Title of Invention	"A PYRIMIDINEDIONE HOMOCARBOCYCLIC COMPOUND"
Abstract	The present invention relates to novel compound of general formula(I) and pharmaceutically acceptable salts thereof, and pocess for the preparation of such derivatives and to pharmaceutical compositions containing the same as active ingredients. wherein R1, R2, and R3 represents independently hydrogen atom, halogen atom, C1-C10 alkyl, C1-C10 thioalkyl, C3-C8 optionally substituted cyclicalkyl, unsaturated alkyl, substituted alkyl hydroxyl or aryl hydroxyl, C1-C10 alkylamine, nitro, C1-C4 lower ester, C1.-C4 lower alkoxy, C1-C4 lower thioalkoxy; Z represents oxygen atom, sulfur atom, carbon atom and carbonyl group; X represents oxygen atom, sulfur atom; n represents an integer of 1-3; and (sub)cycloalk(en)yl represents in which R4 and R5 represents independently hydrogen atom, hydroxymethyl, protected hydroxymethyl, benzyl, substituted carbonyl, substituted alkylsulfonyl or arylsulfonyl, substituted silyl or the like.

Title of Invention

"A PYRIMIDINEDIONE HOMOCARBOCYCLIC COMPOUND"

Abstract

The present invention relates to novel compound of general formula(I) and pharmaceutically acceptable salts thereof, and pocess for the preparation of such derivatives and to pharmaceutical compositions containing the same as active ingredients. wherein R1, R2, and R3 represents independently hydrogen atom, halogen atom, C1-C10 alkyl, C1-C10 thioalkyl, C3-C8 optionally substituted cyclicalkyl, unsaturated alkyl, substituted alkyl hydroxyl or aryl hydroxyl, C1-C10 alkylamine, nitro, C1-C4 lower ester, C1.-C4 lower alkoxy, C1-C4 lower thioalkoxy; Z represents oxygen atom, sulfur atom, carbon atom and carbonyl group; X represents oxygen atom, sulfur atom; n represents an integer of 1-3; and (sub)cycloalk(en)yl represents in which R4 and R5 represents independently hydrogen atom, hydroxymethyl, protected hydroxymethyl, benzyl, substituted carbonyl, substituted alkylsulfonyl or arylsulfonyl, substituted silyl or the like.

