (CH- - C - A - VII wherein n and A are as defined above, and R,£ is hydroxy or a group of the formula -NRgRg wherein Rg and R g are as defined above; or R. is a group of the formula IX O R fi - ' II 16 HO - P - O -C - IX OH R ? wherein R fi and R-, are as defined above; R- is any of the groups II, III, IV, VI, and VII as defined above with the proviso that A solely is the group Ila as defined above; and R e is hydrogen or has the same meaning as R« as defined above, and salts thereof. In the present context, the term "alkyl" designates C, 8 alkyl which may be straight or branched, such as methyl, ethyl, propyl, isopropyi, butyl, tert. butyl, pentyl, hexyl, heptyl, or octyl. Among the alkyl groups, lower alkyl groups are preferred. The term "lower alkyl" designates C._ 4 alkyl which may be straight or branched, such as methyl, ethyl, propyl, isopropyi, butyl, or tert. butyl. The term "phenyl-lower alkyl" designates " a lower alkyl group " (as herein de¬ fined) which, in turn, is substituted with a phenyl group. Preferred phenyl-lower alkyl are benzyl, 1- and 2-phenylethyl, 1-, 2-, and 3-ρhenylpropyl, and 1-methyl-1-phenylethyl The term "lower alkoxy" designates oxy to which a lower alkyl group is attached as defined above; preferred alkoxy groups are methoxy and ethoxy. The term "halogen" designates F, Cl, Br, or I; Cl is preferred. The term "phenyl-lower alkenyl" designates a C-,_ 5 -monounsatu rated aliphatic hydrocarbon group which may be straight or branched, such as propenyl, butenyl or pentenyl, and which in turn is substituted with a phenyl group. Preferred phenyl-lower alkenyl groups are phenyl- substituted propen(2) -yl optionally substituted with methyl or ethyl, such as 3-phenylpropen (2) -yl (both E and Z forms) , 2-methyl-3- phenylpropen (2) -yl (both E and Z forms) , and 3-phenyIbuten (2) -yl (both E and Z forms) . Where phenyl groups are substituted with e.g . halogen, lower alkyl, hydroxy, lower alkoxy; acetoxy or phenoxy, they may be mono-, dι-, or tri-substituted, and when they are di-, or tri-substituted, the substituents may be the same or different. The term "polyhalogenated lower alkyl" designates lower alkyl (as defined above) substituted with two or more halogen atoms, which may be the same or different. A preferred example of polyhalogenated lower alkyl is trichlormethyl . When, in the formula I I , « is an aro- matic 5- or 6-membered heterocyclic ring containing 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen, and sulphur, this may, for instance, be 2-, 3-, or 4-ρyridinyl, 2-, or 3-thienyl, 2-, 4-, or 5-thiazolyl, 2-, 4-, or 5-oxazolyl, 2-imidazolyl, 5-isoxazolyl, 5-isothiazoIyl, 2-furanyl, 2-, or 5-pyrimidinyl, 5-[1 ,3] - oxazinyl, or 5- [1 ,3] -thiazinyI . When, in the formula I I I , Rg and R« together with the adjacent nitrogen atom form a 5- or 6-membered heterocyclic ring which in addition to the nitrogen may contain 1 or 2 further hetero atoms selected from the group consisting of nitrogen, oxygen, and sulphur, it may, for instance, be 1 -ρiperidinyl, 1 -imida- zolyl, 1 -pyrazolyl, morpholinyl, 1 -piρerazinyl, and thiomorpholinyl . The salts of the compounds of the formulas la or lb include any pharmaceutically acceptable acid addition salt. This term as used herein generally includes the non-toxic acid addition salts of compounds of the formulas la or lb, formed with non-toxic inorganic or organic acids . For example, the salts include salts with inorganic acids, such as hydrochloric, hydrobromfc, sulphuric, sulphamic, nitric, phosphoric and the like; and the salts with organic acids such as acetic, propioπic, succinic, fumaric, maleic, tartaric, citric, glycolic, stearic, lactic, malic, pamoic, ascorbic, phenylacetic, glutamic, benzoic, salicylic, sulphonic, sulphanilic, and the like. When one or more asymmetric carbon atoms are present in the side chain ' s, it is understood that the present invention also encompasses all diastereomers or enantiomers, or mixtures thereof. Examples of isomers are D-, L-, and DL-forms . The compound of formula la wherein R- is ethyloxycarbonyl ( R, is a group of formula IV wherein A is a bond and R 3 ' is ethyl) and Re is hydrogen is described in the literatu re (Bergmann et al, 1979) . However, this reference merely teaches a method for preparing this compound and does not disclose or indicate any utility of the compound, nor any properties of the compound that might indicate its utility as a prodrug. I n another aspect the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of the formulas i 'a or lb wherein R, is a group of the formula I I „ R 3 - C - A - I I wherein R^ is alkyl ; phenyl; phenyl substituted with halogen , lower alkyl , hydroxy, lower al koxy, acetoxy, or phenoxy; phenyl-lower alkyl in which the phenyl group may be substituted with halogen, lower al kyl, hydroxy, lower al koxy, acetoxy or phenoxy; or phenyl- lower al kenyl in which the phenyl group may be substituted with halogen, lower al kyl, hydroxy, lower al koxy, acetoxy, or phenoxy; or R- is an aromatic 5- og 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitro¬ gen, oxygen , and sulfur; and A is a single bond or a group of the formula I la O - C ft - wherein the carbon atom is attached to the nitrogen atom of the parent ring system, and wherein R fi and R-, are the same or different and each represent hydrogen or have the same meaning as R- as defined above; or 1 is a group of the formula 111 wherein Rg and Rg are the same or different and each represent hydrogen or have the same meaning as R-, as defined above; or R„ and Rg together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Y is a single bond or a group of the formula I l ia wherein n is an integer from 1 to 5; and A, R g , and R-, are as defined above; or R, is a group of the formula IV O II R-, - O - C - A - IV wherein R« and A are as defined above; or R. is a group of the formula VI O II R 10 - C - A - VI wherein R. -. is a mono- or polyhalogenated lower al kyl group and A is as defined above; or R 1 is a group of the formula VI I O O II II R.-, - C - (CH- - C - A - VI I lό .. n wherein n and A are as defined above, and R- 3 is hydroxy or a group of the formula -N RgRg wherein R g and R g are as defined above; or R- is a group of the formula IX 0 R fi II I 6 HO - P - O - C - IX 1 I * OH R-. wherein R fi and R-, are as defined above; R~ is any of the groups I I , I I I , IV, VI , and VI I as defined above with the proviso that A solely is the group I la as defined above; and Re is hydrogen or has the same meaning as R- as defined above, and salts thereof. I n another aspect the present invention also concerns a method for preparing the above mentioned compositions comprising combin ing a pharmaceutically acceptable carrier or excipient with a compound of the formulas I 'a or lb . OMPI 12 I n a further aspect the invention also concerns a method for preparing compounds of the formulas I'a or lb. In yet another aspect the invention concerns a method for treating and preventing hyperuricemic states comprising administering an amount effective in lowering the level of uric acid, of a compound of the present invention optionally in a pharmaceutical composition as described above, to warm-blooded animals including humans . DETAI LED DESCRI PTION OF THE INVENTION As examples of compounds of formula la or I 'a may be mentioned compounds in which R_. is as defined above, and R, is one of the following groups ("groups ?") : Acetyl Propionyl Butyryl Isobutyryl Valeryl Benzoyl 4-Methylbenzoyl 2,4-Dimethylbenzoyl 4-Chlorobenzoyl 4-Methoxybenzoyl 3,4-Dimethoxybenzoyl 4- Hydroxy benzoyl 2- Hyd roxy benzoyl 4-Acetoxybenzoyl 2-Acetoxy benzoyl 4- Phenoxy benzoyl Phenylacetyl 4-Chlorophenylacetyl 3-Phenylpropioπyl _________ Nicotinoyl Isonicotinoyl Picolyl 2-Thienoyl Cinnamoyl 4-Methylcinnamoyl 4-Chlorocinnamoyl Glycyl N,N-Dimethylglycyl N,N-Diethylglycyl N,N-DipropylglycyI N-Methylglycyl N-Ethylglycyl N-Propylglycyl Alanyl N,N-Dimethyla!anyl N,N-Diethylalanyl Leucyl Norleucyl Norvalyl Valyl Phenylalanyi 3-(N,N-DimethyIamino)propionyl 4-(N,N-Dimethylamino)butyryl 4-(N,N-Diethylamino)butyryl 5-(N,N-Dimethylamino)vaieryI N,N-Dimethylphenylalanyl Methoxycarbonyl Ethoxycarbony.l Butoxycarbonyl Hexyloxycarbonyi Phenoxycarbonyl 4-Chlorophenoxycarbonyl 4-Methoxy phenoxycarbonyl Benzyloxycarbonyl Carbamoyl N-Methylcarbamoyl _N-Ethylcarbamoyl N-Butylcarbamoyl N-PhenylcarbamoyI N, N-Dimethyicarbamoyi Chloroacetyl B romoacety I Trichloroacetyl Trifluoroacetyl 2-ChIoropropϊonyl 2-Bromoprσpionyl Succiήyl Formyloxy methyl Acetyloxymethyl Propionyloxymethyl Butyryloxymethyl I sobuty ryloxymethyl Pivaloyloxymethyl Valeryloxymethyl Benzoyloxymethyl 4-ChIorobenzoyloxymethyl 4-MethylbenzoyIoxymethyl 2,4-DimethyIbenzoyloxymethyI 4-MethoxybenzoyIoxymethyl 3,4-Dimethoxybenzoyloxymethyl 4-HydroxybenzoyIoxymethyi 2-Hydroxybenzoyloxymethyl 4-Acetoxybenzoyloxymethyl 2-Acetoxybenzoyloxymethyi 4-Phenoxybenzoyloxymethyl Phenylacetyloxymethyl 3-PhenyIpropionyloxymethyl Nicotinoyloxy methyl Isonicotinoyloxymethyl Picolyloxymethyl 1 - ( Acetyloxy) ethyl OMPI 1 - (Acetyloxy) propyl 1 - ( Butyryloxy) ethyl 1 - (Butyryloxy) p ropyl (Acetyloxy) (phenyl)methyl Glycyloxymethyl N, N-Dimethylglycyloxymethyl l-(N, N-Dimethylg(ycyloxy)ethyl N, N-Diethylglycyloxymethyl 1 - (N, N-Diethylglycyloxy)ethyl N, N-Dipropy!glycy!oxymethyl 1 -(N, N-DipropylglycyIoxy)ethyl N-Methylglycyloxymethyl N-Ethylglycyloxymethyl N-Propylglycyloxymethyl Alanyloxymethyl N, N-DimethylalanyIoxymethyl 1 -(N, N-Dimethylalanyloxy) ethyl N, N-Diethylalanyloxymethyl 1 -(N, N-Diethylalanyloxy) ethyl Leucyloxymethyl N,N-Dimethyl!eucyloxymethy! Norleucyloxymethyl Valyloxymethyl Norvalyloxymethyl Phenylglycyloxymethyl Phenylalanyloxymethyl N, N-Dimethylphenylalanyloxymethyl N, N-Diethylphenylalanyloxymethyi Methoxycarbonyloxymethyl Ethoxycarbonyloxymethyl Phenoxycarbonyloxymethyl Benzyloxycarbonyloxymethyl Trifluoroacetyloxymethyl Chloroacetyioxymethyl Succinyloxymethyl 3-(N, N-Diethylcarbamoyl)propionyloxymethyl Phosphonooxymethyl and salts thereof. Of the compounds in which R 5 is different from