Title of Invention	A PROCESS FOR PREPARING PURINE DERIVATIVES
Abstract	This invention relates to a process for preparing purine derivatives of e general formula in which R<SUB>1</SUB> represents a myrtanyl group or a C<SUB>1</SUB>-C<SUB>6</SUB> alkyl group optionally substituted by a C<SUB>3</SUB>-C<SUB>8</SUB> cycloalkyl substituent group R<SUB>2</SUB> represents a hydrogen atom, X represents an oxygen or sulphur atom and Y represents a group of formula where Z represents an oxygen or sulphur atom, and R4 represents a hydrogen atom or a C<SUB>1</SUB>-C<SUB>6</SUB> alkylthio group; and m is 0 or an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

Title of Invention

A PROCESS FOR PREPARING PURINE DERIVATIVES

Abstract

This invention relates to a process for preparing purine derivatives of e general formula in which R1 represents a myrtanyl group or a C1-C6 alkyl group optionally substituted by a C3-C8 cycloalkyl substituent group R2 represents a hydrogen atom, X represents an oxygen or sulphur atom and Y represents a group of formula where Z represents an oxygen or sulphur atom, and R4 represents a hydrogen atom or a C1-C6 alkylthio group; and m is 0 or an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

Full Text	The present invention relates to a process for preparing purine derivatives. The worldwide resurgence of human malaria during the past decade (Wyler, DJ.,1983, N. Engl. J. Med., 308, 875-878) has been in part due to the rapid spread of Plasmodium falciparum and Pvivax strains resistant to chloroquine and other commonly used antimalarial drugs (Geary et al., 1986, in Drug resistance in protozoa p.209-238 - W.C.Campbell and R.S.Rew (ed) Chemotherapy of parasitic diseases, Plenum Publication Corp., N.Y. and Peters, W., 1985, Parasitology, 90, 705-715). In view of this resurgence there is an urgent need to develop and identify additional safe and effective drugs (Rieckmann, K., 1983, Ann. Rev. Med., 34, 321-325). In accordance with the present invention, there is provided a process for preparing compound of general formula A-B (I) wherein A represents a group of formula in which R1 represents a myrtanyl group or a C1-C6 alkyl group optionally substituted by a C3-C8 cycloalkyl substituent group, R represents a hydrogen atom, X represents an oxygen or sulphur atom, and Y represents a group of formula where Z represents an oxygen or sulphur atom, and R4 represents a hydrogen atom or a C1-C6 alkylthio group; and B represents a group of formula (IV) in which m is 0 or an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, each R7 and each R8 independently represents a hydrogen atom, or an amido (-CONH2) or C1-C4 alkyl group, when m is 0, R9 represents a hydroxyl (-OH), a C3-C8 cycloalkylmethyl, or a pyrazolyl optionally substituted by a C1-C4 alkyl substituent group, or R9 may, together with the NH group to which it is attached, form a piperazinyl ring optionally substituted by a C1-C4 alkyl substituent group, and when m is other than 0, R9 represents a hydrogen atom or hydroxyl (-OH), amido (-CONH2), a group -N(R10)p where each R10 independently represents a hydrogen atom or a C1-C4 alkyl group and p is an integer from 2 to 3, or R9 represents a group of formula in which A' is a group as defined above for A; or a pharmaceutically acceptable salt or solvate thereof. In the context of the present specification, unless otherwise stated, an alkyl group or an alkyl moiety in an alkoxy or alkylthio group may be linear or branched. When R^ represents a group -N(R^*^)p and p is 3, it should be understood that the nitrogen atom will possess a positive charge. The group R1 represents a myrtanyl group or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n- hexyl) group optionally substituted by a C3-C8, preferably C5-C6, cycloalkyl substituent group. R^ especially represents a myrtanyl, isobutyl or cyclohexylmethyl group. R represents a hydrogen atom or a group -CH2CO2R where R represents a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl) group. R is especially a hydrogen atom. X represents a sulphur, or preferably, oxygen atom. Z represents an oxygen, or preferably, sulphur atom. R4 represents a hydrogen atom or a C1-C6, preferably C1-C4, alkylthio (e.g. methyl-, ethyl-, n-propyl-, n-butyl-, n-pentyl- or n-hexylthio) group. R4 is especially a hydrogen atom. Each R6 independently represents a hydrogen atom or a C1-C6, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy or n-hexoxy) group. In a preferred embodiment, both groups R^ are the same, e.g. hydrogen or methoxy. R6 represents a hydrogen atom or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl) group. Most preferably, R6 represents hydrogen or methyl. Each R6 independently represents a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl) group. Each R and each R independently represents a hydrogen atom, or an amido or C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl) group. When m is 0, R9 represents a hydroxyl, a C3-C8 cycloalkylmethyl, preferably C5-C6 cycloalkylmethyl, or a pyrazolyl optionally substituted by a C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl) substituent group, or R9 may, together with the NH group to which it is attached, form a piperazinyl ring optionally substituted by a C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl) substituent group. When m is other than 0, then R9 represents a hydrogen atom or hydroxyl, amido, a group -N(R10p where each R10 independently represents a hydrogen atom or a C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl) group and p is an integer from 2 to 3, or a group of formula The group A' may be the same or different to the group A. Particularly preferred compounds of the invention include: N-(2-Aminoethyl)-2-(4-{3-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide, N-[2-(Dimethylamino)ethyl]-2-(4- {3-[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide, N-(2-Aminoethyl)-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetamide, 3-[(6,6-Dimethylbicyclo[3.1l]hept-2-yl)methyl]-8-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethoxy]phenyl} -2-thioxo-1,2,3,9-tetrahydro-6H-purin-6-one, 2-(4- {3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[2-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9- tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)ethyl] acetamide, 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[l-(hydroxymethyl)-2-methylpropy 1] acetamide, 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[7-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)heptyl] acetamide, 2-(4-{3-[(6,6-Dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-pu^in-8-yl}phenoxy)-N-[9-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)nonyl] acetamide, 2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)pentyl]acetamide. 2-{4-[3-(Cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)pentyl]acetamide, N 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl} phenoxy)-N-( 1-ethyl-1H-pyrazol-3-yl) acetamide, N-[2-(Diisopropylamino)ethyl]-2-(4-{3-[(6,6-dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetamide, N-(5-Aminopentyl) -2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy] acetamide, 2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide, N,N-Dibutyl-2-(4-{3-[(6,6-dimethylbicyclo[3.1l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetamide, 2-{[2-(4-{3-[(6,6-Dimethylbicyclo[3.1.]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl} phenoxy)acetyl]amino} -pentanediamide, N-(5-Aminopentyl)-2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro- 1 H-purin-8-yl]phenoxy} acetamide, N-hydroxy-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetamide, 2-(4- {3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl }phenoxy)-N-hydroxyacetamide, 2-{4-[3-(Cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-hydroxyacetamide, 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy}-N-pentylacetaniide, 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide, 2-[(2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yI]phenoxy} acetyl)amino] -N,N,N-trimethyl-1 -ethanaminium iodide, and their pharmaceutically acceptable salts and solvates. Reference is made divisional application under no. 326/mas/2002 filed on 26th April, 2002 , wherein a compound of general formula (I) A-B (I) wherein A represents a group of formula in which R1 represents a myrtanyl group or a CrC6 alkyl group optionally substituted by a C3-C8 cycloalkyl substituent group, R represents a hydrogen atom or a group -CH2CO2R , R represents a C1-C6 alkyl group, X represents an oxygen or sulphur atom, and Y represents a group of formula R4 represents a hydrogen atom or a C1-C6 alkylthio group; and B represents a hydrogen atom, a C1-C6 alkyl or carboxyphenyl group, a group of formula in which each R5 independently represents a hydrogen atom or C1-C6 alkoxy group and R6 represents a hydrogen atom or C1-C6 alkyl group, a group of formula (IIIA) in which each R6 independently represents a C1-Ce alkyl group, or B represents a group of formula in which m is 0 or an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, each R7 and each R8 independently represents a hydrogen atom, or an amido (-CONH2) or C1-C4 alkyl group, when m is 0, R9 represents a hydroxyl (-OH), a C3-C8 cycloalkylmethyl, or a pyrazolyl optionally substituted by a C1-C4 alkyl substituent group, or R9 may, together with the NH group to which it is attached, form a piperazinyl ring optionally substituted by a C1-C4 alkyl substituent group, and when m is other than 0, R9 represents a hydrogen atom or hydroxyl (-0H), amido (-CONH2), a group -N(R10)p where each R10 independently represents a hydrogen atom or a C1-C4 alkyl group and p is an integer from 2 to 3, or R9 represents a group of formula in which A' is a group as defined above for A; or a pharmaceutically acceptable salt or solvate thereof is described and claimed. The present invention provides a process for the preparation of a compound of formula (I) as defined above or a pharmaceutically acceptable salt or solvate thereof which comprises reacting a compound of general formula (VI) in which X, Y, R1, R2 are as defined in formula (1), with a compound of general formula wherein m, R7, R8 and R9 are as defined in formula (I); The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as an alcohol, dimethylformamide or dichloromethane at a temperature of, for example, 15°C or above such as a temperature in the range from 20 to 200°C. Compounds of formulae (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) are either commercially available, are well known in the literature or may be prepared easily using known techniques. Compounds of formula (I) can be converted into further compounds of formula (I) by means of standard procedures. For example, compounds of formula (I) in which R9 represents NH2 can be converted to compounds of formula (I) in which R9 represents NH(CrC4 alkyl) or N(C1-C4 alkyl)2 usiing a suitable alkylating agent. It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991). The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. The compounds obtained according to the present invention are advantageous in that they inhibit the growth of malarial parasites such as Plasmodium falciparum and, therefore, are useful as pharmaceuticals in the treatment of malaria. Thus, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as herein before defined in the manufacture of a medicament for use in therapy. