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

Abstract

The invention concerns novel substituted 6-benzyl-4-oxopyrimnidines of general formula (A). These compounds inhibit reverse transcriptase encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof, and find their application in the prevention and treatment of HIV infection and the treatment of the resulting acquired immune deficiency syndrome (AIDS). Pharmaceutical compositions containing the compounds and a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV are also envisaged. 1

Description

[0001] 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

[0002] 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.

[0003] 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.

[0004] Compounds of the present invention are dihydro-alkyloxy-benzyl-oxopyrimidines (DABOs) which potently inhibit HIV multiplication targeting reverse transcriptase without bioactivation.

BRIEF DESCRIPTION OF THE INVENTION

[0005] Novel compounds of formula A: 2

[0006] 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

[0007] 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: 3

[0008] wherein:

[0009] X is —O, —CH2, —CHK (wherein K is —H, —C1-4, alkyl, —C3-6Cycloalkyl), —S, —NK (wherein K is —H, —Cl1-4alkyl, —C3-6cycloalkyl), -aryl, -arylalkyl;

[0010] R is —H, —C1-4alkyl (containing one or more of heteroatoms like O, S, N), —C3-6cycloalkyl (containing one or more of heteroatoms like O, S, N), -aryl, -arylakl, heterocycle;

[0011] Y is —H, —C1-4alkyl, —C3-6cycloalkyl;

[0012] Z is —H, —C1-4alkyl, —C3-6cycloalkyl;

[0013] R1 is —H, —C1-4alkyl, -halogen, —NO2, —OW (wherein W is —H, —CH3, -aryl), —SW (wherein W is —H, —CH3, -aryl);

[0014] R2 is —H, —C1-4alkyl, -halogen, —NO2, (wherein W is —H, —CH3, -aryl); —SW (wherein W is —H, —CH3, -aryl);

[0015] R3 is —H, —C1-4alkyl, -halogen, —NO2, —OW (wherein W is —H, —CH3, -aryl); —SW (wherein W is —H, —CH3, -aryl)

[0016] R4 is —H, —C1-4alkyl, -halogen, —NO2, —OW (wherein W is —H, —CH3, -aryl); —SW (wherein W is —H, —CH3, -aryl)

[0017] R5 is —H, —C1-4alkyl, -halogen, —NO2, —OW (wherein W is —H, —CH3, -aryl), —SW (wherein W is —H, —CH3, -aryl);

[0018] pharmaceutically acceptable salts or soluble derivatives thereof;

[0019] preparation process of derivatives thereof;

[0020] 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;

[0021] a pharmaceutical composition useful for inhibiting HIV reverse transcriptase, comprising an effective amount of compounds claimed, and a pharmaceutically acceptable carrier;

[0022] a pharmaceutical composition useful for preventing or treating infection of HIV or for treating AIDS, comprising an effective amount of compounds claimed, and a pharmaceutically acceptable carrier.

[0023] The most preferred compounds of this invention are those of table 1.

[0024] The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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, O 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 above-defined 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.

[0029] The pharmaceutically-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 compounds, which are formed, e.g.; from inorganic or organic acids or bases.

[0030] In preferred embodiments, a compound of the present invention is administered in combination or alternation with AZT, D4T, FTC (2′,3′-dideoxy-3′-thia-5-fluorocytidine); 3TC (Epivir, Glaxo Wellcome, Inc.), AZDU (3′-Azido-2′,3′-dideoxyuridine); 141W94 (amprenavir. GlaxoWellcome, Inc.); Viramune (nevirapine), Rescriptor (delavirdine); or DMP-266 (efavirenz). Other examples of antiviral agents that can be used in combination or alternation with the compounds disclosed herein for HIV therapy include DDI, DDC, Delaviridine, &bgr;-LddA, &bgr;-L-3′-azido-d5FC, carbovir, acyclovir, interferon, stavudine, CS-92 (3′-azido-2′,3′-dideoxy-5-methyl-cytidine), 3′-azido nucleosides, and &bgr;-D-dioxolane nucleosides such as &bgr;-D-dioxolanylguanine (DXG), &bgr;-D-dioxolanyl-2,6-diaminopurine (DAPD), and &bgr;-D-dioxolanyl-6-chloropurine (ACP).

[0031] Preferred protease inhibitors include indinavir ({1(1,S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erythro-pentoamide sulfate; Merck), nelfinavir (Agouron), ritonavir (Abbot), and saquinavir (Invirase; Roche).

[0032] Nonlimiting examples of other compounds that can be administered in combination or alternation with the compounds of the present invention to augment the properties of the drug on administration include abacavir: (1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate (1592U89, a carbovir analog; Glaxo Wellcome); zidovudine: AZT, 3′-azido-3′-deoxythymidine (Glaxo Wellcome); BILA 1906: N-{1S-[[[3[2S-{(1,1-dimethylethylamino]carbonyl}-4R-]3-pyridinylmethyl)thio]-1-piperidinyl]-2-R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl}-2-quinolinecarboxamide (Bio Mega/Boehringer-Ingelheim); BILA 2185: N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethylphenoxy)-1-oxoethyl]amino]-2R-hydroxy-4-phenylbutyl]4R-pyridinylthio)-2-piperidinecarboxamide (Bio Mega/Boehringer-Ingelheim); BM+51.0836:triazoloisoindolinone derivative; BMS 186,318: aminodiol derivative HIV-1 protease inhibitor (Bristol-Myers-Squibb); d4API: 9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanel]adenine (Gilead); stavudine: d4T, 2′,3′-didehydro-3′-deoxythymidine (Bristol-MyersSquibb); efavirenz: DMP-266, a 1,4-dihydro-2H-3, 1-benzoxazin-2-one; HBY097: S-4-isopropoxycarbonyl -6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione; HEPT: 1-[(2-hydroxyethoxy)methyl]6-(phenylthio)thymine; KNI-272: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid-containing tripeptide; L-697,593; 5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2-(1H)-one; L-735,524: hydroxy-aminopentane amide HIV-1 protease inhibitor (Merck); L-697,661: 3-{[(-4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2-(1H)-one; L-FDDC: (−)-&bgr;-L-5-fluoro-2′,3′-dideoxycytidine; L-FDOC: (−)-p-L-5-fluoro-dioxolane cytosine; 6-benzyl-1-ethoxymethyl-5-isopropyluracil (1-EBU; Triangle/Mitsubishi); nevirapine: 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridol[3,2-b:2′,3′-e]diazepin-6-one (Boehringer-Ingelheim); PFA: phosphonoformate (foscarnet; Astra); PMEA: 9-(2-phosphonylmethoxyethyl) adenine (Gilead); PMPA: (R)-9-(2-phosphonyl-methoxypropyl)adenine (Gilead); Ro 31-8959: hydroxythethylamine derivative HIV-1 protease inhibitor (Roche); RPI-3121: peptidyl protease inhibitor, 1-[(3s)-3-(n-alpha-benzyloxycarbonyl)-1-asparginyl)-amino-2-hydroxy-4-phenylbutyryl]-n-tert-butyl-1-proline amide; 2720: 6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4-dihydro-quinoxalin-2-(1H)thione; SC-52151: hydroxyethylurea isostere protease inhibitor (Searle); SC-55389A: hydroxyethyl-urea isostere protease inhibitor (Searle); TIBO R82150: (+)-(SS)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]-benzodiazepin-2-(1H)-thione (Janssen); TIBO 82913: (+)-(5S)4,5,6,7,-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1jk][1,4]benzodiazepin-2-(1H)-thione (Janssen); TSAO-m3T:[2′,5′-bis-O-(tertbutyldimethylsilyl)3′-spiro-5′-(4′-amino-1′,2′-oxathiole-2′,2′-dioxide)]-&bgr;-D-pentofuranosyl-N3-methylthymine; U90152: 1-[3-[(1-methylethyl)-amino]2-pyridinyl]4-[[5[(methylsulphonyl)-amino]-1H-indol-2-yl]carbonyl]piperazine; UC: thiocarboxanilide derivatives (Uniroyal); UC-781=N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide; UC-82=N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-thiophenecarbothioamide; VB 11,328: hydroxyethylsulphonamide protease inhibitor (Vertex); VX478: amprenavir, 141W94, hydroxyethylsulphonamide protease inhibitor (Vertex/Glaxo Wellcome); XM 323: cyclic urea protease inhibitor (Dupont Merck), delaviridine (Pharmacia Upjohn), famciclovir, gancyclovir, and penciclovir. In another embodiment, a compound of the present invention is administered in combination with LG1350, which has the following structure. 4 5