hydrogen , preferred compounds of the formulas la or I 'a are compounds in which R., and R e are the same, since such compounds are generally easier to prepare. Among these compounds (i. e. R, and R e are the same) more pre¬ ferred compounds are compounds wherein R, and Re are groups of the formulas I I or 1 11 as defined above, wherein A is a group of formula I la, and Y is a group of formula I l ia; and salts thereof. Examples of such compounds are compounds in which R, and Re are one of the following groups ("groups ") : Formyloxymethyl Acetyloxymethyl Propionyloxymethyl Butyryloxymethyl I sobutyry loxymethyl Pivaloyloxymethyl Valeryloxymethyl Benzoy loxymethyl 4-Chlorobenzoyloxymethyl 2, 4-Dimethylbenzoy loxymethyl 4-Methoxybenzoyfoxymethyl 3, 4- Dimethoxy benzoy loxymethyl 4- Hyd roxybenzoy loxymethyl 2-HydroxybenzoyIoxymethyl 4-Acetoxybenzoy loxymethyl 2-AcetyloxybenzoyloxymethyI 4-Phenoxybenzoyioxymethyl Phenylacetyloxymethyl 3-PhenylpropioπyIoxymethyl Nicotinoy loxymethyl 1 son icotinoy loxymethyl Picoiyloxymethyl 1 - (Acetyloxy) ethyl 1 - (Acetyloxy) propyl 1 -( Butyryloxy ) ethyl 1-(Butyryloxy)propyl (Acetyloxy) (phenyl)methyl Glycyloxymethyl 1-(N,N-DimethyIglycyloxy)ethyl N, N-Diethylglycyloxymethyl 1-(N,N-Diethylglycyloxy)ethyl N, N-Dipropylglycyloxymethyl 1-(N,N-Dipropylglycyloxy)ethyl N-Methylglycyloxymethyl N-Ethylglycy loxymethyl N-Propylglycy loxymethyl Alanyloxymethyl N,N-Dimethylalany loxymethyl 1-(N,N-Dimethylalanyloxy)ethyl N,N-Diethylalany loxymethyl 1 - (N , N -Diethylalanyloxy) ethyl Leucy loxymethyl N, N-Dimethylleucyloxymethyl Norleucyloxymethyl Valyloxymethyl Norvaly loxymethyl Phenylglycy loxymethyl Phenyialany loxymethyl N, N-Dimethylphenylalanyloxymethyl N,N-Diethylphenylalany loxymethyl and salts hereof. Other more preferred compounds of the formulas la or I'a are com¬ pounds wherein Re is hydrogen and R * is a group of the formulas II, III, IV, VI, VII or IX; and salts thereof. Examples of such compounds are compounds wherein Re is hydrogen and R- is a group selected from the groups a specified above. OMPI Among these compounds (i . e. R 5 is hydrogen) still more preferred compounds are compounds wherein R, is a group of the formulas I I , I I I wherein Y is a group of formula I l ia, or VII . Examples of such compounds are compounds wherein R 5 is hydrogen and R» is one of the following groups ("groups c") : Acetyl Propionyi Butyryl Isobutyryl Valeryl Benzoyl 4-Methylbenzoyl 2,4-DimethyIbeπzoyl 4-Chlorobenzoyl 4-Methoxybenzoyi 3,4-Dϊmethoxybenzoyl 4-Hydroxybenzoyl 2-Hydroxybenzoyl 4-Acetoxybenzoyl 2-Acetoxybenzoyl 4- Phenoxybeπzoyl Phenylacetyf 4-ChIoroρheny [acetyl 3-Phenylρropionyl Nicotinoyl Isonicotinoyl Picoly! 2-Thienoyl _ Cinnamoyl 4-Methylcinnamoyl 4-Chlorocinnamoyl Glycyi N,N-Dimethylglycyl N , N-Diethylgiycyl N, N-Dipropylglycyl N-Methylglycyl N-Ethylglycyl N- Propylglycyl Alanyl N, N-Dimethylalanyl N, N-Diethylalanyl Leucyl Norleucyi Norvalyl Valyl Phenylalanyl 3- (N, N-Dimethylamino)propionyl 4- ( N , N-Dimethylamino) buty ryl 4- (N, N-DiethyIamino) butyryl 5- (N , N-Dimethylamino) valeryl N , N-Dimethylphenylalanyl Succinyl Formy loxymethyl Acetyloxymethyl Propiony loxymethyl Butyry loxymethyl I sobutyry loxymethyl Pi valoy loxymethyl Valeryloxymethyl Benzoy loxymethyl 4-Chlorobenzoy loxymethyl 4-Methylbenzoy loxymethyl 2, 4-Dimethylbenzoy loxymethyl 4-Methoxybenzoyloxymethyl 3, 4- Dimethoxybenzoy loxymethyl 4-Hydroxybenzoy loxymethyl 2- Hydroxybeπzoy loxymethyl 4- Acetoxy benzoy loxymethyl 2-AcetoxybenzoyloxymethyI 4- Phenoxy benzoy loxymethyl Phenylacety loxymethyl 3-PhenylρropionyIoxymethyl Nicotinoyloxymethyl 1 son icotinoy loxymethyl Picolyloxymethyl 1 - (Acetyloxy) ethyl 1 - (Acetyloxy) p ropy I 1 -(Butyryloxy)ethyl 1 - ( B uty ry loxy) p ropy I (Acetyloxy) (phenyl)methyl Glycyloxymethyl N,N-DimethylgIycyloxymethyl 1 -(N,N-Dimethylglycy loxy) ethyl N , N-Diethylglycyloxymethyl 1 -(N, N-Diethylglycyloxy) ethyl - N, N-Dipropylgiycyloxymethy! l -(N,N-Dipropylglycy loxy) ethyl N-Methylgiycyloxyrfrethyl N-Ethylglycy loxymethyl N-Propy glycy loxymethyl Alany loxymethyl N , N-Dimethylalanyloxymethy I l -(N, N-DimethyiaIanyIoxy)ethyl N, N-DiethylalanyIoxymethyl l -(N, N-DiethyiaIaπyIoxy)ethyl Leucy loxymethyl N,N-DimethyIleucyloxymethyl Norieucyloxymethyl Vaiyloxymethyl Norvalyloxymethyl Phenyigiycyloxymethyl Phenylalanyioxymethyl N , N-Dimethylphenylalanyloxymethyl N , N-Diethylphenylalanyloxymethyl Succinyloxymethyi 3-N, N-Diethy lea rbamoyi)propiony loxymethyl and salts thereof. Still more preferred compounds of the formula la are compounds wherein Re is hydrogen and R, is a group of the formulas II, III wherein Y is a group of formula Ilia, .or VII, wherein A in all the formulas mentioned is a group of formula Ila. Examples of such compounds are compounds wherein Re is hydrogen and R- is one of the groups b specified above. Even more preferred compounds of the formula la are compounds wherein R-. is hydrogen and R, is a group of the formula III wherein A is a group of formula Ila and Y is a group of formula Ilia. Examples of such compounds are compounds wherein Re is hydrogen and R. is one of the following groups ("groups c") : Glycyloxymethyl N, N-Dimethylglycyloxymethyl 1-(N,N-Dimethylglycy loxy) ethyl N,N-Diethylglycyloxymethyi 1-(N,N-Diethylglycy loxy) ethyl N,N-Dipropylglycyloxymethyl l-(N,N-Dipropylglycyloxy) ethyl N-Methylglycy loxymethyl N-Ethylglycyloxymethyl N-Propylglycy loxymethyl Alanyloxymethyl N, N-Dimethylalany!oxymethyl 1-(N,N-Dimethylalany loxy) ethyl N,N-Diethyla!anyioxymethyl 1-(N,N-DiethylaIanyloxy)ethyl Leucy loxymethyl N, N-Dimethylleucyloxymethyl Norleucy loxymethyl Valyloxymethyl Norvaly loxymethyl Phenylglycy loxymethyl Phenyialany loxymethyl N,N-Dimethylρhenylalanyloxymethyl N, N-DiethyIphenylalanyloxymethyl and salts thereof. Particularly preferred compounds of the formula la are compounds in which R_. is hydrogen and R, is N,N-dimethylglycyloxymethyi, N, N- diethylglycyloxymethyl, N , N-diproρylglycy loxymethyl, N,N-dimethyl- alanyloxymethyl, N, N-diethylaIanyloxymethyl, phenylalanyloxymethyl, phenyiglycyloxymethyl, or leucyloxymethyl; and salts thereof. Among the compounds of the formula lb preferred compounds are compounds in which R~ and R_. are the same. Examples of such com¬ pounds .are compounds, in which R- and R,- are groups selected from the groups b specified above. Even more 'preferred compounds of the formula l b are compounds in which R~ and R-. are the same and R~ and Re are groups of the " formula I I I as defined above wherein A is a group of formula I la and Y is a group of formula I l ia . Examples of such compounds are compounds wherein e and R~ are the same and are selected from the groups d specified ^ above; and salts thereof. Other very preferred compounds of the formula lb are compounds wherein Re is hydrogen and R- is a group of the formula I I wherein A is a group of formula I la . Examples of such compounds are compounds wherein R_. is hydrogen and R« is one of the following groups ("groups e") : Formyloxymethyl Acetyioxymethyl Propionyloxymethyl C PT Butyry loxymethyl I sobutyry loxymethyl Pi valoy loxymethyl Valery loxymethyl Benzoyloxymethyl 4-Chlorobenzoy loxymethyl 4-Methylbenzoy loxymethyl 2, 4- Dimethylbenzoy loxymethyl 4-Methoxybenzoy loxymethyl 3, 4-Dimethoxybenzoy loxymethyl 4-Hydroxybenzoy loxymethyl 4- Acetoxy benzoy loxymethyl 4- Phenoxy benzoy loxymethyl Phenylacety loxymethyl 3-Phenylpropionyloxymethyl Nicotinoy loxymethyl I son icotinoy loxymethyl Picoly loxymethyl 1-(Acetyloxy)ethyl 1-(Acetyloxy)propyl 1-(Butyryloxy)ethyl 1- (Butyryloxy) propyl (Acetyloxy) (ρhenyl)methyl and salts thereof. Specific examples of preferred compounds of formula la are: 1 - (Acetyloxymethyl)allopurinol 1-(PropionyIoxymethyl)allopurinol - - 1 -(Butyry loxymethyl) allopurinol 1-(Glycy loxymethyl) allopurinol 1-(DL-AIany loxymethyl) allopurinol 1-(L-Alanyioxymethyl)a!!opurinol 1-(N,N-Dimethylglycyloxymethyl)alIopurinol 1-(N,N-Diethylglycy loxymethyl ) allopurinol f OMPI 1-(N, N -Dip ropy Iglycy loxymethyl) allopurinol 1-(DL-N, N-Dimethylalany loxymethyl) allopurinol 1-(L-N, N-Dimethylalany loxymethyl) allopurinol 1 -(DL-N, N-Diethylalanyloxymethyl)allopurinol l-(L-N, N-DiethylaIanyloxymethyl)allopurinol 1-(DL-Phenylalaπy loxymethyl) allopurinol 1-(L-Phenylalanyloxymethyl)allopurinol l-(DL-Phenylglycyloxymethyl) allopurinol l -(L-Phenylglycyloxymethyl) allopurinol l-(DL-Leucyloxymethy I) allopurinol l-(L-Leucyloxymethyl) allopurinol l-(DL-Norleucy loxymethyl) allopurinol l-(L-Norleucyloxymethyl) allopurinol l-(DL-Norvalyloxymethyl) allopurinol 1-(L-Norvalyloxymethyl)allopurinol l-(DL-Valyloxymethyl)aIloρurinol l -(L-VaIyloxymethyl)allopurinol 1-(DL-N, N-Dimethylρhenylalany loxymethyl) allopurinol 1-(DL-N, N-Diethylphenylalanyloxymethy I) allopurinol and salts thereof. Specific examples of preferred compounds of formula lb are: 2- (Acety loxymethyl) allopurinol 2- (Propiony loxymethyl) allopurinol 2- (Butyryloxymethy!) allopurinol 2-(Benzoyloxymethyi)aIloρurinoi 2, 5-bis(Acetyloxymethyl) allopurinol 2, 5-bis(Propionyloxymethyl) allopurinol 2, 5-bis(Butyryloxymethyl) allopurinol 2, 5-bis( Benzoy loxymethyl) allopurinol 2,5-bis(N, N-Dimethylglycyloxymethyl)allopurinol 2, 5-bis(N,N-Diethy iglycy loxymethyl) allopurinol 2, 5-bis(N, N- Dip ropylglycy loxymethyl allopurinol 2, 5-bis(DL-N, N-DimethyIalany loxymethyl) allopurinol g J E OMPI 2, 5-bis(DL-N,N-Diethylalany loxymethyl) allopurinol 2,5-bis(DL-Phenylalanyloxymethyl)alloρurinol 2, 5-bis(L-Phenylalany loxymethyl allopurinol 2, 5-bis(L-Leucy loxymethyl) allopurinol and salts thereof. Specific examples of especially preferred compounds are: 1- (Butyry loxymethyl) allopurinol, 1-(N,N-dimethy Iglycy loxymethyl) allopurinol, 1-(N,N-diethylglycyloxymethyl)allopurinol, 1-(N,N-diproρylglycyloxymethyl)allopurinol, l-(DL-N,N-dimethylalanyloxymethyl) allopurinol, 1-(DL-N,N-diethylaiany loxymethyl) allopurinol, 1-(L-phenylalanyloxymethyl)alIopurinol, 1-(L-leucy loxymethyl) allopurinol, 1-(L-valyloxymethyl)allopurinol, and l-(DL-N,N-dimethylphenylalany loxymethyl) allopurinol, and salts