Full Text	The present invention relates to new substituted pyrimidinedione derivatives, which are useful as an antiviral agent, treating agent for acquired immunodeficiency syndromes (AIDS), and pharmaceutically acceptable salts thereof. The invention also relates to process for the preparation of such derivatives and to pharmaceutical compositions containing the same as active ingredients. Nowadays, various compounds such as AZT, DDC, DDI and D4T have been used as chemotherapeutic agents of AIDS and have a medical action mechanism with inhibition of the replication of AIDS virus. They also have drug tolerance and undesirable side effects due to their toxicity. 1. In order to overcome these problems, intensive researches have been carried out to develope antiviral chemotherapeutic agents with strong activity and with lower toxicity. Among them, researches have been focused on pyrimidine 6-substituted necleoside compounds. But, N-l substituted homocarbocyclic nucleoside derivatives were not developed as yet. The present inventors carried out an intensive research on the N-l substituted homocarbocyclic necleoside derivatives and unexpectively found out the facts that the compounds have strong activity against HIVCAIDS, Acquired immunodeficiency syndromes) as well as a lower toxicity. Accordingly, the present invention relates to new pyrimidinedione derivatives, 6-substituted pyrimidinedione homocarbocyclic nucleosides which are useful as an antiviral agent for treating acquired immunodeficiency syndromes ( AIDS ), and pharmaceutically acceptable salts thereof. 2. The present compounds have the following general formula(I). Formula Removed wherein Ri, R2, and Rs represents independently hydrogen atom, halogen atom, Ci-Cio alkyl, Ci-Cio thioalkyl, Cs-Cg optionally substituted cyclicalkyl, unsaturated alkyl, substituted alkyl hydroxyl or aryl hydroxyl, Ci-Cio alkylamine, nitro, Ci~C4 lower ester, Ci~C4 lower alkoxy, Ci~C4 lower thioalkoxy; Z represents oxygen atom, sulfur atom, carbon atom and carbonyl group; X represents oxygen atom, sulfur atom; n represents an integer of 1-3; and (sub)cycloalk(en)yl represents in which R4 and R5 represents independently hydrogen atom, hydroxymethyl, protected hydroxymethyl, benzyl, substituted carbonyl, substituted alkylsulfonyl or arylsulfonyl, substituted silyl or the like. C1-C10 alkyl means straight or branch alky] group such as methyl, ethyl, propyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, 2-methyl-pentyl or the like. C1-C10 thioalkyl means straight or branch thioalkyl group such as methylthio, ethylthio, propylthio, butylthio, isobutylthio, t-butylthio, pentylthio, isopentylthio, hexylthio, heptylthio, octylthio, 2-methyl-pentylthio or the like. C3-C8 optionally substituted cyclic alkyl means cyclic propyl, cyclic butyl, cyclic pentyl, methyl cyclic propyl, methyl cyclic butyl, methyl cyclic pentyl or the like. C1-C4 lower ester means a carboxylic group was esterified by lower alkyl group or the like. C1-C4 lower alkoxy means methaxy, ethoxy, propyloxy, butyloxy, isobutyloxy, t-butyloxy or the like. C1-C4 lower thioalkoxy means thiomethoxy, thioethoxy, thiopropyloxy, thiobutyloxy, thioisobutyloxy, thio t-butyloxy or the like. The substituted carbonyl group means acetyl, benzoyl, substituted benzoyl or the like. The substituted alkylsulfonyl, arylsulfonyl group means methanesulfonyl, para-toluenesulfonyl, benzenesulfonyl, para-nitrobenzenesulfonyl or the like The substituted silyl group means trimethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl or the like. The present inventors had studied the active compound as an antiviral agent for long time. As a result, the present inventors unexpectively found out the facts that the compounds of the general forrnula(I) have excellent antiviral activity against HIV and very low toxicity. According to the present invention, there is provided a pyrimidinedione homocarbocychc compound of general Formula (I) and pharmaceutically acceptable salts formed with inorganic or organic acids (Formula Removed) Wherein R1, R2 and R3 represents independently hydrofhen atom, halogen, atom, C1-C10 altyl, C1-C10 thioalkyi, C3-C4optionally substituted cyclic alkyl, unsaturated aflcyl, substituted alkyl hydroxy!, aryl hydroxy!, C1-C10 alkylamine, nitro, C1-C4 lower ester, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy; Z represents oxygen atom, sulfur atom, carbon atom and carbonyl group; X represents oxygen atom, sulfur atom; n represents an integer of 1-3; and (sub) cycloalk(en)yl represents (Formula Removed) in which (Formula Removed) represents (Formula Removed) in which R4 and R3 represents independendy hydrogen atom, hydroxymethyl, protected hydroxymethyl, benzyl, substituted carbonyl, substituted alkylsulfonyl or arylsulfonyl, substituted silyl or the like. In accordance with present invention, there are provided pharmaceutical compositions comprising one or more of the general formula(I) and their salts with a excellent antiviral activity against HIV and very low toxicity. In accordance with still another aspect of the present invention, there are provided with processes for preparing the compounds of the general formula(l) and their salts. The compounds of the present invention can be mixed with pnarmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and the pharmaceutical compositions can be used to prevent or treat various kinds of virus disease. Another object of the present invention is to provide pharmaceutical compositions containing the general formula(I) and their salts. The acids which can be reacted with the compounds of the general formula(I) to form acid salts are pharmaceutical acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid ; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, citric acid, maleic acid malonic acid,; sulfonic acids such as sulfonic acid, methanesulfonic acid, ethanesulfonic acid, bezenesulfonic acid, toluenesulfonic acid ; amino acids such as alanine, glycine, phenyl glycine, serin, cisserin, cystein, asparaginic acid, glutamic acid, lysine, arginine, tylosine, proline or the like. The vehicles which can be used in the preparation of pharmaceutical compositions containing the compounds of the general formula(I) as active ingredient are sweetening; agent, binding agent, dissolving agent, aids for dissolution, wetting agent, emulsifying agent, isotonic agent, adsorbent, degrading agent, antioxident, antiseptics, lubricating agent, filler and perfume or the like such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium carboxy methyl cellulose, agar, talc, stearic' acid, magnesium stearate, calcium stearate, magnesium aluminium silicate, starch, gelatine, tragacanth gum, methyl cellulose, glycine, silica, alginic acid, sodium alginate, water, ethanoi, polyethyleneglycol, polyvinyl pyrrolidone, sodium chloride, potassium chloride, orange essence, vanila aroma or the like. Daily dosage of the compound of the general formula(I) may be varied depending on age, sex of patient and the degree of disease. Daily dosage is l.Omg to 5,000mg and may be administered one to several times. The compounds of the general formula(l) may be prepared by the following scheme 1. Scheme 1 (Scheme Removed) wherein (Sub)cycloalk(en)yl, R1, R2, R3, 2, X, and n have the same meanings as defined above and Lie represents a leaving group as a halogen atom, alkylsulfonyl or arylsulfonyl group. The compounds of the general formula (I) may be prepared by reacting a compound of the general formula(a) and the general formula (b) in the presence of a base. Representative of the base include sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, cesium carbonate Representatives of the solvent include dirnethylformamide, ethanol, acetonitrile, dirnethylsulfoxide or the like. The reaction may be carried out between 10°C and l00°C for 5-48hrs. The compounds of the general formula(I) may be prepared by the following scheme 2. Scheme 2 (Scheme Removed) wherein n has the same meaning and m is an integer of 0-2. The representative reducting agents include sodium borohydride, lithium aluminium hydride and the activating group of hydroxy pant include halogen atom and sulfonyl group or the like. The sulfonyl group include alkylsulfonyl group such as methanesulfonyl and arylsulfonyl group such as para-toluenesulfonyl, benzenesulfonyl and para-nitrobenzenesulfonyl group. The general formula(d) can be effectively obtained by the reaction of the general formula(c) and the : reduction agent. And the general forrnula(b) can be effectively prepared by the introduction of the activating group of the general formula(c). The known compounds of 6-substituted pyrimidinedione derivatives (a) used in the preparation of the- general formula(I) are described in prior paper( WO 93/02044, WO 95/18109 ) or may be prepared in a similar method to the paper. Examples The compounds of the general formula(I) are prepared by the following examples. (Formula Removed) wherein R1, R2, R3, Z, X, (Sub)cycloalk(en)yl and n have the same. meanings above. l~[(Cyclopent-3-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedio ne 1-a) (Cyclopent-3-en-l-yl)methyl toluenesulfonate A mixture of (cyclopent-3-en-l-yl)methanoK 1.96g, 20mmol ) and para-toluenesulfonylchloride( 3.81g, 20mmol ) were stirred at room temperature for 2hrs in pyridine( 30ml ). After the concentration of pyridine, the reaction residues were extracted with dichloromethane, washed IN HC1, dried with MgSO-i, concentrated and separated by the column chroma tography to give the desirable product ( 4.20g ). Yield(%): 83.2 TH NMRCCDCls): 8 2.11 (2H,m), 2.42(3H,s), 2.49(3H,m), 3.82(2H,d), 5.67(2H,s), 7.40(2H,d), 7.65(2H,d). 1-b) l-[(Cyclopent-3-en-l-yl)rnethyl]-5-ethyl-6-phenylthio-2,4-pyrirnidine-dione A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( O.lOg, 0.40mmol ) and (cyclopent-3-en-lyl)methyl toluenesulfonate ( 0.12g, 0.40mmol ) in dimethylformamide( 10ml ) were heated at 90°C for overnight in the presence of sodium bicarbonate( 41mg, 0.48mmol ). After the concentration of dimethylformamide under vacuum distillation, the desirable product was obtained as white solid( 65mg ) by the separation of column chromatography. Yield(%): 49.1 m.p: 1H NMR(CDC13): 8 1.13(3H,t), 2.10(2H,m), 2.38(2H,m), 2.70(2H,q), 3.97(2H,dJ=7.65Hz), 5.67(2H,s), 7.14-7.53(5H,m), 8.51(lH,s). Example 2) l-[(Cyclopent-3-en-l-yl)methyl]-5-ethyl-6-(3,5-dimethylphenylthio)-2,4 -pyrimidinedione 5-ethyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and (cyclo-3-en-l -yOmethyl toluenesulfonate were reacted by the same way with example 1 to obtain the titled compound. Yield(%): 45.2 m.p: 128-130°C 'H NMR(CDCl3): S 1.03(3H,t), 2.10(2H,m), 2,37(2H,m), 2.68(2H,q), 2.83(lH,m), 3.99(2H,dJ=7.65Hz), 5.68(2H,s), 6.73(2H,s), 6.88(lH,s), 8.98(lH,s). Mass: m/e 356(M+), 219( 100 ) Example 3) l-[(Cyclopent-3-en-l-yl)methyl]-5-isopropyl-6-phenylthio-2,4-pyrimidin edione 5-Isopropyl-G-phenylthio-2,4-pyrimidinedione and (cyclopent-3-en-l-yl) methyl toluenesulfonate were reacted by the same way with example 1 to obtain the titled compound. Yield(%): 57.6 m.p: 131-134°C 'li NMR(CDCl3): d 1.21(6H,d,J=6.95Hz), 2.10(2H,m), 2.39(2H,m), 2.80(lH,m), 4.06(2H,dJ=7.65Hz), 5.68(2H,s), 7.14-7,35(5H,m), 9.14(lH,s) Mass: m/e 342(M+), 233(100) Example 4) l-[(Cyclopent-3-en-l-yl)methyl]-5-isopropyl-6-(3,5-dimethylphenylthio) -2,4 -pyrimidinedione 5-Isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and (cyclopent-3-en-l-yl)methyl toluenesulfonate were reacted by the same way with example 1 to obtain the titled compound. Yield(%): 62.8 m.p: 139-141°C TH NMR(CDCb): 8 1.20(6H,dJ=6.95Hz), 2.10(2H,m), 2.28(6H,s), 2.39(2H,m), 2.77(lH,m), 3.51 (lH,m), 4.05(2H,dJ=7.65Hz), 5.68(2H,s), 6.74(2H,s), 6.88(lH,s), 8.34(lH,s). Mass: m/e 370(M"), 233(100) Example 5) l-[(Cyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedi- one 5-a) (Cyclopent-l-en-l-yl)methyl toluenesulfonate A mixture of (cyclopent-l-en-l-yl)methanoK 1.96g, 20mmol ) and para-toluenesulfonylchloride( 3.81g, 20mmol ) were stirred at room temperature for 2hrs in pyridine( 30ml ). After the concentration of pyridine, the reaction residues were extracted with dichloromethane, washed IN HC1, dried with MgSO4, concentrated and separated by the column chromatography to give the desirable product! 4.52g ). Yield(%): 89.6 'IT NMIKCDCk): 8 1.84(2H,m), 2.23(4H,s), 2.49(3H,s), 4.21(2H,s), 5.27(lH,s), 7.40(2H,d), 7.65(2H,d). 5-b) l-[(Cyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidine-dione A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( O.lOg, 0.40mmol ) and (cyclopent-3-en-lyl)methyl toluenesulfonate( 0.12g, 0.40mmol ) in dimethylformamide( 10ml ) were heated at 90°C for overnight in the presence of sodium bicarbonate( 41mg, 0.48mmol ). After the concentration of dimethylformamide under vacuum distillation, the desirable product was obtained as white solid( 45mg ) by the separation of column chromatography. Yield(%): 34.2 m.p: 181-183°C H NMR(CDC13): S 1.01(3H,t), 1.84(2H,m), 2.23(2H,m), 2.69(2H,q), 4.66(2H,s), 5.26(lH,s), 7.15-7.34(5H,m), 8.94(lH,s) Example 6) 1 -[(4-Hydroxymethylcyclopent-l -en-1 -yDmethyl] -5-ethyl-6-phenylthio- 2,4-pyrimidinedione. G~a) (4-t-Butyldimethylsilyloxymethylcyclopent-l -en-1 -yDmethyl bromide The carbon tetrabromideC 1.39g, 4.2mmol ) and triphenylphosphine( 1.37g, 5.2mmol ) were added in dichloromethane solution of (4-t-Butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl alcohoK 0.85g, 3.5mmol ) under ice bath and then stirred for SOmin at 0°C. The reaction mixture was stirred for overnight at room temperature, extracted with dichloromethane, dried with MgSO/i, filtered, concentrated and separated by column chromatography to give a desirable product ( 0.53g ). Yield(%): 49.7 'II NMRCCDCls): 8 0.05(6H,s). 0.90(9H,s), 2.18(2H,m), 2.50(3H,m), 3.50(2H,dJ=6.75Hz), 4.05(2H,s), 5.71(lH,s) 6-b) 1 - [ (4 -My droxymethy Icyclopent-1 -en -1 -yDmethyl] -5-ethyl-6-phenylthio-2,4-pyrimidinedione A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.16g, O.GGmmol ) and (4-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide( 0.20g, O.GGmmol ) in dimethylformamide( lOmmol ) were heated at 50°C for overnight in the presence of sodium bicarbonate( 66mg, 0.79mmol ). After the concentration of dimethylformamide, [(4-t-butyldimethylsilyloxymethyl cyclo- pent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF( 10ml )was reacted with n-tetrabutylammoniumfluoride at room temperature for Ihr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product( 35 mg ). Yield(%): 14.8 m.p: 161-163°C H NMR(CDC13): S 1.01(3H,t), 2.03(2H,m), 2.38(2H,m), 2.50(lH,m), 2.68(2H,q), 3.50(2H,dJ=6.65Hz), 5.23(lH,s), 7.15-7.35(5H,m), 8.62(lH,s). Example 7) l-[(4-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-(3,5-dime-thylphenylthio)-2,4-pyrimidinedione 5-Eihyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (4-t-butyl-dimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were raided by the same way with the example 6 to obtain the titled compound( 48mg ). Yield(%): 21.4 m.p: 57-60°C rll NMR(CDC13): 8 1.02(3H,t), 2.04(2H,m), 2.28(6H,s), 2.39(H,m), 2.51 (lH,m), 2.68(2H,q), 3.51(2H,dJ=9.70Hz), 4.63(2H,q), 5.23(lH,s), 6.75(2H,s), 6.87(lH,s), 9.38(lH,s). Example 8) l-[(4-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-isopropyl-6-phenyl- thio-2,4-pyrimidinedione 5-Isopropyl-6-phenylthio-2,4-pyrimidinedione and [(4-t-butyIdimethylsilyl-oxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound( 67mg ) Yielcl(%): 29.5 m.p: 166-168°C H NMR(CDCl3): S 1.18(3H,d), 1.19(3H,d), 2.05(2H,m), 2.41 (2H,m), 2.50(lH,m), 3.49(lH,m), 3.52(2H,d), 4.70(2H,q), 5.24(lH,s), 7.16-7.34(5H,m), 8.63(lH,s). Example 9) l-[(4-IIydroxymethylcyclopent-l-en-l-yl)methyl]-5-isopropyl-6-(3,5-di -methy Ipheny Ithio ) - 2,4 -py rimidinedione 5-Isopropy 1-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and (4-t-butyldimethysilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound ( 73mg ) (%): 33.1 m.p: 147-148°C 'II NMR(CDCb): S 1.20(3H,d), 1.21(3H,d), 2.05(2H,m), 2.28(6H,s), 2.40(2H,d), 2.59(lH,m), 3.49(lH,m), 3.52(2H,dJ=6.85Hz), 4.70(2H,q), 5.24(lH,s), 6.75(2H,s), 6.87(lH,s), 9.06(lH,s) Mass: m/e 400(M+), 263(100) Example 10) l-[(5-Iiydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio- 2,4-pyrimidinedione 10-a) (5-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide The carbon tetrabromideC 8.5g, 25.7mmol ) and triphenylphosphine( 8.4g, 32.2mmol ) were added in dichloromethane solution of (5-t-Butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl alcohoK 5.2g, 21.4mmol ) under ice bath and then stirred for 30min at 0°C. The reaction mixture was stirred for overnight at room temperature, extracted with dichloromethane, dried with MgSO4, filtered concentrated and separated by column chromatography to give a desirable product ( 3.08g ). Yield(%): 47.2 rH NMRCCDCls): 8 0.05(6H,s). 0.90(9H,s), 1.71 (2H,m), 2.05(2H,m), 2.30(2H,m), 3.62(2H,dJ=5.80Hz), 4.15(2H,s), 5.71 (lH,s). 10-b) l-[(5-Iiydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.16g, O.GGmmol ) and (5-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide( 0.20g, 0.66mmol ) in dimethylformamide( 10ml ) were heated at 50°C for overnight in the presence of sodium bicarbonate( 66mg, 0.79mmol ). After the concentration of dimethylformamide, [(5-t-butyldimethylsilyloxymethyl cyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF( 10ml ) was reacted with n-tetrabutylammoniumfluoride at room temperature for Ihr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product( 35 mg ). Yield(%): 18.2 m.p: 155-156°C ]H NMR(CDCl3): 81.04(3H,t), 1.81-1.90(4H,m), 2.72(3H,m), 3.56-3.7 (2H,dd,J=4.35Hz), 4.70(2H,ddJ=16.9Hz) 5.32(lH,s), 7.17-7.36(5H,m), 9.90(lH,s). Example 11) l-[(5-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-(3,5-dimeth ylphenylthio)-2,4-pyrimidinedione 5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same with the example 10 to obtain the titled compound. Yield(%): 22.7 m.p: 59-GO°C 'II NMR(CDC13): S 1.05(3H,t), 1.83-2.27(4H,m), 2.28(6H,s), 2.73(3H,m), 3.57-3.74(2H,ddJ=4,30Hz), 4.60(2H,dd,J=17Hz), 5.31 (IH.s), 6.77(2H,s), 6.88(lH,s), 9.39(lH,s). Example 12) l-[(5-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-isopropyl-6-(3,5-di methylphenylthio)-2,4-pyrimidinedione 5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-l -en-1 -yDmethyl bromide were reacted by the same with the example 10 to obtain the titled compound. ( 68mg ) Yield(%): 29.9 m.p: 6G-68°C 'H NMR(CDC13): d 1.21(3H,dJ=7.0Hz), 1.24(3H,dJ=7.0Hz), 1.81-2.34(4H,m), 2.73(lH,m), 3.51 (lH,m), 3.57-3.74(2H,ddJ=4.45Hz), 4.66(2H,dd,J=17.0Hz), Example 13) 1 -[ (5-Hydroxymethylcyclopent-l -en-1 -yDmethyl] -5-Isopropyl-6- (3,5~di methyl-phenylthio)-2,4-pyrimidinedione 5-Isopropyl~6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same with the example 10 to obtain the titled compoundC 83mg ). Yield(%): 37.6 m.p: 81-82°C 'II NMR(CDC13): 8 1.22(3H,dJ=6.9Hz), 1.25(3H,dJ=6.9Hz), 1.82-2.25(4H,m) 2.28(6H,s), 2.74 (lH,m), 3.53(lH,m), 3.55-3.77(2H,dd, J=4.25Hz), 4.70(2H,ddJ=17.0Hz), 5.32(lH,s), 6.78(2H,s), 6.88(lH,s), 8.41(lH,s). Example 14) l-[(Cyclopent-3-en-l-yl)methyl]-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-py ri midi nedione. 5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidindione and (cyclopent-3-en-l-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound( 68mg ). Yield(%): 49.9 m.p: 179-180°C XH NMR(CDCls): d 1.02(3H,tJ=7.5Hz), 2.02-2.05(2H,m), 2.32(6H,s), 2.34(2H,m), 2.68(3H,m), 3.66(2H,d,J=7.5Hz), 5.67(2H,s), G.50(2H,s), 6.77(lH,s), 8.92(lH,s). Mass: m/e 340(M+), 219(100) Example 15) l-[(Cyclopent-3-en-l-yl)methyl]-5-isopropyl-6-(3,5-dimethylphenoxy)-2 ,4-pyrimidinedione. 5-Isopropyll-6-(3,5-dimethylphenoxy)-2,4-pyrimidmdione and (cyclopent-3-en-l-y])methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound( 73mg ). Yield(%): 51.5 m.p: 183-184°C 'll NMRCCDCb): 8 1.14(3H,s), 1.15(3H,s), 2.05(2H,ddJ=5.29Hz), 22.31 (6H,s), 2.28(2H,ddJ=8.56Hz), 2.73-2.83(2H,m), 3.65(2H,dJ=7.5Hz) 5.67(2H,s), 6.50(2H,s), 6.77(lH,s), 8.96(lH,s). Example 16) l-[(Cyclopent-3-en-l-yl)methyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4- pyrimidinedione. 5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidindione and (cyclopent-3-en-l-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound ( 84mg ). Yield(%): 59.6 m.p: 209-210°C ]II NMR(CDC13): d 0.98(3H,tJ=7.5Hz), 2.02(2H,m), 2.26-2.37(2H,m), 2.41 (6H,s), 2.68-2.73(3H,m), 3.82(2H,dJ=7.5Hz), 5.58-5.60(2H,m), 7.34(lH,s), 8.82(lH,s). Mass: 352(M+), 219(100) Example 17) l-[(Cyclopent-3-en-l-yl)methyl]-5-isopropyl-6~(3,5-dimethylbenzoyl)-2, 4 -py ri mi dinedione. 5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclopent-3-l-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound( 81mg ). Yield(%): 55.2 m.p: 196-197°C lli NMR(CDCb): d 1.12(3H,dJ=7.0Hz), 1.23(3H,dJ=7.0Hz), 2.01-2.03(2H,m), 2.26-2.34(3H,m), 2.40(6H,s), 2.58-2.62(lH,m), 3.18(111, dd,J=7.56Hz), 3.84(lH,ddJ=7.56Hz), 5.56(lH,m), 5.60 ), 7.34(lH,s), 7.51 (2H,s), 8.77(lH,s). Example 18) l-[(4-IIydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-(3,5-dimeth yl-phenoxy)-2,4-pyrimidinedione 5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (4-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same method with example 6 to obtain the titled compound. ( 52mg ) Yield(%): 21.3 rH NMR(CDCl3): § 0.95(3H,t,J=7.5Hz), 2.05(2H,m), 2.21(2H,q,J=10.0Hz), 2.30(6H,s), 2.38-2.43(2H,m), 2.50-2.55(lH,m), 3.49(2H,dJ=5.0Hz), 4.37(2H,s), 5.35(lH,s), 6.52(2H,s), 6.77(lH,s), 8.99 (lH,s). Example 19) l-[(5-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-(3,5-dime-thyphenoxy ) -2,4-pyrimidinedione 5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (5-t-butyldimethy- lsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same method with example 6 to obtain the titled compound ( 52mg ). Yield(%): 21.3 m.p: 119-120°C ]II NMR(CDC13): S 0.95(3H,t,J=7.5Hz), 1.77-1.82(lH,m), 1.98-2.04(lH,m), 2.17-2.25(2H,m), 2.30(6H,s), 3.57(lH,d,J=5,OHz), 3.66(lH,dJ=5.0Hz), 3.90(2H,dJ-14.0Hz), 5.50(lH,s), 6.53(2H,s), 6.78(lH,s), 8.72(lH,s). Example 20) l~[(Cyclopentyl)methyl]-5-isopropyl-6-(3,5-dimethyphenylthio)-2,4-pyri- midinedione 20-a) (Cyclopentyl)methyl toluenesulfonate To cyclopentanemethanoK 2.0g, 20mmol ) in pyridine( 30ml ) was added para-toluenesulfonyl chloride( 3.81g, 20mmol ) with stirring. After 2hrs at room temperature, the reaction mixture was concentrated for removement of pyridine, extracted with dichloromethane, dried, filtered, concentrated and separated by a column chromatography to give a desirable product! 3.80g ). Yield(%): 74.7 ]H NMR(CDCls): 3 1.26-1.30(2H,m), 1.52-1.53(2H,m), 1.66(4H,m), 2.09(lH,m), 2.48(3H,s), 3.74(2H,d), 7.40(2H,d), 7.72(2H,d). 20-b) l-[(Cyclopentyl)methyl]-5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione. A mixture of 5~isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione( 0. lOg, 0.40mmol ) and cyclopentyl toluenesulfonate( O.lg, 0.4mmol ) in dimethylformamide( 10ml ) were heated at 100°C for overnight in the presence of sodium bicarbonate( 41mg, 0.48mmol ). After the concentration of dimethylformamide, the desirable product was obtained by the separation of the column chromatography to give a desirable product as a white solid ( 75mg ). Yiekl(%): 50.3 m.p: 145-146°C lli NMR(CDCls): 8 1.20(3H,s), 1.22(3H,s), 1.26-1.30(2H,m), 1.52-1.53(2H,m), 1.66(4H,m), 2.28(6H,s), 2.32-2.35(lH,m), 3.48-3.54(lH,m), 4.02(2H,dJ=7.5Hz), 6.74(2H,s), 6.87(lH,s), 9.27(lH,s). Mass: m/e 327(M+), 275(100) Example 21) l-(Cyclopentyl)methyl-5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimi- dinedione 5~Isoproyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclopentyl) methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound ( 53mg ). Yield(%): 37.2 m.p: 157-158°C ]II NMR(CDC13): 8 1.14(3H,s), 1.15(3H,s), 1.21-1.25(2H,m), 1.53-1.55(2H,m), 1.65-1.68(4H,m), 2.26-2.29(lH,m), 2.31 (6H,s), 2.78-2.83(lH,m), 3.61(2H,dJ=7.5Hz), 6.51(2H,s), 6.77(lH,s), 9.04(lH,s). Example 22) l-(Cyclopentyl)methyl-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimi- dinedione 5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclopentyl)methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound ( 84mg ). Yield(%): 57.0 m.p: 167-168°C II NMRCCDCh): 8 1.12(3H,dJ=7.0Hz), 1.23(3H,dJ=7.0Hz), 1.46-1.47(2H,m), 1.57(4H,m), 2.10-2.16(lH,m), 2,30-2,36 (lH,m), 2.41 (6H,s), 3.15(lH,ddJ=7.05Hz), 3.84(lH,ddJ=7.5 Hz), 7.34(lH,s), 7.52(2H,s), Mass: m/e 368(M+), 133(100) Example 23) l-(Cyclopentyl)methyl-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidine- dione 5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclopentyl)- methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound. ( 80mg ) Yieid(%): 56.4 m.p: 186-187°C 1H NMR(CDCla): 8 0.94(3H,tJ=7.5Hz), 1.24(3H,dJ=7.0Hz), 1.46-1.47(2H,m), 1.56-1.58(4H,m), 2.14(lli,m), 2.41 (6H,s), 2.62(2H,q,), 3.18(lH,dJ=7.0Hz), 3.84(lH,dJ=7.0Hz), 7.34(lli,s), 7.51 (2H,s), 8.94(lH,s). Example 24) l-{[4-Bis(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-6-phenyl -thio-2,4-pyrimidinedione 24-a) [4-Bis(t-butyldimethylsilyloxylmethyl)cyclopent-l-en-l-yl] methyl bromide A mixture of carbon tetrabromide( 1.99g, G.Ommol ) and triphenylphosphine( 1.97g, 7.5mmol ) were added to [4- bis (t-butyldimethylsilyloxymethyl)cyclopent-l -en-1 -yljmethyl alcohol ( 1.93g, S.Ommol ) in dichloromethane under ice bath and then, the reaction mixture was stirred for 30min at 0°C. After overnight at room temperature, the reaction mixture was extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product( 1.43g ). Yiekl(%): 63.5 1H NMlKCDCb): d 0.05(6H,s), 0.90(9H,s), 2.09(2H,br), 2.15(2H, br), 3.64(4H,m), 4.04(2H,s), 5.21 (lH,s). 