AU2007234580A1 - Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

Australian Patents Act 1990 Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: Actual Inventors: Idenix (Cayman) Limited LA COLLA, Paolo ARTICO, Marino Address for Service: DAVIES COLLISON CAVE, Patent Trademark Attorneys, of 1 Nicholson Street, Melbourne, 3000, Victoria, Australia Ph: 03 9254 2777 Fax: 03 9254 2770 Attorney Code: DM "Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them" Invention Title: The following statement is a full description of this invention, including the best method of performing it known to us:- Q \OPER\KMC\207\Nov\3O 16759 Div-20- II-2007doc O SUBSTITUTED 6-BENZYL-4-OXOPYRIMIDINES, PROCESS FOR THEIR PREPARATION Z AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM c This is a divisional of Australian patent application No. 2004200446, the entire contents of which are incorporated herein by reference.

0 The present invention is concerned with compounds which inhibit the reverse transcriptase encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). It also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS arid viral infection by HIV.

BACKGROUND OF THE INVENTION A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.

Currently available drugs for AIDS therapy are divided into two groups: those that prevent infection of target cells [nucleoside (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs)], and those that prevent HIV-1-infected cells from yielding infectious viruses (protease inhibitors). Monotherapy with antiretroviral agents has shown limited effects, very likely due to the interplay of phenomena such as: high viral loads and multiplication rates of HIV, incomplete inhibition of viral replication and emergence of drug resistant mutants. For this reason, combination therapies with two or more drugs have been proposed for a more effective treatment of AIDS. Potent suppression of HIV replication over prolonged periods has been accomplished with regimens including reverse transcriptase and protease inhibitors, although on stopping therapies viraemia has rapidly reappeared. In the attempt to obtain better results, research is now focused on exploiting new targets and enhancing the activity of "old" drugs. Among the latter, NNRTs possibly endowed with better pharmacokinetic profiles, capability to inhibit clinically relevant mutants and, hopefully, to minimize HIV multiplication are being pursued.

O 0 0

(M

0t" 00' in O1 2 Compounds of the present invention are dihydro-alkyloxy-benzyl-oxopyrimidines (DABOs) which potently inhibit HIV multiplication targeting reverse transcriptase without bioactivation.

5 BRIEF DESCRIPTION OF THE INVENTION Novel compounds of formula A: 0 O

Y

HN y X N

(A)

as herein defined, are disclosed. These compounds are useful in the inhibition of HIV reverse transcriptase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED

EMBODIMENTS

This invention is concerned with the compounds of formula A described below, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). The compounds of this invention include those with structural formula A: wherein: X is R is Yis Z is R, is R, is

R

3 is -CHK (wherein K is 4 alkyl, -C3.-Cycloalkyl),

-NK

(wherein K is -Cl,.4alkyl,

-C

3 .,cycloalkyl), -aryl, -arylalkyl; 4 alkyl (containing one or more of heteroatoms like 0, S, -C3 6 cycloalkyl (containing one or more of heteroatoms like 0, S, -aryl, -arylakl heterocycle; -Caalkyl,

-C

3 .,cycloalkyl; 4 alkyl, -C3.,cycloalkyl; -C.,alkyl, -halogen, -OW (wherein W is -CH 3 aryl), -SW (wherein W is -CH 3 -aryl); -C,,alkyl, -halogen, (wherein W is -CH 3 -aryl); -SW (wherein W is -CH3, -aryl); -C,.,alkyl, -halogen, -OW (wherein W is -aryl); -SW (wherein W is -CH 3 -aryl) -C,.,alkyl, -halogen, -NO, -OW (wherein W is -CH 3 -aryl); -SW (wherein W is -CH 3 ,-aryl) -C,.,alkyl, -halogen, -OW (wherein W is -CH, -aryl), -SW (wherein W is -CH3, -aryl); R, is 1 is pharmaceutically acceptable salts or soluble derivatives thereof; preparation process of derivatives thereof; a method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS, comprising administering to a mammal an effective amount of compounds claimed; a pharmaceutical composition useful for inhibiting HIV reverse transcriptase, comprising an effective amount of compounds claimed, and a pharmaceutically acceptable carrier; a pharmaceutical composition useful for preventing or treating infection of HIV or for treating AIDS, comprising an effective amount of compounds claimed, and a 00 pharmaceutically acceptable carrier.

Ce The most preferred compounds of this invention are those of table 1.

to 1The compounds of the present invention may have asymmetric centers and occur as O racemates, racemic mixtures, individual diastereomers, or enantiomers. with all isomeric forms being included in the present invention.

When any variable occurs more than one time in any constituent or in formula A of this invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein except where noted, "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "Halogen" or "Hal" as used herein, means fluoro, chloro, bromo and iodo.

As used herein, with exceptions as noted, "aryl" is intended to mean any stable monocyclic. bicyclic or tricyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, biphenyl.

The term heterocycle or heterocyclic, as used herein except where noted represents a stable 5- to 7-membered monocyclic or stable 8- to 11 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, 0 and S; and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the abovedefined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.

The pharmnaceutically-acceptable salts of the novel compounds of this invention that are capable of salt formation (in the form of water- or oil- soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts of these 0 compounds. which are formed, from inorganic or organic acids or bases.

z 5 In preferred embodiments, a compound of the present invention is administered in combination or alternation with AZT, D4T, FTC 2 3 3TC (Epivir, Glaxo Wellcome, Inc.), AZDU (3'-Azido-2' ,3'-di deoxyuridine); 141 W94 00 (amprenavir. GlaxoWellcome, Inc.); Viramune (nevirapine), Rescriptor (delavirdine); or DMP-266 (efavirenz). Other examples of antiviral agents that can be used in combination or o alternation with the compounds disclosed herein for HIV therapy include DDI, DDC, Delaviridine, P-LddA, 1-L-3'-azido..d5FC, carbovir, acyclovir, interferon, stavudine, CS-92 (3 '-azido-2 ideoxy-5-m ethyl cyti dine), 3 -azido nucleosides, and P-D-dioxolane nucleosides such as i 3 -D-dioxolanyl 'guanine (DXG), 3 -D-dioxolanylb2,6-diaminopurine (DAPD), and (-D-dioxolanyl..6.chboropurine

(ACP).

Preferred protease inhibitors include indinavir (Q 1(1,S 2 R),5(S)I.2,35trideoxy-N 2 3 -d ihydro -2-h ydroxy. 1 H-inden- 1 -yl)-5 -dime thyl ethyl)amino ]carbo nyl 4 3 Pyridinylmethyl)- l-piperazinylp2-(phenylmethy)Derythr-pntmde sulfate; Merck), nelfinavir (Agouron), ritonavir (Abbot), and saquinavir (Invirase; Roche).

Nonlimiting examples of other compounds that can be administered in combination or !0 alternation with the compounds of the present invention to augment the properties of the drug on administration include abacavir: (1 S,4R)-4- 2 -amino..6cyclopropy-amino)9Hpurin- 9 ylJ- 2 -cvclopentene- I-methanol succinate (1592U89, a carbovir analog; Glaxo Wellcome); zidovudine: AZT, 3 '-azido..3'-deoxythymidine (Glaxo Wellcome); BILA 1906: 1S-[jj3- 1l-dime thyethyl)aminocarbon R]yrIidil hylti] -piperidinyl -211 hydroxy- lS-(phenylmethyl)propyljaminojcarbonyl]J2-mthylpr 1) -2quinolinecarboxamide (Bio Mega/Boehringer-Ingelheim); BILA 2185: N-(1 ,1dimethylethyl)- I4 2 2 -2,6-dimethylphenoxy)-l-oxoethyl]amino]..2R..hydroxy- 4 phenylbutyl4Rpyridinylthio) piperidibaide (Bio Mega/Boehringerlngelheim); BM+51.O 8 36:triazoloisoindolinone derivative; BMS 186,318: aminodiol derivative HIV-1 protease inhibitor (Bristol -Myers..Squibb); d4API: 9 2 5 -dihydro-5.(phosphonomethoxy).

2 furaneljadenine (Gilead); stavudine: d4T, 2 '-didehydro-3 '-deoxythymidine (Bristol-Myers-.