thereof. Dose and dosage forms The compounds of the present invention are conveniently administered to warm-blooded animals, e.g. humans, via rectal, oral or parenteral dosage forms. The dose of the compounds of the present invention administered to warm-blooded animals, e.g. humans, (either as a single dose, a daily dose, " or other time-presented doses) will, of course, depend on the requirements of the individual under treat- ment. The dosage administered, is, therefore, not subject to specific limits. However, the dose of any compound of the formulas I'a or lb will usually be an amount, which - on a molar basis - is equivalent to the amount of allopurinol necessary to achieve the desired pharmaco¬ logical or physiological effect. Generally, the single medical dose for warm-blooded animals, which include humans and primates, will be in the range of approximately 25-1000 mg allopurinol equivalents. For humans the daily dose is generally in the range of 300-600 mg allo¬ purinol equivalents regardless of administration form. The daily dose may be administered in 1 -3 single doses . The compounds of the formulas I'a or lb may be administered in the for of tablets, capsules, suspensions, emulsions, solutions, inject- ables, suppositories, enemas, various drug delivery devices and in other suitable form. - The route of administration may be orally, paren- terally or rectaily. The formulation and preparation of any of this broad spectrum of dosage forms into which the subject prodrugs can be dispensed is well-known to those skilled in the art of pharmaceuti¬ cal formulation . Specific information can, however, be found in the text entitled "Remington's Pharmaceutical Sciences", Sixteenth Edition, 1980. I n a typical preparation for oral administration, e. g. tablet or cap- sule, any one of the compounds of the present invention in a pharma¬ cologically effective amount is combined with any oral nontoxic phar¬ maceutically acceptable inert carrier such as lactose, starch and microcrystalline cellulose. Additionally, when requi red, suitable bin¬ ders (e. g. gelatin) , lubricants (e. g. talc or magnesium stearate) and disintegrating agents (e.g. starch or various cellulose derivatives) are included. Similarly, in a typical formulation for parenteral application (intra¬ venous, intramuscular, subcutaneous or the like) , any of the highly water-soluble compounds of the present invention , such as 1 - (N, N- dimethylgiycyloxymethyDallopurinol hydrochloride is dissolved in sterile water in a given concentration and sterilized by e. g . membrane filtration, or radiation . The pH of the solution may, if necessary, be adjusted with e.g. hydrochloric acid, sodium hydroxide or a suitable buffer, and a suitable preservative may optionally be added . Similarly, agents like sodium chloride may be added in order to adjust the tonicity of the solution . A suitable parenteral preparation may also consist of the compound formulated as a sterile, solid substance distributed in injection vials . Before dispensing, water for injection is added to dissolve the compound. For the rectal application of the allopu rinol prodrugs of this inven¬ tion, typical dosage forms include suppositories (emulsion and sus¬ pension types) , rectal gelatin capsules (solutions and suspensions) , and enemas or micro-enemas (solutions and suspensions) . Thus, in a typical suppository formulation , any one of ^ the compounds of this invention is combined with any pharmaceutically acceptable supposi¬ tory base such as cocoa butter, esterified fatty acids (C, 0 -C,g) , glycerinated gelatin , and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters . Various additives li ke salicylates or surfactant materials may be incorporated . Enemas or micro-enemas of the solution type may simply be prepared by dissolving the water-soluble prodrugs of this invention in water or in water containing e. g . 0.5% of methylcellulose or another viscosity-increasing agent. The novel and useful allopu rinol prodrugs of the invention are also adaptable for administration to warm-blooded animals from various novel drug delivery systems such as gastrointestinal drug delivery devices and rectaily applied osmotic delivery devices, wherein the delivery device is manufactured from naturally occurring or synthetic ' polymeric materials . Specific information about osmotic delivery sys¬ tems for rectal application can be found in De Leede & De Boer (1981 ) and De Leede et al . (1982) . From the foregoing description , it is obvious that due to the much improved water-solubility of selected members of the claimed prodrugs over allopu rinol per se and derivatives of the prior art, superior parenteral formulation and administration is . achieved . Similarly, an exceptionally improved rectal bioavailability is achieved owing to the increased water-solubijity and/or Iipophilicity of the subject com¬ pounds . The compounds of the present invention may be prepared by various methods . One method (a) for preparing compounds of the formula I 'a wherein Re is hydrogen and A is a bond comprises reacting allopurinol with a compound of the formula XI O II R 12 - C - Z XI wherein R-~ has the same meaning as R- as defined above; R,2 is a group of the formula I I I ' wherein Y is as defined above, and Rg' and Rg' have the same meaning as Rg and R g as defined above; or Rg' or R g ' are an amino protecting group; R.- is a group of the formula IV' R 3 - O - IV wherein R, is as defined above; R,~ has the same meaning as R. Λ as defined above; or R-2 is a group of the formula VI I ' wherein - n is as defined above, and R, - is hydroxy or a group of the formula -NRgR- wherein Rg and Rg are as defined above; and Z is a leaving group; and then, if an amino protecting group has been used, removing the protecting group . Another method (b) for preparing compounds of the formula I 'a wherein R 5 is hydrogen or compounds of formula lb wherein R- and Re are the same, and wherein A is -CH-,-, comprises reacting 1 -hydroxymethyIallopurinol or 2, 5-dihydroxymethylallopu rinol with a compound of the formula XI as shown above and wherein R.» is as defined above; and then, if an amino protecting group has been used, removing the protecting group. A method (c) for preparing compounds of formulas I 'a or lb wherein either R= is hydrogen or R- and R,- are the same or R- and Re are the same, comprises reacting allopu rinol with a compound of the formula XI I O R c II 1 6 R, -, - C - O - C - Z XI I 12 I R 7 wherein R fi , R-,, R, « and Z are as defined above; and then , if an amino protecting group has been used, removing the protecting group. Other methods (d) and (e) for preparing compounds of the formula I 'a wherein R_. is different from hydrogen are contemplated . Method (d) comprises reacting a compound of the formula XI I I wherein R. is as defined above in connection with formula I 'a, with a compound of the formula XI I , wherein R g , R-,, R19 * a nc -' Z are as defined; and then , if an amino protecting group has been used, removing the protecting group. Method (e) comprises reacting a compound of the formula XIV wherein R. is as defined above in connection with formula I 'a with a compound of the formula XI as shown above, wherein R,- and Z are as defined above; and then, if an amino protecting group has been used, removing the protecting group. A method (f) for preparing compounds of the formula lb wherein R 5 is different from hydrogen is contemplated. Method (f) comprises reacting a compound of the formula XV wherein R^ is as defined above, with a compound of the formula XI I , wherein Rg, Ry, 1 2 and Z are as defined above; and then, if an amino protecting group has been used, removing the protecting group. Another method (g) for preparing compounds of the formula I 'a wherein R e is hydrogen or compounds of formula lb wherein R~ and R e are the same comprises reacting allopurinol, 1 -hydroxymethyl- allopurinol, or 2, 5-dihydroxymethylallopurinol with a compound of the formula V" R 3 - N = C = O V" wherein R 3 is as defined above. Still another method (h) for preparing compounds of the formula I 'a wherein R-. is hydrogen or compounds of formula lb wherein R~ and e are the same comprises reacting allopurinol, 1 -hydroxymethyl- allopurinol, or 2,5-dihydroxymethylalloρu rinol with a compound of the formula VI I" ( wherein n is as defined above. A method (i) for preparing compounds of the formula I 'a wherein R_. is hydrogen or compounds of formula lb wherein R- and R_. are the same comprises reacting a compound of the formula XVI wherein Rg and R q are as defined above, with a compound of formula XVI I ( OMPI or with a compound of formula XVI I or with a compound of formula XIX wherein n and Z are as defined above. A method (j) for preparing compounds of the formula I 'a wherein R- is O ■ II HO - P - O - CH 2 OH and R e is hydrogen is contemplated. Method (j) comprises 1) hydrogenation of the corresponding dibenzyj phosphate, or 2) hydrolysis of the corresponding 2-cyanoethyl phosphate, or 3) reacting l-hydroxymethylallopurinol with pyrophosphoryl tetra- chloride followed by hydrolysis. In the present context the name 1-hydroxymethylallopurinol designates the compound 1-(hydroxymethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyri- midin-4-one and tautomeric forms hereof, and the name 2,5-dihy- droxymethylallopurinol designates 2,5-[bis(hydroxymethyl)]-1 ,5-dihy- dro-4H-pyrazolo[3,4-d]pyrimidin-4-one and tautomeric forms hereof. The synthesis of both compounds have been described (Bansal et al (1981)). It is noted that in this reference, the compound which TrT the present context is designated 2,5-[bis(hydroxymethyl)]-1,5-dihydro- 4H-pyrazolo[3,4-d]pyrimidin-4-one in the cited reference is designated as the corresponding 1,5-[bis(hydroxymethyl)]-1 ,5-dihydro-4H-py- razolo[3,4-d]pyrimidin-4-one. However, according to analyses per¬ formed by the present applicants, the compound prepared according to the teaching of the reference is believed in fact to be the 2,5-com- pound, for which reason the compound has been