[0033] Anhydrous pyridine (400 mmoles, 32.5 ml) was added with stirring under nitrogen atmosphere 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 was treated, over a 2 h period at 0° C. under nitrogen atmosphere, with a solution of crude arylacetyl chloride in anhydrous dichloromethane (50 ml). Arylacetyl chloride was prepared 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 temperature, poured into crushed ice and treated with 2N HCl (100 ml). The organic layer was separated and the aqueous solution was extracted twice with dichloromethane (25 ml). 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 refluxed 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 (3×100 ml). The organic layer was washed with brine (2×100 ml), dried and evaporated to give the desired compound, which was purified by passing through a silica gel column (chloroform as eluent).

[0034] In the above reaction, arylacetic acid (Scheme “A”) or arylacetyl chloride can be replaced with the corresponding 1-arylacetylimidazolide (Scheme “B”) 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.

[0035] Preparation of Compounds (I) with X═O (Scheme A).

[0036] 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 (3×50 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-methoxypyrimidin-4-one. 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 atmosphere until starting material disappeared at the TLC control. After cooling, the mixture was concentrated, made acid (pH 5) with 0.5N acetic acid and extracted with ethyl acetate (3×50 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 derivative, which was recrystallized from a suitable solvent or purified by column chromatography (silica gel; ethyl acetate:chloroform 1:1). Physical and chemical data of representative compounds of the invention are reported in table 1; cytotoxicity and anti-HIV-1 activity data are reported in table 2. 6

[0037] 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.

[0038] 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 (3×50 ml). The organic layers were collected, washed with a sodium thiosulfate solution (100 ml), brine (3×50 ml), dried and evaporated to furnish the crude 5-alkyl-6-benzyl-3,4-dihydro-2-methylthiopyrimidin-4 one (2) as a solid purified by crystallization.

[0039] Alternatively, according to methods B and C, potassium carbonate (4.2 mmoles) and the proper alkyl halide (4.4 mmoles) were added to a suspension containing 2-thiouracil derivative (4 mmoles) in anhydrous N,N-dimethylformamide (2 ml). The resulting mixture was stirred at room temperature (method B) or at 80° 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 (3×50 ml). The organic layers were collected, washed with a sodium thiosulfate solution (100 ml), brine (100 ml), dried and evaporated to furnish 5-alkyl-6-benzyl-3,4-dihydro-2-methylthiopyrimidin-4-ones (3) and (4) 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. 7

[0040] Title derivatives were prepared according to the procedure described for the synthesis of compounds with X═S (I), using ethyl arylacetylalkylacetates and guanidine [2-amino-6-benzylpyrimidin-4-ones (5)] as starting materials. 2-Alkylaminoderivatives (6) were synthesized by heating the previously reported 5-alkyl-6-benzyl-3,4-dihydro-2-methylthio 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 (6) are reported in table 1. Cytotoxicity and anti-HIVI activity in vitro are reported in table 2. The compounds of the present invention are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is 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, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.

[0041] 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 compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antiviral to HIV reverse transcriptase e.g., 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 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.

[0042] When administered orally as a suspension, these compositions are prepared according 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 agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

[0043] 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.

[0044] The injectable solutions or suspensions may be formulated according to known art, using suitable non toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0045] 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.

[0046] 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 excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0047] The present invention is also directed to combinations of the HIV reverse transcriptase inhibitor compounds with one or more agents useful in the treatment of AIDS. The D 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 inhibitors. When used in a combination treatment with compounds of the instant invention, dosage levels of HIV protease inhibitors of the order of 1 to 25 or 50 grams-per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five time higher. For example, infection by HIV is effectively treated by the administration of from 5 to 25 milligrams of the HIV protease inhibitor per kilogram of body weight from one to three times per day.

[0048] 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 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 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.

[0049] Antiviral Assay Procedures

[0050] Compounds. Compounds were solubilized in DMSO at 200 mM and then diluted into culture medium.

[0051] Cells and viruses. MT-4, C8166, H9/IIIB and CEM cells were grown at 37° C. in a 5% CO2 atmosphere in RPMI 1640 medium, supplemented with 10% fetal calf serum (FCS), 100 IU/mL penicillin and 100 &mgr;g/mL streptomycin. Cell cultures were checked periodically for the absence of mycoplasma contamination with a MycoTect Kit (Gibco). Human immunodeficiency virus type-1 (HIV-1, IIIB strain) was obtained from supernatants of persistently infected H9/IIIB cells. HIV-1 stock solution had a titres of 4.5×106 50% cell culture infectious dose (CCID50)/ml.

[0052] HIV titration. Titration of HIV was performed in C8166 cells by the standard limiting dilution method (dilution 1:2, four replica wells per dilution) in 96-well plates. The infectious virus titre was determined by light microscope scoring of cytopathicity after 4 days of incubation and the virus titres were expressed as CCID50/mL.

[0053] 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 C8166 cells, respectively. Briefly, 50 &mgr;L of culture medium containing 1×104 cells were added to each well of flat-bottom microtiter trays containing 50 &mgr;l of culture medium with or without various concentrations of the test compounds. Then 20 &mgr;L of an HIV suspension containing 100 CCID50 were added. After a 4-day incubation at 37° C., 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.

[0054] RT assays. Assays were performed as follows. Briefly, purified rRT was assayed for its RNA-dependent polymerase-associated activity in a 50 &mgr;L volume containing: 50 mM TrisHCl (pH 7.8), 80 mM KCII, 6 mM MgC12, 1 mM DTT. 0.1 mg/mL BSA, 0.3 OD260 unit/mL template:primer [poly(rC)-oligo(dG)12-18] and 10 &mgr;M [3H]dGTP (1 Ci/mmol). After incubation for 30 min at 37° C., the samples were spotted on glass fiber filters (Whatman GF/A), and the acid-insoluble radioactivity was determined.