24-b) l-{[4-Bis(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-6-phenylthio-2,4-pyrimidinedione A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.16g, O.GGmmol ) and [4-bis(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl)methyl bromideC 0.30g, 0.66mmol ) in dimethylformamide( 10ml ) were heated at 50°C for overnight in the presence of sodium bicarbonateC 66mg, 0.79mmol ). After the concentration of dimethylformamide, l-{[4-bis(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl)methyl}-5-ethyl-G-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF( 10ml ) was reacted with n-tetrabutylammoniumfluroride at room temperature for Ihr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product( 45mg Yield(%): 17.6 m.p: 170-171°C !H NMR(CDC13): S 1.02(3H,t,J=7.5Hz), 2.09(2H,br), 2.15(2H,br), 2.68(2H, q,J=7.5Hz), 3.64(4H,U=7.5Hz), 4.62(2H,s), 5.20(lH,s), 7.16(2H,dJ=7.5Hz), 8.40(lH,s). Example 25) l-{[4-Bis(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5~ethyl-6-(3,5- dimethyl-phenylthio)-2,4-pyrimidinedione. 5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and [4~bi s (t-butyldimethy IsilyloxymethyDcyclopent- 1 -en-1 -yljmethyl bromide were reacted by the same method with example 24 to obtain the titled compound ( 48mg ). Yield(%): 17.5 m.p: 156-157°C H : 3 1.02(3H,t,J=7.4Hz), 2.08(2H,s), 2.14(2H,s), 2.28(6H,s), 2.68(2H,q,J=7.5Hz), 3.62(4H,tJ=11.2Hz), 4.62(2H,s), 5.21(lH,s), 6.75(lH,s), 6.88(lH,s), 9.61(lH,s). Mass: m/e 416(M+), 91(100) Example 26) l-{[4-Bis(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-isopropyl-6-phenylthio-2,4-pyrimidinedione. 5-Isopropyl-6-phenylthio-2,4-pyrimidinedione and [4-bis(t-butyldimethylsilyl oxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 24 to obtain the titled compound( 52mg ). Yield(%): 19.6 m.p: 148-149°C 'l-I NMR(CDC13): 8 1.19(3H,s), 1.20(3H,s), 2.06(2H,s), 2.17(2H,s), 3.45-3.51 (lH,m), 3.59(4H, tJ=11.0Hz), 4.69(2H,s), 5.21 (lH,s), 7.16(2H,dJ=7.5Hz), 7.25(lH,tJ=7.5Hz), 7.33(2H,t,J=7.5Hz), 9.55(lH,s). Example 27) l-{[4-Bis(hydroxymethyl)cycloi3ent-l-en-l-yl]methyl}-5-isopropyl-6-(3, 5-dimethylphenylthio)-2,4-pyrimidinedione. 5-Isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and [4-bis(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 24 to obtain the titled compound( 44mg ). Yielcl(%): 15.5 m.p: 156-157°C H NMR(CDC13): 8 1.02(3H,s), 1.21(3H,s), 2.08(2H,s), 2.16(2H,s), 2.28(6H,s), 3.45-3.51 (lH,m), 3.62(4H,s), 4.68(2H,s), 5.21(lH,s), 6.76(lH,s), 6.87(lH,s), 6.69(lH,s). Example 28) l-f[3,4-Di(hydroxymethyl)cycloijent-l-en-l-yl]methyl}-5-ethyl-6-phenyl -thio-2,4-pyrimidinedione 28-a) [3,4-Di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide A mixture of carbon tetrabromideC 3.18g, 9.6mmol ) and triphenyl phosphine( 3.15g, 12.9mmol ) were added to [3,4-di(t-butyldimethylsilyl oxymethyl)cyclopent-l-en-l-yl]methyl alcohoK 3.09g, S.Ommol ) in dichloromethane under ice bath and then, the reaction mixture was stirred for 30min at 0°C. After overnight at room temperature, the reaction mixture was extracted with dichloromethane, dried with MgS04, filtered, concentrated and separated by column chromatography to give a desirable product(2.43g). Yield(%): 67.4 'H NMlKCDCla): 3 0.05(6H,s), 0.91(9H,s), 1.85(lH,dJ=15.5Hz), 2.26(2H,m), 2.62-2.70(3H,m), 3.44(lH,t,J=9.0Hz), 3.60(2H,m), 3.78(lH,dJ=7.5Hz), 4.08(2H,s), 5.25(lH,s). 28-b) l-[3,4-Di(hydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenyl-thio-2,4-pyrimidinedione A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.16g, O.GGmmol ) and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide( 0.30g, 0.66mmol ) in dimethylformamide( 10ml ) were heated at 50°C for overnight in the presence of sodium bicarbonate( 66mg, 0.79mmol ). After the concentration of dimethylformamide, l-{[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-G-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF( 10ml ) was reacted with n-tetrabutylammonium fluoride at room temperature for Ihr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product( Yield(%): 18.7 'II NMR(CDCb): S l.Q3(3H,t), 1.84(lH,dJ=15.5Hz), 2.38(2H,m), 2.60(lH,br) 2.70(2H,qJ=7.0Hz), 3.44(lH,tJ=9.0Hz), 3.59-3.63(2H,m), 3.78(lH,dJ=7.5Hz), 4.59(2H,dd, J=4.5, 7.0Hz), 5.25(lH,s), 7.16(lH,d, J=7.5Hz), 7.26(lH,t, J=8.5Hz), 7,34(2H,t, J=7.5 Hz), 9.30(lH,s). Example 29) l-{[3,4-Di(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-6-(3,5-di -methylphenylthio)-2,4-pyrimidinedione 5-Ethyl~6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 53mg ). (%): 19.3 m.p: 156-157°C 'H NMRCCDCb): § 1.03(3H,tJ=7.5Hz), 1.86(lH,d,J-15.5Hz), 2.28(6H,s), 2.42(2H,m), 2.60(lH,m), 2.68-2.73(2H,m), 3.44(lH,t,J=7.5Hz), 3.56-3.64(2H,m), 3.79(lH,dJ=7.5Hz), 4.59(2H,dJ=8.5Hz), 5.27(lH,s), 6.76(2H,s), 6.88(lH,s), 9.44(lH,s). Example 30) l-{[3,4-Di(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-isopropyl-6-(3, 5-dimethylphenylthio)-2,4-pyrimidinedione 5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and [3,4-di (t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 51mg ). Yield(%): 17.9 m.p: 136-137°C NMR(CDC13): 1.20(3H,dJ=7.0Hz), 1.25(3H,dJ=7.0Hz), 1.87(lH,dJ=15.5Hz), 2.28(6H,s), 2.40-2.44(2H,m), 2.60(lH,br), 2.96-3.00(lH,m), 3.44-3.53(2H,m), 3.58-3.65(lH,m), 3.80(1H, ddj=4.0, 6.5Hz), 4.62-4.69(2H,m), 5.27(lH,s), 6.76(2H,s), 6.88(lH,s), 9.01 (lH,s). Example 31) l-{[3,4-Di(hydroxymethyl)cycloi3ent-l-en-l-yl]methyl}-5-ethyl-6-(3,5-di -melhylphenoxy)-2,4-pyrimidinedione 5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 42mg ). Yield(%): 17.9 'H NMR(CDC13): 3 0.94(3H,t), 1.82(lH,dJ=15.5Hz), 2.18-2.22(2H,m), 2.31 (6H,s), 2.38-2.45(2H,m), 2.76(lH,br), 3.42-3.49(2H,m), 3.60(lH,m), 3.94(lH,m), 4.33(2H,ddJ=15.5, 29.5Hz), 5.43(lH,s), 6.52(2H,s), 6.78(lH,s), 9.79(lH,s). Example 32) l-{[3,4-Di(hydroxymethyl)cycloi3ent-l-en-l-yl]methyl}-5-isopropyl-6-(3, 5-dimethylphenoxy)-2,4-pyrimidinedione 5-Iso]jropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and [3,4-di(t- butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 48mg ). Yield(%): 17.5 NMR(CDC13): 1.21(3H,dJ=7.0Hz), 1.24(3H,dJ=7.0Hz), 1.83(lH,dJ=15.5Hz), 2.31 (6H,s), 2.37(2h,m), 2.57(lH,br), 2.74-2.79(lH,m), 3.38-3.50(2H,m), 3.60(lH,qJ=5.0Hz), 3.90(lH,dJ=7.0Hz), 4.25(1H, dJ=16.0Hz), 4.34(lH,dJ=16.0Hz), 5.42(lH,s), 6.51 (2H,s), 6.77(lH,s), 9.33(lH,s). Example 33) l-{[3,4-Di(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-6-(3,5-di -methylbenzoyl)-2,4-pyrimidinedione 5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 68mg ). Yield(%): 25.0 m.p: 79-80"C NMR(CDCls): 0.94-0.97(3H,tJ=7.5Hz). 1.54(lH,dJ=15.5Hz), 2.03-2.04(lH,m), 2.31-2.35(5H,m), 2.39(3H,s), 2.40(3H,s), 3.27-3.33(lH,m), 3.41 (lH,m), 3.50(lH,m), 3.79(lH,m), 4.3 440(lH,d), 5.34(lH,m), 7.49(2H,s), 9.06(lH,s). 7.31 (lH,s), Example 34) l-{[3,4-Di(hydroxymethyl)cycloi3ent-l-en-l-yl]methyl}-5-isopropyl-6-(3, 5-dimethylbenzoyl)-2,4-pyrimidinedione 5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 74mg ). Yield(%): 26.3 m.p: 81-82°C 1H NMR(CDC13): 8 1.20(3H,dJ=7.0Hz), 1.24(3H,dJ=7.0Hz), 1.50(lH,dJ=15.5Hz), 2.24-2.31 (2H.m), 2.39(3h,s), 2.40(3H,s), 2.54(2H,m), 3.29(lH,m), 3.40QH, br), 3.49(lH,m), 3.71-3.84(lH,m), 4.27-4.39(lH,m), 5.20-5.34(lH,m), 7.33(lH,s), 7.49(2H,s), 9.39(lH,s). Ezamijle 35) l-[2-(Cyclopent-l-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4- pyrimidinedione 35-a) 2-(Cyclopent-l-en-yl)ethyl toluenesulfonate A para-toluenesulfonylchloride( 3.81g, 20mmol ) was added to the pyricline( 30ml ) solution of 2-(cyclopent-l-en-l-yl)ethyl alcohoK 2.24g, 20mmol ) and then the reaction mixture was stirred at room temperature for 2hrs. After the removement of pyridine, the residue was extracted with dichloromethane, washed with IN HC1, dried, filtered and separated by column chromatography to give a desirable product ( 2.80g ). Yield(%): 52.6 'li NMR(CDCla): 8 0.82(2H,m), 1.99-2.30(6H,m), 2.49(3H,s), 3. 4.03(lII,m), 5.22(lH,s), 7.41(2H,d), 7.74(2H,d). 35-b) l-[2-(Cyclopent-l-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione A mixture of sodium bicarbonate( O.lOg, 1.2mmol ) and lithium iodide( 13mg, O.lmmol ) were added to dimethylformamide solution( 10ml ) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione( 0.27g, l.Ommol ) and 2-(cyclopent-l-en-l-yl)ethyl toluenesulfonate( 0.27g, l.Ommol ). And then, the reaction mixture was stirred at 90°C for overnight, concentrated for removement of dimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a desirable product as a white solid ( 148mg ). Yield(%): 40.4 m.p: 211-213°C H NMR(CDCk): 3 0.81(2H,dd,J=7.0,1.5Hz), 0.97(3H,t,J=7.5Hz), 1.99-2.30(6H,m), 2.40(6H,s), 3.29(lH,m), 3.91 (lH,m), 5.22(lH,s), 7.35(lH,s), 7.50(2H,s), 8.81 (lH,s). Mass: m/e 366(M+), 94(100) Example 36) l-[2-(Cyclopent-3-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4- pyrimidinedione 36-a) 2-(Cyclopent-3-en-l-yl)ethyl toluenesulfonate A para-toluenesulfonylchloride( 3.81 g, 20mmol ) was added to the pyridine( 30ml ) solution of 2-(cyclopent-3-en-l-yl)ethyl alcohoK 2.24g, 20mmol ) and then the reaction mixture was stirred at room temperature for 2hrs. After the removement of pyridine, the residue was extracted with dichloromethane, washed with IN HC1, dried, filtered and separated by column chromatography to give a desirable product ( 3.24g ). Yield(%): 60.8 NMRCCDCk): 8 1.69(2H,m), 1.85(2H,m), 2.02(2H,m), 2.25(lH,m), 3.42(lH,m), 3.94(lH,m), 5.56(2H,d), 7.4192H,d), 7.74(2H,d). 36-b) l-[2-(Cyclopent-3-en-lyl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione A mixture of sodium bicarbonate( O.lOg, 1.2mmol ) and lithium iodide ( 13mg, O.lmmol ) were added to dime thy Iformamide solution ( 10ml ) of 5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione( 0.27g, l.Ommol ) and 2-(cyclopent-3-en-l-yl)ethyl toluenesulfonate( 0.27g, l.Ommol ). And then, the reaction mixture was stirred at 90°C for overnight, concentrated for removement of ctimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a desirable product as a white solid ( 136mg ). Yield(%): 37.1 m.p: 190-191°C H NMR(CDCls): 0.97(3H,tJ=7.5Hz), 1.69(2H,m), 1.85(2H,m), 2.02(2H,m), 2.25(lH,m), 2.37(3H,m), 2.41 (6H,s), 3.17(lH,m), 3.82(1H, m), 5.56(2H,d), 7.36(lH,s), 7.53(2H,s), 8.64(lH,s). Mass: m/e 366(M+), 94(100) Example 37) l-[2-(Cyclopent-3-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylbenzoyl)-2, 4 -py rimidinedione 5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-(cyclopent- 3-en-l-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound(140mg). Yield(%): 36.8 m.p: 175-176°C H NMR(CDC13): S 1.13(3H,d,J=7.0Hz), 1.20(3H,d,J=7.0Hz), 1.70(2H,m), 1.82(2H,m), 2.03(lH,m), 2.33(3H,m), 2.41(6H,s), 3.13(lH,m), 3.80(lH,m), 5.56(2H,ddJ=40,10.0Hz), 7.36(lH,s), 7.55(2H,s), 8.45(lH,s). Example 38) l-[2-(Cyclopent-3-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylphenoxy)- 2,4-pyrimidinedione 5-Isopropyl-6- (3,5-dimethyl2phenoxy )-2,4-pyrimidinedione and 2-(cyclopent- 3-en~l-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound(109mg). Yield(%): 29.6 m.p: 109-110°C H NMR(CDCla): S 1.14(6H,dJ=7.0Hz), 1.70(2H,m), 1.93(2H,m), 2.15(lH,m), 2.31 (6H,s), 2.45(2H,m), 2.79(lH,m), 3.67(2H,t,J=7.5Hz), 5.62(2H,s), 6.53(2H,s), 6.78(lH,s), 8.83(lH,s). Example 39) l-[2-(Cyclopent-3-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylphenylthio) -2,4-pyrimidinedione 5-Isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and 2-(cyclopent 3-en-l-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound (134mg). (%): 34.8 m.p: 128-129T ]H NMR(CDCls): 8 1.24(6H,dJ=7.0Hz), 1.68(2H,m), 2.03(2H,m), 2.18(lH,m), 2.29(6H,s), 2.48(2H,m), 3.53(lH,m), 4.00(2H,tJ=8.0Hz), 5.64(2H,s), 6.77(2H,s), 6,88(lH,s), 8.95(lH,s). Mass: m/e 384(M+), 247(100) Example 40) l-{2-(Cyclopent-2-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4- pyrimidinedione 40~a) 2-(Cyclopent-2-en-l-yl)ethyl bromide A mixture of carbon tetrabromide( 19.2g, 57.8mmol ) and triphenyl phosphine( 15.2g, 57.8mmol ) were added to 2-(cyclopent-2-en-l-yl)ethyl alcohoK 4.32g, 38.5mmol ) in dichloromethane( 15ml ) under ice bath and then, the reaction mixture was stirred for 2hrs at 0°C The reaction mixture was extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product(5.53g). Yield(%): 82.0 H NMRCCDCls): 8 1.26-2.29(6H,m), 2.80(lH,m), 3.43(2H,t), 5.72(2H,s). 40-b) l-[2-(Cyclopent-2-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione A mixture of sodium bicarbonate( O.lOg, 1.2mmol ) and lithium iodide( 13mg, O.lmmol ) were added to dimethylformamide solution( 10ml ) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione( 0.27g, l.Ommol ) and 2~(cyclopent-2-en-yl))ethyl bromide( 0.18g, l.Ommol ). And then, the reaction mixture was stirred at 90°C for overnight, concentrated for removement of dimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a desirable product as a white solid ( 112mg ). Yield(%): 30.6 m.p: 183-185°C H NMR(CDC13): S 0.97(3H,t), 1.24(lH,m), 1.49(lH,m), 1.70(2H,m), 2.00(lH,m), 2,24(2H,m), 2.41(6H,s), 2.49(lH,m), 3.23(lH,m), 3.81 (lH,m), 5.48(lH,m), 5.66(lH,m), 7.35(lH,s), 7.52(2H,s), 8.73(lH,s). Example 41) l-[2-(Cyclopent-2-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylbenzoyl)-2, 4-pyrimidinedione 5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-(cyclopent- 2-en-l-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound ( 123mg ). Yield(%): 32.3 :H NMRCCDCla): 8 1.15(3H,d,J=6.85Hz), 1.23(3H,dJ=6.85), 1.29(lH,m), 1.42(lH,m), 1.75(2H,m), 1.92(lH,m), 2.05(lH,m), 2.29(2H,m), 2.45(6H,s), 2.52(lH,m), 3.35(lH,m), 3.92(lH,m), 5.50(lH,m), 5.73(lH,m), 7.92(lH,s), 7.48(2H,s), 8.85(lH,s). Example 42) l-[2-(Cyclopent-2-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylphenoxy)- 2,4-pyrimidinedione 5~Isopropyl-6- (3,5-dimethylphenoxy )-2,4-pyrimidinedione and 2-(cyclopent- 2-en-l-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound( 132mg ). Yield(%): 35.8 m.p: 148-149°C XH NMR(CDC13): 3 1.15(6H,d), 1.36(lH,m), 1.55(lH,m), 1.70(lH,m), 2.00(lH,m), 2.27(2H,m), 3.69(2H,m), 5.56(lH,ddJ=2.Q5Hz), 5.71 (lH,ddJ=2.25Hz), 6.54(2H,s), 6.78(lH,s), 8.37(lH,s). Example 43) l-[2-(Cyclopent-2-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylphenylthio) -2,4-pyrimidinedione 5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4~pyrimidinedione and 2-(cyclopent- 2-en-l-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound( 98mg ). Yield(%): 25,5 m.p: 138-140°C 1H NMR(CDC13): d 1.25(6H,ddJ=1.85Hz), 1.45(lH,m), 1.57(lH,m), 1.68(2H,m), 2.01 (lH,m), 2.29(6H,s), 2.35(lH,m), 2.61 (lH,m), 3.53(lH,m), 4.02(2H,t), 5.59(lH,ddJ=2.0Hz), 5.72(lH,ddJ=2.25Hz), 6.77(2H,s), 6.88(lH,s), 8.67(lH,s). Example 44) l-(2-Cyclopentyl)ethyl-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidine- dione 44-a) (2-Cyclopentyl)ethyl toluenesulfonate A para-toluenesulfonyl chloride( IG.Og, 83.8mmol ) was added to the pyridineC 250ml ) solution of (2-cyclopentyl)ethyl alcohol( 8.76g, 76.2mmol ) and then the reaction mixture was stirred at room temperature for 6hrs. After the removement of pyridine, the residue was extracted with ethyl acetate, washed with IN HC1, dried, filtered and separated by column chromatography to give a desirable product ( 15.7g ). Yield(%):73 1H NMR(CDC13): 8 0.90-1.89(llH,m), 2.45(3H,s), 4.05(2H,t), 7.27-7.88(4H,dd). 44-b) l-(2-Cyclopentyl)ethyl-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidine-one A mixture of sodium bicarbonate( O.lOg, 1.2mmol ) and lithium iodide( 13mg, O.lmmol ) were added to dimethylformamide solution( 10ml ) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione( 0.27g, l.Ommol ) and 2-(cyclopentyl)ethyl toluenesulfonate( 0.27g, l.Ommol ). And then, the reaction mixture was stirred at 90°C for overnight, concentrated for removement of dimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a white solid ( 90mg ). Yield(%): 24.5 H NMR(CDCl3): 8 0,95(2H,m), 0.97(3H,t), 1.41-1.62(9H,m), 2.02(lH,m), 2.28(lH,m), 2.41 (6H,s), 3.18(lH,m), 3.79(lH,m), 7.35(lH,s), 7.52(2H,s), 8.64(lH,s). Example 45) l-(2-Cyclopentyl)ethyl-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimi- dinedione 5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (2-cyclopent- yDethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound ( 95mg ). Yield(%): 24.9 m.p: 174-176°C H NMR(CDC13): 8 0.95(2H,m), 1.15(3H,dJ=6.85Hz), 1.23(3H,dJ=6.85Hz), 1.391.69(9H,m), 2.32(lH,m), 2.41(6H,s), 3.15(lH,m), 3.77(lH,m) 7.36(lH,s), 7.55(2H,s), 8.90(lH,s). Example 46) l-(2-Cyclopentyl)ethyl-5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyriini- dinedione 5-Isopropyl-6- (3,5-dimethylphenoxy )-2,4-pyrimidinedione and (2-cyclopent- yDethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound( 105mg ). Yield(%): 28.3 m.p: 136-138°C 1H NMR(CDC13): 3 1.04(2H,m), 1.15(6H,d), 1.46-1.71(9H,m), 2.31 (6H,s) 2.80(lH,m), 3.65(2H,t), 6.53(2H,s), 6.78(lH,s), 8.60(lH,s). Example 47) l-(2-Cyclopentyl)ethyl-5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyri- midinedione 5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (2-cyclopent- yDethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound( 80mg ). Yield(%): 20.7 m.p: 95-97°C :H NMR(CDC13): 8 1.11 (2H,m), 1.25(6H,d), 1.47-l,78(9H,m), 2.29(6H,s), 3.53(lH,m), 4.00(2H,t), 6.77(2H,s), 6,.88(lH,s), 9.1991H,s). Example 48) l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-6-phenylthio- 2,4-pyrimidinedione A sodium bicarbonate( O.lOg, 1.2mmol ) was added to a stirred solution of dimethylformamide( 10ml ) of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.25g, l.Ommol ) and 2-bis(t-butyldimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide( 0.42g, l.Ommol ) and then, the reaction mixture was heated at 90°C for overnight. The reaction mixture was poured into water( 30ml ), extracted with ether ( 2 times ), dried, filtered, concentrated and separated by column chromatography to give l-[2-bis(t-butyldimethylsilyloxymethyl)cyclopropane-l-yl]methyl-5-ethyl -6-phenylthio-2,4-pyrimidinedione as a pale yellow oil( 125mg ). This compound in THF( 5ml ) was reacted with n-tetrabutylammonium fluoride( 1.0ml of l.Omol THF solvent ) at room temperature for 6hrs. The reaction mixture was concentrated for removement of THF and separated by column chromatography to give l-[2-bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-6-phenylthio-2,4-pyrimidinedione( 142mg ) as a white solid. Yield(%): 39.4 m.p: H NMR(CDC13): 8 0.22(lH,t,J=5.5Hz), 0.53(lH,ddJ=5.5, 3.5Hz), 1.05(3H,t,J=7.0Hz), 1.07(lH,m), 2.70-2.75(lH,m), 3.25(lH,dJ=11.0Hz), 3.53(lH,d,J=13.0Hz), 3.75(lH,dJ=11.5Hz), 4.05-4.13(2H,m), 4.20(lH,ddJ=4.0, ll.OHz), 7.20(2H,d), 7.28(lH,t), 7.36(2H,t), 9.36 lH,s). Example 49) l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-(3,5-dimethyl -phenylthio)-2,4-pyrimidinedione 5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and 2-bis(t~butyl dimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide were reacted by the same method with example 48 to obtain the titled compound( 191 mg ). Yield(%): 49.0 m.p: NMRCCDCla): 8 0.22(lH,tJ-5.0Hz), 0.53(lH,ddJ=8.5, 5.5Hz), 1.04(3H,t,J=7.5Hz), 1.37-1.42(lH,m), 2.29(6H,s), 2.71-2.74(2H,m), 3.28(lH,dJ=10.0Hz), 3.53(lH,dJ=12.5Hz), 3.73(lH,dJ=11.0Hz), 4.05-4.14(2H,m), 419(lH,dJ=11.5Hz), 6.79(2H,s), 6.89(lH,s), 9.45(lH,s). Example 50) l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-6-(3,5-dime-thy Iphenoxy) - 2,4-py rimidinedione 5-Ethyl-6- (3,5-dimethylphenoxy )-2,4-pyrimidinedione and 2-bis(t-butyl dimethylsilyloxymethyl)cyclopropane-l-yljmethyl bromide were reacted by the same method with example 48 to obtain the titled compound( 151 mg ). Yield(%): 40.3 H NMR(CDC13): d 0.27(lH,tJ=5.5Hz), 0.59(lH,ddJ=5.0, 3.5Hz), 0.94(3H,tJ=7.5Hz), 1.26(lH,m), 2.17-2.24(2H,m), 2.32(6H,s), 3.29 lH,d,J=11.0Hz), 3.55(lH,dJ=12.5Hz), 3.80(2H,dJ=H.OHz), 3.98(lH,dd,J=8.5, G.OHz), 4.12(lH,dJ=12.5Hz) 6.79(2H,s), 6.80(lH,s), 9.01(lH,s). Example 51) l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-6-(3,5-dimeth ylbenzoyl)-2,4-pyrimidinedione 5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-bis(t~butyl dimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide were reacted by the same method with example 48 to obtain the titled compound( 202 mg ). Yield(%): 52.4 m.p: 79.5-80.4°C !H NMR(CDCls): 8 0.10(lH,tJ=5.5Hz), 0.61(lH,ddJ-9.0, 5.5Hz), 0.98(3H,tJ-7.0Hz), 1.21(lH,m), 2.26(2H,m), 2.41 (6H,s), 3.35(lH,dJ=11.0Hz), 3.45(lH,dJ=12.0Hz), 3.70-3.81 (2H,m), 4.01-4.13(2H,m), 7.36(lH,s), 7.52(lH,s), 7.59(lH,s), 8.97(lH,s). Example 52) l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-isopropyl-6-phenyl -thio-2,4-pyrimidinedione 5-Isopropyl-6-phenylthio-2,4-pyrimidinedione and 2-bis(t-butyldimethyl silyloxy methyl )cyclopropane-l -yl] methyl bromide were reacted by the same method with example 48 to obtain the titled compound ( 106 mg ). Yield(%): 42.5 NMR(CDC13): 0.24(lH,tJ=5.5Hz), 0.55(lH,ddJ=8.0, 5.5Hz), 1.12(lH,m), 1.20(3H,t,J=7.0Hz), 1.26(3H,U=7.0Hz), 2.75-2.81 (lH,m), 3.21(lH,dJ=H.OHz), 3.56(lH,dJ=12.0Hz), 3.84(lH,dJ=H.O Hz), 4.11-4.14(2H,m), 4.25(lH,ddJ=4.0, ll.OHz), 7.21 (2H, d), 7.29(lH,t), 7.36(2H,t), 8.26(lH,s). Example 53) l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-isopropyl-6-(3,5- dimethylphenylthio)-2,4-pyrirnidmedione 5-Isopropyl-6- (3,5-dimethylphenylthio)-2,4-pyrimidinedione and 2-bis(t-butyl dimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide were reacted by the same method with example 48 to obtain the titled compound( 211mg ). Yield(%): 52.1 m.p: 0.24(lH,U=5.5Hz), 1.10(lH,m)f 1.26(3H,dJ=7.0Hz), .26(lH,dJ=11.0Hz), 3.75(lH,dJ=H.OHz), 4.25(lH,ddJ=4.0, 6.89(lH,s), 9.00(lH,s). NMR(CDC13): 8 0.55(lH,dd,J=8.0, 5.5Hz), 1.21(3H,dJ=7.0Hz), 2.75-2.81 (lH,m), 3.56(lH,dJ=12.0Hz), 4.11-4.13(2H,m), ll.OHz), 6.75(2H,s), Example 54) l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-isoi3ropyl-6-(3,5-dimethy Iphenoxy) - 2,4 -py rimidinedione 5-Isopropyl-6- (3,5-dimethylphenoxy )-2,4-pyrimidinedione and [2-bis(t~butyl dimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide were reacted by the same method with example 48 to obtain the titled compound ( 168 mg ). Yield(%): 43.2 m.p: 90.8-91.6°C NMR(CDC13): S 0.24(lH,U=5.5Hz), 0.58(lH,ddJ=5.0, 3.5Hz), 1.12(3H,dJ=7.0Hz), 1.15(3H,d,J=7.0Hz), 1.20-1.22(lH,m), 2.32(6H,s), 2.75-2.81 (lH,m), 3.28(lH,dJ=H.OHz), 3.54(lH,dJ=12.0Hz), 3.75-3.79(2H,m), 3.94(lH,ddJ=8.5, G.OHz), 4.10(lH,d,J=12.0 Hz), 6.57(2H,s), 6.79(lH,s), 8.70(lH,s). Example 55) l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-isopropyl-6-(3,5- dimethylbenzoyl)-2,4-pyrimidinedione 5-Isopropyl-6- (3,5-dimethylbenzoyl)-2,4-pyrimidinedione and [2-bis(t-butyl dimethylsilyloxymethyl)cyclopropane-l-yljmethyl bromide were reacted by the same method with example 48 to obtain the titled compound ( 194 mg ). Yield(%): 48.5 m.p: 91-92°C TH NMlKCDCh): d 0.07(lH,t,J=5.5Hz), 0.60(lH,dd,J=9.0, S.OHz), 1.13(3H,t,J=6.5Hz), 1.23(3H,dJ=8.0Hz), 1.25(lH,m), 2.33-2.35(lH,m), 2.41 (6H,s), 3.28(lH,d,J=12.0Hz), 3.35(lH,d,J=12.5Hz), 3.68-3.77(2H,m), 3.96-4.12(2H,m), 7.36(lH,s), 7.54(lH,s), 7.60(lH,s), 8.84(lH,s). Experimental Example Antiviral activity and Toxicity test The anti-HIV assays were based on the inhibition of the virus-induced cytopathic effect in MT-4 cells as a described method in J. Med. Chem, 34, 357, 1991. Briefly, MT-4 cells were suspended in culture medium at 2.5x105 cells/ml and infected with 1000 CCIDso ( 50% cell culture infective dose ) of HIV. Immediately, after virus infection, 100/^ of the cell suspension was brought into each well of a flat-bottomed microtitray containing various concentrations of the test compounds. After a 4 or 5 days incubation at 37°C, the number of viable cells was determined by the 3-(4, 5-dimethylthiazol-2-yl)-2 , 5-diphenyltetrazolium bromide (MTT) method, as disclosed in J . Virol . Methods, 20, 309, 1988. The cytotoxicity of the compounds of the present invention was assessed in parallel with their antiviral activity. It was based on the viability of mock-infected host cells as determined Table Removed It was found that the compounds of present invention have the superior antiviral activities to this control, AZT. Example of pharmaceutical preparations Injectable preparations were prepared with the ingredients of the following tables by the conventional injection manufacturing method. ingredients the amount used ampul ( 5ml ) compound of example 4 lOmg polyoxy40hydrogenated 2mg caster oil lidocaine • HC1 5mg anhydrous citric acid O.Smg sodium citrate 0.1 mg sodium chloride q.s ethanol 1ml distillation water for injection q.s Vials were prepared with the ingredients of the following tables by the conventional manufacturing method. Vials( 150mg ) compound of example 4 lOOmg methylparaben LOmg propylparaben 0.5mg anhydrous citric acid 30mg sodium citrate 18.5mg Tablets were prepared with the ingredients of the following tables by the conventional manufacturing method. tablet( 700mg ) compound of example 4 250mg corn starch 130mg microcrystalline cellulose 50mg lactose monohydrate 180mg hydroxypropyl cellulose 30mg polyvinylpyroridone k~30 30mg magnesium stearate lOmg carboxymethylcellulose calcium 20mg Capsules were prepared with the ingredients of the following tables by the conventional manufacturing method. capsule ( 400mg ) compound of example 4 250mg lactose monohydrate lOOmg starch 35mg hydroxypropylcellulose 5mg magnesium stearate lOmg We Claim: 1. The pyrimidinedione homocarbocyclic compound of general Formula (I) and pharmaceutically acceptable salts formed with inorganic or organic acids (Formula Removed) Wherein R1, R2 and R3 represents independently hydrogen atom, halogen atom,C1-C10 alkyl, C1-C10 thioalkyl C3-C4 optionally substituted cyclic alkyl, unsaturated alkyl, substituted alkyl hydroxyl, aryl hydroxyl, C1-C10alkylamine, nitro, C1-C4 lower ester,C1-C4lower alkoxy, C1-C4 lower thioalkoxy; Z represents oxygen atom, sulfur atom, carbon atom and carbonyl group; X represents oxygen atom, sulfur atom; n represents an integer of 1-3; and (sub) cycloalk(en)yl represents (Formula Removed) in which (Formula Removed) represents (Formula Removed) in which R4 and R5 represents independently hydrogen atom, hydroxymethyl, protected hydroxymethyl, benzyl, substituted carbonyl, substituted alkylsulfonyl or arylsulfonyl, substituted silyl or the like. 2. A pyrimidinedione homocarbocyclic compound as claimed in claim 1, as and when used to prepare a pharmaceutical composition comprising the compound of formula (I) or acid addition salt thereof as active ingredient and one or more conventional adjuvants. 3.The pyrimidinedione homocarbocyclic compound of general formula (I) and pharmaceutically acceptable salt of inorganic or organic acid thereof, substantially as hereinbefore described with reference to the foregoing examples.