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. The invention also provides a method of treating a malarial disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined. The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition. The pharmaceutical composition may additionally contain another anti-malarial agent and/or various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as herein before defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as herein before defined, with a pharmaceutically acceptable adjuvant, diluent or carrier. The daily dosage of formula (I) compound administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the malarial disease indicated. However, in general, satisfactory results will be obtained when the compound of formula (I) is administered at a daily dosage not exceeding 1 g, e.g. in the range from 10 to 50 mg/kg body weight. The compounds according to the invention may be administered systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions. The invention will now be further explained by reference to the following illustrative examples. Examples General Procedure for Isothiocvanates The preparation of isobutyl isothiocyanate is representative. A solution of isobutylamine (0.287 mol, 29 ml) in dioxane (50 ml) and triethylamine (0.287 mol, 40 ml) was cooled to 0°C and carbon disulphide (0.287 mol, 16.8 ml) was added in small portions to this solution over a period of 0.25 hr. The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 2 hr. It was then cooled to -10°C and ethyl chloroformate (0.31 mol, 30 ml,) was added dropwise over a period of 0.25 hr to the reaction mixture. The reaction mixture was stirred at O°C for 0.5 hr and then at room temperature for 1 hr. The precipitated solid was filtered off and the filtrate was diluted with chloroform (50 ml) and triethylamine (40 ml). This was stirred at room temperature for 1 hr. Volatiles were removed in vacuo and the resulting residue was distilled to give the desired isobutyl isothiocyanate. Yield: 16 gm (50%), b.p. 50°C 4.5 mm Hg. In the case of myrtanyl and cyclohexylmethyl isothiocyanates, the crude product was used as such for further reaction sequence without purification / distillation. General Procedure for Thiourea Preparation of isobutyl thiourea is representative. A solution of isobutyl isothiocyanate (0.139 mol, 16 gm) in anhydrous ether (10 ml) was treated with a large excess of liquid ammonia for 3 hr. Excess ammonia was allowed to evaporate in a fume hood and the residual mass was dried in vacuo and used for further reactions without purification. Yield: 15.6 gm (85%). General Procedure for 6-Amino-3-alkyl-2-thioxopvrimidinones A solution of alkyl thiourea (0.151 mol) in 180 ml of anhydrous methanol was gently refluxed while a solution of sodium methoxide in methanol (0.334 mol, 75 ml) was added over a period of 0.5 hr., followed by the addition of ethyl cyanoacetate (0.174 mol, 18.6 ml). The reaction mixture was refluxed for 10 hr. Methanol was removed in vacuo and the residue was triturated with water (100 ml) and neutralised to pH-7 with conc, hydrochloric acid. The precipitated solid was filtered off, washed repeatedly with water and dried to afford the desired pyrimidinone derivative. Yield: 65-70%. Nitrosation E.g.: 6-amino-l- [(6,6-dimethylbicyclo [3.1.1]hept-2-yl)methyl]-5-nitroso-2-thioxo-2,3-dihydro-4( 1H-pyrimidinone : A suspension of 6-amino-l- [(6,6-dimethylbicyclo [3.1.1] hept-2-yl)methyl]-2-thioxo-2,3-dihydro-4(17/)-pyrimidinone (3.24 mmols, 1 gm) in 5ml of glacial acetic acid at 90°C was treated with a solution of sodium nitrite (0.33 5gm in 1ml of water ) with vigorous stirring. The mixture was allowed to stir at 90°C for 0.5 hr., and the dark pink crystals obtained were filtered off and washed with water. Yield: 0.55gm (50%). Following the same procedure, nitroso derivatives with isobutyl and myrtanyl groups were prepared from the respective thioureas. General Procedure for l-Alkvl-5,6-diaminO-2-thioxo-pvrimidinones E.g. 5,6-diamino-1 -[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-2-thioxo-2,3-dihydro-4( 1 H)-pyrimidinone [II]. Hydrogen gas was bubbled through a suspension of 6-amino-l-[(6,6-dimethylbicyclo[3.1. l]hept-2-yl)methyl]-5-nitroso-2-thioxo-2,3-dihydro-4(lH)-pyrimidinone (1.35 mmols, 0.4 gm) in 50ml of methanol and 0.04 gm of platinum dioxide. The completion of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was then filtered over a bed of celite and the organic portion was concentrated in vacuo to fumish the title compound. Yield: 0.32gm(83%). In a similar way, corresponding isobutyl and cyclohexylmethyl diamino-2-thioxo-pyrimidinones were prepared. General Procedure for 3-Alkvl-2-thioxopurines E.g. 3-[(6,6-dimethylbicyclo [3.1.1] hept-2-yl)methyl]-2-thioxo-l,2,3,9-tetrahydro-6H-purin-6-one: A solution of 5,6-diamino-1 -alkyl-2-thioxo-2,3 -dihydro-4 (1H)-pyrimidinone (1.13 mmols, 0.250 gm) in 15ml of orthoformate was refluxed 0 for 3 hr. at 140 C. After cooling to room temperature, 5ml of n-hexane was added to precipitate the product, which was chromatographed (50% ethyl acetate: hexane). Yield: 0.170 gm (65%). In a similar way, corresponding isobutyl- and cyclohexylmethyl-2-thioxo-l,2,3,9-tetrahydro-6H-purin-6-ones were prepared. General Procedure for 3-Alkvl-8-methvl-2-thioxopurines E.g. 3-[(6,6-dimethylbicyclo [3.1.1]hept -2-yl)methyl]-8-methyl-2-thioxo-l,2,3,9-tetrahydro-6H-purin-6-one: A solution of 5,6-diamino-1 -[(6,6-dimethylbicyclo[3.1.1 ]hept-2"yl)methyl]-2-thioxo-2,3-dihydro-4(lH)-pyrimidinone (1.13 mmols, 0.25 gm) in trimethyl orthoacetate (15 ml) was refluxed for 3 hr. After cooling to room temperature, w-hexane (5 ml) was added. The resulting solid was chromatographed (50% ethyl acetate: hexane). Yield: 0.150 gm (55%). The corresponding purines with isobutyl and cyclohexylmethyl groups were also prepared following the procedure mentioned above. General Procedure for 3-Alkvl-6-thioxopurines E.g.:3-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-3,9-dihydro-lH- A suspension of 3-[(6,6-dimethylbicyclo [3.1.1]hept-2-yl)methyl]-2-thioxo-l,2,359-tetrahydro-6H-purin-6-one (3.28 mmols, 1 gm) in anhydrous toluene (35ml) was refluxed in an oil bath for 0.25 hr. and to this was added Lawessons reagent (1.65 mmols, 0.664 gm) under nitrogen and the reflux continued for 7 hr. Solvent was removed in vacuo and the resulting residue was purified by flash chromatography (5% methanol in chloroform). Yield: 0.53 gm (50%). IHNMR: 0.78(d,y=9.3 Hz, 1H); 1.13(s, 3H); 1.25(s, 3H); 1.6-1.76(m, 1H); 1.78-2.26(m,6H); 2.26-2.39(m, 1H); 2.42(s, 3H) ; 2.8-3.0(m , 1H); 4.5-4.65(m,2H); 10.2-10.3(bs, lH)and 10.4-10.5(brs, 1H). 3-Isobutyl-3,9-dihydro-lH-purine-2,6-dithione and 3-cyclohexylmethyl-3,9-dihydro-lH-purine-2,6-dithione were obtained in a similar way. General Procedure for 3-Alkvl-4-amino-5-[4-f(carboxvmethyl)-oxv)benzvlidene1amino1pyrimidines E.g. 2-{4-[({6-amino-l-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-4-oxo-2-thioxo-l,2,3,4-tetrahydro-5- pyrimidinyl}imino)methyl] phenoxy} acetic acid : A solution of 5,6-diamino-l-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-2-thioxo-2,3-dihydro-4(lH)-pyrimidinone (0.51 mmol, 0.15 gm) in of anhydrous methanol (10 ml) was heated in an oil bath at 609°C for 0.25 hr. 4-Formylphenoxyacetic acid (0.51 mmol, 0.092 gm) was added to this solution > - - - - and reflux continued for 1.5 hr. After cooling to room temperature, the precipitated yellow solid was filtered. The filtrate was evaporated to dryness and taken in ethyl acetate to obtain an additional lot of the desired product. Yield: 0.169 gm (65%). General Procedure for 2-[4-(3-AlkvI-6-oxo-2-thioxo-23^6,9"tetrahvdro-1H'-purin-8-yl}phenoxvl]acetic acids E.g. 2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8- yl)phenoxy]acetic acid: A suspension of 2-{4-[({6-amino-l-[(3-isobutyl-4-oxo-2-thioxo-l,2,3,4-tetrahydro-5-pyrimidinyl}imino)methyl]phenoxy}acetic acid (2.04 mmols, 0.77 gm) in anhydrous dimethyl formamide (20ml) and anhydrous ferric chloride (0.132 gm) was refluxed for 7 hr. The reaction mixture was cooled to room temperature and water was added while stirring to precipitate a pale green solid, which was filtered, washed with water and dried in vacuo. Yield 0.59 gm (78%). 