EXAMPLES

[0055] 2-Cyclopentylthio-6-(2,6-difluorophenylmethyl)-3,4-dihydrogyrimidin-4-(3H)-one (MC867).

[0056] 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 B), 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 (3×50 mL). The organic layers were collected, washed with brine (3×50 mL), dried and evaporated to furnish crude MC867, which was purified by chromatography on silica gel column (eluent: n-hexane/ethyl acetate/methanol 12/3/1).

[0057] Yield (%): 45; mp (CC): 168-169; recrystallization solvent: cyclohexane; formula (molecula-weight): C16H16F2N2OS (322.37).

[0058] 2-Cyclopenlylthio-6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methylpyrimidin-4-(3H)-one (MC922).

[0059] The synthesis of MC922 was accomplished according to the above reported procedure starting from 6-(2,6-difluorophenylmethyl)-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin-4-(3H)-one (see scheme B).

[0060] Yield (%): 54; mp (° C.): 192-193; recrystallization solvent: cyclohexane; formula (molecular weight): C17H18F2N2OS (336.40).

[0061] 2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydropyrimidin-4-(3H-one (MC1008)

[0062] The synthesis of MC1008 was accomplished according to the above reported procedure starting from 6-[1-(2,6-difluorophenyl)ethyl]-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one (see scheme B).

[0063] Yield (%): 54; mp (° C.): 165.5-166.5; recrystallization solvent: cyclohexane; formula (molecular weight): C17H18F2N2OS (336.40).

[0064] 2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin4(3H-one (MC1047)

[0065] The synthesis of MC1047 was accomplished according to the above reported procedure, starting from 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one (see scheme B).

[0066] Yield (%): 60; mp (° C.): 196-197; recrystallization solvent: cyclohexane; formula (molecular weight): CH18F2N2OS (350.43).

[0067] 6-(2,6-DifluoroPhenylmethyl)-3,4-dihydro-2-(methylthiomethylthiopyrimidin-4-(3H)-one (MC1161)

[0068] The synthesis of MC1161 was accomplished according to the above reported procedures, starting from 6-(2,6-difluorophenylmethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one (see scheme B) and chloromethyl methyl sulfide.

[0069] Yield (%): 72; mp (° C.): 159-160; recrystallization solvent: benzene/cyclohexane; formula (molecular weight): C13H12F2N2OS, (314.37).

[0070] 6-(2,6-Difluorophenylmethyl)-3,4-dihydro-5-methyl-2-(methylthiomethyl)thiopyrimidin-4(3H)-one (MC1162).

[0071] The synthesis of MC1162 was accomplished according to the above reported procedure, starting from 6-(2,6-difluorophenylmethyl)-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin 4(3H)-one (see scheme B) and chloromethyl methyl sulfide.

[0072] Yield (%): 70; mp (° C.): 183-184; recrystallization solvent: benzene/cyclohexane; formula (molecular weight): C14H14F2N2OS, (328.39).

[0073] 6-(2,6-Difluorophenylmethyl)-3,4-dihydro-5-(1-methylethyl)-2-(methylthiomethyl) thiopyrimidin-4-(3H)-one MC1145).

[0074] The synthesis of MC1145 was accomplished according to the above reported procedure, starting from 6-(2,6-difluorophenylmethyl)-5-(1-methylethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one (see scheme B) and chloromethyl methyl sulfide.

[0075] Yield (%): 62; mp (° C.): 158.5-160; recrystallization solvent: cyclohexane; formula (molecular weight): C16H18F2N2OS2 (356.45).

[0076] 2-Cyclopenltylamino-6-(2,6-difluorophenylmethyl)-3,4-dihydropyrimidin-4-(3H)-one (MC1022).

[0077] Cyclopentylamine (10 mL) was heated while stirring with 6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4-(3H)-one (0.30 g, 1.12 mmol; prepared as reported in scheme B or C) in a sealed tube at 160° C. for 10 h. After cooling, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected, washed with brine (3×50 mL), dried and evaporated to furnish crude MC1022, which was purified by chromatography on silica get column (eluent: ethyl acetate/chloroform 1/1).

[0078] Yield (%): 74; mp (° C.):—(oil); formula (molecular weight): C16H17F2N3O (305.33).

[0079] 2-Cyclopentylamino-6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methylpyrimidin-4-(3H-one (MC1050).

[0080] The synthesis of MC1050 was accomplished according to the above reported procedure, starting from 6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidirin-4(3H)-one (see scheme B or C).

[0081] Yield (%): 60: mp (° C.): 115-117; recrystallization solvent: n-hexane/cyclohexane; formula (molecular weight): C17H19F2N3O (319.35).

[0082] 2-Cyclopentylamino-6-[1-(2,6-difluorophenylethyl]-3,4-dihydropyrimidin-4-(3H-one (MC1048).

[0083] The synthesis of MC1048 was accomplished according to the above reported procedure, starting from 6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one (see scheme B or C).

[0084] Yield (%): 48; mp (° C.):—(oil); formula (molecular weight) C17H19F2N3O (319.35).

[0085] 2-Cyclopentylamino-6-[1-(2,6-difluorophenylethyl]-3,4-dihydro-5-methylpyrimidin-4-(3H)one (MC1129)

[0086] The synthesis of MC1129 was accomplished according to the above reported procedure, starting from 6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4(3H)-one (see scheme B or C).

[0087] Yield (%): 38; mp (° C.):—(oil); formula (molecular weight): C18H21F2N3O (333.38).

[0088] 6-(2,6-Difluorophenylmethyl)-3,4-dihydro-2-(4-thiomorpholin-1-yl)pyrimidin-4-(3H)-one (MCI 193).

[0089] The synthesis of MC1193 was accomplished according to the above reported procedure, starting from thiomorpholine and 6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one (see scheme B or C).

[0090] Yield (%): 78; mp (° C.): 233-234; recrystallization solvent: acetonitrile; formula (molecular weight): C15H16F2N3OS (323.36).

[0091] 6-(2,6-Difluorophenylmethyl)-3,4-dihydro-2-N,N-dimethylaminopyrimidin-4-(3H)-one (MCI 182).

[0092] To a stirred solution of sodium metal (0.14 g, 6.3 mg-atoms) in absolute ethanol (50 mL) 1,1-dimethylguanidine sulfate (1.17 g, 4.3 mmol) and ethyl 4-(2,6-difluorophenyl)acetylacetate (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 residue was dissolved in water (200 mL) and made acid (pH 5) with 0.5N acetic acid. The 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).

