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

[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:

[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:

[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, β-LddA, β-L-3′-azido-d5FC, carbovir, acyclovir, interferon, stavudine, CS-92 (3′-azido-2′,3′-dideoxy-5-methyl-cytidine), 3′-azido nucleosides, and β-D-dioxolane nucleosides such as β-D-dioxolanylguanine (DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD), and β-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: (−)-β-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)]-β-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.

[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.

[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.

[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 μg/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 μL of culture medium containing 1×104 cells were added to each well of flat-bottom microtiter trays containing 50 μl of culture medium with or without various concentrations of the test compounds. Then 20 μL 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 μL 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 μM [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).

1TABLE 1Physical and Chemical Data of MC Compounds

CompdXYZRR1R2R3R4R5m.p., ° C.Recryst. Solvent% yieldFormulaaMC 507OHH2,5-Me2-c-hexHHHHH130-132Petrol. Ether/diethyl ether22C19H24N2O2MC 508OHH4,5-Me2-c-hexHHHHH132-134Petrol. Ether/diethyl ether28C19H24N2O2MC 512OHH3,5-Me2-c-hexHHHHH178-181Petrol. Ether/diethyl ether12C19H24N2O2MC 531OMeH2,5-Me2-c-hexHHHHH196-198Petrol. Ether/diethyl ether18C20H26N2O2MC 1114OHHSec-butFHHHF87-88Petrol. Ether/diethyl ether28C15H26F2N2O2MC 1103OHHc-pentFHHHF183.5-184.5Benzene52C16H18F2N2O2MC 843SHHbenzyloxymethHHHHH181-183Cyclohexane/benzene38C19H18N2O2SMC 796SHPhSec-butHHHHH157-158n-hexane/cyclohexane78C24H22N2OSMC 890SHMeiso-propHHHHH118-119n-hexane88C15H18N2OSMC 892SHMec-pentHHHHH95-96n-hexane65C17H21N2OSMC 898SHMec-hexHHHHH142-143n-hexane59C18H22N2OSMC 899SHEtIso-propHHHHH144-145Cyclohexane85C16H19N2OSMC 900SHEtc-pentHHHHH168-169Cyclohexane69C18H22N2OSMC 903SHEtc-hexHHHHH175.5-176.5Cyclohexane60C19H24N2OSMC 806SHHSec-butMeHHHH118-119n-hexane/cyclohexane67C18H20N2OSMC 842SHHc-pentMeHHHH142-144Cyclohexane61C17H20N2OSMC 809SHHSec-butHHMeHH107.5-108.5n-hexane56C16H20N2OSMC 817SHHSec-butNO2HHHH148.0-148.5Cyclohexane/benzene68C15H17N3O3SMC 897SHHSec-butHNO2HHH127-128Cyclohexane/benzene54C15H17N3O3SMC 863SHHSec-butHHNO2HH128-130Petrol. Ether/diethyl ether100C15H17N3O3SMC 854SHHSec-butClHHHH120-121n-hexane/cyclohexane58C15H17N3O3SMC 