Squibb); efavirenz: DMP-266, a 1,4-dihydro-2H-3 I -benzoxazin-2-one; HBY097: S-4- 6 ispooyabny--ehx- (ehy homt )34dhyrqunxln2lH-hoe HEPT: 1 -[(2-hydroxyethoxy)methyl J6-(phenylthio)thymine; KNI-272: 2 S,3S)-3-amino-2.

hydroxy-4-phenylbutyric acid-containing tripeptide; L-697,593; 5-e thy]l-6-methyl-3-(2- 0 phthalimido-ethyl)pyridin-2(1H)-one; L-735,524: hydroxy-aminopentane armide HTV-l protease inhibitor (Merck); L-697,66 1: 3 4 7 -dichloro- l,'-benzoxazolx*7 CK Yl)met y )amino} 5ethyl6meth ylpyrid in2(l H)-one; L-FDDC: (-)-f-L-5-fluoro-2',3'd ideoxycvti dine; L-FDOC: (-)-1-L-5-fluoro-dioxolane cytosine; 6 00 i o r p l r cl( B ;T i n l i s b s i; n v r p n :II-y l p o y d h d o 4 ispoyuaiVIEU ragl/isbsi;nvrpn:I -ylpoy-,1dhdo merhyl-6H-dipyridol[3,2-b:2',3 diazepin-6-one (Boehringer-Ingelheim);

PFA:

10 phosphonoformate (foscarnet; Astra); PMEA: 9 2 -phosphonylmethoxyethyl) adenine (Gilead); PMPA: 9 2 -phosphonyl-methoxypropyI)adenine (Gilead); Ro 3 1-8959: hydroxythethylamine derivative HI V-Il protease inhibitor (Roche); RPI-3 121: peptidyl protease inhibitor, 3 s)- 3 -(n-alpha-benzyloxycarbonyl> 1 -asparginyl)-amino-2hydroxy-4 phenylbutyryl]-n.tert-butyl-1-proline amide; 2720: 6 -chloro-3,3-dimethyl-4 (isopropenyloxycarbonyl)34dihydro-quinoxalin-2( 1H)thione; SC-52 151: hydroxyethylurea isostere protease inhibitor (Searle); SC-55389A: hydroxyethyl-urea isostere protease inhibitor (Searle); TIBO R82150: trahydro.5 -me thyl thy 1-2 1 -jk] [1 4 ]-benzodiazepin-2(1H).chione- (Janssen); TIBO 82913: ty 6(-eh l2btnliiao45ljk]- 0 [1A.

4 benzodiazepin-2(1H)-thione (Janssen); TSAO-m3T:[2',5 '-bis-O-(tertbutvldimethylsi lyl)- 3 )'-spiro-5 '-(4'-amino-1 '-oxathiole-2',2 '-dioxide)]- j3-Dpentofuranosyl-N3-methylthymine; U90152: 1-r3-[(1 -methylethyl)-amino]2pyridinyl-4-[[ 5 [(methylsulphonyl)-amino].. 1H-indol-2y1]carbonyl]piperazine; UC: thiocarboxanilide derivatives (Uniroyal); UC-78 1 4 -chloro- 3 3 methyl2butenyloxy)phenyl]I2-methyl 3furancarbo th ioamid e; UC-82 N-[4-chloro-3-(3-methyl 2 -butenyloxy)phenyll2-methyl-3 thiophenecarbothioamide; VB 11,328: hydroxyethylsulphonamide protease inhibitor (Vertex); VX-478: amprenavir, 141 W94, hydroxyethylsulphonamide protease inhibitor (Vertex/Glaxo Wellcome); XM 323: cyclic urea protease inhibitor (Dupont Merck), delaviridine (Pharmacia Upjohn), famciclovir, gancyclovir, and penciclovir. In another embodjment,a compound of the present invention is administered in combination with LG1350, which has the following structure.

2007234580 20 Nov 2007 0 0= z-I 0j 0 8 Preparation Of Methyl Arylacetyl yae tre SCHEME A 00 R, Meidrum's acid

CH

3 Y-hai X 2

CH

3 0 NH

CH

3

O

R-ONa Anhydrous pyridine (400 mmoles, 32.5 ml) was added with stirring under nitrogen Satmosphere into an ice-cooled solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrurm's acid) (165 mmoles, 23.75 g) in anhydrous dichloromethane (50 ml). The resulting solution 0 was treated, over a 2 h period at 0°C under nitrogen atmosphere, with a solution of crude O arylacetyl chloride in anhydrous dichloromethane (50 ml). Arylacetyl chloride was prepared N' before use by refluxing the proper arylacetic acid (43.2 mmoles) with thionyl chloride (21.3 ml) under nitrogen atmosphere for 2 h. Then, the mixture was stirred for 2 h at room S temperature, poured into crushed ice and treated with 2N HCI (100 ml). The organic layer S was separated and the aqueous solution was extracted twice with dichloromethane (25 ml).

0 The organic phase and the extracts were combined, washed with brine, dried and evaporated.

The solid residue was dissolved in anhydrous methanol (250 ml) and the solution was Srefluxed for 20 h. After cooling, metal sodium (0.16 g-atoms, 3.68 g) was carefully added and the mixture was stirred until dissolution was complete. Alkyl halide (160 mmoles) was dropped into the solution and the resulting mixture was heated at reflux for 4-12 h. After cooling, the solvent was removed and the residue treated with water (200 ml) and extracted with chloroform (3 x 100 ml). The organic layer was washed with brine (2 x 100 ml), dried and evaporated to give the desired compound, which was purified by passing through a silica gel column (chloroform as eluent).

In the above reaction, arylacetic acid (Scheme or arylacetyl chloride can be replaced with the corresponding 1-arylacetylimidazolide (Scheme or with arylacetylethoxycarbonylanhydride, whereas the Meldrum's acid can be replaced with ethyl acetylacetate, ethyl alkylmalonate or ethyl alkylmalonate potassium salt, to give the proper ethyl arylacetylalkylacetates in high yields.

Preparation Of Compounds With X O (Scheme A).

The proper methyl arylacetylalkylacetate (10 mmoles) in methanol (50 ml) was added to a well-stirred suspension of O-methylisourea hydrogen sulphate (15 mmoles, 2.58 g) and calcium hydroxide (16 mmoles, 1.18 g) in water (50 ml). The resulting mixture was stirred at room temperature for 72 h, then concentrated, made acid (pH 5) with 0.5N acetic acid and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with brine (100 ml), dried and evaporated to dryness. The residue was purified by crystallization from the proper solvent yielding pure 5-alkyl-6-benzyl-3,4-dihydro-2-methoxypyrmidin-4one. This compound was then refluxed with the proper potassium alkoxide (100 mmoles of potassium metal in 20-30 ml of alcohol freshly distilled on sodium metal) under nitrogen z atmosphere until starting material disappeared at the TLC control. After cooling, the mixture Swas concentrated, made acid (pH 5) with 0.5N acetic acid and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed once with brine (100 ml), dried and evaporated to give the required 2-alkoxy-5-alkyl-6-benzyl-3,4-dihydropyrimidin-4-one 00 V derivative, which was recrystallized from a suitable solvent or purified by column S chromatography (silica gel; ethyl acetate:chloroform Physical and chemical data of o representative compounds of the invention are reported in table 1; cytotoxicity and anti-HIV- I 1 activity data are reported in table 2.

11 Preparation Of Compounads With X =S SCHEME B 00 S NH 2 Method A Method C 12 The proper ethyl arylacetylalkylacetate (31.5 mmoles) was successively added to a stirred solution of sodium metal (0.063 g-atoms) in 50 mL of absolute ethanol (50 ml) thiourea (43 mmoles). The mixture was heated while stirring at reflux for 5 h. After cooling, the solvent was distilled in vacuo at 40-50'C until dryness and the residue was dissolved in water (200 mL) and made acid (pH 5) with 0.5N acetic acid. The resulting precipitate (the crude 2 -thiouracil derivative) was filtered under reduced pressure, washed with diethyl ether, vacuum dried at 80*C for 12 h and then crystallized from the proper solvent.

Then, according to method A, iodomethane (8 mmoles, 1.13 g) was added to a suspension containing the proper 2 -thiouracil derivative (4 mmoles) in anhydrous

N,N-

dimethylformamide (2 ml), and the resulting mixture was stirred at room temperature until the starting material disappeared at the TLC control (silica gel; n-hexane: ethyl acetate: methanol 12:3:1). Then the reaction content was poured on cold water (100 mL) and extracted with ethyl acetate (3 x 50 ml). The organic layers were collected, washed with a sodium thiosulfate solution (100 ml), brine (3 x 50 ml), dried and evaporated to furnish the crude 5-alkyl-6-benzyl-3,4-dihydro-2-methylthiopyrimidin-4.one as a solid purified by crystallization.

Alternatively, according to methods B and C, potssium carbonate (4.2 mmoles) and the proper alkyl halide (4.4 mmoles) were added to a suspension containing 2 -thiouracil !0 derivative (4 mmoles) in anhydrous N,N-dimethylformamide (2 ml). The resulting mixture was stirred at room temperature (method B) or at 80 0 C (method C) until starting material disappeared at the TLC control (silica gel; n-hexane:ethyl acetate:methanol 12:3:1). Then the reaction content was poured on cold water (200 mL), made acid (pH 5) with 0.5N acetic acid and extracted with ethyl acetate (3 x 50 ml). The organic layers were collected, washed with a sodium thiosulfate solution (100 ml), brine (100 ml), dried and evaporated to furnish alkyl-6-benzyl-3,4-dihydro-2-methylthiopyrimidin-4-ones and as crude material which was then purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate:methanol 12:3:1) followed by crystallization. Physical and chemical data of representative compounds of the invention are reported in table 1. Cytotoxicity and anti- HIV-1 activity in vitro are reported in table 2.