[0093] Yield (%): 88; mp (° C.): 210-211; recrystallization solvent: benzene/cyclohexane; formula (molecular weight): C13H13F2N3O (265.26). 1 TABLE 1 Physical and Chemical Data of MC Compounds 8 Compd X Y Z R R1 R2 R3 R4 R5 m.p., ° C. Recryst. Solvent % yield Formulaa MC 507 O H H 2,5-Me2-c-hex H H H H H 130-132 Petrol. Ether/diethyl ether 22 C19H24N2O2 MC 508 O H H 4,5-Me2-c-hex H H H H H 132-134 Petrol. Ether/diethyl ether 28 C19H24N2O2 MC 512 O H H 3,5-Me2-c-hex H H H H H 178-181 Petrol. Ether/diethyl ether 12 C19H24N2O2 MC 531 O Me H 2,5-Me2-c-hex H H H H H 196-198 Petrol. Ether/diethyl ether 18 C20H26N2O2 MC 1114 O H H Sec-but F H H H F 87-88 Petrol. Ether/diethyl ether 28 C15H26F2N2O2 MC 1103 O H H c-pent F H H H F 183.5-184.5 Benzene 52 C16H18F2N2O2 MC 843 S H H benzyloxymeth H H H H H 181-183 Cyclohexane/benzene 38 C19H18N2O2S MC 796 S H Ph Sec-but H H H H H 157-158 n-hexane/cyclohexane 78 C24H22N2OS MC 890 S H Me iso-prop H H H H H 118-119 n-hexane 88 C15H18N2OS MC 892 S H Me c-pent H H H H H 95-96 n-hexane 65 C17H21N2OS MC 898 S H Me c-hex H H H H H 142-143 n-hexane 59 C18H22N2OS MC 899 S H Et Iso-prop H H H H H 144-145 Cyclohexane 85 C16H19N2OS MC 900 S H Et c-pent H H H H H 168-169 Cyclohexane 69 C18H22N2OS MC 903 S H Et c-hex H H H H H 175.5-176.5 Cyclohexane 60 C19H24N2OS MC 806 S H H Sec-but Me H H H H 118-119 n-hexane/cyclohexane 67 C18H20N2OS MC 842 S H H c-pent Me H H H H 142-144 Cyclohexane 61 C17H20N2OS MC 809 S H H Sec-but H H Me H H 107.5-108.5 n-hexane 56 C16H20N2OS MC 817 S H H Sec-but NO2 H H H H 148.0-148.5 Cyclohexane/benzene 68 C15H17N3O3S MC 897 S H H Sec-but H NO2 H H H 127-128 Cyclohexane/benzene 54 C15H17N3O3S MC 863 S H H Sec-but H H NO2 H H 128-130 Petrol. Ether/diethyl ether 100 C15H17N3O3S MC 854 S H H Sec-but Cl H H H H 120-121 n-hexane/cyclohexane 58 C15H17N3O3S MC 857 S H H Sec-but H Cl H H H 98-99 Cyclohexane 92 C15H17N3O3S MC 859 S H H Sec-but H H Cl H H 125-126 Cyclohexane 74 C13H17ClN2OS MC 880 S H H Sec-but F H H H H 106-107 n-hexane/cyclohexane 68 C15H17ClN2OS MC 884 S H H Sec-but H F H H H 96-97 Cyclohexane 67 C15H17FN2OS MC 889 S H H Sec-but H H F H H 98-99 n-hexane 94 C15H17FN2OS MC 825 S H H Sec-but NH2 H H H H 143-144 Cyclohexane/benzene 74 C15H19N3OS MC 960 S H H Sec-but H H NH2 H H 128-130 Cyclohexane 77 C15H19N3OS MC 868 S H H Sec-but CF3 H H H H 125-126 Cyclohexane 89 C16H17F3N2OS MC 950 S H H Sec-but H H CF3 H H 144-145 Cyclohexane 75 C16H17F3N2OS MC 952 S H H Sec-but OMe H H H H 123-124 Cyclohexane 69 C16H20N2O2S MC 957 S H H Sec-but H OMe H H H 78-80 n-hexane/Cyclohexane 71 C16H20N2O2S MC 964 S H H Sec-but H H OMe H H 112-113 Cyclohexane 63 C16H20N2O2S MC 1041 S H H Sec-but H F H H H 122-123 Cyclohexane 68 C15H16F2N2OS MC 1042 S H H Sec-but H Me H H H 119-120 n-hexane 72 C17H22N2OS MC 877 S H H Me Cl H H H Cl 237-238 benzene 98 C12H14Cl2N2OS MC 878 S H H iso-prop Cl H H H Cl 230-231 benzene 81 C14H14Cl2N2OS MC 856 S H H n-but Cl H H H Cl 153-154 cyclohexane 62 C15H16Cl2N2OS MC 885 S H H iso-but Cl H H H Cl 143.5-144.5 cyclohexane 56 C15H16Cl2N2OS MC 815 S H H sec-but Cl H H H Cl 183-184 cyclohexane/benzene 55 C15H16Cl2N2OS MC 888 S H H c-pent Cl H H H Cl 185-186 cyclohexane 54 C16H16Cl2N2OS MC 891 S H H c-hex Cl H H H Cl 200-201 cyclohexane/benzene 49 C17H18Cl2N2OS MC 871 S H H Me F H H H F 197-198 benzene 95 C12H20F2N2OS MC 860 S H H iso-prop F H H H F 174-175 cyclohexane 74 C14H14F2N2OS MC 872 S H H n-but F H H H F 126-127 cyclohexane 46 C15H16F2N2OS MC 866 S H H iso-but F H H H F 136-137 cyclohexane 49 C15H16F2N2OS MC 848 S H H sec-but F H H H F 149-150 n-hexane/cyclohexane 48 C15H16F2N2OS MC 867 S H H c-pent F H H H F 168-169 cyclohexane 45 C16H16FN2OS MC 870 S H H c-hex F H H H F 164-165 cyclohexane 40 C17H18F2N2OS MC 1001 S H Me iso-prop Cl H H H Cl   196-196.5 cyclohexane/benzene 52 C15H16Cl2N2OS MC 996 S H Me c-pent Cl H H H Cl 181-182 cyclohexane 45 C17H18Cl2N2OS MC 1016 S H Me c-hex Cl H H H Cl 211-212 cyclohexane/benzene 42 C18H20Cl2N2OS MC 1000 S H Et iso-prop Cl H H H Cl 166-168 diethyl ether 54 C16H18Cl2N2OS MC 1002 S H Et c-pent Cl H H H Cl 168-169 diethyl ether 40 C18H20Cl2N2OS MC 1003 S H Et c-hex Cl H H H Cl 198-199 cyclohexane 41 C19H22Cl2N2OS MC 1007 S H Me iso-prop F H H H F 155-156 cyclohexane 53 C15H16F2N2OS MC 1044 S H Me iso-but F H H H F 159-160 cyclohexane 49 C16H16F2N2OS MC 1045 S H Me n-but F H H H F 149-150 cyclohexane 58 C16H16F2N2OS MC 1110 S H Me sec-but F H H H F 133-134 n-hexane 75 C16H16F2N2OS MC 1008 S H Me c-pent F H H H F 165.5-166.5 cyclohexane 60 C17H18F2N2OS MC 1013 S H Me c-hex F H H H F 206-207 benzene 44 C18H20F2N2OS MC 1005 S H Et iso-prop F H H H F 149-150 cyclohexane 40 C16H18F2N2OS MC 1006 S H Et c-pent F H H H F 141-143 cyclohexane 45 C16H20F2N2OS MC 1014 S H Et c-pent F H H H F 154-155 cyclohexane 51 C19H22F2N2OS MC 971 S H Me iso-prop CH═CH— H H H 161-162 n-hexane/cyclohexane 58 C19H20N2OS CH═CH MC 972 S H Me c-pent CH═CH— H H H 140-141 n-hexane/cyclohexane 49 C21H22N2OS CH═CH MC 974 S H Me c-hex CH═CH— H H H 177-178 n-hexane 45 C22H24N2OS CH═CH MC 969 S H Et iso-prop CH═CH— H H H 163-164 cyclohexane 54 C20H22N2OS CH═CH MC 973 S H Et c-pent CH═CH— H H H oil — 48 C22H24N2OS CH═CH MC 975 S H Et c-hex CH═CH— H H H 126-127 n-hexane 41 C23H26N2OS MC 844 S Me H sec-but Me H H H H 177-178 cyclohexane 55 C17H22N2OS MC 845 S Me H sec-but H H Me H H 127-128 n-hexane 61 C17H22N2OS MC 925 S Me H sec-but H NO2 H H H 163-164 cyclohexane/benzene 88 C16H19N3O3S MC 924 S Me H sec-but H H NO2 H H 178-180 cyclohexane/benzene 100 