1H NMR: 0.85(d, J= 6.2Hz ,6H) ; 2.6(m, 1H) ; 4.36(d & s , y=7 Hz & 4 Hz, 4H); 6.9(d, 7=8.7 Hz, 2H); and 7.9(d, J=8.7 Hz, 2H). The corresponding purine derivatives with myrtanyl and cyclohexylmethyl were prepared in a similar way. General Procedure for 4-(3-Alkvl-6-oxo-2-thioxo-2,3,6,9-tetrahvdro-lH-purin-8-yl)benzoic acids E.g. 4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9 -tetrahydro-lH-purin-8-yl)benzoic acid: The title compound was prepared using the appropriate l-alkyl-5,6-diamino-2-thioxo-pyrimidinone and 4-carboxybenzaldehyde according to the preceding procedure. 1H NMR: 0.9(d , J= 6.8 Hz , 6H) ; 2.5(m, 1H) ; 4.4(d, J- 7.3 Hz, 2H:); 8.1(d,J=11.5Hz,2H); 8.3(d, J= 11.5 Hz, 2H); 12.6(s, 1H); 13.3(bs,lH); 14.4(s, 1H). The corresponding purine derivatives w^ith myrtanyl and cyclohexylmethyl were prepared in a similar way. General Procedure for Methvl-2-alkvl-6-oxo-2-thioxO-2,3,6^9-tetrahydro-lH-purin-8-vl}phenoxvyacetates E.g. Methyl 2-(4-{3-[(6,6-dimethylbicyclo [3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetate: A solution of the corresponding acid (1.06 mmols, 0.48 gm) in anhydrous methanol (9 ml), 2,2-dimethoxypropane (26 ml) and a drop of conc, sulfuric - acid was refluxed for 5 hr. The resulting pale yellow solid was filtered and washed with ethyl acetate to obtain the title compound. Yield : 0.229 gm (46%). E.g. Methyl 2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-1 H-purin-8-yl]-2,6-dimethoxyphenoxy} acetate: The title compound was prepared using the appropriate l-alkyl-5,6-diamino-2-thioxo-pyrimidinone and 4-formyl-2,6-dimethoxyphenoxy acetate. IHNMR: 1.20(m, 5H,), 1.60(m, 5H,), 2.0(m, 1H,), 3.70(s, 3H), 3.80(s, 6H), 4.20(m, 4H), 7.50(m, 2H), 9.0(bs, 1H), 13.70(bs, 1H). E.g. Methyl 2-{3-(cyclohexylmethyl)-8-[4-(2-methoxy-2-oxoethoxy) phenyl]-6-oxo-2-thioxo-1,2,3,6-tetrahydro-7H-purin-7-yl} acetate: The title compound was prepared by alkylation of methyl 2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-purin-8-yl]-2,6-dimethoxyphenoxy}acetate with ethyl bromoacetate and sodium hydride. IRNMR: 1.20(m, 5H), L60(m, 5H), 2.0(m, 1H), 3.70(s, 3H), 3.80(s, 6H,), 4.10(s, 2H), 4.20(d, 2H), 4.5(s, 2H), 7.50(m, 2H), 13.70(bs, 1H). General Procedure for 3-Alkvl-8-[4-[(carboxvmethvl)oxv1phenvl1-2-thioxopurine amides Procedure I: Using 2-{3-alkyl-8-[4-(2-methoxy-2-oxoethoxy)phenyl]-6-oxo-2-thioxo-l,2,3,6-tetrahydro-7H-purin-7-yl}acetate: A solution of the title ester (1 mmol) in anhydrous dimethyl formamide (1 ml) and the corresponding amine (1.2 mmols ) was stirred at room temperature. (~10h). Water was added to the mixture and the resulting precipitate was filtered off, washed with water and was further purified by flash chromatography on silica gel (methanohchloroform). Yield: (40 -50%). E.g. N-(2-Aminoethyl)-2-(4-{3-[(6,6-dimethylbicyclo[3.1.1]hept-2- yl)methyl]-6-oxo-2-thioxo-2,3,5,6,5,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide: IH NMR: 0.79(d, 7=9.35 Hz , 1H) ; 1.10(s, 3H); 1.37(s,3H); 1.6-1.9(m , 6H); 2.1-2,3(m, 1H); 2.87-2.9(m, 4H); 3.1-3.6(bm, 4H); 4.4-4.6(m & s , 4H); 7.03(d, J=8.O Hz, 2H); 8.05(d, J=8.0 Hz , 2H) and 8.3(bs, 1H). E.g. N-[2-(Dimethylamino)ethyl]-2-(4-{3-[(6,6-dimethylbicyclo[3.1.l]hept- 2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide: IH NMR: 0.78(d, J=9A Hz, 1H); 1.09(s, 3H); 1.36(s, 3H); 1.7-1.9(m, 6H); 2.2(s, 6H); 2,38(bs , 2H); 2.88(m, 1H); 3.25(m, 2H); 4.4-4.7(m & s, 4H); 7.12(d, J=8.8 Hz , 2H); 8.1(bd, 3H); 12.3(bs, 1H). E.g. N-(2-Aminoethyl)-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetamide: IHNMR: 0.9(d, J=6.7 HZ , 6H); 2.49-2.72(bs, 3H); 2.84(bm, 2H:); 3.2(m, 2H); 4.3(d, J=7.4 Hz , 2H); 4.53(s, 2H); 7.0(d, J=8.4 Hz , 2H:); 8.0(d, J=8.4 Hz , 2H) and 8.2(bs , 1H). Procedure II: Using l-({244-(3-Alkyl-6-oxo-24hioxo-23,6,94etrahydro-lJ¥-purin-8-yl) phenoxy] acetyl} oxy)-2,5-pyrrolidinedione: The title N-hydroxysuccinimide derivative (1 mmol) in anhydrous dimethyl formamide(l ml) and amine (1.2 mmols ) was allowed to stir at room temperature until completion of the reaction (-5-1 Oh). Water was added to the mixture and the resulting precipitate was filtered off and washed with water, and further purified by flash chromatography on silica gel (methanol: chloroform). Yield: 45-50%. E.g. 3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-8-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethoxy]phenyl} -2-thioxo-1,2,3,9-tetrahydro-6H-purin-6- one : lHNMR:(0.8(d,J=7Hz,lH); 1.12(s,3H); 1.32(s,3H); 1.5-2.0(m, 5H); 2.24(s, 3H); 2.9(m , 1H); 3.34(m, 8H); 4.45(m, 2H); 4.92(s, 2H); 7.05(d, y=8 Hz , 2H); 8.06(d, J=8 Hz, 2H); 12.35(m, 1H) and 13.9(m, 1H). E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[2-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9- tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)ethyl] acetamide: 1H NMR: 0.8(d, J=9 Hz , 1H); 0.86(s, 3H); ().88(s, 3H); 1.10(s, 3H:); 1.32(s, 3H); 1.5-2.0(m, 5H); 2.15-2.26(m, 1H); 2.65(m, 1H:); 2.75(m , 1H); 3.20(m, 2H); 4.3-4.55(m, 6H); 7.05(m, 4H); 8.10(m, 4H); 8.26(m , 2H); 12.38(s,2H); 13.82(s,2H). E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl}phenoxy)-N-[ 1 -(hydroxymethyl)-2-methylpropyljacetamide: IHNMR: 0.82(d, 3H); 0.89(d & S, 1H & 3H); 1.04(S, 3H); 1.25(S, 3H); 1.75-2.05(m, 5H); 2.20(m, 1H); 3.42-3.65(m, 2H); 6.96(d, 2H); 7.33-7.65(bs,lH); 8.12(d,2H); 11.81(bs , 1H); 13.55(bs , 1H). E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.l]hept-2-yi)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[7-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetyl} amino)heptyl] acetamide: 1H NMR: 0.8(d, J=9 Hz , 1H); 0.86(s, 3H); 0.88(s, 3H); 1.10(s, 3H:); 1.32(s, 3H); 1.5-2.0(m, 5H); 2.15-2.26(m, 1H); 2.90(m, 1H:); 3.20(m, 4H); 3.30(m, lOH); 4.3-4.55(m, 8H); 7.05(m, 4H); 8.10(m, 6H); 12.38(s, 2H); 13.82(s,2H). E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[9-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetyl} amino)nonyl] acetamide: IR NMR: 0.8(d, J=9 Hz , 1H); 0.86(s, 3H); 0.88(s , 3H); 1.10(s, 3H:); 1.32(s, 3H); 1.5-2.0(m, 5H); 2.15-2.26(m, 1H); 2.90(m, 1H:); 3.20(m , 4H); 3.30(m, 14H); 4.3-4.55(m, 8H); 7.05(m, 4H); 8.10(m, 6H); 12.38(s, 2H);.13.82(s,2H). E.g. 2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8- yl)phenoxy]-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)pentyl]acetamide: 1H NMR: 0.90(d, 12H), 2.65(m, 1H), 3.0-3.80(ni, lOH), 4.30(d, 4H), 4.50(s, 4H), 7.05(m, 4H); 8.10(m,6H); 12.38(s,2H); 13.82(s,2H). E.g. 2- {4-[3 -(Cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-1H- purin-8-yl]phenoxy}-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9- tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)pentyl]acetamide: IHNMR: 0.90(d, 6H), 1.0-1.80(m, lOH), 2.20(m, 1H), 3.0-3.80(m, UH), 4.30(d, 4H), 4.50(s, 4H), 7.10(m, 4H); 8.10(m, 6H); 12.38(s, 2H); 13.82(s, 2H). The respective homo and hetero dimers were prepared in a similar way. E.g. N-(Cyclohexylmethyl)-2-(4-{3-[(6,6-dimethylbicyclo[3.1. l]hept-2- yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide: IHNMR: 0.80-2.20(m), 2.90(m, 1H), 3.30(m, 2H), 4.60(m, 4H), 6.60, (m, 1H), 7.0(d, 2H), 8.10(d, 2H), 10.0(m, 1H), 12.90(m, 1H). E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahy dro-1H-purin-8-yl} phenoxy)-Ar-( 1 -ethyl-1H-pyrazol-3 -yl) acetamide: lHNMR:0.8(d,J=9Hz,lH); 1.10(s, 3H); 1.20(t, 3H), 1.30(s,3H); 1.60- 2.0(m, 6H), 2.30(m, 1H), 2.80(m, lH),4.0(m, 1H), 4.40-4.60(m, 2H), 4.90(s, 3H), 6.20(s, 1H), 7.10(d, 2H), 7.40(s, 1H), 8.10(d, 2H), lO.O(lH), 12.30(bs, 1H), 13.90(bs, 1H). E.g.N-[2-(Diisopropylamino)ethyl]-2-(4-{3-[(6,6- dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin- 8-y 1} phenoxy)acetamide: 1H NMR: 0.78(d, J=9.4 Hz , 1H), 1.0(d, 6H), 1.09(s, 3H), 1.36(s , 3H), 1.7- 1.9(m , 6H), 2.20(m.lH), 2.80-3.0(m,4H), 4.40-4.80(m, 4H), 7.0(d, 2H), 7.80(m, 1H), 8.10(d, 2H), 12.40(m, 1H), 13.80(m, 1H). E.g. N-(5-Aminopentyl) -2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9- tetrahydro-1 H-purin-8-yl)phenoxy] acetamide: 1H NMR: 0.9(d , 7=6.7 Hz, 6H), 1.20(m, 2H), 1.40(m ,4H,),2.60(m, 1H, CH(CH3)2), 3.10(m ,4H), 4.40(d, 2H), 4.60(s, 2H), 7.10 (d, 2H), 8.0 (s,lH,), 8.10(d,2H), 12.50(s,lH), 13.80(s, 1H). E.g. 2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide: 1H NMR: 1.20(m, 5H), 1.70((m, 5H), 2.30(m, 2H), 3.35(m, 2H), 4.30(d, 2H), 4.50(s, 2H), 7.10(d, 2H), 8.10(d, 2H), E.g. N,N-Dibutyl-2-(4-{3-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetamide: IHNMR: 0.90(m, 6H), 1.10(s, 3H), 1.20(m, 1H), 1.90(m, 5H), 2.30(m,lH), 2.40(m, 4H), 2.60(m,2H),3.0(m, 2H), 3.40(m,2H), 4.50-4.70(m, 4H), 7.0(d, 2H), 7.40(m, 1H), 8.10(d, 2H). E.g. 2- {[2-(4- {3 -[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2- thioxo-2,3,6,9-tetrahydro-1 H-purin-8- y 1} phenoxy)acety 1] amino } pentanediamide: IR NMR: 0.78(d , J=9.4 Hz , 1H), 1.09(s, 3H), 1.36(s, 3H), 1.7-2.30(m ,13H), 4.40-4.80(m, 4H), 6.80(m, 1H), 7.15(d, 2H),7.30&7.40(2m, 2H), 8.10(d,2H). E.g. N-(5-Aminopentyl)-2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-1 H-purin-8-yl]phenoxy } acetamide: 1H NMR: L0-1.80(m, 16H), 2.30(m, 1H), 2.80 &3.0( 2m, 4H), 4.30(d, 2HX 4.50(s, 2H), 7.0(d, 2H), 8.0(d, 2H), 8.10(m, 1H), General Procedure for 3-AlkvI-8[4-[(carboxvmethvl)oxv1phenvl1-2-thiopurine hvdroxamic acids a) From l-({2-[4-(3-alkyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-y l)phenoxy] acetyl} oxy )-2,5 -pyrrolidinedione: The title N-hydroxysuccinimide deriv. (1 mmol ) in anhydrous dimethyl formamide (1 ml), triethylamine (1.2 mmols, 0.17 ml ) and hydroxylamine hydrochloride (1.2 mmols, 0.084 gm) was allowed to stir at room temperature until completion of the reaction (-l-10h). Water was added to the mixture and the resulting precipitate was filtered off and purified by flash chromatography on silica gel (methanol: chloroform) to furnish the respective hydroxamic acids. Yield : 45 - 50 %. E.g. N-hydroxy-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetamide: 1H NMR: 0.9(d, 6H); 2.40-2.70(m, 1H), 4.30(d, 2H), 4.50(s, 2H), 7.0(d, 2H), 8.0(d, 2H), 9.0(bs, 1H), 10.90(bs, 1H), 12.50(bs, 1H), 14.0 (bs, 1H). E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl }phenoxy)-N-hydroxyacetamide: 1H NMR: 0.79(d, J=9.35 Hz, 1H) ; 1.10(s, 3H): 1.30(s, 3H); 1.6-1.9(m, 3H); 2.1-2.7(m , 5H); 4.30-4.60(m, 4H), 7.0(d, 2H), 8.0(d, 2H), 8.8(bs, 1H), 9.90(bs, 1H), 10.50(bs, 1H), 13.4 (bs, 1H). E.g.: 2-{4-[3-(Cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-hydroxyacetamide: 1H NMR: 0.70(m, 5H), 1.50(m, 5H), 4.40(d, 2H), 4.50(s, 2H), 7.0(d, 2H), 8.0(d, 2H). General Procedure far 3-Alkvl-8- [4[][(carboxvmethvl)oxvlDhenvl1hvpoxanthines E.g. 