Prep-aration Of Compounids With X NIK SCHEME C

NH

2 HN NH 2

A

3 I. Thiourea 2. CHR4 R I 14 Title derivatives were prepared according to the procedure described for the synthesis of compounds with X S using ethyl arylacetylalkylacetates and guanidine [2-amino-6- Sbenzylpyrimidin-4-ones as starting materials. 2-Alkylaminoderivatives were O synthesized by heating the previously reported 5-alkyl-6-benzyl-3.4-dihydro-2-methylthio S pyrimidin-4-ones with 20-30 ml of proper amine in a sealed tube at 170*C for 24 h. Physical and chemical data of some compounds are reported in table 1. Cytotoxicity and anti-HIV- I activity in vitro are reported in table 2. The compounds cf the present invention are useful 00 in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by the c human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is O defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.

The compounds of this invention are also useful in the preparation and execution of screening for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral 0 compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antiviral to HIV reverse transcriptase by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes. For inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS or ARC, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention. These r- pharmaceutical compositions may be in the form of orally administrable suspensions or tablets: nasal sprays: sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.

z When administered orally as a suspension, these compositions are prepared according 0 5 to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending 0 agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the S art. As immediate release tablets, these compositions may-contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients. binders, 0 extenders, disintegrants, diluents and lubricants known in the art.

0 When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

The injectable solutions or suspensions may be formulated according to known art, using suitable non toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3butanediol, water. Ringer's solution or isotonic sodium c:hloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including z0 synthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient; such as cocoa buffer.

synthetic glyceride, esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidity and/or dissolve in the rectal cavity to release the drug.

The compounds of this invention can be administered orally to humans in a dosage range of 1 to 75 mg/kg body weight. One preferred dosage range is 1 to 50 mg/kg body weight orally. Another preferred dosage range is 5 to 75 mg/kg body weight orally. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of 16 excretion, drug combination, the severity of the particular condition, and the host undergoing 0 therapy.

SThe present invention is also directed to combinations of the HIV reverse transcriptase S inhibitor compounds with one or more agents useful in the treatment of AIDS. The 0 compounds of this invention can be administered in combination with other compounds that are HIV reverse transcriptase inhibitors, and/or with compounds that are HIV protease 0 inhibitors. When used in a combination treatment vith compounds of the instant invention, S dosage levels of HIV protease inhibitors of the order of I to 25 or 50 grams-per-day are M useful in the treatment or prevention of the above-indicated conditions, with oral doses two- S to-five time higher. For example, infection by HIV is effectively treated by the S administration of from 5 to 25 milligrams of the HIV protease inhibitor per kilogram of body weight from one to three times per day.

It will be understood. however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including S the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Dosages of HIV reverse transcriptase inhibitors, when used in a combination treatment with compounds of the present invention, are comparable to those 0 dosages specified above for the present compounds. It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals includes any combination with any pharmaceutical composition useful for the treatment of AIDS.

ANTIVIRAL ASSAY PROCEDURES Compounds. Compounds were solubilized in DMSO at 200 mM and then diluted into culture medium.

Cells and viruses. MT-4, C8166, H9/IIIB and CEM cells were grown at 37 *C in a 5% CO, atmosphere in RPMI 1640 medium, supplemented with 10% fetal calf serum (FCS), 100 IU/mL penicillin and 100 ug/mL streptomycin. Cell cultures were checked periodically for the absence of mycoplasma contamination with a MycoTect Kit (Gibco). Human 17 immunodeficiency virus type-1 (HIV-1, III, strain) was obtained from supernatants of S persistently infected

H

9 /IIIB cells. HIV-1 stock solution had a titres of 4.5x10 50% cell culture infectious dose (CCID,,)/ml.

S HIV titration. Titration of HIV was performed in C8166 cells by the standard limiting 0 5 dilution method (dilution 1:2, four replica wells per dilution) in 96-well plates. The S infectious virus titre was determined by light microscope scoring of cytopathicity after 4 days of incubation and the virus titres were expressed as CCIDs 5 mL.

00 kn Anti-HIV assays. Activity of the compounds against HIV-1 and HIV-2 multiplication in acutely infected cells was based on the inhibition of virus-induced cytopathicity in MT-4 and P 0 C8166 cells, respectively. Briefly, 50 uL of culture medium containing 1xl0' cells were S added to each well of flat-bottom microtiter trays containing 50 ul of culture medium with or without various concentrations of the test compounds. Then 20 uL of an HIV suspension containing 100 CCID,,, were added. After a 4-day incubation at 37 the number of viable cells was determined by the 3-(4,5-dimethylthiazol-1-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cytotoxicity of the compounds was evaluated in parallel with their antiviral activity. It was based on the viability of mock-infected cells, as monitored by the MTT method.

RT assays. Assays were performed as follows. Briefly, purified rRT was assayed for its RNA-dependent polymerase-associated activity in a 50 uL volume containing: 50 mM TrisHCl (pH 80 mM KCI1, 6mM MgC12, 1 mM DTT. 0.1 mg/ mL BSA, 0.3 OD,,, unit/mL template:primer [poly(rC)-oligo(dG)12-18] and 10 .M 3 H]dGTP (1 Ci/mmol).

After incubation for 30 min at 37 the samples were spotted on glass fiber filters (Whatman GF/A), and the acid-insoluble radioactivity was determined.

EXAMPLES

2-Cyclopentvlthio-6-(2.6-difluorophenylmethvyl-3.4-dihvdrojgrimidin-4-(3H)-One(MC867).

A mixture of 6-(2,6-difluorophenylmethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one (0.16 g, 0.65 mmol; prepared as reported in scheme cyclopentyl bromide (0.11 g, 0.08 mL., 0.71 mmol) and potassium carbonate (0.09 g, 0.65 mmol) in 1 mL of anhydrous DMF was stirred at room temperature for 24 h. After treatment with cold water (200 mL), the solution was extracted with ethyl acetate (3 x 50 mL). The organic layers were collected, washed with brine (3 x 50 mL), dried and evaporated to furnish crude MC867, which was purified by chromatography on silica gel column (eluent: n-hexane/ethyl acetate/methanol S 12,13/1).

Yield 45; mp 168-169; recrystallization solvent: cyclohexane; formula (moleculaweight): C,,H 1

,,F

2 N.OS (322.37).

LM92Z-).

00 The synthesis of MC922 was accomplished according to the above reported procedure starting from 6-(2,6-difluorophefly methy l)-5 -m ethyl-I ,2.3,4-tetrahydro-2-thiopyrimidin-4 (3JH)-one (see scheme B).

Yield 54; mp 0 192-193; recrystallization solvent: cyclohexane; formula (molecular weig~ht): C 17

H-I

1 F,N.OS (336.40).

2-Cyclopentylthio-6-[l-(2.6-difI jorOhnley 43- .4dhdoprmdf- e The synthesis of MC1008 was accomplished according to the above reported procedure starting from 6- difluo rophe ny1)e:thY!] 1 ,2,3,4-tetrahy dro-2 -th iopyrimi din4(3H)-one (see scheme B).

Yield 54; mp 165.5-166.5; recrystallization solvent: cyclohexane; formula !0 (molecular weight): C 17 H, FNOS(364) 2 -Cycl~pftlho-6[[2.dilorohnl tyl4dhdomehl The synthesis of MC1047 was accomplished according to the above reported procedure, starting from 6-I(,-iloohnlehl--ehl-,,',-erhdo2tiprmdn 4(3H)-one (see scheme B).

Yield 60; mp 196-197; recrystallization solvent: cyclohexane; formula (molecular weight): C,,H,,,FN,0S (350.43).

19 6 2 6 Difluorophnllthl34dhdr2mthmthyomth lttY The synthesis of MCI11 was accomplished according to the above reported procedures, Zstarting from 6 2 6 -difluoropheflylmethyl1,2,3,4tetrahydro2thiopyrimidin-4( 3

TH)-

0 (see scheme B) and chioromethyl methyl sulfide.

Yield 72; mp 159-160; recrystallization solvent: benzene/cyclohexale; formula C) (molecular weight):

C

1 3

H

1 .,N,0S 2 (31I4.37).

00 The synthesis of MCI 162 was accomplished according to the above reported procedure, starting from 6 -(2,6-difluorophenylmethyl)5methyI -1 ,2,3,4-tetrahvdro-2-thiopyrimidin 4(31-)-one (see scheme B) and chioromethyl methyl sulfide.

Yield 70; mp 183-184; recrystallization solvent: benzene/cyclohexale; formula (molecular weight): C,,H,,F 2 N,0S, (328.39).

thiopyrimi din -4-(3ho- one MCi 145).