Full Text

The present invention relates to new substituted pyrimidinedione derivatives, which are useful as an antiviral agent, treating agent for acquired immunodeficiency syndromes (AIDS), and pharmaceutically acceptable salts thereof. The invention also relates to process for the preparation of such derivatives and to pharmaceutical compositions containing the same as active ingredients.
Nowadays, various compounds such as AZT, DDC, DDI and D4T have been used as chemotherapeutic agents of AIDS and have a medical action mechanism with inhibition of the replication of AIDS virus. They also have drug tolerance and undesirable side effects due to their toxicity.
1. In order to overcome these problems, intensive researches have been carried out to develope antiviral chemotherapeutic agents with strong activity and with lower toxicity. Among them, researches have been focused on pyrimidine 6-substituted necleoside compounds. But, N-l substituted homocarbocyclic nucleoside derivatives were not developed as yet.
The present inventors carried out an intensive research on the N-l substituted homocarbocyclic necleoside derivatives and unexpectively found out the facts that the compounds have strong activity against HIVCAIDS, Acquired immunodeficiency syndromes) as well as a lower toxicity.
Accordingly, the present invention relates to new pyrimidinedione derivatives, 6-substituted pyrimidinedione homocarbocyclic nucleosides which are useful as an antiviral agent for treating acquired immunodeficiency syndromes ( AIDS ), and pharmaceutically acceptable salts thereof.