C16H19N3O3S MC 909 S Me H sec-but Cl H H H H 170-171 cyclohexane 68 C16H19ClN2OS MC 910 S Me H sec-but H Cl H H H 145-146 cyclohexane 75 C16H19ClN2OS MC 911 S Me H sec-but H H Cl H H 163-165 cyclohexane 79 C16H19ClN2OS MC 913 S Me H sec-but F H H H H 120.5-121.5 cyclohexane 65 C16H19FN2OS MC 918 S Me H sec-but H F F H H 146-147 cyclohexane 72 C16H16FN2OS MC 919 S Me H sec-but H H H H H 154-155 cyclohexane 69 C26H29FN2OS MC 912 S Me H Me Cl H H H Cl 206-261 benzene 93 C30H42Cl2N2OS MC 914 S Me H iso-prop Cl H H H Cl 241-242 cyclohexane/benzene 78 C25H26Cl2N2OS MC 920 S Me H n-but Cl H H H Cl 179-180 cyclohexane 52 C16H19Cl2N2OS MC 916 S Me H iso-but Cl H H H Cl 208-209 cyclohexane 63 C26H28Cl2N2OS MC 850 S Me H sec-but Cl H H H Cl 204-205 cyclohexane 53 C16H19Cl2N2OS MC 915 S Me H c-pent Cl H H H Cl 252-253 cyclohexane/benzene 49 C17H18Cl2N2OS MC 917 S Me H c-hex Cl H H H Cl 237-238 cyclohexane 48 C16H19Cl2N2OS MC 869 S Me H Me F H H H F 218.5-219.5 benzene 92 C13H12F2N2OS MC 881 S Me H iso-prop F H H H F 164-165 cyclohexane 76 C15H26F2N2OS MC 905 S Me H n-but F H H H F 178-179 cyclohexane 65 C16H18F2N2OS MC 921 S Me H iso-but F H H H F 161-162 cyclohexane 59 C16H18F2N2OS MC 849 S Me H sec-but F H H H F 128-129 n-hexane 49 C16H18F2N2OS MC 922 S Me H c-pent F H H H F 192-193 cyclohexane 54 C17H18F2N2OS MC 923 S Me H c-hex F H H H F 191-192 cyclohexane 49 C18H20F2N2OS MC 1060 S Me Me Me F H H H F 202-203 cyclohexane/benzene 49 C14H14F2N2OS MC 1109 S Me Me sec-but F H H H F 135-136 cyclohexane 55 C17H20F2N2OS MC 1047 S Me Me c-pent F H H H F 196-197 cyclohexane 60 C18H20F2N2OS MC 798 S Et H sec-but H H H H H 140-141 n-hexane 47 C17H22N2OS MC 1037 S Et H iso-prop F H H H F 174-175 benzene 78 C16H18F2N2OS MC 1038 S Et H sec-but F H H H F 150-151 n-hexane/cyclohexane 82 C17H20F2N2OS MC 804 S Et H sec-but CH═CH— H H H 198.5-199.5 cyclohexane 42 C21H24N2OS CH═CH MC 1039 S i-pro H iso-prop F H H H F 167-168 n-hexane 76 C17H20F2N2OS MC 852 S allyl H sec-but H H H H H 127.5-128.5 cyclohexane 68 C16H22N2OS MC 856 S n-pro H sec-but H H H H H 108-109 n-hexane 42 C18H24N2OS MC 834 S n-but H sec-but H H H H H oil — 32 C19H29N2OS MC 1119 NH H H ethyl F H H H F 138-140 n-hexane/cyclohexane 50 C13H13F2N2O MC 1078 NH H H n-prop F H H H F 136-137 cyclohexane 49 C15H15F2N2O MC 979 NH H H iso-prop F H H H F 150-151 diethyl ether 58 C14H15F2N2O MC 980 NH H H c-prop F H H H F 183-184 cyclohexane/benzene 68 C14H13F2N3O MC 1077 NH H H n-but F H H H F 130-131 n-hexane 60 C15H17F2N3O MC 945 NH H H sec-but F H H H F 140-141 diethyl ether 80 C15H17F2N3O MC 1043 NH H H MeOethyl F H H H F 120-121 acetonitrile 78 C14H15F2N3O2 MC 1022 NH H H c-pent F H H H F oil — 74 C16H17F2N2O MC 1049 NH H H c-hex F H H H F 143-144 diethyl ether 45 C17H19F2N2O MC 1048 NH H Me c-pent F H H H F oil — 48 C17FH19F2N3O MC 1118 NH Me H iso-prop F H H H F 165-166 n-hexane 53 C15H17F2N2O MC 1130 NH Me H sec-but F H H H F oil — 56 C16H19F2N3O MC 1050 NH Me H c-pent F H H H F 115-117 n-hexane/cyclohexane 60 C17H19F2N2O MC 1105 NH Me H benzyl F H H H F 182-183 cyclohexane/benzene 82 C19H17F2N3O MC 1129 NH Me Me c-pent F H H H F oil — 38 C16H21F2N2O MC 1167 NH H H Me F H H H F 202-203 acetonitrile 39 C12H14F2N2O MC 1168 NH Me H Me F H H H F 210-211 acetonitrile 48 C13H13F2N2O MC 1186 NH Me H n-prop F H H H F 156-157 acetonitrile 62 C15H17F2N3O MC 1185 NH Me H n-but F H H H F 192-193 acetonitrile 68 C16H19F2N3O MC 1178 NH H Me Me F H H H F 145-146 acetonitrile 34 C13H13F2N3O MC 1190 NH H Me n-prop F H H H F oil — 45 C15H17F2N3O MC 1191 NH H Me iso-prop F H H H F oil — 54 C15H17F2N3O MC 1189 NH H Me n-but F H H H F oil — 55 C16H19F2N2O MC 1192 NH H Me sec-but F H H H F oil — 59 C16H19F2N2O MC 1180 NH H Me c-hex F H H H F oil — 62 C18H21F2N3O MC 1170 NH Me Me Me F H H H F 193-194 cyclohexane/benzene 34 C14H15F2N3O MC 1187 NH Me Me n-but F H H H F oil — 49 C17H21F2N2O MC 1181 NH Me Me c-hex F H H H F oil — 54 C19H22F2N3O MC 1182 N H H Me2 F H H H F 210-211 cyclohexane/benzene 88 C13H15F2N2O MC 1183 N H H Me-piperaz F H H H F 195-196 acetonitrile 84 C16H18F2N4O MC 1188 N H H morph F H H H F 215-216 acetonitrile 75 C15H15F2N3O2 MC 1193 N H H thiomorph F H H H F 233-234 acetonitrile 78 C15H15F2N2OS MC 1194 N H H piperid F H H H F 209-210 acetontrile 68 C16H17F2N3O MC 1196 N H H pyrrolid F H H H F 233-234 acetontrile 52 C15H15F2N3O MC 1202 N H H Et2 F H H H F 159-160 acetontrile 43 C15H17F2N3O MC 1204 N H H (n-prop)2 F H H H F 111-112 n-hexane 32 C17H21F2N3O MC 1195 N Me H Me2 F H H H F 237-238 acetonitrile 80 C14H15F2N3O MC 1203 N Me H Me2 F H H H F 235-236 acetonitrile 62 C17H18F2N4O MC 1205 N Me H morph F H H H F 244-245 acetonitrile 65 C16H17F2N3O2 MC 1206 N Me H thiomorph F H H H F 255-256 acetonitrile 54 C16H17F2N4OS MC 1137 S Me Me iso-prop F H H H F 177-178 n-hexane/cyclohexane 45 C16H18F2N2OS MC 1175 S Me Me n-but F H H H F 122-123 n-hexane 51 C17H18F2N2OS MC 1153 S Me Me iso-but F H H H F 152-153 cyclohexane 58 C17H20F2N2OS MC 1174 S Me Me c-hex F H H H F 208-209 n-hexane/cyclohexane 48 C19H22F2N3OS MC 1161 S H H MeSMe F H H H F 159-160 cyclohexane/benzene 72 C13H12F2N2OS2 MC 1162 S Me H MeSMe F H H H F 183-184 cyclohexane/benzene 70 C14H14F2N2OS2 MC 1157 S Et H MeSMe F H H H F 153-154 cyclohexane 69 C15H16F2N2OS2 MC 1145 S i-pro H MeSMe F H H H F 158.5-160   cyclohexane 62 C16H18F2N3OS2 MC 1140 S H H MeSMe H H H H H 117.5-118   n-hexane 64 C13H14N2OS2 aAll compounds were analyzed for C, H, N, S, and, when required, Cl and F; analytical results were within ±0.4% of theroretical values.