designated as the 2,5-compound above. However, as it can still not be concluded with certainty that the compound is indeed the 2,5-compound, the above designation should be understood as covering alternatively the 1,5- compound provided the synthesis described in the reference is in fact conclusively found to result in the 1,5-compound. The assignment of the actual positions of the substituents is based on the UV and NMR spectra according to the principles set forth in Bergman et al (1979). As examples of leaving groups Z may be mentioned chlorine, bromine and iodine. Group Z may also be an acyloxy group, i.e. the reacting -^JsTEA OMPI compound of e. g. formula XI may be an anhydride or a mixed anhy¬ dride. When Z is hydroxy a dehydrating agent (e.g . a carbodiimide) has to be present and normally, a sulfonic acid is added to suppress side-reactions. The term "amino protecting group" designates groups readily remov¬ able by hydrolysis or hydrogenation . As examples of such amino protecting groups may be mentioned methyloxycarboπyl, ethyloxycar- bonyl, tert. butyloxycarbonyl, benzyloxycarbonyl, formyl, acetyl, trityl, or the like. Methods (a) , (b) and (e) are performed under essentially the same conditions. The reaction is carried out without a solvent or in a sol¬ vent (e. g . pyridine, N^^dimethylformamide, dimethyl sulfoxide, methyleπe chloride, or the like) . Usually a base (e. g. a tertiary amine, pyridine, potassium carbonate, or the like) has to be present. The temperature during the reaction is usually between 0°C and the boiling point of either the solvent or the boiling point of one- of the reactants. The reaction time is normally from 1 to 96 hours. Methods (c) , (d) and (f) are performed under the same conditions. The leaving group Z will often be chlorine, bromine or iodine. The reaction is carried out preferably in a polar solvent (e.g . acetone, N, N-dimethyIformamide, dimethylsulfoxide, or the like) and in the presence of a base (a metal carbonate, a tertiary amine, or the like) . The reaction temperature will normally be between 0°C and 100°C and the reaction time from 1 to 96 hours . In method (c) a mixture of compounds are normally obtained . Dependent on the reation conditions and on the number of equivalents of the compound of the formula XI I used as reagent, compounds with a substituent R alone (i .-e. R e is hydrogen) and compounds in which R~ and Re are the same, are obtained . As by-products, compounds with a substituent R, alone and compounds in which R, and R 5 are the same are also obtained . The mixture of compounds can be separated by manners known per se, i . e. crystallization or column chromatography. "_sUfc£4 __ OMPI Method (g) is performed in an inert solvent (e.g. toluene, methylene chloride, N,N-dimethylformamide, or the like). The reaction is carried out at a temperature from 0°C to the boiling point of the solvent, and for a period of time from 1 to 96 hours. Method (h) is normally performed in a solvent (e.g. pyridine, N,N- dimethylformamide, or the like). The reaction temperature is preferab¬ ly from 0°C to 150°C and the reaction time from 1 hour to 96 hours. Method (i) is normally performed in. a solvent such as an alcohol (e.g. methanol or ethanol), acetone, dimethylsulfoxide, N,N-dimethyl- formamide, pyridine or the like in the presence of a base (e.g. an alkali metal carbonate or a tertiary amine) or in an excess of the compound of formula XVI at a temperature from -20°C to the boiling point of the solvent. Description of the Drawings Fig. 1 shows the time-course of degradation of 1-(N,N-dimethylglycyl- oxymethyl)aliopurinol (o) and the concomitant formation of allopurinol (•) in a 80% human plasma solution (pH 7.4) at 37°C. Fig. 2 shows plots of the logarithm of the observed pseudo-first-order rate constants against pH for the conversion of various allopurinol prodrugs to allopurinol in aqueous solution at 37°C. Key: (Δ), 2,5-bis(Butyryloxymethyl)alIopurinol; (o), 1-(N,N-diethyI- glycyIoxymethyi)allopurinol; and (•), 1-(acetyl)alIopurinol. Fig. 3 shows mean plasma levels of oxipurinol versus time plots ob¬ tained after rectal administration of suppositories of allopurinol (•), 1-(butyryioxymethyl)allopurinol (Δ) and 1-(N,N-diethyIgIycyloxy- methyl)alIopurinol hydrochloride (o) to rabbits at a dose of 25 mg allopurinol equivalents (cross-over study involving rabbits each weighing 2.7 kg). The plasma levels of allopurinol were below 1 μg/ml at all of the three blood sampling times. OMPI Fig. 4 shows mean plasma levels of oxipurinol (o) and allopurinol (•) versus time plots obtained after rectal administration of suppositories of l - (N, N-diethyIglycyloxymethyl)ailopurinol hydrochloride to five human volunteers at a dose of 350 mg allopurinol equivalents . Fig . 5 shows mean plasma levels of oxipurinol versus time plots after intravenous administration of allopurinol (o) and l-(N, N-diethylglycyl- oxymethy allopurinol hydrochloride (•) to four rabbits at a dose of 25 mg allopurinol equivalents . The plasma levels of allopurinol were below 1 μg/ml at all blood sampling times . The present invention is further illustrated by the following examples which, however, are not to be construed as limiting. The examples especially illustrate the preferred embodiments of the invention . Spectral and chromatographical data of the prepared compounds are given in Table 1 . EXAMPLE 1 1 - (Acetyl) allopurinol O II R. = CH 3 C -; R 5 = H [Method (a)] A suspension of allopurinol (500 mg, 3.67 mmole) in acetic acid an- hydride (8 ml) was heated in an oil bath at 130°C for five hours . After cooling, water (10 ml) was added and the mixture was stirred at room- temperature for three hours . -The precipitate was collected and washed with water and dried, yielding 375 mg (57%) . Recrystalli- zation from ethanol-N, N-dimethyiformamide gave an analytically pure compound, m. p. 251 -254°C (dec ) . EXAMPLE 2 1-(Propionyl)allopurinol O II R« = CH CHrt C-; Re = H [Method (a)] The compound was prepared from allopurinol and propionic acid an¬ hydride by the procedure described in Example 1. The yield was 60%. Recrystallization from ethanol-N,N-dimethylformamide gave an analyti¬ cally pure product, m.p. 259-263°C. EXAMPLE 3 1-(Butyryl)allopurinol O II R 1 = CH 3 CH 2 CH 2 C-; R 5 = H [Method (a)] The compound was prepared from allopurinol and butyric acid an¬ hydride by the procedure described in Example 1. The yield was 52%. Recrystallization from ethanol gave an analytically pure product, m.p. 222-225°C. EXAMPLE 4 l-(Chloroacety I) allopurinol O II R, = CICH 2 C-; R 5 = H [Method (a)] A mixture of allopurinol (2.7 g; 20 mmole) and chloroacetic acid an¬ hydride (6.8 g; 40 mmole) in N,N-dimethylformamide (20 ml) was heated to 80°C and a clear solution was obtained. After 1 hour, the solution was cooled and the precipitate was collected and washed with acetone. Yield: 2.6 g (61%), m.p. 233-236°C (dec). EXAMPLE 5 1-(Benzoyl)alloρurinol O R l = C 6 H 5 " C-; 5 = H " [Method (a)] The compound was prepared from allopurinol and benzoic acid an¬ hydride by the procedure described in Example 4. The yield was 50%. Recrystallization from N,N-dimethylformamide gave an analytically pure compound, m.p. 270-273°C (dec). EXAMPLE 6 1-(Acetyloxymethyl)aI!opurinol O II R_ = CH 3 C - OCH 2 -; R 5 = H [Method (b)] A mixture of l-hydroxymethylallopurinol (1.6 g; 10 mmole) and acetic acid anhydride (2.5 ml) in pyridine (10 ml) was stirred at room tem- perature for 20 hours. The precipitate was collected, washed with ethanol, and. dried. Yield: 780 mg (47%), m.p. 257°C. EXAMPLE 7 1-(Benzoyloxymethyl)aIIopurinol O II R- = CgH 5 C - O - CH 2 -; 5 = H [Method (b)] A mixture of 1-hydroxymethylaIIopurinol (0.8 g; 5 mmole) and benzoyl chloride (0.75 ml; 6.5 mmole) in pyridine (10 ml) was stirred at room temperature for 3 hours. Water (30 ml) was added and after standing for 20 hours at 5°C, the precipitate was collected and recrystallized from ethanol. Yield: 900 mg (67%), m.p. 217-219°C. EXAMPLE 8 l-(Nicotinoy loxymethyl) allopurinol O II R- = C 5 H 4 N - C-OCH 2 -; 5 = H [Method (b)] The compound was prepared from 1-hydroxymethylallopurinol and nicotinoylchloride by essentially the same procedure as described in Example 7. After recrystallizaion from ethanol, the yield was 30%, m.p. 242-243°C. EXAMPLE 9 1-(ChloroacetyIoxymethyl)aIlopurinol R- = C1CH 2 C - O - CH 2 -; g = H [Method (b)] A mixture of 1-hydroxymethylailopurinol (0.83 g; 5 mmole) and chlo- roacetic acid anhydride (1.03 g; 6 mmole) in pyridine (20 ml) was stirred at room temperature for 18 hours. Ethanol (20 ml) was added and the precipitate collected, and recrystallized from ethanol. M.p. 203-205°C (dec). EXAMPLE 10 1-(Butyryloxymethyl)alloρurinol O R- = CH 3 CH 2 CH 2 C - OCH-,-; 5 = H [Method (b)] (cf. also Ex. 19) To a suspension of 1-hydroxymethylalIopurinoI (1.44 g; 8.7 mmole) in methylene chloride (100 ml) was added triethylamine (2.64 g; 26 mmole) and butyrylchloride (2.20 g; 20.8 mmole) . The mixture was stirred at room temperature for twenty hours . The resulting clear solution was washed with water (50 ml) , aqueous sodium hydrogen- carbonate (2.5%, 50 ml) , and water (2 50 ml) . The solution was dried and evaporated . The residue was triturated with ethyl acetate yielding 567 mg (28%) of crude product. Recrystallization from ethanol yielded an analytically pu re compound, m. p. 224-226°C. EXAMPLE 11 1-(N, N-Dimethyiglycyloxymethyl)allopurinol (hydrochloride) R 1 = (CH 3 ) 2 NCH 2 C - OCH 2 -; R 5 = H [Method (b) ] A mixture of l-hydroxymethylailopurinol (2.0 g; 12 mmole) , N, N-di- methylglycine (1 .25 g; 12 mmole) , N,N'-dicyclohexylcarbodiimide (2.5 g; 12 mmole) , and 4-toluenesuIfonic acid (150 mg) in pyridine (40 ml) was stirred at room temperature for 48 hours . Methylene chloride (80 ml) was added. The mixture was filtered and the filtrate was evapo¬ rated in vacuo. The residue was extracted with two 50 ml portions of boiling methylene chloride, and the extracts were evaporated. The residue was recrystallized from ethyl acetate. The crude compound obtained was suspended in ethanol (20 ml) and a 2N solution of hy¬ drochloric acid in ethyl acetate (8 ml) was added followed by ethyl - acetate (20 ml) . The precipitate was collected (1 .32 g) and recrystal- lized from methanol-ether yielding an analytically pure product, m. p. 203 -206° C (dec) . EXAMPLE 12 1 - [4- (N, N-Dimethy!ami no) butyryloxymethyl] allopurinol (hydrochloride) O // R- = (CH 3 2 NCH 2 CH 2 CH 2 C - O-CH 2 ~; R 5 = H [Method (b)] -g JRE OMPI WIPO Using the same procedure as described in Example 11, but using N,N-dimethyl-4-aminobutyric acid instead of N,N-dimethylglycine yielded the title compound, m.p. 150-155°C (dec). EXAMPLE 13 1-(DL-N,N-Diethylalany loxymethyl) allopurinol (hydrochloride) CH-, O I 3 II R- = (C 2 H 5 ) 2 N - CH - C - O - CH 2 -; R 5 = H [Method (b)] The compound was prepared from l-hydroxymethylallopurinol and DL-N,N-diethylalanine by the procedure described in Example 11. The yield was 24%, m.p. 165-170°C (dec). EXAMPLE 14 1-(N,N-Dipropylglycy loxymethyl) allopurinol (hydrochloride) O R- = (C 3 H ? ) 2 N.