The synthesis of MCI1145 was accomplished according to-the above reported procedure, 0 starting from 6-(2,6-difluoropheflylmethyl)-5-(l-methy.'ethy I)-1I,2,3",4-tetrahydrothiopyrimidil-4(3H)-orne (see scheme B) and chloromethyl methyl sulfide.

Yield 62; mp 158.5-160; recrystallization solvent: cyclohexane; formula (molecular weight):

C,,H

18

F

2 NOS, (356.45).

2 -CylopeflypnfO(6iur heymty).dY (M C1 22).

Cyclopentylamine (10 mL) was heated while stirring with 6-(2,6-difluoropheflylmethyl)- 3 4 divr--ehlhoprmdn4(H-n (0.30 g, 1.12 mmol; prepared as reported in scheme B or C) in a sealed tube at 1600'C for 10 h. After cooling, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were collected, washed with brine (3 x 50 mL), dried and evaporated to furnish crude MC1022, which was purified by chromatography on silica get column (eluent: ethyl acetate/chloroform C~1Yield 74; mp (oil); formula (molecular weight): CHl 7 FNO (305.33).

0 starting from 6-26dfurpeymty)34dhdr--ehl2mtytiprmdrn rrn 4(3H)-one (see scheme B or C).

r- Yield 60:. mp 115-117; recrystallization solvent: n-hexane/cyclohexafle; formula (molecular weight): C, 7

H,

9 F_,N0(395) 2-ylpnyaio6[-2.- lo~hnlehl-3 .4-dihydropyrimidin-4-(3H)-ofl WC104-8).

The synthesis of MC1048 was accomplished according to the ~above reported procedure, starting from 6-[1-(2,6difluoropheflyl)ethyl]- 34-d ih ydro-2 -me thy thiopyrimidin 4 3 Th1)one (see scheme B or C).

Yield 48; mp (oil); formula (molecular weigh'.) C 7 H 1

,F

2 N3O (3 19.35).

o 2 -Cyclope nty Iamino.-6-[1-(2.6&difl uorophenyl)ethy] 11 3.4 -dih ydro-5 -Tethy lpyimidin-4( 3

LD

The synthesis of MCI1129 was accompiished according to the* above reported procedure, starting from 6-I(,-iloohnlehl-.-iyr--ehl2mtytlprmdn 4(3H)-one (see scheme B or C).

Yield mp (oil); formula (molecular weight):CH 1 2 3 (333.38).

6-(2.6-Difluorophenylmethyl)3.4diydro2(4thiomorpholin-1-yl)pyri iidin- L4L-=O (MCI 193 The synthesis of MCI1193 was accomplished according to the above reported procedure, starting from thiomorpholine and 6-(2,6-difluorophenylmthyl)3,4dihydro- 2 methylthiopyrimidil-4(3H)-ofe (see scheme B or C).

21 S Yield 78; mp 233-234; recrystallization solvent: acetonitrile; formula (molecular 8 weight): CIHF,N 3 OS (323.36).

S~6-(2.6-Difluorohenylmeth 34dih r -NN-methyain rimidin4- 0 ;(MC1182).

To a stirred solution of sodium metal (0.14 g, 6.3 mg-atoms) in absolute ethanol (50 mL) 1,1- S dimethylguanidine sulfate (1.17 g, 4.3 mmol) and ethyl 4-(2,6-difluorophenyl)acetylacetate 00 (0.76 g, 3.15 mmol) were successively added. The mixture was heated while stirring at reflux for 8 h. After cooling, the solvent was distilled in vacuo at 40-50°C until dryness and the S residue was dissolved in water (200 mL) and made acid (pH 5) with 0.5N acetic acid. The S resulting precipitate (the crude isocytosine derivative) was filtered under reduced pressure, washed with diethyl ether, vacuum dried at 80°C for 12 h and then crystallized from benzene/cyclohexane (see scheme C starting from ethyl 4-(2,6-difluorophenyl)acetylacetate and replacing guanidine hydrochloride with 1,1-dimethylguanidine sulfate).

Yield 88; mp 210-211; recrystallization solvent: benzene/cyclohexane: formula (molecular weight): C, 3

H,

3

FN

3 0 (265.26).

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

2007234580 20 Nov 2007 ft.

A.

a Trabic 1. P~hysical and Clictmical Dala tf MC Ctunpounds it, i, it, Rs C IRecryst. Solvcnt ylcld FormiuId Comild. X Y MC 507 0 14 MC 508 If MC 512 0 11 MC 531 0 Me MC 1114 0 If MC: 1103 0) 1I MC 843 S 11 MC 796 S I I MC 890 S It MC 892 S if MC 898 S I I MC: 81)9) S I I MC 900 S It MC 903 S I MC 806 S I MC:842 S I MC 809 S 11 MC 817 S If MC 897 S If MC 863 S I I MC 854 S It MC 857 s It MC 859 S It MC 880 S I I MC 884 S If MC 8H9 S I I MC 825 5 11 MC 960 S I I MC 868 S I I MC 95 1 S I I MC 952 S I I Z R it, 1I 2,5-MeC-helX I-4 It 4,5-Me 2 -c-hex It II 3,5-Me,-c-hex It HI 2,5-Me,-c-hex 11 1I See-but F HI c-pett

I-

It benzyluxynilil 11 I'l Scc-but I Me Iso-prop I Me c-pent I Me c-hex It Ft ISO-prop I I Et c-pent II f:t c-hex It II Sec-hilt Me 1I c-pent Mc HI See-hut 14 If See-hut NO, If See-but I1 1I See-but II II Sec-but Cl II Sce-but 11 II Sec-hut Ii II Sec-but 1: II See-but it If Sec-hut 11 11 See-ht Nil, II See-butl 11 11 See-hutl (Ts I1 See-hut It 11 See-hut OMe

II

it It If If Me If I I If

II

II

If It I1 I I

CF'

I I H 130-132 II 132-134 II 178-181 II 196-198 F 87-88 F 193.5-184.5 It 181-183 If 157-158 it 118-1 19 Hi 95-96 II 142-143 1-1 144-145 It 168-1 h) H 175.5-176.5 II 118-119 II 142-144 II 107.5-108.5 II 148.0-148.5 1I 127-128 If 128-1301 H 120-121 1I 98-99 11 125-126 It 106-1017 11 96-97 11 98-99 1I 143-144 II 128-1303 1I 125-_126) I 1 144-145 11 123-124 Petrol. Ether/dicthyl ether 22 IPetrol. Ethier/diethyl ethecr 28 Pletriil. Ether/diethlyl ether 12 retrol. Ether/diethyl ether 38 Pletiol. Ethert/diethyl ether 28 Blenzenie 52 Cyeclexatne/beizent: 39 n-Ilexane/cyloIlle 78 n-hexalne 88 n-Iimxine 65 i-lexiei 59 Cycllictiine 85 Cyceouhexaine 159 Cyclotxexalie n. i~e xanc/cylohexarne 67 Cyeluolmxine

()I

n-hexa'ne 56 Cyceliax~ne/licrefle 68 (yehohexuneA htnzei3u 54 Petirol. Ethur/diethyl ether I1(K n-hexanc/cyelolhextane 58 (:yclohtexaint 92 Cyelolluxant 74 n -lite xne/cyelithex ant: 68 Cyclollexalle 07 ii-liexagie Y4 (:yclohe x itiw/Ie n zc ii 74 (yelouhexalle 77 C'Ydlhexaie mt) Cyclohexsiie Cyelohexaie (11) C,,I l.N.)S C.I I1,,N,()S C,.l I,,NOS C,JIIN!O~s C14 I N 2 Os C,ji, ,NOS C,,Il I 31,OJS C,.11I,I,N.( 2007234580 20 Nov 2007 Table I.