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl] phenoxy} acetic acid: A suspension of the appropriate purine acetic acid (2.4 mmols, Igm) in 25ml of 5% ammonia solution and Raney-Nickel suspension (3ml in ethanol) was heated to reflux till the reaction was complete (lOhrs). The solution was filtered and acidified with glacial acetic acid (-pH=5.0). The resulting white solid was filtered off, washed with water, ether and dried. Yield: 0.9 gm (97%). 1H NMR: (sodium salt): 0.8-1.10(m, 5H), 1.30-1.60(m 5H), 1.90(m, 1H), 3.90(d, 2H), 4.35(5, 2H), 6.80(d, 2H), 7.80(d, 2H), 7.85(s, 1H). General procedure for 3-Alkvl-8-[4[(carbomethoxvmethvl)oxyl phenyl] hvpoxanthines E.g.: Methyl 2-{4-[3-(cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy} acetate: A solution of 2-{4-[3-(cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl] phenoxy}acetic acid (2 mmols, 0.764gm) in anhydrous methanol (8 ml) and 2,2-dimethoxypropane (25 ml) was refluxed (-8 hrs). Upon cooling, ethyl acetate was added to the dark colored solution and the resulting white solid was filtered off, washed with ethyl acetate, ether and dried. Yield: 0.745 gm (94%). 1H NMR: 1.0-1.30 (m, 5H), 1.70-1.90 (m, 5H), 2.00 (m, 1H), 3.70 (s, 3H), 4.30 (d, 2H), 4.90 (s, 2H), 7.15 (d, 2H), 8.20 (d, 2H), 9.30 (s, 1H). General Procedure for 3-Alkvl-8-[4- f (carboxvmethvl]oxvl phenyl] hvpoxanthine amid es From Methyl 2-{4-[3-(alkyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy} acetates: The title methyl ester (0.63 mmol) in anhydrous dimethyl formamide (1 ml) and the corresponding amine (0.756 mmol) was stirred under nitrogen (-- 8-12hrs). Dimethyl formamide was removed in vacuo and to the residue, was added water. The resulting solid was filtered, washed with water, ether and dried and purified by flash chromatography (methanol:chloroform). Yield: (45-50%). E.g. 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8- yl]phenoxy} -N-pentylacetamide: 1H NMR: 1.0-1.30 (m, 7H), 1.70-1.90 (m, 9H), 2.00(m, 1H), 2.80 (m, 2H,), 3.10 (m, 2H), 4.10(d, 2H), 4.50 (s, 2H), 7.15 (d, 2H), 8.20 (d, 2H), 8.30 (s, 1H). E.g. 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8- yl]phenoxy} -N- [2-(dimethylamino)ethyl] acetamide: 1H NMR: 1.0-1.30 (m, 5H), 1.50-1.80(m, 5H), 2.00 (m, 1H), 2.10 (s, 6H), 2.30 (m, 2H), 3.2 (m, 2H), 4.10 (d, 2H), 4.50 (s, 2H), 7.15 (d, 2H), 8.0 (m, 1H), 8.20 (d, 2H), 8.30 (s, 1H). E.g. 2-[(2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl] phenoxy}acetyl)amino]-N,N,N-trimethyl-l-ethanaminium iodide: 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide (0.061 mmol, 0.03 gm) in anhydrous acetonitrile : tetrahydrofuran mixture (2:1,3 ml) and methyl iodide (2 ml) was stirred at room temperature for 0.5 hr. Further reflux at 40°C for 3 hr. furnished a white precipitate, which was filtered and dried to obtain the title compound. Yield: 0.036 gm (90%). 1HNMR: 1.30-1.50 (m, 5H), 1.50-1.80 (m, 5H), 2,00 (m, 1H), 2.10 (s, 6H), 2.30 (t, 2H), 3.10 (s, 3H), 3.30 (m, 2H), 4.10 (m, 2H), 4.45 (s, 2H), 6.90 (d, 2H), 8.00 (d, 2H). Biological Data A chloroquine resistant P,falciparum strain (T9/106) was maintained in in vitro culture according to the candle jar method of Trager and Jenson, Science, 193. 674-675 (1976). The assay method for screening the compounds of the examples was similar to that described by Desjardins et al., Antimicrob. Agents Chemother., 16,710-718 (1979). The assays were carried out in sterile (nunc) 96 \MQ\\ microtitre plates. The compounds of the examples (test compounds) were solubilised in DMSO (final concentration in the assay was 0.5%) and the susceptibility of the in vitro culture to the compounds was tested in duplicate assays. The extent of incorporation of -3H- hypoxanthine by the compound-treated versus the control wells gave a measure of the level of inhibition achieved by the test compounds. In a typical assay, 220 µ1 of diluted parasite culture (2% haematocrit with 1% parasitemia) was mixed with 20 \|il of the test compound solution and placed in microtitre wells. The positive control wells had 220^il of parasite culture and 20)il of medium containing 0.5% DIVISO whereas four wells containing 2% RBC in culture medium served as the negative control. The plate was incubated at 37°C for 24 hrs in 5% CO2, 5% O2 and 90% nitrogen atmosphere. Later, 10 µl of medium containing 1 \|iCi of -3H-hypoxanthine was added to each well and incubated for 18 hrs. At the end of this duration, the contents of each well were transferred onto Whatman GF/C filters and washed thoroughly with water. Filters were then air-dried and counted in a scintillation counter. The extent of inhibition was determined by comparing the counts incorporated into the nucleic acids of the parasites that were grown in the presence of the test compounds with that of the positive control and expressed as percent inhibition of parasite growth in the presence of the test compounds. All the compounds of the examples were found to inhibit the in vitro growth of P.falciparum at a concentration of 20)µM or less. WE C L A I M 1. A process for preparing purine derivatives of the general formula (I) in which R1 represents a myrtanyl group or a C1-C6 alkyl group optionally substituted by a C3-C8 cycloalkyl substituent group, R represents a hydrogen atom, X represents an oxygen or sulphur atom, and Y represents a group of formula where Z represents an oxygen or sulphur atom, and R4 represents a hydrogen atom or a C1-C6 alkylthio group; and m is 0 or an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, each R7 and each R8 independently represents a hydrogen atom, or an amido t or C1-C4 alkyl group. when m is 0, R9 represents a hydroxyl, a C3-C8 cycloalkylmethyl, or a pyrazolyi optionally substituted by a C1-C4 alkyl substituent group, or R9 may, together with the NH group to which it is attached, form a piperazinyl ring optionally substituted by a C1-C4 alkyl substituent group, and when m is other than 0. R9 represents a hydrogen atom or hydroxyl, amido, a group -N(R10) Pwhere each R10 independently represents a hydrogen atom or a C1-C4 alkyl group and p is an integer from 2 to 3, or R9 represents a group or apharmaceutically acceptable salt or solvate thereof, the process comprising reacting a compound of general formula (VI) in which X, Y, R1 and R2 are as defined in formula (I), by a method such as herein described with a compound of general formula (XIV) H2N - (CR7R8)M - R9 (XIV) wherein m, R7, R8 and R9 are as defined in formula (I). 2. A process as claimed in claim 1, wherein X represents an oxygen atom. 3. A process as claimed in claim 1 or claim 2, wherein Y represents a group of formula 4. A process as claimed in any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate tiiereof obtained is: N-(2-Aminoethyl)-2-(4- {3-[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl} phenoxy) acetamide, N-[2-(Dimethylamino)ethyl]-2-(4- {3-[(6,6-dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide. N-(2-Ammoethyl)-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetamide, 3-[(6,6-Diinethylbicyclo[3.1. l]hept-2-yl)methyl]-8-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethoxy]phenyl}-2-thioxo-l,2,3,9-tetrahydro-6H-puriii-6-one, 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-1 H-purin-S-yl} phenoxy)-N-[2-( {2- [4-(3 -isobutyl-6-oxo- 2-thioxo-2,3,6,9- tetrahydro-lH-purm-8-yl)phenoxy]acetyl}amino)ethyl] acetamide, 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-S-yl} phenoxy)-N-[ 1 -(hydroxymethyl)-2-methylpropyl]acetamide, 2-(4-{3-[(6,6-Dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetahydro-lH-purin-8-yl}phenoxy)-N-[7-({2-[4-(3-isobutyl-6-oxo-2-tWoxo-23,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)heptyl] acetamide, 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[9-({2-[4-(3-isobutyl-6-oxo- 2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetyl} amino)nonyl] acetamide, 2- [4-(3 -isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}ammo)pentyl]acetamde, 2- {4-[3 -(Cy clohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-1H- purin-8-yl]phenoxy} -N-[5-( {2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purm-8-yl)phenoxy]acetyl}amino)pentyl]acetamide, N-(Cyclohexylmethyl)-2-(4- {3-[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purm-8-yl}phenoxy) acetamide, 2-(4- {3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl} phenoxy)-iV-( 1 -ethyl-1H-pyrazol-3 -yl) acetamide, N-[2-(Diisopropylamino)ethyl]-2-(4- {3-[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl} phenoxy)acetamide, N-(5-Aminopentyl) -2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetamide, 2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH- purm-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide, N,N-Dibutyl-2-(4-{3-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetamide, 2-{[2-(4-{3-[(6,6-Dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetyl]amino}-pentanediamide, N-(5-Aminopentyl)-2- {4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-S-yl]phenoxy} acetamide, N-hydroxy-2- [4-(3 -isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy]acetaimde, 2-(4- {3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl} phenoxy)-N-hydroxyacetaniide, 2- {4-[3 -(Cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl]phenoxy} -N-hydroxyacetamide, 2-{4-[3-(Cyclohexyhnethyl)-6-oxo-6,9-dihydro-3H-purui-8-yl]phenoxy} -N-pentylacetamide, 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purm-8-yl]phenoxy} -N-[2-(dmiethylammo)ethyl]acetamide, and 2-[(2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purm-8-yl]phenoxy} acetyl)ammo]-N,N,N-trimethyl--1 -ethanaminium iodide.