- CH 2 - C - O - CH 2 -; R 5 = H [Method (b)] The compound was prepared from l-hydroxymethylallopurinol and N,N-dipropyfglycine by the procedure described in Example 11. The compound crystallized from ethanol 195-198°C (dec). EXAMPLE 15 1-(N,N-DiethyIglycyloxymethyl) allopurinol (hydrochloride) R 1 = (C 2 H 5 ) 2 NCH 2 C - OCH 2 -; R 5 = H [Method (b)] A mixture of 1-hydroxymethyIallopurinol (3.8 g; 16.8 mmole), N,N- diethylglycine hydrochloride (2.88 g; 17 mmole), N,N'-dicyclohexyI- carbodiimide (3.6 g; 17.5 mmole) , and 4-toluenesulfonic acid (270 mg) in pyridine (60 ml) was stirred at room temperature for 24 hours . Methylene chloride (50 ml) was added to the reaction mixture. The precipitate was collected and stirred with water (15 ml) . The insoluble compound was filtered off and washed with water and the combined filtrates were evaporated in vacuo. The residue was recrystallized twice from methanol-ether yielding an analytically pure compound (1 .3 g; 25%) , m. p. 196-198°C (dec ) . EXAMPLE 16 l -(DL-AlaπyIoxymethyI)aIIopurinol (hydrobromide) CH-, O I 3 || R- = H 2 N CH - C - O - CH 2 -; R g = H [Method (b)] A mixture of l-hydroxymethylallopurinol (1 .6 g; 10 mmole) , N-benzyl- oxycarbonyI-D, L-aIanine (2.23 g; 10 mmole) , N, N'-dicyclohexylcarbo- diimide (2.06 g; 10 mmole) , and 4-toluenesulfonic acid (150 mg) in pyridine (60 ml) was stirred at room temperature for 20 hours . Meth¬ ylene chloride (100 ml) was added and the mixture was filtered . The filtrate was evaporated - in vacuo and the residue was extracted with boiling methylene chloride (3 x 50 ml) . The methylene chloride was evaporated and the residue was recrystallized from ethyl acetate- ethanol . To the crude N-protected compound was. added a 33% solution of hydrobromic acid in acetic acid (8 ml) . The mixture was stirred at room temperature for seven minutes and ethyl acetate (50 ml) was added . The precipitate (520 mg, 16%) was collected and recrystallized from methanol . The title compound was crystallized with 2/3 mole of water, m. p. 195-198°C (dec ) . OMPI EXAMPLE 17 1-(Succiny loxymethyl) allopurinol O „ II R 1 = H OC CH 2 CH 2 - C OCH, Re = H [Method (b)] A mixture of l-hydroxymethylallopurinol (1.6 g; 10 mmole) and suc- cinic acid anhydride in pyridine (20 ml) was stirred at room tempera¬ ture for 96 hours. Hydrochloric acid 4N (50 ml) was added and the precipitate was collected. From ethanol - N,N-dimethylformamide the title compound crystallized with 0.25 equivalent of water. M.p. 217- 219°C (dec). EXAMPLE 18 1) tert. butyloxymethyl [Method (c)] R 1 = 2) R- = = tert. butyloxymethyl 3) R- = tert. butyloxymethyl; R_- = hydrogen 4) R- = tert. butyloxymethyl; Re = hydrogen To a solution of allopurinol (2.04 g; 15 mmole) in dimethyl sulfoxide (45 ml) kept at 40°C were added potassium carbonate (2.07 g; 15 mmole) and then dropwise during one hour a solution of chloromethyl pivalate (2.2 g; 15 mmole) in dimethyl sulfoxide (15 ml). The mixture was stirred at 40°C for four hours and poured on ice (75 g). After acidification, the mixture was extracted with chloroform (3 70 ml). The extracts were washed with water, dried, and evaporated. Toluene (5 ml) was added to the residue, and the solid compound formed was collected by filtration and washed on the filter with ether (2 x 5 ml). Recrystallization of the solid from ethyl acetate gave analytically pure 2-(pivaloyioxymethyl)aJlopurinol (813 mg; m.p. 180-181°C). The toluene-ether filtrate from the crude solid was evaporated in vacuo. Column chromatography (CC) (silica gel, eluents toluene-ethyl acetate-methanol) was performed on the residue, and the compounds were collected in the following order: 1) 1,5-bis(Pivaloyloxymethyl)aIlopurinol (90 mg; m.p. 136-137°C, re¬ crystallized fro ' m ether-light petroleum). 2) 2,5-bis(PivaIoyloxymethyl)aIlopurinol (402 mg; m.p. 145-146°C, recrystallized from ethyl acetate-ether-light petroleum). 3) l-(PivaloyloxymethyI)aIlopurinol (151 mg; m.p. 185-187°C, re¬ crystallized from ethyl acetate). EXAMPLE 19 1) R 1 = R 5 = butyloxymethyl [Method (c)] 2) R« = = butyloxymethyl 3) R- = butyloxymethyl; R 5 = hydrogen 4) R 2 = butyloxymethyl; R 5 = hydrogen By using the same procedure as described in Example 18 and equi¬ valent amounts of allopurinol and chloromethyl butyrate, the following compounds were obtained: 1) l,5-bis(ButyryloxymethyI)alIopurinoi, m.p. 122-123°C (from ethyl acetate-ether-light petroleum). 2) 2,5-bis(Butyryloxymethyl)allopuπnol, m.p. 133-135°C (from ethyl acetate-ether- light petroleum). 3) l-(ButyryIoxymethyl)allopuriπol, m.p. 220-225°C (from ethyl ace- tate) . 4) 2-(ButyryIoxymethyI)allopurinol, m.p. 182-183°C (from ethyl acetate) . OMP EXAMPLE 20 1-(N,N-Dimethylglycyl)allopurinol (hydrochloride) R- = (CH 3 ) 2 NCH 2 CO- ; R 5 = H [Method (a)] To a suspension of allopurinol (778 mg, 5.7 mmole) in 5 ml of N,N-di methylformamide was added a solution of N,N-dimethylglycinyl chloride hydrochloride (5.7 mmole) in 10 ml of N,N-dimethylformamide. The mixture was heated to 80°C for 1 hour. After cooling the precipitate was collected and washed with ethanol. Yield: 209 mg, m.p. 192-196°C (dec). EXAMPLE 21 1-(Ethoxycarbonyloxymethyl)allopurinoi R- = CH 3 CH 2 -O-CO-O-CH 2 - ; R 5 = H . [Method (b)] The compound was prepared from l-hydroxymethylallopurinol and ethyl chloroformate by the same procedure as described in Example 7. After recrystallization from ethanol the yield was 38%, m.p. 228°C. EXAMPLE 22 1-(DL-Phenylglycy loxymethyl) allopurinol (hydrobromide) R-. = C 6 H 5 CH(NH 2 )CO-OCH 2 - ; R 5 = H [Method (b)] The compound was prepared from l-hydroxymethylallopurinol and N-(benzyloxycarbonyl)-DL-phenylglycine by the procedure described in Example 16. The analytically pure title compound crystallized from methanol-ether, m.p. 192-195°C (dec). EXAMPLE 23 2, 5-bis(Butyryloxymethyl) allopurinol R 2 = 5 = CH 3 CH 2 CH 2 C /?-OCH 2 - [Method (b) ] A mixture of 400 mg of 2,5-dihydroxymethyIaIlopurinol (prepared as described by Bansa! et al . (1981 ) , where the compound is designated 1 ,5- [bis(hydroxymethyl)] -l ,5-dihydro-4H-pyrazolo[3,4.-<_ *" ]pyrimidin- 4-one) , butyric acid anhydride (1 ml) , and pyridine (5 ml) was stirred at room temperature for 24 hours . Water (20 ml) was added to the solution and after stirring for 2 hours the precipitate was col¬ lected. Recrystallization from ethyl acetate afforded 268 mg of the title compound, which had the same m. p. and spectral data as the compound synthesized according to Example 19. EXAMPLE 24 2,5-bis(AcetoxymethyI)aIIopurinol R 2 = R 5 = - [Method (b) ] The compound was prepared from 2,5-dihydroxymethylalIopurinol and acetic acid anhydride by the procedure described in Example 23. Re- crystallization from ethanol gave an analytically pure product in a yield of 68%, m. p . 153-154°C. EXAMPLE 25 2, 5-bis-(DL-Alany loxymethyl) allopurinol (dihydrobromide) H,C O 3/ // 2 = R 5 = H 2 NCH-C-OCH 2 - [Method (b) ] The compound was prepared from 2,5-dihydroxymethylalIopurinol and the double amounts of N-(benzyloxycarbonyl)-D, L-alanine, N,N'-di- cyclohexylcarbodiimide, and pyridine by essentially the same proce¬ dure as described in Example 16. Recrystallization from methanoi-ethyl acetate-ether yielded 16% of the title compound, m.p. 190-192°C (dec). The compound crystallized with 0.5 mole of methanol. EXAMPLE 26 1-[4-(N,N-Dimethylamino)butyryl]alIopurinol (hydrochloride) O // R. = (CH 3 ) 2 NCH 2 CH 2 CH 2 C- ; R 5 = H [Method (a)] The compound was prepared from allopurinol and 4-(N,N-dimethyl)- butyryl chloride hydrochloride by the same procedure as described in Example 20. The compound crystallized with 1/3 mole of water and did not melt below 270°C. EXAMPLE 27 1-(DL-Phenylalanyloxymethyl)allopurinol (hydrobromide) R 1 = CgH 5 CH 2 CH(N ; R 5 = H [Method (b)] The compound was prepared from l-hydroxymethylallopurinol and N-(benzyloxycarbonyI)-DL-phenyIalanine by the procedure described in Example 16. The analytically pure title compound crystallized with 1/4 mole of water from methanol, m.p. 204-205°C (dec). OMPI_ EXAMPLE 28 l-(L-Leucyloxymethyi)allopurinol (hydrobromide) _ R 1 = (CH 3 ) 2 CHCH 2 CH(NH 2 )C-OCH 2 - ; R 5 = H [Method (b)] The compound was prepared from l-hydroxymethylallopurinol and N-(benzyIoxycarbonyl)-L-Ieucine by essentially the same procedure as described in Example 16. The analytically pure title compound crystal¬ lized from methanol-acetonitrile with 1 mole of water, m.p. 215-217°C (dec). EXAMPLE 29 1-(N-Butylcarbamoyi)alIopurinol O -R 1 = CH 3 CH 2 CH 2 NHC- ; R 5 = H [Method (g)] A mixture of allopurinol (2.7 g, 20 mmole), triethylamine (0.2 ml), butylisocyanate (3 g, 30 mmole) in N,N-dimethyIformamide was stirred at 90°C for 2 hours. Upon cooling 1.05 g of the title compound pre¬ cipitated. The crude product was recrystallized from N,N-dimethyl- formamide-ethanol, m.p. > 270°C . EXAMPLE 30 1- [3- (N,N-Diethy lea rba oy I) propiony loxymethyl] allopurinol R. = ; R 5 = H [Method (b)] A mixture of 1-hydroxymethylaliopurino! (1.47 g; 8.8 mmole), 3-(N,N-diethy!carbamoyl)propionic acid (1.53 g; 8.8 mmole), N,N'- -WZE OMPI dicyclohexylcarbodiimide (1 .8 g; 8.8 mmole) , and 4-toluenesulfonic acid (100 mg) in pyridine (30 ml) was stirred at room temperature for 24 hou rs . Methylene chloride (60 ml) was added, the mixture was filtered, and the filtrate evaporated in vacuo. The residue was ex- tracted with warm methylene chloride (50 ml) and the methylene chloride was evaporated. The residue was recrystallized from ethyl acetate yielding 0.71 g (25%) ; m. p. 128-131 °C. EXAMPLE 31 1 -(Glycyloxymethyl)allopurinol (hydrochloride) O // R-. = H 2 NCH 2 C-OCH 2 - ; R 5 = H [Method (b) ] The compound was prepared from l -hydroxymethylallopurinol and N- (tert. butyIoxycarbonyl)glycine by the same procedure as described in Example 16. The tert. butyloxycarbonyl-protecting group was re- moved with 1 N hydrochloric acid . The title compound melted at 192- 195°C (dec ) . OMPI Table 1 H NMR and UV spectral data, and HPLC chromatographic capacity factors of various allopurinol prodrugs Chroma- λ max (n ) tog arap r-hic ^ NMR (δ) (in pH 5.0 capacity . Compound H(3)and H(6) buffer) factor (k') l-(Acetyl)aflopurinoi a 8.3Q 8.38 274 1.05 L !