857SHHSec-butHClHHH98-99Cyclohexane92C15H17N3O3SMC 859SHHSec-butHHClHH125-126Cyclohexane74C13H17ClN2OSMC 880SHHSec-butFHHHH106-107n-hexane/cyclohexane68C15H17ClN2OSMC 884SHHSec-butHFHHH96-97Cyclohexane67C15H17FN2OSMC 889SHHSec-butHHFHH98-99n-hexane94C15H17FN2OSMC 825SHHSec-butNH2HHHH143-144Cyclohexane/benzene74C15H19N3OSMC 960SHHSec-butHHNH2HH128-130Cyclohexane77C15H19N3OSMC 868SHHSec-butCF3HHHH125-126Cyclohexane89C16H17F3N2OSMC 950SHHSec-butHHCF3HH144-145Cyclohexane75C16H17F3N2OSMC 952SHHSec-butOMeHHHH123-124Cyclohexane69C16H20N2O2SMC 957SHHSec-butHOMeHHH78-80n-hexane/Cyclohexane71C16H20N2O2SMC 964SHHSec-butHHOMeHH112-113Cyclohexane63C16H20N2O2SMC 1041SHHSec-butHFHHH122-123Cyclohexane68C15H16F2N2OSMC 1042SHHSec-butHMeHHH119-120n-hexane72C17H22N2OSMC 877SHHMeClHHHCl237-238benzene98C12H14Cl2N2OSMC 878SHHiso-propClHHHCl230-231benzene81C14H14Cl2N2OSMC 856SHHn-butClHHHCl153-154cyclohexane62C15H16Cl2N2OSMC 885SHHiso-butClHHHCl143.5-144.5cyclohexane56C15H16Cl2N2OSMC 815SHHsec-butClHHHCl183-184cyclohexane/benzene55C15H16Cl2N2OSMC 888SHHc-pentClHHHCl185-186cyclohexane54C16H16Cl2N2OSMC 891SHHc-hexClHHHCl200-201cyclohexane/benzene49C17H18Cl2N2OSMC 871SHHMeFHHHF197-198benzene95C12H20F2N2OSMC 860SHHiso-propFHHHF174-175cyclohexane74C14H14F2N2OSMC 872SHHn-butFHHHF126-127cyclohexane46C15H16F2N2OSMC 866SHHiso-butFHHHF136-137cyclohexane49C15H16F2N2OSMC 848SHHsec-butFHHHF149-150n-hexane/cyclohexane48C15H16F2N2OSMC 867SHHc-pentFHHHF168-169cyclohexane45C16H16FN2OSMC 870SHHc-hexFHHHF164-165cyclohexane40C17H18F2N2OSMC 1001SHMeiso-propClHHHCl 196-196.5cyclohexane/benzene52C15H16Cl2N2OSMC 996SHMec-pentClHHHCl181-182cyclohexane45C17H18Cl2N2OSMC 1016SHMec-hexClHHHCl211-212cyclohexane/benzene42C18H20Cl2N2OSMC 1000SHEtiso-propClHHHCl166-168diethyl ether54C16H18Cl2N2OSMC 1002SHEtc-pentClHHHCl168-169diethyl ether40C18H20Cl2N2OSMC 1003SHEtc-hexClHHHCl198-199cyclohexane41C19H22Cl2N2OSMC 1007SHMeiso-propFHHHF155-156cyclohexane53C15H16F2N2OSMC 1044SHMeiso-butFHHHF159-160cyclohexane49C16H16F2N2OSMC 1045SHMen-butFHHHF149-150cyclohexane58C16H16F2N2OSMC 1110SHMesec-butFHHHF133-134n-hexane75C16H16F2N2OSMC 1008SHMec-pentFHHHF165.5-166.5cyclohexane60C17H18F2N2OSMC 1013SHMec-hexFHHHF206-207benzene44C18H20F2N2OSMC 1005SHEtiso-propFHHHF149-150cyclohexane40C16H18F2N2OSMC 1006SHEtc-pentFHHHF141-143cyclohexane45C16H20F2N2OSMC 1014SHEtc-pentFHHHF154-155cyclohexane51C19H22F2N2OSMC 971SHMeiso-propCH═CH—HHH161-162n-hexane/cyclohexane58C19H20N2OSCH═CHMC 972SHMec-pentCH═CH—HHH140-141n-hexane/cyclohexane49C21H22N2OSCH═CHMC 974SHMec-hexCH═CH—HHH177-178n-hexane45C22H24N2OSCH═CHMC 969SHEtiso-propCH═CH—HHH163-164cyclohexane54C20H22N2OSCH═CHMC 