2. The present compounds have the following general formula(I).
Formula Removed
wherein Ri, R2, and Rs represents independently hydrogen atom, halogen atom, Ci-Cio alkyl, Ci-Cio thioalkyl, Cs-Cg optionally substituted cyclicalkyl, unsaturated alkyl, substituted alkyl hydroxyl or aryl hydroxyl, Ci-Cio alkylamine, nitro, Ci~C4 lower ester, Ci~C4 lower alkoxy, Ci~C4 lower thioalkoxy; Z represents oxygen atom, sulfur atom, carbon atom and carbonyl group; X represents oxygen atom, sulfur atom; n represents an integer of 1-3; and (sub)cycloalk(en)yl represents

in which R4 and R5 represents independently hydrogen atom, hydroxymethyl, protected hydroxymethyl, benzyl, substituted carbonyl, substituted alkylsulfonyl or arylsulfonyl, substituted silyl or the like.
C1-C10 alkyl means straight or branch alky] group such as methyl, ethyl, propyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, 2-methyl-pentyl or the like.
C1-C10 thioalkyl means straight or branch thioalkyl group such as
methylthio, ethylthio, propylthio, butylthio, isobutylthio, t-butylthio,
pentylthio, isopentylthio, hexylthio, heptylthio, octylthio,
2-methyl-pentylthio or the like.
C3-C8 optionally substituted cyclic alkyl means cyclic propyl, cyclic butyl, cyclic pentyl, methyl cyclic propyl, methyl cyclic butyl, methyl cyclic pentyl or the like.
C1-C4 lower ester means a carboxylic group was esterified by lower alkyl group or the like.
C1-C4 lower alkoxy means methaxy, ethoxy, propyloxy, butyloxy, isobutyloxy, t-butyloxy or the like.
C1-C4 lower thioalkoxy means thiomethoxy, thioethoxy, thiopropyloxy, thiobutyloxy, thioisobutyloxy, thio t-butyloxy or the like.
The substituted carbonyl group means acetyl, benzoyl, substituted benzoyl or the like.
The substituted alkylsulfonyl, arylsulfonyl group means
methanesulfonyl, para-toluenesulfonyl, benzenesulfonyl,
para-nitrobenzenesulfonyl or the like
The substituted silyl group means trimethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl or the like.
The present inventors had studied the active compound as an antiviral agent for long time. As a result, the present inventors unexpectively found out the facts that the compounds of the general forrnula(I) have excellent antiviral activity against HIV and very low toxicity.
According to the present invention, there is provided a pyrimidinedione homocarbocychc compound of general Formula (I) and pharmaceutically acceptable salts formed with inorganic or organic acids
(Formula Removed)

Wherein R1, R2 and R3 represents independently hydrofhen atom, halogen, atom, C1-C10 altyl, C1-C10 thioalkyi, C3-C4optionally substituted cyclic alkyl, unsaturated aflcyl, substituted alkyl hydroxy!, aryl hydroxy!, C1-C10 alkylamine, nitro, C1-C4 lower ester, C1-C4 lower alkoxy, C1-C4 lower thioalkoxy; Z represents oxygen atom, sulfur atom, carbon atom and carbonyl group; X represents oxygen atom, sulfur atom; n represents an integer of 1-3; and (sub) cycloalk(en)yl represents

(Formula Removed)
in which
(Formula Removed)
represents
(Formula Removed)

in which R4 and R3 represents independendy hydrogen atom, hydroxymethyl, protected hydroxymethyl, benzyl, substituted carbonyl, substituted alkylsulfonyl or arylsulfonyl, substituted silyl or the like.
In accordance with present invention, there are provided pharmaceutical compositions comprising one or more of the general formula(I) and their salts with a excellent antiviral activity against HIV and very low toxicity.
In accordance with still another aspect of the present invention, there are provided with processes for preparing the compounds of the general formula(l) and their salts.
The compounds of the present invention can be mixed with
pnarmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and the pharmaceutical compositions can be used to prevent or treat various kinds of virus disease. Another object of the present invention is to provide pharmaceutical compositions containing the general formula(I) and their salts.

The acids which can be reacted with the compounds of the general formula(I) to form acid salts are pharmaceutical acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid ; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, citric acid, maleic acid malonic acid,; sulfonic acids such as sulfonic acid, methanesulfonic acid, ethanesulfonic acid, bezenesulfonic acid, toluenesulfonic acid ; amino acids such as alanine, glycine, phenyl glycine, serin, cisserin, cystein, asparaginic acid, glutamic acid, lysine, arginine, tylosine, proline or the like. The vehicles which can be used in the preparation of pharmaceutical compositions containing the compounds of the general formula(I) as active ingredient are sweetening; agent, binding agent, dissolving agent, aids for dissolution, wetting agent, emulsifying agent, isotonic agent, adsorbent, degrading agent, antioxident, antiseptics, lubricating agent, filler and perfume or the like such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium carboxy methyl cellulose, agar, talc, stearic' acid, magnesium stearate, calcium stearate, magnesium aluminium silicate, starch, gelatine, tragacanth gum, methyl cellulose, glycine, silica, alginic acid, sodium alginate, water, ethanoi, polyethyleneglycol, polyvinyl pyrrolidone, sodium chloride, potassium chloride, orange essence, vanila aroma or the like.
Daily dosage of the compound of the general formula(I) may be varied depending on age, sex of patient and the degree of disease. Daily dosage is l.Omg to 5,000mg and may be administered one to several times.
The compounds of the general formula(l) may be prepared by the following scheme 1.
Scheme 1

(Scheme Removed)

wherein (Sub)cycloalk(en)yl, R1, R2, R3, 2, X, and n have the same meanings as defined above and Lie represents a leaving group as a halogen atom, alkylsulfonyl or arylsulfonyl group.
The compounds of the general formula (I) may be prepared by reacting a compound of the general formula(a) and the general formula (b) in the presence of a base.
Representative of the base include sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, cesium carbonate Representatives of the solvent include dirnethylformamide, ethanol, acetonitrile, dirnethylsulfoxide or the like. The reaction may be carried out between 10°C and l00°C for 5-48hrs.
The compounds of the general formula(I) may be prepared by the following scheme 2.
Scheme 2
(Scheme Removed)

wherein n has the same meaning and m is an integer of 0-2. The
representative reducting agents include sodium borohydride, lithium
aluminium hydride and the activating group of hydroxy pant include
halogen atom and sulfonyl group or the like. The sulfonyl group
include alkylsulfonyl group such as methanesulfonyl and arylsulfonyl
group such as para-toluenesulfonyl, benzenesulfonyl and
para-nitrobenzenesulfonyl group. The general formula(d) can be
effectively obtained by the reaction of the general formula(c) and the : reduction agent. And the general forrnula(b) can be effectively prepared by the introduction of the activating group of the general formula(c).
The known compounds of 6-substituted pyrimidinedione derivatives (a) used in the preparation of the- general formula(I) are described in prior paper( WO 93/02044, WO 95/18109 ) or may be prepared in a similar method to the paper.
Examples
The compounds of the general formula(I) are prepared by the following examples.
(Formula Removed)
wherein R1, R2, R3, Z, X, (Sub)cycloalk(en)yl and n have the same. meanings above.

l~[(Cyclopent-3-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedio ne
1-a) (Cyclopent-3-en-l-yl)methyl toluenesulfonate
A mixture of (cyclopent-3-en-l-yl)methanoK 1.96g, 20mmol ) and para-toluenesulfonylchloride( 3.81g, 20mmol ) were stirred at room temperature for 2hrs in pyridine( 30ml ). After the concentration of pyridine, the reaction residues were extracted with dichloromethane, washed IN HC1, dried with MgSO-i, concentrated and separated by the column chroma tography to give the desirable product ( 4.20g ).
Yield(%): 83.2
TH NMRCCDCls): 8 2.11 (2H,m), 2.42(3H,s), 2.49(3H,m), 3.82(2H,d),
5.67(2H,s), 7.40(2H,d), 7.65(2H,d).
1-b)
l-[(Cyclopent-3-en-l-yl)rnethyl]-5-ethyl-6-phenylthio-2,4-pyrirnidine-dione
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( O.lOg, 0.40mmol ) and (cyclopent-3-en-lyl)methyl toluenesulfonate ( 0.12g, 0.40mmol ) in dimethylformamide( 10ml ) were heated at 90°C for overnight in the presence of sodium bicarbonate( 41mg, 0.48mmol ). After the concentration of dimethylformamide under vacuum distillation, the desirable product was obtained as white solid( 65mg ) by the separation of column chromatography.
Yield(%): 49.1
m.p:
1H NMR(CDC13): 8 1.13(3H,t), 2.10(2H,m), 2.38(2H,m), 2.70(2H,q),

3.97(2H,dJ=7.65Hz), 5.67(2H,s), 7.14-7.53(5H,m), 8.51(lH,s).
Example 2)
l-[(Cyclopent-3-en-l-yl)methyl]-5-ethyl-6-(3,5-dimethylphenylthio)-2,4
-pyrimidinedione
5-ethyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and
(cyclo-3-en-l -yOmethyl toluenesulfonate were reacted by the same way with example 1 to obtain the titled compound.
Yield(%): 45.2 m.p: 128-130°C
'H NMR(CDCl3): S 1.03(3H,t), 2.10(2H,m), 2,37(2H,m), 2.68(2H,q),
2.83(lH,m), 3.99(2H,dJ=7.65Hz), 5.68(2H,s), 6.73(2H,s), 6.88(lH,s), 8.98(lH,s).
Mass: m/e 356(M+), 219( 100 )
Example 3)
l-[(Cyclopent-3-en-l-yl)methyl]-5-isopropyl-6-phenylthio-2,4-pyrimidin
edione
5-Isopropyl-G-phenylthio-2,4-pyrimidinedione and
(cyclopent-3-en-l-yl) methyl toluenesulfonate were reacted by the same way with example 1 to obtain the titled compound.
Yield(%): 57.6 m.p: 131-134°C
'li NMR(CDCl3): d 1.21(6H,d,J=6.95Hz), 2.10(2H,m), 2.39(2H,m),
2.80(lH,m), 4.06(2H,dJ=7.65Hz), 5.68(2H,s), 7.14-7,35(5H,m), 9.14(lH,s)

Mass: m/e 342(M+), 233(100)
Example 4)
l-[(Cyclopent-3-en-l-yl)methyl]-5-isopropyl-6-(3,5-dimethylphenylthio) -2,4 -pyrimidinedione
5-Isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and
(cyclopent-3-en-l-yl)methyl toluenesulfonate were reacted by the same way with example 1 to obtain the titled compound.
Yield(%): 62.8 m.p: 139-141°C
TH NMR(CDCb): 8 1.20(6H,dJ=6.95Hz), 2.10(2H,m), 2.28(6H,s),
2.39(2H,m), 2.77(lH,m), 3.51 (lH,m),
4.05(2H,dJ=7.65Hz), 5.68(2H,s), 6.74(2H,s),
6.88(lH,s), 8.34(lH,s).
Mass: m/e 370(M"), 233(100)
Example 5)
l-[(Cyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedi-
one
5-a) (Cyclopent-l-en-l-yl)methyl toluenesulfonate
A mixture of (cyclopent-l-en-l-yl)methanoK 1.96g, 20mmol ) and para-toluenesulfonylchloride( 3.81g, 20mmol ) were stirred at room temperature for 2hrs in pyridine( 30ml ). After the concentration of pyridine, the reaction residues were extracted with dichloromethane, washed IN HC1, dried with MgSO4, concentrated and separated by the column chromatography to give the desirable product! 4.52g ).
Yield(%): 89.6

'IT NMIKCDCk): 8 1.84(2H,m), 2.23(4H,s), 2.49(3H,s), 4.21(2H,s),
5.27(lH,s), 7.40(2H,d), 7.65(2H,d).
5-b)
l-[(Cyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidine-dione
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( O.lOg, 0.40mmol ) and (cyclopent-3-en-lyl)methyl toluenesulfonate( 0.12g, 0.40mmol ) in dimethylformamide( 10ml ) were heated at 90°C for overnight in the presence of sodium bicarbonate( 41mg, 0.48mmol ). After the concentration of dimethylformamide under vacuum distillation, the desirable product was obtained as white solid( 45mg ) by the separation of column chromatography.
Yield(%): 34.2 m.p: 181-183°C
*H NMR(CDC13): S 1.01(3H,t), 1.84(2H,m), 2.23(2H,m), 2.69(2H,q),
4.66(2H,s), 5.26(lH,s), 7.15-7.34(5H,m),
8.94(lH,s)
Example 6)
1 -[(4-Hydroxymethylcyclopent-l -en-1 -yDmethyl] -5-ethyl-6-phenylthio-
2,4-pyrimidinedione.
G~a) (4-t-Butyldimethylsilyloxymethylcyclopent-l -en-1 -yDmethyl
bromide
The carbon tetrabromideC 1.39g, 4.2mmol ) and triphenylphosphine( 1.37g, 5.2mmol ) were added in dichloromethane solution of (4-t-Butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl alcohoK 0.85g, 3.5mmol ) under ice bath and then stirred for SOmin at 0°C. The reaction mixture was stirred for overnight at room temperature,

extracted with dichloromethane, dried with MgSO/i, filtered, concentrated and separated by column chromatography to give a desirable product ( 0.53g ).
Yield(%): 49.7
'II NMRCCDCls): 8 0.05(6H,s). 0.90(9H,s), 2.18(2H,m), 2.50(3H,m),
3.50(2H,dJ=6.75Hz), 4.05(2H,s), 5.71(lH,s)
6-b)
1 - [ (4 -My droxymethy Icyclopent-1 -en -1 -yDmethyl] -5-ethyl-6-phenylthio-2,4-pyrimidinedione
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.16g,
O.GGmmol ) and
(4-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide(
0.20g, O.GGmmol ) in dimethylformamide( lOmmol ) were heated at 50°C
for overnight in the presence of sodium bicarbonate( 66mg, 0.79mmol ).
After the concentration of dimethylformamide,
[(4-t-butyldimethylsilyloxymethyl cyclo-
pent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione was
obtained by the separation of the column chromatography. And then,
this compound in THF( 10ml )was reacted with
n-tetrabutylammoniumfluoride at room temperature for Ihr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product( 35 mg ).
Yield(%): 14.8 m.p: 161-163°C
*H NMR(CDC13): S 1.01(3H,t), 2.03(2H,m), 2.38(2H,m), 2.50(lH,m),
2.68(2H,q), 3.50(2H,dJ=6.65Hz), 5.23(lH,s), 7.15-7.35(5H,m), 8.62(lH,s).
Example 7)

l-[(4-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-(3,5-dime-thylphenylthio)-2,4-pyrimidinedione
5-Eihyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and
(4-t-butyl-dimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were raided by the same way with the example 6 to obtain the titled compound( 48mg ).
Yield(%): 21.4 m.p: 57-60°C
rll NMR(CDC13): 8 1.02(3H,t), 2.04(2H,m), 2.28(6H,s), 2.39(H,m),
2.51 (lH,m), 2.68(2H,q), 3.51(2H,dJ=9.70Hz), 4.63(2H,q), 5.23(lH,s), 6.75(2H,s), 6.87(lH,s), 9.38(lH,s).
Example 8)
l-[(4-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-isopropyl-6-phenyl-
thio-2,4-pyrimidinedione
5-Isopropyl-6-phenylthio-2,4-pyrimidinedione and
[(4-t-butyIdimethylsilyl-oxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound( 67mg )
Yielcl(%): 29.5 m.p: 166-168°C
*H NMR(CDCl3): S 1.18(3H,d), 1.19(3H,d), 2.05(2H,m), 2.41 (2H,m),
2.50(lH,m), 3.49(lH,m), 3.52(2H,d), 4.70(2H,q), 5.24(lH,s), 7.16-7.34(5H,m), 8.63(lH,s).
Example 9) l-[(4-IIydroxymethylcyclopent-l-en-l-yl)methyl]-5-isopropyl-6-(3,5-di