Physical and Chemnical Data or MC C'omponunds tcoflIIIucu) W it, It, it, nI.p.. *C Iecrys'I. srdVCitt 171. Oded 1:01111111a omtrid. X Y NIC 457 s 11 NMC 964 S I Mc 10)41 S I MC 1042 s If M('C877 S 11 MC:878 S If MC886 S H- MC885 s If s It MC888 S If PMc891 I S I I MC871 s 11 MCR86O S I I NIC872 S I I MC866 S H M(:848 S I M(:867 S I MC870 S I MCI(1I s MC996 S I MC1016 S Ht MCIOOO) s I I MCI102 S I I MCI(913 S U MCIOO)7 S I MC1044 S I MC:1045 S I MCIII0 s I MCtOO)8 S I MIC1013 S I S I MCIOK)b s MCIOI4 S I MC971 S I MC972 S I MC2974 S H MC969 S I I MC973 S I MC975 S I I MCB44 S Me MC845 S Me MC925 S Me MC924 S Me s Me Z It If Sec-but 11 Sec-bitt II Me I I iso-prop( I I n-hut IIiso-hut U sec-hut II c-pent II c-hcx II Me II isti-prrop If ti-but 11 iso-but II sec-hut I I c-pent IU c-hex Me iso-prop Me c-pent Me c-hecx Et iso-prop Et c-pent El c-hex Me iso-prop Me iso-but Me n-hut Me sec-hut Mc c-pent Me c-hex Et iso-prop Et c-pent Et c-hex Me iso-prop Me c-pent Me c-hex Et iso-prop Et c-pent Er C-h1ex U sec-bLut II sec-hut If sec-but I I see-bitt I I sec-but I I t)Me it It It If 11 11 If If It It 11 If 11 It 11 It 11 It If 11 If If If Me I-1 No, I I II 78-8 1t i-11msanc/ ycIohiic st 71I ~I 112-113 Cyctdrlexaite 6.3 11 122-123 Cyclohexime 69 11 119-1201 11-Itex.ne 72 CI 237-238 benULrsr 99 CI 230-231 betizette 81 Cl 153-154 cyclohexane 62 CI 143.5-144.5 cyclollexane 56 CIi 183-184 cyclohexan/bcoICtC cl 185-186 cyclobcxirie 54 Cl 200-201 cyclohrexandChenzienc 49 F 197-I198 benzene 95 F 174-175 cyclollexsiic 74 F 126-127 cyclohexarnt 46 F 130-137 cyettliexatie 49 F 149-1501 n-hcxnccycIoIIcLI1'c 48 F 168-169 cyclolsexane 45 F 164-165 cychhezre 40 Ci 196-196.5 cyclohexane/twnzefle CI 181-182 cyclohexane 45 CI1 211-212 cyclrrhexanr/cflizefle 42 CI 166-168 dicthyl ether 54 Cl 168-169 diethyl ether Cl 198-199 cycloltexane 41 F 155-156 cyclohemtte 53 F 159-1601 cycloblexanle 49 F 149-150) cycloltexait 58 F 133-134 ir-hexane 75 F 165.5-166.5 cyctolrextrie 601 F 206-207 benizene 44 F 149-1501 cycluhexarre F 141-143 cyclstllexalle 45 F 154-155 cyclolhexatic 51 H 161-162 n-hexane/cycoliex ane 58 If 140-141 n-hcxancfcycltltcx;ttc 4V It 177-178 n-hcxane HI 163-164 cyclolrexne 54 H oil 48 It 126-127 ti-lexanc 41 If 177-178 cyclohexane It 127-128 ti-hexane 61 II 163-164 cyclohexanc/blcnzcnc 88 H 178-180) cycloltexunc/bcnzetl 1100 11 I17t0-171 cyelsrhsexse 618 C,,l 1 1

,F,.OS

C,H ,Cl,N,OS 1,, 11 C171 1 ,F:IN OS

C

1 j1.

15

FNIOS

C1111I41FN C,5110,I--NOS C, 1lTIN 2 CIJ l 1

.FNS

C,,l Ij.FN,0S Cjl Ij:l'N C,Ilj:,NOS C,,l2IN,OS C,,II1,,FN,OS CIi=CII-CHr=C"II Cl l=CII-CII=CI I CII=CH-CII=Cli CII=Cli-CI I=CH cII=CII-C:II=CII CIF=CI I-CII=CI-I Mc I I it ItI I I

NO,

I I I CI I 2007234580 20 Nov 2007 Table I.

Ph~ysical and Chicnical Dala MC: Comnpounds (continuco) Wt it, IV U' C Rccrysi. S,,tvclit Y ie lId I *o rm tttll Conytd. X Y It (l s Me II s-hi M (79 11 s Me 11 sc-u M C9 13 S Me 11 scc-hul (KlC91? s NMc It sec-hut1 MCII') s Me 11 scc-111t M(:912 s Me 1I Me M C9 14 s Mc I iso-prop MC920 S Me I n-hut MC 916 s Me I iso-hut MiC850 s Me I sec-but MCIS 15 S Me I c-pcnt IC917 S Me II C-Ircx MC869 s Mc Ii Me MC881 S Me Ii iso)-prop MC905 s Me Ii n1-ut MC921 S Me II iso-but MC849 s Me I scc-hut s Me I c-pent MC923 S Me I c-hex MC1060 S Mc Mc Me MC I 09P S Me Mc sec-btro MC11147 s Me Me c-pcnt MC798 s I;t I I sec-but MC1I137 S EL I iso-prop mc,1038 s Et i sce-trut MC8114 s El I sec-hut m CI (13 S i-pro ii iso-Prop MC952 s auiiyI I I see-hut MC856 s n-pro Wsc-hut MC834 s n-hut i sec-hut MCI 119 Nil Ii 1 1 ethyl MC1078 NH [I It n1-prop MC979 Nil I I it iso-prop MC990 Nil 1I it c-pfop MC,1077 Nil It it n-hut MC945 Nil It It sec-hut MC1043 Nil It Hl MeOcthyl MC1022 NH 1I H c-pent MCI049 Nil 11 1i c-hex MC1048 Nil ii Mc c-pent MCIII18 Nil Me It iso-prop MCI 130 Nil Me II sec-hut MC1050 Nil Me It c-pent MCI 105 Nil Me It hcnzyi I it I i CI

I

CI

I

(1

I

F

I

I: Ii I: It F It IF I I F 11 F Ii Fi

I

F: it F: It F It 1. ii It 163-165 It 120.5-121.5~ it 146- 147 11 154-155 CI 2006-201 l 241-242 (CI 179-180 CI 2018-201) C.I 204-20)5 0I 252-253 CI 237-238 F 218.5-219.5 I: 14-165 F 178-179 F 161-162 F 128-121) F 192-193 F vi1-192 F 202-203 F 135-136 F 19)6-197 It 140-141 F 174-175 F 150-151 II 198.5-199.5 j: 167-168 It 127.5-128.5 11 1081-109 It oil 1. 138-1401 F 136-137 F 150-151 F 183-184 F 130-131 IF 140-141 F 120-121 F oil F 143-144 F oil F 165-16 F oil F 115-117 F 182-183 Cyclo dlcs uic cyclithlrute 79 cyclolcXainc(' cycloliexitc 72 cyclolicXaic (4 Iiefuzie 93 cycliilexi/ciiZefl 78 cycloicXxanl 52 cyc(Iolexaioc 63 cycluhexaune 53 cyciohcxauocliuflc 49) eyclollucxie 48 herizenc 9? cyelohexaic 76 cyclohmm~ae 65 C(-eIhcx~itte .59 nt-hexanc 49 eyclihexanci 54 cyeiollexalic 49) cyclollcxatnc/heizeli 49 cyclohtexm i5 cyclohitexuc 0 n-hcxaine 47 heozene 78 n-Itmosne/cyclohmiuit 62 cycollexuuie 42 n-herine 76 cyclohmilie 6m n-hexanc 42 32 n.Iiexamic/I)I'Lcx;ic sit cyciuhtcxane 49 dicihyl ether cyciollexaiw/ticntic 68 n-hexanc diethtyl ciluer 801 aetontilc 78 74 dicithyl C111cr 48 n-Itcxalic 53 56 ur-iicxiuic/eyclohexanc 60 cyclohexaric/hcrtzefl 8? .II.FN OS (-1,Cl i:N,OS I 1,('I!NP(S (ill CI NOS C".1c IiCNOS FNl()S C Ii FlI,'NOS C jIi,,l2NjOS CIII Ij-N N.OS NF OS C,j 1,,F,N.A)S 1 ,1F,N..)S GY,N 'OS L,,iIN

N)S

C NOS I C.jl, F N,) C, 111 IF,N,() 2007234580 20 Nov 2007 iTale 1.