Full Text

The present invention relates to a process for preparing purine derivatives.
The worldwide resurgence of human malaria during the past decade (Wyler, DJ.,1983, N. Engl. J. Med., 308, 875-878) has been in part due to the rapid spread of Plasmodium falciparum and Pvivax strains resistant to chloroquine and other commonly used antimalarial drugs (Geary et al., 1986, in Drug resistance in protozoa p.209-238 - W.C.Campbell and R.S.Rew (ed) Chemotherapy of parasitic diseases, Plenum Publication Corp., N.Y. and Peters, W., 1985, Parasitology, 90, 705-715). In view of this resurgence there is an urgent need to develop and identify additional safe and effective drugs (Rieckmann, K., 1983, Ann. Rev. Med., 34, 321-325).
In accordance with the present invention, there is provided a process for preparing compound of general formula
A-B (I) wherein A represents a group of formula

in which R1 represents a myrtanyl group or a C1-C6 alkyl group optionally
substituted by a C3-C8 cycloalkyl substituent group,
R represents a hydrogen atom,
X represents an oxygen or sulphur atom, and
Y represents a group of formula

where Z represents an oxygen or sulphur atom, and
R4 represents a hydrogen atom or a C1-C6 alkylthio group; and
B represents a group of formula (IV)

in which m is 0 or an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
each R7 and each R8 independently represents a hydrogen atom, or an amido
(-CONH2) or C1-C4 alkyl group,

when m is 0, R9 represents a hydroxyl (-OH), a C3-C8 cycloalkylmethyl, or a pyrazolyl optionally substituted by a C1-C4 alkyl substituent group, or R9 may, together with the NH group to which it is attached, form a piperazinyl ring optionally substituted by a C1-C4 alkyl substituent group, and when m is other than 0, R9 represents a hydrogen atom or hydroxyl (-OH), amido (-CONH2), a group -N(R10)p where each R10 independently represents a hydrogen atom or a C1-C4 alkyl group and p is an integer from 2 to 3, or R9 represents a group of formula

in which A' is a group as defined above for A; or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise stated, an alkyl group or an alkyl moiety in an alkoxy or alkylthio group may be linear or branched. When R^ represents a group -N(R^*^)p and p is 3, it should be understood that the nitrogen atom will possess a positive charge.
The group R1 represents a myrtanyl group or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-

hexyl) group optionally substituted by a C3-C8, preferably C5-C6, cycloalkyl substituent group.
R^ especially represents a myrtanyl, isobutyl or cyclohexylmethyl group.
R represents a hydrogen atom or a group -CH2CO2R where R represents a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl) group. R is especially a hydrogen atom.
X represents a sulphur, or preferably, oxygen atom.
Z represents an oxygen, or preferably, sulphur atom.
R4 represents a hydrogen atom or a C1-C6, preferably C1-C4, alkylthio (e.g.
methyl-, ethyl-, n-propyl-, n-butyl-, n-pentyl- or n-hexylthio) group. R4 is
especially a hydrogen atom.
Each R6 independently represents a hydrogen atom or a C1-C6, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy or n-hexoxy) group. In a preferred embodiment, both groups R^ are the same, e.g. hydrogen or methoxy.

R6 represents a hydrogen atom or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl) group. Most preferably, R6 represents hydrogen or methyl.
Each R6 independently represents a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl) group.
Each R and each R independently represents a hydrogen atom, or an amido or C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl) group.
When m is 0, R9 represents a hydroxyl, a C3-C8 cycloalkylmethyl, preferably C5-C6 cycloalkylmethyl, or a pyrazolyl optionally substituted by a C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl) substituent group, or R9 may, together with the NH group to which it is attached, form a piperazinyl ring optionally substituted by a C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl) substituent group.
When m is other than 0, then R9 represents a hydrogen atom or hydroxyl, amido, a group -N(R10p where each R10 independently represents a

hydrogen atom or a C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl) group and p is an integer from 2 to 3, or a group of formula

The group A' may be the same or different to the group A.
Particularly preferred compounds of the invention include:
N-(2-Aminoethyl)-2-(4-{3-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide,
N-[2-(Dimethylamino)ethyl]-2-(4- {3-[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide,
N-(2-Aminoethyl)-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetamide,
3-[(6,6-Dimethylbicyclo[3.1l]hept-2-yl)methyl]-8-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethoxy]phenyl} -2-thioxo-1,2,3,9-tetrahydro-6H-purin-6-one,

2-(4- {3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[2-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9- tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)ethyl] acetamide,
2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[l-(hydroxymethyl)-2-methylpropy 1] acetamide,
2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[7-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)heptyl] acetamide,
2-(4-{3-[(6,6-Dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-pu^in-8-yl}phenoxy)-N-[9-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)nonyl] acetamide,
2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)pentyl]acetamide.

2-{4-[3-(Cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)pentyl]acetamide,
N 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl} phenoxy)-N-( 1-ethyl-1H-pyrazol-3-yl) acetamide,
N-[2-(Diisopropylamino)ethyl]-2-(4-{3-[(6,6-dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetamide,
N-(5-Aminopentyl) -2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy] acetamide,
2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide,
N,N-Dibutyl-2-(4-{3-[(6,6-dimethylbicyclo[3.1l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetamide,

2-{[2-(4-{3-[(6,6-Dimethylbicyclo[3.1.]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl} phenoxy)acetyl]amino} -pentanediamide,
N-(5-Aminopentyl)-2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro- 1 H-purin-8-yl]phenoxy} acetamide,
N-hydroxy-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetamide,
2-(4- {3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl }phenoxy)-N-hydroxyacetamide,
2-{4-[3-(Cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-hydroxyacetamide,
2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy}-N-pentylacetaniide,
2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide,
2-[(2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yI]phenoxy} acetyl)amino] -N,N,N-trimethyl-1 -ethanaminium iodide, and their pharmaceutically acceptable salts and solvates.

Reference is made divisional application under no. 326/mas/2002 filed on 26th April, 2002 , wherein a compound of general formula (I)
A-B (I) wherein A represents a group of formula
in which R1 represents a myrtanyl group or a CrC6 alkyl group optionally
substituted by a C3-C8 cycloalkyl substituent group,
R represents a hydrogen atom or a group -CH2CO2R ,
R represents a C1-C6 alkyl group,
X represents an oxygen or sulphur atom, and
Y represents a group of formula

R4 represents a hydrogen atom or a C1-C6 alkylthio group; and
B represents a hydrogen atom, a C1-C6 alkyl or carboxyphenyl group, a
group of formula
in which each R5 independently represents a hydrogen atom or C1-C6 alkoxy
group and R6 represents a hydrogen atom or C1-C6 alkyl group,
a group of formula

(IIIA) in which each R6 independently represents a C1-Ce alkyl group, or B represents a group of formula

in which m is 0 or an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
each R7 and each R8 independently represents a hydrogen atom, or an amido
(-CONH2) or C1-C4 alkyl group,

when m is 0, R9 represents a hydroxyl (-OH), a C3-C8 cycloalkylmethyl, or a pyrazolyl optionally substituted by a C1-C4 alkyl substituent group, or R9 may, together with the NH group to which it is attached, form a piperazinyl ring optionally substituted by a C1-C4 alkyl substituent group, and when m is other than 0, R9 represents a hydrogen atom or hydroxyl (-0H), amido (-CONH2), a group -N(R10)p where each R10 independently represents a hydrogen atom or a C1-C4 alkyl group and p is an integer from 2 to 3, or R9 represents a group of formula

in which A' is a group as defined above for A; or a pharmaceutically acceptable salt or solvate thereof is described and claimed.
The present invention provides a process for the preparation of a compound
of formula (I) as defined above or a pharmaceutically acceptable salt or
solvate thereof which comprises reacting a compound of general
formula (VI)

in which X, Y, R1, R2 are as defined in formula (1), with a compound of general formula

wherein m, R7, R8 and R9 are as defined in formula (I);
The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as an alcohol, dimethylformamide or dichloromethane at a temperature of, for example, 15°C or above such as a temperature in the range from 20 to 200°C.
Compounds of formulae (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) can be converted into further compounds of formula (I) by means of standard procedures. For example, compounds of formula (I) in which R9 represents NH2 can be converted to compounds of formula (I) in which R9 represents NH(CrC4 alkyl) or N(C1-C4 alkyl)2 usiing a suitable alkylating agent.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers of the compounds of formula (I) and mixtures

thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention.
The compounds obtained according to the present invention are advantageous in that they inhibit the growth of malarial parasites such as Plasmodium falciparum and, therefore, are useful as pharmaceuticals in the treatment of malaria.
Thus, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as herein before defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. The invention also provides a method of treating a malarial disease in a

patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition. The pharmaceutical composition may additionally contain another anti-malarial agent and/or various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as herein before defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as herein before defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The daily dosage of formula (I) compound administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the malarial disease indicated. However, in general, satisfactory results will be obtained when the compound of formula (I) is administered at a daily dosage not exceeding 1 g, e.g. in the range from 10 to 50 mg/kg body weight.
The compounds according to the invention may be administered systemically, e.g. by oral administration in the form of tablets, capsules,

syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions.
The invention will now be further explained by reference to the following illustrative examples.
Examples
General Procedure for Isothiocvanates
The preparation of isobutyl isothiocyanate is representative. A solution of isobutylamine (0.287 mol, 29 ml) in dioxane (50 ml) and triethylamine (0.287 mol, 40 ml) was cooled to 0°C and carbon disulphide (0.287 mol, 16.8 ml) was added in small portions to this solution over a period of 0.25 hr. The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 2 hr. It was then cooled to -10°C and ethyl chloroformate (0.31 mol, 30 ml,) was added dropwise over a period of 0.25 hr to the reaction mixture. The reaction mixture was stirred at O°C for 0.5 hr and then at room temperature for 1 hr. The precipitated solid was filtered off and the filtrate was diluted with chloroform (50 ml) and triethylamine (40 ml). This was stirred at room temperature for 1 hr.

Volatiles were removed in vacuo and the resulting residue was distilled to give the desired isobutyl isothiocyanate. Yield: 16 gm (50%), b.p. 50°C 4.5 mm Hg. In the case of myrtanyl and cyclohexylmethyl isothiocyanates, the crude product was used as such for further reaction sequence without purification / distillation.
General Procedure for Thiourea
Preparation of isobutyl thiourea is representative.
A solution of isobutyl isothiocyanate (0.139 mol, 16 gm) in anhydrous ether (10 ml) was treated with a large excess of liquid ammonia for 3 hr. Excess ammonia was allowed to evaporate in a fume hood and the residual mass was dried in vacuo and used for further reactions without purification. Yield:
15.6 gm (85%).
General Procedure for 6-Amino-3-alkyl-2-thioxopvrimidinones
A solution of alkyl thiourea (0.151 mol) in 180 ml of anhydrous methanol was gently refluxed while a solution of sodium methoxide in methanol (0.334 mol, 75 ml) was added over a period of 0.5 hr., followed by the

addition of ethyl cyanoacetate (0.174 mol, 18.6 ml). The reaction mixture was refluxed for 10 hr. Methanol was removed in vacuo and the residue was triturated with water (100 ml) and neutralised to pH-7 with conc, hydrochloric acid. The precipitated solid was filtered off, washed repeatedly with water and dried to afford the desired pyrimidinone derivative. Yield: 65-70%.
Nitrosation
E.g.: 6-amino-l- [(6,6-dimethylbicyclo [3.1.1]hept-2-yl)methyl]-5-nitroso-2-thioxo-2,3-dihydro-4( 1H-pyrimidinone :

A suspension of 6-amino-l- [(6,6-dimethylbicyclo [3.1.1] hept-2-yl)methyl]-2-thioxo-2,3-dihydro-4(17/)-pyrimidinone (3.24 mmols, 1 gm) in 5ml of
glacial acetic acid at 90°C was treated with a solution of sodium nitrite (0.33 5gm in 1ml of water ) with vigorous stirring. The mixture was allowed

to stir at 90°C for 0.5 hr., and the dark pink crystals obtained were filtered off and washed with water. Yield: 0.55gm (50%).
Following the same procedure, nitroso derivatives with isobutyl and myrtanyl groups were prepared from the respective thioureas.
General Procedure for l-Alkvl-5,6-diaminO-2-thioxo-pvrimidinones
E.g. 5,6-diamino-1 -[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-2-thioxo-2,3-dihydro-4( 1 H)-pyrimidinone [II].