-methy Ipheny Ithio ) - 2,4 -py rimidinedione
5-Isopropy 1-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and
(4-t-butyldimethysilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound ( 73mg )
(%): 33.1 m.p: 147-148°C
'II NMR(CDCb): S 1.20(3H,d), 1.21(3H,d), 2.05(2H,m), 2.28(6H,s),
2.40(2H,d), 2.59(lH,m), 3.49(lH,m),
3.52(2H,dJ=6.85Hz), 4.70(2H,q), 5.24(lH,s), 6.75(2H,s), 6.87(lH,s), 9.06(lH,s)
Mass: m/e 400(M+), 263(100)
Example 10)
l-[(5-Iiydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-
2,4-pyrimidinedione
10-a) (5-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide
The carbon tetrabromideC 8.5g, 25.7mmol ) and triphenylphosphine( 8.4g, 32.2mmol ) were added in dichloromethane solution of (5-t-Butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl alcohoK 5.2g, 21.4mmol ) under ice bath and then stirred for 30min at 0°C. The reaction mixture was stirred for overnight at room temperature, extracted with dichloromethane, dried with MgSO4, filtered concentrated and separated by column chromatography to give a desirable product ( 3.08g ).
Yield(%): 47.2

rH NMRCCDCls): 8 0.05(6H,s). 0.90(9H,s), 1.71 (2H,m), 2.05(2H,m),
2.30(2H,m), 3.62(2H,dJ=5.80Hz), 4.15(2H,s), 5.71 (lH,s).
10-b)
l-[(5-Iiydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.16g,
O.GGmmol ) and
(5-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide(
0.20g, 0.66mmol ) in dimethylformamide( 10ml ) were heated at 50°C
for overnight in the presence of sodium bicarbonate( 66mg, 0.79mmol ).
After the concentration of dimethylformamide,
[(5-t-butyldimethylsilyloxymethyl
cyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF( 10ml ) was reacted with n-tetrabutylammoniumfluoride at room temperature for Ihr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product( 35 mg ).
Yield(%): 18.2 m.p: 155-156°C
]H NMR(CDCl3): 81.04(3H,t), 1.81-1.90(4H,m), 2.72(3H,m), 3.56-3.7
(2H,dd,J=4.35Hz), 4.70(2H,ddJ=16.9Hz) 5.32(lH,s), 7.17-7.36(5H,m), 9.90(lH,s).
Example 11)
l-[(5-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-(3,5-dimeth
ylphenylthio)-2,4-pyrimidinedione
5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and
(5-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide

were reacted by the same with the example 10 to obtain the titled compound.
Yield(%): 22.7 m.p: 59-GO°C
'II NMR(CDC13): S 1.05(3H,t), 1.83-2.27(4H,m), 2.28(6H,s), 2.73(3H,m),
3.57-3.74(2H,ddJ=4,30Hz), 4.60(2H,dd,J=17Hz), 5.31 (IH.s), 6.77(2H,s), 6.88(lH,s), 9.39(lH,s).
Example 12)
l-[(5-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-isopropyl-6-(3,5-di
methylphenylthio)-2,4-pyrimidinedione
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and
(5-t-butyldimethylsilyloxymethylcyclopent-l -en-1 -yDmethyl bromide
were reacted by the same with the example 10 to obtain the titled
compound. ( 68mg )
Yield(%): 29.9 m.p: 6G-68°C
'H NMR(CDC13): d 1.21(3H,dJ=7.0Hz), 1.24(3H,dJ=7.0Hz),
1.81-2.34(4H,m), 2.73(lH,m), 3.51 (lH,m), 3.57-3.74(2H,ddJ=4.45Hz), 4.66(2H,dd,J=17.0Hz),
Example 13)
1 -[ (5-Hydroxymethylcyclopent-l -en-1 -yDmethyl] -5-Isopropyl-6- (3,5~di
methyl-phenylthio)-2,4-pyrimidinedione
5-Isopropyl~6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and
(5-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same with the example 10 to obtain the titled

compoundC 83mg ). Yield(%): 37.6
m.p: 81-82°C
'II NMR(CDC13): 8 1.22(3H,dJ=6.9Hz), 1.25(3H,dJ=6.9Hz),
1.82-2.25(4H,m) 2.28(6H,s),
2.74 (lH,m), 3.53(lH,m),
3.55-3.77(2H,dd, J=4.25Hz),
4.70(2H,ddJ=17.0Hz), 5.32(lH,s),
6.78(2H,s), 6.88(lH,s), 8.41(lH,s).
Example 14)
l-[(Cyclopent-3-en-l-yl)methyl]-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-py ri midi nedione.
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidindione and
(cyclopent-3-en-l-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound( 68mg ).
Yield(%): 49.9 m.p: 179-180°C
XH NMR(CDCls): d 1.02(3H,tJ=7.5Hz), 2.02-2.05(2H,m), 2.32(6H,s),
2.34(2H,m), 2.68(3H,m), 3.66(2H,d,J=7.5Hz), 5.67(2H,s), G.50(2H,s), 6.77(lH,s), 8.92(lH,s).
Mass: m/e 340(M+), 219(100)
Example 15)
l-[(Cyclopent-3-en-l-yl)methyl]-5-isopropyl-6-(3,5-dimethylphenoxy)-2
,4-pyrimidinedione.
5-Isopropyll-6-(3,5-dimethylphenoxy)-2,4-pyrimidmdione and

(cyclopent-3-en-l-y])methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound( 73mg ).
Yield(%): 51.5 m.p: 183-184°C
'll NMRCCDCb): 8 1.14(3H,s), 1.15(3H,s), 2.05(2H,ddJ=5.29Hz),
22.31 (6H,s), 2.28(2H,ddJ=8.56Hz),
2.73-2.83(2H,m), 3.65(2H,dJ=7.5Hz)
5.67(2H,s), 6.50(2H,s), 6.77(lH,s), 8.96(lH,s).
Example 16)
l-[(Cyclopent-3-en-l-yl)methyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-
pyrimidinedione.
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidindione and
(cyclopent-3-en-l-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound ( 84mg ).
Yield(%): 59.6 m.p: 209-210°C
]II NMR(CDC13): d 0.98(3H,tJ=7.5Hz), 2.02(2H,m), 2.26-2.37(2H,m),
2.41 (6H,s), 2.68-2.73(3H,m), 3.82(2H,dJ=7.5Hz),
5.58-5.60(2H,m), 7.34(lH,s), 8.82(lH,s).
Mass: 352(M+), 219(100)
Example 17)
l-[(Cyclopent-3-en-l-yl)methyl]-5-isopropyl-6~(3,5-dimethylbenzoyl)-2, 4 -py ri mi dinedione.
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
(cyclopent-3-l-yl)methyl toluenesulfonate were reacted by the same

method with the example 1 to obtain the titled compound( 81mg ). Yield(%): 55.2 m.p: 196-197°C
lli NMR(CDCb): d 1.12(3H,dJ=7.0Hz), 1.23(3H,dJ=7.0Hz),
2.01-2.03(2H,m), 2.26-2.34(3H,m),
2.40(6H,s), 2.58-2.62(lH,m),
3.18(111, dd,J=7.56Hz),
3.84(lH,ddJ=7.56Hz), 5.56(lH,m), 5.60 ), 7.34(lH,s), 7.51 (2H,s), 8.77(lH,s).
Example 18)
l-[(4-IIydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-(3,5-dimeth
yl-phenoxy)-2,4-pyrimidinedione
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and
(4-t-butyldimethylsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same method with example 6 to obtain the titled compound. ( 52mg )
Yield(%): 21.3
rH NMR(CDCl3): § 0.95(3H,t,J=7.5Hz), 2.05(2H,m), 2.21(2H,q,J=10.0Hz),
2.30(6H,s), 2.38-2.43(2H,m), 2.50-2.55(lH,m), 3.49(2H,dJ=5.0Hz), 4.37(2H,s), 5.35(lH,s), 6.52(2H,s), 6.77(lH,s), 8.99 (lH,s).
Example 19)
l-[(5-Hydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-(3,5-dime-thyphenoxy ) -2,4-pyrimidinedione
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and
(5-t-butyldimethy- lsilyloxymethylcyclopent-l-en-l-yl)methyl bromide were reacted by the same method with example 6 to obtain the titled

compound ( 52mg ). Yield(%): 21.3 m.p: 119-120°C
]II NMR(CDC13): S 0.95(3H,t,J=7.5Hz), 1.77-1.82(lH,m), 1.98-2.04(lH,m),
2.17-2.25(2H,m), 2.30(6H,s), 3.57(lH,d,J=5,OHz), 3.66(lH,dJ=5.0Hz), 3.90(2H,dJ-14.0Hz), 5.50(lH,s), 6.53(2H,s), 6.78(lH,s), 8.72(lH,s).
Example 20)
l~[(Cyclopentyl)methyl]-5-isopropyl-6-(3,5-dimethyphenylthio)-2,4-pyri-
midinedione
20-a) (Cyclopentyl)methyl toluenesulfonate
To cyclopentanemethanoK 2.0g, 20mmol ) in pyridine( 30ml ) was added para-toluenesulfonyl chloride( 3.81g, 20mmol ) with stirring. After 2hrs at room temperature, the reaction mixture was concentrated for removement of pyridine, extracted with dichloromethane, dried, filtered, concentrated and separated by a column chromatography to give a desirable product! 3.80g ).
Yield(%): 74.7
]H NMR(CDCls): 3 1.26-1.30(2H,m), 1.52-1.53(2H,m), 1.66(4H,m),
2.09(lH,m), 2.48(3H,s), 3.74(2H,d), 7.40(2H,d), 7.72(2H,d).
20-b)
l-[(Cyclopentyl)methyl]-5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione.
A mixture of
5~isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione( 0. lOg,

0.40mmol ) and cyclopentyl toluenesulfonate( O.lg, 0.4mmol ) in dimethylformamide( 10ml ) were heated at 100°C for overnight in the presence of sodium bicarbonate( 41mg, 0.48mmol ). After the concentration of dimethylformamide, the desirable product was obtained by the separation of the column chromatography to give a desirable product as a white solid ( 75mg ).
Yiekl(%): 50.3 m.p: 145-146°C
lli NMR(CDCls): 8 1.20(3H,s), 1.22(3H,s), 1.26-1.30(2H,m),
1.52-1.53(2H,m), 1.66(4H,m), 2.28(6H,s),
2.32-2.35(lH,m), 3.48-3.54(lH,m),
4.02(2H,dJ=7.5Hz), 6.74(2H,s), 6.87(lH,s), 9.27(lH,s).
Mass: m/e 327(M+), 275(100)
Example 21)
l-(Cyclopentyl)methyl-5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimi-
dinedione
5~Isoproyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and
(cyclopentyl) methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound ( 53mg ).
Yield(%): 37.2 m.p: 157-158°C
]II NMR(CDC13): 8 1.14(3H,s), 1.15(3H,s), 1.21-1.25(2H,m),
1.53-1.55(2H,m), 1.65-1.68(4H,m),
2.26-2.29(lH,m), 2.31 (6H,s), 2.78-2.83(lH,m), 3.61(2H,dJ=7.5Hz), 6.51(2H,s), 6.77(lH,s), 9.04(lH,s).

Example 22)
l-(Cyclopentyl)methyl-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimi-
dinedione
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
(cyclopentyl)methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound ( 84mg ).
Yield(%): 57.0 m.p: 167-168°C

II NMRCCDCh): 8

1.12(3H,dJ=7.0Hz),
1.23(3H,dJ=7.0Hz),
1.46-1.47(2H,m), 1.57(4H,m),
2.10-2.16(lH,m), 2,30-2,36 (lH,m),
2.41 (6H,s), 3.15(lH,ddJ=7.05Hz),
3.84(lH,ddJ=7.5 Hz), 7.34(lH,s),
7.52(2H,s),

Mass: m/e 368(M+), 133(100)
Example 23)
l-(Cyclopentyl)methyl-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidine-
dione
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
(cyclopentyl)- methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound. ( 80mg )
Yieid(%): 56.4
m.p: 186-187°C
1H NMR(CDCla): 8 0.94(3H,tJ=7.5Hz), 1.24(3H,dJ=7.0Hz),

1.46-1.47(2H,m), 1.56-1.58(4H,m),
2.14(lli,m), 2.41 (6H,s), 2.62(2H,q,), 3.18(lH,dJ=7.0Hz), 3.84(lH,dJ=7.0Hz), 7.34(lli,s), 7.51 (2H,s), 8.94(lH,s).
Example 24)
l-{[4-Bis(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-6-phenyl
-thio-2,4-pyrimidinedione
24-a) [4-Bis(t-butyldimethylsilyloxylmethyl)cyclopent-l-en-l-yl]
methyl bromide
A mixture of carbon tetrabromide( 1.99g, G.Ommol ) and triphenylphosphine( 1.97g, 7.5mmol ) were added to [4- bis (t-butyldimethylsilyloxymethyl)cyclopent-l -en-1 -yljmethyl alcohol ( 1.93g, S.Ommol ) in dichloromethane under ice bath and then, the reaction mixture was stirred for 30min at 0°C. After overnight at room temperature, the reaction mixture was extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product( 1.43g ).
Yiekl(%): 63.5
1H NMlKCDCb): d 0.05(6H,s), 0.90(9H,s), 2.09(2H,br), 2.15(2H, br),
3.64(4H,m), 4.04(2H,s), 5.21 (lH,s).
24-b)
l-{[4-Bis(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-6-phenylthio-2,4-pyrimidinedione
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.16g,
O.GGmmol ) and
[4-bis(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl)methyl
bromideC 0.30g, 0.66mmol ) in dimethylformamide( 10ml ) were heated
at 50°C for overnight in the presence of sodium bicarbonateC 66mg,
0.79mmol ). After the concentration of dimethylformamide,

l-{[4-bis(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl)methyl}-5-ethyl-G-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF( 10ml ) was reacted with n-tetrabutylammoniumfluroride at room temperature for Ihr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product( 45mg
Yield(%): 17.6 m.p: 170-171°C
!H NMR(CDC13): S 1.02(3H,t,J=7.5Hz), 2.09(2H,br), 2.15(2H,br), 2.68(2H,
q,J=7.5Hz), 3.64(4H,U=7.5Hz), 4.62(2H,s),
5.20(lH,s), 7.16(2H,dJ=7.5Hz), 8.40(lH,s).
Example 25)
l-{[4-Bis(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5~ethyl-6-(3,5-
dimethyl-phenylthio)-2,4-pyrimidinedione.
5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and
[4~bi s (t-butyldimethy IsilyloxymethyDcyclopent- 1 -en-1 -yljmethyl bromide were reacted by the same method with example 24 to obtain the titled compound ( 48mg ).
Yield(%): 17.5
m.p: 156-157°C

H

: 3 1.02(3H,t,J=7.4Hz), 2.08(2H,s), 2.14(2H,s), 2.28(6H,s), 2.68(2H,q,J=7.5Hz), 3.62(4H,tJ=11.2Hz), 4.62(2H,s), 5.21(lH,s), 6.75(lH,s), 6.88(lH,s), 9.61(lH,s).

Mass: m/e 416(M+), 91(100)
Example 26)

l-{[4-Bis(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-isopropyl-6-phenylthio-2,4-pyrimidinedione.
5-Isopropyl-6-phenylthio-2,4-pyrimidinedione and
[4-bis(t-butyldimethylsilyl oxymethyl)cyclopent-l-en-l-yl]methyl
bromide were reacted by the same method with example 24 to obtain the titled compound( 52mg ).
Yield(%): 19.6 m.p: 148-149°C
'l-I NMR(CDC13): 8 1.19(3H,s), 1.20(3H,s), 2.06(2H,s), 2.17(2H,s),
3.45-3.51 (lH,m), 3.59(4H, tJ=11.0Hz), 4.69(2H,s), 5.21 (lH,s), 7.16(2H,dJ=7.5Hz), 7.25(lH,tJ=7.5Hz), 7.33(2H,t,J=7.5Hz), 9.55(lH,s).
Example 27)
l-{[4-Bis(hydroxymethyl)cycloi3ent-l-en-l-yl]methyl}-5-isopropyl-6-(3,
5-dimethylphenylthio)-2,4-pyrimidinedione.
5-Isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and
[4-bis(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 24 to obtain the titled compound( 44mg ).
Yielcl(%): 15.5 m.p: 156-157°C
*H NMR(CDC13): 8 1.02(3H,s), 1.21(3H,s), 2.08(2H,s), 2.16(2H,s),
2.28(6H,s), 3.45-3.51 (lH,m), 3.62(4H,s),
4.68(2H,s), 5.21(lH,s), 6.76(lH,s), 6.87(lH,s),
6.69(lH,s).
Example 28)

l-f[3,4-Di(hydroxymethyl)cycloijent-l-en-l-yl]methyl}-5-ethyl-6-phenyl -thio-2,4-pyrimidinedione
28-a)
[3,4-Di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide
A mixture of carbon tetrabromideC 3.18g, 9.6mmol ) and triphenyl phosphine( 3.15g, 12.9mmol ) were added to [3,4-di(t-butyldimethylsilyl oxymethyl)cyclopent-l-en-l-yl]methyl alcohoK 3.09g, S.Ommol ) in dichloromethane under ice bath and then, the reaction mixture was stirred for 30min at 0°C. After overnight at room temperature, the reaction mixture was extracted with dichloromethane, dried with MgS04, filtered, concentrated and separated by column chromatography to give a desirable product(2.43g).
Yield(%): 67.4
'H NMlKCDCla): 3 0.05(6H,s), 0.91(9H,s), 1.85(lH,dJ=15.5Hz),
2.26(2H,m), 2.62-2.70(3H,m),
3.44(lH,t,J=9.0Hz), 3.60(2H,m),
3.78(lH,dJ=7.5Hz), 4.08(2H,s), 5.25(lH,s).
28-b)
l-[3,4-Di(hydroxymethylcyclopent-l-en-l-yl)methyl]-5-ethyl-6-phenyl-thio-2,4-pyrimidinedione
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.16g,
O.GGmmol ) and
[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl
bromide( 0.30g, 0.66mmol ) in dimethylformamide( 10ml ) were heated
at 50°C for overnight in the presence of sodium bicarbonate( 66mg,
0.79mmol ). After the concentration of dimethylformamide,
l-{[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-G-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF(

10ml ) was reacted with n-tetrabutylammonium fluoride at room temperature for Ihr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product(
Yield(%): 18.7
'II NMR(CDCb): S l.Q3(3H,t), 1.84(lH,dJ=15.5Hz), 2.38(2H,m),
2.60(lH,br) 2.70(2H,qJ=7.0Hz),
3.44(lH,tJ=9.0Hz), 3.59-3.63(2H,m),
3.78(lH,dJ=7.5Hz), 4.59(2H,dd, J=4.5, 7.0Hz), 5.25(lH,s), 7.16(lH,d, J=7.5Hz), 7.26(lH,t, J=8.5Hz), 7,34(2H,t, J=7.5 Hz), 9.30(lH,s).
Example 29)
l-{[3,4-Di(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-6-(3,5-di
-methylphenylthio)-2,4-pyrimidinedione
5-Ethyl~6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and
[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 53mg ).
(%): 19.3 m.p: 156-157°C
'H NMRCCDCb): § 1.03(3H,tJ=7.5Hz), 1.86(lH,d,J-15.5Hz), 2.28(6H,s),
2.42(2H,m), 2.60(lH,m), 2.68-2.73(2H,m),
3.44(lH,t,J=7.5Hz), 3.56-3.64(2H,m),
3.79(lH,dJ=7.5Hz), 4.59(2H,dJ=8.5Hz), 5.27(lH,s), 6.76(2H,s), 6.88(lH,s), 9.44(lH,s).
Example 30)
l-{[3,4-Di(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-isopropyl-6-(3,
5-dimethylphenylthio)-2,4-pyrimidinedione

5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and [3,4-di
(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide
were reacted by the same method with example 28 to obtain the titled compound( 51mg ).
Yield(%): 17.9
m.p: 136-137°C

NMR(CDC13):

1.20(3H,dJ=7.0Hz), 1.25(3H,dJ=7.0Hz),
1.87(lH,dJ=15.5Hz), 2.28(6H,s),
2.40-2.44(2H,m), 2.60(lH,br),
2.96-3.00(lH,m), 3.44-3.53(2H,m),
3.58-3.65(lH,m), 3.80(1H, ddj=4.0, 6.5Hz), 4.62-4.69(2H,m), 5.27(lH,s), 6.76(2H,s), 6.88(lH,s), 9.01 (lH,s).