-(PropionyI)alIopurinol a 8.30 8.37 274 0.66 c l-(ButyryI)aIlopurinol a 8.32 8.40 274 1.10 C l-(Benzoyl)allopurinol 8.32 8.46 250,280(sh) 1.20 c l-(Chloroacetyl)aIIopurinoi 8.29 8.39 274 n.d. l-(Acetyloxymethyl) allo¬ purinol 3 8.20 8.22 251 0.30' 1-(Butyryloxymetyl)alIo- purinol 3 8.20 8.23 251 0.85 1 - 1-(Pivaloyloxymethyl)alIo- purinol 3 8.19 8.23 251 1.50 1 1 - (Benzoyloxymethyl) allo- purinol 8.45 8.49 234 2.00 1 1-(Nicotinoyloxymethyl)allo- purinol 8.41 8.48 251 0.67 c l-(Chloroacetoxymethyl)- allopurinoi 8.31 8.33 251 n.d. 1 - (DL-Alanyloxymethyl) - allopurinol 8.38 8.42 251 1.37 1 1 - (DL-N, N-Diethylalanyloxy- methyl)aIlopurinol b 8.36 8.45 251 17. f 1 - (N , N-Dimethylglycyl- oxymethyl) allopurinol 8.28 8.34 251 4.00 1 - 1-(N,N-Diethylglycyl- oxymethyl)allopurinol 8.27 8.32 251 12.0" l-(N,N-DiρropylglycyI- oxymethyl) allopurinol 8.34 8.40 251 >60 v Table 1 continued 1-[4-(N,N-Dimethylamino)- butyry loxymethyl] allopuri¬ nol 8.29 8.35 251 n.d. 2-(ButyryIoxymethyl)allo- ,a purmol 8.06 8.78 261 0.65 c 2-(Pivaloyloxymethy!)allo- ,a puπnol 8.08 8.70 261 1.07 c 1, 5-bis (Butyryloxymethyl)- allopurinol 8.28 8.62 251 4.82 c 1,5-bis(PivaIόyIoxymethyl)- allopurinol 8.29 8.64 251 13.8 C 2, 5-bis ( Buty ryloxymethyl) - allopurinol 8.40 8.82 259 3.37 C 2, 5-bis (Pi valoy loxymethyl) - allopurinol 8.41 8.85 259 9.9 d 1-(N, N-Dimethylglycyl)- . — allopurinol 8.45 8.46 279 n.d. 1-(GIycy loxymethyl) allo- ,b purmol 8.27 8.32 251 0.89 c 1 - ( Ethoxyca rbony loxy¬ methyl) allopurinol 8.24 8.28 251 n.d. l-(DL-Phenylglycyloxy- methyl) allopurinol 8.15 8.20 n.d n.d. l-(Succinyloxymethyl)- allopurinol 8.23 8.25 251 n.d. 2, 5-bis ( Acety loxymethyl) - allopurinol 8.70 * 9.17 •259 n.d. 2, 5-bis (DL- Ala ny loxymethyl) - allopurinol 8.51 8.97 259 n.d. 1 - ( L- Leucy loxymethyl) - allopurinol 8.32 8.36 251 0.80 d 1-(DL-Pheπylalanyloxy- methyl) allopurinol 8.28 8.30 251 1.05 d a) NMR in DMSO-d, OMPI b) NMR in D-,0 c) Mobile phase: 0.02 M phosphate buffer pH 7.4 - methanol (4: 1 v/v) Mobile phase: 0.01 M acetate buffer pH 4.5 - methanol (1 : 1 v/v) Column: 250mm x 4 mm LiChrosorb RP-8 (Merck) n .d. = Not determined In-vitro cleavage of allopurinol derivatives Reaction conditions. Solutions of various derivatives of allopurinol in aqueous buffer solutions or 80% human plasma solutions fpH 7.4) were kept at 37°C. The initial concentration of the derivatives was in the range 0.01 -0.1 mg/ml . At various times an aliquot of the solutions was withdrawn and analyzed by HPLC for remaining derivative as well as for allopurinol . For the plasma solutions the aliquot withdrawn was deproteinized with ethanol or trichloroacetϊc acid and after centrifuga¬ tion, the clear supernatant was injected on HPLC. Analytical method. An HPLC method was used for the determination of allopurinol and its derivatives. In this method a reversed-phase LiChrosorb RP-8 column (250 x 4 mm) was eluated at ambient tempera¬ ture with mixtures of methanol and 0.01 M acetate buffer pH 4.5 or methanol and 0.03 M phosphate buffer pH 7.0. The composition of the eluant was adjusted for each compound in order to provide an appro¬ priate retention time. The flow rate was 1 .2 ml/min and the column effluent was monitored spectrophotometrϊcally at 252 nm or 274 n . Quantitation of the compounds was done by measurement of peak heights. A complete conversion of the derivatives to allopurinol was found to take place and in all cases, the cleavage of the derivatives displayed strict first-order kinetics . An example is shown in Fig . 1 . The rate of hydrolysis varied greatly with pH of the solutions as illustrated in Fig. 2, showing the pH-rate profiles for some of the derivatives . The half-times of allopurinol formation from various derivatives at physiological conditions of pH and temperature are given in Table 2. OMPI It can be seen that in the presence of human plasma the rate of degradation is strongly accelerated, thus showing the susceptibility of the derivatives to undergo conversion into the parent active compound at conditions similar to those prevailing in vivo. The water-solubility and iipophilicity of the allopurinol drugs The apparent partition coefficients ( P) for some allopurinol derivatives and allopurinol were measured using the widely used 1 -octanol-water system. Similarly, the solubility of the derivatives in water or aqueous buffer solutions was determined . The values found for log P and the water-solubilities are listed in Table 3. The results obtained show clearly that by varying the pro-moieties of the derivatives or the type of derivative it is feasible to obtain prodrugs of allopu rinol with varying and any desirable Iipophilicity or water solubility. Thus, as demonstrated with the compound 1 - (N, N-diethyiglycy!oxymethy!)allo- purinol hydrochloride it is possible to obtain a prodrug form which at the same time possesses both a much higher aqueous solubility (i . e. a factor 5, 000) and a higher Iipophilicity than the parent compound . Bioavailability of some allopurinol derivatives and allopurinol following rectal administration Suppositories were prepared of allopurinol and some derivatives of the present invention using Adeps solidus (Ph . Nord . 63) as the suppo¬ sitory base. Each suppository contained an amount of the appropriate compound (brought to the same particle size by sieving) equivalent to 25 mg of allopurinol . Some water-soluble derivatives were also formu- lated as micro-enemas, the solvent being a 0.5% aqueous solution of methylcellulose. The suppositories or micro-enemas were administered to rabbits . After drug administration, blood samples were taken at various times and the plasma fraction assayed for allopurinol and its major metabolite oxipurinol using the HPLC method described above. Fig . 3 shows some representative plots of plasma oxipurinol concen¬ trations versus time following rectal administration to rabbits . The results clearly demonstrate that the allopurinol derivatives exh ibit a OMPI greatly enhanced bioavailability as compared with allopurinol which showed only a very low degree of absorption (<2% of the dose given) . The plasma samples were also analyzed for intact allopurinol prodrugs but in all cases no measurable concentrations (<0.1 μg/ml) were observed . Thus, it is evident from the results that allopurinol pro- drug forms of the present invention provide an efficient absorption of allopurinol after rectal administration in sharp contrast to the be¬ haviour of allopurinol per se. Moreover, the above studies demon¬ strate that the prodrugs are converted back to allopurinol in vivo in accordance with the "prodrug" definition provided at the outset of this application . In addition to these animal experiments, a micro-enema preparation of the hydrochloride salt of l -(N - N-diethyiglycy!oxymethyl)aliopurino! was administered to a healthy human volunteer. The dose given (2 ml of a 0.5% methylcellulose solution containing 118 mg/ml of the pro¬ drug) corresponded to 100 mg of allopurinol . Urine was collected over 5 days and aliquots were assayed for allopurinol and oxipurinol by a specific HPLC assay. The total urinary excretion of allopurinol and oxipurinol was found to be 11 and 78 mg, respectively. Since it is known (Breithaupt & Tittel, 1982) that about 88% of a dose of allo¬ purinol administered intravenously are recovered in the urine in the form of intact allopurinol (12%) and oxipu rinol (76%) the result of the experiment indicates a virtually complete bioavailability of the parent drug from the prodrug derivative given rectaily. Furthermore, suppositories containing the hydrochloride salt of 1 - (N , N-diethyIg!ycyloxymethyI)allopurino! in an amount equivalent to 350 mg of allopurinol and made using Adeps solidus as the suppository base were administered rectaily to five healthy human volunteers . After drug administration, blood samples were taken at various times and the plasma fraction assayed for allopurinol and oxipurinol by means of HPLC. Fig . 4 shows the average plasma data obtained . The same volunteers were also given a tablet preparation of allopu rinol and from the plasma data obtained, the bioavailability of the supposi¬ tory preparation containing the allopurinol prodrug was estimated to be 42% of that of the oral preparation . Bioavailability after parenteral and oral administration An aqueous solution of 1 - (N, N-diethylglycyloxymethyl) allopurinol hydrochloride (1 ml containing 59 mg of the compound ~ 25 mg of allopurinol) was given intravenously to four rabbits . Fig . 