Hydrogen gas was bubbled through a suspension of 6-amino-l-[(6,6-dimethylbicyclo[3.1. l]hept-2-yl)methyl]-5-nitroso-2-thioxo-2,3-dihydro-4(lH)-pyrimidinone (1.35 mmols, 0.4 gm) in 50ml of methanol and 0.04 gm of platinum dioxide. The completion of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was then filtered over a bed of celite and the organic portion was concentrated in vacuo to fumish the title compound. Yield: 0.32gm(83%).

In a similar way, corresponding isobutyl and cyclohexylmethyl diamino-2-thioxo-pyrimidinones were prepared.
General Procedure for 3-Alkvl-2-thioxopurines
E.g. 3-[(6,6-dimethylbicyclo [3.1.1] hept-2-yl)methyl]-2-thioxo-l,2,3,9-tetrahydro-6H-purin-6-one:

A solution of 5,6-diamino-1 -alkyl-2-thioxo-2,3 -dihydro-4 (1H)-pyrimidinone (1.13 mmols, 0.250 gm) in 15ml of orthoformate was refluxed
0
for 3 hr. at 140 C. After cooling to room temperature, 5ml of n-hexane was added to precipitate the product, which was chromatographed (50% ethyl acetate: hexane). Yield: 0.170 gm (65%).
In a similar way, corresponding isobutyl- and cyclohexylmethyl-2-thioxo-l,2,3,9-tetrahydro-6H-purin-6-ones were prepared.

General Procedure for 3-Alkvl-8-methvl-2-thioxopurines
E.g. 3-[(6,6-dimethylbicyclo [3.1.1]hept -2-yl)methyl]-8-methyl-2-thioxo-l,2,3,9-tetrahydro-6H-purin-6-one:

A solution of 5,6-diamino-1 -[(6,6-dimethylbicyclo[3.1.1 ]hept-2"yl)methyl]-2-thioxo-2,3-dihydro-4(lH)-pyrimidinone (1.13 mmols, 0.25 gm) in trimethyl orthoacetate (15 ml) was refluxed for 3 hr. After cooling to room temperature, w-hexane (5 ml) was added. The resulting solid was chromatographed (50% ethyl acetate: hexane). Yield: 0.150 gm (55%).
The corresponding purines with isobutyl and cyclohexylmethyl groups were also prepared following the procedure mentioned above.
General Procedure for 3-Alkvl-6-thioxopurines
E.g.:3-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-3,9-dihydro-lH-

A suspension of 3-[(6,6-dimethylbicyclo [3.1.1]hept-2-yl)methyl]-2-thioxo-l,2,359-tetrahydro-6H-purin-6-one (3.28 mmols, 1 gm) in anhydrous toluene (35ml) was refluxed in an oil bath for 0.25 hr. and to this was added Lawessons reagent (1.65 mmols, 0.664 gm) under nitrogen and the reflux continued for 7 hr. Solvent was removed in vacuo and the resulting residue was purified by flash chromatography (5% methanol in chloroform). Yield: 0.53 gm (50%).
IHNMR: 0.78(d,y=9.3 Hz, 1H); 1.13(s, 3H); 1.25(s, 3H); 1.6-1.76(m, 1H); 1.78-2.26(m,6H); 2.26-2.39(m, 1H); 2.42(s, 3H) ; 2.8-3.0(m , 1H); 4.5-4.65(m,2H); 10.2-10.3(bs, lH)and 10.4-10.5(brs, 1H).
3-Isobutyl-3,9-dihydro-lH-purine-2,6-dithione and 3-cyclohexylmethyl-3,9-dihydro-lH-purine-2,6-dithione were obtained in a similar way.
General Procedure for 3-Alkvl-4-amino-5-[4-f(carboxvmethyl)-oxv)benzvlidene1amino1pyrimidines
E.g. 2-{4-[({6-amino-l-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-4-oxo-2-thioxo-l,2,3,4-tetrahydro-5- pyrimidinyl}imino)methyl] phenoxy} acetic acid :

A solution of 5,6-diamino-l-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-2-thioxo-2,3-dihydro-4(lH)-pyrimidinone (0.51 mmol, 0.15 gm) in of
anhydrous methanol (10 ml) was heated in an oil bath at 609°C for 0.25 hr. 4-Formylphenoxyacetic acid (0.51 mmol, 0.092 gm) was added to this solution
> - - - -
and reflux continued for 1.5 hr. After cooling to room temperature, the precipitated yellow solid was filtered. The filtrate was evaporated to dryness and taken in ethyl acetate to obtain an additional lot of the desired product. Yield: 0.169 gm (65%).
General Procedure for 2-[4-(3-AlkvI-6-oxo-2-thioxo-23^6,9"tetrahvdro-1H'-purin-8-yl}phenoxvl]acetic acids
E.g. 2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-
yl)phenoxy]acetic acid:

A suspension of 2-{4-[({6-amino-l-[(3-isobutyl-4-oxo-2-thioxo-l,2,3,4-tetrahydro-5-pyrimidinyl}imino)methyl]phenoxy}acetic acid (2.04 mmols, 0.77 gm) in anhydrous dimethyl formamide (20ml) and anhydrous ferric chloride (0.132 gm) was refluxed for 7 hr. The reaction mixture was cooled to room temperature and water was added while stirring to precipitate a pale green solid, which was filtered, washed with water and dried in vacuo. Yield 0.59 gm (78%).
1H NMR: 0.85(d, J= 6.2Hz ,6H) ; 2.6(m, 1H) ; 4.36(d & s , y=7 Hz & 4 Hz, 4H); 6.9(d, 7=8.7 Hz, 2H); and 7.9(d, J=8.7 Hz, 2H).
The corresponding purine derivatives with myrtanyl and cyclohexylmethyl were prepared in a similar way.
General Procedure for 4-(3-Alkvl-6-oxo-2-thioxo-2,3,6,9-tetrahvdro-lH-purin-8-yl)benzoic acids
E.g. 4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9 -tetrahydro-lH-purin-8-yl)benzoic acid:

The title compound was prepared using the appropriate l-alkyl-5,6-diamino-2-thioxo-pyrimidinone and 4-carboxybenzaldehyde according to the preceding procedure.
1H NMR: 0.9(d , J= 6.8 Hz , 6H) ; 2.5(m, 1H) ; 4.4(d, J- 7.3 Hz, 2H:); 8.1(d,J=11.5Hz,2H); 8.3(d, J= 11.5 Hz, 2H); 12.6(s, 1H); 13.3(bs,lH); 14.4(s, 1H).
The corresponding purine derivatives w^ith myrtanyl and cyclohexylmethyl were prepared in a similar way.
General Procedure for Methvl-2-alkvl-6-oxo-2-thioxO-2,3,6^9-tetrahydro-lH-purin-8-vl}phenoxvyacetates
E.g. Methyl 2-(4-{3-[(6,6-dimethylbicyclo [3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetate:

A solution of the corresponding acid (1.06 mmols, 0.48 gm) in anhydrous
methanol (9 ml), 2,2-dimethoxypropane (26 ml) and a drop of conc, sulfuric
-
acid was refluxed for 5 hr. The resulting pale yellow solid was filtered and washed with ethyl acetate to obtain the title compound. Yield : 0.229 gm (46%).
E.g. Methyl 2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-1 H-purin-8-yl]-2,6-dimethoxyphenoxy} acetate:

The title compound was prepared using the appropriate l-alkyl-5,6-diamino-2-thioxo-pyrimidinone and 4-formyl-2,6-dimethoxyphenoxy acetate.
IHNMR: 1.20(m, 5H,), 1.60(m, 5H,), 2.0(m, 1H,), 3.70(s, 3H), 3.80(s, 6H), 4.20(m, 4H), 7.50(m, 2H), 9.0(bs, 1H), 13.70(bs, 1H).

E.g. Methyl 2-{3-(cyclohexylmethyl)-8-[4-(2-methoxy-2-oxoethoxy) phenyl]-6-oxo-2-thioxo-1,2,3,6-tetrahydro-7H-purin-7-yl} acetate:

The title compound was prepared by alkylation of methyl 2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-purin-8-yl]-2,6-dimethoxyphenoxy}acetate with ethyl bromoacetate and sodium hydride.
IRNMR: 1.20(m, 5H), L60(m, 5H), 2.0(m, 1H), 3.70(s, 3H), 3.80(s, 6H,), 4.10(s, 2H), 4.20(d, 2H), 4.5(s, 2H), 7.50(m, 2H), 13.70(bs, 1H).
General Procedure for 3-Alkvl-8-[4-[(carboxvmethvl)oxv1phenvl1-2-thioxopurine amides Procedure I:
Using 2-{3-alkyl-8-[4-(2-methoxy-2-oxoethoxy)phenyl]-6-oxo-2-thioxo-l,2,3,6-tetrahydro-7H-purin-7-yl}acetate:

A solution of the title ester (1 mmol) in anhydrous dimethyl formamide (1 ml) and the corresponding amine (1.2 mmols ) was stirred at room temperature. (~10h). Water was added to the mixture and the resulting precipitate was filtered off, washed with water and was further purified by flash chromatography on silica gel (methanohchloroform). Yield: (40 -50%).
E.g. N-(2-Aminoethyl)-2-(4-{3-[(6,6-dimethylbicyclo[3.1.1]hept-2-
yl)methyl]-6-oxo-2-thioxo-2,3,5,6,5,9-tetrahydro-lH-purin-8-yl}phenoxy)
acetamide:
IH NMR: 0.79(d, 7=9.35 Hz , 1H) ; 1.10(s, 3H); 1.37(s,3H); 1.6-1.9(m , 6H); 2.1-2,3(m, 1H); 2.87-2.9(m, 4H); 3.1-3.6(bm, 4H); 4.4-4.6(m & s , 4H); 7.03(d, J=8.O Hz, 2H); 8.05(d, J=8.0 Hz , 2H) and 8.3(bs, 1H).