Example 31)
l-{[3,4-Di(hydroxymethyl)cycloi3ent-l-en-l-yl]methyl}-5-ethyl-6-(3,5-di
-melhylphenoxy)-2,4-pyrimidinedione
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and
[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 42mg ).
Yield(%): 17.9
'H NMR(CDC13): 3 0.94(3H,t), 1.82(lH,dJ=15.5Hz), 2.18-2.22(2H,m),
2.31 (6H,s), 2.38-2.45(2H,m), 2.76(lH,br),
3.42-3.49(2H,m), 3.60(lH,m), 3.94(lH,m),
4.33(2H,ddJ=15.5, 29.5Hz), 5.43(lH,s), 6.52(2H,s), 6.78(lH,s), 9.79(lH,s).
Example 32)

l-{[3,4-Di(hydroxymethyl)cycloi3ent-l-en-l-yl]methyl}-5-isopropyl-6-(3, 5-dimethylphenoxy)-2,4-pyrimidinedione
5-Iso]jropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and
[3,4-di(t- butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl
bromide were reacted by the same method with example 28 to obtain the titled compound( 48mg ).
Yield(%): 17.5

NMR(CDC13):

1.21(3H,dJ=7.0Hz), 1.24(3H,dJ=7.0Hz),
1.83(lH,dJ=15.5Hz), 2.31 (6H,s),
2.37(2h,m), 2.57(lH,br), 2.74-2.79(lH,m),
3.38-3.50(2H,m), 3.60(lH,qJ=5.0Hz),
3.90(lH,dJ=7.0Hz), 4.25(1H, dJ=16.0Hz),
4.34(lH,dJ=16.0Hz), 5.42(lH,s),
6.51 (2H,s), 6.77(lH,s), 9.33(lH,s).

Example 33)
l-{[3,4-Di(hydroxymethyl)cyclopent-l-en-l-yl]methyl}-5-ethyl-6-(3,5-di
-methylbenzoyl)-2,4-pyrimidinedione
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 68mg ).
Yield(%): 25.0
m.p: 79-80"C

NMR(CDCls):

0.94-0.97(3H,tJ=7.5Hz). 1.54(lH,dJ=15.5Hz),
2.03-2.04(lH,m), 2.31-2.35(5H,m), 2.39(3H,s),
2.40(3H,s), 3.27-3.33(lH,m), 3.41 (lH,m),
3.50(lH,m), 3.79(lH,m), 4.3

440(lH,d), 5.34(lH,m),
7.49(2H,s), 9.06(lH,s).

7.31 (lH,s),

Example 34)
l-{[3,4-Di(hydroxymethyl)cycloi3ent-l-en-l-yl]methyl}-5-isopropyl-6-(3,
5-dimethylbenzoyl)-2,4-pyrimidinedione
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-l-en-l-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound( 74mg ).
Yield(%): 26.3
m.p: 81-82°C

1H NMR(CDC13):

8 1.20(3H,dJ=7.0Hz), 1.24(3H,dJ=7.0Hz),
1.50(lH,dJ=15.5Hz), 2.24-2.31 (2H.m),
2.39(3h,s), 2.40(3H,s), 2.54(2H,m),
3.29(lH,m), 3.40QH, br), 3.49(lH,m),
3.71-3.84(lH,m), 4.27-4.39(lH,m),
5.20-5.34(lH,m), 7.33(lH,s), 7.49(2H,s), 9.39(lH,s).

Ezamijle 35)
l-[2-(Cyclopent-l-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-
pyrimidinedione
35-a) 2-(Cyclopent-l-en-yl)ethyl toluenesulfonate
A para-toluenesulfonylchloride( 3.81g, 20mmol ) was added to the pyricline( 30ml ) solution of 2-(cyclopent-l-en-l-yl)ethyl alcohoK 2.24g, 20mmol ) and then the reaction mixture was stirred at room temperature for 2hrs. After the removement of pyridine, the residue was extracted with dichloromethane, washed with IN HC1, dried, filtered and separated by column chromatography to give a desirable

product ( 2.80g ). Yield(%): 52.6
'li NMR(CDCla): 8 0.82(2H,m), 1.99-2.30(6H,m), 2.49(3H,s), 3.
4.03(lII,m), 5.22(lH,s), 7.41(2H,d), 7.74(2H,d).
35-b)
l-[2-(Cyclopent-l-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione
A mixture of sodium bicarbonate( O.lOg, 1.2mmol ) and lithium iodide( 13mg, O.lmmol ) were added to dimethylformamide solution( 10ml ) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione( 0.27g, l.Ommol ) and 2-(cyclopent-l-en-l-yl)ethyl toluenesulfonate( 0.27g, l.Ommol ). And then, the reaction mixture was stirred at 90°C for overnight, concentrated for removement of dimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a desirable product as a white solid ( 148mg ).
Yield(%): 40.4 m.p: 211-213°C
*H NMR(CDCk): 3 0.81(2H,dd,J=7.0,1.5Hz), 0.97(3H,t,J=7.5Hz),
1.99-2.30(6H,m), 2.40(6H,s), 3.29(lH,m),
3.91 (lH,m), 5.22(lH,s), 7.35(lH,s),
7.50(2H,s), 8.81 (lH,s).
Mass: m/e 366(M+), 94(100)
Example 36)
l-[2-(Cyclopent-3-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-
pyrimidinedione
36-a) 2-(Cyclopent-3-en-l-yl)ethyl toluenesulfonate

A para-toluenesulfonylchloride( 3.81 g, 20mmol ) was added to the pyridine( 30ml ) solution of 2-(cyclopent-3-en-l-yl)ethyl alcohoK 2.24g, 20mmol ) and then the reaction mixture was stirred at room temperature for 2hrs. After the removement of pyridine, the residue was extracted with dichloromethane, washed with IN HC1, dried, filtered and separated by column chromatography to give a desirable product ( 3.24g ).
Yield(%): 60.8

NMRCCDCk): 8

1.69(2H,m), 1.85(2H,m), 2.02(2H,m), 2.25(lH,m), 3.42(lH,m), 3.94(lH,m), 5.56(2H,d), 7.4192H,d), 7.74(2H,d).

36-b)
l-[2-(Cyclopent-3-en-lyl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione
A mixture of sodium bicarbonate( O.lOg, 1.2mmol ) and lithium iodide ( 13mg, O.lmmol ) were added to dime thy Iformamide solution ( 10ml ) of 5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione( 0.27g, l.Ommol ) and 2-(cyclopent-3-en-l-yl)ethyl toluenesulfonate( 0.27g, l.Ommol ). And then, the reaction mixture was stirred at 90°C for overnight, concentrated for removement of ctimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a desirable product as a white solid ( 136mg ).
Yield(%): 37.1

m.p: 190-191°C *H NMR(CDCls):

0.97(3H,tJ=7.5Hz), 1.69(2H,m), 1.85(2H,m),
2.02(2H,m), 2.25(lH,m), 2.37(3H,m),
2.41 (6H,s), 3.17(lH,m), 3.82(1H, m), 5.56(2H,d), 7.36(lH,s), 7.53(2H,s), 8.64(lH,s).

Mass: m/e 366(M+), 94(100)
Example 37)
l-[2-(Cyclopent-3-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylbenzoyl)-2, 4 -py rimidinedione
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
2-(cyclopent- 3-en-l-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound(140mg).
Yield(%): 36.8 m.p: 175-176°C
*H NMR(CDC13): S 1.13(3H,d,J=7.0Hz), 1.20(3H,d,J=7.0Hz), 1.70(2H,m),
1.82(2H,m), 2.03(lH,m), 2.33(3H,m), 2.41(6H,s), 3.13(lH,m), 3.80(lH,m), 5.56(2H,ddJ=40,10.0Hz), 7.36(lH,s), 7.55(2H,s), 8.45(lH,s).
Example 38)
l-[2-(Cyclopent-3-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylphenoxy)-
2,4-pyrimidinedione
5-Isopropyl-6- (3,5-dimethyl2phenoxy )-2,4-pyrimidinedione and
2-(cyclopent- 3-en~l-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound(109mg).
Yield(%): 29.6 m.p: 109-110°C
*H NMR(CDCla): S 1.14(6H,dJ=7.0Hz), 1.70(2H,m), 1.93(2H,m),
2.15(lH,m), 2.31 (6H,s), 2.45(2H,m),
2.79(lH,m), 3.67(2H,t,J=7.5Hz), 5.62(2H,s),

6.53(2H,s), 6.78(lH,s), 8.83(lH,s).
Example 39)
l-[2-(Cyclopent-3-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylphenylthio)
-2,4-pyrimidinedione
5-Isopropyl-6- (3,5-dimethylphenylthio) -2,4-pyrimidinedione and
2-(cyclopent 3-en-l-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound (134mg).
(%): 34.8 m.p: 128-129T
]H NMR(CDCls): 8 1.24(6H,dJ=7.0Hz), 1.68(2H,m), 2.03(2H,m),
2.18(lH,m), 2.29(6H,s), 2.48(2H,m),
3.53(lH,m), 4.00(2H,tJ=8.0Hz), 5.64(2H,s),
6.77(2H,s), 6,88(lH,s), 8.95(lH,s).
Mass: m/e 384(M+), 247(100)
Example 40)
l-{2-(Cyclopent-2-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-
pyrimidinedione
40~a) 2-(Cyclopent-2-en-l-yl)ethyl bromide
A mixture of carbon tetrabromide( 19.2g, 57.8mmol ) and triphenyl
phosphine( 15.2g, 57.8mmol ) were added to
2-(cyclopent-2-en-l-yl)ethyl alcohoK 4.32g, 38.5mmol ) in dichloromethane( 15ml ) under ice bath and then, the reaction mixture was stirred for 2hrs at 0°C The reaction mixture was extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product(5.53g).
Yield(%): 82.0

*H NMRCCDCls): 8 1.26-2.29(6H,m), 2.80(lH,m), 3.43(2H,t), 5.72(2H,s).
40-b)
l-[2-(Cyclopent-2-en-l-yl)ethyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione
A mixture of sodium bicarbonate( O.lOg, 1.2mmol ) and lithium iodide( 13mg, O.lmmol ) were added to dimethylformamide solution( 10ml ) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione( 0.27g, l.Ommol ) and 2~(cyclopent-2-en-yl))ethyl bromide( 0.18g, l.Ommol ). And then, the reaction mixture was stirred at 90°C for overnight, concentrated for removement of dimethylformamide, extracted with dichloromethane, dried, filtered and separated by column chromatography to give a desirable product as a white solid ( 112mg ).
Yield(%): 30.6 m.p: 183-185°C
*H NMR(CDC13): S 0.97(3H,t), 1.24(lH,m), 1.49(lH,m), 1.70(2H,m),
2.00(lH,m), 2,24(2H,m), 2.41(6H,s), 2.49(lH,m),
3.23(lH,m), 3.81 (lH,m), 5.48(lH,m), 5.66(lH,m),
7.35(lH,s), 7.52(2H,s), 8.73(lH,s).
Example 41)
l-[2-(Cyclopent-2-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,
4-pyrimidinedione
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
2-(cyclopent- 2-en-l-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound ( 123mg ).
Yield(%): 32.3
:H NMRCCDCla): 8 1.15(3H,d,J=6.85Hz), 1.23(3H,dJ=6.85), 1.29(lH,m),

1.42(lH,m), 1.75(2H,m), 1.92(lH,m), 2.05(lH,m),
2.29(2H,m), 2.45(6H,s), 2.52(lH,m), 3.35(lH,m),
3.92(lH,m), 5.50(lH,m), 5.73(lH,m), 7.92(lH,s),
7.48(2H,s), 8.85(lH,s).
Example 42)
l-[2-(Cyclopent-2-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylphenoxy)-
2,4-pyrimidinedione
5~Isopropyl-6- (3,5-dimethylphenoxy )-2,4-pyrimidinedione and
2-(cyclopent- 2-en-l-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound( 132mg ).
Yield(%): 35.8 m.p: 148-149°C
XH NMR(CDC13): 3 1.15(6H,d), 1.36(lH,m), 1.55(lH,m), 1.70(lH,m),
2.00(lH,m), 2.27(2H,m), 3.69(2H,m),
5.56(lH,ddJ=2.Q5Hz), 5.71 (lH,ddJ=2.25Hz),
6.54(2H,s), 6.78(lH,s), 8.37(lH,s).
Example 43)
l-[2-(Cyclopent-2-en-l-yl)ethyl]-5-isopropyl-6-(3,5-dimethylphenylthio)
-2,4-pyrimidinedione
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4~pyrimidinedione and
2-(cyclopent- 2-en-l-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound( 98mg ).
Yield(%): 25,5 m.p: 138-140°C

1H NMR(CDC13): d 1.25(6H,ddJ=1.85Hz), 1.45(lH,m), 1.57(lH,m),
1.68(2H,m), 2.01 (lH,m), 2.29(6H,s), 2.35(lH,m),
2.61 (lH,m), 3.53(lH,m), 4.02(2H,t),
5.59(lH,ddJ=2.0Hz), 5.72(lH,ddJ=2.25Hz),
6.77(2H,s), 6.88(lH,s), 8.67(lH,s).
Example 44)
l-(2-Cyclopentyl)ethyl-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidine-
dione
44-a) (2-Cyclopentyl)ethyl toluenesulfonate
A para-toluenesulfonyl chloride( IG.Og, 83.8mmol ) was added to the pyridineC 250ml ) solution of (2-cyclopentyl)ethyl alcohol( 8.76g, 76.2mmol ) and then the reaction mixture was stirred at room temperature for 6hrs. After the removement of pyridine, the residue was extracted with ethyl acetate, washed with IN HC1, dried, filtered and separated by column chromatography to give a desirable product ( 15.7g ).
Yield(%):73
1H NMR(CDC13): 8 0.90-1.89(llH,m), 2.45(3H,s), 4.05(2H,t),
7.27-7.88(4H,dd).
44-b)
l-(2-Cyclopentyl)ethyl-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidine-one
A mixture of sodium bicarbonate( O.lOg, 1.2mmol ) and lithium iodide( 13mg, O.lmmol ) were added to dimethylformamide solution( 10ml ) of 5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione( 0.27g, l.Ommol ) and 2-(cyclopentyl)ethyl toluenesulfonate( 0.27g, l.Ommol ). And then, the reaction mixture was stirred at 90°C for overnight, concentrated for removement of dimethylformamide, extracted with

dichloromethane, dried, filtered and separated by column chromatography to give a white solid ( 90mg ).
Yield(%): 24.5
*H NMR(CDCl3): 8 0,95(2H,m), 0.97(3H,t), 1.41-1.62(9H,m), 2.02(lH,m),
2.28(lH,m), 2.41 (6H,s), 3.18(lH,m), 3.79(lH,m), 7.35(lH,s), 7.52(2H,s), 8.64(lH,s).
Example 45)
l-(2-Cyclopentyl)ethyl-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimi-
dinedione
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
(2-cyclopent- yDethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound ( 95mg ).
Yield(%): 24.9 m.p: 174-176°C
*H NMR(CDC13): 8 0.95(2H,m), 1.15(3H,dJ=6.85Hz), 1.23(3H,dJ=6.85Hz),
1.391.69(9H,m), 2.32(lH,m), 2.41(6H,s), 3.15(lH,m), 3.77(lH,m) 7.36(lH,s), 7.55(2H,s), 8.90(lH,s).
Example 46)
l-(2-Cyclopentyl)ethyl-5-isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyriini-
dinedione
5-Isopropyl-6- (3,5-dimethylphenoxy )-2,4-pyrimidinedione and
(2-cyclopent- yDethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound( 105mg ).
Yield(%): 28.3 m.p: 136-138°C