Ctoiipld. x Y IPlysical and Chemnicatl DZala of MC Compounds (continued) W it' it, it, nI.. o C Recryst. Solvei'l yield Fnrmluhis Z it

N'

N'

IV

1(1129 Nil Me Me C-pentl 1C1167 Nil If 11 Me 1C1168 Nil Me II Me ICI 186 Nil Me it n-prop 4C1185 Nil Mc 1I n-but C(1178 Nil H It Me Me '1190 Nil it M e n-prop 4(1i191 Nil I II Me iso-prop 4(21189 Nil If MC n-hul A1ct 192 NH- it Me Sec-hut AtCI 180 NHl 1I Mc c-hex A1C 170 Nil Me me Me M1CII187 Nil Me Me u-hut M1CI 181 Nil Me MC c-hcx MICI 182 N H H- Me 2 M4CI 183 N If I- Me-piperaz MCI 188 N If 11 morph MCI 193 N it 11 thiownorph MCI 194 N if Hf piperid MCI 196 N II It pyrrolid MC1202 N ii Ii EI, MC1204 N If It (n-prap)2 MCI 195 N Me 11 Me 2 MC1213 N Me If Mc-pipcraz MC12015 N Me If morph MC12016 N Me 11 thioinorph MCI 137 S Me Me iso-prop MCI 175 S Me MC n-hut MICI 153 S Mc Me iso-hut MCI 174 S Me Me c-hex MCI 161 S it Ht MeSMC MC1162 S Me I-1 MeSMC MCI15S7 S Et H Mesme MCI 145 S i-pro H McSMc MCII140 S H Ht MeSMe 1. oil F 202-2(03 F 210-211 F 156-157 F 19J2-193 F 145-146 F oil F oil F oil F oil F o)il F 193-194 IF oil IF oil F 210-211 F 195-196 F 215-216 F 233-234 F 209-210 F 233-234 F 159-160 F 111-112 F 237-238 F 235-236 F 244-245 IF 255-256 F 177-178 F 122-123 F 152-153 F 209-2019 F 159-160 F 183-184 F 153-154 IF 158.5-160 If 117.5-118 accttnitrlC 48 acclinlfitrile 6i2 .icctonitrile 08 ;seetoniLlile 34 45 54 59 62 cycloheacX~ lCCizllhe 34 49 54 cyclollexalc/lIcniZene 88 aiccionitrilc 94 acetonitljic 78 -jcctoititrile 68 accloiitile 52 n-licxanc 32 actonitrile 80 acetrinitrile (15 :icetonitrilc 54 n-lir x~incfcychth xaneI n-Icxasne 51I cyclobeixarne 58 it-hexanc/cyclohexamfl 48 cyclohexanfc/beflzcne 72 cycIohexanfl/hCuzecf 701 cyclohexrrnc 69 cyclohexane 62 n-hexanc 64 C,jIl,,F,N 1 C,,1 12

,F

2 2

N

4 C,,l IIFN,()

C

1 ,H1,,F,N 1 C,lN

C,,

1 2 l 1

C,,

1 1

N

2

OS

C,,

12 1lFNOS CI~l,AFN,O 'All compounds were analyzed for C, N, S, and, when required, Cl and F; analytical results were within of therorelical values.

2007234580 20 Nov 2007 n

R,

R. R Table 2. Cytoitoxicity and ant i-I IlIV- I Activity o)f MC Comlpou nds.

Compd.

MC 507 MC 508 MC 512 MC 531 MC 1114 MC 1103 MC 843 MC 796 IVC 890) MC 892 MC 898 MC 899 MVC 9001 MC 9013 MC806) MC 842 MC 809 MC 817 MC 897 MC 863 MC 854 MC 857 MC 859 MC 881) MC 884 MVC 889 MC 825 MC 960 11 2,5-Mc,-c-licx 4,5-Mc,-c-hcx 3,5-Mc,-c-lhex 2,5-Mc,-c-licx sec-but c-pent bcnzoyloxymcthyl sec-but iso-prop C-pent c-hex iso-prop c-pent c-hex sec-hut.

c-pcnt sec-hut sec-hut sec-hut sec-bitlt sc-but sce-but see-but sec-hut sec-hut sec-hut .sec-b.ut sec-bult If

II

F

F

It It If If 11 Me Me

II

NO,

11

I.'

Cl

F

I.'

N14, 1.1

CCI)EC.

si., Ii

II

II

II

II

II

II

II

11

II

11

II

11

II

It

II

Me

II

I.'

NO,

II

II

('I

II

II

F

II

Nil, 143 58 >2(00 138 130 >200( >200 61 >200) 159 149 20(0 >200 >200( >200 >200 200( >100 157 151 200 116 120 200 >200 >200 >200 >2001 3.5 6.4 30 3.5 25 20 45 >61 .9 .6 .8 1.3 1.9 3.4 0.6 (1.25 0.4(0 1.5 2 (1.26 (0.7 8.7 21.2 23 9 >6-7 39 52 4 >222 333 248 250 >2001 >154 I11 >59 333.3 >800( 392 1(1 200 58 24 769 >286 23 9 8 2007234580 20 Nov 2007 Table 2. Cytotoxicity ind anti-I IIV- I Activity of MC ('onipll.

MC 868 MC 959 MC 952 MC9 957 MC 964 MC: It)41 MC 1t042 MC 877 MC 878 MC 886 MC 885 MC 815 MC 888 MC 891I MC 871 MC 861) MC 872 MC 866 MC 848 MC 867 MC 870 MC 1001 MC 996 MC 1016 MC 1000 MC 1002 MC 10(13 MC 1007 MC 1044 MC 1045 MC 1110 MC 10)8 MC 1013 MC 10)05 MC 1(16 z Ii Ii

II

II

ii

II

II

II

II

II

Et

II

II

It

II

II

Me Mc Mc Me Et Et Et Mc Mc Mc Mc Mc Mc El scc-hu sec-but scc-hut sCC-l)ut scc-lhut sec-but scc-hot Me iso-prop n-but iso-hut scc-hut c-pent c-hcx Me iso-prop n-but iso-hut scc-hut c-pcnt c-hcx iso-prop c-pent c-hcx iso-prop c-pent c-hcx iso-prop iso-but n-hut sec-hut c-pent c-hex iso-prop c-pelll

CF,

II

OMe

II

II

II

II

CI

CI

CI

CI

CI

CI

CI

F

F

F

F

F

1.

F

CI

CI

CI

CI

CI

Cl r

F

F

F

F

1.

II

II

II

OMe If

I:

If

II

II

If if If it

II

II

I I

II

II

II

II

II

I11

II

11

II

11

II

II

II

II

II

II

II

CF,

II

II

O)Me It

II

11

II

11 It

II

II

II

II

II

11 I I

II

II

II

II

II

II

II

II

II

II

Ii

II

II

II

II

[Jim] >200 >21)1 147 133 >2(11) >2)01 >201 >21)0 >200 >21(1 21)1) >2101 162 182 211 2() 117 78.3 >20)) 23.4 >2010 167 >2)1) >20)0 >21)) >21)10 >2(11) 71) 2(0)0

EC'.

32 25 1.96 1.2 14 1.4 11.6 3.2 1.9 11.44 (1.45 0.14 0.4 (0.6 0.81 (1.2 1.18 (1.14 (.04 (1.08 (1.08 1.2 1 .1) 2).9 (1.4 3.6 (1.115 0.115 0.07 (1.03 11.1)3 11.16 (.15 0.2 8 >2(08 >16 >143 222 >62 >1(05 >454 >444 >1,428 >5(10 >333 247 1,000)1 1,3(00 5,0001( >2,51( 2,5(0(0 9)7.5 78.3 >69 >500) 23.4 >55.5 3,34) >4,00011 2,857 >6,666 >6,666 >1,25) 875 1,333 2007234580 20 Nov 2007 Fa I)le 2. Cytolox icily and anti- I I V- I Act ivity of M( Coni"pounuLs tct)flII1uU) Wit, It, R ('oiupd MC 1014 MC 971 MC 972 MC 974 MC 969 MC 973 MC 975 MC 844 MC 845 MC 925 MC 924 MC 909 MC 9)1() MC 911 MC 913 MC 918 MC 9 19 MC 9 12 MC 914 MC 920 MC 9 16 MC 85(0 MC 915 MC 917 MC 869 MC 881 MC 905 MC 921 MC 849 MC 922 MC 923 MC 1(06(0 MC I 109 MC 11047 MC 798

Y

Me Mc Me Me Mc Mc Mc Mc Mc Mc Mc Mc Mc Me Mc Mc Mc Mc Mc Mc Me Me Me Me Me Me Mc Et Mc Mc Mc Et E1 Et Me Mc Me I I c-hlex iso-plop C-pcnt c-h1ex iso-prop C-pCnt C-heCx scc-hut SCC-but smchut scc-hut SCC-h Ut SCe-hut sec-but scc-hut Sce-hul sec-hutl Me iso-prop n-but jso-but scc-bu I c-pcnt c-hcx Me iso-prop n-hut iso-but scc-hut C-pent C-h1Cx Me scc-hut c-pent scc-but I. I I I I CII=CII-CII=CII

I

CI I=CI l-CI.I=CI I I CIi=Cl I-Cl I=CI I I CII=CII-CII=CII

I

CII=CII-CI=CII

I

CII=CIi-CII=CII I I Me I I I I I I I I Mc I I NO, I I I I I1I NO, C1 I I I I I I C1 I I I I I I (I CI~~ I I CI I I C1 I I C1 II CI II C1 1I C1 tI F I I F I-I

FII

F 1I F II F11I F II F III 1301 119 93 45 50 51 16.9 >200 26 >2001 >2001 >2001 >200) 1401 >2001 1115 >2(00 >200Y >2001) >2001 >21001 >21)0 2() >21) >2001 64 80) >2001 >2001 >20( 2(0( >200 >2001 EC;11 1.1 (1.5 (0.14 1.5 3.1) 0.18 1.7 0.8 11.35 1.27 0.96 9.5 10.41 1.2 11 3.2 1.3 1.17 1.2 0.0)5 1.8 22 01.19 0.0)5 01.08 ().1I 0.01) (0.1)8 (1.0)9 0.0)4 (0.1)3 01.0019 I .0 2,6000 1118 186 321.4 33.3 17 94 >118 32 >571 >1100 >741 >218 21) 341 >166 >62 154 >171 >166 >4011)0 >111 >9 1,053 >4,0001( >2,5001 640 8,000 >250)0 >2,222 >5,)11( 6,666 >22,222 >2001 2007234580 20 Nov 2007 Tabk 2. Cytotoxicity and anti-I V- I Activity of MC0Conpounas kcoflh1fucu) C '0iiipd.