973SHEtc-pentCH═CH—HHHoil—48C22H24N2OSCH═CHMC 975SHEtc-hexCH═CH—HHH126-127n-hexane41C23H26N2OSMC 844SMeHsec-butMeHHHH177-178cyclohexane55C17H22N2OSMC 845SMeHsec-butHHMeHH127-128n-hexane61C17H22N2OSMC 925SMeHsec-butHNO2HHH163-164cyclohexane/benzene88C16H19N3O3SMC 924SMeHsec-butHHNO2HH178-180cyclohexane/benzene100C16H19N3O3SMC 909SMeHsec-butClHHHH170-171cyclohexane68C16H19ClN2OSMC 910SMeHsec-butHClHHH145-146cyclohexane75C16H19ClN2OSMC 911SMeHsec-butHHClHH163-165cyclohexane79C16H19ClN2OSMC 913SMeHsec-butFHHHH120.5-121.5cyclohexane65C16H19FN2OSMC 918SMeHsec-butHFFHH146-147cyclohexane72C16H16FN2OSMC 919SMeHsec-butHHHHH154-155cyclohexane69C26H29FN2OSMC 912SMeHMeClHHHCl206-261benzene93C30H42Cl2N2OSMC 914SMeHiso-propClHHHCl241-242cyclohexane/benzene78C25H26Cl2N2OSMC 920SMeHn-butClHHHCl179-180cyclohexane52C16H19Cl2N2OSMC 916SMeHiso-butClHHH Cl208-209cyclohexane63C26H28Cl2N2OSMC 850SMeHsec-butClHHHCl204-205cyclohexane53C16H19Cl2N2OSMC 915SMeHc-pentClHHHCl252-253cyclohexane/benzene49C17H18Cl2N2OSMC 917SMeHc-hexClHHHCl237-238cyclohexane48C16H19Cl2N2OSMC 869SMeHMeFHHHF218.5-219.5benzene92C13H12F2N2OSMC 881SMeHiso-propFHHHF164-165cyclohexane76C15H26F2N2OSMC 905SMeHn-butFHHHF178-179cyclohexane65C16H18F2N2OSMC 921SMeHiso-butFHHHF161-162cyclohexane59C16H18F2N2OSMC 849SMeHsec-butFHHHF128-129n-hexane49C16H18F2N2OSMC 922SMeHc-pentFHHHF192-193cyclohexane54C17H18F2N2OSMC 923SMeHc-hexFHHHF191-192cyclohexane49C18H20F2N2OSMC 1060SMeMeMeFHHHF202-203cyclohexane/benzene49C14H14F2N2OSMC 1109SMeMesec-butFHHHF135-136cyclohexane55C17H20F2N2OSMC 1047SMeMec-pentFHHHF196-197cyclohexane60C18H20F2N2OSMC 798SEtHsec-butHHHHH140-141n-hexane47C17H22N2OSMC 1037SEtHiso-propFHHHF174-175benzene78C16H18F2N2OSMC 1038SEtHsec-butFHHHF150-151n-hexane/cyclohexane82C17H20F2N2OSMC 804SEtHsec-butCH═CH—HHH198.5-199.5cyclohexane42C21H24N2OSCH═CHMC 1039Si-proHiso-propFHHHF167-168n-hexane76C17H20F2N2OSMC 852SallylHsec-butHHHHH127.5-128.5cyclohexane68C16H22N2OSMC 856Sn-proHsec-butHHHHH108-109n-hexane42C18H24N2OSMC 834Sn-butHsec-butHHHHHoil—32C19H29N2OSMC 1119NHHHethylFHHHF138-140n-hexane/cyclohexane50C13H13F2N2OMC 1078NHHHn-propFHHHF136-137cyclohexane49C15H15F2N2OMC 979NHHHiso-propFHHHF150-151diethyl ether58C14H15F2N2OMC 980NHHHc-propFHHHF183-184cyclohexane/benzene68C14H13F2N3OMC 1077NHHHn-butFHHHF130-131n-hexane60C15H17F2N3OMC 945NHHHsec-butFHHHF140-141diethyl ether80C15H17F2N3OMC 1043NHHHMeOethylFHHHF120-121acetonitrile78C14H15F2N3O2MC 1022NHHHc-pentFHHHFoil—74C16H17F2N2OMC 1049NHHHc-hexFHHHF143-144diethyl ether45C17H19F2N2OMC 1048NHHMec-pentFHHHFoil—48C17FH19F2N3OMC 1118NHMeHiso-propFHHHF165-166n-hexane53C15H17F2N2OMC 1130NHMeHsec-butFHHHFoil—56C16H19F2N3OMC 