5. shows the mean plasma oxipu rinol concentration vs . time curve obtained along with the plasma concentration vs . time data observed after similar administration of 25 mg of allopurinol in the form of a 1% al kaline solution of its sodium salt. The results of the experiment indicates an almost complete bioavailability of the parent drug from the prodrug derivative given intravenously . A comparative absorption study was also made of allopu rinol and the above mentioned prodrug following peroral administration . Each com¬ pound was given to a healthy human volunteer in a dose correspon¬ ding to 100 mg allopurinol, allopurinol in the form of a commercially available tablet and 1 - (N, N-diethylglycyloxyrnethyl)allopu rinol hydro¬ chloride as a solution in water (236 mg in 10 ml) . The total urinary excretion of allopu rinol and oxipu rinol was measu red and found to correspond to 67% of the dose given for the allopurinol tablet and 92% for the preparation containing the prodrug derivative. Table 2 Half-times (t« _.) of the conversion of various allopurinol derivatives to allopu rinol at 37°C. Compound L 0.5 pH 7.4 80% human buffer plasma, min l-(Butyryloxymethyl)alIopurinol 193 h 9 2- (Butyryloxymethy!) allopurinol 54 h 22 1 , 5-bis (Butyry loxymethyl) allopurinol 25 h 22 2, 5-bis (Butyry loxymethyl) allopurinol 35 h 32 1 -(Acetoxymethyl)ailopurinol 87 h 31 2,5-bis(Acetoxymethyl)allopurinoI 15 h 51 !-( Benzoy loxymethyl) allopurinol 237 h 4 1 -(Nicotinoy loxymethyl) allopurinol 26 h 21 l- (GIycy loxymethyl) allopurinol 26 min 9 1 -(N, N-Dimethylglycyloxymethyi)- allopurinol 72 min 7 1 -(N, N-DiethyIgIycyIoxymethyl)- allopurinol 49 min 10 l -(DL-N, N-Diethyla!anyloxymethyi) ' allopurinol 21 min 17 1 - (Acetyl) allopurinol 26 min 6 l -(Propionyl) allopurinol 30 min 4 l - (Butyryl) allopurinol 36 min 2.5 1 -(Benzoyi)aIIopurinoI 20 min 4 1 -(DL-AIany loxymethyl) allopurinol 15 min 11 l -(N, N-Diproρylglycyioxymethyl)- allopurinol 50 min 12 l -(DL-Phenylglycyloxymethyl) allopurinol 20 min 3 1 - (L-Leucy loxymethyl) allopurinol 17 min 6 1 - (Ethoxyca rbony loxymethyl) allopurinol 20 Table 2 continued 1-(N,N-Dimethylglycyl)- allopurinol 1.5 min <1 l-(N-Butylcarbamoyl)- • allopurinol 90 1-(DL-Phenylalany loxymethyl) ■ allopurinol 40 min 1[3-(N,N-Diethylcarbamόyl)- propiony loxymethyl] allopurinol 81 h 8.4 h l-(Chloroacetyl) allopurinol <1 min <1 1-[4-(N,N-Dimethylamino)- butyryloxymethy I] allopurinol 145 min 140 2, 5-bis (DL-Alany loxymethyl) - allopurinol <1 min <1 Table 3 Water-solubilities (S) and partition coefficients (P) for allopurinol and various allopurinol prodrugs. Compound S* log P c (mg/ml) Allopurinol 0.50 -0.55 1- (Pivaloyloxymethyl) allopurinol 0.52 1.07 2- (Pivaloyloxymethyl) allopurinol 1.7 0.79 1, 5-bis (Pivaloyloxymethyl) allopurinol 0.02 2.50 2, 5-bis (Pivaloyloxymethyl) allopurinol 0.045 2.34 l-(Butyryloxymethyl) allopurinol 0.35 0.60 2- (Butyry loxymethyl) allopurinol 1.5 0.33 1, 5-bis (Butyry loxymethyl) allopurinol 0.050 1.82 2, 5-bis (Butyryloxymethy I) allopurinol 0.094 1.60 1-(Acetoxymethyl)allopurinol 0.58 -0.35 , 5-bis (Acetoxymethyl) allopurinol 2.9 n.d. Table 3 continued 1 - ( Benzoy loxymethyl ) a I lopu ri nol 0.024 1.50 l-(Nicotinoyloxymethyl) allopurinol 0.093 0.27 l-(GIycyIoxymethyf)allopurinoI hydrochloride >500 n.d. l-(DL-Alanyloxymethyl) allopurinol hydrobromide >500 n.d. 1-(N,N-Dfmethylg!ycyloxymethyl)- allopurinol hydrochloride >500 -0.49 ( 1-(N,N-Diethylglycyloxymethyi)- allopurϊπol hydrochloride >500 0.20' 1-(N,N-Dipropylglycyloxymethyl)- allopurinol hydrochloride >400 1.27 1-(DL-N,N-Diethylalanyloxymethyl)- allopurinol hydrochloride >400 0.72 ( l-(DL-Phenylglycyloxymethyl) allopurinol hydrobromide >200 -0.15 1-(AcetyI)allopurinol 0.75 -0.35 l-(Propionyl) ' allopurinol 0.30 0.30 1-(Butyryl)alIopurinol 0.11 0.85 1- (Benzoy I) allopurinol 0.014 1.20 1 - (Ethoxycarbony loxymethyl - allopurinol n.d. 0.21 1 -(DL-Phenylalanyloxymethyl) - allopurinol hydrobromide >200 0.40 1 l-(L-Leucyloxymethyl)aIIopurinol hydrobromide >400 0.19' 1-[3-(N,N-Diethylcarbamoyl)- propionyloxymethyl]allopurϊnol 33 -0.22 1-(N,N-Dimethylglycyl) allopurinol hydrochloride >200 n.d. d At 21 ± 1°C Between octanol and water B Beettwweeeenn ooccttaannooll aanndd a borate buffer pH 8.0 n.d. = not determined References Cited Appelbaum, S.J., M. 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Biopharm. 10, (1982), p. 525. "Remington's Pharmaceutical Sciences", Sixteenth Edition (1980), Mack Publishing Company, Easton. Spector, T.: Biochem. Pharmacol. 26, (1977), p. 355.

Claims: CLAIMS 1 . Compounds of the formulas la or lb , wherein R. is a group of the formula I I O II R 3 - C - A - I I wherein R 3 is alkyl; phenyl; phenyl substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; phenyl-lower alkyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy or phenoxy; or phenyl- lower al kenyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; or R-. is an aromatic 5- og 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitro- gen, oxygen, and sulfur; and A is a single bond or a group of the formula I la | 6 - O - C - I la I R 7 wherein the carbon atom is attached to the _nitrogen atom of the parent ring system, and wherein R β and Ry are the same or different and each represent hydrogen or have the same meaning as R-, as defined above; OMPI or R-, is a group of the formula I I I w tfherein Rg and R q are the same or different and each represent hydrogen or have the same meaning as R-. as defined above; or Rg and Rg together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Y is a single bond or a group of the formula I l ia wherein n is an integer from 1 to 5; and A, R fi , and Ry are as defined above; or R- is a group of the formula IV IV wherein A is as defined above and R'« has the same meaning as R« defined above, with the proviso that R' 3 is not ethyl when A is a bond; or R. is a group of the formula VI O II R 10 - C VI wherein R, ~ is a mono- or polyhalogenated lower alkyl group and A is as defined above; or R- is a group of the formula VI I OMPI O O II II R 1 l <a - C - (CH _t) n - - C- A - VII wherein n and A are as defined above, and R.., is hydroxy or a group of the formula -N gRg wherein Rg and R« are as defined above; or R. is a group of the formula IX 0 R c II 16 HO - P - O -C - IX 1 I OH R wherein R fi and Ry are as defined above; R-, is any of the groups II, HI, IV, VI, and VII as defined above with the proviso that A solely is the group Ila as defined above; and Re is hydrogen or has the same meaning as R- as defined above, and salts thereof. 2. Compounds according to claim 1 wherein R, and R 5 are the same; and salts thereof. 3. Compounds according to claim 2 wherein R. and Re are groups of the formulas II or III as shown in ciiam 1, wherein A is a group of formula Ila as shown in claim 1 and Y is a group of formula Ilia as shown in claim 1; and salts thereof. 4. Compounds according to claim 1 wherein R_. is hydrogen and R, is a group of the formulas II, III, IV, VII or IX as shown in claim 1; and salts thereof. 5. Compounds according to claim 4 wherein R- is a group of the formulas II, III wherein Y is a group of formula ilia, or VII as shown in claim 1; and salts thereof. 6. Compounds according to claim 5 wherein A is a group of formula Ila as shown in claim 1; and salts thereof. 7. Compounds according to claim 6 wherein R, is a group of the formula III as shown in claim 1 wherein A is a group of formula Ila and Y is a group of formula Ilia; and salts thereof. 8. Compounds according to claim 7 wherein R. is N,N-dimethyl- glycy loxymethyl, N,N-diethy Iglycy loxymethyl, N, N -dip ropy Iglycy I - oxymethyl, N,N-dimethylalanyloxymethyl, N,N-diethylalanyIoxymethyl, phenylalanyloxymethyl, phenylglycyloxymethyl, or leucyloxymethyl; and salts thereof. 9. Compounds according to claim 1 wherein R 2 and R- are the same; and salts thereof. 10. Compounds according to claim 9 wherein R 2 and Re are groups of the formula III as shown in claim 1 wherein A is a group of formula Ila and Y is a group of formula Ilia; and salts thereof. 11. Compounds according to claim 1 wherein R-. is hydrogen and , R-, is a group of the formula II as shown in claim 1 wherein A is a group of formula Ila; and salts thereof. 12. Compounds according to claim 1 selected from the group consisting of l-(butyryloxymethyl)alloρurinol, 1-(N,N-dimethylgIycyloxymethyl)- allopurinol, 1-(N,N-diethylglycy loxymethyl) allopurinol, 1-(N,N-diprop- y Iglycy loxymethyl) allopurinol, l-(DL-N,N-dimethylalanyIoxymethyl) allo¬ purinol, 1-(DL-N,N-diethyIalany loxymethyl) allopurinol, 1-(L-phenyl- alany loxymethyl) allopurinol, 1-(L- leucyloxymethyl ) allopurinol, 1-(L- valyloxymethyDallopurinol and 1-(DL-N, N-dimethylphenylalanyloxy- methyl) allopurinol, and salts thereof. 13. A method for preparing compounds of the formulas I 'a or lb wherein R. is a group of the formula I I 3 - C - A - I I wherein R- is alkyl; phenyl; phenyl substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; phenyl-lower alkyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy or phenoxy; or phenyl- lower alkenyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower al koxy, acetoxy, or phenoxy; or R, is an aromatic 5- og 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitro¬ gen , oxygen, and sulfur; and A is a single bond or a group of the formula I la I 6 - O - C - I la I ^ wherein the carbon atom is attached to the nitrogen atom of the parent ring system, and wherein Rg and Ry are the same or different and each represent hydrogen or have the same meaning as R_- as defined above; OMPI or R, is a group of the formula I I I wherein Rg and Rg are the same or different and each represent hydrogen or have the same meaning as R- as defined above; or R g and Rg together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Y is a single bond or a group of the formula I l ia wherein n is an integer from 1 to 5; and A, R fi , and Ry are as defined above; or R, is a group of the formula IV R 3 - O IV wherein R-. and A are as defined above; or R, is a group of the formula VI O II R 1 Q - O - C - A VI wherein R ι n is a mono- or polyhalogenated lower alkyl group and A is as defined above; or R, is a group of the formula VI! O O II // R 13 - C- CH 2 ) n - C - A - VII wherein n and A are as defined above, and R,« is hydroxy or a group of the formula -NRgRg wherein Rg and R q are as defined above; or R- is a group of the formula IX O II |6 HO P