1H NMR(CDC13): 3 1.04(2H,m), 1.15(6H,d), 1.46-1.71(9H,m), 2.31 (6H,s)
2.80(lH,m), 3.65(2H,t), 6.53(2H,s), 6.78(lH,s), 8.60(lH,s).
Example 47)
l-(2-Cyclopentyl)ethyl-5-isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyri-
midinedione
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and
(2-cyclopent- yDethyl toluenesulfonate were reacted by the same method with example 44 to obtain the titled compound( 80mg ).
Yield(%): 20.7 m.p: 95-97°C
:H NMR(CDC13): 8 1.11 (2H,m), 1.25(6H,d), 1.47-l,78(9H,m), 2.29(6H,s),
3.53(lH,m), 4.00(2H,t), 6.77(2H,s), 6,.88(lH,s), 9.1991H,s).
Example 48)
l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-6-phenylthio-
2,4-pyrimidinedione
A sodium bicarbonate( O.lOg, 1.2mmol ) was added to a stirred
solution of dimethylformamide( 10ml ) of
5-ethyl-6-phenylthio-2,4-pyrimidinedione( 0.25g, l.Ommol ) and 2-bis(t-butyldimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide( 0.42g, l.Ommol ) and then, the reaction mixture was heated at 90°C for overnight. The reaction mixture was poured into water( 30ml ), extracted with ether ( 2 times ), dried, filtered, concentrated and separated by column chromatography to give l-[2-bis(t-butyldimethylsilyloxymethyl)cyclopropane-l-yl]methyl-5-ethyl -6-phenylthio-2,4-pyrimidinedione as a pale yellow oil( 125mg ). This compound in THF( 5ml ) was reacted with n-tetrabutylammonium

fluoride( 1.0ml of l.Omol THF solvent ) at room temperature for 6hrs.
The reaction mixture was concentrated for removement of THF and
separated by column chromatography to give
l-[2-bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-6-phenylthio-2,4-pyrimidinedione( 142mg ) as a white solid.
Yield(%): 39.4 m.p:
*H NMR(CDC13): 8 0.22(lH,t,J=5.5Hz), 0.53(lH,ddJ=5.5, 3.5Hz),
1.05(3H,t,J=7.0Hz), 1.07(lH,m),
2.70-2.75(lH,m), 3.25(lH,dJ=11.0Hz),
3.53(lH,d,J=13.0Hz), 3.75(lH,dJ=11.5Hz),
4.05-4.13(2H,m), 4.20(lH,ddJ=4.0, ll.OHz), 7.20(2H,d), 7.28(lH,t), 7.36(2H,t), 9.36 lH,s).
Example 49)
l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-(3,5-dimethyl
-phenylthio)-2,4-pyrimidinedione
5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and
2-bis(t~butyl dimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide were reacted by the same method with example 48 to obtain the titled compound( 191 mg ).
Yield(%): 49.0
m.p:
NMRCCDCla): 8 0.22(lH,tJ-5.0Hz), 0.53(lH,ddJ=8.5, 5.5Hz),
1.04(3H,t,J=7.5Hz), 1.37-1.42(lH,m), 2.29(6H,s),
2.71-2.74(2H,m), 3.28(lH,dJ=10.0Hz),
3.53(lH,dJ=12.5Hz), 3.73(lH,dJ=11.0Hz),
4.05-4.14(2H,m), 419(lH,dJ=11.5Hz),
6.79(2H,s), 6.89(lH,s), 9.45(lH,s).

Example 50)
l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-6-(3,5-dime-thy Iphenoxy) - 2,4-py rimidinedione
5-Ethyl-6- (3,5-dimethylphenoxy )-2,4-pyrimidinedione and
2-bis(t-butyl dimethylsilyloxymethyl)cyclopropane-l-yljmethyl bromide were reacted by the same method with example 48 to obtain the titled compound( 151 mg ).
Yield(%): 40.3
*H NMR(CDC13): d 0.27(lH,tJ=5.5Hz), 0.59(lH,ddJ=5.0, 3.5Hz),
0.94(3H,tJ=7.5Hz), 1.26(lH,m),
2.17-2.24(2H,m), 2.32(6H,s), 3.29
lH,d,J=11.0Hz), 3.55(lH,dJ=12.5Hz),
3.80(2H,dJ=H.OHz), 3.98(lH,dd,J=8.5, G.OHz),
4.12(lH,dJ=12.5Hz) 6.79(2H,s), 6.80(lH,s),
9.01(lH,s).
Example 51)
l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-ethyl-6-(3,5-dimeth ylbenzoyl)-2,4-pyrimidinedione
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
2-bis(t~butyl dimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide were reacted by the same method with example 48 to obtain the titled compound( 202 mg ).
Yield(%): 52.4 m.p: 79.5-80.4°C
!H NMR(CDCls): 8 0.10(lH,tJ=5.5Hz), 0.61(lH,ddJ-9.0, 5.5Hz),
0.98(3H,tJ-7.0Hz), 1.21(lH,m), 2.26(2H,m),

2.41 (6H,s), 3.35(lH,dJ=11.0Hz),
3.45(lH,dJ=12.0Hz), 3.70-3.81 (2H,m),
4.01-4.13(2H,m), 7.36(lH,s), 7.52(lH,s),
7.59(lH,s), 8.97(lH,s).
Example 52)
l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-isopropyl-6-phenyl
-thio-2,4-pyrimidinedione
5-Isopropyl-6-phenylthio-2,4-pyrimidinedione and
2-bis(t-butyldimethyl silyloxy methyl )cyclopropane-l -yl] methyl bromide were reacted by the same method with example 48 to obtain the titled compound ( 106 mg ).
Yield(%): 42.5

NMR(CDC13):

0.24(lH,tJ=5.5Hz), 0.55(lH,ddJ=8.0, 5.5Hz),
1.12(lH,m), 1.20(3H,t,J=7.0Hz),
1.26(3H,U=7.0Hz), 2.75-2.81 (lH,m),
3.21(lH,dJ=H.OHz), 3.56(lH,dJ=12.0Hz),
3.84(lH,dJ=H.O Hz), 4.11-4.14(2H,m),
4.25(lH,ddJ=4.0, ll.OHz), 7.21 (2H, d),
7.29(lH,t), 7.36(2H,t), 8.26(lH,s).

Example 53)
l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-isopropyl-6-(3,5-
dimethylphenylthio)-2,4-pyrirnidmedione
5-Isopropyl-6- (3,5-dimethylphenylthio)-2,4-pyrimidinedione and
2-bis(t-butyl dimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide were reacted by the same method with example 48 to obtain the titled compound( 211mg ).
Yield(%): 52.1
m.p:

0.24(lH,U=5.5Hz),
1.10(lH,m)f
1.26(3H,dJ=7.0Hz),
.26(lH,dJ=11.0Hz),
3.75(lH,dJ=H.OHz),
4.25(lH,ddJ=4.0,
6.89(lH,s), 9.00(lH,s).
NMR(CDC13): 8

0.55(lH,dd,J=8.0, 5.5Hz), 1.21(3H,dJ=7.0Hz), 2.75-2.81 (lH,m), 3.56(lH,dJ=12.0Hz), 4.11-4.13(2H,m), ll.OHz), 6.75(2H,s),

Example 54)
l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-isoi3ropyl-6-(3,5-dimethy Iphenoxy) - 2,4 -py rimidinedione
5-Isopropyl-6- (3,5-dimethylphenoxy )-2,4-pyrimidinedione and
[2-bis(t~butyl dimethylsilyloxymethyl)cyclopropane-l-yl]methyl bromide were reacted by the same method with example 48 to obtain the titled compound ( 168 mg ).
Yield(%): 43.2
m.p: 90.8-91.6°C

NMR(CDC13): S

0.24(lH,U=5.5Hz), 0.58(lH,ddJ=5.0, 3.5Hz),
1.12(3H,dJ=7.0Hz), 1.15(3H,d,J=7.0Hz),
1.20-1.22(lH,m), 2.32(6H,s),
2.75-2.81 (lH,m), 3.28(lH,dJ=H.OHz),
3.54(lH,dJ=12.0Hz), 3.75-3.79(2H,m),
3.94(lH,ddJ=8.5, G.OHz), 4.10(lH,d,J=12.0 Hz), 6.57(2H,s), 6.79(lH,s), 8.70(lH,s).

Example 55)
l-[2-Bis(hydroxymethyl)cyclopropane-l-yl]methyl-5-isopropyl-6-(3,5-
dimethylbenzoyl)-2,4-pyrimidinedione
5-Isopropyl-6- (3,5-dimethylbenzoyl)-2,4-pyrimidinedione and
[2-bis(t-butyl dimethylsilyloxymethyl)cyclopropane-l-yljmethyl bromide

were reacted by the same method with example 48 to obtain the titled compound ( 194 mg ).
Yield(%): 48.5
m.p: 91-92°C

TH NMlKCDCh): d

0.07(lH,t,J=5.5Hz), 0.60(lH,dd,J=9.0, S.OHz),
1.13(3H,t,J=6.5Hz), 1.23(3H,dJ=8.0Hz),
1.25(lH,m), 2.33-2.35(lH,m), 2.41 (6H,s),
3.28(lH,d,J=12.0Hz), 3.35(lH,d,J=12.5Hz),
3.68-3.77(2H,m), 3.96-4.12(2H,m), 7.36(lH,s), 7.54(lH,s), 7.60(lH,s), 8.84(lH,s).

Experimental Example
Antiviral activity and Toxicity test
The anti-HIV assays were based on the inhibition of the virus-induced cytopathic effect in MT-4 cells as a described method in J. Med. Chem, 34, 357, 1991. Briefly, MT-4 cells were suspended in culture medium at 2.5x105 cells/ml and infected with 1000 CCIDso ( 50% cell culture infective dose ) of HIV. Immediately, after virus infection, 100/^ of the cell suspension was brought into each well of a flat-bottomed microtitray containing various concentrations of the test compounds. After a 4 or 5 days incubation at 37°C, the number of viable cells was determined by the 3-(4, 5-dimethylthiazol-2-yl)-2 , 5-diphenyltetrazolium bromide (MTT) method, as disclosed in J . Virol . Methods, 20, 309, 1988. The cytotoxicity of the compounds of the present invention was assessed in parallel with their antiviral activity. It was based on the viability of mock-infected host cells as determined

Table Removed

It was found that the compounds of present invention have the superior antiviral activities to this control, AZT. Example of pharmaceutical preparations
Injectable preparations were prepared with the ingredients of the
following tables by the conventional injection manufacturing method.
ingredients the amount used
ampul ( 5ml ) compound of example 4 lOmg
polyoxy40hydrogenated 2mg
caster oil
lidocaine • HC1 5mg
anhydrous citric acid O.Smg
sodium citrate 0.1 mg
sodium chloride q.s
ethanol 1ml
distillation water for injection q.s
Vials were prepared with the ingredients of the following tables by
the conventional manufacturing method.
Vials( 150mg ) compound of example 4 lOOmg
methylparaben LOmg
propylparaben 0.5mg
anhydrous citric acid 30mg
sodium citrate 18.5mg
Tablets were prepared with the ingredients of the following tables by
the conventional manufacturing method.
tablet( 700mg ) compound of example 4 250mg
corn starch 130mg
microcrystalline cellulose 50mg
lactose monohydrate 180mg
hydroxypropyl cellulose 30mg

polyvinylpyroridone k~30 30mg
magnesium stearate lOmg
carboxymethylcellulose calcium 20mg
Capsules were prepared with the ingredients of the following tables by the conventional manufacturing method.
capsule ( 400mg ) compound of example 4 250mg
lactose monohydrate lOOmg
starch 35mg
hydroxypropylcellulose 5mg
magnesium stearate lOmg

We Claim:
1. The pyrimidinedione homocarbocyclic compound of general Formula (I) and pharmaceutically acceptable salts formed with inorganic or organic acids

(Formula Removed)
Wherein R1, R2 and R3 represents independently hydrogen atom, halogen atom,C1-C10 alkyl, C1-C10 thioalkyl C3-C4 optionally substituted cyclic alkyl, unsaturated alkyl, substituted alkyl hydroxyl, aryl hydroxyl, C1-C10alkylamine, nitro, C1-C4 lower ester,C1-C4lower alkoxy, C1-C4 lower thioalkoxy; Z represents oxygen atom, sulfur atom, carbon atom and carbonyl group; X represents oxygen atom, sulfur atom; n represents an integer of 1-3; and (sub) cycloalk(en)yl represents
(Formula Removed)
in which
(Formula Removed)
represents
(Formula Removed)

in which R4 and R5 represents independently hydrogen atom, hydroxymethyl, protected hydroxymethyl, benzyl, substituted carbonyl, substituted alkylsulfonyl or arylsulfonyl, substituted silyl or the like.
2. A pyrimidinedione homocarbocyclic compound as claimed in claim 1, as and when used to prepare a pharmaceutical composition comprising the compound of formula (I) or acid addition salt thereof as active ingredient and one or more conventional adjuvants.
3.The pyrimidinedione homocarbocyclic compound of general formula (I) and pharmaceutically acceptable salt of inorganic or organic acid thereof, substantially as hereinbefore described with reference to the foregoing examples.

Documents:

412-DEL-1997-Abstract-(03-03-2008).pdf

412-del-1997-abstract.pdf

412-DEL-1997-Claims-(03-03-2008).pdf

412-DEL-1997-Claims-(06-08-2008).pdf

412-del-1997-claims.pdf

412-DEL-1997-Correspondence-Others-(03-03-2008).pdf

412-DEL-1997-Correspondence-Others-(06-08-2008).pdf

412-del-1997-correspondence-others.pdf

412-DEL-1997-Description (Complete)-(03-03-2008).pdf

412-DEL-1997-Description (Complete)-06-08-2008.pdf

412-del-1997-description (complete).pdf

412-DEL-1997-Form-1-(03-03-2008).pdf

412-del-1997-form-1.pdf

412-del-1997-form-18.pdf

412-DEL-1997-Form-2-(03-03-2008).pdf

412-del-1997-form-2.pdf

412-DEL-1997-Form-3-(03-03-2008).pdf

412-DEL-1997-Form-3-(06-08-2008).pdf

412-del-1997-form-4.pdf

412-del-1997-form-6.pdf

412-del-1997-gpa.pdf

412-DEL-1997-Petition-137-(06-08-2008).pdf

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Patent Number

222437

Indian Patent Application Number

412/DEL/1997

PG Journal Number

36/2008

Publication Date

05-Sep-2008

Grant Date

08-Aug-2008

Date of Filing

20-Feb-1997

Name of Patentee

SAMJIN PHARMACEUTICAL CO., LTD,

Applicant Address

338-8,SEOKYO-DONG, MAPO-KU, SEOUL 121-210 REPUBLIC OF KOREA

Inventors:

#	Inventor's Name	Inventor's Address
1	CHO, EUI-HWAN	105-101, HYUNDAI 1ST APT, KAEPO-DONG KANGNAM,-KU, SEOUL, 135-240 , REPUBLIC OF KOREA
2	CHUNG, SUN-GAN	131-904, MOKHWA, APT, 850 KEUMJEONG-DONG, KUNPO, KYUNGKI-DO, 435-050, REPUBLIC OF KOREA
3	KIM, JOONG-YOUNG	6-1108, SAMSUNG 1ST APT, MAERTON, 4-DONG, PALDAL-KU, SUWEON, KYUNGKID-442-374, REPUBLIC OF KOREA
4	KWON HO-SEOK	506-1105, SINDONGA APT, 1274, SWONSUN-DONG, KWONSUN-KU, SUWEON, KYUNGKI-DO, 441-390, REPUBLIC OF KOREA
5	LEE SUN-HWAN	105-403 DAELIM APT, DOKKOK-DONG, SONGTAN, KYUNGKI-DO, 459-100, REPUBLIC OF KOREA
6	LEE JAE-EUNG	390-3, SINJANG-DONG, HANAM, KYUNGKI, DO ,465-032, REPUBLIC OF KOREA
7	JOO JEONG-HO	289-83, NORYANGJIN 2-DONG, DONGJAK-KU, SEOUL 156-052, REPUBLIC OF KOREA
8	KIM, BYUNG-CHUL	102-412, AJOO 1ST APT JISAN -DONG SONGTAN KYUNGKI-DO, 459-110, REPUBLIC OF KOREA
9	KANG, DONG-WOOK	268-203, JOOKONG APT, 4 WONMOON-DONG, KWACHON, KYUNGKI-DO ,427-030, REPUBLIC OF KOREA

PCT International Classification Number

A61K 31/505

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	1996-4189	1996-02-22	Republic of Korea
2	1996-47458	1996-10-22	Republic of Korea
3	1996-25441	1996-06-28	Republic of Korea
4	1996-47459	1996-10-22	Republic of Korea