[0094] 2 TABLE 2 Cytotoxicity and anti-HIV-1 Activity of MC Compounds. (A) 9 [&mgr;M] Compd. X Y Z R R1 R2 R3 R4 R5 CC50b EC50c SId MC 507 O H H 2,5-Me2-c-hex H H H H H 143 3.5 40 MC 508 O H H 4,5-Me2-c-hex H H H H H 58 6.4 9 MC 512 O H H 3,5-Me2-c-hex H H H H H >200 30 >6.7 MC 531 O Me H 2,5-Me2-c-hex H H H H H 138 3.5 39 MC 1114 O H H sec-but F H H H F 130 25 52 MC 1103 O H H c-pent F H H H F >200 20 >10 MC 843 S H H benzyloxymethyl H H H H H >200 45 >4 MC 796 S H Ph sec-but H H H H H 61 >61 — MC 890 S H Me iso-prop H H H H H >200 .9 >222 MC 892 S H Me c-pent H H H H H 159 .6 333 MC 898 S H Me c-hex H H H H H 149 .6 248 MC 899 S H Et iso-prop H H H H H 200 .8 250 MC 900 S H Et c-pent H H H H H >200 1.0 >200 MC 903 S H Et c-hex H H H H H >200 1.3 >154 MC 806 S H H sec-but Me H H H H >200 1.8 >111 MC 842 S H H c-pent Me H H H H >200 3.4 >59 MC 809 S H H sec-but H H Me H H 200 0.6 333.3 MC 817 S H H sec-but NO2 H H H H >200 0.25 >800 MC 897 S H H sec-but H NO2 H H H 157 0.40 392 MC 863 S H H sec-but H H NO2 H H 151 1.5 101 MC 854 S H H sec-but Cl H H H H 200 1 200 MC 857 S H H sec-but H Cl H H H 116 2 58 MC 859 S H H sec-but H H Cl H H 120 5 24 MC 880 S H H sec-but F H H H H 200 0.26 769 MC 884 S H H sec-but H F H H H >200 0.7 >286 MC 889 S H H sec-but H H F H H >200 8.7 23 MC 825 S H H sec-but NH2 H H H H >200 21.2 >9 MC 960 S H H sec-but H H NH2 H H >200 23 >8 MC 868 S H H sec-but CF3 H H H H >200 32 6.2 MC 959 S H H sec-but H H CF3 H H 200 25 8 MC 952 S H H sec-but OMe H H H H >200 1.96 >208 MC 957 S H H sec-but H OMe H H H >200 1.2 >166 MC 964 S H H sec-but H H OMe H H 147 14 10.5 MC 1041 S H H sec-but H F H F H >200 1.4 >143 MC 1042 S H H sec-but H Me H Me H 133 0.6 222 MC 877 S H H Me Cl H H H Cl >200 3.2 >62 MC 878 S H H iso-prop Cl H H H Cl >200 1.9 >105 MC 886 S H H n-but Cl H H H Cl >200 0.44 >454 MC 885 S H H iso-but Cl H H H Cl >200 0.45 >444 MC 815 S H H sec-but Cl H H H Cl >200 0.14 >1,428 MC 888 S H H c-pent Cl H H H Cl >200 0.4 >500 MC 891 S H H c-hex Cl H H H Cl >200 0.6 >333 MC 871 S H H Me F H H H F 200 0.81 247 MC 860 S H H iso-prop F H H H F >200 0.2 >1,000 MC 872 S H H n-but F H H H F 162 0.18 900 MC 866 S H H iso-but F H H H F 182 0.14 1,300 MC 848 S H H sec-but F H H H F 200 0.04 5,000 MC 867 S H H c-pent F H H H F >200 0.08 >2,500 MC 870 S H H c-hex F H H H F 200 0.08 2,500 MC 1001 S H Me iso-prop Cl H H H Cl 117 1.2 97.5 MC 996 S H Me c-pent Cl H H H Cl 78.3 1.0 78.3 MC 1016 S H Me c-hex Cl H H H Cl >200 2.9 >69 MC 1000 S H Et iso-prop Cl H H H Cl >200 0.4 >500 MC 1002 S H Et c-pent Cl H H H Cl 23.4 1.0 23.4 MC 1003 S H Et c-hex Cl H H H Cl >200 3.6 >55.5 MC 1007 S H Me iso-prop F H H H F 167 0.05 3,340 MC 1044 S H Me iso-but F H H H F >200 0.05 >4,000 MC 1045 S H Me n-but F H H H F >200 0.07 2,857 MC 1110 S H Me sec-but F H H H F >200 0.03 >6,666 MC 1008 S H Me c-pent F H H H F >200 0.03 >6,666 MC 1013 S H Me c-hex F H H H F >200 0.16 >1,250 MC 1005 S H Et iso-prop F H H H F 70 0.08 875 MC 1006 S H Et c-pent F H H H F 200 0.15 1,333 MC 1014 S H Et c-hex F H H H F 130 0.05 2,600 MC 971 S H Me iso-prop CH═CH— H H H 119 1.1 108 CH═CH MC 972 S H Me c-pent CH═CH— H H H 93 0.5 186 CH═CH MC 974 S H Me c-hex CH═CH— H H H 45 0.14 321.4 CH═CH MC 969 S H Et iso-prop CH═CH— H H H 50 1.5 33.3 CH═CH MC 973 S H Et c-pent CH═CH— H H H 51 3.0 17 CH═CH MC 975 S H Et c-hex CH═CH— H H H 16.9 0.18 94 CH═CH MC 844 S Me H sec-but Me H H H H >200 1.7 >118 MC 845 S Me H sec-but H H Me H H 26 0.8 32 MC 925 S Me H sec-but H NO2 H H H >200 0.35 >571 MC 924 S Me H sec-but H H NO2 H H >200 2 >100 MC 909 S Me H sec-but Cl H H H H >200 0.27 >741 MC 910 S Me H sec-but H Cl H H H >200 0.96 >208 MC 911 S Me H sec-but H H Cl H H >200 9.5 20 MC 913 S Me H sec-but F H H H H 140 0.41 341 MC 918 S Me H sec-but H F H H H >200 1.2 >166 MC 919 S Me H sec-but H H F H H 105 11 9.5 MC 912 S Me H Me Cl H H H Cl >200 3.2 >62 MC 914 S Me H