P -- OO -- CC-- IX OH R 7 wherein R~ and Ry are as defined above; R- is any of the groups II, III, IV, VI, and VII as defined above with the proviso that A solely is the group i la as defined above; and Re is hydrogen or has the same meaning as R 2 as defined above, and salts thereof, comprising (a) for preparing compounds of the formula I'a wherein R-. is hydrogen and A is a bond, reacting allopurinol with a compound of the formula XI O R 12 - C - Z XI wherein R, 2 has the same meaning as R«, or R--, is a group of the formula IN' OMPI wherein Y is as defined above, and R g ' and R g ' have the same meaning as Rg and R Q as defined above; or R g ' or R q ' are an amino protecting group; or R- -, is a group of the formula IV' R 3 - O - IV wherein R« is as defined above; or R- 2 has the same meaning as R, fl as defined above; or R, 2 is a group of the formula VI I ' O U R_,C - (CH- - VI I ' ι _> _. n wherein n is as defined above, a ~ ττd R- 3 is hydroxy or a group of the formula -NRgR q wherein R g and R q are as defined above; and Z is a leaving group; and then , if an amino protecting group has been used, removing the protecting group, or (b) for preparing compounds of the formula I 'a wherein R_. is hydrogen or compounds of formula lb wherein R 2 and Re are the same, and wherein A is -CH 2 ~, reacting l -hydroxymethylallopurinol or 2,5-dihydroxymethylaIIopurinol with a compound of the formula XI as defined above and wherein R- 2 is as defined above; and then, if an amino protecting group has been used, removing the protecting group, or • (c) for preparing compounds of the formula I 'a or lb wherein either R e is hydrogen or * and Re are the same or R-, and R e are the same, reacting allopurinol with a compound of the formula XII O R, % 6 R 12 - C- O C- z XII I R wherein Rg, Ry, R^ 2 and Z are as defined above; and then, if an amino protecting group has been used, removing the protecting group, or (d) for preparing compounds of the formula I'a wherein 5 is different from hydrogen, reacting a compound of the formula XIII wherein R. is as defined above with a compound of the formula XII, wherein R fi , Ry, - j2 ' anc ' ^ are as defined above; and then, if an amino protecting group has been used, removing the protecting group, or (e) for preparing compounds of the formula I'a wherein e is different from hydrogen reacting a compound bf the formula XIV wherein R, is as defined above with a compound of the formula XI as shown above, wherein R, 2 and Z are as defined above; and then , if an amino protecting group has been used, removing the protecting group, or (f) for preparing compounds of the formula lb wherein Re is different form hydrogen , reacting a compound of the formula XV wherein R~ is as defined above, with a compound of the formula XI I , wherein Rg, Ry, R- 2 , and Z are as defined above; and then , if an amino protecting group has been used, removing the protecting group, or (g) for preparing compounds of the formula I 'a wherein Re is hydrogen or compounds of the formula lb wherein R 2 and R e are the same, reacting allopurinol, l -hydroxymethylallopurinol, or 2,5-dihydroxy- methylallopu rinol with a compound of the formula V" R 3 - N = C = O V" wherein R- is as defined above, or (h) for preparing compounds of the formula I'a wherein R_. is hydrogen or compounds of the formula lb wherein R 2 and Re are the same, reacting allopurinol, 1 -hydroxymethyialIopuriπol, or 2,5-dihydroxy- methylallopurinol with a compound of the formula VI I" wherein n is as defined above, or (i) for preparing compounds of the formula I'a wherein R e is hydrogen or compounds of the formula lb wherein R-, and Re are the same, reacting a compound of the formula XVI wherein R g and R q are as defined above, with a compound of formula or with a compound of formula XVI I f OMP or with a compound of formula XIX wherein n and Z are as defined above, or (j) for preparing compounds of the formula I 'a wherein R, is O II HO - P - O - CH-, ! OH and Re is hydrogen, 1 ) hydrogenating the corresponding dibenzyl phosphate, or 2) hydrolyzing the corresponding 2-cyanoethyl phosphate, or 3) reacting l -hydroxymethylallopurinol with pyrophosphoryl tetra- chloride followed by- hydrolysis, and thereafter, if desi red, converting the resulting compound of the formulas I 'a or lb into a salt thereof. 14. A pharmaceutical composition for rectal , parenteral, or oral use in the prevention and treatment of hyperuricemic states such as gout comprising a pharmaceutically acceptable carrier or excipient in com¬ bination with a compound of the formulas I'a or lb wherein R. is a group of the formula I I Q 1! R 3 - C - A - I I wherein 3 is alkyl; phenyl; phenyl substituted with halogen , lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; phenyl-lower alkyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy or phenoxy; or phenyl- lower alkenyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; or R is an aromatic 5- og 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitro¬ gen, oxygen, and sulfur; and A is a single bond or a group of the formula I la - O - C ft - I la I R 7 wherein the carbon atom is attached to the nitrogen atom of the parent ring system, and wherein Rg and Ry are the same or different and each represent hydrogen or have the same meaning as R-. as defined above; or R, is a group of the formula i l l wherein R g and R g are the same or different and each represent hydrogen or have the same meaning as R-. as defined above; or R g and Rg together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Y " is a single bond or a group of the formula I l ia wherein n is an integer from 1 to 5 and ' A, Rg and Ry are as defined above; or R, is a group of the formula IV O II R 3 - O - C - A IV wherein R and A are as defined above; or R- is a group of the formula VI. O II R 10 - C - A - VI wherein R.. -. is a mono- or polyhalogenated lower alkyl group and A is as defined above; or R, is a group of the formula VI I O O II , - II R., - C - (CH-) - C - A - VI I ό J. rt wherein n and A are as defined above, and R.-, is hydroxy or a group of the formula -NR g Rg wherein R g and R g are as defined above; or R. is a group of the formula IX O Re II HO - P P -- OO -- C C - IX 1 1 OH R 7 wherein R β and Ry are as defined above; R 2 is any of the groups I I , I I I , IV, VI , and VI I as defined above with the proviso that A solely is the group I la as defined above; and Re is hydrogen or has the same meaning as R 2 as defined above, and salts thereof. 15. A method for preparing a composition according to claim 14 com¬ prising combining a pharmaceutically acceptable carrier or excipient with a compound of the formulas I'a or lb as defined in claim 14. 16. A method for treating and preventing hyperuricemic states com¬ prising administering an amount effective in lowering the level of uric acid, of a compound according to any of claims 1 -12 or prepared according to claim 13 optionally in a pharmaceutical composition accor¬ ding to claim 14, to warm-blooded animals including humans . OMPI .A ALLOPURINOL PRODRUGS ABSTRACT Compounds are disclosed of the general formulas la and lb wherein R- is a group of the formula II O II R 3 - C - A - II wherein R-. is alkyl; phenyl; phenyl substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; phenyl-lower alkyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy or phenoxy; or phenyl- lower alkenyl in which the phenyl group may be substituted with halogen, lower alkyl, hydroxy, lower alkoxy, acetoxy, or phenoxy; or R 3 is an aromatic 5- og 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitro¬ gen, oxygen, and sulfur; and A is a single bond or a group of the formula Ila R β - O - C - Ila I R 7 wherein the carbon atom is attached to the nitrogen atom of the parent ring system, and wherein R fi and y are the same or different and each represent hydrogen or have the same meaning as R-, as defined above; or R, is a group of the formula 1 11 wherein R g and R q are the same or different and each represent hydrogen or have the same meaning as R as defined above; or Rg and R q together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; Y is a single bond or a group of the formula I l ia wherein n is an integer from 1 to 5 and A, R fi and Ry are as defined above; or R.. is a group of the formula IV O II C - A IV wherein A is as defined above and R'o has_ the same meaning as Ro defined above, with the proviso that R' 3 is not ethyl when A is a bond; or R- is a group of the formula VI R fl 10 VI wherein R,-. is a mono- or polyhalogenated lower alkyl group and A is as defined above; or R- is a group of the formula VII O O R.. \-, - C- (CH i-)n - C - A - VII wherein n and A are as defined above, and R.- is hydroxy or a group of the formula -NRgR q wherein R g and R q are as defined above; or R. is a group of the formula IX O R c II 16 HO - P - O- C- IX OH Ry wherein R fi and Ry are as defined above; • R is any of the groups II, III, IV, VI, and VII as defined above with the proviso that A solely is the group Ila as defined above; and R e is hydrogen or has the same meaning as R 2 as defined above, and salts thereof. The compounds of the formulas la and lb are prodrugs of allopurinol and have i.a. a much higher solubility in water and/or a higher Iipophilicity than allopurinol, which makes such compounds extremely useful for oral, parenteral and rectal administration to a warm-blooded animal, such as a human. Such compounds will after administration be converted into allopurinol. Thus, the mean levels of the allopurinol metabolite oxipurinol measured after rectal administration of 1-(butyry!oxymethyl)al!opurinol (Δ) and 1-(N,N-diethylglycyloxymethyl)alIopurinol hydrochloride (o) to rabbits at a level of 25 mg allopurinol equivalents were considerably higher than the level measured after rectal administration of 25 mg allopurinol OMPI

Inventors: BUNDGAARD HANS, FALCH ERIK, BUNDGAARD, HANS, FALCH, ERIK
Applicants: GEA AS, A/S GEA
Application year: 1984
Main classification: C07D487
IPC codes: A61K31, A61P19, A61P43, C07D487, C07F9