E.g. N-[2-(Dimethylamino)ethyl]-2-(4-{3-[(6,6-dimethylbicyclo[3.1.l]hept-
2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)
acetamide:

IH NMR: 0.78(d, J=9A Hz, 1H); 1.09(s, 3H); 1.36(s, 3H); 1.7-1.9(m, 6H); 2.2(s, 6H); 2,38(bs , 2H); 2.88(m, 1H); 3.25(m, 2H); 4.4-4.7(m & s, 4H); 7.12(d, J=8.8 Hz , 2H); 8.1(bd, 3H); 12.3(bs, 1H).
E.g. N-(2-Aminoethyl)-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetamide:

IHNMR: 0.9(d, J=6.7 HZ , 6H); 2.49-2.72(bs, 3H); 2.84(bm, 2H:); 3.2(m, 2H); 4.3(d, J=7.4 Hz , 2H); 4.53(s, 2H); 7.0(d, J=8.4 Hz , 2H:); 8.0(d, J=8.4 Hz , 2H) and 8.2(bs , 1H).

Procedure II:
Using l-({244-(3-Alkyl-6-oxo-24hioxo-23,6,94etrahydro-lJ¥-purin-8-yl) phenoxy] acetyl} oxy)-2,5-pyrrolidinedione:
The title N-hydroxysuccinimide derivative (1 mmol) in anhydrous dimethyl formamide(l ml) and amine (1.2 mmols ) was allowed to stir at room temperature until completion of the reaction (-5-1 Oh). Water was added to the mixture and the resulting precipitate was filtered off and washed with water, and further purified by flash chromatography on silica gel (methanol: chloroform). Yield: 45-50%.
E.g. 3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-8-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethoxy]phenyl} -2-thioxo-1,2,3,9-tetrahydro-6H-purin-6-
one :
lHNMR:(0.8(d,J=7Hz,lH); 1.12(s,3H); 1.32(s,3H); 1.5-2.0(m, 5H); 2.24(s, 3H); 2.9(m , 1H); 3.34(m, 8H); 4.45(m, 2H); 4.92(s, 2H); 7.05(d, y=8 Hz , 2H); 8.06(d, J=8 Hz, 2H); 12.35(m, 1H) and 13.9(m, 1H).

E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[2-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9- tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)ethyl] acetamide:

1H NMR: 0.8(d, J=9 Hz , 1H); 0.86(s, 3H); ().88(s, 3H); 1.10(s, 3H:); 1.32(s, 3H); 1.5-2.0(m, 5H); 2.15-2.26(m, 1H); 2.65(m, 1H:); 2.75(m , 1H); 3.20(m, 2H); 4.3-4.55(m, 6H); 7.05(m, 4H); 8.10(m, 4H); 8.26(m , 2H); 12.38(s,2H); 13.82(s,2H).
E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl}phenoxy)-N-[ 1 -(hydroxymethyl)-2-methylpropyljacetamide:

IHNMR: 0.82(d, 3H); 0.89(d & S, 1H & 3H); 1.04(S, 3H); 1.25(S, 3H); 1.75-2.05(m, 5H); 2.20(m, 1H); 3.42-3.65(m, 2H); 6.96(d, 2H); 7.33-7.65(bs,lH); 8.12(d,2H); 11.81(bs , 1H); 13.55(bs , 1H).
E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.l]hept-2-yi)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[7-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetyl} amino)heptyl] acetamide:

1H NMR: 0.8(d, J=9 Hz , 1H); 0.86(s, 3H); 0.88(s, 3H); 1.10(s, 3H:); 1.32(s, 3H); 1.5-2.0(m, 5H); 2.15-2.26(m, 1H); 2.90(m, 1H:); 3.20(m, 4H); 3.30(m, lOH); 4.3-4.55(m, 8H); 7.05(m, 4H); 8.10(m, 6H); 12.38(s, 2H); 13.82(s,2H).

E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[9-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetyl} amino)nonyl] acetamide:

IR NMR: 0.8(d, J=9 Hz , 1H); 0.86(s, 3H); 0.88(s , 3H); 1.10(s, 3H:); 1.32(s, 3H); 1.5-2.0(m, 5H); 2.15-2.26(m, 1H); 2.90(m, 1H:); 3.20(m , 4H); 3.30(m, 14H); 4.3-4.55(m, 8H); 7.05(m, 4H); 8.10(m, 6H); 12.38(s, 2H);.13.82(s,2H).
E.g. 2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-
yl)phenoxy]-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)pentyl]acetamide:

1H NMR: 0.90(d, 12H), 2.65(m, 1H), 3.0-3.80(ni, lOH), 4.30(d, 4H), 4.50(s, 4H), 7.05(m, 4H); 8.10(m,6H); 12.38(s,2H); 13.82(s,2H).
E.g. 2- {4-[3 -(Cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-1H-
purin-8-yl]phenoxy}-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-
tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)pentyl]acetamide:

IHNMR: 0.90(d, 6H), 1.0-1.80(m, lOH), 2.20(m, 1H), 3.0-3.80(m, UH), 4.30(d, 4H), 4.50(s, 4H), 7.10(m, 4H); 8.10(m, 6H); 12.38(s, 2H); 13.82(s, 2H).

The respective homo and hetero dimers were prepared in a similar way.
E.g. N-(Cyclohexylmethyl)-2-(4-{3-[(6,6-dimethylbicyclo[3.1. l]hept-2-
yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)
acetamide:

IHNMR: 0.80-2.20(m), 2.90(m, 1H), 3.30(m, 2H), 4.60(m, 4H), 6.60, (m, 1H), 7.0(d, 2H), 8.10(d, 2H), 10.0(m, 1H), 12.90(m, 1H).
E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahy dro-1H-purin-8-yl} phenoxy)-Ar-( 1 -ethyl-1H-pyrazol-3 -yl) acetamide:

lHNMR:0.8(d,J=9Hz,lH); 1.10(s, 3H); 1.20(t, 3H), 1.30(s,3H); 1.60-

2.0(m, 6H), 2.30(m, 1H), 2.80(m, lH),4.0(m, 1H), 4.40-4.60(m, 2H), 4.90(s, 3H), 6.20(s, 1H), 7.10(d, 2H), 7.40(s, 1H), 8.10(d, 2H), lO.O(lH), 12.30(bs, 1H), 13.90(bs, 1H).
E.g.N-[2-(Diisopropylamino)ethyl]-2-(4-{3-[(6,6-
dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin- 8-y 1} phenoxy)acetamide:

1H NMR: 0.78(d, J=9.4 Hz , 1H), 1.0(d, 6H), 1.09(s, 3H), 1.36(s , 3H), 1.7-
1.9(m , 6H), 2.20(m.lH), 2.80-3.0(m,4H), 4.40-4.80(m, 4H), 7.0(d, 2H),
7.80(m, 1H), 8.10(d, 2H), 12.40(m, 1H), 13.80(m, 1H).
E.g. N-(5-Aminopentyl) -2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-
tetrahydro-1 H-purin-8-yl)phenoxy] acetamide:

1H NMR: 0.9(d , 7=6.7 Hz, 6H), 1.20(m, 2H), 1.40(m ,4H,),2.60(m, 1H, CH(CH3)2), 3.10(m ,4H), 4.40(d, 2H), 4.60(s, 2H), 7.10 (d, 2H), 8.0 (s,lH,), 8.10(d,2H), 12.50(s,lH), 13.80(s, 1H).
E.g. 2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide:

1H NMR: 1.20(m, 5H), 1.70((m, 5H), 2.30(m, 2H), 3.35(m, 2H), 4.30(d, 2H), 4.50(s, 2H), 7.10(d, 2H), 8.10(d, 2H),
E.g. N,N-Dibutyl-2-(4-{3-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetamide:

IHNMR: 0.90(m, 6H), 1.10(s, 3H), 1.20(m, 1H), 1.90(m, 5H), 2.30(m,lH), 2.40(m, 4H), 2.60(m,2H),3.0(m, 2H), 3.40(m,2H), 4.50-4.70(m, 4H), 7.0(d, 2H), 7.40(m, 1H), 8.10(d, 2H).
E.g. 2- {[2-(4- {3 -[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-
thioxo-2,3,6,9-tetrahydro-1 H-purin-8-
y 1} phenoxy)acety 1] amino } pentanediamide:

IR NMR: 0.78(d , J=9.4 Hz , 1H), 1.09(s, 3H), 1.36(s, 3H), 1.7-2.30(m ,13H), 4.40-4.80(m, 4H), 6.80(m, 1H), 7.15(d, 2H),7.30&7.40(2m, 2H), 8.10(d,2H).
E.g. N-(5-Aminopentyl)-2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo-
2,3,6,9-tetrahydro-1 H-purin-8-yl]phenoxy } acetamide:

1H NMR: L0-1.80(m, 16H), 2.30(m, 1H), 2.80 &3.0( 2m, 4H), 4.30(d, 2HX 4.50(s, 2H), 7.0(d, 2H), 8.0(d, 2H), 8.10(m, 1H),
General Procedure for 3-AlkvI-8[4-[(carboxvmethvl)oxv1phenvl1-2-thiopurine hvdroxamic acids
a) From l-({2-[4-(3-alkyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-y l)phenoxy] acetyl} oxy )-2,5 -pyrrolidinedione:
The title N-hydroxysuccinimide deriv. (1 mmol ) in anhydrous dimethyl formamide (1 ml), triethylamine (1.2 mmols, 0.17 ml ) and hydroxylamine hydrochloride (1.2 mmols, 0.084 gm) was allowed to stir at room temperature until completion of the reaction (-l-10h). Water was added to the mixture and the resulting precipitate was filtered off and purified by flash chromatography on silica gel (methanol: chloroform) to furnish the respective hydroxamic acids. Yield : 45 - 50 %.

E.g. N-hydroxy-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetamide:

1H NMR: 0.9(d, 6H); 2.40-2.70(m, 1H), 4.30(d, 2H), 4.50(s, 2H), 7.0(d, 2H), 8.0(d, 2H), 9.0(bs, 1H), 10.90(bs, 1H), 12.50(bs, 1H), 14.0 (bs, 1H).
E.g. 2-(4-{3-[(6,6-Dimethylbicyclo[3.1.l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl }phenoxy)-N-hydroxyacetamide:

1H NMR: 0.79(d, J=9.35 Hz, 1H) ; 1.10(s, 3H): 1.30(s, 3H); 1.6-1.9(m, 3H); 2.1-2.7(m , 5H); 4.30-4.60(m, 4H), 7.0(d, 2H), 8.0(d, 2H), 8.8(bs, 1H), 9.90(bs, 1H), 10.50(bs, 1H), 13.4 (bs, 1H).
E.g.: 2-{4-[3-(Cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl]phenoxy}-N-hydroxyacetamide:

1H NMR: 0.70(m, 5H), 1.50(m, 5H), 4.40(d, 2H), 4.50(s, 2H), 7.0(d, 2H), 8.0(d, 2H).
General Procedure far 3-Alkvl-8-
[4[][(carboxvmethvl)oxvlDhenvl1hvpoxanthines
E.g. 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]
phenoxy} acetic acid:

A suspension of the appropriate purine acetic acid (2.4 mmols, Igm) in 25ml of 5% ammonia solution and Raney-Nickel suspension (3ml in ethanol) was heated to reflux till the reaction was complete (lOhrs). The solution was filtered and acidified with glacial acetic acid (-pH=5.0). The resulting white solid was filtered off, washed with water, ether and dried. Yield: 0.9 gm (97%).