iso-prop Cl H H H Cl >200 1.3 >154 MC 920 S Me H n-but Cl H H H Cl >200 1.17 >171 MC 916 S Me H iso-but Cl H H H Cl >200 1.2 >166 MC 850 S Me H sec-but Cl H H H Cl >200 0.05 >4,000 MC 915 S Me H c-pent Cl H H H Cl >200 1.8 >111 MC 917 S Me H c-hex Cl H H H Cl >200 22 >9 MC 869 S Me H Me F H H H F 200 0.19 1,053 MC 881 S Me H iso-prop F H H H F >200 0.05 >4,000 MC 905 S Me H n-but F H H H F >200 0.08 >2,500 MC 921 S Me H iso-but F H H H F 64 0.1 640 MC 849 S Me H sec-but F H H H F 80 0.001 8,000 MC 922 S Me H c-pent F H H H F >200 0.08 >2,500 MC 923 S Me H c-hex F H H H F >200 0.09 >2,222 MC 1060 S Me Me Me F H H H F >200 0.04 >5,000 MC 1109 S me Me sec-but F H H H F 200 0.03 6,666 MC 1047 S Me Me c-pent F H H H F >200 0.009 >22,222 MC 798 S Et H sec-but H H H H H >200 1.0 >200 MC 1037 S Et H iso-prop F H H H F 65 0.2 326 MC 1038 S Et H sec-but F H H H F >200 0.1 >2,000 MC 804 S Et H sec-but CH═CH— H H H >200 5.3 >34 CH═CH MC 1039 S iso-prop H iso-prop F H H H F >200 0.4 >500 MC 852 S allyl H sec-but H H H H H >200 3 >67 MC 856 S n-prop H sec-but H H H H H 190 12 16 MC 834 S n-but H sec-but H H H H H >200 >200 — MC 1119 NH H H ethyl F H H H F >200 0.8 >250 MC 1078 NH H H n-prop F H H H F 200 0.11 1,818 MC 979 NH H H iso-prop F H H H F >200 0.38 >526 MC 980 NH H H c-prop F H H H F >200 3.17 >63 MC 1077 NH H H n-but F H H H F 100 0.10 1,000 MC 945 NH H H sec-but F H H H F >200 0.13 >1,540 MC 1043 NH H H MeOethyl F H H H F >200 0.8 >250 MC 1022 NH H H c-pent F H H H F >200 0.09 >2,222 MC 1049 NH H H c-hex F H H H F 66 0.14 471 MC 1048 NH H Me c-pent F H H H F 75 0.03 2,500 MC 1118 NH Me H iso-prop F H H H F 190 0.03 6,333 MC 1130 NH Me H sec-but F H H H F 200 0.07 2,857 MC 1050 NH Me H c-pent F H H H F >200 0.02 >10,000 MC 1105 NH Me H benzyl F H H H F 50 0.50 100 MC 1129 NH Me H c-pent F H H H F 90 0.02 4,500 MC 1187 NH H H Me F H H H F >200 1.5 >133 MC 1168 NH Me H Me F H H H F 135 0.4 335 MC 1186 NH Me H n-prop F H H H F >200 0.02 >10,000 MC 1185 NH Me H n-but F H H H F >200 0.02 >10,000 MC 1178 NH H Me Me F H H H F 106 0.11 964 MC 1190 NH H Me n-prop F H H H F 103 0.02 5,150 MC 1191 NH H Me iso-prop F H H H F 115 0.03 3,830 MC 1189 NH H Me n-but F H H H F 52 0.03 1,730 MC 1192 NH H Me sec-but F H H H F 86 0.04 2,150 MC 1180 NH H Me c-hex F H H H F 56 0.02 2,545 MC 1170 NH Me Me Me F H H H F 200 0.03 >6,666 MC 1187 NH Me Me n-but F H H H F 83 0.01 8,300 MC 1181 NH Me Me c-hex F H H H F 58 0.03 2,231 MC 1182 N H H Me2 F H H H F >200 0.05 >4,000 MC 1183 N H H Me-piperaz F H H H F >200 7.1 >28 MC 1188 N H H morph F H H H F >200 0.6 >333 MC 1193 N H H thiomorph F H H H F >200 0.05 >4,000 MC 1194 N H H piperid F H H H F >200 0.02 >10,000 MC 1196 N H H pyrrolid F H H H F >200 2.1 >95 MC 1202 N H H Et2 F H H H F >200 0.26 >769 MC 1204 N H H (n-prop)2 F H H H F >200 3.8 >53 MC 1195 N Me H Me2 F H H H F >200 0.02 >10,000 MC 1203 N Me H Me-piperaz F H H H F >200 0.36 >555 MC 1205 N Me H morph F H H H F >200 0.047 >4,255 MC 1206 N Me H thiomorph F H H H F >200 0.09 >2,222 MC 1137 S Me Me iso-prop F H H H F 200 0.007 28,571 MC 1175 S Me Me n-but F H H H F 112 0.008 14,000 MC 1153 S Me Me iso-but F H H H F >200 0.01 >20,000 MC 1174 S Me Me c-hex F H H H F >200 0.018 >1,111 MC 1047+ S Me Me c-pent F H H H F >200 0.002 >100,000 MC 1047− S Me Me c-pent F H H H F >200 0.7 >286 MC 1161 S H H MeSMe F H H H F >200 0.80 >250 MC 1162 S Me H MeSMe F H H H F 30 0.12 250 MC 1157 S Et H MeSMe F H H H F 50 0.11 454 MC 1145 S iso-prop H MeSMe F H H H F 200 0.10 2,000 MC 1140 S H H MeSMe H H H H H >200 20 >10 aData represent mean values of at least two separate experiments. bCompound dose required to reduce the viability of mock-infected cells by 50%, as determined by the MMT method. cCompound dose required to achieve 50% protection of MT-4 cells from HIV-1 induced cytopathogenicity, as determined by the MTT method. dSelectivity index, CC50/EC50 ratio.