MC 10137 MC 1038 MC 804 MC 1039 MC 852 MC 856 MC 834 MC 1119 MC 1078 MC 979 MC 980 MC 1077 MC 945 MC 1043 MC 1022 MC 1049 MC 1048 MC 1118 MC 1130 MC 1050) MC 1105 MC 1129 MC 1167 MC 1168 MC 1186 MC 1185 MC 1178 MC 11901 MC 1191 MC 1189 MC 1192 MC 1 18(0 MC I1170 MC 1187 MC 1181 x s

S

S

S

S

S

S

Nil Nil Nil Nil Nil NHl Nil NIl Nil NIl Nil Nil

NI-!

Nil NI I Nil Nl N 11 Nil N11- NilI Nil Nil Nil Nil

NH

NIH

Nil

Y

Et E t isn-Iprop ally] n-prop n-hut

H

17 I I Me I I Me Mce Mc McI Mc Me Me iso-prop scc-hut sec-hut iso-prop sec-hut sec-but sc-hut cihyl n-prop iso-prop c-prop n-but scc-hut McOcthyl C-c-pet c-hex c-pcnt iso-prop .;ec-but c-pcnt benzyl c-pcnt Mc Mc n-prop n-but Me n-prop iso-prop n-hut scc-b ut c-hex Mc n-but C-hcx W R-1 it, it' 1- II I F I I CII=CII-CII=CII I I F I I I I II I1 II II III F II i F I I F 11 1 F I I I- I I F I I F I I1 F I I F H I F H II F II I F 11 I

I

F I f I F II

I

F HI F II FT II F It I F11I F II F iI F 11 If F 11 11 F if If F 11 If F If 11 65 >200 >200) >200 >200( 190 >2001 >200 2(1) >20)0 >20011 1001 >2(00 >200) >2001 66 75 190 2 >200

S(O

901 >201 135 >2001 >2001 1116 103 115 52 86 56 20 83 58 (1.2 1 5.3 (1.4 3 12 >200) (18 0.11 0.38 3.17 (1.10 (1.13 (1.8 (1.09 (1.14 (0.03 0.03 0.07 0.0)2 0.5(0 01.02 1.5 0.4 (1.02 (0.0)2 0.11 01.02 (0.103 (0.1)3 (0.04 01.02 0.1)3 1 0-013 326 >2(1000 >34 >500( >67 16 >2501 1,818 >526 >63 1,0(1() 1,5401 >250 >2,222 471 2,500 6,333 2,857 110(0(0 1001 4,5001 >133 335 >10,001)0 10,(000 964 5,150 3,830 1,730 2, 150 2,545 >6,666 8,3001 2,231I 2007234580 20 Nov 2007 Table 2. Cytotoxicity and anti-IIIV- I Activity of MC Ccnipounas tconiinucuj R2 R' 11-1 Comipd.

MC 1182 MC 1183 MC 118 MC 1193 MC 1194 MC 1196 MC 1202 MC 1204 MC 1195 MC 12(03 MC 1205 MC 1206 MC 1137 MC 1175 MC 1153 MC 1174 MC 1047+ MC 1047- MC 1161 MC 1162 MC 1157 MC 1145 MC 1140

Y

If If 11 11 Me Me Me Mc Me Me Me Mc iso-prop 1-1 Mc, Mc-piperaz miorph thionior 1 )h piperid pyrrolid (nl-prop) 2 Me, Mc-piperaz niorph thiomorph iso-prop n-hut iso-hLt c-hcx c-pent c-pent WeSW WeSW MeSMe McSMC WeSW >2(00 >200 >2001 >200 >200( >2(00 >20( >20( >2(H) 2(00 112 >2101) >20( >200 >2001 >200 3(0 1 >200( 0.015 7.1 (0.6 0.05 (0.0)2 2.1 (1.26 3.8 (0.02 (1.36 0.047 0.09 0.0017 (0.0(08 (1.0 1 0.018 (0.002 (0.7 0.80) (0.12 (0.11 10 201 >4,000 >28 >333 >4,0(1) 10,(000 >769 >53 10,0001 >555 >4,255 >2,222 28,571 14,000 >2(1,000 11, 111 100,1000 >286 >2501 250 454 2,001) >101 Data represent mean values of at least two separatc experiments. "Compound dose required to reduce (lic viability of mock-infected cells by 50%, as dctcrnlincd by thc MMT method. Compound dosc rcquircd to achieve 501% protection of MT-4 cells froin I [IV- I induced cytopathogcnicity, as determined by the MiT method. Selectivity index, CC s/EC ratio.

Claims (12)

1. A compound of the formula: wherein: X is R is -CH-I, -CHK (wherein K is -C,.,alkyl, -C 3 6 CYCloalkyl -NK (wherein K is 4 alkyl, -C 3 6 CYCloalkyl -aryl, -arylalkyl; -C,.,alkyl (containing one or more of heteroatoms like 0, S, N), -C,.cycloalkyl (containing one or more of heteroatoms like 0, S, -aryl, arylalkyl, heterocycle; Y is Z is R, is R, is R. is -C 1 .alkyl, -C 3 .,cycloalkyl; -C 1 4 al1kyl, halogen, -NO,, (wherein W is -aryl); -C 1 4 ,alkyl, -halogen, -NO,, (wherein W is -aryl); -C, 1 4 alkyl, -halogen, -NO,, (wherein W is -CH 3 -aryl); -C,,alkyl, -halogen, -NO, (wherein W is -aryl); 4 alkyl, -halogen, -NO, -OW (wherein W is -CH 3 -aryl), -SW _OW (wherein W is -CH, -aryl), -SW -OW (wherein W is -CH 3 aryl), -SW -OW (wherein W is -aryl), -SW -OW (wherein W is -aryl), -SW R, is 5 is (wherein W is -aryl), or a pharmaceutically acceptable salt or soluble derivative thereof.

2. A compound having formula A as claimed in claim 1 wherein X=O Y=H Z=H R=sBu R=F R, =H R 3 =H R, =H R 5 F X 0O Y =H Z=H R=cPen R,=F R, =H R-I=H R, =H R~j=F.