1050NHMeHc-pentFHHHF115-117n-hexane/cyclohexane60C17H19F2N2OMC 1105NHMeHbenzylFHHHF182-183cyclohexane/benzene82C19H17F2N3OMC 1129NHMeMec-pentFHHHFoil—38C16H21F2N2OMC 1167NHHHMeFHHHF202-203acetonitrile39C12H14F2N2OMC 1168NHMeHMeFHHHF210-211acetonitrile48C13H13F2N2OMC 1186NHMeHn-propFHHHF156-157acetonitrile62C15H17F2N3OMC 1185NHMeHn-butFHHHF192-193acetonitrile68C16H19F2N3OMC 1178NHHMeMeFHHHF145-146acetonitrile34C13H13F2N3OMC 1190NHHMen-propFHHHFoil—45C15H17F2N3OMC 1191NHHMeiso-propFHHHFoil—54C15H17F2N3OMC 1189NHHMen-butFHHHFoil—55C16H19F2N2OMC 1192NHHMesec-butFHHHFoil—59C16H19F2N2OMC 1180NHHMec-hexFHHHFoil—62C18H21F2N3OMC 1170NHMeMeMeFHHHF193-194cyclohexane/benzene34C14H15F2N3OMC 1187NHMeMen-butFHHHFoil—49C17H21F2N2OMC 1181NHMeMec-hexFHHHFoil—54C19H22F2N3OMC 1182NHHMe2FHHHF210-211cyclohexane/benzene88C13H15F2N2OMC 1183NHHMe-piperazFHHHF195-196acetonitrile84C16H18F2N4OMC 1188NHHmorphFHHHF215-216acetonitrile75C15H15F2N3O2MC 1193NHHthiomorphFHHHF233-234acetonitrile78C15H15F2N2OSMC 1194NHHpiperidFHHHF209-210acetontrile68C16H17F2N3OMC 1196NHHpyrrolidFHHHF233-234acetontrile52C15H15F2N3OMC 1202NHHEt2FHHH F159-160acetontrile43C15H17F2N3OMC 1204NHH(n-prop)2FHHHF111-112n-hexane32C17H21F2N3OMC 1195NMeHMe2FHHHF237-238acetonitrile80C14H15F2N3OMC 1203NMeHMe2FHHHF235-236acetonitrile62C17H18F2N4OMC 1205NMeHmorphFHHHF244-245acetonitrile65C16H17F2N3O2MC 1206NMeHthiomorphFHHHF255-256acetonitrile54C16H17F2N4OSMC 1137SMeMeiso-propFHHHF177-178n-hexane/cyclohexane45C16H18F2N2OSMC 1175SMeMen-butFHHHF122-123n-hexane51C17H18F2N2OSMC 1153SMeMeiso-butFHHH F152-153cyclohexane58C17H20F2N2OSMC 1174SMeMec-hexFHHHF208-209n-hexane/cyclohexane48C19H22F2N3OSMC 1161SHHMeSMeFHHHF159-160cyclohexane/benzene72C13H12F2N2OS2MC 1162SMeHMeSMeFHHHF183-184cyclohexane/benzene70C14H14F2N2OS2MC 1157SEtHMeSMeFHHHF153-154cyclohexane69C15H16F2N2OS2MC 1145Si-proHMeSMeFHHHF158.5-160 cyclohexane62C16H18F2N3OS2MC 1140SHHMeSMeHHHHH117.5-118 n-hexane64C13H14N2OS2aAll 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)

[μM]

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

a
Data represent mean values of at least two separate experiments.

b
Compound dose required to reduce the viability of mock-infected cells by 50%, as determined by the MMT method.

c
Compound dose required to achieve 50% protection of MT-4 cells from HIV-1 induced cytopathogenicity, as determined by the MTT method.

d
Selectivity index, CC50/EC50 ratio.

	Number	Date	Country
Parent	09744038	May 2001	US
Child	10689982	Oct 2003	US

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

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Priority Claims (1)

Continuations (1)