Claims

1. A compound of the formula:

10

wherein:

X is —O, —CH2, —CHK (wherein K is —H, —C1-4alkyl, —C3-6cycloalkyl), —S, —NK (wherein K is —H, —C1-4alkyl, —C3-6cycloalkyl), -aryl, -arylalkyl;

R is —H, —C1-4alkyl (containing one or more of heteroatoms like O, S, N), C3-6cycloalkyl (containing one or more of heteroatoms like O, S, N), -aryl, arylalkyl, heterocycle;

Y is —H, —C1-4alkyl, —C3-6cycloalkyl;

Z is —H, —C1-4alkyl, —C3-6cycloalkyl;

R1 is —H, —C1-4alkyl, halogen, —NO2, —OW (wherein W is —H, —CH3, -aryl), —SW (wherein W is —H, —CH3, -aryl);

R2 is —H, —C14alkyl, -halogen, —NO2, —OW (wherein W is —H, —CH3, -aryl), —SW (wherein W is —H, —CH3, -aryl);

R3 is —H, —C1-4alkyl, -halogen, —NO2, —OW (wherein W is —H, —CH3, aryl), —SW (wherein W is —H, —CH3, -aryl);

R4 is —H, —C1-4alkyl, -halogen, —NO2, —OW (wherein W is —H, —CH3, -aryl), —SW (wherein W is —H, —CH3, -aryl);

R5 is —H, —C1-4alkyl, -halogen, —NO2, —OW (wherein W is —H, —CH3, -aryl), —SW (wherein W is —H, —CH3, -aryl), or a pharmaceutically acceptable salt or soluble derivative thereof.

2. A compound having formula A as claimed in claim 1 wherein

3 X = O Y = H Z = H R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = O Y = H Z = H R = cPen R1 = F R2 = H R3 = H R4 = H R5 = F.

3. A compound having formula A as claimed in claim 1 wherein

4 X = S Y = H Z = H R = sBu R1 = NO2 R2 = H R3 = H R4 = H R5 = H X = S Y = H Z = H R = sBu R1 = F R2 = H R3 = H R4 = H R5 = H X = S Y = H Z = H R = CH3 R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = H R = ipr R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = H R = nBu R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = H R = iBu R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = H R = sBu R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = H R = cPen R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = H R = cEs R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = H R = CH3 R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = H R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = H R = nBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = H R = iBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = H R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = H R = cPen R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = H R = cEs R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = CH3 R = iPr R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = CH3 R = cPen R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = CH3 R = cEs R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = Et R = iPr R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = Et R = cPen R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = Et R = cEs R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = H Z = CH3 R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = CH3 R = iBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = CH3 R = nBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = CH3 R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = CH3 R = cPen R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = CH3 R = cEs R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = Et R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = Et R = cPen R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = Et R = cEs R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = CH3 R = cEs —CH═CH—CH═CH R3 = H R4 = H R5 = H X = S Y = H Z = H R = sBu R1 = Cl R2 = H R3 = H R4 = H R5 = H X = S Y = CH3 Z = H R = sBu R1 = F R2 = H R3 = H R4 = H R5 = H X = S Y = CH3 Z = H R = sBu R1 = Cl R2 = H R3 = H R4 = H R5 = Cl X = S Y = CH3 Z = H R = CH3 R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = H R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = H R = nBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = H R = iBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = H R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = H R = cPen R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = H R = cEs R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = CH3 R = CH3 R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = CH3 R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = CH3 R = cPe R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = Et Z = H R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = iPr Z = H R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = CH3 R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = CH3 R = nBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = CH3 R = iBu R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = CH3 R = cEs R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = H Z = H R = MeSMe R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = CH3 Z = H R = MeSMe R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = Et Z = H R = MeSMe R1 = F R2 = H R3 = H R4 = H R5 = F X = S Y = iPr Z = H R = MeSMe R1 = F R2 = H R2 = H R4 = H R5 = F.

4. A compound having formula A as claimed in claim 1 wherein

5 X = NH Y = H Z = H R = Et R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = nPr R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = cPr R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = nBu R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = MeOEt R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = cPe R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = cEs R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = CH3 R = cPe R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = H R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = H R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = H R = cPe R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = H R = benz R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = CH3 R = cPe R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = H R = CH3 R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = H R = CH3 R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = H R = nPr R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = H R = nBu R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = CH3 R = CH3 R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = CH3 R = nPr R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = CH3 R = iPr R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = CH3 R = nBu R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = CH3 R = sBu R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = H Z = CH3 R = cEs R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = CH3 R = CH3 R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = CH3 R = nBu R1 = F R2 = H R3 = H R4 = H R5 = F X = NH Y = CH3 Z = CH3 R = cEs R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = H Z = H R = (CH3)2 R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = H Z = H R = Me-Pip R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = H Z = H R = Morph R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = H Z = H R = S-morp R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = H Z = H R = Piper R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = H Z = H R = Pyrroli R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = H Z = H R = Et2 R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = H Z = H R = (nPr)2 R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = CH3 Z = H R = (CH3)2 R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = CH3 Z = H R = Me-Pip R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = CH3 Z = H R = Morph R1 = F R2 = H R3 = H R4 = H R5 = F X = N Y = CH3 Z = H R = S-morp R1 = F R2 = H R3 = H R4 = H R5 = F.

5. 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═O, wherein the proper methyl arylacetylalkylacetate is reacted with O-methylisourea in presence of calcium hydroxide; the so obtained 2-O-methyl(5-alkyl)-6-benzyl(substituted)uracils are reacted with the proper potassium alkoxide 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-thiouracils are reacted with methyl iodide or with an alkyl halide in a basic medium according to scheme B.

8. A process for the preparation of the compounds having formula A as claimed in claim 1 wherein X═NK (wherein K is —H, —C1-4alkyl, —C3-6cycloalkyl), wherein the proper S-methyl(5-alkyl)-6-benzyl(substituted)-2-thiouracil is reacted with the proper amine according to scheme C.

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.

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, LFDOC, nevirapine, foscarnet, PMEA, PMPA, Ro 31-8959, RPI-3121, SC-52151, SC55389A, 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, &bgr;-LddA, &bgr;-L-3′-azido-d5FC, carbovir, acyclovir, interferon, stavudine, (3′-azido-2′,3′-dideoxy-5-methyl-cytidine), 3′-azido nucleosides, &bgr;-D-dioxoiane nucleosides such as &bgr;-D-dioxolanylguanine (DXG), &bgr;-D-dioxolanyl-2,6-diaminopurine (DAPD), and &bgr;-D-dioxolanyl-6-chloropurine (ACP), D4T, FTC, 3TC, AZDU, and amprenavir.