3. A compound having formula A as claimed in claim 1 wherein 0 X s x S x S x s X S x S x S x s x S x=S x=S x=s x=S x=S D0 X=S X=S x S x S x S X=S X S x S x s x S X=S x S x S x S x S X S x S x=s X =s Y H Y=H Y H Y H Y=H Y=H Y=H Y H Y H Y=H Y =H Y=H Y=H Y =H Y=H Y H Y H Y H Y H Y H Y=H Y=H Y H Y H Y=H Y=H Y H Y=H Y H- Y=H Y=H Y H Y H Z =H Z H Z=H Z H Z H Z=H Z=H Z H Z H Z= H Z= H Z H Z H Z H Z=H Z =H R sBu R sBu R CH, R ipr R nBu R iBu R =sBu R cPen R cEs R OH 3 R iPr R =nBu R iBu R sBu R cPen R cEs Z OH, R iPr Z OH 3 R cPen Z OH, R cES Z=Et R=iPr Z=Et R=cPen Z=Et R=cEs Z =OH, R i~r Z CH3 R iBu Z CH, R ,zBu Z OH, R sBu Z OH, R cPen Z CH, R cEs Z Et R =iTr Z =Et R =cPen Z =Et R =cEs Z=CH, R= cEs Z =H R =sBu NO:R' H R,=F R, H CI R,.=H R, =CI R, H R, =CI R, H R =OCI R,=H CI R, =H R, =OC H R,=OCI R, =H R, F R, H R, F R, H R 1 =F R, H R, F R H R, F R: H R,=F R, H R,=F R, H R, CI R,=H R,=CI R,=H R, CI R,=H R, CI R, =H R, =CI R, =H R CI R, =H R, F R, H R,=F R,=H R, F R, H R=F R, H R, F R, H RI=F R, H F R, H RI=F R,=H RI=F R, H -OH=CH-OH=CHl R,=Cl R.=H H R H R R R3 H R H F R 3 H R= H R3= H R= H R3= H R 3 H R, H R3 H R 3 =H R3 H R3 H R3= H R3= H R3= H R= H R, H R3 H R3 H R3 H R3 H R3 H R3=H R3= H =H =H =H 4 H k, H Z, H 1, H R, H R4 H R4 H R, H R, H R= H R. H R4 H R. H R, H R, H R, H R= H R= H R, H R, H R= H R,= R,=H R, R.,=H R,=Cl CI C1 R CI R5= CI C1 CI R, F R= F R, F R5 F R= F R, F R, F C1 CI R, F R, F R, F R4 F I R,=F R.=H i R =H 0 zO 00, X=S X=S X=S X=S X=S X=S X=S X=S X=S X=S X=S X=S X=S X=S x=S X=s X=S x=S X=S X=S X=S X=S Y CH.,Z H Y CH 3 Z=H Y=CH 3 Z=H Y CHZ =H Y CHZ H Y CH, Z H Y CH, Z H Y OH,Z H Y CH 3 Z H R sBu R sBu R CH 3 R iPr R nBu R iBu R sBu R cPen R cEs Y CH 3 Z CH 3 R CH 3 Y CH 3 Z CH 3 R sBu Y CH 1 Z CH 3 R cPe Y=Et Z=H R=sBu Y=iPr Z=H R=iPr Y CH 3 Z CH 3 R iPr Y CH 3 Z CH, R nBu Y CH 3 Z CH 3 R iBu Y CH,Z CH, R cEs Y=H Z=H R=MeSMe Y=CH 3 Z=H R=MeSMe Y=Et Z=H R=MeSMe Y iPr Z=H R=MeSMe R,=F R 2 =H R, =CI R,=H R, =F R,=H R,=F R,=H R 1 =F R,=H R=F R,=H R=F R,=H R=F R,=H R,=F R,=H R 1 =F R,=H RI=F R=H R,=F R,=H R=F R,=H R 1 =F R=H R =F R, H R,=F R=H R,=F R,=H R,=F R,=H R,=F R,=H R,=F R, H R,=F R=H R,=F R,=H R,=H R H R3=H 3 H R 3 =H R, HH R= H R 3 =[H R3 H R, H R, H R, H R, H R, H R 3 H R, H R. H R 3 =H R 3 =H R, H R= H R, H R, H R, H HH R, H R 4 =H R, H R 4 =H R4 H R, H R, H R, H R, H Rj H R4 H R4H R, H R, HH R= H R4=H R, H R4 =H R, H R, H C1 R 5 =F R, F RF R= F R, F R, F R, FF R, F R, F R, F R, F R F R, F R, F R, F R, F R, F R 5 =F R, =F R 5 =F R, F.

4. A compound having formula A as claimed in claim I wherein X=NH X=NH X=NH X=NH X=NH X NH X NH X=NH X=NH X=NH X=NH X=NH X=NH Y=H Y=H Y=H Y=H Y=H Y=H Y=H Y=H Y=H Y=H Y CH 3 Y CH 3 Y CH. Z=H Z=H Z=H Z=H Z=H Z=H Z=H Z=H Z=H Z CH 3 Z=H Z=H Z=H R Et R nPr R iPr R cPr R nBu R sBu R=MeOEt R cPe R cEs R cPe R iPr R sBu R cPe R =F RI =F R, F R, FF R, F R, FF R, FF R, FF R, =F R, F R =F R, =H R, =H R, =H R3=H R=H R 3 =H R, =H R 3 =H R, =H R, =H R, H R, H R,=H R 3 =H R, =H R 3 =H R, H R3 =H R, =H R 3 =H R.=H R, =H R=H R3=H R,=H R, =H R, =H R 3 =H R, H R, F R, H R, =H R, H R, H R, H R, H Ra= H R 4 H R, H R, HH R 4 =H R= H R, F RS F R, F R, F R, F R= F R, F R, FF

5= F R= F R 3 F RS F R, F R; FF X=NH Y CH 3 Z=H R benz R, F X: X=NH X=NH X=NH o X=NH Z X=NH X=NH X =NH X=NH 00 X=N X=NH X=NH X~ X=NH X=NH X=NH X=N X=N X=N X=N X=N !0 X=N X=N X=N X N X=N X N X N y CH 3 Y=H Y CH 3 Y CH 3 Y CH 3 Y=H Y=H Y =H Y=H Y=H Y=H Y CH., Y =CH 3 Y CH, Y H Y=H Y=H Y=H Y=H Y=H Y=H Y=H Y CH 3 Y CH 3 Y CH, Y =CH 3 Z CH 3 Z=H Z=H Z=H Z=H Z =CHj Z CH 3 Z CH 3 Z CH 3 Z CH 3 Z CH 3 Z CH 3 Z CH 3 Z CH 3 Z=H Z=H Z=H Z=H Z H- Z=H Z H Z=H Z=H Z =H Z=H Z=H R =cPe R=F R =CH, R= F R =CH 3 R= F R =nPr R 1 =F R =nBu R 1 =F R =CH, R, =F R =nPr R =F R =iPr R 1 =F R =nBu R =F R =sBu R 1 =F R =cEs F R =CH, R=F R =nBu R, =F R =cEs R =F R=(CH 3 R, F R=Me-Pip R, F R= Morph R, =F R=S-morp R= F R= Piper R, F R=Pyrroli R, F R =Et, R, =F R=(nPr). R, F R=(CH 3 2 R, F R=Me-Pip R, F R= Morph R, F R=S-morp R, F R, H R, H R, H R, H R: H- RH R.=H R, H RH R, H R, H RH R, H R, H R, H R. H R, H R, H R, H R, H R3 H R, =H R, H R, =H R, H R3 H R3 H R, H R3 H R3 H R 3 =H H R 3 =H R 3 =H R= H R3 H R3 H R, =H R 3 =H R3 H R3 H R 3 H R4 H R, H R, =H R, =H R, =H R, =H =H =H R, =H R, H R, =H R, =H R= H R, H R4 H H K H R4 H R, H R, H R, H K H R4 H R4 H R. H4 R4 H F R= F R, =F R. F R. F R, F R. F R, =F R, F =F R, =F R, =F R, F R, F R. F R, F R= F R, F R= F R. F R, F R, F R, F R, F. A pharmaceutically acceptable salt or soluble derivative of a compound of claim 1.

6. A process for the preparation of a compound having formula A as claimed in claim 1 wherein X 0, wherein the proper methyl ary lace ty lalkylIacetate is reacted with 0- methylisourea in presence of calcium hydroxide; the so obtained 2-0-methyl(5-alkyl)- 6 benzyl(substituted)uracils are reacted with the proper potassium alk oxide according to scheme A.

7. A process for the preparation of a compound having formula A as claimed in claim 1 wherein X S, wherein the proper ethyl arylacetylalkylacetate is reacted with thiourea in presence of sodium methoxide; the so obtained 5-alkyl-6-benzyl(substituted) 2 '7 7 thiouracils are reacted with methyl iodide or with an alkyl halide in a basic medium according to scheme B. S

8. A process for the preparation of the compounds having formula A as claimed in claim I Z wherein X NK (wherein K is -C,.,alkyl. -Ccycloalkyl), wherein the proper S- O methyl(5-alkyl)-6-benzyl(substituted)-2-thiouracil is reacted with the proper amine according to scheme C. O

9. A method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS, comprising administering to a mammal an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof. .0

10. A pharmaceutical composition useful for inhibiting HIV reverse transcriptase, comprising an effective amount of a compound claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof, and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition useful for preventing or treating infection of HIV or for treating AIDS, comprising an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof, and a pharmaceutically acceptable carrier.

12. A method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS, comprising administering to a mammal an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof in combination with another anti-HIV agent selected from the group consisting of abacavir, zidovudine, BILA 1906, BILA 2185, BM+51.0836: triazoloisoindolinone derivative, BMS 186,318: aminodiol derivative HIV-1 protease inhibitor, d4API, stavudine, efavirenz, HBY097, HEPT, KNI-272, L-697,593, L-735,524, L-697,661, L-FDDC, L- FDOC, nevirapine, foscarnet, PMEA, PMPA, Ro 31-8959, RPI-3121, SC-52151, SC- 55389A, TIBO R82150, TIBO 82913, TSAO-m3T, U90152, UC: thiocarboxanilide derivatives, UC-781, UC-82, VB 11,328, amprenavir, XM 323, delaviridine, famciclovir, gancyclovir, penciclovir, indinavir, nelfinavir, ritonavir, saquinavir, DDI, DDC, Delaviridine, 3-LddA, p-L-3'-azido-d5FC, carbovir, acyclovir, interferon, stavudine, (3'-azido-2',3'-dideoxy-5-methyl-cytidine), 3'-azido nucleosides, p-D-dioxolane nucleosides such as p-D-dioxolanylguanine (DXG), p-D-dioxolanyl-2,6-diaminopurine (DAPD), and 3-D-dioxolanyl-6-chloropurine (ACP), D4T, FTC, 3TC, AZDU, and amprenavir.