1H NMR: (sodium salt): 0.8-1.10(m, 5H), 1.30-1.60(m 5H), 1.90(m, 1H), 3.90(d, 2H), 4.35(5, 2H), 6.80(d, 2H), 7.80(d, 2H), 7.85(s, 1H).
General procedure for 3-Alkvl-8-[4[(carbomethoxvmethvl)oxyl phenyl] hvpoxanthines
E.g.: Methyl 2-{4-[3-(cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy} acetate:
A solution of 2-{4-[3-(cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl] phenoxy}acetic acid (2 mmols, 0.764gm) in anhydrous methanol (8 ml) and 2,2-dimethoxypropane (25 ml) was refluxed (-8 hrs). Upon cooling, ethyl acetate was added to the dark colored solution and the resulting white solid was filtered off, washed with ethyl acetate, ether and dried. Yield: 0.745 gm (94%).
1H NMR: 1.0-1.30 (m, 5H), 1.70-1.90 (m, 5H), 2.00 (m, 1H), 3.70 (s, 3H), 4.30 (d, 2H), 4.90 (s, 2H), 7.15 (d, 2H), 8.20 (d, 2H), 9.30 (s, 1H).

General Procedure for 3-Alkvl-8-[4-
f (carboxvmethvl]oxvl phenyl] hvpoxanthine amid es
From Methyl 2-{4-[3-(alkyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy} acetates:
The title methyl ester (0.63 mmol) in anhydrous dimethyl formamide (1 ml) and the corresponding amine (0.756 mmol) was stirred under nitrogen (-- 8-12hrs). Dimethyl formamide was removed in vacuo and to the residue, was added water. The resulting solid was filtered, washed with water, ether and dried and purified by flash chromatography (methanol:chloroform). Yield: (45-50%).
E.g. 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-
yl]phenoxy} -N-pentylacetamide:

1H NMR: 1.0-1.30 (m, 7H), 1.70-1.90 (m, 9H), 2.00(m, 1H), 2.80 (m, 2H,), 3.10 (m, 2H), 4.10(d, 2H), 4.50 (s, 2H), 7.15 (d, 2H), 8.20 (d, 2H), 8.30 (s, 1H).

E.g. 2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-
yl]phenoxy} -N- [2-(dimethylamino)ethyl] acetamide:

1H NMR: 1.0-1.30 (m, 5H), 1.50-1.80(m, 5H), 2.00 (m, 1H), 2.10 (s, 6H), 2.30 (m, 2H), 3.2 (m, 2H), 4.10 (d, 2H), 4.50 (s, 2H), 7.15 (d, 2H), 8.0 (m, 1H), 8.20 (d, 2H), 8.30 (s, 1H).
E.g. 2-[(2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]
phenoxy}acetyl)amino]-N,N,N-trimethyl-l-ethanaminium iodide:

2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purin-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide (0.061 mmol, 0.03 gm) in anhydrous acetonitrile : tetrahydrofuran mixture (2:1,3 ml) and methyl iodide (2 ml)

was stirred at room temperature for 0.5 hr. Further reflux at 40°C for 3 hr. furnished a white precipitate, which was filtered and dried to obtain the title compound. Yield: 0.036 gm (90%).
1HNMR: 1.30-1.50 (m, 5H), 1.50-1.80 (m, 5H), 2,00 (m, 1H), 2.10 (s, 6H), 2.30 (t, 2H), 3.10 (s, 3H), 3.30 (m, 2H), 4.10 (m, 2H), 4.45 (s, 2H), 6.90 (d, 2H), 8.00 (d, 2H).
Biological Data
A chloroquine resistant P,falciparum strain (T9/106) was maintained in in vitro culture according to the candle jar method of Trager and Jenson, Science, 193. 674-675 (1976). The assay method for screening the compounds of the examples was similar to that described by Desjardins et al., Antimicrob. Agents Chemother., 16,710-718 (1979).
The assays were carried out in sterile (nunc) 96 \MQ\\ microtitre plates. The compounds of the examples (test compounds) were solubilised in DMSO (final concentration in the assay was 0.5%) and the susceptibility of the in vitro culture to the compounds was tested in duplicate assays. The extent of
incorporation of -3H- hypoxanthine by the compound-treated versus the

control wells gave a measure of the level of inhibition achieved by the test compounds.
In a typical assay, 220 µ1 of diluted parasite culture (2% haematocrit with 1% parasitemia) was mixed with 20 |il of the test compound solution and placed in microtitre wells. The positive control wells had 220^il of parasite culture and 20)il of medium containing 0.5% DIVISO whereas four wells containing 2% RBC in culture medium served as the negative control.
The plate was incubated at 37°C for 24 hrs in 5% CO2, 5% O2 and 90%
nitrogen atmosphere. Later, 10 µl of medium containing 1 |iCi of -3H-hypoxanthine was added to each well and incubated for 18 hrs. At the end of this duration, the contents of each well were transferred onto Whatman GF/C filters and washed thoroughly with water. Filters were then air-dried and counted in a scintillation counter.
The extent of inhibition was determined by comparing the counts incorporated into the nucleic acids of the parasites that were grown in the presence of the test compounds with that of the positive control and expressed as percent inhibition of parasite growth in the presence of the test compounds.

All the compounds of the examples were found to inhibit the in vitro growth of P.falciparum at a concentration of 20)µM or less.

WE C L A I M
1. A process for preparing purine derivatives of the general formula (I)

in which R1 represents a myrtanyl group or a C1-C6 alkyl group optionally
substituted by a C3-C8 cycloalkyl substituent group,
R represents a hydrogen atom,
X represents an oxygen or sulphur atom, and
Y represents a group of formula

where Z represents an oxygen or sulphur atom, and
R4 represents a hydrogen atom or a C1-C6 alkylthio group; and
m is 0 or an integer 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
each R7 and each R8 independently represents a hydrogen atom, or an amido
t
or C1-C4 alkyl group.

when m is 0, R9 represents a hydroxyl, a C3-C8 cycloalkylmethyl, or a pyrazolyi optionally substituted by a C1-C4 alkyl substituent group, or R9 may, together with the NH group to which it is attached, form a piperazinyl ring optionally substituted by a C1-C4 alkyl substituent group, and when m is other than 0. R9 represents a hydrogen atom or hydroxyl, amido, a group -N(R10) Pwhere each R10 independently represents a hydrogen atom or a C1-C4 alkyl group and p is an integer from 2 to 3, or R9 represents a group

or apharmaceutically acceptable salt or solvate thereof,
the process comprising reacting a compound of general formula (VI)

in which X, Y, R1 and R2 are as defined in formula (I), by a method such as
herein described with a compound of general formula (XIV)
H2N - (CR7R8)M - R9 (XIV)
wherein m, R7, R8 and R9 are as defined in formula (I).
2. A process as claimed in claim 1, wherein X represents an oxygen atom.
3. A process as claimed in claim 1 or claim 2, wherein Y represents a group of formula

4. A process as claimed in any one of claims 1 to 3, wherein the compound
of formula (I) or a pharmaceutically acceptable salt or solvate tiiereof
obtained is:
N-(2-Aminoethyl)-2-(4- {3-[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl} phenoxy) acetamide,
N-[2-(Dimethylamino)ethyl]-2-(4- {3-[(6,6-dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy) acetamide.

N-(2-Ammoethyl)-2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetamide,
3-[(6,6-Diinethylbicyclo[3.1. l]hept-2-yl)methyl]-8-{4-[2-(4-methyl-l-piperazinyl)-2-oxoethoxy]phenyl}-2-thioxo-l,2,3,9-tetrahydro-6H-puriii-6-one,
2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-
2,3,6,9-tetrahydro-1 H-purin-S-yl} phenoxy)-N-[2-( {2- [4-(3 -isobutyl-6-oxo-
2-thioxo-2,3,6,9- tetrahydro-lH-purm-8-yl)phenoxy]acetyl}amino)ethyl]
acetamide,
2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-S-yl} phenoxy)-N-[ 1 -(hydroxymethyl)-2-methylpropyl]acetamide,
2-(4-{3-[(6,6-Dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetahydro-lH-purin-8-yl}phenoxy)-N-[7-({2-[4-(3-isobutyl-6-oxo-2-tWoxo-23,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}amino)heptyl] acetamide,
2-(4-{3-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)-N-[9-({2-[4-(3-isobutyl-6-oxo-

2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetyl} amino)nonyl] acetamide,
2- [4-(3 -isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]-N-[5-({2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl)phenoxy]acetyl}ammo)pentyl]acetamde,
2- {4-[3 -(Cy clohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-1H-
purin-8-yl]phenoxy} -N-[5-( {2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purm-8-yl)phenoxy]acetyl}amino)pentyl]acetamide,
N-(Cyclohexylmethyl)-2-(4- {3-[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purm-8-yl}phenoxy) acetamide,
2-(4- {3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl} phenoxy)-iV-( 1 -ethyl-1H-pyrazol-3 -yl) acetamide,
N-[2-(Diisopropylamino)ethyl]-2-(4- {3-[(6,6-dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl} phenoxy)acetamide,
N-(5-Aminopentyl) -2-[4-(3-isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl)phenoxy]acetamide,

2-{4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo- 2,3,6,9-tetrahydro-lH-
purm-8-yl]phenoxy}-N-[2-(dimethylamino)ethyl]acetamide,
N,N-Dibutyl-2-(4-{3-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetamide,
2-{[2-(4-{3-[(6,6-Dimethylbicyclo[3.1. l]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-lH-purin-8-yl}phenoxy)acetyl]amino}-pentanediamide,
N-(5-Aminopentyl)-2- {4-[3-(cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-S-yl]phenoxy} acetamide,
N-hydroxy-2- [4-(3 -isobutyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)phenoxy]acetaimde,
2-(4- {3-[(6,6-Dimethylbicyclo[3.1.1 ]hept-2-yl)methyl]-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1 H-purin-8-yl} phenoxy)-N-hydroxyacetaniide,
2- {4-[3 -(Cyclohexylmethyl)-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl]phenoxy} -N-hydroxyacetamide,
2-{4-[3-(Cyclohexyhnethyl)-6-oxo-6,9-dihydro-3H-purui-8-yl]phenoxy} -N-pentylacetamide,
2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purm-8-yl]phenoxy} -N-[2-(dmiethylammo)ethyl]acetamide, and

2-[(2-{4-[3-(Cyclohexylmethyl)-6-oxo-6,9-dihydro-3H-purm-8-yl]phenoxy} acetyl)ammo]-N,N,N-trimethyl--1 -ethanaminium iodide.

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Patent Number

219708

Indian Patent Application Number

775/MAS/2000

PG Journal Number

27/2008

Publication Date

04-Jul-2008

Grant Date

13-May-2008

Date of Filing

18-Sep-2000

Name of Patentee

ASTRAZENECA AKTIEBOLAG

Applicant Address

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. JANAKIRAMAN RAMACHANDRAN
2	DR. BALACHANDRA SHANKAR BANDODKAR
3	DR. MILIND VASANTH RANGAISHENVI
4	DR. YELESWARAPU KOTESWAR RAO

PCT International Classification Number

C07D 473/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA